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[Display omitted] • PNS ME penetrates skin capably, and promotes hair growth by comprehensive strategy. • D-panthenol as ME cosurfactant prevents skin from irritation caused by surfactants. • PNS ME has superior effects as well as safety due to plant-derived ingredients. • The multiple mechanisms of PNS ME include upregulation of β-catenin, VEGF and Ki67. The etiology of alopecia is so complex that current therapies with single-mechanism and attendant side-effects during long-term usage, are insufficient for treatment. Panax notoginseng saponins (PNS) is supposed to treat alopecia with multiple mechanisms, but difficult to penetrate skin efficiently due to water-solubility. Here, we designed water-in-oil microemulsion (PNS ME) using jojoba oil, fractioned coconut oil, RH 40 + Span 80 and cosurfactant D-panthenol, to help PNS penetrating the skin. Particularly, D-panthenol not only enlarges the microemulsion area, reduces the usage amounts of surfactants thus relieves skin irritation, but stimulates the migration of dermal papilla cells (DPCs), displaying cooperative effects on anti-alopecia. PNS ME penetrates through sebum-rich corneum via high-affinity lipid fusion, targets to hair follicles (HFs), where it resides in skin for sustained drug release, accelerates angiogenesis to build well-nourished environment for HFs, and facilitates the proliferation and migration of DPCs in vitro. PNS ME markedly improved hair density, skin pigmentation, new hair weight, skin thickness, and collagen generation of telogen effluvium mice. Moreover, PNS also took outstanding curative effects on androgenetic alopecia mice. Upon further exploration, PNS ME caused dramatic upregulations of β-catenin, VEGF and Ki67, suggesting it might function by triggering Wnt/β-catenin pathway, accelerating vessels formation, and activating the hair follicle stem cells. Notably, PNS ME indicated longer-term safety than minoxidil tincture. Together, PNS ME provides a comprehensive strategy for alopecia, especially it avoids defects by high-proportioned surfactants in traditional microemulsion, exhibiting milder and safer, which shows bright prospect of applying microemulsion in hair growth promotion. [ABSTRACT FROM AUTHOR]

[Display omitted] None of transitional lipid-based drug delivery systems (LBDDS) includes compositions containing one lipid and one water-soluble surfactant that form stable microemulsions. The conversion of liquid LBDDS to solid LBDDS has been limited by low drug loading. Previously, we have developed drug solid microemulsions containing one lipid and TPGS (a water-soluble surfactant) that achieved high drug loading and remarkably increased oral bioavailability. This study aimed to test if binary lipid systems (BLS), composed of one lipid and one water-soluble surfactant that form stable self-emulsifying microemulsions, is not an exclusive but widely applicable type of LBDDS for other lipids and surfactants and evaluate the influences of chemical structures of lipids and surfactants on microemulsions and solid microemulsions. We systemically identified new BLS by using a library of lipids and surfactants. Propylene glycol diesters and glycerol triesters were favorable for forming stable microemulsions with Tween 80, Cremophor EL, or TPGS. To the best of our knowledge, this is the first report exploring and confirming that the BLS is a new addition to traditional LBDDS, provides a promising option for researchers, and has the potential to increase drug loading to facilitate the development of solid microemulsions. [ABSTRACT FROM AUTHOR]

After application to the skin surface, a topical formulation is submitted to changes in composition produced by evaporation of volatile components, penetration of components into the skin and extraction of skin components ("vehicle metamorphosis"). The aim of this work was to study the effect of vehicle metamorphosis on skin delivery from microemulsions containing triamcinolone acetonide. The microemulsions were prepared and characterized for water evaporation kinetics, in vitro release and skin permeation and retention. Skin retention experiments were performed on full thickness pig ear skin, in both occluded infinite and un-occluded finite dose conditions. For comparison purposes, two creams, the commercial Ledercort® and a vanishing cream, were tested. With triamcinolone acetonide water evaporation does not modify skin retention, probably for the lipophilic nature of the drug. However, if water is eliminated from the microemulsions, the performance is reduced, probably because drug partitioning from vehicle to stratum corneum is disfavored. If a water-soluble drug (methyl prednisolone sodium succinate) is used, infinite dose application in occlusive conditions increases in a significant way the amount of drug retained in the skin. The involved mechanisms are probably stratum corneum swelling and increase of stratum corneum/viable epidermis partitioning. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Synthesis of a novel erucic acid ester of G 0 -PETIM (poly (propyl ether imine)) dendron based bicephalous heterolipid (BHL). • Heterolipid is basic in nature due to the presence of the tertiary amino group. • BHL as new oil phase in self-microemulsifying drug delivery system (SMEDDS) formulation. • High stability of SEMDDS upon dilution in wide pH range media. • High drug loading efficiency with a significant increase in solubility and 6-fold bioavailability enhancement. • No oral mucosal irritation. Abstract There is an increasing demand for new lipidic biocompatible and safe materials for self-microemulsifying drug delivery system (SMEDDS). The present work reports the synthesis, characterization, oral mucosal irritation study, and application of novel erucic acid ester of G 0 -PETIM dendron based bicephalous heterolipid (BHL) as an oil phase in SMEDDS using Efavirenz (EFA), a BCS class II drug with poor water solubility and poor bioavailability. Studies were conducted to optimize EFA SMEDDS using different ratios of the BHL as oil phase and surfactant: co-surfactant weight ratios (Km). At Km (1.5), the microemulsion was spontaneously formed in water with mean globule size of 22.78 ± 0.25 nm and polydispersity index (PDI) of 0.23 ± 0.031 with high drug loading efficiency of 80.35 ± 3.1%. Standard stability tests were performed on EFA SMEDDS and the results indicated it to be highly stable. The in vitro dissolution profile of EFA SMEDDS showed >95% of the drug release within an hour and expectedly substantial enhancement in in vivo bioavailability was observed; almost 6-fold increase in bioavailability with parameters C max 5.2 µg/mL, T max 3 h, and AUC (0-∞) 23.48 μg/h/mL respectively as compared the plain suspension of the drug. In conclusion, the BHL can be used effectively as an oil phase in SMEDDS to enhance solubility and bioavailability of BCS Class II drugs. Further, it holds, in general, a great promise as a new excipient for solubility and bioavailability enhancements. [ABSTRACT FROM AUTHOR]

[Display omitted] Due to their unique characteristics, microemulsions (ME) represent one of the most promising delivery systems which can conquer poor ocular drug bioavailability providing long residence time. Development of a ME system, relying on the use of a safe and non-irritant surfactant combination derived from sustainable resources and which can consolidate the small ME droplets, is the goal of this work. Herein, we report the design and characterization of a novel biocompatible, eco-friendly ME system loaded with the hydrophilic dexamethasone sodium phosphate (DEXP) using a novel surfactant mixture composed of D-α-tocopherol polyethylene glycol succinate (TPGS) and Plantacare® (coco-Glycosides). Capryol™ PGMC and double-distilled water were used as the respective oil and aqueous phases and the MEs were prepared by the water titration method, suitable for scaling up. Optimization of ME formulae was conducted by varying Plantacare® grades, TPGS to Plantacare® mass ratios and drug loading. The formulae were characterized in terms of physical appearance, droplet size (PS), size distribution (PDI), zeta potential (ZP), and stability. The optimized DEXP-loaded ME formula attained acceptable PS, PDI, and ZP values of 43 ± 5 nm, 0.35 ± 0.07, −12 ± 4 mV, respectively. TEM images confirmed a small PS ≤ 100 nm. The in vivo safety of ME was proved by the Draize test. The ME formula prompted excellent mucoadhesion and transcorneal permeation. The confocal studies showed deep penetration into the rabbits' corneas. In vivo studies using endotoxin-induced uveitis showed high ocular efficacy and a significant reduction in inflammatory cells, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The obtained results elect the novel engineered ME system as a promising tool for the ocular delivery of hydrophilic moieties in the management of various ophthalmic diseases. [ABSTRACT FROM AUTHOR]

