Method and device for pulsating delivery of nitric oxide

Abstract

Methods are described for providing a pulsatile dose of nitric oxide during at least the first two-thirds of the total inspiratory time in each single breath over a therapeutically relevant time period.

Description

Technical Field

[0001] The present application relates generally to devices and methods for administering nitric oxide, and more particularly to pulsatile delivery of nitric oxide to patients in need of therapeutic treatment.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This International PCT Application claims the benefit of U.S. Provisional Application No. 62 / 672,867, filed May 17, 2018, the entire contents of which are incorporated herein by reference. Background Art

[0004] Nitric oxide (NO) is a gas that, when inhaled, acts to dilate blood vessels in the lungs, thereby improving oxygenation of the blood and reducing pulmonary hypertension. Therefore, nitric oxide is provided as a therapeutic gas during the inspiratory breathing phase for patients experiencing shortness of breath (dyspnea) due to disease states such as pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), pulmonary fibrosis with emphysema (CPFE), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), emphysema, interstitial lung disease (ILD), chronic thromboembolic pulmonary hypertension (CTEPH), chronic mountain sickness, or other lung diseases.

[0005] While NO can be therapeutically effective when administered under the appropriate conditions, it can also become toxic if not administered correctly. NO reacts with oxygen to form nitrogen dioxide (NO2), and NO2 can be formed when oxygen or air is present in the nitric oxide delivery tube. NO2 is a toxic gas that can cause numerous side effects, and the Occupational Safety and Health Administration (OSHA) has established a permissible exposure limit of only 5 ppm for general industry. Therefore, it is desirable to limit exposure to NO2 during nitric oxide therapy.

[0006] Effective dosing of NO is based on many different variables, including the amount of drug and the timing of administration. Several patents have been issued related to NO delivery, including U.S. Patent Nos. 7,523,752; 8,757,148; 8,770,199; and 8,803,717, as well as Design Patent D701,963 for the design of a nitric oxide delivery device, all of which are incorporated herein by reference. Additionally, there are pending applications related to the delivery of nitric oxide, including US2013 / 0239963 and US2016 / 0106949, both of which are also incorporated herein by reference. Even in light of these patents and pending disclosures, there remains a need for methods and devices for delivering NO in a precise, controlled manner in order to maximize the benefits of a therapeutic dose and minimize potential harmful side effects. Summary of the Invention

[0007] In one embodiment of the present invention, a method of administering a dose of nitric oxide is described. In one embodiment of the present invention, at least a single pulsatile dose is administered to a patient and is therapeutically effective for treating or alleviating a symptom of a lung disease. In one embodiment of the present invention, the sum of two or more pulsatile doses is therapeutically effective for treating or alleviating a symptom of a lung disease.

[0008] In one embodiment of the invention, nitric oxide is delivered periodically over a minimum of five minutes per day to a period of twenty-four hours per day. In one embodiment of the invention, nitric oxide can be delivered at the convenience of the patient, for example, during a period of time while sleeping. In one embodiment of the invention, the pulsatile delivery of nitric oxide can be spaced evenly or unevenly over a period of time (e.g., ten minutes, one hour, or twenty-four hours). In another embodiment, the delivery of a therapeutically effective dose of nitric oxide can be continuous over a fixed time period.

[0009] In one embodiment, a method includes detecting a patient's breathing pattern. In one embodiment of the invention, the breathing pattern includes total inspiratory time (e.g., the duration of a single inspiration of the patient). In one embodiment of the invention, the breathing pattern is detected using an apparatus including a respiratory sensitivity control. In one embodiment of the invention, the breathing pattern is associated with an algorithm to calculate the timing of administering a dose of nitric oxide. In one embodiment of the invention, a volume of nitric oxide including gas necessary to administer the amount of nitric oxide is calculated on a per-pulsation basis. In one embodiment, nitric oxide is delivered to the patient in a pulsatile manner over a portion of the total inspiratory time.

[0010] In one embodiment of the present invention, the dose of nitric oxide is delivered to the patient within a time period sufficient to deliver a therapeutic dose of nitric oxide to the patient. In one embodiment of the present invention, the device calculates a total time sufficient to deliver a therapeutic dose of nitric oxide to the patient. In one embodiment of the present invention, the total time required to deliver the therapeutic dose of nitric oxide to the patient depends at least in part on the patient's breathing pattern.

[0011] In one embodiment of the invention, nitric oxide is delivered during the first third of the total inspiratory time. In one embodiment, nitric oxide is delivered during the first half of the total inspiratory time. In one embodiment, nitric oxide is delivered during the first two thirds of the total inspiratory time.

[0012] In one embodiment of the present invention, at least fifty percent (50%) of the nitric oxide dose is delivered to the patient during the first one third of the total inspiratory time. In one embodiment of the present invention, at least seventy percent (70%) of the nitric oxide dose is delivered to the patient during the first half of the total inspiratory time. In one embodiment, at least ninety percent (90%) of the nitric oxide dose is delivered to the patient during the first two thirds of the total inspiratory time. In one embodiment of the present invention, at least ninety percent (90%) of the nitric oxide dose is delivered to the patient during the first one third of the total inspiratory time. In one embodiment of the present invention, the entire nitric oxide dose is delivered to the patient during the first half of the total inspiratory time.

