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Biomedical subjects

R H Guy

Publications and source records attributed to R H Guy.

At least 37 records · Page 2Linked to original sources
PubMed2001

Biodegradable polymer nanocapsules containing a sunscreen agent: preparation and photoprotection.

Biodegradable polymer nanocapsules containing the lipophilic sunscreen, Parsol MCX (OMC), as the oil core were prepared by solvent displacement. We investigated the influence of polysorbate 85 (P-85) and poloxamer 188 (P-188) as stabilizing agents, the OMC loading capacity and the photoprotective potential of the formulations. The formation of nanocapsules is probably due to an interfacial instability arising from rapid diffusion of the solvent across the interface. The effectiveness of the stabilizing agents was attributed to their ability to inhibit coalescence during solvent diffusion. P-85 was a better stabilizer of poly(epsilon-Caprolactone)-nanocapsules than P-188. The OMC loading capacity was high (99+/-1% of OMC initial concentration). The in vitro release of OMC-nanocapsules is governed by hydrophobicity and crystallinity of the polymer and by the high lipophilicity of the drug. The OMC-nanocapsules provided partial protection against UV-induced erythema, in a manner significantly better than a conventional gel.

Animals↗
PubMed2001

Supersaturation: enhancement of skin penetration and permeation of a lipophilic drug.

PURPOSE: To increase the dermal delivery of a lipophilic model compound (LAP), and to deduce the underlying mechanism of enhanced absorption. METHODS: Penetration of LAP from mixtures of up to four degrees of saturation into the stratum corneum was evaluated using a tape-stripping method; epidermal permeation of the drug was measured in Franz diffusion cells. The relative diffusion and stratum corneum-vehicle partition coefficients of LAP were determined by fitting the results to the appropriate solutions to Fick's second law of diffusion. RESULTS: Both the skin permeation rate and the amount of LAP in the stratum corneum increased linearly with increasing degree of saturation. The apparent diffusivity and its partition coefficient deduced from the penetration experiments were independent of the degree of saturation of the drug in the applied formulation, and consistent with corresponding parameters derived from the permeation experiments. CONCLUSIONS: Supersaturation can increase the skin penetration and permeation of lipophilic drugs. The diffusion and partition parameters deduced for LAP indicate that supersaturation acts exclusively via increased thermodynamic activity without apparent effect on the barrier function of the skin per se.

Animals↗
PubMed2001

Iontophoretic delivery of 5-aminolevulinic acid (ALA): effect of pH.

PURPOSE: To examine the iontophoretic delivery of ALA as a function of pH and to determine the principal mechanisms responsible for its electrotransport. METHODS: Anodal iontophoretic transport of ALA was measured as a function of its concentration and pH of the donor solution. Experiments were performed in vitro using skin excised from porcine ears as the membrane. To deduce mechanism, the concomitant transport of the electroosmotic marker, mannitol, was also assessed. RESULTS: ALA iontophoresis at pH 7.4 is a linear function of concentration over the range 1-100 mM. The mechanism was deduced to be electroosmosis. By reducing the pH from 7.4 to 4.0, the dominant mechanism of ALA transport was shifted from electroosmosis to electrorepulsion as the skin's net negative charge was progressively neutralized. However, the total delivery of the compound was not altered by lowering the pH suggesting that the increased electrorepulsive contribution was essentially balanced by the concomitantly reduced electroosmosis. CONCLUSIONS: Significant ALA delivery at pH 7.4 can be achieved by increasing the drug concentration in the anodal formulation to 100 mM. Lowering the pH does not result in increased ALA transport. Alternative strategies are therefore required to maximize and optimize ALA delivery by iontophoresis.

Aminolevulinic Acid↗
PubMed2001

Contributions of electromigration and electroosmosis to iontophoretic drug delivery.

