Patent Application
20250134826
Nitric oxide (NO) is an endogenous gas molecule that has been shown to have several important physiological functions, examples of which include its unique vasodilating properties, wound healing properties, angiogenesis promoting properties, cancer-fighting potency, anti-platelet activity, and anti-microbial/anti-viral activity. NO has been used for infection, inflammation, and fibrosis control/minimization, biofilm formation prevention, and inhalation therapy.
Features of examples of the present disclosure will become apparent by reference to the following detailed description and drawings, in which like reference numerals correspond to similar, though perhaps not identical, components. For the sake of brevity, reference numerals or features having a previously described function may or may not be described in connection with other drawings in which they appear.
Inhaled nitric oxide may be useful in a variety of applications, including substance delivery (e.g., inhaled antiseptic agent), treatment plans (e.g., for lung failure or pulmonary hypertension), and invasive medical procedures (e.g., during and after organ transplants, such as lung, heart and kidney transplants). Inhaled NO has been effective in enhancing pulmonary vasodilation, lowering pulmonary vascular resistance, and treating neonates that suffer from hypoxic respiratory failure.
Disclosed herein is an NO releasing film that produces therapeutic and higher levels of NO at a constant rate, due, at least in part, to the inclusion of solid, light sensitive NO donor particles having a diameter of 50 μm or less. The relatively small particles provide a greater surface area per unit mass (compared to larger particles), and thus provide an increased area for light exposure (which triggers NO release).
As used herein, the terms “nitric oxide releasing film” and “NO releasing film” may refer to a single film that is capable of releasing nitric oxide upon exposure to a predetermined wavelength of light, or to a film stack that includes at least one film that is capable of releasing nitric oxide upon exposure to a predetermined wavelength of light. The single film may also be referred to herein as a “nitric oxide donor film” or an “NO donor film.”
The membrane(s)/layer(s) of the NO releasing films disclosed herein are also flexible, which enables them to be coiled and/or spooled. The spooled film can be incorporated into a relatively small device that is able to continuously deliver relatively high ppmv NO doses. A “relatively high ppmv” NO dose refers to NO delivery ranging from 81 ppmv to 400 ppmv. A “moderate ppmv” NO dose refers to NO delivery ranging from 11 ppmv up to, but not including, 81 ppmv. In one example, the NO delivery ranges from 40 ppmv to 60 ppmv (of NO) at a gas flow of 8 L/min. A “low ppmv” NO dose refers to NO delivery ranging from 0.05 ppmv up to, but not including, 11 ppmv. In all NO delivery ranges, gas flow rates may range from 0.05 L/min to 100 L/min. In some examples, the relatively high NO dose may be achieved using single or double sided illumination of either a single sided or double sided film. Lower doses are most easily achieved using the single sided film disclosed herein and single sided illumination. For sustained delivery at these doses, the film is advanced as described herein in connection with the method.
Single sided illumination can be used to produce NO from the film, however double sided illumination of the single sided film may generate a higher dose for a shorter time period than if single sided illumination were used. Both single and double sided illumination may be used to compensate for older films where some unintended NO release may have taken place. Single sided illumination is satisfactory for NO production, however double sided illumination may also drive off NO in a given section of the film more quickly than if single sided illumination were used. Due to the greater efficiency of NO release, faster film advancement speeds are obtainable for double sided illumination and NO delivery, and thus the cartridge may be expended sooner than if single sided illumination were used.
In some of the examples described herein, the NO releasing film includes a substrate and an NO donor film attached to the substrate. As used herein, the term “attached” refers to the state of two things being joined, fastened, adhered, connected or bound to each other, either indirectly or directly. As an example of indirect attachment, a base binding layer may be positioned between the substrate and the NO donor film. As an example of direct attachment, the NO donor film may be in contact with a surface of the substrate, without any intervening layer(s).
As mentioned, the NO releasing film disclosed herein may be a multi-layered structure (e.g., see reference numeral 10 in
The NO releasing film 10″ shown in
In the NO releasing film 10 shown in
The substrate 12 may be any porous or non-porous material formed of a polymer that exhibits low oxygen (O2) permeability/solubility.
Non-porous substrates are materials with non-perforated surfaces that restrict the diffusion of both liquids and gases. If the non-porous substrate has any pores, the size of such pores is ≤1 nm. The non-porous substrate surfaces may be flat or contoured.
Porous substrates include pores or voids that allow the diffusion of liquids and/or gases of a particular size. In general, the pores may have a size ranging from the nanoscale (having a size ranging from about 2 nm to about 50 nm) to the macroscale (having a size ranging from about 100 nm to about 10 μm). In some examples, the pores of the substrate 12 are microporous, i.e., within the range from about 50 nm to about 100 nm. In other examples, the pores of the substrate 12 are about 0.4 μm or about 1.4 μm.
By “low oxygen permeability/solubility” and “low O2 permeability/solubility,” it is meant that the permeability of the polymer used to make the substrate 12 (or polymer matrix 16) is 10*109 cm3 (RTP)*cm/s*cm2*cmHg or less. In one example, the polymer is high-density polyethylene (HDPE) having an O2 permeability of 0.1*109 cm3 (RTP)*cm/s*cm2*cmHg. In another example, the polymer is PET having an O2 permeability of 0.0019*109 cm3 (RTP)*cm/s*cm2*cmHg. It is desirable for the polymer (and thus the substrate 12) to take up as little oxygen (O2) as possible, as O2 reacts with nitric oxide (NO) to generate undesirable nitrogen dioxide (NO2) byproduct. When the polymer that forms the substrate 12 is devoid of oxygen gas, the NO releasing film 10 can effectively photolytically release NO without also releasing appreciable levels of NO2. As such, it is desired that neither oxygen gas nor NO permeate into the substrate 12, which reduces the time that the NO is in contact with O2 prior to its release from the NO releasing film 10 into the gas phase.
The substrate 12 is also flexible. By “flexible,” it is meant that the substrate 12 is able to be coiled and spooled without breaking or cracking. Quantitatively, the substrate 12 can exceed 20,000 folding cycles when tested on an MIT flex tester (TAPPI method T-423).
In some examples disclosed herein, the substrate 12 is polyethylene terephthalate (PET) or a variant thereof (e.g., matte PET). The PET may be untreated or treated with a corona treatment, depending upon the polymeric matrix 16 that is being used. In one example, the PET is an extruded sheet having pores less than 100 nm. In other examples, the PET may also be electrospun with a larger pore size. PET may have a glossy surface finish, which is transparent and smooth. A variant of PET is matte PET, which is a biaxially oriented polyester film. The biaxially oriented polyester film has a medium haze and grainy surface, giving it semi-transparent optical qualities and rougher surface areas. The rougher surface areas may promote improved adhesion of the polymer matrix 16 or a base binding layer 13 to the NO donor film 14. Other PET variants may include a metallized coating, such as aluminum.
In other examples disclosed herein, the substrate 12 is made up of flash-spun or electrospun non-woven materials. Flash-spun or electrospun non-woven materials provide the substrate 12 with a webbed, fibrous surface structure. Any flash-spun or electrospun non-woven material may be used, as long as it is flexible as defined herein. Some examples include flash-spun high-density polyethylene (HDPE) fibers, electrospun polyvinylidene fluoride (PVDF), PVDF membranes, polytetrafluoroethylene (PTFE), polypropylene (PP), PELLON® (80/20 cotton/polyester blend textile), glass fibers (GF), filter membranes, or nylon (polyamide) screen materials. It is believed that other substrate 12 materials, such as mixed cellulose ester (MCE) and benzoin methyl ether (BME), may be used, as long as the solvent mixture used during deposition of the polymer matrix 16 dissolves the polymer matrix 16 without deleteriously affecting the MCE or the BME. One specific example of a suitable substrate 12 material includes high-density polyethylene (HDPE) fibers, such as TYVEK® (a non-woven material made up of synthetic flash-spun high-density polyethylene fibers from DuPont, e.g., medical grade products with a thickness ranging from about 50 μm to about 254 μm (from about 2.0 to about 10.0 mil), such as TYVEK® 1073B and TYVEK® 1059B). In some examples, the substrate 12 material includes a non-woven material made up of synthetic flash-spun high-density polyethylene having a thickness ranging from about 150 μm to about 204 μm (from about 6.2 mil to about 7.8 mil), or from about 101 μm to about 191 μm (from 6.5 mil about to about 7.5 mil). In general, the thickness of the substrate 12 may range from about 10 μm to about 2540 μm (from about 0 mil to about 100 mil), which may depend upon the material used and the desire to coil/spool the substrate 12. In one example, the thickness is 508 μm or less (20 mil or less).
