A cream of desonide and a method of preparing the same

Abstract

The application relates to a desonide cream and a preparation method thereof. The composition of raw materials for preparing the desonide cream, with 100 g of the desonide cream as a unit, is as follows: 0.04-0.06 g of desonide, 10.0-14.0 g of cetearyl alcohol, 1.0-3.0 g of synthetic beeswax, 0.1-7.0 g of light liquid paraffin, 1.0-20.0 g of white vaseline, 4.0-6.0 g of glycerol, 1.5-2.5 g of sodium lauryl sulfate, 0.04-0.06 g of aluminum sulfate, 0.04-0.06 g of calcium acetate, 0.1-0.2 g of methylparaben, 0.01-0.02 g of dextrin, and the rest of water. The application optimizes the content of each raw material component in the desonide cream and improves the preparation process, so that the in-vitro release and transdermal behavior of the desonide cream are consistent with those of a reference preparation, the product quality is more stable, and the application prospect is good.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to a desonide cream and a preparation method thereof. BACKGROUND

[0002] The external use of glucocorticoid drugs has the advantages of high efficacy, fast effect, good compliance, and easy acceptance by patients, and is one of the commonly prescribed drugs for dermatologists. Desonide is a medium-acting glucocorticoid drug, which has the effects of anti-inflammatory, anti-allergic, antipruritic and reducing exudation, and is suitable for the treatment of various skin diseases such as contact dermatitis, neurodermatitis, seborrheic dermatitis, psoriasis, eczema, lichen planus, simple lichen, and skin inflammation and skin itching caused by pompholyx.

[0003] At present, the approved dosage form of desonide preparation is an external use preparation, especially a cream dosage form, which is widely used. Desonide cream was first developed by the American perrigo company, and was approved for marketing by FDA in January 1972, with a specification of 0.05%, which has been discontinued.

[0004] Cream preparations are usually stored in a closed, cool place. The stability of cream preparations is also poorer than that of other solid preparations. Therefore, the shape of the cream preparation can change 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 amounts of impurities of desonide cream increase significantly when placed for a long time or at high temperature, and the content also decreases. These problems have adverse effects on the quality and stability of desonide cream. Therefore, the existing desonide cream formula and preparation method still need to be improved. SUMMARY

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

[0006] Therefore, the first aspect of the present application provides a desonide cream, wherein the composition of the preparation raw materials of the desonide cream is as follows, based on 100g of the desonide cream:

[0007] 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 petrolatum 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 of water.

[0008] Reference the instruction manual of the reference preparation Desowen Cream (perrigo), which contains 0.05% desonide, and the excipient composition is cetearyl alcohol, white petrolatum, light liquid paraffin, synthetic beeswax, aluminum sulfate, calcium acetate, dextrin, glycerin, sodium lauryl sulfate, methylparaben and purified water, but the prescription amount is not available from official sources, and the excipients white petrolatum, light liquid paraffin and synthetic beeswax are complex mixtures, and their prescription amounts cannot be analyzed under the existing technology. In view of this, the prescription amounts of cetearyl alcohol, glycerin, aluminum sulfate, calcium acetate, methylparaben and dextrin in Desowen Cream are analyzed by reverse engineering in the present application, and the prescription amounts of white petrolatum, light liquid paraffin and synthetic beeswax which cannot be analyzed are determined by prescription process research combined with viscosity and stability results, and thus the final formula of Desowen Cream is obtained. The in vitro release and transdermal behavior of Desowen Cream with the prescription amount are consistent with the reference preparation, and the product quality is more stable.

[0009] In the present application, the desonide added in the preparation raw material of Desowen Cream is an effective active ingredient; cetearyl alcohol, synthetic beeswax, light liquid paraffin and white petrolatum are oil phase matrix; sodium lauryl sulfate is an emulsifier which can disperse the oil phase and the water phase, and make them uniformly mixed; glycerin and water are water phase / moisturizing agent; 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; methylparaben is a preservative.

[0010] In some preferred embodiments, the composition of the preparation raw material of Desowen Cream is as follows, based on 100 g of Desowen Cream:

[0011] Desonide 0.05 g; cetearyl alcohol 12.0 g; synthetic beeswax 1.0 g; light liquid paraffin 0.1 g; white petrolatum 10.0 g; glycerin 5.0 g; sodium lauryl sulfate 2.0 g; aluminum sulfate 0.05 g; calcium acetate 0.05 g; methylparaben 0.15 g; dextrin 0.015 g; and the balance of water.

[0012] The present application can further improve the stability, in vitro release and transdermal behavior by optimizing the content of each component in the preparation raw material.

[0013] In the present application, the water in the preparation raw material of Desowen Cream may be, for example, purified water and the like.

[0014] The second aspect of the present application provides a preparation method of Desowen Cream as described in the first aspect of the present application, which comprises the following steps:

[0015] S1, mix cetearyl alcohol, synthetic beeswax, light liquid paraffin and white petrolatum, heat to 60-70℃, melt and stir, then add desonide, stir to dissolve, obtain oil phase, keep warm;

[0016] S2, add glycerin, aluminum sulfate, calcium acetate, dextrin, hydroxybenzyl alcohol and sodium dodecyl sulfate into water, heat and stir to obtain water phase, keep warm;

[0017] S3, add oil phase into water phase, homogenize, cool and stir to obtain desonide cream.

