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WO2017180714A1 - Activité antifongique de polymères séquestrant le fer - Google Patents

Activité antifongique de polymères séquestrant le fer Download PDF

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Publication number
WO2017180714A1
WO2017180714A1 PCT/US2017/027158 US2017027158W WO2017180714A1 WO 2017180714 A1 WO2017180714 A1 WO 2017180714A1 US 2017027158 W US2017027158 W US 2017027158W WO 2017180714 A1 WO2017180714 A1 WO 2017180714A1
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Prior art keywords
composition
chelator
polyamine
polymer
site
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Inventor
Cory Berkland
Jian QIAN
Bradley Paul SULLIVAN
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University of Kansas
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University of Kansas
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • Candida albicans remains the most commonly isolated species in clinical trials capable of causing infections throughout the body, including mucosal surfaces (oropharyngeal candidiasis (OPC)), within the bloodstream (candidemia), as well as disseminated infections (e.g., brain, liver, kidneys).
  • OPC oropharyngeal candidiasis
  • Candidemia within the bloodstream
  • disseminated infections e.g., brain, liver, kidneys.
  • this species is also normally found as a commensal in the oral cavity, gastrointestinal (GI) tract, and vagina of most healthy individuals, in
  • C. albicans can transition from commensal to opportunistic pathogen via dissemination from the GI tract. Little is known about the mechanisms that Candida uses to invade and translocate across the oral and gastric mucosa. Unfortunately, dissemination of Candida from the gastrointestinal tract to systemic organs can lead to invasive candidiasis. Not only are the treatment options for fungal infections such as Candida limited, these options are often associated with toxicity concerns. Thus, a novel approach to anti-fungal therapy is needed that provides effective treatment without toxicity concerns.
  • a polymeric chelator composition comprising a polymer covalently coupled to one or more chelators, wherein the polymer comprises a polyamine, and wherein the one or more chelators has a benzene ring with more than one hydroxyl group at any position that is free, or a derivative of the chelator, or a salt of the chelator.
  • the composition may further comprise an antifungal agent.
  • the polymers of the polymeric chelator composition are cross-linked to one another independent of any cross-linking that may occur as a result of metal binding to the chelator of the polymeric chelator composition.
  • the polymer is a polyamine including, but is not limited to polyallylamine (PAA or PAI), polylysine (PLL), polyethylenimine (PEI), or the like.
  • the chelator is capable of chelating a metal, a heavy metal, and more specifically, one or more of aluminum, arsenic, cadmium, chromium, copper, iron, lead, manganese, and mercury.
  • the chelator is 2,3 dihydroxybenzoic acid (DHBA).
  • the chelator is 2,3 dihydroxybenzaldehyde.
  • the chelator is covalently coupled to a primary amine of the polyamine through an amide bond. In certain embodiments, the chelator is covalently coupled to a primary amine of the polyamine through an amine bond.
  • the chelator may be present in the composition in an amount to provide a molar ratio of chelator to amine of from about 0.03 to about 0.40, from about 0.03 to about 0.22, from about 0.05 to about 0.20, from about 0.07 to about 0.175, and from about 0.10 to about 0.15.
  • the polyamine is polyallylamine and the chelator is
  • the polyamine is polyallylamine and the chelator is 2,3 dihydroxybenzaldehyde. In one particular embodiment, the polyamine is polylysine and the chelator is 2,3 dihydroxybenzoic acid. In one particular embodiment, the polyamine is polylysine and the chelator is 2,3 dihydroxybenzaldehyde. In another particular embodiment, the polyamine is polyethylenimine and the chelator is 2,3 dihydroxybenzoic acid. In yet another particular embodiment, the polyamine is polyethylenimine and the chelator is 2,3 dihydroxybenzaldehyde.
  • the antifungal agent is selected from the group comprising amphotericin B, abifungin, candicidin, filipin, hamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole, epoxiconazole, fluconazole, itraconazole,
  • the polymeric chelator composition is a hydrogel. In certain embodiments, the polymeric chelator composition is a topical formulation for topical administration.
  • the present disclosure also provides a method for treating a subject with a fungal infection.
  • the method comprises administering a polymeric chelator composition to a site on the subject harboring the fungal infection, wherein the composition comprises a polymer covalently coupled to a chelator, wherein the polymer comprises a polyamine, and wherein the chelator has a benzene ring with more than one hydroxyl group at any position that is free.
  • the polymeric chelator composition used in the method comprises a plurality of cross-linked polymers, wherein the plurality of cross-linked polymers comprise a polyamine, with one or more chelators covalently coupled to one or more primary amines, respectively, of the polyamine through one or more amide bonds or amine bonds, wherein each of the one or more chelators has a benzene ring with more than one hydroxyl group at any position that is free, or a derivative of the chelator, or a salt of the chelator.
  • the polyamine includes, but is not limited to polyallylamine (PAA), polylysine (PLL), polyethylenimine (PE1), or the like.
  • the chelator is capable of chelating a metal, a heavy metal, and more specifically, one or more of aluminum, arsenic, cadmium, chromium, copper, iron, lead, manganese, and mercury.
  • the chelator is 2,3 dihydroxybenzoic acid (DHBA).
  • the chelator is 2,3 dihydroxybenzaldehyde.
  • the composition used in the method is a hydrogel.
  • the composition can be a topical formulation for topical administration.