[0013] In one embodiment of the present invention, the respiration sensitivity control of the device is adjustable. In one embodiment of the present invention, the respiration sensitivity control is fixed. In one embodiment of the present invention, the respiration sensitivity control is adjustable from a least sensitive range to a most sensitive range, whereby the most sensitive setting is more sensitive in detecting respiration than the least sensitive setting.

[0014] In one embodiment of the invention, a method of treating or alleviating the symptoms of a cardiopulmonary disease is described. In one embodiment of the invention, the method comprises detecting a patient's breathing pattern using an apparatus comprising a respiratory sensitivity control. In one embodiment of the invention, the breathing pattern comprises a measurement of total inspiratory time. In one embodiment of the invention, the breathing pattern is associated with an algorithm to calculate the timing of administering a dose of nitric oxide. In one embodiment of the invention, at least fifty percent (50%) of the nitric oxide dose is delivered within the first one-third of the total inspiratory time. In one embodiment of the invention, at least seventy percent (70%) of the nitric oxide dose is delivered to the patient within the first half of the total inspiratory time. In one embodiment of the invention, at least ninety percent (90%) of the nitric oxide dose is delivered within the first two-thirds of the total inspiratory time.

[0015] In one embodiment of the invention, the device calculates the total time required to deliver a therapeutically effective amount of nitric oxide to the patient. In one embodiment of the invention, the total time required to deliver a therapeutically effective amount of nitric oxide depends on one or more of the breathing pattern, the concentration of nitric oxide in the gas to be delivered to the patient, the volume of the pulsed dose, and the duration of the pulse.

[0016] In one embodiment of the present invention, the pulmonary disease is selected from idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PAH), chronic obstructive pulmonary disease (COPD), pulmonary fibrosis with emphysema (CPFE), cystic fibrosis (CF), emphysema, interstitial lung disease (ILD), chronic thromboembolic pulmonary hypertension (CTEPH), chronic high altitude sickness or other pulmonary diseases. In one embodiment of the present invention, the cardiopulmonary disease is pulmonary hypertension associated with other pulmonary diseases such as Group IV pulmonary hypertension (PH).

[0017] In one embodiment of the present invention, a programmable device for delivering a dose of nitric oxide is described. In one embodiment of the present invention, the device includes a nasal delivery portion, a cartridge containing nitric oxide, an oxygen source, a breath sensitivity portion that detects the patient's breathing pattern, a breath detection algorithm for determining the dose of nitric oxide delivered to the patient, and a portion for administering the dose of nitric oxide to the patient through a series of pulsations associated with the inspiratory portion of the breathing pattern. In one embodiment of the present invention, the breath sensitivity portion of the device includes an adjustable or fixed breath sensitivity setting. In one embodiment of the present invention, the nasal delivery portion is a nasal cannula, a mask, a nebulizer, or a nasal inhaler. In one embodiment of the present invention, the breath detection algorithm uses a threshold sensitivity and a slope algorithm. In one embodiment of the present invention, the slope algorithm counts detected breaths when the rate of pressure drop reaches a threshold level.

[0018] Various embodiments are listed above and will be described in more detail below. It should be understood that the listed embodiments can be combined not only as listed below, but also in other combinations according to the scope of the present invention.

[0019] The foregoing has generally outlined certain features and technical advantages of the present invention. Those skilled in the art will appreciate that the specific embodiments disclosed may readily serve as a basis for modifying or designing other structures or processes within the scope of the present invention. Those skilled in the art will further appreciate that such equivalent constructions do not depart from the spirit and scope of the present invention as set forth in the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings.

[0021] A more particular description of the invention, having been briefly summarized above, will enable the above features of the invention to be understood in detail, with reference to embodiments thereof, some of which are illustrated in the accompanying drawings. It should be noted, however, that the drawings illustrate only typical embodiments of the invention and are therefore not to be considered limiting of the scope of the invention, for the invention may admit to other equally effective embodiments.

[0022] Figure 1 is a graph representing a single measurement of respiration.

[0023] Figure 2 is a graph showing the measurement of pulsation of nitric oxide delivered to a patient in accordance with the present invention.

[0024] Figure 3 Graph showing breath detection as a percentage of nitric oxide delivery during the total inspiratory time. The dotted line represents eight-tenths of the breath sensitivity setting in Example 1 (e.g., 80% of maximum sensitivity), the solid line represents ten-tenths of the breath sensitivity setting in Example 1 (e.g., maximum sensitivity), and the dashed line represents the fixed breath sensitivity setting of 10 in Example 2. The dashed line indicates that approximately 93% of the nitric oxide dose is delivered during the first 33% (or first third) of the total inspiratory time, and 100% of the nitric oxide dose is delivered during the first 50% (or first half) of the total inspiratory time. The solid line indicates that approximately 62% of the nitric oxide dose is delivered during the first 33% (or first third) of the total inspiratory time, approximately 98% is delivered during the first 50% (or first half) of the total inspiratory time, and 100% is delivered during the first 67% (or first two-thirds) of the total inspiratory time. The dotted line indicates that approximately 17% of the nitric oxide dose is delivered during the first 33% (or first third) of the total inspiratory time, approximately 72% is delivered during the first 50% (or first half) of the total inspiratory time, and approximately 95% is delivered during the first 67% (or first two thirds) of the total inspiratory time.

