A clindamycin phosphate external solution

Abstract

The invention discloses a clindamycin phosphate topical solution, belonging to the technical field of pharmaceutical solutions. The invention prepares a clindamycin phosphate topical solution based on a deep eutectic solvent. The clindamycin phosphate topical solution prepared by the invention has less raw materials used, low concentration, storage stability, drug efficacy maintenance, and can well alleviate side effects such as skin itching and dryness when patients take the medicine.

Description

Technical Field

[0001] The invention relates to a clindamycin phosphate external solution, belonging to the technical field of medical solutions. Background Art

[0002] Acne is a common skin disease, which is mainly caused by factors such as increased sebum secretion, excessive reproduction of Corynebacterium acnes, and hyperkeratosis of hair follicle epithelium. It has been clinically proven that clindamycin phosphate has obvious effects in clearing pathogens and anti-inflammatory effects on skin acne. Common products on the market include clindamycin phosphate gel, clindamycin phosphate rub, clindamycin phosphate ointment, and clindamycin phosphate topical solution. Usually, some antioxidants, preservatives, emulsifiers and other additives can be added to maintain the stability of clindamycin phosphate drugs. The safety and compatibility of additives are particularly important.

[0003] Clindamycin phosphate is the drug salt form of clindamycin. It has good antibacterial activity and can inhibit the growth and reproduction of many bacteria. It is often used to treat bacterial infections such as respiratory tract infections, skin and soft tissue infections, osteomyelitis, abdominal infections, and gynecological infections. Lindamycin phosphate topical solution is a very commonly used topical preparation in dermatology. After absorption, it can be hydrolyzed into clindamycin to exert an antibacterial effect. It is mainly used for the treatment of inflammatory acne and has good antibacterial activity against Propionibacterium acnes. The side effects of topical clindamycin phosphate include allergic reactions such as dry skin, sensitive irritation, skin rash, and occasional gastrointestinal reactions such as gastrointestinal discomfort. A mild and well-moisturizing moisturizer can be added to relieve the symptoms of dry skin, and ingredients that aggravate the symptoms of sensitive skin irritation should be avoided.

[0004] The raw materials of clindamycin phosphate drugs currently prepared are complex, it is difficult to analyze their effects on side effects, and the preservation effect is poor. Patent CN110693823A discloses a method for preparing clindamycin phosphate inclusion complex using ethanol, isopropyl alcohol, propylene glycol, menthol, sulfobutyl ether-β-cyclodextrin, disodium hydrogen phosphate and water, which improves the stability of the solution. Patent CN103893766A discloses a method for preparing a clindamycin phosphate emulsifier using isopropyl myristate solution and an aqueous gel matrix; Patent CN117653595A discloses a method for preparing a clindamycin phosphate topical solution using isopropyl alcohol, disodium ethylenediaminetetraacetic acid, sesamol, anhydrous ethanol, oat kernel extract and allantoin. The above technologies all have the problems of complex raw materials, short storage time, poor stability, and no obvious effect on alleviating drug side effects.

[0005] Therefore, preparing a clindamycin phosphate drug that has simple ingredients, long-term storage stability and can alleviate drug side effects has extremely high practical and economic value. Summary of the invention

[0006] To solve the above problems, the present invention prepares a clindamycin phosphate topical solution based on a deep eutectic solvent. The clindamycin phosphate topical solution prepared by the present invention has storage stability, maintains drug efficacy, and can well alleviate side effects such as skin itching and dryness when patients take the drug.

[0007] The first object of the present invention is to provide a clindamycin phosphate topical solution, which is prepared by mixing and homogenizing a deep eutectic solvent, water, panthenol and clindamycin phosphate; wherein the mass ratio of the deep eutectic solvent to water is 1:8-10; the deep eutectic solvent is prepared from citric acid and menthol, and the molar ratio of citric acid, menthol and panthenol is 1-5:1-2:1-2.

[0008] In one embodiment, the concentration of clindamycin phosphate in the clindamycin phosphate topical solution is 0.01-0.1 g / mL.

[0009] In one embodiment, the preparation method of clindamycin phosphate topical solution comprises:

[0010] (1) preparing a low eutectic solvent aqueous solution: mixing citric acid and menthol, heating and stirring, and cooling to obtain a low eutectic solvent; mixing the low eutectic solvent with water to prepare a low eutectic solvent aqueous solution;

[0011] (2) dissolving clindamycin phosphate: adding clindamycin phosphate to the deep eutectic solvent aqueous solution prepared in step (1), mixing evenly, and preparing a mixed solution;

[0012] (3) Adding panthenol: adding panthenol to the mixed solution, mixing evenly and homogenizing, to prepare a clindamycin phosphate topical solution.

