Fusidic acid cream and preparation method thereof

Abstract

The present invention provides a fusidic acid cream preparation, comprising an active ingredient fusidic acid, an aqueous phase part and an oil phase part, wherein the aqueous phase part comprises glycerol, a preservative and purified water; the oil phase part comprises an oily base and an emulsifier; further, in order to avoid the increase of impurities caused by the addition of antioxidants to the excipients due to their thermal instability, the cream does not contain antioxidants. After testing, the stability of the fusidic acid cream of the present application is better than that of the commercially available reference preparation, and it can maintain the stability of the paste properties and active ingredients under high temperature, high humidity, low temperature, freeze-thaw and light conditions. The maximum single impurity and total impurity content in the product do not increase significantly, and the quality is controllable. At the same time, the preparation process of the fusidic acid cream disclosed in the present application is simple and easy to industrialize.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a fusidic acid cream and a preparation method thereof. Background Art

[0002] Fusidic Acid Cream is an antibiotic topical medication used to treat skin infections caused by Staphylococcus, Streptococcus, Propionibacterium acnes, Corynebacterium parvum, and other fusidic acid-sensitive bacteria. It is primarily indicated for skin infections caused by impetigo, furuncles, carbuncles, paronychia, wound infections, dermatitis barbae, hidradenitis, erythrasma, folliculitis, and acne vulgaris, particularly on the face and head.

[0003] Cream preparations are typically stored in a sealed container at room temperature (10-30°C), and their stability is poorer than other solid preparations. Therefore, cream preparations are prone to changes in properties during daily transportation, storage, and long-term clinical use, such as oil-water separation (emulsification), color change, and odor, which can reduce the quality and effective shelf life of the cream. Furthermore, the total amount of impurities in fusidic acid cream increases and the content of active ingredients decreases during long-term or high-temperature storage. These problems can adversely affect the quality and stability of fusidic acid cream. Therefore, there is an urgent need for a fusidic acid cream with stable properties and better quality for clinical use.

[0004] Currently available fusidic acid creams incorporate antioxidants (such as butylated hydroxytoluene, butylated hydroxyanisole, and EDTA) and preservatives (such as chlorocresol, potassium sorbate, and benzoic acid) to enhance their stability and antibacterial properties. If the preservative's antibacterial efficacy is weak, further antibacterial enhancers are added to improve its effectiveness. Commonly used antioxidants such as butylated hydroxyanisole and butylated hydroxytoluene are synthetic antioxidants with poor thermal stability, easily volatile and ineffective above 70°C. In recent years, the application scope of these synthetic oxidants has gradually narrowed.

[0005] Paraben preservatives, also known as paraben antibacterial preservatives, are low in toxicity, odorless, tasteless, stable, and resistant to high-temperature decomposition. They exhibit good antibacterial activity within a pH range of 4 to 8. Due to the formation of phenolate anions, their antibacterial efficacy increases with decreasing pH, demonstrating a strong inhibitory effect against Gram-negative and Gram-positive bacteria, yeasts, and molds.

[0006] Patent CN104758242 A discloses a sodium fusidate ointment pharmaceutical composition and a preparation method thereof, comprising sodium fusidate, an ointment base, an emulsifier, and an antioxidant, but without a preservative; Patent CN 107224426 A discloses a topical cream composition containing fusidic acid, comprising the main ingredient fusidic acid, an oil phase solvent, an emulsifier, an auxiliary emulsifier, an antioxidant, a thickener, an aqueous phase solvent, and a hydrolysis stabilizer, but without a preservative; both ointments contain antioxidants, which is sufficient to illustrate the important role of antioxidants in the stability of fusidic acid cream preparations.

