Preparation method of pimerolimus emulsifiable paste

Abstract

The invention relates to a preparation method of pimerolimus emulsifiable paste, which comprises the following steps: adding an emulsifier and a water-phase auxiliary material into a part of prescription amount of water, heating and dissolving, then heating and dissolving an oil-phase auxiliary material, adding pimerolimus, continuously stirring and dissolving, mixing to obtain a liquid crystal oil-in-liquid mixture, and adding the liquid crystal oil-in-liquid mixture into the rest prescription amount of water. The pimerolimus emulsifiable paste prepared by the method disclosed by the invention is fine and smooth in appearance, uniform in particle size and complete and clear in liquid crystal structure.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a method for preparing pimecrolimus cream. Background Art

[0002] Pimecrolimus is a lipophilic anti-inflammatory derivative of ascomycin macrolactam that selectively inhibits the production and release of pro-inflammatory cytokines. Pimecrolimus has a high affinity for macrophilin-12 and can inhibit the calcium-dependent phospholipase calcineurin, thereby blocking the synthesis of inflammatory cytokines in T cells. Its chemical name is: (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(1E)-2-[(1R,3R,4S)-4-chloro-3-methoxycyclohexyl]-1-methylvinyl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04.9]octacos-18-ene-2,3,10,16-tetraone, and its molecular formula is C 43 H 68 NO 11 Cl, molecular weight is 810.47, soluble in methanol or ethanol, almost insoluble in water.

[0003] Original pimecrolimus cream trade name: Dosage form: cream, manufacturer: MEDApharma GmbH & Co.K eG, main ingredient: pimecrolimus, 1% per gram The cream contains 10 mg of pimecrolimus, excipients include benzyl alcohol, cetyl alcohol, citric acid, glyceryl mono- and distearate, oleyl alcohol, propylene glycol, sodium cetearyl sulfate, sodium hydroxide, stearyl alcohol, medium chain triglycerides and water.

[0004] Creams are uniform semisolid topical preparations formed by dissolving or dispersing drugs in an emulsion-type matrix. Creams can be divided into oil-in-water creams and water-in-oil creams due to different matrices. The common cream preparation method is direct emulsification, that is, the oil and water phase materials are heated and melted separately, and then one phase is added to the other phase under stirring, mixed, homogenized, cooled, and filled.

[0005] Liquid crystal is a thermodynamically stable state that has both the fluidity and continuity of a liquid and the anisotropy of a crystal. According to the formation conditions, it is divided into thermotropic liquid crystal and lyotropic liquid crystal. Thermotropic liquid crystal is generally a single-component pure compound or a uniform mixture, and its structure and properties depend on the temperature of the system; lyotropic liquid crystal is generally formed by controlling the weak interaction between water and surfactants to form lyotropic liquid crystals with a certain order. This structure has strong birefringence. Lyotropic liquid crystals are mainly used in the fields of pharmaceutical carriers and cosmetics and skin care.

[0006] Lyotropic liquid crystals are generally composed of surfactants and solvents. Changes in the water content of the surfactant / water system can cause a change in the liquid crystal phase structure. As the water content increases, the order of liquid crystal phase transition is generally: lamellar liquid crystal - cubic liquid crystal - hexagonal liquid crystal - micelle - solution. Liquid crystals with different structures exhibit different appearance properties. Lamellar liquid crystals are the most common liquid crystal structures used as pharmaceutical carriers. Their structure is a bilayer formed by a surfactant and arranged in layers with water. The long axes of the molecules are parallel to each other and perpendicular to the layer plane. They come into contact with flowing water and dissolve in it. They have optical anisotropy and a typical smectic structure. Their unique double-layer membrane structure conforms to the bio-mimicry system.

[0007] The lamellar liquid crystal structure has the following remarkable advantages when used in pharmaceutical carriers: First, stability. The liquid crystal structure can significantly reduce the van der Waals force between droplets and reduce the tendency of droplets to coalesce, thereby improving the instability of the emulsion; second, the liquid crystal structure on the oil / water interface makes the rigidity and elasticity of the interface film significantly better than that of the interface film of the general structure, thus having better stability. Second, moisture retention. The lamellar arrangement structure of the lamellar liquid crystal can better enclose bound water, which improves the moisture retention of the emulsion. Third, sustained release. The multilayer structure of the lamellar liquid crystal can control the sustained release effect of the active ingredient, reduce the transfer speed of the active ingredient dissolved in the oil droplets between the interfaces, and thus prolong the duration of the active ingredient's action.

