Development, Characterization and Skin Interaction of Capsaicin-Loaded Microemulsion-Based Nonionic Surfactant.

The aim of this study was to develop novel microemulsions (MEs) for the transdermal delivery of capsaicin. Microemulsion-based nonionic surfactants consisting of isopropyl myristate as the oil phase, various nonionic surfactants as the surfactant (S), various glycols or alcohol as the co-surfactant (CoS), and reverse osmosis water as the aqueous phase were formulated. Based on the optimal ME obtained from Design Expert, MEs containing a fixed concentration of oil, water or surfactant were prepared while varying the amounts of the other two fractions. The results indicated that the skin permeation flux of low dose capsaicin (0.15% (w/w)) was significantly higher for the selected ME than the commercial product and capsaicin in ethanol (control) by approximately two- and four-fold, respectively. We successfully demonstrated the feasibility of the transdermal delivery of capsaicin-loaded ME using a low concentration of nonionic surfactant and ethanol. Moreover, the optimization using computer program helped to simplify the development of a pharmaceutical product.

Transdermal permeation of Kaempferia parviflora methoxyflavones from isopropyl myristate-based vehicles.

Kaempferia parviflora (K. parviflora) rhizomes have long been used in traditional folk medicines and as general health-promoting agents. Several biological activities of K. parviflora, especially its anti-inflammatory effect, are due to its major constituents, methoxyflavones. However, the oral bioavailability of these methoxyflavones has been shown to be low. The aim of this study was to investigate the permeation behaviors of K. parviflora methoxyflavones from isopropyl myristate (IPM)-based vehicles. We studied the effects of ethanol and propylene glycol (PG) as the hydrophilic, solvent-type vehicles as well as fatty acids as the permeation enhancers. A permeation experiment was performed in vitro, using side-by-side diffusion cells through the full thickness of pig ear skin. The solubility and permeation of methoxyflavones were able to be modified by choice and ratio of vehicles. The ethanol/IPM vehicle was shown to be more effective in enhancing the solubility and permeation of methoxyflavones when compared to the PG/IPM vehicle. Regarding an optimal balance between solubility or affinity to vehicle and skin to vehicle partition coefficient, the ethanol/IPM vehicle in the ratio of 1:9 maximized the flux. Among the investigated fatty acids, oleic acid showed the greatest enhancing effect on the permeation of methoxyflavones, indicating that saturated fatty acids are less effective than unsaturated fatty acids. Long chain fatty acids increased diffusion coefficient parameter and shortened the lag time. The number of carbon atoms and double bonds of fatty acids did not show direct relation to the profile of permeation of methoxyflavones.

Anti-tumor effects of cationic hybrid liposomes against colon carcinoma along with apoptosis in vitro.

New-type three-component cationic hybrid liposomes (HLs) composed of dimyristoylphosphatidylcholine (DMPC), polyoxyethylene(21)dodecyl ether (C(12)(EO)(21)) and O,O'-ditetradecanoyl-N-(α-trimethylammonioacetyl) diethanolamine chloride (2C(14)ECl) were produced. Cationic HLs were smaller and more stable than pure DMPC liposomes. It is noteworthy that cationic HLs could remarkably inhibit the growth of human colon cancer (HCT116) cells along with apoptosis in vitro for the first time in this study.

The influence of the structure and the composition of water/AOT-Tween 85/IPM microemulsion system on transdermal delivery of 5-fluorouracil.

The purpose of this study was to investigate the influence of the structure and the composition of water/Aerosol-OT (AOT)-Tween 85/isopropylmyristate (IPM) microemulsion system (WATI) on transdermal delivery of 5-fluorouracil (5-FU). The structure of WATI was characterized by measuring surface tension, density, viscosity, electric conductivity, and differential scanning calorimetry. The effect of the drug loading, water content, component compositions and the amount of mixed surfactant on permeation of 5-FU through mice skin was evaluated by using Franz-type diffusion cells. The results in vitro implied that WATI was W/O microemulsion when the water content was below 20 wt% at fixed 20 wt% of mixed surfactant at 25°C, then might be transformed to a bicontinuous structure, finally, formed O/W microemulsion with water content over 30 wt%. Increase of the drug loading can directly facilitate the penetration of the drug across the skin. Drug diffusion after 12 h from the bicontinuous microemulsion (795.1 ± 22.3 µg·cm(-2)) would be fastest compared to that from the W/O microemulsion (650.2 ± 11.7 µg·cm(-2)) and the O/W microemulsion (676.6 ± 14.8 µg·cm(-2)). The combination of AOT and IPM could bring about synergistic effect on the skin enhancement, however, Tween 85 in WATI decreased the cumulative permeation amount of 5-FU. The content of mixed surfactant had no effect on the permeation of 5-FU at fixed surfactant/cosurfactant ratio (K(m) = 2). Thus, the increased transdermal delivery the hydrophilic drug of 5-FU was found to be concerned with both of the structure and the composition of WATI.