[0018] In the preparation of the desonide cream, desonide is added into the oil phase. Since desonide is more distributed in the oil phase of the cream, directly adding desonide into the oil phase in the preparation process can avoid the diffusion of desonide during the storage of the cream, thereby improving the stability of the desonide cream. Since desonide is unstable at high temperature, the heating temperature of the oil phase during preparation should be controlled at 60-70℃. If the temperature is too high, desonide will decompose, resulting in an increase in the impurity content of the prepared cream. If the temperature is too low, the raw materials in the oil phase cannot be fully melted, which reduces the uniformity and stability of the prepared cream. In some preferred embodiments, the temperature of the oil phase after heating in step S1 is 70℃.

[0019] In some embodiments, the temperature of the water phase is 60-70℃. In some preferred embodiments, the temperature of the water phase is 70℃.

[0020] The temperature of the water phase in the present application will affect the emulsification temperature of the mixed liquid after mixing the water phase and the oil phase. By controlling the temperature of the water phase at 60-70℃, especially at 70℃, the emulsification temperature of the mixed liquid after mixing the water phase and the oil phase can be controlled at 70℃. The inventors of the present application found that by controlling the emulsification temperature of the mixed liquid at 70℃, the decomposition of desonide can be effectively avoided, and the emulsification process can be smoothly carried out, further improving the stability of the prepared desonide cream.

[0021] In some embodiments, the heating and stirring in step S2 is carried out under vacuum condition, and the vacuum degree is -0.06MPa to -0.10MPa. In some preferred embodiments, the vacuum degree is -0.08MPa.

[0022] Since sodium dodecyl sulfate in the water phase is easy to produce bubbles during stirring, and desonide is sensitive to oxygen, the oxygen in the water phase bubbles will cause the degradation of desonide. By vacuumizing during the preparation of the water phase, the bubbles in the water phase before mixing with the oil phase can be minimized, thereby reducing the pressure for vacuumizing and removing bubbles after mixing the water phase with the oil phase.

[0023] In some embodiments, the step S2 specifically comprises the following steps:

[0024] S2-1, glycerin, dextrin, methylparaben and sodium laurylsulfate are added into 80-90 wt% of water of the prescription amount, and after heating and stirring, water phase 1 is obtained and kept warm for standby;

[0025] S2-2, aluminum sulfate is added into 5-8 wt% of water of the prescription amount, and after heating and stirring, water phase 2 is obtained and kept warm for standby;

[0026] S2-3, calcium acetate is added into the remaining water of the prescription amount, and after heating and stirring, water phase 3 is obtained and kept warm for standby.

[0027] The inventors of the present application found through research that the stability of desonide at high temperature is different under different pH conditions, and the stability of desonide at high temperature under neutral conditions is better than that under acidic conditions. Therefore, the pH adjuster (aluminum sulfate and calcium acetate) is prepared separately when the water phase is prepared, so that the water phase solution of the pH adjuster can be added at different times to improve the quality stability of the prepared cream as much as possible.

[0028] In some embodiments, the temperature of the water phase 1, the water phase 2 and the water phase 3 is independently 60-70°C.

[0029] In some preferred embodiments, the temperature of the water phase 1, the water phase 2 and the water phase 3 is 70°C.

[0030] In the present application, the temperature of the water phase 1, the water phase 2 and the water phase 3 will affect the emulsification temperature of the mixed solution after the water phase and the oil phase are mixed. If the temperature of the water phase 1, the water phase 2 and the water phase 3 is too high, it will cause degradation of desonide. If the temperature is too low, it is not conducive to the mixing of the water 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 water phase, resulting in failure of the cream preparation.

[0031] In some embodiments, in step S2-1, the heating and stirring is carried out under vacuum condition, and the vacuum degree is -0.06 MPa to -0.10 MPa. Preferably, the vacuum degree is -0.08 MPa.

[0032] The heating and stirring described in the present application is carried out under vacuum condition to reduce the air bubbles in the water phase 1 as much as possible before the water phase 1 is mixed with the oil phase, and then reduce the pressure for vacuum degassing of the mixed water phase 1 and the oil phase.

[0033] In some specific embodiments, the step S2 specifically comprises the following steps:

[0034] (2-1), glycerin, dextrin, methylparaben and sodium laurylsulfate were added into 90wt% of water, a 70℃ water bath was started, vacuum was drawn to-0.08MPa, stirring was started, and water phase 1 was obtained after dissolution and dispersion, and was kept warm for standby;

[0035] (2-2), aluminum sulfate was added into 5wt% of water, and water phase 2 was obtained after stirring and dissolution under a 70℃ water bath, and was kept warm for standby;

[0036] (2-3), calcium acetate was added into the remaining 5wt% of water, and water phase 3 was obtained after stirring and dissolution under a 70℃ water bath, and was kept warm for standby.

[0037] In some embodiments, the step S3 specifically comprises the following steps:

[0038] S3-1, the oil phase was added into water phase 1, and the mixture was obtained after stirring and cooling;

[0039] S3-2, water phase 2 and water phase 3 were sequentially added into the mixture, and the denbex cream was prepared after homogenization and stirring and cooling again.

