2. Plant phytochemicals: brief introduction to polyphenols and essential oils

Plants are a remarkable source of biologically active compounds with potential applications in cosmetic, pharmaceutical, and food industries. Among the bioactive compounds synthesized as secondary metabolites by plants, phenolic compounds are probably the most relevant ones. Physiologically, they play a vital role in plant protection and contribute to plant odors, plant pigmentation, and/or their flavors. Structurally, phenolic compounds have, at least, one aromatic ring, with one or more hydroxyl groups attached [9]. The great diversity of phenolic compounds present in nature (i.e., more than 8000 different structures have been identified up to now) results from variations in the basic chemical skeleton (e.g., degree of oxidation, hydroxylation, methylation, glycosylation, and conjugation with further molecules, particularly lipids, proteins, other phenolics, and biomolecular metabolites) [9]. Phenolic compounds are grouped by the number of phenol rings they contain and the structural elements that bind these rings to another; flavonoids, phenolic acids, tannins, stilbenes, and lignans are examples of important representatives of these groups [10].

On the other hand, plant essential oils (EOs) are mixtures of numerous highly complex volatile compounds (hydrogenated and oxygenated monoterpenes, sesquiterpenes, phenols, simple alcohols, ketones, coumarins, etc.) present in variable concentrations whose aroma depends on the individual constituents present [11]. Due to their natural properties, EOs have been used as therapeutic remedies and flavoring agents since ancient times. In the last decades, many investigations showed that EOs have a wide range of valuable biological activities, such as antimicrobial, herbicidal, insecticidal, antioxidant, etc.

Although many investigations demonstrated the broad range of biological activities of many phytochemicals, they still have restricted applicability as pharmaceuticals or in food products due to their poor water insolubility and bioavailability, high volatility, rapid oxidation, or degradation when exposed to environmental factors. New approaches have been developed to overcome these drawbacks, and among them, CDs have been suggested as excellent vehicles for the protection of phytochemicals for food and drug delivery proposes [12–14].

#### 2.1. Interaction between phytochemicals and cyclodextrins

1. Cyclodextrins: general considerations

conversion, packing, textiles, and food domain [1, 5].

volatilization, rapid oxidation, destruction by light, etc. [8].

complex is stable.

70 Cyclodextrin - A Versatile Ingredient

oils

Due to its structure, cyclodextrins (CDs) readily form inclusion complexes through noncovalent interactions with molecular guests. The lipophilic cavity of CDs provides a microenvironment into which appropriately sized nonpolar moieties can enter. The hydrophobicity of the cavity enables the accommodation of a broad range of hydrophobic guests such as the alkyl chains of surfactants or different phytochemicals [1]. The hydrophilic exterior usually imparts CDs and their complexes, considerable solubility in water. The charge and polarity of the guest molecule play also an important role in the CD-substrate host-guest interaction [2]. However, this aspect is obviously less important than the geometric fitting. In the case of the charge, the complexation of neutral molecules is easier than the ionized counterpart. In general, molecules can be encapsulated by CDs when they are less hydrophilic or less polar than the solvent and when the formed

The main driving force for the formation of the complex is the release of enthalpy-rich water molecules from the cavity; water molecules are displaced by more hydrophobic guest molecules present in the solution to achieve the apolar-apolar interactions and decrease of CD ring strain resulting in a favorable lower energy state. The beneficial modification of guest molecular properties after the formation of the inclusion complex leads to a large number of applications in areas as diverse as encapsulation of active substances (i.e., flavoring agents, metallic cations, fragrances, and pesticides), enzymatic synthesis, catalysis, and energy transfer studies [3, 4]. Additionally, CDs also find important uses in cosmetics, environment protection, bio-

Less than 10% of all produced CDs and CD derivatives are used by the pharmaceutical industry. The largest CD users are the food and the cosmetic industry. CDs have a high level of biocompatibility, are absorbed in the gastrointestinal tract, and are completely metabolized by the colon microflora [6]. Some of them are approved by the Food and Drug Administration or have been accredited as being "generally recognized as safe" (GRAS) [7]. In the cosmetic area, CD performance stands out in the following: solubilize and stabilize specific sensitive components, stabilize emulsions, improve the absorption of active components onto the skin, reduce or eliminate bad aromas from certain components, and reduce the loss of the active components through

