A method for preparing a fusidic acid cream

Abstract

The application is a preparation method of fusidic acid cream, which comprises fusidic acid in a dispersed form, wherein the concentration of fusidic acid is 2%, the fusidic acid is in a dispersed form through ions, the ions are generated by hydrochloric acid, the drug phase is prepared by an acid combination, the emulsification reaction is carried out at a homogenization head speed of 0.55-1.00 m / s, a stirring speed of less than 0.55 m / s and a temperature of 75 DEG C for 20+ / -5 minutes; and the drug phase is prepared at a stirring speed of 0.3+ / -0.2 m / s and a temperature of 50+ / -5 DEG C for 40+ / -10 minutes. The application has the advantages that: by adding hydrochloric acid in the drug phase and reasonably designing the emulsification, drug phase preparation and adding steps, the fusidic acid is uniformly dispersed in the finished product, and the fusidic acid agglomeration is not formed in the finished product, and the dispersion uniformity is improved.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of fusidic acid cream, belonging to the technical field of fusidic acid composition preparation. BACKGROUND

[0002] US20120040946A1 discloses a pharmaceutical fusidic acid cream made from sodium fusidate, containing a biopolymer, and discloses a preparation process. The drug substance form of sodium fusidate is converted in situ to fusidic acid.

[0003] US20110301138A1 and EP2403480A1 disclose a process for making a fusidic acid-containing cream from sodium fusidate as a starting material, wherein sodium fusidate is converted to fusidic acid in an oxygen-free environment generated using an inert gas, preferably nitrogen.

[0004] US20160303142A1 discloses a topical composition containing fusidic acid. The homogeneity of fusidic acid is 90%-110% of the recommended fusidic acid content, and the amount of air in the cream is less than 5% of the total volume.

[0005] US20110281830A1 discloses a skin cream containing a steroid and an antibacterial agent, formed in situ from sodium fusidate as a starting material, wherein sodium fusidate is converted to fusidic acid in an oxygen-free environment.

[0006] US20110301137A1 discloses a process for making a fusidic acid-containing gel from sodium fusidate as a starting material, wherein sodium fusidate is converted to fusidic acid in an oxygen-free environment containing an inert gas, preferably nitrogen.

[0007] US20110009375A1 discloses a new dosing regimen for the treatment and prevention of bacterial infections using fusidic acid.

[0008] None of the above patent documents discloses the influence of ion pairs on the agglomeration of fusidic acid, which is a key problem in developing a fusidic acid cream with an active ingredient content of 2%.

[0009] Depending on the pH of the cream, fusidic acid can exist in different ionic forms. The addition of hydrochloric acid can lower the pH, but may affect the charge of fusidic acid. Depending on the net charge of fusidic acid at a particular pH, the ionic interaction between fusidic acid molecules can be affected by H + and Cl - .

[0010] The commercially available fusidic acid cream contains 2% fusidic acid dispersed in a cream base consisting of all-rac-alpha-tocopherol, butylated hydroxyanisole, cetyl alcohol, glycerin, hydrochloric acid, white soft paraffin, liquid paraffin, polysorbate 60, potassium sorbate, purified water. The dispersion of fusidic acid in the cream is difficult. SUMMARY

[0011] The present application proposes a preparation method of fusidic acid cream, which aims to overcome the above-mentioned deficiencies in the prior art and improve the dispersibility of fusidic acid in the cream.

[0012] The technical solution of the present application is a fusidic acid cream containing fusidic acid in a dispersed form, wherein the concentration of fusidic acid is 2%, and the fusidic acid is in a dispersed form by ions.

[0013] Preferably, it also includes butylated hydroxyanisole, cetostearyl alcohol, liquid paraffin, white soft paraffin, all-rac-alpha-tocopherol, glycerin (85%), polysorbate 60, potassium sorbate, and purified water.

[0014] Preferably, the ion is generated by using a single acid or any combination of acids selected from hydrochloric acid, sulfuric acid, citric acid, acetic acid, and phosphoric acid.

