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Publication numberUS20040197274 A1
Publication typeApplication
Application numberUS 10/833,182
Publication dateOct 7, 2004
Filing dateApr 27, 2004
Priority dateJun 19, 2001
Also published asUS6749834, US20020192163, WO2004054432A2, WO2004054432A3
Publication number10833182, 833182, US 2004/0197274 A1, US 2004/197274 A1, US 20040197274 A1, US 20040197274A1, US 2004197274 A1, US 2004197274A1, US-A1-20040197274, US-A1-2004197274, US2004/0197274A1, US2004/197274A1, US20040197274 A1, US20040197274A1, US2004197274 A1, US2004197274A1
InventorsHarry Fein, Xueji Zhang
Original AssigneeHarry Fein, Xueji Zhang
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Methods and apparatus for therapeutic treatment of respiratory, cardiac and other pathologies
US 20040197274 A1
A storage and delivery system for directly applying nitric oxide to a user includes a portable and disposable capsule and a source of nitric oxide gas disposed within the cavity. Gas flow control apparatus controls the flow of nitric oxide gas from the cavity. Gas flow initiation apparatus allows the user to initiate the flow of nitric oxide gas. The encapsulated nitric oxide gas is applied by positioning the capsule proximate to the objective site of the user and initiating flow of the nitric oxide gas.
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What is claimed:
1. A method of storing pressurized gas for subsequent therapeutic application comprising encapsulating the pressurized gas in a portable, light-weight gas impermeable capsule.
2. The method of claim 1 wherein the capsule includes means for controlling the concentration of gas delivered from the capsule.
3. The method of claim 2 further comprising the step of maintaining delivered nitric oxide gas at safe concentration levels to avoid toxic effects when applied to body cavities of subjects.
4. A method of providing therapeutic application of a gas as required comprising:
encapsulating chemical reagents which form the gas when mixed and
mixing the chemical reagents when required.
5. The method of claim 3 wherein said gas is nitric oxide.
6. A method of directly applying nitric oxide gas for therapeutic use by humans and animals using a portable nitric oxide gas source.
7. The method of claim 5 wherein the gas source is disposable gas.
8. The method of claim 7 further comprising positioning the nitric oxide gas source for application proximal to or within a nostril of a subject human or animal.
9. The method of claim 7 further comprising positioning elements of said nitric oxide gas source proximal to an objective site so as to provide optimal therapeutic effect.
10. The method of claim 7 further comprising diluting inhaled gas by the respiratory tidal volume of a user.
11. The method of claim 7 further comprising positioning the nitric oxide gas source for application proximal to or within any passage of a subject human or animal.
12. A portable gas storage device for storing pressurized gas comprising:
a gas impermeable capsule;
means for controlling the flow rate of gas when released from the capsule; and
means for user initiation of gas outflow from said capsule.
13. The device of claim 12 wherein the pressurized stored gas is nitric oxide.
14. The device of claim 12 further comprising pressure control means for maintaining a constant gas venting pressure.
15. The device of claim 12 further comprising a porous filter adapted for restricting the rate of gas outflow.
16. The device of claim 15 further comprising means for filtering undesired impurities from the delivered gas stream.
17. The device of claim 15 wherein the porous filter includes chemical reagents for removing nitrogen dioxide gas from the delivered gas stream.
18. The device of claim 12 wherein the device is disposable.
19. A gas generator comprising:
a capsule;
a plurality of chemical reagents disposed within the capsule, the chemical reagents generating a gas when activated; and
means for controlling the rate at which generated gas is vented from the capsule.
20. The gas generator of claim 19 wherein the generated gas is nitric oxide.
21. The gas generator of claim 19 further comprising pressure regulator means for providing a constant gas venting pressure.
22. The gas generator of claim 19 further comprising a porous plug for restricting the rate of gas outflow.
23. The gas generator of claim 22 wherein the porous plug includes reagents for filtering nitrogen dioxide gas from the gas outflow.
