**4.5. Food**

partially in their cavity [14, 35]. This characteristic let the CDs being used for oral, sublingual, ocular, nasal, rectal, pulmonary, dermal, and other drug delivery systems, especially in systems of type 1/1 (one molecule per CD). The encapsulation with CDs enhanced the bioavailability of lipophilic drugs, as they are 17β-estradiol, androstenediol, clomipramine, and others. A limitation of CD in sublingual route is that the quantity used for a proper formulation is too large to be considered. This increase in the bioavailability is also observed in the oral route for drugs such as diltiazem, flufenamic acid, molsidomine, salbutamol, having

In order to optimize pharmacotherapy, drug release should be controlled in accordance with the therapeutic purpose and the pharmacological properties of the active substances. In recent years, the interest regarding the control of rate or time of delivery has significantly increased [88]. The multifunctional characteristics of CDs allow them to be used in most drug delivery systems [84]. The design process of drug delivery systems is currently more focused on the oral route, in which the release of the drug can be controlled by dissolution, diffusion, osmosis, density or pH. Challa et al. [89] give several examples of different uses in oral delivery. The use of β-CD increased the bioavailability of ketoprofen, terfenadine, and griseofulvin; but, the same CD, also demonstrated higher intensity or longer duration of therapeutic activity in tolbutamide or terfenadine. Although there are different effects depending on the modified CD used, for example, the solubility and dissolution rate can be increased using HP-β-CD, for drugs as albendazole, ketoprofen, phenytoin, and gliclazide; or an improvement of hydrolysis stability γ-CD, for drugs as digoxin, camptothesin and paclitaxel. For oral

The improvement of the efficacy and bioavailability of poorly soluble drugs can be achieved by nanoparticles, which are stable systems that are used to create drug delivery systems [83]. Nanoparticles are 100–10,000 times smaller than human cells and their uses revolutionize diagnosis, treatment, therapeutic efficacy, and patient compliance [83, 90]. However, nanoparticles are limited by their low drug loading and entrapment ability, which compromises their safety and efficacy [84]. The use of CDs as a polymer increases the loading capacity of nanoparticle systems [89]. Furthermore, the optimal drug bioavailability and biodistribution can be achieved with a proper manipulation of physico-chemical and biological mechanisms, which can be provided by the hybrid functionalities of CD nanosystems [91]. A new class of colloidal polymer is nanosponges, which consist of solid nanoparticles with colloidal shape and nanocavities. Examples of nanosponges are those based on CDs. It should be noted that the type, number, and position of the substituent on the CD affect the complexation ability of nanosponges. Thus, it is crucial to know which CD derivative to use. Tejashri et al. [92] expose the use of CD to make nanosponge, and the use of it to load drugs and use as carriers. The crosslinking of CDs with compounds, as carbonyl or dicarboxylate, creates the different types of nanosponge, polyamide, carbonate, etc. Authors concluded that this novel class of

administration, all CDs can be used because they are not toxic.

all of them a sustained release [88].

**4.3. Controlled release**

10 Cyclodextrin - A Versatile Ingredient

**4.4. Nano**

In last years the application of CDs in the food-industry have increased mainly due to the use of them as a protective agent against oxygen, to protect flavor of volatile compounds, to enriched food with vitamins and color components (such as anthocyanins) or to stabilize them [93, 94]. Another advantage for the food industry is that CD are tasteless, odorless, and non-caloric saccharides, and that they have an antidiabetic effect due to their low glycemic index and their capability to decrease the glycemic index of the food, and also to improve the cholesterol index. Human gastrointestinal enzymes cannot digest them, so it can be used as a dietary fiber, which is fermented by microflora, what makes them a prebiotic compound. All these properties make them nutraceuticals and bioactive food supplements [95, 96]. López-Nicolás et al. [97] analyzed the positive effects of CDs in the encapsulation of antioxidant, and the repercussion on important factors as KF or pH values. They also reviewed the antioxidant capacity of CDs, but they concluded that there is a necessity of more studies in this aspect.

#### **4.6. Cosmetic**

The cosmetic industry is looking for products with a good biological activity and adequate delivery on the skin [98]. The applications of CDs in cosmetics are similar to the pharmaceutical ones, e.g., stabilizing substances or increasing their solubility [99–101]. Centini et al. [98] associated ferulic acid, which is a photoprotector agent and an antioxidant compound, and CD. However, ferulic acid is not too much used due to the instability of it in the presence of air, UV-light, and heat; so, the aim of the work was to enhance the physico-chemical stability. The authors concluded that the complex ferulic acid/CD have a better photostability and do not generate degradation products. Buschmann and Schollmeyer [99] explained the use of CD against the vaporization of slow release of the volatile compounds in perfumes; or the opposite, they also explained the use of CD to eliminate undesired odors, such as mercapto derivate used in waving lotion. More applications will become possible when CDs price decreases. CDs can also be used in the textile industry as depots of cosmetic molecules providing new cosmetic formulations.

