Nanoencapsulation of food ingredients by niosomes

CHAPTER ELEVEN

Nanoencapsulation of food ingredients by niosomes María Matos1, Daniel Pando2, Gemma Gutiérrez1 1

Department of Chemical and Environmental Engineering, University of Oviedo, Oviedo, Spain Nanovex Biotechnologies SL, Parque Tecnologico de Asturias, CEEI, Llanera, Spain

2

1. Introduction Nanoencapsulation may be defined as a process to entrap one substance (active agent) within another substance (wall material) at a nanoscale (Assadpour and Jafari, 2018; Nedovic et al., 2011). Nanoencapsulation studies have been carried out to protect different bioactive ingredients from degradation and to effectively mitigate their limitations (Akhavan et al., 2018; Faridi Esfanjani and Jafari, 2016). Several methods for the encapsulation of bioactive compounds have been reported in the literature, being the most common described below. Fig. 11.1 shows the schematic illustrations of the main methods used for bioactive compounds encapsulation. Spray drying: Spray drying encapsulation has been used in the food industry since 1950. It is an economical, flexible, and continuous operation that allows to entrap a wide variety of compounds. Spray drying produces spherical particles with diameters ranging from 10 to 100 mm (Arpagaus et al., 2018; Assadpour and Jafari, 2019). The main limitation of this technique is the shortage of shell materials available to produce the particle matrix since these materials must be soluble in water (Desai and Jin Park, 2005; Fang and Bhandari, 2010). Cocrystallization: Cocrystallization is an encapsulation process that involves a modification of the crystalline structure of sucrose from a perfect to an irregular agglomerated crystal, providing a porous matrix in which a second active compound can be incorporated. The spontaneous crystallization of sucrose is carried out at high temperatures (120
C) and, if the compound to encapsulate is added at the same time, the spontaneous crystallization results in its incorporation into the void spaces inside the agglomerates of the microsized crystals, with a size less than 30 mm (Bhandari et al., 1998; Fang and Bhandari, 2010). The main advantages of this method Lipid-Based Nanostructures for Food Encapsulation Purposes ISBN: 978-0-12-815673-5 https://doi.org/10.1016/B978-0-12-815673-5.00011-8

© 2019 Elsevier Inc. All rights reserved.

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Figure 11.1 Schematic illustration of main nanoencapsulation methods of bioactive compounds.

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are the high solubility, homogeneity, and stability of the encapsulated materials (Beristain et al., 1996). Freeze drying: Freeze drying is a technique used, mainly, to encapsulate heat-sensitive and water-soluble compounds (Desai and Jin Park, 2005). Freeze drying works by freezing the material and then reducing the pressure and adding enough heat to allow the frozen water in the material to sublimate directly from the solid phase to the gas phase. The particles obtained have undefined forms, and they are composed by a matrix containing the active compounds to encapsulate ( Jafari et al., 2016). Yeast encapsulation: The structure of yeast cell wall, as well as its natural properties, made it an excellent encapsulating wall material offering many benefits over other microencapsulation technology (Nelson, 2002). Cells are grown in liquid culture medium. The encapsulation process involves mixing an aqueous suspension consisting of yeast cells and the compound to encapsulate, what allows the compound to pass freely through the cell wall and the membrane remaining passively within the cell (Bishop et al., 1998; Mokhtari et al., 2017). It was reported that this encapsulation method is suitable to entrap polyphenols, including resveratrol (RSV), although with low entrapment efficiency values (w15%) (Shi et al., 2008). Emulsification: An emulsion is defined as a two-phase system consisting of two immiscible liquids of different composition, one of which is in the shape of droplets, dispersed in the other one. Typically, the diameters of the droplets in food systems range from 0.1 to 100 mm ( Jafari et al., 2017). Multiple emulsions are a special type of emulsion defined as ternary systems where the dispersed droplets contain smaller droplets of a different phase (Assadpour et al., 2016; Gharehbeglou et al., 2019). They have either a water-in-oil-in-water (W1/O/W2) or an oil-in-water-in-oil (O1/W/O2) structure. The suitability of W1/O/W2 double emulsions to encapsulate trans-resveratrol has been reported with entrapment efficiencies around 40% (Hemar et al., 2010; Matos et al., 2014). Vesicle entrapment: Vesicles are colloidal particles in which a concentric bilayer made up of amphiphilic molecules surrounds an aqueous compartment. These vesicles are commonly used to encapsulate both hydrophilic and lipophilic compounds, for either food, pharmaceutical, or cosmetic applications and also serve as drug carriers. Hydrophilic compounds are entrapped into the aqueous compartments between the bilayers, while the lipophilic components are preferentially located inside the bilayer matrix (Devaraj et al., 2002; Saini et al., 2011; Uchegbu and Vyas, 1998). The most common types of vesicles are liposomes and niosomes.

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Liposomes were first described by Bangham et al. (1965) and are, basically, spherical bilayer vesicles formed by the self-assembly of phospholipids, based on the unfavorable interactions occurring between phospholipids and water molecules, where the polar head groups of phospholipids are exposed to the aqueous phases (inner and outer), and the hydrophobic hydrocarbon tails are forced to face each other in a bilayer (da Silva Malheiros et al., 2010). Due to the presence of both lipid and aqueous phases in the structure of liposomes, they can be used for the encapsulation, delivery, and controlled release of hydrophilic, lipophilic, and amphiphilic compounds (da Silva Malheiros et al., 2010; du Plessis et al., 1994). On the other hand, niosomes are vesicles formed from the self-assembly of nonionic surfactants in aqueous media resulting in closed bilayer structures (Uchegbu and Vyas, 1998). Niosomes are formed based on the unfavorable interactions between surfactants and water molecules, and they can also entrap hydrophilic, lipophilic, and amphiphilic compounds (Mahale et al., 2012; Moghassemi and Hadjizadeh, 2014). Niosome size is ranged from 10 nm to 3 mm (Moghassemi and Hadjizadeh, 2014). The main advantages of niosomes with respect to liposomes are better skin permeation potential, sustained release characteristics, higher stability, and lower cost (Marianecci et al., 2014; Uchegbu and Vyas, 1998). However, a recompilation of all the advantages of this type of innovative vesicles is summarized as: • Encapsulation of bioactive compounds or drugs into niosomes enhances their bioavailability • Niosomes have a higher stability and lower cost than liposomes • Niosomal encapsulation allows a controlled drug delivery since it is possible to modify the release rate of the drug and also to perform a targeted drug delivery into specific locations • Niosomes are osmotically active, chemically stable, and have long storage times • Niosomal surface formation and modifications are simple processes because of the functional groups on their hydrophilic heads • Niosomes are highly compatible with biological and low-toxicity systems because of their nonionic nature • Niosomes are biodegradable and nonimmunogenic • Niosomes can entrap both lipophilic and hydrophilic compounds • Niosomes improves the skin penetration of bioactive compounds or drugs • The variables involved in niosomal formation can be easily controlled

