Rotigotine patch

Abstract

To provide a patch containing rotigotine as an active ingredient, capable of suppressing crystal deposition, having good drug stability and good adhesiveness.SOLUTION: The patch comprises a support layer and an adhesive layer, wherein the adhesive layer contains rotigotine or a pharmaceutically acceptable salt thereof, a rubber-based adhesive, and hydroxypropyl cellulose.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a rotigotine-containing patch. [Background technology]

[0002] Rotigotine is a dopamine receptor agonist and is primarily used to treat the symptoms of Parkinson's disease and restless leg syndrome. TM The "rotigotine patch" is sold both domestically and internationally. In addition to this, various other rotigotine patches have been investigated.

[0003] Rotigotine is a highly polar component, so patches using low-polarity adhesives such as rubber-based or silicone-based adhesives have the problem of precipitation of rotigotine crystals in the adhesive layer. To solve this problem, for example, Patent Document 1 discloses a method for stabilizing rotigotine, which includes a step of blending polyvinylpyrrolidone with rotigotine at a specific weight ratio to provide a solid dispersion containing polyvinylpyrrolidone and amorphous rotigotine. Patent Document 2 describes a patch in which crystal precipitation is suppressed by blending rotigotine with a rosin-based resin in a rubber-based adhesive. Patent Document 3 describes a patch in which crystal precipitation is suppressed by blending rotigotine with oleic acid. Patent Document 4 describes a patch in which crystal precipitation is suppressed by mixing rotigotine with an antioxidant in a specific mass ratio. Patent Document 5 describes a patch in which crystal precipitation is suppressed by blending crosslinked polyvinylpyrrolidone in a rubber-based adhesive. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Special Publication No. 2013-515041 [Patent Document 2] Japanese Patent Application Laid-Open No. 2014-177428 [Patent Document 3] Special Publication No. 2015-522012 [Patent Document 4] Special Publication No. 2017-515871 [Patent Document 5] Re-tabled publication No. 2019-124261 Summary of the Invention [Problem to be solved by the invention]

[0005] However, even in patches in which rotigotine crystal precipitation is suppressed, there is a problem that the stability of the drug is poor, and decomposition products and related substances are generated after a certain period of storage. Furthermore, when a solubilizer or the like is added to suppress crystal precipitation, the physical properties of the adhesive layer are affected, resulting in a deterioration in adhesiveness. For this reason, it has been difficult to obtain a preparation that suppresses crystal precipitation while satisfying the other performance requirements of a patch, i.e., good adhesiveness and drug stability. Therefore, an object of the present invention is to provide a patch containing rotigotine as an active ingredient, which can suppress crystal precipitation, has good drug stability, and has good adhesiveness. [Means for solving the problem]

[0006] In order to solve the above problems, the present inventors have conducted extensive research and found that the inclusion of hydroxypropyl cellulose in a patch containing rotigotine and a rubber-based adhesive as a base component can suppress crystal precipitation. Furthermore, they have found that the production of related substances can be suppressed under harsh conditions without the addition of an antioxidant, and that the patch also has good drug stability and good adhesiveness (tackiness), thereby completing the present invention.

[0007] That is, the present invention provides the following [1] to [5]. [1] A patch having a support layer and an adhesive layer, A patch, wherein the adhesive layer contains rotigotine or a pharmaceutically acceptable salt thereof, a rubber-based adhesive, and hydroxypropyl cellulose. [2] The patch according to [1], wherein the content of hydroxypropyl cellulose in the adhesive layer is 2.5% by mass or more and 15% by mass or less. [3] The patch according to [1] or [2], wherein the mass ratio of rotigotine or a pharmaceutically acceptable salt thereof to hydroxypropyl cellulose in the adhesive layer is 1:0.3 to 1:2 in terms of free rotigotine:hydroxypropyl cellulose. [4] The patch according to any one of [1] to [3], wherein the rubber-based adhesive layer is a styrene-isoprene-styrene block copolymer. [5] The patch according to any one of [1] to [4], wherein the adhesive layer contains a tackifier resin, and the tackifier resin contains at least an alicyclic saturated hydrocarbon resin. [Effects of the Invention]

[0008] The patch of the present invention inhibits the crystallization of rotigotine, and even without the incorporation of an antioxidant as in conventional techniques, it can inhibit the formation of related substances under harsh conditions, has good drug stability, and exhibits good adhesiveness (tackiness). DETAILED DESCRIPTION OF THE INVENTION

[0009] Terms used in this specification are used in the sense commonly used in the art unless otherwise specified.

