Patches for alleviating or treating symptoms of neurodegenerative diseases

Abstract

The problem addressed by the present invention is to provide a novel patch for relieving or treating a symptom of a neurodegenerative disease. According to the present invention, provided is a patch for relieving or treating a symptom of a neurodegenerative disease, containing a salt of scopolamine and / or a hydrate thereof, said patch having an application duration per one time of 48 hours or less.

Description

[Technical Field]

[0001] The present invention relates to a patch containing a salt of scopolamine and / or a hydrate thereof as an active ingredient, for alleviating or treating the symptoms of neurodegenerative diseases. [Background technology]

[0002] Scopolamine is widely known as an anticholinergic drug, and is effective in suppressing oral and airway secretions and preventing harmful parasympathetic reflexes. Pharmaceuticals containing scopolamine as an active ingredient have been developed. For example, in Japan, "Hisco (registered trademark) Subcutaneous Injection, Kyorin Pharmaceutical" is an injection containing scopolamine hydrobromide hydrate, a salt of scopolamine, as the active ingredient, and overseas, "Transderm Scop (registered trademark, Novartis)" is a patch containing scopolamine free base as the active ingredient.

[0003] Non-Patent Document 1 suggests that scopolamine ointment tends to reduce saliva secretion, and Non-Patent Documents 2 to 7 describe that transdermal scopolamine preparations reduce saliva secretion. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Maeda M et al.,Jpn J Clin Pharmacol Ther 2018;49(2):53-58 [Non-patent document 2] Gordon C et al.,J Clin Pharmacol.,1985;25:407-412 [Non-patent document 3] Talmi YP et al.,Otolaryngol Head Neck Surg.,1990,Vol.103,No.4,615-618 [Non-patent document 4] Jongerius PH et al., Pediatrics. 2004, Vol.114, No.3, 620-627

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Summary of the Invention

Problems to be Solved by the Invention

[0005] An object of the present invention is to provide a novel patch for alleviating or treating symptoms of neurodegenerative diseases.

Means for Solving the Problems

[0006] As a result of repeated studies by the present inventors to solve the above problems, it has been found that by transdermally applying a patch containing a salt of scopolamine and / or its hydrate, polyvinylpyrrolidone, and a base at a predetermined usage and dosage, the amount of saliva secretion can be reduced, and it is useful for alleviating or treating symptoms of neurodegenerative diseases, thus completing the present invention. According to the present invention, the following inventions are provided.

[0007] <1> A patch for alleviating or treating symptoms of neurodegenerative diseases, containing a salt of scopolamine and / or its hydrate, wherein the application time per application is within 48 hours. <2> The patch according to <1>, wherein the application time per application is within 24 hours. <3> The patch according to <1>, wherein the application within 48 hours per application is continuously repeated two or more times. <4> The patch according to any one of <1> to <3>, wherein the dosage of the salt of scopolamine and / or its hydrate per day for an adult is 0.75 mg to 50 mg. <5> The patch according to any one of <1> to <4>, wherein the patch is applied to the posterior auricle, shoulder, upper arm, chest, abdomen, lumbodorsal region, buttocks, or thigh. <6> The patch according to any one of <1> to <5>, wherein the salt of scopolamine and / or its hydrate is scopolamine hydrobromide and / or scopolamine hydrobromide hydrate. <7> The patch according to any one of <1> to <6>, further containing polyvinylpyrrolidone and a base. <8> The patch according to <7>, wherein the base is at least one selected from amine compounds. <9> The patch according to <8>, wherein the amine compound is a copolymer of methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate. <10> The patch is a patch comprising a support, a drug-containing adhesive layer, and a release liner, wherein the drug-containing adhesive layer contains a pharmaceutical composition containing a salt of scopolamine and / or its hydrate, polyvinylpyrrolidone, and a base. The patch according to any one of <1> to <8>. <11> The patch according to <10>, wherein the content of the salt of scopolamine and / or its hydrate is 0.5 to 10% by mass based on the total mass of the pharmaceutical composition. <12> The patch according to <10> or <11>, wherein the content of polyvinylpyrrolidone is 0.3 to 12% by mass based on the total mass of the pharmaceutical composition. <13> The patch according to any one of <10> to <12>, wherein the content of the base is 0.3 to 10% by mass based on the total mass of the pharmaceutical composition. <14> The patch according to any one of <10> to <13>, wherein the base component of the drug-containing adhesive layer is at least one selected from acrylic adhesives, rubber adhesives, and silicone adhesives. <15> The patch according to any one of <10> to <14>, wherein the base component of the drug-containing adhesive layer is an acrylic adhesive. <16> The patch according to <15>, wherein the acrylic pressure-sensitive adhesive is at least one selected from a hydroxyl group-containing type and a non-polar type.

Advantages of the Invention

[0008] The patch containing a salt of scopolamine and / or its hydrate as an active ingredient according to the present invention can effectively suppress the amount of saliva secretion and is useful for alleviating or treating symptoms of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).

Brief Description of the Drawings

[0009]

Figure 1

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Figure 10

Mode for Carrying Out the Invention

[0010] The patch of the present invention is a patch for relieving or treating symptoms of neurodegenerative diseases, which contains a salt of scopolamine and / or its hydrate, and the application time per application is within 48 hours.

[0011] Examples of neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), anxiety-related disorders (social anxiety disorder, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD)), polyglutamine diseases, retinitis pigmentosa, neurosis, epilepsy, panic disorder, sleep disorders, depression, reactive depression, epilepsy, Parkinson's disease, Parkinson's syndrome, Down syndrome, schizophrenia, autonomic nervous system disorders, Huntington's disease, Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, mood disorders (including depressive or bipolar disorder), migraine, tension headache, cluster headache, dissociative disorder, neuromyelitis optica, optic neuritis, acute disseminated (disseminated) encephalomyelitis, allergic encephalomyelitis, Marburg virus disease, Binswanger's disease, progressive multifocal leukoencephalopathy, post-infectious encephalitis, central pontine myelinolysis, adrenoleukodystrophy, multiple system atrophy, Krabbe disease, metachromatic leukodystrophy, Alexander disease, Canavan disease, cocaine syndrome, Pelizaeus-Merzbacher disease, Fuller syndrome, Lowe syndrome, spinal cord injury, transverse myelitis, spinocerebellar degeneration, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, phenylketonuria, Refsum disease, Charcot-Marie-Tooth disease, Gaucher disease, Niemann-Pick disease, multiple sclerosis, fragile X syndrome, autism, insomnia, nervous cough, psychogenic spasm attacks, psychogenic absence attacks, writer's cramp, spasmodic torticollis, neuropathy, etc.

