Hot-melt loxoprofen sodium patch and preparation method thereof

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 adhesion layer and a protective layer, the adhesion layer comprises the following components in percentage by weight: 5-6% of loxoprofen sodium or its hydrate, 19-26% of styrene-isoprene-styrene block copolymer, 5-15% of polyisobutene, 5-15% of hydrogenated rosin glyceride and 40-50% of liquid paraffin; by optimizing the model and dosage of the styrene-isoprene-styrene block copolymer and the polyisobutene, the adhesive force and cohesive force of the loxoprofen sodium patch are improved at the same time through the combined action, and the long-term stability can be kept.

Description

Technical Field

[0001] The present 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 non-steroidal anti-inflammatory drug, first developed by Daiichi Sankyo Co., Ltd. in Japan. In 1986, the oral preparation was launched in Japan for the anti-inflammatory and analgesic treatment of rheumatoid arthritis, osteoarthritis, etc. Subsequently, Daiichi Sankyo Co., Ltd. and Rite Chemical Co., Ltd. cooperated to develop loxoprofen sodium topical preparations: gel patches and patches, which have comparable effectiveness and higher safety compared to oral preparations, and thus have become a more advantageous dosage form.

[0003] The original research formulation patent CN101052384A discloses a loxoprofen sodium patch, and the excipients include styrene-isoprene-styrene block copolymer (model: D1107), polyisobutylene, rosin glyceride (model: KE-311), dibutylhydroxytoluene, liquid paraffin, phosphoric acid, L-menthol. Patent CN117159508A discloses a loxoprofen sodium patch, and silica is added on the basis of the original research formulation patent to improve the thermal stability of the initial adhesion: after the stability test at 40°C or 60°C, the initial adhesion still maintains 22 - 30 steel balls.

[0004] However, the adhesive force of the patch includes initial adhesion, holding power, and peel strength. The initial adhesion and peel strength are used to characterize the adhesion strength between the patch and the adherend, and the holding power is used to characterize the internal adhesion strength of the patch. In the adhesion force test of the loxoprofen sodium patch of patent CN117159508A, only the initial adhesion is involved, which is used to characterize the adhesion strength between the patch and the adherend, and the internal adhesion strength of the patch is not characterized. Subsequent research found that the internal adhesion strength of this loxoprofen sodium patch is relatively low, and there are problems with cohesion and conformability.

[0005] Patents CN1424908A and CN1409628A disclose patches containing anti-inflammatory drugs, and the excipients include styrene-isoprene-styrene block copolymer, polyisobutylene, tackifier, and plasticizer. The cohesion and adhesion are adjusted by combining low molecular weight (5,000 - 150,000) polyisobutylene and high molecular weight (50,000 - 200,000) polyisobutylene. Among them, 0.1 - 20% of high molecular weight polyisobutylene is added to improve the cohesion and conformability of the patch, while avoiding the decrease in adhesion due to the increase in cohesion. However, adding high molecular weight polyisobutylene requires increasing the stirring temperature to about 200°C for dissolution, with a high risk of matrix aging and long-term stability problems.

[0006] Therefore, in the case of using low molecular weight (5,000 - 150,000) polyisobutylene, how to optimize the formulation of loxoprofen sodium patch to achieve the technical effect of simultaneously improving adhesion and cohesion and maintaining long-term stability is a technical problem that has not been solved in this field. Summary of the Invention

[0007] The technical problem to be solved by the present invention is: by optimizing the types and dosages of styrene-isoprene-styrene block copolymer and polyisobutylene, the adhesion and cohesion 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: On the one hand, the present invention provides a hot-melt loxoprofen sodium patch, which includes a backing layer, an adhesive layer and a protective layer. By weight percentage, the adhesive layer includes: Loxoprofen sodium or its hydrate 5 - 6%, Styrene-isoprene-styrene block copolymer 19 - 26%, Polyisobutylene 5 - 15%, Hydrogenated rosin glyceride 5 - 15%, Liquid paraffin 40 - 50%.

