Skin Penetration Enhancers Research Articles

Study of plasmonic nanoparticles interactions with skin layers by vibrational spectroscopy

The healing effects of silver and gold nanoparticles (AgNPs, AuNPs) are already known from ancient times. In addition considering to their antibacterial and anti-inflammatory effects speculations are being lead with respect to these nanoparticles (NPs) also about enhancement of skin penetration properties.In this work the interactions of pig skin (PS) layers and ointments with additions of AgNPs or AuNPs prepared by standard procedures and also by “green” synthesis in a different weight proportion by vibrational spectroscopy were studied. Spectra of untreated skin and skin treated by pure ointment were measured, as well as by ointment modified by vitamins without addition of NPs or with different proportion of NPs. Kinetics of interactions of modified ointments with skin was monitored during two hours with a five-minutes interval between each two consecutive measurements. The obtained series of spectra were analyzed by multivariate statistical methods namely Partial Least Squares (PLS), Principal Component Analysis (PCA) and Soft Independent Modelling of Class Analogy (SIMCA) which revealed observation of spectral changes in time-dependent spectra and variations of the peak intensity ratios. The study showed that the effects of quantity and type of NPs on skin penetration characteristics are evident.

Nanoparticle-Enabled Transdermal Drug Delivery Systems for Enhanced Dose Control and Tissue Targeting.

Transdermal drug delivery systems have been around for decades, and current technologies (e.g., patches, ointments, and creams) enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases.

Topical nano-delivery of 5-fluorouracil: Preparation and characterization of water-in-oil nanoemulsion

Purpose: To prepare and characterize a water-in-oil nanoemulsion of 5-fluorouracil (5FU) for enhanced skin penetration. Methods: Nanoemulsions of 5FU were prepared using Capyrol (propylene glycol monocaprylate). Transcutol (highly purified diethylene glycol monoethyl ether) and polyethylene glycol (PEG) 400 as oil, surfactant and co-surfactant, respectively. The optimized formulations were subjected to heating - cooling cycling, centrifugation and freeze - thaw cycling to assess their stability. Particle size distribution and zeta potential of the nanoemulsions were evaluated. Furthermore, in vitro and in vivo skin permeation studies were carried out on the formulations in a rat model. Skin irritation studies were also performed on rats to assess the irritation potential of the formulations. The 1 % w/v of Carbopol 934 gel loaded with 1 % 5FU was used as control (FU gel). Results: The results showed that the mean droplet size of the nanoemulsions was ~100 nm with a zeta potential of ± 15. Significant increase in permeability was also observed for the nanoemulsion formulations compared with control. The steady-state flux (Jss), enhancement ratio and permeability coefficient (Kp) for optimized nanoemulsion formulation were significantly (p < 0.05) higher than those of the conventional gel (control). Both in vitro and in vivo skin retention results indicate higher drug release from the nanoemulsion (292.45 μg/cm 2 ) than for control (121.42 μg/cm 2 ). Mean irritation index for the nanoemulsion was significantly lower than for control. Conclusion: The results suggest that a water-in-oil nanoemulsion is safe and can potentially be used to promote skin penetration of 5FU following topical application on the skin for the treatment of some skin diseases. Keywords: Nanoemulsion, Controlled release, 5-Fluorouracil, Skin penetration, Skin irritation

Transdermal skin patch based on reduced graphene oxide: A new approach for photothermal triggered permeation of ondansetron across porcine skin

