Water-based nitric oxide generating / releasing materials

Abstract

Compositions and methods are presented for water-based production of a polymer that has nitrosothiols. In preferred aspects, a two-component polymer system maintains a thiol compound and a nitrite compound physically separate. The two component system can then be applied to a surface in a water based method and heated to evaporate the water and melt the polymer, thereby allowing formation of the nitrosothiol that will, upon cooling of the polymer, release nitric oxide from the nitrosothiol.

Description

WATER-BASED NITRIC OXIDE GENERATING / RELEASING MATERIALSCross Reference to Related Applications

[0001] This application claims priority to our copending US provisional patent application with the serial number 63 / 589,300, which was filed 10 / 10 / 2023, which is incorporated by reference herein.Field of the Invention

[0002] The field of the invention is compositions and methods of producing and forming polymeric materials that contain nitric oxide donors, especially as it relates to such materials that are suitable for water-based processes.Background of the Invention

[0003] The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0004] All publications and patent applications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

[0005] Certain nitric oxide releasing polymers have shown great promise in a number of areas for improving medical device performance, reducing infection risks, sterilizing medical equipment, improving food preservation, etc. See e.g., WO 2024 / 112667. Most typically, nitric oxide releasing polymers are coated onto a device or materials to so create a film (e.g., as part of a packaging) that release nitric oxide. To date nearly all nitric oxide releasing materials (e.g., using diazeniumdiolates and nitrosothiols) have been formulated in non-aqueous organic solvents because of their ability to dissolve the polymer matrices and deposit the materials on devices and in films. However, due to environmental concerns and other considerations, manyindustrial coating processes use water-based dispersions as such dispersions to reduce or even entirely eliminate issues associated with volatile organic compound (VOC). Unfortunately, such approaches are not suitable for currently known nitric oxide releasing and generating polymers because aqueous based systems accelerate the decomposition of the nitric oxide donors that are incorporated into the polymers. For example, the nitric oxide precursors described in WO 2024 / 112667 are used as additives and combined with other solids as a powder, blended into a molten polymer, or mixed with a polymer that is dissolved in an organic solvent.

[0006] Thus, even though various compositions and methods of producing and forming polymeric materials with nitric oxide donors are known in the art, all or almost all of them suffer from several drawbacks, particularly where such processes are water-based processes. Therefore, there remains a need for improved compositions and methods of producing and forming polymeric materials with nitric oxide donors that are suitable for water-based processes.Summary of The Invention

[0007] The inventive subject matter is directed to various water-based compositions and methods of producing polymeric materials that will allow formation of a nitric oxide donor in and / or on the polymeric material upon drying of a water-based carrier.

[0008] In one aspect of the inventive subject matter, the inventor contemplates a two- component system that includes a solid thiol-containing component and a nitrite-containing component, wherein the solid thiol-containing component, and optionally the nitrite-containing component, comprises a thermoplastic polymer. Most typically, the solid thiol-containing component and the nitrite-containing component have a composition that allows for a reaction between a thiol compound in the thiol-containing component and a nitrite compound in the nitrite-containing component to form a nitrosothiol when the solid thiol-containing component and the solid nitrite-containing component are combined and subjected to heat.

[0009] In some embodiments, the solid thiol-containing component and the nitrite-containing component are configured such that the thiol compound and the nitrite compound are physically separated at room temperature when the solid thiol-containing component and the nitrite-containing component are combined. In further embodiments, the thiol-containing component and / or the nitrite-containing component comprise the thermoplastic polymer. Forexample, suitable thermoplastic polymers include polyethylene, polypropylene, polystyrene, polyvinyl chloride, and acrylonitrile butadiene styrene, or a heteropolymer comprising a modified or unmodified polyethylene, polypropylene, polystyrene, polyvinyl chloride, or acrylonitrile butadiene styrene. Preferably, but not necessarily, the nitrite-containing component comprises an aqueous solvent.

[0010] For example, in some embodiments, the thiol-containing component comprises poly(ethylene-vinyl acetate) and the poly(ethylene-vinyl acetate) further contains a cysteine or derivative thereof, a thiol-derivatized polymer or filler, or combination thereof. Among other choices, the cysteine or derivative thereof may be cysteine, glutathione, acetyl cysteine, penicillamine, acetylpenicillamine, N-acetylpenicillamine, bucillamine, and combinations thereof. As will be readily appreciated, the thiol compound can be covalently linked to the thermoplastic polymer. In further contemplated embodiments, the nitrite-containing component comprises poly(ethylene-vinyl acetate) and further contains a nitrite. Suitable nitrite compounds include sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butylnitrite, isobutylnitrite, t-butylnitrite, amylnitrite, pentylnitrite, nitrite salts, ion paired nitrite, silver nitrite, zinc nitrite, iron nitrite, copper nitrite, transition metal-nitrite compounds, and combinations thereof.

[0011] It is further generally contemplated that the solid thiol-containing component is configured as beads. For example, the beads have an average particle size of equal or less than 1 mm. In such and other examples, the nitrite-containing component may be an aqueous solution and the solid thiol-containing beads are disposed in the aqueous solution. Alternatively, or additionally, the nitrite-containing component may also be configured as beads. In such case, the nitrite-containing component and the solid thiol-containing component are then also disposed in an aqueous solution.

