Development of mucoadhesive adapalene gel for biotherapeutic delivery to vaginal tissue

Abstract

Purpose: Alternate formulation strategies need to be devised for improving the absorption and bioavailability of drug molecules administered through the intravaginal route. Enhancing the coating of vaginal mucosa can aid the achievement of this goal. The aim of the current study is to develop a mucoadhesive formulation having adequate adhesiveness, spreading, and viscosity profiles that can ensure good tissue absorption of adapalene upon intravaginal application. Method: A combination of mucoadhesive agents has been employed, including Carbopol-934, HPMC K-15M, and xanthan gum, in varying ratios to formulate five different gels. Furthermore, a cost-effective UV-spectroscopic analytical method was developed to quantify the amount of adapalene in tested samples, both of in vitro and in vivo origin. The analytical method was validated for different parameters, including specificity, linearity, range, accuracy, precision, and ruggedness. The modified USP-II apparatus was used for dissolution studies, while in vivo pharmacokinetic validation was performed in a murine model. Result: Of all the tested formulations, on the basis of the rheo-mechanical attributes, ACX3 performed better than the rest, including the commercially available intravaginal reference product. ACX3 had an average adhesion time of 12 min and a spread diameter of 37 mm. It showed 35 mm as average distance travelled by the diluted sample for leakage assessment. The analytical method developed for the adapalene muco-adhesive gel was within the range for all the validation parameters. For further evaluating the performance of the formulation, dissolution studies were conducted in simulated vaginal conditions which showed 94.83% of drug release within 5 minutes, while on completion of 30 min, it was measured to be 92.90%. Moreover, approximately 67% of the administered drug was recovered after 5 min of administration as evaluated through tissue recovery procedures in mice. Conclusion: The study aided in development of a formulation which can enhance the muco-adhesion of the drug molecule, resulting in an improved pharmacokinetic profile. Moreover, it established an efficient assay method which can be employed for in vitro and in vivo quantification of adapalene in simulated and physiological fluids.

Keywords: adapalene; assay development; dissolution; intravaginal drug delivery; mucoadhesion.

FIGURE 1

Optimization of the formulation by using Design Expert version 12. The analysis predicted 100 solutions for assessing and predicting the best formulation group. The solution with a desirability value of 1 indicated that an increase in the concentration of Carbopol 934 and xanthan gum would increase the spreadability and adhesiveness of the product along with the viscosity.

FIGURE 2

Representation of the relationship of various formulation factors and responses using Design Expert version 12. The factors included (A) Carbopol, (B) HPMCK-15M, and (C) xanthan gum, while the responses included adhesiveness, spreadability, and viscosity.

FIGURE 3

Graphical representation of the in vitro dissolution study for the assessment of the release of adapalene from the mucoadhesive vaginal gel (n = 3). The numeric values on the y-axis represent the percentage of dissolved adapalene (from the initial loaded dose 1 g of 1% adapalene muco-adhesive gel) and release pattern in the dissolution medium plotted against time.

FIGURE 4

Assessment of in vivo absorption of adapalene from the developed mucoadhesive gel. The numeric values on the y-axis represent the average percentage of adapalene recovered from the cervical tissue of mice plotted against time (n = 3).