酮康唑生物粘附性阴道片的研究
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摘要
酮康唑是第一个可用于口服的咪唑类抗真菌药，它通过抑制麦角甾醇的生物合成，使真菌细胞膜的通透性增加无法维持正常功能，最后抑制真菌生长或使真菌死亡。临床上主要用于治疗各种浅部和深部真菌病，在癌症辅助治疗、治疗抑郁症和内分泌失调等方面也有一定效果。该药口服后对肝脏有损害，不良反应发生率较高，用作系统性治疗上有被取代的趋势，但仍是治疗浅表性真菌感染的推荐药物。将其制成局部给药剂型，可提高用药部位的药物浓度，减少毒副作用。本文首先对几种常用的生物粘附材料的粘附性、溶胀性进行考察，在此基础上筛选合适的粘附材料；采用粉末直接压片法制备酮康唑生物粘附性阴道片，对片剂处方、制备工艺、质量控制项目进行研究，从而选出较优处方。
以Carbopol 934P，Carbopol 974P，HPMC(K4M)，HPC为粘附剂，碳酸氢钠和柠檬酸为泡腾剂，制备空白粘附片。以溶胀速率和粘附力为指标，考察粘附剂用量、泡腾剂用量对空白粘附片粘附性能的影响。结果表明，不添加泡腾剂情况下，Cabopol的粘附力和溶胀速率均大于HPC和HPMC；加入泡腾剂，空白片粘附力下降，溶胀速率增加。增加泡腾剂用量，对HPC的粘附力无影响，但使Carbopol 974P、Carbopol 934P和HPMC的粘附力下降，且Carbopol 974P比Carbopol 934P下降更多。
分别建立紫外分光光度法和高效液相色谱法测定酮康唑的药物浓度，用于含量及释放度测定，经方法学验证，适用于本品的体外质量控制。测定了酮康唑在0.1mol·L~(-1)HCl、pH3.0～7.0的缓冲液中的溶解度：酮康唑在中性及弱酸性条件下溶解度很小(4.76μg·mL~(-1)～0.375mg·mL~(-1))，pH＜3.0时溶解度显著增大(pH1时达35.17mg·mL~(-1))，表现为pH依赖性。测定了酮康唑在正辛醇／介质系统的表观油／水分配系数，logP为-0.76～1.06，在阴道pH下，酮康唑在油水两相中均有一定分配，当pH≥7.0时，在油相中的分配占优。
采用粉末直接压片法，以Carbopol 934P、Carbopol 974P、HPMC和HPC为粘附剂，柠檬酸和碳酸氢钠为泡腾剂，MCC为填充剂，微粉硅胶为助流剂，硬脂酸镁为润滑剂，分别制备不添加和添加泡腾剂的酮康唑生物粘附性阴道片。比较两类阴道片的释放度、粘附力、溶胀速率，结果表明，泡腾剂可促进阴道片的溶胀和药物释放，但使制剂粘附力下降。对含有泡腾剂的5种阴道片进行粘附性和体外释放评价，从中选出较优处方。对粉末中间体和片剂的质量控制项目和释放度影响因素进行考察，中间体和制剂质量可控，制备工艺对药物释放影响不大，处方因素和溶出装置显著影响释放。优选的处方中每片含150mg粘附剂，粘附剂中Carbopol 934P与HPC的质量比为1：9，以柠檬酸和碳酸氢钠为泡腾材料，用量100mg，两者摩尔比为1：3。制得的阴道片具有一定的粘附性，在体外能够维持24h缓慢释放，释放机制符合Fick扩散定律。
建立了反相高效液相色谱法测定大鼠血浆中酮康唑浓度的方法；以酮康唑溶液为参比，进行粘附性阴道片在大鼠体内的药动学和绝对生物利用度研究，采用3P97和统计矩法对大鼠血药浓度数据进行处理。大鼠静脉注射酮康唑后，药时曲线符合三隔室模型，酮康唑粘附性阴道片从阴道内吸收的过程属于单隔室一级吸收。静脉注射的药动学参数：Ke(0.0905±0.0158)h~(-1)；t_(1／2)(7.88±1.50)h；AUC_(0-∞)(115.73±8.91)μg·mL~(-1)·h；MRT(8.92±1.63)h；Cl(0.0185±0.0028)L·h~(-1)；V_(ss)(0.156±0.025)L。阴道给药的药动学参数：Ke(0.117±0.019)h~(-1)；t_(1／2)(6.03±0.97)h；AUC_(0-∞)(1186.0±274.1)μg·mL-~(-1)·h；MRT(35.71±1.65)h；Cl(0.0887±0.023)L·h~(-1)；V_(ss)(0.063±0.014)L。生物粘附性阴道片的绝对生物利用度≤20.7％，表明酮康唑经阴道粘膜吸收进入体循环量有限。
对酮康唑生物粘附性阴道片的用药安全性进行评价，结果表明，阴道片可使阴道pH值上升1～1.5个单位，变化不大，在机体耐受范围内。大鼠阴道给予10倍临床使用剂量的阴道片，大鼠活动正常，体重增加，无一死亡，未见动物毒性反应。用家兔进行皮肤刺激性实验，连续7d给予粘附性阴道片和空白粘附片，结果空白粘附片对皮肤有轻微的刺激性，而阴道片对皮肤无刺激性。大鼠单次及多次阴道给予4倍临床剂量的粘附性阴道片，取阴道组织观察，肉眼未见有充血、水肿、增生、坏死等现象，病理组织照片显示阴道粘膜上皮细胞，可见间质水肿，血管扩张充血，有一些淋巴细胞、浆细胞、少量中性粒细胞、少量嗜酸性粒细胞浸润，呈轻度炎症，属于正常的异物反应，具有可恢复性，实验结果证明酮康唑生物粘附性阴道片对阴道无刺激性。
