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WO2018148382A1 - Compositions chimiquement stables d'un agent pharmaceutique actif dans un système de distribution à chambres multiples pour administration par voie muqueuse - Google Patents

Compositions chimiquement stables d'un agent pharmaceutique actif dans un système de distribution à chambres multiples pour administration par voie muqueuse Download PDF

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Publication number
WO2018148382A1
WO2018148382A1 PCT/US2018/017384 US2018017384W WO2018148382A1 WO 2018148382 A1 WO2018148382 A1 WO 2018148382A1 US 2018017384 W US2018017384 W US 2018017384W WO 2018148382 A1 WO2018148382 A1 WO 2018148382A1
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Prior art keywords
composition
kit
mucosally
administering
gel
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Ceased
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PCT/US2018/017384
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English (en)
Inventor
Madhu Hariharan
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Mucodel Pharma LLC
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Mucodel Pharma LLC
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Publication date
Priority claimed from US15/430,038 external-priority patent/US20170151260A1/en
Priority claimed from US15/682,764 external-priority patent/US10493027B2/en
Application filed by Mucodel Pharma LLC filed Critical Mucodel Pharma LLC
Publication of WO2018148382A1 publication Critical patent/WO2018148382A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/19—Syringes having more than one chamber, e.g. including a manifold coupling two parallelly aligned syringes through separate channels to a common discharge assembly
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/28—Syringe ampoules or carpules, i.e. ampoules or carpules provided with a needle
    • A61M5/284—Syringe ampoules or carpules, i.e. ampoules or carpules provided with a needle comprising means for injection of two or more media, e.g. by mixing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/28—Syringe ampoules or carpules, i.e. ampoules or carpules provided with a needle
    • A61M5/285—Syringe ampoules or carpules, i.e. ampoules or carpules provided with a needle with sealing means to be broken or opened
    • A61M5/286—Syringe ampoules or carpules, i.e. ampoules or carpules provided with a needle with sealing means to be broken or opened upon internal pressure increase, e.g. pierced or burst

Definitions

  • the present invention relates to pharmaceutically active drugs in general, and to
  • rescue therapeutics including without limitation opioid antagonists, and to
  • Mucosal delivery is less often employed with rescue therapeutics because of challenges in effecting rapid mucosal delivery of therapeutically effective blood levels.
  • the challenge of mucosal delivery of therapeutics has very plain real world implications for patients.
  • Diastat® is a rectally administered diazepam gel. That a parent or guardian must take the time to disrobe a child in active seizure to rectally administer a rescue therapeutic speaks to both the reality of the challenge of oromucosal delivery (i.e. that there is not an oral alternative), and to the unmet medical need that is addressed by certain embodiments of the present invention. See,
  • Migraine and post-operative pain are frequently treated with narcotic analgesics - because safer pharmaceutical agents like non-steroidal anti-inflammatory drugs cannot be absorbed rapidly enough and at sufficient blood levels to effectively treat the symptoms - despite the fact that narcotic analgesics carry a known risk of subsequent abuse and addiction.
  • hydrochloride to treat opioid overdose. See, generally,
  • bronchodilators for anaphylactic shock; anti -hypertensives for emergency treatment of high blood pressure; and anti-allergenics for treatment of hypersensitivity and allergic reactions.
  • Naloxone hydrochloride is a specific and effective opioid antagonist which acts competitively at opioid receptors in the brain and has been found to have a wide variety of medical uses, for example, in reversing of the effects of therapeutic or overdose quantities of opioid narcotic drugs.
  • intravenous, intramuscular or subcutaneous naloxone hydrochloride is used in diagnosis and treatment of opioid overdose and is also administered post-operatively to reverse central nervous system depression resulting from the use of opioids during surgery.
  • Naloxone is also used for treatment of overdose of illicit opioid narcotics.
  • the most common method of treatment is the use of an injectable naloxone product (or the newer product EVZIOTM) which are available in the United States. These injectable products are commonly used in emergency room settings, and are also sometimes carried by law enforcement officials to rapidly reverse opioid overdose.
  • a nasally administered naloxone spray to deliver an emergency dose of naloxone is also available in some countries. In the USA, the injectable product is currently used along with Mucosal Atomization Device (MAD ). The USA has also approved NARCANTM nasal spray. Injectable and nasal naloxone are effective but not adequately portable to be routinely and conveniently carried on one's person.
  • MAD Mucosal Atomization Device
  • narcotic antagonists can also be used to dissuade addictive behavior.
  • U.S. Patents 8,673,355 and 7,749,542 and 7,419,686 and 7,172,767 and 6,696,066 and 6,475,494 and 6,277,384 teach the combination of an opioid antagonist and an opioid agonist to discourage patients from diverting the product for illicit parenteral use. However, these patents provide no teaching as to the delivery of an opioid antagonist by itself.
  • Other patents related to the field of the present invention include U.S. Patents 8,652,515, 8,524,275, 8,017,148,
  • U.S. Patent 8,475,832 teaches the combination of an agonist and antagonist and discusses the use of buffers to limit the absorption of Naloxone in the oral cavity using a buffer with a pH of 3-4. However, there is neither a mention of optimizing the absorption of an antagonist, nor mention of how to stabilize the antagonist during storage.
  • U.S. Patent 7,682,634 teaches the use of seal coatings to keep the agonist and the antagonist separated. But again, this art is directed to a combination of the agonist (opioid) and the antagonist (naloxone).
  • Ionizable pharmaceutically active compounds may be classified by their charge state properties as either basic, acidic or zwitterionic.
  • acidic drugs tend to be more soluble at basic pH and basic drugs would be more soluble at acidic pH.
  • basic drugs would have a larger fraction existing as the ionized/unprotonated species at a pH below their pKa.
  • they would be predominantly unionized/protonated at a higher pH above their pKa.
  • acidic drugs would have a larger fraction in the ionized state at higher pH while at lower pH the drug would be predominantly unionized.
  • Bases include, inter alia, aliphatic amines, anilines, basic amides, amidines, guanidines and heterocyclic nitrogen atoms.
  • Drugs with acidic groups include, inter alia, carboxylates, phenols, sulfonamides and also heterocyclic nitrogen atoms and less commonly phosphates, tetrazoles, thiols, alcohols carbamates, hydrazides, imides and sulfates.
  • pharmaceutically active agent herein includes free acids and free bases as well as their salt forms.
  • Pharmaceutical salt refers to an ionizable drug that has been combined with a counter-ion to form a neutral complex. Converting a drug into a salt through this process can increase its chemical stability, render the complex easier to administer and allow
  • pharmaceutically active agent may also mean racemic mixtures of the left- and right-handed enantiomers of chiral drugs or a single purified enantiomer with biological activity.
  • Acid/base character and pKa values are thus generally considered important determinants for absorption and permeation, however it is recognized that other factors such as lipophilicity, molecular size, metabolic lability, hydrophilicity and efflux mechanisms can also influence absorption.
  • Vishwas et al. teaches the benefits of maintaining a pH of 6.8 to 8.2 for improved absorption of Naltrexone.
  • Vishwas et al states: "[s]lightly increasing the pH of NTX (naltrexone) from 6.8 to pH 7.5 and pH 8.5 increased permeation by a factor of 1.6 and 4.4 respectively.” Id. at page 8, Conclusions, Section 4, Sentence 5.
  • Naltrexone is an antagonist with a structure much like Naloxone but has a better affinity for the ⁇ - opioid binding site.
  • Vishwas et al. further teach the use of a particular surfactant to increase the buccal absorption of Naltrexone: "It was found that permeation of NTX across reconstituted human buccal mucosa produced an enhancement of 7.7 with the use of Brij 58.” Id. at page 8, Conclusions, Section 4, Sentence 2.
  • Vishwas et al. make no mention or suggestion of combining a surfactant with a pH buffer nor do they mention the use of two compartments to separate the buffer from the antagonist during the storage of the product. Nor do they teach how to have a storage-stable antagonist with a pH greater than 5 at the point of use.
  • Naloxone hydrochloride injection is formulated at a pH of approximately 4 to ensure chemical stability and physical stability below the equilibrium solubility of naloxone hydrochloride over the life of the product.
  • the pKa of Naloxone is reported to be around 7.9 for the protonated amine. Based upon pH partition theory it may be expected that if the protonated unionized species has higher permeability through the oral mucosa, then maximal absorption could be expected at or around pH 7.9. However, sufficient absorption to elicit a therapeutic response could conceivably occur at pH greater than 5 and up to 12.
  • U.S. Patent 6,110,926 teaches that aqueous solutions of Naloxone with buffers at pH 6.5 are subject to degradation and tests have shown that such solutions are in fact unstable, the naloxone content degrading over the course of a few days.
  • This patent and the Lancet paper, and their contents, are incorporated by reference into this specification as if fully set forth herein. It must also be noted that injectable naloxone is typically at a pH of 4 adjusted with hydrochloric acid presumably to avoid this instability.
  • a rescue drug like naloxone cannot be administered orally to an unconscious patient who is unable to swallow an oral medication. Similar issues are seen with other rescue therapeutics. For example, a child in seizure cannot be instructed to swallow an oral medication. It may be difficult for a patient with severe migraine or post-operative pain to swallow a
  • Naloxone or like antagonists were given orally using conventional methods, they would be subject to first pass metabolism, and degradation and are consequently not bioavailable for blocking of the opioid receptors at the relevant receptor sites in the body.
  • Naloxone is only stable and soluble in a low pH environment e.g., a pH of 5 or less and preferably at pH 4 or lower, but that it needs to be at a higher pH (e.g. a pH greater than 5 and up to a pH of 12) in order for maximum mucosal absorption of the drug. Therefore, there exists a need for a convenient method to administer an opioid antagonist like Naloxone that is stable over the shelf-life of the product but that can successfully deliver naloxone at high pH at the site of absorption.
  • This invention teaches a way to administer a chemically stable (during storage) aqueous liquid or semisolid gel dosage form of an antagonist through a mucosal administration site, such as the oromucosal region (which encompasses buccal, sublingual and gingival areas), intranasal, vaginal or rectal.
  • a mucosal administration site such as the oromucosal region (which encompasses buccal, sublingual and gingival areas), intranasal, vaginal or rectal.
  • the invention shows how to achieve the contrasting requirements for stability and solubility at storage pH and adequate active absorption pH for pharmaceutical active agents in a single dosage unit encompassing two chambers.
  • kits for administering a mucosally absorbable composition to a human patient includes a first compartment comprising a first composition comprising a pharmaceutical active agent that is substantially lipid soluble and substantially water insoluble, in a substantially non-aqueous solution, and a second compartment comprising a second composition comprising a substantially aqueous solution.
  • the first and second compartments maintain separation of the first and second compositions during storage, and allow for mixing of the first and second compositions to form a mixed mucosally absorbable composition for immediate mucosal administration to a human patient.
  • the second composition contains an acidic buffer and the mixed mucosally absorbable composition has an acidic pH; alternatively, the second composition contains a basic buffer and the mixed mucosally absorbable composition has a basic pH.
  • Mucosal administration to a human patient can be to at least one of the following mucosal administration sites, buccal, sublingual, intranasal, vaginal or rectal. Ocular administration is also contemplated.
  • Another aspect of the present invention relates to a kit for administering a mucosally absorbable composition to a human patient.
  • the kit includes a first compartment comprising a first composition containing a substantially water-soluble pharmaceutical active agent in a solution together with one or more optional suitable pharmaceutical excipients, and a second compartment comprising a second composition with one or more optional suitable pharmaceutical excipients. At least one of the first and second compositions contains an effective amount of a crystallization inhibitor.
  • the first and second compartments maintain separation of the first and second compositions during storage and allow for mixing of the first and second compositions to form a mucosally absorbable composition, which may comprise a gel, for immediate mucosal administration to a human patient.
  • a mucosally absorbable composition which may comprise a gel, for immediate mucosal administration to a human patient.
  • the second composition in the second compartment is at an acidic pH and contains an acidic buffer and the mucosally absorbable composition has a pH ⁇ 6;
  • the second composition in the second compartment is at a basic pH and contains an alkaline buffer and the mucosally absorbable composition has a pH > 7.
  • the mucosally absorbable composition when the mucosally absorbable composition is mucosally administered to a patient, it results in mean AUC more than 35% greater than the same dosage delivered orally. In a preferred embodiment, when the mucosally absorbable composition is mucosally administered to a patient, it results in a mean Tmax more than 25% faster than the same dosage delivered orally. In a preferred embodiment, when the mucosally absorbable composition is mucosally administered to a patient, it results in a mean Cmax more than 35% higher than the same dosage delivered orally.
  • Other embodiments of the present invention may offer similarly improved performance at other mucosal sites, as compared with conventional drug formulations used at the reference sites.
