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Biomedical subjects

B W Barry

Publications and source records attributed to B W Barry.

At least 19 recordsLinked to original sources
PubMed1998

Transdermal delivery from eutectic systems: enhanced permeation of a model drug, ibuprofen.

The formation of eutectic systems between ibuprofen (ibu) and seven terpene skin penetration enhancers was studied and, by using the eutectic systems as donors, the effects of melting point depression of the delivery system on transdermal delivery were investigated. A range of ibu:terpene binary mixtures were melted together, cooled, and recrystallised. Composition/melting point phase diagrams were determined by DSC and FT-IR analysis was used to investigated the nature of the interaction. Permeation of ibu across human epidermal membrane from the eutectic system was measured and compared to the flux from a saturated aqueous solution across skin and skin pretreated with the terpenes. The eutectic, i.e. minimum, melting points of these systems ranged from 32 degrees C for ibu:thymol 40:60 (% w/w) to -13 degrees C for ibu:1,8-cineole 40:60 (% w/w) compared to 76 degrees C for ibu alone. FT-IR studies indicated that only the terpenes which formed hydrogen bonds with ibu produced eutectic systems. Each set of ibu:terpene eutectic systems produced a significant (t-test, p = 0.05) increase in flux compared to a saturated aqueous solution applied to untreated and to terpene pretreated skin. For example, ibu:thymol 40:60 (% w/w) produced a flux of 150 micrograms/cm2/h, 5.9 times the flux from a saturated aqueous solution with thymol pretreated skin and 12.7 times the flux from a saturated aqueous solution across non-pretreated skin. In conclusion, a hydrogen bonding interaction is the primary mechanism by which some terpenes form binary eutectic mixtures with ibu. The resultant melting point depression of the delivery system is correlated with a significant increase in transdermal permeation.

Administration, Cutaneous↗
PubMed1998

Thermally induced molecular disorder in human stratum corneum lipids compared with a model phospholipid system; FT-Raman spectroscopy.

The molecular basis of lipid packing in human stratum corneum and a model phospholipid system has been studied as a function of temperature using Fourier Transform (FT) Raman spectroscopy. Thermally induced molecular rearrangements of the model lipid system, dipalmitoylphosphatidyl choline (DPPC), and stratum corneum were investigated using FT Raman spectroscopy coupled to a heating chamber. Spectra were recorded for a range of sample temperatures and the results for the two systems were compared, producing previously unreported information of the thermal behaviour for the different systems. Discrete thermal events were recorded for both systems by plotting band separation of the lipid v(CH2) symmetric and asymmetric stretching modes against temperature. The main thermal events observed for DPPC included a 'pre-melting' between 37 and 39 degrees C, the main transition observed between 41 and 42 degrees C, a 'post-transition' between 42 and 43 degrees C and three minor transitions at 58-60, 65-70 and 75-80 degrees C. No evidence was found for the pre-transition of DPPC, previously observed at 34-35 degrees C. The main transitions for human stratum corneum were observed at 35-45, 55, 72 and 83 degrees C, measured from lipid CH2 stretching and bending vibrations. The keratin thermal transition at about 100 degrees C exerted little effect on the lipid bands and no characterisable structural changes were reflected in the keratotic bands.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1998

Enhancement by terpenes of 5-fluorouracil permeation through the stratum corneum: model solvent approach.