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• Niosomes can enhance absorption of some drugs across cell membranes • Niosomes can be used for drug administration by different routes: transdermal, oral, pulmonary, ocular, parenteral, etc.

2. Niosomes Surfactants are amphiphilic molecules with two distinct regions consisting of a structural group that has very little attraction for the solvent and other group that has strong attraction for the solvent. The hydrophilic part is referred as the head group and the hydrophobic part as the tail. Depending on the nature of hydrophilic group, surfactants can be classified as ionic or nonionic. In the case of nonionic surfactants, the surface-active portion has no apparent ionic charges. Niosomes are a specific type of vesicles consisting of an aqueous core enclosed by a membrane of nonionic surfactants that form closed bilayer structures based on their amphiphilic nature (Uchegbu and Vyas, 1998). Niosomes are mainly used for encapsulation of bioactive compounds in order to enhance their solubility and bioavailability. Lipophilic compounds are incorporated at the lipidic membrane while hydrophilic compounds are encapsulated in the hydrophilic inner compartment (Fig. 11.2). Vesicular systems can be classified as a function of their main compounds used for their formulation. The most common types of vesicles are mentioned in Table 11.1. Although liposomes are able to encapsulate a large amount of bioactive compounds with a high encapsulation efficiency, niosomes offer a number of advantages compared with them such as lower cost and larger stability. For these reasons, niosomes are becoming an interesting alternative to Surfactant headgroup Surfactant tail

Hydrophilic compound Lipophilic compound

Figure 11.2 Schematic structure of niosomes containing biocompounds.

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452 Table 11.1 Main types of vesicles and their main components. Type of vesicle Membrane component

Liposome Niosomes Etosomes Transfersomes Bilosomas

Phospholipids (naturals and synthetic) Nonionic surfactant þ lipids/fat alcohol Phospholipids þ ethanol Phospholipids þ surfactant Phospholipids þ nonionic surfactant þ biliary salt

liposomes, as it can be seen in their applications in cosmetic, pharmaceutical, and food industries. Some of the main applications are early diagnosis of diseases and controlled administration of drugs (Abdelkader et al., 2011; Estanqueiro et al., 2015; Mahale et al., 2012; Marianecci et al., 2014; Moghassemi and Hadjizadeh, 2014; Rajera et al., 2011). According to the size and the number of layers that forms the membrane vesicle, the vesicles can be classified as unilamellar and multilamellar; the specific types have been schematically presented in Fig. 11.3. • Unilamellar vesicles: They are made by a unique double layer which contains an aqueous compartment and can be small unilamellar vesicles (SUV), with an inner diameter of less than 100 nm, large unilamellar vesicles (LUVs), with a diameter between 100 and 1000 nm, and GUV, giant vesicles with a diameter larger than 1 mm. • Multilamellar vesicles (MLVs): They are made by a double layer which contains an aqueous compartment where there are other double layers. Normally, their main size is larger than 1 mm. It can be found as MLVs, if the double layers are concentric, and multivesicular vesicles, formed by a large vesicle that contains small vesicles.

Small unilamellar vesicles

Large unilamellar vesicles

Giant unilamellar vesicles

Miltilamellar vesicles

Figure 11.3 Classification according to vesicles structure.

Miltivesicular vesicles

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3. Formation of niosomes The self-assembly of the surfactants into niosomes is governed by several key parameters (Uchegbu and Vyas, 1998) which is described briefly in the following sections.

3.1 Formulation aspects It is important to understand the role of basic components in niosomal structure before preparation. 3.1.1 Nonionic surfactants Nonionic surfactants as other types of surfactants are amphiphilic molecules, composed by two different regions, one hydrophobic and another hydrophilic. Nonionic surfactants opposed to the other types of surfactants have no charges on their polar groups, and this property makes possible the surfactants self-assembly forming niosomes in aqueous media. Four different categories of nonionic surfactants can be found: alkyl esters, alkyl amides, alkyl ethers, and esters of fatty acids (Kumar and Rajeshwarrao, 2011). The structure of the nonionic surfactant plays an important role in niosome formation. Normally, to form a bilayer membrane in aqueous media, a surfactant with a higher contribution of the hydrophobic parts is necessary. However, with an optimum level of hydrophobic membrane stabilizer (e.g., cholesterol), it seems that niosomes are indeed formed from hydrophilic surfactants (Santucci et al., 1996). In order to select the appropriate surfactant, there are two interesting parameters to consider: hydrophilicelipophilic balance (HLB) and critical packing parameter (CPP). HLB is a good indicator of the vesicle forming capability of any surfactant. This method is used on the bases that all surfactants combine hydrophilic and lipophilic groups in one molecule and that the proportion between the weight percentages of these two groups for nonionic surfactants is an indication of the behavior that may be expected from that product (Griffin, 1955). An HLB value of 1 corresponds to a completely lipophilic surfactant, and a value of 20 corresponds to a completely hydrophilic molecule. Table 11.2 shows the application of surfactants respecting their HLB value. The HLB values compatible with niosomal formation usually ranges between 4 and 8 (Gianasi et al., 1997) although it is also possible to form niosomes using surfactants with HLB values out of this range. As mentioned