[0010] One aspect of the patch of the present invention is a patch having a support layer and an adhesive layer, characterized in that the adhesive layer contains rotigotine or a pharmaceutically acceptable salt thereof, a rubber-based adhesive, and hydroxypropyl cellulose.

[0011] Rotigotine is the active ingredient of the patch of the present invention, and is a dopamine receptor agonist that is primarily used to treat the symptoms of Parkinson's disease and restless legs syndrome. The adhesive layer contains rotigotine or a pharmaceutically acceptable salt thereof as an active ingredient. In the present invention, the rotigotine contained in the adhesive layer may be in the free form or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts of rotigotine include hydrochloride, sulfate, nitrate, phosphate, hydrobromide, maleate, etc. Among these, the free form is particularly preferred because it exhibits good transdermal absorbability. The content of rotigotine or a pharmaceutically acceptable salt thereof in the adhesive layer is preferably 5 to 15% by mass, more preferably 5 to 10% by mass, calculated as the free form of rotigotine, from the viewpoints of maintaining the transdermal absorbability of rotigotine or a pharmaceutically acceptable salt thereof and preventing crystal precipitation of rotigotine or a pharmaceutically acceptable salt thereof during storage. Furthermore, when fentanyl, oxybutynin, fesoterodine, tetracaine or enalapril is used in place of rotigotine, the same effects as those of the present invention can be obtained.

[0012] The adhesive used in the adhesive layer of the patch of the present invention is preferably a rubber-based adhesive from the viewpoints of adhesiveness, shape retention of the adhesive layer, and prevention of peeling of the patch. Examples of rubber-based adhesives include styrene-isoprene-styrene block copolymer (SIS), polyisobutylene (PIB), polyisoprene, polybutadiene, styrene-butadiene-styrene block copolymer, styrene-isoprene rubber, styrene-butadiene rubber, crude rubber, etc. Among these, styrene-isoprene-styrene block copolymer (SIS) is preferred because it exhibits good adhesive properties. Examples of styrene-isoprene-styrene block copolymers include D1111, D1113, D1119, D1161, and D1165 manufactured by Kraton Corporation; SIS5002, SIS5229, SIS5250, SIS5505, and SIS5505P manufactured by JSR Corporation; and Quintac 3620, Quintac 3433, Quintac 3520, Quintac 3450, and Quintac 3280 manufactured by Zeon Corporation. The content of the rubber-based adhesive in the adhesive layer is preferably 10 to 30% by mass, more preferably 15 to 25% by mass, from the viewpoint of the shape retention of the adhesive layer and prevention of peeling of the patch.