[Display omitted] • A one step method to elaborate drug capsules (100 nm) coated with nanoparticles is reported. • The nanoprecipitation diagram of the drug is a useful guide to form capsules. • The molecular form of sorafenib yields submicronic capsules in the Ouzo domain. • Sorafenib tosylate yields submicronic capsules from the Surfactant Free Microemulsion domain. • The final size of the capsule depends on the overall composition and solute molecular structure. • Monodispersed capsules (∼80 nm) can be formed close to the Ouzo boundary. Drug nanocapsules coated with iron oxide nanoparticles (SPION) were elaborated by the simultaneous nanoprecipitation of the drug and the nanoparticles, through solvent shifting. We examined four drugs: sorafenib, sorafenib tosylate, α-tocopherol and paclitaxel, to cover the cases of molecular solids, ionic solids, and molecular liquids. We first investigated the formation of the drug core in the final mixture of solvents at different concentrations. A Surfactant-Free Micro-Emulsion domain (SFME, thermodynamically stable) was observed at low drug concentration and an Ouzo domain (metastable) at high drug concentration, except for the case of paclitaxel which crystallizes at high concentration without forming an Ouzo domain. When co-nanoprecipitated with the molecular drugs in the Ouzo domain (sorafenib or α-tocopherol), the SPION limited the coalescence of the drug particles to less than 100 nm, forming capsules with a drug encapsulation efficiency of ca 80 %. In contrast, larger capsules were formed from the SFME or when using the ionic form (sorafenib tosylate). Finally, the sorafenib-SPION capsules exhibit a similar chemotherapeutic effect as the free drug on the hepatocellular carcinoma in vitro. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Due to their role in immune responses, the skin dendritic cells (i.e. epidermal Langerhans cells and dermal dendritic cells) have become of great interest to researchers in the past decades. A dermal administration of allergens could target these professional antigen-presenting cells directly and build up immunotolerance. Additionally, many of the adverse side effects, which are seen in the current state of the art specific immunotherapy routes, could be avoided. Therefore, in this study a penetration enhancing microemulsion was developed and its physicochemical properties were determined under several storage conditions. The influence of different preservatives on the microemulsion stability was observed. We examined epidermal penetration of Alexa Fluor-647 labelled bee-venom phospholipase A2 (Api m 1) using the Franz diffusion cell set up and confocal laser-scanning microscopy. First results of an in-vivo Api m 1-allergic mouse model indicated the protective efficacy of dermal AIT with our newly developed microemulsion. Summarily, the developed microemulsion is a suitable, stable drug delivery system for the topical administration of proteogenic allergens into the epidermis and is able to reach dendritic cells in the skin. [ABSTRACT FROM AUTHOR]

The purpose of this study was to develop self-microemulsifying (SME-) tablets to improve resveratrol solubility whilst delivering resveratrol in a preferred tablet dosage form. Resveratrol was dissolved in liquid self-microemulsifying drug delivery system (SMEDDS) (10% w/w) and solidified through adsorption on several different solid carriers. Two ranges of synthetic amorphous silica (Sylysia® 290, 350, 470, 580; Syloid® 244FP, AL-1FP) as well as granulated magnesium aluminometasilicate (Neusilin® US2) were screened for their SMEDDS adsorbent capacity. The most efficient carrier from every range was chosen for further SME-tablet development. To counteract the high ratio of liquid in SME-tablets, additional dry binders (microcrystalline cellulose, copovidone) were added to the tableting mixture, as well as superdisintegrant (croscarmellose sodium) and lubricant (magnesium stearate). Finally, approx. 600 mg tablets were directly pressed using 12 mm flat face punch, containing 41.75% SMEDDS. Overall, all tablets exhibited sufficient hardness (>50 N), although it was negatively affected by higher compression force. Tablets with Neusilin® US2 proved to have highest hardness, as granulated structure of Neusilin® US2 provided best compaction properties needed for successful direct compression of tablets. All prepared SME tablet formulations disintegrated in under 10 min and formed microemulsions (droplet size < 100 nm) upon dilution with water, with Neusilin® US2 tablets exhibiting the lowest droplet size (<30 nm). While conventional dissolution test indicated incomplete resveratrol release from solid carriers in both pH 1.2 and 6.8 media, no difference fatty acid amount titrated during fasted state in vitro lipolysis between liquid and solid SMEDDS was observed. Moreover, accelerated stability tests confirmed over 90% of trans-resveratrol remained in solid SMEDDS following 90 days at 40 °C, with no crystallization of resveratrol observed during that time. To sum up, through adsorption on solid carriers, in particular Neusilin® US2, SMEDDS was successfully transformed into a directly compressible mixture and tableted without the loss of its self-microemulsifying ability. [ABSTRACT FROM AUTHOR]

Self-gelling DNA hydrogels with cytosine-phosphate-guanine (CpG) motifs have been shown to exhibit high potency as vaccine adjuvants. However, their oral use is limited because of their thermodynamic and chemical instability in the gastrointestinal tract. In this study, we aimed to develop DNA hydrogel microspheres (Dgel-MS) coated with chitosan to improve their stability. Chitosan-coated Dgel-MS (Cs-Dgel-MS) was prepared by emulsifying Dgel to obtain the D-gel core, followed by mixing with microemulsions of chitosan for electrostatic coating. Fluorescence imaging of Cs-Dgel-MS labeled with fluorescent dyes showed that Dgel-MS (approximately 30 μm) was coated with chitosan. The recovery efficiency of Alexa Fluor 488-DNA was 87.4 ± 7.5%. To load a phosphorothioate CpG oligodeoxynucleotide into Dgel, a modified Dgel (mDgel) was designed and fluorescein isothiocyanate (FITC)-dextran was loaded into Cs-mDgel-MS as a model compound. The recovery efficiency of Alexa Fluor 488-CpG1668 and FITC-dextran was 83.3 ± 3.8% and 67.8 ± 4.6%, respectively. The release of Alexa Fluor 488-CpG1668 from Cs-mDgel-MS was slower than that from mDgel under acidic or DNase conditions. Intra-duodenal administration of FITC-dextran/Cs-mDgel-MS showed prolonged intestinal transition of the encapsulated FITC-dextran. These results indicate that Cs-Dgel-MS can be useful for oral delivery of CpG DNA and other bioactive compounds. [ABSTRACT FROM AUTHOR]

We present the absorption improvement mechanism of fenofibrate (FFB), a Biopharmaceutics Classification System (BCS) class II drug, from self-microemulsifying drug delivery systems (SMEDDS), centered on improving the diffusion of FFB through the unstirred water layer (UWL). Four SMEDDS formulations containing Labrafac™ lipophile WL 1349 (WL1349) or Labrafil ® M 1944CS (M1944) oils and NIKKOL HCO-40 (HCO40) or NIKKOL HCO-60 (HCO60) surfactants were prepared. Every SMEDDS formulation formed microemulsion droplets of approximately 30 nm. In vitro tests showed that the microemulsion droplets containing M1944 had relatively small FFB solubilization capacities, causing larger amounts of FFB to be dissolved in the bulk water phase, compared to the droplets containing WL1349. The diffusivity of the microemulsion droplets through the mucin solution layer was enhanced when using HCO40 compared to HCO60. The oral absorption in rats was the highest when using the SMEDDS formulation containing M1944 and HCO40. High FFB distribution in the bulk water phase and fast diffusion of microemulsion droplets through the mucus layer contributed to the efficient delivery of FFB molecules through the UWL to the epithelial cells, leading to enhanced FFB absorption. [ABSTRACT FROM AUTHOR]

Psoriasis is a widespread chronic disease affecting 2–4% of the population in Western countries. Its mild-to-moderate form, representing approximately 80% of the total cases, is treated by topical application, with corticosteroid being the standard treatment. However, in case of psoriasis, no single treatment works for every patient and optimizing topical therapy is a key aspect. A possible alternative is represented by cyclosporine, an immunosuppressant cyclic peptide administered orally in the treatment of the severe form. Its topical application could avoid the problems related to systemic immunosuppression, but the unfavourable physico-chemical properties (MW: 1202 Da; LogP ≈ 3) hinder its permeation across the stratum corneum. The aim of the paper was the preparation, characterization and ex-vivo evaluation of cyclosporine loaded microemulsions using oleic acid as oil phase, either Tween ® 80 or a soluble derivative of vitamin E (TPGS) as surfactants and either Transcutol ® , propylene glycol or 1,3 propanediol as co-surfactants. The issue of formulation viscosity was also addressed 1) by evaluating the thickening of Tween ® 80-based microemulsions by direct addition of different rheological modifiers, 2) by building pseudo-ternary phase diagrams using TPGS, to identify the water/oil/surfactants proportions resulting in viscous self-gelifying systems. Nine formulations (five Tween ® 80-based and four TPGS-based) were selected, characterized in terms of droplets size (low viscosity systems) or rheological properties (high viscosity systems), loaded with 6 mg/g cyclosporine and applied ex-vivo on porcine skin for 22 h. A relevant skin accumulation was obtained either with a low-viscosity Tween ® 80-based microemulsion (9.78 ± 3.86 µg/cm 2 ), or with a high viscosity TPGS-based microemulsion (18.3 ± 5.69 µg/cm 2 ), with an increase of about 3 and 6 times respectively for comparison with a control cyclosporine solution in propylene glycol. The role of water content, surfactant, co-surfactant and viscosity was also addressed and discussed. The kinetic of skin uptake from the best performing formulation was finally evaluated, highlighting a relatively quick skin uptake and the achievement, after 2 h of contact, of potentially therapeutic cyclosporine skin concentrations. [ABSTRACT FROM AUTHOR]

