Loxoprofen sodium patch and preparation method thereof

Abstract

According to the loxoprofen sodium patch and the preparation method thereof provided by the invention, in the preparation process of the patch, the loxoprofen sodium patch prepared by optimizing the preparation temperature, the coating temperature and an oxygen control mode of vacuumizing and continuously filling nitrogen has the advantages that the increase amplitude of related substances is low under an accelerated test condition; the stability of the patch can be obviously improved, the coating time can be obviously prolonged, and the patch has important significance for increasing the production batch and improving the production capacity.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a sodium loxoprofen patch and a preparation method thereof. BACKGROUND

[0002] Sodium loxoprofen is a new type of 2-phenylpropionic acid non-steroidal anti-inflammatory drug, which was first developed by the First Sanjiyuan Company of Japan, and is mainly used for anti-inflammatory and analgesic treatment of rheumatoid arthritis, osteoarthritis and the like. At present, there are dosage forms such as tablets, granules, capsules and external use patches (gel patches and hot melt patches). The external use patch has considerable effectiveness and higher safety compared with oral preparations, and thus becomes a more advantageous dosage form. The hot melt patch is lighter in weight, stronger in adhesion and more widely used in clinic compared with the gel patch, and thus has become a research hotspot of the product.

[0003] Sodium loxoprofen has poor stability to high temperature, high humidity and light, and the hot melt patch may result in excessive related substances of the finished product due to the long time high-temperature heating process in the preparation process. Meanwhile, the preparation temperature is too high, which seriously affects the coating time of the product and restricts the batch of commercial production of the product.

[0004] Patent CN101052384A discloses a sodium loxoprofen patch, and the adjuvants include styrene-isoprene-styrene block copolymer (model number: D1107), polyisobutylene, glyceryl ester of rosin (model number: KE-311), dibutyl hydroxytoluene, liquid paraffin, phosphoric acid and L-menthol. Patent CN120346189A can improve the adhesion and cohesion of the long-term stability of the sodium loxoprofen patch by optimizing the model number and amount of styrene-isoprene-styrene block copolymer and polyisobutylene. The above patents do not involve the characterization of related substances of the patch. Subsequent research has found that the sodium loxoprofen patch has problems of affecting the ductility of the paste due to the too low temperature in the preparation process and the excessive related substances due to the too high temperature.

[0005] Therefore, optimizing the preparation method of the sodium loxoprofen patch, determining the appropriate coating temperature range, prolonging the coating time, increasing the production batch and improving the production efficiency are technical problems that have not been solved in the art. SUMMARY

[0006] The purpose of the present application is to optimize the preparation method of the sodium loxoprofen patch by optimizing the preparation temperature, coating temperature and oxygen control mode of vacuumizing and continuously filling nitrogen during the preparation process of the patch based on the prior art, so that the sodium loxoprofen patch prepared has a lower increase range of related substances under the accelerated test condition, and the stability of the patch can be obviously improved and the coating time can be prolonged, which has important significance for increasing the production batch and improving the production capacity.

[0007] The second purpose of the present application is to provide the preparation method of the above-mentioned sodium loxoprofen patch.

[0008] The technical solution of the present application is as follows:

[0009] The present application discloses a loxoprofen sodium patch, which comprises a protective layer and an adhesive layer coated on the surface of the protective layer, wherein the ointment layer is made of loxoprofen sodium, styrene-isoprene-styrene block copolymer, polyisobutylene, hydrogenated rosin glyceride, silicon dioxide, dibutylhydroxytoluene, phosphoric acid, L-menthol and liquid paraffin.

[0010] In the present application, the preparation method of the patch comprises the following steps:

[0011] (1) Preparation of silicon dioxide dispersion liquid: mix silicon dioxide and part of liquid paraffin, and stir to disperse uniformly to prepare a silicon dioxide dispersion liquid;

[0012] (2) Preparation of loxoprofen sodium dispersion liquid: mix loxoprofen sodium and part of liquid paraffin, and stir to disperse uniformly to prepare a loxoprofen sodium dispersion liquid;

