Recommendations for the Nonclinical Development of Topical Microbicides for Prevention of HIV Transmission: An Update

Lard-Whiteford, Sheryl L; Matecka, Dorota; O’Rear, Julian J.; Yuen, Ita S.; Litterst, Charles L.; Reichelderfer, Patricia

doi:10.1097/00126334-200405010-00001

Cited by 81 publications

(60 citation statements)

References 62 publications

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“…For a gel to be successfully used as a vaginal formulation, it needs to be nonirritating to the vaginal tissue, as it otherwise may increase the risk of infection (28). The FDA requires the rabbit vaginal irritation model for preclinical safety testing, as it is the gold-standard model to predict vaginal irritation (29).…”

Section: Vaginal Irritation Safety Testing Of Placebo Gel Formulationmentioning

confidence: 99%

Formulation Development and Evaluation of Innovative Two-Polymer (SR-2P) Bioadhesive Vaginal Gel

2014

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The main objective of this investigation was to study the feasibility of developing a vaginal bioadhesive microbicide using a SRI's proprietary two-polymer gel platform (SR-2P). Several formulations were prepared with different combinations of temperature-sensitive polymer (Pluronic® F-127) and mucoadhesive polymer (Noveon® AA-1), producing gels of different characteristics. Prototype polymeric gels were evaluated for pH, osmolality, buffering capacity, and viscosity under simulated vaginal semen dilutions, and bioadhesivity using ex vivo mini pig vaginal tissues and texture analyzer. The pH of the polymeric gel formulations ranged from 5.1 to 6.4; the osmolality varied from 13 to 173 mOsm. Absolute viscosity ranged from 513 to 3,780 cPs, and was significantly reduced (1.5-to 3-fold) upon incubation with simulated vaginal and semen fluid mixture. Among the tested gels (indicated in the middle row as a molar ratio of a mixture of Noveon vs. Pluronic), only SR-2P retained gel structure upon dilution with simulated fluids and mild simulated coital stress. The pH of the SR-2P gel was maintained at about 4.6 in simulated vaginal fluid and also showed high peak force of adhesion in mini pig vaginal tissue. Furthermore, SR-2P gel caused no or only minimal irritation in a mouse vaginal irritation model. The results of this preliminary study demonstrated the potential application of SR-2P gel as a vaginal microbicide vehicle for delivery of anti-HIV agents.

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Section: Vaginal Irritation Safety Testing Of Placebo Gel Formulationmentioning

confidence: 99%

Formulation Development and Evaluation of Innovative Two-Polymer (SR-2P) Bioadhesive Vaginal Gel

2014

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“…A prophylactic anti-HIV-1 vaccine would be ideal in this respect, but no such vaccine is available despite more than a decade of intensive development effort. Another potential mechanism to reduce the transmission of HIV-1 is the use of vaginal and/or rectal topical microbicides (20,32,35).…”

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confidence: 99%

In Vitro Microbicidal Activity of the Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) UC781 against NNRTI-Resistant Human Immunodeficiency Virus Type 1

Hossain

Parniak

2006

J Virol

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The nonnucleoside reverse transcriptase inhibitor (NNRTI) UC781 is under development as a microbicide to prevent sexual transmission of the human immunodeficiency virus type 1 (HIV-1). However, NNRTIresistant HIV-1 is increasingly prevalent in the infected population, and one of the concerns for NNRTI-based microbicides is that they will be ineffective against drug-resistant virus and may in fact selectively transmit NNRTI-resistant virus. We evaluated the microbicidal activity of UC781 against UC781-resistant (UCR), efavirenz-resistant (EFVR), and nevirapine-resistant (NVPR) strains in a variety of microbicide-relevant tests, including inactivation of cell-free virus, inhibition of cell-to-cell HIV-1 transmission, and the ability of UC781 pretreatment to protect cells from subsequent infection in the absence of exogenous drug. UC781 was 10-to 100-fold less effective against NNRTI-resistant HIV-1 compared to wild-type (wt) virus in each of these tests, with UC781 microbicidal activity against the various virus strains being wt > NVPR > UCR > EFVR. Breakthrough experiments using UC781-pretreated cells and mixtures of wt and NNRTI-resistant HIV-1 showed that UC781-pretreatment selected for NNRTI-resistant HIV-1. However, the efficacy of UC781 was dose dependent, and 25 M UC781 provided essentially equivalent microbicidal activity against NNRTI-resistant and wt virus. The amount of UC781 in topical microbicide formulations under current development is approximately 100-fold greater than this concentration, so transmission of NNRTI-resistant virus may not be an issue at these microbicide formulation levels of UC781. Nonetheless, the reduced microbicidal activity of UC781 against NNRTI-resistant HIV-1 suggests that additional antiviral agents should be included in NNRTIbased microbicide formulations.

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“…The consumer's perspectives and their choice of formulation vary depending on the individual, partners, cultural norms, age, and economical, social, and climate conditions of the specific geographical region. Women's preferences regarding the ideal characteristics of a microbicide product have been extensively studied (5,(128)(129)(130). Several important criteria for vaginal microbicides with regard to efficacy have been established.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Vaginal Drug Delivery Systems for HIV Prevention

Rohan

Sassi

2009

AAPS J

140

130

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Abstract. Microbicides have become a principal focus for HIV prevention strategies. The successful design of drug delivery systems for vaginal microbicide drug candidates brings with it a multitude of challenges. It is imperative that the chemical and physical characteristics of the drug candidate and its mechanism of action be clearly understood and considered to successfully deliver and target drug candidates efficiently. In addition, an understanding of the dynamic nature of the vaginal environment, the tissue and innate barriers present, as well as patient preferences are critical considerations in the design of effective microbicide products. Although the majority of drug candidates clinically evaluated to date have been delivered using conventional semisolid aqueous-based gel dosage forms, drug delivery system design has recently been extended to include advanced delivery systems such as vaginal rings, quick-dissolve films, and tablets. Ultimately, it may be necessary to develop multiple dosage platforms for a single active agent to provide users with options that can be used within the constraints of their social environment, personal choice, and environmental conditions.

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Recommendations for the Nonclinical Development of Topical Microbicides for Prevention of HIV Transmission: An Update

Cited by 81 publications

References 62 publications

Formulation Development and Evaluation of Innovative Two-Polymer (SR-2P) Bioadhesive Vaginal Gel

Formulation Development and Evaluation of Innovative Two-Polymer (SR-2P) Bioadhesive Vaginal Gel

In Vitro Microbicidal Activity of the Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) UC781 against NNRTI-Resistant Human Immunodeficiency Virus Type 1

Vaginal Drug Delivery Systems for HIV Prevention

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