[0040] In the present application, aluminum sulfate and calcium acetate were used as pH regulators in the prescription, the water phase without aluminum sulfate and calcium acetate was neutral with a pH value of about 7.1, and the addition of aluminum sulfate and calcium acetate made the pH value of the water phase about 4.4. No aluminum sulfate and calcium acetate were added in water phase 1, so water phase 1 was neutral. Since the temperature of the oil phase and water phase 1 was high (60-70℃), the mixture of the oil phase and water phase 1 was neutral after mixing, and the stability of denbex under neutral conditions at high temperature was better, so the decomposition of denbex could be reduced. The pH value of the cream was adjusted to acidic after the mixture of the oil phase and water phase 1 was cooled and the water phase solution of the pH regulator was added, and the sensitivity of denbex to acidic pH was lower at low temperature, so the degradation of denbex could be effectively avoided and the stability of the prepared product could be improved by the above preparation method.

[0041] In some embodiments, the temperature of the mixture was 40-45℃.

[0042] In the present application, the temperature of the cooled mixture was controlled in the above range, so that the comprehensive performance of the finally prepared cream was better. If the temperature was too high, the mixture and the water phase solution of the pH regulator would cause the degradation of denbex, and if the temperature was too low, the raw materials of the oil phase in the mixture would condense and precipitate, which would reduce the uniformity and stability of the prepared product. In some preferred embodiments, the temperature of the mixture was 43℃.

[0043] In some embodiments, the homogenization and stirring cooling are both carried out under vacuum conditions, and the vacuum degree is -0.06 MPa to -0.10 MPa. Preferably, the vacuum degree is -0.08 MPa.

[0044] Since a large amount of bubbles is brought in after the water phase and the oil phase are mixed, in order to avoid the influence of oxygen in the bubbles on the betamethasone, the bubbles need to be removed by vacuumizing, and therefore the above operations are all carried out under vacuum conditions.

[0045] In the present application, the homogenization conditions can be: a rotation speed of 3000-3500 rpm and a time of 8-10 min.

[0046] In some specific embodiments, the step S3 specifically comprises the following steps:

[0047] (3-1), adding the oil phase into the water phase 1, vacuumizing to -0.08 MPa, stirring and cooling to 40-45°C to obtain a mixture;

[0048] (3-2), sequentially adding the water phase 2 and the water phase 3 into the mixture and stirring uniformly; vacuumizing to -0.08 MPa, starting homogenization, a rotation speed of 3000-3500 rpm and a time of 8-10 min, after the homogenization is completed, starting a cooling water bath, and stirring and cooling to 35°C again to prepare the betamethasone cream.

[0049] The present application has the following beneficial effects: the present application analyzes the prescription amount of cetyl octadecanol, glycerol, aluminum sulfate, calcium acetate, hydroxybenzyl ester and dextrin in the reference betamethasone cream through reverse engineering, and the prescription amount of white petrolatum, light liquid paraffin and synthetic beeswax which cannot be analyzed is determined through prescription process research combined with viscosity and stability results, and thus the final formula of the betamethasone cream provided by the present application is obtained. The in-vitro release and transdermal behavior of the betamethasone cream of the present application are consistent with those of the reference, and the product quality is more stable. At the same time, the preparation process of the betamethasone cream is improved in the present application, the betamethasone is added in the oil phase, and the temperature of the oil phase and the water phase and the addition time of the pH adjuster (aluminum sulfate and calcium acetate) in the water phase are controlled, which can effectively reduce the decomposition of betamethasone in the preparation process, further improve the stability of the product, and has a good application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0050] Figure 1 The design chart for the comparison of the in-vitro release rates of the self-prepared preparation and the reference preparation in the test example 3.

[0051] Figure 2 The chart for the in-vitro release rates of betamethasone in the self-prepared preparation and the reference preparation in the test example 3.

[0052] Figure 3Figure for cumulative permeation amount per unit area at different sampling time points of self-prepared formulation and reference formulation in Test Example 4.

[0053] Figure 4 Figure for flux at different sampling time points of self-prepared formulation and reference formulation in Test Example 4.

[0054] Figure 5 Microscopic picture of droplet particle size of self-prepared formulation in Test Example 6.

[0055] Figure 6 Microscopic picture of droplet particle size of reference formulation 1JT0530 in Test Example 6.

[0056] Figure 7 Microscopic picture of droplet particle size of reference formulation 1FT0533 in Test Example 6 DETAILED DESCRIPTION

[0057] In order to make the present application more easily understood, the present application will be further described in detail below in conjunction with examples, which serve only illustrative purposes and do not limit the scope of application of the present application. The raw materials or components used in the present application can be prepared by commercial means or conventional methods if not specifically stated.

[0058] Examples 1-5: Preparation of Deniide Cream

[0059] 1. Prescription composition: The prescription composition of the Deniide Cream in Examples 1-5 is shown in Table 1, respectively, based on 100 g of Deniide Cream.

[0060] Table 1

[0061]

[0062]

[0063] 2. Preparation process: The preparation processes of Examples 1-5 are the same, and the specific steps are as follows:

[0064] (1) Preparation of oil phase: Cetostearyl alcohol, synthetic beeswax, light liquid paraffin, white vaseline were added to a beaker, heated to 70°C and stirred to melt; then deniide was added and stirred to dissolve, to prepare the oil phase, and keep warm for standby.

