PubMed Health⌕ Search

Biomedical subjects

J Hadgraft

Publications and source records attributed to J Hadgraft.

At least 19 recordsLinked to original sources
PubMed2006

Use of a molecular form technique for the penetration of supersaturated solutions of salicylic acid across silicone membranes and human skin in vitro.

Permeation enhancement of salicylic acid (SA) from supersaturated solutions formed using a 'molecular form' technique was investigated. In a conventional cosolvent technique, two solvents are used, one in which the drug is considerably more soluble than the other. Propylene glycol and water have been predominantly used as cosolvents to create supersaturation in skin permeation enhancement. In this paper, we report the use of buffer solutions with different pHs as media for producing different molecular forms. Supersaturated solutions were prepared using pH 8:pH 2 (80:20 v/v), which gave a nominal pH when mixed of around 5. Model silicone membranes and human skin were used. Hydroxypropyl methyl cellulose (HPMC) was employed to stabilise the supersaturated states. Stability data showed that while the SA supersaturated solutions without HPMC crystallised between 15 min and 46 h depending on the degree of supersaturation, the solutions with HPMC were stable for more than 2 months. The flux of SA increased with the degree of saturation for solutions prepared in a 80:20 buffer pH 8/buffer pH 2 mixture. Although the fluxes of SA with and without HPMC were similar both through silicone membrane and human skin, HPMC was found to be effective in increasing the stability of supersaturated solutions of SA.

Algorithms↗
PubMed2005

The use of colloidal microgels as a (trans)dermal drug delivery system.

A co-polymer of poly(N-isopropylacrylamide) (85%) co-butyl acrylate (10%) co-methacrylic acid (5%) (NIPAM/BA/MAA) (85/10/5) microgel was synthesised and investigated as a potential pH and temperature sensitive transdermal delivery device. Three compounds having different octanol/water partition coefficients and solubilities were incorporated into the microgel, namely: salicylamide (SA), methyl paraben (MP) and propyl paraben (PP). Physico-chemical characterisation of these microgel-drug complexes showed that microgels incorporating MP and SA have smaller volumes after changing environmental pH or temperature when compared with the co-polymer NIPAM/BA/MAA (85/10/5) alone. This reduction in volume could be attributed to the incorporation of the compounds into the microgel particles, having a shielding effect on the charged groups present within the network. Diffusion studies, across human skin, were performed at 305K in the range of pH 3-7 for saturated solutions of SA, MP and PP, and for microgel particles incorporating the three compounds. The transport rate for these microgels incorporating MP was reduced by 2/3-fold compared to the saturated solution, by one order of magnitude for PP, meanwhile the transport rate for these microgels incorporating SA is the same order of magnitude as that for the corresponding saturated solutions. Transdermal release studies of the saturated colloidal dispersions indicated that pH control of the drug release was marginal. The incorporation of compounds into the pH/temperature sensitive co-polymer NIPAM/BA/MAA (85/10/5) and the subsequent release depends on the octanol/water partition coefficient and solubility of the respective compound.

Acrylamides↗
PubMed2005

Inter- and intralaboratory variation of in vitro diffusion cell measurements: an international multicenter study using quasi-standardized methods and materials.

In vitro measurements of skin absorption are an increasingly important aspect of regulatory studies, product support claims, and formulation screening. However, such measurements are significantly affected by skin variability. The purpose of this study was to determine inter- and intralaboratory variation in diffusion cell measurements caused by factors other than skin. This was attained through the use of an artificial (silicone rubber) rate-limiting membrane and the provision of materials including a standard penetrant, methyl paraben (MP), and a minimally prescriptive protocol to each of the 18 participating laboratories. "Standardized" calculations of MP flux were determined from the data submitted by each laboratory by applying a predefined mathematical model. This was deemed necessary to eliminate any interlaboratory variation caused by different methods of flux calculations. Average fluxes of MP calculated and reported by each laboratory (60 +/- 27 microg cm(-2) h(-1), n = 25, range 27-101) were in agreement with the standardized calculations of MP flux (60 +/- 21 microg cm(-2) h(-1), range 19-120). The coefficient of variation between laboratories was approximately 35% and was manifest as a fourfold difference between the lowest and highest average flux values and a sixfold difference between the lowest and highest individual flux values. Intralaboratory variation was lower, averaging 10% for five individuals using the same equipment within a single laboratory. Further studies should be performed to clarify the exact components responsible for nonskin-related variability in diffusion cell measurements. It is clear that further developments of in vitro methodologies for measuring skin absorption are required.

Clinical Laboratory Techniques↗
PubMed2004

Percutaneous delivery of carbamazepine and selected N-alkyl and N-hydroxyalkyl analogues.