[0008] The prescription of this product is a typical liquid crystal cream preparation prescription. There is currently no patent related to pimecrolimus cream preparations in China. Therefore, the purpose of the present invention is to provide a method for preparing pimecrolimus cream: a liquid crystal emulsification method. Summary of the invention

[0009] Problem that the invention aims to solve

[0010] Based on the above problems existing in the prior art, the object of the present invention is to provide a method for preparing pimecrolimus cream.

[0011] Solutions for solving problems

[0012] The present invention provides a method for preparing pimecrolimus cream, the method comprising the following steps:

[0013] (a) adding an emulsifier and an aqueous phase auxiliary material to a portion of the prescribed amount of water and heating to dissolve the emulsifier and the aqueous phase auxiliary material to obtain an aqueous phase;

[0014] (b) heating and dissolving the oil phase auxiliary material, adding pimecrolimus and continuing to stir and dissolve to obtain an oil phase;

[0015] (c) adding the oil phase prepared in step (b) to the water phase prepared in step (a) to obtain a liquid crystal-oil mixture;

[0016] (d) adding the remaining amount of the aqueous phase to the liquid crystal-oil mixture;

[0017] Wherein, the part of the prescription amount of water in step (a) is 50%-90% of the prescription amount of water.

[0018] Preferably, the portion of the prescribed amount of water in step (a) is 60%-80% of the prescribed amount of water; more preferably, the portion of the prescribed amount of water in step (a) is 70% of the prescribed amount of water.

[0019] Preferably, the remaining prescription amount of water in step (d) is 10%-50% prescription amount of water; more preferably, the remaining prescription amount of water in step (d) is 20%-40% prescription amount of water; further preferably, the remaining prescription amount of water in step (d) is 30% prescription amount of water.

[0020] Preferably, the reaction temperature of the method is 60°C-90°C; more preferably, the reaction temperature of the method is 70°C-80°C; further preferably, the reaction temperature of the method is 75°C.

[0021] Preferably, the emulsifier is an anionic surfactant; more preferably, the emulsifier is a long-chain alkyl sodium sulfate; further preferably, the emulsifier is selected from one or more of sodium dodecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate and mixtures thereof; most preferably, the emulsifier is sodium hexadecyl sulfate.

[0022] Preferably, the aqueous phase auxiliary materials include one or more of a preservative, a pH adjuster, a phosphate and hydrochloric acid; more preferably, the preservative is benzyl alcohol; further preferably, the pH adjuster is citric acid and sodium hydroxide; most preferably, the aqueous phase auxiliary materials are benzyl alcohol, citric acid and sodium hydroxide.

[0023] Preferably, the oil phase auxiliary material is a nonionic surfactant; more preferably, the oil phase auxiliary material is selected from one or more of peregal, glyceryl stearate, long-chain fatty alcohols, higher fatty acid polyol esters, unsaturated fatty acids, and polyols; further preferably, the oil phase auxiliary material is mono- and distearic acid glyceryl, cetyl alcohol, stearyl alcohol, oleyl alcohol, medium-chain triglycerides, and propylene glycol.

[0024] Preferably, the method comprises the following steps:

[0025] (a) adding an emulsifier and an aqueous phase auxiliary material to 70% of the prescription amount of water and heating to 75° C. to dissolve the emulsifier and the aqueous phase auxiliary material to obtain an aqueous phase;

[0026] (b) heating the oil phase auxiliary material to 75° C. to dissolve, adding pimecrolimus and continuing to stir and dissolve to obtain an oil phase;

[0027] (c) adding the oil phase prepared in step (b) to the water phase prepared in step (a) to obtain a liquid crystal-oil mixture;

[0028] (d) adding the remaining 30% of the prescribed amount of water at 75° C. to the liquid crystal-in-oil mixture;

[0029] The prescription is as follows:

[0030]

[0031] Preferably, the method further comprises the steps of:

[0032] (e) Mixing, homogenizing, cooling and filling.

[0033] Wherein, the stirring is 100-200 rpm stirring for 5-30 minutes; preferably, the stirring is 200 rpm stirring for 30 minutes;

[0034] The homogenization is carried out at 5000-8000 rpm for 5-15 minutes; preferably, the homogenization is carried out at 5000 rpm for 10 minutes.

