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Biomedical subjects

J Hadgraft

Publications and source records attributed to J Hadgraft.

At least 19 recordsLinked to original sources
PubMed2003

The effect of beta-cyclodextrins on the permeation of diclofenac from supersaturated solutions.

Supersaturation is a very useful method of enhancing the permeation of drugs across membranes such as skin, because unlike other methods, it does not interfere with the ultrastructure of the stratum corneum. Many drugs are able to form inclusion complexes with beta-cyclodextrins (beta-CDs) and this study investigates the anti-nucleating effects of these compounds on supersaturated solutions of diclofenac. The ability of various betaCDs to form inclusion complexes with diclofenac was assessed by measuring their saturated solubilities. Solutions containing hydroxypropyl beta-cyclodextrin (HPbeta-CD, with a molar substitution of 0.9) produced a 7.5-fold increase in the solubility of diclofenac, which suggested that a strong complex was formed between the two compounds. This association was characterized using differential scanning calorimetry. Permeation across silicone membranes of these saturated solutions of diclofenac in the presence of the different betaCDs produced similar flux values suggesting that the overall activity was also similar. The effect of different molar ratios of HPbeta-CD and diclofenac, and the anti-nucleating effect of HPbeta-CD (both on its own and in combination with a known anti-nucleant, hydroxypropylmethyl cellulose (HPMC)) on the diffusion of diclofenac across silicone membranes was investigated. HPbeta-CD appears to have a stabilizing effect on supersaturated solutions of diclofenac as a co-ingredient with HPMC.

Cyclodextrins↗
PubMed2003

Formation and stabilisation of triclosan colloidal suspensions using supersaturated systems.

The aim of this paper is to prepare and stabilise, in situ, colloidal microsuspensions of triclosan using the polymer, hydroxypropyl methylcellulose (HPMC). The suspensions were prepared from supersaturated solutions of triclosan. The cosolvent technique was used to create supersaturation. Propylene glycol and water were used as the cosolvents. The triclosan particles had a large needle-shaped morphology, when grown in the absence of the polymer. Moreover, the particles grew rapidly to sizes greater than 5 micrometer over a period of 7h. When HPMC was added, the particle sizes were in the range 90-250 nm depending on the amount of polymer present in the solutions. The stability of the solutions was evaluated over a period of 40 days during which the particle sizes did not vary. The results were consistent with the mechanism proposed by Raghavan et al. [Int. J. Pharm. 212 (2001b) 213].

Anti-Infective Agents↗
PubMed2003

Influence of lipophilic counter-ions in combination with phloretin and 6-ketocholestanol on the skin permeation of 5-aminolevulinic acid.

In this study, the effect of lipophilic counter-ions on the permeation of 5-aminolevulinic acid (ALA) in combination with skin impregnation by phloretin and 6-ketocholestanol was evaluated. Standard in vitro permeation experiments with porcine skin were performed analysing the ALA content by HPLC and fluorescent detection after ALA derivatisation. The shake flask method in combination with a trinitrobenzensulfonic acid test for ALA analysis was performed to calculate the apparent partition coefficient (logP(Oct)). The permeation of ALA was enhanced by cetylpyridinium chloride and benzalkonium chloride at pH 7.0 and by sodium-1-octanesulfonic acid, sodium-1-heptanesulfonic acid and sodium-1-pentanesulfonic acid monohydrate at pH 4.0. Corresponding effects of these additives were observed on the partitioning of ALA. Pre-impregnation of porcine skin with phloretin and 6-ketocholestanol increased the ALA diffusion about 1.7-fold at pH 7.0. Moreover, this transport enhancement by 6-ketocholestanol was 3.5-fold higher when a combination of ALA and cetylpyridinium chloride was used as donor.

Adjuvants, Pharmaceutic↗
PubMed2001

UV-spectrophotometry study of membrane transport processes with a novel diffusion cell.

A novel diffusion cell has been constructed which allows study of membrane diffusion processes without the need for sampling of the receiver compartment, that is highly sensitive and, being based around a diode array spectrophotometer also allows for continuous, real-time recording of multi-species concentration changes in the receiving compartment. The system is controlled to operate isothermally (via a Peltier control system) at temperatures between 15 and 85 degrees C. To examine the performance of this novel design, the transfer of tetracaine from a preparation in PEG 400 (20% tetracaine in PEG 400) has been studied. The results have been used to determine flux, lag time and related parameters. The performance of the novel cell is compared with results from traditional Franz cell diffusion studies.

Algorithms↗
PubMed2001

Membrane transport of hydrocortisone acetate from supersaturated solutions; the role of polymers.

