Shah Vidhi, Sharma Mukesh, Pandya Radhika, Parikh Rajesh K, Bharatiya Bhavesh, Shukla Atindra, Tsai Hsieh-Chih
Department of Pharmaceutics and Pharmaceutical Technology, L. M. College of Pharmacy, Ahmedabad 380009, Gujarat, India.
Shah-Schulman Center for Surface Science and Nanotechnology, Dharmsinh Desai University, Nadiad 387001, Gujarat, India.
Mater Sci Eng C Mater Biol Appl. 2017 Jun 1;75:1231-1241. doi: 10.1016/j.msec.2017.03.002. Epub 2017 Mar 3.
The present study illustrates the application of the concept of Quality by Design for development, optimization and evaluation of Lorazepam loaded microemulsion containing ion responsive In situ gelator gellan gum and carbopol 934. A novel approach involving interactions between surfactant and polymer was employed to achieve controlled drug release and reduced mucociliary clearance. Microemulsion formulated using preliminary solubility study and pseudo ternary phase diagrams showed significantly improved solubilization capacity of Lorazepam with 54.31±6.07nm droplets size. The effect of oil to surfactant/cosurfactant ratio and concentration of gelling agent on the drug release and viscosity of microemulsion gel (MEG) was evaluated using a 3 full factorial design. The gel of optimized formulation (MEG) showed a drug release up to 6h of 97.32±1.35% of total drug loaded. The change in shear-dependent viscosity for different formulations on interaction with Simulated Nasal Fluid depicts the crucial role of surfactant-polymer interactions on the gelation properties along with calcium ions binding on the polymer chains. It is proposed that the surfactant-polymer interactions in the form of a stoichiometric hydrogen bonding between oxyethylene and carboxylic groups of the polymers used, provides exceptional ME stability and adhesion properties. Compared with the marketed formulation, optimized MEG showed improved pharmacodynamic activity. Ex vivo diffusion studies revealed significantly higher release for MEG compared to microemulsion and drug solution. MEG showed higher flux and permeation across goat nasal mucosa. According to the study, it could be concluded that formulation would successfully provide the rapid onset of action, and decrease the mucociliary clearance due to formation of in situ gelling mucoadhesive system.
本研究阐述了质量源于设计理念在含离子响应性原位凝胶剂结冷胶和卡波姆934的劳拉西泮微乳剂研发、优化及评价中的应用。采用一种涉及表面活性剂与聚合物相互作用的新方法来实现药物的控释并降低黏液纤毛清除率。通过初步溶解度研究和伪三元相图制备的微乳剂显示，劳拉西泮的增溶能力显著提高，液滴尺寸为54.31±6.07nm。采用三因素全因子设计评估油相与表面活性剂/助表面活性剂比例以及胶凝剂浓度对微乳凝胶（MEG）药物释放和黏度的影响。优化制剂（MEG）的凝胶在6小时内释放了总载药量的97.32±1.35%。不同制剂与模拟鼻液相互作用时剪切依赖性黏度的变化表明，表面活性剂-聚合物相互作用以及聚合物链上钙离子的结合对胶凝特性起着关键作用。据推测，所用聚合物的氧乙烯基与羧基之间以化学计量氢键形式存在的表面活性剂-聚合物相互作用提供了优异的微乳稳定性和黏附性能。与市售制剂相比，优化后的MEG显示出更好的药效学活性。体外扩散研究表明，MEG的释放量明显高于微乳剂和药物溶液。MEG在山羊鼻黏膜上表现出更高的通量和渗透率。根据该研究可以得出结论，该制剂能够成功实现快速起效，并由于形成原位凝胶黏附系统而降低黏液纤毛清除率。
