Attny Dkt No. 104323.0013PCT NITRIC OXIDE GENERATING/RELEASING MEDICAL DEVICES Cross Reference to Related Applications [0001] This application claims priority to our copending US provisional patent application with the serial number 63/589,567, which was filed 10/11/2023, and further claims priority to our copending US provisional patent application with the serial number 63/549,227, which was filed 02/02/2024, both of which are incorporated by reference herein. Field of the Invention [0002] The field of the invention is compositions and methods for an extruded article, that is comprised of a homogenous mixture of a thiol-containing component and a nitrite-containing component, especially as it relates to the resulting inclusion of a plurality of nitrosothiol groups. 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] A variety of products and articles, including, for example, medical instruments, devices, and equipment, must be sterilized prior to use to prevent microbial contamination of a wound site, or a biological sample, etc. This is particularly true for medical devices that are in direct contact with a bodily fluid such as blood or urine over an extended period as is the case with most catheters and tubing. To that end, a number of sterilization processes are known that in many cases involve a step of contacting the product or article with a sterilant. Examples of such sterilants include dinitrogen tetroxide, steam, ethylene oxide, hydrogen peroxide, dry heat, and the like.
Attny Dkt No. 104323.0013PCT [0006] Unfortunately, some of the known sterilants will chemically adversely react with a number of materials and are therefore not suitable for use, while other sterilants can be applied but will then relatively quickly react or otherwise decompose. To overcome such difficulties, antimicrobial agents such as zinc complexes, colloidal silver, or triclosan can be included into a material to so provide at least some antimicrobial effect. However, such antimicrobial agents may be problematic for use with medical devices or articles that contact food. [0007] In further examples of sterilization of an article, gaseous nitric oxide may be formed in an enclosure from a precursor such as a nitrosothiol to so expose the article to sterilizing quantities of nitric oxide as is described in WO 2022/164894, using materials prepared as described in US 9884943. Unfortunately, due to the coupling chemistry for the nitric oxide precursor groups used in the ‘894 and ‘943 references, the quantity of nitric oxide precursor groups in the polymer is limited. Unfortunately, even if nitric oxide precursor groups can be coupled to a polymer, the so modified nitric oxide releasing polymers (e.g., comprising diazeniumdiolates and nitrosothiols) have limited thermal stability and are as such unsuitable for most, if not all extrusion processes to form medical devices such as catheters and medical tubing as extrusion generally relies on relatively high temperatures that would destroy the nitric oxide releasing compounds. Thus, even though various compositions and methods of producing and forming nitric oxide releasing materials are known in the art, all or almost all of them suffer from several drawbacks, particularly where such materials are limited in thermal stability. Therefore, there remains a need for improved compositions and methods of producing nitric oxide releasing materials through extrusion. Summary of The Invention [0008] The inventive subject matter is directed to various compositions and methods of forming an extruded article such as a catheter and/or tubing that is produced from a (preferably homogenous) mixture of a thiol-containing component and a nitrite-containing component, in which a thiol compound in the thiol-containing component and a nitrite compound in the nitrite-containing component react at extrusion temperatures to form a nitrosothiol group. As a result, the extruded article includes a nitrosothiol group that can release nitric oxide in response to a change in environmental conditions such that an item stored in the extruded article can be sanitized. Advantageously, environmental conditions leading to nitric oxide release include contact with an aqueous medium such as saline, water, blood, urine, etc., as well as light exposure and/or elevated temperatures.
