WO2025014642A2 - Compositions, procédés de fabrication et procédés d'utilisation de polymères antimicrobiens multifonctionnels - Google Patents

Compositions, procédés de fabrication et procédés d'utilisation de polymères antimicrobiens multifonctionnels Download PDF

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WO2025014642A2
WO2025014642A2 PCT/US2024/035284 US2024035284W WO2025014642A2 WO 2025014642 A2 WO2025014642 A2 WO 2025014642A2 US 2024035284 W US2024035284 W US 2024035284W WO 2025014642 A2 WO2025014642 A2 WO 2025014642A2
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polymer
reaction mixture
construct according
alkyl
formula
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WO2025014642A3 (fr
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Dae Won Park
Lucas DUNCAN
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University of Colorado System
University of Colorado Colorado Springs
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University of Colorado System
University of Colorado Colorado Springs
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/02—Polyamines
    • C08G73/0206—Polyalkylene(poly)amines
    • C08G73/0213—Preparatory process
    • C08G73/0226—Quaternisation of polyalkylene(poly)amines
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/02—Polyamines
    • C08G73/024—Polyamines containing oxygen in the form of ether bonds in the main chain

Definitions

  • Embodiments of the instant disclosure generally relate to multifunctional or multimodal polymers having one or more including, but not limited to, antimicrobial properties, wound healing properties, analgesic, and hemostatic properties.
  • constructs containing at least one of the multifunctional or multimodal polymers, methods of making the multifunctional or multimodal polymers, and methods of using the multifunctional or multimodal polymers are disclosed herein.
  • Traditional sterilization techniques primarily involve heat, chemical agents, radiation, or a combination of these methods.
  • Autoclaving a common heat-based sterilization method, effectively eliminates microorganisms but is not suitable for heat-sensitive materials or treating large surfaces.
  • Chemical disinfection methods including the use of disinfectants and liquid sterilants, are often limited by their compatibility with specific materials and potential toxic side effects.
  • Radiation-based sterilization such as gamma irradiation or electron beam irradiation, can be effective but may alter the properties of certain materials and require space and equipment to prevent exposure to those using such processes.
  • gamma irradiation or electron beam irradiation can be effective but may alter the properties of certain materials and require space and equipment to prevent exposure to those using such processes.
  • residual microorganisms can persist on surfaces and devices due to inadequate penetration or incomplete contact with the sterilizing agents. Microorganisms can also develop resistance to conventional disinfectants over time, diminishing their effectiveness. Additionally, repeated use of sterilization techniques can cause wear and tear on delicate medical devices, potentially compromising their functionality.
  • Embodiments of the present disclosure relate to constructs of multifunctional or multimodal polymers having at least one of antimicrobial, wound healing, analgesic, and/or hemostatic properties, methods of making the constructs, kits, and methods of using the constructs.
  • the present disclosure provides constructs containing a polymer having a formula as illustrated in formula (I), (I); [0007] wherein R1, R2, R5, and R6 are each independently selected from the group consisting of hydrogen, hydroxyl, an alkyl, a heterocycle, an aryl, and a heteroaryl, wherein the heterocycle, the aryl and the heteroaryl are each independently unsubstituted or are optionally, independently substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, and heterocyclic alkylthio; R3 can be a substituted or unsubstituted al
  • R 1 and R 2 can each be independently H, methyl, ethyl, propyl, butyl, pentyl, hydroxyl, or any combination thereof.
  • R 5 can be alkyl, aryl, or any combination thereof
  • R 3 can be methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, or any combinations thereof.
  • R6 can be hydrogen.
  • R 1 and R 2 can be methyl, R 5 can be methyl, R 6 can be hydrogen, n can be 1, and a can be 1.
  • R1, R2, and R6 can be hydrogen, n can be an integer from 1 to 5, and a can be 0.
  • R1 can be methyl
  • R2 and R6 can be hydrogen
  • n can be 1, and a can be 0.
  • R 1 can be hydroxyl
  • R 2 and R 6 can be hydrogen, n can be 1, and a can be 0.
  • R1 and R2 can be methyl, R5 can be phenyl, R6 can be hydrogen, n can be 1, and a can be 1.
  • R 1 , R 2 , and R 6 can be hydrogen, n can be 1, a can be 0, and r can be an integer between 1 and 150.
  • the present disclosure provides constructs containing a polymer having a formula as illustrated in formula (II), (II); wherein R4 can be a substituted or unsubstituted alkyl and the polymer is a quaternized polymer.
  • R1 and R2 can be methyl, R3 can be octyl, R4 can be hexyl, R5 can be methyl, R6 can be hydrogen, n can be 1, and a can be 1.
  • R 1 and R 2 can be methyl, R 3 can be octyl, R 4 can be hexyl, R 5 can be methyl, R 6 can be imidazole-1-yl ethan-1-one, n can be 1, and a can be 1.
  • the present disclosure provides constructs containing a polymer having a formula as illustrated in formula (III),
  • the polymer is a crosslinked polymer.
  • the present disclosure provides constructs containing a polymer having a formula as illustrated in formula (IV), wherein the polymer is a zwitterionic polymer.
  • the present disclosure provides constructs containing a polymer having a formula as illustrated in formula (V) or formula (VI),
  • the present disclosure provides methods of preparing the polymers in the construct.
  • the method of preparing the polymer includes a first reaction mixture of a first organocatalyst, a first solvent, a primary amine, and a terminal di- epoxide.
  • the method further includes performing a first heat treatment to the first reaction mixture for a time period sufficient to allow the formation of the polymer of formula (I)
  • the primary amine can be a compound of formula (VII) or (IX) and the terminal di-epoxide can a compound of formula (X), wherein R 1 , R 2 , R 5 , a, and n are as described previously; and p is an integer between 1 to 20.
