阅读说明：本技术 生物体对药物的吸收性优异且化学稳定性也优异的医药组合物 (Pharmaceutical composition having excellent drug absorbability in living body and excellent chemical stability ) 是由 小川孝行 西村健太 上野洋明 谷悠平 于 2020-03-06 设计创作，主要内容包括：含有东莨菪碱的盐以及/或其水合物、聚乙烯吡咯烷酮以及碱的医药组合物,生物体对药物的吸收性优异,且化学稳定性也优异。(A pharmaceutical composition comprising a scopolamine salt and/or a hydrate thereof, polyvinylpyrrolidone and a base, which is excellent in the absorbability of a drug in a living body and also excellent in chemical stability.)

1. A pharmaceutical composition comprising:

a salt of scopolamine and/or a hydrate thereof, polyvinylpyrrolidone and a base.

2. The pharmaceutical composition of claim 1, wherein,

the salt of scopolamine and/or its hydrate is scopolamine hydrobromide and/or scopolamine hydrobromide hydrate.

3. The pharmaceutical composition according to claim 1 or 2, wherein,

the content of the scopolamine salt and/or the hydrate thereof is 0.5 to 10% by mass relative to the mass of the entire pharmaceutical composition.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein,

the content of the polyvinylpyrrolidone is 0.3 to 12% by mass based on the total mass of the pharmaceutical composition.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein,

the base is at least one selected from amine compounds.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein,

the content of the base is 0.3 to 10% by mass based on the total mass of the pharmaceutical composition.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein,

the amine compound is a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer.

8. A patch preparation is a matrix type patch preparation composed of a support, a drug-containing adhesive layer and a release liner, wherein,

the drug-containing adhesive layer contains the pharmaceutical composition according to any one of claims 1 to 7.

9. The patch of claim 8 wherein,

the base component of the drug-containing adhesive layer is at least one selected from an acrylic adhesive, a rubber adhesive and a silicone adhesive.

10. The patch of claim 8 or 9,

the base component of the drug-containing adhesive layer is an acrylic adhesive.

11. The patch according to any one of claims 8 to 10,

the acrylic adhesive is at least one selected from a hydroxyl group-containing type and an electrodeless type.

Technical Field

The present invention relates to a pharmaceutical composition containing a salt of scopolamine and/or a hydrate thereof as an active ingredient.

Background

Scopolamine is widely known as an anticholinergic drug, and is a drug having effects of suppressing endocrine in the oral cavity and respiratory tract, preventing harmful parasympathetic nerve reflex, and the like. Hitherto, pharmaceuticals containing scopolamine as an active ingredient have been developed, and for example, "HYSCO (ハイスコ) (registered trademark) subcutaneous injection and apricot drug preparation" are manufactured and sold in japan as an injection containing scopolamine hydrobromide hydrate as an active ingredient, which is a salt of scopolamine, and "transdermal patch (registered trademark), Novartis" is manufactured and sold overseas, which contains scopolamine free base as an active ingredient.

It is known that a lipid bilayer (lipid bilayer) is present around a cell and functions as a barrier for limiting the permeability of substances inside and outside the cell, but it is needless to say that water-soluble substances hardly permeate the lipid bilayer and fat-soluble substances easily permeate the lipid bilayer. Therefore, in addition to an injection capable of avoiding the barrier function of a living body such as a mucosa and an epidermis having a lipid bilayer, a drug having a high lipid solubility is generally absorbed into a cell and transferred into the blood more easily than a drug having a high water solubility. Scopolamine hydrobromide hydrate, which is a salt of scopolamine, has high water solubility and must be a free base having high lipid solubility in order to be transferred into cells. However, in general, the drug is preferably in a salt state from the viewpoint of handling and chemical stability. In the present specification, the term chemical stability means stability relating to decomposition of a compound, and the term physical stability means stability relating to crystal precipitation of a compound.

