Desonide cream and preparation method thereof

Abstract

The invention relates to desonide cream and a preparation method thereof. The desonide emulsifiable paste is prepared from the following raw materials by 100 g of the desonide emulsifiable paste: 0.04-0.06 g of desonide; 10.0 to 14.0 g of cetostearyl alcohol; 1.0 to 3.0 g of synthetic beeswax; 0.1 to 7.0 g of light liquid paraffin; 1.0 to 20.0 g of white vaseline; 4.0 to 6.0 g of glycerol; 1.5 to 2.5 g of lauryl sodium sulfate; 0.04 to 0.06 g of aluminum sulfate; 0.04 to 0.06 g of calcium acetate; 0.1 to 0.2 g of methylparaben; 0.01 to 0.02 g of dextrin; and the balance of water. By optimizing the content of each raw material component in the desonide emulsifiable paste and improving the preparation process, the in-vitro release and transdermal behaviors of the desonide emulsifiable paste are consistent with those of a reference preparation, and the desonide emulsifiable paste is more stable in product quality and good in application prospect.

Description

Technical Field

[0001] The present application relates to the field of medical technology, and in particular to a desonide cream and a preparation method thereof. Background Art

[0002] Topical glucocorticoids have the advantages of high efficacy, rapid effect, good compliance, and easy acceptance by patients. They are one of the drugs commonly prescribed by dermatologists. Desonide is a medium-acting glucocorticoid drug with anti-inflammatory, anti-allergic, antipruritic and exudation-reducing effects. It is suitable for the treatment of various skin diseases that are effective in corticosteroid treatment, such as contact dermatitis, neurodermatitis, seborrheic dermatitis, psoriasis, eczema, lichen planus, simple lichen, dyshidrosis, etc., which cause skin inflammation and itching.

[0003] At present, the approved dosage forms of desonide preparations are all external preparations, especially cream dosage forms, which are widely used. Desonide cream was first developed by Perrigo, USA, and approved by FDA for marketing in January 1972, with a specification of 0.05%, and is currently discontinued.

[0004] Cream preparations are usually stored in a closed, cool place. The stability of cream preparations is also poorer than other solid preparations. Therefore, cream preparations are prone to shape changes during daily transportation, storage and long-term clinical use, such as oil-water separation, color change, odor, etc., which reduces the quality and effective use period of the cream. At the same time, the types and quantities of impurities in desonide cream will increase significantly when it is placed for a long time or at high temperatures, and the content will also decrease. These problems have adverse effects on the quality and stability of desonide cream. Therefore, the existing desonide cream formula and preparation method thereof still need to be improved. Summary of the invention

[0005] In order to address the deficiencies of the prior art, the present application provides a desonide cream. By optimizing the content of each raw material component in the desonide cream and improving the preparation process, the desonide cream described in the present application has excellent stability and good in vitro release and transdermal behavior.

[0006] To this end, the first aspect of the present application provides a desonide cream. Based on 100g of desonide cream, the composition of the raw materials for preparing the desonide cream is as follows: Desonide 0.04-0.06g; cetostearyl alcohol 10.0-14.0g; synthetic beeswax 1.0-3.0g; light liquid paraffin 0.1-7.0g; white vaseline 1.0-20.0g; glycerin 4.0-6.0g; sodium lauryl sulfate 1.5-2.5g; aluminum sulfate 0.04-0.06g; calcium acetate 0.04-0.06g; methylparaben 0.1-0.2g; dextrin 0.01-0.02g; and the balance water.

[0007] With reference to the specification of reference preparation desonide cream (perrigo), it contains 0.05% desonide, and the auxiliary material composition is cetostearyl alcohol, white vaseline, light liquid paraffin, synthetic beeswax, aluminum sulfate, calcium acetate, dextrin, glycerol, sodium lauryl sulfate, methylparaben and purified water, but its prescription dosage has no official source to obtain, and auxiliary materials white vaseline, light liquid paraffin and synthetic beeswax are complex mixtures, and its prescription dosage cannot be parsed under existing technology. In view of this, the application is analyzed by reverse engineering, and the prescription dosage of cetostearyl alcohol, glycerol, aluminum sulfate, calcium acetate, methylparaben and dextrin in desonide cream is analyzed, and the prescription dosage of white vaseline, light liquid paraffin and synthetic beeswax that cannot be parsed is determined by prescription process research and combined with viscosity and stability results, and then the final formula of desonide cream is obtained. The in vitro release and transdermal behavior of the desonide cream of this formula dosage are consistent with the reference preparation, and the product quality is more stable.

[0008] In the present application, the desonide added in the raw materials for preparing the desonide cream is an effective active ingredient; cetostearyl alcohol, synthetic beeswax, light liquid paraffin and white vaseline are oil phase matrices; sodium lauryl sulfate is an emulsifier, which can disperse the oil phase and water mutually and make the two evenly mixed; glycerin and water are water phase / humectant; aluminum sulfate and calcium acetate are pH regulators, which are used to adjust the pH value of the cream to about 4.5; dextrin can improve the stability of desonide; and methylparaben is a preservative.

[0009] In some preferred embodiments, based on 100 g of desonide cream, the composition of the raw materials for preparing the desonide cream is as follows: Desonide 0.05g; cetostearyl alcohol 12.0g; synthetic beeswax 1.0g; light liquid paraffin 0.1g; white vaseline 10.0g; glycerin 5.0g; sodium lauryl sulfate 2.0g; aluminum sulfate 0.05g; calcium acetate 0.05g; methylparaben 0.15g; dextrin 0.015g; and the balance water.

