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Biomedical subjects

Jonathan Hadgraft

Publications and source records attributed to Jonathan Hadgraft.

At least 19 recordsLinked to original sources
PubMed2006

Influence of membrane-solvent-solute interactions on solute permeation in model membranes.

The interaction of the components of topical formulations with the skin is an important consideration for effective drug delivery and efficacy. The relative importance of solubility parameters and other solvent properties on membrane diffusion processes has not been fully elucidated in the literature. In this paper, the effect of different vehicles on the permeation of caffeine, salicylic acid and benzoic acid through silicone membranes was evaluated. Polydimethylsiloxane membranes were used as model membranes for comparing the release characteristics of saturated solutions of model permeants because of their homogeneity and uniformity. Log P (octanol-water partition coefficient) and solubility parameter values were calculated for the compounds under study. In vitro diffusion studies indicated that the permeation profiles of all solutes showed a similar pattern. The permeation rates of benzoic acid and salicylic acid through silicone membrane from saturated solutions were higher than those for caffeine reflecting the more lipophilic nature of these compounds in comparison with caffeine. Solvent uptake studies confirmed that the vehicles that were highly sorbed by the membrane altered its properties and hence the flux. Vehicles that were not sorbed by the membrane showed similar steady-state fluxes for the model drugs. This suggests that the diffusion process is mainly influenced by the interactions between the vehicles and the membrane. Solubility parameter alone cannot explain the interactions between the membrane and the vehicles in all cases. Rather, it is likely that membrane flux reflects a combination of different solvent and solute characteristics, such as size, shape and charge distribution.

Administration, Cutaneous↗
PubMed2006

Dermatopharmacokinetic prediction of topical drug bioavailability in vivo.

The overall goal of this study was to explore the potential of using stratum corneum (SC) tape-stripping, post-application of a topical drug formulation, to derive dermatopharmacokinetic parameters describing the rate and extent of delivery into the skin. Ibuprofen was administered in 75:25 v/v propylene glycol-water to the ventral forearms of human volunteers for periods ranging between 15 and 180 minutes. Subsequently, SC was tape-stripped, quantified gravimetrically, and extracted for drug analysis. Together with concomitant transepidermal water loss measurements, SC concentration-depth profiles of the drug were reproducibly determined and fitted mathematically. The SC-vehicle partition coefficient (K) and a first-order rate constant related to ibuprofen diffusivity in the membrane (D/L2, where L=SC thickness) were derived from data-fitting and characterized the extent and rate of drug absorption across the skin. Integration of the concentration profiles yielded the total drug amount in the SC at the end of the application period. Using K and D/L2 obtained from the 30-minute exposure, it was possible to predict ibuprofen uptake as a function of time into the SC. Prediction and experiment agreed satisfactorily suggesting that objective and quantitative information, with which to characterize topical drug bioavailability, can be obtained from this approach.

Absorption↗
PubMed2006

Ibuprofen transport into and through skin from topical formulations: in vitro-in vivo comparison.

The goal was to compare ibuprofen transport into and through skin in vivo in man and in vitro (across silicone membranes and freshly excised pig skin) from four marketed formulations. Ibuprofen gels were administered in vivo for 30 minutes. The stratum corneum (SC) at the application site was then tape-stripped, quantified gravimetrically, and extracted for drug analysis. Together with concomitant transepidermal water loss measurements, SC drug concentration-depth profiles were reproducibly determined and fitted mathematically to obtain a partition coefficient, a first-order rate constant related to ibuprofen diffusivity, and the total drug amount in the SC at the end of the application. All derived parameters were consistent across formulations. Ibuprofen permeation data through both silicone membrane and pig ear skin were also fitted to yield partitioning and diffusion parameters. The former revealed that ibuprofen partitioned differently from the gels into this model barrier. Across pig skin, however, better correlation with in vivo results was found. The dermatopharmacokinetic approach, using SC tape-stripping, offers a valid method to assess equivalency between topical drug formulations. In vitro experiments must be extrapolated cautiously to the clinic, especially when complex interactions between real formulations, which deliver both drug and excipients, and the skin occur.

Administration, Topical↗
PubMed2006

Synthesis and transdermal properties of acetylsalicylic acid and selected esters.