The present inventors have found that when a pharmaceutical composition containing scopolamine hydrobromide hydrate, which is a salt of scopolamine, is attempted to be produced, a pharmaceutical composition having excellent chemical stability but low bioabsorbability is obtained, and when a pharmaceutical composition containing scopolamine hydrobromide hydrate as a free base is attempted to be produced during production or in the pharmaceutical composition, a pharmaceutical composition having excellent bioabsorbability but low chemical stability is obtained. Further, as a result of extensive studies, the inventors of the present invention have found that, in the decomposition of scopolamine in a pharmaceutical composition, an optical isomer of scopolamine and Aposcopolamine (Aposcopolamine) are main decomposition products.

As a technique relating to the absorbability and chemical stability of scopolamine by a living body, for example, patent document 1 discloses a method of improving the absorbability of a living body without deteriorating the chemical stability by using an absorption accelerator other than an acid for a composition containing a compound that causes a decomposition reaction using an acid as a catalyst. However, a method for solving deterioration in chemical stability due to factors other than acid is not described.

Patent document 2 discloses a method for improving the absorbability of a living body without deteriorating the chemical stability and physical stability of scopolamine by using a composition containing no vinyl acetate and no polar component, but does not describe any method for solving the problem of deterioration of the chemical stability in a composition containing a polar component. In the case of using a salt of scopolamine from the viewpoint of handling and chemical stability, in order to obtain a pharmaceutical composition excellent in absorbability of scopolamine in living bodies, it is necessary to contain a base as a polar component in the production or pharmaceutical composition for the purpose of converting the salt of scopolamine into a scopolamine free base, and therefore the method of the patent cannot be applied.

Patent documents 3, 4, and 5 disclose methods for maintaining or improving the absorbability of living bodies by improving the physical stability of scopolamine, but no suggestion is made on a method for improving the chemical stability.

Documents of the prior art

Patent document

Patent document 1: japanese patent No. 4081139

Patent document 2: japanese Kokai publication 2009-528357

Patent document 3: U.S. Pat. No. 4832953

Patent document 4: japanese patent No. 4466977

Patent document 5: japanese patent No. 5695562

Disclosure of Invention

Problems to be solved by the invention

The present invention has been made in view of the above problems, and an object of the present invention is to provide a pharmaceutical composition containing a salt of scopolamine and/or a hydrate thereof, which has high absorbability of scopolamine in living bodies and is also excellent in the chemical stability of scopolamine.

Means for solving the problems

The present inventors have conducted extensive studies to solve the above problems and, as a result, have found that polyvinylpyrrolidone can be incorporated into a pharmaceutical composition in which a salt of scopolamine and/or a hydrate thereof is converted to a free base during production or in the pharmaceutical composition, thereby maintaining high absorbability of scopolamine in a living body and improving chemical stability. As described in patent document 5, polyvinylpyrrolidone improves the physical stability of scopolamine. In general, the dissolved state and the amorphous state are chemically unstable states compared to the crystalline state. Therefore, the inclusion of polyvinylpyrrolidone in the pharmaceutical composition is considered to be disadvantageous in terms of chemical stability of scopolamine. In fact, in the hydroxypropyl cellulose described in patent document 5, which is known to improve the physical stability of scopolamine similarly to polyvinylpyrrolidone, the effect of improving the chemical stability of scopolamine is not obtained by including the substance in a pharmaceutical composition, and conversely, the chemical stability of scopolamine is lowered. However, unexpectedly, in the case where polyvinylpyrrolidone is contained in the pharmaceutical composition, the chemical stability of scopolamine is improved, and the production of both the optical isomer of scopolamine and aposcopolamine, which are major decomposition products, is suppressed. Furthermore, the present inventors have found that the chemical stability of scopolamine can be further improved by using an amine compound as a base for converting a salt of scopolamine and/or a hydrate thereof to a free base during production or in a pharmaceutical composition. That is, the present inventors have found that a pharmaceutical composition having high absorbability of scopolamine in living bodies and improved chemical stability of scopolamine can be obtained by adding polyvinylpyrrolidone and an amine compound as a base for converting a scopolamine salt and/or a hydrate thereof into a free base to a composition containing a scopolamine salt and/or a hydrate thereof, and have completed the present invention.

