CN1839872A - A kind of solution of clindamycin phosphate and preparation method thereof - Google Patents
A kind of solution of clindamycin phosphate and preparation method thereof Download PDFInfo
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- 229960002291 clindamycin phosphate Drugs 0.000 title claims abstract description 150
- UFUVLHLTWXBHGZ-MGZQPHGTSA-N [(2r,3r,4s,5r,6r)-6-[(1s,2s)-2-chloro-1-[[(2s,4r)-1-methyl-4-propylpyrrolidine-2-carbonyl]amino]propyl]-4,5-dihydroxy-2-methylsulfanyloxan-3-yl] dihydrogen phosphate Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](OP(O)(O)=O)[C@@H](SC)O1 UFUVLHLTWXBHGZ-MGZQPHGTSA-N 0.000 title claims abstract description 149
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 57
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims abstract description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 38
- 239000002904 solvent Substances 0.000 claims abstract description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 22
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 claims abstract description 22
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 100
- 229940100613 topical solution Drugs 0.000 claims description 19
- 229960002227 clindamycin Drugs 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- 239000002250 absorbent Substances 0.000 claims description 10
- 230000002745 absorbent Effects 0.000 claims description 10
- 239000002131 composite material Substances 0.000 claims description 10
- -1 isopropyl alcohols Chemical class 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims 18
- 230000001105 regulatory effect Effects 0.000 claims 5
- 238000012856 packing Methods 0.000 claims 3
- 229910019142 PO4 Inorganic materials 0.000 abstract description 5
- 239000010452 phosphate Substances 0.000 abstract description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract description 5
- 238000000034 method Methods 0.000 abstract description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 61
- 238000012360 testing method Methods 0.000 description 14
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- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
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- 230000003285 pharmacodynamic effect Effects 0.000 description 6
- 241000186427 Cutibacterium acnes Species 0.000 description 4
- 230000000845 anti-microbial effect Effects 0.000 description 4
- 150000001875 compounds Chemical group 0.000 description 4
- 238000011835 investigation Methods 0.000 description 4
- 229940055019 propionibacterium acne Drugs 0.000 description 4
- 206010040880 Skin irritation Diseases 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 231100000475 skin irritation Toxicity 0.000 description 3
- 230000036556 skin irritation Effects 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N Propene Chemical group CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 210000003780 hair follicle Anatomy 0.000 description 2
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- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
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- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
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Abstract
Description
技术领域：Technical field:
本发明涉及抗生素类药物克林霉素外用制剂的溶液剂与搽片剂领域，特别是一种克林霉素磷酸酯溶液剂及其搽片的制备方法。The invention relates to the field of solutions and tablets of antibiotic clindamycin external preparations, in particular to a clindamycin phosphate solution and a preparation method of the tablets.
背景技术：Background technique:
