Biophysical elucidation of the mechanism of enhanced drug release and topical delivery from polymeric film-forming systems

Abstract

The effect of incorporating the lipidic medium-chain triglyceride (MCT) into polymeric film-forming systems (FFS) for topical drug delivery has been evaluated. First, the in vitro release of betamethasone-17-valerate (BMV), a representative dermatological drug, was determined from FFS comprising either hydrophobic polyacrylate co-polymers, or hydrophilic hydroxypropyl cellulose, with and without MCT. Release was enhanced from both polymers in the presence of MCT. Atomic force microscopy imaging and nanoindentation of FFS with MCT revealed two-phase structured films with softer inclusions (0.5 to 4μm in diameter) surrounded by a more rigid structure. Chemical mapping with Raman micro-spectroscopy showed that MCT was primarily confined to the inclusions within the polymer, which predominated in the surrounding film. BMV was distributed throughout the film but was more concentrated outside the inclusions. Furthermore, while BMV dissolved better into the hydrophobic films, it was more soluble in the MCT inclusions in hydrophilic films, suggesting its increased availability for diffusion from these softer regions of the polymer and explaining the release enhancement observed. Second, ex vivo skin penetration studies clearly revealed that uptake of BMV was higher from hydrophobic FFS than that from the more hydrophilic polymer due, at least in part, to the superior anti-nucleation efficiency of the former. Drug was quickly taken up into the SC from which it then diffused continuously over a sustained period into the lower, viable skin layers. In the presence of MCT, the overall uptake of BMV was increased and provides the basis for further optimisation of FFS as simple, convenient and sustained formulations for topical therapy.

The potential of polymeric film-forming systems as sustained delivery platforms for topical drugs

“…The incorporation of a lipid excipient, such as medium chain triglycerides (MCT), into a FFS has been shown to result in a structured, two-phase polymeric film (Figure 7). The softer lipid-enriched inclusions provide an environment in which the solubilised drug is released quickly in an initial phase (59,77,92) and then in a sustained fashion thereafter (79,92). With respect to the selection of appropriate drugs for delivery with the FFS approach, it is logical that more lipophilic compounds have been studied in more detail.…”

Controlled Drug Release by the Pore Structure in Polydimethylsiloxane Transdermal Patches

“…where Q t is cumulative amount of the drug released at the time t, D is the diffusion coefficient of the drug in the matrix, c ini , is the initial drug concentration in the matrix and, c s is drug solubility in the matrix. The most common approach to enhance the release of the drug is to increase its solubility in the polymeric matrix, which can be achieved by addition of some excipients [10]. In this study liquid excipients, hydrophilic or lipophilic, were introduced to the PDMS matrix.…”

Film-Forming Systems in Topically Administered Pharmaceutical Formulations

“…This happens because hydrophobic components are capable of creating drug interactions that make them a better reservoir in both the polymeric film on the surface and within the stratum corneum, allowing release to occur over a longer period. This also applies to the incorporation of MCT, which increased the hydrophobic load of the formulation and made a significant increase on the drug delivery after 6 -8 hours of application [13].…”

“…In addition, these conventional formulations generally lack in sensory attractiveness, which may cause the patient's lack of motivation to reapply the product. All of this may be a reason for poor adherence to treatment [2] [4] [13].…”

“…One of the critical points of this type of formulation is the immediate evaporation of volatile components, which may lead to the drug supersaturation and, consequently, its crystallization, as the environment becomes thermodynamically unfavorable to its molecular state. This can be controlled by the addition of nucleation inhibiting excipients [13].…”