ADVANTAGEOUS EFFECTS OF INVENTION

The pharmaceutical composition of the present invention (hereinafter referred to as "the present composition") has high absorbability of scopolamine in living bodies and effectively inhibits the decomposition of scopolamine, and therefore can effectively and continuously utilize the pharmacological effects of scopolamine.

Detailed Description

The composition of the present invention contains (1R, 2R, 4S, 7S, 9S) -9-methyl-3-oxa-9-azatricyclo [3.3.1.0 ] scopolamine ((-) - (S) -3-hydroxy-2-phenylpropionic acid as an active ingredient^2，4]Nonan-7-yl ester) and/or hydrates thereof, polyvinylpyrrolidone, and a base.

Examples of the salt of scopolamine used in the composition of the present invention include acid addition salts with inorganic or organic acids (acid addition salt), specifically, hydrochloride, hydrobromide, nitrate, phosphate, sulfate, acetate, ascorbate, benzoate, cinnamate, citrate, formate, fumarate, glutamate, lactate, maleate, malate, malonate, mandelate, methanesulfonate (methanesulfonate), phthalate, salicylate, stearate, succinate, tartrate, propionate, butyrate, pamoate (pamoate), and p-toluenesulfonate (toluenesulfonate), but are not limited thereto. In the compositions of the present invention, scopolamine hydrobromide and/or scopolamine hydrobromide hydrate is/are preferably used.

The composition of the present invention may contain a therapeutically effective amount of a salt of scopolamine and/or a hydrate thereof, and the state is not particularly limited, but a dissolved state or an amorphous state is preferable from the viewpoint of absorbability in a living body. In order to administer a therapeutically effective amount of an active ingredient to a patient, it is important that a certain amount of the active ingredient is contained in the composition. The content of the scopolamine salt and/or the hydrate thereof in the composition of the present invention is 0.5 to 10% by mass, preferably 1 to 8% by mass, and more preferably 3 to 6% by mass, based on the total composition. When the amount is less than 0.5% by mass, the therapeutic effect may be insufficient, while when the amount exceeds 10% by mass, the economical efficiency may be unfavorable.

The composition of the present invention contains polyvinylpyrrolidone for the purpose of improving the chemical stability of scopolamine. The weight average molecular weight of the polyvinylpyrrolidone used is generally several thousands to several millions, but the weight average molecular weight of the polyvinylpyrrolidone used in the composition of the present invention is not particularly limited. One or more of these polyvinylpyrrolidones can be used.

The content of polyvinylpyrrolidone in the composition of the present invention is 0.3 to 12% by mass, preferably 0.5 to 10% by mass, and more preferably 1 to 8% by mass based on the whole composition. If the amount is less than 0.3% by mass, a sufficient chemical stability-improving effect may not be obtained, while if the amount exceeds 12% by mass, the physical properties of the composition may be adversely affected, which is not preferable. In addition, when the mass ratio of polyvinylpyrrolidone to the salt of scopolamine and/or the hydrate thereof is 2 or more, there is a possibility that the uniformity of the composition is adversely affected, and therefore, the mass ratio of polyvinylpyrrolidone to the salt of scopolamine and/or the hydrate thereof is preferably less than 2.

The composition of the present invention contains a base for converting a salt of scopolamine and/or a hydrate thereof into a free base. The type of the base is not particularly limited, and examples thereof include amine compounds, ammonia, and alkali metal hydroxides. Among these bases, amine compounds are also preferable in terms of chemical stability.