Advantages associated with the transdermal delivery route are well documented, but in the past scientists have concentrated primarily on means of decreasing the barrier function of the skin for improved permeability. Pro-drugs, which possess more favourable physicochemical properties for improved transdermal permeability may have considerable potential. These have been considered in the past but recent information concerning structure activity relationships in dermal penetration has prompted increased interest. During this study, N-methyl (2), N-ethyl (3) and N-(2-hydroxyethyl) carbamazepine (4) analogues were synthesised for transdermal evaluation.

Administration, Cutaneous↗
PubMed2004

Effect of finite doses of propylene glycol on enhancement of in vitro percutaneous permeation of loperamide hydrochloride.

We hypothesised that the depletion of propylene glycol from topical formulations applied at clinically relevant doses (approximately mg/cm2) would limit its penetration enhancement effect. The in vitro percutaneous permeation of a model drug-loperamide hydrochloride-in formulations containing propylene glycol was therefore investigated under finite dose conditions. The flux of loperamide and propylene glycol across dermatomed human skin was measured. The first study examined the effect of topical loading of a gel containing 12% propylene glycol. The second study investigated the effect of propylene glycol content in creams containing 15 and 40%. Both studies showed a correlation between the amount of propylene glycol dosed on the skin and the amount of drug that had permeated. The substantial permeation of propylene glycol and relatively small permeation of loperamide, strongly suggests, that the time dependent permeation of the drug was due to the depletion of propylene glycol at the skin surface and not to the depletion of the drug itself. As often doses applied in in vitro skin permeation experiments do not match the intended clinical dosage-they are usually much greater-this study suggests that the penetration enhancement effect of propylene glycol can be overestimated in in vitro studies.

Administration, Cutaneous↗
PubMed2004

Comparison of Franz cells and microdialysis for assessing salicylic acid penetration through human skin.

The purpose of the present study was to compare Franz cells (FC) and microdialysis (MD) for monitoring the skin absorption of salicylic acid (SA). The influence of pH on SA flux was also assessed by these two techniques. Excised abdominal human skin was used in the experiments. SA was dissolved in phosphate buffer solutions of pH 2, 5 and 7 (2 mg/ml). SA concentrations in the receptor FC solutions and in MD samples were assessed by high performance liquid chromatography (HPLC). The results demonstrate that the flux of SA decreased with increased pH. The profiles permeation determined by Franz cells and microdialysis were similar. However, whatever the pH, the SA flux was higher with microdialysis than with Franz cells. The results showed that SA percutaneous permeation conformed to the pH partition hypothesis. The flux of SA was different when it was determined by the two techniques. The collect of SA, by these two techniques is different. The results of the two techniques are compared and discussed.

Anti-Infective Agents↗
PubMed2004

The effect of solvent on permeant diffusion through membranes studied using ATR-FTIR and chemometric data analysis.

One method of improving the bioavailability of a topical formulation is to add an appropriate solvent that will act as a solubilizer for the permeant and, at the same time, modify the barrier properties of the stratum corneum. It has proved very difficult to determine the precise mechanisms of action involved; this is complicated by the concurrent diffusion of the solvent and the permeant into the skin. Under these circumstances the barrier function may well be changing as a function of time as the solvent disrupts it. We have observed this phenomenon in a model silicone membrane system that we have chosen to study initially to avoid the complexity of the heterogeneous nature of skin and its inherent biological variability. Diffusion experiments were conducted using an established ATR-FTIR approach but the data interpreted using sophisticated chemometric approaches that allowed us to deconvolve the IR signals from the permeant, the solvent, and the membrane. Data are presented that show the concurrent diffusion of benzoic acid (permeant), octanol (solvent), and how the octanol modifies the characteristics of the silicone membrane. Initial data are then presented using human skin to show the power of the diffusion approach coupled to the data deconvolution technique.

Diffusion↗
PubMed2004

GARField magnetic resonance profiling of the ingress of model skin-care product ingredients into human skin in vitro.

A preliminary study of the ingress of mineral oil, decanol, and glycerine into samples of human abdominal skin tissue in vitro made using magnetic resonance profiling with a GARField magnet is reported. Two layers, each circa 50 microm thick and attributed to stratum corneum and viable epidermis, are spatially resolved. Clear differences are observed in the magnetic resonance response of these layers arising from the application of the model skin-care product ingredients. In the case of decanol and glycerine, it is suggested that the profiles show evidence for the effects of moisturization, as distinct from hydration. In the case of glycerine, the effective ingress diffusion coefficient is calculated to be 1.3 +/- 0.5 x 10(-9) cm2s(-1).

Epidermis↗
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↗