[0010] The present application can further improve its stability, in vitro release and transdermal behavior by optimizing the content of each component in the preparation raw materials.

[0011] In the present application, the water in the raw material for preparing desonide cream can be, for example, purified water.

[0012] The second aspect of the present application provides a method for preparing the desonide cream as described in the first aspect of the present application, the method comprising the following steps: S1, cetostearyl alcohol, synthetic beeswax, light liquid paraffin and white vaseline are mixed, heated to 60-70°C, stirred and melted, and then desonide is added, stirred and dissolved to obtain an oil phase, which is kept warm for later use; S2, adding glycerol, aluminum sulfate, calcium acetate, dextrin, methylparaben and sodium lauryl sulfate into water, heating and stirring to obtain an aqueous phase, and keeping the temperature for later use; S3, adding the oil phase into the water phase for homogenization, stirring and cooling to obtain the desonide cream.

[0013] Desonide cream described in the present application is added to the oil phase during the preparation process. Since desonide is distributed more in the oil phase of the emulsifiable paste, desonide is directly added to the oil phase during the preparation process to avoid the diffusion movement of desonide during the storage process of the emulsifiable paste, thereby improving the stability of the desonide cream. Simultaneously, since desonide is unstable under high temperature conditions, the heating temperature of the oil phase during the preparation process needs to be controlled at 60 to 70°C. If the temperature is too high, desonide will be decomposed, resulting in an increase in the impurity content in the obtained emulsifiable paste. If the temperature is too low, the raw materials in the oil phase cannot be fully melted, thereby reducing the homogeneity and stability of the obtained emulsifiable paste. In some preferred embodiments, when step S1 is prepared in the oil phase, the temperature after heating is 70°C.

[0014] In some embodiments, the temperature of the aqueous phase is 60-70°C. In some preferred embodiments, the temperature of the aqueous phase is 70°C.

[0015] In the present application, the temperature of the water phase will affect the emulsification temperature of the mixed solution after the water phase and the oil phase are subsequently mixed. By controlling the temperature of the water phase at 60-70°C, especially at 70°C, the emulsification temperature of the mixed solution after the water phase and the oil phase are mixed can be controlled at 70°C. The inventors of the present application have found through research that controlling the emulsification temperature of the mixed solution at 70°C can effectively avoid the decomposition of desonide, ensure the smooth progress of the emulsification process, and further improve the stability of the prepared desonide cream.

[0016] In some embodiments, in step S2, the heating and stirring is performed under vacuum conditions, and the vacuum degree is -0.06 MPa to -0.10 MPa. In some preferred embodiments, the vacuum degree is -0.08 MPa.

[0017] Since sodium dodecyl sulfate in the water phase is prone to generate bubbles during stirring, and desonide is sensitive to oxygen, the oxygen in the bubbles in the water phase will cause the degradation of desonide. During the preparation and stirring of the water phase, vacuuming can minimize the bubbles in the water phase before the water phase and the oil phase are mixed, thereby reducing the pressure of vacuuming to remove bubbles after the water phase and the oil phase are mixed.

[0018] In some implementations, step S2 specifically includes the following steps: S2-1, adding glycerin, dextrin, methylparaben and sodium lauryl sulfate to 80-90 wt% of the prescribed amount of water, heating and stirring to obtain aqueous phase 1, and keeping warm for later use; S2-2, adding 5-8 wt% of aluminum sulfate to the prescribed amount of water, heating and stirring to obtain aqueous phase 2, and keeping warm for later use; S2-3, adding calcium acetate to the remaining amount of water, heating and stirring to obtain aqueous phase 3, and keeping warm for later use.

[0019] The inventors of the present application have found through research that the stability of desonide at high temperature is different under different pH conditions, and the stability of desonide under high temperature under neutral conditions is better than that under acidic conditions. Therefore, when preparing the aqueous phase, the pH adjusters (aluminum sulfate and calcium acetate) are prepared separately, so that the aqueous phase solution of the pH adjuster can be added at different times later to maximize the quality stability of the prepared cream.

[0020] In some embodiments, the temperatures of the aqueous phase 1, aqueous phase 2, and aqueous phase 3 are each independently 60-70°C.

[0021] In some preferred embodiments, the temperatures of the aqueous phase 1, aqueous phase 2 and aqueous phase 3 are all 70°C.

[0022] In the present application, the temperatures of the aqueous phase 1, aqueous phase 2 and aqueous phase 3 will affect the emulsification temperature of the mixed solution after the aqueous phase and the oil phase are mixed. If the temperatures of the aqueous phase 1, aqueous phase 2 and aqueous phase 3 are too high, desonide will be degraded. If the temperature is too low, it will be unfavorable for the mixing of the aqueous phase and the oil phase. For example, if the temperature is too low, the raw materials in the oil phase will coagulate and solidify during the mixing of the oil phase and the aqueous phase, resulting in failure in the preparation of the cream.

[0023] In some embodiments, in step S2-1, the heating and stirring are performed under vacuum conditions, and the vacuum degree is -0.06 MPa to -0.10 MPa. Preferably, the vacuum degree is -0.08 MPa.

[0024] The heating and stirring described in the present application is carried out under vacuum conditions to reduce as much as possible the bubbles in the water phase 1 before the water phase 1 and the oil phase are mixed, thereby reducing the pressure of vacuuming and removing bubbles after the water phase 1 and the oil phase are mixed.

