Propylene Glycol Monolaurate Research Articles

In Vitro–In Vivo Correlation in Skin Permeation

In vitro skin permeation studies have been used extensively in the development and optimisation of delivery of actives in vivo. However, there are few reported correlations of such in vitro studies with in vivo data. The aim of this study was to investigate the skin permeation of a model active, niacinamide, both in vitro and in vivo. Conventional diffusion cell studies were conducted in human skin to determine niacinamide permeation from a range of vehicles which included dimethyl isosorbide (DMI), propylene glycol (PG), propylene glycol monolaurate (PGML), N-methyl 2-pyrrolidone (NMP), Miglyol 812N® (MG), and mineral oil (MO). Single, binary or ternary systems were examined. The same vehicles were subsequently examined to investigate niacinamide delivery in vivo. For this proof-of-concept study one donor was used for the in vitro studies and one volunteer for the in vivo investigations to minimise biovariability. Analysis of in vitro samples was conducted using HPLC and in vivo uptake of niacinamide was evaluated using Confocal Raman spectroscopy (CRS). The amount of niacinamide permeated through skin in vitro was linearly proportional to the intensity of the niacinamide signal determined in the stratum corneum in vivo. A good correlation was observed between the signal intensities of selected vehicles and niacinamide signal intensity. The findings provide further support for the use of CRS to monitor drug delivery into and across the skin. In addition, the results highlight the critical role of the vehicle and its disposition in skin for effective dermal delivery.

Formulation of carbenoxolone for delivery to the skin

Carbenoxolone (CEX), a semi-synthetic derivative of glycyrrhetinic acid, has previously been used as a disodium salt for the management of dyspepsia and peptic ulcer because of its anti-inflammatory properties. Although glycyrrhetinic acid is available in pharmaceutical and personal care products for skin care, the topical use of the free acid form of CEX, has not previously been reported. In this work we investigated the percutaneous penetration of CEX. Solubility and permeability studies were conducted using a range of solvents or skin permeation enhancers (SPEs) commonly used for skin delivery. Binary combinations of dimethyl isosorbide (DMI) and Transcutol™ (TC) with isopropyl myristate (IPM) were effective in promoting skin permeation of CEX although individual solvents were not. Alternative fatty acid esters to IPM were subsequently investigated with the most promising formulation consisting of TC and propylene glycol laurate (PGL). Interestingly, propylene glycol monolaurate (PGML) did not demonstrate comparable efficacy when combined with TC. A ternary formulation consisting of TC, PGL and IPM demonstrated the best permeation enhancement of CEX compared with all other vehicles. The findings confirm (i) the feasibility of promoting CEX penetration across the skin (ii) the synergistic effect of combinations of solvents and SPEs on dermal and transdermal delivery (iii) the necessity for more fundamental studies to explain the differential effects of fatty acid esters on the skin barrier.

Effect of pH and penetration enhancers on electroosmotic flow and flux through skin

We have investigated the effect of pH and four penetration enhancers on the electroosmotic volume flow (EVF) and flux through skin to get more detailed understanding of this phenomenon and its effect on flux. The results were evaluated in relation EVF and the permeability change by current induced skin damage. At pH 7.4, we have confirmed that the direction of convective solvent flow is from anode to cathode. At pH 4.0, no permselectivity was observed and it seems that this pH is close to the isoelectric point of skin. At pH 3.0, the permselectivity of skin is reversed. From the difference in flux between just before (47 μg/cm2 h) and after (32 μg/cm2 h) cathodal current-off, the magnitude of EVF is estimated to be smaller than 1.5 μl/cm2 h, if we consider the recovery of skin to a lower permeability after current-off. At pH 7.4, Oleic acid (OA) and propylene glycol monolaurate (PGML) increased the passive flux markedly. Synergistic effect in flux between OA and current was observed for both anodal and cathodal current. The use of isopropyl myristate (IPM) in combination with anodal current resulted in reduced flux when compared to the flux of anodal current alone. Cathodal flux of OA or PGML treated skin increased continuously until the current was off. However, to the contrary of our expectation, flux decreased after current-off. We think this is mainly due to the recovery of damaged skin (flux decreasing effect), though the disappearance of EVF may slightly increase the flux. For IPM and propylene glycol, the combination of enhancer with cathodal current inhibited the flux, similar to that observed for anodal delivery. Overall, these results provide further information on the role of electroosmosis and the effect of penetration enhancers in combination with current on flux through skin.

