JP2018104418A - Rotigotine percutaneous absorption type patch formulation containing antipruritic agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide patch formulations capable of suppressing itching caused when a rotigotine-containing percutaneous absorption type patch formulation is attached, in an attachment site, during attachment and at the time of peeling.SOLUTION: In a percutaneous absorption type patch formulation consisting of a support, a drug-containing adhesive layer, and a release liner, the percutaneous absorption type patch formulation contains the drug-containing adhesive layer containing as an active ingredient a rotigotine or a pharmaceutically acceptable salt thereof, and an antipruritic agent as a component for suppressing itching in an attachment site during attachment and at the time of peeling. A substrate component of the drug-containing adhesive layer is a rubber system adhesive component. The antipruritic agent is one or more selected from monoterpenes, crotamiton, an antihistamine, a local anesthetic, and a steroid, preferably monoterpenes and crotamiton, more preferably menthol and crotamiton.SELECTED DRAWING: Figure 3

Description

  The present invention is a transdermal absorption patch preparation comprising a support, a drug-containing pressure-sensitive adhesive layer, and a release liner, and contains a rotigotine and an antipruritic agent as active ingredients in the drug-containing pressure-sensitive adhesive layer. About.

  Rotigotine is a D3 / D2 / D1 dopamine receptor agonist and is a drug having an excellent therapeutic effect on Parkinson's disease, restless legs syndrome (RLS) and the like. So far, preparations containing rotigotine as an active ingredient have been developed. For example, “Nepro” is a transdermal absorption patch preparation containing rotigotine (hereinafter referred to as “rotigotine-containing transdermal absorption patch preparation”). (Registered trademark) "is commercially available in Europe and other regions. In Japan, it is marketed under the trade name “New Pro (registered trademark) patch”.

  As a conventional rotigotine-containing transdermal absorption patch, for example, Patent Document 1 discloses a transdermal absorption patch in which an acrylate or silicone polymer adhesive is blended as a base. Patent Documents 2, 3 and 4 contain an acrylate-based and / or silicone-based polymer adhesive as a base, polyvinylpyrrolidone as a solubilizer, tocopherol and an ester derivative thereof as an antioxidant, ascorbic acid A transdermal absorption patch preparation containing palmitate, sodium pyrosulfite and the like is disclosed.

  In addition, in the Patent Documents 5 and 6, the present inventors have also suppressed the production of decomposition products of rotigotine or suppressed the precipitation of crystal components derived from rotigotine, resulting in a decrease in feeling of use and a decrease in skin adhesion. In order to suppress the above, a rotigotine-containing transdermal absorption patch preparation containing a rubber-based adhesive as a base component is disclosed.

  As a side effect of the commercially available “Nupro (registered trademark) patch”, a transdermal absorption patch preparation containing rotigotine, application site reactions such as erythema and pruritus have been observed in about half of the patients. It is recommended to change daily and to treat with an steroid external preparation or an antihistamine external preparation as needed at the time of onset (Non-patent Document 1). Among the skin irritation reported for the above-mentioned commercial products, there are many patients who are particularly concerned about pruritus during application and immediately after peeling, and the case where the user wakes up at night and the peeling site is caused by scratching the application site Cases have been reported and this pruritus may be a factor in avoiding patches. The cause of the pruritus sensation observed in the above-mentioned commercial products can be chemical stimulation, physical irritation and occlusive effect including pruritus derived from the active ingredient, but it is not clear which is the main factor.

  As described above, many techniques related to a rotigotine-containing transdermal absorption patch preparation have been reported, but no technique for suppressing pruritus sensation during and after application has been reported.

Special table 2002-509878 gazette Special table 2004-536054 gazette JP 2005-535687 A Japanese translation of PCT publication 2010-532390 JP 2013-79220 A JP 2014-177428 A

Drug interview form “New Pro Patch” revised in May 2016 (6th edition)

  An object of the present invention is to provide a technique for suppressing the itching sensation during and at the time of application at the site of application of the rotigotine-containing transdermal absorption patch as described above.

  In order to solve the above problems, as a result of intensive studies by the present inventors, a novel transdermal absorption-type patch preparation containing rotigotine and an antipruritic was developed. Specifically, in a percutaneous absorption type patch preparation comprising a support, a drug-containing pressure-sensitive adhesive layer and a release liner, a therapeutically effective amount of rotigotine and a component for suppressing pruritus sensation during and at the time of application at the application site As a result, it was found that the above problems can be solved by blending an antipruritic agent, and the present invention was completed.

  That is, the present invention relates to a transdermal absorption patch preparation comprising a support, a drug-containing pressure-sensitive adhesive layer and a release liner, wherein the drug-containing pressure-sensitive adhesive layer comprises rotigotine or a pharmaceutically acceptable salt thereof as an active ingredient, and an antipruritic agent. Is a transdermal absorption patch preparation.

  The transdermally absorbable patch preparation of the present invention is a novel patch preparation that suppresses pruritus sensation during and at the time of application at the application site by containing an antipruritic agent together with rotigotine in the drug-containing adhesive layer. This patch preparation does not require a method for dealing with skin irritation, contributes to the improvement of the patient's treatment satisfaction, and can be used without dissatisfaction by patients who refrain from the patch preparation because of itchiness.