The amine compound may be any of a primary amine, a secondary amine, and a tertiary amine, and examples of the primary amine include methylamine, ethylamine, and dodecylamine, examples of the secondary amine include dimethylamine, diethylamine, and N-methylethylamine, and examples of the tertiary amine include N, N-diethylmethylamine, tributylamine, N-dimethyl-p-toluidine, N-diethyl-p-toluidine, and a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer, but are not limited thereto. At least one of these amine compounds can be used. Among these amine compounds, a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer is preferable. Examples of the alkali metal hydroxide include, but are not limited to, sodium hydroxide and potassium hydroxide.

The content of the alkali in the composition of the present invention is 0.3 to 10% by mass, preferably 0.5 to 8.5% by mass, and more preferably 0.9 to 7.5% by mass based on the whole composition. When the content is less than 0.3% by mass, sufficient absorbability into the living body may not be obtained, while when the content exceeds 10% by mass, chemical stability may be adversely affected.

The method for producing the composition of the present invention is not particularly limited, and for example, the above-mentioned essential components may be mixed by stirring. Further, a solvent such as ethyl acetate or methanol may be added as necessary.

The composition of the present invention described above can be formulated in place of the active ingredients and the like of conventional pharmaceutical compositions. The dosage form of the composition of the present invention includes, but is not limited to, oral preparations, injections, and external preparations. Among these dosage forms, external preparations which are easy to administer are preferred.

Examples of the external preparation include, but are not limited to, a powder for spreading, a lotion, an ointment, a cream, a spray, a liquid, a patch, an aerosol, an anal suppository, an ear drop, an eye drop, a nose drop, and an inhalant. Among them, a patch is preferable because complicated operations such as wiping and adjustment of the amount of application are not required, the blood concentration of the active ingredient can be stably maintained, the effect time is long, and the application can be easily interrupted by peeling when an adverse event is found.

The patch includes a matrix type and a reservoir type (reservoir type). The composition of the present invention may be either a matrix type or a depot type, but the matrix type is preferable because the formulation design is easy and the cost at the time of production can be reduced.

The matrix type patch is composed of a support, a drug-containing adhesive layer, and a release liner (hereinafter, this is referred to as "the patch of the present invention").

The drug-containing adhesive layer may contain the composition of the present invention, but preferably further contains a base component. The base component used in the drug-containing pressure-sensitive adhesive layer is not particularly limited, but a rubber-based adhesive component, an acrylic adhesive component, a silicone-based adhesive component, or the like, which is generally used in a patch, is preferable, an acrylic adhesive component is particularly preferable, and a nonpolar acrylic adhesive component and a hydroxyl group-containing acrylic adhesive component are more preferable. At least one of these base components can be used.

The acrylic adhesive component is a polymer or copolymer containing at least one (meth) acrylate.

Examples of the nonpolar acrylic adhesive component having no functional group in the side chain of the monomer constituent unit include, but are not limited to, alkyl (meth) acrylate polymers and copolymers, alkyl (meth) acrylate-vinyl acetate copolymers, and the like, and specifically, 2-ethylhexyl acrylate-2-ethylhexyl methacrylate-dodecyl methacrylate copolymers, 2-ethylhexyl acrylate-vinyl acetate copolymers, methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymers, and the like.

The hydroxyl group-containing acrylic adhesive component is a polymer or copolymer having as a constituent unit at least one kind of (meth) acrylate having a free hydroxyl group in a side chain in a monomer constituent unit, and examples thereof include a copolymer containing hydroxyalkyl (meth) acrylate, specifically, a 2-ethylhexyl acrylate-hydroxyethyl acrylate-vinyl acetate copolymer, 2-ethylhexyl acrylate, vinylpyrrolidone-hydroxyethyl acrylate-vinyl acetate copolymer, 2-ethylhexyl acrylate-hydroxyethyl acrylate-glycidyl acrylate-vinyl acetate copolymer, 2-ethylhexyl acrylate-vinyl acetate-2-hydroxyethyl acrylate Ethyl acrylate copolymer, 2-ethylhexyl acrylate-vinyl acetate-2-hydroxyethyl acrylate-glycidyl methacrylate copolymer, and the like, but are not limited thereto.

