宠物用复方酮康唑香波的药剂学研究
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摘要
随着经济的稳步增长，我国宠物业的迅速发展，动物保健药品的需求量不断增加。为预防和治疗宠物犬和猫的真菌、细菌及混合感染性皮肤病，制备由1％酮康唑和2％葡萄糖酸氯己定组成的宠物用复方酮康唑香波。本研究拟参考Virbac公司2001年上市的ketoconazole／chlorhexidine gluconate香波处方，并依照我国“新兽药审批办法”，对宠物用复方酮康唑香波进行工艺设计、处方筛选、含量测定、稳定性初步研究，制定质量标准。
采用冷混合法制备宠物用复方酮康唑香波。处方筛选中以外观稳定性、泡沫体积、粘度为考察指标，对宠物用复方酮康唑香波中的主要辅料抗氧化剂无水亚硫酸钠、十二烷基硫酸钠、脂肪醇聚氧乙烯醚硫酸钠、十二烷基甜菜碱等4因素3水平进行正交设计。优选结果为0.2％无水亚硫酸钠、7％十二烷基硫酸钠、12％脂肪醇聚氧乙烯醚硫酸钠和4％十二烷基甜菜碱。
建立宠物用复方酮康哗香波含量测定的高效液相色谱法。用流动相稀释香波样品至合适浓度，0.45μm微孔虑膜过滤，即可。采用Inertsil ODS-3柱，柱温40℃，流动相为乙腈-0.1mol／L磷酸氢二钠水溶液(内含0.05mol／L三乙胺)(65∶135)，磷酸调pH值至3.2，流速为1.0mL／min，紫外检测波长为235nm。结果表明，酮康唑和葡萄糖酸氯己定标准溶液浓度均在1～100μg／mL的范围内呈良好线性关系，Y_(KCZ)=34331X+16638(r=0.9999)，Y_(Chlo-G)=32349X+6523.6(r=0.9999)。浓度为100μg／mL、10μg／mL、1μg／mL时，酮康唑的日内和日间精密度分别小于1.5％和2.1％；葡萄糖酸氯己定日内和日间精密度小于1.8％和2.1％。空白样品添加标准品酮康唑和葡萄糖酸氯己定浓度均为1mg／g、0.2mg／g、0.1mg／g时，酮康唑的回收率分别为99.46％、99.60％、99.97％；葡萄糖酸氯己定分别为100.32％、98.79％、100.34％，两药物的精密度均小于1.7％。
用HPLC法测定制备的3批宠物用复方酮康唑香波样品含量，结果为酮康唑分别为标示量的100.84％、100.45％、99.88％，葡萄糖酸氯己定分别为标示量的93.28％、95.05％、94.99％，含量均在中国兽药典规定范围内。
稳定性初步研究结果显示，宠物用复方酮康唑香波在温度25±2℃，相对湿度60％±10％的条件下放置6个月和在温度40±2℃，相对湿度70％±10％的条件下放置3个月，含量测定结果酮康唑和葡萄糖酸氯己定均为90％～110％，粘度、泡沫体积、稳定性均无明显变化。表明宠物用复方酮康唑香波在室温6个月和加速3个月的稳定性均良好。
本研究仿制的宠物用复方酮康唑香波制备工艺简单，稳定性良好。含量测定中，样品处理简便，检测灵敏度高，定量准确，重复性好，符合兽药制剂含量测定要求。所制定的质量标准适用于宠物用复方酮康唑香波的质量控制。
With the development of economic and pets industry, the requirement of animal health drug is more and more. Compound ketoconazole pet shampoo is a compound formulation which consists of 1% ketoconazole and 2% chlorhexidine gluconate. It will be used for prevention and treatment of fungal and bacteria dermatosis for dog and cat. Under the Guidance of Provision for New Animal Drug Approval and Keto-Chlor shampoo, compound ketoconazole pet shampoo has been studied on preparing technology, formulation choosing, determination of content, preliminary stability and quality standard.Compound ketoconazole pet shampoo was preparationed by cold admixture. The best formulation of compound ketoconazole pet shampoo was screened by orthogonal design. Orthogonal design was utilized to optimize the 4 factors in the compound ketoconazole shampoo, namely the antioxidant anhydrous sodium sulfite, sodium lauryl sulfate, fatty alcohol polyoxyethylene lauryl ether sulfate sodium, dodecyl betaine. And the results were anhydrous sodium sulfite 0.2%, sodium lauryl sulfate 7%, fatty alcohol polyoxyethylene lauryl ether sulfate sodium 12% and dodecyl betaine 4%.The quality standard of compound ketoconazole pet shampoo was studied and to establish a HPLC method for the simultaneous determination of ketoconazole and chlorhexidine gluconate in shampoo. The shampoo sample was diluted to suitable concentration with mobile phase, and filtered with microbore membrane. The HPLC system was consisted of Inertsil ODS-3(5μm, 150mm×4.6mm), column temperature was at 40℃, and mobile phase was composed of acetonitrile-0.1mol/L