In-vitro transdermal permeation of oxycodone: (I) effect of PH,delipidization and skin stripping

Abstract

The effect of pH, skin stripping and delipidization on the in-vitro transdermal permeation of a weak base analgesic, oxycodone (pKa=8.53), was studied using hydrodynamically calibrated Valia-Chien diffusion cells. Saturated oxycodone. HCl solutions in citrate-phosphate buffers ranging from pH 4 to 10 were used as the donor solution. Skin samples from the abdominal and dorsal sites of hairless rats, abdominal site of hairless mouse, rabbit pinna ear, as well as human cadaver skin were used in permeation studies. The pHs at which maximum flux attained varied from 6.5 to 7.5 depending upon animal model. The permeabilities of protonated form through intact skin of all the animal models used, was about 7-15 fold lower than that of nonionic form. The unexpected high permeation rate at pHs ranges 4 to 6.5 across human cadaver could be attributed to the possible damage upon storage. The skin stripping and delipidizaton process appeared to increase the permeation rates of oxycodone and the degree enhancement is dependent upon the pH in the donor compartment.     

Kinetic Evaluation of Transdermal Nicotine Delivery Systems

The skin permeation and release kinetics of nicotine from four nicotine-releasing transdermal delivery systems (TDS) marketed recently was investigated under identical conditions to evaluate the effect of system design and the interchangeability of these products. In the study, hairless rat skin was first used as an animal model to evaluate the permeation mechanisms of various TDS's, which were then verified by studying the permeation through human cadaver skin. Three of the four TDS's were found to deliver nicotine at zero^th-order permeation kinetics at steady state with permeation rate ranging from 0.072 - 0.197 mg/cm²/hr, while the fourth one produced a triphasic zero^th-order permeation rate profile. Three TDS's released nicotine at non-linear manner, which could be described by a linear Q vs. t^1/2 relationship, while one TDS yielded a constant release at steady state. The different skin permeation profiles of nicotine delivered by these TDS's could be explained by the difference in their system designs and structural compositions.     

Comparison of Skin Permeation of Dideoxynucleoside-Type Anti-HIV Drugs: Alone Versus Combination

The effects of vehicles and skin permeation enhancer on the skin permeation of dideoxynucleoside-type anti-HN drugs, Zalcitabine (DDC), Didanosine (DDI), and Zidovudine (AZT), alone and in combination, were compared using hairless rat and human cadaver skins. Each drug alone or a combination of three drugs was added to various compositions of ethanol/water or ethanol/tricaprylin cosolvent system to saturation, and in vitro skin permeation studies were conducted using Valia-Chien skin permeation cells. In both ethanol/water and ethanol/tricaprylin systems, the hairless rat skin permeation rates achieved by each drug alone and three drugs in combination were not significantly different. Addition of oleic acid [1.0% (v/v) for each drug alone and 5.0% (v/v) for drug combination] in ethanol/tricaprylin (50:50) could not significantly enhance the skin permeation of these drugs. In hairless rat skin permeation of each drug alone, the permeation rates of all three drugs were dramatically enhanced with the addition of oleic acid in ethanol/water (60:40) cosolvent system and reached plateau level with oleic acid as low as 0.3% (v/v). However, in the case of drug combination, the enhancement of skin permeation rates of these drugs with the addition of oleic acid in ethanol/water (80:20) cosolvent system was not as high as that observed for each drug alone, and plateau level was not observed even at 5.0% (v/v) of oleic acid. Human cadaver skin permeation rates of each drug alone saturated in ethanol/ water (60:40) cosolvent system containing 1.0% (v/v) of oleic acid were 3-4 times lower than those of hairless rat skin. However, in skin permeation of three drugs in combination, saturated in ethanol/water (80:20) cosolvent system containing 5.0% (v/v) of oleic acid, human cadaver skin permeation rates of DDC and DDI were slightly lower than those of hairless rat skin, and there was no significant difference between the two skins for AZT. These results show that mutual skin permeation-enhancing effects of oleic acid and an ethanol/water cosolvent system Made the transdermal delivery of anti-HIV drugs, alone and in combination, feasible.     

