A clindamycin phosphate topical solution and a method of preparing the same

Abstract

The application belongs to the technical field of pharmaceutical preparations and relates to a clindamycin phosphate topical solution and a preparation method thereof.The clindamycin phosphate topical solution comprises clindamycin phosphate 170 g / L, sodium hydroxide 3.8-4.4 g / L, sodium sulfite 0.8-1.5 g / L, thioctic acid 0.6-1.2 g / L and appropriate tartaric acid for adjusting the pH value to 6.1-6.3.The application solves the stability problem of the clindamycin phosphate topical solution by screening the types of antioxidants and pH regulators, the prepared clindamycin phosphate topical solution has good long-term stability, and the preparation process is simple and can be scaled up.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a clindamycin phosphate external solution and its preparation method. Background Technology

[0002] Clindamycin, also known as clindamycin, was first synthesized by Upjohn in 1966 and patented in the United States in 1969. Clindamycin phosphate is commonly used clinically. Its chemical formula is C18H34ClN2O8PS. It is an antibiotic with no in vitro antibacterial activity, but it rapidly hydrolyzes into clindamycin in the body, exhibiting its pharmacological activity. Therefore, its antibacterial spectrum, antibacterial activity, and therapeutic effect are the same as clindamycin, but its lipid solubility and permeability are superior. It can be administered orally, topically, intramuscularly, or intravenously. Its structural formula is as follows: Clindamycin phosphate contains ester bonds, thiomethyl groups, and halogenated groups, making it prone to hydrolysis, oxidation, substitution, elimination, and rearrangement reactions. The molecule contains sulfur atoms, which are easily oxidized to produce high-valence sulfur, or the phosphate ester bonds and thiomethyl groups are easily hydrolyzed under acidic conditions. Under alkaline conditions or when heated, the compound readily undergoes halogen hydrolysis and elimination reactions, and isomerization reactions also occur. The solubility of clindamycin phosphate active pharmaceutical ingredient (API) is pH-dependent; a relatively large amount of sodium hydroxide is required during solution preparation to adjust the pH of the solution for complete dissolution of the API.

[0003] Currently, clindamycin phosphate preparations available domestically and internationally include topical solutions, gels, lotions, injectable solutions, vaginal suppositories, and oral capsules. Topical clindamycin phosphate solution, as a marketed drug, is used to treat acne vulgaris, such as pimples, pustules, papules, comedones, and blackheads. A drawback of currently available topical clindamycin phosphate solutions is the poor stability of clindamycin, leading to a rapid increase in impurities during storage. Therefore, the stability of clindamycin phosphate aqueous solutions has been a long-standing problem that needs to be addressed. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides a clindamycin phosphate topical solution and its preparation method. By screening the types of antioxidants and pH adjusters, the stability problem of the clindamycin phosphate topical solution is solved.

[0005] This invention provides a clindamycin phosphate external solution, comprising 170 g / L clindamycin phosphate, 3.8-4.4 g / L sodium hydroxide, 0.8-1.5 g / L sodium sulfite, 0.6-1.2 g / L thioctic acid, and an appropriate amount of tartaric acid to adjust the pH to 6.1-6.3.

[0006] Preferably, the clindamycin phosphate external solution comprises 170 g / L clindamycin phosphate, 4.1 g / L sodium hydroxide, 0.8-1.5 g / L sodium sulfite, 0.6-1.2 g / L thioctic acid, and an appropriate amount of tartaric acid to adjust the pH to 6.1-6.3.

[0007] Preferably, the clindamycin phosphate external solution comprises 170 g / L clindamycin phosphate, 3.8-4.4 g / L sodium hydroxide, 1.2 g / L sodium sulfite, 0.6-1.2 g / L thioctic acid, and an appropriate amount of tartaric acid to adjust the pH to 6.1-6.3.

