Transdermal preparation and its manufacturing method

Abstract

In the transdermal preparation and its manufacturing method according to the present invention, the transdermal preparation comprises a drug-containing adhesive layer containing rotigotine or a pharmaceutically acceptable salt thereof as an active ingredient; hydroxypropyl cellulose (HPC) as a crystallization inhibitor; and a silicone polymer adhesive.

Description

[Technical Field]

[0001] The present invention relates to a transdermal preparation containing rotigotine and a method for producing the same. [Background technology]

[0002] Rotigotine is a non-ergoline dopamine agonist used for the treatment of Parkinson's disease (PD) and restless legs syndrome (RLS). Rotigotine is commercially available in the form of a patch.

[0003] U.S. Patent No. US7413747B discloses a transdermal therapeutic system containing rotigotine in a self-adhesive matrix layer, where the matrix layer comprises an acrylate or silicone-based polymer adhesive. Commercially available patches containing rotigotine use silicone adhesives to improve rotigotine's skin delivery. However, due to the low solubility of rotigotine in silicone adhesives, rotigotine crystals easily precipitate when rotigotine-containing patches are stored at room temperature, making it difficult to ensure the shelf life required for commercial distribution. Patent WO2011 / 076879 attempts to prevent rotigotine crystal precipitation by adding a polyvinyl pyrrolidone polymer. However, despite these efforts, partial crystal formation still occurs in some commercially available products. Therefore, a method to solve this problem is needed. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Registered US Patent US7413747 [Patent Document 2] International Patent Publication WO2011 / 076879 Summary of the Invention [Problem to be solved by the invention]

[0005] Therefore, the present inventors have been conducting research in various fields to improve the storage stability of rotigotine-containing transdermal patches, and have discovered a transdermal formulation and a method for manufacturing the same, in which rotigotine remains dissolved in the formulation without crystallization even when a silicone adhesive is used, thereby completing the present invention. [Means for solving the problem]

[0006] The transdermal preparation according to the present invention contains rotigotine or a pharmaceutically acceptable salt thereof as an active ingredient; and hydroxypropyl cellulose as a crystallization inhibitor. The transdermal preparation according to the present invention may be a transdermal patch. In the present invention, rotigotine means (-)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthalenol, which is a compound represented by the following chemical formula 1.

[0007] [Chemical formula 1] [ka]

[0008] In the present invention, the pharmaceutically acceptable salt of rotigotine may be an organic acid salt, an inorganic acid salt, a metal salt, or the like, and is not particularly limited.

[0009] In the present invention, the transdermal preparation contains rotigotine or a pharmaceutically acceptable salt thereof at a concentration of 0.1 mg / cm as the free base of rotigotine. 2 ~1.0mg / cm 2 It may also include.

[0010] In the present invention, the transdermal preparation may contain 2 to 20% by weight of rotigotine or a pharmaceutically acceptable salt thereof as the free base, relative to 100% by weight of the total weight of the drug-containing adhesive layer of the transdermal preparation.

[0011] In the present invention, HPC is a crystallization inhibitor for rotigotine and refers to cellulose having a degree of substitution with hydroxypropoxyl groups of at least 20% by mass. For example, the HPC of the present invention may be cellulose having a degree of substitution with hydroxypropoxyl groups of at least 50% by mass.

[0012] In the present invention, HPC has excellent compatibility with silicone polymer adhesives and can exert an excellent effect of preventing crystal formation of the rotigotine component within the preparation.

[0013] In one embodiment, the molecular weight of the HPC of the present invention may be 40,000 to 1,000,000. For example, the molecular weight of the HPC of the present invention may be 40,000 to 280,000. Here, the molecular weight may refer to the weight-average molecular weight.

[0014] In one embodiment, the HPC of the present invention may have a viscosity of 2 to 4000 mPa·s as a 2% aqueous solution at 20°C. In the present invention, the content of the HPC may be 1 to 20 wt % relative to the total weight (100 wt %) of the drug-containing adhesive layer of the transdermal formulation. The total weight of the drug-containing adhesive layer refers to the total weight of the drug-containing adhesive composition after drying. The drug-containing adhesive composition contains rotigotine or a pharmaceutically acceptable salt thereof as an active ingredient; HPC as a crystallization inhibitor; a silicone polymer adhesive; and an organic solvent. The organic solvent may be an alcohol having 1 to 5 carbon atoms.

