Magee Womens Research Institute, Pittsburgh, PA, USA.
AIDS Res Ther. 2011 Mar 7;8:12. doi: 10.1186/1742-6405-8-12.
The objective of this study is to identify the critical formulation parameters controlling distribution and function for the rectal administration of microbicides in humans. Four placebo formulations were designed with a wide range of hydrophilic characteristics (aqueous to lipid) and rheological properties (Newtonian, shear thinning, thermal sensitive and thixotropic). Aqueous formulations using typical polymers to control viscosity were iso-osmotic and buffered to pH 7. Lipid formulations were developed from lipid solvent/lipid gelling agent binary mixtures. Testing included pharmaceutical function and stability as well as in vitro and in vivo toxicity.
The aqueous fluid placebo, based on poloxamer, was fluid at room temperature, thickened and became shear thinning at 37°C. The aqueous gel placebo used carbopol as the gelling agent, was shear thinning at room temperature and showed a typical decrease in viscosity with an increase in temperature. The lipid fluid placebo, myristyl myristate in isopropyl myristate, was relatively thin and temperature independent. The lipid gel placebo, glyceryl stearate and PEG-75 stearate in caprylic/capric triglycerides, was also shear thinning at both room temperature and 37°C but with significant time dependency or thixotropy. All formulations showed no rectal irritation in rabbits and were non-toxic using an ex vivo rectal explant model.
Four placebo formulations ranging from fluid to gel in aqueous and lipid formats with a range of rheological properties were developed, tested, scaled-up, manufactured under cGMP conditions and enrolled in a formal stability program. Clinical testing of these formulations as placebos will serve as the basis for further microbicide formulation development with drug-containing products.
本研究旨在确定控制经直肠给予人类杀微生物剂的分布和功能的关键制剂参数。设计了四种赋形剂，亲水特性（水相至脂质相）和流变学特性（牛顿流体、剪切稀化、热敏和触变）范围很广。使用典型聚合物控制粘度的水性制剂具有等渗性和 pH7 缓冲。脂质制剂是从脂质溶剂/脂质胶凝剂二元混合物开发而来的。测试包括药物功能和稳定性以及体外和体内毒性。
基于泊洛沙姆的水性流体赋形剂在室温下为流体，在 37°C 时变稠并呈剪切稀化。使用卡波姆作为胶凝剂的水性凝胶赋形剂在室温下呈剪切稀化，且随着温度的升高粘度呈典型下降趋势。肉豆蔻酸异丙酯中的肉豆蔻酸肉豆蔻酯为相对较稀且温度不依赖的脂质流体赋形剂。辛酸/癸酸三甘油酯中的甘油硬脂酸酯和 PEG-75 硬脂酸酯也是在室温下和 37°C 下呈剪切稀化，但具有显著的时间依赖性或触变性。所有制剂在兔体内均无直肠刺激，且使用离体直肠外植体模型显示无毒性。
开发了四种赋形剂，从水性和脂质制剂中的流体到凝胶，具有广泛的流变学特性。对这些制剂进行了测试、放大、按照 cGMP 条件制造，并纳入正式的稳定性计划。这些制剂作为安慰剂的临床测试将为含有药物的产品的进一步杀微生物剂制剂开发提供基础。
