Devices and methods for prepackaged on-demand terminal sterilization

Abstract

Compositions and methods are presented in which a nitric oxide precursor, formed (preferably) from the reaction of a thiol-containing compound and a nitrosating compound, decomposes to form nitric oxide within a sealed delivery system that allows for mobile sanitation; from which the sample compartment can be separated from the nitric oxide releasing compartment with a secondary seal, then subsequently detached without altering the sterilized portion of the package.

Description

DEVICES AND METHODS FOR PREPACKAGED ON-DEMAND TERMINAL STERILIZATION

[0001] This application is an International Application which claims priority to Provisional Patent Application No. 63 / 542,089, filed on October 2, 2023, the entire content of which is incorporated by reference herein.Field of the Invention

[0002] The field of the invention is compositions and methods for mobile sanitation, especially as it relates to the use of nitric oxide.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] “ Sanitation is more important than independence.” (Mahatma Gandhi). As alluded to by Ghandi, sanitation is one of the most important aspects of biological well-being and a healthy biological environment. A variety of products and articles, including, for example, medical instruments, devices, and equipment, must be sterilized prior to use to prevent biocontamination of a wound site, a sample, an organism, or the like. Several sterilization processes are used which involve contacting the product or article with a sterilant. Examples of such sterilants include dintitrogen tetraoxide, nitric oxide, steam, ethylene oxide, hydrogen peroxide, dry heat, and the like. However, conventional methods of sterilization tend to be inefficient and expensive. Typical sterilization processes include shipping the contaminated tools to commercial cleaners. This process often takes long periods of time, often weeks, forthe tools to be sterilized then returned for use. Additionally, there are few mobile methods available to quickly sterilize tools if and / or when there is a need for applicable, but unexpected, tools in-field or in-house.

[0006] Currently, [e]thylene oxide sterilization accounts for approximately 50% of the industrial terminal sterilization market. Hemmerich KJ, et al. “Sterilization methods stand the test of time. Medical Device and Diagnostic Industry”. 2004;26(8). However, nitric oxide (NO) is also known to be effective at dispersing / displacing biofilms, but without the environmental or worker-safety issues brought by ethylene oxide sterilization. Barraud N, et al. “Involvement of Nitric Oxide in Biofilm Dispersal of Pseudomonas Aeruginosa.” J Bacteriol 2006, 188 (21), 7344-7353.

[0007] There is only a small body of evidence that substantiates a way in which sterilization could occur in a mobile manner. For example, in Patent Application US2017 / 0136136, a portable medical sanitation device utilizing a UV light source was contemplated. The contemplated device relied on a power source, a solid-state UV light source for outputting UV light, a controller for directing the plurality of solid-state UV light sources to output UV light, a sterilization chamber, and sidewalls configured to reflect the UV light. Although interesting, the portable sanitation device includes an attached power supply and UV light source, neither of which can be separated from the sterilization chamber.

[0008] Additionally, even where sterilization in a mobile manner has been disclosed, as in Patent Application US2008 / 0317626A1, such devices and methods suffer from several drawbacks. For instance, the system disclosed in US2008 / 0317626A1, though portable, does not provide for terminal sterilization.

[0009] Furthermore, to increase efficiency of sterilization with nitric oxide use, few compositions and methods are known. For example, in a study done on a nitric oxide-releasing insert for disinfecting the hub region of tunnel dialysis catheters (TDC), nitric oxide was studied due to its benefits as an endogenous gas molecule that has broad spectrum antimicrobial / anti -biofilm activity. (Nitric Oxide -Releasing Insert (2020); doi: 10.1021 / acsami.0cl3230). In that study, the potential of creating a nitric oxide releasing insert device that is attached onto the hub region cap of TDCs, and locally releases nitric oxide within the TDC hub, was evaluated for its antimicrobial / anti-biofilm effectiveness. (See above). Although interesting, this study only applies to patients in need of hemodialysis treatments asthe use of TDCs in such patients cause a significant number of blood stream infections, with very few viable preventative / treatment methods. (See above). Nonetheless, the use of nitric oxide in the above sense results in an immobile and limited mode of sanitization because it applies in the context of a catheter, which is often mainly used within hospital settings.

[0010] In addition, medical packaging is considered part of a medical device itself and requires 510(k) approval from the FDA as part of the device clearance. Many device manufacturers do not change packaging materials once approval is obtained because of the extensive testing required to prove biocompatibility, safety, sterile barrier properties, and package integrity. As a result, FDA requirements often cause delay and extensive costs in packaging, or altering existing packaging, of medical equipment. Such delay and extensive costs result in an industry reliance on methods that are both expensive and likely outdated.

[0011] Therefore, even though various compositions and methods for sterilization are known in the art, all or almost all of them suffer from several drawbacks. Thus, there remains a need for improved sterilization, and associated packaging, that allows for mobile use, and sealable and removable sample compartments allowing for terminal sterilization.Summary of The Invention

[0012] The inventive subject matter is directed to compositions and methods for mobile sterilization using gaseous nitric oxide (NO) derived from NO precursors within a sealed package. Moreover, the sealed package comprises a NO compartment and a sample compartment which can then be detached from each other following the sterilization process and subsequent sealing of the sample compartment for a tangible separation.

[0013] 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.