  • kits for mucosally administering a metastable supersaturated solution of a pharmaceutical active agent to a human patient includes a first compartment comprising a first composition comprising a pharmaceutical active agent in solution at or below equilibrium solubility, and a second composition comprising an acidic buffer.
  • the first and second compartments maintain separation of the first and second compositions during storage, and allow for mixing of the first and second compositions to form a supersaturated solution above equilibrium solubility of the pharmaceutical active agent for immediate mucosal administration to a human patient.
  • the second composition comprises an acidic buffer and the supersaturated solution has an acidic pH.
  • the second composition comprises a basic buffer and the supersaturated solution has a basic pH.
  • Figure la, lb, lc, Id, 2a, 2b, 2c, 3a, 3b, 3c and 4a, 4b, 4c and 4d show various views of four different embodiments of the device in pouch-type configurations.
  • Figures la, lb, 2a, 3a, 3b, 4a and 4b show top or bottom views of a dual-chambered package in which labeled part 1 denotes its contents as one liquid of the present invention.
  • Figures la, lb, 2a, 3a, 3b, 4a and 4b show top or bottom views of a dual-chambered package in which labeled part 2 denotes its contents as a second liquid of the present invention.
  • Figures lc, 2b, 3c, 4c and 4d show side or edge views of a dual chambered packages which contains the two liquids of the present invention.
  • Figures lb, lc, 2a, 2b, 3a, 3b, 3c, 4a and 4c, labeled part 3 shows the separation barrier between the first and second chambers of the present invention.
  • Figures 5 and 6 show two different embodiments of the device in a syringe configuration.
  • labeled part 1 shows a view of one chamber of a dual-chambered package which contains one liquid of the present invention.
  • labeled part 2 shows a view of a second chamber of dual chambered package which contains a second liquid of the present invention.
  • labeled part 3 shows a view of a syringe of the present invention, which shows a separation barrier between the first and second chambers.
  • the syringe is a double barrel syringe wherein the two barrels are conjoined and each contains the two liquids of the invention separated from one another during storage.
  • the syringe is a single barrel syringe with a frangible barrier between the contents of the upper and lower chambers.
  • Figure 7 is a graph of Naloxone plasma levels for test animals from an animal study.
  • Figure 8 is a graph of Naloxone plasma levels in a human study.
  • Figure 9 is a graph of ketorolac plasma levels in a human study.
  • Figure 10 is a graph of diazepam plasma levels in a human study.
  • Figure 11 is a graph of Naloxone plasma concentration in a human study.
  • Figure 12 is a graph of Nalbuphine plasma concentration in a human study.
  • the drug naloxone is one example of a rescue therapy drug, i.e. used to rescue patients in opioid induced distress. While there is no single accepted definition of a "rescue therapy drug", the term is used herein to refer to treatment of: a life-threatening episode (e.g. opioid overdose), or an episode where severe, episodic symptoms are not effectively controlled or mitigated by the patient's "standard” drug regime (e.g. a severe asthma attack, or a prolonged or unexpected seizure), or episodic symptoms requiring immediate relief (e.g. migraine headache, post-surgical pain, menstrual pain, severe anxiety disorder/panic attack, angina, etc.).
  • the invention may also be used as the primary treatment for any acute or chronic condition for which immediate relief is desired.
  • Oromucosal delivery is uncommonly used to deliver drugs for systemic pharmacologic effects because a drug viable for this route of administration must possess specific amenable attributes - the drug must be potent (low dose); and it must have ideal physicochemical properties of low molecular weight and high lipid solubility (high log P values) that allow a high rate of permeation through the oral mucosa.
  • a few well-known examples of drugs successfully administered by the sublingual or buccal route are nitrates for angina; and fentanyl or buprenorphine for pain and addiction, nicotine, barbiturates and some psychoactives. It is particularly desirable to enhance the mucosal delivery of pharmaceutical actives for rescue use, i.e.
  • a rescue therapy (the pharmaceutical agent being referred to as a rescue therapeutic).
  • a rescue therapeutic the pharmaceutical agent being referred to as a rescue therapeutic.
  • the oromucosal route is preferable and even more so in self-administered rescue applications.
  • this route of administration it is rarely employed in rescue therapeutics because the residence time at the oromucosal route is shorter and drug must rapidly reach the required therapeutic levels in the blood to effect the rescue - this is a particularly tall order for an already daunting oromucosal barrier to absorption for most drugs.
  • Non limitative examples include oromucosally absorbable pharmaceutically actives like analgesics for relief of migraine headache, post-surgical pain, menstrual pain, labor pain; anxiolytics for severe anxiety disorder/panic attack;
  • bronchodilators for anaphylactic shock and acute respiratory distress
  • anti-allergenics for treatment of hypersensitivity and allergic reactions, arterial dilators for angina
  • rescue antiemetics for post-operative nausea, motion sickness and vertigo
  • rescue anti-hypertensives for emergency treatment of high blood pressure
  • opioid and benzodiazepine antagonists for drug overdose reversal and anticholinergics as antidote drugs.
  • drugs can be delivered more rapidly and effectively intranasally or to other mucosal administration sites (e.g. rectal, vaginal) than with traditional formulations.
  • One object of certain embodiments of the present invention is to provide a drug composition and delivery device for the mucosal administration of a pharmaceutically active agent in an oral liquid or gel that is stable and solubilized during the shelf life of the product.
  • Another object of certain embodiments of the present invention is to provide a rapidly buffered pharmaceutically active agent, including without limitation an antagonist, and to rapidly deliver the therapeutically effective blood levels of said pharmaceutically effective agent.
  • the present invention provides a pharmaceutically active agent in a transiently stable solution, where the solution is intended to maximize mucosal delivery.
  • the present invention provides a pharmaceutically active agent in a micellar solution for mucosal delivery.
  • the present invention provides a pharmaceutically active agent in a multi-lamellar liquid crystal phase for mucosal delivery.
  • the present invention provides a pharmaceutically active agent in a microemulsion for mucosal delivery.
  • the present invention provides a pharmaceutically active agent in an optically isotropic microemulsion for mucosal delivery.
  • the present invention provides a pharmaceutically active agent in a nanoemulsion for mucosal delivery. In certain embodiments, the present invention provides a pharmaceutically active agent in an isotropic nanoemulsion for mucosal delivery.
  • the present invention provides a pharmaceutically active agent in an emulsion for mucosal delivery.
  • the present invention provides a pharmaceutically active agent in a gel for mucosal delivery.
  • Said gel (as well as non-gel embodiments) may optionally be mucoadhesive, and may optionally comprise a mucoadhesive agent.
  • the present invention provides a pharmaceutically active agent in a super saturated solution for mucosal delivery.
  • Super saturation may be effected, without limitation, by pH change or by dilution/solvent-change methods.
  • the present invention provides a super saturated solution ex vivo, prior to administration to the mucosa.
  • the pharmaceutically active agent is maintained in solution in a compartment with a pH that is optimized for chemical stability of the drug to prevent oxidation, hydrolysis or other degradation of the pharmaceutically active agent.
  • the pharmaceutically active agent is maintained in a compartment with a pH that is optimized for physical stability by maintaining the pharmaceutically active agent in solution at or below equilibrium solubility.
  • a drug may be described as substantially insoluble in water which means the drug would be insoluble, practically insoluble, very slightly soluble or slightly soluble as defined in the United States Pharmacopoeia (USP).
  • the drug may be substantially soluble in water which means it is very soluble, freely soluble, soluble or sparingly soluble as defined in the USP.
  • a drug maybe substantially lipid soluble where the drug is soluble in a combination of liquids that consist substantially of lipidic or amphiphilic compounds such as a surfactants and non-polar solvents but may also contain some water (i.e. a substantially non-aqueous solution).
  • a substantially aqueous solution means that the solution consists predominantly of water and other polar co-solvents such as PEG, PG and ethanol but may also contain amphiphilic surfactants.
  • a surfactant as defined herein is an organic compound with both hydrophilic (water-soluble) and lipophilic (lipid soluble) groups thereby possessing amphiphilic characteristics that enable the formation of micelles, emulsions and liquid crystal structures when combined with lipids and water.
  • Surfactants may have a range of hydrophilic lipophilic balance (HLB) values.
  • Emulsions are multi -phasic liquid, semi-solid or gel systems formed when one liquid component is dispersed as distinct organized spherical or non-spherical structures within a continuous phase of another liquid.
  • the dispersed phase may spontaneously emulsify in the continuous phase as nanometer- sized, micron-sized or millimeter sized droplets or other ordered multi-lamellar structures.
  • the present invention delivers to the mucosa
  • Pharmaceutically active compounds may either be bases or acids.
  • acidic drugs tend to be more soluble at basic pH and basic drugs would be more soluble at acidic pH.
  • Basic drugs include, inter alia, aliphatic amines, anilines, basic amides, amidines, guanidines and heterocyclic nitrogen atoms.
  • Drugs with acidic groups include, inter alia, carboxylates, phenols, sulfonamides and also heterocyclic nitrogen atoms and less commonly phosphates, tetrazoles, thiols, alcohols carbamates, hydrazides, imides and sulfates.
  • the present invention employs surfactants, buffering agents, polymeric crystallization inhibitors, polymeric gelling agents, anti-oxidants, chelating agents and other stabilization agents, mucoadhesive agents, sweeteners, absorption enhancers, lipidic excipients, alcoholic or poly-alcoholic co-solvents, pH-indicators, and multiple compartments to separate incompatible excipients (e.g. separate a pH buffer from the pharmaceutically active agent).
  • surfactants e.g. separate a pH buffer from the pharmaceutically active agent.
  • Another object of certain embodiments of the present invention is to provide a portable, non- injectable mucosal drug delivery system for drugs including for rescue therapeutics which can be administered in urgent medical circumstances.
  • a non-limitative example is where a patient suffers from an opioid overdose but may not be located in proximity to a medical facility.
  • mucosal drug products generally, with improved PK performance.
  • drugs may be available only in parenteral form because of poor bioavailability when administered orally.
  • mucosally absorbable versions may exist but better absorption performance is desirable.
  • Vishwas et al. also fails to teach how to achieve the use of a buffer of pH of 5 or greater at the 'point of use/site of absorption' without loss of stability of the antagonist. For example, it is well known that at pH > 6, morphine degrades through two oxidation pathways and in both cases, the oxidation rate increases with deprotonation of each functional group. See also U.S. patent 6, 110,926 which, together with its contents is incorporated into this specification by reference as if fully set forth herein.
  • the present invention teaches how to achieve a pH greater than 5 at the point of use and site of administration, for maximal buccal absorption of the opioid antagonist while at the same time maintaining the antagonist in a lower pH environment prior to use to achieve a chemically stable product that can be stored at room temperature.
  • the composition and drug delivery system of the present invention comprises a mucosally absorbable liquid composition for administration to a human patient of pharmaceutically active agent, (e.g. an opioid antagonist) comprising one composition containing pharmaceutical active in solution with other suitable pharmaceutical excipients in a distinct compartment of a multi-compartment device or container comprising two or more chambers; a second composition at a pH greater than 5 containing a buffer or alkaline components with other suitable pharmaceutical excipients in a second distinct compartment of the same multi-compartment device, and a device or system which maintains separation of the first and second liquids during storage and allows for mixing of the two liquids to form a mucosally absorbable composition, which may be of gel-like or cream-like consistency at the point of use to prevent flow of the product away from administration site.
  • pharmaceutically active agent e.g. an opioid antagonist
  • the present invention includes the composition, device and method that will allow for the delivery of a transiently stable composition to a human subjects' oromucosal region, or other mucosal site.
  • aqueous opioid antagonist or other pharmaceutically active agent
  • aqueous opioid antagonist or other pharmaceutically active agent
  • Optimal stability means that the drug retains 90% of its activity for an 18-24 month shelf life. There exists a barrier that separates the chambers, and maintains total separation of the compositions.
  • the buffer composition and the antagonist composition are mixed together either just before being placed in the patient's mouth or within the patient's mouth, thereby delivering a buffered oromucosally absorbable mixed composition at pH greater than 5 and preferably greater than the pKa of the antagonist to maximize absorption by presenting the unionized species at the point of administration.
  • the composition may be delivered to other mucosal sites.
  • the two compositions are mixed to create the final mixed composition within which the drug may no longer be storage stable (transiently stable), however, the mixed composition is intended to be instantly used (oromucosally delivered) within a few minutes of mixing (preferably within one minute, more preferably within ten seconds) and not stored for future use.
  • This mixed composition may be expected to result predominantly in the protonated species of the drug that is typically less soluble in aqueous media at a pH greater than the pKa of the drug.
