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Cyclodextrin Multicomponent Complexes: Pharmaceutical Applications

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Cyclodextrin Multicomponent Complexes: Pharmaceutical Applications pharmaceutics Review Cyclodextrin Multicomponent Complexes: Pharmaceutical Applications Virginia Aiassa †, Claudia Garnero †, Marcela R. Longhi *,† and Ariana Zoppi † Unidad de Investigación y Desarrollo en Tecnología Farmacéutica, UNITEFA-CONICET, Departamento de Ciencias Farmacéuticas, Facultad Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba 5000, Argentina; [email protected] (V.A.); [email protected] (C.G.); [email protected] (A.Z.) * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Cyclodextrins (CDs) are naturally available water-soluble cyclic oligosaccharides widely used as carriers in the pharmaceutical industry for their ability to modulate several properties of drugs through the formation of drug–CD complexes. The addition of an auxiliary substance when forming multicomponent complexes is an adequate strategy to enhance complexation efficiency and to facilitate the therapeutic applicability of different drugs. This review discusses multicomponent complexation using amino acids; organic acids and bases; and water-soluble polymers as auxiliary excipients. Special attention is given to improved properties by including information on the solubility, dissolution, permeation, stability and bioavailability of several relevant drugs. In addition, the use of multicomponent CD complexes to enhance therapeutic drug effects is summarized. Keywords: auxiliary agents; complexation efficiency amino acids; organic acids; organic bases; Citation: Aiassa, V.; Garnero, C.; water-soluble polymers Longhi, M.R.; Zoppi, A. Cyclodextrin Multicomponent Complexes: Pharmaceutical Applications. Pharmaceutics 2021, 13, 1099. 1. Introduction https://doi.org/10.3390/ Cyclodextrins (CDs) are a family of macromolecules composed of α-1,4-linked D- pharmaceutics13071099 glucopyranoside subunits obtained by enzymatic degradation of starch [1]. Their structure resembles a truncated cone, with a somewhat lipophilic central cavity and an external Academic Editors: Paola Mura hydrophilic surface. Antoine Villiers discovered the crystalline dextrins that were later and Marzia Cirri recognized as CDs, and he published the first reference to these compounds in 1891 [2]. The most common natural CDs are αCD, βCD and γCD (Figure1), consisting of 6, 7 and 8 Received: 28 May 2021 D-glucose units, and they are the only ones used for pharmaceutical applications. Several Accepted: 15 July 2021 Published: 20 July 2021 researchers have attempted to develop other CD derivatives of pharmaceutical interest. Chemically modified CDs can be obtained from the introduction of different functional Publisher’s Note: MDPI stays neutral groups at the 2, 3 and 6-hydroxyl groups of the glucose residues. These include, for exam- β β β with regard to jurisdictional claims in ple, the hydroxypropyl, methylated and sulfobutylether -cyclodextrins (HP CD, M CD, published maps and institutional affil- SBEβCD), and (2-hydroxy)propyl-γ-cyclodextrin (HPγCD), among others [3]. iations. CDs have been used in pharmaceutical formulations since the 1970s. The first pharmaceutical product containing CD, marketed in Japan in 1976, was Prostarmon E™ (prostaglandin E2:βCD) [4]. Currently, there are various commercial formulations contain- ing CDs. In addition, CD monographs are included in various pharmacopoeias and are accepted as pharmaceutical excipients by various regulatory agencies. The special interest Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. for CDs in the field of pharmaceutical applications is due to their ability to modulate This article is an open access article several properties affecting the performances and therapeutic profiles of drugs. CDs can be distributed under the terms and used to enhance the aqueous solubility of poorly soluble drugs; increase drug permeability conditions of the Creative Commons through biological membranes; improve drug bioavailability and stability; reduce adverse Attribution (CC BY) license (https:// drug reactions, such as gastrointestinal or ocular irritation and other side effects; convert creativecommons.org/licenses/by/ liquids and oils into free-flowing powders; reduce evaporation and stabilize flavors; im- 4.0/). prove palatability and handling; and prevent admixture incompatibilities [5]. It should be Pharmaceutics 2021, 13, 1099. https://doi.org/10.3390/pharmaceutics13071099 https://www.mdpi.com/journal/pharmaceutics Pharmaceutics 2021, 13, x FOR PEER REVIEW 2 of 27 Pharmaceutics 2021, 13, 1099 2 of 26 convert liquids and oils into free-flowing powders; reduce evaporation and stabilize fla- vors; improve palatability and handling; and prevent admixture incompatibilities [5]. It notedshould that