PURPOSE: To determine the electromigration and electroosmotic contributions to the iontophoretic delivery of lidocaine hydrochloride, in addition to the more-lipophilic quinine and propranolol hydrochlorides, in the presence and absence of background electrolyte. METHODS: In vitro experiments, using excised pig ear skin and both vertical and side-by-side diffusion cells, were performed as a function of drug concentration and with and without background electrolytes in the anodal formulation. Concomitantly, the contribution of electroosmosis in each experimental configuration was monitored by following the transport of the neutral, polar marker molecule, mannitol. RESULTS: Electromigration was the dominant mechanism of drug iontophoresis (typically representing approximately 90% of the total flux). In the presence of background electrolyte, lidocaine delivery increased linearly with concentration as it competed more and more effectively with Na+ to carry the charge across the skin. However, iontophoretic delivery of quinine and propranolol increased non-linearly with concentration. Without electrolytes, on the other hand, electrotransport of the three drugs was essentially independent of concentration over the range 1-100 mM. Transport efficiency of lidocaine was approximately 10%, whereas that of the more lipophilic compounds was significanly less, with the major charge carrier being Cl- moving from beneath the skin into the anodal chamber. Both quinine and propranolol induced a concentration-dependent attenuation of electroosmotic flow in the normal anode-to-cathode direction. CONCLUSION: Dissecting apart the mechanistic contributions to iontophoretic drug delivery is key to the optimization of the formulation, and to the efficient use of the drug substance.

Administration, Cutaneous↗
PubMed2001

Optimizing iontophoretic drug delivery: identification and distribution of the charge-carrying species.

PURPOSE: To identify and quantify, in vitro and in vivo (in humans), the charge-carrying species during transdermal iontophoresis of lidocaine hydrochloride as a function of the concentration of drug relative to that of sodium chloride in the anodal solution. METHODS: In vitro experiments in standard diffusion cells quantified lidocaine delivery and the outward migration of chloride across the skin. Electrotransport of Na+ was inferred by difference, allowing transport numbers of the three main charge-carrying species to be deduced. In vivo, outward electrotransport of Cl- was measured and compared to the corresponding in vitro results. RESULTS: The transport number of lidocaine increased linearly with increasing mole fraction and reached 0.15-0.20 at X(L) = 1.0. In the absence of Na+, most of the charge was carried by Cl- (>80%) despite the skin retaining its net negative charge and cation permselectivity. In vivo data correlated very well with in vitro results. CONCLUSIONS: The mole faction of drug (relative to competing ions of like polarity) is the crucial determinant of the extent to which it can carry charge across the skin during iontophoresis. The outward electromigration of Cl-, in the sense opposite to drug delivery, may offer a useful means by which to optimize iontophoretic efficiency in the absence of competing cations in the anode formulation.

Administration, Cutaneous↗
PubMed2001

Iontophoretic transport across the skin.

There have been many attempts to define the key relationships between passive drug diffusion across the skin and the molecular and physicochemical properties of the permeant. At the present time, the importance of lipophilicity (or hydrogen bond donor and acceptor properties) and of molecular volume are well established, and useful predictive relationships for passive percutaneous permeability exist. With respect to iontophoresis, on the other hand, the situation is far less clear and the mechanisms involved have not been completely defined. The roles of electromigration and electroosmosis (current-induced convective solvent flow) are now beginning to be understood and experimentally separated. In turn, this allows the manner in which certain physicochemical parameters influence the efficiency of drug electrotransport to be deduced. An initial examination of a database drawn from the literature and from our own work (for which the experimental conditions employed were reasonably constant) suggests a rather sharp dependence of cationic drug delivery via electromigration upon molecular size. We suggest that the analysis reveals useful paths for further investigation.

Animals↗
PubMed2001

Assessment of topical bioavailability in vivo: the importance of stratum corneum thickness.

We present a method to determine the cutaneous bioavailability and hence to evaluate the bioequivalence of topically applied drugs in vivo. The procedure uses serial tape-stripping and transepidermal water loss measurements to quantify the thickness of the removed stratum corneum (SC) and to determine the intact membrane thickness. Following tape-stripping, the drug is extracted from the tapes and assayed, e.g., by HPLC. This provides a drug concentration profile as a function of the normalized position within the SC. The data are fitted to a solution of Fick's second law of diffusion in order to calculate characteristic membrane transport parameters. Integration of the concentration profile over the entire SC thickness, that is, the 'area-under-the-curve', provides a measure of the cutaneous bioavailability and hence can be used to assess the bioequivalence of topically applied drugs.

Administration, Topical↗
PubMed2001

Non-invasive assessment of the effects of iontophoresis on human skin in-vivo.