A10, (3-phenylacetylamino-2,6-piperidinedione), is a natural peptide with broad antineoplastic activity. Recently, in vitro antitumor effect of a new A10 analog [3-(4-methoxybenzoylamino)-2,6-piperidinedione] (MPD) has been verified. However, poor aqueous solubility represents an obstacle towards intravenous formulation of MPD and impedes successful in vivo antitumor activity. To surmount such limitation, MPD microemulsion (MPDME) was developed. A 3 1 2 2 full factorial design using Design-Expert® software was adopted to study the influence of different parameters and select the optimum formulation (MPDME1). Transmission electron microscopy (TEM) displayed spherical droplets of MPDME1. The cytotoxicity of MPDME1 in Michigan Cancer Foundation 7 (MCF-7) breast cancer cell line exceeded that of MPD solution (MPDS) and tamoxifen. Compatibility with injectable diluents, in vitro hemolytic studies and in vivo histopathological examination confirmed the safety of parenteral application of MPDME1. Molecular docking results showed almost same binding affinity of A10, MPD and 125 I-MPD with histone deacetylase 8 (HDAC8) receptor. Accordingly, radioiodination of MPDME1 and MPDS was done via direct electrophilic substitution reaction. Biodistribution of 125 I-MPDME1 and 125 I-MPDS in normal and tumor (ascites and solid) bearing mice showed high accumulation of 125 I-MPDME1 in tumor tissues. Overall, the results proved that MPDME represents promising parenteral delivery system capable of improving antineoplastic activity of MPD. [ABSTRACT FROM AUTHOR]

Camptothecin (CPT) has a potent and broad-spectrum anti-tumor activity but its clinical use is limited due to its poor water solubility, stability at physiological conditions and toxicity. The aim of our study was to evaluate bicephalous heterolipid E1E for enhancing the solubility and stability of CPT through the development of a self-microemulsifying drug delivery system (SMEDDS). The solubility of CPT in heterolipid E1E was found to be 82 and 5.86 folds higher than oleic acid and ethyl oleate respectively. Molecular dynamic simulation (MDS) studies revealed that stability of hydrogen bonding between CPT with E1E contributed to solubility enhancement of CPT. SMEDDS of CPT with heterolipid E1E as an oil phase was prepared and evaluated for drug loading, droplet size, morphology, thermodynamic and long-term stability studies as per ICH guidelines. The product, CPT-SMEDDS Fc showed 1.75 mg CPT loading per 1 g of SMEDDS having a droplet size of 20.93 ± 0.41 nm. CPT-SMEDDS Fc was found to be stable, equipotent as compared to doxorubicin and had low toxicity in HeLa, MCF-7, and HL-60 cell lines. These results signify that the delivery system, CPT-SMEDDS Fc could be a very good candidate to be considered for preclinical and clinical investigations. [ABSTRACT FROM AUTHOR]

Hot-melt extrusion (HME) has gained increasing attention in the pharmaceutical industry; however, its potential in the preparation of solid self-emulsifying drug delivery systems (S-SMEDDS) is still unexplored. This study sought to prepare enteric S-SMEDDS by HME and evaluate the effects of the process and formulation variables on S-SMEDDS properties via Box-Behnken design. Liquid SMEDDS were developed, and carvedilol was used as a class II model drug. Mean size, polydispersity index (PdI) and zeta potential of the resulting microemulsions were determined. The extrudates were then obtained by blending the lipid mixture and HPMCAS using a twin-screw hot-melt extruder. SEM, optical microscopy and PXRD were used to characterize the extrudates. In vitro microemulsion reconstitution and drug release were also studied. L-SMEDDS gave rise to microemulsions with low mean size, PdI and zeta potential (140.04 ± 7.22 nm, 0.219 ± 0.011 and −9.77 ± 0.86 mV). S-SMEDDS were successfully prepared by HME, and an HMPCAS matrix was able to avoid microemulsion reconstitution and retain drug release in pH 1.2 (12.97%–25.54%). Conversely, microemulsion reconstitution and drug release were gradual in pH 6.8 and complete for some formulations. Extrudates prepared at the lowest drug concentration and highest temperature and recirculation time promoted a complete and rapid drug release in pH 6.8 giving rise to small and uniform microemulsion droplets. [ABSTRACT FROM AUTHOR]

In the present study, we have synthesized mixed cuprous/copper oxide nanosuspensions by metallosurfactant based microemulsion technique. Three metallosurfactants were synthesized which includes two non-ionic double chained metallosurfactants with C 12 , C 16 chains with coordinated copper i.e. Cudda and Cuhexa, respectively. Another cationic double chained metallosurfactant with loosely bound metal (Cuctac) was also prepared. The prepared metallocomplexes were characterized using FTIR, elemental analysis, and NMR. The effect of the position of metallosurfactant in microemulsion on the fabrication and properties of nanosuspensions was elucidated. In this method, no external reducing agent and capping agent were added and tween 80 acted both as reducing and stabilizing agent for the nanoparticles. The synthesized nanoparticles were characterized and it was observed that mixed copper and cuprous oxide particles are present in colloidal suspension for all the three studied metallosurfactants. The kinetics of formation of mixed copper/cuprous oxide nanosuspensions (Ns) and their stability was estimated using Uv-visible spectroscopy. Further, the binding and interactions of copper nanosuspensions with calf Thymus DNA (CT-DNA) were assessed using Uv–vis spectroscopy, circular dichroism and gel electrophoresis. Additionally, the antioxidant activity of the Cu Ns was checked using DPPH assay. The role of positive charge on nanoparticles as evaluated from Zeta potential was responsible for DNA affinity. The DNA conformational changes in the presence of nanosuspensions and relevant scavengers were investigated. Further, the anti-proliferative activity of copper Ns was assessed using HeLa cells and Cuhexa derived Ns were proved to be active with highest activity at a low concentration and were nontoxic towards normal cell lines. In summary, this work demonstrates a softer approach for the synthesis of copper nanosuspensions with a size range of 2–5 nm and evaluated the role of type and structure of metallosurfactant on size, stability of particles and anti-proliferative activity. [ABSTRACT FROM AUTHOR]

A novel microemulsion was developed and characterized for topical delivery of Dencichine (Den). Two imidazaolium ionic liquid, 1-hydroxyethyl-3-methylimidazolium chloride ([HOEIM]Cl) and 1-butyl-3-methylimidazolium dodecanesulfate ([BMIM]C 12 SO 3 ) were incorporated into the aqueous and surfactant phases respectively for the remarkable enhancement on skin permeation. The nano-carrier was developed and optimized based on a pseudo-ternary phase diagram. The optimized formulation was composed of 50% water/[HOEIM]Cl mix (1:1) as water phase, 20% Tween 80/[BMIM]C 12 SO 3 mix (1:1) as surfactant, 10% propylene glycol as co-surfactant and 20% IPM as oil phase. The o/w microemulsion was then characterized for droplets sizes (47.7 ± 1.5 nm), zeta potential (−14.83 ± 3.64 mV), viscosity (31 ± 4 mPa) and pH (6.71 ± 0.04). In-vitro skin permeation assay suggested the strong enhancement of ILs formulation on the topical delivery of Den, which was approximately 10-fold that of the drug aqueous solution. It was found that the nano-carrier can reduce the skin barrier properties by disrupting the regular and compact arrangements of corneocytes, and moderating the surface properties of the stratum corneum, as evidenced by Transdermal Water Loss Evaluation (TEWL), Differential Scanning Calorimetery (DSC) and attenuated total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR). Furthermore, the in-vivo pharmacodynamic evaluation indicated the significant hemostatic activity of Den by the topical application of the vehicle. Additionally, the formulation showed minor cell toxicity and skin irritation. Therefore, our work suggested that the ionic liquid microemulsion can be a promising nano-scale vehicle for the topical application of Den to produce desirable pharmacological effects. [ABSTRACT FROM AUTHOR]

For drug delivery to the lungs, the aerodynamic size of drug particles plays a predominant role in determining the sites of deposition in the airway, and the particles with the size less than 2 μm are highly expected as they will be preferably delivered to the ideal site of alveolar regions. In this paper, a novel platform technology has been developed, where the water (containing pharmaceutically active agents)-in-oil (w/o) microemulsions were spray-dried to generate nanosized drug particles that were able to be homogeneously dispersed in the propellant to form an exceptionally stable suspensions with no precipitates or flocculates during a long time storage. High fine particle (< 5.8 μm) fraction (∼ 70% w/w) was achieved, irrespectively of drug molecular size and storage time. This platform technology works pretty well on chemical drugs (i.e. salbutamol sulphate) and biotherapeutics (i.e. insulin) for the generation of nanoparticles, and the nanoparticle pMDI formulations were homogeneous, stable and of high delivery efficiency to the lungs, representing an ideal way for pulmonary delivery. [ABSTRACT FROM AUTHOR]