Ketoconazole is an imidazole antifungal agent which is administered topically or by mouth. It is given by mouth in chronic mucocutaneous candidiasis, fungal infections of the gastro-intestinal tract, and dermatophyte infections of the skin and fingernails. Since high doses of ketoconazole have been reported to inhibit the synthesis of adrenal and testicular steroids, it has been investigated in the treatment of various endocrine disorders and malignant neoplasms. However, because of the risk of hepatotoxicity with ketoconazole, its place is now being challenged by newer azole antifungal agents such as fluconazole and itraconazole which are better tolerated. Though its use in systemic fungal infections tends to be restricted, it is still recommended to apply topically. In this study, the bioadhesive strength to mucosa and swelling state of several polymers were investigated to choose the suitable bioadhesives. The Ketoconazole bioadhesive vaginal tablets (KBVT) prepared using powder by direct compression. The factors contributing to bioadhesive behaviour and drug release were studied.The blank adhesive tablets with different composition of Carbopol 934P, Carbopol 974P, HPMC(K4M), HPC, sodium bicarbonate and citric acid were prepared and the adhesive characteristics such as adhesive force, swelling rate were determined. The results showed that the adhesive force and swelling rate of Carbopol tablets were greater than HPC and HPMC ones, while adhesive tablets were not added effervescents. The effervescents, composed by sodium bicarbonate and citric acid, can decreased the adhesive force of adhesive tablets, while increase the swelling. In addition, to increase the ratio of effervescents in tablets, it has no effect on the bioadhesive force of HPC, but can weaken adhesive strength of HPMC, Carbopol 934P and Carbopol 974P, and Carbopol 974P was affected more significantly.HPLC and ultraviolet spetrophotometry were developed for assaying the content in the preparation and drug release from ketoconazole bioadhesive vaginal tablets (KBVT), respectively. According to the solubility of ketoconazole determined in different medium, when pH>3.0, the solubility is poor, and when pH is declined beneath 3.0, the solubility showed increasing significantly. The apparent partition coefficient of ketoconazole in n-octanol/medium system was dertermined, and the logP was -0.76～1.06. The data of apparent partition coefficient showed ketocozole existed in both water and n-octanol at pH value of 4.0～5.0.
