逆向工程在倍美力?结合雌激素片开发中的应用

Application of Reverse Engineering to the Development of Premarin? Binding Estrogen Tablets

关键词:  结合雌激素片  制备工艺  逆向工程  仿制药一致性评价

Key words:  conjugated estrogens tablets  preparation process  reverse engineering  generic drug consistency evaluation

摘要:

目的 基于逆向工程技术对结合雌激素片参比制剂倍美力?进行处方成分和工艺剖析,为结合雌激素片仿制药的开发提供依据。方法 通过文献调研获得结合雌激素片的处方信息；使用扫描电子显微镜(SEM)-能量色散X射线谱仪(EDS)分析片芯处方组成；通过湿法制粒和粉末直压方式制备出与参比制剂抗张强度相当的片剂并借助扫描电镜成像和宏观水化速率判断参比制剂制备工艺；按确定的片芯处方信息和工艺制备一批片剂与参比制剂进行质量和体外溶出行为对比。结果 参比制剂处方组成为:原料药(API)、磷酸钙、巴西棕榈蜡、羟丙基纤维素、羟丙甲纤维素、一水乳糖、硬脂酸镁、微晶纤维素、聚乙二醇 400、粉状纤维素、蔗糖、二氧化钛,着色剂(不同规格片剂不同颜色),片芯主要成分为:原料药(API)、微晶纤维素、磷酸钙、乳糖、羟丙甲纤维素、硬脂酸镁；通过扫描电镜二次成像和宏观水化速率初步判断参比制剂制备工艺可能为粉末直压工艺；根据逆向工程结果制备的自制制剂与参比制剂质量一致并具有相似的体外释放行为。结论 逆向工程可用于结合雌激素片仿制药的开发并制备出与参比制剂质量一致的片剂。

Abstract:

ABSTRACT: OBJECTIVE Based on the reverse engineering technology, we analyzed the formulation composition and process of the reference formulation of Premarin?, a combination of estrogen tablets, to provide a basis for the development of the generic version of the combination of estrogen tablets. METHODS Literature research was conducted to obtain the formulation information of estrogen-binding tablets; scanning electron microscopy -energy dispersive X-ray spectrometry was used to analyze the composition of the tablet core; tablets with comparable tensile strengths to the reference formulation were prepared by wet granulation and powder direct compression, and the process of reference formulation was determined by scanning electron microscopy imaging and macroscopic hydration rate; a batch of tablets was produced in accordance with the determined core formulation information and process to compare the quality and in vitro dissolution behavior of the tablets with the reference formulation. A batch of tablets was produced according to the determined core formulation information and process and compared with the reference formulation in terms of quality and in vitro dissolution behavior. RESULTS Composition of the reference formulation: API, calcium phosphate, carnauba wax, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, powdered cellulose, sucrose, titanium dioxide, coloring agent (different specifications of different colors of the tablets), the core of the tablets main ingredients: API, microcrystalline cellulose, calcium phosphate, lactose, hydroxypropylmethyl cellulose, magnesium stearate. cellulose, magnesium stearate; the reference preparation process may be a powder direct compression process as preliminarily determined by scanning electron microscopy secondary imaging and macroscopic hydration rate; the homemade formulation prepared based on the reverse engineering results was consistent in quality and had similar in vitro release behavior with the reference formulation. CONCLUSIONS Reverse engineering can be used to incorporate the development of generic estrogen tablets and prepare tablets of consistent quality with the reference formulation.