Permeation of hydrocortisone acetate (HA) from supersaturated solutions was studied across a model silicone membrane. Supersaturated solutions were prepared using the cosolvent technique with propylene glycol and water (or aqueous polymer solutions) as the cosolvents. In the absence of the polymer, the flux of HA was similar at all degrees of saturation and was not significantly different from the value obtained for a saturated solution. Flux enhancement, as a result of supersaturation, was observed with all the polymers. The flux increased with increasing polymer concentration, reached a maximum and decreased at higher polymer percentages. The amount of polymer required for maximum enhancement differed for each polymer. The decrease of flux at high polymer concentrations is attributed to changes in microviscosity and a marginal increase in solubility. The infrared spectroscopic and differential scanning calorimetry data suggest that HA-polymer interactions occurred through hydrogen bonding thus explaining the proposed mechanism of the anti-nucleant properties of the polymers.

Biological Transport↗
PubMed2001

Influence of phloretin and 6-ketocholestanol on the permeation of progesterone through porcine skin.

In this study the effect of phloretin (PH) and 6-ketocholestanol (KC) on the permeation of progesterone through porcine skin has been examined. Both PH and KC were incorporated into unilamellar L-alpha-phosphatidylcholine (PC) liposomes at different concentrations (7.5, 15, 30 and 60 mol%). In diffusion experiments with porcine skin, both substances, to a different degree, enhanced the steady state flux of progesterone. It was increased up to 2.4-fold using 15 mol% KC, and 1.4-fold using 30 mol% PH. The results indicate an interaction of these two compounds with the lipid components of the stratum corneum. In order to visualise the interaction, differential scanning calorimetry (DSC) measurements were performed on porcine skin, which had been impregnated with KC and PH. Both showed a lowering ( approximately 5-6 degrees C) in the lipid phase transition temperature that occurs around 75 degrees C in porcine skin.

Animals↗
PubMed2001

ATR-FTIR spectroscopic investigations on the effect of solvents on the permeation of benzoic acid and salicylic acid through silicone membranes.

The effect of a series of alcohols on the permeation of salicylic acid (SA) and benzoic acid (BA) through silicone membrane was evaluated, using Franz-type diffusion cells. Although permeants were applied at the same thermodynamic activity in all vehicles, the resulting fluxes were found to differ significantly. This was a consequence of the interactions between the vehicles and the membrane. The interactions between the vehicles and the membrane were further investigated using ATR-FTIR spectroscopy. With this technique, it was possible to identify two different diffusion processes when the membrane was pre-treated with buffer, whereas one single diffusion process was observed when the membrane was pre-soaked with the vehicle. The technique was successfully used to deconvolute the relative magnitude of partition and diffusion in the permeation process. It was shown that the permeation of both acids was affected by the effect of the vehicles on the diffusion coefficient and the partition coefficient in the silicone membrane. The solubility of the drug in the impregnated membrane was found to be proportional to the saturated solubility in the vehicle used to treat the membrane. The solubility of BA in the impregnated silicone membrane was twice that of SA.

Antifungal Agents↗
PubMed2001

Crystallization of hydrocortisone acetate: influence of polymers.

The influence of hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), polyvinyl pyrrolidone (PVP) and polyethylene glycol (PEG400) on the crystallization of hydrocortisone acetate (HA) was studied. Supersaturation was created by the cosolvent technique. Spontaneous nucleation was observed when no polymer was used as the additive. In the presence of the polymer, nucleation was delayed. The nucleation time decreased with increasing supersaturation at a particular polymer concentration and increased with increasing polymer concentration at a particular supersaturation. Habit modification from a well-defined polar prismatic morphology to a wing-shaped morphology was observed when HPMC was used as the additive. The effect of PVP and PEG400 on the morphology of HA was less pronounced compared to the cellulose polymers. The mechanism of nucleation retardation by the polymers is explained in terms of association of HA with the polymer through hydrogen bonding. The growth may be inhibited by the hydrodynamic boundary layer, in which the polymers accumulate as well as by the adsorption of the polymer onto the crystal surface. The habit modification of HA by HPMC is due to different extents of adsorption on different faces of the crystal, the extent of which is dependent on the hydrogen bonding functional groups that are exposed at each face of the crystal.

Crystallization↗
PubMed2001

Penetration enhancement of ibuprofen from supersaturated solutions through human skin.