In vitro evaluation of the release of albuterol sulfate from polymer gels: effect of fatty acids on drug transport across biological membranes

In this investigation, the diffusion of the beta 2 agonist albuterol sulfate (ABS) across several membranes (cellulose, hairless mouse skin, human cadaver skin) from polymer gels was studied, and the effects of several fatty acids on drug permeation through skin were evaluated. The results were then used to predict whether transdermal delivery would be appropriate for ABS. All in vitro release studies were carried out at 37 degrees C using modified Franz diffusion cells. In preliminary studies, ABS release through cellulose membranes was studied from two polymeric gels, Klucel (hydroxypropylcellulose) and Methocel (hydroxypropylmethylcellulose). Three polymer concentrations were used for each gel (0.5%, 1.0%, and 1.5%). From these experiments, Klucel 0.5% was selected as the optimal formulation to study ABS diffusion across hairless mouse skin. Experiments were conducted to evaluate the effects of capric acid, lauric acid, and myristic acid as penetration enhancers. The results suggested that lauric acid preferentially enhanced ABS diffusion compared to the other fatty acids studied, and follow-up studies were done to evaluate the release through human cadaver skin from a donor containing 2% ABS and lauric acid in 0.5% Klucel. These experiments showed that a 2:1 (lauric acid:ABS) molar ratio gave the best ABS release rates. The release rate across human cadaver skin declined slowly over 24 hr, and an average flux over 24 hr of approximately 0.09 mg/hr cm2 was measured. Using this value as a steady-state flux, extrapolations predicted that transdermal delivery can be used to maintain therapeutic ABS plasma levels (6-14 ng/mL) for extended periods. The results of this research suggest that ABS is a good candidate for transdermal drug delivery.     

Comparison of Skin Permeation of Dideoxynucleoside-Type Anti-HIV Drugs: Alone Versus Combination

Abstract

The effects of vehicles and skin permeation enhancer on the skin permeation of dideoxynucleoside-type anti-HN drugs, Zalcitabine (DDC), Didanosine (DDI), and Zidovudine (AZT), alone and in combination, were compared using hairless rat and human cadaver skins. Each drug alone or a combination of three drugs was added to various compositions of ethanol/water or ethanol/tricaprylin cosolvent system to saturation, and in vitro skin permeation studies were conducted using Valia-Chien skin permeation cells. In both ethanol/water and ethanol/tricaprylin systems, the hairless rat skin permeation rates achieved by each drug alone and three drugs in combination were not significantly different. Addition of oleic acid [1.0% (v/v) for each drug alone and 5.0% (v/v) for drug combination] in ethanol/tricaprylin (50:50) could not significantly enhance the skin permeation of these drugs. In hairless rat skin permeation of each drug alone, the permeation rates of all three drugs were dramatically enhanced with the addition of oleic acid in ethanol/water (60:40) cosolvent system and reached plateau level with oleic acid as low as 0.3% (v/v). However, in the case of drug combination, the enhancement of skin permeation rates of these drugs with the addition of oleic acid in ethanol/water (80:20) cosolvent system was not as high as that observed for each drug alone, and plateau level was not observed even at 5.0% (v/v) of oleic acid. Human cadaver skin permeation rates of each drug alone saturated in ethanol/ water (60:40) cosolvent system containing 1.0% (v/v) of oleic acid were 3-4 times lower than those of hairless rat skin. However, in skin permeation of three drugs in combination, saturated in ethanol/water (80:20) cosolvent system containing 5.0% (v/v) of oleic acid, human cadaver skin permeation rates of DDC and DDI were slightly lower than those of hairless rat skin, and there was no significant difference between the two skins for AZT. These results show that mutual skin permeation-enhancing effects of oleic acid and an ethanol/water cosolvent system Made the transdermal delivery of anti-HIV drugs, alone and in combination, feasible.     

Kinetic Evaluation of Transdermal Nicotine Delivery Systems

Abstract

The skin permeation and release kinetics of nicotine from four nicotine-releasing transdermal delivery systems (TDS) marketed recently was investigated under identical conditions to evaluate the effect of system design and the interchangeability of these products. In the study, hairless rat skin was first used as an animal model to evaluate the permeation mechanisms of various TDS's, which were then verified by studying the permeation through human cadaver skin. Three of the four TDS's were found to deliver nicotine at zero^th-order permeation kinetics at steady state with permeation rate ranging from 0.072 - 0.197 mg/cm²/hr, while the fourth one produced a triphasic zero^th-order permeation rate profile. Three TDS's released nicotine at non-linear manner, which could be described by a linear Q vs. t^1/2 relationship, while one TDS yielded a constant release at steady state. The different skin permeation profiles of nicotine delivered by these TDS's could be explained by the difference in their system designs and structural compositions.     