[0015] Preferably, the acid is hydrochloric acid.

[0016] A preparation method of fusidic acid cream, which comprises preparing the drug phase or the aqueous phase with an acid combination.

[0017] Preferably, it comprises preparing the drug phase with an acid combination.

[0018] Preferably, it comprises emulsifying by using homogenization and / or stirring, preparing the drug phase by using homogenization and / or stirring, and adding the drug phase by using homogenization and / or stirring.

[0019] Preferably, the emulsification reaction temperature is not lower than 70°C, the homogenization head speed is less than 1.0 m / s, the drug phase preparation homogenization head speed is less than 1.0 m / s, and the drug phase addition homogenization head speed is less than 1.0 m / s.

[0020] Preferably, the emulsification reaction homogenization head speed is 0.55-1.00 m / s, the stirring speed is less than 0.55 m / s, and it is carried out at 75°C for 20±5 minutes; the drug phase preparation stirring speed is 0.3±0.2 m / s, and it is stirred at 50±5°C for 40±10 minutes.

[0021] The present application has the advantages that the formula and preparation process are rationally designed, the uniform dispersion of fusidic acid in the product is achieved by adding hydrochloric acid in the drug phase and rationally designing the emulsification, drug phase preparation and adding steps, and the formation of fusidic acid agglomeration in the product is avoided, so that the uniformity of dispersion is effectively improved. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 is an electron microscope graph of the embodiment 1 of the present application.

[0023] Figure 2 is an electron microscope graph of the embodiment 2 of the present application.

[0024] Figure 3 is an electron microscope graph of the commercially available product.

[0025] Figure 4 is a graph of the results of the polymorphism study of the embodiment 6 of the present application.

[0026] Figure 5 is a graph of the results of the in-vitro release study of the embodiment 7 of the present application.

[0027] Figure 6 is a graph of the results of the in-vitro permeation study of the embodiment 8 of the present application. DETAILED DESCRIPTION

[0028] The present application will be further described in detail below in combination with the embodiments and specific implementation manners.

[0029] A fusidic acid cream comprising fusidic acid in a dispersed form, the concentration of the fusidic acid being 2%.

[0030] A preparation method of a fusidic acid cream, comprising uniformly dispersing fusidic acid in a product without forming fusidic acid agglomeration in the product.

[0031] As an embodiment, the fusidic acid cream comprises fusidic acid, butylated hydroxyanisole, cetostearyl alcohol, liquid paraffin, white soft paraffin, all-rac-α-tocopherol, glycerin (85%), Tween 60, potassium sorbate and purified water.

[0032] As an embodiment, the preparation method of the fusidic acid cream comprises a combination of the drug phase or the water phase with an acid for preparation, for uniformly dispersing fusidic acid in a product.

[0033] As an embodiment, the preparation method of the fusidic acid cream comprises a combination of the drug phase with an acid for preparation.

[0034] As a further embodiment, the fusidic acid in the fusidic acid cream is in a dispersed form together with ions to show the influence of the ions.

[0035] As a further embodiment, in the method of preparing the fusidic acid cream, the step of low shear mixing is used to disperse the fusidic acid uniformly in the finished product by stirring or homogenization or a combination of both, specifically comprising three unit steps: emulsification, drug phase preparation and drug phase addition.

[0036] As a further embodiment, in the fusidic acid cream, the ions are produced using a single acid or any combination of acids selected from the group consisting of hydrochloric acid, sulfuric acid, citric acid, acetic acid, phosphoric acid.

[0037] As a most preferred embodiment, the acid is selected from the group consisting of hydrochloric acid.

[0038] As a further embodiment, in the method of preparing the fusidic acid cream, the step of emulsification is performed by using homogenization and / or stirring at suitable temperature, the step of drug phase preparation is performed by using homogenization and / or stirring at suitable temperature, and the step of drug phase addition is performed by using homogenization and / or stirring at suitable temperature.

[0039] As a further embodiment, in the method of preparing the fusidic acid cream, the emulsification reaction temperature is not less than 70°C.