#### **4.7. Miscellaneous applications of cyclodextrins: tabular form**

A more detailed picture of most recent selected applications in various areas, ranging from general reviews to inclusion complexes, metal and organometallic complexes, food, pharmaceutical, pharmacological, medical and biomedical, environmental chemistry, personal care and toiletry, industrial, nanotechnological, industrial and analytical applications to enzyme, biomimetic, bioactive assembles and recognition, as well as miscellaneous applications is compiled in **Table 1**, which gives an idea of the importance and relevance of the CDs field. **Figure 5** shows the number of publications cited per year, whereas in **Figure 6**,


H NMR

Some applications of CD/ substrate inclusion complexes. Crini et al. (2001) [8]

Complexation thermodynamics of CDs. Rekharsky and Inoue (1998) [113]

Cheirsilp and Rakmai (2016) [42]

http://dx.doi.org/10.5772/intechopen.72736

Chaudhary and Patel (2013) [16]

Caira (2011) [40]

Smith et al. (2010) [69]

Song et al. (2009) [36]

Martinez and Gomez (2007) [109]

Miller et al. (2007) [110]

Baker et al. (2002) [111]

Valero et al. (1999) [112]

Muñoz-Botella et al. (1995) [37]

Diaz et al. (1994) [114]

Davies et al. (1983) [115]

Prochowic et al. (2016) [116]

[44]

13

Cyclodextrins: Past and Present

Maazaoui and Abderrahim

(2015)

Summary of method for inclusion complex formation of CD with its

Literature review to characterize the formation of inclusion complexes

Use of CDs as complexing agents to enhance the solubility of poorly soluble drugs and hence to resolve the many issues associated with developing and commercializing poorly water-soluble drugs.

CD inclusion of four phenylurea herbicides: determination of complex

Comparison of the inclusion complexation between host and guest in CD chemistry with the coordination interaction between central ion

Threading CDs molecules onto polymer chains to form crystalline inclusion complexes organized by non-covalent interactions.

Practical considerations in development of solid dosage forms that

CD inclusion complexes with a solvatochromic fluorescent probe: an undergraduate physical chemistry lab experiment to establish the solvatochromic nature of PRODAN and then use the changes in the emission spectra upon inclusion in β- or γ-CD to determine stoichiometry and formation constants for the complexes.

Determination of thermodynamic parameters of the CD inclusion processes: an undergraduate physical chemistry lab experiment.

Applications of CDs to pharmaceutical industry and chemical catalysis. Analytical applications are also considered, since CDs inclusion improves the sensitivity and selectivity of most analytical

undergraduate chemistry experiment.

**Metal and organometallic complexes**

cylindrical, extended structures.

β-CD inclusion complexes with iodine: an advanced and inexpensive

Critical overview about past, present and future of CDs: properties,

Synthesis, reactivity and structural diversity of well-defined metal complexes derived essentially from native CDs. Structural motifs for metal complexes based on CDs: from monomeric species, dinuclear systems, homo- and heterometallic sandwich-type complexes to

studies on CD inclusion compounds and its applications.

Survey of crystal structures of pure CD hosts and CD inclusion compounds carried out during the last six years. The entries range from simple alkylated derivatives to elegant multi-substituted target

CD molecules, with and without included guests.

(Mx+) and ligands in coordination chemistry.

stoichiometries and stability constants using solution 1

by different techniques in the solid and in the solution state

guests and its applications.

complexation.

spectroscopy.

contain CD.

methods.


cylindrical, extended structures.

**Content Authors Refs.**

Duchêne and Bochot (2016) [14]

Szente et al. (2016) [2]

Khan and Durakshan (2013) [7]

Kurkov and Loftsson (2013) [3]

Venturini et al. (2008) [102]

Mosher and Thompson (2007) [103]

Martin del Valle (2004) [93]

Szejtli (2004) [26]

Loftsson (2002) [9]

D'souza and Lipkowitz (1998) [104]

Szejtli (1998) [105]

Szejtli (1992) [106]

Bender and Komiyama (1978) [107]

Matencio et al. (2017) [108]

Overview about the work carried out on CDs concerning with: the general characteristics of CDs and derivatives, the preparation and evaluation of inclusion complexes, the use of CDs in the preparation of drug delivery systems, and their use for the preparation of

Comprehensive overview on the methods used for analysis of CDs and CD-derivatives. The paper intends to act as a guide in looking around the classical and modern instrumental analytical methods suitable for identification, characterization and determination of CDs themselves, CDs in finished products or even in biological samples.

Current review on various aspects of CDs with regard to their chemical characteristics, properties, approaches used for complexation, characterization techniques, uses along with and future

Pharmaceutical applications of CDs with an emphasis on their solubilizing properties, their tendency to self-assemble to form aggregates, CD ternary complexes, and their metabolism and

Overview about several aspects related to the physico-chemical properties of CDs and their potential applications illustrated by recent

Inclusion complexation and CDs: physicochemical parameters of the guest molecule and improvements in the molecule's solubility,

CDs and their use in industrial products, technologies and analytical

Overview about past, present, and future of CD research. Potential uses of CDs in pharmaceuticals, foods, cosmetics, and chemical

CDs: structure, complex formation, drug solubility and non-

Scientific and technological aspects of CDs: from computational

History (the three stages in the development of CD chemistry),

The properties and potential uses of CD derivatives: dimethyl- and

Catalyses by CDs leading to practical usages: covalent, non-covalent

The inclusion complex of oxyresveratrol in modified CDs: a thermodynamic, structural, physicochemical, fluorescent and

fundamentals of CD chemistry and future trends.

stability, taste, safety, bioavailability, etc.

products and technologies.

conventional CD complexes.

chemistry to industrial uses of CDs.

dimethyl-βCD (DIMEB and TRIMEB).

and asymmetric catalyses by CDs.

**Inclusion complexes**

computational study.

**General reviews**

potential.

examples.

methods.

pharmacokinetics.

biomaterials and nanoparticles.