[0015] In one embodiment, the content of HPC may be 10 to 15 wt % relative to the total weight (100 wt %) of the drug-containing adhesive layer of the transdermal preparation.

[0016] In one embodiment, the weight ratio of rotigotine or its pharmaceutically acceptable salt as rotigotine to the weight of HPC (hereinafter referred to as the weight ratio of rotigotine to HPC) may be 1:0.1 to 1:10. For example, the weight ratio of rotigotine to HPC may be 1:1 to 1:5. Specifically, the weight ratio of rotigotine to HPC may be 1:1 to 1:2.

[0017] In one embodiment, the weight ratio of rotigotine to HPC may be 9:12 to 9:15.

[0018] In the present invention, the silicone-based pressure-sensitive adhesive can be any pressure-sensitive adhesive composition containing a silicone-based copolymer, without any particular limitations.

[0019] In one embodiment, the silicone adhesive of the present invention may include a standard decompression silicone adhesive containing dimethylsiloxane-treated trimethylated silica, an amine-resistant silicone adhesive, or a mixture thereof. For example, standard decompression silicone adhesives may include BIO-PSA 7-4401, BIO-PSA 7-4402, BIO-PSA 7-4501, BIO-PSA 7-4502, BIO-PSA 7-4601, BIO-PSA 7-4602, etc., and amine-resistant silicone adhesives may include BIO-PSA 7-4101, BIO-PSA 7-4102, BIO-PSA 7-4201, BIO-PSA 7-4202, BIO-PSA 7-4301, BIO-PSA 7-4302, etc., and these may be used alone or in combination. The silicone adhesive in the present invention may be a product of Dow Corning.

[0020] In the present invention, when the above-described HPC is used together with rotigotine and a silicone adhesive, crystallization of rotigotine can be prevented.

[0021] In one embodiment, the transdermal formulation of the present invention may further comprise a fatty acid.

[0022] In the present invention, the fatty acid may act as a solubilizing agent for rotigotine. In the present invention, the carboxyl group of the fatty acid increases the solubility of rotigotine in the formulation through ion pairing with the basic rotigotine molecule. The fatty acid of the present invention may have a carbon backbone of 4 to 28 carbon atoms. In one embodiment, the fatty acid of the present invention may have a carbon backbone of 6 to 22 carbon atoms, specifically, a carbon backbone of 12 to 18 carbon atoms. In one embodiment, the fatty acid of the present invention may be oleic acid.

[0023] In the present invention, the content of the fatty acid may be 0.01 to 5% by weight relative to the total weight (100% by weight) of the drug-containing adhesive layer.

[0024] In rotigotine or a pharmaceutically acceptable salt thereof, the ratio of the weight of rotigotine to the weight of fatty acid (hereinafter referred to as the weight ratio of rotigotine to fatty acid) may be 1:0.001 to 1:1. For example, the weight ratio of fatty acid to rotigotine may be 1:0.001 to 1:0.7. This range provides excellent skin delivery of the rotigotine component. This is because the fatty acid, acting as a solubilizer, optimally increases the solubility of the main component in the adhesive layer, allowing the rotigotine component in the patch, which delivers the drug by manual diffusion, to be efficiently delivered to the skin. Furthermore, in a transdermal patch, the adhesive layer and the backing layer are not physically separated, and can be maintained in a stably bonded state.

[0025] In one embodiment, the weight ratio of rotigotine to fatty acid may be 9:0.01 to 9:5. For example, the weight ratio of rotigotine to fatty acid may be 9:0.01 to 9:4 or 9:0.01 to 9:3. Within this range, rotigotine may not crystallize. Furthermore, within this range, crystallization does not occur in the transdermal patch, and the adhesive layer and the support layer are not physically separated, allowing them to remain stably bonded together.

[0026] In one embodiment, when the transdermal formulation further contains a fatty acid, the content of hydroxypropyl cellulose may be 10 to 15 wt % relative to the total weight of the drug-containing adhesive layer, and the content of the fatty acid may be 0.01 to 5 wt %, 0.01 to 4 wt %, or 0.01 to 3 wt %.

