Emulsion-based techniques for encapsulation in biomedicine, food and personal care

Emulsion-based techniques for encapsulation inbiomedicine, food and personal careMitali Kakran and Maria N Antipina

Available online at www.sciencedirect.com

ScienceDirect

The manuscript scopes to review the emulsion-based

techniques aimed for encapsulation of active compounds

found in biomedical applications, functional foodstuff, skin care

and cosmetology. The advantages, limitations and outlook are

discussed for each method.

Addresses

Institute of Materials Research and Engineering, A*STAR,

117602 Singapore, Singapore

Corresponding author: Antipina, Maria N ([email protected])

Current Opinion in Pharmacology 2014, 18:47–55

This review comes from a themed issue on New technologies

Edited by Gleb B Sukhorukov

http://dx.doi.org/10.1016/j.coph.2014.09.003

1471-4892/# 2014 Elsevier Ltd. All right reserved.

IntroductionEmulsion systems are essential components of food,

cosmetics, and drugs enhancing the bioavailability of

poorly water-soluble active compounds. Besides, various

emulsion and double emulsion methods are applied in

fabrication of functional microparticles and nanoparticles

used for encapsulation and controlled delivery. For

instance, particles of biocompatible and biodegradable

copolymer of glycolic acid and lactic acid–poly(lactic-co-

glycolic acid) (PLGA) are among the most important

delivery systems in biomedical applications including cell

therapy, anticancer treatment, and tissue engineering

[1��,2��,3]. Hydrogels with embedded oil droplets, the

so-called emulsion hydrogels or emulgels, combine

benefits of both emulsion and hydrogel. Owing to the

possibility of controlled delivery of hydrophobic and

hydrophilic compounds by a single entity, these systems

are useful in drugs and becoming especially popular in

skin care [4��]. The consumer-driven quest for multi-

functional products for personal care and healthier but

still tasty foodstuff has already posed a clear challenge to

researchers to elaborate smart delivery systems capable of

protection and controlled in situ release of active com-

pounds. On a biomedical site, the nature of many diseases

also requires delivery systems with the high level of

complexity. Layer-by-layer (LbL) formed capsules have

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been proven as entities possessing multiple functions [5].

Within emulsions, LbL films can be assembled at the oil/

water interface introducing the opportunities for droplet

navigation and targeting, controlled shell disintegration,

and protection of active compounds against harmful fac-

tors and conditions [6�].

Thermodynamically unstable emulsions utilize emulsi-

fiers, that is, amphiphilic compounds (lipids, some

proteins, peptides, and polymers [7,8]), to stabilize the

dispersed phase preventing the systems from phase sep-

aration. The simplest way to obtain emulsion is physical

fission of the dispersed phase via high speed mixing [9] or

acoustic cavitation [10,11�]. Thus produced samples are

characterized with relatively broad distribution of the

droplet size, and the mean sizes decrease with the increase

of the mixing speed and sonication amplitude, respect-

ively. High pressure homogenization allows decreasing the

size polydispersity within the technical limits of equip-

ment [12,13]. A straightforward but low yield approach to

fabricate monodisperse emulsions is the use of microfluidic

devices [14–17]. Thus, energy input, design of the device

and the type of surfactant should be carefully evaluated to

achieve the desired size of the dispersed phase [18].

Here we review various emulsion-based encapsulating

methods applicable for active compounds of drugs, food-

stuff, cosmetics and skin care products also discussing the

benefits and drawbacks of each technique.

Solvent removal induced encapsulationtechniqueAs the name of this technique suggests, encapsulation

occurs after the removal of organic solvent. Depending on

the way of solvent removal, the technique has two vari-

ations called emulsion–solvent evaporation (ESE) and

emulsion–diffusion (ED). The first common step is emul-

sification of a polymer solution containing the substance

to be encapsulated. In ESE particle hardening occurs

through solvent evaporation and polymer precipitation

[19]. In ED, the emulsification step is followed by

dilution leading to the deposition of the polymer around

the droplets forming the capsules (Figure 1).

In the ESE process, the polymer is dissolved in a volatile

and water immiscible solvent, and the active to be encap-

sulated is dispersed or dissolved in this polymeric solution.

The resultant solution or dispersion is then emulsified in an

aqueous continuous phase (containing a surfactant) to form

discrete droplets. The organic solvent first diffuses into the


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48 New technologies

Figure 1

Emulsification

Aqueous phase(water + stabilizer)

Capsulesin dilute suspension

Capsules(concentrated suspension)

O/W emulsion

HardenedCapsules

Organic phase (solvent+ polymer + active)

(high shear mixing)

Solventevaporation

Wateraddition

Evaporation underreduced pressure

Emulsion–SolventEvaporation (ESE)

Emulsion–Diffusion (ED)

Current Opinion in Pharmacology

Preparation of capsules by the solvent removal induced encapsulation

techniques: emulsion–solvent evaporation (ESE) and emulsion–diffusion

(ED) method.

