[go: up one dir, main page]

WO2018006069A1 - Formule améliorées pour systèmes transdermiques de distribution de médicaments. - Google Patents

Formule améliorées pour systèmes transdermiques de distribution de médicaments. Download PDF

Info

Publication number
WO2018006069A1
WO2018006069A1 PCT/US2017/040488 US2017040488W WO2018006069A1 WO 2018006069 A1 WO2018006069 A1 WO 2018006069A1 US 2017040488 W US2017040488 W US 2017040488W WO 2018006069 A1 WO2018006069 A1 WO 2018006069A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
hydrogel
transdermal patch
weight
fatty acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2017/040488
Other languages
English (en)
Inventor
Anthony DRAGER
Diane Gingrich
Paritosh WATTAMWAR
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Pharmaceuticals International GmbH
Original Assignee
Teva Pharmaceuticals International GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Teva Pharmaceuticals International GmbH filed Critical Teva Pharmaceuticals International GmbH
Publication of WO2018006069A1 publication Critical patent/WO2018006069A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K31/403—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 carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates

Definitions

  • the disclosure is in the field of transdermal formulations for therapeutic agents.
  • Transdermal systems including transdermal gels, transdermal patches, and iontophoretic transdermal patches, often include a hydrogel composition containing an active pharmaceutical ingredient and other excipients.
  • a hydrogel composition containing an active pharmaceutical ingredient and other excipients.
  • one or more components of the hydrogel composition precipitate from the hydrogel after storage at cold temperatures. Precipitation can lead to failure of the hydrogel system, including leakage of the hydrogel from a transdermal patch system or non-effectiveness of the hydrogel system in transdermally delivering the active pharmaceutical ingredient.
  • the present disclosure provides hydrogel compositions for use in transdermal gels and transdermal patches, the hydrogels comprising an active pharmaceutical ingredient or pharmaceutically acceptable salt thereof, a solubilizing agent, and a C 12 to C 14 saturated fatty acid, a Ce to C 10 saturated fatty acid, a Ce to C30 unsaturated fatty acid, or a combination thereof.
  • the hydrogel compositions of the disclosure have an acid-base ratio of between about 0.8 and 1.05. Methods of making and using these hydrogel compositions are also described.
  • transdermal patches including a hydrogel comprising sumatriptan or a pharmaceutically acceptable salt thereof, one or more butylated methacrylate copolymers, one or more e to C30 unsaturated fatty acids, one or more C4-C2 0 dicarboxylic acids, methyl para-hydroxybenzoate, and water.
  • a hydrogel comprising sumatriptan or a pharmaceutically acceptable salt thereof, one or more butylated methacrylate copolymers, one or more e to C30 unsaturated fatty acids, one or more C4-C2 0 dicarboxylic acids, methyl para-hydroxybenzoate, and water.
  • Figure 1 depicts pharmacokinetic data from testing of some transdermal patches having hydrogels of the present disclosure.
  • Figure 2 depicts viscosity data from stability testing of some hydrogels of the present disclosure.
  • Figure 3 depicts conductivity data from stability testing of some hydrogels of the present disclosure.
  • Figure 4 depicts viscosity data from stability testing of some hydrogels of the present disclosure.
  • Figure 5 depicts in vitro pharmacokinetic data from testing of some hydrogels of the present disclosure.
  • Figure 6 depicts in vitro pharmacokinetic data from testing of some hydrogels of the present disclosure.
  • Figure 7 depicts viscosity data from testing of some hydrogels of the present disclosure.
  • the present disclosure is directed to hydrogel compositions, in particular, those hydrogel compositions comprising an active pharmaceutical ingredient (or salt thereof) that are used, for example, in transdermal gels and in transdermal patches, including, for example, ionophoretic transdermal patches.
  • the hydrogel compositions of the disclosure have an acid-base ratio of between about 0.8 and less than 1.1, preferably 1.05 or less. These hydrogel compositions are advantageous over previously described hydrogel compositions not having the recited acid-base ratio, because the described hydrogel compositions do not exhibit precipitation of any hydrogel component after storage of the hydrogel (either alone or as part of a transdermal patch) at or below a threshold temperature for a threshold period of time.
  • substantially identical products that include hydrogels (either alone or as part of a transdermal patch) having an acid-base ratio of 1.05 or greater, for example 1.05 to about 1.8, exhibit precipitation of at least one hydrogel component after storage of the substantially identical hydrogel (either alone or as part of a transdermal patch) at that threshold temperature for that threshold period of time.
  • precipitation refers to the formation of insoluble solids within a hydrogel composition. Precipitation can be qualitatively determined by visual observation. Precipitation in a hydrogel composition will result in a change in the appearance or physical properties of the hydrogel composition. For example, precipitation in a hydrogel composition may result in a transparent hydrogel becoming less transparent. Alternatively, precipitation may result in a lowering of viscosity of the hydrogel composition.
  • the precipitating component may be any of the components of the hydrogels, e.g. one or more of the API, fatty acid, dicarboxylic acid, antioxidant, additive, solubilizing agent, and methylparaben. In some embodiments, the precipitating component is a fatty acid.
  • the threshold temperature at which precipitation of at least one hydrogel component occurs will depend upon the composition of a particular reference hydrogel. In some instances, precipitation can occur in a reference hydrogel composition when the reference hydrogel composition is exposed to a temperature that is at or below a threshold temperature of about 25 °C, about 20 °C, about 15 °C, about 12 °C, about 10 °C, about 8 °C, about 5 °C, or about 0 °C.
  • precipitation may not occur until the reference hydrogel is exposed to the threshold temperature for a threshold period of time, i.e., is stored for a period of time, which may be about 1 minute, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 18 hours, or about 24 hours.
  • the reference hydrogel will exhibit precipitation after being exposed to a temperature of 15 °C for 30 minutes or 15 °C for 60 minutes.
  • storage can refer to storage or shipment conditions, or any combinations thereof, of the hydrogels.
  • the reference hydrogel will exhibit precipitation after being exposed to a temperature of 10 °C for 8 hours, a temperature of 10 °C for 24 hours, a temperature of 5 °C for 8 hours, a temperature of 5 °C for 24 hours, a temperature of 0 °C for 8 hours, or a temperature of 0 °C for 24 hours. In some instances, the reference hydrogel will exhibit precipitation after being exposed to one or more freeze-thaw cycles.
  • a hydrogel composition In a freeze-thaw cycle, a hydrogel composition is first exposed to a sufficiently low temperature for a sufficiently long period of time such that the hydrogel composition freezes into a solid and then exposed to a sufficiently high temperature for a sufficiently long period of time such that the hydrogel composition thaws from the solid state into a gel state.
  • the reference hydrogel will exhibit precipitation after being exposed to one or more freeze-thaw cycles between temperatures of 25 °C and -20 °C.
  • hydrogel compositions of the disclosure do not exhibit precipitation when exposed to a temperature at or below a threshold temperature of about 25 °C, about 20 °C, about 15 °C, about 12 °C, about 10 °C, about 8 °C, about 5 °C, or about 0 °C.