[0027] The transdermal preparation according to the present invention may further contain an antioxidant for the chemical stability of the main ingredient.

[0028] Examples of antioxidants include, but are not limited to, tocopherol, its esters or derivatives, ascorbic acid, ascorbyl palmitate, 2,5-dihydroxybenzoic acid, dibutyldihydroxytoluene (DHT), butylhydroxyanisole, propyl gallate, etc. These may be used alone or in combination of two or more.

[0029] The transdermal preparation of the present invention may further contain polyvinylpyrrolidone.

[0030] In one embodiment, the transdermal formulation of the present invention may further comprise a backing layer that serves as a base for the drug-containing adhesive layer; and a release layer (release liner) that protects the drug-containing adhesive layer and is removed immediately before use. The backing layer and release layer are disposed on both sides of the drug-containing adhesive layer, respectively, with the drug-containing adhesive layer interposed therebetween.

[0031] The method for producing a transdermal formulation according to the present invention comprises the steps of: coating a drug-containing adhesive composition on a support layer, the drug-containing adhesive composition comprising rotigotine or a pharmaceutically acceptable salt thereof as an active ingredient; HPC as a crystallization inhibitor; a silicone polymer adhesive; and an organic solvent; and The method includes a step of drying the drug-containing adhesive composition coated on the backing layer to form a drug-containing adhesive layer.

[0032] The organic solvent may contain an alcohol having 1 to 5 carbon atoms.

[0033] The active ingredient, the crystallization inhibitor, and the polymer adhesive contained in the drug-containing adhesive composition are substantially the same as those described in the adhesive layer of the transdermal preparation, and therefore, a detailed description thereof will be omitted.

[0034] (1) The transdermal preparation of the present invention comprises rotigotine or a pharmaceutically acceptable salt thereof as an active ingredient, hydroxypropyl cellulose (HPC) as a crystallization inhibitor, and a drug-containing adhesive layer containing a silicone polymer adhesive.

[0035] (2) In the above (1), the ratio of the weight of rotigotine or its pharmaceutically acceptable salt as rotigotine to the weight of HPC may be 1:0.1 to 1:10.

[0036] (3) In the above (1) or (2), the ratio of the weight of rotigotine or its pharmaceutically acceptable salt as rotigotine to the weight of HPC may be 9:12 to 9:15.

[0037] (4) In any one of the above (1) to (3), the drug-containing adhesive layer may further contain a fatty acid as a solubilizing agent.

[0038] (5) In the above (4), the ratio of the weight of rotigotine or its pharmaceutically acceptable salt as rotigotine to the weight of the fatty acid may be 9:0.01 to 9:5.

[0039] (6) In the above (4) or (5), the content of hydroxypropyl cellulose may be 10 to 15 wt % based on the total weight of the drug-containing adhesive layer, and the content of fatty acid may be 0.01 to 5 wt % based on the total weight of the drug-containing adhesive layer.

[0040] (7) In any one of the above (1) to (6), the content of hydroxypropyl cellulose may be 10 to 15 wt % based on the total weight of the drug-containing adhesive layer.

[0041] (8) In any one of the above (1) to (7), the drug-containing adhesive layer may further contain an antioxidant.

[0042] (9) In any one of the above (1) to (8), the drug-containing adhesive layer may further contain polyvinylpyrrolidone.

[0043] (10) In any one of the above (1) to (9), the preparation for transdermal absorption may be a transdermal patch.

[0044] (11) In any one of (1) to (10), the transdermal preparation may be a transdermal patch including a support layer and a release layer disposed on both sides of the drug-containing adhesive layer, respectively, with the drug-containing adhesive layer interposed therebetween.

[0045] (12) A method for producing a transdermal preparation according to the present invention includes the steps of: coating a transdermal composition on a support layer, the transdermal composition comprising rotigotine or a pharmaceutically acceptable salt thereof as an active ingredient; hydroxypropyl cellulose (HPC) as a crystallization inhibitor; a silicone polymer adhesive; and an organic solvent; and drying the drug-containing adhesive composition coated on the support layer to form a drug-containing adhesive layer.