aqueous phase and then evaporates at the water/air interface

so that the microspheres can harden [20–22]. This method

has been used extensively to prepare polylactic acid (PLA)

and PLGA microcapsules for encapsulating many different

drugs [23–25]. This method of simple oil-in-water (O/W)

emulsion solvent evaporation is generally used for the

encapsulation of hydrophobic drugs. Conversely, if the

active ingredient is hydrophilic, the double emulsion tech-

nique will be more suitable: in this case, another step

consisting of the dispersion of the primary emulsion (gener-

ally a W/O emulsion) in a second aqueous phase is necessary

before organic solvent evaporation [26]. Pisani et al. [27]

prepared nanocapsules of PLGA encapsulating perfluor-

ooctyl bromide by optimizing the parameters of the ESE

process, however, they showed that several apparently

different interfacial organizations coexist between the

organic and aqueous phases at the same time within a single

emulsion. Therefore, the presence of compounds with high

molecular weights, such as polymers, can restrict solvent

diffusion, which, when removed rapidly during the evap-

oration step, makes nanocapsule formation difficult. In

addition, nanocapsules might not resist direct evaporation

of the solvent in the ESE process, possibly due to the

mechanical stress caused by the gas bubbles formed inside

the aqueous suspension [28]. Thus, being a scalable tech-

nique, ESE can be successfully used to prepare microcap-

sules but not very suitable for nanocapsules and there is a

need of careful selection of encapsulation materials and

various conditions in order to achieve high encapsulation

efficiency and a low residual solvent content.

ED technique to produce nanocapsules based on biode-

gradable polymers has been patented by Quintanar-Guer-

rero et al. [29–31]. The emulsification involves a partially


water-soluble organic solvent previously saturated with

water in order to ensure the initial thermodynamic equi-

librium between the two liquids. Polymer, oil and active

compound are dissolved into the saturated solvent produ-

cing the organic phase. The aqueous phase is previously

saturated with the solvent and contains a stabilizer. The

subsequent addition of water to the system causes the

solvent to diffuse into the external phase which results in

the interfacial deposition of polymer (such as PLA

[32,33], polycaprolactone (PCL) [34], Eudragit1 [35])

to form the nanocapsules [36]. Later the organic solvent

can be safely evaporated under reduced pressure. The

organic solvent is selected such that the oil and polymer

are both soluble in it, and it is partly soluble in water for

the diffusion by dilution to be possible. Ethyl acetate is an

example of such favorable solvent [37]. For the continu-

ous phase, the solvent used is water and polyvinyl alcohol

(PVA) is preferred as the stabilizing agent. Other stabiliz-

ing agents such as poloxamer and ionic emulsifiers have

been used. The control of the mean diameter of the

nanocapsules is given by the choice of the composition

of the organic phase, by the shear rate of the emulsifica-

tion process (which governs the drop size of the primary

emulsion), the polymer concentration and the oil-to-poly-

mer ratio [37]. Nanocapsules encapsulating several lipo-

philic drugs and therapeutics have been prepared using

the ED method, for example, indomethacine [36]; hino-

kitiol [38]; progesterone and estradiol [33]. Preparation of

carriers for osteoporosis treatment using the ED method

has also been reported [39�]. Hallouard et al. synthesized

and formulated iodinated poly(ethylene glycol)–poly(ep-

silon-caprolactone) nanocapsules as new original blood

pool contrast agents for computed tomography [40]. Var-

ious studies have shown successful encapsulation of food

ingredients [41] including fish oil [42], eugenol (a model

aroma compound) [43], and capsicum oleoresin [44]. The

ED method has also been used to encapsulate hydrophilic

compounds by the W/O solvent diffusion technique.

Perez et al. used PLA–PEG nanoparticles as carriers for

the controlled delivery of plasmid DNA [45]. The plas-

mid aqueous solution was emulsified in an organic poly-

mer solution (PLA–PEG dissolved in methylene

chloride). The nanoemulsion was poured into ethanol

with the immediate precipitation of the PLA–PEG,

caused by the diffusion of the polymer solvent to the

external organic phase. This technique provided high

encapsulation efficiency (80–90%) of the plasmid.

Imsombut et al. prepared silk fibroin (SF) microspheres

[46]. Aqueous SF solution and ethyl acetate were used as

water and oil phases, respectively. Span80 was the oil-

soluble emulsifier used. The SF microspheres solidified

after diffusion out of water from the SF emulsion droplets

to the external continuous ethyl acetate phase. Combin-

ing high pressure treatment with ED allows to avoid an

additional diffusion step in the aqueous phase signifi-

cantly reducing the amount of water needed [47,48].

Pressure treatment can produce polymer membranes


Emulsion techniques for encapsulation Kakran and Antipina 49

surrounding the oil surface owing to the precipitation of

polymer, inducing the diffusion of solvent from the

interior to the exterior. Continuous supercritical fluid

processing to extract of the organic solvent was shown

to improve the ED method by the example of the

production of stearic acid nanoparticles [49]. The organic

solvent (benzyl alcohol) was continuously extracted tak-

ing advantage of its high solubility in supercritical carbon

dioxide. The supercritical enhanced diffusion allowed not

only the efficient removal of the solvent, but also the

reduction of the sizes of the resulted nanoparticles by

eliminating the aggregates formed during the traditional

diffusion step.

The ED technique is a widely used simple process highly

suitable for preparing nanocapsules with controlled particle

sizes. The drawbacks are its specific solvent miscibility

requirements, longer time of emulsion agitation and a large

amount of water needed for nanocpasule formation.

