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US20170333354A9 - Abuse deterrent pharmaceutical compositions for controlled release - Google Patents

Abuse deterrent pharmaceutical compositions for controlled release Download PDF

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Publication number
US20170333354A9
US20170333354A9 US15/373,022 US201615373022A US2017333354A9 US 20170333354 A9 US20170333354 A9 US 20170333354A9 US 201615373022 A US201615373022 A US 201615373022A US 2017333354 A9 US2017333354 A9 US 2017333354A9
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Prior art keywords
tablet
daltons
opioid
composition
abuse deterrent
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Abandoned
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US15/373,022
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US20170181974A1 (en
Inventor
Peter Holm Tygesen
Karsten Lindhardt
Martin Rex Olsen
Gina Engslev Fischer
Jan Martin Overgard
Georg Boye
Nikolaj Skak
Torben Elhauge
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Egalet Ltd
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Egalet Ltd
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Application filed by Egalet Ltd filed Critical Egalet Ltd
Priority to US15/373,022 priority Critical patent/US20170333354A9/en
Publication of US20170181974A1 publication Critical patent/US20170181974A1/en
Publication of US20170333354A9 publication Critical patent/US20170333354A9/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine

Definitions

  • compositions relate to pharmaceutical compositions.
  • the pharmaceutical compositions according to the present description are abuse-deterrent and may provide controlled release.
  • Methods for abusing prescription pharmaceutical compositions are varied and can include, for example, extraction, melting, volatilization, physical tampering (e.g., grinding, grating, crushing, etc.), or direct administration.
  • methods of administering active drug substances obtained from prescription pharmaceutical compositions or of the pharmaceutical compositions themselves are similarly diverse and include, for example, injection, smoking, snorting, swallowing, sublingual or buccal administration, chewing, and administration as suppository.
  • Alcohol-induced dose dumping of active drug substance from prescription pharmaceutical compositions also presents potential abuse and safety problems.
  • FIG. 1 shows a drawing of a Moulinex-1411R coffee grinder chamber with stainless steel blades.
  • FIG. 2 shows a drawing of a Krups F203 coffee grinder chamber with stainless steel blades.
  • FIG. 3 shows a drawing of a nutmeg grater surface with a stainless steel star blade.
  • FIG. 4 shows in vitro dissolution results of the release of morphine (%) versus time (minutes) in phosphate buffer solution pH 6.8.
  • the release of morphine is shown for intact tablets (untampered) and ground tablets (tampered) of one embodiment of a pharmaceutical composition, as disclosed herein, comprising PEO 400,000 daltons.
  • FIG. 5 shows particle size reduction results of one embodiment of a ground (tampered) pharmaceutical composition, as disclosed herein, comprising PEO 400,000 daltons.
  • FIG. 6 shows in vitro dissolution results of the release of oxycodone (%) versus time (minutes) in phosphate buffer solution pH 6.8 with and without 40% v/v ethanol.
  • the release of oxycodone is shown for intact tablets (untampered) and ground tablets (tampered) of one embodiment of a pharmaceutical composition, as disclosed herein, comprising PEO 600,000 daltons.
  • FIG. 7 shows particle size reduction results of one embodiment of a ground (tampered) pharmaceutical composition as disclosed herein comprising PEO 600,000 daltons.
  • FIG. 8 shows in vitro dissolution results of the release of hydromorphone (%) versus time (minutes) in phosphate buffer solution pH 6.8.
  • the release of hydromorphone is shown for intact tablets (untampered) and ground tablets (tampered) of one embodiment of a pharmaceutical composition, as disclosed herein, comprising PEO 2,000,000 daltons.
  • FIG. 9 shows particle size reduction results of one embodiment of a ground (tampered) pharmaceutical composition, as disclosed herein, comprising PEO 2,000,000 daltons.
  • FIG. 10 shows in vitro dissolution results of the release of oxymorphone (%) versus time (minutes) in phosphate buffer solution pH 6.8.
  • the release of oxymorphone is shown for intact tablets (untampered) and ground tablets (tampered) of one embodiment of a pharmaceutical composition as disclosed herein comprising PEO 10,000,000 daltons.
  • FIG. 11 shows particle size reduction results of one embodiment of a ground (tampered) pharmaceutical composition as disclosed herein comprising PEO 10,000,000 daltons.
  • FIG. 12 shows in vitro dissolution results of the release of oxycodone (%) versus time (minutes) in phosphate buffer solution pH 6.8. The release of oxycodone is shown for intact tablets (untampered) and ground tablets (tampered) of Oxycontin® OP 40 mg.
  • FIG. 13 shows particle size reduction results of a ground Oxycontin® OP 40 mg tablet.
  • FIG. 14 shows in vitro dissolution results of the release of morphine (%) versus time (minutes) in phosphate buffer solution pH 6.8 with and without 40% v/v ethanol.
  • the release of morphine is shown for intact tablets of one embodiment of a pharmaceutical composition, as disclosed herein.
  • FIG. 15 shows in vitro dissolution results of release of active substance (%) versus time (minutes) in phosphate buffer solution pH 6.8.
  • the release of active substance is shown for intact tablets and ground tablets (ground in a Krups F203 coffee grinder) of Oxycontin® OP 40 mg, MST Continus® 60 mg, and an embodiment of a pharmaceutical composition, as disclosed herein, containing 200 mg of morphine.
  • FIG. 16 shows in vitro dissolution results of release of active substance (%) versus time (minutes) in dilute hydrochloric acid.
  • the release of active substance is shown for grated tablets (Nutmeg grater) of Opana® ER 40 mg, Oxycontin® OP 80 mg, MST Continus® 60 mg, and an embodiment of a pharmaceutical composition, as disclosed herein, containing 200 mg of morphine.
  • FIG. 17 shows particle size reduction results of a grated tablet of an embodiment of a pharmaceutical composition, as disclosed herein, containing 200 mg of morphine.
  • FIG. 18 shows particle size reduction results of a grated MST Continus® 60 mg tablet.
  • FIG. 19 shows particle size reduction results of a grated Opana® ER 40 mg tablet.
  • FIG. 20 shows particle size reduction results of a grated Oxycontin® OP 80 mg tablet.
  • the present disclosure provides novel abuse-deterrent pharmaceutical compositions, which are resistant to abuse and tampering.
  • the pharmaceutical compositions according to the present description even without containing an outer shell, exhibit hardness that is resistant to physical tampering.
  • the pharmaceutical compositions disclosed herein may be formulated in such a way that the composition maintains a desired release profile of the active drug substance, even if the pharmaceutical composition is subjected to physical tampering.
  • an abuse-deterrent pharmaceutical composition comprising: (a) an active drug substance; (b) a polyethylene oxide; and (c) optionally, a plasticizer, wherein the pharmaceutical composition does not provide immediate release of the active drug substance after physical tampering, and wherein when at least one polyethylene oxide has a molecular weight of at least 1,000,000 daltons, then the pharmaceutical composition comprises at least 5% w/w plasticizer.
  • the pharmaceutical compositions disclosed herein may comprise a controlled released abuse-deterrent pharmaceutical composition with a route of administration that may prevent or limit the feeling of euphoria combined with preventing or making it more difficult to abuse the active drug substance from the composition by, for example, injection, smoking, snorting, swallowing, sublingual or buccal administration, chewing, and administration as suppository.
  • the abuse-deterrent pharmaceutical compositions according to the present description can be further understood when studied relative to a comparator. Comparison of the abuse-deterrent pharmaceutical compositions disclosed herein to a comparator assesses the incremental and meaningful improvement in the ability of said pharmaceutical compositions to deter abuse or misuse.
  • certain embodiments of the present disclosure relate to the use of the disclosed pharmaceutical compositions in the treatment of a clinical condition (such as pain) in an individual in need thereof.
  • dose dumping refers to an unintended, rapid release of the entire amount or a significant fraction of the active drug substance contained within a prescription pharmaceutical composition over a short or accelerated period of time.
  • alcohol-induced dose dumping may facilitate isolation or concentration of active drug substances from a prescription pharmaceutical composition.
  • dose dumping in the presence of alcohol may increase the ease with which a prescription pharmaceutical composition can be abused simply through the intake of an alcoholic beverage concomitantly with the prescription pharmaceutical composition.
  • alcohol-induced dose dumping may present safety issues outside the context of abuse.
  • a patient taking a prescription pharmaceutical composition for medicinal purposes may inadvertently cause delivery of a dose of active drug substance that is too high or absorbed too quickly by self-administering a pharmaceutical composition shortly before, simultaneously with, or shortly after, consumption or intake of an alcoholic beverage or another pharmaceutical composition containing alcohol (e.g., an over-the-counter cold or flu medicine).
  • a pharmaceutical composition e.g., an over-the-counter cold or flu medicine
  • compositions that are resistant to physical tampering are formulated in such a way that the composition cannot readily be size reduced to a form that is suitable for abuse, such as, for example, injection or snorting, because the tablet cannot easily be ground, grated, dissolved, and the like.
  • Examples of physical tampering include, but are not limited to, crushing, grinding, grating, cutting, crisping, and other methods of particle size reduction.
  • controlled release denotes pharmaceutical composition that provide extended release of an active drug substance from the composition for an extended period of time.
  • controlled release is used to designate a release at a desired rate during a predetermined release period. Additional or alternative terms, such as, for example, “modified”, “delayed”, “sustained”, “prolonged”, “extended” release may be used, in certain embodiments, as synonyms to the term “controlled release.”
  • immediate release denotes a pharmaceutical composition that releases the active drug substance (80% release) within at the most 30 minutes, when subjected to dissolution test according to USP 35, NF 30, (711), Apparatus 2.
  • the pharmaceutical compositions of the present disclosure comprise a polyethylene oxide.
  • Polyethylene oxides are linear polydisperse nonionic polymers composed of repeating units of ethylene oxide. Their chemical formula is HO[CH 2 CH 2 O] n H, where n represents the average number of oxyethylene groups. See the structural presentation of polyethylene oxide below, wherein n is the average number of oxyethylene groups.
  • high molecular weight PEO may have one terminal methyl group.
  • Polyethylene oxides that are suitable for use in the pharmaceutical compositions according to the present description are those having an average molecular weight of at least about 200,000 daltons, such as an average molecular weight of in the range of about 200,000 to about 10,000,000 daltons, for example in the range of about 250,000 to about 10,000,000 daltons, such as in the range of about 300,000 to about 10,000,000 daltons, for example in the range of about 350,000 to about 10,000,000 daltons, such as in the range of about 400,000 to about 10,000,000 daltons.
  • the polyethylene oxides that are suitable for use in the compositions disclosed herein are those having an average molecular weight of at the most 1,000,000 daltons, such as an average molecular weight of in the range of about 200,000 to about 1,000,000 daltons, for example in the range of about 300,000 to about 1,000,000 daltons, such as in the range of about 400,000 to about 1,000,000 daltons.
  • the polyethylene oxides that are suitable for use in the compositions disclosed herein are those having an average molecular weight of at the most 500,000 daltons, such as an average molecular weight of in the range of about 200,000 to about 500,000 daltons, for example in the range of about 250,000 to about 500,000 daltons, such as in the range of about 300,000 to about 500,000 daltons, for example in the range of about 350,000 to about 500,000 daltons, such as in the range of about 400,000 to about 500,000 daltons.
  • the polyethylene oxides suitable for use in the compositions described herein are those having an average molecular weight of at the most 400,000 daltons, such as in the range of about 100,000 to about 400,000 daltons, for example in the range of about 200,000 to about 400,000 daltons, such as in the range of about 300,000 to 400,000 daltons.
  • the pharmaceutical composition comprises polyethylene oxides having an average molecular weight of 400,000 daltons.
  • the polyethylene oxides suitable for use in the compositions described herein are those having an average molecular weight selected from 200,000 daltons, 250,000 daltons, 300,000 daltons, 350,000 daltons, 400,000 daltons, 450,000 daltons, 500,000 daltons, 550,000 daltons, 600,000 daltons, 650,000 daltons, 700,000 daltons, 750,000 daltons, 800,000 daltons, 850,000 daltons, 900,000 daltons, 950,000 daltons, 1,000,000 daltons, 2,000,000 daltons, 3,000,000 daltons, 4,000,000 daltons, 5,000,000 daltons, 7,000,000 daltons, 10,000,000 daltons.
  • the total concentration of polyethylene oxide for use in the composition is in the range of 5 to 99.9% w/w, such as from 10 to 99.9% w/w, such as from 10 to 98% w/w, such as from 20 to 98% w/w, such as from 30 to 98% w/w, such as from 40 to 98% w/w, such as from 50 to 98% w/w, such as from 60 to 98% w/w, such as from 70 to 98% w/w, calculated as w/w % of the composition.
  • the level of polyethylene oxide 200,000 daltons to achieve the desired viscosity as described herein may be at least 1,020 mg, for polyethylene oxide 300,000 daltons it is at least 544 mg, for polyethylene oxide 400,000 daltons it is at least 435 mg, for polyethylene oxide 600,000 daltons it is at least 324 mg, for polyethylene oxide 900,000 daltons it is at least 243 mg, for polyethylene oxide 1,000,000 daltons it is at least 203 mg for polyethylene oxide 2,000,000 daltons and 4,000,000 daltons it is at least 162 mg and for polyethylene oxide 5,000,000 daltons, 7,000,000 daltons and 10,000,000 daltons it is at least 122 mg.
  • the upper level of polyethylene oxide 200,000 to 10,000,000 daltons to achieve the desired viscosity in pharmaceutical compositions described herein is approximately 1,100 mg.
  • compositions as described herein may comprise mixtures of polyethylene oxides with different average molecular weights, for example, in order to obtain polyethylene oxides with a desirable average molecular weight.
  • the pharmaceutical comprises different polyethylene oxide materials with different average molecular weights.
  • polyethylene oxides in order to obtain polyethylene oxide with a desirable average molecular weight, it is important to note that, in such cases, it is necessary to use polyethylene oxides, which have an average molecular weight closest to the desired molecular weight to ensure a narrow chain length distribution.
  • polyethylene oxide 200,000 daltons and polyethylene oxide 600,000 daltons may be mixed to obtain polyethylene oxide 400,000 daltons.
  • a composition as described herein may comprise more than one different kind of polyethylene oxide, such as 2, for example 3, such as 4, for example 5, such as more than 5 different polyethylene oxides.
  • the composition comprises 1 to 4 different polyethylene oxides.
  • the composition comprises 1 to 3 different polyethylene oxides.
  • the composition comprises 2 different polyethylene oxides.
  • the polyethylene oxide used in compositions according to the present description may have a melting point higher than the body temperature of the individual (e.g., a human) in which the pharmaceutical composition is to be used.
  • the polyethylene oxides employed in the pharmaceutical compositions described herein may have a melting point of in the range of 38° C. to 200° C., such as in the range of 38° C. to 150° C., for example in the range of 38° C. to 120° C., such as in the range of 38° C. to 100° C., for example in the range of 65° C. to 100° C.
  • composition as described herein may also comprise at least one plasticizer.
  • the composition comprises a poloxamer.
  • a composition as described herein may comprise more than one different kind of plasticizer, such as 2, for example 3, such as more than 3 different plasticizers.
  • the composition comprises 1 to 3 different plasticizers.
  • the composition comprises 2 different plasticizers.
  • the different kind of plasticizer is a different kind of poloxamer.
  • the composition comprises one or more plasticizers, preferably one or more plasticizers selected from the group consisting of poloxamers, such as poloxamer 188 and/or poloxamer 407.
  • the composition comprises at least one poloxamer.
  • Poloxamers may be copolymers or block copolymers and are a range of non-ionic surfactants of polyethylene glycol (PEG) and polypropylene glycol (PPG).
  • the poloxamer may be Diol EO/PO block copolymers, which, for example, in chemical abstracts are described under the scientific name hydroxy-hydroxypoly (oxyethylene) poly(oxypropylene)-poly(oxyethylene)-block copolymer in combination with the CAS register number.
  • a suitable poloxamer for use in a composition of the disclosure has a HLB value of at least about 18 such as, for example, at least approximately 20, preferably at least 24.
  • the average molecular weight of a suitable poloxamer is typically at least about 2,000 daltons.
  • Block copolymers of ethylene oxide and propylene oxide that may be included in the composition described herein have a molecular weight of at least 2,000 daltons, typically in the range of 3,000 to 30,000 daltons, such as in the range of 4,000 to 15,000 daltons.
  • Exemplary poloxamers that may be used in the compositions disclosed herein have the formula HO(C 2 H 4 O)a(C 3 H 6 O) b (C 2 H 4 O) a H, where “a” is an integer from 10 to 150, such as from 30 to 140, for example from 50 to 100, such as from 65 to 90, for example from 70 to 90, and “b” is an integer from 10 to 80, such as from 15 to 80, for example from 20 to 60, such as from 25 to 55.
  • plasticizers may be incorporated in the composition of the pharmaceutical compositions as described herein.
  • a suitable plasticizer may be selected from mono- and di-acetylated monoglycerides, diacetylated monoglycerides, acetylated hydrogenated cottonseed glyceride, glyceryl cocoate, polyethylene glycols (for example with a molecular weight below 35,000 daltons) or polyethylene oxides (for example with a molecular weight of about 35,000 to 600,000 daltons), dipropylene glycol salicylate glycerin, fatty acids and esters, phthalate esters, phosphate esters, amides, diocyl phthalate, phthalyl glycolate, mineral oils, hydrogenated vegetable oils, vegetable oils, acetylated hydrogenated soybean oil glycerides, castor oil, acetyl tributyl citrate, acetyl triethyl citrate, methyl abietate, nitrobenzen
  • the composition comprises cetostearyl alcohol, castor oil, dibutyl sebacate, polyethylene oxides and/or poloxamer as plasticizer.
  • the composition comprises polyethylene glycols,cetostearyl alcohol, cetyl alcohol, stearyl alcohol, alfa-tocopheryl polyethylene glycol succinate (TPGS), tocopheryl derivative, diacetylated monoglycerides, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monooleate, glyceryl monostearate, propylene glycol monostearate, macrogol esters, macrogol stearate 400, macrogol stearate 2000, polyoxyethylene 50 stearate, macrogol ethers, poloxamers, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, acetyl tributyl citrate and/or acetyl triethyl citrate as plasticizer.
  • TPGS alf
  • the amount of plasticizer in the composition is in the range of from 0 to 60% w/w, for example in the range of 0 to 50% w/w, such as in the range of 0 to 40% w/w, for example in the range of 0 to 30% w/w, such as in the range of 0 to 20% w/w. In some embodiments, the amount of plasticizer in the composition is at least 1% w/w, for example at least 5% w/w, such as for example at least 10% w/w.
  • the amount of plasticizer in the matrix composition is at the most 20% w/w, such as in the range of 0 to 20% w/w, for example 5 to 20% w/w, such as in the range of 10 to 20% w/w, for example 15 to 20% w/w. In other embodiments the amount of plasticizer in the matrix composition is at least 5% w/w, such as in the range of 5 to 25% w/w, for example 5 to 15% w/w, such as in the range of 5 to 10% w/w.
  • the plasticizer is a poloxamer.
  • the amount of poloxamer in the composition is at the most 20% w/w, such as in the range of 0 to 20% w/w, for example 5 to 20% w/w, such as in the range of 10 to 20% w/w, for example 15 to 20% w/w.
  • the amount of poloxamer in the composition is at least 5% w/w, such as in the range of 5 to 25% w/w, for example 5 to 15% w/w, such as in the range of 5 to 10% w/w.
  • the composition comprises one or more plasticizer(s) and one or more polymer(s).
  • An active drug substance suitable for use in the pharmaceutical compositions described herein is a therapeutically, prophylactically and/or diagnostically active drug substance (herein also abbreviated as “active substance” or “active drug substance”).
  • Examples of specific active drug substances suitable for use in the pharmaceutical compositions provided herein include:
  • Anti-inflammatory and antirheumatic active drug substances such as, for example: butylpyrazolidines, phenylbutazone, mofebutazone, oxyphenbutazone, clofezone, kebuzone, acetic acid derivatives and related substances, indometacin, sulindac, tolmetin, zomepirac, diclofenac, alclofenac, bumadizone, etodolac, lonazolac, fentiazac, acemetacin, difenpiramide, oxametacin, proglumetacin, ketorolac, aceclofenac, bufexamac, oxicams, piroxicam, tenoxicam, droxicam, lornoxicam, meloxicam, methotrexate, propionic acid derivatives, ibuprofen, naproxen, ketoprofen, fenoprofen, fenbufen, benox
  • Analgesics such as, for example: opioids, natural opium alkaloids, morphine, opium, hydromorphone, nicomorphine, oxycodone, dihydrocodeine, diamorphine, tapentadol, papaveretum, codeine, phenylpiperidine derivatives, ketobemidone, pethidine, fentanyl, diphenylpropylamine derivatives, dextromoramide, piritramide, dextropropoxyphene, bezitramide, methadone, benzomorphan derivatives, pentazocine, phenazocine, oripavine derivatives, buprenorphine, morphinan derivatives, butorphanol, nalbuphine, tilidine, tramadol, dezocine, salicylic acid and derivatives, acetylsalicylic acid, aloxiprin, choline salicylate, sodium salicylate, salicylamide, salsalate, ethen
  • Anaesthetics such as, for example: ethers, diethyl ether, vinyl ether, halogenated hydrocarbons, halothane, chloroform, methoxyflurane, enflurane, trichloroethylene, isoflurane, desflurane, sevoflurane, barbiturates, methohexital, hexobarbital, thiopental, narcobarbital, opioid anaesthetics, fentanyl, alfentanil, sufentanil, phenoperidine, anileridine, remifentanil, other general anaesthetics, such as, for example: droperidol, ketamine, propanidid, alfaxalone, etomidate, propofol, hydroxybutyric acid, nitrous oxide, esketamine, xenon, esters of aminobenzoic acid, metabutethamine, procaine, tetracaine, chloropro
  • Antimigraine active drug substances such as, for example: ergot alkaloids, dihydroergotamine, ergotamine, methysergide, lisuride, corticosteroid derivatives, flumedroxone, selective serotonin (5HT1) agonists, sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan, frovatriptan, other antimigraine preparations, pizotifen, clonidine, iprazochrome, dimetotiazine, oxetorone;
  • ergot alkaloids such as, for example: ergot alkaloids, dihydroergotamine, ergotamine, methysergide, lisuride, corticosteroid derivatives, flumedroxone, selective serotonin (5HT1) agonists, sumatriptan, naratriptan, zolmitriptan, riz
  • Antiepileptic active drug substances such as, for example:barbiturates and derivatives, methylphenobarbital, phenobarbital, primidone, barbexaclone, metharbital, hydantoin derivatives, ethotoin, phenytoin, amino(diphenylhydantoin) valeric acid, mephenytoin, fosphenytoin, oxazolidine derivatives, paramethadione, trimethadione, ethadione, succinimide derivatives, ethosuximide, phensuximide, mesuximide, benzodiazepine derivatives, clonazepam, carboxamide derivatives, carbamazepine, oxcarbazepine, rufinamide, fatty acid derivatives, valproic acid, valpromide, aminobutyric acid, vigabatrin, progabide, tiagabine, other antiepileptics, such as
  • Anticholinergic active drug substances such as, for example: tertiary amines, trihexyphenidyl, biperiden, metixene, procyclidine, profenamine, dexetimide, phenglutarimide, mazaticol, bornaprine, tropatepine, ethers chemically close to antihistamines, etanautine, orphenadrine (chloride), ethers of tropine or tropine derivatives, benzatropine, etybenzatropine;
  • Dopaminergic active drug substances such as, for example: dopa and dopa derivatives, levodopa, melevodopa, etilevodopa, adamantane derivatives, amantadine, dopamine agonists, bromocriptine, pergolide, dihydroergocryptine mesylate, ropinirole, pramipexole, cabergoline, apomorphine, piribedil, rotigotine, monoamine, oxidase B inhibitors, selegiline, rasagiline, other dopaminergic agents, such as, for example: tolcapone, entacapone, budipine;
  • Antipsychotic active drug substances such as, for example: phenothiazines with aliphatic side-chain, chlorpromazine, levomepromazine, promazine, acepromazine, triflupromazine, cyamemazine, chlorproethazine, phenothiazines with piperazine structure, dixyrazine, fluphenazine, perphenazine, prochlorperazine, thiopropazate, trifluoperazine, acetophenazine, thioproperazine, butaperazine, perazine, phenothiazines with piperidine structure, periciazine, thioridazine, mesoridazine, pipotiazine, butyrophenone derivatives, haloperidol, trifluperidol, melperone, moperone, pipamperone, bromperidol, benperidol, droperidol, fluanisone, ind
  • Anxiolytic active drug substances such as, for example: benzodiazepine derivatives, diazepam, chlordiazepoxide, medazepam, oxazepam, potassium clorazepate, lorazepam, adinazolam, bromazepam, clobazam, ketazolam, prazepam, alprazolam, halazepam, pinazepam, camazepam, nordazepam, fludiazepam, ethyl loflazepate, etizolam, clotiazepam, cloxazolam, tofisopam, diphenylmethane derivatives, hydroxyzine, captodiame, carbamates, meprobamate, emylcamate, mebutamate, dibenzo-bicyclo-octadiene derivatives, benzoctamine, azaspirodecanedi
  • Hypnotic and sedative active drug substances such as, for example: barbiturates, pentobarbital, amobarbital, butobarbital, barbital, aprobarbital, secobarbital, talbutal, vinylbital, vinbarbital, cyclobarbital, heptabarbital, reposal, methohexital, hexobarbital, thiopental, etallobarbital, allobarbital, proxibarbal, aldehydes and derivatives, chloral hydrate, chloralodol, acetylglycinamide chloral hydrate, dichloralphenazone, paraldehyde, benzodiazepineemepronium derivatives, flurazepam, nitrazepam, flunitrazepam, estazolam, triazolam, lormetazepam, temazepam, midazolam, brotizolam, quazepam,
  • Antidepressant active drug substances such as, for example: non-selective monoamine reuptake inhibitors, desipramine, imipramine, imipramine oxide, clomipramine, opipramol, trimipramine, lofepramine, dibenzepin, amitriptyline, nortriptyline, protriptyline, doxepin, iprindole, melitracen, butriptyline, dosulepin, amoxapine, dimetacrine, amineptine, maprotiline, quinupramine, selective serotonin reuptake inhibitors, zimeldine, fluoxetine, citalopram, paroxetine, sertraline, alaproclate, fluvoxamine, etoperidone, escitalopram, monoamine oxidase inhibitors, isocarboxazid, nialamide, phenelzine, tranylcypromine, iproniazide,
  • Anti-dementia active drug subtances such as, for example: anticholinesterases, tacrine, donepezil, rivastigmine, galantamine, other anti-dementia drugs, memantine, and ginkgo biloba;
  • Other nervous system active drug substances such as, for example: parasympathomimetics, anticholinesterases, neostigmine, pyridostigmine, distigmine, ambenonium, choline esters, carbachol, bethanechol, other parasympathomimetics, such as, for example: pilocarpine, choline alfoscerate;
  • Active drug substances used in addictive disorders such as, for example: nicotine, bupropion, varenicline, disulfiram, calcium carbimide, acamprosate, naltrexone, buprenorphine, methadone, levacetylmethadol, lofexidine, betahistine, cinnarizine, flunarizine, acetylleucine, gangliosides and ganglioside derivatives, tirilazad, riluzole, xaliproden, hydroxybutyric acid, amifampridine;
  • Opium alkaloids and derivatives such as, for example: ethylmorphine, hydrocodone, codeine, opium alkaloids with morphine, normethadone, noscapine, pholcodine, dextromethorphan, thebacon, dimemorfan, acetyldihydrocodeine, benzonatate, benproperine, clobutinol, isoaminile, pentoxyverine, oxolamine, oxeladin, clofedanol, pipazetate, bibenzonium bromide, butamirate, fedrilate, zipeprol, dibunate, droxypropine, prenoxdiazine, dropropizine, cloperastine, meprotixol, piperidione, tipepidine, morclofone, nepinalone, levodropropizine, dimethoxanate.
  • the active drug substance may, for example, be an active drug substance with abuse potential that presents a safety risk.
  • Such active drug substance may, for example, be selected from:
  • active drug substances suitable for use in the pharmaceutical compositions described herein include, for example, alfentanil, allylprodine, alphaprodine, egoidine, benzylmorphine, bezitramide, buprenorphine, butophanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diapromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimephetanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, dextropropoxyphene, ketobemidone, levallor
  • active drug substances suitable for use in the pharmaceutical compositions described herein include anabolic steroids, cannabis, cocaine and diazepam.
  • the active drug substance is selected from the group consisting of the therapeutic classes including non-steroidal anti-inflammatory substances and antirheumatic active drug substances.
  • the active drug substance is selected from therapeutic classes including analgesics, opioids, antipyretics, anaesthetics, antimigraine agents, antiepileptics, anti-parkinson agents, dopaminergic agents, antipsychotics, anxiolytics, sedatives, antidepressants, psychostimulants agents, dopamine, noradrenaline, nicotinic, alfa-andrenergic, serotonin, H3 antagonists used for ADHD and nootropics agents used in addictive disorders.
  • analgesics including opioids, antipyretics, anaesthetics, antimigraine agents, antiepileptics, anti-parkinson agents, dopaminergic agents, antipsychotics, anxiolytics, sedatives, antidepressants, psychostimulants agents, dopamine, noradrenaline, nicotinic, alfa-andrenergic, serotonin, H3 antagonists used for ADHD and nootropics
  • the active drug substance is selected from therapeutic classes including anaesthetics, centrally-acting analgesics, sedative-hypnotics, anxiolytics, appetite suppressants, decongestants, antitussives, antihistamines, antiemetics, antidiarrheals, and drugs used to treat narcolepsy and attention deficit hyperactivity disorder.
  • the active drug substance is associated with abuse syndromes and the active drug substance may, for example, be selected from opioids, CNS depressants, CNS stimulants, cannabinoids, nicotine-like compounds, glutamate antagonists and N-methyl-D-aspartate (NMDA) antagonists.
  • opioids CNS depressants
  • CNS stimulants CNS stimulants
  • cannabinoids nicotine-like compounds
  • glutamate antagonists N-methyl-D-aspartate (NMDA) antagonists.
  • NMDA N-methyl-D-aspartate
  • the active drug substance is an analgesic.
  • analgesics suitable for use in the pharmaceutical compositions described herein include, for example, opioids, natural opium alkaloids, morphine, opium, hydromorphone, nicomorphine, oxycodone, dihydrocodeine, diamorphine, tapentadol, papaveretum, codeine, phenylpiperidine derivatives, ketobemidone, pethidine, fentanyl, diphenylpropylamine derivatives, dextromoramide, piritramide, dextropropoxyphene, bezitramide, methadone, benzomorphan derivatives, pentazocine, phenazocine, oripavine derivatives, buprenorphine, morphinan derivatives, butorphanol, nalbuphine, tilidine, tramadol, dezocine, salicylic acid and derivatives, acetylsalicylic acid, al
  • the active drug substance is an opioid.
  • the opioid may be selected from naturally occurring opioids, synthetic opioids and semisynthetic opioids.
  • the active drug substance is selected from amfetamine, dexamfetamine, lisdexamfetamine, metamfetamine, methylphenidate, dexmethylphenidate and combinations thereof.
  • the pharmaceutical compositions disclosed herein includes an opioid, the opioid is selected from buprenorphine, codeine, dextromoramide, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, morphine, pentazocine, oxycodeine, oxycodone, oxymorphone, norhydrocodone, noroxycodone, morphine-6-glucuronode, tramadol, tapentadol and dihydromorphine.
  • the opioid is selected from buprenorphine, codeine, dextromoramide, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, morphine, pentazocine, oxycodeine, oxycodone, oxymorphone, norhydrocodone, noroxycodone, morphine-6-glucuronode, tramadol, tapentadol and dihydromorphine.
  • an opioid used as an active drug substance
  • the opioid may be present in any of its crystalline, polymorphous, semi-crystalline, and amorphous or polyamorphous forms.
