Cyclodextrins (CDs) are a group of cyclic oligosaccharides produced from starch, consisting of a hydrophobic interior cavity and hydrophilic exterior. Cyclodextrins have gained significant and established attention as versatile carriers for the delivery of bioactive compounds derived from natural sources in various applications, including medicine, food and cosmetics. Their toroidal structure and hydrophobic cavity render them ideal candidates for encapsulating and solubilizing hydrophobic and poorly soluble compounds. Most medicinal, food and cosmetic ingredients share the challenges of hydrophobicity and degradation that can be effectively addressed by various cyclodextrin types.
1. Introduction
Natural compounds have been used since ancient times for their beneficial properties and have played a crucial role in drug discovery. Such natural, biologically active compounds are derived from plants, animals or mineral sources and include, among others, vitamins, phenolic compounds, alkaloids and terpenoids. These groups of bioactive compounds possess antitumor, neuroprotective, antioxidant, anti-inflammatory and antimicrobial properties, so they have numerous applications in the medical, pharmaceutical, food and cosmetic industries
[1][2][3]. However, despite their biological activities, they are characterized by poor solubility, bioavailability and stability in their bulk form, so their incorporation in various commercial health-related products is challenging. These drawbacks can be resolved through their encapsulation in delivery systems, one of which are cyclodextrins (CDs)
[4].
CDs are a group of cyclic oligosaccharides produced from starch, consisting of a hydrophobic interior cavity and hydrophilic exterior. They were first described by Antoine Villiers more than one hundred years ago. In his work, Villiers reported that potato starch fermentation, under certain incubation conditions with
Bacillus amylobacter, could lead to the recovery of dextrins
[5][6]. However, the current term ‘cyclodextrin’ was adopted many years later and is attributed to Friedrich Cramer at the end of the 1940s
[7]. Since then, an increasing number of scientific publications has been focusing on studying their structure, physicochemical properties and applications, as well as the development of new CD-based systems (e.g., nanoparticles)
[8][9][10].
The most common types of CDs used in the delivery of bioactive molecules are alpha-cyclodextrin (α-CD), beta-cyclodextrin (β-CD) and gamma-cyclodextrin (γ-CD). α-CD is the smallest CD with six glucose units in the ring. It has a relatively small hydrophobic cavity and is commonly used for complexing small lipophilic molecules. β-CD is one of the most widely used CDs in bioactive compound delivery. It consists of seven glucose units in the ring, providing a larger hydrophobic cavity than α-CD. It can form inclusion complexes with a wider range of molecules including both lipophilic and hydrophilic compounds. γ-CD has eight glucose units in the ring, offering an even larger hydrophobic cavity compared to β-CD that can encapsulate larger molecules. Apart from the above three commonly used CDs, their derivatives have been introduced and applied to enhance the drug-binding capabilities of native CDs. In the first case, CDs can be chemically modified by adding methyl groups to the hydroxyl groups on the glucose units through a process called O-methylation. Examples of such CDs include heptakis (2,6-di-O-methyl)-β-cyclodextrin (DIMEB) and heptakis (2,3,6-tri-O-methyl)-β-cyclodextrin (TRIMEB). It is interesting to note that methylation affects the hydrogen bond network of CDs, thus influencing the intermolecular interactions’ strength and the host: guest flexibility. This could offer increased inclusion complex (IC) stability through stronger hydrogen bonds and/or Van der Waals interactions
[11]. With another process, called acetylation, hydroxypropyl groups are added to the hydroxyl groups of CDs. So, for example, (2-hydroxy)propylated β-CD (HPβCD) can be produced from β-CD. Similarly to methylation, the degree of substitution (DS) in this case affects the CD’s properties. For example, DS-differentiated HPβCDs present various molecular recognition abilities, while their catalytic abilities also differ regarding organic reactions in water
[12]. The selection of a specific CD type for the delivery of bioactive molecules depends on the physicochemical properties of the latter, the desired release profile and the intended route of administration
[10].
2. Food Applications
The applications of CDs as carriers for bioactive compounds and their incorporation in various food products has been widely studied in the literature. Although CDs were initially tested and applied as drug delivery systems
[8], their characteristics enabled food researchers to also widen their applications in various food matrices. Either as carriers for single bioactive compounds or as carriers for crude essential oils (EOs), CDs are effectively applied in many food products. Usually, such products are fresh, easily perishable ones (e.g., fruits, juice, fresh meat) since their composition (e.g., high moisture content) enables their microbiological and physicochemical degradation
[13]. As delivery systems, CDs offer a variety of advantages in the final food product, mainly by preserving or enhancing the activities of the entrapped bioactive compounds. Firstly, the formation of inclusion complexes with CDs promotes the easier solubility of bioactive compounds in aqueous matrices
[14]. This is of key importance since most of the food products that require preservation are water-based systems. In addition, encapsulation in CDs offers increased stability to the bioactive compounds as they are protected from adverse conditions (e.g., oxygen, heat) during food processing and storage. In this way, their biological activities are prolonged
[15][16]. Especially for volatile compounds such as EOs and their constituents, which are most commonly applied as natural antimicrobial and antioxidant agents in foods, encapsulation in CDs decreases their evaporation rate and promotes their controlled and sustained release in the food matrix
[17]. Moreover, one of the main advantages of bioactive compound encapsulation in CDs is the masking of their intense odor and taste, thus decreasing their negative effect on the organoleptic properties of foods
[18].
