Transdermal absorption preparation and preparation method thereof

Abstract

In the transdermal absorption preparation according to the present invention and a method for preparing the same, the transdermal absorption preparation comprises a drug-containing adhesive layer comprising rotigotine or a pharmaceutically acceptable salt thereof as an active ingredient, hydroxy propyl cellulose (HPC) as a crystallization inhibitor, and a silicone-based polymer binder.

Description

Technical Field

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

[0002] Rotigotine is a non-ergoline dopamine agonist used for the treatment of Parkinson's disease (PD) and restless legs syndrome (RLS). This ingredient, rotigotine, is sold on the market in the form of a patch.

[0003] US 7,413,747 B discloses a transdermal therapeutic system containing rotigotine in a self-adhesive matrix layer, which matrix layer contains an acrylate or silicone-based polymer adhesive. In commercially available patches containing rotigotine, silicone adhesives are used to improve the transdermal permeability of rotigotine. However, due to the low solubility of rotigotine in silicone adhesives, when patches containing rotigotine are stored at room temperature, crystallization of rotigotine easily occurs, resulting in challenges in ensuring the shelf life required for commercial distribution. In WO 2011 / 076879 A, attempts were made to minimize the precipitation of rotigotine crystals by adding polyvinylpyrrolidone polymers. However, despite these efforts, partial crystallization problems still occur on some commercial products. Therefore, there is an urgent need for a method to solve such problems.

[0004] Related Technical Literature

[0005] Patent Literature

[0006] (Patent Document 0001): US Patent No. US 7,413,747 B

[0007] (Patent Document 0002): International Publication No. WO 2011 / 076879 A Summary of the Invention

[0008] Technical Problem

[0009] Therefore, the present inventors conducted various studies to improve the storage stability of transdermal patches containing rotigotine, and found a transdermal absorption preparation and a method for preparing the same, in which even when using a silicone adhesive, rotigotine does not crystallize and rotigotine exists in a dissolved state in the preparation, thus completing the present invention.

[0010] Technical Solution

[0011] The transdermal absorption preparation according to the present invention comprises a drug-containing adhesive layer, and the drug-containing adhesive layer contains rotigotine or a pharmaceutically acceptable salt thereof as an active ingredient; hydroxypropyl cellulose (HPC) as a crystallization inhibitor; and a silicone-based polymer adhesive. The transdermal absorption preparation according to the present invention may be a transdermal patch.

[0012] In the present invention, rotigotine refers to (-)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthol, that is, the compound represented by the following formula 1.

[0013] [Formula 1]

[0014]

[0015] In the present invention, the pharmaceutically acceptable salt of rotigotine may be an organic acid salt, an inorganic acid salt, a metal salt, etc., but is not particularly limited thereto.

[0016] In the present invention, the transdermal absorption preparation may contain rotigotine or a pharmaceutically acceptable salt thereof, and the content thereof is 0.1 mg / cm2 to 1.0 mg / cm2 in terms of rotigotine free base.

[0017] In the present invention, the transdermal absorption preparation may contain rotigotine or a pharmaceutically acceptable salt thereof, and the content thereof is 2% to 20% by weight of the total weight of the drug-containing adhesive layer in the transdermal absorption preparation in terms of rotigotine free base.

[0018] In the present invention, HPC is a crystallization inhibitor of rotigotine and refers to cellulose with a hydroxypropoxy substitution degree of at least 20% by mass or higher. For example, the HPC of the present invention may be cellulose with a hydroxypropoxy substitution degree of at least 50% by mass or higher.

[0019] In the present invention, HPC exhibits excellent compatibility with the silicone-based polymer adhesive and has a significant ability to inhibit the crystallization of rotigotine in the preparation.

[0020] 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. In this case, the molecular weight may refer to the weight average molecular weight.

[0021] In one embodiment, the viscosity of the HPC of the present invention in a 2% aqueous solution at 20 °C may be 2 to 4000 mPa·s.