[0013] (3) Mixing and ointment preparation: under the condition of a temperature of 140-145℃, vacuum extraction and nitrogen filling to positive pressure, polyisobutylene, dibutylhydroxytoluene, hydrogenated rosin glyceride, styrene-isoprene-styrene block copolymer and the remaining liquid paraffin are added into the silicon dioxide dispersion liquid obtained in step (1), and stirring is performed until complete melting and uniform dispersion to obtain a melted dispersion liquid; then the obtained melted dispersion liquid is cooled to 130-135℃, the loxoprofen sodium dispersion liquid obtained in step (2), phosphoric acid and L-menthol are added, and stirring is performed to obtain an ointment, and nitrogen protection is continuously performed during the whole mixing and ointment preparation process;

[0014] (4) Coating and cutting: the ointment obtained in step (3) is uniformly coated on the protective layer to form an adhesive layer, a backing layer is covered on the surface of the adhesive layer, and after cutting, the patch is obtained.

[0015] For the present application, in step (3), when vacuum extraction is performed, nitrogen is filled to positive pressure when the vacuum degree is controlled to be greater than or equal to -95 kpa. The vacuum degree is a relative vacuum degree. When the vacuum degree is controlled to be greater than or equal to -95 kpa, the vacuum degree is in the range of -95 kpa to -101.325 kpa, for example, the vacuum degree is -95 kpa, -100 kpa or -101 kpa. The positive pressure refers to a state of gas with a pressure higher than that of normal pressure (i.e. one atmosphere).

[0016] For the present application, in one aspect, the present application provides a sodium loxoprofen patch comprising a protective layer and an adhesive layer coated on the surface of the protective layer, wherein the adhesive layer is made of the following components in parts by weight: 5-6 parts of sodium loxoprofen, 15-35 parts of styrene-isoprene-styrene block copolymer, 5-25 parts of polyisobutylene, 5-25 parts of hydrogenated rosin glycerin ester, 0.4-2.0 parts of silicon dioxide, 0.4-2.0 parts of dibutyl hydroxytoluene, 0.4-2.0 parts of phosphoric acid, 1-4 parts of L-menthol and 20-50 parts of liquid paraffin.

[0017] For the present application, in one preferred aspect, the present application provides a sodium loxoprofen patch comprising a protective layer and an adhesive layer coated on the surface of the protective layer, wherein the adhesive layer is made of the following components in parts by weight: 5-6 parts of sodium loxoprofen, 20-30 parts of styrene-isoprene-styrene block copolymer, 10-20 parts of polyisobutylene, 10-20 parts of hydrogenated rosin glycerin ester, 0.6-1.0 parts of silicon dioxide, 0.6-1.0 parts of dibutyl hydroxytoluene, 0.8-1.2 parts of phosphoric acid, 2-4 parts of L-menthol and 30-40 parts of liquid paraffin.

[0018] For the present application, in one more preferred aspect, the present application provides a sodium loxoprofen patch comprising a protective layer and an adhesive layer coated on the surface of the protective layer, wherein the adhesive layer is made of the following components in parts by weight: 5.6-5.7 parts of sodium loxoprofen, 23-25 parts of styrene-isoprene-styrene block copolymer, 14-16 parts of polyisobutylene, 14-16 parts of hydrogenated rosin glycerin ester, 0.7-0.9 parts of silicon dioxide, 0.7-0.9 parts of dibutyl hydroxytoluene, 0.9-1.1 parts of phosphoric acid, 2.5-3.5 parts of L-menthol and 33-35 parts of liquid paraffin.

[0019] For the present application, in one especially preferred aspect, the present application provides a sodium loxoprofen patch comprising a protective layer and an adhesive layer coated on the surface of the protective layer, wherein the adhesive layer is made of the following components in parts by weight: 5.67 parts of sodium loxoprofen, 24 parts of styrene-isoprene-styrene block copolymer, 15 parts of polyisobutylene, 15 parts of hydrogenated rosin glycerin ester, 0.8 parts of silicon dioxide, 0.8 parts of dibutyl hydroxytoluene, 1.0 parts of phosphoric acid, 3 parts of L-menthol and 34.73 parts of liquid paraffin.

[0020] For the present application, in step (1), the liquid liquid paraffin is added in an amount of 20%-30% of the total amount, preferably in an amount of 22%-26% of the total amount, more preferably in an amount of 24% of the total amount.