  • hydrogel compositions of the disclosure do not exhibit precipitation when they are exposed to the threshold temperature for a threshold period of time, i.e., are stored for a period of time, which may be about 1 minute, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 18 hours, or about 24 hours.
  • hydrogel compositions of the disclosure will not exhibit precipitation after being exposed to a temperature of 15 °C for 30 minutes or 15 °C for 60 minutes. In further preferred aspects, hydrogel compositions of the disclosure will not exhibit precipitation after being exposed to a temperature of 10 °C for 8 hours, a temperature of 10 °C for 24 hours, a temperature of 5 °C for 8 hours, a temperature of 5 °C for 24 hours, a temperature of 0 °C for 8 hours, or a temperature of 0 °C for 24 hours. In further preferred aspects, hydrogel compositions of the disclosure will not exhibit precipitation after being exposed to one or more freeze-thaw cycles. In some preferred aspects, hydrogel compositions of the disclosure will not exhibit precipitation after being exposed to one or more freeze-thaw cycles between temperatures of 25 °C and -20 °C.
  • the hydrogel compositions of the disclosure can be part of a transdermal hydrogel.
  • the hydrogel compositions of the disclosure are part of a transdermal patch, for example, an iontophoretic transdermal patch.
  • the hydrogel compositions of the disclosure comprise water, an active pharmaceutical ingredient (or a pharmaceutically acceptable salt thereof), a solubilizing agent, and a C 12 to C 14 saturated fatty acid, a Ce to C 10 saturated fatty acid, a Ce to C30 unsaturated fatty acid, or a combination thereof.
  • the hydrogel compositions of the disclosure comprise water, an active pharmaceutical ingredient (or a salt form thereof), a solubilizing agent, and a Ce to C lo saturated fatty acid, while excluding a C 12 to C 14 saturated fatty acid.
  • Other hydrogel compositions of the disclosure comprise water, an active pharmaceutical ingredient (or a salt form thereof), a solubilizing agent, and a Ce to C30 unsaturated fatty acid, while excluding a C12 to C M saturated fatty acid.
  • Other hydrogel compositions of the disclosure comprise water, an active pharmaceutical ingredient (or a salt form thereof), a solubilizing agent, and a C12 to C M saturated fatty acid.
  • Hydrogel compositions of the disclosure may also include one or more C 4 to C20 dicarboxylic acids. Hydrogel compositions of the disclosure may further comprise methylparaben. Hydrogel compositions of the disclosure may further comprise one or more antioxidants. Hydrogel compositions of the disclosure may further comprise one or more additives. Active Pharmaceutical Iri2redients
  • hydrogels of the present disclosure include one or more active pharmaceutical ingredients (“APIs”) or a pharmaceutically acceptable salt thereof.
  • APIs active pharmaceutical ingredients
  • the hydrogels of the disclosure include one active pharmaceutical ingredient, or a pharmaceutically acceptable salt thereof.
  • the API may be a cationic molecule as a salt of an acid or diacid.
  • the API is suitable for use in transdermal treatments of drug responsive states.
  • the API can be suitable for use in iontophoretic systems. Suitable APIs or pharmaceutically acceptable salts thereof include, but are not limited to, baclofen, acyclovir, prilocaine, terbinafine
  • hydrochloride bupivacaine, dexamethasone sodium phosphate, epinephrine, fentanyl citrate, ketoprofen sodium, lidocaine HC1, methylprednisolone sodium succinate, morphine sulfate, naproxen sodium, sodium salicylate, triamcinolone diacetate, tretinoin, triptans, metoprolol tartarate, propranolol HC1, nadolol, timolol maleate, captopril, atenolol, buprenorphine, diclofenac, nalbuphine, and sumatriptan succinate.
  • the API, combination of APIs, or pharmaceutically acceptable salts thereof, are present in the hydrogel compositions of the disclosure at a concentration of between about 0.1 wt.% and about 30 wt.%, about 1 wt.% and about 10 wt.%, about 1 wt.% and about 9 wt.%, about 3 wt.% and about 5 wt.%, between about 3.5 wt.% and about 4.5 wt.%, or about 4 wt.%, based on the weight of the hydrogel composition.
  • the API can be present in the hydrogel composition at a concentration of about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6,
  • the hydrogel compositions of the disclosure include a solubilizing agent.
  • Suitable solubilizing agents can aid in the dissolution of acidic components in the transdermal hydrogel compositions and are toxicologically safe and suitable for use in transdermal pharmaceutical products.
  • the solubilizing agents are compounds having at least two positively charged functional groups, e.g., at least two positively charged nitrogen- containing groups, upon being dissolved in water or an aqueous solvent.
  • the solubilizing agent can be a butylated methacrylate copolymer, chitosan, poly(lysine), polyethylenimine, triethanolamine, triethylamine, HEPES (4-(2-hydroxyethyl)- 1-piperazineethanesulfonic acid), a cation exchange resin, or a combination thereof.
  • the solubilizing agent forms a complex with acidic components of the hydrogel compositions.
  • the solubilizing agents may be water soluble or water insoluble on their own.
  • the solubilizing agents contained in the hydrogels of the present disclosure are polyamine compounds. Suitable polyamine compounds are described more fully in U. S. Patent No. 8,366,600, which is incorporated herein in its entirety.
  • Polyamine compounds of the disclosure have at least two amino groups that can be primary amino groups, secondary amino groups, tertiary amino groups, or a combination thereof.
  • the polyamine compounds may also comprise, for instance, pyrrolidinyl, piperidinyl, and/or morpholinyl groups.
  • any polyamine compounds containing at least two amino groups may be used in the hydrogels of the present disclosure, provided that they are toxicologically safe and suitable for use in transdermal pharmaceutical products.
  • Polyamine compounds useful for producing the hydrogels of the present disclosure may further be selected from, for example, cyclic and macrocyclic polyamines (e.g., cyclen), polyamines based on the aziridine monomer(e.g., polyethylene imines), polyethylene amines, putrescine, cadaverine, spermidine, spermine, polypropyleneimine, polyvinylamine, polyvinylimine, polyvinylimidazol, polyvinylpyridine, and polyguanidines.
  • the polyamine compounds of the present invention have a weight average molar mass of 1500 grams per mole or above. Weight average molar mass may be determined based on size exclusion chromatography (SEC) methods.
  • the polyamine compound may be an acrylate copolymer, a methacrylate copolymer, an alkylated acrylate copolymer, an alkylated methacrylate copolymer, or a combination thereof. These copolymers contain two or more amino groups as defined above.
  • the polyamine compounds to be used in accordance with the hydrogel compositions of the disclosure can be present in the hydrogel compositions in the form of polyamine salts, particularly water-soluble polyamine salts. Suitable salts are obtainable by combining the above-mentioned polyamines with suitable acids, preferably organic acids, by standard procedures known in the art.
  • the solubilizing agent can be a butylated methacrylate copolymer.
  • butylated methacrylate copolymer refers to a copolymer based on butyl methacrylate and that includes two or more primary amino (-NH 2 ) moieties.
  • the hydrogels of the disclosure can include one butylated methacrylate copolymer. In other aspects, the hydrogels of the disclosure include two or more independently selected butylated methacrylate copolymers.
  • Exemplary butylated methacrylate copolymers include, but are not limited to, the "basic butylated methacrylate copolymer” described in the Pharmacopoea Europaea (Ph. Eur.), the “amino methacrylate copolymer” described in the United States
  • EUDRAGIT® Evonik Industries, Essen, Germany
  • EUDRAGIT® RL 100 a copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quatemary ammonium groups
