biomolecules Review Inclusion Complexes of Non-Steroidal Anti-Inflammatory Drugs with Cyclodextrins: A Systematic Review Gustavo Marinho Miranda 1 , Vitória Ohana Ramos e Santos 1, Jonatas Reis Bessa 2 , Yanna C. F. Teles 3 , Setondji Cocou Modeste Alexandre Yahouédéhou 1, Marilda Souza Goncalves 1 and Jaime Ribeiro-Filho 1,* 1 Laboratory of Investigation in Genetics and Translational Hematology, Gonçalo Moniz Institute (IGM), Oswaldo Cruz Foundation (FIOCRUZ), Salvador, BA 40296-710, Brazil; [email protected] (G.M.M.); [email protected] (V.O.R.eS.); [email protected] (S.C.M.A.Y.); marilda.goncalves@fiocruz.br (M.S.G.) 2 Institute of Psychology (IPS), Federal University of Bahia (UFBA), Salvador, BA 40170-055, Brazil; [email protected] 3 Agrarian Sciences Center (CCA), Department of Chemistry and Physics (DQF), Federal University of Paraiba (UFPB), Areia, PB 58397-000, Brazil; [email protected] * Correspondence: jaime.ribeiro@fiocruz.br; Tel.: +55-71-3126-2226 Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most widely used classes of medicines in the treatment of inflammation, fever, and pain. However, evidence has demonstrated that these drugs can induce significant toxicity. In the search for innovative strategies to overcome NSAID-related problems, the incorporation of drugs into cyclodextrins (CDs) has demonstrated promising results. This study aims to review the impact of cyclodextrin incorporation on the biopharmaceutical and pharmacological properties of non-steroidal anti-inflammatory drugs. A systematic search for papers published between 2010 and 2020 was carried out using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol and the following Citation: Miranda, G.M.; Santos, search terms: “Complexation”; AND “Cyclodextrin”; AND “non-steroidal anti-inflammatory drug”. V.O.R.e; Bessa, J.R.; Teles, Y.C.F.; A total of 24 different NSAIDs, 12 types of CDs, and 60 distinct inclusion complexes were identified, Yahouédéhou, S.C.M.A.; Goncalves, with meloxicam and β-CD appearing in most studies. The results of the present review suggest that M.S.; Ribeiro-Filho, J. Inclusion CDs are drug delivery systems capable of improving the pharmacological and biopharmaceutical Complexes of Non-Steroidal properties of non-steroidal anti-inflammatory drugs. Anti-Inflammatory Drugs with Cyclodextrins: A Systematic Review. Biomolecules 2021, 11, 361. https:// Keywords: cyclodextrins; non-steroidal anti-inflammatory drugs; inclusion complexes doi.org/10.3390/biom11030361 Received: 28 January 2021 Accepted: 22 February 2021 1. Introduction Published: 27 February 2021 Inflammation is the body’s response to tissue damage, which aims to restore the integrity of the injured tissue through different mechanisms of induction, regulation, and Publisher’s Note: MDPI stays neutral resolution. Regardless of the aggressor stimulus, this response is essential for the restoration with regard to jurisdictional claims in of homeostasis and, therefore, plays an important physiological role [1,2]. published maps and institutional affil- While inflammation is essential for the host defense against pathogens, it frequently iations. occurs in the absence of infection, a phenomenon known as sterile inflammation [3,4]. Ac- cordingly, despite the existence of efficient control mechanisms, failures in the resolution of inflammation often occur, which contributes significantly to the pathogenesis of several chronic diseases [5,6]. In these cases, the inflammatory response is the main cause of tissue in- Copyright: © 2021 by the authors. jury and disease progression, besides contributing to the severity of other comorbidities [7,8]. Licensee MDPI, Basel, Switzerland. The classical therapeutic strategies for inflammatory diseases are mostly based on This article is an open access article the use of anti-inflammatory drugs that act by either inhibiting the production of pro- distributed under the terms and inflammatory mediators or preventing the recruitment and activation of leukocytes at the conditions of the Creative Commons inflammatory site [9,10]. In this context, non-steroidal anti-inflammatory drugs (NSAIDs) Attribution (CC BY) license (https:// are one of the most widely used drug classes in the treatment of inflammation, fever, creativecommons.org/licenses/by/ and pain. The mechanism of action underlying the anti-inflammatory, antipyretic, and 4.0/). Biomolecules 2021, 11, 361. https://doi.org/10.3390/biom11030361 https://www.mdpi.com/journal/biomolecules BiomoleculesBiomolecules 20212021,,, 1111,,, xxx 22 ofof 2424 areare oneone ofof thethe mostmost widelywidely usedused drugdrug classesclasses inin thethe treatmenttreatment ofof inflammation,inflammation, fever,fever, andand pain.pain. TheThe mechanismmechanism ofof actionaction underlyingunderlying thethe anti-inflammatory,anti-inflammatory, antipyretic,antipyretic, andand anal-anal- gesicgesic effectseffects ofof NSAIDsNSAIDs involvesinvolves thethe inhibiinhibitiontion ofof cyclooxygenasescyclooxygenases (COXs),(COXs), enzymesenzymes thatthat areare criticallycritically responsibleresponsible forfor thethe synthesissynthesis ofof prostaglandins,prostaglandins, thromboxanes,thromboxanes, andand otherother Biomolecules 2021, 11, 361 prostanoidsprostanoids [11,12].