[0025] Figure 4 depiction Figure 3 The combined results described in .

[0026] Figure 5A and 5B Depicts the algorithm used for breath detection and nitric oxide delivery. Figure 5A Indicates the threshold algorithm. Figure 5B Indicates the slope algorithm. DETAILED DESCRIPTION

[0027] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference in their entirety.

[0028] Before describing several exemplary embodiments of the present invention, it should be understood that the present invention is not limited to the details of construction or process steps set forth in the following description. The present invention is capable of other embodiments and can be practiced or carried out in various ways.

[0029] Throughout this specification, references to "one embodiment," "some embodiments," "one or more embodiments," or "an embodiment" mean that a particular feature, structure, material, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearance of phrases such as "in one or more embodiments," "in some embodiments," "in an embodiment," or "in an embodiment" throughout this specification are not necessarily referring to the same embodiment of the present invention. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments.

[0030] Although the present invention has been described herein with reference to specific embodiments, it should be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It will be apparent to those skilled in the art that various modifications and variations may be made to the methods and apparatus of the present invention without departing from the spirit and scope of the present invention. Therefore, the present invention is intended to include modifications and variations within the scope of the appended claims and their equivalents.

[0031] definition

[0032] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or combination of compounds as described herein that is sufficient to achieve the intended application, including but not limited to disease treatment. The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo) or the subject and disease condition being treated (e.g., the subject's weight, age, and sex), the severity of the disease condition, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The term also applies to a dose that will induce a specific response in the target cell (e.g., a decrease in platelet adhesion and / or cell migration). The specific dose will vary depending on the specific compound selected, the dosage regimen followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system carrying the compound.

[0033] As used herein, the term "therapeutic effect" includes therapeutic benefit and / or prophylactic benefit. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof.

[0034] The disease state of "interstitial lung disease" or "ILD" shall include all subtypes of ILD, including but not limited to idiopathic interstitial pneumonia (IIP), chronic hypersensitivity pneumonitis, occupational or environmental lung disease, idiopathic pulmonary fibrosis (IPF), non-IPF IIP, granulomatous degeneration (e.g., sarcoidosis), connective tissue disease-associated ILD, and other forms of ILD.

[0035] When ranges are used herein to describe an aspect of the invention, such as dosage ranges, amounts of components of a formulation, and the like, all combinations and subcombinations of ranges and specific embodiments thereof are intended to be included. When referring to a number or a numerical range, the use of the term "about" means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and therefore the number or numerical range may vary. This variation is typically 0% to 15%, preferably 0% to 10%, and more preferably 0% to 5% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes those embodiments, such as, for example, embodiments of any composition of matter, method, or process that "consists of" or "essentially consists of" the stated features.

[0036] For the avoidance of doubt, unless incompatible therewith, it is intended that a particular feature (such as an integer, characteristic, value, use, disease, chemical formula, compound or group) described in conjunction with a particular aspect, embodiment or example of the invention be understood to be applicable to any other aspect, embodiment or example described herein. Therefore, such features may be used in conjunction with any definition, claim or embodiment defined herein, where appropriate. All features disclosed in this specification (including any accompanying claims, abstract and drawings) and / or all steps of any method or process so disclosed may be combined in any combination, except combinations in which at least some of the features and / or steps are mutually exclusive. The invention is not limited to any details of any disclosed embodiment. The invention extends to any novel feature or novel combination of features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel step or any novel combination of steps of any method or process so disclosed.

[0037] About the present invention, in certain embodiments, during patient's inspiration, a certain dose of gas (such as NO) is given to the patient in a pulsatile form. It has been surprisingly found that nitric oxide delivery can be accurately and precisely delivered within the first two-thirds of the total respiratory inspiration time, and the patient obtains benefits from this delivery. This delivery minimizes the risk of loss and harmful side effects of the drug product, increases the efficacy of the pulsatile dose, which in turn leads to the need to give the patient in order to effectively reduce the total amount of NO. This delivery can be used to treat various diseases, such as but not limited to idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), including IV group pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD), pulmonary fibrosis combined with emphysema (CPFE), cystic fibrosis (CF), emphysema, interstitial lung disease (ILD), chronic thromboembolic pulmonary hypertension (CTEPH), chronic altitude sickness or other lung diseases, and can also be used as, for example, an antimicrobial agent in the treatment of pneumonia.

[0038] This precision has the further advantage that only certain poorly ventilated lung regions are exposed to NO. Problems with hypoxia and hemoglobin levels can also be reduced with this pulsatile delivery, and NO2 exposure is more limited.

[0039] The device of the present invention

[0040] In certain embodiments, the present invention includes a device, such as a programmable device for delivering a dose of gas, such as nitric oxide, to a patient in need thereof. The device may include a delivery portion, a cartridge comprising a compressed gas for delivery to the patient, a breathing sensitivity portion for detecting the patient's breathing pattern including a breathing sensitivity setting, at least one breath detection algorithm for determining when to administer the compressed gas to the patient, and a portion for administering the dose of nitric oxide to the patient via a series of one or more pulses.

