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Biomedical subjects

G L Flynn

Publications and source records attributed to G L Flynn.

At least 19 recordsLinked to original sources
PubMed1996

Controlled transdermal delivery of fentanyl: characterizations of pressure-sensitive adhesives for matrix patch design.

Transdermal delivery of fentanyl from various adhesive matrix formulations to achieve a steady-state skin flux was investigated. For this purpose, various pressure-sensitive adhesives selected from the three chemical classes of polymers (polyisobutylene (PIB), acrylate, and silicone adhesives) were characterized with respect to fentanyl's solubility, diffusion coefficient, and permeability coefficient. The solubility of fentanyl in various pressure-sensitive adhesives at 32 degrees C was determined by the drug absorption-desorption method. The solubilities of fentanyl in these adhesives were in the following order: acrylate > silicones > PIB. The permeability coefficient and diffusion coefficient of fentanyl in these adhesives were determined by the membrane diffusion method. The diffusion coefficient rank order was silicone-2920 > silicone-2675 > or = acrylate > PIB. The release profiles of fentanyl in the aqueous buffer from these adhesives with 2-4% drug loading was evaluated. The release rate of fentanyl from the acrylate polymer was significantly higher than those of silicone and PIB adhesives. The in vitro flux of fentanyl through cadaver skin from various adhesives with 2% drug loading was determined at 32 degrees C using modified Franz diffusion cells. The skin fluxes of fentanyl from silicone-2920 and PIB adhesives were 6.3 +/- 0.7 and 3.1 +/- 0.3 micrograms/cm2/h, respectively. On the other hand, the skin fluxes of fentanyl from acrylate and silicone-2675 adhesive matrices were about 1 microgram/cm2/h. The effect of drug loading on skin flux was investigated using PIB as a model adhesive. The drug released in the phosphate buffer (pH = 6.0) increased linearly as the drug loading in the PIB was increased from 1% to 4%; and as the drug loading exceeded 4%, an initial burst effect followed by a zero-order release was observed. The skin flux of fentanyl increased proportionally as the drug loading in the PIB adhesive was increased from 1 to 4%, and a plateau was reached beyond 4% drug loading. These results suggest that fentanyl concentration in the PIB adhesive might have reached saturation above 4% drug loading and that the optimum skin flux was accomplished from such a system because of attainment of maximum thermodynamic activity.

Acrylates↗
PubMed1996

Permeation of buprenorphine and its 3-alkyl-ester prodrugs through human skin.

PURPOSE: Homologous 3-alkyl-ester prodrugs (C2 to C4) of buprenorphine with decreased crystallinity have been synthesized and evaluated for transdermal delivery commensurate with opioid dependence treatment. METHODS: To assess the influence of derivatization on delivery, the permeation of the prodrugs through human skin was determined in vitro. Prodrug metabolism was measured in human blood and skin supernatant in vitro along with chemical hydrolysis controls. The prodrugs octanol/water partition coefficients were measured. RESULTS: Without exception, the prodrugs were completely hydrolyzed on passing through the skin and appeared as buprenorphine in the receptor compartment. However, using saturation conditions, in no instance did the buprenorphine flux through skin from a prodrug solution exceed the flux of buprenorphine base itself in vitro. Moreover, the flux of the acetyl ester, the least hydrophobic of the prodrugs, was not significantly elevated upon stripping the skin. Whether in blood or the skin supernatant, the prodrugs hydrolyzed in an apparent first-order fashion and rate constants and half-lives were calculated. CONCLUSIONS: We conclude from the results that the prodrugs' very high octanol/water partition coefficients (hydrophobicity) placed them in viable tissue layer controlled diffusion. Consequently, one does not derive the potential flux-increasing benefit of reducing crystallinity that was expected.

Administration, Cutaneous↗
PubMed1996

Systemic uptake and clearance of chloroform by hairless rats following dermal exposure. I. Brief exposure to aqueous solutions.

The systemic uptake of chloroform from dilute aqueous solutions into live hairless rats under conditions simulating dermal environmental exposure was studied. Whole blood was sampled during a 30-min immersion of an animal within water containing a known concentration of chloroform and then for 5.5 h following its removal from the bath. The amount of chloroform systemically absorbed was determined by comparing the AUCs of the blood concentration vs. time plots from dermal exposure to that obtained after i.v. infusion (for a period of 30 min) of an aqueous solution containing a known amount of chloroform (positive control). Although dermal data implied two-compartment disposition characteristics, i.v. infusion data fit best to a three-compartment disposition. Linear pharmacokinetics was observed both by i.v. administration and percutaneous absorption at the dose levels studied. Chloroform was detected in the rat blood as early as 4 min following exposure. Our findings suggest that about 10.2 mg of chloroform was systemically absorbed after dermal exposure of a rat to an aqueous solution of 0.44 mg/ml. This amount is substantially higher than the predictions of mathematical risk-models put forth by some investigators. However, when expressed as the "effective" permeability coefficient (Kpeff), close agreement was noticed between our value and those estimated by others using physiologically based pharmacokinetic (PBPK) models. Also, in terms of Kpeff, reasonable agreement existed between our and another investigator's past estimates of uptake based on depletion of bath level of chloroform and the actual uptake measured in our current experiments. The estimated onset of systemic entry seen here is entirely consistent with our estimate of how long it takes to establish the diffusion gradient across the stratum corneum based on tape stripping.

