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The Development of Oral Amphotericin B to Treat Systemic Fungal and Parasitic Infections: Has the Myth Been Finally Realized?

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The Development of Oral Amphotericin B to Treat Systemic Fungal and Parasitic Infections: Has the Myth Been Finally Realized? pharmaceutics Perspective The Development of Oral Amphotericin B to Treat Systemic Fungal and Parasitic Infections: Has the Myth Been Finally Realized? Grace Cuddihy 1, Ellen K. Wasan 1, Yunyun Di 1 and Kishor M. Wasan 1,2,* 1 College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 2Z4, Canada; [email protected] (G.C.); [email protected] (E.K.W.); [email protected] (Y.D.) 2 Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada * Correspondence: [email protected] Received: 30 January 2019; Accepted: 19 February 2019; Published: 26 February 2019 Abstract: Parenteral amphotericin B has been considered as first-line therapy in the treatment of systemic fungal and parasitic infections, however its use has been associated with a number of limitations including affordability, accessibility, and an array of systemic toxicities. Until very recently, it has been very challenging to develop a bioavailable formulation of amphotericin B due to its physical chemical properties, limited water and lipid solubility, and poor absorption. This perspective reviews several novel oral Amphotericin B formulations under development that are attempting to overcome these limitations. Keywords: oral formulation; amphotericin B; fungal infections; parasitic infections; developing world; drug delivery 1. Preamble One of the authors (KMW) was presenting grand rounds to the infectious disease group at Vancouver General Hospital, discussing combination therapies to treat systemic fungal infections, particularly those patients who were about to go through organ transplantation. An infectious disease physician asked if it was possible to develop an oral formulation of amphotericin B to treat patients. This physician commented that if an oral formulation could be developed, then it would be widely used, because it would have the potential to overcome many of the limitations of intravenous administration. These limitations include affordability, accessibility, and the well-known systemic toxicities associated with amphotericin B. At the time, KMW considered it extremely challenging to develop a bioavailable formulation of amphotericin B that would achieve the tissue concentrations required to have a pharmacological effect and ameliorating the dose-dependent nephrotoxicity associated with the drug. Factors include the large molecular weight of amphotericin B, its amphoteric physical chemical nature, very poor water and lipid solubility, as well as acid lability. However, as KMW thought about it, it became clear that with a growing understanding of dietary and excipient lipid processing in the gastrointestinal tract (GIT) as well as associated new drug delivery technologies, it could in fact be possible to develop an efficacious oral formulation. 2. Purpose The aim of this perspective is firstly to provide sufficient background information on both amphotericin B (AmB) and the target disease leishmaniasis, as well as to explain the need for an oral formulation of this life-saving medication. Secondly, our purpose is to describe pharmaceutical advances that have led to several novel AmB formulations which have emerged over the last decade. Pharmaceutics 2019, 11, 99; doi:10.3390/pharmaceutics11030099 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2019, 11, x FOR PEER REVIEW 2 of 16 Pharmaceutics 2019, 11, 99 2 of 16 Equally important is to discuss the role of formulation in reducing specific barriers to treatment in Equallyhighly endemic important regions is to discussof visceral the leishmaniasi role of formulations, such as in cost reducing and storage specific considerations. barriers to treatment in highly endemic regions of visceral leishmaniasis, such as cost and storage considerations. 3. Chemistry of AmB 3. Chemistry of AmB 3.1. Structure Overview 3.1. Structure Overview AmB has a large, highly complex structure (Figure 1). It is classified as a polyene macrolide antibiotic;AmB hasspecifically, a large, highlyit is known complex as a macrolide structure (Figurebecause1). it Itcontains is classified a polyketide as a polyene that is macrolidelinked to a antibiotic;mycosamine specifically, sugar. Furthermore, it is known it as is a classified macrolide as because a polyene it contains macrolide a polyketide due to the that presence is linked of the to ahydrophobic mycosamine polyene sugar. Furthermore,subunit, whic ith isis classifiedattached asto athe polyene hydrophilic macrolide polyol due portion to the of presence the molecule of the hydrophobic[1]. Overall, polyeneit consists subunit, of a which 38-membered is attached macrolactone to the hydrophilic