In some examples, the NO donor film 14 is attached directly to the substrate 12. The porous, and in some instances fibrous, structure of the substrate 12 provides several surfaces for the NO donor film 14 to anchor to during immobilization (e.g., solvent evaporation). In some examples, the non-porous or porous substrate may be exposed to a corona treatment in order to improve the adhesion between the substrate and the NO donor film 14. Corona treatment increases the surface energy of plastic films to increase wettability and adhesion of inks, coatings and adhesives. It is believed that at least some of the NO donor film 14 may be physically restrained within at least some of the pores of the porous substrate 12 examples, which results in stronger binding than surface adsorption alone. For example, films bound to porous, non-fibrous substrates via surface adsorption, without being restrained or adhered with an additional adhesive material, may delaminate, crack, and peel off from the underlying substrate, especially when coiled or spooled. These examples may exhibit overall flexibility and may resist sticking when coiled.
In other examples, the NO donor film 14 is indirectly attached to the substrate 12 through the base binding layer 13 (shown in phantom in
The NO donor film 14 of
The polymer matrix 16 exhibits low O2 permeability/solubility, as it is defined herein.
The polymer matrix 16 is selected from the group consisting of non-UV curable polyurethane, polyvinyl butyral, polystyrene, copolymers of styrene, block copolymers of styrene, poly(ethersulfone), polyvinylpyrrolidone, polyvinyl acetate, poly(ethylene-co-vinylacetate), and combinations. Other polymer materials that exhibit the low O2 permeability/solubility and flexibility may also be suitable.
When the polymer matrix 16 is a non-UV curable polyurethane, the backbone of the polymer matrix 16 includes urethane linkages formed between diisocyanate monomers and isocyanate reactive groups, such as hydroxyls (e.g., as part of a diol or other polyol). Chain extenders and/or capping agents can also be used, respectively, to extend the polyurethane chain and terminate chain extension.
Suitable diisocyanate monomers include hexamethylene-1,6-diisocyanate (HDI), 2,2,4-trimethyl-hexamethylene-diisocyanate (TDMI), 1,12-dodecane diisocyanate, 2,4,4-trimethyl-hexamethylene diisocyanate, 2-methyl-1,5-pentamethylene diisocyanate, isophorone diisocyanate (IPDI), methylene diphenyl diisocyanate (MDI), or 1-Isocyanato-4-[(4-isocyanatocyclohexyl)methyl]cyclohexane) (H12MDI, i.e., 4,4′-Methylenedicyclohexyl diisocyanate). Suitable diols or polyols include pentyl glycols (e.g., neopentyl glycol); C4 to C10 alkyldiol (e.g., 1,4-butanediol, hexane-1,6-diol); C4 to C10 alkyl dicarboxylic acids (e.g., adipic acid); and aromatic dicarboxylic acids, e.g., phthalic acid. The polyurethane is a non-UV curable polyurethane, meaning that it does not include UV curable functional groups, such as acrylate groups.
The polyurethane example of the polymer matrix 16 may include both soft and hard segments, where the soft segments are composed of a polyether or polyester polyol and the hard segments are composed of diisocyanate and, when used, the chain extender. In an example, the ratio of soft segments to hard segments ranges from about 65:35 (13:7) to about 60:40 (3:2). The ratio of soft segments to hard segments may be adjusted so that the polyurethane polymer matrix 16 has a Shore hardness value ranging from about 35A to about 80D.
In one example, the polyurethane example of the polymer matrix 16 is an aliphatic polyether-based thermoplastic polyurethane having a Shore A hardness value of 72 (measured using a Shore durometer tool) and a flexural modulus (psi) of 1,000. An example of this polyurethane is commercially available under the tradename TECOFLEX™ TPU (from Lubrizol Corp.). The backbone of this particular polyurethane is shown below:
Polyvinyl butyral is another suitable polymer matrix 16 material. Polyvinyl butyral consists of three monomeric subunits—vinyl butyral, vinyl alcohol, and vinyl acetate, each of which is shown below:
In an example, the polyvinyl butyral has a hardness ranging from about 18D to about 60D. In one specific example, the polyvinyl butyral has the following properties: average molecular weight ranging from about 1,000 to about 15,000; viscosity from about 30 to about 300 mPa-s in a 5 wt % to 10 wt % solution; from 16 wt % to 25 wt % alcohol content, 19 wt % or less acetate content, and from about 65 wt % to about 83 wt % of acetal content; and a glass transition temperature ranging from about 65° C. to about 115° C. Any of the polyvinyl butyral formulations commercially available from multiple manufactures, example: Sekisui Co. (whose formulations may have different percentages of the repeating unit) may be used, as long as they exhibit the properties set forth herein for the polymer matrix 16.
Still another suitable polymer matrix 16 is polystyrene or styrene copolymers or styrene block copolymers. As shown below, examples of styrene block copolymers include units of styrene and isoprene in blocks or units of styrene and butadiene in blocks.
Polystyrene has the structure:
and is made up of polymerized styrene monomers. In an example, the polystyrene has a hardness ranging from about 90A to about 90D. In one specific example, the average molecular weight of the polystyrene ranges from about 10,000 to about 600,000 and the glass transition temperature ranges from about 90° C. to about 212° C.
Polystyrene-block-polybutadiene-block-polystyrene is one example of a styrene block copolymer:
In one example, the hardness of this block copolymer ranges from about 60D to about 80D based on the content of butadiene in the block copolymer. In one specific example, the polystyrene-block-polybutadiene-block-polystyrene has the following properties: a hardness ranging from about 40 to about 80 (Shore A); and from about 20 wt % to about 40 wt % styrene content and from about 60 wt % to about 80 wt % butadiene content. It is to be understood that other percentages of the monomers may be used, and that a higher butadiene content results in a softer copolymer or block copolymer.
Polystyrene-block-polyisoprene-block-polystyrene is another example of a styrene block copolymer:
In one example, the hardness of this block copolymer ranges from about 25A to about 70A. In one specific example, the polystyrene-block-polyisoprene-block-polystyrene has the following properties: density ranging from about 0.80 g/mL to about 0.98 g/mL at 25° C.; and from about 5 wt % to about 30 wt % styrene content and from about 60 wt % to about 90 wt % isoprene content. It is to be understood that other percentages of the monomers may be used, and that a higher isoprene content results in a softer copolymer or block copolymer.
In any of these examples, the styrene polymer, styrene copolymer, or styrene block copolymer may be incorporated into a stock solution at 2.5-40 wt % so that a viscosity of the solution ranges from about 20 cP to about 20000 cP (measured at 25° C.).
The polymer matrix 16 should also take up (absorb) little to no water, as water and humidity may react with the NO donor particles 18 and prematurely release NO and degrade the NO donor particles 18. In an example, the water uptake exhibited by the polymer matrix 16 ranges from about 0.0 mg H2O/mg polymer to about 0.5 mg H2O/mg polymer. In one specific example, the water uptake exhibited by the polymer matrix 16 is about 0.2±0.18 mg H2O/mg polymer.
Additionally, the polymer matrix 16 should not absorb the majority of the activating wavelengths for the solid, light sensitive NO donor particles 18. In one example, the polymer matrix 16 has >60% transmission of light with wavelengths in the range of 250 nm to 600 nm, to allow the NO donor particles 18 to be photolyzed to release the desired NO product.
The solid, light sensitive NO donor particles 18 are both in solid form and are light sensitive. By “solid form,” it is meant that the NO donor particles 18 are not a liquid or a fluid, but rather, are firm and stable in shape. In some examples, the NO donor particles 18 are in crystalline or powder form. By “light sensitive,” it is meant that the NO donor particles 18 are photolyzable, i.e., are capable of undergoing photolysis when exposed to an activating wavelength or wavelengths of light. In particular, the NO donor particles 18 are capable of releasing NO gas molecules when exposed to the activating wavelength or wavelengths of light. Examples of the solid, light sensitive NO donor particles 18 include light sensitive S-nitrosothiols. Some specific examples of light sensitive S-nitrosothiols are selected from the group consisting of S-nitroso-N-acetyl-penicillamine (SNAP), S-nitrosoglutathione (GSNO), S-nitroso-N-acetylcysteine (SNAC), S-nitroso-3-β-mercaptopropionic acid (SN3-MPA), and combinations thereof. These light sensitive S-nitrosothiols are capable of undergoing photolysis when exposed to activating wavelength(s) ranging from 250 nm to 600 nm. As specific examples, light emitting diodes (LEDs) emitting anywhere from 300 nm to 565 nm wavelengths may be used to activate the SNAP and GSNO crystals. As other examples, a bulb or laser emitting anywhere from 250 nm to 600 nm wavelengths may be used.
The light sensitive NO donor particles 18 have a volume-weighted mean diameter of 50 μm or less. In some examples, the volume-weighted mean diameter is less than 50 μm. In an example, the volume-weighted mean diameter ranges from about 0.1 μm to 50 μm. In another example, the volume-weighted mean diameter ranges from about 5 μm to less than 40 μm. In another example, the volume-weighted mean diameter ranges from about 1 μm to less than 25 μm. In still another example, the volume-weighted mean diameter ranges from about 0.5 μm to less than 5 μm.