[0013] In one embodiment, the heating and stirring in step (1) is heating and stirring at 75-85° C. for 1-3 hours.

[0014] In one embodiment, the homogenization condition in step (3) is 1000-3000 rpm for 3-5 min.

[0015] The second object of the present invention is to provide the use of any of the above-mentioned clindamycin phosphate external solution in the preparation of medicines.

[0016] In one embodiment, the medicament is for treating psoriasis or dry skin or itchy skin.

[0017] The third object of the present invention is to provide a product, which contains any of the above-mentioned clindamycin phosphate external solutions.

[0018] The fourth object of the present invention is to provide a method for improving the storage time and storage stability of clindamycin phosphate, and to prepare a clindamycin phosphate external solution; the clindamycin phosphate external solution is prepared by mixing and homogenizing a deep eutectic solvent, water, panthenol and clindamycin phosphate;

[0019] The mass ratio of the low eutectic solvent to water is 1:8-10; the low eutectic solvent is prepared from citric acid and menthol, and the molar ratio of citric acid, menthol and panthenol is 1-5:1-2:1-2; the concentration of clindamycin phosphate is 0.01-0.1 g / mL; the preparation method of clindamycin phosphate topical solution comprises:

[0020] (1) preparing a low eutectic solvent aqueous solution: mixing citric acid and menthol, heating and stirring, and cooling to obtain a low eutectic solvent; mixing the low eutectic solvent with water to prepare a low eutectic solvent aqueous solution;

[0021] (2) dissolving clindamycin phosphate: adding clindamycin phosphate to the deep eutectic solvent aqueous solution prepared in step (1), mixing evenly, and preparing a mixed solution;

[0022] (3) Adding panthenol: adding panthenol to the mixed solution, mixing evenly and homogenizing, to prepare a clindamycin phosphate topical solution.

[0023] In one embodiment, the heating and stirring in step (1) is heating and stirring at 75-85° C. for 1-3 hours.

[0024] In one embodiment, the homogenization condition in step (3) is 1000-3000 rpm for 3-5 min.

[0025] Beneficial effects of the present invention

[0026] The present invention prepares a clindamycin phosphate topical solution based on a deep eutectic solvent. The clindamycin phosphate topical solution prepared by the present invention uses less raw materials and has a low concentration, is stable in storage, maintains drug efficacy, and can well alleviate side effects such as skin itching and dryness when patients take the drug.

[0027] Specific:

[0028] (1) The clindamycin phosphate topical solution of the present invention has no turbidity, no precipitation and uniform droplets when stored for 24 months at 30° C. and 60% humidity when the clindamycin phosphate concentration is 0.01 g / mL to 0.05 g / mL;

[0029] (2) The clindamycin phosphate topical solution of the present invention has a good moisturizing effect, which is 46.9% higher than that of the solution without the drug;

[0030] (3) The clindamycin phosphate topical solution of the present invention still retains 100% of its therapeutic effect after being stored for 12 months, and can effectively alleviate side effects such as itching and dryness of the skin when the patient takes the drug. DETAILED DESCRIPTION

[0031] The preferred embodiments of the present invention are described below. It should be understood that the embodiments are for better explaining the present invention and are not used to limit the present invention.

[0032] The raw materials used in the examples are:

[0033] The CAS number of clindamycin phosphate is 24729-96-2;

[0034] The CAS number of anhydrous citric acid is 77-92-9;

[0035] DL-Menthol CAS number is 89-78-1;

[0036] D-panthenol was purchased from CAS No. 81-13-0;

[0037] The above raw materials are all pharmaceutical agents.

[0038] Example 1: Preparation of clindamycin phosphate topical solution

[0039] To prepare clindamycin phosphate topical solution, follow these steps:

[0040] (1) preparing a low eutectic solvent: mixing citric acid and menthol in a molar ratio of 3:1, heating in a water bath at 80° C. with stirring for 2 h, and cooling to obtain a low eutectic solvent; adding the low eutectic solvent to water, mixing evenly, wherein the mass ratio of the low eutectic solvent to water is 1:9, and preparing a low eutectic solvent aqueous solution;

[0041] (2) dissolving clindamycin phosphate: adding clindamycin phosphate to the deep eutectic solvent aqueous solution prepared in step (1), mixing evenly to make the final concentration of clindamycin phosphate be 0.01 g / mL, and preparing a mixed solution;

[0042] (3) Adding panthenol: adding panthenol to the mixed solution in a molar ratio of 1:1, mixing evenly, and homogenizing at 2000 rpm for 5 minutes to prepare a clindamycin phosphate topical solution.