[0025] In some specific implementations, the step S2 specifically includes the following steps: (2-1), add glycerol, dextrin, methylparaben and sodium lauryl sulfate to 90 wt % of the prescribed amount of water, start a 70° C. water bath, evacuate to -0.08 MPa, start stirring, dissolve and disperse to obtain aqueous phase 1, and keep warm for later use; (2-2), adding aluminum sulfate to 5 wt% of the prescribed amount of water, stirring and dissolving in a 70° C. water bath to obtain aqueous phase 2, which was kept warm for later use; (2-3), add calcium acetate to the remaining 5 wt % of the prescribed amount of water, stir and dissolve in a 70° C. water bath to obtain aqueous phase 3, and keep warm for later use.

[0026] In some implementations, step S3 specifically includes the following steps: S3-1, adding the oil phase to the water phase 1, stirring and cooling to obtain a mixture; S3-2, adding aqueous phase 2 and aqueous phase 3 to the mixture in sequence, mixing and homogenizing, stirring and cooling again to obtain the desonide cream.

[0027] In the present application, aluminum sulfate and calcium acetate are used as pH regulators in the prescription, and the aqueous phase without aluminum sulfate and calcium acetate is neutral, with a pH value of about 7.1. The addition of aluminum sulfate and calcium acetate makes the pH value of the aqueous phase about 4.4. Aluminum sulfate and calcium acetate are not added to aqueous phase 1, so aqueous phase 1 is neutral. Since the temperature of the oil phase and aqueous phase 1 is relatively high (60-70° C.), after the oil phase and aqueous phase 1 are mixed, aqueous phase 1 is neutral, and the stability of desonide under neutral conditions is better at high temperature, so the decomposition of desonide can be reduced. Subsequently, the mixture of the oil phase and aqueous phase 1 is cooled and then the aqueous phase solution of the pH regulator is added to adjust the pH value of the cream to acidic, and desonide is less sensitive to acidic pH at low temperatures, so the above-mentioned preparation method can effectively avoid the degradation of desonide and improve the stability of the obtained product.

[0028] In some embodiments, the temperature of the mixture is 40-45°C.

[0029] The present application can make the comprehensive performance of the final cream better by controlling the temperature of the cooled mixture within the above range. If the temperature is too high, the subsequent mixture and the aqueous solution of the pH regulator will cause the degradation of desonide. If the temperature is too low, the raw materials for the preparation of the oil phase in the mixture will condense and precipitate, reducing the uniformity and stability of the obtained product. In some preferred embodiments, the temperature of the mixture is 43°C.

[0030] In some embodiments, the homogenization and stirring cooling are both performed under vacuum conditions, with a vacuum degree of -0.06 MPa to -0.10 MPa. Preferably, the vacuum degree is -0.08 MPa.

[0031] After the water phase and the oil phase are mixed, homogenization and stirring will bring in a large number of bubbles. In order to avoid the influence of oxygen in the bubbles on desonide, vacuum extraction is required to remove the bubbles. Therefore, the above operations are all carried out under vacuum conditions.

[0032] In the present application, the homogenization conditions may be: a rotation speed of 3000 to 3500 rpm and a time of 8 to 10 min.

[0033] In some specific implementations, the step S3 specifically includes the following steps: (3-1), add the oil phase to the water phase 1, evacuate to -0.08 MPa, stir and cool to 40-45°C to obtain a mixture; (3-2), adding aqueous phase 2 and aqueous phase 3 to the mixture in sequence and stirring evenly; evacuating to -0.08 MPa, starting homogenization, rotating speed 3000-3500 rpm, time 8-10 min, after homogenization is completed, starting a cooling water bath, stirring again and cooling to 35° C., to obtain the desonide cream.

[0034] The beneficial effects of the present application are as follows: the present application analyzes the prescription dosage of cetostearyl alcohol, glycerol, aluminum sulfate, calcium acetate, methylparaben and dextrin in the reference preparation desonide cream by reverse engineering, and the prescription dosage of white vaseline, light liquid paraffin and synthetic beeswax that cannot be analyzed is determined by prescription process research and combined with viscosity and stability results, thereby obtaining the final formula of the desonide cream provided by the present application, and the in vitro release and transdermal behavior of the desonide cream of the present application are consistent with the reference preparation, and the product quality is more stable. At the same time, the present application improves the preparation process of desonide cream, adds desonide to the oil phase, and controls the temperature of the oil phase and the water phase and the timing of adding the pH regulator (aluminum sulfate and calcium acetate) in the water phase, which can effectively reduce the decomposition of desonide in the preparation process, further improve the stability of the product, and has good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is the design diagram for the in vitro release rate comparison study between the self-developed preparation and the reference preparation when conducting in vitro release characteristics testing in Test Example 3.

[0036] Figure 2 This is the in vitro release rate graph of desonide in the self-developed preparation and the reference preparation in Test Example 3.

[0037] Figure 3 This is a graph showing the cumulative permeation results per unit area of ​​the self-developed preparation and the reference preparation at different sampling time points in Test Example 4.

[0038] Figure 4 This is a graph showing the flux results at different sampling time points for the self-developed preparation and the reference preparation in Test Example 4.

[0039] Figure 5 This is a microscopic picture of the particle size of the self-made agent droplets in Test Example 6.

