A clobetasol propionate ointment and process for its preparation

Abstract

This invention belongs to the field of pharmaceutical formulation technology and relates to a clobetasol propionate ointment and its preparation process. The ointment comprises clobetasol propionate, an emulsifier, a solubilizer, a stabilizer, a secondary stabilizer, and an ointment base. The emulsifier is Tween-80, the solubilizer is propylene glycol, the stabilizer is povidone K15 or povidone K25, the secondary stabilizer is potassium chloride, and the ointment base is white petrolatum. This invention, by adding a stabilizer and a secondary stabilizer and screening their types, prepares a clobetasol propionate ointment that exhibits low impurity content and good stability during long-term storage. Furthermore, the preparation process is simple and easy to operate, facilitating industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology and relates to a clobetasol propionate ointment and its preparation process. Background Technology

[0002] Skin diseases are common and prevalent, with a high incidence rate, seriously affecting people's daily lives and work. Skin diseases are diverse, with complex causes, and are difficult to cure completely, causing varying degrees of suffering for patients. Clobetasol propionate is a potent topical corticosteroid with strong anti-inflammatory, antipruritic, and vasoconstrictive effects. It is widely used to treat pruritic and non-infectious inflammatory skin diseases that respond well to topical corticosteroids, such as chronic eczema, neurodermatitis, psoriasis, palmoplantar pustulosis, lichen planus, and discoid lupus erythematosus. The clinical application of clobetasol propionate is mainly in the form of topical ointment. However, clobetasol propionate ointment is unstable during storage and impurities may form. The main impurity is Impurity J, listed in the European Pharmacopoeia, with the following structural formula: How to ensure that the content of impurities J in clobetasol propionate ointment is reduced and the product quality remains stable during long-term storage by selecting appropriate formulations is an urgent problem that pharmaceutical manufacturers need to solve. Summary of the Invention

[0003] The main objective of this invention is to provide a clobetasol propionate ointment and its preparation process. The prepared clobetasol propionate ointment has a low content of impurities J during long-term storage, good storage stability, and a simple preparation process that is easy for industrial production.

[0004] The present invention provides a clobetasol propionate ointment, the ointment comprising clobetasol propionate, emulsifier, solubilizer, stabilizer, auxiliary stabilizer, and ointment base.

[0005] The clobetasol propionate ointment comprises, by mass percentage, 0.05% clobetasol propionate, 0.45%-0.55% emulsifier, 4.75%-5.62% solubilizer, 0.01%-0.25% stabilizer, 0.002%-0.008% auxiliary stabilizer, and the balance being ointment base.

[0006] Preferably, the emulsifier is Tween-80, the solubilizer is propylene glycol, the stabilizer is povidone, the auxiliary stabilizer is potassium chloride, and the ointment base is white petrolatum.

[0007] More preferably, the stabilizer is povidone K15 or povidone K25.

[0008] Preferably, the ointment comprises, by mass percentage, 0.05% clobetasol propionate, 0.5% emulsifier, 5.2% solubilizer, 0.1% stabilizer, 0.006% auxiliary stabilizer, and the remainder being ointment base.

[0009] Preferably, the ointment comprises, by mass percentage, 0.05% clobetasol propionate, 0.5% emulsifier, 5.2% solubilizer, 0.01% stabilizer, 0.006% auxiliary stabilizer, and the remainder being ointment base.

[0010] Preferably, the ointment comprises, by mass percentage, 0.05% clobetasol propionate, 0.5% emulsifier, 5.2% solubilizer, 0.25% stabilizer, 0.006% auxiliary stabilizer, and the remainder being ointment base.

[0011] Preferably, the ointment comprises, by mass percentage, 0.05% clobetasol propionate, 0.5% emulsifier, 5.2% solubilizer, 0.1% stabilizer, 0.002% auxiliary stabilizer, and the balance being ointment base.

[0012] Preferably, the ointment comprises, by mass percentage, 0.05% clobetasol propionate, 0.5% emulsifier, 5.2% solubilizer, 0.1% stabilizer, 0.008% auxiliary stabilizer, and the balance being ointment base.