[0007] Patent CN104706579 A discloses a fusidic acid eye drop and a preparation method thereof, comprising fusidic acid, a thickener, an osmotic pressure regulator, a preservative, a metal ion chelating agent, a pH regulator, and water for injection, which does not contain an antioxidant. Because the eye drop is directly applied to the eyeball, it has strict quality requirements for pH value, osmotic pressure, viscosity, and sterility and preservation. Although preservatives have been added, it is easily contaminated by tears and microorganisms during storage and application. Therefore, the Pharmacopoeia "General Rules for Preparations" clearly stipulates that the use time of ophthalmic preparations after activation shall not exceed four weeks. Fusidic acid cream preparations are directly used on the skin surface. Because they are in an environment exposed to air and light for a long time, they should meet the requirements of long-term use and storage. The antioxidant and antiseptic requirements of the product during the preparation process are relatively strict, thereby increasing the complexity of the preparation prescription and production process. The fusidic acid cream products currently on sale all contain antioxidants and preservatives at the same time, and there is no patent literature report on fusidic acid cream preparations that do not contain antioxidants. Summary of the Invention

[0008] To solve the quality and stability problems of fusidic acid cream and avoid the increase of impurities caused by the thermal instability of antioxidants added to excipients, the present application provides a fusidic acid cream without antioxidants. The quality stability of the fusidic acid cream is better than that of the commercially available product (Lisdin), and it has good antiseptic and antioxidant effects. It can still maintain the stability of the paste properties and active ingredients under different environments (temperature, humidity, light); at the same time, the present application also provides a preparation method of fusidic acid cream, which has a simple process and is easy to industrialize. To achieve the above purpose, the present invention adopts the following technical solutions:

[0009] A fusidic acid cream comprises fusidic acid as an active ingredient, an aqueous phase part and an oil phase part; the aqueous phase part comprises glycerin, a preservative and purified water; the oil phase part comprises an oily base and an emulsifier; further, the cream does not contain an antioxidant.

[0010] In one embodiment of the present application, the preservative is a hydroxyphenyl ester preservative; further, the hydroxyphenyl ester preservative is methylparaben or ethylparaben.

[0011] In one embodiment of the present application, the emulsifier is selected from one or more of polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan stearate, and polyoxyethylene sorbitan monooleate.

[0012] In one embodiment of the present application, the oil phase base includes white petrolatum, liquid paraffin and cetyl alcohol.

[0013] In one embodiment of the present application, every 100 parts by weight of fusidic acid cream comprises the following components in parts by weight: 1.0-3.0 parts of fusidic acid, 25.0-35.0 parts of oily base, 4.0-6.0 parts of emulsifier, 8.0-12.0 parts of glycerin, 0.1-0.3 parts of preservative and 50.0-55.0 parts of purified water.

[0014] Furthermore, the oily base comprises the following components in parts by weight: 4.0-10.0 parts of white vaseline, 10.0-15.0 parts of liquid paraffin and 10.0-15.0 parts of hexadecanol.

[0015] In one embodiment of the present application, the pH of the cream is further adjusted to 4.0-6.5 using hydrochloric acid or sodium hydroxide.

[0016] The present application also provides a method for preparing the above-mentioned fusidic acid cream, which specifically comprises the following steps:

[0017] (1) Preparation of the aqueous phase: Heat purified water to 70-75°C, add preservatives and glycerin, stir and mix, and keep warm for later use;

[0018] (2) Preparation of the oil phase: Heat the oily base and emulsifier until they are melted to obtain the oil phase, and keep the temperature at 70-75°C for later use;

[0019] (3) Total mixing: the aqueous phase and the oil phase are mixed, the active ingredient is added, and the mixture is stirred to obtain a total mixture;

[0020] (4) Cooling: Cool the total mixture to room temperature to obtain fusidic acid cream.

[0021] Furthermore, in the preparation method of the above-mentioned fusidic acid cream, the step (3) also includes the process of adding an appropriate amount of hydrochloric acid or sodium hydroxide to adjust the pH value of the total mixture to a range of 4.0-6.5.

[0022] The beneficial effects of this application are:

[0023] The fusidic acid cream formulation disclosed herein does not contain antioxidants. By combining a polysorbate emulsifier with a hydroxyphenyl ester preservative, it produces a fusidic acid cream formulation with stable properties and controllable quality. Testing has shown that the fusidic acid cream disclosed herein is more stable than a commercially available reference formulation, maintaining stable properties under conditions of high temperature, high humidity, low temperature, freeze-thaw, and light exposure, with no significant increase in the maximum single or total impurity levels in the product. Furthermore, the fusidic acid cream disclosed herein has a simple preparation process and is amenable to industrial production. DETAILED DESCRIPTION

[0024] The technical solution of the present application is further described below with reference to specific embodiments, but is not intended to limit the present application.

