Kinds of stabilizers added to improve long-term stability of nanoemulsions.
\r\n\t
\r\n\tThis book intends to provide the reader with a comprehensive overview of the current epidemiology, valuable information in relation to the management of specific poisoning agents, and important evidence-based developments in the toxicology field, with special focus on children, who are a more vulnerable population for severe poisonings. Its aim is to be a practical handbook to aid health care professionals involved in individual care of patients poisoning.
Saliva is a aqueous, transparent and odorless liquid produced and secreted by the major and minor salivary glands, which combined with the gingival crevicular fluid, cellular debris, upper airway secretions and microorganisms of the oral cavity, makes up the total human saliva [1, 2].
The saliva is responsible for maintaining the homeostasis of the oral cavity and its pH normally lies around 6-7, which makes it slightly acidic. Initially, it shows up isotonic, becoming hypotonic as it passes through the network of ducts [3].
The daily average flow of total saliva in healthy people varies between 500 and 1500 mL, and the mean volume of saliva in the oral cavity is approximately 1 mL; however, there is always a great variability in individual rates of salivary flow [3]. This flow provides important information about the health quality not only oral but also systemic [4, 5].
The main constituent of saliva is water, which accounts for 99% of its composition. Solid components, which are characterized by organic and inorganic molecules, are dissolved in the aqueous medium. The salivary composition has significant changes from one individual to another and in the same individual under different circumstances; however, the rate of salivary flow is considered the main factor affecting its composition [6].
Saliva is composed of a number of inorganic ions, including sodium, potassium, chloride, calcium, magnesium, bicarbonate, phosphate, sulfate, thiocyanate and fluoride, which are responsible for osmotic balance, buffering capacity and dental remineralization [7]. Humphrey and Williamson (2001), [3] consider that bicarbonate, phosphate and urea act as pH modulators being responsible for salivary buffering capacity.
The salivary organic components are represented by immunoglobulins, proteins, enzymes, mucins, and nitrogen products such as urea and ammonia. The salivary proteins (amylase, lipase, proteases, nucleases, mucins and gustin) act assisting in the digestive process, with antibacterial properties for hydrolysis of cellular membranes (lactoferrin, lysozyme and lactoperoxidase) besides inhibiting the adherence of microorganisms (immunoglobulins) [7].
The saliva keeps the oral health and creates a proper ecological balance. Among its functions (Figure 1) are the protection and lubrication of oral tissues, acting as a barrier against irritants, with buffering and cleaning action, maintaining the integrity of the teeth and antibacterial activity, besides acting improving the taste and starting the digestive process [8]. The saliva’s lubricity capacity is provided mainly by mucins, they are secreted by the minor salivary glands, having low solubility, high viscosity, high elasticity and strong adhesiveness [6, 9, 10].
Saliva functions
Saliva was used for a long time as a method to monitor the caries risk, being used as biological environment extremely useful as buffering capacity and microbiological evaluation. Today, it is an object of detailed study for the diagnosis of systemic diseases that affect the function of the salivary glands and saliva composition, for example, Sjögren\'s syndrome, alcoholic cirrhosis, cystic fibrosis, sarcoidosis, diabetes mellitus and adrenal cortex diseases [11, 12]).
According to [13], saliva is a valuable source of clinically relevant information, since its many components, besides protecting the oral tissues integrity, act as biomarkers of diseases and systemic conditions of the individual. The qualitative changes in the composition of these biomarkers have been used to identify patients with increased susceptibility to some diseases, identification of sites with active disease, prediction of sites with greater disease activity in the future and / or serving as a tool for monitoring effectiveness of therapies.
There have been significant advances in techniques for detection of biomarkers in the oral cavity in recent years, especially by ELISA for proteins and PCR for RNA and DNA. With these advances in biotechnology, it has become possible to use saliva as a diagnostic mean for different conditions such as caries and periodontal disease, infectious and autoimmune diseases, genetic and psychological disorders, malignancies, legal issues, among others (Figure 2).
Major diseases with possibility of salivary diagnostics.
Caries [14] and periodontal disease [15]) are the most occurring diseases in the oral cavity. Both considered infectious diseases and primarily responsible for tooth loss in adults. In recent years, remarkable achievements have been made in the field of oral microbiology, especially with regard to diagnosis. Techniques have been sought to predict the availability of patients to certain diseases; and this is not different with caries. The counts of bacteria present in saliva associated with other factors, such as diet and systemic conditions, may provide an estimate of the risk of caries in the individual. The increased number of lactobacilli and Streptococcus mutans in saliva have been associated with increased prevalence of caries and root caries [16]. Similarly, the methods of diagnosis in current clinical practice are able not only to detect the presence of inflammation, but also to identify patients at higher risk for progression of periodontal disease [17].
The human salivary buffer systems consist of an important natural defense against tooth decay [18]. The saliva’s buffer capacity varies with glandular activity. The bicarbonate raises the pH of saliva and its buffering capacity, especially during stimulation [19]). Thus, the levels of bicarbonate and other important ions showing abnormalities can also suggest a predisposition to dental caries.
There has been an association between periodontal disease and increased levels of aspartate aminotransferase (AST) and alkaline phosphatase (ALP). The salivary AST can be used as a marker for monitoring periodontal disease. In addition, lower uric acid levels and albumin in saliva were associated with periodontitis and diabetes [20]. The development of new devices for periodontal monitoring probably would require less training and fewer resources than current diagnostic tests and may lead to better use by properly trained professionals for simpler and less intensive treatment, and may result in the provision of health care at low cost [21]. For determination of periodontal disease, it would be necessary a large body of research previously focused on fluid gingival biomarkers that provide the local disease status, but represents a technically difficult approach to implement in the clinical area [13, 17].
Currently, it is possible to use saliva tests for evaluating the microbiota associated with periodontal diseases, regardless of the degree of periodontal impairment of the patient. PCR tests can detect DNA of periodontal bacteria in oral fluids, such as ggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Campylobacter rectus, Eikenella corrodens and Fusobacterium nucleatum. The analysis of the salivary microbial content reflects periodontal conditions and various socio-economic, cultural and behavioral aspects of patients [22].
In addition to exercising extremely important functions for the organism’s homeostasis, saliva is currently an important tool for the diagnosis of infectious diseases. Besides the usual microorganisms in oral cavity, saliva may contain viruses and/or bacteria responsible for systemic diseases that can be identified by PCR. Another way to diagnose infectious disease by the salivary examination is through monitoring the presence of antibodies to the organisms [23].
Today, it is possible to identify, for example, the herpes virus associated with Kaposi\'s sarcoma and the presence of bacteria such as Helicobacter pylori, which is associated with gastritis, peptic ulcers and possible stomach cancer [11, 12]. Studies conducted in order to detect immunoglobulin M (IgM) against rubella showed 96% specificity when compared to standard considered as ideal test blood serum, which means that the use of saliva for epidemiological surveillance and control of this virus can be valid [24, 25]. It is also possible to detect the presence of Epstein-Barr virus (EBV) associated with infectious mononucleosis, highly communicable disease by contacting saliva and hairy leukoplakia [26].
