Recent Applications of Cyclodextrins As Food Additives and in Food Processing

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Send Orders of Reprints at [email protected] Current Nutrition & Food Science, 2013, 9, 00-00 1 Recent Applications of Cyclodextrins as Food Additives and in Food Processing

Katia Martinaa, Arianna Binelloa, Dale Lawsona, Laszlo Jicsinszkyb, Giancarlo Cravottoa* aDipartimento di Scienza e Tecnologia del Farmaco, Università di Torino. Via Giuria 9, 10125 Torino, Italy bCyclolab R&D Laboratory, Illatos ùt 7, H-1097 Budapest, Hungary

Abstract: Nowadays the application of cyclodextrin-assisted molecular encapsulation in foods offers many advantages. Cyclodextrins, their derivatives and their cross-linked polymers can all improve the quality of food in storage, remove specific components and stabilize and increase the presence components that are important for a healthy diet. The application of cyclodextrins and their complexes in packaging materials can help not only transport previously non-transportable foods, but may also prevent, or at least decelerate, the spread of microbial infections. The number of publications, particularly analytical papers, on this matter is constantly increasing. Although the application of modern analytical methods and equipment allows for the quantitation of previously subjectively characterized parameters, bio-sensory methods are still important. The application of cyclodextrins in the nutraceutical industry has many advantages; however, some side effects connected with the inclusion complexation ability of these carbohydrates should lead scientists to study cases on an individual basis. Recent developments in the major fields of cyclodextrin related food research are herein summarized.

Keywords: Cyclodextrin, Food Additives, Food Industry, Molecular Encapsulation.

INTRODUCTION complex formation to affect an advantage. In such a way, inclusion can beneficially increase the solubility and/or sta- Cyclodextrins (CDs) are a group of structurally related bility of guest molecules and may also go some way to con- natural carbohydrates which are formed during the bacterial trolling volatility [5]. CDs are nontoxic, edible (-CD has digestion of starch and were discovered by A. Villiers in been on the GRAS list since 1992), non hygroscopic, chemi- 1891. They are characterized by unique structure and proper- cally stable, easy to separate and readily available. They ties [1]. These cyclic oligosaccharides consist of (1,4)- have attracted the interest of science and industry in various linked D-anhydroglucopyranose units. Nowadays, CDs con- sectors, including the fields of textiles, agricultural and envi- taining up to 39 glucopyranose units have been well charac- ronmental technologies and, being practically nontoxic, they terized. Even 150-membered cyclic oligosaccharides have are also employed in the pharmaceutical, biomedical, cos- been reported, although, in that case it was as a poorly char- metic and alimentary fields [6, 7]. acterized mixture [2]. The most common and commercially available CDs are -, -, and –CDs which are composed of -CD has always been the most commercially successful 6, 7 and 8 glucose units, respectively (Fig. 1) [3]. These CDs of the family, while - and -CD have considerably smaller are conical toroids in shape rather than perfect cylinders be- markets. However, due to their peculiar properties and cavity cause of the chair conformation of the glucopyranose units. sizes, scientific interest in - and -CD is constantly increasing. This is particularly true for the latter which can accom- The hydroxyl functions are oriented to the cone exterior modate large organic compounds such as macrocycles and with the primary hydroxyl groups of the sugar residues at the steroids [8]. The synthesis and the application of modified narrow edge of the cone and the secondary hydroxyl groups CDs have also been well explored and, in fact, the substitu- at the wider edge. The central cavity is lined with the skeletal tion of the hydroxyl groups results in dramatic improvements carbons and glycosidic oxygens of the glucopyranose resi- in aqueous solubility and guest specificity particularly in the dues. This conformation gives this cavity a less hydrophilic case of -CD. Water-soluble CD derivatives of commercial character than the hydroxyl rims, or the aqueous environ- interest include the (2-hydroxy)propyl derivatives of - and ment [4]. As a consequence, CDs can capture hydrophobic -CD (HPBCD and HPGCD), partially acetylated - and - molecules of appropriate dimensions inside their cavities CD, randomly methylated -cyclodextrin (RAMEB), hep- (inclusion complexation). The physicochemical and biologi- takis(2,6-di-O-methyl)--CD (DIMEB), permethylated -CD cal properties of the guest molecule can be altered during (TRIMEB), and sulfobutyl -cyclodextrin sodium salt (SBE- -CD).

The yearly number of publications on the subject of CDs *Address correspondence to this author at the Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino. Via Giuria 9, 10125 Torino, has been steadily increasing over the last 10-15 years, as can Italy; Tel: ------; Fax: ------; E-mail - [email protected] be seen in (Fig. 2). This represents the large, constant interest

OH HO O OH O O OH HO HO O O HO O O O OH O OH HO HO OH OH O O OH HO O OH OH OH O HO HO O O HO HO HO O O HO OH OH O O OH OH OH O -CD -CD OH O -CD O O HO O OH OH OH HO OH OH OH O O O OH O OH OH OH OH OH OH O OH O O O OH OH O HO OH OH O OH OH O O OH OOH O OH HO O OH O O HO O OH OH HO Fig. (1). Chemical structure of CDs.

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0 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

Fig. (2). a) number of relevant publications on CD per year, b) number of Relevant Publications on food application of CD per year (red line: patent, blue line: journal).

