Controlled Release in Food

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Review Fundamental aspects ofcontrolled release in foodsThe fundamen tal equations governing the controlled releaseof active ingredients and the application of controlled-releasetechnology in food system s are reviewed in this art icle. T he

method o f microencap sulation, among others, can be appliedto achieve controlled release in foods. Som e of the releasemech anism s employed in the food industry invo lve one or acombination of the following stimuli: a change in tempera-ture, moisture or pH; the application of pressure or shear; andthe addit ion of surfacta nts. Encapsulation is a method of pro-tecting food ingredients that are sensit ive to temperature,moisture, microorganisms or other components of the foodsystem. Such food ingredients inc lude f lavors, sweeteners,enzy mes , food preservatives and antioxidants, and are encap-sulated using carbohyd rates, gum s, lipids and/or proteins.With a properly designed controlled-release delivery sys tem ,the food ingredient is released at the desired site and time at adesired rate.

Food ingredients may be of natural origin or chemicallyprepared. In some cases, the natural ingred ients can beless potent than the chemical counterparts. On the otherhand, the permitted leve ls of chemical ingredients arelow. In either case, it may be difficu lt to achieve thedesired effect without adding high leve ls of the ingred i-ent. Controlled release is a novel technology that can beused to increase the effectiveness of many ingredients.The performance of natural ingredients can be im-proved, thereby offering viable alternat ives to the lessacceptable chemical additives. The technology of con-trolled release, with its initial roots in the drug industry,has spread to other areas such as the agrochemicals, ferti-lizers, veterinary drugs and food industries.Controlled release may be defined as a method bywhich one or more ac tive agents or ingredients are madeavailable at a desired site and time at a specific rate.With the emergence of controlled-release technology,some heat-, temperature- or pH-sensitive additives canbe used very conveniently in food systems. Such addi-tives are introduced into the food system mostly in theform of microcapsules.

The additive present in the microcapsule is releasedunder the influence of a specific stimulus at a specifiedstage. For example, flavors and nutrients may bereleased upon consumption, whereas sweeteners that aresuscep tible to heat may be released towards the endof baking, thus preventing undesirable ca rameliza tionin the baked product. Also, carbon dioxide is releasedwhen an acid reacts with sodium carbonate duringbaking. Thus, controlled-release delivery systems mayUsha R. Pothakamury and Gustav0 V. Barbosa-Cinovas (correspondingauthor) are at the Department of Biological Systems Eng ineering, WashingtonState Univers ity , Pul lman , WA 99164.6120 , USA (fax: t l -509-335-2722;e-mai l : barbosa@mall .wsu.edui .

Usha R. Pothakamury andGustav0 V. Barbosa-Gnovas

be categorized according to whether they involvephysical or chemical methods of release of the activeagent. Some of the physically and/or chemically con-trolled delivery systems that are available are presentedin Fig. 1. This article first describes the variety ofcontrolled-release mechanisms available, then givessome food industry applications, focusing especially onalternative approaches to microencapsulation, the mostcommonly used controlled -release system in the foodindustry.Methods of achieving controlled release in foodsThe most commonly used method to achieve con-trolled release in the food industry is microencapsu-lation. Microencapsula tion is defined as the technology ofpackaging solid, liquid or gaseous materials in m iniaturesealed capsules that release their contents at controlledrates under the influence of certain stimuli. The shapeand size of the microcapsule depend on the shape ofthe food-additive material. The simplest microcapsulemay consist of a core surrounded by a wall or barrier ofuniform or non-uniform thickness. The core may becomposed of just one or several different types of ingre-dients, and the wall may be single or multi-layered.The techniques used for microencapsulat ion arespray drying, coating, extrusion, liposome entrapment,coacervat ion and freeze drying2. Of these methods,spray drying is the most commonly used. Generally,water-so luble polymers are used to encapsulate organiccore materials and water-insoluble polymers for aque-ous core materials. Because few suitable polymers havebeen approved for use in foods, certa in food materialscan be modified to increase their porosity and to alterother characteristics, thus enabling their use as coatingmaterials in microencapsulation3.Other methods of achieving cont rolled release offood ingredients, besides microencapsulation, are mol-ecular inclusion, adsorption and co-crystallizatiot?.The advantages of controlled release are3,4:l the active ingredients are released at controlled ratesover prolonged pe riods of time;l loss of ingredients, such as vitamins and minerals,during processing and cooking can be avoided orreduced;l reactive or incompatible components can be separated.