Synergistic effect of isopropyl myristate and glyceryl monocaprylate on the skin permeation of pentazocine.

The aim of this investigation was to assess the applicability of lipid bilayer alteration using a combination of isopropyl myristate (IPM) and glyceryl monocaprylate (GEFA-C(8)) to the enhancement of pentazocine (PTZ) permeation through hairless mouse skin. The skin permeability of PTZ was enhanced by increasing the concentration of GEFA-C(8) up to 10% w/w in combination with IPM. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) and small angle X-ray diffraction (SAXD) were carried out to analyze the effects of these enhancers on the biophysical properties of the stratum corneum (SC) of the skin, and on the permeation of PTZ. ATR-FTIR studies revealed that IPM/GEFA-C(8) induced higher CH(2) stretching frequencies of SC lipids than IPM alone. SAXD showed the disappearance of long lamellar diffraction of SC lipids with IPM/GEFA-C(8), resulting in a complete loss of order of the SC lipid bilayers. When 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (DiI), a hydrophobic fluorescence probe, was applied in IPM alone, the amount of DiI which penetrated into the intercellular space of the SC was very low, but this was markedly increased when DiI was applied in IPM/GEFA-C(8). These results indicate that the synergistic effects of IPM and GEFA-C(8) enhance transdermal permeation of PTZ by disrupting SC lipids.

Microemulsion systems to enhance the transdermal permeation of ivermectin in dogs: A preliminary in vitro study.

This study aims to evaluate the influence of the phase behavior of microemulsions in the transdermal administration ("spot-on") of ivermectin, an antiparasitic drug widely used in the treatment of endoparasites and ectoparasites in dogs. In this regard, pseudoternary phase diagrams composed of water (aqueous phase), isopropyl myristate (oil phase), tween 80 (surfactant) and labrasol (cosurfactant) were obtained in a different surfactant: cosurfactant (S:CS) ratios. S:CS in 1:3 ratio presented a larger region of microemulsion formation and three microemulsions were selected from it and characterized. Subsequently, in vitro permeation and retention studies were conducted using canine skin as membrane. SAXS, rheology and conductivity data were employed to confirm the phase behavior of the microemulsions (w/o, bicontinuous or o/w). The cutaneous permeation and retention tests showed that the w/o microemulsion, followed by bicontinuous microemulsion, resulted in a higher amount of drug permeated through canine skin, suggesting better transdermal permeation. On the other hand, o/w microemulsion resulted in a higher amount of drug accumulated into the skin, suggesting better topical activity. Thus, it can be concluded that phase behavior of microemulsions influenced the drug permeation in the canine skin differently from other animal models. Microemulsions, especially w/o and bicontinuous, can be promising vehicles regarding the transdermal delivery of ivermectin.

A nano-sized gel-in-oil suspension for transcutaneous protein delivery.

We developed a new oil-based delivery system for transdermal protein delivery, a gel-in-oil (G/O) nanosuspension, where gelatin-based hydrogel was coated with hydrophobic surfactants. The high entrapment efficiency of a model protein, phycocyanin (PC), into nano-sized gelatin hydrogel particles was achieved. Spectroscopic evaluation of PC suggested that the G/O nanosuspension could retain the functional form of PC in isopropyl myristate. In vitro skin permeation studies showed that the G/O nanosuspension facilitated the delivery of PC through the stratum corneum of Yucatan micropig skin.

Transdermal Delivery of Compounds with Different Lipophilicity and Molecular Weight from W/O Microemulsions Analyzed by UPLC-QTOF/ MS and LC-MS/MS.