[0040] Figure 6 This is a microscopic picture of the droplet particle size of the reference preparation 1JT0530 in Test Example 6.

[0041] Figure 7 Microscopic picture of the droplet size of the reference preparation 1FT0533 in Test Example 6 DETAILED DESCRIPTION

[0042] In order to make the present application easier to understand, the present application will be further described in detail below in conjunction with the examples, which are merely illustrative and are not intended to limit the scope of application of the present application. The raw materials or components used in the present application can be obtained through commercial routes or conventional methods unless otherwise specified.

[0043] Example 1-5: Preparation of Desonide Cream 1. Prescription composition: Based on 100 g of desonide cream, the prescription compositions of the desonide cream in Examples 1-5 are respectively shown in Table 1.

[0044] Table 1 2. Preparation process: The preparation process of Examples 1-5 is the same, and the specific steps are as follows: (1) Preparation of oil phase: Add cetostearyl alcohol, synthetic beeswax, light liquid paraffin and white vaseline into a beaker, heat to 70°C and stir to melt; then add desonide and stir to dissolve to obtain the oil phase, which is kept warm for later use.

[0045] (2) Preparation of aqueous phase: Add glycerol, aluminum sulfate, calcium acetate, dextrin, methylparaben and sodium lauryl sulfate into purified water, start a 70°C water bath, evacuate to -0.08 MPa, start stirring, stir until dissolved and dispersed, to obtain an aqueous phase, and keep warm for later use.

[0046] (3) The oil phase was added to the water phase, and the mixture was evacuated to -0.08 MPa. The vacuum homogenization was started, the homogenization speed was 3000 rpm, and the homogenization time was 15 min. After the homogenization was completed, a cooling water bath was started, and the mixture was stirred and cooled to 35° C. at a stirring speed of 100 rpm to prepare a desonide cream.

[0047] The physicochemical properties and high temperature stability of the desonide cream prepared in Examples 1-5 were tested. The indicators of the physicochemical property test included pH value, appearance and viscosity, and the test results are shown in Table 2; the high temperature stability test was performed by placing the desonide cream at a temperature of 40° C. for 30 days and testing the total impurity content therein, and the test results are shown in Table 3.

[0048] Table 2 Table 3 According to the test results of Table 3, when the amount of white vaseline is 1-25g, the stability of desonide cream has no obvious effect. After the desonide cream is placed at 40°C for 30 days, the impurity content is not significantly improved, and when the amount of white vaseline is 1-15g, the impurity content is less. According to the test results of Table 2, when the amount of white vaseline is 10g, the viscosity of the prepared desonide cream is moderate (viscosity is about 65000). Too high a content will make the viscosity of the product too high, and too low a content will make the viscosity of the product too low, which is not conducive to the application of the cream. The optimum content of white vaseline in the prescription is determined to be 10g based on the comprehensive viscosity and stability results.

[0049] Example 6-10: Preparation of Desonide Cream 1. Prescription composition: Based on 100 g of desonide cream, the prescription compositions of the desonide creams in Examples 6-10 are respectively shown in Table 4.

[0050] Table 4 2. Preparation process: The preparation process of Examples 6-10 is the same as that of Example 1.

[0051] The physicochemical properties and high temperature stability of the desonide creams prepared in Examples 6-10 were tested. The testing methods of the physicochemical properties and high temperature stability were the same as those in Example 1, wherein the test results of the physicochemical properties are shown in Table 5, and the test results of the high temperature stability are shown in Table 6.

[0052] Table 5 Table 6 According to the test results in Table 6, the amount of light liquid paraffin in the range of 0.1 to 7 g has no significant effect on the stability of desonide cream, and the impurity content of desonide cream has not increased significantly after being placed at 40°C for 30 days. According to the test results in Table 5, when the amount of light liquid paraffin is 0.1 to 0.2 g, the viscosity of the prepared desonide cream is moderate, and the viscosity is more suitable when the amount is 0.1 g. The most suitable content of light liquid paraffin in the prescription is determined to be 0.1 g based on the viscosity, stability results and production cost.

[0053] Example 11-12: Preparation of Desonide Cream 1. Prescription composition: Based on 100 g of desonide cream, the prescription compositions of the desonide cream in Examples 11-12 are respectively shown in Table 7.

[0054] Table 7 2. Preparation process: The preparation process of Examples 11-12 is the same as that of Example 1.

[0055] The physicochemical properties and high temperature stability of the desonide cream prepared in Examples 11-12 were tested. The physicochemical properties and high temperature stability were tested in the same manner as in Example 1, wherein the test results of the physicochemical properties are shown in Table 8, and the test results of the high temperature stability are shown in Table 9.

[0056] Table 8 Embodiment 11 Example 12 pH 4.59 4.48 Appearance White cream White cream Viscosity (mPa·s) 66800 70600 Table 9 According to the test results in Table 9, the amount of synthetic beeswax in the range of 1 to 3 g has no significant effect on the stability of desonide cream. The impurity content of desonide cream has not increased significantly after being placed at 40°C for 30 days, and the impurity content is even less when the amount of synthetic beeswax is 1 g. According to the test results in Table 8, when the amount of synthetic beeswax is 1 g, the viscosity of the prepared desonide cream is moderate. The optimum content of synthetic beeswax in the prescription is determined to be 1 g based on the viscosity, stability results and production cost.

[0057] Example 13: Effect of Oil Phase Temperature and Water Phase Temperature on Stability during Preparation of Desonide Cream Prescription composition: The prescription of desonide cream is the same as that in Example 11.