The disease that generates more discussion regarding the use of saliva for diagnostic procedures is undoubtedly the Acquired Immunodeficiency Syndrome (AIDS). Until recently, oral HIV transmission through saliva of infected individuals during dental treatment or as a result of biting or contact stemmed by cough or kiss droplets has been considered less likely than vaginal or rectal transmission [27]. However, concerns about the way of transmission have increased. Studies have shown that these tests based on specific salivary antibodies are equivalent in reliability as compared to those in the serum, therefore being useful in the clinical use and epidemiological studies [28]. In recent years, researchers have shown that salivary tests for detection of antibodies to HIV [29] represents a non-invasive alternative for quantification of antibodies in blood to monitor the effectiveness of antiretroviral therapy and progression of Acquired Immunodeficiency Syndrome [30].
For this class of diseases, the most studied in parameters of salivary diagnostics is the Sjogren\'s syndrome. It is an autoimmune disease characterized by decreased secretion of the salivary and lacrimal glands, associated with endocrine disorders. The sialochemistry (analysis of saliva’s chemical components) offers great value for the diagnosis of this syndrome. Increased immunoglobulin levels, inflammatory mediators, albumin, sodium and chloride and, decreased phosphate level are indicative of Sjögren\'s syndrome. Analysis of proteins in saliva showed increased level of lactoferrin, beta 2 microglobulin, lysozyme C, and cystatin C. However, levels of salivary amylase and carbonic anhydrase showed reduced [31, 32]. Thus, these references of protein chemical analysis associated with detailed history may show effectiveness for an accurate diagnosis.
Salivary changes that may reveal the presence of multiple sclerosis, an inflammatory disease characterized by loss of myelin and scarring caused due to failure in producing cells by the immune system have also sought. However, no significant changes were found except for a reduction in the production of IgA, which is inconclusive to suggest the diagnosis [33].
Sarcoidosis is an autoimmune and inflammatory disease, which affects the lymph nodes, lungs, liver, eyes, skin, or other tissues. Salivary diagnostics has demonstrated a decreased amount of saliva secretion associated with reduced activity of the enzyme alpha-amylase and kallikrein in most patients carrying the disease. However, there was no correlation between the decrease in enzyme activity and the volume of secretion, which complicates the understanding of salivary changes and possible diagnosis [34].
The total salivary flow and its characteristics had already been correlated with xerostomia, symptoms of anxiety, depression, Burning Mouth Syndrome and aphthous stomatitis [35, 36, 37]. The salivary cortisol levels may represent an important biological marker of stress. The salivary cortisol concentration increases after 20 the beginning of a stressful situation, besides increased pH and protein levels. However, there are no indications of changes in concentrations of fluoride under conditions of acute mental stress [38, 39].
The sialochemistry evaluation reveals significant elevation in the levels of phosphate, chloride and potassium in subjects with BSA symptoms, and also differences in expression pattern of salivary proteins of low molecular weight compared to healthy individuals. Levels of phosphate, potassium and chloride are increased in individuals with intense activity of the sympathetic nervous system, something common in situations of emotional stress [40].
The salivary alpha-amylase has its release regulated by the sympathetic autonomic nervous system, and has importance in the psychobiology of stress. The levels of salivary alpha-amylase in humans increase under various conditions of physical and psychological stress before any other clinical signs can be perceived [37, 41, 42]. Therefore, the salivary alpha-amylase may act as effective biomarker which can be used alternatively non-invasive way to evaluate psychological and metabolic stress, or including diseases whose etiology just seems to be related to stress.
Results are controversial and not always enlightening. For aphthous stomatitis significant changes in the levels of TCD4+ and TCD8+ lymphocytes have been associated and abnormal cytokine cascade arising from the oral mucosa. It is known that for aphthous stomatitis there are 41 genes expressed differently and increased activity of lymphocytes T-helper 1 (Th1), responsible for the production of interferon-gamma, interleukin 2 (IL-2) and alpha tumor necrosis factor (TNF-α). The levels of IL-2 are higher in patients with aphthous stomatitis compared with control subjects and may serve as markers in immunodiagnoses [43, 44, 45, 46, 47].
The secretory immunoglobulin A (IgA-s) can be used as the oral mucosa immune status parameter. It acts as a barrier to infectious agents, environmental allergens and carcinogens, as well as it participates in innate protection mechanisms. IgA deficiency is the most common humoral immune defect in humans and causes, in a large proportion, gastrointestinal and respiratory infections [48, 49, 50, 51].
The identification of exogenous genetic material in saliva may have forensic significance, or in cases of sexual assaults. The genetic material shared after a kiss is present and can be detected up to an hour after the kiss [52].
Cystic fribose, an autosomal recessive genetic disease caused by a disturbance in salivary glands secretions. Cystic fibrosis affects the chromosome 7, which is responsible for the production of a protein which will regulate the passage of sodium and chloride throuh cell membranes. The effects of this regulation can be analyzed through saliva. The Sodium and Potassium elements showed higher levels, while the trace elements vanadium, chromium, selenium and arsenic have lower levels in individuals with cystic fibrosis [53].
There is a growing interest worldwide for the saliva analysis through genomics, transcriptomics and proteomics, since this is a non-invasive source of rich genetic information. In the case of saliva, two main aspects of cancer diagnosis must be distinguished - one being the diagnosis of oral cancer (which has direct contact with saliva) and other the cancer diagnoses in other locations. Mouth cancer in advanced stages can usually be detected by inspection of the oral cavity. On the other hand, initial oral carcinomas are not visible and cannot be diagnosed and treated on time. The salivary proteomecan also be used for tumor detection [54].
The study of Streckfus et al. (2000) [55], demonstrated the role of saliva in the diagnosis of breast cancer, in which salivary tests for markers of disease were studied combined with mammography. From the analysis in saliva, the soluble fragment of the oncogene c-erbB-2, a prognostic marker for breast cancer, as well as the antigen for cancer were significantly higher in the saliva and serum of women diagnosed with cancer than that observed in a control group of healthy women and patients with benign tumors group, indicating that the saliva test for this oncogene is sensitive and reliable, and it is potentially useful in the early detection and monitoring of screening for breast cancer [56].
Additionally, the use of saliva test may be important in monitoring the levels of c-erbB-2 in patients undergoing chemotherapy and/or surgery, so that serves as an assessment of therapy effectiveness in question, and may be useful in preservation [57].
Franzmann et al. (2005) [58], evaluated the soluble CD44 in saliva as a potential molecular marker for head and neck cancer and concluded that the test can be effective to detect this cancer at all stages.
