A hot-melt loxoprofen sodium patch and its preparation method

Abstract

The invention discloses a hot-melt loxoprofen sodium patch and a preparation method thereof. The hot-melt loxoprofen sodium patch comprises a backing layer, an adhesive layer and a protective layer. The adhesive layer comprises, by weight percentage, 5-6% of loxoprofen sodium or a hydrate thereof, 19-26% of a styrene-isoprene-styrene block copolymer, 5-15% of polyisobutylene, 5-15% of hydrogenated rosin glycerol ester, and 40-50% of liquid paraffin. By optimizing the type and amount of the styrene-isoprene-styrene block copolymer and the polyisobutylene, the adhesive force and cohesive force of the loxoprofen sodium patch are simultaneously improved through their combined action, and the long-term stability of the patch can be maintained.

Description

Technical Field

[0001] The invention belongs to the technical field of loxoprofen sodium preparations, and particularly relates to a hot-melt loxoprofen sodium patch and a preparation method thereof. Background Art

[0002] Loxoprofen sodium is a potent nonsteroidal anti-inflammatory drug (NSAID) originally developed by Daiichi Sankyo Co., Ltd. Its oral formulation was launched in Japan in 1986 for anti-inflammatory and analgesic treatment of rheumatoid arthritis, osteoarthritis, and other conditions. Subsequently, Daiichi Sankyo Co., Ltd. collaborated with Litaku Chemical Co., Ltd. to develop topical loxoprofen sodium: a gel plaster and a patch. These formulations offer comparable efficacy and improved safety compared to oral formulations, making them a more advantageous dosage form.

[0003] The original formulation patent, CN101052384A, discloses a loxoprofen sodium patch. Its excipients include styrene-isoprene-styrene block copolymer (model: D1107), polyisobutylene, rosin glycerol ester (model: KE-311), butylated hydroxytoluene, liquid paraffin, phosphoric acid, and L-menthol. Patent CN117159508A discloses a loxoprofen sodium patch that, based on the original formulation patent, incorporates silica to improve the thermal stability of initial adhesion: after stability tests at 40°C or 60°C, the initial adhesion remains at the level of a 22-30 steel ball.

[0004] But, patch adhesion comprises initial adhesion, holding adhesion and peel strength, and initial adhesion and peel strength are used to characterize the adhesion strength between patch and adherend, and holding adhesion is used to characterize the internal adhesion strength of patch.The adhesion detection of the loxoprofen sodium patch of patent CN117159508A only relates to initial adhesion, is used to characterize the adhesion strength between patch and adherend, does not relate to the characterization of internal adhesion strength of patch.And subsequent study finds that the internal adhesion strength of this loxoprofen sodium patch is lower, has cohesion and conformability problem.

[0005] Patents CN1424908A and CN1409628A disclose patches containing anti-inflammatory drugs. Excipients include styrene-isoprene-styrene block copolymer, polyisobutylene, a tackifier, and a plasticizer. Cohesion and adhesion are adjusted by combining low-molecular-weight (5,000-150,000) polyisobutylene with high-molecular-weight (50,000-200,000) polyisobutylene. The addition of 0.1-20% high-molecular-weight polyisobutylene improves the patch's cohesion and conformability while preventing increased cohesion from decreasing adhesion. However, the addition of high-molecular-weight polyisobutylene requires a corresponding increase in stirring temperature to approximately 200°C for dissolution, increasing the risk of matrix aging and raising long-term stability concerns.

[0006] Therefore, how to optimize the formulation of loxoprofen sodium patches to achieve the technical effects of simultaneously improving adhesion and cohesion while maintaining long-term stability when using low molecular weight (5,000~150,000) polyisobutylene is an unresolved technical problem in this field. Summary of the Invention

[0007] The technical problem to be solved by the present invention is: by optimizing the type and amount of styrene-isoprene-styrene block copolymer and polyisobutylene, the adhesive force and cohesive force of the loxoprofen sodium patch are simultaneously improved, and long-term stability can be maintained.