[0014] In one aspect of the inventive subject matter, the inventor contemplates a package configured to sterilize a sample on demand that includes an open and sealable end, wherein the package comprises a sample compartment, and a nitric oxide (NO) releasing compartment, wherein the NO releasing compartment comprises an NO releasing composition, and wherein the package is configured to allow sealing and removal of thesample compartment from the NO releasing compartment while maintaining the sample compartment in a sealed state.

[0015] Viewed from a different perspective, the inventor additionally contemplates a method of sterilizing a sample on demand which comprises placing the sample into a sample compartment of a package, wherein the package further includes a NO releasing compartment, sealing the package, releasing NO into the sample compartment from the NO releasing compartment, wherein the NO releasing compartment comprises an NO releasing composition and removing the NO releasing compartment from the sample compartment while maintaining the sample compartment in a sealed state.

[0016] In some embodiments, the sample comprises one or more medical device, bandage, dressing, electronic device, surgical equipment, tissue sample, and / or biohazard waste. Where release of NO into the sample compartment is triggered by a change in temperature, pressure, pH, humidity, and / or illumination with visible or UV light. Most typically, but not necessarily, the subsequent sealing of the sample compartment is performed by ultrasound, heat, laser, clamp, zip lock, or adhesive. Then removal of the NO releasing compartment from the sample compartment comprises cutting, heating, tearing, or separating with a laser or ultrasonic.

[0017] Preferably, NO is released for an amount of time sufficient to sterilize the sample, or for at least 5 min, or for at least 15 min, or for an amount of time sufficient to sterilize the sample at room temperature or at elevated temperature.

[0018] Additionally viewed from a different perspective, the inventor also contemplates the method of manufacturing a package configured to sterilize equipment on demand, which comprises forming a package to include a sample compartment and a NO releasing compartment, wherein the sample compartment is fluidly coupled to the NO releasing compartment, wherein the sample compartment is configured to allow placement of an object inside the sample compartment, placing a NO releasing composition into the NO releasing compartment, and wherein the package is further configured to allow sealing of the package after placement of the object into the sample compartment, and wherein the package is further configured to allow removal of the NO releasing compartment from the sample compartment while maintaining the sample compartment in a sealed state.

[0019] Moreover, some embodiments comprise a sample object to be sterilized enclosed in the package as well as instructions for use on a sticker, booklet, or printed on a surface of the packaging kit.

[0020] In additional embodiments, considering all contemplated compositions and methods herein, the open and sealable end is configured to be sealable as a Ziploc®, glue strip, heat weld, adhesive, or clamp or other compression. Additionally, the open and sealable end can comprise an entire length or side of the package, or a portion thereof. Further embodiments comprise a second open and sealable end.

[0021] In a further aspect of the inventive subject matter, considering all contemplated compositions and methods herein, the sample compartment and the nitric oxide (NO) releasing compartment are contiguous. Nonetheless, the sample compartment and the nitric oxide (NO) releasing compartment are physically separated. In addition, the sample compartment comprises one or more sub-compartments, each fluidly coupled to the nitric oxide (NO) releasing compartment. Whereas the nitric oxide (NO) releasing compartment comprises a sub-compartment in which the NO releasing composition is retained.

[0022] In some embodiments, for all contemplated compositions and methods herein, the NO releasing composition comprises a NO releasing polymer, a nitrosothiol, or a plurality of reagents that form a nitrosothiol upon reaction. In further embodiments, the NO releasing composition comprises a reaction product of an acetylpenicillamine thiolactone and a nitrosating compound, or wherein the NO releasing composition comprises a reaction product of a thiol compound and a nitrosating compound.

[0023] Most typically, for all contemplated compositions and methods herein, the NO releasing composition is a liquid and / or a solid, wherein the NO releasing compartment releases NO in response to a change in temperature, pressure, pH, humidity, and / or illumination with visible or UV light.

[0024] Furthermore, for all contemplated compositions and methods herein, the package is configured to allow heat sealing or ultrasonic or laser or adhesive sealing, and the packaging is configured to allow removal of the NO releasing compartment by perforation or cutting, or by exposure to thermal, acoustic, or light energy. In some embodiments, the package comprises a Nylon portion, a Tyvek® portion, a Mylar® portion, a portion of other plastics, or a polyethylene terephthalate-glycol (PETG) portion. Particularly, the sample compartment5comprises an outer and inner sample compartment, wherein the outer sample compartment is open and sealable, and wherein the inner sample compartment is open and sealable.

[0025] Preferably, for all contemplated compositions and methods herein, a material of the package between the NO releasing compartment and the sample compartment is NO- permeable. Moreover, the package is configured as a bag, a pouch, or a tray with a lid, and / or wherein the entire package is flexible. Most typically, but not necessarily, the package has an inner volume between 10 cm3and 1,000 cm3. Additionally, the NO releasing composition is present in an amount between 10 mg and 2,500 mg, but the NO releasing composition is present in an amount sufficient to sterilize via gaseous NO an object contained in the package within 15 minutes.Brief Description of The Drawing

[0026] FIG.l is a schematic illustration of an exemplary embodiment of the inventive subject matter.Detailed Description

[0027] The inventor has now contemplated a system that allows for mobile and on-demand nitric oxide (NO) sterilization of a sample. Most typically, such sterilization is terminal sterilization. In preferred embodiments of the inventive subject matter, it is contemplated that this system includes conventional packaging that can be opened and sealed, wherein a sample can be placed in a sample compartment of the packaging. The inventor further contemplates a nitric oxide (NO) releasing compartment on a portion of the packaging, wherein the NO releasing compartment comprises an NO releasing composition. In further embodiments of the disclosed invention, the package is configured to allow secondary sealing and subsequent removal of the sample compartment from the NO releasing compartment.