The development of a skin-mounted patch capable of controlled transcutaneous delivery of therapeutics through thermal activation provides a unique solution for the controlled release of active principles over long-term periods. Here, we report on a flexible transdermal patch for photothermal triggered release of ondansetron (ODS), a commonly used drug for the treatment of chemotherapy-induced nausea and vomiting and used as model compound here. To achieve this, a dispersion of ODS-loaded reduced graphene oxide (rGO-ODS) nanosheets were deposited onto Kapton to produce a flexible polyimide-based patch. It is demonstrated that ODS loaded Kapton/rGO patches have a high drug delivery performance upon irradiation with a continuous laser beam at 980nm for 10min due to an induced photothermal heating effect. The ability of ODS impregnated Kapton/rGO patches as transdermal delivery scaffolds for ODS across the skin is in addition investigated using porcine ear skin as a model. We show that the cumulative quantity and flux of ODS passing the skin are highly depending on the laser power density used. At 5Wcm−2 irradiation, the ODS flux across pig skin was determined to be 1.6μgcm−2h−1 comparable to other approaches. The use of tween 20 as skin enhancer could significantly increase the ODS flux to 13.2μgcm−2h−1. While the skin penetration enhancement is comparable to that obtained using other well-known permeation enhancers, the actual superiority and interest of the proposed approach is that the Kapton/rGO photoactivatable skin patch can be loaded with any drugs and therapeutics of interest, making the approach extremely versatile. The on demand delivery of drugs upon local laser irradiation and the possibility to reload the interface with the drug makes this new drug administration route very appealing.

Co-delivery of curcumin and STAT3 siRNA using deformable cationic liposomes to treat skin cancer

Skin cancer is one of the most widely prevalent cancer types with over expression of multiple oncogenic signaling molecules including STAT3. Curcumin is a natural compound with effective anti-cancer properties. The objective of this work was to investigate the liposomal co-delivery of curcumin and STAT3 siRNA by non-invasive topical iontophoretic application to treat skin cancer. Curcumin was encapsulated in cationic liposomes and then complexed with STAT3 siRNA. The liposomal nanocomplex was characterized for particle size, zeta-potential, drug release and stability. Human epidermoid (A431) cancer cells were used to study the cell uptake, growth inhibition and apoptosis induction of curcumin-loaded liposome–siRNA complex. Topical iontophoresis was applied to study the skin penetration of nanocomplex in excised porcine skin model. Results showed that curcumin-loaded liposome–siRNA complex was rapidly taken up by cells preferentially through clathrin-mediated endocytosis pathway. The co-delivery of curcumin and STAT3 siRNA using liposomes resulted in significantly (p < .05) greater cancer cell growth inhibition and apoptosis events compared with neat curcumin and free STAT3 siRNA treatment. Furthermore, topical iontophoresis application enhanced skin penetration of nanocomplex to penetrate viable epidermis. In conclusion, cationic liposomal system can be developed for non-invasive iontophoretic co-delivery of curcumin and siRNA to treat skin cancer.

Lipase-Sensitive Transfersomes Based on Photosensitizer/Polymerizable Lipid Conjugate for Selective Antimicrobial Photodynamic Therapy of Acne.

Acne vulgaris is a common skin problem affecting nearly 90% of adolescents and its development is associated with a colonization of Propionibacterium acnes (P. acnes). Although antibiotics have commonly been used to treat acne, antibiotic resistance of P. acnes is an emerging issue to be solved. In this study, a new way of photodynamic acne therapy is developed using P. acnes lipase-sensitive transfersome (DSPE-PEG-Pheo A (DPP) transfersome). For enhanced selectivity and skin penetration efficiency, DPP transfersomes are prepared from 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000], pheophorbide A (Pheo A), cholesterol, and Tween-80. Incorporation of Tween-80 as an edge activator increases the deformability of DPP transfersomes, enhancing skin penetration efficiency to four times that of free Pheo A. The photoactivity of Pheo A quenched by DPP transfersomes is gradually recovered by selective cleavage of the ester linkage in DPP transfersomes by P. acnes lipases. In vitro P. acnes-specific photoactivity and subsequent selective antimicrobial effect exhibit a greater than 99% loss of P. acnes viability. In vivo antiacne therapeutic effect is confirmed by reduction of swelling volume and thickness of P. acnes-induced nude mice skin. These results demonstrate that DPP transfersome-mediated photodynamic therapy can be used as an alternative method to treat bacterial skin infections.