In one example, a larger form (e.g., crystals) of the NO donor material (which forms the particles 18) are exposed to grinding and/or milling processes, which may be manual or automated to obtain smaller particles. In one example of automated milling, the NO donor material may be processed by ball mill. The milling processing can range from about 1 hour to about 48 hours to achieve a desired mean particle size distribution. The milling media can be composed of stainless steel, zirconia, ceramic, or other inert material. The milling container can be composed of stainless steel, zirconia, ceramic, HDPE, PTFE, or other inert material. The NO donor material can be milled as a dry powder formulation or milled as a slurry, which contains the NO donor material and a solvent or the NO donor material, a solvent, the polymer matrix 16, and one or more of the additives set forth herein. In yet another example of automated milling, the NO donor material may be processed by jet-mill. In one example the powder feed rate to the mill may range from 1 g to 6 kg per hour with feed and grind pressures ranging from 10 PSI to 20 PSI to achieve the desired mean particle size distribution. While examples have been provided, it is to be understood that the process parameters may be altered depending upon the type of equipment used.
After grinding and/or milling, the small particles may be sifted through a sieve screen in a humidity-controlled environment (e.g., less than 10% relative humidity) in order to avoid particle agglomeration. The size of the pores of the sieve screen may be 50 μm or smaller, so that each of the particles in the sieved sample has a particle size less than the pore size. In some examples, the ground particles may be sieved twice, where the first sieve screen is used to filter out particles that are too large and the second sieve screen is used to filter out particles that are too small. In one example, the first sieve screen may have a pore size of 25 μm and the particles that pass through the pores are collected. The collected particles have a diameter less than 25 μm. The collected particles are then filtered using a second sieve screen having a pore size of 10 μm. The particles that do not pass through the second sieve screen are collected and used as the solid, light sensitive NO donor particles 18. In this particular example then, the solid, light sensitive NO donor particles 18 have a diameter ranging from 10 μm to 25 μm. In other examples, the solid, light sensitive NO donor particles 18 have a diameter ranging from about 0.5 μm to 25 μm. In still other examples, the solid, light sensitive NO donor particles 18 have a diameter ranging from about 0.1 μm to about 5.0 μm.
The solid, light sensitive NO donor particles 18 are distributed throughout the polymer matrix 16. The method described herein enables the relatively uniform distribution of the solid, light sensitive NO donor particles 18 throughout the polymer matrix 16.
The weight ratio of the solid, light sensitive NO donor particles 18 to the polymer matrix 16 ranges from about 0.1:1 to about 50:1. In one example, the weight ratio of the solid, light sensitive NO donor particles 18 to the polymer matrix 16 ranges from about 1:1 to about 35:1. In still other examples, the weight ratio of the solid, light sensitive NO donor particles 18 to the polymer matrix 16 ranges from about 0.2:1 to about 9:1.
Some examples of the NO donor film 14 or the NO releasing film 10″ consist of the polymer matrix 16 and the NO donor particles 18. Other examples of the NO donor film 14 or the NO releasing film 10″ include one or more additives, such as NO2 scrubber particles, radical stabilizers, dispersants/wetting agents, and/or anti-skinning agents. Example NO2 scrubber particles include ascorbic acid, soda lime, calcium hydroxide, and/or sodium hydroxide. Example radical stabilizers include 2,6-Di-tert-butyl-methoxyphenol and/or 4-tert-butylcatechol. In an example, a mole ratio of 0.1:1 up to 1:1 of NO2 scrubber particles or radical stabilizers to NO donor particles 18 may be present in the slurry and the NO donor film 14 or NO releasing film 10″. In other examples, an additional coating (not shown) containing the NO2 scrubber particles or radical stabilizers may be positioned over the NO donor film 14 and beneath the protective coating 20 (if present). Example dispersants and pigment wetting agents include Kutsumoto Chemicals DISPARLON® series of dispersants or Lubrizol SOLSPERSE™ series of dispersants. In an example, a mass ratio of 1% to 25% of dispersant, with respect to NO donor particle mass, may be present in the coating slurry and NO donor film 14 or NO releasing film 10″. As another example, the mass ratio of 1% to 12.5% of dispersant, with respect to NO donor particle mass, may be present. The stock solution of the dispersant may be a diluted form (e.g., 50% active dispersant in n-butylacetate), and thus the amount may be adjusted in accordance with the concentration in the stock solution. In another example, anti-skinning agents, (e.g. ASCININ® from Milliken) may be present in mass ratios of 0.05% to 2.0% with respect to total slurry mass in the coating slurry and with respect to a total film mass in the NO donor film 14 or the NO releasing film 10″. In still another example, the slurry or film 14 or 10″ includes from about 0.2% to about 0.6% based on a total mass of the respective slurry or film 14 or 10″.
While a single layer of the NO donor film 14 is shown in
The NO releasing film 10 shown in
When included, the NO permeable and light transparent film 20 serves as a protective layer, helping to ensure that the NO donor particles 18 are not removed by abrasion or physical contact of the film 10 with other surfaces (the film itself, rollers, guides, or the like) during use.
An example of the NO permeable and light transparent film 20 includes the polymer matrix 16 without the inclusion of the solid, light sensitive NO donor particles 18. The NO permeable and light transparent film 20 may help immobilize the NO donor layer 14 to the substrate 12. The NO permeable and light transparent film 20 may also increase the NO releasing film's robustness, as it can reduce the propensity of NO donor layer 14 removal when the NO releasing film 10 is brushed or scraped.
While a single layer of the NO permeable and light transparent film 20 is shown in
The total thickness of the NO donor film 14 and the NO permeable and light transparent film 20 or the NO releasing film 10″ should be at most 2 mm. In
The length of the NO releasing film 10, 10″ may range from about 10 m to about 50 m. When rolled, the diameter of the rolled NO releasing film 10, 10″ may range from about 8 cm to about 10 cm. These dimensions may be smaller, depending upon the size of the cartridge in which the film 10, 10″ is to be introduced.
An example method for making the NO releasing film 10 or 10″ includes dissolving the polymer matrix 16 into a solvent mixture, thereby producing a polymer solution; mixing the solid, light sensitive NO donor particles 18 into the polymer solution, thereby producing a coating slurry, wherein a volume-weighted mean diameter of the solid, light sensitive NO donor particles 18 is 50 μm or less; depositing the coating slurry on a support selected from the group consisting of a temporary substrate 12′ (see
The polymer matrix 16 is dissolved into the solvent mixture to form a polymer solution. Dissolution of the polymer in the solvent enables rapid mixing, and homogenization of the dissolved polymer with other slurry components (if included). The solvents of the solvent mixture are selected so that they dissolve the polymer matrix 16 and so that they have no effect on the underlying support (e.g., substrate 12 or temporary substrate 12′). As such, the substrate 12 or 12′ is chemically inert to the solvent mixture. In other words, the solvent mixture does not dissolve the substrate 12 or 12′ or penetrate into the fibers of the substrate 12 or 12′. Examples of the solvent mixture may include 1:4 to 4:1 wt:wt of a low vapor pressure solvent (e.g., cyclohexanone) to a high vapor pressure solvent (e.g., ethanol, tetrahydrofuran) or 90:10 to 10:90 n-butylacetate:ethanol. Other examples of solvents that may be used neat or in the solvent mixture include methyl alcohol, isopropyl alcohol, ethyl acetate, hexanes, xylenes, toluene, decane, and dodecane.
The amount of the polymer matrix 16 in the solvent mixture may range from about 2.5 wt % to 40 wt %, based on the total weight of the resulting polymer solution. The weight percentage of polymer may vary depending upon the solubility of the particular polymer in the solvent mixture.
In a first example, the polymer solution may be used as is to create a coating slurry for producing the film 14 or 10″, or, in a second example, the polymer solution may be prepared as a stock solution for preparation of a coating slurry that contains a lower wt % of the polymer than the stock solution. In the first example, the amount of the polymer matrix 16 in the solvent mixture ranges from about 2.5 wt % to about 15 wt % (based on the total weight of the polymer solution) and is used undiluted. In this example, the solid, light sensitive NO donor particles 18 are added to the undiluted polymer solution to produce the coating slurry. In the second example, the initial polymer solution is prepared as a stock solution containing from about 10 wt % to about 40 wt % of the polymer matrix 16. Some of the stock solution is combined with additional solvent and the solid, light sensitive NO donor particles 18 (described below) to produce a final coating slurry where the polymer content ranges from 2.5 wt % to about 25.0 wt % based on the total weight of the coating slurry.
Once the polymer matrix 16 and the solvent mixture are combined, they may be stirred, shaken, or otherwise mixed until the polymer matrix 16 is completely dissolved. This forms the polymer solution. While several examples have been provided, it is to be understood that the weight percentage of the polymer matrix 16 in the polymer solution may also depend upon the deposition technique that is to be used to apply the slurry. For example, when a pneumatic spraying application is to be used, the concentration of the polymer matrix 16 in the polymer solution may be at the middle to lower end of the given range so that the solution can be sprayed. For another example, when a knife-edge film application is to be used, the concentration of the polymer matrix 16 in the polymer solution may be at the middle to upper end of the given range so that the viscosity of the polymer solution and the final coating slurry is increased.
