WO2018006069A1

WO2018006069A1 - Improved formulations for transdermal pharmaceutical systems

Info

Publication number: WO2018006069A1
Application number: PCT/US2017/040488
Authority: WO
Inventors: Anthony DRAGER; Diane Gingrich; Paritosh WATTAMWAR
Original assignee: Teva Pharmaceuticals International GmbH
Current assignee: Teva Pharmaceuticals International GmbH
Priority date: 2016-06-30
Filing date: 2017-06-30
Publication date: 2018-01-04
Anticipated expiration: 2018-12-30

Abstract

The present disclosure provides hydrogel compositions comprising an active pharmaceutical ingredient (or pharmaceutically acceptable salt thereof), a solubilizing agent, and a C₁₂ to C₁₄ saturated fatty acid, a C₆ to C₁₀ saturated fatty acid, a C₆ to C₃₀ unsaturated fatty acid, or a combination thereof. The hydrogel compositions of the disclosure have molar acid-base ratios of between about 0.8 and 1.05. Methods for producing and using these hydrogel compositions are also described. The active pharmaceutical ingredient may be sumatriptan, and the hydrogel compositions may be used in methods for treating sumatriptan responsive states, such as migraines, with transdermal patches.

Description

IMPROVED FORMULATIONS FOR TRANSDERMAL PHARMACEUTICAL

SYSTEMS

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Nos. 62/356,659, filed June 30, 2016, and 62/356,665, filed June 30, 2016, the entireties of which are incorporated by reference herein.

FIELD

[0002] The disclosure is in the field of transdermal formulations for therapeutic agents.

BACKGROUND

[0003] Transdermal systems, including transdermal gels, transdermal patches, and iontophoretic transdermal patches, often include a hydrogel composition containing an active pharmaceutical ingredient and other excipients. In some instances, 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.

[0004] In some instances where precipitation occurs, extensive reformulation of the hydrogel composition and active pharmaceutical ingredient must be investigated. In some situations, reformulation is not possible and extraordinary procedures must be implemented to ensure that the hydrogel is not exposed to cold temperatures. Some of these procedures can include establishing a temperature-controlled supply chain with specific packaging requirements to ensure that the temperature of the hydrogel-containing product remains stable during distribution. Temperature-controlled supply chains significantly increase the costs associated with the hydrogel-containing product.

[0005] As such, methods for reducing the temperature sensitivity of transdermal hydrogels are needed.

SUMMARY [0006] 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 C₁₂ to C₁₄ saturated fatty acid, a Ce to C₁₀ 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.

[0007] The present disclosure also provides 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-C2₀ dicarboxylic acids, methyl para-hydroxybenzoate, and water. Methods of using these transdermal patches to treat, for example, sumatriptan responsive states, are also described.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 depicts pharmacokinetic data from testing of some transdermal patches having hydrogels of the present disclosure.

[0009] Figure 2 depicts viscosity data from stability testing of some hydrogels of the present disclosure.

[0010] Figure 3 depicts conductivity data from stability testing of some hydrogels of the present disclosure.

[0011] Figure 4 depicts viscosity data from stability testing of some hydrogels of the present disclosure.

[0012] Figure 5 depicts in vitro pharmacokinetic data from testing of some hydrogels of the present disclosure.

[0013] Figure 6 depicts in vitro pharmacokinetic data from testing of some hydrogels of the present disclosure.

[0014] Figure 7 depicts viscosity data from testing of some hydrogels of the present disclosure.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0015] The present invention may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures and examples, which form a part of this disclosure. It is to be understood that this invention is not limited to the specific devices, methods, applications, conditions or parameters described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed invention. Also, as used in the specification including the appended claims, the singular forms "a," "an," and "the" include the plural, and reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. When a range of values is expressed, another embodiment includes from the one particular value and/or to the other particular value. As used herein, the term "about" refers to a variation of 10% from the indicated values, or in the case of a range of values, means a 10% variation from both the lower and upper limits of such ranges. All ranges are inclusive and combinable.

[0016] It is to be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. Further, reference to values stated in ranges include each and every value within that range.

[0017] 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. By comparison, 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.

[0018] As used herein, "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.

[0019] 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. At a particular threshold temperature, 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. In many instances, the reference hydrogel will exhibit precipitation after being exposed to a temperature of 15 °C for 30 minutes or 15 °C for 60 minutes. The term "storage" can refer to storage or shipment conditions, or any combinations thereof, of the hydrogels. In some instances, 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. 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. In some instances, the reference hydrogel will exhibit precipitation after being exposed to one or more freeze-thaw cycles between temperatures of 25 °C and -20 °C.