  • the site is an external wound on the subject.
  • the site is a mucosal surface such as bronchial, endometrial, gastric, penile, vaginal, olfactory, intestinal, anal, or oral.
  • the fungal infection is caused by at least one of the group comprising the following: Coccidioides species such as Coccidioides immitis; Candida species such as Candida parapsilosis, Candida krusei, Candida glabrata, Candida guilliermondii, and Candida albicans; Paecilomyces species such as Paecilomyces variotii; Cryptococcus neoformans; Cryptococcus gattii; Aspergillus species such as Aspergillus fumigatus and
  • Aspergillus flavus Fusarium species such as Fusarium oxysporum and Fusarium solani; Rhizopus oryzae; Scedosporium species such as Scedosporium prolificans and Scedosporium apiospermum; Lomentospora prolificans; Blasotmyces dermatitidis; Pneumocystis jirovecii; Sporothrix schenckii; Saksenaea species such as Saksenaea vasiformis; Histoplasma
  • the administering step is performed by applying the composition topically to a site of fungal infection on the skin, nail, or on a mucosal surface.
  • the method can further comprise the step of
  • the composition used in the method may further comprise an antifungal agent.
  • the antifungal agent is selected from the group comprising amphotericin B, abifungin, candicidin, filipin, hamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole,
  • Voriconazole posaconazole, amorolfin, butenafine, naftifine, anidulafungin, caspofungin, micafungin, terbinafine, cyclopirox, flucytosine, griseofulvin, haloprogin, tolnaftate, and undecylenic acid.
  • compositions and methods of the present disclosure may also be used to prevent fungal infections in subjects at risk for exposure to a fungal or having a wound that is susceptible to fungal infection.
  • the subject was previously treated with an antifungal agent prior to administering the composition.
  • the present disclosure further provides a process for preparing a polymeric composition.
  • the process comprises the following steps: obtaining a first solution comprising an activated chelator; obtaining a second solution comprising a polymer and a cross-linker, wherein the polymer comprises a polyamine; adding the first solution to the second solution at a desired ratio to form a third solution; mixing the third solution until it is transparent; and incubating the third solution at room temperature.
  • the activated chelator comprises 2,3-dihydroxybenzoic acid activated with N-hydroxysuccinimide.
  • the polyamine is selected from the group consisting of polyallylamine, polylysine, and polyethylenimine.
  • the cross-linker is N,N-methylene bisacrylamide.
  • the first solution is added to the second solution in an amount sufficient to provide a composition having a molar ratio of chelator to amine of from about 0.03 to about 0.40, from about 0.03 to about 0.22, from about 0.05 to about 0.20, from about 0.07 to about 0.175, and from about 0.10 to about 0.15.
  • a composition having a molar ratio of chelator to amine of from about 0.03 to about 0.40, from about 0.03 to about 0.22, from about 0.05 to about 0.20, from about 0.07 to about 0.175, and from about 0.10 to about 0.15.
  • the first solution is added to the second solution in an amount sufficient to provide a molar ratio of chelator to amine of from about 5% to about 40%.
  • the third solution is incubated at room temperature for at least 48 hours.
  • a polymeric chelator comprises a plurality of polyamine polymer backbone chains and one or more chealtors, wherein the polamine polymer backbone chains are polyallylamine or polylysine, wherein the one or more chealtors are covalently coupled to the one or more primary amines, respectively, of at least one of the plurality of polyamine polymer backbone chains through one or more amide bonds, respectively, wherein each of the one or more chealtors has a benzene ring with more than one hydroxyl group at any position that is free, and wherein the plurality of polyamine polymer backbone chains are cross- linked to one another independent of any cross-linking that may result from interactions with the one or more chelators.
  • a polymeric metal sequestrant can have a structure (I), wherein the structure (I) is
  • a method for treating a subject with a fungal infection comprises administering a composition to a site on the subject harboring the fungal infect, wherein the composition comprises the polymeric metal sequestrant of structure (I).
  • a polymeric metal sequestrant can have a structure (II), wherein the structure (II) is
  • a method for treating a subject with a fungal infection comprises administering a composition to a site on the subject harboring the fungal infect, wherein the composition comprises the polymeric metal sequestrant of structure (II).
  • a polymeric metal sequestrant can have a structure (III), wherein the structure (III) is
  • a method for treating a subject with a fungal infection comprises administering a composition to a site on the subject harboring the fungal infect, wherein the composition comprises the polymeric metal sequestrant of structure (III).
  • compositions of polymeric metal [00027] In some embodiments, the foregoing compositions of polymeric metal
  • sequestrants may further comprise an antifungal agent.
  • the antifungal agent is selected from the group comprising amphotericin B, abifungin, candicidin, filipin, hamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole, epoxiconazole,
  • compositions further comprising an antifungal agent may be used in methods for treating a subject with a fungal infection comprising administering such composition to a site on the subject harboring the fungal infection.
  • FIGURE 1 provides the reaction scheme for synthesis of cross-linked PAI-DHBA polymer.
  • FIGURE 2 provides the iron affinity indexes of PAI-DHBA polymers as measured using a ligand competition assay.
  • FIGURE 3 provides iron sequestration capacities of PAI-DHBA polymers, expressed as mg Fe/g PAI-DHBA.
  • ⁇ Theoretical Fe Sequestration Capacity
  • T Experimental Fe Sequestration Capacity.