[0012] The therapeutic effect of amyotrophic lateral sclerosis can be evaluated by the ALS Functional Rating Scale (ALSFRS-R), etc.

[0013] Examples of symptoms of neurodegenerative diseases include an increase in the amount of saliva secreted. Alleviation or treatment of symptoms of neurodegenerative diseases includes reducing the amount of saliva secreted.

[0014] The application time per application of the patch of the present invention is within 48 hours, preferably within 36 hours, more preferably within 30 hours, and even more preferably within 24 hours. The application time per application of the patch of the present invention is particularly preferably 24 hours.

[0015] The patch of the present invention can repeatedly perform the application within 48 hours (preferably within 36 hours, more preferably within 30 hours, still more preferably within 24 hours) per application two or more times continuously. When repeatedly performing the application two or more times continuously, the lower limit of the number of applications is not particularly limited, and it may be two or more times, three or more times, four or more times, five or more times, six or more times, or seven or more times. The upper limit of the number of applications is also not particularly limited, and it may be within 100 times, within 50 times, within 40 times, within 30 times, within 20 times, or within 10 times.

[0016] In the patch of the present invention, the dosage of scopolamine salt and / or its hydrate per day for an adult is preferably 0.75 mg to 50 mg, more preferably 0.75 mg to 30 mg, still more preferably 0.75 mg to 20 mg, and particularly preferably 0.75 mg to 9 mg. Specific examples of the dosage of scopolamine salt and / or its hydrate per day include 0.75 mg, 1.5 mg, 3 mg, 6 mg, 9 mg, or 18 mg.

[0017] The application site of the patch of the present invention is not particularly limited, and examples thereof include the posterior auricle, shoulder, upper arm, chest, abdomen, lumbodorsal region, buttocks, or thigh, etc. Preferably, it is the posterior auricle, upper arm, chest, or abdomen, and particularly preferably the posterior auricle.

[0018] The active ingredient used in the patch of the present invention is scopolamine ((−)-(S)-3-hydroxy-2-phenylpropionic acid (1R,2R,4S,7S,9S)-9-methyl-3-oxa-9-azatricyclo[3.3.1.0 2,4It is a salt and / or hydrate of scopolamine (non-7-yl ester). Examples of the salt of scopolamine include acid addition salts with inorganic acids or organic acids, such as hydrochloride, hydrobromide, nitrate, phosphate, sulfate, acetate, ascorbate, benzoate, cinnamate, citrate, formate, fumarate, glutamate, lactate, maleate, malate, malonate, mandelate, methanesulfonate (mesylate), phthalate, salicylate, stearate, succinate, tartrate, propionate, butyrate, pamoate, p-toluenesulfonate (tosylate), etc., but are not limited thereto. In the patch of the present invention, it is preferable to use scopolamine hydrobromide and / or its hydrate.

[0019] The patch of the present invention only needs to contain a therapeutically effective amount of a salt of scopolamine and / or its hydrate, and its state is not particularly limited, but from the viewpoint of absorbability into the living body, a dissolved state or an amorphous state is preferable. In order to administer a therapeutically effective amount of the active ingredient to the patient, it is important to contain a certain amount of the active ingredient.

[0020] The patch of the present invention is a patch containing a support, a drug-containing adhesive layer, and a release liner, and it is preferable that the drug-containing adhesive layer contains a pharmaceutical composition containing a salt of scopolamine and / or its hydrate, polyvinylpyrrolidone, and a base.

[0021] The content of the salt of scopolamine and / or its hydrate in the above pharmaceutical composition is 0.5 to 10% by mass, preferably 1 to 8% by mass, more preferably 3 to 6% by mass based on the whole composition. If it is less than 0.5% by mass, the therapeutic effect may not be sufficient, while if it exceeds 10% by mass, it is economically disadvantageous.

[0022] The above pharmaceutical composition contains polyvinylpyrrolidone to improve the chemical stability of scopolamine. Generally used polyvinylpyrrolidones have weight average molecular weights ranging from several thousand to several million. One or more of these polyvinylpyrrolidones can be used.

[0023] The content of polyvinylpyrrolidone in the above pharmaceutical composition is in the range of 0.3 to 12% by mass, preferably 0.5 to 10% by mass, more preferably 1 to 8% by mass, based on the whole composition. If it is less than 0.3% by mass, a sufficient effect of improving chemical stability may not be obtained. On the other hand, if it exceeds 12% by mass, it may adversely affect the physical properties of the composition, so it is not preferable. In addition, since a weight ratio of polyvinylpyrrolidone to the salt of scopolamine and / or its hydrate of 2 or more may adversely affect the uniformity of the composition, the weight ratio of polyvinylpyrrolidone to the salt of scopolamine and / or its hydrate is preferably less than 2.

[0024] The above pharmaceutical composition preferably contains an amine compound in order to make the salt of scopolamine and / or its hydrate a free base and to improve the chemical stability of scopolamine. The amine compound may be any of a primary amine, a secondary amine, and a tertiary amine. Examples of the primary amine include methylamine, ethylamine, dodecylamine, etc. Examples of the secondary amine include dimethylamine, diethylamine, N-methyl-ethanamine, etc. Examples of the tertiary amine include N,N-diethylmethylamine, tributylamine, N,N-dimethyl-p-toluidine, N,N-diethyl-p-toluidine, a copolymer of methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate, etc., but are not limited thereto. One or more of these amine compounds can be used.

[0025] The content of the amine compound in the above pharmaceutical composition is in the range of 0.3 to 10% by mass, preferably 0.5 to 8.5% by mass, more preferably 0.9 to 7.5% by mass, based on the whole composition. If it is less than 0.3% by mass, sufficient absorbability into the living body may not be obtained. On the other hand, if it exceeds 10% by mass, it may adversely affect the chemical stability.

[0026] Examples of the patch of the present invention include a matrix type and a reservoir type. The patch of the present invention may be either a matrix type or a reservoir type, but the matrix type is preferred because formulation design is easy and the cost during production can be reduced.

[0027] The matrix type patch consists of a support, a drug-containing adhesive layer, and a release liner.

[0028] The drug-containing adhesive layer contains a pharmaceutical composition containing an active ingredient and a base component. The base component used in this drug-containing adhesive layer is not particularly limited, but adhesive components generally used in patches, such as rubber-based adhesive components, acrylic-based adhesive components, and silicone-based adhesive components, are preferred, and acrylic-based adhesive components are particularly preferred, and non-polar type acrylic-based adhesive components and hydroxyl group-containing type acrylic-based adhesive components are more preferred.

[0029] The acrylic-based adhesive component is a polymer or copolymer containing at least one (meth)acrylate.

