In vitro percutaneous absorption of genistein from topical gels through human skin

The objective of this study was to formulate genistein as a topical gel with various penetration enhancers for increased permeation and retention in human skin. The high performance liquid chromatography assay method was validated for precision and reproducibility. The intra-day and inter-day precision as represented by the coefficient of variation (CV) of the peak areas were <0.44% and <0.67%, respectively. Further, the reproducibility was demonstrated by the CV of the assay at different genistein concentrations, which were <1.64%. Genistein was subjected to various stress conditions to obtain basic information on the appropriate pH and aqueous vehicle for formulating topical gels. Genistein was highly stable under neutral and oxidative conditions, but degraded to highly polar and nonpolar compounds under basic and acidic conditions, respectively. Menthol produced a 9- and 22-fold increase in the flux and skin retention of genistein, respectively, after 24?h of gel application as compared with the control (no enhancer). Cineole showed an approximately 7-fold increase in flux, but skin retention did not increase significantly. Transcutol increased the flux and skin retention of genistein by 5- and 7-fold, respectively. When Transcutol was formulated with Lauroglycol, there was a 13- and 9-fold increase in the flux and skin retention, respectively. Incorporation of penetration enhancers into the topical gel increased the skin permeation of genistein, so that the target delivery rate for its therapeutic effects can be achievable based on the in vitro human skin data generated in this study.     

In vivo skin permeation of sodium naproxen formulated in pluronic F-127 gels: effect of Azone and Transcutol

The objective of this study was to determine the penetration of sodium naproxen, formulated in Pluronic F-127 (PF-127) gels containing Azone and Transcutol as penetration enhancers, through human skin in vivo. It was found that the combination of Azone and Transcutol in PF-127 gels enhanced sodium naproxen penetration, with enhancement ratios of up to two fold compared with the formulation containing only Transcutol. These results were confirmed by TEWL and ATR-FTIR spectroscopy, suggesting a synergic action for Azone and Transcutol. Because of the thermo-reversible behavior of Pluronic gels, the influence of the components added to the gel formulations on viscosity, as a function of temperature, was also studied.     

Development of the bioadhesive tetracaine gels for enhanced local anesthetic effects

To develop the new local anesthetic formulations with a suitable bioadhesive property, hydroxypropyl methylcellulose (HPMC)-based gel was formulated. As the drug concentration in the gels, and the temperature of surrounding solutions increased, the drug release increased. The activation energy of tetracaine permeation was 4.47 kcal/mol. The effects of permeation enhancers on the permeation rate of drug through skin were studied using various enhancers, such as the glycols, the nonionic surfactants, and the bile salts. Among the enhancers used, polyoxyethylene 2-oleyl ether showed the highest enhancing effects on drug permeation through skin. The analgesic activity was examined using a tail-flick analgesimeter. In the AUEC (area under the efficacy curve) of the rat-tail flick test, tetracaine gel containing polyoxyethylene 2-oleyl ether showed about 3.2-fold increase in analgesic activity compared with the control. The results of this study support that the tetracaine gels with efficient anesthetic effects could be developed using HPMC and poloxamer with combination of enhancer and vasoconstrictor.     

Development and in-vivo evaluation of ondansetron gels for transdermal delivery

Nausea and vomiting are some of the major side effects caused by certain drug therapies, e.g. chemotherapy, radiotherapy and general anesthesia. Because of the nature of the symptoms, oral delivery is inappropriate, while intravenous administration may be unpractical. The aim of the present study was to develop a transdermal gel (2% Klucel®) for ondansetron, a first line 5-HT3-receptor-antagonist antiemetic. The effects of the penetration enhancer camphor and isopropyl-myristate (IPM) were first investigated in-vitro using modified Franz diffusion-cells and then tested in-vivo in a rabbit model by measuring skin and plasma concentrations. Since a disadvantage of transdermal delivery is a prolonged lag-time, the effect of skin treatment with a micro-needle roller was tested. The in-vitro permeation studies through excised porcine ear skin showed that the presence of 2.5% camphor or IPM increased steady state flux by 1.2- and 2.5-fold, respectively, compared to the control gel. Ondansetron was not detectable in either skin or plasma following in-vivo application of the base-gel, whereas the camphor gel and IPM gel delivered 20 and 81?µg/cm² of ondansetron, respectively. Microporation led to an increase in plasma C_max and AUC by 10.47?±?1.68-fold and 9.31?±?4.91-fold, respectively, for the camphor gel, and by 2.31?±?0.53-fold and 1.59?±?0.38-fold, respectively for the IPM gel. In conclusion, the 2.5% IPM gel demonstrated optimal in-vivo transdermal flux. Skin pretreatment with a micro-needle roller slightly improved the delivery of the IPM gel, whereas dramatically increased the transdermal delivery of the camphor gel.     