Fig. (3). Distribution of Publications from 2000. in the widespread applications of native and modified CDs. solubilize food colorants, to incorporate functional ingredi- The majority of publications deal with complexation related ents (like polyunsaturated fatty acids, vitamins) and to entrap topics while the pharmaceutical and analytical use of CDs or remove undesirable components from products, such as has become a standard methodology (see Fig. 3). Neverthe- bitterness from coffee and tea, milk, ginseng extract, juices, less, one can observe that, over and above these previously etc. Reducing the cholesterol in food is probably one of the described applications, the interest in food applications and major commercial uses of CDs in the food industry. In the polymer synthesis has been growing over the last decade. recent years, an increased number of publications have re- ferred to the immobilization of native CDs and CD deriva- Currently CDs have a wide range of applications in the tives in a number of polymeric supports to create active food industry.Flavor compounds can be complexed by CDs (“smart”) packages. These are based on the controlled re- to protect them against oxidation, light-induced reactions, lease of complexed agents, or the retention of undesirable heat-promoted decomposition, loss by volatility or sublima- food components. The inclusion of bioactive compounds in tion and to ease the impact of undesirable tastes/odors. It is CD cavities has been the cause of a surge in interest from the also true that the selective complexation of components, par- fields of functional foods and nutraceutical components; ticularly of the minor components, may result in an unnatural foods can be designed to prevent nutrition-related diseases taste or scent. CDs are also being used in the food industry to and improve a consumer’s physical and mental wellness [9]. Recent Applications of Cyclodextrins as Food Additives Current Nutrition & Food Science, 2013, Vol. 9, No. 2 3

Table 1. Regulatory Status of the Natural CDs and HPCD.

Cyclodextrin Food Approval Pharmacopeia Monographs US Europe Japan USP/NF Ph. Eur. JPN

-CD “GRAS” Planned Yes Yes Yes Yes -CD “GRAS” Food Additivea Yes Yes Yes Yes -CD “GRAS” Pending Yes In Progress In Progress Yes HPBCD - - - In Progress Yes - a = Commission Regulation (EU) No 1130/2011 GRAS = Generally Recognized As Safe list of the Food and Drug Administration in the USA USP/NF = United States Pharmacopoeia/National Formulary Ph.Eur. = European Pharmacopoeia JPC = Japanese Pharmaceutical Codex

Table 2. General Standard for Food Additives (GSFA) Provisions for -CD.

Food Category Max Level

Chewing gum 20,000 mg/kg Pre-cooked pastas and noodles and like products 1,000 mg/kg Water-based flavored drinks, including "sport," "energy," or "electrolyte" drinks and particulated drinks 500 mg/kg Snacks - potato, cereal, flour or starch based (from roots and tubers, pulses and legumes) 500 mg/kg