be thenoted modified that theγ -CDmodified sugammadex, γ-CD sugammadex developed, bydeveloped the pharmaceutical by the pharmaceutical company Organon,company is Organon used as a, is drug used to as reverse a drug the to neuromuscular reverse the neuromuscular blockade induced blockade by rocuronium induced by androcuronium vecuronium and in vecuronium adults undergoing in adults surgery undergoing [6]. surgery [6]. Figure 1. Molecular structures and three-dimensional side and top views of: (A) αCD, (B) βCD and Figure 1. Molecular structures and three-dimensional side and top views of: (A) αCD, (B) βCD and (C) γCD. The surfaces shown represent the solvent-accessible surface areas (SASAs) in regard to (C) γCD. The surfaces shown represent the solvent-accessible surface areas (SASAs) in regard to water. Colors by atom-type indicate the regions of the molecule that are accessible (red: oxygen; water.grey: Colorscarbon). by SASA atom-types were indicatecalculated the using regions cyclodextrin of the molecule structures that aredeposited accessible in the (red: Cambridge oxygen; grey:Crystallographic carbon). SASAs Data were Centre calculated under 1100537, using cyclodextrin 1107195 and structures 1126611 depositeddeposition innumbers the Cambridge for αCD, CrystallographicβCD and γCD, respec Data Centretively. The under image 1100537, was prepared 1107195 and using 1126611 Pymol deposition v.2.1 and in numbers-house developed for αCD, βPythonCD and scripts.γCD,respectively. The image was prepared using Pymol v.2.1 and in-house developed Python scripts. All these pharmaceutical applications are mostly related to the ability of CDs to form inclusionAll these complexes. pharmaceutical An inclusion applications complex are is mostly formed related by interaction to the abilitys between of CDs guest to form(drug) inclusion and host complexes. (CD) molecules An inclusion, and thus complex requires is formed structural by interactions complementarity between between guest (drug)the interacting and host compounds. (CD) molecules, A drug and–CD thus complex requires that structural can be optimized complementarity with the between addition theof interactingan auxiliary compounds. substance can A drug–CD be called complex a multicomponent that can be optimizedor ternary withcomplex. the addition In these of an auxiliary substance can be called a multicomponent or ternary complex. In these cases, a synergic effect is desired to allow the use of low concentrations of the non-drug cases, a synergic effect is desired to allow the use of low concentrations of the non-drug compounds. The use of multicomponent complex formation with CDs and a third auxil- compounds. The use of multicomponent complex formation with CDs and a third auxiliary iary substance has become more frequent in order to facilitate the therapeutic applicability substance has become more frequent in order to facilitate the therapeutic applicability of of different drugs. The incorporation of small amounts of various additives, such as amino different drugs. The incorporation of small amounts of various additives, such as amino acids; organic acids and bases; and water-soluble polymers in aqueous complexation me- acids; organic acids and bases; and water-soluble polymers in aqueous complexation me- dia can increase the complexation efficiency, which permits the use of considerably lower dia can increase the complexation efficiency, which permits the use of considerably lower quantities of CDs, thereby optimizing the cost, toxicity and formulation volume in the quantities of CDs, thereby optimizing the cost, toxicity and formulation volume in the final product [7–10]. These additives might also interact with CDs in order to improve and final product [7–10]. These additives might also interact with CDs in order to improve modulate the drugs’ physicochemical and transport properties. This interaction can mod- and modulate the drugs’ physicochemical and transport properties. This interaction can ulate in vitro and in vivo drug dissolution, thereby modifying the drug’s pharmacokinetic modulate in vitro and in vivo drug dissolution, thereby modifying the drug’s pharmacoki- neticprofile. profile. Moreover, Moreover, it is itpossible is possible to reduce to reduce other other problematic problematic behaviors behaviors of the of drugs, the drugs, such suchas their as their toxicological toxicological properties, properties, by specifica by specificallylly selecting selecting an auxiliary an auxiliary substance substance that that will willbe beadded added to tothe the multicomponent multicomponent complex. complex. Regarding Regarding the methodologicalmethodological aspects,aspects, the the techniquestechniques commonly commonly usedused toto obtainobtain binary complexes can can be be used used in in the the preparation preparation
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