The primary aim of this study was to determine the transdermal penetration of acetylsalicylic acid and some of its derivatives, to establish a correlation, if any, with selected physicochemical properties and to determine if transdermal application of acetylsalicylic acid and its derivatives will give therapeutic drug concentrations with respect to transdermal flux. Ten derivatives of acetylsalicylic acid were prepared by esterification of acetylsalicyloyl chloride with ten different alcohols. The experimental aqueous solubility, logD and transdermal flux values were determined for acetylsalicylic acid and its derivatives at pH 4.5. In vitro penetration was measured through excised female human abdominal skin in diffusion cells. The experimental aqueous solubility of acetylsalicylic acid (6.56 mg/ml) was higher than that of the synthesised acetylsalicylate derivatives (ranging from 1.76 x 10(-3) to 3.32 mg/ml), and the logD of acetylsalicylic acid (-0.85) was lower than that of its derivatives (ranging from -0.25 to 1.95). There was thus an inverse correlation between the aqueous solubility data and the logD values. The experimental transdermal flux of acetylsalicylic acid (263.83 nmol/cm(2)h) was much higher than that of its derivatives (ranging from 0.12 to 136.02 nmol/cm(2)h).

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2006

Pig ear skin ex vivo as a model for in vivo dermatopharmacokinetic studies in man.

OBJECTIVE: The objective was to investigate pig ear skin as a surrogate for human skin in the assessment of topical drug bioavailability by sequential tape-stripping of the stratum corneum (SC). The potential benefits of ex vivo investigations are manifold: ethical approval is not required, multiple replicate experiments are more easily performed, and toxic compounds can be evaluated. MATERIALS AND METHODS: Ex vivo experiments on isolated pig ears were compared with in vivo studies in human volunteers. Four formulations, comprising the model drug, ibuprofen, in different propylene glycol (PG)-water mixtures (25:75, 50:50, 75:25 and 100:0), were compared. RESULTS: Derived dermatopharmacokinetic parameters characterizing the diffusion and partitioning of the drug in the SC ex vivo were consistent with those in vivo following a 30-minute application period. Further, the non-steady-state ex vivo results could be used to predict the in vivo concentration profile of the drug across the SC when a formulation was administered for 3 h (i.e., close to steady-state). CONCLUSIONS: Taken together, the results obtained suggest that pig ear skin ex vivo has promise as a tool for topical formulation evaluation and optimization.

Adult↗
PubMed2005

Skin permeation: the years of enlightenment.

Considerable advances in our understanding of the mechanisms by which drugs permeate the skin barrier have been made over the past 60 years. The key publications, which have influenced the field of skin permeation research are highlighted in the present review. The methodologies commonly employed for estimation of skin permeability are discussed as are the mechanisms proposed for skin permeation. The principal findings from the commonly employed in vitro and in vivo models are considered as well as the applications of enhancers and surfactants for optimization of skin delivery. As these studies presaged the emergence of transdermal drug delivery research in the 1970s, early approaches to model and predict dermal and transdermal absorption are also outlined. The published work on skin permeability in this period embodies the fundamental literature sources for consultation by scientists new to and currently engaged in transdermal drug delivery.

Administration, Cutaneous↗
PubMed2005

Synthesis and transdermal penetration of NSAID glycoside esters.

The glucoside and mannoside derivatives of the NSAIDs flurbiprofen, ibuprofen, ketoprofen and naproxen were synthesised and their penetration through human skin was determined. Experimental transdermal flux data showed that the parent NSAIDs penetrated human skin to a much higher extent than the glycosides.

Administration, Cutaneous↗
PubMed2005

Interaction of phloretin and 6-ketocholestanol with DPPC-liposomes as phospholipid model membranes.

Phloretin and 6-ketocholestanol are penetration enhancers for percutaneous delivery of certain topically applied drugs. In the present study some physicochemical experiments have been performed to elucidate the mechanism of action of phloretin and 6-ketocholestanol. The penetration enhancing effect of phloretin and 6-ketocholestanol is believed to be due to their increase of the fluidity of the intercellular lipid bilayers of the stratum corneum. Phospholipid vesicles were chosen as a simple model to represent these bilayers. The effect of phloretin and 6-ketocholestanol on phase transition temperature and enthalpy was studied using differential scanning calorimetry. Beside of that the size of liposomes was monitored when the amount of penetration enhancer in the liposome preparation was changed. Addition of increasing amounts of phloretin and 6-ketocholestanol to the bilayer resulted in lowering of phase transition temperatures and increasing the enthalpy. Additionally the size of the liposomes was increased when penetration enhancer was added. The results suggest that phloretin as well as 6-ketocholestanol would interact with stratum corneum lipids in a similar manner, both reduce the diffusional resistance of the stratum corneum to drugs with balanced hydrophilic-lipophilic characteristics.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2005

Percutaneous absorption of cyclizine and its alkyl analogues.