  • the drug concentration in the mixed composition may now be significantly higher than the saturation solubility of the drug causing the transient existence of a metastable supersaturated solution.
  • This metastable state is a relatively long-lived state of precarious stability but not a permanent equilibrium state. It will eventually convert via phase transition to the more stable lower energy state of a crystallized solid.
  • crystallization inhibitors at suitable (effective) concentrations is important in such embodiments, to effect and maintain the transient metastable state of the supersaturated solution long enough to ensure rapid absorption in the oromucosal cavity or other mucosal administration site.
  • the transiently metastable super saturated solution lasts more than five minutes, more preferably more than ten minutes, most preferably more than fifteen minutes.
  • the transiently stable super saturated solution is preferably a gel or solution substantially free of a precipitated solid phase of pharmaceutically active agent.
  • the transiently stable super saturated solution is a clear gel.
  • a fraction of the oromucosally administered drug may be absorbed quickly in this way while the remaining fraction of drug may be expectorated or otherwise intentionally or
  • the rapidly absorbed oromucosal fraction may thus serve as an initial loading dose followed by slower and more sustained absorption from the gastrointestinal tract.
  • One basic drug (as free base or as a salt) in a chamber is present as a solution in water (or water plus alcohol or other co-solvents).
  • the solution within this chamber may also have polymer/s (or other gelling agents) to provide a viscous liquid or semi-solid or gel-like consistency.
  • It may also have an acidic component or a buffer pair to bring the pH to the acidic region of pH 6 or lower to improve drug stability and solubility (similarly, basic components or buffer pairs may be used to bring the pH to the basic region where the pharmaceutically active agent is more stable at basic pH).
  • It may also have colorant, permeation enhancer, an antioxidant, a pH-indicating dye, and/or other components as described in this specification.
  • the other chamber contains a base or buffer pair in solution (or acid or buffer pair where the rescue drug is better absorbed at an acidic pH).
  • the other chamber has a stronger acid or base or buffer pair capacity to control the pH of the combined solution (overcoming the acid or base or buffer pair of the chamber containing the pharmaceutically active agent) and maintain such pH at or above the pKa (for basic pharmaceutical actives), or at a pH at or below the pKa (for acidic pharmaceutical active agents) at the site of mucosal administration.
  • pH at the mucosal administration site is maintained > 5 minutes, more preferably > 10 minutes, and most preferably > 15 minutes.
  • This chamber may also contain a polymer to make it a viscous liquid or gel, and it may contain dye, permeation enhancer and other pharmaceutical excipients, but an antioxidant is optional here because there is no drug in this chamber.
  • an acidic drug (as free acid or as a salt) in a chamber is present as a solution in water (or water plus alcohol or other co-solvents).
  • the solution within this chamber may also have polymer/s to provide a viscous liquid or semisolid or gel-like consistency. It may be at neutral pH or have a basic component or a buffer pair to bring the pH to the basic region above pH 7 to improve drug stability and/or solubility. It may also have colorant, permeation enhancer, an antioxidant, a pH-indicating dye, and/or other components as described in this specification.
  • the other chamber contains an acid or acidic buffer pair in solution (where the rescue drug is better absorbed at an acidic pH).
  • one or both chambers will comprise a crystallization inhibitor.
  • kits in which the compositions in each of the two compartments are single phase compositions such as solutions.
  • one or both of the individual compositions within each compartment of the kit may also contain another dispersed phase.
  • Each individual liquid composition may either be a single phase solution or a multi-phasic emulsion.
  • the resulting mucosally absorbable composition may be a single phase solution as a hydrogel or a multi-phasic emulsion as a cream.
  • the system of the present invention may be employed with multi-active ingredient combination products, i.e. more than one pharmaceutically active agents.
  • the multi -chambered architecture may be particularly valuable to ensure stability of each pharmaceutically active agents, by segregating such agents in different environments (akin to other embodiments of the present invention). Different environments may be particularly desirable to maintain product stability.
  • the pharmaceutically active agents used in the system of the present invention may be free bases and any suitable salt thereof as well as free acids and any suitable salts thereof.
  • the pharmaceutically active agents may comprise prodrugs.
  • the present invention is directed in part to a mucosally absorbable liquid composition for administration to a human patient, comprising one liquid containing an ionizable pharmaceutically active agent together with one or more optional suitable pharmaceutical excipients in a first compartment at a pH ⁇ 6; and a second liquid at pH >6 containing a buffer or alkaline components together with one or more optional suitable pharmaceutical excipients in a second distinct compartment; wherein the first and second compartments maintain separation of the first and second liquids during storage such that the pH-sensitive drug is maintained in solution at a storage-stable pH and allow for mixing of the first and second liquids to form a mucosally absorbable composition having a pH >6 for immediate mucosal administration to a human patient.
  • the pH-sensitive pharmaceutically active agent is an opioid antagonist (e.g., naloxone).
  • the pH of the resultant composition is greater than 6, e.g., from about 6 to about 12.
  • the pH of the resultant composition is from about 6.5 to about 9.5.
  • the pH of the resultant composition is from about 7.5 to about 9. In other preferred embodiments
  • the pH of the resultant composition after mixing the contents of the first and second chamber, is 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5 or 12. In the most preferred embodiment, after mixing the contents of the first and second chamber, the pH of the resultant composition is at or above the pKa of the drug. In further preferred
  • the pH of the liquid contained in the first compartment prior to mixing is from about 1 to about 6. In further preferred embodiments, the pH of the liquid contained in the first compartment prior to mixing is 1, 1.5., 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 5.6, 5.7 5.8, 5.9 or 6. In certain preferred embodiments, the pH of the liquid contained in the first compartment prior to mixing is from about 3 to about 6.
  • the present invention is directed in part to a mucosally absorbable liquid composition for administration to a human patient, comprising one composition containing an ionizable acidic pharmaceutical active agent in solution together with one or more optional suitable pharmaceutical excipients in a first compartment at a pH > 6; and a second composition at pH ⁇ 6 containing a buffer or acidic components together with one or more optional suitable pharmaceutical excipients in a second distinct compartment; wherein the first and second compartments maintain separation of the first and second compositions during storage such that the pharmaceutically active agent is maintained in solution at a storage-stable pH and allow for mixing of the first and second compositions to form a mucosally absorbable composition having a pH ⁇ 6 for immediate oromucosal or mucosal administration to a human patient.
  • the drug may be pH- sensitive which means that the pharmaceutical active is chemically unstable over the shelf life of the active i.e. does not maintain at least 90% of its biological activity or analytical identity and/or a pH wherein the active has insufficient equilibrium solubility to keep the drug in solution over its shelf life.
  • the pharmaceutically active agent is a rescue therapy or other drug best absorbed at an acidic pH.
  • the pH of the resultant composition is from about 6 to about 1.
  • the pH of the resultant composition is from about 3 to about 6, preferably less than 5.5.
  • the pH of the resultant composition is from about 3.5 to about 5.5. In other preferred embodiments, after mixing the contents of the first and second chamber, the pH of the resultant composition is 1, 1.5. 2. 2.5, 3, 3.5, 4, 4.5, 5, or 5.5. In the most preferred embodiment, after mixing the contents of the first and second chamber, the pH of the resultant composition is at or below the pKa of the drug. In further preferred embodiments, the pH of the liquid contained in the first compartment prior to mixing is from about 6 to about 12. In further preferred embodiments, the pH of the liquid contained in the first compartment prior to mixing is 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, or 14. In certain preferred embodiments, the pH of the liquid contained in the first compartment prior to mixing is from about 6.5 to about 11.
  • the present invention is further directed to a method of treating a human patient in need of treatment with a pharmaceutically active agent, comprising administering to a human patient the mucosally absorbable liquid composition comprising the steps of opening the first and second compartment; causing the first and second liquids to mix; and delivering the resultant mixture to a mucosal surface of a human patient.
  • the contents of the compartments are preferably delivered to the buccal, sublingual or gingival areas of the oral cavity.
  • the present invention is further directed to a method of treating a human patient in need of treatment with a pharmaceutically active agent that is only stable and soluble in a low (or high) pH environment, comprising administering to a human patient the mucosally absorbable liquid composition comprising the steps of opening the first and second compartment; causing the first and second liquids to mix; and delivering the resultant mixture to the intended mucosal surface.
  • the present invention will deliver a total combined liquid (preferably a gel) dose of less than 2 grams, more preferably less than 1.5 grams and most preferably less than 1 gram.
  • Limited amounts are important for comfortable delivery to intended oromucosal sites, e.g. buccal cavity, sublingual area, etc. Limited amounts are also important to maintain relatively high levels of concentration of the pharmaceutically active agent.
  • the concentration of the pharmaceutically active agent comprising >5mg/g of the delivered gel formulation, more preferably >20 mg/g of the delivered gel formulation, most preferably >40 mg/g of the delivered gel formulation.
  • the fluid containing the active drug component is deposited into one compartment labeled 1 and a buffer greater than pH 6 is deposited into a second compartment labeled part 2 (where an acidic drug is better absorbed at an acidic pH, the second compartment may be filled with an acidic buffer solution with pH less than 6).
  • Labeled part 3 represents the separation barrier between the two compartments labeled 1 and 2.
  • tearing along labeled part 4 causes both chambers to be opened and the compositions to exit from the pouch (labeled part 5 in figure Id) and allow the contents (labeled part 6) to exit and be mixed at the point of use.
  • FIGs 2a and 2c show that the package folded along the axis part labeled 4 breaches a frangible seal labeled part 5 thereby allowing the two compositions to mix and exit the device as shown in labeled part 6.
  • each of the two chambers has a frangible seal shown by labeled part 4 which may be breached by squeezing the two chambers between the fingers prior to use causing the contents of each chamber to enter a mixing zone (labeled part 5) with final exit of the mix (labeled part 6) through nozzle (labeled part 7).
  • Figure 4a shows how a first frangible seal (labeled part 4a) may be breached by squeezing the pouch such that contents of chamber labeled 1 and chamber labeled 2 are mixed together as shown in figure 4b prior to exiting from the pouch via nozzle labeled 7 after a second frangible seal (labeled 4b) is breached with further squeezing of the pouch to enable exit of the mixed composition (labeled part 6).
  • the contents of compartment 1 and 2 are then brought together during use by various means as shown in the Figures Id, 2c, 3c and 4b.
  • the pouch is squeezed between fingers thereby breaching the frangible seals and allowing the two liquid streams to flow into a mixing zone prior to expulsion of the combined liquids from the dual compartment package.
  • An opioid antagonist is instantly buffered to a pH greater than 5 at the point of use, for example, in the patient's buccal, sublingual or gingival regions.
  • Other pharmaceutically active agents may be buffered to acidic or basic pH, as desired.
  • syringe designs may also be used to achieve the same objective.
  • plunger labeled part 4
  • the contents of the both chambers, 1 and 2 pass through a mixing zone/nozzle (labeled part 5) to exit as a combined liquid mixture (labeled part 6).
  • plunger labeled part 4
  • the contents of chamber 1 are forced through contents of chamber 2 and then exit through a mixing zone/nozzle (labeled part 5) to exit as a combined liquid mixture (labeled part 6).
  • the mixing zones (labeled part 5) of Figure 5 and 6 may take the form of a barrel, nozzle or tip that may contain in-line mixing configurations using screw threads or other designs known in the art.
  • the plunger may be operated by hand, by spring, pneumatic pressure or other automatic system.
  • the current depiction of the pouch type embodiments in Figures la, lb, lc, Id, 2a, 2b, 2c, 3a, 3b, 3c and 4a, 4b, 4c and 4d are composed of flexible aluminum laminate foil; however, plastic, paper, metal, glass or any reasonably useful material is within the scope of the present invention.
  • the syringe type embodiments are composed of polypropylene or polyethylene; however, glass, metal or any other suitable polymeric resin or other useful material is within the scope of the invention.
  • the package or containers can be any design that can house two flowable compositions and maintain a barrier between the two compositions and allows the two compositions to mix during use at or before the site of administration.
  • compositions may be slightly viscous liquids or very viscous liquids or shear-thinning liquids or shear-thinning gels or shear-thinning creams.
  • a flowable liquid-like consistency is preferred for each of the individual liquid compositions so that it flows easily out of the syringe and mixes readily together.
  • a less flowable liquid or a gel-like consistency is preferred after the compositions have combined and mixed in order to reduce flowability and reduce salivary dilution at the site of administration in the mouth. This would also allow the gel to stay in place in the oromucosal (or vaginal or rectal) cavity and impede involuntary or inadvertent swallowing of the composition (or other evacuation by bodily fluids).
