Biomedical subjects

Audra L Stinchcomb

Publications and source records attributed to Audra L Stinchcomb.

27 records · Page 2Linked to original sources

PubMed2004

In vitro/in vivo correlation studies for transdermal delta 8-THC development.

The present study was carried out in order to develop a transdermal therapeutic system (TTS) for Delta(8)-THC. The in vitro permeability studies of Delta(8)-THC in human skin and hairless guinea pig skin with and without a rate-controlling membrane were conducted in flow-through diffusion cells. Delta(8)-THC pharmacokinetic parameters were determined after topical application of transdermal patches and intravenous administration in guinea pigs. The in vitro results indicated that there was no significant difference in the mean flux or in the permeability coefficient of Delta(8)-THC in human skin versus hairless guinea pig skin. The flux of Delta(8)-THC through the human skin/membrane composite was not significantly lower than that through the hairless guinea pig skin/membrane composite; and the skin controlled the Delta(8)-THC delivery rate. Intravenous doses of Delta(8)-THC followed a two-compartment model with a significant distribution phase. On application of the TTS patch, the plasma concentration of Delta(8)-THC reached a mean steady-state level of 4.4 ng/mL within 1.4 h and was maintained for at least 48 h. Significant amounts of metabolites were observed in the plasma after topical application. The in vitro-study predicted plasma concentration following application of the transdermal patch was in agreement with the observed guinea pig plasma concentrations of Delta(8)-THC.

Administration, Cutaneous↗

PubMed2004

Transdermal delivery of the synthetic cannabinoid WIN 55,212-2: in vitro/in vivo correlation.

PURPOSE: The aim of the current investigation was to evaluate the percutaneous absorption of the synthetic cannabinoid WIN 55,212-2 in vitro and in vivo. METHODS: The in vitro permeation studies of WIN 55,212-2 in human skin, hairless guinea pig skin, a polymer membrane with adhesive, and a skin/polymer membrane composite were conducted in flowthrough diffusion cells. The pharmacokinetic parameters for WIN 55,212-2 were determined after intravenous administration and topical application of Hill Top Chambers and transdermal therapeutic systems (TTS) in guinea pigs. RESULTS: The in vitro permeation studies indicated that the flux of WIN 55,212-2 through hairless guinea pig skin was 1.2 times more than that through human skin. The flux of WIN 55,212-2 through human and guinea pig skin was not significantly higher than that through the corresponding skin/polymer membrane composites. The mean guinea pig steady-state plasma concentrations after topical 6.3 cm2 chamber and 14.5 cm2 TTS patch applications were 5.0 ng/ml and 8.6 ng/ml, respectively. CONCLUSIONS: The topical drug treatments provided significant steady-state plasma drug levels for 48 h. The observed in vivo results from the Hill Top Chambers and TTS patches in the guinea pigs were in good agreement with the predicted plasma concentrations from the in vitro data.

Adhesives↗

PubMed2004

Physicochemical evaluation, in vitro human skin diffusion, and concurrent biotransformation of 3-O-alkyl carbonate prodrugs of naltrexone.

PURPOSE: The purpose of this study was to evaluate the physicochemical properties and in vitro human skin diffusion of the 3-O-alkyl carbonate prodrugs of naltrexone (NTX). METHODS: Melting points and heats of fusion (deltaHf) were determined using differential scanning calorimetry. In vitro human skin permeation rates of NTX and its prodrugs were measured using a flowthrough diffusion cell system. Drug disposition in the skin was quantified at the end of the diffusion experiment. The solubilities of the drugs were determined in mineral oil and isotonic buffer. Partitioning of the prodrugs from vehicle to skin was determined using isolated sheets of human stratum corneum (SC). RESULTS: All the prodrugs hydrolyzed to NTX on passing through the skin, and the methyl NTX-3-O-carbonate (ME-NTX) provided the highest NTX flux, apparent permeability coefficient (Kp), and calculated relative thermodynamic activity from the melting point and deltaHf. The ME-NTX SC/vehicle partition coefficient was the highest of the prodrug series, although similar to the NTX SC/vehicle partition coefficient value. The shortest chain prodrugs underwent the highest extent of bioconversion to NTX upon passing through the skin. CONCLUSIONS: Within this 3-O-alkyl carbonate prodrug series, the shortest chain prodrug was the most skin-permeable compound with the highest partition coefficient and a significant extent of bioconversion.