  • an opioid used as an active drug substance may be present in one or more forms selected from its crystalline, polymorphous, semi-crystalline, and amorphous or polyamorphous forms.
  • compositions disclosed herein include an opioid as an active drug substance
  • the active drug substance is selected from morphine, oxycodone, hydrocodone, hydromorphone, norhydrocodone, oxymorphone, noroxycodone, morphine-6-glucuronode and pharmaceutically acceptable salts of any of the aforementioned, such as from the group consisting of oxycodone hydrochloride, hydrocodone bitartrate, hydromorphone hydrochloride and morphine sulphate pentahydrate.
  • compositions as described herein are suitable for use for water soluble as well as slightly soluble or insoluble active drug substances.
  • all of the above mentioned active drug substances may also be in the form of pharmaceutically acceptable salts, uncharged or charged molecules, molecular complexes, solvates, or anhydrates thereof, and, if relevant, isomers, enantiomers, racemic mixtures, and mixtures thereof.
  • compositions described herein may comprise pharmaceutically acceptable salts of any of the above mentioned active drug substances.
  • salts of an active drug substance includes alkali metal salts such as, for example, sodium or potassium salts, alkaline earth metal salts such as, for example, calcium and magnesium salts, and salts with organic or inorganic acid such as, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, succinic acid, tartaric acid, methansulphonic acid, toluenesulphonic acid etc.
  • alkali metal salts such as, for example, sodium or potassium salts
  • alkaline earth metal salts such as, for example, calcium and magnesium salts
  • organic or inorganic acid such as, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, succinic acid, tartaric acid, methansulphonic acid, toluenesulphonic acid etc.
  • pharmaceutically acceptable salts of an opioid includes alkali metal salts such as, for example, sodium or potassium salts, alkaline earth metal salts such as, for example, calcium and magnesium salts, and salts with organic or inorganic acids such as, for example hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, succinic acid, tartaric acid, methansulphonic acid, toluenesulphonic acid etc or tartrate acid.
  • pharmaceutically acceptable opioid salts may be selected from the group consisting of sulphate salts, hydrochloride salts and bitartrate salts.
  • solvates includes hydrates or solvates wherein other solvates than water are involved such as, for example, organic solvents like chloroform and the like.
  • the active drug substance may be in any of its crystalline, polymorphous, semi-crystalline, amorphous or polyamorphous forms and mixtures thereof.
  • the concentration of the active drug substance in the pharmaceutical composition for use according to the disclosure depends on the specific active drug substance, the disease to be treated, the condition of the patient, the age and gender of the patient etc.
  • the above-mentioned active drug substances may be known active drug substances and a person skilled in the art will be able to find information as to the dosage of each active drug substance and, accordingly, will know how to determine the amount of each active drug substance in the pharmaceutical composition.
  • the active drug substance may be a new chemical entity for which the amount of information is limited. In such cases, the dosage has to be evaluated based on available preclinical and/or clinical data.
  • the active drug substance is typically present in the composition in an amount of from 5 to about 90% w/w such as, for example, from about 5 to about 80% w/w, from about 5 to about 70% w/w, from about 5 to about 60% w/w, from about 5 to about 50% w/w, from about 5 to about 40% w/w, from about 5 to about 30% w/w, from about 5 to about 20% w/w, from about 5 to about 10% w/w.
  • w/w such as, for example, from about 5 to about 80% w/w, from about 5 to about 70% w/w, from about 5 to about 60% w/w, from about 5 to about 50% w/w, from about 5 to about 40% w/w, from about 5 to about 30% w/w, from about 5 to about 20% w/w, from about 5 to about 10% w/w.
  • the active drug substance is an opioid, such as, for example, morphine, oxycodone, hydromorphone or oxymorphone or pharmaceutically acceptable salts thereof
  • said opioid is typically present in the compositions in a concentration of in the range of 5 to 70% w/w, for example in the range of 5 to 60% w/w, such as in the range of 5 to 50% w/w, for example in the range of 5 to 45% w/w, such as in the range of 5 to 40% w/w, for example in the range of 5 to 35% w/w, such as in the range of 5 to 30% w/w, for example in the range of 5 to 25% w/w, such as in the range of 5 to 20% w/w, for example in the range of 5 to 15% w/w, such as in the range of 5 to 10% w/w.
  • an opioid such as, for example, morphine, oxycodone, hydromorphone or oxymorphone or pharmaceutically acceptable salts thereof
  • said opioid is typically present in the composition
  • the active drug substance is typically present in the composition in an amount of from 1 to about 90% w/w such as, for example, from about 1 to about 80% w/w, from about 1 to about 70% w/w, from about 1 to about 60% w/w, from about 1 to about 50% w/w, from about 1 to about 40% w/w, from about 1 to about 30% w/w, from about 1 to about 20% w/w, from about 1 to about 10% w/w.
  • w/w such as, for example, from about 1 to about 80% w/w, from about 1 to about 70% w/w, from about 1 to about 60% w/w, from about 1 to about 50% w/w, from about 1 to about 40% w/w, from about 1 to about 30% w/w, from about 1 to about 20% w/w, from about 1 to about 10% w/w.
  • the active drug substance is an opioid, such as, for example, morphine, oxycodone, hydromorphone or oxymorphone or pharmaceutically acceptable salts thereof
  • said opioid is typically present in the compositions in a concentration of in the range of 1 to 70% w/w, for example in the range of 1 to 60% w/w, such as in the range of 1 to 50% w/w, for example in the range of 1 to 45% w/w, such as in the range of 1 to 40% w/w, for example in the range of 1 to 35% w/w, such as in the range of 1 to 30% w/w, for example in the range of 1 to 25% w/w, such as in the range of 1 to 20% w/w, for example in the range of 1 to 15% w/w, such as in the range of 1 to 10% w/w.
  • an opioid such as, for example, morphine, oxycodone, hydromorphone or oxymorphone or pharmaceutically acceptable salts thereof
  • said opioid is typically present in the composition
  • the compositions comprise a load of the active drug substance, such as an opioid.
  • a load is generally less than 50% w/w of the active drug substance.
  • the compositions may include an active drug substance in an amount selected from less than 40% w/w and less than 30% w/w.
  • a pharmaceutical composition as described herein may comprise one active drug substance or more than one different active drug substances.
  • the amount of the active drug substance corresponds to a daily or part of a daily therapeutic dose.
  • the pharmaceutical composition provides for administration 1-6 times a day, normally 1-4 times daily, such as 1-3 times daily, such as 1-2 times daily or 1 time daily.
  • the pharmaceutical composition provides for twice-daily administration. In another embodiment, the pharmaceutical composition provides for once-daily administration.
  • compositions described herein may also contain other excipients in order to achieve one or more desired properties, such as, for example, better stability of the active drug substance or the pharmaceutical composition itself, enhance the abuse-deterrent properties, loading of the active drug substance or delivery characteristics, such as release rate or release profile of an active drug substance.
  • the compositions described herein may include excipients that facilitate manufacture and production of dosage forms such as, for example, tablets suitable for administration to individuals in need thereof.
  • a suitable pharmaceutically acceptable excipient for use in compositions according to the present description may be selected from fillers, diluents, disintegrants, glidants, pH-adjusting agents, viscosity adjusting agents, solubility increasing or decreasing agents, osmotically active agents and solvents.
  • suitable excipients include conventional tablet or capsule excipients. These excipients may be, for example, diluents such as dicalcium phosphate, calcium sulfate, lactose or sucrose or other disaccharides, cellulose, cellulose derivatives, kaolin, mannitol, dry starch, glucose or other monosaccharides, dextrin or other polysaccharides, sorbitol, inositol or mixtures thereof; binders such as alginic acid, calcium alginate, sodium alginate, starch, gelatin, saccharides (including glucose, sucrose, dextrose and lactose), carboxymethylcellulose, methylcellulose, veegum, larch arabolactan, polyethylene glycols, ethylcellulose, water, alcohols, waxes, polyvinylpyrrolidone such as PVP K90 or mixtures thereof; lubricants such as talc, silicium dioxide,
  • the composition may comprise an additional polymer such as polyglycols selected from substantially water soluble, thermoplastic, crystalline, semi-crystalline or amorphous or a mixture of substantially water soluble, crystalline, semi-crystalline or amorphous polymers.
  • the polyglycol is at least thermoplastic.
  • Suitable polyglycols for use in the composition include, for example, polyethylene glycols (for example with a molecular weight below 35,000 daltons), as well as derivatives of polyethylene glycol, such as mono or dimethoxypolyethylene glycols (mPEGs), polyethylene oxides and/or block copolymers of ethylene oxide and propylene oxide.
  • the composition may comprise an additional polymer, such as, for example, at least one polymer selected from: modified or unmodified water soluble natural polymers such as glucomannan, galactan, glucan, polygalacturonic acid, polyxylane, polygalactomannans, rhanogalacturonan, polyxyloglycan, arabinogalactan, and starch, cellulose, chitosan, alginate, fibrin, collagen, gelatin, hyaluronic acid, amylopectin, pectin including low methylated or methoxylated pectins, dextran and fatty acids and alcohols; synthetic polymers such as Carbopol, carbomer, carbomer homopolymer, carboxyvinyl polymer, polyvinylpyrrolidone (PVP), PVA, PVB, Eudragit L methyl ester, Eudragit L, Eudragit RL, Eudragit
  • the composition as described herein may comprise one or more gelling agents.
  • examples are polymers selected from the group consisting of modified or unmodified water soluble natural polymers such as glucomannan, galactan, glucan, polygalacturonic acid, polyxylane, polygalactomannans, polyxyloglycan, arabinogalactan, starch, cellulose, chitosan, alginate, fibrin, collagen, gelatin, amylopectin, pectin including low methylated or methoxylated pectins, dextran; synthetic polymers such as PVA and PVB; and hydrogels made from the polymers or combined polymers mentioned above and or from polymers originated from: HEMA, HEEMA, MEMA, MEEMA, EDGMA, NVP, VAc, AA, acrylamide, MAA, HPMA, PEGA, PEGMA, PEGDMA, PEGDA, and/or PEGDMA, hydroxypropyl cellulose, methylcellulose, hydroxyethoxy
  • exemplary stabilizers include TPG, for example, in the form of TPGS (Vitamin E Polyethylene glycol succinate) and BHT, BHA, t-butyl hydroquinone, butylhydroxy toluene, calcium ascorbate, gallic acid, hydroquinone, maltol, octyl gallate, sodium bisulfite, sodium metabisulfite, tocopherol and derivates thereof, citric acid, tartaric acid, and ascorbic acid.
  • TPGS Volitamin E Polyethylene glycol succinate
  • BHT t-butyl hydroquinone
  • butylhydroxy toluene calcium ascorbate
  • gallic acid hydroquinone
  • maltol maltol
  • octyl gallate sodium bisulfite, sodium metabisulfite, tocopherol and derivates thereof, citric acid, tartaric acid, and ascorbic acid.
  • stabilisers include trivalent phosphorous, such as, for example, phosphite, phenolic antioxidants, hydroxylamines, lactones such as substituted benzofuranones, hindered phenols, thiosynergists and/or hindered amines, acids (ascorbic acid, erythorbic acid, etidronic acid, hypophosphorous acid, nordihydroguaiaretic acid, propionic acid etc.), phenols, dodecyl gallate, octyl gallate, 1,3,5-trihydroxybenzene, organic and inorganic salts (calcium ascorbate, sodium ascorbate, sodium bisulphite, sodium metabisulfite, sodium sulfite, potassium bisulphite, potassium metabisulphite), esters (calcium ascorbate, dilauryl thiodipropionate, dimyristyl thiodipropionate, distearyl thiodi
  • a composition as described herein comprises one or more stabilizers selected from above mentioned group of stabilizers.
  • the composition comprises butylhydoxytoluene and/or TPGS as a stabilizer.
  • the composition comprises gallic acid and/or ascorbic acid as a stabilizer.
  • a release modifier may be incorporated in a composition as described herein.
  • a suitable release modifier may be selected from fatty acids and esters, fatty alcohols, cetyl alcohol, stearyl alcohol, mineral oils, hydrogenated vegetable oils, vegetable oils, acetylated hydrogenated soybean oil glycerides, Castor oil, phosphate esters, amides, phthalate esters, glyceryl cocoate oleyl alcohol, myristyl alcohol, sucrose octaacetate, diacetylated monoglycerides, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monooleate, glyceryl monostearate, propylene glycol monostearate, macrogol esters, macrogol stearate 400, macrogol stearate 2000, polyoxyethylene 50 stearate, macrogol ethers, cetomacrogol 1000, lauromacrogols, poloxamers, polyvinyl alcohols,
  • other suitable release modifiers may be selected from inorganic acids, inorganic bases, inorganic salts, organic acids or bases and pharmaceutically acceptable salts thereof, saccharides, oligosaccharides, polysaccharides, polyethylene glycol derivatives and cellulose and cellulose derivatives.
  • a composition according to the present description may include a pharmaceutically acceptable excipient selected from a mono-, di-, oligo, polycarboxylic acid or amino acids such as, for example, acetic acid, succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, sorbic acid etc., aspartic acid or glutamic acid etc.
  • a pharmaceutically acceptable excipient selected from a mono-, di-, oligo, polycarboxylic acid or amino acids such as, for example, acetic acid, succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, sorbic acid etc., aspartic acid or glutamic acid etc.
  • suitable organic acids that may be included in the compositions described herein include, for example, acetic acid/ethanoic acid, adipic acid, angelic acid, ascorbic acid/vitamin C, carbamic acid, cinnamic acid, citramalic acid, formic acid, fumaric acid, gallic acid, gentisic acid, glutaconic acid, glutaric acid, glyceric acid, glycolic acid, glyoxylic acid, lactic acid, levulinic acid, malonic acid, mandelic acid, oxalic acid, oxamic acid, pimelic acid, or pyruvic acid.
  • suitable inorganic acids that may be included in the compositions described herein include, for example, pyrophosphoric, glycerophosphoric, phosphoric such as ortho and meta phosphoric, boric acid, hydrochloric acid, or sulfuric acid.
  • examples of suitable inorganic compounds that may be included in the compositions described herein include, for example, aluminium, calcium or kalium.
  • examples of organic bases that may be included in the compositions described herein include, for example, p-nitrophenol, succinimide, benzenesulfonamide, 2-hydroxy-2cyclohexenone, imidazole, pyrrole, diethanolamine, ethyleneamine tris (hydroxymethyl) aminomethane, hydroxylamine and derivates of amines, sodium citrate, aniline or hydrazine.
  • examples of inorganic bases that may be included in the compositions described herein include, for example, aluminium oxide such as, for example, aluminium oxide trihydrate, alumina, sodium hydroxide, potassium hydroxide, calcium carbonate, ammonium carbonate, ammnonium hydroxide or KOH.
  • pharmaceutically acceptable salts of an organic acid that may be included in the compositions described herein include, for example, an alkali metal salt or an alkaline earth metal salt such as, for example, sodium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate etc., potassium phosphate, potassium dihydrogenphosphate, potassium hydrogenphosphate etc., calcium phosphate, dicalcium phosphate etc., sodium sulfate, potassium sulfate, calcium sulfate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, calcium carbonate, magnesium carbonate etc., sodium acetate, potassium acetate, calcium acetate, sodium succinate, potassium succinate, calcium succinate, sodium citrate, potassium citrate, calcium citrate, sodium tartrate, potassium tartrate or calcium tartrate.
  • an alkali metal salt or an alkaline earth metal salt such as, for example, sodium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate etc., potassium phosphate, potassium dihydrogenphosphate,
  • suitable inorganic salts for that may be used in a composition as described herein include, for example, sodium chloride, potassium chloride, calcium chloride or magnesium chloride.
  • the composition may comprise at least one saccharide.
  • a saccharide is included in a composition as described herein, the saccharide may be selected from, for example, glucose, ribose, arabinose, xylose, lyxose, xylol, allose, altrose, inosito, glucose, sorbitol, mannose, gulose, glycerol, idose, galactose, talose, mannitol, erythritol, ribitol, xylitol, maltitol, isomalt, lactitol, sucrose, fructose, lactose, dextrin, dextran, amylase or xylan.
  • the composition may also comprise cellulose and/or cellulose derivatives selected from the group consisting of methylcellulose, carboxymethylcellulose and salts thereof, microcrystalline cellulose, ethylhydroxyethylcellulose, ethylcellulose, cellulose acetate, cellulose proprionate, cellulose nitrate, cellulose acetate phthalate, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose and hydroxymethylpropylcellulose.
  • cellulose and/or cellulose derivatives selected from the group consisting of methylcellulose, carboxymethylcellulose and salts thereof, microcrystalline cellulose, ethylhydroxyethylcellulose, ethylcellulose, cellulose acetate, cellulose proprionate, cellulose nitrate, cellulose acetate phthalate, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose and hydroxymethyl
  • compositions described herein may comprise one or more agents selected from sweetening agents, flavouring agents and colouring agents in order to provide an elegant and palatable preparation.
  • agents selected from sweetening agents, flavouring agents and colouring agents in order to provide an elegant and palatable preparation.
  • agents include maltol, citric acid, water soluble FD&C dyes and mixtures thereof with corresponding lakes and direct compression sugars such as Di-Pac from Amstar.
  • coloured dye migration inhibitors such as; tragacanth, acacia or attapulgite talc may be added.
  • Specific examples include calcium carbonate, 1,3,5-trihydroxybenzene, chromium-cobalt-aluminium oxide, ferric ferrocyanide, ferric oxide, Iron ammonium citrate, iron (III) oxide hydrated, iron oxides, carmine red, magnesium carbonate and titanium dioxide.
  • compositions of the disclosure may be produced by various methods which are either known per se in the pharmaceutical industry or which, for example, are used in the production of polymer-based materials, depending upon the desired embodiment and the materials employed in the pharmaceutical composition in question.
  • the pharmaceutical compositions according to the present description may be produced by methods that are relatively simple and inexpensive.
  • Suitable preparation methods for pharmaceutical compositions according to the present description include conventional tablet compression, hot melt-processing and other methods of preparing pharmaceutical compositions.
  • hot melt-processing technology and the use of thermoplastic and thermosetting plastic polymers are able to give pharmaceutical compositions with low porosity, high viscosity and breaking strengths, like properties such as for example plastic which is difficult to tear down.
  • a combination of one or more of the aforementioned methods may be employed for use in the preparation of pharmaceutical compositions disclosed herein.
  • the pharmaceutical compositions described herein are prepared by hot melt-processing.
  • the pharmaceutical compositions are prepared by, for example, 1, 2 or multiple component extrusion, molding, 1, 2 or multiple component injection molding.
  • the pharmaceutical compositions are prepared by 1, 2 or multiple component injection molding.
  • the preparation may also comprise separate steps, such as, for example, wet granulation, dry granulation, melt granulation, pelletizing, curing, spray coating, electrostatic coating, dip coating or other forms of preparation methods.
  • the pharmaceutical composition is prepared by conventional tablet compression.
  • the pharmaceutical compositions are prepared by conventional tablet compression and hot melt processing.
  • compositions according to the present description may be formed as cylindrical compositions.
  • the pharmaceutical compositions are formed as a cylindrical shape optionally with one or two tapered end(s).
  • the cylindrical shape may be any geometrical shape having the same cross section area throughout the length of the geometrical shape.
  • cross sections are perpendicular to the axis of the cylinder.
  • the cross sections are perpendicular to the longitudinal axis.
  • the cylindrical shape is elongated.
  • the cross section of a cylinder within the meaning of the present disclosure may have any two-dimensional shape, for example the cross section may be circular, oval, parabola, hyperbola, rectangular, triangular, otherwise angular, star shaped or an irregular shape.
  • the cylindrical shape may for example be an elliptic cylinder, a parabolic cylinder, a hyperbolic cylinder or a prism.
  • a prism within the present context is a cylinder whose cross-section is a polygon.
  • the pharmaceutical composition according to the present description may have any common tablet shapes.
  • Exemplary tablet shapes may include, for example, standard convex, standard convex bisect not flush, standard convex quadrisect flush, standard convex straight-through bisect, compound cup, convex with bevel, flat-faced plain, flat-faced bevel-edged, flat-faced bevel-edged bisect, flat-faced bevel-edged quadrisect, flat-faced radius-edged, lozenge, modified ball, core rod type (hole in center), capsule, modified capsule, oval, bullet, arrowhead, triangle, arc triangle, square, pillow (arc square), rectangle, modified rectangle, diamond, pentagon, hexagon, octagon natural edge, heart, half moon and almond.
  • a skilled person would know the various kinds of shape that a tablet may be formed in.
  • the pharmaceutical composition is prepared for oral intake, preferably for oral intake by swallowing. Accordingly, the size of the pharmaceutical composition may be in a range that allows for oral intake by swallowing.
  • the pharmaceutical composition according to the present description may also contain a cosmetic coat that fully covers the composition.
  • the cosmetic coat may be selected from the group consisting of taste-masking coats, coats with aqueous moisture barriers and/or oxidative barriers to improve the stability of the composition, and coat containing colouring agents, sweetening agents and/or flavouring agents in order to provide an elegant and palatable pharmaceutical composition and/or to easy distinguishable dose strengths.
  • compositions having different dose strengths or active drug substances with cosmetic coats of different colours so that the different actives and dose strengths are easily distinguished.
  • the cosmetic coat contains an active drug substance.
  • the cosmetic coat may, in particular embodiments, be easily soluble in aqueous media in order to facilitate contact of the composition with the surrounding aqueous media rapidly after administration.
  • the cosmetic coat is dissolved within 30 minutes after immersed in aqueous media such as, for example, phosphate buffer solution pH 6.8.
  • the pharmaceutical composition according to the present description can be designed for oral administration.
  • the pharmaceutical compositions may be produced as tablets, for oral intake by swallowing one or more intact tablets of the pharmaceutical composition.
  • a pharmaceutical composition as described herein may comprise one active drug substance or more than one different active drug substance.
  • a pharmaceutical composition containing an active drug substance according to the present description is typically formulated for oral administration. Due to the possibility of controlling the release rate of the active drug substance, in particular embodiments, the pharmaceutical composition may be adapted for oral administration 1-6 times a day, such as 1-4 times daily, including 1-3 times, 1-2 times or twice or once daily.
  • the pharmaceutical compositions according to the present description can be prepared for delivery of the desired dosage of active drug substance.
  • the dosage may be dependent on the individual to whom the pharmaceutical composition as described herein is being administered and the active drug substance.
  • the dosage for each administration wherein dosages are in the range of 1 to 1,000 mg, such as in the range of 5 to 1,000 mg, for example in the range of 8 to 1,000 mg, such as in the range of 10 to 1,000 mg, for example in the range of 30 to 1,000 mg, such as in the range of 1 to 750 mg, for example in the range of 1 to 500 mg, such as in the range of 1 to 250 mg of an active drug substance.
  • the dosage for each administration is in a range selected from 5 to 500 mg and 5 to 250 mg of an active drug substance.
  • the dosage when the active drug substance included in the pharmaceutical compositions is an opioid, the dosage may be selected from a range of 1 to 1000 mg, a range of 10 to 1000 mg, a range of 15 to 1000 mg, a range of 20 to 1000 mg, a range of 30 to 1000 mg, a range of 1 to 500 mg, a range of 1 to 250 mg, a range of 10 to 500 mg, a range of 15 to 500 mg, a range of 15 to 250 mg, a range of 20 to 500 mg, a range of 20 to 250 mg, a range of 30 to 500 mg, a range of 30 to 250 mg, a range of 10 to 200 mg, a range of 15 to 200 mg, a range of 20 to 200 mg, and a range of 30 to 200 mg of the opioid.
  • the pharmaceutical composition includes opioid or a pharmaceutically acceptable salt thereof as an active drug substance and the dosage is selected from 10, 15, 20, 30, 50, 60, 80, 100 or 200 mg.
  • the pharmaceutical composition includes morphine as an active drug substance and the dosage is selected from 10, 15, 20, 30, 50, 60, 80, 90, 100, 120, 180 or 200 mg.
  • the dosage when the active drug substance included in the pharmaceutical compositions is an opioid, the dosage may be selected from a range of 1 to 1,000 mg, a range of 10 to 1,000 mg, a range of 1 to 500 mg, a range of 1 to 250 mg, a range of 10 to 500 mg, a range of 10 to 250 mg, a range of 1 to 150 mg, a range of 10 to 150 mg, a range of 1 to 100 mg a range of 10 to 100 mg, a range of 1 to 80 mg and a range of 10 to 80 mg of the opioid.
  • the pharmaceutical composition includes opioids or a pharmaceutically acceptable salt thereof as an active drug substance and the dosage is selected from 10, 15, 20, 30, 40, 60 or 80 mg.
  • the pharmaceutical composition includes hydrocodone as an active drug substance and the dosage is selected from 10, 15, 20, 30, 40, 60 or 80 mg. In another such embodiments, the pharmaceutical composition includes oxycodone as an active drug substance and the dosage is selected from 10, 15, 20, 30, 40, 60 or 80 mg.
  • the dosage when the active drug substance included in the pharmaceutical compositions is an opioid, the dosage may be selected from a range of 1 to 1,000 mg, a range of 8 to 1,000 mg, a range of 1 to 500 mg, a range of 1 to 250 mg, a range of 8 to 500 mg, a range of 8 to 250 mg a range of 1 to 100 mg, a range of 8 to 100 mg, a range oft to 75 mg, a range of 8 to 75 mg, a range of 1 to 64 mg and a range of 8 to 64 mg of the opioid.
  • the pharmaceutical composition includes opioids or a pharmaceutically acceptable salt thereof as an active drug substance and the dosage is selected from 8, 12, 16, 32 or 64 mg.
  • the pharmaceutical composition includes hydromorphone as an active drug substance and the dosage is selected from 8, 12, 16, 32 or 64 mg.
  • the dosage when the active drug substance included in the pharmaceutical compositions is an opioid, the dosage may be selected from a range of 1 to 1,000 mg, a range of 5 to 1,000 mg, a range of 1 to 500 mg, a range of 1 to 250 mg, a range of 5 to 500 mg, a range of 5 to 250 mg a range of 1 to 100 mg, a range of 5 to 100 mg, a range of 1 to 50 mg, a range of 5 to 50 mg, a range of 1 to 40 mg, and a range of 5 to 40 mg of the opioid.
  • the pharmaceutical composition includes opioids or a pharmaceutically acceptable salt thereof as an active drug substance and the dosage is selected from 5, 7.5, 10, 15, 20, 30 or 40 mg.
  • the pharmaceutical composition includes oxymorphone as an active drug substance and the dosage is selected from 5, 7.5, 10, 15, 20, 30 or 40 mg.
  • the above-mentioned dosages are relevant when the individual in need of treatment is a human being, such as an adult human being.
  • the pharmaceutical composition of the disclosure is prepared for administration to an individual in need thereof.
  • the individual may be a mammal, and in specific embodiments the individual is a human being.
  • the pharmaceutical composition is for treatment of pain and accordingly, the individual in need of treatment is an individual suffering from pain.
  • the pharmaceutical compositions are suitable for treatment of moderate to severe pain such as severe pain.
  • examples of individuals, who may benefit from treatment with the pharmaceutical compositions according to the disclosure include, for example, the following:
  • the individual may be an individual suffering from chronic pain, such as moderate to severe chronic pain;
  • the individual may also be an individual who has suffered a moderate to severe injury
  • the individual may be an individual suffering from pain associated with surgical conditions, such as a pre-surgical individual (an individual in need of surgery) or a post surgical individual (an individual who has undergone surgery);
  • the individual may also be an individual suffering from or having suffered from a myocardial infarction, sickle cell crises, kidney stone or severe back pain;
  • the individual may also be an individual suffering from degenerative pain, herniated disc pain, fibromyalgia, neuropathic pain and/or nociceptive pain; and
  • the individual may also be an individual suffering from arthritis, such as arthritis osteo, arthritis rheumatoid, arthritis psoriatica and/or arthritis urica.
  • arthritis such as arthritis osteo, arthritis rheumatoid, arthritis psoriatica and/or arthritis urica.
  • compositions according to the present description may be formulated or configured to provide a reduced risk for alcohol-induced dose dumping.
  • the pharmaceutical compositions according to the present description may be formulated or configured such that the pharmaceutical composition does not exhibit alcohol induced dose-dumping.
  • the composition exhibits a solubility and/or active drug substance release rate in alcohol containing media (for example, ethanol containing media) that is lower than or equal to the solubility and/or release rate in aqueous media that does not include alcohol (for example, water, phosphate buffer medium pH 6.8 or dilute hydrochloric acid).
  • the polyethylene oxide and excipients selected for use in the pharmaceutical composition are provided in relative amounts that result in an unchanged or lower dissolution rate and/or release rate of the active drug substance in alcohol containing media (for example, ethanol containing media) as compared to the solubility and/or release rate exhibited in aqueous media that does not include alcohol (for example, water, phosphate buffer medium pH 6.8 or dilute hydrochloric acid).
  • alcohol containing media for example, ethanol containing media
  • aqueous media that does not include alcohol (for example, water, phosphate buffer medium pH 6.8 or dilute hydrochloric acid).
  • the dissolution and/or release rate of the active drug substance from the pharmaceutical composition in alcohol containing media is at least 1.25 times lower, such as at least 1.5 times lower, such as at least 2 times lower, such as at least 5 times, such as at least 10 times lower than the dissolution and/or release rate of the active drug substance in aqueous media that does not include alcohol (for example, water, phosphate buffer medium pH 6.8, dilute hydrochloric acid, and the like).
  • the pharmaceutical composition may be formulated or configured to mitigate or prevent alcohol-induced dose dumping.
  • the solubility or release rate of the composition is lower or substantially the same in alcohol than that in water.
  • the solubility or release rate of the composition is equal or at least 1.25 times lower such as at least 1.5 times lower; at least 2 times lower in alcohol than in water, notably 5 times or 10 times lower.
  • the pharmaceutical compositions according to the present description may be configured or formulated to mitigate or prevent alcohol-induced dose dumping.
  • the pharmaceutical compositions are formulated such that the ratio (R 50 ) between t 50% w/w (40% v/v ethanol in medium 1) and t 50% w/w (medium 1) is 1 or more.
  • t 50% w/w (medium 1) denotes the time it takes to release 50% w/w of the active drug substance from the pharmaceutical composition in an in vitro dissolution test according to USP 35, NF 30, (711), Apparatus 2, paddle employing water optionally buffered to a specific pH as dissolution medium (medium 1), and t 50% w/w (40% v/v ethanol in medium 1) denotes the time it takes to release 50% w/w of the active drug substance from the pharmaceutical composition in an in vitro dissolution test according to USP 35, NF 30, (711), Apparatus 2, paddle employing 40% v/v ethanol in medium 1 as dissolution medium.
  • the ratio R 50 is at the most 3 or at the most 2.
  • the ratio R 50 provided by the pharmaceutical compositions described herein is from 1 to 1.5 such as, for example, from 1 to 1.4, from 1 to 1.3, from 1 to 1.2, from 1 to 1.1, from 1 to 1.05, about 1, from 1 to 0.95 or from 1 to 0.9.
  • ratios determined for example, when 25%, 30%, 40%, 60%, 70%, 80%, 90% and/or 95% w/w has been released, the conditions being as described above.
  • compositions according to the present description are abuse-deterrent such that abuse administration is reduced, prevented or avoided.
  • Abuse administration typically includes injection and/or snorting.
  • Injection may be avoided by providing a non-injectable composition having such high viscosity that injection is difficult or impossible, because a liquid solution cannot be obtained.
  • non-injectable composition refers to pharmaceutical compositions having a viscosity of at least 95 mPa ⁇ s, for example at least about 100 mPa ⁇ s, such as at least about 105 mPa ⁇ s, for example at least about 110 mPa ⁇ s, such as at least about 120 mPa ⁇ s, for example at least about 130 mPa ⁇ s, such as at least about 140 mPa ⁇ s, for example at least about 150 mPa ⁇ s, such as at least about 160 mPa ⁇ s, for example, at least about 170 mPa ⁇ s, such as at least about 180 mPa ⁇ s, for example at least about 190 mPa ⁇ s, such as at least about 200 mPa ⁇ s.