[0030] The non-polar type acrylic-based adhesive component has no functional group in the side chain in the monomer constitutional unit. Examples include (meth)acrylic acid alkyl polymers or copolymers, (meth)acrylic acid alkyl-vinyl acetate copolymers, etc. Specifically, 2-ethylhexyl acrylate-2-ethylhexyl methacrylate-dodecyl methacrylate copolymer, 2-ethylhexyl acrylate-vinyl acetate copolymer, methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer, etc. can be mentioned, but it is not limited thereto.

[0031] The hydroxyl group-containing type of acrylic pressure-sensitive adhesive component is a polymer or copolymer having at least one (meth)acrylic acid ester containing a free hydroxyl group in the side chain of the monomer constituent unit. For example, a copolymer containing a (meth)acrylic acid hydroxyalkyl ester can be mentioned. Specifically, 2-ethylhexyl acrylate-hydroxyethyl acrylate-vinyl acetate copolymer, 2-ethylhexyl acrylate-vinyl pyrrolidone-hydroxyethyl acrylate-vinyl acetate copolymer, 2-ethylhexyl acrylate-hydroxyethyl acrylate-vinyl acetate copolymer, 2-ethylhexyl acrylate-hydroxyethyl acrylate-glycidyl acrylate-vinyl acetate copolymer, 2-ethylhexyl acrylate-vinyl acetate-2-hydroxyethyl acrylate copolymer, 2-ethylhexyl acrylate-vinyl acetate-2-hydroxyethyl acrylate-glycidyl methacrylate copolymer, etc. can be mentioned, but it is not limited thereto.

[0032] Considering the formation of the drug-containing adhesive layer and sufficient drug release properties, the content of the base component in the drug-containing adhesive layer is 60 to 98.9% by mass, preferably 63 to 98% by mass, more preferably 66 to 96% by mass with respect to the entire drug-containing adhesive layer. If it is less than 60% by mass, the physical properties as an adhesive such as anchoring property will deteriorate. Also, if the amount exceeds 98.9%, the active ingredient and other additives cannot be sufficiently blended, which is not preferable.

[0033] The drug-containing adhesive layer may contain an absorption enhancer as needed. Any compound that has been conventionally recognized as having an absorption-enhancing effect in transdermal administration may be used as the absorption enhancer. Examples include fatty acids and their esters such as lauric acid, oleic acid, isostearic acid, isopropyl myristate, octyldodecyl myristate, glycerin monooleate, and hexyl decyl isostearate; alcohols and their esters or ethers such as oleyl alcohol, propylene glycol, and polyethylene glycol monooleate; sorbitan esters or ethers such as sorbitan sesquioleate, polyoxyethylene sorbitan monooleate, sorbitan monolaurate, and sorbitan monooleate; phenolic ethers such as polyoxyethylene nonylphenyl ether and polyoxyethylene octylphenyl ether; castor oil or hydrogenated castor oil; ionic surfactants such as oleoyl sarcosine, lauryl dimethylaminoacetic acid betaine, and sodium lauryl sulfate; nonionic surfactants such as polyoxyethylene oleyl ether and polyoxyethylene lauryl ether; alkyl methyl sulfoxides such as dimethyl sulfoxide and decyl methyl sulfoxide; azacycloalkanes such as 1-dodecylazacycloheptan-2-one and 1-geranylazacycloheptan-2-one; and pyrrolidones other than polyvinylpyrrolidone, etc.

[0034] The support used in the patch of the present invention is not particularly limited. For example, a drug-impermeable, stretchable or non-stretchable support can be used. Examples of the support include synthetic resin films or sheets such as polyethylene, polypropylene, polybutadiene, ethylene-vinyl acetate copolymer, polyvinyl chloride, polyester (such as polyethylene terephthalate), nylon, and polyurethane, or laminates thereof, porous bodies, foams, paper, woven fabrics, non-woven fabrics, etc.

[0035] The release liner used in the patch of the present invention is not particularly limited. For example, a drug-impermeable release liner can be used. Examples of the release liner include films made of polymer materials such as polyethylene, polypropylene, and polyester, films with aluminum vapor-deposited thereon, and papers coated with silicone oil or the like. Among them, a polyester film is preferable in terms of no permeation of the active ingredient and processability and low cost, and a polyethylene terephthalate (PET) film is particularly preferable. Further, as the release liner, a laminated film or the like obtained by laminating a plurality of materials may be used.

[0036] The patch of the present invention is stored in a packaging material until use. The packaging material is not particularly limited, and examples thereof include plastic films, metal (such as aluminum) laminated plastic films, metal vapor-deposited plastic films, ceramic (such as silicon oxide) vapor-deposited plastic films, metal foils such as aluminum foils, metals such as stainless steel, and glass. Among them, it is preferable to use a metal laminated plastic film, a metal vapor-deposited plastic film, or the like in terms of manufacturing cost and the like.

[0037] In the patch of the present invention, if necessary, a release control film may be added to the skin-attaching side of the drug-containing adhesive layer to control the transdermal absorption of the active ingredient, or an adhesive layer may be added for attaching to the skin.

[0038] The patch of the present invention preferably comprises a support, a drug-containing adhesive layer, and a release liner. The thickness of the support is 1 to 1000 μm, preferably 10 to 700 μm; the thickness of the drug-containing adhesive layer is 10 to 200 μm, preferably 30 to 150 μm; and the thickness of the release liner is 1 to 500 μm, preferably 10 to 200 μm.

[0039] The patch of the present invention can be produced according to a known method for producing a patch. Preferred methods for producing the patch of the present invention include, for example, the following methods.

[0040] <Method 1> A salt of scopolamine and / or its hydrate as an active ingredient, an amine compound, polyvinylpyrrolidone, a base component, and, if necessary, an absorption promoter, etc. are dissolved in an organic solvent such as ethyl acetate, methanol or a mixed solvent thereof, and the resulting solution is spread on a release liner or a support. After evaporating the organic solvent in the solution to form a drug-containing adhesive layer, a patch is obtained by laminating the support or the release liner.

[0041] <Method 2> A salt of scopolamine and / or its hydrate as an active ingredient, an amine compound, polyvinylpyrrolidone, a base component, and, if necessary, an absorption promoter, etc. are dissolved by heating, and the resulting melt is spread on a release liner or a support. After forming a drug-containing adhesive layer, a patch is obtained by laminating the support or the release liner.

Example

[0042] The present invention will be specifically described by the following examples, but the present invention is not limited to these examples.

[0043] <Example 1> According to the formulation ratio shown in Table 1, scopolamine hydrobromide hydrate, isopropyl myristate, and dodecylamine were dissolved in a mixed solution of ethyl acetate / methanol, and an acrylic adhesive component (trade name: DURO-TAK 87-4287, manufactured by Henkel) was added and mixed with stirring to obtain a uniform solution. Next, this solution was spread on a release film to a thickness of 100 μm after drying using a doctor knife coater, dried to form a drug-containing adhesive layer, and then a support was laminated. Then, it was cut to a desired size to obtain a patch.

