Nanoemulsion Delivery System Research Articles

Eugenol improves physical and chemical stabilities of nanoemulsions loaded with β-carotene

Food-grade nanoemulsions are potential vehicles of labile lipophilic compounds such as β-carotene, but much work is needed to improve physical and chemical stabilities. The objective of this work was to study impacts of eugenol on physical and chemical stabilities of β-carotene-loaded nanoemulsions prepared with whey protein and lecithin. The combination of whey protein and lecithin resulted in stable nanoemulsions with eugenol added at 10% mass of soybean oil. Nanoemulsions, especially with eugenol, drastically reduced the degradation of β-carotene during ambient storage, heating at 60 and 80°C, and UV radiation at 254, 302, and 365nm. The droplet diameter of the nanoemulsion without eugenol increased from 153.6 to 227.3nm after 30-day ambient storage, contrasting with no significant changes of nanoemulsions with eugenol. Heating or UV radiation up to 8h did not significantly change the droplet diameter. Therefore, eugenol can be used to improve the stability of nanoemulsion delivery systems.

Nanoemulsion delivery systems for oil-soluble vitamins: Influence of carrier oil type on lipid digestion and vitamin D3 bioaccessibility

The influence of carrier oil type on the bioaccessibility of vitamin D3 encapsulated within oil-in-water nanoemulsions prepared using a natural surfactant (quillaja saponin) was studied using a simulated gastrointestinal tract (GIT) model: mouth; stomach; small intestine. The rate of free fatty acid release during lipid digestion decreased in the following order: medium chain triglycerides (MCT)>corn oil≈fish oil>orange oil>mineral oil. Conversely, the measured bioaccessibility of vitamin D3 decreased in the following order: corn oil≈fish oil>orange oil>mineral oil>MCT. These results show that carrier oil type has a considerable impact on lipid digestion and vitamin bioaccessibility, which was attributed to differences in the release of bioactives from lipid droplets, and their solubilization in mixed micelles. Nanoemulsions prepared using long chain triglycerides (corn or fish oil) were most effective at increasing vitamin bioaccessibility.

Nanoemulsions as delivery systems of hydrophobic silybin from silymarin extract: Effect of oil type on silybin solubility, in vitro bioaccessibility and stability

The potential of nanoemulsion delivery systems to carry silybin from silymarin extract was studied. To this purpose, sunflower oil, extra virgin olive oil and castor oil were used to prepare silymarin loaded nanoemulsions. The effect of oil type on the silybin solubility and in vitro bioaccessibility was evaluated. Moreover, the changes in particle size, silybin concentration, oxygen consumption and hydroperoxide concentration were studied in nanoemulsions during storage at 20 °C. Results showed that silybin can be successfully incorporated into physically stable nanoemulsions prepared with the different oils. The oil type slightly influenced the silybin in vitro bioaccessibility, while it affected the nanoemulsion particle size as well as silybin stability during storage. In particular, silybin underwent degradation, showing lower stability in extra virgin oil and sunflower oil than in castor oil. Results also showed that the presence of the silymarin extract containing silybin did not affect the oxidation kinetics of the carrier oils.

Comparative Biodistribution and Pharmacokinetic Analysis of Cyclosporine-A in the Brain upon Intranasal or Intravenous Administration in an Oil-in-Water Nanoemulsion Formulation.

