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Assessment of the bioavailability of topically applied drugs designed to act within or beneath the skin is a challenging objective. A number of different, but potentially ...complementary, techniques are under evaluation. The objective of this work was to evaluate in vitro skin penetration and stratum corneum tape-stripping in vivo as tools with which to measure topical diclofenac bioavailability from three approved and commercialized products (two gels and one solution). Drug uptake into, and its subsequent clearance from, the stratum corneum of human volunteers was used to estimate the input rate of diclofenac into the viable skin layers. This flux was compared to that measured across excised porcine skin in conventional diffusion cells. Both techniques clearly demonstrated (a) the superiority in terms of drug delivery from the solution, and (b) that the two gels performed similarly. There was qualitative and, importantly, quantitative agreement between the in vitro and in vivo measurements of drug flux into and beyond the viable skin. Evidence is therefore presented to support an in vivo − in vitro correlation between methods to assess topical drug bioavailability. The potential value of the stratum corneum tape-stripping technique to quantify drug delivery into (epi)dermal and subcutaneous tissue beneath the barrier is demonstrated.
Transdermal administration offers a non-invasive and convenient method for paediatric drug delivery. The competent skin barrier function in term infants and older children limits both water loss and ...the percutaneous entry of chemicals including drugs; but the smaller doses required by children eases the attainment of therapeutic concentrations. Transdermal patches used in paediatrics include fentanyl, buprenorphine, clonidine, scopolamine, methylphenidate, oestrogens, nicotine and tulobuterol. Some patches have paediatric labelling supported by clinical trials whereas others are used unlicensed. Innovative drug delivery methods, such as microneedles and sonophoresis are being tested for their safety and efficacy; needleless injectors are primarily used to administer growth hormone; and two iontophoretic devices were approved for paediatrics. In contrast, the immature and rapidly evolving skin barrier function in premature neonates represents a significant formulation challenge. Unfortunately, this population group suffers from an absence of approved transdermal formulations, a shortcoming exacerbated by the significant risk of excessive drug exposure via the incompletely formed skin barrier.
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Purpose
To examine the potential of stratum corneum (SC) sampling via tape-stripping in humans to assess bioequivalence of topical acyclovir drug products, and to explore the potential value of ...alternative metrics of local skin bioavailability calculable from SC sampling experiments.
Methods
Three acyclovir creams were considered in two separate studies in which drug amounts in the SC after uptake and clearance periods were measured and used to assess bioequivalence. In each study, a “reference” formulation (evaluated twice) was compared to the “test” in 10 subjects. Each application site was replicated to achieve greater statistical power with fewer volunteers.
Results
SC sampling revealed similarities and differences between products consistent with results from other surrogate bioequivalence measures, including dermal open-flow microperfusion experiments. Further analysis of the tape-stripping data permitted acyclovir flux into the viable skin to be deduced and drug concentration in that ‘compartment’ to be estimated.
Conclusions
Acyclovir quantities determined in the SC, following a single-time point uptake and clearance protocol, can be judiciously used both to objectively compare product performance in vivo and to assess delivery of the active into skin tissue below the barrier, thereby permitting local concentrations at or near to the site of action to be determined.
Summary
Background Amino acid (AA) levels in stratum corneum (SC) are potential biomarkers of skin health while their systemic levels may be used to diagnose inherited metabolic diseases.
Objectives ... To examine reverse iontophoresis, in human volunteers, as a minimally invasive tool to analyse AAs within the skin and subdermally.
Methods In four volunteers, the amounts of iontophoretically extracted AAs were compared with those determined in the SC following repetitive tape stripping and with the plasma concentrations. Glucose levels, evaluated in the different compartments, were used as a control.
Results SC concentrations of 13 essentially zwitterionic AAs were ∼100‐fold higher than the respective plasma levels. Passive and reverse iontophoretic extraction for 4 h did not deplete the SC depot of AAs, a fact reinforced by postextraction tape stripping, which revealed that AAs remained in the SC at this time. In contrast, glucose was much less abundant in the SC and was fully and relatively quickly extracted by reverse iontophoresis.
Conclusions It follows that reverse iontophoresis is useful for quantifying AAs in the SC and these data are highly correlated with levels obtained by tape stripping. However, reverse iontophoresis is impractical for the routine monitoring of AA plasma concentrations (unlike the situation for glucose, the skin reservoir of which is much smaller).
This work aimed to (a) characterize the microstructure and porosity of human nail and bovine hoof by mercury intrusion porosimetry and SEM image analysis, (b) study the effects of hydration and of ...N-acetyl-l-cysteine treatment on the microstructure of both membranes, and (c) determine whether the microstructural modifications were associated with changes in drug penetration measured by standard diffusion studies. Bovine hoof surface is more porous than nail surface although there were no differences between the mean surface pore sizes. Hydration and N-acetyl-l-cysteine increased the roughness and apparent surface porosity, and the porosity determined by mercury intrusion porosimetry of both membranes. Pore-Cor
TM was used to generate tridimensional structures having percolation characteristics comparable to nail and hooves. The modeled structures were horizontally banded having an inner less-porous area which disappeared upon treatment. Treatment increased the predicted permeability of the simulated structures. Triamcinolone permeation increased significantly for hooves treated N-acetyl-l-cysteine, i.e., the membranes for which microstructural and permeability changes were the largest. Thus, microstructural changes determined via mercury intrusion porosimetry and subsequently modeled by Pore-Cor
TM were related to drug diffusion. Further refinement of the technique will allow fast screening of penetration enhancers to be used in ungual drug delivery.
