Pimerolimus cream and preparation method thereof

Abstract

The invention belongs to the field of external medicine preparations, and particularly relates to pimerolimus emulsifiable paste and a preparation method thereof. Compared with commercially available products, the pimerolimus emulsifiable paste obtained by matching the polyoxyethylene alkyl ether emulsifier and the specific humectant has more ideal drug skin permeability and product quality stability; the pimerolimus emulsifiable paste disclosed by the invention takes effect quickly, the use experience of a patient is relatively good, the compliance of the patient is high, and the requirement on the treatment of the patient with specific dermatitis at present can be met.

Description

TECHNICAL FIELD

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

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

[0003] Atopic dermatitis is a chronic and recurrent inflammatory skin disease, and is usually treated with external drugs. The treatment principle is to restore the normal barrier function of the skin, relieve or eliminate clinical symptoms, find and eliminate the inducing and / or aggravating factors, reduce and prevent recurrence, and improve the quality of life of patients. Pimecrolimus cream was first developed by Novartis Pharmaceutical Company, and was approved for marketing by the US FDA in December 2001. It is suitable for mild to moderate atopic dermatitis (eczema) in patients aged 2 years and older without immune impairment: 1) short-term treatment of signs and symptoms of the disease; 2) long-term intermittent treatment to prevent disease exacerbation. In September 2005, the pimecrolimus cream of Novartis Pharmaceutical was approved for import and marketing by the China Drug Administration, and the trade name is Ailindinga.

[0004] However, since the solubility of pimecrolimus in water is poor, the currently marketed pimecrolimus cream still has the problems of unsatisfactory drug skin permeability and slow drug effect, and therefore it is necessary to develop a prescription-optimized pimecrolimus cream to meet the current needs for the treatment of atopic dermatitis patients. SUMMARY

[0005] In view of the defects in the prior art, the present application provides a pimecrolimus cream with improved drug skin permeability and stable product quality by optimizing the prescription of the commercially available pimecrolimus cream. The preparation method of the pimecrolimus cream of the present application is simple and is very suitable for industrial production.

[0006] To achieve the above-mentioned purpose, the present application adopts the following scheme:

[0007] The present application provides a pimecrolimus cream, which comprises pimecrolimus as an active ingredient, a polyoxyethylene alkyl ether emulsifier, a humectant, an oily base, propylene glycol, benzyl alcohol and purified water. The humectant is selected from at least one of hyaluronic acid and urea.

[0008] In one specific embodiment of the present application, the polyoxyethylene alkyl ether emulsifier is selected from one or more of polyoxyethylene (4) lauryl ether, polyoxyethylene (23) lauryl ether and polyoxyethylene (2) cetyl alcohol ether.

[0009] The applicant discovered that replacing the glyceryl monostearate and sodium cetearyl sulfate in commercially available pimecrolimus cream with the polyoxyethylene alkyl ether emulsifier of this invention, combined with the use of the moisturizer of this invention, results in a pimecrolimus cream with significantly improved drug skin penetration and stable product quality. Furthermore, the pimecrolimus cream of this invention exhibits lower skin irritation, possibly due to the synergistic effect of the polyoxyethylene alkyl ether emulsifier and the moisturizer, which better promotes drug penetration through the skin barrier to exert its therapeutic effect. In addition, the applicant also discovered that not all moisturizers can synergistically enhance drug skin penetration with the polyoxyethylene alkyl ether emulsifier of this invention; the use of the moisturizer of this invention plays a crucial role in synergistically improving the drug skin penetration of pimecrolimus cream.

[0010] In one specific embodiment of the present invention, the oily matrix comprises hexadecyl alcohol, octadecanol, oleyl alcohol, and medium-chain triglycerides.

[0011] The pimecrolimus cream of the present invention comprises the following components in parts by weight: 1.0 part pimecrolimus, 1.5 to 4.0 parts polyoxyethylene alkyl ether emulsifier, 1.0 to 3.0 parts humectant, 27.0 to 45.0 parts oily matrix, 2.5 to 8.0 parts propylene glycol, 0.5 to 1.5 parts benzyl alcohol, and 40.0 to 75.0 parts purified water.

[0012] In one specific embodiment, the weight ratio of cetyl alcohol, octadecanol, oleyl alcohol and medium-chain triglycerides in the oily matrix is ​​2-6:2-6:10-15:12-20.