克林霉素磷酸酯溶液剂已经在临床应用，用于治疗感染性痤疮等。痤疮是一种常见的毛囊、皮脂腺慢性炎症疾病。治疗痤疮比较有效的方法是应用能减少皮脂排出、减轻毛囊潴留性角化过度、减少痤疮丙酸杆菌数量的药物进行治疗。克林霉素磷酸酯(Clindamycin Phosphate)为克林霉素的衍生物，它是美国普强公司1969年开发成功的化合物结构专利产品，克林霉素磷酸酯主要对革兰氏阳性球菌及革兰氏阳性和阴性厌氧菌有很强的抗菌活性，普强公司的研究报告指出，克林霉素磷酸酯能有效杀灭痤疮丙酸杆菌，用药四周后，药物在痤疮组织的浓度能达到597μg/g，而抑制痤疮丙酸杆菌只需0.4μg/g，在6～10周内可完全杀死开放性痤疮内的细菌，使皮肤内的游离脂肪酸由14％降到2％。用放射线标记的克林霉素治疗痤疮有效时，血浆中测不出其浓度，正由于局部外用克林霉素制剂安全有效，所以在国外上市后迅速得到广泛应用。已上市的克林霉素磷酸酯外用溶液是由1％克林霉素磷酸酯溶液、异丙醇、丙二醇和水作为溶剂。为了制备更稳定的克林霉素磷酸酯溶液剂，本发明对丙二醇的有效使用量进行了研究，并将溶液中加入了一种药用相转移试剂，即四丁基氢氧化铵，并且制备成了搽片剂，使其用药剂量更准确，更安全、可靠。Clindamycin phosphate solution has been used clinically for the treatment of infectious acne and the like. Acne is a common chronic inflammatory disease of hair follicles and sebaceous glands. The more effective way to treat acne is to apply drugs that can reduce sebum discharge, reduce hair follicle retention hyperkeratosis, and reduce the number of Propionibacterium acnes. Clindamycin Phosphate (Clindamycin Phosphate) is a derivative of Clindamycin. It is a compound structure patent product successfully developed by Upjohn Company in 1969. Clindamycin Phosphate is mainly effective against Gram-positive cocci and gram-positive bacteria. Lambert-positive and negative anaerobic bacteria have strong antibacterial activity. According to the research report of Upjohn Company, clindamycin phosphate can effectively kill Propionibacterium acnes. After four weeks of medication, the concentration of the drug in acne tissue can reach 597μg/g, while only 0.4μg/g is needed to inhibit Propionibacterium acnes, it can completely kill the bacteria in open acne within 6-10 weeks, and reduce the free fatty acid in the skin from 14% to 2%. When the radiation-labeled clindamycin is effective in treating acne, its concentration cannot be detected in the plasma. Because of the safety and effectiveness of topical clindamycin preparations, it has been widely used after being marketed abroad. The clindamycin phosphate topical solution that has been on the market is made of 1% clindamycin phosphate solution, isopropanol, propylene glycol and water as solvents. In order to prepare a more stable clindamycin phosphate solution, the present invention studies the effective amount of propylene glycol, and adds a pharmaceutical phase transfer reagent, namely tetrabutylammonium hydroxide, to the solution, and prepares it into Putting on tablets makes the dosage more accurate, safer and more reliable.
发明内容：Invention content:
本发明的目的是提供一种治疗痤疮更有效、制剂更稳定的克林霉素磷酸酯溶液剂及其搽片的制备方法。The object of the present invention is to provide a clindamycin phosphate solution and a preparation method thereof which is more effective in treating acne and has a more stable preparation.
按照本发明的克林霉素磷酸酯溶液剂，由克林霉素磷酸酯和溶解克林霉素磷酸酯的溶剂所组成，克林霉素磷酸酯溶液剂中含有克林霉素磷酸酯浓度按克林霉素计算为：3-30克/升，溶解克林霉素磷酸酯的溶剂含有四丁基氢氧化铵10-50毫升/升，异丙醇350-550毫升/升，丙二醇60-100毫升/升和水加至1000毫升，调节PH值为4.0-7.0的稀盐酸。According to the clindamycin phosphate solution of the present invention, it is made up of clindamycin phosphate and a solvent for dissolving clindamycin phosphate, and the clindamycin phosphate solution contains clindamycin phosphate concentration Calculated according to clindamycin: 3-30 g/L, the solvent for dissolving clindamycin phosphate contains tetrabutylammonium hydroxide 10-50 mL/L, isopropanol 350-550 mL/L, propylene glycol 60-100 mL/L and water are added to 1000 mL, and the pH value is adjusted to 4.0-7.0 of dilute hydrochloric acid.
按照本发明的克林霉素磷酸酯溶液剂，由克林霉素磷酸酯和溶解克林霉素磷酸酯的溶剂所组成，克林霉素磷酸酯溶液剂中含有克林霉素磷酸酯浓度按克林霉素计算为：5-20克/升，溶解克林霉素磷酸酯的溶剂含有四丁基氢氧化铵15-30毫升/升，异丙醇400-500毫升/升，丙二醇70-90毫升/升和水加至1000毫升，调节PH值为5.6-6.0的稀盐酸。According to the clindamycin phosphate solution of the present invention, it is made up of clindamycin phosphate and a solvent for dissolving clindamycin phosphate, and the clindamycin phosphate solution contains clindamycin phosphate concentration Calculated by clindamycin: 5-20 g/L, the solvent for dissolving clindamycin phosphate contains tetrabutyl ammonium hydroxide 15-30 mL/L, isopropanol 400-500 mL/L, propylene glycol 70-90 Milliliters/liter and water are added to 1000 milliliters, adjust the dilute hydrochloric acid that pH value is 5.6-6.0.