[11,12]. ProstaglandinProstaglandin EE22 (PGE(PGE(PGE22)) isis producedproduced inin aa widewide varietyvariety ofof tissues,tissues, 2 play-play- of 22 inging crucialcrucial rolesroles inin vasodilationvasodilation andand hyperalgesiahyperalgesia inin additionaddition toto interactinginteracting withwith pro-in-pro-in- flammatoryflammatory cytokinescytokines thatthat generategenerate feverfever [13,14].[13,14]. Thus,Thus, thethe mechanismmechanism ofof actionaction ofof NSAIDsNSAIDs resultsresults inin thethe inhibitioninhibition ofof keykey clinicclinicalal signssigns suchsuch asas redness,redness, warmth,warmth, pain,pain, andand analgesic effects of NSAIDs involves the inhibition of cyclooxygenases (COXs), enzymes swellingswelling [2].[2]. that are critically responsible for the synthesis of prostaglandins, thromboxanes, and other WhileWhile non-selectivenon-selective NSAIDsNSAIDs inhibitinhibit bothboth COX-1COX-1 andand COX-2COX-2 isoforms,isoforms, selectiveselective prostanoids [11,12]. Prostaglandin E2 (PGE2) is produced in a wide variety of tissues, NSAIDsNSAIDs werewere developeddeveloped toto preferentiallypreferentially iinhibitnhibit COX-2,COX-2, whichwhich waswas expectedexpected toto potenti-potenti- playing crucial roles in vasodilation and hyperalgesia in addition to interacting with pro- ate anti-inflammatory effects and reduce adverse effects. However, accumulating evi- ateinflammatory anti-inflammatory cytokines effects that generateand reduce fever ad [verse13,14 ].effects. Thus, However, the mechanism accumulating of action evi- of dence has demonstrated that these drugs can induce significant toxicity [15]. Therefore, denceNSAIDs has results demonstrated in the inhibition that these of keydrugs clinical can in signsduce suchsignificant as redness, toxicity warmth, [15]. Therefore, pain, and the development of innovative, safe, and effective anti-inflammatory drugs remains chal- theswelling development [2]. of innovative, safe, and effective anti-inflammatory drugs remains chal- lenging [16]. lengingWhile [16]. non-selective NSAIDs inhibit both COX-1 and COX-2 isoforms, selective NSAIDsInIn thethe were searchsearch developed forfor innovativeinnovative to preferentially strategiesstrategies inhibit toto overcomeovercome COX-2, which NSAID-relatedNSAID-related was expected problems,problems, to potentiate nano-nano- technology-basedanti-inflammatorytechnology-based effectsformulationsformulations and reduce havehave adverse beenbeen developeddeveloped effects. However, toto improveimprove accumulating thethe pharmacokineticpharmacokinetic evidence has propertiesdemonstratedproperties ofof drugsdrugs that these asas wellwell drugs asas theirtheir can interactioninteraction induce significant withwith theirtheir toxicity molecularmolecular [15]. Therefore, targets.targets. InIn thethisthis develop- context,context, thementthe incorporationincorporation of innovative, ofof safe, drugsdrugs and intointo effective cyclodextrinscyclodextrins anti-inflammatory representedrepresented drugs aa revolutionrevolution remains challenginginin drugdrug deliverydelivery [16]. systemssystemsIn the[17,18].[17,18]. search for innovative strategies to overcome NSAID-related problems, nanotechnology-basedCyclodextrinsCyclodextrins (CDs)(CDs) formulations areare cycliccyclic oligosaccharidesoligosaccharides have been developed formedformed to improve byby αα-D-glucopyranose-D-glucopyranose the pharmacokinetic unitsunits linkedpropertieslinked byby αα of-1.4-1.4 drugs bonds,bonds, as well whichwhich as containcontain their interaction aa hydrophobichydrophobic with their centralcentral molecular cavitycavity andand targets. aa hydrophilichydrophilic In this context, outerouter surfacethesurface incorporation [19].[19]. TheyThey are ofare drugs classifiedclassified into accordingaccording cyclodextrins toto thethe represented numbernumber ofof aglucopyranoseglucopyranose revolution in units drugunits in deliveryin αα-CD,-CD, βsystemsβ-CD,-CD, oror [ γ17γ-CD-CD,18]. asas theythey presentpresent six,six, seven,seven, andand eighteight units,units, respectively.respectively. TheyThey maymay bebe pre-pre- sentedsentedCyclodextrins asas derivativesderivatives (CDs) suchsuch are asas