Thiol-containing alcohols for producing nitric oxide and methods for forming same

Abstract

Compositions and methods are presented for nitric oxide precursors that release nitric oxide upon decomposition. The nitric oxide precursors include the reaction products of thiol-containing alcohols, silanes, and nitrosated compounds, allowing for technically simple (e.g., solventless, one-pot synthesis) and flexible synthesis of nitric oxide precursors and mixtures thereof, and allowing for control of the nitric oxide release rate (e.g., via the use of primary, secondary, and / or tertiary nitrosothiols, alone or in combination with additives).

Description

[Technical Field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims priority to our co-pending U.S. Provisional Patent Application No. 63 / 428,048, filed November 26, 2022, and incorporated herein by reference.

[0002] Technical Field The present disclosure generally relates to nitric oxide precursors comprising the reaction product of a thiol-containing alcohol, a silane, and a nitrosated compound. [Background technology]

[0003] A variety of products and articles, including medical instruments, devices, and tools, must be sterilized before use to prevent biological contamination of wound sites, specimens, organisms, etc. Several sterilization processes are used that involve contacting the product or article with a sterilant. Examples of such sterilants include dinitrogen tetroxide, nitric oxide, water vapor, ethylene oxide, hydrogen peroxide, dry heat, etc. For example, when the sterilant is nitric oxide, the most common methods use catalytic or enzymatic generation of nitric oxide (NO) from nitrite or NO-donor compounds, such as diazeniumdiolates, and typically require relatively complex systems for generating, maintaining, and disposing of nitric oxide.

[0004] Alternatively, nitric oxide can be generated at the site of use from precursor compounds that release nitric oxide upon decomposition. Most typically, such precursors contain chemically unstable nitrosothiol groups. For example, WO 2017 / 156078 presents implantable devices containing nanostructured lipid particles capable of releasing nitric oxide. Here, the inventors used the thiol-lipid DPPTE (1,2-dipalmitoyl-sn-glycero-3-phosphothioethanol), incorporated into lipid nanoparticles after nitrosylation, to treat subjects suffering from nitric oxide-mediated diseases. Although conceptually attractive, such nitric oxide precursors have been limited to in vivo use with lipid-based therapeutics. In addition, besides the complex manufacturing procedures, the concentration of nitric oxide from such precursors is generally insufficient for sterilization in ex vivo situations.

[0005] Other known approaches have reported that certain polymers can be modified to provide amounts of nitrosothiol groups useful in NO-based sterilization processes. For example, in WO 2023 / 205125, polymeric materials modified to contain pendant nitrosothiol groups capable of releasing nitric oxide were prepared. Here, polycarbonate-polydimethylsiloxane (PCPDMS) block copolymer, polyurethane-polydimethylsiloxane (PUPDMS) block copolymer, polyurethane (PU), poly(ethylene-co-vinyl acetate) copolymer (EVA), or polydimethylsiloxane were first reacted with 3-aminopropyltrimethoxysiloxane to form pendant amine groups, which were subsequently reacted with acetylpenicillamine thiolactone to introduce thiol groups, which were subsequently reacted with t-butyl nitrite to convert the exposed thiol groups to the corresponding S-nitrosothiols. Unfortunately, such approaches are limited to specific reactive groups present only in the polymer.

[0006] Additionally, known methods for forming these nitric oxide precursors require expensive reactants and multiple reaction sequences, making the synthesis relatively complex. Furthermore, the small molecule nitrosothiols that decompose to form nitric oxide are highly unstable, especially in solution, and typically do not offer flexibility in the preparation of primary, secondary, or tertiary RSNOs. Furthermore, the chemical properties of currently known precursors often limit composite materials containing these precursors. Summary of the Invention [Problem to be solved by the invention]

[0007] Thus, there remains a need for improved compositions and methods that allow for the simple and flexible synthesis of nitric oxide precursors, particularly those that allow for the use of such precursors in a wide range of applications, shapes and forms, and / or that allow for the tuning of the rate at which such precursors release nitric oxide. [Means for solving the problem]

[0008] The present subject matter refers to various compositions and methods for nitric oxide precursors that allow for technically simple (e.g., solvent-free one-pot synthesis) and flexible synthesis of nitric oxide precursors and mixtures thereof that allow for control of the release rate of nitric oxide (e.g., via the use of primary, secondary, and / or tertiary nitrosothiols, alone or in combination with additives). Advantageously, the nitric oxide precursors presented herein can be produced in a wide variety of forms, shapes, and sizes and can be easily combined with / into other materials.

[0009] In one aspect of the inventive subject matter, the inventors contemplate a composition comprising a carrier comprising a polymeric or inorganic material bound to or admixed with a compound having a structure according to Formula I. [ka] Formula I

[0010] Preferably, but not necessarily, X is selected from the group consisting of: [ka] Formula II [ka] Formula III, and [ka] Formula IV X is covalently bonded to O in Formula I through the R4 group in Formulas II-IV. Most typically, Y is O or absent, and each R1, R2, R3, R4, R5, and R6 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and aryl, and optionally, each R1, R2, R3, R4, R5, and R6, when not hydrogen, is independently substituted with a thiol group, an epoxy group, a nitro group, and / or an amino group.

[0011] In some embodiments, the carrier is a polymeric carrier that at least partially coats the compound. For example, suitable carriers include synthetic polymeric carriers configured as packaging materials, films, or pellets. In additional examples, suitable carriers also include natural polymeric carriers configured as fibers, fabrics, or woven fabrics.

[0012] In a further embodiment, the compound is granulated and has a largest dimension of 500 μm or less. Preferably, but not necessarily, the compound is present in the composition in an amount of 0.01% to 0.1% by weight. Nevertheless, the compound is typically present in the carrier in an amount sufficient to release an antimicrobially effective amount of nitric oxide from the carrier. It is further generally contemplated that the compound be covalently bound to the carrier.

[0013] In further contemplated embodiments, X has a structure according to Formula II, or X has a structure according to Formula III, or X has a structure according to Formula IV. Alternatively, or additionally, a composition includes a compound of Formula I (wherein Y is absent) and further includes an additional compound of Formula I (wherein Y is O). For example, a composition includes a compound of Formula I (wherein X has a structure according to one of Formulas II, III, or IV) and further includes an additional compound of Formula I (wherein X has a structure according to one of Formulas II, III, or IV), where Y in the compound of Formula I is absent and Y in the additional compound is O. Also, X in the compound and X in the additional compound do not have to be the same.

[0014] In some embodiments, the composition further comprises an additive, in such cases, the additive is selected from the group consisting of a pH adjuster, a moisture absorber, a hydrophobic agent, a light filter, a photosensitizer, a transition metal, a chelator, glutathione, and a reducing agent.

[0015] Viewed from a different perspective, the inventors additionally contemplate a method of forming a nitrosothiol-containing nitric oxide precursor, comprising combining a thiol-containing alcohol, a silane, and a nitrosating compound in a reactor to form a reaction mixture, and reacting the thiol-containing alcohol with the silane in the reaction mixture, thereby forming a thiol-containing intermediate, and reacting the thiol-containing intermediate with the nitrosating compound in the reaction mixture, thereby forming a nitrosothiol-containing nitric oxide precursor.

[0016] Desirably, the thiol-containing alcohol comprises a primary thiol, or the thiol-containing alcohol comprises a secondary thiol, or the thiol-containing alcohol comprises a tertiary thiol.

[0017] In various embodiments, the thiol-containing alcohol is selected from the group consisting of 3-mercapto-3-methyl-1-butanol, 2-mercaptoethanol, 3-mercaptohexanol, 4-mercapto-3-methyl-2-butanol, 3-mercapto-2-methyl-1-butanol, 3-mercapto-2-methyl-1-pentanol, (+ / -)-4-mercapto-4-methyl-2-pentanol, 2-mercapto-2-methyl-1-pentanol, 4-mercapto-4-methylpentan-2-ol, 3-mercaptohexan-1-ol, mercaptoethanol, 1-mercapto-3-propanol, 1-mercapto-4-butanol, and α-mercapto-ω-hydroxyoligoethylene oxide.

[0018] In further embodiments, the silane is a tetraalkoxysilane, trialkoxysilane, or cyclic azasilane. Alternatively, or additionally, the silane is selected from the group consisting of tetraethylorthosilicate (TEOS), methyltrimethoxysilane (MTMS), vinyltrimethoxysilane, methylvinyldimethoxysilane, dimethyldiethoxysilane, vinyltriethoxysilane, tetra-n-propylorthosilicate, trisacetamidomethylsilane, bisacetamidodimethylsilane, methylmethoxybis-(ethylmethylketoximo)silane, methyldimethoxyethylaminosilane, dimethyldi-N,N-dimethylaminosilane, methyldimethoxyisopropylaminosilane, triacetoxyvinylsilane, tris-(2-methoxyethoxy)vinylsilane, 3-chloropropyltriethoxysilane, 3-mercaptotriethoxysilane, ethyltrimethoxysilane, phenyltriacetoxysilane, methyltrimethoxysilane, and phenyltri-methoxysilane.

[0019] In some embodiments, the nitrosating compound is an inorganic nitrite. In further embodiments, the nitrosating compound is selected from the group consisting of sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butyl nitrite, isobutyl nitrite, t-butyl nitrite, amyl nitrite, pentyl nitrite, ion paired nitrite, silver nitrite, zinc nitrite, iron nitrite, copper nitrite, and transition metal nitrite compounds.

[0020] Advantageously, the steps of reacting the thiol-containing alcohol with the silane and reacting the thiol-containing intermediate with the nitrosated compound do not require a solvent to form the nitrosothiol-containing nitric oxide precursor. Also, the steps of reacting the thiol-containing alcohol with the silane and reacting the thiol-containing intermediate with the nitrosated compound can be carried out without pH adjustment. Alternatively, or additionally, the steps of reacting the thiol-containing alcohol with the silane and reacting the thiol-containing intermediate with the nitrosated compound are carried out at ambient temperature and pressure. Some embodiments include the additional step of removing the nitrosothiol-containing nitric oxide precursor by filtration. Further embodiments include the step of adding at least one of an acid and a catalyst to the reaction mixture, wherein the acid is acetic acid and the catalyst is di-n-butyldilaurate. Preferably, but not necessarily, the nitrosothiol-containing nitric oxide precursor has a structure according to Formula I:

[0021] From an additional perspective, the inventors further contemplate a sterilization method, which includes the steps of placing a non-sterile object into an enclosed space, the enclosed space further comprising a contemplated NO-releasing composition; sealing the enclosed space, whereby the non-sterile object and the contemplated NO-releasing composition are physically separated from an environment outside the enclosed space; and releasing nitric oxide (NO) from the contemplated NO-releasing composition into the enclosed space.