[0020] In contrast, 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. In particular, 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. In preferred aspects, 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.

[0021] The hydrogel compositions of the disclosure can be part of a transdermal hydrogel. In other aspects, 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 C₁₂ to C₁₄ saturated fatty acid, a Ce to C₁₀ saturated fatty acid, a Ce to C30 unsaturated fatty acid, or a combination thereof. In some aspects, 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 C₁₂ to C₁₄ 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 C₄ 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

[0022] The hydrogels of the present disclosure include one or more active pharmaceutical ingredients ("APIs") or a pharmaceutically acceptable salt thereof.

Preferably, the hydrogels of the disclosure include one active pharmaceutical ingredient, or a pharmaceutically acceptable salt thereof. In some aspects, the API may be a cationic molecule as a salt of an acid or diacid. In some implementations, the API is suitable for use in transdermal treatments of drug responsive states. In further implementations, 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.

[0023] 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. For example, 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,

1.7, 1.8, 1.9, 2.0, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 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, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9,

6.0, 6.1 , 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9. 7.0, 7.1 , 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0,

8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 27, 28, 29, or about 30 wt.%, based on the weight of the hydrogel composition.

Solubilizing Agents

[0024] 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. Preferably 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. In some

implementations, 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. In some aspects of the disclosure, 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.

[0025] In some aspects, 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. Generally, 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. In some embodiments, 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.

[0026] According to some aspects of the invention, 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. By combining polyamines with one or more acids selected from the group of fatty acids and dicarboxylic acids, the corresponding polyamine salts are obtained. These polyamine salts are generally water-soluble and, upon dissolution in water, form a polymeric electrolyte. [0027] In some implementations, the solubilizing agent can be a butylated methacrylate copolymer. As used herein, "butylated methacrylate copolymer" refers to a copolymer based on butyl methacrylate and that includes two or more primary amino (-NH₂) 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.

[0028] 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

Pharmacopeia-National Formulary (USP/NF), and the "aminoalkyl methacrylate copolymer E" described in "Japanese Pharmaceutical Excipients." Such copolymers are commercially available under the tradename EUDRAGIT® (Evonik Industries, Essen, Germany), for example, 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 quatemary ammonium groups), and EUDRAGIT® E 100 (a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate in a 2: 1 : 1 ratio). 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.

[0029] 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. For example, 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. Saturated Fatty Acids

[0030] Hydrogel compositions described herein may include one or more Ce to C M saturated fatty acids. As used herein, "C₆ to C₁₄ saturated fatty acid" encompasses an aliphatic chain having the designated number of carbon atoms (i.e., six to 14 carbon atoms) and one carboxylic acid moiety.

[0031] C₆ to Ci4 saturated fatty acids include, for example, a C₆, C₇, C₈, C9, C ₁₀, C11, C12, Ci3, or C M saturated fatty acids. In other aspects, 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 C₆, C₇, C₈, C9, C_LO, Cn, C12, Ci3, or Ci4 saturated fatty acids.

[0032] In some aspects, one or more of the saturated fatty acids is a C₁₂ to C₁₄ saturated fatty acid for example, lauric acid (C ₁₂), myristic acid (C₁₄), 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.

[0033] In other aspects, one or more of the unsaturated fatty acids is a Ce to C _LO saturated fatty acid, for example, hexanoic acid (C₆), octanoic acid (C₈), 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.%. For example, 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 C₁₄ 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.

Unsaturated Fatty Acids

[0034] The hydrogel compositions described herein may include one or more Ce to C30 unsaturated fatty acids. As used herein, "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.

[0035] The Ce to C30 unsaturated fatty acids include, for example, a C₆, C₇, C₈, C9,

Cio, Cll, C12, Cl3, Cl4, Cl5, Cl6, Cl7, Cl8, Cl9, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, or

C30 unsaturated fatty acids. In other aspects, 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, C₇, C₈, C9, C₁₀, Cn, C₁₂,

Cl3, Cl4, Cl5, Cl6, Cn, Cl8, Cl9, C20, C₂₁, C22, C23, C24, C25, C26, C27, C28, C29, ΟΓ C30 unsaturated fatty acids. In some aspects, 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 C2₀ unsaturated fatty acid. In yet other aspects, one or more of the unsaturated fatty acids is a C 12 to C20 unsaturated fatty acid.

[0036] 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.