[0013] By containing hydroxypropyl cellulose in addition to the rotigotine or a pharmaceutically acceptable salt thereof and a rubber-based adhesive in the adhesive layer of the patch of the present invention, it is possible to prevent the precipitation of crystals of rotigotine or a pharmaceutically acceptable salt thereof, suppress the production of related substances, and provide good adhesiveness (tackiness). Hydroxypropyl cellulose (HPC) is a hydroxypropyl ether of cellulose, and preferably contains 53.4 to 77.5% by mass of hydroxypropoxyl groups. Like general polymeric substances, the viscosity of the solution in which hydroxypropyl cellulose is dissolved varies depending on the degree of polymerization of the molecules. Various hydroxypropyl celluloses conforming to the Japanese Pharmacopoeia can be used. Examples of commercially available products include the following: HPC-SSL (trade name, manufactured by Nippon Soda Co., Ltd., kinematic viscosity of 2% by weight aqueous solution at 20°C: 2.0 to 2.9 mPa·s, average molecular weight: approximately 40,000), HPC-SL (trade name, manufactured by Nippon Soda; kinematic viscosity of a 2% by weight aqueous solution at 20°C: 3.0 to 5.9 mPa·s; average molecular weight: approximately 100,000), HPC-L (trade name, manufactured by Nippon Soda; kinematic viscosity of a 2% by weight aqueous solution at 20°C: 6.0 to 10.0 mPa·s; average molecular weight: approximately 140,000), HPC-M (trade name, manufactured by Nippon Soda; kinematic viscosity of 2% by mass aqueous solution at 20°C: 150 to 400 mPa·s; average molecular weight: approximately 620,000). Among these, those having a kinematic viscosity of 2.0 to 10.0 mPa·s in a 2% by mass aqueous solution at 20° C. are preferably used. Such hydroxypropyl cellulose is easily soluble in ethanol, allowing for a reduction in the amount of ethanol used in preparing the coating liquid, resulting in good manufacturability. The content of hydroxypropyl cellulose in the adhesive layer is preferably 2.5 to 15% by mass, more preferably 2.5 to 12.5% ​​by mass, and even more preferably 5 to 12.5% ​​by mass, from the viewpoints of preventing crystal precipitation of rotigotine or a pharmaceutically acceptable salt thereof, suppressing the production of related substances, and imparting good adhesiveness (tackiness). Furthermore, the mass ratio of rotigotine or a pharmaceutically acceptable salt thereof to hydroxypropyl cellulose in the adhesive layer is preferably 1:0.3 to 1:2, and more preferably 1:0.3 to 1:1.7, in terms of free rotigotine:hydroxypropyl cellulose, from the viewpoints of preventing crystal precipitation of rotigotine or a pharmaceutically acceptable salt thereof, suppressing the production of related substances, and imparting good adhesiveness (tackiness).

[0014] The adhesive layer of the patch of the present invention may contain, in addition to the above-mentioned components, a tackifying resin, a plasticizer, a transdermal absorption enhancer, an antioxidant, an excipient, and the like. Examples of tackifying resins include alicyclic saturated hydrocarbon resins, aliphatic saturated hydrocarbon resins, hydrogenated rosin glycerin esters, rosin, terpene resins, ester gums, and phenolic resins. Among these, from the viewpoint of improving the stability of the drug, it is preferable to include at least an alicyclic saturated hydrocarbon resin. Furthermore, an alicyclic saturated hydrocarbon resin and a rosin-based resin may be used in combination. The alicyclic saturated hydrocarbon resin is a resin that is a homopolymer or copolymer of an alicyclic saturated hydrocarbon monomer. Commercially available alicyclic saturated hydrocarbon resins include Alcon P-70, Alcon P-85, Alcon P-90, Alcon P-100, Alcon P-115, and Alcon P-125 (all trade names, manufactured by Arakawa Chemical Industries, Ltd.). The content of the tackifier resin in the pressure-sensitive adhesive layer is preferably from 20 to 50% by mass, more preferably from 25 to 45% by mass.

[0015] Examples of the plasticizer include polybutene, liquid paraffin, light liquid paraffin, medium-chain fatty acid triglyceride, triacetin, squalane, squalene, and castor oil. Among these, liquid paraffin is preferred because it exhibits good adhesive properties. The content of the plasticizer in the adhesive layer is preferably 20 to 50% by mass, and more preferably 20 to 40% by mass.

[0016] Examples of the percutaneous absorption enhancer include fatty acid esters such as isopropyl myristate, butyl myristate, isopropyl palmitate, isopropyl isostearate, diethyl sebacate, diisopropyl sebacate, and diethyl adipate; polyhydric alcohol fatty acid esters such as propylene glycol monocaprylate and propylene glycol dicaprylate; and aliphatic alcohols such as lauryl alcohol.

