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J Hadgraft

Publications and source records attributed to J Hadgraft.

At least 73 records · Page 4Linked to original sources
PubMed1989

Topical application of penetration enhancers to the skin of nude mice: a histopathological study.

Eighteen potential penetration enhancers, some at concentrations that might be used for that purpose, have been examined to evaluate their irritancy potential on nude mouse skin. A biopsy technique was employed followed by histological examination. Up to 50% glycerol, 10% hydroxyethyl lactamide (HELA), 10% oleyl alcohol, 10% Solketal, 10% glycofurol, 100% tetrahydrofurfuryl alcohol (THFA) and 10% urea induced no discernible change in the histological appearance of the skin whereas 100% dimethyl sulphoxide (DMSO), 100% dimethyl formamide (DMF), 100% N-methyl-2-pyrrolidone, 10% Azone, 10% oleic acid, 10% methyl laurate, 10% benzyl alcohol and 10% glycerol formal caused severe skin irritation.

Animals↗
PubMed1988

Physicochemical aspects of percutaneous penetration and its enhancement.

The classic diffusion model-based interpretation of percutaneous absorption is compared to a simple kinetic analysis. The physicochemical significance and the major deductions of the two approaches are shown to be in general agreement. In particular, the effect of penetrant oil/water partition coefficient on transdermal flux is consistently predicted by the two models. Diffusional and kinetic assessments of skin penetration enhancement are then shown to reveal similar dependencies upon penetrant physical chemistry. It is demonstrated that the requirements for successful promotion of a lipophilic drug's transdermal flux are quite different from those necessary for a hydrophilic penetrant. Finally, in light of published transport data and our increased comprehension of the stratum corneum barrier function, the evidence for (and significance of) different absorption paths across the stratum corneum is considered. In addition, the impact of penetrant "size" on transport is addressed. It is argued that currently held beliefs concerning (i) a putative "polar" route through the stratum corneum and (ii) the dependence of flux on molecular weight warrant considerable further attention before their unequivocal acceptance is appropriate.

Diffusion↗
PubMed1987

Skin permeability in the newborn.

Skin permeability to drugs was assessed in the newborn infant using an in vitro method. Excised skin samples were studied in a Franz-type cell, and permeability to 0.1 M sodium salicylate was measured. Fourteen samples were studied, from infants of 25-41 weeks gestation and up to 8 days old. Gestation markedly affected skin permeability to salicylate, absorption being 10(2)-10(3) times greater in infants of 30 weeks gestation or less than in term infants. There are important implications for the high permeability of the preterm infant's skin; accidental poisoning from absorption of topically applied agents can easily occur, and the percutaneous route offers an alternative method of therapeutic drug administration.

Cell Membrane Permeability↗
PubMed1987

Percutaneous absorption in preterm infants.

The skin of preterm infants varies considerably in its level of maturity. To understand skin absorption in premature infants better, we report a technique for the assessment of percutaneous absorption at various gestational and postnatal ages using stable, isotope-labeled (13C6) benzoic acid. Our results indicate that in the preterm infant, this method detects enhanced skin absorption in the first postnatal days, which declines over three weeks to that expected of a full-term infant. This approach also indicates an inverse relationship between gestational age and skin absorption, as well as postnatal age and skin absorption. The reported technique is a safe and noninvasive method using a model skin penetrant for the study of percutaneous absorption in preterm infants from which basic data may be derived to add to our understanding of skin barrier function.

Benzoates↗
PubMed1987

A gamma scintigraphic evaluation of the precorneal residence of liposomal formulations in the rabbit.

Multilamellar liposomes were prepared from dipalmitoyl phosphatidylcholine or egg lecithin in combination with cholesterol and either dicetyl phosphate or stearylamine. The size and charge of the colloidal preparations were characterized before labelling with [111In]8-hydroxyquinoline. Freshly labelled liposomes were instilled into the eyes of unanaesthetized NZW rabbits and their disposition and drainage followed using gamma scintigraphy. A positive surface charge was found to affect significantly liposomal drainage rate, whereas an increase in size restricted drainage from the inner canthal region. Drainage of the suspending medium was directly compared with liposomes by labelling the medium with [99mTc] sodium pertechnetate and following the simultaneous change in removal of 99mTc and 111In from the precorneal area. Slower drainage rates were obtained for the suspending medium compared with solutions of the isotopes suggesting that the liposomes restricted solution drainage.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1987

Transdermal drug delivery and cutaneous metabolism.