Preferably, 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 (C₁₃), myristoleic acid (C₁₄), pentadecenoic acid (C 15), palmitoleic acid (C₁₆), sapienic acid (C₁₆), heptadecenoic acid (Cn), oleic acid (C₁₈), elaidic acid (C₁₈), vaccenic acid (C₁₈), nonadecenoic acid(Ci₉), gadoleic acid (C₂₀), gondoic acid (C20), paullinic acid (C₂₀), erucic acid (C₂₂), nervonic acid (C₂₄), or ricinoleic acid (C₁₈). Suitable di-unsaturated fatty acids include, for example, linoleic acid (C₁₈), linoelaidic acid (C₁₈), eicosadienoic acid (C₂₀), or docosadienoic acid (C₂₂), or combinations thereof. Suitable tri-unsaturated fatty acids include, for example, linolenic acid (C₁₈), pinolenic acid (C₁₈), eleostearic acid (C₁₈), mead acid (C₂₀), dihomo-Y-linolenic acid (C₂₀), or eicosatrienoic acid (C20), or combinations thereof. In preferred embodiments, the Ce to C30 unsaturated fatty acid is oleic acid.

[0037] In some aspects, the hydrogel composition comprising a Ce to C30 unsaturated fatty acid and excludes Ce to C₁₄ saturated fatty acids.

[0038] 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. For example, 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.

Dicarboxylic Acids

[0039] The hydrogel compositions of the disclosure can include one or more C4 to C20 dicarboxylic acids. As used herein, "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.

[0040] The C4 to C20 dicarboxylic acids include, for example a C₄, C5,C6, C7,Cg, C₉,Cio, C11, C12, Ci3, C M, Ci5, Ci6, Civ, Ci8, Ci9, or C₂₀, dicarboxylic acid. In other aspects, the hydrogels of the disclosure can include a combination of two or more independently selected C₄ to C20 dicarboxylic acids, for example, a combination of two or more

independently selected C₄, C₅,C₆, C₇,C₈, C₉,C₁₀, C_n, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, C₁₈, C₁₉, or C20, dicarboxylic acids. Preferred C4 to C20 dicarboxylic acids include, for example, glutaric acid (C5), adipic acid (C₆), pimelic acid (C7), and combinations thereof. Preferably, 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. For example, 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,

2.6, 2.7, 2.8, 2.9, 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 wt.%, based on the weight of the hydrogel. 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.

Additional Hydrogel Composition Components

[0041] 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. For example, 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.

[0042] In certain embodiments, 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

Recognized As Safe by the United States Food and Drug Administration (FDA). For example, the antioxidant may be a phenolic antioxidant, a polyphenol antioxidant, and/or a phenolic acid antioxidant. In some aspects, the antioxidant may be one or more of butylated hydroxy toluene (BHT), also known as dibutylhydroxytoluene, butylated hydroxyanisole, and tocopherol. 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. For example, 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.

[0043] 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. As used herein, "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. For example, 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 Ratios

[0044] The term "acid-base ratio" refers to the molar ratio between the total acidic functional groups and total basic functional groups in a hydrogel composition. In preferred aspects, the acid-base ratio is an acid-amine ratio.

[0045] 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.

[0046] 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. For example, 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.

[0047] 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. For example, 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.

[0048] 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. As an example, adipic acid is known to be a diprotic acid with two acidic functional groups per molecule. [0049] 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. For example, 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. In some methods of the present disclosure, 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.

Methods of Preparation

[0050] The 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.

However, various alternative methods for manufacturing the compositions may be used, as will be readily realized by the skilled person.

[0051] The 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. In operation ions are carried into the skin by an electrical current that is supplied by a positive and negative electrode. Positive ions are carried away from the positive anode, while negative ions are carried away from the negative cathode. Suitable current densities (calculated as current level divided by the contact surface area) during operation can be between about 0.05 mA/cm² and about 0.5 mA/cm².

Methods of Use

[0052] The transdermal patches of the disclosure that include the described hydrogel compositions can be used to treat a drug responsive state. As used herein, the term "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. In some implementations, 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. In certain embodiments, the drug responsive state is a migraine. To treat a drug responsive state, 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.

Formulation Methods

[0053] In addition to the hydrogel compositions described herein, 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 C₁₂ 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.

[0054] 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. At a particular threshold temperature, 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. In contrast, 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. For example, 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. In further preferred aspects, 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.

[0055] Some methods of the disclosure include reducing the acid-base ratio of the reference hydrogel composition. In preferred methods, 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. In some aspects, the acid-base ratio of the hydrogel composition prepared according to the described methods is about 0.9 and about 1.0. In other aspects, 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.