[0028] As used herein, the term “mobile” refers to the ability to move or be moved freely and be of use on-demand. On-demand includes unexpected and / or planned uses whenever and / or wherever required. The contemplated system is intended for ex-vivo use, where nitric oxide is delivered onto a fomite as needed in-field and / or in-house. Additionally, as expressed here, “sterilization” occurs when microorganisms are destroyed and / or reduced to a very low cell count. Whereas “terminal sterilization” is the “process whereby [a] product is sterilized within its sterile barrier system.” ISO / TS 11139:2006. For example, in especially preferredembodiments of the subject matter disclosed herein, a product may be terminally sterilized when the product is sterilized in its final packaging or container. This is in contrast to nonterminal sterilization where, for instance, an autoclave sterilizes a product with steam only for the product to be removed from the sterilized chamber of the autoclave.

[0029] As expressed here, removal of the sample compartment from the NO releasing compartment includes detachment, and / or dissociation of the two compartments in a manner such that they cannot be reunited. The aforementioned terms will be used synonymously with “removal.” As used herein, an “embodiment” means that a particular feature, structure, or characteristic is included in at least one or more manifestations, examples, or implementations of this invention. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art. Combinations of features of different embodiments are all meant to be within the scope of the invention, without the need for explicitly describing every possible permutation by example. Thus, any of the claimed embodiments can be used in any combination.

[0030] Notably, the devices and methods presented herein solve a long-recognized problem in the world of medical packaging. Particularly, when medical packaging forms part of a medical device, FDA regulations require in most cases 510(k) approval for clearance and use. To avoid the temporal delays and increased expenses associated with achieving 510(k) clearance, there tends to be an industry-reliance on methods of sanitation that are not classified as either medical packaging or medical devices. Currently, this reliance results in the use of third-party sterilization facilities, which involve alternative delays and expenses due to associated shipping and processing. However, the contemplated invention allows for mobile terminal sterilization, which significantly reduces the time and expense typically associated with sanitization through third-party facilities. Additionally, the medical packaging will not be considered a medical device.

[0031] In one typical embodiment, a package configured to sterilize a sample on demand, comprises an open and sealable end wherein the package comprises a sample compartment, and a nitric oxide (NO) releasing compartment. The NO releasing compartment comprises an NO releasing composition, where the package is configured to allow secondary sealing and subsequent detachment of the sample compartment from the NO releasing compartment while maintaining the sample compartment in a sealed state. FIG.l depicts one exemplary embodiment where a flexible plastic pouch encloses a medical device within a samplecompartment that is continuous with a NO releasing compartment containing an immobilized nitrosothiol as a NO releasing compound. Here, the medical device is introduced into the pouch through the NO releasing compartment into the sample compartment. Once placed into the sample compartment, the pouch is sealed (typically with via a heat seal) such that the pouch forms now a single and contained inner volume that includes the immobilized NO releasing compound and the sample. Energy (e.g., heat or UV light) is then directed to the NO releasing compound in the NO releasing compartment and NO is generated by decomposition of the NO releasing compound (typically a nitrosothiol, e.g., coupled to a polymer or other solid carrier). The so generated NO will be present in the inner volume at a concentration and for a time sufficient to sterilize the medical equipment. After conclusion of the sterilization, a further heat seal is formed between the sample compartment and the NO releasing compartment to sealingly enclose the sterilized medical device within the sample compartment. The NO releasing compartment can then be cut off from the sample compartment, resulting in a terminally sterilized medical device.

[0032] In some embodiments, contemplated sterilization systems can be used with a number of different packaging systems. For example, the package may comprise a pouch, including, but not limited to, Nylon / Nylon pouches, Tyvek® / Mylar® pouches, Foil / Nylon pouches, Foil / Mylar® pouches, and Foil / Foil pouches. In other examples, the package may comprise a thermoformed polyethylene terephthalate-glycol (PETG) tray with a lid. Such lid can be made of synthetic flashspun high-density polyethylene fibers, foil, medical grade paper, or a number of other materials. In further embodiments, the package may be made in whole or in part of flexible material that is woven, stretched, and / or a loose fiber aggregate. As expressed here, “flexible” refers to the ability to be elastically deformable with or without manual force.

[0033] In some embodiments of the contemplated invention, the open and sealable end of the package may comprise a zipper, zipper lock, adhesive, snap latch, squeeze clamp, Luer lock, rubber stopper, glue strip or other instrument capable of sealing the package. In other embodiments, the open and sealable end is configured to allow sealing by heat, vacuum, induction, ultrasound, pressure, or magnetic means.

[0034] In some embodiments, the inventor contemplates that the open and sealable end can comprise an entire length and / or side of the package, or a portion thereof. For example, the open and sealable end may comprise at least 1 / 3, or at least ’A, or at least 2 / 3 of an edge of thepackage. However, the open and sealable end may comprise an entire edge of the package, as well as at least 1 / 3, or at least ’A, or at least 2 / 3 of an additional adjacent edge of the package.

