JP2015151370A - patch preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a patch preparation that has a small amount of generation of a ropinirole analog and shows excellent ropinirole skin permeability.SOLUTION: A patch preparation comprises an adhesive layer comprising ropinirole on at least one face of a support, the adhesive layer comprising ropinirole in crystal state.

Description

  The present invention relates to a patch preparation containing ropinirole.

  Ropinirole is a nonergot-type dopamine agonist and is used as a treatment for Parkinson's disease. Various patch preparations have been studied in order to avoid side effects in the gastrointestinal tract and improve patient compliance.

  In the case of transdermal absorption preparations, when the drug is in a salt state, the absorption from the skin is generally low, so a neutralizing agent such as sodium hydroxide is added to the preparation and desalted or previously desalted. There is known a technique for increasing the absorbability of a drug by blending a free form. However, the free form of ropinirole is very poor in drug stability compared to the hydrochloride, and mixing the ropinirole free form with the adhesive will produce a large amount of related substances and may not satisfy the storage stability of the preparation. I know.

  So far, various techniques have been proposed to stabilize the drug in the preparation. For example, in patent document 1, the production | generation of a related substance can be suppressed by making ropinirole hydrochloride free with the sodium hydroxide of 1 times mole or less. Moreover, in patent document 2, the drug is stabilized by making indomethacin which is easily hydrolyzed into α-type crystals in the preparation.

  However, in Patent Document 1, it is necessary to strictly adjust the freeness of ropinirole. If the free rate changes due to some external factor, the amount of related substances generated increases. In addition, since only the initial related substance generation amount is described in Patent Document 1, it is not certain whether there is a sufficient inhibitory effect of related substances against changes over time. Further, in Patent Document 2, it was confirmed that the crystalline preparation was effective against hydrolysis of indomethacin, but it is unclear whether it is effective against heat, oxidation, light, and the like. In addition, in order for indomethacin to exist as α-type crystals in the preparation, it is necessary to prepare very strict conditions such as pH, water content, type and blending amount of the solvent used, and blending amount of the drug, It cannot be easily applied to other drugs.

International Publication No. 2009/107478 International Publication No. 99/18955

  The problem to be solved by the present inventors is to provide a patch preparation that produces a small amount of ropinirole-related substance and exhibits excellent skin permeability of ropinirole.

  As a result of intensive studies to solve the above problems, the present inventors have found a method for improving the stability of a drug by crystallizing ropinirole in a preparation. In general, it is known that drug crystallization increases the stability of the drug in the formulation, but the drug motility in the formulation decreases, resulting in a decrease in drug release. I know. In addition, when the amount of crystals formed is small, the release of the drug does not decrease, but a large amount of the dissolved substance exists, so that a large amount of a related substance is generated in the preparation. However, the present inventors use a liquid component in which ropinirole is soluble in an amount in a specific range less than the solubility of ropinirole in the liquid component, and an adhesive layer containing the liquid component together with ropinirole. A patch preparation precursor sheet is prepared, and the patch preparation precursor sheet is placed in a specific environment to produce ropinirole in a crystalline state in the adhesive layer, and then a patch preparation is produced from the patch preparation precursor sheet. By doing so, the present inventors have succeeded in obtaining a patch preparation that produces a small amount of ropinirole-related substance and exhibits excellent ropinirole skin permeability.

That is, the gist of the present invention is as follows.
[1] A patch preparation comprising an adhesive layer containing ropinirole on at least one side of a support,
A patch preparation, wherein the pressure-sensitive adhesive layer contains ropinirole in a crystalline state.
[2] The pressure-sensitive adhesive layer contains a first liquid additive in which the solubility of ropinirole at 23 ° C. is less than 0.10 g / g, and the crystallinity of ropinirole calculated based on the following formula (I) is 68 The adhesive preparation according to [1] above, which is ˜99%.
Crystalline ratio of ropinirole = {(A−B ₁ × C ₁ ) / A} × 100 (I)
A: Content of ropinirole in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
B ₁ : Content of first liquid additive in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
C ₁ : Solubility of ropinirole in the first liquid additive at 23 ° C. (unit: g / g)
[3] The adhesive preparation according to [2] above, wherein the content of the first liquid additive in the pressure-sensitive adhesive layer is 5 to 45% by weight with respect to the total weight of the pressure-sensitive adhesive layer.
[4] The first liquid additive is one or more selected from the group consisting of squalane, squalene, light liquid paraffin, liquid paraffin, silicone oil, α-olefin oligomer, oleyl oleate and octyldodecyl myristate. The patch preparation according to [2] or [3] above.
[5] Ropinirole, wherein the pressure-sensitive adhesive layer includes a second liquid additive having a saturation solubility of ropinirole at 23 ° C. of 0.10 to 1.0 g / g, and is calculated based on the following formula (II) The patch preparation of the above-mentioned [1], wherein the crystal ratio is 74 to 99% by weight.
Ropinirole crystal ratio = {(A−B ₂ × C ₂ ) / A} × 100 (II)
A: Content of ropinirole in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
B ₂ : Content of the second liquid additive in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
C ₂ : Solubility of ropinirole in the second liquid additive at 23 ° C. (unit: g / g)
[6] The adhesive preparation according to [5] above, wherein the content of the second liquid additive in the pressure-sensitive adhesive layer is 2.5 to 12.5% by weight based on the total weight of the pressure-sensitive adhesive layer.
[7] The above-mentioned [5] or [6], wherein the second liquid additive is one or more selected from the group consisting of isopropyl myristate, hexyl laurate, isopropyl palmitate and liquid lanolin. Patch preparation.
[8] The adhesive preparation according to any one of [1] to [7] above, wherein the polymer constituting the adhesive layer is a rubber-based polymer.
[9] A laminated sheet laminated in the order of a support / ropinirole and a pressure-sensitive adhesive layer / release liner containing a liquid additive in which the ropinirole is soluble is stored at a temperature of 25 ° C. or lower, and the pressure-sensitive adhesive layer A method for producing a patch preparation, comprising: a first step of producing ropinirole in a crystalline state; and a second step of cutting the laminated sheet having undergone the first step into the shape and size of the patch preparation.
[10] The method according to [9] above, wherein the liquid additive in which ropinirole is soluble is the first liquid additive having a solubility of ropinirole at 23 ° C. of less than 0.10 g / g.
[11] The pressure-sensitive adhesive layer containing ropinirole and the first liquid additive is a pressure-sensitive adhesive layer having a crystallinity of ropinirole of 68 to 99% calculated based on the following formula (I): 10] The method of description.
Crystalline ratio of ropinirole = {(A−B ₁ × C ₁ ) / A} × 100 (I)
A: Content of ropinirole in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
B ₁ : Content of first liquid additive in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
C ₁ : Solubility of ropinirole in the first liquid additive at 23 ° C. (unit: g / g)
[12] The method according to [9] above, wherein the liquid additive in which ropinirole is soluble is a second liquid additive having a ropinirole solubility at 23 ° C. of 0.10 to 1.0 g / g.
[13] The pressure-sensitive adhesive layer containing ropinirole and the second liquid additive is a pressure-sensitive adhesive layer having a crystallinity of ropinirole of 74 to 99% by weight calculated based on the following formula (II): [12] The method described.
Ropinirole crystal ratio = {(A−B ₂ × C ₂ ) / A} × 100 (II)
A: Content of ropinirole in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
B ₂ : Content of the second liquid additive in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
C ₂ : Solubility of ropinirole in the second liquid additive at 23 ° C. (unit: g / g)