Fig. 1 shows the number of scratching behaviors in male ICR mice after application of New Pro (registered trademark) patch and blank preparation (Comparative Example 1) [(A) Number of scratching behaviors every hour after application, (B) 5 hours after application The number of scratching behaviors for each time, (C) Total number of scratching behaviors during application and after peeling, *: p <0.05]. FIG. 2 shows the number of scratching behaviors in male ICR mice after application of the preparations (Examples 1-2 and Comparative Examples 2-3) ((A) number of scratching behaviors every hour after application, (B) every 2 hours after application) Or the number of scratching behaviors every 5 hours, (C) Total number of scratching behaviors during and after application, **: p <0.05, *: p <0.1 (Comparative Example 3 and Example 1, or Comparative Example 3 The significance test of Example 2)] is shown. FIG. 3 shows the number of scratching actions in male ICR mice after application of the preparations (Examples 3 to 10 and Comparative Example 4) [(A) number of scratching actions every hour after application, (B) 1 to 3 hours after application and Number of scratching actions at 16-17 hours, (C) Total number of scratching actions at 5 hours after application, **: p <0.05, *: p <0.1 (significant difference test between Comparative Example 4 and Examples 3-10) )].

  The transdermally absorbable patch preparation of the present invention (hereinafter referred to as “the preparation of the present invention”) comprises a support, a drug-containing pressure-sensitive adhesive layer, and a release liner. In the preparation of the present invention, a drug-containing pressure-sensitive adhesive layer is provided on a support, and a release liner is provided on the drug-containing pressure-sensitive adhesive layer for the purpose of protection until use.

  The drug-containing pressure-sensitive adhesive layer used in the preparation of the present invention has rotigotine ((−)-5,6,7,8-tetrahydro-6- [propyl- [2- (2-thienyl) ethyl] -amino] as an active ingredient. 1-naphthalenol) or a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts of rotigotine include acid addition salts with inorganic 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. is not. In the preparation of the present invention, it is preferable to use a free form of rotigotine.

  The preparation of the present invention only needs to contain a therapeutically effective amount of rotigotine or a pharmaceutically acceptable salt thereof, and the state is not particularly limited, but a dissolved state and a crystalline state are preferable, and a dissolved state is more preferable. In addition, when the preparation of the present invention contains rotigotine or a pharmaceutically acceptable salt thereof in a dissolved state, for example, in a rotigotine solution dissolved in an organic solvent such as toluene, acetone, methanol, hexane, ethyl acetate or a mixed solvent thereof. The base component is stirred and mixed to obtain a uniform dissolved product, which may be used in the preparation of the present invention. In order to allow a patient to transdermally administer an effective amount of an active ingredient effective for treating Parkinson's disease or RLS to a patient for a long time, it is important that the drug-containing adhesive layer contains a certain amount of the active ingredient. The content of rotigotine in the drug-containing adhesive layer of the preparation of the present invention is 1 to 50% by mass, preferably 5 to 30% by mass, and more preferably 7 to 20% by mass with respect to the entire drug-containing adhesive layer. If the amount is less than 1% by mass, the therapeutic effect may not be sufficient. If the amount is more than 50% by mass, the content of the base component constituting the drug-containing adhesive layer becomes low, and sufficient skin adhesiveness cannot be obtained. It is possible and also disadvantageous economically.

  In the present specification, the transdermal absorption patch preparation is a medical adhesive patch preparation, which is attached to the skin and means that a therapeutically effective amount of an active ingredient reaches the bloodstream through the skin.

  The drug-containing pressure-sensitive adhesive layer used in the preparation of the present invention contains an antipruritic agent for suppressing pruritus sensation during and at the time of application at the application site that occurs when a rotigotine-containing transdermal absorption-type adhesive preparation is applied to the skin. To do. Examples of antipruritic agents include, but are not limited to, monoterpenes, crotamitons, antihistamines, local anesthetics, steroids and the like. One or more of these antipruritic agents can be used. Among these antipruritic agents, monoterpenes and crotamiton are preferable because the effect of suppressing pruritus is remarkable. Among the monoterpenes, menthol is preferable, and l-menthol is more preferable.

  Content of the antipruritic agent in this invention formulation is 0.1-50 mass% with respect to a drug containing adhesive layer, Preferably it is 0.5-20 mass%, More preferably, it is the range of 1-10 mass%. If it is less than 0.1% by mass, a sufficient antipruritic effect may not be obtained. On the other hand, if it exceeds 50% by mass, it may be difficult to keep the physical properties of the patch preparation good.

  When menthol is used as the antipruritic agent used in the preparation of the present invention, the content thereof is 0.5 to 30% by mass, preferably 0.5 to 20% by mass, more preferably 1 to 2%, based on the drug-containing pressure-sensitive adhesive layer. 10% by mass. Moreover, when using crotamiton, the content is 0.1-20 mass% with respect to a drug-containing adhesive layer, Preferably it is 0.5-10 mass%, More preferably, it is 0.5-5 mass%. Furthermore, when using menthol and crotamiton together, it is preferable that the mass blending ratio of both is 1: 4 to 4: 1 within the above-mentioned content range.

  The preparation of the present invention may be either a matrix type or a reservoir type, but the matrix type is preferred because the preparation design is easy and the cost for manufacturing the patch preparation can be reduced.

  The matrix-type drug-containing pressure-sensitive adhesive layer contains rotigotine, which is an active ingredient, and a base component. The base component used in the drug-containing pressure-sensitive adhesive layer is not particularly limited, but a pressure-sensitive adhesive component generally used in a patch preparation is preferable, and a rubber-based pressure-sensitive adhesive component is particularly preferable. This rubber-based adhesive component is cheaper than other non-aqueous adhesive components such as acrylic and silicone polymer adhesives, and controls manufacturing costs, physical properties and quality. That is, the formulation design is easy.