In order to improve skin penetration of tacrolimus we aimed to develop potentially non-irritant, lecithin-based microemulsions containing ethanol, isopropanol and/or propylene glycol as cosurfactants, varying caprylic/capric triglycerides and propylene glycol monocaprylate as oil phase. The influence of excipients on the size of microemulsion region in pseudo-ternary phase diagrams and their ability to form different types of microemulsions was evaluated. The comprehensive physicochemical characterization of microemulsions and the evaluation of their structure was performed, while the localization of tacrolimus in microemulsions was further investigated using electron paramagnetic resonance spectroscopy. Moreover, stability studies proved no change in tacrolimus content during one year of storage at room temperature. In addition, in vivo skin performance indicated no skin irritation potential of blank microemulsions, whereas in vitro release testing using Franz diffusion cells showed superior release rate of tacrolimus from microemulsions (0.98 ± 0.10 and 0.92 ± 0.11 μg/cm 2 /h for two bicontinuous and 1.00 ± 0.24 μg/cm 2 /h for oil-in-water microemulsion) compared to referent Protopic ointment (0.15 ± 0.08 μg/cm 2 /h). Furthermore, ex vivo penetration assessed through porcine ear skin using tape stripping, confirmed superiority of two microemulsions related to the reference, implying developed microemulsions as promising carriers for dermal delivery of tacrolimus. [ABSTRACT FROM AUTHOR]

The present review deals with the progress of Polysorbates (Tween) based microemulsions in drug delivery. PEGylated Sorbitan Fatty Acid Esters (Tweens/Polysorbates) are one of the most used non-ionic surfactants. Particularly, Polysorbates based microemulsion has been widely used for enhancing solubilization of poorly soluble drugs. This article deals with underlying the preclinical factors which affect the solubilization efficacy of Tween formulations, implication of pharmaceutically accepted vectors in terms of absorption, bioavailability, biological fate and potential toxicity. Antimicrobial activity of Tween microemulsion formulations has also been addressed emphasising the role of Tween. The review contains comprehensive knowledge/literature related to physicochemical parameters and biological fate of different Polysorbates and takes into account all the parameters and observations that make Tween a very convenient and safe choice for the use as pharmaceutical excipient for microemulsion formulations. [ABSTRACT FROM AUTHOR]

Rosmarinic acid-loaded polyacrylamide-chitosan-poly(lactide- co -glycolide) nanoparticles (RA-PAAM-CH-PLGA NPs) were grafted with cross-reacting material 197 (CRM197) and apolipoprotein E (ApoE) for targeting of the blood–brain barrier (BBB) and rescuing degenerated neurons. The polymeric nanocarriers were prepared by microemulsion, solvent diffusion, grafting, and surface modification, and CRM197-ApoE-RA-PAAM-CH-PLGA NPs were used to treat human brain-microvascular endothelial cells, RWA264.7 cells, and Aβ-insulted SK-N-MC cells. Experimental results revealed that an increase in the weight percentage of PAAM decreased the particle size, zeta potential, and grafting efficiency of CRM197 and ApoE. In addition, surface DSPE-PEG(2000) could protect CRM197-ApoE-RA-PAAM-CH-PLGA NPs against uptake by RWA264.7 cells. An increase in the concentration of CRM197 and ApoE decreased the transendothelial electrical resistance and increased the ability of propidium iodide and RA to cross the BBB. The order in the viability of apoptotic SK-N-MC cells was CRM197-ApoE-RA-PAAM-CH-PLGA NPs > CRM197-RA-PAAM-CH-PLGA NPs > RA. Thus, CRM197-ApoE-RA-PAAM-CH-PLGA NPs can be a promising formulation to deliver RA to Aβ-insulted neurons in the pharmacotherapy of Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

The aim of this study was to improve the analgesic effect of evodiamine and rutaecarpine, using a microemulsion-based hydrogel (ME-Gel) as the transdermal co-delivery vehicle, and to assess hyaluronic acid as a hydrogel matrix for microemulsion entrapment. A microemulsion was formulated with ethyl oleate as the oil core to improve the solubility of the alkaloids and was loaded into a hyaluronic acid-structured hydrogel. Permeation-enhancing effects of the microemulsion enabled evodiamine and rutaecarpine in ME-Gel to achieve 2.60- and 2.59-fold higher transdermal fluxes compared with hydrogel control ( p < 0.01). The hyaluronic acid hydrogel-containing microemulsion exhibited good skin biocompatibility, whereas effective ME-Gel co-delivery of evodiamine and rutaecarpine through the skin enhanced the analgesic effect in mouse pain models compared with hydrogel. Notably, evodiamine and rutaecarpine administered using ME-Gel effectively down-regulated serum levels of prostaglandin E 2 , interleukin 6, and tumor necrosis factor α in formaldehyde-induced mouse pain models, possibly reflecting the improved transdermal permeability of ME-Gel co-delivered evodiamine and rutaecarpine, particularly with hyaluronic acid as the hydrogel matrix. [ABSTRACT FROM AUTHOR]

The study aimed to develop semisolid self-microemulsifying drug delivery systems (SMEDDSs) as carriers for oral delivery of aciclovir in hard hydroxypropylmethyl cellulose (HPMC) capsules. Six self-dispersing systems (SD1-SD6) were prepared by loading aciclovir into the semisolid formulations consisting of medium chain length triglycerides (lipid), macrogolglycerol hydroxystearate (surfactant), polyglyceryl-3-dioleate (cosurfactant), glycerol (hydrophilic cosolvent), and macrogol 8000 (viscosity modifier). Their characterization was performed in order to identify the semisolid system with rheological behaviour suitable for filling in hard HPMC capsules and fast dispersibility in acidic and alkaline aqueous media with formation of oil-in-water microemulsions. The optimal SMEDDS was loaded with aciclovir at two levels (2% and 33.33%) and morphology and aqueous dispersibility of the obtained systems were examined by applying light microscopy and photon correlation spectroscopy (PCS), respectively. The assessment of diffusivity of aciclovir from the SMEDDSs by using an enhancer cell model, showed that it was increased at a higher drug loading. Differential scanning calorimetry (DSC) analysis indicated that the SMEDDSs were semisolids at temperatures up to 50 °C and physically stable and compatible with HPMC capsules for 3 months storage at 25 °C and 4 °C. The results of in vitro release study revealed that the designed solid dosage form based on the semisolid SMEDDS loaded with the therapeutic dose of 200 mg, may control partitioning of the solubilized drug from in situ formed oil-in-water microemulsion carrier into the sorrounding aqueous media, and hence decrease the risk for precipitation of the drug. [ABSTRACT FROM AUTHOR]

In this study, we demonstrate for the first time the dual roles of Tocopheryl Polyethylene Glycol 1000 Succinate (TPGS) based microemulsion (ME) for tacrolimus (TAC) to enhance TAC percutaneous delivery and anti-psoriatic efficacy. The ME formulation was developed and optimized based on pseudo-ternary phase diagrams combined with in vitro permeation. The result of Fourier transform infrared spectroscopy (FTIR) demonstrated that TAC was completely solubilized in the TPGS-ME. In vitro permeation studies showed that TPGS-ME enhanced TAC permeation through and into the skin, and the enhanced deposition of TAC in the normal or psoriatic skin was further confirmed in vivo. The cellular uptake performed with HaCaT cells presented more pronounced uptake of TPGS-ME. Topical TAC-TPGS-ME treated imiquimod-induced psoriasis in mice more efficaciously than the commercial formulation of TAC (Protopic ® ), which is consistent with the enhanced TAC levels by TAC-TPGS-ME in the psoriatic skin. Haematoxylin and Eosin (HE) staining revealed that TAC-TPGS-ME significantly diminished the severity of the psoriasis-like skin inflammation. Moreover, TPGS-ME vehicle exhibited a moderate anti-inflammatory activity, which indicated that TPGS acted as a potential adjuvant in the TAC anti-psoriasis process, and the synergism was identified in anti-proliferation against HaCaT cells. The colloidal nano-carrier combined ME with TPGS is a potential approach for percutaneous delivery of TAC, which exploited both virtues of ME and TPGS to obtain the synergetic effects of enhanced permeability and anti-psoriatic efficacy. [ABSTRACT FROM AUTHOR]