[0012] Consequently, the inventor contemplates a method of making a two-component system that includes a step of providing a solid first component and a second component. In such method, a thiol compound is incorporated into the first component to thereby form a solid thiol- containing component, and a nitrite compound is incorporated into the second component to thereby form a nitrite-containing component. It is generally preferred that the solid first component comprises a thermoplastic polymer as the solid component, and that the second component comprises a thermoplastic polymer or an aqueous solvent. Most typically, the solid thiol-containing component and the nitrite-containing component have a composition thatallows for a reaction between a thiol compound in the thiol-containing component and a nitrite compound in the nitrite-containing component to so form a nitrosothiol when the solid thiol- containing component and the solid nitrite-containing component are combined and subjected to heat.

[0013] Preferably, but not necessarily, the thermoplastic polymer is or comprises polyethylene, polypropylene, polystyrene, polyvinyl chloride, or acrylonitrile butadiene styrene, or a heteropolymer comprising a modified or unmodified polyethylene, polypropylene, polystyrene, polyvinyl chloride, or acrylonitrile butadiene styrene. Where desired, the thiol compound is covalently linked to the thermoplastic polymer. Among other options, preferred thiol compounds include cysteine, glutathione, acetyl cysteine, penicillamine, acetylpenicillamine, N-acetylpenicillamine, bucillamine, and combinations thereof. Preferred nitrite compounds include sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butylnitrite, isobutylnitrite, t- butylnitrite, amylnitrite, pentylnitrite, nitrite salts, ion paired nitrite, silver nitrite, zinc nitrite, iron nitrite, copper nitrite, transition metal-nitrite compounds, and combinations thereof.

[0014] In some embodiments, second component comprises the thermoplastic polymer while in other embodiments the second component comprises the aqueous solvent. Most typically, the solid thiol-containing component is shaped as a bead, and / or the nitrite-containing component is shaped as a bead. For example, contemplated beads may have an average particle size of equal or less than 1 mm.

[0015] Therefore, the inventor also contemplates a method of forming a polymeric article containing nitrosothiol groups in an aqueous process that includes a step of providing an aqueous solution that contains a solid thiol-containing component and a nitrite-containing component, wherein the solid thiol-containing component, and optionally the nitrite-containing component, comprises a thermoplastic polymer. In another step, a surface of an object is coated with the solution, and in still another step, the aqueous solution is heated and evaporated to thereby remove water and liquefy the thermoplastic polymer. As will be appreciated, the step of heating is performed at a temperature and for a time sufficient to allow a thiol in the thiol- containing component and a nitrite to react to form a nitrosothiol. Contemplated methods also include a step of cooling to form a solidified the article containing the nitrosothiol. In typical examples, the solid thiol-containing component, and optionally the nitrite-containingcomponent, will be micronized, and / or the article is a mold or an object of commerce. Where desired, the aqueous solution may further comprise a co-solvent.

[0016] Preferred thermoplastic polymers include polyethylene, polypropylene, polystyrene, polyvinyl chloride, and / or acrylonitrile butadiene styrene, or a heteropolymer comprising a modified or unmodified polyethylene, polypropylene, polystyrene, polyvinyl chloride, or acrylonitrile butadiene styrene. As noted above, it is contemplated that the thiol compound can be covalently linked to the thermoplastic polymer. Suitable thiol compounds include cysteine, glutathione, acetyl cysteine, penicillamine, acetylpenicillamine, N-acetylpenicillamine, bucillamine, and combinations thereof, while suitable nitrite compounds include sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butylnitrite, isobutylnitrite, t-butylnitrite, amylnitrite, pentylnitrite, nitrite salts, ion paired nitrite, silver nitrite, zinc nitrite, iron nitrite, copper nitrite, transition metal-nitrite compounds, and combinations thereof. As desired, the nitrite-containing component comprises the thermoplastic polymer, or the nitrite-containing component comprises the aqueous solution.

[0017] In further embodiments, the step of heating and evaporating comprises heating the aqueous solution to a temperature of at least 100 °C, and / or is performed for a period of between 15 seconds and 300 seconds. Therefore, in some embodiments, the step of heating and evaporating will form a polymer film having a thickness of between 50 micron and 5 millimeter. As will be appreciated, the step of cooling may be an active or a passive step of cooling.

[0018] Consequently, and viewed from a different perspective, the inventor also contemplates polymeric article containing nitrosothiol groups produced by the process presented herein. Therefore, the polymeric article may be configured as a polymeric film, as a container, or may be configured as a shape-conforming layer on an object of commerce.

[0019] Various objects, features, aspects, and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments, along with the accompanying drawing figures in which like numerals represent like components.Brief Description of The Drawing

[0020] FIG.l is an exemplary schematic illustration of a water-based system according to the inventive subject matter.