OBJECTIVE: The aim of this study was to develop a novel W/O microemulsion for a natural extract of Wen-Luo-Tong (WLT) containing mainly icariin, hydroxysafflor yellow A (HSYA) and gallic acid to be applied to skin as a potential treatment for peripheral neuropathy. METHODS: The oil phase was selected on the basis of affinity with the surfactant and co-surfactant. Pseudo-ternary diagrams were constructed to optimize microemulsions and finally stability studies were performed on the selected formulations. Droplet sizes were analyzed by using a zetasizer and were found to be within the desired range. Selected microemulsions with acceptable viscosities, containing 5%, 8% and 10% of water extract solution, were used for in vitro skin penetration studies using Franz diffusion cells and excised rat skin. New LC-MS/MS and UPLC-Q-TOF/MS methods were employed for quantitative and qualitative analysis. RESULTS: The optimized formulation (ME-4) consisting of 10% (w/w) water extract solution, 60% isopropyl myristate, 30%(w/w) Smix: Propylene glycol (5:2) significantly increased the cumulative permeated amounts of HSYA, icariin and gallic acid compared with the water extract solution controls. CONCLUSION: This novel formulation also increased the number of components penetrating rat skin. Ten components were detected in the Franz cell receptor solution using a UPLC-Q-TOF/MS system after the application of formulation ME-4 for 24h on the skin in vitro. However, only one component was detected after applying the control. Therefore, the microemulsion ME-4 was selected for future in vivo pharmacodynamic studies.

Liquid versus gel handrub formulation: a prospective intervention study.

INTRODUCTION: Hand hygiene is one of the cornerstones of the prevention of health care-associated infection, but health care worker (HCW) compliance with good practices remains low. Alcohol-based handrub is the new standard for hand hygiene action worldwide and usually requires a system change for its successful introduction in routine care. Product acceptability by HCWs is a crucial step in this process. METHODS: We conducted a prospective intervention study to compare the impact on HCW compliance of a liquid (study phase I) versus a gel (phase II) handrub formulation of the same product during daily patient care. All staff (102 HCWs) of the medical intensive care unit participated. Compliance with hand hygiene was monitored by a single observer. Skin tolerance and product acceptability were assessed using subjective and objective scoring systems, self-report questionnaires, and biometric measurements. Logistic regression was used to estimate the association between predictors and compliance with the handrub formulation as the main explanatory variable and to adjust for potential risk factors. RESULTS: Overall compliance (phases I and II) with hand hygiene practices among nurses, physicians, nursing assistants, and other HCWs was 39.1%, 27.1%, 31.1%, and 13.9%, respectively (p = 0.027). Easy access to handrub improved compliance (35.3% versus 50.6%, p = 0.035). Nurse status, working on morning shifts, use of the gel formulation, and availability of the alcohol-based handrub in the HCW's pocket were independently associated with higher compliance. Immediate accessibility was the strongest predictor. Based on self-assessment, observer assessment, and the measurement of epidermal water content, the gel performed significantly better than the liquid formulation. CONCLUSION: Facilitated access to an alcohol-based gel formulation leads to improved compliance with hand hygiene and better skin condition in HCWs.

Evaluation of chemical enhancers in the transdermal delivery of lidocaine.

The effect of various classes of chemical enhancers was investigated for the transdermal delivery of the anesthetic lidocaine across pig and human skin in vitro. The lipid disrupting agents (LDA) oleic acid, oleyl alcohol, butenediol, and decanoic acid by themselves or in combination with isopropyl myristate (IPM) showed no significant flux enhancement. However, the binary system of IPM/n-methyl pyrrolidone (IPM/NMP) improved drug transport. At 2% lidocaine dose, this synergistic enhancement peaked at 25:75 (v/v) IPM:NMP with a steady state flux of 57.6 +/- 8.4 microg cm(-2) h(-1) through human skin. This observed flux corresponds to a four-fold enhancement over a 100% NMP solution and over 25-fold increase over 100% IPM at the same drug concentration (p < 0.001). NMP was also found to co-transport through human skin with lidocaine free base and improve enhancement due to LDA. These findings allow a more rational approach for designing oil-based formulations for the transdermal delivery of lidocaine free base and similar drugs.

Design of a transdermal delivery system for aspirin as an antithrombotic drug.