Attny Dkt No. 104323.0013PCT [0009] In one aspect of the inventive subject matter, the inventor contemplates a two- component system, that includes a solid thiol-containing component and a solid nitrite- containing component, wherein one component, or both, comprises a thermoplastic polymer, and wherein the solid thiol-containing component and the solid 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 blended and subjected to heat (e.g., to thereby form a melted mixture). [0010] In some embodiments, the thiol-containing component and/or the nitrite-containing component comprise a thermoplastic resin, and suitable resins include polypropylene, polyethylene, polyvinyl chloride, polystyrene, polyethylene terephthalate, polyetherimide, polyetheretherketone, polycarbonate, and poly(ethylene-vinyl acetate). Contemplated thermoplastic resins will also include resins that are chemically modified to include a pendant thiol group (e.g., comprising a N-acetylpenicillamine group). [0011] Consequently, the thiol-containing component may comprise a thermoplastic polymer that is combined with a cysteine or derivative thereof, a thiol-derivatized polymer or filler, or combination thereof. Furthermore, the thiol-containing component may comprise an inorganic matter coated with a cysteine or derivative thereof, a thiol-derivatized polymer or filler, or combination thereof. For example, the cysteine or derivative thereof may be cysteine, glutathione, acetyl cysteine, penicillamine, acetylpenicillamine, S-nitroso-N-acetyl- penicillamine, bucillamine, and combinations thereof. [0012] Moreover, the nitrite-containing component may comprise a thermoplastic polymer combined with a nitrite. Alternatively or additionally, the nitrite containing component may also comprise inorganic matter coated with 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. [0013] In addition, it is contemplated that the thiol-containing component and the nitrite- containing component have a composition suitable for thermal extrusion. Preferably, the thiol- containing component and the nitrite-containing component are stored separately, and/or the
Attny Dkt No. 104323.0013PCT thiol compound and the nitrite compound are non-reactive at room temperature. In further contemplated aspects, it should be appreciated that the solid thiol-containing component and the solid nitrite-containing component can be mixed and melted together to form a mixture that can be cooled and extruded at a later point in time, or that the solid thiol-containing component and the solid nitrite-containing component can be coextruded together to form the desired article such as a catheter or tubing. [0014] In some embodiment, the melting of either the thiol-containing component or the nitrite-containing component, or both, will form a nitrosothiol upon heating, combination, and cooling. The so formed nitrosothiol is then capable of releasing NO in response to a change in temperature, pressure, pH, humidity, and/or illumination with visible or UV light, or combination thereof. [0015] Viewed from a different perspective, the inventor additionally contemplates a method of making a two-component system that includes providing a solid first component and a solid second component, incorporating (by admixing or derivatizing) a thiol compound into the first component to thereby form a thiol-containing component, and incorporating a nitrite compound into the second component to thereby form a solid nitrite-containing component, wherein the first or second component, or both components, comprise a thermoplastic resin as the solid component, and wherein the solid thiol-containing component and the solid 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 blended and subjected to heat. [0016] Preferably, the thermoplastic resin is polypropylene, polyethylene, polyvinyl chloride, polystyrene, polyethylene terephthalate, polyetherimide, polyetheretherketone, polycarbonate, and/or poly(ethylene-vinyl acetate). In addition, the thermoplastic resin optionally further comprises an acidic component. [0017] In some embodiments, the solid first component or the solid second component comprise an inorganic matter such as a mineral, a metal, a metal alloy, and a carbonaceous material. [0018] Most typically, but not necessarily, a thiol compound is incorporated into the first solid component by melting and combining, applied as a coating, or by derivatizing the first
Attny Dkt No. 104323.0013PCT component. For example, the thiol-containing component may comprise a thermoplastic polymer homogeneously combined or coated with a cysteine or derivative thereof, a thiol- derivatized polymer or filler, or combination thereof. Furthermore, the thiol-containing component may also comprise an inorganic matter homogeneously combined or coated with a cysteine or derivative thereof, a thiol-derivatized polymer or filler, or combination thereof. In some embodiments, the cysteine or derivative thereof is cysteine, glutathione, acetyl cysteine, penicillamine, acetylpenicillamine, S-nitroso-n-acetylpenicillamine, bucillamine, and combinations thereof. [0019] Most typically, but not necessarily, a nitrite compound is incorporated into the second solid component by melting and combining or applied as a coating. For example, the nitrite- containing component may comprise a thermoplastic polymer homogeneously combined or coated with a nitrite. Furthermore, the nitrite-containing component may also comprise inorganic matter homogeneously combined or coated with 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. [0020] In further embodiments, the thiol-containing component and the nitrite-containing component have a composition suitable for thermal extrusion. Preferably, the thiol-containing component and the nitrite-containing component are stored in separate containers. But in some embodiments, the solid thiol-containing component and the solid nitrite-containing components are stored in a single container. Nonetheless, it is generally preferred that the solid thiol-containing component and the solid nitrite containing-component are non-reactive at room temperature. [0021] Most typically, but not necessarily, the nitrosothiol is formed during cooling after the heating and combining of the solid thiol-containing component and the solid nitrite-containing component. Thus, coextrusion of the thiol-containing component and the solid nitrite- containing component and extrusion of previously mixed and melted thiol-containing component and solid nitrite-containing component are specifically contemplated herein. Consequently, the so formed nitrosothiol in the extruded article can release NO in response to exposure to an aqueous medium (e.g., water, saline, humidity, blood urine, etc.), and/or a