The main objective of this study was to evaluate comparative biodistribution and pharmacokinetics of cyclosporine-A (CsA) following intranasal (IN) administration versus intravenous (IV) administration in Sprague-Dawley rats using an oil-in-water nanoemulsion delivery system. CsA, a hydrophobic peptide that is also a substrate for P-glycoprotein, is a well-known immunosuppressive agent. In the brain, CsA has been shown to be a potent anti-inflammatory and neuroprotective agent. CsA nanoemulsions (CsA-NE) and solution formulations (CsA-S) were prepared using an ultrasonication method and were characterized for drug content, encapsulation efficiency, globule size, and zeta potential. We compared the uptake of CsA-NE and CsA-S in brain regions and peripheral organs following IN and IV administration using LC-MS/MS based bioanalytical method. CsA-NE IN resulted in the highest accumulation compared to that with any other treatment and route of administration; this was consistent for all three regions of brain that were evaluated (olfactory bulbs, mid brain, and hind brain). The brain/blood exposure ratios of 4.49, 0.01, 0.33, and 0.03 for CsA-NE (IN), CsA-NE (IV), CsA-S (IN), and CsA-S (IV), respectively, indicated that CsA-NE is capable of direct nose-to-brain transport, bypassing the blood-brain barrier. Furthermore, CsA-NE administration reduces nontarget organ exposure. These studies show that IN delivery of CsA-NE is an effective way of brain targeting compared to that of other treatment strategies. This approach not only enhances the brain concentration of the peptide but also significantly limits peripheral exposure and the potential for off-target toxicity.

A Cationic Nanoemulsion for the Delivery of Next-generation RNA Vaccines

Nucleic acid-based vaccines such as viral vectors, plasmid DNA, and mRNA are being developed as a means to address a number of unmet medical needs that current vaccine technologies have been unable to address. Here, we describe a cationic nanoemulsion (CNE) delivery system developed to deliver a self-amplifying mRNA vaccine. This nonviral delivery system is based on Novartis's proprietary adjuvant MF59, which has an established clinical safety profile and is well tolerated in children, adults, and the elderly. We show that nonviral delivery of a 9 kb self-amplifying mRNA elicits potent immune responses in mice, rats, rabbits, and nonhuman primates comparable to a viral delivery technology, and demonstrate that, relatively low doses (75 µg) induce antibody and T-cell responses in primates. We also show the CNE-delivered self-amplifying mRNA enhances the local immune environment through recruitment of immune cells similar to an MF59 adjuvanted subunit vaccine. Lastly, we show that the site of protein expression within the muscle and magnitude of protein expression is similar to a viral vector. Given the demonstration that self-amplifying mRNA delivered using a CNE is well tolerated and immunogenic in a variety of animal models, we are optimistic about the prospects for this technology.

Extraction of catechins from decaffeinated green tea for development of nanoemulsion using palm oil and sunflower oil based lipid carrier systems

Catechins were extracted using hot water at various temperatures from supercritical CO2 decaffeinated green tea. The catechins extract were encapsulated at a concentration of 0.1% (w/w) in lipid based nanoemulsion delivery systems using sunflower oil and palm oil with the combination of hydrophilic and lipophilic emulsifiers. Four different formulations were prepared in a two-step process involving high shear and high pressure homogenization. The formulations were characterized for their physicochemical properties such as mean emulsion size, pH, conductivity, refractive index, peroxide value and physical stability under accelerated aging. The presence of catechins in the encapsulated matrix was confirmed by conducting different chemical assays. The oxidation of nanoemulsions was successfully arrested by the catechins in all the formulations. Physically and chemically stable emulsions were obtained from sunflower oil with no significant variation in droplet diameter, conductivity, refractive index and pH up to 14days.

Potent immune responses in rhesus macaques induced by nonviral delivery of a self-amplifying RNA vaccine expressing HIV type 1 envelope with a cationic nanoemulsion.

Self-amplifying messenger RNA (mRNA) of positive-strand RNA viruses are effective vectors for in situ expression of vaccine antigens and have potential as a new vaccine technology platform well suited for global health applications. The SAM vaccine platform is based on a synthetic, self-amplifying mRNA delivered by a nonviral delivery system. The safety and immunogenicity of an HIV SAM vaccine encoding a clade C envelope glycoprotein formulated with a cationic nanoemulsion (CNE) delivery system was evaluated in rhesus macaques. The HIV SAM vaccine induced potent cellular immune responses that were greater in magnitude than those induced by self-amplifying mRNA packaged in a viral replicon particle (VRP) or by a recombinant HIV envelope protein formulated with MF59 adjuvant, anti-envelope binding (including anti-V1V2), and neutralizing antibody responses that exceeded those induced by the VRP vaccine. These studies provide the first evidence in nonhuman primates that HIV vaccination with a relatively low dose (50 µg) of formulated self-amplifying mRNA is safe and immunogenic.