  • the mucosally absorbable composition can be of a water viscosity but preferably a viscosity of 25 cps or more is employed, and more preferably, an aqueous gel of 100 cps and above is employed, and most preferably a gel of 1500 cps and above.
  • the viscosities of the liquids in compartments 1 and 2 should be such that efficient mixing of the liquids can be achieved.
  • the antagonist composition is housed in compartment 1 of Fig 1-6.
  • the aqueous buffer composition of pH greater than 5 is housed in the second compartment, 2 of Fig. 1-6, of the two-chambered package and the composition can be like water viscosity but preferably a viscosity of 2000 cps or less and more preferably an aqueous gel and can contain a water soluble polymer.
  • the viscosity of the mixed composition (labeled part 6) of Figure 1-6 should be such that the liquids or gels from both compartments, 1 and 2 are readily miscible.
  • Both the buffer and pharmaceutical active containing composition can contain a permeation enhancer. Skilled artisans will appreciate, based on the disclosure herein, that acidic buffer compositions may also be employed for acid drugs.
  • the two chambered delivery device is arranged such that a barrier exists ( Figures 1-6) between the two chambers in such a way that no contact between the two compositions in the two chamber occurs during storage. It is this barrier that allows for the separation of the stable aqueous antagonist solution or gel from the higher pH solution to maintain drug stability until the point of use.
  • the solution may comprise any pharmaceutically active agent, and that the pH may be acidic or basic to facilitate drug stability and solubility until the point of use in the oral cavity or other mucosal surface.
  • the two compositions (antagonist and buffer) in compartments 1 and 2 of Figures. 1-6 are mixed either through turbulent mixing during expulsion from the package, or at the point of use.
  • a buffer of greater than 5 is present during the actual use of the product but does not subject the antagonist to undue storage instability or insolubility by coming in direct contact with the buffer at pH greater than 5.
  • the solution may comprise any pharmaceutically active agent, and that the buffers may be inverted (acidic) as desired.
  • a commercially available double barrel syringe similar to that shown in Figure 5 was a commercially obtained along with a mixing tip nozzle commonly used in dental resin mixing applications.
  • This mixing tip nozzle contained an embedded static screw type mixer.
  • This system was used for animal and human studies and also functions in a similar manner to the devices shown in figure 1-6.
  • the two conjoined barrels of the syringe house the active gel and buffer gel separate from each other and are combined together as they are ejected through a static mixing nozzle which was attached prior to administration.
  • the first pharmaceutical active containing chamber may be larger than the second buffer containing chamber (or the inverse may be true).
  • Different fill volumes may be achieved in a number of ways.
  • a non-limitative example is to employ different chamber sizes (e.g. chambers with different diameters).
  • Different fill volumes may be employed as a strategy to minimize total volume of the mixed composition. Minimizing fill volume may be particularly desirable where the intended mucosal site of administration is not (or may be perceived to not be) amenable to larger administered volumes.
  • administration sites may accommodate smaller delivered volumes than rectal or vaginal sites. In other cases, consumer preference simply may favor smaller administered volumes.
  • compositions may also help to speed evacuation time from the delivery device.
  • the formulation can be optimized including the minimization of optimal mixing volumes, based on the desired duration of transient stability, as well as buffer capacity that is desired for various administration sites (and their relative flows of bodily secretions which must be accounted for in thinking about pH for the intended duration of absorption).
  • the antagonist is most stable at pH 5 or less; therefore, suitable acidic components or buffer pairs are used to keep the antagonist at lower pH in the composition.
  • the preferable pH for this composition is less than 5, more preferably less than 4, and most preferably 3 or less.
  • the antagonist's low pH buffer's capacity will be overcome by the mixing of the antagonist composition with greater than pH 5 buffer composition, which is contained in the second compartment.
  • the final pH at the point of use will be greater than 5.
  • different pharmaceutically active agents may be used, buffers may be changed, such that the final pH at the point of use is acidic or basic.
  • Further stability of the antagonist can be maintained during storage by the use of antioxidants and/or metal chelators and/or polyols.
  • Either compartment can contain a pH indicator or other mixing indicators for observation and confirmation of mixing during use of the product.
  • a low pH buffer or high pH buffer, as appropriate for a given pharmaceutically active agent
  • an antagonist preferably 3 or less in the case of an antagonist, with one or more of the following: antioxidants (e.g. 0.0001-10%), metal chelators (e.g. 0.0001-2%) and polyols (e.g. 0.0001- 15%).
  • Both liquid compositions may contain one or more of the following: pH indicators (e.g.
  • sweeteners e.g. 0.01- 10%
  • flavorings e.g. 0.01 - 2%
  • polymers e.g. 0.01- 80%
  • permeation enhancers e.g. 0.01- 20%
  • crystallization inhibitors e.g. 0.01-20%>
  • other suitable pharmaceutically acceptable ingredients e.g. 0.001-80%>. Effective amounts of each such agent may be employed.
  • Naloxone injections are reported to be stable at pH 2.5-5. Following dilution in 5% dextrose or 0.9% sodium chloride injection to a concentration of 0.004 mg/mL (4 ug/mL), naloxone hydrochloride solutions are apparently stable for 24 hours; after 24 hours, any unused solution should be discarded.
  • the injections also may contain methylparaben and
  • Naloxone injection may be diluted for intravenous infusion in normal saline or 5% dextrose solutions. The addition of 2 mg of naloxone injection in 500 mL of either solution provides a concentration of 0.004 mg/mL. Mixtures should be used within 24 hours. After 24 hours, the remaining unused mixture must be discarded. The rate of administration should be titrated in accordance with the patient's response. (See, e.g., The Syringe Driver: Continuous
  • pharmaceutically active agent(s) which are not stable at high pH means that the pharmaceutically active agent(s) should or must be discarded after 24 hours when maintained at a pH greater than 7.
  • "not stable at high pH” means that the pharmaceutically active agent may be chemically or physically unstable— it may degrade by about 10-25% over a time period of 180 days after constitution at a pH greater than 7; or it may fall out of solution (drug may precipitate) when dissolved; or it may settle over a short period of time when present in a dispersed state within a liquid thus making it unsuitable as a commercially viable product (e.g., that can be stored at room temperature).
  • the term "stable in a low pH environment” means that the pharmaceutically active agent (e.g., opioid antagonist) in liquid 1 (pH ⁇ 5, or, e.g., pH from about 1 to ⁇ 5) may be expected to be stable with less than 10% degradation of naloxone over 12 months.
  • pharmaceutically active agent e.g., opioid antagonist
  • pharmaceutically active agent(s) which are not stable at low pH means that the pharmaceutically active agent(s) should or must be discarded after 24 hours when maintained at a pH less than 7.
  • not stable at low pH means that the pharmaceutically active agent may be chemically or physically unstable— it may degrade by about 10-25%) over a time period of 180 days after constitution at a pH less than 7; or it may fall out of solution (drug may precipitate) when set aside, thus making it unsuitable as a commercially viable product (e.g., that can be stored at room temperature).
  • the term "stable in a high pH environment” means that the pharmaceutically active agent in the composition 1 (pH >7, or, e.g., pH from about 7 to 14) may be expected to be stable with less than 10%> degradation of the pharmaceutically active agent over 18-24 months.
  • Opioid Antagonists :
  • Opioid Antagonist or simply "Antagonist” as used in connection with the present invention is meant to include full and partial antagonists and may include one or more of the following and/or derivatives: Naloxone, Naltrexone, methyl-naltrexone, 6B-naltrexol, Nalmefene, Nalorphine, Levallorphan, Cyprodine, Naltrindole, Axelopran, Bevenopran, Alvimopan, Nalbuphine, Naldemedine, Nalodeine and Norbinaltorphimine. It also includes mixed opioid agonist/antagonist drugs including without limitation nalbuphine,
  • buprenorphine pentazocine and butorphanol.
  • pharmaceutical active or pharmaceutically active agent as used in connection with the present invention is meant to also include, in addition to opioid antagonists, any other pharmaceutical active or pharmaceutically active agent, including for systemic or topical delivery, and which may benefit from preparation and administration as set forth herein.
  • Preferred pharmaceutically active agents are those suitable for rescue therapy (rescue drugs).
  • the pharmaceutical active agent may be a seizure rescue medication such as anticonvulsant benzodiazepines including, inter alia, alprazolam, midazolam, phenazepam, nitrazepam, lorazepam, flutoprazepam, etizolam, flubromazepam, diclazepam, diazepam, cloxazolam, clonazolam, clobazam and bretazenil.
  • anticonvulsant benzodiazepines including, inter alia, alprazolam, midazolam, phenazepam, nitrazepam, lorazepam, flutoprazepam, etizolam, flubromazepam, diclazepam, diazepam, cloxazolam, clonazolam, clobazam and bretazenil.
  • anticonvulsant benzodiazepines including, inter alia,
  • the pharmaceutical active agent may be a migraine rescue medication including inter alia sodium valproate, propranolol, metoprolol, topiramate, pregabalin, gabapentin and the triptans (sumatriptan, zolmitriptan, rizatriptan, naratriptan, frovatriptan, almotriptan and eletriptan) and any NSAID including, inter alia, acetylsalicylic acid, Diflunisal, Salicylic acid and other salicylates, Salsalate, Ibuprofen, Dexibuprofen, Naproxen, Fenoprofen, Ketoprofen, Dexketoprofen, Flurbiprofen, Oxaprozin, Loxoprofen, Indomethacin, Tolmetin, Sulindac, Etodolac, Diclofenac,
  • the pharmaceutical active may be a NSAID for pain rescue (e.g. post-operative pain, dental pain or other short term pain treatments) such as ketorolac, or any of the other NSAIDs listed above.
  • the active may also be a narcotic analgesic for pain rescue such as morphine, oxycodone, buprenorphine, butorphanol, codeine, hydrocodone, hydromorphone, meperidine, methadone, nalbuphine, oxymorphone, pentazocine, propoxyphene, tramadol, tapentadol, oliceridine and fentanyl. These examples are non-limitative.
  • the pharmaceutical active may be ondansetron, scopolamine or other anti-emetics for post-operative or opioid-induced nausea.
  • the pharmaceutical active may include anti-emetics such as prochlorperazine, promethazine, ondansetron, granisetron, metoclopramide, droperidol, trimethobenzamide, and scopolamine.
  • anti-emetics such as prochlorperazine, promethazine, ondansetron, granisetron, metoclopramide, droperidol, trimethobenzamide, and scopolamine.
  • combination therapies may be employed for treatment of multiple symptoms or for alleviating the side effect of one of the pharmaceutical actives.
  • a combination of an anxiolytic and an analgesic may be used for post-operative pain (e.g. diazepam with ketorolac).
  • a combination of an anti-emetic with an analgesic may be used for the emergency treatment of pain (e.g. scopolamine with nalbuphine).
  • the pharmaceutical active when the mixed mucosally absorbable composition is buccally administered to a human subject, the pharmaceutical active achieves a Tmax in plasma at less than ninety minutes (preferably at less than forty five minutes) with a therapeutic level in plasma reached within 30 minutes or fewer. It is desired that, when the mixed mucosally absorbable composition is intranasally administered to a human subject, the pharmaceutical active achieves a Tmax in plasma at less than twenty minutes, preferably less than fifteen minutes, more preferably less than ten minutes.
  • Permeation enhancers that are useful to increase the absorption of the pharmaceutically active agent consist of the following with the more preferable permeation enhancers being the non- ionic surfactants; however, at least most of the listed compounds below have utility as permeation enhancers. Effective amounts may be employed.
  • Anionic surfactants :
  • ChemBetaine CAS ChemBetaine Oleyl
  • ChemBetaine C Hexadecyldimethyl ammonio propane sulfonate, Decyldimethyl ammonio propane sulfonate, Dodecyldimethyl ammonio propane sulfonate, and Myristyldimethyl ammonio propane sulfonate.
  • Benzyl pyridinium chloride Dodecyl pyridinium chloride, Cetyl pyridinium chloride, Benzyldimethyl dodecyl ammonium chloride, Benzyldimethyl myristyl ammonium chloride, Benzyldimethyl stearyl ammonium chloride, Octyltrimethyl ammonium bromide, Decyltrimethyl ammonium bromide, Dodecyltrimethyl ammonium bromide,
  • Myristyltrimethyl ammonium chloride and Cetyltrimethyl ammonium bromide.
  • Sorbitan monolaurate Sorbitan monopalmitate, Sorbitan monostearate, Sorbitan
  • Polyoxyethylene (20) Cetyl Ether (Brij 58), Brij 97, Brij 30, Brij 56, and Triton X-,100
  • Polyoxyethylene ethers Polyoxyethylene esters, Polyethylene glycol esters, Sucrose esters, Sucrose ethers, D-alpha Tocopheryl polyethylene glycol 1000 succinate (TPGS or Vitamin E TPGS), Polyethoxylated castor oil (e.g Cremophor RH40), Poloxamers (eg. Pluronic F-127 or Kolliphor P407)
  • soyabean oil Hydrogenated vegetable oils, Soybean oil, Peanut oil, Beeswax.