dipotassium hydrogen phosphate (65∶135), adjust pH to 3.2 by phosphoric acid. The flow rate was 1.0mL/min, detection wavelength was at 235nm. The results show that both of the ketoconazole and chlorhexidine gluconate were fine linear in the range of 1 - 100μg/mL respectively, and standard curve and coefficient were Y_(KCZ)=34331X+16638 (r=0.9999) and Y_(Chlo-G)= 32349X+6523.6 (r=0.9999) respectively. Intra-day and extra-day RSD values of ketoconazole were less than 1.5% and 2.1%. And intra-day and extra-day RSD values of chlorhexidine gluconate were less than 1.8% and 2.1% respectively. The recoverise of ketoconazole and chlorhexidine gluconate in control shampoo were 99.46%, 99.60%, 99.97% and 100.32%, 98.79%, 100.34% respectively, and both RSD values of the drug were less than 1.7%.
Quality of the three groups compound ketoconazole pet shampoo samples were determined by HPLC, and the results were 100.84%, 100.45%, 99.88% and 93.28%, 95.05%, 94.99% respectively, and suit to China Veterinary Drugs Pharmacopeia.
Preliminary stability tests showed that the compound ketoconazole shampoo pet for is stable during 6 months in 25℃±2℃, correspond humidity 60%±10% and during 3 months in 40℃±2℃, correspond humidity 70%±10%. Results of quality determination of ketoconazole and chlorhexidine gluconate in compound shampoo were 90%～110%.
The preparation method of compound ketoconazole pet shampoo was simple and the quality was stable. The HPLC method of quality determination was easy and suitalbe and sensitivity and specificity. It's well adapted for quality control of compound ketoconazole pet shampoo.
采用冷混合法制备宠物用复方酮康唑香波。处方筛选中以外观稳定性、泡沫体积、粘度为考察指标，对宠物用复方酮康唑香波中的主要辅料抗氧化剂无水亚硫酸钠、十二烷基硫酸钠、脂肪醇聚氧乙烯醚硫酸钠、十二烷基甜菜碱等4因素3水平进行正交设计。优选结果为0.2％无水亚硫酸钠、7％十二烷基硫酸钠、12％脂肪醇聚氧乙烯醚硫酸钠和4％十二烷基甜菜碱。
建立宠物用复方酮康哗香波含量测定的高效液相色谱法。用流动相稀释香波样品至合适浓度，0.45μm微孔虑膜过滤，即可。采用Inertsil ODS-3柱，柱温40℃，流动相为乙腈-0.1mol／L磷酸氢二钠水溶液(内含0.05mol／L三乙胺)(65∶135)，磷酸调pH值至3.2，流速为1.0mL／min，紫外检测波长为235nm。结果表明，酮康唑和葡萄糖酸氯己定标准溶液浓度均在1～100μg／mL的范围内呈良好线性关系，Y_(KCZ)=34331X+16638(r=0.9999)，Y_(Chlo-G)=32349X+6523.6(r=0.9999)。浓度为100μg／mL、10μg／mL、1μg／mL时，酮康唑的日内和日间精密度分别小于1.5％和2.1％；葡萄糖酸氯己定日内和日间精密度小于1.8％和2.1％。空白样品添加标准品酮康唑和葡萄糖酸氯己定浓度均为1mg／g、0.2mg／g、0.1mg／g时，酮康唑的回收率分别为99.46％、99.60％、99.97％；葡萄糖酸氯己定分别为100.32％、98.79％、100.34％，两药物的精密度均小于1.7％。
用HPLC法测定制备的3批宠物用复方酮康唑香波样品含量，结果为酮康唑分别为标示量的100.84％、100.45％、99.88％，葡萄糖酸氯己定分别为标示量的93.28％、95.05％、94.99％，含量均在中国兽药典规定范围内。
稳定性初步研究结果显示，宠物用复方酮康唑香波在温度25±2℃，相对湿度60％±10％的条件下放置6个月和在温度40±2℃，相对湿度70％±10％的条件下放置3个月，含量测定结果酮康唑和葡萄糖酸氯己定均为90％～110％，粘度、泡沫体积、稳定性均无明显变化。表明宠物用复方酮康唑香波在室温6个月和加速3个月的稳定性均良好。
本研究仿制的宠物用复方酮康唑香波制备工艺简单，稳定性良好。含量测定中，样品处理简便，检测灵敏度高，定量准确，重复性好，符合兽药制剂含量测定要求。所制定的质量标准适用于宠物用复方酮康唑香波的质量控制。