按照本发明的克林霉素磷酸酯溶液剂，由克林霉素磷酸酯和溶解克林霉素磷酸酯的溶剂所组成，克林霉素磷酸酯溶液剂中含有克林霉素磷酸酯浓度按克林霉素计算为：10克/升，溶解克林霉素磷酸酯的溶剂含有四丁基氢氧化铵20毫升/升，异丙醇500毫升/升，丙二醇80毫升/升和水加至1000毫升，调节PH值为5.5的稀盐酸。According to the clindamycin phosphate solution of the present invention, it is made up of clindamycin phosphate and a solvent for dissolving clindamycin phosphate, and the clindamycin phosphate solution contains clindamycin phosphate concentration Calculated by clindamycin: 10 g/l, the solvent for dissolving clindamycin phosphate contains 20 ml/l tetrabutylammonium hydroxide, 500 ml/l isopropanol, 80 ml/l propylene glycol and water up to 1000 mL of dilute hydrochloric acid to adjust the pH to 5.5.
按照本发明的克林霉素磷酸酯溶液剂的搽片的制备方法，其特征在于将克林霉素磷酸酯3-30克加水200毫升，搅拌使溶解，再加入四丁基氢氧化铵10-50毫升，异丙醇350-550毫升，丙二醇60-100毫升，搅拌使克林霉素磷酸酯全部溶解并加水至1000毫升，混匀，用稀盐酸调节PH值为4.0-7.0，制得克林霉素磷酸酯溶液剂，将此克林霉素磷酸酯溶液剂罐装于已装入吸水纸的铝塑复合袋中，封口，制得克林霉素磷酸酯溶液剂的搽片。According to the preparation method of the smear of clindamycin phosphate solution of the present invention, it is characterized in that 3-30 grams of clindamycin phosphate is added with 200 milliliters of water, stirred to dissolve, and then tetrabutylammonium hydroxide 10-50 ml, 350-550 ml of isopropanol, 60-100 ml of propylene glycol, stir to dissolve all clindamycin phosphate and add water to 1000 ml, mix well, and adjust the pH value to 4.0-7.0 with dilute hydrochloric acid to obtain clindamycin phosphate For the clindamycin phosphate solution, the canned clindamycin phosphate solution is placed in an aluminum-plastic composite bag packed with absorbent paper, sealed to obtain a smear of the clindamycin phosphate solution.
按照本发明的克林霉素磷酸酯溶液剂的搽片的制备方法，其特征在于将克林霉素磷酸酯5-20克加水200毫升，搅拌使溶解，再加入四丁基氢氧化铵15-30毫升，异丙醇400-500毫升，丙二醇70-90毫升，搅拌使克林霉素磷酸酯全部溶解并加水至1000毫升，混匀，用稀盐酸调节PH值为5.0-6.0，制得克林霉素磷酸酯溶液剂，将此克林霉素磷酸酯溶液剂罐装于已装入吸水纸的铝塑复合袋中，封口，制得克林霉素磷酸酯溶液剂的搽片。According to the preparation method of the smear of clindamycin phosphate solution of the present invention, it is characterized in that 5-20 grams of clindamycin phosphate is added with 200 milliliters of water, stirred to dissolve, and then tetrabutylammonium hydroxide 15-30 milliliter, 400-500 milliliters of isopropanol, 70-90 milliliters of propylene glycol, stir to dissolve all clindamycin phosphate and add water to 1000 milliliters, mix well, and adjust the pH value to 5.0-6.0 with dilute hydrochloric acid to prepare clindamycin phosphate For the clindamycin phosphate solution, the canned clindamycin phosphate solution is placed in an aluminum-plastic composite bag packed with absorbent paper, and sealed to obtain a smear of the clindamycin phosphate solution.