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COATED SOLIDPARTICLES SOLUTIONS

Spheres

Aggregate

Multip lecoating

COMPOSITES CONTAINERS COMBINATIONS

Beadlets

Cubes, slabs orcylinders

Spheres

Strip

Capsules In liquid

In capsule

In solid matrix

The active agent is released from the controlled-release delivery systems by diffusion, biodegradation,swelling or osmotic pressure.Release of active agent by diffusionReservoir systemsA reservoir system consists of an active agent con-tained within a rate-controlling barrier (Fig. 2a).Barriers may be microporous, macroporous or non-porou@. The most commonly used barrie r is the non-porous homogeneous film7. The release rate from areservoir system depends on the thickness, the area andthe permeability of the barrier5 (Fig . 3a). In a reser -voir containing an excess of act ive agent, the releaserate follows zero-order kinetics (i.e. the release rate isconstant).The principal steps in the release of an active ingredi-ent from a reservoir system are?l diffusion of the active agent within the reservoir;l dissolu tion or partitioning of the active agent betweenthe reservoir carrier fluid and the barrier;l diffusion through the barrier and partitioning betweenthe barrier and the elution medium (i.e. the surround-ing food);l transport away from the barrier surface into the food.

Physical an d chemical types of controlled-releas e systems. Ada pted f rom Ref. 1.

The rate-limit ing step in the release of the activeingredient is diffusion through the polymer. Severalexcellen t reviews of the mathematical equationsdescrib ing the rates of release of active ingredients inreservoir systems have been published5,6*8,9.The finalform of the mathematical equations is presented here.The pattern of release of the active agent depends on thegeometry of the system. The reservoir system contain-ing the active agent i s considered as the source , and themedium into which the active agent is released istermed the sink. If the amount of active agent present inthe reservoir system is relatively high and the solubilityof the active agent relatively low, the system is con-sidered as an infinite source. Three idealized situationsfor the reservoir system (source) and the mediuminto w hich the active ingredient is released (sink) are

/ (a) (b)Activeagent depotModeratingbarrier

Active agentuniformlydistributedthroughoutthe matrix

Fig. 2Sim ple reservoir-type (a) and matrix-type (b) systems. Reproduced

with permission from Ref. 5.

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(4Initial high release of agent that hasmigrated into the barrier on storage

Constant release, as long as aconstant concentration ismaintained in reservoir

Release rapidly declines when thereservoir approaches exhaustion

Fig.3(a), Rate of release of an active agent f rom a reservoir system.Reproduced with permission form Ref. 5. (b), Release patternof an active agent dissolved in a slab-shaped, cylindrical orspherical matrix. Reproduced with permission from Ref. 9.(c), Release pattern of an active agent dispersed in aslab-shaped, cylindrical or spherical m atrix. Reproduced withpermission from Ref. 9. M , is the amount of active agentreleased in time t; MI is the total amount of active agent thatcan b e released: r is the radius of the matrix.

Time

6)0.8

0.6

0 0 0.1 0.2 0.3 0.4 0.5Time

- Cylinder

Cd 1

- Sphere-- - Cylinder- . - - SlabI I I

0 0 0.2 0.4 0.6 0.8 1 .oTime

considered. The amount of active agent released, Ml, in surface of the barrier has to be accounted for:time t is given by the following equations:(1) for an infinite, well-agitated source and an infinitewell-agitated sink:

M = AQr,k(C~ - G)tt s(2) for a finite source and a finite sink:

where A is the barrier area, Dm is the diffusion co-(1) efficient of the active agent through the barrier, k is themass transfer coefficient, C, and C, are the respectiveconcentrations of the active agent in the source and inthe sink, 6 is the thickness of the barrier, M, and M, arethe respective masses of the active agent in the source

M, = WV2 -M2V1VI + v2 i [1 _ exp (VI + V2 W m k t and in the sink, and V, and V, are the respective vol-

v,v2s(2) umes of the source and the sink, CIm s the concentrationin the bulk of the reservoir, k, and k, are the mass trans-fer coefficients on the reservoir and sink side, respec-

(3) for a sink and source that are not well-agitated, tively, and K, and K, are the partition coefficients on thesuch that the boundary-layer resistance on the inner reservoir and sink side, respectively8,9.

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When the sink and source are not well-agitated, bound-ary-layer resistanceson the surface of the barrier have to beconsidered. The release of the active agent in a system withboundary-layer resistance may be controlled either by bar-rier diffusion or by boundary- layer d iffusion. If the time fordiffusion of the active agent through the ba rrier is greaterthan the time for mass transfer across the boundary layers,the system is essentially barrier-diffusion controlled8.