[0008] The technical problem of the present invention is solved by the following technical solutions:

[0009] In one aspect, the present invention provides a hot-melt loxoprofen sodium patch comprising a backing layer, an adhesive layer, and a protective layer, wherein the adhesive layer comprises, by weight percentage:

[0010] Loxoprofen sodium or its hydrate 5~6%,

[0011] Styrene-isoprene-styrene block copolymer 19~26%,

[0012] Polyisobutylene 5~15%,

[0013] Hydrogenated rosin glycerol ester 5~15%,

[0014] Liquid paraffin 40~50%.

[0015] Preferably, the weight ratio of styrene to isoprene in the styrene-isoprene-styrene block copolymer is 15 / 85 to 16 / 84. Specific models include, but are not limited to, one or more of D1107, D1161, D1163, 1106, 5505, 5229, and 5403.

[0016] More preferably, the weight ratio of styrene to isoprene in the styrene-isoprene-styrene block copolymer is 16 / 84.

[0017] Preferably, the viscosity average molecular weight of the polyisobutylene is 70,000 to 90,000. Specific models include but are not limited to one or more of B15N and B15SF.

[0018] More preferably, the viscosity average molecular weight of the polyisobutylene is 85,000.

[0019] Preferably, the viscosity of liquid paraffin is 50~59 mm 2 / s.

[0020] More preferably, the viscosity of the liquid paraffin is 55 mm 2 / s.

[0021] Preferably, the hot-melt loxoprofen sodium patch has an adhesive layer comprising, by weight percentage:

[0022] Loxoprofen sodium or its hydrate 5~6%,

[0023] Styrene-isoprene-styrene block copolymer 25%,

[0024] Polyisobutylene 7.5~15%,

[0025] Glycerol ester of hydrogenated rosin 7.5%,

[0026] Liquid paraffin 40~50%.

[0027] Preferably, the hot-melt loxoprofen sodium patch further comprises one or more of an antioxidant, a pH regulator, a stabilizer, and a transdermal enhancer.

[0028] More preferably, the antioxidant includes, but is not limited to, one or more of tocopherol and its ester derivatives, ascorbic acid, ascorbyl stearate, butylated hydroxytoluene, butylated hydroxyanisole, and butylated hydroxyanisole, and the amount used is 0-2% by mass.

[0029] More preferably, the pH regulator is phosphoric acid, and the amount used is 0-2% by mass.

[0030] More preferably, the stabilizer is silicon dioxide, and the amount used is 0-2% by mass.

[0031] More preferably, the transdermal enhancer includes, but is not limited to, one or more of menthol, azone, oleic acid, isopropyl myristate, diisopropyl adipate, and crotamiton, and the amount used is 0-5% by mass.

[0032] Most preferably, the hot-melt loxoprofen sodium patch has an adhesive layer comprising, by weight percentage:

[0033] Loxoprofen sodium dihydrate 5.67%,

[0034] Styrene-isoprene-styrene block copolymer 25.00%,

[0035] Polyisobutylene 15.00%,

[0036] Silicon dioxide 0.50%,

[0037] Glycerol ester of hydrogenated rosin 7.50%,

[0038] Butylated hydroxytoluene 0.50%,

[0039] Phosphoric acid 1.00%,

[0040] Menthol 3.00%,

[0041] Liquid paraffin 41.83%.

[0042] In another aspect, the present invention provides a method for preparing a hot-melt loxoprofen sodium patch, comprising the following steps:

[0043] Add styrene-isoprene-styrene block copolymer, polyisobutylene and hydrogenated rosin glycerol ester to a portion of liquid paraffin, heat to melt, and stir evenly; optionally add an antioxidant, a pH adjuster, a stabilizer, and a transdermal enhancer, heat to melt, and stir evenly; add loxoprofen sodium or its hydrate and the remaining liquid paraffin, heat to melt, and stir evenly to obtain a paste;

[0044] The paste is evenly applied to the protective layer, and then laminated to the backing layer, and cut to the appropriate size to obtain the patch.