  • non-injectable composition refers to pharmaceutical compositions having a viscosity of at least 170 mPa ⁇ s, where the viscosity is measured according to “Viscosity Test #2,” described in the “Viscosity test” disclosure.
  • non-injectable composition may also refer to pharmaceutical compositions having a viscosity in a range selected from between about 0.5 Pa ⁇ s to about 3,000 Pa ⁇ s, between about 0.5 Pa ⁇ s to about 2,500 Pa ⁇ s, between about 0.5 Pa ⁇ s to about 2,000 Pa ⁇ s, between about 0.5 Pa ⁇ s to about 1,700 Pa ⁇ s, between about 5 Pa ⁇ s to about 3,000 Pa ⁇ s, between about 10 Pa ⁇ s to about 3,000 Pa ⁇ s, between about 20 Pa ⁇ s to about 3,000 Pa ⁇ s, between about 30 Pa ⁇ s to about 3,000 Pa ⁇ s, between about 40 Pa ⁇ s to about 3,000 Pa ⁇ s, between about 45 Pa ⁇ s to about 3,000 Pa ⁇ s, between about 45 Pa ⁇ s to about 2,500 Pa ⁇ s, between about 45 Pa ⁇ s to about 2,000 Pa ⁇ s, between about 45 Pa ⁇ s to about 1,700 Pa ⁇ s, between about between about 46 Pa ⁇ s to about 1,700 Pa ⁇ s, where the viscosity is measured according to “Viscos
  • non-injectable composition refers to pharmaceutical compositions having a viscosity of at least about 46 Pa ⁇ s, where the viscosity is measured according to Viscosity Test #1, described in the “Viscosity test” disclosure.
  • Snorting may be avoided by providing a non-snortable composition, which cannot be tampered into small particles or powder form such that snorting is made impossible.
  • non-snortable composition refers to compositions wherein at least 90 wt % of the particles obtained after physical tampering of the composition is larger than about 1,050 ⁇ m, such as larger than about 1,100 ⁇ m, such as larger than about 1,150 ⁇ m.
  • non-snortable composition refers to a composition where at least 90 wt % of the particles obtained after physical tampering of the pharmaceutical composition is larger than 1,100 ⁇ m.
  • an abuser may tamper with pharmaceutical compositions in a manner or by using a method that achieves maximal size reduction of the pharmaceutical composition in a minimal amount of time, while obtaining small particles, a powder, or other similar products, which can be dissolved or administered as easily as possible.
  • a pharmaceutical composition disintegrates into particles, then it may be possible to dissolve or suspend the particles and use them for abuse purposes. Moreover, if it is possible to disintegrate (e.g., crush) a pharmaceutical composition, then it is possible to use the powder for snorting or sniffing and, in this way, abuse the composition. However, if it is not possible to crush a pharmaceutical composition, then there will be no particles to use for such abuse purposes. In particular embodiments, the pharmaceutical compositions described herein cannot be crushed into particles by the apparatus (e.g., tablet hardness tester) specified in Ph. Eur.
  • a particle size reduction test method has been developed to evaluate abuse potential when the pharmaceutical composition is subjected to physical tampering.
  • a pharmaceutical composition is abuse-deterrent, provided that the pharmaceutical composition does not change its release profile from a controlled release to an immediate release of the active drug substance subsequent to physical tampering (e.g., particle size reduction test, where the test program is successfully completed), which indicates that the pharmaceutical composition is abuse-deterrent.
  • physical tampering e.g., particle size reduction test, where the test program is successfully completed
  • tests on a pharmaceutical composition subjected to physical tampering may also result in equipment failure, and in such an instance, the test program is considered successfully completed, indicating a pharmaceutical composition as abuse-deterrent.
  • a pharmaceutical composition is crushed or broken into small pieces or small particles, an increased exposed surface area is created, which may increase the release rate of the active drug substance. Such an increase in release rate may lead to an increased potential for abuse. If a change in the release profile of the active drug substance from a controlled release to an immediate release is noticed, the pharmaceutical composition is considered to have failed. At such a point, the pharmaceutical composition is considered to have potential for abuse, such as by snorting or chemical extraction and it is evaluated. If the active drug substance can be extracted from the compromised pharmaceutical composition, the ease with which such extracted active drug substance can be injected is evaluated.
  • the crisping test methods as described herein include methods intended to circumvent the controlled release mechanism in or interfere with the controlled release profile of a pharmaceutical composition.
  • Crisping is a heating process designed to remove, reduce, or degrade at least some of the unwanted or undesired excipients contained within a dosage form and make the dosage form easier to abuse the active drug substance.
  • Crisping may be employed to make it easier to crush the composition into small particles or a powder form so that snorting is made possible, or to make it easier to dissolve the composition into an injectable liquid solution, dispersion, or suspension.
  • Crisping or heating methods such as, for example, heating in an oven, a microwave oven, a spoon over an open flame, and the like, may be employed by a potential abuser to it make it easier to reduce the particle size and/or the viscosity of the pharmaceutical compositions.
  • the heating is normally stopped when the pharmaceutical composition starts to turn a brown colour.
  • Further processes designed to facilitate or enable abuse such as, for example, particle size reduction, extraction and/or injection are typically initiated after the crisping process is completed.
  • the pharmaceutical compositions according to the present description are not made easier to crush into snortable particles or powder form or to dissolve into an injectable liquid solution by crisping.
  • stearate may be added to the pharmaceutical composition as described herein to facilitate the colour change of the composition to a brown and/or dark colour or even to facilitate the composition burning when exposed to a crisping process.
  • the stearate added is magnesium stearate, calcium stearate and/or stearic acid.
  • the particle size reduction test methods described herein include methods for reducing the particle size of the pharmaceutical compositions via physical tampering, such as, for example, crushing, hammering, chopping, grinding, grating, cutting, and other means of particle size reduction.
  • the particle size reduction test can be carried out using a number of mechanical and electrical tools that are common household items or are readily commercially available.
  • Tools that may be used in carrying out particle size reduction testing include, for example, a mortar and pestle, a hammer, a grater, a food chopper, a coffee grinder, and the like.
  • compositions and dosage forms may be further analyzed by use of image processing and/or particle size analysis.
  • Pharmaceutical compositions subjected to physical tampering may be analyzed by collecting the different fractions and analyzing, such as, for example, by weighing and/or dissolving to assess the contents of active drug substance in the different fractions and/or to assess the dissolution rate.
  • a control dissolution test as described in the “Dissolution test” disclosure may be performed using intact tablets (e.g., tablets that have not been subjected to physical tampering), and the results from the control dissolution test may be used as control data.
  • the extraction test methods described herein include methods for evaluating the extractability of active drug substance(s) from pharmaceutical compositions in different types of solvents.
  • the extraction test can be carried out using approximately 3 ml of water to prepare a solution of, for example, MS Contin® for injection.
  • shaking is selected as an extraction method.
  • extraction of an active drug substance from a pharmaceutical composition may be facilitated by placing a pharmaceutical composition in at least one solvent and shaking the pharmaceutical composition and the at least one solvent.
  • continuous shaking is selected as an extraction method.
  • extraction of an active drug substane from a pharmaceutical composition may be facilitated by placing a pharmaceutical composition in at least one solvent and continuously shaking the pharmaceutical composition and the at least one solvent.
  • continuous shaking refers to shaking for at least 1 second, for at least 5 seconds, for at least 30 seconds, for at least 1 min, for at least 5 minutes, for at least 10 minutes, for at least 15 minutes, for at least 30 minutes, for at least 45 minutes, for at least 60 minutes, for at least 2 hours, for at least 4 hours, for at least 8 hours, for at least 12 hours, for at least 24 hours, for at least 2 days, for at least 3 days, for at least 4 days, for at least 5 days, for at least 6 days, for at least 1 week, for at least 2 weeks, for at least a month.
  • the pharmaceutical composition may be placed in at least one solvent and left unshaken and/or undisturbed for a period of time.
  • the pharmaceutical composition may be placed in at least one solvent and left unshaken and/or undisturbed for at least 4 hours, at least 8 hours, at least 12 hours, at least 24 hours, at least 48 hours, and at least 72 hours.
  • the pharmaceutical composition may be placed in at least one solvent and left unshaken and/or undisturbed, and the active drug substance in the solvent may be first measured after at least 24 hours.
  • the amount of active drug substance in the solvent may be measured at select time points within the first 60 minutes.
  • the amount of active drug substance in the solvent may be measured at least one time, at least two times, at least three times, at least four times, at least five times, and at least six times, within the first 60 minutes of placing the pharmaceutical composition in the at least one solvent.
  • the amount of active substance in the solvent may be measured at least one time, at least two times, at least three times, at least four times, at least five times, and at least six times, within the first 24 hours of placing the pharmaceutical composition in the at least one solvent.
  • the amount of active drug substance in the solvent may be measured at at least three time points within the first 60 minutes, so as to evaluate the rate at which the active drug substance is released into the solvent.
  • Extraction of active drug substance from pharmaceutical compositions can be performed by dissolving, for example, tablets in different types of solvents.
  • the tablets in different solvents may be shaken and/or continuous shaken.
  • the tablets in different solvents may be unshaken or undisturbed.
  • the solvents can be chosen to cover a broad range of liquids with low and high pH, with some being some polar and some non-polar.
  • the solvents may be categorized into five groups: such as for example, aqueous solutions, such as, for example, solution pH 1.2; buffer pH 6.8; buffer pH 10.0; water; and water+ethanol (40% v/v); beverages, such as, for example; Coca-Cola®; quinine containing soft drinks, such as, for example; tonic water and bitter lemon; Coca-Cola® +ethanol (40% v/v); and vodka; common household liquids, such as, for example, 1% acetic acid; ethanol; methylethylketone; and acetone.
  • aqueous solutions such as, for example, solution pH 1.2; buffer pH 6.8; buffer pH 10.0; water; and water+ethanol (40% v/v
  • beverages such as, for example; Coca-Cola®; quinine containing soft drinks, such as, for example; tonic water and bitter lemon; Coca-Cola® +ethanol (40% v/v); and vodka
  • common household liquids such as, for example, 1% acetic acid;
  • the injection test methods described herein include methods for evaluating the abuse potential of active drug substance from pharmaceutical compositions both quantitatively (i.e., such as, for example, time, yield, and unit operations required) and qualitatively (i.e., such as, for example, appearance).
  • the general strategy behind the injection test methods is to mimic the actual procedures applied by drug abusers when preparing a pharmaceutical composition for injection and injecting it.
  • the study design is therefore divided into three parts, such as, for example, preparation, filtration, and injection.
  • the objective is to record the time and effort required to prepare a solution or dispersion that can be used for injection and the obtained yield of the active drug substance.
  • drug abusers are, typically, only prepared to spend a limited amount of time for preparing a pharmaceutical composition for abuse.
  • all of the tests disclosed herein can be performed in an aqueous media, which is a commonly-used solvent for injection.
  • the appearance of the resulting solution/dispersion is assessed in order to evaluate the likelihood that a drug abuser would inject the resulting injectable mass.
  • the pharmaceutical compositions described herein have predominantly high viscous properties analogous to plastic.
  • the pharmaceutical compositions described herein transforms from having high viscous properties to having predominately elastic properties that control the release rate of active drug substance, and which resist rapid extraction and/or injection.
  • the predominately elastic properties of the pharmaceutical compositions in an aqueous medium or in the gastrointestinal tract provides a controlled-release profile of the active drug substance in an individual.
  • the high viscosity of the composition turns not only the composition into a non-injectable dispersion/gel, but also significantly delays the solubility of the composition to completely form into a gelatinous mass.
  • the high viscosity of the composition turns not only the composition into a non-injectable dispersion/gel, but also significantly deters the abuse of the pharmaceutical composition by eluting at least one polymer from the composition into the solvent, which turns the solvent into a gelatinous mass.
  • the at least one polymer is a polyethylene oxide.
  • the average molecular weight of the at least one polyethylene oxide eluting from the composition into the solvent is less than 5,000,000 daltons, for example less than 4,000,000 daltons, such as less than 3,000,000 daltons, for example less than 2,000,000 daltons, such as less than 1,000,000 daltons, for example less than 800,000 daltons, such as less than 600,000 daltons, for example less than 500,000 daltons.
  • the high viscosity of the composition is in a range selected from between about 0.5 Pa ⁇ s to about 3,000 Pa ⁇ s, between about 0.5 Pa ⁇ s to about 2,500 Pa ⁇ s, between about 0.5 Pa ⁇ s to about 2,000 Pa ⁇ s, between about 0.5 Pa ⁇ s to about 1,700 Pa ⁇ s, between about 5 Pa ⁇ s to about 3,000 Pa ⁇ s, between about 10 Pa ⁇ s to about 3,000 Pa ⁇ s, between about 20 Pa ⁇ s to about 3,000 Pa ⁇ s, between about 30 Pa ⁇ s to about 3,000 Pa ⁇ s, between about 40 Pa ⁇ s to about 3,000 Pa ⁇ s, between about 45 Pa ⁇ s to about 3,000 Pa ⁇ s, between about 45 Pa ⁇ s to about 2,500 Pa ⁇ s, between about 45 Pa ⁇ s to about 2,000 Pa ⁇ s, between about 45 Pa ⁇ s to about 1,700 Pa ⁇ s, between about between about 46 Pa ⁇ s to about 1,700 Pa ⁇ s, where the viscosity is measured according to “Viscosity Test #1,” described in the “Viscosity test” disclosure.
  • the high viscosity of the composition is at least 95 mPa ⁇ s, for example at least about 100 mPa ⁇ s, such as at least about 105 mPa ⁇ s, for example at least about 110 mPa ⁇ s, such as at least about 120 mPa ⁇ s, for example at least about 130 mPa ⁇ s, such as at least about 140 mPa ⁇ s, for example at least about 150 mPa ⁇ s, such as at least about 160 mPa ⁇ s, for example, at least about 170 mPa ⁇ s, such as at least about 180 mPa ⁇ s, for example at least about 190 mPa ⁇ s, such as at least about 200 mPa ⁇ s.
  • the high viscosity of the composition is at least 170 mPa ⁇ s, where the viscosity is measured according to “Viscosity Test #2,” described in the “Viscosity test” disclosure.
  • the high viscosity of the composition deters direct injection and also serves as a significant barrier to prevent volatilization (e.g., inhalation) of the incorporated active drug substance at elevated temperature or snorting if the composition is crushed or broken into small pieces or small particles.
  • the composition results in a highly viscous and/or unclear, opaque or cloudy dispersion/gel upon contact with and/or immersion in an aqueous medium, which may form a strong adhesion to the nose and nasal tissue walls and, thereby, result in discomfort in the nasal cavity of the abuser.
  • the viscosity of the composition is at least 46 Pa ⁇ s, where the viscosity is measured according to Viscosity Test #1, described in the “Viscosity test” disclosure.
  • the abuse-deterrent pharmaceutical compositions may form a gel that resists passage or is difficult to inject through a needle.
  • the abuse-deterrent pharmaceutical compositions may further include a viscosity increasing agent, such as, for example, a gelling agent, and the like.
  • Dissolution tests were performed in accordance with USP 35, NF 30, (711), Apparatus 2 (paddle method).
  • the dissolution medium consisted either of phosphate buffer solution pH 6.8 with/without ethanol or of dilute hydrochloric acid with/without ethanol.
  • the volume of the dissolution medium was 900 ml and the rotation speed of the paddles was 50 rpm or 75 rpm throughout the dissolution run.
  • Samples were withdrawn at suitable time intervals and analysed for content of active drug substance by means of UV-detector or HPLC with UV-detector.
  • the dissolution medium consisted of dilute hydrochloric acid.
  • the volume of the dissolution medium was 900 ml and the rotation speed of the paddles was 75 rpm throughout the dissolution run.
  • the dissolution medium consisted of phosphate buffer solution pH 6.8.
  • the volume of the dissolution medium was 900 ml and the rotation speed of the paddles was 50 rpm throughout the dissolution run.
  • the dissolution medium consisted of phosphate buffer solution pH 6.8 with/without 40% v/v ethanol.
  • the volume of the dissolution medium was 900 ml and the rotation speed of the paddles was 50 rpm throughout the dissolution run.
  • Three (3) whole tablets were placed in a 50 ml glass bottle.
  • the bottle was placed in the center of a microwave oven and heated for a predetermined amount of time (e.g., 8 and 16 minutes) at maximum effect (900 W). Afterwards, 9 ml of purified water was added to the bottle.
  • the bottle was placed on a flatbed laboratory shaker (IKA-Werke HS-501 digital) and was shook continuously (speed 150/min) for 3 days at ambient temperature to dissolve the tablets and to reduce clumping.
  • Viscosity can be measured using a Brookfield RVDV-E viscometer (Brookfield Engineering, Middleboro, Mass. USA) with spindle number 15 (0.5-1700 Pa ⁇ s), a 7R tube, a small sample adapter SC4-45Y and tested in the range of 1, 5, 10 and 20 rpm, respectively, or with spindle number 21 (0.05-170 Pa ⁇ s), a 13R tube, and a small sample adapter SC4-45Y at 20 rpm. The temperature was controlled and in the range of 21-22° C.
  • Viscosity Test #1 the viscosity can be measured using a Brookfield RVDV-E viscometer (Brookfield Engineering, Middleboro, Mass. USA) with spindle number 15 (0.5-1700 Pa ⁇ s), a 7R tube, and a small sample adapter SC4-45Y at 5 rpm. The temperature was controlled and in the range of 21-22° C.
  • Viscosity Test #2 the viscosity can be measured using a Brookfield RVDV-E viscometer (Brookfield Engineering, Middleboro, Mass. USA) with spindle number 21 (0.05-170 Pa ⁇ s), a 13R tube, and a small sample adapter SC4-45Y at 20 rpm. The temperature was controlled and in the range of 21-22° C.
  • Particle size reduction of pharmaceutical compositions was tested using a coffee grinder and/or a nutmeg grater.
  • the methods described herein are used to evaluate the efforts required to reduce the particle size of the pharmaceutical compositions via physical grinding or grating of the tablets.
  • Tablets were ground in either a Moulinex-1411 R coffee grinder with stainless steel blades (model: the original grinder; 50 g -180W AR100G31/6W0) at 10 000-20 000 rpm or a Krups F203 coffee grinder with stainless steel blades (Model: 75 g—200 W F2034210/6W0-1512 R) at 30 000-50 000 rpm for 15 seconds or to no more particle size reduction or equipment failure and, afterwards, analyzed by use of Image Processing.
  • a drawing of the coffee grinder chamber is shown in FIGS. 1 and 2 .
  • Tablets were grated by using a nutmeg grater with a stainless steel star blade or a Microplane® grater with stainless steel zester grater or a fine or spice blade for 11 ⁇ 2 minutes.
  • a drawing of the nutmeg grater with stainless steel star blade is shown in FIG. 3 .
  • the samples were analyzed using an image processing setup comprising a digital SLR with RAW or TIFF capabilities (Canon EOS 350D, resolution 3466 ⁇ 2306 (8MP) or Nikon D3100, resolution 4608 ⁇ 3272 (14.2MP)), a fixed lens (Canon EF 100 mm 1:2:8 USM Macro or Tamron 90 mm 1:2:8 Macro), a stable camera stand, a suitable background for the particles (e.g., a black paper square) and light (to avoid reflections) plus a calibrated light microscopy scale bar from Leitz.
  • a digital SLR with RAW or TIFF capabilities Canon EOS 350D, resolution 3466 ⁇ 2306 (8MP) or Nikon D3100, resolution 4608 ⁇ 3272 (14.2MP)
  • a fixed lens Canon EF 100 mm 1:2:8 USM Macro or Tamron 90 mm 1:2:8 Macro
  • a suitable background for the particles e.g., a black paper square
  • light to avoid reflections
  • a sample was spread onto the black background, and the particles were separated.
  • the position of the camera setup was adjusted and focused such that entire sample was inside the approximate view-area for the camera before pictures were taken.
  • RawTherapee 3.0.1.0 Conversion of RAW-files to uncompressed TIFF.
  • ImageJ 1.45b Three-dimensional Analysis of TIFF images (binarization) and particle size measuring (data rendering))
  • Microsoft Excel 2010 data analysis
  • An accurate amount of the polymer i.e., in the examples below: polyethylene oxide
  • polyethylene oxide i.e., polyethylene oxide
  • the mixing is performed at 900-2000 rpm and at a time period up to 20 min. At the start of the mixing the temperature is about 19-21 ° C. and the final temperature of the mixture is about 30-50 ° C.
  • the mixture is then allowed to cool to room temperature and is ready to be fed into an injection moulding machine.
  • the injection moulding machine used is an Arburg Allrounder 420 C 1000-60/60.
  • composition (batch No. 1577-051A) according to the disclosure was prepared from the following ingredients:
  • composition was prepared as described above.
  • composition was subjected to the dissolution test (controlled release) described above.
  • the results are shown in FIG. 4 as the release of morphine (%) versus time (minutes) in phosphate buffer solution pH 6.8.
  • the release of morphine is shown for intact tablets and ground tablets (ground in a Moulinex-1411 R coffee grinder).
  • the viscosity of the composition was measured as described above. The viscosity was found to be 93 Pa ⁇ s at 5 rpm (using Viscosity Test #1).
  • Particle size reduction of the composition was measured as described above.
  • the average particle size was 0.706 ⁇ 1.63 mm and the five largest particles were; 12.1 mm; 3.0 mm; 2.7 mm; 2.2 mm; and 1.9 mm.
  • the results are shown in FIG. 5 .
  • composition (batch No. 1577-051B) according to the disclosure was prepared from the following ingredients:
  • composition was prepared as described above.
  • the composition was subjected to the dissolution test (controlled release) described above.
  • the results are shown in FIG. 6 as the release of oxycodone (%) versus time (minutes) in phosphate buffer solution pH 6.8 with and without 40% v/v ethanol.
  • the release of oxycodone is shown for intact tablets and ground tablets (ground in a Moulinex-1411 R coffee grinder).
  • the viscosity of the composition was measured as described above. The viscosity was found to be 74 Pa ⁇ s at 5 rpm (using Viscosity Test #1).
  • Particle size reduction of the composition was measured as described above.
  • the average particle size was 0.455 ⁇ 0.639 mm and the five largest particles were; 12.1 mm; 4.0 mm; 3.9 mm; 3.8 mm; and 3.7 mm.
  • the results are shown in FIG. 7 .
  • composition (batch No. 1581-065) according to the disclosure was prepared from the following ingredients:
  • composition was prepared as described above.
  • composition was subjected to the dissolution test (controlled release) described above.
  • the results are shown in FIG. 8 as the release of hydromorphone (%) versus time (minutes) in phosphate buffer solution pH 6.8 for intact tablets and ground tablets (ground in a Moulinex-1411 R coffee grinder).
  • the viscosity of the compositions was measured as described above. The viscosity was found to be 46 Pa ⁇ s at 5 rpm (using Viscosity Test #1).
  • Particle size reduction of the composition was measured as described above.
  • the average particle size was 0.495 ⁇ 0.643 mm and the five largest particles were 10.5 mm; 3.6 mm; 3.6 mm; 3.5 mm; and 3.5 mm.
  • the results are shown in FIG. 9 .
  • composition (batch no. 1581-066) according to the disclosure was prepared from the following ingredients:
  • composition was prepared as described above.
  • composition was subjected to the dissolution test (controlled release) described above.
  • the results are shown in FIG. 10 as the release of oxymorphone (%) versus time (minutes) in phosphate buffer solution pH 6.8 for intact tablets and ground tablets (ground in a Moulinex-1411 R coffee grinder).
  • the viscosity of the composition was measured as described above. The viscosity was found to be 79.6 Pa ⁇ s at 5 rpm (using Viscosity Test #1).
  • Particle size reduction of the composition was measured as described above.
  • the average particle size was 0.547 ⁇ 0.640 mm and the five largest particles were 5.8 mm; 4.8 mm; 4.7 mm; 4.7 mm; and 4.4 mm.
  • the results are shown in FIG. 11 .
  • Oxycontin® OP 40 mg was subjected to the dissolution test (controlled release) described above. The results are shown in FIG. 12 as the release of oxycodone (%) versus time (minutes) in phosphate buffer solution pH 6.8 for intact tablets and ground tablets (ground in a Moulinex-1411 R coffee grinder).
  • the viscosity of Oxycontin® OP 40 mg was measured as described above. The viscosity was found to be 46 Pa ⁇ s at 5 rpm (using Viscosity Test #1).
  • Particle size reduction of Oxycontin® OP 40 mg was measured as described above.
  • the average particle size was 0.341 ⁇ 0.301 mm and the five largest particles were 3.0 mm; 2.7 mm; 2.7 mm; 2.6 mm; and 2.4 mm.
  • the results are shown in FIG. 13 .
  • a 200 mg morphine composition (batch No. 12-0060-067) according to the disclosure was prepared from the following ingredients:
  • composition was subjected to the no alcohol-induced dose dumping test described above.
  • the results are shown in FIG. 14 as release of morphine (%) versus time (minutes) in phosphate buffer solution pH 6.8 with/without 40% v/v ethanol.
  • the release of morphine is shown for intact tablets.
  • a 60 mg morphine composition (batch No. 12-066-067) according to the disclosure was prepared from the following ingredients:
  • composition was subjected to the crisping test described above.
  • MST Continus® 60 mg, Oxycontin® OP 80 mg and Opana® ER 40 mg (containing hydroxypropyl methylcellulose (HPMC)) were subjected to the same crisping test.
  • MST Continus® is the European trademark and MS Contin® is the American trademark.
  • a 200 mg morphine composition (batch No. 2654-056) according to the disclosure was prepared from the following ingredients:
  • the composition was subjected to the dissolution test (controlled release) described above.
  • the results are shown in FIG. 15 as the release of active substance (%) versus time (minutes) in phosphate buffer solution pH 6.8.
  • the release of active substance is shown for intact tablets and ground tablets (ground in a Krups F203 coffee grinder).
  • MST Continus® 60 mg and Oxycontin® OP 40 mg were subjected to the same test. The results are shown in FIG. 15 .
  • a 200 mg morphine composition (batch No. 2654-056) according to the disclosure was prepared from the following ingredients:
  • the composition was subjected to the dissolution test (immediate release) described above.
  • the results are shown in FIG. 16 as the release of active substance (%) versus time (minutes) in dilute hydrochloric acid.
  • the release of active substance is shown for grated tablets (Nutmeg grater).
  • MST Continus® 60 mg, Oxycontin® OP 80 mg and Opana® ER 40 mg were subjected to the same test.
  • the results are shown in FIG. 16 .
  • Particle size reduction of the composition was measured as described above.
  • the average particle size was 1.94 ⁇ 2.57 mm and the five largest particles were 21.4 mm; 15.1 mm; 12.8 mm; 8.7 mm; and 7.8 mm.
  • the results are shown in FIG. 17 .
  • MST Continus® 60 mg, Oxycontin® OP 80 mg and Opana® ER 40 mg were subjected to the same test.
  • MST Continue 60 mg the average particle size was 0.410 ⁇ 0.250 mm and the five largest particles were 4.9 mm; 4.7 mm; 4.1 mm; 3.7 mm; and 3.5 mm.
  • Oxycontin® OP 80 mg the average particle size was 0.596 ⁇ 0.337 mm and the five largest particles were 5.9 mm; 5.0 mm; 4.3 mm; 3.4 mm; and 3.1 mm.
  • the five largest particles were lumps; some were big lumps and also big and flakey.
  • a 60 mg morphine composition (batch No. 12-066-067) according to the disclosure was prepared from the following ingredients:
  • composition was subjected to the extraction test described above. Two (2) tablets were placed in a 50 ml beaker, 10 ml solvent (purified water or Coca-Cola®) was added, and the beaker was sealed with Parafilm®. The beaker with tablets was left undisturbed at 25° C./60% RH for 24 hours. The free solvent was poured into a tared empty beaker, the viscosity of the free solvent was measured by the viscosity test as described above (Viscosity Test #2), and the active drug substance content in the free solvent (assay) was determined using HPLC with UV-detector.
  • solvent purified water or Coca-Cola®
  • MST Continus® 60 mg, Oxycontin® OP 80 mg, and Opana® ER 40 mg were subjected to the same extraction test.

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Abstract

The present disclosure relates to pharmaceutical compositions that are abuse resistant and may also provide controlled release. The present disclosure also relates to the use of pharmaceutical compositions in the treatment of pain.

Description

  • All patent and non-patent references cited in the application are hereby incorporated by reference in their entirety.
    • RELATED APPLICATIONS
  • This application claims the benefit of U.S. Provisional Application No. 61/668,741, filed on Jul. 6, 2012, the contents of which are incorporated herein by reference.
    • FIELD OF INVENTION
  • The present disclosure relates to pharmaceutical compositions. In certain embodiments, the pharmaceutical compositions according to the present description are abuse-deterrent and may provide controlled release.
  • BACKGROUND OF INVENTION
  • Increased attention has been drawn to the abuse of prescription pharmaceutical compositions. The abuse, or non-medicinal use, of prescription pharmaceutical compositions has been reported to be an increasing problem. In North America, abuse of prescription pharmaceutical compositions has become an important issue for the U.S. Food and Drug Administration (FDA), and the pharmaceutical industry is striving to develop abuse-deterrent pharmaceutical compositions in order to reduce the potential for misuse of prescription pharmaceutical compositions. Prescription pharmaceutical compositions that are typically misused fall, primarily, into three groups: 1) Opioids prescribed for pain; 2) Central Nervous System (CNS) depressants prescribed for anxiety or sleep problems; and 3) Stimulants, prescribed, for example, for attention deficit hyperactivity, narcolepsy, or obesity.
  • Methods for abusing prescription pharmaceutical compositions are varied and can include, for example, extraction, melting, volatilization, physical tampering (e.g., grinding, grating, crushing, etc.), or direct administration. For purposes of abuse, methods of administering active drug substances obtained from prescription pharmaceutical compositions or of the pharmaceutical compositions themselves are similarly diverse and include, for example, injection, smoking, snorting, swallowing, sublingual or buccal administration, chewing, and administration as suppository. Alcohol-induced dose dumping of active drug substance from prescription pharmaceutical compositions also presents potential abuse and safety problems.
    • DESCRIPTION OF DRAWINGS
  • FIG. 1 shows a drawing of a Moulinex-1411R coffee grinder chamber with stainless steel blades.
  • FIG. 2 shows a drawing of a Krups F203 coffee grinder chamber with stainless steel blades.
  • FIG. 3 shows a drawing of a nutmeg grater surface with a stainless steel star blade.
  • FIG. 4 shows in vitro dissolution results of the release of morphine (%) versus time (minutes) in phosphate buffer solution pH 6.8. The release of morphine is shown for intact tablets (untampered) and ground tablets (tampered) of one embodiment of a pharmaceutical composition, as disclosed herein, comprising PEO 400,000 daltons.
  • FIG. 5 shows particle size reduction results of one embodiment of a ground (tampered) pharmaceutical composition, as disclosed herein, comprising PEO 400,000 daltons.
  • FIG. 6 shows in vitro dissolution results of the release of oxycodone (%) versus time (minutes) in phosphate buffer solution pH 6.8 with and without 40% v/v ethanol. The release of oxycodone is shown for intact tablets (untampered) and ground tablets (tampered) of one embodiment of a pharmaceutical composition, as disclosed herein, comprising PEO 600,000 daltons.
  • FIG. 7 shows particle size reduction results of one embodiment of a ground (tampered) pharmaceutical composition as disclosed herein comprising PEO 600,000 daltons.
  • FIG. 8 shows in vitro dissolution results of the release of hydromorphone (%) versus time (minutes) in phosphate buffer solution pH 6.8. The release of hydromorphone is shown for intact tablets (untampered) and ground tablets (tampered) of one embodiment of a pharmaceutical composition, as disclosed herein, comprising PEO 2,000,000 daltons.
  • FIG. 9 shows particle size reduction results of one embodiment of a ground (tampered) pharmaceutical composition, as disclosed herein, comprising PEO 2,000,000 daltons.
