Utilization of pH-driven methods to fortify nanoemulsions with multiple polyphenols

Simple but effective methods are required to incorporate multiple bioactive polyphenols into delivery systems to increase their dispersibility,stability and bioavailability.We developed and tested three p Hdriven protocols for creating nanoemulsions loaded with multiple lipophilic polyphenols.These protocols differed in how the different polyphenols were incorporated into the nanoemulsions.The impact of these three methods on the formation,properties,and gastrointestinal fate of nanoemulsions loaded with curcumin,resveratrol,and quercetin was investigated.The three methods produced nanoemulsions with similar initial particle properties:droplet diameters(0.15,0.16,and 0.15μm)and zeta-potentials(–59,–58,and–58 m V),respectively.However,the average encapsulation efficiencies(82%,88%,and 61%),gastrointestinal stabilities(83%,97%,and 29%)and bioaccessibilities(77%,90%,and 73%)for curcumin,resveratrol,and quercetin were somewhat different.In particular,more quercetin degradation occurred using the approach that held it under alkaline conditions for extended periods.In general,the p H-driven method provides researchers with a versatile approach of incorporating multiple polyphenols with different characteristics into functional food and beverages using a simple and inexpensive method.

Evaluation of the Antibacterial and Antifungal Capacity of Nanoemulsions Loaded with Synthetic Chalcone Derivatives Di-Benzyl Cinnamaldehyde and Benzyl 4-Aminochalcone

With the increase in antimicrobial resistance,it has become necessary to explore alternative approaches for combating and preventing diseases.DB-cinnamaldehyde(CNM)and Benzyl4-amino(B4AM)are bioactive compounds derived from chalcones but with restricted solubility in aqueous media.Nanoemulsions can enhance the solubility of compounds and can be a promising alternative in the development of novel antimicrobials,with reduced side effects and prolonged release.The objective of this study was to evaluate the stability of oil-in-water nanoemulsions loaded with two distinct types of chalcones at two different dosages,to propose a stable formulation with antimicrobial properties.Results showed that nanoemulsions presented high encapsulation efficiency,low polydispersity index(PDI)and particle size below 200 nm,indicating that emulsification was a suitable method for nanoemulsion preparation.Nanoemulsions with higher dosages exhibited significant antimicrobial effects when compared to free chalcones and positive controls.Notably,B4AM nanoemulsions at higher dosages showed expressive activity against Salmonella minnesota,with a 420%greater inhibitory response compared to the free form and showing equivalence to the positive control.CNM nanoemulsions showed excellent inhibitory activity at the highest dosage,equivalent to the positive control against S.minnesota and Staphylococcus aureus.The greater number of conjugated bonds in CNM increased the antimicrobial activity in comparison with B4AM,and the formation of nanometric domains enhanced the bioavailability,being a promising alternative for antimicrobial applications.

Exploring the potential to enhance drug distribution in the brain subregion via intranasal delivery of nanoemulsion in combination with borneol as a guider

The number of people with Alzheimer’s disease(AD)is increasing annually,with the nidus mainly concentrated in the cortex and hippocampus.Despite of numerous efforts,effective treatment of AD is still facing great challenges due to the blood brain barrier(BBB)and limited drug distribution in the AD nidus sites.Thus,in this study,using vinpocetine(VIN)as a model drug,the objective is to explore the feasibility of tackling the above bottleneck via intranasal drug delivery in combination with a brain guider,borneol(BOR),using nanoemulsion(NE)as the carrier.First of all,the NE were prepared and characterized.In vivo behavior of the NE after intranasal administration was investigated.Influence of BOR dose,BOR administration route on drug brain targeting behavior was evaluated,and the influence of BOR addition on drug brain subregion distribution was probed.It was demonstrated that all the NE had comparable size and similar retention behavior after intranasal delivery.Compared to intravenous injection,improved brain targeting effect was observed by intranasal route,and drug targeting index(DTI)of the VIN–NE group was 154.1%,with the nose-to-brain direct transport percentage(DTP)35.1%.Especially,remarkably enhanced brain distribution was achieved after BOR addition in the NE,with the extent depending on BOR dose.VIN brain concentration was the highest in the VIN-1-BOR-NE group at BOR dose of 1 mg/kg,with the DTI reaching 596.1%and the DTP increased to 83.1%.BOR could exert better nose to brain delivery when administrated together with the drug via intranasal route.Notably,BOR can remarkably enhance drug distribution in both hippocampus and cortex,the nidus areas of AD.In conclusion,in combination with intranasal delivery and the intrinsic brain guiding effect of BOR,drug distribution not only in the brain but also in the cortex and hippocampus can be enhanced significantly,providing the perquisite for improved therapeutic efficacy of AD.