[0021] FIG.2 is another exemplary schematic illustration of a water-based system according to the inventive subject matter.Detailed Description

[0022] The inventor has discovered various compositions and methods of forming a polymeric material in a water-based process in which the formed polymer carries a nitrosothiol group that is (preferably) covalently coupled to an organic polymer (R-SNO, also identified as RSNO). As will be readily appreciated, nitric oxide can then be released from the polymer to effect reduction in microbial cell count and / or deodorization. As should also be appreciated, previous water-based production methods for polymers would not yield product with nitrosothiol groups as these groups would readily hydrolyze under the process conditions of the water-based production methods.

[0023] To overcome these problems, the inventor has now discovered that when precursor reagents used for the production of a nitrosothiol group are maintained separate during a waterbased process, nitrosothiol groups can be formed in a polymer upon heating and evaporation of water. More specifically, the inventor has discovered a two component system that comprises a solid thiol-containing component and a nitrite-containing component. In a typical embodiment, the solid thiol-containing component, and in some cases also the nitritecontaining component, comprises a thermoplastic polymer. For example, solid thiol-containing component may comprise an EVA polymer that includes a thiol group covalently coupled to the polymer, while the nitrite-containing component may comprise an EVA polymer that is coated with and / or to which is admixed a nitrite salt (e.g. , sodium nitrite). Both thusly modified polymer components are typically micronized or otherwise comminuted or produced in a small scale form factor to allow suspending the modified polymer components in water or other aqueous solvent. Alternatively, the nitrite-containing component need not contain a polymer, but may be an aqueous solution containing a nitrite compound.

[0024] Regardless of the particular configuration, the two-component mixture / suspension can then be coated onto a surface of an article or mold to form a film. Once deposited, the aqueoussolvent is then removed, typically by heating, which effects not only the evaporation of water, but will also lead to melting of the polymer to so form a liquefied film in which the thiol compound and the nitrite compound can react to form a nitrosothiol. It should be appreciated that in such scenario the water is evaporated and as such will prevent hydrolysis of the nitrosothiol that would otherwise occur. Thus, and viewed from a different perspective, it should be recognized that the solid thiol-containing component and the nitrite-containing component will have a composition that allows for a reaction between the thiol compound in the thiol-containing component and the nitrite compound in the nitrite-containing component to thereby form a nitrosothiol when the solid thiol-containing component and the solid nitritecontaining component are combined and subjected to heat. As will be readily appreciated, the polymer can be shaped in such water based process into any desired geometry such as a film or other generally flat geometry, or may be applied to a surface in a conforming manner to so coat a regular or irregularly shaped object.

[0025] Thus, it should be recognized that the components necessary to react to form the S- nitrosothiol can be incorporated into the water-based system in form of precursor compounds that will form the S-nitrosothiol as the water carrier is dried from the system. The resin(s) dispersed in the water-solvent hold(s) the thiol groups and the nitrite groups separately and are not allowed to react until the polymeric component(s) is / are liquified and react as the water solvent is removed during drying. As the reactive groups combine, the RSNO is formed as the resultant polymer solidified and cools. The so formed S-nitrosothiol is held intact when the layer is fully dried and is able to donate NO in response to light, heat, transition metal catalysis, or reaction with ascorbic acid or the like.

