Chonkar Ankita D, Rao J Venkat, Managuli Renuka S, Mutalik Srinivas, Dengale Swapnil, Jain Prateek, Udupa N
Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka 576 104, India.
Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka 576 104, India.
Eur J Pharm Biopharm. 2016 Jun;103:179-191. doi: 10.1016/j.ejpb.2016.04.001. Epub 2016 Apr 5.
Lercanidipine is a vasoselective dihydropyridine calcium antagonist, mainly used for the treatment of hypertension and angina pectoris. However, it suffers from food dependent absorption, poor solubility, low permeability and considerable first pass metabolism, resulting in highly variable and low bioavailability of 10%. Nanoparticles of lercanidipine were incorporated in fast dissolving oral films (FDO) via preparation of nanosuspension by evaporative antisolvent precipitation method. Prepared nanosuspensions were incorporated in FDO without lyophilizing or spray drying. Two nanosuspensions containing PEG 400 and TPGS 1000 as stabilizers, were selected further for incorporation in FDO. Physicochemical and mechanical properties of the optimized films were observed to be within acceptance criteria. SEM images as well as FTIR chemical images of oral films show uniform distribution of nanoparticles in polymeric matrix. The DSC and XRD results proved the poorly crystalline nature of lercanidipine. However thermal processing of film induces crystallinity in hypromellose which results in embedding of amorphous drug nanoparticles in semicrystalline polymeric matrix. Superior dissolution and permeability properties of nanoparticles were confirmed by in vitro dissolution studies and about 4.5-folds higher ex vivo drug permeation was observed from formulation through porcine buccal mucosa. This may give the clue for enhancement of bioavailability in vivo via improving orotransmucosal absorption.
乐卡地平是一种血管选择性二氢吡啶类钙拮抗剂，主要用于治疗高血压和心绞痛。然而，它存在食物依赖性吸收、溶解度差、渗透性低以及显著的首过代谢问题，导致其生物利用度高度可变且仅为10%。通过蒸发抗溶剂沉淀法制备纳米混悬液，将乐卡地平纳米颗粒载入速溶口腔膜（FDO）中。制备的纳米混悬液无需冻干或喷雾干燥即可载入FDO。进一步选择了两种含有聚乙二醇400（PEG 400）和维生素E聚乙二醇1000琥珀酸酯（TPGS 1000）作为稳定剂的纳米混悬液载入FDO。观察到优化后薄膜的物理化学和机械性能符合验收标准。口腔膜的扫描电子显微镜（SEM）图像以及傅里叶变换红外光谱（FTIR）化学图像显示纳米颗粒在聚合物基质中分布均匀。差示扫描量热法（DSC）和X射线衍射（XRD）结果证明乐卡地平的结晶性较差。然而，薄膜的热加工会诱导羟丙甲纤维素结晶，导致无定形药物纳米颗粒嵌入半结晶聚合物基质中。体外溶出度研究证实了纳米颗粒具有优异的溶出和渗透性能，并且观察到该制剂通过猪颊黏膜的离体药物渗透比约高4.5倍。这可能为通过改善口腔黏膜吸收来提高体内生物利用度提供线索。