[0017] The patch of the present invention has good stability of rotigotine even without the addition of an antioxidant. However, from the viewpoint of improving the stability of the patch as a whole, for example, by suppressing discoloration of the adhesive layer, an antioxidant may be added. Examples of antioxidants include dibutylhydroxytoluene, butylhydroxyanisole, benzotriazole, mercaptobenzimidazole, sodium edetate, sulfites, and hydrogen sulfites.

[0018] Examples of excipients include kaolin, talc, bentonite, light anhydrous silicic acid, anhydrous silicic acid, aluminum silicate, titanium oxide, zinc oxide, starch acrylate, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, povidone, and sodium polyacrylate.

[0019] The patch of the present invention has a pressure resistance of 30 N / cm from the viewpoint of preventing peeling or rolling up after application. 2 It is preferable that the tack value is equal to or greater than this.

[0020] Examples of the backing for the patch of the present invention include a single plastic film such as polyethylene terephthalate, polyethylene, polypropylene, nylon, or ethylene vinyl alcohol. These plastic films may be subjected to discharge corona treatment, sandblasting, or anchor coating to facilitate attachment of the adhesive layer. Alternatively, a film laminated with a nonwoven fabric such as polyethylene terephthalate, polyethylene, or polypropylene may also be used.

[0021] The adhesive patch of the present invention preferably has a release liner on the adhesive layer side. Examples of the release liner include plastic films such as polyethylene terephthalate, polyethylene, and polypropylene that have been treated with silicone or fluorine.

[0022] Methods for producing the patch of the present invention include the solvent method, in which each component is dissolved / mixed in an organic solvent such as toluene, hexane, or ethyl acetate, and then the organic solvent is evaporated after coating, and the hot melt method, in which the base component is thermally melted, and then the active ingredient and other ingredients are added, and the mixture is coated. Of these, the solvent method is preferred because it can reduce the thermal load on the drug. When using the solvent method, a preferred method is to separately prepare a base solution containing a pressure-sensitive adhesive, a tackifying resin, and a plasticizer, and an active ingredient solution containing an active ingredient and hydroxypropyl cellulose, and then mix them to form a coating liquid.

[0023] Various organic solvents can be used as the solvent for the base solution, including toluene, ethyl acetate, butyl acetate, hexane, heptane, tetrahydrofuran, etc. Among these, toluene or ethyl acetate is preferred because they have a boiling point suitable for production and have good solubility for the base components. The solvent for the active ingredient solution is preferably a mixture of an organic solvent and a lower alcohol (having 1 to 3 carbon atoms). The lower alcohol can dissolve highly polar hydroxypropyl cellulose and the drug. However, a mixture with an organic solvent is preferred because the amount of liquid required to dissolve the solid ingredients is insufficient when using only the lower alcohol, and because it allows for rapid mixing when added to the base solution. Examples of lower alcohols include methanol, ethanol, 1-propanol, and 2-propanol. Among these, ethanol is preferred because it can dissolve rotigotine and hydroxypropyl cellulose and is less irritating to the skin. That is, the solvent for the active ingredient solution is preferably a mixture of ethanol and one or more organic solvents selected from the group consisting of toluene, ethyl acetate, butyl acetate, hexane, heptane, and tetrahydrofuran. Among these, a mixture of ethanol and ethyl acetate and / or toluene is particularly preferred because it reduces skin irritation and provides good drug solubility.

[0024] The mass ratio of organic solvent to ethanol in the coating solution, which is a mixture of the base solution and the active ingredient solution, is preferably adjusted appropriately depending on the organic solvent used. When the organic solvent is ethyl acetate, the ratio is preferably 1:0.01 to 1:0.09. When the organic solvent is toluene, the ratio is preferably 1:0.12 to 1:0.45. [Example]

