Akil, Ayman
(2013)
VAGINAL POLYMERIC FILM CONTAINING ANTIRETROVIRAL COMBINATION FOR PREVENTION OF HIV SEXUAL TRANSMISSION.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The HIV epidemic is an ongoing global health challenge. Prevention strategies are one means to combat HIV. Part of prevention incudes behavior modifications, circumcision, vaccine product development and oral and topical pre-exposure prophylaxis (PrEP). Topical PrEP products, also referred to as topical microbicides, are designed for vaginal or rectal application for the purpose of prevention of HIV-1 sexual transmission. Products being designed are coitally or pericoitally dependent or provide sustained release of the active agent for long term protection. The potency of antiretrovirals (ARVs) in HIV therapy promoted the exploration of their use as topical microbicides. Dapivirine (DPV) and Tenofovir (TFV) are replication inhibitors which have been explored as topical microbicides most widely in clinical trials. A 1% TFV vaginal gel applied in a coitally dependent fashion was shown to reduce HIV acquisition by 39%. However, other trials have not been able to show similar successful results with use of the same TFV gel. Therefore, to improve efficacy, combinations of ARVs are being pursued as topical microbicides. The development and characterization of a polymeric vaginal film containing DPV and TFV is presented in this dissertation. Drug – drug compatibility and a solid state solubility for polymer selection process are described. Physical and chemical characterization of the film demonstrated acceptable film properties. Efficacy testing in vitro showed the film to be effective at preventing HIV infection. Finally, stability testing proved the film to be stable at different environmental conditions for 6 months. Moreover, as ARVs drug tissue level is important for their bioactivity, the impact of the co-delivery of TFV and DPV on their tissue accumulation and distribution was assessed in an excised human ecto-cervical model. Results showed that the film was able to release both agents from the film for subsequent delivery into the target tissue. Interestingly, the data showed that the combination film product resulted in achieving higher DPV tissue amounts in the stroma whereas no impact on TFV tissue accumulation was observed. Collectively, these results provide evidence of the ability of polymeric films to accommodate ARVs combinations and illustrate the impact of co-delivery on drug tissue accumulation and distribution.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
10 December 2013 |
| Date Type: |
Publication |
| Defense Date: |
12 November 2013 |
| Approval Date: |
10 December 2013 |
| Submission Date: |
25 November 2013 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
153 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Dapivirine, Microbicides, HIV, Tenofovir, Drug Delivery, Films, Formulation, Antiretrovirals |
| Date Deposited: |
10 Dec 2013 15:30 |
| Last Modified: |
10 Dec 2018 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/20099 |
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