[0035] In further embodiments, the inventive subject matter is preferably provided in various sizes. For example, the total packaging, including the NO releasing compartment and the sample compartment, may preferably comprise an inner volume between 0.1 cm3and 100 cm3, or between 1 cm3and 500 cm3, or between 10 cm3and 1,000 cm3. It may be typical for the package to also comprise at least 1 pint, or at least 1 quart, or at least 1 gallon, or at least 2 gallons of internal storage space. Suitable package size may further include external measurements of 2"x2", 3"x3”, 4"x4”, 5"x5", 6"x6”, 7"x7”, 8"x8”, 9"x9", 10"xl0", H"xH", or 12"xl2". In additional contemplations, the package size may also include 2"-12" x 2"-12".

[0036] For instance, when implemented to sterilize objects for field medicine, the inventive subject matter may be preferably provided in a size large enough to fit many of the medical tools used in the field. A typical medical kit includes combine pads for treating heavy bleeding, and such pads are most typically 5” x 9”. Because combine pads are typically the largest items in these kits, it would be especially beneficial for a field medic to carry an embodiment of the disclosed subject matter in a size of at least 10” x 10”.

[0037] In other embodiments, the inventor contemplates that a material coupling the NO releasing compartment and sample compartment is a NO-permeable material such as a titanosilicate (ETS-4 and ETS-10 types), Tyvek, clay-based material, silicone rubber, polyurethane, metal, or other NO-permeable material. In still other embodiments, the package comprises a gas dispersion mechanism coupling the NO releasing compartment and sample compartment. For example, the gas dispersion mechanism may comprise a gas dispersion tube or membrane coupling the NO releasing compartment to the sample compartment.

[0038] In additional embodiments, the NO compartment and sample compartment are separated by space that is available to provide a secondary seal after the NO is released and the sanitization is complete. Preferably, the secondary seal typically comprises a zipper, zipper lock, adhesive, snap latch, squeeze clamp, Luer lock, rubber stopper, or another instrument capable of sealing the package. In other embodiments, the secondary seal is configured to allow sealing by heat, vacuum, induction, ultrasound, pressure, or magnetic sealing.

[0039] In further embodiments, the inventor contemplates that the sample compartment contains an inner sample compartment and an outer sample compartment. In someembodiments, both the inner and outer sample compartments comprise an open and sealable end. The inner sample compartment may be comprised of a NO-permeable material such as a titanosilicate (ETS-4 and ETS-10 types), Tyvek, clay -based materials, silicone rubber, polyurethane, metal, or other NO-permeable materials. Alternatively, in another embodiment of the instant invention, the inner sample compartment may be coupled to the NO releasing compartment by a gas dispersion mechanism.

[0040] In preferred embodiments, the NO releasing compartment is contiguous to the sample compartment. However, in other embodiments, the NO releasing compartment is not contiguous with the sample compartment. As an arbitrary example, in one embodiment, the package comprises more than two compartments, wherein a first compartment is the NO releasing compartment, a second compartment is a gas dispersion compartment, wherein the gas dispersion compartment is a buffer between the NO releasing compartment and the sample compartment, and a third compartment is the sample compartment. Nonetheless, the compartments are enclosed within the same packaging, but are distinct from each other.

[0041] The inventor contemplates that in another embodiment of the present disclosure, the package may be configured to allow detachment of the sample compartment, after a secondary sealing, from the NO releasing compartment by mechanical separation and / or exposure to thermal, acoustic, or light energy. For example, the package may be configured such that a blade can cut the package to physically separate the sample compartment from the NO releasing compartment. In other embodiments, the package may be configured to allow laser cutting, heat sealing, water cutting, ultrasonic cutting, and / or chemical separation. In still other embodiments, the sample compartment is coupled to the NO releasing compartment via an adhesive, allowing separation of the compartments by applying an adhesive-releasing agent to the adhesive. In further example, the sample compartment may be coupled to the NO releasing compartment by perforated material, that can manually be tom to detach the two compartments after sanitization and the secondary seal is installed. Importantly, and regardless of the specific manner of implementation, it should be appreciated that the sample compartment after the sterilization step can be detached or otherwise removed from the NO releasing compartment in a manner that preserves the seal and sterility of the contents in the sample compartment.

[0042] Viewed from a different perspective, the inventor therefore also contemplates a method of sterilizing a sample on demand that includes placing the sample into a sample compartment of a package, wherein the package further includes a NO releasing compartment, sealing thepackage, releasing nitric oxide (NO) into the sample compartment from the NO releasing compartment, wherein the NO releasing compartment comprises an NO releasing composition, and then removing the NO releasing compartment from the sample compartment while maintaining the sample compartment in a sealed state.

[0043] Consequently, it should be appreciated that a method of manufacturing a package configured to sterilize equipment on demand is also contemplated. Such a method comprises forming a package to include a sample compartment and a NO releasing compartment, wherein the sample compartment, which comprises one or more sub-compartments, is fluidly coupled to the NO releasing compartment, which comprises one or more sub-compartments. Preferably, the sample compartment is configured to allow placement of an object inside the sample compartment and placement of a NO releasing composition into the NO releasing compartment. It is further contemplated that the package is further configured to allow sealing of the package after placement of the object into the sample compartment, and wherein the package is further configured to allow removal of the NO releasing compartment from the sample compartment while maintaining the sample compartment in a sealed state.

