Study of the vaginal tolerance to acidform, an acid-buffering, bioadhesive gel

Abstract

Vaginal tolerance tests were performed with a new potential microbicidal and spermicidal product, an acid-buffering vaginal gel (Acidform) without or with nonoxynol-9 (N-9). The potential advantages over other vaginal products include keeping a low pH, decrease of the irritating effect of N-9 on the cervix or vaginal mucosa associated with greater retention of the product after application, and decreasing “messiness” as compared to other vaginal products. Three groups of six women were admitted and randomly assigned to use Acidform with 0%, 2.5%, and 5% N-9. Colposcopic evaluation for vulvar, vaginal, and cervical signs of irritation was performed and photographs were taken, following a specific World Health Organization protocol, at time 0, and after 24 h and 6 days of application of the gel. No irritation or symptom was reported by users of Acidform without N-9. A generalized and intense erythema in cervix was observed in 10 of 12 Acidform/N-9 users and abrasion occurred in nine of them. Vulvar irritation was seen in seven of these 10 volunteers. N-9 concentration in the gel (2.5% or 5.0%) was not related to the findings. No ulcer, exulceration, or de-epithelialization was observed. Acidform without N-9 was well tolerated by volunteers, but it was unable to protect the cervix, vagina, and vulva from the N-9 effects.

Introduction

Since the world became aware of the severity and pandemic proportions of human immunodeficiency virus (HIV) infection, and that no sexually active individual was free of the risk of acquiring AIDS, the need to develop protection from HIV contamination became a priority in medical research. Until then, sexually active couples felt well protected against the risk of unwanted pregnancy through the use of the highly effective contraceptives available, including hormonal, intrauterine, and surgical methods. None of them, however, reduce the risk of being infected by sexually transmitted diseases (STD) during intercourse.

The only method that has been proved to be effective in reducing HIV transmission, as well as other STD, is the male condom.1 The condom, however, has relatively low contraceptive effectiveness,2 which has led to the recommendation of “dual protection,” consisting of the concomitant use of a highly effective contraceptive method and the condom. The problem with the condom is that cooperation of men is required. In a few countries, such a cooperation has significantly increased, but not satisfactorily so in many other countries.3 Thus, research to develop a controlled method for women that would protect them against STD/AIDS transmission of HIV and other STD-causing organisms, with or without concomitant contraceptive effect, should be given high priority to improve women’s sexual and reproductive health. The female condom was the first product made available, but adherence and cost are its main problems.4 As an option, female vaginal methods can conceivably fulfill this purpose.

The acidic pH of the vagina appears to be an efficient mechanism for the defense against cervico-vaginal infections, but this has only been poorly explored. The vaginal contents with a pH of 3.5–4.5 was capable of inhibiting the appearance of Chlamydia inclusions in McCoy cell cultures.4 Other authors have reported that the increase in vaginal pH coincided with higher rates of bacterial vaginosis and trichomoniasis.5

Studies of the spermicide nonoxynol-9 (N-9) as a method to prevent STD infections in women, have suggested its efficacy in reducing Neisseria gonorrhoeae infections, and in vitro tests had demonstrated its capacity to kill HIV.1, 4, 6 Clinical studies had given conflicting results concerning protection against HIV infection.7, 8

On the other hand, much controversy exists about the vaginal/cervical irritation caused by substances such as N-9.9, 10, 11 As a frequent finding in some clinical studies, epithelial disruption may increase the risk of infection. Therefore, alternative solutions are being studied.

The Program for the Topical Prevention of Conception and Disease (TOPCAD) is a university-based initiative with the specific purpose of developing a women’s controlled method that would protect against disease and pregnancy. One of TOPCAD’s approaches has been to develop a product that maintains the acidity (pH 3.5–4.5) of the normal vaginal environment, even in the presence of semen. A number of STD-causing organisms, including HIV, are inactivated at such a low pH.4, 5 A pH < 5.0 causes rapid decline in sperm motility and fertility.12 In addition, it was deemed desirable for such a product to form a bioadhesive layer over the vaginal and cervical walls, protecting the mucosa from contact with HIV or other STD-causing microbes. Such a layer might also protect against the irritating properties of N-9 by incorporating the agent and releasing it slowly. As a result of TOPCAD’s efforts, a new bioadhesive, acid-buffering gel, called Acidform, was formulated consisting entirely of GRAS (generally regarded as safe) components except for one which, although not a GRAS ingredient, is frequently used in marketed vaginal preparations. The gel is buffered at pH 3.55. Preclinical studies showed the in vitro buffering capacity and spermicidal efficacy of Acidform as well as its vaginal tolerance in rats and rabbits. When diluted 1:1 with semen, the pH becomes 4.0. Even if a twofold excess of semen is used, the pH is still 4.5. Acidform itself (without nonoxynol-9) is also quite spermicidal, immobilizing 100% of the spermatozoa even when diluted 10-fold before addition to semen.13

The goal of this study was to evaluate whether Acidform in the absence or presence of N-9, is irritating to the lower genital tract mucosa, when careful colposcopic observations are performed.