  • FIGURE 4 provides the results of metal selective studies for essential metals, expressed as mmol metals/g PAI-DHBA.
  • FIGURE 5 provides the results of metal selectivity studies for PAI-DHBA polymers in M63 media.
  • FIGURE 6 depicts the structure of various polymeric metal sequestrants of the present disclosure.
  • Structure I is an exemplary polymeric metal sequestrant comprising polyallylamine covalently coupled to 2,3 dihydroxybenzaldahyde.
  • Structure II is an exemplary polymeric metal sequestrant comprising polyethylenimine covalently coupled to 2,3
  • Structure III is an exemplary polymeric metal sequestrant comprising polylysine covalently coupled to 2,3 dihydroxybenzaldahyde.
  • FIGURE 7 depicts the structure of various polymeric metal sequestrants of the present disclosure.
  • Structure I is an exemplary polymeric metal sequestrant comprising polyallylamine covalently coupled to 2,3 dihydroxybenzoic acid.
  • Structure II is an exemplary polymeric metal sequestrant comprising polyethylenimine covalently coupled to 2,3 dihydroxybenzoic acid.
  • Structure III is an exemplary polymeric metal sequestrant comprising polylysine covalently coupled to 2,3 dihydroxybenzoic acid.
  • FIGURE 8 depicts the results of metal selectivity studies for polyallylamine (PAA)-DHBA8, polyethylenimine (PEI)-DHBA9, and polylysine (PLL)-DHBAIO in simulated intestinal fluid.
  • the present disclosure provides a composition that is effective in the treatment of fungal infections.
  • the composition is a polymeric metal sequestrant (i.e. polymers that bind and retain metals such as iron). Polymers, especially cross-linked polymeric materials, cannot be absorbed through skin, thereby limiting concerns of toxicity that have plagued the prior art.
  • polymeric metal sequestrant i.e. polymers that bind and retain metals such as iron.
  • Polymers especially cross-linked polymeric materials, cannot be absorbed through skin, thereby limiting concerns of toxicity that have plagued the prior art.
  • the combination of polymeric metal sequestrant with traditional antifungals provide a synergistic therapeutic effect and reduce the minimum inhibitory concentrations (MICs) of antifungals.
  • MICs minimum inhibitory concentrations
  • the polymeric metal sequestrants described herein are designed with several key features such as high affinity, a large binding capacity, and selectivity for iron.
  • primary amine groups on polyallylamine PAI or PAA
  • MCA methylenebisacrylamide
  • DHBA 2,3- dihydroxybenzoic acid
  • the resultant iron-sequestering polymer demonstrates strong affinity and high selectivity for iron.
  • polymeric metal sequestrants are demonstrated herein as an effective antifungal alone and in combination with traditional antifungals such as imidazoles, triazoles, thiazoles, and echinocandins, which are commonly used for treatment of a variety of fungal infections.
  • the polymeric metal sequestrants of the present disclosure comprise a polymer covalently coupled to a chelator, wherein the polymer comprises a polyamine.
  • the chelator coupled to the polymer may include 2,3 dihydroxybenzoic acid (DHBA) and other iron chelators, such as 2,3 dihydroxybenzaldehyde.
  • FIG. 6 depicts various polymers comprising PAA, PLL, or PEI each covalently coupled to 2,3 dihydroxybenzaldehyde providing exemplary polymeric metal sequestrants of the present disclosure.
  • FIG. 7 depicts various polymers comprising PAA, PLL, or PEI each covalently coupled to 2,3 dihydroxybenzoic acid providing additional exemplary polymer metal sequestrants of the present disclosure.
  • Chelators of other metals, including heavy metals that can be coupled to a polymer may also be included.
  • heavy metals are chemical elements with a specific gravity that is at least 5 times the specific gravity of water.
  • the polymeric metal sequestrants selectively bind iron.
  • the chelator may be coupled to the polymer via a carboxyl group of the chelator. In some embodiments, the chelator may be coupled to the polymer via a peptide bond. In some embodiments, the chelators can include a feature for coupling with the polymer, such as carboxy groups that can be coupled to the amines of the polymer through amide bonds. In other embodiments, the chelator, such as or 2,3 dihydroxybenzaldehyde, can be coupled to the amines of the polymer through an amine bond. Other crosslinking or coupling reagents can be included in the polymer and chelator system in order to prepare a polymeric chelator having the ability to chelate iron.
  • the present disclosure provides a polymeric chelator, polymer or hydrogel, made by reacting 2,3 dihydroxybenzoic acid (DHBA) or 2,3
  • the polymeric chelators in polymer or hydrogel form, can be fabricated as solids or equilibrated in aqueous solution as a solution or suspension.
  • the polyamine polymer may comprise PVAm and PAAm.
  • PVAm and PAAm are polycation hydrogels consisting of reactive primary amine side groups for the conjugation of DHBA.
  • Cross-linked PVAm hydrogel may be synthesized by hydrolyzing a precursor polymer, PNVF, in a basic medium.
  • Cross-linked PAAm hydrogel may be synthesized by cross-linking the precursor PAAm chains.
  • thioglycolic acids in combination with the siderophore moiety dihydroxybenzoic acid (DHBA) may be introduced onto PAAm and PVA to from the polymeric chelator.
  • the polymeric metal sequestrants of the present disclosure comprise a plurality of cross-linked polyamine-containing polymers covalently coupled to one or more chelators that form hydrogels.
