Skin permeation of lidocaine from crystal suspended oily formulations

In vitro permeation of lidocaine (lidocaine base, LID) through excised rat skin was investigated using several LID-suspended oily formulations. The first skin permeation of LID from an LID-suspended oily solution such as liquid paraffin (LP), isopropyl myristate (IPM), polyoxyethylene (2) oleylether (BO-2), and diethyl sebacate (DES) was evaluated and compared with that from polyethylene glycol 400 (PEG400) solution, a hydrophilic base. The obtained permeation rate of LID, Japp, from PEG400, LP, IPM, BO-2, and DES was in the order of DES>BO-2=IPM>LP>PEG400, and increased with LID solubility in the oily solvents, although LID crystals were dispersed in all solvents. Subsequently, oily formulations that consisted of different ratios of the first oily solvent (IPM, BO-2, or DES) (each 0-20%), the second oily solvent (LP) and an oily mixture of microcrystalline wax/white petrolatum/paraffin (1/5/4) were evaluated. BO-2 groups at a concentration of 5% and 10% had the highest Japp among the oily formulations, although a higher BO-2 resulted in lower skin permeation. In addition, pretreatment with BO-2 increased the skin permeation of LID. These results suggest that the penetration enhancing effect by the system may be related to the skin penetration of BO-2 itself. Finally, mathematical analysis was done to evaluate the effect of BO-2, and it was shown that BO-2 improved the LID solubility in stratum corneum lipids to efficiently enhance the LID permeation through skin.     

Skin Permeation of Lidocaine from Crystal Suspended Oily Formulations

ABSTRACT

In vitro permeation of lidocaine (lidocaine base, LID) through excised rat skin was investigated using several LID-suspended oily formulations. The first skin permeation of LID from an LID-suspended oily solution such as liquid paraffin (LP), isopropyl myristate (IPM), polyoxyethylene (2) oleylether (BO-2), and diethyl sebacate (DES) was evaluated and compared with that from polyethylene glycol 400 (PEG400) solution, a hydrophilic base. The obtained permeation rate of LID, J_app, from PEG400, LP, IPM, BO-2, and DES was in the order of DES>BO-2 = IPM>LP>PEG400, and increased with LID solubility in the oily solvents, although LID crystals were dispersed in all solvents. Subsequently, oily formulations that consisted of different ratios of the first oily solvent (IPM, BO-2, or DES) (each 0–20%), the second oily solvent (LP) and an oily mixture of microcrystalline wax/white petrolatum/paraffin (1/5/4) were evaluated. BO-2 groups at a concentration of 5% and 10% had the highest J_app among the oily formulations, although a higher BO-2 resulted in lower skin permeation. In addition, pretreatment with BO-2 increased the skin permeation of LID. These results suggest that the penetration enhancing effect by the system may be related to the skin penetration of BO-2 itself. Finally, mathematical analysis was done to evaluate the effect of BO-2, and it was shown that BO-2 improved the LID solubility in stratum corneum lipids to efficiently enhance the LID permeation through skin.     

Transdermal Absorption of Zidovudine from Ethanol-Isopropyl Myristate Mixed System and Influence of Probenecid on It in Rats

Transdermal absorption of zidovudine (AZT) from an ethanol-isopropyl myristate (IPM) mixed system was examined in rats. For comparison of bioavailability (BA) after topical applications, 0.25 ml of the ethanol/IPM system containing 40% ethanol and 60 mM AZT was applied as a standard formulation. Values of the area under the plasma concentration-time curves of AZT for 8 hr (AUC_0-8), as indices of BA, following application of various formulations were compared with that of the standard formulation. Then the influence of content of the drug and ethanol, and application volume of the system was evaluated. BA was effectively improved only when the total amount of ethanol applied on the skin was increased. On the other hand, simultaneous transdermal application of AZT and probenecid increased the AU_0-8, of AZT without necessitating the increase in ethanol content in the formulation. In addition, coadministered probenecid improved cerebrospinal fluid/plasma concentration ratio of AZT.     