[0021] For the present application, in step (2), the amount of liquid liquid paraffin added is 30%-40% of the total amount, preferably the amount of liquid liquid paraffin added is 36%-38% of the total amount, more preferably 37% of the total amount.

[0022] For the present application, in step (3), the weight ratio of styrene and isoprene in the styrene-isoprene-styrene block copolymer is 15:85.

[0023] For the present application, in step (3), the viscosity average molecular weight of the polyisobutylene is 50,000-90,000; preferably, the type of polyisobutylene is one or more of 5H, 5.5H, 6H, B12N, B15, N50 or N100; more preferably, the type of polyisobutylene is B15.

[0024] For the present application, in step (3), during the mixing process, the preparation temperature needs to be strictly controlled, in the present application, when the temperature is controlled at 140-145℃, the polyisobutylene, the dibutyl hydroxytoluene, the hydrogenated rosin glyceride and the styrene-isoprene-styrene block copolymer are added into the silica dispersion liquid, and the stirring is continued until the complete melting and dispersion, to obtain a melted dispersion liquid. When the temperature is too low, the colloidal fluidity is poor; when the temperature is too high, the adhesion of the patch decreases, the related substance increases and other aging risks further increase, and it is difficult to maintain long-term stability.

[0025] For the present application, in step (4), the dimethyl silicone oil polyester film is the protective layer, and the polyester fiber cloth is the backing layer.

[0026] In step (4), the coating temperature is 120-140℃; when the cutting specification is controlled at 10cm*14cm, the weight of the paste is 2.0g±10%.

[0027] By using the technical scheme of the present application, the following advantages are achieved:

[0028] The present application provides a loxoprofen sodium patch, in the preparation process of the patch, by optimizing the preparation temperature, the coating temperature and the oxygen control mode of vacuumizing and continuously filling nitrogen, the prepared loxoprofen sodium patch has a lower increase amplitude of related substances under the accelerated test condition, and the stability of the patch can be obviously improved and the coating time can be prolonged, which has important significance for increasing the production batch and improving the production capacity. DETAILED DESCRIPTION

[0029] The present application can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the content described in the examples is only used to illustrate the present application, and should not and will not limit the present application described in detail in the claims.

[0030] Example 1

[0031] A sodium loxoprofen patch comprising a protective layer and an adhesive layer coated on the surface of the protective layer, wherein the adhesive layer is made of the following components in parts by weight: 5.67 parts of sodium loxoprofen, 24 parts of styrene-isoprene-styrene block copolymer, 15 parts of polyisobutylene, 15 parts of hydrogenated rosin glyceride, 0.8 parts of silicon dioxide, 0.8 parts of dibutyl hydroxytoluene, 1.0 parts of phosphoric acid, 3 parts of L-menthol, and 34.73 parts of liquid paraffin; the weight ratio of styrene and isoprene in the styrene-isoprene-styrene block copolymer is 15:85; and the model of the polyisobutylene is B15.

[0032] The preparation method of the patch comprises the following steps:

[0033] (1) Preparation of a silicon dioxide dispersion liquid: silicon dioxide and a total amount of 24% of liquid paraffin are mixed and uniformly dispersed by stirring to prepare a silicon dioxide dispersion liquid;

[0034] (2) Preparation of a sodium loxoprofen dispersion liquid: sodium loxoprofen and a total amount of 37% of liquid paraffin are mixed and uniformly dispersed by stirring to prepare a sodium loxoprofen dispersion liquid;

[0035] (3) Mixing and paste preparation: under the condition that the temperature is 140-145℃ and the vacuum degree is greater than or equal to -95kpa, nitrogen is filled to positive pressure, and then polyisobutylene, dibutyl hydroxytoluene, hydrogenated rosin glyceride, styrene-isoprene-styrene block copolymer, and the remaining liquid paraffin are added to the silicon dioxide dispersion liquid obtained in step (1), and the mixture is stirred until it is completely melted and uniformly dispersed to obtain a melted and dispersed liquid; then the melted and dispersed liquid is cooled to 130-135℃, and the sodium loxoprofen dispersion liquid obtained in step (2), phosphoric acid, and L-menthol are added, and the mixture is stirred uniformly to prepare a paste, and nitrogen is continuously filled for protection during the whole mixing and paste preparation process;

[0036] (4) Coating and cutting: a dimethyl silicone oil polyester film and a polyester fiber cloth are loaded into a coating machine, and when the temperature of the coating machine is raised to 120-140℃, the paste obtained in step (3) is uniformly coated on the protective layer to form an adhesive layer, and a backing layer is covered on the surface of the adhesive layer; when the coating is performed, the cutting specification is controlled to be 10cm*14cm, the weight of the paste is 2.0g±10%, and the patch is obtained.