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1e3 3e6 7e9 8e18 13e15 15e18

Antifoaming Water-in-oil emulsions/niosomes Dispersants Oil-in-water emulsions/micelles Detergents Solubilization

Table 11.3 Hydrophilicelipophilic balance (HLB) values of surfactant and their impact in niosomes formation. HLB Impact on formation

3e6 7e12 8e14 14e20

Form niosomes Need to add additive to form niosome Increase niosome encapsulation efficiency and niosome stability Do not form niosomes

in Table 11.2, there are some surfactants suitable for the formation of niosomes. Therefore, there are some surfactants that are not able to produce niosomes by itself but can be used as cosurfactants or additives increasing stability or encapsulation efficiency. Table 11.3 indicates which HLB values are frequently used for the formation of niosomes which are more appropriate for increasing niosome properties. The most nonionic surfactants used for the formation of niosomes are Span, Brij, and Tween series. Table 11.4 lists HLB values of this three series of surfactants. All Tween surfactants and some Brij (the ones with high HLB values) are frequently used in combination with other surfactants or cholesterol, since their high HLB values make them not suitable to form niosomes individually. The CPP is also a useful parameter to know the suitability of a surfactant to form niosomes. This parameter compares the contribution of hydrophobic and hydrophilic groups with the following equation: v CPP ¼ (11.1) lc a0 where v ¼ hydrophobic group volume, lc ¼ the critical hydrophobic group length, and a0 ¼ the area of the hydrophilic head group. Values of CPP between 1/2 and 1 indicates that the surfactant is suitable to form vesicles,

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Table 11.4 Hydrophilicelipophilic balance (HLB) values of surfactants frequently used in niosomes formation. Span series Brij series Tween series Name

HLB

Name

HLB

Name

Span Span Span Span Span Span

1.8 2.1 4.3 5.0 6.7 8.6

Brij Brij Brij Brij Brij Brij

4.0 4.9 5.3 9.7 16.0 16.9

Tween Tween Tween Tween Tween Tween

85 65 80 60 40 20

93 72 52 30 58 35

HLB

65 85 60 80 40 20

10.5 11.0 14.9 15.0 15.6 16.7

while values less than 1/3 form spherical micelles, values from 1/3 to 1/2 form cylindrical micelles, values around 1 lead to planar bilayers, and values higher than 1 form inverted micelles (Israelachvili, 2011). 3.1.2 Additives In order to obtain niosomes with a high stability, the use of additives in niosomal formulation is very common. Depending on where they exert their function, they can be classified as follows: • Membrane additives: The most common one is cholesterol, which is known to abolish the gel to liquid-phase transition of liposomal and niosomal systems changing the fluidity of the bilayer membrane providing a greater stability (Kumar and Rajeshwarrao, 2011). The presence of cholesterol tends to improve the main vesicular properties, such as entrapment efficiency, stability under storage, release, and stability (Biswal et al., 2008; Rogerson et al., 1987; Shilpa et al., 2011). It was also reported that dodecanol could replace cholesterol as a stabilizer in formulations of food-grade niosomes (Pando et al. 2015). • Surface additives: These additives act in the surface of the niosomes. The most common compound is dicetyl phosphate (DCP) which has a charge inducing role and is usually used to impart negative charges on the surface of niosomes in order to stabilize them by electrostatic repulsion (Waddad et al., 2013). • Steric additives: These additives stabilize the niosomes by steric repulsion. The most common ingredient is polyethylene glycol (PEG). The particular efficiency of surface-attached PEG chains has been explained by the combination of their water solubility and their flexibility, which sterically stabilize the vesicles, mainly preventing them

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Membrane additives E.g.: Cholesterol

NIOSOMES ADDITIVES

Surface additives E.g.: DCP

Steric additives E.g.: PEG

Figure 11.4 Different types of niosomal additives. DCP, dicetyl phosphate; PEG, polyethylene glycol.

from self-aggregation and/or fusion processes (Lasic, 1994; Needham et al., 1992a, 1992b; Torchilin, 1996). Fig. 11.4 shows the different types of stabilizers used in niosomal formulation. 3.1.3 Encapsulated drug or bioactive compound The biocompounds incorporated into niosomes can also affect the morphology and stability of the sample. However, it seems that amphiphilic drugs are the most problematic in this regard (Kumar and Rajeshwarrao, 2011; Uchegbu and Vyas, 1998). Doxorubicin is an example of amphiphilic drugs, when encapsulated in niosomes, aggregation occurred and was overcome by the addition of a steric stabilizer (Kumar and Rajeshwarrao, 2011).

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3.2 Surfactant concentration The concentration of surfactant used to produce niosomal dispersions is generally 10e30 mM (1%e2.5% w/w) (Baillie et al., 1985; Lawrence et al., 1996; Lesieur et al., 1990; Okahata et al., 1981; Saettone et al., 1996; Uchegbu et al., 1992, 1996; Zarif et al., 1994) although it is possible to produce niosomal dispersions using concentrations ranged out of this interval. Normally, the use of higher surfactant concentrations results in a higher entrapment efficiency of the drug but also leads to an increase of the viscosity of the niosomal dispersion (Pando et al., 2013; Uchegbu and Vyas, 1998).

3.3 Temperature The hydrating temperatures used to make niosomes should usually be above the gel to liquid phase transition temperature (Tc) of the system (Kumar and Rajeshwarrao, 2011; Marianecci et al., 2014; Uchegbu and Vyas, 1998). Niosomes prepared above the Tc showed higher entrapment efficiencies than niosomes prepared bellow Tc (Biswal et al., 2008; Hao et al., 2002; Kumar and Rajeshwarrao, 2011).