  • the terminal di-epoxide can be neopentyl glycol diglycidyl ether, alkyl diglycidyl ethers, propylene glycol diglycidyl ether, glycerol diglycidyl ether, bisphenol A diglycidyl ether, and/or polyethylene glycol diglycidyl ether.
  • the first organocatalyst is 4-dimethylamino pyridine (DMAP) or optionally, triphenyl phosphate (TPP).
  • the first solvent is a polar solvent.
  • the first heat treatment includes heating the first reaction mixture to a first temperature.
  • the present disclosure provides methods of preparing polymers in the construct.
  • the method of preparing the polymer can include forming a second reaction mixture using the polymer of formula (I), an alkyl halide, a second solvent, and a bicarbonate salt.
  • the method further includes performing a second heat treatment to the second reaction mixture allowing formation of a quaternized polymer of formula (II).
  • the second solvent is a polar solvent.
  • the second reaction mixture is heated to a second temperature.
  • the present disclosure provides methods of preparing polymers in the construct.
  • the method of preparing the polymer includes forming a third reaction mixture using the quaternized polymer, a diglycidyl ether, and a third organocatalyst.
  • the method can include performing a third heat treatment to the third reaction mixture to form the crosslinked polymer of formula (III).
  • the third organocatalyst is a Lewis acid.
  • the third reaction mixture is heated to a third temperature.
  • the method can include forming a fourth reaction mixture using the polymer and a sultone forming the anionic quaternized polymer of formula (IV).
  • the method can include forming a fifth reaction mixture using the quaternized polymer and a coupling agent, performing a fourth heat treatment to the fifth reaction mixture to form a coupled-quaternized polymer, forming a sixth reaction mixture using the coupled-quaternized polymer and a peptide, and performing a fifth heat treatment to the sixth reaction mixture to form the peptide coupled-quaternized polymer of formulae (V) or (VI).
  • the present disclosure provides methods of preparing a substrate with antimicrobial activity, hemostatic activity, or both.
  • the method includes coating or spraying the substrate with the construct of formulae (I) to (VI).
  • the present disclosure provides methods of providing an antimicrobial agent to a subject, medical device, or surface, the method including applying to the subject, medical device, or surface a composition of at least one construct of formula (I).
  • the present disclosure provides a pharmaceutical composition.
  • the pharmaceutical composition can include the construct of formula (I) to (VI) and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition can include aqueous formulation, gelatinous formulation, a formulation on a pad, a patch, a gelatinous material or other wound dressing or a paste formulation.
  • the pharmaceutical composition can include a topical formulation.
  • kits can include one or more constructs disclosed herein and/or one or more anyone pharmaceutically-acceptable formulations disclosed herein and at least one container.
  • kits disclosed herein can be used for antimicrobial and hemostatic effect.
  • FIG. 1 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 1 ((poly(octyl neopentyl diglycidyl ether amine) or pONDEA) in accordance with certain embodiments of the present disclosure.
  • FIG. 2 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 2 (hexyl-poly(octyl neopentyl diglycidyl ether amine) or H-pONDEA) in accordance with certain embodiments of the present disclosure.
  • FIG. 1 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 1 ((poly(octyl neopentyl diglycidyl ether amine) or pONDEA) in accordance with certain embodiments of the present disclosure.
  • FIG. 2 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 2 (hexyl-poly(octyl neopenty
  • FIG. 3 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 3 in accordance with certain embodiments of the present disclosure.
  • FIG. 4 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 4 (propane sultone-poly(octyl neopentyl diglycidyl ether amine) or PS- pONDEA) in accordance with certain embodiments of the present disclosure.
  • FIG. 5 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 5 in accordance with certain embodiments of the present disclosure.
  • FIG. 6 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 6 in accordance with certain embodiments of the present disclosure.
  • FIG. 7 represents a schematic correlating properties and structure of multifunctional polymer constructs and certain applications of the constructs in accordance with certain embodiments of the present disclosure.
  • FIGS.8A-8D represent 1 H-NMR spectra of Polymer 1, Polymer 2, Polymer 4, and a hybrid polymer of Polymer 2 and Polymer 4 in accordance with certain embodiments of the present disclosure.
  • FIGS. 9A-9C represent data traces for thromboelastography (TEG) assay with untreated whole blood (FIG. 9A), kaolin treated blood (FIG. 9B), and Polymer 4 treated blood (FIG.9C) in accordance with certain embodiments of the present disclosure.
  • FIGS.10A-10C represent cytotoxicity results of Polymer 4 using AlamarBlue Assay on L929 cells in accordance with certain embodiments of the present disclosure.
  • DEFINITIONS can mean relative to the recited value, e.g., amount, dose, temperature, time, percentage, etc., ⁇ 10%, ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, or ⁇ 1%.
  • an analog refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.
  • isomers refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
  • alkyl refers to a saturated aliphatic hydrocarbon group including C1- C20 straight chain and branched chain groups.
  • Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, I-ethyl propyl, 2-methylbutyl, 3- methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4- methylhexyl,
  • An alkyl group can be a lower alkyl having 1 to 6 carbon atoms.
  • Representative examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2- dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1- ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2- dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and etc.
  • the alkyl group can be substituted or unsubstituted.
  • the substituent group(s) can have one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, heterocyclic alkylthio, carbonyl, carboxy or carboxylic ester.
  • cycloalkyl refers to saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group and have 3 to 20 carbon atoms.
  • monocyclic cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl etc.
  • a polycyclic cycloalkyl can include the cycloalkyl having Spiro ring, fused ring, and bridged ring.