This review focuses on the recent applications of CDs in strated that -, , -CDs, including HPBCD and SBE-- food processing; in particular, we intend to summarize rele- CD, are neither mutagenic nor genotoxic [15-17]. Studies on vant publications from 2005 until April 2012 in order to the developmental and reproductive effects of CDs in rats complete the previous review on this topic [10]. demonstrate that -CD and -CD are not embryotoxic nor teratogenic and that HPBCD and SBE--CD caused no teratogenic effects at any dose level [18]. Several in vitro studies REGULATORY ISSUES ON CDS AS FOOD ADDI- reported physiologically adaptive responses that generate TIVES AND USE IN FOOD PROCESSING diarrhea and cecal enlargement in experimental animals CDs, in their wider uses, have applications in many ar- when CDs were administrated orally. A hemolytic effect has eas, including the pharmaceutical, chemical and food indus- also been observed, however, in vivo toxicological implica- tries, which have all seen an increase in interest in recent tions have been considered negligible [19-22]. years. This has lead to numerous studies into the safe use of -, - and -CDs are listed in the generally regarded as these cyclic oligomers, particularly so in the biomedical field safe (GRAS) FDA list for use as food additives and HPBCD [11]. is cited in the FDA list of Inactive Pharmaceutical Ingredi- Because of their bulky and hydrophilic nature, only in- ents (see also Table 1). The recommendations of the Joint significant amounts of intact CDs are absorbed from the gas- FAO/WHO Expert Committee on Food Additives (JECFA) trointestinal tract and any absorption is via passive diffusion. identify the maximum quantity of -CD in foods as 5mg/kg The parent -CD and -CD cannot be hydrolyzed by human per day, while no Acceptable Daily Intake (ADI) was de- salivary and pancreatic amylases, whereas -CD is partly fined for - and -CDs because of their favorable toxicologi- digested by pancreatic amylases. Lipophilic CD derivatives, cal profiles [23-25]. A recent study demonstrated that -CD such as the methylated CDs, are to some extent absorbed can be tolerated in quantities of up to 20% of the diet without from the gastrointestinal tract. The absorbed CDs are essen- any adverse effects [26]. tially excreted in the urine without undergoing significant Updated up to the 35th Session of the Codex Alimen- metabolism. CDs can form inclusion complexes with sub- tarius Commission (2012). -CD (E459) belongs to the func- stances present in the digestive tract (i.e. biliary salts) in a tional classes of carrier, stabilizer and thickener. General reversible manner [12]. Orally administered -CD can cause Standard for Food Additives (GSFA) provisions for -CD a reduced postprandial glucose response and a minor insulin are indicated in Table 2. secretion effect that is similar to that generated by a slowly digested carbohydrate [13]. The metabolism of -CD closely resembles that of starch and linear dextrins. No differences CHOLESTEROL SEQUESTRATION in gastrointestinal tolerance between the oral administration Dietary fats have been implicated in the progression of of 8g -CD and 8g maltodextrin were observed in humans coronary heart disease, and therefore cholesterol lowering [14]. procedures have attracted a great deal of attention ever since Nowadays many publications on CD toxicological tests the link between cholesterol and coronary heart disease was can be found in the literature; recently it has been demon- formally established [27]. Furthermore, the demand for low 4 Current Nutrition & Food Science, 2013, Vol. 9, No. 2 Martina et al. cholesterol food has increased as both the World Health Or- linked to bitterness, during ripening. Not too much differ- ganization and the American Heart Association have rec- ence was found in granularity and spreadability, however, ommended the reduced consumption of saturated fatty acids the smoothness score in the cholesterol-reduced cheese was and cholesterol in the fight to reduce cardiovascular risks. significantly higher than in the control. The authors also re- Butter, cream cheese, ice cream and other dairy products ported rheological and sensory differences during the ripening of cholesterol reduced Cheddar cheese with differing salt are high in cholesterol content because of their principal content levels. component; cream. Despite the existence of a lower cholesterol content alternative in milk, people suffering from hy- The properties of cholesterol reduced ice cream made pertension or atherosclerosis may often desire a cholesterol- with cross-linked -CD with adipic acid and stored at -12, - free product. Of the numerous techniques developed by food 18 and -28 °C were also studied by Ha et al. Acceptability companies to reduce cholesterol in foods, the most effective scores were, generally, highest at -18 °C, although most of method for reducing cholesterol content in dairy produce is the cholesterol-reduced ice cream properties were compara- currently the sequestering action of CDs. -CD’s interaction ble to the control ice cream [36]. Adipic acid cross-linked - with cholesterol has been investigated using molecular dy- CD was also used to produce cholesterol reduced Camem- namics and proved by spectroscopic studies [28]. The nutri- bert, Blue, Feta and cream cheeses. Unlike Cheddar cheese, tional characteristics of animal products such as milk, cream, no significant differences were found in most physicochemi- yogurt, egg, mayonnaise, butter, cheese and lard are im- cal and sensory properties in comparisons with the control proved thanks to this technique [23, 29, 30]. -CD has a cen- [37-41]. The same procedure was also applied to cheese tral cavity which is considerably less polar than the rest of spread and most properties were comparable to the control. the molecule and is also similar in dimensions to cholesterol However, the flavor was not as good and the texture slimier which allows it to form an insoluble inclusion complex that in cholesterol-reduced cheese spread [42]. can be removed by centrifugation. -CD easily absorbs cho- Although many studies reported the use of CDs in the lesterol at temperatures below 4 °C, so that it is effective in removal of cholesterol from dairy foods, the effect of water maintaining the quality of milk. Alonso et al. [31] reported a in encapsulation efficiency and on the stability of sterols in method for cholesterol removal from pasteurized non- complex is relatively unknown. Dos Santos et al. evaluated homogenized milk at 4°C on an industrial scale (15.000 L). the inclusion properties, main encapsulation parameters, the They obtained 65 % to 95% cholesterol reduction by adding stability of cholesterol in -CD and the stability of the com- -CD (0.4 - 1% w/v) after 6h of treatment in a pre-tank plexes as a function of storage time and water content in a shaker in recirculation. The complex was then removed by search for optimal encapsulation conditions [43]. A phase centrifugation. The best results were obtained using 0.6 % - solubility study pointed to the formation of 1:1 stoichiomet- CD, although approximately 0.35% residual -CD was found ric complexes between cholesterol and -CD. This process is in the skimmed milk and 0.15% in the cream. The authors, in exothermic and influenced by temperature changes. The sta- a subsequent publication, investigated the effect of -CD on bility of a freeze-dried complex was studied in different stor- milk fat composition and observed that individual fatty acid age conditions. and triglyceride composition did not change in treated milk. In particular trans C18:1 fatty acid isomers, conjugated lino- Park et al. have determined the effects of dietary -CD leic acid, polyunsaturated fatty acids (PUFA) and phosphol- on the cholesterol content of egg yolk [44] in an attempt to ipids do not undergo significant changes when -CD is used raise the prospects for the production of healthier functional for the removal of cholesterol in pasteurized milk. It can foods. 