[0025] Example 1

[0026]

[0027]

[0028] Preparation method:

[0029] (1) Preparation of the aqueous phase: Heat purified water to 70°C to 75°C, add methylparaben and glycerin, stir and mix, and keep warm for later use;

[0030] (2) Preparation of the oil phase: Heat the oily base (white vaseline, liquid paraffin, hexyl alcohol) and polyoxyethylene sorbitan monopalmitate until they are melted to obtain the oil phase, and keep the mixture at 70°C to 75°C for later use;

[0031] (3) Total mixing: the oil phase and the aqueous phase are mixed, fusidic acid as the main drug is added, and the mixture is stirred to obtain a total mixture; further, an appropriate amount of hydrochloric acid or sodium hydroxide is added to adjust the pH value of the total mixture to a range of 4.0 to 6.5;

[0032] (4) Cooling: Cool the total mixture to room temperature to obtain fusidic acid cream.

[0033] Example 2

[0034]

[0035] Preparation method:

[0036] (1) Preparation of the aqueous phase: Heat purified water to 70-75°C, add methylparaben and glycerin, stir and mix, and keep warm for later use;

[0037] (2) Preparation of the oil phase: Heat the oily base (white vaseline, liquid paraffin, hexyl alcohol) and polyoxyethylene sorbitan stearate until they are melted to obtain the oil phase, and keep the mixture at 70-75°C for later use;

[0038] (3) Total mixing: the oil phase and the aqueous phase are mixed, fusidic acid as the main drug is added, and the mixture is stirred to obtain a total mixture; further, an appropriate amount of hydrochloric acid or sodium hydroxide is added to adjust the pH value of the total mixture to a range of 4.0 to 6.5;

[0039] (4) Cooling: Cool the total mixture to room temperature to obtain fusidic acid cream.

[0040] Example 3

[0041]

[0042] Preparation method:

[0043] (1) Preparation of the aqueous phase: Heat purified water to 70-75°C, add ethyl hydroxybenzoate and glycerin, stir and mix, and keep warm for later use;

[0044] (2) Preparation of the oil phase: Heat the oily matrix (white vaseline, liquid paraffin, hexadecanol) and polyoxyethylene sorbitan monooleate until they are melted to obtain the oil phase, and keep the mixture at 70-75°C for later use;

[0045] (3) Total mixing: the oil phase and the aqueous phase are mixed, fusidic acid as the main drug is added, and the mixture is stirred to obtain a total mixture; further, an appropriate amount of hydrochloric acid or sodium hydroxide is added to adjust the pH value of the total mixture to a range of 4.0 to 6.5;

[0046] (4) Cooling: Cool the total mixture to room temperature to obtain fusidic acid cream.

[0047] Example 4

[0048]

[0049] Preparation method:

[0050] (1) Preparation of the aqueous phase: Heat purified water to 70-75°C, add ethyl hydroxybenzoate and glycerin, stir and mix, and keep warm for later use;

[0051] (2) Preparation of the oil phase: Heat the oily matrix (white vaseline, liquid paraffin, hexadecanol) and polyoxyethylene sorbitan monopalmitate until they are melted to obtain the oil phase, and keep the mixture at 70-75°C for later use;

[0052] (3) Total mixing: the oil phase and the aqueous phase are mixed, fusidic acid as the main drug is added, and the mixture is stirred to obtain a total mixture; further, an appropriate amount of hydrochloric acid or sodium hydroxide is added to adjust the pH value of the total mixture to a range of 4.0 to 6.5;

[0053] (4) Cooling: Cool the total mixture to room temperature to obtain fusidic acid cream.

[0054] Example 5

[0055]

[0056]

[0057] Preparation method:

[0058] (1) Preparation of the aqueous phase: Heat purified water to 70-75°C, add methylparaben and glycerin, stir and mix, and keep warm for later use;

[0059] (2) Preparation of the oil phase: Heat the oily matrix (white vaseline, liquid paraffin, hexadecanol) and polyoxyethylene sorbitan monopalmitate until they are melted to obtain the oil phase, and keep the mixture at 70-75°C for later use;

[0060] (3) Total mixing: the oil phase and the aqueous phase are mixed, fusidic acid as the main drug is added, and the mixture is stirred to obtain a total mixture; further, an appropriate amount of hydrochloric acid or sodium hydroxide is added to adjust the pH value of the total mixture to a range of 4.0 to 6.5;

[0061] (4) Cooling: Cool the total mixture to room temperature to obtain fusidic acid cream.

