Matthew J. Traynor

Transdermal Drug Delivery Systems: Skin Perturbation Devices

Human skin serves a protective function by imposing physicochemical limitations to the type of permeant that can traverse the barrier. For a drug to be delivered passively via the skin it needs to have a suitable lipophilicity and a molecular weight < 500 Da. The number of commercially available products based on transdermal or dermal delivery has been limited by these requirements. In recent years various passive and active strategies have emerged to optimize delivery. The passive approach entails the optimization of formulation or drug carrying vehicle to increase skin permeability. However, passive methods do not greatly improve the permeation of drugs with molecular weights >500 Da. In contrast, active methods, normally involving physical or mechanical methods of enhancing delivery, have been shown to be generally superior. The delivery of drugs of differing lipophilicity and molecular weight, including proteins, peptides and oligonucletides, has been shown to be improved by active methods such as iontophoresis, electroporation, mechanical perturbation and other energy-related techniques such as ultrasound and needleless injection. This chapter details one practical example of an active skin abrasion device to demonstrate the success of such active methods. The in vitro permeation of acyclovir through human epidermal membrane using a rotating brush abrasion device was compared with acyclovir delivery using iontophoresis. It was found that application of brush treatment for 10 s at a pressure of 300 N m(-2) was comparable to 10 min of iontophoresis. The observed enhancement of permeability observed using the rotating brush was a result of disruption of the cells of the stratum corneum, causing a reduction of the barrier function of the skin. However, for these novel delivery methods to succeed and compete with those already on the market, the prime issues that require consideration include device design and safety, efficacy, ease of handling, and cost-effectiveness. This chapter provides a detailed review of the next generation of active delivery technologies.

Influence of Alcohol on the Release of Tramadol from 24-h Controlled-Release Formulations During In Vitro Dissolution Experiments

Recent warnings by regulatory bodies and a product recall by the FDA have generated much interest in the area of dose dumping from controlled-release opioid analgesic formulations when coingested with alcohol. It was the aim of this study to address this issue and in doing so, gain understanding on how alcohol-induced effects may be avoided. In this study, tramadol release from Ultram® ER tablets and T-long® capsules was significantly increased in the presence of ethanol. Conversely, a decrease in the rate of tramadol release was seen from Tridural™ extended-release tablets in the presence of alcohol.

Effect of a novel penetration enhancer on the ungual permeation of two antifungal agents.

Objectives The aim of this study was to demonstrate the effect of a novel permeation enhancer system using two existing marketed nail lacquers and the delivery of terbinafine through human nail samples in vitro.

Effect of ethnicity, gender and age on the amount and composition of residual skin surface components derived from sebum, sweat and epidermal lipids

The superficial layer on the skin surface, known as the acid mantle, comprises a mixture of sebum, sweat, corneocyte debris and constituents of natural moisturizing factor. Thus, the phrase ‘residual skin surface components’ (RSSC) is an appropriate term for the mixture of substances recovered from the skin surface. There is no general agreement about the effects of ethnicity, gender and age on RSSC. The aim of this human volunteer study was to evaluate RSSC in relation to ethnicity, gender and age. A suitable acquisition medium for RSSC collection was identified and samples of RSSC were subsequently analysed using gas chromatography‐mass spectrometry (GC‐MS) and gravimetry.

Vinyl polymer-coated lorazepam particles for drug delivery to the airways

A particle engineering method that adsorbs a microfine vinyl polymer coat to crystalline drug microparticles has been shown to be an effective way to control delivery. However, the means by which the functional performance of such microparticles is altered by the behaviour of the polymers in the microparticle coat remains unclear. The aim of this study was to determine the influence of vinyl polymer coating on the in vitro delivery characteristics of intranasal lorazepam microparticles. A series of four, similarly sized (ca. 10 μm), lorazepam-rich microparticles with different polymer coats were generated. The absorption of the polymer coats appeared to disrupt lorazepam solid state dimer formation in the microparticles, which manifested in a reduction in drug melting point. Mildly cohesive particles (aerodynamic diameter of 32 μm) that allowed rapid drug release (ca. 80% in 5 min) were generated when partially hydrolysed PVA dominated the microparticle coat, whilst fully hydrolysed PVA reduced particle cohesion and retarded drug release (ca. 15% release in 5 min). Infrared analysis showed that the properties of the microparticles were dictated by the strength of the hydrogen bonding in the polymer coat and not the strength of coat adsorption that was facilitated by hydrogen bond formation between the hydroxyl groups of the PVA and the hydroxyl group at position C3 of the lorazepam diazepine ring.

