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.     

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.     

Enhancement in skin permeation of 5-aminolevulinic acid using l-menthol and its derivatives

Enhancing effect of l-menthol and its derivatives, l-menthyl formate, l-menthyl acetate, and l-menthyl propionate, on skin permeation of 5-aminolevulinic acid (ALA) through Yucatan micropig full-thickness skin was investigated using a Franz-type diffusion cell. ALA solutions were prepared using ethanol-water mixed solvents with l-menthol or the derivative. Skin permeation coefficients (Kp) of ALA with more than 3.0 wt% of l-menthol was significantly larger than that without l-menthol. In addition, Kp of ALA with the derivative increased as follows: l-menthol approximately l-menthyl propionate < l-menthyl formate < l-menthyl acetate. These results suggest that l-menthol and the derivative are effective to enhance ALA skin permeation.     

Enhancement effect of p-menthane-3,8-diol on in vitro permeation of antipyrine and indomethacin through Yucatan micropig skin

The enhancing effect of p-menthane-3,8-diol (MDO) on skin permeation of antipyrine (ANP) and indomethacin (IM) through Yucatan micropig skin in vitro was compared with l-menthol. p-menthane-3,8-diol is a metabolite of l-menthol and has little odor. It is easy to combine the vehicle because of lower lipophilicity than l-menthol. All formulations contained 40% (v/v) ethanol. The permeation of ANP increased with MDO about three times that without enhancer by increasing ANP concentration in the skin. However, the MDO effect was about a quarter that of l-menthol. The permeation of IM with MDO was about 15 times that with no enhancer and it was almost the same as that with l-menthol. The lag time of permeation was not significantly changed by MDO, which was not so in the case of l-menthol. Skin concentration of IM increased about 11 times and six times with MDO and l-menthol, respectively. MDO and l-menthol partitioned to the skin relatively high concentrations, 5.9 and 2.5 mg/cm³, respectively. The solubility of IM in the skin was improved by MDO, and consequently, the permeation of IM was enhanced.     

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.     

Basil oil is a promising skin penetration enhancer for transdermal delivery of labetolol hydrochloride

The present work investigates effectiveness of basil oil, a volatile oil containing alcoholic terpenes, as a potential penetration enhancer for improved skin permeation of labetolol hydrochloride (LHCl) with reference to camphor, geraniol, thymol, and clove oil. Saturation solubilities of LHCl were determined in water, vehicle (ethanol:water, 60:40 v/v) and vehicle containing 5% w/v terpenes. Comparable (P > 0.05) saturation solubilities were found suggesting an insignificant increase in LHCl flux across rat skin on account of thermodynamic activity. Permeation of LHCl in vehicle per se and in presence of 5% w/v enhancer was investigated by performing in vitro rat abdominal skin permeation studies using a side-by-side glass diffusion cell. Various parameters viz. steady state flux, permeability coefficient, lag time, partition coefficient, diffusion coefficient, and enhancement ratios (ER) were calculated from the permeation data. Basil oil produced the maximum enhancement (ER = 46.52) over neat vehicle, among all enhancers. Activation energies for LHCl permeation in water, vehicle per se and in presence of 5% w/v basil oil were found to be 23.16, 18.71, and 10.98 kcal/mole, respectively. Lowering of activation energy in presence of basil oil suggests creation of new polar pathways in the skin for enhanced permeation of LHCl. Basil oil is proposed as a promising penetration enhancer for improved transdermal drug delivery of labetolol.     

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.     

Basil Oil is a Promising Skin Penetration Enhancer for Transdermal Delivery of Labetolol Hydrochloride