[0044] <Example 2> A patch was obtained in the same manner as in Example 1, except that diethylamine was used instead of dodecylamine so that the amount of free scopolamine base was equal to that in Example 1 according to the formulation ratio shown in Table 1.

[0045] <Example 3> According to the formulation ratio described in Table 1, except that a copolymer of methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate (trade name: Eudragit EPO, manufactured by Evonik) was blended instead of dodecylamine so that the amount of scopolamine free base was equal to that in Example 1, an adhesive patch was obtained in the same manner as in Example 1.

[0046] <Example 4> According to the formulation ratio described in Table 1, except that sodium hydroxide was blended instead of dodecylamine and polyvinylpyrrolidone was further blended so that the amount of scopolamine free base was equal to that in Example 1, an adhesive patch was obtained in the same manner as in Example 1.

[0047] <Example 5> According to the formulation ratio described in Table 1, except that Eudragit EPO was blended instead of dodecylamine and polyvinylpyrrolidone was further blended so that the amount of scopolamine free base was equal to that in Example 1, an adhesive patch was obtained in the same manner as in Example 1.

[0048] <Example 6> According to the formulation ratio described in Table 1, scopolamine hydrobromide monohydrate, Eudragit EPO, and polyvinylpyrrolidone were dissolved in an ethyl acetate / methanol mixed solution, DURO-TAK 87-4287 was added and mixed with stirring to obtain a uniform solution. Next, this solution was spread on a release film using a doctor knife coater so that the thickness after drying was 100 μm, dried to form a drug-containing adhesive layer, and then a support was laminated. Then, it was cut to a desired size to obtain an adhesive patch.

[0049] <Example 7> According to the formulation ratio described in Table 1, except that the blending amount of polyvinylpyrrolidone was increased, an adhesive patch was obtained in the same manner as in Example 6.

[0050] <Example 8> According to the formulation ratio described in Table 1, scopolamine hydrobromide hydrate, isopropyl myristate, Eudragit EPO, and polyvinylpyrrolidone were dissolved in a mixed solution of ethyl acetate / methanol, and DURO-TAK 87-4287 was added and mixed with stirring to obtain a uniform solution. Next, this solution was spread on a release film using a doctor knife coater so that the thickness after drying would be 100 μm, dried to form a drug-containing adhesive layer, and then a support was laminated. Then, it was cut into a desired size to obtain a patch.

[0051] <Example 9> According to the formulation ratio described in Table 1, scopolamine hydrobromide hydrate, isopropyl myristate, Eudragit EPO, and polyvinylpyrrolidone were dissolved in a mixed solution of ethyl acetate / methanol, and DURO-TAK 87-4287 was added and mixed with stirring to obtain a uniform solution. Next, this solution was spread on a release film using a doctor knife coater so that the thickness after drying would be 50 μm, dried to form a drug-containing adhesive layer, and then a support was laminated. Then, it was cut into a desired size to obtain a patch.

[0052] <Example 10> A patch was obtained in the same manner as in Example 9, except that the amount of isopropyl myristate was increased according to the formulation ratio described in Table 1.

[0053]

Table 1

[0054] <Test Example 1> Plasma Concentration Measurement Test in Single Oral Administration in Rats (Administration) Scopolamine patch (Example 5) was administered transdermally once (occlusive application for 24 hours) to 5 male rats (Crl:CD(SD) strain; age at administration: 6 weeks old) (animal numbers 10101 - 10105). Before administration on the administration day, hair was removed with an electric clipper. After checking the back condition, the test substance was applied to the back (right side from the midline). The application site was covered with a lint cloth (approx. 4.0 cm × 4.0 cm), and an elastic adhesive bandage was wrapped around to occlude it. The dose was 1 patch / rat (content: 0.75 mg / patch). The area per patch was 2.5 cm 2 / patch.

[0055] (Observation and Measurement) The general condition was observed before administration on the administration day and at each blood sampling time point. Body weight was measured before administration on the administration day. Blood was sampled at 4 time points: 3, 6, 12, and 24 hours after administration, and the scopolamine concentration in plasma at 3, 6, 12, and 24 hours after administration was measured.

[0056] (Results) The measurement results of the scopolamine concentration in plasma are shown in Table 2. * indicates that the measured value exceeded the upper limit of quantification, so the sample was reanalyzed. In a, animal number 10101 was excluded from the calculation of the mean value and SD. As shown in Table 2, scopolamine was detected in plasma from 3 hours to 24 hours after administration. AUC 0-24h was 8659 pg·h / mL.

[0057]

Table 2

[0058] The observation results of the general condition (observation time points: before administration on the administration day and at each blood sampling time point) and the body weight (g) before administration on the administration day are shown in Table 3 and Table 4, respectively. No abnormalities were observed in the general condition.

[0059]

Table 3

[0060]

Table 4

[0061] <Test Example 2> (Administration) The inhibitory effect of the patch of the present invention on salivary secretion induced by intravenous administration of pilocarpine hydrochloride to rats was examined. Ten male Crl:CD(SD) rats per group were used (at the time of administration: 6 weeks old). The test groups were a control group (non-administration), a scopolamine placebo preparation (a patch not containing scopolamine), and a scopolamine patch (Example 5) (as hydrobromide hydrate of scopolamine at 0.75 mg / 2.5 cm 2 ) at 0.4, 1.2, and 3.6 mg / kg groups. The group composition is shown in Table 5 below.

[0062]

Table 5

[0063] The hair on the back of the animal was removed using an electric clipper and an electric shaver. A point was marked at the administration site with an oil-based felt pen. A scopolamine placebo or scopolamine was applied at the center of the hair-removed area. A non-woven adhesive bandage (Meshpoa (registered trademark), Nichiban Co., Ltd.) larger than the applied preparation was applied so as to overlap the preparation. An adhesive fabric stretch bandage (Elastopore Scopolamine, Nichiban Co., Ltd.) was wrapped to occlude the application site. The control group was covered with a non-woven adhesive bandage (Meshpoa (registered trademark), Nichiban Co., Ltd.) of the same size as when the preparation was used at the hair-removed site, and then an adhesive fabric stretch bandage (Elastopore (registered trademark), Nichiban Co., Ltd.) was wrapped to occlude it. A mixture of medetomidine hydrochloride 0.4 mg / kg (Domitor (registered trademark), Nippon Zenyaku Kogyo Co., Ltd.) + midazolam 2 mg / kg (Midazolam Injection 10 mg, Fujifilm Pharmaceutical Co., Ltd.) + butorphanol tartrate 5 mg / kg (Vetorphal (registered trademark), Meiji Seika Pharma Co., Ltd.) was administered intraperitoneally. To prevent asphyxiation by saliva, the skin was incised under anesthesia, the trachea was exposed, and a cannula was inserted. At 4 hours after the patch administration when the plasma concentration of scopolamine increased and stabilized (within the allowable range: within +10 minutes), pilocarpine hydrochloride 1 mg / kg (2 mL / kg) was administered intravenously, and a cotton ball whose weight had been measured in advance with an electronic analytical balance (a cotton ball in the range of 0.082 - 0.085 g was used) was inserted into the oral cavity. At 30 minutes after the administration of pilocarpine hydrochloride, the cotton ball moistened with saliva was taken out and immediately weighed with an electronic analytical balance. The weight before insertion was subtracted to obtain the saliva secretion volume. In addition, the cotton ball was replaced with a new one during the process depending on the degree of saliva secretion volume.