  • the substituent group(s) can be one or more groups independently selected from of alkyl, alkenyl, alkynyl, alkoxyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, heterocyclic alkylthio, carbonyl, carboxy or carboxylic ester.
  • hydroxyl refers to an —OH group.
  • hydroxyalkyl refers to -alkyl-OH, wherein alkyl as defined above.
  • halo or “halogen” refers to fluoro, chloro, bromo, or iodo.
  • thiol refers to an organosulfur compound according to the form R ⁇ SH, where R represents an alkyl or other organic substituent.
  • carbonyl refers to —C( ⁇ O)—.
  • nitro refers to —NO2.
  • cyano refers to —CN.
  • amino refers to —NH2.
  • “carboxy” refers to —C( ⁇ O)OH.
  • “carboxylic ester” refers to —C( ⁇ O)O-alkyl.
  • “optionally substituted” indicates that a group can be unsubstituted or can be substituted with one or more substituents as provided herein or known in the art.
  • substituted in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced.
  • substituted includes the provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (e.g. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination).
  • a single atom can be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom.
  • Suitable substituents are defined herein for each substituted or optionally substituted group.
  • polymers can be in liquid form, and can be applied to a subject, medical device, or surface as a suspension (e.g., alcohol suspension or other aqueous suspension).
  • Anti- microbial activity of the polymer can be beneficial in preventing pathogenic microbial infections in healthcare settings among other uses.
  • polymers disclosed herein can provide active bactericidal activity, minimizing the risk of any incidentally introduced bacteria or eliminating any existing bacterial contaminants.
  • materials disclosed herein can be non-cytotoxic, biocompatible, and biodegradable. Unlike traditional sterilization methods, the antimicrobial polymers disclosed herein provide continuous and broad-spectrum antimicrobial activity, ensuring immediate elimination of any contaminants and sustained anti-bacterial protection over time.
  • application methods used for distributing these compositions can permit even coverage on various surfaces and complex-shaped devices, overcoming the limitations of penetration and accessibility and improving accessibility for improved sterility.
  • the polymer coating is compatible with a wide range of substrates, including heat-sensitive materials, enabling its application in diverse settings (e.g., medical, military, for surfaces susceptible to contamination, etc.).
  • Some embodiments disclosed herein concern agents, methods, and processes of use in preparing the disclosed constructs and compositions containing constructs disclosed herein. It is understood that combinations, subsets, interactions, agents disclosed herein where specific reference of each individual and collective combinations and permutation of these constructs cannot be explicitly disclosed, each is contemplated. Additional embodiments of the disclosure are described below. I.
  • the present disclosure provides anti-microbial constructs in the form of polymers for eliminating microbes and providing protection from pathogenic microbes on surfaces and to treat, prevent, or ameliorate a microbial infection in a subject in need thereof (e.g., a wound).
  • the different elements of the polymer can be modified to increase or decrease hydrophobicity for tailored use for a given purpose.
  • a polymer can include a construct according to formula (I), ( ); an analog, an isomer, a pharmaceutically acceptable salt, and/or a prodrug thereof, and/or formulation thereof; wherein R 1 , R 2 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, hydroxyl, an alkyl, a heterocycle, an aryl, and a heteroaryl.
  • the heterocycle, the aryl and the heteroaryl are each independently unsubstituted or are optionally independently substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, and heterocyclic alkylthio;
  • R 3 can include a substituted or unsubstituted alkyl; n is independently an integer from 1 to 15; or from 1 to 12; a is independently 0 or an integer from 1 to 5; r is independently an integer from 1 to 150; or from 1 to 135; and m is independently an integer from 10 to 200 [0071]
  • R1 and R2 are each independently H,
  • R 5 is alkyl, aryl, or any combination thereof.
  • R 3 can be methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, or any combinations thereof.
  • R 6 can be hydrogen.
  • R 1 and R 2 are methyl, R 5 is methyl, R 6 is hydrogen, n is 1, and a is 1.
  • R1, R2, and R6 can be hydrogen, n can be an integer from 1 to 5, and a can be 0.
  • R 1 is methyl, R 2 and R 6 are hydrogen, n is 1, and a is 0. In some embodiments, R 1 is hydroxyl, R 2 and R 6 are hydrogen, n is 1, and a is 0. In yet other embodiments, R1 and R2 are methyl, R5 is phenyl, R6 is hydrogen, n is 1, and a is 1. In some embodiments, R1, R2, and R6 are hydrogen, n is 1, a is 0, and r is an integer between 1 and 150. [0073] In some embodiments, polymers of the present disclosure can include Formula (XI), wherein m can range [0074] In some embodiments, the polymer can include Formula (II), wherein R 4 is a aryl.
  • Linear polymeric units can also be crosslinked to form gels of varying mechanical properties, which can be delivered via syringe to fill a three-dimensional space.
  • the polymer can include Formula (III), wherein the [0078]
  • the polymer can include zwitterionic groups, which can enhance hemostatic abilities and/or biocompatibility.
  • the polymer can include Formula (IV), wherein the [0079]
  • polymers of the present disclosure can include Formula (XIII),
  • polymers of the present disclosure can include Formula (XV), ; wherein m can [0082] In some embodiments, polymers of the present disclosure can include Formula (XVI),
  • constructs of the present disclosure can be in the form of a pharmaceutically acceptable salt.
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt it is meant those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use.
  • a salt can refer to a salt, which can be formed when a polymer herein has an acidic group such as carboxyl or a basic group such as amino or imino.
