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Novel liquid crystal nanoparticles (LCNs) composed of isostearyl glyceryl ether (GE-IS) and ethoxylated hydrogenated castor oil (HCO-60) were developed for the enhanced transdermal delivery of 4-biphenyl acetic acid (BAA). The physical properties and pharmaceutical properties of the LCNs were measured. The interaction between the intercellular lipid model of the stratum corneum and the LCNs was observed to elucidate the skin permeation mechanism. In the formulation, the LCNs form niosomes with mean particles sizes of 180-300 nm. The skin absorption mechanisms of LCNs are different, depending upon the application and buffer concentration. The LCNs composed of GE-IS and HCO-60 are attractive tools for use as transdermal drug delivery systems carriers for medicines and cosmetics, due to their high efficiency and safety., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Despite the great potential of peptides as therapeutics, there is an unmet challenge in sustaining delivery of sufficient amounts in their native forms. This manuscript describes a novel nanocarrier capable of delivering functional small peptides in its native form. Self-assembling multi-layered nanomicelles composed of two polymers, polyoxyethylene hydrogenated castor oil 40 (HCO-40) and octoxynol 40 (OC-40), were designed to combine hydrophilic interaction and solvent-induced encapsulation of peptides and proteins. The polymers are employed to encapsulate peptide or protein in the core of the organo-nanomicelles which are further encapsulated with another layer of the same polymers to form an aqueous stable nanomicellar solution. The size of the multi-layered nanomicelles ranges from ~ 16 to 20 nm with zeta potential close to neutral (~ - 2.44 to 0.39 mV). In vitro release studies revealed that octreotide-loaded multi-layered nanomicelles released octreotide at much slower rate in simulated tear fluid (STF) (~ 27 days) compared to PBST (~ 11 days) in its native form. MTT assay demonstrated negligible toxicity of the multi-layered nanomicelles at lower concentrations in human retinal pigment epithelial (HRPE, D407), human conjunctival epithelial (CCL 20.2), and rhesus choroid-retinal endothelial (RF/6A) cells. This work demonstrates an efficient small peptide delivery platform with significant advantages over existing approaches, as it does not require modification of the peptide, is biodegradable, and has a small size and high loading capacity.

Background: The use of dihydroartemisinin (DHA) for effective malaria treatment is challenged by its poor aqueous solubility and inadequate bioavailability leading to treatment failures and emergence of resistant strains. A review of some novel drug delivery systems developed to address these challenges and their patents revealed that no study has reported the application of surface modified lipid nanoemulsions for improved antimalarial activity of DHA., Objective: The main thrust of this study is to develop oral dihydroartemisinin formulations solubilized in surface modified lipid nanoemulsions, characterize, and evaluate their activity against murine malaria., Method: Lipid nanoemulsions containing dihydroartemisinin were formulated by high pressure homogenization using soybean oil, and polyethylene glycol 4000 was employed for surface modification. The formulations were characterized for droplet size, surface charge, pH, fouriertransform infrared spectroscopy, and surface morphology, viscosity and drug content efficiency. In vitro haemolytic study as a function of cytotoxicity using red blood cells as well as in vivo anti-malarial study using murine malaria model was also investigated., Results: Nanoemulsions recorded droplet sizes ranging from 26 - 56 nm, and zeta potential in the range of -28 to -35 mV. The formulations were slightly acidic (pH 4.4 - 5.8) with the drug molecularly dispersed as seen using infrared spectroscopy. The formulations showed non- Newtonian flow with significant drug content efficiency in the range of 77-96%. The formulations did not induce haemolysis of cells and showed good clearance of parasitaemia., Conclusion: Surface-modified lipid nanoemulsion is a perfect carrier system for improving the anti-malarial activity of dihydroartemisinin., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Lipid-based drug delivery systems, a well-tolerated class of formulations, have been evaluated extensively to enhance the bioavailability of poorly soluble drugs. However, it has been difficult to predict the in vivo performance of lipid dosage forms based on conventional in vitro techniques such as cell monolayer permeability studies because of the complexity of the gastrointestinal processing of lipid formulations. In the current study, we explored the feasibility of coupling Caco-2 and Madin-Darby canine kidney monolayer permeability studies with lipolysis, a promising in vitro technique to evaluate lipid systems. A self-emulsifying lipid delivery system was formulated using a blend of oil (castor oil), surfactant (Labrasol® or PL497), and co-surfactant (lecithin). Formulations demonstrating high drug solubility and rapid self-emulsification were selected to study the effect of lipolysis on in vitro cell permeability. Lipolysis of the formulations was carried out using pancreatin as the digestive enzyme. All the digested formulations compromised monolayer integrity as indicated by lowered trans-epithelial electrical resistance (TEER) and enhanced Lucifer yellow (LY) permeability. Further, the changes in TEER value and LY permeability were attributable to the digestion products of the formulation rather than the individual lipid excipients, drug, digestion enzyme, or the digestion buffer. The digested formulations were fractionated into pellet, oily phase, and aqueous phase, and the effect of each of these on cell viability was examined. Interestingly, the aqueous phase, which is considered important for in vivo drug absorption, was responsible for cytotoxicity. Because lipid digestion products lead to disruption of cell monolayer, it may not be appropriate to combine lipolysis with cell monolayer permeability studies. Additional in vivo studies are needed to determine any potential side effects of the lipolysis products on the intestinal permeability barrier, which could determine the suitability of lipid-based systems for oral drug delivery.

