Formulation and application of a new generation of lipid nano-carriers for the food bioactive ingredients

Accepted Manuscript Formulation and application of a new generation of lipid nano-carriers for the food bioactive ingredients Iman Katouzian, Afshin Faridi Esfanjani, Seid Mahdi Jafari, Sahar Akhavan PII:

S0924-2244(16)30596-9

DOI:

10.1016/j.tifs.2017.07.017

Reference:

TIFS 2056

To appear in:

Trends in Food Science & Technology

Received Date: 8 December 2016 Revised Date:

23 June 2017

Accepted Date: 24 July 2017

Please cite this article as: Katouzian, I., Esfanjani, A.F., Jafari, S.M., Akhavan, S., Formulation and application of a new generation of lipid nano-carriers for the food bioactive ingredients, Trends in Food Science & Technology (2017), doi: 10.1016/j.tifs.2017.07.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Formulation and application of a new generation of lipid nano-carriers for the food bioactive ingredients

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Iman Katouzian, Afshin Faridi Esfanjani, Seid Mahdi Jafari*, Sahar Akhavan

Graphical Abstract:

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Water insoluble ingredient

Solid lipid (Bioactive-enriched matrix)

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Water insoluble ingredient

(Bioactive-enriched shell)

Solid lipid

(Bioactive-enriched core)

Solid lipid nanoparticles (SLNs), typical size<100 nm

Water insoluble ingredient

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Solid Lipid with different dimensions

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Liquid Lipid

Solid Lipid

Liquid Lipid

Amorphous Lipid

(Imperfect Type)

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(Amorphous type)

(Multiple Type)

Nanostructured lipid carriers (NLCs) typical size<100 nm

ACCEPTED MANUSCRIPT Formulation and application of a new generation of lipid nano-carriers for the food bioactive

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ingredients

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Running title: Novel lipid nanocarriers for the food industry

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Iman Katouziana, Afshin Faridi Esfanjanib, Seid Mahdi Jafaric*, Sahar Akhavanc Young Researchers and Elites club, Science and Research Branch, Islamic Azad University, Tehran, Iran b Young Researchers and Elites club, Islamic Azad University, Tabriz, Iran c Department of Food Materials and Process Design Engineering, Faculty of Food Technology, Gorgan University of

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Agricultural Science and Natural Resources, Gorgan, Iran

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*Corresponding Details: Tel/Fax: +98 17 34426 432. E-mails: [email protected]

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Abstract Background

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Lipid nanoparticles are innovative delivery systems, which are similar to the prevalently used

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in a combination of solid and liquid lipids stabilized by surfactants. Solid lipid nanoparticles (SLNs)

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plus nanostructured lipid carriers (NLCs) are novel and promising nano-vehicles, which are of great

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interest to be applied in the food sector owing to their exclusive properties, as investigated in this

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revision.

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Scope and approach

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emulsions, with the differences in size and structure in which the water-insoluble core is dispersed

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and they can be formulated to achieve desirable protection and release of food bioactive ingredients.

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This review highlights the pros and cons of using SLNs and NLCs in the food industry.

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Furthermore, the commonly applied production methods and formulations along with the recently

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conducted studies in the field of food science and technology are underlined.

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Key findings and conclusions

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These nano-vehicles have the potential to be employed in the food industrial applications in regard

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to their beneficial properties like simple production technology, low cost and scale up ability. These

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nanocarriers have been mostly applied in the pharmaceutical industries and are recently being

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utilized in the food sector, which seems to have great impacts on this industry as well as their

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commercialization in the near future.

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Key words: Solid lipid nanoparticles (SLNs); Nanostructured lipid carriers (NLCs); Food industry;

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Delivery systems; Formulation.

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SLNs and NLCs are produced to unite the advantages of structures like liposomes and emulsions

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Today, the benefits of nanotechnology has influenced many branches in the food sector such as,

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packaging, bioactives compound delivery systems, and designing optimized formulations with the

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aim of increased bioavailability(F. Gibbs, 1999). Nanoencapsulation of food ingredients via various

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1. Introduction

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improve the quality of food products. The nanoencapsulation bodies can be carbohydrate, protein or

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lipid based. Carbohydrate and protein networks are not suitable for industrial purposes because of

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the execution of intricate chemical or heat processing, which cannot be entirely controlled (Fathi et

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al., 2012). On the other hand, lipid-based nanoparticles bear the advantages of (Fathi, et al., 2012;

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Mohammadi et al., 2016):

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nanocarriers may elevate the stability and viability of bioactives as well as other applications to

biocompatibility

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more encapsulation efficiency

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targeted effect

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modified release

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low toxicity

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lack of organic solvent for the formulation

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ease of continuous production

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That is why recent investigations are focused on lipid-based carriers to be applied in pharmaceutical

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and food sectors. Lipid-based nanocarriers in the food industry encompass nanospheres,

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nanoliposomes, nanoemulsions and lipid nanoparticles with solid/liquid networks including Solid

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Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs) (Fang et al., 2008).

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Most of the bioactives and nutrients; such as polyphenols, carotenoids, lipophilic vitamins,

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phytosterols, etc. are naturally hydrophobic. In addition, the absorption of bioactives is facilitated in

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the small intestine if it is accompanied with an edible lipid due to the amplification in the content of

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al., 2007; Pouton, 2006). In comparison to other lipid-based nanocarriers, such as nanoliposomes

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and nanoemulsions, SLNs and NLCs have lately attracted much attention from the food and

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pharmaceutical industries due to their advantages. A schematic representation of these carriers is

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shown in Fig. 1. Fig. 1

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mixed micelles responsible for the solubilization and transportation of lipophilic agents (Porter et

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unanswered questions concerning this topic. For instance, do the release kinetics and profile differ

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between SLNs and NLCs? Does different guest-molecule loading affect the release profile in SLNs

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However, the benefits of using NLCs and SLNs are not completely proved yet and there are several

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does the administration route affect the release profile in both nanovehicles (Kovacevic et al.,

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2011)? Therefore, further studies should be designed and executed to answer these questions and

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elucidate the future applications of these nanocarriers in the food sector (Das et al., 2012).

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In this review paper, the latest progress made in the nanoencapsulation of nutrients within the SLNs

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and NLCs networks are discussed. Also, the production techniques, physicochemical features,

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release profiles and modeling plus their functions within the food systems are explored. Finally,

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and NLCs? How is the stability of NLCs at various storage conditions compared to SLNs? How

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are provided.