  • the polymeric metal sequestrants may comprise a swelling ratio of from about 5 to about 20, or alternatively less than 5 wherein the swelling ratio is determined by (W s -W d )/W d where W s and W d represent the weight of polymer after full swelling in PBS, and the weight of dried polymer, respectively.
  • the polymeric metal sequestrants may further comprise a molar ratio of chelator to amine of from about 0.03 to about 0.40, from about 0.03 to about 0.22, from about 0.05 to about 0.20, from about 0.07 to about 0.175, and from about 0.10 to about 0.15.
  • the molar ratio of chelator to amine is 0.07, 0.08, 0.09, 0.10, 0.1 1, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, or 0.25.
  • the polymeric metal sequestrants possesses an iron affinity index from about 25 to about 35 and more preferably from about 28 to about 32. Determination of the iron affinity index is described in the Examples herein below.
  • the polymeric metal sequestrants possesses an iron sequestration capacity of from about 5 mg Fe/g polymeric metal sequestrant to about 25 mg Fe/g polymeric metal sequestrant, and more preferably about 20 mg Fe/g polymeric metal sequestrant.
  • Iron sequestration capacity describes the maximum iron adsorption by the polymeric metal sequestrants.
  • the polymeric metal sequestrants can be fabricated as solids, gels, pastes, liquids, such as being equilibrated in aqueous solution as a solution or suspension.
  • the polymeric metal sequestrants may further be formulated for topical administration.
  • Compositions for topical administration may include the polymeric metal sequestrants formulated for a medicated application such as an ointment, paste, cream or powder.
  • Ointments include all oleaginous, adsorption, emulsion and water-soluble based compositions for topical application, while creams and lotions are those compositions that include an emulsion base only.
  • Topically administered medications may contain a penetration enhancer to facilitate adsorption of the active ingredients through the skin.
  • Suitable penetration enhancers include glycerin, alcohols, alkyl methyl sulfoxides, pyrrolidones and laurocapram.
  • Possible bases for compositions for topical application include polyethylene glycol, lanolin, cold cream and petrolatum as well as any other suitable absorption, emulsion or water-soluble ointment base.
  • Topical preparations may also include emulsifiers, and gelling agents, as necessary to preserve the composition and provide for a homogenous mixture.
  • Transdermal administration of the present invention may also comprise the use of a "patch".
  • the patch may supply one or more active substances at a predetermined rate and in a continuous manner over a fixed period of time.
  • Topical preparation such as, for example, 5% PLL-DHBA10 iron binding polymer or 5% PAA-DHBA8 iron binding polymer formulations, may include excipients for topical formulation which include, by way of example, but not limitation, aloe barbadensis leaf juice, avena sativa (oat) kernel extract, benzyl alcohol, pyrogallol, butylated hydroxytoluene, cetostearyl alcohol, cetyl alcohol, chamomilla recutita (matricaria) flower extract, diazolidinyl urea, dimethicone, distearyldimonium chloride, edetate disodium, glycerin, glyceryl monstearate, hydrolyzed collagen, hydrozed elastin, hydrolyzed jojoba esters, jojoba esters, magneiusm ascorbyl phosphate, menthyl lactate, methyl gluceth-20, methylpara
  • the polymeric metal sequestrants can be incorporated into textiles, fabrics, absorbent members, gauze, wipes, bandages, or the like.
  • the polymeric metal sequestrants can be present in the compositions at a range of from about 1 mg/ml to about 2,000 ⁇ g/ml, from about 10 ⁇ g/ml to about 1,000 ⁇ g/ml, from about 20 ⁇ g/ml to about 500 ⁇ g/ml, from about 30 ⁇ g/ml to about 400 ⁇ g/ml, from about 40 ⁇ g/ml to about 300 ⁇ g/ml, from about 50 ⁇ g/ml to about 200 ⁇ g/ml, and from about 100 ⁇ g/ml to about 150 ⁇ g/ml, and any range there between.
  • the composition of the present disclosure further comprises an antifungal agent in addition to the polymeric metal sequestrant.
  • Suitable antifungal agents of the composition include, but are not limited to amphotericin B, abifungin, candicidin, filipin, hamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole,
  • Voriconazole posaconazole, amorolfin, butenafine, naftifine, anidulafungin, caspofungin, micafungin, terbinafine, cyclopirox, flucytosine, griseofulvin, haloprogin, tolnaftate, and undecylenic acid.
  • the antifungal agent may be dispersed in the polymeric metal sequestrant by methods known for administering antifungals in other polymeric hydrogels. Examples for comparison could include topical gels or creams containing clotrimazole, intravaginal gels containing miconazole, and oral gels containing miconazole. In many of these products, polymers are used to form a viscosified vehicle to facilitate placement or retention of the dose, which could also be achieved by the polymeric metal sequestrant.
  • the polymeric metal sequestrants may be formulated as a pharmaceutical composition comprising an effective amount of one or more polymeric metal sequestrants and optionally, one or more antifungals dissolved or dispersed in a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate.
  • the preparation of a pharmaceutical composition that contains at least one polymeric metal sequestrants and optionally, one or more antifungals will be known to those of skill in the art in light of the present disclosure.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives, isotonic agents, absorption delaying agents, salts, preservatives, stabilizers, gels, binders, excipients,
  • the composition is combined with the carrier in any convenient and practical manner, i.e., by solution, suspension, emulsifi cation, admixture, encapsulation, absorption and the like. Such procedures are routine for those skilled in the art.
