A mechanistic approach to modelling the formation of a drug reservoir in the skin

Abstract

It has been shown that prolonged systemic presence of a drug can cause a build-up of that drug in the skin. This drug 'reservoir', if properly understood, could provide useful information about recent drug-taking history of the patient. We create a pair of coupled mathematical models which combine to explore the potential for a drug reservoir to establish based on the kinetic properties of the drug. The first compartmental model is used to characterise time-dependent drug concentrations in plasma and tissue following a customisable drug regimen. Outputs from this model provide boundary conditions for the second, spatio-temporal model of drug build-up in the skin. We focus on drugs that are highly bound as this will restrict their potential to move freely into the skin but which are lipophilic so that, in the unbound form, they would demonstrate an affinity to the outer layers of the skin. Buprenorphine, a drug used to treat opiate addiction, is one example of a drug satisfying these properties. In the discussion we highlight how our study might be used to inform future experimental design and data collection to provide relevant parameter estimates for reservoir formation and its potential to contribute to enhanced drug monitoring techniques.

Development of a Self-Emulsifying Drug Delivery System for Optimized Topical Delivery of Clofazimine

“…In order for topically applied SEDDSs to establish a localised pharmacological effect, they must reach the epidermis skin layer [ 29 ]. Topical delivery of the highly lipophilic clofazimine presented challenges due to the fact that drugs as hydrophobic as clofazimine tend to partition into and accumulate in the SC after being released from the applied dosage form [ 32 , 33 ]. The lipophilic nature of the SC creates an ideal environment for lipophilic drugs to establish a reservoir effect while these substances avoid full partitioning into the hydrophilic epidermis [ 32 , 43 ].…”

“…Topical delivery of the highly lipophilic clofazimine presented challenges due to the fact that drugs as hydrophobic as clofazimine tend to partition into and accumulate in the SC after being released from the applied dosage form [ 32 , 33 ]. The lipophilic nature of the SC creates an ideal environment for lipophilic drugs to establish a reservoir effect while these substances avoid full partitioning into the hydrophilic epidermis [ 32 , 43 ]. Hence, the rate limiting step for clofazimine is the partitioning into the hydrophilic epidermis [ 29 ].…”

“…Argan, avocado, coconut, macadamia and olive oil were chosen due to the unique fatty acid composition of each natural oil. Fatty acid profiles of natural oils can significantly influence dermal clofazimine delivery since drugs as lipophilic as clofazimine generally tend to accumulate in the fatty environment of the SC instead of partitioning into the underlying, hydrophilic epidermis [ 32 , 33 ]. Skin penetration enhancers, such as natural oils, can facilitate SC lipid disruption by mechanisms such as fluidization and loosening the ordered SC lipid structure to allow improved partitioning of clofazimine into underlying skin layers in order to achieve successful topical delivery [ 29 ].…”

Development of Topical/Transdermal Self-Emulsifying Drug Delivery Systems, Not as Simple as Expected

“…The lipophilic or hydrophilic nature of incorporated drug(s) can also influence the choice of where the optimised formulation area is located, since the nature of the drug can contribute towards the time required to establish drug release from the formulation [108,109]. Hence, theoretically, a lipophilic drug will portray swift release if incorporated into a formulation containing an increased water concentration, as the lipophilic drug tends to desire escape from the hydrophilic vehicle into the lipophilic SC [108,110]. Therefore, pseudo-ternary-phase diagrams might be seen as an old authentication technique, but in terms of SEDDS development, it remains an irreplaceable prediction that enables the selection of desirable formulation properties [33].…”

Mathematical Modeling of Anomalous Diffusive Behavior in Transdermal Drug-Delivery Including Time-Delayed Flux Concept

“…Many papers have addressed various aspects of transdermal drug delivery [1][2][3][4] where different models of skin permeability have been proposed [1,[5][6][7]. The good review of the state-of-the-art of skin transport modeling can be find in [8,9].…”