  According to the present invention, it is possible to obtain a patch preparation having high ropinirole stability in the pressure-sensitive adhesive layer and excellent ropinirole skin permeability.

  The patch preparation of the present invention (hereinafter sometimes simply referred to as “preparation”) is a patch preparation comprising an adhesive layer containing ropinirole on at least one side of a support, and the adhesive layer is in a crystalline state. The main feature is the inclusion of ropinirole.

  In the present invention, “ropinirole (hereinafter sometimes abbreviated as“ RPR ”)” is 4- [2- (dipropylamino) ethyl] -1,3-dihydro-2H-indol-2-one. is there.

  In the present invention, whether the pressure-sensitive adhesive layer contains ropinirole in a crystalline state is determined by observing the surface and the inside of the pressure-sensitive adhesive layer visually and with an optical microscope (500 times magnification), and confirming ropinirole crystals. Judge by no. When ropinirole crystals are observed, the pressure-sensitive adhesive layer contains ropinirole in a crystalline state. When ropinirole crystals are not observed, ropinirole can be said to be in a dissolved state.

  In the present invention, as "ropinirole", not only ropinirole free form but also ropinirole salt can be used. The salt of ropinirole means a compound produced by the reaction of ropinirole with an inorganic acid or an organic acid. Specific examples of inorganic acids include, for example, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, hydrobromic acid, and specific examples of organic acids include, for example, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid. Succinic acid, lactic acid, salicylic acid, benzoic acid and the like. In addition, it is preferable from the viewpoint of skin permeability that ropinirole is present in a free state in the pressure-sensitive adhesive layer, and even if a pre-demineralized free body is used or a pressure-sensitive adhesive layer containing ropinirole is formed. As a raw material for this purpose, a desalinating agent (neutralizing agent) may be added together with the salt of ropinirole to produce a free form of ropinirole in the pressure-sensitive adhesive layer during the production process of the patch preparation. When a desalting agent is used, examples of the desalting agent include sodium hydroxide, aluminum hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, sodium hydrogen carbonate, organic amine derivatives (for example, mono Ethanolamine, diethanolamine, triethanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine, ethylenediamine, meglumine, and the like), and sodium hydroxide is preferred. The desalting agent is used in an amount necessary for desalting all of the salt of ropinirole. For example, when the desalting agent is a monovalent base (alkali), the desalting agent is usually 0 relative to ropinirole salt. Used in the range of 8 moles to 1.2 moles.

  The content of ropinirole in the pressure-sensitive adhesive layer is not particularly limited as long as its pharmacological effect is obtained and does not impair the adhesive properties of the pressure-sensitive adhesive layer, etc. It is preferably 0.1% by weight or more, more preferably 5.5% by weight or more, further preferably 7.5% by weight or more, and particularly preferably 10% by weight or more. Moreover, from a viewpoint of the possibility of a side effect, 50 weight% or less is preferable with respect to the whole adhesive layer, More preferably, it is 40 weight% or less.

  As the support used in the present invention, the polymer and liquid component contained in the pressure-sensitive adhesive layer, those in which RPR passes through the support and is lost from the back surface thereof (that is, with respect to RPR) Those having impermeability are preferred.

  Specifically, polyester (for example, polyethylene terephthalate (PET)), nylon, saran (trade name), polyvinyl chloride, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, polytetrafluoroethylene, ionomer resin, etc. A single film; a metal foil, or a laminate film obtained by laminating two or more films selected from these. Further, in order to improve the adhesion (throwing property) between the support and the pressure-sensitive adhesive layer, a laminate film of a nonporous film made of the above material and the following porous film is used as a support, and the porosity of the support is determined. It is preferable to form an adhesive layer on the adhesive film side. In addition, 2-100 micrometers is preferable and, as for the thickness of a nonporous film, 2-50 micrometers is more preferable.

