Abstract:
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.

Description:
BACKGROUND OF THE INVENTION  
         [0001]    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.  
           [0002]    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).  
           [0003]    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.  
           [0004]    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.  
           [0005]    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.  
           [0006]    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.  
           [0007]    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).  
           [0008]    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.  
           [0009]    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.  
           [0010]    Historically, NO gas is commercially manufactured using the Ostwald process (U.S. Pat. Nos. 4,774,069, 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.  
           [0011]    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.  
           [0012]    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.  
         SUMMARY OF THE INVENTION  
         [0013]    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.  
           [0014]    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.  
           [0015]    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.  
           [0016]    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. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0017]    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:  
         [0018]    [0018]FIG. 1 is a schematic, cross-sectional view of a first embodiment of a NO storage and delivery system in accordance with the invention;  
         [0019]    [0019]FIG. 2 is a schematic, cross-sectional view of a second embodiment of a NO storage and delivery system in accordance with the invention;  
         [0020]    [0020]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  
         [0021]    [0021]FIG. 4 is a schematic, cross-sectional view of a fourth embodiment of a NO storage and delivery system in accordance with the invention. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0022]    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.  
         [0023]    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. Nos. 5,389,675, 5,366, 977, and 5,250, 550. The nitric oxide-releasing functional group is R-[NONO], where R is an organic or inorganic moiety bonded to the [NONO].  
         [0024]    NO may be generated from S-nitrosothiols (RSNO) in presence of catalyst Cu(1), as outlined in the reaction below:  
         2RSN0→2NO+RS−SR  (1)  
         [0025]    The concentration of generated NO is equal to the original RSNO concentration after the addition of the catalyst Cu(I).  
         [0026]    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:  
         2KNO 2 +2KI+2H 2 SO 4 →2NO+I 2 +2H 2 O+2K 2 SO 4   (2)  
         [0027]    The concentration of NO is determined by the nitrite and iodide concentrations. Ascorbic acid may be used above to replace KI as a reductant.  
         [0028]    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):  
         NO 2 —+2H +   +e →NO+H 2 O  (3)  
         [0029]    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.  
         [0030]    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.  
         [0031]    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.  
         [0032]    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.  
         [0033]    [0033]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.  
         [0034]    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.  
         [0035]    The embodiment  10 ″ shown is 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.  
         [0036]    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.  
         [0037]    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&#39;s respiration. The concentration of nitric oxide gas is diluted by the respiratory tidal volume of the user. Consequently, the user&#39;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 NO 2  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&#39;s own respiration safely delivers NO gas at low ppm concentration levels to the subject&#39;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.  
         [0038]    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.  
         [0039]    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.