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Biomedical subjects

J Hadgraft

Publications and source records attributed to J Hadgraft.

At least 55 records · Page 3Linked to original sources
PubMed1999

In vitro percutaneous absorption of fusidic acid and betamethasone 17-valerate across canine skin.

The penetration of betamethasone 17-valerate and fusidic acid through dog skin was measured in vitro. In order to detect the small amounts of diffused compounds, a liquid chromatography-mass spectrometric method was developed with sensitivity limits for both compounds of 5 ng/ml. After application to the skin surface of a topical gel preparation containing these compounds at the anticipated therapeutic dose rate, about 10 per cent of the betamethasone 17-valerate penetrated the skin over a 24-hour period, with no significant metabolism of the ester. About 1.3 per cent of the applied dose of fusidic acid was similarly recovered. The results demonstrated rapid penetration of both compounds through the epidermis.

Administration, Cutaneous↗
PubMed1998

Modeling of percutaneous drug transport in vitro using skin-imitating Carbosil membrane.

A comparative study of the barrier function of human skin and polydimethylsiloxane-polycarbonate block copolymer Carbosil membrane was performed in vitro using 14 drugs spanning a wide range of structures and therapeutic classes. The drug permeability coefficients across the skin and the Carbosil membrane wee examined as an explicit dependence of permeant molecular weight, melting point, solubility in aqueous solution in aqueous solution and octanol-water partition coefficient. Owing to heterophase and heteropolar structure, Carbosil membranes and human skin epidermis share a common solubility-diffusion mechanism of drug transport. This synthetic membrane is shown to provide a mechanistically substantiated model for percutaneous drug absorption. Carbosil membrane can be used both foe quantitative prediction for transdermal drug delivery rate and as a skin-imitating standard membrane in the course of in vitro drug delivery kinetics evaluation.

Administration, Cutaneous↗
PubMed1998

The selection and design of topical and transdermal agents: a review.

One of the major problems in topical and transdermal drug delivery is the efficiency of the barrier property of the stratum corneum. Topical and transdermal agents were often originally designed as drugs to be given orally. In this paper a mechanistic evaluation of skin penetration shows that topical and transdermal drugs should be designed using different strategies. The relative effects of basic physicochemical parameters are examined. An understanding, at a molecular level, of the permeation process will enable us to produce more effective topical agents and to extend the repertoire of transdermal drugs.

Administration, Cutaneous↗
PubMed1996

The relative effect of Azone and Transcutol on permeant diffusivity and solubility in human stratum corneum.

PURPOSE: The purpose of this work was to analyse the mechanism of the enhancement of percutaneous penetration demonstrated by the known enhancers Azone and Transcutol. METHODS: Enhancer induced changes in the diffusivity and solubility of a model permeant (4-cyanophenol) in human stratum corneum were monitored (in-vitro) using Attenuated total reflectance Fourier transform infra-red (ATR-FTIR) spectroscopy and compared to the gross effects of the enhancers on flux as measured using simple Franz-type diffusion cells. RESULTS: It has been shown by both the well-established Franz diffusion cell technique and the use of ATR-FTIR spectroscopy that the enhancers studied both increase the flux of cyanophenol across human skin in-vitro by a factor of approximately two. Furthermore, it has been demonstrated by ATR-FTIR that these enhancers are likely to exert their effects by different mechanisms. It is probable that Azone reduces the diffusional resistance of the stratum corneum and that Transcutol increases the solubility of the penetrant in this barrier. CONCLUSIONS: There is increasing interest in the apparently synergistic nature in which certain enhancers appear to work. The exact nature of these multiplicative and/or additive effects is not known although there are numerous suggestions in the current literature. The application of ATR-FTIR spectroscopy to such enhancing systems will allow the mechanisms of the observed enhancements to be probed in greater depth.

Analysis of Variance↗
PubMed1996

Ion-pairing interactions between 99MTc-based myocardial imaging agents and oleic acid.

