Accepted Manuscript

Nano-encapsulation as a promising approach for targeted delivery and controlled

release of vitamins

Iman Katouzian, Seid Mahdi Jafari

PII: S0924-2244(16)30001-2
DOI: 10.1016/j.tifs.2016.05.002
Reference: TIFS 1804

To appear in: Trends in Food Science & Technology

Received Date: 1 January 2016

Revised Date: 3 May 2016
Accepted Date: 4 May 2016

Please cite this article as: Katouzian, I., Jafari, S.M., Nano-encapsulation as a promising approach for
targeted delivery and controlled release of vitamins, Trends in Food Science & Technology (2016), doi:
10.1016/j.tifs.2016.05.002.

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 ACCEPTED MANUSCRIPT
Nano-encapsulation as a promising approach for targeted delivery and controlled
release of vitamins

Iman Katouzian, Seid Mahdi Jafari

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Graphical Abstract

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1 Nano-encapsulation as a promising approach for targeted delivery and controlled release of
2 vitamins
3 Running Title: Nano-encapsulation of vitamins
4 Iman Katouzian1,3, Seid Mahdi Jafari1,2,3*
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5 Department of Food Materials and Process Design Engineering, Faculty of Food Technology, University of
6 Agricultural Science and Natural Resources, Gorgan, Iran.

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7 Cereals Health Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
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8 Nano-encapsulation in the Food, Nutraceutical, and Pharmaceutical Industries Group (NFNPIG), Universal
9 Scientific Education and Research Network (USERN), Tehran, Iran

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10 *Corrseponding author at Pishro Food Technology Research Group, Gorgan, Iran:
11 Tel./fax: +98 17 324 26 432. E-mail address: smjafari@gau.ac.ir (S.M. Jafari).

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12 Structural abstract
13 Background

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14 Vitamins are bioactive molecules necessary for human health, which are sensible to degradation. During
15 consumption, the bioavailability of these compounds might be limited due to structure break-down and low
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16 absorption. Today, nanoencapsulation can be a promising approach for targeted delivery of vitamins and
17 protecting these bioactive components against destructive environment during processing and delivery.
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18 Regarding the benefits of utilizing nanotechnology in the food sector, safety aspects of these tiny carriers
19 should also be clarified as this technology develops. Due to the possible negative effects of nanomaterials,
20 several agencies have legislated regulatory policies to prevent potential harms to the consumers, which are
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21 underlined in this article.

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22 Scope and approach

23 Nanoencapsulation-based technologies are a unique and novel field of investigation in the food and
24 pharmaceutical industry with benefits, such as higher bioavailability, high shelf-stability and controlled release
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25 of active compounds. This review highlights recent works on these techniques and advances made in
26 nanoencapsulation of lipophilic and hydrophilic vitamins, safety issues and health risks regarding the
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27 consumption of these products, which opens new horizons in food technology and nutrition with possibilities
28 of commercialization in the near future.
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29 Key findings and conclusions

30 Recently, considerable progresses are being carried out in the field of food nanoencapsulation involving novel
31 nanovehicles to encapsulate vitamins. Nanofibers and nanohydrogels are some examples of efficient and
32 modern nanocarriers. Overall, the vitamins encapsulated within nanovehicles are considered safe since they
33 are mostly produced from food components, meanwhile more studies should be performed regarding the
34 safety issues of nanodelivery of vitamins. In near future, it is assumed that nanoencapsulated vitamins will be
35 broadly applied the in the food and beverage products.
36 Keywords: Nanoencapsulation; vitamins; food industry; safety; bioavailability.

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37 1. Introduction
38 Vitamins and antioxidants are rudimentary elements for human health as they assist the body to grow and
39 develop. Furthermore, they are able to prevent diseases and to promote general health. Unfortunately, most
40 of these bioactive agents are either produced in trifle amounts or not made in the body. Thus, vitamins need
41 to be supplied from food products and through dietary supplements if needed (Wildman, Wildman, &
42 Wallace, 2006). Some of the beneficial functions of vitamins are as follows: enhancing the immune system

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43 and vision, supporting skin health and cell growth and helping to prevent cancer (vitamin A); empowering
44 the immune system, alleviate anxiety and depression, reduce stroke risk and relieve PMS (premenstrual
45 syndrome) (vitamin B-complex); raising immunity, treating common cold symptoms, maintaining healthy

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46 skin, healing wounds, reducing cholesterol levels and regulating the blood sugar level, reducing neurological
47 disorders (vitamin C)(Hickey, 2009), preventing cancer and cardiovascular diseases as well as promoting

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48 vigorous bones and teeth (vitamin D), restraining brain and nervous system diseases; such as, Alzheimer and
49 other dementias, boosting physical endurance and avoiding skin disorders (vitamin E), helping blood clot,

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50 nerve signaling, improving bone health and regulating cellular functions (Zempleni, Suttie, Gregory III, &
51 Stover, 2013). AN
52 Vitamins are sensitive molecules; therefore they should be preserved from harmful agents like heat and
53 oxidants. Encapsulation is a promising and novel method for preserving the innate characteristics of vitamins
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54 over time (Sanguansri & Augustin, 2006). This process includes coating or trapping a biomaterial or a
55 combination into another element. The entrapped substance is normally a liquid, while a gas or solid state
56 substance can also be carried. The coating substance is known as capsule, wall material, membrane, or
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57 carrier.
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58 Our body has nanoscale structures like DNA, amino acids, etc. (Weiss, Takhistov, & McClements, 2006).
59 Considering these natural nanoparticles, scientists have engineered nanomaterials for the usage in human’s
60 food and recently, there has been a tremendous progress in food nanoencapsulation.
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61 In this study, after a brief review on pros and cons of food nanotechnology and microencapsulation of
62 vitamins, we will highlight recent fundamental and novel techniques used to nanoencapsulate different
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63 vitamins in the food industry. Besides, issues on the characterization, controlled release and safety-
64 consumption of these vital elements are described. Future trends will also be explained in the last section.
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65 2. Pros and cons of applying nanotechnology in the food industry

66 Today, the entry of nanotechnology within the food sector has brought new hopes and is expected to be the
67 key to food industry’s concerns as it may bring various benefits, nevertheless like the other emerging
68 technologies it could also have risks for consumers. According to Aguilera (cited in Yaktine & Pray, 2009),
69 exerting nanotechnology in food industry may bring about various advantages and opportunities; such as,
70 developing promising nano-processes, fabricating eco-friendly processes and intelligent nano-packaging,
71 manufacturing products with desirable texture and tastes, producing low-calorie food and beverage products

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72 with the aim of changing the lifestyles into healthy ones. He also suggested that there are still more
73 opportunities which will be accomplished by carefully studying how food components are formed,
74 disintegrated, ingested and absorbed and without this perception it wouldn’t be possible to overcome the
75 potential risks and uncertainties within this technology.
76 Regarding the risks and disadvantages of applying nanotechnology in food industry, most of the
77 nanoparticles enter the gut through oral administration and absorption via intestine cells (enterocytes) is

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78 designed in a way that they do not allow large or foreign particles to pass through them, nevertheless the
79 nano-sized ingredients are able to cross these barriers, therefore there is a potential risk in bringing up gastric
80 diseases which should investigated through in vivo and clinical studies.

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81 3. Microencapsulation vs. nanoencapsulation of vitamins
82 Micro/nanoencapsulation is defined as the creation of a barrier to inhibit unfavorable chemical interactions

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83 and for the controlled release of bioactive ingredients especially vitamins. Importance of using the
84 microencapsulation processes for vitamins and their key features could be summarized as below:
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Protection of vitamins from external environment
• Controlled release of vitamins AN
• Improved flow properties
• Reduce overages
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• Measuring the precise level of vitamin delivery
• Forming Light-scattering vitamin solutions
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• Being cost effective especially for spray drying method

• Undesirable flavor of some vitamins are masked
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• Enriching the food products with a complex of vitamins

85 While for nano-encapsulation of vitamins, the following advantages can be mentioned:
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Faster dissociation

Higher surface area compared to mass proportion

High intracellular uptake
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Pass along the smallest body fenestrations

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Enable precision targeting

Reduce the reactions between vitmains and other molecules plus surrounding medium

Formulating optically transparent vitamin solutions

Reduction in the quantity of utilized core-shell material

Rendering long-shelf life coated vitamins

Reinforced physical stability against coalescence and gravitational separations
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87 The capsule size in microencapsulation ranges between 5-300µm in diameter (F. Gibbs, 1999). When the
88 particle size reduces to the nanoscale during nanoencapsulation, surface-to-volume ratio increases.
89 Therefore, the reactions are speeded by many folds; moreover, the mechanical, optical and electrical
90 properties of the materials will also change (Neethirajan & Jayas, 2011). Physicochemical characteristics of
91 vitamins strongly depend on the applied nanoencapsulation approach and delivery system. Thus, an
92 appropriate nanoencapsulation technique must be chosen considering the required size, physicochemical

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93 properties, nature of the encapsulated vitamin and the wall material. Nanoencapsulation process is more
94 complex than microencapsulation because of the difficulty in acquiring an intricate morphology for the
95 capsule entrapping the vitamin (Chau, Wu, & Yen, 2007).

