**4. A primer on pharmaceutical, food and cosmetic cyclodextrin studies**

#### **4.1. Bioavailability**

Finally, the stability of the inclusion complex, in general, decreases when temperature increases [46]. Enthalpy and entropy changes can be obtained from the temperature dependence of the equilibrium constant. An important issue, often overlooked in the CD field, is that the magnitudes of the standard free energy and entropy changes are dependent on the

In the last years, CDs and their derivatives have been used in a variety of fields of analytical chemistry, especially in analytical separations [45, 58–63]. Spectral properties of CD and guest molecules can be altered due to the changes of the electrons distribution in the CD hole. CDs are used as reagent in different analyses such as UV-visible spectrophotometry, fluorescence [64, 65], phosphorescence [66, 67], and nuclear magnetic resonance methods [45, 68, 69].

The complexation of the analyte and/or the colored reagent can effectively change its properties. Among the most notable uses of this effect are: (i) enhancing the solubility of polar or non-polar analyte; (ii) enhancing the stability in polar or non-polar solution of reagents and colored complexes; (iii) increasing UV-visible absorption which improves the sensitivity of the colored reactions; and (iv) enhancing colored reactions selectivity. Luminescence techniques, in terms of fluorimetry and phosphorimetry, have reached a rapid development in routine analysis. However, many compounds luminesce very weakly in aqueous solution and the addition of CDs protects the excited (singlet or triplet) states of the possible dampers present in the solution since the rotation of the molecules is impeded due to the formation of the complex of inclusion with the result of a decrease in vibrational relaxation processes. The formation of inclusion complexes also increases the quantum fluorescence yield and hence the fluorescence intensities of numerous compounds. Sensitivity to certain characteristic reac-

CDs also increase the emission intensity of the chemiluminescent reactions. This improvement can be attributed to a number of factors, including an increase in the reaction rate and a greater efficiency in the process of excitation and protection of species that emit quenching phenomena. One of the most relevant applications of CDs is to allow the observation of phosphorescence at room temperature [67]. This is because they protect the excited triplet state of the molecules of the shock absorbers present in the solution, and in the case of molecular quenching phosphorescence. They are used as chiral reagents in NMR. In many cases, the formation of inclusion compounds modifies the general characteristics and chemical shifts of two enantiomers. Differences in the chemical shifts of two diastereoisomers can be used for the determination of the isomeric purity of the samples. The formation of inclusion complexes can very significantly modify the redox characteristics [13, 70, 71] of the included molecules. Voltammetric sensors capable of responding to anionic compounds have been developed. The changes produced after the complexation (selective interaction) allow the voltammetry to be used in the study of the complexation between CDs and

standard state chosen by the experimentalist.

8 Cyclodextrin - A Versatile Ingredient

tions also increases.

organic molecules.

**3. Analytical and physicochemical applications**

CDs have mainly been used as complexing agents to improve the aqueous solubility of molecules. This allows the use of CDs to reduce or prevent gastrointestinal or ocular irritation by lowering the local concentration of the free drug below the irritancy threshold. Also, unpleasant odor or taste of drugs can be hidden by complexation of the functional groups that produce them with CDs, occulting them from the sensory receptors [83–85], furthermore, reducing their hydrophobicity using CDs. Finally, CDs can increase percutaneous or rectal absorption of drugs and their derivatives can increase the guest molecule bioavailability [84]. Recently, CDs and their derivatives have been used in dispersed vehicle systems such as emulsions, microcapsules, microspheres, nanospheres, nanocapsules, liposomes, and beads [86]. Additionally, the host-guest property allows CDs to be used as building blocks in supramolecular chemistry [7]. Suvarna et al. [87] explain an insight in the use of CDs to increase the bioavailability to resolve the problem of solubility and stability of phytochemicals. The authors describe that some chemicals as quercetin, curcumin, arteminsinin, resveratrol or naringenin increased their bioavailability due to the inclusion complexes with CDs. Authors concluded that CDs need to be more explored to cover some molecules that have potential biological activity but have not been approached.

#### **4.2. Encapsulation**

The encapsulation with CDs is gaining interest in different industries; this is reflected in the large number of publication and products related with it, such as drug delivery systems [7, 35]. This capacity of encapsulating compounds is used for a wide variety of things, among them is to protect the compounds, or to transport them to a target. This ability is due to the toroidal shape of CDs which makes possible to encapsulate hydrophobic molecules fully or 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 all of them a sustained release [88].

CD-based nanosponge let drugs to be released in a controlled form at the target place, and its spherical shape let nanosponge to be administered as parental, aerosol, topical, tablets, and

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

capacity of CDs, but they concluded that there is a necessity of more studies in this aspect.

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 pro-

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**,

or pH values. They also reviewed the antioxidant

Cyclodextrins: Past and Present

11

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

capsules forms.

the repercussion on important factors as KF

viding new cosmetic formulations.

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

**4.5. Food**

**4.6. Cosmetic**

#### **4.3. Controlled release**

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

#### **4.4. Nano**

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 CD-based nanosponge let drugs to be released in a controlled form at the target place, and its spherical shape let nanosponge to be administered as parental, aerosol, topical, tablets, and capsules forms.