The stratum corneum (SC), the outermost layer of the skin, presents a formidable barrier to transdermal drug delivery. As a result, different strategies have been developed to enhance drug transport into and through skin. Iontophoresis involves the application of a small electrical current which drives molecules across the skin and controls relatively well the rate of delivery. Although the technique has been widely investigated in-vitro, the evaluation of skin integrity in-vivo after iontophoresis is absolutely necessary for the future clinical application of this approach. This paper reviews the non-invasive biophysical techniques which have been used to assess the effects of current application on human skin in-vivo. Specifically, transepidermal water loss, infrared spectroscopy, impedance spectroscopy and skin blood flow measurements are discussed. After first presenting the basic principles of these methods, their application to the determination of SC barrier function and skin integrity is addressed, and the criteria for selecting the most appropriate approach are considered.

Administration, Cutaneous↗
PubMed2000

Iontophoresis: electrorepulsion and electroosmosis.

Over the last 10-15 years, the electrical enhancement of drug delivery across the skin has undergone intense investigation. During this period, considerable amounts of experimental data have been generated, and the successful enhancement of a diverse array of molecules has been achieved. Indeed, the commercial exploitation of the method can be envisaged within the next few years. Despite this progress, however, the mechanistic understanding of iontophoresis remains a challenging scientific question that is yet to be fully resolved. The routes of permeation under the influence of an applied electrical potential, and the molecular interactions of the transporting drug with these pathways, have resisted unequivocal and unambiguous identification. Equally, the relative contributions of electrorepulsion and electroosmosis to the total iontophoretic flux have proven difficult to quantify, due to the difficulty of designing appropriate experiments. The situation is further complicated by the fact that it has now been established that certain lipophilic cations, in particular, can associate strongly with the skin during their iontophoretic delivery, thereby altering the electrical properties of the membrane, and changing the mechanism of transport. In this short communication, the roles of electrorepulsion and electroosmosis have been reconsidered from a simple theoretical point of view, and experimental approaches by which their relative importance may be estimated have been proposed and subjected to initial evaluation.

Administration, Cutaneous↗
PubMed2000

Does epidermal turnover reduce percutaneous penetration?

PURPOSE: After its removal from the skin surface, chemical remaining within the skin can become systemically available. The fraction of chemical in the skin that eventually enters the body depends on the relative rates of percutaneous transport and epidermal turnover (i.e., stratum corneum desquamation). Indeed, some investigators have claimed that desquamation is an efficient mechanism for eliminating dermally absorbed chemical from the skin. METHODS: The fate of chemical within the skin following chemical contact was examined using a mathematical model representing turnover of and absorption into the stratum corneum and viable epidermis. The effects of turnover rate, exposure duration, penetrant lipophilicity, and lag time for chemical diffusion were explored. RESULTS: These calculations show that significant amounts of chemical can be removed from skin by desquamation if epidermal turnover is fast relative to chemical diffusion through the stratum corneum. However, except for highly lipophilic and/or high molecular weight (>350 Da) chemicals, the normal epidermal turnover rate is not fast enough and most of the chemical in the skin at the end of an exposure will enter the body. CONCLUSIONS: Epidermal turnover can significantly reduce subsequent chemical absorption into the systemic circulation only for highly lipophilic or high molecular weight chemicals.

Epidermal Cells↗
PubMed2000

Recovery of human skin impedance in vivo after iontophoresis: effect of metal ions.

The objective of this study was to investigate the effect of the counter-ion (cation) on the recovery of human skin impedance after iontophoresis in vivo. A series of metal chloride aqueous solutions (NaCl, KCl, CaCl2, and MgCl2) was investigated: first at the same concentration (133 mmol/L) and then at the same ionic strength as a NaCl solution at 133 mmol/L. The influence of hydration alone was also examined as a control. The recovery of human skin impedance was followed in the frequency range 1-1,000 Hz, over a 30-minute period after iontophoresis during which 3 impedance spectra were recorded. The results revealed that at t = 30 minutes post-iontophoresis, skin impedance was approximately 3 times greater than the value immediately after the cessation of current passage. However, the results showed that the nature of the cation had no effect on recovery, regardless of whether the ions were at the same concentration or at an equivalent ionic strength. A simple parallel RC-equivalent circuit model for skin was used to determine the resistive (R) and capacitive (C) contributions to skin impedance. An analysis of variance on the calculated R and C values did not show any differences between the electrolytes used at the 2 different ionic strengths.

Adult↗
PubMed1999

The determination of a diffusional pathlength through the stratum corneum.