Barrier-diffusion-controlled reservoir systems aremore efficient than most of the other controlled-releasesystems. The system can be designed so that the activeagent makes up 90% of the volume of the system.However, such core-and-shell-type delivery systems arenot common ly used in the food industry becausemanipulation of the release rate of the active ingredien tis not simple, and leaks may alter the release rates5.Matr ix systems

In matrix systems, the active agent is homogeneouslydisso lved or dispersed throughout the polymer mass(Fig. 2b). The release pattern depends on the geometryof the system, the type of carr ier mater ial and the load-ing of the active agent. The principal steps involved inthe release of the active agent from a matrix systemdepend on whether the active agent is dissolved or dis-persed in the matrix.The steps involved in the release of an active agentthat is dissolved in the matrix are?l diffusion of the active agent to the surface of the matrix;l partition of the active agent between the matrix andthe elution medium (i.e. the surrounding food);l transport away from the matrix surface.

The sim plest way to model the release rate from sucha system is to consider an infinite, flat matrix system ofthickness S and with the active agent dissolved in thepolymer at or below the saturation concentration. Theamount of active agent released when the device i s dis-solved in a well-agitated, infinite medium is given by?

gf=*-c 8n=O (2n + 1)2& exp [ n,,,(2;~+l)7rI (4)1where M, is the amount of active agent released at in-finite time. During the early stages of release, when 4 /M,is ~0.6, the release rate va ries as t-0.5, whereas during thelater stages of release when Y/M, is >0.6 and ~1.0, therelease rate decays exponentially with time (Fig. 3b).The steps involved in the release of an active agentthat is dispersed in the matrix are*:l dissolution into the matrix:l diffusion to the surface;l transport away from the surface of the matrix.

Assuming pseudo steady-state release kinetics, theamount of active agent released at the surface of thepolymer is given by:

M, = 4D,,,Ca,(2Ca,C.Jl~where C,, is the solubili ty of the active agent in thepolymer, and CaOs the concentration of the active agentin the polymer (Fig. 3~).Manipulation of the release rates from matr ix system sis easier than from reservoir systems. Unlike the casewith reservoir systems, leaks do not substantially alterthe release rate from a matrix system.Release of active agent by biodegradation

Biodegradable systems may be reservoir-type ormatrix-type delivery systems. In a matrix-type deliverysystem, the active agent is dispersed within the polymerand is released when the polymer degrades or erodes8(Fig. 4a). Biodegradation of the polymer must result inthe formation of nontoxic components. For one clas s ofbiodegradable polymers, the surface area of the matrixdecreases with time, resulting in decreasing releaserates. Such systems are designed to contain a higherconcentration of the active agent in the interior than inthe surface layers. For a second class of biodegradablepolymers, the polymer degrades very slowly in theinit ial stages, but the degradation rate increases rapid lyin the later stages owing to autocatalysis, and the bulkerodes over a comparatively short period.The release of an active agent from a matrix-typedelivery system may be controlled by diffusion, erosionor a combination of both. If erosion of the matrix ismuch s lower than diffusion, the release kinet ics can bepredicted by Eqns 4 and 5. In addition, erosion-controlled processes may involve heterogeneous orhomogeneous erosion. Heterogeneous erosion occurswhen degradation is confined to a thin layer at the sur-face of the delivery system, whereas homogeneous ero-sion is a result of degradation occurring at a uniformrate throughout the polymer matrix. The type of erosion,heterogeneous or homogeneous, depends on the hydro-phobici ty and morphology of the polymer. Hetero-geneous erosion is more common with hydrophobicpolymers, whereas homogeneous eros ion is commonwith hydrophilic polymers.Heterogeneous erosion is more des irable because itcan lead to a constant release rate that is independent ofthe chemical and physical properties of the active agent.The release rate can be varied by varying the active-agent loading while m aintaining the integri ty becauseerosion is limited to the surface. The amount of activeagent released in heterogeneous erosion is given by?

-L=]-*-k,tM m [ 1r

where M m is the total amount of active agent that can bereleased, k, is the erosion rate constant, C,, is the initia l



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concentration of active agent in thematrix, r is the radius of a spherical orcylindrical matrix or the half-thick-ness of a slab (rectangular) matrix andn = 3 for a spherical, n = 2 for a cylin -drical and R= 1 for a slab-shapedmatrix.Release of active agent by swellingIn swelling-controlled systems, theactive agent dissolved or dispersed ina polymeric matrix is unable to diffuseto any significant extent within thematrix. When the polymer matrix isplaced in a thermodynamically com-patible medium, the polymer swellsowing to absorption of fluid (pen-etrant) from the medium. The activeagent in the swollen part of the matrixthen diffuses outs. In diffusion-con-trolled systems the barrier or matrix isassumed to be unaffected during therelease process, whereas in swelling-controlled systems, the membraneundergoes a transition from a glassy toa gel state upon interaction with thepenetrant. The polymer chains in thegel state, being more mobile thanthose in the glassy state, allow theactive agent to diffuse out of thematrix more rapidly. The release rateis determined by the glass-to-gel tran-sition process. The quantity of activeagent, Mf, released at any time t isgiven by:

M2 = ,I@M , (7)where M, is the initial active-agentloading of the polymer, and k, and nare system parameters that depend onthe nature of the polymer-penetrant-active-agent interaction.