In Vitro Evaluation of the Release of Albuterol Sulfate from Polymer Gels: Effect of Fatty Acids on Drug Transport Across Biological Membranes

ABSTRACT

In this investigation, the diffusion of the beta₂ agonist albuterol sulfate (ABS) across several membranes (cellulose, hairless mouse skin, human cadaver skin) from polymer gels was studied, and the effects of several fatty acids on drug permeation through skin were evaluated. The results were then used to predict whether transdermal delivery would be appropriate for ABS. All in vitro release studies were carried out at 37°C using modified Franz diffusion cells. In preliminary studies, ABS release through cellulose membranes was studied from two polymeric gels, Klucel® (hydroxypropylcellulose) and Methocel® (hydroxypropylmethylcellulose). Three polymer concentrations were used for each gel (0.5%, 1.0%, and 1.5%). From these experiments, Klucel 0.5% was selected as the optimal formulation to study ABS diffusion across hairless mouse skin. Experiments were conducted to evaluate the effects of capric acid, lauric acid, and myristic acid as penetration enhancers. The results suggested that lauric acid preferentially enhanced ABS diffusion compared to the other fatty acids studied, and follow-up studies were done to evaluate the release through human cadaver skin from a donor containing 2% ABS and lauric acid in 0.5% Klucel®. These experiments showed that a 2:1 (lauric acid:ABS) molar ratio gave the best ABS release rates. The release rate across human cadaver skin declined slowly over 24 hr, and an average flux over 24 hr of ?0.09 mg/hr cm² was measured. Using this value as a steady-state flux, extrapolations predicted that transdermal delivery can be used to maintain therapeutic ABS plasma levels (6–14 ng/mL) for extended periods. The results of this research suggest that ABS is a good candidate for transdermal drug delivery.     

Mechanism of Transdermal Controlled Nitroglycerin Administration (III) Control of Skin Permeation Rate and Optimization

A mathematical model was developed to correlate the drug permeation rate through the skin with the drug release rate from a matrix-type drug delivery system. Experiments were carried out using hairless mouse abdominal skin mounted on a recently-developed and hydrodynamically well-calibrated Keshary-Chien skin permeation system. A matrix-type drug delivery system was designed to contain different loading doses of nitroglycerin and to study the effect of drug loading variation on the rate of drug release, the rate of skin permeation and the equilibrium concentration of nitroglycerin in the skin.

Results indicated that the stratum corneum plays a significant rate-limiting role in the skin permeation of nitroglycerin across the intact skin, yielding a constant skin permeation profile. The permeation rate across the intact skin was observed to increase with the increase in the drug release flux initially and then levelled off in a hyperbolic fashion. Various constants were obtained from the reciprocal plot of skin permeation rate vs. drug release flux. These constants could be used for the prediction of the skin permeation rate. A very good correlation between the predicted and the observed values of skin permeation rates was observed.

After the stratum corneum was removed by stripping technique, the mechanism and the rate of skin permeation became dominated by the mechanism and the release rate of the delivery system.

A linear correlation was observed between the drug permeation rate through the skin and the equilibrium concentration of drug in the skin. This correlation was observed in both intact and viable skins.     

Mechanism of Transdermal Controlled Nitroglycerin Administration (III) Control of Skin Permeation Rate and Optimization

Abstract

A mathematical model was developed to correlate the drug permeation rate through the skin with the drug release rate from a matrix-type drug delivery system. Experiments were carried out using hairless mouse abdominal skin mounted on a recently-developed and hydrodynamically well-calibrated Keshary-Chien skin permeation system. A matrix-type drug delivery system was designed to contain different loading doses of nitroglycerin and to study the effect of drug loading variation on the rate of drug release, the rate of skin permeation and the equilibrium concentration of nitroglycerin in the skin.

Results indicated that the stratum corneum plays a significant rate-limiting role in the skin permeation of nitroglycerin across the intact skin, yielding a constant skin permeation profile. The permeation rate across the intact skin was observed to increase with the increase in the drug release flux initially and then levelled off in a hyperbolic fashion. Various constants were obtained from the reciprocal plot of skin permeation rate vs. drug release flux. These constants could be used for the prediction of the skin permeation rate. A very good correlation between the predicted and the observed values of skin permeation rates was observed.

After the stratum corneum was removed by stripping technique, the mechanism and the rate of skin permeation became dominated by the mechanism and the release rate of the delivery system.

A linear correlation was observed between the drug permeation rate through the skin and the equilibrium concentration of drug in the skin. This correlation was observed in both intact and viable skins.     

Improvement in Transdermal Bioavailability of Nitroglycerin by Formulation Design

Controlled skin permeation kinetics of nitroglycerin delivered by the three once-a-day transdermal therapeutic systems was recently evaluated and compared using the freshly excised hairless mouse abdominal skin mounted in a finite-dosing Frantz diffusion cell assembly. The kinetics of skin permeation from the conventional ointment formulation was also studied using the same in vitro skin permeation system.