  • the polymeric metal sequestrants of the present disclosure can be used as an antifungal therapy to treat or prevent fungal infections in connection with external wounds and burns and also in the treatment or prevention of fungal infections present on mucosal membranes.
  • the polymeric metal sequestrants are applied topically to the wound or burn surface or directly on the mucosal surface.
  • a traditional antifungal can be added to the site of fungal infection simultaneously with the polymeric metal sequestrant or following an initial treatment with the polymeric metal sequestrant. More generally, such an agent would be provided in a combined amount with a polymeric metal sequestrant effective to kill or inhibit proliferation of the fungal infection. This process may involve contacting the cell(s) with an antifungal agent and the polymeric metal sequestrant at the same time or within a period of time wherein separate administration of the polymeric metal sequestrant and antifungal to a cell, tissue or organism produces a desired therapeutic benefit.
  • This may be achieved by contacting the cell, tissue or organism with a single composition or pharmacological formulation that includes both a polymeric metal sequestrant and one or more antifungals, or by contacting the wound or infection site with two or more distinct compositions or formulations, wherein one composition includes a polymeric metal sequestrant and the other includes one or more antifungals.
  • the polymeric metal sequestrants may be applied daily, or one to four times daily, based on the location of the infection, the severity of the infection, or the fungus causing the infection.
  • compositions of the invention can be used to achieve methods of the invention.
  • NHS-activated DHBA was synthesized before preparing the polymer.
  • a solution of DHBA (770 mg, 5 mmol) and NHS (690 mg, 6 mmol) in 5 mL of DMF was mixed with a solution of EDC (1200 mg, 6.2 mmol) in 5 mL of DMF. The mixture was stirred at room temperature for 8 h and used for the next step without any purification.
  • the PAI cross-linking and DHBA conjugation were conducted in a single step.
  • a 15% w/w PAI hydrochloride (56 kDa) solution containing a predetermined amount of ⁇ , ⁇ -methylene bisacrylamide (BMA; 5%, molar ratio of cross-linker to total amines) was prepared in H 2 0/DMF (50/50 v/v) mixture.
  • BMA ⁇ , ⁇ -methylene bisacrylamide
  • the NHS-activated DHBA solution with a desired DHBA/amine molar ratio (5-40%) was added to the solution.
  • TEA was added to the solution and mixed thoroughly, and then the solution was incubated at room temperature for 48 h.
  • the cross-linked polymer gels were washed with 0.1 M sodium hydroxide for several days under the protection of nitrogen, and then lyophilized.
  • the polymer gels were ground to powder for subsequent studies.
  • the particle size of the ground powder was -100 ⁇ measured by optical microscopy.
  • the DHBA conjugation ratios could not be characterized directly by NMR analysis. Instead, the unconjugated DHBA left in the solution after the reaction was determined by NMR.
  • the real conjugated DHBA ratio was calculated by deducting the unconjugated DHBA ratio from the feed DHBA ratio.
  • W s , and W d represent the weight of polymer after full swelling in PBS, and the weight of dried polymer, respectively.
  • the iron affinity index of the polymer was measured using a ligand competition assay.
  • the competitive chelation of iron by the polymers in equilibrium with EDTA (a water- soluble chelator) was used to determine the affinity index. Briefly, 1.5 mL of 10 mM EDTA solution, 2 mL of 5 mM FeCl 3 solution, 21.5 mL PBS and a known mass of polymer were mixed together and rotated at 25 °C for 5 days. Then, the concentration of the soluble iron complex was determined by inductively coupled plasma optical emission spectrometry (ICP-OES; Optima 2000 DV, PerkinElmer, USA).
  • ICP-OES inductively coupled plasma optical emission spectrometry
  • the affinity index of the polymer was determined following the procedure reported in literature (Feng et al., Iron (III) chelating resins. VI Stability constants of iron(III)-ligand complexes on insoluble polymeric matrices, J. Appl. Poly. Sci., 1995;56(10): 1231-7). In the equilibrium situation, the system could be represented in the following way (for brevity, all charges have been omitted):
  • the iron stability constant of DHBA (Q) could be defined as follows:
  • the iron stability constant of EDTA (K) could be defined as:
  • Iron affinity index was defined as LogQ. Based on equation (1), (2) and (3):
  • Kq Iron affinity index
  • the value of K was known, and Kq could be easily calculated based on the iron concentration, EDTA concentration, and the concentration of DHBA groups in polymers as described in literature (Feng, et al.).
  • the iron affinity index showed how strong the polymers chelated with iron versus EDTA.
  • PAI hydrochloride was first cross-linked with ⁇ , ⁇ -methylene bisacrylamide (BMA) by a Michael-type addition reaction and then the formed PAI hydrogel was further conjugated to DHBA via EDC/NHS conjugation chemistry.
  • BMA ⁇ , ⁇ -methylene bisacrylamide
  • This two-step strategy was time consuming, and in the second step, DHBA conjugation may be favored near the particle surface.
  • the polymer cross-linking and DHBA conjugation were conducted in a single step.
  • DHBA conjugation was controlled by adjusting the DHBA/polymer feed ratios.