  • N-Lauryl sarcosinate Sodium caprylate, Sodium decanoate, Sodium palmitate, and Sodium oleate.
  • Methyl pyrrolidone Cyclohexyl pyrrolidone, Octyl pyrrolidone, Decyl pyrrolidone, Decyl methyl pyrrolidone, Methyl piperazine, Phenyl piperazine, Octanamide, Hexadecanamide, and Caprolactam.
  • EGTA Ethylene Glycol Tetraacetic Acid and salts thereof
  • EDTA Ethylene Diamine Tetraacetic Acid and salts thereof
  • Itoic Acid Kojic Acid
  • EDTA is especially useful. Effective amounts may be employed.
  • Antioxidants useful in connection with the present invention include primary and secondary antioxidants, including thiols, polyphenols such as Vitamin C, Tocopherols, Carotenes,
  • Ubiquinol, Glutathione, Lipoic Acid, Eugenol, Lycopene, Resveratrol, Flavonoids, Lutein, butylated hydroxy anisole (BHA), tertiary butyl hydroquinone, and butylated hydroxy toluene (BHT) are useful.
  • BHA, BHT are especially useful as is Vitamin C and Tocopherols. Effective amounts may be employed.
  • Crystallization inhibitors useful in connection with the present invention include polyvinyl pyrrolidone (PVP), polyethylene-polypropylene glycol copolymers (PluronicsTM), inulin lauryl carbamate, polyacrylate, hydroxypropyl methylcellulose (HPMC), HPMC with low glass transition temperature (Affinisol), hydroxypropyl methylcellulose acetate succinate (HPMCAS), Vinyl Pyrrolidone- Vinyl Acetate Co-Polymer (e.g Kollidon VA64), Caprolactam/polyvinyl acetate/polyethylene glycol copolymer (Soluplus). Effective amounts may be employed.
  • PVP polyvinyl pyrrolidone
  • PluronicsTM polyethylene-polypropylene glycol copolymers
  • inulin lauryl carbamate polyacrylate
  • HPMC hydroxypropyl methylcellulose
  • HPMC with low glass transition temperature Advantisol
  • HPMCAS hydroxypropyl methyl
  • polyol as used in connection with the present invention is meant to include one or more of the following: sugar alcohols, including maltitol, sorbitol, xylitol, lactitol, erythritol, hydrogenated starch hydroxysates, isomalt, glycerin, pentaerythritol, ethylene glycol, and mannitol. Effective amounts may be employed.
  • Buffer compositions useful with the present invention are set forth below:
  • Pharmaceutically acceptable buffers of pH 5 or greater that are useful for the immediate adjustment of the active (e.g. naloxone) at the point of use and include one or more of the following (without limitation): Citric Acid/Potassium Dihydrogen Phosphate, Monosodium Phosphate/Di sodium Phosphate using phosphoric acid to lower the pH or sodium hydroxide to raise the pH, Citric acid/Sodium citrate, DL-Cysteine/Sodium DL Cysteinate, Boric Acid/Sodium Hydroxide, Sodium Bicarbonate/Sodium Carbonate.
  • Citric Acid/Potassium Dihydrogen Phosphate Monosodium Phosphate/Di sodium Phosphate using phosphoric acid to lower the pH or sodium hydroxide to raise the pH
  • Citric acid/Sodium citrate DL-Cysteine/Sodium DL Cysteinate
  • Boric Acid/Sodium Hydroxide Sodium Bicarbonate/Sodium Carbonate.
  • biologically acceptable strong bases may be used in the buffer compartment, which may include Calcium hydroxide, Magnesium hydroxide, Aluminum hydroxide, Magnesium acetate, sodium hydroxide, calcium carbonate, potassium hydroxide, sodium carbonate, potassium carbonate etc.
  • These same buffers can be used for stability protection where the active ingredient is stable at a basic pH, and may be a direct combination with the active ingredient.
  • These buffers may also be used to effect a basic pH at the point of use. Effective amounts may be employed.
  • acids or acidic buffers are useful for the stability protection of the antagonist and are in direct combination with the active ingredient (or, for adjustment at the point of use where the active ingredient is best absorbed at an acidic pH).
  • These acids or buffers will include all systems that will create a pH less than 5, most preferably 3 or less and can include one or more of the following (without limitation): Formic Acid/Sodium Formate, Hydrogen Chloride/Potassium Chloride, Hydrogen Chloride/Glycine, Hydrogen Chloride/Potassium Hydrogen Phthalate, Citric Acid/Sodium Citrate, Acetic Acid/Sodium Acetate, Citric Acid/Disodium Hydrogen Phosphate, Citric Acid/Tri sodium Citrate Dihydrate, etc. Effective amounts may be employed.
  • buffers leverage the pH-solubility profile of the drug to induce super saturation after combination of the liquid containing compartments.
  • Water Soluble Polymer as used in connection with the present invention and is intended to include one or more of the following polymers for imparting viscosity to the liquid and/or forming a gel: pullulan, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone (PVP), carboxymethyl cellulose, polyvinyl alcohol, sodium aginate, polyethylene glycol, xanthan gum, chitosan, tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, Crosslinked polyacrylic acid polymer (Carbopols), polycarbophils (acrylic acid polymer cross-linked with divinylglycol), starch, gelatin, Carbomers, Poylyethylene Oxides, carrageenan, pectins and combinations thereof.
  • water soluble polymer and variants thereof refer to a polymer that is at least partially soluble in water, and desirably fully or predominantly soluble in water, or absorbs water or may form colloidal dispersions in water.
  • the materials useful with the present invention may be water soluble at room temperature and other temperatures, such as temperatures exceeding room temperature. Moreover, the materials may be water soluble at pressures less than atmospheric pressure. Desirably, the water soluble polymers are water soluble having at least 20 percent by weight water uptake. Dosage forms of the present invention formed from such water soluble polymers are desirably sufficiently water soluble to be dissolvable upon contact with bodily fluids. Effective amounts may be employed, including sufficient amounts to form a gel and maintain a gel against expected salivary flow (or other bodily fluid) for longer than five minutes, preferably for longer than ten minutes.
  • the system does not have to start as a gel and envisioned are gels that are formed in-situ when the two fluids from the chambers are brought together during use.
  • Certain polymers which on their own can increase viscosity when used at low levels but when mixed with certain other excipients the viscosity changes to a semi-solid gel.
  • Non-limitative examples of such systems are carrageenan + a mono, di, trivalent cation such as calcium; gellan gum + a mono, di, or trivalent cation; sodium alginate + a cation.
  • viscous polymers that are synergistic with other polymers and will form gels such as xanthan or kappa carrageenan with locust bean gum.
  • shear thinning gels which upon mechanical shear will become quite fluid to enable complete evacuation of the fluids from each compartment but will set to a gel very quickly once the shear is removed.
  • An example of such a system is gellan gum.
  • thermo-reversible gels which are low viscosity at room temperature but upon entering the oral cavity (or other bodily cavity like vaginal or rectal) at body temperature will quickly form a gel.
  • Pluronic F127 alone or mixed with other polymers.
  • Ethanol Propylene glycol, Polyethylene glycol, Propylene carbonate, DMSO, Tetrahydrofurfuryl alcohol polyethylene glycol ether (Glycofurol), propylene glycol monolaurate, propylene glycol monocaprylate and diethylene glycol monoethyl ether.
  • the present invention includes the use of certain excipients for identifying a change in pH, such as phenol red, bromothymol blue, bromo cresol purple, bromo phenol blue, litmus granules, neutral red, thymol blue, methyl orange and phenolphthalein. Also included is the use of FD & C colors and their color change to determine when fluid from chamber one mixes with fluid from chamber two. An example of such a system is yellow #5 in one chamber and blue #1 in the other chamber when brought together form green. Flavors, sweeteners and fillers are also envisioned as well as surface active agents. Effective amounts may be employed.
  • the present invention contemplates the use of precipitation inhibitors to maintain super saturation of acidic or basic pharmaceutical active(s) in combined liquid, and the use of a transiently stable combined liquid for mucosal delivery of pharmaceutical actives.
  • the supersaturation is a means to provide higher thermodynamic activity that enhances
  • the maintenance of a state of supersaturation (where the concentration of solute within the solution is above the thermodynamic equilibrium solubility) needs only to be very transient ( ⁇ 20 minutes).
  • the state of supersaturation is invoked by a rapid change in the solubility effected by the rapid pH change or rapid dilution.
  • the transient supersaturation may lead to very rapid mucosal drug absorption if the speed of drug precipitation and reversion to equilibrium from this metastable state of high thermodynamic activity is slowed down for long enough by the use of suitable polymeric precipitation inhibitors.
  • the naloxone HC1 salt is soluble in water and is reported to be >50 mg/g and also as high as 200 mg/g.
  • the reported solubility of the base form of Naloxone is 1,400 mg in one liter of water or 1.4 mg/g of water. See, US EPA. [2012].
  • Naloxone evidently possesses the suitable physicochemical properties and sufficient permeability to function as an effective CNS drugs - it has sufficient aqueous solubility while also possessing the lipophilicity to cross the blood-brain barrier and indeed also sufficient to cross the nasal mucosa at sufficiently rapid rates (a nasal spray formulation is approved for use).
  • an oromucosal formulation does not yet exist because the buccal mucosal barrier represents a comparatively more daunting barrier due to the greater thickness of the keratinized membrane and smaller surface area.
  • naloxone low pH gel when the naloxone low pH gel is combined with the high pH buffer gel, there is a rapid change in the pH of the entire system as it becomes alkaline and the drug exceeds its equilibrium solubility at those conditions.
  • concentration of 30 mg of naloxone base per gram of water is more than 20 times the amount of free base form expected to be soluble. Therefore, a super-saturated state exists - temporarily— until phase change occurs in the form of crystallization.
  • certain excipients are used to slow down the crystallization process - thereby effecting a transient stability.
  • the slowing down or inhibition of crystallization is required - - in the case of naloxone the charged ionic species in solution loses its charge at higher pH and would instantly crystallize due to its inherent insolubility.
  • the transiently stable supersaturated solution in a liquid in the primary embodiment, the transiently stable supersaturated solution in a liquid
  • embodiments of the present invention may be directed to other mucosal sites and any pharmaceutical active.
  • the compounded product is a gel because over-dilution of the gel formulation with saliva (and or other bodily fluids at the administration site) would not only reduce the concentration of drug (which reduces the driving force for absorption) but also reduces the effectiveness of the crystallization inhibitors because their overall concentration is lowered.
  • salivary (or bodily fluid) dilution will tend to reduce the time period during which the dosage form is transiently stable, whereas it is Applicant's intention to increase or maximize the time period during which the dosage form is transiently stable.
  • the pressure required to mix the starting solutions must be proportionate to the hand strength of a typical user in a situation that requires manual dexterity to aim the dosage form into the intended oromucosal cavity or other mucosal surface. If the pressure exceeds or challenges the hand strength of the user, dexterity and dosage form placement will be less accurate.
  • the "absorption time window" for the naloxone (and many other) rescue therapeutic is about 15 minutes, preferably ten minutes, more preferably under five minutes, the crystallized form is not desirable and needs to be delayed for that period of time.
  • “absorption time window” Applicant means the time period during which the active ingredient reaches blood levels that are considered to exert therapeutic effect based upon known pharmacokinetic-pharmacodynamic relationships. This will depend upon the nature of the rescue situation, and the time period for other existing therapies (typically using other routes of administration) to reach efficacious blood levels.
  • oromocusal route of administration is more convenient, safer (no needle stick risk), and requires less training than injection, is likely faster than existing oral therapies, and may otherwise be more convenient compared to existing therapies (e.g. rectal administration of diazepam), marginal increases in the time to reach efficacious blood levels comparable with injectable and intranasal routes may be an acceptable trade-off for the benefits of oromucosal delivery.
  • the use of two liquid gels, a delivery/mixing device, and at least one crystallization inhibitor excipient allows the finished buffered formulation to reach a super-saturated state at the point of use thereby delivering a high concentration of solubilized un-ionized or protonated form of the active of a given pKa directly to the mucosal tissue.
  • the pH is not conducive to physical or chemical stability, the absorption of the drug occurs too rapidly for crystallization and/or degradation to substantially occur.
  • the canine example below is important because it demonstrates effective, rapid uptake of drug using the present invention where the subject animal is in opioid induced respiratory distress. This is important in the case of naloxone, which is typically administered to patients in distress, and yet clinical studies to approve the medication are typically performed upon healthy patients.