[0064] (Results and Discussion) The results are shown in Table 6 below. 1) is the saliva secretion volume 30 minutes after the administration of pilocarpine hydrochloride. *: P < 0.05, **: P < 0.01, significant difference from the control group (Dunnett’s multiple comparison test) No statistically significant difference was observed in the salivary secretion volume between the control group and the scopolamine placebo group. A significant decrease in the salivary secretion volume was observed in the 0.4 and 3.6 mg / kg scopolamine groups compared with the control group. Although no significant decrease in the salivary secretion volume was observed in the 1.2 mg / kg scopolamine group compared with the control group, it was judged that the variation in the plasma concentration of the test substance did not result in a statistically significant decrease in the salivary secretion volume because of the tendency of the salivary secretion volume to decrease. From the above results, it was demonstrated that scopolamine exhibits an inhibitory effect on pilocarpine-induced salivary secretion at a dose of 0.4 mg / kg or higher.

[0065]

Table 6-1

Table 6-2

[0066] <Clinical Trial 1> (Test drug) Scopolamine patch: A patch containing 0.75 mg of scopolamine hydrobromide hydrate in 1 piece (2.5 cm 2 )(hereinafter also referred to as NPC-22) Scopolamine placebo: A preparation indistinguishable from the appearance of a placebo drug that does not contain scopolamine (active ingredient) Scopolamine injection: An injection containing 0.5 mg of scopolamine hydrobromide hydrate in 1 tube of 1 mL (Hyosco subcutaneous injection)

[0067] (Dosage and administration) Scopolamine group In the case of scopolamine administration: 0.75 mg group; Apply 1 piece of scopolamine patch once to the back of the auricle for 24 hours. 1.5 mg group; Apply 2 pieces of scopolamine patch once to the back of the auricle for 24 hours. 3 mg group; Apply 4 pieces of scopolamine patch once to the back of the auricle for 24 hours. 6 mg group; Apply 8 pieces of scopolamine patch once to the back of the auricle for 24 hours. 9 mg group: Twelve scopolamine patches are applied once to the posterior auricle for 24 hours.

[0068] In the case of scopolamine placebo administration: The placebo is applied once to the posterior auricle for 24 hours according to the number of patches administered for each scopolamine patch dosage.

[0069] Scopolamine injection group: Scopolamine injection is subcutaneously administered once at a dose of 0.25 mg. The subjects are the same as those in the 3 mg group.

[0070] (Administration period) A single administration is performed. The scopolamine patch is applied for 24 hours. The scopolamine injection is subcutaneously administered once.

[0071] (Evaluation items) Scopolamine patch group: Safety: Adverse events, skin findings (according to the criteria of the Patch Test Study Group), vital signs, 12-lead electrocardiogram (including QT / QTc evaluation), clinical test values, Pharmacodynamics: Saliva volume, saliva secretion score (VAS by the subject), heart rate (Holter electrocardiogram) Pharmacokinetics: Plasma concentration of unchanged scopolamine, urinary excretion rate, and pharmacokinetic parameters (Cmax, Tmax, AUC, and half-life, etc.) Others: Amount of drug remaining in the scopolamine patch

[0072] Scopolamine injection group: Safety: Adverse events, vital signs, 12-lead electrocardiogram, clinical test values Pharmacokinetics: Plasma concentration of unchanged scopolamine, urinary excretion rate, and pharmacokinetic parameters (Cmax, Tmax, AUC, and half-life, etc.)

[0073] (Measurement of saliva volume) From one hour before the measurement, the subject should be in a lying position and kept at rest. Intake of food and drink is prohibited. Ten minutes before the measurement, the subject should sit up, and then, in order to collect saliva, absorbent cotton is placed in three locations: between the left and right molar teeth and the cheek, and under the tongue, to absorb saliva. The amount of saliva secreted is calculated by measuring the weight of the absorbent cotton that has absorbed the saliva.

[0074] Measurement time: Measure at before administration, 2, 4, 8, 12, 24 (after measurement, drug removal), 26, 28, 32, 36, 48, and 72 hours after administration. Also, measure at the same time as the measurement time on the first day of administration on the day before administration as the baseline. Note that in the scopolamine injection group, the saliva volume is not measured.

[0075] (Measurement of plasma concentration) Measure the unchanged form of scopolamine. Blood sampling time: Scopolamine patch group: Conduct at immediately before administration, 0.5, 1, 2, 4, 6, 8, 10, 12, 24 (after blood sampling, drug removal), 26, 28, 32, 36, 48, 72 hours and on the 7th day after administration. Scopolamine injection group: Conduct at immediately before injection, 0.08 (5 minutes), 0.25 (15 minutes), 0.5 (30 minutes), 1, 2, 4, 6, 12, 24 hours after administration.

[0076] (Urinary excretion) Measure the unchanged form of scopolamine Urine collection time: Scopolamine patch group: Conduct urine collection at before administration (random urine), 0 - 4, 4 - 8, 8 - 12, 12 - 24 (after urine collection, drug removal), 24 - 32, 32 - 48, 48 - 72 hours after administration. Scopolamine injection group: Conduct urine collection at before administration (random urine), 0 - 4, 4 - 8, 8 - 12, 12 - 24 hours after administration.

