Distribution of a vaginal gel (Invisible Condom) before, during and after simulated sexual intercourse and its persistence when delivered by two different vaginal applicators: a magnetic resonance imaging study.

OBJECTIVE: The objective of this study was to evaluate the vaginal distribution of a microbicidal gel (Invisible Condom) before, during and after simulated intercourse using an artificial phallus. The gel was delivered using either a new proprietary vaginal applicator (PVA), which has multiple lateral and apical holes, or a commercial applicator (CA), which has a single apical hole. The persistence of the gel was evaluated up to 24 h after its administration. STUDY DESIGN: Nine women (five women using the PVA and four women using the CA) applied the vaginal gel once, and pelvic images were taken immediately after application. An artificial phallus was inserted and the women had 30 vaginal thrusts, then another set of images was taken while the phallus was still inside the vagina. On exit of the phallus, one more set of images was taken. Images were subsequently taken at 30 min, 2 h, 6 h and 24 h after gel application. RESULTS: Immediately after gel application, the PVA distributed the gel throughout the vaginal/cervical mucosae, while the CA delivered the gel only to the cervical area. During simulated intercourse, the phallus further pushed the gel delivered with the CA into the fornix, whereas it spread the gel delivered with the PVA more evenly throughout the mucosal surface. After simulated intercourse, both applicators gave similar gel distributions between 30 min and 6 h after application. However, at 24 h, using the PVA, only 5% of the gel persisted in the vagina, compared to 40% of the gel using the CA. DISCUSSION AND CONCLUSION: Using the new PVA, the Invisible Condom covered the vaginal/cervical mucosae before and during simulated intercourse, offering immediate protection, whereas only the cervical mucosa was covered using the CA. Forty percent of the gel persisted mostly in the upper vaginal/cervical area at 24 h following its administration with the CA, while only 5% of the gel was left using the PVA. The new applicator, with its unique design, ensures an even and immediate coating lasting throughout the first 6 h and could prevent potential microbicide vaginal toxicity at 24 h.

Update on nonoxynol-9 as vaginal spermicide.

Nonoxynol-9 (N-9) is a typical surfactant. For more than 30 years that very property of N-9 has been successfully exploited for its spermicidal action. It is available as an over-the-counter, locally acting vaginal spermicide. The suitability of N-9 as a spermicide is elaborated in this article. The reasons why N-9 may fail as a contraceptive are discussed. In spite of many drawbacks, which are mentioned in the article, N-9 is still often resorted to as a locally acting contraceptive. The review ends with suggestions to alter the molecular structure of N-9 and to adjust the dosages.

Distribution of a 3.5-mL (1.0%) C31G vaginal gel using magnetic resonance imaging.

C31G (Savvy) has been developed as a topical vaginal microbicide with broad-spectrum antibacterial and antiviral properties. The objective of this study was to evaluate the distribution of a 1.0% concentration of (3.5 mL) C31G vaginal gel in the human pelvis using magnetic resonance imaging (MRI). Gel delivery with a standard applicator was primarily to the upper vagina and was well tolerated. Vaginal mucosal coverage at 18 min was excellent with 92% linear coverage and 75% surface contact coverage of the vagina. The upper vagina was almost completely covered and gel was also noted in the lower vagina. Coverage 6 h after application was substantially decreased, with 60% of maximal linear coverage and 41% surface contact. There was a very minimal coverage of the vaginal mucosa noted 24 h following insertion. Simulated intercourse resulted in relatively little change in overall distribution at all three time points. Repeat application of the gel may be necessary if intercourse has not occurred within the first few hours after initial insertion.

Distribution of topical medication in the human vagina as imaged by magnetic resonance imaging.