  • EUDRAGIT® RL PO a copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups
  • EUDRAGIT® RS 100 a copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups
  • EUDRAGIT® RS PO a copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups
  • EUDRAGIT® RS PO a copolymer of ethyl acrylate
  • EUDRAGIT® E 100 is a preferred butylated methacrylate copolymer having a weight average molar mass of approximately 47,000 grams per mole. EUDRAGIT® E 100 provides 169, or about 169, basic functional groups or base equivalents per mole of EUDRAGIT® E 100.
  • the total concentration of solubilizing agent present in the hydrogels of the disclosure is between about 3.0 wt.% and about 12.0 wt.%, between about 4.0 wt.% and about 9.0 wt.%, between about 7.0 wt.% and about 9.0 wt.%, about 8.5 wt.%, or about 8.0 wt.%, based on the weight of the hydrogel composition.
  • the total concentration of solubilizing agent present in the hydrogels of the disclosure is about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or about 12 wt.%, based on the weight of the hydrogel composition.
  • the total concentration of the solubilizing agent present in the hydrogels of the disclosure may be selected in order to form hydrogel compositions having a desired molar acid-base ratio, as described more fully herein.
  • Hydrogel compositions described herein may include one or more Ce to C M saturated fatty acids.
  • Ce to C M saturated fatty acids encompasses an aliphatic chain having the designated number of carbon atoms (i.e., six to 14 carbon atoms) and one carboxylic acid moiety.
  • C 6 to Ci4 saturated fatty acids include, for example, a C 6 , C 7 , C 8 , C9, C 10 , C11, C12, Ci3, or C M saturated fatty acids.
  • the hydrogels of the disclosure include a combination of two or more independently selected Ce to C 14 saturated fatty acids, for example, a combination of two or more independently selected C 6 , C 7 , C 8 , C9, C LO , Cn, C12, Ci3, or Ci4 saturated fatty acids.
  • one or more of the saturated fatty acids is a C 12 to C 14 saturated fatty acid for example, lauric acid (C 12 ), myristic acid (C 14 ), or a combination thereof.
  • Some hydrogel compositions of the disclosure include fatty acids that are C 12 to C 14 saturated fatty acids and exclude fatty acids having 11 carbons or less or 15 or more carbons.
  • one or more of the unsaturated fatty acids is a Ce to C LO saturated fatty acid, for example, hexanoic acid (C 6 ), octanoic acid (C 8 ), decanoic acid (C LO ), or a combination thereof.
  • Some hydrogel compositions of the disclosure include fatty acids that are Ce to C LO saturated fatty acids and exclude fatty acids having 5 carbons or less or 11 or more carbons.
  • the Ce to C 14 saturated fatty acid can be present in a total concentration of between about 1 wt.% and about 12 wt.%, between about 2 wt.% and about 7 wt.%, between about 2 wt.% and about 6 wt.%, or between about 2 wt.% and about 4 wt.%.
  • the total concentration of the Ce to C 14 saturated fatty acid can be about 1 , 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 1 1, 1 1.5, or about 12 wt.%, based on the weight of the hydrogel.
  • the total concentration of the Ce to C 14 saturated fatty acid present in the hydrogels of the disclosure may be selected in order to form hydrogel compositions having a desired molar acid-base ratio, as described more fully herein.
  • the hydrogel compositions described herein may include one or more Ce to C30 unsaturated fatty acids.
  • Ce to C30 unsaturated fatty acid encompasses an aliphatic chain having the designated number of carbon atoms (i.e., six to 30 carbon atoms), at least one double bond within that chain, and one carboxylic acid moiety.
  • the at least one double bond can reside within the aliphatic chain or more than one double bond can be combined to form an aromatic moiety (e.g., phenyl) within the aliphatic chain.
  • the Ce to C30 unsaturated fatty acids include, for example, a C 6 , C 7 , C 8 , C9,
  • Cio Cio, Cll, C12, Cl3, Cl4, Cl5, Cl6, Cl7, Cl8, Cl9, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, or
  • the hydrogels of the disclosure include a combination of two or more independently selected Ce to C30 unsaturated fatty acids, for example, a combination of two or more independently selected Ce, C 7 , C 8 , C9, C 10 , Cn, C 12 ,
  • one or more of the unsaturated fatty acids is a C lo to C24 unsaturated fatty acid. In other aspects, one or more of the unsaturated fatty acids is a C lo to C2 0 unsaturated fatty acid. In yet other aspects, one or more of the unsaturated fatty acids is a C 12 to C20 unsaturated fatty acid.
  • the Ce to C30 unsaturated fatty acids can be selected from mono- (includes one double bond) or polyunsaturated (includes more than one double bond) fatty acids.
  • the Ce to C30 unsaturated fatty acids are selected from mono-, di-, and tri- unsaturated fatty acids.
  • Suitable mono-unsaturated fatty acids include, for example, undecylenic acid (Cn), tridecenoic acid (C 13 ), myristoleic acid (C 14 ), pentadecenoic acid (C 15), palmitoleic acid (C 16 ), sapienic acid (C 16 ), heptadecenoic acid (Cn), oleic acid (C 18 ), elaidic acid (C 18 ), vaccenic acid (C 18 ), nonadecenoic acid(Ci 9 ), gadoleic acid (C 20 ), gondoic acid (C20), paullinic acid (C 20 ), erucic acid (C 22 ), nervonic acid (C 24 ), or ricinoleic acid (C 18 ).
  • Suitable di-unsaturated fatty acids include, for example, linoleic acid (C 18 ), linoelaidic acid (C 18 ), eicosadienoic acid (C 20 ), or docosadienoic acid (C 22 ), or combinations thereof.
  • Suitable tri-unsaturated fatty acids include, for example, linolenic acid (C 18 ), pinolenic acid (C 18 ), eleostearic acid (C 18 ), mead acid (C 20 ), dihomo-Y-linolenic acid (C 20 ), or eicosatrienoic acid (C20), or combinations thereof.
  • the Ce to C30 unsaturated fatty acid is oleic acid.
  • the hydrogel composition comprising a Ce to C30 unsaturated fatty acid and excludes Ce to C 14 saturated fatty acids.
  • the Ce to C30 unsaturated fatty acid is present in a total concentration of between about 1 wt.% and about 12 wt.%, between about 2 wt.% and about 7 wt.%, between about 3 wt.% and about 6 wt.%, between about 4 wt.% and about 5.5 wt.%, between about 4.5 wt.% and about 5.0 wt.%, or about 4.8 wt.%, based on the weight of the hydrogel.
  • the total concentration of the Ce to C30 unsaturated fatty acid can be about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or about 12 wt.%, based on the weight of the hydrogel.
  • the total concentration of the Ce to C30 unsaturated fatty acid present in the hydrogels of the disclosure may be selected in order to form hydrogel compositions having a desired molar acid-base ratio, as described more fully herein.
  • the hydrogel compositions of the disclosure can include one or more C4 to C20 dicarboxylic acids.
  • C4 to C20 dicarboxylic acid refers to an aliphatic chain having the designated number of carbon atoms (i.e., four to 20 carbon atoms) and two carboxylic acid moieties.
  • the C4 to C20 dicarboxylic acids include, for example a C 4 , C5,C6, C7,Cg, C 9 ,Cio, C11, C12, Ci3, C M, Ci5, Ci6, Civ, Ci8, Ci9, or C 20 , dicarboxylic acid.
  • the hydrogels of the disclosure can include a combination of two or more independently selected C 4 to C20 dicarboxylic acids, for example, a combination of two or more
  • C4 to C20 dicarboxylic acids include, for example, glutaric acid (C5), adipic acid (C 6 ), pimelic acid (C7), and combinations thereof.
  • the total concentration of the C4 to C20 dicarboxylic acids in the hydrogels of the disclosure is between about 0.05 wt.% and about 5 wt.%, between about 0.1 wt.% and about 2.0 wt.%, between about 0.2 wt.% and about 0.4 wt.%, or about 0.3 wt.%, based on the weight of the hydrogel.
  • the total C4 to C20 dicarboxylic acid concentration in the hydrogels of the disclosure is about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5,
  • the total concentration of the C4 to C20 dicarboxylic acid present in the hydrogels of the disclosure may be selected in order to form hydrogel compositions having a desired molar acid-base ratio, as described more fully herein.