按照本发明的克林霉素磷酸酯溶液剂的搽片的制备方法，其特征在于将克林霉素磷酸酯10克加水200毫升，搅拌使溶解，再加入四丁基氢氧化铵20毫升，异丙醇500毫升，丙二醇80毫升，搅拌使克林霉素磷酸酯全部溶解并加水至1000毫升，混匀，用稀盐酸调节PH值为5.5，制得克林霉素磷酸酯溶液剂，将此克林霉素磷酸酯溶液剂罐装于已装入吸水纸的铝塑复合袋中，封口，制得克林霉素磷酸酯溶液剂的搽片。According to the preparation method of the smear of clindamycin phosphate solution of the present invention, it is characterized in that 10 grams of clindamycin phosphate is added with 200 milliliters of water, stirred to dissolve, and then 20 milliliters of tetrabutylammonium hydroxide, isopropyl 500 milliliters of alcohol, 80 milliliters of propylene glycol, stir to make clindamycin phosphate completely dissolve and add water to 1000 milliliters, mix well, adjust the pH value to 5.5 with dilute hydrochloric acid, and make clindamycin phosphate solution. The lindamycin phosphate solution can be packed in an aluminum-plastic composite bag filled with absorbent paper, and sealed to prepare the smear of the clindamycin phosphate solution.
为了提高本发明克林霉素磷酸酯溶液的稳定性，对溶剂中选用丙二醇比例进行研究试验如下：In order to improve the stability of clindamycin phosphate ester solution of the present invention, select propylene glycol ratio to carry out research test as follows in the solvent:
不同浓度丙二醇样品的制备Preparation of different concentrations of propylene glycol samples
样品(1)：2％丙二醇的克林霉素磷酸酯异丙醇溶液Sample (1): 2% propylene glycol solution of clindamycin phosphate in isopropanol
称取克林霉素磷酸酯0.5g(按克林霉素计)，置50毫升量瓶中，加水10毫克使克林霉素溶解，精密加入1毫升丙二醇，1毫升四丁基氢氧化铵和25毫升的异丙醇，摇匀，加水至刻度，使充分溶解，作为样品(1)。Weigh 0.5 g of clindamycin phosphate (according to clindamycin), put it in a 50 ml measuring bottle, add 10 mg of water to dissolve the clindamycin, accurately add 1 ml of propylene glycol, 1 ml of tetrabutylammonium hydroxide and 25 Mix 1 ml of isopropanol, shake well, add water to the mark, fully dissolve, and use as sample (1).
样品(2)：5％丙二醇的克林霉素磷酸酯异丙醇溶液Sample (2): 5% propylene glycol solution of clindamycin phosphate in isopropanol
称取克林霉素磷酸酯0.5g(按克林霉素计)，置50毫升量瓶中，加水10毫升使克林霉素溶解，精密加入2.5毫升丙二醇，1毫升四丁基氢氧化铵和25毫升的异丙醇，摇匀，加水至刻度，使充分溶解，作为样品(2)。Weigh 0.5 g of clindamycin phosphate (calculated by clindamycin), put it in a 50 ml measuring bottle, add 10 ml of water to dissolve the clindamycin, add 2.5 ml of propylene glycol, 1 ml of tetrabutylammonium hydroxide and 25 Mix 1 ml of isopropanol, shake well, add water to the mark, fully dissolve, and use as sample (2).
样品(3)：8％丙二醇的克林霉素磷酸酯异丙醇溶液.Sample (3): 8% propylene glycol in isopropanol solution of clindamycin phosphate.
称取克林霉素磷酸酯0.5g(按克林霉素计，)，置50毫升量瓶中，加水10毫升使克林霉素溶解，精密加入4毫升丙二醇，1毫升四丁基氢氧化铵和25毫升的异丙醇，摇匀，加水至刻度，使充分溶解，作为样品(3)。Weigh 0.5 g of clindamycin phosphate (calculated as clindamycin), put it in a 50 ml measuring bottle, add 10 ml of water to dissolve the clindamycin, accurately add 4 ml of propylene glycol, 1 ml of tetrabutylammonium hydroxide and 25 ml of isopropanol, shake well, add water to the mark, fully dissolved, as sample (3).
样品(4)：上市克林霉素磷酸酯外用溶液直接作为样品，其处方配比为：克林霉素磷酸酯为1％，异丙醇45％，丙二醇10％。Sample (4): The marketed clindamycin phosphate solution for external use is directly used as a sample, and its prescription ratio is: 1% of clindamycin phosphate, 45% of isopropanol, and 10% of propylene glycol.