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recent studies and applications of SLNs and NLCs in the field of food and nutraceutical industries

2. Solid Lipid Nanoparticles (SLNs)

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Among the mentioned lipid nanoparticles, SLNs contain lipid droplets that are fully crystallized and

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have an organized crystalline structure with the bioactive components accommodated within the

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lipid matrix (Weiss et al., 2008). The advent of SLNs dates back to 1990 when these nano-structures

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were manufactured by replacing the liquid state lipid (oil) with the solid one in the emulsion and

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thus the lipids are solid at ambient temperature as well as the body temperature (Müller et al.,

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lipid-based carriers, such as nanoliposomes, nanoemulsions, etc. According to (Müller et al., 2000),

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SLNs are able to prolong the release period according to their solid state, protecting the active

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agents against unwanted chemical reactions like oxidation. Some of the advantages of the

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2002). SLNs are novel nanoparticulate vehicles developed to overcome the drawbacks of other nano

employment of SLNs as efficient nanovehicles are listed below (Madureira et al., 2015; Mozafari,

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2006; Sagalowicz and Leser, 2010).

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• Organic solvents are not used in the production methods

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• High entrapment efficiency

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• Being low-cost and simple so as to make it possible for large-scale manufacturing • Able to protect the core bioactive compounds (both lipophilic and hydrophilic) against external harsh conditions

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• Prolonged release due to slow disintegration

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• Can be utilized in both liquid and solid state food products

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• No biotoxicity is considered for these carriers as they are made from naturally occurring food

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• Providing a flexible release profile via their solid matrix

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components.

However, like other nanocarriers, SLNs also have their own disadvantages which are (Aditya and

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o Possible gelation phenomenon

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o Unexpected transitions in fat crystalline structures leading to the expulsion of core materials

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Ko, 2015; Weiss et al., 2008):

during storage

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o Assembly and growth of particles

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o Low capacity for the incorporation of bioactives within the nanoparticles.

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2.1. Structure of SLNs

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mobility of bioactive components can be controlled by altering the physical state of the lipid matrix

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within the SLNs (Müller et al., 2002). The bioactive substance has a much lower diffusion rate

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within these applicable nanovehicles hence prolonged release occurs. According to Üner (2006), the

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SLNs are formulated from one solid lipid or a blend of solid lipids (Müller, 2002). In general, the

dispersion of the bioactive compounds inside the SLNs is classified into three types (Fig. 2) known

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as solid solution model, bioactive enriched shell and bioactive enriched core.

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Fig. 2

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no surface active agent and surfactant are used for the fabrication of this type. Considering the

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In the first model, the bioactive ingredients are dispersed throughout the lipid matrix; in addition,

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partitioning during the hot homogenization preparation. The partitioning rate scales directly with the

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solubility of the bioactive ingredient in the water phase as well as increase in temperature. After the

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cooling process, the solubility of the bioactive ingredient in the water phase decreases gradually and

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re-partitioning occurs in a way that the bioactive compounds are transferred to the lipid phase owing

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to their decreased solubility in water. Ultimately, the bioactive compounds are located in the

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external shell/surface of the SLNs. The third and last type is the bioactive-enriched core model in

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bioactive-enriched shell type, the bioactive ingredients are transferred to the water phase because of

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Afterwards, the cooling process of the mixture results in the supersaturation of the bioactive

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which the bioactive ingredient is dissolved in the molten lipid nearly to its saturation level.

ingredient in the molten lipid and its precipitation before the recrystallization of lipids. In this mode

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of entrapment, the level of the SLN related bioactive ingredient is associated with the nature and

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concentration of the surfactant encircling the SLN’s core.

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2.2. Application of SLNs in the food industry

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SLNs, as the modern type of nano lipid carriers have found their way in different fields. Because of

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their remarkable stability and high loading capacity, they are widely applied in the pharmaceutical

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greatly limited concerning the following considerations (Jaiswal et al., 2016):

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such as flavors, biocidal compounds and drugs into aqueous-based foods. Yet, incorporating

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SLNs are particularly suitable for encapsulating and delivery of lipophilic bioactive compounds,

hydrophilic bioactives in lipid nanoparticles is difficult due to the tendency of partitioning,

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related to the encapsulated molecules in the water during the production process of nanoparticles

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(Singh et al., 2010).

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Since many substances that are utilized in the pharmaceutical industries are not allowed in food

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SLNs can be formulated on an industrial scale but GRAS or food-grade ingredients are required.

in large quantity, further studies are then required for the selection of appropriate materials to be

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incorporated within the food systems (Tamjidi et al., 2013).

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The ingredients should not have a negative effect on the sensory properties of SLNs-incorporated

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foods (Du, 2011).

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and physicochemical stresses, such as pressure, stirring, thermal processing, light, drying,

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freezing, pH, and environmental storage conditions (Tamjidi et al., 2013).

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Stability of SLNs must be examined during processing and storage of foods against mechanical

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can be digested in the body by lipase but its digestion rate is much lower in comparison to the

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SLNs should remain solid at room and GI tract temperatures. The solid lipid, like liquid lipid,

liquid state lipid (McClements and Li, 2010). Moreover, if the bioactive is introduced to the

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crystalline form inside the lipid nanoparticle, its bioavailability may decrease than that of non-

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crystalline form.

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Nevertheless, the usage of SLNs in the food area has developed greatly. SLNs are practical delivery

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systems for lipophilic nutraceuticals, which may increase their stability and bioavailability as well

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as dispersibility in aqueous media e.g. beverages. Hence, as enlisted in Table 1, a broad range of

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for various food applications, such as α-tocopherol in glyceryl behenate (de Carvalho et al., 2013),

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beta-carotene in 50:50 cocoa butter and hydrogenated palm oil (Qian, Decker et al., 2013),

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resveratrol in stearic acid (Pandita, Kumar, Poonia, & Lather, 2014), rosmarinic acid within

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bioactive compounds have been tested and incorporated into these versatile nano-delivery systems

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monostearate (Nayak et al., 2010), copaiba oil and allantoin in cetyl palmitate (Svetlichny et al.,

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2015), Zataria multiflora essential oil within glyceril mono stearate and Precirol® ATO 5 (Nasseri et

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al., 2016) and peppermint essential oil loaded in fully hydrogenated soybean oil (J. Yang and Ciftci,

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2016). These investigations reflect the enhanced rate of bioavailability plus the stability of the

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carnauba wax (Madureira et al., 2015), curcuminoids in tristearin, trimyristin and glyceryl

active compounds being entrapped in SLNs. Furthermore, the encapsulation efficiency, size,

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stability and other characteristics may be altered as a result of the emulsifier type and amount, nano-

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lipid vehicle type, environmental factors and temperature.

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Table 1

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NLCs, as another type of lipid-based vehicles entered the nanoencapsulation field lately to cover the

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deficiencies found in SLNs. The main purpose was to enhance the loading capacity and to inhibit

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3. Nano-structured Lipid Carriers (NLCs)

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of solid and liquid lipids plus the bioactive ingredients (as inner phase) in water along with

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the expulsion of bioactive compounds. These nanovehicles are produced by dispersion of a mixture

emulsifiers (as outer phase). In contrast to SLNs, the presence of liquid lipid in inner phase of NLCs

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causes the possibility of entrapping bioactive ingredients, which are better solubilized in liquid

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lipid. On the other hand, the mixture of lipids in NLCs causes slower polymorphic transition and

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low crystallinity index. In brief, the composition of inner phase of NLCs can provide higher loading

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capacity, higher encapsulation efficiency, and higher bioavailability of nano-encapsulated

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ingredients in comparison to SLNs (R. Müller et al., 2002), which were described in the previous

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application of NLCs.