[0008] Preferably, the clindamycin phosphate external solution comprises 170 g / L clindamycin phosphate, 3.8-4.4 g / L sodium hydroxide, 0.8-1.5 g / L sodium sulfite, 0.9 g / L thioctic acid, and an appropriate amount of tartaric acid to adjust the pH to 6.1-6.3.

[0009] Preferably, the clindamycin phosphate external solution comprises 170 g / L clindamycin phosphate, 3.8-4.4 g / L sodium hydroxide, 0.8-1.5 g / L sodium sulfite, 0.6-1.2 g / L thioctic acid, and an appropriate amount of tartaric acid to adjust the pH to 6.2.

[0010] Preferably, the clindamycin phosphate external solution comprises 170 g / L clindamycin phosphate, 4.1 g / L sodium hydroxide, 1.2 g / L sodium sulfite, 0.9 g / L thioctic acid, and an appropriate amount of tartaric acid to adjust the pH to 6.2.

[0011] This invention also provides a method for preparing clindamycin phosphate external solution, comprising the following preparation steps: Add a portion of water for injection to the mixing tank, then add the prescribed amounts of sodium hydroxide, the antioxidant sodium sulfite, and thioctic acid. Stir to dissolve, then add the prescribed amounts of clindamycin phosphate and stir until completely dissolved. Adjust the pH value with an appropriate amount of acid, bring the volume to a final volume with water for injection, measure the pH value, filter through a filter membrane, and fill into vials to obtain the clindamycin phosphate external solution.

[0012] Preferably, 75-90% water for injection is added to the solution preparation tank.

[0013] Preferably, the material is filtered through PVDF membranes with a diameter of 0.45 μm or 0.22 μm.

[0014] This invention solves the stability problem of clindamycin phosphate topical solution by screening the types of antioxidants and pH adjusters. The prepared clindamycin phosphate topical solution has good long-term stability and the preparation process is simple and can be scaled up for production. Detailed Implementation

[0015] In view of the deficiencies of the prior art, the inventors, through long-term research and extensive practice, have proposed the technical solution of this invention. The invention is further illustrated below by means of embodiments, but these embodiments do not constitute a limitation of the invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without inventive effort are within the scope of protection of this invention.

[0016] Example 1 Preparation method: Add 85% water for injection to a mixing tank, add the prescribed amount of sodium hydroxide and antioxidant, stir to dissolve, then add the prescribed amount of clindamycin phosphate, stir until completely dissolved, adjust the pH value to 6.2 with an appropriate amount of acid, make up to volume with water for injection, measure the pH value, filter through 0.45μm and 0.22μm PVDF filter membranes, and fill into the container to obtain clindamycin phosphate external solution.

[0017] The clindamycin phosphate external solutions prepared according to prescriptions 1-8 were placed at 40℃ for 3 months, and samples were taken for testing of relevant items. The results are as follows: The results in the table above show that, when the clindamycin phosphate topical solution prepared by prescription 4 without the antioxidant sodium sulfite and prescription 5 without the antioxidant lipoic acid was placed under accelerated stabilization conditions for 3 months, the impurities increased rapidly. When prescriptions 2 and 3 replaced sodium sulfite with sodium thiosulfate and sodium metabisulfite, respectively, and prescription 6 replaced lipoic acid with glutathione, the impurities increased after 3 months of accelerated stabilization conditions, with the total impurities exceeding 1%. When prescription 7 was prepared by adjusting the pH with hydrochloric acid, the pH of the clindamycin phosphate topical solution was unstable and the impurities increased significantly after 3 months of accelerated stabilization conditions. When prescription 8 was prepared by adjusting the pH with citric acid, the pH of the clindamycin phosphate topical solution was stable after 3 months of accelerated stabilization conditions, but the impurities increased, with the total impurities exceeding 1%. Formula 1 uses sodium sulfite and thioctic acid as oxidants, and tartaric acid to adjust the pH. The prepared clindamycin phosphate external solution was placed under accelerated stabilization conditions for 3 months. The pH was stable, and there was no significant increase in impurities. The total impurities did not exceed 1%, and the quality was stable.