To take Carbopol 934P, Carbopol 974P, HPMC, HPC as bioadhesives, MCC as diluent, aerosil as glidant, magnesium stearate as lubricant prepared two kinds of KBVT, one with effervescents and the other without. The drug release, adhesion strength and swelling rate of the two kinds of tablets were investigated. The results showed that effervescents employed in formulation made advantages of drug release and swelling, but declined adhesive strength. An optimum formulation was chosen from five formulations by evaluating their adhesive forces and drug releases. The influence factors on the release of KBVT were investigated and the results demonstrated that the preparing methods had no effect on drug releasing, but the composition of formulations and dissolution devices affected releasing. The optimum formulation contained 150mg adhesives which composed of Carbopol 934P and HPC, with weight fraction of 1:9, and contained 100mg effervescents which composed of sodium bicarbonate and citric acid, with moler ratio of 3:1. The drug release showed obviously sustained-released effect, and the release profiles in vitro followed the Fick low.
The pharmacokinetics of KBVT and ketoconazole solution in rats were investigated. The absolute bioavailability of KBVT was also evaluated. The plasma concentration-time data were analyzed by 3p97 program and non-compartmental model. It was found that the plasma concentration-time curve of ketoconazole solution was fitted into a three-compartment model, while the absorption of KBVT from vagina was fitted into a one-compartent absorption model. The main pharmacokinetic parameters of iv ketoconazole were Ke(0.0905±0.0158)h~(-1); t_(1/2)(7.88±1.50)h; AUC_(0-∞) (115.73±18.91)μg·mL~(-1)·h; MRT(8.92±1.63)h; Cl(0.0185±0.0028)L·h~(-1); V_(ss)(0.156±0.025)L. The main pharmacokinetic parameters of KBVT were Ke(0.117±0.019)h~(-1); t_(1/2)(6.03±0.97)h; AUC_(0-∞)(1186.0±274.1)μg-mL~(-1)·h; MRT(35.71±1.65)h; Cl(0.0887±0.023) L·h~(-1); V_(ss)(0.063±0.014)L. The absolute bioavailability of KBVT was less than or equal to 20.7%. It demonstrates that ketoconazole was absorbed poorly at vaginal mucosa.
The safety of KBVT was investigated that the preparation has not any toxic reaction under the given dose. The stimulation tests show that KBVT does no stimulation to the skin and vagina mucosa.
以Carbopol 934P，Carbopol 974P，HPMC(K4M)，HPC为粘附剂，碳酸氢钠和柠檬酸为泡腾剂，制备空白粘附片。以溶胀速率和粘附力为指标，考察粘附剂用量、泡腾剂用量对空白粘附片粘附性能的影响。结果表明，不添加泡腾剂情况下，Cabopol的粘附力和溶胀速率均大于HPC和HPMC；加入泡腾剂，空白片粘附力下降，溶胀速率增加。增加泡腾剂用量，对HPC的粘附力无影响，但使Carbopol 974P、Carbopol 934P和HPMC的粘附力下降，且Carbopol 974P比Carbopol 934P下降更多。
分别建立紫外分光光度法和高效液相色谱法测定酮康唑的药物浓度，用于含量及释放度测定，经方法学验证，适用于本品的体外质量控制。测定了酮康唑在0.1mol·L~(-1)HCl、pH3.0～7.0的缓冲液中的溶解度：酮康唑在中性及弱酸性条件下溶解度很小(4.76μg·mL~(-1)～0.375mg·mL~(-1))，pH＜3.0时溶解度显著增大(pH1时达35.17mg·mL~(-1))，表现为pH依赖性。测定了酮康唑在正辛醇／介质系统的表观油／水分配系数，logP为-0.76～1.06，在阴道pH下，酮康唑在油水两相中均有一定分配，当pH≥7.0时，在油相中的分配占优。