Preparation and Characterization of Bifenthrin Nanoemulsions

[ Objective] The paper was to prepare bifenthrin nanoemulsions, and to characterize its property. [ Method ] Oil in water type of bifenthrin nanoemul- sions was prepared using emulsion phase transition method at constant temperature of 25℃. The formation mechanism of nanoemulsions was investigated, and the property of bffenthrin nanoemulsions was characterized by dynamic light scattering（DIS）, transmission electron microscopy （TEM）, contact angle meter, interfa- cial tension meter and high performance liquid chromatogTaphy （HPLC）. [ Result ] Phase transition occurred during the formation progress of bifenthrin nanoemul- sions ; the particles of nancomulsions system was spherical, and the particle size was mainly distributed in the range of 25 -30 ran; the contact angle on paraffin was less than 90° with good wetting effect; the surface tension was less than 40 mN/m, and the emulsification effect was also good, so the utilization rate of bifenthrin nancomulsions was improved. HPLC results showed that bffenthrin was not easy to decompose or precipitate with good stability. [ Conclusion] The result provided basis for the preparation of new types of insecticides.

Preparation on Nanoemulsion of Pomegranate Peel Polyphenol

[Objective] The aim was to obtain the preparation technology of the pomegranate peel polyphenol nanoemulsion. [Method] The pomegranate peel polyphe- nol nanoemulsion was prepared by the titration methods and the pseudo ternary dia- gram. The effect of various elements on the formation of the nanoemulsion was stud- ied. [Results] The optimal prescription of the pomegranate peel polyphenol nanoemul- sion was 4.4%（w/w） of pomegranate peel polyphenol, 34.1%（w/w） of EL-40, 17.1%（w/w） of anhydrous ethanol, 5.7%（w/w） of IPM and 38.7%（w/w） of distilled water. [Conclusion] It is feasible to produce the pomegranate peel polyphenol nanoemulsion by the titration methods and the pseudo ternary diagram. It consists of pomegranate peel polyphe- nol, EL-40, anhydrous ethanol, IPM and distilled water. There is 4.4%（w/w） of the pomegranate peel polyphenol in the nanoemuJsion.

The effect of surfactant on the physical properties of coconut oil nanoemulsions

The aim of this study was to develop the water compatible form of coconut oil through nanoemulsification. The effect of different types and amounts of surfactants on the physical characteristics of nanoemulsions containing coconut oil was investigated. Coconut oil nanoemulsions containing varied amounts of surfactants including polyethylene glycol octyl phenyl ether(PGO), polyoxyethylene sorbitan monostearate(POS), polyethylene glycol hydrogenated castor oil(PHC), sodium lauryl sulfate(SLS) and poloxamer 407(PLX) were formulated and comparatively evaluated for their physical properties. The results showed that the coconut oil nanoemulsions using PGO, POS and PHC as surfactants exhibited low percent creaming index indicating excellent stability, while those containing SLS and PLX demonstrated the higher percent creaming index suggesting lesser physical stability. The droplet sizes of nanoemulsions consisting of 5%(w/w) PGO, POS and PHC were 22.843, 4.458 and 0.162 μm, respectively. Thus, coconut oil nanoemulsions with the smallest size could be obtained when PHC was applied. Furthermore, the droplet size of nanoemulsions decreased from 33 μm to less than 200 nm with an increase in the amount of PHC from 1% to 10%(w/w). Additionally, the properties of coconut oil based nanoemulsions containing PHC were not changed through temperature cycling test. From these results, it was suggested that the fabrication of stable coconut oil nanoemulsions with small particle size could be easily achieved by using 5%(w/w) PHC as a surfactant. The knowledge gained from the study might provide the basic guideline for the fabrication of stable nanoemulsions for food, cosmetic and pharmaceutical fields in the future.