[0009] Preferably, the weight ratio of styrene / isoprene in the styrene-isoprene-styrene block copolymer is 15 / 85 - 16 / 84. Specific types include but are not limited to one or more of D1107, D1161, D1163, 1106, 5505, 5229, 5403.

[0010] More preferably, the weight ratio of styrene / isoprene in the styrene-isoprene-styrene block copolymer is 16 / 84.

[0011] Preferably, the viscosity-average molecular weight of polyisobutylene is 70,000 - 90,000. Specific types include but are not limited to one or more of B15N, B15SF.

[0012] More preferably, the viscosity-average molecular weight of polyisobutylene is 85,000.

[0013] Preferably, the viscosity of liquid paraffin is 50 - 59 mm 2 / s.

[0014] More preferably, the viscosity of liquid paraffin is 55 mm 2 / s.

[0015] Preferably, for the hot-melt loxoprofen sodium patch, by weight percentage, the adhesive layer includes: Loxoprofen sodium or its hydrate 5 - 6%, 25% styrene-isoprene-styrene block copolymer, 7.5 - 15% polyisobutene, 7.5% hydrogenated rosin glyceride, 40 - 50% liquid paraffin.

[0016] Preferably, the hot-melt loxoprofen sodium patch further comprises one or more of an antioxidant, a pH regulator, a stabilizer, and a transdermal enhancer.

[0017] More preferably, the antioxidant includes, but is not limited to, one or more of tocopherol and its ester derivatives, ascorbic acid, ascorbyl stearate, dibutylhydroxytoluene, dibutylhydroxyanisole, and butylated hydroxyanisole, and the dosage is 0 - 2% by mass percentage.

[0018] More preferably, the pH regulator is phosphoric acid, and the dosage is 0 - 2% by mass percentage.

[0019] More preferably, the stabilizer is silica, and the dosage is 0 - 2% by mass percentage.

[0020] More preferably, the transdermal enhancer includes, but is not limited to, one or more of menthol, azone, oleic acid, isopropyl myristate, diisopropyl adipate, and cromolyn, and the dosage is 0 - 5% by mass percentage.

[0021] Most preferably, the hot-melt loxoprofen sodium patch, by weight percentage, the adhesive layer comprises: 5.67% loxoprofen sodium dihydrate, 25.00% styrene-isoprene-styrene block copolymer, 15.00% polyisobutene, 0.50% silica, 7.50% hydrogenated rosin glyceride, 0.50% dibutylhydroxytoluene, 1.00% phosphoric acid, 3.00% menthol, 41.83% liquid paraffin.

[0022] On the other hand, the present invention provides a method for preparing a hot-melt loxoprofen sodium patch, comprising the following steps: Add the styrene-isoprene-styrene block copolymer, polyisobutene, and hydrogenated rosin glyceride to a part of the liquid paraffin, heat to melt, and stir evenly; optionally add an antioxidant, a pH regulator, 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; The paste is evenly coated on the protective layer, then laminated with the backing layer, and cut into appropriate sizes to obtain the patch.

[0023] Preferably, the heating and melting temperature is 120-135 °C. If the heating and melting temperature further increases, the risks of aging such as the decrease in the cohesive force of the patch and the increase in related substances will further increase, and it is difficult to maintain long-term stability.

[0024] The beneficial effects of the hot-melt loxoprofen sodium patch of the present invention compared with the prior art are as follows: 1) By preferably setting the weight ratio of styrene / isoprene in the styrene-isoprene-styrene block copolymer to 15 / 85-16 / 84, the viscosity-average molecular weight of polyisobutylene to 70,000-90,000, and the viscosity of liquid paraffin to 55-59 mm 2 / s, the initial adhesion, holding 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 simultaneously improving the adhesive force and cohesive force by the combined action of the three.

[0025] 2) By further optimizing the dosages of components such as styrene-isoprene-styrene block copolymer, polyisobutylene, and liquid paraffin, the initial adhesion of the obtained loxoprofen sodium patch is increased to more than 25#, the holding adhesion is increased to more than 3 min, the peel strength is increased to more than 0.07, and long-term stability can be maintained. Detailed implementation manners

[0026] The technical solutions of the present invention will be further described below in conjunction with 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.