Enhance intestinal lymphatic transport of lipophilic bioactive food components by nanoemulsion delivery system (1044.16)

One way to enhance bioavailability of lipophilic nutraceuticals is to facilitate their intestinal lymphatic transport. We studied the effects of triglycerides‐based nanoemulsion delivery systems with different fatty acid chain lengths on the intestinal lymphatic transport of a highly lipophilic flavonoid, 5‐demethylnobiletin (5DN). 5DN was encapsulated in medium chain triglycerides (MCT) or long chain triglycerides (LCT) based nanoemulsions. These systems were subject to a simulated gastrointestinal digestion model. The resulted mixed micelle phase that contained bioaccessible portion of 5ND was applied to Caco‐2 monolayer cell model that mimics intestinal absorption. We observed that 30% of 5DN underwent intestinal lymphatic transport when 5DN was encapsulated in LCT‐based emulsion, while only 5% of 5DN underwent intestinal lymphatic transport in case of MCT‐based emulsion. Moreover, much more Apo B protein was secreted in the enterocytes by the stimulation of the digesta produced from LCT‐based emulsion in comparison to MCT‐based emulsion. This suggested more chylomicrons were formed in the enterocytes as the result of digestion of LCT‐based emulsion. In conclusion, we demonstrated that LCT‐based emulsion was more potent in enhancing the bioavailability of lipophilic components through increased lymphatic transport in comparison to MCT‐based emulsion.Grant Funding Source: Supported by USDA

New lumefantrine self nanoemulsifying delivery system – will it by-pass lymphatic transport mechanisms?

Dear editor-in-chief The recently published article in the esteemed journal entitled “Design and evaluation of Lumefantrine – Oleic acid self nanoemulsifying ionic complex for enhanced dissolution” [1], describes an in-depth research pertaining to the formulation attributes of lumefantrine, an important ani-malarial drug, to enhance its in vitro dissolution and thereby improving its bioavailability upon oral administration. As discussed by authors’ poor solubility of novel chemical entities (NCEs) leads to lack of in vivo translation of the promising in vitro attributes of NCEs because they fail to achieve adequate exposure needed to modulate the target or receptors under in vivo conditions [1]. Since lumefantrine has a low and variable bioavailability dependent on the food intake, it is extremely challenging to maintain the threshold levels of the drug needed to combat malarial infections [2]. While the dosing recommendation of lumefantrine takes into consideration food intake especially milk consumption to improve its solubility and bioavailability, it may be difficult to maintain the same food intake conditions within the same individual or across individuals who are suffering from malaria. Therefore, the need of a formulation strategy to overcome this barrier and maximize the delivery of lumefantrine was warranted. In this context, the development and complete characterization of a self nanoemulsifying delivery system is the step in the right direction as it potentially eliminates the influence of food on the bioavailability of lumefantrine [1]. In this interesting work, a complete optimization of the nanoemulsifying delivery system has been achieved – consideration has been given to the various excipients and the composition needed to maximize the dissolution of lumefantrine [1]. Interestingly, comparative dissolution profiles of the current marketed formulation vs the newly developed lumefantrine nanoemulsifying delivery system,

Design and evaluation of Lumefantrine – Oleic acid self nanoemulsifying ionic complex for enhanced dissolution