[0035] The present invention also provides a pimecrolimus cream prepared according to the method.

[0036] Effects of the Invention

[0037] This patent provides a method for preparing pimecrolimus cream. The sample prepared by this method has a delicate appearance, uniform particle size, and a complete and clear liquid crystal structure. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 These are the test results of the samples of preparation process 1, A: liquid crystal test chart, B: particle size test chart.

[0039] Figure 2 These are the test results for the samples of preparation process 2, A: liquid crystal test chart, B: particle size test chart.

[0040] Figure 3 These are the test results of the samples from preparation process 3, A: liquid crystal test chart, B: particle size test chart.

[0041] Figure 4These are the test results of the samples of preparation process 4, A: liquid crystal test chart, B: particle size test chart.

[0042] Figure 5 These are the test results for the samples of preparation process 5, A: liquid crystal test diagram, B: particle size test diagram.

[0043] Figure 6 These are the test results for the samples of preparation process 6, A: liquid crystal test diagram, B: particle size test diagram.

[0044] Figure 7 These are the test results for the sample of preparation process 7, A: liquid crystal test diagram, B: particle size test diagram.

[0045] Figure 8 These are the test results for the samples of preparation process 8, A: liquid crystal test diagram, B: particle size test diagram.

[0046] Fig. 9 These are the test results for the sample of preparation process 9, A: liquid crystal test diagram, B: particle size test diagram.

[0047] Fig.10 These are the test results of the original samples, A: liquid crystal test chart, B: particle size test chart. DETAILED DESCRIPTION

[0048] In order to make the technical solutions and beneficial effects of the present invention more clearly understandable, the following is a detailed description by listing specific embodiments. The drawings are not necessarily drawn to scale, and local features may be enlarged or reduced to more clearly show the details of the local features; unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application belongs.

[0049] The specific experimental steps or conditions not specified in the examples are all carried out according to the operations or conditions of the conventional experimental steps described in the literature in the field. The materials, consumables and equipment used are all conventional products that can be purchased commercially, including but not limited to the materials, consumables and equipment used in the examples of this application.

[0050] The present invention provides a method for preparing pimecrolimus cream, the method comprising the following steps:

[0051] (a) adding an emulsifier and an aqueous phase auxiliary material to a portion of the prescribed amount of water and heating to dissolve the emulsifier and the aqueous phase auxiliary material to obtain an aqueous phase;

[0052] (b) heating and dissolving the oil phase auxiliary material, adding pimecrolimus and continuing to stir and dissolve to obtain an oil phase;

[0053] (c) adding the oil phase prepared in step (b) to the water phase prepared in step (a) to obtain a liquid crystal-oil mixture;

[0054] (d) adding the remaining amount of the aqueous phase to the liquid crystal-oil mixture;

[0055] Wherein, the part of the prescription amount of water in step (a) is 50%-90% of the prescription amount of water.

[0056] In certain embodiments, the portion of the prescribed amount of water in step (a) is 60%-80% of the prescribed amount of water.

[0057] In certain embodiments, the portion of the prescribed amount of water in step (a) is 70% of the prescribed amount of water.

[0058] In certain embodiments, the remaining prescribed amount of water in step (d) is 10%-50% of the prescribed amount of water.

[0059] In certain embodiments, the remaining prescribed amount of water in step (d) is 20%-40% of the prescribed amount of water.

[0060] In certain embodiments, the remaining prescription amount of water in step (d) is 30% prescription amount of water.

[0061] In certain embodiments, the reaction temperature of the method is 60°C-90°C.

[0062] In certain embodiments, the reaction temperature of the method is 70°C-80°C.

[0063] In certain embodiments, the reaction temperature of the method is 75°C.

[0064] In certain embodiments, the emulsifier is an anionic surfactant.

[0065] In certain embodiments, the emulsifier is a long chain alkyl sodium sulfate.

[0066] In certain embodiments, the emulsifier is selected from one or more of sodium lauryl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate and mixtures thereof.

[0067] In certain embodiments, the emulsifier is sodium cetearyl sulfate.

[0068] In certain embodiments, the aqueous phase auxiliary material includes one or more of a preservative, a pH adjuster, a phosphate, and hydrochloric acid.

