Polymeric film-forming systems for dermal drug delivery represent an advantageous alternative to more conventional topically applied formulations. Their mechanical properties and homogeneity can be characterized with atomic force microscopy (AFM), using both imaging and nanoindentation modes, and Raman microspectroscopy mapping. Film-forming polymers, with and without a plasticizer and/or betamethasone 17-valerate (a representative topical drug), were dissolved in absolute ethanol. Polymeric films were then cast on glass slides and examined in ambient air using AFM imaging and Raman microspectroscopy. Using nanoindentation, the elastic moduli of various films were determined and found to decrease with increasing plasticizer content. Films with 20% w/w plasticizer had elastic moduli close to that of skin. AFM images showed little difference in the topography of the films on incorporation of plasticizer. Raman microspectroscopy maps of the surface of the polymeric films, with a spatial resolution of approximately 1 μm, revealed homogeneous distributions of plasticizer and drug within the films.
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.
Laser poration of the skin locally removes its outermost, barrier layer, and thereby provides a route for the diffusion of topically applied drugs. Ideally, no thermal damage would surround the pores created in the skin, as tissue coagulation would be expected to limit drug diffusion. Here, a femtosecond pulsed fiber laser is used to porate mammalian skin ex vivo. This first application of a hollow core negative curvature fiber (HC-NCF) to convey a femtosecond pulsed, visible laser beam results in reproducible skin poration. The effect of applying ink to the skin surface, prior to ultra-short pulsed ablation, has been examined and Raman spectroscopy reveals that the least, collateral thermal damage occurs in inked skin. Pre-application of ink reduces the laser power threshold for poration, an effect attributed to the initiation of plasma formation by thermionic electron emission from the dye in the ink. Poration under these conditions significantly increases the percutaneous permeation of caffeine in vitro. Dye-enhanced, plasma-mediated ablation of the skin is therefore a potentially advantageous approach to enhance topical/transdermal drug absorption. The combination of a fiber laser and a HC-NCF, capable of emitting and delivering femtosecond pulsed, visible light, may permit a compact poration device to be developed.
Medicines designed to deliver the active pharmaceutical ingredient either into or through the skin�often referred to as topicals and transdermals, respectively�are generally considered to be complex drug products. A particular challenge faced by these formulations is identifying a suitable method (ideally, in terms of specificity, accuracy, precision, and robustness) or combination of methods with which to assess the amount and rate of drug delivery to the target site. Significant research currently aims to identify and validate relevant and minimally invasive techniques that can be used to quantify both the levels of the drug attained within different parts of the skin and the kinetics with which the drug is taken up into the skin and cleared therefrom into the systemic circulation. Here, the application of confocal Raman microspectroscopy and imaging to interrogate events integral to the performance of topical and transdermal drug products at the formulation-skin interface is illustrated. Visualization, depth slicing, and profiling are used (a) to elucidate key chemical properties of both the delivery system and the skin that have impact on their interaction and the manner in which drug transfer from one to the other may occur, (b) for the transformation of a drug product from that manufactured into a residual phase post-application and inunction into the skin (including the potential for important changes in solubility of the active compound), and (c) for drug absorption into the skin and its subsequent '"clearance" into deeper layers and beyond. Overall, the Raman tools described offer both qualitative and potentially semi-quantitative insights into topical and transdermal drug product performance and provide information useful for formulation improvement and optimization.
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