TONG, XIN
(2022)
DESIGNING Q-GRIFFITHSIN-INCORPORATED RECTAL AND VAGINAL PRODUCTS FOR HIV PREVENTION.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) remains a global health concern, with the majority of infections caused by sexual transmission. Due to biological, behavioral, and social factors, key populations including men who have sex with men (MSM), women, and adolescent girls are disproportionally at risk of HIV infection. The urgent need for novel approaches to prevent disease spread has prompted the research of topical microbicides, including both rectal and vaginal products. The work presented within this dissertation contributes to the development of dosage form options for rectal and vaginal application as topical pre-exposure prophylactics (PrEP) for HIV infection. Specifically, it focuses on developing novel formulations for the delivery of Q-Griffithsin (Q-GRFT) which can be utilized in these highly susceptible populations to prevent HIV infection.
We hypothesize that by manipulating excipients, Q-GRFT can remain stable in both liquid and solid dosage forms. We further hypothesize that the designed rectal/vaginal products can achieve physicochemical properties suitable as topical microbicides.
Pre-formulation assessments, including excipient screening and stability study in the manufacturing environment, were performed for Q-GRFT. Experimental and computational methods were explored to investigate strategies for preventing aggregation. Physicochemical properties, including appearance, pH, osmolality, flowability, crystallinity, water content, puncture strength, and drug content, were characterized for different products respectively. The bioactivity (gp120 binding efficacy), permeability, and toxicity were also assessed for selected formulations.
Major findings from this dissertation indicate that: (1) Q-GRFT can remain stable with tenofovir (TFV), a nucleotide reverse transcriptase inhibitor (NRTI) that has synergetic effects against HIV infection; (2) protein-excipient interactions impact the stability of Q-GRFT; (3) formulation modifications can overcome the challenges during manufacturing processes.
Overall, this dissertation (1) explored the potential of combining Q-GRFT and TFV in liquid and solid dosage forms; (2) investigated the protein-excipient interactions and their impact on Q-GRFT stability; (3) developed stable Q-GRFT-incorporated formulations that meet critical quality attributes (CQAs) as topical PrEP options. Furthermore, the products generated from this work can be used as topical PrEP options that expand the current HIV prevention strategies for the key population at risk.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
22 April 2022 |
| Date Type: |
Publication |
| Defense Date: |
4 March 2022 |
| Approval Date: |
22 April 2022 |
| Submission Date: |
20 April 2022 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
206 |
| 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: |
Q-Griffithsin, Pre-Exposure Prophylactics, HIV Prevention, Topical Products, Drug Delivery Systems |
| Related URLs: |
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| Date Deposited: |
22 Apr 2022 17:05 |
| Last Modified: |
22 Apr 2022 17:05 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/42681 |
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