JP6100150B2 - 4-Aminopyridine-containing patch - Google Patents

Description

  The present invention relates to a patch containing 4-aminopyridine.

  4-Aminopyridine is known to have an action of inhibiting various potassium channels in nerve cells. 4-Aminopyridine is thought to improve neurological symptoms in patients such as multiple sclerosis (MS), particularly gait disturbance, by sustaining the nerve action potential.

  Multiple sclerosis is one of the inflammatory autoimmune diseases in the nervous system. It is an acute onset, relapse / remission type that repeats relapse and remission, a primary progressive type that shows a progressive course from the onset, and In the initial stage, the disease is classified into three types of secondary progressive type in which recurrence and remission are repeated, followed by a progressive course. Multiple sclerosis occurs in the central nervous system, including the brain, medulla oblongata and optic nerve, by demyelination (depletion of myelin sheath from nerve fibers), resulting in impaired vision, diplopia, cerebellar ataxia, limb paralysis (single Paralysis, paraplegia, hemiplegia), sensory disorder, bladder rectal disorder, urinary retention, gait disorder, etc., and various symptoms are shown depending on the lesion site. In addition, multiple sclerosis has a Uthoff sign as a characteristic symptom. Wutf's sign is a condition in which neuropathy worsens with an increase in body temperature, and returns to its original state due to a decrease in body temperature. Under conditions where nerve conduction is decreased due to demyelination, potassium channels open due to an increase in body temperature and conduct. This is because the efficiency further decreases. As a Utofu sign, for example, visual acuity may deteriorate temporarily due to bathing or going out in hot weather, or muscle strength of the extremities may be reduced.

  4-Aminopyridine is also referred to as darfanpridin or darfampyridine, and has a symptom-improving effect on gait function in patients with multiple sclerosis. As for 4-aminopyridine, an oral preparation is currently being marketed for multiple sclerosis (patent documents 1 to 3). In the United States, Europe, Australia, and the like, tablets containing 10 mg of 4-aminopyridine (AMPYRA tablets (registered trademark), Elan Corporation, Accorda Therapeutics) are used to improve the symptoms of multiple sclerosis. The dosage of the tablet is 1 tablet at a time, oral administration twice a day. In addition, 4-aminopyridine is undergoing clinical trials for spinal cord injury due to trauma or compression, and formulation into an injection or the like is also being studied (Patent Documents 1 and 4).

JP-A-4-273820 Special table 2007-532578 Special table 2013-501805 gazette Japanese National Patent Publication No. 8-504472

  However, 4-aminopyridine is sold only as an oral agent and may be difficult for use by patients with neurological symptoms. In view of the above circumstances, an object of the present invention is to provide a preparation containing 4-aminopyridine and having excellent drug stability.

  As a result of intensive studies, the present inventors have found that a pressure-sensitive adhesive having a carboxy group improves the stability of 4-aminopyridine in a preparation, and completed the present invention. That is, the present invention is a patch comprising a support and a pressure-sensitive adhesive layer laminated on the support, wherein the pressure-sensitive adhesive layer comprises 4-aminopyridine and a pressure-sensitive adhesive having a carboxy group. The patch which contains and the molar ratio with respect to the said 4-aminopyridine of the carboxy group contained in the said adhesive is 0.13 or more.

  The content of 4-aminopyridine may be 5 to 20% by mass based on the total amount of the pressure-sensitive adhesive layer. When the content of 4-aminopyridine is within the above range, occurrence of side effects can be reduced and potassium channels can be sufficiently inhibited.

  The pressure-sensitive adhesive may be an acrylate copolymer having a carboxy group. The pressure-sensitive adhesive layer may further contain an acrylate copolymer having a hydroxy group.

  You may enclose in a packaging material with a desiccant. It becomes possible to preserve | save for a long period of time by enclosing in a packaging material with a desiccant.

  According to the patch of the present invention, since it can be applied to the skin and does not require swallowing, it is easy to administer 4-aminopyridine even for patients who exhibit neurological symptoms.

It is a graph which shows the skin permeability of the patch of Examples 1 and 2 and Reference Examples 1 and 2.

  The patch according to the present embodiment includes a support and a pressure-sensitive adhesive layer laminated on the support. And this adhesive layer contains 4-aminopyridine and the adhesive which has a carboxy group.

  In the present specification, “excellent drug stability” is included in the adhesive layer after the patch according to this embodiment is stored under conditions of a specific temperature and a period (for example, 60 ° C., 2 weeks). It means that 95% or more of the drug (4-aminopyridine) remains.