[0041] In certain embodiments, the cartridge is replaceable.

[0042] In some embodiments, the delivery portion comprises one or more of a nasal cannula, a mask, a nebulizer, and a nasal inhaler. In some embodiments, the delivery portion may further comprise a second delivery portion to allow for simultaneous administration of one or more other gases (e.g., oxygen) to the patient.

[0043] In certain embodiments, and as detailed elsewhere herein, the device includes an algorithm, wherein the algorithm uses one or both of a threshold sensitivity and a slope algorithm, wherein the slope algorithm detects respiration when the rate of pressure drop reaches a predetermined threshold.

[0044] In one embodiment of the present invention, pulsed dosing of gas can mechanically reduce, if not eliminate, the Venturi effect that can often be problematic for other gas sensors. For example, without the pulsed dosing of the present invention, an O2 backpressure sensor can override the delivery of O2 when O2 is administered simultaneously with another gas, such as NO.

[0045] Breathing patterns, detection, and triggering

[0046] Breathing patterns vary based on the individual, time of day, activity level, and other variables; therefore, it is difficult to predetermine an individual's breathing pattern. A delivery system that delivers a therapeutic agent to a patient based on breathing patterns should be able to handle a range of potential breathing patterns in order to be effective.

[0047] In certain embodiments, the patient or individual can be of any age, however, in still certain embodiments, the patient is sixteen years of age or older.

[0048] In one embodiment of the present invention, the breathing pattern includes a measure of total inspiratory time, which, as used herein, is determined for a single breath. However, depending on the context, "total inspiratory time" may also refer to the sum of all inspiratory times for all detected breaths during treatment. The total inspiratory time may be observed or calculated. In another embodiment, the total inspiratory time is a validation time based on a simulated breathing pattern.

[0049] In one embodiment of the invention, respiration detection comprises at least one, and in some embodiments at least two, separate triggers acting together, namely a respiration level trigger and / or a respiration slope trigger.

[0050] In one embodiment of the present invention, a respiration level trigger algorithm is used for respiration detection. When a threshold level of pressure (e.g., a threshold negative pressure) is reached during inspiration, the respiration level trigger detects respiration.

[0051] In one embodiment of the present invention, a breath slope trigger detects a breath when the slope of the pressure waveform indicates inspiration. In some cases, a breath slope trigger is more accurate than a threshold trigger, particularly when used to detect short, shallow breaths.

[0052] In one embodiment of the present invention, the combination of these two triggers provides a more accurate breath detection system overall, particularly when multiple therapeutic gases are being administered to a patient simultaneously.

[0053] In one embodiment of the invention, the respiration sensitivity control for detecting either respiration level and / or respiration slope is fixed. In one embodiment of the invention, the respiration sensitivity control for detecting either respiration level or respiration slope is adjustable or programmable. In one embodiment of the invention, the respiration sensitivity control for detecting either respiration level and / or respiration slope is adjustable from a least sensitive to a most sensitive setting, whereby the most sensitive setting is more sensitive in detecting respiration than the least sensitive setting.

[0054] In certain embodiments where at least two triggers are used, the sensitivity of each trigger is set at different relative levels. In one embodiment where at least two triggers are used, one trigger is set to maximum sensitivity while the other trigger is set to less than maximum sensitivity. In one embodiment where at least two triggers are used and one of the triggers is a respiration level trigger, the respiration level trigger is set to maximum sensitivity.

[0055] Often, not every inhalation / exhalation of a patient is detected and then classified as an inhalation / exhalation event for administering a pulse of gas (e.g., NO). Errors in detection can occur, particularly when multiple gases are administered to a patient simultaneously, such as in combination nitric oxide and oxygen therapy.

[0056] Embodiments of the present invention, and particularly embodiments incorporating a respiration slope trigger, alone or in combination with another trigger, can maximize the correct detection of inspiratory events, thereby maximizing the effectiveness and efficiency of therapy, while also minimizing waste due to false identification or errors in timing.

[0057] In some embodiments, greater than 50% of the total number of inhalations of the patient within the time frame used for gas delivery to the patient are detected. In some embodiments, greater than 75% of the total number of inhalations of the patient are detected. In some embodiments, greater than 90% of the total number of inhalations of the patient are detected. In some embodiments, greater than 95% of the total number of inhalations of the patient are detected. In some embodiments, greater than 98% of the total number of inhalations of the patient are detected. In some embodiments, greater than 99% of the total number of inhalations of the patient are detected. In some embodiments, between 75% and 100% of the total number of inhalations of the patient are detected.

[0058] Dosage and administration schedule

[0059] In one embodiment of the invention, the nitric oxide delivered to the patient is formulated at a concentration of about 3 to about 18 mg NO per liter, about 6 to about 10 mg NO per liter, about 3 mg NO per liter, about 6 mg NO per liter, or about 18 mg NO per liter. NO can be administered alone or in combination with alternative gas therapy. In certain embodiments, oxygen (e.g., concentrated oxygen) can be administered to the patient in combination with nitric oxide.