Biotransformation↗

PubMed2004

Intranasal delivery of recombinant human parathyroid hormone [hPTH (1-34)], teriparatide in rats.

The aim of this study was to explore the nasal route as an alternative to daily subcutaneous injections of hPTH (1-34). Anesthetized rats were surgically prepared and nasally dosed with aqueous solutions of hPTH (1-34). Plasma samples were assayed by radioimmunoassay and data generated fit to two-(intravenous) and one-(intranasal) compartment pharmacokinetic models using WinNonlin. The toxicity of hPTH (1-34) solution administered to the rats was assessed by screening its effect on transepithelial electrical resistance, potential difference, paracellular marker permeation, tissue viability, and protein leakage using the EpiAirway tissue model. The intranasal absorption of hPTH (1-34) was rapid; the absorption rate constants (alpha) were 33.2+/-24 h(-1) [without bovine serum albumin (BSA)] and 9.8+/-5.1 h(-1) (with 1% BSA). The maximum plasma concentrations (Cmax): 151+/-24 pg/mL (without BSA) and 176+/-37 (with 1% BSA) were attained within approximately 15 min. The intranasal bioavailabilities (Fabs) were 12.1+/-3.4% (without BSA) and 17.6+/-1.5% (with 1% BSA). The hPTH (1-34) formulation administered to the rats had no detrimental effect on the EpiAirway tissue epithelial electrical parameters and functional integrity. Based on the results of this study, the nasal route appears to be a prospective alternative to subcutaneous injections of hPTH (1-34).

Administration, Intranasal↗

PubMed2004

Human skin permeation of Delta8-tetrahydrocannabinol, cannabidiol and cannabinol.

The purpose of this study was to quantify the in-vitro human skin transdermal flux of Delta8-tetrahydrocannabinol (Delta8-THC), cannabidiol (CBD) and cannabinol (CBN). These cannabinoids are of interest because they are likely candidates for transdermal combination therapy. Differential thermal analysis and in-vitro diffusion studies with human tissue were completed for the compounds. Heats of fusion, melting points and relative thermodynamic activities were determined for the crystalline compounds, CBD and CBN. Flux, permeability, tissue concentration and lag times were measured in the diffusion experiments. CBN had a lower heat of fusion and corresponding higher calculated relative thermodynamic activity than CBD. Ethanol concentrations of 30 to 33% significantly increased the transdermal flux of Delta8-THC and CBD. Tissue concentrations of Delta8-THC were significantly higher than for CBN. Lag times for CBD were significantly smaller than for CBN. The permeabilities of CBD and CBN were 10-fold higher than for Delta8-THC. Combinations of these cannabinoids with ethanol will be further studied in transdermal patch formulations in vitro and in vivo, as significant flux levels of all the drugs were obtained. CBD, the most polar of the three drugs, and other more polar cannabinoids will also be the focus of future drug design studies for improved transdermal delivery rates.

Abdomen↗

PubMed2003

Xenobiotic bioconversion in human epidermis models.

There is a great need for alternative experimental methods for measuring percutaneous xenobiotic biotransformation. Animal testing and excised human skin studies have been the historical standards for confirmation of therapeutic and toxic effects that occur in the skin as a result of drug and other chemical metabolism. Human skin epidermal bioequivalents have become progressively more used for these types of pharmacological/toxicological studies in recent years. These epidermal models have been used in the form of cell culture, tissue sheets, and highly differentiated epidermal and epidermal/dermal systems. This review highlights the existing published data on the utility of these skin bioequivalent models for various types of metabolism and toxicology studies that should be of interest to the dermatopharmaceutical scientist.