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96 According to Gutiérrez, et al., (2013) casein nanoparticles were found to be more stable, cost efficient and
97 environmentally friendly when compared with microemulsions. Moreover, Danino, Livney, Ramon, Portnoy,

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98 & Cogan, (2014) and Semo, Kesselman, Danino, & Livney, (2007) suggested that nanoencapsulation via ẞ-
99 cyclodextrins produced satisfactory sensory properties and created optically transparent solutions, however,

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100 microemulsions tend to scatter light. In a recent investigation, it was suggested that nanoliposomes have the
101 benefits to minimize the reactions between bioactives and other molecules, increasing the shelf-life of food
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102 products and reducing the amount of used core-shell material compared to conventional liposomes, which are
103 biocompatible and their surface is easily modified (Fathima, Fathima, Abhishek, & Khanum, 2016).
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104 Fig. 1 presents the forms of microcapsuls. The shell is responsible for protecting vitamins from water,
105 oxygen or sunlight. On the other hand, nanostructured delivery forms applied in nanoencapsulation of
106 vitamins are summarized in Fig. 2.
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107 Fig. 1
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108 Fig. 2
109 There are some commercially approved biopolymers for the encapsulation of vitamins. Starches and
110 cyclodextrins are carbohydrate-based biopolymers that protect these sensitive compounds from the outside
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111 environment. Gum Arabic is also used in microencapsulating according to its solubility, viscosity and
112 emulsification features. However, economically it is not profitable. Alginates can also be used as a wall
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113 material at environment temperatures. Ethylcellulose has been approved to be a good substance for
114 encapsulating water-soluble vitamins, because as the wall materials width rises, the water permeability of the
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115 dispersed vitamins is reduced. Protein based shells may also be utilized in encapsulating different vitamins.
116 Nevertheless, their high cost is limiting factor for using them in an industrial scale.
117 4. Conventional microencapsulation techniques of vitamins
118 Before explaining the recent nanoencapsulation techniques applied in protection of vitamins, it is necessary
119 to be familiar with common microencapsulation methods used for different vitamins. Table 1 summarizes the
120 works performed on the microencapsulation of vitamins. In this section, some of the most important
121 techniques plus the literatures are presented.

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122 Table 1
123 4. 1 Spray-drying
124 It is one of the oldest encapsulation methods capable of producing encapsulated powders with different
125 particle sizes mostly utilized for encapsulating lipo-soluble vitamins in an industrial scale (Jafari, He, &
126 Bhandari, 2007a). In this procedure, all matrix substances; like, Arabic gum and maltodextrin are drenched
127 and the oil-based material is added during mixing. Later, homogenization is used to achieve an emulsion and

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128 finally the yield powder is achieved through spray-drying process. The resulting powder contains 1-50%
129 (w/w) oil (Boyle & Chang, 1999). These microencapsulated vitamins are commonly used in tablets in which
130 oxidation stability and tablet properties are affected by the type of the matrix material. (Shi & Tan, 2002)

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131 trapped vitamin D2 in a chitosan/ethylcellulose coating, and then examined morphology and release traits of
132 the capsuls. In vitro results showed that microcapsuls are able to remain unchanged in the intestine juice.

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133 High-DE maltodextrins are hygroscopic, thus the produced powder is not desirable. A maltodextrin with a
134 25DE combined with lactose, galactose or glucose has been shown to extend the shelf life of encapsulated

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135 trans-ẞ-carotene compared with commercial 25 DE maltodextrin alone (Desobry, Netto, & Labuza, 1999).
136 Spray drying has also been applied for encapsulation of water-soluble vitamins too. For example, Ascorbic
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137 acid (vitamin C) is an antioxidant or vitamin supplement vastly used in the food and beverage industry,
138 which is so unstable and can be degraded by many mechanisms (Kirby, Whittle, Rigby, Coxon, & Law,
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139 1991). (Desai & Park, 2005) analyzed the encapsulation of vitamin C regarding trypolyphosphate cross-
140 linked chitosan microspheres as the wall material. As a result, cross-linking factor influenced the particle size
141 between 6.1-9µm.
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142 4.2 Spray chilling and spray cooling

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143 Both techniques involve diffusing the vitamins in a molten fat or wax. Next, this dispersion is atomized
144 through heated nozzles into a case at room temperature (spray-cooling) or low temperatures (spray-chilling).
145 At the room temperature, the melting point of the encapsulated material is between 45-122°C. At low
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146 temperatures (refrigerate temperature), substances tend to melt at 32-42°C (Risch & Reineccius, 1995).
147 These microcapsuls won’t dissolve in water and as the temperature rises, the fat or wax membrane will be
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148 molten. Thus, the fat-crystallization in the spray- chilling or cooling process needs to be monitored carefully.
149 This is a suitable technique for encapsulating lipid-soluble vitamins. (Wegmüller, Zimmermann, Bühr,
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150 Windhab, & Hurrell, 2006) microencapsulated iron, vitamin A and iodine in hydrogenated palm fat by spray
151 cooling. After 6 months, an excellent stability of retinyl palmitate was observed and losses occurred during
152 this period was nearly 12%.
153 4.3 Emulsion technique
154 This process includes dispersing vitamins into an immiscible liquid phase, which possesses the shell
155 material. Second, adjustments are made in order to form shells around the scattered vitamins in the solution.
156 O/W is the most prevalent two phase system applied in encapsulation. (Wang, MacGillivray, & Macartney,

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157 2009) encapsulated cob (III) alamins; like, CNCbl and AdoCbl with 5,6dimethylbenzimidazole and
158 cucurbituril. The cucurbituril combined with vitamin B12 imitate the applications of chemical, photochemical
159 and electrochemical of these and other cob (III) alamins. (Leonard, Good, Gugger, & Traber, 2004)
160 encapsulated vitamin E in a breakfast cereal and compared its bioavailability to vitamin E encapsulated in
161 supplements. The capsule was made from d9-α-tocopheryl acetate (400-IU capsule). Results showed that
162 encapsulated vitamin E in supplements are poorly absorbed; however the bioavailability is increased by

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163 using it in fortified-foods. (Van Hasselt, et al., 2009) used polymeric micelles to encapsulate vitamin K. They
164 compared the capsule´s absorption in bile duct legated and sham rats. As a result, the gastrointestinal
165 absorption of the microcapsuls was affected through free bile, furthermore the uptake of micelles via

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166 pinocytosis was considered inconsiderable.
167 4.4 Fluidized bed coating

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168 It is also known as air suspension coating. Solid particles are suspended in an upward moving flow of air
169 which can be either cool or hot. Afterwards, the solid particles are sprayed through the top of the atomized

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170 particles of coating wall material, which can be molten or dissolved in an evaporable solvent (Risch &
171 Reineccius, 1995). The coating’s material can be cellulose derivatives, dextrins, emulsifiers, lipids, protein
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172 derivatives and starch derivatives. This method is prevalent in nutritional supplements that contain
173 encapsulated versions of vitamin C, vitamin B complex and a variety of vitamin/mineral premixes.
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174 Moreover, it can be consumed in a variety of food products including: seasonings, fillings, desserts and
175 puddings (Risch & Reineccius, 1995). (Xie, et al., 2010) reported encapsulation of vitamin C using this
176 method with the use of gelatin as the wall material. They fed larval shrimps (Penaeus japonicas) with this
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177 micro-diet; as a result the wet weight of shrimps rose 300% in 10 to 30 days after hatching. The retention
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178 efficiency of vitamin C estimated 88.2% in the coating procedure.

179 4.5 Liposome entrapment
180 Liposomes can be defined as single or multi-layered vesicles, which include the complete entrapment of an
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181 aqueous phase in a phospholipid-based membrane. Aqueous or lipid-soluble vitamins, but not both are
182 encapsulated in these membranes. (Kirby, et al., 1991) encapsulated vitamin C with high efficiency using this
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183 technique. The most stable liposomes are made of lecithin, cholesterol and negatively charged phospholipids.
184 A prevalent method for producing liposomes is dehydration-rehydration and no organic solvents are used.
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185 4.6 Coacervation

186 In this method, the liquid phase of coating material is separated from a polymeric solution, and the phase is
187 wrapped around the core particles as a uniform layer (F. Gibbs, 1999). It encompasses the dissolving gelling
188 protein and the emulsification of the core compound into the protein. The liquid coating is separated from the
189 polymer solution and is used to cover the material to be encapsulated through controlled physical mixing. It
190 is solidified by thermal, cross-linking or de-solvation methods. Finally, the microcapsuls are obtained by
191 centrifugation or filtration and the results are discrete particles. Coacervation can be simple or complex. The

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192 former, contains merely one colloidal solute like gelatin. The latter, is obtained through the usage of a second
193 oppositely charged hydrophilic colloid such as gelatin and gum acacia or gelatin and polysaccharide (F.
194 Gibbs, 1999). (Junyaprasert, Mitrevej, Sinchaipanid, Boonme, & Wurster, 2001) investigated the effect of
195 process variables on microencapsulating vitamin A palmitate via complex coacervation with gelatin and
196 acacia.
197 5. Nanoencapsulation technologies applied on different vitamins