Cyclizine (I) alkyl analogues (II-IV) were synthesized and their skin permeation parameters evaluated in vitro. It was hoped that these compounds would possess physicochemical properties more favourable for percutaneous delivery than (I). The identification and levels of purity for the compounds were confirmed by mass spectrometry (MS), nuclear magnetic resonance (NMR) spectrometry, and infrared spectrometry (IR) while melting points were determined by an electrothermal digital Bupsilonchi melting point apparatus. Aqueous solubilities (25 degrees C) and partition coefficients were determined and in vitro permeation studies were performed in buffer (37 degrees C) at pH 7.4 over a period of 24 h, using Franz diffusion cells fitted with human epidermal membranes. Generally, the analogues were more lipophilic, but nevertheless possessed higher aqueous solubilities as compared to (I). (II) and (IV) exhibited two- to three-fold increase in aqueous solubility and their melting temperatures dropped by more than 55 degrees C. Compound (III) had similar aqueous solubility to (I), but its melting point dropped by about 35 degrees C. Measured steady-state fluxes indicated that (II) is a far better penetrant (J=6.95 microg/cm(2)/h) of human epidermis than (I). Although fluxes of (III) and (IV) drop off markedly from that of (II), they remained above the flux of (I), which is (0.132 microg/cm(2)/h). In conclusion, (II) was the best skin permeant and also exhibited the highest aqueous solubility and lowest level of crystallinity as compared to (I) and other analogues. (III) and (IV) were more lipophilic. The overall permeation data of this series indicated that the more water-soluble and the lowest melting point compound was the best skin permeant.

Administration, Cutaneous↗
PubMed2004

Skin deep.

Over the past 30 or so years there has been a considerable advance in our knowledge of the mechanisms of skin permeation. This has largely been brought about by the development of sophisticated biophysical techniques and increased computing powers. The advanced technology has clearly provided indications, at a molecular level, about routes of permeation and how the barrier function can be modulated by excipients with which actives are formulated. This publication reviews some of the advances that have been made and mathematical models that have been constructed to predict percutaneous penetration and transdermal delivery. The models also indicate the various enhancement strategies that can be used in dermal penetration. In the past, it has been difficult to identify precise mechanisms of action of the different classes of enhancer but a combination of appropriate biophysical techniques, mathematical modelling and chemometric analysis can help identify the contributing processes. The models can also be used to indicate rate control in transdermal delivery, whether it is in the applied delivery device or in the skin.

Administration, Cutaneous↗
PubMed2003

Antimicrobial properties of silver-containing wound dressings: a microcalorimetric study.

The studies reported here have been undertaken to assess the potential use of isothermal microcalorimetry in studying the antimicrobial efficacy of wound dressings that contain antimicrobial agents. The microcalorimetric technique allows non-invasive and non-destructive analysis to be performed directly on a test sample, regardless of whether it is homogeneous or heterogeneous in nature. Microcalorimetry is an established procedure that offers quantitative measurements and has the distinct advantage over traditional antimicrobial test methodologies in that calorimetric measurements are made continuously over real-time, thus the dynamic response of microorganisms to an antimicrobial agent is observed in situ. The results described in this paper are for interaction of two silver-containing wound care products AQUACEL Ag Hydrofiber (ConvaTec, Deeside, UK) and Acticoat 7 with SILCRYST (Smith and Nephew Healthcare, UK) with the wound pathogenic organisms Staphylococcus aureus and Pseudomonas aeruginosa. Both dressings are shown, microcalorimetrically, to have the capacity to kill these common wound pathogens within 1-2 h of contact. A dose-response study was conducted with the AQUACEL Ag dressing. Microcalorimetry is shown to be rapid, simple and effective in the study of the antimicrobial properties of gel forming wound dressings.

Anti-Infective Agents↗
PubMed2003

Influence of phloretin and 6-ketocholestanol on the skin permeation of sodium-fluorescein.

In the present study, we investigated the feasibility of enhancing the transport of the model drug sodium-fluorescein across rat, porcine and human skin by treating it with phloretin and 6-ketocholestanol. Both 6-ketocholestanol and phloretin were incorporated into unilamellar liposomes and used as a skin pre-treatment. Afterwards standard diffusion experiments with Franz-type diffusion cells were performed. The results indicate a positive effect of 6-ketocholestanol on the sodium-fluorescein diffusion in all skin types, whereas phloretin had no significant influence compared to the control in human skin. In contrast to this, phloretin had a significant positive effect in rat as well as in porcine skin after 30 h of diffusion. In addition to the permeation studies, the human skin samples were analysed by confocal laser scanning microscopy for direct visualisation of the sodium-fluorescein. As expected the results of the diffusion experiments were confirmed by this microscopic method.

Animals↗
PubMed2003

Prediction of skin penetration using artificial neural network (ANN) modeling.