[0065] (2) Preparation of water phase: Glycerol, aluminum sulfate, calcium acetate, dextrin, hydroxybenzyl ester and sodium dodecyl sulfate were added to purified water, a 70°C water bath was started, vacuum was extracted to-0.08 MPa, stirring was started, and stirring was continued until dissolution and dispersion were completed, to prepare the water phase, and keep warm for standby.

[0066] (3) Add the oil phase into the water phase, vacuumize to -0.08 MPa, start the vacuum homogenization, the homogenization speed is 3000 rpm, the homogenization time is 15 min, after the homogenization, start the cooling water bath, stir at 100 rpm, cool to 35℃, prepare the desonide cream.

[0067] The physicochemical properties and high temperature stability of the desonide cream prepared in Examples 1-5 were detected. The indexes of the physicochemical property detection include pH value, appearance and viscosity, and the detection results are shown in Table 2; the high temperature stability detection was performed by placing the desonide cream at a temperature of 40℃ for 30 days, and detecting the total impurity content, and the detection results are shown in Table 3.

[0068] Table 2

[0069]

[0070]

[0071] Table 3

[0072]

[0073] According to the detection results in Table 3, it can be known that the white petrolatum amount has no obvious influence on the stability of the desonide cream, the impurity content of the desonide cream is not obviously increased after being placed at 40℃ for 30 days, and when the white petrolatum amount is 1-15 g, the impurity content is less. According to the detection results in Table 2, when the white petrolatum amount is 10 g, the viscosity of the prepared desonide cream is moderate (the viscosity is about 65000), too high content will make the product viscosity too high, and too low content will make the product viscosity too low, which are not conducive to the cream application. The optimal content of the white petrolatum in the prescription is determined to be 10 g according to the viscosity and stability results.

[0074] Examples 6-10: Preparation of desonide cream

[0075] 1. Prescription composition: the prescription composition of the desonide cream in Examples 6-10 is shown in Table 4, respectively, based on 100 g of the desonide cream.

[0076] Table 4

[0077]

[0078]

[0079] 2. Preparation process: the preparation process of Examples 6-10 is the same as that of Example 1.

[0080] The physicochemical properties and high-temperature stability of the denileukin diftitox cream prepared in Examples 6-10 were detected. The detection methods of the physicochemical properties and high-temperature stability were the same as in Example 1, and the detection results of the physicochemical properties are shown in Table 5, and the detection results of the high-temperature stability are shown in Table 6.

[0081] Table 5

[0082]

[0083] Table 6

[0084]

[0085] According to the detection results in Table 6, it can be seen that the amount of light liquid paraffin has no obvious effect on the stability of the denileukin diftitox cream when the amount is 0.1-7 g, and the impurity content of the denileukin diftitox cream does not increase obviously after being placed at 40°C for 30 days. According to the detection results in Table 5, it can be seen that when the amount of light liquid paraffin is 0.1-0.2 g, the viscosity of the prepared denileukin diftitox cream is moderate, and the viscosity is more suitable when the amount is 0.1 g. The most suitable amount of light liquid paraffin in the prescription is 0.1 g, which is determined by comprehensively considering the viscosity, stability results and production cost.

[0086] Examples 11-12: Preparation of denileukin diftitox cream

[0087] 1. Prescription composition: The prescription compositions of the denileukin diftitox cream in Examples 11-12 are shown in Table 7, respectively, based on 100 g of the denileukin diftitox cream.

[0088] Table 7

[0089]

[0090] 2. Preparation process: The preparation processes of Examples 11-12 are the same as those of Example 1.

[0091] The physicochemical properties and high-temperature stability of the denileukin diftitox cream prepared in Examples 11-12 were detected. The detection methods of the physicochemical properties and high-temperature stability were the same as in Example 1, and the detection results of the physicochemical properties are shown in Table 8, and the detection results of the high-temperature stability are shown in Table 9.

[0092] Table 8

[0093] Example 11 Example 12 pH 4.59 4.48 Appearance White cream White cream Viscosity (mPa-s) 66800 70600

[0094] Table 9

[0095]

[0096] According to the detection results of Table 9, it can be known that the amount of synthetic beeswax has no obvious effect on the stability of the desonide cream, and the impurity content of the desonide cream does not increase obviously after being placed at 40℃ for 30 days. When the amount of synthetic beeswax is 1g, the impurity content is less. According to the detection results of Table 8, when the amount of synthetic beeswax is 1g, the viscosity of the prepared desonide cream is moderate. The optimal amount of synthetic beeswax in the prescription is determined to be 1g by comprehensively considering the viscosity, stability and production cost.

[0097] Example 13: Effect of oil phase temperature and water phase temperature on stability during preparation of desonide cream

[0098] Prescription composition: The prescription of the desonide cream is the same as that of Example 11.

[0099] 1. Investigation of oil phase temperature:

[0100] Preparation of oil phase 1: Cetostearyl alcohol, synthetic beeswax, light liquid paraffin and white vaseline were added into a beaker, and then heated to 60℃ for melting and stirring. Then desonide was added and dissolved by stirring to prepare oil phase 1.