Poly[acrylonitrile-co-(N-vinyl pyrrolidone)] nanoparticles – Composition-dependent skin penetration enhancement of a dye probe and biocompatibility

Nanoparticles can improve topical drug delivery: size, surface properties and flexibility of polymer nanoparticles are defining its interaction with the skin. Only few studies have explored skin penetration for one series of structurally related polymer particles with systematic alteration of material composition. Here, a series of rigid poly[acrylonitrile-co-(N-vinyl pyrrolidone)] model nanoparticles stably loaded with Nile Red or Rhodamin B, respectively, was comprehensively studied for biocompatibility and functionality. Surface properties were altered by varying the molar content of hydrophilic NVP from 0 to 24.1% and particle size ranged from 35 to 244nm. Whereas irritancy and genotoxicity were not revealed, lipophilic and hydrophilic nanoparticles taken up by keratinocytes affected cell viability. Skin absorption of the particles into viable skin ex vivo was studied using Nile Red as fluorescent probe. Whilst an intact stratum corneum efficiently prevented penetration, almost complete removal of the horny layer allowed nanoparticles of smaller size and hydrophilic particles to penetrate into viable epidermis and dermis.Hence, systematic variations of nanoparticle properties allows gaining insights into critical criteria for biocompatibility and functionality of novel nanocarriers for topical drug delivery and risks associated with environmental exposure.

Correlation between the chemical composition of thermoresponsive nanogels and their interaction with the skin barrier

In this paper we present a comprehensive study for the ability of thermoresponsive nanogels (tNG) to act as cutaneous penetration enhancers. Given the unique properties of such molecular architectures with regard to their chemical composition and thermoresponsive properties, we propose a particular mode of penetration enhancement mechanism, i.e. hydration of the stratum corneum. Different tNG were fabricated using dendritic polyglycerol as a multifunctional crosslinker and three different kinds of thermoresponsive polymers as linear counterpart: poly(N-isopropylacrylamide) (pNIPAM), p(di(ethylene glycol) methyl ether methacrylate - co - oligo ethylene glycol methacrylate) (DEGMA-co-OEGMA475), and poly(glycidyl methyl ether - co - ethyl glycidyl ether) (tPG). Excised human skin was investigated by means of fluorescence microscopy, which enabled the detection of significant increment in the penetration of tNG as well as the encapsulated fluorescein. The morphology of the treated skin samples was thoroughly investigated by transmission electron microscopy and stimulated Raman spectromicroscopy. We found that tNG can perturbate the organization of both proteins and lipids in the skin barrier, which was attributed to tNG hydration effects. Interestingly, different drug delivery properties were detected and the ability of each investigated tNG to enhance skin penetration correlated well with the degree of induced stratum corneum hydration. The differences in the penetration enhancements could be attributed to the chemical structures of the nanogels used in this study. The most effective stratum corneum hydration was detected for nanogels having additional or more exposed polyether structure in their chemical composition.

Psoralen loaded liposomal nanocarriers for improved skin penetration and efficacy of topical PUVA in psoriasis

Psoralen in combination with ultraviolet A radiation (PUVA) is an FDA recommended therapy for clinical application in the management of severe recalcitrant psoriasis. Psoralen acts by intercalation of DNA and upon exposure to UV-A, it forms monoadducts which in turn induce apoptosis. Poor skin deposition, weak percutaneous permeability of psoralen and adverse effects of severe burning, blisters, pigmentation associated with conventional topical psoralen vehicles hinders the therapeutic efficacy and safety of topical PUVA. The aim of the present study is to formulate psoralen loaded liposomal nanocarriers for enhanced skin penetration, safety and efficacy of topical PUVA in psoriasis. Two different liposomal compositions i.e., cationic liposomes composed of DC-Chol, cholesterol and anionic liposomes composed of egg lecithin, cholesterol, tetramyristoyl cardiolipin were prepared for the topical delivery of psoralen. Liposomal carriers were characterized with respect to size, zeta potential, entrapment efficiency, stability, in vitro drug release and in vivo studies. Both liposomes were prepared with particle size of nearly 100nm. Zeta potential and entrapment efficiency of cationic liposomes were +25.8mV, 75.12% and anionic liposomes were −28.5mV, 60.08% respectively. Liposomal dermal distribution demonstrated higher penetration of both liposomal carriers over solution. Similarly, skin permeation study indicated 5 fold increase in permeation of psoralen with liposomal carriers. Topical application of psoralen liposomal gels on imiquimod induced psoriatic plaque model reduced the symptoms of psoriasis and levels of key psoriatic cytokines such as tumor necrosis factor-α, IL-17 and IL-22. In conclusion, the developed liposomal carriers of psoralen were found to be promising and can find application for optimal safety and efficacy of topical PUVA in psoriasis.

