A phase I comparative study of contraceptive vaginal films containing benzalkonium chloride and nonoxynol-9. Postcoital testing and colposcopy.

Benzalkonium chloride (BZK) has been shown in in vitro and in vivo studies to immobilize sperm, to be active against STD-causing organisms, and to penetrate and thicken cervical mucus. A US clinical study of a sponge containing 60 mg BZK showed life table pregnancy rates at 6 and 12 months of 11.7 and 18.9 per 100 women, respectively. BZK is not currently marketed in the US as a contraceptive. The present study aimed to assess 1) the ability of a new contraceptive vaginal film containing either of two doses of BZK to prevent the penetration of sperm into midcycle cervical mucus; 2) the effect of the film on the vaginal epithelium; and 3) the acceptability of the film. All results were compared with VCF, a currently marketed film containing nonoxynol-9 (N-9). Ten women underwent two baseline cycles of postcoital testing in which no film was used, followed by three test cycles in which Allendale-BZK film, a new film containing either 19 or 25 mg BZK, or VCF, containing 70 mg N-9, was used. The sequence of testing cycles was randomized. In each cycle, condoms were used prior to midcycle, then a midcycle cervical mucus specimen was examined to ensure midcycle characteristics and the absence of sperm. Each woman then had intercourse using either no film (baseline cycles) or a test film (test cycles) and returned 2-3 h afterwards. Cervical mucus was again assessed for adequacy and the presence of sperm. Each woman also underwent colposcopy, using a protocol developed by the World Health Organization. The average number of progressively motile sperm seen per high power field was as follows: first baseline cycle, 22.2; second baseline cycle, 22.1; test cycle with film containing 19 mg BZK, 0.2; test cycle with film containing 25 mg BZK, 0.0; and test cycle with VCF containing 70 mg N-9, 0.0. There was no significant difference between baseline cycles or among test cycles in the average number of progressively motile sperm seen (p = 0.78 and p > or = 0.75, respectively). The average number of progressively motile sperm seen in each test cycle did, however, differ significantly from the average number seen in either baseline cycle (p < 0.01). Colposcopy showed superficial de-epithelialization without underlying inflammation in 15-20% of baseline cycles, regardless of whether colposcopy was done before or after coitus; in 50% of cycles in which either dose of BZK was used; and in 69% of cycles in which VCF was used. In all cases women were asymptomatic. Erythema and petechiae were also seen on colposcopy although at a lower frequency than de-epithelialization. There was no difference in the acceptability of the films. A vaginal contraceptive containing either 19 or 25 mg BZK in a new film base appears to be comparable with VCF in preventing sperm from entering midcycle cervical mucus and may be somewhat less disruptive to the vaginal epithelium.

PIP: Both in vitro and in vivo studies have confirmed the capability of benzalkonium chloride (BZK) to immobilize sperm, protect against sexually transmitted pathogens, and penetrate and thicken cervical mucus. In this Phase I study, 10 US women underwent 2 baseline cycles followed by 3 experimental cycles in which either a new contraceptive vaginal film containing 19 or 25 mg of BZK or a currently marketed film containing 70 mg of nonoxynol-9 (N-9) was used. After a midcycle cervical mucus specimen was analyzed, each woman had intercourse using either no film or a test film and was evaluated 2-3 hours later. The average number of progressively motile sperm seen per high power field was as follows: first baseline cycle, 22.2; second baseline cycle, 22.1; test cycle with film containing 19 mg BZK, 0.2; test cycle with film containing 25 mg BZK, 0.0; and test cycle with film containing 70 mg N-9, 0.0. Colposcopy revealed superficial de-epithelialization without underlying inflammation in 15-20% of baseline cycles, 50% of BZK test cycles, and 69% of cycles in which the N-9 film was used. Women rated both films as neutral or pleasant in terms of appearance, smell, and feel. These findings suggest that contraceptive vaginal films containing either 19 or 25 mg of BZK are as effective as N-9 containing films and may be somewhat less disruptive to the vaginal epithelium. However, since each woman used each BZK film only once, the effects of multiple use on the vaginal epithelium and microflora require further study.

An evaluation of the amount of nonoxynol-9 remaining in the vagina up to 4 h after insertion of a vaginal contraceptive film (VCF) containing 70 mg nonoxynol-9.

The objectives of this study were to determine the amount of nonoxynol-9 (N-9) remaining in the vagina 30 min and 1, 1.5, 2, and 4 h after vaginal insertion of a single sheet of VCF containing 70 mg N-9 and to compare these results to the manufacturer's instructions for use of this product. A new method of vaginal lavage was used to obtain samples for N-9 determination. This was an open-label, noncomparative, pharmacokinetic study in 12 healthy women volunteers not at risk for pregnancy. The study consisted of a screening visit followed by five test visits approximately 1 month apart and a final visit 1 week after all test visits were completed. At each test visit, the investigator inserted a single sheet of VCF in the vagina of the volunteer at midcycle. The volunteer remained in the clinic and underwent vaginal lavage with normal saline after one of five specified time intervals had elapsed. The sequence of the intervals completed by each volunteer was determined by randomization. When undissolved film was found in the vagina, it was removed prior to lavage and assayed for N-9 content separately from that recovered in lavage fluid. It was assumed that the N-9 in undissolved film would not contribute significantly to sperm immobilization. Between 18.5 and 28.5 mg of N-9 were recovered in lavage fluid after intervals of 0.5, 1, 1.5, and 2 h. These levels did not differ statistically (p > 0.05). The amount of N-9 recovered dropped significantly at 4 h to 11.0 mg. If it is assumed that an N-9 concentration of 0.100 mg/mL is required to immobilize sperm in vitro, this study suggests that the amount of N-9 remaining in the vagina in the form of dissolved film up to 4 h after insertion of VCF is sufficient to immobilize sperm. The lavage procedure may not have recovered all N-9 remaining in the vagina. However, intercourse did not take place between insertion and lavage; if it had, the proportion of the film remaining undissolved and the total amount N-9 remaining in the vagina at the time of examination might have been affected.

PIP: The amount of nonoxynol-9 (N-9) remaining in the vagina 0.5, 1.0, 1.5, 2.0, and 4.0 hours after vaginal insertion of a single sheet of a contraceptive film (VCP) containing 70 mg of N-9 was investigated in a pharmacokinetic study involving 12 US women. At each of 5 test visits, approximately 1 month apart, a single sheet of VCF was inserted at midcycle. Vaginal lavage with normal saline was then performed after 1 of the 5 specified time intervals had elapsed. At 30 minutes, an average of 34.4 mg (49% of the total N-9) could be recovered. After intervals of 1.0, 1.5, and 2.0 hours, 18.5-28.5 mg of N-9 was recovered in lavage fluid. The amount of recovered N-9 dropped significantly to 11.0 mg after 4.0 hours. It is assumed that an N-9 concentration of 0.100 mg/mL is required to immobilize sperm. Thus, the amount of N-9 remaining in the vagina up to 4.0 hours after insertion of VCF is sufficient for contraception. The VCF label states that intercourse may take place 15 minutes after film insertion. Although lavage was not performed at this time point, it can be assumed that at least 49% of the original N-9 would be present. Since this study is limited by the fact that intercourse did not take place, future studies should include postcoital measures of the amount of N-9 persisting at various intervals.