[0101] Preparation of oil phase 2: Cetostearyl alcohol, synthetic beeswax, light liquid paraffin and white vaseline were added into a beaker, and then heated to 70℃ for melting and stirring. Then desonide was added and dissolved by stirring to prepare oil phase 2.

[0102] Preparation of oil phase 3: Cetostearyl alcohol, synthetic beeswax, light liquid paraffin and white vaseline were added into a beaker, and then heated to 75℃ for melting and stirring. Then desonide was added and dissolved by stirring to prepare oil phase 3.

[0103] The prepared oil phases 1, 2 and 3 were respectively incubated at the corresponding temperatures for 8h, and samples were taken at 0h, 3h, 6h and 8h for detection, and the detection indexes included appearance and impurity content, and the results are shown in Table 10.

[0104] Table 10

[0105]

[0106] From the above results, it can be known that when the oil phase temperature is 70℃ and the incubation time is 8h, the appearance and related substances do not change obviously, and the impurity content does not increase within 3h. When the oil phase temperature is 60℃ and the incubation time is 8h, the related substances do not change obviously, but when the oil phase temperature is too low and the incubation time is too long, the raw materials of the oil phase will coagulate and solidify, resulting in turbidity of the liquid. When the oil phase temperature is 75℃ and the incubation time is 8h, the appearance does not change obviously, but when the oil phase temperature is too high and the incubation time is too long, the impurity content increases obviously. Therefore, the optimal temperature for preparing the oil phase is 70℃.

[0107] 2. Investigation of water phase temperature

[0108] Preparation of the first aqueous phase: glycerin, aluminum sulfate, calcium acetate, dextrin, methylparaben and sodium laurylsulfate were added to purified water, a water bath at 60°C was turned on, vacuum was drawn to -0.08 MPa, stirring was turned on, and stirring was performed until dissolution and dispersion, thereby preparing the first aqueous phase.

[0109] Preparation of the second aqueous phase: glycerin, aluminum sulfate, calcium acetate, dextrin, methylparaben and sodium laurylsulfate were added to purified water, a water bath at 70°C was turned on, vacuum was drawn to -0.08 MPa, stirring was turned on, and stirring was performed until dissolution and dispersion, thereby preparing the second aqueous phase.

[0110] Preparation of the third aqueous phase: glycerin, aluminum sulfate, calcium acetate, dextrin, methylparaben and sodium laurylsulfate were added to purified water, a water bath at 75°C was turned on, vacuum was drawn to -0.08 MPa, stirring was turned on, and stirring was performed until dissolution and dispersion, thereby preparing the third aqueous phase.

[0111] The oil phase at 70°C was mixed with the first aqueous phase, the second aqueous phase and the third aqueous phase, respectively, and emulsification was performed at the corresponding temperature under stirring with incubation, and sampling was performed at 5 min, 1 h, 2 h, 3 h, 6 h and 8 h, respectively, and the detection indexes included appearance and impurity content, and the results are shown in Table 11.

[0112] Table 11

[0113]

[0114]

[0115] From Table 11, it can be seen that when the temperature of the aqueous phase is controlled at 70°C, the temperature for emulsification after mixing the oil phase and the aqueous phase is 70°C, and the appearance does not change obviously under stirring emulsification at this temperature for 8 h, and the related substances gradually increase with the increase of the incubation time, the impurities increase less within 2 h, and the total impurities are still small within 8 h. If the temperature of the aqueous phase is too low, the emulsification effect is poor, and if the temperature of the aqueous phase is too high, the impurity content increases obviously.

[0116] Example 14: Preparation of desonide cream

[0117] 1. Prescription composition: the prescription of desonide cream is the same as that of Example 11.

[0118] 2. Preparation process:

[0119] (1) Preparation of the oil phase: cetearyl alcohol, synthetic beeswax, light liquid paraffin and white petrolatum were added to a beaker, and stirring and melting were performed at 70°C; then desonide was added, and stirring was performed until dissolution, thereby preparing the oil phase, which was incubated for standby use.

[0120] (2) Preparation of water phase 1: Glycerin, dextrin, methylparaben and sodium lauryl sulfate were added into 90wt% purified water, and a water bath at 70°C was started. The vacuum was extracted to -0.08 MPa, and the stirring was started. The stirring was continued until the solution was dissolved and dispersed. The water phase 1 was prepared and kept warm for standby. Preparation of water phase 2: Aluminum sulfate was added into 5wt% purified water, and a water bath at 70°C was started. The stirring was continued until the solution was dissolved. The water phase 2 was prepared and kept warm for standby. Preparation of water phase 3: Calcium acetate was added into 5wt% purified water, and a water bath at 70°C was started. The stirring was continued until the solution was dissolved. The water phase 2 was prepared and kept warm for standby.

[0121] (3) The oil phase was added into the water phase 1, and the vacuum was extracted to -0.08 MPa. The stirring speed was 100 rpm, and the temperature was cooled to 43°C to obtain a mixture. The water phase 2 and the water phase 3 were added into the mixture in sequence, and the stirring was continued until the solution was dissolved. The vacuum was extracted to -0.08 MPa, and the homogenization was started. The homogenization speed was 3000 rpm, and the homogenization time was 15 min. After the homogenization was completed, the cooling water bath was started, and the stirring was continued until the temperature was cooled to 35°C. The denileukin diftitox cream was prepared.

