A pimecrolimus cream and a method for preparing the same

Abstract

The application provides a pimecrolimus cream and a preparation method thereof. The pimecrolimus cream is prepared from an oil phase and an aqueous phase, and the preparation method comprises the following steps: (1) oil phase preparation: adding oleyl alcohol, medium-chain triglyceride, propylene glycol, hexadecanol, octadecanol and glycerol monostearate into an oil phase container in sequence, heating in a water bath and stirring to dissolve; after complete dissolution, adding pimecrolimus and stirring to dissolve, and after complete dissolution, keeping warm for standby use; (2) aqueous phase preparation: adding purified water, sodium hydroxide, citric acid, benzyl alcohol and sodium cetylstearyl sulfate into an aqueous phase container in sequence, heating in a water bath and stirring to dissolve; (3) mixing and emulsifying: slowly adding the oil phase into the aqueous phase, stirring first, and then homogenizing and emulsifying; (4) cooling and filling: stirring and cooling, and filling. The pimecrolimus cream prepared by the method has a low total impurity content, a content close to 100% and good stability, and is beneficial to improving the drug quality.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, in particular to a pimecrolimus cream and a preparation method thereof. BACKGROUND

[0002] Pimecrolimus is a lipophilic anti-inflammatory ascomycin lactam derivative, which is an external calcineurin inhibitor. Pimecrolimus has high affinity with macrophilin-12, can inhibit calcineurin, thereby inhibiting the proliferation of T cells and the production and release of inflammatory cytokines, and has strong anti-inflammatory activity.

[0003] Pimecrolimus cream was first developed by Novartis Pharmaceutical Company, and was approved for marketing by the US FDA in December 2001, with the trade name of The specification is 1%, which is suitable for 2 years old and above 2 years old patients with mild to moderate atopic dermatitis (eczema) without immune impairment: 1) short-term treatment of signs and symptoms of the disease; 2) long-term intermittent treatment to prevent disease exacerbation. It was approved for marketing in Denmark in March 2002, and then was approved for marketing in all EU member states except Ireland through mutual recognition.

[0004] In September 2005, the pimecrolimus cream of Novartis Pharmaceutical was approved for import marketing by the National Medical Products Administration (hereinafter referred to as “NMPA”), with the registration certificate number H20050485 and the trade name The specification is 1%, and the packaging specification is 15g / box / box, 30g / box / box; in 2006, Novartis Pharmaceutical submitted a supplementary application to increase the packaging specification of 10g / box / box, with the registration certificate number H20060261.

[0005] It is of great significance to develop a new preparation process of pimecrolimus cream and further improve the quality of the drug. SUMMARY

[0006] In view of this, the present application provides a pimecrolimus cream and a preparation method thereof.

[0007] The technical scheme of the present application is implemented as follows: a pimecrolimus cream is prepared by using an oil phase and a water phase, the oil phase is prepared by using the following components: pimecrolimus, oleyl alcohol, medium-chain triglyceride, cetyl alcohol, stearyl alcohol, propylene glycol and glycerin monostearate; the water phase is prepared by using the following components: sodium cetylstearyl sulfate, citric acid, sodium hydroxide, benzyl alcohol and purified water; the components are used in the following proportions by weight: pimecrolimus 9-11 parts, oleyl alcohol 90-110 parts, medium-chain triglyceride 120-160 parts, cetyl alcohol 30-60 parts, stearyl alcohol 30-50 parts, propylene glycol 35-55 parts, glycerin monostearate 15-45 parts, sodium cetylstearyl sulfate 8-20 parts, anhydrous citric acid 0.4-2 parts, sodium hydroxide 0.1-1.5 parts, benzyl alcohol 8-12 parts and purified water 500-600 parts.

[0008] Table 1 Prescription composition of pimecrolimus cream

[0009]

[0010] The preparation method of the pimecrolimus cream of the present application comprises the following steps:

[0011] (1) Preparation of the oil phase: oleyl alcohol, medium-chain triglyceride, propylene glycol, cetyl alcohol, stearyl alcohol, glycerin monostearate are sequentially added into an oil phase container, heated in a water bath and stirred to dissolve; after complete dissolution, pimecrolimus is added and stirred to dissolve; after complete dissolution, the mixture is kept warm for standby use;

[0012] (2) Preparation of the water phase: purified water, sodium hydroxide, anhydrous citric acid, benzyl alcohol and sodium cetylstearyl sulfate are sequentially added into a water phase container, heated in a water bath and stirred to dissolve;

[0013] (3) Mixing and emulsification: the oil phase is slowly added into the water phase, stirred and then homogenized and emulsified;

[0014] (4) Cooling and filling: stirred and cooled, and then filled.