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198 According to the recent studies in the field of nanoencapsulation of vitamins, it is expected that in future the
199 novel nanoencapsulation techniques seek to (1) employ naturally occurring food components for encasing
200 bioactives especially vitamins (Chapeau, et al., 2016; David & Livney, 2016; Lee, et al., 2016; Santiago &

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201 Castro, 2016), (2) fabricating novel and efficient nanovehicles by the combination of biopolymers,
202 manufacturing nanocomposites, modifying the nanocarriers (Assadpour, Maghsoudlou, Jafari, Ghorbani, &

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203 Aalami, 2016; Bochicchio, Barba, Grassi, & Lamberti, 2016; Chapeau, et al., 2016; Lee, et al., 2016; Tan,
204 Feng, Zhang, Xia, & Xia, 2016), (3) exerting novel low energy methods such as, spontaneous emulsification

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205 rather than high energy preparation approaches to retain bioactives against harsh processing conditions,
206 decline the surfactant and eliminate the cosurfactant (Assadpour, et al., 2016; Dasgupta, Ranjan, Mundra,
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207 Ramalingam, & Kumar, 2016; Mehrnia, Jafari, Makhmal-Zadeh, & Maghsoudlou, 2016) and (4) using novel
208 computational and numerical methods like Monte-Carlo simulations to predict the release profile and
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209 optimize targeted delivery of bioactive compounds (Dan, 2016; H. H. Liu, Surawanvijit, Orkoulas, & Cohen,
210 2016; Malik, Genzer, & Hall, 2015).
211 In this section, novel methods for nanoencapsulating vitamins are explained. Table 2 and 3 represents
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212 different approaches used for nanoencapsulating hydrophilic and lipophilic vitamins, respectively.
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213 Table 2
214 Table 3
215 5.1 Nanoemulsification methods
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216 Most prevalent uses of emulsion technology are in aqueous solutions, and nanoemulsions are produced in
217 this medium. Nanoemulsion droplet sizes ranges between 50 to 1000 nm (Sanguansri & Augustin, 2006).
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218 There are two ways to prepare nanoemulsions; low energy and high energy techniques such as phase
219 inversion temperature and microfluidization respectively. Nanoemulsions can be used in the liquid state;
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220 meanwhile a spray-drying process will be performed to obtain the powder form of the encapsulated material
221 (Jafari, He, & Bhandari, 2007b). Furthermore, it is possible to increase the stability and encapsulation
222 efficiency of the bioactive compounds via multiple emulsions containing a complex of biopolymers
223 (Mohammadi, Jafari, Assadpour, & Esfanjani, 2015).
224 Different vitamins can be encapsulated and transmitted via nanoemulsions (Gonnet, Lethuaut, & Boury,
225 2010; Mohammadi, et al., 2015). For instance, (Cho, Seo, Yim, & Lee, 2013) stated that nanoencapsulation
226 of thiamine dilauryl sulfate (TDS), a vitamin B derivative encased with lecithin as an edible encapsulant,

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227 restricted the spore germination of Fusarium oxypansum f.sp. Moreover, this compound obstructed its
228 mycelial growth.
229 There has been some studies in the area of natural surfactants. For instance, (Ozturk, Argin, Ozilgen, &
230 McClements, 2014) encapsulated vitamin D3 in O/W emulsions with quillaja saponin as a natural surfactant.
231 In the experiment bioacessiblity of vitamin D3 declined in the following order: corn oil≈ fish oil ˃ orange oil
232 ˃ mineral oil ˃ medium chain triglycerids (MCT). Long chain triglycerids (corn or fish oil) was considered

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233 the optimum compound, which enhance the vitamin bioaccessibility.
234 Double emulsions can be another form of nanoencapsulation of bioactive ingredients (Esfanjani, Jafari,
235 Assadpoor, & Mohammadi, 2015; Mohammadi, et al., 2015). (Bou, Cofrades, & Jiménez-Colmenero, 2014)

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236 assessed the physicochemical properties of riboflavin, encapsulated in food-grade W1/O/W2 double
237 emulsions with different types of lipid sources (chia oil, sunflower oil, olive oil or rendered pork backfat).

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238 Riboflavin was effectively encapsulated in chia oil at start, nevertheless the double emulsions in rendered
239 pork backfat protected vitamin B2 more efficiently after 8 days at 4 °C. All in all, double emulsions were

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240 stable to the stresses that normally exist in the food industry.
241 (Hategekimana, Chamba, Shoemaker, Majeed, & Zhong, 2015; Hategekimana, Masamba, Ma, & Zhong,
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242 2015) produced vitamin E- loaded nanocapsuls by octenyl succinic anhydride starches as emulsifiers and
243 wall materials and then stabilized them via spray-drying method. High degree of substitution, low molecular
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244 weight and low interfacial tension improved emulsification properties, whereas oxygen permeability and
245 water vapor permeability influenced the film forming characteristics. The degradation profile of vitamin E
246 was best fitted with Weibull model. Overall, low molecular weights formed stable vitamin E nanocapsuls,
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247 which can be applied in drug and beverage sector.

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248 (Saberi, Fang, & McClements, 2013) fabricated vitamin E-enriched nanoemulsions via spontaneous
249 emulsification. It can be defined as the formation of little oil droplets when an oil/surfactant mixture is
250 titrated in an aqueous solution. When 30% propylene glycol (PG) or 20% ethanol was present in the aqueous
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251 phase, the smallest droplets (d<50nm) and highest transparency were acquired. However, Ostwald ripening
252 occurred as nanoemulsions were unstable during storage especially at high temperatures. Undiluted
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253 nanoemulsions showed a high and irreversible increase in turbidity upon heating (53°C) for the system with
254 30% PG and 38°C for the one containing 20% ethanol. Considering diluted compounds, a much better
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255 thermal stability with a high rate in turbidity at 75.5 °C for both systems. The release criteria of poorly water-
256 soluble active vitamin E acetate from oil/water nanoemulsions was reported by (Morais & Burgess, 2014),
257 which used a low energy emulsification method. Nanoemulsions consisted of canola oil, cremophorRH40®
258 and span80®. Dialysis sac and reverse dialysis sac techniques were carried out as well as USP1 dissolution
259 apparatus fitted with dialysis sac adapters to measure the vitamin E release. Micellar solubilization increased
260 vitamin E transport from canola oil to buffer solution; however no concentration active increase in the

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261 nanoemulsion external aqueous phase was seen considering the presence of micelles. (Guttoff, Saberi, &
262 McClements, 2015) prepared vitamin D nanoemulsions through spontaneous emulsification. They
263 investigated the effect of vitamin D and MCT for surfactant to oil ratio, surfactant type (Tween 20,40,60,80
264 and 85) and stirring criteria on the initial particle size of vitamin D. Results showed that small droplet
265 diameters (d<200nm) was produced using Tween at high stirring speeds (800rpm). These systems were
266 unstable to heating (T˃80°C). The thermal stability could be increased by choosing a suitable cosurfactant

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267 (sodium dodecyl sulphate).
268 Assadpour, et al., (2016) nano-encapsulated folic acid (vitamin B9) in maltodextrin-whey protein double
269 emulsions via spontaneous emulsification method, which is a low energy technique. They utilized Span 80 as

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270 a nonionic surfactant in three phase/surfactant proportions (0.2, 0.6 and 1), moreover the applied folic acid
271 amount was 1.0, 2.0 and 3.0 mg/ml in the dispersed phase. In summary, the formulation containing 3mg/ml

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272 folic acid in the 12% dispersed phase and water to surfactant proportion of 0.9 was considered as the
273 optimum sample, thus suggesting that spontaneous technique is beneficial in formulating water in oil

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274 nanoemulsions.
275 Dasgupta, et al., (2016) formulated vitamin E acetate nanoemulsions (NE) by edible mustard oil and Tween
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276 80 as surfactant. NE was produced via low-energy wash-out technique, in which there is a continuous
277 addition of the water phase to the oil phase and vitamin E acetate. In conclusion, the nanoemulsions
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278 (encapsulation efficiency 99.65%) can be used to improve the shelf life of beverages along with their
279 increased antimicrobial and bioavailability characteristics.
280 5.2 Nanoliposomes
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281 Hydrophobic/hydrophilic interactions among lipid/lipid and lipid/water interfaces are responsible for the
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282 formation of liposomes. Liposomes are formed in single and bilayer arrangements. Lipo-soluble and water-
283 soluble vitamins can be entrapped in these nanocarriers for maintaining their stability in different mediums.
284 In a study by (Ma, Kuang, Hao, & Gu, 2009), they inserted vitamin E into nanoliposomes with tea
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285 polyphenol (water-soluble). The encapsulation efficiencies reported for hydrophobic and hydrophilic agents
286 were 94% and 50%, respectively. The combined nanoencapsulation of vitamin E with vitamin C has also
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287 been carried out (Marsanasco, Márquez, Wagner, Alonso, & Chiaramoni, 2011). Liposome’s structure was
288 influenced by incubation in buffer solution and stomach pH. The higher absorption of the bioactive
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289 compound is attributed to the greater bioavailability of vitamin E.

