AbstractsMedical & Health Science

Development of Tenofovir Prodrugs as Rectal Microbicides for HIV Prevention

by Yafei Lyu

Institution: University of Pittsburgh
Year: 2016
Posted: 02/05/2017
Record ID: 2113654
Full text PDF: http://d-scholarship.pitt.edu/29219/1/Yafei%20thesis%20Final.pdf


Receptive anal intercourse is common among men who have sex with men (MSM), transgender women, and practiced by women around the world. The risk of becoming infected with HIV through receptive anal intercourse is 20 times greater than vaginal intercourse. Hence, there is an urgent need for the development of rectal specific topical pre-exposure prophylaxis (PrEP) products. In the current study, our lab developed enemas containing tenofovir (TFV) for rectal application, which may provide some advantages with respect to user acceptability and compliance. In addition to evaluation of TFV in enemas, prodrugs of TFV: tenofovir alafenamide fumarate (TAF) and hexadecyloxypropyl (HDP)-tenofovir (CMX157) were evaluated due to their increased potency and better safety profile. In this project, a high performance liquid chromatography (HPLC) method for TAF was developed and qualified. Preformulation studies for TAF including solubility, hydrolytic, thermal, photolytic, and oxidative stability and preservative compatibility were conducted. TAF was found to be susceptible to hydrolytic degradation in acidic pH (pH≤4) and degraded when exposed in an aqueous solution to temperatures greater than 25°C. TAF hypotonic and isotonic enema formulations (1.76 mg/mL) were developed and characterized with respect to pH, osmolality, and drug content. One-week stability of these enemas was assessed in 40°C/75% RH, 30°C/65% RH and 25°C/60% RH environmental chambers. TAF enemas were stable for one week. In addition to the TAF enema, formulation efforts were initiated with CMX157. A preliminary HPLC method for CMX157 was developed. Prototype CMX157 enemas were prepared and pH and osmolality testing conducted. Additional formulation optimization is required to enhance TAF stability in an enema format. Further investigation of the prototype CMX157 enema developed with respect to its physiochemical characteristics and stability is needed.