Depot-forming microarray patches for the long-acting delivery of atorvastatin

Abstract

Poorly soluble drugs pose a major challenge in the field of drug delivery, as they are considered difficult to deliver. Many techniques can be possibly used to aid in improving the solubility profiles of those compound and improve their delivery. Those techniques has shown to be effectively used in the preparation of orally-administered dosage forms. Nonetheless, they can also be useful in delivering those compounds via other routes of administration as well. Transdermal drug delivery involves the application of a drug onto the skin to exert systematic effects. This administration route had drawn the attention of scientists over the last few decades, as the skin is considered to be the largest and most accessible organ in the human body. However, relatively few drugs possess the required characteristics to penetrate the skin passively. Microarray patches (MAPs) are novel transdermal drug delivery devices, capable of increasing the permeability of the skin by creating micro pores within the skin surface, thus, reduce its barrier function and enhance the permeation of molecules. Furthermore, long-acting dosage forms, capable of delivering therapeutic doses of drugs over prolonged periods of times, can enhance the compliance of patients to their treatment regimens, and thereby improve the quality of their lives. This thesis had focused on the development of polymeric MAPs systems, using solubility enhancing techniques, to facilitate the depot delivery of the hydrophobic atorvastatin (ATR) to obtain a long-acting effect. For this purpose, hydrogel-forming MAPs (HF-MAPs) were initially explored. Four Gantrez® S-97-based HF-MAPs formulations were initially prepared and characterised in terms of their mechanical properties, swelling and ATR diffusion across their swollen films. Afterwards, a solid dispersion (SD) technique was used to formulate ATR-reservoirs using PEG 200 and PEG 6,000 as a matrix. A drug loading of ~ 15 mg was obtained in each SD reservoir. Furthermore, dissolving MAPs (D-MAPs) were also investigated, where either ATR microparticles (MPs) or nanocrystals (NCs) were formulated into D-MAPs, in combination with the biocompatible water-soluble excipients: poly(vinyl) pyrrolidone (PVP) and poly(vinyl) alcohol (PVA). In this part, particle size reduction was explored as a solubility enhancing technique. MP-loaded MAPs had a drug content of ~ 5 mg, whereas NC-loaded MAPs contained ~ 2.5 mg of ATR. Both HF-MAPs combined with ATR PEG-based SD reservoirs system and ATR-containing D-MAPs where characterised in terms of drug content, thermal behaviour, insertion efficiency, mechanical properties, and in vitro drug release and recovery studies. Subsequently, ex vivo permeation, and skin deposition studies of the candidates of all formulations were conducted, from which the lead HF-MAPs and ATR SD reservoir formulation along with the lead D-MAPs formulation were brought forward for further in vivo pharmacokinetics investigation using Sprague Dawley rats. The result had shown, for the first time, the long-acting delivery of ATR via polymeric MAPs system (HF-MAPs and D-MAPs) over two weeks, where therapeutically-relevant concentrations of ATR (> 20 ng/mL) were obtained throughout the study from both MAP cohorts. It had also verified for the first time, the versality of HF-MAPs in the depot-delivery of ATR, from which therapeutically-relevant plasma concentrations were achieved for over 14 days. When compared to the oral group, the use of MAPs improved the overall pharmacokinetics profile of ATR in plasma, where significantly higher AUC values resulting in ~10 folds higher systemic exposure levels were obtained. The findings of this thesis provide a promising alternative for the oral administration of ATR, as the long-acting features of this method can ultimately be highly effective in enhancing the patients compliance and improving the quality of their lives. Looking towards large-scale production, this work provides evidence of a suitable formulation strategy for poorly soluble drugs to be delivered using polymeric MAPs. Nonetheless, pharmacodynamic assessment of the efficacy of ATR in hyperlipidaemia animal models must be initially determined, as well as considering industrial regulatory standards.