4. Preparation methods of niosomes According to Lasic (1990), the formation of liposomes is not spontaneous, and some energy input is required. This affirmation can also be extrapolated to niosomes. Niosomal formation is not spontaneous and some energy input is required. There are more than 20 different methods reported to produce niosomes (Moghassemi and Hadjizadeh, 2014; Walde and Ichikawa, 2001) although in this section only the most common techniques are discussed. The selection of the most appropriate method of preparation is performed according to the surfactants and stabilizers selected, as well as the active compound that will be encapsulated and the characteristics required depending on their final application.

4.1 Agitationdsonication method This method consists application of energy input to produce niosomes in an aqueous media, by agitation (Liu and Guo, 2007), sonication (Pando et al., 2013a), or combination of both (Pando et al., 2013b). An aqueous solution containing the bioactive compound is added into the surfactant/stabilizers

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Addition of aqueous solution containing bioactive compound to surfactant/stabilizers

Sample homogenization by agitation

Sonication

Figure 11.5 Schematic protocol of niosomes preparation through agitatione sonication method.

mixture. Then, this mixture is agitated or sonicated to form the niosomes. The best operational procedure seems to be an initial sample homogenization by agitation followed by sonication. Sonication is a technique broadly used to obtain SUVs with a narrow size distribution. By contrast, the use of other procedures such as mechanical agitation leads to production of MLVs (Pando et al., 2013b; Walde and Ichikawa, 2001). A schematic diagram of this method is shown in Fig. 11.5.

4.2 Thin-film hydration method This method was first described by Bangham et al. (1965) and is widely used. It involves surfactant/stabilizers dissolution using organic solvents, as chloroform or methanol, followed by an evaporation process where these organic solvents are removed under vacuum conditions using a rotary evaporator to form a thin film on the wall of the flask. Then, the film is hydrated with an aqueous solution containing the bioactive compound of interest (Hao and Li, 2011; Manconi et al., 2006). Depending on the final application of the niosomes formulated, different techniques can be applied to homogenize the solution obtained after thin-film hydration (TFH) process: manual shaking or agitation leads to MLV niosomes, while sonication leads to SUV niosomes. But, in general terms, this method provides good dispersion of niosomes. Schematic diagram of this method is shown in Fig. 11.6.

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Surfactant/Additives are dissolved using an organic solvent

Organic solvent is removed to form a thin film

Addition of aqueous drug solution to hydrate the thin film

Sonication

Figure 11.6 Schematic protocol of niosome preparation through thin-film hydration method.

4.3 Dehydrationerehydration vesicle method This method was first described by Kirby and Gregoriadis (1984). To apply this preparation method, niosomes are normally prepared previously by TFH method. Then, they are frozen in liquid nitrogen and freeze drying overnight. Finally, the dried cake formed is hydrated and sonicated again to form the final niosomes. This method results in high entrapment efficiencies and higher niosome sizes (Kawano et al., 2003; Mugabe et al., 2006; Uchegbu and Duncan, 1997). A schematic protocol of niosome preparation through dehydrationerehydration vesicle method is shown in Fig. 11.7.

Niosomal dispersion is frozen

Freeze-drying to form a cake containing the bioactive compound

Rehydration

Sonication

Figure 11.7 Schematic protocol of niosome preparation through dehydratione rehydration vesicle method.

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Organic phase is added to aqueous phase containing the bioactive compound

An emulsion is formed after

Organic phase removalby vacuum evaporation

Figure 11.8 Schematic protocol of niosome preparation through reverse phase evaporation method.

4.4 Reverse phase evaporation method In this method, surfactant and additives are previously dissolved in an organic solvent. Then, the organic phase is added to an aqueous phase, containing the bioactive compound, and the mixture is sonicated forming an emulsion. Finally, the organic solvent is slowly removed under vacuum evaporation until hydration is completed leading to niosomal formation (Abdelkader et al., 2011; Guinedi et al., 2005). With this method, LUVs are prepared (Moghassemi and Hadjizadeh, 2014). Schematic protocol for niosome preparation using reverse phase evaporation (REV) method is shown in Fig. 11.8.

4.5 Ether injection method In this method, surfactant and additives are first dissolved in an organic solvent, as diethyl ether or ethanol, and then injected slowly through a needle in an aqueous phase containing the bioactive. After that, the organic solvent is removed under vacuum evaporation using a rotary evaporator. When ethanol is used as organic solvent, niosomes are formed during the injection process, while niosomes are formed after organic solvent removing when diethyl ether injection is used (Wagner et al., 2002). Depending on the conditions used, vesicle sizes range from 50 to 1000 nm. This method can be easily scaled-up (Wagner et al., 2002). Fig. 11.9 shows a schematic protocol of niosome preparation through ether injection method method.

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Injection of the organic phase into the aqueous phase

Niosome formation after organic solvent removal

Figure 11.9 Schematic protocol of niosome preparation through ether injection method.

4.6 Freeze and thaw method A suspension of multilamellar vesicles, previously prepared by TFH method, is cyclically freezing and thawing, first in direct contact with liquid nitrogen and second the temperature is elevated over the Tm. Each step takes 1 minute. This method provides vesicles with a high encapsulation efficiency and narrow size distribution.

4.7 Injection of melted surfactants A melted mixture of surfactant and additives is injected into a hot-stirred aqueous phase containing the hydrophilic compound to be encapsulated. In the case of hydrophobic compounds, the aqueous phase will be injected into the melted mixture (surfactant and additives) that will contain the hydrophobic compound. This method does not require the use of solvents, which are expensive and potentially dangerous and not always easy to be eliminated. A limitation of this method is that it cannot be applied for heat-sensitive compounds.

4.8 Hydration of solid surfactants It is similar to the method described for injection of melted surfactants, but here surfactants are not previously melted, and the hot aqueous phase is directly incorporated into the solid surfactants. This method offers the same disadvantages than the previous one.

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4.9 Enzymatic method Niosomes are formed by enzymatic method that takes place in a micellar dissolution. The process consists the hydrolysis of surfactant ester unions by esterases, which produces smaller components such us cholesterol and polyethene. These components are combined with other lipids producing multilamellar vesicles.