[0026] As will be readily appreciated, numerous thiol compounds are deemed suitable for use in conjunction with the teachings presented herein. For example, contemplated thiol compounds include 1,2-ethane dithiol, 2,3 -dimercaptopropanol, pyrithione, dithioerythritol, 3,4-dimercaptotoluene, 2,3-butanedithiol, 1,3 -propanedithiol, 2-hydroxypropane thiol, 1- mercapto-2-propanol, di thioerythritol and dithiothreitol. Other exemplary thiol-containing compounds include alpha-lipoic acid, methanethiol (CH3SH [m-mercaptan]), ethanethiol (C2H5SH [e-mercaptan]), 1 -propanethiol (C3H7SH [n-P mercaptan]), 2-propanethiol (CH3CH(SH)CH3 [2C3 mercaptan]), butanethiol (C4H9SH ([n-butyl mercaptan]), tert-butyl mercaptan (C(CH3)3SH [t-butyl mercaptan]), pentanethiols (C5H11SH [pentyl mercaptan]), coenzyme A, lipoamide, glutathione, cysteine, cystine, 2-mercaptoethanol, dithiothreitol,dithioerythritol, 2-mercaptoindole, transglutaminase, (1 l-mercaptoundecyl)hexa(ethylene glycol), (l l-mercapto-undecyl)tetra(ethylene glycol), (1 l-mercaptoundecyl)tetra(ethylene glycol) functionalized gold nanoparticles, l,r,4',l"-terphenyl-4-thiol, 1,11 -undecanedithiol, 1,16-hexadecanedithiol, 1,2-ethanedithiol, 1,3-propanedithiol, 1,4-benzenedimethanethiol, 1,4-butanedithiol, 1,4-butane-dithiol diacetate, 1,5-pentanedithiol, 1,6-hexanedithiol, 1,8- octanedithiol, 1,9-nonanedithiol, adamantanethiol, 1 -butanethiol, 1 -decanethiol, 1- dodecanethiol, 1 -heptanethiol, 1 -heptanethiol, 1 -hexadecanethiol, 1 -hexanethiol, 1-mercapto- (tri ethylene glycol), l-mercapto-(tri ethylene glycol) methyl ether functionalized gold nanoparticles, l-mercapto-2-propanol, 1 -nonanethiol, 1 -octadecanethiol, 1 -octanethiol, 1- octanethiol, 1 -pentadecanethiol, 1 -pentanethiol, 1 -propanethiol, 1 -tetradecanethiol, 1- undecanethiol, l l-(lH-pyrrol-l-yl)undecane-l-thiol, 11 -amino- 1-undecane-thiol hydrochloride, 11 -bromo- 1 -undecanethiol, 11 -mercapto- 1 -undecanol, 11 -mercapto- 1 -undecanol, 11-mercaptoundecanoic acid, 11-mercaptoundecanoic acid, 11 -mercaptoundecyl trifluoroacetate, 11 -mercaptoundecylphosphoric acid, 12-mercaptododecanoic acid, 12- mercaptododecanoic acid, 15-mercaptopentadecanoic acid, 16-mercaptohexadecanoic acid, 16-mercaptohexadecanoic acid, lH,lH,2H,2H-perfluorodecanethiol, 2,2'-(ethylenedioxy)di- ethanethiol, 2,3 -butanedithiol, 2-butanethiol, 2-ethylhexanethiol, 2-methyl-l -propanethiol, 2- methyl-2-propanethiol, 2-phenylethanethiol, 3,3,4,4,5,5,6,6,6-nonafluoro-l-hexanethiol purum, 3-(dimethoxymethylsilyl)-l-propanethiol, 3 -chi oro-1 -propanethiol, 3-mercapto-l- propanol, 3 -mercapto-2 -butanol, 3-mercapto-N-nonylpropionamide, 3 -mercaptopropionic acid, 3-mercaptopropyl-functionalized silica gel, 3 -methyl- 1 -butanethiol, 4,4'-bis(mercapto- methyl)biphenyl, 4,4'-dimercaptostilbene, 4-(6-mercaptohexyloxy)benzyl alcohol, 4-cyano-l- butanethiol, 4-mercapto-l -butanol, 6-(ferrocenyl)hexanethiol, 6-mercapto-l -hexanol, 6- mercaptohexanoic acid, 8-mercapto-l -octanol, 8-mercaptooctanoic acid, 9-mercapto-l- nonanol, biphenyl-4,4'-dithiol, butyl 3 -mercaptopropionate, copper(I) 1 -butanethiolate, cyclohexanethiol, cyclopentanethiol, decanethiol functionalized silver nanoparticles, dodecanethiol functionalized gold nanoparticles, dodecanethiol functionalized silver nanoparticles, hexa(ethylene glycol)mono-l l-(acetylthio)undecyl ether, mercaptosuccinic acid, methyl 3 -mercaptopropionate, octanethiol functionalized gold nanoparticles, PEG dithiol, 5-(l l-bromoundecyl)thioacetate, 5-(4-cyanobutyl)thioacetate, thiophenol, triethylene glycol mono- 11 -mercaptoundecyl ether, trimethylolpropane tris(3-mercaptopropionate), [11- (methylcarbonylthio)undecyl]tetra (ethylene glycol), m-carborane-9-thiol, p-terphenyl-4,4"- dithiol, tert-dodecylmercaptan, or tert-nonyl mercaptan.

[0027] In certain embodiments, the thiol-containing compound includes a cysteine or derivative thereof, a thiol-derivatized polymer or filler, or a combination thereof. In embodiments when the cysteine or derivative thereof is utilized, the cysteine or derivative thereof may comprise cysteine, glutathione, acetyl cysteine, penicillamine, acetylpenicillamine, S-nitroso-n-acetylpenicillamine, bucillamine, or combinations thereof.

[0028] In various embodiments, the thiol-containing compound has a weight average molecular weight of no greater than 500,000 g / mol, alternatively no greater than 100,000 g / mol, alternatively no greater than 10,000 g / mol, alternatively no greater than 1,000 g / mol, or alternatively no greater than 500 g / mol. Viewed from a different perspective, the thiol- containing compound may have a weight average molecular weight of from about 10 g / mol to about 500,000 g / mol, alternatively from about 10 g / mol to about 100,000 g / mol, alternatively from about 10 g / mol to about 1,000 g / mol, or alternatively from about 10 g / mol to about 500 g / mol. For example, cysteine has a weight average molecular weight of 121 g / mol, glutathione has a weight average molecular weight of 307.33 g / mol, butylthiol has a weight average molecular weight of 90.19 g / mol, and serum albumin has a weight average molecular weight of 66 kDa. Without being bound by theory, it is believed that reaction kinetics of forming the reaction product is improved by utilizing the thiol-containing compounds having lower weight average molecular weights. This improved reaction kinetics provides rapid generation of nitric oxide resulting from the in situ formation of the reaction product. Moreover, primary nitrosothiol compounds will generally more rapidly decompose to form nitric oxide than secondary or tertiary nitrosothiols.

[0029] Similarly, numerous nitrite compounds are deemed suitable for use herein, and particularly contemplated nitrite compounds include sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butylnitrite, isobutylnitrite, t-butylnitrite, amylnitrite, pentylnitrite, nitrite salts, ion paired nitrite, silver nitrite, zinc nitrite, iron nitrite, copper nitrite, transition metal-nitrite compounds, or combinations thereof.

