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Stabilization of a Tenofovir Alafenamide Fumarate Formulation for Use in a Subcutaneous Implant

Shah, Tanvi (2019) Stabilization of a Tenofovir Alafenamide Fumarate Formulation for Use in a Subcutaneous Implant. Master's Thesis, University of Pittsburgh. (Unpublished)

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Scientific advances in the last three decades have helped transform HIV from a fatal disease into a chronic condition for many people. There has been an increase in interest to explore strategies for the prevention of HIV, commonly known as Pre-exposure prophylaxis (PrEP). Currently Truvada®, a once-a-day oral pill, is the only FDA approved marketed regimen for HIV PrEP. Long-acting (LA) systems requiring less frequent dosing remain a major unmet need. A LA system currently under development is a polycaprolactone (PCL)-based biodegradable subcutaneous implant of Tenofovir alafenamide fumarate salt (TAF) in a castor oil paste. This implant showed sustained zero-order release of TAF over 3 months but failed to release drug in zero-order kinetics post 90 days due to poor drug stability. The present work involves the optimization of this implant to achieve stabilization of the TAF formulation inside the PCL device. First, a stability-indicating HPLC method was developed and validated. Then, a suite of pre-formulation studies were performed to better elucidate the mechanisms of TAF degradation in the device. Additionally, a novel stability model was developed that accelerated TAF degradation inside the implant over 8-folds for rapid formulation screening. This model was utilized to study a wide range of excipients belonging to the class of pH and HLB modifiers. Oil substitutes for castor oil were also explored. Controlling the intra-device pH between 5 – 5.5 was found to be the key determinant of TAF stability. pH modifiers showed most promise in stabilizing TAF, with TAF percent recovery between 90 – 110 % vs. control (<5%). Viable pH modifiers were further optimized for processability in scale-up efforts. Final optimized formulations containing either dibasic sodium phosphate or sodium citrate were found to stabilize TAF in the accelerated model for over 9 weeks. A percent recovery of 90 – 110 % vs. control (0 %) was obtained. In conclusion, two formulations were identified that increased the stability of TAF in the implant. These formulations can be potentially used as bi-annual, long acting subcutaneous systems for HIV PrEP.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Shah, Tanvitas214@pitt.eduTAS214
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRohan,
Committee MemberLi, Songsol4@pitt.edusol4
Committee MemberSant, Vinayakvis45@pitt.eduvis45
Date: 10 April 2019
Date Type: Publication
Defense Date: 20 March 2019
Approval Date: 10 April 2019
Submission Date: 9 April 2019
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 126
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Tenofovir Alafenamide Fumarate stabilization, Formulation, Subcutaneous Implant, HIV Prevention, Accelerated Model Development, HPLC Method Validation
Date Deposited: 10 Apr 2019 16:03
Last Modified: 10 Apr 2021 05:15

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  • Stabilization of a Tenofovir Alafenamide Fumarate Formulation for Use in a Subcutaneous Implant. (deposited 10 Apr 2019 16:03) [Currently Displayed]


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