With the development of economic and pets industry, the requirement of animal health drug is more and more. Compound ketoconazole pet shampoo is a compound formulation which consists of 1% ketoconazole and 2% chlorhexidine gluconate. It will be used for prevention and treatment of fungal and bacteria dermatosis for dog and cat. Under the Guidance of Provision for New Animal Drug Approval and Keto-Chlor shampoo, compound ketoconazole pet shampoo has been studied on preparing technology, formulation choosing, determination of content, preliminary stability and quality standard.Compound ketoconazole pet shampoo was preparationed by cold admixture. The best formulation of compound ketoconazole pet shampoo was screened by orthogonal design. Orthogonal design was utilized to optimize the 4 factors in the compound ketoconazole shampoo, namely the antioxidant anhydrous sodium sulfite, sodium lauryl sulfate, fatty alcohol polyoxyethylene lauryl ether sulfate sodium, dodecyl betaine. And the results were anhydrous sodium sulfite 0.2%, sodium lauryl sulfate 7%, fatty alcohol polyoxyethylene lauryl ether sulfate sodium 12% and dodecyl betaine 4%.The quality standard of compound ketoconazole pet shampoo was studied and to establish a HPLC method for the simultaneous determination of ketoconazole and chlorhexidine gluconate in shampoo. The shampoo sample was diluted to suitable concentration with mobile phase, and filtered with microbore membrane. The HPLC system was consisted of Inertsil ODS-3(5μm, 150mm×4.6mm), column temperature was at 40℃, and mobile phase was composed of acetonitrile-0.1mol/L dipotassium hydrogen phosphate (65∶135), adjust pH to 3.2 by phosphoric acid. The flow rate was 1.0mL/min, detection wavelength was at 235nm. The results show that both of the ketoconazole and chlorhexidine gluconate were fine linear in the range of 1 - 100μg/mL respectively, and standard curve and coefficient were Y_(KCZ)=34331X+16638 (r=0.9999) and Y_(Chlo-G)= 32349X+6523.6 (r=0.9999) respectively. Intra-day and extra-day RSD values of ketoconazole were less than 1.5% and 2.1%. And intra-day and extra-day RSD values of chlorhexidine gluconate were less than 1.8% and 2.1% respectively. The recoverise of ketoconazole and chlorhexidine gluconate in control shampoo were 99.46%, 99.60%, 99.97% and 100.32%, 98.79%, 100.34% respectively, and both RSD values of the drug were less than 1.7%.
Quality of the three groups compound ketoconazole pet shampoo samples were determined by HPLC, and the results were 100.84%, 100.45%, 99.88% and 93.28%, 95.05%, 94.99% respectively, and suit to China Veterinary Drugs Pharmacopeia.
Preliminary stability tests showed that the compound ketoconazole shampoo pet for is stable during 6 months in 25℃±2℃, correspond humidity 60%±10% and during 3 months in 40℃±2℃, correspond humidity 70%±10%. Results of quality determination of ketoconazole and chlorhexidine gluconate in compound shampoo were 90%～110%.
The preparation method of compound ketoconazole pet shampoo was simple and the quality was stable. The HPLC method of quality determination was easy and suitalbe and sensitivity and specificity. It's well adapted for quality control of compound ketoconazole pet shampoo.