  The content of the base component in the drug-containing pressure-sensitive adhesive layer is 1 to 98% by mass, preferably 5 with respect to the drug-containing pressure-sensitive adhesive layer in consideration of formation of the drug-containing pressure-sensitive adhesive layer and sufficient drug release properties. It is -70 mass%, More preferably, it is 10-60 mass%. If the amount is less than 1% by mass, the physical properties of the patch such as anchoring properties are deteriorated. If the amount exceeds 98% by mass, good adhesive strength to the skin cannot be obtained when the patch is applied to the human body. It is not preferable.

  The rubber-based adhesive component is not particularly limited. For example, styrene / isoprene / styrene block copolymer (SIS) (for example, commercially available Kraton D-KX401CS, D-1161JP (manufactured by JSR Kraton Elastomer), Califlex TR-1107) , TR-1111, TR-1112, TR-1117 (manufactured by Shell Chemical), JSR-5000, 5002, SR-5100 (manufactured by Nippon Synthetic Rubber), QUINTAC 3530, 3570C, 3421 (manufactured by Nippon Zeon), etc.), styrene・ Butadiene / styrene block copolymer (SBS) (for example, commercially available Califlex TR-1101 (manufactured by Shell Chemical)), styrene / butadiene rubber (SBR), isoprene rubber (IR) (for example, commercially available Nipol IR2200 ( Nippon Zeon), Claprene LIR-50 (Kuraray), etc.), Polyisobutylene (PIB) (for example, commercially available Tetrax 3T (manufactured by Shin Nippon Petrochemical), Opanol B10 (BASF JA) Emissions, Ltd.)), polybutene (PB) (e.g., commercially available HV300F (Nippon Petrochemicals Ltd.)), butyl rubber (IIR), natural rubber (NR), and the like. One or more of these rubber-based adhesive components can be used.

  The content of the rubber-based pressure-sensitive adhesive component in the drug-containing pressure-sensitive adhesive layer is 1 to 98% by mass with respect to the drug-containing pressure-sensitive adhesive layer, preferably considering the formation of the drug-containing pressure-sensitive adhesive layer and sufficient drug release properties. It is 5-70 mass%, More preferably, it is 10-60 mass%. If the amount is less than 1% by mass, the physical properties of the patch such as anchoring properties are reduced. If the amount exceeds 98% by mass, good adhesive strength to the skin cannot be obtained when the patch is applied to the human body. It is not preferable.

  The drug-containing pressure-sensitive adhesive layer may contain additional components such as a plasticizer, a tackifier, an antioxidant, an absorption accelerator, a crosslinking agent, a colorant, an ultraviolet absorber, and a fragrance as necessary. .

  Plasticizers include petroleum oils such as paraffinic process oil, naphthenic process oil, and aromatic process oil, and liquid fatty acid esters such as isopropyl myristate, hexyl laurate, diethyl sebacate, diisopropyl sebacate, and isopropyl linoleate. , Olive oil, camellia oil, castor oil, tall oil, peanut oil and other vegetable oils, liquid rubber such as liquid polyisobutylene, liquid polybutene, liquid polyisoprene, glycerin, chlorobutanol, vinyl acetate resin, dimethylpolysiloxane / silicon dioxide mixture , D-sorbitol, medium chain fatty acid triglyceride, triacetin, pyrrolidones, phytosterol, propylene glycol, polyethylene glycol, polysorbate 80, glyceryl monostearate Emissions, and the like. One or more of these plasticizers can be used.

  Examples of tackifiers include rosin resins [rosin, rosin glycerin ester, hydrogenated rosin, rosin derivatives such as hydrogenated rosin glycerin ester, etc. (for example, commercially available Pine Crystal KE-311 (Arakawa Chemical Industries), etc.) ], Petroleum resin [aliphatic, aromatic, copolymer, hydrogenated, etc. (eg, commercially available Alcon P-100 (Arakawa Chemical Industries) etc.)], terpene resin, epoxy resin, phenol resin, urethane Resin, polyester resin, ketone formamide resin, cresol resin, xylene resin, diallyl phthalate resin, styrene resin, guanamine resin, acrylic resin, polyolefin resin or modified products thereof, Narnauba wax, carmellose sodium, xanthan gum, chitosan, glycerin, silicic acid Magnesium aluminum, light anhydrous silicic acid, acetic acid base Jill, talc, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, polyacrylic acid, sodium polyacrylate, partially neutralized polyacrylic acid, polyvinyl alcohol and the like. One or more of these tackifiers can be used.

  The content of the tackifier in the drug-containing pressure-sensitive adhesive layer is 0 to 98% by weight, preferably 0 to 70% by weight, more preferably 0, based on the drug-containing pressure-sensitive adhesive layer in consideration of sufficient skin adhesiveness. -60 mass%.

  Antioxidants include sulfites such as sodium pyrosulfite, sodium bisulfite, sodium sulfite, and potassium pyrosulfite, phenolic antioxidants such as mercaptobenzimidazole, dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate, L- Ascorbic acid, L-ascorbic acid palmitate, ascorbic acid and its ester derivatives such as sodium isoascorbate, sodium edetate, citric acid, potassium diisocyanurate, soy lecithin, thymol, tocopherol and its ester derivatives, 1, Examples include 3-butylene glycol, benzotriazole, and monothioglycerin. One or more of these antioxidants can be used. Among them, sulfites such as sodium pyrosulfite and sodium bisulfite, ascorbic acid such as mercaptobenzimidazole, L-ascorbic acid, L-ascorbic acid palmitate, sodium isoascorbate and ester derivatives thereof are preferable.

