Performance and Stability of Tenofovir Alafenamide Formulations within Subcutaneous Biodegradable Implants for HIV Pre-Exposure Prophylaxis (PrEP)
A critical need exists to develop diverse biomedical strategies for the widespread use of HIV Pre-Exposure Prophylaxis (HIV PrEP). This manuscript describes a subcutaneous reservoir-style implant for long-acting delivery of tenofovir alafenamide (TAF) for HIV PrEP. We detail key parameters of the TA...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-11-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/12/11/1057 |
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| author | Linying Li Leah M. Johnson Sai Archana Krovi Zach R. Demkovich Ariane van der Straten |
| author_facet | Linying Li Leah M. Johnson Sai Archana Krovi Zach R. Demkovich Ariane van der Straten |
| author_sort | Linying Li |
| collection | DOAJ |
| description | A critical need exists to develop diverse biomedical strategies for the widespread use of HIV Pre-Exposure Prophylaxis (HIV PrEP). This manuscript describes a subcutaneous reservoir-style implant for long-acting delivery of tenofovir alafenamide (TAF) for HIV PrEP. We detail key parameters of the TAF formulation that affect implant performance, including TAF ionization form, the selection of excipient and the exposure to aqueous conditions. Both in-vitro studies and shelf stability tests demonstrate enhanced performance for TAF freebase (TAF<sub>FB</sub>) in this long-acting implant platform, as TAF<sub>FB</sub> maintains higher chemical stability than the TAF hemifumarate salt (TAF<sub>HF</sub>). We also examined the hydrolytic degradation profiles of various formulations of TAF and identified inflection points for the onset of the accelerated drug hydrolysis within the implant using a two-line model. The compositions of unstable formulations are characterized by liquid chromatography-mass spectrometry (LC-MS) and are correlated to predominant products of the TAF hydrolytic pathways. The hydrolysis rate of TAF is affected by pH and water content in the implant microenvironment. We further demonstrate the ability to substantially delay the degradation of TAF by reducing the rates of drug release and thus lowering the water ingress rate. Using this approach, we achieved sustained release of TAF<sub>FB</sub> formulations over 240 days and maintained > 93% TAF purity under simulated physiological conditions. The opportunities for optimization of TAF formulations in this biodegradable implant supports further advancement of strategies to address long-acting HIV PrEP. |
| first_indexed | 2024-03-10T15:04:07Z |
| format | Article |
| id | doaj.art-73cb1c8ef2e4442085f655fd6d3a2f58 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T15:04:07Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-73cb1c8ef2e4442085f655fd6d3a2f582023-11-20T19:54:55ZengMDPI AGPharmaceutics1999-49232020-11-011211105710.3390/pharmaceutics12111057Performance and Stability of Tenofovir Alafenamide Formulations within Subcutaneous Biodegradable Implants for HIV Pre-Exposure Prophylaxis (PrEP)Linying Li0Leah M. Johnson1Sai Archana Krovi2Zach R. Demkovich3Ariane van der Straten4Engineered Systems, RTI International, 3040 E Cornwallis Road, Research Triangle Park, Durham, NC 27709, USAEngineered Systems, RTI International, 3040 E Cornwallis Road, Research Triangle Park, Durham, NC 27709, USAEngineered Systems, RTI International, 3040 E Cornwallis Road, Research Triangle Park, Durham, NC 27709, USAWomen’s Global Health Imperative, RTI International, 2150 Shattuck avenue, Berkeley, CA 94704, USAWomen’s Global Health Imperative, RTI International, 2150 Shattuck avenue, Berkeley, CA 94704, USAA critical need exists to develop diverse biomedical strategies for the widespread use of HIV Pre-Exposure Prophylaxis (HIV PrEP). This manuscript describes a subcutaneous reservoir-style implant for long-acting delivery of tenofovir alafenamide (TAF) for HIV PrEP. We detail key parameters of the TAF formulation that affect implant performance, including TAF ionization form, the selection of excipient and the exposure to aqueous conditions. Both in-vitro studies and shelf stability tests demonstrate enhanced performance for TAF freebase (TAF<sub>FB</sub>) in this long-acting implant platform, as TAF<sub>FB</sub> maintains higher chemical stability than the TAF hemifumarate salt (TAF<sub>HF</sub>). We also examined the hydrolytic degradation profiles of various formulations of TAF and identified inflection points for the onset of the accelerated drug hydrolysis within the implant using a two-line model. The compositions of unstable formulations are characterized by liquid chromatography-mass spectrometry (LC-MS) and are correlated to predominant products of the TAF hydrolytic pathways. The hydrolysis rate of TAF is affected by pH and water content in the implant microenvironment. We further demonstrate the ability to substantially delay the degradation of TAF by reducing the rates of drug release and thus lowering the water ingress rate. Using this approach, we achieved sustained release of TAF<sub>FB</sub> formulations over 240 days and maintained > 93% TAF purity under simulated physiological conditions. The opportunities for optimization of TAF formulations in this biodegradable implant supports further advancement of strategies to address long-acting HIV PrEP.https://www.mdpi.com/1999-4923/12/11/1057HIV pre-exposure prophylaxistenofovir alafenamideimplantlong-acting drug deliverypoly(ε-caprolactone) (PCL)biodegradable polymer |
| spellingShingle | Linying Li Leah M. Johnson Sai Archana Krovi Zach R. Demkovich Ariane van der Straten Performance and Stability of Tenofovir Alafenamide Formulations within Subcutaneous Biodegradable Implants for HIV Pre-Exposure Prophylaxis (PrEP) Pharmaceutics HIV pre-exposure prophylaxis tenofovir alafenamide implant long-acting drug delivery poly(ε-caprolactone) (PCL) biodegradable polymer |
| title | Performance and Stability of Tenofovir Alafenamide Formulations within Subcutaneous Biodegradable Implants for HIV Pre-Exposure Prophylaxis (PrEP) |
| title_full | Performance and Stability of Tenofovir Alafenamide Formulations within Subcutaneous Biodegradable Implants for HIV Pre-Exposure Prophylaxis (PrEP) |
| title_fullStr | Performance and Stability of Tenofovir Alafenamide Formulations within Subcutaneous Biodegradable Implants for HIV Pre-Exposure Prophylaxis (PrEP) |
| title_full_unstemmed | Performance and Stability of Tenofovir Alafenamide Formulations within Subcutaneous Biodegradable Implants for HIV Pre-Exposure Prophylaxis (PrEP) |
| title_short | Performance and Stability of Tenofovir Alafenamide Formulations within Subcutaneous Biodegradable Implants for HIV Pre-Exposure Prophylaxis (PrEP) |
| title_sort | performance and stability of tenofovir alafenamide formulations within subcutaneous biodegradable implants for hiv pre exposure prophylaxis prep |
| topic | HIV pre-exposure prophylaxis tenofovir alafenamide implant long-acting drug delivery poly(ε-caprolactone) (PCL) biodegradable polymer |
| url | https://www.mdpi.com/1999-4923/12/11/1057 |
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