  • a salt of a polymer disclosed herein can be formed with an acidic group, can include, but is not limited to alkali metal salts such as a sodium salt, potassium salt or lithium salt, alkaline earth metal salts such as a calcium salt or magnesium salt, metal salts such as an aluminum salt or iron salt; amine salts, e.g., inorganic salts such as an ammonium salt and organic salts such as a t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N′-dibenzy
  • polymers of the present disclosure can be in a crystalline form or a crystalline and amorphous form combination or mixture.
  • polymers in a solid state can exist in a crystalline, powder, or non-crystalline form, or as a mixture thereof.
  • polymers disclosed herein in crystalline form can be used to form acceptable solvates. A skilled artisan can appreciate that acceptable solvates can be formed where solvent molecules are incorporated into the crystalline lattice during crystallization.
  • solvates for uses disclosed herein can include nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc, or they can include water as the solvent incorporated into the crystalline lattice.
  • Solvates where water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates can include stoichiometric hydrates as well as compositions containing variable amounts of water. The present disclosure encompasses all such solvates known in the art.
  • polymers of the present disclosure can exist in crystalline form, including various solvates thereof, and can exhibit polymorphism (e.g., the capacity to occur in different crystalline structures). These different crystalline forms are referred to herein as "polymorphs.” Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and/or other descriptive properties of the crystalline solid state. Polymorphs, therefore, can have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X- ray powder diffraction patterns, NMR signatures, which can be used for identification. In certain embodiments, polymers of the present disclosure can be polymorphs.
  • FIG.7 is a schematic illustration of a multimodal composition contemplated herein.
  • Polymer systems known in the art can either be impregnated with bactericidal agents that are gradually released into the surrounding environment or can include bactericidal agents bound to the polymer backbone that do not leech into the environment.
  • Agent leaching coatings have a limited lifetime for bactericidal activity as the active agent is removed from the coating and must be regenerated via subsequent bactericide treatments for continued activity.
  • non- leeching leaching polymeric systems such as poly(quaternary ammonium) compounds (QAC) can possess bactericidal activity almost indefinitely without release of agents into the environment.
  • QAC poly(quaternary ammonium) compounds
  • the antimicrobial action of QACs is mostly attributed to their ability to increase cell permeability and disrupt the cell membrane.
  • the structure should possess a long alkyl chain to provide a hydrophobic segment.
  • the cationic sites of the QACs bind to anionic sites of the cell-wall surface by electrostatic interaction. Subsequently, the long alkyl chains disrupt the cytoplasmic membrane, leading to the death of the cells. Alkyl chain lengths between C6 and C8 could kill various strains of Gram-negative and Gram- positive bacteria, and even viruses.
  • polyQACs with a long alkyl chain can provide reliable anti-microbial properties against a variety of pathogens causing disease in humans and other mammals.
  • Bacteria and other cells commonly exhibit an anionic or net negative charge, due to surface protein charge and ion exchange across the membrane.
  • bacteria In contrast to mammalian cells, bacteria exhibit a significantly higher density of negatively charged phospholipid head groups, enhancing their susceptibility to electrostatic interactions.
  • Cell membranes of bacteria are selectively permeable, with embedded channels that control the flow of ions, metabolites, and other substances across the membrane. The ability of bacteria to control and expel contents of the cytoplasm are important to resisting effects of antibiotics.
  • quaternized polymers as disclosed herein can have anti- microbial properties.
  • an anionic cell surface can be electrostatically attracted to the positively charged quaternized nitrogen atoms on the polymer.
  • hydrophobic acyl chains can penetrate bacterial cell membranes, lysing the bacterium and killing the bacteria.
  • one advantage of polymer constructs disclosed herein, and other polymeric based microbicides is their non-reliance on uptake into the bacterial envelope in order to function. Adaptation of membrane channels and improved elimination of bactericidally active compounds from within the bacteria is a main mechanism for antibacterial resistance.
  • the mechanism utilized by cationic, hydrophobic polymers is such that the material does not rely on uptake into the bacterial interior, and thus, bypasses any sort of bacterial resistance mechanism.
  • antibacterial function of the polymer constructs disclosed herein can also operate partly upon this principle, providing a strong attraction and lysing bacterial cells.
  • Hemostasis describes the natural ability of blood to clot, thereby preventing uncontrolled hemorrhage.
  • a variety of mechanisms can be responsible for adjunct mediated hemostasis. Common to all hemostatic materials is the catalytic effect on the coagulation cascade, an enzymatically mediated process which facilitates clot formation and the beginning of the wound healing process. For some materials, this can be a simple mechanism such as fluid absorption leading to a concentration of proteins and cells, to biologically active factors such as thrombin that are direct factors in the coagulation cascade.
  • Cationic polymers initially support this process by the electrostatic attraction mechanism, which leads to the aggregation of cellular components of whole blood, including red blood cells and platelets. This supports the coagulation cascade with activation of platelets and concentration of coagulation factors. While effective, interactions with exclusively cationic polymers can be cytotoxic, through the same membrane disruption mechanism that is effective against bacterial cells. Therefore, to achieve the results of effective hemostasis while preserving biocompatibility and bactericidal action, the material’s design must be tuned. [0096] In contrast with cationic polymers, zwitterionic materials contain a balance of negatively and positively charged functional groups. These materials are well characterized as biocompatible, and non-inflammatory.
  • Positively charged polymeric materials can accelerate hemostasis by electrostatic interaction between positively charged groups and negatively charged red blood cell membranes, which result in a formation of a strong hemostatic plug at the injury sites. In addition, they facilitate platelet adhesion, activation, and agglomeration by increasing the glycoprotein complex.
  • Some biologically-derived materials such as chitosan, collagen, and keratin have shown hemostatic properties. Although these materials are readily available, there are risks of disease transmission and toxicity associated with the use of those materials. Based on these facts, synthetic-based positively charged materials can be a good alternative hemostatic material.