[0122] Example 15: Preparation of denileukin diftitox cream

[0123] 1. Prescription composition: The prescription of the denileukin diftitox cream was the same as that of Example 11.

[0124] 2. Preparation process: The preparation process was basically the same as that of Example 14, except that in step (3), the oil phase was added into the water phase 1, and the vacuum was extracted to -0.08 MPa. The stirring speed was 100 rpm, and the temperature was cooled to 40°C to obtain a mixture.

[0125] Example 16: Preparation of denileukin diftitox cream

[0126] 1. Prescription composition: The prescription of the denileukin diftitox cream was the same as that of Example 11.

[0127] 2. Preparation process: The preparation process was basically the same as that of Example 14, except that in step (3), the oil phase was added into the water phase 1, and the vacuum was extracted to -0.08 MPa. The stirring speed was 100 rpm, and the temperature was cooled to 45°C to obtain a mixture.

[0128] Example 17: Preparation of denileukin diftitox cream

[0129] 1. Prescription composition: The prescription of the denileukin diftitox cream was the same as that of Example 11.

[0130] 2. Preparation process:

[0131] Steps (1) and (2) were the same as those of Example 1, and step (3) was as follows:

[0132] (3) The oil phase was added into the water phase, vacuumized to -0.08 MPa, and cooled to 43°C under stirring at 100 rpm to obtain a mixture; vacuumized to -0.08 MPa, homogenized at 3000 rpm for 15 min, and cooled to 35°C under stirring at 100 rpm to prepare the denileukin diftitox cream.

[0133] Test Example 1

[0134] The physicochemical properties and high-temperature stability of the denileukin diftitox cream prepared in Examples 14-17 and two batches of reference preparations (reference preparation 1 JT0530 and reference preparation 1 FT0533) were detected. The indicators for the physicochemical property detection included pH value, appearance, and viscosity, and the detection results are shown in Table 12; the high-temperature stability detection was performed by placing the denileukin diftitox cream at a temperature of 40°C for 30 days and at a temperature of 30°C and a humidity of 65% for 6 months, respectively, and detecting the total impurity content, and the detection results are shown in Table 13.

[0135] Table 12

[0136] Example 14 Example 15 Example 16 Example 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

[0137] Table 13

[0138]

[0139] From the detection results in Table 13, it can be seen that the stability of the related substances of the denileukin diftitox cream is obviously improved by changing the addition order of the pH adjuster (aluminum sulfate, calcium acetate). At the same time, when the temperature of the mixture is cooled to 43°C before the pH adjuster (aluminum sulfate, calcium acetate) is added (Example 14), the stability of the prepared denileukin diftitox cream is better. At the same time, from the detection results in Table 12, it can be seen that changing the addition order of the pH adjuster (aluminum sulfate, calcium acetate) has no obvious effect on the physicochemical properties of the prepared denileukin diftitox cream.

[0140] Test Example 2

[0141] The rheological properties of the denileukin diftitox cream prepared in Example 14 (self-prepared preparation) and two batches of reference preparations (reference preparation 1 JT0530 and reference preparation 1 FT0533) were detected. The flow curve detection results are shown in Table 14, and the yield stress, creep, and linear viscoelastic region detection results are shown in Table 15.

[0142] Table 14

[0143]

[0144] Table 15

[0145]

[0146] From Table 14, it can be seen that the viscosity of the self-prepared preparation and the two batches of reference preparations all significantly decreases with the increase of shear rate. From low shear rate (0.01 s -1 ) to medium shear rate (10 s -1 ), the viscosity change trend of the self-prepared preparation and the two batches of reference preparations is consistent. This result shows that the stability of the self-prepared preparation and the two batches of reference preparations in the process of product storage, transportation, stirring and shaking is consistent with that of the reference preparations.

[0147] The yield stress is the critical stress that characterizes the start of flow or stop of flow of the sample, and can be used to evaluate the spreadability of the skin external preparation in use and the ease of realization of the product during filling. According to the yield stress values in Table 15, the yield stress of the self-prepared preparation is slightly higher than that of the two batches of reference preparations, indicating that the self-prepared preparation has better stability without affecting the extrusion filling and spreading.

[0148] The creep recovery ability of the product reflects the ability of the internal structure of the product to resist slip deformation. The γ-max reflects the maximum deformation of the product under a certain external force, and the γ-r / γ-max reflects the degree of creep recovery after the external force is removed. According to the data in Table 15, the maximum deformation of the self-prepared preparation under the same external force is similar to that of the reference preparations, and the degree of creep recovery is also similar to that of the reference preparations.

[0149] Generally speaking, after the sample is subjected to an external force, it will slowly deform, showing viscous behavior; after the deformation force is removed, the sample gradually recovers to the original structure, showing elastic behavior. Good viscosity can ensure the close fit of the skin external preparation with the medicinal site, ensure that the preparation will not fall off during use, and will not flow easily; good elasticity can make the preparation have better storage stability. From the linear viscoelastic region in Table 15, the viscoelasticity test results of the self-prepared preparation and the two batches of reference preparations are relatively close, indicating that the close fit degree of the self-prepared preparation with the medicinal site and the storage stability are close to those of the reference preparations.