[0022] Desirably, non-sterile items may include medical devices, bandages, clothing, electronic devices, surgical tools, tissue samples, biohazardous materials, recreational items, kitchen products and / or cleaning implements.

[0023] Preferably, but not necessarily, the enclosed space is configured as a bag, pouch, or container with a lid, or the entire enclosed space is flexible. In a further embodiment, the enclosed space is 10 cm 3 ~1,000 cm 3 Most typically, the enclosed space is configured to be sealable using heat, ultrasonic energy, laser radiation, adhesives, or manual sealing. Also, contemplated NO-releasing compositions release NO in response to changes in temperature, pressure, pH, humidity, illumination with visible or UV light, or a combination thereof.

[0024] In additional embodiments, contemplated NO-releasing compositions are present in an amount sufficient to sterilize non-sterile items contained within an enclosed space via gaseous NO. Most typically, the NO is released at room temperature or elevated temperature for a time sufficient to sterilize the non-sterile items within the enclosed space. For example, sterilization can occur within 10 minutes. -6 It is performed to the following sterility assurance levels:

[0025] Thus, the inventors also contemplate a method of forming a composite article configured to sterilize an object, comprising the steps of forming or obtaining a contemplated composition, incorporating the composition into an article configured to hold a non-sterile object, thereby forming a composite article, the composite article configured to enable delivery of a sterilizing amount of nitric oxide to the object.

[0026] As will be appreciated, the forming step may include compressing or extruding the composition, or combining the composition with a packing material. In some embodiments, the packing material is a thermoplastic polymer material. Preferably, but not necessarily, the composite article is configured as a bag, tray, or flask.

[0027] Desirably, the incorporating step comprises enclosing the composition in a gas-permeable pouch and placing the pouch into the article. In a further embodiment, the incorporating step comprises combining the composition with a packing material and forming the article from the combination. As described above, sterilization is preferably performed within 10 -6 It is performed to the following sterility assurance levels:

[0028] Various objects, features, aspects and advantages of the present disclosure will become more apparent from the following detailed description of preferred embodiments, taken in conjunction with the accompanying drawings in which like numerals represent like elements. [Brief explanation of the drawings]

[0029] [Figure 1] FIG. 1 is an image illustrating a non-limiting embodiment of a reaction schematic for forming a nitric oxide precursor. [Figure 2] FIG. 2 is an image illustrating a non-limiting embodiment of the chemical structure of a nitric oxide precursor. [Figure 3] FIG. 3 is an image and graph illustrating non-limiting embodiments of nitric oxide precursors and composite articles including same. [Figure 4] FIG. 4 is an image and graph illustrating non-limiting embodiments of nitric oxide precursors and composite articles including same. [Figure 5] FIG. 5 is an image and graph illustrating non-limiting embodiments of nitric oxide precursors and composite articles including same. [Figure 6] FIG. 6 is an image and graph illustrating non-limiting embodiments of nitric oxide precursors and composite articles including same. DETAILED DESCRIPTION OF THE INVENTION

[0030] The present inventors have provided a reaction system that uses a solvent-free, one-pot synthesis to react a thiol-containing alcohol compound with a silane and a nitrosating agent, such as tert-butyl nitrite, in the presence or absence of a metallocatalyst, such as dibutyltin dilaurate or dimethyltin dineodecanoate, to provide a flexible synthesis of nitric oxide precursors and their mixtures, with controlled release rates of nitric oxide.

[0031] In various embodiments, the reaction system produces a nitric oxide precursor, and a carrier (including, for example, a polymeric or inorganic material) can be covalently bonded thereto or mixed therewith (homogeneously or heterogeneously). Preferably, the nitric oxide precursor has a structure according to Formula I, as depicted below: [ka] Formula I

[0032] In some embodiments, the nitrosothiol-containing nitric oxide precursor has a structure according to Formula I:

[0033] As can be readily appreciated, X is most typically selected from the group consisting of Formula II, Formula III, and Formula IV, and X is covalently bonded to O in Formula I via the R4 group in Formulas II-IV. [ka] Formula II [ka] Formula III [ka] Formula IV

[0034] Desirably, Y is O or absent. In addition, each R1, R2, R3, R4, R5, and R6 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and aryl. Preferably, but not necessarily, each R1, R2, R3, R4, R5, and R6, when not hydrogen, is independently substituted with a thiol group, an epoxy group, a nitro group, and / or an amino group.

[0035] In some embodiments, contemplated compositions include a compound of Formula I, where X has a structure according to one of Formulas II, III, or IV, and further include an additional compound of Formula I, where X has a structure according to one of Formulas II, III, or IV, wherein X in the compound and X in the additional compound are not identical.

[0036] Most typically, a thiol-containing alcohol (primary, secondary, tertiary) and a silane can react to form an intermediate, and the intermediate and a nitrosated compound can react to form a nitric oxide precursor. Example reaction schematics (A), (B), and (C) are shown below and in Figure 1. An example of a nitric oxide precursor is shown in Figure 2.

[0037] Schematic A [ka]

[0038] Schematic diagram B [ka]

[0039] Schematic diagram C [ka]

[0040] Preferably, but not necessarily, R is independently a methyl group, a methylene oxide group, or an ethylene oxide group, each R is independently a methylene oxide group or an ethylene oxide group, R is a mercaptoalkyl group, and each R is independently an alkyl group.

[0041] Desirably, the components utilized to form the reaction product can be combined in a reaction mixture. The components of the reaction mixture should be understood as not having reacted with each other yet. The reaction mixture for forming the reaction product can include a thiol-containing alcohol in an amount of about 1 to about 80 wt %, alternatively about 1 to about 70 wt %, or alternatively about 50 to about 80 wt %, based on the total weight of the reaction mixture. The reaction mixture for forming the reaction product can include a silane in an amount of about 1 to about 80 wt %, alternatively about 1 to about 70 wt %, or alternatively about 50 to about 80 wt %, based on the total weight of the reaction mixture. The reaction mixture for forming the reaction product can include a nitrosated compound in an amount of about 1 to about 75 wt %, alternatively about 1 to about 10 wt %, or alternatively about 10 to about 75 wt %, based on the total weight of the reaction mixture.

[0042] Thus, contemplated nitric oxide precursors should be understood to be the reaction product of a thiol-containing alcohol, a silane, and a nitrosated compound. In these and other embodiments, the reaction mixture is substantially solvent-free. In various embodiments, the thiol-containing alcohol and the silane can react to form an intermediate, and the intermediate and the nitrosated compound can react (typically in the same reactor) to form the nitric oxide precursor.

[0043] Most typically, filtration is used to remove the nitrosothiol-containing nitric oxide precursor from the reaction mixture. In some embodiments, the resulting nitric oxide precursor is ground or otherwise comminuted to produce a fine powder. Alternatively, the nitric oxide precursor can be used in a crystalline form, which may delay or slow the release of nitric oxide.

[0044] In various embodiments, the nitric oxide precursor comprises a nitrosothiol that can decompose to form nitric oxide. It is contemplated that the reaction of nitric oxide and air results in a mixture containing various nitrogen oxides. In particular, the addition of nitric oxide to air, or air to nitric oxide, results in the formation of nitrogen dioxide when the nitric oxide reacts with oxygen in the air. The concentration of each nitrogen oxide species present in the mixture can vary depending on the temperature, pressure, and initial concentration of nitric oxide.

[0045] Nitric oxide is lipid-soluble and has the ability to disrupt the lipid membranes of microorganisms, modulate cellular and tissue responses, control coagulation and biological integrity, and confer antimicrobial properties. Furthermore, nitric oxide can inactivate thioproteins, thereby destroying functional proteins in microorganisms. Nitric oxide is more water-soluble than nitric oxide. Finally, nitric oxide and nitrogen dioxide are potent destroyers of DNA, causing strand breaks and other damage, resulting in the inability of cells to function.

[0046] Nitric oxide precursors can be used in a wide range of medical and consumer applications. The properties of the nitric oxide precursor can be tailored to suit specific applications based on the selection of the thiol-containing alcohol and silane. Non-limiting examples of suitable tailoring include nitric oxide generating capacity and nitric oxide release rate. As described in more detail below, the nitric oxide precursor can be incorporated into a variety of carriers such that nitric oxide is released from the carrier as a result of decomposition of the nitric oxide precursor. In addition to adjusting the decomposition of the nitric oxide precursor, the release of nitric oxide can also be tailored based on the composition and characteristics of the carrier, further controlling the release of nitric oxide from the carrier. This controlled release of nitric oxide is useful for sterilization and sanitization of medical and consumer devices.

[0047] In some embodiments, the nitric oxide precursor is included in a detergent or cleaning composition. As used herein, the term "detergent composition" or "cleaning composition" includes compositions and formulations designed to clean soiled materials. Such compositions include, but are not limited to, article cleaning compositions, medical device cleaning compositions, hard surface cleaning compositions, dish cleaning compositions, laundry cleaning compositions and detergents, spray products, dry cleaning agents or compositions, unit dose formulations, delayed delivery formulations, detergents contained on or in porous substrates or nonwoven sheets, detergents contained on or in water-soluble films, and other suitable forms that may be apparent to those skilled in the art in light of the teachings herein. Multi-component compositions may have a form selected from liquid, powder, single-phase or multi-phase unit dose, two-ply paper carrier, pouch, tablet, gel, paste, bar, or flake.