测定法：精密量取样品1μL注入气相色谱仪，测定，以标准溶液作为对照计算，即得。结果见表1：Determination method: Precisely measure 1 μL of the sample and inject it into a gas chromatograph for measurement, and calculate with the standard solution as a comparison. The results are shown in Table 1:
表1丙二醇含量测定结果
根据放置中溶剂挥散及样品残留情况和皮肤的刺激性试验结果，确定含丙二醇8％的样品(3)用为最佳配方比例。与上市样品溶剂比较挥散较好，皮肤刺激性小。According to the volatilization of the solvent during placement, the residual situation of the sample and the skin irritation test results, it is determined that the sample (3) containing 8% propylene glycol is used as the optimal formula ratio. Compared with the listed sample solvent, it has better volatilization and less skin irritation.
表2溶剂挥散及样品残留情况
表3皮肤刺激性试验结果
具体实施方式Detailed ways
按照本发明的克林霉素磷酸酯溶液剂，由克林霉素磷酸酯和溶解克林霉素磷酸酯的溶剂所组成，克林霉素磷酸酯溶液剂中含有克林霉素磷酸酯浓度按克林霉素计算为：3-30克/升，溶解克林霉素磷酸酯的溶剂含有四丁基氢氧化铵10-50毫升/升，异丙醇350-550毫升/升，丙二醇60-100毫升/升和水加至1000毫升，调节PH值为4.0-7.0的稀盐酸。According to the clindamycin phosphate solution of the present invention, it is made up of clindamycin phosphate and a solvent for dissolving clindamycin phosphate, and the clindamycin phosphate solution contains clindamycin phosphate concentration Calculated according to clindamycin: 3-30 g/L, the solvent for dissolving clindamycin phosphate contains tetrabutylammonium hydroxide 10-50 mL/L, isopropanol 350-550 mL/L, propylene glycol 60-100 mL/L and water are added to 1000 mL, and the pH value is adjusted to 4.0-7.0 of dilute hydrochloric acid.
按照本发明的克林霉素磷酸酯溶液剂，由克林霉素磷酸酯和溶解克林霉素磷酸酯的溶剂所组成，克林霉素磷酸酯溶液剂中含有克林霉素磷酸酯浓度按克林霉素计算为：5-20克/升，溶解克林霉素磷酸酯的溶剂含有四丁基氢氧化铵15-30毫升/升，异丙醇400-500毫升/升，丙二醇70-90毫升/升和水加至1000毫升，调节PH值为5.6-6.0的稀盐酸。According to the clindamycin phosphate solution of the present invention, it is made up of clindamycin phosphate and a solvent for dissolving clindamycin phosphate, and the clindamycin phosphate solution contains clindamycin phosphate concentration Calculated by clindamycin: 5-20 g/L, the solvent for dissolving clindamycin phosphate contains tetrabutyl ammonium hydroxide 15-30 mL/L, isopropanol 400-500 mL/L, propylene glycol 70-90 Milliliters/liter and water are added to 1000 milliliters, adjust the dilute hydrochloric acid that pH value is 5.6-6.0.
按照本发明的克林霉素磷酸酯溶液剂，由克林霉素磷酸酯和溶解克林霉素磷酸酯的溶剂所组成，克林霉素磷酸酯溶液剂中含有克林霉素磷酸酯浓度按克林霉素计算为：10克/升，溶解克林霉素磷酸酯的溶剂含有四丁基氢氧化铵20毫升/升，异丙醇500毫升/升，丙二醇80毫升/升和水加至1000毫升，调节PH值为5.5的稀盐酸。According to the clindamycin phosphate solution of the present invention, it is made up of clindamycin phosphate and a solvent for dissolving clindamycin phosphate, and the clindamycin phosphate solution contains clindamycin phosphate concentration Calculated by clindamycin: 10 g/l, the solvent for dissolving clindamycin phosphate contains 20 ml/l tetrabutylammonium hydroxide, 500 ml/l isopropanol, 80 ml/l propylene glycol and water up to 1000 mL of dilute hydrochloric acid to adjust the pH to 5.5.