The porous film is not particularly limited as long as the anchoring property with the pressure-sensitive adhesive layer is improved. For example, paper, woven fabric, non-woven fabric (for example, polyethylene terephthalate (PET) non-woven fabric), the above film (polyester) (For example, polyethylene terephthalate (PET), etc.), nylon, saran (trade name), polyvinyl chloride, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, polytetrafluoroethylene, ionomer resin and other single films; metal foil, Or a film obtained by mechanically perforating a laminate film obtained by laminating two or more kinds of films selected from these, and particularly supported by paper, woven fabric, and non-woven fabric (for example, polyester non-woven fabric and polyethylene terephthalate non-woven fabric). It is preferable from the viewpoint of body flexibility. For example, when paper, woven fabric, non-woven fabric, or the like is used as the porous film, the basis weight thereof is preferably 5 to 30 g / m ^{2 from} the viewpoint of improving the anchoring force. Although the thickness of a support body is not specifically limited, Preferably it is 2-200 micrometers, More preferably, it is 10-50 micrometers.

  Examples of the polymer used for the pressure-sensitive adhesive layer (that is, the matrix polymer of the pressure-sensitive adhesive layer) include, for example, an acrylic polymer containing a (meth) acrylic acid ester polymer; a styrene-isoprene-styrene block copolymer, and styrene-butadiene- Examples thereof include rubber polymers such as styrene block copolymer, polyisoprene, polyisobutylene, and polybutadiene; silicone polymers such as silicone rubber, dimethylsiloxane base, and diphenylsiloxane base.

  As the acrylic polymer, for example, a polymer obtained by copolymerizing a functional monomer with (meth) acrylic acid alkyl ester as a main component is preferable. That is, a copolymer containing 50 to 99% by weight (preferably 60 to 95% by weight) of a monomer component made of (meth) acrylic acid alkyl ester, and the remaining monomer component being a functional monomer. Is preferred. The main component here means a monomer component contained in an amount of 50% by weight or more based on the total weight of the monomer components constituting the copolymer.

  The (meth) acrylic acid alkyl ester (hereinafter also referred to as main component monomer) is usually a linear or branched alkyl group having an alkyl group of 4 to 13 carbon atoms (for example, butyl, pentyl, hexyl, octyl, 2- Ethylhexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, etc.), and one or more of these are used.

  The functional monomer has at least one unsaturated double bond involved in the copolymerization reaction in the molecule and has a functional group in the side chain. For example, (meth) acrylic acid, itaconic acid, Carboxyl group-containing monomers such as maleic acid and maleic anhydride; hydroxyl group-containing monomers such as (meth) acrylic acid hydroxyethyl ester and (meth) acrylic acid hydroxypropyl ester; (meth) acrylic acid aminoethyl ester; Amino group-containing monomers such as (meth) acrylic acid dimethylaminoethyl ester, (meth) acrylic acid tert-butylaminoethyl ester; (meth) acrylamide, dimethyl (meth) acrylamide, N-methylolpropane (meth) acrylamide, Amide group-containing monomers such as N-vinylacetamide; Methoxyethyl laurate, ethoxyethyl (meth) acrylate, methoxyethylene glycol (meth) acrylate, methoxydiethylene glycol (meth) acrylate, methoxypolyethylene glycol (meth) acrylate, methoxy (meth) acrylate Examples thereof include alkoxyl group-containing monomers such as polypropylene glycol esters.

  As the acrylic polymer, use a copolymer of the above (meth) acrylic acid alkyl ester (main monomer) and a functional monomer, which is copolymerized with another monomer. You can also.

  Examples of the other monomers include (meth) acrylonitrile, vinyl acetate, vinyl propionate, N-vinyl-2-pyrrolidone, methyl vinyl pyrrolidone, vinyl pyrrolidone, vinyl piperidone, vinyl pyrimidine, vinyl piperazine, vinyl pyrrole and vinyl. Examples thereof include imidazole, vinyl caprolactam, vinyl oxazole and the like, and one or more of them can be used.

  In the acrylic polymer, if there is a highly polar functional group such as a hydroxyl group or a carboxyl group, the solubility of the RPR in the pressure-sensitive adhesive layer increases, so that it takes time to form crystals. Therefore, a non-functional acrylic polymer having no functional group other than the ester group is particularly preferable.

  Examples of the rubber polymer include polyisobutylene, polyisoprene, styrene-diene-styrene block copolymer (styrene-butadiene-styrene block copolymer (SBS)), and styrene-isoprene-styrene block copolymer (SIS). A rubber-based polymer whose main component is at least one selected from the above is preferred. Among these, polyisobutylene is particularly preferable as a rubber-based polymer because it has high RPR stability and can achieve both necessary adhesive strength and cohesive strength. The polyisobutylene has a viscosity average molecular weight of 3,000,000. It is preferable to use a high molecular weight polyisobutylene having a molecular weight of ˜5,000,000 and a low molecular weight polyisobutylene having a viscosity average molecular weight of 40,000 to 85,000 in a weight ratio of 95: 5 to 5:95.

  The content of the polymer in the pressure-sensitive adhesive layer is not particularly limited, but is generally 20% to 90% by weight, preferably 40% to 70% by weight, based on the total weight of the pressure-sensitive adhesive layer.