[0077] <Results of Clinical Trial 1> (1) Pharmacokinetic analysis (1 - 1) Plasma pharmacokinetics of scopolamine (1 - 1 - 1) Plasma concentration changes Figure 1 shows the plasma scopolamine concentration profile (mean ± standard deviation) after a single administration (24-hour patch application) of NPC-22 to healthy adult males. Figure 2 shows the plasma scopolamine concentration profile (mean ± standard deviation) after a single subcutaneous administration of 0.25 mg of scopolamine hydrobromide hydrate injection to healthy adult males. After the administration of NPC-22, the plasma scopolamine concentration increased during the administration period, continued to increase for several hours even after the removal of NPC-22, and then gradually decreased approximately 28 hours (4 hours after removal). The plasma scopolamine concentration showed a trend of increasing at higher concentrations with an increase in the dose. In the dose groups of 1.5 mg or more, plasma scopolamine concentration was still observed on the 7th day (6th day after removal). In the 6 and 9 mg dose groups, the plasma scopolamine concentration on the 7th day was above the lower limit of quantification (1.0 pg / mL) in all subjects, and the plasma concentrations showed approximately 13% and approximately 11% of the maximum concentration, respectively. In the 0.75 mg dose group, the plasma scopolamine concentration in 2 out of 6 subjects was below the lower limit of quantification at all measurement time points. The coefficient of variation (CV%) of the plasma scopolamine concentration at the time of NPC-22 removal (24 hours after administration) was 42.2% - 90.6%, and a large variation was observed among subjects. After a single subcutaneous administration of 0.25 mg of scopolamine hydrobromide hydrate injection, the plasma scopolamine concentration increased rapidly and reached a maximum concentration of 1337.5 pg / mL 15 minutes after administration. Thereafter, it decreased monoexponentially, and the plasma scopolamine concentration was less than 1 / 500 of the maximum concentration 24 hours after administration.

[0078] (1-1-2) Pharmacokinetic parameters Table 7 shows the plasma scopolamine pharmacokinetic parameters (mean and standard deviation) after a single administration (24-hour patch application) of NPC-22 to healthy adult males. Two cases in the 0.75 mg dose group, where the concentration was below the lower limit of quantification at all measurement time points, were excluded from the analysis. The C of the plasma spocopolamine concentration after a single administration (24-hour patch application) of NPC-22 max , AUC 0-24 and AUC inf increased with an increase in the dose. The plasma concentration (C) at the time of NPC-22 removal24 ) is C max is about 69.6% - 88.6% of C, and also AUC inf is about 6 - 16 times that of AUC 0-24 . t max is 23.1 - 36.8 hours after administration, and t 1 / 2 is 42.0 - 54.8 hours.

[0079]

Table 7

[0080] (1 - 1 - 3) Dose proportionality The dose proportionality of scopolamine plasma concentration when NPC - 22 was administered once (patched for 24 hours) at 0.75 mg, 1.5 mg, 3 mg, 6 mg, or 9 mg was examined by regression analysis [power model: ln(C max or AUC) = ln(α) + β·ln(Dose)]. Two cases in the 0.75 mg administration group that were below the lower limit of quantification at all measurement time points were excluded from the analysis. The results are shown in Figures 3 - 5. C max , AUC 0-24 and AUC inf The point estimate (90% confidence interval) of β was 1.247 (0.962 - 1.532), 1.299 (0.917 - 1.681), and 1.137 (0.931 - 1.343), respectively. Linearity was observed in the drug concentration within the dose range of 0.75 - 9 mg of NPC - 22.

[0081] (1 - 1 - 4) Urinary concentration and excretion rate of scopolamine The change in the cumulative urinary excretion rate of scopolamine (mean ± standard deviation) when NPC - 22 was administered once (patched for 24 hours) is shown in Figure 6. The urinary excretion rate of scopolamine after NPC - 22 administration was only 0.024% - 0.065% by 24 hours and 0.093% - 0.190% by 72 hours, and no significant difference was observed in the urinary excretion rate among any of the doses. Also, the change in the urinary excretion rate after NPC - 22 detachment corresponded well to the change in the plasma scopolamine concentration.

[0082] Figure 7 shows the change in the cumulative urinary excretion rate of scopolamine (mean ± standard deviation) when 0.25 mg of scopolamine hydrobromide monohydrate injection was administered subcutaneously once. The urinary excretion rate of scopolamine up to 24 hours after subcutaneous administration of 0.25 mg of scopolamine hydrobromide monohydrate injection was 5.767%, which was higher than that up to 72 hours after NPC-22 administration (0.093% - 0.190%).

[0083] (1-1-5) Comparison of the exposure amounts between NPC-22 and scopolamine hydrobromide monohydrate injection The comparison of the exposure amounts between the scopolamine subcutaneous administration group (8 subjects in total) and the NPC-22 administration groups of 3 mg - 9 mg was examined using pharmacokinetic parameters (C max , t max , AUC 0-24 , AUC inf and t 1 / 2 ), and the results are shown in Table 8. In the scopolamine subcutaneous administration group, C max , t max , AUC inf and t 1 / 2 of scopolamine in plasma were 1388.7 pg / mL, 0.396 hours, 1796.253 pg*hr / mL and 4.584 hours, respectively. Compared with the NPC-22 administration groups of 3 mg - 9 mg, t max and t 1 / 2 were shorter. C max of the scopolamine subcutaneous administration group was about 191 times that of the NPC-22 3 mg administration group, and AUC inf was 2.15 times. Also, compared with the NPC-22 6 mg and 9 mg administration groups, C max was about 42 times and about 27 times, respectively, but AUC inf was 0.81 times and 0.57 times, showing values similar to those of the 0.25 mg subcutaneous administration group.

[0084]

Table 8

[0085] (2) Drug dose, drug concentration, and their relationship to response (2-1) Relationship between plasma scopolamine concentration and saliva secretion The changes and rates of change from baseline in plasma scopolamine concentrations and saliva secretion at the same time points for all subjects in the NPC-22 group who received the NPC-22 tape were plotted in a scatter plot. The regression parameters, correlation coefficients, and 90% confidence intervals were calculated and are shown in Figure 8. There was a weak negative correlation (correlation coefficient: -0.248, -0.289) between the plasma scopolamine concentration and the amount and rate of change in saliva secretion, and a tendency for saliva secretion to decrease as the plasma scopolamine concentration increased was observed.

[0086] (2-2) Relationship between plasma scopolamine concentration and heart rate (12-lead electrocardiogram) The measured plasma scopolamine concentrations and the change and rate of change from baseline in heart rate (12-lead electrocardiogram) for all subjects in the NPC-22 group who received the NPC-22 tape were plotted in a scatter plot, and the regression parameters, correlation coefficients, and 90% confidence intervals were calculated (Figure 9). There was a weak negative correlation (correlation coefficient: -0.229, -0.230) between the plasma scopolamine concentration and the amount and rate of change in heart rate, and a tendency for heart rate to decrease as the plasma scopolamine concentration increased.

