**Abstract**

In recent years, the development of various cyclodextrin (CD)-based nanosponges (NSs) has gained great importance in the controlled and-or targeted release of drugs due to their versatility and simple preparation. In this chapter, an introduction of different administration routes is explained. Further, different ways to obtain CD-NSs and their classification are shown with a brief explanation of the characterization of the inclusion complexes. Finally, illustrative examples in diverse processes or diseases will be reviewed and explained to demonstrate the potential of CD-NSs. Therefore, this division will serve to compile information on CD-NSs in recent years and to illustrate to readers how to generate and apply different derivatives of interest.

**Keywords:** Cyclodextrin nanosponges, drug delivery, synthesis, nanocarrier, release

## **1. Introduction**

Society demands better treatments for each disease and therefore the industry tries to obtain them. Novel drugs with better bioactivity are researched to achieve the best result in our bodies. However, several novel drugs present problems related to their chemical properties that prevent them from being used as a pharma or nutraceutical product. The molecule can be unstable in water solution, and/or easily oxidized, and presents poor bioavailability. Different strategies might improve the current therapy. One possibility is to find a good formulation, which stabilizes the drug or carries it to the desired tissue. Moreover, the adverse effect due to the dosage can also be reduced. For this reason, a great number of carriers are been proposed to challenge the previous problems.

One of them is called cyclodextrin (CD), truncated cone-shaped oligosaccharides made up of α-(1→4) linked glucopyranoside units with six, seven and eight glucose units, α, β and γ-CD, respectively [1, 2]. A derivative called 2-Hydroxypropyl-βCD (HPβ-CD) is used as an orphan drug for Niemann Pick disease type C [3, 4]. Complexes formed of molecules and cyclodextrins (CDs) are called "inclusion complexes". Generally, CDs encapsulate poorly water-soluble compounds and hydrophobic moieties of amphiphilic molecules. Nevertheless, the solubility of these complexes not only depends on the CD used but also on different factors such as pH or guess molecule [5–8]. The capacity of CDs to increase solubility and protect several molecules has increased their use in the pharmaceutical and food industries [1, 9, 10].

However, the improvement achieved by adding CDs is sometimes insufficient. Then, researchers developed a novel material based on these excipients baptized as Cyclodextrin-based Nanosponge (CD-NS), innovative cross-linked polymer structures with a three-dimensional network, and with a crystalline and amorphous structure, spherical and possessing good swelling properties [11]. Recent reviews [12–14] point to their wide potential and minimal toxicity [15, 16]. Some applications of these polymers include i) increasing the apparent solubility of poorly soluble drugs, ii) modulating drug release and activity, iii) protecting drugs against several agents, iv) enhancing bioactivities, v) absorbing contaminants ability, vi) delivering the drug, etc.

Cross-linking CDs brings significant benefits to CD-NSs compared with the respective native CDs. In general, CD-NSs can form complexes with a series of different molecules due to their structure. They achieve a hindered diffusion of loaded guest molecules, thus promoting slower release kinetics [17, 18]. Another important property of CD-NSs is that they can be easily recovered from aqueous media and recycled. Although they are insoluble, soluble hyperbranched NS can also be synthesized [19]. Finally, one of their principal disadvantages has been recently solved, they have been tested as a good carrier not only for small molecules but also for higher ones like proteins [20, 21].

This chapter tends to be a first step for the researcher who starts with CD-NSs: i) an introduction of the routes of administration, including advantages and disadvantages is explained, ii) an explanation about the various types of CD-NSs, including its synthesis and classification is written, iii) the different ways to characterize the inclusion complexes are reported and iv) examples of smart delivery are displayed as an encourage study to demonstrate their potential.

#### **2. Routes of administration, advantages, and disadvantages**

The choice of the route of administration is crucial as it dramatically affects drug bioavailability and thus requires specific delivery strategies. Parenteral routes include intravenous, intramuscular, and subcutaneous routes, whereas the enteral routes are the oral, sublingual, and rectal routes [22]. Others are inhalation, intranasal, etc. [23]. In this section, each route will be described briefly and special attention will be paid to the oral route, which is the most desired but, at the same time, the most challenging.

When administered via intravenous injection (IV), the drug reaches the systemic circulation directly bypassing absorption and carrying out its effect rapidly. This route is ideal for unstable or scarcely absorbed drugs (e.g. blood products), and irritating drug formulations, the administration of which via subcutaneous and intramuscular routes will be painful. It is also intended for patients who are not able to take the formulations orally, due to mental disorders, nausea, or vomiting.