[0069] In certain embodiments, the preservative is benzyl alcohol.

[0070] In certain embodiments, the pH adjusters are citric acid and sodium hydroxide.

[0071] In certain embodiments, the aqueous phase excipients are benzyl alcohol, citric acid, and sodium hydroxide.

[0072] In certain embodiments, the oil phase excipient is a nonionic surfactant.

[0073] In certain embodiments, the oil phase adjuvant is selected from one or more of peregal, glyceryl stearate, long-chain fatty alcohols, higher fatty acid polyol esters, unsaturated fatty acids, and polyols.

[0074] In certain embodiments, the oil phase excipients are glyceryl mono- and distearate, cetyl alcohol, stearyl alcohol, oleyl alcohol, medium chain triglycerides, and propylene glycol.

[0075] In certain embodiments, the step (a) is to add an emulsifier and an aqueous phase auxiliary material to 70% of the prescribed amount of water and heat to 75° C. to dissolve the mixture to obtain an aqueous phase.

[0076] In certain embodiments, the step (a) is to add sodium cetearyl sulfate, benzyl alcohol, citric acid, and sodium hydroxide to 70% of the prescribed amount of water and heat to 75° C. to dissolve and obtain an aqueous phase.

[0077] In certain embodiments, the step (b) is to heat the oil phase excipient at 75° C. to dissolve it, then add pimecrolimus and continue stirring to dissolve it to obtain an oil phase.

[0078] In certain embodiments, the step (b) is to heat mono- and distearic acid glyceryl, cetyl alcohol, stearyl alcohol, oleyl alcohol, medium chain triglycerides, and propylene glycol to 75° C. to dissolve, then add pimecrolimus and continue stirring to dissolve to obtain an oil phase.

[0079] In certain embodiments, the step (c) is to add the oil phase prepared in the step (b) to the water phase prepared in the step (a) to obtain a liquid crystal-oil mixture.

[0080] In certain embodiments, the step (d) is to add the remaining 30% of the prescribed amount of water at 75° C. to the liquid crystal-in-oil mixture.

[0081] In certain embodiments, the prescription is as follows:

[0082]

[0083] In certain embodiments, the method further comprises the steps of:

[0084] (e) Mixing, homogenizing, cooling and filling.

[0085] In certain embodiments, the stirring is 100-200 rpm for 5-30 minutes.

[0086] In certain embodiments, the stirring is 200 rpm for 30 minutes.

[0087] In certain embodiments, the homogenization is performed at 5000-8000 rpm for 5-15 minutes.

[0088] In certain embodiments, the homogenization is performed at 5000 rpm for 10 minutes.

[0089] The present invention also provides a pimecrolimus cream prepared according to the method.

[0090] Example 1: Preparation process of pimecrolimus cream 1

[0091] The prescription information of pimecrolimus cream is shown in Table 1. First, add the emulsifier and aqueous phase excipients to 30% of the prescription amount of water and heat to 75°C to dissolve to obtain the aqueous phase. After the oil phase excipients are heated to 75°C to dissolve, add pimecrolimus and continue stirring to dissolve to obtain the oil phase. The oil phase is added to the aqueous phase to obtain a liquid crystal-oil mixture. Then, the remaining 70% of the prescription amount of water at 75°C is added to the liquid crystal-oil mixture, stirred at 200 rpm for 10 minutes, homogenized at 5000 rpm for 10 minutes, cooled, and filled. The final sample is observed under an upright polarizing microscope at 500 times the magnification for properties, particle size, liquid crystal structure, density and uniformity.

[0092] Table 1: Pimecrolimus cream prescription

[0093]

[0094]

[0095] Example 2: Preparation process of pimecrolimus cream 2

[0096] The prescription information of pimecrolimus cream is shown in Table 1. First, add the emulsifier and aqueous phase excipients to 50% of the prescription amount of water and heat to 75°C to dissolve to obtain the aqueous phase. After the oil phase excipients are heated to 75°C to dissolve, add pimecrolimus and continue stirring to dissolve to obtain the oil phase. The oil phase is added to the aqueous phase to obtain a liquid crystal-oil mixture. Then, the remaining 50% of the prescription amount of water at 75°C is added to the liquid crystal-oil mixture, stirred at 200 rpm for 10 minutes, homogenized at 5000 rpm for 20 minutes, cooled, and filled. The final sample is observed under an upright polarizing microscope at 500 times the magnification for properties, particle size, liquid crystal structure, density and uniformity.