12 Cyclodextrin - A Versatile Ingredient


CDs: application to food processing. Yoshii (2004) [127]

CD-based pharmaceutics: past, present and future applications. Davis and Brewster (2004) [130]

Main impetus for the research into CD-drug combinations. Frömming and Szejtli (1994) [131]

Cabral Marques (2010) [33]

http://dx.doi.org/10.5772/intechopen.72736

Cyclodextrins: Past and Present

15

Moreira da Silva (2009) [125]

Astray et al. (2009) [94]

Szente et al. (2006) [35]

Szente and Szejtli (2004) [126]

Kanaka Durga Devi et al. (2010) [83]

Loftsson and Brewster (2010) [128]

Funasaki et al. (2008) [10]

Loftsson and Duchêne (2007) [129]

Loftsson (2002) [9]

Adeoye et al. (2017) [91]

Antoniuk and Amiel (2016) [132]

Zheng and Wyman (2016) [133]

CD encapsulation of essential oils and volatiles: methods for the preparation of inclusion complexes, analytical techniques and

Use of CDs in the food industry: properties from a technological point of view, such as solubility and their capability to form inclusion

compounds to food manufacture, focusing on the technical advantages

Isolation and identification of native and branched-type (glucosylated and maltosylated) CDs in different enzyme- and heat-processed

Practical aspects of the utilization of CDs and CD complexes in the food industry: molecular encapsulation of lipophilic food ingredients, long-term storage stability and technological advantages and food

CDs: history, chemical structure, synthesis, physicochemical properties, uses, complexation phenomenon, approaches for making inclusion complexes, and its characterisation, advantages of inclusion complexes, mechanism of drug release, regulatory status and its

Basic science information and data on the development of drugs in

Critical review about experimental methods for determination of the

Historical development of CDs with emphasis on their use in

CDs: structure, complex formation and drug solubility and non-

Application of CD nanosystems for oral drug delivery: strategies for the synthesis of these nanosystems, and their potential for the intelligent navigation of the gastrointestinal tract for optimal

CD-mediated hierarchical self-assembly and its potential in drug

Supramolecular nanostructures based on CD and poly(ethylene oxide): syntheses, structural characterizations and applications for

binding constant between CD and a guest molecule.

Practical aspects of the utilization of CDs and CD inclusion

of their use in food processing and as food additives.

applications.

complexes are described.

processing technologies.

*Reviews*

applications.

**Pharmaceutical applications**

CD-containing formulations.

pharmaceutical formulations.

conventional CD complexes.

bioavailability and biodistribution.

*Delivery release*

delivery applications.

drug delivery.

starch-containing food products.


CDs as supramolecular hosts for organometallic complexes. Hapiot et al. (2006) [121]

Hong et al. (2015) [117]

Macaev and Boldescu (2015) [118]

Smith et al. (2015) [49]

Bellia et al. (2009) [119]

Norkus (2009) [120]

Suvarna et al. (2017) [87]

Fenyvesi et al. (2016) [95]

Li et al. (2014) [122]

López-Nicolás et al. (2014) [97]

Martina et al. (2013) [123]

Zipp (2012) [96]

Astray et al. (2010) [124]

[44]

drug delivery.

Maazaoui and Abderrahim

(2015)

Overview of recent advances of CD catalyzed reactions, which is organized in the order of the following reaction types: the modified CD catalyzed organic reaction, CD catalyzed organic reaction of metal ion present, CD catalyzed organic reaction without metal ion, and CD catalyzed organic reactions in application of asymmetric synthesis and

Research and application of CDs and their derivatives in asymmetric and stereospecific syntheses, with their division into three main groups: (1) CDs promoting asymmetric and stereospecific catalysis in water; (2) CDs' complexes with transition metals as asymmetric and stereospecific catalysts; and (3) CDs' non-metallic derivatives as

Preparation and analysis of CD-based metal–organic frameworks: laboratory experiments adaptable for high school students.

Selectively functionalized CDs and their metal complexes: recent applications as chiral receptors and catalytic center in the mimicking

Metal complexing properties of native CDs (including deprotonation in alkaline medium) and a report on some recent results on composition and stability of metal–CD complexes.

Complexation of poorly water-soluble phytochemicals (flavonoids, phenolic derivatives, coumestans to triterpenes) with CDs to improve their aqueous solubility, stability, rate of dissolution and

CDs in food technology and human nutrition: benefits and limitations. The recent applications of CDs for reducing unwanted components, such as trans-fats, allergens, mycotoxins, acrylamides, bitter compounds, as well as in smart active packaging of foods are also

History, chemistry, methods of complexation and application of CDs into different areas, particularly in the pharmaceutical and food

Properties, enzymatic production, and food applications of α-CD, as

Studies on the complexes formed between several important types of

CDs as novel solutions for the food industry concerning with their role as dietary fiber, in food and drink with health-promoting additives, protect sensitive ingredients, improve taste and odor, or their positively influence to the texture and consistency of food.

Applications of CDs as food additives and in food processing: transport of previously nontransportable foods and prevention of the

Factors controlling flavors binding constants to CDs and their

well as its differences with β- and γ-CDs.

antioxidant compounds and CDs.

spread of microbial infections.

applications in foods.

photochemical reactions.

14 Cyclodextrin - A Versatile Ingredient

of metalloenzymes.

**Food applications**

bioavailability.

overviewed.

industry.

asymmetric and stereospecific catalysts.


