Abstract
Purpose: To develop an ethylene-vinyl acetate (EVA) matrix system containing a permeation enhancer for enhanced transdermal delivery of torasemide.Methods: The solubility of torasemide was studied at various volume fraction of polyethylene glycol (PEG) 400. The effect of drug concentration was tested at 1.0, 2.0 and 3.0 %, respectively while the effect of temperature on drug release from drug-EVA matrix was evaluated at 27, 32, 37 and 42 oC. To increase pore size and flexibility of the EVA matrix, plasticizers with citrate and phthalate groups were added to the matrix containing torasemide. To improve the penetration of torasemide from the EVA matrix across the skin, enhancers (propylene glycol derivatives, fatty acids, glycerides, pyrrolidones and non-ionic surfactants) were incorporated into the torasemide-EVA matrix. The effects of the enhancers on the skin penetration were evaluated using Franz diffusion cell fitted with the intact excised rat skin. Results: Solubility and permeation of torasemide was highest at 40 %v/v PEG 400. The release rate of drug from drug-EVA matrix increased with increased loading dose and temperature. Release rate was proportional to the square root of loading dose. The activation energy (Ea), which was derived from the slope of log P versus 1000/T, was 14.95 kcal/mol for 2.0% loading dose. Among the plasticizers used, diethyl phthalate showed the highest release rate of torasemide. Among the enhancers used, polyoxyethylene 2-oleyl ether showed the greatest enhancing effect.Conclusion: For the enhanced controlled transdermal delivery of torasemide, the application of the EVA matrix containing plasticizer and penetration enhancer could be useful in the development of atransdermal drug delivery system.Keywords: Torasemide, Ethylene-vinyl acetate, Controlled transdermal delivery, Matrix, Plasticizer, Permeation enhancer
Highlights
Torasemide has been used to treat edema and primary hypertension and to prevent kidney stones [1]
Transdermal drug delivery is able to avoid the harmful effects due to transient high blood concentration of drug caused by repeated oral administration and to provide sustained drug release for an extended period of time from the drug reservoir or matrix [2,3,4,5]
Preparation of ethylene-vinyl acetate (EVA) matrix containing an enhancer freshly excised full-thickness skin was mounted on the receptor site of the diffusion cell with the stratum corneum side facing upwards, i.e., the donor compartment, and the dermal side facing the receptor compartment
Summary
Torasemide has been used to treat edema and primary hypertension and to prevent kidney stones [1]. We optimized the use of a penetration enhancer in the EVA matrix and measured drug permeation across rat skin. Two grams of EVA copolymer beads was dissolved in 20 ml of chloroform in a beaker, and drug solution (torasemide-methanol) was added. This mixture was poured onto a glass plate and the solvent allowed to be evaporated at room temperature over a 24-h period. Preparation of EVA matrix containing an enhancer freshly excised full-thickness skin was mounted on the receptor site of the diffusion cell with the stratum corneum side facing upwards, i.e., the donor compartment, and the dermal side facing the receptor compartment.
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