[0097] Example 3: Preparation process of pimecrolimus cream 3

[0098] The prescription information of pimecrolimus cream is shown in Table 1. First, add the emulsifier and aqueous phase excipients to 70% of the prescription amount of water and heat to 75°C to dissolve to obtain the aqueous phase. After the oil phase excipients are heated to 75°C to dissolve, add pimecrolimus and continue stirring to dissolve to obtain the oil phase. The oil phase is added to the aqueous phase to obtain a liquid crystal-oil mixture. Then, the remaining 30% of the prescription amount of water at 75°C is added to the liquid crystal-oil mixture, stirred at 200 rpm for 10 minutes, homogenized at 5000 rpm for 10 minutes, cooled, and filled. The final sample is observed under an upright polarizing microscope at 500 times the magnification for properties, particle size, liquid crystal structure, density and uniformity.

[0099] Example 4: Preparation process of pimecrolimus cream 4

[0100] The prescription information of pimecrolimus cream is shown in Table 1. First, add the emulsifier and aqueous phase excipients to 30% of the prescription amount of water and heat to 75°C to dissolve to obtain the aqueous phase. After the oil phase excipients are heated to 75°C to dissolve, add pimecrolimus and continue stirring to dissolve to obtain the oil phase. The oil phase is added to the aqueous phase to obtain a liquid crystal-oil mixture. Then, the remaining 70% of the prescription amount of water at 75°C is added to the liquid crystal-oil mixture, stirred at 100 rpm for 10 minutes, homogenized at 5000 rpm for 10 minutes, cooled, and filled. The final sample is observed under an upright polarizing microscope at 500 times the magnification for properties, particle size, liquid crystal structure, density and uniformity.

[0101] Example 5: Preparation process of pimecrolimus cream 5

[0102] The prescription information of pimecrolimus cream is shown in Table 1. First, add the emulsifier and aqueous phase excipients to 50% of the prescription amount of water and heat to 75°C to dissolve to obtain the aqueous phase. After the oil phase excipients are heated to 75°C to dissolve, add pimecrolimus and continue stirring to dissolve to obtain the oil phase. The oil phase is added to the aqueous phase to obtain a liquid crystal-oil mixture. Then, the remaining 50% of the prescription amount of water at 75°C is added to the liquid crystal-oil mixture, stirred at 200 rpm for 10 minutes, homogenized at 5000 rpm for 10 minutes, cooled, and filled. The final sample is observed under an upright polarizing microscope at 500 times the magnification for properties, particle size, liquid crystal structure, density and uniformity.

[0103] Example 6: Preparation process of pimecrolimus cream 6

[0104] The prescription information of pimecrolimus cream is shown in Table 1. First, add the emulsifier and aqueous phase excipients to 70% of the prescription amount of water and heat to 75°C to dissolve to obtain the aqueous phase. After the oil phase excipients are heated to 75°C to dissolve, add pimecrolimus and continue stirring to dissolve to obtain the oil phase. The oil phase is added to the aqueous phase to obtain a liquid crystal-oil mixture. Then, the remaining 30% of the prescription amount of water at 75°C is added to the liquid crystal-oil mixture, stirred at 200 rpm for 30 minutes, homogenized at 5000 rpm for 10 minutes, cooled, and filled. The final sample is observed under an upright polarizing microscope at 500 times the magnification for properties, particle size, liquid crystal structure, density and uniformity.

[0105] Example 7: Preparation process of pimecrolimus cream 7

[0106] The prescription information of pimecrolimus cream is shown in Table 1. First, add the emulsifier and aqueous phase excipients into 70% of the prescription amount of water and heat to 75°C to dissolve to obtain the aqueous phase. After the oil phase excipients are heated to 75°C to dissolve, add pimecrolimus and continue stirring to dissolve to obtain the oil phase. The oil phase is added to the aqueous phase to obtain a liquid crystal-oil mixture. Then, the remaining 30% of the prescription amount of water at 75°C is added to the liquid crystal-oil mixture, stirred at 200rpm for 5min, homogenized at 5000rpm for 10min, cooled, and filled. The final sample is observed under an upright polarizing microscope at 500 times the magnification for properties, particle size, liquid crystal structure, density and uniformity.