[0056] Hydrogel compositions prepared according to the described methods will exhibit pharmacokinetic profiles that are similar to a reference compositions'

pharmacokinetic profiles. In some aspects, 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. In other aspects, 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. [0057] Hydrogel compositions of the disclosure can exhibit a tackiness that is about the same as the tackiness of the reference hydrogel composition. In other aspects, the tackiness of a hydrogel composition of the disclosure is about 2 times greater than the tackiness of the reference hydrogel composition. In other aspects, the tackiness is about 3, 4, 5, 6, 7, 8, 9, or about 10 times greater than the tackiness of the reference hydrogel composition. In other aspects, the tackiness is about 3, 4, 5, 6, 7, 8, 9, or about 10 times lower than the tackiness of the reference hydrogel composition.

A.

[0058] For example, in one aspect, 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 C₁₂ to CM saturated fatty acid that is less than the amount present in the reference hydrogel composition. The C₁₂ to C₁₄ saturated fatty acid can be any C₁₂ to C₁₄ saturated acid previously described herein. For example, the C₁₂ to C₁₄ saturated fatty acid can be lauric acid (C₁₂), myristic acid (C₁₄), or a combination thereof.

[0059] For example, the amount of the C₁₂ to C₁₄ 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 C₁₂ to C₁₄ saturated fatty acid in the produced hydrogel is between about 5 wt.% and about 95 wt.% of the amount of the C₁₂ to Ci4 saturated fatty acid present in the reference hydrogel composition. For example, the amount of the C₁₂ to C₁₄ 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.

[0060] In these aspects, in addition to reducing the amount of the C₁₂ to C₁₄ saturated fatty acid, the methods further comprise adding a Ce to C₁₀ 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. For example, 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. For example, the methods may comprise adding hexanoic acid (C₆), octanoic acid (C₈), 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 C₁₂ to C₁₄ saturated fatty acid present in the reference hydrogel composition. [0061] As a result, 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 C₁₀ saturated fatty acid, and optionally, a C₁₂ to C₁₄ 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.

]},

[0062] In another aspect, the acid-base ratio of a reference hydrogel composition that includes an API (or salt form thereof), a C₁₂ to C₁₄ saturated fatty acid, and a solubilizing agent can be reduced by producing a hydrogel composition that includes an amount of the C₁₂ to CM saturated fatty acid that is less than the amount present in the reference hydrogel composition. For example, the C₁₂ to C₁₄ saturated fatty acid present in the reference hydrogel composition can be lauric acid (C₁₂), myristic acid (C₁₄), or a combination thereof. For example, the amount of the C₁₂ to C₁₄ 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 C₁₂ to C M saturated fatty acid in the produced hydrogel is between about 5% and about 95% of the amount of the C₁₂ to C₁₄ saturated fatty acid present in the reference hydrogel composition. For example, 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 C₁₂ to C₁₄ saturated fatty acid present in the reference hydrogel composition.

[0063] In these aspects, in addition to reducing the amount of the C₁₂ to C₁₄ saturated fatty acid, 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. For example, 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. For example, the Ce to C30 unsaturated fatty acid that is added to the produced hydrogel composition can be undecylenic acid (Cn), tridecenoic acid (C₁₃), myristoleic acid (C₁₄), pentadecenoic acid (C15), palmitoleic acid (C₁₆), sapienic acid (C₁₆), heptadecenoic acid (Cn), oleic acid (C₁₈), elaidic acid (C₁₈), vaccenic acid (C₁₈),

nonadecenoic acid(Ci9), gadoleic acid (C₂₀), gondoic acid (C₂₀), paullinic acid (C₂₀), erucic acid (C₂₂), nervonic acid (C₂₄), ricinoleic acid (C₁₈), linoleic acid (C₁₈), linoelaidic acid (C₁₈), eicosadienoic acid (C₂₀), or docosadienoic acid (C₂₂), linolenic acid (C₁₈), pinolenic acid (C₁₈), eleostearic acid (C₁₈), mead acid (C₂₀), dihomo-Y-linolenic acid (C₂₀), or eicosatrienoic acid (C20), or combinations thereof. In some instances, the Ce to C30 unsaturated fatty acid that is added to the produced hydrogel composition is oleic acid (C₁₈). For example, 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 C₁₂ to C₁₄ saturated fatty acid present in the reference hydrogel composition.

[0064] As a result, 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 C₆ to C30 unsaturated fatty acid, and optionally, a C₁₂ to C₁₄ 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.

C.

[0065] In another aspect, 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. For example, 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. For example, 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. For example, 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. For example, 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. In some instances, 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, butyl methacrylate, and methyl methacrylate), or a combination thereof.

[0066] As a result, 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 C₁₂ to C₁₄ 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.

Definitions

[0067] The term "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.

[0068] The term "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.