In view of the formation of the drug-containing adhesive layer and sufficient drug releasability, the content of the base component in the drug-containing adhesive layer is 60 to 98.9 mass%, preferably 63 to 98 mass%, and more preferably 66 to 96 mass% with respect to the entire drug-containing adhesive layer. If the amount is less than 60% by mass, the physical properties of the patch such as anchoring properties are deteriorated, and if the amount exceeds 98.9%, the active ingredient and other additives cannot be sufficiently blended, which may not be preferable.

The drug-containing pressure-sensitive adhesive layer may contain an absorption enhancer as needed. Examples of the absorption enhancer include any of the compounds which have been conventionally considered to have an absorption-enhancing effect in transdermal administration, and examples thereof include fatty acids and esters thereof such as lauric acid, oleic acid, isostearic acid, isopropyl myristate, octyldodecyl myristate, glyceryl monooleate, hexyldecyl isostearate and the like, alcohols and esters or ethers thereof such as oleyl alcohol, propylene glycol, polyethylene glycol monooleate and the like, sorbitan sesquioleate, sorbitan esters or ethers such as polyoxyethylene sorbitan monooleate, sorbitan monolaurate, sorbitan monooleate and the like, phenol ethers such as polyoxyethylene nonylphenyl ether, polyoxyethylene octylphenyl ether and the like, castor oil or hardened castor oil, oleoyl sarcosine, lauryldimethylaminoacetic acid betaine (laurindiamthylamine Acetaine), sodium lauryl sulfate and the like surfactants such as 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 (decamethyl sulfoxide), azacyclane hydrocarbons such as 1-dodecylazacyclane-2-one and 1-geranylazacyclane-2-one, and pyrrolidones other than polyvinylpyrrolidone.

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

The release liner used in the patch of the present invention is not particularly limited, and for example, a release liner impermeable to a drug can be used. Examples of the release liner include films made of a polymer material such as polyethylene, polypropylene, and polyester, films obtained by vapor-depositing aluminum on films, and papers obtained by coating silicone oil on papers. Among them, a polyester film is preferable, and a polyethylene terephthalate (PET) film is particularly preferable, from the viewpoints of impermeability to active ingredients, processability, low cost, and the like. Further, a laminate film obtained by laminating a plurality of materials may be used as the release liner.

The adhesive patch of the present invention is stored in a packaging material before use. The packaging material used for the patch of the present invention is not particularly limited, and examples thereof include plastic films, metal (e.g., aluminum) laminated plastic films, metal vapor-deposited plastic films, ceramic (e.g., silicon oxide) vapor-deposited plastic films, metal foils such as aluminum foils, metals such as stainless steel, and glass. Among them, a metal laminated plastic film, a metal vapor-deposited plastic film, or the like is preferably used in terms of production cost or the like.

In the adhesive patch of the present invention, a release controlling film and an adhesive layer for adhering to the skin may be added to the skin-adhering side of the drug-containing adhesive layer as necessary in order to control percutaneous absorption of the active ingredient.

The adhesive patch of the present invention described above is composed of a support, a drug-containing adhesive layer, and a release liner, but in terms of thickness, the support is 1 to 1000 μm, preferably 10 to 700 μm, the drug-containing adhesive layer is 10 to 200 μm, preferably 30 to 150 μm, and the release liner is 1 to 500 μm, preferably 10 to 200 μm.

The adhesive patch of the present invention can be produced by a known method for producing an adhesive patch. Preferred examples of the method for producing the adhesive patch of the present invention include the following methods.

< method 1 >

The adhesive patch is obtained by dissolving a salt of scopolamine and/or a hydrate thereof, an alkali, polyvinylpyrrolidone, a base component, and, if necessary, an absorption enhancer or the like as an active ingredient in an organic solvent such as ethyl acetate, methanol or the like or a mixed solvent thereof, spreading the obtained dissolved matter on a release liner or a support, evaporating the organic solvent in the dissolved matter to form a drug-containing adhesive layer, and then attaching the support or the release liner.