[0048] Compared to other conventional methods for forming nitric oxide precursors, this method for forming nitric oxide precursors can be carried out in a single reaction mixture. The nitric oxide precursor can exist under atmospheric conditions with minimal pH manipulation. A variety of thiol-containing alcohols (e.g., primary, secondary, or tertiary thiol-containing alcohols) and silanes (e.g., primary, secondary, or tertiary silanes) can be utilized to form the nitric oxide precursor. This variety of reactants allows for the formation of primary, secondary, and tertiary nitrosothiols (RSNOs). The resulting nitric oxide precursor can be easily and quickly coated with a variety of polymers for controlled release of nitric oxide. The method can incorporate a variety of particle sizes, additives, and carriers / polymers, including blends thereof.

[0049] In some embodiments, contemplated systems can be performed under atmospheric conditions without pH manipulation. Atmospheric conditions typically refer to an environment with an ambient temperature of about 18° C., or about 20° C., or about 22° C. (all + / - 3° C.), and atmospheric pressure conditions of about 1013.25 mbar (+ / - 100 mbar). However, it should be recognized that numerous alternative temperatures (higher and lower) are also considered suitable for use herein.

[0050] As noted above, the decomposition rate of a nitric oxide precursor can depend on a variety of factors and can be fine-tuned to achieve a desired decomposition profile. Among other factors, the decomposition rate can be altered by selecting the type of nitrosothiol obtained. For example, primary nitrosothiols have substantially faster decomposition rates than secondary or tertiary nitrosothiols. In further embodiments, different alcohols containing primary, secondary, or tertiary thiols with varying chain lengths of alkane, alkyl, or alkyne carbon and heteroatoms can be used to react with the silane, providing different decomposition rates. Additionally, the primary, secondary, or tertiary thiols may be in the "R" or "S" configuration.

[0051] In various embodiments, the subject matter of the present invention can also be quickly and easily bound to or mixed with polymeric or inorganic materials that function as carriers for controlled NO release characteristics. For example, nitrosothiol particles or powders can be coated with a thin coating of a synthetic polymeric material, such as polyvinyl chloride, polyvinyl alcohol, or polydimethylsiloxane, to adjust the NO release characteristics. As a result, the bare or coated powder can be blended into a polymer matrix that can then be formed into a film or coated onto a device (e.g., to create a packaging system) to provide controlled nitric oxide release characteristics.

[0052] In some embodiments, various packaging systems may include pouches, including, but not limited to, nylon / nylon pouches, Tyvek® / Mylar® pouches, foil / nylon pouches, foil / Mylar® pouches, and foil / foil pouches. In another example, the package may include a thermoformed polyethylene terephthalate-glycol (PETG) tray with a lid. Such a lid may be made of synthetic flash-spun high-density polyethylene fibers, foil, medical-grade paper, or many other materials. In further embodiments, the package may be made in whole or in part of a flexible material that is a collection of woven, stretched, and / or loose fibers. As used herein, "flexible" refers to the ability to be elastically deformed using manual force.

[0053] In other embodiments, the synthetic polymer carrier is configured as a packaging material, for example, a tray or film or pellets or sachets.

[0054] In terms of utilizing a pouch, a contemplated composition can be enclosed within a gas-permeable pouch and subsequently placed adjacent to a non-sterile item.

[0055] In a further embodiment, the carrier of the nitrosothiol is a natural polymeric material that may be configured as a fabric, or woven fabric, or assembly of loose fibers.

[0056] In terms of the polymeric carrier composition, the polymeric carrier can be coated with at least 10% of the nitrosothiol compound, or at least 20% of the nitrosothiol compound, or at least 50% of the nitrosothiol compound, or at least 100% of the nitrosothiol compound, and yet the nitrosothiol compound can be present in an amount of at least 0.01% by weight, or at least 0.05% by weight, or at least 0.10% by weight, or at least 1.0% by weight, or at least 5.0% by weight, or at least 10% by weight of the total composition including the carrier.

[0057] Desirably, the nitrosothiol particles or powders may also be provided in a wide variety of sizes and size distributions, as needed, so that they can be mixed or matched into blends to define the NO release profile of the composite. For example, the compounds may be granulated and have a maximum dimension of at least 10 μm, or at least 25 μm, or at least 50 μm, or at least 100 μm, or at least 150 μm, or at least 200 μm, or at least 300 μm, or at least 400 μm, or at least 500 μm.

[0058] Additives may optionally be blended into the composite to provide additional control points for NO release. For example, transition metals, chelators, ascorbic acid, or reducing sugars may be added. In some embodiments, additives may also be pH adjusters, moisture absorbers, hydrophobic agents, light filters, or photosensitizers. Such additives may be present in trace amounts to equimolar ratios, or may be present in molar excess relative to the thiol-containing agent. Preferably, the compound is present in the carrier in an amount sufficient to release an antimicrobially effective amount of NO from the carrier (typically within 1, or 6, or 12, or 24 hours). For example, the antimicrobially effective amount of NO is sufficient to release an antimicrobially effective amount of NO from the carrier within 10 minutes of subsequent sterilization. -6 The amount to be administered to the following sterility assurance levels:

[0059] The inventors further contemplate methods of forming composite articles configured to sterilize an object. In some embodiments, nitrosothiols can be formed or obtained. Most typically, the NO-releasing composition is incorporated into an article configured to hold a non-sterile object. Examples of incorporation methods involve extrusion, compression, or combining with a packing material. As a result, a composite article is formed that is typically configured to allow delivery of sufficient concentrations of nitric oxide to the article for sterilization.

[0060] Various packaging systems may include pouches, including, but not limited to, nylon / nylon pouches, Tyvek® / Mylar® pouches, foil / nylon pouches, foil / Mylar® pouches, and foil / foil pouches. In another example, the package may include a thermoformed polyethylene terephthalate-glycol (PETG) tray with a lid. Such a lid may be made of synthetic flash-spun high-density polyethylene fibers, foil, medical-grade paper, or many other materials. In further embodiments, the package may be made in whole or in part of a flexible material that is a woven, stretched, and / or loose fiber assembly. Additional embodiments may include a bag, tray, or flask. As used herein, "flexible" refers to the ability to be elastically deformed with or without manual force.

[0061] The inventors further contemplate sterilization methods, which most typically involve placing a non-sterile object into an enclosed space that further comprises (or may be made at least in part from) the NO-releasing composition discussed above. In some embodiments, the enclosed space is then sealed, such that the non-sterile object and the NO-releasing composition discussed above are physically separated from the environment outside the enclosed space. Preferably, NO is then released from the NO-releasing composition discussed above into the enclosed space.

[0062] In various embodiments, the inventors contemplate utilizing nitric oxide precursors to form nitric oxide for a variety of medical and consumer applications. In various embodiments, an article (e.g., a device or object) can be treated with the nitric oxide precursor in the form of, for example, a liquid, powder, film, coating, etc. Non-limiting examples of suitable uses of nitric oxide precursors (e.g., as liquids, powders, films, or coatings) include: detergents or cleaning solutions to sanitize or sterilize items to be treated with the solution (e.g., sports equipment, such as hockey gloves and cycling gloves, cleaning surgical instruments, the inner lumen of an endoscope, the surface of a medical device, tissue samples, biohazardous materials, etc.); detergents or cleaning powders to sanitize or sterilize items to be treated with the powder sanitizing device sanitizing containers (e.g., desiccants, etc.); medical device containers to sanitize medical instruments (e.g., stethoscopes, otoscopes, etc.), medical devices (e.g., portable ultrasound devices, communication devices, etc.); components of devices exposed to moisture (e.g., washing machines, boat compartments, etc.) to resist the growth of mold or mildew; liners for sports equipment bags for sanitizing sports equipment (e.g., shoes, hockey equipment, ski equipment, face masks, goggles, helmets, etc.); food packaging for preserving food ingredients (e.g., meat, fruit, vegetables, cheese, their components, etc.); vehicle components for sanitizing vehicles (e.g., headliners, seat cushion liners, carpet liners, etc.); for eliminating musty odors in drawers of cabinets, desks, boxes, etc.; kitchen products (e.g., for cleaning counters, appliances, utensils, etc.); and cleaning implements (e.g., for use on floors, toilets, sinks, showers, door handles, etc.).

[0063] Desirably, the enclosed space may be configured as a bag, or a pouch, or a container with a lid. In some embodiments, the enclosed space is at least 10 cm 3 , or at least 50 cm 3, or at least 100 cm 3 , or at least 250 cm 3 , or at least 500 cm 3 , or at least 750 cm 3 , or at least 1,000 cm 3 It has a capacity of.

[0064] In some embodiments, the NO-releasing composition releases NO in response to changes in temperature, pressure, pH, humidity, illumination with visible or UV light, or a combination thereof.

[0065] The inventors contemplate that the nitric oxide precursor may exhibit decomposition to nitric oxide within a predetermined time after formation of the reaction product, for example, within 1 hour, alternatively within 30 minutes, alternatively within 5 minutes, alternatively within 1 minute, alternatively within 10 seconds, alternatively within 1 second, or alternatively within 0.1 seconds. Alternatively, the nitric oxide precursor exhibits minimal decomposition to nitric oxide for a period of at least 5 minutes, alternatively at least 10 minutes, alternatively at least 15 minutes, alternatively at least 30 minutes, alternatively at least 45 minutes, alternatively at least 1 hour, alternatively at least 2 hours, alternatively at least 3 hours, alternatively at least 4 hours, alternatively at least 5 hours, alternatively at least 6, alternatively at least 7 hours, alternatively at least 8 hours, alternatively at least 9 hours, alternatively at least 10 hours, alternatively at least 11 hours, alternatively at least 12, alternatively at least 13 hours, alternatively at least 14 hours, alternatively at least 15 hours, alternatively at least 16 hours, alternatively at least 17 hours, alternatively at least 18 hours, alternatively at least 19 hours, alternatively at least 20 hours, alternatively at least 21 hours, alternatively at least 22 hours, alternatively at least 23 hours, alternatively at least 24 hours, alternatively at least 48 hours, or alternatively at least 365 days after formation of the nitric oxide precursor, depending on the particular thiol-containing alcohol and silane used and how the precursor is stored. Alternatively, the nitric oxide precursor may exhibit minimal decomposition to nitric oxide for a period of 5 minutes to 365 days, or 5 minutes to 48 hours, or 5 minutes to 24 hours, or 1 hour to 24 hours, or 4 hours to 24 hours, or 8 hours to 24 hours, or 16 hours to 24 hours, or 20 hours to 24 hours after formation of the nitric oxide precursor, depending on the particular thiol-containing alcohol and silane used and how the precursor is stored. From a different perspective, the nitric oxide precursor may exhibit decomposition to nitric oxide within a predetermined time after formation of the reaction product, for example, from about 0.01 seconds to about 1 hour, or from about 0.01 seconds to about 30 minutes, or from about 1 second to about 5 minutes, or alternatively, from about 1 second to about 1 minute. In various embodiments, decomposition to nitric oxide may be maintained for a predetermined time, for example, from about 1 minute to about 1 year, or from about 1 hour to about 6 months, or from about 24 hours to about 3 months, or alternatively, from about 1 week to about 8 weeks.From different perspectives, the decomposition to nitric oxide can be sustained for a period of at least 1 minute, or at least 1 hour, or at least 24 hours, or at least 1 week. Without being bound by theory, it is believed that the properties of the nitric oxide precursor can be tailored based on the selection of the thiol-containing alcohol and silane to tailor the decomposition to nitric oxide to suit a particular application.