  • quaternized polymers functionalized with peptides or other agents disclosed herein can have hemostatic properties.
  • analgesic agent Although the precise molecular mechanisms of analgesic agent action remain elusive, clinical studies report that the administration of analgesic agents at a dose of about 1.0 mg/kg to about 3.0 mg/kg reduces different types of pain including but not limited to neuropathic pain, diabetic neuropathy, peripheral nerve injury, chronic regional pain, and central pain.
  • FDA approved analgesic agents such as lidocaine jelly product to control local pain.
  • An analgesic strategy can be to develop a system capable of sustained and local delivery of analgesic agents such as lidocaine.
  • polymer constructs disclosed herein can be used as a vehicle for sustained delivery of analgesic agents such as lidocaine.
  • compositions of the instant disclosure include at least one polymer according to the instant disclosure for use to treat, prevent, or ameliorate a microbial infection in a subject in need thereof.
  • the polymer can be, for example as described in Section I.
  • pharmaceutical compositions can include at least one polymer disclosed herein and at least one pharmaceutically acceptable carrier.
  • pharmaceutical compositions can include pharmaceutically acceptable carriers, excipients, and/or stabilizers are nontoxic to recipients at dosages and/or concentrations used to practice the methods disclosed herein.
  • the pharmaceutically acceptable excipient can include, but is not limited to a diluent, a binder, a filler, a buffering agent, a pH modifying agent, a disintegrant, a dispersant, a preservative, a lubricant, or a coloring agent.
  • concentrations and types of excipients utilized to form pharmaceutical compositions disclosed herein and contemplated herein can be selected according to known principles of pharmaceutical science and knowledge in the art.
  • the excipient can be a diluent.
  • the diluent can be compressible (i.e., plastically deformable) or abrasively brittle.
  • Non-limiting examples of suitable compressible diluents can include, but are not limited to, microcrystalline cellulose (MCC), cellulose derivatives, cellulose powder, cellulose esters (i.e., acetate and butyrate mixed esters), ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, corn starch, phosphated corn starch, pregelatinized corn starch, rice starch, potato starch, tapioca starch, starch-lactose, starch-calcium carbonate, sodium starch glycolate, glucose, fructose, lactose, lactose monohydrate, sucrose, xylose, lactitol, mannitol, malitol, sorbitol, xylitol, maltodextrin, dextran, and trehalose or the like.
  • MCC microcrystalline cellulose
  • cellulose derivatives i.e., acetate
  • Non-limiting examples of suitable abrasively brittle diluents include dibasic calcium phosphate (anhydrous or dihydrate), calcium phosphate tribasic, calcium carbonate, and magnesium carbonate.
  • the excipient can be a binder.
  • Suitable binders include, but are not limited to, starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C 12 -C 18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof.
  • the excipient can be a filler.
  • Suitable fillers include, but are not limited to, carbohydrates, inorganic compounds, and polyvinylpyrrolidone.
  • the filler can be calcium sulfate, both di- and tri-basic, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starches, lactose, sucrose, mannitol, or sorbitol.
  • the excipient can be a buffering agent.
  • Suitable buffering agents include, but are not limited to, phosphates, carbonates, citrates, tris buffers, polysaccharide buffers, and buffered saline salts (e.g., Tris buffered saline, or phosphate buffered saline).
  • the excipient can be a pH modifier.
  • the pH modifying agent can be sodium carbonate, sodium bicarbonate, sodium citrate, citric acid, or phosphoric acid.
  • the excipient can be a disintegrant. The disintegrant can be non-effervescent or effervescent.
  • non- effervescent disintegrants include, but are not limited to, starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro- crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, and tragacanth.
  • suitable effervescent disintegrants include sodium bicarbonate in combination with citric acid and sodium bicarbonate in combination with tartaric acid.
  • the excipient can be a dispersant or dispersing enhancing agent.
  • Suitable dispersants can include, but are not limited to, starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isomorphous silicate, and microcrystalline cellulose.
  • the excipient can be a preservative.
  • suitable preservatives include antioxidants, such as BHA, BHT, vitamin A, vitamin C, vitamin E, or retinyl palmitate, citric acid, sodium citrate; chelators such as EDTA or EGTA; and antimicrobials, such as parabens, chlorobutanol, or phenol.
  • the excipient can be a lubricant.
  • suitable lubricants include minerals such as talc or silica; and fats such as vegetable stearin, magnesium stearate, or stearic acid.
  • the excipient can be a coloring agent. Suitable color additives include, but are not limited to, food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).
  • Other pharmaceutically acceptable carriers, excipients, and/or stabilizers can include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3- pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or ly
  • the present disclosure provides anti-microbial compositions. In some embodiments, the present disclosure provides anti-microbial and hemostatic compositions. In some embodiments, the present disclosure provides for constructs having at least one of anti- microbial, hemostatic, and wound healing compositions. In some embodiments, the present disclosure provides multimodal compositions including any one or more of anti-microbial compositions, hemostatic compositions, wound healing compositions, analgesic compositions, or compositions of any combinations thereof.
  • anti-microbial polymers disclosed herein provide a diverse range of forms and applications to combat microbial growth and to eliminate existing contaminations.
  • these compositions can manifest as sprays, enabling convenient and efficient disinfection of various surfaces and objects.
  • sprays disclosed herein can be applied to a wound and can cure into a layer or uniform layer that can protect the wound.
  • Sprayable compositions can be easily applied relative to surgical incision drapes that require labor intensive placement to avoid bubble and wrinkles.
  • these polymers can also take the form of foams, providing a versatile means of targeting specific areas or achieving controlled coverage.