290 (Zhou, et al., 2014) produced a drug delivery system using high methoxyl pectin (HMP) or low methoxyl
291 pectin (LMP) coated with vitamin C liposomes. FTIR and morphology assays demonstrated that the
292 hydrogen binding interactions coated pectin to the vitamin C liposomes. Overall, the skin permeation of
293 vitamin C increased 1.7-fold for HMP-L and 2.1-fold for LMP-L after 1 day respectively, whereas vitamin C
294 nanoliposomes showed a lower number. (N. Liu & Park, 2009) used chitosan-coated nanoparticles made

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295 from phosphatidilecholine (pc) and cholesterol (cho) to encase vitamin C. The nanocapsuls contaning pc:cho
296 ratio 60:40 were promising carriers, which had a loading efficiency about 96.5% and a payload of 46.82%.
297 Tan, et al., (2016) employed composite phospholipid-chitosan to coat the nanoliposomes (chitosomes),
298 which entailed carotenoids, lycopene, ẞ-carotene, lutein and canthaxanthin. The composite covered the
299 liposomes via layer self-assembly deposition method. To sum up, the biopolymer-covered nanoliposomes
300 protected lutein and ẞ-carotene to a greater extent compared to canthaxanthin and lycopene. Considering the

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301 arrangement of free lipid molecules at the hydrophilic heads and the non-polar membrane core were
302 enhanced, which directly represents the stability of these biopolymer nanoparticles against undesirable
303 conditions; such as, GI stress, etc. Also, Bochicchio, et al., (2016) loaded various vitamins (vitamin E,

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304 vitamin B12 and vitamin D2) via nano liposomes including multilamellar large vesicles (MLVs) and small
305 unilamellar vesicles (SUVs). All in all, great encapsulation efficiencies were achieved by both MLVs

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306 (between 72% to 95%) and SUVs (between 56% to 76%).
307 5.3 Nanoprecipitation

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308 This method is also called solvent displacement. In this process, the organic internal phase containing the
309 dissolved vitamin is emulsified into the aqueous external phase. The precipitation of polymer from an
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310 organic solution and the diffusion of the organic solvent in the aqueous medium is occurred in this technique
311 (Galindo-Rodriguez, Allemann, Fessi, & Doelker, 2004).
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312 (Khayata, Abdelwahed, Chehna, Charcosset, & Fessi, 2012) produced vitamin E-loaded nanocapsuls via
313 nanoprecipitation technique at laboratory and pilot-scale. The effect of several formulation variables was
314 investigated on the nanocapsuls properties (mean diameter, zeta potential and entrapment efficiency). The
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315 optimized formulation of the vitamin E-loaded nanocapsule at laboratory and pilot-scale had the mean
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316 diameter of 165 and 172 nm, respectively with a high entrapment rate (98% and 97%, respectively).
317 (Duclairoir, Orecchioni, Depraetere, & Nakache, 2002) encapsulated vitamin E in the matrix of protein
318 fractions of wheat gluten (gliadins). They co-precipitated aqueous ethanolic solution of vitamin E and gliadin
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319 in water.
320 Emulsification-solvent evaporation is an improved sort of solvent evaporation technique which includes
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321 emulsification of the polymer solution into an aqueous. Afterwards, the solvent is evaporated and the
322 polymer precipitation remains as the nanoparticles (Reis, Neufeld, Ribeiro, & Veiga, 2006). The size of the
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323 particles can be modified by adjusting the stir rate, type and the amount of dispersing substance, viscosity of
324 the phases and temperature. High-speed homogenization and ultrasonication are applied in order to obtain a
325 small particle size (Dehnad, Mirzaei, Emam-Djomeh, Jafari, & Dadashi, 2014).
326 David & Livney, (2016) engaged potato proteins (Patatin, protease inhibitors and other high molecular
327 weight proteins comprising 40%, 50% and 10% of the whole soluble proteins sequentially) as a natural food-
328 based material to protect and deliver vitamin D3 (VD) in model beverage solutions. VD was encapsulated
329 within the protein nanoparticles using the liquid antisolvent precipitation method in which two solvents are

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330 employed; one is a good solvent for the bioactive, while the other represents poor solvent activity, finally by
331 adding an antisolvent the bioactive compound is precipitated. To sum up, VD- potato proteins nanocomlexes
332 increased the shelf life of the samples and declined the vitamin loss through pasteurization rendering clear
333 and enriched solutions.
334 5.4 Solid lipid nanoparticles (SLNs)
335 It is a nice alternative for nanodispersions. The nanoparticles are produced through congealing. The vitamins

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336 are nanoencapsulated in a solid lipid matrix which has a good stability. (Patel, Martin‐Gonzalez, & Fernanda,
337 2012), encapsulated vitamin D2 (ergocalciferol) using SLNs as the carrier. They observed that the
338 concentration of vitamin D2 increased, and enhanced dispersion clarity. SLNs also brought protection to

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339 vitamin D2 from oxygen and light. Higher the ergocalciferol loading power, the lower turbidity of the SLN
340 dispersions. (Jenning, Gysler, Schäfer-Korting, & Gohla, 2000) nanoencapsulated vitamin A in SLNs for

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341 dermal release. The release kinetic was estimated over a period of 24h via Franz diffusion cells. In the first 6
342 h, Vitamin A-SLN showed controlled release and in longer periods (12-24h), the release rate exceeded the

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343 release rate of comparable nanoemulsions. Drug release is caused due to the decline of amorphous regions in
344 the carrier lattice through a polymorphic transition (ẞ´→ẞ).
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345 5.5 Cyclodextrins (CDs)
346 Liposoluble vitamins can be encapsulated in cage molecules such as CDs or assemblies formed from
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347 micelles-like systems. CDs-vitamin combination enhances molecule apparent solubility but the stability
348 depends on pH and dissolution media structure (Lin, Chean, Ng, Chan, & Ho, 2000). Solubility enhancing
349 effect on vitamin A using these capsuls has been reported, like the increase in solubility of all trans retinoic
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350 acid in inclusion complexes considering ẞ-CD and hydroxyl propyl ẞ-CD (Lin, Chean, Ng, Chan, & Ho,
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351 2000). Vitamin D has also been encapsulated using this technique, by means of ethanol as a common solvent
352 (Soares, Murhadi, Kurpad, Chan She Ping‐Delfos, & Piers, 2012).
353 5.6 Biopolymer nanoparticles
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354 Recently, there have been some studies on nanoencapsulation of food bioactive ingredients including
355 vitamins by nanoparticles made from biopolymers such as milk proteins, gelatin, chitosan, starch and many
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356 other natural polymers. For example, (Abbasi, Emam-Djomeh, Mousavi, & Davoodi, 2014) used whey
357 protein isolates (WPI) nanoparticles for encapsulating vitamin D3 and investigated its stability for 7 days in
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358 presence of air. According to their results, nanoparticles had a higher content residual of vitamin D compared
359 to the control sample (water, native WPI and denaturized WPI). Dense structures were produced because of
360 the presence of calcium in the particles, therefore inhibition of oxygen diffusion was also observed in
361 particles. These nanoparticles are applicable in the beverage industry.
362 In another study, (Penalva, et al., 2015) exerted casein nanoparticles as a surrounding material for folic acid.
363 Lysine and arginine provided the stability of nanoparticles, eventually the mixture was dried through spray-
364 drying. It was observed that the mean size of produced nanoparticles were 150 nm, meanwhile the folic acid

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365 value estimated around 25µg/mg in the nanoparticle. For the in vitro release properties, folic acid exposed
366 gastroresistant characteristics and release was possible under controlled intestinal conditions. Regarding in
367 vivo studies carried out in this project, laboratory animals were orally administered by this vitamin. Overall, a
368 higher serum could be distinguished in animals treated with casein nanoparticles in which the bioavailability
369 assessed to be 50-52% higher than the traditional solution. At the same time, both bioavailability and release
370 profile of the nanoparticles remained unchanged by high hydrostatic pressure treatment.

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371 Jiménez-Fernández, et al., (2014) produced chitosan-based nanoparticles as a tool to deliver
372 vitamin C to marine organisms. Zebrafish liver cell-line was chosen for in vitro studies and in vivo
373 studies were done in fish and rotifers to estimate the viable use of nanoencapsulated particles. A

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374 significant increase observed in the overall antioxidant capacity of nanoencapsulated-vitamin C in
375 cells, compared to the non-loaded nanoparticles. In post-metamorphic larvae of S. senegalensis

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376 nanoparticles entered the intestinal epithelium after 2h. In rotifers fed with vitamin C-
377 nanoparticles the level of ascorbic acid raised up to 2-fold in comparison to control groups.