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Some of the advantages of employing NLCs in the nanoencapsulation of food components are

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(Fathi et al., 2012; http://www.pharmasol-berlin.de/lipidnano.php3; R. Müller et al., 2002):

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More available space for the accommodation of bioactives

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More loading content

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Higher solid content (30-50%) may be formed in the suspensions

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Enhanced dosage of the core material in the produced nanocapsules

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•

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3.1. Structure of NLCs

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The structure of NLCs with respect to the aim of nanoencapsulation, makeup, production methods,

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and type of core materials can be classified in three different morphologies (R. Müller et al., 2002),

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which are imperfect crystal, amorphous and multiple categories as shown in Fig. 3.

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Fig. 3

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between the lipids and therefore more guest agents are accommodated among the lipid structures. In

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order to achieve the best results, solid lipids are mixed with oils (liquid state); this model is known

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In the First model, using different lipids with distinct dimensions may lead to higher distances

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to the perfect crystal lattice of solid lipid matrix and induce the expulsion of the nano-encapsulated

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as the imperfect type NLC. In SLNs, the bioactive ingredients are incorporated in limited space due

ingredient. In contrast, the application of a combination of lipids containing liquid and solid lipid

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renders an imperfect crystal in NLCs and the bioactive ingredients are incorporated in the

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amorphous building blocks. Thus, the barriers of SLNs can be removed by deviation of

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crystallization. The imperfection rate can be increased by using a mixture of glycerides with

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variable fatty acid chains that form a solid matrix with fluctuating distances best suited for the

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accommodation of bioactive compounds (R. Müller et al., 2002).

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solid lipids are dissolved in oils, therefore they are not decomposed by the solid lipids. To minimize

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the expulsion of nano-encapsulated ingredients, NLCs can be fabricated by blending solid lipids

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with certain lipids, such as hydroxyoctacosanylhydroxystearate, isopropyl myristate or MCT. In this

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In the second model termed as multiple type NLCs, bioactives which are more soluble in oils than

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form of an amorphous body. This is an amorphous type of NLC and can be used for the retardation

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of release of nano-encapsulated ingredients by maintaining the polymorphicity of the lipid matrix

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(R. Müller et al., 2002).

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manner, the non-crystalline lipid nanoparticles are formed in which the lipid core congeals in the

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Lastly, the third group called amorphous type NLCs, does prevent the problem of expulsion induced

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particular lipids, such as isopropyl myristate and hydroxyl stearate. In other words, the third type of

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NLCs namely multiple is an oil in solid lipid in water solution (like the water in oil in water

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emulsions). These multiple networks are especially applied to the entrapment of ingredients being

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highly soluble in liquid lipids. Indeed, the liquid lipid nano-compartments contain labile ingredients

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that are scattered in a solid-state lipid matrix. Hence, the release of a high amount of bioactive

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compounds inside the liquid lipid nano-compartments may be regulated by the encircling solid lipid

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by the crystallization of solid lipids. Here, crystallization is reduced after cooling by blending

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account: selection of appropriate liquid and solid lipid for complete miscibility and mixing a solid

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barrier. Generally, in the production phase of multiple NLCs, two basic points should be taken into

lipid with a higher amount of liquid lipid. The liquid lipid nano-compartments are created by phase

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separation. This occurs during cooling step of production; NLCs contain a high amount of liquid

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lipids by the hot homogenization method, the solubility of the liquid lipid in the solid lipid matrix is

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exceeded and the nano-droplet of liquid lipid being incorporated into the solid lipid matrix (R.

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Müller et al., 2002).

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3.2. Application of NLCs in the food industry

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pharmaceutical industries. The bioavailability, penetration, absorption, protection and release of

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bioactive ingredients can be optimized by their encapsulation in NLCs. So, NLCs are introduced as

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fine lipid-based systems for delivery of drugs to different organs of the body and to prepare

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NLCs are one of the practical delivery systems not only in food but also in the cosmetic and

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structure depends on the purpose of encapsulation plus the type of the encased ingredient.

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Lately, the public interest of healthy foods namely functional has dramatically extended. Functional

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foods are fortified by bioactive ingredients, such as antioxidant, antimicrobial, antidiseases,

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essential oils, natural coloring and flavoring agents, etc. (H. Chen et al., 2006). Meanwhile, these

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functional foods. Currently, NLCs are widely employed as practical delivery systems and their final

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and etc.), expulsion from the vector, rapid excretion from the body and low absorption by intestinal

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cells. Therefore, the bioactive ingredients are encased by practical vehicles in order to protect them

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against undesirable factors and produce fortified food products. NLCs, as one of the lipid-based

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encapsulation vehicles, can be successfully used as a fundamental delivery system for the

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fortification of foods accommodating a variety of bioavailable ingredients (Fathi et al., 2012).

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Up to now, many investigations have been carried out in order to encapsulate nutrients within the

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bioactive ingredients are prone to degradation by environmental stresses (e.g., pH, light, oxygen,

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glycerin monostearate and glyceride (Wang et al., 2014), astaxanthin in glyceryl behenate and oleic

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NLCs. Some of the recent studies performed in this area are entrapment of alpha-lipoic acid in

acid (Tamjidi et al., 2014), beta-carotene in palmitic acid and corn oil (Hejri et al., 2013), quercetin

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in glyceryl monostearate and caprylic capric triglyceride (Ni et al., 2015), green tea extract in

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glyceryl stearate, cetyl palmitate, grape seed oil and sea buckthorn oil (Manea et al., 2014), rutin in

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cocoa butter and oleic acid (Babazadeh et al., 2016), mono, di and triterpenes in beeswax together

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with caprylic/capric triglyceride (Lasoń, Sikora et al., 2016), cold pressed fruit and kernel seed oils

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in paraffin oil, beeswax, glycerol and mono, di and tri acylglycerols (Krasodomska et al., 2016),

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plus Cremophor EL (Lv et al., 2016), and curcumin accommodation within soybean phospholipids,

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glyceryl monostearate, medium chain triglyceride and steric acid with the aim of improving oral

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delivery (Chanburee and Tiyaboonchai, 2016).

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Brucea javanica oil incorporated in glyceryl monostearate, medium-chain triglyceride, stearic acid

More information about the food application of NLCs and some recently pursued investigations in

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this area are gathered in Table 2.