  • a single bolus is used, however it is also possible to delivery multiple boluses particularly where a higher dose is required.
  • the same approach for creating a supersaturated state by rapid change in the pH of a solution may be carried out in the reverse direction for an acidic drug, for example ketorolac for the treatment of pain.
  • the acidic drug is present as a solution in water (or water plus alcohol or other water-miscible polar co-solvents) and may also have polymer/s to provide a viscous liquid or semi-solid or gel-like consistency. It may be at neutral pH or have a basic component or a buffer pair to bring the pH to the basic region above pH 7 to improve drug stability and maintain equilibrium solubility.
  • This gel is combined prior to use with an acidic buffer gel.
  • ketorolac gel at high pH is combined with the low pH buffer gel, there is a rapid change in the pH of the entire system as it becomes acidic and the drug exceeds its equilibrium solubility at those conditions. Therefore, a super-saturated state exists - temporarily— until phase change occurs by crystallization of the drug.
  • the transiently stable supersaturated solution of ketorolac with the supersaturated gel solution being compounded just prior to administration is suitable for oromucosal or other mucosal use in the rapid treatment of pain indications. Phase change may be delayed through use of crystallization inhibitors.
  • the supersaturated state of the drug may continue to exist even after the gel is swallowed after initial buccal application. This is because the gastric pH, especially in the fasted state may be similarly low as the combined gel. This may allow the continued maintenance of the unionized protonated species in solution for a longer period of time, however, the rate of absorption may fall due to dilution within a large volume of gastric fluid.
  • the state of supersaturation may also be invoked by a rapid change in the solubility effected by rapid dilution with a solvent in which the drug is insoluble.
  • diazepam the therapeutic dose of diazepam (5-15 mg) is relatively poorly soluble in water (0.012 mg/ml) and across the physiological pH range.
  • diazepam is quite soluble in lipidic excipients and this fact may be leveraged to produce a drug-containing gel formulation that serves as a lipidic pre-emulsion component of an oil-in-water combined gel.
  • the pre-emulsion phase may contain lipid solvents, amphiphilic co-solvents, surfactant and surfactant combinations as well as precipitation/crystallization inhibitors.
  • the dispersed internal phase of the microemulsion contains drug at high apparent solubility.
  • the fraction of dissolved diazepam in the acid-buffered continuous phase remains predominantly unionized and may exist as a supersaturated solution at the pH of maximum absorption.
  • the dispersed oily phase may also be saturated with aqueous phase and may now have reduced solubility for the drug which may exist as a supersaturated solution within micellar or multi-lamellar liquid crystal structures or as a microemulsion or nanoemulsion.
  • Mucosal tissue of the nasal cavity is generally understood to be a membrane more readily traversed by pharmaceutical actives, due inter alia to the rich vascular plexus of the nasal cavity.
  • embodiments of the present invention can be useful to with intranasal delivery of pharmaceutical actives, particularly where such actives are not readily, rapidly or otherwise insufficiently absorbed through standard formulation strategies.
  • the comparator may be an existing, approved drug or a formulation that is not approved but for which PK data otherwise exists.
  • the comparator may be a formulation reported in the literature.
  • the comparator may be the same (or different) route of administration.
  • Applicant describes an embodiment of the present invention that buccally delivers diazepam with improved PK performances relative to the approved, rectal diazepam
  • Diastat Applicant describes an embodiment of the present invention that intranasally delivers naloxone with improved PK performance relative to the existing approved naloxone nasal spray. Applicant describes an embodiment of the present invention that intranasally and intraorally (sublingually or buccally) delivers nalbuphine with improved PK performance relative to oral and parenteral versions of nalbuphine described in the literature. Applicant describes an embodiment of the present invention that buccally delivers ketorolac with improved PK performance relative to approved oral and intranasal versions of ketorolac.
  • Applicant does not only describe embodiments of the present invention with improvements in PK performance relative to a comparator. Applicant also describes embodiments where PK performance is nearly as good as a comparator where the comparator uses a less challenging route of administration. For example, Applicant describes an embodiment of the present invention that delivers naloxone buccally with PK performance that is nearly as good as the approved nasal spray.
  • comparisons in PK performances be made at the same dose.
  • comparisons may also be made on a dose adjusted basis, preferably where there is linearity/proportionality of PK response up to the dose administered.
  • nalbuphine hydrochloride is understood to have a bioavailability when delivered orally of approximately 12%. Surprisingly, Applicant achieved more than double the bioavailability (200%) for intranasally delivered nalbuphine hydrochloride on a dose adjusted basis using an embodiment of the present invention, as further described in example 14.
  • an intranasally delivered pharmaceutical active will have 35% or more greater relative bioavailability than when the drug is delivered in conventional oral form (i.e. tablet or capsule) or intraoral form, preferably 50% or more greater, more preferably 80% or more greater bioavailability, most preferably 125% or more greater bioavailability and even more preferably more than 250% greater bioavailability than when delivered in conventional oral form or intraoral form.
  • oral form i.e. tablet or capsule
  • intraoral form preferably 50% or more greater, more preferably 80% or more greater bioavailability, most preferably 125% or more greater bioavailability and even more preferably more than 250% greater bioavailability than when delivered in conventional oral form or intraoral form.
  • mucosal sites i.e. buccal, sublingual, rectal vaginal
  • bioavailability improvements may similarly be achieved relative to other comparator routes of administration (i.e. intranasal, buccal, sublingual, vaginal, rectal).
  • an intranasally delivered pharmaceutical active may achieve peak plasma concentration (Tmax) faster than when an equivalent dose of the drug is delivered orally in conventional form (i.e tablet or capsule) or intraorally, 25% to 1500% faster, preferably more than 100% faster, more preferably more than 200% faster, even more preferably more than 500% faster, still more preferably more than 800% faster.
  • peak plasma was achieved approximately ten times - 1000%)— faster than intraoral administration as reported in the literature (see Example 14 below).
  • Such improved results may similarly be achieved using embodiments of the present invention for other mucosal sites (i.e. buccal, sublingual, vaginal, rectal), including with different route of administration comparators.
  • an intranasally delivered pharmaceutical active may achieve a maximum drug plasma concentration that is greater after intranasal administration than when the drug is delivered in conventional oral form (i.e. tablet or capsule) or intraoral administration.
  • maximum drug plasma concentration may be approximately or more than 50%> higher, preferably approximately or more than 150%) higher, approximately or more preferably more than 300%) higher and most preferably or more than 500%> higher.
  • Applicant achieved a maximum nalbuphine drug plasma concentration, after intranasal delivery of an embodiment of the present invention, approximately five times (500%>) higher than that achieved by an equivalent dose of the drug administered as a conventional oral formulation. Such results may similarly be achieved using embodiments of the present invention for other
  • administration sites i.e. buccal, sublingual, vaginal rectal as compared with other comparator administration sites.
  • Tmax may occur within thirty minutes, preferably within twenty minutes, more preferably within 12.5 minutes, yet more preferably within ten minutes, and most preferably within 7.5 minutes.
  • Embodiments of the present invention may also achieve surprisingly rapid Tmax using the buccal, sublingual, vaginal or rectal routes.
  • Tmax may be achieved within 60 minutes, preferably within 45 minutes, more preferably within 30 minutes.
  • Embodiments of the present invention may also achieve PK results that are nearly as good as another route of administration, where the compared route of administration is understood to be easier to penetrate with drug (e.g. buccal versus intranasal).
  • a buccal embodiment of the present invention may achieve Tmax, Cmax and AUC that is nearly as good as an intranasal version of the same drug.
  • Tmax may be 30% slower or less, preferably 20%) slower or less, more preferably 10%> slower or less.
  • Cmax may be 30%> lower or less, preferably 20% lower or less, more preferably 10%> slower or less.
  • AUC may be at least 70%) of the comparator, preferably at least 80%> of the comparator, more preferably at least 90% of the comparator.
  • relatively lower viscosity and relatively higher flowabihty of the composition may be desirable to increase the coated area of the nasal mucosa, and or the flow and spreading of the product over a larger geography of the nasal cavity's mucosa.
  • An additional advantage of the nasal mucosa site, as compared with oromucosal sites, is the lower potential for dilution by secretions in the nasal mucosa. This means that the administered composition is less likely to be quickly diluted from salivary secretions. This allows the pH to remain in the intended range of maximum absorption because the buffer capacity of the formulation is not quickly exceeded. The duration of the existence of the uncharged species may therefore be longer in the case of nasal administration as compared with buccal or sublingual administration. Additionally, lower salivary wash out (e.g.
  • swallowing means the time period the pharmaceutical active is in mucosal contact prior to swallowing may be longer, as compared with buccal or sublingual use.
  • Nasal mucosa sites may be particularly suitable when delivering pharmaceutical actives with a low log p value, e.g. less than or equal to 1.5.
  • Nasal mucosa sites may be particularly suitable when delivering pharmaceutical actives for which oral formulations are understood to have low bioavailability in standard oral formulations (i.e. tablet, capsule) , i.e. less than 25%, or less than 20%, or less than 15%.
  • standard oral formulations i.e. tablet, capsule
  • the nasal mucosa - being more subject to irritation than the oral mucosa— is understood to tolerate pH ranges of approximately 3 to 10. It is desirable that embodiments of the present invention intended for nasal use have a pH in the range of 3 to 10, even where absorption may be favored by a more extreme pH outside of the 3 to 10 range.
  • the intended dose may be delivered to one, or both nostrils, either contemporaneously, or sequentially. In some cases, follow on intranasal doses will be given on an as needed basis.
  • Embodiments of the present invention may be used to allow for non-parenteral delivery of pharmaceutical actives not otherwise available in commercially approved non-parenteral form.
  • intranasal formulations will comprise a flavor or other olfactory agents for pleasing aroma, or to mask flavors in the case of any product reaching the mouth.
  • a sensory agent in effective amounts to substantially mitigate sensory response to particularly acidic or basic
  • Embodiments of the present invention may be used buccally, sublingually, intranasally, vaginally, rectally and intraocularly.
  • embodiments of the present invention may be used to effect rapid, preferential delivery of a pharmaceutical agent to the uterus using the first uterine pass effect.
  • a 1 kg batch of a solution with a carbomer gelling agent is prepared as follows. Percentages are w/w% of the final 1 kg batch.
  • Purified water (96.45%; 964.54g) is added to a 0.5 gallon kettle equipped with a mixing apparatus (counter-rotating mixer or propeller mixer). The water is heated to about 40 °C and is stirred. The temperature is maintained, the stirring speed is increased to about 1200 RPM, and Carbomer 940 (0.546%; 5.46 g) is slowly added until a homogeneous mixture is formed. The mixture is stirred for an additional 45 minutes at about 40 °C. and propylene glycol (3%; 30 g; heated to about 40 °C) is added to the mixture and stirred for 15 minutes. Water is added back to the mixture to obtain 1000 grams and mixing is continued at about 12 RPM, avoiding aeration.
  • a mixing apparatus counter-rotating mixer or propeller mixer
  • the temperature is maintained for about 15-30 minutes to form Liquid Mixture A.
  • two buffers are prepared.
  • the first buffer is prepared at a target pH of 5.8 and the second buffer is prepared at a target pH of 8.
  • the first buffer of pH 5.8 contains 0.207 ml of 2 mol/1 of Acetic Acid and 2.294 ml of a 2 mol/1 of Sodium Acetate.
  • the second buffer of pH 8 contains 0.204 ml of a 2 mol/1 of sodium dihydrogen phosphate and 2.296 ml of a 2 mol/1 of disodium hydrogen phosphate.
  • the buffers are designated as Buffer 5.8 and Buffer 8.
  • Five hundred grams of Liquid Mixture A is weighed into a separate stirring vessel and the 5.8 buffer is added with slow mixing. The mixture is stirred under 28 in. Hg. vacuum for 12 minutes and is designated Liquid Mixture B.
  • Liquid Mixture C Five hundred grams of Liquid Mixture A is weighed into a separate stirring vessel and buffer 8 is added with slow mixing. The mixture is stirred under 28 in. Hg. vacuum for 12 minutes and is designated Liquid Mixture C.
  • Liquid Mixture D a repeat of Liquid Mixture A is performed into which 12.2 grams of Naloxone HC1 is added. The pH is adjusted to 3 using citric acid and sodium citrate. EDTA (1% wt/wt%) is added to the solution. This will equate to 10 mg of Naloxone base per gram of gel and is designated Liquid Mixture D.
  • Liquid Mixture D is added to compartment 1 of Fig. 1-6 of the two sided pouch or syringe and one gram of Liquid Mixture B is added to the other compartment 2 of Fig. 1-6 of the pouch or syringe.