[0043] Example 2: Preparation of high concentration clindamycin phosphate topical solution

[0044] On the basis of Example 1, the final concentration of clindamycin phosphate in step (2) was changed to 0.05 g / mL, and the remaining steps were consistent with Example 1 to prepare a high-concentration clindamycin phosphate topical solution.

[0045] Comparative Example 1: Changing the order of adding panthenol

[0046] To prepare clindamycin phosphate topical solution, follow these steps:

[0047] (1) preparing a low eutectic solvent: mixing citric acid, menthol and panthenol in a molar ratio of 3:1:1, heating in a water bath at 80° C. with stirring for 2 h, and cooling to obtain a low eutectic solvent; adding the low eutectic solvent to water, mixing evenly, wherein the mass ratio of the low eutectic solvent to water is 1:9, and preparing a low eutectic solvent aqueous solution;

[0048] (2) dissolving clindamycin phosphate: adding clindamycin phosphate to the deep eutectic solvent aqueous solution prepared in step (1), mixing evenly to make the final concentration of clindamycin phosphate be 0.01 g / mL, and preparing a mixed solution;

[0049] (3) Adding menthol: The mixed solution was homogenized at 2000 rpm for 5 min to prepare a clindamycin phosphate topical solution.

[0050] Comparative Example 2: Changing the molar ratio of panthenol and menthol

[0051] On the basis of Example 1, the molar ratio of panthenol to menthol in step (3) was changed to 2:1, and the remaining steps were consistent with Example 1 to prepare a clindamycin phosphate topical solution.

[0052] Comparative Example 3: No panthenol added

[0053] On the basis of Example 1, step (3) was changed as follows: panthenol was not added, the mixed solution was homogenized at 2000 rpm / min for 5 min, and the remaining steps were consistent with Example 1 to prepare a clindamycin phosphate topical solution.

[0054] Comparative Example 4: No homogenization

[0055] On the basis of Example 1, step (3) is changed as follows: panthenol is added to the mixed solution, the molar ratio of panthenol to menthol is 1:1, and the mixture is mixed evenly to prepare a clindamycin phosphate topical solution.

[0056] Comparative Example 5: Preparation of Clindamycin Phosphate External Solution Using Lactic Acid

[0057] On the basis of Example 1, the citric acid in step (1) was changed to lactic acid, and the remaining steps were consistent with Example 1 to prepare a clindamycin phosphate topical solution.

[0058] Comparative Example 6: Preparation of clindamycin phosphate topical solution using choline chloride

[0059] On the basis of Example 1, the menthol in step (1) was replaced with choline chloride, and the remaining steps were the same as those in Example 1 to prepare a clindamycin phosphate topical solution.

[0060] Example 3: Testing the performance of clindamycin phosphate topical solution

[0061] The clindamycin phosphate external-use solutions prepared in Example 1, Example 2, and Comparative Examples 1 to 6 were taken to test their various properties.

[0062] 1. Storage stability test

[0063] The clindamycin phosphate topical solution prepared in Examples 1 to 2 and Comparative Examples 1 to 6 was sealed in a 50 mL spray bottle and kept in the dark at 30° C. and 60% humidity for 12 months. The bottle was observed every 3 months to see if turbidity or precipitation appeared; and whether the droplets after the sample was sprayed were uniform. The results are shown in Table 1.

[0064] Table 1 Storage stability

[0065]

[0066] The results show that the clindamycin phosphate topical solutions prepared in Examples 1 and 2 have good stability, while the stability of Comparative Examples 1 to 6 is at most 12 months and all have problems such as turbidity, precipitation, droplet dispersion, and uneven size. It can be seen that the citric acid / panthenol / menthol system is stable as a solvent for clindamycin phosphate; among them, the amount and timing of addition of panthenol are particularly important, and adding panthenol during the preparation of a low eutectic solvent will lead to poor system stability; and using choline chloride and lactic acid as a low eutectic solvent also has poor stability for clindamycin phosphate.

