ABSTRACT
Cabotegravir (CAB) is an antiretroviral therapy (ARV) used for Human Immunodeficiency Virus (HIV) treatment. CAB has low solubility, which affects its bioavailability in oral therapy. Moreover, the injection form of CAB has difficulty in the administration process. Therefore, it is essential to develop a new drug delivery system for CAB. Vaginal drug delivery system offers many advantages such as a large surface area, increased drug bioavailability, and improved drug delivery. CAB was developed in thermosensitive and mucoadhesive vaginal gel preparations that provided optimal distribution in the vaginal mucosa. To support the process of formulation development, in this study, UV-visible spectrophotometry method was validated in methanol, simulated vaginal fluid (SVF) and vaginal tissue to quantify the amount of CAB in the gel preparations, in vitro, and ex vivo studies, respectively. The developed analytical method was subsequently validated according to ICH guidelines. The calibration curves in these matrices were found to be linear with correlation coefficient values (R2) ≥ 0.998. The LLOQ values in methanol, SVF and vaginal tissue were 2.15 µg/mL, 2.22 µg/mL, and 5.13 µg/mL, respectively. The developed method was found to be accurate and precise without being affected by dilution integrity. These methods were successfully applied to quantify the amount of CAB in gel preparations, in vitro, and ex vivo studies, showing uniformity of drug content and controlled release manner in the permeation profile for 24 h for both thermosensitive and mucoadhesive vaginal gels. Further analytical method is required to be developed for the quantification of CAB in in vivo studies.
Subject(s)
Pyridones , Vagina , Animals , Drug Delivery Systems , Female , Gels , Humans , Spectrophotometry , SwineABSTRACT
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.