  The content of the antioxidant in the drug-containing pressure-sensitive adhesive layer is 0.005 to 2.0% by mass, preferably 0.01 to 2.0% by mass with respect to the drug-containing pressure-sensitive adhesive layer. If the amount is less than 0.005% by mass, a sufficient inhibitory effect on the production of decomposition products of rotigotine may not be obtained. If the amount exceeds 2.0% by mass, an improvement in the production inhibitory effect correlated with the blending amount is observed. It is not preferable.

  As the absorption enhancer, any compound that has been recognized as an absorption enhancing effect in conventional percutaneous administration may be used. For example, dianpropanolamine, anisoanolamine such as triisopropanolamine, lauric acid, oleic acid, isostearic acid Fatty acids such as isopropyl myristate, octyldodecyl myristate, glycerol oleic acid monoester, hexyldecyl isostearate, alcohols such as oleyl alcohol, propylene glycol, polyethylene glycol monooleate and esters or ethers thereof, Sorbitan esters or ethers such as sorbitan sesquioleate, polyoxyethylene sorbitan monooleate, sorbitan monolaurate, sorbitan monooleate , Phenol ethers such as polyoxyethylene nonyl phenyl ether, polyoxyethylene octyl phenyl ether, castor oil or hardened castor oil, oleoyl sarcosine, lauric dimethylaminoacetic acid betaine, sodium lauryl sulfate, Nonionic surfactants such as oxyethylene oleyl ether, polyoxyethylene lauryl ether, dimethyl lauryl amine oxide, alkylmethyl sulfoxides such as dimethyl sulfoxide and decylmethyl sulfoxide, 2-pyrrolidone, 1-methyl- Examples include pyrrolidones such as 2-pyrrolidone and azacycloalkanes such as 1-dodecylazacycloheptan-2-one and 1-geranylazacycloheptan-2-one. One or more of these absorption promoters can be used.

  Examples of the crosslinking agent include thermosetting resins such as amino resins, phenol resins, epoxy resins, alkyd resins, and unsaturated polyesters, isocyanate compounds, organic crosslinking agents, and inorganic crosslinking agents such as metals or metal compounds. One or more of these crosslinking agents can be used.

  Colorants include indigo carmine, yellow iron oxide, yellow iron sesquioxide, carbon black, caramel, photosensitive element 201, Kumazasa extract, black iron oxide, ketket, zinc oxide, titanium oxide, iron sesquioxide, amaranth, hydroxide Examples include sodium, talc, copper chlorophyllin sodium, green leaf extract, d-borneol, octyldodecyl myristate, methyl rosaniline chloride, methylene blue, manganese ammonium phosphate, and rose oil. One or more of these colorants can be used.

  Examples of UV absorbers include amino acid compounds such as urocanic acid, benzophenone compounds such as 2,4-dihydroxybenzophenone and 2-hydroxy-4-n-octoxybenzophenone, and cinnamic acids such as sinoxate and p-methoxycinnamic acid diethanolamine. Derivatives, cyanoacrylate derivatives such as 2-ethylhexyl-2-cyano-3,3'-diphenyl acrylate, p-aminobenzoic acid derivatives such as ethyl p-aminobenzoate and propyl p-aminobenzoate, anthranilic acid menthyl ester, etc. Anthranilic acid derivatives, salicylic acid derivatives such as phenyl salicylate and p-octylphenyl salicylate, and coumarin derivatives such as 7-ethylamino-4-methylcoumarin and 7,8-dihydroxycoumarin. One or more of these ultraviolet absorbers can be used.

  The support used in the preparation 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 (polyethylene terephthalate, etc.), nylon, polyurethane, etc., or a laminate or porous body thereof. , Foam, paper, woven fabric and non-woven fabric.

  The release liner used in the preparation of the present invention is not particularly limited. For example, a drug-impermeable release liner can be used. Examples of the release liner include a film made of a polymer material such as polyethylene, polypropylene, and polyester, a film in which aluminum is vapor-deposited on a film, and a film in which silicone oil is coated on paper. Among them, a polyester film is preferable from the viewpoints of no penetration of active ingredients, processability and low cost, and a polyethylene terephthalate (PET) film is particularly preferable. Further, the release liner may be a laminate film obtained by bonding a plurality of materials.

  In order to control the percutaneous absorption of the active ingredient, the preparation of the present invention is further provided with a release control film on the skin application side of the drug-containing adhesive layer and an adhesive layer for application to the skin. Also good.

  The preparation of the present invention described above consists of a support, a drug-containing pressure-sensitive adhesive layer and a release liner, and the thickness of each layer is not particularly limited. For example, the support is 1-1000 μm, preferably 10-100 μm, The drug-containing pressure-sensitive adhesive layer has a thickness of 10 to 200 μm, preferably 20 to 100 μm, and the release liner has a thickness of 1 to 500 μm, preferably 10 to 100 μm.

The preparation of the present invention can be produced according to a known method for producing a patch. As a preferable production method of the preparation of the present invention, for example, the following methods may be mentioned.
<Method 1>
Rotigotine, an active ingredient, a base ingredient, an antipruritic agent, and if necessary, an antioxidant, a transdermal absorption accelerator, etc., for example, an organic solvent such as toluene, acetone, methanol, hexane, ethyl acetate or a mixture thereof A solution dissolved in a solvent is spread on a release liner or support, the organic solvent in the solution is evaporated to form a drug-containing pressure-sensitive adhesive layer, and then the support or release liner is bonded to the skin. An absorption type patch preparation is obtained.
<Method 2>
Rotigotine, which is an active ingredient, base ingredient, antipruritic agent, and if necessary, antioxidants, percutaneous absorption accelerators, etc. are heated and dissolved, and this melt is spread on a release liner or support to contain a drug. After forming the pressure-sensitive adhesive layer, a transdermal absorption type patch preparation is obtained by laminating a support or a release liner.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples, and various modifications can be made without departing from the technical idea of the present invention. It is. In the following examples and comparative examples, a PET-treated PET film (SC-01, manufactured by Japan Vilene) was used as the release film, and a PET / PET nonwoven fabric laminate film (EH-0712, Japan) was used as the support. Bileen) was used.