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Table 2

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4. Formulation of SLNs and NLCs

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The SLNs and NLCs as nano-scale delivery systems are basically composed of an inner phase

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systems are derived from O/W emulsion, with the exception that the inner phase of SLNs contain

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100% solid lipid and NLCs contain 30% liquid lipid (oil) and 70% solid lipid. The solid lipids have

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a melting point above room and body temperature, but the liquid lipid exhibits a melting point much

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lower than the ambient and body temperature. Besides, the application of suitable emulsifiers is

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necessarily needed for achieving a fine dispersion of these lipids in water medium. Therefore, an

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effectively engineered delivery system of bioactive ingredients by SLNs and NLCs can be provided

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containing lipids (solid or solid and liquid), surface active materials (emulsifiers), and water. These

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2016; Wissing et al., 2004). In the following subsections, more details have been presented on these

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by the accurate and pre-designed formulation of lipids, emulsifiers, and water (Katouzian and Jafari,

components.

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4.1. Lipids

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The lipid matrix is a fundamental element in SLNs and NLCs so that bioactive ingredients could be

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incorporated in this matrix. Therefore, the appropriate selection of lipids is necessary for the

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entrapment of bioactive ingredients. There are some items that should be considered in regard to the

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lipids being utilized in the formulation of SLN and NLC structures, which include:

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High stability against decomposition factors, such as oxidation

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Being biodegradable, health-promoting and safe

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A rational proportion between the solid and liquid lipids in the matrix (for NLCs).

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•

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include glyceryl behenate (Compritol®888 ATO), glyceryl monostearate (monostearate), glyceryl

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palmitostearate plus stearic acid. Compritol®888 ATO is an amphiphilic material with a relatively

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high melting point (∼70°C). The employment of Compritol®888 ATO in NLCs bring numerous

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benefits, such as enhanced encapsulation efficiency, increased physical stability plus the reduction

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The common solid lipids (rigid at the ambient and body temperature) used in SLNs and NLCs

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crystalline lattice (Souto et al., 2006). Nonetheless, formulating NLCs with narrow size distribution

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is somehow complicated due to higher melting point and viscosity of Compritol®888 ATO. In

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contrast, the small and narrow-size-distributed NLCs can be obtained by compounds like

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in the rate of unwanted release, which can be attributed to the labile α-polymorphic form in the

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behavior (Zhuang et al., 2010).

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Glyceryl palmitostearate has a high melting point (52-55oC) and can be used to modify the release

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monostearin. Monostearin is also used as an emulsifier, which is able to induce a controlled release

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Wen et al., 2010). Also, NLCs can be formulated by some main solid lipids comprising fatty acids

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profile of solid networks in the oral cavity (lipid matrix for sustained release) (Deore et al., 2010;

,such as stearic acid, cholesterol, and waxes (e.g. cetyl palmitate) (C.-L. Fang et al., 2013). Stearic

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acid, also recognized as octadecanoic acid, is a biocompatible and food-grade substance and is one

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of the most common long-chain fatty acids, found in animal tissues and vegetable fats. The melting

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point of stearic acid is 69.6°C and thus it is a good candidate for delivery purposes (F.-Q. Hu et al.,

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2005).

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digestible oils. There are two typical types of liquid lipids for the application in NLCs: saturated

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oils, such as medium chain triglycerides (MCTs), paraffin oil, isopropyl palmitate plus

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capric/caprylic triglyceride; and unsaturated oils like oleic acid, squalene, vegetable and seed oils

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Liquid lipids (oils) are the key elements within the formulation of NLCs and mostly comprise

(Fang et al., 2013; R. Müller et al., 2002).

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similar structure with some common solid lipids like the glyceryl behenate (Compritol® 888 ATO)

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and can be easily combined with them in the inner phase of NLCs. The MCTs have a high stability

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against oxidation, however incorporating them in healthy formulations (like functional foods) can

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MCTs, such as Miglyol® 812, are most commonly used in NLCs as a liquid lipid. These oils have a

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to cardiovascular diseases. On the other hand, NLCs can be formulated by some healthy fatty acids,

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such as oleic acid and linoleic acid. These are usually obtained by the hydrolysis of various animal

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and vegetable lipids (e.g. olive) followed by separation of the liquid fatty acids. Oleic and linoleic

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acid are susceptible to oxidation more than triglycerides due to their unsaturated nature

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(DiNicolantonio, et al., 2016; Zhuang et al., 2010).

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It is of utmost importance to prepare NLC structures by including novel, biocompatible and healthy

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be problematic due to their saturation. Saturated oils can raise the blood cholesterol levels and lead

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healthy bioactive ingredients, such as α-tocopherol (vitamin E) or other agents can be used as liquid

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oils in the formulations that are intended to be applied in the food and related industries. Some

lipids in the inner phase of NLCs. Tocopherols are functional elements and possess the advantages

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of being available, affordable, augmenting the solubility of lipophilic ingredients and to be applied

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in large-scale production processes (Tsai et al., 2012). The plants and seeds oil, such as soybean oil,

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olive oil, sunflower oil, sesame oil and cottonseed oil are also proper candidates for the production

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of NLCs (Joshi et al., 2008; Manea et al., 2014; Pardeike et al., 2011; X.-y. Yang et al., 2013;

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Zhang et al., 2008). Food manufacturers are eager to utilize plant and seed oils in the formulation of

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like antioxidants.

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4.2. Emulsifiers

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Emulsifiers have a key role in the stabilization of lipid matrix systems. Most of the properties of

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NLCs according to their cheapness, commercial availability, and bearing some healthy compounds

324

efficiency, optical and physical characteristics along with the stability of SLNs and NLCs are

325

influenced by emulsifiers. As a result, picking a proper emulsifier is necessary for designing the

326

intended type of SLNs and NLCs (Müller et al., 2002).

327

SC

SLNs and NLCs, such as particle size distribution, zeta-potential of the particle, encapsulation

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Food-grade emulsifiers, which are employed in the food and pharmaceutical areas are classified into

328 329

concentrate) and small molecule surfactants (e.g., Tween series). Currently, biopolymers have been

330

utilized as typical emulsifiers for fabricating stable emulsions. Proteins (e.g., whey protein and

331

casein) and polysaccharides (e.g., gums and pectin) are main biopolymers that can be used

332

individually or in combination with the formulation of oil in water emulsions (Esfanjani et al., 2015;

333

Mohammadi et al., 2016). Nevertheless, macromolecule biopolymers have not been wieldy

334

introduced into NLC formulations, which can be referred to their very slow rate of diffusivity and

335

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two main categories: macromolecular emulsifiers, also known as biopolymers (e.g., whey protein

336

Consequently, the hydrophilic small molecule surfactants are normally implemented as emulsifying

337

AC C

adsorbance onto the fresh interface in comparison to small surfactants (S. M. Jafari et al., 2007).

agents in the formulation of NLCs. Lipophilic surfactants, such as Span 80, Myverol® 18-04K, Span

338

20, Span 40, and Span 60 are also used to develop NLCs (Fang et al., 2013).