[0107] Comparative Example 1: Preparation Process 8 of Pimecrolimus Cream

[0108] The prescription information of pimecrolimus cream is shown in Table 1. The water phase and oil phase are preheated to 75°C for dissolution, and the oil phase is added to the water phase under stirring. The mixture is stirred at 150 rpm for 30 min, homogenized at 8000 rpm for 5 min, cooled, and filled. The final sample is observed under an upright polarizing microscope at 500 times magnification for properties, particle size, liquid crystal structure, density, and uniformity.

[0109] Comparative Example 2: Preparation Process of Pimecrolimus Cream 9

[0110] The prescription information of pimecrolimus cream is shown in Table 1. The water phase and oil phase are preheated to 75°C to dissolve, and the oil phase is added to the water phase under stirring. The mixture is stirred at 200 rpm for 30 min, homogenized at 5000 rpm for 10 min, cooled, and filled. The final sample is observed under an upright polarizing microscope at 500 times to observe its properties, particle size, liquid crystal structure, density, and uniformity.

[0111] Example 8: Properties of Pimecrolimus Cream

[0112] The samples prepared by each process are all white creams. Visually, the creams of samples of Examples 2, 3, 5, 6, and 7 are more delicate and lustrous, among which the samples of Examples 3 and 6 are the most delicate and smooth.

[0113] Example 9: Liquid crystal detection of pimecrolimus cream

[0114] The liquid crystal detection diagrams of the samples prepared in Example 1-7 and Comparative Example 1-2 and the original samples are shown in FIG. Figure 1-10 As shown in A, the results show:

[0115] 1. According to the comparison of the inspection results of the samples of Examples 1, 3, 5, and 6, it can be obtained that when the process parameters are the same, the 70% + 30% ratio is better than other concentration ratios. Compared with the liquid crystals formed by other ratios, the liquid crystals of this ratio are more complete and clear in structure. Therefore, the solution of a certain concentration formed by the emulsifier dissolved in 70% of the prescription amount of water has the highest probability of being arranged in layers, and the largest number of layered liquid crystals are formed. Comparing all process samples, the results of the samples of Examples 3, 6, and 7 and the samples of Comparison 2 are closest to the original samples.

[0116] 2. By comparing the inspection results of the sample liquid crystals of Examples 3, 6, and 7, it can be seen that when the concentration of the emulsifier solution and other process parameters are consistent, there is no obvious difference in the size and density of the liquid crystal particles prepared under different stirring times, indicating that the stirring time has little effect on the properties of the liquid crystal.

[0117] 3. By comparing the inspection results of the sample liquid crystals of Examples 1 and 4, it can be seen that when the concentration of the emulsifier solution and other process parameters are consistent, there is no obvious difference in the size and density of the liquid crystal particles prepared at different stirring speeds, indicating that the stirring speed has little effect on the properties of the liquid crystal.

[0118] 4. By comparing the liquid crystal inspection results of samples in Examples 2 and 5, it can be seen that when the concentration of the emulsifier solution and other process parameters are consistent, the longer the homogenization time, the greater the liquid crystal density, the smaller and more uniform the particle size, and the more complete the structure. This is because the longer the homogenization time, the higher the energy given to the emulsification system, and the more uniform and smaller the particles are dispersed.

[0119] 5. The inspection results of the sample liquid crystal in Comparative Example 1 show that the size of the liquid crystal is uneven when the sample is tested under a microscope. This is because the rotation speed is too high, the shear force on the emulsion is too large, which easily destroys the structure that maintains the stability of the system, reduces the stability of the system, and makes the liquid crystal particles in the emulsion unevenly distributed, so the homogenization speed should not be too high.

[0120] Example 10: Pimecrolimus cream particle size detection

[0121] The particle size detection diagrams of the samples prepared in Example 1-7 and Comparative Example 1-2 and the original samples are shown in FIG. Figure 1-10 As shown in B, the results show:

[0122] 1. There is no significant difference in the particle size and distribution of samples in Examples 1 and 4, and the stirring speed has little effect on the particle size;

[0123] 2. Compared with the particle size results of samples in Examples 3, 6, and 7, the stirring time has little effect on the particle size;

[0124] 3. Compared with the particle size results of samples in Examples 2 and 5, the particle size and distribution are more uniform as the homogenization time increases;

[0125] 4. The sample of comparative example 1 has a much smaller particle size than other processes due to the high rotation speed;

[0126] 5. Except for comparative example 1, the particle sizes of the other samples have no significant difference from the original samples.