Layer-by-layer encapsulationLbL coating of water dispersed oil microdroplets with

polymers can be considered as a particular case of the ED

process. Figure 2 schematically represents the process on

Figure 2

argon, 20 psi argon, 20 psi

1 2

54

(a) (b)

argon, 20 psi argon, 20 psi

Coating of water dispersed fragrance-containing oil microdroplets with alter

washing out uncoupled emulsifier (BSA); (2) coating with tannic acid (TA); (3

washing out uncoupled BSA; (6) coating with the second TA layer and wash


the example of a fragrance-containing oil microdroplets

being coated by layers of bovine serum albumin (BSA)

and tannic acid (TA) [50��]. Assembly of complementary

macromolecules on oil microdroplets is performed after

placement of an emulsifier (e.g. BSA [50��]) at the oil/

water interface. In agreement with the concept of the

LbL method, emulsifier has to form a complex with the

material used to form the consequent layer. Amphiphilic

polymers [51], proteins [52–55], polysaccharides [55], and

phospholipids [13] have been successfully used to

stabilize the dispersed phase prior to the LbL encapsula-

tion. Adsorption of the consequent layers is usually per-

formed with washing steps to remove non-adsorbed

molecules (Figure 2).

Food emulsions with the multilayer coated dispersed

phase were pioneered and actively developed by the

group of McClements [56,57]. Thus coated droplets of

different vegetable and fish oils demonstrated better

stability towards coalescence and flocculation [57,58].

Antioxidants embedded in bi-layer or multilayer coating

assemblies affected peroxidation in the encapsulated oils

[13,53,59]. LbL shell was also shown to slow down the

speed of the gravitational separation in O/W emulsions

3

Fragrancecontainingoil droplet

BSA

tannic acid

safety valve

primaryemulsion

washedemulsion

LbL-coatedemulsion

6(c)

A

B

C

argon, 20 psi

argon, 20 psi


nate layers of bovine serum albumin (BSA) and tannic acid (TA): (1)

) washing out uncoupled TA; (4) coating with the second BSA layer; (5)

ing out uncoupled TA [50��].


50 New technologies

owing to the increased average mass density of the dis-

persed phase [54].

LbL multilayer capsules on oil microdroplets are com-

monly made of oppositely charged polymers [13,51–54,56–58,60], although hydrogen-bonded films have been

also demonstrated [50��].

Enzymatic degradation is one of the most obvious release

triggers in biomedical, food, and personal care appli-

cations. Detergents, instant beverages, and processed

food can also explore other release triggers available for

the LbL assembled shells, the pH and temperature

triggers [61]. For the purpose of targeted delivery of

hydrophobic drugs, the magnet responsive LbL shells

can be assembled [62,63].

Prolonged release of fragrances from aqueous or water/

ethanol-based products still remains a challenging task.

Recently, Sadovoy et al. reported on the LbL encapsu-

lation of oil microdroplets containing a 10 component

model fragrance. Aqueous dispersion of the microdro-

plets coated with two bi-layers of bovine serum albumin

and tannic acid ([BSA/TA]2) was placed in an open vial

and kept at 408C. It was found, that the [BSA/TA]2 shell

allowed the fragrance to release from the capsules

Figure 3

(a)

Monomer Emulsification

In

(p

Water

Surfactant

Template particle

Water

Monomer

Surfactant

(high shear mixer)

(b)

Emulsion polymerization technique: (a) monomer solubilized in an aqueous m

and initiates the polymerization and eventually a polymer micro/nanoparticle

produce a core–shell micro/nanosphere.


keeping the fragrance composition constant over 3 days

[50��].

LbL method remains unique regarding the possibility to

create smart and multifunctional microcapsules and nano-

capsules. A big variety of compounds commonly used in

the multifunctional LbL assemblies have got FDA

approval, opening an avenue to explore the LBL method

in drug delivery, food, derma care and cosmetology.

However, some difficulties to scale up the fabrication

process are expected.

Emulsion polymerizationFirst reported in 1932 by Luther and Heuck [64], the

emulsion polymerization (EP) process is carried out in

heterogeneous systems with an aqueous phase and a

non-aqueous phase. The monomer and polymer usually

belong to the non-aqueous phase (Figure 3). Usually,

monomer is sparingly soluble in water and generates a

water-insoluble polymer. The particle polymeric shell

is obtained from monomer polymerization after the

addition of an initiator that may be an ion or a radical

but a monomer itself can be transformed to an initiator

following the application of a high-energy radiation,

such as gamma-radiation, ultraviolet and strong visible

light [65]. Polyacrylamides, poly(methyl-methacrylates),

Initiator addition

(polymerization)

itiator addition

olymerization)


edium by a surfactant. A water-soluble initiator diffuses into the micelle

is produced; (b) polymerization on the surface of a template particle to



poly(ethyl-cyanoacrylates) and poly(butyl-cyanoacry-

lates) are among polymers that can be produced by this

method [66].

A reproducible EP process was used to prepare core/shell

colloidal nanospheres, loaded with an antitumor hydro-

philic drug, 5-fluorouracil, and consisting of a magnetic

core (magnetite) and a biodegradable polymeric shell

[poly(ethyl-2-cyanoacrylate), poly(butylcyanoacrylate),

poly(hexylcyanoacrylate), or poly(octylcyanoacrylate)]

[67] to be used as a drug delivery system responsive to

external magnetic fields [67]. In another study, nan-

ometer-sized poly(acrylic acid) hydrogels were synthes-

ized by EP of methyl acrylate and subsequent acidic

hydrolysis [68] and used for the pH-controlled uptake

and subsequent release of oligothiophene fluorophore.