Animals↗
PubMed1996

Transdermal prodrug concepts: permeation of buprenorphine and its alkyl esters through hairless mouse skin and influence of vehicles.

In vitro skin permeation of buprenorphine (BUP) and three of its alkyl ester prodrugs was evaluated using hairless mouse skin. The three esters selected were the acetyl ester (Ac-BUP), butyl ester (Bu-BUP), and isobutyl ester (Isb-BUP). These drugs were applied on the skin as saturated slurries in three vehicles commonly used to formulate agents for transdermal purposes: propylene glycol, polyethylene glycol 400 (PEG 400), and light mineral oil. Unique solubilities were found for each drug on each vehicle. Fluxes through hairless mouse skin were evaluated for each combination of drug and vehicle using Franz diffusion cells. From PEG 400 formulations, the skin fluxes of BUP, Ac-BUP, Bu-BUP, and Isb-BUP were 0.47 +/- 0.08, 1.64 +/- 0.31, 0.33 +/- 0.05, 0.75 +/- 0.20 micrograms/cm2/h, respectively. Thus, among the three potential prodrugs chosen, only Ac-BUP showed significantly higher skin flux than BUP. There were no inter-vehicle differences in the fluxes from saturated slurries between the vehicles. Moreover, all the esters were detected substantially in the form of regenerated parent drug (BUP) in the receptor compartment. Indeed, only Ac-BUP exited the skin in a measurably intact form, but the fraction escaping metabolism in transit was small (approximately 2%). However, based on drug dispositions in the skin, the regeneration of buprenorphine seems to depend on the alkyl chain length of the ester moiety. The molar percentages of regenerated parent drug in whole drug collected from the skin following the permeation experiments were: Ac-BUP, 9.2%; Bu-BUP, 40.7%; Isb-BUP, 9.6%, respectively. Thus, only Ac-BUP appears promising as a prodrug of buprenorphine, because it is not overly hydrophilic for skin permeation and is also highly metabolized to the parent compound while in the skin.

Analgesics, Opioid↗
PubMed1995

Percutaneous absorption and dermal delivery of cyclosporin A.

The present study deals with attempts to deliver cyclosporin A into the deeper skin and some of the fundamental reasons why this proves so difficult. Because of different physicochemical requirements for the solution and activity of cyclosporin A and the enhancer, n-decylmethyl sulfoxide, it was hard to demonstrate increases in permeation of cyclosporin A by the enhancer in either aqueous or ethanol/water formulation. Cyclosporin A was prohibitively insoluble in aqueous media and the activity of the enhancer is diminished to ineffectiveness when it is applied in alcoholic media. However, n-decylmethyl sulfoxide action on the stratum corneum could be obtained by pretreating the skin. The effect of pretreatment with this compound on the permeation of cyclosporin A through hairless mouse skin and human skin was studied with side-by-side diffusion cells. The skin was pretreated with 10 mM n-decylmethyl sulfoxide for various durations. Cyclosporin A in an ethanol/water formulation was then placed in the donor cell, with the amount of ethanol being controlled to maintain the highest possible thermodynamic activity. Accumulations of cyclosporin A in receiver cell media, aqueous or ethanol/water, were then assessed. Permeation from two different concentrations of cyclosporin A was compared. The permeability of hairless mouse skin to cyclosporin A was increased by the pretreatment, but results with human skin were more equivocal. It appears that it will take very long pretreatments to ready human skin for topical cyclosporin A therapy.

Administration, Cutaneous↗
PubMed1995

Formulation factors affecting release of drug from topical vehicles. II. Effect of solubility on in vitro delivery of a series of n-alkyl p-aminobenzoates.