Rational formulation design

To be efficacious and to satisfy the requirements for claim substantiation, a cosmetic formulation must achieve effective targeting of an active in the skin. Although the basic principles governing the skin permeation and disposition of molecules have been known for many years, attention has been far less focused on the role of the vehicle, particularly at cosmetically relevant doses. In this article, we discuss the necessity to understand the fate of the formulation components as well as the active once applied onto skin. Recent data confirm that the residence time of the formulation constituents can have a profound impact on the fate of the active. Approaches to identify the ideal vehicle for skin delivery are considered critically, specifically the recent work on 'formulating for efficacy' (FFE) by the late Johann Wiechers. Essentially, FFE aims to match the active with the optimal vehicle for skin delivery based on matching polarity/solubility values of the trinity of skin, active and vehicle. The emerging importance of techniques that provide insight to how the vehicle distributes in and on skin is highlighted.

Effects of vehicles on the percutaneous absorption of donepezil hydrochloride across the excised hairless mouse skin

Objectives: This study aimed to examine the feasibility of developing donepezil transdermal delivery systems (TDSs).Methods: Solution and pressure-sensitive adhesive (PSA) TDS were formulated using various vehicles and fatty acids, and the in vitro permeation study was conducted using the hairless mouse skin.Key findings: Permeation fluxes (μg/cm2/h) from solution formulations were generally low (0.05–3.40), except for formulations including isopropyl alcohol (IPA, 51.19), ethyl alcohol (27.32) and water (24.07). Dose-dependent permeation fluxes were obtained (r2 = 0.9754). Even though the addition of fatty acids to IPA failed to increase donepezil permeation rates, it shortened lag times. Compared to those from solution formulations, permeation profiles from PSA TDS were totally different, and penetration rates were considerably low. PSA TDS comprising diethylene glycol monoethyl ether (DGME)-propylene glycol monolaurate (PGML) co-solvents (40:60) showed the highest permeation flux (0.10 ± 0.0024 μg/cm2/h).Conclusions: IPA-containing solution formulations and DGME-PGML (40: 60)-containing PSA TDS were found to be favorable candidates for donepezil transdermal delivery.

무모생쥐 피부에 리제드로네이트 소디움의 이온토포레시스 경피전달

Osteoporosis was traditionally defined by the occurrence of nontraumatic fractures, especially of the spine, in the setting of low bone mass. Bisphosphonates are an important group of therapeutic agents for the management of osteoporosis, as they inhibit bone resorption and increase bone density, thereby potentially decreasing fracture risk. Risedronate sodium is a bisphosphonate class used by oral formulation. In this study, risedronate was transdermally delivered by iontophoresis. Effects of polarity, pH, current density, and drug concentration were studied using a side-by-side diffusion cell including the hairless mice skin. In addition we studied effect of enhancers. The flux was evaluated by HPLC/UV system. The amount of transported drug under iontophoretic delivery was approximately 186 fold higher than that under passive delivery. Flux was proportional to the increase of drug concentration and current density. The flux was observed about 0.68mg/ when the amout of Propyleneglycol monolaurate (PGML) used 1% as enhancer. Results indicated that iontophoresis is an effective method for transdermal administration of risedronate sodium

