1. Novel Intravaginal Delivery of Antiretroviral-based Microbicides for HIV Prevention HIV/AIDS research Simi Gunaseelan, Ph.D. Assistant Professor of Pharmaceutical Sciences Ben and Maytee Fisch College of Pharmacy The University of Texas at Tyler Texas, USA

2. Global HIV / AIDS estimates published by UNAIDS (by end of 2012)

3. Viral Attack after Sexual Exposure to HIV This is how HIV gets in. Now how do we stop it?

4. Potential Mechanisms for HIV Transmission across Vaginal and Rectal Mucosal Epithelium Viral attack after sexual exposure to HIV

5. How to Prevent Viral Attack Pre - & Post- Sexual Exposure to HIV? With an HIV vaccine likely to be years away, encouraging the development of new preventative technologies such as Pre-Exposure Prophylaxis and Post-Exposure Prophylaxis (such as “Microbicides”) ……….….

6. PrEP & Microbicides – New Hope for HIV Prevention Pre-Exposure Prophylaxis (PrEP) strategies: Drug administered orally or topically (including “microbicides”) to prevent HIV infection by any of several routes of transmission

7. PrEP & Microbicides – New Hope for HIV Prevention “Microbicides”, a subset of PrEP strategies, are drug products applied topically to the vaginal or rectal mucosa in a variety of formulations (gel, cream, suppository, film, sponge, foam, vaginal or rectal ring - that release the active ingredient gradually) prior to sexual intercourse, for the purpose of preventing or substantially reducing sexually transmitted infections, including HIV, in a sexually receptive partner. These topical microbicide products might be applied to condoms or directly to the genitals (vagina or rectum) to block HIV

8. How do Microbicide Work Pre - & Post- Sexual Exposure to HIV?

9. Current HIV Microbicide Formulations Vaginal Gel with Applicator Vaginal Film Vaginal Ring with pods Vaginal Tablet Vaginal Tablet Applicator At present there is no agreed “gold standard” around microbicide formulation  Recent research focuses on highly potent and specific anti-retroviral based microbicides (formulated as primary dosage forms e.g., vaginal gels or alternative dosage forms such as fast dissolve films and tablets)

10. Limitations of Current HIV Microbicide Delivery (Formulation) Technologies Current Diffusion /Hydrolysis /Dissolution – based Microbicide Delivery Technologies Degradable Matrix With Drug Entrapped Diffusion Dissolution Released Drug Un-degraded Matrix Released Drug Degraded Matrix Un-degraded Matrix Vaginal Gel Vaginal Tablet Vaginal Film Current Problems:  Microbicide release is more Dependent on the Size, Structure, and Physicochemical properties of a Microbicide rather than on the ‘Intrinsic Performance of the Delivery System’  Stability of microbicides in Aqueous Gels and Films – ‘Big Challenge’ if drug is unstable in water

11. ‘Novel’ Subliming Solid-based Intravaginal Microbicide Delivery Formulation ‘Novel’ Vaginal Formulations Sublimable Matrix With Drug Entrapped Sublimation Released Drug Sublimed Vapors Un-sublimed Matrix 37 °C Advantages:  Drug release NOT due to conventional hydrolysis or dissolution of matrix material or diffusion of water into or drug out of a matrix  Release of Microbicide is INDEPENDENT of the Size, Structure, and Physicochemical properties of the Microbicide

12. ‘Novel’ Subliming Solid-based Intravaginal Microbicide Delivery Formulation ‘Novel’ Vaginal Formulations Sublimable Matrix With Drug Entrapped Sublimation Released Drug Sublimed Vapors Un-sublimed Matrix 37 °C Sublimation Mechanism: ‘This process entails incorporation of drug into a matrix, and subsequent matrix erosion, where, release of drug from chemically inert and water insoluble hydrophobic matrices occur by surface erosion achieved through sublimation (direct conversion of solid to a gas) of matrix, allowing newly exposed drug particles to be delivered to the environment of the intravaginal administration site’

13. What can these ‘Novel’ Intravaginal Microbicide Delivery Formulations do? ‘Novel’ Vaginal Formulations Sublimable Matrix With Drug Entrapped Sublimation Released Drug Sublimed Vapors Un-sublimed Matrix 37 °C Unique Performances of Subliming Solid Matrices:  Provide continuous and controlled delivery of a broad structural array of HIV microbicides (dissimilar), at rates independent of their size and physicochemical properties  Stabilize ‘unstable microbicides’  Extend antiviral efficacy of microbicides of high clinical importance by sustained release from subliming solids

14. Choice of Antiretroviral-based Microbicides for ‘Novel’ Delivery System Evaluation ‘Novel’ Vaginal Formulations Antiretroviral Microbicides:  Emtricitabine (un-charged, highly water soluble) and Tenofovir (charged, poorly water soluble) – which have achieved clinical confirmation of microbicidal efficacy in recent CAPRISA (topical- Vaginal Gel) and iPrEx (oral) administration trials  C5A Peptide (charged, hydrophobic, low aqueous solubility) - peptide microbicide with promising pre-clinical results Tenofovir Emtricitabine 18 amino acid – C5A Peptide Vaginal Defence Enhancer Antiretroviral NRTI Antiretroviral NRTI

15. In Vitro Release Rates of Microbicides were Independent of Physicochemical Properties In Vitro Release Rates of Microbicides were Independent of Physicochemical Properties PF-11 Matrix HMCS Matrix

16. Subliming Solid Matrices were Non-Toxic to HIV-1 Target Cells Human PBMCs Human T-Lymphocytes Human Macrophages Human Ectocervical Tissue

17. Subliming Matrices Prolonged Antiviral Activity in Human Macrophages & TZM Cells Tenofovir / Human Macrophages Emtricitabine / Human Macrophages C5A / Human Macrophages Tenofovir / TZM Cells Emtricitabine / TZM Cells C5A / TZM Cells

18. Subliming Matrices Prolonged Antiviral Activity in Human Ectocervical Explants

19. This Work Resulted in 2 Publications Simi Gunaseelan, Philippe Gallay, Michael Bobardt, Charlene S. Dezzutti, Timothy Esch and Richard Maskiewicz. Sustained local delivery of structurally diverse HIV-1 microbicides released from sublimation enthalpy controlled matrices. Pharmaceutical Research, 2012; 29, 3156-3168. Richard Maskiewicz, Michael Bobardt, Udayan Chatterji, Simi Gunaseelan, Charlene S. Dezzutti, Francois Penin and Philippe A. Gallay. Sublimable C5A delivery provides sustained and prolonged anti-HIV microbicidal activities. Antimicrobial Agents and Chemotherapy, 2012; 56, 3336- 3343.

20. Research Collaborations Dr. Charlene S. Dezzutti (University of Pittsburgh, PA) Dr. Philippe A. Galla (Scripps Research Institute, CA) Dr. Richard Maskiewicz (Loma Linda University, CA)