[0013] In a preferred embodiment of the present invention, the pimecrolimus cream comprises the following components in parts by weight: 1.0 part pimecrolimus, 2.75 parts polyoxyethylene alkyl ether emulsifier, 2.0 part humectant, 35.0 parts oily matrix, 5.0 parts propylene glycol, 1.0 part benzyl alcohol, and 60.0 parts purified water; wherein the oily matrix contains cetyl alcohol, octadecanol, oleyl alcohol, and medium-chain triglycerides in a weight ratio of 4:4:12:15.

[0014] In one specific embodiment of the present invention, the pimecrolimus cream further comprises a pH adjuster; the pH adjuster is selected from at least one of potassium hydroxide or sodium hydroxide; the pH adjuster can adjust the pH value of the pimecrolimus cream to between 5.5 and 6.5, further improving the comfort of using the cream.

[0015] In one specific embodiment of the present invention, the pimecrolimus cream comprises the following components in parts by weight: 1.0 part pimecrolimus, 1.5 to 4.0 parts polyoxyethylene alkyl ether emulsifier, 1.0 to 3.0 parts humectant, 27.0 to 45.0 parts oily matrix, 2.5 to 8.0 parts propylene glycol, 0.5 to 1.5 parts benzyl alcohol, 40.0 to 75.0 parts purified water, and 0.01 to 0.06 parts pH adjuster.

[0016] Another aspect of the present invention provides a method for preparing the above-mentioned pimecrolimus cream, specifically comprising the following steps:

[0017] (1) Preparation of aqueous phase: Propylene glycol, benzyl alcohol and purified water are heated and stirred until dissolved to obtain aqueous phase;

[0018] (2) Preparation of oil phase: The oily matrix and polyoxyethylene alkyl ether emulsifier are heated and stirred until dissolved to obtain the oil phase;

[0019] (3) Preparation of active pharmaceutical ingredient solution: Pimecrolimus was added to the oil phase of step (2), and heated and stirred to dissolve to obtain active pharmaceutical ingredient solution;

[0020] (4) Mixing: Add the active pharmaceutical solution and humectant from step (3) to the aqueous phase of step (1), mix evenly, and cool to obtain pimecrolimus cream.

[0021] The present invention provides a method for preparing pimecrolimus cream, wherein step (1) further includes the process of adding a pH adjuster; the pH adjuster is selected from at least one of potassium hydroxide or sodium hydroxide.

[0022] The beneficial effects of this invention are as follows:

[0023] Compared with commercially available products, the pimecrolimus cream obtained by the present invention through the combined use of polyoxyethylene alkyl ether emulsifiers and specific moisturizers has more ideal drug skin penetration and product quality stability. Detailed Implementation

[0024] To better understand the technical solution of the present invention, further explanation is provided below with reference to specific implementation examples. However, those skilled in the art should recognize that the present invention is not limited to these embodiments.

[0025] Example 1

[0026]

[0027]

[0028] The preparation method is as follows:

[0029] (1) Preparation of aqueous phase: Propylene glycol, benzyl alcohol and purified water are heated and stirred to dissolve and obtain aqueous phase.

[0030] (2) Preparation of oil phase: Cetyl alcohol, octadecanol, oleyl alcohol, medium-chain triglyceride and polyoxyethylene (4) lauryl ether are heated and stirred until dissolved to obtain oil phase;

[0031] (3) Preparation of active pharmaceutical ingredient solution: Pimecrolimus was added to the oil phase of step (2), and heated and stirred to dissolve to obtain active pharmaceutical ingredient solution;

[0032] (4) Mixing: Add the drug solution and urea from step (3) to the aqueous phase of step (1), mix evenly, and cool to obtain pimecrolimus cream.

[0033] Example 2

[0034] Ingredients Wt. parts Pimecrolimus Polyoxyl (23) lauryl ether 1.0 Hyaluronic acid 1.5 Cetyl alcohol 3.0 Stearyl alcohol 2.0 Oleyl alcohol 3.0 Medium chain triglycerides 10.0 Propylene glycol 12.0 Benzylic alcohol 2.5 Purified water 1.5 Ingredients Wt. parts 75.0

[0035] The preparation method is as follows:

[0036] (1) Preparation of aqueous phase: Propylene glycol, benzyl alcohol and purified water are heated and stirred to dissolve and obtain aqueous phase.

