The Prodrug Approach: a Successful Tool for Improving Drug Solubility
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Review The Prodrug Approach: A Successful Tool for Improving Drug Solubility Daniela Hartmann Jornada, Guilherme Felipe dos Santos Fernandes, Diego Eidy Chiba, Thais Regina Ferreira de Melo, Jean Leandro dos Santos and Man Chin Chung * Received: 14 October 2015 ; Accepted: 15 December 2015 ; Published: 29 December 2015 Academic Editors: Thomas Rades, Holger Grohganz and Korbinian Löbmann Faculdade de Ciências Farmacêuticas, UNESP—University Estadual Paulista, Rodovia Araraquara Jaú Km 01, 14801-902 Araraquara, São Paulo, Brasil; [email protected] (D.H.J.); [email protected] (G.F.S.F.); [email protected] (D.E.C.); [email protected] (T.R.F.M.); [email protected] (J.L.S.) * Correspondence: [email protected]; Tel.: +55-16-3301-6962; Fax: +55-16-3301-6960 Abstract: Prodrug design is a widely known molecular modification strategy that aims to optimize the physicochemical and pharmacological properties of drugs to improve their solubility and pharmacokinetic features and decrease their toxicity. A lack of solubility is one of the main obstacles to drug development. This review aims to describe recent advances in the improvement of solubility via the prodrug approach. The main chemical carriers and examples of successful strategies will be discussed, highlighting the advances of this field in the last ten years. Keywords: prodrug; solubility; water-soluble prodrugs; solubility of prodrugs; molecular modification 1. Introduction Poor solubility is one of the main problems faced by researchers during drug development. Commonly, even with the use of current computational “filters” to minimize this problem, compounds that are active in vitro may lack adequate pharmacokinetic properties and/or may be difficult to formulate [1]. A study conducted with the top 200 oral drug products in Japan, Great Britain, United States and Spain revealed that approximately 37% of drugs had solubilities of less than 0.1 mg/mL. One explanation may include the need for drugs that are highly potent in low doses, however, this issue represents a challenge in drug discovery [2]. Although the prodrug approach is often considered only when the prototype presents unexpected problems, this strategy offers a versatile approach to drug development and should not be considered a last resort. The prodrug approach is a promising molecular modification by which drug developers and designers can modulate drug pharmacokinetics, pharmacodynamics and toxicology [3]. A prodrug is a poorly active or inactive compound containing the parental drug that undergoes some in vivo biotransformation through chemical or enzymatic cleavage, enabling the delivery of the active molecule at efficacious levels [1,3,4]. Prodrugs are conventionally classified in two major classes: carrier-linked prodrugs and bioprecursors. Carrier-linked prodrugs can be classified as bipartite prodrugs, in which the carrier is linked directly to the parent drug, and tripartite prodrugs, in which a spacer links the carrier to the parent drug [5]. Carriers are commonly attached by chemical groups such as ester, amide, carbamate, carbonate, ether, imine, phosphate, among others [1,6,7] (Figure1). Mutual prodrugs are a type of carrier-linked prodrug in which two active compounds are linked each acting as the carrier to the other. These prodrugs have increased effectiveness through synergistic action [5,8]. Another type of carrier-linked prodrug is the macromolecular prodrug; these prodrugs use polymeric backbones as carriers. Macromolecular prodrugs are commonly used to design prodrugs that will be cleaved inside of a cell and in targeted drug-delivery systems. This approach offers improved drug Molecules 2016, 21, 42; doi:10.3390/molecules21010042 www.mdpi.com/journal/molecules Molecules 2016, 21, 42 2 of 31 Molecules 2016, 21, 42 2 of 30 solubility,offers improved stability, drug drug solubility, release and stability, pharmacokinetics. drug release Additionally, and pharmacokinetics. it can facilitate Additionally, the accumulation it can offacilitate a drug at the the accumulation site of action of and a drug improve at the site safety of action [9,10]. and Bioprecursors improve safety are [9,10]. inactive Bioprecursors compounds are that doinactive not have compounds a carrier and that are do rapidly not have converted a carrier to and an activeare rapidly drug converted after metabolic to an reactionsactive drug (normally after redoxmetabolic reactions) reactions [5,8]. (normally redox reactions) [5,8]. FigureFigure 1. 