Fig. 4(a), Erosion-cont rolled system; (b), elementary osmotic pu mp. Reproduced with permission from Ref. 8.

The parameter n can take a range of values that indi-cate the type of active-agent transport. When II = 0.5, theactive agent is released by simple F ickian diffusion.When II = 1.0, diffusion is described as case II dif-fusion. In case II diffusion, the rate of solvent uptakeby the polymer is largely determined by the rate ofswelling and relaxation of the polymer chain?. Supercase II transport occurs when n > 1 O. In the 0.5


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Table 1. Swelling-controlled release systems

nType of activeagent transport

Time (t) dependenceof diffisional release

0.5 Fickian0.5 < rll.O Super case II transportData taken f rom Ref . 8n, The system parameter

t-O st-l

Time independenty-1

l Barrier-controlled release: release of active ingredientdepends on the concentration difference acros s thewall of the microcapsules, thickness of the wall, per-meabi lity through the wall, and diffusion coefficien tof the active ingredient in the surrounding environ-ment [analogous to the reservoir systems describedin Eqns l-31.

an aqueous environment, water permeates through themembrane into the core. If the active agent has high solu-bility in water, a large osmotic pressure is created insidethe microcapsule. The active agent is released when theosmotic pressure exceeds the maximum force that thewalls of the microcapsule can tolerate3,*.The net volumetric flux of water, J,,,, nto the core isgiven by?

where L, is the hydraulic permeability of the membrane,u is the reflection coefficien t of the membrane,RT(C,,-C,,) is the osmotic pressure difference, Ca, isthe concentration of active agent in the surroundingmedium, C,, is the concentration of active agent withinthe microcapsule, (P2-PI) is the hydrostatic back press-ure, and 8 is the thickness of the barrier. The reflectioncoefficient charac terizes the porosity of the membrane,with CT=1 for an ideal semipermeable membrane, andCT 0 for a porous membrane.Controlled release in foodsThe food indust ry is taking advantage of the technol-ogy of controlled release for food additives includingflavoring agents (flavor oils, spices, seasonings), sweet-eners, colors, nutrients (vitamins, amino acids, minerals),essential oils, acids, salts, bases, antioxidants, anti-microbial agents, preservatives, ingredients with undesir-able flavor and crosslinking agents11~*2.ontrolled releasehelps to overcome both the ineffective utiliza tion andthe loss of food additi ves during the process ing steps.The release of an active agent may be based on one or acombination of release mechanism sr3; these can be timespecific, site specific, rate specific and/or stimulus specific.Brannon-Peppas categorized the release mechanismsas follows3.

Applications of controlled release in foodsl Diffusion-controlled release: active ingredient is re- Food additives, such as acidulants, flavoring agents,leased by diffusion through the polymer (car rier of the sweeteners, colorants, lipids, vitamins, minerals, en-system) or through the pores pre-existing in the poly- zymes, microorganisms, gases such as carbon dioxide in

mer [analogous to the matrix systems described in candies, antioxidants and food preservatives are some-Eqns 4 and 51. times used in encapsulated form in the food industryi2.

l Pressure-activated release: active ingredient is re-leased when pressure is applied on the walls of themicrocapsules [an example would be the release ofsweetener and/or flavor in gum when chewed; therelease kinetics cannot easily be characterized be-cause of the nature of the activation mechanism].

l Solvent-activated release: active ingredient is releasedwhen the food material comes in contact with a solvent,resulting in swelling of the microcapsule [analogous tothe swelling-controlled systems described in Eqn 71.l Osmotically-controlled release: active ingredient is re-

leased owing to large osmotic pressures created insidethe microcapsules [see Eqn 81.l pH-contro lled release: active ingredient (e.g. anenzyme) is released at a specific pH [this system canbe used alone or may be combined with solven t-activated or osmotically controlled release systems].l Temperature-sensitive release: active ingredient isreleased owing to a change in temperature [tempera-ture may affect the melting rate (see below), theosmotic pressure, the glassy or gel state of the poly-

mer in swelling-controlled systems, and the partitioncoefficients in some other systems].l Melting-ac tivated release: fat or wax used as a coatingmaterial melts when the food product is heated andthe active ingredients are released.l Combined systems: active ingredient is released as a

result of the combination of different mechanisms.Controlled-release systems in foods are developedbased on the above-mentioned fundamental conceptsand release mechanisms [the classification scheme of