The term "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, eicosanoids and the like.

Sumatriptan Transdermal Formulations [0069] According to some aspects of the disclosure, transdermal formulations including a hydrogel comprising sumitriptan can be provided.

[0070] ZECUITY™ is an iontophoretic transdermal system currently marketed in the United States by Teva Pharmaceuticals USA, Inc. for the treatment of migraines.

ZECUITY™ 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 ZECUITY™ also reduces the nausea, sensitivity to sound, and sensitivity to light that are commonly associated with migraines.

[0071] The ZECUITY™ 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, ZECUITY™ 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.

[0072] ZECUITY™'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 ZECUITY™ product.

[0073] In some aspects, 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 C₆ to C30 unsaturated fatty acids, one or more C4-C20 dicarboxylic acids, methyl para-hydroxybenzoate, and water. Methods of using these transdermal patches to treat, for example, sumatriptan responsive states are also described.

[0074] In some aspects, 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 C₆ to C30 unsaturated fatty acids, one or more C4-C20 dicarboxylic acids, methyl para-hydroxybenzoate, and water.

[0075] In some aspects, the hydrogel comprises sumatriptan. In preferred aspects, 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. For example, 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.

[0076] In some aspects, the transdermal patches of the disclosure that include the described hydrogels can be used to treat a sumatriptan responsive state. As used herein, the term "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

pharmaceutically acceptable salt of sumatriptan. 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. In certain embodiments, the sumatriptan responsive state is a migraine. To treat a sumatriptan responsive state, 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.

[0077] The following examples are provided to illustrate compositions, processes, and properties described herein. The examples are merely illustrative and are not intended to limit the disclosure to the materials, conditions, or process parameters set forth therein.

EXAMPLES

Example 1: Sumatriptan Compositions.

[0078] Five sumatriptan-containing hydrogel formulations were prepared, as described in Table 1.

Table 1

Wt%

Hydrogel Hydrogel Hydrogel Hydrogel Hydrogel A B C D E

Sumatriptan Succinate 4.00 4.00 4.00 4.00 4.00

EUDRAGIT® E 100 5.87 8.62 8.62 5.87 7.92

Laurie Acid 3.40 3.40 0.00 0.00 0.00

Adipic Acid 0.27 0.27 0.27 0.27 0.27

Methylparaben 0.10 0.10 0.10 0.10 0.10

Water 86.37 83.62 82.12 86.84 82.81

Oleic Acid 0.00 0.00 4.79 0.00 4.79 Wt%

Hydrogel Hydrogel Hydrogel Hydrogel Hydrogel A B C D E

BHT 0.00 0.00 0.10 0.00 0.10

Decanoic Acid 0.00 0.00 0.00 2.92 0.00

TOTAL 100.00 100.00 100.00 100.00 100.00

Theoretically Calculated Molar Acid-Base Ratio

1.446 0.985 0.985 1.446 1.071

[0079] The formulations, Hydrogels A, B, C, D, and E, were manufactured using conventional methods. Hydrogel A is equivalent to the hydrogel used within the ZECUITY™ 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.

[0080] The five sumatriptan-containing hydrogels of Example 1, were formed into transdermal patches and tested for sumatriptan pharmacokinetics in Hanford minipigs following dermal application. Transdermal patches containing 120 mg sumatriptan succinate per patch were formed. Male Hanford minipigs (Minipig-HA) were obtained from Sinclair Research Center, Inc. (Auxvasse, MO) One day prior to dermal patch application, the dorsal area of each animal was shaved of any hair. On the day of dosing, a single dermal patch was applied to the dry, intact, non-irritated dorsal surface of each animal and the patch was secured, as appropriate, with wrapping material to ensure that the patch remained secured for approximately 4 hours. For each patch application, the total time of drug delivery and operation was 4 hours, with a stepped current profile of 4 mA for 1.0 hour, then 2 mA for 3.0 hours (for a total of 600 mA-minutes).

[0081] Blood samples of approximately 1 mL were collected via a jugular vein into tubes containing K₂ EDTA anticoagulant from each animal predose and at 0.25, 0.5, 1, 1.5, 2,

3, 4, 6, 8, 10, 12, and 24 hours postdose. Blood collection times were made relative to the time of patch current activation. The blood samples were placed on wet ice until centrifuged.

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.

[0082] The pharmacokinetic data are shown in Table 2 and graphically, in-part, by FIG. 1, which depicts plasma mean sumatriptan concentration (+SD) following dermal application of the five sumatriptan-containing hydrogels of Example 1 :

Table 2

[0083] Pharmacokinetic exposure was comparable between patches formed from Hydrogel A and patches formed from Hydrogels B, C, D, and E.