按照本发明的克林霉素磷酸酯溶液剂的搽片的制备方法，其特征在于将克林霉素磷酸酯3-30克加水200毫升，搅拌使溶解，再加入四丁基氢氧化铵10-50毫升，异丙醇350-550毫升，丙二醇60-100毫升，搅拌使克林霉素磷酸酯全部溶解并加水至1000毫升，混匀，用稀盐酸调节PH值为4.0-7.0，制得克林霉素磷酸酯溶液剂，将此克林霉素磷酸酯溶液剂罐装于已装入吸水纸的铝塑复合袋中，封口，制得克林霉素磷酸酯溶液剂的搽片。According to the preparation method of the smear of clindamycin phosphate solution of the present invention, it is characterized in that 3-30 g of clindamycin phosphate is added with 200 milliliters of water, stirred to dissolve, and then tetrabutylammonium hydroxide 10-50 ml, 350-550 ml of isopropanol, 60-100 ml of propylene glycol, stir to dissolve all clindamycin phosphate and add water to 1000 ml, mix well, and adjust the pH value to 4.0-7.0 with dilute hydrochloric acid to obtain clindamycin phosphate For the clindamycin phosphate solution, the canned clindamycin phosphate solution is placed in an aluminum-plastic composite bag packed with absorbent paper, and sealed to obtain a smear of the clindamycin phosphate solution.
按照本发明的克林霉素磷酸酯溶液剂的搽片的制备方法，其特征在于将克林霉素磷酸酯5-20克加水200毫升，搅拌使溶解，再加入四丁基氢氧化铵15-30毫升，异丙醇400-500毫升，丙二醇70-90毫升，搅拌使克林霉素磷酸酯全部溶解并加水至1000毫升，混匀，用稀盐酸调节PH值为5.0-6.0，制得克林霉素磷酸酯溶液剂，将此克林霉素磷酸酯溶液剂罐装于已装入吸水纸的铝塑复合袋中，封口，制得克林霉素磷酸酯溶液剂的搽片。According to the preparation method of the smear of clindamycin phosphate solution of the present invention, it is characterized in that 5-20 grams of clindamycin phosphate is added with 200 milliliters of water, stirred to dissolve, and then tetrabutylammonium hydroxide 15-30 milliliter, 400-500 milliliters of isopropanol, 70-90 milliliters of propylene glycol, stir to dissolve all clindamycin phosphate and add water to 1000 milliliters, mix well, and adjust the pH value to 5.0-6.0 with dilute hydrochloric acid to prepare clindamycin phosphate For the clindamycin phosphate solution, the canned clindamycin phosphate solution is placed in an aluminum-plastic composite bag packed with absorbent paper, and sealed to obtain a smear of the clindamycin phosphate solution.
按照本发明的克林霉素磷酸酯溶液剂的搽片的制备方法，其特征在于将克林霉素磷酸酯10克加水200毫升，搅拌使溶解，再加入四丁基氢氧化铵20毫升，异丙醇500毫升，丙二醇80毫升，搅拌使克林霉素磷酸酯全部溶解并加水至1000毫升，混匀，用稀盐酸调节PH值为5.5，制得克林霉素磷酸酯溶液剂，将此克林霉素磷酸酯溶液剂罐装于已装入吸水纸的铝塑复合袋中，封口，制得克林霉素磷酸酯溶液剂的搽片。According to the preparation method of the smear of clindamycin phosphate solution of the present invention, it is characterized in that 10 grams of clindamycin phosphate is added with 200 milliliters of water, stirred to dissolve, and then 20 milliliters of tetrabutylammonium hydroxide, isopropyl 500 milliliters of alcohol, 80 milliliters of propylene glycol, stir to make clindamycin phosphate completely dissolve and add water to 1000 milliliters, mix well, adjust the pH value to 5.5 with dilute hydrochloric acid, and make clindamycin phosphate solution. The lindamycin phosphate solution can be packed in an aluminum-plastic composite bag filled with absorbent paper, and sealed to prepare the smear of the clindamycin phosphate solution.