[0150] Test Example 3

[0151] The in vitro release characteristics of the denbex cream (self-prepared preparation) prepared in Example 14 and the reference preparation 1FT0533 were detected. The specific detection method was as follows: a modified Franz stereoscopic diffusion device was used, and a pretreated artificial synthetic membrane was fixed between the donor chamber and the receiver chamber. About 0.2 g of the self-prepared preparation and the reference preparation denbex cream were evenly applied on the selected artificial synthetic membrane, respectively (see Figure 1, keep the closed state to prevent the solution from evaporating and the ingredients from changing, add 12 mL of in-vitro release medium warmed to 32 ± 1 °C to the receiving chamber, make the artificial membrane just contact the liquid surface of the in-vitro release medium, open the magnetic stirrer (speed: 600 rpm / min) for continuous stirring, and make the drug release naturally, take 12 mL of sample at 0.5, 1.0, 2.0, 3.0, 4.0, and 6.0 hours, respectively, to obtain the test sample solution, detect the content of desonide in the test sample solution, conduct 4 sets of parallel experiments, and take the average value of the 4 sets of parallel experiments as the experimental result. After each sampling is completed, supplement the receiving chamber with the same amount of blank in-vitro release medium at the same temperature. After the detection is completed, draw the in-vitro release rate diagram of desonide, as shown in Figure 2 , and the in-vitro release summary result of desonide is shown in Table 16.

[0152] Table 16

[0153]

[0154] From Figure 2 and Table 16, it can be seen that the desonide release amount per unit area of the self-prepared preparation and the reference preparation (batch number: 1FT0533) at different sampling points has a linear relationship with the square root of time, and r 2 is greater than 0.90; and the release rate RSD of the 4 parallel test samples of the self-prepared preparation and the reference preparation is less than 15%, which meets the requirements of the recognized standard. At the same time, the 90% confidence interval of the desonide in-vitro release rate ratio of the self-prepared preparation and the reference preparation is 102.3%-112.0%, which falls within the range of 75%-133.33%, indicating that the in-vitro release behaviors of desonide in the self-prepared preparation and the reference preparation are equivalent.

[0155] Test Example 4

[0156] The in-vitro transdermal properties of the desonide cream prepared in Example 14 (self-prepared preparation) and the reference preparation 1FT0533 were detected. The specific detection method was as follows: the detection used a modified Franz stereoscopic diffusion device, the contact area was 1.77 cm 2, the volume of the receptor chamber is 12 mL, the pretreated small Bama miniature pigskin (cleaned with normal saline) is fixed between the donor chamber and the receptor chamber, the sample amount (about 200 mg) of the uniformly applied betamethasone cream is applied on the selected small Bama miniature pigskin, the sample amount difference between parallel samples is within ± 5%, 12 mL of the in-vitro percutaneous medium heated to 32 ± 0.5 ℃ is added to the receptor chamber, the pigskin is just in contact with the liquid surface of the in-vitro percutaneous medium, the magnetic stirrer (speed: 600 rpm / min) is started for continuous stirring, the drug is allowed to penetrate naturally, 1.0 mL of sample is taken at 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 20.0, 24.0 hours, respectively, to obtain the test solution, and the remaining solution is discarded. After each sampling is completed, 12 mL of blank in-vitro percutaneous medium is added to the receptor chamber. The concentration of betamethasone in the test solution is determined by HPLC method. After the experiment is completed, the pigskin is taken out, the skin surface is cleaned with normal saline for extraction, the skin is cut into pieces and placed in a 50 mL plastic tube, 10 mL of acetonitrile is added, heating is performed in a water bath at 70 ℃ for 20 min, and then the tube is taken out, vortexed for 5 min while hot, and cooled to room temperature, followed by centrifugation at 10,000 rpm for 10 min, the supernatant is filtered and injected into HPLC for determination of the concentration, 6 sets of parallel experiments are performed, and the experimental results are taken as the average value of the 6 sets of parallel experiments.

[0157] Among them, the results of the residual amount on the skin, the intradermal retention amount, the 24-hour cumulative permeation amount and the total recovery rate of the self-prepared preparation and the reference preparation are shown in Table 17, the cumulative permeation amount per unit area of the self-prepared preparation and the reference preparation at different sampling time points is shown in Table 18 and Figure 3 , the average permeation rate (flux) of the self-prepared preparation and the reference preparation at different sampling time points is shown in Table 19 and Figure 4 , the permeation rate of the self-prepared preparation and the reference preparation is shown in Table 20.