4.10 Transformation of liquid lamellar crystals A homogenous lamellar phase is produced when a mixture of surfactant/ additives is placed in an aqueous phase containing the component to be encapsulated. The resulting mixture should be accurately mixed by ultracentrifugation or agitation.

4.11 Extrusion Its main goal is to reduce the size of the previously produced niosomes. A suspension containing MLVs obtained by other methods is filtered (from 8 to 10 times) with a moderate pressure through membranes with a decreasing pore size (400, 200, and 100 nm).

4.12 The single pass technique It is a patented process which consists a continuous process in which a lipid/ surfactant suspension is passed through a porous device and a nozzle; a combination of homogenization and high-pressure extrusion is applied. Niosomes around 50e500 nm are obtained (Wiggenhom et al., 2010).

4.13 Microfluidization In this process, the surfactant/additives solution is pumped at a high pressure (100 mL/min) into a chamber refrigerated with ice. At the chamber exit, the sample is cooled in order to reduce the heat produce during microfluidization. The sample is recirculated into the process as many times as it is necessary in order to obtain the final desired niosomal size.

4.14 Microfluidic flow-focusing method This method requires the use of microchannels of a specific design. An alcoholic mixture containing surfactant/additives is forced to circulate through a central channel while two aqueous flows are circulating in side channels. A rapid mixture of the fluids from the three channels is produced which results in a good control of the noisome size and size distribution. The main

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operating parameters that have an influence on the resulting noisome size are flow rate, ratio of aqueous/alcoholic phases, and microchannel material (Lo et al., 2010).

4.15 Membrane contactors It consists equipment similar to the one used for membrane emulsification. An organic phase containing surfactants and additives is located in a pressurized vessel and forced to pass through membrane pores. On the other side of the membrane, an aqueous phase circulates. The contact of both phases produces niosomes (Pham et al., 2012). This technique allows to scale up the noisome production.

4.16 Mozafari method It is a patent method by Mozafari (2005). The surfactant and additives are separately hydrated for an hour at room temperature and nitrogen atmosphere. The solution containing the additives is heated at 120
C and stirred for 15e20 min, then is cooled up to 60
C, and the other components such as surfactants are incorporated into the mixture. Final mixture is stirred for 15 min to get the niosomes. The main advantage of this method is that there is no application of any type of solvents.

4.17 Bubbling nitrogen method It is a method that produces niosomes without using organic solvents. Surfactants, additives, and aqueous phases are introduced in a glass reactor placed in a thermostatically controlled water bath. The reactor should have three necks: one for a thermometer, another for a nitrogen feed, and the third with a condenser. The mixture is stirrer at 70
C during 15 s and immediately followed by the bubbling of nitrogen gas at the same temperature.

4.18 Supercritical carbon dioxide method Recently a new method of niosomal preparation has been developed. It is similar to REV method but uses supercritical carbon dioxide (scCO2) fluid (Manosroi et al., 2008). The carbon dioxide is a liquid below its critical pressure and temperature (74 bar and 32
C) and can be used instead of the solvent used in REV method. The main advantages include the use of a volatile solvent, nonflammable, nontoxic, and low price. The vesicles produced are LUV of sizes around 100e400 nm.

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4.19 Proniosome method In this method, a soluble water precursor is used such as sucrose, maltodextrin, or mannitol which is covered by nonionic surfactants. The result of this process is a dried powder in which a soluble water particle is covered by a thin layer of nonionic surfactant; these particles are named proniosomes (Hu and Rhodes, 1999). The main advantages are the reduction of physical instability of the niosomes and increase of their encapsulation efficiency. Moreover, the powder containing the proniosomes allows to have an easy storage and distribution and are easily rehydrated when mixed with water.

4.20 Transmembrane pH gradient method All methods described above are included in the group of passive loading or direct entrapment methods. This is the easiest technique to encapsulate biocompounds in niosomes since the loading takes place at the same time that the niosomes are formed. Lipophilic compounds can be encapsulated by solving them in the organic phase while hydrophilic compounds can be solved in water. Another method to increase the encapsulation efficiency of niosomes is the use of active loading or remote loading techniques. This method is based on the introduction of an ionized basic compound passing the niosome membrane if the pH is higher in the external part of the niosome. The ionized basic compound precipitates in the inner part of the vesicle due to the acid value of pH which hinders its release. First the organic phase containing the surfactant and additives are evaporated to get a thin film by TFH method; the film is rehydrated with citric acid (pH 4.0) applying mechanical agitation forming MLVs. Then several freeze thaw cycles and further sonication takes place. Once the niosomes are formed, the aqueous phase containing the compound to be encapsulated is vigorously stirred. The pH is elevated up to 7.0e7.2 and heated up to 60
C to enhance the encapsulation efficiency. The different ways for loading biocompounds into niosomes are described in the following section.

5. Loading methods for preparing niosomes As it is briefly described in the previous section, we can distinguish two main loading methods in vesicles, active and passive loading. Most niosomal preparation methods imply passive loading of biocompounds. Just