  • FIG. 10 shows in vitro dissolution results of the release of oxymorphone (%) versus time (minutes) in phosphate buffer solution pH 6.8. The release of oxymorphone is shown for intact tablets (untampered) and ground tablets (tampered) of one embodiment of a pharmaceutical composition as disclosed herein comprising PEO 10,000,000 daltons.
  • FIG. 11 shows particle size reduction results of one embodiment of a ground (tampered) pharmaceutical composition as disclosed herein comprising PEO 10,000,000 daltons.
  • FIG. 12 shows in vitro dissolution results of the release of oxycodone (%) versus time (minutes) in phosphate buffer solution pH 6.8. The release of oxycodone is shown for intact tablets (untampered) and ground tablets (tampered) of Oxycontin® OP 40 mg.
  • FIG. 13 shows particle size reduction results of a ground Oxycontin® OP 40 mg tablet.
  • FIG. 14 shows in vitro dissolution results of the release of morphine (%) versus time (minutes) in phosphate buffer solution pH 6.8 with and without 40% v/v ethanol. The release of morphine is shown for intact tablets of one embodiment of a pharmaceutical composition, as disclosed herein.
  • FIG. 15 shows in vitro dissolution results of release of active substance (%) versus time (minutes) in phosphate buffer solution pH 6.8. The release of active substance is shown for intact tablets and ground tablets (ground in a Krups F203 coffee grinder) of Oxycontin® OP 40 mg, MST Continus® 60 mg, and an embodiment of a pharmaceutical composition, as disclosed herein, containing 200 mg of morphine.
  • FIG. 16 shows in vitro dissolution results of release of active substance (%) versus time (minutes) in dilute hydrochloric acid. The release of active substance is shown for grated tablets (Nutmeg grater) of Opana® ER 40 mg, Oxycontin® OP 80 mg, MST Continus® 60 mg, and an embodiment of a pharmaceutical composition, as disclosed herein, containing 200 mg of morphine.
  • FIG. 17 shows particle size reduction results of a grated tablet of an embodiment of a pharmaceutical composition, as disclosed herein, containing 200 mg of morphine.
  • FIG. 18 shows particle size reduction results of a grated MST Continus® 60 mg tablet.
  • FIG. 19 shows particle size reduction results of a grated Opana® ER 40 mg tablet.
  • FIG. 20 shows particle size reduction results of a grated Oxycontin® OP 80 mg tablet.
    •  DETAILED DESCRIPTION OF THE INVENTION
  • The present disclosure provides novel abuse-deterrent pharmaceutical compositions, which are resistant to abuse and tampering. In certain embodiments, the pharmaceutical compositions according to the present description, even without containing an outer shell, exhibit hardness that is resistant to physical tampering. In particular embodiments, the pharmaceutical compositions disclosed herein may be formulated in such a way that the composition maintains a desired release profile of the active drug substance, even if the pharmaceutical composition is subjected to physical tampering.
  • One embodiment of the present disclosure provides an abuse-deterrent pharmaceutical composition, comprising: (a) an active drug substance; (b) a polyethylene oxide; and (c) optionally, a plasticizer, wherein the pharmaceutical composition does not provide immediate release of the active drug substance after physical tampering, and wherein when at least one polyethylene oxide has a molecular weight of at least 1,000,000 daltons, then the pharmaceutical composition comprises at least 5% w/w plasticizer.
  • In particular embodiments, the pharmaceutical compositions disclosed herein may comprise a controlled released abuse-deterrent pharmaceutical composition with a route of administration that may prevent or limit the feeling of euphoria combined with preventing or making it more difficult to abuse the active drug substance from the composition by, for example, injection, smoking, snorting, swallowing, sublingual or buccal administration, chewing, and administration as suppository.
  • The abuse-deterrent pharmaceutical compositions according to the present description can be further understood when studied relative to a comparator. Comparison of the abuse-deterrent pharmaceutical compositions disclosed herein to a comparator assesses the incremental and meaningful improvement in the ability of said pharmaceutical compositions to deter abuse or misuse.
  • In addition, certain embodiments of the present disclosure relate to the use of the disclosed pharmaceutical compositions in the treatment of a clinical condition (such as pain) in an individual in need thereof.
    • Definitions
  • For purposes of the present disclosure, “dose dumping” refers to an unintended, rapid release of the entire amount or a significant fraction of the active drug substance contained within a prescription pharmaceutical composition over a short or accelerated period of time. For purposes of abuse, alcohol-induced dose dumping may facilitate isolation or concentration of active drug substances from a prescription pharmaceutical composition. Alternatively, dose dumping in the presence of alcohol may increase the ease with which a prescription pharmaceutical composition can be abused simply through the intake of an alcoholic beverage concomitantly with the prescription pharmaceutical composition. Moreover, alcohol-induced dose dumping may present safety issues outside the context of abuse. For example, a patient taking a prescription pharmaceutical composition for medicinal purposes may inadvertently cause delivery of a dose of active drug substance that is too high or absorbed too quickly by self-administering a pharmaceutical composition shortly before, simultaneously with, or shortly after, consumption or intake of an alcoholic beverage or another pharmaceutical composition containing alcohol (e.g., an over-the-counter cold or flu medicine).
  • The term “physical tampering,” as used herein, refers to any kind of physical interference or manipulation that may result in particle size reduction of a pharmaceutical composition. Hence, compositions that are resistant to physical tampering are formulated in such a way that the composition cannot readily be size reduced to a form that is suitable for abuse, such as, for example, injection or snorting, because the tablet cannot easily be ground, grated, dissolved, and the like. Examples of physical tampering include, but are not limited to, crushing, grinding, grating, cutting, crisping, and other methods of particle size reduction.
  • The term “controlled release,” as used herein, denotes pharmaceutical composition that provide extended release of an active drug substance from the composition for an extended period of time. In certain circumstances, the term “controlled release” is used to designate a release at a desired rate during a predetermined release period. Additional or alternative terms, such as, for example, “modified”, “delayed”, “sustained”, “prolonged”, “extended” release may be used, in certain embodiments, as synonyms to the term “controlled release.”
  • The term “immediate release,” as used herein, denotes a pharmaceutical composition that releases the active drug substance (80% release) within at the most 30 minutes, when subjected to dissolution test according to USP 35, NF 30, (711), Apparatus 2.
    • Polyethylene Oxide
  • The pharmaceutical compositions of the present disclosure comprise a polyethylene oxide. Polyethylene oxides (PEOs) are linear polydisperse nonionic polymers composed of repeating units of ethylene oxide. Their chemical formula is HO[CH2CH2O]nH, where n represents the average number of oxyethylene groups. See the structural presentation of polyethylene oxide below, wherein n is the average number of oxyethylene groups. Depending on preparation method, high molecular weight PEO may have one terminal methyl group.
  • Figure US20170333354A9-20171123-C00001
  • Polyethylene oxides that are suitable for use in the pharmaceutical compositions according to the present description are those having an average molecular weight of at least about 200,000 daltons, such as an average molecular weight of in the range of about 200,000 to about 10,000,000 daltons, for example in the range of about 250,000 to about 10,000,000 daltons, such as in the range of about 300,000 to about 10,000,000 daltons, for example in the range of about 350,000 to about 10,000,000 daltons, such as in the range of about 400,000 to about 10,000,000 daltons. In certain embodiments, the polyethylene oxides that are suitable for use in the compositions disclosed herein are those having an average molecular weight of at the most 1,000,000 daltons, such as an average molecular weight of in the range of about 200,000 to about 1,000,000 daltons, for example in the range of about 300,000 to about 1,000,000 daltons, such as in the range of about 400,000 to about 1,000,000 daltons. In another embodiment, the polyethylene oxides that are suitable for use in the compositions disclosed herein are those having an average molecular weight of at the most 500,000 daltons, such as an average molecular weight of in the range of about 200,000 to about 500,000 daltons, for example in the range of about 250,000 to about 500,000 daltons, such as in the range of about 300,000 to about 500,000 daltons, for example in the range of about 350,000 to about 500,000 daltons, such as in the range of about 400,000 to about 500,000 daltons. In yet another embodiment, the polyethylene oxides suitable for use in the compositions described herein are those having an average molecular weight of at the most 400,000 daltons, such as in the range of about 100,000 to about 400,000 daltons, for example in the range of about 200,000 to about 400,000 daltons, such as in the range of about 300,000 to 400,000 daltons. In one embodiment, the pharmaceutical composition comprises polyethylene oxides having an average molecular weight of 400,000 daltons.
  • In certain embodiments, the polyethylene oxides suitable for use in the compositions described herein are those having an average molecular weight selected from 200,000 daltons, 250,000 daltons, 300,000 daltons, 350,000 daltons, 400,000 daltons, 450,000 daltons, 500,000 daltons, 550,000 daltons, 600,000 daltons, 650,000 daltons, 700,000 daltons, 750,000 daltons, 800,000 daltons, 850,000 daltons, 900,000 daltons, 950,000 daltons, 1,000,000 daltons, 2,000,000 daltons, 3,000,000 daltons, 4,000,000 daltons, 5,000,000 daltons, 7,000,000 daltons, 10,000,000 daltons.
  • In certain embodiments, the total concentration of polyethylene oxide for use in the composition is in the range of 5 to 99.9% w/w, such as from 10 to 99.9% w/w, such as from 10 to 98% w/w, such as from 20 to 98% w/w, such as from 30 to 98% w/w, such as from 40 to 98% w/w, such as from 50 to 98% w/w, such as from 60 to 98% w/w, such as from 70 to 98% w/w, calculated as w/w % of the composition.
  • In particular embodiments, the level of polyethylene oxide 200,000 daltons to achieve the desired viscosity as described herein may be at least 1,020 mg, for polyethylene oxide 300,000 daltons it is at least 544 mg, for polyethylene oxide 400,000 daltons it is at least 435 mg, for polyethylene oxide 600,000 daltons it is at least 324 mg, for polyethylene oxide 900,000 daltons it is at least 243 mg, for polyethylene oxide 1,000,000 daltons it is at least 203 mg for polyethylene oxide 2,000,000 daltons and 4,000,000 daltons it is at least 162 mg and for polyethylene oxide 5,000,000 daltons, 7,000,000 daltons and 10,000,000 daltons it is at least 122 mg.
  • In some embodiments, the upper level of polyethylene oxide 200,000 to 10,000,000 daltons to achieve the desired viscosity in pharmaceutical compositions described herein is approximately 1,100 mg.
  • The compositions as described herein may comprise mixtures of polyethylene oxides with different average molecular weights, for example, in order to obtain polyethylene oxides with a desirable average molecular weight. Thus, in some embodiments, the pharmaceutical comprises different polyethylene oxide materials with different average molecular weights.
  • In certain embodiments, in order to obtain polyethylene oxide with a desirable average molecular weight, it is important to note that, in such cases, it is necessary to use polyethylene oxides, which have an average molecular weight closest to the desired molecular weight to ensure a narrow chain length distribution. In certain such embodiments, for example, equal amounts of polyethylene oxide 200,000 daltons and polyethylene oxide 600,000 daltons may be mixed to obtain polyethylene oxide 400,000 daltons.
  • A composition as described herein may comprise more than one different kind of polyethylene oxide, such as 2, for example 3, such as 4, for example 5, such as more than 5 different polyethylene oxides. In certain such embodiments, the composition comprises 1 to 4 different polyethylene oxides. In one such embodiment, the composition comprises 1 to 3 different polyethylene oxides. In another such embodiment, the composition comprises 2 different polyethylene oxides.
  • The polyethylene oxide used in compositions according to the present description may have a melting point higher than the body temperature of the individual (e.g., a human) in which the pharmaceutical composition is to be used. Thus, in particular embodiments, the polyethylene oxides employed in the pharmaceutical compositions described herein may have a melting point of in the range of 38° C. to 200° C., such as in the range of 38° C. to 150° C., for example in the range of 38° C. to 120° C., such as in the range of 38° C. to 100° C., for example in the range of 65° C. to 100° C.
    • Plasticizer
  • A composition as described herein may also comprise at least one plasticizer.
  • In particular embodiments, the composition comprises a poloxamer.
  • A composition as described herein may comprise more than one different kind of plasticizer, such as 2, for example 3, such as more than 3 different plasticizers. In certain such embodiments, the composition comprises 1 to 3 different plasticizers. In one such embodiment, the composition comprises 2 different plasticizers. In another such embodiment, the different kind of plasticizer is a different kind of poloxamer.
  • In one embodiment, the composition comprises one or more plasticizers, preferably one or more plasticizers selected from the group consisting of poloxamers, such as poloxamer 188 and/or poloxamer 407.
  • In some embodiments, the composition comprises at least one poloxamer. Poloxamers may be copolymers or block copolymers and are a range of non-ionic surfactants of polyethylene glycol (PEG) and polypropylene glycol (PPG).
  • The poloxamer may be Diol EO/PO block copolymers, which, for example, in chemical abstracts are described under the scientific name hydroxy-hydroxypoly (oxyethylene) poly(oxypropylene)-poly(oxyethylene)-block copolymer in combination with the CAS register number. In specific embodiments, a suitable poloxamer for use in a composition of the disclosure has a HLB value of at least about 18 such as, for example, at least approximately 20, preferably at least 24. In certain embodiments, the average molecular weight of a suitable poloxamer is typically at least about 2,000 daltons.
  • Block copolymers of ethylene oxide and propylene oxide that may be included in the composition described herein have a molecular weight of at least 2,000 daltons, typically in the range of 3,000 to 30,000 daltons, such as in the range of 4,000 to 15,000 daltons.
  • Exemplary poloxamers that may be used in the compositions disclosed herein have the formula HO(C2H4O)a(C3H6O)b(C2H4O)aH, where “a” is an integer from 10 to 150, such as from 30 to 140, for example from 50 to 100, such as from 65 to 90, for example from 70 to 90, and “b” is an integer from 10 to 80, such as from 15 to 80, for example from 20 to 60, such as from 25 to 55.
  • Other plasticizers may be incorporated in the composition of the pharmaceutical compositions as described herein. A suitable plasticizer may be selected from mono- and di-acetylated monoglycerides, diacetylated monoglycerides, acetylated hydrogenated cottonseed glyceride, glyceryl cocoate, polyethylene glycols (for example with a molecular weight below 35,000 daltons) or polyethylene oxides (for example with a molecular weight of about 35,000 to 600,000 daltons), dipropylene glycol salicylate glycerin, fatty acids and esters, phthalate esters, phosphate esters, amides, diocyl phthalate, phthalyl glycolate, mineral oils, hydrogenated vegetable oils, vegetable oils, acetylated hydrogenated soybean oil glycerides, castor oil, acetyl tributyl citrate, acetyl triethyl citrate, methyl abietate, nitrobenzene, carbon disulfide, beta-naphtyl salicylate, sorbitol, sorbitol glyceryl tricitrate, fatty alcohols, cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, myristyl alcohol, sucrose octaacetate, alfa-tocopheryl polyethylene glycol succinate (TPGS), tocopheryl derivative, diacetylated monoglycerides, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monooleate, glyceryl monostearate, propylene glycol monostearate, macrogol esters, macrogol stearate 400, macrogol stearate 2,000, polyoxyethylene 50 stearate, macrogol ethers, cetomacrogol 1000, lauromacrogols, nonoxinols, octocinols, tyloxapol, poloxamers, polyvinyl alcohols, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate and sucrose esters, amyl oleate, butyl oleate, butyl stearate, diethylene glycol monolaurate, glycerol tributyrate, Cumar W-1, Cumar MH-1, Cumar V-1, Flexol B-400, monomeric polyethylene ester, Piccolastic A-5, Piccalastic A-25, Beckolin, Clorafin 40, acetyl tributyl citrate, acetyl triethyl citrate, benzyl benzoate, butoxyethyl stearate, butyl and glycol esters of fatty acids, butyl diglycol carbonate, butyl ricinoleate, butyl phthalyl butyl glycolate, camphor, dibutyl sebacate, dibutyl tartrate, diphenyl oxide, glycerine, HB-40, hydrogenated methyl ester of rosin, methoxyethyl oleate, monoamylphthalate, Nevillac 10, Paracril 26, technical hydroabietyl alcohol, Methylene glycol dipelargonate, solid aliphatic alcohols, and mixtures thereof.
  • In particular embodiments, the composition comprises cetostearyl alcohol, castor oil, dibutyl sebacate, polyethylene oxides and/or poloxamer as plasticizer. In another embodiment, the composition comprises polyethylene glycols,cetostearyl alcohol, cetyl alcohol, stearyl alcohol, alfa-tocopheryl polyethylene glycol succinate (TPGS), tocopheryl derivative, diacetylated monoglycerides, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monooleate, glyceryl monostearate, propylene glycol monostearate, macrogol esters, macrogol stearate 400, macrogol stearate 2000, polyoxyethylene 50 stearate, macrogol ethers, poloxamers, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, acetyl tributyl citrate and/or acetyl triethyl citrate as plasticizer. However, in other embodiments, other plasticizers may also be used to provide desired material properties.
  • In certain embodiments, the amount of plasticizer in the composition is in the range of from 0 to 60% w/w, for example in the range of 0 to 50% w/w, such as in the range of 0 to 40% w/w, for example in the range of 0 to 30% w/w, such as in the range of 0 to 20% w/w. In some embodiments, the amount of plasticizer in the composition is at least 1% w/w, for example at least 5% w/w, such as for example at least 10% w/w. In some embodiments, the amount of plasticizer in the matrix composition is at the most 20% w/w, such as in the range of 0 to 20% w/w, for example 5 to 20% w/w, such as in the range of 10 to 20% w/w, for example 15 to 20% w/w. In other embodiments the amount of plasticizer in the matrix composition is at least 5% w/w, such as in the range of 5 to 25% w/w, for example 5 to 15% w/w, such as in the range of 5 to 10% w/w.
  • In some embodiments, the plasticizer is a poloxamer. In certain such embodiments, the amount of poloxamer in the composition is at the most 20% w/w, such as in the range of 0 to 20% w/w, for example 5 to 20% w/w, such as in the range of 10 to 20% w/w, for example 15 to 20% w/w. In other embodiments, the amount of poloxamer in the composition is at least 5% w/w, such as in the range of 5 to 25% w/w, for example 5 to 15% w/w, such as in the range of 5 to 10% w/w.
  • In particular such embodiments, the composition comprises one or more plasticizer(s) and one or more polymer(s).
    • Active Drug Substance
  • An active drug substance suitable for use in the pharmaceutical compositions described herein is a therapeutically, prophylactically and/or diagnostically active drug substance (herein also abbreviated as “active substance” or “active drug substance”).
  • Examples of specific active drug substances suitable for use in the pharmaceutical compositions provided herein include:
  • Anti-inflammatory and antirheumatic active drug substances, such as, for example: butylpyrazolidines, phenylbutazone, mofebutazone, oxyphenbutazone, clofezone, kebuzone, acetic acid derivatives and related substances, indometacin, sulindac, tolmetin, zomepirac, diclofenac, alclofenac, bumadizone, etodolac, lonazolac, fentiazac, acemetacin, difenpiramide, oxametacin, proglumetacin, ketorolac, aceclofenac, bufexamac, oxicams, piroxicam, tenoxicam, droxicam, lornoxicam, meloxicam, methotrexate, propionic acid derivatives, ibuprofen, naproxen, ketoprofen, fenoprofen, fenbufen, benoxaprofen, suprofen, pirprofen, flurbiprofen, indoprofen, tiaprofenic acid, oxaprozin, ibuproxam, dexibuprofen, flunoxaprofen, alminoprofen, dexketoprofen, fenamates, mefenamic acid, tolfenamic acid, flufenamic acid, meclofenamic acid, coxibs, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, nabumetone, niflumic acid, azapropazone, glucosamine, benzydamine, glucosaminoglycan polysulfate, proquazone, orgotein, nimesulide, feprazone, diacerein, morniflumate, tenidap, oxaceprol, chondroitin sulfate, feprazone, dipyrocetyl, acetylsalicylic acid, quinolines, oxycinchophen, gold preparations, sodium aurothiomalate, sodium aurotiosulfate, auranofin, aurothioglucose, aurotioprol, penicillamine and bucillamine;
  • Analgesics, such as, for example: opioids, natural opium alkaloids, morphine, opium, hydromorphone, nicomorphine, oxycodone, dihydrocodeine, diamorphine, tapentadol, papaveretum, codeine, phenylpiperidine derivatives, ketobemidone, pethidine, fentanyl, diphenylpropylamine derivatives, dextromoramide, piritramide, dextropropoxyphene, bezitramide, methadone, benzomorphan derivatives, pentazocine, phenazocine, oripavine derivatives, buprenorphine, morphinan derivatives, butorphanol, nalbuphine, tilidine, tramadol, dezocine, salicylic acid and derivatives, acetylsalicylic acid, aloxiprin, choline salicylate, sodium salicylate, salicylamide, salsalate, ethenzamide, morpholine salicylate, dipyrocetyl, benorilate, diflunisal, potassium salicylate, guacetisal, carbasalate calcium, imidazole salicylate, pyrazolones, phenazone, metamizole sodium, aminophenazone, propyphenazone, nifenazone, anilides, paracetamol, phenacetin, bucetin, propacetamol, other analgesics and antipyretics, such as, for example: rimazolium, glafenine, floctafenine, viminol, nefopam, flupirtine, ziconotide;
  • Anaesthetics, such as, for example: ethers, diethyl ether, vinyl ether, halogenated hydrocarbons, halothane, chloroform, methoxyflurane, enflurane, trichloroethylene, isoflurane, desflurane, sevoflurane, barbiturates, methohexital, hexobarbital, thiopental, narcobarbital, opioid anaesthetics, fentanyl, alfentanil, sufentanil, phenoperidine, anileridine, remifentanil, other general anaesthetics, such as, for example: droperidol, ketamine, propanidid, alfaxalone, etomidate, propofol, hydroxybutyric acid, nitrous oxide, esketamine, xenon, esters of aminobenzoic acid, metabutethamine, procaine, tetracaine, chloroprocaine, benzocaine, amides, bupivacaine, lidocaine, mepivacaine, prilocaine, butanilicaine, cinchocaine, etidocaine, articaine, ropivacaine, levobupivacaine, esters of benzoic acid, cocaine, other local anaesthetics, such as, for example: ethyl chloride, dyclonine, phenol, capsaicin;
  • Antimigraine active drug substances, such as, for example: ergot alkaloids, dihydroergotamine, ergotamine, methysergide, lisuride, corticosteroid derivatives, flumedroxone, selective serotonin (5HT1) agonists, sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan, frovatriptan, other antimigraine preparations, pizotifen, clonidine, iprazochrome, dimetotiazine, oxetorone;
  • Antiepileptic active drug substances, such as, for example:barbiturates and derivatives, methylphenobarbital, phenobarbital, primidone, barbexaclone, metharbital, hydantoin derivatives, ethotoin, phenytoin, amino(diphenylhydantoin) valeric acid, mephenytoin, fosphenytoin, oxazolidine derivatives, paramethadione, trimethadione, ethadione, succinimide derivatives, ethosuximide, phensuximide, mesuximide, benzodiazepine derivatives, clonazepam, carboxamide derivatives, carbamazepine, oxcarbazepine, rufinamide, fatty acid derivatives, valproic acid, valpromide, aminobutyric acid, vigabatrin, progabide, tiagabine, other antiepileptics, such as, for example: sultiame, phenacemide, lamotrigine, felbamate, topiramate, gabapentin, pheneturide, levetiracetam, zonisamide, pregabalin, stiripentol, lacosamide, beclamide;
  • Anticholinergic active drug substances, such as, for example: tertiary amines, trihexyphenidyl, biperiden, metixene, procyclidine, profenamine, dexetimide, phenglutarimide, mazaticol, bornaprine, tropatepine, ethers chemically close to antihistamines, etanautine, orphenadrine (chloride), ethers of tropine or tropine derivatives, benzatropine, etybenzatropine;
  • Dopaminergic active drug substances, such as, for example: dopa and dopa derivatives, levodopa, melevodopa, etilevodopa, adamantane derivatives, amantadine, dopamine agonists, bromocriptine, pergolide, dihydroergocryptine mesylate, ropinirole, pramipexole, cabergoline, apomorphine, piribedil, rotigotine, monoamine, oxidase B inhibitors, selegiline, rasagiline, other dopaminergic agents, such as, for example: tolcapone, entacapone, budipine;
  • Antipsychotic active drug substances, such as, for example: phenothiazines with aliphatic side-chain, chlorpromazine, levomepromazine, promazine, acepromazine, triflupromazine, cyamemazine, chlorproethazine, phenothiazines with piperazine structure, dixyrazine, fluphenazine, perphenazine, prochlorperazine, thiopropazate, trifluoperazine, acetophenazine, thioproperazine, butaperazine, perazine, phenothiazines with piperidine structure, periciazine, thioridazine, mesoridazine, pipotiazine, butyrophenone derivatives, haloperidol, trifluperidol, melperone, moperone, pipamperone, bromperidol, benperidol, droperidol, fluanisone, indole derivatives, oxypertine, molindone, sertindole, ziprasidone, thioxanthene derivatives, flupentixol, clopenthixol, chlorprothixene, tiotixene, zuclopenthixol, diphenylbutylpiperidine derivatives, fluspirilene, pimozide, penfluridol, diazepines, oxazepines, thiazepines, loxapine, clozapine, olanzapine, quetiapine, neuroleptics, tetrabenazine, benzamides, sulpiride, sultopride, tiapride, remoxipride, amisulpride, veralipride, levosulpiride, lithium, other antipsychotics, such as, for example prothipendyl, risperidone, clotiapine, mosapramine, zotepine, aripiprazole, paliperidone;
  • Anxiolytic active drug substances, such as, for example: benzodiazepine derivatives, diazepam, chlordiazepoxide, medazepam, oxazepam, potassium clorazepate, lorazepam, adinazolam, bromazepam, clobazam, ketazolam, prazepam, alprazolam, halazepam, pinazepam, camazepam, nordazepam, fludiazepam, ethyl loflazepate, etizolam, clotiazepam, cloxazolam, tofisopam, diphenylmethane derivatives, hydroxyzine, captodiame, carbamates, meprobamate, emylcamate, mebutamate, dibenzo-bicyclo-octadiene derivatives, benzoctamine, azaspirodecanedione derivatives, buspirone, other anxiolytics, such as, for example: mephenoxalone, gedocarnil, etifoxine;
  • Hypnotic and sedative active drug substances, such as, for example: barbiturates, pentobarbital, amobarbital, butobarbital, barbital, aprobarbital, secobarbital, talbutal, vinylbital, vinbarbital, cyclobarbital, heptabarbital, reposal, methohexital, hexobarbital, thiopental, etallobarbital, allobarbital, proxibarbal, aldehydes and derivatives, chloral hydrate, chloralodol, acetylglycinamide chloral hydrate, dichloralphenazone, paraldehyde, benzodiazepineemepronium derivatives, flurazepam, nitrazepam, flunitrazepam, estazolam, triazolam, lormetazepam, temazepam, midazolam, brotizolam, quazepam, loprazolam, doxefazepam, cinolazepam, piperidinedione derivatives, glutethimide, methyprylon, pyrithyldione, benzodiazepine related drugs, zopiclone, zolpidem, zaleplon, ramelteon, other hypnotics and sedatives, such as, for example: methaqualone, clomethiazole, bromisoval, carbromal, scopolamine, propiomazine, triclofos, ethchlorvynol, valerian, hexapropymate, bromides, apronal, valnoctamide, methylpentynol, niaprazine, melatonin, dexmedetomidine, dipiperonylaminoethanol;
  • Antidepressant active drug substances, such as, for example: non-selective monoamine reuptake inhibitors, desipramine, imipramine, imipramine oxide, clomipramine, opipramol, trimipramine, lofepramine, dibenzepin, amitriptyline, nortriptyline, protriptyline, doxepin, iprindole, melitracen, butriptyline, dosulepin, amoxapine, dimetacrine, amineptine, maprotiline, quinupramine, selective serotonin reuptake inhibitors, zimeldine, fluoxetine, citalopram, paroxetine, sertraline, alaproclate, fluvoxamine, etoperidone, escitalopram, monoamine oxidase inhibitors, isocarboxazid, nialamide, phenelzine, tranylcypromine, iproniazide, iproclozide, monoamine oxidase A inhibitors, moclobemide, toloxatone, other antidepressants, such as, for example: oxitriptan, tryptophan, mianserin, nomifensine, trazodone, nefazodone, minaprine, bifemelane, viloxazine, oxaflozane, mirtazapine, medifoxamine, tianeptine, pivagabine, venlafaxine, milnacipran, reboxetine, gepirone, duloxetine, agomelatine, desvenlafaxine, centrally acting sympathomimetics, such as, for example: amfetamine, dexamfetamine, lisdexamfetamine, metamfetamine, methylphenidate, dexmethylphenidate, pemoline, fencamfamin, modafinil, fenozolone, atomoxetine, fenetylline, xanthine derivatives, caffeine, propentofylline, other psychostimulants and nootropics, such as, for example meclofenoxate, pyritinol, piracetam, deanol, fipexide, citicoline, oxiracetam, pirisudanol, linopirdine, nizofenone, aniracetam, acetylcarnitine, idebenone, prolintane, pipradrol, pramiracetam, adrafinil, vinpocetine;
  • Anti-dementia active drug subtances, such as, for example: anticholinesterases, tacrine, donepezil, rivastigmine, galantamine, other anti-dementia drugs, memantine, and ginkgo biloba;
  • Other nervous system active drug substances, such as, for example: parasympathomimetics, anticholinesterases, neostigmine, pyridostigmine, distigmine, ambenonium, choline esters, carbachol, bethanechol, other parasympathomimetics, such as, for example: pilocarpine, choline alfoscerate;
  • Active drug substances used in addictive disorders, such as, for example: nicotine, bupropion, varenicline, disulfiram, calcium carbimide, acamprosate, naltrexone, buprenorphine, methadone, levacetylmethadol, lofexidine, betahistine, cinnarizine, flunarizine, acetylleucine, gangliosides and ganglioside derivatives, tirilazad, riluzole, xaliproden, hydroxybutyric acid, amifampridine;
  • Opium alkaloids and derivatives, such as, for example: ethylmorphine, hydrocodone, codeine, opium alkaloids with morphine, normethadone, noscapine, pholcodine, dextromethorphan, thebacon, dimemorfan, acetyldihydrocodeine, benzonatate, benproperine, clobutinol, isoaminile, pentoxyverine, oxolamine, oxeladin, clofedanol, pipazetate, bibenzonium bromide, butamirate, fedrilate, zipeprol, dibunate, droxypropine, prenoxdiazine, dropropizine, cloperastine, meprotixol, piperidione, tipepidine, morclofone, nepinalone, levodropropizine, dimethoxanate.