[0022] In the present invention, the content of HPC may be 1% to 20% by weight relative to 100% by weight of the total weight of the drug-containing adhesive layer in the transdermal absorption preparation. The total weight of the drug-containing adhesive layer refers to the total weight of the drug-containing adhesive composition after drying. In this case, the drug-containing adhesive composition comprises: rotigotine or a pharmaceutically acceptable salt thereof as an active ingredient, HPC as a crystallization inhibitor, a silicone-based polymer adhesive, and an organic solvent. In this case, the organic solvent may be an alcohol having 1 to 5 carbon atoms.

[0023] In one embodiment, the content of HPC may be 10% to 15% by weight relative to 100% by weight of the total weight of the drug-containing adhesive layer in the transdermal absorption preparation.

[0024] In one embodiment, the weight ratio of rotigotine or a pharmaceutically acceptable salt thereof (calculated 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.

[0025] In one embodiment, the weight ratio of rotigotine to HPC may be 9:12 to 9:15.

[0026] In the present invention, the silicone-based adhesive can be used without particular limitation as long as it is an adhesive composition containing a silicone-based copolymer.

[0027] In one embodiment, the silicone-based adhesive in the present invention may include: a standard silicone pressure-sensitive adhesive containing trimethylated silica treated with dimethylsiloxane, an amine-resistant silicone adhesive, or a mixture thereof. Examples of the standard silicone pressure-sensitive adhesive include BIO-PSA 7-4401, BIO-PSA 7-4402, BIO-PSA 7-4501, BIO-PSA7-4502, BIO-PSA 7-4601, BIO-PSA 7-4602, etc.; examples of the amine-resistant silicone adhesive 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.; the listed components can be used alone or in combination of two or more. The silicone-based adhesive in the present invention may be a product manufactured by Dow Corning Corporation.

[0028] In the present invention, even when rotigotine and the above-mentioned HPC are used together with the silicone-based adhesive, crystallization of rotigotine can be inhibited.

[0029] In one embodiment, the transdermal absorption preparation according to the present invention may further comprise a fatty acid.

[0030] In the present invention, the fatty acid may act as a solubilizer for rotigotine. In the present invention, the carboxyl group of the fatty acid forms an ion pair with the basic rotigotine molecule, playing a role in increasing the solubility of rotigotine in the preparation. The fatty acid according to the present invention may have a main chain with 4 to 28 carbon atoms. In one embodiment, the fatty acid according to the present invention may have a main chain with 6 to 22 carbon atoms, particularly a main chain with 12 to 18 carbon atoms. In one embodiment, the fatty acid in the present invention may be oleic acid.

[0031] In the present invention, relative to 100% by weight of the total weight of the drug-containing adhesive layer, the content of the fatty acid may be 0.01% to 5% by weight.

[0032] The weight ratio of rotigotine or its pharmaceutically acceptable salt (calculated as rotigotine) to the weight of the 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 rotigotine to fatty acid may be 1:0.001 to 1:0.7. Within the above weight ratio range, the rotigotine component exhibits excellent transdermal permeability. As a solubilizer, the fatty acid optimally enhances the solubility of the active ingredient in the adhesive layer, enabling rotigotine to achieve excellent skin delivery within the patch preparation through passive diffusion. In addition, in the transdermal patch, the adhesive layer and the backing layer can maintain a stable bond without physical separation.

[0033] 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 the above weight ratio range, rotigotine does not crystallize. In addition, within the above weight ratio range, crystallization is avoided in the transdermal patch, and the adhesive layer and the backing layer can maintain a stable bond without physical separation.

[0034] In one embodiment, when the transdermal absorption preparation further comprises a fatty acid, relative to the total weight of the drug-containing adhesive layer, the content of hydroxypropyl cellulose may be 10% to 15% by weight, while the content of the fatty acid may be 0.01% to 5% by weight, 0.01% to 4% by weight, or 0.01% to 3% by weight.

