Chitosan gel containing polymeric nanocapsules: a new formulation for vaginal drug delivery

Abstract

The vaginal route of administration is an alternative for several treatments for either local or systemic pharmacological effects. However, the permanence of a drug in this route represents a challenge for formulation development that can be overcome by using nanoencapsulation and chitosan gel. Thus, this work aimed to evaluate the performance of chitosan hydrogels containing cationic and anionic acrylic-based nanocapsules (Eudragit RS 100 and Eudragit S 100, respectively) with Nile red as a model of lipophilic substance in the vaginal route of administration, as measured by increases in the residence time and the penetration of these formulations. Several formulations were prepared with increasing chitosan concentrations, and were analyzed in terms of pH and rheological behavior so that the most suitable formulation could be selected. The enhancement of the adhesion (tensile stress test and washability profile) and penetration (confocal laser scanning microscopy and extraction followed by quantification) properties of the formulations, when applied to porcine vaginal mucosa, were evaluated. The nanocapsule suspensions produced presented adequate properties: size of approximately 200 nm (polydispersity index of ≤0.2); zeta potential around +10 mV for the cationic formulation and -10 mV for the anionic formulation; and pH values of 6.1±0.1 (Eudragit RS 100), 5.3±0.2 (Eudragit S 100), 6.2±0.1 (Nile red loaded Eudragit RS 100), and 5.1±0.1 (Nile red loaded Eudragit S 100). The chitosan formulation presented suitable viscosity for vaginal application and acidic pH (approximately 4.5). The tensile stress test showed that both formulations containing polymeric nanocapsules presented higher mucoadhesion when compared with the formulation without nanocapsules. In the washability experiment, no significant differences were found between formulations. Confocal microscopy and fluorescence quantification after extraction from the mucosa showed higher penetration of Nile red when it was nanoencapsulated, particularly in cationic nanocapsules. The formulations developed based on chitosan gel vehicle at 2.5% weight/weight containing polymeric nanocapsules, especially the cationic nanocapsules, demonstrated applicability for the vaginal delivery of hydrophobic substances.

Keywords: Eudragit® RS 100; Eudragit® S 100; nanotechnology; vaginal route.

Figures

Figure 1

Viscosity as a function of shear rate graphs. Notes: (A) Chitosan hydrogels, (B) chitosan hydrogels with Eudragit® RS 100 nanocapsules, and (C) chitosan hydrogels with Eudragit® S 100 nanocapsules (Evonik Industries AG, Essen, Germany). Mean ± standard deviation, n=3. Abbreviations: CH, chitosan hydrogel; CH-RS, chitosan hydrogel with Eudragit RS 100 nanocapsules; CH-S, chitosan hydrogel with Eudragit S 100 nanocapsules.

Figure 2

Mucoadhesion of chitosan hydrogels (2.5% chitosan) determined by the force of detachment and the distance of stretching to detach from the mucosa (mean, n=6). Notes: Eudragit® RS 100 and Eudragit® S 100 (Evonik Industries AG, Essen, Germany). The area under the curve represents the work (ie, the product of force and distance) necessary to detach a formulation from the mucosa. Such work values [W(CH); W(CH-RS); W(CH-S)] are a representation of the mucoadhesive properties of each formulation. Abbreviations: CH, chitosan hydrogel; CH-RS, chitosan hydrogel with Eudragit RS 100 nanocapsules; CH-S, chitosan hydrogel with Eudragit S 100 nanocapsules.

Figure 3

Nile red washability profiles after incorporation into chitosan hydrogels (mean ± standard error, n=3). Notes: 2.5% chitosan. Eudragit® RS 100 and Eudragit® S 100 (Evonik Industries AG, Essen, Germany). Abbreviations: CH, chitosan hydrogel; CH-RS, chitosan hydrogel with Eudragit RS 100 nanocapsules; CH-S, chitosan hydrogel with Eudragit S 100 nanocapsules; NR, Nile red.

Figure 4

Quantification of Nile red accumulation into vaginal mucosa as a function of mucosa depth, after incorporation into chitosan hydrogels (mean ± standard error, n=3). Notes: 2.5% chitosan. *P<0.001. Eudragit® RS 100 and Eudragit® S 100 (Evonik Industries AG, Essen, Germany). Abbreviations: CH, chitosan hydrogel; CH-RS, chitosan hydrogel with Eudragit RS 100 nanocapsules; CH-S, chitosan hydrogel with Eudragit S 100 nanocapsules; NR, Nile red.

Figure 5

Confocal laser scanning microscopy images of the vaginal mucosa after application of chitosan gels containing Nile red. Notes: 2.5% chitosan. The pictures are representatives of the measurement of three different batches: (A) blank; (B) CH–NR; (C) CH-RS–NR, (D) CH-S–NR. Eudragit® RS 100 and Eudragit® S 100 (Evonik Industries AG, Essen, Germany). Abbreviations: CH, chitosan hydrogel; CH-RS, chitosan hydrogel with Eudragit RS 100 nanocapsules; CH-S, chitosan hydrogel with Eudragit S 100 nanocapsules; NR, Nile red.