Administration, Cutaneous↗

PubMed2002

In vitro experiment optimization for measuring tetrahydrocannabinol skin permeation.

The purpose of this study was to optimize in vitro experimental conditions for the measurement of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) permeation across human skin using a flow-through diffusion cell system. The drug permeation rates through intact and stripped (stratum corneum (SC) removed) skin were also compared in order to determine if the SC provided significant resistance to the diffusion of hydrophobic Delta(9)-THC. The receiver fluids evaluated were HEPES-buffered Hank's balanced salt solution (HHBSS) with either 4 or 6% bovine serum albumin (BSA), Polyoxyethylene 20 Oleyl Ether (Brij 98) solution (0.5 and 6.0%), and hydroxypropyl-beta-cyclodextrin (HPBCD). The Delta(9)-THC permeability was significantly higher into Brij 98 solutions than into 4% BSA. BSA 6% receiver solutions showed significantly higher Delta(9)-THC permeation over BSA 4%. There were no significant differences in Delta(9)-THC permeability or lag time values between 0.5 and 6% Brij 98 receiver solutions. HPBCD failed to work as a suitable receiver solution. The Delta(9)-THC flux in the stripped skin experiments exceeded the flux in the intact skin experiments. It appears that the SC provides some resistance to the diffusion of Delta(9)-THC across human skin. These experimental results have confirmed the utility of several receiver solutions for the in vitro human skin diffusion study of Delta(9)-THC.

Chromatography, High Pressure Liquid↗

PubMed2002

Straight-chain naltrexone ester prodrugs: diffusion and concurrent esterase biotransformation in human skin.

Naltrexone (NTX) is an opioid antagonist used for treatment of narcotic dependence and alcoholism. Transdermal naltrexone delivery is desirable to help improve patient compliance. The purpose of this study was to increase the delivery rate of NTX across human skin by using lipophilic alkyl ester prodrugs. Straight-chain naltrexone-3-alkyl ester prodrugs of 2-7 carbons in chain length were synthesized and evaluated. In vitro human skin permeation rates were measured using a flow-through diffusion cell system. The melting points, solubilities, and skin disposition of the drugs were determined. The prodrugs were almost completely hydrolyzed on passing through the skin and appeared as NTX in the receiver compartment. The mean NTX flux from the prodrug-saturated solutions exceeded the flux of NTX base by approximately 2-7-fold. The amount of drug detected in the skin was significantly greater after treatment with the prodrug solutions compared with treatment with NTX base. The extent of parent drug (NTX) regeneration in the intact skin ranged from 28 to 91%. Higher NTX regeneration percentages in skin appeared to correlate with increased drug delivery rates. Definitively, the highly oil-soluble prodrugs provide a higher NTX flux across human skin in vitro and undergo significant metabolic conversion in the skin.

Biotransformation↗

PubMed2002

Determining dermal absorption parameters in vivo from tape strip data.

PURPOSE: Tape stripping the outermost skin layer, the stratum corneum (sc), is a popular method for assessing the rate and extent of dermal absorption in vivo. Results from tape strip (TS) experiments can be affected significantly by chemical diffusion into the sc during the time required to apply and remove all of the TSs, tTS. Here, we examine the effects of this problem on the interpretation of TS experimental results. METHODS: Dermal absorption of 4-cyanophenol (4CP) in humans was studied using TS experiments to assess conditions in which diffusion alters TS results. Mathematical models were developed to assess the effects of diffusion on parameter estimation. RESULTS: For an experiment with tTS > tlag (i.e., the lag time for a chemical to cross the sc), the permeability coefficient for 4CP, P(sc,v), calculated including tTS, was consistent with values from the literature (i.e., 0.0019 cm/h). When diffusion during stripping was not included in the model, P(sc,v) was 70% smaller. CONCLUSIONS: Calculations show that chemical concentrations in TSs can be affected by diffusion during tape stripping, but if tTS < 0.2 tlag and the exposure time is > 0.3 tlag, TS concentrations are not significantly affected by tTS.

Humans↗