  • anti- microbial polymers can be incorporated to offer enhanced hygiene benefits during handwashing or body cleansing routines. Additionally, these compositions can be found in gels, creams, and ointments, providing localized anti-microbial properties for skincare or wound care applications. Overall, the versatility of anti-microbial polymer compositions allows for their integration into numerous products, enabling effective microbial control across a wide range of settings.
  • the polymers of the instant disclosure can include, but is not limited to, suspensions in organic solvents. In some embodiments, the solvent is a protic solvent.
  • protic solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, s-butanol, t-butanol, formic acid, acetic acid, water, and combinations thereof.
  • protic solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, s-butanol, t-butanol, formic acid, acetic acid, water, and combinations thereof.
  • the method of preparing the polymer includes a first reaction mixture of a first organocatalyst, a first solvent, a primary amine, and a terminal di- epoxide.
  • the method further includes performing a first heat treatment to the first reaction mixture for a period of time sufficient to allow the formation of the polymer of formula (I)
  • the primary amine can be a polymer of formula (VII) or (IX) and the terminal di-epoxide can be a polymer of formula (X), wherein R 1 , R 2 , R 5 , a, and n are as described previously; and p is an integer between 1 to 20.
  • the terminal di-epoxide can include a structure selected from the group including, but not limited to: [00119] In some embodiments, the terminal di-epoxide can be neopentyl glycol diglycidyl ether, alkyl diglycidyl ethers, propylene glycol diglycidyl ether, glycerol diglycidyl ether, bisphenol A diglycidyl ether, and/or polyethylene glycol diglycidyl ether. [00120] In some embodiments, the first organocatalyst is triphenyl phosphine (TPP).
  • TPP triphenyl phosphine
  • the first organocatalyst is 4-dimethylaminopyridine (DMAP); optionally where the first organocatalyst is triphenyl phosphine (TPP ).
  • the first solvent is a polar solvent.
  • the first heat treatment includes heating the first reaction mixture to a first temperature.
  • the present disclosure provides methods of preparing polymers in the construct. The method of preparing the polymer can include forming a second reaction mixture using the polymer of formula (I), an alkyl halide, a second solvent, and a bicarbonate salt.
  • the method further includes performing a second heat treatment to the second reaction mixture allowing formation of a quaternized polymer of formula (II).
  • a quaternized polymer can have antibacterial properties.
  • the second solvent is a polar solvent.
  • the second reaction mixture is heated to a second temperature.
  • the present disclosure provides methods of preparing polymers in the construct.
  • the method of preparing the polymer includes forming a third reaction mixture using the quaternized polymer, a diglycidyl ether, and a third organocatalyst.
  • the method can include performing a third heat treatment to the third reaction mixture to form the crosslinked polymer of formula (III).
  • the third organocatalyst is a Lewis acid.
  • the third reaction mixture is heated to a third temperature.
  • the method can include forming a fourth reaction mixture using the polymer and a sultone forming the anionic quaternized polymer of formula (IV).
  • the anionic quaternized polymer can have antibacterial and wound healing properties.
  • the method can include forming a fifth reaction mixture using the quaternized polymer and a coupling agent, performing a fourth heat treatment to the fifth reaction mixture to form a coupled-quaternized polymer, forming a sixth reaction mixture using the coupled-quaternized polymer and a peptide, and performing a fifth heat treatment to the sixth reaction mixture to form the peptide coupled-quaternized polymer of formulae (V) or (VI).
  • the peptide coupled-quaternized polymer can have both antibacterial and hemostatic properties. IV.
  • the present disclosure provides methods of providing an antimicrobial agent to a subject, medical device, or surface such as a table or military items or other surfaces for quick and rapid elimination of bacterial contamination and prevention of future contamination, these methods can include applying to the subject, medical device, or surface a composition of at least one construct of formula (I).
  • the pharmaceutical composition can include an aqueous formulation, gelatinous formulation, a sprayable formulation, a wipeable formulation, a formulation on a pad or other wound dressing or a paste formulation, or any applicable formulation.
  • the present disclosure encompasses methods of preparing a substrate with antimicrobial activity, hemostatic activity, or both using a polymer of the instant disclosure.
  • the polymers can be as described in Section (I) herein above.
  • the method includes coating or spraying the substrate with the construct of formulae (I) to (VI).
  • Coating a substrate with an antimicrobial polymer can include applying a specially formulated polymer solution onto the substrate to provide antimicrobial properties. This process is particularly useful in medical facilities, kitchens, industrial food facilities, and other settings where controlling the growth and spread of harmful microorganisms is crucial.
  • the method can include spraying a liquid form of the polymer onto a substrate to provide an antimicrobial coating to the substrate.
  • methods of the instant disclosure can include preparing the polymers of the instant disclosure in a sprayable liquid suspension, allowing for easy application and effective dispersion of the active antimicrobial agents.
  • the composition and nature of the polymer can vary depending on the specific requirements and desired performance characteristics.
  • the liquid form of the polymer can include a suspension of the polymer in a buffer or solution (e.g., alcohol, for example for quick drying).
  • a gel form of the polymer can be formulated to be syringable and able to be injected via a syringe.
  • the polymer(s) can be a viscous fluid or a spreadable fluid.
  • the polymer can be formulated as a firm gel that can be placed or cut and used as needed.
  • methods can include applying to an affected area a therapeutically effective amount of a polymer according to the instant disclosure alone or as combination therapies in treating, reducing onset or ameliorating the health condition in the subject in need thereof.
  • the polymer can be in the form of a therapeutic composition including at least one polymer according to the instant disclosure. Certain embodiments of the method and health conditions are described below. Disclosed polymers and therapeutic compositions and formulations are described herein, for example, in Sections I and II. Kits [00138] In some embodiments, the present disclosure provides kits for harboring or storing any of the constructs and/or compositions and for practicing any of the methods disclosed herein.