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378 (Alishahi, et al., 2011) used chitosan nanoparticles in order to enhance the shelf life and delivery
379 of vitamin C. pH dependency observed in the release of vitamin C, as quick release took place in
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380 0.1 M phosphate buffer solution (PBS, pH 7.4), whereas the release was slow in 0.1 M HCl. As a
381 result, the shelf life of vitamin C was increased by this method and in vivo release rate in intestinal
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382 tract of rainbow trout was similar to the in vitro one.
383 Lee, et al., (2016) utilized commercial soy protein isolate (SPI) as natural nano-carrier materials,
384 perepared via ultrasonication for 5 minutes, treatment at pH= 12 and using canola oil to protect
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385 vitamin D3 against undesirable conditions, especially when exposed to UV rays. Ultimately,
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386 retention of 73.5% was achieved using these natural building blocks compared to the non-coated
387 control (5.2%), which highlights the potential of these nano-vehicles to be used in foods and
388 pharmaceutical industry.
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389 5.7 Coacervation

390 Coacervation nanoencapsulation technique is based on phase separation because of macromolecules
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391 desolvatation. It can get started through environmental changes, which may affect polymer solubility in the
392 solvent, such as; addition of salt or an opposite charged polymer. This process can be adapted to industrial
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393 scale (Renard, et al., 2002). (Comunian, Abbaspourrad, Favaro-Trindade, & Weitz, 2014) nanoencapsulated
394 vitamin C via complex coacervation using both gelatin and gum Arabic as encapsulating agents. Low
395 hygroscopicity values were obtained, thus the produced powder could be easily stored and handled. The
396 application and flow of the nanocapsuls were facilitated as they had spherical structures. To summarize, the
397 treatment composed of ratio of 1:1:0.75 of gelatin, gum Arabic and ascorbic acid with 0.025 g/ml of polymer
398 had the best stability at room temperature (20°C).

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399 Chapeau, et al., (2016) used ẞ-lactoglobulin (BLG) and Lactoferrin (LF) co-assemblies to bind vitamin B9
400 (B9). The resulting B9-LF-BLG co-assemblies generated via coacervation and aggregation were thereupon
401 analyzed through compiling screening maps. All in all, B9-LF-BLG coacervates displayed great performance
402 in entrapping vitamin B9 (≈10 mg B9/g protein), showing that natural food components has a great potential
403 to be utilized as biocarriers in designing functional and healthy foods.
404 5.8 Electrospinning and Electrospraying

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405 In electrospinning, a polymer solution is provided from a spinneret and produces a droplet at the spinneret
406 exit. Applying an electrical field (103 V/cm), the electric charges will gather on the surface of the droplet.
407 Next, the droplets will be deformed by the electric field and they will form a shape of cone, called the Taylor

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408 cone. As the field strength increases, a fluid jet originates under the electric field adjacent to the spinneret tip
409 and moves toward the conductive collector (counter electrode). Whipping and circular movements trigger a

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410 fast evaporation of the solvent due to the high surface charge jet under the electric field. After the process,
411 solid thin fibers are acquired in the form of nonwoven mats (Kessick, Fenn, & Tepper, 2004).

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412 Electrospraying would be defined liquid atomization applied through electrical forces. The difference
413 between these techniques lies in the solution concentration. With this in mind, for low-concentrated solutions
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414 the jet attached to cone is destabilized owing to varicose, then the output is fine particles. On the contrary, if
415 the concentration is high the jet is stabilized and the yield will be elongated fibers by whipping instability
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416 procedure (Bhushani & Anandharamakrishnan, 2014).
417 Pérez-Masiá, et al., (2015) successfully applied this technique to nanoencapsulate folic acid, entrapped by
418 whey protein concentrate (WPC) matrix and commercial resistant starch. According to the results,
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419 electrospraying yielded smaller particle sizes compared to nanospray-drying. Likewise, WPC capsuls
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420 enhanced the bioavailability and stability of folic acid. The answer of this phenomena lies within the
421 interaction between the protein matrix and folic acid which bolsters the stability. Taepaiboon,
422 Rungsardthong, & Supaphol, (2007) encapsulated all-trans vitamin E and retinoic acid via cellulose
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423 nanofibers, moreover the encapsulated bioactive compounds showed a gradual release.
424 Wu, Branford-White, Yu, Chatterton, & Zhu, (2011) encapsulated vitamin C and E, using electrospun
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425 polyacrylonitrile nanofibers as the wall material. They demonstrated that this technique has a better sustained
426 release behavior considering bioactive compounds. Vitamin A and E were encapsulated via electrospun
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427 cellulose acetate nanofibers having a smooth and round cross-sectional morphology (Taepaiboon, et al.,
428 2007). (Madhaiyan, Sridhar, Sundarrajan, Venugopal, & Ramakrishna, 2013) investigated producing vitamin
429 B12 loaded polycaprolactone nanofiber with constant release of hydrophilic drug as a transdermal delivery
430 procedure. The drug fibers produced through electrospinning technique were observed with SEM for
431 morphology; moreover pore size measurements, mechanical properties and FTIR experiments were also
432 applied on the nano-fibers. The fiber was plasma treated in different periods and made hydrophilic slowly in
433 order to elevate the vitamin release. Due to the drug release profile in PBS buffer in vitro medium, the

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434 cyanocobalamin loaded nanofiber considered suitable for transdermal patch. (Sheng, et al., 2013) entrapped
435 vitamin E in silk fibroin (SF) nanofibers. The incorporation of vitamin E improved the protecting ability of
436 SF nanofibrous to protect the skin fibroblast cells against oxidation stress caused by tert-butyl hydroperoxide.
437 These loaded nanofibers, offered an applicative potential for personal skin care, tissue regeneration and the
438 related aspects.
439 5.9 Ionotropic gelation

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440 This method is based on polyelectrolytes that form cross links in the presence of ions to produce hydrogel
441 beads termed as gelispheres. Gelispheres can be defined as spherical cross linked hydrophilic polymeric
442 entity showing extensive gelation and swelling in simulated bio-fluids. The release of vitamin is controlled

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443 by polymer relaxation in this process. As the drug-loaded polymeric solution enters the aqueous solution of
444 polyvalent cations, the hydrogel beads are formed. Next, a 3-dimensional lattice of ionically crosslinked

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445 moiety is formed. Bioactive compounds and vitamins are loaded in to these gelispheres so that their natural
446 structures will not be distorted.

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447 Azevedo, Bourbon, Vicente, & Cerqueira, (2014) encapsulated vitamin B2 using alginate/chitosan
448 nanoparticles. The encapsulation efficiency and loading capacity values of the nanoparticles were 55.9±5.6%
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449 and 2.2±0.6%, respectively. Release profiles showed that polymeric relaxation was the most common
450 phenomenon in vitamin B2 release. Considering the terms of size and PDI (Polydispersity index), vitamin B2-
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451 loaded nanoparticles were more stable than the one’s without it. (de Britto, de Moura, Aouada, Mattoso, &
452 Assis, 2012) synthesized nanoparticles containing water-soluble chitosan derivative (N,N,N-trimethyl
453 chitosan, TMC) through ionic gelation with tripolyphosphate (TPP) anions. Three vitamins (B9, B12 and C)
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454 were encased by this technique, then zeta potential, morphology and spectroscopy properties were measured.
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455 When nanoparticles were loaded with vitamin C, a maximum diameter of 534±20 nm was reached.
456 Moreover, the zeta potential decreased as the vitamins were applied, except vitamin C. They concluded that
457 TMC/TPP nanoparticles are a suitable medium for transporting vitamins in the food sector.
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458 6. Characterization methods for nanoencapsulated vitamins

459 The most common ways to determine nanoparticles morphology are cryogenic transmission electron
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460 microscopy (cryo-TEM), transmission electron microscopy (TEM), scanning electron microscopy (SEM)
461 and atomic force microscopy (AFM). Dynamic light scattering (DLS) is extensively used by scientists to
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462 specify the size distribution of vitamin nanoparticles. Zeta potential is measured via laser Doppler
463 anemometry. This factor gives us information about the stability and size of nanoparticles in the in vitro
464 environment (Garti, 2008). Considering surface modification of the nanoparticles, Fourier transform infrared
465 spectroscopy (FTIR) is an appropriate method to analyze this feature. High pressure liquid chromatography
466 (HPLC) or spectroscopy at defined wavelengths can be used to determine the quantitative characteristics of
467 entrapped vitamins within nanocapsuls (Garti, 2008).