Example 3: In vitro iontophoretic assay of Hydrogels A, B, C, D, and E

[0084] 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 μηι and area of 0.8 cm², 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/cm² 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. Oneway analysis of variance ("Anova") was used to determine whether there were any significant differences in sumatriptan flux ^g/cm²/min) for the hydrogel samples. For the data depicted in FIG. 5, One-way Anova F(4,25)=7.40, p value = 0.0004. For the data depicted in FIG. 6, One-way Anova F(4,25)=7.70, p value = 0.0003.

Example 4: Formulation properties of Hydrogels A, B, C, D, and E in transdermal patches.

[0085] The five sumatriptan-containing hydrogels of Example 1, were tested for stability and physical properties. Viscosity testing results of Hydrogels A, C, and D are shown in FIG. 7, with yield points indicated with arrows. The effect on viscosity of freeze- thaw cycles between ambient (25°C) and -20°C was tested, with results shown in FIG. 4. For each cycle, formulations were stored at -20°C for at least 24 hours and then allowed to thaw on benchtop at ambient temperature for more than 24 hours. After one freeze-thaw cycle, test samples of Hydrogel A exhibited a thick layer of precipitate. No observable precipitate was present in samples of Hydrogels B, C, D, and E after three freeze-thaw cycles.

[0086] Conductivity and viscosity stability of Hydrogels A, B, C, D, and E was tested under storage at 25°C, with results shown in FIGs. 2 and 3 for measurements taken at the time of formulation, after 37 days, and after 61 days. Bulk hydrogel was aliquoted in several 4 and 20 ml glass vials which were then stored at 25, 30 and 40 °C. Vials were removed at various timepoints and allowed to cool to room temperature for at least two hours before analyzing them for viscosity and conductivity. For viscosity measurements, an Anton- Paar MCR-302 rheometer instrument was used for cone and plate method measurements with a 50 mm cone (CP50). 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 Toledo™ 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

[0087] 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. For the titration assay, 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 (C₄H₁₀N). The endpoint can be determined

potentiometrically to yield the alkali value and base equivalents:

mg KOH mL 0.1 N HC10₄ * 561

g DS ^J 0.2 g DS

Base equivalents of EE100 = moles of DMAE per g of dry substance

Alkali Value (mg of KOH / g o/ DS)

Base Equivalents of Eudragit E100 =

MW of KOH (g per mol)

AV (mg of KOH per g of DS)

Base Equivalents of Eudragit E100 =

56.11 (g per mol)

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. For an average alkali value of 180 mg KOH, there are 0.0032 moles of base equivalents per gram of dry substance of EUDRAGIT® E 100.

Example 6: Calculation of base equivalents of EUDRAGIT® E 100 via theoretically calculated repeating units

[0088] The alkali value 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.

Table 3

Equivalents of Eudragit £100

I g of DS

* moles of DMAE per moles of DS

MW (g per mol) l g DS

Base Equivalents of Eudragit £100 = X 168.84

47000 (g per mol)

Base Equivalents of Eudragit £100 = 0.0036 moles of DMAE per g of DS

[0089] Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention.

Claims

What is Claimed:

1. A transdermal patch including a hydrogel composition comprising:

an active pharmaceutical ingredient, or a pharmaceutically acceptable salt thereof; a C 12 to C i4 saturated fatty acid, a Ce to C₁₀ saturated fatty acid, a Ce to C30

unsaturated fatty acid, or a combination thereof; and

a solubilizing agent;

wherein the hydrogel composition has an acid-base ratio between about 0.8 and 1.05.

2. The transdermal patch of claim 1 , wherein the hydrogel compositions does not exhibit precipitation of a hydrogel component after storage of the transdermal patch at or below a threshold temperature for a threshold period of time;

3. The transdermal patch of claim 2, wherein the threshold temperature is about 10 °C and the threshold period of time is about 8 hours.

4. The transdermal patch of claim 2, wherein the threshold temperature is about 5 °C and the threshold period of time is about 24 hours.

5. The transdermal patch of claim 2, wherein the threshold temperature is about 0 °C and the threshold period of time is about 8 hours.

6. The transdermal patch of claim 2, wherein the threshold temperature is about 0 °C and the threshold period of time is about 24 hours.

7. The transdermal patch of any one of the claims 1 to 6, which is an iontophoretic

transdermal patch.

8. The transdermal patch of claim 7, wherein the iontophoretic transdermal patch

includes an anode reservoir and a cathode reservoir and wherein the hydrogel composition is present in the anode reservoir.