Six experimental formulations of nitroglycerin were developed, aiming to enhance the permeation rate of nitroglycerin through intact skin. The kinetics of skin permeation of nitroglycerin from these experimental formulations was also investigated, using the same in vitro skin permeation system, and compared to the conventional ointment formulation as well as the newly marketed once-a-day transdermal therapeutic systems. Results indicated that the rates of skin permeation can be greatly improved by proper formulation design.     

Improvement in Transdermal Bioavailability of Nitroglycerin by Formulation Design

Abstract

Controlled skin permeation kinetics of nitroglycerin delivered by the three once-a-day transdermal therapeutic systems was recently evaluated and compared using the freshly excised hairless mouse abdominal skin mounted in a finite-dosing Frantz diffusion cell assembly. The kinetics of skin permeation from the conventional ointment formulation was also studied using the same in vitro skin permeation system.

Six experimental formulations of nitroglycerin were developed, aiming to enhance the permeation rate of nitroglycerin through intact skin. The kinetics of skin permeation of nitroglycerin from these experimental formulations was also investigated, using the same in vitro skin permeation system, and compared to the conventional ointment formulation as well as the newly marketed once-a-day transdermal therapeutic systems. Results indicated that the rates of skin permeation can be greatly improved by proper formulation design.     

Influence of Electrical Factors on In Vitro Iontophoretic Delivery of Timolol Maleate

The in vitro iontophoretic delivery of timolol maleate (TM) was carried out using a modified two-chambered, horizontal diffusion cell. The effect of various electrical factors on iontophoretic permeation of drug was analyzed. The iontophoretic permeation of TM through human cadaver skin was more greatly enhanced than the passive permeation. The increase in current intensity linearly increased the permeation of drug. The sine wave form showed the highest permeation than other wave forms used. Pulsed mode iontophoresis seems to be more efficient than constant current drug permeation through skin.     

Effect of Penetration Enhancers on Transdermal Delivery of Timolol Maleate

In vitro skin permeation of Timolol maleate through human cadaver skin was studied using Franz diffusion cell. The results indicate that the drug penetrates poorly through human cadaver skin. However, skin penetration enhancers such as dimethyl sulfoxide (DMSO), oleic acid (OA) and lauryl chloride (LC) enhanced the permeability of Timolol maleate (TM) through human cadaver skin. The permeation enhancement of drug was maximum by lauryl chloride amongst the three enhancers. Moreover, lauryl chloride increases the permeation of drug through skin with increase in the time of application and concentration on skin. The change in lag time was also observed.     

Effect of Ph on Enhancement of in Vitro Percutaneous Transport of Isoproterenol Hcl by Azone

This in vitro study examined the effect of Azone on skin permeability of isoproterenol HC1 at pH of 2.0, 8.0, 6.5 and 9.0. Azone was found to enhance the percutaneous transport of the drug from an aqueous vehicle under the pH conditions studied. The flux across human cadaver skin increased with increasing vehicle pH for Azone-treated and untreated skin with an observed maximum at pH 9.0.     

Transdermal delivery of valsartan: I. Effect of various terpenes

The objective of the present study was to investigate the effect of various terpenes, including a diterpene, forskolin (FSK; a putative penetration enhancer), on skin permeation of valsartan. Permeation studies were carried out with Automated Transdermal Diffusion Cells Sampling System (SFDC 6, LOGAN Instruments Corp., NJ, USA) through rat skin and human cadaver skin (HCS) using ethanol: IPB (pH 7.4) (40:60) as vehicle. The efficacy of the study terpenes for permeation of valsartan across rat skin and human cadaver skin was found in the order of cineole > d-limonene > l-menthol > linalool > FSK and cineole > d-limonene > linalool > l-menthol > FSK, respectively. No apparent skin irritation (erythema, edema) was observed on treatment of skin with terpenes including FSK. FT-IR, DSC, and histopathological studies revealed that FSK enhanced the skin permeation of the active drug by disruption and extraction of lipid bilayers of SC in consonance with other terpenes.     

Effect of Several Electrolyzed Waters on the Skin Permeation of Lidocaine,Benzoic Acid,and Isosorbide Mononitrate

The effects of several electrolyzed waters were evaluated on the permeation of model base, acid and non-ionized compounds, lidocaine (LC), benzoic acid (BA), and isosorbide mononitrate (ISMN), respectively, through excised hairless rat skin. Strong alkaline-electrolyzed reducing water (ERW) enhanced and suppressed the skin permeation of LC and BA, respectively, and it also increased the skin permeation of ISMN, a non-ionized compound. On the contrary, strong acidic electrolyzed oxidizing water (EOW) enhanced BA permeation, whereas suppressing LC permeation. Only a marginal effect was observed on the skin permeation of ISMN by EOW. These marked enhancing effects of ERW on the skin permeation of LC and ISMN were explained by pH partition hypothesis as well as a decrease in skin impedance. The present results strongly support that electrolyzed waters, ERW and EOW, can be used as a new vehicle in topical pharmaceuticals or cosmetics to modify the skin permeation of drugs without severe skin damage.     

