Pimerolimus cream and preparation method thereof

Abstract

The invention provides pimerolimus emulsifiable paste and a preparation method thereof. The pimerolimus emulsifiable paste is prepared from an oil phase and a water phase, and the preparation method of the pimerolimus emulsifiable paste comprises the following steps: (1) oil phase preparation: sequentially adding oleyl alcohol, medium chain triglyceride, propylene glycol, hexadecanol, octadecanol and glyceryl monostearate and glyceryl distearate into an oil phase container, heating in a water bath, and stirring for dissolving; adding pimerolimus after complete dissolution, stirring and dissolving, and preserving heat for later use after complete dissolution; (2) preparing a water phase: sequentially adding purified water, sodium hydroxide, citric acid, benzyl alcohol and cetostearyl sodium sulfate into a water phase container, heating in a water bath, and stirring for dissolving; (3) mixing and emulsifying: slowly adding the oil phase into the water phase, stirring, and homogenizing and emulsifying; and (4) cooling and filling: stirring, cooling and filling. The pimerolimus emulsifiable paste prepared by adopting the process disclosed by the invention is relatively low in total impurity content (the content is close to 100%), good in stability and favorable for improving the medicine quality.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical preparations, and in particular to a pimecrolimus cream and a preparation method thereof. Background Art

[0002] Pimecrolimus is a lipophilic anti-inflammatory derivative of ascomycin macrolactam and is a topical calcineurin inhibitor. Pimecrolimus has a high affinity for macrophilin-12 and can inhibit calcineurin, thereby inhibiting the proliferation of T cells and the production and release of inflammatory cytokines, thus having strong anti-inflammatory activity.

[0003] Pimecrolimus cream was first developed by Novartis Pharmaceuticals and was approved by the U.S. FDA in December 2001 under the trade name The specification is 1%, and it is suitable for patients aged 2 years and above with mild to moderate atopic dermatitis (eczema) who are not immunocompromised: 1) short-term treatment of signs and symptoms of the disease; 2) long-term intermittent treatment to prevent worsening of the disease. It was approved for marketing in Denmark in March 2002, and subsequently marketed in all EU member states except Ireland through the mutual recognition approval procedure.

[0004] In September 2005, Novartis Pharmaceuticals' pimecrolimus cream was approved for import and marketing by the National Medical Products Administration (hereinafter referred to as "NMPA"), with registration number H20050485 and trade name The specification is 1%, and the packaging specifications are 15g / stick / box and 30g / stick / box. In 2006, Novartis Pharmaceuticals filed a supplementary application to add a packaging specification of 10g / stick / box, with the registration number H20060261.

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

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

[0007] The technical scheme of the present invention is achieved as follows: a pimecrolimus cream comprises an oil phase and an aqueous phase, wherein the oil phase comprises the following components: pimecrolimus, oleyl alcohol, medium-chain triglycerides, hexadecanol, octadecyl alcohol, propylene glycol and mono- and distearic acid glyceryl; the aqueous phase comprises the following components: sodium cetearyl sulfate, citric acid, sodium hydroxide, benzyl alcohol and purified water; in parts by weight, the pimecrolimus comprises 9-11 parts, oleyl alcohol comprises 90-110 parts, medium-chain triglycerides comprises 120-160 parts, hexadecanol comprises 30-60 parts, octadecyl alcohol comprises 30-50 parts, propylene glycol comprises 35-55 parts, mono- and distearic acid glyceryl comprises 15-45 parts, sodium cetearyl sulfate comprises 8-20 parts, anhydrous citric acid comprises 0.4-2 parts, sodium hydroxide comprises 0.1-1.5 parts, benzyl alcohol comprises 8-12 parts and purified water comprises 500-600 parts.

[0008] Table 1 Composition of pimecrolimus cream prescription

[0009]

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

[0011] (1) Preparation of oil phase: oleyl alcohol, medium chain triglycerides, propylene glycol, hexadecanol, stearyl alcohol, and glyceryl mono- and distearate are added to the oil phase container in sequence, heated in a water bath, and stirred to dissolve; after complete dissolution, pimecrolimus is added and stirred to dissolve, and after complete dissolution, the mixture is kept warm for later use;

[0012] (2) Preparation of aqueous phase: Add purified water, sodium hydroxide, anhydrous citric acid, benzyl alcohol, and sodium cetyl sulfate into an aqueous phase container in sequence, heat in a water bath, and stir to dissolve;

[0013] (3) Mixing and emulsification: slowly add the oil phase into the water phase, stir first, and then homogenize and emulsify;

[0014] (4) Cooling and filling: Stirring to cool and then filling.