Brannon-Peppas does not clearly include the case ofbiodegradation (Eqn 6); the closest case is the solvent-activated system, but here the release is due to swelling,not to erosion]. The development of a controlled -releasesystem that will adequately protect the food additive andrelease it at the desired time and site at a desired ratepresents quite a challenge.



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The food additive (active agent) can be encapsulatedusing carbohydrates, gums, lipids, proteins, polymerssuch as poly(viny1) acetate (PVA) , a fiber matrix madeof polymers, and/or liposomes1~13-6.One or more ma-teria ls may be used for encapsulation depending on thetype of application.The active agent is released by one or a combinationof the release mechanisms described earlier. In an idealsystem, the release of the active agent from the systemmay follow zero-, half- or first-order kinetics. Zero-order release (constant release rate) occurs when thecore is a pure material that is released from the systemas a pure material. Half-order release generally occurswith matrix particles, and first-order release occurswhen the core is actually a solution. In practical sys-tems, the release rate of the active agent might not bezero, half or first order. Thus, the kinetics of therelease of the active agent is complicated . However, therelease mechanism s and release-rate equations de-scribed earlier provide a basis for the design of con-trolled-release systems. The application of controlledrelease in the use of additives, such as flavors, sweeten-ers, enzymes, food preservatives and antioxidants, willbe discussed.FlavorsThe loss of flavors during the processing or storage offoods is a very common occurrence in the food industry.Flavors are very volatile, react with other componentsand are suscept ible to heat and moisture. Because flavoris a desirable characteristic of foods, it is necessary tofind methods that allow flavors to be retained in food fora longer time period. Microencapsulation and controlledrelease offer a method for protecting flavor compounds.When a flavor is added to chewing-gum base in thefree form, only 5-40% of the flavor is released uponchewing; the remainder becomes irre vers ibly bound tothe gum base and cannot be chewed out. It is desirableto be able to obtain increased intensities and the con-trolled release of such flavors.Encapsulation is one method that can be used toachieve both improved and prolonged release of flavorcompounds and other food additives. Encapsula tion byspray drying and extrusion are the two major processesused commercially. Freeze drying, coacervation, fat orwax encapsulation, plating and inclusion in cyclodex-u-ins are less commonly used for commercial purposes7.Flavor encapsulation by spray drying, extrusion, coacer-vation and molecular inclusion in cyclodextrins hasbeen reviewed by Reineccius17.Some methods ut ilizing fat or wax encapsulationhave been described in patents by Cherukuri et uZ.~ ,Rutherford et a1.19,and Reed and Hook*O. Fat-encapsu-lated cheese flavor used in microwave popcorn givesuniform distribution of the flavor*l. The flavor isreleased when the temperature rises to 57-90C. Flavo rsthat are released at microwave temperatures have thepotential to become popular.Molecula r inclus ion is one of the methods of avoidingthe loss of flavors during storage of the food product or

as a result of exposure to light or oxygen. Molecu larinclusion with B-cyclodextrin is a suitable method forreducing the loss of coffee flavors as well as for reduc-ing the bitterness of coffee drinks2*. Cyclodextrin, amodified starch derivative, behaves like an empty mol-ecular capsule with the ability to entrap guest mol-ecules of appropriate geometry and polarity . The guestmolecu les are protected from light, heat and oxidationwhen the comp lex is in the dry state. The entrappedmolecules are released from the molecular-inclusionsystem on contact with water23. Molecular inclusion ofcoffee flavors improves the storage stability, heat stabil-ity and UV-l ight stab ility compared with an unprotected(exposed) system composed of coffee flavor adsorbedonto lactose. Although cyclodextr ins offer good protec-tion to flavoring agents, the cost of cyclodextrins is alimiting factor in their applicability on a commercialscale. It is estimated that the cost of cyclodex trins can-not be reduced below $5.5-$6.6perkg (Ref. 17). Also ,cyclodextrins do not have generally recognized as safe(GRAS) status.