2%, 4% or 6% dietary -CD concentration solutions easily be said that this process maintains the quality of the were added to the hens’ feed and the observations indicate milk [32]. Recently Dias et al. evaluated the removal of but- that appropriate supplementation of the hens’ diets with - ter cholesterol using three complexation -CD based meth- CD can significantly reduce the cholesterol content of egg ods; co-precipitation, kneading, and physical mixture. Co- yolks. precipitation, based on the addition of the guest to a stirred solution of CD, was found to be the best protocol. A photo- PRODUCT STABILITY AND FOOD PRESERVA- acoustic spectroscopy technique was used to analyze the TIVES – IMPROVING SHELF LIFE results and it was shown, for the first time, that the process The ability to control browning during the various stages does not extract fatty-acids, it also showed that the amount of of food processing is important for the preservation of the -CD needed can be reduced [33]. organoleptic and nutritional properties of food products. A cross-linked -CD made with adipic acid was used to Color is a sensory property that has a strong influence on reduce cholesterol in butter [34]. A 90% reduction level was food acceptance. The degree of browning depends on the reached using the 10% cross-linked -CD treatment and no presence of oxygen, reducing substances, metallic ions, pH, significantly adverse effects on the chemical, rheological and temperature and the activity of a number of oxidizing en- bio-sensory properties of the butter were observed. The same zymes (among them polyphenol oxidase (PPO)) and light. procedure was applied to Cheddar cheese; 91-92% choles- CDs have emerged, in recent decades, as a means to control terol reduction was observed and no change was found in fat the PPO caused enzymatic browning of various foods. and protein content in a primary study. Subsequently, an Nicolás et al. monitored the color of fresh pear juice in the increase in moisture content, which resulted from slow curd presence of some natural and modified CDs and observed drainage, was usually observed in reduced-fat Cheddar that the stabilizing effect of CDs on ascorbic acid is respon- cheese, as were accelerated ripening times [35]. -CD treat- sible for its affect [45]. A more specific study into the effects ment resulted in enhanced proteolysis, which is directly of the addition of -CD on the pear juice quality showed that Recent Applications of Cyclodextrins as Food Additives Current Nutrition & Food Science, 2013, Vol. 9, No. 2 5 the addition of -CD at 15 mM significantly increases global In horticulture, pre- and post-harvest applications of juice quality by reducing browning without any significant methylcyclopropene (MCP) and ethylene were studied in an changes to the aroma [46]. The use of CDs was also studied attempt to maintain production quality [60]. Pre-harvest - to slow the enzymatic browning of apple juice, fresh banana CD-MCP complex application in “stark spur golden” apples, juice and peach juice and several differences were found. seven days before the harvest time, showed good results Kinetically modeled apple juice enzymatic browning in the when fruit flesh firmness, soluble solid quantity and fruit absence and presence of maltosyl--CD was used to clarify skin color were measured as parameters [61]. The encapsula- the controversy that exists in the literature about the mecha- tion of ethylene into -CD for subsequent controlled release nism of enzymatic browning [47-49]. In peach juice, -CD provided some benefits, especially in fruit ripening and other was incapable of inhibiting the enzymatic browning, how- aspects linked to plant growth regulation. The characteriza- ever, -CD presented the highest affinity constant with tion of ethylene--CD complex physicochemical properties diphenols [50]. The evolution of several fresh banana juice at various gas quantities was carried out in order to establish color parameters in the presence of various CDs was the ex- maximum loading level [62]. act opposite of what has been found in other fruit juices. In The ability of CDs to include molecules with antibacte- fact, the ability of CDs to complex the natural browning in- rial activity has been studied in depth. Inclusion complexes hibitors present in banana and its inability to complex dopa- present many advantages; gaseous, antibacterial, unstable mine, a main PPO substrate, means that a recognized anti- and insoluble molecules can be handled and stabilized. The browning agent, such as CD, can be converted to a pro- efficacy of these compounds can be also improved by the browning agent in banana juice [51]. A combination of -CD slow release achieved by complexation. Many examples in and 4-hexylresorcinol (HR) and methyl jasmonate (MJ) was the literature refer to the inclusion of volatile antimicrobials. also studied. The -CD-HR mixture showed a positive syn- Garlic oil has antimicrobial activity but its volatility and ergic effect on PPO [52]. Alternatively, randomly methylated strong odor can cause problems for handling and sensorial -CD Cavasol W7M, which is both bulk-commercialized acceptability. Its encapsulation in -CD was undertaken in and cheap, can be employed as an anti-browning agent in order to obtain a natural microbial agent controlled release virtue of its ability to chelate several naturally occurring and system and it was tested on microbial growth and sensory synthetic PPO o-diphenolic substrates [53]. quality in freshly-cut tomatoes [63]. The encapsulated garlic Besides color, aroma also plays an important role in con- oil lead to reduced microbial growth and the highest tomato sumer satisfaction. For this reason a study into the intensities sensory quality in this study of natural oil treatments. Cin- of odor and aroma on the global quality of pear juice in the namon leaf and garlic oils were encapsulated with -CD and presence of different concentrations of -CD was studied. At antifungal activity against Alternaria alternate was success- high CD concentrations, the pear juices possessed the best fully proved [64, 65]. color but produced reduced aromatic intensity and low sen- Allyl isothiocyanate, a major pungent compound in sory quality in general. On the other hand, the addition of - plants of the Cruciferae family, has strong antimicrobial ac- CD at 15 mM lead to the best appreciated juice [54]. The tivity in its vapor form, but its application in food systems is main sensory parameters of pear juice were also studied by limited. The complexation of allyl isothiocyanate by - and comparing the effect of -, -, and -CDs [55]. -CD was -CD and its controlled release characteristics were investi- identified as the best additive because it significantly in- gated by Li et al. [66]. In a separate study, hexanal was increases the global quality of pear juice and reduces its serted into -CD to develop a controlled release mechanism, browning without significant changes in aroma. -CD gave and then evaluated in vitro against Colletotrichum acutatum, the lowest total volatiles concentration and the global quality Alternaria alternata and Botrytis cinerea, the three main of juice with -CD was good but not the best. The combina- causes of post-harvest diseases in berries. Results showed tion of blended carrot-orange juice with HPBCD was also that the -CD-hexanal complex was able to reduce