The solid, light sensitive NO donor particles 18 may then be added to the polymer solution to form the coating slurry. The concentration of the solid, light sensitive NO donor particles 18 in the coating slurry ranges from about 0.5 wt % to about 70 wt %, based on the total weight of the coating slurry. It is to be understood that the amount of the NO donor particles 18 in the coating slurry may also depend upon the deposition technique that is to be used to apply the coating slurry. In one example, the amount of the solid, light sensitive NO donor particles 18 in the coating slurry ranges from about 0.5 wt % to 20.0 wt % (based on the total slurry weight), while in another example, the concentration of the NO donor particles 18 in the slurry ranges from about 15.0 wt % to 60.0 wt % (based on the total slurry weight).
If included, the additive(s) may be added to the polymer solution before, with, or after the NO donor particles 18. As such, one example of the method further includes adding an additive to the polymer solution, wherein the additive is selected from the group consisting of NO2 scrubber particles, a radical stabilizer, a dispersant, an anti-skinning additive, and combinations thereof. In one example, the dispersant is added to the solvent mixture, and then the polymer matrix 16 is added.
The slurry may be sonicated or blended in a homogenizer to help ensure that the NO donor particles 18 and any additives are substantially uniformly dispersed.
In some instances, the coating slurry consists of the solvent, the polymer 16, and the NO donor particles 18. In other instances, the slurry consists of the solvent, the polymer 16, the NO donor particles 18, and the additive(s).
The viscosity of the slurry may range from about 1 mPa-s to about 10000 mPa-s at room temperature (measured with a rotary viscometer).
When the support is the substrate 12, the slurry may be applied to the substrate 12 using any suitable deposition technique. With any of the techniques and when the substrate 12 is porous, it is believed that at least some of the slurry is able to penetrate into the nanopores or micropores of the substrate 12 and to form a relatively homogeneous layer of the slurry over the entire surface of the substrate 12.
In one example, a pneumatic paint spray nozzle is used to spray the slurry over the substrate 12. In another example, a knife-edge film coating technique is used to apply the slurry. With the knife-edge film coating technique, the substrate 12 can be dipped in a reservoir of the slurry, or the slurry can be poured or pipetted onto the surface of the substrate 12. A knife edge or doctor blade made of glass or solvent-resistant plastic is then passed over the slurry with the application of light pressure. By “light pressure,” it is meant that the pressure that is applied is not enough to completely scrape the slurry from the surface but is enough to remove excess slurry from the surface. As an example, the light pressure applied by the knife edge or doctor blade ranges from greater than 0 bar to about 5 bar. In still another example, the slurry can be applied via the flow channel of a slot die coater so that a reproducible layer is deposited on the substrate 12. In another example, the slurry can be applied via a gravure rod with a doctor blade such that a reproducible layer is deposited on the substrate 12.
The solvent mixture is then evaporated from the applied slurry layer. Evaporation may take place at ambient temperatures (from about 22° C. to about 26° C.), or may be accelerated by brief exposure of the applied slurry layer to heat up to 120° C. As examples, a suitable drying temperature for a slurry containing: ethanol, toluene, or n-butyl acetate ranges from 30° C. to 120° C. with drying times ranging from 10 seconds to 360 seconds, or ranges from 22° C. to 26° C. with drying times ranging from 12 hours to 24 hours.
In some examples, evaporation is accelerated at a temperature ranging from 40° C. up to 100° C. In one example, quick flash drying at temperatures ranging from 70° C. up to 120° C. may be used to accelerate evaporation of the solvent mixture. Prolonged exposure to higher temperatures could cause the NO donor particles 18 to decompose. In an example, brief exposure ranges from about 30 s to about 360 s.
It has been observed with some polymer matrices 16, that both drying conditions and polymer may cause a dense layer of the polymer matrix 16 at the film 14 surface. This dense layer acts like a crust that can trap NO gas released from the NO donor particles 18, that can retain solvent residuals in the film 14, and that can promote the formation of excess NO2 gas byproduct. The weight percent of the polymer matrix 16 in the coating slurry, vapor pressure of the solvent, drying time, and drying temperatures can all affect the polymer's propensity to form this dense crust layer. Specifically, when thick films are rapidly dried at elevated temperatures, the surface of the film may dry first, causing skin formation prior to complete solvent evaporation from the remainder of the film. When the content of the polymer matrix 16 in the polymer solution and slurry is greater than or equal to (≥) 20 wt % (with respect to the weight NO donor particles in the slurry), or when the total film thickness is greater than or equal to 20 μm, a stepwise ramping drying temperature or an extended drying time may be utilized to prevent the formation of the dense crust layer.
As the solvent mixture evaporates, the polymer matrix 16 remains along with any other additives, if included, providing a dried polymeric matrix for the solid, light sensitive NO donor particles 18. The polymer matrix 16 securely anchors to the substrate 12 or base binding layer 13, while also providing the NO donor film 14 with flexibility so that it can bend and move with the substrate 12 without cracking or breaking.
With the porous substrates 12, the NO donor film 14 may be present in at least some of the pores located at/near the substrate surface upon which the slurry was deposited, and across the surface.
The process for generating the NO donor film 14 may be repeated any number of times to generate several layers stacked on top of one another, thus creating a multi-layered NO donor film 14. In this example, at least partial evaporation of one layer takes place before the application of more slurry. At least partial evaporation reduces the amount of liquid or eliminates the liquid, the presence of which can result in uneven film coating.
Some examples of the method further include forming a base binding layer 13 on the substrate 12 before forming the NO donor film 14. To form the base binding layer 13, a polymer solution without any of the solid, light sensitive NO donor particles 18 therein is deposited over substrate 12 before the slurry is applied, and the solvent mixture is evaporated. The polymer solution may be applied using the same techniques for applying the slurry, and evaporation may be allowed to occur or accelerated as described for the slurry. The polymer solution may include the same polymer that is used for the polymer matrix 16 or any other polymer disclosed herein for the base binding layer 13. The polymer solution used to form the base binding layer 13 may also include any of the additives set forth herein.
After the single layer or multi-layered NO donor film 14 is generated, the method may further involve forming the NO permeable and light transparent film 20 over the layer(s) making up the NO donor film 14.
To form the NO permeable and light transparent film 20, the polymer solution without any of the solid, light sensitive NO donor particles 18 therein is deposited over the NO donor film 14, the solvent mixture is evaporated. The polymer solution may be applied using the same techniques for applying the slurry, and evaporation may be allowed to occur or accelerated as described for the slurry. The polymer solution used to form the NO permeable and light transparent film 20 may also include any of the additives set forth herein.
The process for generating the NO permeable and light transparent film 20 may be repeated any number of times to generate several layers stacked on top of one another, thus creating a multi-layered NO permeable and light transparent layer 20. In this example, at least partial evaporation of one layer takes place before the application of more polymer solution. At least partial evaporation reduces the amount of liquid or eliminates the liquid, the presence of which can result in uneven film coating.
Another example method uses the temporary substrate 12′ instead of the substrate 12. This example method includes dissolving the polymer matrix 16 into a solvent mixture, thereby producing a polymer solution; mixing solid, light sensitive NO donor particles 18 into the polymer solution, thereby producing a coating slurry; casting the coating slurry on a temporary substrate 12′; and evaporating the solvent mixture, thereby generating an NO donor film 10′ that is removable from the temporary substrate 12′. In this example method, the polymer matrix 16, the NO donor particles 18, and polymer solution may be any of the examples set forth herein.
This method generates an NO releasing film 10′ (similar to film 14) that can be removed from the temporary substrate 12′. The temporary substrate 12′ may be any material from which the film 10′ can be removed. In one example, the NO releasing film 10′ can be peeled off of the temporary substrate 12′. In an example, the temporary substrate 12′ is stainless steel. Other suitable temporary substrate materials include TEFLON® (polytetrafluoroethylene from DuPont) or TEFLON® coated material or ceramics. With the temporary substrate 12′, the adhesion described between the polymer matrix 16 and the substrate 12 does not take place.
In this example method, the slurry preparation, deposition, and evaporation may be performed as described herein. In one specific example, the slurry is cast on the temporary support 12′.
Once formed, the NO releasing film 10′ can be removed from the temporary substrate 12′. Removal may be accomplished, for example, by peeling the NO releasing film 10′ from the temporary substrate 12′.