The maximum skin permeation rate is preferably 10 μg / cm ² / hr or more, more preferably 15 μg / cm ² / hr or more from the viewpoint that the pharmacological action of 4-aminopyridine can be sufficiently exhibited. In addition, the maximum skin permeation rate is preferably 50 μg / cm ² / hr or less from the viewpoint of reducing side effects.

  As the support, a stretchable or non-stretchable material that can be usually used for a patch is used. Specifically, polyesters such as polyethylene terephthalate, polybutylene terephthalate, and polyethylene naphthalate; polyolefins such as polyethylene, polypropylene, and polybutadiene; synthesis of ethylene vinyl acetate polymer, polyvinyl chloride, nylon, polyurethane, cellulose derivatives, polyacrylonitrile, and the like A film or sheet made of a synthetic resin such as resin or cotton, or a laminate thereof, a porous membrane, a foam, a fabric such as a woven fabric or a nonwoven fabric, a porous membrane, a foam, or a paper material is preferably used. be able to.

4-aminopyridine is a compound having a structure represented by the following chemical formula (1), and its molecular weight is 94.1. 4-Aminopyridine is known as an inhibitor of potassium channels.

  The content of 4-aminopyridine is preferably 5 to 20% by mass and more preferably 5 to 15% by mass based on the total amount of the pressure-sensitive adhesive layer. When the content of 4-aminopyridine is 5% by mass or more, drug stability in the patch is increased, and the pharmacological action of 4-aminopyridine can be sufficiently exhibited. Moreover, it is preferable from the point which does not produce the side effect by administration of 4-aminopyridine as content of 4-aminopyridine is 20 mass% or less.

  The pressure-sensitive adhesive layer according to this embodiment contains a pressure-sensitive adhesive having a carboxy group. The pressure-sensitive adhesive having a carboxy group is preferably an acrylate copolymer having a carboxy group (hereinafter also referred to as “acrylate copolymer (carboxy group-containing type)”).

  Examples of the acrylate copolymer (carboxy group-containing type) include acrylate copolymers containing acrylic acid. The monomer component copolymerized with acrylic acid is not particularly limited as long as it can be copolymerized with acrylic acid. For example, acrylic acid esters such as methyl acrylate and 2-ethylhexyl acrylate; Examples include acrylic acid amides such as acid morpholine amide; vinyl acetate; vinyl alcohol; styrene. The monomer component copolymerized with acrylic acid may be one kind alone, or two or more kinds. Examples of the acrylate copolymer (carboxy group-containing type) include Duro-tak (registered trademark, Henkel Corporation) 87-2852, Duro-tak (registered trademark) 87-2194, GELVA753, and the like.

  It is preferable that content of the adhesive which has a carboxy group is 25-95 mass% on the basis of the adhesive layer whole quantity.

  In the adhesive layer of the patch according to this embodiment, the molar ratio of the carboxy group contained in the adhesive with respect to 4-aminopyridine is 0.13 or more. The molar ratio is preferably 0.2 or more, and more preferably 0.5 or more.

  In this specification, “the molar ratio of the carboxy group contained in the pressure-sensitive adhesive having a carboxy group with respect to 4-aminopyridine” means the number of moles of the carboxy group in the pressure-sensitive adhesive having a carboxy group in one pressure-sensitive adhesive layer. , And the value divided by the number of moles of 4-aminopyridine.

  As a calculation method of the number of moles of the carboxy group contained in the pressure-sensitive adhesive having a carboxy group, for example, according to the method of JIS-0070, the number of moles of the carboxy group can be determined by measuring the acid value.

  Moreover, when the composition of the pressure-sensitive adhesive having a carboxy group is known, it can be calculated from the composition as follows. For example, according to U.S. Patent Application Publication No. 2004/0137046, Duro-tak® 87-2194 is poly (2-ethylhexyl acrylate-co-vinyl acetate-co-acrylic acid). The contents of 2-ethylhexyl acrylate, vinyl acetate and acrylic acid are 75% by mass, 20% by mass and 5% by mass, respectively. Therefore, when the content of Duro-tak (registered trademark) 87-2194 in the pressure-sensitive adhesive layer is 90% by mass with respect to the total amount of the pressure-sensitive adhesive layer, the pressure-sensitive adhesive layer contains 4.5 mass of acrylic acid as a monomer unit. %contains. Further, since the molecular weight of acrylic acid is 72.1, the number of moles of acrylic acid contained as a monomer unit in the patch can be easily determined.

