Rational Formulation Design of Oestradiol Transdermal Preparations

Abstract

Abstract The outermost layer of the skin, the stratum corneum (SC), is the principle barrier to transdermal drug delivery. A common passive approach to promote skin penetration is the use of chemical penetration enhancers (CPEs). Although their exact mechanism of action (MOA) is not definitely known yet, CPEs are believed to increase permeation by increasing the solubility and/or the diffusivity of the drug in the SC as well as by increasing the degree of drug saturation (thermodynamic activity) in the vehicle. In the literature, various CPEs have been reported that were investigated in animal or human tissue to elucidate their penetration enhancing action. The aim of the present work was therefore to utilise a data mining and modelling approach to examine the effects of CPEs on the partitioning and diffusivity of a model lipophilic active, oestradiol, through the skin. Oestradiol is a steroid hormone that is widely used transdermally for the treatment of menopausal symptoms and prophylaxis of osteoporosis. In vitro permeation profiles for oestradiol through porcine or human skin were collected from the literature. Data were extracted using the Data Thief III software and subsequently, a modelling software, Scientist 3.0, was used to fit the linear portion of the data to an infinite dose permeation model. The data modelling enabled the deconvolution of the influence of the CPEs on the partition and diffusion of the active. Thirteen formulations, ranging from simple vehicles to more complex transdermal drug delivery systems, containing at least one CPE were assessed. The simple vehicles were: water, N-methyl-2-pyrrolidone (NMP), propylene glycol (PG), propylene glycol monolaurate (PG-ML), and the novel lipid (Z)-1-(Octadec-9-en-1-yl)- piperidine (CY6T). More complex formulations i.e. microemulsions (ME) and patches were also investigated. All CPEs had a greater impact on partitioning of oestradiol rather than its diffusivity through the SC, with the exception of water. The effects of the CPEs obtained from the modelling software generally agreed with the proposed MOA from the literature, particularly for the simple vehicle formulations. For the simple vehicle formulations, PG-ML gave the greatest permeability coefficient (Kp), while water gave the lowest. For the more complex formulations, the o/w microemulsion composed of oleic acid, isopropyl myristate, span 80, ethanol and phosphate buffer saline (PBS), resulted in the highest Kp, which was also superior to all thirteen formulations. The Kp value varied greatly for the different CPEs investigated, highlighting the importance of CPE selection and formulation design for transdermal formulations. In the future, the data mining and modelling approach adopted in this project will be expanded by assessing additional actives and formulations. Further validation of this approach will allow a more rational design of effective and safe transdermal formulations.