The nitric oxide (NO) releasing film 10, 10″ may be part of a nitric oxide releasing system. An example of the system 22 is shown in
The NO releasing system 22 may be part of a gas delivery device. An example of the gas delivery device 40 is shown in
The system 22 and gas delivery device 40 will be described together in reference to both
The NO releasing system 22 includes the chamber 24 where photolysis takes place (i.e., a photolysis chamber). The chamber 24 may be defined within a housing 80 that is made of any suitable material that is not permeable to oxygen-containing gas OC or to NO. If the light source 30 is positioned outside of the chamber 24 (as shown in
The chamber 24 provides a sealed environment where the released NO can mix with a desired inspiratory gas. The housing 80 includes both an inlet 34 and an outlet 36. The housing 80, and thus the chamber 24, may be sealed around the inlet 34 (connected to a conduit that is used to introduce the oxygen-containing gas OC) and the outlet 36 (connected to a conduit that is used to transport a stream of the output gas OG). The housing 80, and thus the chamber 24, may also be disposable so that the entire NO releasing system 22 can be discarded at the end of its useful life, or the housing 80, and thus the chamber 24, can include an opening through which the NO releasing film 10, 10″ can be replaced.
One example of the system 22 includes the supply reel 26 and the motor-controlled pick-up reel 28. In this example, both the supply reel 26 and the motor-controlled pick-up reel 28 are positioned within the chamber 24. The rods of each of the reels 26, 28 may be connected to a mechanism (not shown) that enables their operation. In one example, the supply reel 26 may include a stationary central rod that is securely attached to the housing 80 and an outer spool that is positioned on the stationary central rod and rotates about the stationary central rod. The fresh NO releasing film 10, 10″ is wound around the outer spool. The motor-controlled pick-up reel 28 includes a rotating rod that is operatively connected to a stepper motor 44 via a shaft or by other connection means such as a belt drive(s), gears and/or gear chain(s) (
The linear film advancement speed depends, at least in part, on the diameter of the axle of the motor-controlled pick-up reel 28. The following table illustrates example speeds for a 7.6 mm diameter axle.
In another example of the system 22, the supply reel 26 is used with a transfer reel 29 and a waste apparatus 31, which may be a waste reel or a waste container. Each of these components is also positioned within the chamber 24, and thus within the housing 80. In this example, the supply reel 26 is as described herein. The transfer reel 29 may also include a rotating rod that is operatively connected to a shaft of a stepper motor 44, which may be positioned inside the chamber 24 or outside of the chamber 24. Unlike the pick-up reel 28, the transfer reel 29 does not collect the expended film 10′. Rather, the transfer reel 29 may be configured to guide the expended film 10′ into the waste apparatus 31. As such, the transfer reel 29 is not secured to an end of the film 10, 10″, but rather allows the expended film 10′ to slide across its surface and into a suitably positioned waste container. The waste apparatus 31. As shown in
The NO releasing system 22 also includes the NO releasing film 10 or 10″. The NO generating film 10, 10″ may be any of the examples described in reference to
The NO releasing system 22 also includes the light source 30. Any light source may be used that is capable of emitting light that initiates photolysis of the solid, light sensitive NO donor particles 18. In other words, any light source 30 may be used that is capable of emitting the particular wavelength or wavelengths of light that cause the NO to be released from the solid, light sensitive NO donor particles 18. As such, the light source 30 may depend, in part, upon the NO donor particles 18 used and the desired rate of NO release. As examples, the light source 30 may be a high intensity light emitting diode (LED), a laser diode, a lamp, a bulb, etc. Suitable LEDs may be those having a nominal wavelength ranging or peaking at/from about 300 nm to about 700 nm, such as 340 nm, or 365 nm, or 375 nm, or 385 nm, or 395 nm, or 405 nm, or 450 nm, or 470 nm, or 527 nm, or 565 nm, or 595 nm. Suitable light source(s) could also be wide range LEDs that emit a board range of wavelengths, such as from 300 nm to 700 nm, simultaneously.
When the light source(s) 30 emits UV wavelengths (e.g., 100 to 400 nm), the NO releasing system 22 may also be self-sterilizing. The ultraviolet light has an anti-microbial effect and thus may sterilize the system 22 as well as the NO gas that is generated.
One or more light sources 30 may be used to release NO from the NO releasing film 10 or 10″. The use of multiple light sources 30 may enable further control over the NO release. In one example, one, or two, or eight, or more banks of LEDs may be used. For example, if higher levels of NO are desirable, all of the light sources 30 facing the NO donor film 14 of the NO releasing film 10 or facing the NO releasing film 10″ may be activated to emit light toward the film 14 or 10″, and if lower levels of NO are desirable, less than all of the light sources 30 may be activated. Additionally, the intensity of the light source(s) 30 may be adjusted to increase or decrease NO release, and to achieve substantially uniform illumination when an array of light sources 30 is utilized.
The light source(s) 30 is/are positioned to selectively expose the NO donor film 14 or NO releasing film 10″ to light hv. The light source(s) 30 may be positioned outside of a light transparent housing 80 or may be positioned inside of a transparent or non-transparent housing 80. In some examples, the light source(s) 30 may be attached to the housing 80 (e.g., either inside or outside). In these examples, and when the housing 80 is disposable, the light source(s) 30 may be disposed with the housing 80. In these examples, and when the housing 80 is not disposable (but rather receives a disposable NO releasing film 10 or 10″), the light source 30 may be reused with several different NO releasing films 10 or 10″. The light source(s) 30 may also be removable from the inside or outside of the housing 80 so that it/they can be replaced at the end of its/their useful life. In some other examples, the light source(s) 30 may be attached to a main body 78 of a gas delivery device 40, such as the example devices 40′, 40″ shown in
When the light source(s) 30 is/are attached to the inside of the chamber 24 or to an interior surface of the main body 78, any adhesive or other suitable securing mechanism may be used to attach the light source(s) 30 to an interior wall or structure of the housing 80 or the main body 78. This adhesive may not be light transparent because it is not positioned between the light source(s) 30 and the film 14 or 10″. When the light source(s) 30 is/are attached to the outside surface of the housing 80 that defines the chamber 24 (as shown in
The proximity of the light source(s) 30 and the NO releasing film 10 or 10″ may also be controlled. In an example, a desirable distance between the light source(s) 30 and the NO releasing film 10 or 10″ may range from about 1 mm to about 80 mm. In one example, the distance is about 30 mm.
The angle of the light source(s) 30 with respect to the surface of the NO releasing film 10 or 10″ may also be adjusted.
While not shown in either
The NO releasing system 22 may be part of a gas delivery device 40, as shown in
An example of the electronic circuitry 32 includes Raspberry Pi based electronic boards and components. Another example of the electronic circuitry 32 includes custom printed circuit boards specifically designed to control electronics, such as the light sources 30 and stepper motor(s) 44, as well as other electronic components in the system 40. The electronic circuitry 32 may include components to store (i.e., computer memory; e.g.; SD cards, EEPROM, RAM, flash memory, etc.) and run (e.g., microcontrollers (MCU), graphics processing units (GPU), graphic card(s), etc.) a graphical user interface (GUI) 46 (
The electronic circuitry 32 may also be part of a sensing and feedback system (i.e., a monitoring system, also referred to herein as a feedback and sensing system) that includes NO and NO2 sensors 48, 50 for detecting, respectively, the NO level and the NO2 level (if any) in the output gas OG. These sensors 48, 50 may be in gas flow communication with a sampling line 54, which is in gas flow communication with the outlet conduit 42, which is connected to the outlet 36, as shown in
While not shown, it is to be understood that the sensing and feedback system may also include an oxygen sensor, gas flow sensors and/or differential pressure sensors in gas flow communication with the sampling line 54 and/or with the outlet conduit 42. The oxygen sensor may be used to measure the O2 concentration in the output gas OG and/or for measuring the dilution of the air/O2 in the outlet conduit 42. The gas flow sensors and/or differential pressure sensors may be used for integration of the sensing and feedback system with a ventilator. In particular, these sensors may be used to adjust the output gas OG to patient/ventilator breathing rate.
One example NO releasing system 22 or gas release and delivery device 40 includes at least two sets of sensors (48, 50 and an oxygen sensor) to monitor NO, NO2 and O2; and the feedback and monitoring system to receive data from the at least two sets of sensors. In this example, the feedback and monitoring system can compare measurements from the two or more sets of sensors to determine when sensor calibration should be run or to analyze sensor failure.
Still further, the NO releasing system 22 may include a manual or electronic backup system. This system enables the continued delivery of the NO when the gas(es) supplied by the ventilator is/are manually delivered. When the ventilator is undergoing maintenance or experiences a malfunction, the NO releasing system 22 can enter static mode, where the dosage of the NO that is generated and delivered is based on the last measurement from the feedback system before static mode is entered. As such, the same amount of NO can be continuously delivered for some predetermined amount of time.
When in use, the light source(s) 30 may be turned ON for any time interval, for example, 8 hours per NO releasing film 10 or 10″, and thus may photolytically release NO during this time interval. Longer time intervals, and thus longer NO release lifetimes, may be possible, depending upon the size of the substrate 12 and/or the amount of NO donor particles 18 in the NO releasing film 10 or 10″. During this time interval, the stepper motor 44 controls the reel 28 so that it is turned ON continuously to bring fresh NO donor film 14 or NO releasing film 10″ within proximity of the light source(s) 30. When it is desirable to stop releasing NO, the light source(s) 30 is/are turned OFF so that light hv is no longer emitted on the NO releasing film 10 or 10″ and the stepper motor 44 is turned OFF so that fresh NO releasing film 10 or 10″ is not wasted.