Thepresent work investigates effectiveness of basil oil, a volatile oil containing alcoholic terpenes, as a potential penetration enhancer for improved skin permeation of labetolol hydrochloride (LHCl) with reference to camphor, geraniol, thymol, and clove oil. Saturation solubilities of LHCl were determined in water, vehicle (ethanol:water, 60:40 v/v) and vehicle containing 5% w/v terpenes. Comparable (P > 0.05) saturation solubilities were found suggesting an insignificant increase in LHCl flux across rat skin on account of thermodynamic activity. Permeation of LHCl in vehicle per se and in presence of 5% w/v enhancer was investigated by performing in vitro rat abdominal skin permeation studies using a side-by-side glass diffusion cell. Various parameters viz. steady state flux, permeability coefficient, lag time, partition coefficient, diffusion coefficient, and enhancement ratios (ER) were calculated from the permeation data. Basil oil produced the maximum enhancement (ER?=?46.52) over neat vehicle, among all enhancers. Activation energies for LHCl permeation in water, vehicle per se and in presence of 5% w/v basil oil were found to be 23.16, 18.71, and 10.98 kcal/mole, respectively. Lowering of activation energy in presence of basil oil suggests creation of new polar pathways in the skin for enhanced permeation of LHCl. Basil oil is proposed as a promising penetration enhancer for improved transdermal drug delivery of labetolol.     

Controlled Transdermal Occlusive Delivery Device of Primaquine

Abstract

Primaquine an antimalarial drug was studied for its permeation behavior across the human cadaver skin. Ethylene vinyl acetate copolymer (E.V.A. cop) was used for the preparation of drug reservoir. To optimize the drug delivery from the drug reservoir E.V.A. cop of different vinyl acetate mole content (40%, 25%, 18%) was used. To achieve an enhanced skin permeation an occlusive face adhesive type delivery system was fabricated. The prepared systems were characterized for in-vitro studies. The system that delivered the drug in accordance with the theortically calculated required delivery rate was selected for in-vivo performance evaluation. The prepared system functions over an predicted definite time period in an uniform and defined fashion. The drug transdermal application has therapeutic potential.     

Decomposition of Terpenes by Ozone during Sampling on Tenax

The ozonolytic decomposition of terpenes and terpenoids during sampling on Tenax is investigated in an artificial air system at ambient concentration levels. The detrimental effect of 8-150 ppbv ozone depends on the chemical structure of the compounds: saturated terpenoids such as 1,8-cineole, camphor, and bornyl acetate are unaffected by ozone. The terpenes and terpenoids which containing one C-C double bond are slightly decomposed in the order camphene < β-pinene ≈ myrtenal < α-pinene < sabinene ≈ citronellal. The compounds containing two or more double bonds are significantly decomposed in the order d-limonene ≈ citral < linalool < β-ocimene < terpinolene < α-terpinene ≈ β-caryophyllene. For α-pinene, sabinene and d-limonene, their ozonolysis products are found on the tubes: pinonaldehyde, 5-(1-methylethyl)bicyclo[3.1.0]hexan-2-one, and 3-(1-methylethenyl)-6-oxoheptanal. The analytical recoveries are significantly enhanced for many compounds when the sampling duration is reduced from 10 min to 30 s, explained by the time available for ozonolysis. A miniature ozone scrubber with multiple layers of MnO(2)-coated copper nets was developed and thoroughly tested. The optimal number of plies is found to be 8, which ensures quantitative recoveries for all test compounds except α-terpinene, β-caryophyllene, citral, and citronellal. The results that are reported here call into question previous data on terpenes and terpenoids and/or their oxidation products where measurements have been carried out without the prior removal of ozone.     

Evaluation of in vitro percutaneous absorption of olanzapine and fluoxetine HCl: enhancement properties of olanzapine

The diffusion characteristics of fluoxetine HCl (FLX HCl) and olanzapine (OLZ) alone and in combination with each other were studied to determine their in vitro permeation behavior across a series of gelling agents through a cellulose membrane and human cadaver skin. Klucel 0.5% was selected as the optimal formulation to study their diffusion through human cadaver skin. The release profiles of drugs acting alone and in combinations were identical in the case of the cellulose membrane. However, with human cadaver skin, the permeation of FLX HCl in combination with OLZ drastically increased (732 μg) compared with the release of FLX HCl alone (43.7 μg), while the release of OLZ remained the same whether alone or in combination with FLX HCl (183.7 μg). The results indicate that OLZ enhances the diffusion of FLX HCl through the cadaver skin. Follow-up studies with OLZ were conducted to further investigate this phenomenon and have shown that OLZ enhancement properties are skin reversible as well as concentration dependent. Also, a variety of experiments with different hydrophilic and lipophilic molecules were conducted, and it was found that OLZ enhances the permeation of hydrophilic compounds, while it has no influence on lipophilic compounds. Finally, a number of compounds structurally related to OLZ were investigated as enhancers, and it was determined that piperazine ring attached to the tricyclic system of OLZ is essential for enhancement of FLX HCl (1,837 μg).     