9. The transdermal patch of any one of the preceding claims, wherein the hydrogel composition comprises a C 12 to C 14 saturated fatty acid.

10. The transdermal patch of any one of claims 1 to 7, wherein the hydrogel composition comprises a Ce to C₁₀ saturated fatty acid.

1 1. The transdermal patch of any one of claims 1 to 7, wherein the hydrogel composition comprises a Ce to C30 unsaturated fatty acid.

12. The transdermal patch of any one of the preceding claims, wherein the hydrogel composition further comprising a C₄ to C2₀ dicarboxylic acid.

13. The transdermal patch of any one of the preceding claims, wherein the solubilizing agent is a butylated methacrylate copolymer.

14. A method of treating a drug responsive state in a subject comprising applying the transdermal patch of any one of the preceding claims to the skin of the subject.

15. A method comprising combining:

an active pharmaceutical ingredient, or a salt form thereof;

a C 12 to C 14 saturated fatty acid, a Ce to C_lo saturated fatty acid, a Ce to C30 unsaturated fatty acid, or a combination thereof, and

a solubilizing agent;

to form a hydrogel composition;

wherein the acid-base ratio of the components of the hydrogel composition is between about 0.8 and 1.05.

16. The method of claim 15, wherein the hydrogel composition comprises

the active pharmaceutical ingredient, or salt form thereof;

the solubilizing agent; and

a Ce to Cio saturated fatty acid.

17. The method of claim 15, wherein the hydrogel composition comprises

the active pharmaceutical ingredient, or salt form thereof;

the solubilizing agent; and

a C₆ to C30 unsaturated fatty acid.

18. The method of claim 15, wherein the hydrogel composition comprises

the active pharmaceutical ingredient, or salt form thereof; the solubilizing agent; and

a C 12 to C i4 saturated fatty acid.

19. The method of any one of claims 15 to 18, further comprising combining a C4 to C20 dicarboxylic acid with the active pharmaceutical ingredient, or salt form thereof; the solubilizing agent; and the C₁₂ to C₁₄ saturated fatty acid, the Ce to C₁₀ saturated fatty acid, the Ce to C30 unsaturated fatty acid, or the combination thereof.

20. The method of any one of claims 15 to 19, wherein at least one component of the hydrogel composition does not precipitate from the hydrogel composition after storage of the hydrogel composition at the temperature below a threshold temperature for a threshold period of time.

21. The method of any one of claims 15 to 20, wherein the acid-base ratio is between about 0.9 and about 1.0.

22. The method of any one of claims 15 to 21, wherein the acid-base ratio is about 1.0.

23. The method of claim 20, wherein the threshold temperature is about 10 °C and the threshold period of time is about 8 hours.

24. The method of claim 20, wherein the threshold temperature is about 5 C and the threshold period of time is about 24 hours.

25. The method of claim 20, wherein the threshold temperature is about 0 °C and the threshold period of time is about 8 hours.

26. The method of claim 20, wherein the threshold temperature is about 0 °C and the threshold period of time is about 24 hours.

27. A transdermal patch including a hydrogel comprising:

between about 3% and about 5% by weight of sumatriptan, or a pharmaceutically acceptable salt thereof, based on the weight of the hydrogel;

between about 3.0% and about 12.0% by weight of a butylated methacrylate

copolymer, based on the weight of the hydrogel;

between about 1 % and 12% by weight of a Ce to C30 unsaturated fatty acid, based on the weight of the hydrogel; between about 0.05% and about 5% by weight of a C4-C20 dicarboxylic acid, based on the weight of the hydrogel;

between about 0.09% and about 0.2% by weight of methyl para-hydroxybenzoate, based on the weight of the hydrogel; and

water.

28. The transdermal patch of claim 27, comprising a pharmaceutically acceptable salt of sumatriptan.

29. The transdermal patch of claim 27 or claim 28, wherein the pharmaceutically

acceptable salt of sumatriptan is sumatriptan succinate.

30. The transdermal patch of any one of claims 27-29, comprising between about 4.0% and about 9.0% by weight of the butylated methacrylate copolymer, based on the weight of the hydrogel.

31. The transdermal patch of any one of claims 27-30, comprising between about 7.0% and about 9.0% by weight of the butylated methacrylate copolymer, based on the weight of the hydrogel.

32. The transdermal patch of any one of claims 27-31 , comprising about 8.0% by weight of the butylated methacrylate copolymer, based on the weight of the hydrogel.

33. The transdermal patch of any one of claims 27-32, comprising about 8.5% by weight of the butylated methacrylate copolymer, based on the weight of the hydrogel.