339

There are three broad classes of hydrophilic surfactants used in the formulation of SLNs and NLCs

340

including (1) neutral, e.g., lecithin, (2) ionic, e.g., sodium cholate, sodium lauryl sulphate, sodium

341

deoxycholate (SDC), sodium dodecyl sulfate (SDS), sodium oleate and sodium taurodeoxycholate,

342

and (3) non-ionic, e.g., poloxamer 188, poloxamer 407, Tween 20, Tween 40, Tween 80, Pluronic

343

14

ACCEPTED MANUSCRIPT 344

al., 2004).

345

When the SLNs and NLCs are generated, the surface properties would change dramatically during

346

the formation of nano-particles via solidification (cooling crystallization) of colloid nano-droplets.

347

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F-127, Brij78, Tego care 450, and Solutol HS15 (C.-L. Fang et al., 2013; Shah et al., 2015; Souto et

348

Lecithin is a major neutral surfactant that is abundantly used in SLN and NLC formulations. Yet,

349

the formed bilayer membrane by only using lecithin could not reach the particle surface. Therefore,

350

it is highly recommended to use a mixture of ionic and non-ionic surfactants with lecithin in order

351

to obtain the best results.

352

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Thus, it is necessary to create a resistant membrane around the lipids with the help of surfactants.

353

elevated stability (Ninham, 1999). Generally, two layers (stern layer as an ion layer and diffuse

354

layer as loosely associated ions) encompass the particles in solution commonly known as electrical

355

double layer. Another factor influencing the stability of delivery systems is the zeta-potential, which

356

is actually the electrostatic potential in the outer limit separating the stern layer and the diffuse layer

357

(Mitri et al., 2011). Ionic surfactants are accommodated within the stern layer of the SLNs and

358

NLCs and therefore the charge of SLNs and NLCs mainly emanates from the ionic properties of the

359

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The electrostatic repulsion potential among the surfactant-covered nanoparticles results in their

360

the stern layer. Thereupon, the ionic surfactant can increase the electrostatic repulsion potential

361

AC C

surfactants. The highest zeta-potential can be achieved by using sufficient ionic surfactants within

energy among the particles and yield stable SLNs and NLCs. On the other hand, steric stabilization

362

of SLNs and NLCs can be provided by the non-ionic surfactants. Small particles can also be

363

provided by applying non-ionic surfactants due to the formation of a closely packed mixed film by

364

intercalation of the non-ionic surfactant molecules between the phospholipids monolayer. In

365

conclusion, by using a mixture of surfactants (ionic, non-ionic, and neutral), stable SLNs and NLCs

366

15

ACCEPTED MANUSCRIPT 367

(Han et al., 2008; Tan et al., 2010).

368

5. Production techniques for SLNs and NLCs

369

Different techniques have been developed for the production of SLNs and NLCs with miscellaneous

370

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could be obtained rather than stabilizing the intended system by employing only one surfactant

371

parameter considered to compare the various techniques. The production process is identical for

372

both systems (SLNs and NLCs). Although there are several methods adopted in order to prepare

373

SLNs and NLCs (Table 3), two processes of the high-pressure homogenization plus hot and cold

374

methods are prevalently implemented to fabricate these delivery systems (Torchilin, 2006).

375

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sizes and shapes. The size of particles scales directly with their functions but it is not the unique

376

SLNs and NLCs are principally produced by two main methods: (i) the first method needs high

377

energy, which is provided by high energy machines, such as high-pressure homogenization (hot and

378

cold temperature), high-speed homogenization and ultrasound. (ii) the second method namely low

379

energy include using the controllable mixtures at low stirring (usually by using a magnetic stirrer)

380

such as micro-emulsions, phase inversion temperature (PIT) and solvent based methods (solvent

381

diffusion and solvent injection); besides NLCs can be produced by membrane contactors as a source

382

EP

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Table 3

383

5.1. High energy methods

384

AC C

of low energy (Weyhers, 1995; Müller et al., 2002).

One of the most common methods for producing SLNs and NLCs is high-pressure

385

homogenization method (HPH). Concerning the temperature of HPH process, SLNs and NLCs

386

can be prepared by hot or cold homogenization. The hot homogenization method is carried out at a

387

temperature above the melting point of the utilized lipid. As mentioned earlier, NLCs are composed

388

of an inner phase (liquid and solid lipid) together with an outer phase (emulsifier and water). In

389

order to fabricate NLC structures via the hot homogenization method, initially, the lipid matrix

390

16

ACCEPTED MANUSCRIPT 391

stirrer at a temperature above the melting point of lipid matrix. This combination is then dispersed

392

in a hot surfactant solution at the same temperature to form a hot pre-emulsion by high-speed

393

stirring. Subsequently, the final pre-emulsion is then fed to the high-pressure homogenizer. Finally,

394

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containing a mixture of solid and liquid lipid is mixed with the bioactive ingredient by a simple

the NLCs are formed by cooling the hot O/W nano-emulsion in the ambient temperature, cold water

395

or a heat exchanger to solidify the lipid droplet and precipitate the lipid nanoparticles, which leads

396

to the formation of crystals (R. H. Müller et al., 2002).

397 398

homogenization is an ideal alternative to the nanoencapsulation of heat-sensitive ingredients

399

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Sensitive ingredients cannot be encapsulated by hot homogenization method. In this manner, cold

400

applied to hydrophilic bioactive ingredients. This practice has already been tested for SLNs,

401

however its application in the preparation of NLCs has not been reported. In this method, bioactive

402

ingredients are dispersed into a melt lipid phase followed by quick cooling of the overall lipid

403

mixture. After solidification, the bulk lipid is milled to produce lipid micro-particles. The obtained

404

lipid micro-particles are then scattered in a cold surfactant solution by simple stirring to yield a

405

macro-suspension. Eventually, the micro-particles are degraded by the help of the high-pressure

406

EP

TE D

occurring at temperatures below the melting point of the lipid. Moreover, this method is best

407

homogenization of SLNs requires high energy input which in turn demands the harsh

408

AC C

homogenizer apparatus and SLNs are achieved (R. H. Müller et al., 2002). The cold

homogenization processing conditions. On the contrary, the fine monodispersed miniscule particles

409

can be prepared by homogenizing molten lipids through hot homogenization method (Shah et al.,

410

2015).

411

High-speed homogenization and ultrasonication: similar to high-pressure homogenization, this

412

technique can be developed for the production of NLCs. In this method, the molten lipids are

413

gradually added into the aqueous phase during blending via high-speed homogenization and

414

17

ACCEPTED MANUSCRIPT 415

high-speed homogenization (C.-C. Chen et al., 2010).

