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Formulation of diclofenac for dermal delivery

Goh CF, Lane ME

Int J Pharm, 2014 Oct 1;473(1-2):607-16.
PMID: 25091375 DOI: 10.1016/j.ijpharm.2014.07.052

Diclofenac (DF) was first synthesized in the 1960's and is currently available as ophthalmic, oral, parenteral, rectal and skin preparations. This review focuses on the administration of DF to the skin. As a member of the non-steroidal anti-inflammatory (NSAID) group of drugs the primary indications of DF are for the management of inflammation and pain but it is also used to treat actinic keratosis. The specific aims of this paper are to: (i) provide an overview of the pharmacokinetics and metabolism of DF following oral and topical administration; (ii) examine critically the various formulation approaches which have been investigated to enhance dermal delivery of DF; and (iii) identify new formulation strategies for enhanced DF skin penetration.
Advanced structural characterisation of pharmaceuticals using nano-thermal analysis (nano-TA)

Goh CF, Lane ME

Adv Drug Deliv Rev, 2022 01;180:114077.
PMID: 34896130 DOI: 10.1016/j.addr.2021.114077

The production of drug delivery systems fabricated at the nano scale comes with the challenges of identifying reliable characterisation tools, especially for solid dosage forms. A full understanding of physicochemical properties of solid-state systems at a high spatial resolution is essential to monitor their manufacturability, processability, performance (dissolution) and stability. Nano-thermal analysis (nano-TA), a hybrid of atomic force microscopy (AFM) and thermal analysis, has emerged as a solution to address the need for complete characterisation of samples with surface heterogeneity. Nano-TA provides not only physical information using conventional AFM but also the thermal behaviour of these systems as an additional chemical dimension. In this review, the principles and techniques of nano-TA are discussed with emphasis on recent pharmaceutical applications. Building on nano-TA, the combination of this approach with infrared spectroscopic analysis is briefly introduced. The challenges and considerations for future development of nano-TA characterisation are also outlined.
Thermal analysis of mammalian stratum corneum using differential scanning calorimetry for advancing skin research and drug delivery

Goh CF, Hadgraft J, Lane ME

Int J Pharm, 2022 Feb 25;614:121447.
PMID: 34998922 DOI: 10.1016/j.ijpharm.2021.121447

For effective topical and transdermal drug delivery, it is necessary for most actives to penetrate and permeate through the stratum corneum (SC). Extensive investigation of the thermal behaviour of mammalian SC has been performed to understand the barrier function of the skin. However, little attention has been paid to the related experimental variables in thermal analysis of the SC using differential scanning calorimetry that may influence the results obtained from such studies. In this review, we provide a comprehensive overview of the thermal transitions of the SC of both porcine and human skin. More importantly, the selection and impact of the experimental and instrumental parameters used in thermal analysis of the SC are critically evaluated. New opportunities for the use of thermal analysis of mammalian SC in advancing skin research, particularly for elucidation of the actions of excipients employed in topical and transdermal formulations on the skin are also highlighted.
Profiling of drug crystallization in the skin

Goh CF, Boyd BJ, Craig DQM, Lane ME

Expert Opin Drug Deliv, 2020 09;17(9):1321-1334.
PMID: 32634033 DOI: 10.1080/17425247.2020.1792440

BACKGROUND: Drug crystallization following application of transdermal and topical formulations may potentially compromise the delivery of drugs to the skin. This phenomenon was found to be limited to the superficial layers of the stratum corneum (~7 µm) in our recent reports and tape stripping of the skin samples was necessary. It remains a significant challenge to profile drug crystallization in situ without damaging the skin samples.
METHODS: This work reports the application of an X-ray microbeam via synchrotron SAXS/WAXS analysis to monitor drug crystallization in the skin, especially in the deeper skin layers. Confocal Raman spectroscopy (CRS) was employed to examine drug distribution in the skin to complement the detection of drug crystallization using SAXS/WAXS analysis.
RESULTS: Following application of saturated drug solutions (ibuprofen, diclofenac acid, and salts), CRS depth profiles confirmed that the drugs generally were delivered to a depth of ~15 - 20 µm in the skin. This was compared with the WAXS profiles that measured drug crystal diffraction at a depth of up to ~25 µm of the skin.
CONCLUSION: This study demonstrates the potential of synchrotron SAXS/WAXS analysis for profiling of drug crystallization in situ in the deeper skin layers without pre-treatment for the skin samples. [Figure: see text].
The application of ATR-FTIR spectroscopy and multivariate data analysis to study drug crystallisation in the stratum corneum