In the past, biomarkers were used primarily as prognostic indicators for patients with tumors of the head and neck. More recently, the role of biomarkers has been greatly expanded to cover all aspects of patient care, from early cancer detection to the more accurate tumor staging and even the selection of those patients most likely to benefit from specific therapies to post-treatment tumor surveillance. One of the most promising avenues regarding the early diagnosis of cancer has been the ability to use saliva as a substrate for the evaluation of biomarkers [59].
Recently, Jiang et al. (2005)[60], reported increased content of mitochondrial DNA in saliva of patients with head and neck cancer. Multivariate analysis revealed a significant and independent association of SCC diagnosis of head and neck, age and smoking with increased content of mitochondrial or nuclear DNA. Salivary proteins such as CEA, defensin-1, TNF-alpha, IL-1, 6 and 8 and CD44 showed increase in their detection in patients with oral cancer.
Most of these studies relied on immunological assays of individual gene products 2,137. It is expected that proteomic biomarkers, when combined, increase the sensitivity and specificity of detection of human cancer [61, 62].
Increased levels of salivary defensin-1, CA15-3 cancer antigen, tumor marker proteins, such as c-erbB-2 or CA-125 and antibodies against tumor suppressor protein p53 are promising markers of oral malignant neoplasms and other cancers. In the future, a global proteomic profile of saliva with methods newly developed for proteome analysis is likely to result in other peptide sequences candidates for detection with high sensitivity [62, 54].
When compared to blood, saliva can express more sensitive and specific markers for certain local oral diseases. For example, saliva contains expressed proteins locally different from serum that can be best indicators of the oral disease. There are compelling reasons to use saliva as a diagnostic fluid to monitor the onset and progression of oral cancer. Saliva is the fluid that drains the lesions and there is increased RNA and proteins of oral cancer on it [63].
The forensic dentistry method is efficient for human identification, but is endowed with certain limitations: it suffers distortion from the moment of the bite until the act of expertise, especially when the mark is left on the skin. The salivary DNA emerges as a complement or even to replace the first, since it is a test of excellence [64]. However, the use of saliva in the identification was only feasible after the development of molecular biology techniques applied to forensic dentistry. In forensic uses, the PCR technique is the most used as it drastically increases the chances of DNA analysis, allowing determining the individual’s molecular profile. It was from then that saliva became a great focus on looking for traces, as they provide enough genetic material and excellent qualities for the exam in most cases [65].
The DNA can be degraded depending on the conditions of their preservation. Moisture, excessive heat, pH, enzymes and other are variables for its ideal preservation under the various surfaces that can be found [66].This being the object of several recent studies. In the study by [67], the authors concluded that saliva is able to provide genetic material, even when stored under conditions below those considered optimal.
The human salivary proteome (HSP), using 2D gel electrophoresis coupled to mass spectrometry, is able to identify approximately 100 different salivary proteins [68]. A significant number of spots on a typical 2-DE gel can capture fragments of abundant salivary proteins such as amylases, cystatins and immunoglobulins [69]. For the identification of less abundant salivary proteins, analysis by advanced techniques of mass spectrometry ensures a significant increase in resolution when compared to two-dimensional gel electrophoresis [70]. Generally, a pre fractionation of intact salivary proteins employing high resolution separation techniques is required to achieve a wide coverage of the human salivary proteome [71].
Human saliva stains can be found at crime scenes, alone or mixed with other biological fluids. The most common sites of occurrence are: the surface of objects such as envelopes [72], tissues cigarette butts, cups, sites near bites and often victims of rape [73].
For the salivary diagnosis become routine in clinical practice, it is necessary to know specific salivary biomarkers of disease states or health, besides technology necessary for their detection [74]. The genomics, epigenomics, transcriptomics, proteomics and metabolomics (Figure 3) approaches are currently being used to characterize these diagnostic biomarkers in saliva [75].
Study of omics to identify salivary biomarkers.
Biomarkers of DNA, mRNA, or protein biomarkers can provide useful diagnostic information that can identify the effect of disease or medication on salivary constituents. However, there is still not a complete characterization of the salivary proteome for disease biomarkers. Five hundred salivary proteins have been described, but this number is very small when compared to the more than 4,000 proteins listed for plasma [76].
The analysis of salivary genome and epigenoma allows identification of the presence of invading pathogens, as well as profiles transcription of anomalous genes that reflect genetic pathological processes such as cancer. The salivary genome consists of DNAs representing the individual’s genome and the oral microbiota. The quality and yield of DNA that can be obtained from saliva is relatively good compared to blood and urine, which can be used for genotyping, amplification or sequencing [54], and can be stored for a long time without significant degradation [77].Thus, the salivary DNA is an analyte suitable for diagnosis but limited to reflect the presence or absence of specific genes or alterations in the sequences (mutations) and also cannot provide information about upregulation and downregulation of gene expression.
Regarding the salivary transcriptome, mRNAs and miRNAs are secreted by cells into the extracellular medium and can be found in biofluids remote cellular sources [78, 79, 80]. In the disease state, the transcription of specific miRNAs and mRNAs has changed. Despite suffering some criticism initially, the use of salivary RNAs as diagnostic biomarkers, is now widely accepted [81]. However, the precise sources of salivary RNAs and other molecules remain unclear.
The standard procedures for the isolation and analysis of salivary mRNA require low temperatures, besides being expensive and time consuming, precluding its clinical application. Currently, simple methods of stabilization of mRNA in saliva samples have been developed, allowing for storage at room temperature without the use of stabilizers, and are so-called \'direct-saliva-transcriptomic-analysis\' [82]. However, this approach also involves centrifugation. An alternative method has been described [83], but it was based on the use of an expensive stabilizing agent (expensive). Thus, neither method is completely suitable for all applications. The mRNAs of saliva and plasma can be remarkably stable. The microarray technology is considered the gold standard for the identification of salivary transcripts. In this technique, the salivary transcriptome is determined using microarrays and is validated by means of qPCR. However, low concentrations of certain biomarkers, as well as small sample volumes require innovations in technology [84].
For proteins detection, the use surface - enhanced laser desorption/ionization time - of - flight (SELDI - TOF) mass spectrometry (MS), has been reported for several diseases. Recently, analysis of saliva for protein biomarker discovery has mainly been performed using two - dimensional difference gel electrophoresis (2D - DIGE) coupled with MS (which can identify around 300 proteins in a sample, and liquid chromatograpy - MS (LC - MS) based techniques (which can identify more than 1,050 proteins in a sample; reviewed in [85]. Thus, liquid chromatographic separation appears to resolve protein species more precisely than gel electrophoresis methods. A multiplex protein array was also employed, providing high - throughput analysis [86]; however, this method requires some prior knowledge of likely analytes. Despite these advances, the discovery and validation of protein salivary biomarkers still has some challenges. Proteins have short half-lives, making them unstable. Both the nature of peptides, as the oral environment makes them vulnerable to degradation. Thus, the diagnosis based on salivary protein requires immediate processing of samples, or the use of freezers and expensive protease inhibitors. In the clinical environment, these requirements are not easily circumvented.