[0015] Preferably, in steps (1) and (2), the temperature of water bath heating is 60-80℃; in step (3), the homogenization temperature is 60-80℃.

[0016] Preferably, in step (3), the homogenization and emulsification is performed for 1-10 min, and the homogenization and emulsification speed is 1500-12000 rpm.

[0017] Preferably, in step (3), gradient homogenization is adopted, first homogenized at 3000 rpm for 8-12 s, then at 5000 rpm for 25-35 s, and finally at 10000 rpm for 15-25 s.

[0018] Preferably, in step (3), the stirring time is 4-10 min.

[0019] Preferably, the stirring speed in steps (1)-(4) is 100-500 rpm.

[0020] The preparation method of the pimecrolimus cream of the present application comprises the following steps:

[0021] (1) Weigh oleic alcohol, medium-chain triglyceride, propylene glycol, cetyl alcohol, stearyl alcohol, and glycerol monostearate, and add them into an oil phase container in sequence, heat in a water bath at 60-80℃, and stir to dissolve, with a stirring speed of 150-500 rpm; after complete dissolution, add pimecrolimus, stir to dissolve, with a stirring speed of 150-500 rpm, and keep at 50-80℃ for standby use after complete dissolution;

[0022] (2) Weigh purified water, sodium hydroxide, anhydrous citric acid, benzyl alcohol, and sodium cetylstearyl sulfate, and add them into a water phase container in sequence, heat in a water bath at 60-80℃, and stir to dissolve, with a stirring speed of 150-500 rpm;

[0023] (3) Under the condition of 60-80℃, slowly add the oil phase into the water phase, stir for 4-10 min, with a stirring speed of 150-500 rpm, and homogenize and emulsify;

[0024] (4) Stir to cool, with a stirring speed of 150-500 rpm; and fill.

[0025] Preferably, the weight parts of pimecrolimus, oleic alcohol, medium-chain triglyceride, cetyl alcohol, stearyl alcohol, propylene glycol, glycerol monostearate, sodium cetylstearyl sulfate, anhydrous citric acid, sodium hydroxide, benzyl alcohol, and purified water are 10, 95-105, 125-135, 45-55, 35-45, 35-45, 25-35, 15-20, 1.0-1.5, 1.0-1.5, 9-11, and 560-580, respectively.

[0026] More preferably, the weight parts of pimecrolimus, oleic alcohol, medium-chain triglyceride, cetyl alcohol, stearyl alcohol, propylene glycol, glycerol monostearate, sodium cetylstearyl sulfate, anhydrous citric acid, sodium hydroxide, benzyl alcohol, and purified water are 10, 100, 130, 50, 40, 40, 30, 18, 1.5, 1.2, 10, and 569.3, respectively.

[0027] A pimecrolimus cream prepared by any one of the preparation methods of the present application.

[0028] Compared with the prior art, the present application has the following beneficial effects:

[0029] (1)The present application prepares an oil phase with pimecrolimus (active ingredient), oleyl alcohol (oil phase base), medium-chain triglyceride (oil phase base), cetyl alcohol (thickening agent), stearyl alcohol (thickening agent), propylene glycol (moisturizing agent) and glycerol monostearate (emulsifying agent), prepares an aqueous phase with sodium cetylstearyl sulfate (emulsifying agent), citric acid (pH regulator), sodium hydroxide (pH regulator), benzyl alcohol (bacteriostatic agent) and purified water (aqueous phase diluent), and the pimecrolimus cream prepared by the process of the present application meets the requirements of various inspection items, has a lower total impurity content, the content is close to 100%, and has good stability, which is beneficial to improving the quality of the drug.