Example 1
In accordance with the mixing ratio shown in Table 1, a rotigotine solution obtained by mixing an aqueous solution of sodium pyrosulfite with a toluene / acetone mixture of rotigotine, a styrene-isoprene-styrene block copolymer (Clayton D-KX401CS, manufactured by JSR Kraton elastomer), liquid paraffin (High Coal M-352, manufactured by Kaneda) and hydrogenated rosin glycerin ester (Pine Crystal KE-311, manufactured by Arakawa Chemical Industry Co., Ltd.) in toluene are mixed with stirring. The mixture was stirred and mixed to obtain a uniform dissolved product. Next, this dissolved product was spread on a release film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 50 μm, and the solvent was distilled off to form a drug-containing pressure-sensitive adhesive layer. The support was bonded. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation.

Example 2
According to the blending ratio shown in Table 1, a transdermal absorption patch preparation was obtained in the same manner as in Example 1 except that crotamiton was used in place of l-menthol in a toluene solution of l-menthol.

Example 3
According to the mixing ratio shown in Table 1, a rotigotine solution obtained by mixing an aqueous solution of sodium pyrosulfite with a toluene / acetone mixture of rotigotine, a styrene-isoprene-styrene block copolymer, polyisoprene (Nipol IR2200, manufactured by Nippon Zeon), hydrogenated Rosin glycerin ester, liquid polyisoprene rubber (Kuraprene LIR-50, manufactured by Kuraray) and polyisobutylene (Opanol B10, manufactured by BASF Japan) were stirred and mixed in toluene, mixed with stirring, and further l-menthol in toluene. Were added and mixed with stirring to obtain a uniform dissolved product. Next, this dissolved product was spread on a release film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 50 μm, and the solvent was distilled off to form a drug-containing pressure-sensitive adhesive layer. The support was bonded. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation.

Example 4
According to the blending ratio shown in Table 1, a transdermal absorption patch preparation was obtained in the same manner as in Example 3.

Example 5
According to the blending ratio shown in Table 1, a transdermal absorption patch preparation was obtained in the same manner as in Example 3.

Example 6
According to the blending ratio shown in Table 1, a transdermal absorption patch preparation was obtained in the same manner as in Example 3.

Example 7
According to the blending ratio shown in Table 1, a transdermal absorption patch preparation was obtained in the same manner as in Example 3.

Example 8
According to the blending ratio shown in Table 1, a transdermal absorption patch preparation was obtained in the same manner as in Example 3 except that crotamiton was used instead of l-menthol in a toluene solution of l-menthol.

Example 9
According to the blending ratio shown in Table 1, a transdermal absorption patch preparation was obtained in the same manner as in Example 8.

Example 10
In accordance with the mixing ratio shown in Table 1, a rotigotine solution obtained by mixing an aqueous solution of sodium pyrosulfite with a toluene / acetone mixture of rotigotine into a styrene-isoprene-styrene block copolymer, polyisoprene, hydrogenated rosin glycerin ester, liquid polyisoprene rubber Then, an adhesive component obtained by stirring and mixing polyisobutylene in toluene was added and mixed by stirring. Further, a toluene solution of l-menthol and crotamiton were added and mixed by stirring to obtain a uniform dissolved product. Next, this dissolved product was spread on a release film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 50 μm, and the solvent was distilled off to form a drug-containing pressure-sensitive adhesive layer. The support was bonded. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation.

Comparative Example 1
According to the blending ratio shown in Table 1, an adhesive component obtained by stirring and mixing styrene-isoprene-styrene block copolymer, polyisoprene, liquid paraffin, and hydrogenated rosin glycerin ester in toluene was added to the toluene / acetone mixed solution, followed by stirring and mixing. A homogeneous lysate was obtained. Next, this dissolved product was spread on a release film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 50 μm, and the solvent was distilled off to form a drug-containing pressure-sensitive adhesive layer. The support was bonded. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation.

Comparative Example 2
According to the mixing ratio shown in Table 1, an aqueous solution containing sodium pyrosulfite mixed with a toluene / acetone mixture, and a styrene-isoprene-styrene block copolymer, liquid paraffin, and hydrogenated rosin glycerin ester were stirred and mixed in toluene. The mixture was stirred and mixed to obtain a uniform dissolved product. Next, this dissolved product was spread on a release film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 50 μm, and the solvent was distilled off to form a drug-containing pressure-sensitive adhesive layer. The support was bonded. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation.

Comparative Example 3
According to the mixing ratio shown in Table 1, styrene-isoprene-styrene block copolymer, liquid paraffin and hydrogenated rosin glycerin ester are stirred in toluene to a rotigotine solution obtained by mixing an aqueous solution of sodium pyrosulfite with a toluene / acetone mixture of rotigotine. The mixed adhesive component was added and mixed by stirring to obtain a uniform dissolved product. Next, this dissolved product was spread on a release film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 50 μm, and the solvent was distilled off to form a drug-containing pressure-sensitive adhesive layer. The support was bonded. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation.