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

[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 homogenizing at 3000 rpm for 8 to 12 s; finally homogenizing at 5000 rpm for 25 to 35 s; and then homogenizing at 10000 rpm for 15 to 25 s.

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

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

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

[0021] (1) Weigh oleyl alcohol, medium chain triglycerides, propylene glycol, hexadecanol, stearyl alcohol, and glyceryl mono- and distearate in order and add them to an oil phase container, heat in a water bath at 60-80° C., stir to dissolve, and stir at a speed of 150-500 rpm; after complete dissolution, add pimecrolimus and stir to dissolve, and stir at a speed of 150-500 rpm; after complete dissolution, keep warm at 50-80° C. for later use;

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

[0023] (3) Slowly add the oil phase into the water phase at 60-80°C, stir for 4-10 min, and stir at 150-500 rpm for homogenization and emulsification;

[0024] (4) Stirring and cooling, with a stirring speed of 150-500 rpm; filling.

[0025] Preferably, by weight, the ingredients include 10 parts of pimecrolimus, 95-105 parts of oleyl alcohol, 125-135 parts of medium chain triglycerides, 45-55 parts of hexadecanol, 35-45 parts of octadecanol, 35-45 parts of propylene glycol, 25-35 parts of mono- and distearic glyceryl, 15-20 parts of sodium cetearyl sulfate, 1.0-1.5 parts of anhydrous citric acid, 1.0-1.5 parts of sodium hydroxide, 9-11 parts of benzyl alcohol, and 560-580 parts of purified water.

[0026] More preferably, by weight, 10 parts of pimecrolimus, 100 parts of oleyl alcohol, 130 parts of medium chain triglycerides, 50 parts of hexadecanol, 40 parts of octadecyl alcohol, 40 parts of propylene glycol, 30 parts of mono- and distearic glyceryl, 18 parts of sodium cetearyl sulfate, 1.5 parts of anhydrous citric acid, 1.2 parts of sodium hydroxide, 10 parts of benzyl alcohol, and 569.3 parts of purified water.

[0027] A pimecrolimus cream is prepared by any preparation method of the present invention.

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

[0029] (1) The present invention uses pimecrolimus (active ingredient), oleyl alcohol (oil phase matrix), medium chain triglycerides (oil phase matrix), hexadecanol (thickener), stearyl alcohol (thickener), propylene glycol (humectant) and glyceryl mono- and distearate (emulsifier) ​​to prepare the oil phase, and uses sodium cetearyl sulfate (emulsifier), citric acid (pH regulator), sodium hydroxide (pH regulator), benzyl alcohol (antibacterial agent) and purified water (aqueous phase diluent) to prepare the aqueous phase. The pimecrolimus cream prepared by the process of the present invention meets the requirements for various inspection items, wherein the total impurity content is low and the content is close to 100%, and the stability is good, which is conducive to improving the quality of the drug.

[0030] (2) After the present invention adopts the gradient homogenization method, the total impurity content of the prepared pimecrolimus cream is lower, which is beneficial to improving product quality, and further improves the droplet 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 invention, specific embodiments are provided below to further illustrate the present invention.

[0032] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0033] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0034] Table 2 Raw material manufacturers

[0035] Serial number raw material factory 1 Oleyl alcohol Sinocare Pharmaceutical Development (Suzhou) Co., Ltd. 2 Medium Chain Triglycerides Jiangsu Baoyi Pharmaceutical Co., Ltd. 3 Cetyl Alcohol Fumei Lipid Chemical (Henan) Co., Ltd. 4 Octadecanol Sinocare Pharmaceutical Development (Suzhou) Co., Ltd. 5 Propylene glycol Jiangxi Hanjiang Pharmaceutical Co., Ltd. 6 Glyceryl mono- and distearate BASF (China) Co., Ltd. 7 Sodium cetostearyl sulfate Chengdu Huayi Pharmaceutical Excipients Manufacturing Co., Ltd. 8 Anhydrous citric acid Chengdu Huayi Pharmaceutical Excipients 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 API

[0037]

[0038] Table 4 Impurity structures and chemical names

[0039]

[0040] Example 1

[0041] 1Prescription of pimecrolimus cream

[0042] Table 5 Prescription

[0043]

[0044] 2. Process

[0045] (1) Weigh oleyl alcohol, medium-chain triglycerides, propylene glycol, hexadecanol, stearyl alcohol, and mono- and distearic glycerols in order and add them to an oil phase container, heat in a water bath at 60° C., stir to dissolve, and stir at a speed of 400 rpm; after complete dissolution, add the API (pimecrolimus) and stir to dissolve, stirring at a speed of 400 rpm; after complete dissolution, keep warm at 40° C. for later use; the complete dissolution time of the oil phase excipients is 20 min, and the complete dissolution time of the API is 60 min.