[0030] (2)After the gradient homogenization method is used, the total impurity content of the prepared pimecrolimus cream is lower, which is beneficial to improving the product quality, and further improves the liquid drop particle size, which is beneficial to improving the quality of the drug. DETAILED DESCRIPTION

[0031] In order to better understand the technical content of the present application, specific examples are provided below to further illustrate the present application.

[0032] The experimental methods used in the embodiments of the present application are all conventional methods unless otherwise specified.

[0033] The materials, reagents and the like used in the embodiments of the present application can be obtained from commercial channels unless otherwise specified.

[0034] Table 2 Raw material manufacturer

[0035] Serial number Raw material Factory 1 Oleyl alcohol Zhongnuo Kai Lin Pharmaceutical Development (Suzhou) Co., Ltd. 2 Medium-chain triglyceride Jiangsu Baoyi Pharmaceutical Co., Ltd. 3 Hexadecanol Fume Lipid Chemistry (Henan) Co., Ltd. 4 Octadecanol Zhongnuo Kai Lin Pharmaceutical Development (Suzhou) Co., Ltd. 5 Propylene glycol Jiangxi Hanjiang Pharmaceutical Co., Ltd. 6 Glyceryl monostearate BASF (China) Co., Ltd. 7 Sodium cetylstearyl sulfate Chengdu Huayu Pharmaceutical Auxiliary Material Manufacturing Co., Ltd. 8 Anhydrous citric acid Chengdu Huayu Pharmaceutical Auxiliary Material Manufacturing Co., Ltd. 9 Sodium hydroxide Merck Chemical Technology (Shanghai) Co., Ltd. 10 Benzyl alcohol Jiangsu Baoyi Pharmaceutical Co., Ltd.

[0036] Table 3 Basic information of raw material drug

[0037]

[0038] Table 4 Impurity structure and chemical name

[0039]

[0040] Example 1

[0041] 1 Pimecrolimus cream formula

[0042] Table 5 Formula

[0043]

[0044] 2 Process

[0045] (1) Take the oil alcohol, medium-chain triglyceride, propylene glycol, cetyl alcohol, stearyl alcohol, and glycerin monostearate and distearate in sequence into an oil phase container, heat in a 60℃ water bath, and dissolve with stirring at a stirring speed of 400 rpm; after complete dissolution, add the raw material drug (pimecrolimus) and dissolve with stirring at a stirring speed of 400 rpm, and keep at 40℃ after complete dissolution for standby; the complete dissolution time of the oil phase auxiliary materials is 20 min, and the complete dissolution time of the raw material drug is 60 min.

[0046] (2) Take the purified water, sodium hydroxide, anhydrous citric acid, benzyl alcohol, and sodium cetylstearyl sulfate in sequence into a water phase container, heat in a 60℃ water bath, and dissolve with stirring at a stirring speed of 400 rpm;

[0047] (3) Under the condition of 70℃, slowly add the oil phase into the water phase, stir for 5 min at a stirring speed of 400 rpm, homogenize for 5 min at a homogenization speed of 5000 rpm;

[0048] (4) Stir and cool, stir at a stirring speed of 400 rpm, specifically set the vacuum to -0.2 MPa, pass 40℃ water into the jacket, stir and cool to 45-40℃, continuously stir, defoam by repeatedly vacuumizing (-0.06 MPa) for multiple times until no obvious foam is generated, and stop under normal pressure at 40℃.

[0049] (5) Fill into a blank aluminum medicinal ointment tube.

[0050] The prepared pimecrolimus cream is tested, and the test results are compared with those of a reference preparation,

[0051] The reference preparation holding company is MEdA Pharma GmbH & Co. KG, the English name is Pimecrolimus Cream, the trade name is Elidel, and the specification is 1% (the packaging specification is 10 g).

[0052] Table 6 Test standards and test results

[0053]

[0054]

[0055] The results show that the prepared pimecrolimus cream meets the requirements of each test item, the total impurity content is low, and the content is close to 100%. The pimecrolimus cream prepared by the process has the advantages of improving the quality of the drug.

[0056] Example 2

[0057] 1 The pimecrolimus cream prescription is consistent with that of Example 1.