  The pressure-sensitive adhesive layer according to this embodiment may further contain an acrylate copolymer having a hydroxy group (hereinafter also referred to as “acrylate copolymer (hydroxy group-containing type)”). Examples of the acrylate copolymer (hydroxy group-containing type) include hydroxyalkyl acrylates such as 2-hydroxyethyl acrylate. The hydroxyalkyl acrylate may be further substituted with a halogen atom, an alkyl group, an alkenyl group, an alkynyl group or the like.

  The pressure-sensitive adhesive having a carboxy group may also have a hydroxy group.

  Examples of the acrylate copolymer (hydroxy group-containing type) include Duro-tak (registered trademark) 87-2516, GELVA788, GELVA737, and the like.

  When the pressure-sensitive adhesive layer further contains an acrylate copolymer (hydroxy group-containing type), the content of the acrylate copolymer (hydroxy group-containing type) is 80% by mass or less based on the total amount of the pressure-sensitive adhesive layer. It is preferable that it is 20-80 mass%, and it is more preferable that it is 40-70 mass%. In this case, the content of the acrylate copolymer (carboxy group-containing type) is preferably 20% by mass or more and less than 100% by mass, and more preferably 45% by mass or more and less than 100% by mass.

  The pressure-sensitive adhesive layer may further contain a tackifier resin, a plasticizer, a filler, an ultraviolet absorber, an antioxidant, a solvent, and the like as necessary.

  Examples of tackifying resins include alicyclic saturated hydrocarbon resins; rosin, rosin glycerin ester, hydrogenated rosin, hydrogenated rosin glycerin ester or rosin pentaerythritol ester, rosin derivatives; terpene resin, petroleum resin or maleic acid Resins and the like can be suitably used. Specifically, for example, ester gum (trade name, manufactured by Arakawa Chemical Industry Co., Ltd.), Harrier Star (trade name, manufactured by Harima Chemical Co., Ltd.), pentalin (registered trademark, product manufactured by Eastman Chemical Co., Ltd.), and formal (east Man Chemical Co., Ltd., trade name), rosin resin such as KE-311 (Arakawa Chemical Industries, trade name), YS resin (Yasuhara Chemical Co., trade name), picolite (Rusu & Dilworth, trade name) Terpene resins such as Alcon (registered trademark, manufactured by Arakawa Chemical Co., Ltd., trade name), Rigarets (trade name, manufactured by Eastman Chemical Co., Ltd.), Picorastic (trade name, manufactured by Eastman Chemical Co., Ltd.), Escolez (Exxon) Company name, product name), Wingtack (Goodyear company name, product name), Quinton (registered trademark, Nippon Zeon company name, product name), etc. , Phenolic resins, xylene resins and the like can be used.

  The tackifier resins may be used alone or in combination of two or more. Further, the content of the tackifying resin can be appropriately set by those skilled in the art in consideration of sufficient adhesive strength of the patch and local irritation at the time of peeling, but it is 10 to 10 based on the total amount of the adhesive layer. It is preferably 60% by mass, and more preferably 20-50% by mass.

  Examples of the plasticizer include saturated hydrocarbon plasticizers; petroleum oils such as paraffinic process oil, naphthenic process oil and aromatic process oil; plants such as olive oil, camellia oil, castor oil, tall oil and peanut oil Base oils; dibasic acid esters such as dibutyl phthalate and dioctyl phthalate; liquid rubbers such as polybutene and liquid isoprene rubber; squalane; squalene; diethylene glycol; polyethylene glycol; propylene glycol; These can be used individually by 1 type or in combination of 2 or more types. As the plasticizer, liquid paraffin or polybutene is particularly preferable.

  The content of the plasticizer in the pressure-sensitive adhesive layer can be appropriately adjusted by those skilled in the art in consideration of maintaining sufficient adhesive strength as the pressure-sensitive adhesive, but is 5 to 60% by mass based on the total amount of the pressure-sensitive adhesive layer. It is preferably 10 to 30% by mass.

  Fillers include silicates such as aluminum silicate and magnesium silicate, aluminum hydroxide, aluminum carbonate, magnesium carbonate, silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc stearate, zinc oxide, titanium oxide Etc. can be illustrated.

  Examples of the ultraviolet absorber include p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino acid derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives and the like.

  As the antioxidant, tocopherol and its ester derivative, ascorbic acid and its ester derivative, dibutylhydroxytoluene, butylhydroxyanisole and the like can be suitably used.