Systematic investigations on the diffusion of ibuprofen (IBU) from supersaturated solutions through human epidermis are reported. Significant flux enhancement was obtained from supersaturated solutions compared to the saturated solution. Hydroxypropyl methylcellulose (HPMC), when used as an additive was found to be effective in maintaining the high activity state at high degrees of saturation (DS). The increase in the flux was proportional to the DS. In the presence of 2-hydroxypropyl-beta-cyclodextrin (CD) at DS 2 and 3 a lower flux was observed compared to HPMC. At DS 5 a higher flux enhancement was found suggesting that CD might act as a penetration enhancer at certain CD/drug ratios. Studies on the mechanism of stabilisation of HPMC and CD on IBU crystallisation from supersaturated systems showed that HPMC acts as a growth inhibitor and habit modifier whereas CD does not influence the crystallisation process.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2001

Effect of phloretin on the percutaneous absorption of lignocaine across human skin.

The potential use of phloretin, a polyphenolic compound, as a penetration enhancer in the transdermal delivery of lignocaine hydrochloride (L-HCl) has been investigated. Standard in vitro skin permeation methods, using excised human skin, were used to characterize the percutaneous absorption of L-HCl. Initially, phloretin was applied to the skin surface as a methanolic solution. The skin samples were treated 12 h prior to application of the lignocaine donor solution, which was buffered at pH 4.0 and 7.0. The data obtained from the methanolic solutions at pH 4.0 show a 3.2-fold increase of the cumulative amount permeated after 24 h compared with the control. A second series of experiments were conducted using unilamellar phosphatidylcholine liposomes instead of methanol as a vehicle for the phloretin. The L-HCl amount permeated from liposomal-pretreated skin was 5.4-fold (p < 0.05) higher than the control within 24 h. In addition to the diffusion experiments, pressure area isotherms were recorded on a Langmuir-Blodgett trough using the model skin lipid ceramide-2. They showed a slight increase in the area occupied per lipid molecule of 1.04 nm(2) at constant surface pressure. This result indicates an interaction between the model lipid and phloretin. The results suggest the potential use of phloretin as penetration enhancer in the delivery of L-HCl through skin.

Chromatography, High Pressure Liquid↗
PubMed2001

The effect of hydrogen bonding on diffusion across model membranes: consideration of the number of H-bonding groups.

The diffusion of a series of phenols across simple silicone membranes impregnated with either octanol or toluene was studied. These solvents are taken up and saturate the membrane. The presence of the solvents in a solid membrane allows them to interact with any permeant that cross the membrane. This membrane was used to simulate a bio-membrane, e.g. the skin, capable of hydrogen bonding with the permeant. As the number of H-bonding groups was increased the flux across both the octanol and toluene impregnated membranes decreased. However, deconvolution of the data showed that for the octanol impregnated membrane the diffusion coefficient (Dm) decreased significantly with the number of H-bonding groups. This was not the case for the toluene impregnated membrane. Furthermore the spatial configuration of the -OH groups around the aromatic ring had a significant effect on the decrease in Dm. These findings have considerable implications in understanding the absorption of permeants across bio-membranes capable of H-bonding.

Catechols↗
PubMed2001

Probing the effect of vehicles on topical delivery: understanding the basic relationship between solvent and solute penetration using silicone membranes.

PURPOSE: In the present study we examined the relationship between solvent uptake into a model membrane (silicone) with the physical properties of the solvents (e.g., solubility parameter, melting point, molecular weight) and its potential predictability. We then assessed the subsequent topical penetration and retention kinetics of hydrocortisone from various solvents to define whether modifications to either solute diffusivity or partitioning were dominant in increasing permeability through solvent-modified membranes. METHODS: Membrane sorption of solvents was determined from weight differences following immersion in individual solvents, corrected for differences in density. Permeability and retention kinetics of 3H-hydrocortisone, applied as saturated solutions in the various solvents, were determined over 48 h in horizontal Franz-type glass diffusion cells. RESULTS: Solvent sorption into the membrane could be related to differences in solubility parameters, MW and hydrogen bonding (r2=0.76). The actual and predicted volume of solvent sorbed into the membrane was also found to be linearly related to Log hydrocortisone flux, with changes in both diffusivity and partitioning of hydrocortisone observed for the different solvent vehicles. CONCLUSIONS: A simple structure-based predictive model can be applied to the sorption of solvents into silicone membranes. Changes in solute diffusivity and partitioning appeared to contribute to the increased hydrocortisone flux observed with the various solvent vehicles. The application of this predictive model to the more complex skin membrane remains to be determined.

Administration, Topical↗
PubMed2001

Modulation of the barrier function of the skin.