实施例1：将克林霉素磷酸酯10克加水200毫升，搅拌使溶解，再加入四丁基氢氧化铵20毫升，异丙醇500毫升，丙二醇80毫升，搅拌使克林霉素磷酸酯全部溶解并加水至1000毫升，混匀，用适量的稀盐酸，调节PH值为5.5，制得克林霉素磷酸酯溶液剂1000毫升，取克林霉素磷酸酯溶液剂1毫克罐装已装入吸水纸的铝塑复合袋中，封口，制得克林霉素磷酸酯溶液剂的搽片1000片。Example 1: Add 10 grams of clindamycin phosphate to 200 milliliters of water, stir to dissolve, then add 20 milliliters of tetrabutylammonium hydroxide, 500 milliliters of isopropanol, and 80 milliliters of propylene glycol, and stir to completely dissolve the clindamycin phosphate And add water to 1000 ml, mix well, adjust the pH value to 5.5 with an appropriate amount of dilute hydrochloric acid, and prepare 1000 ml of clindamycin phosphate solution, take 1 mg of clindamycin phosphate solution and pack it into In the aluminum-plastic compound bag of water-absorbing paper, seal, make the 1000 pieces of smear of clindamycin phosphate solution.
实施例2：将克林霉素磷酸酯5克加水200毫升，搅拌使溶解，再加入四丁基氢氧化铵15毫升，异丙醇400毫升，丙二醇70毫升，搅拌使克林霉素磷酸酯全部溶解并加水至1000毫升，混匀，用适量的稀盐酸，调节PH值为5.0，制得克林霉素磷酸酯溶液剂1000毫升，取克林霉素磷酸酯溶液剂1毫克罐装已装入吸水纸的铝塑复合袋中，封口，制得克林霉素磷酸酯溶液剂的搽片1000片。Example 2: Add 5 grams of clindamycin phosphate to 200 milliliters of water, stir to dissolve, then add 15 milliliters of tetrabutylammonium hydroxide, 400 milliliters of isopropanol, and 70 milliliters of propylene glycol, and stir to completely dissolve the clindamycin phosphate And add water to 1000 ml, mix well, adjust the pH value to 5.0 with an appropriate amount of dilute hydrochloric acid, and prepare 1000 ml of clindamycin phosphate solution, take 1 mg of clindamycin phosphate solution and pack it into In the aluminum-plastic compound bag of water-absorbing paper, seal, make the 1000 pieces of smear of clindamycin phosphate solution.
实施例3：将克林霉素磷酸酯20克加水200毫升，搅拌使溶解，再加入四丁基氢氧化铵30毫升，异丙醇550毫升，丙二醇90毫升，搅拌使克林霉素磷酸酯全部溶解并加水至1000毫升，混匀，用适量的稀盐酸，调节PH值为6.0，制得克林霉素磷酸酯溶液剂1000毫升，取克林霉素磷酸酯溶液剂1毫克罐装已装入吸水纸的铝塑复合袋中，封口，制得克林霉素磷酸酯溶液剂的搽片1000片。Example 3: Add 20 grams of clindamycin phosphate to 200 milliliters of water, stir to dissolve, then add 30 milliliters of tetrabutylammonium hydroxide, 550 milliliters of isopropanol, and 90 milliliters of propylene glycol, and stir to completely dissolve the clindamycin phosphate And add water to 1000 ml, mix well, adjust the pH value to 6.0 with an appropriate amount of dilute hydrochloric acid, and prepare 1000 ml of clindamycin phosphate solution, take 1 mg of clindamycin phosphate solution and pack it into In the aluminum-plastic compound bag of water-absorbing paper, seal, make the 1000 pieces of smear of clindamycin phosphate solution.
各实施例与上市处方配制的样品对比稳定性及体外抗菌药效学试验结果见表4、5、6、7。See Tables 4, 5, 6, and 7 for the comparative stability and in vitro antibacterial pharmacodynamics test results of each embodiment and the sample prepared by the marketed prescription.
稳定性考查Stability test
按照本发明实施例1制备的样品与按上市的克林霉素磷酸酯溶液处方配制的样品进行稳定性考察。The stability of the sample prepared according to Example 1 of the present invention and the sample prepared according to the prescription of the marketed clindamycin phosphate solution was investigated.