采用粉末直接压片法，以Carbopol 934P、Carbopol 974P、HPMC和HPC为粘附剂，柠檬酸和碳酸氢钠为泡腾剂，MCC为填充剂，微粉硅胶为助流剂，硬脂酸镁为润滑剂，分别制备不添加和添加泡腾剂的酮康唑生物粘附性阴道片。比较两类阴道片的释放度、粘附力、溶胀速率，结果表明，泡腾剂可促进阴道片的溶胀和药物释放，但使制剂粘附力下降。对含有泡腾剂的5种阴道片进行粘附性和体外释放评价，从中选出较优处方。对粉末中间体和片剂的质量控制项目和释放度影响因素进行考察，中间体和制剂质量可控，制备工艺对药物释放影响不大，处方因素和溶出装置显著影响释放。优选的处方中每片含150mg粘附剂，粘附剂中Carbopol 934P与HPC的质量比为1：9，以柠檬酸和碳酸氢钠为泡腾材料，用量100mg，两者摩尔比为1：3。制得的阴道片具有一定的粘附性，在体外能够维持24h缓慢释放，释放机制符合Fick扩散定律。
建立了反相高效液相色谱法测定大鼠血浆中酮康唑浓度的方法；以酮康唑溶液为参比，进行粘附性阴道片在大鼠体内的药动学和绝对生物利用度研究，采用3P97和统计矩法对大鼠血药浓度数据进行处理。大鼠静脉注射酮康唑后，药时曲线符合三隔室模型，酮康唑粘附性阴道片从阴道内吸收的过程属于单隔室一级吸收。静脉注射的药动学参数：Ke(0.0905±0.0158)h~(-1)；t_(1／2)(7.88±1.50)h；AUC_(0-∞)(115.73±8.91)μg·mL~(-1)·h；MRT(8.92±1.63)h；Cl(0.0185±0.0028)L·h~(-1)；V_(ss)(0.156±0.025)L。阴道给药的药动学参数：Ke(0.117±0.019)h~(-1)；t_(1／2)(6.03±0.97)h；AUC_(0-∞)(1186.0±274.1)μg·mL-~(-1)·h；MRT(35.71±1.65)h；Cl(0.0887±0.023)L·h~(-1)；V_(ss)(0.063±0.014)L。生物粘附性阴道片的绝对生物利用度≤20.7％，表明酮康唑经阴道粘膜吸收进入体循环量有限。
对酮康唑生物粘附性阴道片的用药安全性进行评价，结果表明，阴道片可使阴道pH值上升1～1.5个单位，变化不大，在机体耐受范围内。大鼠阴道给予10倍临床使用剂量的阴道片，大鼠活动正常，体重增加，无一死亡，未见动物毒性反应。用家兔进行皮肤刺激性实验，连续7d给予粘附性阴道片和空白粘附片，结果空白粘附片对皮肤有轻微的刺激性，而阴道片对皮肤无刺激性。大鼠单次及多次阴道给予4倍临床剂量的粘附性阴道片，取阴道组织观察，肉眼未见有充血、水肿、增生、坏死等现象，病理组织照片显示阴道粘膜上皮细胞，可见间质水肿，血管扩张充血，有一些淋巴细胞、浆细胞、少量中性粒细胞、少量嗜酸性粒细胞浸润，呈轻度炎症，属于正常的异物反应，具有可恢复性，实验结果证明酮康唑生物粘附性阴道片对阴道无刺激性。
Ketoconazole is an imidazole antifungal agent which is administered topically or by mouth. It is given by mouth in chronic mucocutaneous candidiasis, fungal infections of the gastro-intestinal tract, and dermatophyte infections of the skin and fingernails. Since high doses of ketoconazole have been reported to inhibit the synthesis of adrenal and testicular steroids, it has been investigated in the treatment of various endocrine disorders and malignant neoplasms. However, because of the risk of hepatotoxicity with ketoconazole, its place is now being challenged by newer azole antifungal agents such as fluconazole and itraconazole which are better tolerated. Though its use in systemic fungal infections tends to be restricted, it is still recommended to apply topically. In this study, the bioadhesive strength to mucosa and swelling state of several polymers were investigated to choose the suitable bioadhesives. The Ketoconazole bioadhesive vaginal tablets (KBVT) prepared using powder by direct compression. The factors contributing to bioadhesive behaviour and drug release were studied.The blank adhesive tablets with different composition of Carbopol 934P, Carbopol 974P, HPMC(K4M), HPC, sodium bicarbonate and citric acid were prepared and the adhesive characteristics such as adhesive force, swelling rate were determined. The results showed that the adhesive force and swelling rate of Carbopol tablets were greater than HPC and HPMC ones, while adhesive tablets were not added effervescents. The effervescents, composed by sodium bicarbonate and citric acid, can decreased the adhesive force of adhesive tablets, while increase the swelling. In addition, to increase the ratio of effervescents in tablets, it has no effect on the bioadhesive force of HPC, but can weaken adhesive strength of HPMC, Carbopol 934P and Carbopol 974P, and Carbopol 974P