2. Plant phytochemicals: brief introduction to polyphenols and essential

Plants are a remarkable source of biologically active compounds with potential applications in cosmetic, pharmaceutical, and food industries. Among the bioactive compounds synthesized as secondary metabolites by plants, phenolic compounds are probably the most relevant ones. Physiologically, they play a vital role in plant protection and contribute to plant odors, plant pigmentation, and/or their flavors. Structurally, phenolic compounds have, at least, one aromatic ring, with one or more hydroxyl groups attached [9]. The great diversity of phenolic According to a recent review by Suvarna et al., there are many phytochemicals whose solubility, bioavailability, or therapeutic activity is significantly improved by complexation with CDs (e.g., quercetin, curcumin, artemisinin, resveratrol, naringenin, etc.) [12]. The methods used for the formation of inclusion complexes between CDs and bioactive compounds are essentially neutralization, slurry, solution, coprecipitation, kneading, and grinding [15].

The encapsulation of phytochemicals with CDs usually involves the formation of 1:1 inclusion complexes with the most versatile CD, the β-CDs, and its derivatives. These derivatives can be classified according to their interaction with the water molecules in hydrophilic, hydrophobic, and ionizable derivatives [13]. Examples of used hydrophilic β-CDs are the methylated β-CDs—2,6-dimethyl-β-CD (DM-β-CD) and 2,3,6-trimethyl-β-CD (TM-β-CD) the hydroxyalkylated β-CDs such as 2-hydroxypropyl-β-CD (HP-β-CD), and the branched β-CDs, glycosyl-β-CD (G-β-CD). These molecules are suitable for the formation of host-guest inclusion complexes with poor water-soluble compounds. On the other hand, the hydrophobic derivatives, such as the alkylated β-CD 2,6-diethyl-β-CD (DE-β-CD), are used to decrease and modulate the released rate of water-soluble molecules. Finally, the ionizable β-CD can enhance the dissolution rate and the inclusion capacity and even decrease the side effects of some molecules [16, 17]. Among the ionizable CDs, O-carboxymethyl-β-CD (CM-β-CD), O-carboxymethyl-O-ethyl-β-CD (CME-β-CD), and sulfate and sulfobutylether-β-CD (SBEβ-CD) should be highlighted.

Owing to their potential health promotion effects particularly the antioxidant, anti-inflammatory, and antimicrobial properties, one of the actual promising applications of phenolic compounds is their use in the food industry as additives, e.g., in the development of functional foods. Nevertheless, the efficacy of these natural compounds is dependent on the preservation or improvement of their stability, bioactivity, and bioavailability [18]. Inclusion complexation with CDs improves water solubility of phenolics and enhances their shelf life and biological activity [15]. Additionally, it has been shown that the inclusion of phenolic compounds (e.g., hydroxycinnamic and chlorogenic acids) with CD (β-CD) strongly limited their interactions with proteins, which is important regarding the use of phenolics as food additives [19, 20]. Note that the interactions of these compounds with proteins, frequently added to functional foods to improve nutritional value and proper texture characteristics, often decrease the bioavailability of both proteins and phenolics [21].

organoleptically acceptable levels and even providing controlled release-rate kinetics. Recent studies encourage the use of CD-EO (e.g., β-CD/Satureja montana EO; γ-CD inclusion complex encapsulated electrospun zein nanofibrous webs/thymol) complexes as part of active packaging systems [30, 31] as well as promising candidates to be used as safe and effective antimicrobial

Interactions between Bio-Based Compounds and Cyclodextrins

http://dx.doi.org/10.5772/intechopen.73531

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There are scientific evidences that inclusion complexation with CDs improves the pharmacological effects of EOs or their components [28, 32, 33]. For instance, the complexation of Hyptis pectinata L. EO with β-CD improved its analgesic effect in a mice model [34]. Also Bomfim et al. observed that β-CD complexation increased in vivo tumor growth inhibition capacity of Annona vepretorum EO [32]. Recently, Lima et al. reviewed the preclinical and clinical studies published on complexes between CDs and terpenes [33]. These are the major components of EOs that exhibit a wide range of biological activities on the human body. Their survey shows that there is robust experimental evidence that CDs improve the oral absorption and pharmacological properties of terpenes. Nevertheless, more pharmacokinetic and clinical studies are

