Mucoadhesive vaginal film of fluconazole using cross-linked chitosan and pectin

Human immunodeficiency virus (HIV) infection and unintended pregnancy, which can lead to life-threatening complications, are two major burdens for female reproductive health. To address these pressing health issues, multipurpose prevention technologies (MPTs) are proposed to deliver two or more drugs simultaneously. MPTs could offer several benefits for users such as improved convenience, increased effectiveness, reduced cost, and decreased environmental burden. Here, we report the development, and in vitro and in vivo assessment of a bioadhesive vaginal film as a coitally-independent MPT dosage form for delivering dapivirine (DPV) and levonorgestrel (LNG) to prevent HIV infection and unintended pregnancy, respectively. After confirming the feasibility of bioadhesive film use for weekly drug delivery in vivo through colpophotography and MRI evaluation, the pharmacokinetics (PK) of DPV/LNG single entity and combination bioadhesive films was investigated in pigtailed macaques (n = 5). Both drugs from single entity or combination films were able to provide sustained drug release in vivo. The combination film showed lower local tissue clearance for DPV and exhibited significantly increased plasma concentration for LNG as compared to the single entity film. This proof-of-concept study demonstrates the ability of this novel bioadhesive film platform to deliver LNG and DPV simultaneously as an MPT product for the prevention of HIV infection and unintended pregnancy.

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Comparison of the Pharmacokinetics and Pharmacodynamics of Single-Dose Tenofovir Vaginal Film and Gel Formulation (FAME 05)

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/qai.0000000000001587 ◽

2018 ◽

Vol 77 (2) ◽

pp. 175-182 ◽

Cited By ~ 13

Author(s):

Jennifer A. Robinson ◽

Mark A. Marzinke ◽

Edward J. Fuchs ◽

Rahul P. Bakshi ◽

Hans M. L. Spiegel ◽

...

Keyword(s):

Single Dose ◽

Pharmacokinetics And Pharmacodynamics ◽

Vaginal Film

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Acceptability of Vaginal Film, Soft-Gel Capsule, and Tablet as Potential Microbicide Delivery Methods Among African Women

Journal of Women s Health ◽

10.1089/jwh.2010.2476 ◽

2011 ◽

Vol 20 (8) ◽

pp. 1207-1214 ◽

Cited By ~ 54

Author(s):

Annalene M. Nel ◽

Lynne B. Mitchnick ◽

Peter Risha ◽

Lungwani Tyson Makoye Muungo ◽

Pamela M. Norick

Keyword(s):

African Women ◽

Delivery Methods ◽

Vaginal Film

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Retention of a Vaginal Film

Fertility and Sterility ◽

10.1016/j.fertnstert.2013.11.090 ◽

2014 ◽

Vol 101 (2) ◽

pp. e21

Author(s):

J. Lucas ◽

D. Patton ◽

K. Maravilla

Keyword(s):

Vaginal Film

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Hexavalent Sperm-Binding IgG Antibody Released from Self-Dissolving Vaginal Film Enables Potent, On-Demand Non-Hormonal Female Contraception

10.1101/2021.04.19.440503 ◽

2021 ◽

Author(s):

Bhawana Shrestha ◽

Kathleen Vincent ◽

Alison Schaefer ◽

Yong Zhu ◽

Gracie Vargas ◽

...

Keyword(s):

Molecular Orientation ◽

Expression System ◽

Hormonal Contraception ◽

Water Soluble ◽

Motile Sperm ◽

Igg Antibody ◽

On Demand ◽

Sperm Binding ◽

Vaginal Film ◽

Work Supports

Non-hormonal products for on-demand contraception are a global health technology gap, motivating us to pursue the use of sperm-binding monoclonal antibodies as a strategy to enable safe, effective, desirable, on-demand contraception. Here, using cGMP-compliant Nicotiana-expression system, we produce an ultra-potent sperm-binding IgG antibody possessing 6 Fab arms per molecule that bind a well-established contraceptive antigen target, CD52g. We term this hexavalent antibody Fab-IgG-Fab (FIF) to reflect its molecular orientation. The Nicotiana-produced FIF exhibits at least 10-fold greater sperm agglutination potency and kinetics than the parent IgG, while preserving Fc-mediated trapping of individual spermatozoa in mucus. We formulate the Nicotiana-produced FIF into a polyvinyl alcohol-based water-soluble contraceptive film, and evaluate its potency in reducing progressively motile sperm in the sheep vagina. Two minutes after vaginal instillation of human semen, no progressively motile sperm are recovered from the vaginas of sheep receiving FIF-Film. In contrast, high numbers of progressively motile sperm are recovered from sheep receiving a placebo film control. Our work supports the potential of highly multivalent contraceptive antibodies to provide safe, effective, on-demand non-hormonal contraception.

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The vaginal sheet: an innovative form of vaginal film for the treatment of vaginal infections

Drug Development and Industrial Pharmacy ◽

10.1080/03639045.2019.1711386 ◽

2020 ◽

Vol 46 (1) ◽

pp. 135-145 ◽

Cited By ~ 1

Author(s):

Rita Monteiro Machado ◽

Mariana Tomás ◽

Ana Palmeira-de-Oliveira ◽

José Martinez-de-Oliveira ◽

Rita Palmeira-de-Oliveira

Keyword(s):

Vaginal Infections ◽

Vaginal Film

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Engineering monoclonal antibody-based contraception and multipurpose prevention technologies†

Biology of Reproduction ◽

10.1093/biolre/ioaa096 ◽

2020 ◽

Vol 103 (2) ◽

pp. 275-285

Author(s):

Deborah J Anderson ◽

Joseph A Politch ◽

Richard A Cone ◽

Larry Zeitlin ◽

Samuel K Lai ◽

...

Keyword(s):

Monoclonal Antibody ◽

Phase 1 ◽

Unmet Need ◽

Human Sperm ◽

Infertile Woman ◽

Sexually Transmitted ◽

Female Reproductive Health ◽

Vaginal Film ◽

Technology Products ◽

Hiv 1

Abstract Sexually transmitted infections are highly prevalent, and over 40% of pregnancies are unplanned. We are producing new antibody-based multipurpose prevention technology products to address these problems and fill an unmet need in female reproductive health. We used a Nicotiana platform to manufacture monoclonal antibodies against two prevalent sexually transmitted pathogens, HIV-1 and HSV-2, and incorporated them into a vaginal film (MB66) for preclinical and Phase 1 clinical testing. These tests are now complete and indicate that MB66 is effective and safe in women. We are now developing an antisperm monoclonal antibody to add contraceptive efficacy to this product. The antisperm antibody, H6-3C4, originally isolated by Shinzo Isojima from the blood of an infertile woman, recognizes a carbohydrate epitope on CD52g, a glycosylphosphatidylinositol-anchored glycoprotein found in abundance on the surface of human sperm. We engineered the antibody for production in Nicotiana; the new antibody which we call “human contraception antibody,” effectively agglutinates sperm at concentrations >10 μg/ml and maintains activity under a variety of physiological conditions. We are currently seeking regulatory approval for a Phase 1 clinical trial, which will include safety and “proof of principle” efficacy endpoints. Concurrently, we are working with new antibody production platforms to bring the costs down, innovative antibody designs that may produce more effective second-generation antibodies, and delivery systems to provide extended protection.

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