[0037] (2) Preparation of oil phase: Cetyl alcohol, octadecanol, oleyl alcohol, medium-chain triglyceride and polyoxyethylene (23) lauryl ether are heated and stirred until dissolved to obtain oil phase;

[0038] (3) Preparation of active pharmaceutical ingredient solution: Pimecrolimus was added to the oil phase of step (2), and heated and stirred to dissolve to obtain active pharmaceutical ingredient solution;

[0039] (4) Mixing: Add the drug solution and hyaluronic acid from step (3) to the aqueous phase of step (1), mix evenly, and cool to obtain pimecrolimus cream.

[0040] Example 3

[0041] Pimecrolimus Polyoxyl (2) cetyl ether Hyaluronic acid 1.0 Cetyl alcohol 4.0 Stearyl alcohol 1.0 Oleyl alcohol 6.0 Medium chain triglycerides 4.0 Propylene glycol 15.0 Benzylic alcohol 20.0 Purified water 8.0 Sodium hydroxide 0.5 Ingredients Wt. parts 40.0 Pimecrolimus 0.06

[0042] The preparation method is as follows:

[0043] (1) Preparation of aqueous phase: Propylene glycol, benzyl alcohol, sodium hydroxide and purified water are heated and stirred to dissolve and obtain aqueous phase.

[0044] (2) Preparation of the oil phase: Hexadecyl alcohol, octadecanol, oleyl alcohol, medium-chain triglycerides and polyoxyethylene (2) cetyl alcohol ether are heated and stirred until dissolved to obtain the oil phase;

[0045] (3) Preparation of active pharmaceutical ingredient solution: Pimecrolimus was added to the oil phase of step (2), and heated and stirred to dissolve to obtain active pharmaceutical ingredient solution;

[0046] (4) Mixing: Add the drug solution and hyaluronic acid from step (3) to the aqueous phase of step (1), mix evenly, and cool to obtain pimecrolimus cream.

[0047] Example 4

[0048] Polyoxyl (4) lauryl ether Polyoxyl (2) cetyl ether Urea 1.0 Cetyl alcohol 2.0 Stearyl alcohol 1.0 Oleyl alcohol 2.5 Medium chain triglycerides 4.0 Propylene glycol 2.0 Benzylic alcohol 13.0 Water 16.0 Potassium hydroxide 6.0 Ingredients Wt. parts 1.0 Pimecrolimus 60.0 Polyoxyl (4) lauryl ether 0.01

[0049] The preparation method is as follows:

[0050] (1) Preparation of aqueous phase: Propylene glycol, benzyl alcohol, potassium hydroxide and purified water are heated and stirred to dissolve and obtain aqueous phase.

[0051] (2) Preparation of oil phase: Cetyl alcohol, octadecanol, oleyl alcohol, medium chain triglyceride, polyoxyethylene (4) lauryl ether, and polyoxyethylene (2) cetyl ether are heated and stirred until dissolved to obtain oil phase;

[0052] (3) Preparation of active pharmaceutical ingredient solution: Pimecrolimus was added to the oil phase of step (2), and heated and stirred to dissolve to obtain active pharmaceutical ingredient solution;

[0053] (4) Mixing: Add the drug solution and urea from step (3) to the aqueous phase of step (1), mix evenly, and cool to obtain pimecrolimus cream.

[0054] Example 5

[0055] Hyaluronic acid Cetyl alcohol Stearyl alcohol 1.0 Oleyl alcohol 2.75 Medium chain triglycerides 2.0 Propylene glycol 4.0 Benzylic alcohol 4.0 Purified water 12.0 Sodium hydroxide 15.0 Sample 5.0 Example 1 1.0 Example 2 60.0 Example 3 0.03

[0056] The preparation method is as follows:

[0057] (1) Preparation of aqueous phase: Propylene glycol, benzyl alcohol, sodium hydroxide and purified water are heated and stirred to dissolve and obtain aqueous phase.

[0058] (2) Preparation of oil phase: Cetyl alcohol, octadecanol, oleyl alcohol, medium-chain triglyceride and polyoxyethylene (4) lauryl ether are heated and stirred until dissolved to obtain oil phase;

[0059] (3) Preparation of active pharmaceutical ingredient solution: Pimecrolimus was added to the oil phase of step (2), and heated and stirred to dissolve to obtain active pharmaceutical ingredient solution;

[0060] (4) Mixing: Add the drug solution and hyaluronic acid from step (3) to the aqueous phase of step (1), mix evenly, and cool to obtain pimecrolimus cream.