24. The gas generator of claim 19 further comprising a porous plug for preventing water vapor from leaving the capsule.
25. The gas generator of claim 19 further comprising a gas permeable tube.
26. The gas generator of claim 19 wherein the capsule is completely enclosed by a gas permeable polymer jacket.
27. The gas generator of claim 26 wherein the polymer jacket is impermeable to water and chemical reagents.
28. The gas generator of claim 19 wherein the chemical reagents are selected from the group consisting of water, sodium nitrite, potassium nitrite, sodium iodide, potassium iodide, ascorbic acid, hydrochloric acid, nitric acid and sulfuric acid, cupric chloride, cuprous chloride, and vanadium.
29. The gas generator of claim 19 wherein the chemical reagents are selected from the group of S-Nitrosothiols (RSNO) consisting of S-nitroso-N-acetyl-D-, -dimethylcysteine (SNAP), S-nitroso-L-glutathione (GSNO), S-Nitrosocysteine, S-nitrosated amino acid, S-nitrosated peptides, and S-nitrosated protein.
30. The gas generator of claim 19 further comprising breakable vessel means, disposed within the capsule a first of the chemical reagents being stored within the vessel and a second of the chemical regents being stored between the vessel and the capsule, for allowing the first chemical reagent to mix with the second chemical reagent when broken.
31. The gas generator of claim 19 wherein the chemical reagents include NONOate.
  • [0001]
    This is a division of application Ser. No. 09/884,786, filed Jun. 19, 2001 to which this application claims benefit under 35 U.S.C. 120.
  • [0002]
    The perception that nitric oxide (NO), a chemically active gas, plays an essential role in human and animal physiology was first demonstrated in 1987 with the publication of Nitric Oxide Accounts for the Biological Activity of Endothelium Derived Relaxing Factor; Palmer, R. M., Ferridge, A. G., Moncada, S; Nature 1987; 327:524-526. The authors demonstrated that the endothelial-derived relaxation factor (EDRF) was indeed nitric oxide. Many research publications have since defined more clearly the multiple and complex roles of NO in human, animal and plant physiology. Synthesized endogenously in humans, animals and plants, NO plays many very important physiological roles. For example, research reports have shown that NO may be effective in the treatment of sickle cell anemia.
  • [0003]
    Nitric oxide, in conjunction with ventilatory support and other appropriate agents, is used for the treatment of term and near-term (greater than 34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation. It has also been reported to be useful as a selective pulmonary vasodilator in patients with adult respiratory distress syndrome. Lack of systemic vasodilatory effects with nitric oxide is an advantage over other vasodilators (e.g., epoprostenol (prostacyclin), nitroprusside).
  • [0004]
    Among the increasing range of pathologies which can be successfully treated with gaseous NO is anal disease. Anal fissure (or fissure-in-ano), anal ulcer, acute hemorrhoidal disease, and levator spasm (proctalgia fugax) are common, benign conditions of the anal canal which affect men and women. An anal fissure or ulcer is a tear or ulcer of the mucosa or lining tissue of the distal anal canal. An anal fissure/ulcer can be associated with other systemic or local diseases, but it is more frequently present as an isolated finding. The typical, idiopathic fissure or ulcer is confined to the anal mucosa, and usually lies in the posterior midline, distal to the dentate line. The person with an anal fissure or ulcer suffers from anal pain and bleeding, more pronounced during and after bowel movements.
  • [0005]
    Hemorrhoids are specialized vascular areas lying subjacent to the anal mucosa. Symptomatic hemorrhoidal disease is manifest by bleeding, thrombosis or prolapse of the hemorrhoidal tissues. Men and women are affected. Most commonly, internal hemorrhoidal tissue bulges into the anal canal during defecation causing bleeding. As the tissue enlarges, prolapse pain, thrombosis, and bleeding can ensue. Thrombosis of internal or external hemorrhoids is another cause of pain and bleeding.
