Combination drug therapies with pde-5 inhibitors and nitric oxide for inhalation

Abstract

To provide a method for preventing additive hemodynamic effect when a hypertension patient is treated with a therapeutically effective amount of a pharmaceutical composition.SOLUTION: The method comprises co-administering a therapeutically effective amount of inhaled nitric oxide with the pharmaceutical composition, where the nitric oxide is delivered in a pulsatile manner by the steps of: a. detecting a breath pattern in the patient including a total inspiratory time; b. correlating the breath pattern with an algorithm to calculate the timing of administration of the dose of nitric oxide; and c. delivering the nitric oxide to the patient in a pulsatile manner over a portion of the total inspiratory time.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a joint publication of "Combination Drug This application claims the benefit of U.S. Provisional Patent Application No. 62 / 792,329, entitled "Therapies of PDE-5 Inhibitors and Inhaled Nitric Oxide," which is incorporated herein by reference in its entirety.

[0002] This application relates generally to combination therapy of PDE-5 inhibitors with inhaled nitric oxide (iNO). Regarding the law. [Background technology]

[0003] Nitric oxide (NO) is a gas that, when inhaled, dilates the blood vessels in the lungs. It improves blood oxygenation and reduces pulmonary hypertension. NO acts on the cGMP pathway, causing vasodilation in the lungs. For this reason, nitric oxide is provided as a therapeutic gas during the inspiration phase in patients with dyspnea due to pathologies such as pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), emphysema, or other pulmonary diseases.

[0004]

[0004] When administered under the right conditions, NO can be therapeutically effective; It can also be toxic if not administered properly. NO reacts with oxygen to form nitrogen dioxide (NO2), which can form if oxygen or air is present in the NO delivery tubing. NO2 is a toxic gas that can cause many side effects, and the Occupational Safety & Health Administration (OSHA) has set a permissible exposure limit for it in general industry of only 5 ppm. For this reason, it is advisable to limit exposure to NO2 during NO therapy.

[0005] Effective administration of NO depends on several different factors, including the amount of drug and the timing of delivery. Based on variables. Several patents related to NO delivery have been granted, including U.S. Patent Nos. 7,523,752, 8,757,148, 8,770,199, and 8,803,717, and Design Patent No. D701,963 for the design of NO delivery devices, all of which are incorporated herein by reference. In addition, there are pending applications related to NO delivery, including US2013 / 0239963 and US2016 / 0106949, both of which are incorporated herein by reference. In light of these patents and pending publications, there remains a need for methods and devices that deliver NO in a precisely controlled manner to maximize the benefits of therapeutic doses and minimize potentially harmful side effects.

[0006] Pharmaceutical compositions used to treat hypertension and other vasodilators, e.g. Inhibitors of cGMP-specific phosphodiesterase type 5 (PDE-5), such as riociguat or sildenafil and tadalafil, are used to treat pulmonary arterial hypertension (PAH) due to their vasodilatory effects. Many commercially available vasodilators, including riociguat and PDE-5 inhibitors, currently carry warnings against the use of nitrates while taking such drugs due to the risk of hypotension. Because NO is a source of nitrates, NO is not typically used as a combination therapy with PDE-5 inhibitors. The present invention demonstrates that the use of iNO has no additive hemodynamic effects when co-administered with hypertension medications, and thus iNO is safe to co-administer with such vasodilators. Summary of the Invention [Means for solving the problem]

[0007] In one embodiment, a therapeutically effective amount of a pharmaceutical composition for the treatment of hypertension is provided. Described herein is a method for preventing additive hemodynamic effects when treating a patient with nitric oxide, the method comprising co-administering a therapeutically effective amount of inhaled nitric oxide with the pharmaceutical composition.

[0008] In one embodiment, nitric oxide is administered to the patient at a concentration of 0.1% to 10% by measuring the respiratory rate in the patient, including total inspiration time. Nitric oxide is delivered in a pulsed manner by detecting a breathing pattern; correlating the breathing pattern with an algorithm for calculating when to administer a dose of nitric oxide; and delivering nitric oxide to the patient in a pulsed manner for a portion of the total inspiration time. In one embodiment, the dose of nitric oxide occurs within the first half of the total inspiration time. In another embodiment, the nitric oxide is delivered in a series of pulses over a period of time.

[0009] In one embodiment, the pharmaceutical composition is a PDE-5 inhibitor. In another embodiment, the PDE-5 inhibitor is sildenafil. In another embodiment, the PDE-5 inhibitor is tadalafil. In another embodiment, the PDE-5 inhibitor is vardenafil. In another embodiment, the PDE-5 inhibitor is a non-specific PDE-5 inhibitor, such as dipyridamole or theophylline. In yet another embodiment, the pharmaceutical composition is a stimulator of soluble guanylate cyclase. In another embodiment, the pharmaceutical composition is riociguat.