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.     

Magnetophoresis in combination with chemical enhancers for transdermal drug delivery

Purpose: The objective of the present work was to investigate the effect of combination of a novel physical permeation enhancement technique, magnetophoresis with chemical permeation enhancers on the transdermal delivery of drugs.

Methods: The in vitro drug transport studies were carried out across the freshly excised abdominal skin of Sprague-Dawley rats using transdermal patch systems (magnetophoretic and non-magnetophoretic) of lidocaine hydrochloride (LH). LH gel prepared using hydroxypropyl methylcellulose (HPMC) was spread over the magnets as a thin layer. To investigate the effect of chemical permeation enhancers, menthol, dimethyl sulfoxide, sodium lauryl sulfate and urea (5% w/v) were incorporated in the gels prior to loading on the patch system.

Results: The flux of lidocaine from magnetophoretic patch was ~3-fold higher (3.07?±?0.43 µg/cm²/h) than that of the control (non-magnetophoretic patch) (0.94?±?0.13 µg/cm²/h). Incorporation of chemical permeation enhancers in the gel enhanced the magnetophoretic delivery flux by ~4 to 7-fold.

Conclusions: The enhancement factor due to combination of chemical permeation enhancer was additive and not synergistic. Mechanistic studies indicated that magnetophoresis mediated drug delivery enhancement was via appendageal pathway.     

Effects of Adhesives and Permeation Enhancers on the Skin Permeation of Captopril

To formulate a transdermal drug delivery system of captopril, monolithic adhesive matrix type patches containing 20% captopril, different pressure-sensitive adhesives, and various permeation enhancers were prepared using a labcoater. The effects of the adhesives and permeation enhancers on skin permeation of captopril from the prepared patches were evaluated using Franz diffusion cells fitted with excised rat skins. The permeation rate of the drug through the excised skin was dependent on the type of polyacrylate copolymers studied. Fatty alcohols resulted in a pronounced enhancing effect on the skin permeation of captopril, while dimethyl sulfoxide,N-methyl-2-pyrrolidone, oleic acid, Transcutol, and polysorbate 20 showed no significant enhancing effect. The permeation-enhancing effect of the fatty alcohols reached the maximum at the level of 10%. Based on these results, a captopril patch may be developed with further optimization.     

Permeation and skin retention of quercetin from microemulsions containing Transcutol® P

A microemulsion for the cutaneous release of quercetin was prepared. An aqueous phase, containing 40% Transcutol(?) P as solubilizing agent and permeation enhancer, was emulsified with Labrafil(?) as oil phase and Labrasol(?)/Capryol(?) 90 as Solvent/Co-solvent. Quercetin was dissolved in the microemulsion at the concentration of 1%. Ternary phase diagrams were generated to determine the optimal concentration of each excipient composing the microemulsion. The physicochemical properties of the microemulsion, such as pH, viscosity, refractive index, and particle size distribution were determined. The microemulsion was stable for 12 months at the storing conditions of 25.0 ± 1.0°C. The in vitro quercetin permeability into and through the abdominal hairless pig skin was determined by vertical Franz's cells. Quercetin showed hardly any permeability through the skin when dissolved in water- and Transcutol(?) P-free media, whereas a remarkable increase in cutaneous permeability was observed when quercetin was formulated in the microemulsion or when simply dissolved in Transcutol(?) P. These two last formulations are those showing the lower skin retention.     