Shah et al. reported multifunctional magnetic nanoparti-

cles surface modified with bilayer oleic acid, and coated

with a thermo-responsive copolymer poly(N-isopropyla-

crylamide-co-acrylamide) by EP, for controlled drug

delivery and magnetic hyperthermia treatment of cancer

[69].

Miniemulsion polymerization (mini-EP) has become

quite an important process for preparing nanosized

particles. Generally, in mini-EP, miniemulsion droplets

of 50–500 nm of the monomer and the costabilizer in the

aqueous continuous phase are prepared by shearing a

system containing the monomer, the costabilizer, the

water soluble surfactant, and the initiator [70]. The key

difference between EP and mini-EP is the utilization of a

low molecular mass compound as the co-stabilizer and

also the use of a high-shear device (ultrasound, etc.).

Landfester and Mailander have reported the latest devel-

opments in the miniemulsion technique for the formation

of complex carriers for the encapsulation of different

kinds of reporter molecule and drugs [71�].

Various inorganic nanoparticles such as silica, gold, silver,

iron oxide and quantum dots have been encapsulated

using EP and have shown a narrow particle size distri-

bution as compared to the encapsulation using preformed

polymers which results in aggregation and large size

distribution [72�]. In addition, Gao et al. have shown that

the incorporation efficiency of quantum dots was greater

when single quantum dots were embedded into polymer

particles by the EP procedure as compared to a secondary

dispersion approach employing premade polymer [73].

Mamaghani et al. prepared silver nanoparticles encapsu-

lated with poly-{methyl methacrylate-butyl acrylate-

acrylic acid} by two methods: in situ polymerization of

acrylate monomers by mini-EP and dispersion of silver

nanoparticles in preformed acrylic latex. The in situ mini-

EP yields a better dispersion of nanosilver in the poly-

meric particles and showed high antibacterial activity

compared to the blend of silver nanoparticles and acrylic

latex [74].


EP performed in the absence of added emulsifier often

referred as surfactant-free emulsion polymerization, in

which the surfactants are created in situ. This is realized

either by copolymerization of a hydrophilic comonomer or

by oligomerization of the hydrophobic monomer by a hydro-

philic, generally an ionic initiator fragment [75]. The gener-

ally used reagents are: deionized water, a water-soluble

initiator (e.g. potassium persulfate, 2,20-Azobis(2-methylpro-

panimidamide) dihydrochloride), monomers (more com-

monly vinyl or acryl monomers) and orionic co-monomers

(e.g. quaternary ammonium cationic monomers, poly(eth-

ylene glycol)-ethyl ether methacrylate macromonomer used

as a polymerizable stabilizer) [76].

The polymer nanoparticles prepared by emulsifier-free

EP were also employed as a template for forming a

functional shell of metal nanoparticles. For instance,

the monodisperse poly(styrene-co-acrylic acid) cores syn-

thesized by this method were coated by a shell of silver

nanoparticles through interfacial reduction of silver nitrate

with polyvinylpyrrolidone [77] or sodium borohydride [78].

These PSA/Ag hybrid nanospheres served as the optimal

metal enhancer for surface enhanced Raman spectroscopy

[77] and showed excellent antibacterial activity against

both gram-positive Staphylococcus aureus and gram-negative

Escherichia coli [78]. In another study, oleic acid modified

magnetite Fe3O4 nanoparticles were used as cores and a

copolymer shell was prepared by emulsifier-free EP [79].

The shell comprised of styrene, butyl acrylate and a

cationic comonomer of [2-(methacryloxy)ethyl]trimethy-

lammoniumchloride for assisting in consequent binding of

negatively charged DNA. Recently polyethylenimine

(PEI)-immobilized core–shell particles possessing various

types of polymer cores were prepared via a visible light-

induced surfactant-free EP of three vinyl monomers: styr-

ene, methyl methacrylate, and 2-hydroxyethyl methacry-

late [80]. These particles have potential for various

biomedical applications, including gene transfection and

intracellular drug delivery.

Ultrasound induced interfacial chemical linking of pre-

formed polymers with low interfacial activity can be

considered as a particular case of the surfactant-free EP

method [81,82]. Moreover, a treatment with high fre-

quency ultrasound was proved to enable stable emulsions

without any emulsifier by providing a double ionic layer

around oil particles [83��].

EmulgelsEmulgel systems, also referred as emulsion hydrogels, are

polymer assemblies integrating dispersed oil microdro-

plets within an abundant water-rich hydrogel phase

[4��,84]. Similar to common hydrogels, the emulgels

can have different geometries and sizes ranging from

casted macroscopic mass to microparticles depending

on the hardness of the hydrogel component. Soft emul-

gels characterized with the internal phase reorganization


52 New technologies

imposed by the lipids’ release and uptake by the droplets

embedded in a hydrogel network [85,86]. The process

can be affected in three ways, that is, by increasing the

amount of a surfactant, increasing the concentration of a

gelling agent, or by chemical bonding of a surfactant to a

gel matrix [84,86,87]. The second and the third ways

eventually result in formation of solid-like systems shar-

ing the properties of both hydrogel and emulsion. The

parameters such as the oil volume fraction and the

concentration of a gelling agent predetermine the mech-

anical properties of the construct, swelling and release

[84,87].