[0061] Comparative Examples 1-5

[0062]

[0063]

[0064] The preparation methods of Comparative Examples 1-5 are the same as those of Example 1.

[0065] Compared with Example 1, the difference between Comparative Example 1 and Comparative Example 2 lies in the different emulsifiers added to the creams. In Comparative Example 1, the emulsifier is polyoxyethylene hydrogenated castor oil 60, and in Comparative Example 2, the emulsifier is polyoxyethylene (20) polyoxypropylene (8) hexadecyl ether. The difference between Comparative Example 3 and Comparative Example 4 lies in the different moisturizers added to the creams. In Comparative Example 3, the moisturizer is mannitol 1, and in Comparative Example 4, the moisturizer is sorbitol. The difference in Comparative Example 5 lies in the fact that no moisturizer was added to the cream.

[0066] Example 1: Transdermal Absorption Test

[0067] The pimecrolimus creams of Examples 1-5 and Comparative Examples 1-5 of this invention, as well as commercially available products, were used as test samples for in vitro transdermal absorption tests. The drug content of each part of the test samples was determined by HPLC to obtain the cumulative subcutaneous permeation of the drug through the skin, and the transdermal permeation performance of each test sample was evaluated.

[0068] The specific experimental results are shown in Tables 1 and 2:

[0069] Table 1. Cumulative subcutaneous drug penetration (%)

[0070] Example 4 Example 5 Average RSD value (%) Sample Comparative Example 1 1 0.0987 0.1033 0.1023 0.1129 0.1034 2 0.1017 0.1057 0.0999 0.1029 0.1022 3 0.1023 0.0989 0.1032 0.1111 0.1101 4 0.0999 0.1018 0.1018 0.0987 0.0999 5 0.1021 0.1015 0.1024 0.1077 0.1034 6 0.1023 0.1088 0.1008 0.1056 0.1024 7 0.1032 0.0959 0.1030 0.1026 0.1031 8 0.1055 0.1017 0.1070 0.0988 0.1019 9 0.0978 0.1005 0.1056 0.1021 0.1015 10 0.0933 0.1015 0.1049 0.0999 0.1003 11 0.0999 0.1001 0.0989 0.1033 0.1064 12 0.1033 0.1043 0.1004 0.1027 0.0973 Comparative Example 2 0.1008 0.1020 0.1025 0.1040 0.1027 Comparative Example 3 3.17％ 3.24％ 2.35％ 4.36％ 3.15％

[0071] Table 2. Cumulative subcutaneous drug penetration (%)

[0072] Comparative Example 4 Comparative Example 5 Commercial product Average RSD value (%) ​ ​ 1 0.0440 0.0431 0.0480 0.0349 0.0312 0.0580 2 0.0412 0.0389 0.0512 0.0512 0.0222 0.0612 3 0.0436 0.0399 0.0501 0.0482 0.0311 0.0601 4 0.0407 0.0401 0.0513 0.0509 0.0309 0.0613 5 0.0456 0.0391 0.0468 0.0444 0.0298 0.0568 6 0.0449 0.0413 0.0526 0.0511 0.0315 0.0626 7 0.0425 0.0387 0.0498 0.0439 0.0325 0.0598 8 0.0437 0.0402 0.0513 0.0512 0.0308 0.0613 9 0.0426 0.0411 0.0588 0.0399 0.0299 0.0588 10 0.0446 0.0469 0.0633 0.0502 0.0315 0.0633 11 0.0426 0.0396 0.0492 0.0611 0.0321 0.0592 12 0.0444 0.0397 0.0512 0.0511 0.0290 0.0612 ​ 0.0434 0.0407 0.0520 0.0482 0.0302 0.0603 ​ 3.42％ 5.64％ 8.91％ 13.87％ 8.96％ 3.13％

[0073] As can be seen from Tables 1 and 2, compared with the pimecrolimus creams of Comparative Examples 1-5, the pimecrolimus creams of Examples 1-5 of the present invention have a higher cumulative subcutaneous drug penetration and a smaller RSD value, indicating that the pimecrolimus creams of Examples 1-5 of the present invention have good skin penetration performance and a low coefficient of variation. Compared with commercially available products, the pimecrolimus cream of the present invention, which contains polyoxyethylene alkyl ether emulsifiers and specific moisturizers, still has significant advantages.