This study investigates the effect of monoacyl phospholipid incorporation on the in vitro and in vivo performance of self-emulsifying drug delivery systems (SEDDS). Monoacyl phosphatidylcholine (Lipoid S LPC 80 (LPC)) was incorporated into four different fenofibrate (FF)-loaded long-chain SEDDS to investigate the impact of LPC on the emulsion droplet size, extent of digestion, colloidal structure evolution and drug precipitation during in vitro lipolysis simulating human conditions and drug bioavailability in a rat model. The four investigated SEDDS containing long-chain glycerides, polyoxyl 35 castor oil or polyoxyl 8 caprylocaproyl glycerides with or without LPC. In situ synchrotron small/wide-angle X-ray scattering (SAXS/WAXS) was used to simultaneously real-time monitor the kinetics of lamellar phase structure development and FF crystalline precipitation. Adding LPC increased the particle size and polydispersity of the dispersed SEDDS. The two LPC-free SEDDS generated lamellar phase structures (Lα) with d-spacing=4.76nm during digestion. Incorporating LPC into these systems inhibited the formation of lamellar phase structures. The amount of precipitated crystalline FF from the four SEDDS was similar during the first 15min but differed during the last 45min of in vitro digestion. The kinetics of colloidal structure development and FF precipitation was related to the digestion kinetics. The in vivo bioavailability data showed no significant differences between the four SEDDS, which correlates with the in vitro FF precipitation during the first 15min of lipolysis. Thus, the presence of LPC, different emulsion droplet sizes and concentration of lamellar phase structures observed in vitro did not correlate with the FF absorption in rats. The study suggests that later time points of the in vitro lipolysis overestimated FF precipitation in rats because of the high enzyme activity, the lack of gastric and absorption steps, and the low bile salts and phospholipid concentrations of the in vitro model., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Context: Levosulpiride (LSP) is a hydrophobic benzamide derivative used in the treatment of schizophrenia. SNEDDS were extensively practiced for systemic delivery of poorly aqueous soluble drugs to achieve maximum bioavailability., Objective: The present study was focussed on the formulation, optimisation and evaluation of LSP SNEDDS using castor oil, for enhancement of drug absorption and bioavailability., Materials and Methods: Pseudo-ternary phase diagram was plotted to identify the range of SNEDDS components. Twenty formulations were designed, prepared and characterised by its particle size, zeta potential, viscosity, and stability. In vitro dissolution data modelling was performed. Microscopy, FTIR and in vivo bioavailability studies were conducted for optimum formulation. Results, discussion and conclusion: F18 containing castor oil, 0.9 mL; PEG 600, 1.36 mL and Tween 80, 2.74 mL was found to be optimum. The optimised formulation had shown uniform globule size, no interactions of LSP with SNEDDS components and higher pharmacokinetic parameters than that of commercial preparation.

The oral absorption of dronedarone (DRN), a benzofuran derivative with anti-arrhythmic activity, is significantly affected by food intake. The absolute bioavailability of the marketed product (Multaq, Sanofi, U.S.) was about 4% without food, but increased to 15% when administered with a high fat meal. Therefore, to reduce the food-effect on the intestinal absorption of DRN, a novel self-microemulsifying drug delivery system (SMEDDS) was formulated and the comparative in vivo absorption studies with the marketed product were carried out using male beagle dogs either in the fasted or fed state. The SMEDDS consisted of the drug, Labrafil M 1944CS, and Kolliphor EL in a weight ratio of 1 : 1 : 2, rapidly formed a fine oil-in-water emulsion with a droplet size less than 50 nm. An in vivo absorption study revealed that the area-under-curve (AUC0-24 h) and maximal plasma concentration (Cmax) were 10.4-fold (p<0.05) and 8.6-fold (p<0.05) higher, respectively, after the marketed product was orally administered to beagles in the fed state when compared to those in the fasted state. This food-effect were remarkably alleviated by SMEDDS formulation, with AUC0-24 h and Cmax 2.9-fold (p<0.05) and 2.6-fold (p<0.05) higher in the fed state when compared to the fasted state, by facilitating intestinal absorption of DRN in the fasted state. The results of this study suggest that SMEDDS may decrease the differences in oral absorption of DRN between the prandial states, improving therapeutic efficacy as well as patient compliance.