In one example of the method, the supply reel 26 is 1.2 mm in diameter, the motor-controlled pick-up reel 28 is 3.77 mm in diameter, and the rotation ranges from about 0.5° per second to about 5° per second. In another example, the rotation of the reels 26, 28 may range from about 0.2° per second to about 14.5° per second.
In another example of the method, the pick-up reel 28 does not rotate, and the NO releasing film 10 or 10″ remains stationary.
In general, the operation of the NO releasing system 22 depends upon several factors, including the loading of the NO donor particles 18, the flow rate of gas to the patient, and the level of NO being delivered. As mentioned, the process is feedback controlled and the parameters can be adjusted to achieve the maximum delivery of NO from a specific area of film 10 or 10″.
The NO gas released from the NO donor particles 18 permeates through the NO donor film 14 (and the NO permeable and light transparent film 20 if used) or through the NO releasing film 10″ and into the chamber 24.
The gas delivery device 40 shown in
The inspiratory gas conduit 38 may be a tube that has low or no permeability to at least the oxygen-containing gas OC and the nitric oxide. Examples of suitable tubing material include poly(vinyl chloride) (PVC), polyurethane (PU), polyethylene (PE), fluorinated polymers (e.g., polytetrafluoroethylene (PTFE), fluorinated ethylene propylene (FEP)), polycarbonates (PC), etc.
In the chamber 24, the oxygen-containing gas OC mixes with the photolytically released NO gas to form an output gas stream OG. A stream of the output gas OG may exit the NO releasing system 22 through the outlet 36 into the outlet conduit 42. The outlet conduit 42 may be a tube that has low or no permeability to at least the oxygen-containing gas OC and the nitric oxide in the output gas OG. The length of the outlet conduit 42 may also be relatively short in order to avoid nitrogen dioxide (NO2) formation before the stream is delivered to a desirable destination (e.g., a recipient, such as a human patient). Since the oxygen-containing gas OC is introduced prior to delivery to the recipient, the impact on the NO concentration is minimal or nil due to the short contact time between the NO and the oxygen-containing gas OC.
In some examples, the output gas OG stream may be transported as a result of pressure from the gas source 52, which may include a regulator to control the flow rate. In other examples, the output gas OG stream may be transported as a result of pressure from a vacuum positioned downstream.
The outlet conduit 42 may be operatively connected to a delivery conduit (not shown). The delivery conduit may be operatively connected to an inhalation unit (not shown), which is capable of transporting the output gas stream OG to a recipient/patient. The delivery conduit may be any suitable polymeric or other tubing that is impermeable to the output gas stream OG. In an example, the delivery conduit may also have a one-way valve so that the output gas stream OG does not flow back into the NO releasing system 22. The inhalation unit may be a face mask, a nasal cannula, or some other suitable apparatus for delivering the output gas stream OG to the airways of the recipient.
While not shown, it is to be understood that the gas delivery device 40 may also include a nitrogen dioxide (NO2) absorption filter or scrubbing module. The NO2 absorption filter may be positioned in the delivery conduit to receive the output gas stream OG before it is delivered to the inhalation unit, and ultimately, to the recipient. Some examples of the NO2 absorption filter remove at least some of the NO2 from the output gas stream OG. As examples, a silica gel filter (with pre-conditioned silica particles) or a soda lime scrubber may be used as the NO2 absorption filter. These filters may reduce the NO2 to a level that is not physiologically relevant. Other examples of the NO2 absorption filter convert the nitrogen dioxide back into nitric oxide. This conversion is desirable because no NO payload is lost in the form of scavenged (absorbed) NO2, but rather is reduced back into NO. An example of this type of NO2 absorption filter includes ascorbic acid (pure solid) or ascorbic acid impregnated silica particles.
Also while not shown, it is to be understood that the gas delivery device 40 may also include a dry scrubber to control the humidity (e.g., 5% to 90%) within the chamber 24. Examples of suitable scrubber materials include soda lime (most effective at higher humidity), calcium hydroxide (Ca(OH)2) (effective at high humidity), sodium hydroxide (NaOH) (effective at lower humidity), potassium hydroxide (KOH) (effective at lower humidity), calcium chloride (Ca(Cl)2), or any combination thereof.
Other examples of the gas delivery device 40′, 40″ are respectively shown in
Each cartridge A, B includes a housing 80A, 80B that defines regions 58, 60 for the supply reel 26 and pick-up reel 28 and a chamber (similar to chamber 24) where photolysis takes place. When inserted into the portable main body 78 and in operation, the regions 58, 60 are not exposed to the excitation light. A cover 64 (which, in some instances, is opaque (in cartridges A, B), and in other instances, is transparent (in cartridges C, D)) may be integrally formed with the housing 80A, 80B, or may be a separate piece that is secured to the housing 80A, 80B. In either instance, the cover 64 seals the regions 58, 60. As mentioned, in the cartridges A, B, the cover 64 prevents light from reaching the film 10, 10″ or 10′. Example of opaque cover materials include polytetrafluoroethylene (PTFE), high density polyethylene (HDPE), acrylic, polycarbonate (PC), stainless steel, etc. The cover 64 in the cartridges A, B may also include one or more light transparent or translucent windows 56 that is/are positioned adjacent to the chamber 24 so that light can be delivered to the NO releasing film 10 or 10″ within the chamber 24. Alternatively, the housing 80A, 80B may include an opaque outer shell which defines openings for receiving respective covers 64, and that has a frame that supports the transparent/translucent window(s) 56. In this example, the cover 64 does not include the window 56, but rather two separate covers 64 are used to seal the respective regions 58, 60. One window 56 may be used to allow the film 10 or 10″ to be exposed on a single side. Two windows 56 positioned on opposed sides of the chamber 24 may allow the film 10 or 10″ to be exposed to the excitation light simultaneously on both sides of the film 10 that is positioned on a light transparent substrate 12, or of the film 10″, or to respective films 10 that are applied to opposed sides of a non-light transparent substrate 12. A transparent version of the cover 64 is described in reference to the cartridges C, D.
Perspective and side views of three examples of the cartridge housing 80A, 80B are shown, respectively, in
In some example housings 80A, 80B, the cover 64 can open so that a fresh NO releasing film 10 or 10″ can be loaded and a spent NO releasing film 10 or 10″ can be removed. In these examples, the housing 80A, 80B is reusable. It is to be understood, however, that the entire cartridge A, B (including the housing 80A, 80B) may be disposable. In these instances, the entire cartridge A, B can be removed and replaced.
The interior chamber 24 that is adjacent to the window(s) 56 is where fresh film 10 or 10″ is introduced from the supply reel 26 and is exposed to light. This chamber 24 has dimensions that help to minimize NO2 build up within the cartridge A, B (i.e., dead space within the chamber 24 is minimized while allowing the NO that is released from the releasing film to flow). For example, the thickness of the chamber 24 is less than 1 cm. The area leading to outlet(s) 36 of the housings 80A, 80B of the cartridges A, B, may also function as an absorber housing to absorb NO2 from the NO containing gas stream that is exiting the cartridge A, B. For example, the section of the cartridge A, B leading to the outlet 36 may be formed of an NO2 absorbing material or may have an NO2 filter secured therein. Each of the cartridge housings 80A, 80B includes apertures where the stepper motor 44 (see
In the example of the housing 80A, 80B of the cartridge A, B depicted in
The main body 78 of one example of the portable nitric oxide releasing device (gas delivery device 40′) is shown in
At the exterior of the device 40′, the gas inlet port 86 is capable of attaching to the inlet conduit 38 and to the gas source 52. Acceptable gas sources 52 are described above and include compressed oxygen/air sources, medical ventilators, etc. Within the device 40′, the gas inlet port 86 is fluidly connected to the inlets 34 of each of the cartridges A, B.
Also at the exterior of the device 40′, the outlet port 88 is capable of attaching to the outlet conduit 42. Within the device 40′, the outlet port 88 is fluidly connected to the outlet 36 of each of the cartridges A, B.
The gas generating device 40′ may also include one or more vents 112 positioned adjacent to the cartridge slots 82. In the example in
The sampling pump 102 pumps a portion of the output gas OG through the sampling gas port 54. The sampling gas flow mechanism 104 may include a valve that opens the sampling gas port 54. Together, these components enable a sample of the output gas OG to be redirected to the sensor manifold 106, which holds the sensors 48, 50.
The flow change manifold 108 may instead be a selector value (see reference numeral 94 in
The flow change manifold 108 (or selector valve 94) interfaces with a gas flow sensor, which can measure the gas flow at the inlet and outlet of the cartridges A, B (or C and D described below) in order to detect a leak.