The major influence on the rate of drug transfer out of its vehicle and into the skin is the thermodynamic activity of the drug within its formulation. This study addresses certain thermodynamic dependencies of topical delivery in a model system. Prototypical water-in-oil (W/O) and oil-in-water (O/W) emulsions and their component phases are used as the test vehicles, polydimethylsiloxane is the membrane, and three homologous n-alkyl p-aminobenzenzoate esters are the test permeants. In an emulsion, the interaction of the compound between the water and oil phase can determine the extent of lowering of the thermodynamic activity in the external phase in contact with the membrane. The emulsifiers (surfactants) impact strongly on partitioning and permeation as a result of the extra solubilizing capacity contributed by the surfactant micelles. The lower flux in the aqueous phase of the O/W emulsion is the result of micellar solubilization, and this solubilization increased with increasing ester chain length. Solubilization is also an influence in nonaqueous phases, but permeant hydrophobicity is without specific influence; therefore, transport become less dependent upon the structure of the compound.

4-Aminobenzoic Acid↗
PubMed1995

Penetration of minoxidil from ethanol/propylene glycol solutions: effect of application volume and occlusion.

We have previously established that the relative concentrations of propylene glycol and ethanol as a binary solvent system have a significant effect on the skin penetration of 2% solutions of minoxidil at 50 microL/cm2. The present work extends these studies and investigates the penetration of minoxidil from the different vehicle combinations as functions of application volume and occlusion. Decreasing the application volume has a variable effect which depends on vehicle composition. Penetration of minoxidil from 100% ethanol solutions decreased linearly with application volume. Generally, irrespective of the volume applied, the penetration of minoxidil increased with increasing ethanol fraction with a maximum penetration at 90% ethanol. Penetration from all the formulations was enhanced upon occluding the skin, with greatest increase evident in solutions with higher volatile fraction. Penetration of minoxidil in vivo showed trends similar to those seen in vitro.

Administration, Topical↗
PubMed1995

Transfollicular drug delivery.

The hair follicle, hair shaft, and sebaceous gland collectively form what is recognized as the pilosebaceous unit. This complex, three-dimensional structure within the skin possesses a unique biochemistry, metabolism and immunology. Recent studies have focused on the hair follicle as a potential pathway for both localized and systemic drug delivery. Greater understanding of the structure and function of the hair follicle may facilitate rational design of drug formulations to target follicular delivery. Targeted drug delivery may enhance current therapeutic approaches to treating diseases of follicular origin. Presented here is a review of follicular drug delivery and a discussion of the feasibility of the pilosebaceous unit as a target site.

Administration, Topical↗
PubMed1995

Uptake of chloroform by skin during short exposures to contaminated water.

Uptake of chloroform into hairless rat stratum corneum from dilute aqueous solutions was studied using tape-stripping to determine amounts deposited in the skin under various environmental exposure scenarios. The length of exposure of sedated animals to the chloroform-containing medium, the frequency and duration of tape-stripping, and the number of tape-strips per location were varied to map the stratum corneum substantivity of chloroform. Eight minutes immersion of the rat within a well-stirred solution at 36 degrees C was found to be adequate time for the gradient to be established fully across the stratum corneum. Penetration was progressively deeper as the exposure time increased. Substantial evaporative loss of chloroform from the aqueous medium of application seem to be responsible for lower cumulative amounts taken up when the same solution was held on the rat's skin within a stainless steel template of fixed area. Of the total uptake (29 mg) from a dilute stirred solution of chloroform (0.44 mg/ml) at 36 degrees C, about 95% was systematically absorbed after a 30 min exposure as determined by residuals (measurement of bath concentrations).

Animals↗
PubMed1994

Formulation factors affecting release of drug from topical formulations. 1. Effect of emulsion type upon in vitro delivery of ethyl p-aminobenzoate.

There are numerous kinetic and thermodynamic processes which occur during the transport of a topically applied drug from within its vehicle to the site of action in the skin. The present study compares the release and permeation of a model compound, ethyl p-aminobenzoate, from water, mineral oil, a mineral oil in water (O/W) emulsion, and a water in mineral oil (W/O) emulsion. These formulations are compared for differences in transport characteristics using in vitro diffusion studies and a synthetic polydimethylsiloxane membrane. Two factors appear prominent in influencing the release kinetics of the drug from its formulation. The first is the observation that the drug is released 2 times slower from mineral oil than from water at approximately equivalent thermodynamic activities, and the second is the appreciable lowering of the thermodynamic activity as a result of substantial micellar solubilization of the drug in the aqueous phase of the O/W emulsion. The thermodynamic activity effect predominants, resulting in a lower release rate from the O/W emulsion as compared to the W/O emulsion.

Administration, Topical↗
PubMed1994

Transdermal delivery of narcotic analgesics: comparative metabolism and permeability of human cadaver skin and hairless mouse skin.

