Transdermal delivery of Diltiazem HCl from matrix film: Effect of penetration enhancers and study of antihypertensive activity in rabbit model

Abstract

The present investigation focused on the development of Diltiazem HCl (DTH) matrix film and its characterization by in-vitro, ex-vivo and in-vivo methods. Films were prepared by solvent casting method by taking different ratios of hydroxypropyl methylcellulose K4M (HPMC K4M) and Eudragit RS100. Various parameters of the films were analyzed such as mechanical property using tensile tester, interaction study by Fourier transform infrared spectroscopy (FTIR) and Thermogravimetric analysis (TGA), in-vitro drug release through cellulose acetate membrane, ex-vivo permeation study using abdominal skin of rat employing Franz diffusion cell, and in-vivo antihypertensive activity using rabbit model. The FTIR studies confirmed the absence of interaction between DTH and selected polymers. Thermal analysis showed the shifting of endothermic peak of DTH in film, indicating the dispersion of DTH in molecular form throughout the film. Incorporation of 1,8-cineole showed highest flux (89.7 μg/cm(2)/h) of DTH compared to other penetration enhancers such as capsaicin, dimethyl sulfoxide (DMSO), and N-methyl pyrrolidone (NMP). Photomicrographs of histology study on optimized formulation (DF9) illustrated disruption of stratum corneum (SC) supporting the ex-vivo results. The in-vivo antihypertensive activity results demonstrated that formulation DF9 was effective in reducing arterial blood pressure in normotensive rabbits. SEM analysis of films kept for stability study (40 ± 2 °C/75% ± 5%RH for 3 months) revealed the formation of drug crystals which may be due to higher temperature. The findings of the study provide a better alternative dosage form of DTH for the effective treatment of hypertension with enhanced patient compliance.

Keywords: Antihypertensive activity; Eudragit RS100; Matrix film; Penetration enhancers; Stratum corneum.

Fig. 1

(a) Percentage of moisture content and moisture absorption by different films containing DTH, and (b) percentage of water vapor permeation through the films containing DTH.

Fig. 2

Interaction studies: (a) FTIR spectra of pure drug, polymers and their physical mixture, and (b) thermograms of pure drug, polymers and optimized film (DF9).

Fig. 3

The in-vitro and ex-vivo study results: (a) comparison of in-vitro DTH release from different films (DF1–DF10), and (b) ex-vivo permeation profiles of DTH from various films (DF6–DF10) having different permeation enhancers.

Fig. 4

Invasive arterial blood pressure comparisons of rabbit groups treated with oral DTH solution and film with DTH with respect to control group.

Fig. 5

Photomicrographs of section of rat skin: (a) untreated; (b) treated with optimized film (DF9).

Fig. 6

Scanning electron micrographs of the optimized film: (a) fresh film; (b) 3 months aged film.