Current State of Nanoemulsions in Drug Delivery

Nanoemulsions have attracted great attention in research, dosage form design and pharmacotherapy. This is as a result of a number of attributes peculiar to nanoemulsions such as optical clarity, ease of preparation, thermodynamic stability and increased surface area. Nanoemulsions also known as submicron emulsions serve as vehicles for the delivery of active pharmaceutical ingredients as well as other bioactives. They are designed to address some of the problems associated with conventional drug delivery systems such as low bioavailability and noncompliance. The importance of design and development of emulsion nanocarrier systems aimed at controlling and/or improving required bioavailability levels of therapeutic agents cannot be overemphasized. Reducing droplet sizes to the nanoscale leads to some very interesting physical properties, such as optical transparency and unusual elastic behaviour. This review sheds light on the current state of nanoemulsions in the delivery of drugs and other bioactives. The morphology, formulation, characteristics and characterization of nanoemulsions were also addressed.

The accelerated blood clearance phenomenon of PEGylated nanoemulsion upon cross administration with nanoemulsions modified with polyglycerin

For investigating the accelerated blood clearance(ABC) phenomenon of polyglycerin modified nanoemulsions upon cross administration with polyethylene glycol(PEG) covered nanoemulsion, we used the 1,2-distea-royl-sn-glycero-3-phosphoethanolamine-npolyglycerine-610 and the 1,2-distearoyl-n-glycero-3-phosphoethanolamine-n-[methoxy(polyethylene glycol)-2000] as modify materials, the dialkylcarbocyanines as fluorescence indicator. Exhausted macrophages rat model was established and new material containing polycarboxyl structure was synthesized. The microplate reader and the in vivo optical imaging system were applied to measure the concentration of nanoemulsions in tissues.The results show that the first dose of polyglycerin modified nanoemulsion can induce the ABC phenomenon of the second dose of PEGylated nanoemulsion. With the increase in the amount of the surface polyglycerin, the extent of the ABC phenomenon decreases. Liver accumulation has positive relationship with the ABC phenomenon. Furthermore, kupffer cells in liver can get more immune information from polyhydroxy structure than polycarboxyl group in the modify compound. The results of our work imply that the polycarboxyl structure has advantages to eliminate the ABC phenomenon.

Nanoemulsion containing a synergistic combination of curcumin and quercetin for nose-to-brain delivery:In vitro and in vivo studies

Objective:To characterize a nanoemulsion containing a synergistic combination of curcumin(CUR)and quercetin(QUE)for brain targeting through the nose.Methods:The synergistic activity of the combination of two phytoconstituents,curcumin and quercetin(CUR-QUE)was determined at a 2:1 ratio.Nanoemulsions containing the synergistic combination were prepared using high-pressure homogenization technique.Nanoemulsion formulation was characterized for globule size,drug content,thermodynamic stability,zeta potential measurement,and drug release.Histological studies were performed using isolated nasal mucosa of sheep.Moreover,in vivo studies using allograft model were performed.Results:CUR-QUE in a 2:1 ratio combination showed the lowest combination index values 0.99(combination index<1)for treatment of human glioblastoma U373-MG cell.The combination inhibited the growth of human glioblastoma U373 MG cells.The significant drug targeting efficiency percentage(178.25±2.86 for CUR and 170.54±6.11 for QUE)and nose to brain drug direct transport percentage(44.05±0.93 for CUR and 38.25±0.83 for QUE)of optimized nanoemulsion(F9)indicated effective central nervous system targeting via the intranasal route.In vivo anticancer study using allograft model of nude mice demonstrated potential anticancer activity of the synergistic combination of CUR-QUE as compared to doxorubicin.Conclusions:This study demonstrates that synergistic combination of CUR-QUE was optimal for treatment of human glioblastoma.Moreover,significant site-specific delivery to the brain was achieved by administering nanoemulsion through the nose.The study also reveals that intranasal delivery of nanoemulsion containing synergistic combination of CUR and QUE could be a promising strategy for brain tumor treatment.