34. The transdermal patch of any one of claims 27-33, wherein the butylated methacrylate copolymer is EUDRAGIT E100.

35. The transdermal patch of any one of claims 27-34, wherein the Ce to C30 unsaturated fatty acid is a C 10 to C24 unsaturated fatty acid.

36. The transdermal patch of any one of claims 27-35, wherein the Ce to C30 unsaturated fatty acid is a C 10 to C20 unsaturated fatty acid.

37. The transdermal patch of any one of claims 27-36, wherein the Ce to C30 unsaturated fatty acid is a C 12 to C20 unsaturated fatty acid.

38. The transdermal patch of any one of claims 27-37, wherein the Ce to C30 unsaturated fatty acid is a monounsaturated fatty acid.

39. The transdermal patch of claim 38, wherein the monounsaturated fatty acid is

myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, eicosenoic acid, erucic acid, nervonic acid, or ricinoleic acid, or a combination thereof.

40. The transdermal patch of any one of claims 27 to 37, wherein the Ce to C30

unsaturated fatty acid is a di-unsaturated fatty acid.

41. The transdermal patch of claim 40, wherein the di-unsaturated fatty acid is linoleic acid, eicosadienoic acid, or docosadienoic acid, or a combination thereof.

42. The transdermal patch of any one of claims 27 to 37, wherein the Ce to C30

unsaturated fatty acid is a tri-unsaturated fatty acid.

43. The transdermal patch of claim 42, wherein the tri-unsaturated fatty acid is linolenic acid, pinolenic acid, eleostearic acid, mead acid, dihomo-Y-linolenic acid, or eicosatrienoic acid, or a combination thereof.

44. The transdermal patch of any one of claims 27 to 38, wherein the Ce to C30

unsaturated fatty acid is oleic acid.

45. The transdermal patch of any one of claims 27 to 44, comprising between about 2% and about 7% by weight of the Ce to C30 unsaturated fatty acid, based on the weight of the hydrogel.

46. The transdermal patch of any one of claims 27 to 45, comprising between about 3% and about 6% by weight of the Ce to C30 unsaturated fatty acid, based on the weight of the hydrogel.

47. The transdermal patch of any one of claims 27 to 46, comprising between about 4% and about 5.5% by weight of the Ce to C30 unsaturated fatty acid, based on the weight of the hydrogel.

48. The transdermal patch of any one of claims 27 to 47, comprising between about 4.5% and about 5.0% by weight of the Ce to C30 unsaturated fatty acid, based on the weight of the hydrogel.

49. The transdermal patch of any one of claims 27 to 48, comprising about 4.8% by

weight of the Ce to C30 unsaturated fatty acid, based on the weight of the hydrogel.

50. The transdermal patch of any one of claims 27 to 49, further comprising an

antioxidant.

51. The transdermal patch of claim 50, comprising about 0.1% by weight of the

antioxidant, based on the weight of the hydrogel.

52. The transdermal patch of any one of claims 50 or 51 wherein the antioxidant

comprises butylated hydroxytoluene.

53. The transdermal patch of any one of claims 27 to 52, wherein the C4-C10 dicarboxylic acid is glutaric acid, adipic acid, or pimelic acid, or a combination thereof.

54. The transdermal patch of any one of claims 27 to 53, wherein the hydrogel comprises between 0.1 % and about 2.0% by weight of the C4-C10 dicarboxylic acid, based on the weight of the hydrogel.

55. The transdermal patch of any one of claims 27 to 54, wherein the hydrogel comprises between 0.2% and about 0.4% by weight of the C4-C10 dicarboxylic acid, based on the weight of the hydrogel.

56. The transdermal patch of any one of claims 27 to 55, wherein the hydrogel comprises about 0.3% by weight of the C4-C10 dicarboxylic acid, based on the weight of the hydrogel.

57. The transdermal patch of any one of claims 27 to 56, wherein the hydrogel comprises between about 0.09% and about 0.1 % by weight of the methyl para-hydroxybenzoate, based on the weight of the hydrogel.

58. The transdermal patch of any one of claims 27 to 57, wherein the hydrogel further comprises an additive, preferably cholesterol.

59. The transdermal patch of any one of claims 27 to 58, which is an iontophoretic transdermal patch.

60. The transdermal patch of claim 59, wherein the iontophoretic transdermal patch includes an anode reservoir and a cathode reservoir and wherein the hydrogel is present in the anode reservoir.

61. A method of treating a sumatriptan responsive state in a subject comprising applying the transdermal patch of any one of claims 27 to 60 to the skin of the subject.

62. The method of claim 61, wherein the sumatriptan responsive state is a migraine.