Also depicted are gas cylinders 110, which may be included for delivering gases during calibration. The calibration gas cylinders 110 may be housed with the device 40′, or stored externally (not shown) and connected when to be used for calibration. In the latter instance, the small calibration cylinders 110 of a known concentration of compressed NO or NO2 gas will be temporarily connected to the device 40′ to calibrate the respective sensors (e.g., sensors 48, 50 in
Another example of the device 40″ is shown in
At the exterior of the device 40″, the gas inlet port 86′ is capable of attaching to the inlet conduit 38 and to the gas source 52. Acceptable gas sources 52 are described above and include compressed oxygen/air sources, medical ventilators, etc.). Within the device 40″, the gas inlet port 86′ is fluidly connected to the inlets 34 of each of the cartridges C, D.
Also at the exterior of the device 40″, the outlet port 88′ is capable of attaching to the outlet conduit 42. Within the device 40″, the outlet port 88′ is fluidly connected to the outlet 36 of each of the cartridges C, D.
The main body 78′ of the gas generating device 40″ may also include one or more vents 112′ positioned adjacent to the cartridge slot 82′. In the example shown in
In
Adjacent to one side of the cartridge slot 82 is an LED board, which is one example of the light source 30 disclosed herein. The light source 30 is positioned along one side of the slot 82 so that the window 56 faces the light source 30 when the cartridge C, D is inserted into the slot 82′.
The battery 100 is similar to that shown and described in reference to
The stepper motor 44C is operatively connected to the cartridge C when it is inserted into the slot 82′. Similar to the example shown in
The sensor manifold 106 is operable in the same manner as described for the device 40′.
The selector valve 94 may be operated as described herein in reference to
The sampling gas pump 102 may be operated as described herein in reference to
An example of the cartridges C, D is shown in
The housing 80C, 80D is shown in
The cartridge C, D also includes the cover 64, which, in this example is transparent to the light hv used to release NO from the film 10 or 10″. The cover 64 may be placed on or secured to the housing 80C, 80D in order to create the chamber 24 where the film 10 or 10″ is exposed to light hv. As such, the chamber 24 is defined between the cap 136 and the cover 64. The attachment between the cover 64 and the housing 80C, 80D creates an airtight seal.
In the example shown in
The frame of the interior housing 114 supports the cap 136 in a position adjacent to a region 124 of the interior housing 114 where the supply and pick-up reels 26, 28 are positioned, and also supports the lid 138 in a position adjacent to a region 120 where gases are removed from the cartridge C, D.
The cap 136 is formed of any material that is opaque to the light hv used to release NO from the film 10 or 10″. Examples of suitable materials for the cap 136 include polytetrafluoroethylene (PTFE), high density polyethylene (HDPE), acrylic, polycarbonate (PC), stainless steel, etc. The cap 136 is secured to the interior housing 114 so that the region 124, the supply and pick-up reels 26, 28 contained therein, and the film 10 or 10″ contained therein are covered by the cap 136. The securing mechanism may be an adhesive or a mechanical fastener. The cap 136 helps to keep NO from prematurely releasing from the cartridge C, D.
As shown in
Also during operation, the oxygen-containing gas OC (not shown in
The lid 138 is secured to the interior housing 114 so that the region 120 is sealed. Sealing this region 120 enables the output gas OG transported therethrough to exit through the aperture 122″ alone. The securing mechanism may be an adhesive or a mechanical fastener. The lid 138 is formed of any of the opaque or light transparent materials disclosed herein.
As mentioned, the region 120 houses an NO2 scrubber material. Any of the NO2 scrubber materials described herein may be incorporated into the region 120. By sequestering NO2 scrubber material in the region 120 between the chamber 24 and the outlet 36, NO2 contained in the output gas OG is removed before the output gas OG is transported out of the cartridge C, D.
As shown in
The exterior and the interior of the cartridge C, D is depicted in
Referring back to
In this example, the gas source 52 is a ventilator that is operatively connected, via the inspiratory gas conduit 38 to the inlet port 86′ of the device 40″. The ventilator supplies the oxygen-containing gas OC to the device 40″ where it is mixed with the released nitric oxide via the film 10 or 10″ and method disclosed herein.
The output gas OG is transported through the conduit 42. In the example shown in
As shown, the sampling line 54 is positioned to send a portion of the humidified output gas back to the gas generating device 40″ for purposes of monitoring and feedback control, with use of sampling gas pump 102 (
As depicted in
To further illustrate the present disclosure, examples are given herein. It is to be understood that these examples are provided for illustrative purposes and are not to be construed as limiting the scope of the present disclosure.
0.047 g of TECOFLEX™ TPU was dissolved in 13 mL of a solvent mixture containing 10:3 cyclohexane:tetrahydrofuran to form a polymer solution. 1 g of GSNO was added to the polymer solution to form a slurry. The slurry was spray coated onto a TYVEK® film (having 0.45 μm pores, and dimensions of 7 cm×133 cm), and the solvent mixture was allowed to evaporate.
The NO releasing film secured to a spooling system similar to that shown in
A target setpoint experiment was performed. In this experiment, the goal was to produce a target amount of NO (in parts per million (ppm)) at a given time by adjusting the light exposure and the speed of the belt of the spooling system. The light source was a light emitting diode (λ=395 nm), and a PID controller adjusted the voltage between 0 V (target NO=0 ppm) and 4.5 V (target NO=60 ppm). The stepper motor speed was initially set at 3 rpm, and then was stepped up 0.25 rpm for each interval going from the 0 ppm target interval to the 60 ppm target interval and then down 0.25 rpm for each interval going from the 60 ppm target interval to the 0 ppm target interval. Each interval ranged from 5 minutes to 8 minutes.
Air was transported through the spooling system housing and into the outlet conduit, which was in fluid communication with a sampling line containing nitric oxide (NO) and nitrogen dioxide (NO2) sensors. The air in the housing of the spooling system picked up the generated NO and nitrogen dioxide NO2, and then the mixed gaseous stream was directed into the outlet conduit. The flow rate of the air was 4.0 LPM (liters per minute), and 200 SCCM (standard cubic centimeters per minute) was directed into the sampling line and toward the sensors. More specifically, 4 LPM of air was directed into the chamber where it picked up the generated NO. The combination exited the chamber at 4 LPM. A sampling line pulled the 200 SCCM over the sensors for measurement.
The results from this experiment are shown in
A slurry was generated as described in Example 1. The slurry was spray coated onto a polypropylene (PP) films (having 0.45 μm pores, and dimensions of 7 cm×133 cm), and the solvent mixture was allowed to evaporate.
The NO releasing film secured to a spooling system similar to that shown in
A target setpoint experiment was performed. In this experiment, the goal was to produce a target amount of NO (in parts per million (ppm)) at a given time by adjusting the light exposure and the speed of the belt of the spooling system. The light source was a light emitting diode (λ=395 nm), and a PID controller adjusted the voltage between 0 V (target NO=0 ppm) and 4.5 V (target NO=60 ppm). The stepper motor speed was initially set at 3 rpm, and then was stepped up 0.25 rpm for each interval going from the 0 ppm target interval to the 60 ppm target interval and then down 0.25 rpm for each interval going from the 60 ppm target interval to the 0 ppm target interval. Each interval ranged from 5 minutes to 8 minutes.
Air was transported through the spooling system housing and into the outlet conduit, which was in fluid communication with a sampling line containing nitric oxide (NO) and nitrogen dioxide (NO2) sensors. The air in the housing of the spooling system picked up the generated NO and nitrogen dioxide NO2, and then the mixed gaseous stream was directed into the outlet conduit. The flow rate of the air was 4.0 LPM (liters per minute), and 200 SCCM (standard cubic centimeters per minute) was directed into the sampling line and toward the sensors.
The results from this experiment are shown in
While not reproduced herein, additional data was collected with PP films with 1.0 μm pores and 5.0 μm pores. The larger pore size did not promote significantly better adhesion.
A slurry was generated as described in Example 1. The slurry was spray coated onto a synthetic polyamide film (having 0.45 μm pores, and dimensions of 7 cm×133 cm), and the solvent mixture was allowed to evaporate.
The NO releasing film secured to a spooling system similar to that shown in
A target setpoint experiment was performed. In this experiment, the goal was to produce a target amount of NO (in parts per million (ppm)) at a given time by adjusting the light exposure and the speed of the belt of the spooling system. The light source was a light emitting diode (λ=395 nm), and a PID controller adjusted the voltage between 0 V (target NO=0 ppm) and 4.5 V (target NO=60 ppm). The stepper motor speed was initially set at 3 rpm, and then was stepped up 0.25 rpm for each interval going from the 0 ppm target interval to the 60 ppm target interval and then down 0.25 rpm for each interval going from the 60 ppm target interval to the 0 ppm target interval. Each interval ranged from 5 minutes to 8 minutes.