416

Another simple laboratory method for the fabrication of NLCs is called emulsification-

417

evaporation, which involves an organic solvent together with high-speed/high-pressure

418

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subsequently, the NLCs are prepared by ultrasonication of produced coarse lipid particles from

419

are dissolved in a water-immiscible organic solvent (like chloroform and cyclohexane) to form a

420

pre-emulsion. The resulted pre-emulsion is then emulsified in the aqueous phase containing

421

hydrophilic surfactant via high-speed/high-pressure homogenization or ultrasound technique.

422

Subsequently, the organic solvent of this solution is discarded by agitation at a certain temperature

423

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SC

homogenization or ultrasound technique. In this approach, the oil phase and bioactive ingredients

(emulsifying temperature) and definite time period (emulsifying time). Lastly, the prepared

424

emulsion is cooled in the aqueous phase under mechanical agitation in order to fabricate NLCs

425

(Wissing et al., 2004).

426

5.2. Low energy methods

427 428

in which these emulsions are spontaneously formed and no mechanical energy is required to initiate

429

their formation. In this method, the lipids comprising a surfactant (and a co-surfactant, if needed)

430

EP

TE D

There is a thermodynamically stable method for the preparation of NLCs, so-called microemulsion

431

a transparent micro-emulsion is observable. The hot micro-emulsion is then diluted with cold water

432

AC C

and the water phase are heated separately, mixed and subsequently titrated with the surfactant until

(2–3°C) under stirring so that solid lipid and/or surfactant is obtained in the micelle (H. Chen et al.,

433

2006).

434

Phase Inversion Temperature (PIT) technique is considered as a low energy method for

435

producing nano-emulsions. Also, PIT has the potential for the production of NLCs. In this

436

procedure, surfactant, lipids and water mixture are heated nearly above the phase inversion

437

temperature and then the cooling process starts with continuous stirring. The mixture is treated with

438

18

ACCEPTED MANUSCRIPT 439

last cycle, when the mixture is cooled, ice cold deionized water (0◦C) is added to the combination.

440

The rapid cooling-dilution action leads to the formation of NLCs (Heurtault et al., 2002).

441

Solvent diffusion and solvent injection are two typical solvent-based, low energy methods that

442

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three temperature cycles, starting from the room temperature to PIT during magnetic stirring. In the

443

soluble solvents (e.g., benzyl alcohol, butyl lactate, isobutyric acid and isovaleric acid). Concisely,

444

the lipid phase (blend of liquid and solid lipid) together with the bioactive ingredient are dissolved

445

in partially hydrophillic solvents. The final product is poured into the aqueous phase (water plus the

446

surfactant) under stirring (usually by magnetic stirrer). The obtained suspension is then cooled to

447

M AN U

SC

can be used for the production of NLCs. Solvent diffusion includes the usage of partially water-

the ambient temperature in order to form NLCs. Solvent injection approach is akin to solvent

448

diffusion technique, with the exception that in solvent injection the solvent that scatters quickly in

449

water (e.g., DMSO and ethanol) is used to dissolve lipids (Hejri et al., 2013; F. Hu et al., 2004; F.

450

Hu et al., 2002).

451 452

deficiencies and limitations in their further implementation in the food sector. For instance, SLNs

453

exhibit unpredictable gelation behavior and low space for the entrapment of bioactvies owing to

454

EP

TE D

Having discussed the beneficial application of these novel nanostructures, they also have their own

455

unwanted liberation of bioactive compounds (Aditya et al., 2017; Gharibzahedi and Jafari, 2017). In

456

AC C

their dense crystalline architecture and propensity to polymorphic transitions resulting to the

addition to the advantages offered by NLCs, there may be some challenges in the employment of

457

NLCs in the food area, such as the proper selection of food-grade ingredients, which can endure

458

processing circumstances, crystallines may penetrate the liquid oil moiety in the system during

459

collision and lead to the aggregation of particles termed “partial coalescence” causing instability.

460

Ultimately, due to the increasing tendency of lowering the saturated fat crystals in food products,

461

this solid portion of the NLCs must be chosen wisely to cover the human health concerns

462

19

ACCEPTED MANUSCRIPT 463

6. Bioavailability and potential toxicity of SLNs/NLCs

464

About a decade ago, there was a positive attitude toward the Nano definition. Nevertheless, the

465

public viewpoint toward nanotechnology has changed due to the potential toxicity induced by some

466

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(Katouzian and Jafari, 2016; Puglia et al., 2017; Tamjidi et al., 2013).

467

Generally, there are three elemental routes by which consumers are exposed to the fabricated

468

nanomaterials including oral, dermal and respiratory pathways (Jafari, 2017). Following the oral

469

administration of nanofoods, due to their extraordinarily small size they are rapidly absorbed by

470

enterocytes in the intestine (high rate of bioavailability) and enter the circulatory system (Fig. 4).

471

M AN U

SC

nanomaterials (Jafari and McClements, 2017; Katouzian and Jafari, 2016; Mokhtari et al., 2017).

472

excreted from the body. Some strategies that are responsible for the higher rate of bioavailability

473

when using SLNs and NLCs for transports of nutrients are indeed based on the conception of

474

absorption process in the gastrointestinal tract. As illustrated in Fig.4, these mechanisms are uptake

475

by Peyer’s patches, circulation of P-glycoprotein efflux from intestinal epithelium, and targeting of

476

intestinal lymphoid tissue plus the development in digestive solubility (Jafari and McClements,

477

2017; Park et al., 2017; Yang et al., 2017).

478

EP

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Accordingly, they are carried throughout the body and may be deposited in different organs or

479

The long-term effects of consuming SLN and NLC structures are still an enigma and the studies

480

AC C

Fig 4.

determining their toxicological effects are in the infant stage. However, there are some works,

481

which have discussed the effect of these nanocarriers inside the biological systems. As an example,

482

Madureira et al., (2016) analyzed the imparted genotoxicity by SLNs (prepared by witepsol and

483

carnauba waxes) bearing rosmarinic acid (RA) via in vivo tests. Lymphocytes were tested for

484

possible DNA damage and apoptosis. Wistar rats were gavaged with free and encapsulated RA,

485

subsequently samples were collected from their blood, urine and some tissues. In a nutshell, the

486

20

ACCEPTED MANUSCRIPT 487

genotoxicity observed by the necrosis of Lymphocytes. In another study, Rahman et al., (2014)

488

looked at toxicological effect of NLCs loaded with zerumbone (an anti-inflammatory

489

phytochemical substance) following its oral administration to BALB/c mice. They isolated samples

490

RI PT

levels below 1.5mg/ml revealed no toxicity, however concentrations higher than that induced

491

parameters to assess the possible toxicity of the administered nanostructures. To sum up, the

492

oral levels of 100 and 200 mg/kg were considered safe in the tested animals and the lethal

493

SC

from the kidney, liver, spleen, heart, brain tissues and analyzed the serum biochemical

494

detected to be safe for consumption via the oral route.