PURPOSE: The purpose was to test the hypothesis that ion-paired facilitated transport is of importance in successful myocardial uptake of cationic imaging complexes. In vitro ion-pairing interactions between oleic acid and seven cationic technetium-99m complexes based on the ligands 1,2-bis[bis(2-ethoxyethyl) phosphino ethane] (tetrofosmin), 1,2-bis(dimethyl phosphino ethane) (DMPE) and 1,2-bis(diethyl phosphino ethane) (DEPE) has been studied. The complexes studied were: [99mTc O2 (tetrafosmin)2]+ (commercially available as myocardial perfusion imaging kit, Myoview), [99mTc O2 (DMPE)2]+, [99mTc O2 (DEPE)2]+, [99mTc Cl2 (DMPE)2]+, [99mTc Cl2 (DEPE)2]+, [99mTc (DMPE)3]+ and [99mTc (DEPE)3]+. METHODS: Ion-pairing interactions were monitored using a rotating diffusion cell containing a solid supported liquid membrane and by formation of lipid monolayers. RESULTS: Depletion of complex from the donor phase into an isopropyl myristate model membrane was generally in proportion to distribution coefficient and transfer to the receptor compartment was in all cases very small. However, by the inclusion of 5% w/v oleic acid, which is used in myocardial metabolism, partitioning was enhanced by amounts which varied depending on the tendency to form complex/oleate ion-pairs. Transfer to the receptor compartment was increased for most complexes when given sufficient time to diffuse through the membrane. The complex [99mTc O2 (tetrofosmin)2]+ appeared to form particularly stable ion-pairs with oleic acid. Monolayer formation also indicated ion-pairing interactions. CONCLUSIONS: The results suggested that whether or not a complex is taken up by the myocyte may depend on its ability to 'hitch a ride' by ion-pairing with the myocytes energy source--a molecule of long chain fatty acid.

Cations↗
PubMed1995

In vitro percutaneous absorption of arildone, a highly lipophilic drug, and the apparent no-effect of the penetration enhancer Azone in excised human skin.

PURPOSE: Arildone, a novel lipophilic antiviral drug when evaluated in Clinical Trials showed limited skin absorption and antiviral efficacy. These studies were conducted to explain the apparent poor absorption characteristics and attempt to promote skin absorption by using Azone, a penetration enhancer. METHODS: Standard in vitro skin permeation methods using excised human skin were employed to characterise the absorption of Arildone. 14C-Arildone was used to estimate the distribution in skin layers by scintigraphic and autoradiographic procedures. RESULTS: The aqueous solubility and distribution constant values for Arildone were 2 micrograms ml-1 and 5 x 10(5) (isopropyl myristate/water), respectively. Absorption through full thickness skin or stratum corneum-viable epidermal membranes (diffusional resistant dermis removed), from a propylene glycol vehicle, was slow and the addition of Azone had no effect on the permeation rate. Distribution studies showed accumulation of Arildone in the stratum corneum. The concentration of Arildone in the viable epidermis was estimated from sectioning the skin and was found to be in sufficient amounts (400 micrograms cm-3) to have potential antiviral activity. CONCLUSIONS: The apparent accumulation of Arildone in the stratum corneum suggested that the hydrophilic skin region presented the main barrier to permeation. Azone which affected the permeability of the stratum corneum was therefore not effective at enhancing Arildone absorption. Vehicles which readily permeate and enhance the transfer of lipophilic drugs from the stratum corneum into the viable epidermis were recommended.

Aged↗
PubMed1995

Use of ATR-FTIR spectroscopy to study the diffusion of ethanol through glycerogelatin films.

The use of ATR-FTIR spectroscopy to study the permeability of a glycerogelatin film is described. Measurement of the diffusion coefficient of ethyl alcohol-d in the film showed excellent reproducibility. Comparison of results from this technique with those previously obtained using an air-flow receptor phase diffusion cell show good agreement in terms of lag time assessed diffusion coefficients. ATR-FTIR spectroscopy revealed time-dependent changes in the composition of the glycerogelatin film during the diffusional process. It was also demonstrated that the concurrent assessment of both diffusant penetration and film composition is feasible.

Diffusion↗
PubMed1993

Phonophoresis of methyl nicotinate: a preliminary study to elucidate the mechanism of action.