[0013] The present invention also provides a method for preparing clobetasol propionate ointment, comprising the following steps: (1) mixing emulsifier and solubilizer under stirring conditions to form a uniform emulsion; (2) adding stabilizer and auxiliary stabilizer to the emulsion, stirring evenly, then adding clobetasol propionate, mixing evenly to obtain a mixture; (3) heating and melting the ointment base at 80-85°C, and then cooling to about 50°C; (4) mixing and homogenizing the mixture obtained in step (2) with the pretreated ointment base, and cooling to room temperature to obtain clobetasol propionate ointment.

[0014] Compared with the prior art, the beneficial effects of the present invention are as follows: the clobetasol propionate ointment prepared by the present invention by adding stabilizers and auxiliary stabilizers and screening their types has a low content of impurities J during long-term storage and has good stability. Moreover, the preparation process is simple and easy to operate, and is easy to industrialize. Detailed Implementation

[0015] In view of the deficiencies of the prior art, the inventors, through long-term research and extensive practice, have proposed the technical solution of this invention. The invention is further illustrated below by means of embodiments, but these embodiments do not constitute a limitation of the invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without inventive effort are within the scope of protection of this invention.

[0016] Example 1: Stabilizer Addition and Type Screening The concentrations of each component by mass percentage are shown in the table below. Preparation method: (1) Tween-80 and propylene glycol are mixed into a uniform emulsion under stirring conditions; (2) Stabilizer and auxiliary stabilizer potassium chloride are added to the emulsion, stirred evenly, and then clobetasol propionate is added and mixed evenly to obtain a mixture; (3) White petrolatum is heated to melt at 85°C and then cooled to about 50°C; (4) The mixture obtained in step (2) is mixed with pretreated white petrolatum, homogenized, and cooled to room temperature to obtain clobetasol propionate ointment.

[0017] The ointment samples were placed at 60℃ for 10 days to investigate the effect of temperature on impurity J in clobetasol propionate ointment. The results are shown in the table below.

[0018] The results in the table above show that, without the addition of a stabilizer, the clobetasol propionate ointment prepared by Formula 1 had a high content of impurity J after being stored at 60℃ for 10 days. Formulas 3 and 4, using polyethylene glycol 400 and sodium dodecyl sulfate as stabilizers respectively, also showed a significant increase in the content of impurity J in the clobetasol propionate ointment after being stored at 60℃ for 10 days. However, Formula 2, using povidone K15 as a stabilizer, maintained essentially unchanged impurity J content and stable quality after being stored at 60℃ for 10 days.

[0019] Example 2: Screening of Povidone Species The concentrations of each component by mass percentage are shown in the table below. The preparation method is the same as in Example 1.

[0020] The ointment samples were placed at 60℃ for 10 days to investigate the effect of temperature on impurity J in clobetasol propionate ointment. The results are shown in the table below.

[0021] The results in the table above show that, in formulations 5 and 7, which use povidone K12 and povidone K30 as stabilizers respectively, the impurity content J of the prepared clobetasol propionate ointment increased significantly after being placed at 60°C for 10 days. In contrast, in formulations 2 and 6, which use povidone K15 and povidone K25 as stabilizers respectively, the impurity content J of the prepared ointments remained essentially unchanged after being placed at 60°C for 10 days, indicating stable quality.

[0022] Example 3: Addition and screening of auxiliary stabilizers The concentrations of each component by mass percentage are shown in the table below. The preparation method is the same as in Example 1.

[0023] The ointment samples were placed at 60℃ for 10 days to investigate the effect of temperature on impurity J in clobetasol propionate ointment. The results are shown in the table below.

[0024] The results in the table above show that when the stabilizer povidone K15 is added, the content of impurity J is relatively high in formulation 8 without the addition of auxiliary stabilizers. When formulations 9 and 10 use sodium chloride and calcium chloride as auxiliary stabilizers, the content of impurity J in the prepared clobetasol propionate ointment is also significantly increased after being placed at 60°C for 10 days.