ring, polyol which portion is β-glycosylated of the molecule with [1]. Overall,mycosamine it consists at the of C-19 a 38-membered hydroxyl position macrolactone [1]. Seven ring, conjugated which is βdouble-glycosylated bonds comprise with mycosamine the polyene at thesubunit, C-19 hydroxylwhile an positionester and [1 ].a Sevenketone conjugated separated doubleby 12 carbons bonds comprise and substituted the polyene with subunit, six hydroxyl while angroups ester comprise and a ketone the separatedpolyol subunit by 12 of carbons the molecule. and substituted with six hydroxyl groups comprise the polyol subunit of the molecule. Figure 1. Structure of amphotericin B in zwitterionic form. Figure 1. Structure of amphotericin B in zwitterionic form. 3.2. Structure-Activity Relationship 3.2. Structure-Activity Relationship The structure-activity relationship of AmB has been the focus of numerous studies over the last threeThe structure-activity decades, which are relationship briefly outlined of AmB below. has been Generalizations the focus of numerous can be made studies with over regard the last to thethree pharmacophore decades, which of are this briefly molecule: outlined The positivelybelow. Generalizations charged amino can group be made is required with regard for activity; to the thepharmacophore polyene subunit of this is importantmolecule: forThe activity; positively if thecharged carboxyl amino group group is negatively is required charged, for activity; it leads the topolyene decreased subunit selectivity is important for ergosterol for activity; over if cholesterol; the carboxyl and group conversely, is negatively N-aminoacylation charged, it leadsleads toto improveddecreased selectivityselectivity [ 1for]. ergosterol over cholesterol; and conversely, N-aminoacylation leads to improved selectivity [1]. 3.3. Mechanism of Action of AmB 3.3. Mechanism of Action of AmB Polyene antifungals such as AmB act by binding with ergosterol of the fungal cell walls and formingPolyene pores antifungals which permit such leakage as AmB of cell act contents,by binding which with eventually ergosterol results of the in fungal apoptosis cell [walls2,3]. Thisand bindingforming of pores AmB which to ergosterol permit occursleakage through of cell contents, hydrophobic which interactions, eventually disrupting results in apoptosis the lipid membrane [2,3]. This integritybinding andof AmB resulting to ergosterol in the formation occurs ofthrough pores [4hydrophobic,5]. These channels interactions in the, celldisrupting membrane the allowlipid effluxmembrane of small integrity ions and and other resulting macromolecules, in the formation such of aspores potassium [4,5]. These and channels magnesium in the [6, 7cell]. Simulation membrane ofallow the AmB–ergosterolefflux of small structureions and findsother that macromolecules, the formed pores such promote as potassium water transport and magnesium across the [6,7]. cell membrane,Simulation whichof the mightAmB–ergosterol further disrupt structure the intracellular finds that the environment formed pores [8]. Recentpromote evidence water indicatestransport thatacross ergosterol the cell bindingmembrane, and which pore formation might further may notdisr beupt the the only intracellular mechanism environment leading to fungal[8]. Recent cell death.evidence It has indicates been reported that ergosterol that AmB binding could killand yeasts pore byformation extracting may ergosterols not be the from only cell mechanism membrane lipidleading layers to fungal [9,10]. cell Furthermore, death. It has it hasbeen been reported proposed that AmB that AmB could causes kill yeasts accumulation by extracting of intracellular ergosterols reactivefrom cell oxygen membrane species lipid (ROS), layers which [9,10]. also contributes Furthermore, to the it antifungal has been effect proposed of this that drug AmB [11]. Severalcauses studiesaccumulation have described of intracellular elevated reactive ROS in oxygen fungal specie cells treateds (ROS), with which AmB also [12 contributes,13]. However, to the it antifungal is still not cleareffect how of this AmB drug induces [11]. Several ROS production. studies have described elevated ROS in fungal cells treated with AmB [12,13]. However, it is still not clear how AmB induces ROS production. Pharmaceutics 2019, 11, 99 3 of 16 3.4. Bioavailability of AmB The complexity of the AmB molecule is partly due to the individual functional groups present but also due to the asymmetry of the important subunits that make up the molecule. For instance, the polyol subunit is highly hydrophilic with many hydrogen bond donors and acceptors available to interact with molecules of water. By contrast, the polyene subunit is highly hydrophobic, as it consists of seven conjugated double bonds in a hydrocarbon chain 14 carbons in length. In addition to the amphiphilic nature of AmB,
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