Pharmacokinetics of formulated tenoxicam transdermal delivery systems

To investigate the feasibility of developing a new tenoxicam transdermal delivery system (TDS), the pharmacokinetics of tenoxicam from various formulated TDS were evaluated and compared with values following oral administration of tenoxicam and with application of a piroxicam plaster (Trast) marketed in Korea. Based on previous in-vitro study results, a mixture of diethylene glycol monoethyl ether (DGME) and propylene glycol monolaurate (PGML) (40:60) was used as a vehicle, and caprylic acid, capric acid, lauric acid, oleic acid or linoleic acid (each at 3%) was added as an enhancer. Triethanolamine (5%) was used as a solubilizer, and Duro-Tak 87-2510 as a pressure-sensitive adhesive. Among these fatty acids used for the formulation of tenoxicam TDS, caprylic acid showed the greatest enhancing effect; the area under the plasma concentration-time profile (AUC) decreased in the order of caprylic acid>linoleic acid>or=oleic acid>lauric acid>capric acid. Compared with oral administration, maximum plasma concentration (Cmax) was significantly lower, and time to reach Cmax (Tmax) delayed with all formulated tenoxicam TDS. All formulated TDS resulted in a lower AUC than with the oral formulation, except for TDS containing caprylic acid, although the difference was statistically significant only with capric acid. The AUC for all the formulated tenoxicam TDS was significantly higher than that of the piroxicam plaster; TDS with caprylic acid increased AUC 8.53-fold compared with the piroxicam plaster. Even though the Tmax of tenoxicam TDS was not significantly different from that of the piroxicam plaster, Cmax was higher; formulations containing caprylic acid and linoleic acid increased Cmax by 7.39- and 8.76-fold, respectively. In conclusion, a formulation containing 1.5 mL DGME-PGML (40:60) with 3% caprylic acid and 5% triethanolamine mixed with 6 g Duro-Tak 87-2510 could be a good candidate for developing a new tenoxicam TDS to maintain a comparable extent of absorption to oral delivery while attaining a prolonged effect with fewer toxic events.

Formulation and evaluation of ubidecarenone transdermal delivery systems

Purpose: This study is aimed to examine the feasibility of developing ubidecarenone (coenzyme Q10, CoQ10) transdermal delivery systems (TDS). Method: In vitro permeation study using solution formulation and pressure-sensitive adhesive (PSA) TDS and in vivo pharmacokinetic study were conducted. Results: When using solution formulations, isopropyl alcohol (103.39 ± 1.61), ethyl alcohol (81.55 ± 7.27), and the mixture of diethylene glycol monoethyl ether (DGME)/propylene glycol monolaurate (PGML) at the ratio of 60:40 (91.08 ± 26.07) showed high flux (μg/cm2/hour). The addition of fatty acids to DGME-PGML failed to show profound enhancing effects; only unsaturated fatty acids such as linoleic acid and oleic acid at 3% and caprylic acid at 3% and 10% slightly increased permeation flux. CoQ10 from the acrylic PSA TDS showed biphasic permeation profile that was permeated very rapidly up to the first 12 hours, and after that, permeation rate became slower. Overall, 6% fatty acids showed high permeation rates and the highest maximum flux of 9.3 μg/cm2/hour was obtained with a formulation containing 6% lauric acid in DGME-PGML (60:40). The in vivo pharmacokinetic study using TDS with 6% fatty acids in DGME-PGML (60:40) showed that the absorption of CoQ10 decreased in the following order: TDS containing linoleic acid > oral dosage form > TDS with oleic acid > TDS with lauric acid > TDS with caprylic acid > TDS with capric acid. TDS containing oleic acid showed preferable pharmacokinetic profile with respect to lower Cmax, comparable AUC, and prolonged t1/2 and Tmax compared to oral administration of drug. Conclusions: For effective transdermal delivery system of CoQ10, 6% linoleic acid or oleic acid in DGME-PGML (60:40) could be employed.

Potential Mucoadhesive Dosage Form of Lidocaine Hydrochloride: II. In Vitro and In Vivo Evaluation

ABSTRACTThe aim of this study was to develop a controlled release buccal mucoadhesive delivery system for systemic delivery of lidocaine hydrochloride as a model drug. In vitro release and buccal permeation as well as in vivo permeation of LDHCL patches were evaluated. The drug release and the permeability of the drug through porcine buccal mucosa were evaluated using Franz diffusion cell. In vivo evaluation of patches was carried out on rabbits as an animal model.Patches were designed in two fashions, bi-layer (BLP; LDHCL, carbopol, glycerin, pentration enhancer, and Tween 20 as the first layer; and EVA as the second layer) and triple layer (TLP; LDHCL, carbopol and glycerin as the first layer; carbopol, glycerin, pentration enhancer and pluronic F-127 as the middle layer; and EVA as the third layer) patches, respectively.Presence of oleic acid as PE in the formulation significantly enhanced the in vitro permeability of LDHCL (p < 0.05), while propylene glycol monolaurate as PE suppressed it (p < 0.05). The in vivo evaluation in rabbits showed that TLP had significantly higher Cmax and AUC0–8 (p < 0.05) than BLP. Furthermore, TLP showed a well-controlled drug plasma concentration over 6 hr which was significantly longer than BLP (p < 0.05). Patches were well adhered to buccal mucosa of the rabbits over the 8-hr study period. It was postulated that the hypothetical release mechanism of the drug and oleic acid from TLP was controlled by their diffusion through the swollen polymer network and micelled gel.

