Novel Intravaginal Delivery Novel Intravaginal Delivery of Antiretroviral-based of Antiretroviral-based

Microbicides for HIV Microbicides for HIV PreventionPrevention

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

Global HIV / AIDS estimates Global HIV / AIDS estimates published by UNAIDS (by end of published by UNAIDS (by end of

2012) 2012)

Viral Attack after Sexual Viral Attack after Sexual Exposure to HIVExposure to HIV

This is how HIV gets in. Now how do we stop it?

Potential Mechanisms for HIV Potential Mechanisms for HIV Transmission across Vaginal and Transmission across Vaginal and

Rectal Mucosal Epithelium Rectal Mucosal Epithelium Viral attack after sexual exposure to HIV

How to Prevent Viral Attack Pre - How to Prevent Viral Attack Pre - & Post- Sexual Exposure to HIV?& 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”) ……….….

PrEP & Microbicides – PrEP & Microbicides – New Hope for HIV PreventionNew 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

PrEP & Microbicides – PrEP & Microbicides – New Hope for HIV PreventionNew 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

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

Current HIV Microbicide Current HIV Microbicide FormulationsFormulations

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)

Limitations of Current HIV Limitations of Current HIV Microbicide Delivery Microbicide Delivery

(Formulation) Technologies(Formulation) TechnologiesCurrent 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

‘‘Novel’ Subliming Solid-based Novel’ Subliming Solid-based Intravaginal Microbicide Delivery Intravaginal Microbicide Delivery

FormulationFormulation

‘Novel’ Vaginal Formulations

Sublimable Matrix With Drug Entrapped

Sublimation Released Drug

SublimedVapors

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 matrixRelease of Microbicide is INDEPENDENT of the Size, Structure, and Physicochemical properties of the Microbicide

‘‘Novel’ Subliming Solid-based Novel’ Subliming Solid-based Intravaginal Microbicide Delivery Intravaginal Microbicide Delivery

FormulationFormulation

‘Novel’ Vaginal Formulations

Sublimable Matrix With Drug Entrapped

Sublimation Released Drug

SublimedVapors

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’

What can these ‘Novel’ What can these ‘Novel’ Intravaginal Microbicide Delivery Intravaginal Microbicide Delivery

Formulations do?Formulations do?

‘Novel’ Vaginal Formulations

Sublimable Matrix With Drug Entrapped

Sublimation Released Drug

SublimedVapors

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 propertiesStabilize ‘unstable microbicides’ Extend antiviral efficacy of microbicides of high clinical importance by sustained release from subliming solids

Choice of Antiretroviral-based Choice of Antiretroviral-based Microbicides for ‘Novel’ Delivery Microbicides for ‘Novel’ Delivery

System EvaluationSystem 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 PeptideVaginal Defence Enhancer

AntiretroviralNRTI

AntiretroviralNRTI

In Vitro In Vitro Release Rates of Release Rates of Microbicides were Microbicides were IndependentIndependent of of

Physicochemical PropertiesPhysicochemical Properties

PF-11Matrix

HMCSMatrix

Subliming Solid Matrices were Subliming Solid Matrices were Non-Toxic Non-Toxic to HIV-1 Target Cellsto HIV-1 Target Cells

Human PBMCs

HumanT-Lymphocytes

HumanMacrophages

Human EctocervicalTissue

Subliming Matrices Subliming Matrices ProlongedProlonged Antiviral Activity Antiviral Activity in Human in Human

Macrophages & TZM CelMacrophages & TZM Cel lsls

Tenofovir / Human

Macrophages

Emtricitabine / Human

Macrophages

C5A / Human

Macrophages

Tenofovir / TZM Cells

Emtricitabine / TZM Cells

C5A / TZM Cells

Subliming Matrices Subliming Matrices ProlongedProlonged Antiviral Activity Antiviral Activity in Human in Human

Ectocervical ExplantsEctocervical Explants

This Work Resulted in 2 This Work Resulted in 2 PublicationsPublications

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.

Research CollaborationsResearch Collaborations

Dr. Charlene S. Dezzutti (University of Pittsburgh, PA)

Dr. Philippe A. Galla (Scripps Research Institute, CA)

Dr. Richard Maskiewicz (Loma Linda University,

CA)