The metabolome is the set of small metabolites and changes continuously, reflecting the gene and protein expression. Metabolomics investigations can generate quantitative data to elucidate metabolic dynamics related to disease and exposure to drugs [87]. However, a metabolomics limitation comparative to genomics, transcriptomics and proteomics is the inability to identify differentially the metabolites expressed [88, 89, 90].
In recent years, many important biological questions have been answered by the study of the "omics" (genomics, transcriptomics, proteomics, metabolomics, etc.), allowing the discovery of various salivary biomarkers. However, few of these markers have exceeded the identification phase. The transfer of scientific knowledge of salivary biomarkers for clinical applications is a challenging process that rarely has resulted in clinical implementation. Its successful application in clinical practice will depend on collaborative studies including physicians, epidemiologists, molecular biologists and bioinformaticians with a relevant clinical question and with well-defined parameters of recruitment and characterization of patients and samples. Thus, the use of saliva as a diagnostic fluid will be increasingly accepted, allowing for enhanced systemic and oral health.
Serious health-related problems contribute to the worldwide distribution of healthier, safer, and cost-effective food products. Additionally, functional foods were introduced as a tool to give an additional function to food. This can be achieved by increasing the production of existing biologically active molecules or adding new bioactive ingredients. Therefore, food products in addition to their nutritional value, they usually have health-promotion or disease prevention values. Nevertheless, it has become evident that the low bioavailability or inefficient long-term stability of these health-promoting products may not sustain their benefits. Subsequently, a great attention has been received in the last few years for nanotechnology in food applications. Nanoemulsions are one of the most interesting delivery systems in food industry. Nanoemulsion-based delivery systems improve the bioavailability of the encapsulated bioactive components and increase food stability [1].
Nanoemulsions are emulsions that have very small particle size [2]. They have some unique characteristics such as small size, increased surface area and less sensitivity to physical and chemical changes, making them ideal formulas in food industry [3, 4].
Food grade nanoemulsions are being increasingly used in for improving digestibility, efficient encapsulation, increasing bioavailability and targeted delivery [3, 4, 5]. The aforementioned advantages of nanoemulsions over the conventional emulsions increased the utility of nanoemulsions in food industry. The kinetic stability of nanoemulsions can be improved by incorporating stabilizers such as emulsifiers, ripening retarders, weighting agents or texture modifiers [3]. Emulsifiers such as small molecule surfactants (Tweens or Spans), amphiphilic polysaccharides (gum Arabic or modified starch), phospholipids (soy, egg or dairy lecithin) and amphiphilic proteins (caseinate or whey protein isolate) can be used in food industry to formulate nanoemulsions. Texture modifiers, substances that increase the viscosity such as proteins (whey protein isolate, gelatin or soy protein isolate), sugars (high-fructose corn syrup or sucrose), polysaccharides (carrageenan, xanthan, pectin, alginate) and polyols (sorbitol or glycerol) can be also used as stabilizers. Dense lipophilic materials such as brominated vegetable oil, sucrose acetate isobutyrate, ester gums can be used as a weighting agent to balance the densities of the liquids nanoemulsions [1, 3, 5, 6, 7, 8, 9].
In this chapter, we provide an overview on the terminology used in emulsions, formulation of nanoemulsions and diverse approaches for production of nanoemulsions. Additionally, we summarize the recent applications of nanoemulsions in food industry.
Emulsions are defined by International Union of Pure and Applied Chemistry (IUPAC) as “a fluid colloidal system in which liquid droplets and/or liquid crystals are dispersed in a liquid” [10]. If the continuous phase of the emulsion is an aqueous solution, the emulsion is oil-in-water and denoted by the symbol O/W, whereas, if the continuous phase is oil, the emulsion is referred to W/O (Figure 1) [10]. An emulsifier is a surfactant or surface-active agent, a substance that lowers the surface tension and/or the interfacial tension [10].
Schematic representation of oil in water (O/W, A) and water in oil (W/O, B) emulsions.
Nanoemulsions are emulsions that have a particle size at the nanometer range (20–500 nm) [2, 5, 6, 11]. Nanoemulsions have major differences in size, shape and stability from the classical macroemulsions and microemulsions [5]. While microemulsions are thermodynamically stable, both macroemulsions and nanoemulsions are thermodynamically unstable [5, 11].
A typical nanoemulsion consists of a water phase, an oil phase and an emulsifier [5]. When present in small amounts, an emulsifier facilitates the formation of emulsions by decreasing the interfacial tension between the oil and water phases [5]. Additionally, emulsifiers aid the stabilization of nanoemulsions [11]. Formation and stabilization of nanoemulsions depend largely on the physico-chemical properties of the three aforementioned constituents.
O/W nanoemulsions have the greatest application in commercial products [9]. The particles in O/W nanoemulsion have a core-shell-type structure with a shell of surface-active amphiphilic material covers a core made of lipophilic material.
The oil phase used to prepare food-grade nanoemulsions can be formulated from a variety of nonpolar molecules, such as free fatty acids (FFA), monoacylglycerols (MAG), diacylglycerols (DAG), triacylglycerols (TAG), waxes, mineral oils or various lipophilic nutraceuticals [9]. TAG oils extracted from soybean, safflower, corn, flaxseed, sunflower, olive, algae or fish are the most commonly used in nanoemulsions primarily due to their low cost and nutritional value [9]. Physical and chemical characteristics of the oil phase such as viscosity, water solubility, density, polarity, refractive index and interfacial tension and chemical stability greatly influence the properties of nanoemulsions [1, 3, 5, 6, 7, 8].
The aqueous phase used to prepare food-grade nanoemulsions can be formulated from water with a variety of polar molecules, carbohydrates, proteins, acids, minerals or alcoholic cosolvents [9]. The selection of the aqueous phase has a great impact on the physicochemical properties of the produced nanoemulsion.
Stabilizers influence the long-term stability of nanoemulsions; therefore, the selection of the appropriate stabilizer is one of the most important factors to consider for the proper production of nanoemulsions. Various kinds of stabilizers are added to improve the long-term stability of nanoemulsions, and they are summarized in Table 1 [1, 3, 5, 6, 7, 8, 9]. Stabilizers can be emulsifiers, ripening retarders, texture modifiers and weighting agents. Emulsifiers are the most common stabilizers added in nanoemulsions. Emulsifiers of different kinds may be added such as phospholipids, small molecule surfactants, polysaccharides, and proteins. Examples of small molecule surfactants are listed in Table 2.
Stabilizers | Function | Examples |
---|---|---|
Emulsifiers | Single emulsifier or combination of emulsifiers are added to stabilize emulsions by increasing their kinetic stability |
|
Ripening retarders | Hydrophobic substances that stabilize nanoemulsions by retarding or inhibiting Ostwald ripening |
|
Texture modifiers | Substances that increase the viscosity of nanoemulsions |
|
Weighting agents | Substances that balance the densities of the liquids nanoemulsions |
|
Kinds of stabilizers added to improve long-term stability of nanoemulsions.