Intensification of enzymatic synthesis of propylene glycol monolaurate from 1,2-propanediol and lauric acid under microwave irradiation: Kinetics of forward and reverse reactions

Several organic syntheses have been carried out very effectively using microwave irradiation. In the current studies, immobilized lipases were used for the esterification of lauric acid with 1,2-propanediol under conventional heating and microwave irradiation. These esters are commercially valuable. Various commercially available lipases, such as Novozym 435, Lipozyme RM IM, Lipozyme TL IM and Lipase PS-C were screened among which Novozym 435 was found to be the best catalyst. Optimization of reaction conditions included speed of agitation, catalyst loading, mole ratio of reactants and effect of temperature under the microwave irradiation as well as conventional heating. A kinetic model was developed for both forward and backward reactions. A synergistic effect microwave irradiation on reaction rate and specificity of lipases was observed in comparison with the conventional heating. The initial rate and progress curve data were used to arrive at a suitable model and various parameters were estimated for both forward as well as reversible reaction at 30 °C. The forward reaction follows ping-pong bi-bi mechanism for the reactants 1,2-propanediol and lauric acid with inhibition by 1,2-propanediol whereas the reverse reaction also follows the same mechanism for the reactants propylene glycol monolaurate and water with inhibition by water. This model was used to stimulate the rate data, which were in excellent agreement with experimental values.

이온토포레시스를 이용한 케토프로펜의 경피전달

We have studied the effect of polarity, current density, current duration, crosslinking density, swelling ratio, and permeation enhancers on the transdermal flux of ketoprofen from acrylamide hydrogel. Hydrogel was prepared by free radical crosslinking polymerization of acrylamide. Drug loading was made just before transport experiment by soaking the hydrogel in solution containing drug. In vitro flux study using hairless mouse skin was performed at using side-by-side diffusion cell, and the drug was analysed using HPLC/UV system. The result showed that, compared to passive flux, the total amount of drug transported increased about 18 folds by the application of cathodal current. Anodal delivery with same current density also increased the total amount of drug transported about 13 folds. It seemed that the increase in flux was due to the electrorepulsion and the increase in passive permeability of the skin by the current application. Flux increased as current density, the duration of current application and loading amount (swelling duration) increased. As the cross linking density of the hydrogel increased, flux clearly decreased. The effect of hydrophilic enhancers (urea, N-methyl pyrrolidone, Tween 20) and some hydrophobic enhancers (propylene glycol monolaurate and isopropyl myristate) was minimal. However, about 3 folds increase in flux was observed when 5% oleic acid was used. Overall, these results provide some useful information on the design of an optimized iontophoretic delivery system of ketoprofen.

The effect of vehicles and pressure sensitive adhesives on the percutaneous absorption of quercetin through the hairless mouse skin.

To investigate the feasibility of developing a new quercetin transdermal system, a preformulation study was carried out. Therefore, the effects of vehicles and pressure-sensitive adhesives (PSA) on the in vitro permeation of quercetin across dorsal hairless mouse skin were studied. Among vehicles used, propylene glycol monocaprylate (PGMC) and propylene glycol monolaurate were found to have relatively high permeation flux from solution formulation (i.e., the permeation fluxes were 17.25 +/- 1.96 and 9.60 +/- 3.87 microg/cm2/h, respectively). The release rate from PSA formulations followed a matrix-controlled diffusion model and was mainly affected by the amount of PSA and drug loaded. The overall permeation fluxes from PSA formulations were less than 0.30 microg/cm2/h, which were significantly lower compared to those obtained from solution formulations. The lower permeation fluxes may be due to the decrease of solubility and diffusivity of quercetin in the PSA layer, considering the fact that the highest flux of 0.26 microg/cm2/h was obtained with the addition of 0.2% butylated hydroxyanisole in PGMC-diethylene glycol monoethyl ether co-solvents (80-85 : 15-20, v/v). Taken together, these observations indicate that improvement in the solubility and diffusivity of quercetin is necessary to realize fully the clinically applicable transdermal delivery system for the drug.