[0087] (3) Analysis of remaining drug levels Analysis of the amount of drug remaining in the preparation collected after NPC-22 administration Table 9 shows summary statistics of the remaining amount and percentage of scopolamine hydrobromide hydrate in the preparations collected after a single administration (24-hour patch) of 0.75 mg, 1.5 mg, 3 mg, 6 mg, or 9 mg of NPC-22. The mean residual rate (min, max) of NPC-22 (0.75 mg / strip) was 71.3% (58.3%, 79.8%), with a coefficient of variation (CV%) of 6.88%, indicating no significant variation in the amount of remaining drug. Furthermore, the mean absorption rate (SD) of scopolamine estimated from the amount of drug remaining in the formulation after administration was 28.7% (4.90).

[0088]

Table 9

[0089] <Safety> (1) Adverse events and side effects The adverse events and side effects that occurred in this study are shown in Table 10. Adverse events were observed in 4 / 30 cases (13.3%) in the NPC-22 group, 2 / 10 cases (20.0%) in the placebo group, and 5 / 8 cases (62.5%) in the scopolamine injection group. However, no serious adverse events or adverse events leading to discontinuation of the study were observed in any of the groups. The adverse events according to the dose of NPC-22 were 1 / 6 cases in the 0.75 mg group, 1 / 6 cases in the 1.5 mg group, 0 / 6 cases in the 3 mg group, 1 / 6 cases in the 6 mg group, and 1 / 6 cases in the 9 mg group. Among these, the one judged as a side effect was 1 / 6 cases in the 0.75 mg group. The side effect in the 0.75 mg group was a mild increase in white blood cell count, a decrease in lymphocyte count, and an increase in neutrophil count observed on the 7th day after administration (6th day after detachment), and they disappeared on the 11th day after administration, respectively.

[0090]

Table 10

[0091] (2) Skin findings according to the judgment criteria of the Japanese Patch Test Research Group The skin findings according to the judgment criteria of the Japanese Patch Test Research Group are shown in Table 11. Only "mild erythema" was observed at any judgment time. At 1 hour after detachment, mild erythema was observed in 6 / 6 subjects in the 0.75 mg group, 1 / 6 subjects in the 1.5 mg group, 2 / 6 subjects in the 3 mg group, 5 / 6 subjects in the 6 mg group, and 2 / 6 subjects in the 9 mg group. At 24 hours after detachment, mild erythema was observed in 3 / 6 subjects, 0 / 6 subjects, 0 / 6 subjects, 0 / 6 subjects, and 2 / 6 subjects in order, respectively. However, there was no deterioration of skin findings with the increase in dose, and it was not a major clinical problem. On the other hand, mild erythema was also observed in 7 / 10 subjects at 1 hour after detachment and 2 / 10 subjects at 24 hours after detachment in the skin findings of the placebo group, and the skin findings were similar to those of the NPC-22 group.

[0092]

Table 11

[0093] <Conclusions on Pharmacokinetics, Pharmacodynamics, Drug Residue Levels, and Safety> After NPC-22 administration, the plasma scopolamine concentration increased during the administration period and continued to increase even after NPC-22 detachment. It gradually decreased approximately 28 hours (4 hours after detachment) after remaining elevated for several hours. The plasma scopolamine concentration showed a high level with an increase in the dose, and there were cases where the plasma scopolamine concentration was still observed on the 7th day (6th day after detachment) in the dose groups of 1.5 mg or more. The coefficient of variation (CV%) of the plasma scopolamine concentration at the time of NPC-22 detachment (24 hours after administration) was 42.2% - 90.6%, indicating a large variation among the subjects. C of the plasma scopoamine concentration after single administration of NPC-22 max , AUC 0-24 and AUC inf increased with an increase in the dose. The t max in the NPC-22 administration group was 23.1 - 36.8 hours after administration, and the t 1 / 2 was 42.0 - 54.8 hours. Also, AUC inf was about 6 - 16 times that of AUC 0-24 . As a result of examining the dose proportionality of NPC-22 when administered once using a power model, linearity was observed in the drug concentration in the dose range of NPC-22 0.75 - 9 mg. The urinary excretion rate of scopolamine up to 72 hours after NPC-22 administration was 0.093% - 0.190%, indicating only a small amount of excretion into urine. The change in the urinary excretion rate after NPC-22 detachment corresponded well to the change in the plasma scopolamine concentration. C of the subcutaneous scopolamine administration group max was 191 times, 42 times, and 27 times, respectively, compared to the NPC-22 3 mg, 6 mg, and 9 mg administration groups. AUC of the subcutaneous scopolamine administration group inf was 2.15 times, 0.81 times, and 0.57 times, respectively, compared to the NPC-22 3 mg, 6 mg, and 9 mg administration groups. There was a weak negative correlation (correlation coefficients: -0.248, -0.289) between the change amount and change rate of scopolamine concentration in plasma and the salivary secretion amount, and a decreasing tendency of salivary secretion amount was observed as the scopolamine concentration in plasma increased. There was a weak negative correlation (correlation coefficients: -0.229, -0.230) between the change amount and change rate of scopolamine concentration in plasma and the heart rate, and a decreasing tendency of heart rate was observed as the scopolamine concentration in plasma increased. The average residual rate (minimum value, maximum value) of NPC-22 (0.75 mg / tablet) was 71.3% (58.3%, 79.8%), and the coefficient of variation (CV%) was 6.88%, and no significant variation was observed in the remaining drug amount. Also, the average absorption rate (SD) of scopolamine estimated from the drug amount remaining in the formulation after administration was 28.7% (4.90). For NPC-22, there was no dose-dependent increase in adverse events, the degree of adverse events that occurred was mild, and no problem was observed in terms of tolerance.

[0094] <Clinical Trial 2> (Test drug) Scopolamine patch: One tablet (2.5 cm 2 ) containing 0.75 mg of scopolamine hydrobromide hydrate (Example 10) (hereinafter also referred to as NPC-22)

[0095] (Dosage and administration) NPC-22 9 mg (12 tablets of NPC-22) is applied once for 24 hours to the posterior auricle, chest, upper arm, or abdomen of the same subject by a 4-site 4-period crossover method (open-label). The washout period (the period from drug removal to the next drug application) is 14 days.

[0096] (Administration period) Single administration is performed. Apply for 24 hours.

[0097] (Evaluation items) Safety: Adverse events, skin findings (according to the judgment criteria of the Japanese Patch Test Research Group), vital signs, 12-lead electrocardiogram, clinical tests Pharmacokinetics: Plasma concentration of unchanged scopolamine and pharmacokinetic parameters (Cmax, Tmax, AUC, half-life, etc.) Other: Amount of drug remaining in scopolamine patches

[0098] (Plasma concentration measurement) The unchanged scopolamine is measured. Blood collection time: Blood samples will be taken before administration, 8, 12, 24 hours after administration (before removing the investigational drug), 26, 28, 32, 36, 48, 72 hours after administration, and on the 7th and 14th days.

