Enhanced stability and skin permeation of ibuprofen-loaded solid lipid nanoparticles based binary solid lipid matrix: Effect of surfactant and lipid compositions.

Hypothesis: The type of emulsifier selected has an impact on the physicochemical properties of solid lipid nanoparticles (SLNs). This study was designed to compare the effects of emulsifiers on the physicochemical properties and in vitro skin performance of SLNs prepared from a binary mixture of Softisan® 378 (S378) and cetyl palmitate (CP) to those of SLNs prepared from only CP and S378. Experiments: SLNs were prepared from CP, S378, or a binary mixture of CP and S378 (1:1 w/w) as the lipid phase and stabilized with Tego®Care 450 (TG450) or poloxamer 188 (P188) containing 1.0% w/w ibuprofen loading. The physicochemical properties including the particle size, polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (E.E.), crystallinity (%CI), and polymorphism were determined after production and after storage for 180 days under different conditions. In addition, in vitro drug release and permeation through human skin was studied after production and storage at room temperature for 180 days. Finding: The particle sizes of ibuprofen-loaded SLNs (IBSLNs) stabilized with P188 (IBSLN-P188) were smaller than those of SLNs stabilized with TG450 (IBSLN-TG450) (p < 0.05). After 180 days, the particle sizes of the IBSLNs were slightly increased compared to those at the initial time but were <250 nm. The IBSLN-TG450 sample showed a higher %CI than IBSLN-P188 prepared with similar propotions of CP and S378, and ibuprofen crystals were observed in the IBSLN1-TG450 sample after storage at 4 °C for 180 days. Based on the result of the in vitro release study and the in vitro skin permeation test, the addition of S378 into the CP-matrix modified ibuprofen release and skin permeation both permeated ibuprofen through the epidermis and retained ibuprofen in the epidermis. In addition, the storage time affected the release and skin permeation of ibuprofen from the SLNs, which depended on the composition of the IBSLNs.

Influence of the emulsifier on nanostructure and clinical application of liquid crystalline emulsions.

Liquid crystals are appealing in pharmaceutical and cosmetic fields due to their unique structures that combine the properties of both liquid and solid states. Forming an emulsion into liquid crystals can be affected by a number of factors, including the emulsion composition and temperature. Changing the types and concentrations of surfactants could be another factor that affects liquid crystals. Currently, most liquid crystal research focuses on the nanostructure of liquid crystal systems without evaluating the efficacy of liquid crystals clinically. In this study, liquid crystalline emulsions made from camellia seed oil with four different surfactants (Olivem 1000, Polyaquol-2W, Nikkomulese LC, and Lecinol S-10 with Tween 80) were created. The liquid crystal emulsions were formulated in the form of oil-in-water (o/w) emulsions with Camellia oleifera seed oil serving as the main ingredient in the oil phase (10% w/w). All formulations exhibited liquid crystal characteristics with lamellar structures as determined by the polarized light microscopy and small-angle X-ray scattering with supporting data of the nanostructure from wide-angle X-ray scattering and differential scanning calorimetry (DSC). They all showed good stability under normal (room temperature) and accelerated conditions (4 °C and 40 °C) in long-term storage (6 months). Using the reconstructed human epidermis as a skin model, all formulations did not cause skin irritation. In the clinical trial, all formulations were able to reduce transepidermal water loss (TEWL) and increase skin hydration immediately after application. This lasted at least 10 h. All formulations showed distinct Maltese crosses under the polarized light microscope with a positive result for liquid crystals in wide angle X-ray scattering (WAXS) and small angle X-ray scattering (SAXS) methods. Moreover, among all formulations tested, Formulation D, which contained Lecinol S-10 and Tween 80 as emulsifiers, showed the most robust interaction between the surfactant and water molecules in the lamellar structure under DSC. The formulation was stable in long-term normal and accelerated conditions. Above all, Formulation D, which was formulated with Lecinol S-10 with Tween 80, had the best clinical result, was nonirritating to the skin, and can be used as a cream base in the pharmaceutical and cosmeceutical sectors.

Preliminary Bioequivalence of an Oral Pimobendan Solution Formulation with Reference Solution Formulation in Beagle Dogs.