  • kits can include one or more polymers disclosed herein and/or one or more anyone pharmaceutically-acceptable formulations disclosed herein and at least one container. In some embodiments, kits disclosed herein can be used for antimicrobial and hemostatic effect. [00139] In certain embodiments, kits are provided herein for use in providing an antimicrobial agent to a subject, medical device, or surface, the method including applying to the subject, medical device, or surface a composition of at least one construct of formula (I). In some embodiments, the pharmaceutical composition can include aqueous formulation, gelatinous formulation, a formulation on a pad or other wound dressing or a paste formulation.
  • the kit can include at least one polymer or composition containing at least one polymer disclosed herein, and at least one container.
  • the kit can include instructions for use in accordance with any of the methods described herein.
  • instructions can include a description for applying to a surface or administering at least one polymer and/or pharmaceutical composition disclosed herein to a subject.
  • kits can include instructions that provide information as to dosage, dosing schedule, and route of administration for the intended treatment.
  • kits disclosed herein can include at least one container.
  • containers can be any container capable of storing at least one polymer or at least one composition containing at least one polymer disclosed herein such as spray bottles, tubes, vials, bottles, syringe, such as unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • Instructions supplied in the kits of the invention can be written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine- readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.
  • the label or package insert indicates that the composition is used for treating, delaying the onset and/or alleviating onset of a health condition or disease contemplated herein.
  • kits disclosed herein can include suitable packaging.
  • suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like.
  • packages for use in combination with a specific device such as an inhaler, nasal administration device (e.g., an atomizer), patch or an infusion device such as a minipump.
  • a kit can have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • kits can optionally provide additional components such as buffers and interpretive information. Normally, the kit includes a container and a label or package insert(s) on or associated with the container. In some embodiments, the invention provides articles of manufacture including contents of the kits described above. EXAMPLES [00144] The following examples are included to illustrate certain embodiments.
  • Example 1 Synthesis of Polymer 1 (pONDEA) [00145]
  • poly(octyl neopentyl diglycidyl ether amine) or pONDEA (Polymer 1) was synthesized.
  • FIG.1 illustrates the chemical reaction equation for synthesis of Polymer 1.
  • pONDEA Polymer 1(6670 mg or mL), 1-bromohexane (0.5 mL, 2.57 mmol), and sodium carbonate (100 mg) were dissolved in dry dimethylformamide (DMF) (0.5 mL). The resulting mixture was stirred at 120 °C for 24 hrs forming H-pONDEA (Polymer 2)in an inert nitrogen atmosphere. The reaction was stopped by cooling to room temperature. The resulting polymer was purified by washing in hexane three times to remove unreacted reagents. The resulting polymer was obtained by roto-evaporating the residual hexane and DMF.
  • FIG.3 illustrates the chemical reaction equation for synthesis of Polymer 3.
  • Polymer 2 144 mg
  • polyethylene glycol diglycidyl ether Mn 526, 72 mg
  • catalytic amount of boron trifluoride diethyl etherate 55.8 ⁇ l
  • the reaction was stopped by cooling to room temperature.
  • the resulting polymer was purified by washing in hexane three times to remove unreacted reagents.
  • Example 4 Synthesis of Polymer 4 (poly sultone-pONDEA) – Zwitterionic functionalization
  • Polymer 4 PS-pONDEA
  • FIG. 4 illustrates the chemical reaction equation for synthesis of Polymer 4.
  • Polymer 1 and 1,2-oxathiolane 2,2-dioxide (1.5x to 5x molar excess) were reacted at 70 °C for 24 hrs. The reaction was stopped by cooling to room temperature. A resulting polymer was purified by washing in diethyl ether to remove unreacted reagents.
  • a solution of N-hexyl-N-(2-hydroxy-3-(3-(2-hydroxybutoxy)-2,2- dimethylpropoxy)propyl)-N-(2-hydroxypropyl)octan-1-aminium and di(2H-1 ⁇ 4 -imidazol-1- yl)methanone in DMF will be stirred at 60 °C for 3 hrs forming N-(3-(3-(2-((2H-1 ⁇ 4 -imidazole- 1-carbonyl)oxy)butoxy)-2,2-dimethylpropoxy)-2-hydroxypropyl)-N-hexyl-N-(2- hydroxypropyl)nonan-1-a
  • Example 6 Peptide conjugation II [00156] In one exemplary method, 1,6-diamino-12-carboxy-16-ethyl-N-hexyl-24-hydroxy-N- (2-hydroxypropyl)-1-imino-20,20-dimethyl-N-nonyl-7,10,14-trioxo-15,18,22-trioxa-2,8,11- triazapentacosan-25-aminium (Polymer 6) was synthesized.
  • FIG. 6 illustrates the chemical reaction equation for synthesis of Polymer 6.
  • Example 7 Characterization of Polymers 1, 2, and 4 by Gel Permeation Chromatography
  • GPC Gel Permeation Chromatography
  • a size exclusion column filled with porous beads to separate molecules of different size. Smaller molecules enter the pores and take longer to elute, while larger molecules bypass these pores and elute more quickly. This technique is used primarily to determine the molecular weight distribution of the resultant polymer.
  • GPC was used to determine how the polymers changed during course of the reaction.
  • GPC was used to determine the range of polymer sizes (molecular weight) and polydispersity to determine the distribution of molecular weights of the synthesized polymers.