Quercetin is a dietary flavonoid with potential chemoprotective effects, but has low bioavailability because of poor aqueous solubility and low intestinal absorption. A quercetin-containing self-nanoemulsifying drug delivery system (Q-SNEDDS) was developed to form oil-in-water nanoemulsions in situ for improving quercetin oral bioavailability. On the basis of the quercetin solubility, emulsifying ability, and stability after dispersion in an aqueous phase, an optimal SNEDDS consisting of castor oil, Tween® 80, Cremophor® RH 40, and PEG 400 (20:16:34:30, w/w) was identified. Upon mixing with water, Q-SNEDDS formed a nanoemulsion having a droplet size of 208.8 ± 4.5 nm and zeta potential of -26.3 ± 1.2 mV. The presence of Tween® 80 and PEG 400 increased quercetin solubility and maintained supersaturated quercetin concentrations (5 mg/mL) for >1 month. The optimized Q-SNEDDS significantly improved quercetin transport across a human colon carcinoma (Caco-2) cell monolayer. Fluorescence imaging demonstrated rapid absorption of the Q-SNEDDS within 40 min of oral ingestion. Following oral administration of Q-SNEDDS in rats (15 mg/kg), the area under the concentration curve and maximum concentration of plasma quercetin after 24 h increased by approximately twofold and threefold compared with the quercetin control suspension. These data suggest that this Q-SNEDDS formulation can enhance the solubility and oral bioavailability of quercetin for appropriate clinical application., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Objective: To develop the self-emulsifying drug delivery system (SEDDS) of curcumin, and evaluate its quality in vitro., Methods: The excipients of curcumin SEDDS were selected via its solubility study in various oils, surfactants and co-surfactants and the formulation was optimized using ternary phase diagram study and central composite design-response surface methodology (oil, surfactant and co-surfactant percentages as factors; solubility, droplet size, polydispersity index and emulsifying time as responses). The appearance, droplet size and polydispersity index after emulsifying and the emulsifying time of optimized curcumin SEDDS were studied. The solubility of curcumin in the solution of SEDDS was determined., Results: Castor oil-(tween-80) -ethanol = 28: 55: 20 (w/ w/w) was selected for optimum curcumin SEDDS. The droplet size was 222. 2 nm, polydispersity index was 0. 171. The time of self-emulsifying was 10 s and the solubility of curcumin in SEDDS was 1.93 mg/mL., Conclusion: Curcumin SEDDS formulation is selected and optimized successfully, and the preparation of curcumin SEDDS is simple, the quality is stable.

Poly (lactic-co-glycolic acid) (PLGA) was used as a co-emulsifier in the preparation of insulin-loaded solid lipid nanoparticles (SLN) with hydrogenated castor oil as lipid matrix and lecithin as surfactant by double-emulsion technique. The effects of PLGA on the preparation and hypoglycaemic activity of insulin-loaded SLN were studied. The results showed that with the supplement of PLGA, the encapsulation efficiency and loading capacity were increased significantly from 79.08 +/- 1.62 to 85.57 +/- 3.21% and 1.58 +/- 0.03 to 1.71 +/- 0.06%, whereas the surface charge and particle size were changed insignificantly from -25.87 +/- 2.65 to -22.67 +/- 1.19 mv and 431.0 +/- 16.1 to 397.0 +/- 68.0 nm, respectively. In vivo studies demonstrated that PLGA increased the sustained hypoglycaemic activity from 12 to 36 h and 24 to 120 h in normal and steptozotocin-induced diabetic mice after a single intramuscular injection of the insulin-loaded SLN. These results demonstrated that PLGA could enhance the entrapment of insulin in the nanoparticles, and more importantly, prolong the time of hypoglycaemic activity of the insulin-loaded SLN.