Oral capsule and tablet formulations of pimobendan are widely used but may present difficulties for accurately dosing small patients. This study aimed to compare the pharmacokinetic (PK) characteristics, bioequivalence, and cardiovascular effects of a custom-made oral pimobendan solution (PS) formulation compared to a reference solution (RS) formulation in conscious, healthy dogs. A randomized crossover design was performed on dogs that received RS and PS formulations at a dose of 0.3 mg/kg. Blood samples were collected at 0, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, and 24 h after oral administration for PK analysis; bioequivalence was also calculated. Echocardiography was also performed to assess the cardiovascular effects. The results revealed that the plasma concentrations of pimobendan and o-desmethyl-pimobendan (active metabolite) in the case of both formulations were comparable. The relative ratios of geometric mean concentrations for all significant parameters of PK were within a range of 80-125%, indicating bioequivalence. In addition, both formulations increased cardiac contraction significantly when compared with the baseline, and no differences in cardiac contractility were detected between the formulations. The PS formulation can be used as alternative to the RS formulation for the management of congestive heart disease because of the bioequivalence between the two formulations.

Passive and iontophoretic transport of pramipexole dihydrochloride across human skin microchannels created by microneedles in vitro.

Skin microchannels (MCs) created by microneedles (MNs) provide a promising route for enhancing transdermal drug delivery. This study investigated passive and iontophoretic transport of pramipexole dihydrochloride (PXCl) across skin MCs created by polymer MN patches made of 1:2 polymethyl-vinyl-ether-co-maleic acid (PMVEMA) to polyvinyl alcohol (PVA) ratio. Permeation studies were performed in vitro using excised human skin under the conditions of (i) "poke-and-patch" and "poke-and-release" delivery approaches with varying concentration of PXCl in the formulations, (ii) drug-loaded dissolving MN (DMN) and hydrogel-forming MN (HGMN) type patches and (iii) combination of MNs and iontophoresis. The results showed that DMN patch greatly enhanced transdermal delivery of PXCl for both "poke-and-patch" and "poke-and-release" approaches as compared with the conventional delivery method. PXCl flux mainly resulted from the contribution of MC pathway created in skin and increased with increasing drug amounts in the formulations. Compared to DMN patch, HGMN patch provided more linear sustained drug delivery over 72 h. Electromigration was the main mechanism of PXCl iontophoresis through MCs and flux enhancement was found to be larger for HGMN patch than DMN patch. These results demonstrated the potential application of MN patches individually or combined with iontophoresis as an alternative method for PXCl administration.

Effect of Pulsed Direct Current on Iontophoretic Delivery of Pramipexole across Human Epidermal Membrane In Vitro.

PURPOSE: Pulsed direct current (PDC) iontophoresis, by allowing skin depolarization, was suggested to provide more efficient ion transport, but the extent of its enhancement effect was unclear. PDC could also offer electric-customized drug delivery. This study examined the effect of PDC iontophoresis on transdermal delivery of pramipexole dihydrochloride (PXCl). METHODS: Iontophoretic delivery of PXCl across human epidermal membrane from pH 7.0 solution was conducted in vitro using continuous direct current (DC) and 6- and 12-cycle PDC iontophoresis (0.5 mA/cm2 and total applied duration of 6 h). Different parameters of PDC iontophoresis were studied, including current density (0.1, 0.2 and 0.5 mA/cm2) and on-off current dosing pattern (1 h/3 h, 0.5 h/3.5 h, and 0.2 h/3.8 h). RESULTS: Both 6- and 12-cycle PDC iontophoresis protocols provided modulation of the permeation profile but delivered smaller amounts of PXCl (396 and 400 µg/cm2, respectively) as compared with continuous DC iontophoresis (482 µg/cm2) at 24 h after 0.5 mA/cm2 and 180 mA/cm2 × min current dose application. Increasing applied current density from 0.1 to 0.5 mA/cm2 increased the PDC iontophoretic flux of PXCl linearly from 5.3 to 14.6 µg/cm2·h (R2 = 0.887). Varying the current level and duration but at the same applied current dose (36 mA/cm2 × min), the total amount of PXCl delivered by PDC iontophoresis at 24 h was independent of the on-off dosing pattern studied (114-128 µg/cm2). CONCLUSIONS: The results indicate that PDC iontophoresis can benefit transdermal delivery of PXCl in terms of controlling its permeation but does not enhance iontophoretic transport compared to continuous DC iontophoresis under the conditions studied.

Effect of pH on Iontophoretic Transport of Pramipexole Dihydrochloride across Human Epidermal Membrane.