[0058] 1. Investigation of oil phase temperature: Preparation of oil phase 1: add cetostearyl alcohol, synthetic beeswax, light liquid paraffin and white vaseline into a beaker, heat to 60°C and stir to melt; then add desonide and stir to dissolve to obtain oil phase 1.

[0059] Preparation of oil phase 2: add cetostearyl alcohol, synthetic beeswax, light liquid paraffin and white vaseline into a beaker, heat to 70°C and stir to melt; then add desonide and stir to dissolve to obtain oil phase 2.

[0060] Preparation of oil phase 3: add cetostearyl alcohol, synthetic beeswax, light liquid paraffin and white vaseline into a beaker, heat to 75°C and stir to melt; then add desonide and stir to dissolve to prepare oil phase 3.

[0061] The prepared oil phase 1, oil phase 2 and oil phase 3 were kept at the corresponding temperature for 8 hours, and samples were taken for testing at 0 hours, 3 hours, 6 hours and 8 hours respectively. The test indicators included appearance and impurity content. The results are shown in Table 10.

[0062] Table 10 From the above results, it can be seen that when the oil phase temperature is kept at 70℃ for 8h, the appearance and related substances have no obvious changes, and the impurity content does not increase within 3h of keeping. When the oil phase temperature is kept at 60℃ for 8h, the related substances have no obvious changes, but the oil phase temperature is too low, and the oil phase raw materials condense and solidify after the holding time is too long, causing the liquid to become turbid. When the oil phase temperature is kept at 75℃ for 8h, the appearance and properties have no obvious changes, but the oil phase temperature is too high, and the impurity content increases significantly after the holding time is too long. Therefore, the optimal temperature for oil phase preparation is 70℃.

[0063] 2. Investigation of water phase temperature Preparation of the first aqueous phase: Add glycerol, aluminum sulfate, calcium acetate, dextrin, methylparaben and sodium lauryl sulfate into purified water, start a 60°C water bath, evacuate to -0.08 MPa, start stirring, and stir until dissolved and dispersed to obtain the first aqueous phase.

[0064] Preparation of the second aqueous phase: Add glycerol, aluminum sulfate, calcium acetate, dextrin, methylparaben and sodium lauryl sulfate into purified water, start a 70°C water bath, evacuate to -0.08 MPa, start stirring, and stir until dissolved and dispersed to obtain the second aqueous phase.

[0065] Preparation of the third aqueous phase: Add glycerol, aluminum sulfate, calcium acetate, dextrin, methylparaben and sodium lauryl sulfate into purified water, start a 75°C water bath, evacuate to -0.08 MPa, start stirring, and stir until dissolved and dispersed to obtain the third aqueous phase.

[0066] The oil phase at a temperature of 70°C was mixed with the first aqueous phase, the second aqueous phase and the third aqueous phase respectively, and then emulsified with stirring at the corresponding temperature. Sampling and testing were carried out at 5 minutes, 1 hour, 2 hours, 3 hours, 6 hours and 8 hours respectively. The test indicators included appearance and impurity content. The results are shown in Table 11.

[0067] Table 11 As shown in Table 11, when the water phase temperature is controlled at 70°C, the temperature of the emulsification after the oil phase and the water phase are mixed is 70°C. When the emulsification is kept and stirred at this temperature for 8 hours, there is no obvious change in the appearance. The related substances gradually increase with the increase of the insulation time. The increase of impurities within 2 hours is small, and the total impurities within 8 hours are still relatively small. If the water phase temperature is too low, the emulsification effect will be poor, and if the water phase temperature is too high, the impurity content will increase significantly.

[0068] Example 14: Preparation of Desonide Cream 1. Prescription composition: The prescription of desonide cream is the same as that in Example 11.

[0069] 2. Preparation process: (1) Preparation of oil phase: Add cetostearyl alcohol, synthetic beeswax, light liquid paraffin and white vaseline into a beaker, heat to 70°C and stir to melt; then add desonide and stir to dissolve to obtain the oil phase, which is kept warm for later use.

[0070] (2) Preparation of aqueous phase 1: Add glycerol, dextrin, methylparaben and sodium lauryl sulfate to 90 wt % of the prescribed amount of purified water, start a 70° C. water bath, evacuate to -0.08 MPa, start stirring, stir until dissolved and dispersed, to obtain aqueous phase 1, and keep warm for later use; Preparation of aqueous phase 2: Add aluminum sulfate to 5 wt % of the prescribed amount of purified water, stir to dissolve in a 70° C. water bath, to obtain aqueous phase 2, and keep warm for later use; Preparation of aqueous phase 3: Add calcium acetate to 5 wt % of the prescribed amount of purified water, stir to dissolve in a 70° C. water bath, to obtain aqueous phase 2, and keep warm for later use.

[0071] (3) adding the oil phase to the aqueous phase 1, evacuating to -0.08 MPa, and cooling to 43° C. at a stirring speed of 100 rpm to obtain a mixture; sequentially adding the aqueous phase 2 and the aqueous phase 3 to the mixture and stirring evenly; evacuating to -0.08 MPa, starting homogenization, the homogenization speed is 3000 rpm, the homogenization time is 15 min, and after the homogenization is completed, turning on the cooling water bath, stirring and cooling to 35° C. at a stirring speed of 100 rpm to obtain the desonide cream.

[0072] Example 15: Preparation of Desonide Cream 1. Prescription composition: The prescription of desonide cream is the same as that in Example 11.