Development of Patches for the Controlled Release of Dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) and its sulfate conjugate (DHEAS) are the major secretory steroidal products of the adrenal gland. Some epidemiologic studies have found an association between low DHEA serum levels in patients and many important diseases. To prevent all such pathological conditions and, in any case, in aging, a DHEA supplementation has been proposed. DHEA shows a low oral bioavailability; taking the bioavailability obtained by the subcutaneous route as 100%, it was estimated that the potencies of DHEA by the percutaneous and oral routes were approximately 33% and 3%, respectively. Thus, transdermal patches could be considered a promising formulation as a continuous and controlled delivery of DHEA in replacement therapy is desired. With the aim of evaluating the effect of the matrix composition in terms of polymers and enhancers on the DHEA skin permeation flux, 10 types of monolayer self - adhesive patches containing 0.25 mg/cm² of active ingredient were designed. The matrices were based on three different acrylic copolymers: an acrylate-vinylacetate copolymer, a polyaminomethylmethacrylate (PAMA), and a polymethylmethacrylate. Transcutol (TR), mint essential oil, Lauroglycol, Brij 58, and propylene glycol (PG) were evaluated as DHEA skin permeation enhancers. All prepared patches were characterized by drug content, light microscopy, and in vitro skin permeation, performed using a modified Franz - type diffusion cell and human stratum corneum and epidermis as a membrane. The in vitro skin permeation studies are particularly significant in the development studies of DHEA patches as the in vivo determination of DHEA is affected by the fact that the endogen substance in the plasma is not constant over time. Among the tested patches, highest DHEA fluxes were obtained using the formulation based on PAMA. Moreover, the introduction in the matrix of binary mixtures of TR and PG, used also for their plasticizer properties, permitted enhancing DHEA skin permeation. On the basis of these studies, the transdermal administration of DHEA using patches seems feasible.     

Preparation and evaluation of pranoprofen gel for percutaneous administration

The percutaneous delivery of nonsteroidal anti-inflammatory drug (NSAID) has the advantages of avoiding the hepatic first pass effect and delivering the drug to the inflammation site at a sustained, concentrated level over an extended period of time. Hydroxypropyl methylcellulose (HPMC) and poloxamer 407 were used in an attempt to develop new topical formulations of pranoprofen. The effects of the drug concentration (0.04, 0.08, 0.12, 0.16, and 0.20%) on the rate of drug release from HPMC-poloxamer 407 gels were examined using a synthetic cellulose membrane at 37±0.5°C. The rate of drug permeation increased significantly with increasing drug concentration in the gels until the concentration reached 0.16%, and increased slightly thereafter. The effects of temperature on the rate of drug release from the 0.16% pranoprofen gels were evaluated at 32, 37, and 42°C. The rate of drug release from the 0.16% pranoprofen gels increased with increasing temperature with activation energy (E_a) of 8.88 kcal/mol. Various penetration enhancers, such as nonionic surfactants and fatty acids, were incorporated in the gel formulation in an attempt to increase the level of drug permeation. Among the enhancers used, octanoic acid had the strongest enhancing effects with an enhancement factor of 3.09. The anti-inflammatory effect of the pranoprofen gel was evaluated using a rat paw-edema model. The 0.16% pranoprofen gel containing octanoic acid as an enhancer reduced the edema size by approximately 73% compared with that of the control group. These results highlight the feasibility of a topical gel formulation of pranoprofen containing an enhancer.     

Non-ionic surfactant based vesicular drug delivery system for topical delivery of caffeine for treatment of cellulite: design,formulation, characterization,histological anti-cellulite activity,and pharmacokinetic evaluation

Cellulite is a common topographical alteration where skin acquires an orange peel or mattress appearance with alterations in adipose tissue and microcirculation. This work aims to develop and evaluate a topical niosomal gel formulae with good permeation to reach the subcutaneous fat layer. Several caffeine niosomal dispersions were prepared and incorporated into gel formulae using Carbopol 940 polymer, chemical penetration enhancers, and iontophoresis, then the prepared gels were applied onto the skin of rats and anticellulite activity of caffeine from the prepared gels compared to that of the commercial product Cellu Destock^® was evaluated by histological study of the skin and measurement of plasma level of caffeine passing through the skin using liquid chromatography (LC/MS–MS). Results of histology revealed reduction of size and thickness of fatty layer of rat skin in the following order: FVII?>?FXIV?>?Cellu Destock^®?>?FVII?+?Iontophoresis?>?FXIV?+?Iontophoresis. Pharmacokinetic results of caffeine in plasma revealed that C_max, T_max, and AUC_0–12h decreased in the following order: FXIV?>?FVII?>?Cellu Destock^®. These results conclude that incorporation of caffeine niosomal dispersion into gel matrix with penetration enhancers and iontophoresis resulted in improvement in penetration of caffeine through the skin into the underlying fatty layer in treatment of cellulite.     

