The Effect of Heat and Chemical Penetration Enhancers on the Follicular Absorption of Topically Applied Drugs

Abstract

The stratum corneum (SC) is the primary barrier regulating the penetration of substances into the lower layers of skin. A number of strategies have been used to increase drug transport across skin, with chemical penetration enhancers (CPEs) being the most common approach. Heat is another strategy that has been shown to render skin more permeable to drugs. The synergistic effects of heat in combination with CPEs is an under-investigated and promising strategy to enhance the dermal delivery of drugs. In this thesis, the effect of physiologically tolerable heat (≤ 45 °C) on the in vitro percutaneous absorption of minocycline, isotretinoin and finasteride was investigated, with an aim to develop an optimised delivery system. Furthermore, the employment of heat coupled with CPEs as a targeting strategy for improving follicular transport and skin penetration of drugs with a wide range of lipophilicities was investigated. Three active pharmaceutical ingredients; minocycline, isotretinoin and finasteride were selected based their differing lipophilic properties (minocycline: Log P = -0.61, isotretinoin: Log P = 6.6 and finasteride: Log P= 3.2). All drugs were delivered from saturated suspensions from various dermatological vehicles commonly used as CPEs. Two of the major parameters influencing percutaneous absorption, the diffusion and partition coefficients (as pathlength normalised), were determined with a view to gain insight into the mechanisms through which heat can enhance drug delivery to the skin. The findings of this thesis have shown that the application heat ( 45 C) can significantly enhance skin permeation of hydrophilic and hydrophobic drugs (up to 27-fold when isotretinoin was delivered from EtOH) mainly through improvements in partitioning of the drug from the formulation into the SC. Heat was found to enhance the flux of hydrophobic drugs more when delivered from diisopropyl adipate (DPA) and propylene glycol (PG). Therefore, the level of enhancement achieved was found to be dependent on both the physicochemical properties of the drugs and formulation components (CPEs). In the presence of magnesium chloride, the majority of minocycline was recovered from the epidermis. However, the application of heat was found alter the skin distribution of minocycline (in the presence of magnesium chloride) so that most of the drug was recovered from the dermis (the target site for minocycline), potentially improving its efficacy. Also, localised heating for short periods (15-25 min) in combination with fatty acid esters and alcohols and their derivatives demonstrated the positive impact heat and CPEs can have on follicular transport (up to 2-fold increase). This strategy potentially allows for targeted delivery through hair follicles which is likely to be a significant advance for drugs like isotretinoin, which have significant side effects profiles. In conclusion, this work has demonstrated that the novel strategy employing the customised use of physiologically tolerable heat (≤ 45°C) to target the follicular structures and enhance drug delivery is a highly promising approach which, following further investigations will be highly beneficial in the optimisation of current topical formulations and the development of new drug delivery systems.