Emulsion technology has been utilized extensively in the pharmaceutical industry. This article presents a comprehensive review of the literature on an important subcategory of emulsions, microemulsions. Microemulsions are optically transparent, thermodynamically stable colloidal systems, 10–100 nm diameter, that form spontaneously upon mixing of oil, water and emulsifier. This review is the first to address advantages and disadvantages, as well as considerations and challenges in multi-drug delivery. For the period 1 January 2011–30 April 2016, 431 publications related to microemulsion drug delivery were identified and screened according to microemulsion, drug classification, and surfactant types. Results indicate the use of microemulsions predominantly in lipophilic drug delivery (79.4%) via oil-in-water microemulsions and non-ionic surfactants (90%) for oral or topical administration. Cancer is the disease state most targeted followed by inflammatory diseases, microbial infections and cardiovascular disease. Key generalizations from this analysis include: 1) microemulsion formulation is largely based on trial-and-error despite over 1200 publications related to microemulsion drug delivery since their discovery in 1943; 2) characterization using methods including interfacial tension, droplet size, electrical conductivity, turbidity and viscosity may provide additional information for greater predictability; 3) microemulsion drug delivery publications arise primarily from China (27%) and India (21%) suggesting additional research opportunities elsewhere. [ABSTRACT FROM AUTHOR]

Solubilisation of the poorly-water soluble drug, testosterone propionate, in co-surfactant-free, dilutable, oil-in-water microemulsions stabilized by zwitterionic surfactants of varying alkyl chain length, namely 3-( N,N -dimethyloctylammonio)propanesulfonate and 3-( N,N -dimethyldodecylammonio)propanesulfonate and containing one of four ethyl ester oils, has been investigated. Both 3-( N,N -dimethyloctylammonio)propanesulfonate and 3-( N,N -dimethyldodecylammonio)propanesulfonate-stabilized microemulsions containing two short chain length oils, ethyl butyrate and ethyl caprylate, while only 3-( N,N -dimethyldodecylammonio)propanesulfonate formed microemulsions incorporating the longer chain length oils, ethyl palmitate and ethyl oleate, albeit to a very much reduced extent. Significantly the microemulsions containing the short chain length oils, ethyl butyrate and ethyl caprylate solubilised more testosterone propionate than the corresponding micelles. However, an inverse correlation existed between testosterone propionate solubility in the bulk oil and solubilisation in the microemulsions, in that ethyl caprylate containing microemulsions solubilised more testosterone propionate than those containing an equivalent amount of ethyl butyrate, despite the drug being more soluble in ethyl butyrate. These results suggest that drug solubility in bulk oil is a poor indicator of drug solubility in microemulsions containing that oil, and whether or not the addition of oil improves drug solubility is dependent upon on how it is incorporated within the microemulsion. The longer the chain length of the oil, the more likely the oil is to form a core in the microemulsion droplet, resulting in an additional locus of drug solubilisation and the possibility of an enhanced solubilisation capacity. [ABSTRACT FROM AUTHOR]

The effect of surfactant chain lengths [sodium caprylate (C 8 ), Tween 20 (C 12 ), Tween 80 (C 18 )] and the molecular weight of block copolymers [Pluronic F68 and Pluronic F 127] were studied to determine the stability of the microemulsion and its effect on release kinetics from cyclosporine-loaded microemulsion-laden hydrogel contact lenses in this work. Globule size and dilution tests (transmittance) suggested that the stability of the microemulsion increases with increase in the carbon chain lengths of surfactants and the molecular weight of pluronics. The optical transmittance of direct drug-laden contact lenses [DL-100] was low due to the precipitation of hydrophobic drugs in the lenses, while in microemulsion-laden lenses, the transmittance was improved when stability of the microemulsion was achieved. The results of in vitro release kinetics revealed that drug release was sustained to a greater extent as the stability of microemulsion was improved as well. This was evident in batch PF127-T80, which showed sustained release for 15 days in comparison to batch DL-100, which showed release up to 7 days. An in vivo drug release study in rabbit tear fluid showed significant increase in mean residence time (MRT) and area under curve (AUC) with PF-127-T80 lenses (stable microemulsion) in comparison to PF-68-SC lenses (unstable microemulsion) and DL-100 lenses. This study revealed the correlation between the stability of microemulsion and the release kinetics of drugs from contact lenses. Thus, it was inferred that the stable microemulsion batches sustained the release of hydrophobic drugs, such as cyclosporine from contact lenses for an extended period of time without altering critical lens properties. [ABSTRACT FROM AUTHOR]

[Display omitted] • Epoxy-α-lapachone was incorporated successes into a microemulsion (ELAP-ME). • Selected ELAP-ME showed acceptable stability for preclinical tests. • ELAP-ME decreased parasite load in mice infected with L.(L.) amazonensis. Epoxy-α-lapachone (ELAP), an oxirane-functionalized molecule synthesized from naturally occurring lapachol, has shown promising activity against murine infection with Leishmania (Leishmania) amazonensis. Herein, we report the successful development of oil-in-water-type (o/w) microemulsions (ME) loaded with ELAP (ELAP-ME) using Capmul MCM, Labrasol, and PEG 400. Stability studies revealed that ELAP-ME (100 µg/mL of ELAP), which was comprised of globule size smaller than 120.4 ± 7.7 nm, displayed a good stability profile over 73 days. ELAP-ME had an effect in BALB/c mice infected with L. (L.) amazonensis , causing reductions in paw lesions after two weeks of treatment (∼2-fold) when compared to untreated animals. Furthermore, there was also a reduction in the parasite load both in the footpad (60.3%) and in the lymph nodes (31.5%). Based on these findings, ELAP-ME emerges as a promising treatment for tegumentar leishmaniasis. [ABSTRACT FROM AUTHOR]

In this work, the sizing of microemulsion droplets of a lipid-based pharmaceutical excipient (Labrasol ® ALF) is performed by Taylor dispersion analysis (TDA) using fluorescent detection. An hydrophobic fluorescent marker is used to tag the microemulsion droplet and to increase the sensitivity of detection (compared to UV detection). Combined with the frontal TDA mode, fluorescent detection was mandatory for an accurate sizing of microemulsions containing large coacervates. Microemulsion sizing of Labrasol was performed at various concentrations from 1 to 70 g.L −1 and at two different temperature (25 °C and 37 °C). Results obtained by TDA are compared to those derived from DLS measurements. The combination of both techniques allows estimating the size and proportion of coacervates in the microemulsion, as well as the polydispersity in size of the sample. [ABSTRACT FROM AUTHOR]

Drug solubility and lymphatic transport enhancements are two main pathways to improve drug oral bioavailability for microemulsions. However, it is not easy to have both achieved simultaneously because excipients used for improving lymphatic transport were usually insufficient in forming microemulsions and solubilizing drugs. Our research is to explore whether ethyl oleate, an oil effective in developing microemulsions with desired solubilizing capability, could increase bioavailability to a higher extent by enhancing lymphatic transport. As a long-chain oil, ethyl oleate won larger microemulsion area than short-chain tributyrin and medium-chain GTCC. In contrast, long-chain soybean oil failed to prepare microemulsions. The solubility of piroxicam in ethyl oleate microemulsions (ME-C) increased by about 30 times than in water. ME-C also won significantly higher AUC 0−t compared with tributyrin microemulsions (ME-A) and GTCC microemulsions (ME-B). Oral bioavailability in ME-C decreased by 38% after lymphatic transport was blocked by cycloheximide, severer than those in ME-A and ME-B (8% and 34%). These results suggest that improving lymphatic transport and solubility simultaneously might be a novel strategy to increase drug oral bioavailability to a higher extent than increasing solubility only. Ethyl oleate is a preferred oil candidate due to its integrated advantages of high solubilizing capability, large microemulsion area and effective lymphatic transport. [ABSTRACT FROM AUTHOR]

To improve the dissolution and oral bioavailability (BA) of atorvastatin calcium (ATV), we previously introduced an optimized self-microemulsifying drug delivery system (SMEDDS) using Capmul ® MCM (oil), Tween ® 20 (surfactant), and tetraglycol (cosurfactant). In this study, various solid carriers were employed to develop a solidified SMEDDS (S-SMEDDS): mannitol (M) and lactose (L) as water-soluble carriers, and Sylysia ® 350 (S) and Aerosil ® 200 (A) as water-insoluble carriers. Maximum solidifying capacities (SC max ) of water-insoluble carriers were significantly greater than those of water-soluble carriers were. The resultant powders were free flowing with an angle of repose <40° and Carr’s index 5–20%, regardless of the solid carrier types. S-SMEDDS with mannitol (S(M)-SMEDDS) or lactose (S(L)-SMEDDS) had a smaller droplet size and greater dissolution than S-SMEDDS with Sylysia ® 350 (S(S)-SMEDDS) or Aerosil ® 200 (S(A)-SMEDDS). Following oral administration of various formulations to rats at a dose equivalent to 25 mg/kg of ATV, plasma drug levels were measured by LC–MS/MS. The relative BAs (RBAs) of SMEDDS, S(M)-SMEDDS, and S(S)-SMEDDS were 345%, 216%, and 160%, respectively, compared to that of ATV suspension. Additionally, at a reduced dose of ATV equivalent to 5 mg/kg, the RBAs of S(M)-SMEDDS and S(S)-SMEDDS compared to that of SMEDDS were 101% and 65%, respectively. These results suggest that S(M)-SEMDDS offers great potential for the development of solid dosage forms with improved oral absorption of drugs with poor water solubility. [ABSTRACT FROM AUTHOR]