[0046] (13) In the above (12), in the step of coating the composition for transdermal absorption on the support layer, the composition for transdermal absorption may further contain a fatty acid.

[0047] (14) In the above (12) or (13), the organic solvent may contain an alcohol having 1 to 5 carbon atoms. [Effects of the Invention]

[0048] The transdermal formulation of the present invention, even when used with a silicone polymer adhesive, can maintain a stable dissolved state without crystallization of the active ingredient rotigotine. Therefore, even in the drug-containing adhesive layer of a transdermal patch containing the same, rotigotine can be maintained in a stable dissolved state without crystallization, maximizing rotigotine's skin delivery. The transdermal formulation of the present invention also has excellent skin adhesion. In particular, the transdermal formulation of the present invention can improve initial adhesion by using both a silicone polymer adhesive and HPC. Furthermore, the adhesive layer and the backing layer can be maintained stably bonded without being physically separated, and when the transdermal formulation of the present invention is applied to the user's skin, the cold flow phenomenon, in which the silicone polymer adhesive remains on the skin surface, does not occur. [Brief explanation of the drawings]

[0049] [Figure 1] FIG. 1 is a micrograph of a transdermal patch according to an embodiment of the present invention. [Figure 2] FIG. 1 is a micrograph of a transdermal patch according to Comparative Example 1. [Figure 3] 1 is a graph showing the transdermal absorption performance of the transdermal patches according to Examples 4, 6 and 7 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0050] Hereinafter, the embodiments of the present invention will be described in detail. Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the art to which the present invention belongs. Terms defined in commonly used dictionaries should be interpreted in accordance with the context of the relevant art, and should not be interpreted in an idealized or overly formal sense unless expressly defined in this application. [Example]

[0051] Examples 1 to 24

[0052] Drug-containing adhesive layers having the compositions shown in Tables 1 to 4 below were prepared in the following manner. In Tables 1 to 4, the content of each component refers to the content of each component based on 100% by weight of the drug-containing adhesive layer.

[0053] First, HPC (Nisso HPC purchased from NIPPON SODA CO., LTD.) was placed in a 50 mL light-shielding vial as a crystallization inhibitor, and an appropriate amount of ethanol was added to dissolve the HPC. After that, the antioxidant and fatty acid dissolved in ethanol were mixed, and rotigotine was added and dissolved. Thereafter, a silicone polymer adhesive purchased from DuPont was added, and a magnetic bar was added and mixed for 1 hour to prepare a composition for transdermal absorption.

[0054] After leaving it for 30 minutes to remove air bubbles, the prepared transdermal composition was coated on a fluoropolymer-treated polyester (PET) film on a coating machine using a knife coater. After drying for 6 minutes in an oven at 80°C, a support film was laminated on the dried coating layer, pressed using a pressing roller, and then cut into patches with an area of ​​10 cm using a patch cutter. 2 A transdermal patch was produced as a transdermal absorption formulation.

[0055] [Table 1]

[0056] [Table 2]

[0057] [Table 3]

[0058] [Table 4]

[0059] Comparative Example 1

[0060] Comparative Example 1 was prepared using substantially the same process as in Examples 1 to 24, with the ingredients and compositions shown in Table 5, except that HPC and fatty acids were not used.

[0061] [Table 5]

[0062] Experimental Example 1: Evaluation of rotigotine crystal precipitation

[0063] The transdermal patches of Examples 1 to 24 and Comparative Example 1 were observed for crystal precipitation and cold flow (a phenomenon in which adhesive leaks out of the cut edge of the product) for 60 days.

[0064] As a result, it was confirmed that no crystals were precipitated in any of Examples 1 to 24 containing rotigotine and HPC, regardless of the antioxidant content or silicone adhesive content. Specifically, referring to Figure 1, which is a photograph of the transdermal patches according to Examples 1, 3, 8, 12, 14, 16, and 19 to 24, it can be seen that no crystals of rotigotine were precipitated.

[0065] Meanwhile, referring to FIG. 2, which is a photograph of the transdermal patch according to Comparative Example 1, it can be seen that in Comparative Example 1 without HPC, rotigotine crystals were precipitated.