Attny Dkt No. 104323.0013PCT change in temperature, pressure, pH, humidity, and/or illumination with visible or UV light, or combination thereof. [0022] Viewed from another perspective, the inventor further contemplates a method of making an extruded article such as a catheter or tubing that comprises providing or receiving the two-component system discussed herein, mixing the two-component system to form a substantially homogenous mixture or ascertaining that the two-component system forms a substantially homogenous mixture, and heating the mixture and extruding the heated mixture through a die to thereby form the extruded article. Alternatively, the two-component system can also be mixed, heated and cooled to form a nitrosothiol-containing material that is then heated and extruded through a die. As will be readily appreciated, the two-component system or nitrosothiol-containing material can also be used in thermal processes other than extrusion, and particularly preferred alternative processes include injection molding, blow-fill-seal molding, 2-shot or multi-shot molding, insert molding [0023] In some embodiments the two-component system comprises one component with a mixed-in thiol compound, coated with thiol compound, or wherein the thiol compound is covalently attached to a thermoplastic polymer. In additional embodiments, the two-component system comprises one component with a mixed-in nitrite compound or coated with a nitrite compound. [0024] Most typically, but not necessarily, the extruded article contains less than 10% unreacted thiol groups after extrusion as compared to before extrusion, and/or the extruded article contains less than 10% unreacted nitrite groups after extrusion as compared to before extrusion. Preferably, the extruded article is configured to hold an item requiring sterilization. In addition, the extruded article has a sealable portion. [0025] In some embodiments, the extrusion process is selected from the group consisting of blow molding extrusion, sheet film extrusion, and tubing extrusion. Nonetheless, the extrusion process is typically performed a temperature of between 300 °C and 600 °C. For example, the two-component system may be subjected to a temperature of between 300 °C and 600 °C for a time of between about 5 seconds to 300 seconds. In some embodiments, the extrudable article comprises a portion having a wall thickness of 0.025 mm to 25 mm. [0026] Additionally, and viewed from a different perspective, the inventor also contemplates a packaging article that includes a portion containing an extruded polymer material that
Attny Dkt No. 104323.0013PCT includes a plurality of nitrosothiol groups, and wherein the portion is produced, or received, in a homogenous mixture and then extruded as discussed herein. For example, the extruded polymer material is configured as a transparent film or a tray. Preferably, the extruded polymer material has a color that is indicative of the presence of a nitrosothiol. Therefore, in at least some embodiments, the formed nitrosothiol is S-nitroso-N-acetylpenicillamine (SNAP) or S- nitrosocysteine. [0027] 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 [0028] FIG.1 is an exemplary schematic illustration of a first exemplary process of forming an extruded article according to the inventive subject matter. [0029] FIG.2 is an exemplary schematic illustration of a second exemplary process of forming an extruded article according to the inventive subject matter. [0030] FIG.3 is an exemplary schematic illustration of a third exemplary process of forming an extruded article according to the inventive subject matter. Detailed Description [0031] The inventor has discovered various compositions and methods that allow for the formation of an extruded polymeric article that contains nitrosothiol groups. Advantageously, the nitrosothiol groups are formed in the process of extrusion by reaction of a thiol compound and a nitrite compound, each of which may be associated with respective solid phases, or, in some embodiments, only the thiol compound is associated with a solid phase. Upon heating and melting of the polymer, the nitrite and thiol compounds can contact and react to form the nitrosothiol group, leading to a nitrosothiol containing polymer that will rapidly cool to form the desired article. The nitrosothiol groups present in the extruded article may decompose to form nitric oxide, resulting in sanitization of an item stored within or near the extruded article. [0032] As should be appreciated, nearly all nitric oxide releasing materials (diazeniumdiolates and nitrosothiols) are limited in thermal stability, making extrusion of such materials
Attny Dkt No. 104323.0013PCT impossible. To overcome these problems, the inventor has now discovered that when precursor reagents used to produce a nitrosothiol group are maintained separate prior to the extrusion process, nitrosothiol groups can be formed in a polymer article upon heating and extrusion. More specifically, the inventor has discovered a two-component system that comprises a solid thiol-containing component and a solid nitrite-containing component. In a typical embodiment, the solid thiol-containing component, and in some cases also the solid nitrite-containing component, comprises a thermoplastic polymer. For example, the solid thiol-containing component may comprise an EVA polymer that includes a thiol group covalently coupled to the polymer, while the solid 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). Alternatively, the nitrite-containing component or thiol-containing component need not contain a polymer but may be inorganic matter coated or impregnated with the thiol-containing component or the nitrite-containing component. Both thusly modified components are typically homogeneously combined, and then extruded to form a nitrosothiol-containing article. During extrusion, the carrier matrix melts, the thiol compound and the nitrite compound react, and during cool down the nitrosothiol remains intact and able to donate nitric oxide in response to