Pharmaceutics, Preformulation and Drug Delivery
Development of a Combination Microbicide Gel Formulation Containing IQP-0528 and Tenofovir for the Prevention of HIV Infection

https://doi.org/10.1002/jps.23026Get rights and content

ABSTRACT:

In light of the increasing worldwide AIDS pandemic, there is a continuing need to develop new prevention strategies to inhibit the transmission of HIV-1. In the absence of a successful vaccine, topical microbicides represent the best strategies to reduce the epidemic. Following the success of HIV therapeutic cocktail strategies, combinations of microbicides including nucleotide reverse transcriptase inhibitors (NtRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) may offer significant protection from infection over single agents. We have developed a combination microbicide gel formulation for the delivery of IQP-0528, a novel NNRTI, and tenofovir (TFV), a NtRTI. Gel formulations were evaluated based on quantitative viscoelastic and physiochemical evaluations defined by a target product profile (TPP). For the majority of the evaluations, the gel formulations behaved similarly; all showed shear thinning behavior, were stable, nontoxic, and active against HIV-1 infection. Gel formulation F2759 displayed increased drug release of 289 ± 100 µg/(cm2 h1/2) and a tissue permeability of 60 times the half maximal effective concentration (EC50) of TFV and 800 times the EC50 of IQP-0528. In addition, F2759 showed osmolality within TPP and the highest performance in gel spreading. We have identified a gel formulation to deliver a combination microbicide of IQP-0528 and TFV that has significant potential to prevent infection of HIV-1.

Section snippets

INTRODUCTION

With over 33 million HIV-positive individuals worldwide, it is of particular importance to provide women with female controlled prevention methods such as vaginally applied gel microbicides to reduce the increased frequency of male to female virus transmission.1., 2. Several gel formulations of microbicide products that showed promising anti-HIV activity have been considered for clinical development, such as PRO20003 and BufferGel.4 More recently, HIV reverse transcriptase inhibitors such as

Compounds

IQP-0528 was provided by Samjin Pharmaceutical Company (Seoul, Korea) and is exclusively licensed to ImQuest BioSciences Inc. (Frederick, Maryland). TFV was provided by the International Partnership for Microbicides (GS-1278 PMPA; Bethlehem, Pennsylvania).

Virus and Cells

The HIV-1IIIB11 and HIV-1BaL were obtained from the NIAID AIDS Research and Reference Reagent Program (Rockville, Maryland). TZM-bl-FcRI cells were a gift from David Montefiori at Duke University (Durham, North Carolina).

Active Pharmaceutical Ingredients, APIA–APIB, Compatibility in the Formulation Base

The compatibility of

API–API Compatibility

The IQP-0528 was used as received as it was measured to have a sufficiently small and uniform particle size with a mean of approximately 3 µm. Poloxamer 407, Polyoxyl 40 hydrogenated castor oil, and Polysorbate 80 were identified as materials capable of effectively dispersing IQP-0528 at a concentration of dispersant as low as 0.05%. Chemical stability of both APIs as measured via UPLC analysis was found to be acceptable for each dispersant through 4 weeks (data not shown). Polyoxyl 40

DISCUSSION

In this study, the formulation of a combination microbicide gel product was developed comprising of the dual-acting NNRTI IQP-0528 and the NtRTI TFV. Instead of using the universal placebo HEC “baseline” gel formulation and evaluating the performance of the microbicides in a well-established gel,26 unique formulations tailored to the IQP-0528–TFV combination were developed to deal with the specific solubility and chemical properties of the two APIs. Therefore, all excipients chosen for the gels

Acknowledgements

This research was supported by the International Partnership for Microbicides and the National Institutes of Health (grant NIH 5 U19 AI077289).

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