Cyclic Dipeptide Shuttles as a Novel Skin Penetration Enhancement Approach: Preliminary Evaluation with Diclofenac.

This study demonstrates the effectiveness of a peptide shuttle in delivering diclofenac into and through human epidermis. Diclofenac was conjugated to a novel phenylalanyl-N-methyl-naphthalenylalanine-derived diketopiperazine (DKP) shuttle and to TAT (a classical cell penetrating peptide), and topically applied to human epidermis in vitro. DKP and TAT effectively permeated into and through human epidermis. When conjugated to diclofenac, both DKP and TAT enhanced delivery into and through human epidermis, though DKP was significantly more effective. Penetration of diclofenac through human epidermis (to receptor) was increased by conjugation to the peptide shuttle and cell penetrating peptide with enhancement of 6x by DKP-diclofenac and 3x by TAT-diclofenac. In addition, the amount of diclofenac retained within the epidermis was significantly increased by peptide conjugation. COX-2 inhibition activity of diclofenac was retained when conjugated to DKP. Our study suggests that the peptide shuttle approach may offer a new strategy for targeted delivery of small therapeutic and diagnostic molecules to the skin.

Microemulsion and Microemulsion-Based Gels for Topical Antifungal Therapy with Phytochemicals.

Skin fungal infections are regular injuries suffered by people living in tropical areas. Most common pathogens are Trichophyton, Microsporum and Epidermophyton which can cause skin lesions in many parts of body. Topical antifungal phytochemicals are commonly used to avoid systemic adverse events and are more convenient for patient application than those administered by other routes. However, the effectiveness of topical treatments in eradicating fungal infection is more limited since the stratum corneum acts as the skin barrier, resulting in long treatment duration and low patient's compliance. The goal of this work is to identify optimized drug delivery systems to improve topic clinical efficacy. Microemulsions i.e. liquid dispersions of oil and water stabilized with an interfacial film of surfactant are well known drug delivery systems. A thickening agent may be included to form microemulsion-based gels to increase skin adhesion. Microemulsions and microemulsion-based gels can be loaded with several hydrophilic and lipophilic drugs because they are composed of both water and oil phases. Microemulsions and microemulsion-based gels can also be used for the delivery of many drugs including antifungal drugs through stratum corneum due to their capacity to act as skin penetration enhancement. In addition to a comprehensive review of microemulsion and microemulsion-based gels as suitable carriers for skin delivery of various antifungal drugs, this review also aims to discuss the delivery of antifungal phytochemicals.

Solid lipid microparticles for enhanced dermal delivery of tetracycline HCl

Acne vulgaris (commonly called acne) is a most common skin disease during adolescence, afflicting more than 85% of teenagers. Topical tetracycline (Tc) is used for mild inflammatory acne and as an adjunct to systemic treatment in more severe forms. Solid lipid microparticles (SLMs) are useful tool for topical delivery because of their biodegradable, biocompatible and low toxic characteristic accompanying with excellent skin hydration, occlusiveness and controlled release properties. The purpose of this study was to prepare Tc-loaded SLMs were produced by the spray drying technique and characterized by scanning electron microscopy, powder X-ray diffractometry and differential scanning calorimetry. In vitro and ex vivo release characteristics of Tc through SLMs and control formulations (aqueous carbopol gel) were evaluated over 24h using a vertical Franz diffusion cell through cellulose acetate membranes and exercised rat skin, respectively. SLM formulations present high encapsulation values above 97% without significant different among formulations (p<0.05). The sustained release pattern of Tc through SLMs was illustrated by in vitro release study. The ex vivo drug skin permeation study revealed that Tc dermal deposition of optimum SLMs formulation was about 7 times that of the control formulations. The enhanced skin penetration and accumulation of Tc observed for Tc-loaded SLMs may increase the efficiency of acne therapy and decrease the associated Tc side effects.