  • the hydrogel compositions of the disclosure may also include methyl parahydroxybenzoate, also known as methylparaben.
  • the methyl para-hydroxybenzoate can be present in the hydrogels of the disclosure a concentration between about 0.09 wt.% and about 0.2 wt.%, preferably between about 0.09 wt% and about 0.1 wt.%, based on the weight of the hydrogel.
  • the methyl parahydroxybenzoate can be present in the hydrogels of the disclosure at a concentration of about 0.09, 0.1 , 0.1 1 , 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or about 0.2 wt.%, based on the weight of the hydrogel composition.
  • the hydrogel compositions of the disclosure comprise an antioxidant or a combination of antioxidants.
  • the antioxidant may be added to, for example, prevent oxidation of the fatty acids, particularly unsaturated fatty acids, within the hydrogel compositions.
  • Preferred antioxidants include those that are Generally
  • the antioxidant may be a phenolic antioxidant, a polyphenol antioxidant, and/or a phenolic acid antioxidant.
  • the antioxidant may be one or more of butylated hydroxy toluene (BHT), also known as dibutylhydroxytoluene, butylated hydroxyanisole, and tocopherol.
  • BHT butylated hydroxy toluene
  • the antioxidant can be present in the hydrogels of the disclosure at a
  • concentration of between about 0.01 wt.% and about 0.2 wt.%, between about 0.01 wt.% and about 0.15 wt.%, between about 0.05 wt.% and about 0.12 wt.%, between about 0.09 wt.% and about 0.11 wt.%, or about 0.10 wt.%, based on the weight of the hydrogel.
  • the antioxidant can be present in the hydrogels of the disclosure at a concentration of about 0.01 , 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11 , 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or about 0.2 wt.%, based on the weight of the hydrogel.
  • the hydrogel compositions of the disclosure can also include additives. Additives can be added to modulate physical properties of the hydrogels, for example, viscosity, rigidity, and water permeability. For example, cholesterol can be added to the hydrogels of the disclosure.
  • the hydrogels of the disclosure may also include one or more fatty alcohols. Hydrogels of the disclosure may also include one or more triglycerides, phospholipids, sterols, lecithins, and steryl glucosides.
  • fatty alcohol refers to a straight or branched aliphatic chain including a primary -OH moiety. Fatty alcohols can include from four to 26 carbon atoms (C4-C26).
  • Some fatty alcohols include from four to six carbons (C4-C6). Other fatty alcohols can include 22 to 26 carbons (C22-C26).
  • the additives can be present in the hydrogels of the disclosure at a concentration of between about 0.01 wt.% and about 0.2 wt.%, between about 0.01 wt.% and about 0.15 wt.%, between about 0.05 wt.% and about 0.12 wt.%, between about 0.09 wt.% and about 0.11 wt.%, or about 0.10 wt.%, based on the weight of the hydrogel.
  • the additives can be present in the hydrogels of the disclosure at a concentration of about 0.01 , 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11 , 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or about 0.2 wt.%, based on the weight of the hydrogel.
  • the total concentration of the additional hydrogel composition components present in the hydrogels of the disclosure may be selected in order to form hydrogel compositions having a desired molar acid-base ratio, as described more fully herein.
  • acid-base ratio refers to the molar ratio between the total acidic functional groups and total basic functional groups in a hydrogel composition.
  • the acid-base ratio is an acid-amine ratio.
  • the acid-base (or acid-amine) ratio can be calculated by calculating the total moles of basic functional groups (e.g, amine groups), also referred to as the total number of base equivalents, and the total moles of acidic functional groups provided by the components in a particular hydrogel composition.
  • basic functional groups e.g, amine groups
  • acidic functional groups provided by the components in a particular hydrogel composition.
  • the number of base equivalents provided by a component may be known in the art for the component or can be determined by methods known in the art including titration.
  • EUDRAGIT® E 100 provides about 169 base equivalents per mole of EUDRAGIT® E 100 via amine equivalents.
  • the number of base equivalents provided by a component can be calculated from a known alkali value, which refers to an amount (mg KOH) that are equivalent to the basic groups contained in 1 gram of dry substance of the component.
  • the alkali value can be determined by a titration assay such as Ph. Eur. 2.2.20 "Potentiometric titration" or USP ⁇ 541> “Titrimetry", which are incorporated herein by reference in their entirety, or other titration methods for various materials as known in the art.
  • the number of base equivalents provided by a component can also be calculated by theoretically calculating the number of repeating units that provide base equivalents.
  • EUDRAGIT® E 100 is a copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate with a ratio of 2: 1 : 1 and an average molecular weight of approximately 47,000 g/mol. Calculations based on the 2: 1 : 1 ratio and the known monomer molecular weights of the three co-monomers determine that there are approximately 169 moles of dimethylaminoethyl groups, i.e. 169 moles of amine equivalents, per mole of EUDRAGIT® E 100.
  • the acidity of acidic components i.e. the number of acidic functional groups per mole of an acidic component, may be known in the art for particular acidic components or can be determined by methods known in the art including titration.
  • adipic acid is known to be a diprotic acid with two acidic functional groups per molecule.
  • the hydrogels of the present disclosure and provided by the methods of the present disclosure can have molar acid-base ratios of between about 0.80 and about 1.1 , between about 0.85 and 1.07, between about 0.90 and 1.05, between about 0.95 and 1.05, between about 0.98 and 1.02, or about 1.0.
  • the hydrogels of the present disclosure and provided by the methods of the present disclosure can have molar acid-base ratios of 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91 , 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.00, 1.01 , 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, or about 1.1.
  • the acid-base ratio of a hydrogel can be adjusted by increasing or decreasing the total concentration of acid-solubilizing agent or the concentration of polyamine present in the hydrogels.
  • hydrogel compositions of the disclosure can be prepared using conventional formulation methods known in the art. Those methods can include dissolving or dispersing the various ingredients in water or an aqueous solvent mixture while heating. The resulting mixtures may then be spread on a flat surface, and then allowed to gel to obtain hydrogel compositions having the desired properties (e.g. viscosity). During these process steps, or after gelling, the composition may be combined with additional components as required to produce the final product, generally a pharmaceutical administration form.
  • desired properties e.g. viscosity
  • compositions may be used, as will be readily realized by the skilled person.
  • hydrogels of the disclosure can be manufactured into transdermal gels or transdermal patches, including iontophoretic patches and iontophoretic drug delivery systems, using methods known in the art.
  • Preferred iontophoretic patch manufacturing is described in U. S. Patent No. 8,366,600, which is incorporated by reference herein.
  • Iontophoretic drug delivery systems are described more fully in U. S. Published Application No. US2013/0296766 Al , which is incorporated by reference herein.
  • Iontophoretic patches can comprise an anode reservoir, a cathode reservoir, and appropriate electrical circuitry.