Comparative Example 4
In accordance with the mixing ratio shown in Table 1, a rotigotine solution obtained by mixing an aqueous solution of sodium pyrosulfite with a toluene / acetone mixture of rotigotine into a styrene-isoprene-styrene block copolymer, polyisoprene, hydrogenated rosin glycerin ester, liquid polyisoprene rubber Then, an adhesive component obtained by stirring and mixing polyisobutylene in toluene was added and mixed by stirring to obtain a uniform dissolved product. Next, this dissolved product was spread on a release film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 50 μm, and the solvent was distilled off to form a drug-containing pressure-sensitive adhesive layer. The support was bonded. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation.

Test example 1
The scratching behavior when each formulation obtained in Examples 1 to 10 and Comparative Examples 1 to 4 and a commercially available Newpro (registered trademark) patch was applied to a mouse was measured, and the effect on the scratching behavior by the combination of an antipruritic agent (Each formulation n = 4). The method is shown below.
Six days before the test, the rostral back of a 7-week-old male ICR mouse was removed with a clipper and a shaver. One hour before the start of the test, the mouse was moved to the observation cage in order to acclimatize to the recording / observation environment in advance (acclimation in an unattended environment). The hair removal site was lightly wiped with a professional wipe moistened with water, lightly pressed with a professional wipe to remove moisture, and visually confirmed that the hair removal site was not damaged. Each preparation [1.01 mg rotigotine content per sheet (rotigotine dose of about 25.3 mg / kg, Comparative Examples 1 and 2 do not contain rotigotine), preparation area 2.25 cm ² ] was affixed to the hair removal site. All individuals were taped onto the test formulation.
One mouse with the test preparation was placed in an observation cage, and the behavior of the mouse was recorded with a video camera for 24 hours in an unattended environment. In any group, the preparation was peeled off and collected 20 hours after application. After recording, the moving image was reproduced, and the number of scratching behaviors by the hind limbs was measured by a manual counting method (commercial product New Pro (registered trademark) patch and Comparative Example 1: Counting was performed for 24 hours after administration. Examples 1-2 And Comparative Examples 2-3: Counting was performed for 5 hours, 10-11 hours, 16-17 hours, and 21-22 hours after administration Examples 3-10 and Comparative Example 4: 3 hours and 16-17 hours after administration (Only for behavioral observations at other times). For each preparation group, the scratching behavior was measured every hour after the application, and a statistically significant difference test (t test) was performed on the difference between groups in each group. The results are shown in FIGS.

  When comparing the number of scratching behaviors per hour after the application of Comparative Example 1 (blank preparation) and a commercially available Newpro (registered trademark) patch, the scratching behavior was observed in the Newpro (registered trademark) patch group at any measurement point. The number of scratches was particularly high in the New Pro (registered trademark) patch application group at points 1 to 6 hours after application, 9 hours, 13 to 15 hours, and 1 hour after peeling. Moreover, when the number of scratching behaviors every 5 hours after application was compared, the number of scratching behaviors was significantly higher in the New Pro (registered trademark) patch application group at any measurement point except 16 to 20 hours after application. Furthermore, when the number of scratching behaviors during or after application was totaled, the number of patients in the Newpro (registered trademark) patch application group was significantly higher.

When comparing the number of scratching behaviors of Comparative Example 2 (blank preparation) and Comparative Example 3 (with no antipruritic agent), the number of scratching behaviors was clearly lower in Comparative Example 2 at any measurement point during application. Moreover, when the number of scratching behaviors during the pasting is totaled (the total number of scratching behaviors at 5 hours, 10 to 11 hours, and 16 to 17 hours after the pasting), Comparative Example 2 is 62.3 ± 62.4 times and Comparative Example 3 is 365.8 It was ± 217.9 times, and the comparative example 2 was clearly less. On the other hand, when the total number of scratching behaviors after the preparation was peeled off (21-22 hours after application) was compared, Comparative Example 2 showed the same value as Comparative Example 3, but the blank preparation (Comparison) Example 2) It was estimated that the increase in the number of scratching behaviors in the patch group was due to physical stimulation during peeling. From the above results, it is considered that the increase in the number of scratching behaviors detected in the active pharmaceutical preparation (Comparative Example 3) patch group is due to itching derived from rotigotine.
Next, comparing the number of scratching behaviors of Examples 1 to 10 (with antipruritic agent) and Comparative Examples 3 to 4 (with no antipruritic agent), Comparative Examples 3 and 4 with no antipruritic agent at any measurement point Compared to Examples 1 to 10 in which l-menthol and / or crotamiton, which are antipruritic agents, are used in comparison, 0.7 to 1.0% l-menthol formulation (Examples 4 to 5) and crotamiton formulation (implementation) About Example 2 and Example 8-9) and both antipruritic combination combination preparation (Example 10), it was significantly less than the antipruritic combination preparation (Comparative Example 3 or 4) at any measurement point during application. . In addition, for the preparations (Examples 1 and 3) having an l-menthol compounding ratio of 1.5% or more, no significant difference was observed at some measurement points. It was significantly less than (Comparative Example 3 or 4). On the other hand, for the preparations (Examples 6 to 7) having a l-menthol compounding ratio of less than 0.5%, when compared with the total number of scratching behaviors, there is a significant difference compared to the preparation with no antipruritic agent (Comparative Example 4). Although it was recognized, the effect of suppressing itchiness may be lower compared to other antipruritic combination preparations, and considering the sustainability of the effect, it was considered that the effect was slightly weaker with l-menthol less than 0.5% alone . From the above results, it was predicted that l-menthol and crotamiton, which are antipruritic agents, show a strong inhibitory effect on itch produced when a rotigotine-containing transdermal absorption patch is applied.