[0127] It should be understood that the above embodiments are exemplary and are not intended to include all possible implementations included in the claims. Various modifications and changes may be made on the basis of the above embodiments without departing from the scope of the present disclosure. Similarly, the various technical features of the above embodiments may be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only express several implementations of the present invention and do not limit the scope of protection of the patent of the present invention.

Claims

1. A method for preparing pimecrolimus cream, characterized in that: The method comprises the following steps: (a) adding an emulsifier and an aqueous phase auxiliary material to a portion of the prescribed amount of water and heating to dissolve the emulsifier and the aqueous phase auxiliary material to obtain an aqueous phase; (b) heating and dissolving the oil phase auxiliary material, adding pimecrolimus and continuing to stir and dissolve to obtain an oil phase; (c) adding the oil phase prepared in step (b) to the water phase prepared in step (a) to obtain a liquid crystal-oil mixture; (d) adding the remaining amount of water to the liquid crystal-oil mixture; Wherein, the part of the prescription amount of water in step (a) is 50%-90% of the prescription amount of water.

2. The method according to claim 1, characterized in that The part of the prescribed amount of water in step (a) is 60%-80% of the prescribed amount of water; preferably, the part of the prescribed amount of water in step (a) is 70% of the prescribed amount of water.

3. The method according to claim 1, characterized in that The remaining prescription amount of water in step (d) is 10%-50% prescription amount of water; preferably, the remaining prescription amount of water in step (d) is 20%-40% prescription amount of water; more preferably, the remaining prescription amount of water in step (d) is 30% prescription amount of water.

4. The method according to claim 1, characterized in that: The reaction temperature of the method is 60°C-90°C; preferably, the reaction temperature of the method is 70°C-80°C; more preferably, the reaction temperature of the method is 75°C.

5. The method according to claim 1, characterized in that The emulsifier is an anionic surfactant; preferably, the emulsifier is a long-chain alkyl sodium sulfate; more preferably, the emulsifier is selected from one or more of sodium dodecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate and mixtures thereof; further preferably, the emulsifier is sodium hexadecyl sulfate.

6. The method according to claim 1, characterized in that The aqueous phase auxiliary materials include one or more of a preservative, a pH adjuster, a phosphate and hydrochloric acid; preferably, the preservative is benzyl alcohol; more preferably, the pH adjuster is citric acid and sodium hydroxide; further preferably, the aqueous phase auxiliary materials are benzyl alcohol, citric acid and sodium hydroxide.

7. The method according to claim 1, characterized in that The oil phase auxiliary material is a nonionic surfactant; preferably, the oil phase auxiliary material is selected from one or more of peregal, stearin, long-chain fatty alcohols, higher fatty acid polyol esters, unsaturated fatty acids, and polyols; more preferably, the oil phase auxiliary material is mono- and distearic acid glyceryl, cetyl alcohol, stearyl alcohol, oleyl alcohol, medium-chain triglycerides, and propylene glycol.

8. The method according to any one of claims 1 to 7, characterized in that The method comprises the following steps: (a) adding an emulsifier and an aqueous phase auxiliary material to 70% of the prescription amount of water and heating to 75° C. to dissolve the emulsifier and the aqueous phase auxiliary material to obtain an aqueous phase; (b) heating the oil phase auxiliary material to 75° C. to dissolve, adding pimecrolimus and continuing to stir and dissolve to obtain an oil phase; (c) adding the oil phase prepared in step (b) to the water phase prepared in step (a) to obtain a liquid crystal-oil mixture; (d) adding the remaining 30% of the prescribed amount of water at 75° C. to the liquid crystal-in-oil mixture; The prescription is as follows:

9. The method according to claim 8, characterized in that The method further comprises the steps of: (e) Mixing, homogenizing, cooling and filling; The stirring is performed at 100-200 rpm for 5-30 minutes, preferably, the stirring is performed at 200 rpm for 30 minutes; The homogenization is carried out at 5000-8000 rpm for 5-15 minutes. Preferably, the homogenization is carried out at 5000 rpm for 10 minutes.

10. A pimecrolimus cream prepared according to the method according to any one of claims 1 to 9.

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