[0066] The nitric oxide precursor may exhibit improved storage stability compared to a nitric oxide precursor formed without the reaction product. In various embodiments, the nitric oxide precursor exhibits minimal degradation at 4° C. for a period of at least 1 month, alternatively at least 2 months, alternatively at least 3 months, alternatively at least 6 months, or alternatively at least 12 months. In other embodiments, the nitric oxide precursor exhibits minimal degradation at 23° C. for a period of at least 1 month, alternatively at least 2 months, alternatively at least 3 months, alternatively at least 6 months, or alternatively at least 12 months. The term “minimal degradation” means that the nitric oxide precursor exhibits a minimal color difference of 10% ΔE*ab, alternatively at least 5% ΔE*ab, alternatively at least 4% ΔE*ab, alternatively at least 3% ΔE*ab, alternatively at least 2% ΔE*ab, alternatively at least 1% ΔE*ab, or alternatively at least 0.1% ΔE*ab, according to ASTM D2244-21, over the desired period of time.

[0067] The nitric oxide precursor is capable of decomposing to form nitric oxide. In various embodiments, the nitric oxide precursor comprises a nitrosothiol capable of decomposing to form nitric oxide. It is contemplated herein that nitric oxide can be formed at temperatures between 0°C and 100°C, in the presence or absence of visible light, or a combination thereof. To accomplish this, the inventors contemplate that the nitric oxide precursor can decompose to form nitric oxide at a predetermined rate and / or for a predetermined time period based on the particular combination of thiol-containing alcohol and silane utilized, along with the temperature of the nitric oxide precursor and the amount of light exposure.

[0068] With respect to the reaction product silane, there is a wide range of candidate silanes that can be used, depending on the design constraints of the desired application of the nitric oxide precursor. Exemplary silanes can have a structure according to the following formulas (I), (II), (III), or combinations thereof: [ka] (I) [ka] (II), and [ka] (III)

[0069] Most typically, each R is independently a methyl group, a methylene oxide group, or an ethylene oxide group, each R is independently a methylene oxide group or an ethylene oxide group, and R is a mercaptoalkyl group. In certain embodiments, the silane comprises tetramethoxysilane, tetraethoxysilane, or a combination thereof. In an exemplary embodiment, the silane comprises tetraethoxysilane. Thus, in some embodiments, the silane is a tetraalkoxysilane, or a trialkoxysilane, or a cyclic azasilane.

[0070] Other non-limiting examples of suitable silanes include tetraethyl orthosilicate (TEOS), polycondensates of TEOS, methyltrimethoxysilane (MTMS), vinyltrimethoxysilane, methylvinyldimethoxysilane, dimethyldiethoxysilane, vinyltriethoxysilane, tetra-n-propylorthosilicate, vinyltris(methylethylketoxime)silane, methyltris(methylethylketoxime)silane, trisacetamidomethylsilane, bisacetamidodimethylsilane, tris(N-methylacetamidomethylsilane), bis ... (N-methylacetamido)methylsilane, bis(N-methylacetamido)dimethylsilane, (N-methyl-acetamido)methyldialkoxysilane, trisbenzamidomethylsilane, trispropenoxymethylsilane, alkyldialkoxyamidosilane, alkylalkoxybisamidosilane, CH3Si(OC2H5)1-2(NHCOR)2-1, (CH3Si(OC2H5)(NCH3COC6H5)2, CH3Si(OC2H5)-(NHCOC6H5)2, methyldimethoxy(ethylmethyl-ketoximo)silane; Methylmethoxybis-(ethylmethylketoximo)silane; Methyldimethoxy(acetal-doximo)silane; Methyldimethoxy(N-methylcarbamato)silane; Ethyldimethoxy(N-methyl-carbamato)silane; Methyldimethoxyisopropenoxysilane; Trimethoxyisopropenoxysilane; Methyltri-isopropenoxysilane; Methyldimethoxy(but-2-en-2-oxy)silane; Methyldimethoxy(1-phenylethenoxy)silane; Methyldimethoxy-2(1-carbethoxypropenoxy)silane; Methylmethoxydi-N-methylaminosilane; Vinyldimethoxymethylaminosilane; Tetra-N,N-diethylaminosilane; Methyldimethoxymethylaminosilane; Methyltricyclohexylaminosilane; Methyldimethoxy-ethylaminosilane; Dimethyldi-N,N-dimethylaminosilane; Methyldimethoxyisopropylaminosilane Dimethyldi-N,N-diethylaminosilane; Ethyldimethoxy(N-ethylpropionamido)silane; Methyldimethoxy(N-methylacetamido)silane; Methyltris(N-methylacetamido)silane;Ethyldimethoxy(N-methylacetamido)silane; Methyltris(N-methylbenzamido)silane; Methylmethoxybis(N-methylacetamido)silane; Methyldimethoxy(caprolactam)silane; Trimethoxy(N-methylacetamido)silane; Methyldimethoxyethylacetimidatosilane; Methyldimethoxypropylacetimidatosilane; Methyldimethoxy(N,N',N'-trimethylureido)silane; Methyldimethoxy(N-allyl-N',N'-dimethylureido)silane; Methyldimethoxy(N-phenyl-N',N'-dimethylureido)silane; Methyldimethoxyisocyanatosilane; Dimethoxydiisocyanatosilane; MethyldimethoxythioisocyanatosilaneMethylmethoxydithioisocyanatosilane, N-(2-aminoethyl)-3-aminopropyltrimethoxysilane, 3-methacryloxypropyltrimethoxysilane, 3-(2-(vinylbenzylamino)ethylamino)propyltrimethoxysilane, 3-glycidoxypropyltrimethoxysilane, triacetoxyvinylsilane, tris-(2-methoxyethoxy)vinylsilane, 3-chloropropyltrimethoxysilane, 1-trimethoxysilyl-2-(p,m-chloromethyl)phenylethane, 3-chloropropyltriethoxysilane, N-(aminoethylaminomethyl)phenyltrimethoxysilane, N-(2-aminoethyl)-3-aminopropyl Tris(2-ethylhexoxy)silane, 3-aminopropyltrimethoxysilane, trimethoxysilylpropylenetriamine, beta(3,4-epoxycyclohexyltrimethoxysilane, 3-mercaptopropyltrimethoxysilane, 3-mercaptotriethoxysilane, 3-mercaptopropylmethyldimethoxysilane, bis(2-hydroxyethyl)-3-aminopropyltrimethoxysilane, 1,3-divinyltetramethyldisilazane, vinyltrimethoxysilane, 2-(diphenylphosphino)ethyltriethoxysilane, 2-methacryloxyethyldimethyl[3-trimethoxysilylpropyl]ammonium chloride, 3-isocyanatopropyldimethylethoxysilane, N-(3-acryloxy-2-hydroxypropyl)-3-aminopropyltriethoxysilane, vinyl tris(t-butylperoxy)silane, methyltrimethoxysilane, ethyltrimethoxysilane, phenyltrimethoxysilane, phenyltriacetoxysilane, methyltrimethoxysilane, phenyltrimethoxysilane, or combinations thereof;

[0071] Returning to the reaction product thiol-containing alcohol, there is a wide range of candidate thiol-containing alcohols that can be used, depending on the design constraints of the desired application of the nitric oxide precursor. Thiol-containing alcohols may also be referred to in the art as "mercaptoalcohols" or "hydroxymercaptans." Thiol-containing alcohols may have a structure according to the following formula (I), (II), (II), or a combination thereof: [ka] (I) [ka] (II), and [ka] (III) (wherein each R2 is independently an alkyl group). In certain embodiments, the thiol-containing alcohol comprises 3-mercapto-3-methyl-1-butanol, 2-mercaptoethanol, 3-mercaptohexanol, 4-mercapto-3-methyl-2-butanol, 3-mercapto-2-methyl-1-butanol, 3-mercapto-2-methyl-1-pentanol, (+ / -)-4-mercapto-4-methyl-2-pentanol, 2-mercapto-2-methyl-1-pentanol, 4-mercapto-4-methylpentan-2-ol, 3-mercaptohexan-1-ol, mercaptoethanol, 1-mercapto-3-propanol, 1-mercapto-4-butanol, α-mercapto-ω-hydroxyoligoethylene oxide, or a combination thereof. In an exemplary embodiment, the thiol-containing alcohol comprises 3-mercapto-3-methyl-1-butanol.

[0072] In certain embodiments, the thiol-containing alcohol comprises a thiol-derivatized polymer or bulking agent. It should be understood that the thiol-containing alcohol can be included as part of a peptide or other macromolecule, so long as the thiol-containing alcohol is compatible with the components of the reaction mixture of the reaction product.

[0073] In various embodiments, when utilized, the thiol-containing alcohol has a weight average molecular weight of 500,000 g / mol or less, alternatively 100,000 g / mol or less, alternatively 10,000 g / mol or less, alternatively 1,000 g / mol or less, or alternatively 500 g / mol or less. From a different perspective, the thiol-containing alcohol can 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.