  • PAI-DHBA polymers with various DHBA content (5-40% of total amines) but the same cross-linking density (5%) were prepared via this one step strategy as shown in Figure 1.
  • DHBA conjugation ratios which are shown in Table 1 were determined by MR analysis. As the DHBA content increased from 5% to 30%, the swelling ratios decreased from 11.8 to 5.3, indicating that the gel became more hydrophobic as DHBA conjugation increased. When incubated with Fe 3+ solution, all the PAI-DHBA samples exhibited dark color indicating chelation with Fe , while the PAI gel did not show a color change.
  • the strength of iron chelation is an important parameter for iron chelating materials; however, affinity cannot be calculated for materials in the conventional sense. Since the polymers are cross-linked particles, the chelation between the polymer materials and iron ions presents a heterogeneous system and direct equilibrium constants are not obtainable. Thus, the term iron affinity index was used to assess how strong the polymers bind and trap iron relative to a reference iron chelator with a documented stability constant. The iron affinity index was determined by a ligand competition method in equilibrium with EDTA (iron stability constant 10 25 ). The iron affinity index was calculated based on the equation for the calculation of stability constant as described in the preceding materials and methods part entitled "Determination of the Iron Affinity Index".
  • the iron sequestration capacity which describes the maximum iron adsorption by the polymers, was also investigated. In order to reach the maximum iron sequestration, all the samples were incubated in a Fe 3+ solution for one week. The theoretical and experimental iron sequestration capacities of the polymers with various DHBA contents were determined (Fig. 3). As the DHBA content increased, the experimental iron sequestration capacities also went up for low DHBA conjugation (5-20%), and reached a plateau (20-30%) around 20 mg Fe/g polymer. For all the samples tested, only the samples with low DHBA content achieved the theoretical iron sequestration capacities. The increased hydrophobicity of the polymers at higher DHBA conjugation percentages probably limited Fe 3_r access to the gel particle interior.
  • the iron selectivity of PAI-DHBA polymer was determined in the presence of copper, zinc, manganese, calcium, nickel and potassium. A solution containing all these metal ions, each at a concentration of 0.4 mM, was prepared in a phosphate buffer at pH 7.2 containing 2 mM EDTA. A predetermined amount of polymer was added into the solution and incubated at 25 °C for 5 days. The concentration of each metal ion remaining in solution was determined by ICP-OES. For the selectivity in M63 media, a predetermined amount of polymer was added into the M63 solution and incubated at 25 °C for 3 days. The concentrations of the metals (Fe 3+ and Mg 2+ ) remaining in the solution were determined by ICP-OES.
  • the selectivity of the polymer (G25) was also tested in the M63 media used in the P. aeruginosa studies.
  • the M63 media only contained Fe 3T and Mg 2" metals. All the " and only about 12% of the Mg 2+ in the solution were sequestered by the polymer (Fig. 5).
  • Mg 2 is likely primarily physically absorbed with imbibed water, rather than specifically chelated
  • EXAMPLE 3 SYNTHESIS AND CHARACTERIZATION OF PAA-DHBA, PEI-DHBA,
  • NHS-activated DHBA was synthesized before preparing the polymer.
  • a solution of DHBA (308 mg, 2 mmol) and NHS (345 mg, 3 mmol) in 5 mL of DMF was mixed with a solution of EDC (402 mg, 2.1 mmol) in 3 mL of DMF. The mixture was stirred at room temperature for 8 h and used for the next step without any purification.
  • Polyallylamine (1140 mg, 20 mmol amine groups) was dissolved in 200 mL FLQ/DMF (50/50 v/v) solution by stirring. Under the protection of nitrogen, the as-prepared NHS-activated DHBA solution was added dropwise into the polyallylamine solution with vigorous stirring.
  • the solution was sealed and stirred at room temperature under the protection of light for 24 h. Then the solution was acidified by adding 15 mL of 2M HCl and transferred into a dialysis bag (MWCO 3400) to remove unreacted agents under the protection of nitrogen. After 3 days of dialysis, the purified polymer was obtained by lyophilization. The DHBA conjugated ratio was 8% as analyzed by NMR.
  • NHS-activated DFIBA was synthesized before preparing the polymer.
  • a solution of DHBA (308 mg, 2 mmol) and NHS (345 mg, 3 mmol) in 5 mL of DMF was mixed with a solution of EDC (402 mg, 2.1 mmol) in 3 mL of DMF. The mixture was stirred at room temperature for 8 h and used for the next step without any purification.
  • Poly-L-Lysine (1460 mg, 10 mmol amine groups) was dissolved in 300 mL H 2 0 DMF (50/50 v/v) solution by stirring.
  • the as-prepared NHS-activated DHBA solution was added dropwise into the Poly-L-Lysine (PLL) solution with vigorous stirring. After purged with nitrogen for 1 h, the solution was sealed and stirred at room temperature under the protection of light for 24 h. Then the solution was acidified by adding 10 mL of 2M HCl and transferred into a dialysis bag (MWCO 3400) to remove unreacted agents under the protection of nitrogen. After 3 days of dialysis, the purified polymer was obtained by lyophilization. The DHBA conjugated ratio was 10% as analyzed by NMR.
  • NHS-activated DHBA was synthesized before preparing the polymer.
  • a solution of DFIBA (308 mg, 2 mmol) and NHS (345 mg, 3 mmol) in 5 mL of DMF was mixed with a solution of EDC (402 mg, 2.1 mmol) in 3 mL of DMF. ' The mixture was stirred at room temperature for 8 h and used for the next step without any purification.