[0045] Preferably, the heating and melting temperature is 120-135° C. If the heating and melting temperature is further increased, the risk of aging such as decreased cohesion and growth of related substances in the patch will further increase, making it difficult to maintain long-term stability.

[0046] The hot-melt loxoprofen sodium patch of the present invention has the following advantages compared to the prior art:

[0047] 1) The present invention is characterized by preferably selecting a weight ratio of styrene / isoprene in the styrene-isoprene-styrene block copolymer of 15 / 85 to 16 / 84, a viscosity-average molecular weight of polyisobutylene of 70,000 to 90,000, and a viscosity of liquid paraffin of 55 to 59 mm 2 / s, the initial adhesion, lasting adhesion and peel strength of the obtained loxoprofen sodium patch are significantly improved compared with the prior art (Comparative Example 1), achieving the technical effect of the three working together to simultaneously improve the adhesion and cohesion.

[0048] 2) By further optimizing the dosages of styrene-isoprene-styrene block copolymer, polyisobutylene, and liquid paraffin, the initial adhesion of the resulting loxoprofen sodium patch was increased to above 25#, the sustained adhesion to above 3 minutes, and the peel strength to above 0.07, while maintaining long-term stability. DETAILED DESCRIPTION

[0049] The technical solution of the present invention will be further described below with reference to the embodiments. However, the protection scope of the present invention includes but is not limited to these embodiments, and any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0050] The instruments and reagents used in the examples of the present invention are all commercially available products. As examples, the models and manufacturer information of some reagents are as follows:

[0051] Loxoprofen sodium dihydrate (manufacturer: Dijia Pharmaceutical);

[0052] Styrene-isoprene-styrene block copolymer (SIS) (model: 5229, manufacturer: JSR);

[0053] SIS (model: 5505, manufacturer: JSR);

[0054] SIS (model: D1161, manufacturer: Kraton);

[0055] Polyisobutylene (PIB) (model: B15N, manufacturer: BASF);

[0056] PIB (model: B12N, manufacturer: BASF);

[0057] Glycerol ester of hydrogenated rosin (model: KE-311, manufacturer: Arakawa Chemical);

[0058] Liquid paraffin (viscosity: 55 mm 2 / s, manufacturer: Tianjin Hongshan New Materials).

[0059] Example 1

[0060] A hot-melt loxoprofen sodium patch, the formulation and process of which are as follows.

[0061] prescription:

[0062]

[0063] Process:

[0064] Disperse silicon dioxide in a portion of the liquid paraffin and disperse loxoprofen sodium or its hydrate in the remaining liquid paraffin. Under a carbon dioxide atmosphere, set the temperature to 120-135°C and stir at 80-200 rpm. Add PIB, hydrogenated rosin glycerol ester, butylated hydroxytoluene, SIS, loxoprofen sodium dispersion, phosphoric acid, and menthol to the silicon dioxide dispersion and stir until uniformly mixed to obtain a paste.

[0065] The paste is evenly applied to the protective layer, and then laminated to the backing layer, and cut to the appropriate size to obtain the patch.

[0066] Example 2-4 Investigation of excipient types and dosages

[0067] Based on Example 1, the effects of polyisobutylene type and dosage were investigated.

[0068] prescription:

[0069]

[0070] Comparative Example 1

[0071] On the basis of Example 2 of the original preparation patent CN101052384A, the stabilizer silicon dioxide disclosed in CN117159508A was added as Comparative Example 1.

[0072] prescription:

[0073]

[0074] Test Example 1 Adhesion Test

[0075] The adhesion force of the loxoprofen sodium patches of Examples 1-4 and Comparative Example 1 was measured.

[0076] Adhesion strength determination method: Refer to the 2020 edition of the Chinese Pharmacopoeia, Part IV, 0952 Adhesion Determination Method to determine the initial adhesion, lasting adhesion, and peel strength.