  The total amount of the filler, ultraviolet absorber and antioxidant is preferably 0.01 to 10% by mass, more preferably 0.01 to 5% by mass, and particularly preferably 0. 0% by mass based on the total amount of the pressure-sensitive adhesive layer. It mix | blends in the quantity of 1-2 mass%.

  Moreover, in order to protect the adhesive layer from the external environment during storage, the adhesive layer of this embodiment may be coated with a release liner. When the patch is provided with a release liner, the release liner is peeled and removed when the patch is used.

  As the release liner, paper, film, foil, laminates thereof and the like that can be generally used as a release liner for patches can be used, and a substantially drug-impermeable plastic film is preferable. In particular, polyesters such as polyethylene terephthalate (PET), polybutylene terephthalate and polyethylene naphthalate, polyolefins such as polyethylene and polypropylene, metals such as aluminum, cellulose and the like can be preferably used.

  The surface of the release liner facing the pressure-sensitive adhesive layer may be subjected to a release treatment using silicone, Teflon (registered trademark), or the like. By performing the mold release treatment, it is possible to facilitate peeling and removal. In particular, a release treatment with silicone is more preferable, and the release characteristics are stably maintained over time.

  The patch according to the present embodiment is preferably stored in an aluminum packaging material. It is more preferable to enclose preservatives such as desiccant and oxygen scavenger together with the patch according to the present embodiment in the aluminum packaging material. Examples of such preservatives include calcined diatomaceous earth, unfired diatomaceous earth, crystalline silica, sorbic acid, and the like. Specifically, Pharmakeep (registered trademark, manufactured by Mitsubishi Gas Chemical Company), Ageless (registered trademark) , Mitsubishi Gas Chemical Co., Ltd.) can be used.

  The patch according to the present embodiment can be produced, for example, by the following method. First, 4-aminopyridine, an adhesive, and, if necessary, other components are mixed in a solvent to obtain a coating solution. Next, after applying the obtained coating liquid on a release liner, the solvent is removed by drying to form an adhesive layer, and a support is laminated on the adhesive layer to obtain a patch. Therefore, the obtained patch is laminated | stacked in order of a release liner, an adhesive layer, and a support body. Moreover, in order to suppress precipitation of 4-aminopyridine crystals, the obtained patch may be heated.

  The present invention will be described in more detail using examples, comparative examples, and reference examples, but the present invention is not limited to the examples. In addition, the numerical value of Table 1, Table 2, and Table 4 which shows the compounding ratio of a patch means mass (g) unless otherwise indicated.

1. Stability of 4-aminopyridine due to differences in functional groups contained in acrylate copolymer (1) Method for producing patches of Example 1 and Comparative Examples 1 to 4 According to the ratios shown in Table 1, 4-aminopyridine Components other than were dissolved in ethyl acetate and mixed, and then 4-aminopyridine was added and mixed well to obtain a coating solution. The obtained coating liquid was applied onto a release liner made of polyethylene terephthalate, and then the solvent was removed by drying to form an adhesive layer (drug-containing layer) having a predetermined plaster thickness (100 μm). Next, a support made of polyethylene terephthalate was bonded to the pressure-sensitive adhesive layer, and a release liner, a pressure-sensitive adhesive layer, and a support were laminated in this order to obtain patches.

(2) Manufacturing method of patch of Reference Example 1 To an acrylate (hydroxy group-containing type) 95.0 g of ethyl acetate solution, 5.0 g of 4-aminopyridine was added and sufficiently stirred to obtain a coating solution. The obtained coating liquid was applied onto a release liner made of polyethylene terephthalate, and then the solvent was removed by drying to form an adhesive layer (drug-containing layer) having a predetermined plaster thickness (100 μm). Next, a support made of polyethylene terephthalate was bonded to the pressure-sensitive adhesive layer, and a release liner, a pressure-sensitive adhesive layer, and a support were laminated in this order to obtain a patch.