Design of acid-responsive polymeric nanoparticles for 7,3&amp;#39;,4&amp;#39;-trihydroxyisoflavone topical administration

7,3′,4′-Trihydroxyisoflavone (734THIF) is a secondary metabolite of daidzein and has been recently found to possess antioxidant, melanin inhibition, and skin cancer chemopreventive activities. However, the poor water solubility of 734THIF impedes its absorption and skin penetration and, therefore, limits its pharmacological effects when applied topically to the skin. We seek to use the nanoprecipitation method to prepare optimal eudragit E100 (EE)–polyvinyl alcohol (PVA)-loaded 734THIF nanoparticles (734N) to improve its physicochemical properties and thereby increase its water solubility, skin penetration, and biological activities. EE–PVA-loaded 734THIF nanoparticles (734N) were prepared, and their morphology and particle size were evaluated using a particle size analyzer and by electron microscopy. The drug loading and encapsulation efficiencies and in vitro solubility were determined using high-performance liquid chromatography. Hydrogen-bond formation was evaluated by 1H-nuclear magnetic resonance and Fourier transform infrared spectroscopy, and crystalline-to-amorphous transformation was determined by differential scanning calorimetry and X-ray diffractometry. In vitro skin penetration was analyzed using fresh pig skin mounted on Franz diffusion cells, and cytotoxicity against human keratinocyte HaCaT cells was evaluated using the MTT assay. Antioxidant activity was determined by 2,2-diphenyl-1-picrylhydrazyl-free radical scavenging ability. EE–PVA-loaded 734THIF nanoparticles showed good drug loading and encapsulation efficiencies and were characterized by improved physicochemical properties, including reduction in particle size, amorphous transformation, and intermolecular hydrogen-bond formation. This is associated with increased water solubility and enhanced in vitro skin penetration, with no cytotoxicity toward HaCaT cells. In addition, 734THIF nanoparticles retained their antioxidant activity. In conclusion, 734THIF nanoparticles are characterized by improved physicochemical properties, increased water solubility, and enhanced skin penetration, and these may have potential use in the future as a topical delivery formulation for the treatment of skin diseases.

ABSORPTION PROMOTER: AN OVERVIEW

Dermal or transdermal route is more convenient route of administration than oral or parentral route of drug delivery. Outer most layer of the human skin is stratum corneum and it is main barrier for penetration of drug through skin and causes reduction in bioavailability of drug. Most of the drugs don’t have ability to cross the stratum corneum for that purpose skin penetration enhancers are developed to improve bioavailability of drug and increase range of drugs which can be given by transdermal or topical route. The present review article include need, different approaches of permeation or penetration enhancement contain drug vehicle based, chemical methods physical methods etc and list of patented penetration enhancers. Drug vehicle based method includes complexes, vesicles etc. Chemical method includes use of different chemicals like surfactants, terpenes, alcohol, urea etc. Physical method includes use of methods like microneedle, use of ultrasonic waves, electroporation etc.

Development of ibuprofen-loaded nanostructured lipid carrier-based gels: characterization and investigation of in vitro and in vivo penetration through the skin.

An ibuprofen-loaded nanostructured lipid carrier (IBU-NLC) was developed for enhanced skin penetration to improve the treatment of osteoarthritis and other musculoskeletal diseases. The mean particle size was 106 nm, with a spherical morphology, a smooth surface, and a zeta potential of −18.4 mV. X-ray diffraction studies revealed the amorphous state of the lipid matrix. Both Raman spectroscopy and Fourier transformation infrared analysis indicated no major shifts in the spectra of the formulations, which suggest rapid drug dissolution from the nanoparticles. The drug loading was 9.85%, and the entrapment efficiency was 98.51%. In vitro release of the NLC dispersion, in vitro permeation, and in vivo animal studies of IBU-NLC gel all confirmed that the permeation of IBU was significantly better than that of a reference after 6 hours. In conclusion, IBU-NLC gel is of great potential to enhance drug permeation through the skin and hence the efficacy of the treatment of chronic joint inflammation.