PURPOSE: Drugs with higher molecular charges generally show higher flux enhancement when electromigration is the main mechanism in transdermal iontophoresis. This study evaluated the effect of decreasing the formulation pH to increase the positive charges of pramipexole dihydrochloride (PXCl) on its iontophoretic transport across skin. METHODS: In vitro transdermal iontophoresis of PXCl in buffer solution isotonized with either sodium chloride or mannitol were performed in a pH range of 3.0-7.0. Experiments of iontophoresis under symmetric condition with respect to donor and receiver pH and passive transport of the drugs after pretreatment with iontophoresis were conducted to investigate the transport mechanism involved. RESULTS: Iontophoretic permeation of PXCl was pH-dependent in drug solution isotonized with mannitol. The iontophoretic flux of PXCl with valence z = +2 at pH 3.0 was half of that of PXCl with z = +1 at pH 7.0. The results suggest that the decrease in PXCl delivery at higher valence at pH 3 was mainly due to pH-dependent selectivity of PX ion permeation across the skin and not electroosmosis. CONCLUSIONS: Skin permselectivity is a significant factor for iontophoretic transport of PXCl, and reducing formulation pH to increase the positive charges on PX ions did not enhance PXCl delivery.

Formulation and Pharmaceutical Evaluation of Extemporaneous α-arbutin Creams for the Treatment of Melasma.

Concentrated 7% w/w a-arbutin cream was formulated and evaluated using O/W and W/O emulsion bases as an extemporaneous preparation for melasma treatment. Cream bases were formulated with two pH values, 4.0 and 5.5, using a hot process. The stability of the creams was studied for 60 days under three storage conditions (i.e., 2°C to 8°C, 30°C, 40°C). Cream characteristics and all aspects of product stability including physical, chemical, and microbial were investigated. Stability was defined as no dramatic change in color, viscosity, pH, and no visible microbial growth. For stability, at least 90% of the initial a-arbutin concentration quantified by stability-indicating high-performance liquid chromatography must be obtained. It was found that pH had no influence on the a-arbutin or formulations' stability. All formulations had a-arbutin remaining higher than 90% (approximately 92%) after being stored for 60 days in all storage conditions with no significant changes in pH or viscosity. All samples complied with the microbial limits test for nonsterile pharmaceutical preparation for cutaneous products. However, a color change was detected in O/W and W/O emulsions, especially at 40°C storage condition within 28 and 14 days, respectively. Drug crystals were observed in W/O emulsion stored at 2°C to 8°C. Concerning the in vitro drug release, a-arbutin was released from O/W emulsion but not from W/O emulsion. From the above results, the O/W emulsion that was developed in this study can be used as a cream base for concentrated a-arbutin as an extemporaneous preparation. The developed a-arbutin cream prepared using O/W emulsions can be used as an extemporaneous preparation with a beyond-use date of 60 days when stored at room temperature (30°C) and in the refrigerator (2°C to 8°C).

Correction: Chantasart et al. "Structure Enhancement Relationship of Chemical Penetration Enhancers in Drug Transport across the Stratum Corneum" Pharmaceutics 2012, 4, 71-92.

The authors wish to make the following corrections to their paper [...].

Skin Permeation Enhancement in Aqueous Solution: Correlation With Equilibrium Enhancer Concentration and Octanol/Water Partition Coefficient.

The effectiveness of skin penetration enhancers and the enhancer concentration required for effective skin permeation enhancement are difficult to predict. A comprehensive quantitative structure-enhancement relationship of chemical penetration enhancers for skin permeation is not currently available. The present study (a) investigated the relationship between skin permeation enhancement and chemical enhancer concentration and (b) examined a simple quantitative structure-enhancement relationship for predicting skin permeation enhancement to guide enhancer formulation development. In the present analysis, data from previous skin permeation studies that used the symmetric/equilibrium configuration and skin parallel pathway model were summarized to determine the relationship between enhancement factor and enhancer concentration. Under the equilibrium conditions, semilogarithmic linear relationships between enhancement factor (E) and enhancer aqueous concentration (C) were observed and an enhancer potency parameter (α) was defined. A correlation between the potency parameter α and enhancer octanol/water partition coefficient (Koct) was obtained. The enhancement factor relationship was derived: Log E = 0.32 ∙ C ∙ Koct. The results suggest that a "threshold" of (C ∙ Koct) > 0.5 M is required to induce effective skin permeation enhancement under these conditions. Consistent with the analyses in previous studies, the data suggest that octanol represents the skin barrier microenvironment for the penetration enhancers.