3. Natural surfactants: brief introduction to sugar-based amphiphiles

Despite the production of surfactants based on fats, oils, and carbohydrates, being a known area for several decades, on an industrial scale, this is a relatively new issue [35]. These amphiphilic molecules that have one of the main building blocks from a natural source are often called "natural surfactants" [36, 37]. For example, alkyl glycosides which are synthesized from a "natural" sugar unit and a "nonnatural" fatty alcohol are often regarded as natural surfactants. Considering their amphiphilic nature, it has been always a challenge to attach a carbohydrate molecule, such as the hydrophilic group (due to the numerous hydroxyl groups) to a fat and oil derivative, such as a fatty acid or a fatty alcohol. However, nowadays, several successful synthesis routes are well established, and numerous types of natural surfactants are known and available, even on a commercial scale [38]. Nowadays, carbohydrate-based surfactants (CBS) are among the most important classes of amphiphilic compounds [39–41]. Their structure results from the combination of sugar and lipids, naturally biosynthesized within living cells or, alternatively, synthetically prepared by sequential reactions using carbohydrate and fatty materials. The growing interest in such compounds is due to, inter alia, their preparation from renewable raw materials, biodegradability, mildness to the skin, and biocompatibility, among other reasons [42, 43]. In particular, CBS can be relatively easily prepared from the most abundant renewable vegetable raw materials (e.g., cellulose, pectin, hemicellulose, starch, etc.) in a wide range of structures and geometries by modular synthesis thanks to the presence of numerous reactive hydroxyl groups. Such structural diversity makes CBS excellent models to get insight on the surfactant mechanisms in modifying interfacial properties. This knowledge is crucial for the control of the formation and stability of diverse colloidal systems such as micelles, vesicles, foams, and emulsions [44]. An important structural feature of these surfactants is the typical sugar headgroup, a voluminous and relatively rigid moiety that can be functionalized by a myriad of reagents and synthetic schemes. Numerous properties and

agents (β-CD/eugenol) to control postharvest diseases in fruits [27].

required before they can be effectively used in clinical targets.

There are many examples showing that the complexation of β-CD, or some of its derivatives, increases the biological activity of phenolics. For instance, Shao et al. observed that the complexation of chlorogenic acid (CGA) with CDs (β-CD and HP-β-CD) improved its antioxidant activity [22]. Moreover, the addition of CGA-CD complexes to grape juice reduced the degradation of anthocyanins due to copigmentation effect with the CGA/HP-β-CD complex showing the superior activity and copigmentation effects. Gabaldon et al. also used HP-β-CD to increase the aqueous solubility of kaempferol, quercetin, and myricetin and to improve their antioxidant activity due to the protection toward free radical attack [23]. The complexation of curcumin with an ionizable β-CD (SBE-β-CD) enhanced its water solubility and, thus, improved the in vitro cytotoxic (on HepG-2 cells) and antioxidant activity of these compounds [24]. This β-CD derivative and the HP-β-CD are the most used derivatives on the pharmaceutical industry due to their low toxicity and high solubility [16, 25, 26].

EOs can be regarded as mixtures of phytochemicals, and there are several studies reporting the complexation of EOs or their components with CDs mainly to overcome problems related with EO water insolubility, high volatility, rapid oxidation, heat damage, and degradation on exposure to air [14]. Although many studies focus the complexation of EO components with β-CDs or its derivatives, e.g., eugenol/HP-β-CD [27] and linalool/HP-β-CD [28], it has been observed that sometimes γ-CD is a better complexing agent. Ciobanu et al. showed that menthol, menthone, and pulegone are capable to form stable 1:1 inclusion complexes with β-CD, but eucalyptol forms a more stable inclusion complex with γ-CD due to the size of its cavity [29]. Polymeric CDs, which can be synthesized using cross-linking agents such as epichlorohydrin, also revealed promising results in some specific cases but are not matter of discussion in this chapter [29].

The inclusion complexes of EOs (or their components) with CDs have been mainly tested for food and pharmaceutical applications, but they could be an efficient tool to improve the use of EOs in aromatherapy, cosmetic, and household cleaning products. An interesting application of EOs is related to their incorporation in food packaging systems or edible films due to their antimicrobial, antioxidant, and insect repellent capacity. However, this is often limited due to flavoring and organoleptic considerations. CD inclusion complexes could overcome these limitations allowing EOs to reach effective concentrations in the food matrices without exceeding organoleptically acceptable levels and even providing controlled release-rate kinetics. Recent studies encourage the use of CD-EO (e.g., β-CD/Satureja montana EO; γ-CD inclusion complex encapsulated electrospun zein nanofibrous webs/thymol) complexes as part of active packaging systems [30, 31] as well as promising candidates to be used as safe and effective antimicrobial agents (β-CD/eugenol) to control postharvest diseases in fruits [27].