  • Poiyethyleneimine (1460 mg, 10 mmol amine groups) was dissolved in 300 mL H?Q/DMF (50/50 v/v) solution by stirring. Under the protection of nitrogen, the as-prepared NHS-activated DHBA solution was added dropwise into the polyethylenimine solution with vigorous stirring.
  • the solution was sealed and stirred at room temperature under the protection of light for 24 h. Then the solution was acidified by adding 20 mL of 2M HCl and transferred into a dialysis bag (MWCO 3400) to remove unreacted agents under the protection of nitrogen. After 3 days of dialysis, the purified polymer was obtained by lyophilization. The DFIBA conjugated ratio was 13% as analyzed by NMR.
  • the preceding methods are one example of synthesizing the polymeric chelators of the present invention, and one of skill in the art would appreciate that other methods could be used.
  • the concentration of Ferric-DHBA complex (Fe(DHBA)-j) was determined using UV-vis spectroscopy, and the concentration of ferric-EDTA complex (Fe(EDTA)), DHBA., and EDTA could be calculated accordingly based on equations (1), (2) and (3) above.
  • PAA-DHBA8, PEI-DHBA9 and PLL-DHBA10 were subjected to iron selectivity testing.
  • the selectivity of the polymers was determined in the presence of copper, zinc, manganese, nickel, calcium and magnesium.
  • a solution (20 mL) containing all of these metal ions (1 mM), iron binding polymer (total DHBA concentration 3 mM) and EDTA (6 mM) was prepared in a simulated intestinal fluid (pH 6.5, without lecithin and sodium taurocholate). The solution was incubated at 37°C under the protection of light for 8 h. Then the solution was transferred to a dialysis bag (MWCO 3400) and diaiysed for 48 h. The metal concentration in the solution was determined by ICP-OES.
  • Table 2 for different conjugation ratios and different polymers. Table 2: Iron Binding Capacities and Iron Stability Constants for Various Polymers
  • EXAMPLE 3 IRON DEPLETION USING PAI-DHBA or PEL -DHBA INHIBITS FUNGAL
  • Susceptibility testing was performed according to the CLSI M-27 A3 broth microdilution reference method for yeasts and M38-A2 method for molds. For Blastomyces, Histoplasma, and Cryptococcus isolates testing was performed by macro dilution but still using the M38-A2 method. Results of investigational agents reported in mg ml. Those of comparators fluconazole (FLU), posaconazole (POS), and voriconazole (VOR) are reported in mcg/ ' mf .
  • FLU fluconazole
  • POS posaconazole
  • VOR voriconazole
  • PAEC QC ⁇ 0.0 ⁇ 0.0 ⁇ 0.0 ⁇ 0.0 — — — —
  • PAEC QC ⁇ 0.0 ⁇ 0.0 ⁇ 0.0 ⁇ 0.0 — — — —
  • PAEC QC ⁇ 0.0 ⁇ 0.0 ⁇ 0.0 ⁇ 0.0 — — — —
  • Rhizopus oryzae RO-2 ⁇ 0.01 0.02 D 0.25
  • EXAMPLE 4 FORMULATIONS FOR TOPICAL USE
  • Antioxidants will be titrated into a topical formulation and to reduce the oxidation of DHBA.
  • antioxidants that improve DHBA stability and do not interfere with iron binding will be identified.
  • antioxidants that did not improve the solubility of iron will be identified.
  • EXAMPLE 5 EVALUATION OF AN IRON SEQUESTRANT POLYMER FOR THE PREVENTION OF CANDIDA DISSEMINATION FROM THE GASTROINTESTINAL
  • the objective of this study is to assess the ability of a polymeric chelator of the present disclosure in preventing dissemination of C albicans from the GI tract in the setting of immunosuppression.
  • an established murine model of diet-associated GI colonization and dissemination will be utilized as described below.
  • mice Male BALB/c mice weighing -25 grams will be used. Mice will be housed 5 animals per cage and will have access to food and water ad libitum throughout the course of the evaluations.
  • cyclophosphamide 150 mg/kg intraperitoneally
  • prednisolone sodium succinate 50 mg/kg, subcutaneously
  • mice will receive drinking water with enrofloxacin (50 ppM) as antibacterial prophylaxis.
  • Mice will be placed on one of three purified rodent diets based on the commercially available AIN-93G diet (Dyets, Inc., Table 1 1) beginning 14 days prior to inoculation (day 0).
  • One diet group will be the standard AIG-93G diet (3-8 ppm iron citrate base + 35 ppm iron citrate added), another the AIN-93G diet with a reduced iron citrate content (3-8 ppm), the third diet will consist of the AIG-93G diet with reduced iron citrate content plus the polymeric chelator of the present disclosure at concentrations of 0.5%, 1, %, 2.5%, or 5%), the fourth diet will consist of the AIG-93G diet with reduced iron citrate content plus an anti-fungal agent such as amphotericin B, abifungin, candicidin, filipin, hamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulcon
  • mice that receive the Group 1 and 2 diets will receive the standard diet beginning two weeks prior to inoculation. These diets will continue through the end of the study (day 21). Mice that receive the Groups 3-6 diet will be administered the Group 2 diet (AIN-93G with 3-5 ppm iron citrate) for 11 days prior to inoculation. Three days prior to inoculation, these mice will be switched to one of the Groups 3-6 diet (addition of the polymeric chelator, anti-fungal agent or combination thereof, and iron-chelating agent, respectively). They will then be maintained on this diet until day 21 post-inoculation.
