(W1130-03-15) On-Demand Multi-Indication Fast-Dissolving Inserts (FDIs) for Birth Control and HIV Prevention

Purpose: There is an emerging demand for Multipurpose Prevention Technology (MPT) for pregnancy and HIV prevention over products with a single indication. Most of the MPT being developed contain hormonal contraceptives, which could limit their acceptability. The present vaginal MPT fast-dissolving inserts contain non-hormonal contraceptive ingredients, which reduce health risks due to contraceptive hormones and can be used by women who are breastfeeding or are unable/unwilling to use hormonal contraception. Q-Griffithsin, a non-antiretroviral (non-ARV) lectin with potent anti-HIV activity, was incorporated into the formulation for anti-HIV indication. The developed FDIs are off-white freeze-dried formulations that promptly dissolve into clear mucoadhesive gels in an aqueous environment.

Methods: Non-hormonal-contraceptive ingredients were prepared using combinations of natural acids and optimized to match the buffer capacity of a marketed non-hormonal contraceptive gel (Phexxi). Freeze-dried formulations containing the contraceptive ingredients, gelling, and bulking excipients were prepared by a lyophilizer (Millrock Technology, NY). The freeze-dried formulations were characterized by their appearance, disintegration time in aqueous solution by Vaginal Tablet Tester (Copley Scientific, UK), buffer capacity by pH meter (Thermo Fisher Scientific,MA), moisture content by Karl Fischer titrator (Mettler Toledo, OH), hardness by hardness tester (SOTAX, MA) and friability by friability tester (SOTAX, MA). The top two formulations> (159G and 164G) that meet the quality targeted product profile were selected for future development into vaginal MPT. Pre-formulation studies were performed for QGRFT compatibility with the contraceptive actives, where the recovery of QGRFT was assayed by UPLC (Waters, NJ). MPT FDIs were formulated by incorporating QGRFT into formulations 159G and 164G. The physicochemical properties of 159G+QGRFT and 164G+QGRFT FDIs were characterized, and QGRFT content was assayed via UPLC. Lastly, the FDI formulations were assessed on the anti-sperm and anti-HIV activities.

Results: Formulations 159G and 164G with and without QGRFT exhibit white to off-white bullet shape with a smooth finish, disintegration time in aqueous solution below 1 min, moisture content below 5%, hardness of at least 18N, and friability below 5%. The pH after the dissolution of the FDIs is within the range of pH 3.5-4.5, equivalent to healthy vaginal pH. The buffer capacities of 0.5cc size FDI formulations 159G and 164G is comparable to a 1g dose of marketed contraceptive gel (Phexxi), i.e., 0.40 ± 0.03 µmol of NaOH is required to raise the pH of the FDI solutions to pH 7.5, an average pH of semen. 159G+QGRFT and 164G+QGRFT showed efficient inhibition of sperm motility within 30 sec from 1:10 dilution. QGRFT is stable upon 24h exposure with contraceptive actives used in the formulation, confirmed by UPLC analysis. The UPLC spectra showed negligible changes in the QGRFT area under the curve (AUC), peak height, and retention time. There was no sign of peak splitting, implicating an absence of degradants formed during the compatibility study.159G+QGRFT and 164G+QGRFT FDIs-based formulations showed effective anti-HIV activity in TZM-bl assay with EC50 < 0.2 nM QGRFT.

Conclusion: In conclusion, we developed novel vaginal MPT FDIs loaded with contraceptive agents and QGRFT by lyophilization. The optimized final formulations (159G+QGRFT and 164G+QGRFT) demonstrated physicochemical properties that met our quality target product profile and showed efficient inhibition of sperm motility and anti-HIV activity in vitro. For future development of the MPT FDIs, these formulations will be further assessed in preclinical animal models for safety and PK/PD studies. The innovative MPT FDI has great potential to help protect women from unintended pregnancy and HIV transmission. We envision that the fast-dissolving attribute of the vaginal MPT FDIs permits their use for pre-coital administration. Furthermore, as a solid dosage form, FDIs have the advantage of portability and ease of use over MPT gel counterparts.

Acknowledgements: The research was supported by NIH R01- 5R01AI150324, "Novel pre-coital, non-hormonal multipurpose prevention technology (MPT)."

Fig: Disintegration testing of FDI in in vitro aqueous media: A. FDI before disintegration, B. FDI after disintegration in petri dish transforming into gel like consistency, C. FDI disintegration in aqueous media in Vaginal tablet tester at 37 °C.