was affected more significantly.HPLC and ultraviolet spetrophotometry were developed for assaying the content in the preparation and drug release from ketoconazole bioadhesive vaginal tablets (KBVT), respectively. According to the solubility of ketoconazole determined in different medium, when pH>3.0, the solubility is poor, and when pH is declined beneath 3.0, the solubility showed increasing significantly. The apparent partition coefficient of ketoconazole in n-octanol/medium system was dertermined, and the logP was -0.76～1.06. The data of apparent partition coefficient showed ketocozole existed in both water and n-octanol at pH value of 4.0～5.0.
To take Carbopol 934P, Carbopol 974P, HPMC, HPC as bioadhesives, MCC as diluent, aerosil as glidant, magnesium stearate as lubricant prepared two kinds of KBVT, one with effervescents and the other without. The drug release, adhesion strength and swelling rate of the two kinds of tablets were investigated. The results showed that effervescents employed in formulation made advantages of drug release and swelling, but declined adhesive strength. An optimum formulation was chosen from five formulations by evaluating their adhesive forces and drug releases. The influence factors on the release of KBVT were investigated and the results demonstrated that the preparing methods had no effect on drug releasing, but the composition of formulations and dissolution devices affected releasing. The optimum formulation contained 150mg adhesives which composed of Carbopol 934P and HPC, with weight fraction of 1:9, and contained 100mg effervescents which composed of sodium bicarbonate and citric acid, with moler ratio of 3:1. The drug release showed obviously sustained-released effect, and the release profiles in vitro followed the Fick low.
The pharmacokinetics of KBVT and ketoconazole solution in rats were investigated. The absolute bioavailability of KBVT was also evaluated. The plasma concentration-time data were analyzed by 3p97 program and non-compartmental model. It was found that the plasma concentration-time curve of ketoconazole solution was fitted into a three-compartment model, while the absorption of KBVT from vagina was fitted into a one-compartent absorption model. The main pharmacokinetic parameters of iv ketoconazole were Ke(0.0905±0.0158)h~(-1); t_(1/2)(7.88±1.50)h; AUC_(0-∞) (115.73±18.91)μg·mL~(-1)·h; MRT(8.92±1.63)h; Cl(0.0185±0.0028)L·h~(-1); V_(ss)(0.156±0.025)L. The main pharmacokinetic parameters of KBVT were Ke(0.117±0.019)h~(-1); t_(1/2)(6.03±0.97)h; AUC_(0-∞)(1186.0±274.1)μg-mL~(-1)·h; MRT(35.71±1.65)h; Cl(0.0887±0.023) L·h~(-1); V_(ss)(0.063±0.014)L. The absolute bioavailability of KBVT was less than or equal to 20.7%. It demonstrates that ketoconazole was absorbed poorly at vaginal mucosa.
The safety of KBVT was investigated that the preparation has not any toxic reaction under the given dose. The stimulation tests show that KBVT does no stimulation to the skin and vagina mucosa.