or com- studied as a means of avoiding carotene loss during the clari- pletely eliminate post-harvest berry diseases thanks to its fication process. As a demonstration of its effect, the addi- capacity to provide antifungal volatiles during storage, dis- tion of HPBCD prior to clarification resulted in a threefold tribution and consumer purchase [67]. increase in carotene content over the clear juice [56]. Plant essential oils show some level of antimicrobial ac- The effects of -CD addition on the quality of pre- tivity and can be used as safe alternatives to sodium benzo- cooked, vacuum packed potatoes were also studied. Color ate, but many exhibit poor solubility in aqueous solutions. parameters, microbial decay, resistant starch content at vari- Complexes with - and -CD were tested both in water and ous storage times and fat content after frying were studied. in apple juice and showed increases in solubility that were up The CD appeared to ensure greater brightness factor stability to ten fold [68]. Even cinnamic acid, a natural protection and a generally more attractive appearance, however, aerobic against pathogenic organisms, was solubilized by inclusion mesophilic bacteria growth was observed. Nutritionally, the into -CD. The antimicrobial efficacy of the -CD-cinnamic effect of -CD on the resistant starch content of potatoes acid inclusion complex against Escherichia coli O157:H7 may be related to storage time [57]. The addition of Na+ and and Salmonella enterica in apple cider or orange juice at two -CD to the whey protein coating solution of freeze-dried different incubation temperatures indicated that it can be strawberry pieces was also studied in order to evaluate their considered an alternative to traditional heat processes [69]. ability to improve the hydration capacity of the fruit and to Cevallos et al. have studied and characterized the inclusion protect its color [58]. -CD addition to pasteurized pineapple complexes of thymol and cinnamaldehyde [70] and the en- juice was beneficial in reducing the crystallization rate of capsulation of antifungal volatile constituents of thyme es- added sugar and hygroscopicity of the juice powder [59]. 6 Current Nutrition & Food Science, 2013, Vol. 9, No. 2 Martina et al. sential oil in -CD in order to create a system in which natu- slower plasticizer leaching from the polymer matrix. A de- ral antimicrobials undergo controlled release [71, 72]. tailed study into the morphological, thermal and barrier properties of an ethylene-vinyl alcohol copolymer that in- The potent antimicrobial and antifungal stilbenoid pino- cludes -CD was proposed by Lopez-de-Dicastillo et al. sylvin was complexed with natural (-, -, -CD) and modi- [81]. The authors showed that the films were continuous and fied (HPBCD, RAMEB, ethyl--CD) CDs in a 1:1 transparent and that their thermal properties did not change stoichiometric ratio [73]. Although the pinosylvin interaction upon -CD inclusion. However, it was noticeable that the was more efficient with -CD than with - or -CD, the presence of -CD increased the film’s apolar organic com- complex stability constants were high with all the modified pound sorption capacity, thus confirming their usefulness in CDs and especially so with HPBCD. This kind of complexa- active packaging design. Subsequently, in a second publication may well become very useful in intelligent packaging and nutraceutical applications as it improves stilbenoid bioa- tion, the same group used these materials with real food products in order to reduce the levels of undesired compo- vailability. In the same study, complexes between HPBCD nents. The films were successfully used to reduce the choles- and other efficient stilbene derivatives, such as complexes terol content of milk via direct contact with the packaging with resveratrol, were reported. films. It was demonstrated that they reduced the presence of It is known that carbohydrates cause a number of affects oxidation byproducts (aldehydes obtained from oxidative on starch functional properties. They can influence swelling, processes) in the package headspace of fried peanuts leading gelatinization, pasting and retrogradation. Usually, these to a 50% reduction in the presence of hexanal over a short properties are not optimal in native starch, and thus need to period (1-5 weeks), beyond which the films were exhausted be modified by various techniques to suit the relevant end [82]. Lopez-de-Dicastillo et al. [83] added CDs to glyoxal product. Tian et al. reported that the addition of -CD slows cross-linked polyvinyl alcohol, using different procedures, to short-term rice starch retrogradation via amylose- -CD obtain polyvinyl alcohol/-CD composite films. The objec- complex formation [74]. An increase in granular swelling, tive of this study was to prepare a biodegradable material amylose leaching and native and heat-moisture treated that is resistant to water and actively helps retain undesirable wheat, potato, cereal, tuber and root starch solubility was compounds in the package walls during food storage. As demonstrated by Gunaratne et al. in the presence of -CD reported with other films, the study demonstrated a signifi- and HPBCD (these effects are consistent with the disruption cant reduction in the milk sample cholesterol concentration of the amylose-lipid complex) [75-77]. The potential impact when they were exposed to these materials. Various polylac- of -CD on the retrogradation of wheat starch or wheat flour tide biodegradable biopolymers, derived from renewable induced interest in a study into the effect of -CD addition resources, were prepared, characterized and evaluated by on bread staling. In this study, texture profile analysis, X-ray Plackett et al. [84]. The study tests indicated that a CD- diffraction and a differential scanning calorimeter showed encapsulated antimicrobial species (allyl isothiocyanate) that the slowing effect of -CD on bread staling is significant incorporated into L-polylactide–polycaprolactone co- and that smaller changes in hardness, cohesiveness and polymer films would be effective in controlling fungi on springiness were observed over the storage period [78]. packaged cheeses. Another example of biodegradable and bio-based materials containing -CD mixed with polymers PACKAGING (poly(lactic acid) in this case) has been proposed by Joo et al. [85]. In this study, the relevant properties of the polymer Over the past decade, an emerging field of interest in were studied and it was found that poly(lactic acid) is in- CDs is their application in the release of active components compatible with -CD. The addition of -CD, in the form of from active, controlled and intelligent packaging. The prom- a master-batch (pellets containing 30% -CD content), nota- ulgation of European Commission Regulation 1935/2004 on bly reduced these effects and increased the compatibility of materials and articles intended to come into contact with poly(lactic acid) and -CD. food facilitated the development of controlled release packaging concepts (Regulation EC N° 1935/2004 of the Euro- The use of CDs to carry antimicrobial compounds is an pean Parliament and of the Council of 27 October 2004, Di- important objective for the active packaging field. Inside a rectives 80/590/EEC and 89/109/EEC. Official Journal of the CD, an inclusion complex can be easily manipulated without European Union L 338:4-17). Many publications refer to the loss in activity and the high concentrations of the antimicro- successful application of CDs in polymer syntheses in aque- bial compounds (traditionally essential oils) do not interact ous solution [79], and also to the study of relevant properties with the food at