[0030] In various embodiments, the nitrosating compound has a weight average molecular weight of no greater than 10,000 g / mol, alternatively no greater than 1,000 g / mol, alternatively no greater than 500 g / mol, or alternatively no greater than 250 g / mol. From a different perspective, the nitrosating compound may have a weight average molecular weight of from about 10 g / mol to about 10,000 g / mol, alternatively from about 10 g / mol to about 1,000 g / mol,alternatively from about 10 g / mol to about 500 g / mol, or alternatively from about 10 g / mol to about 250 g / mol. For example, NaNO2 has a weight average molecular weight of 69 g / mol and butyl nitrite has a weight average molecular weight of 103 g / mol. Without being bound by theory, it is believed that reaction kinetics of forming the reaction product is improved by utilizing the nitrosating compounds having lower weight average molecular weights. As described above, this improved reaction kinetics provides rapid generation of nitric oxide resulting from the in-situ formation of the reaction product.

[0031] In still further embodiments, it is contemplated that the thiol or the nitrite compound may be admixed with a polymer, typically when the polymer is in a molten or otherwise fluidized state e.g., via a solvent). In such case, the thiol or the nitrite compound will be homogenously distributed in the polymer. Alternatively, the thiol or the nitrite compound may also be coated onto the polymer. In still further contemplated aspects, the thiol compound may also be covalently coupled to the polymer. For example, a polymer having carbonyl or siloxyl groups may be reacted with an organosilane to produce a silane-modified polymer that includes a pendant amino or epoxy group, which is then reacted with a sulfur-containing reagent to so produce a thiol-modified polymer that includes a pendant thiol group. Exemplary processes for such polymers are described in WO PCT / US23 / 18910, incorporated by reference herein.

[0032] As will be readily appreciated, the specific nature and type of polymer used within the context of this disclosure may vary considerably, and the type of polymer will typically be a function of the desired product. However, it is generally preferred that the polymer is a thermoplastic homopolymer, and especially a polyethylene, a polypropylene, a polystyrene, a polyvinyl chloride, or an acrylonitrile butadiene styrene, or a thermoplastic heteropolymer comprising a modified or unmodified polyethylene, polypropylene, polystyrene, polyvinyl chloride, or acrylonitrile butadiene styrene. In further contemplated embodiments, and especially where the thermoplastic polymer does not have an acidic nature, an acidic compound (e.g., sodium acetate, sodium citrate, etc.) can be added to create the mildly acidic reaction conditions needed for the nitrosothiol to form.

[0033] Regardless of the specific chemistry of the thermoplastic polymer, thiol compound, and nitrite compound, it is generally preferred that the two-component system will be prepared in form of a water-based dispersion or slurry that is suitable for coating or spraying onto a target surface. Therefore, in most embodiments, the thermoplastic polymer will have a particle size that is suitable for such applications, and contemplated average particle sizes will rangebetween 1-10 micron, 10-50 micron, 25-100 micron, 50-250 micron, 100-500 micron, 250-750 micron, 500-1,000 micron, 1-5 mm, and even larger. As will be appreciated, the size of the particles (and the thiol and nitrite concentrations present) will determine the reaction kinetics to form the nitrosothiol, along with the temperature and duration of heating.

[0034] Once the two-component system is applied to the target surface, it is contemplated that the system will be subjected to an evaporation step (typically by heating, but sublimation or vacuum application are also deemed suitable) that reduces or entirely eliminates the water content. Most typically, residual water content will be no more than 5 wt% of the applied water, and more preferably no more than 4%, or no more than 3%, no more than 2%, no more than 1%. With regard to suitable temperatures, it is contemplated that the temperature is sufficient to (a) remove the water from the system, and (b) melt the thermoplastic polymer to a degree such as to enable contact between the thiol compound and the nitrite compound. Thus, contemplated temperatures will be at least 100 °C, or at least 150 °C, or at least 200 °C, or at least 250 °C, or at least 300 °C, or at least 350 °C, or at least 400 °C, or at least 450 °C, or even higher. Depending on the temperature and selected polymer, the heating may be sustained over a period of at least 10 s, or at least 20 s, or at least 30 s, or at least 60 s, or at least 120 s, or at least 180 s, or at least 240 s, or at least 300 s, and even longer.

[0035] Thus, it should be recognized that upon application of the two-component system (typically in a water or aqueous dispersion or suspension) thermal energy will remove the water as the polymer material melts. In the molten state, the thiol compound and the nitrite compound are now able to contact and react to form a nitrosothiol in the absence of water that would otherwise rapidly degrade the nitrosothiol. As will be readily recognized, the quantitative ratios between the thiol compound and the nitrite compound as well as the temperature and time at the temperature will determine the yield of the nitrosothiols. Preferably, the nitrosothiol- containing polymer will have less than 30%, or less than 20%, or less than 10%, or less than 5% residual unreacted thiol compounds or nitrite compounds. As such, the so formed polymer will be able to emit NO over extended periods in response to UV light, changes in H, temperature, moisture, etc.