[0037] Comparative Example 1

[0038] A sodium loxoprofen patch comprising a protective layer and an adhesive layer coated on the surface of the protective layer, wherein the adhesive layer is made of the following components in parts by weight: sodium loxoprofen 5.67 parts, styrene-isoprene-styrene block copolymer 24 parts, polyisobutylene 15 parts, hydrogenated rosin glyceride 15 parts, silicon dioxide 0.8 parts, dibutyl hydroxytoluene 0.8 parts, phosphoric acid 1.0 part, L-menthol 3 parts, and liquid paraffin 34.73 parts; the weight ratio of styrene and isoprene in the styrene-isoprene-styrene block copolymer is 15:85; and the model of the polyisobutylene is B15.

[0039] The preparation method of the patch comprises the following steps:

[0040] (1) Preparation of a silicon dioxide dispersion liquid: silicon dioxide and a total amount of 24% liquid paraffin are mixed and uniformly dispersed by stirring to prepare a silicon dioxide dispersion liquid;

[0041] (2) Preparation of a sodium loxoprofen dispersion liquid: sodium loxoprofen and a total amount of 37% liquid paraffin are mixed and uniformly dispersed by stirring to prepare a sodium loxoprofen dispersion liquid;

[0042] (3) Mixing and paste preparation: under the condition that the temperature is 140-145℃, polyisobutylene, dibutyl hydroxytoluene, hydrogenated rosin glyceride, styrene-isoprene-styrene block copolymer, and the remaining liquid paraffin are added to the silicon dioxide dispersion liquid obtained in step (1), and the mixture is stirred until it is completely melted and uniformly dispersed to obtain a melted dispersion liquid; then the melted dispersion liquid is cooled to 130-135℃, the sodium loxoprofen dispersion liquid obtained in step (2), phosphoric acid, and L-menthol are added, and the mixture is uniformly stirred to prepare a paste;

[0043] (4) Coating and cutting: a dimethyl silicone oil polyester film and a polyester fiber cloth are loaded into a coating machine, and the temperature of the coating machine is raised to 120-140℃; under this condition, the paste obtained in step (3) is uniformly coated on the protective layer to form an adhesive layer, and a backing layer is covered on the surface of the adhesive layer; when the cutting specification is controlled to be 10cm*14cm, the weight of the paste is 2.0g±10%, and the patch is obtained.

[0044] Comparative Example 2

[0045] A sodium loxoprofen patch comprising a protective layer and an adhesive layer coated on the surface of the protective layer, wherein the adhesive layer is made of the following components in parts by weight: sodium loxoprofen 5.67 parts, styrene-isoprene-styrene block copolymer 24 parts, polyisobutylene 15 parts, hydrogenated rosin glyceride 15 parts, silicon dioxide 0.8 parts, dibutyl hydroxytoluene 0.8 parts, phosphoric acid 1.0 part, L-menthol 3 parts, and liquid paraffin 34.73 parts; the weight ratio of styrene and isoprene in the styrene-isoprene-styrene block copolymer is 15:85; and the model of the polyisobutylene is B15.

[0046] The preparation method of the patch comprises the following steps:

[0047] (1) Preparation of a silica dispersion liquid: silica and a total amount of 24% of liquid paraffin are mixed and uniformly dispersed by stirring to prepare a silica dispersion liquid;

[0048] (2) Preparation of a sodium loxoprofen dispersion liquid: sodium loxoprofen and a total amount of 37% of liquid paraffin are mixed and uniformly dispersed by stirring to prepare a sodium loxoprofen dispersion liquid;