引文
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59. Hill P B. A review of systemic antifungal agents. Vet Dermatol. 1995, 6 (2): 59-66
60. Invader Heyden, A Nguyen Minh Nguyet, M R Detaevernier, D L Massart, J Plaizier Vercammen. Simultaneous determination of ketoconazole and formaldehyde in a shampoo: liquid chromatography method development and validation, J of Chromato A. 2002,958: 191-201
61. Ketoconazole shampoo, Animal Pharm. 2001.11.2:21
62. L Bernal, M J del Nozal. Separation of ketoconazole enantiomers by chiral subcritical fluid chromatography, J Biochem Biophys Methods. 2000, 43: 241-250
63. Larry E, Stevens, J Robert Durrwachter, Danny O Helton. Analysis of Chlorhexidine Sorption in Soft Contact Lenses by Catalytic Oxidation of [～(14)C]Chlorhexidine and by Liquid Chromatography, J of Pharmaceu Sci. 1986, 75:1, 83-86
64. Lemarie R J and Hosgood G. Antiseptics and disinfectants in small animal practice. Compendium of Continuing Animal Education. 1995, 17: 25-34
65. Linda R Brougham, Haiyung Cheng, Kenneth A, Pittman. Sensitive high-Performance Liquid Chromatographic Method for the Determination of Chlorhexidine in Human Serum and Urine. J of Chromato. 1986, 383: 365-373
66. Lloyd D H and Lamport A I. Activity of chlorhexidine shampoos in vitro against Staphylococcus intermedius, Pseudomonas aeruginosa and Malassezia pachydermatitis. Veterinary Record. 1999, 144: 536-537
67. Marcus H, Gaffney, Michael Cooke, Rosemary Simpson. Improved method for the determination of chlorhexidine in urine. J of Chromato. 1984, 306: 303-313
68. Moriello K A: Management of dermatophyte infections in catteries and multiple cat households. V C N A S A P. 1990, 20: 1457
69. Ortonne J P. Comparative study of ketoconazole 2% foaming gel and betamethasone dipropionate 0.05% Iltion in the treatment of seborrhoeic dermatitis in adults. Dermatology. 1992, 184(4): 275-280
70. Pepin G A, Qcenham M: Feline dermatohpytosis:The diagnosis of subclinical Infection and its relevence to control. V D N. 1987, 11:21
71. Perry Romanowski, Randy Schueller. Polymers in personal-care products. Cosmetics Toiletries. 1998, 11 (113): 51 -56
72. Pierard G E. Ketoconazole 2% emulsion in the treatment of seboorrheic dermatitis. Int J Dermatol. 1991, 30 (11): 806-809
73. R Odorel, V Colombatti Valle and G Re, Efficacy of Chlorhexidine against Some Strains of Cultured and Clinically Isolated Microorganisms, V R C. 2000, 24: 229-238
74. Randy Schueller, Petty Romanowski. Conditioning agents for hair and skin. Cosmetics & Toiletries .1995, 8 (110): 43-47
75. Russell A D. Chlorhexidine: antibacterial action and bacterial resistance. Infection. 1986,14:212-215
76. Scott D W. Antifungal therapy Muller & Kirk's Small Animal Dermatology, 6th Ed (D W Scott et al, eds.). W B Saunders, Philadelphia, Pa., 2001; 336-422, 409-415
77. Shryock T R. NCCLS quality control values for veterinary use fluoroquinolones. J of CM. 2001,39(4): 1680-1681
78. Swaim S F, Riddell K P, Geiger D L, Hatchcock T L and McGuire J A. Evaluation of surgical scrub and antiseptic solutions for surgical preparation of canine paws. J A V M A. 1998, 1941-1945
79. Timo Pesonen, Jussi Holmalahti, Juhani Pohjola. Determination of chlorhexidine in saliva using high-performance liquid chromatography, J of Chromato B. 1995, 665:222-225
80. Van Cutsem J. The antiinflammatory effects of ketoconazole. J Am Acad Dermatol. 1991, 25(2): 257-261
81. Willard M D. Ketoconazole induced changes in selected canine hormone concentrations. A J V R. 1986, 47 (12): 2504-2509
82. Y W Francis Lam, Daniel C.N.Chan, Sandra Y.Rodriguez, John H.Lintakoon, Thu Hong Lam. Sensitive high-performance liquid chromatography assay for the determination of chlorhexidine in saliva, J of Chromato. 1993, 612:166-171
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47. A Nguyen Minh Nguyet, L Tallieu, J Plaizier-Vercammen, D L Massart, Invader Heyden. Validation of an HPLC method on short columns to assay ketoconazole and formaldehyde in shampoo, J of Pharma and Bio Ana. 2003, 32: 1-19
