Transdermal delivery of selected statins formulated in apricot kernel oil emulsions

Abstract

Statins are the leading active pharmaceutical ingredient (API) in the oral treatment of elevated cholesterol levels in the bloodstream. Oral administered statins claim to have gastro-intestinal side-effects, which could affect life quality and low bioavailability due to hepatic clearance. The goal was to formulate statins within nano-emulsions and nano-emulgels, to avoid first-pass clearance, produce an increased bioavailability and improve patient compliance. A single high performance liquid chromatographic (HPLC) method was developed and validated to produce accurate and reproducible analytical results of the statins (atorvastatin, fluvastatin, pitavastatin and pravastatin). Since these statins are incompliant to the ideal physiochemical characteristics for effective transdermal delivery of APIs, nano-emulsions and nano-emulgels containing apricot kernel oil (a natural penetration enhancer) and surfactants were used as transport systems. Subsequently, characterisation techniques were performed on the different formulas (nano-emulsions and nano-emulgels) to ensure these formulas complied with the required parameters. Cytotoxicity studies were performed on the pre-malignant human immortalised keratinocytes (HaCaT) to determine whether HaCaT cell lines were adversely affected by the statins and/or other compounds in the formulas. The Franz diffusion cell method was utilised to conduct membrane release studies to determine if the statins were released from formulas. Finally, skin diffusion studies and tape stripping were performed to evaluate the transdermal and/or topical delivery of the statins, respectively. Statistical analyses were performed to analyse the variances between the means of the data obtained from membrane release studies, as well as skin studies (transdermal and topical). Membrane release studies concluded that the nano-emulsion containing fluvastatin (NE1F) had the highest median flux amongst the nano-emulsions, while the nano-emulgel containing pravastatin (NEGPr) prevailed amongst the nano-emulgels and of all nano-formulas (nano-emulsions and nano-emulgels). Skin diffusion studies revealed that the nano-emulgels had higher median amount of statins per area that diffused through the skin when compared to their respective nano-emulsions, as the nano-emulgel containing fluvastatin (NEGF) dominated all tested nano-formulas. Tape stripping data indicated that the median statin concentrations of the nano-emulsions were generally higher in the skin layers than the nano-emulgels. Average receptor concentrations after transdermal delivery of the statins (obtained in this study) were compared to the research found on the plasma concentrations after oral administration; it was observed that nano-formulas had higher receptor concentrations, except for NEGF, NE1F and nano-emulsion containing pitavastatin (NE1Pi)