[0025] Example 4 Long-term stability test The concentrations of each component by mass percentage are shown in the table below. Formula 15: Prepare an ointment according to the formula and preparation method of Implementation 1 of CN109833291B.

[0026] Formula 16: Prepare an ointment according to the formula and preparation method of 0.3% (w / w) carbomer 980 in Implementation 6 of CN109833291B.

[0027] The clobetasol propionate ointments prepared according to formulas 2, 6, and 11-16 were placed at 18°C ​​for 24 months for long-term stability testing. The results are as follows: The results in the table above show that when clobetasol propionate ointment is prepared using povidone K15 or povidone K25 as a stabilizer and potassium chloride as an auxiliary stabilizer, the content of impurity J is low after being stored at 18°C ​​for 24 months. It has good stability, can be stored for a long time, and its stability is better than that of the formulation in the existing technology CN109833291B.

[0028] It should be understood that the technical solutions of the present invention are not limited to the specific embodiments described above. Any technical modifications made to the technical solutions of the present invention without departing from the spirit and scope of the claims are within the scope of protection of the present invention.

Claims

1. A clobetasol propionate ointment, characterized in that, The ointment comprises clobetasol propionate, emulsifier, solubilizer, stabilizer, auxiliary stabilizer, and ointment base. The emulsifier is Tween-80, the solubilizer is propylene glycol, the stabilizer is povidone K15 or povidone K25, the auxiliary stabilizer is potassium chloride, and the ointment base is white petrolatum.

2. The clobetasol propionate ointment according to claim 1, characterized in that, The ointment comprises, by mass percentage, 0.05% clobetasol propionate, 0.45%-0.55% emulsifier, 4.75%-5.62% solubilizer, 0.01%-0.25% stabilizer, 0.002%-0.008% auxiliary stabilizer, and the balance being ointment base.

3. The clobetasol propionate ointment according to any one of claims 1-2, characterized in that, The ointment comprises, by mass percentage, 0.05% clobetasol propionate, 0.5% emulsifier, 5.2% solubilizer, 0.1% stabilizer, 0.006% auxiliary stabilizer, and the remainder being ointment base.

4. The clobetasol propionate ointment according to any one of claims 1-2, characterized in that, The ointment comprises, by mass percentage, 0.05% clobetasol propionate, 0.5% emulsifier, 5.2% solubilizer, 0.01% stabilizer, 0.006% auxiliary stabilizer, and the remainder being ointment base.

5. The clobetasol propionate ointment according to any one of claims 1-2, characterized in that, The ointment comprises, by mass percentage, 0.05% clobetasol propionate, 0.5% emulsifier, 5.2% solubilizer, 0.25% stabilizer, 0.006% auxiliary stabilizer, and the remainder being ointment base.

6. The clobetasol propionate ointment according to any one of claims 1-2, characterized in that, The ointment comprises, by mass percentage, 0.05% clobetasol propionate, 0.5% emulsifier, 5.2% solubilizer, 0.1% stabilizer, 0.002% auxiliary stabilizer, and the remainder being ointment base.

7. The clobetasol propionate ointment according to any one of claims 1-2, characterized in that, The ointment comprises, by mass percentage, 0.05% clobetasol propionate, 0.5% emulsifier, 5.2% solubilizer, 0.1% stabilizer, 0.008% auxiliary stabilizer, and the remainder being ointment base.

8. The method for preparing clobetasol propionate ointment according to any one of claims 1-7, characterized in that, The preparation method includes the following steps: (1) mixing emulsifier and solubilizer under stirring conditions to form a uniform emulsion; (2) adding stabilizer and auxiliary stabilizer to the emulsion, stirring evenly, then adding clobetasol propionate, mixing evenly to obtain a mixture; (3) heating and melting the ointment base at 80-85°C, and then cooling to about 50°C; (4) mixing and homogenizing the mixture obtained in step (2) with the pretreated ointment base, and cooling to room temperature to obtain clobetasol propionate ointment.

9. The method for preparing clobetasol propionate ointment according to claim 8, characterized in that, The ointment base is heated and melted at 85°C.

10. Clobetasol propionate ointment prepared by the preparation method according to any one of claims 8-9.

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