Development of thermosensitive and mucoadhesive gels of cabotegravir for enhanced permeation and retention profiles in vaginal tissue: A proof of concept study.

Abstract As an effective anti-HIV drug, cabotegravir (CAB) is currently administered via oral and injection routes, leading to several drawbacks, such as poor oral bioavailability and problems in the injection application process, as well as low drug concentration in vaginal tissue of woman patients. To overcome these issues, for the first time, we formulated CAB into three types of vaginal gels, considering the benefits of vaginal tissue as a delivery route. Thermosensitive gel, mucoadhesive gel, and the combination of these gels were developed as suitable carriers for CAB. Pluronics®, hydroxy propyl methyl cellulose (HPMC), Carbomer and poly(ethylene glycol) (PEG) 400 were used as thermosensitive, mucoadhesive and permeation enhancer agents, respectively. The gels were evaluated for their thermosensitive and mucoadhesive properties, as well as their pH values, viscosities, gel erosions, drug content recovery, in vitro drug release, ex vivo permeation, ex vivo retention, hemolytic activities, Lactobacillus inhibition activities and in vivo irritation properties. The results showed that all formulations showed desired characteristics for vaginal administration. Importantly, all formulations did not show hemolytic activities and inhibitions to Lactobacillus as normal bacteria in the vagina. Furthermore, no irritation in the vaginal tissues of the rats was observed by histopathological studies. Considering the thermosensitive and mucoadhesive properties, the combination of Pluronic® F127, Pluronic F68, and HPMC in thermosensitive-mucoadhesive vaginal gels was selected as the optimum dosage form for CAB as this formulation was able to provide ease administration due to its liquid form at room temperature. The use of PEG in this formulation was able to increase the penetrability of CAB through vaginal tissue with 0.61 ± 0.05 mg and 17.28 ± 0.95 mg of CAB being able to penetrate and localize in the vagina, respectively. Essentially, the optimum formulation was retained in the vaginal mucosa for>8 h. To conclude, further extensive in vivo studies should now be conducted to evaluate the efficacy of this approach.