[0077] The test results are shown in Table 1:

[0078] Table 1. Adhesion test results of loxoprofen sodium patches of Examples 1-4 and Comparative Example 1

[0079]

[0080] Test results show that by optimizing the polyisobutylene viscosity-average molecular weight to 85,000 (Examples 1-4), the holding force increased to over 1 minute, significantly improving cohesion compared to Comparative Example 1. Furthermore, by optimizing the polyisobutylene dosage to 15% (Examples 1 and 4), the initial tack increased to over 25#, the holding force increased to over 3 minutes, and the peel strength increased to over 0.07, significantly improving both adhesion and cohesion compared to Comparative Example 1.

[0081] Test Example 2 Peeling Pain Perception and Skin Reaction

[0082] The pain perception and skin reaction after application of the loxoprofen sodium patches of Example 1 and Comparative Example 1 were evaluated.

[0083] Ten volunteers were recruited and the patches were cut into 10 cm × 14 cm pieces using a 10 cm × 14 cm mold for testing. Each volunteer applied the loxoprofen sodium patches of Example 1 and Comparative Example 1 to different locations on their left and right arms for 0.5 h. The patches were then peeled off to assess pain and record skin reactions. Recovery of the skin reactions was observed 2 h after patch peeling. The loxoprofen sodium patch peeling pain and post-peeling skin reactions were scored with reference to Tables 2 and 3 below.

[0084] Table 2. Peeling pain scoring criteria

[0085]

[0086] Table 3. Scoring criteria for peeling skin reaction

[0087]

[0088] The scoring results are shown in Table 4:

[0089] Table 4. Peeling pain and skin reaction scores of loxoprofen sodium patches in Example 1 and Comparative Example 1

[0090]

[0091] The scoring results showed that there was no significant difference in peeling pain and skin reaction between Example 1 of the present invention and Comparative Example 1. At 0 h after patch peeling, only 1 to 2 volunteers developed mild erythema on their skin, which disappeared at 2 h. The loxoprofen sodium patch of the present invention was acceptable to all volunteers when its peel strength was within 0.100 kN / m.

[0092] Test Example 3 Stability Test

[0093] Example 1 was placed under long-term conditions (25°C ± 2°C, 60% RH ± 5% RH) to conduct a long-term stability test.

[0094] The test results are shown in Table 5:

[0095] Table 5. Long-term stability test results of Example 1

[0096]

[0097] The test results show that the adhesion of the loxoprofen sodium patch of the present invention does not change significantly after long-term placement, and the patch has long-term stability.

Claims

1. A hot-melt loxoprofen sodium patch, characterized in that The hot-melt loxoprofen sodium patch, in terms of weight percentage, comprises an adhesive layer: Loxoprofen sodium dihydrate 5.67%, Styrene-isoprene-styrene block copolymer 25.00%, Polyisobutylene 15.00%, Silicon dioxide 0.50%, Glycerol ester of hydrogenated rosin 7.5%, Butylated hydroxytoluene 0.50%, Phosphoric acid 1.0%, Menthol 3.00%, Liquid paraffin 41.83%; The weight ratio of styrene / isoprene in the styrene-isoprene-styrene block copolymer is 15 / 85 or 16 / 84; The viscosity average molecular weight of the polyisobutylene is 85,000; The viscosity of the liquid paraffin is 55 mm 2 / s.

2. A method for preparing the hot-melt loxoprofen sodium patch as claimed in claim 1, comprising the following steps: Add styrene-isoprene-styrene block copolymer, polyisobutylene and hydrogenated rosin glycerol ester to part of liquid paraffin, heat to melt, and stir evenly; add antioxidant, pH adjuster, stabilizer, and transdermal enhancer, heat to melt, and stir evenly; add loxoprofen sodium or its hydrate and the remaining liquid paraffin, heat to melt, and stir evenly to obtain a paste; The paste is evenly applied to the protective layer, and then laminated to the backing layer, and cut to the appropriate size to obtain the patch.

3. The method for preparing hot-melt loxoprofen sodium patch according to claim 2, wherein The heating and melting temperature is 120-135°C.

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