Small molecule surfactants | Type | Examples | Remarks |
---|---|---|---|
Ionic surfactants | Negatively charged | Sodium lauryl sulfate (SLS) Diacetyl tartaric acid ester of mono- and diglycerides (DATEM) Citric acid esters of mono and diglycerides (CITREM) |
|
Positively charged | Lauric arginate | ||
Nonionic surfactants | Sugar esters | Sucrose monopalmitate Sorbitan monooleate |
|
Polyoxyethylene alkyl ethers (POE) | Brij-97 | ||
Ethoxylated sorbitan esters | Tweens 20 and 80 Spans 20, 40, 60 and 80 | ||
Zwitterionic surfactants | Positively and negatively charged groups | Phospholipids (lecithin) | pH influences the net positive, negative or neutral charge |
Examples of small molecule surfactants added to nanoemulsions.
Nanoemulsion is a nonequilibrium system which needs external or internal energy source to be successfully formed [12]. Nanoemulsions can be fabricated using many approaches that can be classified as high-energy or low-energy approaches.
The used techniques for the production of nanoemulsion has a great effect on the droplet size and consequently affect the stability mechanisms of the emulsion system through operating conditions and composition. Generally, preparation of nanoemulsions applies lower concentrations of surfactant (5–10%) than the microemulsion (20% and higher) [13].
Mechanical devices which can produce strong disruptive forces are used in high-energy approaches to mix and disrupt oil and water phases allowing the formation of tiny oil droplets [2, 14, 15, 16]. On the other hand, low energy approaches depend on the spontaneous formation of tiny oil droplets in the oil-water-emulsifier mixed systems when either the solution or the environmental conditions such as temperature and composition are changed [14, 17, 18, 19, 20, 21]. The used approach in nanoemulsion formation, together with the operating conditions, and the composition of the system affect the size of the formed droplets. In this section, we have a brief overview on the most commonly used high-energy and low-energy approaches for nanoemulsion formation.
The preparation of nanoemulsions by high-energy methods is strongly dependent on the surfactants used as well as the functional compounds in addition to the quantity of energy applied [1]. Accordingly, the nanoemulsions formed by high-energy approaches constitute a natural method for the preservation of the nanoemulsions against formulation modification such as addition of monomer, surfactant, cosurfactants [17].
High-energy methods employ mechanical devices to produce disruptive forces that can mix and disrupt oil and water phases leading to the formation of the tiny oil droplets, such devices as high-pressure valve homogenizers, microfluidizers, and sonication methods [14, 16]. To keep the droplets in spherical shapes, intense energies are applied in order to generate disruptive forces that exceed the restoring forces, and these restoring forces could be calculated by the Laplace Pressure: ΔP = γ /2r, which increases by reducing droplet radius (r) and increasing interfacial tension (γ) [22]. Generally, the droplet size produced by high-energy approaches is controlled by a balance between two opposing processes that occur within the homogenizer, which are the droplet disruption and droplet coalescence [23]. Smaller droplets can be obtained by increasing the homogenization intensity or duration, increasing the concentration of the used emulsifier or by controlling the viscosity ratio [14, 22, 24]. The smallest droplet size that can be obtained using certain high-energy device is governed by the flow and force profiles of the homogenizer, the operating conditions such as the energy intensity and duration of the process, the environmental conditions meaning the applied temperature, the sample composition which includes the oil type, emulsifier type and concentrations, and the physicochemical properties of the phases which means the interfacial tension and viscosity [14, 25, 26]. In more clear words, the droplet size decreases as the intensity or duration of energy increases, the interfacial tension decreases, the emulsifier adsorption rate increases, and the disperse-to-continuous phase viscosity ratio falls within a certain range (0.05 < ηD/ηC < 5) [12, 13, 27]. Production of small droplets depends on the extent of the ηD/ηC range and the nature of the disruptive forces produced by the particular homogenizer used, that is, simple shear versus extensional flow. Thus, the smaller the droplet radius, the more difficult is to break them up further.
High-energy approaches are the most suitable methods for the production of food-grade nanoemulsions as they can be applied to various types of oils such as triacylglycerol oils, flavor oils, and essentials oils as the oil phase as well as different emulsifier types such as proteins, polysaccharides, phospholipids, and surfactants. Even so, the size of the formed particles is strongly dependent on the oil characteristics and the used emulsifier. For instance, it is easier to produce very small droplets when flavor oils, essential oils or alkanes are used as the oil phase because they have low viscosity and/or interfacial tension [9]. Now we present the most commonly used devices in high-energy approaches.
In high-pressure valve homogenization, first a very high pressure is applied on the mixture and then it is pumped through a restrictive valve (Figure 2). The very fine emulsion droplets are generated by the very high shear stress [28, 29]. High-pressure and multiple passes are necessary to produce the required droplet size [9]. The combination of intensive disruptive forces such as shear stress, cavitation, and turbulent flow conditions can break the large droplets into smaller ones [30]. Production of conventional emulsions with small droplet sizes in food industry is commonly done using high-pressure valve homogenizers [22, 31]. Some of the food nanoemulsions prepared by high-pressure valve homogenization technique is β-carotene, thyme oil, and curcumin nanoemulsions [32, 33, 34].
Schematic representation of three devices utilized in high-energy approach for production of food-grade nanoemulsions: A. high-pressure valve homogenization; B. ultrasonic homogenization; C. microfluidizer; and D.D. droplet disruption.
These devices are more suitable for reducing the size of the droplets in preexisting coarse emulsions than in making emulsions directly from two separate liquids [9]. To describe the operation in the high-pressure valve homogenizer, the coarse emulsion is produced by the high shear mixer and is then passed into a chamber by the pump through the inlet of the high-pressure valve homogenizer and then forced through a narrow valve at the end of the chamber on its forward stroke. The coarse emulsion particles are broken down into smaller ones by a combination of intense disruptive forces when it passes through the valve. Different nozzle designs are available to increase the efficiency of droplet disruption [9].
The droplet size produced using a high-pressure valve homogenizer usually decreases as the number of passes and/or the homogenization pressure increases. It also depends on the viscosity ratio of the two phases (usually oil and water) being homogenized. As mentioned before, small droplets can only usually be produced when the disperse-to-continuous phase viscosity ratio falls within a certain range (0.05 < ηD/ηC < 5) [12, 13, 27]. Moreover, sufficient emulsifier is required to cover the surfaces of the new droplet formed during homogenization, and the emulsifier should be rapidly adsorbed on the droplet surfaces to prevent re-coalescence [23].
As a summary, to obtain the required droplet size in nanoemulsions, we need to operate at extremely high pressures and to use multiple passes through the homogenizer. Even then, high emulsifier levels, low interfacial tensions, and appropriate viscosity ratios are required to obtain droplets less than 100 nm in radius [9].