[0099] <Results of Clinical Trial 2> One subject in this study discontinued the study due to an adverse event that occurred during post-auricular administration in crossover period I, and therefore administration to the chest, upper arm, and abdomen as planned from period 2 onwards was not performed. Therefore, the number of subjects in this study by injection site was post-auricular in 16 subjects, and chest, upper arm, or abdomen in 15 subjects each.

[0100] (1) Pharmacokinetic analysis (1-1) Plasma pharmacokinetics of scopolamine (1-1-1) Changes in plasma concentration FIG. 10 shows the time course of scopolamine plasma concentrations (mean ± standard deviation) at each administration site when NPC-22 was administered once (applied for 24 hours) to a healthy adult male. After NPC-22 was administered to the post-auricular region, plasma scopolamine concentrations increased throughout the administration period, and continued to increase for several hours after NPC-22 removal, then gradually decreased approximately 28 hours later (4 hours after removal). When administered to the chest, upper arm, and abdomen other than the postauricular region, the maximum plasma scopolamine concentration was significantly lower at all sites than at the postauricular region, and scopolamine was also eliminated from the plasma more slowly.

[0101] (1-1-2) Pharmacokinetic parameters Table 12 shows the plasma scopolamine pharmacokinetic parameters (mean and standard deviation) at each administration site when NPC-22 was administered once (applied for 24 hours) to healthy adult males. Cmax and AUC of plasma scopolamine concentration 0-312 were 85.093 pg / mL and 4716.497 pg·hr / mL, respectively, when administered behind the auricle, and 3.5749 pg / mL to 6.8708 pg / mL and 522.618 pg·hr / mL to 756.356 pg·hr / mL at other sites. The Cmax and AUC when NPC-22 was administered behind the auricle 0-312 were much higher than those when administered to the chest, upper arm, or abdomen. Also, t 1 / 2 was 38.774 hours behind the auricle, while it was 176.587 to 440.550 hours at other sites, showing a large difference between behind the auricle and other sites.

[0102]

Table 12

[0103] (2) Analysis of drug residue amount The amount of drug remaining in the formulation recovered after administration of NPC-22 Based on the formulation recovered after administration of NPC-22, the drug residue rate and estimated absorption rate were examined. The average residue rate for each administration site of NPC-22 (0.75 mg / tablet) was 66.8 - 68.5%, and the coefficient of variation (CV%) was 6 - 9.29%, with no significant variation in the residue rate. Also, the average estimated absorption rate of scopolamine estimated from the amount of drug remaining in the formulation after administration was 31.5 - 33.2%, and no difference was observed in the average residue rate and average estimated absorption rate regardless of the administration site.

[0104] <Safety> (1) Adverse events and side effects Table 13 shows the adverse events that occurred in this study. Adverse events were observed in 2 / 16 patients (12.5%) after postauricular administration and 1 / 15 patients (6.7%) after abdominal administration, but all were mild, and no serious adverse events or adverse events leading to study discontinuation occurred. Furthermore, all adverse events were determined to be "unrelated" to the drug, and none were considered side effects.

[0105] [Table 13]

[0106] (2) Skin findings according to the criteria of the Japanese Patch Test Research Group Skin findings according to the Japanese Patch Test Study Group's assessment criteria are shown in Table 14. At each site, only mild erythema (±) was observed at all assessment times. One hour after removal, mild erythema was observed in 1 / 16 patients behind the ear, 4 / 15 patients on the chest, 8 / 15 patients on the upper arm, and 1 / 15 patients on the abdomen. At 24 hours after removal, mild erythema was observed in 1 / 15 patients on the upper arm, but none of these were clinically significant.

[0107] [Table 14]

[0108] <Conclusions regarding pharmacokinetics, residual drug levels, and safety> When NPC-22 was administered as a single dose to each administration site, the plasma scopolamine concentration remained high when administered behind the ear, but remained extremely low when administered to the chest, upper arm, and abdomen. The Cmax and AUC of plasma scopolamine when administered behind the ear were significantly higher than when administered to the chest, upper arm, and abdomen, with Cmax being 12.4-fold, 16.4-fold, and 27.1-fold, respectively, and AUC 0-312 were 6.2-fold, 7.7-fold, and 9.1-fold, respectively. The average residual rate of NPC-22 recovered after administration (24-hour application) to the post-auricular, chest, upper arm, and abdomen was 66.8% to 68.5%, and the average estimated absorption rate was 31.5% to 33.2%, with no significant differences between administration sites. All of the adverse events that occurred with NPC-22 administration were mild, there were no problems with tolerance, and there were no significant differences between the administration sites. Also, only mild erythema was observed in the skin findings, which was not a major clinical problem and there were no significant differences between the administration sites. In a single-dose study of NPC-22 in healthy adults conducted prior to this study, a tendency for a decrease in salivary secretion volume was observed as the plasma scopolamine concentration increased. Although no significant differences in adverse events and skin findings were observed between the administration sites in this study, since the plasma scopolamine concentration at the time of administration to the chest, upper arm, or abdomen was very low compared to that at the posterior auricle in all sites, the administration site of NPC-22 should be the posterior auricle.

Claims

1. A patch for suppressing salivary secretion, containing a salt of scopolamine and / or its hydrate, polyvinylpyrrolidone, and a copolymer of methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate, wherein the application time per application is within 48 hours, and the patch is applied to the back of the auricle.

2. The patch according to Claim 1, wherein the application time per application is within 24 hours.

3. The patch according to Claim 1, wherein the application within 48 hours per application is continuously repeated two or more times.

4. The patch according to any one of Claims 1 to 3, wherein the daily dose of the salt of scopolamine and / or its hydrate for an adult is 0.75 mg to 50 mg.

5. The patch according to any one of Claims 1 to 4, wherein the salt of scopolamine and / or its hydrate is scopolamine hydrobromide and / or scopolamine hydrobromide hydrate.

6. The patch is a patch comprising a support, a drug-containing adhesive layer, and a release liner, wherein the drug-containing adhesive layer contains a pharmaceutical composition containing a salt of scopolamine and / or its hydrate, polyvinylpyrrolidone, and a copolymer of methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate. The patch according to any one of Claims 1 to 5.

7. The patch according to Claim 6, wherein the content of the salt of scopolamine and / or its hydrate is 0.5 to 10% by mass based on the total mass of the pharmaceutical composition.

8. The patch according to Claim 6 or 7, wherein the content of polyvinylpyrrolidone is 0.3 to 12% by mass based on the total mass of the pharmaceutical composition.

9. The patch according to any one of Claims 6 to 8, wherein the content of the copolymer of methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate is 0.3 to 10% by mass based on the total mass of the pharmaceutical composition. ​ ​ ​ ​ ​ ​

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