[0046] (2) Weigh purified water, sodium hydroxide, anhydrous 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°C, stir to dissolve, and stir at 400 rpm;

[0047] (3) At 70°C, the oil phase was slowly added to the water phase, stirred for 5 min at a stirring speed of 400 rpm, and homogenized and emulsified for 5 min at a homogenization speed of 5000 rpm;

[0048] (4) Stirring and cooling, stirring speed 400 rpm, specifically set vacuum -0.2 MPa, pass 40°C water into the jacket, stirring and cooling to 45-40°C, continue stirring, repeatedly vacuum (-0.06 MPa) to defoam until no obvious foam is generated, cool to 40°C at normal pressure, and stop.

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

[0050] The prepared pimecrolimus cream was tested and the test results were compared with the reference preparation.

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

[0052] Table 6 Test standards and test results

[0053]

[0054]

[0055] The results show that the pimecrolimus cream prepared by the present invention meets the requirements for various inspection items, wherein the total impurity content is low and the content is close to 100%. The pimecrolimus cream prepared by the process of the present invention is conducive to improving the quality of the drug.

[0056] Example 2

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

[0058] 2. Process

[0059] (1) Weigh oleyl alcohol, medium chain triglycerides, propylene glycol, hexadecanol, stearyl alcohol, and mono- and distearic glyceryls in order and add them to an oil phase container, heat in a water bath at 70° C., stir to dissolve, and stir at a speed of 100 rpm; after complete dissolution, add the raw material drug (pimecrolimus) and stir to dissolve, and stir at a speed of 100 rpm; after complete dissolution, keep warm at 70° C. for later use;

[0060] (2) Weigh purified water, sodium hydroxide, anhydrous citric acid, benzyl alcohol, and sodium cetyl sulfate in the water phase container in sequence, heat in a 70°C water bath, stir to dissolve, and stir at a speed of 100 rpm;

[0061] (3) At 70°C, the oil phase was slowly added to the water phase, stirred for 5 min at a stirring speed of 100 rpm, and homogenized and emulsified for 5 min at a homogenization speed of 10,000 rpm;

[0062] (4) Stirring and cooling, stirring speed 100 rpm, specifically set vacuum -0.06 MPa, pass 45 ° C water into the jacket, stirring and cooling to 55-50 ° C, continue stirring, repeatedly vacuum (-0.06 MPa) to defoam until no obvious foam is generated, cool to 48 ° C (45-50 ° C) at normal pressure, and stop.

[0063] (5) Fill into blank aluminum ointment tubes at a rate of 10 g per tube.

[0064] Example 3

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

[0066] 2. Process

[0067] (1) Weigh oleyl alcohol, medium-chain triglycerides, propylene glycol, hexadecanol, stearyl alcohol, and mono- and distearic acid glyceryl in turn and add them to an oil phase container, heat in a water bath at 60°C, and stir to dissolve at a speed of 300 rpm; after complete dissolution, add the API (pimecrolimus) and stir to dissolve at a speed of 300 rpm; after complete dissolution, keep warm at 60°C for later use; the complete dissolution time of the oil phase excipients is 30 min, and the complete dissolution time of the API is 2 h.

[0068] (2) Weigh purified water, sodium hydroxide, anhydrous 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°C, stir to dissolve, and stir at 300 rpm;

[0069] (3) At 60°C, the oil phase was slowly added to the water phase, stirred for 5 min at a stirring speed of 300 rpm, and homogenized and emulsified for 8 min at a homogenization speed of 3000 rpm;

[0070] (4) Stirring and cooling, stirring speed 300 rpm, specifically set vacuum -0.06 MPa, pass 45 ° C water into the jacket, stirring and cooling to 55-50 ° C, continue stirring, repeatedly vacuum (-0.06 MPa) to defoam until no obvious foam is generated, cool to 48 ° C (45-50 ° C) at normal pressure, and stop.