  • the gels are combined prior to use and extruded, from the package (labeled part 6 in Figures 1-6) and the sample is designated Combined Gel Mixture 1 at 5.8 pH.
  • Liquid Mixture D is added to the first compartment 1 of Fig. 1-6 of the two side pouch or syringe and one gram of Liquid Mixture C is added to the other compartment 2 of Fig. 1-6 of the pouch or syringe.
  • the gels are combined prior to use and extruded, from the package (labeled part 6 in Figures 1-6) and the sample is designated Combined Gel Mixture 2 at pH 8.
  • HPMC El 5 + Polyethylene Oxide N80 + Maltitol at a ratio of 2: 1 : 1 are combined with 1% (wt.%) Citric Acid and 1% (wt.%) Edetate Disodium and 1% (wt.%) Etocas 35 and 0.5% (wt.%)) Glycerol Monooleate.
  • the combination (20 grams) is combined with water (80 grams) and stirred for 3 hour using a gate impeller. During the last hour of mixing, vacuum was set at 27-28 inches of Hg to deaerate the mixture. To 97.58 grams of this mixture is added 2.42 grams of naloxone HC1 dihydrate to obtain 20 mg of Naloxone base per gram of polymer gel solution.
  • Liquid Mixture A2 Another polymer mixture of 20 grams is made using HPMC El 5 + PEO N80 + Maltitol + Propylene Glycol Alginate in 2: 1 : 1 : 1 ratio. The polymer blend is added to 75 grams of water. To this mixture 4 grams of a buffer pH 8 is added, which contains 0.204 ml of a 2 mol/1 of sodium dihydrogen phosphate and 2.296 ml of a 2 mol/1 of disodium hydrogen phosphate, and 1 gram of Glycerol Monooleate are added to the polymer mixture and the combination is mixed 3 hours using a gate impeller. During the last hour, vacuum is applied at 27 to 28 in Hg. to de-aerate the polymer mixture. This mixture is designated as Liquid Mixture B2.
  • Liquid Mixture A2 (20 mg of Naloxone base) is added to compartment 1 of Fig. 1-6, and one gram of Liquid Mixture B2 is added to the other compartment 2 of Fig. 1-6.
  • the gels are combined prior to use and extruded, from the package (labeled part 6 in Figures 1-6) and the sample is designated Combined Gel Mixture 3 at pH 8.
  • a prototype antagonist formulation was prepared consisting of two component gels, Liquid Mixture A and Liquid Mixture B. This formulation was tested in a preliminary animal study. Table 1 shows the composition of Liquid Mixture A. Liquid Mixture A was made in the following manner.
  • Ingredients 1, 2, 3, 4, 5 and 7 were dry blended together. Ingredient 6 and 8 were added to a 250 ml beaker and mixed for 20 minutes using a magnetic stirrer. Ingredients 1, 2, 3, 4, 5 and 7 were added slowly to the beaker with continued stirring. Once all the ingredients were wetted the mixture was sealed and placed in a refrigerator (2-8 °C) for 24 hrs. After 24 hours the solution/suspension was removed and allowed to reach room temperature. A drop placed on the skin gelled upon contact indicating a proper thermal gelation at body temperature. The sample was designated as Liquid Mixture A pH 3.0. A quantity of naloxone slightly in excess of the solubility limit of naloxone at room temperature was added to the Liquid Mixture A pH 3.0.
  • Liquid Mixture B composition is shown in table 2 below. Liquid Mixture B was made in the following manner.
  • Ingredient 4 was added to a 250 ml beaker and stirred with a magnetic stirrer. Ingredients 1, 2 and 3 were dry blended and added slowly to the beaker and stirred with the magnetic stirrer until all ingredients were wetted. The mixture was placed in a refrigerator (2-8 °C) for 24 hrs. After 24 hours the solution was brought to room temperature and a drop placed on the skin gelled upon contact indicating a proper thermal gelation at body temperature. The sample was designated Liquid Mixture pH 10. This was Liquid Mixture B.
  • This formulation was used in a preliminary animal overdose reversibility study which was presented in the parent application. Two Beagle dogs approximately 10 months old, weighing 11.3 kg and 10.5 kg were used in this study. The animals were fasted overnight, weighed, and observed for clinical observations, including baseline heart and respiration rates.
  • Fentanyl was initiated at 0.005 mg/kg and was increased up to 0.250 mg/kg to achieve sedation characterized by recumbence/reluctance to stand, central nervous system (CNS) depression (head hung low), ataxia, decreased response to stimuli, slow response to toe pinch, bradycardia ( ⁇ 70 bpm), miosis, and/or decreased respiratory rate ( ⁇ 16 breaths per minute).
  • CNS central nervous system
  • the 4 mg and 8 mg were provided by administering 1 mL (0.5mL Gel A + 0.5mL Gel B) or 2mL (1 mL Gel A + 1 mL Gel B) respectively of the gel compositions in Table 3 and 4 below.
  • a more concentrated formulation was used to administer 30 mg of naloxone by combining 1 mL of Gel A and 1 mL of Gel B as shown in Table 5 and 6 below.
  • the effective concentrations of the drug in the three combined gel doses were 2 mg/g, 4 mg/g and 15 mg/g respectively for a corresponding total administered dose of 4 mg, 8mg & 30 mg.
  • the dosing was carried out using a double barrel syringe fitted with a mixing nozzle similar to that shown in the figure 5. Two control animals were also included in the study
  • Blood from these animals was sampled at 3, 6, 10, 15, 30, 45, 60, 90, 120 and 240 minutes post dose and the plasma analyzed for naloxone using an un-validated method with an LLOQ of 0.1 ng/ml. As shown in figure 2, the rate of absorption was dependent on the drug concentration in the formulation. Maximum plasma concentration were seen between 15-45 minutes post dose for all animals. The highest dose/concentration (30mg/g) formulation that showed very rapid and high absorption (tmax of 15 minutes and Cmax of 853 ng/ml was chosen for further development.
  • Buffer Gel Sodium hydroxide and sodium carbonate were pre-dissolved in water followed by the addition of the Pluronic F127. The mixture was manually stirred with a spatula in order to disperse the polymer. The samples were cooled for 24 hours at 2-8 °C for 24 hrs. The samples were allowed to reach room temperature prior to testing.
  • Naloxone base has very poor solubility in water (1.4 mg/mL), whereas the HCl salt is soluble at room temperature (RT) at greater than 70 mg/g in water.
  • RT room temperature
  • Naloxone HCl salt dissolved at above 1.4 mg/g of water at RT will instantly fall out of solution when buffer is added to neutralize the HCl and reach a basic pH. This is a rapid and conclusive test wherein the gel/solution immediately turns opaque when pH change occurs. The crystallization is confirmed by observation of the crystals using 100X magnification (See "Control" example in Table 10).
  • Absorption of the active can only occur when the active is in solution - the rate of absorption of the un-ionized species of naloxone is much higher than that of the ionized species.
  • a high proportion of naloxone exists as the unionized species at the boundary of the two pKa's for the drug - this occurs at a basic pH of around 9.
  • hydrochloride is immediately neutralized and the uncharged naloxone molecule instantly crystallizes and falls out of solution.
  • Combination Al which contained F127, HPMC and Brij 58 showed no crystal growth for up to 10 minutes indicating a synergistic effect when using all excipients together. Applicant concluded that for some crystallization inhibition, at least one surfactant at a minimum is required with superior crystallization inhibition performance occurring with a surface active agent in combination with a cellulosic polymer.
  • naloxone gels Fifteen different composition of naloxone gels were made as shown in Table 12. These were combined with Buffer 2 from Table 9 and examined for naloxone crystals over time under the microscope. Table 13 shows the results from microscopic examination which demonstrates the ability to maintain a supersaturated solution at a pH which is conducive for absorption. As seen with the control example which does not contain surfactant, gel former, and polymeric crystallization inhibitor, the naloxone base falls out of solution instantaneously upon addition of the buffer. The best inhibition of crystallization of naloxone occurs when a gelling agent is combined with a polymeric crystallization inhibitor and/or surfactant.
  • crystallization inhibitor it is possible in some cases for the crystallization inhibitor to function both as the gelling agent and the inhibitor as seen with Pluronic F127 and Carbopol 974 (Carbomer). Some crystallization inhibitors can also function as gel formers and serve dual functions within the formulation.
  • Useful crystallization inhibitors include, without limitation: HPMC (hydroxyl propyl methyl cellulose), HPC (hydroxyl propyl cellulose), Kollidon VA64 (Vinyl Pyrrolidone- Vinyl
  • a combination of approaches may also be brought to bear to further improve the rate of
  • DMSO dimethyl methacrylate
  • pH indicators may be used in the formulation to verify proper mixing by the end user.
  • the following example demonstrates that the target pH was obtained during the mixing using a syringe and mixing tip as described in the parent application and shown in Figure 5.
  • the example shown in table 15 is similar to Example 4 in this application with the additional inclusion of a pH-indicating dye.
  • the dye used was an anthocyanin isolated from black carrot. This dye can function either as a pH indicator or mixing indicator and will turn from red at low pH to blue/violet color at basic pH or vice versa.
  • Table 15 one gram of the naloxone gel solution (Table 15) was placed in one chamber of a dual chambered syringe and one gram of the basic buffer gel (Table 2) was placed in the other chamber.
  • the syringe was equipped with a spiral mixing tip. The syringe plunger was depressed and the two fluids mixed together as they exited the syringe tip.
  • anthocyanins are instantaneous pH indicator dyes that visually confirm complete mixing of the gels to attain the desired basic pH. This is important for emergency responders and users to confirm that the active was properly administered at the point of use.
  • naloxone buccal gel Three formulations of naloxone buccal gel were employed in this study - Formulation 8, 9 and 14 from Table 12 in combination with Buffer system 1 from Table 9 to form the combined gel.
  • Each formulation used a different type of crystallization inhibitor - formulation 8 used a combination of two molecular weight grades of HPMC, Formulation 9 used hydroxypropyl cellulose and Formulation 14 used Soluplus along with HPMC as well as propylene glycol as a co-solvent.
  • the active Gel A formulation in each experiment had a concentration of 30 mg/g, and in each case an 8 mg dose of naloxone was administered (0.27 grams of a 30 mg/g Gel A).
  • the basic buffer gel was also administered in the same amount for a combined gel weight of about 0.54 g.
  • the naloxone gel was administered buccally in the left or right lower buccal cavity.
  • the subjects were in supine position simulating an unconscious subject while formulation 8 and 9 were dosed with the subjects in the upright position.
  • the patient retained the gel in the mouth for twenty minutes after dosing placement followed by swallowing the mouth contents.
  • time pointes for blood draw were employed: pre-dose, and at 2.5, 5, 7.5, 10, 15, 20, 30, 45 , 60 , 120 , 180, 240, 300 ,and 360 minutes.
  • the study for formulation 9 was continued only until the 120 minute timepoint.
  • LC-MS/MS liquid chromatography -tandem mass spectrometry
  • the average Cmax of the applicant's gel formulation ranged from 5.3 to 8 ng/mL with Tmax ranging from 30 to 45 minutes. Applicant believes, based on this data (and other clinical results herein using different embodiment of the invention), that the results of this clinical study would correspond to the mean results of a larger study.
  • Opioid agonist drugs may also be delivered by a similar approach for the treatment of pain.
  • Other Therapeutic Agents include:
  • the parent application describes the use of a two gel system separated by a barrier and combined together at the point of use.
  • the prior examples shown were for weakly basic actives that required alkaline pH for maximum uncharged species to exist to promote absorption.
  • Examples 11 and 12 below demonstrate the inverse approach where a weakly acidic drug is maintained at an acidic pH after compounding to maximize absorption while optionally maintaining a basic environment for the active gel to keep it stable during storage.
  • the active drugs chosen to illustrate this related but inverse approach are ketorolac tromethamine and diazepam.
  • Ketorolac Tromethamine was added to a mixture of water and PEG 400 and stirred to dissolve the drug. A dry blend of the remaining ingredients was mixed into the ketorolac solution. The mixture was refrigerated overnight to obtain a clear Gel A solution shown in Table 16 containing 40 mg/g of KT base. Tween 80, propylene glycol and water were mixed to obtain a solution. A dry blend of remaining ingredients was added with mixing to disperse the ingredients. The mixture was kept at room temperature to obtain a solution, Gel B at pH between 3 and 3.5.
  • ketorolac gel 1 g of Gel A from Table 16 along with 1 gram of Gel B from Table 17.
  • the combined gel was administered using a double barrel syringe similar to that shown in Figure 12.