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transmembrane pH gradient method corresponds active loading due to a change of pH between each side of niosome. Another variant of active loading method used in vesicles is the transmembrane ion gradient (Biswal et al., 2008; Barenholz, 2001). It consists an ion gradient of ammonium in both sides of the membrane vesicle, enhancing the precipitation of ammonium sulfate inside the vesicle. This method is not being largely used for recent applications. Regarding passive loading methods, there are some appropriate techniques for encapsulation of lipophilic surfactants or hydrophilic ones. As a general trend, it can be concluded that the encapsulation of lipophilic drugs obtains larger encapsulation efficiencies than the encapsulation of hydrophilic drugs. As it is indicated in the introduction section of the present chapter, the encapsulation of lipophilic compounds is within the vesicle membrane, while the encapsulation of hydrophilic compounds takes place in the inner part of the vesicle. Since hydrophilic drugs are soluble in external aqueous media, their encapsulation is being hindered and moreover their release is enhanced. As a general trend, it can be defined that when the hydrophobicity of the surfactant or surfactant combination used to produce the niosomes increases (lower HLB values), the entrapment efficiency and niosomal stability increases. On other hand, when the hydrophilicity of the surfactant or surfactant combination used to produce the niosomes increases (higher HLB values), niosomal stability decreases, but the transdermal delivery of hydrophilic drugs improves. The type of encapsulated compound has also an important role on niosomal characteristics. The encapsulation of a hydrophobic drug decreases leakage, improves niosome stability due to the location at the niosome membrane, and increases transdermal delivery. However, the encapsulation of hydrophilic drug increases leakage and decreases niosomal stability. Furthermore, the encapsulation of macromolecules increases niosomal stability, decreases leakage, and increases niosome size (Mahale et al., 2012).

6. Purification of niosomes Once the bioactive compound is encapsulated, a solution which contains the bioactive-loaded vesicles, surfactant and stabilizer molecules, and free bioactives is obtained. In order to study the effect of the encapsulated compound, it is necessary to remove the unencapsulated ingredients from

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Feed Sample

Retention of free biocompounds

Purified loaded niosomes

Free biocompounds

Purified loaded niosomes

Free biocompounds Purified loaded niosomes

Dialysis

Gel filtration

Centrifugation/ Ultracentrifugation

Figure 11.10 Niosomal purification methods.

the solution. Moreover, this effect is also important on the calculation of encapsulation efficiency (EE), depending on the method used. Five different methods are commonly used for the purification of niosomes: dialysis, gel filtration, centrifugation and ultracentrifugation, and minicolumns, which will be briefly discussed in the following sections. Fig. 11.10 shows schematic diagram of these methods.

6.1 Dialysis This method consists the diffusion of small molecules (unencapsulated bioactives) through a bag of semipermeable membrane material. This bag contains small amount of prepared niosomal sample and is placed under gentle agitation in a tank containing aqueous media (water or buffer). The ratio of the volume inside the bag and the total amount of water in the tank should be at least 1:1000 in order to enhance molecules diffusion. The time that sample should be gently agitated changes between different authors, but it goes from 2 to 24 h (Gutierrez et al., 2016; Pando et al., 2013; Muzzalupo et al., 2005, 2007; Manconi et al., 2005). It is important to consider salinity of both sides of the dialysis bag, since it could avoid filtration or even produce external aqueous media be swelled to the inner part of the dialysis bag exposed to the sample due to the difference of osmotic pressure at both sides of the sample.

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To define the dialysis time, it is necessary to prepare a blank in which a sample with free drug is located and produce dialysis up to the point in which all the drug is being levered through the dialysis bag. It is also important not to leave samples in a longer time than necessary since this procedure could also enhance the liberation of encapsulated drug though the niosomal membrane.

6.2 Gel filtration This technique consists passage of the niosomal sample though a bed packed with a gel which is frequently used in analytical chemistry for size characterization of samples. The gel is composed of a porous material in which small molecules have higher retention than larger ones. First the sample is passed though the packed gel, and then a buffer is passed in order to remove the drug from the retained sample. The first amount collected will correspond to the sample with larger size, which in this case will be the loaded vesicles (García-Manrique et al., 2016; Carafa et al., 2002, 2006; Terzano et al., 2005; Manconi et al., 2003; Tabbakhian et al., 2006). This technique is relay versatile and offers a high separation efficiency in a high yield. However, samples prepared in a media that could chemically interact with the gel could not be purified by this method.

6.3 Centrifugation and ultracentrifugation The difference between centrifugation and ultracentrifugation is just the velocity used, being below 7000 g for centrifugation. In these techniques, the untrapped drug is separated from the vesicles due to a different density (Marianecci et al., 2014).

6.4 Minicolumns When combining a gel filtration and centrifugation, the method is called minicolumn which consists of a small cell where the gel and the sample are placed. The cell is centrifuged, and hence centrifugation helps to the filtration of the large molecules (loaded vesicles) though the gel and the retention of the free biocompounds that are not encapsulated (Marianecci et al., 2014). It is important to make a correct selection of the method used for each system to be collected, since each of them have some advantages and disadvantages. And not all authors agree in what is the more appropriate technique for each particular type of system.

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7. Niosomal characterization The most important parameters to characterize the niosomes are the following:

7.1 Vesicle size and size distribution Niosomes are assumed to be spherical in shape, therefore their size is presented as the mean (Z-average) size, which can range from 20 nm to 50 mm (Moghassemi and Hadjizadeh, 2014). The size distribution is usually represented as polydispersity index (PDI or PI), and measures the distribution of niosome sizes in the sample (Pando et al., 2013a). A PDI value of 0 indicates completely monodispersed particles, while a value of 1 implies highly polydispersed vesicles.

7.2 Zeta potential (z-potential) The zeta potential is the potential at the plane of shear (located approximately between the compact and diffuse layers) between charged surface and liquid moving with respect to each other (Szymczyk et al., 1998). The zeta potential of niosomes plays an important role in the behavior of niosomes. In general, high absolute values indicate electrostatic repulsion between vesicles which are linked to a high stability since it prevents niosomal aggregation and fusion (Pando et al., 2013a).

7.3 Stability The main problems associated with vesicles storage are aggregation, fusion, and leakage of the bioactive compound encapsulated. Stability can be measured by light scattering techniques. Changes on the transmission and the backscattering of the light along the cell that contains the sample will indicate instability. These profiles provide a macroscopic fingerprint of the niosomes at a given time, providing useful information about changes in vesicle size distribution and/or appearance of a creaming layer or a clarification front with time (Pando et al., 2013b).

7.4 Morphology In order to obtain information about the niosomal structure and geometry, as well as to confirm vesicles formation, morphology analysis of niosomes can be characterized by electron microscopy (NS-TEM).