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.

용제 중 염산온단세트론의 용해성 및 안정성

The solubility and stability of ondansetron hydrochloride (OS) in various vehicles were determined. The effect of cyclodextrins (CD) on the solubility of OS in water was determined by equilibrium solubility method. The solubility of OS at increased in the rank order of isopropyl myristate (IPM) propylene glycol monolaurate propylene glycol (PG) (283 mg/ml). The addition of PG or DGME to non-aqueous vehicles such as IPM, PGL and PGMC markedly increased the solubility of OS. The addition of CDs in water increased the solubility. Apparent stability constant for the CD complexation with OS was calculated to be for . Twenty mM , 69.4 mM sulfobutyl ether and 115.4 mM increased the aqueous solubilty of OS 1.27, 2.18 and 1.85 times, respectively. OS was stable in buffered aqueous solution (pH 5.0). However, OS was relatively unstable in non-aqueous vehicles in the order of PG

Optimized enzymatic synthesis of propylene glycol monolaurate by direct esterification

Propylene glycol monoesters with low hydrophile–lipophile balance value are widely used in the food industry. The ability of immobilized lipase, from Rhizomucor miehei (Lipozyme IM-77), to catalyze the direct esterification of propylene glycol with lauric acid was investigated in this study. Response surface methodology (RSM) and 3-level-4-factor fractional factorial design were adopted to evaluate the effects of synthesis variables, such as reaction time (3–9 h), temperature (25–65 °C), enzyme amount (15–45%) and substrate molar ratio of lauric acid to propylene glycol (1:1 to 3:1), on the percentage molar conversion to propylene glycol monolaurate. Results showed that reaction temperature and reaction time were the most important parameters and enzyme amount had less effect on percent molar conversion. Based on ridge max analysis, optimum synthesis conditions were: reaction time 7.6 h, temperature 37.6 °C, enzyme amount 37.1% and substrate molar ratio 2.6:1 with 100% molar conversion in this study. An actual experimental value of 96% molar conversion was obtained.

Effect of vehicles and enhancers on the in vitro permeation of melatonin through hairless mouse skin.

The effects of vehicles and penetration enhancers on the in vitro permeation of melatonin through dorsal hairless mouse skin were investigated. Propylene glycol laurate (PGL), isopropyl myristate (IPM), propylene glycol monolaurate (PGML) and propylene glycol monocaprylate (PGMC) showed high permeation fluxes and PGL, PGML and PGMC decreased lag time significantly. In both of the binary co-solvents of diethylene glycol monoethyl ether (DGME)-PGL and DGME-IPM, the highest fluxes were achieved at 20% of DGME, which were 10.5 +/- 1.5 and 9.1 +/- 2.4 microg/cm2/h, respectively. Among fatty acids used as a permeation enhancer, capric acid and oleic acid in DGME-PGL (80:20 v/v) showed relatively high enhancing effects. Capric acid also shortened the lag time of melatonin from 2.4 +/- 0.7 to 1.3 +/- 0.2 h. Oleic acid, however, failed to shorten the lag time. Therefore, for effective solution formulations in terms of permeation flux and lag time, capric acid-containing DGME-PGL (80:20 v/v) could be used to enhance the skin permeation of melatonin.

Effect of vehicles and penetration enhancers on the in vitro percutaneous absorption of tenoxicam through hairless mouse skin

The effects of vehicles and penetration enhancers on the in vitro permeation of tenoxicam from saturated solutions through dorsal hairless mouse skin were investigated. Various types of vehicles, including ester-, alcohol-, and ether-types and their mixtures, were used as vehicles, and then a series of fatty acids and amines were employed as enhancers, respectively. Even though the fluxes of tenoxicam from saturated pure vehicles were generally low (0.1–1.1 μg/cm 2 per h), the skin permeability of tenoxicam was significantly increased by the combination of diethylene glycol monoethyl ether (DGME) and propylene glycol monolaurate (PGML) or propylene glycol monocaprylate (PGMC); the highest fluxes were achieved at 40% of DGME in both of the two cosolvents. The marked synergistic enhancement was also obtained by using propylene glycol (PG)–oleyl alcohol (OAl) cosolvent. The greatest flux was attained by the addition of unsaturated fatty acids at 3% concentration to PG. But saturated fatty acids failed to show a significant enhancing effect. The enhancement factors with the addition of oleic acid (OA) or linoleic acid (LOA) to PG were 348 and 238, respectively. Tromethamine (TM) showed an enhancing effect by the increased solubility; however, triethanolamine (TEA) did not show a significant enhancing effect. Rather, it decreased the fluxes of tenoxicam when added to PG with fatty acids. The above results indicate that the combinations of lipophilic vehicles like OA, LOA or OAl and hydrophilic vehicles like PG can be used for enhancing the skin permeation of tenoxicam.