ß-Cyclodextrin-based ternary complexes of haloperidol and organic acids: the effect of organic acids on the drug solubility enhancement.

Haloperidol (HALO) is a weak base with very low aqueous solubility that is used as an antipsychotic drug. This study aimed to improve its solubility by forming HALO/ß-cyclodextrin (ß-CD)-based ternary complexes with organic acids. The solubility of HALO/ß-CD binary and HALO/ß-CD/organic acid ternary complexes in different media (i.e. citrate buffer pH 3 and 6) was explored. The stoichiometric ratio between the drug and ß-CD was 1:1 in all complexes formed. The solubility of HALO/ß-CD binary complexes significantly increased in citrate buffer pH 3 compared with citrate buffer pH 6. For the ternary complexes, HALO/ß-CD/tartaric acid and HALO/ß-CD/lactic acid in citrate buffer pH 3 increased HALO solubility compared with HALO/ß-CD/succinic acid due to their higher unionized species. The highest stability constant and complexation efficiency values in citrate buffer pH 3 were shown by the ternary complexes with lactic acid followed by tartaric acid and succinic acid, respectively. Results indicated that lactic acid provided the greatest binding strength and solubilization efficiency for the complex.

Fabrication and evaluation of Eudragit® polymeric films for transdermal delivery of piroxicam.

The aims of this work were to develop and characterize the prolonged release piroxicam transdermal patch as a prototype to substitute oral formulations, to reduce side effects and improve patient compliance. The patches were composed of film formers (Eudragit®) as a matrix backbone, with PVC as a backing membrane and PEG200 used as a plasticizer. Results from X-ray diffraction patterns and Fourier transform-infrared spectroscopy indicated that loading piroxicam into films changed the drug crystallinity from needle to an amorphous or dissolved form. Piroxicam films were prepared using Eudragit® RL100 and Eudragit® RS100 as film formers at various ratios from 1:0 to 1:3. Films prepared solely by Eudragit® RL100 showed the toughest and softest film, while other formulations containing Eudragit® RS100 were hard and brittle. Drug release kinetic data from the films fitted with the Higuchi model, and the piroxicam release mechanism was diffusion controlled. Among all formulation tested, Eudragit® RL100 films showed the highest drug release rate and the highest drug permeation flux across human epidermal membrane. Increasing drug loading led to an increase in drug release rate. Eudragit® can be used as a film former for the fabrication of piroxicam films.

Enhanced transmucosal delivery of itraconazole by thiolated d-ɑ-tocopheryl poly(ethylene glycol) 1000 succinate micelles for the treatment of Candida albicans.

This study aimed to investigate the transmucosal delivery of itraconazole (ITZ) by thiolated d-ɑ-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS-Cys) micelles. TPGS-Cys polymer was successfully synthesized by the simple coupling between carboxyl-activated TPGS and Cys as confirmed by NMR and FTIR techniques. Afterwards, the TPGS/TPGS-Cys micelles were prepared using the blend of TPGS and TPGS-Cys at 10:0, 7:3, 5:5, 3:7 and 0:10mass ratios. All micelles had the size ranged from 8 to 10nm with narrow size distribution and showed spherical in shape. The surface of the 10:0 TPGS micelles exhibited negatively charge while, the TPGS-Cys micelles demonstrated the slightly positive surface charge. The critical micelle concentration, loading capacity and release profiles of TPGS/TPGS-Cys micelles were comparable to the TPGS micelles. The release of ITZ from all micelles was biphasic and sustained in simulated saliva fluid over 48h. The 3:7 and 0:10 TPGS/TPGS-Cys micelles had a good mucoadhesive property. Meanwhile, only 0:10 TPGS/TPGS-Cys micelles enhanced the permeability through buccal mucosa and potentiated the antifungal activity of ITZ against Candida albicans by at least 1.35 folds as compared to ITZ alone. Therefore, this formulation can be further developed for the transmucosal delivery of ITZ for the treatment of C. albicans.

Effect of binary solid lipid matrix of wax and triglyceride on lipid crystallinity, drug-lipid interaction and drug release of ibuprofen-loaded solid lipid nanoparticles (SLN) for dermal delivery.