495

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dose (LD50) of the utilized nanostructure was reported to be higher than 200 mg/kg and thus

496

application in food systems since it influences the liberation and absorption of the payloads

497

dramatically (Assadpour et al., 2017; Mehrnia et al., 2017; Mokhtari et al., 2017).

498

7. Conclusion and future trends

499

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As a final point, the structure of the utilized SLNs and NLCs must be studied in detail prior to their

500

compounds in the food industry, with the ability to boost the encapsulation efficiency and

501

bioavailability of the food bioactives. SLNs can incorporate complex bioactive molecules in

502

EP

SLNs and NLCs have opened new horizons in the field of nanoencapsulation of bioactive

503

preparation method should also be based on the encased nutrient to enhance the encapsulation

504

efficiency as well as the stability of the core material; thus the environmental conditions plus the

505

processing terms should be meticulously defined before the nanoencapsulation process.

506

Furthermore, NLCs are capable of overcoming the disadvantages of other lipid-based nanovehicles;

507

such as low bioactives loading, low encapsulation efficiency, and system instability. If the physical

508

conditions of the entrapped lipid are controlled, burst release may be achieved, which is useful in

509

the food sector, like flavor release due to heating in ready-meals. Both NLC and SLN ingredients

510

AC C

themselves. As each entrapped molecule has its own physicochemical and stability features, the

21

ACCEPTED MANUSCRIPT 511

green formulations in the food and pharmaceutical industries. Meanwhile, there are also some

512

challenges in utilizing these nanovesicles. For instance, the formulations need to be carefully

513

designed since the ranges of approved emulsifiers used in the food products are narrow. Besides, the

514

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can be provided from low-cost, naturally occurring food components which can be employed as

515

pasteurization or sterilization during the processing. Ultimately, case-by-case toxicological assays

516

and clinical trials must be carried out to assure that these novel nano-vehicles are safe for

517

consumption.

518

SC

stability of nanocarriers should be tested as most food components undergo the conditions of

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Table 1- List of bioactive compounds incorporated into SLNs applied in the food industry Method of preparation

Results

Fully hydrogenated soy bean oil

Atomization of CO2expanded lipid mixture

The obtained novel hollow solid lipid nanoparticles are effective alternatives to the solid lipid nanoparticles, and to overcome the issues associated with the solid lipid nanoparticles

(Yang & Ciftci, 2016)

Zataria multiflora essential oil (ZEO)

Glyceryl mono stearate and precirol® ATO 5

High shear homogenization and ultrasonication

The ZEO and ZEO-loaded SLNs had 54 and 79% inhibition on the growth of fungal pathogens, respectively

Vitamin B2

Fully hydrogenated canola oil

It is possible to generate nano-scale solid lipid particles with a high content of a hydrophilic bioactive; however, further fine tuning is needed

Vitamin B12

Compritol®

Supercritical co-injection process and production of particles from gas-saturated solutions (PGSS) Hot homogenization

(Nasseri, Golmohammadzadeh, Arouiee, Jaafari, & Neamati, 2016) (Couto, Alvarez, & Temelli, 2016)

Palm or coconut oil

Palm or coconut oil

Copaiba oil and allantoin

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Bioactive compound Peppermint essential oil

Reference

(Genç, Kutlu, & Güney, 2015)

High speed homogenization plus ultrasonication

Viability of L. plantarum of palm or coconut oil SLNs in ultra-high temperature milk was higher than that of SLNs in distilled water

(Jo, Choi, & Kwon, 2015)

Copaiba oil and cetyl palmitate

High homogenization

Nanoencapsulation improved the antifungal activity of copaiba oil, which was enhanced by the presence of allantoin

(Svetlichny, et al., 2015)

Rosmarinic acid

Carnauba wax

Hot melt ultrasonication

The optimum range values to obtain highly stable formulations included 1.0 and 1.5% (w/v) of lipid and 2% (v/v) of ploysorbate 80

(Madureira, et al., 2015)

Resveratrol

Stearic acid/poloxamer 188

Solvent diffusion-solvent evaporation

The lipid formulation produced a significant improvement in the oral bioavailability of resveratrol as compared to the intact suspension

(Pandita, Kumar, Poonia, & Lather, 2014)

Hesperetine

Glycerol monostearate, stearic acid, glyceryl behenate and oleic acid Cocoa butter and hydrogenated palm oil

High mechanical shear

The bitter taste of hesperetine fortified milk samples was well masked and poor solubility of hesperetine was declined

(Fathi, Varshosaz, Mohebbi, & Shahidi, 2013)

Hot high pressure homogenization

Solid lipid nanoparticles may not be better than liquid lipid nanoparticles for encapsulation of bioactive food ingredients.

(Qian, Decker, Xiao, & McClements, 2013)

α-tocopherol

Glyceryl behenate/soy lecithin

Hot high pressure homogenization

The stability of the SLN formulation was improved as well as the retention of α-tocopherol

(de Carvalho, et al., 2013)

Vitamin D2 (ergocalciferol)

Tripalmitin

Hot homogenization

As the concentration of vitamin D2 increased, a clear dispersion was obtained, which is practical for the fortification of milk and margarine

(Patel, Martin‐Gonzalez, & Fernanda, 2012

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Table 2. List of bioactive compounds incorporated into NLCs applied in the food industry Bioactive compound

Lipid formulation

Method of preparation

Results

Reference

Tristearin, labrasol and phospholipid-90NG

High pressure homogenization

The co-administration of vitamin C led to an adjunct effect in acne therapy in physiological conditions

(Jain, et al., 2016)

Rutin

Cocoa butter and oleic acid

High shear homogenization

The results indicated that the developed rutin-loaded NLCs could provide a method for designing new functional foods based on nanocarriers

(Babazadeh, Ghanbarzadeh, & Hamishehkar, 2016)

Mono, di and triterpene

Beeswax along with caprylic/capric triglyceride

Ultrasound homogenization

The obtained results confirmed a high physical stability of the formulations and showed that the achieved systems are suitable carriers for all, mono- di- and triterpenes

(Lasoń, Sikora, Ogonowski, Tabaszewska, & Skoczylas, 2016)

Blackcurrant, blackberry, raspberry, strawberry and plum fruit seed oils Brucea javanica oil (BJO)

Paraffin oil, beeswax, glycerol and mono, di plus tri acylglycerols Glyceryl monostearate, medium-chain triglyceride, stearic acid plus Cremophor EL Soybean phospholipids, glyceryl monostearate, medium chain triglyceride and steric acid Glyceryl monostearate and caprylic capric triglyceride

Hot homogenization

The oxidative stability tests showed that the NLC was an effective method of protection of the polyunsaturated fatty acids The newly designed delivery system has the potential to exhibit improved BJO bioavailability