[0025] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0026] The patches of Examples 1 to 22 shown in Tables 1 to 3 were prepared by the following method. (Preparation of coating liquid) (1) Liquid paraffin (HYDROBRITE 380 PO, manufactured by Sonneborn), styrene-isoprene-styrene block copolymer (SIS5505P, manufactured by JSR Corporation), and alicyclic saturated hydrocarbon resin (Arcon P-100, manufactured by Arakawa Chemical Industries, Ltd.) were added to ethyl acetate or toluene, and the mixture was stirred and mixed at 60°C to prepare a base solution. (2) Hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda Co., Ltd.) and rotigotine were added to a mixture of ethyl acetate or toluene and ethanol, and the mixture was stirred and mixed at 80°C to prepare a solution of the active ingredient. The above (1) base solution and (2) active ingredient solution were mixed with stirring at 80°C to obtain a coating liquid.

[0027] (Coating, drying, cutting) The coating solution cooled to room temperature (25°C) was applied onto a liner (a silicone-treated PET film) and dried at 70°C to remove the solvent. A support was attached to the resulting adhesive layer, and a sheet of a predetermined size (5 cm 2 ) to obtain patches. The amount of coating was adjusted so that the amount of rotigotine per patch was 2.25 mg. The obtained patches were packaged individually in aluminum bags. Comparative Example 1 was prepared in the same manner as in Example 1, except that hydroxypropyl cellulose was not used. Comparative Example 2 was prepared in the same manner as in Example 1, except that polyvinylpyrrolidone (PVP K30, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was used instead of hydroxypropyl cellulose. Comparative Example 3 was prepared in the same manner as in Example 1, except that hydroxypropyl methylcellulose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.) was used instead of hydroxypropyl cellulose. Comparative Example 4 was prepared in the same manner as in Example 1, except that a rosin-based resin (KE-311, manufactured by Arakawa Chemical Industries, Ltd.) was used instead of the alicyclic saturated hydrocarbon resin.

[0028] (Confirmation of crystal precipitation) The packaged patches were stored at 25°C. After one month, the presence or absence of rotigotine crystals in the adhesive layer was determined by peeling off the liner to expose the adhesive surface, and observing the adhesive surface from the adhesive side using an optical microscope. Crystal precipitation was observed in two locations: the outer periphery (edge) of the adhesive surface, and the inner portion (inside) of the outer periphery, and was evaluated according to the following scores. ◯: No crystal precipitation is observed at either the edge or the inside of the applied surface, or if any, it is slight. ×: Crystals were precipitated over the entire surface of the applied surface.

[0029] (Drug stability test) The packaged patches were stored for 3 weeks at 60°C. After that, the rotigotine content and decomposition products in the adhesive layer were measured by high performance liquid chromatography to evaluate the drug stability.

[0030] (Adhesion test) The prepared patches were subjected to a probe tack test using a texture analyzer (manufactured by Eiko Seiki Co., Ltd., model number: XTPL / 5) to measure the tack value. A stainless steel probe (diameter 5 mm, material SUS304, surface roughness Rq 250-500 nm) was used. The probe was brought into contact with the patch surface at a speed of 0.5 ± 0.01 mm per second, and a force of 0.98 ± 0.01 N / cm was applied. 2 The probe was held at this contact load for 1.0±0.1 seconds. Immediately afterwards, the probe was peeled off perpendicularly from the adhesive surface at a speed of 10±0.01 mm per second. The maximum load required for peeling was measured.

[0031] (Skin permeability test) Skin removed from the abdomen of a hairless mouse was mounted in a Franz diffusion cell. A patch was applied to the stratum corneum side, and isotonic phosphate buffer (pH 7.4) was applied to the dermis side. During the test, the isotonic phosphate buffer in the receptor phase was kept at a constant temperature of 32°C. 1.0 mL of the solution was collected at designated times and immediately replaced with the same volume of isotonic phosphate buffer. Rotigotine in the collected samples was quantified using high-performance liquid chromatography. The cumulative amount of rotigotine permeated per unit area at 24 hours was calculated as a relative value, with the value for a 2.25 mg Neupro Patch (Otsuka Pharmaceutical) set at 1.