[0066] It was also confirmed that the examples of the present invention did not exhibit the cold flow phenomenon in which the silicone polymer adhesive remains on the skin surface.

[0067] Experimental Example 2: In vitro percutaneous absorption experiment

[0068] To evaluate the transdermal absorption performance of the transdermal patch, a transdermal absorption experiment was conducted using a Franz cell (vertical diffusion cell) with a commercially available product (NEUPRO® (rotigotine transdermal system)) as a control drug. The results are shown in Figure 2.

[0069] 3, it can be seen that the transdermal patches of Examples 4, 6, and 7 exhibited substantially the same transdermal absorption performance as the control drug. While transdermal patches using acrylic adhesives and the like exhibit significantly reduced transdermal absorption performance, the present invention, as confirmed in Experimental Example 1, prevents crystal precipitation and maintains excellent transdermal absorption performance.

[0070] Although the present invention has been described above with reference to preferred embodiments, it will be understood by those skilled in the art that various modifications and variations of the present invention may be made without departing from the spirit and scope of the present invention as set forth in the following claims. [Industrial Applicability]

[0071] The transdermal preparation and the method for producing the same according to the present invention are While having the same percutaneous absorption performance as the rotigotine-containing product, the rotigotine can be kept in a completely dissolved state within the preparation, preventing precipitation, thereby achieving excellent therapeutic effects using rotigotine.

Claims

1. rotigotine or a pharmaceutically acceptable salt thereof as an active ingredient; Hydroxypropyl cellulose (HPC) as a crystallization inhibitor; and A transdermal preparation comprising a drug-containing adhesive layer containing a silicone polymer adhesive.

2. 2. The transdermal preparation according to claim 1, wherein the weight ratio of rotigotine or its pharmaceutically acceptable salt as rotigotine to HPC is 1:0.1 to 1:

10.

3. 2. The transdermal preparation according to claim 1, wherein the weight ratio of rotigotine or its pharmaceutically acceptable salt as rotigotine to HPC is 9:12 to 9:

15.

4. The transdermal preparation according to claim 1, wherein the drug-containing adhesive layer further comprises a fatty acid as a solubilizing agent.

5. 5. The transdermal preparation according to claim 4, wherein the ratio of the weight of rotigotine or its pharmaceutically acceptable salt as rotigotine to the weight of the fatty acid is 9:0.01 to 9:

5.

6. the content of hydroxypropyl cellulose is 10 to 15% by weight based on the total weight of the drug-containing adhesive layer; 5. The transdermal preparation according to claim 4, wherein the fatty acid is contained in an amount of 0.01 to 5% by weight based on the total weight of the drug-containing adhesive layer.

7. 2. The transdermal preparation according to claim 1, wherein the content of hydroxypropyl cellulose is 10 to 15% by weight based on the total weight of the drug-containing adhesive layer.

8. The transdermal preparation according to claim 1, wherein the drug-containing adhesive layer further comprises an antioxidant.

9. 2. The transdermal preparation according to claim 1, wherein the drug-containing adhesive layer further comprises polyvinylpyrrolidone.

10. 2. The transdermal preparation according to claim 1, wherein the transdermal preparation is a transdermal patch.

11. 2. The transdermal preparation according to claim 1, which is a transdermal patch comprising a support layer and a release layer disposed on both sides of the drug-containing adhesive layer with the drug-containing adhesive layer interposed therebetween.

12. a step of coating a composition for transdermal absorption on a support layer, the composition comprising rotigotine or a pharmaceutically acceptable salt thereof as an active ingredient; hydroxypropyl cellulose (HPC) as a crystallization inhibitor; a silicone-based polymer adhesive; and an organic solvent; and 2. A method for producing a transdermal formulation according to claim 1, comprising the step of drying the drug-containing adhesive composition coated on the support layer to form a drug-containing adhesive layer.

13. The method for producing a preparation for transdermal absorption according to claim 12, wherein in the step of coating the composition for transdermal absorption on a support layer, the composition for transdermal absorption further contains a fatty acid.

14. The method for producing a preparation for transdermal absorption according to claim 12, wherein the organic solvent contains an alcohol having 1 to 5 carbon atoms.

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