Poster CC19 - Hypotonic, gel-forming delivery system for vaginal drug administration

Introduction: Drug delivery systems for diseases and conditions of the female reproductive tract (FRT) are severely lacking. Local delivery to the FRT offers an opportunity to achieve high drug concentrations at the target site while minimizing systemic effects. However, vaginal delivery has unique challenges such as hindered distribution due to the folded architecture of the vaginal canal and intra-abdominal pressure. Current dosage forms include gels, creams, rings and washes which are difficult to administer, cause unpleasant discharge, and are often hypertonic resulting in product clearance. Pluronic F127 is a thermosensitive tri-block co-polymer that gels at or above its critical gel concentration (CGC). Formulating F127 below its CGC in a hypotonic vehicle creates a delivery vehicle that gels uniformly along the vaginal epithelium upon administration.

Materials and

Methods: The gelling vehicle was formed by dissolving F127 in water and mixing overnight at 4°C. In order to characterize the behavior of F127 gels in vitro, the F127 concentration must be above the CGC (~15.5-16%), thus we used 20% F127 w/w. The ability of the gel to resist erosion was evaluated 37°C while flowing fluid at a controlled rate tangentially over the surface of the gel and sampling the exit fluid. Viscosity as a function of temperature and gel tackiness and adhesion force was measured using an Anton Paar cone and plate rheometer. Excipients “generally regarded as safe” (GRAS) and used in other gel and cream products, HPMC, PEG400 and HEC, were added to assess the impact on F127 gelation. Various polymer concentrations ranging 2 to 20% F127 from were tested in female mice for vaginal retention and distribution to determine the ideal polymer concentration for application. Progesterone (P4) in the form of a nanosuspension was loaded in the gelling vehicle (ProGel) to assess efficacy of drug delivery in a mouse model and compared to Crinone, a commercially available product that has been tested for prevention of preterm birth (PTB). After repeated dosing in mice, tissues were collected and histology assessments were made in partnership with Johns Hopkins Phenotyping and Experimental Pathology Core.

Results, Conclusions, and Discussions: None of the excipients caused a significant difference in erosion time of the gel. At 17°C none of the excipients significantly changed the viscosity but at 37°C all of the excipients significantly increased the viscosity by similar amounts. Only HPMC significantly increased the maximum tack force and adhesion forces by about 1.5-fold. Formulating F127 at 10% w/w in a hypotonic solution resulted in a thin, evenly distributed gel coating on the vaginal epithelium in mice. This gel coating did not cause tissue toxicity, affect the mucosa, or result in unpleasant discharge. Additionally, ProGel delivered P4 at an equivalent concentration and was equally as effective as Crinone in preventing PTB, with reduced toxicity. Using F127 as a gel forming delivery system for local delivery to the FRT provides an effective dose of drug and an improved delivery system for vaginally administered drugs while limiting potential systemic side effects. The F127 gel vehicle is versatile and has the potential to be adapted to deliver a variety of drugs to the FRT.

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