The delivery of drugs via the skin to achieve systemic therapeutic effect is currently under intense investigation. The skin offers unique advantages and limitations for drug input into the body. For example, while hepatic first pass may be circumvented, the excellent barrier function of the stratum corneum (the thin outermost layer of skin) precludes, at present, all but the most potent drugs from this route of administration. Examples of approved transdermally delivered drugs are scopolamine, nitroglycerin, clonidine and estradiol. The delivery systems which have been formulated for these agents have been designed to provide essentially zero-order input kinetics for between 1 and 7 days. The impact of cutaneous metabolism on transdermal drug delivery has not yet been evaluated rigorously. Limited in vivo data for nitroglycerin suggest a cutaneous first pass effect of between 10 and 20%. More work has been directed towards the use of topical prodrugs and the design of molecules better able to transport across the stratum corneum and then undergo local enzymatic activation. Further research in this area will require a more specific quantitative understanding of the metabolic capabilities of human skin in vivo.

Administration, Topical↗
PubMed1987

Transdermal drug delivery: problems and possibilities.

Transdermal drug delivery has, in recent years, attracted considerable interest. However, despite the obvious advantages of this novel route of drug administration to achieve systemic therapeutic effect, there remain important, and sometimes severe, limitations on the physiochemical and pharmacological properties of the agent to be delivered. This article reviews the present status and accomplishments of transdermal drug delivery. The benefits, disadvantages, and, as yet, unresolved problems inherent to drug input via the skin are addressed. Deficiencies in our knowledge of the percutaneous absorption process in man are identified, and approaches to elucidate these unknowns are discussed. Finally, with respect to the future potential of transdermal drug delivery, experimental and modeling techniques, which can be employed to assess the feasibility and promise of a therapeutic candidate, are described and illustrated with pertinent examples.

Administration, Cutaneous↗
PubMed1985

Percutaneous absorption in man: a kinetic approach.

A biophysically based kinetic model of chemical absorption via human skin was developed and applied to the penetration kinetics of 12 chemicals: aspirin, benzoic acid, benzyl nicotinate, caffeine, chloramphenicol, colchicine, dinitrochlorobenzene, diethyltoluamide, malathion, methyl nicotinate, nitrobenzene, and salicylic acid. The pharmacokinetic model is linear and includes four first-order rate constants: (1) k1 describes penetrant diffusion through the stratum corneum; (2) k2 relates to further transport across the viable epidermal tissue to the cutaneous blood vessels; (3) k3 is a parameter which delays the partitioning of penetrant at the stratum corneum-viable tissue interface and, in conjunction with k2, reflects the penetrant's relative affinity for the stratum corneum over the viable tissue; and (4) k4 characterizes the elimination rate of chemical from blood to urine. Previously determined diffusion coefficients and molecular weight corrections were used to estimate k1 and k2; k4 values employed were those measured experimentally. Urinary excretion rate data following topical administration were simulated and k3 was estimated for each penetrant by optimizing the fit of the model to the data points. Ratios of k3/k2 should be related to the partition coefficients for the chemicals between stratum corneum and viable tissue and it was shown that these ratios agreed reasonably well with the corresponding octanol-water partition coefficients. This approach may have potential for predicting the general percutaneous absorption kinetics of chemicals based on recognized cutaneous biology and penetrant molecular weight and lipophilicity.

Epidermis↗
PubMed1985

Percutaneous administration of theophylline in the preterm infant.

The preterm infant's skin is a poor barrier to the absorption of chemical agents. The possibility of turning this to the infant's advantage was explored by using the percutaneous route to administer theophylline. A standard dose of theophylline gel, equivalent to 17 mg anhydrous theophylline, was applied to an area of skin 2 cm in diameter over the upper abdomen under an occlusive dressing, and serial theophylline levels were measured; 25 studies were performed in 20 infants of less than or equal to 30 weeks gestation. Therapeutic theophylline levels (greater than 4 mg/L) were achieved in 11 of 13 infants who had not previously received the drug, and were maintained for up to 72 hours. In 12 studies in infants who were previously receiving aminophylline intravenously, theophylline levels were maintained for up to 70 hours. There was a significant decline in the amount of theophylline absorbed in the first 24 hours after application as the infant's postnatal age increased, but satisfactory blood levels were achieved in infants up to 20 days of age. The percutaneous route is a feasible method of administering theophylline in preterm infants.