5-Fluorouracil permeates the stratum corneum through the intercellular pathway. 5-Fluorouracil is hydrophilic and, therefore, its partitioning from the aqueous region into the hydrocarbon interior of stratum corneum lipids is expected to be an important stage of its permeation and a target for some permeation enhancers. It has also been reported that complexation plays a role in the enhancement effect of some accelerants. These mechanisms have been investigated. For partitioning-permeation studies, isooctane was chosen as a model of the hydrocarbon interior of stratum corneum lipid bilayers and the effects of 26 different terpene enhancers on the solubility of 5-fluorouracil in isooctane were measured. Results were then compared with the effects of the same enhancers on the permeation of 5-fluorouracil through the epidermis in man. The stoichiometry of interaction of cineole and limonene with 5-fluorouracil were also studied to reveal possible complex formation. Solubility studies revealed good correlation between solubility and enhancement ratios for the majority of terpenes, indicating that one mechanism by which terpenes increase permeation of the stratum corneum by 5-fluorouracil is by improvement of partitioning. Stoichiometry studies showed that cineole can form 1:1 or higher complexes with 5-fluorouracil. With limonene, only a weak 1:1 complex was indicated. Data obtained using epidermis from man show that the enhancement effect of cineole toward 5-fluorouracil is much higher than that of limonene. These data reveal that terpenes might increase the permeation of 5-fluorouracil through the stratum corneum as a result of complex formation and a form of facilitated transport.

Antimetabolites↗
PubMed1998

Interaction of salicylic acid with verrucae assessed by FT-Raman spectroscopy.

FT-Raman spectroscopy has been used to investigate treated verrucae (warts from the sole of the foot) with a local application of a salicylic acid paint. Differences in the molecular structure of the stratum corneum across the verruca sample were observed, and by comparison with normal and hyperkeratotic skin it was concluded that the tissue around the edges of the verrucae was typically hyperkeratotic skin. In the centre of the verruca, the molecular structure of the skin was altered showing evidence of the interaction with salicylic acid. Salicylic acid was not observed in its characteristic dimerised acid structure, but spectroscopic evidence suggested that fission of the intermolecular H-bonding essentially cleaved the dimer. Observed changes in the v(CCO) stretching mode of the carboxyl and hydroxyl groups indicate the inter H-bonds have broken. These spectral changes are believed to be more consistent with salicylic acid bonding within the human papillomavirus-containing verruca tissue rather than simple acid dissociation upon dissolution in water within the tissue. No evidence for the presence of the other paint components, lactic acid and flexible collodion, was found in the verrucae spectra. This Raman approach may help to elucidate the molecular basis for therapeutic agents interacting with diseased skin.

Humans↗
PubMed1998

Transdermal permeation modulation by cyclodextrins: a mechanistic study.

The purpose of this study was to investigate permeation modulation by beta- and 2-hydroxypropyl-beta-cyclodextrins (beta-CD and HP-beta-CD, respectively) alone and complexed with penetration enhancers for the test drugs 5-fluorouracil and estradiol through human skin, and to probe the value of the CDs in a barrier cream against toluene exposure. Methods include phase solubility studies, permeation experiments, and thermal analysis of stratum corneum; inclusion complexes were characterized by Karl Fischer titrimetry, infrared spectroscopy, and thermal analysis. Results show that complexes of terpenes or toluene with beta-CD were insoluble, whereas those with HP-beta-CD were soluble. The CDs did not enhance flux of either the polar or lipophilic drugs through skin; estradiol permeation was reduced following membrane pretreatment with either CD. Complexation of the lipophilic terpenes with the CDs reduced enhancer efficacy. When formulated into a barrier ointment both CDs, but particularly beta-CD, retarded toluene permeation through the skin and delayed the onset of maximum flux. It is concluded that the CDs themselves are not penetration enhancers for 5-fluorouracil or estradiol in human skin, and that they may be usefully incorporated into a barrier formulation to reduce percutaneous absorption of toxic materials on occupational exposure.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1996

Permeation characteristics of 8-methoxypsoralen through human skin; relevance to clinical treatment.