  In addition, when using a rubber-type polymer, in order to provide adhesiveness at normal temperature to an adhesive layer, it is preferable to further mix | blend a tackifier with an adhesive layer. The tackifier may be appropriately selected from those known in the art. Examples of the tackifier include petroleum resins (for example, aromatic petroleum resins and aliphatic petroleum resins), terpene resins, rosin resins, coumarone indene resins, styrene resins (for example, styrene resins, (Α-methylstyrene, etc.), hydrogenated petroleum resins (for example, aliphatic saturated hydrocarbon resins, alicyclic saturated hydrocarbon resins, etc.). Among these, an aliphatic saturated hydrocarbon resin and an alicyclic saturated hydrocarbon resin are preferable because the storage stability of RPR is improved. The tackifier can be used alone or in combination of two or more, and the content of the tackifier is usually 33 to 300% by weight, preferably 50 to 200% by weight, based on the total weight of the rubber-based polymer. is there.

In the present invention, the pressure-sensitive adhesive layer may contain a first liquid additive having a RPR solubility at 23 ° C. of less than 0.10 g / g (first preferred embodiment). In the present invention, “liquid additive” means an organic compound having fluidity at 32 ° C., and “having fluidity” means 0.5 RPM measured with a conical disk type rotational viscometer, 32 It means that the viscosity at 1 ° C. is 1 × 10 ⁶ mPa · s or less. In addition, 32 degreeC is equivalent to a human body surface temperature, and what has fluidity | liquidity at 32 degreeC has fluidity | liquidity when it affixes on human skin.

  Specific examples of the first liquid additive include, for example, squalane, squalene, light liquid paraffin, liquid paraffin, silicone oil, α-olefin oligomer, oleyl oleate, octyldodecyl myristate, and preferably squalane. Liquid paraffin. According to squalane, a patch preparation with particularly high drug release can be obtained, and a preparation capable of securing a sufficient dose even when the plane area of the preparation (adhesive layer) is relatively small can be realized. The 1st liquid additive can use 1 type (s) or 2 or more types.

  The first liquid additive preferably has an RPR solubility at 23 ° C. of 0.001 g / g or more and less than 0.10 g / g, more preferably an RPR solubility at 23 ° C. of 0.001. The solubility of RPR at 23 ° C. is particularly preferably 0.005 to 0.02 g / g.

  When the pressure-sensitive adhesive layer contains the first liquid additive, the content of the first liquid additive is preferably 5 to 45% by weight, more preferably 15 to 45%, based on the total weight of the pressure-sensitive adhesive layer. % By weight, particularly preferably 20 to 40% by weight. If the amount is less than 5% by weight, sufficient release of RPR may not be obtained and the required permeation amount may not be achieved. Conversely, if it exceeds 45% by weight, the amount of RPR crystal in the adhesive layer decreases. As a result, a large amount of a related substance tends to be generated.

  When the pressure-sensitive adhesive layer contains the first liquid additive, the RPR crystal ratio calculated based on the following formula (I) (that is, the RPR crystallization index in the presence of the first liquid additive) Is preferably 68 to 99% by weight, more preferably 75 to 99% by weight, still more preferably 79 to 99% by weight, and particularly preferably 93 to 99% by weight.

Crystalline ratio of ropinirole = {(A−B ₁ × C ₁ ) / A} × 100 (I)
A: Content of ropinirole in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
B ₁ : Content of first liquid additive in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
C ₁ : Solubility of ropinirole in the first liquid additive at 23 ° C. (unit: g / g)

  In the first preferred embodiment, even when a relatively large amount of the first liquid additive is contained in the pressure-sensitive adhesive layer, RPR crystals are easily formed in the pressure-sensitive adhesive layer. A patch preparation that is stabilized in the patch preparation and exhibits high drug permeability can be realized.

  In this invention, an adhesive layer can contain the 2nd liquid additive whose solubility of RPR in 23 degreeC is 0.10-1.0 g / g (2nd preferable embodiment).

  Examples of the second liquid additive include fatty acid esters, glycerin fatty acid esters, glycols, fats and oils, liquid surfactants, plasticizers, hydrocarbons, and the like. Specific examples include isopropyl myristate, hexyl laurate, isopropyl palmitate, liquid lanolin, and the like. 1 type (s) or 2 or more types can be used for a 2nd liquid additive.

  The second liquid additive preferably has an RPR solubility at 23 ° C. of 0.10 to 0.50 g / g, more preferably an RPR solubility at 23 ° C. of 0.10 to 0.40 g. Particularly preferably, the solubility of RPR at 23 ° C. is 0.10 to 0.25 g / g.

  When the pressure-sensitive adhesive layer contains the second liquid additive, the content of the second liquid additive is preferably 2.5 to 12.5% by weight based on the total weight of the pressure-sensitive adhesive layer, More preferably, it is 3.0 to 12.0% by weight. If the amount is less than 2.5% by weight, sufficient release of RPR may not be obtained, and the required permeation amount may not be achieved. Conversely, if the amount exceeds 12.5% by weight, crystals of RPR in the patch preparation may be obtained. Since the amount is small, a similar substance tends to be produced in a large amount.

  When the pressure-sensitive adhesive layer contains the second liquid additive, the RPR crystal ratio calculated based on the following formula (II) (that is, the RPR crystallization index in the presence of the second liquid additive) Is preferably 74 to 99% by weight, more preferably 74 to 95% by weight, and particularly preferably 76 to 90% by weight.

Ropinirole crystal ratio = {(A−B ₂ × C ₂ ) / A} × 100 (II)
A: Content of ropinirole in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
B ₂ : Content of the second liquid additive in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
C ₂ : Solubility of ropinirole in the second liquid additive at 23 ° C. (unit: g / g)

  In such a second preferred embodiment, RPR crystals are easily formed in the pressure-sensitive adhesive layer by blending a small amount of the second liquid additive, so that the effect of the present invention (ie, drug stability) can be efficiently produced. A patch preparation having a high drug permeability and a high drug permeability.