Hydration and N-acetyl-l-cysteine treatment alter the porosity (A) and surface pore size distribution (B) of the nail. Modeled structures of the nail (C) emulate the porosity changes caused by N-acetyl-l-cysteine
.
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It has proven challenging to quantify ‘drug input’ from a formulation to the viable skin because the epidermal and dermal targets of topically applied drugs are difficult, if not impossible, to ...access
in vivo
. Defining the drug input function to the viable skin with a straightforward and practical experimental approach would enable a key component of dermal pharmacokinetics to be characterised. It has been hypothesised that measuring drug uptake into and clearance from the stratum corneum (SC) by tape-stripping allows estimation of a topical drug’s input function into the viable tissue. This study aimed to test this idea by determining the input of nicotine and lidocaine into the viable skin, following the application of commercialised transdermal patches to healthy human volunteers. The known input rates of these delivery systems were used to validate and assess the results from the tape-stripping protocol. The drug input rates from
in vivo
tape-stripping agreed well with the claimed delivery rates of the patches. The experimental approach was then used to determine the input of lidocaine from a marketed cream, a typical topical product for which the amount of drug absorbed has not been well-characterised. A significantly higher delivery of lidocaine from the cream than from the patch was found. The different input rates between drugs and formulations
in vivo
were confirmed qualitatively and quantitatively
in vitro
in conventional diffusion cells using dermatomed abdominal pig skin.
8-Methoxsalen (8-MOP) and related furocumarins have been extensively used for the treatment of hyperproliferative skin diseases in association with long-wavelength UVA light. In order to develop ...alternative formulations for the topical administration of 8-MOP, microemulsions were evaluated as delivery vehicles. Six microemulsion formulations were prepared using water, isopropyl myristate (IPM) and Tween
® 80: Span
® 80: 1,2-Octanediol (3:1:1.2 w/w). The microemulsions were characterized using conductimetric and dynamic light scattering analyses. The ability of the systems to deliver 8-MOP into and through the skin was evaluated in vitro using newborn pig-skin. The in vitro permeation data showed that the novel microemulsions increased the 8-MOP total penetration through the skin by order of 1.9–4.5, as compared with IPM. In general, the accumulation of 8-MOP into the skin was increased by a factor of 1.5–4.5 by the microemulsion systems with respect to their total amount of drug delivered across the skin. These results suggest that the studied microemulsion systems may be appropriate vehicles for the topical delivery of 8-MOP.
Concurrent use of cocaine and heroin is a major public health issue with no effective relapse prevention treatment currently available. To this purpose, a combination of buprenorphine and naltrexone, ...a mixed very‐low efficacy mu‐opioid receptor agonist/kappa‐opioid receptor antagonist/nociceptin receptor agonist, was investigated. The tail‐withdrawal and the conditioned place preference (CPP) assays in adult Sprague Dawley rats were used to show that naltrexone dose‐dependently blocked the mu‐opioid receptor agonism of buprenorphine. Furthermore, in the CPP assay, a combination of 0.3 mg/kg buprenorphine and 3.0 mg/kg naltrexone was aversive. A combination of 0.3 mg/kg buprenorphine and 1.0 mg/kg naltrexone was neither rewarding nor aversive, but still possessed mu‐opioid receptor antagonist properties. In the CPP extinction and reinstatement method, a combination of 0.3 mg/kg buprenorphine and 1.0 mg/kg naltrexone completely blocked drug‐primed reinstatement in cocaine‐conditioned rats (conditioned with 3 mg/kg cocaine, drug prime was 3 mg/kg cocaine) and attenuated drug‐primed reinstatement in morphine‐conditioned rats (conditioned with 5 mg/kg morphine, drug prime was 1.25 mg/kg morphine). These data add to the growing evidence that a buprenorphine/naltrexone combination may be protective against relapse in a polydrug abuse situation.
Clinical trials have suggested that a combination of buprenorphine and naltrexone might be effective as a treatment for opioid and cocaine addiction. In this rat study we find a ratio of buprenorphine/naltrexone that is neither aversive nor rewarding, and that attenuated drug‐primed reinstatement to conditioned place preference to both morphine and cocaine. Further in vitro and in vivo studies characterised mu‐opioid receptor occupancy by this drug combination.
•A novel mechanistic model linking a drug reservoir in skin to plasma concentration.•Binding and unbinding found to be significant in reservoir formation.•Time to form reservoir depends on drug ...properties.•System lends itself to the exploration of non-invasive drug monitoring via the skin.
It has been shown that prolonged systemic presence of a drug can cause a build-up of that drug in the skin. This drug ‘reservoir’, if properly understood, could provide useful information about recent drug-taking history of the patient. We create a pair of coupled mathematical models which combine to explore the potential for a drug reservoir to establish based on the kinetic properties of the drug. The first compartmental model is used to characterise time-dependent drug concentrations in plasma and tissue following a customisable drug regimen. Outputs from this model provide boundary conditions for the second, spatio-temporal model of drug build-up in the skin. We focus on drugs that are highly bound as this will restrict their potential to move freely into the skin but which are lipophilic so that, in the unbound form, they would demonstrate an affinity to the outer layers of the skin. Buprenorphine, a drug used to treat opiate addiction, is one example of a drug satisfying these properties. In the discussion we highlight how our study might be used to inform future experimental design and data collection to provide relevant parameter estimates for reservoir formation and its potential to contribute to enhanced drug monitoring techniques.
Iontophoresis: electrorepulsion and electroosmosis Guy, Richard H.; Kalia, Yogeshvar N.; Delgado-Charro, M.Begoña ...
Journal of controlled release,
02/2000, Letnik:
64, Številka:
1
Journal Article, Conference Proceeding
Recenzirano
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.
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