OBJECTIVE: To assess the use of magnetic resonance imaging (MRI) to determine the varying distribution of a vaginally placed gel over time and with different levels of patient activity. DESIGN: Prospectives interventional trial. SETTING: University medical center. PATIENT(S): One nulliparous volunteer with normal menstrual cycles and no gynecologic disease who underwent seven MRI scans of the pelvis. INTERVENTION(S): Five mL of a commercially available topical spermicide was mixed with gadolinium-chelate magnetic resonance contrast material and introduced with a standard applicator. T1-weighted three-dimensional MRI was done to assess the distribution of the gel. MAIN OUTCOME MEASURE(S): Gel thickness and distribution. RESULT(S): The initial bolus of gel was delivered into the upper portion of the vagina, above the urogenital diaphragm. Thereafter, it spread into the vaginal fornices and "flattened" to cover the lateral aspects of the vagina. Without ambulation, the majority of spread was confined to the upper vagina. With ambulation and longer elapsed time, the gel spread further in the upper vagina and into the lower vagina, and significant vaginal surface coverage increased significantly. CONCLUSION(S): Magnetic resonance imaging can be used to monitor the spread of vaginally placed products and to evaluate coverage of topical drugs used for prevention and treatment, including those used for HIV prophylaxis.

Distribution of a spermicide containing Nonoxynol-9 in the vaginal canal and the upper female reproductive tract.

Topical, intravaginal microbicides and spermicides are greatly needed to prevent transmission of sexually transmitted diseases and/or unwanted pregnancies. The development of such compounds is a high research priority. The presumed method of action of existing, or novel, microbicides/spermicides is to provide a chemical barrier to the vaginal epithelium preventing exposure to micro-organisms. Other intravaginal products are used to treat vaginal bacteria of fungal infections. Little is known, however, about the actual or optimal initial distribution and subsequent spread of medications placed in the vagina. We describe a sensitive new technique to quantify the spread of a gel placed in the vagina using magnetic resonance imaging (MRI). Five millilitres of an over-the-counter spermicide containing Nonoxynol-9 was mixed with Gadolinium. MRI was used to quantify spread of the mixture 10 min after insertion with a standard applicator. We demonstrated contiguous spread of gel throughout the vagina. The coverage of material was thicker in the upper vagina than in the lower vagina. We also demonstrated, for the first time, that spermicidal compounds may migrate from the vaginal canal into the endocervix within 10 min of insertion. This finding suggests that topical microbicides/spermicides may act both in the vaginal canal and in the upper female genital tract.

Intravaginal toxicity studies of a gel-microemulsion formulation of spermicidal vanadocenes in rabbits.

Bis-cyclopentadienyl complexes of vanadium(IV) or vanadocenes are rapid and potent inhibitors of human sperm motility with potential as a new class of contraceptive agents. We investigated the toxicity potential of intravaginally administered gel-microemulsion formulation of two representative vanadocenes, vanadocene acetylacetonato monotriflate (VDACAC) and vanadocene dithiocarbamate (VDDTC), in the rabbit model. New Zealand White rabbits in subgroups of three were exposed intravaginally to a gel-microemulsion with and without 0.1 or 0.25% VDACAC and VDDTC for 10 consecutive days. The doses of vanadocenes used were nearly 500- to 1250-fold and 2000- to 5000-fold higher than their respective in vitro spermicidal EC50 values. Animals were euthanized on day 11 and vaginal tissues were evaluated for local toxicity by histopathology, cell proliferating activity by immunohistochemical detection of proliferating cell nuclear antigen (PCNA), and in situ apoptosis by the terminal deoxynucleotidyl transferase-mediated FITC-deoxyuridine triphosphate nick end-labeling (TUNEL) assay and confocal laser scanning microscopy (CLSM). Blood was analyzed for clinical chemistry profiles. Vanadium content in selected organs and body fluids was determined by atomic absorption spectroscopy. None of the rabbits given 0.1% VDACAC and VDDTC intravaginally developed epithelial ulceration, edema, leukocyte influx, or vascular congestion characteristic of inflammation. Only minimal to moderate irritation was observed at 0.25% VDACAC and VDDTC. A significant decrease in epithelial and stromal PCNA expression was observed in the 0.25% dose group. However, TUNEL assay and CLSM revealed no staining in the vaginal epithelium and only minimal nonspecific staining in the stroma. Repetitive intravaginal application of 0.1 or 0.25% VDACAC and VDDTC had no adverse effects on clinical chemistry profiles. Vanadium was not incorporated into rabbit tissues and body fluids at levels above 1 microg/g. Thus, intravaginal administration of VDACAC and VDDTC at concentrations nearly 500 and 2000 times higher than their respective in vitro spermicidal EC50 values did not induce marked vaginal irritation, mucosal toxicity, or systemic absorption of vanadium in the rabbit model. The lack of significant mucosal or systemic toxicity of intravaginal vanadocenes observed may have particular clinical utility as a new class of contraceptive agents.