[0044] One contemplated benefit of the packages and methods disclosed herein is the simplified manufacturing process that may be used to practice the invention. Because all components of the invention are part of one continuous package until the NO releasing compartment is removed, the inventors contemplate that one or few assembly lines may be used to manufacture the invention rather than a separate assembly line for each individual element. For instance, a device such as that disclosed in US 2008 / 0317626A1 may require separate manufacturing systems to produce the gas generating chamber, sterilizing chamber, and the pipes and tubes that connect them. The manufacturing benefits of the subject matter disclosed herein may allow for easier mass production. This is especially true when considering that the storage of the inventive subject matter herein may be further simplified, as the packages may be stacked upon one another or rolled up.

[0045] Further, the portability and mobility of the subject matter disclosed herein provides advantages over the prior art. Particularly, the packages disclosed herein do not require tubes or pipes to direct the flow of sterilizing gas to the sample compartment. This may allow for an on-demand, mobile terminal sterilization of products without the need for transporting additional tools or components.

[0046] Viewed from one perspective, the subject matter disclosed herein may be in any one of three states at a time: an open state, a sterilizing state, or a sealed state. The open state represents the time before the sample compartment is sealed. The sterilizing state represents the time from when the NO releasing compartment has released NO into the sample compartment to the time the NO releasing compartment is removed from the sample compartment. The sealed state represents the time after the NO releasing compartment has been removed, which is alternatively known as the state of terminal sterilization. During the open state, the package may be flexible, rollable, elastic, and / or flat. Further during the open state, the sample compartment may have a large or small opening. During the sterilizing state, the package may appear slightly more bloated, inflated, dilated, enlarged and / or expanded when compared to the open state. Finally, during the sealed state, the package may be described as less inflated than it is in the sterilizing state.

[0047] In another embodiment, the package contains one or more sensors in the sample compartment. Said sensors may be coupled electronically or mechanically to a control unit, and may further be coupled to a display, wherein the display allows a user to view information obtained by the one or more sensors. The one or more sensors may be configured to measure the NO content within the sample compartment, allowing the user to verify that sterilization is successful after NO releases from the NO releasing compartment. Still, in other embodiments, the one or more sensors may be configured to measure the content of contaminant in the sample compartment, including but not limited to pathogens, bacteria, mold, fungus, or volatile chemicals.

[0048] In additional embodiments, the package contains one or more indicators for detecting the presence of nitric oxide, along with quantifying the amount within the package. For example, a sterilization indicator may compromise a chromophore-containing compound capable of undergoing a color change in the presence of nitric oxide (e.g., from clear to bright green-colored). However, the colorant component may also comprise a colorant including, but not limited to, one or more pigments, dyes, or combinations thereof to achieve a coating / diffusion layer that may be adjusted to tune the sensitivity and timing of response of the sterilization indicator to the nitric oxide. Preferably, the sterilization indicator further comprises a support layer comprising the chromophore-containing compound and / or a polymer layer overlying at least a portion of the support layer for purposes of reducing diffusion of afluid through the polymer layer to the chromophore-containing compound. Additional embodiments suitable for use herein are incorporated by reference in WO 2022 / 164905.

[0049] In yet further embodiments, the sample compartment is configured to have an access point designed specifically for easy transfer of its contents to another environment. The access point remains sealed but can be pierced or open through other means when needed. For instance, if a product was sterilized and sealed into a sample compartment and the NO releasing compartment has been removed, but it is later desired to simply transfer the product into another sterile environment without the need to re-sterilize it, the access point may be opened to allow the easy transfer of the product. Alternatively, the access point may be used simply to remove the product from the sample compartment so that the product may be used as normal. For instance, once a medical tool is sterilized, a medical expert may pierce or open the access point to remove the medical tool so that the tool may be used for its intended purpose.

[0050] Viewed from a different perspective, the packages disclosed herein may come in various shapes. This may be especially beneficial if the packages are used for specific industries or products that fit most comfortably in particularly shaped packages. For instance, a cylindrical package may be beneficial if used to sterilize rolls of gauze or other cylindrical products. As another example, a package may be shaped like a bowl, which can be preferable if used to sterilize glassware or lab equipment that fit appropriately. In another example, a much smaller cylindrical or rectangular package may be used to comfortably fit pipettes or pipette tips.

[0051] As used herein, the term “NO releasing composition” may comprise any composition or mixture of compositions capable of releasing nitric oxide. In some embodiments, such composition may comprise a S-nitrosothiol, such as S-nitrosoglutathione (GSNO), S- nitrosoacetylpenicillamine (SNAP), and S-nitrosocysteine (SNOC), or a precursor to a S- nitrosothiol. Therefore, and in a more general aspect of the inventive subject matter, an NO releasing composition can comprise a mixture of precursors to an S-nitrosothiol, such as a thiol and a nitrite.

[0052] In some embodiments, the NO releasing composition comprises the reaction product of an acetylpenicillamine thiolactone and a nitrosating compound, such as a nitrite. The nitrite may comprise 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.