Controlled -release system s may be designed tochange the composition of the flavor mixtu re beingreleased with time, thus compensating for the differen-tial ra tes of the loss of the components of the originalfood flavor12. The delivery system described in Eqn 4considers the change in the rate of release of activeagent with time.Sweeteners

Artificia l sweeteners are widely used in a variety offoods such as chewing gum and confectionery products,pharmaceutical preparations, and oral hygiene productssuch as mouthwash and toothpaste. One of the com-monly used sweeteners is L-aspartyl-L-phenylalaninemethyl ester (aspartame or APM). The delivery systemdescribed by Chau et a1.24consists of O.Ol-60% sweet-ener, 40-93% PVA , O.l-20% waxy material andO.l-20% emulsifying agent. Like flavor compounds,APM is susceptible to heat, moisture and other com-ponents of the food. Sweeteners, in general, are protectedby encapsulation in fat, PVA, starch, zein or shellac,amongst others.Encapsulation by spray drying or by using fluidized-bed techniques requires both an investment in equip-ment with sophisticated process controls and skilledoperating personnel. Another method believed to be moreeconomical for producing encapsulated sweetener hasbeen described in a patent by Zib ell et ~1.~ ~ he methodinvolves mixing uncoated APM with an agglomeratingagent, such as hydroxypropyl methyl cellulose, anddampening it with water so that it is dust free, non-flowable, non-extrudable and crumb ly. The mixture i sthen dried, ground and sieved to produce a maximumpartic le size of 0.43 mm. The release rate of thesweetener when incorporated in chewing gum dependson the partic le size (Table 2). More than one agglomer-ating agent, each with different solubilit y properties,may be used to obtain a stepped release of thesweetener.



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Table 2. Dependence of particle size on the rate of release ofsweetener

Active agents such as sweeteners, acidulants and fla-vors can also be encapsulated by dispers ion throughouta fiber matrix26. The fiber matrix is made up ofpolyethylene, PVA , polyester or chitosan. The fibers(+60 mesh) have open ends, exposing the active ingredi-ents. Gradual release of the active agent occurs whenthe fiber is brought into contact with a solvent. The fiberis either insoluble or less soluble in the solvent than theactive agent. The active agent at the openings of thefiber ends is dissolved by the solvent, resulting in thecreation of channels within the fiber. The solvent fillsthe channels and dissolves the newly exposed activeagent. Thus, the release of the active agent is based onswelling of the delivery system.The incorporation of several controlled-release deliv-ery systems that release the sweetner at different ratescan provide improved and prolonged sweetener intens i-ties in a food system.Enzymes

One of the methods of controll ing the release ofenzymes is to encapsulate them in liposomes. A lipo-some is a versatile carrier system used in the foodindustry, mainly for the encapsulation of enzymes.Liposomes are artificiall y made, microscopic barriervesicles, consisting of one or more concentric layers oflipid, generally phospholipid. The permeability, stabil-ity, affinity and surface activity of liposomes depend onthe size of the vesicle and the lipid compositioni3. Theencapsulation efficiency, defined as the fraction of theaqueous compartment sequestered by the lipid layers, isdirectly proportional to the lipid concentration; whenmore lipid is present, more solute can be sequesteredwithin the liposome27. Liposome-encapsulated enzymescan be used in two different waysi4: (1) as delivery sys-tems for the controlled release of enzymes in food sys-tems, and (2) as enzyme reactors for immobilizing andimproving the stability of an enzyme while allowing theentry and exit of substrates and products.Liposome encapsulation of the enzyme neutrasereduces the enzyme requirement by loo- fold and thetime required for ripening of Cheddar cheese by 50%compared with the conventional ripening processes**. Inthe conventional cheese ripening process , the enzyme i sadded before or at the curd stage. Addition of neutrase

404

before the curd stage results in the premature break-down of casein into amino acids and also loss of theenzyme, amino acids and protein to the whey. Additionof the enzyme at the curd stage avoids premature break-down of case in, but produces cheese that has a crumb lytexture after three months. Add ition of liposome-encap-sulated enzyme to cheese milk prevents the prematurebreakdown of casein and loss of the enzyme to thewhey. The enzyme is released after the removal of thewhey and is uniformly distributed in the milk. Thecheese obtained develops the Cheddar flavor much earl-ier than when free enzyme i s used. In addition, the nor-mal Cheddar texture is retained for at least eight monthswhen encapsulated enzyme is used. Although the rate ofripening of the cheese s higher when the enzyme is used inthe free form, use of encapsulated enzyme is more favo r-able because the resultant cheese has a better texture.The enzymes lysozyme and pepsin, encapsulated inliposome, are released by one or a combination of thefollowing stimu li: change in pH from 1.5 to 2.5, tem-perature change, or the addition of surfactants29, such asTween 80, and food-grade additives, such as Ca2+ on.Tween 80 exerts a mild effect on the release of theenzymes at 10C while increasing the release rate at37C. Addit ion of Ca2+ 25 mu) results in 17-25% of thelysozyme and pepsin being pulse released during thefirst hour. Very little additional release of enzyme takesplace with an increase in the temperature. There is nochange in the activities of the enzymes when present inthe encapsulated form.