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.     

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.     

Development of Patches for the Controlled Release of Dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) and its sulfate conjugate (DHEAS) are the major secretory steroidal products of the adrenal gland. Some epidemiologic studies have found an association between low DHEA serum levels in patients and many important diseases. To prevent all such pathological conditions and, in any case, in aging, a DHEA supplementation has been proposed. DHEA shows a low oral bioavailability; taking the bioavailability obtained by the subcutaneous route as 100%, it was estimated that the potencies of DHEA by the percutaneous and oral routes were approximately 33% and 3%, respectively. Thus, transdermal patches could be considered a promising formulation as a continuous and controlled delivery of DHEA in replacement therapy is desired. With the aim of evaluating the effect of the matrix composition in terms of polymers and enhancers on the DHEA skin permeation flux, 10 types of monolayer self - adhesive patches containing 0.25 mg/cm² of active ingredient were designed. The matrices were based on three different acrylic copolymers: an acrylate-vinylacetate copolymer, a polyaminomethylmethacrylate (PAMA), and a polymethylmethacrylate. Transcutol (TR), mint essential oil, Lauroglycol, Brij 58, and propylene glycol (PG) were evaluated as DHEA skin permeation enhancers. All prepared patches were characterized by drug content, light microscopy, and in vitro skin permeation, performed using a modified Franz - type diffusion cell and human stratum corneum and epidermis as a membrane. The in vitro skin permeation studies are particularly significant in the development studies of DHEA patches as the in vivo determination of DHEA is affected by the fact that the endogen substance in the plasma is not constant over time. Among the tested patches, highest DHEA fluxes were obtained using the formulation based on PAMA. Moreover, the introduction in the matrix of binary mixtures of TR and PG, used also for their plasticizer properties, permitted enhancing DHEA skin permeation. On the basis of these studies, the transdermal administration of DHEA using patches seems feasible.     

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.     

Enhancing Effects of Fatty Acids on Piroxicam Permeation Through Rat Skins

To increase the skin permeation of piroxicam from the Poloxamer 407 gel, fatty acid was added as a penetration enhancer to the Poloxamer 407 gel containing 1% piroxicam. The enhancing effects of the enhancer on the skin permeation of piroxicam were evaluated using Franz diffusion cells fitted with intact excised rat skins. To elucidate the modes of the action of enhancers, thermal analysis and histological examinations were conducted. Among fatty acids tested, linoleic acid showed the highest enhancing effects, with an enhancement factor (EF) of 1.76. From the thermal analysis results, fatty acids have fluidizing effects on the stratum corneum. The skin pretreated with the Poloxamer 407 gels containing piroxicam including linoleic acid showed a loosely layered stratum corneum and wide intercellular space.     

Enhancing effects of fatty acids on piroxicam permeation through rat skins

To increase the skin permeation of piroxicam from the Poloxamer 407 gel, fatty acid was added as a penetration enhancer to the Poloxamer 407 gel containing 1% piroxicam. The enhancing effects of the enhancer on the skin permeation of piroxicam were evaluated using Franz diffusion cells fitted with intact excised rat skins. To elucidate the modes of the action of enhancers, thermal analysis and histological examinations were conducted. Among fatty acids tested, linoleic acid showed the highest enhancing effects, with an enhancement factor (EF) of 1.76. From the thermal analysis results, fatty acids have fluidizing effects on the stratum corneum. The skin pretreated with the Poloxamer 407 gels containing piroxicam including linoleic acid showed a loosely layered stratum corneum and wide intercellular space.     