Studies on safety aspects of contraceptive Magainin-A in rabbits.

We have previously reported the contraceptive potential of Magainin-A in rats and rabbits under in vitro and in vivo condition. In this report we evaluated the effect of Magainin-A on the structural organisation of vaginal epithelium in rabbits. The effect of this compound on the erythrocytes and its rate of absorption and clearance from systemic circulation was also studied. The effective contraceptive dose of Magainin-A (1 mg) when administered intra-vaginally for five consecutive days did not induce any structural or morphological abnormalities in vaginal epithelial cells. No adverse effect was observed on the erythrocytes. The rate of Magainin-A absorption and clearance from the circulation was found to be rapid. These results suggest that Magainin-A may be used as a safe intra-vaginal contraceptive compound in future.

Duration of vaginal retention and potential duration of antiviral activity for five nonoxynol-9 containing intravaginal contraceptives.

OBJECTIVE: The purpose of this study was to determine the vaginal retention of five nonoxynol-9 intravaginal contraceptives. METHOD: An open-label crossover study in 10 premenopausal volunteers was performed at an outpatient clinical research center. The outcomes are described utilizing the median and range. RESULT: At 8 h post-instillation, the median amounts of nonoxynol-9 present in the vagina were: Delfon 7.68 mg, Conceptrol 5.18 mg, Advantage 24 1.95 mg, VCF 1.74 mg, and Semicid 1.51 mg respectively. Our calculated theoretical minimal amount needed to protect against HIV infection is 2.00 mg. CONCLUSION: The best vehicle for retaining nonoxynol-9 in the vagina appears to be foam. Further research in the effectiveness of nonoxynol-9 in prevention of the spread of HIV infection should be directed toward the use of foam vehicles to deliver nonoxynol-9 to the vagina.

Factors influencing nonoxynol-9 permeation and bioactivity in cervical mucus.

The effects of delivery gel pH and osmolarity on both the mass transport and 'biodiffusion' of the spermicide nonoxynol-9 (N9) in bovine cervical mucus were evaluated. Delivery gels were calcium chloride crosslinked alginate containing 3% N9, and were manufactured over a pH range of 3.4 to 5.9 and an osmolarity range of 300 to 900 mosmol. Mass transfer parameters (diffusion coefficients and total drug loading) were determined using a new UV spectrophotometric technique while biodiffusion (the diffusion distance into mucus at which sperm are killed) was assessed using the Double Ended Test. It was found that delivery gel pH had a significant effect on spermicidal efficacy of the alginate-N9 system; biodiffusion increased with decreasing pH. Actual N9 diffusion into mucus was found to be influenced by both the delivery gel pH and osmolarity. At high N9 concentration (near the gel/mucus interface), mass transport tended to decrease with decreasing pH at the highest osmolarity. At low concentration, mass transport tended to decrease with increasing osmolarity and decrease with increasing pH at the highest osmolarity. The difference between low and high concentration behavior can be attributed to N9 micelle formation. These findings are interpreted in the context of the design of intravaginal drug delivery vehicles for spermicides.

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.

Alteration of human sperm kinematics in cervical mucus due to nonoxynol-9.