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.     

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.     

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.     

Formulation and in vitro evaluation of transdermal patches of melatonin

The present study was undertaken to prepare and evaluate monolithic drug-inadhesive type transdermal patches of melatonin containing penetration enhancers such as fatty alcohols, fatty acids, and terpenes. The patches were prepared using Eudragit E 100 as the adhesive polymer. The release profile of melatonin from control as well as enhancer-containing patches showed an initial burst of melatonin release for up to 4 hours and then a plateau after 8 hours. The release profiles of melatonin from patches containing various enhancers were similar to the control patch. However, the addition of enhancers in the patch increased the permeation of melatonin through hairless rat skin. The flux values of patches containing octanol, nonanoic acid, and myristic acid were higher than the control patch (no enhancer), but the differences were not statistically significant (P>0.05). Decanol, myristyl alcohol, and undecanoic acid at 5% concentrations showed significantly higher flux values through hairless rat skin (enhancement ratios 1.7, 1.5, and 1.6 for decanol, myristyl alcohol, and undecanoic acid, respectively) (P<0.05). Menthol and limonene at 5% w/w showed maximum permeation of melatonin among all enhancers studied (enhancement ratios=2.1 and 2.0 for menthol and limonene, respectively) (P<0.001). In general, there was about 4-6 hours of lag time observed before a steady state flux of melatonin was achieved. Though the flux of melatonin observed in the present study is 5-10 times higher than the required delivery rate in humans, it must be noted that the present study was performed using hairless rat skin, which is generally more permeable compared to human skin. Further studies using human skin would prove the usefulness of these patches.     

Transdermal Nicotine Delivery Systems: Multi-institutional Cooperative Bioequivalence Studies

Abstract

Nicotine transdermal delivery systems (nicotine-TDSs) have been evaluated clinically and found to provide effective assistance to smokers in smoking cessation with minimal occurrence of withdrawal symptoms. However, substantial skin reactions have been reported with the four nicotine-TDSs marketed recently. To reduce the skin reactions, a new type of nicotine-TDS has been recently developed. In vitro skin permeation studies demonstrated that this nicotine-TDS yields a constant skin permeation profile with a rate of permeation across the human cadaver skin comparable to the steady-state permeation rates attained by Habitrol? and Nicoderm® systems. Clinical studies completed in two ethnic groups have demonstrated that this newly-developed nicotine-TDS is clinically effective and has yielded minimal skin irritation. As part of technical transfer program, a clinical study was initiated in 18 non-obese non-smoking Taiwanese, using Latin-square design, to compare the systemic bioavailability and pharmacokinetic profile of nicotine delivered transdermally from the nicotine-TDSs fabricated at technology licensee (Sintong nicotine-TDS) in comparison with that from the technology developer (TBS nicotine-TDS), using one marketed nicotine-TDS (Habitrol? system) as the reference product. In vitro release and skin permeation studies of nicotine from the nicotine-TDSs manufactured at both licensor and licensee were found similar in kinetic profiles and comparable in rates. Since the patch size of these nicotine-TDSs studied was smaller than the marketed product used (10 cm² for both Sintong and TBS nicotine-TDSs, versus 20 cm² for Habitrol? system), the daily doses of nicotine delivered to the volunteers are equivalent between Sintong and TBS nicotine-TDSs [9.58 (± 2.23) vs. 8.76 (± 1.88) mg/day/patch] but are lower than that from Habitrol? system [15.13 (± 4.05) mg/day/patch]. Thus, for the statistical analysis of the pharmacokinetic parameters obtained need to be corrected for the difference in patch size and daily nicotine dose delivered. The results of statistical analysis suggested that Sintong and TBS nicotine-TDSs are bioequivalent to Habitrol? system.     

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.     

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.     

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.     

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

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.