The stratum corneum possesses a very heterogenous structure. As such a diffusing molecule can access a number of different pathways. It is probable that the excellent barrier properties of the stratum corneum result from a tortuous diffusional pathway around the dead cells. However, there are considerable problems in designing diffusion experiments and analysing the data to prove, without doubt, which is the predominant pathway. The mathematical problems posed are discussed in this article.

Animals↗
PubMed1999

Noninvasive sampling of phenylalanine by reverse iontophoresis.

While iontophoresis is typically associated with drug delivery across the skin, the symmetry of the technique permits its application to the essentially noninvasive withdrawal of biologically important analytes from the subcutaneous space to the body's surface. The identification of other substances which can be monitored by this procedure, and to its optimization and development as a more general clinical chemistry tool, is a long-term objective. In this paper, we describe a preliminary in vitro investigation into the feasibility of extracting and analyzing the amino acid, phenylalanine, with the ultimate aim to develop a diagnostic test for phenylketonuria, a potentially fatal metabolic disease in infants. Over a subdermal concentration range of 1-10 mM phenylalanine, reverse iontophoretic extraction was rapid, easily detectable and highly linear. Manipulation of the electrolyte composition surrounding the cathode (i.e., the site of collection of the iontophoretically-extracted material) enabled phenylalanine to be electrotransported at a rate of approximately 6 nmol/cm(2)/h when present subdermally at 1 mM. The potential exists, therefore, to use this approach for the noninvasive detection of systemic amino acid levels in vivo. However, such a development will necessitate a suitable and convenient analytical approach (e.g., a biosensor), with a sensitivity about 10-times greater than that used in this work, which can be combined successfully with the reverse iontophoretic extraction technology.

Edetic Acid↗
PubMed1999

Chemical uptake into human stratum corneum in vivo from volatile and non-volatile solvents.

PURPOSE: Simple, safe and quick in vivo methods for estimating chemical uptake into the stratum corneum (SC) from volatile and non-volatile solvents are invaluable to health risk assessors. This study compares the human in vivo SC uptake of a model compound (4-cyanophenol) from water and acetone using quantitative attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. METHODS: Small areas on the ventral forearms of human volunteers were treated with 4-cyanophenol (CP) dissolved either in water or acetone. After the skin was cleansed of remaining surface CP, SC samples were taken by a standard tape-stripping method. CP concentration profiles across the SC were quantitated by direct measurement of the permeant on the individual tape-strips using ATR-FTIR. RESULTS: Increasing the duration of exposure to CP aqueous solutions resulted in increasing CP uptake into the SC; the kinetics of uptake correlated well with predictive diffusion equations. Increasing the 'dose' of CP in acetone also resulted in increasing uptake into the SC, but uptake eventually plateaued at a maximum level. The amount of CP taken up into the SC from acetone was 2 to 8-fold greater than that from water following similar short-time exposures. CONCLUSIONS: These safe, simple experimental methods provide practical and predictive assessments of chemical uptake into human SC in vivo.

Adult↗
PubMed1999

Electrorepulsion versus electroosmosis: effect of pH on the iontophoretic flux of 5-fluorouracil.

PURPOSE: To delineate the contributions of electrorepulsion and electroosmosis to the iontophoretic flux of 5-FU across porcine skin in vitro. Also, the isoelectric point (pI) of the skin model was determined. METHODS: The electrotransport of 5-FU, anode-to-cathode ("anodal") and cathode-to-anode ("cathodal") was determined as a function of the pH of the electrolyte bathing the skin. RESULTS: At pH 8.5, the drug (pKa approximately 8) is negatively charged and "cathodal", viz. electrorepulsive, transport is much greater than that in the opposite direction. At pH 7.4, where approximately 25% of 5-FU is charged, electrorepulsive and electroosmotic ("anodal") fluxes are balanced. Decreasing the pH to 6, and then 5, reduces the percentage of ionized 5-FU such that "anodal" electroosmosis dominates across the negatively-charged membrane. But, at pH 4, "anodal" and "cathodal" fluxes are again equal suggesting neutralization of the skin (i.e., pI approximately 4). This is confirmed at pH 3, where "cathodal" electroosmosis dominates across the now net-positively charged barrier. CONCLUSIONS: Electrotransport is sensitive, mechanistically, to the properties of the permeant and of the skin; interactions of, for example, the drug or constituents of a formulation, that alter the barrier's net charge, can affect iontophoretic delivery. The pI of porcine ear skin is approximately 4.

Administration, Cutaneous↗