[0036] Moreover, it should be recognized that the application of heat to the aqueous system not only thermodynamically accelerates the formation of the nitrosothiols, but also kinetically accelerates formation of the nitrosothiol as the concentration of the reactants in the evaporatingaqueous phase continuously increases. In addition, due to the decreasing presence of water, decomposition of the newly formed nitrosothiols will be significantly reduced.

[0037] As will be readily appreciated, heating or subjecting the thiol and nitrite compounds to heat may occur in various forms. For instance, an object or surface coated with a mixture of thiol and nitrite in aqueous solvent can simply be placed in a space or room with radiant heat. Alternatively, the coated object or surface could be exposed to a stream of hot air. In other examples, the coated object or surface could be placed inside an oven or microwave, or be placed on a hot plate or electric stove. Still further, the coated object or surface could be surrounded by a heating pad or placed on a heating mat. Additionally, chemical processes may be used to heat the mixture such as dissolving certain salts in the aqueous solvent which cause exothermic reactions.

[0038] Additionally, or alternatively, application of reduced pressure (e.g., partial vacuum of equal or less than 700 mm Hg, or equal or less than 500 mm Hg, or equal or less than 200 mm Hg, or equal or less than 50 mm Hg) may be used to evaporate the aqueous solvent. Such process will advantageously reduce thermal decomposition of the newly formed nitrosothiol, as well as kinetically accelerate formation of nitrosothiols due to increasing concentration of reactants in the remaining aqueous solvent.

[0039] The inventors contemplate that in one embodiment of the disclosed invention, the mixture of aqueous solvent having thiol and nitrite could be homogenous over a surface and / or form a film on the surface of an object or other structure. In further embodiments, it is contemplated that the heating of the mixture causes a melting of thiol and nitrite and a melting of part of the surface of the object or structure such that, when heat is removed, the remaining nitrosothiol fuses into the surface of the object or structure. Viewed from another perspective, the systems and methods disclosed herein may result in a surface having a non-fused portion, a fused portion, and a nitrosothiol portion. In such examples, the fused portion represents the portion of the surface in direct contact with the nitrosothiol which has fused with the nitrosothiol after heating. The fused portion is typically directly in between the non-fused portion and the nitrosothiol portion.

[0040] In other embodiments, a surface may be coated using the systems and / or methods herein, optionally fused with the resulting nitrosothiol, and then covered with a second surface. In these embodiments, nitrosothiol would solidify and remain in between two or more surfaces.This may be especially beneficial for the securing of a nitric oxide precursor within a container or device for later sterilization. In some embodiments, the surface or surfaces are biodegradable, or otherwise removable by mechanical, chemical, electrical, or other means. In still other embodiments, the surface or surfaces are the surfaces of catheters or tubing for medical implementation. In still further embodiments, one or more of the surfaces may have pores or nitric oxide-permeable structures which may allow the release of nitric oxide on demand.

[0041] In still further embodiments, the inventors contemplate that, once the aqueous solvent is heated and evaporated, the mixture may then be cooled. As will be readily appreciated, cooling may be achieved in a number of ways. For example, the product may be placed in a cool room or exposed to a cooling stream of inert gas or air, and especially contemplated cooling media include those that will not cause or catalyze decomposition of the nitrosothiol.

[0042] The inventors further contemplate that the rate of decay or decomposition of the nitrosothiol to nitric oxide can be modified by a variety of factors, especially as it relates to adding pH modifiers. Because lower acidity in the local environment makes the nitrosothiol more stable, thereby causing slower decay of the nitrosothiol to nitric oxide, pH modifiers that increase local pH, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium bicarbonate, sodium carbonate, tris buffer, borax, and / or other basic pH modifiers may be added to one or both components to effect faster release of nitric oxide. Conversely, the inventors contemplate that the rate of nitric oxide formation may be faster by adding pH modifiers that decrease the pH in the local environment, such as hydrochloric acid, sulfuric acid, citric acid, acetic acid, phosphoric acid, lactic acid, and / or other pH modifiers. Typically, but not necessarily, such modifiers will be included into the aqueous phase at a specific concentration to achieve a desired rate of NO generation or in polymer resins, etc.

[0043] In still further embodiments, the inventors contemplate that the decay or decomposition of the nitrosothiol to nitric oxide may be also modified by introducing compounds that increase or decrease the rate of decay. For example, and in one embodiment, ascorbic acid, threose, furoic acid, transition metals, glutathione, thiocyanate, iodide, and / or other compounds may be selectively added to the nitrosothiol to accelerate the decay of nitrosothiol, such as by donating electrons to the S-N bond of the nitrosothiol, breaking the bond, and causing the release of NO. In other embodiments, compounds like sodium acetate, sodium citrate, zinc stearate, and / or other compounds may be added to influence the decay or decomposition of nitrosothiol to nitricoxide. Additionally, it is contemplated that one or more UV absorbing agents may be added to one or both components (or the final product) to reduce UV-mediated decomposition of the nitrosothiol and with that reduce the rate of NO release.Example

[0044] Example 1: Resin A poly(ethylene-vinyl acetate)(40% acetate) derivatized with pendant acetylpenicillamine groups (Sterile State polymer derivatization chemistry as described in WO PCT / US23 / 18910). Resin B consists of poly(ethylene-vinyl acetate)(40% acetate) melted and combined with sodium nitrite. Resin A and Resin B are formed as microparticles and blended in a water-based suspension. When this suspension is coated onto a film substrate with an air knife or other industrial coating equipment, it is dried. As the water is driven off, the EVA microparticles Resins A and B melt and mix, allowing the nitrosation of the thiol group, forming intact S-nitrosothiols. As the combined material completely dries, a green color develops, indicative of the formation of S-nitroso-N-acetylpenicillamine (SNAP) covalently linked to the EVA polymer backbone. FIG.l exemplarily depicts such process scheme.