Goh CF, Craig DQ, Hadgraft J, Lane ME

Eur J Pharm Biopharm, 2017 Feb;111:16-25.
PMID: 27845181 DOI: 10.1016/j.ejpb.2016.10.025

Drug permeation through the intercellular lipids, which pack around and between corneocytes, may be enhanced by increasing the thermodynamic activity of the active in a formulation. However, this may also result in unwanted drug crystallisation on and in the skin. In this work, we explore the combination of ATR-FTIR spectroscopy and multivariate data analysis to study drug crystallisation in the skin. Ex vivo permeation studies of saturated solutions of diclofenac sodium (DF Na) in two vehicles, propylene glycol (PG) and dimethyl sulphoxide (DMSO), were carried out in porcine ear skin. Tape stripping and ATR-FTIR spectroscopy were conducted simultaneously to collect spectral data as a function of skin depth. Multivariate data analysis was applied to visualise and categorise the spectral data in the region of interest (1700-1500cm(-1)) containing the carboxylate (COO(-)) asymmetric stretching vibrations of DF Na. Spectral data showed the redshifts of the COO(-) asymmetric stretching vibrations for DF Na in the solution compared with solid drug. Similar shifts were evident following application of saturated solutions of DF Na to porcine skin samples. Multivariate data analysis categorised the spectral data based on the spectral differences and drug crystallisation was found to be confined to the upper layers of the skin. This proof-of-concept study highlights the utility of ATR-FTIR spectroscopy in combination with multivariate data analysis as a simple and rapid approach in the investigation of drug deposition in the skin. The approach described here will be extended to the study of other actives for topical application to the skin.
Spatial resolution of drug crystallisation in the skin by X-ray micro-computed tomography

Goh CF, O'Flynn D, Speller R, Lane ME

Micron, 2021 06;145:103045.
PMID: 33689970 DOI: 10.1016/j.micron.2021.103045

Drug crystallisation in the skin is recognised as a significant problem in topical and transdermal drug delivery. Our recent investigations provided new evidence of drug crystallisation in the skin, however, confirming the precise location of crystals remains challenging. Of note, most approaches used have required disruption of the membrane by tape stripping, with crystal detection limited to the superficial skin layers. Hence, a non-destructive method for complete spatial resolution of crystallised drug in skin is still lacking. In this communication, we report the application of X-ray micro-computed tomography (microCT) to examine drug crystallisation in mammalian skin ex vivo. Permeation studies of a saturated solution of diclofenac sodium were conducted in porcine skin; subsequently, tissue samples were scanned using microCT to generate 2D and 3D maps. A layer of drug crystals was observed on the skin surface; microCT maps also confirmed the distribution of drug crystals up to a skin depth of 0.2 - 0.3 mm. MicroCT also allowed the identification of drug crystallisation as a distinct and confirmed event in the skin and as an extension from drug crystals formed on the skin. These preliminary results confirm the potential of microCT to study this important phenomenon in topical and transdermal drug delivery.
Monitoring Drug Crystallization in Percutaneous Penetration Using Localized Nanothermal Analysis and Photothermal Microspectroscopy

Goh CF, Moffat JG, Craig DQM, Hadgraft J, Lane ME

Mol Pharm, 2019 01 07;16(1):359-370.
PMID: 30525649 DOI: 10.1021/acs.molpharmaceut.8b01027

Drug crystallization on and in the skin has been reported following application of topical or transdermal formulations. This study explored novel probe-based approaches including localized nanothermal analysis (nano-TA) and photothermal microspectroscopy (PTMS) to investigate and locate drug crystals in the stratum corneum (SC) of porcine skin following application of simple ibuprofen (IBU) formulations. We also conducted in vitro skin permeation studies and tape stripping. The detection of drug crystals in the SC on tape strips was confirmed using localized nano-TA, based on the melting temperature of IBU. The melting of IBU was also evident as indicated by a double transition and confirmed the presence of drug crystals in the SC. The single point scans of PTMS on the tape strips allowed collection of the photothermal FTIR spectra of IBU, confirming the existence of drug crystals in the skin. The combined methods also indicated that drug crystallized in the SC at a depth of ∼4-7 μm. Future studies will examine the potential of these techniques to probe crystallization of other commonly used actives in topical and transdermal formulations.