Challa et al. (2005) [89]

http://dx.doi.org/10.5772/intechopen.72736

Cyclodextrins: Past and Present

17

Loftsson et al. (2005) [145]

Rajewski and Stella (1996) [54]

Arima et al. (2017) [146]

González-Gaitano et al. (2017) [147]

Duchêne et al. (2016) [148]

Rasheed et al. (2008) [88]

Uekama et al. (1998) [149]

Jambhekar and Breen (2016) [18]

Chaudhary and Patel (2014) [16]

Loftsson and Brewster (2011) [150]

Brewster and Loftsson (2007) [15]

Loftsson and Brewster (1996) [19]

Oliveri and Vecchio (2016) [151]

Martínez et al. (2013) [152]

Varca et al. (2010) [153]

Interesting findings and applications of CDs and their derivatives in different areas of drug delivery, particularly in protein and peptide drug delivery and gene delivery. Applications in the design of various novel delivery systems like liposomes, microspheres, microcapsules,

CDs in drug delivery. Pharmaceutical products worldwide containing

Recent findings and applications of both unmodified and modified CDs for in vivo drug delivery. Use of CDs for parenteral, oral, ophthalmic, and nasal drug delivery. Other routes including dermal,

Potential therapeutic application of dendrimer/CD conjugates with targeting ligands as advanced carriers for gene and oligonucleotide

Drug carrier systems based on CD supramolecular assemblies and

CD-based polymeric nanoparticles as efficient carriers for anticancer

Potential use of chemically modified CDs as high-performance drug carriers in drug delivery systems with emphasis on the more recent

CDs in pharmaceutical formulations: solubilization, binding constant,

CD drug carrier systems: characteristics, improvements of drug properties by CD complexation and CD-based drug delivery systems.

Use of CDs as complexing agents to enhance the solubility of poorly soluble drugs and issues associated with developing and

Pharmaceutical applications of CDs: effects on drug permeation

General background to the use of CD as solubilizers as well as highlight kinetic and thermodynamic tools and parameters useful in

CDs as solubilizers as well as highlight kinetic and thermodynamic tools and parameters useful in the study of drug solubilization

Use of CDs and their derivatives as antiaggregant agents in a number

CD-based multivalent glycodisplays: covalent and supramolecular

CD interactions with protein-like structures in order to describe their possible applications in the formulation of pharmaceutical proteins.

conjugates to assess carbohydrate–protein interactions.

commercializing poorly water soluble drugs.

the study of drug solubilization by CDs.

of proteins and some multimeric enzymes.

rectal, and pulmonary delivery are also briefly addressed.

and nanoparticles.

*Carrier*

drugs.

drugs.

*Protein*

developments.

*Solubilization and permeation*

and complexation efficiency.

through biological membranes.

drug/CD complexes on the market.

polymers: present and perspectives.

juxtaposed to the membrane of interest.


Arima et al. (2015) [134]

Bonnet et al. (2015) [135]

Gidwani and Vyas (2015) [90]

Nascimento et al. (2015) [136]

Lakkakula and Krause (2014) [137]

Zafar et al. (2014) [138]

Zhang and Ma (2013) [139]

Laza-Knoerr et al. (2010) [140]

Tiwari et al. (2010) [84]

Li and Loh (2008) [141]

Rasheed et al. (2008) [88]

Vyas et al. (2008) [142]

Centini et al. (2007) [98]

Loftsson et al. (2007) [144]

[86]

Chordiya Mayur and Senthilkumaran (2012)

Recent advances in drug delivery techniques utilizing CDs, and cyclic oligosaccharides consisting of α-1,4-linked α-D-glucopyranose units. Especially, drug delivery system consisting of combination systems of CDs and functional materials such as dendrimer, liposome and PEG

Relationship between CDs structure and physicochemical characteristics: self assembly and drug delivery. Importance of the nanoparticle technology preparation for the stability and application

CD-based carriers for delivery of chemotherapeutic cytotoxic

A vision for CD nanoparticles in drug delivery systems and

CD containing biodegradable particles: from preparation to drug

State of the art and recent advances in the construction of CD-based assemblies and their applications for controlled drug delivery.

CD in drug delivery: complexing agents, bioavailability and industrial

Recent developments of CDs in drug delivery using various routes of

Advantages of CD inclusion complexation, effects on important drug properties in formulation and applications in delivery systems (oral drug, rectal dug, nasal drug, transdermal drug, ocular drug, controlled and targeted drug, peptide and protein delivery, gene and oligonucleotide delivery, dermal and transdermal delivery, brain drug

CD-based supramolecular architectures: syntheses, structures, and

Applications of CDs and their derivatives in different areas of drug delivery: parenteral, oral, ophthalmic and nasal drug delivery. Other routes including dermal, rectal, sublingual and pulmonary delivery

Applications and comparative benefits of use of CDs and their derivatives in the design of novel delivery systems like liposomes, microspheres, microcapsules, nanoparticles, CD grafted cellulosic fabric, hydrogels, nano- sponges, beads, nanogels/nanoassemblies and

CDs as cosmetic delivery systems: study of ferulic acid/ CD association complexes at the light of its possible use as sunscreen.

Effects of hydrophilic CDs on drug permeation through membranes and possible mechanism of action based on the current knowledge of the structural characteristics of water and the unstirred water layer

The utility of CDs for enhancing oral bioavailability. Carrier et al. (2007) [143]

CD-based delivery systems for arthritic diseases: from development to

are introduced.

16 Cyclodextrin - A Versatile Ingredient

of this nanodevice.

anticancer drugs.

experimental therapeutics.

pharmaceutical applications.

delivery applications.

applications.

administration.

delivery or brain targetting).

are also briefly addressed.

CD-containing polymers.

applications for drug and gene delivery.

juxtaposed to the membrane of interest.