This device is similar in design to high-pressure valve homogenizer in that it employs high pressure to force the premix of emulsion through a narrow orifice to facilitate the disruption of droplet but differs only in the channels in which the emulsion flows (Figure 2). The emulsion flowing in a microfluidizer is divided through a channel into two streams, each passes through a separate fine channel, and then both streams are redirected into interaction chamber, in which they are exposed to intense disruptive forces leading to highly efficient droplet disruption [3]. Increasing the homogenization pressure, number of passes, and emulsifier concentration can efficiently reduce the droplet size formed. McClements and Rao have practically proved that the logarithm of the mean droplet diameter decreased linearly as the logarithm of the homogenization pressure increased for both ionic surfactant and a globular protein (β-lactoglobulin). But it could be noticed that this relation was appreciably steeper for the surfactant than for the protein, and this could be explained by the slow rate of the protein to adsorption to the droplet surfaces, with the formation of a viscoelastic coating which inhibits further droplet disruption [9].
In addition, there is an optimum range of disperse-to-continuous phase viscosity ratio, which facilitates the formation of small droplets [14]. But this relation is highly affected by the surfactant used, for the ionic surfactant mean droplet diameter decreases when the viscosity ratio decreases. On the other hand, the mean droplet size is hardly affected by viscosity ratio when a globular protein was used as an emulsifier, which may be also attributed to the relatively slow adsorption of the protein and its ability to form a coating that inhibits further droplet disruption [9].
Microfluidizers have been extensively used for the preparation of pharmaceutical products as nutraceutical emulsions, food and beverages such as homogenized milk in addition to the production of flavor emulsion [9]. Nanoemulsions of various bioactive compounds such as β-carotene and lemon grass essential oil were prepared using microfluidization technique [35, 36, 37].
When two immiscible liquids in the presence of a surfactant are subjected to high-frequency sound waves (frequency > 20 kHz) using sonicator probes that contain piezoelectric quartz crystals that expand and contract in response to an alternating electrical voltage, this causes strong shock waves produced in the surrounding liquid by the tip of the sonicator placed within the liquid (Figure 2). The mechanical vibrations lead to the formation of liquid jets at high speed, the collapse of the micro-bubbles formed by cavitation generates intense disruptive forces that lead to droplet disruption and the formation of emulsion droplets of nano size (70 nm). The emulsion should spend sufficient time within the region where droplet disruption occurs to ensure efficient and uniform homogenization [9, 16, 25, 38]. Practically, the droplet size decreases when the intensity of ultrasonic waves, sonication time, power level, and emulsifier concentration increase [25, 39, 40]. The type and amount of the emulsifier used, as well as the viscosity of the oil and aqueous phases affect the homogenization efficiency [16, 23, 25, 40]. All the above parameters should be first optimized to produce nanoemulsions of the right droplet size. It is noteworthy to mention that sonication methods may lead to protein denaturation, polysaccharide depolymerization, or lipid oxidation during homogenization. Thus, this technology has not yet been proved as efficient for industrial-scale applications [3].
Rotor/stator devices (such as Ultra-Turrax) do not provide a good dispersion in terms of droplet sizes when compared to other high-energy techniques. The efficiency of such devices when calculated was 0.1%, where 99.9% is dissipated as heat during the homogenization process, so the energy provided mostly being dissipated, generating heat [12, 13, 17].
The low-energy methods are dependent on the internal chemical energy of the system [13, 41]. The nanoemulsions here are formed as a result of phase transitions that occur during the emulsification process due to the change in the environmental conditions such as temperature or composition [20], applying constant temperature and changing the composition or using constant composition and changing the temperature [42, 43, 44]. The composition of the emulsion such as surfactant-oil-water ratio, surfactant type and ionic strength in addition to the environmental conditions temperature, time history and stirring speeds greatly affect the droplet size [17, 44].
Low-energy approaches can produce smaller droplet sizes than high-energy approaches; however, low-energy approaches can be applied to limited types of oils and emulsifiers. For example, proteins or polysaccharides cannot be used as emulsifiers; alternatively, high concentrations of synthetic surfactants should be used to form nanoemulsions by low-energy approaches. This factor limits the use of such approaches in many food applications [4, 9]. The low-energy approaches are listed in the next section and represented in Figure 3.
Schematic representation of four devices utilized in low-energy approach for production of food-grade nanoemulsions: A. membrane emulsification method; B. spontaneous emulsification method; C. phase inversion temperature method; D. emulsion inversion point method; a, rotating membrane; b, disperse phase; stabilized droplets of colloidal particles; d, surfactant and oil phase, e, aqueous phase; f, surfactant moves to water phase; g, oil in water emulsion; H. W/O emulsion; I. O/W emulsion; and J. O/W nanoemulsion.
This technique involves the formation of a dispersed phase (droplets) through a membrane into a continuous phase (Figure 3). It requires less surfactant and produces emulsions with a narrow size distribution range than the high-energy techniques. Unfortunately, the low flux of the dispersed phase through the membrane is a strong limitation during scale-up of this method [29].
This technique involves spontaneous formation of nanoemulsion as a result of the movement of a water miscible component from the organic phase into the aqueous phase when the two phases are mixed together (Figure 3) [17]. The organic phase is usually a homogeneous solution of oil, lipophilic surfactant and water-miscible solvent, and the aqueous phase consists of water and hydrophilic surfactant [19]. The spontaneous characteristic of this technique results from the initial nonequilibrium states when the two liquids are mixed without stirring. Accordingly, spontaneous emulsification is brought about by various methods such as diffusion of solutes between two phases, interfacial turbulence, surface tension gradient, dispersion mechanism or condensation mechanism. These mechanisms are highly influenced by the systems’ compositions and their physicochemical features such as the physical properties of the oily phase and nature of the surfactants [19]. The size of the droplets produced can be controlled by varying the compositions of the two initial phases, as well as the mixing conditions [9].
There are many physicochemical mechanisms that can be utilized for spontaneous emulsification [45]. When two immiscible phases like water and oil are brought into contact with each other, and one of the phases contains a component that is partially miscible with both phases such as amphiphilic alcohol or surfactant. In this case, some of the components that are partially miscible with both phases will move from its original phase into the other one causing an increase in oil-water interfacial area, interfacial turbulence, and spontaneous formation of droplets. In this method, the variation in the compositions of the two initial phases, and the mixing conditions can control the size of the droplets produced.
McClements and Rao [9] compared the spontaneous emulsification method of producing nanoemulsions with the high-energy method named the microfluidizer. The surfactant-oil-water system used consisted of 15.4 wt% nonionic surfactant, 23.1 wt% medium-chain triglycerides (MCT), and 61.5% water, with the surfactant containing a 50:50 mixture of a hydrophilic (Tween 80) and lipophilic (Tween 85) surfactant. The microfluidization method produced droplets with a diameter of about 110 nm, whereas the spontaneous emulsification method could produce droplets with diameters around 140 nm. This simple experiment demonstrated that nanoemulsions could be produced using the spontaneous emulsification method, provided that the system composition was optimized, that is, surfactant, oil, and water contents.