Emulgels offer increased stability and the advantage of

dual controlled delivery of hydrophilic and lipophilic

compounds especially demanded in topical products for

skin care. Due to the lack of excess oily bases and

insoluble excipients, they show better drug release as

compared to other topical drug delivery systems. Gel

phase makes them non greasy and favors good patient

compliance [4��].

In the food industry, emulgels are appeared to be an

effective strategy to develop reduced calorie products

with desirable sensory attributes [88��].

Conclusions and outlookED and EP methods have proven success for encapsula-

tion of bioactive compounds and fabrication of drugs,

therapeutic aids and functional elements of controlled

delivery systems. Further development of these tech-

niques is envisioned to involve reducing the amount of

water and surfactants. Thus, the methods allowing the

surfactant-free emulsions (for instance, the sonochemical

method) would become important. Smart emulsion-

based encapsulating systems, such as the LbL coated

capsules and emulgels, are being actively developed and

highly demanded in many application areas. Elaboration

of these systems for biomedical, personal care and food

industries will strongly depend on the progress in

material engineering, owing to the material toxicity

issues and the need for approval by the administrating

authorities. In addition, the developments for personal

care applications should avoid contamination by proteins

of animal origin as potentially causing allergic reactions

in humans. Transparency is a crucial consumer require-

ment for some cosmetic products. We expect a break-

through on LbL encapsulation of nanoemulsions

contributing to the development of multifunctional

transparent formulations.

Conflict of interest statementNothing declared.

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21. Voigt A, Donath E, Moehwald H: Preparation of microcapsulesof strong polyelectrolyte couples by one-step complexsurface precipitation. Macromol Mater Eng 2000, 282:13-16.

22. Borodina T, Grigoriev D, Moehwald H, Shchukin D: Hydrogenstorage materials protected by a polymer shell. J Mater Chem2010, 20:1452-1456.

23. Gasparini G, Kosvintsev SR, Stillwell MT, Holdich RG: Preparationand characterization of PLGA particles for subcutaneouscontrolled drug release by membrane emulsification. ColloidsSurf B Biointerfaces 2008, 61:199-207.

24. Panyam J, Williams D, Dash A, Leslie-Pelecky D, Labhasetwar V:Solid-state solubility influences encapsulation and release ofhydrophobic drugs from PLGA/PLA nanoparticles. J Pharm Sci2004, 93:1804-1814.

25. Kassab R, Parrot-Lopez H, Fessi H, Menaucourt J, Bonaly R,Coulon J: Molecular recognition by Kluyveromyces ofamphotericin B-loaded, galactose-tagged, poly (lactic acid)microspheres. Bioorg Med Chem 2002, 10:1767-1775.

26. Giri TK, Choudhary C, Ajazuddin, Alexander A, Badwaik H,Tripathi DK: Prospects of pharmaceuticals andbiopharmaceuticals loaded microparticles prepared bydouble emulsion. Saudi Pharm J 2012, 21:125-141.

27. Pisani E, Fattal E, Paris J, Ringard C, Rosilio V, Tsapis N:Surfactant dependent morphology of polymeric capsules ofperfluorooctyl bromide: influence of polymer adsorption at thedichloromethane–water interface. J Colloid Interface Sci 2008,326:66-71.


28. Moinard-Checot D, Chevalier Y, Briancon S, Beney L, Fessi H:Mechanism of nanocapsules formation by the emulsion–diffusion process. J Colloid Interface Sci 2008, 317:458-468.

29. Quintanar-Guerrero D, Fessi H, Doelker E, Allemann E: Methodsfor preparing vesicular nanocapsules, PCT Patent no.W09904766A, 1999.

30. Quintanar D, Fessi H, Doelker E, Alleman, E: Method for preparingvesicular nanocapsules. US Patent 6,884,438, 2005.

31. Quintanar-Guerrero D, Allemann E, Doelker E, Fessi H: Amechanistic study of the formation of polymer nanoparticlesby the emulsification–diffusion technique. Colloid Polym Sci1997, 275:640-647.

32. Quintanar D, Allemann E, Fessi H, Doelker E: Preparationtechniques and mechanisms of formation of biodegradablenanoparticles from preformed polymers. Drug Dev Ind Pharm1998, 24:1113-1128.

33. Quintanar D, Allemann E, Doelker E, Fessi H: Preparation andcharacterization of nanocapsules from preformed polymersby a new process based on emulsification–diffusiontechnique. Pharm Res 1998, 15:1056-1062.

34. Lee MY, Min SG, Bourgeois S, Choi MJ: Development of anovel nanocapsules formulation by emulsion–diffusioncombined with high hydrostatic pressure. J Microencapsul2009, 26:122-129.

35. Mora-Huertas CE, Fessi H, Elaissari A: Polymer-basednanocapsules for drug delivery. Int J Pharm 2010, 385:113-142.

36. Guinebretiere S, Briancon S, Fessi H, Teodorescu VS,Blanchin MG: Nanocapsules of biodegradable polymers:preparation and characterization by direct high resolutionelectron microscopy. Mater Sci Eng C 2002, 21:137-142.