Effect of application volume of ethanol-isopropyl myristate mixed solvent system on permeation of zidovudine and probenecid through rat skin

Permeation of zidovudine (AZT) and probenecid from an ethanol-isopropyl myristate (IPM) mixed system through rat skin was studied in a finite system. Several volume sizes of the ethanol-IPM mixed systems containing AZT and probenecid, both as suspensions, were applied on the skin of the hairless rat using a vertical glass cell, and the fractions of the drugs permeated in 8 hr Q_%,8hr were determined. For the systems containing 40% ethanol, the Q_%,8hr value decreased with the reduction of volume of the system applied, and the decreasing profile was similar to that calculated on the assumption that the permeability of the drug does not change with the volume of the sample applied. On the other hand, in the systems containing 10% or 20% ethanol, the Q_%,8hr value showed a maximum when a specific volume of the sample was applied. Therefore, the effect of sample volume on the Q_%,8hr value was different between the 40% ethanol-IPM system and the 10% or 20% ethanol-IPM system. Following pretreatment of the skin with 0.105 ml/cm² of drug-free 40% ethanol-IPM for 2 hr, several volume sizes of 10% ethanol-IPM systems containing the drugs were applied on the skin to explain why the different profiles were observed in the system containing 10% or 20% ethanol. The results for pretreated skin suggest that the amount of ethanol in the systems with low ethanol concentration and small application volume is too small to exert an effect that enhances permeation of the drugs. In those systems, the integrated effect of ethanol on the skin would be important for the enhancing effect. Total volume, as well as concentration, of an enhancer should be set precisely in designing an efficient transdermal delivery system.     

Effect of Application Volume of Ethanol-Isopropyl Myristate Mixed Solvent System on Permeation of Zidovudine and Probenecid Through Rat Skin

Permeation of zidovudine (AZT) and probenecid from an ethanol-isopropyl myristate (IPM) mixed system through rat skin was studied in a finite system. Several volume sizes of the ethanol-IPM mixed systems containing AZT and probenecid, both as suspensions, were applied on the skin of the hairless rat using a vertical glass cell, and the fractions of the drugs permeated in 8 hr Q_%,8hr were determined. For the systems containing 40% ethanol, the Q_%,8hr value decreased with the reduction of volume of the system applied, and the decreasing profile was similar to that calculated on the assumption that the permeability of the drug does not change with the volume of the sample applied. On the other hand, in the systems containing 10% or 20% ethanol, the Q_%,8hr value showed a maximum when a specific volume of the sample was applied. Therefore, the effect of sample volume on the Q_%,8hr value was different between the 40% ethanol-IPM system and the 10% or 20% ethanol-IPM system. Following pretreatment of the skin with 0.105 ml/cm² of drug-free 40% ethanol-IPM for 2 hr, several volume sizes of 10% ethanol-IPM systems containing the drugs were applied on the skin to explain why the different profiles were observed in the system containing 10% or 20% ethanol. The results for pretreated skin suggest that the amount of ethanol in the systems with low ethanol concentration and small application volume is too small to exert an effect that enhances permeation of the drugs. In those systems, the integrated effect of ethanol on the skin would be important for the enhancing effect. Total volume, as well as concentration, of an enhancer should be set precisely in designing an efficient transdermal delivery system.     

Transdermal Absorption of Zidovudine from Ethanol-Isopropyl Myristate Mixed System and Influence of Probenecid on It in Rats

Abstract

Transdermal absorption of zidovudine (AZT) from an ethanol-isopropyl myristate (IPM) mixed system was examined in rats. For comparison of bioavailability (BA) after topical applications, 0.25 ml of the ethanol/IPM system containing 40% ethanol and 60 mM AZT was applied as a standard formulation. Values of the area under the plasma concentration-time curves of AZT for 8 hr (AUC_0-8), as indices of BA, following application of various formulations were compared with that of the standard formulation. Then the influence of content of the drug and ethanol, and application volume of the system was evaluated. BA was effectively improved only when the total amount of ethanol applied on the skin was increased. On the other hand, simultaneous transdermal application of AZT and probenecid increased the AU_0-8, of AZT without necessitating the increase in ethanol content in the formulation. In addition, coadministered probenecid improved cerebrospinal fluid/plasma concentration ratio of AZT.     