This process itself increases entropy and thus decreases the Gibbs free energy of the system [17]. In pharmaceutical industry, the systems prepared by spontaneous emulsification method are referred to either as self-emulsifying drug-delivery systems (SEDDS) or as self-nano-emulsifying drug delivery systems (SNEDDS).
This method depends on the rapid diffusion of a water-miscible organic solvent that contains a lipophilic functional compound in the aqueous phase promoting the formation of nanoemulsions. This rapid diffusion enables the one-step preparation of nanoemulsion at low-energy input with high yield of encapsulation. At the end, the organic solvent is evaporated from the nanodispersion under vacuum [20, 21]. However, the use of this technique is limited to water-miscible solvents [21].
Another low-energy approaches are the phase inversion methods that use the chemical energy released as a result of phase transitions that occur during the emulsification. Nanoemulsions have been formed by inducing phase inversion in emulsion from a W/O to O/W form or vice versa by either changing the temperature in the phase-inversion temperature (PIT), the composition in phase-inversion composition (PIC) or emulsion-inversion point (EIP) [6].
This method depends on that at a fixed composition and by changing temperature, the nonionic surfactants changes their affinities to water and oil through the changes in the optimum curvature (molecular geometry) or relative solubility of nonionic surfactants [46, 47]. Using the PIT method, nanoemulsions are spontaneously formed by varying the temperature-time profile of certain mixtures of oil, water, and nonionic surfactant, thus nanoemulsions are formed by suddenly breaking-up the microemulsions maintained at the phase inversion point by a rapid cooling [48] or by a dilution in water or oil [17] the formed nanoemulsions are kinetically stable and can be considered as irreversible [3]. PIT also involves the controlled transformation of W/O emulsion to O/W emulsion or vice versa through an intermediate liquid crystalline or bicontinuous microemulsion phase [9].
The key for this phase inversion is the temperature-induced changes in the physicochemical properties of the surfactant (Figure 3). Here the molecular geometry of a surfactant is dependent on the packing parameter, p = aT/ aH, where, aT is the cross-sectional area of the lipophilic tail-group and aH is the cross-sectional areas of the hydrophilic head-group [49].
In water, the surfactant molecules tend to associate with each other forming a monolayer due to the hydrophobic effects, and these monolayers have an optimum curvature that causes the most efficient packing of the molecules [49]. The packing parameter p determines the optimum curvature of the surfactant monolayer, when p < 1, the optimum curvature is convex and the surfactant favors the formation of O/W emulsions, for p > 1 the optimum curvature is concave favoring W/O emulsions, while for p = 1, monolayers have zero curvature, where surfactants do not favor either O/W or W/O systems and instead lead to the formation of form liquid crystalline or bicontinuous systems (Figure 3).
The relative solubility of surfactants in oil and water phases usually changes with temperature due to the physicochemical properties and packing parameter (p) of nonionic surfactants [50, 51]. At a particular temperature, the solubility of the surfactant in the oil and water phases is approximately equal, and this is known as phase inversion temperature or PIT at which an oil-water-surfactant system changes from an O/W emulsion to a W/O emulsion as the packing parameter equals unity (p = 1). At temperatures greater than the PIT (≈ T > PIT +20°C), the head group becomes progressively dehydrated and the solubility of the surfactant in water decreases, it becomes more soluble in oil, its p > 1, and the formation of a W/O emulsion is favored. When the temperature is decreased (≈T < PIT-30°C), the head group of a nonionic surfactant becomes highly hydrated and tends to be more water soluble (p < 1), favoring the formation of O/W emulsions [9].
Above PIT, the surfactant molecules are being present predominantly within the oil droplets as they are more oil-soluble at this temperature. When this system is quench-cooled below the PIT, the surfactant molecules rapidly move from the oil phase into the aqueous phase just like the movement of water-miscible solvent in the spontaneous-emulsification method, which leads to the spontaneous formation of small oil droplets because of the increase in interfacial area and interfacial turbulent flow generated. For this reason, Anton et al. [51] proposed that he formation of nanoemulsions by the PIT method has a similar physicochemical basis to the spontaneous emulsification method.
This process is characterized by being simple, prevents the encapsulated drug being degraded during processing, consumes low amounts of energy, and allows an easy industrial scale-up [17].
PIC method is very close to PIT method, but here the optimum curvature of the surfactant is altered by changing the formulation of the system, rather than the temperature [51]. For example, an O/W emulsion can be phase inverted to a W/O emulsion by adding salt as in this case the packing parameter increased and becomes greater than unity (p > 1) due to the ability of the salt ions to screen the electrical charge on the surfactant head groups [52]. Alternatively, a W/O emulsion containing a high salt concentration can be phase inverted to O/W emulsion by dilution with water in order to reduce the ionic strength below some critical level. Another PIC method for preparation of nanoemulsions is to change the electrical charge and stability of emulsions by changing the pH. The carboxyl groups of fatty acids are uncharged at low pH (pH < pKa) and have a relatively high oil solubility (p > 1), so they could stabilize W/O emulsions, but at high pH, they become ionized so they become more water-soluble (p < 1) and stabilize O/W emulsions. Consequently, nanoemulsions can be formed by increasing the pH of a fatty acid-oil-water mixture from below to above the pKa value of the carboxyl groups [41, 52].
This method involves changing the composition of the system at a constant temperature. In order to create kinetically stable nanoemulsions, the structures are formed through a progressive dilution with water or oil [17]. In EIP methods, the change from W/O to O/W or vice versa needs a catastrophic-phase inversion, rather than a transitional-phase inversion as with the PIC or PIT methods [53]. A transitional-phase inversion occurs when the characteristics of a surfactant are changed through adjusting one of the formulation variables, such as the temperature, pH, or ionic strength. A catastrophic-phase inversion occurs by changing the ratio of the oil-to-water phases while the surfactant properties remain constant. The emulsifiers used in catastrophic-phase inversion are usually limited to small molecule surfactants that can stabilize both W/O emulsions (at least over the short term) and O/W emulsions (over the long term) [9].
McClements and Rao [9] showed practically that increasing the amount of water in a W/O emulsion consisting of water droplets dispersed in oil with continuous stirring can cause the formation of additional water droplets within the oil phase at low amounts of added water; however, once a critical water content is exceeded, the coalescence rate of water droplets exceeds the coalescence rate of oil droplets, and so phase inversion occurs from a W/O to an O/W system (Figure 3). Thus, the catastrophic-phase inversion is usually induced by either increasing (or decreasing) the volume fraction of the dispersed phase in an emulsion above (or below) some critical level.