Owing to their potential health promotion effects particularly the antioxidant, anti-inflammatory, and antimicrobial properties, one of the actual promising applications of phenolic compounds is their use in the food industry as additives, e.g., in the development of functional foods. Nevertheless, the efficacy of these natural compounds is dependent on the preservation or improvement of their stability, bioactivity, and bioavailability [18]. Inclusion complexation with CDs improves water solubility of phenolics and enhances their shelf life and biological activity [15]. Additionally, it has been shown that the inclusion of phenolic compounds (e.g., hydroxycinnamic and chlorogenic acids) with CD (β-CD) strongly limited their interactions with proteins, which is important regarding the use of phenolics as food additives [19, 20]. Note that the interactions of these compounds with proteins, frequently added to functional foods to improve nutritional value and proper texture characteristics, often decrease the bioavailability

There are many examples showing that the complexation of β-CD, or some of its derivatives, increases the biological activity of phenolics. For instance, Shao et al. observed that the complexation of chlorogenic acid (CGA) with CDs (β-CD and HP-β-CD) improved its antioxidant activity [22]. Moreover, the addition of CGA-CD complexes to grape juice reduced the degradation of anthocyanins due to copigmentation effect with the CGA/HP-β-CD complex showing the superior activity and copigmentation effects. Gabaldon et al. also used HP-β-CD to increase the aqueous solubility of kaempferol, quercetin, and myricetin and to improve their antioxidant activity due to the protection toward free radical attack [23]. The complexation of curcumin with an ionizable β-CD (SBE-β-CD) enhanced its water solubility and, thus, improved the in vitro cytotoxic (on HepG-2 cells) and antioxidant activity of these compounds [24]. This β-CD derivative and the HP-β-CD are the most used derivatives on the pharmaceu-

EOs can be regarded as mixtures of phytochemicals, and there are several studies reporting the complexation of EOs or their components with CDs mainly to overcome problems related with EO water insolubility, high volatility, rapid oxidation, heat damage, and degradation on exposure to air [14]. Although many studies focus the complexation of EO components with β-CDs or its derivatives, e.g., eugenol/HP-β-CD [27] and linalool/HP-β-CD [28], it has been observed that sometimes γ-CD is a better complexing agent. Ciobanu et al. showed that menthol, menthone, and pulegone are capable to form stable 1:1 inclusion complexes with β-CD, but eucalyptol forms a more stable inclusion complex with γ-CD due to the size of its cavity [29]. Polymeric CDs, which can be synthesized using cross-linking agents such as epichlorohydrin, also revealed promising results in some specific cases but are not matter of

The inclusion complexes of EOs (or their components) with CDs have been mainly tested for food and pharmaceutical applications, but they could be an efficient tool to improve the use of EOs in aromatherapy, cosmetic, and household cleaning products. An interesting application of EOs is related to their incorporation in food packaging systems or edible films due to their antimicrobial, antioxidant, and insect repellent capacity. However, this is often limited due to flavoring and organoleptic considerations. CD inclusion complexes could overcome these limitations allowing EOs to reach effective concentrations in the food matrices without exceeding

tical industry due to their low toxicity and high solubility [16, 25, 26].

of both proteins and phenolics [21].

72 Cyclodextrin - A Versatile Ingredient

discussion in this chapter [29].

There are scientific evidences that inclusion complexation with CDs improves the pharmacological effects of EOs or their components [28, 32, 33]. For instance, the complexation of Hyptis pectinata L. EO with β-CD improved its analgesic effect in a mice model [34]. Also Bomfim et al. observed that β-CD complexation increased in vivo tumor growth inhibition capacity of Annona vepretorum EO [32]. Recently, Lima et al. reviewed the preclinical and clinical studies published on complexes between CDs and terpenes [33]. These are the major components of EOs that exhibit a wide range of biological activities on the human body. Their survey shows that there is robust experimental evidence that CDs improve the oral absorption and pharmacological properties of terpenes. Nevertheless, more pharmacokinetic and clinical studies are required before they can be effectively used in clinical targets.