[0035] The transdermal absorption preparation according to the present invention may further comprise an antioxidant for the chemical stability of the active ingredient.

[0036] Examples of antioxidants include tocopherols, their esters or derivatives, ascorbic acid, ascorbyl palmitate, 2,5-dihydroxybenzoic acid, dibutylhydroxytoluene (DHT), butylated hydroxyanisole, and propyl gallate, but are not particularly limited thereto. These may be used alone or in combination of two or more.

[0037] The transdermal absorption preparation according to the present invention may further contain polyvinylpyrrolidone.

[0038] In one embodiment, the transdermal absorption preparation of the present invention may further include: a backing layer as the base of the drug-containing adhesive layer; and a release film that protects the drug-containing adhesive layer and is removed immediately before use. The backing layer and the release film are disposed on two surfaces of the drug-containing adhesive layer such that the drug-containing adhesive layer is sandwiched therebetween.

[0039] The method for preparing the transdermal absorption preparation according to the present invention includes the following steps:

[0040] Coating a backing layer with a drug-containing adhesive composition, the composition containing 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

[0041] Drying the drug-containing adhesive composition coated on the backing layer to form a drug-containing adhesive layer.

[0042] The organic solvent may include an alcohol having 1 to 5 carbon atoms.

[0043] The active ingredient, crystallization inhibitor, and polymer adhesive contained in the drug-containing adhesive composition are the same as those described in the adhesive layer of the transdermal absorption preparation, respectively. Therefore, their redundant detailed descriptions will not be repeated.

[0044] (1) A transdermal absorption preparation, which includes a drug-containing adhesive layer, wherein the drug-containing adhesive layer contains: rotigotine or a pharmaceutically acceptable salt thereof as an active ingredient; hydroxypropyl cellulose (HPC) as a crystallization inhibitor; and a silicone-based polymer adhesive.

[0045] (2) According to (1), the weight ratio of rotigotine or a pharmaceutically acceptable salt thereof to HPC is 1:0.1 to 1:10 in terms of rotigotine.

[0046] (3) According to (1) or (2), the weight ratio of rotigotine or a pharmaceutically acceptable salt thereof to HPC is 9:12 to 9:15 in terms of rotigotine.

[0047] (4) According to any one of (1) to (3), the drug-containing adhesive layer further contains a fatty acid as a solubilizer.

[0048] (5) According to (4), the weight ratio of rotigotine or its pharmaceutically acceptable salt to fatty acid is 9:0.01 to 9:5 in terms of rotigotine.

[0049] (6) According to (4) or (5), the content of hydroxypropyl cellulose is 10% to 15% by weight relative to the total weight of the drug-containing adhesive layer, and the content of fatty acid is 0.01% to 5% by weight relative to the total weight of the drug-containing adhesive layer.

[0050] (7) According to any one of (1) to (6), the content of hydroxypropyl cellulose is 10% to 15% by weight relative to the total weight of the drug-containing adhesive layer.

[0051] (8) According to any one of (1) to (7), the drug-containing adhesive layer may further contain an antioxidant.

[0052] (9) According to any one of (1) to (8), the drug-containing adhesive layer may further contain polyvinylpyrrolidone.

[0053] (10) According to any one of (1) to (9), the transdermal absorption preparation may be a transdermal patch.

[0054] (11) According to any one of (1) to (10), the transdermal absorption preparation may be a transdermal patch, which comprises a backing layer and a release liner respectively disposed on two surfaces of the drug-containing adhesive layer, such that the drug-containing adhesive layer is sandwiched between the backing layer and the release liner.

[0055] (12) A method for preparing a transdermal absorption preparation according to the present invention, the method comprising the steps of: coating a backing layer with a transdermal absorption composition, the composition comprising rotigotine or its pharmaceutically acceptable salt as an active ingredient, hydroxypropyl cellulose (HPC) as a crystallization inhibitor, a silicone-based polymer adhesive, and an organic solvent; and drying the drug-containing adhesive composition coated on the backing layer to form a drug-containing adhesive layer.