The value of the critical concentration where phase inversion occurs, as well as the size of the oil droplets produced, depends on process variables, such as the stirring speed, the rate of water addition, and the emulsifier concentration [53].
Nanoemulsions have diverse applications such as drug delivery, pharmaceuticals, cosmetics, and food [5]. In this section, we focus on the applications of nanoemulsions in food industry. Nanoemulsions have been used as a suitable form to improve the digestibility of food, bioavailability of active components, pharmacological activities of certain compounds, and solubilization of drugs. Some applications are listed below.
One of the most important applications of nanoemulsions in food industries is the encapsulation of lipophilic components such as vitamins, flavors, and nutraceuticals [9]. Encapsulation is a useful tool to entrap a bioactive ingredient in a core or a fill within a carrier (coating, matrix, membrane, capsule, or shell) for improving the delivery of bioactive molecules within living cells [54].
This technology has many applications in food industry for masking the unpleasant taste or smell of some bioactive materials, increasing the bioavailability of some components, improving the stability of food ingredients, decreasing air-induced food degradation or decreasing the evaporation of food aroma [54]. One of the most interesting applications of encapsulation in food industry is probiotics. Probiotics are defined as microorganisms that provide health benefits when consumed in adequate amounts [55, 56]. Encapsulation of bioactive compounds in nanoemulsion-based delivery system was achieved for resveratrol (Figure 4) [57].
Applications of nanoemulsions-based delivery systems in food industry.
Nanoemulsions from food-grade ingredients are being increasingly utilized to encapsulate biologically active lipids such as Omega-3 fatty acids, polyunsaturated fatty acids (PUFAs) [9]. Omega-3 fatty acid supplementation may be protective effect against cancer, cardiac death, sudden death, cognitive aging, asthma, inflammation and myocardial infarction. α-Linolenic acid (ALA), an Omega−3 fatty acid, is one of two essential fatty acids together with linoleic acid (Figure 4). ALA is necessary for health and cannot be synthesized within the human body.
Low bioavailability of some naturally occurring active compounds hinders their efficient pharmacological activities. Nanoemulsions have been used as a suitable form to increase bioavailability of natural extracts. Curcumin, 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (Figure 4), is a yellow-colored polyphenolic compound isolated from the rhizomes of turmeric (Curcuma longa, family Zingiberaceae) [58]. Curcumin has been used as a natural coloring agent health benefits such as anticarcinogenic, antioxidant, anti-inflammatory, and antimicrobial [59]. Curcumin nanoemulsions showed significant inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation [60]. However, low bioavailability hinders the efficiency of orally administrated curcumin. Flavored nanoemulsions have been prepared with improved curcumin digestibility compared to directly taken curcumin [60, 61].
Additionally, nanoemulsion formulation of oil-soluble vitamins such as alpha-tocopherol enhanced their oral bioavailability and pharmacological effects [62, 63]. α-Tocopherol, a type of vitamin E, is mainly present in olive and sunflower oils (Figure 4). Vitamin E supplements have important antioxidant, anticancer as well as cardiovascular protective activities.
Moreover, nanoemulsion preparations improved the bioavailability quercetin or methylquercetin [64]. Quercetin, a polyphenol from the flavonoid group of, has been found in many fruits, vegetables, leaves, and grains (Figure 4). Quercetin supplements have been promoted as antioxidant and anticancer.
Food digestibility is a measure of how much of food is absorbed by the gastro-intestinal tract into the bloodstream. Nanoemulsions have been used as a suitable form to improve digestibility characters of food and natural extracts.
β-Carotene is a red-orange pigment that is found in plants such as carrots and colorful vegetables. β-Carotene is a member of the carotenes, which are terpenoids (isoprenoids), biosynthesized from geranylgeranyl pyrophosphate (Figure 4). β-Carotene is the best-known provitamin A carotenoid. β-Carotene flavored nanoemulsion with improved digestibility has been applied [20, 33, 65].
Nanoemulsion formulation has been applied to increase the solubilization of phytosterols [66]. Phytosterols have been shown to lower the blood cholesterol, and therefore, they reduce the risk of coronary heart diseases. Among phytosterols, β-sitosterol has been isolated from many vegetables and fruits (Figure 4). Moreover, nanoemulsions formulas increased also the solubilization of lycopene [66]. Lycopene, a carotenoid pigment and phytochemical, has been found in tomatoes, other red fruits and vegetables (Figure 4). Lycopene has potential effects on prostate cancer and cardiovascular diseases.
Nanoemulsions have gained great attention and popularity during the last decade due to their exceptional properties such as high surface area, transparent appearance, robust stability, and tunable rheology. The most commonly known preparation approaches for nanoemulsions include high-energy approaches such as high-pressure valve homogenization, microfluidizers and ultrasonic homogenization, and low energy methods such as spontaneous emulsification, phase inversion composition, phase inversion temperature and emulsion inversion point. There is little understanding of the possible industrial relevance of many of these approaches as the physics of nanoemulsion formation is still semi-empirical and rational scale-up procedure have not been widely explored. The interest in nano-emulsion preparation and application is growing, but few of the numerous ideas reported become commercial final applications. Nanoemulsions are considered one of the most promising systems to improve solubility, bioavailability, and functionality of nonpolar active compounds. Food industry seeks to use these systems for the incorporation of the lipophilic functional compounds for the development of innovative food products. The application of nanoemulsions to food systems still poses challenges that need to be addressed both in terms of the production process, especially their cost, and of the characterization of both the resulting nanoemulsions and the food systems to which they will be applied in terms of product safety and acceptance.
Although nanoemulsions have potential advantages over conventional emulsions such as the preparation of transparent foods and beverages, their improved bioavailability, and physical stability. However, there are a number of regulatory aspects that should be overcome first to allow the wide applications of nanoemulsions.
First of all, most of the components used in formulation of nanoemulsions either in low-energy or high-energy approaches are unsuitable for widespread utilization within the food industry such as synthetic surfactants, synthetic polymers, synthetic oils, or organic solvents. Thus, food-grade ingredients such as flavor oils, triglyceride oils, proteins, and polysaccharides must be utilized in the formulation of food nanoemulsions as these ingredients are legally accepted, label-friendly and economically viable.
Second, in order to fabricate food-grade nanoemulsions on the industrial scale, suitable processing operations should be employed to obtain economic and robust products. Accordingly, many of the identified approaches which were developed in the research laboratories are not suitable for industrial production especially the low-intensity approaches, which could not be yet investigated in industrial scale production. At present, the high-intensity approaches only are utilized for production of nanoemulsions in the food industry.
Finally, there are certain safety concerns associated with the utilization of very small lipid droplets in foods. For example, the route of absorption, the bioavailability or potential toxicity of a lipophilic component encapsulated within nanometer-sized lipid droplets are considerably different from those dispersed within a bulk lipid phase. For these reasons, extensive studies are strongly needed in the area of nanoemulsion safety.
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