[0071] (5) Fill into blank aluminum ointment tubes at a rate of 10 g per tube.

[0072] Compared with Example 1, there are no obvious differences in the properties and related substances of the samples prepared in this example.

[0073] Example 4

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

[0075] 2. Process

[0076] (1) Weigh oleyl alcohol, medium-chain triglycerides, propylene glycol, hexadecanol, stearyl alcohol, and mono- and distearic acid glyceryl in turn and add them to an oil phase container, heat in a water bath at 80°C, and stir to dissolve at a speed of 300 rpm; after complete dissolution, add the API (pimecrolimus) and stir to dissolve at a speed of 300 rpm; after complete dissolution, keep warm at 80°C for later use; the complete dissolution time of the oil phase excipients is 15 min, and the complete dissolution time of the API is 1 h.

[0077] (2) Weigh purified water, sodium hydroxide, anhydrous citric acid, benzyl alcohol, and sodium cetyl sulfate and add them to the water phase container in sequence, heat in a water bath at 80°C, stir to dissolve, and stir at 300 rpm;

[0078] (3) At 80°C, the oil phase was slowly added to the water phase, stirred for 5 min at a stirring speed of 300 rpm, and homogenized and emulsified for 2 min at a homogenization speed of 10,000 rpm;

[0079] (4) Stirring and cooling, stirring speed 300 rpm, specifically set vacuum -0.06 MPa, pass 45 ° C water into the jacket, stirring and cooling to 55-50 ° C, continue stirring, repeatedly vacuum (-0.06 MPa) to defoam until no obvious foam is generated, cool to 48 ° C (45-50 ° C) at normal pressure, and stop.

[0080] (5) Fill into blank aluminum ointment tubes at a rate of 10 g per tube.

[0081] Compared with Example 1, there are no obvious differences in the properties and related substances of the samples prepared in this example.

[0082] Example 5

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

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

[0085] (1) Weigh oleyl alcohol, medium chain triglycerides, propylene glycol, hexadecanol, stearyl alcohol, and mono- and distearic glyceryls in order and add them to an oil phase container, heat in a water bath at 70° C., stir to dissolve, and stir at a speed of 300 rpm; after complete dissolution, add the raw material drug (pimecrolimus) and stir to dissolve, and stir at a speed of 300 rpm; after complete dissolution, keep warm at 70° C. for later use;

[0086] (2) Weigh purified water, sodium hydroxide, anhydrous citric acid, benzyl alcohol, and sodium cetyl sulfate and add them to the water phase container in sequence, heat in a water bath at 70°C, stir to dissolve, and stir at 300 rpm;

[0087] (3) At 70°C, the oil phase was slowly added to the water phase, stirred for 5 min at a stirring speed of 300 rpm, and then homogenized and emulsified, wherein the homogenization was first performed at 3000 rpm for 10 s; finally, the homogenization was performed at 5000 rpm for 30 s; and then, the homogenization was performed at 10000 rpm for 20 s;

[0088] (4) Stirring and cooling, stirring speed 300 rpm, specifically set vacuum -0.06 MPa, pass 45 ° C water into the jacket, stirring and cooling to 55-50 ° C, continue stirring, repeatedly vacuum (-0.06 MPa) to defoam until no obvious foam is generated, cool to 48 ° C (45-50 ° C) at normal pressure, and stop.

[0089] (5) Fill into blank aluminum ointment tubes at a rate of 10 g per tube.

[0090] Comparative Example 1

[0091] On the basis of Example 1, mono- and distearic glyceryl was added to the water phase, and mono- and distearic glyceryl was not added to the oil phase. The order of adding the auxiliary materials was: oleyl alcohol → medium-chain triglycerides → propylene glycol → hexadecanol → octadecyl alcohol → completely dissolved → pimecrolimus. Specifically: oleyl alcohol, medium-chain triglycerides, propylene glycol, hexadecanol, and octadecyl alcohol were added to the oil phase container in sequence, heated in a 70°C water bath, stirred to dissolve, and stirred at a speed of 300 rpm; after complete dissolution, the raw material (pimecrolimus) was added and stirred to dissolve, and the stirring speed was 300 rpm. After complete dissolution, it was kept warm at 70°C for standby use. It was found that the complete dissolution time of the oil phase auxiliary material was 5 minutes, but the complete dissolution time of the raw material was 90 minutes.