  • the iontophoretic drug delivery systems can include a first electrode, a second electrode, a power controller (e.g., a power controller containing a microprocessor) configured to control a current flow between the first electrode and the second electrode, an anode reservoir holding an API-containing hydrogel of the disclosure, a cathode reservoir holding a sodium salt formulation, with said components contained within a housing.
  • ions are carried into the skin by an electrical current that is supplied by a positive and negative electrode.
  • Suitable current densities (calculated as current level divided by the contact surface area) during operation can be between about 0.05 mA/cm 2 and about 0.5 mA/cm 2 .
  • transdermal patches of the disclosure that include the described hydrogel compositions can be used to treat a drug responsive state.
  • drug responsive state refers to a disease or disorder that can be ameliorated by the administration of an active pharmaceutical ingredient, or a pharmaceutically acceptable salt of an active pharmaceutical ingredient.
  • drug responsive states include, for example, spasticity, hypersensitivity, inflammation, cancer, emesis, osteoarthritis, rheumatoid arthritis, fever, acne vulgaris, hypertension, glaucoma, pain, hormonal imbalances, diabetes, hypoglycemia, migraines, familiar hemiplegic migraines (with and without aura), chronic paroxysmal headaches, cluster headaches, migraine headaches, basilar migraines, and atypical headaches accompanied by autonomic symptoms.
  • the drug responsive state is a migraine.
  • a transdermal patch of the disclosure is applied to the skin of a subject in need of treatment and the current activated to initiate transdermal delivery of the active pharmaceutical ingredient or pharmaceutically acceptable salt thereof.
  • the present disclosure is also directed to methods of preparing hydrogel compositions, as well as methods of reformulating reference hydrogel compositions.
  • Particularly preferred reference hydrogel compositions that are suitable for reformulation comprise an API (or salt form thereof), a C 12 to CM saturated fatty acid, and a solubilizing agent.
  • the reformulation methods are particularly well-suited for reformulating reference hydrogel compositions having an acid- base ratio of from 1.05 and about 1.8 and that exhibit precipitation of a hydrogel component after storage at a threshold temperature for a threshold period of time, for example, that exhibit precipitation after storage at 15 °C for 30 minutes or after storage at 15 °C for 60 minutes.
  • Threshold temperatures can be about 25 °C, about 20 °C, about 15 °C, about 12 °C, about 10 °C, about 8 °C, about 5 °C, or about 0 °C.
  • precipitation will not occur until the reference hydrogel composition is exposed to the threshold temperature for a threshold period of time, which may be about 1 minute, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 18 hours, or about 24 hours.
  • a hydrogel composition produced according to the methods described herein will not exhibit precipitation when exposed to the threshold temperature for a threshold period of time, which may be about 1 minute, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 18 hours, or about 24 hours.
  • hydrogel compositions prepared according to the methods described herein will not exhibit precipitation after storage at 15 °C for 30 minutes or after storage at 15 °C for 60 minutes.
  • hydrogel compositions prepared according to the methods described herein will not exhibit precipitation after being exposed to a temperature of 10 °C for 8 hours, a temperature of 10 °C for 24 hours, a temperature of 5 °C for 8 hours, a temperature of 5 °C for 24 hours, a temperature of 0 °C for 8 hours, or a temperature of 0 °C for 24 hours.
  • Some methods of the disclosure include reducing the acid-base ratio of the reference hydrogel composition.
  • the acid-base ratio of the hydrogel composition prepared according to the described methods is between about 0.8 and less than 1.1, preferably 1.05 or less.
  • the acid-base ratio of the hydrogel composition prepared according to the described methods is about 0.9 and about 1.0.
  • the acid-base ratio of the hydrogel composition prepared according to the disclosure is about 1.0.
  • the acid-base ratio of the hydrogel compositions prepared according to the disclosure can be achieved by any number of methods, which are described herein.
  • Hydrogel compositions prepared according to the described methods will exhibit pharmacokinetic profiles that are similar to a reference compositions'
  • the hydrogel compositions of the disclosure will exhibit a viscosity that is similar to the viscosity of the reference hydrogel composition. In other aspects, the hydrogel compositions will exhibit a viscosity that is less than the viscosity of the reference composition. In yet other aspects, the hydrogel compositions will exhibit a viscosity that is greater than the viscosity of the reference hydrogel composition. For example, the hydrogel composition of the disclosure can exhibit a viscosity that is about 5- fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, or about 50-fold higher than the viscosity of the reference hydrogel composition.
  • the hydrogel composition of the disclosure can exhibit a viscosity that is about 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold-40-fold, 45-fold, or about 50-fold lower than the viscosity of the reference hydrogel composition.
  • Hydrogel compositions of the disclosure can exhibit a tackiness that is about the same as the tackiness of the reference hydrogel composition.
  • the tackiness of a hydrogel composition of the disclosure is about 2 times greater than the tackiness of the reference hydrogel composition.
  • the tackiness is about 3, 4, 5, 6, 7, 8, 9, or about 10 times greater than the tackiness of the reference hydrogel composition.
  • the tackiness is about 3, 4, 5, 6, 7, 8, 9, or about 10 times lower than the tackiness of the reference hydrogel composition.
  • the acid-base ratio of a reference hydrogel composition that comprises an API (or a salt form thereof), a C u to CM saturated fatty acid, and a solubilizing agent can be reduced by producing a hydrogel composition that includes an amount of the C 12 to CM saturated fatty acid that is less than the amount present in the reference hydrogel composition.
  • the C 12 to C 14 saturated fatty acid can be any C 12 to C 14 saturated acid previously described herein.
  • the C 12 to C 14 saturated fatty acid can be lauric acid (C 12 ), myristic acid (C 14 ), or a combination thereof.
  • the amount of the C 12 to C 14 saturated fatty acid in the produced hydrogel compositions can be about 0 wt.%, based on the weight of the produced hydrogel composition. In other aspects, the amount of the C 12 to C 14 saturated fatty acid in the produced hydrogel is between about 5 wt.% and about 95 wt.% of the amount of the C 12 to Ci4 saturated fatty acid present in the reference hydrogel composition.
  • the amount of the C 12 to C 14 saturated fatty acid in the produced hydrogel can be about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or about 95 wt.% of the amount of the C to Ci4 saturated fatty acid present in the reference hydrogel composition.
  • the methods further comprise adding a Ce to C 10 saturated fatty acid to the produced hydrogel composition, to produce a hydrogel composition having an acid-base ratio of between about 0.8 and less than 1.1, preferably 1.05 or less.
  • the produced hydrogel compositions can have an acid-base ratio of between about 0.9 and about 1.0 or an acid-base ratio of about 1.0.
  • the methods may comprise adding hexanoic acid (C 6 ), octanoic acid (C 8 ), decanoic acid (C lo ), or a combination thereof to the produced hydrogel in an amount of about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 wt.% of the amount of the C 12 to C 14 saturated fatty acid present in the reference hydrogel composition.
  • C 6 hexanoic acid
  • C 8 octanoic acid
  • decanoic acid C lo
