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VAGINAL DELIVERY OF A HYDROPHOBIC ANTIRETROVIRAL DRUG CSIC FOR HIV PREVENTION: NOVEL FORMULATION STRATEGIES FOR IMPROVED DRUG SOLUBILIZATION AND LYMPHATIC TARGETING

Gong, Tiantian (2015) VAGINAL DELIVERY OF A HYDROPHOBIC ANTIRETROVIRAL DRUG CSIC FOR HIV PREVENTION: NOVEL FORMULATION STRATEGIES FOR IMPROVED DRUG SOLUBILIZATION AND LYMPHATIC TARGETING. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

HIV epidemic is an ongoing health concern globally. Sexual transmission accounts for the overwhelming majority of new infections. Vaginal microbicides are under investigation as pre-exposure prophylaxis (PrEP) products for HIV prevention. Although progress has been made, the development of more efficacious products is warranted. Cervicovaginal tissue and draining lymph nodes contain an adequate amount of HIV target cells and play critical roles in HIV replication and sedimentation at the early stage of infection. Improved efficacy can be achieved with the use of specially designed drug delivery systems which achieve greater drug concentrations in these two sites of action.
In this dissertation, we hypothesized that the hydrophobic microbicide candidate CSIC can be formulated in a polymeric vaginal film and a nanocrystal formulation with high loading capacities using multiple formulation strategies. We further hypothesized that the nano-delivery strategy can improve cervicovaginal tissue drug penetration and achieve lymphatic drug delivery. Series of preformulation studies were conducted to evaluate the physicochemical and biological properties of the drug candidate CSIC. The major challenge for CISC formulation development was identified as its hydrophobicity. Therefore, a cosolvent system comprising PEG 400, propylene glycol, and glycerin at a ratio of 5:2:1 has been optimized and utilized in a polymer based vaginal film formulation for increased drug solubility, long term stability, and lack of leakage. Additionally, a CSIC nanocrystal formulation, with a particle size of 243nm and near neutral surface charge, was developed. CSIC nanocrystals have been proved to possess increased drug saturation solubility, rapid mucus penetration properties, and improved drug permeation in the cervicovaginal tissue. More importantly, the pharmacokinetic study provided the first evidence of lymphatic targeting after intravaginal application without causing any epithelial damage. Furthermore, CSIC was able to release from the nanocrystals in a sustained mode, indicating its potential use as a coitally independent PrEP product that could improve user adherence. In summary, this work sets the stage to create new opportunities for sexually transmitted HIV prevention through the development of a novel dual targeting delivery system. The developed approaches can be used to deliver other drugs that lack solubility or require lymphatic targeting.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Gong, Tiantiantig8@pitt.eduTIG8
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorRohan, Lisa Clrohan@mwri.magee.edu
Committee MemberBallou, Byronbbal@andrew.cmu.edu
Committee MemberEmpey, Kerry Mkme33@pitt.eduKME33
Committee MemberParniak, Michael Amap167@pitt.eduMAP167
Committee MemberLi, Songsol4@pitt.eduSOL4
Date: 16 December 2015
Date Type: Publication
Defense Date: 10 August 2015
Approval Date: 16 December 2015
Submission Date: 1 December 2015
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 203
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: HIV microbicide vaginal drug delivery
Date Deposited: 16 Dec 2015 14:11
Last Modified: 16 Dec 2017 06:15
URI: http://d-scholarship.pitt.edu/id/eprint/26515

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