37. Moinard-Checot D, Chevalier Y, Briancon S, Beney L, Fessi H:Mechanism of nanocapsules formation by the emulsion–diffusion process. J Colloid Interface Sci 2008, 317:458-468.

38. Joo HH, Lee HY, Guan YS, Kim JC: Colloidal stability and in vitropermeation study of poly(e-caprolactone) nanocapsulescontaining hinokitiol. J Ind Eng Chem 2008, 14:608-613.

39.�

Miladi K, Sfar S, Fessi H, Elaissari A: Drug carriers inosteoporosis: preparation, drug encapsulation andapplications. Int J Pharm 2013, 445:181-195.

The review reports the carrier systems used in osteoporosis therapydescribing all types of carriers used in this area, their elaboration andproperties, the drug characteristics used in such an application, and drugrelease and efficiency. Various processes used to obtain well-definedcapsules, spheres and more complex carriers are described, illustratedand discussed.

40. Hallouard F, Briancon S, Anton N, Li X, Vandamme T, Fessi H:Poly(ethylene glycol)–poly(epsilon-caprolactone) iodinatednanocapsules as contrast agents for x-ray imaging.Pharmaceut Res 2013, 30:2023-2035.

41. Zambrano-Zaragoza ML, Mercado-Silva E, Gutierrez-Cortez E,Castano-Tostado E, Quintanar-Guerrero D: Optimization ofnanocapsules preparation by the emulsion-diffusionmethod for food applications. LWT-Food Sci Technol 2011,44:1362-1368.

42. Choi MJ, Ruktanonchai U, Soottitantawat A, Min SG:Morphological characterization of encapsulated fish oil withbeta-cyclodextrin and polycaprolactone. Food Res Int 2009,42:989-997.

43. Choi MJ, Soottitantawa A, Nuchuchu O, Min SG, Ruktanonchai U:Physical and light oxidative properties of eugenolencapsulated by molecular inclusion and emulsion–diffusionmethod. Food Res Int 2009, 42:148-156.

44. Surassmo S, Min SG, Bejrapha P, Choi MJ: Effects of surfactantson the physical properties of capsicum oleoresin-loadednanocapsules formulated through the emulsion–diffusionmethod. Food Res Int 2010, 43:8-17.

45. Perez C, Sanchez A, Putnam D, Ting D, Langer R, Alonso MJ:Poly(lactic acid)–poly(ethylene glycol) nanoparticles as new




















































































































54 New technologies

carriers for the delivery of plasmid DNA. J Control Release 2001,75:211-224.

46. Imsombut T, Srisuwan Y, Srihanam P, Baimark Y: Genipin-cross-linked silk fibroin microspheres prepared by the simple water-in-oil emulsion solvent diffusion method. Powder Technol 2010,203:603-608.

47. Lee MY, Min SG, Bourgeois S, Choi MJ: Development of a novelnanocapsule formulation by emulsion-diffusion combinedwith high hydrostatic pressure. J Microencapsulation 2009,26:122-129.

48. Surassmo S, Min SG, Bejrapha P, Choi MJ: Efficacy of capsicumoleoresin nanocapsules formulation by the modifiedemulsion–diffusion method. J Nanosci Nanotechnol 2011,11:642-646.

49. Campardelli R, Cherain M, Perfetti C, Iorio C, Scognamiglio M,Reverchon E, Port GD: Lipid nanoparticles production bysupercritical fluid assisted emulsion–diffusion. J SupercritFluids 2013, 82:34-40.

50.��

Sadovoy A, Lomova MV, Antipina MN, Braun NA, Sukhorukov GB,Kiryukhin M: Layer-by-layer assembled multilayer shells forencapsulation and release of fragrance. ACS Appl MaterInterfaces 2013, 5:8948-8954.

Prolonged release of fragrance remains an extremely challenging task.The breakthrough will contribute a lot to the level of consumer satisfactionwith fine perfumes and fabric conditioners. A shell comprising fouralternative layers of a protein and a polyphenol is employed to encapsu-late the dispersed phase of a fragrance-containing oil-in-water emulsion.The model fragrance used in this work consists of 10 ingredients, cover-ing a range of typically employed aroma molecules. The composition ofreleased fragrance remains almost constant over three days of incuba-tion, upon further incubation it becomes enriched with two ingredientshaving the lowest vapor pressure.

51. Tjipto E, Cadwell KD, Quinn JF, Johnston APR, Abbott NL,Caruso NL: Tailoring the interfaces between nematic liquidcrystal emulsions and aqueous phases via layer-by-layerassembly. Nano Lett 2006, 6:2243-2248.

52. Wackerbarth H, Schoen P, Bindrich U: Preparation andcharacterization of multilayer coated microdroplets:droplet deformation simultaneously probed by atomic forcespectroscopy and optical detection. Langmuir 2009,25:2636-2640.

53. Lomova MV, Sukhorukov GB, Antipina MN: Antioxidantcoating of micronsize droplets for prevention of lipidperoxidation in oil-in-water emulsion. ACS Appl MaterInterfaces 2010, 2:3669-3676.

54. Sadovoy AV, Kiryukhin MV, Sukhorukov GB, Antipina MN: Kineticstability of water-dispersed oil droplets encapsulated in apolyelectrolyte multilayer shell. Phys Chem Chem Phys 2011,13:4005-4012.

