【作者】 杨洪斌；

【导师】 胡一桥；

【作者基本信息】 南京大学 ， 制药工程（专业学位）， 2013， 硕士

【摘要】 硝酸咪康唑是属于咪唑类的抗真菌药物,主要治疗真菌引起的感染。它也经常用于治疗阴道念珠菌病。市场上含有硝酸咪康唑的阴道制剂主要有片剂,膏剂,胶囊剂和栓剂,但是这些传统制剂都有泄漏、弄脏衣服等缺点,而且还导致了滞留时间短,药物分散等的问题。基于此,本实验制作了能改善这些缺点的硝酸咪康唑阴道温敏型凝胶,这种新型凝胶在一定程度上能弥补传统制剂的一些不足。处方前研究主要对辅料的某些性质做了考察如吸湿性的考察,辅料间相容性的考察以及原辅料之间相容性的考察。同时,考察了硝酸咪康唑的稳定性,初步建立了用高效液相色谱法来进行分析其有关物质和含量测定。通过溶液的沉降体积比、溶液的粘度、相变温度、稳定性等筛选处方。如当泊洛沙姆407与羟丙甲基纤维素混在一起时,发现羟丙甲基纤维素的粘度便降低或消失了；海藻酸钠具有很好的相容性,但是在低温或常温长期放样时,发现药物非常容易析出。进过处方筛选,最后处方的组成是：1.9%羧甲基纤维素钠800-1200,16.8%泊洛沙姆407,5%泊洛沙姆188,5%的甘油,4%硝酸咪康唑,适量的水。同时,对制剂的工艺也做了必要研究,实验证明,只有当将助悬剂与泊洛沙姆进行分开溶胀,然后让硝酸咪康唑先与泊洛沙姆进行预混,出去药物表面的水膜,并且静置,待气泡散尽后再与助悬剂溶液混合。这样才可保证混悬剂的稳定和溶液中没有小气泡。在样品制备好之后,通过对其性状、离心实验、粘附力、沉降体积比、含量、有关物质和释放等做了评价,从而建立了硝酸咪康唑阴道温敏型凝胶的质量标准。对于硝酸咪康唑的分析方法充分参考了最新的各个国家的药典,发现美国药典和中国药典2010版的记载大体相同。在具体的液相条件摸索中选择了含量测定的条件为药典的条件甲醇：乙腈：1.5%乙酸铵=40：40：20;而有关物质条件由于分离度要大于10,且所有的有关物质要分开,最后选择了有关物质的分析方法为甲醇：乙腈：1.5%乙酸铵=40：35：25。释放没有采用美国食品药品监督推荐的Franz池的释放方法,因为其容积太小,虽然转篮法可以满足将单位剂量的药物装进去,但是空间也太狭窄,影响了药物的释放,最后使用了自制的改良的桨法。溶出介质参照美国药典,但是由于制剂,方法以及药物性质本身的原因提高了十二烷基硫酸钠的浓度,通过和国内已上市的含硝酸咪康唑的阴道制剂做释放对比,发现硝酸咪康唑阴道温敏型凝胶确实具有缓释的功能。实验还考察了制剂的稳定性,发现在遇到强碱或氧化时药物容易降解出现各种杂质,这为包装和储存提供了参考价值。更多还原

【Abstract】 Miconazole Nitrate(MN) is an imidazole antifungal agent, commonly used to treat fungal infections. It is also an therapeutic agent that can be used for treatment of vaginal candidiasis(VC).There are several vaginal formulations contained Miconazole Nitrate,such as tablets,creams,capsules,suppositories,however,they have some limitations:leakage,messiness,leading to short time of retention and distribution.Finally,a novel vaginal dosage form has been designed and developed which can meet these requirements,the new formulation is thermosensitive vaginal gel.In preformulation firstly investigated excipients properties of moisture absorption, in addition,the compatibilities have been researched between Miconazole Nitrate and excipients.meanwhile, high performance liquid chromatography was applied to studies of the physicochemical properties of inpurity,contents,and so on.In order to select desirable formulation,the solution of sedimentation rate and adhesion and stability have been measured.we found that when poloxamer407mixed with hydroxypropylmethylcellulose(HPMC),the viscosity of HPMC was reduced or disappeared; sodium alginate have a good compatibility,but Miconazole Nitrate was easily deposited,as the suspension liquid contained sodium alginate was placed at low-temperature environment or at room temperature for a long period of time.Finally,the better prescription was composition of1.9%sodium carboxymethyl cellulose800-1200(CMC-Na800-1200),16.8%poloxamer407,5%poloxamer188,5%glycerol,4%Miconazole Nitrate,water.meanwhile,the process of preparation of gel had been studied.it showed that suspending agent and poloxamer should separately swell, as to get rid of the surface water film,drug had to premix with liquid of poloxamer,and then mixed with solution of suspension agent.this process can ensure the stability of suspension and no small bubbles in the solution.We did some experiments to evaluate the sample,such as traits,centrifugal experiment,adhesion,sedimentation ratio,contents,release profils,etc,and then standard of quality of gel had been established.The pharmacopoeias referenced to the methods of analysis of MN were similar between the china and the united states over the world.The phase of HPLC used to determine the contents was:methanol:acetonitrile:1.5%ammonium acetate=40:40:20;and the phase of substances were:methanol: acetonitrile:1.5%ammonium acetate=40:35:25.Franz pool that FDA recommended and basket method were not adopted to evaluate the drug release,because their volumes were too small,finally,the improvement paddle method had been applied.Due to the formulation and methods were different with FDA,the concentration of dissolution medium contained SDS had been increase. The result of release profile of the in stiu gel showed that it had good sustained release compare to other vaginal dosage forms which contained MN.The stability of the gel had been studied,found that alkali and oxidation could increase impurities,it is valuable for packaging and storage of the prodct.更多还原