(Krasodomska, Paolicelli, Cesa, Casadei, & Jungnickel, 2016)

Quercetin

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(Lv, et al., 2016)

Maintenance of the particle size of polymer-coated NLCs reflected their considerable stability physiological fluids

(Chanburee & Tiyaboonchai, 2016)

The nanostructure showed potential application in soft beverage, also Particle size remained relatively steady in simulated beverage solutions for 2 months

(Ni, Sun, Zhao, & Xia, 2015)

NLCs stabilized with 6% Poloxamer showed significantly lower particle size and particle size distribution with the encapsulation efficiency of 98.5%

(Pezeshki, Ghanbarzadeh, Mohammadi, Fathollahi, & Hamishehkar, 2014)

The prepared NLC formulation is appropriate for the delivery of astaxanthin and other lipophilic nutraceuticals into foods and transparent beverages

(Tamjidi, Shahedi, Varshosaz, & Nasirpour, 2014)

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High pressure homogenization

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Vitamin C

Precirol and Octyloctanoat

Hot homogenization method

Astaxanthin

Oleic acid and glyceryl behenate

Melt-emulsification and ultra-sonication

α-lipoic acid (ALA)

Glycerin monostearate, glyceride and glyceryl triacetate

Hot high pressure homogenization

The photostability of ALA was significantly enhanced by NLC formulation compared to the free ALA

(Wang, Tang, Zhou, & Xia, 2014)

Green tea extract

Glyceryl stearate, cetyl palmitate, grape seed oil and sea buckthorn oil

Modified high shear homogenization

In vitro tests show that green tea extract could be utilized as a valuable natural source of antioxidant and antimicrobial agent with improved activity within NLCs

(Manea, Vasile, & Meghea, 2014)

ẞ-carotene

Palmitic acid and corn oil

Solvent diffusion

The optimum formulations indicated minimum particle size (8–15 nm) and low ẞ-carotene degradation (0–3%)

(Hejri, Khosravi, Gharanjig, & Hejazi, 2013)

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Table 3. Overview of production methods for SLNs and NLCs

High pressure homogenization

Process steps Melting of the lipid and dissolving/dispersing of the bioactive in the lipid Dispersing of the bioactive -loaded lipid in hot aqueous surfactant mixture Pre-mix using a stirrer to form a coarse pre-emulsion High pressure homogenization at temperature above lipid melting point Hot O/W nanoemulsion Solidification of the nanoemulsion by cooling down to room temperature Melting the lipid and dissolving/dispersing of the bioactive in the lipid Solidification of the bioactive loaded lipid in liquid nitrogen or dry ice Grinding in a powder mill (50-100µm) Dispersing the powder in an aqueous surfactant dispersion medium (pre-mix) High pressure homogenization at room temperature or below The lipid is pushed with high pressure (100 – 2000 bars) through a very high shear stress Disruption of particles down to the submicrometer or nanometer range

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Technology Hot homogenization technique

1. 2. 3. 1. 2. 3.

Lipids and bioactive compound are dissolved in a water immiscible organic solvent with low boiling point The solution is then emulsified in the aqueous emulsifier solution. Evaporation in a rotary evaporator at 50-60°C Both the solvent and water are mutually saturated in order to ensure the initial thermodynamic equilibrium of both liquids. Lipid and bioactive are dissolved in water saturated solvent and this organic phase is stirred using mechanical stirrer. After the formulation of O/W emulsion, water in typical ratio from 1:5 to 1:10, is added to the system in order to allow solvent diffusion into the continuous phase, thus leading to the aggregation of the lipid in the nanoparticles.

Microemulsion technique

1. 2.

Lipids are melted and bioactive is incorporated in molten lipid. A mixture of water, co-surfactant(s) and the surfactant is heated to the same temperature as the lipids and added under mild stirring to the lipid melt. A transparent, thermodynamically stable system is formed when the compounds are mixed in the correct ratios for microemulsion formation. Thus the microemulsion is the basis for the formation of nanoparticles of a requisite size. This microemulsion is then dispersed in a cold aqueous medium under mild mechanical mixing of hot microemulsion with water in a ratio in the range 1:25 – 1:50.

Ultrasonication technique Solvent injection Double emulsion technique

1.

(Mehnert & Mäder, 2001)

(Liedtke, Wissing, Müller, & Mäder, 2000) (Wissing, Kayser, & Müller, 2004) (Hu, Yuan, Zhang, & Fang, 2002)

(Joshi, Pathak, Sharma, & Patravale, 2008; Pardeike, Hommoss, & Müller, 2009)

(Müller, Radtke, & Wissing, 2002)

2. 3.

Bioactive and solid lipid are melted in an organic solvent regarded as oil phase. Simultaneously water phase is also heated to the same temperature as oil phase. The oil phase is added to a small volume of water phase and the resulting emulsion is stirred at high speed for few hours. The emulsion is cooled down to room temperature to yield nanoparticles

1. 2. 3. 1. 2. 1. 2. 3.

The core material is melted Addition of phospholipids along with an aqueous medium Dispersing the melted material at increased temperature by ultra-sonication. Lipids are dissolved in a water-miscible solvent (e.g. acetone, isopropanol and methanol) or water-miscible solvent mixture Quickly injected into an aqueous solution of surfactants through an injection needle bioactive (mainly hydrophilic ones) is dissolved in aqueous solution emulsified in melted lipid. The primary emulsion is stabilized by adding stabilizer that is dispersed in aqueous phase containing hydrophilic emulsifier Emulsion is stirred and filtered.

(Puglia, et al., 2008)

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Solvent emulsification– evaporation method Solvent emulsificationdiffusion technique

Reference (Radtke & Müller, 2001)

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(Schubert & MüllerGoymann, 2003) (Garcıa-Fuentes, Torres, & Alonso, 2003)

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Fig. 1. Schematic representations and differences between NLCs and SLNs

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Fig. 2. Different forms of incorporating bioactive compounds into SLNs (white color specifies the solid lipid and

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Fig. 3. Classification of NLCs: (a) Imperfect type (b) Amorphous type (c) Multiple type (yellow color specifies the

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solid lipid and orange illustrates the liquid oil phase).

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Fig 4. Schematic illustration of the role of lipid-based nanodelivery systems in enhancing the absorption mechanisms leading to improved bioavailability: Reprinted with permission from Thanki, K., Gangwal, R. P., Sangamwar, A. T., & Jain, S. (2013). Oral delivery of anticancer drugs: Challenges and opportunities. Journal of Controlled Release, 170(1), 15–40.

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Research Highlights:

Solid lipid nano-structures (SLNs) and nano structured lipid carriers (NLCs) are green formulations in the nano-delivery of bioactive compounds.

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Formulation and preparation methods for loading bioactive compounds into SLNs and NLCs are summarized and listed.

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Recent studies on application of SLNs and NLCs in the food industry are reviewed.

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