light, heat, transition metal catalysis, or a reaction with ascorbic acid. [0033] Regardless of the use of thermoplastic polymer or inorganic matter, the two-component system can be stored in its distinct parts, where the thiol-containing component and the nitrite- containing component are stored in separate containers. Typically, at room temperature, the two components will not react to form nitrosothiol; so alternatively, the two-component system may also be stored in one container, where the thiol-containing component and the nitrite- containing component are stored together. The two-component system can then be melted and combined to form a homogeneous mixture, if not already mixed, prior to extrusion. The extrusion process will lead to melting of the two-component system such that the thiol- containing component and the nitrite-containing component can react to form a nitrosothiol- containing extruded article. [0034] 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 nitrite-containing component are combined and
Attny Dkt No. 104323.0013PCT subjected to heat. As will be readily appreciated, the polymer can be shaped in such extrusion process into any desired geometry such as a film or other generally flat geometry, may be applied to a surface in a conforming manner to so coat a regular or irregularly shaped object, or may be formed into a cylindrical or rectangular shaped object with internal storage space. For example, the melted mixture of thiol and nitrite compounds may, before solidifying, be run through a die or poured into a mold to thereby form a desired shape or structure upon solidifying. [0035] Thus, it should be recognized that the components necessary to react to form the S- nitrosothiol can be incorporated into the two-component system in the form of precursor compounds that will form the S-nitrosothiol as the two-component mixture is extruded. The thiol-containing component holds the thiol compound and the nitrite-containing component holds the nitrite compound separately and the two components are not allowed to react until the polymeric component(s) is/are liquified and react during and/or subsequent to the extrusion through a die, and/or during cooling. In some embodiments, as the two-component mixture melts, the reactive groups will form the RSNO group in the melted state and to some extent also as the resultant polymer solidifies and cools. The so formed S-nitrosothiol is held intact when the extruded article is fully cooled and is then able to donate NO in response to light, heat, transition metal catalysis, or reaction with ascorbic acid or the like. [0036] 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, dithioerythritol 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, (11-mercaptoundecyl)hexa(ethylene glycol), (11-mercapto-undecyl)tetra(ethylene glycol), (11-mercaptoundecyl)tetra(ethylene glycol) functionalized gold nanoparticles, 1,1′,4′,1″-terphenyl-4-thiol, 1,11-undecanedithiol, 1,16-hexadecanedithiol, 1,2-ethanedithiol, 1,3-propanedithiol, 1,4-benzenedimethanethiol,
Attny Dkt No. 104323.0013PCT 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- (triethylene glycol), 1-mercapto-(triethylene glycol) methyl ether functionalized gold nanoparticles, 1-mercapto-2-propanol, 1-nonanethiol, 1-octadecanethiol, 1-octanethiol, 1- octanethiol, 1-pentadecanethiol, 1-pentanethiol, 1-propanethiol, 1-tetradecanethiol, 1- undecanethiol, 11-(1H-pyrrol-1-yl)undecane-1-thiol, 11-amino-1-undecane-thiol hydro- chloride, 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, 1H,1H,2H,2H-perfluorodecanethiol, 2,2′-(ethylenedioxy)di- ethanethiol, 2,3-butanedithiol, 2-butanethiol, 2-ethylhexanethiol, 2-methyl-1-propanethiol, 2- methyl-2-propanethiol, 2-phenylethanethiol, 3,3,4,4,5,5,6,6,6-nonafluoro-1-hexanethiol purum, 3-(dimethoxymethylsilyl)-1-propanethiol, 3-chloro-1-propanethiol, 3-mercapto-1- 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-1- butanethiol, 4-mercapto-1-butanol, 6-(ferrocenyl)hexanethiol, 6-mercapto-1-hexanol, 6- mercaptohexanoic acid, 8-mercapto-1-octanol, 8-mercaptooctanoic acid, 9-mercapto-1- 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-11-(acetylthio)undecyl ether, mercaptosuccinic acid, methyl 3-mercaptopropionate, octanethiol functionalized gold nanoparticles, PEG dithiol, S-(11-bromoundecyl)thioacetate, S-(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. [0037] 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
Attny Dkt No. 104323.0013PCT thereof may comprise cysteine, glutathione, acetyl cysteine, penicillamine, acetylpenicillamine, S-nitroso-n-acetylpenicillamine, bucillamine, or combinations thereof. [0038] In various embodiments, the thiol-containing compound has an 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 an 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 an average molecular weight of 121 g/mol, glutathione has an average molecular weight of 307.33 g/mol, butylthiol has an average molecular weight of 90.19 g/mol, and serum albumin has an 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. [0039] 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. [0040] In various embodiments, the nitrosating compound has an 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 an 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 an average molecular weight of 69 g/mol and butyl nitrite has an 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
Attny Dkt No. 104323.0013PCT 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. [0041] 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. [0042] 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. In regard to acidity, the amount of acidic compound added for the desired reaction conditions may vary considerably based on the thermoplastic polymer utilized. Added acidic amounts may range from at least 10%, or at least 30%, or at least 40%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 100% of the overall thermoplastic polymer used. [0043] In various embodiments, the specific nature and type of inorganic matter used within the context of this disclosure may also vary considerably, and the type of inorganic matter will typically be a function of the desired product but may also be a filler. However, it is generally preferred that the inorganic matter is a mineral, a metal, a metal alloy, and a carbonaceous material. Further examples of inorganic matter include aragonite, chalk, or talcum.