In vitro percutaneous absorption of tenoxicam from pressure-sensitive adhesive matrices across the hairless mouse skin.

To investigate the feasibility of developing a new tenoxicam plaster, the effects of vehicles and penetration enhancers on the in vitro permeation of tenoxicam from a pressure-sensitive adhesive (PSA) matrices across the dorsal hairless mouse skin were studied. Vehicles employed in this study were propylene glycol (PG)-oleyl alcohol (OAI), PG-oleic acid (OA), and diethylene glycol monoethyl ether (DGME)-propylene glycol monolaurate (PGML) cosolvents with/without fatty acids. In this study, amines such as triethanolamine (TEA) and tromethamine (TM) were additionally used as a solubilizer. Among PSAs used, Duro-Tak 87-2510 showed much higher release rate than either Duro-Tak 87-2100 or Duro-Tak 87-2196. The relatively high flux rate was obtained with the formulation of DGME-PGML (40:60, v/v) with 3% OA and 5% TM, and the flux increased as a function of the dose; the initial flux up to 12 h was 4.98 +/- 1.38 microg/cm2/h at the tenoxicam dose of 50 mg/70 cm2. This flux was much higher than that of a commercial piroxicam patch (Trast) (1.24 +/- 0.73 microg/ cm2/hr) with almost only one-third that of the commercial patch. Therefore, these observations indicated that these composition of tenoxicam plaster may be practically applicable.

Fluorescence spectroscopic investigation of effect of excipients on epidermal barrier and transdermal systems.

Excipients are often used in transdermal formulations to overcome the formidable barrier offered by the epidermis in order to achieve the target flux. In this study we describe the use of frequency-domain fluorescence spectroscopy to characterize the effect of two commonly used excipients, propyleneglycol monolaurate (PGML) and oleic acid on stratum corneum and in a silicone-based transdermal delivery system. Fluorescence lifetime and limiting anisotropy for the probe 1,6-diphenyl-1,3,5-hexatriene in isolated human epidermis were measured as a function of formulation treatment. The drop in lifetime ranged from 0.5 to 2.3 ns, indicative of an increased dielectric constant of the lipophilic barrier exposed to all formulations. This increase is due to increased partitioning of the polar excipients from the delivery system into the stratum corneum. The limiting anisotropy showed a drop of 0.1 in the case of the epidermis exposed to oleic acid formulation and not the PGML formulations, indicative of the different modes of action for these two excipients. The fluorescence data suggested fluidization of the silicone matrix by both oleic acid and PGML. The dynamic fluorescence measurements described in this study are a powerful way to screen formulations while gaining valuable mechanistic insight into the mode of flux enhancement in transdermal formulations.

Effect of PGML excipient mixture in a transdermal system on the in vitro transport of estradiol across skin.

To measure the effect of a combination of excipients from a silicone based pressure sensitive adhesive (PSA) on drug transport across skin. Partitioning of propylene glycol monolaurate (PG-ML) from silicone PSA and a solution formulation into the stratum corneum (SC) was measured using radiolabeled PG-ML. Transport of a model drug, estradiol, as well as PG-ML across skin were measured in vitro using heat separated epidermis from human cadaver skin. The PG-ML partitioning into SC showed a saturation and was independent of the formulation. The local dielectric of the lipid bilayers of the SC showed an increase as a result of PG-ML uptake, as determined by the decrease in fluorescence lifetime of a lipophilic probe incorporated into the SC. However, there was no alteration of lipid packing in SC. The PG-ML and estradiol transport showed a good correlation over 3 days, suggesting that the two species are co-transported across the epidermis.