**Content Authors Refs.** Self-assembly of CDs and their complexes in aqueous solutions. Ryzhakov et al. (2016) [48]

Improving the therapeutic response of analgesic drugs by CDs. De Oliveira et al. (2015) [167]

Basic and clinical pharmacology of sulfobutylether-β-CD. Loftsson and Brewster (2010) [128] Basic and clinical pharmacology of sulfobutylether-β-CD. Luke et al. (2010) [169]

Takazawa et al. (2016) [165]

http://dx.doi.org/10.5772/intechopen.72736

Cyclodextrins: Past and Present

19

Won et al. (2016) [166]

Lakkakula and Krause (2014) [137]

Vecsernyés et al. (2014) [168]

Welliver (2007) [170]

Irie and Uekama (1997) [162]

Abdolmaleki et al. (2017) [171]

Feng et al. (2016) [172]

Leclercq (2016) [163]

Radu et al. (2016) [173]

Vecsernyés et al. (2014) [168]

Parrot-Lopez et al. (2010) [174]

Smith (2005) [175]

Szejtli (1994) [176]

Leudjo Taka et al. (2017) [177]

Diagnostic utility of flow cytometry and improvement of rocuronium-

Sugammadex for reversal of rocuronium-induced neuromuscular blockade in pediatric patients: a systematic review and meta-analysis.

Types of CDs, and their efficacy, physicochemical properties and transformation into nanoparticles with interesting in vitro and in vivo

neurodegenerative diseases, stroke, neuroinfections and brain tumors.

Potential therapeutic use of CDs and CD nanoparticles in

CD introduction to anesthesia practice: form, function, and

Findings on the safety profiles of three natural CDs and several

Key features of the CDs therapeutic discovery. Application of computational chemistry approaches such as QSAR/QSPR, molecular docking, and molecular/quantum mechanics for modeling of CD-drug

Recent development of copolymeric delivery system for anticancer

General features and applications of CDs and their interactions with isolated biomolecules leading to the formation of inclusion or

Data on the general properties and complexing ability of CDs and assessment methods (phase solubility, DSC tests and X-ray diffraction,

CD interactions with protein-like structures: possible applications in

Amphiphilic CDs and their applications: preparation of nanoparticles

A supramolecular approach to medicinal chemistry: essential roles played by intermolecular forces in mediating the interactions between

Medicinal applications of CDs: improvement of drug properties, use of drug/CD complexes, CDs in tabletting and direct treatment with

Nanosponge CD polyurethanes and their modification with nanomaterials for the removal of pollutants from waste water.

exclusion complexes: potential medical applications.

based on amphiphilic CDs for biomedical applications.

the formulation of pharmaceutical proteins.

chemical molecules and biological systems.

**Environmental Chemistry and Applications**

induced anaphylaxis with the use of sugammadex.

applications.

application.

system.

FTIR spectra).

CDs.

chemically modified.

**Medical and biomedical**

agents based on CD derivatives.


Background review for CDs used as excipients. EMA/CHMP/333892/ (2013) [155]

Use of CD in the different routes of drug administration. Shimpi et al. (2005) [161]

Gharib et al. (2015) [154]

Pinho et al. (2014) [35]

Loftsson and Brewster (2012) [156]

Jambhekar and Breen (2016) [17]

Akasha et al. (2014) [157]

Loftsson and Masson, (2001) [158]

Benkovics et al. (2017) [159]

di Cagno and Pio (2017) [160]

Irie and Hekama (1997) [162]

Saokham et al. (2017) [15]

Leclercq (2016) [163]

Lima et al. (2016) [164]

[34]

Nardello-Rataj and Leclercq

(2014)

Encapsulation of CD/drug inclusion complex into conventional, deformable and double loaded liposomes: characteristics of these systems and advantages and disadvantages of each one.

Encapsulation of biocides by CDs: toward synergistic effects against

Use of CDs as encapsulating agents for bioactive plant molecules in

CDs as functional excipients: methods to enhance complexation

CDs in pharmaceutical formulations: structure and physicochemical properties, formation of complexes, and types of complex.

Evaluation of CDs drug complexes in pharmaceutical formulation: preparation of sodium valproate phenytoin sodium/ β-CD inclusion complex in a trial to stabilize the drug against moisture absorption and forming non-hygroscopic powders and preparation of phenytoin sodium/β-CD inclusion complex in a trial to stabilize the drug against

CDs in topical drug formulations: drug delivery from aqueous CD

Types of fluorophores which have been used for CD tagging: synthetic strategies used for the conjugation and pharmaceutical applications of these 'visualized' macrocycles including their use in photodynamic

CDs' legacy as complexing agents and future prospects of this class of chemical entities in pharmaceutics as new active pharmaceutical

Recent findings on the safety profiles of three natural CDs and several chemically modified CDs: stability against non-enzymatic and enzymatic degradations in various body fluids and tissue homogenates and their pharmacokinetics via parenteral, oral, transmucosal, and dermal routes of administration.

Production, physiochemical properties, pharmacokinetics, toxicity and

Interactions between CDs and cellular components: medical

Inclusion of terpenes in CDs: preparation, characterization and

moisture absorption and mask its bitter taste.

solutions by diffusion and membrane controlled.

*Encapsulation*

pathogens.

*Excipients*

efficiency.

*Formulations*

*Miscellaneous*

therapy.

ingredients.

**Pharmacology**

applications.

applications of γ-CD and its derivatives.

pharmacological approaches.

the pharmaceutical field.