HYPOTHESIS: The physicochemical properties of solid lipid nanoparticles (SLN) depend on lipid compositions. An addition of secondary solid complex triglycerides (Softisan 378; S378) into solid wax (cetyl palmitate; CP) is expected to influence the properties of obtained SLN compared to SLN prepared from sole CP. EXPERIMENTS: Ibuprofen-loaded SLN (IBSLN-TG) composed of different ratios of CP and S378 were prepared and evaluated in term of size, zeta potential (ZP), entrapment efficiency (E.E.), crystallinity, lipid-drug interaction and in vitro drug release. FINDINGS: After production, all developed IBSLN-TG prepared from different ratios of CP and S378 had the particle size in the nanometer range (180-200nm) with the ZP values of higher than |-40mV| and possessed approximately 100% E.E. The release of IBSLN-TG demonstrated the biphasic pattern with a fast release followed by sustained release, which was fitted to Higuchi's kinetics. The addition of S378 into CP-matrix led to a slight decrease in particle size and surface charge, and distortion of CP crystallization. The results from 1H-NMR indicated the formation of tiny liquid S378 nanocompartments within CP-matrix. The localization of ibuprofen in the S378 nanocompartments and the interaction between ibuprofen and S378 had an impact on the release profiles of IBSLN-TG depending on the ratios of CP and S378.

Investigation of pH Influence on Skin Permeation Behavior of Weak Acids Using Nonsteroidal Anti-Inflammatory Drugs.

As a continuing effort to understand the skin permeation behavior of weak acids and bases, the objectives of the present study were to evaluate skin permeation of nonsteroidal anti-inflammatory drugs (NSAIDs) under the influence of pH, investigate the mechanism of pH effect, and examine a previous hypothesis that the effective skin pH for drug permeation is different from donor solution pH. In vitro permeability experiments were performed in side-by-side diffusion cells with diclofenac, ibuprofen, flurbiprofen, ketoprofen, and naproxen and human skin. The donor solution pH significantly affected skin permeation of NSAIDs, whereas no effect of the receiver pH was observed. Similar to previous observations, the apparent permeability coefficient versus donor solution pH relationships deviated from the predictions (fractions of unionized NSAIDs) according to the acid/base theory. The influences of the viable epidermis barrier, polar pathway transport, ion permeation across skin, and effective skin pH were investigated. The effective pH values for skin permeation determined using the NSAIDs (weak acids) in this study were different from those obtained previously with a weak base at the same donor solution pH conditions, suggesting that the observed permeability-pH relationships could not be explained solely by possible pH differences between skin and donor solution.

Evaluation of ß-blocker gel and effect of dosing volume for topical delivery.

Although topical administration of ß-blockers is desired because of the improved therapeutic efficacy and reduced systemic adverse effects compared with systemic administration in the treatment of infantile hemangioma, the permeation of ß-blockers across skin under finite dose conditions has not been systematically studied and an effective topical ß-blocker formulation for skin application is not available. The present study evaluated the permeation of ß-blockers propranolol, betaxolol, and timolol across human epidermal membrane (HEM) from a topical gel in Franz diffusion cells in vitro under various dosing conditions. The effects of occlusion and dosing volume on percutaneous absorption of ß-blockers from the gel were studied. The permeation data were compared with those of finite dose diffusion theory. The results showed that skin permeation of ß-blockers generally could be enhanced two to three times by skin occlusion. The cumulative amounts of ß-blockers permeated across HEM increased with increasing dosing volume. An adequate fit was obtained between the theoretical curve and experimental permeation data, indicating that the experimental results of the gel are consistent with finite dose diffusion theory. In conclusion, the findings suggest the feasibility of using topical gels of ß-blockers for infantile hemangioma treatment and topical application with skin occlusion is preferred.

Investigation of pH Influence on Skin Permeation Behavior of Weak Acids Using Nonsteroidal Anti-Inflammatory Drugs.