Attny Dkt No. 104323.0013PCT [0044] Regardless of the specific chemistry of the thermoplastic polymer, inorganic matter, thiol compound, and nitrite compound, it is generally preferred that the two-component system will be prepared in form of a homogeneous mixture that is suitable for thermal extrusion. Therefore, in most embodiments, the thermoplastic polymer will have a particle size that is suitable for such use and contemplated average particle sizes will range between 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. [0045] Once the two-component system is homogeneously combined, it is contemplated that the system will be subjected to an extrusion step that involves heating the mixture and extruding the heated mixture through a die to form the extruded article. With regard to preferable extrusion processes, contemplated techniques involve blow molding extrusion, or sheet film extrusion, or tubing extrusion. With regard to suitable temperatures, it is contemplated that the temperature is sufficient to 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 125 °C, or at least 150 °C, or at least 175 °C, or at least 200 °C, or at least 225 °C, or at least 250 °C, or at least 275 °C, or at least 300 °C, or at least 325 °C, or at least 350 °C, or at least 400 °C, or even higher. With regard to suitable periods of time, it is contemplated that the time at a certain temperature is sufficient to (a) melt the thermoplastic polymer to a degree such as to enable contact between the thiol compound and the nitrite compound, and (b) avoid a premature decomposition of the resulting nitrosothiol into nitric oxide. 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. 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 and/or nitrite compounds. It is further contemplated that thermoplastic polymers of varying melting points may be used, especially where the melting points of the selected thermoplastic polymers correspond to the ideal temperature conditions for reactions between nitrite and thiol compounds.
Attny Dkt No. 104323.0013PCT [0046] Upon extrusion, the extrudable article is configured to be a sealable container, or a portion thereof, wherein contemplated wall thickness will be at least 0.025 mm, or at least 0.050 mm, or at least 0.075 mm, or at least 0.1 mm, or at least 0.5 mm, or at least, 1 mm, or at least 5 mm, or at least 10 mm, or at least 15 mm, or at least 20 mm, or at least 25 mm, or even higher. In some embodiments of the inventive subject matter, the sealable container comprises a biodegradable material, such as a biodegradable plastic that can break down into water, carbon dioxide, and biomass when exposed to moisture. [0047] Thus, it should be recognized that upon extrusion of the two-component system, thermal energy will promote a reaction between the thiol compound in the thiol-containing component and the nitrite compound in the nitrite-containing component 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 that will be included in the resulting extruded article. In some embodiments, the extruded article is a packaging article, or portion thereof, that can be used to store an item requiring sterilization with NO. As such, the extruded article, or portion thereof, may serve as a packaging article that includes a plurality of nitrosothiol groups embedded in the article structure. For example, contemplated nitrosothiol groups include S- nitroso-N-acetylpenicillamine (SNAP), or S-nitrosocysteine. Consequently, the extruded article most typically has a color that is indicative of the presence of a nitrosothiol, such as red, or pink, or green. Yet in further embodiments, the extruded article is configured as a transparent film or tray. Nonetheless, the so formed article will be able to emit NO over extended periods in response to UV light, changes in H, temperature, moisture, etc. [0048] The various embodiments disclosed herein provide several advantages over the prior art. For example, the methods and devices disclosed herein reduce residual waste and/or reactants in the extrusion process. In certain embodiments, for instance, the amount of unreacted thiol present after extrusion is typically less than 10%, or less than 7.5%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5% of an amount of thiol in the thiol- containing component. Further, and in other embodiments, the amount of unreacted nitrite present after extrusion is less than 10%, or less than 7.5%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5% of an amount of nitrite in the nitrite-containing component. In other embodiments, the disclosed subject matter provides the benefit of increasing the yield of the chemical reaction between the thiol and nitrite, with the yield typically being more than