Liposomes are used as enzymatic reactors to removethe undesirable phenolic compounds from food prod-ucts, drinking water and waste streams. Liposomes offerthe advantages of structural versatility, biodegradability,stability under storage, nontoxicity and the ability toencapsulate more than one active ingredient14.Encapsulated amylases and proteases may be usedfor taste modification and texture controliO . Lipases,lipoxidases and isomerases may be important in aromaformationO.Food preservativesThe addition of large amounts of preservatives tointermediate-m oisture foods is not desirab le from a sen-sory point of view. One alternative is to concentrate thepreservative at the surface, and to use one or more lay-ers of edible coa ting, such as zein, on the surface of thefood. The ze in coating acts as a barrier regulating thediffusion of the food preservative from the surface intothe bulk; the preservative diffuses into the food throughthe coating at a rate that depends on the thickness of thezein layer. The thickness of the zein coating varies inthe range 0.03-0.04mm. The surface becomes moresuscep tible to contamination as the concentration of thepreservative at the surface decreaseslO.When the bulk of the food material needs to be pro-tected from contamination, encapsulated organic acidssuch as citric acid, ascorbic acid and lactic acid can beused as antimicrobial agents. The acid may be encapsu-lated in a matrix comprising PVA , recently approved for

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use in foods (S.M. Faust, pers. commun.), and an emulsi-fier. The molecular weight of PVA chosen depends onthe water solubility of the acid (Table 3). The emulsifiermay be lecithin, stearates, palmitates or ester deriva-tives of stearates. The acid is released when the sys-tem swells in the presence of water. The food acidamounts to 20-40% (w/w) of the controlled-releasedelivery system16.

Table 3. Water solubilities of food acid based on molecularweight

Levi and KarePl studied the release of an organicvolatile probe (n-propanol) incorporated in crysta llizingor non-c rystallizing amorphous carbohydrate glasses.The temperature at which the glasses were held, theglass transition temperature (T,), moisture content andmatrix deformation under gravity had significant e ffectson the retention of the probe. The release rates of theprobe as a function of temperature above T, can be wellpredicted by using the William-Landel-Ferry equation.Food ingredients such as acidulants and preservativescan be incorporated in these types of glass matrices.

Water solubilityof the food acid

LowMediumHigh

Molecular weight ofpoly(vinyl) acetate (Da)

2000-l 8 00015 000-25 000

20 000-65 000 Data taken f rom Ref . 16

Miscellaneous additives

Lysozyme encapsulated in liposomes is used to pre-vent spoilage due to spore-forming bacteria in Gouda,Edam and Emmental cheeses13. The bacteria produceundesirable flavor and texture changes in cheese as aresult of butyric acid fermentation. The application offree lysozyme is limited because it binds with casein inthe milk, thereby reducing its efficacy to prevent mi-crobial spoilage. Also, the use of nitrates in many countriesfor the control of bacterial spoilage is a matter of healthconcern. Liposome-encapsulated nisin is instead used toprevent the growth of Listeria monocytogenes in low-fatcheeses13.AntioxidantsThe recent trend in food consumption has resulted inthe replacement of saturated fat with unsaturated fatsin the diet. However, unsaturated fats are prone tothe problem of oxidation. The natural lipid-solublecw-tocopherol (vitamin E) can be used as an antioxi-dant. cw-Tocopherol can be regenerated from its oxidizedform using ascorbic acid, but in a food system, thecw-tocopherol is soluble in the lipid phase and cannotinteract with the water-soluble ascorbate. Therefore,the food industry uses lipid-solub le derivatives of ascor-bate. Unfortunately, however, the effective dispersal ofthe lipid-solub le derivatives of vitamin C requires hightemperatures, thus increasing the risk of oxidation of theunsaturated fats3*.