引文
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[19] 程群，黄缨，罗爱鄢．念珠菌性外阴阴道炎研究概况[J]．光明中医，2004，20(1)：26-29
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[54] 陈绳林，张川，刘琦等．酮康唑及其栓剂在山羊体内的药代动力学研究[J]，第二军医大学学报，1998，19(4)：367～369．
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[56] 胡晓渝，杨雄志．酮康唑对沙奎那韦体外代谢和药物代谢动力学的影响[J]，安徽医药，2005．9(11)：808～809．
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[59] 《化学药物刺激性、过敏性和溶血性研究技术指导原则》：《化学药物刺激性、过敏性和溶血性研究技术指导原则》课题研究组，2005，3．
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[15] 陆继伟，裴元英．阴道给药系统的剂型发展[J]．中国临床药学杂志，2003，12(2)：123-127．
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[19] 程群，黄缨，罗爱鄢．念珠菌性外阴阴道炎研究概况[J]．光明中医，2004，20(1)：26-29
[20] 王健．生物粘附材料的研究进展[J]．沈阳药科大学学报，2002，19(5)：373-380．
[21] 陈庆才，邵志高，王爱琴等．酮康唑阴道粘附缓释片的研制与体内释药分析[J]．南京医学院学报，1992，12(4)：371-375．
[22] 杜青，平其能，刘国杰．影响卡波姆-羟丙基甲基纤维素粘附片粘附性质的因素考察[J]．中国医院药学杂志，2002，22(12)：709-711．
[23] KAST E C, VALENTA C, MARTINA, et al. Design and in vitro evaluation of a navel bioadhesive vaginal drug delivery system for clotrimazole[J]. J Controlled Realease, 2002, 81: 347-354.
[24] AHUJA A, KHAR K R, ALI J. Mucoadhesive drug delivery system[J]. DrugDev Ind Pharm. 1997, 23(5): 489-515.
[25] BALOGLU E, OZYAZICI M, HIZARCIOGLU Y S, et al. An in vitro investigation for vaginal bioadhesive formulations: bioadhesive properties and swelling states of polymer mixtures[J]. Il Farmco, 2003, 58: 391-396.
[26] Duchene D, Touchard F, Peppas NA. Pharmaceutical and medical aspects of bioadhesive systems for drug administration[J]. Drug Dev Ind Pharm. 1988, 14(2-3): 283-313.
[27] Longer MA，Robinson JR．生物粘合的基本原理[J]．国外医学·药学分册，1986，6：367．
[28] 王大林，盛坤贤．生物粘附与粘膜粘贴剂的进展[J]．国外医药·合成药、生化药、制剂分册，1989，10(4)：224．
[29] 平其能等．现代药剂学[M]．北京：中国医药科技出版社，1998，1-9．
[30] N P Chotai. The effect of disintegrates and pH on disintegration of vaginal tablets[J], Indian Drugs, 1993, 31: 122-124.
[31] Ahuja A, Khar K R, Ali J. Mucoadhesive drug delivery system[J]. Drug Development and Industrial Pharmacy. 1997, 23(5): 489-515.
[32] 郑俊民主编．经皮给药新剂型[M]．北京：人民卫生出版社，1997，255．
[33] M T Esclusa-Diaz, M Guimaraens-Mendez, M B Perez-Marcos et al[J]. Int J Pharm. 1996, 143: 203-210.
[34] 梁文权主编．生物药剂学与药物动力学[M]．北京：人民卫生出版社，2003，23．
[35] Moore W J, FLANNER H H. Mathematical comparison of dissolution profiles[J]. Pharm. Tech, 1996, 6: 64-74.
[36] Wan LSC, Heng PWS, Wong LF. The effect of hydroxypropyl on water penetration into a matrix system [J]. Int J Pharm, 1991, 73(2): 111-116
[37] Wan LSC, Heng PWS, Wong LF. Relationship between swelling and drug release in a hydrophilic matrix [J]. Drug Dev Ind Pharm, 1993, 19(10): 1201-1210.
[38] Bettini R, Colombo P, Massimo G, et al. Sweelling and drug release in hydrogel matrices: polymer viscosity and matrix porosity effect [J]. Eur J Pharm Sci, 1994, 2(3): 213-219.