Aspirin has become the gold standard to which newer antiplatelet drugs are compared for reducing risks of cardiovascular diseases, while keeping low cost. Oral aspirin has a repertoire of gastrointestinal side effects even at low doses and requires high frequent dosing because it undergoes extensive presystemic metabolism. Transdermal delivery offers an alternative route that bypasses the gut and may be more convenient and safer for aspirin delivery especially during long-term use. This study comprised formulation of aspirin in different topical bases. Release studies revealed that hydrocarbon gel allowed highest drug release. In vitro permeation studies revealed high drug permeation from hydrocarbon gel. Several chemical penetration enhancers were monitored for augmenting the permeation from this base. Combination of propylene glycol and alcohol showed maximum enhancing effect and, hence, was selected for biological investigation. The biological performance of the selected formulation was assessed by measuring the inhibition of platelet aggregation relevant to different dosage regimens aiming to minimize both drug dose and frequency of application. The results demonstrated the feasibility of successfully influencing platelet function and revealed that the drug therapeutic efficacy in transdermal delivery system is dose independent. Biological performance was re-assessed after storage and the results revealed stability and persistent therapeutic efficacy.

Encapsulation of Cancer Therapeutic Agent Dacarbazine Using Nanostructured Lipid Carrier.

The only formula of dacarbazine (Dac) in clinical use is intravenous infusion, presenting a poor therapeutic profile due to the low dispersity of the drug in aqueous solution. To overcome this, a nanostructured lipid carrier (NLC) consisting of glyceryl palmitostearate and isopropyl myristate was developed to encapsulate Dac. NLCs with controlled size were achieved using high shear dispersion (HSD) following solidification of oil-in-water emulsion. The synthesis parameters, including surfactant concentration, the speed and time of HSD were optimized to achieve the smallest NLC with size, polydispersion index and zeta potential of 155 ± 10 nm, 0.2 ± 0.01, and -43.4 ± 2 mV, respectively. The optimal parameters were also employed for Dac-loaded NLC preparation. The resultant NLC loaded with Dac possessed size, polydispersion index and zeta potential of 190 ± 10 nm, 0.2 ± 0.01, and -43.5 ± 1.2 mV, respectively. The drug encapsulation efficiency and drug loading reached 98% and 14%, respectively. This is the first report on encapsulation of Dac using NLC, implying that NLC could be a new potential candidate as drug carrier to improve the therapeutic profile of Dac.

IPM/DOSS/water microemulsions as reactors for silver sulfadiazine nanocrystal synthesis.

The first goal of this work was the preparation of a water-in-oil microemulsion from components generally regarded as safe for use in humans. Stable formulations without need of a co-surfactant were prepared from isopropyl myristate (IPM), dioctyl sodium sulfosuccinate (DOSS), and water. A ternary phase diagram was prepared for the IPM/DOSS/water system. The IPM/DOSS/water microemulsions were characterized by conductivity and dynamic laser light scattering (DLS). The results obtained from conductivity experiments indicate conductivity values of less than 1 muS/cm and were consistent with the formation of w/o microemulsions. The DLS results showed that the emulsified water droplets had an average diameter range of 9.2 to 19.7 nm, depending on composition. Modulation of the droplet size is possible by varying the water to DOSS molar ratio and DOSS to IPM ratio. The second goal of this work was the preparation of silver sulfadiazine (AgSD) nanoparticles. It was hypothesized that two separate microemulsions containing dispersed aqueous droplets of either sodium sulfadiazine or silver nitrate would react when mixed. The DLS results are consistent with the successful formation of submicron AgSD crystals.

Effects of ionization and penetration enhancers on the transdermal delivery of 5-fluorouracil through excised human stratum corneum.

The purpose of this study was to determine the effects of ionization and penetration enhancers on the transdermal delivery of 5-fluorouracil (5-FU) through excised human stratum corneum. The in vitro transport of 5-FU was determined at three physiologically relevant pH values of 5.0, 7.4 and 8.0, and in the presence of suitable penetration enhancers, namely Azone (AZ), lauryl alcohol (LA), and isopropyl myristate (IPM). The results showed that passive permeation of 5-FU is dependent upon the pH of the donor solution, although did not fully conform to the pH-partition hypothesis. A further analysis of data suggested an inverse relationship (i.e., negative correlation) between steady-state flux and aqueous solubility of 5-FU at these pH values (correlation coefficient = -0.4205), although correlation was not statistically significant (p = 0.7237). In the absence of a penetration enhancer, the in vitro permeability of 5-FU was quite low (0.82+/-0.06 x 10(4) cm/h). This delivery rate was enhanced by approximately by 3, 4 and 24-fold, respectively, when IPM, LA, and AZ were incorporated into the donor solution. All these enhancements were statistically significant (p < 0.05) compared to control, and occurred regardless of the polarity (solubility parameters) of these enhancers. Out of three examined enhancers, AZ appears to be a suitable enhancer for enhancing transport of 5-FU, which merits in vivo investigation in a suitable animal model. Possible mechanisms of enhancement by these penetration enhancers are also discussed.