Microemulsion containing pentoxifylline was developed and characterized for use as a topical alternative to treat skin disorders. The transparent formulation was developed and optimized based on a pseudoternary phase diagram. Pentoxifylline-loaded microemulsion (PTX-ME) was composed of 44% Tween 80™/Brij 52™ mix as surfactants (S), 51% of caprylic/capric triglycerides as the oil phase (O) and 5% of water as aqueous phase (A). It was classified as an isotropic water-in-oil (W/O) system with droplets that had a heterogeneous spherical shape within the nanosized range (67.36 ± 8.90 nm) confirmed by polarized light microscopy, differential scanning calorimetry (DSC), transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis. In vitro studies using static diffusion Franz cells revealed that the release of PTX from ME followed the Higuchi kinetic model. Topical PTX-ME application developed superior anti-inflammatory activity when compared to the PTX solution, reducing the paw edema up to 88.83%. Our results suggested that this colloidal nanosystem is a promising agent for the delivery of pentoxifylline, increasing its ability to modulate the inflammatory aspects of skin disorders. [ABSTRACT FROM AUTHOR]

Colloidal systems such as emulsions, microemulsions and nanoemulsions are able to transport active molecules, enhance their solubility and stability and minimize their side effects. However, since they are dispersions with an aqueous continuous phase they have some disadvantages such as the risk of microbiological contamination, degradation by hydrolysis, physico-chemical instability and loss of pharmacological activity of the drug. Freeze drying, in which the water is removed from the preparation by sublimation under vacuum, has been suggested as a means to resolve these problems. Lyophilized products are very stable and are easy to transport and store. However, there is very little information in the literature about the application of this technique to emulsified systems. The aim of this review is to evaluate the lyophilization process as a tool for increasing the shelf life of emulsified systems such as emulsions, microemulsions and nanoemulsions. In addition, the mechanism of cryoprotection and the techniques that can be used to characterize the freeze-dried systems are discussed. [ABSTRACT FROM AUTHOR]

A hepatic tumor bitargeted microemulsions drug delivery system using coix seed oil and coix seed polysaccharide (CP) acting as anticancer components, as well as functional excipients, was developed for enhanced tumor-specific accumulation by CP-mediated enhancement on passive tumor targeting and modification of galactose stearate (tumor-targeted ligand). In the physicochemical characteristics studies, galactose stearate-modified coix seed multicomponent microemulsions containing 30% CP (w%) (Gal-C-MEs) had a well-defined spherical shape with a small size (47.63 ± 1.41 nm), a narrow polydispersity index (PDI, 0.101 ± 0.002), and a nearly neutral surface charge (−4.37 ± 1.76 mV). The half-maximal inhibitory concentration (IC 50 ) of Gal-C-MEs against HepG2 cells was 70.2 μg/mL, which decreased by 1.8-fold in comparison with that of coix seed multicomponent microemulsions (C-MEs). The fluorescence intensity of fluorescein isothiocyanate (FITC)-loaded Gal-C-MEs (FITC-Gal-C-MEs) internalized by HepG2 cells was 1.8-fold higher than that of FITC-loaded C-MEs (FIT C-C-MEs), but the cellular uptake of the latter became reduce by 1.6-fold when the weight ratio of CP decreased up to 10%. In the cell apoptosis studies, C-MEs (containing 30% CP) did not show a significant difference with Gal-C-MEs, but exhibited 3.3-fold and 1.5-fold increase relative to C-MEs containing 10% CP and 20% CP, respectively. In the in vivo tumor targeting studies, Cy5-loaded Gal-C-MEs (Cy5-Gal-C-MEs), notably distributed in the tumor sites and still found even at 48 h post-administration, displayed the strongest capability of tumor tissue accumulation and retention among all the test groups. Most importantly, Gal-C-MEs had stronger inhibition of tumor growth, prolonged survival time and more effectively tumor cell apoptosis induction in comparison with C-MEs containing different amounts of CP, which further confirmed that a certain amount of CP and tumor-targeted ligand were of great importance to potent anticancer efficacy. The aforementioned results suggested that Gal-C-MEs presented promising potential as a highly effective and safe anticancer drug delivery system for enhanced liver cancer delivery. [ABSTRACT FROM AUTHOR]

Lithium biocompatible microemulsion based on Peceol ® , lecithin, ethanol and water was studied in attempt to identify the optimal compositions in term of drug content, physicochemical properties and stability. Lithium solubilization in microemulsion was found to be compatible with a drug-surfactant binding model. Lithium ions were predominantly solubilized within lecithin head group altering significantly the interfacial properties of the system. Pseudo-ternary phase diagrams of drug free and drug loaded microemulsions were built at constant ethanol/lecithin weight ratio (40/60). Lithium loaded microemulsion has totally disappeared in the Peceol ® rich part of phase diagram; critical fractions of lecithin and ethanol were required for the formation of stable microemulsion. The effect of lithium concentration on the properties and physical stability of microemulsions were studied using microscopy, Karl Fischer titrations, rheology analyses, conductivity measurements and centrifugation tests. The investigated microemulsions were found to be stable under accelerated storage conditions. The systems exhibited low viscosity and behaved as Newtonian fluid and no structural transition was shown. [ABSTRACT FROM AUTHOR]

Poor aqueous solubility and moderate permeability of Nelfinavir mesylate (NFM) leads to high variability in absorption after oral administration. To improve the solubility and bioavailability of NFM, the self microemulsifying drug delivery system (SMEDDS) was developed. For this purpose, Quality by design (QbD) approach employing D-optimal mixture design was used to prepare SMEDDS of NFM. Further, the software generated numerically optimized SMEDDS were developed by utilizing desirability function. Maisine 35-1, Tween 80, and Transcutol HP were identified as oil, surfactant, and co-surfactant that had best solubility for NFM. Ternary phase diagrams were plotted to identify the self-emulsification region. Dissolution of putative NFM in simulated fasted or fed small intestinal conditions, respectively, predicted that there is a positive food effect. However, NFM loaded SMEDDS showed absence of food effect with no significant difference in dissolution performance either in Fasted or fed state simulated intestinal fluid (FaSSIF or FeSSIF) biorelevent dissolution media. The prepared SMEDDS were thermodynamically stable with droplet size (121 nm), poly dispersity index (PDI) (0.198) and emulsification time (<1 min). Transmission electron microscopy (TEM) analysis confirmed the spherical shape of the reconstituted SMEDDS droplets. The ex vivo performance revealed 4.57 fold enhancement in the apparent permeability of NFM as compared to NFM suspension. The animal pharmacokinetic analysis in New Zealand strain rabbits indicated food effect on pure NFM suspension. However, absence of food effect and 3.5–3.6 fold enhancement in the oral bioavailability was observed when NFM was formulated into SMEDDS. Thus, it could be envisaged that development of SMEDDS formulation of NFM could be one of the best alternative to enhance oral bioavailability of NFM. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine skin irritation and phototoxicity potentials of several microemulsions (ME), all comprising approximately the same percentage of surfactant mixture, but varying oil/water content and consequently inner structure being either droplet-like (o/w ME, o/w ME carbomer, w/o ME and w/o ME white wax) or lamellar (gel-like ME). Two different in vitro methods were used: MTT assay (performed either on reconstructed human epidermis (RHE) or NCTC 2544 cells) and pig ear test. Neither assay revealed the difference among ME with droplet-like structure. Then again, pig ear test and MTT assay performed on RHE indicated that gel-like ME is more irritant compared to other tested ME, whereas no difference among formulations were observed by MTT assay on NCTC 2544 cells. The reasonable explanation is destruction and consequently uniform structure of ME upon dilution that is inevitable for testing on cell cultures. The results of phototoxicity test again indicated the increased potential of gel-like ME to cause adverse effects on skin. It can be concluded that for ME consisting of the same amount of identical surfactants but having different structure the latter represent a crucial factor that determines their dermal toxicity. [ABSTRACT FROM AUTHOR]