  • the Group 2 diet AIN-93G with 3-5 ppm iron citrate
  • C. albicans SC5314 will be the strain, as this is the most commonly used wild-type C. albicans strain and reference strain from which most other C. albicans strains are derived. In addition, this strain was used to establish this diet associated model of GI candidiasis.
  • the isolate will be sub-cultured at 37°C for 48 hours on Sabouraud dextrose agar twice. Prior to inoculation, the isolate taken from the second subculture will be placed into brain heart infusion broth and grown overnight at 37°C with shaking at 200 rpm; cells will then be collected by centrifugation and washed three times in sterile saline.
  • Cells will then be serially diluted and number of cells/mL will be determined using a hemocytometer.
  • the inoculum will be adjusted to 1.0 X 10 8 cells/mL in sterile PBS and 0.5 mL of a target inoculum size of 5 X 10 7 C. albicans cells will be used to inoculate each mouse by oral gavage.
  • Inoculum viability will be confirmed by carrying out serial dilutions of the inoculum in sterile PBS, plating 100 ⁇ _, in duplicate onto Sabouraud dextrose agar, and counting the number of colonies following growth at 37°C overnight.
  • mice will be monitored at least twice daily to prevent and minimize unnecessary pain or distress post-inoculation. Moribund animals will be identified by the following criteria: (1) ruffled/matted fur; (2) hypothermia; (3) weight loss (e.g., > 20%); (4) inability to eat or drink; and (5) hunched posture. Any animal
  • mice will be placed in wired bottom cages with paper liners for 24 hours so that feces could be collected immediately prior to inoculation (Day 0) and on days 14 and 21 to determine the level of colonization by measuring colony -forming units*.
  • Days 0 prior to inoculation
  • 14 start of immune suppression
  • 5 mice in each of the infected groups will be humanely euthanized as described above.
  • 10 mice in each of the infected groups and 5 in each of the uninfected groups will be humanely euthanized.
  • the liver and kidneys will be aseptically removed to measure fungal burden and assess for dissemination of C. albicans from the GI tract.
  • the organs will be weighed, and will then be homogenized and plated onto Sabouraud dextrose agar. The plates will be incubated at 37°C, and the number of CFU/g will be calculated.

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Abstract

La présente invention concerne un séquestrant de métal polymère produisant une activité antifongique. Le séquestrant de métal polymère comprend un polymère de polyamine couplé de façon covalente à un chélateur, le chélateur comportant un cycle benzénique avec plus d'un groupe hydroxyle à une quelconque position qui est libre. Le séquestrant de métal polymère est efficace dans l'inhibition et la prévention d'infections fongiques et présente des effets synergiques en combinaison avec des agents antifongiques classiques.
PCT/US2017/027158 2016-04-12 2017-04-12 Activité antifongique de polymères séquestrant le fer Ceased WO2017180714A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110448554A (zh) * 2019-09-12 2019-11-15 济南市儿童医院（山东大学齐鲁儿童医院） D-青霉胺联合氟康唑在制备抗真菌产品中的应用
CN111514146A (zh) * 2020-04-28 2020-08-11 山西振东泰盛制药有限公司 含有泊沙康唑的药物组合物
WO2023018994A1 (fr) * 2021-08-13 2023-02-16 The University Of Kansas Agents chélateurs polymères réticulés avec des agents de réticulation de poids moléculaire élevé

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030125528A1 (en) * 1998-06-26 2003-07-03 Hay Bruce A. Process for preparing schiff base adducts of amines with o-hydroxy aldehydes and compositions of matter based thereon
US20130056211A1 (en) * 2010-03-02 2013-03-07 Cory Berkland Polyamine-dihydroxybenzoic acid conjugate hydrogels as iron chelators
WO2014059417A1 (fr) * 2012-10-12 2014-04-17 Arch Chemicals, Inc. Compositions biocides comportant des chélateurs du fer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030125528A1 (en) * 1998-06-26 2003-07-03 Hay Bruce A. Process for preparing schiff base adducts of amines with o-hydroxy aldehydes and compositions of matter based thereon
US20130056211A1 (en) * 2010-03-02 2013-03-07 Cory Berkland Polyamine-dihydroxybenzoic acid conjugate hydrogels as iron chelators
WO2014059417A1 (fr) * 2012-10-12 2014-04-17 Arch Chemicals, Inc. Compositions biocides comportant des chélateurs du fer

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110448554A (zh) * 2019-09-12 2019-11-15 济南市儿童医院（山东大学齐鲁儿童医院） D-青霉胺联合氟康唑在制备抗真菌产品中的应用
CN110448554B (zh) * 2019-09-12 2022-06-07 山东省妇幼保健院 D-青霉胺联合氟康唑在制备抗真菌产品中的应用
CN111514146A (zh) * 2020-04-28 2020-08-11 山西振东泰盛制药有限公司 含有泊沙康唑的药物组合物
WO2023018994A1 (fr) * 2021-08-13 2023-02-16 The University Of Kansas Agents chélateurs polymères réticulés avec des agents de réticulation de poids moléculaire élevé

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