Transdermal delivery of ketorolac tromethamine: permeation enhancement, device design, and pharmacokinetics in healthy humans.

Transdermal delivery of ketorolac tromethamine, a potent non-narcotic analgesic, through human skin in vitro and in vivo was investigated. In order to enhance and sustain the flux of ketorolac through human skin, various compositions of isopropyl alcohol (IPA), water, and isopropyl myristate (IPM) were evaluated. The solubility of ketorolac acid in an IPA/water binary vehicle mixture increased as the volume fraction of IPA increased from 0 to 90%. The solubility of ketorolac acid in an IPA/water/IPM (saturated) ternary vehicle mixture was practically the same as in the IPA/water binary vehicle mixture. The permeation of ketorolac acid through cadaver skin was evaluated using modified Franz diffusion cells. The skin flux increased as the IPA volume fraction was increased from 0 to 50% and then leveled off beyond 80% IPA loading. When IPM was added to the IPA/water binary vehicle mixture, a significant increase in the skin flux of ketorolac was observed. The skin flux decreased exponentially as the donor solution pH was raised from 3.5 to 7.0. The permeability of ketorolac through various membranes such as a microporous membrane and pressure-sensitive adhesive was evaluated. While a microporous membrane offered practically no diffusion resistance, the in vitro flux of ketorolac through cadaver skin decreased substantially upon lamination of pressure-sensitive adhesive onto a microporous membrane. Three liquid-reservoir type transdermal devices were fabricated using 6.5% ketorolac tromethamine gel, a microporous membrane, an adhesive membrane, and polyester backing film: TD-A (microporous membrane/acrylic adhesive), TD-B (microporous membrane/silicone adhesive), and TD-C (microporous membrane). The pharmacokinetics of ketorolac in 10 healthy humans following application of a transdermal device for 24 h was evaluated. The maximum plasma concentrations (Cmax) were 0.20, 0.18, and 0.82 microgram/mL for TD-A, TD-B, and TD-C, respectively. The total AUC values for the concentration-time curves were TD-C > TD-A > TD-B, and the terminal half-life ranged from 6.6 to 9.7 h.

A hairless mouse model for assessing the chronic toxicity of topically applied chemicals.

An enormous number of synthetic chemicals are incorporated in topical drugs, cosmetics and toiletries. These have the potential to cause irritant reactions when chronically applied to human skin. In predictive tests for assessing the irritancy potential of these chemicals, haired species, especially rabbits, guinea pigs and mice, have figured prominently. Customarily these tests, including the renowned Draize rabbit test, have entailed a single acute exposure or at most daily exposures over a few weeks. Estimation of inflammation and tissue injury in these models have relied on visual assessment. We submit that this approach is no longer acceptable. Visual assessments are unreliable. Reactions which are scored equivalently by the naked eye may differ strikingly when examined histologically. Moreover, tissue injury may be present in clinically normal skin. Short-term results. even when abetted by routine histological evaluations, cannot predict the degree of injury from long-term exposures. Cosmetics and toiletries, for example, are used daily for decades, often over most of the lifespan of persons who are well groomed. We present the hairless mouse as a convenient, reliable model for assessing the chronic toxicity of diverse chemicals. Histological examination enables a detailed description of the different tissue components which participate in the complex cascade of changes that comprise the inflammatory response.

Influence of penetration enhancer on drug permeation from volatile formulations.

