A Preformulation Strategy for the Selection of Penetration Enhancers for a Transungual Formulation

Abstract

Onychomycosis is associated with the cutaneous fungal infection of the nail and the nail folds (skin surrounding the nail). It is therefore important to target drug delivery into the nail folds along with nail plate and the nail bed. Systematic and strategic selection of the penetration enhancers specific for the skin and the nail is discussed. Twelve penetration enhancers were screened for their ability to improve solubility, in vitro nail penetration, in vitro skin permeation, and in vitro skin penetration of the antifungal drug ciclopirox olamine. In contrast to transdermal drug delivery, the main selection criteria for skin penetration enhancer in topical drug delivery were increased drug accumulation in the epidermis and minimal permeation across the skin. Thiourea improved the solubility and nail penetration of ciclopirox olamine. It also showed enhancement in the transungual diffusion of the drug. Propylene glycol showed a 12-fold increase in solubility and 3-fold increase in epidermal accumulation of ciclopirox olamine, while minimizing the transdermal movement of the drug. Thiourea was the selected nail permeation enhancer and propylene glycol was the selected skin penetration enhancer of ciclopirox olamine. A combination of the selected enhancers was also explored for its effect on drug delivery to the nail and nail folds. The enhancer combination reduced the penetration of ciclopirox in the skin and also the permeation through the nail. The proposed preformulation strategy helps to select appropriate enhancers for optimum topical delivery and paves way towards an efficient topical formulation for passive transungual drug delivery.

Novel nail penetration enhancer containing vesicles “nPEVs” for treatment of onychomycosis

“…Upon preparation of nPEVs, formulae N7-N12 prepared using thioglycolic acid showed instant aggregation, similar to what was reported with Palliyil et al, (2013) when encapsulating the drug ciclopirox olamine, hence, they were excluded from further experiments. Furthermore, formulae N13-N18 prepared using thiourea displayed an overall micrometer sized aggregates, hence they were excluded from further experiments as well.…”

“…The glass vials were sealed and incubated at room temperature for 24 hours and then the nail clippings were reweighed after thorough tissue paper wiping to calculate weight gain (Chouhan & Saini, 2012 For the transungual drug uptake experiment, quantification of the amount of sertaconazole which penetrated into the nail clippings was determined using HPLC. The nail clippings of groups 2 and 3 were washed three times with methanol to remove any traces of drug on the surface, then they were dissolved in 1 M sodium hydroxide (1 ml) by constant overnight stirring (Chouhan & Saini, 2012;Palliyil et al, 2013). After complete digestion of the nail clippings, the solutions were filtered by 0.22 mm syringe filter, and an aliquot was taken and diluted with methanol followed by HPLC analysis.…”

“…After complete digestion of the nail clippings, the solutions were filtered by 0.22 mm syringe filter, and an aliquot was taken and diluted with methanol followed by HPLC analysis. The enhancement factor (EF nail ); denoting the improvement of sertaconazole penetration into the nail clippings from nPEVs compared to Dermofix Õ cream was calculated according to the following equation (Chouhan & Saini, 2012;Palliyil et al, 2013):…”

“…The concentration of nail penetration enhancers was restricted to a maximum of 5%, since higher concentrations were reported to significantly soften the nail to a clinically undesirable level (Palliyil et al, 2013).…”

“…In addition, transcutol was reported to increase the permeation through bovine hooves membrane which is structurally similar to the human nails, through the induction of conformational changes in the keratin structure (Shivakumar et al, 2012). The chosen nail penetration enhancers (N-acetyl-L-cysteine, thiourea and thioglycolic acid) were reported to increase the flux across the nail plate through reduction of disulphide linkages in the keratin of the nail, associated with pore formation and consequent swelling and softening of the nail plate, leading to reduction of nail barrier integrity (Brown et al, 2009;Nogueiras-Nieto et al, 2013;Palliyil et al, 2013;Miron et al, 2014). Ethanol was reported to be a nail uptake enhancer as well (Gupta & Paquet, 2013).…”