[39] Sujja-areevath J, Munday DL, Coxetal PJ. Relationship between sweeling, erosion and drug release in hydrophilic natural gum mini-matrix forMulation [J]. Eur J Pharm Sci, 1998, 6(3): 207-217
[40] Colombo P, Bettini R, Massimo G, et al. Drug diffusioin front movement is important in drug release control from swellable matrix tablets [J]. J Pharm Sci, 1995, 84(8): 991-997
[41] Wan LSC, Heng PWS, Wong LF. Matrix swelling: A simple model describing extent of swelling of HPMC matrices [J]. Int J Pharm, 1995, 116(2): 159-168
[42] Colombo P. Swellable matrices for oral controlled release: an update on delivery mechanism [J]. Eur J Pharm Sci, 1998, 6(suppl. 1): 11-15
[43] Dredan J, Antal 1, Racz 1. Evaluation of mathematical models describing drug release from lopopilic matrices [J]. Int J Pharm, 1996, 145: 61-64
[44] Upadrasha SM, Katikaneni PR, Hileman GA, et al. Direct compression controlled release tablets using ethyl cellμlose matrices [J]. Drug Dev Int Pharm, 1993, 19: 449-460
[45] 陆彬主编．药物新剂型与新技术[M]．北京：人民卫生出版社，1998，218-225
[46] Kormeyer RW, Gurny R, Doelker E, et al. Mechanisms of solute release from porous hydrophilic polymer [J]. Int J Pharm, 1983, 15(1): 25-35.
[47] Ritger PL, Peppas NA. A simple equation for description of solute release. Ⅰ. Fickian and non-Fickian release from non-swellable devices [J]. J Control Release, 1987, 5(1): 23-26.
[48] Ritger PL, Peppas NA. A simple equation for description of solute release. Ⅱ. Fickian and anomalous release from swellable devices [J], J Control Release, 1987, 5(1): 37-42.
[49] 董志超，蒋雪涛．HPMC的物理性质对口服骨架型制剂释放的影响[J]．国外医药-合成药、生化药、制剂分册，1995，16(2)：103-105
[50] 何林，蒋学华，李芚．粘膜给药系统质量评价[J]．中国药学杂志，1998，33(2)：68-72．
[51] Gilles P, Frederic T, Denis W et al. Bioahesive analysis of controlled-released system. Ⅲ. Bioadhesive and release behavior of metronidazole-containing poly(acrylic acid)-hydroxypropyl methylcellulose systems[J]. Int J Pharm, 1987, 38: 65-70.
[52] Maclean-McDavitt DS, Roberson J D, Jay M. Monitoring the in vivo delivery of proteins from carbomer hydrogels by X-ray fluorescence[J]. Pharm Res. 2003, 20(3): 435-441.
[53] 张兴英，李其芳．高分子科学实验[M1．北京：化学工业出版社，2002：202．
[54] 陈绳林，张川，刘琦等．酮康唑及其栓剂在山羊体内的药代动力学研究[J]，第二军医大学学报，1998，19(4)：367～369．
[55] 王汝琴，康建功，刘树刚，酮康唑的不良反应[J]，现代中西医结合杂志，1999，8(9)：1391～1392．
[56] 胡晓渝，杨雄志．酮康唑对沙奎那韦体外代谢和药物代谢动力学的影响[J]，安徽医药，2005．9(11)：808～809．
[57] K. Vermani, S. Garg. The scope and potential of vaginal drug delivery[J]. PSTT, 2000(3): 359-364.
[58] 刘婕，马凤荣，付连英等．正常人与阴道炎病人阴道微生物的分析[J]．中国微生态学杂志，1994，6(5)：62-62．
[59] 《化学药物刺激性、过敏性和溶血性研究技术指导原则》：《化学药物刺激性、过敏性和溶血性研究技术指导原则》课题研究组，2005，3．
[60] 《中药、天然药物刺激性和溶血性研究的技术指导原则》：《中药、天然药物刺激性和溶血性研究的技术指导原则》课题研究组，2005，3．