< method 2 >

The patch is obtained by heating and dissolving a salt of scopolamine and/or a hydrate thereof, an alkali, polyvinylpyrrolidone, a base component, and if necessary, an absorption enhancer, etc. as an active ingredient, spreading the molten substance on a release liner or a support, forming a drug-containing adhesive layer, and then attaching the support or the release liner.

Examples

The present invention will be described in more detail below by showing production examples and the like, but the present invention is not limited to these production examples and the like, and various modifications can be made without departing from the technical spirit of the present invention.

Production example 1

Scopolamine hydrobromide hydrate, isopropyl myristate and dodecylamine were dissolved in an ethyl acetate/methanol mixed solution at the blending ratio described in table 1, and an acrylic adhesive component (trade name: DURO-TAK87-4287, manufactured by Henkel) was added thereto, and the mixture was mixed and stirred to obtain a uniform dissolved substance. Then, the dissolved substance was spread into a release film using a blade coater so that the thickness after drying became 100 μm, and after drying and forming a drug-containing adhesive layer, a support was attached. Thereafter, the resulting material was cut into a desired size to obtain a patch.

Production example 2

Patches were obtained in the same manner as in production example 1, except that diethylamine was added in place of dodecylamine so that the amount of scopolamine free base was the same as that in production example 1, in the blending ratio shown in table 1.

Production example 3

Adhesive preparations were obtained in the same manner as in production example 1, except that a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer (trade name: Eudragit EPO, product of Evonik) was blended in such a blending ratio as described in Table 1 so that the amount of scopolamine free base was equal to that in production example 1.

Production example 4

An adhesive patch was obtained in the same manner as in production example 1, except that sodium hydroxide was added in place of dodecylamine in such an amount that the amount of scopolamine free base was the same as that in production example 1, and polyvinylpyrrolidone (trade name: Kollidon30, manufactured by BASFSE) was further added in the compounding ratio described in Table 1.

Production example 5

Patches were obtained in the same manner as in production example 1, except that Eudragit EPO was prepared in place of dodecylamine and polyvinylpyrrolidone was further prepared in the same formulation ratio as in production example 1 so that the amount of scopolamine free base was the same as that in production example 1.

Production example 6

Scopolamine hydrobromide hydrate, Eudragit EPO, and polyvinylpyrrolidone were dissolved in an ethyl acetate/methanol mixture at the formulation ratios described in table 1, followed by adding DURO-TAK87-4287 thereto, followed by mixing and stirring to obtain a uniform dissolved product. Then, the dissolved substance was spread into a release film using a blade coater so that the thickness after drying became 100 μm, and after drying and forming a drug-containing adhesive layer, a support was attached. Thereafter, the resulting material was cut into a desired size to obtain a patch.

Production example 7

A patch was obtained in the same manner as in production example 6, except that the amount of polyvinylpyrrolidone to be added was increased in accordance with the compounding ratio shown in table 1.

Production example 8

Scopolamine hydrobromide hydrate, isopropyl myristate, Eudragit EPO, and polyvinylpyrrolidone were dissolved in an ethyl acetate/methanol mixture at the blending ratios described in table 1, followed by adding DURO-TAK87-4287 thereto, followed by mixing and stirring to obtain a uniform dissolved substance. Next, the dissolved substance was spread into a release film using a knife coater so that the thickness after drying became 100 μm, and after drying, a drug-containing adhesive layer was formed, and a support was attached. Thereafter, the resulting material was cut into a desired size to obtain a patch.

Production example 9

Scopolamine hydrobromide hydrate, isopropyl myristate, Eudragit EPO, and polyvinylpyrrolidone were dissolved in an ethyl acetate/methanol mixture at the formulation ratios described in table 1, followed by adding DURO-TAK87-4287 thereto, followed by mixing and stirring to obtain a uniform dissolved product. Next, the dissolved substance was spread into a release film using a knife coater so that the thickness after drying became 50 μm, and after drying, a drug-containing adhesive layer was formed, and a support was attached. Thereafter, the resulting material was cut into a desired size to obtain a patch.