[0074] Returning to the nitrosating compound utilized to form the reaction product, the nitrosating compound can be any compound that serves as a source of a nitroso group and can generally be a compound of the formula NOX, where X is an organic or inorganic anion or an OR group (where R is an organic group). Thus, X can be an organic anion derived from a carboxylic acid, such as an alkanecarboxylic acid containing 2 to 7 carbon atoms; nitrosating agents of this type include acetyl nitrite and propionyl nitrite. When X is an inorganic anion, it can be derived, for example, from a mineral acid, such as a halide ion, e.g., chloride, bromide, or sulfate, or from a Lewis acid, e.g., fluoroborate. Other inorganic anions include hydroxides and sulfonates. Thus, nitrosating compounds of this type include nitrosyl chloride, nitrosyl sulfate, nitrosyl fluoroborate, nitrous acid, and Fremy's salt (potassium nitrosyl disulfonate). When X is a group of formula OR2, the organic group R2 can be, for example, a lower alkyl group, such as one containing 1 to 9 carbon atoms, such as ethyl, n-propyl, isopropyl, n-butyl, t-butyl, or isopentyl.

[0075] In certain embodiments, the nitrosating compound comprises a nitrite. The nitrite may include sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butyl nitrite, isobutyl nitrite, t-butyl nitrite, amyl nitrite, pentyl nitrite, nitrite salts, ion-pair nitrite salts, silver nitrite, zinc nitrite, iron nitrite, copper nitrite, transition metal-nitrite compounds, or combinations thereof. Similarly, nitric oxide gas may be used as a nitrosating agent.

[0076] In various embodiments, the nitrosated compound has a weight average molecular weight of 10,000 g / mol or less, alternatively 1,000 g / mol or less, alternatively 500 g / mol or less, or alternatively 250 g / mol or less. From a different perspective, the nitrosated compound can have a weight average molecular weight of about 10 g / mol to about 10,000 g / mol, alternatively about 10 g / mol to about 1,000 g / mol, alternatively about 10 g / mol to about 500 g / mol, or alternatively 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 the reaction kinetics to form the reaction product are improved by utilizing a nitrosated compound with a lower weight average molecular weight.

[0077] In various embodiments, the thiol-containing alcohol and the silane can be reacted in the presence of an acid. When utilized, the catalyst can be included in various amounts. The acid can be utilized to improve the formation and / or stability of the reaction product, for example, when utilizing primary amines, including amino acids, such as cysteine. In certain embodiments, the acid can include hydrochloric acid. Other non-limiting examples of suitable acids include citric acid, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, butanesulfonic acid, acetic acid, hydroxyacetic acid, propionic acid, hydroxypropionic acid, α-ketopropionic acid, butyric acid, mandelic acid, valeric acid, succinic acid, tartaric acid, malic acid, oxalic acid, fumaric acid, adipic acid, maleic acid, sorbic acid, benzoic acid, succinic acid, glutaric acid, adipic acid, α-hydroxy acid, ethylenediaminetetraacetic acid (EDTA), phosphonic acid, octylphosphoric acid, acrylic acid, polyacrylic acid, aspartic acid, polyaspartic acid, p-hydroxybenzoic acid, iminoacetic acid, or combinations thereof. It should be understood that the acid can be included as part of any component of the composition (e.g., carrier, solvent, etc.) or as part of the reactants of the reaction product.

[0078] In certain embodiments, the thiol-containing alcohol and the silane are reacted in the presence of a catalyst. When utilized, the catalyst can be included in various amounts. The catalyst can include any suitable catalyst or mixture of catalysts known in the art. In certain embodiments, the catalyst can include a transition metal catalyst (e.g., an organotin catalyst). In an exemplary embodiment, the catalyst includes a dimethyl dineodecaneoate tin catalyst.

[0079] Other non-limiting examples of suitable catalysts include metal catalysts, amine catalysts, and combinations thereof. Examples of suitable metal catalysts include tin, iron, lead, bismuth, mercury, titanium, hafnium, zirconium, iron(II) chloride, zinc chloride, lead octoate, stabilized stannous octoate, tin(II) salts of organic carboxylic acids such as tin(II) acetate, tin(II) octoate, tin(II) ethylhexanoate, and tin(II) laurate, and dialkyltin(IV) salts of organic carboxylic acids such as dibutyltin dilaurate, dibutyltin diacetate, dibutyltin maleate, and dioctyltin diacetate, and combinations thereof. In certain embodiments, a component of the polymerization catalyst comprises dimethylethanolamine. Examples of suitable amine catalysts include amidines such as 2,3-dimethyl-3,4,5,6-tetrahydropyrimidine, tertiary amines such as triethylamine, tributylamine, dimethylbenzylamine, N-methylmorpholine, S-ethylmorpholine, N-cyclohexylmorpholine, N,N,N',N'-tetramethylethylenediamine, N,N,N',N'-tetramethylbutanediamine, N,N,N',N'-tetramethylhexane-1,6-diamine, amine), pentamethyldiethylenetriamine, bis(dimethylaminoethyl) ether, bis(dimethylaminopropyl) urea, dimethylpiperazine, 1,2-dimethylimidazole, 1-azabicyclo[3.3.0]octane, and typically 1,4-diazabicyclo[2.2.2]octane, and alkanolamine compounds such as triethanolamine, triisopropanolamine, N-methyldiethanolamine, and N-ethyldiethanolamine, dimethylethanolamine, and combinations thereof.

[0080] In various embodiments, the reaction mixture is substantially free of solvent. Alternatively, the reaction product is formed in the substantial absence of solvent. As used herein, the term "substantially free" refers to either the complete absence of acid or a minimal amount thereof only as an impurity, an unintended by-product of another component, or an amount that has a negligible effect on the composition or nitric oxide precursor. In certain embodiments, "substantially free" refers to the solvent being present in the reaction mixture in an amount of less than 0.5 wt.%, less than 0.25 wt.%, less than 0.1 wt.%, less than 0.05 wt.%, or less than 0.01 wt.%, or even 0 wt.%, based on the total weight of the reaction mixture.

[0081] In other embodiments, the thiol-containing alcohol and silane can be formed in the presence of a solvent. When utilized, the solvent can be present in various amounts. In certain embodiments, the solvent can include an organic solvent, such as tetrahydrofuran. Other non-limiting examples of suitable solvents include aromatics, aliphatics, ketones such as methyl ethyl ketone, isobutyl ketone, ethyl amyl ketone, acetone, alcohols such as methanol, ethanol, n-butanol, isopropanol, esters such as ethyl acetate, glycols such as ethylene glycol, propylene glycol, ethers such as tetrahydrofuran, ethylene glycol monobutyl ether, or combinations thereof.

[0082] Also provided herein are methods for sterilizing or sanitizing an article (e.g., a device or object). The methods include applying the nitric oxide precursor described above to the article. Also provided are methods for forming a nitric oxide precursor. The methods include combining a thiol-containing alcohol, a silane, and a nitrosating compound to form a reaction mixture, and allowing the reaction mixture to react for a period of at least 1 hour, alternatively at least 4 hours, alternatively at least 8 hours, or alternatively at least 12 hours. In some embodiments, the combining step is further defined by combining a thiol-containing alcohol, a silane, a nitrosating compound, an acid, and a catalyst to form a reaction mixture.

[0083] From a different perspective, the nitric oxide precursor may be incorporated into or with a carrier to form a composite article (e.g., a film, coating, or coated particle) capable of providing nitric oxide via decomposition of the nitric oxide precursor to form nitric oxide. To accomplish this, the inventors contemplate that the nitric oxide precursor of the composite article may decompose to form nitric oxide at a predetermined rate and / or for a predetermined time period, depending on, for example, the chemical and physical makeup of the carrier, the mechanical properties of the carrier, the surface chemistry and hydrophobicity of the carrier, the temperature and light exposure of the nitric oxide precursor, and the particular combination of thiol-containing alcohol and silane utilized.

[0084] In certain embodiments, the composite article may exhibit minimal release of nitric oxide for a period of at least 5 minutes after forming the nitric oxide precursor. In various embodiments, the composite article exhibits minimal release of nitric oxide for a period of at least 10 minutes, alternatively at least 15 minutes, alternatively at least 30 minutes, alternatively at least 45 minutes, alternatively at least 1 hour, alternatively at least 2 hours, alternatively at least 3 hours, alternatively at least 4 hours, alternatively at least 5 hours, alternatively at least 6, alternatively at least 7 hours, alternatively at least 8 hours, alternatively at least 9 hours, alternatively at least 10 hours, alternatively at least 11 hours, alternatively at least 12, alternatively at least 13 hours, alternatively at least 14 hours, alternatively at least 15 hours, alternatively at least 16 hours, alternatively at least 17 hours, alternatively at least 18 hours, alternatively at least 19 hours, alternatively at least 20 hours, alternatively at least 21 hours, alternatively at least 22 hours, alternatively at least 23 hours, alternatively at least 24 hours, alternatively at least 48 hours, or alternatively at least 365 days after formation of the nitric oxide precursor, depending on the particular thiol-containing alcohol and silane used and how the precursor is stored.

[0085] The carrier material can be thermoplastic or thermosetting. Non-limiting examples of suitable thermoplastic materials include polyvinyl chloride ("PVC"), polyethylene terephthalate ("PET"), polyethylene terephthalate glycol-modified ("PETG"), polypropylene ("PP"), polyethylene ("PE"), polyamides such as nylon, and combinations thereof. Non-limiting examples of suitable thermosetting materials include UV-curable materials, heat-curable materials, chemically curable materials such as free radicals, room-temperature-curable materials, and low-temperature-curable materials. In some embodiments, the carrier comprises an aqueous-based heat-sealable adhesive coating, which can be formed from polymeric materials such as ethylene vinyl acetate, ethylene-acrylate copolymers, and polyurethanes. The aqueous-based heat-sealable adhesive coating can comprise a basic, neutral, or acidic pH solution. Non-limiting examples of suitable aqueous-based heat-sealable adhesive coatings are disclosed in WO 2015 / 160939 A1, the entire contents of which are incorporated by reference.