Traditional endpoints of the double-ended test (DET), a contraceptive screening assay used to evaluate the ability of a compound to permeate cervical mucus and inhibit sperm progression, ignore important information about sublethal effects upon sperm cells. Improved contraceptive agents may capitalize on such sublethal aspects. This study utilized a DET testing protocol that included measurement of human sperm motion characteristics as an indicator of cell function within spermicide-exposed human mucus. The currently available spermicide nonoxynol-9 (N9) was used as the test compound and was dissolved in two different delivery solutions, deionized (DI) water and saline, to evaluate the effects of the osmolarity and pH of the delivery vehicle on test results. The N9-water treatment demonstrated significantly greater activity than the N9-saline treatment in terms of all measured variables, exhibiting an apparent "biopermeation" distance approximately 3 mm further into the mucus. The DI water control treatment displayed less activity than N9-saline in terms of the vanguard penetration distance, but comparable or greater activity in terms of inhibiting kinematic variables. The saline control treatment had no effect in terms of any measured variable. Dose responses to N9 of sperm in mucus were inferred from DET results combined with direct measures of N9 diffusion. These were compared to dose responses to N9 of seminal sperm, indicating that N9 inhibits sperm motion at lower concentrations in mucus than in semen.

PIP: The double-ended test (DET) generally used to assess the ability of new spermicidal compounds to permeate cervical mucus and inhibit sperm progression overlooks the importance of sublethal effects on sperm cells. This study utilized a DET protocol that incorporated measurement of human sperm motion characteristics as an indicator of cell function within nonoxynol-9-exposed human mucus. Nonoxynol-9 was dissolved in both deionized water and saline to assess the effects of the osmolarity and pH of the delivery vehicle. All variables exhibited significant effects due to the nonoxynol-9-water treatment at distances as far as 13 mm into the mucus. The water treatment exhibited a biopermeation distance approximately 3 mm further into the mucus than the saline treatment and greater activity in terms of inhibiting kinematic variables. On the other hand, penetration of vanguard sperm was inhibited more by nonoxynol-9-saline. The reduction in straightline velocity of sperm was due more to a disruption in the pattern of motion than a reduction in overall sperm vigor. The measurements of sperm motility obtained in this study can be combined with information about local nonoxynol-9 concentrations in mucus to infer the dose-response of nonoxynol-9 against sperm in mucus. Overall, these findings indicate that the use of hypotonic solutions to deliver contraceptive agents can significantly increase the efficacy of the compounds through both increased transport rates and added bioactivity due to the carrier itself.

Evaluation of the amount of nonoxynol available in condoms for the inhibition of HIV using a method based on HPLC.

A method is described for detection of nonoxynol in condoms, based on methanol-water extraction followed by reverse-phase high-performance liquid chromatography. Using this method, we found that approximately 50% of the nonionic surfactant lubricant nonoxynol migrated into elastomers (rubber latex), resulting in a concentration of nonoxynol insufficient to inhibit human immunodeficiency virus (HIV) (less than 0.05%). In order to minimize the risk of sexual transmission of HIV, and to ensure spermicidal effect and optimal rubber properties, the concentration of nonoxynol in condoms, therefore, should either be increased, or nonoxynol should be packed separately. Further studies are needed to clarify and determine the solubility and migration of nonoxynols into elastomers.

Ceramic systems for long-term delivery of chemicals and biologicals.

Evaluation of devices, drugs, and drug delivery systems have been investigated by both in vitro and in vivo procedures. Ceramic drug delivery systems can be used to evaluate chemicals and biologicals by both in vitro and in vivo procedures. The system can also reduce handling of the animals and facilitate long-term evaluations before conducting clinical trials. To date, ceramic systems have been used to deliver aldosterone, androstanedione, beta-lactoglobulin, bovine serum albumin, chymotrypsin, danazol, difluoromeythylornithine, dihydrotestosterone, estradiol, gamma globulin, gonadotrophic releasing hormone, gossypol, growth hormone, insulin, methylene blue, pepsin, progesterone, and testosterone. The data obtained suggest that ceramic delivery systems can be used in the near future to treat diseases requiring long-term chronic drug therapy as well as disorders caused by deficiency of certain hormones.