[0040] As a further embodiment, in the method of preparing the fusidic acid cream, the emulsification reaction temperature is 75±5°C and the homogenization head speed is less than 1.0 m / s.

[0041] As a further embodiment, in the method of preparing the fusidic acid cream, the drug phase preparation is performed using a homogenization head speed less than 1.0 m / s.

[0042] As a further embodiment, in the method of preparing the fusidic acid cream, the drug phase addition is performed using a homogenization head speed less than 1.0 m / s.

[0043] As a further embodiment, in the method of preparing the fusidic acid cream, the emulsification is performed using a homogenization head speed of 0.55-1.00 m / s, a stirring speed less than 0.55 m / s, the drug phase preparation is performed using stirring at a speed of 0.3±0.2 m / s for 40±10 min, and the temperature during the process is 50±5°C.

[0044] Example 1

[0045] Formulation:

[0046]

[0047]

[0048] Production process:

[0049] 1) Water phase: Purified water, 5.1% Tween 60 and glycerin (85%) are mixed at a stirring speed of 0.3 ± 0.2 m / s, potassium sorbate is added, and dissolved for 15 min or more at a stirring speed of 0.3 ± 0.2 m / s until visual dissolution is complete, and the temperature during this process is 75 ± 5 °C.

[0050] 2) Oil phase: White soft paraffin, all-rac-a-tocopherol, liquid paraffin and cetostearyl alcohol are mixed and heated to melt, and stirred at a stirring speed of 0.3 ± 0.2 m / s for 30 min or more until visual dissolution is complete, and the temperature during this process is 75 ± 5 °C.

[0051] 3) Emulsification: The main manufacturing vessel is preheated to 75 ± 5 °C, and the water phase and the oil phase are sequentially transferred to the main manufacturing vessel. Homogenization is performed at a stirring speed of 0.3 ± 0.2 m / s and a homogenizer head speed of 0.8 ± 0.2 m / s for 20 ± 5 min, while vacuuming to -0.04 Mpa ± 0.01 Mpa.

[0052] 4) Intermediate cooling: Stirring is performed at a speed of 0.3 ± 0.2 m / s to reduce the temperature to a target temperature of 50 ± 2 °C, and the cooling time is maintained for 40 ± 10 min or more.

[0053] 5) Drug phase: The drug phase vessel is heated to 55 ± 2 °C, 10% purified water and 0.5% Tween 60 are added to the drug phase vessel, and mixed at a stirring speed of 0.3 ± 0.2 m / s, and after complete dissolution, hydrochloric acid is added and stirred uniformly. The stirring speed is maintained, and homogenization is performed at a homogenizer head speed of 0.8 ± 0.2 m / s for 20 ± 10 min.

[0054] 6) Addition of drug phase: The drug phase is slowly transferred to the main manufacturing vessel. The drug phase vessel and the homogenizer head are rinsed with preheated 3% purified water, and the rinsed dispersion is transferred to the main manufacturing vessel, and stirring is performed at a speed of 0.3 ± 0.2 m / s for 40 ± 10 min, and the temperature during this process is 50 ± 5 °C.

[0055] 7) Final cooling: Cooling is performed at a stirring speed of 0.3 ± 0.2 m / s to 40 ± 2 °C, and the cooling time is 40 ± 10 min.

[0056] 8) Filling: At 40 ± 2 °C, the filling speed is set to 120-180 rpm / min, and the filling amount per unit is controlled to be ≥ 15 g.

[0057] Example 2

[0058] The formulation is the same as in Example 1.

[0059] The production process differs from Example 1 in that the hydrochloric acid is added at the end of step 1), the pH is adjusted to 5.0, and stirred until uniform.

[0060] Example 3: Electron Microscopy

[0061] The products of Examples 1 and 2, and the commercially available product were observed under an electron microscope to determine the percentage of agglomeration in the cream samples by observing the agglomeration.