  • [0006]
    Levator spasm (or proctalgia fugax) is a condition of unknown etiology affecting women more frequently than men. This syndrome is characterized by spasticity of the levator ani muscle, a portion of the anal sphincter complex. The patient suffering from levator spasm complains of severe, episodic rectal pain. Physical exam may reveal spasm of the puborectalis muscle. Pain may be reproduced by direct pressure on this muscle. Bleeding is not associated with this condition.
  • [0007]
    The underlying causes of these problems are poorly understood. However, all of these disorders are associated with a relative or absolute degree of anal sphincter hypertonicity. In the case of anal fissure/ulcer the abnormality appears to be an as yet unidentified problem of the internal and sphincter muscle. The internal sphincter is a specialized, involuntary muscle arising from the inner circular muscular layer of the rectum. Intra-anal pressure measurements obtained from people suffering from typical anal fissure/ulcer disease show an exaggerated pressure response to a variety of stimuli. The abnormally high intra-anal pressure is generated by the internal sphincter muscle. The abnormally elevated intra-anal pressure is responsible for non-healing of the fissure/ulcer and the associated pain. U.S. Pat. No. 5,504,117 teaches methods to treat anal pathologies by the topical application of preparations that stimulate the production of endogenous nitric oxide synthase (NOS) which, in turn, causes NO to be generated in endothelial tissue and in the nervous system, by the catalytic action of NOS upon L-Argenine.
  • [0008]
    Although safe NO dosage values are at present still evolving, the Occupational Safety and Health Administration (OSHA) has set the time-weighted average inhalation limit for NO at 25 ppm for 10 hours and NOsub2 not to exceed 5 ppm. NIOSH Recommendations for Occupational Safety and Health Standards: Morbidity and Mortality Weekly Report, Vol. 37, No. S-7, p. 21 (1988). The Environmental Protection Agency (EPA) has stated that a health-based national (maximum ambient) air quality standard for NOsub2 is 0.053 ppm (measured as an annual average).
  • [0009]
    When exposed to oxygen, NO gas will, depending on environmental conditions, undergo oxidation to NOsub2, also to higher oxides of nitrogen. Gaseous nitrogen dioxide, if inhaled in sufficient concentration (for example, as little as 10 ppm for ten minutes), is toxic to lung tissue and can produce pulmonary edema and this concentration and exposure time, or more, could result in death. Standards with regard to nitrogen dioxide toxicity have not been firmly established. Nitrogen dioxide is a deep lung irritant that can produce pulmonary edema and death if inhaled at high concentrations. The effects of NOsub2 depend on the level and duration of exposure. Exposure to moderate NOsub2 levels, 50 ppm for example, may produce cough, hemoptysis, dyspnea, and chest pain. Exposure to higher concentrations of NOsub2 (greater than 100 ppm) can produce pulmonary edema, that may be fatal or may lead to bronchiolitis obliterans. Some studies suggest that chronic exposure to nitrogen dioxide may predispose to the development of chronic lung diseases, including infection and chronic obstructive pulmonary diseases.
  • [0010]
    It is common practice in therapeutic NO inhalation procedures both to monitor and also to remove NOsub2 before it can be inhaled by a subject to whom NO is being applied. For example, the NO respiratory gas mixture may be transported through a soda lime mixture to scavenge nitrogen dioxide. However, NO gas in the therapeutic concentration range (i.e. 1 ppm to as much as 100 ppm) can be administered safely, for short time periods, in dry normal air (21% oxygen) without the formation of toxic concentrations of NOsub2. Moreover, the present invention may include intra-capsular means to adsorb NOsub2.