A leavening system is used to provide a porous andcellular structure in baked products. The porous struc-ture is imparted to the product by a gas being releasedunder appropriate conditions of moisture and tempera-ture. A leavening system, commonly consisting ofsodium carbonate or bicarbonate and an acid, is found inself-raising flours, prepared baking mixes, householdand commercial baking powders and refrigerated doughproducts. The acid is either present in the dough or isincorporated as an additive. Leavening acids used infoods include potassium acid tartarate, sodium alu-minum sulfate, &gluconolactone, and ortho- and pyro-phosphates. The reaction between acid and bicarbonateresults in the release of carbon dioxide, which impartsthe porous structure to the product. To allow the slowrelease of carbon dioxide, slow-acting leavening ac idssuch as monocalcium phosphate coated with a lkalimetal phosphates are used34.Changes in flowability, solub ility and water sorptioncan be avoided by encapsulating salts, including sodiumchloride. Encapsulation of salt also helps to avoid thecatalytic peroxidation of lipids .

LiposomesWater

The problem of the solubility of ascorbate and therecent ban on the use of synthetic antioxidants has led tothe use of liposome-encapsulated natural antioxidantssuch as a-tocopherol. The liposome-encapsulated sys-tem is used as an emulsifier to stabilize an oil-in-waterfood emulsion3 (Fig. 5). a-Tocopherol is incorporatedinto the liposome barrier whereas the ascorbate isentrapped in the aqueous interior. The encapsulated sys-tem is added to the aqueous phase and encouraged toaccumulate at the water-oil interphase. Thus, theantioxidant can be targeted at the site where oxidativereactions generally occur, and also avoid the reaction ofascorbate with other food ingredients3.

Free-radicalinitiation

w Oxidation --+

a-TocopherolAscorbic acid

Fig. 5Protection of a food emulsion by the liposome antioxidant system.Reproduced with permission from Ref. 13.



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Concluding remarksSome of the fundamental aspects of controlled -releasetechnology have been discussed, and the basic equationsused to predict the rate of release of active agents fromvarious delivery systems have been reviewed. It is quitea challenge to apply the knowledge gained from theencapsulation of drugs to the food industry . It is poss-ible to incorporate more than one food add itive in thecontrolled-release delivery system; for example, sweet-ener and flavor compounds may be combined by encapsu-lating flavors in a matrix comprising sweetener enhancerssuch as thaumatin, monellin or dihydrochalcones*.Because few polymers have been approved by the USFood and Drug Adm inistration for use in the foodindustry, research is still being conducted to m odifyfood polymers to facilitate the encapsulation of activeingredients. Some of the applicat ions of controlled-release delive ry system s in foods mentioned here arepatented information. It is not clear whether these sys -tems are used on a commercial basis.References

Zeol i , L.T. and Kydonieus, A.F. (1983) in Control led ReleaseTechnology (Das, KG., ed.), pp. 61-120, John Wiley & Sons

Jackson, L .S. and Lee, K. (1991) lebensm-t&s. Tecbnol . 24(4),289-297Brannon-Peppas, L. (1993) in Polymeric Del ivery Systems: Propert iesand Appl icat ions (ACS Symposium Series 520) (ECNokaly , M.A. ,Piat t , D.M. and Charpent ier, B.A. , eds), pp. 42-52, AmericanChemical Soc ietyDziezak, J .D. (1988) Food Jechnol . 42136-151Baker, R.W. (1986) Control led Release of Bio/ogica/ /y Ache Agents ,Wiley-InterscienceLanger, R. and Peppas, N. (1983) jAGRev. Macromol. Cbem. Pbys.(X23),61-126Langer, R. and Karel , M. (1981) Polym. News 7 , 250-258Fan, L.T. and Sin gh, S.K. (1989) Control led Release: A Quant i tat iveTreatment , Springer-VerlagBaker, R.W. and Lonsdale, H.K. (1974) in Control led Release:Mechanisms and Rates in Control led Release of Biological ly AcheAgents (Tanquary, A.C. and Lacey, R.E. , eds), pp. 15-71, Plenum Press

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Any suggestions?Although articles published in TIFS are usually specially invited, we welcome ideas from readers for articles on newand develop ing areas. A brief synopsis of the proposal should be sent to the Editor , who can provide more detaile dinformation on manuscript preparation.Reviews focus on promis ing areas of food research that are advancing rapidly, or are in need of re-review in thelight of recent advances or changing priorities with in the food industry. Thus they are shorter t han reviews inconventional review journals, focusing on the latest developments, and speculating on likely future applicationsand research needs.Features are simila r in style to reviews, high light ing specific topics of broad app eal to the food science community.The View point section provides a forum for the expression of personal opinion s, observations or hypotheses, topresent new perspectives and to help advance understandi ng of controversial issues by provoking debate andcomment.Conference Reports hig hlig ht a nd assess importa nt new developmen ts presented at relevant conferencesworldwide.All Review-style articles are subject to editorial and independent peer review by at least two international expertsin the appropriate field.


Controlled Release in Food

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