18 Cyclodextrin - A Versatile Ingredient


Industrial applications of CDs. Production and analysis of complexes. Hedges (1998) [188]

Overview about industrial uses of CDs and their derivatives. Duchêne and Wouessidjewe

Singh et al. (2002) [186]

http://dx.doi.org/10.5772/intechopen.72736

Cyclodextrins: Past and Present

21

Arenskötter et al. (2001) [187]

Szejtli (1997) [189]

Saenger (1980) [191]

Leudjo et al. (2017) [177]

Mejia-Ariza et al. (2017) [192]

Duchene et al. (2016) [148]

Swanimathan et al. (2016) [193]

Zheng and Wyman (2016) [133]

Karoyo and Wilson (2015) [194]

Simoes et al. (2015) [195]

Kang et al. (2014) [196]

Lakkakula and Krause (2014) [137]

Concheiro and Alvarez-Lorenzo

(2013)

Adeoye and Cabral-Marques

[190]

[91]

[197]

(1992)

(2017)

Applications of CDs in pharmaceuticals with a major emphasis on drug delivery systems. Utility in a variety of foods, flavors cosmetics,

Utilization of CDs in industrial products and processes: (i) textiles, fibers and papers; (ii) foods and cosmetics; (iii) plastics and rubber; (iv) photographic and recording materials; (v) biotechnology and (vi)

CD inclusion compounds in research and industry: production of pharmaceuticals, pesticides, foodstuffs, and toilet articles among

General overview of CDs and pharmaceutical nanotechnology in oral delivery systems. Strategies for the synthesis of these nanosystems, and their potential for the intelligent navigation of the gastrointestinal

tract for optimal bioavailability and biodistribution.

Nanosponge CD polyurethanes and their modification with nanomaterials for the removal of pollutants from waste water.

supramolecular nanoparticles: biomedical applications.

CD-based nanosponges: a versatile platform for cancer

nanotherapeutics development.

perfluorinated compounds.

and biomimetic fields.

pharmaceutical applications.

preformed medical devices.

last five years, including clinical trials.

CD-based supramolecular host–guest interactions for engineering

CD-based polymeric nanoparticles as efficient carriers for anticancer

Supramolecular nanostructures based on CD and poly(ethylene oxide): syntheses, structural characterizations and applications for

Nano-sized CD-based molecularly imprinted polymer adsorbents for

Overall view of the diversity of designs of CD-based supramolecular nanosystems with a special focus on the advances materialized in the

Recent advances in the construction of nanoassemblies driven by CD-based inclusion complexation and their application in biomedical

Approaches tested to synthesize nano- to macro-size covalently crosslinked CD networks: (i) direct cross-linking through condensation with di- or multifunctional reagents, (ii) copolymerization of CD derivatives with acrylic/vinyl monomers, and (iii) grafting of CDs to

A vision for CD nanoparticles in drug delivery systems and

Applications of CDs in pharmaceuticals, foods and flavours, cosmetics, chemical industry, agricultural industry and adhesives,

packaging and textiles.

coatings and other polymers.

environmental protection.

others.

**Nano**

drugs.

drug delivery.


preformed medical devices.

**Content Authors Refs.**

H NMR

Han et al. (2016) [178]

Letort et al. (2016) [179]

Smith et al. (2010) [69]

Fakayode et al. (2007) [27]

Crini and Morcellet (2002) [180]

Centini et al. (2007) [98]

Cheirsilp and Rakmai (2016) [42]

Cravotto et al. (2016) [181]

Jemli et al. (2016) [24]

Radu et al. (2016) [173]

Sharma and Baldi (2016) [182]

Bhaskara-Amrit et al. (2011) [183]

Bilensoy (2011) [184]

Grigoriu and Popescu (2011) [185]

Parrot-Lopez et al. (2010) [174]

[99]

Buschmann and Schollmeyer

(2002)

Progress in the immobilization of β-CD and their application in

stoichiometries and stability constants using solution 1

the development of chemical and environmental sensors.

chromatographic separations and in waste water treatment.

Inclusion complex formation of CD with its guest and their applications in foods and flavors, personal care and toiletry, environment protection, pharmaceuticals among others.

Enabling technologies and green processes in CD chemistry: microwaves, ultrasound and ball mills have become irreplaceable tools in the synthesis of CD derivatives. Examples of sonochemical selective modification of native α-, β- and γ-CDs including heterogeneous phase Pd- and Cu-catalysed hydrogenations and couplings.

Interactions of CDs and their derivatives with toxic organophosphorus

CD inclusion of four phenylurea herbicides: determination of complex

Synthesis and applications of adsorbents containing CDs in the field of

CDs as cosmetic delivery system: study of ferulic acid/CD association

Possible applications of CDs in cosmetic products and some examples

Major fields of enzyme application and overview on previous protein engineering studies wherein natural enzymes were modified to meet the operational conditions required for industrial application.

Applications of CDs in medical textiles: general data properties and complexing ability of CDs and assessment methods (phase solubility, DSC tests and X-ray diffraction, FTIR spectra, analytical method).

Applications of CDs in various industrial products, technologies, analytical and chemical processes and recent industrial advancements.

attachment technique of β-CD to the textile's surface.

based on amphiphilic CDs for biomedical applications.

General features of β-CD and their applications in the textile industry:

CDs in pharmaceutics, cosmetics, and biomedicine: current and future

Role of CDs in the textile chemical technology: remove the surfactants from the material or to inactivate them in liquid phase, to intensify the enzyme processes or as balancers in dyeing with reactive pigments.

Amphiphilic CDs and their applications. Preparation of nanoparticles

Fluorescence spectroscopy as a tool to study the properties of CD host-guest complexes. Overview of recent studies concerned with exploiting the properties of CDs and their inclusion complexes to study energy transfer through the use of photochemical antennas and

adsorption of environmental pollutants.

20 Cyclodextrin - A Versatile Ingredient

compounds.

spectroscopy.

complexes.

**Personal care and toiletry**

of their present uses.

**Industrial applications**

industrial applications.