  • a 30 mg/ml sample of polymer was prepared using chromatography grade Dimethyl Formamide (DMF) as a solvent. This sample was placed into a sampling vial, which was loaded into a Malvern Viscotek GPCmax sampling rack. A 100 ⁇ l aliquot was pulled and run through the GPC column at a flow rate of 1 ml/min. The column separates the resultant sample, and contents are analyzed with laser light scattering to determine the dwell time, and therefore size, of the sample contents. Polymer Mn Mw PD unit mw Mn units Mw units an lar weight, consists of 45 repeating units.
  • DMF Dimethyl Formamide
  • FIGS.8A-8D show NMR spectra and analysis of the NMR spectra of the synthesized polymers. Analysis of the NMR spectra determined that the reaction resulted in the predicted backbone polymer, in the case of non-functionalized pONDEA. Spectra of the functionalized polymers confirmed the presence of a quaternized ammonia, as well as successful functionalization reactions with propane sultone. The data further demonstrates that the backbone polymer can be modified with both propane sultone and hexyl bromide, to customize the charge balance of functional groups.
  • Example 9 Solubility of synthesized polymers
  • Polymer 1 poly(octyl neopentyl diglycidyl ether amine) (pONDEA) consists of several hydrophobic elements, with a relatively high density of hydroxyl groups. In its basic form, Polymer 1 is a highly viscous amber liquid. This liquid polymer was readily solubilized in alcohols, such as isopropyl alcohol, for use. Dimethyl formamide was used in the synthesis and further functionalization of the polymer, due to the high boiling point and good solubility with the polymer, monomers, and constituent elements.
  • the base polymer was soluble in diethyl ether, so hexanes were used to wash the polymer of unreacted monomers and catalyst materials.
  • the resultant polymer was insoluble in diethyl ether. This insolubility is diethyl ether was because of the ionic nature.
  • Polymer 2 was functionalized with alkyl halides. Polymer 2 forms the cationic quaternary ammonium salt form of the Polymer 1. Polymer 2 was highly hydrophobic and very insoluble in water.
  • Polymer 4 was zwitterionic and displays some ability to be hydrated. This form of the polymer was water miscible up to around 30% water by weight, at which point separation of water from the polymer phase was observed.
  • Example 10 Blood clotting properties
  • TAG thromboelastography
  • Thromboelastography is a viscoelastic analysis technique, wherein coagulation of blood is monitored under the conditions to assess changes to the clotting process. This technique is used clinically to rapidly evaluate the presence of coagulopathy in trauma patients, and simply characterizes the clotting characteristics of the blood samples.
  • the blood was mixed with either kaolin or polymer sample.
  • the sample was placed in a disposable cup, which oscillates through a 4.75 degree arc around a fixed plastic pin. As a clot forms in the blood, the pin is torqued, with the relative levels of deflection related to clot formation and strength.
  • Table 2 shows variables and values associated with thromboelastography readings. Table 2. Variables and values associated with thromboelastography readings.
  • test method defines several options for evaluation, of which the extraction method was used. Briefly, this method consists of extracting a polymer sample with cell growth media, then culturing cells using the extracted media and assessing cell viability and growth compared to an untreated control culture. [00178] Two concentrations, 2 mg/ml and 10 mg/ml Polymer 4 (PS-pONDEA in 3T3 cell growth media) were selected for testing. Polymer 4 was selected as a test material, as this was functionalized to serve as the baseline high-biocompatibility material, due to the presence of sulfonate functional groups.
  • concentration selections was determined by the high end of what was observed in publications (2 mg/ml), and a significant challenge to those conditions (10 mg/ml). Each sample was extracted in the 3T3 cell growth media for 24 hours at 37°C. The resulting media was filtered using a 0.45 ⁇ m filter to remove any particulate.
  • L929 mouse fibroblasts were selected, based on the similarity to cell types in the relevant treatment environment. The plates were seeded at a rate of 10,000 cells/well of a 24 well plate. The cells were incubated in control media, 2mg/ml extract media, or 10mg/ml extract media. Each two days after incubation, up to day 6, an Alamar Blue assay was performed to identify cell viability.
  • This assay utilizes a cell permeable, non-toxic compound to identify living cells.
  • the compound is blue in color, but upon absorption to a living cell, is reduced to a red compound.
  • the assay can be assessed by detection in an absorbance or fluorescence-based plate reader.
  • the cell viability of the test groups can easily be compared to the control groups to determine if any cytotoxic effect is observed.
  • Each group was incubated with 1 ml of 10% Alamar Blue solution for 2 hours at 37 °C, then assessed by microplate reader.
  • FIGS. 10 A-C illustrate cytoxicity of Polymer 4 (PS-pondea) at two different concentrations using the AlamarBlue Assay. These results depict each day of testing, grouped by test group.
  • compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods have been described in terms of embodiments, it is apparent to those of skill in the art that variations can be applied to the compositions and methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope herein. More specifically, certain agents that are both chemically and physiologically related can be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept as defined by the appended claims.

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Abstract

Des modes de réalisation de la présente divulgation concernent de nouvelles constructions comprenant des constructions ayant des applications antimicrobiennes, des applications hémostatiques, des applications de cicatrisation de plaie, une activité analgésique, ou une combinaison de celles-ci et des compositions, ainsi que des procédés de fabrication et d'utilisation de celles-ci. Dans certains modes de réalisation, la présente divulgation concerne des procédés de fourniture d'un agent antimicrobien à un sujet, un dispositif médical ou une surface, le procédé comprenant l'application au sujet, au dispositif médical ou à la surface d'une composition d'au moins une construction présentement divulguée.
PCT/US2024/035284 2023-07-12 2024-06-24 Compositions, procédés de fabrication et procédés d'utilisation de polymères antimicrobiens multifonctionnels Pending WO2025014642A2 (fr)

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