[0049] (3) Mixing and paste preparation: under the condition that the temperature is 140-145°C and the vacuum degree is greater than or equal to -95 kPa, polyisobutylene, dibutylhydroxytoluene, hydrogenated rosin glyceride, styrene-isoprene-styrene block copolymer and the remaining liquid paraffin are added to the silica dispersion liquid obtained in step (1) and stirred until completely melted and uniformly dispersed to obtain a melted dispersion liquid; then the melted dispersion liquid is cooled to 130-135°C, the sodium loxoprofen dispersion liquid obtained in step (2), phosphoric acid and L-menthol are added and uniformly stirred to prepare a paste, and nitrogen protection is continuously provided during the whole mixing and paste preparation process;

[0050] (4) Coating and cutting: a dimethyl silicone oil polyester film and a polyester fiber cloth are loaded into a coating machine, the temperature of the coating machine is raised to 120-140°C, the paste obtained in step (3) is uniformly coated on the protective layer to form an adhesive layer, and a backing layer is covered on the surface of the adhesive layer; when the coating is performed, the cutting specification is controlled to be 10 cm*14 cm, the weight of the paste is 2.0 g±10%, and the patch is obtained.

[0051] Comparative Example 3

[0052] A sodium loxoprofen patch comprises a protective layer and an adhesive layer coated on the surface of the protective layer, wherein the adhesive layer is prepared from the following components in parts by weight: sodium loxoprofen 5.67 parts, styrene-isoprene-styrene block copolymer 24 parts, polyisobutylene 15 parts, hydrogenated rosin glyceride 15 parts, silica 0.8 parts, dibutylhydroxytoluene 0.8 parts, phosphoric acid 1.0 part, L-menthol 3 parts and liquid paraffin 34.73 parts; the weight ratio of styrene and isoprene in the styrene-isoprene-styrene block copolymer is 15:85; and the model number of the polyisobutylene is B15.

[0053] The preparation method of the patch comprises the following steps:

[0054] (1) Preparation of a silica dispersion liquid: silica and a total amount of 24% of liquid paraffin are mixed and uniformly dispersed by stirring to prepare a silica dispersion liquid;

[0055] (2) Preparation of the dispersoid of sodium loxoprofen: sodium loxoprofen and liquid paraffin with a total amount of 37% were mixed and stirred to be uniformly dispersed to prepare the dispersoid of sodium loxoprofen;

[0056] (3) Mixing and preparation of the paste: under the condition that the temperature was 130-135°C and the vacuum was controlled to be greater than or equal to -95 kPa, nitrogen was filled to positive pressure, and the dispersoid of silicon dioxide obtained in step (1) was added with polyisobutylene, dibutylhydroxytoluene, hydrogenated rosin glyceride, styrene-isoprene-styrene block copolymer and the remaining liquid paraffin, and stirred until completely melted and uniformly dispersed to obtain a melted and dispersed solution; then the melted and dispersed solution was added with the dispersoid of sodium loxoprofen obtained in step (2), phosphoric acid and L-menthol, and stirred to be uniformly dispersed to prepare the paste, and nitrogen was continuously filled to protect the whole process of mixing and preparation of the paste;

[0057] (4) Coating and cutting: the dimethyl silicone polyester film and the polyester fiber cloth were loaded into the coating machine, and the temperature of the coating machine was raised to 120-140°C, and then the paste obtained in step (3) was uniformly coated on the protective layer to form the adhesive layer, and the backing layer was covered on the surface of the adhesive layer; when the coating was controlled to be 10 cm*14 cm in size and 2.0 g±10% in weight, the patch was obtained.

[0058] Comparative Example 4

[0059] A sodium loxoprofen patch, which comprises a protective layer and an adhesive layer coated on the surface of the protective layer, wherein the adhesive layer is prepared from the following components in parts by weight: sodium loxoprofen 5.67 parts, styrene-isoprene-styrene block copolymer 24 parts, polyisobutylene 15 parts, hydrogenated rosin glyceride 15 parts, silicon dioxide 0.8 parts, dibutylhydroxytoluene 0.8 parts, phosphoric acid 1.0 part, L-menthol 3 parts and liquid paraffin 34.73 parts; the weight ratio of styrene and isoprene in the styrene-isoprene-styrene block copolymer is 15:85; and the type of polyisobutylene is B15.