  • [0011]
    Historically, NO gas is commercially manufactured using the Ostwald process (U.S. Pat. No. 4,774,069, U.S. Pat. No. 5,478,549) in which ammonia is catalytically converted to NO and Nitrous Oxide at a temperature above 800 degrees centigrade. This process thus involves the mass production of NO at high temperatures in an industrial setting. The therapeutic advantages of NO over other pulmonary and cardiovascular drugs have led researchers to attempt the design of an instrument that can deliver variable concentrations of NO accurately. For example, U.S. Pat. No. 5,396,882 describes a process for generating NO in an electric arc discharge in air where the electrodes are separated by an air gap in an arc chamber. The application of a high voltage across the air gap produces a localized plasma that breaks down oxygen and nitrogen molecules and generates a mixture of NO, ozone, and other NOx species. The concentration of NO in this system can be varied by adjusting the operating current. The gas mixture is then purified and mixed with air in order to obtain therapeutically significant concentrations of NO prior to administration to a patient. However, the quantification of generated NO by this system is purely empirical making the instrument extremely susceptible to the slightest fluctuations in the internal and external parameters such as ambient humidity and the surface area of the electrodes in the arc chamber.
  • [0012]
    Although inhalation of nitric oxide gas has been shown to be effective for treatment of pulmonary hypertension, there are several drawbacks and limitations of this particular mode of therapy. For example, current art therapy requires large and heavy gas tanks, expensive monitoring equipment, and a trained anesthesiologist to operate the tanks and equipment so as to deliver NO gas to a patient with safety. Therefore, NO inhalation therapy is at present limited to hospitals or similar clinical facilities. Thus there is a great needed for a more flexible, portable and less expensive means with which NO may be delivered safely in an organ specific manner without causing systemic vasodilation.
  • [0013]
    For over a century, nitroglycerin has been used as a vasodilating agent in the treatment of cardiovascular disease. Nitroglycerin, or glyceryl trinitrate, is an organic nitrate ester which when administered to a subject is converted biologically to nitric oxide by stimulating an enzyme, nitric oxide synthase (NOS), which in turn, catalyzes the production of endogenous NO from L-argenine. However, the effectiveness of nitroglycerin is greatly diminished because the recipient of therapeutic administration of nitroglycerin rapidly develops a tolerance to the beneficial effects of nitroglycerin. Therefore, onset of nitroglycerin tolerance significantly limits the therapeutic value of nitroglycerin because increased nitroglycerin dosages have little or no effect on vasorelaxation or vasodilatation. A further limitation may result from the fact that nitroglycerin is physiologically non specific. That is, vascular response to the drug will be generally distributed over the entire circulatory system.
  • [0014]
    The present invention teaches new and novel methods and means with which NO can be rapidly delivered to alveolar vascular tissue so as to bring about a rapid increase in the concentration of NO in lung and heart vascular epithelia. The effect is to cause rapid dilation of blood vessels in the lung and heart and to a considerably lesser degree, in more distal blood vessels through which blood circulates owing to the rapid absorption of NO by red blood cells.
  • [0015]
    The present invention features methods for prevention and treatment of asthma attacks and other forms of bronchial constriction, acute respiratory failure, or reversible pulmonary vasoconstriction (i.e., acute or chronic pulmonary vasoconstriction which has a reversible component). An affected subject may be identified, for example, by acute physical distress symptoms or by traditional diagnostic procedures. The subject will then inhale a therapeutically-effective concentration of gaseous nitric oxide so as to achieve therapeutic relief.
  • [0016]
    The present invention teaches methods and devices that produce NO from the inside of portable and disposable capsules containing NO under pressure and from chemical reagents which, when appropriately combined or activated, generate a controlled outflow of pure NO gas to the capsule exterior in free air. It is essential that the concentration of gas inhaled from the above mentioned capsular NO source be large enough to effect therapeutically beneficial results and at the same time not exceed a safe NO concentration maximum for gas inhalation. Both exposure time and gas concentration values together dictate what safe dosage may be.
  • [0017]
    The present invention teaches the principles of new devices and new procedures that will provide effective therapeutic application of inhaled NO during coronary and respiratory emergencies such as angina, thrombosis in heart and lung blood vessels; also hypertension in lung vasculature, as well as reversible asthma attacks.