  • In certain embodiments, the active drug substance may, for example, be an active drug substance with abuse potential that presents a safety risk. Such active drug substance may, for example, be selected from:
  • 1-(1-phenylcyclohexyl)pyrrolidine, 1-(2-phenylethyl)-4-phenyl-4-acetoxypiperidine, 1-[1-(2-thienyl)-cyclohexylpiperidine, 1-[1-(2-thienyl)cyclohexyl]pyrrolidine, 1-methyl-4-phenyl-4-propionoxy-piperidine, 1-phenylcyclohexylamine, 1-piperidinocyclohexanecarbonitrile, 2,5-dimethoxy-4-ethylamphetamine, 2,5-dimethoxyamphetamine, 2C-B-(4-bromo-2,5-dimethoxypenethylamine), 2C-D (2,5-dimethoxy-4-methylphenethylamine), 2C-I (4-iodo-2,5-dimethoxy-phenethylamine), 2C-T-2 (2,5-dimethoxy-4-ethylthiophenethylamine), 2C-T-4 (2,5-dimethoxy-4-isopropyl thiophenethylamine), 2C-T-7 (2,5-dimethoxy-4-(n)-propylthiopenethylamine), 3,4-methylene-dioxymethamphetamine, 3,4,5-trimethoxyamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxy-N-ethylamphetamine, 3-methylfentanyl, 3-methylthiofentanyl, 4-bromo-2,5-dimethoxyamphetamine, 4-bromo-2,5-dimethoxyphenethylamine, 4-methoxyamphetamine, 4-methyl-2,5-dimethoxyamphetamine, 4-methylaminorex (cis isomer), 5-MeO-DIPT (5-methoxy-N,N-diisopropyltryptamine), 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine), 5-methoxy-3,4-methylenedioxyamphetamine, acetorphin, acetorphine, acetyl-alpha-methylfentanyl, acetyl-alpha-methylfentanyl, acetyldihydrocodeine, acetylmethadol, acetylmethadol, alfentanil, allobarbital, allylprodin, allylprodine, alphacetylmethadol except levo-alphacetylmethadol, alpha-ethyltryptamine, aphameprodine, alphamethadol, alphamethadol, alpha-methylfentanyl, alpha-methylthiofentanyl, alphaprodine, alprazolam, amfepramon, amfetaminil, amineptin, aminorex, amobarbital, amphetamine, dextroamphetamine, amylnitrit (all isomers of the amyl group), anabolic steroids, anileridine, aprobarbital, barbital, barbituric acid derivative, BDB (3,4-methylenedioxyphenyl)-2-butanamine), benzethidin, benzethidine, benzoylecgonine, benzphetamine, benzphetamine, benzylmethylketon, benzylmorphine, betacetylmethadol, beta-hydroxy-3-methylfentanyl, beta-hydroxyfentanyl, betameprodine, betameprodine, betamethadol, betaprodine, bezitramide, bezitramide, boldenone, brolamfetamin, bromazepam, brotizolam, bufotenine, buprenorphine, butabarbital, butalbital, butobarbital, butorphanol, BZP (A 2)(1-benzylpiperazin), camazepam, cannabis, carfentanil, catha edulis, cathine, cathinone, chloral betaine, chloral hydrate, chlordiazepoxide, chlorhexadol, chlorotestosterone (same as clostebol), chlorphentermine, clobazam, clonazepam, clonitazene, clonitazene, clorazepate, clortermine, clostebol, clotiazepam, cloxazolam, coca leaves, cocaine, codeine, codeine & isoquinoline alkaloid, codeine methylbromide, codeine-N-oxide, codoxim, cyclobarbital (hexemal NFN), cyprenorphine, dehydrochlormethyltestosterone, delorazepam, desomorphine, dexamfetamine, dexfenfluramine, dexmethylphenidate, dextromoramide, dextropropoxyphene, diacetylmorphine, diampromide, diazepam, dichloralphenazone, diethylpropion, diethylthiambutene, diethyltryptamine, difenoxin, dihydrocodeine, dihydroetorphine, dihydromorphine, dihydrotestosterone, dimenoxadol, dimepheptanol, dimethylthiambutene, dimethyltryptamine, dioxaphetyl butyrate, diphenoxylate, dipipanone, diprenorphine, dronabinol, drostanolone, drotebanol, ecgonine, estazolam, ethchlorvynol, ethinamate, ethyl loflazepate, ethylestrenol, ethylmethylthiambutene, ethylmorphine, ethylmorphine, eticyclidin, etilamfetamine, etonitazene, etorphine, etoxeridine, etryptamine, fencamfamin, fenethylline, fenetylline, fenfluramine, fenproporex, fentanyl, fludiazepam, flunitrazepam, fluoxymesterone, flurazepam, formebolone, fungi and spores of the sepcies psilocype semilanceata, furethidine, gammahydroxybutanic acid, glutethimide, halazepam, haloxazolam, heroine, hydrocodone, hydrocodone & isoquinoline alkaloid, hydromorphinol, hydromorphone, hydroxypethidine, ibogaine, isobutylnitrit, isomethadone, ketamine, ketazolam, ketobemidone, levamfetamine, levo-alphacetylmethadol, levo-methamphetamine, levomethorphan, levomoramide, levophenacylmorphan, levorphanol, lisdexamfetamin, loprazolam, lorazepam, lormetazepam, lysergic acid, lysergic acid amide, lysergic acid diethylamide, marijuana, mazindol, MBDN (N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine), mCPP (1-(3-chlorphenyl)piperazine), mebutamate, mecloqualone, medazepam, mefenorex, MeOPP (1-(4-methoxyphenyl)piperazine), meperidine, meperidine intermediate, meprobamate, mescaline, mesocarb, mesterolone, metamfetamine, metazocine, methadone, methadone intermediate, methamphetamine, methandienone, methandranone, methandriol, methandrostenolone, methaqualone, methcathinone, methenolone, methohexital, methyldesorphine, methyldihydromorphine, methylphenidate, methylphenobarbital (mephobarbital), methyltestosterone, methyprylone, metopone, mibolerone, midazolam, modafinil, moramide-intermediate, morpheridine, morphine, morphine methylbromide, morphine methylsulfonate, morphine-N-oxide, myrophine, N,N-dimethylamphetamine, nabilone, nalorphine, nandrolone, N-ethyl-1-phenylcyclohexylamine, N-ethyl-3-piperidyl benzilate, N-ethylamphetamine, N-hydroxy-3,4-methylenedioxyamphetamine, nicocodeine, nicocodine, nicodicodine, nicomorphine, nimetazepam, nitrazepam, N-methyl-3-piperidyl benzilate, noracymethadol, norcodeine, nordiazepam, norethandrolone, norlevorphanol, normethadone, normorphine, norpipanone, norpipanone, opium, oxandrolone, oxazepam, oxazolam, oxycodone, oxymesterone, oxymetholone, oxymorphone, para-fluorofentanyl, parahexyl, paraldehyde, pemoline, pentazocine, pentobarbital, petrichloral, peyote, phenadoxone, phenampromide, phenazocine, phencyclidine, phendimetrazine, phenmetrazine, phenobarbital, phenomorphan, phenoperidine, phentermine, phenylacetone, pholcodine, piminodine, pinazepam, pipradrole, piritramide, PMMA (paramethyxymethyl amphetamine), prazepam, proheptazine, properidine, propiram, psilocybine, psilocyn, pyrovalerone, quazepam, pacemethorphane, racemoramide, racemorphane, remifentanil, salvia divinorum, salvinorin A, secobarbital, secobarbital, sibutramine, SPA, stanolone, stanozolol, sufentanil, sulfondiethylmethane, sulfonethylmethane, sulfonmethane, talbutal, temazepam, tenamfetamin, testolactone, testosterone, tetrahydrocannabinols, tetrazepam, TFMPP (1-(3-triflourmethylphenyl)piperazine), thebacon, thebaine, thiamylal, thiofentanyl, thiopental, tiletamine & zolazepam in combination, tilidine, trenbolone, triazolam, trimeperidine, vinbarbital, zaleplon, zipeprol, zolpidem and zopiclon.
  • Other suitable examples of active drug substances suitable for use in the pharmaceutical compositions described herein include, for example, alfentanil, allylprodine, alphaprodine, aniloridine, benzylmorphine, bezitramide, buprenorphine, butophanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diapromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimephetanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, dextropropoxyphene, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, morphine 6-glucuronide, morphine 3-glucuronide, myrophine, nalbuphine, narccine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxycodeine, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, thebaine, levo-alphacetylmethadol (LAAM), remifentanil, carfentanyl, ohmefentanyl, MPPP, prodine, PEPAP, levomethorphan, etorphine, lefetamine, loperamide, diphenoxylate or pethidine.
  • Even further examples of active drug substances suitable for use in the pharmaceutical compositions described herein include anabolic steroids, cannabis, cocaine and diazepam.
  • In one embodiment, the active drug substance is selected from the group consisting of the therapeutic classes including non-steroidal anti-inflammatory substances and antirheumatic active drug substances.
  • In other embodiments, the active drug substance is selected from therapeutic classes including analgesics, opioids, antipyretics, anaesthetics, antimigraine agents, antiepileptics, anti-parkinson agents, dopaminergic agents, antipsychotics, anxiolytics, sedatives, antidepressants, psychostimulants agents, dopamine, noradrenaline, nicotinic, alfa-andrenergic, serotonin, H3 antagonists used for ADHD and nootropics agents used in addictive disorders.
  • In still further embodiments, the active drug substance is selected from therapeutic classes including anaesthetics, centrally-acting analgesics, sedative-hypnotics, anxiolytics, appetite suppressants, decongestants, antitussives, antihistamines, antiemetics, antidiarrheals, and drugs used to treat narcolepsy and attention deficit hyperactivity disorder.
  • In certain embodiments, the active drug substance is associated with abuse syndromes and the active drug substance may, for example, be selected from opioids, CNS depressants, CNS stimulants, cannabinoids, nicotine-like compounds, glutamate antagonists and N-methyl-D-aspartate (NMDA) antagonists.
  • In specific embodiments, the active drug substance is an analgesic. Examples of analgesics suitable for use in the pharmaceutical compositions described herein include, for example, opioids, natural opium alkaloids, morphine, opium, hydromorphone, nicomorphine, oxycodone, dihydrocodeine, diamorphine, tapentadol, papaveretum, codeine, phenylpiperidine derivatives, ketobemidone, pethidine, fentanyl, diphenylpropylamine derivatives, dextromoramide, piritramide, dextropropoxyphene, bezitramide, methadone, benzomorphan derivatives, pentazocine, phenazocine, oripavine derivatives, buprenorphine, morphinan derivatives, butorphanol, nalbuphine, tilidine, tramadol, dezocine, salicylic acid and derivatives, acetylsalicylic acid, aloxiprin, choline salicylate, sodium salicylate, salicylamide, salsalate, ethenzamide, morpholine salicylate, dipyrocetyl, benorilate, diflunisal, potassium salicylate, guacetisal, carbasalate calcium, imidazole salicylate, pyrazolones, phenazone, metamizole sodium, aminophenazone, propyphenazone, nifenazone, anilides, paracetamol, phenacetin, bucetin, propacetamol, other analgesics and antipyretics such as, for example, rimazolium, glafenine, floctafenine, viminol, nefopam, flupirtine, ziconotide.
  • In certain such embodiments, the active drug substance is an opioid. Where an opioid is included as an active drug substance, the opioid may be selected from naturally occurring opioids, synthetic opioids and semisynthetic opioids.
  • In another embodiment, the active drug substance is selected from amfetamine, dexamfetamine, lisdexamfetamine, metamfetamine, methylphenidate, dexmethylphenidate and combinations thereof.
  • In some embodiments, the pharmaceutical compositions disclosed herein includes an opioid, the opioid is selected from buprenorphine, codeine, dextromoramide, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, morphine, pentazocine, oxycodeine, oxycodone, oxymorphone, norhydrocodone, noroxycodone, morphine-6-glucuronode, tramadol, tapentadol and dihydromorphine.
  • Where an opioid is used as an active drug substance, the opioid may be present in any of its crystalline, polymorphous, semi-crystalline, and amorphous or polyamorphous forms. Furthermore, in some embodiments, an opioid used as an active drug substance may be present in one or more forms selected from its crystalline, polymorphous, semi-crystalline, and amorphous or polyamorphous forms.
  • Specific embodiments of the pharmaceutical compositions disclosed herein include an opioid as an active drug substance, the active drug substance is selected from morphine, oxycodone, hydrocodone, hydromorphone, norhydrocodone, oxymorphone, noroxycodone, morphine-6-glucuronode and pharmaceutically acceptable salts of any of the aforementioned, such as from the group consisting of oxycodone hydrochloride, hydrocodone bitartrate, hydromorphone hydrochloride and morphine sulphate pentahydrate.
  • In certain embodiments, the pharmaceutical compositions as described herein are suitable for use for water soluble as well as slightly soluble or insoluble active drug substances.
  • In some embodiments, all of the above mentioned active drug substances may also be in the form of pharmaceutically acceptable salts, uncharged or charged molecules, molecular complexes, solvates, or anhydrates thereof, and, if relevant, isomers, enantiomers, racemic mixtures, and mixtures thereof.
  • In particular embodiments, the pharmaceutical compositions described herein may comprise pharmaceutically acceptable salts of any of the above mentioned active drug substances.
  • The term “pharmaceutically acceptable salts” of an active drug substance includes alkali metal salts such as, for example, sodium or potassium salts, alkaline earth metal salts such as, for example, calcium and magnesium salts, and salts with organic or inorganic acid such as, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, succinic acid, tartaric acid, methansulphonic acid, toluenesulphonic acid etc.
  • The term “pharmaceutically acceptable salts” of an opioid includes alkali metal salts such as, for example, sodium or potassium salts, alkaline earth metal salts such as, for example, calcium and magnesium salts, and salts with organic or inorganic acids such as, for example hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, succinic acid, tartaric acid, methansulphonic acid, toluenesulphonic acid etc or tartrate acid. In particular embodiments, pharmaceutically acceptable opioid salts may be selected from the group consisting of sulphate salts, hydrochloride salts and bitartrate salts.
  • The term “solvates” includes hydrates or solvates wherein other solvates than water are involved such as, for example, organic solvents like chloroform and the like.
  • Furthermore, in some embodiments, the active drug substance may be in any of its crystalline, polymorphous, semi-crystalline, amorphous or polyamorphous forms and mixtures thereof.
  • The concentration of the active drug substance in the pharmaceutical composition for use according to the disclosure depends on the specific active drug substance, the disease to be treated, the condition of the patient, the age and gender of the patient etc. The above-mentioned active drug substances may be known active drug substances and a person skilled in the art will be able to find information as to the dosage of each active drug substance and, accordingly, will know how to determine the amount of each active drug substance in the pharmaceutical composition.
  • The active drug substance may be a new chemical entity for which the amount of information is limited. In such cases, the dosage has to be evaluated based on available preclinical and/or clinical data.
  • In some embodiments, the active drug substance is typically present in the composition in an amount of from 5 to about 90% w/w such as, for example, from about 5 to about 80% w/w, from about 5 to about 70% w/w, from about 5 to about 60% w/w, from about 5 to about 50% w/w, from about 5 to about 40% w/w, from about 5 to about 30% w/w, from about 5 to about 20% w/w, from about 5 to about 10% w/w.
  • In certain embodiments, when the active drug substance is an opioid, such as, for example, morphine, oxycodone, hydromorphone or oxymorphone or pharmaceutically acceptable salts thereof, then said opioid is typically present in the compositions in a concentration of in the range of 5 to 70% w/w, for example in the range of 5 to 60% w/w, such as in the range of 5 to 50% w/w, for example in the range of 5 to 45% w/w, such as in the range of 5 to 40% w/w, for example in the range of 5 to 35% w/w, such as in the range of 5 to 30% w/w, for example in the range of 5 to 25% w/w, such as in the range of 5 to 20% w/w, for example in the range of 5 to 15% w/w, such as in the range of 5 to 10% w/w.
  • In certain embodiments, the active drug substance is typically present in the composition in an amount of from 1 to about 90% w/w such as, for example, from about 1 to about 80% w/w, from about 1 to about 70% w/w, from about 1 to about 60% w/w, from about 1 to about 50% w/w, from about 1 to about 40% w/w, from about 1 to about 30% w/w, from about 1 to about 20% w/w, from about 1 to about 10% w/w.
  • In certain embodiments, when the active drug substance is an opioid, such as, for example, morphine, oxycodone, hydromorphone or oxymorphone or pharmaceutically acceptable salts thereof, then said opioid is typically present in the compositions in a concentration of in the range of 1 to 70% w/w, for example in the range of 1 to 60% w/w, such as in the range of 1 to 50% w/w, for example in the range of 1 to 45% w/w, such as in the range of 1 to 40% w/w, for example in the range of 1 to 35% w/w, such as in the range of 1 to 30% w/w, for example in the range of 1 to 25% w/w, such as in the range of 1 to 20% w/w, for example in the range of 1 to 15% w/w, such as in the range of 1 to 10% w/w.
  • In certain embodiments, the compositions comprise a load of the active drug substance, such as an opioid. A load is generally less than 50% w/w of the active drug substance. For example, in certain such embodiments, the compositions may include an active drug substance in an amount selected from less than 40% w/w and less than 30% w/w.
  • In some embodiments, a pharmaceutical composition as described herein may comprise one active drug substance or more than one different active drug substances. Typically, the amount of the active drug substance corresponds to a daily or part of a daily therapeutic dose.
  • In certain embodiments, the pharmaceutical composition provides for administration 1-6 times a day, normally 1-4 times daily, such as 1-3 times daily, such as 1-2 times daily or 1 time daily.
  • In one embodiment, the pharmaceutical composition provides for twice-daily administration. In another embodiment, the pharmaceutical composition provides for once-daily administration.
    • Pharmaceutically Acceptable Excipients
  • The pharmaceutical compositions described herein may also contain other excipients in order to achieve one or more desired properties, such as, for example, better stability of the active drug substance or the pharmaceutical composition itself, enhance the abuse-deterrent properties, loading of the active drug substance or delivery characteristics, such as release rate or release profile of an active drug substance. Further, in some embodiments, the compositions described herein may include excipients that facilitate manufacture and production of dosage forms such as, for example, tablets suitable for administration to individuals in need thereof.
  • In certain embodiments, a suitable pharmaceutically acceptable excipient for use in compositions according to the present description may be selected from fillers, diluents, disintegrants, glidants, pH-adjusting agents, viscosity adjusting agents, solubility increasing or decreasing agents, osmotically active agents and solvents.
  • In some embodiments, suitable excipients include conventional tablet or capsule excipients. These excipients may be, for example, diluents such as dicalcium phosphate, calcium sulfate, lactose or sucrose or other disaccharides, cellulose, cellulose derivatives, kaolin, mannitol, dry starch, glucose or other monosaccharides, dextrin or other polysaccharides, sorbitol, inositol or mixtures thereof; binders such as alginic acid, calcium alginate, sodium alginate, starch, gelatin, saccharides (including glucose, sucrose, dextrose and lactose), carboxymethylcellulose, methylcellulose, veegum, larch arabolactan, polyethylene glycols, ethylcellulose, water, alcohols, waxes, polyvinylpyrrolidone such as PVP K90 or mixtures thereof; lubricants such as talc, silicium dioxide, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, sodium benzoate, sodium chloride, leucine, carbowax 4000, magnesium lauryl sulfate, Sodium laurilsulfate, Stearyl alcohol, Polysorbate 20, Polysorbate 60, Polysorbate 80, Macrogol stearate, Macrogol lauryl ether, Stearoyl macrogolglycerides, Sorbitan stearate, Sorbitan laurate, Macrogol glycerol hydroxystearat, colloidal silicon dioxide and mixtures thereof, disintegrants such as starches, clays, cellulose derivatives including crosscarmellose, gums, aligns, various combinations of hydrogencarbonates with weak acids (e.g., sodium hydrogencarbonate/tartaric acid or citric acid) crosprovidone, sodium starch glycolate, agar, cation exchange resins, citrus pulp, veegum, glycollate, natural sponge, bentonite, sucralfate, calcium hydroxyl-apatite or mixtures thereof.
  • In certain embodiments, in addition to a polymer of a polyethylene oxide, the composition may comprise an additional polymer such as polyglycols selected from substantially water soluble, thermoplastic, crystalline, semi-crystalline or amorphous or a mixture of substantially water soluble, crystalline, semi-crystalline or amorphous polymers. In particular, in certain embodiments, the polyglycol is at least thermoplastic. Suitable polyglycols for use in the composition include, for example, polyethylene glycols (for example with a molecular weight below 35,000 daltons), as well as derivatives of polyethylene glycol, such as mono or dimethoxypolyethylene glycols (mPEGs), polyethylene oxides and/or block copolymers of ethylene oxide and propylene oxide.
  • In some embodiments, in addition to a polymer of a polyethylene oxide, the composition may comprise an additional polymer, such as, for example, at least one polymer selected from: modified or unmodified water soluble natural polymers such as glucomannan, galactan, glucan, polygalacturonic acid, polyxylane, polygalactomannans, rhanogalacturonan, polyxyloglycan, arabinogalactan, and starch, cellulose, chitosan, alginate, fibrin, collagen, gelatin, hyaluronic acid, amylopectin, pectin including low methylated or methoxylated pectins, dextran and fatty acids and alcohols; synthetic polymers such as Carbopol, carbomer, carbomer homopolymer, carboxyvinyl polymer, polyvinylpyrrolidone (PVP), PVA, PVB, Eudragit L methyl ester, Eudragit L, Eudragit RL, Eudragit RS, Eudragit E, Eudragit S, PHPV, PHA, PCL, PLGA and PLA; and hydrogels made from the polymers or combined polymers mentioned above and or from polymers originated from HEMA, HEEMA, MEMA, MEEMA, EDGMA, NVP, VAc, AA, acrylamide, MAA, HPMA, PEGA, PEGMA, PEGDMA, PEGDA, and PEGDMA.
  • In certain embodiments, the composition as described herein may comprise one or more gelling agents. Examples are polymers selected from the group consisting of modified or unmodified water soluble natural polymers such as glucomannan, galactan, glucan, polygalacturonic acid, polyxylane, polygalactomannans, polyxyloglycan, arabinogalactan, starch, cellulose, chitosan, alginate, fibrin, collagen, gelatin, amylopectin, pectin including low methylated or methoxylated pectins, dextran; synthetic polymers such as PVA and PVB; and hydrogels made from the polymers or combined polymers mentioned above and or from polymers originated from: HEMA, HEEMA, MEMA, MEEMA, EDGMA, NVP, VAc, AA, acrylamide, MAA, HPMA, PEGA, PEGMA, PEGDMA, PEGDA, and/or PEGDMA, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, ethylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate or other cellulose derivates, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carrageenans, guar gum, gellan gum, xanthan gum, tragacanth, and arabic gum.
  • In some embodiments, exemplary stabilizers (chemical) include TPG, for example, in the form of TPGS (Vitamin E Polyethylene glycol succinate) and BHT, BHA, t-butyl hydroquinone, butylhydroxy toluene, calcium ascorbate, gallic acid, hydroquinone, maltol, octyl gallate, sodium bisulfite, sodium metabisulfite, tocopherol and derivates thereof, citric acid, tartaric acid, and ascorbic acid. Other stabilisers include trivalent phosphorous, such as, for example, phosphite, phenolic antioxidants, hydroxylamines, lactones such as substituted benzofuranones, hindered phenols, thiosynergists and/or hindered amines, acids (ascorbic acid, erythorbic acid, etidronic acid, hypophosphorous acid, nordihydroguaiaretic acid, propionic acid etc.), phenols, dodecyl gallate, octyl gallate, 1,3,5-trihydroxybenzene, organic and inorganic salts (calcium ascorbate, sodium ascorbate, sodium bisulphite, sodium metabisulfite, sodium sulfite, potassium bisulphite, potassium metabisulphite), esters (calcium ascorbate, dilauryl thiodipropionate, dimyristyl thiodipropionate, distearyl thiodipropionate), pyranon (maltol), and vitamin E (tocopherol, D-[alpha]-tocopherol, DL-[alpha]-tocopherol, tocopheryl acetate, d-[alpha]-tocopheryl acetate, dl-[alpha]-tocopheryl acetate. However, other anti-oxidative agents known in the art may also be used. Other suitable stabilizers may be selected from, for example, sorbitol glyceryl tricitrate, and sucrose octaacetate.
  • In one embodiment, a composition as described herein comprises one or more stabilizers selected from above mentioned group of stabilizers. In one such embodiment, the composition comprises butylhydoxytoluene and/or TPGS as a stabilizer. In another such embodiment, the composition comprises gallic acid and/or ascorbic acid as a stabilizer.
  • In certain embodiments, a release modifier may be incorporated in a composition as described herein. A suitable release modifier may be selected from fatty acids and esters, fatty alcohols, cetyl alcohol, stearyl alcohol, mineral oils, hydrogenated vegetable oils, vegetable oils, acetylated hydrogenated soybean oil glycerides, Castor oil, phosphate esters, amides, phthalate esters, glyceryl cocoate oleyl alcohol, myristyl alcohol, sucrose octaacetate, diacetylated monoglycerides, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monooleate, glyceryl monostearate, propylene glycol monostearate, macrogol esters, macrogol stearate 400, macrogol stearate 2000, polyoxyethylene 50 stearate, macrogol ethers, cetomacrogol 1000, lauromacrogols, poloxamers, polyvinyl alcohols, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate, ethylcellulose, cellulose acetate, cellulose propionate, cellulose nitrate, cellulose derivative selected from the group consisting of methylcellulose, carboxymethylcellulose and salts thereof, cellulose acetate phthalate, microcrystalline cellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose and hydroxymethylpropylcellulose, cellulose acetate, polylactic acid or polyglycolic acid and copolymers thereof, methacrylates, a co-polymer of methacrylate-galactomannan etc., polyvinyl alcohols, glycerinated gelatine and cocoa butter.
  • In some embodiments, other suitable release modifiers may be selected from inorganic acids, inorganic bases, inorganic salts, organic acids or bases and pharmaceutically acceptable salts thereof, saccharides, oligosaccharides, polysaccharides, polyethylene glycol derivatives and cellulose and cellulose derivatives.
  • Alternatively or additionally, in particular embodiments, a composition according to the present description may include a pharmaceutically acceptable excipient selected from a mono-, di-, oligo, polycarboxylic acid or amino acids such as, for example, acetic acid, succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, sorbic acid etc., aspartic acid or glutamic acid etc.
  • In some embodiments, suitable organic acids that may be included in the compositions described herein include, for example, acetic acid/ethanoic acid, adipic acid, angelic acid, ascorbic acid/vitamin C, carbamic acid, cinnamic acid, citramalic acid, formic acid, fumaric acid, gallic acid, gentisic acid, glutaconic acid, glutaric acid, glyceric acid, glycolic acid, glyoxylic acid, lactic acid, levulinic acid, malonic acid, mandelic acid, oxalic acid, oxamic acid, pimelic acid, or pyruvic acid.
  • In certain embodiments, suitable inorganic acids that may be included in the compositions described herein include, for example, pyrophosphoric, glycerophosphoric, phosphoric such as ortho and meta phosphoric, boric acid, hydrochloric acid, or sulfuric acid.
  • In particular embodiments, examples of suitable inorganic compounds that may be included in the compositions described herein include, for example, aluminium, calcium or kalium.
  • In particular embodiments, examples of organic bases that may be included in the compositions described herein include, for example, p-nitrophenol, succinimide, benzenesulfonamide, 2-hydroxy-2cyclohexenone, imidazole, pyrrole, diethanolamine, ethyleneamine tris (hydroxymethyl) aminomethane, hydroxylamine and derivates of amines, sodium citrate, aniline or hydrazine. Examples of inorganic bases that may be included in the compositions described herein include, for example, aluminium oxide such as, for example, aluminium oxide trihydrate, alumina, sodium hydroxide, potassium hydroxide, calcium carbonate, ammonium carbonate, ammnonium hydroxide or KOH.
  • In some embodiments, pharmaceutically acceptable salts of an organic acid that may be included in the compositions described herein include, for example, an alkali metal salt or an alkaline earth metal salt such as, for example, sodium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate etc., potassium phosphate, potassium dihydrogenphosphate, potassium hydrogenphosphate etc., calcium phosphate, dicalcium phosphate etc., sodium sulfate, potassium sulfate, calcium sulfate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, calcium carbonate, magnesium carbonate etc., sodium acetate, potassium acetate, calcium acetate, sodium succinate, potassium succinate, calcium succinate, sodium citrate, potassium citrate, calcium citrate, sodium tartrate, potassium tartrate or calcium tartrate.
  • In certain embodiments, suitable inorganic salts for that may be used in a composition as described herein include, for example, sodium chloride, potassium chloride, calcium chloride or magnesium chloride.
  • In some embodiments, the composition may comprise at least one saccharide. Where a saccharide is included in a composition as described herein, the saccharide may be selected from, for example, glucose, ribose, arabinose, xylose, lyxose, xylol, allose, altrose, inosito, glucose, sorbitol, mannose, gulose, glycerol, idose, galactose, talose, mannitol, erythritol, ribitol, xylitol, maltitol, isomalt, lactitol, sucrose, fructose, lactose, dextrin, dextran, amylase or xylan.
  • In certain embodiments, the composition may also comprise cellulose and/or cellulose derivatives selected from the group consisting of methylcellulose, carboxymethylcellulose and salts thereof, microcrystalline cellulose, ethylhydroxyethylcellulose, ethylcellulose, cellulose acetate, cellulose proprionate, cellulose nitrate, cellulose acetate phthalate, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose and hydroxymethylpropylcellulose.
  • Furthermore, in particular embodiments, the compositions described herein may comprise one or more agents selected from sweetening agents, flavouring agents and colouring agents in order to provide an elegant and palatable preparation. Examples include maltol, citric acid, water soluble FD&C dyes and mixtures thereof with corresponding lakes and direct compression sugars such as Di-Pac from Amstar. In addition, coloured dye migration inhibitors such as; tragacanth, acacia or attapulgite talc may be added. Specific examples include calcium carbonate, 1,3,5-trihydroxybenzene, chromium-cobalt-aluminium oxide, ferric ferrocyanide, ferric oxide, Iron ammonium citrate, iron (III) oxide hydrated, iron oxides, carmine red, magnesium carbonate and titanium dioxide.
    • Preparation
  • The pharmaceutical compositions of the disclosure may be produced by various methods which are either known per se in the pharmaceutical industry or which, for example, are used in the production of polymer-based materials, depending upon the desired embodiment and the materials employed in the pharmaceutical composition in question. The pharmaceutical compositions according to the present description may be produced by methods that are relatively simple and inexpensive.
  • Suitable preparation methods for pharmaceutical compositions according to the present description include conventional tablet compression, hot melt-processing and other methods of preparing pharmaceutical compositions. In certain embodiments, hot melt-processing technology and the use of thermoplastic and thermosetting plastic polymers are able to give pharmaceutical compositions with low porosity, high viscosity and breaking strengths, like properties such as for example plastic which is difficult to tear down. In particular embodiments, a combination of one or more of the aforementioned methods may be employed for use in the preparation of pharmaceutical compositions disclosed herein.
  • In some embodiments, the pharmaceutical compositions described herein are prepared by hot melt-processing. In one such embodiment, the pharmaceutical compositions are prepared by, for example, 1, 2 or multiple component extrusion, molding, 1, 2 or multiple component injection molding. In another such embodiment, the pharmaceutical compositions are prepared by 1, 2 or multiple component injection molding.
  • In embodiments where a preparation is needed in order to make the pharmaceutical composition either before or after the above-mentioned preparation steps, the preparation may also comprise separate steps, such as, for example, wet granulation, dry granulation, melt granulation, pelletizing, curing, spray coating, electrostatic coating, dip coating or other forms of preparation methods.
  • In one embodiment, the pharmaceutical composition is prepared by conventional tablet compression.
  • In another embodiment, the pharmaceutical compositions are prepared by conventional tablet compression and hot melt processing.
    • Geometry
  • The pharmaceutical compositions according to the present description may be formed as cylindrical compositions. In certain embodiments, the pharmaceutical compositions are formed as a cylindrical shape optionally with one or two tapered end(s).
  • For purposes of the pharmaceutical compositions according to the present description, the cylindrical shape may be any geometrical shape having the same cross section area throughout the length of the geometrical shape. Within the present context, cross sections are perpendicular to the axis of the cylinder. By way of example, if the cylindrical shape is elongated then the cross sections are perpendicular to the longitudinal axis. Preferably, the cylindrical shape is elongated. The cross section of a cylinder within the meaning of the present disclosure may have any two-dimensional shape, for example the cross section may be circular, oval, parabola, hyperbola, rectangular, triangular, otherwise angular, star shaped or an irregular shape. Accordingly, the cylindrical shape may for example be an elliptic cylinder, a parabolic cylinder, a hyperbolic cylinder or a prism. A prism within the present context is a cylinder whose cross-section is a polygon.