Impact of formulation parameters on physical characteristics of spray dried nanoemulsions and their reconstitutions

Nanoemulsion as small droplet dispersion allows them to uniformly deposit on substrates,increases the rate of bioavailability,absorption and has a better uptake.Although it is generally accepted that nanoemulsions are stable for years,Oswald ripening which can damage nanoemulsion has been reported[1].In this study,converting nanoemulsion as liquid formulation into solid powders was attempted by using spray drying method.The obtained powders were then characterized,reconstituted and compared to the initial nanoemulsion.

Fabrication and characterization of spearmint oil loaded nanoemulsions as cytotoxic agents against oral cancer cell

Spearmint oil(SMO), a commonly used essential oil for oral care products, possesses various interesting functions, especially for anticancer property. However, the application of SMO for cancer treatment is limited due to water insoluble. In the present study, nanoemulsions, which have been widely accepted as dosage forms for poorly water-soluble drugs, were selected as candidate carriers for SMO to inhibit oral cancer cell. The nanoemulsions were fabricated using phase inversion temperature method. The factors affecting formation and properties of nanoemulsions including type and amount of surfactants, oil loading and ratio of SMO to virgin coconut oil(VCO) were investigated. Among the surfactants used, the nanoemulsions containing polyoxyethylene castor oil derivatives(Kolliphor ?EL; PCO35, Cremophor ?RH40; PCO40, Eumulgin ?CO60; PCO60) and polyoxyethylene sorbitan fatty acid esters(PSF80) showed 100% creaming after temperature cycling test indicating excellent physical stability while those containing PCO40 demonstrated more transparency and better physical stability. With an increasing amount of PCO40, the droplet size tended to decrease and was in the nano-size range( < 1000 nm) after increasing to more than 5%(w/w). SMOVCO loading also influenced on the droplet size. At 5%(w/w) PCO40, the maximum SMO-VCO loading of 25%(w/w) to attain nanoemulsions was observed. Moreover, the composition of oils had an impact on size of emulsions. The transparent nanoemulsions were only prepared in the range of SMO-VCO from 40:60 to 80:20, suggesting the optimum ratio of SMO tosurfactant and the composition of oils were the critical factors for formation of nanoemulsions. NMR study disclosed that the interaction between PCO40 with both VCO and SMO should be a possible stabilization mechanism. Furthermore, the SMO-VCO nanoemulsions exhibited significant cytotoxic effect against oral carcinoma(KON) cell line using MTT assay. The finding, therefore, revealed the good feasibility of SMO-VCO nanoemulsions as novel carriers for treating of oral cancer.

Factors affecting formation of nanoemulsions containing modified coconut oil and spearmint oil

Dental caries is one of the major oral health problems in most countries,affecting more than 50%of school children and majority of adults.Normally,we can prevent the disease by utilization of suitable antiseptics,e.g.alcohols and chlorhexidine[1].However,most antiseptics cause irritation or straining of the mucous membrane and teeth.Therefore,finding a more safe and efficient antiseptics is still a matter of interest to eradicate the causative pathogen.Volatile oils from plants including spearmint oil(SMO)could reduce the number of Streptococcus mutans counts in plaques and saliva.