Attny Dkt No. 104323.0013PCT 75%, or more than 80%, or more than 85%, or more than 90%, or more than 95%, or more than 98%, or more than 99.5% of the maximum yield. [0049] Further, it should be appreciated that the residence time, which represents the time in which the polymers containing thiol and nitrite respectively are melted together, will be selected such that the residence time is long enough to support the reaction between nitrite and thiol compounds, yet short enough to prevent degradation or decomposition of nitrosothiol to a significant degree (e.g., no more than 10%, or no more than 7 %, or no more than 5%, or no more than 3% of the newly formed nitrosothiol is degraded/decomposed. Therefore, in some embodiments, the residence time may be 1-5 seconds, 5-10 seconds, 10-30 seconds, 30-60 seconds, 1-2 minutes, 2-5 minutes, 5-10 minutes, or more than 10 minutes. Viewed from another perspective, the residence time is no more than 20 minutes, 10 minutes, 5 minutes, 2 minutes, 1 minute, 30 seconds, 10 seconds, or 5 seconds long. Thus, it should be noted that a proper choice of the residence time may allow for dual advantages, wherein the amount of unreacted nitrite and thiol is limited, while the yield of nitrosothiol is further optimized. [0050] It is further contemplated that pressure conditions may be controlled during extrusion to similarly support the reaction between thiol and nitrite compounds while preventing degradation of nitrosothiol (e.g., by reducing temperature). Specific pressure conditions may be advantageous to affect the speed or rate of the reaction between the thiol and nitrite compounds. For example, it is contemplated that the pressure conditions during extrusion are pressures of 1-10 Pounds per Square Inch Gauge (PSIG), 10-50 PSIG, 50-100 PSIG, 100-200 PSIG, 200-500 PSIG, 500-1000 PSIG, 1000-1500 PSIG, 1500-2000 PSIG, 2000-3000 PSIG, 3000-5000 PSIG, 5000-10000 PSIG, or more than 10000 PSIG. But typically, and viewed from another point of view, the pressure is no more than 5000 PSIG. [0051] The inventors still further contemplate that in other embodiments of the inventive subject matter, “cooling” of the melted polymer(s) may involve many different mechanisms, especially as it relates to decreasing the temperature of the melted mixture of thiol and nitrite compounds. For instance, cooling may involve blowing colder air on the mixture until the mixture reaches a desired lower temperature and/or until the mixture solidifies. In another example, the mixture, after being molded into a particular shape or run through a die to form a particular shape, may be submerged, partially immersed, floated, suspended, and/or resting in a liquid having a lower temperature than the mixture. The liquid may, for instance, be an ice bath. Alternatively, the mixture may simply be placed in a space or a room with a lower
Attny Dkt No. 104323.0013PCT temperature for a time period sufficient to allow the mixture to reach a desired lower temperature or until it solidifies. Such space may be a refrigerator, freezer, cold room, or any other space. Other examples of cooling may be placing the mixture on a cold plate, or alternatively surrounding the mixture with a cooling jacket. [0052] In still other embodiments, the reaction between thiol compounds and nitrite compounds may be done in the presence of chelators. Chelators may provide several benefits, such as minimizing or reducing the degradation of nitrosothiol during or after extrusion, especially by binding to metal ions to thereby remove catalytic metal ions. Thereby, the presence of chelators may maximize or otherwise increase the final yield of nitrosothiol. In other instances, chelators like EDTA may act as buffers that maintain a desired pH during a reaction. Chelators may provide many other benefits related to stability of reaction. For instance, the binding of chelators to metal ions sequesters such ions to thereby increase the rate of reaction between thiol and nitrite. Further, chelators may help prevent the formation of insoluble metal hydroxides or other precipitates that could form in the presence of metal ions, maintaining the desired reaction environment for the formation of nitrosothiol. [0053] 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. [0054] 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
Attny Dkt No. 104323.0013PCT other compounds may be added to influence the decay or decomposition of nitrosothiol to nitric oxide. 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. [0055] In yet further embodiments, the extrusion process may be done in the absence of light, or with low intensity light, or dim light. Certain frequencies of light, such as UV light, may cause the degradation of nitrosothiol, making it preferable to minimize the amount of light exposure on the yield of nitrosothiol. Viewed from another perspective, once formed, selective exposure to certain frequencies of light may be advantageous to cause the release of nitric oxide on demand via decomposition of nitrosothiol to nitric oxide. [0056] Moreover, it should be recognized that an additional benefit of the disclosed methods over the prior art is an even distribution of thiol and nitrite throughout an article to achieve homogenous distribution of the nitrosothiol formed. A homogenous mixture formed according to the disclosed subject matter may, in some embodiments, allow the thiol and nitrite to disperse uniformly throughout the reaction medium, resulting in equal concentration of thiol and nitrite compounds, and potentially polymer