The skin penetration enhancement effect of ultrasound (phonophoresis) on methyl nicotinate was investigated in 10 healthy volunteers in a double-blind, placebo-controlled, crossover clinical trial. Each treatment consisted of the application of ultrasound massage (3.0 MHz, 1.0 W/cm2 continuous output) or placebo massage (0 MHz) for 5 min to the forearms of the volunteers, followed by a standardized application of methyl nicotinate at intervals of 15 sec, 1 min, and 2 min post-massage. Percutaneous absorption of methyl nicotinate was monitored using laser Doppler velocimetry. Ultrasound treatment applied prior to methyl nicotinate led to enhanced percutaneous absorption of the drug, for example, ultrasound treatment data versus control data at 2 min showed significant increases (P < 0.05; analysis of variance) in the peak blood flow (125.8 +/- 12.0 vs 75.3 +/- 10.4% flux) and in the area under the curve for blood flow (2630.3 +/- 387.5 vs 1567.6 +/- 183.5% flux.min). The results of this study suggest that ultrasound affects the skin structure to provide skin penetration enhancement. This finding is consistent with the proposed hypothesis that phonophoresis acts by disordering the structured lipids in the stratum corneum.

Double-Blind Method↗
PubMed1992

Evaluation of mucoadhesive polymers in ocular drug delivery. II. Polymer-coated vesicles.

Association of Carbopol 934P and Carbopol 1342 (a hydrophobic modified Carbopol resin) with phospholipid vesicles was assessed by photon correlation spectroscopy and microelectrophoresis at pH 7.4 and 5. The precorneal clearance of the polymer-coated vesicles was compared to that of uncoated vesicles by lacrimal dacryoscintigraphy in the rabbit. The mucoadhesive polymer-coated vesicles demonstrated significantly enhanced precorneal retention compared to noncoated vesicles only at pH 5 (P less than 0.005). The entrapment and subsequent release of tropicamide from Carbopol 1342-coated and uncoated liposomes were determined in vitro together with an in vivo evaluation of the vesicles formulated at the lower pH. Mucoadhesive polymer-coated vesicles failed to increase significantly the bioavailability of the entrapped tropicamide compared to uncoated vesicles and aqueous solution.

Acrylic Resins↗
PubMed1992

An evaluation of structure-penetration relationships in percutaneous absorption.

Prediction of chemical transport across skin is important both to the optimization of topical and transdermal drug delivery and to the assessment of risk following dermal exposure. To facilitate estimation of percutaneous absorption, a number of model in vitro experimental systems have been developed. However, the predictive applicability of the different approaches (with respect to human skin penetration), and the quantitative aspects of the structure-permeation behavior revealed, have not been critically evaluated. The objectives of this paper are to collect, from the literature, the more systematic investigations pertaining to chemical transport across the skin, to quantify the dependence of permeation on the lipophilicity of the penetrants studied, and to assess the relative utility of model systems for the prediction of percutaneous absorption. The categories of chemicals addressed in the survey include n-alkanols, para-substituted phenols, steroids and non-steroidal anti-inflammatory drugs. The experimental systems, used in the studies considered, involve, primarily, steady-state transport measurements across excised skin taken from either human cadavers or hairless mice. Favorable comparisons of these data to solute flux across simple organic liquid membranes are possible. Overall, general patterns of behavior emerge from the analysis such that qualitative predictions can be made. From a quantitative standpoint, though, it is clear that additional "structure-activity" work is necessary to provide appropriate equations that can relate penetration between different test systems and between different chemical classes.

Adult↗
PubMed1992

Epidermal lipids and topical drug delivery.

When a topical formulation is placed on the skin, the active drug is usually required to penetrate through the stratum corneum into the viable tissue. The major control to this process is the slow diffusion through the dead horny layer. The major route of drug penetration through the stratum corneum is via the tortuous intercellular channels. It is therefore important to ascertain the nature of the environment that the drug experiences within the intercellular pathway and how it is affected by the presence of formulation components. The lipids within the intercellular channels are a complex mixture but they are structured into bilayer arrays. Extraction of the lipids by solvents within the formulation will lead to enhanced permeability of the skin. Some penetration enhancers act by creating disorder in the alkyl chains of the lipid bilayers; others modify the solubility characteristics within the stratum corneum. The different interactions that are possible will be discussed in this article.

Administration, Topical↗
PubMed1991

Evaluation of mucoadhesive polymers in ocular drug delivery. I. Viscous solutions.