Flexosomes for transdermal delivery of meloxicam: characterization and antiinflammatory activity

The study aims to investigate the impact of flexosomes (FLs) on transdermal delivery of meloxicam (MLX). FLs are composed of phospholipid, Tween 80, and ethanol which were prepared by film hydration method. The prepared FLs were characterized for particle size, zeta potential, and entrapment efficiency (EE). Ex vivo skin penetration studies were perfomed, and the best formulation was further evaluated using in vivo antiinflammatory activity test. FLs were in nano-size scale carring negative charge and observed high EE% and enhanced skin penetration of MLX compared to conventional liposomes (CLs). The best formula was FL4 which was composedof phospholipid (10%), Tween 80 (1.5%), and ethanol (40%). FL4 showed 143.4 nm vesicle size, 84% EE, and 31-fold ex vivo permeation enhancement through skin compared to CLs. The antiinflammatory activity of FL4 gel showed significant increase compared to control. This study observed the effectiveness of using FLs as carriers for transdermal delivery of MLX.

Particulate Drug Delivery Systems in Dermal Applications

Copyright © 2016, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited. Physical form of drug delivery systems can be molecular or particulate. One of the limitations of molecular systems is loading of drug. In contrast, particulate delivery systems can carry a large number of drug molecules in one entity (1). A high potential for drug delivery has been attributed to particulate drug carriers that show promise to obtain systems with optimized drug loading, release properties and low toxicity. The principal factors involved in the localization and/or percutaneous absorption of substances are the properties of the drug, the tissue and the used vehicle. Alteration in chemical structures may lead to alteration in biological activity and there are limitations to the manipulation of the physicochemical properties of the active ingredients as well as the skin. Therefore, the best chance to alter the fate of the topically applied drug is to manipulate the physicochemical properties of the vehicle. Bangham first discovered liposomes in the early 1960s. They were envisioned as ideal drug delivery systems because of their high degree of biocompatibility. They were first shown to be of potential value for topical therapy by Mezei in 1980 (2) and entered the market in 1986 in the cosmetic formulation and the first therapeutically using lipid vesicles on the skin was commercialized shortly before 1990 and contained the antimycotic agent, econazole. During the past decades, there has been wide interest in exploring new techniques to increase drug absorption through skin. Intensive research led to the introduction and development of a new class of lipid vesicles, the highly deformable (elastic or ultraflexible) liposomes that have been termed Transfersomes®, which were first introduced by Cevc in the early 1990s. Elasticity is generated by incorporation of an edge activator in the lipid bilayer structure (3). Ethosome is another novel lipid carrier, developed by Touitou, and it is composed of phospholipid, ethanol and water. Ethanol allows for better solubility of many drugs and also confers a surface negative charge to the liposome which causes high encapsulation efficiency for a wide range of molecules. Ethanol is a well-known permeation enhancer and studies showed that permeation enhancement from ethosomes are much greater than ethanol alone. A synergistic mechanism is suggested between ethanol and vesicle and skin lipids (4). Lipid nanoparticles (solid lipid nanoparticles) were introduced in 1991 and made of solid pure lipids. Their enhanced skin penetration is due to an increase in skin hydration caused by occlusive film formed on skin surface (5). Nano-structured lipid carriers are next generation of lipid nanoparticles, composed of mixture of solid lipids with liquid lipids which leads to the production of an irregular structure resulting in improved drug maintenance and release properties (5). Lipid drug conjugates (LDC) are another class of lipid nanoparticles. Water soluble molecules are transferred to non-water soluble ones by covalent linkage with lipids and produce a lipophilic compound named LDC which has the ability to transform into nanoparticles by high-pressure homogenization (6). Research is still being done on a variety of aforementioned systems and among pharmaceutical companies active in this area, the following can be named: • IDEA AG (Munich, Germany) has focused on transfersomes and one of its products with the brand name of Diractin® containing ketoprofen has entered the Swiss pharmaceutical market. • NTT (novel therapeutic technology) in collaboration with University of Jerusalem in US is studying on ethosomes. • Pharmasol GmbH (Berlin, Germany) has focused on Nano lipid particles.

Formation of microemulsions for using as cosmeceutical delivery systems: effects of various components and characteristics of some formulations.