  In the present invention, the pressure-sensitive adhesive layer can contain a first liquid additive (such as liquid paraffin) and a second liquid additive (such as isopropyl myristate) (third preferred embodiment). In this embodiment, it is possible to promote the percutaneous absorption of RPR while suppressing the production of a related substance of RPR, and in particular, the percutaneous absorption of RPR is synergistically promoted.

  From this viewpoint, when the pressure-sensitive adhesive layer contains the first liquid additive (liquid paraffin, etc.) and the second liquid additive (isopropyl myristate, etc.), the first liquid additive (liquid paraffin, etc.) The total amount of the second liquid additive (such as isopropyl myristate) in the pressure-sensitive adhesive layer is preferably 10 to 50% by weight, more preferably 20 to 40% by weight, based on the total weight of the pressure-sensitive adhesive layer. The weight ratio of the first liquid additive (liquid paraffin, etc.) to the second liquid additive (isopropyl myristate, etc.) is preferably 1: 0.05 to 0.35, and 1: 0.05 to 0. .30 is more preferable.

  When the pressure-sensitive adhesive layer contains a first liquid additive (such as liquid paraffin) and a second liquid additive (such as isopropyl myristate), the RPR crystallinity calculated based on the following formula (III) (that is, , The RPR crystallization index in the presence of the first and second liquid additives) is preferably 79 to 100% by weight, more preferably 82 to 99% by weight, and 85 to 99% by weight. Is particularly preferred.

RPR crystal ratio = {A− (B ₁ · C ₁ + B ₂ · C ₂ )} / A × 100 (III)
A: Content of RPR in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
B ₁ : Content of first liquid additive in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
C ₁ : Solubility of RPR in the first liquid additive at 23 ° C. (unit: g / g)
B ₂ : Content of the second liquid additive in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
C ₂ : Solubility of RPR in the second liquid additive at 23 ° C. (unit: g / g)

  In the third preferred embodiment, the first liquid additive is preferably liquid paraffin. In the third preferred embodiment, RPR is applied in the patch preparation in a state where the content of each liquid additive is reduced as compared with the case where the first liquid additive or the second liquid additive is used alone. Can be stabilized. In addition, since the first liquid additive and the second liquid additive coexist, it becomes easy to improve the release of RPR, and a sufficient dose can be secured in a small area.

In the present specification, the content of RPR (free body) in the pressure-sensitive adhesive layer is measured by the following method:
Tetrahydrofuran 5 mL is added to the specimen punched out to 5 cm ² from the patch preparation, and the adhesive layer is dissolved. Methanol was added to this to make up to 50 mL (constant volume), then the RPR content was measured by high performance liquid chromatography (HPLC), divided by 5 and the RPR in the adhesive layer per unit area. The content (unit: g / cm ² ) is obtained. Here, the conditions of high performance liquid chromatography (HPLC) are as follows:
(HPLC conditions)
・ HPLC-column: Symmetry C8 (particle size 5μm, 4.6mmID × 250mm)
・ Column temperature: 45 ℃
・ Mobile phase: A pH6.0 0.035M Phosphate buffer solution / Triethylamine / Acetonitrile
(= 90 / 0.5 / 10) 95%,
B pH6.0 Acetonitrile / water / triethylamine (= 80/20 / 0.2) 5%
Time (min) / (% B) = 0/5, 20/5, 37/60, 47/60, 50/5, 60/5
Gradient and analysis time: 60 min
・ Flow rate: 1.0 mL / min
・ Detection: 250 nm
・ Retention time: 14-15 min

  In the present invention, the pressure-sensitive adhesive layer may contain an antioxidant in order to stabilize RPR. Antioxidants include tocopherol and ester derivatives thereof, ascorbic acid and derivatives thereof, propyl gallate, dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), 2-mercaptobenzimidazole, sodium pyrosulfite, sodium sulfite Sodium bisulfite, sodium thiosulfate, disodium edetate, tetrasodium edetate, and the like. BHT is particularly preferably used because of its compatibility with the pressure-sensitive adhesive layer and the effect of inhibiting related substances.

  The antioxidant is not particularly limited as long as it does not impair the adhesive properties of the pressure-sensitive adhesive layer, but is preferably 0.01% by weight to 10% by weight, preferably 0.1% by weight to the total weight of the pressure-sensitive adhesive layer. 5% by weight is more preferred.

In the adhesive preparation of the present invention, the thickness of the pressure-sensitive adhesive layer can be set to 20 to 300 μm, for example. The pressure-sensitive adhesive layer is preferably formed so that the weight of the pressure-sensitive adhesive layer per unit area after drying is ² to 30 mg / cm ² , so that the weight is 4 to 25 mg / cm ^2. More preferably it is formed.

  In the medicated patch of the present invention, in order to protect the adhesive surface of the adhesive layer until use, it is preferable to laminate a release liner on the adhesive surface. The release liner is not particularly limited as long as it can be peeled and a sufficiently light peeling force can be secured. For example, the release treatment can be performed by applying a silicone resin, a fluororesin or the like on the surface in contact with the adhesive layer. Polyester (for example, polyethylene terephthalate, etc.), polyvinyl chloride, polyvinylidene chloride, polyethylene terephthalate, etc., high quality paper, paper such as glassine paper, laminated paper of high quality paper or glassine paper, etc. and polyolefin, etc. Is used. From the viewpoint of barrier properties and cost, those made of polyester (particularly polyethylene terephthalate) are preferred. The thickness of the release liner is usually 10 to 200 μm, preferably 25 to 100 μm.