[0032] (Confirmation of manufacturability) For Examples 1 to 4 and Comparative Examples 1 to 4, the properties of the coating liquids prepared according to each formulation were evaluated. In Examples 5 to 22, the properties of the coating liquid were evaluated when only the composition of the preparation solvent was changed for the same formulation. The coating liquid was visually inspected immediately after preparation and evaluated according to the following scores. ○: No localization of components, uniform. ×: Aggregation, separation, sedimentation, etc. occurred, and the components were localized to such an extent that coating was hindered.

[0033] (Result 1: Rotigotine crystal precipitation) As can be seen from Table 1, in Examples 1 to 4 containing hydroxypropyl cellulose, crystal precipitation was suppressed. On the other hand, in Comparative Example 1, which did not contain hydroxypropyl cellulose, and Comparative Example 3, which contained hydroxypropyl methylcellulose, crystals were precipitated over the entire application surface. In Comparative Example 2, which contained polyvinylpyrrolidone, crystal precipitation was suppressed, but the amount of related substances (total amount) produced tended to be large, and the tack strength was also 30 N / cm. 2 In Comparative Example 4, in which only a rosin-based resin was used as the tackifier resin, crystal precipitation was suppressed, but the drug stability was poor and the skin permeability was also low. The prepared coating liquids were homogeneous for all of the preparations of Examples 1 to 4 and Comparative Examples 1 to 4 in Table 1. Furthermore, no crystal precipitation was observed on the application surface immediately after production.

[0034] (Result 2: Drug stability) As shown in Table 1, Examples 1 to 4, which contain hydroxypropyl cellulose, all showed high drug retention rates of 98.0% or more, despite not containing any antioxidants. Furthermore, Examples 1 to 4 also showed reduced production of related substances (total amount) compared to the preparations of Comparative Examples 1 and 2. Furthermore, a comparison between Comparative Examples 1 and 4 reveals that the drug stability of rotigotine decreases when only a rosin-based resin is used as a tackifier resin. In other words, it is believed that drug stability can be improved by including an alicyclic saturated hydrocarbon resin in the tackifier resin.

[0035] (Result 3: Adhesion (tackiness)) From Table 1, Examples 1 to 4 containing hydroxypropyl cellulose had a compressive strength of 30 N / cm 2On the other hand, Comparative Examples 1 to 4 showed a tack value of 30 N / cm 2 It was less than. The patch should be applied to the skin with a pressure of 30N / cm to prevent peeling or rolling up. 2 It is desirable that the tack value be equal to or greater than this.

[0036] (Result 4: Skin permeability) From Examples 1 to 4 in Table 1, it was found that increasing the amount of hydroxypropyl cellulose added tended to improve skin permeability.

[0037] (Result 5: Manufacturability) Tables 2 and 3 show the properties of the coating solution when a mixture of ethyl acetate and ethanol was used as the solvent, and when a mixture of toluene and ethanol was used as the solvent. In both cases, there was no localization of components in the coating solution, and uniform coating was possible.

[0038] [Table 1]

[0039] [Table 2]

[0040] [Table 3]

Claims

1. A patch having a support layer and an adhesive layer, A patch, wherein the adhesive layer contains rotigotine or a pharmaceutically acceptable salt thereof, a rubber-based adhesive, and hydroxypropyl cellulose.

2. 2. The patch according to claim 1, wherein the content of hydroxypropyl cellulose in the adhesive layer is from 2.5% by mass to 15% by mass.

3. 2. The patch according to claim 1, wherein the mass ratio of rotigotine or a pharmaceutically acceptable salt thereof to hydroxypropyl cellulose in the adhesive layer is 1:0.3 to 1:2, in terms of free rotigotine:hydroxypropyl cellulose.

4. 2. The patch according to claim 1, wherein the rubber-based adhesive layer is a styrene-isoprene-styrene block copolymer.

5. 2. The patch according to claim 1, wherein the adhesive layer contains a tackifier resin, and the tackifier resin contains at least an alicyclic saturated hydrocarbon resin.

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