[0018] Example 2 The preparation method is the same as in Example 1.

[0019] The clindamycin phosphate external solutions prepared from prescriptions 1 and 9-14 were placed at 25°C for 24 months, and samples were taken for testing of relevant items. The results are as follows: The results in the table above show that the clindamycin phosphate external solution prepared by using sodium sulfite and thioctic acid as oxidants and tartaric acid to adjust the pH remained stable after 24 months of long-term stability, with no significant increase in impurities and a total impurity level not exceeding 1%, indicating stable quality.

[0020] It should be understood that the technical solutions of the present invention are not limited to the specific embodiments described above. Any technical modifications made to the technical solutions of the present invention without departing from the spirit and scope of the claims are within the scope of protection of the present invention.

Claims

1. A clindamycin phosphate external solution, characterized in that, The solution includes 170 g / L clindamycin phosphate, 3.8-4.4 g / L sodium hydroxide, 0.8-1.5 g / L sodium sulfite, 0.6-1.2 g / L thioctic acid, and an appropriate amount of tartaric acid to adjust the pH to 6.1-6.

3.

2. The clindamycin phosphate external solution according to claim 1, characterized in that, The solution includes 170 g / L clindamycin phosphate, 4.1 g / L sodium hydroxide, 0.8-1.5 g / L sodium sulfite, 0.6-1.2 g / L thioctic acid, and an appropriate amount of tartaric acid to adjust the pH to 6.1-6.

3.

3. The clindamycin phosphate external solution according to claim 1, characterized in that, The formula includes 170 g / L clindamycin phosphate, 3.8-4.4 g / L sodium hydroxide, 1.2 g / L sodium sulfite, 0.6-1.2 g / L thioctic acid, and an appropriate amount of tartaric acid to adjust the pH to 6.1-6.

3.

4. The clindamycin phosphate external solution according to claim 1, characterized in that, The solution includes 170 g / L clindamycin phosphate, 3.8-4.4 g / L sodium hydroxide, 0.8-1.5 g / L sodium sulfite, 0.9 g / L thioctic acid, and an appropriate amount of tartaric acid to adjust the pH to 6.1-6.

3.

5. The clindamycin phosphate external solution according to claim 1, characterized in that, The solution includes 170 g / L clindamycin phosphate, 3.8-4.4 g / L sodium hydroxide, 0.8-1.5 g / L sodium sulfite, 0.6-1.2 g / L thioctic acid, and an appropriate amount of tartaric acid to adjust the pH to 6.

2.

6. The clindamycin phosphate external solution according to claim 1, characterized in that, The solution contains 170 g / L clindamycin phosphate, 4.1 g / L sodium hydroxide, 1.2 g / L sodium sulfite, 0.9 g / L thioctic acid, and an appropriate amount of tartaric acid to adjust the pH to 6.

2.

7. The method for preparing clindamycin phosphate external solution according to any one of claims 1-6, characterized in that, The process includes the following steps: adding a portion of water for injection to a mixing tank, adding the prescribed amounts of sodium hydroxide, sodium sulfite, and thioctic acid, stirring to dissolve, then adding the prescribed amounts of clindamycin phosphate, stirring until completely dissolved, adjusting the pH value with an appropriate amount of acid, making up to volume with water for injection, measuring the pH value, filtering through a filter membrane, and filling to obtain the clindamycin phosphate external solution.

8. The method for preparing clindamycin phosphate external solution according to claim 7, characterized in that, Add 75-90% water for injection to the mixing tank.

9. The method for preparing clindamycin phosphate external solution according to claim 7, characterized in that, Filtered through 0.45μm and 0.22μm PVDF membranes.

10. A clindamycin phosphate external solution prepared by the preparation method according to any one of claims 7-9.

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