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57. G T Wilkinson. Acolour Atlas of Small Animal Dermatology. 1991, 45-49, 57-59
58. Heel R C. Ketoconazole: a review of its therapeutic efficacy in superficial and systemic fungal diseases. Drugs. 1982, 22: 3
59. Hill P B. A review of systemic antifungal agents. Vet Dermatol. 1995, 6 (2): 59-66
60. Invader Heyden, A Nguyen Minh Nguyet, M R Detaevernier, D L Massart, J Plaizier Vercammen. Simultaneous determination of ketoconazole and formaldehyde in a shampoo: liquid chromatography method development and validation, J of Chromato A. 2002,958: 191-201
61. Ketoconazole shampoo, Animal Pharm. 2001.11.2:21
62. L Bernal, M J del Nozal. Separation of ketoconazole enantiomers by chiral subcritical fluid chromatography, J Biochem Biophys Methods. 2000, 43: 241-250
63. Larry E, Stevens, J Robert Durrwachter, Danny O Helton. Analysis of Chlorhexidine Sorption in Soft Contact Lenses by Catalytic Oxidation of [～(14)C]Chlorhexidine and by Liquid Chromatography, J of Pharmaceu Sci. 1986, 75:1, 83-86
64. Lemarie R J and Hosgood G. Antiseptics and disinfectants in small animal practice. Compendium of Continuing Animal Education. 1995, 17: 25-34
65. Linda R Brougham, Haiyung Cheng, Kenneth A, Pittman. Sensitive high-Performance Liquid Chromatographic Method for the Determination of Chlorhexidine in Human Serum and Urine. J of Chromato. 1986, 383: 365-373
66. Lloyd D H and Lamport A I. Activity of chlorhexidine shampoos in vitro against Staphylococcus intermedius, Pseudomonas aeruginosa and Malassezia pachydermatitis. Veterinary Record. 1999, 144: 536-537
67. Marcus H, Gaffney, Michael Cooke, Rosemary Simpson. Improved method for the determination of chlorhexidine in urine. J of Chromato. 1984, 306: 303-313
68. Moriello K A: Management of dermatophyte infections in catteries and multiple cat households. V C N A S A P. 1990, 20: 1457
69. Ortonne J P. Comparative study of ketoconazole 2% foaming gel and betamethasone dipropionate 0.05% Iltion in the treatment of seborrhoeic dermatitis in adults. Dermatology. 1992, 184(4): 275-280
70. Pepin G A, Qcenham M: Feline dermatohpytosis:The diagnosis of subclinical Infection and its relevence to control. V D N. 1987, 11:21
71. Perry Romanowski, Randy Schueller. Polymers in personal-care products. Cosmetics Toiletries. 1998, 11 (113): 51 -56
72. Pierard G E. Ketoconazole 2% emulsion in the treatment of seboorrheic dermatitis. Int J Dermatol. 1991, 30 (11): 806-809
73. R Odorel, V Colombatti Valle and G Re, Efficacy of Chlorhexidine against Some Strains of Cultured and Clinically Isolated Microorganisms, V R C. 2000, 24: 229-238
74. Randy Schueller, Petty Romanowski. Conditioning agents for hair and skin. Cosmetics & Toiletries .1995, 8 (110): 43-47
75. Russell A D. Chlorhexidine: antibacterial action and bacterial resistance. Infection. 1986,14:212-215
76. Scott D W. Antifungal therapy Muller & Kirk's Small Animal Dermatology, 6th Ed (D W Scott et al, eds.). W B Saunders, Philadelphia, Pa., 2001; 336-422, 409-415
77. Shryock T R. NCCLS quality control values for veterinary use fluoroquinolones. J of CM. 2001,39(4): 1680-1681
78. Swaim S F, Riddell K P, Geiger D L, Hatchcock T L and McGuire J A. Evaluation of surgical scrub and antiseptic solutions for surgical preparation of canine paws. J A V M A. 1998, 1941-1945
79. Timo Pesonen, Jussi Holmalahti, Juhani Pohjola. Determination of chlorhexidine in saliva using high-performance liquid chromatography, J of Chromato B. 1995, 665:222-225
80. Van Cutsem J. The antiinflammatory effects of ketoconazole. J Am Acad Dermatol. 1991, 25(2): 257-261
81. Willard M D. Ketoconazole induced changes in selected canine hormone concentrations. A J V R. 1986, 47 (12): 2504-2509
82. Y W Francis Lam, Daniel C.N.Chan, Sandra Y.Rodriguez, John H.Lintakoon, Thu Hong Lam. Sensitive high-performance liquid chromatography assay for the determination of chlorhexidine in saliva, J of Chromato. 1993, 612:166-171