Artificial neural network (ANN) analysis was used to predict the skin permeability of selected xenobiotics. Permeability coefficients (log k(p)) were obtained from various literature sources. A previously reported equation, which was shown to be useful in the prediction of skin permeability, uses the partial charges of the penetrants, their molecular weight, and their calculated octanol water partition coefficient (log K(oct)). The equation was used to predict the skin permeability for the set of 40 compounds (r(2) = 0.672). A successful ANN was developed and the ANN produced log k(p) values that correlated well with the experimental ones(r(2) = 0.997). The penetration properties of a selection of compounds through human skin that have not been previously investigated, etodolac, famotidine, nimesulide, nizatidine, ranitidine, were investigated. Their permeability coefficients were determined. It was then possible to compare the experimental data with that predicted using the partial charge equation and the trained ANN. ANN modeling for predicting skin permeability was found to be useful for predicting skin permeability coefficients of compounds. In conclusion, the developed and described ANN model in this publication does not require any experimental parameters; it could potentially provide useful and precise prediction of skin penetration for new drugs or toxic penetrants.

Artificial Intelligence↗
PubMed2003

Influence of molecular dipoles on human skin permeability: Use of 6-ketocholestanol to enhance the transdermal delivery of bacitracin.

In the present work, we report the possibility of modifying the electrostatic properties of the skin by treating human epidermis with compounds whose structures possess a large molecular dipole moment. Data are presented showing that such a modification can be used to enhance dermal drug delivery. Inclusion of such compounds in biological membranes affects the so-called membrane dipole potential, an electrical potential originating from molecular dipoles present on the lipid molecules. Modifications in the magnitude of this potential are known to affect the interaction of hydrophobic ions and peptides with model membranes. Using fluorescein-labeled bacitracin and confocal microscopy, we show that the penetration of the antibiotic peptide bacitracin into the epidermis is enhanced when the skin has been pretreated with liposomes loaded with 30 mol % 6-ketocholestanol, a compound known to increase the magnitude of the membrane dipole potential. Studies using the fluorescent indicators fluoresceinphosphatidylethanolamine and 1-(3-sulfonatopropyl)-4-[beta [2-(di-n-octylamino)-6-naphthyl] vinyl] pyridinium betaine show that the interaction of bacitracin with model membranes is also enhanced by the presence of 6-ketocholestanol in the bilayer and offers some indication to the mechanism of penetration enhancement.

Adjuvants, Pharmaceutic↗
PubMed2003

Effect of vehicle pretreatment on the flux, retention, and diffusion of topically applied penetrants in vitro.

PURPOSE: The flux of a topically applied drug depends on the activity in the skin and the interaction between the vehicle and skin. Permeation of vehicle into the skin can alter the activity of drug and the properties of the skin barrier. The aim of this in vitro study was to separate and quantify these effects. METHODS: The flux of four radiolabeled permeants (water, phenol, diflunisal, and diazepam) with log Koct/water values from 1.4 to 4.3 was measured over 4 h through heat-separated human epidermis pretreated for 30 min with vehicles having Hildebrand solubility parameters from 7.9 to 23.4 (cal/cm3)1/2. RESULTS: Enhancement was greatest after pretreatment with the more lipophilic vehicles. A synergistic enhancement was observed using binary mixtures. The flux of diazepam was not enhanced to the same extent as the other permeants, possibly because its partitioning into the epidermis is close to optimal (log Koct 2.96). CONCLUSION: An analysis of the permeant remaining in the epidermis revealed that the enhancement can be the result of either increased partitioning of permeant into the epidermis or an increasing diffusivity of permeants through the epidermis.

Administration, Cutaneous↗
PubMed2003

Permeation of naproxen from saturated solutions and commercial formulations through synthetic membranes.

The release of naproxen through synthetic membranes, mounted in modified Franz-type diffusion cells, was evaluated, either from saturated solutions or from commercially available topical formulations containing 10% naproxen. The results obtained showed that the porous type synthetic membranes chosen (cellulose acetate and polyethersulphone) can be used for assessing product performance in quality control procedures. The formulations interacted with the solid membranes (silicone and EVA) to change their diffusional characteristics. However, transfer in the membrane, and not the formulation was rate controlling. These membranes could not therefore be used in assessing product release performance for quality control.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2002

The effect of the nature of H-bonding groups on diffusion through PDMS membranes saturated with octanol and toluene.

The permeation of a series of structurally related compounds across silicone membranes (PDMS) was studied. The PDMS was saturated either with toluene, to mimic a functionally inert barrier, or octanol, to mimic the polar/hydrogen bonding environment of the stratum corneum lipid barrier. Phenol, salicylic acid, benzoic acid, anisole, phenylethanol and benzyl alcohol were chosen in an attempt to relate permeation to their different H-bonding capabilities. The flux was lower through the octanol system suggesting retardation by polar/H-bonding interactions. Separation of the permeability coefficient into its thermodynamic (partition coefficient) and kinetic (diffusion coefficient) terms suggests that the effect of altering polarity within the membrane has a greater impact on the diffusion of permeant rather than its chemical potential within the membrane.

Diffusion↗