Absorption↗
PubMed1985

Facilitated transport of sodium salicylate across an artificial lipid membrane by Azone.

The ability of Azone (1-dodecylazacylcoheptan-2-one), a recently developed penetration enhancer, to facilitate the transport of sodium salicylate across an artificial lipid membrane has been investigated using the rotating diffusion cell, a well defined model for percutaneous absorption. Azone was found to be capable of enhancing the transport of the salicylate anion across an isopropyl myristate membrane, by using a pH gradient as the chemical driving force. The results indicate that Azone may be capable of forming ion pairs with anionic drugs.

Azepines↗
PubMed1984

Prediction of drug disposition kinetics in skin and plasma following topical administration.

The development of a physically based pharmacokinetic model for percutaneous absorption is described. The simulation includes four first-order rate constants assigned the following significance: (a) absorption across the stratum corneum; (b) diffusion through the viable tissue; (c) a retardation process which retains penetrant in the stratum corneum (and hence provides a means to mathematically produce a "reservoir" effect, for example); and (d) uptake from the skin into the systemic circulation and subsequent elimination from the body. The kinetic equations of the model are solved and expressions are obtained for the concentration of penetrant within the stratum corneum (and available to subsequently partition into the viable epidermis) and the plasma concentration of the administered substance, as a function of time. Using example values for the four rate parameters, disposition profiles for the penetrant in skin and plasma were derived. The cases considered cover slow and fast stratum corneum penetrants, substances which are excreted rapidly or slowly from the body, and absorbing molecules with a variety of relative stratum corneum-viable tissue affinities. The results suggest a framework for the prediction of pharmaceutically and clinically relevant information following the topical administration of therapeutic agents for local or systemic effect.

Administration, Topical↗
PubMed1983

Thermodynamics of steroid partitioning in dimyristoylphosphatidylcholine liposomes.

The thermodynamics of partitioning of some steroids into dimyristoylphosphatidylcholine (DMPC) liposomes determined above and below the phase-transition temperature (Tc) revealed that: (1) delta Gw leads to 1 for all steroids studied is negative. (2) The process is entropy dominated. (3) delta Hw leads to 1 and delta Sw leads to 1 is more positive below Tc than above it for C-21 steroids. (4) Partitioning occurs into areas slightly more hydrophilic than n-octanol. (5) Ketones substituted on the 11 position of a 21-OH steroid have greater hydrogen-bonding capability than 11-OH compounds. (6) Hydroxyl groups at different positions on the steroid nucleus are non-equivalent, and (7) The group contribution for 21-ester methylenes is greater than that reported for other solutes in DMPC liposome systems.

Dimyristoylphosphatidylcholine↗
PubMed1983

Kinetics and thermodynamics of interfacial transfer.

The kinetic barrier against the transport of methyl and ethyl nicotinates across the water-isopropyl myristate interface has been studied as a function of temperature using a rotating diffusion cell. The temperature dependence of the interfacial transfer kinetics has enabled calculation of the thermodynamic parameters for the process. It is evident from the results that, for the transferring solutes considered, the activation energy barrier is enthalpic, because there is a large positive entropy for transfer into the interfacial region.

Diffusion↗
PubMed1983

Physicochemical interpretation of the pharmacokinetics of percutaneous absorption.

Theoretical expressions are derived to predict the amount of a drug reaching the dermal capillaries as a function of simple physicochemical parameters. The mathematical approach involves the solution of the diffusion equation for the drug in the skin using the technique of Laplace transformation. First-order kinetics are assumed for the absorption of drug from the vehicle into the skin and for uptake into the capillaries. The relative importance of these different processes (absorption from vehicle, diffusion through the skin, and capillary removal) involved in the percutaneous penetration of a drug is discussed, and their influence upon the time course of the absorption phenomenon is illustrated.

Chemical Phenomena↗