[0056] (13) According to (12), in the step of coating the backing layer with the transdermal absorption composition, the transdermal absorption composition may further contain a fatty acid.

[0057] (14) According to (12) or (13), the organic solvent comprises an alcohol having 1 to 5 carbon atoms.

[0058] Beneficial effects

[0059] The transdermal preparation according to the present invention can stably maintain the active ingredient rotigotine in a dissolved state without crystallization even when used together with a silicone-based polymer adhesive. Therefore, rotigotine can be stably dissolved in the drug-containing adhesive layer of the transdermal patch containing the silicone-based polymer adhesive without precipitating in the form of crystals, while maximizing the transdermal delivery of rotigotine. In addition, the transdermal preparation according to the present invention also exhibits excellent skin adhesiveness. Specifically, the transdermal absorption preparation according to the present invention can improve the initial adhesiveness by using the silicone-based polymer adhesive together with HPC. In addition, the preparation can maintain a stable bond between the adhesive layer and the backing layer without physical separation. When the transdermal preparation according to the present invention is applied to the skin of a user, no cold flow phenomenon of the silicone-based polymer adhesive remaining on the skin contact surface is observed. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 A micrograph of a transdermal patch according to an embodiment of the present invention is shown.

[0061] Figure 2 A micrograph of a transdermal patch according to Comparative Example 1 is shown.

[0062] Figure 3 Graphs showing the transdermal absorption performance of the transdermal patches according to Examples 4, 6, and 7 of the present invention are shown. DETAILED DESCRIPTION OF THE INVENTION

[0063] Embodiments of the present invention will be described in detail below. Unless otherwise specified, all terms used herein, including technical or scientific terms, have the meanings commonly understood by those of ordinary skill in the art to which the present invention pertains. Terms defined in a general dictionary should be interpreted as having a meaning consistent with the context of the related art, and should not be interpreted in an idealized or overly formal sense unless explicitly defined as such in the present application.

[0064] Examples 1 to 24

[0065] A drug-containing adhesive layer having the compositions shown in Tables 1 to 4 below was prepared in the following order. In Tables 1 to 4, the content of each component refers to the content of that component relative to 100% by weight of the total weight of the drug-containing adhesive layer.

[0066] First, HPC (Nisso HPC, purchased from NIPPON SODACO., Ltd.), which is a crystallization inhibitor, was added to a 50 mL light-shielded vial. An appropriate amount of ethanol was added to dissolve HPC. The antioxidant dissolved in ethanol was mixed with a fatty acid, rotigotine was added and dissolved, and then a silicone-based polymer adhesive purchased from DuPont de Nemours, Inc. was added. Then, the mixture was mixed with a magnetic stir bar for one hour to prepare a transdermal absorption composition.

[0067] Thereafter, the prepared transdermal absorption composition was allowed to stand for 30 minutes to remove air bubbles, and the fluoropolymer-treated polyester (PET) film was coated with the above-prepared transdermal absorption composition using a knife coater on a coater. Then, the coating was dried in an oven at 80 °C for 6 minutes, the backing layer film was applied to the dried coating, pressed together with a pressing roller, and cut into an area of 10 cm2 using a patch cutter to prepare a transdermal patch as a transdermal absorption preparation.

[0068] [Table 1]

[0069]

[0070] [Table 2]

[0071]

[0072] [Table 3]

[0073]

[0074]

[0075] [Table 4]

[0076]

[0077] Comparative Example 1

[0078] Comparative Example 1 was prepared according to substantially the same steps as in Examples 1 to 24, and the components and composition were based on Table 5, except that HPC and fatty acids were not used.

[0079] [Table 5]

[0080]

[0081] Experimental Example 1: Evaluation of Rotigotine Crystallization

[0082] The transdermal patches prepared in Examples 1 to 24 and Comparative Example 1 above were observed for 60 days for crystallization and cold flow (the phenomenon of the adhesive oozing to the edges of the product cut surface).