As a continuing effort to understand the skin permeation behavior of weak acids and bases, the objectives of the present study were to evaluate skin permeation of nonsteroidal anti-inflammatory drugs (NSAIDs) under the influence of pH, investigate the mechanism of pH effect, and examine a previous hypothesis that the effective skin pH for drug permeation is different from donor solution pH. In vitro permeability experiments were performed in side-by-side diffusion cells with diclofenac, ibuprofen, flurbiprofen, ketoprofen, and naproxen and human skin. The donor solution pH significantly affected skin permeation of NSAIDs, whereas no effect of the receiver pH was observed. Similar to previous observations, the apparent permeability coefficient versus donor solution pH relationships deviated from the predictions (fractions of unionized NSAIDs) according to the acid/base theory. The influences of the viable epidermis barrier, polar pathway transport, ion permeation across skin, and effective skin pH were investigated. The effective pH values for skin permeation determined using the NSAIDs (weak acids) in this study were different from those obtained previously with a weak base at the same donor solution pH conditions, suggesting that the observed permeability-pH relationships could not be explained solely by possible pH differences between skin and donor solution. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3459-3470, 2015.

Development and characterization of lyophilized diazepam-loaded polymeric micelles.

Polymeric micelles were studied as delivery carriers of diazepam, a practically insoluble drug in water, for rectal administration. The diazepam-loaded polymeric micelles were developed by using poloxamer 407 (P407), poloxamer 188, and D-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS). Among the used polymers, TPGS resulted in polymeric micelles with good characteristics for encapsulation of diazepam which had the small particle size of 8-12 nm and narrow size distribution (PI 0.053-0.275). Additionally, 7.5% w/v of TPGS could entirely entrap the desired concentration of diazepam (5 mg/mL). To improve the physical stability upon lyophilization, an addition of P407 of 1% w/v prevented aggregation, increased physical stability, and maintained chemical stability of the lyophilized powders of diazepam-loaded polymeric micelles for 3 months storage at 4°C. The rate and amount of diazepam release from TPGS polymeric micelles mainly depended on the concentration of TPGS. The release data were fitted to Higuchi's model suggesting that the drug release mechanism was controlled by Fickian diffusion. In conclusion, 10% w/v TPGS and 1% w/v P407 were the optimum formulation of lyophilized diazepam-loaded polymeric micelles.

Evaluation of skin permeation of ß-blockers for topical drug delivery.

PURPOSE: ß-Blockers have recently become the main form of treatment of infantile hemangiomas. Due to the potential systemic adverse effects of ß-blockers, topical skin treatment of the drugs is preferred. However, the effect and mechanism of dosage form pH upon skin permeation of these weak bases is not well understood. To develop an effective topical skin delivery system for the ß-blockers, the present study evaluated skin permeation of ß-blockers propranolol, betaxolol, timolol, and atenolol. METHODS: Experiments were performed in side-by-side diffusion cells with human epidermal membrane (HEM) in vitro to determine the effect of donor solution pH upon the permeation of the ß-blockers across HEM. RESULTS: The apparent permeability coefficients of HEM for the ß-blockers increased with their lipophilicity, suggesting the HEM lipoidal pathway as the main permeation mechanism of the ß-blockers. The pH in the donor solution was a major factor influencing HEM permeation for the ß-blockers with a 2- to 4-fold increase in the permeability coefficient per pH unit increase. This permeability versus pH relationship was found to deviate from theoretical predictions, possibly due to the effective stratum corneum pH being different from the pH in the donor solution. CONCLUSIONS: The present results suggest the possibility of topical treatment of hemangioma using ß-blockers.

Structure Enhancement Relationship of Chemical Penetration Enhancers in Drug Transport across the Stratum Corneum.

The stratum corneum is a major barrier of drug penetration across the skin in transdermal delivery. For effective transdermal drug delivery, skin penetration enhancers are used to overcome this barrier. In the past decades, a number of research studies were conducted to understand the mechanisms of skin penetration enhancers and to develop a structure enhancement relationship. Such understanding allows effective prediction of the effects of skin penetration enhancers, assists topical and transdermal formulation development, and avoids extensive enhancer screening in the transdermal delivery industry. In the past two decades, several hypotheses on chemical enhancer-induced penetration enhancement for transport across the skin lipoidal pathway have been examined based on a systematic approach. Particularly, a hypothesis that skin penetration enhancement is directly related to the concentration of the enhancers in the stratum corneum lipid domain was examined. A direct relationship between skin penetration enhancer potency (based on enhancer aqueous concentration in the diffusion cell chamber) and enhancer n-octanol-water partition coefficient was also established. The nature of the microenvironment of the enhancer site of action in the stratum corneum lipid domain was found to be mimicked by n-octanol. The present paper reviews the work related to these hypotheses and the relationships between skin penetration enhancement and enhancer concentration in the drug delivery media and stratum corneum lipids.