Production example 10

A patch was obtained in the same manner as in production example 9, except that the amount of isopropyl myristate added was increased in accordance with the blending ratio shown in table 1.

Production example 11

A patch was obtained in the same manner as in production example 1, except that sodium hydroxide was added instead of dodecylamine so that the amount of scopolamine free base was the same as that in production example 1 in the compounding ratio shown in table 1.

Production example 12

A patch was obtained in the same manner as in production example 6, except that polyvinylpyrrolidone was not added in the compounding ratio shown in table 1.

Production example 13

Patch preparations were obtained in the same manner as in production example 1, except that dodecylamine was not added in the compounding ratio shown in table 1.

[ Table 1]

Test example 1 (chemical stability test 1)

Each of the patches obtained in production examples 1 to 13 was packed in a bag of a composite film (aluminum laminated film of innermost heat-sealed PET, manufactured by Meiwa Pax), stored for 3 days or 28 days using a constant temperature and humidity apparatus (temperature: 60 ℃, CSH-110, manufactured by Tabai Espec), and the amount of an optical isomer, which is a main decomposition product, was measured. For 3 patches, the pad was removed, and the patch was transferred to a 10mL centrifugal precipitation tube, and 1mL of tetrahydrofuran and 0.5mL of methanol were added thereto, followed by shaking for 10 minutes to completely dissolve the paste. 1mL of water was added to the solution, and the mixture was shaken for 10 minutes to completely coagulate and precipitate the binder component. The supernatant was used as a sample solution and quantified by high performance liquid chromatography (measurement wavelength: 210 nm). The amounts of the optical isomers after storage measured by this method are shown in tables 2 and 3.

Test example 2 (chemical stability test 2)

Each of the patches obtained in production examples 1 to 13 was filled in a bag of a composite film (aluminum laminated film of innermost heat-sealed PET, manufactured by Meiwa Pax), stored for 3 days or 28 days using a constant temperature and humidity apparatus (temperature: 60 ℃, CSH-110, manufactured by Tabai Espec), and the amount of aposcopolamine as a main decomposition product was measured. For 3 patches, the pad was removed, and the patch was transferred to a 10mL centrifugal precipitation tube, and 1mL of tetrahydrofuran and 0.5mL of methanol were added thereto, followed by shaking for 10 minutes to completely dissolve the paste. 1mL of water was added to the solution, and the mixture was shaken for 10 minutes to completely coagulate and precipitate the binder component. The supernatant was used as a sample solution and quantified by high performance liquid chromatography (measurement wavelength: 220 nm). The amounts of aposcopolamine after storage, measured by this method, are shown in tables 2 and 3.

Test example 3 (Release test)

The release rate of scopolamine from the patches was measured for each of the patches obtained in production example 5, production example 8, production example 9, production example 10, and production example 13. Each patch was cut with a skin Punch (Leather Punch) having a diameter of 15mm, attached to filter paper, covered with a cover tape, cut with a skin Punch having a diameter of 23mm so that the test piece was centered, and subjected to a release test using a percutaneous absorption tester (TRANS VIEW C12, manufactured by Cosmed pharmaceuticals). The operation of the transdermal absorption test device is as follows: a stirrer was placed in the diffusion cell, the test piece and the hole of the diffusion cell were aligned, a collar and a lid were attached from above, a test solution (potassium dihydrogen phosphate 3.40g and disodium hydrogen phosphate 3.55g dissolved in 1000mL of water) kept at 32 ℃ was poured into the receiving tank of the diffusion cell, the diffusion cell was placed in a heating block thermostatic bath (temperature: 32. + -. 2 ℃), and the sample solution after 24 hours was sampled and quantified by high performance liquid chromatography (measurement wavelength: 210 nm). The release rate of scopolamine in each patch after 24 hours, measured by this method, is shown in table 4.