[0053] In other embodiments, the NO releasing composition comprises the reaction product of a thioester, a primary amine, and the nitrosating compound. The thioester may comprise a thiolactone. In certain embodiments, the thiolactone is an amine-containing thiolactone (e.g., thietanone). The primary amine may comprise a cysteine or derivative thereof, such as cysteine, glutathione, acetyl cysteine, penicillamine, acetylpenicillamine, S-nitroso-n- acetylpenicillamine, bucillamine, or combinations thereof.

[0054] In still other embodiments, the NO releasing composition comprises a primary amine. The primary amine may comprise a cysteine or derivative thereof, such as cysteine, glutathione, acetyl cysteine, penicillamine, acetylpenicillamine, S-nitroso-n-acetylpenicillamine, bucillamine, or combinations thereof.

[0055] When an NO releasing composition comprises multiple different compounds, the inventor contemplates that the different compounds can either be pre-mixed or mix on demand by a user. The inventor contemplates that small molecular nitric oxide precursors can be blended into polymers, solution phases, or powders and used to generate nitric oxide for creating a wide array of NO donating / generating entities by blending the nitric oxide precursor into the matrix (polymer or powder or embedded in and on solid carriers) or for creating solutions that generate NO in a controlled and predicable manner from the matrix / solution phase. Further embodiments contemplated by the inventor relating to the NO releasing composition are described in PCT / US23 / 20331, WO 2022 / 164894, PCT / US23 / 18910, and U.S. provisional application 63 / 447,811, 2 / 23 / 2023, each incorporated in their entirety by reference herein.

[0056] The nitric oxide precursor may be used in a wide variety of medical and consumer applications. The properties of nitric oxide precursor may be adjusted based on the selection of the thiol-containing compound and the nitrosating compound to suit specific applications. Nonlimiting examples of suitable adjustments include nitric oxide generation capabilities and the rate of release of nitric oxide from the nitric oxide precursor. As described in greater detail herein, the nitric oxide precursor may be formed in situ from a multi-component composition. This in situ formation of the nitric oxide precursor may also be adjusted to suit specific applications by tuning formation and stability properties of the nitric oxide precursor such thatnitric oxide can be, for example, generated rapidly and in a controlled manner. This controlled nitric oxide release is useful for sterilizing and sanitizing medical devices.

[0057] Viewed from a different perspective, the inventor contemplates utilizing the nitric oxide precursor and / or the multi-component composition to form nitric oxide for a variety of medical and consumer applications. In various embodiments, the nitric oxide precursor and / or the multi-component composition may be in the form of a liquid, a powder, a film, a coating, a gel, a solid strip coated with the nitric oxide precursor, or the like within the NO releasing compartment. Non-limiting examples of suitable uses include sterilization of sports equipment, such as hockey gloves and cycling gloves, cleaning surgical instruments, internal lumens of endoscopes, surfaces of medical equipment and the like such as scalpels, clamps, forceps, tubing, portable ultrasound devices, bandages, dressing, as well as tissue samples and / or biohazard waste. In some or all of the examples above, it should be appreciated that the nitric oxide precursor can be supplied as an already formed compound, or that the nitric oxide precursor can be generated in situ by reaction of the thiol-containing compounds with a nitrosating compound, typically in the presence of a solvent (that may be derived from air humidity, supplied separately, or that may be used as a solvent for the thiol-containing compound and / or the nitrosating compound). In some embodiments, and depending on the specific the NO releasing compound, the NO releasing compartment may release the NO in response to a change in temperature, pressure, pH, humidity, and / or illumination with visible or UV light.

[0058] With respect to suitable NO releasing compounds generated from reactants, the inventor contemplates that the nitric oxide precursor may exhibit decomposition to nitric oxide after forming the reaction product within a predetermined amount of time, such as within 1 hour, alternatively within 30 minutes, alternatively within 15 minutes, alternatively within 5 minutes, alternatively within 1 minute, or alternatively within 10 seconds, alternatively within 1 second, or alternatively within 0.1 seconds. Viewed from a different perspective, the multicomponent composition may exhibit decomposition to nitric oxide after forming the nitric oxide precursor within a predetermined amount of time, such as from about 0.01 seconds to about 1 hour, alternatively from about 0.01 seconds to about 30 minutes, alternatively 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 sustained for a predetermined amount of time, such as a time period of from about 1 minutes to about 1 year, alternativelyfrom about 1 hour to about 6 months, alternatively from about 24 hours to about 3 months, or alternatively from about 1 week to about 8 weeks. Viewed from a different perspective, decomposition to nitric oxide may be sustained for a period of at least 1 minute, alternatively at least 1 hours, alternatively at least 24 hours, or alternatively at least 1 week. Without being bound by theory, it is contemplated that in situ formation of the reaction product provides controlled decomposition of the nitric oxide precursor (e.g., nitrosothiol) to nitric oxide within the predetermined amount of time for the predetermined amount of time.