Transport of xenobiotics across the stratum corneum, the rate-controlling membrane of skin, is slow and the mechanism appears complex. However, the basic transfer is controlled by fundamental physicochemical concepts, the predominant of which are partition (K), diffusion (D) and solubility (C(s)). In order to change the rate of penetration it is therefore clear that it is these parameters that should be targeted. In most instances enhancement strategies are adopted to improve D, K or C(s), however there are instances in which permeation reduction may be beneficial. Examples include the topical application of sunscreens or insect repellents. This publication demonstrates the way in which modulation effects can be assessed and the difficulties involved in determining which of the physicochemical parameter(s) are being affected. If the formulation influences more than one, synergism can often be seen. Advances in computer modelling have provided an insight into the mechanisms of action of some of the chemical enhancers at a molecular level. Enhanced skin absorption has been reported for the delivery of macromolecules such as insulin (associated with transfersomes) or DNA (as a DOTAP complex). The barrier property of the skin must be modulated for this to be achieved. However the precise mechanisms of action have not been elucidated.

Animals↗
PubMed2000

Examination of the biophysical interaction between plasmid DNA and the polycations, polylysine and polyornithine, as a basis for their differential gene transfection in-vitro.

The impetus to develop non-viral gene delivery vectors has led to examination of synthetic polycationic polymers as plasmid DNA (pDNA) condensing agents. Previous reports have highlighted superiority (up to x 10-fold) in the in-vitro transfection of pDNA complexes formed by poly-(L)-ornithine (PLO) compared to those formed with poly-(L)-lysine (PLL). The apparent basis for this consistent superiority of PLO complexes remains to be established. This comparative study investigates whether physico chemical differences in the supramolecular properties of polycation:pDNA complexes provide a basis for their observed differential gene transfection. Specifically, particle size distribution and zeta potential of the above complexes formulated over a wide range of polycation:pDNA ratios were found to be consistent with a condensed (150-200 nm) cationic ( + 30-40 mV) system but not influenced by the type of cationic polymer used. A spectrofluorimetric EtBr exclusion assay showed that polycation:pDNA complexes display different pDNA condensation behaviour, with PLO able to condense pDNA at a lower polycation mass compared to both polylysine isomers, and form complexes that were more resistant to disruption following challenge with anionic counter species, i.e. poly-(L)-aspartic acid and the glycosaminoglycan molecule. heparin. We conclude that particle size and surface potential as gross supramolecular properties of these complexes do not represent, at least in a non-biological system, the basis for the differential transfection behaviour observed between these condensing polymers. However, differences in the ability of the polylysine and polyornithine polymers to interact with pDNA and to stabilise the polymer-pDNA assembly could have profound effects upon the cellular and sub-cellular biological processing of pDNA molecules and contribute to the disparity in cell transfection efficiency observed between these complexes.

Adenocarcinoma↗
PubMed2000

The selection of non-steroidal anti-inflammatory agents for dermal delivery.

An analysis has been conducted to show how the penetration of a selection of non-steroidal anti-inflammatory agents (NSAIDs) through the skin may be predicted. The calculations are based on physicochemical parameters that can be predicted using commercially available software. Where available the predictions compare favourably with the literature values. The bio-effectiveness of the NSAID will be a function of both its penetration through the skin and its potency. The variation in potency has also been considered. Most NSAIDs are carboxylic acids, therefore the pK(a) will be an important determinant in ionisation and hence permeation. pH partition behaviour into the skin has been considered together with the relative impact of decreased permeation but increased solubility with degree of ionisation.

Administration, Cutaneous↗
PubMed2000

pH, pK(a) and dermal delivery.

The effect of pH on the permeation of ibuprofen and lignocaine through human skin has been modelled using a modification to the equation derived by Potts and Guy, which is normally applied to unionized entities. The results show that permeation is related to the distribution coefficient. The physicochemical properties have been predicted ab initio using commercially available software and compared to literature values. The approach is successful and shows that there is significant permeation of the ionized drugs through a lipophilic pathway, possibly as a result of ion pairing. Since the aqueous solubility of the ionized material is significantly higher than the unionized, the maximum flux through the skin may occur at a pH where ionization is high. Optimum topical or transdermal formulations may not therefore be for the free acid or free base.

Administration, Cutaneous↗
PubMed2000

Membrane penetration enhancement of ibuprofen using supersaturation.

Permeation enhancement of ibuprofen from supersaturated solutions formed using the cosolvent technique was investigated using silicone as a model membrane. Hydroxpropyl methyl cellulose and hydroxpropyl-beta-cyclodextrin were used to stabilise the supersaturated states. Physical stability studies showed best results for low drug concentrations in a 40:60 propylene glycol/water cosolvent system. Variations in flux across model silicone membranes from saturated solutions were observed as the PG content was increased. The flux of IBU increased with the degree of saturation for solutions prepared in a 40:60 PG/water cosolvent mixture. HPMC and CD were found to be effective in enhancing the stability of supersaturated solutions of IBU. The mechanisms of action are different for the two additives and are discussed.

Anti-Inflammatory Agents, Non-Steroidal↗