[0045] Example 2: Resin A poly(ethylene-vinyl acetate)(40% acetate) derivatized with pendant acetylpenicillamine groups (Sterile State polymer derivatization chemistry as described in WO PCT / US23 / 18910). Resin A is formed as microparticles and blended in a water-based suspension. The water-based suspension contains sodium nitrite dissolved in the solution. When this suspension is coated onto a film substrate with an air knife or other industrial coating equipment, it is dried. As the water is driven off, the EVA Resin A microparticles begin to melt, allowing the thiol group and nitrite in the suspension solvent to mix and react mix, allowing the nitrosation of the thiol groups. This forms intact S- nitrosothiols. As the combined material completely dries, a green color develops, indicative of the formation of S-nitroso-N-acetylpenicillamine (SNAP) covalently linked to the EVA polymer backbone. FIG.l exemplarily depicts such process scheme.

[0046] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” As used herein, the terms "about" and "approximately", when referring to a specified, measurable value (such as a parameter, an amount, a temporal duration, and the like),is meant to encompass the specified value and variations of and from the specified value, such as variations of + / -10% or less, alternatively + / -5% or less, alternatively + / -1% or less, alternatively + / -0.1% or less of and from the specified value, insofar as such variations are appropriate to perform in the disclosed embodiments. Thus, the value to which the modifier "about" or "approximately" refers is itself also specifically disclosed. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.

[0047] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0048] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise. As also used herein, and unless the context dictates otherwise, the term "coupled to" is intended to include both direct coupling (in which two elements that are coupled to each other contact each other) and indirect coupling (in which at least one additional element is located between the two elements). Therefore, the terms "coupled to" and "coupled with" are used synonymously.

[0049] It should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the scope of the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms “comprises” and “comprising” should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced. Where the specification or claims refer to at least one of somethingselected from the group consisting of A, B, C . . . . and N, the text should be interpreted as requiring only one element from the group, not A plus N, or B plus N, etc.

Claims

CLAIMSWhat is claimed is:

1. A two-component system, comprising: a solid thiol-containing component and a nitrite-containing component, wherein the solid thiol-containing component, and optionally the nitrite-containing component, comprises a thermoplastic polymer; wherein the solid thiol-containing component and the nitrite-containing component have a composition that allows for a reaction between a thiol compound in the thiol-containing component and a nitrite compound in the nitrite-containing component to form a nitrosothiol when the solid thiol-containing component and the solid nitrite-containing component are combined and subjected to heat.

2. The two-component system of claim 1, wherein the solid thiol-containing component and the nitrite-containing component are configured such that the thiol compound and the nitrite compound are physically separated at room temperature when the solid thiol-containing component and the nitrite-containing component are combined.

3. The two-component system of claim 1, wherein the thiol-containing component and / or the nitrite-containing component comprise the thermoplastic polymer.

4. The two-component system of claim 2, wherein the thermoplastic polymer is selected form the group consisting of a polyethylene, a polypropylene, a polystyrene, a polyvinyl chloride, and an acrylonitrile butadiene styrene, or a heteropolymer comprising a modified or unmodified polyethylene, polypropylene, polystyrene, polyvinyl chloride, or acrylonitrile butadiene styrene.

5. The two-component system of claim 1, wherein the nitrite-containing component comprises an aqueous solvent.

6. The two-component system of claim 1, wherein the thiol-containing component comprises poly(ethylene-vinyl acetate) and wherein the poly(ethylene-vinyl acetate) further contains a cysteine or derivative thereof, a thiol-derivatized polymer or filler, or combination thereof.

7. The two-component system of claim 6, in which the cysteine or derivative thereof is selected from the group of cysteine, glutathione, acetyl cysteine, penicillamine, acetylpenicillamine, N-acetylpenicillamine, bucillamine, and combinations thereof.

8. The two-component system of claim 1, wherein the thiol compound is covalently linked to the thermoplastic polymer.

9. The two-component system of claim 1, wherein the nitrite-containing component comprises poly(ethylene-vinyl acetate) and further contains a nitrite.

10. The two-component system of claim 1, wherein the nitrite compound is selected from the group consisting of sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butylnitrite, isobutylnitrite, t-butylnitrite, amylnitrite, pentylnitrite, nitrite salts, ion paired nitrite, silver nitrite, zinc nitrite, iron nitrite, copper nitrite, transition metal-nitrite compounds, and combinations thereof.

11. The two-component system of claim 1, wherein the solid thiol-containing component is configured as beads.

12. The two-component system of claim 11, wherein the beads have an average particle size of equal or less than 1 mm.

13. The two-component system of claim 11, wherein the nitrite-containing component is an aqueous solution and wherein the beads are disposed in the aqueous solution.