[0067] 2. Moisturizing effect test

[0068] Considering that the concentration of clindamycin phosphate in Example 2 is relatively high, only the moisturizing effects of the clindamycin phosphate topical solutions prepared in Example 1 and Comparative Examples 1 to 6 were tested, and the steps were as follows:

[0069] The skin of the test area was cleaned twice with a 1% sodium dodecyl sulfate solution, rinsed with clean water and dried, and the skin moisture value was 32 using an Italian skin tester softplus (SOFT PLUS CPU) 30 minutes later; 50 μL of clindamycin phosphate topical solution was taken on the skin of the test area and gently spread evenly, and the test value was started again after 30 minutes. The skin moisture was tested every 30 minutes. The results are shown in Table 2.

[0070] Table 2 Moisturizing effect test

[0071] 30min 60min 120min Example 1 56 52 47 Comparative Example 1 50 44 32 Comparative Example 2 57 46 37 Comparative Example 3 43 35 33 Comparative Example 4 58 50 42 Comparative Example 5 53 44 39 Comparative Example 6 50 41 33

[0072] The results show that the clindamycin phosphate topical solution prepared in Example 1 has a good moisturizing effect. After 120 minutes of application, the skin moisture is higher than that of the skin without application and Comparative Examples 1 to 6, with an increase of up to 46.9%.

[0073] 3. Effectiveness test

[0074] Considering that the concentration of clindamycin phosphate in Example 2 is relatively high, only the newly prepared clindamycin phosphate topical solution prepared in Example 1 and the clindamycin phosphate topical solution prepared in Comparative Examples 1 to 6 were tested, and the specific steps were as follows:

[0075] 56 patients with facial acne were selected and divided into 8 groups with 7 cases in each group. The acne cure rate (cure rate = number of cured patients / total number of patients) and the relief rate of side effects (itchy and dry skin) during medication (relief rate = number of relieved patients / total number of patients) in each group were calculated. During the treatment period, the medication was applied three times a day to the acne area, 3 to 5 sprays each time, for a course of 3 weeks. The results are shown in Table 3.

[0076] Table 3 Validity test

[0077] Symptom recovery rate Side effect relief rate Example 1 (newly prepared) 100％ 100％ Example 1 (Storage for 12 months) 100％ 100％ Comparative Example 1 71.4％ 28.6％ Comparative Example 2 100％ 42.9％ Comparative Example 3 100％ 28.6％ Comparative Example 4 100％ 85.7％ Comparative Example 5 85.7％ 42.9％ Comparative Example 6 85.7％ 42.9％

[0078] The results show that the newly prepared clindamycin phosphate topical solution in Example 1 and the clindamycin phosphate topical solution stored at room temperature and away from light for 12 months both have good therapeutic effects and can relieve skin itching and dryness caused by medication. It can be seen that storage at room temperature for 12 months has no effect on the efficacy. Although comparative examples 1 to 6 also have certain efficacy, the effect of relieving side effects is poor.

[0079] Although the present invention has been disclosed as above in the form of a preferred embodiment, it is not intended to limit the present invention. Anyone familiar with this technology can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be based on the definition of the claims.

Claims

1. A clindamycin phosphate topical solution, characterized in that: The preparation method of clindamycin phosphate topical solution comprises: (1) Preparing a low eutectic solvent aqueous solution: mixing citric acid and menthol, heating and stirring, and cooling to obtain a low eutectic solvent; mixing the low eutectic solvent with water to prepare a low eutectic solvent aqueous solution; (2) dissolving clindamycin phosphate: adding clindamycin phosphate to the aqueous solution of the deep eutectic solvent prepared in step (1), mixing evenly, and preparing a mixed solution; (3) Adding panthenol: adding panthenol to the mixed solution, mixing evenly and homogenizing, to prepare a clindamycin phosphate topical solution; The mass ratio of the low eutectic solvent to water is 1:8-10; the low eutectic solvent is prepared from citric acid and menthol, and the molar ratio of citric acid, menthol and panthenol is 1-5:1:

1.

2. The clindamycin phosphate topical solution according to claim 1, characterized in that In the clindamycin phosphate external solution, the concentration of clindamycin phosphate is 0.01-0.1 g / mL.

3. The clindamycin phosphate topical solution according to claim 1, characterized in that The heating and stirring in step (1) is performed at 75-85° C. for 1-3 h.

4. The clindamycin phosphate topical solution according to claim 1, characterized in that The homogenization condition in step (3) is 1000~3000rpm homogenization for 3~5min.

5. Use of the clindamycin phosphate external solution according to any one of claims 1 to 4 in the preparation of a medicine for treating acne.

6. A pharmaceutical product, characterized in that The pharmaceutical product contains the clindamycin phosphate external solution according to any one of claims 1 to 4.

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