[0092] Comparative Example 2

[0093] Based on Example 1, propylene glycol and mono- and distearic glyceryl were added to the water phase, and propylene glycol and mono- and distearic glyceryl were not added to the oil phase. Oleyl alcohol, medium-chain triglycerides, hexadecanol, and octadecyl alcohol were weighed and added to the oil phase container in sequence, heated in a 70°C water bath, stirred to dissolve, and stirred at a speed of 300 rpm; after complete dissolution, the raw material drug (pimecrolimus) was added and stirred at a speed of 300 rpm. It was found that the raw material drug was not completely dissolved for 3 hours.

[0094] Comparative Example 3

[0095] Based on Example 1, oleyl alcohol and medium-chain triglycerides were added, and then the raw material drug (pimecrolimus) was added. It was found that the raw material drug was not completely dissolved even after 3 hours.

[0096] Comparative Example 4

[0097] Based on Example 1, medium chain triglycerides were added first, and then the raw material drug (pimecrolimus) was added. It was found that the raw material drug was not completely dissolved even after 3 hours.

[0098] Comparative Example 5

[0099] Based on Example 1, oleyl alcohol was added, and then the raw material drug (pimecrolimus) was added. It was found that the raw material drug was not completely dissolved even after 3 hours.

[0100] Comparative Example 6

[0101] Based on Example 1, sodium cetostearyl sulfate was added to the oil phase. Oleyl alcohol, medium chain triglycerides, cetyl alcohol, stearyl alcohol, propylene glycol, mono- and distearic glycerides, and sodium cetostearyl sulfate were weighed and added to the oil phase container in sequence, heated in a water bath at 70°C, stirred to dissolve, and stirred at a stirring speed of 300 rpm. It was found that sodium cetostearyl sulfate was not completely dissolved in the oil phase for 3 hours, which was not conducive to subsequent scale-up production.

[0102] Comparative Example 7

[0103] Based on Example 1, the water bath temperature was adjusted to 90°C.

[0104] 1. The prescription of pimecrolimus cream is consistent with that of Example 1.

[0105] 2. Process

[0106] (1) Weigh oleyl alcohol, medium chain triglycerides, propylene glycol, hexadecanol, stearyl alcohol, and mono- and distearic glyceryls in order and add them to an oil phase container, heat in a water bath at 90° C., stir to dissolve, and stir at a speed of 300 rpm; after complete dissolution, add the raw material drug (pimecrolimus) and stir to dissolve, and stir at a speed of 300 rpm; after complete dissolution, keep warm at 90° C. for later use;

[0107] (2) Weigh purified water, sodium hydroxide, anhydrous citric acid, benzyl alcohol, and sodium cetyl sulfate and add them to the water phase container in sequence, heat in a water bath at 90°C, stir to dissolve, and stir at a speed of 300 rpm;

[0108] (3) At 90°C, the oil phase was slowly added to the water phase, stirred for 5 min at a stirring speed of 300 rpm, and homogenized and emulsified for 5 min at a homogenization speed of 3000 rpm;

[0109] (4) Stirring and cooling, stirring speed 300 rpm, specifically set vacuum -0.06 MPa, pass 45 ° C water into the jacket, stirring and cooling to 55-50 ° C, continue stirring, repeatedly vacuum (-0.06 MPa) to defoam until no obvious foam is generated, cool to 48 ° C (45-50 ° C) at normal pressure, and stop.

[0110] (5) Fill into blank aluminum ointment tubes at a rate of 10 g per tube.

[0111] 1. The test results of the pimecrolimus cream prepared in Example 5 and Comparative Example 7 were compared with those in Example 1. The results 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 after treatment by the gradient homogenization method of Example 5 is lower; while Comparative Example 7 adopts a higher temperature for preparation, which is conducive to accelerating dissolution, but its impurity content is significantly increased, which is not conducive to improving product quality.

[0116] 2. Stability inspection

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

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

[0119]

[0120] As shown in Table 8, the pimecrolimus creams prepared in Examples 1 and 5 have good stability, and the stability of Example 5 is even better.