The study investigated the influence of formulation parameters for design of self-microemulsifying drug delivery systems (SMEDDSs) comprising oil (medium chain triglycerides) (10%), surfactant (Labrasol ® , polysorbate 20, or Kolliphor ® RH40), cosurfactant (Plurol ® Oleique CC 497) (q.s. ad 100%), and cosolvent (glycerol or macrogol 400) (20% or 30%), and evaluate their potential as carriers for oral delivery of a poorly permeable antivirotic aciclovir (acyclovir). The drug loading capacity of the prepared formulations ranged from 0.18–31.66 mg/ml. Among a total of 60 formulations, three formulations meet the limits for average droplet size ( Z -ave) and polydispersity index (PdI) that have been set for SMEDDSs ( Z -ave ≤ 100 nm, PdI < 0.250) upon spontaneous dispersion in 0.1 M HCl and phosphate buffer pH 7.2. SMEDDSs with the highest aciclovir loading capacity (24.06 mg/ml and 21.12 mg/ml) provided the in vitro drug release rates of 0.325 mg cm −2 min −1 and 0.323 mg cm −2 min −1 , respectively, and significantly enhanced drug permeability in the parallel artificial membrane permeability assay (PAMPA), in comparison with the pure drug substance. The results revealed that development of SMEDDSs with enhanced drug loading capacity and oral delivery potential, required optimization of hydrophilic ingredients, in terms of size of hydrophilic moiety of the surfactant, surfactant-to-cosurfactant mass ratio (Km), and log P of the cosolvent. [ABSTRACT FROM AUTHOR]

To elaborate the decisive role of surfactants in promotion of aceclofenac’ skin absorption, potentially avoiding irritation, we developed non-ionic microemulsions varying natural or synthetic surfactants: sucrose esters (laurate or myristate) vs. polysorbate 80. A comprehensive physicochemical characterization indicated no significant influence of the solubilized nonsteroidal anti-inflammatory drug on the bicontinuous structure of blank formulations. To evaluate skin tolerability of isopropyl alcohol, a sucrose ester-based microemulsion containing transcutol P as a cosurfactant was also developed. The measured skin parameters strongly depended on the (co)surfactant type, showing higher compatibility of the microemulsions containing sucrose ester and isopropyl alcohol. In vitro release results, in vivo tape stripping and pharmacokinetics in rats confirmed superiority of the sucrose ester- over polysorbate-based microemulsions (total amounts of aceclofenac penetrated 60.81 ± 5.97 and 60.86 ± 3.67 vs. 27.00 ± 5.09 μg/cm 2 , and its maximum plasma concentrations 275.57 ± 109.49 and 281.31 ± 76.76 vs. 150.23 ± 69.74 ng/ml for sucrose laurate- and myristate- vs. polysorbate 80-based microemulsions, respectively). Hence, sugar-based excipients increased delivery of aceclofenac through stratum corneum by increasing its fluidity, showing overall more satisfying safety profiles. In conclusion, sucrose ester-based microemulsions proved to be promising carriers for dermal/transdermal aceclofenac delivery. [ABSTRACT FROM AUTHOR]

This paper reports studies on preparation and evaluation of amoxicillin loaded dual molecularly imprinted nanoparticles (Amo/Dual-MIPs) designed for anti- H. pylori therapy. Both MNQA and AmoNa were chosen as templates to prepare Dual-MIPs using inverse microemulsion polymerization method. NQA was modified with myristic acid (MNQA) to become amphiphilic and assist in leaving NQA cavities on the surface of Dual-MIPs for H. pylori adhesion. AmoNa was applied to produce imprinting sites in Dual-MIPs for rebinding AmoNa to exert its anti- H. pylori effect. Batch rebinding test demonstrated a preferential rebinding effect of NQA toward the Dual-MIPs. In vivo fluorescence imaging showed the prolonged residence time of Dual-MIPs in H. pylori infected mice stomachs after intragastric administration of nanoparticles. In vivo H. pylori clearance tests indicated Amo/Dual-MIPs had a better aniti- H. pylori effect than amoxicillin powder did. In conclusion, Amo/Dual-MIPs may provide an alternative drug delivery strategy for anti- H. pylori therapy. [ABSTRACT FROM AUTHOR]

In this paper, we report an ionic liquid-in-water (IL/w) microemulsion (ME) formulation which is able to solubilize etodolac (ETO), a poorly water soluble drug for topical delivery using BMIMPF 6 (1-butyl-3-methylimidazolium hexafluorophosphate) as IL, Tween 80 as surfactant and ethanol as co-surfactant. The prepared ME was characterized for physicochemical parameters, subjected to ex-vivo permeation studies as well as in-vivo pharmacodynamic evaluation. The ex-vivo drug permeation studies through rat skin was performed using Franz-diffusion cell and the IL/w based ME showed maximum mean cumulative percent permeation of 99.030 ± 0.921% in comparison to oil-in-water (o/w) ME (61.548 ± 1.875%) and oily solution (48.830 ± 2.488%) of ETO. In-vivo anti-arthritic and anti-inflammatory activities of the prepared formulations were evaluated using different rodent models and the results revealed that ETO loaded IL/w based ME was found to be more effective in controlling inflammation than oily solution, o/w ME and marketed formulation of ETO. Histopathological studies also demonstrated that IL/w based ME caused no anatomical and pathological changes in the skin. [ABSTRACT FROM AUTHOR]

Due to their high interfacial area and capability of loading hydrophobic, hydrophilic and amphiphilic drugs, self-assembled nanoparticles are the subject of much attention in view of an application of these dispersions as carrier systems for a variety of different active ingredients. Therefore, the effect of the internal nanostructure of oil-loaded monoglyceride-based nanoparticles on the dermal delivery of diclofenac sodium was investigated. The different self-assembled phases of the nanostructured aqueous dispersions were characterized by small angle X-ray scattering (SAXS). The influence of the different phases ranging from cubic-bicontinuous, over hexagonal and cubic-micellar phases to emulsified microemulsions on the dermal delivery of the incorporated active was examined by Franz-type diffusion cell and in vitro tape stripping experiments on porcine skin. These studies revealed a dependency of the skin permeation of diclofenac sodium on the formulation's internal structure, which could be modified by varying the amount of R -(+)-limonene in the oil phase. A superiority of the emulsified microemulsion, possessing the highest amount of R -(+)-limonene, over cubic or hexagonal phases was evidenced in terms of dermal drug delivery. [ABSTRACT FROM AUTHOR]

The study was designed to identify the safety and antitumor activity of teniposide self-microemulsified drug delivery system (TEN-SMEDDS) previously developed, and to provide evidence for the feasibility and effectiveness of TEN-SMEDDS for application in clinic. The TEN-SMEDDS could form fine emulsion with mean diameter of 279 ± 19 nm, Zeta potential of −6.9 ± 1.4 mV, drug loading of 0.04 ± 0.001% and entrapment efficiency of 98.7 ± 1.6% after dilution with 5% glucose, respectively. The safety, including hemolysis, hypersensitivity, vein irritation and toxicity in vivo , and antitumor activity were assessed, VUNON as a reference. Sulforhodamine B assays demonstrated that the IC50 of TEN-SMEDDS against C6 and U87MG cells were higher than that of VUMON. But the effect of TEN-SMEDDS on the cell cycle distribution and cell apoptotic rate was similar to that of VUMON as observed by flow cytometry. Likewise, the antitumor activity of TEN-SMEDDS was considerable to that of VUMON. Finally, the TEN-SMEDDS exhibited less body weight loss, lower hemolysis and lower myelosuppression as compared with VUMON. In conclusion, promising TEN-SMEDDS retained the antitumor activity of teniposide and was less likely to cause some side effects compared to VUMON. It may be favorable for the application in clinic. [ABSTRACT FROM AUTHOR]

Pseudolaric acid B (PAB) possesses comparable fungicidal activity against Candida albicans to amphotericin B and antifungal activity against azole-resistant Candida species. However, its poor water solubility makes the formulation a considerable challenge for dermal permeation of PAB. The aim of this project was to improve the solubility and eventually the dermal permeability and bioavailability by developing a microemulsion based gel for PAB (PAB ME-gel). PAB ME-gel was formulated using isopropyl myristate as oil phase, cremphor EL as surfactant, transcutol P as cosurfactant, and carbopol as gel matrix, and characterized by droplet size, morphology, pH, and rheology. The 3 month storage test showed that PAB ME-gel possessed good physicochemical stability. In vitro permeation of PAB through rat skin from ME-gel was investigated in comparison with PAB microemulsion (PAB ME) and PAB hydrogel (PAB gel), and results showed that ME significantly enhanced PAB retention in the skin and permeation through the skin whether it was incorporated into the gel or not. In vivo dermatopharmacokinetics study using microdialysis further confirmed that ME-gel significantly increased PAB dermal bioavailability compared with the gel (41.95 ± 8.89 μg/ml vs. 13.90 ± 2.22 μg/ml). In vitro sensitivity against C. albicans test indicated that the antifungal activity of PAB ME-gel increased with the increase of PAB loading, and 8 mg/g of PAB ME-gel exhibited a higher antifungal activity than that of 20 mg/g miconazole nitrate cream. In vivo antifungal activity evaluation in C. albicans infected guinea pigs showed that 8 mg/g of PAB ME-gel exhibited a higher efficacy than that of 20 mg/g miconazole nitrate cream after 7 day treatment. Overall, the results indicated that the ME enhanced in vitro permeability, in vivo dermal bioavailability, and antifungal activity of PAB. Therefore, ME-gel may be a promising approach for topical dermal delivery of PAB to treat skin fungal infection . [ABSTRACT FROM AUTHOR]