  • [0018]
    The present invention may be better understood and its numerous objects and advantages will become apparent to those skilled in the art by reference to the accompanying drawings in which:
  • [0019]
    [0019]FIG. 1 is a schematic, cross-sectional view of a first embodiment of a NO storage and delivery system in accordance with the invention;
  • [0020]
    [0020]FIG. 2 is a schematic, cross-sectional view of a second embodiment of a NO storage and delivery system in accordance with the invention;
  • [0021]
    [0021]FIG. 3 is a schematic, cross-sectional view of a third embodiment of a NO storage and delivery system in accordance with the invention; and
  • [0022]
    [0022]FIG. 4 is a schematic, cross-sectional view of a fourth embodiment of a NO storage and delivery system in accordance with the invention.
  • [0023]
    A number of compounds have been developed that are capable of delivering nitric oxide in a pharmacologically useful way. Such compounds include compounds that release nitric oxide after being metabolized and compounds that release nitric oxide spontaneously in aqueous solutions. Compounds capable of releasing NO upon being metabolized include the widely used nitrovasodilators glyceryl trinitrate (nitroglycerin) and sodium nitroprusside (SNP). These compounds are relatively stable but they release or cause the release of NO upon activation.
  • [0024]
    Many nitric oxide-nucleophile complexes also have been described. Some of these compounds, known as NONOates, evolve nitric oxide upon heating or hydrolysis. These compounds, unlike nitroglycerin or SNP, release NO without requiring activation. NONOates have reproducible half-lives ranging from 2 seconds to 20 hours. Nitricoxide/nucleophile complexes (NONOates) that release nitric oxide in aqueous solution are disclosed in U.S. Pat. No. 5,389,675, U.S. Pat. No. 5,366,977, and U.S. Pat. No. 5,250,550. The nitric oxide-releasing functional group is R—[NONO], where R is an organic or inorganic moiety bonded to the [NONO].
  • [0025]
    NO may be generated from S-nitrosothiols (RSNO) in presence of catalyst Cu(I), as outlined in the reaction below:
  • 2RSNO→2 NO+RS−SR  (1)
  • [0026]
    The concentration of generated NO is equal to the original RSNO concentration after, the addition of the catalyst Cu(I).
  • [0027]
    NO may be generated chemically. In a first example, based on the reaction of nitrite with iodide in an acidic medium as in the reaction:
  • 2 KNO2+2 KI+2 H2SO4→2 NO+I2+2 H2O+2 K2SO4  (2)
  • [0028]
    The concentration of NO is determined by the nitrite and iodide concentrations. Ascorbic acid may be used above to replace KI as a reductant.
  • [0029]
    In a second example, at room temperature, vanadium (III) rapidly reduces nitrite to nitric oxide in an acidic solution. Vanadium (III), as a reductant is oxidized to vanadium (IV):
  • NO2−+2H++e→NO+H2O  (3)
  • [0030]
    The NO storage and delivery system 10 shown in FIG. 1 employs a gas impermeable capsule 12 as the storage vessel for a gas source 14 composed of compressed NO gas. NO gas is injected into the capsule 12 under pressure in an anaerobic environment. The internal gas-filled cavity 16 has preferably a 1 to 5 ml inner volume. Internal NO gas pressure is typically 15 to 30 psi. The capsule casing is impermeable to gas leakage.
  • [0031]
    Gas is released from the capsule 12 via an opening 18 extending through the capsule wall and an applicator sleeve 20 enclosing the opening 18 and extending outwardly from the capsule 12. Gas release can be effected, for example, by removal of a gas-tight cap 22 from the neck 24 of the applicator sleeve 20. Alternative capsule sealing methods can be easily implemented by conventional art means.
  • [0032]
    A miniature pressure controller 26 within the sleeve 20 limits the exit pressure of the stored gas so as to release NO gas at a constant pressure which is less than that of the initial internal capsule gas pressure. An outlet filter 28 downstream of the pressure controller 26 restricts the rate of gas outflow. For example, gas release pressure regulated at 5 psi would be adequate to assure constant gas outflow for periods of time which can be made to range from a few seconds to hours. The flow rate of exiting gas can be limited to a few micro liters per minute. Prior to use, the capsule 12 is stored in a sterile bag that is gas and moisture impermeable to prevent environmental and bacterial infiltration.