[0060] The preparation method of the patch comprises the following steps:

[0061] (1) Preparation of the dispersoid of silicon dioxide: silicon dioxide and liquid paraffin with a total amount of 24% were mixed and stirred to be uniformly dispersed to prepare the dispersoid of silicon dioxide;

[0062] (2) Preparation of the dispersoid of sodium loxoprofen: sodium loxoprofen and liquid paraffin with a total amount of 37% were mixed and stirred to be uniformly dispersed to prepare the dispersoid of sodium loxoprofen;

[0063] (3) Mixing and preparing the paste: Under the condition of 160-180℃, when the vacuum degree is controlled to be ≥-95kpa, nitrogen gas is purged to positive pressure. Polyisobutylene, dibutylhydroxytoluene, hydrogenated rosin glycerol, styrene-isoprene-styrene block copolymer and the remaining liquid paraffin are added to the silica dispersion obtained in step (1). The mixture is stirred until it is completely melted and dispersed evenly to obtain a melted dispersion. The melted dispersion is then cooled to 130-135℃. Loxoprofen sodium dispersion, phosphoric acid and L-menthol obtained in step (2) are added. The mixture is stirred evenly to form a paste. Nitrogen gas is continuously purged for protection throughout the mixing and preparing the paste.

[0064] (4) Coating and cutting: Load the dimethyl silicone oil polyester film and polyester fiber cloth into the coating machine. When the temperature of the coating machine rises to 120-140℃, the paste obtained in step (3) is evenly coated on the protective layer to form an adhesive layer. Cover the surface of the adhesive layer with a backing layer. When coating, control the cutting size to 10cm*14cm and the paste weight to be 2.0g±10%, and the patch is obtained.

[0065] Comparative Example 5: A patch prepared according to Example 2 in patent CN 101052384A.

[0066] Comparative Example 6: A patch prepared according to Example 1 in patent CN120346189A.

[0067] Stability test under accelerated conditions

[0068] Example 1, comparative example, and commercially available product (trade name: PAP (Licensed by: LEAD CHEMICAL CO., LTD) was placed under accelerated conditions (40℃±2℃, 75%RH±5%RH) for stability testing. The results are shown in Table 1. Related substances determination method: Related substances were determined according to the imported registration standard JX20210065 for loxoprofen sodium patches; Butylated hydroxytoluene content determination method: High performance liquid chromatography (HPLC) was used according to Part IV, 0512 of the 2025 edition of the Chinese Pharmacopoeia.

[0069] Table 1 Results of accelerated test stability assessment

[0070]

[0071] From Table 1, it can be seen that, in comparison of Example 1 and Comparative Examples 1-2, under the same stirring temperature, the increase of related substances is smaller, the content of antioxidant increases, and the content of related substances is lower and the increase is not obvious in the vacuum extraction + nitrogen protection mode (Example 1), followed by the vacuum extraction mode (Comparative Example 2), and the content of related substances is higher and the increase is larger in the mode without vacuum extraction and nitrogen protection (Comparative Example 1), indicating that the vacuum extraction and nitrogen protection conditions can significantly improve the stability of the sample.

[0072] It can be seen from the comparison of Example 1 and Comparative Examples 3-4 that, under the condition of vacuum extraction and nitrogen protection, the stability is the worst and the increase of related substances is obvious at the mixing temperature of 160-180°C (Comparative Example 4) at 0 days and under the accelerated condition for 6 months, the total impurities increase by 0.64% and the antioxidant decreases by 4% under the accelerated condition for 6 months, and there is no obvious difference in stability at the mixing temperature of 130-145°C.

[0073] It can be seen from the comparison of Example 1 and Comparative Examples 5-6 that, in Comparative Example 5, oxygen is not controlled and vacuum extraction is not performed, and the change trend of related substances and antioxidant is similar to that of Comparative Example 1 (oxygen is not controlled and vacuum extraction is not performed), and the stability result is obviously worse than that of Example 1; in Comparative Example 6, the preparation method is to protect with carbon dioxide at 120-135°C, and the change trend of related substances and antioxidant is similar to that of Comparative Example 3 (130-135°C + nitrogen protection + vacuum extraction) at 0 days and under the accelerated condition for 6 months, indicating that controlling oxygen (nitrogen protection or carbon dioxide protection) and reducing the preparation temperature can significantly improve the related substances and improve the stability under the accelerated condition.