[0062] Control Example

[0063] To investigate the effects of polysorbate emulsifiers and hydroxyphenyl ester preservatives on the stability of fusidic acid cream formulations, fusidic acid creams of Reference Examples 1-5 were prepared according to the formulation recipes in the table below. The preparation methods of the reference examples were similar to those of Example 1. The preservative in Reference Example 1 was potassium sorbate; methylparaben was not added as a preservative in Reference Example 2; sodium lauryl sulfate was used as an emulsifier in Reference Example 3; glyceryl mono- and distearate was used as an emulsifier in Reference Example 4; and butylated hydroxyanisole, an antioxidant, was added to Reference Example 5. The reference preparation (commercially available Lisdin) differs from our fusidic acid cream in that the reference preparation contains an antioxidant and potassium sorbate as a preservative.

[0064]

[0065]

[0066] Stability test

[0067] In accordance with the Stability Test Guidelines (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 9001) and the Technical Guidelines for Stability Studies of Chemical Drugs (APIs and Preparations), fusidic acid cream preparations were tested for influencing factors and uniformity stability. The samples tested were fusidic acid creams of Examples 1-5, Control Examples 1-5, and the reference preparation (commercially available Lisdin).

[0068] 1. Investigation of influencing factors

[0069] High temperature 40℃ test with packaging materials: Take 3 samples of each type and place them in a 40℃ constant temperature box for 30 days. Take 1 sample each on the 5th, 10th and 30th days to observe the properties and detect related substances.

[0070] Light tape packaging material test: Take 3 samples of each type, place them in a light box, and place them under the conditions of illumination of 5000 Lux and ultraviolet energy of 0.9 W / m2 for 30 days. Take 1 sample each on the 5th, 10th and 30th days, observe the properties and detect related substances.

[0071] High humidity belt packaging material test: Take 3 pieces of each sample and place them in a RH92.5% desiccator for 30 days. Take 1 piece of sample each on the 5th, 10th and 30th days to observe the properties and test for related substances.

[0072] Low-temperature packaging material test: Take three samples of each type and place them at 2-8°C for two days. Then, place them at 40°C for two days. Take one sample and observe its properties and test for related substances. This is one cycle, and there are three cycles in total.

[0073] Freeze-thaw zone packaging material test: Take three samples of each type and place them at -20 to -10°C for 2 days, then at 40°C for 2 days. Take one sample and observe its properties and test for related substances. This is one cycle, and there are 3 cycles in total.

[0074] Table 1 Summary of test results of factors affecting fusidic acid cream samples (high temperature, high humidity, light)

[0075]

[0076]

[0077] Table 2 Summary of results of related substances (%) in the test of factors affecting fusidic acid cream samples (high temperature, high humidity, light)

[0078]

[0079]

[0080]

[0081] Table 3 Summary of test results of factors affecting fusidic acid cream samples (low temperature, freeze-thaw)

[0082]

[0083] Table 4 Summary of results of related substances (%) in the test of factors affecting fusidic acid cream samples (low temperature, freeze-thaw)

[0084]

[0085]

[0086] The above stability test results show that the properties of the fusidic acid creams of Examples 1-5 did not change significantly under high temperature, high humidity, light, low temperature and freeze-thaw, and the maximum single impurities and total impurities did not increase significantly; the control examples 3-4 showed demulsification after long-term high temperature, high humidity and freeze-thaw; the control examples 1-5 showed significant increases in the maximum single impurities and total impurities under high temperature, high humidity, light, low temperature and freeze-thaw, and the maximum single impurities and total impurities of the commercially available reference preparations also increased significantly. Examples 1-5 of the present application performed better than the commercially available reference preparations.

[0087] In summary, it can be seen that the stability of the fusidic acid creams of Examples 1-5 under different environmental conditions is not only significantly better than that of the fusidic acid creams of Control Examples 1-5, but also better than the commercially available reference preparation, Lisdin. This shows that by combining the polysorbate emulsifier and the hydroxyphenyl ester preservative without adding an antioxidant, a fusidic acid cream preparation with stable properties and controllable quality can be obtained.