The growth and applications of CDs as chiral discriminator. Pathak and Pathak (2008) [210]

CD inclusion complexes probed by NMR techniques. Pessine et al. (2012) [45]

Scriba (2016) [77]

http://dx.doi.org/10.5772/intechopen.72736

Cyclodextrins: Past and Present

23

Zhou and Scriba (2016) [75]

Al-Othman et al. (2014) [207]

Jac and Scriba (2013) [208]

Tang et al. (2013) [76]

Mandrioli et al. (2011) [209]

Scriba (2008) [90]

Contradi et al. (1997) [82]

Ogawa and Takahashi (2015) [52]

Mura (2015) [51]

Mura (2014) [47]

Valente and Söderman (2014) [30]

Takahashi et al. (2012) [211]

Recent contributions to the understanding of the binding mechanism between chiral selectors and selectands in analytical enantioseparations including polysaccharide derivatives, CDs, cyclofructans, macrocyclic glycopeptides, proteins, brush-type selectors, ion-exchangers, polymers, crown ethers, ligand-exchangers, molecular micelles, ionic liquids, metal-organic frameworks and

Development of cationic CDs for chiral separation. Update of the research endeavors of synthetic and analytical chemists in evaluating enantioselectivity of cationic CDs using different analytical methods

Advances in enantiomeric resolution on monolithic chiral stationary phases in liquid chromatography and electrochromatography.

Recent examples of mechanistic aspects of capillary enantioseparations with regard to mathematical modeling of enantioseparations, investigations of the analyte-complex structures as well as new chiral selectors and applications of chiral analyses by CE and CEC.

Review of the latest advances in developing modified CDs as chiral selectors for various chromatographic and electromigration

Chiral analysis of amphetamines, methadone and metabolites in

Separation of enantiomeric barbiturates by capillary electrophoresis using a CD containing run buffer: a laboratory experiments for degree

Physicochemical characterization of CD-drug interactions in the solid

Analytical techniques for characterization of CD complexes in the

Analytical tools which can be employed for the characterization of drug-CD inclusion complexes in solution, with emphasis on their

Surfactant-CD host-guest association: fundamentals, drawbacks and advantages of techniques commonly used to obtain insights on the structural and bulk solutions changes resulting from host-guest association mechanism, and corresponding methods for binding

A literature review of CD inclusion complexes characterization: X-ray diffraction, infrared spectroscopy and nuclear magnetic resonance.

CDs in capillary electrophoresis enantioseparations: recent

biological samples by electrodriven methods.

state and the effect of water on these interactions.

respective potential merits, disadvantages and limits.

developments and applications.

*Complexes characterization*

and the study of the chiral recognition mechanism.

nucleotide-derived selectors.

techniques.

students.

solid state.

quantification.


Tejashri et al. (2013) [92]

Moya-Ortega et al. (2012) [198]

Purkayastha et al. (2012) [199]

Martín-Banderas et al. (2011) [200]

Zhang and Ma (2013) [139]

Bilensoy and Hincal (2009) [201]

Szente et al. (2016) [2]

Szente and Szeman (2013) [28]

Dodziuk (2006) [202]

Mosinger et al. (2001) [203]

Armstrong (1998) [204]

Adly et al. (2016) [205]

Guo et al. (2016) [206]

Saz and Marina (2016) [80]

Development of nanosponges as drug delivery systems, with special

Preparation, characterization and advantages for pharmaceutical and

Formation and applications of CD nanoaggregates induced by guest molecules, the concerned thermodynamics behind the process and the effect of concentration of the guest molecules on the morphology of

Approaches employed in delivering drugs to the central nervous system. Changes in blood-brain barrier function in several

Fabrication technologies of supramolecular systems including nanoplatforms and hydrogels as well as their applications in

Classification, physicochemical properties, efficacy and safety of nanoparticles prepared from different amphiphilic CDs are discussed in light of the current literature work with in vitro and in vivo findings.

Classical and modern instrumental analytical methods suitable for identification, characterization and determination of CDs themselves,

CDs in in sample preparation, sensitivity and selectivity improvement,

CDs in finished products or even in biological samples.

enantio-separation, creating single-molecule sensors, and

CDs: from molecular recognition to CDs as enzyme models. Reactivity and chemistry, chromatography, X-ray, NMR plus other physicochemical methods, as well as model calculations, rotaxane and catenane structures, and applications in the pharmaceutical industry

Use of CDs in major areas of analytical chemistry such as

chromatography, electrophoresis, spectroscopy, electrochemistry and

Role of CDs in three of the major areas of modern instrumental analysis: separations, spectroscopy and electrochemical analysis.

CD-functionalized monolithic capillary columns: preparation and

Recent developments in CD functionalized monolithic columns for the

Advances on the use of CDs in the chiral analysis of drugs by capillary

reference to CD based nanosponges.

22 Cyclodextrin - A Versatile Ingredient

the aggregates.

*Reviews*

neurological disorders.

biomedical applications of CD-based nanogels.

nanomedicine and pharmaceutical sciences.

**Analytical and physicochemical applications**

automatizing DNA sequencing.

are overviewed.

*Chirality*

as analytical sensors.

chiral applications.

electrophoresis.

enantioseparation of chiral drugs.


Zhu et al. (2016) [70]

http://dx.doi.org/10.5772/intechopen.72736

Cyclodextrins: Past and Present

25

Szente and Szejtli (1998) [216]

Bersier et al. (1991) [71]

Jemli et al. (2016) [24]

Liu et al. (2015) [217]

Chen and Liu (2010) [218]

Breslow (2009) [23]

Breslow and Dong (1998) [22]

Breslow (1980) [219]

Takachima and Harada (2017) [29]

Zhao et al. (2017) [220]

Wang et al. (2016) [32]

[21]

Aghahosseini and Ramazani

(2016)

*Electrochemical Methods*

electrochemical sensing.

of CD based sensors and detectors.