Previously we have reported the influence of supersaturation on the permeation of fentanyl across model membranes and skin. The findings indicated that the vehicle and, specifically its residence time in skin, influence the ability of the formulation to enhance membrane drug permeation. The aim of the present study was to probe the role of vehicle components on (trans)dermal drug delivery in more detail. To this end, three commonly used chemical penetration enhancers were selected for investigation namely, propylene glycol (PG), octyl salicylate (OSAL) and isopropyl myristate (IPM). A further objective was to clarify the mechanism of action of OSAL. Model spray formulations were prepared consisting of 10% (v/v) of individual enhancers in ethanol. Saturated and supersaturated systems were evaluated for their ability to promote fentanyl transport across human skin in vitro. Mass balance studies and determination of the extent of uptake of enhancers by skin were also conducted. The results indicated that increasing the degree of drug saturation (DS) does not promote drug permeation for formulations in PG but increasing drug DS did promote drug permeation for IPM and some OSAL systems. This probably reflects faster depletion of PG compared with IPM and OSAL. Non-linear modelling of the permeation data indicated that PG and IPM act to promote drug solubility in the membrane whereas OSAL appears to act as a skin penetration enhancer by increasing drug diffusivity in the skin.

Myristic acid-conjugated polyethylenimine for brain-targeting delivery: in vivo and ex vivo imaging evaluation.

To investigate the potential of myristic acid (MC) to mediate brain delivery of polyethylenimine (PEI) as a gene delivery system, a covalent conjugate (MC-PEI) of MC, and PEI was synthesized. A near-infrared fluorescence probe, IR820 was conjugated to MC-PEI to explore its in vivo distribution after intravenous (i.v.) administration in mice. The brain targeting ability of MC-PEI was evaluated by near-infrared fluorescence imaging and analyzed semiquantitatively by fluorescence intensity, respectively. Significant NIR fluorescent signal was detected in the brain 12 h after i.v. administration and further confirmed by imaging the whole brain and brain slices. Semiquantitative results from fluorescence intensity further supported the successful brain delivery of MC-PEI which led to a very significant increase ( approximately 200%) in the brain uptake after i.v. injection in comparison with unmodified PEI. The capability of MC-PEI to condense DNA was further confirmed using agarose gel retardation assay, indicating its potential for gene delivery. The significant in vivo and ex vivo results suggest that MC-PEI is a promising brain-targeting drug delivery system, especially for gene delivery.

Increased efficiency of cisplatin-resistant cell lines to DNA-mediated gene transfer with cationic liposome.

AIM: Because of its effectiveness against many gynecologic malignancies, chemotherapy including cisplatin is mainly used as the first-line chemotherapy for epithelium ovarian cancer. However, one of the major problems that is well recognized is that tumor cells can easily acquire resistance to cisplatin. Various trials were carried out in order to establish treatment against cisplatin-resistant tumor cells. METHOD: Using both in vivo and in vitro studies, we examined whether or not the newly developed liposome could be used to demonstrate sufficient transfection activity as the anticancer reagent for cisplatin-resistant tumor cells. RESULT: With our newly developed liposome, GTE 319 and GTE 321, the lac-Z gene was more efficiently transfected in cisplatin-resistant variant cells, mEIIL-R, KF-ra and KF-rb, than in parental cells, mEIIL and KF, using X-gal staining. In cytotoxic assay, transfection of herpes simplex thymidine kinase (HSV-tk) gene conjugated with GTE319 or GTE 321, and cultivation with aciclovir for 5 days revealed accelerated tumor-inhibition activity in all of the cisplatin-resistant tumor cells compared with that in the naive parental cells. In addition, the high anti-tumor effect was obtained from intratumoral local injection of the tk gene conjugated with GTE-321 liposome following aciclovir administration against KF-rb-transplanted tumor formed in nude mouse hypodermic. CONCLUSION: These results suggest that gene therapy using a newly developed liposome-conjugated suicide gene can be an attractive approach for treatment against cisplatin-resistant ovarian cancer cells.

Influence of vehicle composition variations on the in vitro and ex vivo clonazepam diffusion from hydrophilic ointment bases.

A systematic study of formulation factors influencing the release of clonazepam from hydrophilic ointment bases was performed. Diffusion experiments were carried out using both artificial membranes (cellulose nitrate membrane impregnated with lauryl alcohol or isopropylmiristate or vaseline oil) and natural ones (rabbit ear skin). The formulation variables were the percentage of polyethylene glycol 400, polyethylene glycol 6000 and water, and the type of lipophilic component (lauryl alcohol, isopropylmyristate or vaseline oil) added to the vehicle. In vitro and ex vivo results were compared and the best formulation was found, even if it was not possible to establish a precise correlation between the in vitro and ex vivo flux values.