  • some methods of the disclosure comprise preparing a hydrogel composition having an acid-base ratio of between about 0.8 and less than 1.1, preferably 1.05 or less, by combining an API (or salt for thereof), a solubilizing agent, a Ce to C 10 saturated fatty acid, and optionally, a C 12 to C 14 saturated fatty acid. These methods may further comprise combining the hydrogel composition components with a dicarboxylic acid, methyl paraben, an antioxidant, an additive, water, or any combination thereof.
  • the acid-base ratio of a reference hydrogel composition that includes an API (or salt form thereof), a C 12 to C 14 saturated fatty acid, and a solubilizing agent can be reduced by producing a hydrogel composition that includes an amount of the C 12 to CM saturated fatty acid that is less than the amount present in the reference hydrogel composition.
  • the C 12 to C 14 saturated fatty acid present in the reference hydrogel composition can be lauric acid (C 12 ), myristic acid (C 14 ), or a combination thereof.
  • the amount of the C 12 to C 14 saturated fatty acid in the produced hydrogel compositions can be about 0 wt.%, based on the weight of the produced hydrogel composition.
  • the amount of the C 12 to C M saturated fatty acid in the produced hydrogel is between about 5% and about 95% of the amount of the C 12 to C 14 saturated fatty acid present in the reference hydrogel composition.
  • the amount of the C to Ci4 saturated fatty acid in the produced hydrogel can be about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or about 95% of the amount of the C 12 to C 14 saturated fatty acid present in the reference hydrogel composition.
  • the reformulation methods further comprise adding a Ce to C30 unsaturated fatty acid to the produced hydrogel composition to result in an acid-base ratio of between about 0.8 and less than 1.1 , preferably 1.05 or less.
  • the produced hydrogel compositions can have an acid-base ratio of between about 0.9 and about 1.0 or an acid-base ratio of about 1.0.
  • the Ce to C30 unsaturated fatty acid that is added to the produced hydrogel composition can be any of the Ce to C30 unsaturated fatty acids described previously herein.
  • the Ce to C30 unsaturated fatty acid that is added to the produced hydrogel composition can be undecylenic acid (Cn), tridecenoic acid (C 13 ), myristoleic acid (C 14 ), pentadecenoic acid (C15), palmitoleic acid (C 16 ), sapienic acid (C 16 ), heptadecenoic acid (Cn), oleic acid (C 18 ), elaidic acid (C 18 ), vaccenic acid (C 18 ),
  • nonadecenoic acid(Ci9) gadoleic acid (C 20 ), gondoic acid (C 20 ), paullinic acid (C 20 ), erucic acid (C 22 ), nervonic acid (C 24 ), ricinoleic acid (C 18 ), linoleic acid (C 18 ), linoelaidic acid (C 18 ), eicosadienoic acid (C 20 ), or docosadienoic acid (C 22 ), linolenic acid (C 18 ), pinolenic acid (C 18 ), eleostearic acid (C 18 ), mead acid (C 20 ), dihomo-Y-linolenic acid (C 20 ), or eicosatrienoic acid (C20), or combinations thereof.
  • the Ce to C30 unsaturated fatty acid that is added to the produced hydrogel composition is oleic acid (C 18 ).
  • the reformulation methods may comprise adding e to C30 unsaturated fatty acid to the produced hydrogel composition in an amount of about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 wt.% of the amount of the C 12 to C 14 saturated fatty acid present in the reference hydrogel composition.
  • some methods of the disclosure comprise preparing a hydrogel composition having an acid-base ratio of between about 0.8 and less than 1.1, preferably 1.05 or less, by combining an API (or salt for thereof), a solubilizing agent, a C 6 to C30 unsaturated fatty acid, and optionally, a C 12 to C 14 saturated fatty acid. These methods may further comprise combining the hydrogel composition components with a dicarboxylic acid, methyl paraben, an antioxidant, an additive, water, or any combination thereof.
  • the acid-base ratio of a reference hydrogel composition that includes an API (or salt for thereof), a C 12 to C 14 saturated fatty acid, and a solubilizing agent can be reduced by producing a hydrogel composition that includes an amount of the solubilizing agent that is greater than the amount present in the reference hydrogel composition.
  • the amount of the solubilizing agent can be about 10 wt.% to about 70 wt.% greater than the amount of the solubilizing agent present in the reference hydrogel composition.
  • the amount of the solubilizing agent can be about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or about 70 wt.% greater than the amount of the solubilizing agent present in the reference hydrogel composition.
  • the amount of the solubilizing agent can be increased so as to produce a hydrogel composition having an acid- base ratio of between about 0.8 and less than 1.1, preferably 1.05 or less.
  • the produced hydrogel compositions can have an acid-base ratio of between about 0.9 and about 1.0 or an acid-base ratio of about 1.0.
  • the solubilizing agent can be any of the solubilizing agents previously described herein.
  • the solubilizing agent can be a butylated methacrylate copolymer, chitosan, poly(lysine), polyethylenimine, triethanolamine, triethylamine, HEPES (4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid), a cation exchange resin, or a combination thereof.
  • the solubilizing agent can be EUDRAGIT® RL 100 (a copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups), EUDRAGIT® RL PO (a copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups), EUDRAGIT® RS 100 (a copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups), EUDRAGIT® RS PO (a copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups), EUDRAGIT® E 100 (a cationic copolymer based on dimethylaminoethyl methacrylate, EU
  • some methods of the disclosure comprise preparing a hydrogel composition having an acid-base ratio of between about 0.8 and less than 1.1, preferably 1.05 or less, by combining an API, a solubilizing agent, and a C 12 to C 14 saturated fatty acid. These methods may further comprise combining the hydrogel composition components with a dicarboxylic acid, methyl paraben, an antioxidant, an additive, water, or any combination thereof.
  • treat refers to the reduction or amelioration of one or more symptoms of a drug responsive state. It also may include the prevention of the occurrence or reoccurrence of a drug responsive state.
  • subject refers to living organisms capable of having drug responsive states (e.g., mammals). Examples of subjects include humans, dogs, cats, horses, cows, goats, rats and mice. In one embodiment, the subject is a human. In a further embodiment, the term includes subjects suffering from a drug responsive state.
  • drug responsive states e.g., mammals. Examples of subjects include humans, dogs, cats, horses, cows, goats, rats and mice. In one embodiment, the subject is a human. In a further embodiment, the term includes subjects suffering from a drug responsive state.
  • pharmaceutically acceptable salt refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature.
  • Pharmaceutically acceptable salts of active pharmaceutical ingredients which may be used in the methods, hydrogels, and transdermal patches of the invention include, but are not limited to, chloride, bromide, iodide, sulfuric, phosphate, lactate, citrate, tartarate, salicylate, succinate, maleate, gluconate, mesylate, laurate, dodecylate, myristate, palmitate, stearate, coconoate, behinate, oleate, linoleate, linolenate, eicosapentaenoate, eicosahexaenoate, docosapentaenoate,
  • docosahexaenoate docosahexaenoate, eicosanoids and the like.
  • transdermal formulations including a hydrogel comprising sumitriptan can be provided.
  • ZECUITYTM is an iontophoretic transdermal system currently marketed in the United States by Teva Pharmaceuticals USA, Inc. for the treatment of migraines.
  • ZECUITYTM contains a hydrogel poly amine formulation of sumatriptan (l-[3-(2- dimethylaminoethyl)-lH-indol-5-yl]-N-methyl-methanesulfonamide) and it is highly effective in treating migraine headache pain within two hours of application. Patients report that ZECUITYTM also reduces the nausea, sensitivity to sound, and sensitivity to light that are commonly associated with migraines.