将样品存放于温度40℃、相对湿度75％的恒温箱中，放置6个月，进行加速破坏性实验，分别于第0、1、2、3、6个月取样，采用HPLC法测定克林霉素磷酸酯的含量，检查除主药外的其它杂质，并与0月的检测结果相比较。试验结果表明：经加速试验考察6个月，本专利制备的样品pH值、含量及杂质均无明显变化，各项考察指标均在规定范围内。所购已上市样品在同样条件下有分解现象，经加速试验考察6个月时，含量下降6.7％，杂质增加4.5％，结果见表4：Store the samples in an incubator with a temperature of 40°C and a relative humidity of 75%, and place them for 6 months for accelerated destructive experiments. Samples were taken at the 0, 1, 2, 3, and 6 months respectively, and HPLC was used to determine Klin The content of mycin phosphate, check other impurities except the main drug, and compare with the test results in 0 months. The test results show that after 6 months of accelerated test investigation, the pH value, content and impurities of the samples prepared by this patent have no obvious changes, and all the inspection indicators are within the specified range. The purchased samples that have been on the market decompose under the same conditions. After 6 months of accelerated testing, the content decreased by 6.7%, and the impurities increased by 4.5%. The results are shown in Table 4:
表4加速破坏试验测定结果表 Table 4 Determination Results of Accelerated Destruction Test
体外抗菌药效学试验考察Antimicrobial Pharmacodynamics Test in Vitro
通过测定最小抑菌浓度(MIC)比较体外抗菌效果。实验菌株为：金黄色葡萄球菌、表葡球菌和痤疮丙酸杆菌。取上述细菌稀释液适量，点种于各药物平板上，37℃培养24h后观察结果，以无细菌生长平皿所含药物的最小浓度即为最小抑菌浓度，结果见表5、表6、表7：The in vitro antibacterial effect was compared by measuring the minimum inhibitory concentration (MIC). The experimental strains were: Staphylococcus aureus, Staphylococcus epidermidis and Propionibacterium acnes. Take an appropriate amount of the above-mentioned bacterial dilution, plant them on each drug plate, and observe the results after culturing at 37°C for 24 hours. The minimum concentration of the drug contained in the plate without bacterial growth is the minimum inhibitory concentration. The results are shown in Table 5, Table 6, and Table 1. 7:
表5体外抗菌药效学试验考察结果表 Table 5 In vitro antimicrobial pharmacodynamics test investigation results table
表6体外抗菌药效学试验考察结果表 Table 6 In vitro antimicrobial pharmacodynamics test investigation results table
表7体外抗菌药效学试验考察结果表 Table 7 In vitro antimicrobial pharmacodynamics test investigation results table
本发明在克林霉素磷酸酯溶液中加入了一种药用相转移试剂，即四丁基氢氧化铵，经动物药效学试验证明疗效更好，稳定性更高，广泛适用于感染性痤疮的治疗，将本发明的克林霉素磷酸酯溶液剂灌装于已放入吸水纸的铝塑复合袋中，封口制成克林霉素磷酸酯溶液剂的搽片，保证了用药剂量的准确性和安全性，使用方便。In the present invention, a pharmaceutical phase transfer reagent, i.e. tetrabutylammonium hydroxide, is added to the clindamycin phosphate solution, which is proved to have better curative effect and higher stability by animal pharmacodynamic tests, and is widely applicable to the treatment of infectious acne Treatment, the clindamycin phosphate solution of the present invention is filled in the aluminum-plastic composite bag that has been put into absorbent paper, and the seal is made into a tablet of the clindamycin phosphate solution, which ensures the accurate dosage. Safety and security, easy to use.
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| CN103893766A (en) * | 2014-04-22 | 2014-07-02 | 白玲强 | External preparation containing clindamycin phosphate |
| CN117653595A (en) * | 2023-12-18 | 2024-03-08 | 深圳大佛药业股份有限公司 | Clindamycin phosphate external solution |
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| CN103893766B (en) * | 2014-04-22 | 2015-11-18 | 顾祥茂 | A kind of external preparation containing clindamycin phosphate |
| CN117653595A (en) * | 2023-12-18 | 2024-03-08 | 深圳大佛药业股份有限公司 | Clindamycin phosphate external solution |
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