[0059] As will be readily appreciated, decomposition rate of the nitric oxide precursor will depend on a variety of factors which can be fine-tuned to achieve a desired decomposition profile. Among other factors, the decomposition rate can be modified by selecting the type of nitrosothiol, the molar ratios of the thiol-containing compound and the nitrosating compound, the presence / quantity of reduction equivalents or other catalysts that influence the in situ formation of the nitric oxide precursor, the pH of the solution, and availability of solvent. For example, it should be appreciated that primary nitrosothiols have a substantially higher rate of decomposition than secondary or tertiary nitrosothiols. Moreover, in situ formation of the nitrosothiols may be accelerated in the presence of various reduction equivalents such as thiols, NADH, transition metals, ascorbic acid, etc. (such reducing agents could be present in trace amounts to equimolar ratio, or even be present in molar excess relative to the thiol-containing agent). Likewise, acidic pH (e.g., pH <4.0) will generally favor stability of nitrosothiols whereas basic pH (e.g., pH >7.0) will favor decomposition of the nitrosothiol. Still further, where the solvent is water from humid air, the degree of humidity will determine the rate of the in situ formation of the nitric oxide precursor.

[0060] Regardless of the reaction conditions, it is generally contemplated that in some embodiments the rate of decomposition of the nitric oxide precursor to form nitric oxide will be greater than the rate of in situ formation such as 1.5 time greater, or 2.5 times greater, or 5 times greater or ten times greater, or even more. In other embodiments, the rate of decomposition of the nitric oxide precursor to form nitric oxide will be lesser than the rate of in situ formation such as 1.5 time less, or 2.5 times less, or 5 times less or ten times less, or even less. Moreover, and depending on the particular formulation and nitric oxide precursor, it is contemplated that in some embodiments the nitric oxide released within 1 hour will be at least 25%, or at least 50%, or at least 70%, or at least 80%, or at least 90%, or at least 95% of all releasable nitric oxide in the formulation. In further embodiments, it is contemplated thatthe nitric oxide released within 24 hours will be at least 25%, or at least 50%, or at least 70%, or at least 80%, or at least 90%, or at least 95% of all releasable nitric oxide in the formulation, and in still other embodiments, it is contemplated that the nitric oxide released within 7 days will be at least 25%, or at least 50%, or at least 70%, or at least 80%, or at least 90%, or at least 95% of all releasable nitric oxide in the formulation. In additional embodiments, it is contemplated that the nitric oxide released within 1 month will be at least 25%, or at least 50%, or at least 70%, or at least 80%, or at least 90%, or at least 95% of all releasable nitric oxide in the formulation.

[0061] Consequently, the inventor contemplates that the NO releasing composition (preformed or generated in situ) is present, preferably, in an amount of at least 0.1 mg, or at least 1 mg, or at least 10 mg, or at least 100 mg, or at least 200 mg, or at least 300 mg, or at least 400 mg, or at least 500 mg, or at least 750 mg, or at least 1,000 mg, or at least 1,500 mg, or at least 2,000 mg, or at least 2,500 mg. For example, suitable amounts of the NO releasing composition will be between 10-100 mg, or between 100-200 mg, or between 200-400 mg, or between 300-600 mg, or between 400-800 mg, or between 600-1,000 mg, or between 750-1,500 mg or between 750-2,000 mg, or between 1,500-2,500 mg.

[0062] The preferred amount of the NO releasing composition most typically depends on the size of the package because larger packages are likely used to sterilize products with larger surface areas. In addition, the preferred amount of NO releasing composition used may be dependent upon the target concentration of NO used to sterilize the content within the sample compartment. One skilled in the art can apply the Ideal Gas Law (n = PV / RT), the moles of NO released from the various NO-releasing compounds, the molecular weight of the compound in question and derive the weight of the compound necessary to achieve a desired percent of NO added to any specified volume that comprises the sample compartment. For instance, if the target NO concentration is 10% for a 12” x 12” bag with a height of 2” (4.72 liters), and the NO precursor used is cysteine reacting with a nitrite, applying the ideal gas law, the desired nitric oxide concentration would be 10% of 4.72 liters, or 0.472 liters, “n” or the moles of NO, could be calculated as (1 atm)(0.472 liters) / (R)(298.15 K), equal to 0.0208 moles of NO. The molecular weight of cysteine is 121.16 g / mol, and thus, assuming a 2: 1 molar ratio of cysteine to nitric oxide, the mass of cysteine required would be 5.03 grams to achieve the desired 10% NO concentration.

[0063] In one embodiment of the present disclosure, the invention includes a means for providing instructions to a user. These instructions may be provided through various mediums, including but not limited to stickers adhered to a surface of the package, a sheet of paper or pamphlets attached to the package or found in a kit containing the package, or through direct printing on a surface of the package. The instructions may serve to guide the user through setup, opening, initial sealing, use, secondary sealing, and separating the compartments of the package. The instructions may further provide guidance on maintenance and / or disposal of the package.

[0064] 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.

[0065] 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.

[0066] 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 twoelements 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.

[0067] It should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the scope of the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms “comprises” and “comprising” should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced. Where the specification or claims refer to at least one of 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.

Claims

AMENDED CLAIMS received by the International Bureau on 06 March 2025 (06.03.2025)CLAIMSWhat is claimed is:

1. A package configured to sterilize a sample on demand, comprising: an open and sealable end; wherein the package comprises a sample compartment, and a nitric oxide (NO) releasing compartment, wherein the NO releasing compartment comprises an NO releasing composition; and wherein the package is configured to allow sealing and removal of the sample compartment from the NO releasing compartment while maintaining the sample compartment in a sealed state to so allow for mobile and terminal sterilization of the sample.

2. The package of claim 1, wherein the open and sealable end is configured to be sealable as a Ziploc®, glue strip, heat weld, adhesive, or clamp or other compression.