  • Blood was drawn pre-dose and at 5, 10, 15, 20, 30, 45, 60, 90, 120, 180, 240, 480 and 720 minutes post- dose using Vacutainer® tubes containing sodium heparin.
  • Plasma Ketorolac concentrations were determined using a non-validated liquid chromatography -tandem mass spectrometry (LC-MS/MS) assay.
  • Ketorolac is employed for treatment of post-surgical pain and also off-label for migraine rescue treatment, typically via intramuscular or intravenous injection.
  • Tmax is achieved for oral Ketorolac (10 mg tablets) in 44 ⁇ 34 minutes whereas Tmax for intramuscular Ketorolac injection ranged between 33 and 44 minutes.
  • the Cmax for a single dose 10 mg oral tablet was 0.87 ⁇ g/mL and for the intramuscular injection it was 1.14 ⁇ g/ml, 2.42 ⁇ g/mL and 4.55 ⁇ g/mL for the 15 mg, 30 mg and 60 mg respectively. See,
  • Ketorolac is also available as an approved single dose strength (15.75 mg/spray) nasal spray formulation (Sprix®).
  • the prescribing information shows that after administration of two 100 ⁇ , sprays (total dose 31.5 mg) the average Tmax for the nasal spray is 45 minutes with a range from 30 to 120 minutes.
  • the Cmax was found to be 1.806 ⁇ g/mL with a standard deviation of 0.88. See
  • Applicant's gel formulation dosed at a 40 mg resulted in a Cmax of 5.2 ⁇ g/mL. Assuming dose proportionality of response and re-calculating the Cmax for an equivalent dose this amounts to 4.1 ⁇ g/mL at a 31.5 mg dose. Applicant believes based on this data (and other clinical results herein using different embodiment of the invention), that the results of this clinical study would correspond to the mean results of a larger study.
  • the Cmax for the gel is calculated to be 3.9 ⁇ g/mL which is also significantly better when compared to the 30 mg intramuscular dose which showed a Cmax of 2.42 ⁇ g/mL.
  • the Tmax of the gel is also comparable to the approved intramuscular injection and superior to the approved oral and intranasal formulations.
  • the Tmax is 25% faster than either of the oral or intranasal formulation, more preferably 35% faster, even more preferably 45% faster, most preferably 50% faster.
  • Such Tmax may be achieved with embodiments of the present invention at any mucosal administration site.
  • ketorolac The rapid uptake of ketorolac via the oromucosal route in the clinical study validates the inventiveness of the combined gel approach.
  • one chamber of the syringe contained the ketorolac solution and also included co-solvents, chelator, surfactant and polymers to attain a gel-like consistency. It exists at neutral to basic pH. In addition, it may also have permeation enhancers, antioxidants, a pH-indicating dye, and/or other components as described in this specification.
  • the second chamber contained a citric-sodium citrate buffer in solution along with additional polymers, surfactants and co-solvents.
  • NSAID drug candidates that could be delivered by a similar approach: Mefenamic acid, naproxen, flurbiprofen, oxaprozin and diclofenac. These examples are non-limitative.
  • Diazepam is indicated for the management of anxiety disorders, alcohol withdrawal, delirium tremens, agitation, tremor, hallucinosis, relief of skeletal muscle spasm, spasticity caused by cerebral palsy and paraplegia, athetosis, and adjunctively in convulsive disorders. Diazepam is commercially available as an oral tablet, oral liquid, injectable and rectal gel
  • Diazepam has literature reported solubility in water of 50 ⁇ g/g of water and may therefore be expected to have practically no solubility at acidic pH. It is also well documented in the published literature that diazepam undergoes acid hydrolysis during storage and that stability and solubility are improved in non-aqueous solvent systems. However, the pH for the predomination of the maximally absorbable unionized form of diazepam is below its pKa of 3.4. Therefore, this molecule must ideally be formulated as a non-aqueous gel at a neutral pH for chemical stability and acidified to pH 3.4 at the point of use to maximize absorption.
  • Diazepam, TPGS (tocopherol polyethylene glycol succinate) and PG (propylene glycol) were mixed together and warmed to melt the TPGS and dissolve the diazepam and set aside as Pre-emulsion Gel A. Overnight, phase separation occurred but remixed with stirring to produce a translucent viscous liquid. When this pre-emulsion was added to water, a clear solution was obtained. Under a light microscope, the mixture appears to be a microemulsion. When 1 gram of diazepam pre-emulsion Gel A (Table 18) is added to 1 g of the acidic buffer (Table 19) and 1 g of human saliva, no drug crystals were observed under the microscope.
  • Diazepam is poorly soluble in water ( ⁇ 0.05 mg/g). Diazepam is quite soluble in PG (> 15mg/g). In the pre-emulsion Gel A formulation a combination of PG is used with TPGS - diazepam is even more soluble >20 mg/g in this formulation. This does not exist as a supersaturated solution but a shelf-life stable solution at or below equilibrium solubility.
  • the drug is formulated as a pre-emulsion that spontaneously emulsifies upon the addition of the acidic buffer to form a visually clear, isotropic microemulsion.
  • a fraction of the drug stays within the non-polar micelles or mixed micelles or lamellar liquid crystal structures of TPGS and another fraction that is 'carried along' with the PG into the PG/water/saliva acidic solution.
  • the system that is administered is therefore essentially a clear micellar microemulsion of a non-aqueous TPGS phase dispersed within a PG-water continuous aqueous phase.
  • both the phases contain drug - the aqueous phase contains unionized drug at supersaturated concentration in an acidic environment and the non-aqueous phase also contains dissolved unionized drug.
  • This combines a self- microemulsifying system with the combined gel system of extemporaneously mixing the drug solution with a pH adjusting acidic buffer to achieve a super saturated, microemulsion at the point of use.
  • the dispersed internal phase of the microemulsion contains drug at high concentration.
  • the literature contains many references to a self-emulsifying drug delivery system wherein a lipidic self-emulsifying solution of drug is encapsulated within a softgel capsule where it is expected to emulsify when it comes in contact with the acidic stomach contents.
  • mucosal absorption by extemporaneously forming the microemulsion prior to administration by combining with buffer to present the protonated drug species at the mucosal absorption surface is novel.
  • PI prescribing information
  • Diazepam rectal gel is gel formulation of diazepam intended for rectal administration in the management of selected, refractory, patients with epilepsy on stable regiments of anti- epileptic drugs on who require diazepam intermittently to control bouts of increased seizure activity.
  • the drug Per the prescribing information (PI) for the diazepam rectal gel, the drug is well absorbed reaching peak plasma concentrations in 1.5 hours.
  • the absolute bioavailability of the rectal gel relative to the injectable is 90%.
  • the Cmax of after a 15 mg rectal dose is estimated from the graph provided in the PI to be about 380 ng/mL
  • the pharmacokinetic performance of the applicant's diazaepam gel formulation is shown in Figure 10.
  • the peak plasma concentration (Cmax) reached was 124 ng/mL.
  • Cmax peak plasma concentration
  • a theoretical Cmax of 372 ng/mL was comparable to the average rectal gel Cmax of 380 ng/mL.
  • the Tmax of the buccal gel was 60 minutes which was comparable or superior to the oral tablet (1-1.5 hours) and the rectal gel (1.5 hours).
  • Applicant notes the excellent Tmax, and further noted that compared with the ninety minute Tmax of the rectal gel, 70 minutes or less would be a substantial improvement but 60 minute Tmax demonstrated by the buccal gel of the present invention represented a substantial advance. Applicant believes based on this data (and other clinical results herein using different embodiment of the invention), that the results of this clinical study would correspond to the mean results of a larger study.
  • Applicant prepared a naloxone formulation as shown in Table 20 using the following procedure. Kolliphor RH40 was dissolved into water. Naloxone was added to the above solution and stirred until dissolved. The remaining ingredients were dry blended and added with mixing for 30 minutes. The mixture was stored in a refrigerator overnight at 4°C to obtain clear viscous solution.
  • a corresponding buffer formulation was prepared as shown in Table 21 using the following procedure. Sodium hydroxide and sodium bicarbonate were added to water and dissolved. Kolliphor was mixed into the solution for 30 minutes. The solution was stored in a refrigerator overnight to achieve a clear solution.
  • Naloxone Gel formulations shown in Table 20 and buffer shown in Table 21 were extemporaneously mixed in a 1 : 1 ratio and administered to healthy human subjects via the buccal, sublingual and intranasal routes at an 8 mg dose in a crossover study.
  • a 0.4 mg intramuscular injection (commercially available naloxone solution) was administered as an injectable control.
  • the data are shown in figure 11.
  • the intranasal dose resulted in rapid absorption of the drug with a Cmax superior to that reported in the literature after intranasal administration of a simple naloxone solution (see Krieter et. al, Pharmacokinetic Properties and Human Use Characteristics of an FDA Approved Intranasal Naloxone Product for the Treatment of Opioid Overdose (J Clin Pharmacol. 2016 Oct; 56(10): 1243-53. doi:
  • Nalbuphine is indicated for the relief of moderate to severe pain. It can be used for preoperative and postoperative analgesia, and for obstetrical analgesia during labor and delivery.
  • Nalbuphine is a mixed opioid K-agonist ⁇ -antagonist and is known to be about equi- analgesic on a mg basis to morphine.
  • Nalbuphine is soluble in water up to about 35 mg/g and has a very low log P value of 1.4.
  • a nalbuphine containing gel was prepared as shown in Table 22. The flavors were mixed together and stirred into water. All other excipients were dry blended and added to above mixture with mixing for 30 minutes. Mixture was stored in a refrigerator at 4° C overnight to obtain a clear solution.
  • a corresponding buffer formulation was prepared as shown in Table 23 using a similar procedure as in Example 13.
  • a nalbuphine containing gel was prepared as shown in Table 24. All ingredients except Bittermask flavor were dry blended. The dry ingredient blend was added to water with stirring. Bittermask flavor was then added to the above solution with stirring. The entire mixture was stored overnight in a refrigerator at 4°C to obtain clear viscous solution.
  • a corresponding buffer formulation was prepared as shown in Table 25 using a similar procedure as in Example 13.
  • Plasma nalbuphine concentrations were determined using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay.
  • the concentration-time profiles are ashown in Figure 12.
  • the concentration-time profiles were analyzed using the non-compartmental analysis model of Phoenix® WinNonlin® 6.4.0.768.
  • dose-normalized PK parameters after i.v. and oral administration were used from Aitkenhead et al., Br. J. Clin. Pharmac. (1988) 25, 264-268 as summarized below: Table 26.
  • Pharmacokinetics after IV and Oral Administration from Literature
  • Model-independent PK parameters estimated for the one subject dosed with 20 mg of the nalbuphine gel intraorally are summarized below in Table 27.
  • Model-independent PK parameters estimated for two subjects dosed with 16.8 mg of the nalbuphine gel intranasally are summarized below in Table 28:
  • PK parameters estimated after intranasal gel administration suggest that nalbuphine reaches the systemic circulation about 40 minutes faster than after oral or intraoral administration.
  • dose-normalized maximum drug plasma concentration is almost 5-fold greater after intranasal administration than measured after conventional oral administration implying more effective pharmacodynamic efficacy (i.e., pain relief).
  • Estimated bioavailability after intranasal administration is almost twice of the value calculated for oral or intraoral administration despite a substantially greater total clearance. Reduced half-life correlates with increased total clearance.

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Abstract

La présente invention concerne une trousse pour l'administration par voie muqueuse d'une solution sursaturée métastable d'un agent pharmaceutique actif à un patient humain qui comprend un premier compartiment comprenant une première composition comprenant un agent pharmaceutique actif en solution à ou au-dessous de la solubilité à l'équilibre, et une deuxième composition comprenant un tampon acide. Les premier et deuxième compartiments maintiennent la séparation des première et deuxième compositions pendant le stockage, et permettent le mélange des première et deuxième compositions pour former une solution sursaturée au-dessus de la solubilité à l'équilibre de l'agent pharmaceutique actif pour une administration immédiate par voie muqueuse à un patient humain. Dans un mode de réalisation, la deuxième composition comprend un tampon acide et la solution sursaturée a un pH acide. En variante, la deuxième composition comprend un tampon basique et la solution sursaturée a un pH basique.
PCT/US2018/017384 2017-02-10 2018-02-08 Compositions chimiquement stables d'un agent pharmaceutique actif dans un système de distribution à chambres multiples pour administration par voie muqueuse Ceased WO2018148382A1 (fr)

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US12303472B2 (en) 2021-11-25 2025-05-20 Orexo Ab Pharmaceutical device for use in intranasal administration
US12472154B2 (en) 2021-11-25 2025-11-18 Orexo Ab Pharmaceutical composition comprising adrenaline

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