The permeation characteristics through human skin of 8-methoxypsoralen (8-MOP) and its physical attributes were investigated. The log octanol/water partition coefficient and saturated aqueous solubility of 8-MOP at 32 degrees C were 1-98 and 55.8 micrograms mL-1 respectively, 8-MOP showed Fickian diffusion, with its flux being linearly related to the concentration of drug in the donor solution. The permeability coefficient of 8-MOP through human skin from different concentrations of aqueous solutions and a 2.6 micrograms mL-1 bath lotion (as used in clinics) were statistically identical with mean values of 1.76 +/- 0.12 x 10(-2) and 1.70 +/- 0.32 x 10(-2) cm h-1 respectively (P > or = 0.05). An ethanol/water (1:1 w/v) receptor solution did not improve the clearance of 8-MOP from the dermis when compared with an aqueous vehicle. Complete removal of the stratum corneum by tape stripping from full-thickness membranes produced a threefold increase in the flux of 8-MOP thus suggesting that the main barrier to 8-MOP permeation resides in the stratum corneum although the aqueous epidermal and dermal tissue provide a significant resistance to transdermal drug permeation. The equilibrium uptake of 8-MOP into psoriatic plaques and the 8-MOP aqueous plaque partition coefficient were found to be more than twofold greater than for normal stratum corneum. The absorption of 8-MOP from the total applied topical dose (396 mg) was assessed as approximately 0.25% and only 2.5% of an oral dose, a significant reduction in the possible toxic hazard. The peak concentration of 8-MOP permeating through the skin was observed at about 35 min after limited exposure for 15 min. Our results suggest that following a 15 min bath in the drug solution, there may be a need for an interval of about 20 min before patients are irradiated to ensure the optimization of photosensitizer with UVA irradiation (PUVA) therapy. Alternatively, UV irradiation could be applied at a lower flux over a longer time.

Chemical Phenomena↗
PubMed1995

The 'Iceman': molecular structure of 5200-year-old skin characterised by Raman spectroscopy and electron microscopy.

The molecular state of about 5200-year-old skin from the so-called 'Iceman' (Similaun man or Otzi) has been characterised using Fourier transform Raman spectroscopy, and has been compared with that of contemporary man. Contemporary skin was also freeze-dried (to mimic the conditions under which the ancient skin was preserved) and its molecular structure was compared with that of Iceman skin. The results showed that the proteinaceous moiety of the ancient skin had degraded considerably and, although olefinic bonds had probably oxidised, the lipoidal component was largely unaltered. Electron microscopical comparisons of Iceman and contemporary skin showed that the gross structure of Iceman skin had survived essentially intact for five millennia.

Animals↗
PubMed1995

Terpene penetration enhancers in propylene glycol/water co-solvent systems: effectiveness and mechanism of action.

The effects of propylene glycol/water co-solvent systems and terpene penetration enhancers (1,8-cineole, menthone, (+)-limonene and nerolidol) on the absorption rate of the model hydrophilic permeant, 5-fluorouracil, were investigated using excised human skin. Similar fluxes for 5-fluorouracil were obtained from saturated enhancer-free co-solvent systems. Co-application of each terpene with the drug, both at saturation, in propylene glycol co-solvent systems increased drug flux significantly. Terpene activity depended on the propylene glycol content in the vehicles. Maximum fluxes were obtained from formulations containing the terpenes in 80% propylene glycol systems (highest concentration used), which when normalized to the flux from the pure vehicles yielded enhancement ratios of about 24, 21, 4 and 18, with 1,8-cineole, menthone, (+)-limonene and nerolidol, respectively. Combining the permeation studies with differential scanning calorimetry (DSC) and partitioning experiments revealed that increased lipid disruption is probably an important mechanism involved in the enhancing ability of formulations containing 1,8-cineole, menthone and nerolidol. This was clearly demonstrated by applying thermodynamic principles to interpret DSC results. This approach has indicated that these terpenes are probably able to disrupt stratum corneum lipids at physiological temperature as manifested by reductions in the entropy changes associated with the lipid-related transitions, particularly T2, the first major lipid transition. Additionally, increased drug partitioning contributed to the effect of the high propylene glycol content formulations. (+)-Limonene, as interpreted from DSC results, produced a freezing point-depression effect on stratum corneum lipids, suggesting little interaction with lipids at skin temperature; its small enhancement effect may involve phase separation of the oil in stratum corneum lipids. Terpenes in co-solvent systems such as propylene glycol/water at appropriate propylene glycol content might thus be useful vehicles for the delivery of drugs from topical formulations.