Intramuscular injection (IM) can involve various muscles, including the gluteal muscle to which up to 5 ml of the formulation can be administered. Via this route, aqueous or oil-based solutions, suspensions, and emulsions are accepted. Aqueous solutions are generally absorbed in 10–30 minutes, whereas drugs insoluble at interstitial pH or suspended in oil-based solutions present a long time of absorption. Vascularisation of the muscle, the volume, and the osmolarity of the injected formulations also affect the absorption time. A depot preparation of the drug can

#### *Strategies to Develop Cyclodextrin-Based Nanosponges for Smart Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.100182*

be given via this route with a sustained release of the drug into the bloodstream. IM injection is selected when the drug has a low oral bioavailability or when the patient is not compliant. Vaccines are also administered via this route.

Subcutaneous injections can be given in the forearm or abdomen. Up to 2 ml of the formulation can be administered. Together with aqueous solutions and suspensions, adrenalin can be added to induce vasoconstriction and therefore increase the residence time of drugs (e.g. local anesthetics) or hyaluronidase to make the extracellular matrix more fluid, thus improving the absorption rate.

The absorption rate is extremely variable as it is influenced by the blood flow. Subcutaneous injections are also used for depot formulations. It is easy to administer and requires minimal skills, thus allowing self-administration. Insulin and heparin are given via this route.

Among all, oral delivery has been recognized as the most attractive route, as it is cheap, simple, accepted by patients, requires fewer sterility restrictions, and offers more possibilities in the design of the formulation (including sustained and controlled delivery) [24]. It is used for drugs with topical action in the gut and systemic effects when they reach the bloodstream. However, it is not suitable for emergencies in which an immediate effect is fundamental.

Over the past few years, many efforts have been made to develop oral delivery systems able to overcome the obstacles in the gastrointestinal tract (GI) in which the mechanism of absorption is complex with multiple levels of barriers [24].

There is a long list of variables that influence the GI absorption of drugs, which are grouped in technical challenges, physicochemical properties of the drug, and environmental factors [25].

The technical challenges concern the pharmaceutical form, i.e. liquid or solid. In solid forms, *the rate* and extent of disintegration, and dissolution of the formulation are important to a drug, and to carry out its effect, needs to be in a solution for developing the absorption.

Most drugs are absorbed in the small intestine, characterized by a large surface area of absorption and having a crucial influence on bioavailability.

The walls of the GI tract are characterized by the presence of mucus, which has been a target for drug delivery systems (DDS) capable of mucopenetration or mucoadhesion [24]. Mucopenetration consists in regulating the hydrophobicity/ hydrophilicity of the carrier's matrix or combining mucolytic enzymes to promote drug penetration. On the contrary, mucoadhesive carriers, which have attracted significant attention [26–28], can adhere to mucus, thus increasing the residence time. CD NSs have proven to possess this property, making them particularly promising for oral delivery [20].

Last but not least, the first-pass effect should be borne in mind when dealing with the oral route as it is certainly a limiting factor. It refers to the metabolism (mainly in the liver) of the drug before it reaches the systemic circulation, which may lead to a drop in bioavailability [29]. For this reason, several drugs are administered via other enteral routes (e.g. rectal and sublingual).

The sublingual route offers the benefit of bypassing the first-pass effect due to the passive diffusion through the highly permeable mucosa underneath the tongue. It is simple with a low risk of infection and the effect is rapid. Nitroglycerin is administered via this route.

The rectal route exploits the highly vascularized rectal mucosa for drug absorption. The first-pass effect is partially avoided. It is indicated for patients with gastrointestinal motility problems, nausea, vomiting, and children.

Inhalation is used to obtain a rapid effect as the drug crosses the large surface area of the respiratory tract epithelium and reaches the systemic circulation. It avoids the first-pass metabolism. The particle size and morphology of the


**Table 1.**

*Advantages and disadvantages of the main routes of administration.*

formulation inhaled are crucial. It is mainly used for the treatment of respiratory diseases. The intranasal route enables the drug to be absorbed via passive diffusion across the highly-vascularised respiratory epithelium directly into the systemic circulation. Nasal decongestants and anti-allergic drugs are administered via this route (**Table 1**).