Effect of Penetration Enhancers on Transdermal Absorption of Insulin Across Human Cadaver Skin

The transdermal diffusion of insulin, a model polypeptide drug, across the human cadaver skin (HCS) was evaluated in vitro, in presence of penetration enhancing solvents, anionic surfactants, biosurfactants, a natural moisturizing agent and combinations thereof. Also, an attempt was made to relate the enhanced penetration to physical parameters like distribution coefficient, surface tension and viscosity. The results of the permeation experiments indicate that the permeation enhancers used in the present investigation significantly enhance the amount of drug entering into the HCS and the amount reaching to the skin. A synergistic effect on permeation enhancement was observed in cases where combination of permeation enhancers were selectively used. Reasons for this synergism were critically examined and established.     

Effect of Penetration Enhancers on Transdermal Absorption of Insulin Across Human Cadaver Skin

The transdermal diffusion of insulin, a model polypeptide drug, across the human cadaver skin (HCS) was evaluated in vitro, in presence of penetration enhancing solvents, anionic surfactants, biosurfactants, a natural moisturizing agent and combinations thereof. Also, an attempt was made to relate the enhanced penetration to physical parameters like distribution coefficient, surface tension and viscosity. The results of the permeation experiments indicate that the permeation enhancers used in the present investigation significantly enhance the amount of drug entering into the HCS and the amount reaching to the skin. A synergistic effect on permeation enhancement was observed in cases where combination of permeation enhancers were selectively used. Reasons for this synergism were critically examined and established.     

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.     

Transdermal delivery of ketorolac tromethamine: effects of vehicles and penetration enhancers

The effects of vehicles and penetration enhancers on the in vitro permeation of ketorolac tromethamine (KT) across excised hairless mouse skins were investigated. Among pure vehicles examined, propylene glycol monolaurate (PGML) showed the highest permeation flux, which was 94.3 ± 17.3 µg/cm²/h. Even though propylene glycol monocaprylate (PGMC) alone did not show high permeation rate, the skin permeability of KT was markedly increased by the addition of diethylene glycol monoethyl ether (DGME); the enhancement factors were 19.0 and 17.1 at 20% and 40% of DGME, respectively. When DGME was added to PGML, the permeation fluxes were almost two times at 20-60% of DGME compared to PGML alone. In the cosolvent system consisting of propylene glycol (PG)-oleyl alcohol, the permeation rate increased as the ratio of PG increased. In the study to investigate the effect of drug concentration on the permeation rate of KT, the permeation rates increased as the drug concentration increased in all vehicles used, and the dramatic increase in permeation rate was obtained when the drug concentration was higher than its solubility. For the effects of fatty acids on the permeation of KT, five fatty acids were added to PG at concentrations of 1%-, 3%-, 5%- and 10%-caprylic acid, capric acid, lauric acid, oleic acid, and linoleic acid. The enhancing effects of fatty acids were different, depending on the concentration as well as the sort of fatty acids. The highest enhancing effect was attained with 10% caprylic acid in PG; the permeation flux was 113.6 ± 17.5 µg/cm²/h. The lag time of KT was reduced as the concentration of fatty acids increased except for caprylic acid.     

Effect of (E)-2-isopropyl-5-methylcyclohexyl octadec-9-enoate on transdermal delivery of Aconitum alkaloids