[0060] In one embodiment of the invention, the volume of nitric oxide is administered in an amount of about 0.350 mL to about 7.5 mL per breath (e.g., in a single pulse). In some embodiments, the volume of nitric oxide in each pulse dose can be the same during the course of a single treatment session. In some embodiments, the volume of nitric oxide in some pulse doses can be different during a single time period of gas delivery to the patient. In some embodiments, the volume of nitric oxide in each pulse dose can be adjusted during the course of a single time period of gas delivery to the patient as the breathing pattern is monitored. In one embodiment of the invention, the amount of nitric oxide delivered to a patient on a per-pulse basis ("pulse dose") (in ng) to treat or alleviate the symptoms of a lung disease is calculated as follows and rounded to the nearest nanogram:

[0061] Dose μg / kg-IBW / hr × ideal body weight in kg (kg-IBW) × ((1 hr / 60 min) / (respiratory rate in bpm)) × 1,000 ng / μg.

[0062] As an example, patient A, with an ideal body weight of 75 kg, has a respiratory rate of 20 breaths per minute (or 1200 breaths per hour) at a dose of 100 μg / kg IBW / hr:

[0063] 100 μg / kg-IBW / hr × 75 kg × (1 hr / 1200 breaths) × 1,000 ng / μg = 6250 ng per pulse

[0064] In certain embodiments, the 60 / respiratory rate (ms) variable may also be referred to as dose event time. In another embodiment of the invention, the dose event time is 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, or 10 seconds.

[0065] In one embodiment of the invention, a single pulsatile dose provides a therapeutic effect (e.g., a therapeutically effective amount of NO) to the patient. In another embodiment of the invention, the sum of two or more pulsatile doses provides a therapeutic effect (e.g., a therapeutically effective amount of NO) to the patient.

[0066] In one embodiment of the invention, at least about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 400, about 410, about 420, about 430, about 440, about 450, about 460, about 470, about 480, about 490, about 500, about 510, about 520, about 530, about 540, about 550, about 560, about 570, about 580, about 590, about 600, about 625, about 650, about 675, about 700, about 750, about 800, about 850, about 900, about 950, or about 1000 pulses of nitric oxide are administered to the patient every hour.

[0067] In one embodiment of the invention, the nitric oxide therapy course occurs over a timeframe, In one embodiment, the timeframe is at least about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, or about 24 hours per day.

[0068] In one embodiment of the invention, nitric oxide treatment is given within the time range of minimum treatment process. In one embodiment of the invention, minimum treatment process is about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes or about 90 minutes. In one embodiment of the invention, minimum treatment process is about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours or about 24 hours. In one embodiment of the invention, the minimum treatment course is about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, or about 8 weeks, or about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 18, or about 24 months.

[0069] In one embodiment of the invention, a course of nitric oxide treatment is administered once or more per day. In one embodiment of the invention, a course of nitric oxide treatment can be administered once, twice, three times, four times, five times, six times, or more than six times per day. In one embodiment of the invention, a course of treatment can be administered monthly, biweekly, weekly, every other day, daily, or multiple times per day.

[0070] Timing of NO pulsation

[0071] In one embodiment of the invention, the breathing pattern is correlated with an algorithm to calculate the timing of administration of the dose of nitric oxide.

[0072] Accurate detection of inhalation / inspiration events also enables timing of gas (eg, NO) pulses to maximize their efficacy by administering the gas within a specified time range of the total inspiratory time of a single detected breath.

[0073] In one embodiment of the present invention, at least fifty percent (50%) of the pulsatile dose of gas is delivered within the first third of the total inspiratory time for each breath. In one embodiment of the present invention, at least sixty percent (60%) of the pulsatile dose of gas is delivered within the first third of the total inspiratory time. In one embodiment of the present invention, at least seventy-five percent (75%) of the pulsatile dose of gas is delivered within the first third of the total inspiratory time for each breath. In one embodiment of the present invention, at least eighty-five percent (85%) of the pulsatile dose of gas is delivered within the first third of the total inspiratory time for each breath. In one embodiment of the present invention, at least ninety percent (90%) of the pulsatile dose of gas is delivered within the first third of the total inspiratory time. In one embodiment of the present invention, at least ninety-two percent (92%) of the pulsatile dose of gas is delivered within the first third of the total inspiratory time. In one embodiment of the present invention, at least ninety-five percent (95%) of the pulsatile dose of gas is delivered within the first third of the total inspiratory time. In one embodiment of the present invention, at least ninety-nine percent (99%) of the pulsatile dose of gas is delivered within the first third of the total inspiratory time. In one embodiment of the invention, 90% to 100% of the pulsed dose of gas is delivered within the first third of the total inspiratory time.

[0074] In one embodiment of the present invention, at least seventy percent (70%) of the pulsatile dose is delivered to the patient within the first half of the total inspiratory time. In another embodiment, at least seventy-five percent (75%) of the pulsatile dose is delivered to the patient within the first half of the total inspiratory time. In one embodiment of the present invention, at least eighty percent (80%) of the pulsatile dose is delivered to the patient within the first half of the total inspiratory time. In one embodiment of the present invention, at least ninety percent (90%) of the pulsatile dose is delivered to the patient within the first half of the total inspiratory time. In one embodiment of the present invention, at least ninety-five percent (95%) of the pulsatile dose is delivered to the patient within the first half of the total inspiratory time. In one embodiment of the present invention, between 95% and 100% of the pulsatile dose of gas is delivered within the first half of the total inspiratory time.