compounds, at every point within the system. Such equal distribution may be advantageous to allow for even release of nitric oxide from every point on an article of nitrosothiol, providing consistency. [0057] Beneficially, the inventors contemplate that in addition to the extrusion of thiol and nitrite compounds to form nitrosothiol, other substances may be coextruded to form desired shapes or structures. For example, a third substrate may be coextruded to form a core having a cylindrical or other shape, while the nitrite and thiol compounds may be extruded to form a sheath around said core, or vice versa. Any number of variations of such coextrusions may be possible to form articles having nitrosothiol and other components. In another example, nitrosothiol may be coated with protective layers formed by coextrusion. Said protective layers may be selectively permeable to nitric oxide such that, when the nitrosothiol product releases nitric oxide, the protective layer may selectively either allow the nitric oxide to be released (e.g., at a predetermined rate via selected NO diffusion coefficients of the protective layer) or not allow the nitric oxide to be released. Thus, te protective layer may be configured to allow a user to make selections as to which state the protective layer may be in at a given moment. For example, a user may be able to set the protective layer to be permeable to nitric oxide, semi-permeable to nitric oxide (potentially in varying degrees, such as 10%, 50% or 90%
Attny Dkt No. 104323.0013PCT permeable), or non-permeable to nitric oxide, depending on the intention of the user. In another example, a user may be able to specify the amount, in mass, of nitric oxide that should be released. Still further, a user can instead specify the volume of space to be filled with nitric oxide gas, the desired percentage of nitric oxide to fill the space, and a computer can calculate and direct the permeability of the surface to release the corresponding amount of nitric oxide. A user may be a person or a computer. In still other embodiments, the nitrosothiol product may be coated with protective layers that are removable. Such protective layers may be useful for packaging the nitrosothiol for easier transportation. Alternatively, the protective layers may be biodegradable, or degradable in response to exposure to water or other substances. [0058] In still other embodiments, the disclosed subject matter provides an ability to preserve nitrosothiol on demand, thus allowing sterilization using nitric oxide on demand. The methods and devices provided herein may yield a solid nitrosothiol article which may be mobile, movable, and transportable. Alternatively, or in addition, the inventive subject matter discloses a medical device comprising a portion containing an extruded polymer material that includes a plurality of nitrosothiol groups. Both such embodiments may be helpful, for example, in a hospital setting where nitrosothiol articles or medical devices containing nitrosothiol groups are stored such that the articles may be used to sterilize equipment on demand. In another example, an extruded article may be brought into field work and used by a medical professional to sterilize a medical instrument on demand. Because the article is solid, yet it may release nitric oxide liquid and gas under certain conditions, the article provides the convenience of transporting a solid material as opposed to storing liquid or gaseous nitric oxide.Additionally, because one or both components of the two-component system comprise a thermoplastic polymer, the storage of the components before extrusion is especially simplified. For example, any number of thiol-containing components held within a thermoplastic polymer can be stored in a same container as any number of nitrite-containing components. The thermoplastic polymer will not be permeable to either the thiol compound in the thiol-containing component or the nitrite compound in the nitrite-containing component until the components are heated. Therefore, the necessary components may be stored in the same location for convenience. [0059] It is further contemplated that the two-component system comprises a computer configured to measure the amount of the thiol compound and the nitrite compound before the thiol-containing component and nitrite-containing component are blended or subjected to heat. The computer may, in some embodiments, display such amounts on a screen viewable by a