Objective: The aim of this work was to evaluate the percutaneous absorption of Aconitum alkaloids using (E)-2-isopropyl-5-methylcyclohexyl octadec-9-enoate (M-OA) as an enhancer as well as to investigate the effect of M-OA in isopropyl palmitate (IPP) solution (5% ethanol in IPP, w/v), with or without an enhancer, on the stratum corneum (SC) barrier properties in vitro. Methods: The in vitro permeation studies of Aconitum alkaloids were conducted in isopropyl myristate (IPM) solution in side-by-side diffusion cells. In addition, scanning electron microscopy (SEM) and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy were used to evaluate the M-OA biophysical changes in SC barrier function in vitro. Results: The in vitro permeation studies indicated that M-OA had significant enhancing effect on the permeation of mesaconitine (MA) and hypaconitine (HA); however, aconitine (AC) was too low to be detected on the receiver side, and L-menthol had no effect on the penetration of all the Aconitum alkaloids. Morphological changes in the skin after enhancer treatment demonstrated that the extraction of the SC lipids by the enhancers led to disruption of the SC and the desquamation of SC flake. ATR-FTIR spectra of C–H asymmetric/symmetric stretching peak shifts and amide II stretching vibrations were indicative of SC lipid fluidization and changes in protein conformation, respectively. Conclusion: The results showed that M-OA was worthy of further investigation as a potential candidate for inclusion in transdermal formulations as a penetration enhancer.     

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.     

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.     

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.     

Characterization of the Enhancing Effect of a Vehicle in a Transdermal System

The percutaneous absorption of Morphine and Morphine hydrochloride is optimized using binary solvent systems as vehicle of the drugs. Release kinectics through hairless mouse skin are performed in vitro: variations of the flux, of the lagtime and of the cumulative released quantities as a function of the vehicle composition point out a synergistic effect of the two solvents (Labrafac hydrophile and Transcutol). Independant determinations of the skin/vehicle partition coefficient, of the solubility and of the diffusion coefficient are realized; the results allow us to explain the different enhancing effects of each solvent: the first one has an enhancing effect on the drug concentration in the skin, and the second one modifies the mobility of the drug in the skin

The rate of the drug release is usually optimized increasing the drug activity in the donor in relation with the solubility variation. With transdermal system (matrix, film) a more accurate approach is to increase the skin permeation of the drug (1) (2). This effect is commonly attempted with enhancers contained in the system, but a particular vehicle can act as an enhancer and as a solvent (3-7). In this case, we optimize the permeation coefficient, P = (K D/e), where K is the skin/vehicle partition coefficient, D is the diffusion coefficient and e is the skin thickness. The partition coefficient allows variation of the drug concentration in the skin, while the diffusion coefficient represents the mobility of the drug in the skin

The aim of this presentation is to analyze, on experimental data, the variation of the permeation to identifie, to localize, and to explain the role of a such vehicle. We studied the morphine permeation through hairless mouse skin with a binary solvents system. The solvents used are a diethylene glycol monoether (T) and a glycolysed ethoxylated glyceride (L). We propose to analyze the influence of the mixture composition on the partition and diffusion coefficient of morphine. We used an hydrophilic specie, morphine hydrochloride (MHCl), and a lipophilic specie, basic morphine (M), assuming that their routes of penetration are different: etheir hydrophilic inter or intra cellular route, or lipidic intercellular route. We suppose that each solvent can modifie the physical or chemical structure of these routes and consequently, the permeation of one particular specie of morphine     

Effect of fatty acid diesters on permeation of anti-inflammatory drugs through rat skin

Four fatty acid diesters (diethyl succinate, diethyl adipate, diethyl sebacate, and diisopropyl adipate) were used to study their enhancement effect on the permeation of four non-steroidal anti-inflammatory drugs (NSAIDs: ketoprofen, indomethacin, diclofenac sodium, and ibuprofen) through rat abdominal skin. With the diester pretreatment, drug permeation increased and the lag times decreased. No relationship was observed between the solubilities of the drugs in the diesters and the diester enhancement effects. The enhancement effect decreased with an increase of the drug lipophilicity, but increased with an increase of the lipophilic index of the diester up to about 3.5, after which the enhancement effect decreased or remained constant. Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) was employed to investigate the biophysical changes in the stratum corneum lipids caused by the diesters. The FTIR results showed that treatment of the skin with diesters did not produce a blue shift in the asymmetric and symmetric C-H stretching peak positions. However, all of the above diesters showed a decrease in peak heights and areas for both asymmetric and symmetric C-H stretching absorbances in comparison with water treatment.