Planar size of the patch preparation of the present invention is not particularly limited, preferred area was ^{1 cm} 2 100 cm ^2, and more preferably an area of ^{2cm 2 ~80cm} 2. If it is smaller than 1 cm ² , the handleability tends to be difficult, and if it is larger than 100 cm ² , itching and skin irritation tend to increase.

  The patch preparation of the present invention can be packaged in a packaging container known per se, if desired. As the packaging container, a packaging container made of a resin film, a metal foil, and a laminated film thereof is usually used.

Although the manufacturing method of the patch preparation of this invention is not specifically limited, For example, it can manufacture with the following method.
That is, a laminated sheet (a patch preparation precursor sheet) laminated in the order of a support / ropinirole and a pressure-sensitive adhesive layer / release liner containing a liquid additive in which ropinirole is soluble, or this laminated sheet (a patch preparation precursor) Sheet) is stored in an environment having a temperature of 25 ° C. or lower (preferably 10 ° C. or lower, more preferably 5 to 10 ° C.) to produce crystalline ropinirole in the pressure-sensitive adhesive layer. And a method including a second step of cutting the laminated sheet that has undergone the first step, or the laminated sheet obtained by cutting the laminated sheet into the shape and size of the patch preparation.
In addition, the storage of the laminated sheet or the laminated sheet obtained by cutting the laminated sheet is a temperature of 25 ° C. or less (preferably 10 ° C. or less, more preferably 5 to 10 ° C.) and a relative humidity of 50% RH or more ( It is preferably carried out in an environment of 60 to 100% RH, more preferably 70 to 100% RH.

  The method for laminating the pressure-sensitive adhesive layer in the laminated sheet in the first step is not particularly limited, and examples thereof include coating, adhesion, fusion, welding, and the like. Ropinirole, a liquid additive in which ropinirole exhibits solubility, a pressure-sensitive adhesive polymer A method for forming a pressure-sensitive adhesive layer by preparing a composition for forming a pressure-sensitive adhesive layer containing at least an organic solvent and applying the composition on a release liner or a support, followed by drying and removing the organic solvent. The organic solvent used for the preparation of the pressure-sensitive adhesive layer-forming composition is not particularly limited, but those having a boiling point of less than 150 ° C. at normal pressure so that they can be sufficiently removed by drying when forming the pressure-sensitive adhesive layer. preferable. Therefore, methanol, ethanol, benzene, n-hexane, ethyl acetate, acetone, toluene, xylene, heptane, isopropyl alcohol and the like are preferable. Further, the storage temperature of the laminated sheet (or the laminated sheet obtained by cutting the laminated sheet) is particularly preferably 5 ± 2 ° C. at which crystals are easily formed.

  The above-mentioned storage period is less than 6 months, and within the period of less than 6 months, those in which ropinirole crystals are formed on the pressure-sensitive adhesive layer are the “adhesive layers in which the pressure-sensitive adhesive layer contains ropinirole in a crystalline state” “Formulation”. When the storage period is less than 6 months, ropinirole crystals are not formed in the pressure-sensitive adhesive layer, but when ropinirole crystals are formed in the pressure-sensitive adhesive layer after the storage period has reached 6 months, ropinirole crystals are not formed. Therefore, the amount of ropinirole-related substance produced is sufficiently small, and it does not result in a patch preparation exhibiting excellent ropinirole skin permeability.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, and appropriate modifications are made within the scope that can meet the gist of the present invention described above. Of course, it is also possible to implement them, and they are all included in the technical scope of the present invention. In the following text, “part” and “%” mean “part by weight” and “% by weight”, respectively, unless otherwise specified.

(1) Preparation of rubber adhesive solution In the presence of 456 parts of toluene, 24 parts of high molecular weight polyisobutylene having a viscosity average molecular weight of 4,000,000, 36 parts of low molecular weight polyisobutylene having a viscosity average molecular weight of 55,000, and tackifier 40 parts of an alicyclic saturated hydrocarbon resin (Arakawa Chemical Co., Ltd., Alcon P100) was mixed to obtain a toluene solution (18% solution) of a rubber-based adhesive.

(2) Preparation of ropinirole-containing patch preparation precursor sheets of Examples 1 to 10 Adhesion according to the blending ratios in Tables 1, 3, and 5 (% by weight based on the total weight of the adhesive layer after removing toluene by drying) A toluene solution of the composition for forming the agent layer was prepared (the weight of the rubber-based pressure-sensitive adhesive was calculated as a solid content), and the resulting solution was treated with a silicone terephthalate (PET) liner (thickness). 75 [mu] m) was applied so that the thickness after drying would be 50 [mu] m, and this was dried with a hot-air circulating drier to produce an adhesive layer. This pressure-sensitive adhesive layer was bonded to a PET support to obtain a patch preparation precursor sheet (laminated sheet). Finally, the edge part of the obtained patch preparation precursor sheet | seat was cut | disconnected using the cutter knife, and it packed in the packaging container, and stored in the thermostat kept at 5 +/- 2 degreeC.
In this example, RPR used a free form in which ropinirole hydrochloride was desalted in advance.

  The patch preparation precursor sheets of Examples 1 to 10 were evaluated as follows.

(1) Observation of crystal formation The patch preparation precursor sheet is packaged in a packaging container composed of a three-layer laminate film of polyethylene terephthalate film / aluminum foil / polyacrylonitrile film and placed in a 5 ± 2 ° C. incubator (incubator). (Relative humidity of 95% RH) was stored for 6 months, and the patch preparation precursor sheet was periodically taken out during the storage period, and the adhesive layer was observed visually and with an optical microscope (500 times magnification). Those in which ropinirole crystals were observed were evaluated as “formation” of crystal formation, and those in which no crystal formation was clearly observed by visual observation and observation with an optical microscope (magnification 500 times) were evaluated as “none”.