Air was transported through the spooling system housing and into the outlet conduit, which was in fluid communication with a sampling line containing nitric oxide (NO) and nitrogen dioxide (NO2) sensors. The air in the housing of the spooling system picked up the generated NO and nitrogen dioxide NO2, and then the mixed gaseous stream was directed into the outlet conduit. The flow rate of the air was 4.0 LPM (liters per minute), and 200 SCCM (standard cubic centimeters per minute) was directed into the sampling line and toward the sensors.
The results from this experiment are shown in
While not reproduced herein, additional data was collected with polyamide films with 1.0 μm pores and 5.0 μm pores. The larger pore size did not promote significantly better adhesion.
Seven slurries were generated as described in Example 1. Each slurry was spray coated onto a different 7 cm×7 cm substrate including: TYVEK® (having about 0.22 μm pores), polypropylene (having 0.45 μm pores), PELLON® (80/20 cotton/polyester blend), polyamide (having 0.45 μm pores), polytetrafluoroethylene (having 0.45 μm pores), glass fibers (having 0.45 μm pores), and polyvinylidene fluoride (having 0.45 μm pores). The solvent mixture was allowed to evaporate.
The NO releasing films were secured to a spooling system similar to that shown in
A depletion experiment was performed with each of the NO releasing films. In this experiment, the goal was to determine how much NO (in parts per million (ppm)) could be generated from each of the NO releasing films. The light source was a light emitting diode (λ=395 nm), and the voltage maintained at 4.5 V. The stepper motor speed was set at 0 rpm, so that the film was stationary. The same portion of the film was exposed to the light for the entire experiment.
Air was transported through the spooling system housing and into the outlet conduit, which was in fluid communication with a sampling line containing nitric oxide (NO) and nitrogen dioxide (NO2) sensors. The air in the housing of the spooling system picked up the generated NO and nitrogen dioxide NO2, and then the mixed gaseous stream was directed into the outlet conduit. The flow rate of the air was 4.0 LPM (liters per minute), and 200 SCCM (standard cubic centimeters per minute) was directed into the sampling line and toward the sensors.
For each film, light exposure was performed for about 45 minutes. The results for the NO releasing film including the TYVEK® substrate are shown in
The area under the NO curve was determined for each of the NO releasing film, and these results are shown in Table 2.
Each of the first five NO releasing films generated desirable amounts of NO, while the last two NO releasing films (made with glass fibers and PVDF) generated mediocre amounts of NO. It was noted that some of the substrate materials, including glass fibers and polyvinylidene fluoride, may be less desirable as the NO releasing film could be rubbed off of these substrates.
A slurry was generated as described in Example 1. The slurry was spray coated onto four different 7 cm×7 cm TYVEK® substrates, and the solvent was allowed to evaporate from each.
The NO releasing films were held stationary for this experiment, and each was exposed to a different UV-A wavelength. The light sources were light emitting diodes (λ=365 nm, λ=385 nm, λ=395 nm, and λ=405 nm), and light exposure was continued for about 15 minutes.
Air was transported through the system housing the stationary films and into an outlet conduit, which was in fluid communication with a sampling line containing nitric oxide (NO) sensors. The air in the housing of the system picked up the generated NO from the film surface, and then the gaseous stream was directed into the outlet conduit. The flow rate of the air was 4.0 LPM (liters per minute), and 200 SCCM (standard cubic centimeters per minute) of the total airflow was directed into the sampling line and toward the NO sensors.
The results from this experiment are shown in
GSNO was exposed to ball milling to generate differently sizes particles. The ball mill size, the ball mill exposure time, and resulting GSNO particle size varied from one sample to the next. A total of six different samples of GSNO were generated.
Respective slurries were generated with the GSNO samples and ethanol as the solvent. The slurries were respectively micro gravure printed onto PET substrates that had been coated with polyvinyl butyral and dried. The solvent was allowed to evaporate from each at a drying temperature of 60° C.
The NO releasing films were held stationary for this experiment, and each was exposed to a UV-A wavelength of 395 nm, and light exposure was continued for about 15 minutes.
Air was transported through the system housing the stationary films and into an outlet conduit, which was in fluid communication with a sampling line containing nitric oxide (NO) sensors. The air in the housing of the system picked up the generated NO from the film surface, and then the gaseous stream was directed into the outlet conduit. The flow rate of the air was 4.0 LPM (liters per minute), and 200 SCCM (standard cubic centimeters per minute) of the total airflow was directed into the sampling line and toward the NO sensors.
The results from this experiment are shown in
78.3 g of polystyrene-block-polyisoprene-block-polystyrene was dissolved in 13.4 g ethanol and 120.7 g n-butylacetate to form a polymer solution. The polymer solution was combined with 600.0 g of GSNO, 75.6 g of a 50 wt % solution of Lubrizol Solsperse™ M-389 dispersant (37.8 g dispersant+37.8 g n-butylacetate), and an additional 52.5 g ethanol and 384.4 g n-butylacetate was added to form a suspension. This suspension was ball-milled for 1 hour to generate a desirable particle size distribution and slurry. The slurry was then applied onto a PET film via slot-die coating and the solvent residue was allowed to evaporate.
The resulting NO releasing film was secured to a stationary test bed with an illumination window similar to that of the cartridge window shown in
A depletion experiment was performed. In this experiment, the goal was to evaluate how much NO (in parts per million (ppm)) could be generated from the NO releasing film that had been coated by slot-die coating. The light source was a 6×4 array of light emitting diodes (λ=395 nm), and the voltage was maintained at 13.3 V. The film was kept stationary such that the same portion of the film was exposed to the light for the entire experiment.
Air was transported through the housing of the stationary test bed and into an outlet conduit, which was in fluid communication with a sampling line containing nitric oxide (NO) and nitrogen dioxide (NO2) sensors. The air in the housing of the stationary test bed picked up the generated NO and nitrogen dioxide NO2, and then the mixed gaseous stream was directed into the outlet conduit. The flow rate of the air was 10.0 LPM (liters per minute), and 200 SCCM (standard cubic centimeters per minute) was directed into the sampling line and toward the sensors.
Light exposure was performed for about 15 minutes. The results for the NO film are shown in
53.1 g of polystyrene-block-polyisoprene-block-polystyrene was dissolved in 7.7 g ethanol and 69.6 g n-butyl acetate to form a polymer solution. The polymer solution was combined with 150.0 g GSNO and an additional 51.5 g ethanol and 451.3 g n-butyl acetate to form a suspension. This suspension was ball-milled for 6 hours to generate a desirable particle size distribution and slurry. The slurry was then applied onto a PET film via gravure and the solvent residue was allowed to evaporate.
The NO releasing film was secured to a spooling system similar to that shown in
A target setpoint experiment was performed. In this experiment, the goal was to produce a target amount of NO (in parts per million (ppm)) at a given time by adjusting the speed of the belt of the spooling system at a constant LED intensity. The light source was a 2×4 light emitting diode array (Δ=395 nm). The stepper motor speed was initially set at a step rate of 1, and was stepwise ramped to step rates of 2, 3, 4, and 6 after sustained levels of NO and NO2 were generated (around 7 to 20 minutes per step).
Air was transported through the spooling system housing and into the outlet conduit, which was in fluid communication with a sampling line containing nitric oxide (NO) and nitrogen dioxide (NO2) sensors. The air in the housing of the spooling system picked up the generated NO and nitrogen dioxide NO2, and then the mixed gaseous stream was directed into the outlet conduit. The flow rate of the air was 10.0 LPM (liters per minute), and 200 SCCM (standard cubic centimeters per minute) was directed into the sampling line and toward the sensors.
The results from this experiment are shown in
It is to be understood that the ranges provided herein include the stated range and any value or sub-range within the stated range, as if the value(s) or sub-range(s) within the stated range were explicitly recited. For example, a range from about 250 nm to about 600 nm should be interpreted to include not only the explicitly recited limits of from about 250 nm to about 600 nm, but also to include individual values, such as about 375 nm, about 520.5 nm, 450 nm, 599 nm, etc., and sub-ranges, such as from about 395 nm to about 595 nm, etc. Furthermore, when “about” is utilized to describe a value, this is meant to encompass minor variations (up to +/−10%) from the stated value.
Reference throughout the specification to “one example”, “another example”, “an example”, and so forth, means that a particular element (e.g., feature, structure, and/or characteristic) described in connection with the example is included in at least one example described herein, and may or may not be present in other examples. In addition, it is to be understood that the described elements for any example may be combined in any suitable manner in the various examples unless the context clearly dictates otherwise.
In describing and claiming the examples disclosed herein, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.
While several examples have been described in detail, it is to be understood that the disclosed examples may be modified. Therefore, the foregoing description is to be considered non-limiting.
This application claims the benefit of U.S. Provisional Application Ser. No. 63/594,380, filed Oct. 30, 2023, the content of which is incorporated by reference herein in its entirety.
This invention was made with government support under 1 R43 HL149556-01 and 1 R44 HL149556-02A1, each of which was awarded by the National Institutes of Health (NIH). The government has certain rights in the invention.
| Number | Date | Country | |
|---|---|---|---|
| 63594380 | Oct 2023 | US |