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468 As an example, Vilanova & Solans, (2015) characterized vitamin A palmitate (VAP) complexed by ẞ-
469 cyclodextrins (ẞ-CDs) molecules through FTIR and UV-Vis spectroscopy. According to the spectroscopy
470 results, as the concentration of ẞ-CDs increased, the solubility of VAP declined continuously, thus a less
471 water-soluble complex will be formed (ultimately two ẞ-CDs molecules encapsulate a unit VAP molecule).
472 For the investigation of functional groups participating in inclusion complexation, FTIR assay was carried
473 out. As a result, at the bands of 3050 and 950 cm-1 (belongs to =CH bond) the double bond was not present

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474 showing that the VAP is incorporated within the moiety of =CH section.
475 7. Controlled release of vitamins through nanoencapsulation
476 Degradation of polymeric matrix is responsible for releasing the vitamins (passive release) from

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477 micro/nanocapsuls, and dispersing the vitamin throughout the matrix (active release). When the vitamin is
478 released, diffusion of the particles plays an important role in this stage. In this period, the vitamins diffuse in

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479 the hydrophilic environment (Dan, 2016). Furthermore, water molecules are dispersed through the
480 nanoparticle matrix. Diffusion rate is closely related to the hydrophilicity of the polymeric matrix. Afterward,

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481 the vitamin and the nanocapsuls are eroded gradually (Lamprecht, Schäfer, & Lehr, 2001). Initially the
482 vitamins in the nanoparticles are released fast in reaction to the apt environment (burst effect), followed by a
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483 more stationary release rate. The burst effect is advantageous when the high releases strengthen the
484 performance of the active particle or it might be hazardous when a constant release rate is expected.
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485 The basic approaches to quantify the release of vitamins are illustrated in Fig 4. The first method (a) uses
486 centrifugation to separate the core material from the nanoparticle suspension; meanwhile the second method
487 (b) uses dialysis or filtration for separation. PBS (phosphate bovine serum) is a common suspension medium,
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488 which is applied here. Considering the first method, volume is kept constant by addition of PBS. In the other
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489 approach, sample is divided into many sub-samples to study the release profile for the desired period of time.
490 Concentration gradient is kept constant in the second approach for the occurrence of diffusion process.
491 Fig. 3
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492 The main factors which influence release profile of vitamins are explained below along with the recent
493 investigations.
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494 7.1 Vitamin type and concentration

495 Chemical and physical interactions such as, hydrophilic-hydrophobic interactions, Van der Waals forces, etc.
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496 among the vitamin and polymeric matrix influence the release mechanism of the entrapped agent. The
497 amount of the vitamin is an important factor, which controls the release rate. The higher the amount of the
498 vitamin, the faster the release rate becomes. There are two terms to express the amount of entrapped vitamin.
499 First, the vitamin content is attributed to a mass of vitamins in nanoparticles divided by mass of
500 nanoparticles, expressed in %w/w. An ordinary value for the vitamin quantity ranges between 0.5 to 4% w/w
501 for hydrophilic components, and 10 to 15% w/w for hydrophobic components. Second, the entrapment

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502 efficiency is computed through dividing the content of the vitamin entrapped by theoretical amount of
503 vitamin (the amount first used in nanoparticle formation)(Garti, 2008).
504 Li, et al., (2012) investigated the effects of whey protein-polysaccharide complexes on the controlled release
505 of vitamin B2 and vitamin E in double emulsion medium (W/O/W), besides the employed polysaccharides
506 were low methoxyl pectin (LMP) and ߢ-carageenan (KCG). This study underlines the release rate of
507 lipophilic and hydrophilic vitamins as after the coated capsules were exposed to pancreatin at pH= 7.4; the

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508 release rate of both vitamins illustrated somehow similar release rates (≈90%) after 6 h, meanwhile the
509 release profile of vitamin B2 was a bit higher than vitamin E and lastly the encapsulation efficiency of
510 vitamin E was higher than vitamin B (66% to 64%). Seidenberger, Siepmann, Bley, Maeder, & Siepmann,

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511 (2011) controlled the release profile of multiple vitamins (Nicotinamide, riboflavin 5’- phosphate, pyridoxine
512 hydrochloride, thiamine chloride hydrochloride, riboflavin and thiamine nitrate) via the variation of total

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513 vitamin concentration. They enhanced the whole vitamin concentration from 10 to 16% and observed that
514 diffusivity was directly proportional to the total vitamin content.

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515 7.2 Biopolymer (variety, copolymer ratio, MW)
516 Various polymers have been synthesized as nanoparticles. Chitosan, dextran, albumin, pullulan, poly lactic
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517 acid (PLA), poly ethyl oxide (PEO), poly caprolactone, poly 3-hydroxybutyrate are typical examples of the
518 natural and synthetic polymers used in nanoencapsulation of vitamins. The break-down of these
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519 nanoparticles affect the vitamin release profile. For instance, poly lactic acid, poly lactide-co-glycolide acid
520 (PLGA) are nanoparticles which seem to degrade homogenously, while no autocatalysis takes place
521 (Lemarchand, Couvreur, Vauthier, Costantini, & Gref, 2003; Y.-P. Li, et al., 2001; Zweers, Engbers,
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522 Grijpma, & Feijen, 2006).

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523 The hydrophilic-hydrophobic ratio of the polymer plays a key role in the release of the entrapped vitamin.
524 For example, PLGA is a hydrophobic complex, consisted of lactide and glycolide monomers. The
525 hydrophilic balance of the PLGA can be changed through altering the copolymer ratio (The most prevalent
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526 PLGA molar ratios are: 50:50, 75:25 and 85:15). Thus, the degradation pace will be altered (Bala, Hariharan,
527 & Kumar, 2004). The more hydrophobic the polymer, the stronger interactions between the polymer and
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528 bioactive compounds are, so the release process will happen slower. Also, the molecular weight of the
529 polymer affects the release profile, which ranges between a few thousands Da to above 100 000 Da. The
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530 higher the molecular weight, the slower the vitamin is released.
531 To highlight the effect of biopolymer in the release of vitamins, Messaoud, et al., (2016) analyzed the effect
532 of alginate nanocapsules coated with shellac in three different concentrations (1,5 and 10% w/w) and two
533 various coating mechanisms including Ca2+ reticulation and acid development on release properties of
534 vitamin B2. As a result, coated nanocapsules displayed pH-dependant release trend, particularly after binding
535 to calcium cations. By declining pH, the release rate of coated nanovehicles decreased, moreover the 5% w/w

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536 shellac concentration created the best results. However, using the 1% w/w the coating polymer became labile
537 and the 10% w/w caused the alginate membrane to be degraded.
538 7.3 Nanoparticle size
539 Nanoparticle size also influences the release process. As the nanoparticles get bigger, their dissociation
540 occurs more slowly. Moreover, the initial burst phase is declined with the slow release according to the slow
541 nanoparticle degradation (Prabha, Zhou, Panyam, & Labhasetwar, 2002). Microparticles are released slower

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542 than the nanoparticles according to lower surface toward nanoparticles (Bala, et al., 2004; Panyam &
543 Labhasetwar, 2003).
544 Kulkarni & Feng, (2013) investigated the effects of nanoparticle size and vitamin E TGPS coating on the

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545 release rate and cellular uptake of the nanoparticles across the GI via in vivo and in vitro assays. They
546 reported that nanoparticle size and the coating substance can considerably alter the nanopartilces release rate

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547 and biodistribution. The prepared commercial fluorescent nanoparticles size ranged from 20nm to 500nm, as
548 a result the distribution of nanoparticles were 50nm>200nm>500nm>100nm>25nm, which approves the

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549 aforementioned information that as nanoparticles get smaller, the release rate and distribution will become
550 higher. All in all, the 100 and 200nm TGPS-coated nanoparticles efficiently delivered the drugs in the GI
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551 cells.
552 7.4 Environmental circumstances (pH, temperature and release medium)
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553 Environmental conditions alter the release rate and diffusion process. The polymer´s action changes
554 according to the factors like; pH, temperature or other parameters. As an example, poly ortho esters are
555 stable at higher pH (alkaline), while it is disintegrated at acidic pH. Physiological pH is around 7; however,
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556 organelles have a distinct pH. Endosomes are more acidic, and lysosomes pH is around 5. Exposing to this
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557 pH, the degradation mechanism or polymer configuration initiate, thus the entrapped vitamin will be
558 released. Temperature can also affect the release of the entrapped vitamins. Poly butyl methacrylate and poly
559 N-isopropylacrylamide are some examples of temperature release components (Chung et al., 2000).
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560 Recently, Yang, Decker, Xiao, & McClements, (2015) exerted simulated small intestinal fluid (SSIF)
561 medium to examine the release rate and bioaccessibility of vitamin E trapped in O/W emulsions. Applying
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562 the medium chain triacylglycerol (MCT) and long chain triacylglycerol (LCT), they noticed that the addition
563 of calcium cations to LCT emulsions will increase the release rate of vitamin E in the prepared medium.
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564 Moreover, the degradation rate was higher for MCT-emulsions compared to LCT-emulsions, which
565 highlights the importance of environmental conditions and the encapsulant structure on the release rate.
566 7.5 Complexation
567 A decrease in diffusion may result as a response to the polymer and vitamin conjugation, thus the release of
568 the component can hardly take place. As an example, Pereira, et al., (2016) formulated nanoencapsulated
569 vitamin E conjugated with polymeric films including Aloe vera extract, hyaluronic acid, polyethyleneoxide,
570 hyaluronic acid and polyvinyl alcohol to heal skin wounds. To sum up, the polymeric films and their

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571 conjugation effects lead to the prolonged release of vitamin E for the purpose of treating damaged skin
572 tissue.
573 8. Safety regulations and risks of nanoencapsulated vitamins
574 Considering food safety, FDA has confirmed the approaches related to the nanotechnology-based food
575 components for mass production (Chau, et al., 2007). However, questions are being posed that the increased
576 bioavailability, uptake and modified biokinetics of the nanosized vitamins might be hazardous to the

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577 biological system. It is assumed that biodegradable natural materials which are used for nanoencapsulation
578 are considered low-risk compared to synthesized polymeric nanocapsuls. Until now, ambiguities on
579 consuming nano-scale food materials still exist, besides their effects on human health and environment needs

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580 to be further analyzed (Dowling, 2004).
581 Still, there is no certain legislation in which nanomaterials (especially encased vitamins) in food industry are

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582 markedly addressed; nevertheless agencies and government insist that current legislations made by them
583 ensure the safety of nano-food products (Amenta, et al., 2015).