55. Bouyer E, Mekhloufi G, Rosilio V, Grossiord JL, Agnely F:Proteins, polysaccharides, and their complexes used asstabilizers for emulsions: Alternatives to syntheticsurfactants in the pharmaceutical field? Int J Pharm 2012,436:359-378.

56. Aoki T, Decker EA, McClements DJ: Influence of environmentalstresses on stability of O/W emulsions containing dropletsstabilized by multilayered membranes produced by a layer-by-layer electrostatic deposition technique. Food Hydrocolloid2004, 19:209-220.

57. Guzey D, McClements DJ: Influence of environmental stresseson O/W emulsions stabilized by b-lactoglobulin–pectin and b-lactoglobulin–pectin–chitosan membranes produced by theelectrostatic layer-by-layer deposition technique. FoodBiophys 2006, 1:30-40.

58. Grigoriev DO, Miller R: Mono- and multilayer covered drops ascarriers. Curr Opin Colloid Interface Sci 2009, 14:48-59.

59. Alamed J, Chaiyasit W, McClements DJ, Decker EA:Relationships between free radical scavenging andantioxidant activity in foods. J Agric Food Chem 2009,57:2969-2976.


60. Szczepanowicz K, Dronka-Gora D, Para G, Warszynski P:Encapsulation of liquid cores by layer-by-layer adsorption ofpolyelectrolytes. J Microencapsulation 2010, 27:198-204.

61. Delcea M, Moehwald H, Skirtach AG: Stimuli responsive LbLcapsules and nanoshells for drug delivery. Adv Drug Del Rev2011, 63:730-747.

62. Han Y, Radzuik D, Shchukin DG, Moehwald H: Sonochemicalsynthesis of magnetic protein container for targeted delivery.Macromol Rapid Commun 2008, 29:1203-1207.

63. Mu B, Liu P, Du PC, Dong Y, Lu CY: Magnetic-targeted pH-responsive drug delivery system via layer-by-layer self-assembly of polyelectrolytes onto drug-containing emulsiondroplets and its controlled release. J Polym Sci Part A: PolymChem 2011, 49:1969-1976.

64. Luther M, Heuck C: Products of latex character and a process forproducing the same. US Patent 1,864,078, assigned to IGFarbenindustrie AG, June 21, 1932.

65. Pinto Reis C, Neufeld RJ, Ribeiro AJ, Veiga F:Nanoencapsulation. I. Methods for preparation of drug-loadedpolymeric nanoparticles. Nanomed Nanotechnol Biol Med 2006,2:8-21.

66. Rao JP, Geckeler KE: Polymer nanoparticles: preparationtechniques and size-control parameters. Prog Polym Sci 2011,36:887-913.

67. Arias JL, Gallardo V, Ruiz MA, Delgado AV: Magnetite/poly(alkylcyanoacrylate) (core/shell) nanoparticles as 5-fluorouracil delivery systems for active targeting. Eur J PharmBiopharm 2008, 69:54-63.

68. Argentiere S, Blasi L, Ciccarella G, Barbarella G, Cingolani R,Gigli G: Nanogels of poly(acrylic acid): uptake and releasebehavior with fluorescent oligothiophene-labeled bovineserum albumin. J Appl Polym Sci 2010, 116:2808-2815.

69. Shah SA, Asdi MH, Hashmi MU, Umar MF, Awan S-U: Thermo-responsive copolymer coated MnFe2O4 magneticnanoparticles for hyperthermia therapy and controlled drugdelivery. Mater Chem Phys 2012, 137:365-371.

70. Baruch-Sharon S, Margel S: Synthesis and characterization ofpolychloromethylstyrene nanoparticles of narrow sizedistribution by emulsion and miniemulsion polymerizationprocesses. Colloid Polym Sci 2010, 288:869-877.

71.�

Landfester K, Mailander V: Nanocapsules with specifictargeting and release properties using miniemulsionpolymerization. Expert Opin Drug Deliv 2013, 10:593-609.

The field of application for nanosized materials ranges from mere tech-nical purposes to a growing field of applications in biomedicine. Amongthe different techniques and processes to produce these materials forencapsulation of reporter molecules and drugs, the miniemulsion processhas been proven to be highly adaptable. The review covers the recentdevelopments in the field of miniemulsion. The use of a wide variety ofpolymerization techniques in the miniemulsion process and possibleutilization of a wide range of monomers as requested by the biomedicalapplications is demonstrated.

72.�

Ladj R, Bitar A, Eissa MM, Fessi H, Mugnier Y, Le Dantec R,Elaissari A: Polymer encapsulation of inorganic nanoparticlesfor biomedical applications. Int J Pharm 2013, 458:230-241.

Hybrid inorganic colloidal particles are largely used in biomedical nano-technology. As a general tendency, to be conveniently used in biomedicalapplications, the encapsulation of the inorganic nanoparticles in a poly-mer matrix is incontestably needed. The manuscript discusses variouschemistry-based encapsulation processes showing promising results ascompared to the encapsulation using preformed polymers.

73. Gao Y, Reischmann S, Huber J, Hanke T, Bratschitsch R,Leitenstorfer A, Mecking S: Encapsulating of single quantumdots into polymer particles. Colloid Polym Sci 2008, 286:1329-1334.