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7.5 Entrapment efficiency Entrapment (encapsulation) efficiency (EE) is determined by measuring the difference between the entrapped and the total amount of the bioactive compound incorporated initially. In order to obtain the entrapment efficiency of the bioactive compound into niosomes, it is necessary to apply different analytical techniques as can be used to determine biocompound concentration such us liquid chromatography or spectroscopy. In order to determine the amount of biocompound encapsulated, niosomes are separated from the nonencapsulated compound by either ultracentrifugation, chromatography, or dialysis. Once vesicles are separated, they are ruptured by using methanol, hence the liberation of the encapsulated biocompound is done and the concentration can be easily determined (Fig. 11.11). EE is calculated by Eq. (11.2): EE ¼

DE DT

(11.2)

DE being the concentration of the entrapment drug, measured by the purified sample, and DT the total drug concentration measured by the unpurified sample. Fig. 11.11 shows a schematic diagram of the EE from purified and unpurified samples.

8. Drug administration by niosomes Niosomes were first used in the cosmetic industry and then have also gained attention in pharmaceutical companies due to their high efficiency to entrap different types of bioactive compounds or drugs (Shilpa et al., 2011). For this reason, and taking into account the other advantages aforementioned, niosomes can be used as nanocarriers in several activities such as antioxidant, anticancer, antiinflammatory, antiasthma, antimicrobial, antiamyloid, anti-Alzheimer, antibacterial, antimalarial, antifungal, gene delivery, nutraceuticals, etc. (Moghassemi and Hadjizadeh, 2014).

8.1 Dermal and transdermal delivery Dermal delivery consists the topical application of a bioactive compound or drug into the skin for the treatment of diseases or cosmetic applications. Niosomes can increase the residence time of the drug in the deeper layer of skin as epidermis and dermis, allowing to obtain higher concentrations

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D D D

D

D

D

D

D D

Aliquot

Aliquot

D

D D

PurificaƟon

D

D

D

D

D

D D D D Methanol(1:10)

D D

D

D D

D

Figure 11.11 Scheme used for encapsulation efficiency calculation.

at specific locations or sites of action, reducing the systemic absorption of the drug and increasing the treatment efficiency (Marianecci et al., 2014; Pando et al., 2013a). On the other side, transdermal drug delivery is used as an alternative route of drug administration instead of oral or parental routes. This drug delivery route shows several advantages such as avoidance of the risk and inconvenience of intravenous therapy, avoidance of first pass hepatic metabolism, no gastrointestinal degradation and avoidance of several issues due to oral administration (e.g., vomiting) (Marianecci et al., 2014). Fig. 11.12 shows the dermal and transdermal delivery of the drug into the skin through niosomes.

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Stratum corneum Epidermis Dermis

Dermal delivery

Transdermal delivery

Figure 11.12 Dermal and transdermal delivery using niosomes.

8.2 Oral delivery Oral route is one of the most popular routes of drug administration. In addition, nowadays the use of functional foods and nutraceuticals is increasing due to the health benefits provided by these products (Shahidi, 2009). Compounds administrated by oral route can present bioavailability problems due to several reasons as, inter alia, poor solubility, low dissolution rate, degradation, and unpredictable absorption. Niosomal encapsulation is able to protect the encapsulated compounds, increasing their bioavailability (Gurrapu et al., 2012; Pando et al., 2013b) and could help to mask undesirable flavors (Tavano et al., 2014).

8.3 Pulmonary delivery In inflammatory diseases, such as infections or cancer of the respiratory tract, the pulmonary delivery is an interesting route of administration, instead of oral or parenteral routes, due to the high drug concentrations located at the specific site of action. On the other hand, some lipophilic drugs do not easily permeate through the hydrophilic mucus in order to reach this site of action. For this reason, targeted delivery using niosomes helps to carry the drugs to specific locations amplifying the therapeutic effect (Marianecci et al., 2014; Terzano et al., 2005). Among different aerosol delivery technologies, nebulizers represent a simple device because vesicular structures may be delivered without further processing (Saari et al., 1999).

8.4 Ocular delivery In topical ocular drug delivery, there are many anatomical and physiological barriers to overcome and therefore a strategy to cross them is required which implies the use of carriers (Marianecci et al., 2014). Several authors confirm that controlled delivery of some ophthalmic drugs improves their ocular

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bioavailability with respect to traditional eye drops (Abdelbary and El-gendy, 2008; Di Colo and Zambito, 2002). The advantage of using niosomal systems as ophthalmic nanocarriers does not only reside in providing prolonged and controlled delivery at the corneal surface but also prevents drug metabolism from the enzymes present at the tear/corneal epithelial surface (Abdelbary and El-gendy, 2008).

8.5 Parenteral delivery Parenteral route is one of the most common and effective routes of administration for bioactive compounds or drugs. Normally, parenteral route requires frequent injections to maintain an effective concentration of the therapeutic drug. One of the major progresses in the field of drug delivery systems is the development of vesicles capable to provide targeted and sustained drug release in predictable manner to overcome the problems associated with conventional parenteral delivery systems (Marianecci et al., 2014). Nowadays, niosomes containing active drugs for parental administration are developed for the treatment of several diseases such as melanoma, fungal and viral diseases, etc. This niosomes showed high efficiencies compared with conventional treatments (Manosroi et al., 2013; Shi et al., 2006; Wang et al., 2012).

8.6 Gene delivery Gene therapies, using genetic materials (DNA, oligonucleotides, small interfering RNAs, ribozymes, DNAzymes), rather than traditional drugs, are being investigated for treatment of different inherited or acquired disorders. Gene therapy has the theoretical potential to treat almost any disease (Marianecci et al., 2014). Niosomes seemed to be a great tool especially for topical gene delivery since topical immunization using niosomes has received a great deal of interest due to their painless and easy administration (Mahale et al., 2012).