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584 8.1 An overview of nano regulations in different countries
585 In 2011, a guidance document entitled “Guidance for the risk assessment of the application of nanoscience
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586 and nanotechnologies in the food and feed chain” was prepared by The European Food Safety Authority
587 (ESFA). In essence, this guidance provides as assessment for the risks of employing nanomaterials in food
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588 products. Nevertheless, considering the physico-chemical properties of the nanomaterials, these minute
589 particles are also needed to be analyzed in five stages: (a) When prepared; (b) for the usage in food product;
590 (c) within the food network; (d) In the toxicity assays; (e) inside the biological fluids and cells.
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591 Another important factor, which should be considered, is the interactions occurred between nanomaterials
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592 and food structure. Regarding the catalytic function of the nanomaterials, radical oxygens or photoreactions
593 might be formed, thus these factors should be carefully characterized within the nanofood products.
594 According to the EU principle suggested in December 2011 (Amenta, et al., 2015), engineered nanomaterials
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595 (ENM) should be mentioned in the label of nano-food products. This legislation was considered to be exerted
596 till in December 2014. Regarding article 2 from this legislation, ENMs are considered to be 100nm or less in
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597 one or more dimensions either inside or at the surface moreover aggregates or agglomerates above the size of
598 100nm, which represent the nano characteristics, are also referred as ENMs.
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599 The US Food and Drug Administration (FDA) believes that emerging nano-food products can be regulated
600 under its authorities, nevertheless there is not a delicate principle attributed to the nanomaterials within food
601 industry. On the other hand, this organization has prepared a guidance for the manufacturers entitled “Draft
602 Guidance for Industry” regarding the safety and regulatory issues in novel food industry technologies (FDA,
603 2011). This definition of nanomaterials described by this draft guidance is mentioned below:
604 • Agents or products lying within the nanoscale range at least in one dimension (from 1 to 100nm).

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605 • Agents or products that reveal physical, chemical and biological characteristics related to the
606 nanomaterials, albeit they are not nano-sized.
607 Besides, the guidance has defined some responsibilities for the manufacturers, which are as follows:
608 • Monitor the changes being exerted to the food materials; such as, physicochemical properties and
609 impurities.
610 • Evaluate the safety of food products after their modifications.

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611 • Submit a regulatory assessment to US FDA
612 • Specify a regulatory issue for the consumption of the novel food product

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613 Regarding the mentioned guidance, USA FDA insists that the current legislations are adequate for evaluating
614 nanomaterials safety, moreover the organization accentuates that all manufactured nano-food products
615 should be approved in accordance with the principles present in their guidance.

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616 The regulatory organization of other countries including Australia and New Zealand (FSANZ), and Korea
617 (MFDS) believe that food products treated with nanomaterials should be evaluated through safety

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618 experiments before releasing in the food market and they have published some related guidelines too.
619 8.2 Nanoparticles fate in the digestive system AN
620 In general, after the oral administration of the nanoparticles, three options are considered for both the vitamin
621 and the nanocapsule/matrix (Fig 4):
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622 1. The nanoparticle plus the vitamin are released in the gastrointestinal (GI) tract and full digestion with
623 absorbance is carried out. At the same time, the surfactants used in the complex should be assessed through
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624 safety assays.

625 2. Nanovehicles will be broken down partially; therefore the encapsulated vitamin is released slightly.
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626 Moreover, conjugates will be formed between the residual nanovehicles and the vitamin, hence different
627 traits and biokinetic behavior is expected from these conjugates. Another possible risk is that these unknown
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628 conjugates may translocate to the other organs because of their miniature size. It is possible that these
629 compounds may act as allergens and trigger immunogenic responses in human body. With this intention,
630 further studies need to be performed for evaluating the absorption, distribution, metabolism and excretion
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631 (ADME) data regarding the nonovehicle-vitamin complexes. For example, gelatin nanoparticles are formed
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632 via cross-linking which cause immunogenic responses and the content of antibodies will rise in this situation.
633 As stated before, immunological concerns are more likely to happen in a multicomponent formulation rather
634 than a uniform structure.
635 3. The nonovehicle is resistant to digestion, and then vitamins are not released in the GI tract. Here two
636 options are assumed:
637 a. The nanoparticle plus the core material is thoroughly excreted from the GI tract. However, this is not a
638 suitable option; hence the engineered nanomaterial would not be commercially useful in the food sector
639 (Sabliov, 2015).

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640 b. Due to nanosize scale, the nanovehicle and entrapped vitamin can pass the biological barriers in the
641 intestine and enter the circulatory system. This is where immunologic and toxicokinetics assays may be
642 crucial. When a nanoengineered carrier is applied in the food sector, investigations must be done to evaluate
643 its biodistrubution properties, toxicological effects and improper alterations in the nanoengineered material
644 properties (Sabliov, 2015).
645 To sum up, a precise design for nanovehicles can mask the safety problems to a great extent and the safety

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646 can be assessed in a straightforward approach. Moreover, being conscious in full features of safety concerns
647 are the key to a better design and to make commercially nanodelivery systems possible.
648 Fig. 4

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649 9. Conclusions and future trends
650 Nanoencapsulation of vitamins with different techniques is expected to be a crucial field of research in the

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651 following years. By entrapping several vitamins in the nanocapsuls, a synergistic effect can be achieved that
652 enriches human food. Techniques like nanoemulsification, coacervation, nanoprecipitation, nanoliposomes

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653 and solvent evaporation are enduring methods for nanoencapsulating not only vitamins but also other
654 ingredients. Furthermore, solvent evaporation and nanoprecipitation remains to be exclusive approaches to
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655 encapsulate lipophilic vitamins. Nonetheless, all these techniques require suitable drying methods in order to
656 produce nanoencapsulates in the powder form. Today, spray-drying and freeze drying are widely used as
M
657 drying methods in order to nanoencapsulate the bioactive materials, especially vitamins. The disadvantages
658 of freeze drying and spray-drying are the high costs and changes needed for retaining the nanoparticle size,
659 respectively. Therefore, special apparatuses are required to produce the nano-sized powders. Besides, each
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660 encapsulation technique has its own operating characteristics that influence the final nano product. Most of
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661 the nanoencapsulated products have represented excellent bioavailability. The release of the vitamins is
662 considerably related to the nanoparticle size among the other physical features, thus many scientists are
663 trying to decline the size of the nanoparticles due to the increase in the surface and better absorption in the
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664 epithelial cells. More work need to be done on carefully designing the nanoparticle to interact in the
665 appropriate conditions (i.e. pH, temperature). Challenging questions might come up with this end; like
C

666 synthesizing novel nanopolymers for optimizing the delivery process. Furthermore, the safety of vitamin
667 nanoencapsulation in food needs further investigation. It includes the complicated interactions among
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668 nanoparticles and the cellular system. Finally, the process of the delivery in the reaction site needs to be
669 carefully studied.
670 References
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Table 1. Microencapsulation techniques for different vitamins

Microencapsulation Wall material Vitamin Purpose Reference
technique
Spray-drying Granules of rice starch & Vitamin C Examining the stability Trindade & Grosso,
gum Arabic of ascorbic acid and 2000
determining the size
distribution of
microcapsuls
Spray-drying Trypolyphosphate cross- Vitamin C Investigating the Desai & Park, 2005

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linked chitosan release rate and stability
microspheres in the capsule
Liposome Egg phosphatidylcholine, Vitamin C Comparing the half-life Kirby et al., 1991
cholesterol, DL-α- of pure vitamin C and

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tocopherol capsulated one

Emulsion technique Starch, Glycerin of Vitamin E bioavailability of Leonard et al., 2002

vegetable origin, vitamin E in fortified

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Carrageenan, Disodium breakfast cereal
Phosphate, Medium Chain
Triglycerides

Spray-drying Chitosan/ethylcellulose Vitamin D2 Morphology and Shi & Tan, 2002

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release properties of the
microcapsuls
Emulsion technique mPEG5000-b-p(HPMAm-
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lac2), a thermosensitive
Vitamin K Evaluating the
influence of bile acids
Van Hasselt et al.,
2008
block copolymer on the oral
bioavailability
Emulsion technique Α-axial 5,6- Vitamin B12 Stabilizing Wang et al., 2009
M
dimethylbenzimidazole cob(III)almins such as
ligand with cucurbit-7-uril CNCbl and AdoCbl
with the suggested
capsuls
D

Fluidized bed coating Gelatin Vitamin C Encapsulation Xie et al., 2010

efficiency and
microdiet effect on
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larval shrimps
Coacervation Gelatin and gum Arabic Vitamin A Effect of process Junyaprasert et al.,
variables on the (2001)
encapsulation process
Spray-drying Starch and ẞ-cyclodextrin Vitamin C Analyzing the Uddin et al., (2001)
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encapsulation
efficiency and the
degradation of ascorbic
acid
C