[0058] 2 Process

[0059] (1) Take the oil alcohol, medium-chain triglyceride, propylene glycol, cetyl alcohol, stearyl alcohol, and glycerol monostearate, respectively, and add them to an oil phase container. Heat in a 70°C water bath and stir to dissolve. The stirring speed is 100 rpm. After complete dissolution, add the raw material drug (pimecrolimus) and stir to dissolve. The stirring speed is 100 rpm. After complete dissolution, keep it at 70°C for standby;

[0060] (2) Take the purified water, sodium hydroxide, anhydrous citric acid, benzyl alcohol, and sodium cetylstearyl sulfate, respectively, and add them to a water phase container. Heat in a 70°C water bath and stir to dissolve. The stirring speed is 100 rpm.

[0061] (3) Slowly add the oil phase to the water phase under the condition of 70°C, stir for 5 min at a stirring speed of 100 rpm, and homogenize for 5 min at a homogenization speed of 10,000 rpm.

[0062] (4) Stir and cool, with a stirring speed of 100 rpm. Specifically, set the vacuum to -0.06 MPa. Pass 45°C water into the jacket. Stir and cool to 55-50°C. Continue stirring. Defoam by repeatedly vacuuming (-0.06 MPa) multiple times until no obvious foam is generated. Cool to 48°C (45-50°C) under normal pressure. Stop.

[0063] (5) Fill into blank aluminum medicinal ointment tubes, and fill according to 10 g / branch.

[0064] Example 3

[0065] 1 The prescription of pimecrolimus cream is consistent with Example 1.

[0066] 2 Process

[0067] (1) Take the oil alcohol, medium-chain triglyceride, propylene glycol, cetyl alcohol, stearyl alcohol, and glycerol monostearate, respectively, and add them to an oil phase container. Heat in a 60°C water bath and stir to dissolve. The stirring speed is 300 rpm. After complete dissolution, add the raw material drug (pimecrolimus) and stir to dissolve. The stirring speed is 300 rpm. After complete dissolution, keep it at 60°C for standby. The complete dissolution time of the oil phase auxiliary materials is 30 min, and the complete dissolution time of the raw material drug is 2 h.

[0068] (2) Take the purified water, sodium hydroxide, anhydrous citric acid, benzyl alcohol, and sodium cetylstearyl sulfate, respectively, and add them to a water phase container. Heat in a 60°C water bath and stir to dissolve. The stirring speed is 300 rpm.

[0069] (3) Slowly add the oil phase to the water phase under the condition of 60°C, stir for 5 min at a stirring speed of 300 rpm, and homogenize for 8 min at a homogenization speed of 3,000 rpm.

[0070] (4) Stirring cooling, stirring speed 300 rpm, specific set vacuum -0.06 MPa, 45 ℃ water into the jacket, stirring cooling to 55-50 ℃, continuous stirring, defoaming by repeatedly vacuum (-0.06 MPa) multiple times, to no longer produce obvious foam, atmospheric cooling to 48 ℃ (45-50 ℃), stop.

[0071] (5) Filling to blank aluminum medicinal ointment tube, filling according to 10 g / branch.

[0072] Compared with Example 1, the sample prepared in this example has no obvious difference in properties and related substances.

[0073] Example 4

[0074] 1 The prescription of pimecrolimus cream is consistent with Example 1.

[0075] 2 Process

[0076] (1) Take the oil alcohol, medium-chain triglyceride, propylene glycol, cetyl alcohol, stearyl alcohol, and glycerol monostearate and distearate in turn and add them to the oil phase container. Heat in a water bath at 80 ℃ and stir to dissolve. The stirring speed is 300 rpm. After complete dissolution, add the raw material drug (pimecrolimus) and stir to dissolve. The stirring speed is 300 rpm. After complete dissolution, keep at 80 ℃ for standby. The complete dissolution time of the oil phase auxiliary material is 15 min, and the complete dissolution time of the raw material drug is 1 h.

[0077] (2) Take the purified water, sodium hydroxide, anhydrous citric acid, benzyl alcohol, and sodium cetylstearyl sulfate in turn and add them to the water phase container. Heat in a water bath at 80 ℃ and stir to dissolve. The stirring speed is 300 rpm.

[0078] (3) Under the condition of 80 ℃, slowly add the oil phase to the water phase, stir for 5 min, the stirring speed is 300 rpm, homogenize for 2 min, the homogenization speed is 10,000 rpm.