[0027] The instruments and reagents used in the embodiments of the present invention are all commercially available products. As an example, the model and manufacturer information of some reagents are as follows: Loxoprofen sodium dihydrate (manufacturer: Dijia Pharmaceutical); Styrene-isoprene-styrene block copolymer (SIS) (model: 5229, manufacturer: JSR); SIS (model: 5505, manufacturer: JSR); SIS (model: D1161, manufacturer: Kraton); Polyisobutylene (PIB) (model: B15N, manufacturer: BASF); PIB (model: B12N, manufacturer: BASF); Hydrogenated rosin glyceride (model: KE-311, manufacturer: Arakawa Chemical); Liquid paraffin (viscosity: 55 mm2 / s, Manufacturer: Tianjin Hongshan New Materials).

[0028] Example 1 A hot-melt loxoprofen sodium patch, the prescription and process are as follows.

[0029] Prescription:

[0030] Process: Disperse silica in part of the liquid paraffin, and disperse loxoprofen sodium or its hydrate in the remaining liquid paraffin. Under the protection of carbon dioxide gas, set the temperature at 120 - 135 °C and the stirring speed at 80 - 200 rpm. Add PIB, hydrogenated rosin glyceride, dibutylhydroxytoluene, SIS, loxoprofen sodium dispersion, phosphoric acid, and menthol to the silica dispersion and stir evenly to obtain the paste.

[0031] Apply the paste evenly on the protective layer, then laminate it with the backing layer, and cut it into appropriate sizes to obtain the patch.

[0032] Examples 2 - 4 Investigation of excipient types and dosages On the basis of Example 1, investigate the influence of the type and dosage of polyisobutene.

[0033] Prescription:

[0034] Control Example 1 On the basis of Example 2 of the original developed formulation patent CN101052384A, add the stabilizer silica disclosed in CN117159508A as Control Example 1.

[0035] Prescription:

[0036] Test Example 1 Adhesion force measurement Measure the adhesion force of the loxoprofen sodium patches of Examples 1 - 4 and Control Example 1.

[0037] Adhesion force measurement method: Refer to the Adhesion Force Measurement Method in Section 0952 of the Fourth Part of the Chinese Pharmacopoeia 2020 Edition to measure the initial adhesion force, holding adhesion force, and peel strength.

[0038] The test results are shown in Table 1: Table 1. Adhesion force measurement results of the loxoprofen sodium patches of Examples 1 - 4 and Control Example 1

[0039] The test results show that by optimizing the viscosity-average molecular weight of polyisobutene to 85,000 (Examples 1-4), the holding tack is increased to more than 1 minute, and the cohesive force is significantly increased compared to Comparative Example 1. Further optimizing the dosage of polyisobutene to 15% (Examples 1 and 4), the initial tack is increased to more than 25#, the holding tack is increased to more than 3 minutes, and the peel strength is increased to more than 0.07. The adhesive force and cohesive force are significantly increased compared to Comparative Example 1 at the same time.

[0040] Test Example 2: Peeling pain sensation and skin reaction

[0041] Evaluate the peeling pain sensation and skin reaction after applying the loxoprofen sodium patch of Example 1 and Comparative Example 1.

[0042] Recruit 10 volunteers, cut the patch into a size of 10 cm × 14 cm with a mold of 10 cm × 14 cm for testing. Each volunteer applies the loxoprofen sodium patches of Example 1 and Comparative Example 1 on different parts of the left and right arms, with an application duration of 0.5 h. Then, peel off the patch to evaluate the peeling pain and record the skin reaction, and observe the recovery of the skin reaction 2 h after peeling off the patch. Refer to Tables 2 and 3 below to score the peeling pain sensation and skin reaction after peeling off the loxoprofen sodium patch.