[0073] 2. Preparation process: The preparation process is basically the same as that of Example 14, except that, in step (3), the oil phase is added to the water phase 1, evacuated to -0.08 MPa, and cooled to 40° C. at a stirring speed of 100 rpm to obtain a mixture.

[0074] Example 16: Preparation of Desonide Cream 1. Prescription composition: The prescription of desonide cream is the same as that in Example 11.

[0075] 2. Preparation process: The preparation process is basically the same as that of Example 14, except that, in step (3), the oil phase is added to the water phase 1, evacuated to -0.08 MPa, and cooled to 45° C. at a stirring speed of 100 rpm to obtain a mixture.

[0076] Example 17: Preparation of Desonide Cream 1. Prescription composition: The prescription of desonide cream is the same as that in Example 11.

[0077] 2. Preparation process: Steps (1) and (2) are the same as in Example 1, and step (3) is specifically as follows: (3) adding the oil phase to the water phase, evacuating to -0.08 MPa, cooling to 43° C. at a stirring speed of 100 rpm to obtain a mixture; evacuating to -0.08 MPa, starting homogenization, the homogenization speed is 3000 rpm, the homogenization time is 15 min, and after the homogenization is completed, turning on the cooling water bath, stirring and cooling to 35° C. at a stirring speed of 100 rpm to obtain a desonide cream.

[0078] Test Example 1 The physicochemical properties and high temperature stability of the desonide cream prepared in Examples 14-17 and two batches of reference preparations (reference preparation 1JT0530 and reference preparation 1FT0533) were tested. The indicators of the physicochemical property test include pH value, appearance and viscosity, and the test results are shown in Table 12; the high temperature stability test method is: the desonide cream is placed at a temperature of 40°C for 30 days, and at a temperature of 30°C and a humidity of 65% for 6 months, and the total impurity content is tested respectively, and the test results are shown in Table 13.

[0079] Table 12 Embodiment 14 Embodiment 15 Example 16 Embodiment 17 pH 4.67 4.63 4.60 4.58 Appearance White cream White cream White cream White cream Viscosity (mPa·s) 65400 66800 65900 66300 Table 13 As can be seen from the test results of Table 13, by changing the order of addition of pH adjusting agents (aluminum sulfate, calcium acetate), the stability of the related substances of desonide cream is significantly improved. At the same time, before the pH adjusting agents (aluminum sulfate, calcium acetate) are added, when the temperature of the mixture is cooled to 43°C (Example 14), the stability of the obtained desonide cream can be better. At the same time, as can be seen from the test results of Table 12, changing the order of addition of pH adjusting agents (aluminum sulfate, calcium acetate) has no obvious effect on the physicochemical properties of the obtained desonide cream.

[0080] Test Example 2 The rheological properties of the desonide cream (self-made preparation) prepared in Example 14 and two batches of reference preparations (reference preparation 1JT0530 and reference preparation 1FT0533) were tested. The flow curve test results are shown in Table 14, and the yield stress, creep and linear viscoelastic region test results are shown in Table 15.

[0081] Table 14 Table 15 As shown in Table 14, the viscosity of the self-made preparation and the two batches of reference preparations decreased significantly with the increase of shear rate, from the low shear rate (0.01s -1 ) to medium shear rate (10s -1), the viscosity change trend of the self-made preparation and the two batches of reference preparations was consistent. This result shows that the stability of the self-made preparation and the two batches of reference preparations during product storage, transportation, stirring, and shaking is consistent with that of the reference preparation.

[0082] Yield stress is the critical stress that characterizes the start or stop flow of a sample, and can be used to evaluate the spreadability of topical skin preparations during use and the ease of product filling. According to the yield stress values ​​in Table 15, the yield stress of the self-made preparation is slightly higher than that of the two batches of reference preparations, indicating that the self-made preparation has better stability without affecting extrusion filling and spreading.

[0083] The creep recovery ability of the product reflects the ability of the internal structure of the product to resist slip deformation. γ-max reflects the maximum deformation of the product under a certain external force, and γ-r / γ-max reflects the degree of creep recovery of the product after the external force is removed. According to the data in Table 15, the maximum deformation of the self-developed preparation under the same external force is similar to that of the reference preparation, and the degree of creep recovery is also similar to that of the reference preparation.

[0084] Generally speaking, the sample slowly deforms after being acted upon by an external force, showing viscous behavior; after the deformation force is eliminated, the sample gradually returns to its original structure, showing elastic behavior. Good viscosity can ensure that the skin topical preparation fits tightly with the medicinal part, ensuring that the preparation will not fall off during use and will not flow easily; good elasticity can give the preparation better storage stability. From the linear viscoelastic region in Table 15, the viscoelastic test results of the self-developed preparation and the two batches of reference preparations are relatively close, indicating that the self-developed preparation is close to the reference preparation in terms of the degree of close fit with the medicinal part and storage stability.