[0074] The stability of the sample of Example 1 under the condition of controlling oxygen and vacuum extraction at the preparation temperature of 140-145°C is better than that of the commercially available product under the accelerated condition for 6 months.

[0075] Evaluation of matrix dissolution time

[0076] The melting time and properties of Example 1, Comparative Examples 1, 3, 4 and 6 were statistically analyzed. The test results are shown in Table 2.

[0077] Table 2 Statistical results of melting time of loxoprofen sodium patch

[0078]

[0079] The experimental results show that the lower the sol temperature, the longer the colloid preparation time, and the sol temperature is reduced from 140-145°C to 130-135°C (comparative example 3), and the paste preparation time is prolonged by about 1.5 h. The above samples are laboratory scale, with a batch size of about 1 kg, and if the batch size is increased to a commercial production scale, the colloid melting preparation time will only be longer. Therefore, if the preparation temperature is too high (160-180°C), the related substances of the paste will obviously increase, and the paste will be slightly yellow; if the preparation temperature is reduced, the stability of the sample can be significantly improved, but if the preparation temperature is too low (comparative example 6, 120-135°C), the flowability of the colloid will be significantly poor and the preparation time will be too long. In summary, the preparation temperature of 140-145°C can combine the related substances and flowability of the paste, shorten the production time, and increase the production capacity.

[0080] Coating time investigation

[0081] The coating time of the loxoprofen sodium patches of example 1, comparative example 1 and comparative examples 5-6 was investigated, and the results are shown in Table 3.

[0082] Table 3 Coating time investigation results

[0083]

[0084] The above test results show that comparative example 1 and comparative example 5 do not control oxygen and vacuum during the preparation process, and the total impurities have exceeded 2.5% when the coating time is 14 h; example 1 and comparative example 6 control oxygen during the preparation process, and the growth trend of the related substances during the coating process is significantly lower than that of comparative examples 1 and 5, and example 1 controls vacuum during the production process, and the growth rate of the total impurities during the coating process is significantly slower than that of comparative example 6, indicating that controlling oxygen and vacuum during the production process can significantly improve the growth of the related substances during the coating process of the sample and prolong the production coating time.

[0085] The above examples are only used to illustrate the technical solutions of the present application, and not to limit them; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that they can still modify the technical solutions described in the foregoing examples, or make equivalent replacements for part of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A loxoprofen sodium patch, characterized in that, It includes a protective layer and an adhesive layer coated on the surface of the protective layer. The paste layer is made of loxoprofen sodium, styrene-isoprene-styrene block copolymer, polyisobutylene, hydrogenated rosin glycerol ester, silica, butylated hydroxytoluene, phosphoric acid, L-menthol, and liquid paraffin. The preparation method of the patch includes the following steps: (1) Preparation of silica dispersion: Silica and some liquid paraffin are mixed and stirred to disperse evenly to prepare silica dispersion; (2) Preparation of loxoprofen sodium dispersion: Loxoprofen sodium and some liquid paraffin are mixed and stirred to disperse evenly to prepare loxoprofen sodium dispersion; (3) Mixing and preparing the paste: Under the condition of 140-145℃, vacuum and nitrogen gas are introduced to positive pressure. Polyisobutylene, dibutylhydroxytoluene, hydrogenated rosin glycerol, styrene-isoprene-styrene block copolymer and the remaining liquid paraffin are added to the silica dispersion obtained in step (1). The mixture is stirred until it is completely melted and dispersed evenly to obtain a melted dispersion. The melted dispersion is then cooled to 130-135℃. Loxoprofen sodium dispersion, phosphoric acid and L-menthol obtained in step (2) are added. The mixture is stirred evenly to form a paste. Nitrogen gas is continuously introduced for protection throughout the mixing and preparing the paste. (4) Coating and cutting: The paste obtained in step (3) is evenly coated on the protective layer to form an adhesive layer. A backing layer is then placed on the surface of the adhesive layer and cut to obtain the patch.

2. The loxoprofen sodium patch according to claim 1, characterized in that, In step (3), when evacuating, nitrogen gas is added to positive pressure when the vacuum level is controlled to be ≥-95 kPa.