Spray cooling Fully hydrogenated palm fat Vitamin A Food fortification to Wegmüller et al.,
and 1% lecithin combat health problems (2006)
in developing countries
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Table 2. Examples of nanoencapsulated hydrophilic vitamins
Nanoencapsulation Wall material Hydrophilic Purpose Reference
technique vitamin type
Coacervation lactoferrin and Folic acid Designing a naturally occurring Chapeau et al.,
ẞ-lactoglobulin (vitamin B9) biocarrier for vitamin B9 (2016)
co-assembly

Nano emulsification maltodextrin-whey Folic acid Exerting a low-energy method Assadpour et al.,
(Spontaneous) protein (vitamin B9) to encapsulate Folic acid (2016)
double emulsions (vitamin B9)

Nano-liposome L-α- Vitamin B12 Fabricating multi/uni lamellar Bochicchiu et al.,

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Phosphatidylcholine, food-grade nanoliposomes to (2016)
Cholesterol and egg encase three different vitamins
yolk lecithin

Ionotropic gelation Alginate/chitosan Vitamin B2 Evaluating encapsulation and Azevedo et al.,

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nanoparticles controlled release of vitamin B2 (2014)
considering the wall materials

Electrospraying and Whey protein Folic acid Analyzing the encapsulation Pérez-Masiá et

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Nanospray drying concentrate (WPC) and (Vitamin B9) yield and stability al., (2014)
commercial resistant
starch
Coacervation Casein nanoparticles Folic acid Evaluating the oral Penalva et al.,
(Vitamin B9) bioavailability through in vitro (2015)

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Ionotropic gelation Chitosan-based Vitamin C Investigating the loaded and Jiménez-
nanoparticles non-loaded vitamin C Fernández et
nanoparticles in marine al., (2014)
organisms
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Ionotropic gelation Chitosan Vitamin C Extending shelf life and Alishahi et al.,
nanoparticles delivery of vitamin C (2010)

Ionotropic gelation Water-soluble chitosan Vitamins B9, Incorporating stabilized Britto et al.,
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derivative (N,N,N- B12 and C vitamins into biopolymeric (2011)

trimethyl chitosan, nanoparticles especially for
TMC) food applications
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Electrospinning Electrospun Vitamin C Fabricating core-shell Wu et al., (2011)

polyacrylonitrile nanofibers encapsulating
nanofibers vitamins for photoprotection
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Electrospinning Polycaprolactone Vitamin B12 Investigating water-soluble Madhaiyan et al.,

nanofiber vitamin delivery with (2013)
hydrophobic polymer
nanofibers for transdermal
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applications

Coacervation Gelatin and gum Vitamin C Studying transparent solid Renard et al.,
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Arabic matrices resulting from the (2002)

dehydration of new protein gels

Cyclodextrins Dextran nanoparticles Vitamin B12 Optimizing the effectiveness of Kishore et al.,
vitamin B12 conjugates with (2007)
various levels of cross linking

Nano-liposome Soy Vitamin C Investigating liposomes as Marsanasco et al.,

phosphatidylcholine vitamin transporters 2011
incorporated in orange juice

Nano-liposome High methoxyl pectin Vitamin C Studying transdermal drug Zhou et al.,
(HMP) and low delivery to acquire a better (2013)
methoxyl pectin (LMP) storage ability and skin
permeation

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Vitamin C Improving the vitamin Liu and Park
nanoparticles hydrophobicity and stability in (2009)
the delivery system

Nano emulsification Lecithin Thiamine Inhibiting spore germination of Cho et al., (2013)
dilauryl sulfate Fusarium oxysporum f. sp.
(TDS), a Raphani using TDS in
vitamin B nanocapsuls
derivative

Nano emulsification W1/O/W2 double Vitamin B2 Using this process as functional Bou et al., (2014)
emulsions with 4 healthier-fat food ingredients

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Table 3. Examples of nanoencapsulated lipophilic vitamins
Nanoencapsulation Wall material Lipophilic Purpose Reference
technique Vitamin type
Nanoprecipitation Potato proteins Vitamin D3 Utilizing potato proteins as natural David and Livney
nanovehicles for the encapsulation (2016)
of vitamin D3

Nano emulsification Edible mustard oil with Vitamin E Employing a simple and low Dasgupta et al.,
Tween-80 energy method to formulate (2016)
nanoemulsions with vitamin E

Nano-liposome coated Egg yolk phospholipid ẞ-carotene Developing a novel structure for an Tan et al., (2016)

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by chitosan (chitosome) with Tween 80 and efficient delivery of ẞ-carotene
chitosan

Nano emulsification Soy protein isolate plus Vitamin D3 Treatment of soy protein isolate to Lee et al., (2016)
canola oil prepare resistant nano structures

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Nano-liposome L-α-Phosphatidylcholine, Vitamin E and Fabricating multi/uni lamellar Bochicchiu et al.,
Cholesterol and egg yolk D2 food-grade nanoliposomes to (2016)
lecithin encase three different vitamins

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Electrospinning Cellulose nanofibers Vitamin A and E Using nanofibers as carriers for Taepaiboon et al.,
delivery model of vitamins (2007)

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Electrospinning Electrospun Vitamin E Fabricating core-shell nanofibers Wu et al., (2011)
polyacrylonitrile encapsulating vitamins for
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nanofibers photoprotection

Electrospinning Silk fibroin (SF) Vitamin E Fabrication and viewing the skin Sheng et al.,
nanofibrous mats benefit of vitamin E loaded with (2013)
these nanofibers
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Cyclodextrins ẞ-CD and hydroxyl propyl Vitamin A To produce All-trans-retinoic acid Lin et al., 2000; Qi
ẞ-CD with high aqueous solubility and Shieh, 2002
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Cyclodextrins Dextran nanoparticles Vitamin D Encapsulating vitamin D to Soares et al., 2012

increase its regulation of body
weight effect
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Solid lipid Tripalmitin vitamin D2 Increasing the stability of vitamin Mandar and
nanoparticles (SLNs) (ergocalciferol) D2 to enrich milk and margarine Martin-Gonzalez
(2012)
Solid lipid Glyceryl behenate Vitamin A Sustained release for the skin over Jenning et al.,
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nanoparticles (SLNs) a prolonged period of time (2000)

Nanoprecipitation Polycaprolactone and Vitamin E Preparing vitamin E nanocapsuls at Khayata et al.,

vitamin E dissolved in lab-scale and pilot-scale (2011)
acetone
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Nanoprecipitation Matrix of protein fractions Vitamin E Protecting vitamin E against light, Duclairoir et al.,
of wheat gluten (gliadins) heat and oxygen (2002)
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Nano-liposome Soy phosphatidylcholine Vitamin E Investigating liposomes as vitamin Marsanasco et al.,

transporters in orange juice 2011

Nano emulsification Octenyl succinic anhydride Vitamin E Investigating physicochemical Hategekimana et

(OSA) modified starches stability and thermal degradation al., (2015)
of vitamin E

Nano emulsification O/W emulsions containing Vitamin E incorporating vitamin E into Yang and
saponin as a surfactant functional foods and beverage McClements
products (2012)

Nano- emulsification Medium chain triglyceride Vitamin D Investigating particle size and Guttoff et al.,
oil (MCT) stability of vitamin D (2014)

Nano emulsification Whey protein isolate Vitamin D3 Studying the stability of vitamin Abbasi et al.,

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(WPI) nanoparticles D3 (2013)

Nano emulsification Canola oil and Span80® Vitamin E Developing a practical HPLC Morais et al.,
acetate method to estimate vitamin E (2014)

Nano emulsification Medium chain triglyceride Vitamin E Studying the influence of Saberi et al.,
oil (MCT) cosolvents on formation and (2013)
stability of vitamin E

Nano emulsification Carrier oil (MCT, corn oil, Vitamin D3 Emulsifying and stabilizing Ozturk et al.,
fish oil, mineral oil or capacities of natural surfactants (2014)
orange oil)

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Fig. 1. Microcapsule forms applied in vitamin encapsulation.
Fig. 2. Types of nanostructured delivery systems applied in vitamin encapsulation.
Fig. 3. Prevalent approaches used to determine in vitro vitamin release profile
Fig. 4. Remarking the safety evaluation for vitamin Nanocarriers. GIT, gastrointestinal tract;
ADME, adsorption, distribution, metabolism and excretion

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Fig. 1. Microcapsule forms applied in vitamin encapsulation.
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Fig. 2. Types of nanostructured delivery systems applied in vitamin encapsulation.

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Figure 3. Prevalent approaches used to determine in vitro vitamin release profile

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Figure 4. Remarking the safety evaluation for vitamin Nanocarriers. GIT, gastrointestinal
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Research Highlights
• Importance of vitamin nanoencapsulation is compared to microencapsulation.
• Microencapsulation techniques applied in vitamins are discussed.
• Nanoencapsulation methods and nanocarriers applied in vitamins are reviewed.
• Factors influencing the release rate of vitamins are highlighted.
• Safety and risk evaluation issues are analyzed.

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