Antineoplastic Agents↗
PubMed1994

Comparison of Fourier transform Raman spectra of mammalian and reptilian skin.

Human skin offers potential advantages for the administration of therapeutic agents for both local and systemic use. However, in studies of transdermal drug delivery, problems with the supply, storage, and use of human tissue have encouraged workers to seek alternative animal materials to model drug diffusion across human skin. We obtained Fourier transform Raman spectra from mammalian (human and pig) and reptilian (snake) skins, and considered structural dissimilarities in the light of differences observed in the diffusion of drugs across the tissues.

Animals↗
PubMed1994

Wide-angle X-ray diffraction of human stratum corneum: effects of hydration and terpene enhancer treatment.

Wide-angle X-ray-diffraction experiments were used to investigate the molecular organization of barrier components of human stratum corneum. Diffraction lines related to the side-by-side lipid packing arrangements in the intercellular bilayers were identified as were patterns arising from secondary protein structures in intracellular keratin. Reflections were also identified which may be produced by proteins in the corneocyte envelopes. The effects of hydration on stratum corneum structure were monitored using 0, 20-40, 40-60, 60-80 and approximately 300% hydrated samples. The packing arrangements in the intercellular lipid bilayers remained the same over the entire hydration range, as did keratin structures. A new diffraction ring, attributable to liquid water, was produced by 300% hydrated samples with a repeat spacing of 0.35 to 0.30-0.29 nm. The effects of three terpene enhancers, (+)-limonene, nerolidol and 1,8-cineole, on stratum corneum structure were monitored. Treatment with each of the terpenes produced additional reflections which were attributed to the presence of the respective liquid enhancers within the stratum corneum. (+)-Limonene produced an additional reflection at 0.503-0.489 nm, nerolidol, an additional reflection at 0.486-0.471 nm and 1,8-cineole, an intense reflection at 0.583-0.578 nm. Reflections characteristic of gel-phase lipids and crystalline lipids also remained after all terpene treatments. These results provide no clear evidence of lipid bilayer disruption by the terpenes and suggest that areas of liquid terpene exist within the stratum corneum. The mechanisms underlying propylene glycol synergy with terpene enhancers were investigated. Treatment of stratum corneum with each terpene mixed with propylene glycol gave rise to two additional reflections. One reflection, always positioned at 0.452-0.448 nm, had been observed in control studies following propylene glycol treatment and may have been associated with bilayer structures disrupted by propylene glycol or altered keratin structures. The second reflection was developed by the respective terpene enhancer. For example, treatment with a 1,8-cineole/propylene glycol mixture produced reflections at 0.457-0.451 nm (propylene glycol-disrupted lipids or altered keratin) and 0.591-0.578 nm (liquid 1,8-cineole). Since the reflection at 0.452-0.448 nm was unaffected by co-application of propylene glycol with terpene enhancers, this study offers no evidence to support the theory that propylene glycol synergy with the terpenes occurs through enhanced lipid disruption.

Adult↗
PubMed1994

Sesquiterpene components of volatile oils as skin penetration enhancers for the hydrophilic permeant 5-fluorouracil.