[0079] (4) Stirring cooling, stirring speed 300 rpm, specific set vacuum -0.06 MPa, 45 ℃ water into the jacket, stirring cooling to 55-50 ℃, continuous stirring, defoaming by repeatedly vacuum (-0.06 MPa) multiple times, to no longer produce obvious foam, atmospheric cooling to 48 ℃ (45-50 ℃), stop.

[0080] (5) Filling to blank aluminum medicinal ointment tube, filling according to 10 g / branch.

[0081] Compared with Example 1, the sample prepared in this example has no obvious difference in properties and related substances.

[0082] Example 5

[0083] 1 The prescription of pimecrolimus cream is consistent with Example 1.

[0084] 2 The main difference between the process and example 1 is that a gradient homogenization method is used.

[0085] (1) Take the oleyl alcohol, medium-chain triglyceride, propylene glycol, cetyl alcohol, stearyl alcohol, and glyceryl monostearate in turn and add them to the oil phase container. Heat in a 70°C water bath and stir to dissolve. The stirring speed is 300 rpm. After complete dissolution, add the raw material drug (pimecrolimus) and stir to dissolve. The stirring speed is 300 rpm. After complete dissolution, keep it at 70°C for standby.

[0086] (2) Take the purified water, sodium hydroxide, anhydrous citric acid, benzyl alcohol, and sodium cetylstearyl sulfate in turn and add them to the water phase container. Heat in a 70°C water bath and stir to dissolve. The stirring speed is 300 rpm.

[0087] (3) Under the condition of 70°C, slowly add the oil phase to the water phase. First stir for 5 min at a stirring speed of 300 rpm, then homogenize at 3000 rpm for 10 s. Finally, homogenize at 5000 rpm for 30 s and at 10000 rpm for 20 s.

[0088] (4) Stir and cool down. The stirring speed is 300 rpm. Specifically, set the vacuum to -0.06 MPa. Pass 45°C water into the jacket. Stir and cool down to 55-50°C. Continue stirring. Defoam by repeatedly vacuumizing (-0.06 MPa) multiple times until no obvious foam is generated. Cool down to 48°C (45-50°C) under normal pressure. Stop.

[0089] (5) Fill into blank aluminum medicinal ointment tubes and fill according to 10 g / branch.

[0090] Comparative Example 1

[0091] On the basis of Example 1, add glyceryl monostearate to the water phase and do not add glyceryl monostearate to the oil phase. The order of adding the excipients is oleyl alcohol → medium-chain triglyceride → propylene glycol → cetyl alcohol → stearyl alcohol → complete dissolution → pimecrolimus. Specifically, add oleyl alcohol, medium-chain triglyceride, propylene glycol, cetyl alcohol, and stearyl alcohol in turn to the oil phase container. Heat in a 70°C water bath and stir to dissolve. The stirring speed is 300 rpm. After complete dissolution, add the raw material drug (pimecrolimus) and stir to dissolve. The stirring speed is 300 rpm. After complete dissolution, keep it at 70°C for standby. It is found that the complete dissolution time of the oil phase excipients is 5 min, but the complete dissolution time of the raw material drug is 90 min.

[0092] Comparative Example 2

[0093] On the basis of Example 1, propylene glycol, monodiglyceride stearate is added to the water phase, and no propylene glycol, monodiglyceride stearate is added to the oil phase. The oleyl alcohol, medium-chain triglyceride, cetyl alcohol, and stearyl alcohol are weighed and sequentially added to the oil phase container, heated in a 70°C water bath, and stirred and dissolved at a stirring speed of 300 rpm. After complete dissolution, the drug substance (pimecrolimus) is added and stirred at a stirring speed of 300 rpm. It is found that the drug substance is not completely dissolved after 3 hours.

[0094] Comparative Example 3

[0095] On the basis of Example 1, the oleyl alcohol and medium-chain triglyceride are added, and then the drug substance (pimecrolimus) is added. It is found that the drug substance is not completely dissolved after 3 hours.

[0096] Comparative Example 4

[0097] On the basis of Example 1, the medium-chain triglyceride is added first, and then the drug substance (pimecrolimus) is added. It is found that the drug substance is not completely dissolved after 3 hours.