(2) Evaluation method of skin permeability test Stored in a 5 ± 2 ° C incubator (relative humidity in the incubator is 95% RH) for 6 months, and a patch preparation precursor sheet with crystals formed is 6 mm in diameter Was cut into a circular shape to prepare a patch preparation. The obtained patch preparation was affixed to the stratum corneum side of the hair-extracted skin of the hairless mouse, and attached to a skin permeation experiment cell (effective area 9 mmφ) so that the dermis layer side became the receptor phase. Time skin permeation experiments were performed. A degassed PBS (−) solution (phosphate buffered saline) was used as the receptor solution. The receptor solution was sampled over time, and the concentration of permeated ropinirole was quantified by high performance liquid chromatography (ODS column, UV detector). If the value of the cumulative permeation amount after 24 hours exceeds the 200μg / cm ² / 24hr, it determines drug permeation amount sufficiently high.

(3) Impurity production rate evaluation method Store in an incubator at 5 ± 2 ° C. (relative humidity in the incubator is 95% RH) for 6 months, and the patch preparation precursor sheet on which crystals are formed to 5 cm ² This was punched out to prepare a patch preparation, and the obtained patch preparation was packaged in a packaging container and stored in a thermostat at 40 ± 2 ° C. (relative humidity in the thermostat was 95% RH) for one month. The patch preparation is taken out and the adhesive layer is dissolved using 5 mL of tetrahydrofuran. Methanol was added thereto to make up to 50 mL (constant volume), and then the components in the preparation were extracted. This solution was analyzed using high performance liquid chromatography (HPLC) under the following conditions to evaluate the impurity production rate of RPR. The impurity generation rate was the ratio of the sum of the peak areas corresponding to ropinirole impurities to the peak area corresponding to ropinirole in the HPLC chart. When the impurity generation rate was 2.0% or less, the generation amount of impurities was sufficiently low, and when it was higher than 2.0%, it was determined that the generation amount of impurities was not sufficiently low.

・ HPLC-column: Symmetry C8 (particle size 5μm, 4.6mmID × 250mm)
・ Column temperature: 45 ℃
・ Mobile phase: A pH6.0 0.035M Phosphate buffer solution / Triethylamine / Acetonitrile
(= 90 / 0.5 / 10) 95%
B pH6.0 Acetonitrile / water / triethylamine (= 80/20 / 0.2) 5%
Time (min) / (% B) = 0/5, 20/5, 37/60, 47/60, 50/5, 60/5
Gradient and analysis time: 60 min
・ Flow rate: 1.0 mL / min
・ Detection: 250 nm
・ Retention time: 14-15 min

(4) RPR crystal ratio For the patch preparation containing the first liquid additive but not containing the second liquid additive, the RPR crystal ratio was calculated based on the above-mentioned formula (I). In addition, for a patch preparation containing the second liquid additive but not containing the first liquid additive, the RPR crystallinity was calculated based on the above-mentioned formula (II). For the patch preparation containing the first liquid additive and the second liquid additive, the RPR crystallinity was calculated based on the above formula (III).

(5) Solubility test Weigh out a predetermined amount of any of the following liquid additives in a glass bottle, add light as appropriate until RPR (free form) does not dissolve, and stir for 12 hours or more in an environment of 23 ° C ± 2 ° C. did. After stirring, the mixture was allowed to stand for 5 days or more in an environment of 23 ° C. ± 2 ° C., and the obtained suspension was filtered using a filter having a pore size of 0.45 μm. The obtained filtrate was diluted to a predetermined amount using a tetrahydrofuran / methanol mixed solution, and RPR dissolved in the liquid additive was quantified using high performance liquid chromatography (HPLC) under the following conditions.
(Liquid additive)
Hexyl laurate, isopropyl myristate, isopropyl palmitate, liquid lanolin, oleyl oleate, octyldodecyl myristate, liquid paraffin, squalane (HPLC conditions)
・ HPLC-column: Symmetry C8 (particle size 5μm, 4.6mmID × 250mm)
・ Column temperature: 45 ℃
・ Mobile phase: A pH6.0 0.035M Phosphate buffer solution / Triethylamine / Acetonitrile
(= 90 / 0.5 / 10) 95%,
B pH6.0 Acetonitrile / water / triethylamine (= 80/20 / 0.2) 5%
Time (min) / (% B) = 0/5, 20/5, 37/60, 47/60, 50/5, 60/5
Gradient and analysis time: 60 min
・ Flow rate: 1.0 mL / min
・ Detection: 250 nm
・ Retention time: 14-15 min

[Test results]
Tables 1, 3 and 5 show the test results of each patch preparation, and Tables 2 and 4 show the solubility of the liquid additive.

(1) For Example Example 1 using isopropyl myristate as a 1-3 test results liquid additives, but the amount of transmitted RPR reaches the target value ^{(200μg / cm 2 / 24hr)} , formation of impurities The rate exceeded 2.0%. On the other hand, as a liquid additive, in the case of Examples 2 and 3 using the liquid paraffin and squalane, reaches the transmission amount of RPR is the target value ^{(200μg / cm 2 / 24hr)} , production rate of impurities 2.0 %. From the above results and the solubility data in Table 2, a patch preparation using liquid paraffin or squalane with low RPR solubility can produce a preparation with high RPR permeability and excellent RPR storage stability. I understood that.