Book Review

The objective of the present study was to investigate the effect of various terpenes, including a diterpene, forskolin (FSK; a putative penetration enhancer), on skin permeation of valsartan. Permeation studies were carried out with Automated Transdermal Diffusion Cells Sampling System (SFDC 6, LOGAN Instruments Corp., NJ, USA) through rat skin and human cadaver skin (HCS) using ethanol: IPB (pH 7.4) (40:60) as vehicle. The efficacy of the study terpenes for permeation of valsartan across rat skin and human cadaver skin was found in the order of cineole > d-limonene > l-menthol > linalool > FSK and cineole > d-limonene > linalool > l-menthol > FSK, respectively. No apparent skin irritation (erythema, edema) was observed on treatment of skin with terpenes including FSK. FT-IR, DSC, and histopathological studies revealed that FSK enhanced the skin permeation of the active drug by disruption and extraction of lipid bilayers of SC in consonance with other terpenes.     

Effect of Ph on Enhancement of in Vitro Percutaneous Transport of Isoproterenol Hcl by Azone

Abstract

This in vitro study examined the effect of Azone on skin permeability of isoproterenol HC1 at pH of 2.0, 8.0, 6.5 and 9.0. Azone was found to enhance the percutaneous transport of the drug from an aqueous vehicle under the pH conditions studied. The flux across human cadaver skin increased with increasing vehicle pH for Azone-treated and untreated skin with an observed maximum at pH 9.0.     

Effect of vehicle systems, pH and enhancers on the permeation of highly lipophilic aripiprazole from Carbopol 971P gel systems across human cadaver skin

The objective of this study was to investigate the effect of vehicle systems, pH and enhancers on the permeation of a highly lipophilic basic drug aripiprazole (ARPZ) through human cadaver skin. Solubility of ARPZ in single, binary, tertiary, and quaternary vehicle systems of N-methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), water, ethanol and isopropyl myristate (IPM) was studied. Gel formulations of 5% ARPZ were developed with 0.5% Carbopol 971P in quaternary vehicle systems consisting of NMP, DMSO, water and ethanol or IPM at optimum ratio of 40/40/5/15. The effect of pH of the gel formulations and fatty acids with different chain lengths on the permeation was studied. The flux of ARPZ from gel formulation with IPM and ethanol was comparable. A four fold increase in APRZ flux was observed when the pH of the gel systems was lowered from pH 8.2 to pH 6 or pH 7. For fatty acids, the order of flux is lauric acid > myristic acid > caprylic acid > oleic acid. In all the cases, in vitro permeation rate of ARPZ through human cadaver skin followed zero order kinetics. This study demonstrated that ARPZ in tertiary vehicle system of NMP/DMSO/water/IPM at ratio of 40/40/5/15 and gel system of Carbopol 971P with pH 7 is a promising candidate for transdermal delivery.     

The effects of pH and chemical enhancers on the percutaneous absorption of indomethacin

The absorption of indomethacin through excised hairless mouse skin from aqueous solution was determined at different pH values. We found that the rate of its absorption increased with decreasing pH. Its distribution coefficient in octanol-phosphate buffer was also pH dependent. Furthermore, the change of permeability coefficient with pH correlated well with the distribution coefficient by a two-degree polynominal equation. The individual incorporation of five chemical enhancers into a polymeric patch at optimal pH resulted in an increase or decrease in the in vitro absorption rate and in the amount absorbed during the first 24 hours depending on the enhancer and its concentration used. Both sodium cholate at 4 and 6 %, and sodium lauryl sulfate at 4 % increased the absorption rate about four to seven times compared to the control. The in vivo absorption using rabbits from patch containing 6% sodium cholate also showed an increase in rate and the AUC compared to that from the control; however, the extent of the increase was much less compared to that obtained from the in vitro study. The stability of this drug in aqueous solution was also studied as a function of pH. It was confirmed that indomethacin was more stable at lower pH values. The pH-rate constant profile also indicated a specific base catalysis for its degradation at pH above 6.5. Due to its small solubilities at lower pHs, an optimal pH near 5 was suggested for the preparation of a transdermal delivery system for indomethacin.