Test example 4 (blending test)

The preparation is that the mixing ratio of the scopolamine free alkali to the polyvinylpyrrolidone is 1: 0. 2: 1. 1: 1. 1: 2 (production examples 14 to 17). The obtained drug solutions were collected in 10mL centrifugal precipitation tubes, stored for 1 day in a hot air dryer (temperature: 70 ℃, LC-110, manufactured by Tabai Espec), and the amounts of the stored optical isomers and aposcopolamine were quantified by high performance liquid chromatography (measurement wavelengths: 210nm and 220 nm). The amounts of the optical isomer and aposcopolamine after storage measured by this method are shown in table 5.

[ Table 2]

[ Table 3]

[ Table 4]

	Release Rate (%, after 24 hours)
		Production example 13	3.4
Production example 5	54.8
		Production example 6	38.6
Production example 7	35.7
		Production example 8	82.0
Production example 9	80.0
		Production example 10	82.2

[ Table 5]

In production example 1 (free basification using dodecylamine), production example 2 (free basification using diethylamine), and production example 3 (free basification using Eudragit EPO) in which an amine compound was used as a base for converting scopolamine to a free base, the amounts of the optical isomer and aposcopolamine were small compared to production example 11 (free basification using sodium hydroxide). From the above results, it was found that the use of an amine compound as a base for converting a salt of scopolamine and/or a hydrate thereof to a free base is effective for improving the chemical stability of scopolamine.

In the blending test, the amounts of the optical isomer and aposcopolamine were reduced by blending polyvinylpyrrolidone (production examples 15 to 17) compared to the case of not blending polyvinylpyrrolidone (production example 14). In addition, as the formulation ratio of polyvinylpyrrolidone to scopolamine free base increased, the amounts of optical isomer and aposcopolamine decreased. From the above results, it can be seen that the formulation of polyvinylpyrrolidone is effective for improving the chemical stability of scopolamine.

In production example 4 in which polyvinylpyrrolidone was blended, the amounts of the optical isomer and aposcopolamine were small as compared with that in production example 11. In addition, in production example 5 in which polyvinylpyrrolidone was blended, the amounts of the optical isomer and aposcopolamine were small as compared with production example 3. Furthermore, the amounts of the optical isomer and aposcopolamine were less in production examples 6 and 7, which contained polyvinylpyrrolidone, than in production example 12. From the above results, it was found that the formulation of polyvinylpyrrolidone is effective for improving the chemical stability of scopolamine even when the patch is selected as a dosage form.

Preparation example 8 was a formulation in which the amount of Eudragit EPO was increased so that the amount of scopolamine free base became 2 times that of preparation example 12 and the chemical stability conditions were severer than those of preparation example 12. Production examples 9 and 10 were prepared under more severe chemical stability conditions than production example 12 by increasing the amounts of scopolamine hydrobromide hydrate and Eudragit EPO so that the amount of scopolamine free base became 4.7 times that of production example 12. Under these conditions, although the formulation of polyvinylpyrrolidone did not inhibit the increase in the amount of optical isomer as compared with production example 12, the amount of aposcopolamine was reduced and the total amount of decomposition products was also reduced. From the above results, it was found that the formulation of polyvinylpyrrolidone is effective for improving the chemical stability of scopolamine even under conditions where the chemical stability is too severe.

In production examples 5, 6, 7, 8, 9 and 10, the emission rate after 24 hours was higher than that in production example 13. From the above results, it is found that the use of an amine compound as a base to convert scopolamine hydrobromide into a free base is effective for improving the absorbability in the living body.

Industrial applicability

As described above, the composition of the present invention is a pharmaceutical composition produced by adding polyvinylpyrrolidone and a base to a composition containing a salt of scopolamine and/or a hydrate thereof, and is a novel pharmaceutical composition having high absorbability in living bodies and excellent chemical stability of scopolamine. The composition of the invention can effectively and continuously utilize the pharmacological effect of scopolamine.