(3) Drug stability test The drug stability of the patches of Example 1, Comparative Examples 1 to 4 and Reference Example 1 was evaluated as follows.
The manufactured patch was punched into a substantially 25 mm × 25 mm rectangle and individually sealed in an aluminum packaging material. The packaging material was stored according to the conditions shown in Table 2 (60 ° C., 2 weeks). After 2 weeks, the patch was taken out from the packaging material, and tetrahydrofuran and methanol were added to the obtained patch, and the mixture was shaken and sonicated to give a drug (4- Aminopyridine) was extracted. After the obtained extract was concentrated, the absorbance was measured by high performance liquid chromatography (HPLC). From the obtained absorbance, the drug content per patch was calculated based on the calibration curve. The drug content in the patch before storage was calculated in the same manner as the initial 4-aminopyridine content. The drug residual rate in the patch in the drug stability test was calculated by the following formula (1) and used as a value indicating drug stability. The results are shown in Table 2.
Drug residual ratio = (Drug content per patch after test) / (Drug content per patch before test) × 100 (%) (1)

  As shown in Table 2, the patch of Example 1 showed no degradation of 4-aminepyridine even after 2 weeks at 60 ° C., whereas in Comparative Examples 1 to 4 and Reference Example 1 In the patch, the drug content decreased by about 8 to 17%. Therefore, the patch of Example 1 using Duro-tak (registered trademark) 87-2194 is the same as the patch of Comparative Examples 1, 3, and 4 using an acrylate copolymer (non-functional type), and the acrylate copolymer. It was revealed that the stability of 4-aminopyridine was superior to the patches of Comparative Example 2 and Reference Example 1 using a combination (hydroxy group-containing type).

2. Mixing examination of acrylate copolymer (carboxy group-containing type) and acrylate copolymer (hydroxy group-containing type) (1) Manufacturing method of patches of Examples 2-7 and Comparative Examples 5-6 Ratios described in Table 3 Thus, components other than 4-aminopyridine were dissolved in ethyl acetate and mixed, and then 4-aminopyridine was added and mixed well to obtain a coating solution. The obtained coating liquid was applied onto a release liner made of polyethylene terephthalate, and then the solvent was removed by drying to form an adhesive layer (drug-containing layer) having a predetermined plaster thickness (100 μm). Next, a support made of polyethylene terephthalate was bonded to the pressure-sensitive adhesive layer, and a release liner, a pressure-sensitive adhesive layer, and a support were laminated in this order to obtain patches.

(2) Drug stability test The drug stability of the patches of Examples 1 to 7 and Comparative Examples 5 to 6 was evaluated as follows.
The manufactured patch was punched into a substantially 25 mm × 25 mm rectangle and individually sealed in an aluminum packaging material. The packaging material was stored according to the conditions described in Table 4 (60 ° C., 2 weeks). After 2 weeks, the patch was taken out from the packaging material, and tetrahydrofuran and methanol were added to the obtained patch, and the mixture was shaken and sonicated to give a drug (4- Aminopyridine) was extracted. After the obtained extract was concentrated, the absorbance was measured by high performance liquid chromatography (HPLC). From the obtained absorbance, the drug content per patch was calculated based on the calibration curve. The drug content in the patch before storage was calculated in the same manner as the initial 4-aminopyridine content. The drug residual rate in the patch in the drug stability test was calculated by the following formula (1) and used as a value indicating drug stability. The results are shown in Table 5.
Drug residual ratio = (Drug content per patch after test) / (Drug content per patch before test) × 100 (%) (1)

  As shown in Table 4, when the concentration of 4-aminopyridine is 5 to 20% by mass, the stability of 4-aminopyridine improves as the proportion of the acrylate copolymer (carboxy group-containing type) increases. The tendency to do was seen. In particular, the patch of Comparative Example 5 contained Duro-tak (registered trademark) 87-2194, but the residual ratio of 4-aminopyridine was less than 90%.

  As shown in Table 4, in the patches of Examples 1 to 7, the molar ratio of the carboxy group contained in the pressure-sensitive adhesive having a carboxy group with respect to 4-aminopyridine was 0.13 or more, and Comparative Examples 5 to 6 Compared with the patch, the drug residual rate was high. It was revealed that the patches of Examples 1 to 7 were excellent in drug stability in the patches.

3. Comparison of skin permeability between pressure-sensitive adhesive having carboxy group and pressure-sensitive adhesive having no carboxy group (1) Manufacturing method of patch of Reference Example 2 Styrene-isoprene-styrene block copolymer according to the ratio shown in Table 5 (SIS) 27.9 g, alicyclic saturated hydrocarbon resin 50.3 g and saturated hydrocarbon plasticizer 16.8 g were dissolved in toluene and mixed, and 5.0 g of 4-aminopyridine was further added. The obtained mixture was stirred to obtain a coating solution. The obtained coating liquid was applied onto a release liner made of polyethylene terephthalate, and then the solvent was removed by drying to form an adhesive layer (drug-containing layer) having a predetermined plaster thickness (100 μm). Next, a support made of polyethylene terephthalate was bonded to the pressure-sensitive adhesive layer, and a release liner, a pressure-sensitive adhesive layer, and a support were laminated in this order to obtain a patch.