BackgroundLumefantrine, an antimalarial molecule has very low and variable bioavailability owing to its extremely poor solubility in water. It is recommended to be taken with milk to enhance its solubility and bioavailability. The aim of present study was to develop a Self Nanoemulsifying Delivery system (SNEDs) of lumefantrine (LF) to achieve rapid and complete dissolution independent of food-fat and surfactant in dissolution media.MethodsSolubility of LF in oil, co-solvent/co-surfactant and surfactant solution and emulsification efficiency of surfactant were analyzed to optimize the LF loaded self nanoemulsifying preconcentrate. Effect of LF-oleic acid complexation on emulsification, droplet size, zeta potential and dissolution were investigated. Effect of milk concentration and fat content on saturation solubility and dissolution of LF was investigated. Dissolution of marketed formulation and LF-SNEDs was carried out in pH 1.2 and pH 6.8 phosphate buffer.ResultsLF exhibited very high solubility in oleic acid owing to complexation between tertiary amine of LF and carboxyl group of oleic acid (OA). Cremophore EL and medium chain monoglyceride were selected surfactant and co-surfactant, respectively. Significantly smaller droplet size (37 nm), shift in zeta potential from negative to positive value, very high drug loading in lipid based system (> 10%), no precipitation after dissolution are the major distinguish characteristics contributed by LF-OA complex in the SNED system. Saturation solubility and dissolution study in milk containing media pointed the significant increment in solubility of LF in the presence of milk-food fat. LF-SNEDs showed > 90% LF release within 30 min in pH 1.2 while marketed tablet showed almost 0% drug release.ConclusionSelf nanoemulsification promoting ionic complexation between basic drug and oleic acid hold great promise in enhancing solubility of hydrophobic drugs.

Nanoemulsion delivery systems: Influence of carrier oil on β-carotene bioaccessibility

Consumption of carotenoids may reduce the incidences of certain chronic diseases, but their use in foods is currently limited because of their poor water-solubility, low bioavailability and chemical instability. We examined the impact of carrier oil type on the bioaccessibility of β-carotene encapsulated within nanoemulsion-based delivery systems. Oil-in-water nanoemulsions (d<200nm) were formed using a non-ionic surfactant (Tween 20) as emulsifier and long chain triglycerides (LCT), medium chain triglycerides (MCT) or orange oil as carrier oils. The influence of carrier oil type on β-carotene bioaccessibility was established using an in vitro model to simulate the oral, gastric and small intestinal phases of the gastrointestinal tract. The rate and extent of free fatty acid production in the intestine decreased in the order LCT≈MCT≫orange oil; whereas β-carotene bioaccessibility decreased in the order LCT≫MCT>orange oil. The bioaccessibility of β-carotene was negligible (≈0%) in orange oil nanoemulsions because no mixed micelles were formed to solubilise β-carotene, and was relatively low (≈2%) in MCT nanoemulsions because the mixed micelles formed were too small to solubilise β-carotene. In contrast, β-carotene bioaccessibility was relatively high (≈66%) in LCT nanoemulsions. Our results have important implications for the design of effective delivery systems for encapsulation of carotenoids and other lipophilic bioactive components.

Design of nanoemulsion-based delivery systems of natural antimicrobials: Effect of the emulsifier

This work aims at investigating the effect of the nanoemulsion delivery systems on the antimicrobial activity of different essential oil components. Carvacrol, limonene and cinnamaldehyde were encapsulated in the sunflower oil droplets of nanoemulsions prepared by high pressure homogenization and stabilized by different emulsifiers: (a) lecithin, (b) pea proteins, (c) sugar ester and (d) a combination of Tween 20 and glycerol monooleate. The antimicrobial activity was measured against three different microorganisms, such as Escherichia coli, Lactobacillus delbrueckii and Saccharomyces cerevisiae. The measured antimicrobial activity was significantly affected by the formulation of the nanoemulsion, where the different bioactive compounds were encapsulated. In particular, the effect of the delivery systems on the antimicrobial activity was correlated to the concentration of the essential oil components in the aqueous phase in equilibrium with the nanoemulsion droplets, suggesting that the ability of the active molecules to interact with cell membranes is associated to their dissolution in the aqueous phase. These considerations can lead to a more rational design of the nanoemulsion-based delivery systems for essential oils, based on the opportune choice of the emulsifiers in dependence of the desired function of the antimicrobials within the food system.