The permeation of hairless mouse skin and human cadaver skin by narcotic analgesics was investigated to determine the interspecies variation. Permeability coefficients of morphine, fentanyl, and sufentanil across full-thickness hairless mouse skin were 1 order of magnitude higher than those found for human epidermis. The permeability coefficient of morphine for stripped hairless mouse skin was 500-fold higher than that for intact skin, showing the stratum corneum to be the principal barrier to its penetration. The permeability coefficient of fentanyl for stripped hairless mouse skin was also raised, but stripping caused an inappreciable increase in the permeation rate of sufentanil. The thick dermis of excised mouse skin obviously offered a significant resistance to the permeation of these lipophilic compounds. In comparison, the permeability coefficients of fentanyl and sufentanil through stripped cadaver epidermis (n > or = 25) were 67 and 37 higher than for intact human epidermis, respectively. The skin metabolism of the narcotics was investigated. No significant metabolic degradation of morphine, fentnayl, and sufentanil was observed in either fresh human cadaver skin or hairless mouse skin homogenates in the presence of NADPH cofactor, suggesting a low monooxygenase enzyme presence in skin. Moreover, no measurable glucuronidation of morphine took place in human skin or hairless mouse skin. Both processes proceeded rapidly in liver homogenates (mouse) under identical circumstances. It thus appears that these drugs pass through in intact form.

Administration, Cutaneous↗
PubMed1994

Drug and vehicle deposition from topical applications: localization of minoxidil within skin strata of the hairless mouse.

The cutaneous bioavailability of topical 2% minoxidil solution was verified in live hairless mice. Minoxidil and propylene glycol deposition on the skin surface, epidermis and dermis from the single-dose in vivo study were compared with the results from previous in vitro studies. A distinct difference is apparent in the epidermis where the in vitro values are 11-22 times higher than the in vivo values for minoxidil and 8-16 times higher for propylene glycol. The differences were not as great in the dermis. Percutaneous absorption of the drug appeared to be a very small fraction of the applied dose. Similarly shaped stratum corneum and plasma concentration profiles and the relatively constant dermal profiles of minoxidil and propylene glycol open the possibility of transappendageal routes being involved in percutaneous absorption. The greater amount of drug and vehicle found in the dermis from in vitro studies can be explained by the absence of dermal clearance. The overestimation in the amount of drug found in the epidermis in vitro may also be attributable to poor dermal clearance. On the whole, the study raises questions about the use of in vitro tissue dispositions for bioavailability assessment and bioequivalence demonstration.

Administration, Cutaneous↗
PubMed1994

Influence of application time and formulation reapplication on the delivery of minoxidil through hairless mouse skin as measured in Franz diffusion cells.

Relationships are drawn between the extent of topical delivery of test compounds in solution and the period of residence of their formulation on the skin. The studies were performed using in vitro diffusion cell techniques and a test formulation containing 2% 3H-minoxidil dissolved in 60% ethanol, 20% water and 20% 14C-propylene glycol. The permeation of propylene glycol was effectively halted upon cleansing the skin surface; the skin had very little reservoir capacity for this substance. However, the rate of delivery of minoxidil was only slowed but not stopped upon cleansing. The suggestion here is that a reservoir of minoxidil is formed in the skin which is capable of sustaining an appreciable input of drug even after the skin's surface is scrupulously cleaned. Assay of epidermal concentrations of these species not only confirms the existence of the minoxidil reservoir but also shows that the degree of its tissue concentration is proportional to the time of residence of the formulation on the skin surface. Reapplication of blank vehicle to the cleansed surface had little to no effect on the permeation of the minoxidil and was similarly without effect on that of propylene glycol. While it comes as no surprise that formulation residence time is an important variable in topical delivery, this study demonstrates the complexities of quantitative dependencies of delivery on residence time.

Administration, Cutaneous↗
PubMed1992

Drug and vehicle deposition from topical applications: use of in vitro mass balance technique with minoxidil solutions.

The disposition of minoxidil and propylene glycol from topical solutions was measured by using an in vitro mass balance technique. The experimental approach included assessment of the following compartments of the skin and the diffusion cell as a function of time: (1) donor compartment; (2) hairless mouse skin surface, epidermis, and dermis; and (3) receiver compartment. Excellent mass balance was achieved for minoxidil at three doses. However, the recovery of propylene glycol depended on both application volume and time. The experiment involving the evaporation of propylene glycol and water from the propylene glycol:ethanol:water (20:60:20, v/v) mixture, which was placed in the well of a tissue culture plate at room temperature and 37 degrees C, substantiated the loss of vehicles to the air. When a thin application of 20 microL/cm2 was used, 60% of the propylene glycol was unaccounted for after 16 h. The evaporation of propylene glycol concentrated the solution to supersaturation, precipitated out the drug, and then stabilized the thermodynamic activity of the drug in the vehicle. The amount of formulation applied influences the rate of concentration and, thus, the time at which minoxidil precipitates. The precipitation limits the amount of minoxidil that can be absorbed and leads to poor percutaneous absorption of drug from the formulation.

Administration, Topical↗