Optimization of sulfobutyl-ether-β-cyclodextrin levels in oral formulations to enhance progesterone bioavailability
Optimization of sulfobutyl-ether-β-cyclodextrin levels in oral formulations to enhance progesterone bioavailability
复制标题
DOI：
10.1016/j.ijpharm.2021.120212
复制
发表时间：
2021-02-04
影响因子：
5.8
通讯作者：
Murthy, S. Narasimha
中科院分区：
文献类型：
--
作者：
Shankar, Vijay Kumar;Police, Anitha;Murthy, S. Narasimha
黄体期缺乏症和雌激素优势症的治疗应采用口服黄体酮方案。黄体酮的水溶性较差，导致口服吸收不稳定，导致血浆水平不理想或过高。开发一种提高黄体酮在胃肠道中的溶解度的制剂将有助于减少药物吸收变异性和提高生物利用度。在400 mM的浓度下，孕酮的溶解度比其固有溶解度大7000倍，形成了sbe - β - cd -孕酮复合物。采用差示扫描比色计、傅里叶变换红外（FTIR）和核磁共振（NMR）技术对配合物进行了表征。配合物的FTIR和NMR研究证实了sbe - β - cd的官能团与黄体酮之间的相互作用，形成包合物。分子模型研究表明黄体酮与四种可能的sbe - β - cd异构体结合，这些结果与NMR和FTIR数据相匹配。通过提高制剂中sbe - β - cd的含量来优化黄体酮口服制剂，以防止黄体酮被胃肠道内容物排出复合物。黄体酮在大鼠体内的口服生物利用度与黄体酮API胶囊相比提高了5倍。研究表明，优化后的配方可以防止黄体酮在肠道中的沉淀，提高黄体酮在大鼠体内的口服生物利用度。
Progesterone oral dose regimens are indicated for the treatment of luteal phase deficiency and estrogen dominance. The poor aqueous solubility of progesterone leads to erratic oral absorption, resulting in suboptimal or excessive plasma levels. Developing a formulation to enhance the solubility of progesterone in the gastrointestinal tract would be beneficial to decrease drug absorption variability and increase bioavailability. The solubility of progesterone at 400 mM sulfobutyl-ether-beta-cyclodextrin (SBE-beta-CD) concentration was similar to 7000-fold greater than its intrinsic solubility, aided by the formation of SBE-beta-CD-progesterone complex. The complex was characterized using differential scanning colorimeter, Fourier-transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy techniques. FTIR and NMR studies of the complex confirm the interaction between functional groups of SBE-beta-CD and progesterone to form an inclusion complex. Molecular modeling studies demonstrated progesterone binding poses with four probable SBE-beta-CD isomers and these results matched with NMR and FTIR data. The progesterone oral formulations were optimized by increasing the levels of SBE-beta-CD in the formulation to prevent the displacement of progesterone from the complex by gastrointestinal contents. The oral bioavailability of progesterone in rats was increased 5-fold when administered with the optimized formulation compared to administration with progesterone API capsules. Studies demonstrated that the optimized formulation prevents precipitation of progesterone in the intestinal tract and increases progesterone oral bioavailability in rats.