74. Mamaghani MY, Pishvaei M, Kaffashi B: Synthesis of latex basedantibacterial acrylate polymer/nanosilver via in situminiemulsion polymerization. Macromol Res 2011, 19:243-249.

75. Cochin D, Laschewsky A: Emulsion polymerization of styreneusing conventional polymerizable, and polymeric surfactants.A comparative study. Macromolecules 1997, 30:2278-2287.






















































































































76. Liu QQ, Li YL, Duan YX, Zhou H: Research progress on thepreparation and application of monodisperse cationicpolymer latex particles. Polym. Int. 2012, 61:1593-1602.

77. Li JM, Ma WF, Wei CA, Guo J, Hu J, Wang CC: Poly(styrene-co-acrylic acid) core and silver nanoparticle/silica shellcomposite microspheres as high performance surface-enhanced Raman spectroscopy (SERS) substrate andmolecular barcode label. J Mater Chem 2011, 21:5992-5998.

78. Song C, Chang Y, Cheng L, Xu Y, Chen X, Zhang L, Zhong L, Dai L:Preparation, characterization, and antibacterial activitystudies of silver-loaded poly(styrene-co-acrylic acid)nanocomposites. Mater Sci Eng C 2014, 36:146-151.

79. Li X, Liu G, Yan W, Chu PK, Yeung KWK, Wu S, Yi C, Xu Z:Preparation of Fe3O4/poly(styrene-butyl acrylate-[2-(methacryloxy)ethyl]trimethylammonium chloride) byemulsifier-free emulsion polymerization and its interactionwith DNA. J Magn Magn Mater 2012, 324:1410-1418.

80. Ratanajanchai M, Soodvilai S, Pimpha N, Sunintaboon P:Polyethylenimine-immobilized core-shell nanoparticles:synthesis, characterization, and biocompatibility test. MaterSci Eng C Mater Biol Appl 2014, 34:377-383.

81. Borodina T, Grigoriev D, Markvicheva E, Moehwald H, Shchukin D:Vitamin E microspheres embedded within a biocompatiblefilm for planar delivery. Adv Eng Mater 2011, 13:B123-B130.

82. Borodina TN, Grigoriev DO, Carillo MA, Hartmann J, Moehwald H,Shchukin DG: Preparation of multifunctional polysaccharidemicrocontainers for lipophilic bioactive agents. ACS ApplMater Interfaces 2014, 6:6570-6578.

83.��

Kaci M, Meziani S, Arab-Tehrany E, Gillet G, Desjardins-Lavisse I,Desobry S: Emulsification by high frequency ultrasound usingpiezoelectric transducer: Formation and stability of emulsifierfree emulsion. Ultrason Sonochem 2014, 21:1010-1017.

Emulsifier-free emulsions are envisioned as a trend in development ofdouble phase delivery systems for food and personal care applications.Emulsifier free emulsion was developed with a new patented techniquefor food and cosmetic applications. This emulsification process dis-persed oil droplets in water without any emulsifier. The results revealed


that oil droplets average size decreased significantly (P < 0.05) during thefirst six hours of emulsification process and that from 160 to 1 mm foremulsions with 5%, 10% and from 400 to 29 mm for emulsion with 15%of initial oil ratio. The data reviled that emulsion stability was providedby a double ionic layer around oil particles. The study also showed astrong correlation between turbidity measurement and proportion ofemulsified oil.

84. Shingel KI, Roberge C, Zabeida O, Robert M, Klemberg-Sapieha JE: Solid emulsion gel as a novel construct for topicalapplications: synthesis, morphology and mechanicalproperties. J Mater Sci Mater Med 2009, 20:681-689.

85. Gulsen D, Chauhan A: Dispersion of microemulsion drops inHEMA hydrogel: a potential ophthalmic drug delivery vehicle.Int J Pharm 2005, 292:95-117.

86. Iglesias GR, Pirolt F, Sadeghpour A, Tomsic M, Glatter O: Lipidtransfer in oil-in-water isasome emulsions: influence ofarrested dynamics of the emulsion droplets entrapped in ahydrogel. Langmuir 2013, 29:15496-15502.

87. Thakur G, Naqvi MA, Rousseau D, Pal K, Mitra A, Basak A:Gelatin-based emulsion gels for diffusion-controlled releaseapplications. J Biomater Sci Polym 2012, 23:645-661.

88.��

Chung C, Degner B, Decker EA, McClements DJ: Oil-filledhydrogel particles for reduced-fat food applications:Fabrication, characterization, and properties. Innov Food SciEmerg Technol 2013, 20:324-334.

Emulsion hydrogels are seen as an effective strategy to developreduced calorie products with desirable sensory attributes. This studyutilizes controlled phase separation of biopolymer mixtures to form oil-filled hydrogel particles suitable for use in food products. The multistepmethod involved inducing segregative phase separation of the mixedbiopolymers at pH 7, and then reducing to pH 5 to promote aggregativephase separation. The simple method involved mixing all the compo-nents together at pH 7 and then adjusting to pH 5. The oil-filledhydrogel particles were spheroid in shape, with mean particle dia-meters (d43) around 10 mm. The hydrogel particles increased thelightness and viscosity of aqueous solutions, and suggested to besuitable to replace fat droplets or starch granules in reduced calorieproducts.






















































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Emulsion-based techniques for encapsulation in biomedicine, food and personal care