The most widely studied and applied CD in food products is β-CD due to its affordability and compatibility with a variety of molecules
[19]. β-CD is essentially odorless and white/whitish, while its aqueous solution is clear and colorless. Although β-CD is moderately soluble in water, it can easily be dissolved in warm water, whereas its solubility in ethanol is low (Regulation (EU) No 231/2012)
[20]. As an approved food additive, β-CD is listed in Annexes II and III of Regulation (EC) No. 1333/2008, under the code E 459
[21]. Derivatives of β-CD, such as HPβCD, are also used. As reported by
[22], CDs do not passively diffuse through biological membranes due to their hydrophilic nature, characterized by numerous hydrogen bond donors and acceptors and very low octanol–water partition coefficients. In addition, CDs present very low bioavailability when administered orally; β-CD, α-CD and their derivatives are mainly digested by bacteria in the colon, and γ-CD is completely digested in the gastrointestinal tract. In this way, they are practically nontoxic, and no CD accumulation is observed in healthy individuals with normal kidney function, even at high doses, whereas caution is recommended in the case of severely renally impaired patients
[22].
Many studies in the literature have evaluated the effect of IC incorporation, between CDs and bioactive compounds, in the final food product in terms of microbiological, oxidative, color stability, and organoleptic characteristics. Guest moieties commonly studied are EOs (e.g., clove, rosemary, lemongrass) and their constituents (e.g., cuminaldehyde, thymol, citral) and phenolic compounds that are mainly hydrophobic (e.g., resveratrol, oxyresveratrol, ferulic acid, gingerols, curcumin). All the above are well-known natural compounds with important antioxidant and antimicrobial activities. Apart from direct incorporation of ICs in the food products, there are also indirect applications via active food packaging
[23]. This method of preservation has been widely studied through the last years, where edible materials can be used to form a film/coating incorporating various bioactive compounds and applied externally in the food product of interest. In this way, the respective products are protected from external factors and can be preserved for a longer period of time (extension of shelf-life)
[24]. Applications of active food packaging containing CD-based ICs or ICs directly incorporated in different food systems and their main effects are presented in
Table 1 and
Table 2, respectively.
Table 1. Applications of active packaging containing CD-based ICs in different food systems and their main effects.
CD Type |
Bioactive Compound/Guest Moiety |
IC 1 Preparation Methods |
Packaging Material |
Food System/Model |
Effects in the Final Product |
Reference |
β-CD |
Cinnamaldehyde (CIN) |
Mixing and freeze-drying |
Non-woven polyethylene terephthalate (PET) |
Cold fresh pork |
Packaged pork samples with the highest tested CIN concentration were preserved for 11 days under refrigerated storage compared to control samples (7 days). |
[25] |
Methyl-β-CD |
Satureja montana L. essential oil (SEO) |
Mixing, ultrasonication and freeze-drying |
Soy soluble polysaccharide (SSPS) hydrogel |
Meat slices |
Methyl-β-CD/SEO-SSPS hydrogel effectively reduced S. aureus counts by 3.5 log CFU/g after 7 days of storage at 4 °C. |
[26] |
β-CD |
Octyl gallate (OG) |
Co-precipitation and freeze-drying |
Chitosan film |
Fresh fruits vegetables (blueberries and asparagus) |
Lower weight loss was reported in coated asparagus samples containing 0.5%, 1.0% and 2.0% β-CD/OG (3.87%, 3.12% and 2.85%, respectively), compared to control (7%) after 25 days storage at 4 °C. TVC 2 was maintained close to the initial 102–103 CFU/g in the coated asparagus samples compared to control (107 CFU/g) after 25 days of storage at 4 °C. |
[27] |
Coated blueberries with films containing 1.0% and 2.0% β-CD/OG presented lower weight loss (2%) compared to control (7%) after 25-day storage at 4 °C. Films containing 2.0% β-CD/OG effectively preserved freshness in blueberries with a 6% rotting rate compared to control (20%). |
β-CD |
Trans-cinnamaldehyde (TC) and citral (CI) |
Co-precipitation and vacuum-drying |
Ethylene vinyl alcohol copolymer (EVOH) film |
Beef |
Shelf-life of EVOH-β-CD-CI and EVOH-β-CD-TC coated samples was extended about 4 days at 4 °C, compared to control and coated samples without ICs. |
[28] |
β-CD |
Curcumin (Cur) |
Mixing and freeze-drying |
κ-Carrageenan (κ-Car) film |
Chilled pork |
Extension of chilled pork shelf life from 4–5 days to 10 days with application of κ-Car-β-CD-Cur film combined with light treatment, compared to pure κ-Car film and other treatments. |
[29] |
β-CD |
Lemongrass essential oil (LEO) |
Co-precipitation and drying |
Chitosan–gelatin (CS-Gel) coating |
Fresh cherry tomatoes |
CS/Gel coating with 7% β-CD/LEO presented high antibacterial activity against P. aurantiogriseum in cherry tomatoes artificially during 20 days of cold storage at 8 °C. |
[30] |
α-CD |
Benzyl isothiocyanate (BITC) |
Mixing, ultrasonication and vacuum freeze-drying |
Chitosan (CS) film |
Beef |
CS-α-CD-BITC-coated beef samples presented lower TVC, TVB-N 3 and TBARS 4 values and higher overall acceptability score, compared to PET- 5 and CS-coated samples after 12 days of refrigerated storage. |
[31] |
This entry is adapted from the peer-reviewed paper 10.3390/ph16091274