  • [0033]
    As an alternative to charging the capsule 12 from an external pressurized NO gas source, the NO gas source 14 can be a NO bearing polymer. The polymer material is sealed within the capsule cavity 16 and slowly decomposes to release the NO gas stored therein, and thus constitutes the intra capsular NO gas supply 14. The polymer material, is initially loaded into the capsule 12 in an oxygen-free environment. If NONOate is to be the NO source 14, de-aerated water must be applied to initiate NO release.
  • [0034]
    [0034]FIG. 2 illustrates a second embodiment of the system 10′ having a NO gas source 30 in which NO gas is created by activation of stored chemical reagents 32, 34. Capsule 36 is flexible and gas impermeable. The gas source 30 comprises stored reagents 32 and 34, which are physically isolated by a breakable divider 38, for example a glass tube, containing reagent 32. Bending capsule 38 breaks reagent vessel 38 causing chemical reagents 32 and 34 to mix, resulting in the rapid formation of NO gas within the capsule 36. The known stoichiometry of the chemical reaction and the volume of the capsule interior allows accurate prediction of the resulting intra capsular NO gas pressure. A single example of several feasible chemical reactions is illustrated in equation (1) above. In this example, reagent 32 is a solution of potassium nitrite and reagent 34 is a mixture of potassium iodide and sufric acid.
  • [0035]
    Compressed NO gas flows out of the capsule 36 via a check valve 40 comprised, for example, by a ball 42 and spring 44. The outflow filter 46 controls the gas outflow rate and also filters water vapor from the fluid reagents in the capsule 36. The filter 46 may be treated with a nitrogen dioxide adsorbent so as to insure that, if present, virtually no nitrogen dioxide will be present in the generated gas. Prior to use, the capsule 36 is stored in a sterile bag that is gas and moisture impermeable to prevent environmental and bacterial infiltration.
  • [0036]
    The embodiment 10″ shown in FIG. 3 is similar in form and function to the embodiment 10′ of FIG. 2 except that outlet filter 46 of FIG. 2 is replaced by a NO gas permeable capped tube 48 which delivers a diffuse gentle flow of NO into the nostrils or, alternatively, other body cavities of subject humans or animals for therapeutic effect. Internal tubular gas pressure and the gas permeability of the capped tube 48 both determine the rate of the resulting NO gas outflow. Prior to use, the capsule 36 is stored in a sterile bag that is gas and moisture impermeable to prevent environmental and bacterial infiltration.
  • [0037]
    The embodiment 10′″ illustrated in FIG. 4 has an ovoid or lozenge shaped capsule 50. The capsule 50 is impermeable to acid or water or other interior reagents 32, 34 employed therein. The capsule 50 is also NO gas permeable and flexible. Active chemical reagents 32′ and 34′ are similar in function to reagents 32 and 34 of FIG. 2. Reagent 32′ is contained in a breakable compartment 38′ or tube as in FIG. 2. In use, the capsule 50 is activated by applying sufficient force to break the reagents tube 38′ which initiates a NO gas producing reaction as discussed above. After activation, the capsule 50 may be lubricated with a gas permeable fluid 52 such as silicone and gently inserted into the appropriate body cavity of a subject requiring NO gas therapy as discussed above. Upon completion of the NO treatment, the capsule 50 may be withdrawn by using the attached cord 54. For respiratory therapy, the capsule 50 may be held under the nostrils for the duration of the treatment. Prior to use, the capsule 50 is stored in sterile bags that are gas and moisture impermeable to prevent environmental or bacterial infiltration and possible contamination.
  • [0038]
    It should be appreciated that by using a system 10, 10′, 10″, 10′″ in accordance with the invention, pure NO gas is generated for inhalation proximal to or within the nostrils of the subject and transported to the lungs by the tidal action of the subject's respiration.