once. Usually, both the complexation proc- of CD containing films. The preparation of CD containing ess and reverse case, controlled release, require the presence polymers has been studied, by those working in the alimen- of water. Ayala-Zavala et al. suggested and confirmed that tary field, with the aim of including complexed antimicrobial the high relative humidity in packages of fresh-cut fruit or and antioxidizing compounds in them. In 2007 Fenyvesi et vegetables, which usually causes microbial spoilage, can be al. described the pilot scale production of CD-containing used as an advantageous trigger to deliver antimicrobial polyvinyl chloride (PVC) and polyethylene (PE) films [80]. compounds from CD containing packaging systems [86]. In The permeation properties of these films were characterized fact, the release of -CD complexed allyl isothiocyanate using model flavors like carvone, vanillin, and diacetyl. The from electrospun fibers of a soy protein isolate/poly (ethyl- results suggested that the CD cavities within the film are able ene oxide) blend and poly(lactic acid) is negligible under dry to form inclusion complexes enabling the penetration of sub- conditions, but increases with increasing humidity. In this stances, which otherwise do not penetrate through the film. case the release of active compounds can be achieved via the In addition, the presence of -CD in the film results in control of the relative humidity of the system. Furthermore, Recent Applications of Cyclodextrins as Food Additives Current Nutrition & Food Science, 2013, Vol. 9, No. 2 7 this study suggests that the CDs appear to protect the antimi- Although we expect certain foods to be bitter, bitterness crobial compound from evaporation loss during the electro- is one of the main reasons why certain foods are rejected. spinning process, and that increasing allyl isothiocyanate Furthermore, certain foods have peculiar odors or flavors loading can affect controlled release behavior [87]. Raouche that are not always appreciated by consumers. Minimizing et al. [88] used the same bio-sourced poly(lactic acid) based the bitterness of food products can enhance palatability and film to separately carry carvacrol and allyl isothiocyanate in result in more favorable products. CDs can be used to re- the presence of -CD. Their antimicrobial properties were move or mask these undesirable components. assessed on Botrytis cinerea during storage and after high Cross-linked insoluble CD polymers obtained from the pressure “pasteurization-like” treatment. -CD was useful in reaction of -CD with diphenyl carbonate, epichlorohydrin protecting the antimicrobial species against thermal degrada- or hexamethylene diisocyanate were tested for activity as tion and controlling its release from the films during use, and sequestering agents for naringin and naringenin and other therefore, the films showed significant activity against the macromolecular water soluble derivatives. Water-soluble bacteria. According to the microbiological hurdle concept, CD-grafted carboxymethyl chitosan and carboxymethyl cel- films containing antimicrobial agents can also be used to lulose were used to de-bitter aqueous solutions of caffeine, produce shelf-stable foods. Films containing Cryptococcus naringin and limonin [96]. Likewise the use of a -CD laurentii in combination with alginate, glycerol, palmitic polymer was proposed by Mongkolkul at al. as a means to acid, glycerol monostearate and -CD were prepared and de-bitter Thai tangerine Citrus reticulata Blanco juice [97]. some strawberries were observed. The study showed no The incorporation of ginseng into drinks is possible only changes in external color parameters but significantly re- after treatments that minimize its bitterness. - and -CD duced microbial decay, decreased weight loss, improved fruit were selected as the most efficient complexation agents for quality and storage properties and, finally, the fruit main- this task in a pilot study. The production of a ginseng con- tained its firmness better [89]. The microencapsulation of taining energy drink using this method has been described by Lactobacillus acidophilus, used as a probiotic, increases its Tamamoto et al. [98]. The capability of -CD to form mo- survival rate, extends product shelf- life and improves dis- lecular inclusion complexes with lipophilic molecules can be pensability in the final products. As a wall material, a mix- exploited to solve the off-flavor problem in soy protein that ture of -CD and acacia gum (9:1) at a concentration of 20% is caused by autoxidation during storage of PUFA and resid- (w/v) gave round and oval microcapsules of relatively uni- ual phospholipids as well as to mask the bitter taste of ami- form size with L. acidophilus cells located in the center [90]. noacids liberated in solution from the protein lisate. In fact, a As has already been reported, -CD has been used to -CD based process has been described by Arora and Damo- carry MCP and enable its controlled release in order to main- daran who achieved 99% phospholipid and free fatty acid removal by using a combination of treatments involving tain fruit and vegetable quality. The -CD-MCP complex was incorporated into several common packaging films by sonication, phospholipase A2 and -CD [99]. Linde et al. studied amino acid affinity for the -CD cavity and demon- heat-pressing and solution-casting methods. The release of strated its potential in de-bittering protein hydrolyzates in MCP from the films allowed several physico-chemical pa- acidic beverages [100]. A different approach based on some rameters to be quantified and the results suggested that both sensory evaluations of bulk fish oil and reconstituted micro- the polymer processing method and temperature strongly encapsulated fish oil was published by Y. Serfert et al. [101]. affect the release properties [91]. A sensory panel specifically trained in fish oil-containing Natural antioxidants and their cyclodextrin inclusion matrices was employed to determine the lipid oxidation complexes may play a dual role in packaging; firstly, they status, the hydroperoxide and volatile secondary lipid oxida- protect the polymer from oxidative degradation during melt- tion product content of the microencapsulated oil. The influ- processing, and secondly, they delay the onset of packaged ence of flavor compounds and -CD on the odor quality of food oxidation during storage. For this reason, Sirò et al. reconstituted microencapsulated fish oil was investigated and investigated the inclusion and release of -tocopherol from the study demonstrated that -CD improved odor quality -CD in low-density polyethylene [92]. The study revealed while the addition of flavor compounds effectively increased that -CD has a significant effect on the release rate and the its palatability. Two studies [102, 103] refer to the encapsu- migration profile of the antioxidant into a fatty food stimu- lation of fish oil ingredients in the beverage industry or as lant, highlighting how complexation might be key to a long- food seasoning, for example, in fish sauce, by spray drying lasting antioxidant effect in active packaging. - or by spray granulation with CD but, unfortunately, CDs do Tocopherol/-CD and quercetin/-CD complexes were also not show acceptable results. Anwar et al. investigated a pro- included in linear low-density polyethylene and their great duction process based on spray granulation followed by film potential to stabilize polymers from oxidative degradation coating. Oil was emulsified with soluble soybean polysac- was also confirmed [93-95]. charide and maltodextrin to produce 25% oil powders, then a 15% film coating of HPBCD was applied to the