1.In In vivo vivobioactivation bioactivation of of prodrugsprodrugs byby enzymaticenzymatic and/or and/or chemical chemical transformations. transformations. Undesirable properties, including poor aqueous solubility, chemical instability, insufficient oral or Undesirablelocal absorption, properties, fast pre-syst includingemic poor metabolism, aqueous solubility,low half-life, chemical toxicity instability, and local insufficient irritation oralare or localcommonly absorption, resolved fast pre-systemic using the prodrug metabolism, approach. low In half-life, addition, toxicity problems and related local irritation to drug formulation are commonly resolvedand delivery using thecan prodrugalso be overcome approach. by In using addition, this st problemsrategy [1,11–13]. related toOccasionally, drug formulation strategies and such delivery as canparticle-size also be overcome reduction, by solubilizing using this strategy excipients, [1, 11complexation–13]. Occasionally, agents and strategies use of suchsurfactants as particle-size fail to reduction,improve solubilizingthe solubility excipients,in water profile complexation and reduce agents toxicity and to usedesirable of surfactants levels [13,14]. fail toFor improve example, the solubilitysome surfactants in water profileused in and parenteral reduce toxicityformulations to desirable frequently levels have [13 ,toxic14]. Foreffects example, such as some anaphylactic surfactants usedreactions in parenteral [14]. formulations frequently have toxic effects such as anaphylactic reactions [14]. However,However, in in some some cases, cases, low-solubility low-solubility compoundscompounds yield yield false-positive false-positive results results on on in invitro vitro assaysassays duedue to to non-specific non-specific binding binding [15[15].]. Moreover,Moreover, in clinical trials, trials, low-solubility low-solubility drugs drugs can can lead lead to to precipitationprecipitation and and crystalluria, crystalluria, raising raising additionaladditional safety concerns. concerns. Poorly Poorly soluble soluble drugs drugs have have recently recently beenbeen discontinued discontinued in in clinical clinical assays assays forfor thisthis reasonreason [[15,16].15,16]. ForFor these these reasons, reasons, the the prodrug prodrug approach approach presents presents a safe a andsafe effectiveand effective strategy strategy by which by which to improve to theimprove solubility the ofsolubility drugs. Thisof drugs. review This aims review to presentaims to thepresent latest the strategies latest strategies in prodrug in prodrug design design used to obtainused water-solubleto obtain water-soluble compounds comp forounds oral andfor oral parenteral and parenteral uses. We uses. selected We selected research research from thefrom last the ten last ten years (2005 through August of 2015) showing increased solubility through the prodrug years (2005 through August of 2015) showing increased solubility through the prodrug approach. approach. In the literature search, we used the following terms: “water-soluble prodrugs”, “increased In the literature search, we used the following terms: “water-soluble prodrugs”, “increased solubility solubility prodrugs” and “enhanced solubility prodrugs” in published databases including PubMed, prodrugs” and “enhanced solubility prodrugs” in published databases including PubMed, LILACS, LILACS, Scielo, Cochrane, Web of Science and Scopus. Scielo, Cochrane, Web of Science and Scopus. 2. Ester Prodrugs 2. Ester Prodrugs The features of an ideal prodrug include the following: (a) hydrolysis resistance during The features of an ideal prodrug include the following: (a) hydrolysis resistance during absorption; absorption; (b) weak or no activity; (c) aqueous solubility; (d) good permeability through the cells; (b) weak or no activity; (c) aqueous solubility; (d) good permeability through the cells; (e) chemical Molecules 2016, 21, 42 3 of 31 stabilityMolecules at different 2016, 21, 42 pHs; (f) kinetics that allow release of the parental drug [17]. Among the3 chemicalof 30 bonds(e) used chemical to link stability the parentalat different drug pHs; and (f) kinetics carrier, that esters allow have release proven of the parental to be promising drug [17]. dueAmong to their amenabilitythe chemical to hydrolysis bonds used both to linkin vivothe parentaland in vitrodrug. and Some carrier, examples esters have of the proven use of to estersbe promising in prodrug designdue are to discussedtheir amenability below. to hydrolysis both in vivo and in vitro. Some examples of the use of esters in Theprodrug enzyme design thioredoxin–thioredoxin are discussed below. reductase plays an important role in thioredoxin system by catalyzingThe the enzyme reduction thioredoxin–thioredoxin of thioredoxin. Specifically, reductase play the thioredoxins an important system role in participatesthioredoxin system in protecting by DNAcatalyzing against oxidativethe reduction damage of thioredoxin. and has Specifically been implicated,