  • [0039]
    The concentration of nitric oxide gas is diluted by the respiratory tidal volume of the user. Consequently, the user's own respiration performs the dual function of transporting and diluting the NO gas. Moreover, negligible nitrogen dioxide formation occurs within the time interval in which NO gas is transported by the respiratory tidal volume to the lung alveoli. Theoretical analysis and experimental results indicate the NO2 concentration is much less than 1 ppm for the time periods used by the inventive methods of the present invention. It should also be appreciated that the subject system 10, 10′, 10″, 10′″ does not require an expensive and complex gas mixing and delivery system because the subject's own respiration safely delivers NO gas at low ppm concentration levels to the subject's lungs. It should further be appreciated that the subject system 10, 10′, 10″, 10′″ does not utilize industrial NO gas tanks, which are expensive, heavy and potentially dangerous.
  • [0040]
    The above disclosed embodiments are generally single use systems with the amount of pressurized NO gas or reagents sized accordingly. It should be appreciated that once the reagents of embodiments 10′, 10″, and 10′″ are mixed together, the resulting reaction will continue to completion. Further, the absence of a gas-tight cap 22 on the applicator sleeve of the second embodiment 10′ and the permeable nature of the capped tube 48 of the third embodiment 10″, and the capsule 50 of the fourth embodiment 10′″, preclude retention of the NO gas within the capsule 36, 36′, 50 after the reagents 32, 32′, 34, 34′ have been mixed. While it is possible that the gas-tight cap 22 of the first embodiment 10 may be replaced before all of the pressurized NO gas is dispensed through the applicator sleeve 20, the escaping NO gas will interfere with such replacement and there is no way of assuring that the remaining amount of NO gas will be therapeutically useful.
  • [0041]
    While preferred embodiments have been shown and described, various modifications and substitutions may be made thereto without departing from the spirit and scope of the invention. Accordingly, it is to be understood that the present invention has been described by way of illustration and not limitation.
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US7827983Nov 9, 2010Hewlett-Packard Development Company, L.P.Method for making a pharmaceutically active ingredient abuse-prevention device
US8434475 *May 7, 2013Genosys, Inc.Nitric oxide reactor and distributor apparatus and method
US8647680 *May 27, 2010Feb 11, 2014Abbott Cardiovascular Systems Inc.Methods and compositions for treatment of lesioned sites of body vessels
US8790715Feb 16, 2006Jul 29, 2014Ino Therapeutics LlcMethod and apparatus for generating nitric oxide for medical use
US9278111Jun 18, 2014Mar 8, 2016Ino Therapeutics LlcMethod and apparatus for generating nitric oxide for medical use
US20060130828 *Dec 20, 2004Jun 22, 2006Sexton Douglas AMethod for making a pharmaceutically active ingredient abuse-prevention device
US20070190184 *Feb 16, 2006Aug 16, 2007Ino Therapeutics LlcMethod and apparatus for generating nitric oxide for medical use
US20100018526 *Jan 28, 2009Jan 28, 2010Miller Randy JNitric oxide reactor and distributor apparatus and method
US20100233263 *Sep 16, 2010Florian Niklas LudwigMethods and compositions for treatment of lesioned sites of body vessels
US20160136376 *Jan 27, 2016May 19, 2016Ino Therapeutics LlcMethod and apparatus for generating nitric oxide for medical use
EP1984052A1 *Jan 25, 2007Oct 29, 2008INO Therapeutics LLCMethod and apparatus for generating nitric oxide for medical use
EP1984052A4 *Jan 25, 2007Mar 21, 2012Ino Therapeutics LlcMethod and apparatus for generating nitric oxide for medical use
U.S. Classification424/45, 128/200.23, 424/718
International ClassificationA61M15/00, A61M15/08
Cooperative ClassificationY10S514/958, A61M2202/0275, A61M2205/8225, A61M15/08, A61M15/0025
European ClassificationA61M15/08