  • In some embodiments, the pharmaceutical composition according to the present description may have any common tablet shapes. Exemplary tablet shapes may include, for example, standard convex, standard convex bisect not flush, standard convex quadrisect flush, standard convex straight-through bisect, compound cup, convex with bevel, flat-faced plain, flat-faced bevel-edged, flat-faced bevel-edged bisect, flat-faced bevel-edged quadrisect, flat-faced radius-edged, lozenge, modified ball, core rod type (hole in center), capsule, modified capsule, oval, bullet, arrowhead, triangle, arc triangle, square, pillow (arc square), rectangle, modified rectangle, diamond, pentagon, hexagon, octagon natural edge, heart, half moon and almond. A skilled person would know the various kinds of shape that a tablet may be formed in.
  • In a particular embodiment, the pharmaceutical composition is prepared for oral intake, preferably for oral intake by swallowing. Accordingly, the size of the pharmaceutical composition may be in a range that allows for oral intake by swallowing.
    • Cosmetic Coat
  • In some embodiments, the pharmaceutical composition according to the present description may also contain a cosmetic coat that fully covers the composition. In certain such embodiments, the cosmetic coat may be selected from the group consisting of taste-masking coats, coats with aqueous moisture barriers and/or oxidative barriers to improve the stability of the composition, and coat containing colouring agents, sweetening agents and/or flavouring agents in order to provide an elegant and palatable pharmaceutical composition and/or to easy distinguishable dose strengths.
  • It can be particularly useful to coat compositions having different dose strengths or active drug substances with cosmetic coats of different colours so that the different actives and dose strengths are easily distinguished.
  • In certain embodiments, the cosmetic coat contains an active drug substance.
  • Where provided, the cosmetic coat may, in particular embodiments, be easily soluble in aqueous media in order to facilitate contact of the composition with the surrounding aqueous media rapidly after administration. In one such embodiment, the cosmetic coat is dissolved within 30 minutes after immersed in aqueous media such as, for example, phosphate buffer solution pH 6.8.
    • Administration
  • The pharmaceutical composition according to the present description can be designed for oral administration. For example, in certain embodiments, the pharmaceutical compositions may be produced as tablets, for oral intake by swallowing one or more intact tablets of the pharmaceutical composition.
  • A pharmaceutical composition as described herein may comprise one active drug substance or more than one different active drug substance.
  • In certain embodiments, a pharmaceutical composition containing an active drug substance according to the present description is typically formulated for oral administration. Due to the possibility of controlling the release rate of the active drug substance, in particular embodiments, the pharmaceutical composition may be adapted for oral administration 1-6 times a day, such as 1-4 times daily, including 1-3 times, 1-2 times or twice or once daily.
  • In some embodiments, the pharmaceutical compositions according to the present description can be prepared for delivery of the desired dosage of active drug substance. In particular embodiments, the dosage may be dependent on the individual to whom the pharmaceutical composition as described herein is being administered and the active drug substance.
  • In particular embodiments, the dosage for each administration, wherein dosages are in the range of 1 to 1,000 mg, such as in the range of 5 to 1,000 mg, for example in the range of 8 to 1,000 mg, such as in the range of 10 to 1,000 mg, for example in the range of 30 to 1,000 mg, such as in the range of 1 to 750 mg, for example in the range of 1 to 500 mg, such as in the range of 1 to 250 mg of an active drug substance. In certain such embodiments, the dosage for each administration is in a range selected from 5 to 500 mg and 5 to 250 mg of an active drug substance.
  • In some embodiments, when the active drug substance included in the pharmaceutical compositions is an opioid, the dosage may be selected from a range of 1 to 1000 mg, a range of 10 to 1000 mg, a range of 15 to 1000 mg, a range of 20 to 1000 mg, a range of 30 to 1000 mg, a range of 1 to 500 mg, a range of 1 to 250 mg, a range of 10 to 500 mg, a range of 15 to 500 mg, a range of 15 to 250 mg, a range of 20 to 500 mg, a range of 20 to 250 mg, a range of 30 to 500 mg, a range of 30 to 250 mg, a range of 10 to 200 mg, a range of 15 to 200 mg, a range of 20 to 200 mg, and a range of 30 to 200 mg of the opioid. In certain such embodiments, the pharmaceutical composition includes opioid or a pharmaceutically acceptable salt thereof as an active drug substance and the dosage is selected from 10, 15, 20, 30, 50, 60, 80, 100 or 200 mg. In certain such embodiments, the pharmaceutical composition includes morphine as an active drug substance and the dosage is selected from 10, 15, 20, 30, 50, 60, 80, 90, 100, 120, 180 or 200 mg.
  • In another embodiment, when the active drug substance included in the pharmaceutical compositions is an opioid, the dosage may be selected from a range of 1 to 1,000 mg, a range of 10 to 1,000 mg, a range of 1 to 500 mg, a range of 1 to 250 mg, a range of 10 to 500 mg, a range of 10 to 250 mg, a range of 1 to 150 mg, a range of 10 to 150 mg, a range of 1 to 100 mg a range of 10 to 100 mg, a range of 1 to 80 mg and a range of 10 to 80 mg of the opioid. In certain such embodiments, the pharmaceutical composition includes opioids or a pharmaceutically acceptable salt thereof as an active drug substance and the dosage is selected from 10, 15, 20, 30, 40, 60 or 80 mg. In certain such embodiments, the pharmaceutical composition includes hydrocodone as an active drug substance and the dosage is selected from 10, 15, 20, 30, 40, 60 or 80 mg. In another such embodiments, the pharmaceutical composition includes oxycodone as an active drug substance and the dosage is selected from 10, 15, 20, 30, 40, 60 or 80 mg.
  • In still another embodiment, when the active drug substance included in the pharmaceutical compositions is an opioid, the dosage may be selected from a range of 1 to 1,000 mg, a range of 8 to 1,000 mg, a range of 1 to 500 mg, a range of 1 to 250 mg, a range of 8 to 500 mg, a range of 8 to 250 mg a range of 1 to 100 mg, a range of 8 to 100 mg, a range oft to 75 mg, a range of 8 to 75 mg, a range of 1 to 64 mg and a range of 8 to 64 mg of the opioid. In certain such embodiments, the pharmaceutical composition includes opioids or a pharmaceutically acceptable salt thereof as an active drug substance and the dosage is selected from 8, 12, 16, 32 or 64 mg. In certain such embodiments, the pharmaceutical composition includes hydromorphone as an active drug substance and the dosage is selected from 8, 12, 16, 32 or 64 mg.
  • In still another embodiment, when the active drug substance included in the pharmaceutical compositions is an opioid, the dosage may be selected from a range of 1 to 1,000 mg, a range of 5 to 1,000 mg, a range of 1 to 500 mg, a range of 1 to 250 mg, a range of 5 to 500 mg, a range of 5 to 250 mg a range of 1 to 100 mg, a range of 5 to 100 mg, a range of 1 to 50 mg, a range of 5 to 50 mg, a range of 1 to 40 mg, and a range of 5 to 40 mg of the opioid. In certain such embodiments, the pharmaceutical composition includes opioids or a pharmaceutically acceptable salt thereof as an active drug substance and the dosage is selected from 5, 7.5, 10, 15, 20, 30 or 40 mg. In certain such embodiments, the pharmaceutical composition includes oxymorphone as an active drug substance and the dosage is selected from 5, 7.5, 10, 15, 20, 30 or 40 mg.
  • In particular embodiments, the above-mentioned dosages are relevant when the individual in need of treatment is a human being, such as an adult human being.
    • Individuals in Need of Treatment
  • In some embodiments, the pharmaceutical composition of the disclosure is prepared for administration to an individual in need thereof. In certain such embodiments, the individual may be a mammal, and in specific embodiments the individual is a human being.
  • In certain embodiments, the pharmaceutical composition is for treatment of pain and accordingly, the individual in need of treatment is an individual suffering from pain.
  • In certain embodiments, wherein the active drug substance is an opioid, then the pharmaceutical compositions are suitable for treatment of moderate to severe pain such as severe pain.
  • In some embodiments, examples of individuals, who may benefit from treatment with the pharmaceutical compositions according to the disclosure, include, for example, the following:
  • The individual may be an individual suffering from chronic pain, such as moderate to severe chronic pain;
  • The individual may be an individual suffering from cancer and the pharmaceutical composition may be useful for continuous treatment of pain or even moderate to severe pain, such as severe pain in an individual suffering from cancer;
  • The individual may also be an individual who has suffered a moderate to severe injury;
  • The individual may be an individual suffering from pain associated with surgical conditions, such as a pre-surgical individual (an individual in need of surgery) or a post surgical individual (an individual who has undergone surgery);
  • The individual may also be an individual suffering from or having suffered from a myocardial infarction, sickle cell crises, kidney stone or severe back pain;
  • The individual may also be an individual suffering from degenerative pain, herniated disc pain, fibromyalgia, neuropathic pain and/or nociceptive pain; and
  • The individual may also be an individual suffering from arthritis, such as arthritis osteo, arthritis rheumatoid, arthritis psoriatica and/or arthritis urica.
    • No Alcohol-Induced Dose Dumping
  • The pharmaceutical compositions according to the present description may be formulated or configured to provide a reduced risk for alcohol-induced dose dumping.
  • In specific embodiments, the pharmaceutical compositions according to the present description may be formulated or configured such that the pharmaceutical composition does not exhibit alcohol induced dose-dumping. In such embodiments, the composition exhibits a solubility and/or active drug substance release rate in alcohol containing media (for example, ethanol containing media) that is lower than or equal to the solubility and/or release rate in aqueous media that does not include alcohol (for example, water, phosphate buffer medium pH 6.8 or dilute hydrochloric acid). In some such embodiments, the polyethylene oxide and excipients selected for use in the pharmaceutical composition are provided in relative amounts that result in an unchanged or lower dissolution rate and/or release rate of the active drug substance in alcohol containing media (for example, ethanol containing media) as compared to the solubility and/or release rate exhibited in aqueous media that does not include alcohol (for example, water, phosphate buffer medium pH 6.8 or dilute hydrochloric acid). In certain such embodiments, the dissolution and/or release rate of the active drug substance from the pharmaceutical composition in alcohol containing media (for example, ethanol containing media) is at least 1.25 times lower, such as at least 1.5 times lower, such as at least 2 times lower, such as at least 5 times, such as at least 10 times lower than the dissolution and/or release rate of the active drug substance in aqueous media that does not include alcohol (for example, water, phosphate buffer medium pH 6.8, dilute hydrochloric acid, and the like).
  • More specifically, in some embodiments, the pharmaceutical composition may be formulated or configured to mitigate or prevent alcohol-induced dose dumping. In certain embodiments, the solubility or release rate of the composition is lower or substantially the same in alcohol than that in water. In certain such embodiments, the solubility or release rate of the composition is equal or at least 1.25 times lower such as at least 1.5 times lower; at least 2 times lower in alcohol than in water, notably 5 times or 10 times lower.
  • In particular embodiments, the pharmaceutical compositions according to the present description may be configured or formulated to mitigate or prevent alcohol-induced dose dumping. In certain such embodiments, the pharmaceutical compositions are formulated such that the ratio (R50) between t50% w/w (40% v/v ethanol in medium 1) and t50% w/w (medium 1) is 1 or more. t50% w/w (medium 1) denotes the time it takes to release 50% w/w of the active drug substance from the pharmaceutical composition in an in vitro dissolution test according to USP 35, NF 30, (711), Apparatus 2, paddle employing water optionally buffered to a specific pH as dissolution medium (medium 1), and t50% w/w (40% v/v ethanol in medium 1) denotes the time it takes to release 50% w/w of the active drug substance from the pharmaceutical composition in an in vitro dissolution test according to USP 35, NF 30, (711), Apparatus 2, paddle employing 40% v/v ethanol in medium 1 as dissolution medium.
  • In certain embodiments, the ratio R50 is at the most 3 or at the most 2. Notably, in certain such embodiments, the ratio R50 provided by the pharmaceutical compositions described herein is from 1 to 1.5 such as, for example, from 1 to 1.4, from 1 to 1.3, from 1 to 1.2, from 1 to 1.1, from 1 to 1.05, about 1, from 1 to 0.95 or from 1 to 0.9.
  • In particular embodiments, the same may also apply for ratios determined, for example, when 25%, 30%, 40%, 60%, 70%, 80%, 90% and/or 95% w/w has been released, the conditions being as described above.
    • Abuse-Deterrent
  • The pharmaceutical compositions according to the present description are abuse-deterrent such that abuse administration is reduced, prevented or avoided. Abuse administration typically includes injection and/or snorting.
  • Injection may be avoided by providing a non-injectable composition having such high viscosity that injection is difficult or impossible, because a liquid solution cannot be obtained.
  • The term “non-injectable composition,” as used herein, refers to pharmaceutical compositions having a viscosity of at least 95 mPa·s, for example at least about 100 mPa·s, such as at least about 105 mPa·s, for example at least about 110 mPa·s, such as at least about 120 mPa·s, for example at least about 130 mPa·s, such as at least about 140 mPa·s, for example at least about 150 mPa·s, such as at least about 160 mPa·s, for example, at least about 170 mPa·s, such as at least about 180 mPa·s, for example at least about 190 mPa·s, such as at least about 200 mPa·s. for example at least about 220 mPa·s, such as at least about 240 mPa·s, where the viscosity is measured according to “Viscosity Test #2,” described in the “Viscosity test” disclosure. In particular embodiments, the term “non-injectable composition,” as used herein, refers to pharmaceutical compositions having a viscosity of at least 170 mPa·s, where the viscosity is measured according to “Viscosity Test #2,” described in the “Viscosity test” disclosure.
  • Furthermore, the term “non-injectable composition,” as used herein, may also refer to pharmaceutical compositions having a viscosity in a range selected from between about 0.5 Pa·s to about 3,000 Pa·s, between about 0.5 Pa·s to about 2,500 Pa·s, between about 0.5 Pa·s to about 2,000 Pa·s, between about 0.5 Pa·s to about 1,700 Pa·s, between about 5 Pa·s to about 3,000 Pa·s, between about 10 Pa·s to about 3,000 Pa·s, between about 20 Pa·s to about 3,000 Pa·s, between about 30 Pa·s to about 3,000 Pa·s, between about 40 Pa·s to about 3,000 Pa·s, between about 45 Pa·s to about 3,000 Pa·s, between about 45 Pa·s to about 2,500 Pa·s, between about 45 Pa·s to about 2,000 Pa·s, between about 45 Pa·s to about 1,700 Pa·s, between about between about 46 Pa·s to about 1,700 Pa·s, where the viscosity is measured according to “Viscosity Test #1,” described in the “Viscosity test” disclosure. In particular embodiments, the term “non-injectable composition,” as used herein, refers to pharmaceutical compositions having a viscosity of at least about 46 Pa·s, where the viscosity is measured according to Viscosity Test #1, described in the “Viscosity test” disclosure.
  • Snorting may be avoided by providing a non-snortable composition, which cannot be tampered into small particles or powder form such that snorting is made impossible.
  • In certain embodiments of the pharmaceutical compositions described herein, the term “non-snortable composition” refers to compositions wherein at least 90 wt % of the particles obtained after physical tampering of the composition is larger than about 1,050 μm, such as larger than about 1,100 μm, such as larger than about 1,150 μm. In particular embodiments, the term “non-snortable composition,” as used herein, refers to a composition where at least 90 wt % of the particles obtained after physical tampering of the pharmaceutical composition is larger than 1,100 μm.
  • In certain circumstances, an abuser may tamper with pharmaceutical compositions in a manner or by using a method that achieves maximal size reduction of the pharmaceutical composition in a minimal amount of time, while obtaining small particles, a powder, or other similar products, which can be dissolved or administered as easily as possible.
  • A series of abuse or tampering methods have been developed to illustrate the extent of the pharmaceutical compositions described herein of being abuse-deterrent.
  • If a pharmaceutical composition disintegrates into particles, then it may be possible to dissolve or suspend the particles and use them for abuse purposes. Moreover, if it is possible to disintegrate (e.g., crush) a pharmaceutical composition, then it is possible to use the powder for snorting or sniffing and, in this way, abuse the composition. However, if it is not possible to crush a pharmaceutical composition, then there will be no particles to use for such abuse purposes. In particular embodiments, the pharmaceutical compositions described herein cannot be crushed into particles by the apparatus (e.g., tablet hardness tester) specified in Ph. Eur.
  • A particle size reduction test method has been developed to evaluate abuse potential when the pharmaceutical composition is subjected to physical tampering.
  • In some embodiments, a pharmaceutical composition is abuse-deterrent, provided that the pharmaceutical composition does not change its release profile from a controlled release to an immediate release of the active drug substance subsequent to physical tampering (e.g., particle size reduction test, where the test program is successfully completed), which indicates that the pharmaceutical composition is abuse-deterrent. In some such embodiments, tests on a pharmaceutical composition subjected to physical tampering may also result in equipment failure, and in such an instance, the test program is considered successfully completed, indicating a pharmaceutical composition as abuse-deterrent.
  • If a pharmaceutical composition is crushed or broken into small pieces or small particles, an increased exposed surface area is created, which may increase the release rate of the active drug substance. Such an increase in release rate may lead to an increased potential for abuse. If a change in the release profile of the active drug substance from a controlled release to an immediate release is noticed, the pharmaceutical composition is considered to have failed. At such a point, the pharmaceutical composition is considered to have potential for abuse, such as by snorting or chemical extraction and it is evaluated. If the active drug substance can be extracted from the compromised pharmaceutical composition, the ease with which such extracted active drug substance can be injected is evaluated.
    • Crisping
  • The crisping test methods as described herein include methods intended to circumvent the controlled release mechanism in or interfere with the controlled release profile of a pharmaceutical composition. Crisping is a heating process designed to remove, reduce, or degrade at least some of the unwanted or undesired excipients contained within a dosage form and make the dosage form easier to abuse the active drug substance. Crisping may be employed to make it easier to crush the composition into small particles or a powder form so that snorting is made possible, or to make it easier to dissolve the composition into an injectable liquid solution, dispersion, or suspension.
  • Crisping or heating methods, such as, for example, heating in an oven, a microwave oven, a spoon over an open flame, and the like, may be employed by a potential abuser to it make it easier to reduce the particle size and/or the viscosity of the pharmaceutical compositions. The heating is normally stopped when the pharmaceutical composition starts to turn a brown colour. Further processes designed to facilitate or enable abuse such as, for example, particle size reduction, extraction and/or injection are typically initiated after the crisping process is completed.
  • In certain embodiments, the pharmaceutical compositions according to the present description are not made easier to crush into snortable particles or powder form or to dissolve into an injectable liquid solution by crisping. In certain embodiments, stearate may be added to the pharmaceutical composition as described herein to facilitate the colour change of the composition to a brown and/or dark colour or even to facilitate the composition burning when exposed to a crisping process. In a particular embodiment, the stearate added is magnesium stearate, calcium stearate and/or stearic acid.
    • Particle Size Reduction
  • The particle size reduction test methods described herein include methods for reducing the particle size of the pharmaceutical compositions via physical tampering, such as, for example, crushing, hammering, chopping, grinding, grating, cutting, and other means of particle size reduction.
  • The particle size reduction test can be carried out using a number of mechanical and electrical tools that are common household items or are readily commercially available. Tools that may be used in carrying out particle size reduction testing include, for example, a mortar and pestle, a hammer, a grater, a food chopper, a coffee grinder, and the like.
  • Pharmaceutical compositions and dosage forms (including, for example, tablets), that have been subjected to physical tampering may be further analyzed by use of image processing and/or particle size analysis. Pharmaceutical compositions subjected to physical tampering may be analyzed by collecting the different fractions and analyzing, such as, for example, by weighing and/or dissolving to assess the contents of active drug substance in the different fractions and/or to assess the dissolution rate. For comparison, a control dissolution test as described in the “Dissolution test” disclosure may be performed using intact tablets (e.g., tablets that have not been subjected to physical tampering), and the results from the control dissolution test may be used as control data.
    • Extraction
  • The extraction test methods described herein include methods for evaluating the extractability of active drug substance(s) from pharmaceutical compositions in different types of solvents. The extraction test can be carried out using approximately 3 ml of water to prepare a solution of, for example, MS Contin® for injection.
    • Shaking
  • Different amount of solvents and ways of handling the solutions have been tested. In certain embodiments, in order to ensure that as much as possible of the active drug substance has been extracted, shaking is selected as an extraction method. In certain such embodiments, extraction of an active drug substance from a pharmaceutical composition may be facilitated by placing a pharmaceutical composition in at least one solvent and shaking the pharmaceutical composition and the at least one solvent.
  • In particular embodiments, in order to ensure that as much as possible of the active drug substance has been extracted, continuous shaking is selected as an extraction method. In one embodiment, extraction of an active drug substane from a pharmaceutical composition may be facilitated by placing a pharmaceutical composition in at least one solvent and continuously shaking the pharmaceutical composition and the at least one solvent. In some embodiments, “continuous shaking,” as used herein, refers to shaking for at least 1 second, for at least 5 seconds, for at least 30 seconds, for at least 1 min, for at least 5 minutes, for at least 10 minutes, for at least 15 minutes, for at least 30 minutes, for at least 45 minutes, for at least 60 minutes, for at least 2 hours, for at least 4 hours, for at least 8 hours, for at least 12 hours, for at least 24 hours, for at least 2 days, for at least 3 days, for at least 4 days, for at least 5 days, for at least 6 days, for at least 1 week, for at least 2 weeks, for at least a month.
    • Unshaken/Undisturbed
  • In another embodiment, as an extraction method, the pharmaceutical composition may be placed in at least one solvent and left unshaken and/or undisturbed for a period of time. In certain embodiments, the pharmaceutical composition may be placed in at least one solvent and left unshaken and/or undisturbed for at least 4 hours, at least 8 hours, at least 12 hours, at least 24 hours, at least 48 hours, and at least 72 hours. In certain such embodiments, the pharmaceutical composition may be placed in at least one solvent and left unshaken and/or undisturbed, and the active drug substance in the solvent may be first measured after at least 24 hours.
  • The amount of active drug substance in the solvent may be measured at select time points within the first 60 minutes. In some embodiments, the amount of active drug substance in the solvent may be measured at least one time, at least two times, at least three times, at least four times, at least five times, and at least six times, within the first 60 minutes of placing the pharmaceutical composition in the at least one solvent. In particular embodiments, the amount of active substance in the solvent may be measured at least one time, at least two times, at least three times, at least four times, at least five times, and at least six times, within the first 24 hours of placing the pharmaceutical composition in the at least one solvent. In an embodiment, the amount of active drug substance in the solvent may be measured at at least three time points within the first 60 minutes, so as to evaluate the rate at which the active drug substance is released into the solvent.
  • Extraction of active drug substance from pharmaceutical compositions can be performed by dissolving, for example, tablets in different types of solvents. In particular embodiments, the tablets in different solvents may be shaken and/or continuous shaken. In other embodiments, the tablets in different solvents may be unshaken or undisturbed. The solvents can be chosen to cover a broad range of liquids with low and high pH, with some being some polar and some non-polar. In certain embodiments, the solvents may be categorized into five groups: such as for example, aqueous solutions, such as, for example, solution pH 1.2; buffer pH 6.8; buffer pH 10.0; water; and water+ethanol (40% v/v); beverages, such as, for example; Coca-Cola®; quinine containing soft drinks, such as, for example; tonic water and bitter lemon; Coca-Cola® +ethanol (40% v/v); and vodka; common household liquids, such as, for example, 1% acetic acid; ethanol; methylethylketone; and acetone.
  • In some embodiments, it has been shown to be difficult to extract active substances from the pharmaceutical composition described herein in solvents such as beverages. In certain such embodiments, it has been shown to be difficult to extract active substances from the pharmaceutical composition described herein in solvents such as carbonated and/or soft drinks, including Coca-Cola®, and the like.
    • Injection
  • The injection test methods described herein include methods for evaluating the abuse potential of active drug substance from pharmaceutical compositions both quantitatively (i.e., such as, for example, time, yield, and unit operations required) and qualitatively (i.e., such as, for example, appearance).
  • In some embodiments, the general strategy behind the injection test methods, as described herein, is to mimic the actual procedures applied by drug abusers when preparing a pharmaceutical composition for injection and injecting it. In some such embodiments, the study design is therefore divided into three parts, such as, for example, preparation, filtration, and injection.
  • In certain embodiments, the objective is to record the time and effort required to prepare a solution or dispersion that can be used for injection and the obtained yield of the active drug substance. As described herein, drug abusers are, typically, only prepared to spend a limited amount of time for preparing a pharmaceutical composition for abuse. In certain such embodiments, all of the tests disclosed herein can be performed in an aqueous media, which is a commonly-used solvent for injection. Finally, the appearance of the resulting solution/dispersion is assessed in order to evaluate the likelihood that a drug abuser would inject the resulting injectable mass.
  • In certain embodiments, the pharmaceutical compositions described herein have predominantly high viscous properties analogous to plastic. In an aqueous medium or in the gastrointestinal tract, the pharmaceutical compositions described herein transforms from having high viscous properties to having predominately elastic properties that control the release rate of active drug substance, and which resist rapid extraction and/or injection. In particular embodiments, the predominately elastic properties of the pharmaceutical compositions in an aqueous medium or in the gastrointestinal tract provides a controlled-release profile of the active drug substance in an individual.
  • The high viscosity of the composition turns not only the composition into a non-injectable dispersion/gel, but also significantly delays the solubility of the composition to completely form into a gelatinous mass. In some embodiments, the high viscosity of the composition turns not only the composition into a non-injectable dispersion/gel, but also significantly deters the abuse of the pharmaceutical composition by eluting at least one polymer from the composition into the solvent, which turns the solvent into a gelatinous mass. In some such embodiments, the at least one polymer is a polyethylene oxide. In certain embodiments, the average molecular weight of the at least one polyethylene oxide eluting from the composition into the solvent is less than 5,000,000 daltons, for example less than 4,000,000 daltons, such as less than 3,000,000 daltons, for example less than 2,000,000 daltons, such as less than 1,000,000 daltons, for example less than 800,000 daltons, such as less than 600,000 daltons, for example less than 500,000 daltons.
  • In particular embodiments, the high viscosity of the composition is in a range selected from between about 0.5 Pa·s to about 3,000 Pa·s, between about 0.5 Pa·s to about 2,500 Pa·s, between about 0.5 Pa·s to about 2,000 Pa·s, between about 0.5 Pa·s to about 1,700 Pa·s, between about 5 Pa·s to about 3,000 Pa·s, between about 10 Pa·s to about 3,000 Pa·s, between about 20 Pa·s to about 3,000 Pa·s, between about 30 Pa·s to about 3,000 Pa·s, between about 40 Pa·s to about 3,000 Pa·s, between about 45 Pa·s to about 3,000 Pa·s, between about 45 Pa·s to about 2,500 Pa·s, between about 45 Pa·s to about 2,000 Pa·s, between about 45 Pa·s to about 1,700 Pa·s, between about between about 46 Pa·s to about 1,700 Pa·s, where the viscosity is measured according to “Viscosity Test #1,” described in the “Viscosity test” disclosure. In a specific embodiment, the viscosity of the composition at least about 46 Pa·s, where the viscosity is measured according to Viscosity Test #1, described in the “Viscosity test” disclosure.
  • In certain embodiments, the high viscosity of the composition is at least 95 mPa·s, for example at least about 100 mPa·s, such as at least about 105 mPa·s, for example at least about 110 mPa·s, such as at least about 120 mPa·s, for example at least about 130 mPa·s, such as at least about 140 mPa·s, for example at least about 150 mPa·s, such as at least about 160 mPa·s, for example, at least about 170 mPa·s, such as at least about 180 mPa·s, for example at least about 190 mPa·s, such as at least about 200 mPa·s. for example at least about 220 mPa·s, such as at least about 240 mPa·s, where the viscosity is measured according to “Viscosity Test #2,” described in the “Viscosity test” disclosure. In particular embodiments, the high viscosity of the composition is at least 170 mPa·s, where the viscosity is measured according to “Viscosity Test #2,” described in the “Viscosity test” disclosure.
  • The high viscosity of the composition deters direct injection and also serves as a significant barrier to prevent volatilization (e.g., inhalation) of the incorporated active drug substance at elevated temperature or snorting if the composition is crushed or broken into small pieces or small particles. In certain embodiments, the composition results in a highly viscous and/or unclear, opaque or cloudy dispersion/gel upon contact with and/or immersion in an aqueous medium, which may form a strong adhesion to the nose and nasal tissue walls and, thereby, result in discomfort in the nasal cavity of the abuser.
  • In some embodiments, it has been shown to be difficult to inject the abuse-deterrent pharmaceutical composition when the viscosity of the composition is at least 46 Pa·s, where the viscosity is measured according to Viscosity Test #1, described in the “Viscosity test” disclosure.
  • In certain embodiments, it has been shown to be difficult to inject the abuse-deterrent pharmaceutical composition when the viscosity of the composition is at least 100 mPa·s, where the viscosity is measured according to “Viscosity Test #2,” described in the “Viscosity test” disclosure.
  • In some embodiments, the abuse-deterrent pharmaceutical compositions, as described herein, may form a gel that resists passage or is difficult to inject through a needle.
  • In further embodiments, the abuse-deterrent pharmaceutical compositions, as described herein, may further include a viscosity increasing agent, such as, for example, a gelling agent, and the like.
    • EXAMPLES
  • Certain embodiments of the disclosure are further illustrated in the following non-limiting examples.
    • Dissolution Test
  • Dissolution tests were performed in accordance with USP 35, NF 30, (711), Apparatus 2 (paddle method). The dissolution medium consisted either of phosphate buffer solution pH 6.8 with/without ethanol or of dilute hydrochloric acid with/without ethanol. The volume of the dissolution medium was 900 ml and the rotation speed of the paddles was 50 rpm or 75 rpm throughout the dissolution run. Samples were withdrawn at suitable time intervals and analysed for content of active drug substance by means of UV-detector or HPLC with UV-detector.
    • Dissolution Test (Immediate Release)
  • For the immediate-release test, the dissolution medium consisted of dilute hydrochloric acid. The volume of the dissolution medium was 900 ml and the rotation speed of the paddles was 75 rpm throughout the dissolution run.
    • Dissolution Test (Controlled Release)
  • For the controlled-release test, the dissolution medium consisted of phosphate buffer solution pH 6.8. The volume of the dissolution medium was 900 ml and the rotation speed of the paddles was 50 rpm throughout the dissolution run.
    • No Alcohol-Induced Dose Dumping Test
  • For the no alcohol-induced dose dumping test, the dissolution medium consisted of phosphate buffer solution pH 6.8 with/without 40% v/v ethanol. The volume of the dissolution medium was 900 ml and the rotation speed of the paddles was 50 rpm throughout the dissolution run.
    • Crisping Test
  • Three (3) whole tablets were placed in a 50 ml glass bottle. The bottle was placed in the center of a microwave oven and heated for a predetermined amount of time (e.g., 8 and 16 minutes) at maximum effect (900 W). Afterwards, 9 ml of purified water was added to the bottle. The bottle was placed on a flatbed laboratory shaker (IKA-Werke HS-501 digital) and was shook continuously (speed 150/min) for 3 days at ambient temperature to dissolve the tablets and to reduce clumping.
    • Viscosity Test
  • Four (4) tablets were weighed and placed in a bottle with 12 ml purified water. The bottle was placed on a flatbed laboratory shaker (IKA-Werke HS-501 digital) and was shook continuously (speed 150/min) for 3 days at ambient temperature to dissolve the tablets and to reduce clumping.
  • Viscosity can be measured using a Brookfield RVDV-E viscometer (Brookfield Engineering, Middleboro, Mass. USA) with spindle number 15 (0.5-1700 Pa·s), a 7R tube, a small sample adapter SC4-45Y and tested in the range of 1, 5, 10 and 20 rpm, respectively, or with spindle number 21 (0.05-170 Pa·s), a 13R tube, and a small sample adapter SC4-45Y at 20 rpm. The temperature was controlled and in the range of 21-22° C.
    • Viscosity Test #1
  • In one viscosity test (Viscosity Test #1), the viscosity can be measured using a Brookfield RVDV-E viscometer (Brookfield Engineering, Middleboro, Mass. USA) with spindle number 15 (0.5-1700 Pa·s), a 7R tube, and a small sample adapter SC4-45Y at 5 rpm. The temperature was controlled and in the range of 21-22° C.