3. The package of claim 1, wherein the open and sealable end can comprise an entire length or side of the package, or a portion thereof.

4. The package of claim 1, further comprising a second open and sealable end.

5. The package of claim 1, wherein the sample compartment and the nitric oxide (NO) releasing compartment are contiguous.

6. The package of claim 1, wherein the sample compartment and the nitric oxide (NO) releasing compartment are physically separated.

7. The package of claim 1, wherein the sample compartment comprises one or more subcompartments, each fluidly coupled to the nitric oxide (NO) releasing compartment.

8. The package of claim 1, wherein the nitric oxide (NO) releasing compartment comprises a sub-compartment in which the NO releasing composition is retained.

9. The package of claim 1, wherein the NO releasing composition comprises a NO releasing polymer, a nitrosothiol, or a plurality of reagents that form a nitrosothiol upon reaction.

10. The package of claim 1, wherein the NO releasing composition is a liquid and / or a solid.AMENDED SHEET (ARTICLE 19)11. The package of claim 1, wherein the package is configured to allow heat sealing or ultrasonic or laser or adhesive sealing.

12. The package of claim 1, wherein the packaging is configured to allow removal of the NO releasing compartment by perforation or cutting, or by exposure to thermal, acoustic, or light energy.

13. The package of claim 1, wherein the NO releasing composition comprises a reaction product of an acetylpenicillamine thiolactone and a nitrosating compound, or wherein the NO releasing composition comprises a reaction product of a thiol compound and a nitrosating compound.

14. The package of claim 1, wherein the NO releasing compartment releases NO in response to a change in temperature, pressure, pH, humidity, and / or illumination with visible or UV light.

15. The package of claim 1, wherein the package comprises a Nylon portion, a Tyvek® portion, a Mylar® portion, a portion of other plastics, or a polyethylene terephthalate-glycol (PETG) portion.

16. The package of claim 1, wherein the sample compartment comprises an outer and inner sample compartment, wherein the outer sample compartment is open and sealable, and wherein the inner sample compartment is open and sealable.

17. The package of claim 1, wherein a material of the package between the NO releasing compartment and the sample compartment is NO-permeable.

18. The package of claim 1, wherein the package is configured as a bag, a pouch, or a tray with a lid, and / or wherein the entire package is flexible.

19. The package of claim 1, wherein the package has an inner volume between 10 cm3and 1,000 cm3.

20. The package of claim 1, wherein the NO releasing composition is present in an amount between 10 mg and 2,500 mg.AMENDED SHEET (ARTICLE 19)21. The package of claim 1, wherein the NO releasing composition is present in an amount sufficient to sterilize via gaseous NO an object contained in the package within 15 minutes.

22. A method of sterilizing a sample on demand, comprising: placing the sample into a sample compartment of a package, wherein the package further includes a NO releasing compartment; sealing the package; releasing nitric oxide (NO) into the sample compartment from the NO releasing compartment, wherein the NO releasing compartment comprises an NO releasing composition; and removing the NO releasing compartment from the sample compartment while maintaining the sample compartment in a sealed state to so allow for mobile and terminal sterilization of the sample.

23. The method of claim 22, wherein the NO releasing composition comprises a reaction product of an acetylpenicillamine thiolactone and a nitrosating compound, or wherein the NO releasing composition comprises a reaction product of a thiol compound and a nitrosating compound.

24. The method of claim 22, wherein the sample comprises one or more medical device, bandage, dressing, electronic device, surgical equipment, tissue sample, and / or biohazard waste.

25. The method of claim 22, wherein the package is the package as claimed in any one of claims 1-22.

26. The method of claim 22, wherein the sealing is performed by ultrasound, heat, laser, clamp, zip lock, or adhesive.

27. The method of claim 22, wherein releasing NO into the sample compartment is triggered by a change in temperature, pressure, pH, humidity, and / or illumination with visible or UV light.

28. The method of claim 22, wherein releasing NO into the sample compartment comprises releasing NO from NO precursors that react to form nitrosothiol, or from nitrosothiol directly.AMENDED SHEET (ARTICLE 19)29. The method of claim 22, wherein NO is released for an amount of time sufficient to sterilize the sample, or for at least 5 min, or for at least 15 min, or for an amount of time sufficient to sterilize the sample at room temperature or at elevated temperature.

30. The method of claim 22, wherein removing the NO releasing compartment from the sample compartment comprises cutting, heating, tearing, or separating with a laser or ultrasonic.

31. A method of manufacturing a package configured to sterilize equipment on demand, the method comprising: forming a package to include a sample compartment and a NO releasing compartment, wherein the sample compartment is fluidly coupled to the NO releasing compartment; wherein the sample compartment is configured to allow placement of an object inside the sample compartment; placing a NO releasing composition into the NO releasing compartment; and wherein the package is further configured to allow sealing of the package after placement of the object into the sample compartment, and wherein the package is further configured to allow removal of the NO releasing compartment from the sample compartment while maintaining the sample compartment in a sealed state to so allow for mobile and terminal sterilization of the object.

32. A sterilization packaging kit, comprising: the package of any one of claims 1-21; and a sample object to be sterilized enclosed in the package.

33. The packaging kit of claim 32, further comprising instructions for use on a sticker, booklet, or printed on a surface of the packaging kit.AMENDED SHEET (ARTICLE 19)

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