  • the ZECUITYTM hydrogel is highly temperature sensitive. At temperatures below 15 °C, components of the hydrogel precipitate and the viscosity drops significantly, resulting in leakage of the hydrogel from the patch. As a result, ZECUITYTM must be stored and shipped within a narrow temperature window - between 20 °C and 25 °C - with only limited excursion times permitted between 15 °C and 30 °C. Winter-time distribution is particularly problematic.
  • ZECUITYTM's temperature-sensitivity requires a temperature-controlled supply chain with specific packaging requirements to ensure that the temperature remains stable during distribution.
  • the temperature-controlled supply chain significantly increases the costs associated with the ZECUITYTM product.
  • the present disclosure is directed to transdermal patches including a hydrogel comprising sumatriptan or a pharmaceutically acceptable salt thereof, one or more butylated methacrylate copolymers, one or more C 6 to C30 unsaturated fatty acids, one or more C4-C20 dicarboxylic acids, methyl para-hydroxybenzoate, and water.
  • a hydrogel comprising sumatriptan or a pharmaceutically acceptable salt thereof, one or more butylated methacrylate copolymers, one or more C 6 to C30 unsaturated fatty acids, one or more C4-C20 dicarboxylic acids, methyl para-hydroxybenzoate, and water.
  • the present disclosure is directed to transdermal patches including a hydrogel comprising sumatriptan or a pharmaceutically acceptable salt thereof, one or more butylated methacrylate copolymers, one or more C 6 to C30 unsaturated fatty acids, one or more C4-C20 dicarboxylic acids, methyl para-hydroxybenzoate, and water.
  • the hydrogel comprises sumatriptan.
  • the hydrogel comprises a pharmaceutically acceptable salt of sumatriptan, with sumatriptan succinate being particularly preferred.
  • the sumatriptan is present in the hydrogel at a concentration of between about 3 wt.% and about 5 wt.%, between about 3.5 wt.% and about 4.5 wt.%, or about 4 wt.%, based on the weight of the hydrogel.
  • the sumatriptan can be present in the hydrogel at a concentration of about 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or about 5.0 wt.%, based on the weight of the hydrogel.
  • the transdermal patches of the disclosure that include the described hydrogels can be used to treat a sumatriptan responsive state.
  • a sumatriptan responsive state is a type of drug responsive state and refers to a disease or disorder that can be ameliorated by the administration of sumatriptan, or a
  • Sumatriptan responsive states include, for example, migraines, familiar hemiplegic migraines (with and without aura), chronic paroxysmal headaches, cluster headaches, migraine headaches, basilar migraines, and atypical headaches accompanied by autonomic symptoms.
  • the sumatriptan responsive state is a migraine.
  • a transdermal patch of the disclosure is applied to the skin of a subject in need of treatment and the current activated to initiate transdermal delivery of the sumatriptan or pharmaceutically acceptable salt thereof.
  • Example 1 Sumatriptan Compositions.
  • Hydrogel A is equivalent to the hydrogel used within the ZECUITYTM transdermal system.
  • the theoretically calculated molar acid-base ratios were based on a value of 168 base equivalents per mole of EUDRAGIT® E 100, 0.0036 moles of DMAE per gram of dry substance.
  • the number of acid equivalents was determined by counting one mole of acid equivalent per mole of sumatriptan succinate, oleic acid, and decanoic acid and two moles of acid equivalents per mole of adipic acid.
  • Example 2 Sumatriptan delivery of Hydrogels A, B, C, D, and E within transdermal patches.
  • Blood samples of approximately 1 mL were collected via a jugular vein into tubes containing K 2 EDTA anticoagulant from each animal predose and at 0.25, 0.5, 1, 1.5, 2,
  • the blood samples were placed in a refrigerated centrifuge within 20 minutes of collection and spun at high speed (2500 RPM) for 10 to 15 minutes at 4°C to obtain plasma. For each sample collected, plasma was transferred into an appropriately labeled polypropylene microcentrifuge tube. The cellular fraction of the blood was discarded. The plasma samples were immediately placed on dry ice and then frozen at approximately -20°C within 2 hours after collection. All samples were shipped on sufficient dry ice to Pharmaceutical Product Development (PPD), Inc. (Richmond, VA; PPD), for the determination of sumatriptan concentrations.
  • PPD Pharmaceutical Product Development
  • FIG. 1 depicts plasma mean sumatriptan concentration (+SD) following dermal application of the five sumatriptan-containing hydrogels of Example 1 :
  • Example 3 In vitro iontophoretic assay of Hydrogels A, B, C, D, and E
  • the five sumatriptan-containing hydrogels of Example 1 were tested in an in vitro iontophoretic assay.
  • the five formulations were compared for total sumatriptan delivered and the flux of sumatriptan.
  • the results are shown in FIGs. 5 and 6.
  • the testing apparatus was an iontophoretic diffusion cell, as described in Glikfeld et. al., "A New System for Vitro Studies of Iontophoresis," Pharmaceutical Research, 5(7), 1988, 443-446, which is incorporated by reference herein in its entirety for all purposes.
  • the testing apparatus used pig skin with a thickness of 800 ⁇ and area of 0.8 cm 2 , a zinc sheet anode, a Ag/AgCl sheet electrode (Ag sheet electroplated with AgCl, prepared fresh for each test), a current density of 0.4 mA/cm 2 with current profile of 0.32 mA for 4 hours.
  • the sheet electrodes were dipped in each testing sample, a portion of the bulk hydrogel in direct contact with the epidermal side of the pig skin, and an external potentiometer was used to drive the current. Samples were collected every 30 minutes for four hours per test sample, in 4-5 mL aliquots. Samples were analyzed by HPLC and UV Spectroscopy by conventional methods known in the art.
  • Anova Oneway analysis of variance
  • Example 4 Formulation properties of Hydrogels A, B, C, D, and E in transdermal patches.
  • Shear rate was ramped from 0.001 to 100 s "1 with viscosity values reported at a shear rate of 1 s "1 .
  • Conductivity was measured with a Mettler ToledoTM conductivity meter and probe, with the probe dipped in bulk hydrogel for measurements.
  • Example 5 Calculation of alkali value and base equivalents of EUDRAGIT® E 100 via titration
  • EUDRAGIT® E 100 The alkali value of EUDRAGIT® E 100 can be determined via titration assays.
  • EUDRAGIT® E 100 is a copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate with a ratio of 2: 1 : 1 and an average molecular weight of approximately 47,000 g/mol.
  • 0.2 g of EUDRAGIT® E 100 dry substance (DS) can be dissolved in 96 ml glacial acetic acid and 4 ml water.
  • 0.1 N perchloric acid can be used as the titrant.
  • One mL of 0.1 N perchloric acid is equivalent to 7.21 mg of dimethylaminoethyl (DMAE) groups (C 4 H 10 N).
  • DMAE dimethylaminoethyl
  • EUDRAGIT® E 100 can have alkali values from 162 to 198 mg KOH per gram of dry substance.
  • KOH has a molecular weight of 56.1 g/mol.
  • EUDRAGIT® E 100 can be determined via theoretical calculations of repeating units of the co-monomers.
  • EUDRAGIT® E 100 is a copolymer of dimethylaminoethyl methacrylate (monomer molecular weight 157.21 g/mol), butyl methacrylate (monomer molecular weight 142.20 g/mol), and methyl methacrylate (monomer molecular weight 100.12 g/mol) with a ratio of 2: 1 : 1 and an average molecular weight of approximately 47,000 g/mol.
  • Calculations can be used to iteratively solve for the number of repeating units of each co-monomer to yield the approximate molecular weight, based on the known 2: 1 : 1 ratio and the molecular weights of the three co-monomers. These calculations determine that there are approximately 169 moles of dimethylaminoethyl groups, i.e. 169 moles of base equivalents, per mole of EUDRAGIT® E 100, which is equivalent to 0.0036 moles of base equivalents per gram of dry substance.

