Mechanisms of chemical and physical transdermal penetration enhancement

The underlying theme of this thesis is one of exploring the processes involved in the enhancement of percutaneous absorption. The development of an attenuated total reflectance Fourier-Transform infrared (ATR-FTIR) spectroscopic method to analyse diffusion of suitable topically applied compounds in membrane is described. Diffusion coefficients (D/h2) and membrane solubility (AO) for topically applied compounds were determined using a solution to Fick's second law of diffusion. This method was employed to determine the diffusional characteristics of a model permeant, 4-cyanophenol (CP), across silicone membrane as a function of formulation applied and permeant physicochemical properties. The formulations applied were able to either affect CP diffusivity and/or its membrane solubility in the membrane; such parameters partially correlated with permeant physicochemical properties in each formulation. The interplay during the diffusion process between drug, enhancer and vehicle in stratum corneum (SC) was examined. When enhancers were added to the applied formulations, CP diffusivity and solubility were significantly enhanced when compared to the neat propylene glycol (PG) application. Enhancers did not affect PG diffusivity in SC but enhancers did affect PG solubility in SC. PG diffusion closely resembled that of CP, implying that the respective transport processes were inter-related. Additionally, a synergistic effect, which increases CP diffusivity and membrane solubility in SC, was found to occur between PG and water. Using 12-azidooleic acid (AOA) as an IR active probe for oleic acid, the simultaneous penetration of CP, AOA and PG into human stratum corneum was determined. It was found that the diffusion profiles for all three permeants were similar. This indicated that the diffusion of each species through SC was closely related and most likely occurred via the same route or SC microenvironment.

Chemical and physical characterization of clay bodies

Suitable methods for the assessment of the effect of freeze-thaw action upon ceramic tiles have been determined. The results obtained have been shown to be reproducible with some work in this area still warranted. The analysis of Whichford Potteries clays via a variety of analytical techniques has shown them to be a complex mix of both clay and non-clay minerals. 57Fe Mössbauer spectroscopy has highlighted the presence of both small and large particleα-Fe203, removable via acid washing. 19F MAS NMR has demonstrated that the raw Whichford Pottery clays examined have negligible fluorine content. This is unlikely to be detrimental to ceramic wares during the heating process. A unique technique was used for the identification of fluorine in solid-state systems. The exchange of various cations into Wyoming Bentonite clay by microwave methodology did not show the appearance of five co-ordinate aluminium when examined by 27Al MAS NMR. The appearance of Qo silicate was linked to an increase in the amount of tetrahedrally bound aluminium in the silicate framework. This is formed as a result of the heating process. The analysis of two Chinese clays and two Chinese clay raw materials has highlighted a possible link between the two. These have also been shown to be a mix of both clay and non-clay minerals. Layered double hydroxides formed by conventional and microwave methods exhibited interesting characteristics. The main differences between the samples examined were not found to be solely attributable to the differences between microwave and conventional methods but more attributable to different experimental conditions used.

Chemical and physical methods of enhancing the percutaneous absorption of antimicrobial agents

Contrary to previously held beliefs, it is now known that bacteria exist not only on the surface of the skin but they are also distributed at varying depths beneath the skin surface. Hence, in order to sterilise the skin, antimicrobial agents are required to penetrate across the skin and eliminate the bacteria residing at all depths. Chlorhexidine is an antimicrobial agent with the widest use for skin sterilisation. However, due to its poor permeation rate across the skin, sterilisation of the skin cannot be achieved and, therefore, the remaining bacteria can act as a source of infection during an operation or insertion of catheters. The underlying theme of this study is to enhance the permeation of this antimicrobial agent in the skin by employing chemical (enhancers and supersaturated systems) or physical (iontophoresis) techniques. The hydrochloride salt of chlorhexidine (CHX), a poorly soluble salt, was used throughout this study. The effect of ionisation on in vitro permeation rate across the excised human epidennis was investigated using Franz-type diffusion cells. Saturated solutions of CHX were used as donor and the variable studied was vehicle pH. Permeation rate was increased with increasing vehicle pH. The pH effect was not related to the level of ionisation of the drug. The effect of donor vehicle was also studied using saturated solutions of CHX in 10% and 20% ethanol as the donor solutions. Permeation of CHX was enhanced by increasing the concentration of ethanol which could be due to the higher concentration of CHX in the donor phase and the effect of ethanol itself on the membrane. The interplay between drug diffusion and enhancer pretreatment of the epidennis was studied. Pretreatment of the membrane with 10% Azone/PG demonstrated the highest diffusion rate followed by 10% olcic acid/PG pretreatment compared to other pretreatment regimens (ethanol, dimethyl sulfoxide (DMSO), propylene glycol (PG), sodium dodecyl sulphate (SDS) and dodecyl trimethyl ammonium bromide (DT AB). Differential Scanning Calorimetry (DSC) was also employed to study the mode of action of these enhancers. The potential of supersaturated solutions in enhancing percutaneous absorption of CHX was investigated. Various anti-nucleating polymers were screened in order to establish the most effective agent. Polyvinylpyrrolidone (PVP, K30) was found to be a better candidate than its lower molecular weight counterpart (K25) and hydroxypropyl methyleellulose (HPMC). The permeation studies showed an increase in diffusion rate by increasing the degree of saturation. Iontophoresis is a physical means of transdemal drug delivery enhancement that causes an increased penetration of molecules into or through the skin by the application of an electric field. This technique was employed in conjunction with chemical enhancers to assess the effect on CHX permeation across the human epidermis. An improved transport of CHX, which was pH dependant was observed upon application of the current. Combined use of iontophoresis and chemical enhancers further increased the CHX transport indicating a synergistic effect. Pretreatment of the membrane with 10% Azone/PG demonstrated the greatest effect.