[0086] In certain embodiments, the carrier is formed from cellulose, polyvinyl chloride, polyurethane, carbocyl, polydimethylsiloxane, phenylcarboxylpolydimethylsiloxane, acrylic polymer, polyester, poly(lactic acid), poly(lactic-co-glycolic acid), poly(vinyl acetate), ethylene vinyl acetate, tetraethene, pellethane, hydrogel, polytetrafluoroethylene, copolymers thereof, or combinations thereof. In one exemplary embodiment, the carrier is formed from polyvinyl chloride. Such carriers are known to those skilled in the art and are described in textbooks such as Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985, the entire contents of which are incorporated by reference.

[0087] In another exemplary embodiment, the carrier is formed from a hydrogel selected from the group consisting of polymacron, polyacrylamide, collagen, agarose, hyaluronic acid, poly(organophosphazene), chitosan, poly(ethylene glycol), poly(vinyl alcohol), and combinations thereof. Non-limiting examples of suitable hydrogels are described in the journal article entitled "S-Nitrosothiol Detection via Amperometric Nitric Oxide Sensor with Surface Modified Hydrogel Layer Containing Immobilized Organoselenium Catalyst" in Langmuir 2006, 22, 25, 10830-10836, which is incorporated by reference in its entirety.

[0088] Thus, in further contemplated embodiments, the composite article can include the nitric oxide precursor in an amount of about 5 to about 25 weight percent, alternatively about 20 to about 60 weight percent, or alternatively about 40 to about 90 weight percent, based on the total weight of the composite article. The composite article can include the carrier in an amount of about 10 to about 95 weight percent, alternatively about 10 to about 80 weight percent, or alternatively about 80 to about 95 weight percent, based on the total weight of the composite article.

[0089] In further embodiments, the carrier may have a permeability to permit nitric oxide transport in an amount of at least 0.001, alternatively at least 0.01, alternatively at least 0.1, alternatively at least 1, or alternatively at least 5 g / (m·s·Pa) according to ASTM E2945 - 14(2021).

[0090] The inventors contemplate that the composite article may further include various additives, including but not limited to ascorbates, reducing equivalents, oxidizing equivalents, acids, bases, pH buffers, ionophores, enzymes, any agents that can affect the formation and stability of thiols (e.g., disulfide formation or disulfide bond cleavage), any agents that can affect the formation and stability of nitrosothiols (e.g., acid / base, ion mobility, gas permeability, NO gas reaction / buffering), plasticizers, surfactants, colorants, fillers, or combinations thereof.

[0091] When utilized, plasticizers may include plasticizers used to modify various characteristics, including, but not limited to, permeability, altered hydrophobicity, tensile strength, elongation, etc. Such plasticizers include, but are not limited to, phthalates, trimellitates, benzoates, adipates, sebacates, maleates, citrates, epoxidized vegetable oils, sulfonamides, organic phosphates, glycols / polyethers, polymeric plasticizers, and polybutenes, or combinations thereof. However, it should be understood that plasticizers may include any other plasticizer understood in the art, so long as the plasticizer is compatible with the components of the functionalized polymeric material.

[0092] The plasticizer may be an ester plasticizer. Examples of suitable ester plasticizers include, but are not limited to, dioctyl phthalate (DOP), n-hexyl-n-decyl phthalate (NHDP), n-octyl-decyl phthalate (NODP), di(isononyl) phthalate (DINP), di(isodecyl) phthalate (DIDP), diundecyl phthalate (DUP), di(isotridecyl) phthalate (DTDP), di-2-ethylhexyl adipate (DOA), di-n-octyl-n-decyl adipate (DNODA), diisononyl adipate (DINA), di-2-ethylhexyl azelate (DOZ), di-2-ethylhexyl sebacate (DOS), trioctyl trimellitate (TOTM), trioctyl phosphate (TOP), tricresyl phosphate (TCP), aliphatic polyester plasticizers, aliphatic polyol plasticizers, or combinations thereof. In certain embodiments, the plasticizer component includes trioctyl trimellitate (TO™). It should be understood that the plasticizer can include any phthalate known in the art, so long as it is compatible with the composite article.

[0093] If utilized, the surfactant may include an anionic surfactant, a nonionic surfactant, a cationic surfactant, a zwitterionic surfactant, or a combination thereof, however, it should be understood that the surfactant may include any other surfactant understood in the art so long as the surfactant is compatible with the components of the composite article.

[0094] Examples of suitable anionic surfactants include, but are not limited to, fatty alcohol sulfates, alkylphenol sulfates, fatty alcohol ether sulfates, fatty alcohol ether sulfates, alkylphenol ether sulfates, alkylbenzene sulfonic acids, alkyl ether carboxylic acids and their salts, alkyl sulfosuccinates, alkyl sulfosuccinamates, phosphate esters, α-olefin sulfonates, or combinations thereof. Examples of suitable nonionic surfactants include, but are not limited to, alcohol ethoxylates, alkylphenol ethoxylates, polyethylene oxide / polyethylene oxide block copolymers, polyvinyl alcohol, polyvinylpyrrolidone, sorbitan fatty acid esters, sorbitan ester ethoxylates, or combinations thereof. Examples of suitable cationic surfactants include, but are not limited to, alkyldimethylamines, quaternary ammonium compounds, or combinations thereof. In certain embodiments, the surfactant component comprises a nonionic surfactant. The nonionic surfactant may include an acetylene glycol surfactant, 2-ethylhexanol, or a combination thereof.

[0095] When utilized, the filler may include any filler that can be used for various purposes, including, but not limited to, cost control, rheology control, lubricity modification, and prevention of seizing or galling. The filler component may include an inorganic filler. Examples of suitable inorganic fillers include, but are not limited to, powdered nickel, copper, zinc, and aluminum. Suitable mineral fillers include, but are not limited to, talc, calcium carbonate, silicates such as mica, wollastonite, titanium dioxide, quartz, fumed silica, precipitated silica, graphite, boron nitride, or combinations thereof. Also included are modifiers, such as stearates, including zinc stearate, magnesium stearate, sodium stearate, and the like.

[0096] Other components that may be present in the composite article include trace amounts of antioxidants, inhibitors, antifoaming agents, dispersing aids, heat stabilizers, UV stabilizers, etc., such as one or more of the components described in U.S. Patent Application Publication No. 2004 / 0258922 A1, U.S. Patent No. 9,404,015 B2, and U.S. Patent No. 10,214,668 B2, the disclosures of which are incorporated herein by reference in their entireties. In various embodiments, one or more of such additives are individually present in the composite article in an amount of less than about 5 wt. %, based on the total weight of the composite article.

[0097] Methods for forming a composite article are also provided. The composite article can be formed using conventional techniques understood in the art. The methods include providing a carrier (e.g., polyvinyl chloride), providing a nitric oxide precursor, and combining the carrier and the nitric oxide precursor to form the composite article. In various embodiments, the methods further include providing a solvent (e.g., tetrahydrofuran) and a plasticizer (e.g., diisononyl phthalate). In these embodiments, the combining step includes combining the solvent, carrier, and plasticizer to form a mixture, and combining the mixture and the nitric oxide precursor to form the composite article. The methods may further include removing excess mixture from the nitric oxide precursor using vacuum filtration to form the composite article. Additionally, the methods may include drying the composite article. The composite article can be air-dried for a period of 1 minute to 24 hours, or more. The composite article can be stored in an airtight container at room temperature or 2-8°C.

[0098] In these and other embodiments, the detergent or cleaning composition further comprises a cleaning agent. The cleaning agent may comprise a detergent, an enzyme, or a combination thereof. Non-limiting examples of suitable cleaning agents include Alconox powder. In embodiments where the detergent comprises a detergent, the cleaning agent may comprise a surfactant, such as an amine oxide, alkyl benzene sulfonate, alkyl ether sulfate, fatty alcohol ethoxylate, alkyl glycoside, alkoxylated fatty acid alkyl ester, amine oxide, fatty acid alkanolamide, hydroxy mixed ether, sorbitan fatty acid ester, polyhydroxy fatty acid amide, and alkoxylated alcohol.

[0099] In embodiments where the cleaning agent includes an enzyme, the enzyme may include one or more enzymes capable of exhibiting catalytic activity in the cleaning agent, such as proteases, amylases, lipases, cellulases, hemicellulases, mannanases, pectin-cleaving enzymes, tannases, xylanases, xanthanases, β-glucosidases, carrageenases, perhydrolases, oxidases, oxidoreductases, and mixtures thereof. In certain embodiments, the enzyme includes proteases, amylases (e.g., α-amylases), cellulases, lipases, hemicellulases, pectinases, mannanases, β-glucanases, or combinations thereof. The enzyme's properties should be compatible with the multi-component composition (i.e., pH-optimal, compatibility with other enzymes and non-enzyme components, etc.). When utilized, the enzyme should be present in an effective amount.

[0100] When utilized, the protease may be of animal, plant, or microbial origin, including chemically or genetically modified variants. Microbial origin is preferred. It may be an alkaline protease, such as a serine protease or a metalloprotease. The serine protease may be, for example, from the Si family, such as trypsin, or from the S8 family, such as subtilisin. The metalloprotease protease may be, for example, from the M4, M5, M7, or M8 family, such as thermolysin.

[0101] Where utilized, suitable lipases and cutinases include those of bacterial or fungal origin, including chemically modified or protein engineered variants. Examples include lipases from Thermomyces, e.g. from T. lanuginosus (formerly named Humicola lanuginosa), described in EP 258 068 and EP 305 216, cutinases from Humicola, e.g. from H. insolens, described in WO 96 / 13580, Pseudomonas lipases, e.g. from P. alcaligenes or P. pseudoalcaligenes (EP 218 272), P. cepacia (EP 331 376), P. stutzeri (GB 100444), P. sulphurum ... 1,372,034), P. fluorescens, Pseudomonas sp. strain SD 705 (WO 95 / 06720 and WO 96 / 27002), P. wisconsinensis (WO 96 / 12012), Bacillus lipase, for example, from B. subtilis (Dartois et al., 1993, Biochemica et Biophysica Acta, 1131: 253-360), B. stearothermophilus (JP 64 / 744992), or B. pumilus (WO 91 / 16422).