Microemulsions are interesting formulations for cosmeceutical applications due to their good appearance, high solubilization power, thermodynamic stability, and enhancement of skin penetration. In addition, they can spontaneously form when suitable types and amounts of components are simply mixed. In this study, the phase behavior of the nonionic systems with various parameters was studied by construction of phase diagrams using titration method. Natural oils, i.e., coconut oil (CO), rice bran oil (RBO), and palm oil (PO), were analyzed for their fatty acid compositions and then mixed with blends of nonionic surfactants (Tween80: Span80) and water or mixtures of water and a cosolvent, propylene glycol (PG), to find the microemulsion regions. Subsequently, some microemulsions were selected for physical characterization. The largest microemulsion regions which were obtained from CO, RBO, and PO covered the sizes of 11.65, 9.84, and 9.24%, respectively. The surfactant mixture at weight ratio of 1:1 was the most suitable for CO and PO, but for RBO, it was 2:1. PG could increase the microemulsion regions of PO from 9.24 to 15.33%, depending on PG concentrations. Hence, the sizes of the microemulsion regions were related to oil types, surfactant mixtures, and ratios between water and PG. The studied microemulsions were water-in-oil (w/o) type, and their internal droplets were in the nanosize range. They exhibited Newtonian flow behavior and their mean viscosity values were from 247.53 to 690.35cP which were correlated with the types and concentrations of the components in the formulations. In conclusion, natural oils could form w/o microemulsions with nonionic surfactants. The microemulsion formation and characteristics were related to many parameters of the components.

Synergistic Skin Penetration Enhancer and Nanoemulsion Formulations Promote the Human Epidermal Permeation of Caffeine and Naproxen

We examined the extent of skin permeation enhancement of the hydrophilic drug caffeine and lipophilic drug naproxen applied in nanoemulsions incorporating skin penetration enhancers. Infinite doses of fully characterized oil-in-water nanoemulsions containing the skin penetration enhancers oleic acid or eucalyptol as oil phases and caffeine (3%) or naproxen (2%) were applied to human epidermal membranes in Franz diffusion cells, along with aqueous control solutions. Caffeine and naproxen fluxes were determined over 8 h. Solute solubility in the formulations and in the stratum corneum (SC), as well as the uptake of product components into the SC were measured. The nanoemulsions significantly enhanced the skin penetration of caffeine and naproxen, compared to aqueous control solutions. Caffeine maximum flux enhancement was associated with a synergistic increase in both caffeine SC solubility and skin diffusivity, whereas a formulation-increased solubility in the SC was the dominant determinant for increased naproxen fluxes. Enhancements in SC solubility were related to the uptake of the formulation excipients containing the active compounds into the SC. Enhanced skin penetration in these systems is largely driven by uptake of formulation excipients containing the active compounds into the SC with impacts on SC solubility and diffusivity.

Development and Characterization of a Novel Vesicular System for Topical Delivery: An Opportunity for Dimethylsulfoxide

Current use of Dimethylsulfoxide (DMSO) in dermatology and in topical formulations is scarce despite its potential as a skin penetration enhancer and as a pharmacological active itself. The aim of this work is to develop and characterize a new type of semisolid formulation of Soybean Phosphatidylcholine (SPC) - DMSO deformable nanovesicles for topical application. Tretinoin is used in this work as a model substance. The formulation presents a non-newtonian pseudoplastic behaviour and a pH compatible with the skin. Stability-on-storage at different temperatures indicate an excellent physical and chemical stability and SPC-DMSO vesicles show high deformability when forced to pass through pores much smaller than their own size. These new nanovesicles show a high Tretinoin yield. Calorimetric analysis indicates a possible interaction between Tretinoin and DMSO in the lipid vesicle bilayer and vesicles formulation exhibit low cytotoxic effect below 1.25% SPC. Moreover, these vesicles once applied on the skin do not cause irritation. This study presents a new opportunity in dermal delivery for a controversial molecule such as DMSO. SPC-DMSO vesicles have plenty of advantages for topical application and future studies should confirm their superiority as drug carriers for topical application as well as for clinical evaluations in managing skin disorders.