Cyclodextrin Inclusion Complexes for Improved Drug Bioavailability and Activity: Synthetic and Analytical Aspects

Abstract

Many active pharmaceutical ingredients show low oral bioavailability due to factors such as poor solubility and physical and chemical instability. The formation of inclusion complexes with cyclodextrins, as well as cyclodextrin-based polymers, nanosponges, and nanofibers, is a valuable tool to improve the oral bioavailability of many drugs. The microencapsulation process modifies key properties of the included drugs including volatility, dissolution rate, bioavailability, and bioactivity. In this context, we present relevant examples of the stabilization of labile drugs through the encapsulation in cyclodextrins. The formation of inclusion complexes with drugs belonging to class IV in the biopharmaceutical classification system as an effective solution to increase their bioavailability is also discussed. The stabilization and improvement in nutraceuticals used as food supplements, which often have low intestinal absorption due to their poor solubility, is also considered. Cyclodextrin-based nanofibers, which are polymer-free and can be generated using environmentally friendly technologies, lead to dramatic bioavailability enhancements. The synthesis of chemically modified cyclodextrins, polymers, and nanosponges based on cyclodextrins is discussed. Analytical techniques that allow the characterization and verification of the formation of true inclusion complexes are also considered, taking into account the differences in the procedures for the formation of inclusion complexes in solution and in the solid state.

Keywords: anticancer drug carriers; bioavailability enhancement; cyclodextrin analytical techniques; cyclodextrin nanofibers; cyclodextrin synthesis; drug–cyclodextrin inclusion complexes; nanosponges.

Figure 1

General structure of the natural cyclodextrins. The glucopyranose rings are identified with the letters A–H. Positions 2, 3, and 6 bear hydroxyl groups. The secondary hydroxyls (C₂ and C₃) are oriented toward the broader rim of the cyclodextrin cavity and the primary hydroxyls (C₆) are oriented toward the narrower rim.

Figure 2

Main factors affecting bioavailability.

Figure 3

The biopharmaceutical classification system.

Figure 4

A general illustration of the comparison of the percentage of drug release (% D.R.) in oral formulations. Enhancement of drug release for a drug-CD inclusion complex with respect to the free drug.

Figure 5

General illustration of the comparison of plasma concentration–time profiles of drugs after oral administration of an aqueous drug solution, commercially available oral pharmaceutical dosage form, and the corresponding CD inclusion complexes and polymers based on CD complexes.

Figure 6

Some compounds whose bioavailability is increased by cyclodextrin inclusion due to improved solubility.

Figure 7

Representative members of the camptothecin family of anticancer drugs.

Figure 8

Drugs for which specific cyclodextrin-related formulations have overcome administration issues.

Figure 9

The Enhanced Permeability Retention (EPR) effect. The arrows represent drug movement across the membrane.

Figure 10

Cyclodextrin-based nanoparticles for combined photothermal therapy/chemotherapy.

Figure 11

Structures of curcumin and naringenin—two diet components that increase their bioavailability upon CD complexation.

Figure 12

Some drugs and agrochemicals that have been formulated as cyclodextrin nanofibers.

Figure 13

(A) Basic functionalization rules for cyclodextrins. (B) Positional isomers of difunctionalized (upper row) and trifunctionalized (bottom row) derivatives of α-cyclodextrin. The capital letters represent the individual glucose units.

Figure 14

Representative monofunctionalization reactions at the cyclodextrin primary rim.

Figure 15

Regioselective AC and AD capping of β-cyclodextrin.

Figure 16

Selective debenzylation of the AD primary hydroxyls in α-cyclodextrin by DIBAL-H.

Figure 17

Mechanism of atom transfer radical polymerization (ATRP).

Figure 18

(A) Synthesis of per-acylated β-CD via treatment with 2-bromoisobutyryl anhydride. (B) Selective functionalization of the cyclodextrin primary rim using a radical thiol–ene reaction. (C) Core-based synthesis of a 21-arm star polymer using the ATRP method.

Figure 19

(A) Synthesis of a β-cyclodextrin derivative containing an acrylate moiety by opening of the epoxide moiety in glycidyl methacrylate with 6-monopiperazino-β-cyclodextrin. (B) Synthesis of a β-cyclodextrin derivative containing an acrylate moiety via a CuAAC reaction. (C) Synthesis of a CD-pendant polymer using the ATRP method.

Figure 20

Simplified mechanism of the RAFT polymerization process.

Figure 21

Application of the RAFT polymerization process to a cyclodextrin substrate.

Figure 22

Ring-opening polymerization carried out on a cyclodextrin substrate.

Figure 23

(A) Synthesis of PNIPAM, a polymer containing an alkyne moiety joined to poly(N-isopropylacrylamide. (B) Coupling of PNIPAM to a primary rim azido-CD via the CuAAC reaction. (C) Synthesis of a 21-star polymer via a CuAAC reaction of a per-azidocyclodextrin with PNIPAM.

Figure 24

Main methodologies to access covalently CD-embedded hydrogels.

Figure 25

Structure and synthesis of CD-based nanosponges.