(2) Skin permeability test For the patches of Examples 1 and 2 and Reference Examples 1 and 2, a skin permeability test was performed in the following procedure.
The back skin of the hairless mouse was peeled off, and the peeled skin was attached to a flow-through cell in which warm water at 37 ° C. was circulated to the outer peripheral portion so that the dermis side of the peeled skin became the receptor layer side. Next, a patch is applied to the stratum corneum side of the skin, and the receptor layer is applied with physiological saline to which a phosphate buffer (pH 7.4) is added, and then 0 (immediately after application), 2, 6 The receptor solution was sampled after 10, 14, 18 and 22 hours, and the 4-aminopyridine concentration was measured using high performance liquid chromatography (HPLC). The drug permeation rate per hour was calculated from the obtained measured values, and was defined as the skin permeation rate of the drug per unit area in a steady state.

The results of the skin permeability test are shown in FIG. As is clear from FIG. 1, the patches of Examples 1 and 2 both had a maximum skin permeation rate of 10 μg / cm ² / hr or more, and the skin permeation rate was 10 μg / cm even after 14 hours had passed since the application. cm ² / hr was maintained. On the other hand, the patch of Reference Example 1 obtained a stable local concentration because the skin permeation rate exceeded 50 μg / cm ² / hr and the skin permeation rate suddenly decreased after 6 hours had passed since the pasting. However, the possibility of side effects was expected. Further, the patch of Reference Example 2 had significantly low skin permeability.

4). Effect on drug stability due to difference in packaging material (1) Manufacturing method of patch of Reference Example 3 According to the ratio shown in Table 6, lactic acid and 4-aminopyridine were dissolved in ethyl acetate, and an acrylate copolymer ( Hydroxyl group-containing type) 35.5 g and acrylate copolymer (carboxy group-containing type) 35.5 g were added and stirred sufficiently to obtain a coating solution. The obtained coating liquid was applied onto a release liner made of polyethylene terephthalate, and then the solvent was removed by drying to form an adhesive layer (drug-containing layer) having a predetermined plaster thickness (100 μm). Next, a support made of polyethylene terephthalate was bonded to the pressure-sensitive adhesive layer, and a release liner, a pressure-sensitive adhesive layer, and a support were laminated in this order to obtain a patch.

(2) Drug stability test The manufactured patch is punched into a roughly 25 mm x 25 mm rectangle, and the innermost packaging material is PE (polyethylene) packaging material, PAN (polyacrylonitrile) packaging material, or PP (polypropylene). After individually enclosing each of the packaging materials, the packaging materials were stored according to the conditions described in Table 7 (60 ° C., 2 weeks). After 2 weeks, the patch was taken out from the packaging material, and tetrahydrofuran and methanol were added to the obtained patch, followed by shaking and sonication, whereby the drug contained in the patch (4-amino (Pyridine) was extracted. After the obtained extract was concentrated, the absorbance was measured by high performance liquid chromatography (HPLC). From the obtained absorbance, the drug content per patch was calculated based on the calibration curve. The drug content in the patch before storage was calculated in the same manner as the initial 4-aminopyridine content. The results are shown in Table 7.

  As shown in Table 7, the drug stability in the patch of Reference Example 3 was improved in the order of PE packaging material, PP packaging material, and PAN packaging material.

Claims (6)

A patch having a support and an adhesive layer laminated on the support,
The pressure-sensitive adhesive layer contains 4-aminopyridine and a pressure-sensitive adhesive having a carboxy group,
The patch, wherein the molar ratio of the carboxy group contained in the pressure-sensitive adhesive having a carboxy group to the 4-aminopyridine is 0.13 or more.   The patch according to claim 1, wherein the content of 4-aminopyridine is 5 to 20% by mass based on the total amount of the pressure-sensitive adhesive layer. The patch of Claim 1 or 2 whose content of the adhesive which has the said carboxy group is 25-95 mass% on the basis of the adhesive layer whole quantity. The patch as described in any one of Claims 1-3 in which the adhesive which has the said carboxy group contains the acrylate copolymer which has a carboxy group. The patch according to any one of claims 1 to 4 , wherein the pressure-sensitive adhesive layer further contains an acrylate copolymer having a hydroxy group. The patch according to any one of claims 1 to 5 , which is enclosed in a packaging material together with a desiccant.

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