14. The two-component system of claim 11, wherein the nitrite-containing component is configured as beads, and wherein the nitrite-containing component and the solid thiol- containing component are disposed in an aqueous solution.

15. A method of making a two-component system, comprising: providing a solid first component and a second component; incorporating a thiol compound into the first component to thereby form a solid thiol- containing component, and incorporating a nitrite compound into the second component to thereby form a nitrite-containing component; wherein the solid first component comprises a thermoplastic polymer as the solid component, and wherein the second component comprises a thermoplastic polymer or an aqueous solvent;wherein the solid thiol-containing component and the nitrite-containing component have a composition that allows for a reaction between a thiol compound in the thiol-containing component and a nitrite compound in the nitrite-containing component to form a nitrosothiol when the solid thiol-containing component and the solid nitrite-containing component are combined and subjected to heat.

16. The method of claim 15, wherein the thermoplastic polymer is selected from the group consisting of a polyethylene, a polypropylene, a polystyrene, a polyvinyl chloride, and an acrylonitrile butadiene styrene, or a heteropolymer comprising a modified or unmodified polyethylene, polypropylene, polystyrene, polyvinyl chloride, or acrylonitrile butadiene styrene.

17. The method of claim 15, wherein the thiol compound is covalently linked to the thermoplastic polymer.

18. The method of claim 15, wherein the thiol compound is selected from the group of cysteine, glutathione, acetyl cysteine, penicillamine, acetylpenicillamine, N-acetylpenicillamine, bucillamine, and combinations thereof.

19. The method of claim 15, wherein the nitrite compound is selected from the group consisting of sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butylnitrite, isobutylnitrite, t-butylnitrite, amylnitrite, pentylnitrite, nitrite salts, ion paired nitrite, silver nitrite, zinc nitrite, iron nitrite, copper nitrite, transition metal-nitrite compounds, and combinations thereof.

20. The method of claim 15, wherein the second component comprises the thermoplastic polymer.

21. The method of claim 15, wherein the second component comprises the aqueous solvent.

22. The method of claim 15, wherein the solid thiol-containing component is shaped as a bead, and / or wherein the nitrite-containing component is shaped as a bead.

23. The method of claim 15, wherein the bead has an average particle size of equal or less than1 mm.

24. A method of forming a polymeric article containing nitrosothiol groups in an aqueous process, comprising: providing an aqueous solution that contains a solid thiol-containing component and a nitrite-containing component, wherein the solid thiol-containing component, and optionally the nitrite-containing component, comprises a thermoplastic polymer; coating a surface of an object with the solution; heating and / or evaporating the aqueous solution to thereby remove water and liquefy the thermoplastic polymer, wherein the step of heating is performed at a temperature and for a time sufficient to allow a thiol in the thiol-containing component and a nitrite to react to form a nitrosothiol; and cooling to form a solidified the article containing the nitrosothiol.

25. The method of claim 24, wherein the solid thiol-containing component, and optionally the nitrite-containing component, is micronized.

26. The method of claim 24, wherein the article is a mold or an object of commerce.

27. The method of claim 24, wherein the aqueous solution comprises a co-solvent.

28. The method of claim 24, wherein the thermoplastic polymer is selected from the group consisting of a polyethylene, a polypropylene, a polystyrene, a polyvinyl chloride, and an acrylonitrile butadiene styrene, or a heteropolymer comprising a modified or unmodified polyethylene, polypropylene, polystyrene, polyvinyl chloride, or acrylonitrile butadiene styrene.

29. The method of claim 24, wherein the thiol compound is covalently linked to the thermoplastic polymer.

30. The method of claim 24, wherein the thiol compound is selected from the group of cysteine, glutathione, acetyl cysteine, penicillamine, acetylpenicillamine, N-acetylpenicillamine, bucillamine, and combinations thereof.

31. The method of claim 24, wherein the nitrite compound is selected from the group consisting of sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butylnitrite, isobutylnitrite, t-butylnitrite, amylnitrite,pentylnitrite, nitrite salts, ion paired nitrite, silver nitrite, zinc nitrite, iron nitrite, copper nitrite, transition metal-nitrite compounds, and combinations thereof.

32. The method of claim 24, wherein the nitrite-containing component comprises the thermoplastic polymer.

33. The method of claim 24, wherein the nitrite-containing component comprises the aqueous solution.

34. The method of claim 24, wherein the step of heating and evaporating comprises heating the aqueous solution to a temperature of at least 100 °C.

35. The method of claim 24, wherein the step of heating and evaporating is performed for a period of between 15 seconds and 300 seconds.

36. The method of claim 24, wherein the step of heating and evaporating forms a polymer film having a thickness of between 50 micron and 5 millimeter.

37. The method of claim 24, wherein the step of cooling is passive cooling.

37. A polymeric article containing nitrosothiol groups produced by the process of any one of claims 24-27.

38. The polymeric article of claim 37, configured as a polymeric film.

39. The polymeric article of claim 37, configured as a container.

40. The polymeric article of claim 37, configured as a shape-conforming layer on an object of commerce.

Images