granules. TASTE MODIFIERS The results obtained suggest that this film coating ineffec- tively protects fish oil as the coating process may induce Flavor plays an important role in consumer satisfaction further oxidation. Another publication of note is a compari- and influences further consumption of foods. Commercial son between freeze-dried fish oil in encapsulated complexes processes that remove unpleasant tastes or smells are needed. with -CD or polycaprolactone [104]. Fish oil release rates at However, it is important that the nutritional value of prod- different relative humidity and storage temperatures showed ucts not undergo changes. that better results were achieved with polycaprolactone 8 Current Nutrition & Food Science, 2013, Vol. 9, No. 2 Martina et al. rather than with -CD. This is principally due to its water and nutraceutical industries thanks to their ability to protect insolubility. Additionally, olive biophenol complexes, well against several diseases. CD inclusion has been studied as it known antioxidant agents and radical scavengers, decreased appears to be a promising way to include, protect and per- the strength of the bitter taste and, at the same time, pre- form the controlled release of these active components. An served the bioactive compounds against chemical and physi- example of this is orange juice; it is well known that intense cal decomposition reactions [105]. thermal treatment, such as pasteurization, adversely affects the nutritional and sensory quality of this fruit juice and that CDs (particularly -CD) have been studied as a means to the addition of -CD causes significant loss of product qual- encapsulate flavors. Reineccius et al. investigated the incor- ity to be avoided. Furthermore, Navarro et al. [114, 115] poration and retention, during storage, of a variety of spray- studied the effects of the addition of -CD or HPBCD (1%) dried flavor/natural CD complexes [106]. The apparent sta- on the protection of antioxidant compounds in mandarin bility constants of 14 different flavors with -CD and -CD juices enriched with pomegranate extract and goji berry were determined by Astray et al. [107], while an optimiza- juice. Experimental data, after 145 days storage at room tion study into the microencapsulation of pine aroma spray temperature, showed that -CD addition did not cause any drying showed that a mixture of maltodextrin -CD dis- improvement over the control juice, whereas the benefits of played less dispersibility than a maltodextrin-gum arabic HPBCD addition to this particular juice were evident in al- mixture [108]. Mixtures of -CD and HPBCD have been successfully exploited for flavor retention in spray-dried rice most all studied parameters. The HPBCD treated juices presented the highest values of color intensity, antioxidant activ- flavor powders that also contain 2-acetylpyridine, benzyl ity, vitamin C content, retinol equivalents and overall qual- alcohol, palmitic acid, and stearic acid [109]. Another appli- ity. The solid inclusion complex can also be used for the cation of CDs as flavor retainers can be found in the release formulation of functional foods or as a food supplement. of (–)-menthol from various encapsulating powders in chew- With this aim in mind, important flavonoid antioxidant ing gum. Tests were run to study the release kinetics of (–)- menthol from these powders and the results demonstrated products have been encapsulated in -CDs. Detailed studies into the stability of the galagine complex with three different that the -CD complex powder provided longer (–)-menthol CDs, -CD, HPBCD, and DIMEB were carried out [116]. retention than the -CD complex powder and (–)-menthol Flavonoid dihydromyricetin forms an inclusion complex encapsulated in modified starches [110]. Similarly, a terpene with HPBCD that significantly improves its poor stability mint flavor, pulegone, which is obtained from the essential and solubility in water, whilst an extract of Hypericum per- oils of a variety of plants and is permitted as a food additive at low concentration (<1%), has been encapsulated in - and foratum (St John’s wort) which is rich in flavonoids, showed better stability when included in -CD using a freeze-drying -CDs [111]. protocol [117, 118]. A molecular dynamics simulation study and experimental The utilization of encapsulated polyphenols instead of ultraviolet spectrum were used to determine the structure of free compounds can overcome the drawbacks of their insta- the most stable complex between -CD and 2-phenylethyl alcohol, a popular flavor commonly used as crude rose oil bility, alleviate unpleasant tastes or flavors as well as improve the bioavailability and half-life of the compound in and orange oil in food and cosmetics [112]. Clove oil, a clear vivo and in vitro [119]. The encapsulation of an olive leaf yellow liquid with a characteristic aromatic odor that has extract, rich in oleuropein, was achieved and an inclusion been extensively used as a flavoring agent by the food indus- complex with -CD formed when the components were try, has also been included in -CD. Seeing as it is a semi- mixed in aqueous media and subsequently freeze-dried [105, natural mixture, mainly comprising 4-allyl-2- methoxyphenol, a detailed investigation of its thermal de- 120]. Various stilbenoids that all present high antioxidant activity, such as resveratrol, oxyresveratrol, pterostilbene and composition behavior was investigated by P. Xu et al. [113]. pinosylvin were complexed by natural and modified CDs in a series of studies [121, 122]. It was shown that the poor NUTRACEUTICAL CARRIERS – FUNCTIONAL stability, bioavailability and solubility of trans-resveratrol FOODS can be ameliorated by complexation with -CD. The effect The effectiveness of nutraceutical products in preventing of the complexation on its antioxidant activity was validated diseases depends on preserving the bioavailability of the by means of the oxygen radical absorbance capacity method, active ingredients. Only a small portion of the molecules using fluorescein as the fluorescent probe. Based on these remain available following oral administration because of results it can be said that resveratrol can be successfully used their insufficiently long gastric residence times, low perme- in the food industry as a functional food ingredient [123, ability and/or solubility within the gut as well as their insta- 124]. An inclusion complex of trans-ferulic acid with bility under conditions encountered in food processing and HPBCD was prepared using the freeze-drying method in a storage (temperature, oxygen, light) or in the gastrointestinal stoichiometry of 1:1 [125]. Phase solubility studies showed tract (pH, enzymes, presence of other nutrients). All of these that the acid displayed improved water solubility and its irra- factors limit the activity and potential health benefits of nu- diation induced decomposition in aqueous solution was traceutical components. The delivery of these compounds markedly reduced. The all-trans-lycopene obtained from therefore requires the development of protective mechanisms tomatoes was encapsulated in -CD using a supercritical that can keep the molecule active until it is consumed, and fluid and a freeze-drying process [126, 127]. The complexa- delivered, unchanged, to the physiological target within the tion of retinoids with molecular carriers, such as CDs and organism. Dietary intake of natural antioxidants has recently proteins can also improve their stability, as demonstrated by been the focus of high level attention in the functional foods Yap et al. [128]. Recent Applications of Cyclodextrins as Food Additives Current Nutrition & Food Science, 2013, Vol. 9, No. 2 9