These results suggested that the diesters were more effective for enhancing the penetration of hydrophilic drugs than lipophilic drugs, and the enhancing effect of lipophilic diesters was more effective than that of hydrophilic diesters. The enhancement effects of diesters may be due to their causing lipid extraction in the skin.     

Release of benzimidazole and benzylidene camphor from topical sunscreen formulations

Absorption of two ultraviolet (UV) filters was evaluated through a lipophilic synthetic membrane (Folioxane®) and excised hairless rat skin using a flow-through diffusion cell. Folioxane membrane is an artificial skin used in the treatment of third-degree burns. Diffusion tests were performed with aqueous solutions and galenic formulations (one water-in-oil [W/O] emulsion and two oily gels). Analyses were achieved with high-performance liquid chromatography (HPLC) with UV detection at 295 nm. Diffusion kinetics of 17 β estradiol, a reference compound, through rat skin, human skin, and Folioxane membrane were performed to validate the in vitro model. Phenylbenzimidazole and methylbenzylidene camphor in aqueous solutions were diffused at a regular rate through the Folioxane film. The release of phenylbenzimidazole was very slow, whereas the release of benzylidene camphor was more pronounced: a decrease of the quantity was observed in the donor compartment (30 % at 6 hr and 93% after 72 hr). A significant flow of benzylidene camphor was also measured through excised skin of rat in the first 3 hr. The skin absorption was 38% over 72 hr. The W/O emulsion had low penetration of UV filter: 20% of the initial amount for Folioxane membrane and 0.4% for rat skin. In contrast, the penetration of two oily gels was identical: 28% on Folioxane membrane and 0.6% on rat skin. This study demonstrates the transcutaneous diffusion of two important classes of sunscreens through a lipophilic Folioxane membrane and through excised hairless rat skin. From the results, Folioxane membrane appears to be an alternative model for studying diffusion of topical molecules and as a tool for guiding formulation choices.     

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.     

Characterization of the Enhancing Effect of a Vehicle in a Transdermal System

Abstract

The percutaneous absorption of Morphine and Morphine hydrochloride is optimized using binary solvent systems as vehicle of the drugs. Release kinectics through hairless mouse skin are performed in vitro: variations of the flux, of the lagtime and of the cumulative released quantities as a function of the vehicle composition point out a synergistic effect of the two solvents (Labrafac hydrophile and Transcutol). Independant determinations of the skin/vehicle partition coefficient, of the solubility and of the diffusion coefficient are realized; the results allow us to explain the different enhancing effects of each solvent: the first one has an enhancing effect on the drug concentration in the skin, and the second one modifies the mobility of the drug in the skin

The rate of the drug release is usually optimized increasing the drug activity in the donor in relation with the solubility variation. With transdermal system (matrix, film) a more accurate approach is to increase the skin permeation of the drug (1) (2). This effect is commonly attempted with enhancers contained in the system, but a particular vehicle can act as an enhancer and as a solvent (3–7). In this case, we optimize the permeation coefficient, P = (K D/e), where K is the skin/vehicle partition coefficient, D is the diffusion coefficient and e is the skin thickness. The partition coefficient allows variation of the drug concentration in the skin, while the diffusion coefficient represents the mobility of the drug in the skin

The aim of this presentation is to analyze, on experimental data, the variation of the permeation to identifie, to localize, and to explain the role of a such vehicle. We studied the morphine permeation through hairless mouse skin with a binary solvents system. The solvents used are a diethylene glycol monoether (T) and a glycolysed ethoxylated glyceride (L). We propose to analyze the influence of the mixture composition on the partition and diffusion coefficient of morphine. We used an hydrophilic specie, morphine hydrochloride (MHCl), and a lipophilic specie, basic morphine (M), assuming that their routes of penetration are different: etheir hydrophilic inter or intra cellular route, or lipidic intercellular route. We suppose that each solvent can modifie the physical or chemical structure of these routes and consequently, the permeation of one particular specie of morphine     

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.