[0083] The results confirmed that in any of Examples 1 to 24 containing rotigotine and HPC, crystallization did not occur regardless of the antioxidant content or the silicone adhesive content. Specifically, referring to Figure 1 the photographs of the transdermal patches according to Examples 1, 3, 8, 12, 14, 16, and 19 to 24 shown, it was confirmed that rotigotine did not crystallize.

[0084] In contrast, referring to Figure 2The photograph of the transdermal patch according to Comparative Example 1 shown can confirm that crystal precipitation of rotigotine occurred in Comparative Example 1 without using HPC.

[0085] In addition, it was also confirmed that cold flow phenomenon of the silicone-based polymer adhesive remaining on the skin adhesion surface did not occur in the examples of the present invention.

[0086] Experimental Example 2: In vitro transdermal absorption experiment

[0087] To evaluate the transdermal absorption performance of the transdermal patch, a transdermal absorption experiment was conducted using a Franz diffusion cell (vertical diffusion cell), with a commercially available product ( (Rotigotine transdermal system)) as the control drug, and the results are as Figure 2 shown.

[0088] Reference Figure 3 , it can be confirmed that the transdermal patches according to Examples 4, 6, and 7 exhibit transdermal absorption performance substantially equivalent to that of the control drug. Although transdermal patches using acrylic adhesives etc. exhibit significantly reduced transdermal absorption performance, it can be confirmed that the present invention can prevent crystal precipitation as confirmed in Experimental Example 1 while maintaining excellent transdermal absorption performance.

[0089] Although the present invention has been described with reference to preferred exemplary embodiments, those skilled in the art should understand that various changes and modifications can be made to the present invention without departing from the spirit and scope of the present invention (as described in the appended claims).

[0090] Industrial applicability

[0091] According to the transdermal absorption preparation and its preparation method of the present invention, even if rotigotine is included as an active ingredient in the preparation and remains in a completely dissolved state, it can provide the same transdermal absorption performance as the commercial product, thereby minimizing precipitation to obtain an excellent therapeutic effect of using rotigotine.

Claims

1. A transdermal absorption preparation, which comprises a drug-containing adhesive layer, wherein the drug-containing adhesive layer comprises: rotigotine or a pharmaceutically acceptable salt thereof as an active ingredient, hydroxypropyl cellulose (HPC) as a crystallization inhibitor, and a silicone-based polymer adhesive.

2. The transdermal absorption preparation according to claim 1, wherein the weight ratio of rotigotine or a pharmaceutically acceptable salt thereof to the HPC is 1:0.1 to 1:10 based on rotigotine.

3. The transdermal absorption preparation according to claim 1, wherein the weight ratio of rotigotine or a pharmaceutically acceptable salt thereof to the HPC is 9:12 to 9:15 based on rotigotine.

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

5. The transdermal absorption preparation according to claim 4, wherein the weight ratio of rotigotine or a pharmaceutically acceptable salt thereof to the fatty acid is 9:0.01 to 9:5 based on rotigotine.

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

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

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

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

11. The transdermal absorption preparation according to claim 1, wherein the transdermal absorption preparation is a transdermal patch, and the transdermal patch comprises a backing layer and a release liner respectively disposed on two surfaces of the drug-containing adhesive layer, such that the drug-containing adhesive layer is sandwiched between the backing layer and the release liner.

12. A method for preparing the transdermal absorption preparation according to claim 1, the method comprising the following steps: Coating a backing layer with a transdermal absorption composition, 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 Drying the drug-containing adhesive composition coated on the backing layer to form a drug-containing adhesive layer.

13. The method for preparing a transdermal absorption preparation according to claim 12, wherein in the step of coating the backing layer with the transdermal absorption composition, the transdermal absorption composition further comprises a fatty acid.

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

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