The potential of a mucoadhesive polymer as an ophthalmic vehicle is evaluated within the rabbit. Precorneal clearance of a mucoadhesive polymer solution (Carbopol 934P) is compared to that of an equiviscous nonmucoadhesive poly(vinyl alcohol) solution (PVA) and buffer (PBS). The precorneal retention of the Carbopol 934P, as studied by lacrimal dacryoscintigraphy, is shown to be significantly greater (P less than 0.05) than that of PVA, which, in turn, is significantly greater than that of PBS. The effect of the polymer solution on the bioavailability of pilocarpine is subsequently assessed by measuring the relative miotic response intensities produced by a 1% solution of the drug. Carbopol 934P solution produces a significant increase (P less than 0.05) in bioavailability as compared to PVA and PBS. The bioavailability from PVA is significantly greater (P less than 0.05) than that from PBS. Studies evaluating vehicle-drug association indicated no binding of the drug to the polymer.

Acrylic Resins↗
PubMed1991

Influence of ultrasound on the percutaneous absorption of nicotinate esters.

The influence of ultrasound on the percutaneous absorption of three nicotinate esters was investigated in 10 healthy volunteers in a double-blind placebo controlled crossover clinical trial. Using a specially designed experimental protocol, the effect of continuous output ultrasound (at frequency 3.0 MHz and intensity 1.0 W/cm2 for 5 min) on the percutaneous absorption of methyl, ethyl, and hexyl nicotinates, from gel bases, was investigated. A placebo control, involving massage with each of the gels, without ultrasound for 5 min, was also incorporated. The pharmacodynamic parameter of vasodilation caused by the nicotinates was used to monitor the percutaneous absorption of the drugs. Laser Doppler velocimetry, a noninvasive optical technique, was used to measure vasodilation of the cutaneous vessels within the treatment site. Ultrasound treatment led to enhanced vasodilator response to the nicotinates, therefore indicating an enhancement of their percutaneous absorption. These agents may prove to be useful compounds in examination of the mechanism of action of phonophoresis.

Adult↗
PubMed1990

Investigations on the percutaneous absorption of the antidepressant rolipram in vitro and in vivo.

In vitro experiments using full-thickness human skin showed that it was feasible to deliver therapeutic amounts of the new antidepressant drug rolipram. Simple transdermal devices were constructed, and the presence of isopropyl myristate (IPM) in a silicone adhesive (Dow Corning X7-2920) enhanced the flux across excised human skin. The steady-state fluxes from adhesive mixtures containing 0, 5, and 10% IPM were 3, 5.2, and 6 micrograms/cm2/hr, respectively. The in vitro experiments were confirmed in a clinical study involving six healthy male volunteers. The formulations tested were an alcoholic solution and adhesive patches containing 5 and 10% IPM. The dose of drug administered was 0.5 mg/cm2 and the device size 25 cm2. Blood samples were withdrawn over a 24-hr period and analyzed using radioimmunoassay. The topical applications were well tolerated, with only mild or no side effects. A lag time of approximately 2 hr was found for the detection of rolipram in the plasma (detection limit, 50 pg/ml). Interindividual variations both for the peak drug levels and throughout the delivery were quite high but this magnitude of variation has been observed in many other transdermal studies. Plasma levels between 1 and 2 ng/ml were found for all formulations and the AUC0-30 hr was significantly higher for the patch containing 5% IPM.

Administration, Cutaneous↗
PubMed1989

Enhanced in vitro skin permeation of cationic drugs.

The lipophilicity of cationic drugs can be increased by forming ion pairs with the carboxylate anion of fatty acids. Transport of cations across an isopropyl myristate (IPM) membrane was facilitated in the presence of oleic acid and lauric acid, providing an appropriate pH gradient existed. Enhancement of in vitro skin permeation of various drugs, in the presence of fatty acids, was shown to be more dramatic with the slow-permeating neutral caffeine and anionic salicylate. Since both molecules are unable to form ion pairs it is probable that the fatty acids are capable of exerting a disruptive influence on the skin. The cationic drugs appeared to traverse excised human skin more rapidly than predicted by the model membrane data. This may be due to ion pairing with free fatty acids or other anionic groups within the skin. Consequently, the enhancing ability of fatty acids was less marked for neutral or anionic permeants.

Chemical Phenomena↗