    • Viscosity Test #2
  • In another viscosity test (Viscosity Test #2), the viscosity can be measured using a Brookfield RVDV-E viscometer (Brookfield Engineering, Middleboro, Mass. USA) with spindle number 21 (0.05-170 Pa·s), a 13R tube, and a small sample adapter SC4-45Y at 20 rpm. The temperature was controlled and in the range of 21-22° C.
    • Particle Size Reduction Test
  • Particle size reduction of pharmaceutical compositions was tested using a coffee grinder and/or a nutmeg grater. The methods described herein are used to evaluate the efforts required to reduce the particle size of the pharmaceutical compositions via physical grinding or grating of the tablets.
  • Tablets were ground in either a Moulinex-1411 R coffee grinder with stainless steel blades (model: the original grinder; 50 g -180W AR100G31/6W0) at 10 000-20 000 rpm or a Krups F203 coffee grinder with stainless steel blades (Model: 75 g—200 W F2034210/6W0-1512 R) at 30 000-50 000 rpm for 15 seconds or to no more particle size reduction or equipment failure and, afterwards, analyzed by use of Image Processing. A drawing of the coffee grinder chamber is shown in FIGS. 1 and 2.
  • Tablets were grated by using a nutmeg grater with a stainless steel star blade or a Microplane® grater with stainless steel zester grater or a fine or spice blade for 1½ minutes. A drawing of the nutmeg grater with stainless steel star blade is shown in FIG. 3.
  • The samples were analyzed using an image processing setup comprising a digital SLR with RAW or TIFF capabilities (Canon EOS 350D, resolution 3466×2306 (8MP) or Nikon D3100, resolution 4608×3272 (14.2MP)), a fixed lens (Canon EF 100 mm 1:2:8 USM Macro or Tamron 90 mm 1:2:8 Macro), a stable camera stand, a suitable background for the particles (e.g., a black paper square) and light (to avoid reflections) plus a calibrated light microscopy scale bar from Leitz.
  • A sample was spread onto the black background, and the particles were separated. The position of the camera setup was adjusted and focused such that entire sample was inside the approximate view-area for the camera before pictures were taken.
  • Data were processed by using the software: RawTherapee 3.0.1.0 (Conversion of RAW-files to uncompressed TIFF.), ImageJ 1.45b (Thresholding of TIFF images (binarization) and particle size measuring (data rendering)) and Microsoft Excel 2010 (data analysis).
    • Preparation of Pharmaceutical Compositions
  • A general method for the preparation of a pharmaceutical composition, as disclosed herein, is described below.
  • An accurate amount of the polymer (i.e., in the examples below: polyethylene oxide) is loaded into a MTI mixer followed by an accurate amount of the active drug substance and/or plasticizer and/or other pharmaceutically acceptable excipient(s), if any. The mixing is performed at 900-2000 rpm and at a time period up to 20 min. At the start of the mixing the temperature is about 19-21 ° C. and the final temperature of the mixture is about 30-50 ° C. The mixture is then allowed to cool to room temperature and is ready to be fed into an injection moulding machine. The injection moulding machine used is an Arburg Allrounder 420 C 1000-60/60.
    • Example 1
  • Preparation of a Pharmaceutical Composition Containing PEO 400,000 for Use According to the Disclosure
  • A composition (batch No. 1577-051A) according to the disclosure was prepared from the following ingredients:
  • Composition mg
    PEO 400,000 436.2
    Poloxamer 188 116.3
    Morphine Sulphate 29.1
    Pentahydrate
  • The composition was prepared as described above.
  • The composition was subjected to the dissolution test (controlled release) described above. The results are shown in FIG. 4 as the release of morphine (%) versus time (minutes) in phosphate buffer solution pH 6.8. The release of morphine is shown for intact tablets and ground tablets (ground in a Moulinex-1411 R coffee grinder).
  • The viscosity of the composition was measured as described above. The viscosity was found to be 93 Pa·s at 5 rpm (using Viscosity Test #1).
  • Particle size reduction of the composition was measured as described above. The average particle size was 0.706±1.63 mm and the five largest particles were; 12.1 mm; 3.0 mm; 2.7 mm; 2.2 mm; and 1.9 mm. The results are shown in FIG. 5.
    • Example 2
  • Preparation of a Pharmaceutical Composition Containing PEO 600,000 for Use According to the Disclosure
  • A composition (batch No. 1577-051B) according to the disclosure was prepared from the following ingredients:
  • Composition mg
    PEO 600,000 348
    Poloxamer 188 93
    Oxycodone HCl 23.25
  • The composition was prepared as described above.
  • The composition was subjected to the dissolution test (controlled release) described above. The results are shown in FIG. 6 as the release of oxycodone (%) versus time (minutes) in phosphate buffer solution pH 6.8 with and without 40% v/v ethanol. The release of oxycodone is shown for intact tablets and ground tablets (ground in a Moulinex-1411 R coffee grinder).
  • The viscosity of the composition was measured as described above. The viscosity was found to be 74 Pa·s at 5 rpm (using Viscosity Test #1).
  • Particle size reduction of the composition was measured as described above. The average particle size was 0.455±0.639 mm and the five largest particles were; 12.1 mm; 4.0 mm; 3.9 mm; 3.8 mm; and 3.7 mm. The results are shown in FIG. 7.
    • Example 3
  • Preparation of a Pharmaceutical Compositions Containing PEO 2,000,000 for Use According to the Disclosure
  • A composition (batch No. 1581-065) according to the disclosure was prepared from the following ingredients:
  • Composition mg
    PEO 2,000,000 188
    Poloxamer 188 50.2
    Hydromorphone HCl 12.55
  • The composition was prepared as described above.
  • The composition was subjected to the dissolution test (controlled release) described above. The results are shown in FIG. 8 as the release of hydromorphone (%) versus time (minutes) in phosphate buffer solution pH 6.8 for intact tablets and ground tablets (ground in a Moulinex-1411 R coffee grinder).
  • The viscosity of the compositions was measured as described above. The viscosity was found to be 46 Pa·s at 5 rpm (using Viscosity Test #1).
  • Particle size reduction of the composition was measured as described above. The average particle size was 0.495±0.643 mm and the five largest particles were 10.5 mm; 3.6 mm; 3.6 mm; 3.5 mm; and 3.5 mm. The results are shown in FIG. 9.
    • Example 4
  • Preparation of a Pharmaceutical Composition Containing PEO 10,000,000 According to the Disclosure
  • A composition (batch no. 1581-066) according to the disclosure was prepared from the following ingredients:
  • Composition mg
    PEO 10,000,000 110
    Poloxamer 188 80
    Oxymorphone HCl 10
  • The composition was prepared as described above.
  • The composition was subjected to the dissolution test (controlled release) described above. The results are shown in FIG. 10 as the release of oxymorphone (%) versus time (minutes) in phosphate buffer solution pH 6.8 for intact tablets and ground tablets (ground in a Moulinex-1411 R coffee grinder).
  • The viscosity of the composition was measured as described above. The viscosity was found to be 79.6 Pa·s at 5 rpm (using Viscosity Test #1).
  • Particle size reduction of the composition was measured as described above. The average particle size was 0.547±0.640 mm and the five largest particles were 5.8 mm; 4.8 mm; 4.7 mm; 4.7 mm; and 4.4 mm. The results are shown in FIG. 11.
    • Example 5
  • Oxycontin® OP 40 mg
  • Oxycontin® OP 40 mg was subjected to the dissolution test (controlled release) described above. The results are shown in FIG. 12 as the release of oxycodone (%) versus time (minutes) in phosphate buffer solution pH 6.8 for intact tablets and ground tablets (ground in a Moulinex-1411 R coffee grinder).
  • The viscosity of Oxycontin® OP 40 mg was measured as described above. The viscosity was found to be 46 Pa·s at 5 rpm (using Viscosity Test #1).
  • Particle size reduction of Oxycontin® OP 40 mg was measured as described above. The average particle size was 0.341±0.301 mm and the five largest particles were 3.0 mm; 2.7 mm; 2.7 mm; 2.6 mm; and 2.4 mm. The results are shown in FIG. 13.
    • Example 6
  • Preparation of Morphine Prolonged Release Pharmaceutical Composition for Use According to the Disclosure
  • A 200 mg morphine composition (batch No. 12-0060-067) according to the disclosure was prepared from the following ingredients:
  • Composition Mg
    PEO
    200 000 291.6
    PEO 600 000 291.6
    Morphine Sulphate 197.2
    Pentahydrate
    BHT 0.8
  • The composition was subjected to the no alcohol-induced dose dumping test described above. The results are shown in FIG. 14 as release of morphine (%) versus time (minutes) in phosphate buffer solution pH 6.8 with/without 40% v/v ethanol. The release of morphine is shown for intact tablets.
    • Example 7
  • Crisping Test
  • A 60 mg morphine composition (batch No. 12-066-067) according to the disclosure was prepared from the following ingredients:
  • Composition Mg
    PEO
    200 000 354.3
    PEO 600 000 354.3
    Morphine Sulphate 60
    Pentahydrate
    BHT 0.8
  • The composition was subjected to the crisping test described above. For comparison, MST Continus® 60 mg, Oxycontin® OP 80 mg and Opana® ER 40 mg (containing hydroxypropyl methylcellulose (HPMC)) were subjected to the same crisping test.
  • The composition of MST Continus® and the composition of MS Contin® are identical. MST Continus® is the European trademark and MS Contin® is the American trademark.
  • The results are shown in Table 1 below.
  • TABLE 1
    Morphine MST Oxycontin ®
    Crisping composition
    60 Continus ® OP Opana ®
    (minutes) mg 60 mg 80 mg ER 40 mg
    0 Viscosity >2400 75 >2400 >2400
    (mPas)
    Injectable No Yes No No
    Assay (%) 100 98 99 98
    8 Viscosity >2400 93 60 >2400
    (mPas)
    Injectable No Yes Yes No
    Assay (%) 99 99 99 98
    16 Viscosity >2400 0 0 30
    (mPas)
    Injectable No Yes Yes Yes
    Assay (%) 97 96 73 99
    • Example 8
  • Test of Particle Size Reduction of Pharmaceutical Compositions by Use of a Coffee Grinder
  • A 200 mg morphine composition (batch No. 2654-056) according to the disclosure was prepared from the following ingredients:
  • Composition Mg
    PEO
    200 000 291.6
    PEO 600 000 291.6
    Morphine Sulphate 197.2
    Pentahydrate
    BHT 0.8
  • The composition was subjected to the dissolution test (controlled release) described above. The results are shown in FIG. 15 as the release of active substance (%) versus time (minutes) in phosphate buffer solution pH 6.8. The release of active substance is shown for intact tablets and ground tablets (ground in a Krups F203 coffee grinder). For comparison, MST Continus® 60 mg and Oxycontin® OP 40 mg were subjected to the same test. The results are shown in FIG. 15.
    • Example 9
  • Test of Particle Size Reduction of Pharmaceutical Compositions by Use of a Nutmeg Grater
  • A 200 mg morphine composition (batch No. 2654-056) according to the disclosure was prepared from the following ingredients:
  • Composition Mg
    PEO
    200 000 291.6
    PEO 600 000 291.6
    Morphine Sulphate 197.2
    Pentahydrate
    BHT 0.8
  • The composition was subjected to the dissolution test (immediate release) described above. The results are shown in FIG. 16 as the release of active substance (%) versus time (minutes) in dilute hydrochloric acid. The release of active substance is shown for grated tablets (Nutmeg grater). For comparison, MST Continus® 60 mg, Oxycontin® OP 80 mg and Opana® ER 40 mg were subjected to the same test. The results are shown in FIG. 16.
  • Particle size reduction of the composition was measured as described above. The average particle size was 1.94±2.57 mm and the five largest particles were 21.4 mm; 15.1 mm; 12.8 mm; 8.7 mm; and 7.8 mm. The results are shown in FIG. 17.
  • For comparison, MST Continus® 60 mg, Oxycontin® OP 80 mg and Opana® ER 40 mg were subjected to the same test. For MST Continue 60 mg, the average particle size was 0.410±0.250 mm and the five largest particles were 4.9 mm; 4.7 mm; 4.1 mm; 3.7 mm; and 3.5 mm. For Oxycontin® OP 80 mg, the average particle size was 0.596±0.337 mm and the five largest particles were 5.9 mm; 5.0 mm; 4.3 mm; 3.4 mm; and 3.1 mm. For Opana® ER 40 mg, the average particle size was 0.513±0.489 mm and the five largest particles were 9.4 mm; 8.7 mm; 7.8 mm; 6.8 mm; and 6.4 mm. The results are shown in FIGS. 18-20.
  • The five largest particles were lumps; some were big lumps and also big and flakey.
  • The dimensions of the tablets are shown in Table 2 below.
  • TABLE 2
    Depth, mm
    Length, Height, Width, (convex
    Tablet mm mm mm tablet)
    Morphine composition 19.5 6.2 7.4 N/A
    200 mg
    MST Continus ® 60 mg 7.25 4.5 7.25 N/A
    Oxycontin ® OP 80 mg 9.5 4.25 9.5 N/A
    Opona ® ER 40 mg 8.6 3.5 8.6 0.5
    • Example 10
  • Extraction Test
  • A 60 mg morphine composition (batch No. 12-066-067) according to the disclosure was prepared from the following ingredients:
  • Composition Mg
    PEO
    200 000 354.3
    PEO 600 000 354.3
    Morphine Sulphate 60
    Pentahydrate
    BHT 0.8
  • The composition was subjected to the extraction test described above. Two (2) tablets were placed in a 50 ml beaker, 10 ml solvent (purified water or Coca-Cola®) was added, and the beaker was sealed with Parafilm®. The beaker with tablets was left undisturbed at 25° C./60% RH for 24 hours. The free solvent was poured into a tared empty beaker, the viscosity of the free solvent was measured by the viscosity test as described above (Viscosity Test #2), and the active drug substance content in the free solvent (assay) was determined using HPLC with UV-detector.
  • By comparison, MST Continus® 60 mg, Oxycontin® OP 80 mg, and Opana® ER 40 mg were subjected to the same extraction test.
  • The results of are shown in table 3 below.
  • TABLE 3
    Free
    solvent Assay Viscosity In-
    Formulation (ml) (%) (mPa s) jectable Note
    Morphine composition
    60 mg
    Water 5.8 30.8 >2400 No Tablet shape
    disappeared
    Coca- 3.2 24.4 >2400 No Partly dissolved
    Cola ® the rest having
    a white core
    MST Continus ® 60 mg
    Water 9.3 87.9 0 Yes Intact Spongy
    looking
    Coca- 8.8 92.9 0 Yes Intact Spongy
    Cola ® looking
    Oxycontin ® OP 80 mg
    Water 5.5 36.5 160 Yes Swollen
    transparent
    tablets
    Coca- 5.5 48.4 68 Yes Swollen
    Cola ® transparent
    tablets
    Opana ® ER 40 mg
    Water 5.0 50.1 73 Yes Swollen
    transparent
    tablets
    Coca- 4.6 45.8 105 Yes Swollen
    Cola ® transparent
    tablets

Claims (29)

1-21. (canceled)
22. An abuse-deterrent tablet formulated for oral administration of an opioid, the tablet consisting of a tablet composition and, optionally, a cosmetic coat, wherein:
the tablet composition comprises:
(a) about 1-60% w/w of the opioid; and
(b) about 40-98% w/w of a polyethylene oxide (PEO) selected from the group consisting of (i) a single PEO having an average molecular weight of from about 400,000 daltons to about 900,000 daltons and (ii) two or more PEOs having a combined average molecular weight of from about 400,000 daltons to about 900,000 daltons,
wherein the cosmetic coat, when present, covers at least a portion of the tablet composition, and dissolves within 30 minutes after contact with aqueous media,
wherein the tablet composition exhibits a viscosity of at least 170 mPas when measured by Viscosity Test #2, or a viscosity of at least 46 Pas when measured by Viscosity Test #1, such that the tablet composition, when subjected to a liquid environment, forms a viscous hydrogel that resists passage through a hypodermic needle.
23. The abuse deterrent tablet of claim 22, wherein the opioid is selected from the group consisting of buprenorphine, codeine, dextromoramide, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, morphine, pentazocine, oxycodeine, oxycodone, oxymorphone, norhydrocodone, noroxycodone, morphine-6-glucuronode, tramadol, tapentadol, dihydromorphine, and pharmaceutically acceptable salts thereof.
24. The abuse deterrent tablet of claim 22, wherein the opioid is selected from the group consisting of morphine and pharmaceutically acceptable salts thereof.
25. The abuse deterrent tablet of claim 22, wherein the opioid comprises morphine sulfate.
26. The abuse deterrent tablet of claim 22, wherein the opioid is selected from the group consisting of oxycodone and pharmaceutically acceptable salts thereof.
27. The abuse deterrent tablet of claim 22, wherein the opioid comprises oxycodone hydrochloride.
28. The abuse deterrent tablet of claim 22, wherein the opioid is selected from the group consisting of hydrocodone and pharmaceutically acceptable salts thereof.
29. The abuse deterrent tablet of claim 22, wherein the opioid comprises hydrocodone bitartrate.
30. The abuse deterrent tablet of claim 22, wherein the tablet composition exhibits a release rate of opioid in phosphate buffered saline with 40% v/v ethanol that is equal to or lower than the release rate of opioid in phosphate buffered saline.
31. The abuse deterrent tablet of claim 22, wherein the tablet yields a non-snortable composition when subjected to physical tampering selected from crushing, hammering, grinding, grating, and cutting.
32. The abuse deterrent tablet of claim 22, wherein the tablet composition comprises a single PEO having an average molecular weight of from about 400,000 daltons to about 600,000 daltons.
33. The abuse deterrent tablet of claim 22, wherein the tablet composition comprises a single PEO having an average molecular weight of about 400,000 daltons.
34. The abuse deterrent tablet of claim 22, wherein the tablet composition comprises a single PEO having an average molecular weight of about 600,000 daltons.
35. The abuse deterrent tablet of claim 22, wherein the tablet composition comprises two or more PEOs having a combined average molecular weight of from about 400,000 daltons to about 600,000 daltons.
36. The abuse deterrent tablet of claim 22, wherein the tablet composition comprises two or more PEOs having a combined average molecular weight of about 400,000 daltons.
37. The abuse deterrent tablet of claim 22, wherein the tablet composition comprises two or more PEOs having a combined average molecular weight of about 600,000 daltons.
38. The abuse deterrent tablet of claim 22, wherein the tablet composition comprises a first PEO having an average molecular weight of about 200,000 daltons and a second PEO having an average molecular weight of about 600,000 daltons, wherein the combined average molecular weight of the PEO present in the tablet composition is about 400,000 daltons.
39. The abuse deterrent tablet of claim 22, further comprising at least 1% w/w of a plasticizer.
40. The abuse deterrent tablet of claim 39, wherein the plasticizer is selected from the group consisting of poloxamers having an average molecular weight from about 3,000 to about 30,000 daltons.
41. A method for treating an individual suffering from moderate to severe pain, the method comprising administering to the individual an abuse-deterrent tablet according to claim 22, wherein the tablet composition, when subjected to a liquid environment, forms a viscous hydrogel that resists passage through a hypodermic needle.
42. The method of claim 41, wherein the opioid is selected from morphine and pharmaceutically acceptable salts thereof.
43. The method of claim 41, wherein the opioid comprises morphine sulfate.
44. The method of claim 41, wherein the opioid is selected from oxycodone and pharmaceutically acceptable salts thereof.
45. The method of claim 41, wherein the opioid comprises oxycodone hydrochloride.
46. The method of claim 41, wherein the opioid is selected from hydrocodone and pharmaceutically acceptable salts thereof.
47. The method of claim 41, wherein the opioid comprises hydrocodone bitartrate.
48. The method of claim 41, wherein the method comprises twice daily administration.
49. The method of claim 41, wherein the method comprises once daily administration.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020081762A1 (en) * 2018-10-19 2020-04-23 Temple University-Of The Commonwealth System Of Higher Education Tamper-resistant drug dosage forms and methods of making and use thereof

Families Citing this family (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003024430A1 (en) 2001-09-21 2003-03-27 Egalet A/S Morphine polymer release system
EP2957281A1 (en) 2001-09-21 2015-12-23 Egalet Ltd. Polymer release system
DE602004031096D1 (en) 2003-03-26 2011-03-03 Egalet As MORPHINE SYSTEM WITH CONTROLLED RELEASE
AU2008258596B2 (en) 2007-06-04 2013-02-14 Egalet Ltd Controlled release pharmaceutical compositions for prolonged effect
EP2393484A1 (en) 2009-02-06 2011-12-14 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
CA2766179A1 (en) 2009-06-24 2010-12-29 Egalet Ltd. Controlled release formulations
CA2877183A1 (en) 2012-07-06 2014-01-09 Egalet Ltd. Abuse deterrent pharmaceutical compositions for controlled release
JP6539274B2 (en) * 2013-08-12 2019-07-03 ファーマシューティカル マニュファクチュアリング リサーチ サービシズ，インコーポレーテッド Extruded immediate release abuse deterrent pills
US9770514B2 (en) 2013-09-03 2017-09-26 ExxPharma Therapeutics LLC Tamper-resistant pharmaceutical dosage forms
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
JP6403780B2 (en) * 2013-12-17 2018-10-10 ファーマシューティカル マニュファクチュアリング リサーチ サービシズ，インコーポレーテッド Extruded sustained release abuse deterrence pills
JP6850131B2 (en) 2014-07-03 2021-03-31 スペックジーエックス エルエルシー Abuse-suppressing immediate release formulation containing non-cellulosic polysaccharides
WO2016010771A1 (en) 2014-07-17 2016-01-21 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US9132096B1 (en) * 2014-09-12 2015-09-15 Alkermes Pharma Ireland Limited Abuse resistant pharmaceutical compositions
JP2017531026A (en) 2014-10-20 2017-10-19 ファーマシューティカル マニュファクチュアリング リサーチ サービシズ，インコーポレーテッド Sustained release abuse deterrent liquid filler form
CA3091771A1 (en) 2015-03-13 2016-09-22 The Jackson Laboratory A three-component crispr/cas complex system and uses thereof
US9943513B1 (en) 2015-10-07 2018-04-17 Banner Life Sciences Llc Opioid abuse deterrent dosage forms
WO2017087373A1 (en) * 2015-11-16 2017-05-26 Actavis Elizabeth Llc Modified release abuse deterrent tablet
MX2018008868A (en) * 2016-02-08 2018-09-21 SpecGx LLC Glucomannan containing pharmaceutical compositions with extended release and abuse deterrent properties.
US10335405B1 (en) 2016-05-04 2019-07-02 Patheon Softgels, Inc. Non-burst releasing pharmaceutical composition
WO2018126182A1 (en) 2016-12-31 2018-07-05 Bioxcel Therapeutics, Inc. Use of sublingual dexmedetomidine for the treatment of agitation
US10335375B2 (en) 2017-05-30 2019-07-02 Patheon Softgels, Inc. Anti-overingestion abuse deterrent compositions
EP3473246A1 (en) 2017-10-19 2019-04-24 Capsugel Belgium NV Immediate release abuse deterrent formulations
MX2020005438A (en) * 2017-12-20 2020-12-03 Purdue Pharma Lp Abuse deterrent morphine sulfate dosage forms.
US10624856B2 (en) 2018-01-31 2020-04-21 Dharma Laboratories LLC Non-extractable oral solid dosage forms
BR112020023882A2 (en) 2018-06-27 2021-02-09 Clexio Biosciences Ltd. method to treat major depressive disorder
KR102824967B1 (en) 2018-06-27 2025-06-25 바이오엑셀 테라퓨틱스 인코포레이티드 Film formulation containing dexmedetomidine and method for producing same
CA3112030A1 (en) 2018-09-25 2020-04-02 SpecGx LLC Abuse deterrent immediate release capsule dosage forms
WO2020070706A1 (en) 2018-10-05 2020-04-09 Clexio Biosciences Ltd. Dosage regime of esketamine for treating major depressive disorder
EP3860579A1 (en) 2018-10-05 2021-08-11 Clexio Biosciences Ltd. Dosage regime of esketamine for treating major depressive disorder
WO2020070547A1 (en) 2018-10-05 2020-04-09 Clexio Biosciences Ltd. Dosage regime of esketamine for treating major depressive disorder
EP3863617A1 (en) 2018-10-11 2021-08-18 Clexio Biosciences Ltd. Esketamine for use in treating major depressive disorder
KR20220049526A (en) 2019-07-19 2022-04-21 바이오엑셀 테라퓨틱스 인코포레이티드 Non-sedative dexmedetomidine treatment regimen
WO2021137148A1 (en) 2019-12-30 2021-07-08 Clexio Biosciences Ltd. Dosage regime with esketamine for treating neuropsychiatric or neurological conditions
US12478592B2 (en) 2019-12-30 2025-11-25 Clexio Biosciences Ltd. Dosage regime with esketamine for treating neuropsychiatric or neurological conditions
US12268658B2 (en) 2019-12-30 2025-04-08 Clexio Biosciences Ltd. Dosage regime with esketamine for treating major depressive disorder
KR102461699B1 (en) * 2021-05-21 2022-11-03 현대약품 주식회사 Gargle solution with improved stability comprising benzidamine hydrochloride
US20230230401A1 (en) * 2022-01-14 2023-07-20 Medicircle Inc. Methods and systems for redistributing medication
WO2023168023A1 (en) 2022-03-04 2023-09-07 Reset Pharmaceuticals, Inc. Co-crystals or salts comprising psilocin
US11806334B1 (en) 2023-01-12 2023-11-07 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens
CN117169351A (en) * 2023-04-23 2023-12-05 福建警察学院 In vivo biomarkers screened by 5-MeO-MiPT zebrafish model for new tryptamine psychoactive substances and their applications
US20250082587A1 (en) 2023-09-12 2025-03-13 Clexio Biosciences Ltd. Method Of Treating Major Depressive Disorder

Family Cites Families (268)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2685553A (en) 1951-03-30 1954-08-03 Winthrop Stearns Inc Cement coated tablets
DE2010416B2 (en) 1970-03-05 1979-03-29 Hoechst Ag, 6000 Frankfurt Orally applicable dosage form with sustained release effect
DE2815926A1 (en) 1978-04-13 1979-10-18 Boehringer Mannheim Gmbh NEW CARBAZOLYL- (4) -OXY-PROPANOLAMINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
CA1018456A (en) 1972-06-26 1977-10-04 Hans Lowey Prolonged release lozenges
JPS5518694B2 (en) 1973-04-02 1980-05-21
US4034758A (en) 1975-09-08 1977-07-12 Alza Corporation Osmotic therapeutic system for administering medicament
US4330338A (en) 1978-10-02 1982-05-18 Purdue Research Foundation Pharmaceutical coating composition, and preparation and dosages so coated
US4449983A (en) 1982-03-22 1984-05-22 Alza Corporation Simultaneous delivery of two drugs from unit delivery device
US4389393A (en) 1982-03-26 1983-06-21 Forest Laboratories, Inc. Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose
DE3320583A1 (en) 1983-06-08 1984-12-13 Dr. Karl Thomae Gmbh, 7950 Biberach NEW GALENIC PREPARATION FORMS OF ORAL ANTIDIABETICS AND METHOD FOR THE PRODUCTION THEREOF
AU591171B2 (en) 1983-11-02 1989-11-30 Alza Corporation Dispenser for delivering thermo-responsive composition
US4844984A (en) 1984-03-19 1989-07-04 Alza Corporation Dispensing system with means for increasing delivery of beneficial agent from the system
JPH0246008B2 (en) 1984-06-01 1990-10-12 Takada Seiyaku Kk NIFUEJIPINJIZOKUSEISEIZAINOSEIZOHOHO
GB2170104A (en) 1985-01-30 1986-07-30 Warner Lambert Co Coated pharmaceutical dosage forms
IE59066B1 (en) 1985-02-19 1993-12-15 Key Pharma Controlled release potassium chloride
US4898733A (en) 1985-11-04 1990-02-06 International Minerals & Chemical Corp. Layered, compression molded device for the sustained release of a beneficial agent
US4892742A (en) 1985-11-18 1990-01-09 Hoffmann-La Roche Inc. Controlled release compositions with zero order release
US4824675A (en) 1987-07-13 1989-04-25 Alza Corporation Dispenser with movable matrix comprising a plurality of tiny pills
WO1989009066A1 (en) 1988-03-24 1989-10-05 Bukh Meditec A/S Controlled release composition
FI101344B1 (en) 1988-03-31 1998-06-15 Tanabe Seiyaku Co Process for the preparation of a composition for controlled release of a pharmaceutically active substance
JPH07100191B2 (en) 1989-01-04 1995-11-01 古河電気工業株式会社 Blanking method
FI913608A7 (en) 1989-01-30 1991-07-29 Alza Corp Dosage form for administering a calcium antagonist
US5019396A (en) 1989-05-12 1991-05-28 Alza Corporation Delivery dispenser for treating cardiac arrhythmias
DK469989D0 (en) 1989-09-22 1989-09-22 Bukh Meditec PHARMACEUTICAL PREPARATION
IT1237904B (en) 1989-12-14 1993-06-18 Ubaldo Conte CONTROLLED SPEED RELEASE TABS OF ACTIVE SUBSTANCES
DE69014092T2 (en) 1989-12-29 1995-06-01 Bristol Myers Squibb Co Combination of a capsule and a capsule.
US5102668A (en) 1990-10-05 1992-04-07 Kingaform Technology, Inc. Sustained release pharmaceutical preparation using diffusion barriers whose permeabilities change in response to changing pH
GB9025372D0 (en) 1990-11-22 1991-01-09 Nat Res Dev Pharmaceutical dosage forms
GB9101502D0 (en) 1991-01-23 1991-03-06 Controlled Therapeutics Sct Controlled release compositions
US5656295A (en) 1991-11-27 1997-08-12 Euro-Celtique, S.A. Controlled release oxycodone compositions
US5266331A (en) 1991-11-27 1993-11-30 Euroceltique, S.A. Controlled release oxycodone compositions
US5968551A (en) 1991-12-24 1999-10-19 Purdue Pharma L.P. Orally administrable opioid formulations having extended duration of effect
US5478577A (en) 1993-11-23 1995-12-26 Euroceltique, S.A. Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level
SE9202250D0 (en) 1992-07-29 1992-07-29 Gacell Lab Ab CONTROLLED RELEASE MORPHINE PREPARATION
US5609885A (en) 1992-09-15 1997-03-11 Alza Corporation Osmotic membrane and delivery device
US5869097A (en) 1992-11-02 1999-02-09 Alza Corporation Method of therapy comprising an osmotic caplet
US5881926A (en) 1993-03-11 1999-03-16 Taro Pharmaceutical Industries, Ltd. Pharmaceutical compositions in semisolid form and a device for administration thereof
US5656291A (en) 1994-03-16 1997-08-12 Pharmacia & Upjohn Aktiebolag Controlled release preparation
SE9301057L (en) 1993-03-30 1994-10-01 Pharmacia Ab Controlled release preparation
IL110014A (en) 1993-07-01 1999-11-30 Euro Celtique Sa Solid controlled-release oral dosage forms of opioid analgesics
US5879705A (en) 1993-07-27 1999-03-09 Euro-Celtique S.A. Sustained release compositions of morphine and a method of preparing pharmaceutical compositions
US6183778B1 (en) 1993-09-21 2001-02-06 Jagotec Ag Pharmaceutical tablet capable of liberating one or more drugs at different release rates
US5419917A (en) 1994-02-14 1995-05-30 Andrx Pharmaceuticals, Inc. Controlled release hydrogel formulation
AU1806895A (en) 1994-02-23 1995-09-11 Bm Research A/S Controlled release composition
US5411745A (en) 1994-05-25 1995-05-02 Euro-Celtique, S.A. Powder-layered morphine sulfate formulations
US7060293B1 (en) 1994-05-25 2006-06-13 Purdue Pharma Powder-layered oral dosage forms
US6077533A (en) 1994-05-25 2000-06-20 Purdue Pharma L.P. Powder-layered oral dosage forms
US5460826A (en) 1994-06-27 1995-10-24 Alza Corporation Morphine therapy
US6491945B1 (en) 1994-09-16 2002-12-10 Alza Corporation Hydrocodone therapy
US5965161A (en) 1994-11-04 1999-10-12 Euro-Celtique, S.A. Extruded multi-particulates
IL139728A (en) 1995-01-09 2003-06-24 Penwest Pharmaceuticals Compan Aqueous slurry composition containing microcrystalline cellulose for preparing a pharmaceutical excipient
ATE268591T1 (en) 1995-06-27 2004-06-15 Takeda Chemical Industries Ltd METHOD FOR PRODUCING DELAYED RELEASE PREPARATIONS
GB9519363D0 (en) 1995-09-22 1995-11-22 Euro Celtique Sa Pharmaceutical formulation
US6245351B1 (en) 1996-03-07 2001-06-12 Takeda Chemical Industries, Ltd. Controlled-release composition
ES2168610T3 (en) 1996-03-12 2002-06-16 Alza Corp COMPOSITION AND GALENIC FORM CONTAINING AN OPIOID ANTAGONIST.