[0085] Test Example 3 The in vitro release characteristics of the desonide cream (self-made preparation) prepared in Example 14 and the reference preparation 1FT0533 were tested. The specific detection method is: the detection adopts a modified Franz three-dimensional diffusion device, the pre-treated artificial synthetic membrane is fixed between the donor chamber and the receiving chamber, and about 0.2g of the self-made preparation and the reference preparation desonide cream are respectively taken and evenly applied on the selected artificial synthetic membrane (the typical in vitro release rate comparison study design is shown in Figure 1, where T represents the self-developed preparation and R represents the reference preparation), keep the closed state to prevent the solution from evaporating and changing the composition, add 12mL of in vitro release medium heated to 32±1℃ into the receiving chamber, make the artificial membrane just in contact with the liquid surface of the in vitro release medium, turn on the magnetic stirrer (speed: 600 min / rev) and stir continuously to allow the drug to be released naturally, take samples of 12mL at 0.5, 1.0, 2.0, 3.0, 4.0, and 6.0 hours, respectively, to obtain the test solution, and detect the desonide content in the test solution. Perform 4 groups of parallel experiments, and take the average value of the experimental results of the 4 groups of parallel experiments. After each sampling is completed, add an equal amount of blank in vitro release medium at the same temperature into the receiving chamber. After the test, draw the in vitro release rate graph of desonide, as shown in Figure 2 The results of in vitro release of desonide are shown in Table 16.

[0086] Table 16 from Figure 2 As shown in Table 16, the release amount of desonide per unit area at different sampling points of the self-made preparation and the reference preparation (batch number: 1FT0533) is linearly related to the square root of time, r 2 The RSD of the release rate of the four parallel samples of the self-made preparation and the reference preparation was less than 15%, which met the requirements of the approval standard. At the same time, the 90% confidence interval of the ratio of the in vitro release rate of desonide between the self-made preparation and the reference preparation was 102.3%-112.0%, which fell within the range of 75%-133.33%, indicating that the in vitro release behavior of desonide in the self-made preparation and the reference preparation was equivalent.

[0087] Test Example 4 The in vitro transdermal properties of the desonide cream (self-made preparation) prepared in Example 14 and the reference preparation 1FT0533 were tested. The specific testing method is as follows: the test adopts a modified Franz stereoscopic diffusion apparatus with a contact area of ​​1.77 cm 2The volume of the receiving chamber is 12 mL. The pretreated small Bama Xiang pig skin (washed with physiological saline) is fixed between the donor chamber and the receiving chamber. The sample amount (about 200 mg) of desonide cream is evenly applied on the selected small Bama Xiang pig skin. The difference in the sample weight between the parallel samples is within ±5%. 12 mL of in vitro transdermal medium heated to 32 ± 0.5 ° C is added to the receiving chamber so that the pig skin is just in contact with the surface of the in vitro transdermal medium. The magnetic stirrer (speed: 600 min / rev) is turned on and stirred continuously to allow the drug to penetrate naturally. 1.0 mL of samples are taken at 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 20.0, and 24.0 hours, respectively, to obtain the test solution, and the remaining solution is discarded. After each sampling, 12 mL of blank in vitro transdermal medium is added to the receiving chamber. The concentration of desonide in the test solution is determined by HPLC. After the experiment, the pig skin was removed, the skin surface was wiped clean with physiological saline for extraction, the skin was cut into pieces and placed in a 50mL plastic tube, 10mL of acetonitrile was added, and the tube was heated in a water bath at 70°C for 20min. The tube was taken out and vortexed for 5min while hot. After cooling to room temperature, the tube was centrifuged at 10000rpm for 10min. The supernatant was filtered and injected into HPLC to determine the concentration. Six parallel experiments were performed, and the experimental results were taken as the average value of the six parallel experiments.

[0088] Among them, the results of the residual amount on the skin, the amount retained in the skin, the cumulative amount permeated within 24 hours and the overall recovery rate of the self-made preparation and the reference preparation are shown in Table 17, and the results of the cumulative amount permeated per unit area at different sampling time points of the self-made preparation and the reference preparation are shown in Tables 18 and Figure 3 The average permeability (flux) results of the self-made preparation and the reference preparation at different sampling time points are shown in Tables 19 and Figure 4 The permeation rate results of the self-developed preparation and the reference preparation are shown in Table 20.

[0089] Table 17 Table 18 Table 19 Table 20 From the above test results, it can be seen that the ratio of the intradermal retention of the self-developed preparation to the reference preparation (batch number: 1FT0533) is in the range of 0.7 to 1.3, indicating that there is no significant difference in the results of the intradermal retention of the self-developed preparation and the reference preparation. The ratio of the 24-hour cumulative permeation of the self-developed preparation to the reference preparation (batch number: 1FT0533) is in the range of 0.7 to 1.3, indicating that there is no significant difference in the cumulative permeation of the self-developed preparation and the reference preparation. The overall recovery rate (%, (intradermal retention + skin residue + cumulative permeation) / sample amount) of the self-developed preparation and the reference preparation (batch number: 1FT0533) is between 80% and 120%, and the material balance meets the requirements. The ratio of the average permeation rate of the self-made preparation and the reference preparation (batch number: 1FT0533) at the specified test time point and the time point of half the permeation rate at the same time point was between 0.7 and 1.3, indicating that the in vitro permeation behavior of the self-made preparation and the reference preparation is equivalent. (Refer to PMDA: Guidance on Biological Equivalence Testing Guidelines for Changes in Prescriptions for Topical Skin Applications (Semi-solid Preparations and Patches)).

[0090] Test Example 5 The desonide cream (self-made preparation) prepared in Example 14 and the reference preparation 1FT0530 were placed at 40°C for 30 days, and the appearance, pH value, desonide content and total impurity content of the samples before and after placement were tested. The results are shown in Table 21. At the same time, the in-tube uniformity of the self-made preparation during high temperature stability was tested, and the results are shown in Table 22.