Antimicrobial Oil-in-Water Nanoemulsions： Synergistic Effect of Nisin and Carvacrol against Bacillus subtilis

The aim of this study was to elucidate the mode of action of two antimicrobial compounds, nisin, which is hydrophilic, and the lipophilic compound carvacrol. For that purpose, both antimicrobials were loaded into Oil-in-/Water nanoemulsions, and their antimicrobial activity against Bacillus subtilis was investigated. The experimental results indicated that the O/W nanoemulsions loaded with both, nisin and carvacrol, having Sauter mean diameter （d3,2） of around 120 nm, were considerably stable under the conditions investigated （up to 1 week storage at room temperature）. The interfacial tension between nisin aqueous solutions and soybean oil could be reduced up to 12 mN/m, as compared to that of pure water and soybean oil （21 mN/m）, so that demonstrating the potential of nisin to be used as emulsifier. The results obtained for O/W nanoemulsions loaded with both antimicrobial compounds indicated a reduction of nearly two log cycles （around 100 times） on B. subtilis population upon incubation for 24 h, compared to the blank （10 mM phosphate buffer）.

Synthesis of Calcium Phosphate Controllable Coating Thickness on Oil-in-Water Nanoemulsion with Performance of Oxygen Release as Oxygen Carrier

Perfluorocarbon emulsion has been studied as an oxygen carrier, due to its high oxygen content. In clinical trials, it has shown stability in delivering oxygen to the target region. The purpose of the present study was to increase the stability of the emulsion by coating its surface with calcium phosphate. A layer-by-layer method was employed to coat the flexible emulsion surface. Considering the ionic affinity of calcium and phosphate to the lecithin emulsion surface, the first layer of coating was calcium and the second layer was comprised of phosphate ion. The coated emulsion demonstrated various oxygen release times depending on the thickness of the layers: from 0.04 sec. for a thickness of 8 nm to 0.17 sec. for a thickness 38 nm. Overall, the stability of the calcium phosphate coated emulsion was increased, while its original function as an oxygen carrier was maintained.

In vitro and in vivo study of formulated valproic acid loaded nanoemulsion in rats for epilepsy treatment

OBJECTIVE To investigate the in vitro and in vivo potential of formulated valproic acid-encapsulated nanoemulsion in terms of drug penetrability across the blood-brain barrier. METHODS Human cerebral microvascular endothelial cells(hCMEC/D3)and human cortical astrocytes(SC-1800)were cultured on the membrane of the transwell inserts as to build the co-culture model of in vitro BBB model.Drug penetration analysis was then conducted at various time intervals for 24 h.The in vivostudy of this formulated nanoemulsion was also investigated using Sprague Dawley rats.They were treated with VANE 60mg·kg-1 or valproic acid 60mg·kg-1 via intraperitoneal route before being anesthetized and sacrificed by cardiac puncture at different time points after administration.The blood and brain were collected and processed.The samples were analyzed with HPLC to determine the pharmacokinetic profile and biodistribution of the drug in the brain.RESULTS The formulated VANE had apparent permeability coefficient of 0.205cm·s-1 in vitro studies.It was 1.06-fold better than the drug solution.It showed that the VANE can penetrate across the BBB faster than the drug solution.The cumulative amount was reported to be 1.12-fold higher that the drug solution.This briefly suggests the VANE can be good candidate to promote the uptake of drug into the brain.In in vivo study,the formulated nanoemulsion showed remarkably improved pharmacokinetic parameters with 3.85-fold higher of total area under the curve-time curve(AUC)and 2.81-fold higher in maximum concentration of drug in blood plasma(cmax).More interestingly,the half-life(T1/2)is prolonged by 1.80-fold and its clearance(Cl)was reduced by 3.85-fold.CONCLUSION The formulated nanoemulsions were able to improve most of the pharmacokinetic parameter thus this formulation technique improves the bioavailability of the drug in the brain compared to the drug solution alone.