Twelve sesquiterpene compounds, derived from natural volatile oils, were investigated as putative skin penetration enhancers for human skin. Pretreatment of epidermal membranes with sesquiterpene oils, or solid sesquiterpenes saturated in dimethyl isosorbide, increased the rate of absorption of the model hydrophilic permeant, 5-fluorouracil (5-FU). Enhancers with polar functional groups were generally more potent than pure hydrocarbons. Furthermore, enhancers with the least bunched structures were the most active. The largest effect was observed following pretreatment with nerolidol, which increased pseudo-steady-state 5-FU flux over 20-fold. Molecular modelling suggested that terpenes with structures suitable for alignment within lipid lamellae were the most potent enhancers. Sesquiterpene enhancers had long durations of action implying that they did not wash out of the skin easily. This study attempted to improve enhancer clearance by replacing the aqueous donor and receptor phases by ethanol:water (1:1) solutions. Ethanol increased the permeability coefficient for 5-FU 13-fold, demonstrating that, in aqueous solution, it is a moderately potent penetration enhancer. Sesquiterpene and ethanol enhancement effects were approximately additive. Sesquiterpene effects were almost fully maintained for at least 4.5 days following pretreatment, illustrating poor reversibility. Stratum corneum/water drug partitioning studies suggested that an important mechanism of action of the enhancers was to increase the apparent drug diffusivity in the stratum corneum. Increases in drug partitioning into the entire stratum corneum following enhancer pretreatment were relatively small. Diffusivity increases were directly related to overall rises in permeability. This study has shown that sesquiterpene compounds, which are of low toxicity and cutaneous irritancy, can promote 5-FU absorption across human skin. Sesquiterpene compounds, therefore, show promise as clinically-acceptable skin penetration enhancers.

Aged↗
PubMed1993

A critical comparison of some Raman spectroscopic techniques for studies of human stratum corneum.

This study evaluates a variety of techniques and sampling conditions for Raman spectroscopic investigations of human stratum corneum. Using a Fourier-transform Raman system and samples of stratum corneum in vitro, we demonstrated minimal inter- and intracadaver variations in molecular vibrations. We have also shown Raman spectroscopy to be relatively insensitive to the hydration state of human stratum corneum, indicating that the technique should be valuable for monitoring the transdermal delivery of drugs from aqueous solutions. The stability of human stratum corneum to near-infrared laser excitation was verified by spectral collection for approximately 1 hr. We have also compared FT-Raman spectra from human stratum corneum in vitro and in vivo. Of the different types of Raman instruments used in this study (visible-light excitation microprobe, visible-light excitation macroscopic sampling, and Fourier-transform Raman), the FT-Raman system provided good-quality spectra with high sample throughput, but systems using visible-light excitation should provide unique information for use in specialist applications.

Epidermis↗
PubMed1992

Skin absorption enhancers.

When we try to maximize drug flux through the skin, we usually meet major difficulties because of the impervious nature of the stratum corneum. A popular solution incorporates penetration enhancers into transdermal products. Such materials ideally possess the sole property of reversibly reducing the barrier resistance of the horny layer, allowing the drug to reach the living tissues at a greater rate. This article considers examples of accelerant action that support a general concept explaining enhancer activity in human skin. The core of the proposal is that enhancers usually work by one or more of three main mechanisms: alteration of the lipid or protein domains of the stratum corneum or increase in tissue partitioning of a drug, a coenhancer, water, or any combination of these three chemicals. We may usefully refer to the overall hypothesis as the lipid-protein-partitioning (LPP) concept.

Administration, Cutaneous↗
PubMed1991

Terpenes and the lipid-protein-partitioning theory of skin penetration enhancement.

A series of terpenes has been assessed as skin penetration enhancers towards the model polar penetrant 5-fluorouracil (5-FU). Cyclic terpenes were selected from the chemical classes of hydrocarbons (e.g., alpha-pinene), alcohols (e.g., alpha-terpineol), ketones (e.g., carvone), and oxides (e.g., 1.8-cineole, ascaridole). Permeation experiments were performed on excised human epidermal membranes and the terpenes varied in their activities; alpha-pinene only doubled the permeability coefficient of aqueous 5-FU, whereas 1.8-cineole caused a near 95-fold increase. Essential oils, e.g., chenopodium (70% ascaridole), were less effective than the corresponding isolated terpenes, 5-FU is less soluble in the terpenes than in water, and the terpenes did not exert their action by increasing partitioning of the drug into the membranes as illustrated by stratum corneum:water partitioning studies. The penetration enhancers increased drug diffusivity through the membranes, an effect which correlated empirically with the enhancer activities. The principal mode of action of these accelerants may be described by the lipid-protein-partitioning theory: the terpenes interacted with intercellular stratum corneum lipids to increase diffusivity, and the accelerant effects were not due to partitioning phenomena. Keratin interaction was assumed negligible.