[0075] In one embodiment of the invention, at least ninety percent (90%) of the pulsatile dose is delivered within the first two thirds of the total inspiratory time. In one embodiment of the invention, at least ninety five percent (95%) of the pulsatile dose is delivered within the first two thirds of the total inspiratory time. In one embodiment of the invention, between 95% and 100% of the pulsatile dose is delivered within the first two thirds of the total inspiratory time.

[0076] When combined, multiple pulsatile doses administered over a treatment session / timeframe may also meet the above ranges. For example, when combined, greater than 95% of all pulsatile doses administered during a treatment session may be administered within the first two-thirds of all inspiratory times for all detected breaths. In a more precise embodiment, greater than 95% of all pulsatile doses administered during a treatment session may be administered within the first one-third of all inspiratory times for all detected breaths, when combined.

[0077] Taking into account the high accuracy of the detection method of the present invention, the pulsatile dose can be administered during any specified time window of inspiration. For example, the pulsatile dose can be administered with the first third, middle third or last third of the patient's inspiration as the target. Alternatively, the first half or the second half of the inspiration can be targeted for the pulsatile dose administration. In addition, the target of administration can vary. In one embodiment, the first third of the inspiratory time can be targeted at one or a series of inspirations, wherein the second third or the second half can be targeted at one or a series of subsequent inspirations during the same or different treatment courses. Alternatively, after the first quarter of the inspiratory time has passed, the pulsatile dose begins and continues to the middle half (the next two quarters), and can be targeted so that the pulsatile dose ends at the beginning of the last quarter of the inspiratory time. In some embodiments, the pulse may be delayed by 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, or 750 milliseconds (ms), or a range from about 50 to about 750 ms, from about 50 to about 75 ms, from about 100 to about 750 ms, or from about 200 to about 500 ms.

[0078] Utilizing pulsed dosing during inhalation reduces exposure of hypoventilated lung regions and alveoli to pulsed doses of gas (e.g., NO). In one embodiment, less than 5% of hypoventilated lung regions (a) or alveoli (b) are exposed to NO. In one embodiment, less than 10% of hypoventilated lung regions (a) or alveoli (b) are exposed to NO. In one embodiment, less than 15% of hypoventilated lung regions (a) or alveoli (b) are exposed to NO. In one embodiment, less than 20% of hypoventilated lung regions (a) or alveoli (b) are exposed to NO. In one embodiment, less than 25% of hypoventilated lung regions (a) or alveoli (b) are exposed to NO. In one embodiment, less than 30% of hypoventilated lung regions (a) or alveoli (b) are exposed to NO. In one embodiment, less than 50% of hypoventilated lung regions (a) or alveoli (b) are exposed to NO. In one embodiment, less than 60% of hypoventilated lung regions (a) or alveoli (b) are exposed to NO. In one embodiment, less than 70% of the hypoventilated lung region (a) or alveoli (b) are exposed to NO. In one embodiment, less than 80% of the hypoventilated lung region (a) or alveoli (b) are exposed to NO. In one embodiment, less than 90% of the hypoventilated lung region (a) or alveoli (b) are exposed to NO.

[0079] Although preferred embodiments of the present invention have been shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the present invention. Various alternatives to the described embodiments of the present invention may be employed in practicing the present invention.

[0080] Example

[0081] The embodiments encompassed herein will now be described with reference to the following examples. These examples are provided for illustrative purposes only, and the disclosure encompassed herein should in no way be construed as limited to these examples, but rather should be construed to encompass any and all variations that become apparent as a result of the teachings provided herein.

[0082] Example 1: Determining precise breath sensitivity for appropriate trigger / arming thresholds

[0083] In this example (Example 1), a device that uses a threshold algorithm to detect breathing was used. The threshold algorithm uses pressure to detect breathing; that is, a pressure drop below a certain threshold must be met upon inspiration to detect and count a breath. This pressure threshold can be modified as a result of changing the detection sensitivity of the device of Example 1. Several breathing sensitivity settings were tested in this example. Settings from 1 to 10 were tested, with 1 being the least sensitive and 10 being the most sensitive. The trigger threshold, shown in cm H2O, is the threshold level at which nitric oxide is delivered. The arming threshold, also shown in cm H2O, is the threshold level at which the device arming for the next delivery of nitric oxide. The data is shown in Table 1 below.

[0084] Table 1 below shows the data set collected in this example. Variations in the breath sensitivity setting resulted in an increase in the trigger threshold (measured in cm H2O) from -1.0 at the least sensitive setting (1) to -0.1 at the most sensitive setting (10). In addition, the arming threshold (measured in cm H2O) remained constant at 0.1 from sensitivity setting 1 to setting 6, and thereafter decreased by 0.02 for each sensitivity setting up to 10. This indicates that the most sensitive breath sensitivity setting allowed for more precise detection of breaths, which allowed for more accurate pulsed delivery of nitric oxide within a shorter time window, i.e., early in the inspiratory portion of the breath. Based on these data, additional tests were performed at sensitivity settings of 8 and 10.