Metabolism of Butoxyethanol in excised human skin in vitro

Glycol ethers are widely used in industrial and household applications because their chemical and physical properties make them versatile solvents, miscible with both water and organic media. Due to the ease with which the glycol ethers are absorbed through the skin and the potential for development of adverse health effects it is important to understand the extent to which local metabolism can contribute to local and systemic toxicity. Sections of previously frozen, full thickness excised human skin samples were placed on transwell supports and placed with the underside of the skin in contact with receptor fluid. The skin surface was dosed with 115.2 mg of neat butoxyethanol and the absorption and metabolism of butoxyethanol to butoxyacetic acid monitored over time. In total 64.94+/-0.04 mg of butoxyethanol or its metabolites were removed from the surface of the skin at 24h, representing the equivalent of 56% of the applied dose, the equivalent of 17.5% of the applied dose was recovered from the receiver fluid, 3% from within the skin and the remaining 23.5% of the dose was lost to the atmosphere through evaporation. After 24h a total of 31.5 microg of butoxyacetic acid had been produced representing approximately 0.03% of the applied dose. Therefore approximately 0.16% (31.5 microg as a percentage of the total amount of butoxyethanol reaching the receiver fluid (20.17 mg) of the absorbed butoxyethanol was metabolised to butoxyacetic acid during its passage through the skin. This suggested that, although enzyme activities capable of converting butoxyethanol to butoxyacetic acid are present in skin, metabolic conversion during percutaneous absorption was small and systemic exposure to the parent compound rather than the metabolite would occur following dermal exposure to butoxyethanol. This experiment demonstrates that it is possible to maintain metabolic activity in skin samples in an in vitro setup for short, but experimentally useful, periods.

An investigation of how fungal infection influences drug penetration through onychomycosis patient's nail plates.

Graphical abstract

Free radical facilitated damage of ungual keratin

Thioglycolic acid (TA) and urea hydrogen peroxide (urea H(2)O(2)) are thought to disrupt alpha-keratin disulfide links in the nail. However, optimal clinical use of these agents to improve the treatment of nail disorders is currently hindered by a lack of fundamental data to support their mechanism of action. The aim of this study was to investigate how the redox environment of ungual keratin, when manipulated by TA and urea H(2)O(2), influenced the properties of the nail barrier. Potentiometric and voltammetric measurements demonstrated that urea H(2)O(2) obeyed the Nernst equation for a proton coupled one-electron transfer redox process while TA underwent a series of redox reactions that was complicated by electrode adsorption and dimer formation. The functional studies demonstrated that nail permeability, measured through TBF penetration (38.51+/-10.94 microg/cm(2)/h) and nail swelling (244.10+/-14.99% weight increase), was greatest when relatively low concentrations of the thiolate ion were present in the applied solution. Limiting the thiolate ion to low levels in the solution retards thiolate dimerisation and generates thiyl free radicals. It appeared that this free radical generation was fundamental in facilitating the redox-mediated keratin disruption of the ungual membrane.

Application of sebomics for the analysis of residual skin surface components to detect potential biomarkers of type-1 diabetes mellitus

Metabolic imbalance in chronic diseases such as type-1 diabetes may lead to detectable perturbations in the molecular composition of residual skin surface components (RSSC). This study compared the accumulation rate and the composition of RSSC in type-1 diabetic patients with those in matched controls in order to identify potential biomarkers of the disease. Samples of RSSC were collected from the foreheads of type-1 diabetic (n = 55) and non-diabetic (n = 58) volunteers. Samples were subsequently analysed to identify individual components (sebomic analysis). There was no significant difference in the rate of accumulation of RSSC between type-1 diabetics and controls. In terms of molecular composition, 171 RSSC components were common to both groups, 27 were more common in non-diabetics and 18 were more common in type-1 diabetic patients. Statistically significant (P < 0.05) differences between diabetic and non-diabetic volunteers were observed in the recovered amounts of one diacylglyceride (m/z 594), six triacylglycerides (m/z 726–860) and six free fatty acids (m/z 271–345). These findings indicate that sebomic analysis can identify differences in the molecular composition of RSSC components between type-1 diabetic and non-diabetic individuals. Further work is required to determine the practical utility and identity of these potential biomarkers.

Investigation into the functionality of controlled drug denaturing/destruction kits

Abstract Context: Throughout the UK a large amount of unwanted, expired or patient returned controlled drugs are disposed of every day, in community and hospital pharmacies, veterinary surgeries, hospices, private hospitals and industrial settings. This is mostly achieved through the use of commercially available controlled drug destruction/denaturing kits, but what do these kits actually do to the drug within them? Objective: The primary aim of this study was to investigate the effect of six commercially available kits on morphine, a chosen model controlled drug. The secondary aim was to establish if the kits could be adapted to chemically destroy any drug disposed within it. Materials and methods: Morphine was dispensed in to six commercially available controlled drug destruction kits at a known concentration. The instructions on the kits were followed and after 48 h the amount of drug remaining was determined by HPLC. In addition a new kit containing sodium perborate was tested in the same way. Results: Between 78 and 111% of the parent drug was found to still be present in the commercial kits tested after 48 h. In the sodium perborate 5% kit this level fell to 22%. Discussion and conclusions: In conclusion all the commercially available CD denaturing kits tested do not destroy the controlled drug (morphine) tested but simply encapsulated it in gel. This means the parent form of the drug is still present and could potentially be recovered and abused. The new kit containing sodium perborate was much more effective in chemically destroying the parent drug but care must be taken in its use.