Attny Dkt No. 104323.0013PCT user. Further, the computer preferably enables the user to input the desired yield, and based on the input, the computer calculates the precise quantity of thiol and nitrite required. The quantities may be measured in predetermined increments corresponding to the sizes of standardized plastic packages containing the thiol and/or nitrite, ensuring ease of use and accurate dosing. Examples [0060] Example 1: Resin A comprises poly(ethylene-vinyl acetate)(40% acetate) melted and combined with cysteine (free base). Resin B comprises poly(ethylene-vinyl acetate)(40% acetate) melted and combined with sodium nitrite. Resin A and Resin B are mixed and melted together. As the combined material cools, a pink color develops, indicative of the formation of S-nitrosocysteine. FIG.1 exemplarily depicts such process scheme. Among other uses, such mixture can be extruded to form a medical device such as medical tubing and catheters. As will be readily appreciated, the medical device can be wetted by immersion in an aqueous solution and/or water, saline, or a bodily fluid flowing through and/or around the device. Humidified air will also initiate the release of NO, and the devices will also release NO when exposed to light or increased temperature (e.g., between 25 °C and 45 °C, or between 35 °C and 55 °C, or between 45 °C and 75 °C). [0061] Example 2: Resin C comprises poly(ethylene-vinyl acetate)(40% acetate) melted and combined with N-acetylpenicillamine (free base). Resin B consists of poly(ethylene-vinyl acetate)(40% acetate) melted and combined with sodium nitrite. Resin C and Resin B are mixed and melted together. As the combined material cools, a green color develops, indicative of the formation of S-nitriso-N-acetylpeniciliiamine(SNAP). FIG.2 exemplarily depicts such process scheme. Among other uses, such mixture can be extruded to form a medical device such as medical tubing and catheters. As noted above, the medical device can be wetted by immersion in an aqueous solution and/or water, saline, or a bodily fluid flowing through and/or around the device. Humidified air will also initiate the release of NO, and the devices will also release NO when exposed to light or increased temperature (e.g., between 25 °C and 45 °C, or between 35 °C and 55 °C, or between 45 °C and 75 °C). [0062] Example 3: Resin D comprises poly(ethylene-vinyl acetate)(40% acetate) derivatized with pendant acetylpenicillamine groups (as is, for example, described in WO 2023/205125, incorporated in its entirety by reference herein). Resin B comprises poly(ethylene-vinyl
Attny Dkt No. 104323.0013PCT acetate)(40% acetate) melted and combined with sodium nitrite. Resin D and Resin B are mixed and melted together. As the combined material cools, a green color develops, indicative of the formation of S-nitroso-N-acetylpenicillamine (SNAP) covalently linked to the EVA polymer backbone. FIG.3 exemplarily depicts such process scheme. Once more, such mixture can be extruded to form a medical device such as medical tubing and catheters. As noted earlier, the medical device can be wetted by immersion in an aqueous solution and/or water, saline, or a bodily fluid flowing through and/or around the device. Humidified air will also initiate the release of NO, and the devices will also release NO when exposed to light or increased temperature (e.g., between 25 °C and 45 °C, or between 35 °C and 55 °C, or between 45 °C and 75 °C). [0063] Example 4: Resin A of Example 1 is coextruded with Resin B of Example 1 without prior mixing and heating such that S-nitrosocysteine is formed in the extrusion and cooling process. Such coextrusion can be used to form a medical device such as medical tubing and catheters. As noted earlier, the medical device can be wetted by immersion in an aqueous solution and/or water, saline, or a bodily fluid flowing through and/or around the device. Humidified air will also initiate the release of NO, and the devices will also release NO when exposed to light or increased temperature (e.g., between 25 °C and 45 °C, or between 35 °C and 55 °C, or between 45 °C and 75 °C). [0064] Example 5: Resin E comprises polyethylene melted and combined with cysteine (free base). Resin F comprises polyethylene melted and combined with sodium nitrite. Resin E and Resin F are mixed and melted together. As the combined material cools, a pink color develops, indicative of the formation of S-nitrosocysteine. Upon extrusion to form a medical device such as a catheter or tubing, the medical device can be wetted by immersion in an aqueous solution and/or water, saline, or a bodily fluid flowing through and/or around the device. Humidified air will also initiate the release of NO, and the devices will also release NO when exposed to light or increased temperature (e.g., between 25 °C and 45 °C, or between 35 °C and 55 °C, or between 45 °C and 75 °C). [0065] Example 5: Resin E from Example 5 is coextruded with Resin F from Example 5 to form a medical device such as a catheter or tubing, the medical device can be wetted by immersion in an aqueous solution and/or water, saline, or a bodily fluid flowing through and/or around the device. Humidified air will also initiate the release of NO, and the devices will also
Attny Dkt No. 104323.0013PCT release NO when exposed to light or increased temperature (e.g., between 25 °C and 45 °C, or between 35 °C and 55 °C, or between 45 °C and 75 °C). [0066] 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. [0067] 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. [0068] 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. [0069] 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
Attny Dkt No. 104323.0013PCT 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 something selected 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.