[0158] Table 17

[0159]

[0160] Table 18

[0161]

[0162]

[0163] Table 19

[0164]

[0165] Table 20

[0166]

[0167] From the above test results, the ratio of the intradermal retention amount of the self-prepared preparation to the reference preparation (batch number: 1FT0533) was in the range of 0.7-1.3, indicating that there was no significant difference in the intradermal retention amount between the self-prepared preparation and the reference preparation. The ratio of the 24-hour cumulative permeation amount of the self-prepared preparation to the reference preparation (batch number: 1FT0533) was in the range of 0.7-1.3, indicating that there was no significant difference in the cumulative permeation amount between the self-prepared preparation and the reference preparation. The overall recovery rate (%) of the self-prepared preparation and the reference preparation (batch number: 1FT0533) ((intradermal retention amount + amount of residue on the skin + cumulative permeation amount) / amount of sample applied) was between 80%-120%, and the material balance met the requirements. At the specified test time points and the time points at which the permeation rate of the self-prepared preparation and the reference preparation was halved, the ratio of the average permeation rate of the self-prepared preparation to that of the reference preparation was between 0.7-1.3, indicating that the in vitro permeation behaviors of the self-prepared preparation and the reference preparation were equivalent. (Refer to PMDA: Guideline for Biological Equivalence Test for Formulation Change of Topical Skin Application Preparations (Semisolid Preparations and Adhesive Preparations).

[0168] Test Example 5

[0169] The denbex cream prepared in Example 14 (self-prepared preparation) and the reference preparation 1FT0530 were placed at 40°C for 30 days, and the appearance, pH value, denbex content, and total impurity content of the samples before and after the placement were detected, and the results are shown in Table 21. At the same time, the in-tube uniformity of the self-prepared preparation during the high-temperature stability test was detected, and the results are shown in Table 22.

[0170] Table 21

[0171]

[0172] Table 22

[0173]

[0174] From the high-temperature test results in Table 21, after being placed at 40°C for 30 days, the impurity level and impurity growth trend of the self-prepared preparation were much smaller than those of the reference preparation, indicating that the self-prepared preparation was more stable.

[0175] The content limit of the in-tube uniformity of the denbex cream was 90.0%-110.0%, and from the detection results in Table 22, after being placed at 40°C for 30 days in the commercial packaging material, the three contents (the capped end, the middle, and the coiled end) of the in-tube uniformity of the self-prepared preparation did not exceed the limit, and the range was much smaller than 10%, and the in-tube uniformity also met the requirements during the high-temperature stability test.

[0176] Test Example 6

[0177] The particle size of the denileukin diftitox cream (self-prepared) prepared in Example 14 and two batches of reference preparations (reference preparation 1 JT0530 and reference preparation 1 FT0533) was detected, the microscopic picture of the droplet particle size of the self-prepared preparation is shown in Figure 5 , the microscopic picture of the droplet particle size of the reference preparation 1 JT0530 is shown in Figure 6 , and the microscopic picture of the droplet particle size of the reference preparation 1 FT0533 is shown in Figure 7 .

[0178] From the microscopic picture results of Figures 5-7 , it can be seen that the droplet particle size of the self-prepared preparation is more uniform and controllable, indicating that the preparation process of the self-prepared preparation is more optimal.

[0179] It should be noted that the above-described examples are only used to explain the present application and do not constitute any limitation on the present application. The present application is described by referring to typical examples, but it should be understood that the words used therein are descriptive and explanatory words, rather than limiting words. The present application can be modified as specified within the scope of the claims of the present application, and the present application can be revised within the scope and spirit of the present application. Although the present application described therein relates to specific methods, materials and examples, 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 function.

Claims

1. A desonide cream, characterized in that, The composition of the raw materials for preparing the desonide cream is as follows, based on 100 g of the desonide cream: Desonide 0.04-0.06 g; cetostearyl alcohol 10.0-14.0 g; synthetic beeswax 1.0 g; light liquid paraffin 0.1-0.2 g; white petrolatum 10.0 g; glycerin 4.0-6.0 g; sodium lauryl sulfate 1.5-2.5 g; aluminum sulfate 0.04-0.06 g; calcium acetate 0.04-0.06 g; methylparaben 0.1-0.2 g; dextrin 0.01-0.02 g; and the balance of water; The method for preparing the desonide cream comprises the following steps: S1, mixing cetostearyl alcohol, synthetic beeswax, light liquid paraffin and white petrolatum, melting by stirring at a temperature of 60-70℃, then adding desonide, dissolving by stirring, and obtaining an oil phase, and keeping warm for standby; S2-1, adding glycerin, dextrin, methylparaben and sodium lauryl sulfate into 80-90 wt% of the amount of water in the prescription, heating and stirring to obtain water phase 1, and keeping warm for standby; S2-2, adding aluminum sulfate into 5-8 wt% of the amount of water in the prescription, heating and stirring to obtain water phase 2, and keeping warm for standby; S2-3, adding calcium acetate into the remaining amount of water in the prescription, heating and stirring to obtain water phase 3, and keeping warm for standby; S3-1, adding the oil phase into water phase 1, and stirring and cooling to obtain a mixture; S3-2, adding water phase 2 and water phase 3 into the mixture in sequence, mixing and homogenizing, and stirring and cooling again to obtain the desonide cream.

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

3. The desonide cream according to claim 1, wherein The temperature of the water phase 1, the water phase 2 and the water phase 3 is independently 60-70℃; and / or in step S2-1, the heating and stirring is performed under vacuum condition, and the vacuum degree is -0.06 MPa to -0.10 MPa.

4. The desonide cream of claim 1, wherein, The temperature of the mixture is 40-45℃.

5. The desonide cream according to claim 1, wherein The homogenization and the stirring and cooling are both performed under vacuum condition, and the vacuum degree is -0.06 MPa to -0.10 MPa.

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