Tilmicosin-loaded solid lipid nanoparticles (SLN) were prepared with hydrogenated castor oil (HCO) by o/w emulsion-solvent evaporation technique. The nanoparticle diameters, surface charges, drug loadings and encapsulation efficiencies of different formulations were 90 approximately 230 nm, -6.5 approximately -12.5 mV, 40.3 approximately 59.2% and 5.7 approximately 11.7% (w/w), respectively. In vitro release studies of the tilmicosin-loaded nanoparticles showed a sustained release and the released tilmicosin had the same antibacterial activity as that of the free drug. Pharmacokinetics study after subcutaneous administration to Balb/c mice demonstrated that a single dose of tilmicosin-loaded nanoparticles resulted in sustained serum drug levels (>0.1 microg/mL) for 8 days, as compared with only 5 h for the same amount of tilmicosin phosphate solution. The time to maximum concentration (Tmax), half-life of absorption (T(1/2) ab) and half-life of elimination (T(1/2) el) of tilmicosin-loaded nanoparticles were much longer than those of tilmicosin phosphate solution. Tissue section showed that drug-loaded nanoparticles caused no inflammation at the injection site. Cytotoxicity study in cell culture and acute toxicity test in mice demonstrated that the nanoparticles had little or no toxicity. The results of this exploratory study suggest that the HCO-SLN could be a useful system for the delivery of tilmicosin by subcutaneous administration.

Silymarin has been used to treat hepatobiliary diseases. However, it has a low bioavailability after being administered orally on account of its low solubility in water. In order to improve the dissolution rate, silymarin was formulated in the form of a self-microemulsifying drug delivery system (SMEDDS). The optimum formulation of SMEDDS containing silymarin was obtained based on the study of pseudo-ternary phase diagram. The SMEDDS consisted of 15% silymarin, 10% glyceryl monooleate as the oil phase, a mixture of polysorbate 20 and HCO-50 (1:1) as the surfactant, Transcutol as the cosurfactant with a surfactant/cosurfactant ratio of 1. The mean droplet size of the oil phase in the microemulsion formed from the SMEDDS was 67 nm. The % release of silybin from the SMEDDS after 6 hours was 2.5 times higher than that from the reference capsule. After its oral administration to rats, the bioavailability of the drug from the SMEDDS was 3.6 times higher than the reference capsule.

To improve transgene expression of a non-viral gene delivery system, an Epstein-Barr virus (EBV)-based plasmid and cationic emulsion complex was prepared and evaluated. Cationic emulsion was formulated with castor oil, 3-N-(N',N'-dimethylaminoethane)-carbamoyl cholesterol (DC-Chol) and other co-emulsifiers. An EBV-based plasmid containing the two EBV components, origin of replication (oriP) and EBV nuclear antigen 1 (EBNA-1), was constructed. The physical characteristics of the emulsion and the emulsion/DNA complex were determined. After cells were transfected with cationic emulsion/EBV-based plasmid complex, transfection efficiency and expression pattern were evaluated using green fluorescent protein (GFP) as a reporter. The average particle size and zeta potential of the emulsion itself were 96 nm and + 17 mV, respectively. The emulsion showed stable size distribution up to at least one month. With an increase of emulsion to DNA ratio, zeta-potential increased from negative to positive and the particle size decreased to 200-300 nm. The complex was stable against DNase I digestion and showed comparable transfection efficiency with Lipofectin for several tested cell lines. An enhanced and prolonged gene expression was achieved using EBV-based plasmid and cationic emulsion complex. Combining physically stable emulsion with self-replicating EBV-based plasmid may confer more effective gene expression.

The aim of the present study was to prepare and evaluate an optimized, self-nanoemulsified drug delivery system of ubiquinone. A 3-factor, 3-level Box-Behnken design was used for the optimization procedure with the amounts of Polyoxyl 35 castor oil (X1), medium-chain mono- and diglyceride (X2), and lemon oil (X3) as the independent variables. The response variable was the cumulative percentage of ubiquinone emulsified in 10 minutes. Different ubiquinone release rates were obtained. The amount released ranged from 11% to 102.3%. Turbidity profile revealed 3 regions that were used to describe the progress of emulsion formation: lag phase, pseudolinear phase, and plateau turbidity. An increase in the amount of surfactant decreased turbidity values and caused a delay in lag time. Addition of cosurfactant enhanced the release rates. Increasing the amount of the eutectic agent was necessary to overcome drug precipitation especially at higher loading of surfactants and cosurfactants. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The regression equation generated for the cumulative percentage emulsified in 10 minutes was Y1 = 90.9 - 22.1X1 + 5.03X2 + 13.95X3 + 12.13X1X2 + 15.13X1X3 - 14.40X1(2) - 6.25X3(2). The optimization model predicted a 93.4% release with X1, X2, and X3 levels of 35, 35, and 30 respectively. The observed responses were in close agreement with the predicted values of the optimized formulation. This demonstrated the reliability of the optimization procedure in predicting the dissolution behavior of a self-emulsified drug delivery system.