Adult↗
PubMed1990

Shed snake skin and hairless mouse skin as model membranes for human skin during permeation studies.

Difficulties in obtaining and using human skin have tempted many workers to employ animal membranes for percutaneous absorption studies. We have investigated the suitability of two species of snake (Elaphe obsoleta, Python molurus) for this purpose and compared our in vitro experimental results for human skin and for hairless mouse, a currently popular model. The effects of long-term hydration on the membranes were investigated over 8 d using tritiated water as a model permeant. The initial permeability coefficients of all the membranes were similar (0.74-2.2 X 10(-3) cm 2h-1). Although the human and squamate skins did not change significantly over the test period, the permeability of hairless mouse skin increased 37 times. The actions of typical enhancers on the permeabilities of the membranes to a model penetrant 5-fluorouracil (5-FU) were tested using 3% Azone in Tween 20/saline, propylene glycol (PG), 2% Azone in PG, and 5% oleic acid in PG. While the data from snake membranes tended to underestimate the enhancer effects, those from hairless mouse skin greatly overestimated the changes. None of the membranes was a completely reliable model for assessing human percutaneous absorption as modified by accelerants. Pretreatment with acetone did not significantly change the permeability of human or squamate skins to 5-FU, although that of hairless mouse increased twentyfold. An overall conclusion is that, wherever possible, human skin should be used in absorption studies and not hairless mouse or snake skin; otherwise, misleading results may be obtained.

Acetone↗
PubMed1988

Limitations of hairless mouse skin as a model for in vitro permeation studies through human skin: hydration damage.

Hairless mouse skin currently provides a popular model membrane for studies in human percutaneous absorption. Although some similarities between the two skin types have been demonstrated, the effects of prolonged hydration on hairless mouse skin have not previously been rigorously examined. We have measured in vitro the effects of hydration at 31 degrees C on the permeabilities of hairless mouse skin and human abdominal and scalp skin to a model polar compound (water) and a lipid material (hexanol). The permeability of hairless mouse skin rose dramatically, especially to water (fiftyfold increase), whereas the human skin was more stable. We also compared the effects of stripping the stratum corneum with the effects of 8-d hydration for hairless mouse and human abdominal skin. Hydration of hairless mouse skin was as effective as tape-stripping in eliminating the stratum corneum barrier, whereas stripping human skin was far more damaging than hydration, suggesting that prolonged hydration mechanically disrupted mouse skin but not human skin. Histological examination of fresh and hydrated tissues confirmed this suggestion. We therefore recommend that hairless mouse skin is not used as a model for human tissue during in vitro permeation studies under conditions of long-term hydration, i.e., greater than three days.

Animals↗
PubMed1988

Hairless mouse skin is limited as a model for assessing the effects of penetration enhancers in human skin.

The permeability coefficient of 5-fluorouracil through human abdominal and hairless mouse skins was used as an indicator of the relative effects of 12-h pretreatment of the skins with either penetration-enhancer mixtures [including laurocapram (Azone), decylmethylsulfoxide, oleic acid, and propylene glycol] or saline (control). After treatment with saline, fluxes of 5-fluorouracil through the two skin types were similar, but the mouse skin showed exaggerated responses to all the penetration-enhancer formulations. There was no consistent relationship between enchancer effects on the two skin types, and we conclude that the hairless mouse model should not be used to predict the effects of penetration enhancers in human skin. After treatment with saline, hairless mouse skin sharply increased in permeability after approximately 50 h hydration, suggesting that the stratum corneum had started to disrupt, whereas the flux through human skin remained unchanged.

Animals↗