[0043] Table 2. Scoring criteria for peeling pain sensation

[0044] Table 3. Scoring criteria for peeling skin reaction

[0045] The scoring results are shown in Table 4: Table 4. Scoring results of peeling pain sensation and skin reaction of loxoprofen sodium patches in Example 1 and Comparative Example 1

[0046] The scoring results show that there is no significant difference in the peeling pain sensation and skin reaction between Example 1 of the present invention and Comparative Example 1. Only 1-2 volunteers had slight erythema on the skin 0 h after peeling off the patch, and the erythema had disappeared 2 h later. When the peel strength of the loxoprofen sodium patch of the present invention is within 0.100 kN / m, it can be accepted by volunteers.

[0047] Test Example 3: Stability test

[0048] Place Example 1 under long-term conditions (25°C ± 2°C, 60% RH ± 5% RH) for long-term stability testing.

[0049] The test results are shown in Table 5: Table 5. Results of long-term stability test of Example 1

[0050] The test results show that after the long-term stability test of the loxoprofen sodium patch of the present invention, the adhesion force has no significant change, indicating that the patch has long-term stability.

Claims

1. A hot-melt type loxoprofen sodium patch, comprising a backing layer, an adhesive layer and a protective layer, characterized in that: By weight percentage, the adhesive layer comprises: Loxoprofen sodium or its hydrate 5 - 6%, Styrene-isoprene-styrene block copolymer 19 - 26%, Polyisobutene 5 - 15%, Glycerol ester of hydrogenated rosin 5 - 15%, Liquid paraffin 40 - 50%; The weight ratio of styrene / isoprene in the styrene-isoprene-styrene block copolymer is 15 / 85 - 16 / 84; The viscosity-average molecular weight of the polyisobutene is 70,000 - 90,000; The viscosity of the liquid paraffin is 55 to 66 mm 2 / s.

2. The hot-melt type loxoprofen sodium patch according to claim 1, wherein The weight ratio of styrene / isoprene in the styrene-isoprene-styrene block copolymer is 15 / 85.

3. The hot-melt type loxoprofen sodium patch according to claim 1, wherein The viscosity-average molecular weight of the polyisobutene is 85,000.

4. The hot-melt type loxoprofen sodium patch according to claim 1, wherein The viscosity of the liquid paraffin is 66 mm 2 / s.

5. The hot-melt loxoprofen sodium patch according to claim 1, wherein, For the hot-melt loxoprofen sodium patch, by weight percentage, the adhesive layer comprises: Loxoprofen sodium or its hydrate 5 - 6%, Styrene-isoprene-styrene block copolymer 22.5%, Polyisobutene 7.5 - 13%, Glycerol ester of hydrogenated rosin 13%, Liquid paraffin 40 - 47%.

6. The hot-melt type loxoprofen sodium patch according to claim 1, characterized in that, The hot-melt loxoprofen sodium patch further comprises one or more of an antioxidant, a pH regulator, a stabilizer, and a transdermal enhancer.

7. The hot-melt type loxoprofen sodium patch according to any one of claims 1 to 6, characterized in that, For the hot-melt loxoprofen sodium patch, by weight percentage, the adhesive layer comprises: Loxoprofen sodium dihydrate 5.67%, Styrene-isoprene-styrene block copolymer 22.50%, Polyisobutene 13.00%, Silica 0.50%, Glycerol ester of hydrogenated rosin 13.00%, Butylated hydroxytoluene 0.50%, Phosphoric acid 0.90%, Menthol 3.00%, Liquid paraffin 40.93%.

8. The preparation method of the hot-melt loxoprofen sodium patch according to any one of claims 1 to 6, comprising the following steps: Adding the styrene-isoprene-styrene block copolymer, polyisobutene, and glycerol ester of hydrogenated rosin to a part of the liquid paraffin, heating to melt and stirring evenly; adding the antioxidant, pH regulator, stabilizer, and transdermal enhancer, heating to melt and stirring evenly; adding loxoprofen sodium or its hydrate and the remaining liquid paraffin, heating to melt and stirring evenly to obtain a paste; Evenly coating the paste on the protective layer, then laminating it with the backing layer, and cutting it into appropriate sizes to obtain the patch.

9. The preparation method of the hot-melt type loxoprofen sodium patch according to claim 8, characterized in that, The heating and melting temperature is 120 - 135 °C.

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