[0091] Table 21 Table 22 From the high temperature test results in Table 21, it can be seen that after being placed at 40°C for 30 days, the impurity level and impurity growth trend of the self-prepared preparation are much smaller than those of the reference preparation, indicating that the self-prepared preparation is more stable.

[0092] The content limit of uniformity of desonide cream in the tube is 90.0%-110.0%. From the test results in Table 22, it can be seen that when the self-developed preparation is placed at high temperature in commercially available packaging materials for 30 days, the three contents of uniformity in the tube (capped end, middle and curled end) do not exceed the limit, and the extreme difference is far less than 10%. The uniformity in the tube also meets the requirements during the high temperature stability period.

[0093] Test Example 6 The particle sizes of the desonide cream (self-made preparation) prepared in Example 14 and two batches of reference preparations (reference preparation 1JT0530 and reference preparation 1FT0533) were tested. The microscopic images of the droplet size of the self-made preparation are shown in FIG. Figure 5As shown, the microscopic picture of the droplet size of the reference preparation 1JT0530 is as follows Figure 6 As shown, the microscopic picture of the droplet size of the reference preparation 1FT0533 is as follows Figure 7 shown.

[0094] from Figure 5-7 Judging from the results of the microscopic images, the droplet size of the self-developed agent is more uniform and controllable, indicating that the preparation process of the self-developed agent is better.

[0095] It should be noted that the embodiments described above are only used to explain the present application and do not constitute any limitation to the present application. The present application is described with reference to typical embodiments, but it should be understood that the words used therein are descriptive and explanatory words, rather than restrictive words. The present application may be modified as specified within the scope of the claims of the present application, and the present invention may be revised without departing from the scope and spirit of the present application. Although the present application described therein relates to specific methods, materials and embodiments, it does not mean that the present application is limited to the specific examples disclosed therein. On the contrary, the present application can be extended to all other methods and applications with the same functions.

Claims

1. A desonide cream, characterized in that, Based on 100g of desonide cream, the composition of the preparation raw materials of the desonide cream is as follows: Desonide 0.04~0.06g; cetostearyl alcohol 10.0~14.0g; synthetic beeswax 1.0~3.0g; light liquid paraffin 0.1~7.0g; white vaseline 1.0~20.0g; glycerin 4.0~6.0g; sodium lauryl sulfate 1.5~2.5g; aluminum sulfate 0.04~0.06g; calcium acetate 0.04~0.06g; methylparaben 0.1~0.2g; dextrin 0.01~0.02 g; and the balance water.

2. Desonide cream according to claim 1, characterized in that, Based on 100g of desonide cream, the composition of the preparation raw materials of the desonide cream is as follows: Desonide 0.05g; cetostearyl alcohol 12.0g; synthetic beeswax 1.0g; light liquid paraffin 0.1g; white vaseline 10.0g; glycerin 5.0g; sodium lauryl sulfate 2.0g; aluminum sulfate 0.05g; calcium acetate 0.05g; methylparaben 0.15g; dextrin 0.015g; and the balance water.

3. A method for preparing the desonide cream according to claim 1 or 2, characterized in that: The method comprises the following steps: S1, cetostearyl alcohol, synthetic beeswax, light liquid paraffin and white vaseline are mixed, the temperature is raised to 60-70°C, and desonide is added after stirring and melting, and the oil phase is prepared after stirring and dissolving, and the oil phase is kept warm for later use; S2, adding glycerol, aluminum sulfate, calcium acetate, dextrin, methylparaben and sodium lauryl sulfate into water, heating and stirring to obtain an aqueous phase, and keeping the temperature for later use; S3, adding the oil phase into the water phase for homogenization, stirring and cooling to obtain the desonide cream.

4. The method according to claim 3, characterized in that The temperature of the water phase is 60-70°C.

5. The method according to claim 3 or 4, characterized in that: In step S2, the heating and stirring are performed under vacuum conditions, and the vacuum degree is -0.06MPa~-0.10MPa.

6. The method according to claim 3 or 4, characterized in that: The step S2 specifically includes the following steps: S2-1, adding glycerin, dextrin, methylparaben and sodium lauryl sulfate to 80-90 wt% of the prescribed amount of water, heating and stirring to obtain aqueous phase 1, and keeping warm for later use; S2-2, adding aluminum sulfate to 5-8 wt% of the prescribed amount of water, heating and stirring to obtain aqueous phase 2, and keeping warm for later use; S2-3, adding calcium acetate to the remaining amount of water, heating and stirring to obtain aqueous phase 3, and keeping warm for later use.

7. The method according to claim 6, characterized in that The temperatures of the aqueous phase 1, aqueous phase 2 and aqueous phase 3 are independently 60-70° C.; and / or in step S2-1, the heating and stirring are carried out under vacuum conditions with a vacuum degree of -0.06 MPa to -0.10 MPa.

8. According to the method of claim 7, the step S3 specifically comprises the following steps: S3-1, adding the oil phase to the water phase 1, stirring and cooling to obtain a mixture; S3-2, adding aqueous phase 2 and aqueous phase 3 to the mixture in sequence, mixing and homogenizing, stirring and cooling again to obtain the desonide cream.

9. The method according to claim 8, characterized in that The temperature of the mixture is 40-45°C.

10. The method according to claim 8, characterized in that The homogenization and stirring cooling are all carried out under vacuum conditions, and the vacuum degree is -0.06MPa~-0.10MPa.

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