[0085] Table 1: Respiration sensitivity and trigger / arm threshold

[0086] Respiratory sensitivity 1 2 3 4 5 6 7 8 9 10 <![CDATA[Trigger threshold (cm H2O)]]> -1.0 -0.9 -0.8 -0.7 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 <![CDATA[Threshold for transmission (cm H2O)]]> +0.1 +0.1 +0.1 +0.1 +0.1 +0.1 +0.08 +0.06 +0.04 +0.02

[0087] In conclusion, higher respiratory sensitivity settings are associated with lower trigger thresholds and higher arming thresholds, which can prepare the device to deliver short, precise pulses of nitric oxide during therapeutic treatment.

[0088] Example 2: Testing of devices for various breathing patterns

[0089] As mentioned above, the accurate and timely delivery of nitric oxide is critical for the present invention. In order to ensure that the device will deliver an accurate dose of gas within a precise time window, ten different breathing patterns were tested using a mechanical lung and nose model. Ten different simulated breathing patterns were analyzed, and the breathing patterns had varying respiratory rates (8 to 36 bpm), tidal volumes (316 to 912 ml), and inhalation: exhalation (I / E) ratios (1:1 to 1:4). These variable breathing patterns are the patterns of subjects aged 16 and above, and are summarized in Table 2. Simulate the conditions of the real world as much as possible.

[0090] Table 2: Summary of breathing patterns tested

[0091] Respiratory rate (bpm) Male / Female Height (cm) Ideal body weight (kg) Tidal volume (mL) Respiration time (sec) I:E ratio 8 F 174 68.1 456 1.5 1:4 8 M 186 86.4 564 1.5 1:4 12 F 152 51.9 316 1.25 1:3 12 M 186 86.4 564 1.25 1:3 18 F 174 68.1 456 1.1 1:2 18 M 186 86.4 564 1.1 1:2 24 F 152 51.9 316 1.0 1:1.5 24 F 174 68.1 456 1.0 1:1.5 36 F 152 51.9 632 0.8 1:1 36 F 174 68.1 912 0.8 1:1

[0092] Two device embodiments were tested - Example 1 at sensitivity level 8 and sensitivity level 10, and another device embodiment (Example 2, which further included a slope algorithm) was tested at sensitivity level 10. The investigation consisted of two parts. Part 1 measured the time delay between the onset of an inspiratory breath and the start of nitric oxide delivery using 10 different simulated breathing patterns. Two data points were used - inspiratory onset ( Figure 1 , point A) and breath detection with simultaneous opening of the delivery valve ( Figure 1 This time delay is measured as the time between breath detection and simultaneous opening of the delivery valve, which corresponds to the start of gas delivery ( Figure 2 , point A) to the completion of gas delivery ( Figure 2 , point B). The volume of the delivered pulse is measured by integrating the airflow over the pulse duration. In addition, the data from part 1, the measured time delay, and the data from part 2, the measured pulse duration, are added together to calculate the dose delivery time, sometimes referred to as the "delivered pulse width."

[0093] Part 1: Measurement of the time delay between the onset of inspiration and the start of NO delivery. This portion of the test was conducted at a dose of 75 μg / kg-IBW / hour, with a drug concentration input of 6 mg / L (4880 ppm). This test was conducted using nitrogen only. The primary output of Part 1 was the duration between the onset of inspiration and the valve opening / breath detection indication. Figure 1 Point A in the diagram is the point where the pulmonary airflow rises just above the resting line. The valve opens at Figure 1 This is represented as point B in the figure and displayed as a sudden voltage drop in the detector. The time interval between points A and B is the valve time delay or trigger delay and is calculated for each breathing pattern. The total inspiratory time corresponds to the interval from point A to point C (which is the end of inspiration).

[0094] Part 2: Measuring the duration and volume of the delivered pulses. The same breathing pattern was used in this part of the investigation. Doses of 10, 15, 30, and 75 μg / kg-IBW / hour were tested. The device was programmed for each dose, patient IBW, and respiratory rate (breaths per minute). The resulting pulsatile airflow was determined by the flow meter. The pulsatile duration was the point at which the valve opened and the airflow returned to baseline (in Figure 2 The time between the times at point B in the figure, where the point indicating valve opening is shown as a sudden voltage drop in the detector, corresponds to Figure 2The volume of the delivered pulse is the airflow integrated during the pulse duration. The pulse duration is added to the pulse delay from part 1 to give the dose delivery time or "delivery pulse width". Figure 1 The results of Part 1 are shown. Figure 1 Four panels are shown in FIG. The second and fourth panels show a representation of the breath detection and breathing pattern corresponding to the flow control valve operation, respectively. Point A shows the start of inspiration, point B shows the breath detection corresponding to the flow valve opening, and point C shows the end of inspiration. From this data, the time delay between points A and B can be calculated.