[0062] Specifically, the Olympus digital microscope was used to observe the agglomeration, and the Motic Image Pro software was used to determine the percentage of agglomeration and the particle size of the fusidic acid in the cream samples.

[0063] As can be seen from the results in the following table, the ion impact modification process of Example 1 is most suitable for uniformly distributing fusidic acid in the cream base.

[0064]

[0065] Example 4: Chemical Stability Study

[0066] The chemical stability of the samples was studied under room temperature and accelerated storage conditions.

[0067] As can be seen from the results in the following table, Example 1 has better stability than Example 2, and is comparable to the commercially available product. The chemical stability of all three samples is acceptable under accelerated storage conditions.

[0068]

[0069]

[0070] Example 5: Microscopic Stability Study

[0071] The particle size distribution, percentage of agglomeration, and spheroid size distribution were measured for Examples 1 and 2, and the commercially available product. As can be seen from the results in the following table, the results of the initial and stability studies remain unchanged. The ion impact modification process of Example 1 is most suitable for uniformly distributing fusidic acid in the cream base.

[0072]

[0073]

[0074] Example 6: Polymorphic Study

[0075] The polymorphic study of the samples after the addition of acid in the drug phase or the water phase showed similar patterns. This indicates that the drug form also remains intact after the addition of acid.

[0076] The main peak of the API extracted from the cream could be co-correlated with the actual fusidic acid API peak. However, the peak intensity was significantly reduced, which could explain the difference in API concentration between the raw material and the sample extracted from the cream matrix. The peak widths were also similar, but with subtle differences, indicating that the particle size was not significantly different from that of the API extracted from the formulation. Higher peak intensities indicate a greater number of crystals or molecules with different spacings. Peak width is inversely proportional to crystal size. Thinner peaks correspond to larger crystals.

[0077] Example 7: In vitro release study

[0078] In vitro diffusion studies of the formulation samples were conducted over 24 hours in phosphate-buffered saline using a modified Franz diffusion cell with a dialysis membrane. The examples were compared to commercially available product samples. The example samples showed release patterns equivalent to those of the commercially available product samples; however, the Example 2 samples exhibited both initial burst release and stalled release. This indicates that the addition of acid to the drug phase has a positive effect and contributes to a uniform and sustained release of the drug over a period of time. The initial burst release in Example 2 was due to particle aggregation and the release of aggregates.

[0079]

[0080]

[0081] Example 8: In vitro permeation study

[0082] The study used surgically removed pigskin, which was immediately frozen post-surgery and stored at -20°C until thawed and used immediately upon need. Comparative experiments were conducted. Samples were sealed with paraffin membranes using sterile physiological saline solution as the receptor culture medium. The Example 1 sample, in which acid was added to the drug phase to generate ion bombardment and prevent aggregation, showed similar good skin permeability to commercially available products.

[0083] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A method for preparing fusidic acid cream, characterized in that, The mixture comprises fusidic acid, butylated hydroxyanisole, cetearyl alcohol, liquid paraffin, white soft paraffin, all-rac-α-tocopherol, 85% glycerol, Tween 60, potassium sorbate, and purified water in dispersed form, wherein the concentration of fusidic acid is 2%, and the fusidic acid is dispersed in hydrochloric acid. The preparation method includes emulsification using homogenization and / or stirring, preparation of the drug phase using homogenization and / or stirring, and addition of the drug phase using homogenization and / or stirring. The emulsification reaction temperature is not lower than 70°C, the homogenizing head speed is less than 1.0 m / s, the homogenizing head speed for drug phase preparation is less than 1.0 m / s, and the homogenizing head speed for drug phase addition is less than 1.0 m / s.

2. The preparation method according to claim 1, characterized in that, The emulsification reaction is carried out at a homogenizing head speed of 0.55-1.00 m / s, a stirring speed of less than 0.55 m / s, and at 75°C for 20±5 minutes; the drug phase preparation is carried out at a stirring speed of 0.3±0.2 m / s and at 50±5°C for 40±10 minutes.

3. Fusidic acid cream prepared by the preparation method according to any one of claims 1-2.

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