[0102] Other examples are lipase variants such as those described in WO 92 / 05249, WO 94 / 01541, EP 407 225, EP 260 105, WO 95 / 35381, WO 96 / 00292, WO 95 / 30744, WO 94 / 25578, WO 95 / 14783, WO 95 / 22615, WO 97 / 04079, WO 97 / 07202, WO 00 / 060063, WO2007 / 087508, and WO 2009 / 109500, which are incorporated by reference in their entirety.

[0103] Suitable amylases, if utilized, include those of bacterial or fungal origin, including chemically modified or protein-engineered variants. Amylases include, for example, α-amylases obtained from specialized strains of Bacillus, such as Bacillus licheniformis, as described in more detail in GB 1,296,839. Examples of useful amylases are the variants described in WO 94 / 02597, WO 94 / 18314, WO 96 / 23873, and WO 97 / 43424, the entire contents of which are incorporated by reference.

[0104] Where utilized, suitable cellulases include those of bacterial or fungal origin, including chemically modified or protein engineered variants. Suitable cellulases include cellulases from the genera Bacillus, Pseudomonas, Humicola, Fusarium, Thielavia, and Acremonium, such as fungal cellulases produced by Humicola insolens, Myceliophthora thermophila, and Fusarium oxysporum, as disclosed in U.S. Pat. No. 4,435,307, U.S. Pat. No. 5,648,263, U.S. Pat. No. 5,691,178, U.S. Pat. No. 5,776,757, and WO 89 / 09259, the entire contents of which are incorporated by reference.

[0105] Suitable peroxidases / oxidases, if utilized, include those derived from plants, bacteria, or fungi, including chemically modified or protein-engineered variants. Examples of useful peroxidases include peroxidases from Coprinus, e.g., C. cinereus, and variants thereof, as described in WO 93 / 24618, WO 95 / 10602, and WO 98 / 15257, the entire contents of which are incorporated by reference.

[0106] The washing or cleaning composition may further comprise additives such as builders, bleaching agents, electrolytes, non-aqueous solvents, pH adjusters, fragrances, perfume carriers, fluorescent agents, dyes, hydrotropes, foam inhibitors, silicone oils, anti-resoiling agents, anti-graying agents, anti-shrinkage agents, anti-wrinkle agents, dye transfer inhibitors, antimicrobials, germicides, fungicides, antioxidants, preservatives, corrosion inhibitors, antistatic agents, bittering agents, ironing aids, hydrophobizing and impregnating agents, swelling and anti-slip agents, softening components, and UV absorbers.

[0107] The detergent or cleaning composition may contain the nitric oxide precursor in an amount of about 0.01 to about 40% by weight, alternatively about 0.01 to about 5% by weight, alternatively about 5 to about 10% by weight, or alternatively about 10 to about 40% by weight, based on the total weight of the composition. The detergent or cleaning composition may contain the cleaning agent in an amount of about 1 to about 99% by weight, based on the total weight of the composition. The detergent or cleaning composition may contain the solvent in an amount of about 1 to about 99% by weight, based on the total weight of the composition.

[0108] In various embodiments, the cleaning or sanitizing compositions described herein can be filled into a water-soluble envelope and thus become part of a water-soluble package. The water-soluble envelope can be formed from a water-soluble film material. Such water-soluble packages can be produced by either a vertical fill and seal (VFFS) process or a thermoforming process. In certain embodiments, the nitric oxide precursor can be incorporated into the water-soluble film material, disposed within the envelope formed by the water-soluble film material, or both.

[0109] The envelope can be made of one or more layers of water-soluble film material. The water-soluble film material of the first layer and, if present, of the other layers can be the same or different. The water-soluble envelope is made, for example, from a water-soluble film material selected from a group including a polymer or a polymer mixture. The water-soluble envelope can contain polyvinyl alcohol or a polyvinyl alcohol copolymer. A polymer selected from a group including acrylic acid-containing polymers, polyacrylamides, oxazoline polymers, polystyrene sulfonates, polyurethanes, polyesters, polyether polylactic acids, and / or mixtures of the above polymers can be added to a film material suitable for producing the water-soluble envelope.

[0110] The thermoforming process generally includes the steps of forming a first layer from a water-soluble film material to create a convex portion for receiving the composition therein, filling the convex portion with the composition, covering the convex portion filled with the composition with a second layer of a water-soluble film material, and sealing the first and second layers together around at least the convex portion. The water-soluble package containing the liquid detergent and the water-soluble envelope can have one or more chambers. The water-soluble package can have substantially dimensionally stable spherical and pillow-shaped shapes, with a basic shape of a circle, oval, square, or rectangle. The chambers may be separated from each other. [Example]

[0111] The following examples are included to demonstrate various embodiments as contemplated herein. Those of skill in the art should understand that the techniques disclosed in the examples that follow represent techniques discovered by the inventor(s) to function well in the practice of the invention, and therefore can be considered to constitute desired modes for its implementation. However, those of skill in the art should, in light of the present disclosure, understand that many changes can be made in the specific embodiments that are disclosed and still obtain like or similar results without departing from the spirit and scope of the invention. Unless otherwise indicated, all percentages are by weight and all measurements are performed at 23°C.

[0112] Example 1 Nitric oxide-releasing particles The following components were mixed in one vial to form a reaction mixture: 2 mL of silane (tetraethoxysilane), 0.5 mL of thiol-containing alcohol (3-mercapto-3-methyl-1-butanol), 50 μL of acid (10% acetic acid), 10 μL of catalyst (20 mg / mL di-n-butyldilaurate), and 0.75 mL of nitrosating compound (cleaned tert-butyl nitrite).

[0113] The reaction mixture was thoroughly mixed and then left in the air in a fume hood at room temperature for an additional overnight reaction. After the reaction, the nitric oxide precursor was formed as a crystalline product. The crystalline product was ground into powder with a mortar and pestle to form the nitric oxide precursor powder, which was stored in an airtight vial at room temperature or 2-8°C.

[0114] Example 2 Polyvinyl chloride (PVC) coated nitric oxide-releasing particles A carrier (polyvinyl chloride) was dissolved in a solvent (tetrahydrofuran) with a plasticizer (diisononyl phthalate) at a final concentration of 0.5% (w / v) and a final weight ratio of carrier to plasticizer of 3:1 to form a PVC solution. The nitric oxide-releasing particles obtained from Example 1 were placed on filter paper. The particles were washed with a 0.5% PVC solution under vacuum filtration, and excess PVC solution was quickly removed to form PVC-coated nitric oxide-releasing particles. The PVC-coated particles were air-dried. The PVC-coated nitric oxide-releasing particles were stored in airtight vials at room temperature or 2-8°C.

[0115] Example 3 Particles and composite articles of examples and comparative examples Figure 3 provides (A) an image comparing a nitric oxide-releasing silane to the same material without RSNO, (B) an image comparing a PCPDMS film containing the ground compound in powder form depicted in A to a control powder, and (C) an image of nitric oxide release from a film containing an NO-releasing powder that uses light to trigger NO production.

[0116] Example 4 Particles and composite articles of examples and comparative examples FIG. 4 provides images of (A) the nitric oxide-releasing silane compound uncoated, coated in PVC, and coated in PCPDMS, (B) the uncoated powder and the powder coated in PVC, and (C) the nitric oxide release from films containing the NO-releasing uncoated and coated powders using light to trigger NO production.

[0117] Example 5 Particles and composite articles of examples and comparative examples Figure 5 provides (A) images of a nitric oxide-releasing silane compound in PCPDMS and PDMS, and (B) images of nitric oxide release from a film containing an NO-releasing compound that uses light to trigger NO production. The silane compound was mixed with the polymer solution before complete crosslinking (and crystallization).

[0118] Example 6 Examples of Particles and Composite Articles of Examples and Comparative Examples Figure 6 provides (A) images of nitric oxide-releasing silane compounds (primary (red) and tertiary (green)) in silastic adhesive and RTV-3140 (PDMS), and (B) images of nitric oxide release from a film containing an NO-releasing compound that uses light to trigger NO production. The silane compound was mixed with the polymer solution before complete crosslinking (and crystallization).

[0119] In some embodiments, numbers expressing quantities of ingredients, properties, such as concentrations, reaction conditions, and various other quantities, are used to describe and claim particular embodiments of the present invention and should be understood to be modified in some instances by the term "about." As used herein, the terms "about" and "approximately," when referring to a specified measurable value (e.g., a parameter, amount, temporal duration, etc.), are meant to encompass the specified value and variations from the specified value, to the extent that such variations are appropriate for the disclosed embodiments, e.g., variations of ±10% or less, or ±5% or less, or ±1% or less, or ±0.1% or less. Thus, values ​​referred to by the "about" or "approximately" modifier are themselves expressly disclosed. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each individual value falling within the range. Unless otherwise stated herein, each individual value is incorporated into the specification as if individually set forth herein.

[0120] Practice within the stated numerical limits is generally preferred. Similarly, unless expressly stated to the contrary, percents, "part of," and ratio values ​​are by weight; the description of a group or class of materials as suitable or preferred for a given purpose in connection with this invention does not imply that mixtures of any two or more members of the group or class are equally suitable or preferred; the description of components in chemical terms refers to the components when added in any combination specified in the description and does not necessarily exclude chemical interactions between the components of the mixture after mixing; the first definition of an acronym or other abbreviation applies to all subsequent uses herein of the same abbreviation, mutatis mutandis, of normal grammatical variations of the initially defined abbreviation; and unless expressly stated to the contrary, measurements of properties are determined by the same techniques as earlier or later referenced for the same property.

[0121] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of exemplary language (e.g., "such as") or any and all examples provided with respect to specific embodiments herein is intended only to further clarify the invention and does not limit the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0122] As used throughout this specification and the claims that follow, the meanings of "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Similarly, as used herein, the meaning of "in" includes "in" and "on," unless the context clearly dictates otherwise. Similarly, as used herein, and unless the context clearly dictates otherwise, the term "coupled to" is intended to include both direct coupling (the two elements that are coupled together touch each other) and indirect coupling (at least one additional element is located between the two elements). Thus, the terms "coupled to" and "coupled with" are used interchangeably.