Landscapes

  • Health & Medical Sciences (AREA)
  • Dermatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Les composés d'hydrogel comprenant un ingrédient pharmaceutique actif (ou un sel comparable de celui-ci), un agent de solubilisation et un acide gras saturé C 12 à C 14 , un acide gras saturé C 6 à C 10 , un acide gras insaturé C 6 à C 30 , ou une combinaison de ceux-ci. Les compositions d'hydrogel de l'invention a des rapports molaires acide-base compris entre 0,8 et 1,05. Les procédés de production et d'utilisation de ces composés d'hydrogel sont également discutés. L'ingrédient pharmaceutique actif étant le sumatriptan, les composés d'hydrogel sont utilisés dans des procédés pour traiter des conditions sensibles au sumatriptan, telles que les migraines, avec des timbres transdermiques.
PCT/US2017/040488 2016-06-30 2017-06-30 Formule améliorées pour systèmes transdermiques de distribution de médicaments. Ceased WO2018006069A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201662356665P 2016-06-30 2016-06-30
US201662356659P 2016-06-30 2016-06-30
US62/356,659 2016-06-30
US62/356,665 2016-06-30

Publications (1)

Publication Number Publication Date
WO2018006069A1 true WO2018006069A1 (fr) 2018-01-04

Family

ID=59351113

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2017/040488 Ceased WO2018006069A1 (fr) 2016-06-30 2017-06-30 Formule améliorées pour systèmes transdermiques de distribution de médicaments.

Country Status (1)

Country Link
WO (1) WO2018006069A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11464760B2 (en) * 2017-12-20 2022-10-11 Lts Lohmann Therapie-Systeme Ag Frigostable composition for iontophoretic transdermal delivery of a triptan compound

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0913158A1 (fr) * 1997-09-17 1999-05-06 Permatec Technologie Ag Patch transdermal comprenant une combinaison de deux ou plus de deux acides ou alcools gras comme agents favorisant la pénétration cutanée
EP1253913A1 (fr) * 2000-01-26 2002-11-06 F.T. Holdings S.A. Timbre destine a l'administration transdermique et locale de principes actifs contenant des groupes anioniques ou electroattracteurs
US6503532B1 (en) * 2001-04-13 2003-01-07 Murty Pharmaceuticals, Inc. Pharmaceutical composition containing tetrahydrocannabinol and a transdermal/transcutaneous delivery method thereof
WO2006008320A2 (fr) * 2004-07-23 2006-01-26 Laboratorio Italiano Biochimico Farmaceutico Lisapharma S.P.A. Nouveau dispositif de distribution de principes actifs
EP2011488A1 (fr) * 2006-03-06 2009-01-07 Chongqing Pharmaceutical Research Institute Co., Ltd. Timbre transdermique contenant de la rasagiline utilise dans le traitement ou la prevention de maladies du systeme nerveux et procede de preparation associe
US8366600B2 (en) 2008-06-19 2013-02-05 Nupathe Inc. Polyamine enhanced formulations for triptan compound iontophoresis
US20130296766A1 (en) 2010-11-23 2013-11-07 Nupathe Inc. User-activated self-contained co-packaged iontophoretic drug delivery system

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0913158A1 (fr) * 1997-09-17 1999-05-06 Permatec Technologie Ag Patch transdermal comprenant une combinaison de deux ou plus de deux acides ou alcools gras comme agents favorisant la pénétration cutanée
EP1253913A1 (fr) * 2000-01-26 2002-11-06 F.T. Holdings S.A. Timbre destine a l'administration transdermique et locale de principes actifs contenant des groupes anioniques ou electroattracteurs
US6503532B1 (en) * 2001-04-13 2003-01-07 Murty Pharmaceuticals, Inc. Pharmaceutical composition containing tetrahydrocannabinol and a transdermal/transcutaneous delivery method thereof
WO2006008320A2 (fr) * 2004-07-23 2006-01-26 Laboratorio Italiano Biochimico Farmaceutico Lisapharma S.P.A. Nouveau dispositif de distribution de principes actifs
EP2011488A1 (fr) * 2006-03-06 2009-01-07 Chongqing Pharmaceutical Research Institute Co., Ltd. Timbre transdermique contenant de la rasagiline utilise dans le traitement ou la prevention de maladies du systeme nerveux et procede de preparation associe
US8366600B2 (en) 2008-06-19 2013-02-05 Nupathe Inc. Polyamine enhanced formulations for triptan compound iontophoresis
US20130296766A1 (en) 2010-11-23 2013-11-07 Nupathe Inc. User-activated self-contained co-packaged iontophoretic drug delivery system

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GLIKFELD: "A New System for In Vitro Studies of Iontophoresis", PHARMACEUTICAL RESEARCH, vol. 5, no. 7, 1988, pages 443 - 446

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11464760B2 (en) * 2017-12-20 2022-10-11 Lts Lohmann Therapie-Systeme Ag Frigostable composition for iontophoretic transdermal delivery of a triptan compound

Similar Documents

Publication Publication Date Title
US10881606B2 (en) Composition for transdermal delivery of cationic active agents
AU2013278403B2 (en) Adhesive preparation composition obtained by blending drug, organic solvent, lipophilic ointment base, and powder
CN102065807B (zh) 用于曲坦类化合物离子电渗疗法的多胺增强制剂
WO2018006069A1 (fr) Formule améliorées pour systèmes transdermiques de distribution de médicaments.
JP7263359B2 (ja) トリプタン化合物のイオントフォレーシス経皮送達のための寒冷安定性組成物
CN111491618B (zh) 用于曲坦化合物的离子电渗透皮递送的耐低温的组合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17740211

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17740211

Country of ref document: EP

Kind code of ref document: A1