rectal microbicides clinically relevant approach to the design of rectal specific placebo formulations直肠杀微生物剂临床相关的直肠特定安慰剂配方的设计方法.pdfVIP

Wang et al. AIDS Research and Therapy 2011, 8:12 /content/8/1/12 RESEARCH Open Access Rectal microbicides: clinically relevant approach to the design of rectal specific placebo formulations 1 1 1,2 3 1,2,4* Lin Wang , Roger L Schnaare , Charlene Dezzutti , Peter A Anton , Lisa C Rohan Abstract Background: 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. Results: 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. Conclusions: F