3. The loxoprofen sodium patch according to claim 2, characterized in that, The adhesive layer is made of the following components in parts by weight: 5-6 parts of loxoprofen sodium, 15-35 parts of styrene-isoprene-styrene block copolymer, 5-25 parts of polyisobutylene, 5-25 parts of hydrogenated rosin glycerol ester, 0.4-2.0 parts of silica, 0.4-2.0 parts of butylated hydroxytoluene, 0.4-2.0 parts of phosphoric acid, 1-4 parts of L-menthol, and 20-50 parts of liquid paraffin.

4. The loxoprofen sodium patch according to claim 3, characterized in that, The adhesive layer is made of the following components in parts by weight: 5-6 parts of loxoprofen sodium, 20-30 parts of styrene-isoprene-styrene block copolymer, 10-20 parts of polyisobutylene, 10-20 parts of hydrogenated rosin glycerol ester, 0.6-1.0 parts of silica, 0.6-1.0 parts of butylated hydroxytoluene, 0.8-1.2 parts of phosphoric acid, 2-4 parts of L-menthol, and 30-40 parts of liquid paraffin.

5. The loxoprofen sodium patch according to claim 4, characterized in that, The adhesive layer is made of the following components in parts by weight: 5.6-5.7 parts of loxoprofen sodium, 23-25 ​​parts of styrene-isoprene-styrene block copolymer, 14-16 parts of polyisobutylene, 14-16 parts of hydrogenated rosin glycerol ester, 0.7-0.9 parts of silica, 0.7-0.9 parts of butylated hydroxytoluene, 0.9-1.1 parts of phosphoric acid, 2.5-3.5 parts of L-menthol, and 33-35 parts of liquid paraffin; preferably, 5.67 parts of loxoprofen sodium, 24 parts of styrene-isoprene-styrene block copolymer, 15 parts of polyisobutylene, 15 parts of hydrogenated rosin glycerol ester, 0.8 parts of silica, 0.8 parts of butylated hydroxytoluene, 1.0 part of phosphoric acid, 3 parts of L-menthol, and 34.73 parts of liquid paraffin.

6. The method for preparing the loxoprofen sodium patch according to claim 1, characterized in that, Includes the following steps: (1) Preparation of silica dispersion: Silica and some liquid paraffin are mixed and stirred to disperse evenly to prepare silica dispersion; (2) Preparation of loxoprofen sodium dispersion: Loxoprofen sodium and some liquid paraffin are mixed and stirred to disperse evenly to prepare loxoprofen sodium dispersion; (3) Mixing and preparing the paste: Under the condition of 140-145℃, vacuum and nitrogen gas are introduced to positive pressure. Polyisobutylene, dibutylhydroxytoluene, hydrogenated rosin glycerol, styrene-isoprene-styrene block copolymer and the remaining liquid paraffin are added to the silica dispersion obtained in step (1). The mixture is stirred until it is completely melted and dispersed evenly to obtain a melted dispersion. The melted dispersion is then cooled to 130-135℃. Loxoprofen sodium dispersion, phosphoric acid and L-menthol obtained in step (2) are added. The mixture is stirred evenly to form a paste. Nitrogen gas is continuously introduced for protection throughout the mixing and preparing the paste. (4) Coating and cutting: The paste obtained in step (3) is evenly coated on the protective layer to form an adhesive layer. A backing layer is then placed on the surface of the adhesive layer and cut to obtain the patch.

7. The loxoprofen sodium patch according to claim 6, characterized in that, In step (1), the amount of liquid paraffin added is 20%-30% of its total amount, preferably 22%-26%, and more preferably 24%.

8. The loxoprofen sodium patch according to claim 6, characterized in that, In step (2), the amount of liquid paraffin added is 30%-40% of its total amount, preferably 36%-38%, and more preferably 37%.

9. The loxoprofen sodium patch according to claim 6, characterized in that, In step (3), the weight ratio of styrene to isoprene in the styrene-isoprene-styrene block copolymer is 15:85; the viscosity-average molecular weight of the polyisobutylene is 50,000-90,000; preferably, the polyisobutylene is one or more of 5H, 5.5H, 6H, B12N, B15, N50 or N100; more preferably, the polyisobutylene is B15.

10. The loxoprofen sodium patch according to claim 6, characterized in that, In step (4), the coating temperature is 120-140℃; when coating, the weight of the paste is controlled to be 2.0g±10% when the cutting size is 10cm*14cm.

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