[0088] 2. Uniformity inspection

[0089] Long-term test: The fusidic acid cream samples of Examples 1-5, Control Examples 1-5, and the reference preparation Lisdin were placed vertically under accelerated conditions (40°C ± 2°C; RH 75% ± 5%) for 6 months; samples were taken at 0 and 6 months, and the active ingredient content in the neck, middle, and tail of the fusidic acid cream tube was tested. The active ingredient content limit requirement was 95.0%-105.0%.

[0090] The sampling test results are shown in Table 5 below. It can be clearly seen that the uniformity of the active ingredient content of the fusidic acid creams of Control Examples 1-5 is poor and does not meet the prescribed content limit requirements; the uniformity of the active ingredient content of the fusidic acid creams of Examples 1-5 is significantly better than that of Control Examples 1-5, which are within the content limit requirements, and the uniformity of the active ingredient content is better than that of the commercially available reference preparation.

[0091] Table 5 Fusidic acid cream sample content uniformity stability long-term test results

[0092]

[0093]

[0094] 3. Microbial limit investigation

[0095] Long-term test: Fusidic acid cream samples from Examples 1-5, Control Examples 1-5, and the reference preparation, Lisdin, were placed vertically under accelerated conditions (40°C ± 2°C; RH 75% ± 5%) for 6 months. Samples were taken at 0 and 6 months, and the microbial limits in the creams were tested. The results of the microbial limit test are shown in Table 6 below. It can be seen that the microbial limits of Examples 1-5 and Control Examples 3-5 all met the requirements, while the microbial limits of Control Examples 1 and 2 (both of which did not contain the preservative hydroxypropyl methyl ester) did not meet the requirements after 6 months of acceleration. This demonstrates the necessity of adding a hydroxypropyl ester preservative to the fusidic acid cream formulation of the present application.

[0096] Table 6 Results of long-term microbial stability test of fusidic acid cream samples

[0097]

[0098] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application should be included in the scope of protection of the present application.

Claims

1. A fusidic acid cream, characterized in that, The cream contains the active ingredient fusidic acid, an aqueous phase part and an oil phase part; the aqueous phase part includes glycerin, a preservative and purified water; the oil phase part includes an oily matrix and an emulsifier; the cream does not contain an antioxidant; the preservative is a hydroxyphenyl ester preservative; the emulsifier is selected from one or more of polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan stearate, and polyoxyethylene dehydrated sorbitan monooleate.

2. Fusidic acid cream according to claim 1, is characterized in that, The hydroxybenzoate preservative is methylparaben or ethylparaben.

3. Fusidic acid cream according to claim 1, is characterized in that, The oily base includes white petrolatum, liquid paraffin and cetyl alcohol.

4. Fusidic acid cream according to claim 1, characterized in that, Every 100 parts by weight of the fusidic acid cream comprises the following components in parts by weight: 1.0-3.0 parts of fusidic acid, 25.0-35.0 parts of oily base, 4.0-6.0 parts of emulsifier, 8.0-12.0 parts of glycerin, 0.1-0.3 parts of preservative and 48.0-55.0 parts of purified water.

5. Fusidic acid cream according to claim 4, characterized in that, The oily base comprises the following components in parts by weight: 4.0-10.0 parts of white vaseline, 10.0-15.0 parts of liquid paraffin and 10.0-15.0 parts of hexadecanol.

6. The fusidic acid cream according to claim 1, wherein The pH of the cream is also adjusted to a range of 4.0 to 6.5 using hydrochloric acid or sodium hydroxide.

7. A method for preparing the fusidic acid cream according to any one of claims 1 to 6, characterized in that: The specific steps include: (1) Preparation of the aqueous phase: Heat purified water to 70-75°C, add preservatives and glycerin, stir and mix, and keep warm for later use; (2) Preparation of the oil phase: Heat the oily base and emulsifier until they are melted to obtain the oil phase, and keep the temperature at 70-75°C for later use; (3) Total mixing: the aqueous phase and the oil phase are mixed, the active ingredient is added, and the mixture is stirred to obtain a total mixture; (4) Cooling: Cool the total mixture to room temperature to obtain fusidic acid cream.

8. The preparation method of fusidic acid cream according to claim 7, wherein The step (3) further comprises adding an appropriate amount of hydrochloric acid or sodium hydroxide to adjust the pH value of the total mixture to a range of 4.0-6.5.

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