In this work, Taylor dispersion analysis was applied to the measurement of micelles (or microdroplets) molecular diffusion coefficient in micellar (or microemulsion) systems based on neutral/anionic/cationic or zwitterionic surfactants. The choice of the micellar marker and the influence the surfactant/marker concentrations on this determination are studied. Experimental results are compared to those derived from the literature using other experimental techniques. Taylor dispersion analysis, experienced in narrow capillaries, was found to be an efficient and suitable method for micelle (or microdroplet) size measurement due to: the low sample consumption, the absence of filtration requirement of the sample, the broad range of size determination (with no lower limit down to angstroms), the simplicity of the protocol, the possibility to measure the viscosity of surfactant solutions in given conditions and the determination of the weight-average micelle hydrodynamic radius. Application to the size-characterization of commercial microemulsions (Gelucire ® 44/14), used as an excipient in the pharmaceutical formulation, is provided with a comparison to DLS measurements. It was found that the polydispersity in size of the micelle did not influence the Gaussian peak shape of the taylorgram due to rapid surfactant exchange compared to the time-scale of the experiments (a few minutes). [ABSTRACT FROM AUTHOR]

Curcumin (CUR) is a poorly water-soluble drug and its absorption is very low. In this study, CUR and piperine (PIP) were co-encapsulated into the nanoformulation called self-microemulsifying drug delivery system (SMEDDS) to improve the stability and water-solubility of CUR and enhance its anti-colitis activity. The formulation of CUR-PIP-SMEDDS was prepared to encapsulate two hydrophobic components CUR and PIP, and then was characterized by assessing appearance, morphology, particle size, zeta potential and drug encapsulation efficiency. The appearance of CUR-PIP-SMEDDS remained clarified and transparent, and the microemulsion droplets appeared spherical without aggregation. The mean size of microemulsion droplet formed from CUR-PIP-SMEDDS was 15.87 ± 0.76 nm, and the drug encapsulation efficiency of SMEDDS for CUR and PIP were (94.34 ± 2.18)% and (90.78 ± 2.56)%, respectively. The vitro stability investigation of CUR-PIP-SMEDDS in colon tissue suggested that using SMEDDS as a delivery vehicle and co-encapsulated with PIP, CUR was more stable than drug solution in colons site. Meanwhile, the anti-inflammatory activity of CUR-PIP-SMEDDS was evaluated on DSS-induced colitis model. The results showed that CUR-PIP-SMEDDS exhibited definite anti-colitis activity by directing CUR-PIP-SMEDDS to inflammatory colon tissue through retention enema administration. Our study illustrated that the developed CUR-PIP-SMEDDS formulation was a potential carrier for developing colon-specific drug delivery system of CUR for ulcerative colitis treatment. [ABSTRACT FROM AUTHOR]

Microemulsions are well known penetration enhancing delivery systems. Several properties are described that influence the transdermal delivery of active components. Therefore, this study aimed to characterize fluorosurfactant-based microemulsions and to assess the impact of formulation variables on the transdermal delivery of incorporated flufenamic acid. The microemulsion systems prepared in this study consisted of bistilled water, oleic acid, isopropanol as co-solvent, flufenamic acid as active ingredient and either Hexafor TM 670 (Hex) or Chemguard S-550-100 (Sin) as fluorosurfactant. Characterization was performed by a combination of techniques including electrical conductivity measurements, small-angle X-ray scattering (SAXS) and nuclear magnetic resonance (NMR) self-diffusion experiments. In vitro skin permeation experiments were performed with each prepared microemulsion using Franz type diffusion cells to correlate their present microstructure with their drug delivery to skin. Electrical conductivity increased with added water content. Consequently, the absence of a conductivity maximum as well as the NMR and SAXS data rather suggest O/W type microemulsions with spherical or rod-like microstructures. Skin permeation data revealed enhanced diffusion for Hex- and Sin-microemulsions if the shape of the structures was rather elongated than spherical implying that the shape of droplets had an essential impact on the skin permeation of flufenamic acid. [ABSTRACT FROM AUTHOR]

A new biomembrane-mimetic liquid chromatographic method using a C 8 stationary phase and phosphatidylcholine-modified (PC-modified) microemulsion mobile phase was used to estimate unionized and ionized drugs lipophilicity expressed as an n -octanol/water partition coefficient (logP and logD). The introduction of PC into sodium dodecyl sulfate (SDS) microemulsion yielded a good correlation between logk and logD ( R 2 = 0.8). The optimal composition of the PC-modified microemulsion liquid chromatography (PC-modified MELC) mobile phase was 0.2% PC—3.0% SDS—6.0% n -butanol—0.8% ethyl acetate—90.0% water (pH 7.0) for neutral and ionized molecules. The interactions between the analytes and system described by this chromatographic method is more similar to biological membrane than the n -octanol/water partition system. The result in this paper suggests that PC-modified MELC can serve as a possible alternative to the shake-flask method for high-throughput unionized and ionized drugs lipophilicity determination and simulation of biological processes. [ABSTRACT FROM AUTHOR]

The toxicity and irritation associated with high amounts of surfactants restrict the extensive utilization of microemulsions. To address these shortcomings, employing mixed oils to enlarge microemulsion areas therefore reducing surfactant contents is a promising strategy. However, what kinds of mixed oils are more efficient in enlarging microemulsion areas still remains unclear. In this research, we found that the chain length and degree of unsaturation of oils play a key role in enlarging microemulsion areas. The combination of moderate chain saturated oil caprylic/capric triglyceride (GTCC) with long chain unsaturated oil glycerol trioleate significantly increased the microemulsion areas. Solubility of ibuprofen in the mixed oils was unexpectedly and remarkably increased (almost 300 mg/mL) compared with that (around 100 mg/mL) of the single oil (GTCC), which also resulted in greatly increased solubility of ibuprofen in mixed oils-containing microemulsions. By optimizing the mixed oil formulation, the absolute amount of surfactant in drug-loaded microemulsions was reduced but increased drug oral bioavailability in rats was maintained. It could be concluded that the combined use of moderate chain oils and long chain unsaturated oils could not only acquire enlarged microemulsion areas but also enhanced drug solubility, therefore doubly reducing surfactant amount, which is extremely beneficial for developing safe microemulsions. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the transdermal delivery potential of a new curcumin-containing microemulsion system. Three series of experiments were carried out to comprehend the system characteristics: (a) examining the influence of water content on curcumin permeation, (b) studying the effect of curcumin loading on its permeability, and (c) assessing the contribution of the vesicular nature of the microemulsion on permeability. The skin permeability of curcumin from microemulsions, which contained 5%, 10%, and 20% of water content (1% curcumin), was measured in vitro using excised rat skin. It has been shown that the permeability coefficient of CUR in a formulation containing 10% aqueous phase (ME-10) was twofold higher than the values obtained for formulations with 5% and 20% water ( P app = 0.116 × 10 −3 ± 0.052 × 10 −3 vs . 0.043 × 10 −3 ± 0.022 × 10 −3 and 0.047 × 10 −3 ± 0.025 × 10 −3 cm/h, respectively. A reasonable explanation for this phenomenon may be the reduction of both droplet size and droplets’ concentration in the microemulsion as the aqueous phase decreased from 20% to 5%. It has also been shown that a linear correlation exists between the decrease in droplet size and the increase of curcumin loading in the microemulsion. In addition, it has been demonstrated that a micellar system, S/O-mix, and a plain solution of curcumin resulted in a significantly lower curcumin permeation relative to that presented by the microemulsion, P app = 0.018 × 10 −3 ± 0.011 × 10 −3 , 0.005 × 10 −3 ± 0.002 × 10 −3 , and 0.002 × 10 −3 ± 0.000 × 10 −3 cm/h, respectively, vs . 0.110 × 10 −3 ± 0.021 × 10 −3 cm/h for the microemulsion. The enhancement ratio (ER = J ss-ME / J ss-solution ) of CUR permeated via 1% loaded microemulsion was 55. [ABSTRACT FROM AUTHOR]