8.7 Therapeutics/diagnostics The use of vesicles as nanocarriers has also emerged as a successful strategy to enhance targeted delivery into specific cells using antibody/antigen recognition (Simard and Leroux, 2009). In the last 15 years, this technology (specially focused on liposomes) has matured, and now several vaccines containing vesicles-based adjuvants have been approved for human use or have reached late stages of clinical evaluation (Watson et al., 2012). But it is

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important to remark that niosomes are also able to use with these purposes. In addition, niosomes can be used as imaging agents for tumors or to produce biosensors to detect diseases thereby increasing the potential for diagnosis at an earlier stage (Uchegbu and Vyas, 1998; Yu et al., 2011).

9. Food applications of niosomes As it mentioned, niosomes have been used for several applications, with special attention on cosmetic and pharmaceutical industries. Niosomes have been used to encapsulate biocompounds of different interest resulting as a promising technique to be administrated through the skin. Some of the compounds typically used as niosomal membrane stabilizers result in a great penetration agent, being then niosomes a suitable vehicle for the delivery of compounds to be administrated with dermal or transdermal delivery. Less work is found in other type of administrations and even less for food applications. Other types of colloids are frequently used for food applications such as emulsions and nanoparticles (Aditya et al., 2017). In this section, the works recently done with niosomes for food applications are detailed.

9.1 Yogurts prepared with loaded niosomes Niosomes prepared with different types of surfactants by ethanol injection method are used to encapsulate Fe2þ and incorporate into yogurt (Gutierrez et al., 2016). The niosomal system was characterized in terms of size, stability, EE, and rheological behavior. Niosomal systems result in high stability with a high EE of Fe2þ, the best formulation in those terms was the one prepared with Span 60 as surfactant and dodecanol as membrane stabilizer, which resulted in 80% EE as obtained with this formulation. Once the niosomal system is prepared, 2% (v/v) was added into a yogurt and the influence of the addition of niosomal system to the yogurt was analyzed in terms of rheology and texturometry. Measurements of a regular yogurt and yogurt-containing niosomes were compared, no significant influence was found in yogurt properties when the loaded niosomes were incorporated. The possible interaction between the niosomes and the whey proteins present in the yogurt was evaluated. For this, measurements of niosomal size were made at several concentrations of whey proteins, and no difference was found in niosome size, indicating that niosome was not interacting with whey proteins. Also yogurts containing RSV-loaded niosomes have been prepared (Pando et al., 2015). Niosomes were prepared by thin hydration method;

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Figure 11.13 Preparation of functional yogurts loaded with niosomes.

several surfactants were tested for niosomes formation: Span 60, Labrasol, Maisine 35, and dodecanol in all cases were used as a membrane stabilizer. EE was around 50%e60% depending on the surfactant used. Niosomes formulated using Span 60 or Maisine 35 as surfactants resulted in high EEs and a high stability. Influence of niosome incorporation to the yogurt was analyzed in terms of rheology and texturometry. Results showed that the addition of loaded niosomes into the yogurt did not have a significant influence on their properties. Then, niosomes are a suitable system to incorporate into the dairy products. In Fig. 11.13, a schematic diagram of functional yogurts is presented.

9.2 Loaded niosomes with a-tocopherol a-Tocopherol, also known as vitamin E, is commonly used as food additive because it inhibits lipid oxidation. Niosomes prepared with several ratios of Span 60 and Tween 60 were prepared, using cholesterol and DCP as membrane stabilizers. The niosomes were loaded with a-tocopherol and were characterized in terms of size, stability, zeta potential, and EE. The optimum formulation resulted in an EE of 98% (Basiri et al., 2017). Niosomes prepared were applied in vitro with simulated gastric fluid for 2 h, pH ¼ 1.2, and with simulated intestinal fluid for 6 h, pH ¼ 7.4. Results indicated that around 20% of the release occurred in the gastric fluid while around the 50% occurred in the intestinal fluid. Niosomal systems formulated

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with ratio of 25:12.5:2.5 (surfactant:cholesterol: DCP), being the surfactant ratio of Span 60:Tween 60 3:1, resulted in a suitable system to encapsulate a-tocopherol for the preparation of functional foods. a-Tocopherol-loaded niosomes were also prepared and incorporated into a whey protein cold-set hydrogel in order to fabricate a novel functional food formulation considering high nutritional value of whey proteins and superb delivery potential of niosomes and to preserve niosomes from adverse environmental and/or gastrointestinal conditions (Abaee and Madadlou, 2016). Niosomes were prepared with molar ratio of Span 60:cholesterol of 3:1 by thin hydration method; the optimum conditions leading to an EE around 80% and high stability.

9.3 Vitamin A protection Several colloidal systems have been tested as carriers for vitamin A (Loveday and Singh, 2008). However, some of them do not offer satisfactory results, since vitamin A oxidation occurs quicker in contact with some chemicals frequently used in emulsion preparation. In this sense, vesicles offer a promising alternative, which could be used for food fortification. Encapsulation of vitamin A using Span/Tween surfactants and cholesterol showed slow light degradation (Palozza et al., 2006; Manconi et al., 2003). However, some work needs to be done in that sense, since for niosome preparation, authors used chloroform which is not possible to be used for food applications.

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Further reading Caddeo, C., Manca, M.L., Matos, M., Gutierrez, G., Díez-Sales, O., Peris, J.E., Usach, I., Fernandez-Busquets, X., Fadda, A.M., Manconi, M., 2017. Functional response of novel bioprotective poloxamer-structured vesicles on inflamed skin. Nanomedicine: Nanotechnology, Biology and Medicine 13, 1127e1136. Vitonyte, J., Manca, M.L., Caddeo, C., Valenti, D., Peris, J.E., Usach, I., Nacher, A., Matos, M., Gutiérrez, G., Orr u, G., Fernandez-Busquets, X., Fadda, A.M., Manconi, M., 2017. Bifunctional viscous nanovesicles co-loaded with resveratrol and gallic acid for skin protection against microbial and oxidative injuries. European Journal of Pharmaceutics and Biopharmaceutics 114, 278e287.