Example 11
In accordance with the blending ratio shown in Table 2, polyisoprene, hydrogenated rosin glycerin ester, liquid polyisoprene rubber and polyisobutylene were stirred and mixed in toluene in a rotigotine solution obtained by mixing an aqueous solution of sodium pyrosulfite with a toluene / acetone mixture of rotigotine. An adhesive component was added and stirred and mixed, and a toluene solution of isopropyl myristate and l-menthol was added and stirred and mixed to obtain a uniform dissolved product. Next, this dissolved product was spread on a release film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 50 μm, and the solvent was distilled off to form a drug-containing pressure-sensitive adhesive layer. The support was bonded. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation.

Example 12
A transdermal absorption patch preparation was obtained in the same manner as in Example 11 except that crotamiton was used in place of l-menthol in a toluene solution of l-menthol according to the blending ratio shown in Table 2.

Comparative Example 5
According to the mixing ratio shown in Table 2, an aqueous solution of sodium pyrosulfite is mixed with a toluene / acetone mixture, and an adhesive component obtained by stirring and mixing polyisoprene, hydrogenated rosin glycerin ester, liquid polyisoprene rubber and polyisobutylene in toluene is added and stirred. After mixing, a toluene solution of isopropyl myristate and l-menthol was added and mixed by stirring to obtain a uniform dissolved product. Next, this dissolved product was spread on a release film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 50 μm, and the solvent was distilled off to form a drug-containing pressure-sensitive adhesive layer. The support was bonded. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation.

Comparative Example 6
According to the blending ratio shown in Table 2, a transdermal absorption patch preparation was obtained in the same manner as in Comparative Example 5 except that crotamiton was used instead of l-menthol in a toluene solution of l-menthol.

Example 13
According to the mixing ratio shown in Table 2, rotigotine solution in which sodium pyrosulfite aqueous solution was mixed with toluene / acetone mixture of rotigotine, polyisoprene, hydrogenated rosin glycerin ester, alicyclic saturated hydrocarbon resin (Arcon P-100, Arakawa) Chemical industry), liquid polyisoprene rubber and polyisobutylene in toluene mixed with a sticky ingredient, stirred and mixed, isopropyl myristate, l-menthol toluene solution and crotamiton added, stirred and mixed, uniform dissolved product Got. Next, this dissolved product was spread on a release film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 50 μm, and the solvent was distilled off to form a drug-containing pressure-sensitive adhesive layer. The support was bonded. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation.

Example 14
In accordance with the blending ratio shown in Table 2, rotigotine solution in which sodium pyrosulfite aqueous solution is mixed with toluene / acetone mixture of rotigotine, polyisoprene, hydrogenated rosin glycerin ester, alicyclic saturated hydrocarbon resin, liquid polyisoprene rubber and poly An adhesive component in which isobutylene was stirred and mixed in toluene was added and mixed by stirring. Further, a toluene solution of isopropyl myristate and l-menthol was added and mixed by stirring to obtain a uniform dissolved product. Next, this dissolved product was spread on a release film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 50 μm, and the solvent was distilled off to form a drug-containing pressure-sensitive adhesive layer. The support was bonded. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation.

Example 15
According to the blending ratio shown in Table 2, a transdermal absorption patch preparation was obtained in the same manner as in Example 13.

Example 16
In accordance with the mixing ratio shown in Table 2, a rotigotine solution in which a sodium pyrosulfite aqueous solution is mixed with a toluene / acetone mixture of rotigotine, polyisoprene, hydrogenated rosin glycerin ester, alicyclic saturated hydrocarbon resin, liquid polyisoprene rubber, and ascorbine An adhesive component obtained by stirring and mixing an ethanol solution of acid palmitate in toluene was added and mixed by stirring. Further, a toluene solution of l-menthol and crotamiton were added and stirred and mixed to obtain a uniform dissolved product. Next, this dissolved product was spread on a release film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 50 μm, and the solvent was distilled off to form a drug-containing pressure-sensitive adhesive layer. The support was bonded. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation.

Example 17
According to the blending ratio shown in Table 2, a transdermal absorption patch preparation was obtained in the same manner as in Example 16.

Example 18
According to the blending ratio shown in Table 2, a transdermal absorption patch preparation was obtained in the same manner as in Example 16.

Example 19
In accordance with the blending ratio shown in Table 2, rotigotine solution in which sodium pyrosulfite aqueous solution is mixed with toluene / acetone mixture of rotigotine, polyisoprene, hydrogenated rosin glycerin ester, alicyclic saturated hydrocarbon resin and ascorbyl palmitate An adhesive component obtained by stirring and mixing an ethanol solution in toluene was added and mixed by stirring. Further, a toluene solution of l-menthol and crotamiton were added and mixed by stirring to obtain a uniform dissolved product. Next, this dissolved product was spread on a release film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 50 μm, and the solvent was distilled off to form a drug-containing pressure-sensitive adhesive layer. The support was bonded. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation.

Example 20
In accordance with the mixing ratio shown in Table 2, a rotigotine solution in which a sodium pyrosulfite aqueous solution is mixed with a toluene / acetone mixture of rotigotine, a styrene-isoprene-styrene block copolymer, polyisoprene, hydrogenated rosin glycerin ester, alicyclic saturation A sticky component obtained by stirring and mixing an ethanol solution of a hydrocarbon resin and ascorbyl palmitate in toluene was added and mixed by stirring. Further, a toluene solution of l-menthol and crotamiton were added and mixed by stirring to obtain a uniform dissolved product. Next, this dissolved product was spread on a release film using a doctor knife coating machine so that the thickness after evaporation of the solvent was 50 μm, and the solvent was distilled off to form a drug-containing pressure-sensitive adhesive layer. The support was bonded. Then, it was cut into a desired size to obtain a transdermal absorption patch preparation.

