Pharmaceutical development of microbicide drug products

Abstract

HIV infection rates in the developing world remain a serious problem. One potential approach to reduce infection rates is to use products known as microbicides, referred to herein as microbicide drug products (MDPs). These are drugs capable of, when administered topically to the vagina (or rectum), interfering with infection by one or more mechanisms. This review article covers the latest pharmaceutical developments in the area of microbicides dosage forms and delivery systems. These products are principally designed for use in the developing world and must therefore address cultural and societal issues generally unknown in the developed world. The first-generation microbicides evaluated clinically were principally polyanions. These drugs, administered intravaginally as gels, were found to be ineffective in preventing transmission of HIV from men to women. Second-generation drugs such as tenofovir, dapivirine, and UC781 are reverse transcriptase inhibitors developed as gels formulations and intravaginal rings (IVRs). Gels are considered coitally-related products while IVRs are coitally-independent systems designed to release the drug over a four-week period or possibly longer (up to 3 or 4 months). Other dosage forms under development include fast dissolving films, tablets/capsules, and possibly vaginal sponges. Dual protection systems are also under development. These systems include formulations capable of preventing HIV infection along with a second drug capable of preventing conception or other viral infections such as HSV.

UC781 Microbicide Gel Retains Anti-HIV Activity in Cervicovaginal Lavage Fluids Collected following Twice-Daily Vaginal Application

“…A previous preclinical study of UC781 microbicide gel in macaques was unable to detect UC781 in clarified CVL samples, as most UC781 was likely pelleted and removed prior to analysis of clarified CVL samples (20). Focusing on insoluble and pelletable fractions of CVL samples may be especially important when examining other candidate hydrophobic compounds with low solubility, such as dapivirine (14).…”

“…A primary concern of clinical evaluations of microbicides is that the compound being tested should demonstrate anti-HIV activity following exposure to the female genital tract. In this study, we investigated whether UC781 was inactivated in vivo, possibly through contact with enzymes or microflora in the vaginal mucosa that might render intravaginal products ineffective over time, as was suggested previously (14). Testing T 8-24 h CVL-p samples for anti-HIV activity indicated that UC781 blocked large inocula (Ն4 TCID 50 ) of a virus most likely to be sexually transmitted to HIVnegative Thai women.…”

A Hot-Melt Extruded Intravaginal Ring for the Sustained Delivery of the Antiretroviral Microbicide UC781

“…10 Intravaginal rings (IVRs) are the leading dosage form being considered for the development of long-acting microbicide products. [15][16][17] UC781 is a nonnucleoside reverse transcriptase inhibitor (NNRTI) that has undergone preclinical and clinical investigation as a microbicide. [18][19][20] UC781 demonstrates nanomolar potency in vitro against both wild-type and NNRTI-resistant HIV-1 strains.…”

3-Hydroxyphthalic Anhydride-Modified Human Serum Albumin as a Microbicide Candidate Against HIV Type 1 Entry by Targeting Both Viral Envelope Glycoprotein gp120 and Cellular Receptor CD4

“…1 Therefore, an alternate strategy to prevent sexually transmitted infections (STIs) and decrease HIV infection rates is to develop female-controlled microbicides. [2][3][4] Up to now, almost two decades of research on microbicide candidates for the prevention of sexual HIV transmission have resulted in limited success. 5 The reports of earlygeneration microbicides tested clinically have shown them to be ineffective in protecting against HIV infection because of their low in vivo anti-HIV activities or high toxicity on vaginal epithelium.…”