(2) Test results of Examples 1 and 4 to 7 In Examples 1 and 4 containing the second liquid additive as the liquid additive and not containing the first liquid additive, the permeation amount of RPR is the target. It exceeds the value (200μg / cm ² / 24hr), but the production rate of impurities exceeds 2.0%. This is probably because the RPR crystal ratio was low. In Example 7 in which the first liquid additive and the second liquid additive were not included at all, the impurity generation rate was less than 2.0%, but the RPR permeation amount was the target value (200 μg). / it did not reach the cm ² / 24hr). On the other hand, in Examples 5 and 6, in which the RPR crystallinity is 79.0% or more and the second liquid additive is contained by 5% by weight or more, the impurity generation rate is less than 2.0%, and permeation amount target value of the RPR reached ^{(200μg / cm 2 / 24hr)} , the permeability of RPR that is sufficiently high has been confirmed.

（３）実施例１、２、８〜１０の試験結果
流動パラフィンを使用した場合、ロピニロールの薬物透過性は相乗的に増強された。すなわち、実施例８、実施例９、実施例１０のＲＰＲの透過量は、実施例１と実施例２のＲＰＲの透過量の相加平均値を上回った。

(3) Test results of Examples 1, 2, and 8 to 10 When liquid paraffin was used, the drug permeability of ropinirole was synergistically enhanced. That is, the RPR permeation amount in Examples 8, 9, and 10 exceeded the arithmetic average value of the RPR permeation amounts in Example 1 and Example 2.

  According to the patch preparation of the present invention, a patch preparation containing a free form of ropinirole is provided, and a patch preparation containing a small amount of related substances and a drug permeation amount reaching the required amount is provided. It can be widely used as a preparation.

Claims (13)

A patch preparation comprising an adhesive layer containing ropinirole on at least one side of a support,
A patch preparation, wherein the pressure-sensitive adhesive layer contains ropinirole in a crystalline state. The pressure-sensitive adhesive layer contains a first liquid additive having a solubility of ropinirole at 23 ° C. of less than 0.10 g / g, and the crystallinity of ropinirole calculated based on the following formula (I) is 68 to 99%. The patch preparation according to claim 1, wherein
Crystalline ratio of ropinirole = {(A−B ₁ × C ₁ ) / A} × 100 (I)
A: Content of ropinirole in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
B ₁ : Content of first liquid additive in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
C ₁ : Solubility of ropinirole in the first liquid additive at 23 ° C. (unit: g / g)   The adhesive preparation according to claim 2, wherein the content of the first liquid additive in the pressure-sensitive adhesive layer is 5 to 45% by weight based on the total weight of the pressure-sensitive adhesive layer.   The first liquid additive is one or more selected from the group consisting of squalane, squalene, light liquid paraffin, liquid paraffin, silicone oil, α-olefin oligomer, oleyl oleate and octyldodecyl myristate, The patch preparation according to claim 2 or 3. The crystallinity of ropinirole, wherein the pressure-sensitive adhesive layer includes a second liquid additive having a saturation solubility of ropinirole at 23 ° C. of 0.10 to 1.0 g / g, and is calculated based on the following formula (II) The patch preparation according to claim 1, wherein is 74 to 99% by weight.
Ropinirole crystal ratio = {(A−B ₂ × C ₂ ) / A} × 100 (II)
A: Content of ropinirole in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
B ₂ : Content of the second liquid additive in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
C ₂ : Solubility of ropinirole in the second liquid additive at 23 ° C. (unit: g / g)   The adhesive preparation according to claim 5, wherein the content of the second liquid additive in the pressure-sensitive adhesive layer is 2.5 to 12.5% by weight based on the total weight of the pressure-sensitive adhesive layer.   The patch preparation according to claim 5 or 6, wherein the second liquid additive is one or more selected from the group consisting of isopropyl myristate, hexyl laurate, isopropyl palmitate and liquid lanolin.   The patch preparation according to any one of claims 1 to 7, wherein the polymer constituting the pressure-sensitive adhesive layer is a rubber polymer.   A laminated sheet in which a support / ropinirole and a pressure-sensitive adhesive layer / release liner containing a liquid additive in which ropinirole is soluble is laminated in this order and stored at a temperature of 25 ° C. or lower, and the adhesive layer is in a crystalline state. A method for producing a patch preparation, comprising: a first step of producing ropinirole; and a second step of cutting the laminated sheet having undergone the first step into the shape and size of the patch preparation.   The method according to claim 9, wherein the liquid additive in which ropinirole is soluble is the first liquid additive having a ropinirole solubility at 23 ° C of less than 0.10 g / g. The pressure-sensitive adhesive layer containing ropinirole and the first liquid additive is a pressure-sensitive adhesive layer having a crystallinity of ropinirole of 68 to 99% calculated based on the following formula (I). Method.
Crystalline ratio of ropinirole = {(A−B ₁ × C ₁ ) / A} × 100 (I)
A: Content of ropinirole in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
B ₁ : Content of first liquid additive in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
C ₁ : Solubility of ropinirole in the first liquid additive at 23 ° C. (unit: g / g)   The method according to claim 9, wherein the liquid additive in which ropinirole is soluble is a second liquid additive having a ropinirole solubility at 23 ° C of 0.10 to 1.0 g / g. The pressure-sensitive adhesive layer containing ropinirole and the second liquid additive is a pressure-sensitive adhesive layer having a crystallinity of ropinirole of 74 to 99% by weight calculated based on the following formula (II). the method of.
Ropinirole crystal ratio = {(A−B ₂ × C ₂ ) / A} × 100 (II)
A: Content of ropinirole in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
B ₂ : Content of the second liquid additive in the pressure-sensitive adhesive layer per unit area (unit: g / cm ² )
C ₂ : Solubility of ropinirole in the second liquid additive at 23 ° C. (unit: g / g)