Systemic enhancement of papaverine transdermal gel for erectile dysfunction

To enhance the systemic transdermal delivery of papaverine for the treatment of erectile dysfunction, several factors that influence transdermal delivery of papaverine HCl were studied. The effects of membrane types for in vitro permeation study, human skin layers, solvent/cosolvent systems and the penetration enhancers on the transdermal permeation of papaverine HCl were investigated. A combination of caproic acid, ethanol and water in the volume ratio of 50%:30%:20% was chosen as penetration enhancer and incorporated in two gel bases: 18% Pluronic F-127 and 2% Carbopol 940. In vivo skin permeation studies were performed with two loading doses (0.6% and 2%) in rabbits. The flux and permeability coefficient of papaverine HCl through different human skin layers suggested that the major barrier layer for papaverine HCl was residing primarily in the stratum corneum. However, the viable epidermis and dermis layer also contributed certain degrees of diffusion resistance. Differential Scanning Calorimetry study showed that penetration enhancer exhibited a counter effect with papaverine HCl on the temperature and enthalpy in both gels. In vitro drug release study demonstrated significant increases in the steady-state flux, permeability coefficient and enhancement ratio in these gels. Faster drug transports and higher bioavailability were also observed in rabbits. Skin irritation test performed in rabbits demonstrated a mild skin reaction with mean PII scores of 2 and below; however the recovery was fast. In conclusion, caproic acid, ethanol and water in the volume ratio of 50%:30%:20% is an effective penetration enhancer to deliver papaverine HCl transdermally for systemic absorption.     

Transdermal delivery of ondansetron hydrochloride: effects of vehicles and penetration enhancers

The effects of vehicles and penetration enhancers on the in vitro permeation of ondansetron hydrochloride (OS) across dorsal hairless mouse skins were investigated. Various types of vehicles, including ester, alcohol, and ether and their mixtures were used, and then a series of fatty acids and fatty alcohols were employed as enhancers. Among pure vehicles used, water and ethanol showed high permeation fluxes, which were 48.2 ± 23.7 and 41.9 ± 17.9 µg/cm² per h, respectively. Even though propylene glycol monocaprylate (PGMC) alone did not show a high permeation rate, the skin permeability of OS was increased by the addition of diethylene glycol monoethyl ether (DGME); the highest flux was achieved at 40% of DGME. Also, the combination of PGMC and ethanol (80:20) or PGMC and propylene glycol (PG) (60:40) increased the permeation flux by six- and two-fold, respectively, compared to PGMC alone. The synergistic enhancement was also obtained by using PG-oleyl alcohol (OAl) cosolvent. The greatest flux was attained by the addition of unsaturated fatty acids at 3% concentration to PG. The enhancement factors with the addition of oleic acid or linoleic acid to PG were about 1250 and 450, respectively. But saturated fatty acids failed to show a significant enhancing effect. When the PGMC-DGME (60:40) cosolvent system was used as a vehicle, all fatty acids, including unsaturated fatty acids, failed to show significant enhancing effects. The results indicate that the combinations of oleic acid, linoleic acid, or oleyl alcohol with PG, or PGMC-DGME (60:40) cosolvent could be used for the design of the OS transdermal system.     

Systemic enhancement of papaverine transdermal gel for erectile dysfunction

To enhance the systemic transdermal delivery of papaverine for the treatment of erectile dysfunction, several factors that influence transdermal delivery of papaverine HCl were studied. The effects of membrane types for in vitro permeation study, human skin layers, solvent/cosolvent systems and the penetration enhancers on the transdermal permeation of papaverine HCl were investigated. A combination of caproic acid, ethanol and water in the volume ratio of 50%:30%:20% was chosen as penetration enhancer and incorporated in two gel bases: 18% Pluronic F-127 and 2% Carbopol 940. In vivo skin permeation studies were performed with two loading doses (0.6% and 2%) in rabbits. The flux and permeability coefficient of papaverine HCl through different human skin layers suggested that the major barrier layer for papaverine HCl was residing primarily in the stratum corneum. However, the viable epidermis and dermis layer also contributed certain degrees of diffusion resistance. Differential Scanning Calorimetry study showed that penetration enhancer exhibited a counter effect with papaverine HCl on the temperature and enthalpy in both gels. In vitro drug release study demonstrated significant increases in the steady-state flux, permeability coefficient and enhancement ratio in these gels. Faster drug transports and higher bioavailability were also observed in rabbits. Skin irritation test performed in rabbits demonstrated a mild skin reaction with mean PII scores of 2 and below; however the recovery was fast. In conclusion, caproic acid, ethanol and water in the volume ratio of 50%:30%:20% is an effective penetration enhancer to deliver papaverine HCl transdermally for systemic absorption.