[0095] Figure 2 The results of Part 2 are shown. Figure 2 Four panels are shown in Figure 1. The second and third panels show a representation of breath detection and pulsatile airflow, respectively, corresponding to the flow control valve operation. Point A shows a breath detection corresponding to the opening of the flow valve, and point B shows the end of the pulsatile flow. From this data, the duration of the pulsation between points A and B can be calculated.

[0096] Table 3 below summarizes Figure 3 and Figure 4 The results depicted in .

[0097]

[0098] Figure 3 The results of the breath detection counts for each device listed in Table 3 are depicted. Example 2 or Figure 3 The square / dotted data in the Figure 3 shows that at least 93% of the nitric oxide is delivered in the first third of the inspiratory portion of the breath. 100% of the nitric oxide is delivered in the first half of the inspiratory portion of the breath. In contrast, for Example 1, at a sensitivity setting of 8, at least 17% of the nitric oxide is delivered in the first third of the inspiratory portion of the breath, at least 77% in the first half, and at least 95% in the first two thirds of the inspiratory portion of the breath. Example 1, with a sensitivity setting of 10, shows results of at least 62% of the nitric oxide delivered in the first third of the inspiratory portion of the breath, at least 98% in the first half, and 100% in the first two thirds of the inspiratory portion of the breath. Figure 4 Data curves for the combination of all three tests are depicted.

[0099] This data suggests that lower doses of nitric oxide may be needed within a single treatment session because more nitric oxide is delivered more precisely with each pulse over a shorter period of time during the treatment session. Lower doses of nitric oxide may result in less medication being used overall and may also result in less risk of harmful side effects.

Claims

1. A computer program product for determining the dosage and timing of pulsatile delivery of nitric oxide, the computer program product having stored thereon instructions that, when executed, cause a computing device to: a) detecting, using a device including a respiratory sensitivity control via at least two separate triggers, a breathing pattern of the patient, the breathing pattern comprising a total inspiratory time of a single inspiration, the total inspiratory time having a first third, a middle third, and a last third; b) correlating the breathing pattern with an algorithm to calculate the timing of administering a dose of nitric oxide; and c) target either the first third or the middle third of total inspiratory time; in, The delivery of the nitric oxide dose occurs during the targeted portion of the total inspiratory time. wherein the at least two separate triggers include a respiration level trigger for detecting respiration when a threshold level of pressure is reached during inspiration and a respiration slope trigger for detecting when the slope of the pressure waveform indicates inspiration, and The delivery of the nitric oxide dose occurs within the first two-thirds of the total inspiratory time.

2. The computer program product according to claim 1, wherein Delivery of the dose of nitric oxide occurs within the first third of the total inspiratory time.

3. The computer program product according to claim 1, wherein Delivery of the dose of nitric oxide occurs during the first half of the total inspiratory time.

4. The computer program product of claim 1 , wherein: At least fifty percent of the dose of nitric oxide is delivered within the first third of the total inspiratory time.

5. The computer program product of claim 1 , wherein: At least ninety percent of the dose of nitric oxide is delivered within the first two thirds of the total inspiratory time.

6. The computer program product of claim 1 , wherein: Delivery of at least 70% of the dose of nitric oxide occurs within the first half of the total inspiratory time.

7. The computer program product of claim 1 , wherein: Nitric oxide is delivered in a series of pulses over a period of time.

8. The computer program product of claim 1, wherein: The breath sensitivity control is adjustable.

9. The computer program product of claim 1 , wherein: The breathing sensitivity control is fixed.

10. The computer program product of claim 1, wherein: Nitric oxide delivery has antimicrobial effects.

11. The computer program product of claim 1 , wherein: Less than 10% of the area of ​​the hypoventilated lung (a) or alveoli (b) are exposed to nitric oxide.

12. A programmable device for delivering a dose of nitric oxide to a patient in need thereof, the device comprising: a) Conveying part; b) Cartridges comprising nitric oxide; c) oxygen source; d) a breathing sensitivity portion for detecting a breathing pattern of the patient, the breathing pattern including a total inspiratory time of a single inspiration, the breathing sensitivity portion including a breathing sensitivity setting; e) a breath detection algorithm for determining the dose of nitric oxide; and f) administering a dose of nitric oxide to the patient via a series of pulses, wherein the respiration sensitivity portion includes a respiration level trigger for detecting respiration when a threshold level of pressure is reached during inspiration, and a respiration slope trigger for detecting when the slope of the pressure waveform indicates inspiration, and wherein the breathing detection algorithm calculates timing of a dose of nitric oxide when the breathing sensitivity portion detects a breathing pattern, and the portion that doses nitric oxide to the patient through a series of pulses targets one of a first third and a middle third of the total inspiratory time to administer the dose of nitric oxide.

13. The apparatus according to claim 12, wherein The respiration sensitivity may be fixed or adjustable from a least sensitive value to a most sensitive value.

14. The apparatus according to claim 12, wherein The breathing sensitivity setting is fixed at most sensitive.

15. The apparatus according to claim 12, wherein The cartridge is replaceable.

16. The apparatus according to claim 12, wherein The delivery portion is selected from the group consisting of a nasal cannula, a mask, a nebulizer, and a nasal inhaler.

17. The computer program product of claim 1, wherein: The dose of nitric oxide is a therapeutically effective dose.

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