[0074] Example 2: Application Test

[0075] Take a sample from the fingertip, gently and evenly spread the cream in a clockwise direction, and observe the irritation on the back of the hand; the samples examined are pimecrolimus creams from Examples 1-5 and Comparative Examples 1-5.

[0076] The specific experimental results are shown in Table 3:

[0077]

[0078] As can be seen from Table 3, the pimecrolimus cream of the present invention, which contains polyoxyethylene alkyl ether emulsifiers and specific moisturizers, has a better patient application experience and higher product compliance compared to the comparative example.

[0079] Example 3: Stability Test

[0080] Pimecrolimus creams from Examples 1-5, Comparative Examples 1-5, and commercially available products were placed at 40°C for 30 days, and the properties and content of related substances of the creams at 0 days and 30 days were investigated.

[0081] The specific experimental results are shown in Tables 4 and 5:

[0082] Table 4. Test results of samples on day 0

[0083]

[0084] Table 5. Sample test results after 30 days

[0085]

[0086] As can be seen from Tables 4 and 5, compared with the pimecrolimus creams of Comparative Examples 1-5 and commercially available products, the pimecrolimus creams of Examples 1-5 of this invention contain fewer types of impurities, and after being placed at 40°C for 30 days, the cream properties and the content of related substances did not change significantly. The pimecrolimus cream of this invention, which contains polyoxyethylene alkyl ether emulsifiers and specific moisturizers, has excellent cream stability.

[0087] It should be understood that the specific embodiments described above are merely illustrative or explanatory of the principles of the invention and do not constitute a limitation thereof. Therefore, any modifications, equivalent substitutions, improvements, etc., made without departing from the spirit and scope of the invention should be included within the protection scope of the invention. Furthermore, the appended claims are intended to cover all variations and modifications falling within the scope and boundaries of the appended claims, or equivalent forms of such scope and boundaries.

Claims

1. A pimecrolimus cream, characterized in that, The cream comprises pimecrolimus as an active ingredient, polyoxyethylene alkyl ether emulsifier, humectant, oily base, propylene glycol, benzyl alcohol and purified water; the humectant is selected from at least one of hyaluronic acid and urea.

2. The pimecrolimus cream according to claim 1, characterized in that, The polyoxyethylene alkyl ether emulsifier is selected from one or more of polyoxyethylene (4) lauryl ether, polyoxyethylene (23) lauryl ether and polyoxyethylene (2) cetyl alcohol ether.

3. The pimecrolimus cream according to claim 1, characterized in that, The oily base comprises cetyl alcohol, stearyl alcohol, oleyl alcohol and medium-chain triglyceride.

4. The pimecrolimus cream according to claim 1, characterized in that, The cream comprises the following components in parts by weight: pimecrolimus 1.0 part, polyoxyethylene alkyl ether emulsifier 1.5-4.0 parts, humectant 1.0-3.0 parts, oily base 27.0-45.0 parts, propylene glycol 2.5-8.0 parts, benzyl alcohol 0.5-1.5 parts and purified water 40.0-75.0 parts.

5. The pimecrolimus cream according to claim 3 or 4, characterized in that, The parts by weight ratio of cetyl alcohol, stearyl alcohol, oleyl alcohol and medium-chain triglyceride in the oily base is 2-6:2-6:10-15:12-20.

6. The pimecrolimus cream according to claim 1, characterized in that, The cream further comprises a pH regulator.

7. The pimecrolimus cream according to claim 6, characterized in that The pH regulator is selected from at least one of potassium hydroxide or sodium hydroxide.

8. A method of preparing the pimecrolimus cream according to claim 1, characterized by, Specifically comprising the following steps: (1) Preparation of an aqueous phase: heat and stir to dissolve propylene glycol, benzyl alcohol and purified water to obtain an aqueous phase; (2) Preparation of an oil phase: heat and stir to dissolve the oily base and polyoxyethylene alkyl ether emulsifier to obtain an oil phase; (3) Preparation of a main drug solution: add pimecrolimus to the oil phase of step (2), heat and stir to dissolve to obtain a main drug solution; (4) Total mixing: add the main drug solution of step (3) and the humectant to the aqueous phase of step (1), mix uniformly, cool and obtain pimecrolimus cream.

9. The method of preparing pimecrolimus cream according to claim 8, characterized in that, The step (1) further comprises a process of adding a pH regulator.

Images