  As described above, the preparation of the present invention is a novel patch preparation that suppresses pruritus sensation during and at the time of application at the application site by containing an antipruritic agent together with rotigotine in the drug-containing adhesive layer. This patch preparation does not require a method for dealing with skin irritation, contributes to the improvement of the patient's treatment satisfaction, and can be used without dissatisfaction by patients who refrain from the patch preparation because of itchiness. In addition, by suppressing the itch during sticking, it is possible to prevent peeling due to scratching the sticking site, and to further maintain the pharmacological effect of rotigotine.

Therefore, the transdermal absorption type patch preparation of the present invention is an effective preparation for the treatment of Parkinson's disease or RLS.

Claims (25)

  In a transdermal absorption patch preparation comprising a support, a drug-containing pressure-sensitive adhesive layer and a release liner, the drug-containing pressure-sensitive adhesive layer contains rotigotine or a pharmaceutically acceptable salt thereof as an active ingredient and an antipruritic agent. Skin absorption type patch preparation.   The transdermal patch preparation according to claim 1, wherein the base component of the drug-containing adhesive layer is a rubber-based adhesive component.   The transdermal patch preparation according to any one of claims 1 to 2, wherein the antipruritic agent is at least one selected from monoterpenes, crotamiton, antihistamines, local anesthetics, and steroids.   The transdermal patch preparation according to any one of claims 1 to 2, wherein the antipruritic agent is at least one selected from monoterpenes and crotamiton.   The transdermal patch preparation according to any one of claims 1 to 2, wherein the antipruritic agent is at least one selected from menthol and crotamiton.   The antipruritic agent is menthol or crotamiton, The transdermal absorption patch preparation according to any one of claims 1 to 2.   Menthol is l-menthol, The transdermal absorption patch preparation in any one of Claims 5-6.   The transdermal patch preparation according to any one of claims 1 to 2, wherein the content of the antipruritic agent is 0.1 to 50 mass% with respect to the drug-containing adhesive layer.   The transdermal patch preparation according to any one of claims 1 to 2, wherein the content of the antipruritic agent is 0.5 to 20% by mass with respect to the drug-containing adhesive layer.   The transdermal patch preparation according to any one of claims 1 to 2, wherein the content of the antipruritic agent is 1 to 10 mass% with respect to the drug-containing adhesive layer.   The transdermal absorption patch preparation according to claim 5 or 6, wherein the menthol content is 0.5 to 30% by mass relative to the drug-containing pressure-sensitive adhesive layer.   The transdermal patch preparation according to any one of claims 5 and 6, wherein the menthol content is 0.5 to 20% by mass relative to the drug-containing pressure-sensitive adhesive layer.   The transdermal patch preparation according to any one of claims 5 and 6, wherein the menthol content is 1 to 10% by mass relative to the drug-containing pressure-sensitive adhesive layer.   The transdermal absorption patch preparation according to any one of claims 3 to 6, wherein the content of crotamiton is 0.1 to 20% by mass relative to the drug-containing adhesive layer.   The transdermal patch preparation according to any one of claims 3 to 6, wherein the content of crotamiton is 0.5 to 10 mass% with respect to the drug-containing adhesive layer.   The transdermal absorption patch preparation according to any one of claims 3 to 6, wherein the content of crotamiton is 0.5 to 5 mass% with respect to the drug-containing adhesive layer.   The transdermal patch preparation according to claim 6, wherein the mass blending ratio of menthol and crotamiton is 1: 4 to 4: 1.   The transdermal patch according to any one of claims 1 to 17, wherein the drug-containing adhesive layer contains rotigotine or a pharmaceutically acceptable salt thereof in a dissolved state.   The transdermal absorption patch preparation according to any one of claims 1 to 18, wherein the content of rotigotine or a pharmaceutically acceptable salt thereof is 1 to 50 mass% with respect to the whole drug-containing pressure-sensitive adhesive layer.   The transdermal absorption patch preparation according to any one of claims 1 to 18, wherein the content of rotigotine or a pharmaceutically acceptable salt thereof is 5 to 30% by mass with respect to the entire drug-containing adhesive layer.   The transdermal absorption patch preparation according to any one of claims 1 to 18, wherein the content of rotigotine or a pharmaceutically acceptable salt thereof is 7 to 20 mass% with respect to the whole drug-containing pressure-sensitive adhesive layer.   The rubber-based adhesive component is at least one selected from styrene / isoprene / styrene block copolymer, styrene / butadiene / styrene block copolymer, styrene / butadiene rubber, isoprene rubber, polyisobutylene, polybutene, butyl rubber and natural rubber. The percutaneous absorption type patch preparation according to claim 2.   The transdermal patch preparation according to claim 2 or 22, wherein the content of the rubber-based adhesive component is 1 to 98% by mass with respect to the entire drug-containing adhesive layer.   The transdermal patch preparation according to any one of claims 2 and 22, wherein the content of the rubber-based adhesive component is 5 to 70 mass% with respect to the entire drug-containing adhesive layer. The transdermal patch preparation according to claim 2 or 22, wherein the content of the rubber-based adhesive component is 10 to 60% by mass with respect to the entire drug-containing adhesive layer.