The use of apricot oil emulsions for the transdermal delivery of selected statins

Abstract

Familial hypercholesterolemia can be described as a condition associated with significantly high levels of low-density lipoprotein (LDL) in the plasma, caused by an autosomal-dominant genetic disorder of lipid metabolism. To date, statins are considered as the first-line therapy. However effective, statin side-effects can hinder the reach of LDL target levels due to poor patient compliance. It is proposed that by utilising safe alternative ways of administration, complications with the current dosage form, might be overcome. One such route is transdermal delivery, which poses as a preferred safer alternative to oral administration. For transdermal delivery, ideal physiochemical properties of the active pharmaceutical ingredient (API) are essential. Upon investigation, it became evident that the statins possessed some ideal properties; however, inadequacies with regard to the log P and aqueous solubility were observed. Hence, the aim was to formulate and investigate oil-in-water (o/w) nano-emulsions (droplet size 20 – 200 nm), containing 2% (w/w) of the respective statin and 8% (w/w) apricot kernel oil, since literature suggests this system can aid in the delivery of molecules, which otherwise would not penetrate the skin. In this study, it is proposed that the use of apricot kernel oil as the oil phase of the nano-emulsions, would act as a chemical penetration enhancer, due to the fatty acids present in this oil, such as oleic and linoleic acid. Initially, two o/w nano-emulsion formulas were characterised, both containing 2% (w/w) API and different amounts of apricot kernel oil. Thereafter, the optimised formula was utilised to formulate a nano-emulgel. After characterisation, it was apparent that both formulas attained properties considered ideal for transdermal delivery. Firstly, membrane studies were conducted to determine whether API release from the vehicle occurred, the flux values obtained were indicative that release of the four statins occurred from each of the two respective vehicles. Thereafter skin diffusion studies were performed to assess the extent of drug absorption through the skin. Tape stripping was performed after the 12 h extraction of the receptor phase (phosphate buffer solution (PBS):ethanol (9:1 at pH 7.4)) to determine the amount of API within the skin, which is an indication to whether topical or transdermal delivery was achieved. Concentrations of each of the statins within each of the respective formulas were quantified in the receptor phase, as well as the stratum corneum-epidermis (SCE) and epidermis-dermis (ED) respectively. Thus, the aim of transdermal delivery was achieved. Lastly, in vitro cytotoxicity studies were conducted on normal immortalised human keratinocytes (HaCaT) cells, by means of a methylthiazol tetrazolium (MTT) assay and neutral red (NR) assay to determine whether the excipients used in the formulation of nano-emulsions could be considered safe for application on human skin. Subsequently, the half-maximal inhibitory concentration (IC50) of the respective statins and excipient could be established. Simvastatin alone, and within the optimised nano-emulsion, was found to be the most cytotoxic, although the concentrations tested still exceeded the amounts that diffused through the skin, suggesting only a small possibility of side-effects