Formulation and in vitro release evaluation of newly synthesized palm kernel oil esters-based nanoemulsion delivery system for 30% ethanolic dried extract derived from local Phyllanthus urinaria for skin antiaging.

BackgroundRecently there has been a remarkable surge of interest about natural products and their applications in the cosmetic industry. Topical delivery of antioxidants from natural sources is one of the approaches used to reverse signs of skin aging. The aim of this research was to develop a nanoemulsion cream for topical delivery of 30% ethanolic extract derived from local Phyllanthus urinaria (P. urinaria) for skin antiaging.MethodsPalm kernel oil esters (PKOEs)-based nanoemulsions were loaded with P. urinaria extract using a spontaneous method and characterized with respect to particle size, zeta potential, and rheological properties. The release profile of the extract was evaluated using in vitro Franz diffusion cells from an artificial membrane and the antioxidant activity of the extract released was evaluated using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH) method.ResultsFormulation F12 consisted of wt/wt, 0.05% P. urinaria extract, 1% cetyl alcohol, 0.5% glyceryl monostearate, 12% PKOEs, and 27% Tween® 80/Span® 80 (9/1) with a hydrophilic lipophilic balance of 13.9, and a 59.5% phosphate buffer system at pH 7.4. Formulation F36 was comprised of 0.05% P. urinaria extract, 1% cetyl alcohol, 1% glyceryl monostearate, 14% PKOEs, 28% Tween® 80/Span® 80 (9/1) with a hydrophilic lipophilic balance of 13.9, and 56% phosphate buffer system at pH 7.4 with shear thinning and thixotropy. The droplet size of F12 and F36 was 30.74 nm and 35.71 nm, respectively, and their nanosizes were confirmed by transmission electron microscopy images. Thereafter, 51.30% and 51.02% of the loaded extract was released from F12 and F36 through an artificial cellulose membrane, scavenging 29.89% and 30.05% of DPPH radical activity, respectively.ConclusionThe P. urinaria extract was successfully incorporated into a PKOEs-based nanoemulsion delivery system. In vitro release of the extract from the formulations showed DPPH radical scavenging activity. These formulations can neutralize reactive oxygen species and counteract oxidative injury induced by ultraviolet radiation and thereby ameliorate skin aging.

Development of dorzolamide hydrochloride in situ gel nanoemulsion for ocular delivery

Background: Several in situ gel-forming systems have been developed to prolong the precorneal residence time of a drug and to improve ocular bioavailability. Poloxamer 407 with its thermoreversible gelation and surface active properties was utilized to formulate a novel dorzolamide hydrochloride in situ gel nanoemulsion (NE) delivery system for ocular use. Objective: Improvement of both ocular bioavailability and duration of action for dorzolamide hydrochloride was the aim of this study. Methods: Physicochemical properties, in vitro drug release studies and biological evaluation of the prepared NEs were investigated. Results: The optimum formulation of in situ gel NE consisted of Triacetin (7.80%), Poloxamer 407 (13.65%), Poloxamer 188 (3.41%), Miranol C2M (4.55%), and water (70.59%). Biological evaluation of the designed dorzolamide formulation on normotensive albino rabbits indicated that this formulation had better biological performance, faster onset of action, and prolonged effect relative to either drug solution or the market product. The formula showed a superior pharmacodynamic activity compared to the in situ gel dorzolamide eye drops. This indicated the effectiveness of the in situ gel properties of poloxamer 407, besides formulating the drug in an NE form for improving the therapeutic efficacy of the drug. Conclusion: These results demonstrate the superiority of in situ gel NE to conventional ocular eye drops and in situ gels to enhance ocular drug bioavailability.