DE69739215D1 (en) 1996-05-20 2009-03-05 Otsuka Pharma Co Ltd CURE FOR ROSAZLA
US6348216B1 (en) 1996-06-10 2002-02-19 Knoll Pharmaceutical Company Ibuprofen and narcotic analgesic compositions
US6361794B1 (en) 1996-06-12 2002-03-26 Basf Corporation Method of making ibuprofen and narcotic analgesic composition
AU3691297A (en) 1996-08-15 1998-03-06 Losan Pharma Gmbh Easy to swallow oral medicament composition
US5948787A (en) 1997-02-28 1999-09-07 Alza Corporation Compositions containing opiate analgesics
US6046177A (en) 1997-05-05 2000-04-04 Cydex, Inc. Sulfoalkyl ether cyclodextrin based controlled release solid pharmaceutical formulations
EP0999830A1 (en) 1997-07-01 2000-05-17 Pfizer Inc. Sertraline salts and sustained-release dosage forms of sertraline
US6730326B2 (en) 1997-07-22 2004-05-04 Roche Diagnostics Gmbh Thermodynamically stable modification of 1-(4-carbazolyl-oxy-3[2-(2-methoxyphenoxy)-ethylamino]-2-propanol process for its preparation and pharmaceutical compositions containing it
US6607751B1 (en) 1997-10-10 2003-08-19 Intellipharamaceutics Corp. Controlled release delivery device for pharmaceutical agents incorporating microbial polysaccharide gum
US6066339A (en) 1997-10-17 2000-05-23 Elan Corporation, Plc Oral morphine multiparticulate formulation
US20020054911A1 (en) 2000-05-11 2002-05-09 Boehringer Mannheim Pharmaceutical Corporation-Sm Ithkline Beckman Corporation, Limited Partnershi Novel oral dosage form for carvedilol
US6375957B1 (en) 1997-12-22 2002-04-23 Euro-Celtique, S.A. Opioid agonist/opioid antagonist/acetaminophen combinations
EP1685839B8 (en) 1997-12-22 2013-06-26 Euro-Celtique S.A. Pharmaceutical oral dosage form comprising a combination of an opioid agonist and opioid antagonist
FR2774910B1 (en) 1998-02-16 2001-09-07 Ethypharm Lab Prod Ethiques MORPHINE SULFATE MICROGRANULES, METHOD OF MANUFACTURE AND PHARMACEUTICAL PREPARATIONS
US8524277B2 (en) 1998-03-06 2013-09-03 Alza Corporation Extended release dosage form
US6245357B1 (en) 1998-03-06 2001-06-12 Alza Corporation Extended release dosage form
US6350470B1 (en) 1998-04-29 2002-02-26 Cima Labs Inc. Effervescent drug delivery system for oral administration
DK1067910T3 (en) 1998-04-03 2004-10-04 Egalet As Controlled release composition
US7906143B1 (en) 1998-10-05 2011-03-15 Intellipharmaceutics Corp Controlled release pharmaceutical delivery device and process for preparation thereof
US20080102121A1 (en) 1998-11-02 2008-05-01 Elan Pharma International Limited Compositions comprising nanoparticulate meloxicam and controlled release hydrocodone
US20080113025A1 (en) 1998-11-02 2008-05-15 Elan Pharma International Limited Compositions comprising nanoparticulate naproxen and controlled release hydrocodone
DE60042352D1 (en) 1999-02-10 2009-07-23 Pfizer Prod Inc Osmotic system for administering active substances containing solid amorphous dispersions
IL138990A0 (en) 1999-02-12 2001-11-25 Biostream Inc Matrices for drug delivery and methods for making and using the same
US6267985B1 (en) 1999-06-30 2001-07-31 Lipocine Inc. Clear oil-containing pharmaceutical compositions
US6383471B1 (en) 1999-04-06 2002-05-07 Lipocine, Inc. Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents
FR2794646B1 (en) 1999-06-09 2001-09-21 Ethypharm Lab Prod Ethiques MORPHINE SULFATE MICROGRANULES, METHOD OF PREPARATION AND COMPOSITION CONTAINING THEM
US6225343B1 (en) 1999-06-16 2001-05-01 Nastech Pharmaceutical Company, Inc. Compositions and methods comprising morphine gluconate
US20030118641A1 (en) 2000-07-27 2003-06-26 Roxane Laboratories, Inc. Abuse-resistant sustained-release opioid formulation
US6562375B1 (en) 1999-08-04 2003-05-13 Yamanouchi Pharmaceuticals, Co., Ltd. Stable pharmaceutical composition for oral use
US6534085B1 (en) 1999-09-23 2003-03-18 Bioresponse L.L.C. Phytochemicals for promoting weight loss
JP4806507B2 (en) 1999-10-29 2011-11-02 ユーロ−セルティーク エス．エイ． Controlled release hydrocodone formulation
CA2392085A1 (en) 1999-11-15 2001-05-25 Smithkline Beecham Corporation Carvedilol methanesulfonate
US6458824B1 (en) 1999-11-30 2002-10-01 Dainippon Pharmaceutical Co., Ltd. Solid preparation
US6491949B2 (en) 2000-01-14 2002-12-10 Osmotica Corp. Osmotic device within an osmotic device
US6352721B1 (en) 2000-01-14 2002-03-05 Osmotica Corp. Combined diffusion/osmotic pumping drug delivery system
AR028253A1 (en) 2000-03-16 2003-04-30 Pfizer Prod Inc INHIBITORS OF THE GLUCOGENO FOSFORILASA
EP1272180B1 (en) 2000-04-03 2004-09-29 F. Hoffmann-La Roche Ag Concentrated solutions of carvedilol
US20010036959A1 (en) 2000-04-03 2001-11-01 Gabel Rolf Dieter Carvedilol-hydrophilic solutions
US6488962B1 (en) 2000-06-20 2002-12-03 Depomed, Inc. Tablet shapes to enhance gastric retention of swellable controlled-release oral dosage forms
CA2426811A1 (en) 2000-10-24 2002-08-29 Smithkline Beecham Corporation Novel formulations of carvedilol
MXPA03003895A (en) 2000-10-30 2003-07-28 Euro Celtique Sa Controlled release hydrocodone formulations.
ES2240313T3 (en) 2000-12-07 2005-10-16 Warner-Lambert Company Llc PROCEDURE AND SYSTEM FOR THE UNIFORM RELEASE OF A PHARMACO.
US6800668B1 (en) 2001-01-19 2004-10-05 Intellipharmaceutics Corp. Syntactic deformable foam compositions and methods for making
US20110104214A1 (en) 2004-04-15 2011-05-05 Purdue Pharma L.P. Once-a-day oxycodone formulations
UA81224C2 (en) 2001-05-02 2007-12-25 Euro Celtic S A Dosage form of oxycodone and use thereof
IN191028B (en) 2001-05-17 2003-09-13 Sun Pharmaceutical Ind Ltd
US7144587B2 (en) 2001-08-06 2006-12-05 Euro-Celtique S.A. Pharmaceutical formulation containing opioid agonist, opioid antagonist and bittering agent
US20030068375A1 (en) 2001-08-06 2003-04-10 Curtis Wright Pharmaceutical formulation containing gelling agent
US7332182B2 (en) 2001-08-06 2008-02-19 Purdue Pharma L.P. Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant
US7842307B2 (en) 2001-08-06 2010-11-30 Purdue Pharma L.P. Pharmaceutical formulation containing opioid agonist, opioid antagonist and gelling agent
KR20040025741A (en) * 2001-08-06 2004-03-25 유로-셀티크 소시에떼 아노뉨 Compositions and methods to prevent abuse of opioids
DK1429734T3 (en) 2001-09-21 2008-05-13 Egalet As Solid dispersions of carvedilol for controlled release
WO2003024430A1 (en) 2001-09-21 2003-03-27 Egalet A/S Morphine polymer release system
EP2957281A1 (en) 2001-09-21 2015-12-23 Egalet Ltd. Polymer release system
CN1592610A (en) 2001-09-28 2005-03-09 麦克内尔-Ppc股份有限公司 Modified release dosage forms
US20060039958A1 (en) 2003-05-28 2006-02-23 Monosolrx, Llc. Multi-layer films having uniform content
US20070281003A1 (en) 2001-10-12 2007-12-06 Fuisz Richard C Polymer-Based Films and Drug Delivery Systems Made Therefrom
US7666337B2 (en) 2002-04-11 2010-02-23 Monosol Rx, Llc Polyethylene oxide-based films and drug delivery systems made therefrom
US8765167B2 (en) 2001-10-12 2014-07-01 Monosol Rx, Llc Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions
US8603514B2 (en) 2002-04-11 2013-12-10 Monosol Rx, Llc Uniform films for rapid dissolve dosage form incorporating taste-masking compositions
ITMI20012366A1 (en) 2001-11-09 2003-05-09 Farmatron Ltd THERAPEUTIC SYSTEMS STABILIZED WITH IMMEDIATE RELEASE AND / OR MODIFIED FOR THE ORAL ADMINISTRATION OF ACTIVE AND / OR EXCIPIENT PRINCIPLES AND / OR WINGS
EP1471891A4 (en) 2002-02-08 2007-04-11 Alkermes Inc POLYMER-BASED COMPOSITIONS FOR PROLONGED RELEASE
ITMI20020514A1 (en) 2002-03-12 2003-09-12 Jagotec Ag THERAPEUTIC SYSTEM FOR THE CONTROLLED RELEASE OF ONE OR MORE ACTIVE PRINCIPLES
US20030203055A1 (en) 2002-03-15 2003-10-30 Cypress Bioscience, Inc. Methods of treating visceral pain syndromes
EP1578350B1 (en) 2002-03-26 2009-05-27 Euro-Celtique S.A. Sustained-release gel coated compositions
US8017150B2 (en) 2002-04-11 2011-09-13 Monosol Rx, Llc Polyethylene oxide-based films and drug delivery systems made therefrom
CN1665482A (en) 2002-04-29 2005-09-07 阿尔扎公司 Methods and dosage forms for controlled delivery of oxycodone
US20050106249A1 (en) 2002-04-29 2005-05-19 Stephen Hwang Once-a-day, oral, controlled-release, oxycodone dosage forms
DE10223844B4 (en) 2002-05-28 2013-04-04 Danfoss A/S Water hydraulic machine
CN1671358A (en) 2002-05-31 2005-09-21 阿尔扎公司 Dosage forms and compositions for osmotic delivery of variable dosages of oxycodone
AR039744A1 (en) 2002-06-26 2005-03-09 Alza Corp METHODS AND DOSAGE FORMS TO INCREASE THE SOLUBILITY OF PHARMACOS COMPOSITIONS FOR CONTROLLED ADMINISTRATION
US6632832B1 (en) 2002-09-10 2003-10-14 Dabur Research Foundation Anti-cancer activity of carvedilol and its isomers
US20040151772A1 (en) 2002-11-08 2004-08-05 Egalet A/S Controlled release carvedilol compositions
US20040089605A1 (en) 2002-11-08 2004-05-13 Harry Brandt Reverse osmosis liquid purification system and method
US20040102476A1 (en) 2002-11-25 2004-05-27 Chan Tai Wah High concentration formulations of opioids and opioid derivatives
PT2218448E (en) 2002-12-13 2016-01-26 Durect Corp Oral drug delivery system comprising high viscosity liquid carrier materials
US20040224020A1 (en) 2002-12-18 2004-11-11 Schoenhard Grant L. Oral dosage forms with therapeutically active agents in controlled release cores and immediate release gelatin capsule coats
ATE454886T1 (en) 2003-03-26 2010-01-15 Egalet As MATRIX PREPARATIONS FOR THE CONTROLLED PRESENTATION OF MEDICINAL MEDICINAL PRODUCTS
DE602004031096D1 (en) 2003-03-26 2011-03-03 Egalet As MORPHINE SYSTEM WITH CONTROLLED RELEASE
US20040202717A1 (en) 2003-04-08 2004-10-14 Mehta Atul M. Abuse-resistant oral dosage forms and method of use thereof
WO2004093819A2 (en) 2003-04-21 2004-11-04 Euro-Celtique, S.A. Tamper resistant dosage form comprising co-extruded, adverse agent particles and process of making same
PL1631251T3 (en) 2003-04-24 2011-12-30 Jagotec Ag Delayed release tablet with defined core geometry
US20060177507A1 (en) 2003-05-22 2006-08-10 Joaquina Faour Controlled release device containing lercanidipine
US8029822B2 (en) 2003-05-22 2011-10-04 Osmotica Kereskedelmi és Seolgáltató KFT Rupturing controlled release device having a preformed passageway
CN102670568A (en) 2003-05-28 2012-09-19 莫诺索尔克斯有限公司 Polyethylene oxide-based films and drug delivery systems made therefrom
TWI357815B (en) 2003-06-27 2012-02-11 Euro Celtique Sa Multiparticulates
US20060165790A1 (en) 2003-06-27 2006-07-27 Malcolm Walden Multiparticulates
EP1646367A4 (en) 2003-07-21 2011-06-15 Nesher Solutions Ltd Gellan gum based oral controlled release dosage forms- a novel platform technology for gastric retention
US8075872B2 (en) 2003-08-06 2011-12-13 Gruenenthal Gmbh Abuse-proofed dosage form
DE10336400A1 (en) 2003-08-06 2005-03-24 Grünenthal GmbH Anti-abuse dosage form
DE10361596A1 (en) 2003-12-24 2005-09-29 Grünenthal GmbH Process for producing an anti-abuse dosage form
US20070048228A1 (en) 2003-08-06 2007-03-01 Elisabeth Arkenau-Maric Abuse-proofed dosage form
JP4939217B2 (en) 2003-08-06 2012-05-23 グリューネンタ−ル・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Abuse prevention dosage form
DE102004020220A1 (en) 2004-04-22 2005-11-10 Grünenthal GmbH Process for the preparation of a secured against misuse, solid dosage form
DE102005005446A1 (en) 2005-02-04 2006-08-10 Grünenthal GmbH Break-resistant dosage forms with sustained release
DE102004032051A1 (en) 2004-07-01 2006-01-19 Grünenthal GmbH Process for the preparation of a secured against misuse, solid dosage form
US20050053655A1 (en) 2003-09-05 2005-03-10 Pharmaceutical Industry Technology And Development Center Rapid disintegrating tablets (RDTs) for pharmaceutical use and method for preparing the same
WO2005027878A1 (en) 2003-09-19 2005-03-31 Penwest Pharmaceuticals Co. Delayed released dosage forms
KR20120106757A (en) 2003-09-26 2012-09-26 알자 코포레이션 Controlled release formulations of opioid and nonopioid analgesics
US20050074493A1 (en) 2003-10-03 2005-04-07 Mehta Atul M. Extended release formulations of opioids and method of use thereof
US7201920B2 (en) 2003-11-26 2007-04-10 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of opioid containing dosage forms
US8883204B2 (en) 2003-12-09 2014-11-11 Purdue Pharma L.P. Tamper resistant co-extruded dosage form containing an active agent and an adverse agent and process of making same
ES2293143T3 (en) 2003-12-17 2008-03-16 Ksb Aktiengesellschaft PRESSURE CHANGING SYSTEM.
CA2550866A1 (en) 2003-12-23 2005-07-14 Alza Corporation Methods and dosage forms for increasing solubility of drug compositions for controlled delivery
WO2005065654A2 (en) 2003-12-31 2005-07-21 Alpharma, Inc. Rosiglitazone formulations
EP1740156B8 (en) 2004-04-22 2012-07-11 Grünenthal GmbH Method for the production of an abuse-proof, solid form of administration
CA2566793C (en) 2004-05-11 2013-07-16 Egalet A/S A novel dosage form
ES2653568T3 (en) 2004-06-12 2018-02-07 Collegium Pharmaceutical, Inc. Drug formulations for abuse prevention
BRPI0513300B1 (en) 2004-07-01 2018-11-06 Gruenenthal Gmbh oral dosage form, protected from abuse, containing (1r, 2r) -3- (3-dimethylamino-1-ethyl-2-methyl-lpropyl) -phenol
DE102004032049A1 (en) 2004-07-01 2006-01-19 Grünenthal GmbH Anti-abuse, oral dosage form
PL1765303T5 (en) 2004-07-01 2023-05-22 Grünenthal GmbH Oral dosage form safeguarded against abuse
EP1765298B1 (en) 2004-07-01 2012-10-24 Gruenenthal Gmbh Method for producing a solid dosage form, which is safeguarded against abuse, while using a planetary gear extruder
DE102004032103A1 (en) 2004-07-01 2006-01-19 Grünenthal GmbH Anti-abuse, oral dosage form
DE102004038440A1 (en) 2004-08-07 2006-03-16 Ksb Aktiengesellschaft Variable speed pressure exchanger
US7214315B2 (en) 2004-08-20 2007-05-08 Scott Shumway Pressure exchange apparatus with integral pump
US20070281007A1 (en) 2004-08-27 2007-12-06 Jacob Jules S Mucoadhesive Oral Formulations of High Permeability, High Solubility Drugs
WO2006030402A2 (en) 2004-09-17 2006-03-23 Ranbaxy Laboratories Limited Dual compartment osmotic delivery device
US20080152595A1 (en) 2004-11-24 2008-06-26 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products
US20060110327A1 (en) 2004-11-24 2006-05-25 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products
US20070231268A1 (en) 2004-11-24 2007-10-04 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products
US20060177380A1 (en) 2004-11-24 2006-08-10 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products
FR2889810A1 (en) 2005-05-24 2007-02-23 Flamel Technologies Sa ORAL MEDICINAL FORM, MICROPARTICULAR, ANTI-MEASUREMENT
FR2881652B1 (en) 2005-02-08 2007-05-25 Flamel Technologies Sa MICROPARTICULAR ORAL PHARMACEUTICAL FORM ANTI-MEASURING
WO2006088305A1 (en) 2005-02-15 2006-08-24 Chong Kun Dang Pharmaceutical Corp. Gastric-retentive controlled release mono-matrix tablet
US20060193911A1 (en) 2005-02-28 2006-08-31 Penwest Pharmaceuticals Co., Controlled release venlafaxine formulations
KR20080002788A (en) 2005-03-28 2008-01-04 오렉쏘 에이비 Pharmaceutical composition for the treatment of pain
GB0506982D0 (en) 2005-04-06 2005-05-11 Mw Encap Ltd Abuse resistant capsules
CN101188999B (en) 2005-06-03 2012-07-18 尹格莱特股份有限公司 Drug delivery system for delivering active substances dispersed in a dispersion medium
PE20070325A1 (en) 2005-06-29 2007-05-12 Alza Corp ORAL DOSAGE FORMS THAT INCLUDE CARBAMATE-DERIVED COMPOUNDS
US8858993B2 (en) 2005-07-25 2014-10-14 Metrics, Inc. Coated tablet with zero-order or near zero-order release kinetics
US20080166407A1 (en) 2005-07-29 2008-07-10 Shalaby Shalaby W Solid oral formulations for combination therapy
CA2621263A1 (en) 2005-09-09 2007-03-15 Garry L. Myers Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions
PL116330U1 (en) 2005-10-31 2007-04-02 Alza Corp Method for the reduction of alcohol provoked rapid increase in the released dose of the orally administered opioide with prolonged liberation
US8652529B2 (en) 2005-11-10 2014-02-18 Flamel Technologies Anti-misuse microparticulate oral pharmaceutical form
WO2007085024A2 (en) 2006-01-21 2007-07-26 Abbott Gmbh & Co. Kg Dosage form and method for the delivery of drugs of abuse
US20100172989A1 (en) 2006-01-21 2010-07-08 Abbott Laboratories Abuse resistant melt extruded formulation having reduced alcohol interaction
US20090022798A1 (en) 2007-07-20 2009-01-22 Abbott Gmbh & Co. Kg Formulations of nonopioid and confined opioid analgesics
US20090317355A1 (en) 2006-01-21 2009-12-24 Abbott Gmbh & Co. Kg, Abuse resistant melt extruded formulation having reduced alcohol interaction
US20070264346A1 (en) 2006-02-16 2007-11-15 Flamel Technologies Multimicroparticulate pharmaceutical forms for oral administration
ZA200807571B (en) 2006-03-01 2009-08-26 Ethypharm Sa Crush-resistant tablets intended to prevent accidental misuse and unlawful diversion
EP1993519A4 (en) 2006-03-15 2011-12-21 Acura Pharmaceuticals Inc Methods and compositions for deterring abuse of orally administered pharmaceutical products
ES2378573T3 (en) 2006-03-16 2012-04-16 Tris Pharma, Inc. Modified release formulations containing ion exchange drug-resin complexes
WO2007112285A2 (en) 2006-03-24 2007-10-04 Auxilium Pharmaceuticals, Inc. Process for the preparation of a hot-melt extruded laminate
JP5536446B2 (en) 2006-03-24 2014-07-02 オクシリウム インターナショナル ホールディングス，インコーポレイティド Stabilized composition comprising an alkali labile drug
PL2457562T3 (en) 2006-05-09 2017-09-29 Mallinckrodt Llc Zero-order modified release solid dosage forms
US10960077B2 (en) 2006-05-12 2021-03-30 Intellipharmaceutics Corp. Abuse and alcohol resistant drug composition
US9023400B2 (en) 2006-05-24 2015-05-05 Flamel Technologies Prolonged-release multimicroparticulate oral pharmaceutical form
FR2901478B1 (en) 2006-05-24 2015-06-05 Flamel Tech Sa MULTIMICROPARTICULATED ORAL PHARMACEUTICAL FORM WITH PROLONGED RELEASE
US20080069891A1 (en) 2006-09-15 2008-03-20 Cima Labs, Inc. Abuse resistant drug formulation
CA2660650A1 (en) 2006-06-23 2007-12-27 Elan Pharma International Limited Compositions comprising nanoparticulate meloxicam and controlled release hydrocodone
KR20090024284A (en) 2006-06-23 2009-03-06 엘란 파마 인터내셔널 리미티드 Compositions Comprising Nanoparticulate Naproxen and Controlled-Release Hydrocodone
EP2046285B1 (en) 2006-08-04 2018-02-21 Ethypharm Granule and orally disintegrating tablet comprising oxycodone
SA07280459B1 (en) * 2006-08-25 2011-07-20 بيورديو فارما إل. بي. Tamper Resistant Oral Pharmaceutical Dosage Forms Comprising an Opioid Analgesic
WO2008028047A2 (en) 2006-08-30 2008-03-06 Lab International Srl Bioadhesive film drug delivery system
WO2008027442A2 (en) 2006-08-30 2008-03-06 Theraquest Biosciences, Llc Abuse deterrent oral pharmaceutical formulations of opioid agonists and method of use
US8445018B2 (en) 2006-09-15 2013-05-21 Cima Labs Inc. Abuse resistant drug formulation
US8211905B1 (en) 2007-05-22 2012-07-03 Pisgah Laboratories, Inc. Opioid salts and formulations exhibiting anti-abuse and anti-dose dumping properties
DE102006057364B4 (en) 2006-12-04 2011-08-25 Danfoss A/S Water hydraulic machine
WO2008068471A1 (en) 2006-12-04 2008-06-12 Orexo Ab New non-abusable pharmaceutical composition comprising opioids
EP2104493A2 (en) * 2007-01-16 2009-09-30 Egalet A/S Use of i) a polyglycol and n) an active drug substance for the preparation of a pharmaceutical composition for i) mitigating the risk of alcohol induced dose dumping and/or ii) reducing the risk of drug abuse
DE102007011485A1 (en) 2007-03-07 2008-09-11 Grünenthal GmbH Dosage form with more difficult abuse
US8329720B1 (en) 2007-05-22 2012-12-11 Pisgah Laboratories, Inc. Opioid salts and formulations exhibiting abuse deterrent and anti-dose dumping properties
AU2008258596B2 (en) 2007-06-04 2013-02-14 Egalet Ltd Controlled release pharmaceutical compositions for prolonged effect
ES2611794T3 (en) 2007-09-13 2017-05-10 Cima Labs Inc. Formulation of drugs resistant to abuse
EP2219622A1 (en) 2007-12-06 2010-08-25 Durect Corporation Methods useful for the treatment of pain, arthritic conditions, or inflammation associated with a chronic condition
AU2008335360A1 (en) 2007-12-06 2009-06-18 Pain Therapeutics, Inc. Micronized opioid compositions, formulations and dosage forms and methods of making same
WO2009076764A1 (en) 2007-12-17 2009-06-25 Labopharm Inc. Misuse preventative, controlled release formulation
MX2010008138A (en) 2008-01-25 2010-08-10 Gruenenthal Gmbh Pharmaceutical dosage form.
KR101094231B1 (en) 2008-02-18 2011-12-14 하나제약 주식회사 Sustained release solid preparations and preparation methods thereof
MX2010009990A (en) 2008-03-11 2010-12-15 Depomed Inc Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic.
US8372432B2 (en) 2008-03-11 2013-02-12 Depomed, Inc. Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic
EP2361082A1 (en) 2008-08-14 2011-08-31 Bar-Shalom, Daniel Coated tablets with a remaining degradation surface over the time
DE102008044869A1 (en) 2008-08-29 2010-03-04 Danfoss A/S Reverse osmosis device
NZ592276A (en) 2008-09-18 2012-12-21 Purdue Pharma Lp PHARMACEUTICAL DOSAGE FORMS COMPRISING POLY(epsilon-CAPROLACTONE) AND AN OPIOID
WO2010066034A1 (en) 2008-12-12 2010-06-17 Paladin Labs Inc. Methadone formulation
ES2509497T3 (en) 2008-12-16 2014-10-17 Paladin Labs Inc. Controlled release formulation to prevent misuse
EP2389169A1 (en) 2009-01-26 2011-11-30 Egalet A/S Controlled release formulations with continuous efficacy
EP2393487B1 (en) 2009-02-06 2016-11-02 Egalet Ltd. Pharmaceutical compositions resistant to abuse
EP2393484A1 (en) 2009-02-06 2011-12-14 Egalet Ltd. Immediate release composition resistant to abuse by intake of alcohol
GB0909680D0 (en) 2009-06-05 2009-07-22 Euro Celtique Sa Dosage form
CA2766179A1 (en) 2009-06-24 2010-12-29 Egalet Ltd. Controlled release formulations
WO2010151741A1 (en) 2009-06-25 2010-12-29 Elite Laboratories, Inc. Abuse resistant oral dosage forms
CA2765971C (en) 2009-07-22 2017-08-22 Gruenenthal Gmbh Hot-melt extruded controlled release dosage form
EP2456425B1 (en) * 2009-07-22 2015-10-21 Grünenthal GmbH Tamper-resistant dosage form for oxidation-sensitive opioids
EP2488029B1 (en) 2009-09-30 2016-03-23 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse
WO2011079074A1 (en) 2009-12-24 2011-06-30 Acura Phamaceuticals, Inc. Pharmaceutical compositions for deterring misuse, abuse, and diversion
US20120321674A1 (en) 2011-02-17 2012-12-20 Michael Vachon Technology for Preventing Abuse of Solid Dosage Forms
US20130022646A1 (en) 2010-02-09 2013-01-24 Rudnic Edward M Controlled Release Formulations of Opioids
US20110195989A1 (en) 2010-02-09 2011-08-11 Rudnic Edward M Controlled Release Formulations of Opioids
MX347753B (en) 2010-02-24 2017-05-10 Cima Labs Inc Abuse-resistant formulations.
KR20130137627A (en) 2010-09-02 2013-12-17 그뤼넨탈 게엠베하 Tamper resistant dosage form comprising an anionic polymer
CN103179956A (en) 2010-09-02 2013-06-26 格吕伦塔尔有限公司 Shatter-resistant dosage forms containing anionic polymers
EP2611426B1 (en) 2010-09-02 2014-06-25 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
JP2013537915A (en) 2010-09-24 2013-10-07 キューアールエックスファーマ リミテッド Opioid controlled release formulations
US20120202838A1 (en) 2010-11-04 2012-08-09 Abbott Laboratories Drug formulations
GB201020895D0 (en) 2010-12-09 2011-01-26 Euro Celtique Sa Dosage form
US9233076B2 (en) 2010-12-13 2016-01-12 Purdue Pharma L.P. Controlled release dosage forms
DK2826467T3 (en) 2010-12-22 2017-10-16 Purdue Pharma Lp INCLUDED, MANIPULATION-PROPOSED SLOW-DELIVERY DOSAGE FORMS
PH12013501345A1 (en) 2010-12-23 2022-10-24 Purdue Pharma Lp Tamper resistant solid oral dosage forms
CN103476401A (en) 2011-02-17 2013-12-25 Qrx制药有限公司 Technology for preventing abuse of solid dosage forms
ES2544735T3 (en) 2011-03-25 2015-09-03 Purdue Pharma L.P. Pharmaceutical controlled release dosage forms
KR20140053159A (en) 2011-07-29 2014-05-07 그뤼넨탈 게엠베하 Tamper-resistant tablet providing immediate drug release
CN103857386A (en) 2011-07-29 2014-06-11 格吕伦塔尔有限公司 Tamper-resistant tablet providing immediate drug release
EP3078370B1 (en) 2011-09-16 2018-11-07 Purdue Pharma L.P. Tamper resistant immediate release formulations
ES2641437T3 (en) 2011-09-16 2017-11-10 Purdue Pharma Lp Pharmaceutical formulations resistant to improper handling
AU2012320496C1 (en) 2011-10-06 2017-09-28 Grünenthal GmbH Tamper-resistant oral pharmaceutical dosage form comprising opioid agonist and opioid antagonist
JP6246720B2 (en) 2011-10-18 2017-12-13 パーデュー、ファーマ、リミテッド、パートナーシップ Acrylic polymer formulation
BR112014011504A2 (en) 2011-11-17 2017-05-09 Gruenenthal Gmbh inviolable oral pharmaceutical dosage form comprising pharmacologically active ingredient, opioid antagonist and / or aversive agent, polyalkylene oxide and anionic polymer
CA2853764C (en) 2011-11-22 2017-05-16 Watson Pharmaceuticals, Inc. Immediate release abuse deterrent tablet
CN107854434A (en) 2011-12-09 2018-03-30 普渡制药公司 Include poly- (ε caprolactones) and polyoxyethylated pharmaceutical dosage form
CA2877183A1 (en) 2012-07-06 2014-01-09 Egalet Ltd. Abuse deterrent pharmaceutical compositions for controlled release
AU2014273227B2 (en) 2013-05-29 2019-08-15 Grunenthal Gmbh Tamper-resistant dosage form containing one or more particles
AU2014273226B2 (en) 2013-05-29 2019-06-27 Grunenthal Gmbh Tamper resistant dosage form with bimodal release profile

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020081762A1 (en) * 2018-10-19 2020-04-23 Temple University-Of The Commonwealth System Of Higher Education Tamper-resistant drug dosage forms and methods of making and use thereof
US12458601B2 (en) 2018-10-19 2025-11-04 Temple University-Of The Commonwealth System Of Higher Education Tamper-resistant drug dosage forms and methods of making and use thereof

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