Therapeutic Effects of Curcumin Nanoemulsions on Prostate Cancer

The therapeutic potential of curcumin(Cur) is hampered by its poor aqueous solubility and low bioavailability. The aim of this study was to determine whether Cur nanoemulsions enhance the efficacy of Cur against prostate cancer cells and increase the oral absorption of Cur. Cur nanoemulsions were developed using the self-microemulsifying method and characterized by their morphology, droplet size and zeta potential. The results showed that the cytotoxicity and cell uptake were considerably increased with Cur nanoemulsions compared to free Cur. Cur nanoemulsions exhibited a significantly prolonged biological activity and demonstrated better therapeutic efficacy than free Cur, as assessed by apoptosis and cell cycle studies. In situ single-pass perfusion studies demonstrated higher effective permeability coefficient and absorption rate constant for Cur nanoemulsions than for free Cur. Our study suggested that Cur nanoemulsions can be used as an effective drug delivery system to enhance the anticancer effect and oral bioavailability of Cur.

Preparation and physical properties of itraconazole-loaded nanoemulsions using pineapple starch as co-emulsifier

Pineapple plant(Ananascomosus L.Merr.)is a leading edible member of the Bromeliaceae family[1].Nanoemulsions containing itraconazole,a poorly water-soluble drug using pectin as a polymeric emulsifier,are currently under investigation[2].The physicochemical and rheological properties as well as structural characterizations of cassava and mungbean starches have been reported[3].However,the application of pineapple starch as co-emulsifier of pharmaceutical excipients for pharmaceutical industry has not been investigated.

Effect of virgin olive oil nanoemulsion combined with ajowan(Carum copticum)essential oil on the quality of lamb loins stored under chilled condition

This survey was conducted to evaluate the impact of virgin olive oil nanoemulsion(ONE) combined with ajowan(Carum copticum) essential oil(AEO) on quality of lamb loin under refrigerated condition. The treatments were control, ONE, ONE + 1% AEO, and ONE + 2% AEO. The treatments caused a delay in growth of mesophilic and psychrotrophic bacteria, Enterobacteriaceae, and lactic acid bacteria during chilled storage. The increasing rate of total volatile nitrogen content, lipid and protein oxidation, metmyoglobin formation, and color deterioration was more retarded in treatment groups. The treatments including ONE + 1% AEO and ONE + 2% AEO were more efficient than ONE alone to delay microbial flora growth, slow down oxidative processes, and improve color in the loins. According to the results of microbial, chemical, and sensory parameters, shelflife of lamb loins was 4 days in control, 8 days in ONE, and at least 16 days in ONE + 1% AEO and ONE + 2% AEO groups. In conclusion, combination of ONE and AEO is appropriate as natural preservative to extend the shelflife of lamb loins stored under chilled condition.

Preparation and Quality Evaluation of Toltrazuril Nanoemulsion

To determine the prescription and preparation method of toltrazuril nanoemulsion, we selected liquid paraffin, ethyl acetate, soybean oil, IPM and oleic acid as the oil phases, while RH-40, EL-40, OP-10, Tween-80 and Span-80 were the surfactants, and alcohol, 1,2-ropanediol, ispropanl, glycerol and PEG-400 were the co-surfactants. The best prescription was acquired through pseudo-ternary phase diagrams. The result showed that ethyl acetate, Tween-80 and 1,2-propanediol could facilitate the formation of nanoemulsion. The optimum prescription was surfactant：co-surfactant：oil phase：water phase =2：1：2：5, with the solubilizer of 10%. This prescription can prepare stable toltrazuril nanoemulsion.

Influence of Ozonized Oil Nanoemulsions on B-16 Melanoma Cells: An <i>in Vitro Study</i>

In this study, we aimed to use a novel approach to overcome the current limitations of ozone therapy in medicine through ozonized oil nanoemulsions (OZNEs). We evaluated dose-dependency on the cellular activities of B-16 melanoma cell line which were incubated with various OZNE doses (v/v). Antitumor effects of OZNE against cancer cell lines were evaluated by cellular morphology, apoptosis and cell cycle analysis. Flow cytometry results showed that OZNE induced DNA damage, apoptosis, and arrested cell cycle in G0-1 phase in B-16 melanoma cells. Thus, OZNE treatment could pose an effective way to act as a potential therapeutic for patients with tumors in the future.