Effect of medications with anti-cholinergic properties on cognitive function, delirium, physical function and mortality:a systematic review

Objectives: to determine the effect of drugs with anti-cholinergic properties on relevant health outcomes.Design: electronic published and unpublished literature/trial registries were systematically reviewed. Studies evaluating medications with anti-cholinergic activity on cognitive function, delirium, physical function or mortality were eligible.Results: forty-six studies including 60,944 participants were included. Seventy-seven percent of included studies evaluating cognitive function (n = 33) reported a significant decline in cognitive ability with increasing anti-cholinergic load (P < 0.05). Four of five included studies reported no association with delirium and increasing anti-cholinergic drug load (P > 0.05). Five of the eight included studies reported a decline in physical function in users of anti-cholinergics (P < 0.05). Three of nine studies evaluating mortality reported that the use of drugs with anti-cholinergic properties was associated with a trend towards increased mortality, but this was not statistically significant. The methodological quality of the evidence-base ranged from poor to very good.Conclusion: medicines with anti-cholinergic properties have a significant adverse effect on cognitive and physical function, but limited evidence exists for delirium or mortality outcomes. © The Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved.

Comparative physical, mechanical and crystallographic properties of a series of gemfibrozil salts

Objectives Understanding the impact of the counterion on the properties of an acidic or basic drug may influence the choice of salt form, especially for less potent drugs with a high drug load per unit dose. The aim of this work was to determine the influence of the hydrogen bonding potential of the counterion on the crystal structure of salts of the poorly soluble, poorly compressible, acidic drug gemfibrozil and to correlate these with mechanical properties. Methods Compacts of the parent drug and the salts were used to determine Young's modulus of elasticity using beam bending tests. Crystal structures were determined previously from X-ray powder diffraction data. Key findings The free acid, tert-butylamine, 2-amino-2-methylpropan-1-ol and 2-amino-2-methylpropan-1, 3-diol salts had a common crystal packing motif of infinite hydrogen-bonded chains with cross-linking between pairs of adjacent chains. The tromethamine (trsi) salt, with different mechanical properties, had a two-dimensional sheet-like network of hydrogen bonds, with slip planes, forming a stiffer compact. Conclusions The type of counter ion is important in determining mechanical properties and could be selected to afford slip and plastic deformation. © 2010 Royal Pharmaceutical Society of Great Britain.

The biotechnological applications of transglutaminases

Transglutaminases catalyse a diverse range of reactions leading to the modification of proteins and peptides such that their physical, chemical and biological properties become changed. They are found in many different living organisms and as a consequence display subtle differences in their biochemical and physical properties. it is therefore not surprising that this group of enzymes have been exploited as applied biocatalysts in a wide range of commercial sectors varying from the textile industry to the highly lucrative cosmetic industry. in addition the pathophysiological importance of this group of enzymes has increased significantly over the last decade with their involvement noted in a number of human diseases. As a consequence their identification as therapeutic targets or as monitoring aids for a range of different diseases has caused significant interest from the diagnostics and pharmaceutical industries. This review describes some of the current applications of transglutaminases; together with their potential strategic importance and future uses.