Astaxanthin is related to other carotenoids such as - IMPROVING SOLUBILITY – COLORANTS carotene and has antioxidant activity that is equivalent to The complexation of natural colorants with CDs has about 550 times that of -tocopherol. Many publications many different applications; these include stabilizing effects, refer to the preparation of astaxanthin inclusion complexes increasing water solubility and color intensification. In fact, and the best results have so far been achieved with -CD. the complexation methods and the stability of curcumin and Studies revealed that complexation enhanced water- bixin complexes in -CD were evaluated by Marcolino et al. solubility, up to 110 fold, at pH 6.5 and 25°C and that stabil- who predicted their use in the food industry [142]. Analo- ity against heat, light and oxidation was enhanced 7-9 fold gously, hypocrellin A, a natural pigment with a bright red [129-131]. color, showed much better water solubility and dissolution Conjugated linoleic acids (CLA) have been shown to properties when complexed with HPBCD than when it was possess antidiabetic, antiadipogenesis and anticarcinogenesis in its free form [143]. -CD was successfully employed to effects, among others. However, they are extremely unstable prevent the light-caused-fading of a mixture of phycoerythrin in air because they are susceptible to oxidative degradation. and phycocyanin extracted from discolored nori seaweed and Good nanoparticle thermal stability can be observed in CD to assess its usefulness as violet food coloring [144]. In fact, complexes, especially for the linoleic acid/-CD complex -CD can be used to protect the fluorescent groups necessary [132]. Encapsulation in -, -, and -CDs completely pro- for the development of fluorescence based detection chemo- or bio-sensors which can recognize mycotoxins in the agro- tected CLA from oxidation [133]. A comparative study be- food industry [145]. tween complexes of CLA with -CD and those with amylose was carried out by Yang et al. with the intention of indirectly The stability of anthocyanin pigments encapsulated with understanding how amylose and -CD interact with each different carrier agents, including maltodextrin/-CD, was other in the food system. The amylose-CLA complex evaluated in an isotonic soft drink model system (Cabernet showed a better antioxidative protection effect on CLA than Sauvignon grapes) under different light and temperature the -CD-CLA complex which supports the strong complex- conditions [146]. Despite the promising results obtained with ing interaction between CLA and amylose shown by ther- maltodextrin/-CD, better anthocyanin protection was mogravimetric analysis. An amylose-CD complex could be achieved with maltodextrin/arabic gum encapsulation. used to improve the delivery efficiency of CLA and other bioactive compounds [134, 135]. Furthermore, as previously CONCLUSION described, CD inclusion has been studied and employed to The yearly number of publications on the subject of CDs mask the taste and smell of polyunsaturated fatty acids con- has been steadily increasing in recent years. This represents tained in fish oil [101-105]. the widespread and constant interest in the numerous appli- The stability of Coenzyme Q10 (CoQ10) in some forti- cations of native and modified CDs. As has already been fied products, (fruit-based products, milk, and yoghurt) that mentioned in the previous review [10], the use of CDs in were enriched in water-soluble inclusion complexes of food is still growing. In particular, functional foods and CoQ10 and -CD, was studied by Pravst et al. [136]. In- packaging are a true emerging area of interest. creased water-solubility and dispersibility were observed which allow the fortification of aqueous products, whilst an CONFLICT OF INTEREST improvement in the pharmacokinetic parameters over crys- The author(s) confirm that this article content has no con- talline CoQ10 was observed by Hatanaka et al. [137]. flict of interest. CDs can also be employed to include inorganic salts. ACKNOWLEDGEMENTS With this aim in mind, Valente et al. [138] demonstrated that the presence of -CD leads to an unexpected effect on the The authors are grateful to Regione Piemonte (Project transport properties of the aqueous solutions of calcium lac- NUTRATEC 2009) for financial support. tate, a nutrient supplement applied to manage, treat and prevent calcium deficiency. The study observed an increase in REFERENCES the effective concentration of calcium lactate in solution [1] Villiers A. Sur la transformation de la fécule en dextrine par le which contributed to an increase in the diffusion coefficients. ferment butyrique. Compt Rend Fr Acad Sci 1891; 112: 435-8. [2] Endo T, Ueda H. Large-ring cyclodextrins-recent progress. FA- The sequestering activity of -CD toward cholesterol has BAD J Pharm Sci 2004; 29: 27-38. also been used in synergy with the presence of nutraceutics. [3] Szejtli J. 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