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

[0122] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing pimecrolimus cream, characterized in that: The pimecrolimus cream comprises an oil phase and an aqueous phase, wherein the oil phase comprises the following components: pimecrolimus, oleyl alcohol, medium-chain triglycerides, hexadecanol, octadecyl alcohol, propylene glycol and mono- and distearic acid glyceryl; the aqueous phase comprises the following components: sodium cetearyl sulfate, citric acid, sodium hydroxide, benzyl alcohol and purified water; the preparation method of the pimecrolimus cream comprises the following steps: (1) Preparation of oil phase: oleyl alcohol, medium chain triglycerides, propylene glycol, hexadecanol, stearyl alcohol, and glyceryl mono- and distearate are added to the oil phase container in sequence, heated in a water bath, and stirred to dissolve; after complete dissolution, pimecrolimus is added and stirred to dissolve, and after complete dissolution, the mixture is kept warm for later use; (2) Preparation of aqueous phase: Add purified water, sodium hydroxide, citric acid, benzyl alcohol, and sodium cetyl sulfate into an aqueous phase container in sequence, heat in a water bath, and stir to dissolve; (3) Mixing and emulsification: slowly add the oil phase into the water phase, stir first, and then homogenize and emulsify; (4) Cooling and filling: Stirring to cool down and then filling.

2. The method for preparing pimecrolimus cream according to claim 1, wherein Calculated by weight, the ingredients include 9-11 parts of pimecrolimus, 90-110 parts of oleyl alcohol, 120-160 parts of medium chain triglycerides, 30-60 parts of hexadecanol, 30-50 parts of octadecyl alcohol, 35-55 parts of propylene glycol, 15-45 parts of mono- and distearic glyceryl, 8-20 parts of sodium cetearyl sulfate, 0.4-2 parts of anhydrous citric acid, 0.1-1.5 parts of sodium hydroxide, 8-12 parts of benzyl alcohol, and 500-600 parts of purified water.

3. The preparation method of pimecrolimus cream according to claim 1, characterized in that, In step (1) and step (2), the water bath heating temperature is 60-80°C; and in step (3), the homogenization temperature is 60-80°C.

4. The preparation method of pimecrolimus cream according to claim 1, characterized in that, Step (3), homogenization and emulsification for 1-10 min, homogenization and emulsification speed 1500-12000 rpm.

5. The method for preparing pimecrolimus cream according to claim 4, wherein Step (3) adopts gradient homogenization, first homogenizes at 3000 rpm for 8 to 12 s; finally homogenizes at 5000 rpm for 25 to 35 s; and then homogenizes at 10000 rpm for 15 to 25 s.

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

7. The method for preparing the pimecrolimus cream according to claim 1 or 6, characterized in that, In steps (1) to (4), the stirring speed is 100-500 rpm.

8. The method for preparing pimecrolimus cream according to claim 1, wherein The following steps are involved: (1) Weigh oleyl alcohol, medium chain triglycerides, propylene glycol, hexadecanol, stearyl alcohol, and glyceryl mono- and distearate in order and add them to an oil phase container, heat in a water bath at 60-80° C., stir to dissolve, and stir at a speed of 150-500 rpm; after complete dissolution, add pimecrolimus and stir to dissolve, and stir at a speed of 150-500 rpm; after complete dissolution, keep warm at 60-80° C. for later use; (2) Weigh purified water, sodium hydroxide, citric acid, benzyl alcohol, and sodium cetyl sulfate and add them to the water phase container in sequence, heat in a water bath at 60-80° C., stir to dissolve, and stir at a speed of 150-500 rpm; (3) At 60-80°C, slowly add the oil phase into the water phase, stir for 4-10 min, stir at 150-500 rpm, homogenize and emulsify for 1-10 min, and homogenize and emulsify at a speed of 3000-12000 rpm; (4) Stirring and cooling, with a stirring speed of 150-500 rpm; filling.

9. The method for preparing pimecrolimus cream according to claim 1, wherein By weight, the invention comprises 10 parts of pimecrolimus, 95-105 parts of oleyl alcohol, 125-135 parts of medium chain triglycerides, 45-55 parts of hexadecanol, 35-45 parts of octadecyl alcohol, 35-45 parts of propylene glycol, 25-35 parts of mono- and distearic glyceryl, 15-20 parts of sodium cetearyl sulfate, 1.0-1.5 parts of anhydrous citric acid, 1.0-1.5 parts of sodium hydroxide, 9-11 parts of benzyl alcohol and 560-580 parts of purified water.

10. A pimecrolimus cream, characterized in that: Prepared by the preparation method according to any one of claims 1 to 9.

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