[0098] Comparative Example 5

[0099] On the basis of Example 1, the oleyl alcohol is added, and then the drug substance (pimecrolimus) is added. It is found that the drug substance is not completely dissolved after 3 hours.

[0100] Comparative Example 6

[0101] On the basis of Example 1, sodium cetylstearyl sulfate is added to the oil phase. The oleyl alcohol, medium-chain triglyceride, cetyl alcohol, stearyl alcohol, propylene glycol, monodiglyceride stearate, and sodium cetylstearyl sulfate are weighed and sequentially added to the oil phase container, heated in a 70°C water bath, and stirred and dissolved at a stirring speed of 300 rpm. It is found that the sodium cetylstearyl sulfate is not completely dissolved in the oil phase after 3 hours, which is not conducive to subsequent scale-up production.

[0102] Comparative Example 7

[0103] On the basis of Example 1, the water bath temperature is adjusted to 90°C.

[0104] 1 Pimecrolimus cream prescription is consistent with Example 1.

[0105] 2 Process

[0106] (1) The oleyl alcohol, medium-chain triglyceride, propylene glycol, cetyl alcohol, stearyl alcohol, and monodiglyceride stearate are weighed and sequentially added to the oil phase container, heated in a 90°C water bath, and stirred and dissolved at a stirring speed of 300 rpm. After complete dissolution, the drug substance (pimecrolimus) is added and stirred and dissolved at a stirring speed of 300 rpm. After complete dissolution, the mixture is kept at 90°C for standby use;

[0107] (2) Take purified water, sodium hydroxide, anhydrous citric acid, benzyl alcohol, and sodium cetyl sulfate in turn into the water phase container, heat in a 90°C water bath, and dissolve with stirring at a stirring speed of 300 rpm;

[0108] (3) Slowly add the oil phase into the water phase at 90°C, stir for 5 min at a stirring speed of 300 rpm, and homogenize for 5 min at a homogenization speed of 3000 rpm;

[0109] (4) Stir and cool, stir at a stirring speed of 300 rpm, set the vacuum to -0.06 MPa, pass 45°C water into the jacket, stir and cool to 55-50°C, continue stirring, defoam by repeatedly vacuumizing (-0.06 MPa) multiple times until no obvious foam is generated, and cool to 48°C (45-50°C) under normal pressure, and stop.

[0110] (5) Fill into blank aluminum medicinal ointment tubes, and fill at 10 g per tube.

[0111] I. Test results of the pimecrolimus cream prepared in Example 5 and Comparative Example 7, compared with Example 1, are shown in Table 7.

[0112] Table 7 Comparison of test results of pimecrolimus cream

[0113]

[0114]

[0115] The above results show that, compared with Example 1, the total impurity content of the prepared pimecrolimus cream is lower after being treated by the gradient homogenization method of Example 5; and the impurity content of Comparative Example 7 is obviously increased, which is not conducive to improving the product quality, although higher temperature is used for preparation, which is conducive to accelerating dissolution.

[0116] II. Stability investigation

[0117] The pimecrolimus creams prepared in Example 1 and Example 5 were stored at high temperature 40°C (humidity 65%±5%) for 30 d, and the stability was investigated. The results were compared with those at 0 d, as shown in Table 8.

[0118] Table 8 Comparison of test results of pimecrolimus cream

[0119]

[0120] As shown in Table 8, the stabilities of the pimecrolimus creams prepared in Example 1 and Example 5 are both good, and the stability of Example 5 is better.

[0121] In addition, the pimecrolimus cream prepared in Example 1 and Example 5 was stored under light of 5000 Lx ± 500 Lx (aluminum tube packaging) for 30 days, and no significant changes in impurities and properties were observed.

[0122] The above description is merely that of the preferred embodiments of the application and is not to be taken in a limiting sense but is made merely for the purpose of providing one with the best description of the application under the present state of the art. Any modification, equivalent replacement, improvement, etc. made within the principle of the application shall be included in the scope of the protection of the application.