[0123] It should be apparent to those skilled in the art that many more modifications than those already described are possible without departing from the inventive concepts herein. The subject matter of the present invention is, therefore, not intended to be limited except as by 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 in a non-exclusive manner as referring to elements, components, or steps, where a referenced element, component, or step may be present in, utilized with, or combined with other elements, components, or steps not expressly referenced. When the specification or claims refer to at least one selected from the group consisting of A, B, C... and N, the language should be interpreted as requiring only one element from the group, and not A and N or B and N, etc.

Claims

1. A carrier comprising a polymeric or inorganic material bound to or mixed with a compound having a structure according to Formula I 【Chemistry 1】 Formula I (wherein X is 【Chemistry 2】 Formula II 【Transformation 3】 Formula III, and 【Chemistry 4】 Formula IV is selected from the group consisting of X is covalently bonded to O in formula I via the R4 group in formulas II-IV; Y is O or absent; Each R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and aryl, and optionally, each R 1 , R 2 , R 3 , R 4 , R 5 and R 6 if not hydrogen, are independently substituted with a thiol group, an epoxy group, a nitro group, and / or an amino group. A composition comprising:

2. The composition of claim 1 , wherein the carrier is a polymeric carrier at least partially coating the compound.

3. The composition of claim 2 , wherein the carrier is a synthetic polymer carrier configured as a packaging material, a film, or a pellet.

4. The composition of claim 2 , wherein the carrier is a natural polymer carrier configured as a fiber, fabric, or woven fabric.

5. 10. The composition of claim 1, wherein the compound is granular and has a largest dimension of 500 μm or less.

6. The composition of claim 1, wherein the compound is present in the composition in an amount of 0.01% to 0.1% by weight.

7. 10. The composition of claim 1, wherein the compound is present in the carrier in an amount sufficient to release an antimicrobially effective amount of nitric oxide from the carrier.

8. 10. The composition of claim 1, wherein X has a structure according to Formula II.

9. 10. The composition of claim 1, wherein X has a structure according to Formula III.

10. 10. The composition of claim 1, wherein X has a structure according to formula IV.

11. 10. The composition of claim 1, wherein the composition comprises a compound of Formula I, where X has a structure according to one of Formulas II, III, or IV, and further comprises an additional compound of Formula I, where X has a structure according to one of Formulas II, III, or IV, wherein X in the compound and X in the additional compound are not identical.

12. 10. The composition of claim 1, wherein the composition comprises a compound of Formula I, wherein Y is absent, and further comprises an additional compound of Formula I, wherein Y is O.

13. 12. The composition of claim 11, wherein Y in the compound of formula I is absent and Y in the additional compound is O.

14. The composition of claim 1 , wherein the compound is covalently bound to the carrier.

15. The composition of claim 1 , wherein the composition further comprises an additive.

16. 2. The composition of claim 1, wherein the additive is selected from the group consisting of a pH adjuster, a moisture absorber, a hydrophobic agent, a light filter, a photosensitizer, a transition metal, a chelator, glutathione, and a reducing agent.

17. combining a thiol-containing alcohol, a silane, and a nitrosated compound in a reactor to form a reaction mixture; and reacting the thiol-containing alcohol with the silane in the reaction mixture, thereby forming a thiol-containing intermediate, and reacting the thiol-containing intermediate with the nitrosating compound in the reaction mixture, thereby forming a nitrosothiol-containing nitric oxide precursor.

1. A method for forming a nitrosothiol-containing nitric oxide precursor, comprising:

18. 20. The method of claim 17, wherein the thiol-containing alcohol comprises a primary thiol.

19. 18. The method of claim 17, wherein the thiol-containing alcohol comprises a secondary thiol.

20. 18. The method of claim 17, wherein the thiol-containing alcohol comprises a tertiary thiol.

21. 18. The method of claim 17, wherein the thiol-containing alcohol is selected from the group consisting of 3-mercapto-3-methyl-1-butanol, 2-mercaptoethanol, 3-mercaptohexanol, 4-mercapto-3-methyl-2-butanol, 3-mercapto-2-methyl-1-butanol, 3-mercapto-2-methyl-1-pentanol, (+ / -)-4-mercapto-4-methyl-2-pentanol, 2-mercapto-2-methyl-1-pentanol, 4-mercapto-4-methylpentan-2-ol, 3-mercaptohexan-1-ol, mercaptoethanol, 1-mercapto-3-propanol, 1-mercapto-4-butanol, and α-mercapto-ω-hydroxyoligoethylene oxide.

22. 18. The method of claim 17, wherein the silane is a tetraalkoxysilane, trialkoxysilane, or cyclic azasilane.

23. 18. The method of claim 17, wherein the silane is selected from the group consisting of tetraethylorthosilicate (TEOS), methyltrimethoxysilane (MTMS), vinyltrimethoxysilane, methylvinyldimethoxysilane, dimethyldiethoxysilane, vinyltriethoxysilane, tetra-n-propylorthosilicate, trisacetamidomethylsilane, bisacetamidodimethylsilane, methylmethoxybis-(ethylmethylketoximo)silane, methyldimethoxyethylaminosilane, dimethyldi-N,N-dimethylaminosilane, methyldimethoxyisopropylaminosilane, triacetoxyvinylsilane, tris-(2-methoxyethoxy)vinylsilane, 3-chloropropyltriethoxysilane, 3-mercaptotriethoxysilane, ethyltrimethoxysilane, phenyltriacetoxysilane, methyltrimethoxysilane, and phenyltrimethoxysilane.

24. 18. The method of claim 17, wherein the nitrosated compound is an inorganic nitrite.

25. 18. The method of claim 17, wherein the nitrosating compound is selected from the group consisting of sodium nitrite, calcium nitrite, potassium nitrite, tetrabutylammonium nitrite, dicyclohexylammonium nitrite, butyl nitrite, isobutyl nitrite, t-butyl nitrite, amyl nitrite, pentyl nitrite, ion pair nitrites, silver nitrite, zinc nitrite, iron nitrite, copper nitrite, and transition metal nitrite compounds.

26. 18. The method of claim 17, wherein the steps of reacting the thiol-containing alcohol with the silane and reacting the thiol-containing intermediate with the nitrosated compound do not require a solvent to form the nitrosothiol-containing nitric oxide precursor.

27. 20. The method of claim 17, wherein the steps of reacting the thiol-containing alcohol with the silane and reacting the thiol-containing intermediate with the nitrosated compound are carried out without pH adjustment.

28. 20. The method of claim 17, wherein the steps of reacting the thiol-containing alcohol with the silane and reacting the thiol-containing intermediate with the nitrosated compound are carried out at atmospheric temperature and pressure.

29. 18. The method of claim 17, further comprising removing the nitrosothiol-containing nitric oxide precursor by filtration.

30. 20. The method of claim 17, further comprising adding at least one of an acid and a catalyst to the reaction mixture.

31. 31. The method of claim 30, wherein the acid is acetic acid and the catalyst is di-n-butyltin dilauryl.

32. 18. The method of claim 17, wherein the nitrosothiol-containing nitric oxide precursor has a structure according to formula I of claim 1.

33. placing a non-sterile object into an enclosed space, said enclosed space further comprising an NO-releasing composition according to any one of claims 1 to 16; sealing the enclosed space, so that the non-sterile material and the NO-releasing composition according to any one of claims 1 to 16 are physically separated from the environment outside the enclosed space; and Releasing nitric oxide (NO) from the NO-releasing composition according to any one of claims 1 to 16 into the enclosed space. A sterilization method comprising:

34. 34. The method of claim 33, wherein the non-sterile item comprises a medical device, a bandage, a garment, an electronic device, a surgical tool, a tissue sample, a biohazardous material, a recreational item, a kitchen product, and / or a cleaning tool.

35. 34. The method of claim 33, wherein the enclosed space is configured as a bag, pouch, or container with a lid, or the entire enclosed space is flexible.

36. The closed space is 10 cm 3 ~1,000 cm 3 34. The method of claim 33, having a capacity of

37. 34. The method of claim 33, wherein the enclosed space is configured to be sealable using heat, ultrasonic energy, laser radiation, adhesives, or manual sealing.

38. 34. The method of claim 33, wherein the NO-releasing composition of any one of claims 1 to 16 is made according to the method disclosed in any one of claims 17 to 32.

39. 34. The method of claim 33, wherein the NO-releasing composition of any one of claims 1 to 16 releases NO in response to changes in temperature, pressure, pH, humidity, illumination with visible or UV light, or a combination thereof.

40. 34. The method of claim 33, wherein the NO-releasing composition of any one of claims 1 to 16 is present in an amount sufficient to sterilize the non-sterile material contained within the enclosed space via gaseous NO.

41. 34. The method of claim 33, wherein NO is released at room temperature or elevated temperature for a time sufficient to sterilize the non-sterile items within the enclosed space.

42. Sterilization, 10 -6 34. The method of claim 33, performed to the following sterility assurance level:

43. forming or obtaining a composition according to any one of claims 1 to 16; incorporating the composition into an article configured to hold a non-sterile item, thereby forming a composite article, the composite article configured to allow delivery of a sterilizing sufficient amount of nitric oxide to the item.

10. A method of forming a composite article configured to sterilize an item, comprising:

44. 44. The method of claim 43, wherein the forming step comprises compressing or extruding the composition, or combining the composition with a packing material.

45. 45. The method of claim 44, wherein the packing material is a thermoplastic polymer material.

46. 44. The method of claim 43, wherein the composite article is configured as a bag, tray, or flask.

48. 44. The method of claim 43, wherein the incorporating step comprises enclosing the composition in a gas-permeable pouch and placing the pouch in an article.

49. 44. The method of claim 43, wherein the incorporating step comprises combining the composition with a packing material and forming the article from the combination.

50. Sterilization, 10 -6 44. The method of claim 43, performed to the following sterility assurance level:

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