Advantages and detecting mechanism of electrochemical sensors based on CDs functionalized materials, and recent advances for CDsbased materials (including CDs/carbon nanotubes, CDs/graphene, CDs/conducting polymers and other CDs-based nanomaterials) in

Substrate/analyte solubilization and stabilization to the development

State of the art of the electrochemistry of α-, β-, and γ-CDs and CD inclusion complexes and their polarographic and voltammetric assay.

General overview of three different categories of CD-based artificial enzymes including metal free CD-based artificial enzymes, CD-based artificial metalloenzymes and CD-based artificial enzymes with computational design, focusing on their rate acceleration factor.

Major fields of enzyme application and overview on previous protein engineering studies wherein natural enzymes were modified to meet the operational conditions required for industrial application.

Macromolecules based on recognition between CD and guest

Representative contributions in the construction and the structural characteristics of CD-based supramolecular assemblies and their

New chemistry based on the principles used by Nature: biomimetic

Literature overview on reactions in which CDs bind substrates and then either catalyze their reactions or mimic a step in an enzymatic

Adjusting the lock and adjusting the key in CD chemistry. An

Functioning via host–guest interactions: achievement of selective molecular adhesion, self-healing, toughness, and actuation properties. These functions have been achieved by reversible bond formation with

Qualitative and quantitative analysis of research outputs on molecular

Superstructures with CDs: chemistry and applications. Wenz and Monflier (2016) [221]

Supramolecular polymer assembly in aqueous solution arising from CD host-guest complexation. Effects of such complexation on

properties at the molecular and macroscopic levels.

molecules: synthesis, properties and functions.

interactions with biologically important substrates.

chemistry.

catalytic sequence.

**Miscellaneous**

modeling in CDs.

CDs.

introduction in biomimetic chemistry.

**Enzyme—Biomimetic-Bioactive assemblies recognition**


Takahashi et al. (2012) [68]

Boccio et al. (2006) [212]

Schneider et al. (1998) [213]

Connors (1997) [46]

Lay et al. (2016) [214]

Escuder-Gilabert et al. (2014) [79]

Zhang et al. (2011) [59]

Cserhat and Forgaes (2003) [71]

Crini and Morcellet (2002) [180]

Schneiderman and Stalcup (2000) [61]

Szejtli (1987) [215]

Hinze (1981) [73]

Elbashir et al. (2014) [64]

A literature review of CD inclusion complexes characterization: differential scanning calorimetry and thermogravimetry.

A bilogarithmic method for the spectrophotometric evaluation of stability constants of 1:1 weak complexes from mole ratio data.

NMR studies of CDs and CD complexes. Comprehensive overview about the most important approaches to structural problems with

The stability of CD complexes in solution: binding equilibria and kinetics, strengths and structures of CD complexes, the sources of CD

State-of-the-art applications of CDs as functional monomers in

Separation processes in the presence of CDs using molecular imprinting technology and ionic liquid cooperating approach.

Role of CDs in chromatography. Influence of The formation the physicochemical parameters of the guest molecule (adsorption

Summary of the information concerning the synthesis of materials containing CDs and general overview of the different possible applications of CDs as sorbents in the field of separation techniques.

CDs as a versatile tool in separation science. The techniques examined include gel electrophoresis, isotachophoresis, isoelectric focusing, preparative scale electrophoretic techniques, thinlayer chromatography, electrochemically modulated liquid chromatography, use of monolithic media in liquid chromatography,

microdialysis, separation on hollow fibers, foam flotation enrichment, solid- and liquid-phase extractions, countercurrent chromatography, separation through liquid and composite membranes, and CD applications in molecularly imprinted

Utilization of CDs and their derivatives in gas-liquid and gas-solid-, gel-, inclusion-, thin-layer-, affinity-, and high performance liquid

Applications of CDs in chromatographic separations and purification

Spectrofluorometric analytical applications of CDs based on host-

Room temperature phosphorescence in CDs: analytical applications. Muñoz de la Peña et al. (2000) [66]

CDs in capillary electrophoresis: recent contributions, practical uses (e.g. solute-CD binding constant estimation and further potentials), developments and applications (mainly chiral and achiral analysis).

complex stability and prediction of CD complex stability.

CDs, mainly in solution.

24 Cyclodextrin - A Versatile Ingredient

*Separation Methods*

polymers.

methods.

chromatography.

inclusion complex.

*Spectrofluorometric Methods*

molecular imprinting techniques.

Recent developments and new trends.

capacity, polarity, hydrophobicity, etc.).


**Table 1.** Selected papers on food, pharmaceutical, pharmacology, cosmetic, industrial, and analytical applications of cyclodextrins (CDs).

the number of papers cited by journal for the most cited journal (number of references ≥2) appears. Emphasis is stressed on reviews and taking into account the high number of references available, the authors apologize for those they may have overlooked or inadvertently omitted.

**5. Conclusion**

**Figure 6.** Number of papers cited by journal.

Currently, there are a large number of drugs with poor solubility, bioavailability, permeability issues, undesirable properties as taste and odor, and irritation potential, and CDs can become an useful tool for optimizing drugs problematic [84]. Additionally, new uses of cyclodextrins are being explored, in different fields as nanoparticles, liposome and microsphere. The ability of making inclusion complexes with drugs makes CDs have a great future, as reflected by the rising number of publications and patents having been filed. Some researchers also believe that there will be more a still wider use for CDs as the knowledge about their properties increase [7]. The studies of CD-based nanosystems have recently increased, as they become platforms providing pharmacokinetic and formulation design efficiency without posing security problems [91]. CDs are also generating interest for gene therapy and exploration of non-viral methods,

Cyclodextrins: Past and Present

27

http://dx.doi.org/10.5772/intechopen.72736

**Figure 5.** Number of publications cited per year.

**Figure 6.** Number of papers cited by journal.