Claims

1. A method for preparing pimecrolimus cream, characterized in that, The pimecrolimus cream is prepared from an oil phase and an aqueous phase. The oil phase is prepared from the following components: pimecrolimus, oleyl alcohol, medium-chain triglycerides, cetyl alcohol, octadecanol, propylene glycol, and mono- and di-stearyl glycerides. The aqueous phase is prepared from the following components: sodium cetyl octadecyl sulfate, citric acid, sodium hydroxide, benzyl alcohol, and purified water. The preparation method of the pimecrolimus cream includes the following steps: (1) Preparation of oil phase: Add oleyl alcohol, medium chain triglyceride, propylene glycol, cetyl alcohol, octadecanol and mono- and di-stearate glycerides to the oil phase container in sequence, heat in a water bath and stir to dissolve; after complete dissolution, add pimecrolimus and stir to dissolve, and keep warm for later use. (2) Preparation of aqueous phase: Purified water, sodium hydroxide, citric acid, benzyl alcohol, and sodium cetyl sulfate were added sequentially to the aqueous phase container, heated in a water bath, and stirred to dissolve; (3) Mixing and emulsification: Slowly add the oil phase to the aqueous phase, stir first, and then homogenize and emulsify; (4) Cooling and filling: Stirring to cool down, then filling; In steps (1) and (2), the water bath heating temperature is 60-80℃; Step (3) uses gradient homogenization: first homogenize at 3000 rpm for 8-12 s; then homogenize at 5000 rpm for 25-35 s; and then homogenize at 10000 rpm for 15-25 s; the homogenization temperature is 60-80℃. The citric acid is anhydrous citric acid; By weight, the following components are present: pimecrolimus 9-11 parts, oleyl alcohol 90-110 parts, medium-chain triglycerides 120-160 parts, cetyl alcohol 30-60 parts, octadecyl alcohol 30-50 parts, propylene glycol 35-55 parts, glyceryl monostearate and distearate 15-45 parts, sodium cetyl octadecyl sulfate 8-20 parts, anhydrous citric acid 0.4-2 parts, sodium hydroxide 0.1-1.5 parts, benzyl alcohol 8-12 parts, and purified water 500-600 parts.

2. The method for preparing pimecrolimus cream according to claim 1, characterized in that, Step (3), stirring time is 4-10 min.

3. The method for preparing pimecrolimus cream according to claim 1 or 2, characterized in that, Steps (1)-(4), the stirring speed is 100-500 rpm.

4. The method for preparing pimecrolimus cream according to claim 1, characterized in that, Includes the following steps: (1) Weigh out oleyl alcohol, medium-chain triglycerides, propylene glycol, cetyl alcohol, octadecanol, and mono- and di-stearyl glycerides and add them sequentially to the oil phase container. Heat in a water bath at 60-80℃ and stir to dissolve at a stirring speed of 150-500 rpm. After complete dissolution, add pimecrolimus and stir to dissolve at a stirring speed of 150-500 rpm. After complete dissolution, keep warm at 60-80℃ for later use. (2) Weigh out purified water, sodium hydroxide, citric acid, benzyl alcohol and sodium cetyl sulfate and add them to the aqueous phase container in sequence. Heat in a water bath at 60-80℃ and stir to dissolve. Stir at 150-500 rpm. (3) At 60-80℃, slowly add the oil phase to the water phase and stir for 4-10 min at a stirring speed of 150-500 rpm to homogenize and emulsify. Use gradient homogenization: first homogenize at 3000 rpm for 8-12 s; then homogenize at 5000 rpm for 25-35 s; and then homogenize at 10000 rpm for 15-25 s. The homogenization temperature is 60-80℃. (4) Stirring and cooling, stirring speed 150-500 rpm; filling.

5. The method for preparing pimecrolimus cream according to claim 1, characterized in that, By weight, the ingredients are: 10 parts pimecrolimus, 95-105 parts oleyl alcohol, 125-135 parts medium-chain triglycerides, 45-55 parts cetyl alcohol, 35-45 parts octadecyl alcohol, 35-45 parts propylene glycol, 25-35 parts mono- and di-stearyl glycerides, 15-20 parts sodium cetyl octadecyl sulfate, 1.0-1.5 parts anhydrous citric acid, 1.0-1.5 parts sodium hydroxide, 9-11 parts benzyl alcohol, and 560-580 parts purified water.

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