[0010] In one embodiment of the present invention, a method is described herein for preventing a systemic additive decrease in blood pressure in a patient being treated for hypertension while maintaining an overall improvement in the treatment of said hypertension, comprising co-administering a PDE-5 inhibitor and inhaled nitric oxide. In one embodiment, nitric oxide is delivered by detecting a breathing pattern in the patient, the breathing pattern having a total inhalation time and a total exhalation time; correlating the breathing pattern with an algorithm for calculating the timing of administration of a dose of nitric oxide; and delivering the dose of nitric oxide to the patient in a pulsed manner for a portion of the total inhalation time for a time required to deliver a therapeutically effective amount of nitric oxide to the patient. In one embodiment, the PDE-5 inhibitor is sildenafil. In another embodiment, the PDE-5 inhibitor is tadalafil.

[0011]

[0011] In addition to the summary above, the following detailed description will be better understood when read in conjunction with the accompanying drawings.

[0012] So that the above-recited features of the invention may be understood in detail, a more particular description of the invention briefly summarized above may be had by reference to embodiments, some of which are illustrated in the accompanying drawings. It should be noted, however, that the accompanying drawings illustrate only typical embodiments of the invention and are therefore not to be considered as limiting the scope of the invention, since the invention may include other equally effective embodiments. [Brief description of the drawings]

[0012] [Figure 1]

[0013] 1 is a graph showing the systolic and diastolic blood pressure (in mmHg) of five different patients undergoing sildenafil and iNO therapy at various times during, before, and after administration of sildenafil. The top plot represents the systolic measurements and the bottom plot represents the diastolic measurements, with a diastolic cutoff of 60 mmHg and a systolic cutoff of 90 mmHg, and the straight lines within each plot represent the linear systolic and diastolic pressures over the entire administration period. [Diagram 2]

[0013] Figure 1 is a graph showing systolic and diastolic blood pressure (in mmHg) for five different patients undergoing sildenafil and iNO therapy at various times during, before, and after administration of sildenafil. The top plot represents the systolic measurements and the bottom plot represents the diastolic measurements, with a diastolic cutoff of 60 mmHg and a systolic cutoff of 90 mmHg, and the straight lines within each plot represent linear systolic and diastolic pressures over the entire administration period. [Diagram 3]

[0013] Figure 1 is a graph showing systolic and diastolic blood pressure (in mmHg) for five different patients undergoing sildenafil and iNO therapy at various times during, before, and after administration of sildenafil. The top plot represents the systolic measurements and the bottom plot represents the diastolic measurements, with a diastolic cutoff of 60 mmHg and a systolic cutoff of 90 mmHg, and the straight lines within each plot represent linear systolic and diastolic pressures over the entire administration period. [Figure 4]

[0013] Figure 1 is a graph showing systolic and diastolic blood pressure (in mmHg) for five different patients undergoing sildenafil and iNO therapy at various times during, before, and after administration of sildenafil. The top plot represents the systolic measurements and the bottom plot represents the diastolic measurements, with a diastolic cutoff of 60 mmHg and a systolic cutoff of 90 mmHg, and the straight lines within each plot represent linear systolic and diastolic pressures over the entire administration period. [Diagram 5]

[0013] Figure 1 is a graph showing systolic and diastolic blood pressure (in mmHg) for five different patients undergoing sildenafil and iNO therapy at various times during, before, and after administration of sildenafil. The top plot represents the systolic measurements and the bottom plot represents the diastolic measurements, with a diastolic cutoff of 60 mmHg and a systolic cutoff of 90 mmHg, and the straight lines within each plot represent linear systolic and diastolic pressures over the entire administration period. [Figure 6]

[0014] Graph showing average iNO metabolites (mean plus standard deviation bars) for all patients over time, including 7 doses of sildenafil (lower bump of graph), and coadministration of sildenafil doses 4-7 with iNO (dotted line). [Figure 7]

[0015] FIG. 1 is a diagram showing a protocol design of the first embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013]

[0016] Unless otherwise defined, 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.

[0014]

[0017] Before describing some exemplary embodiments, it is to be understood that the invention is not limited to the details of construction or process steps set forth in the following description, as the invention is capable of other embodiments and of being practiced or carried out in various ways.

[0015]

[0018] References throughout this specification to "one embodiment," "a particular embodiment," "one or more embodiments," or "an embodiment" mean that a particular feature, structure, material, or characteristic described in connection with an embodiment is included in at least one embodiment of the invention. Thus, the appearances of phrases such as "in one or more embodiments," "in a particular embodiment," "in one embodiment," or "in an embodiment" in various places throughout this specification do not necessarily refer to the same embodiment of the invention. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments.

[0016]

[0019] Although the present invention has been described herein with reference to particular 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 can be made to the method and apparatus of the present invention without departing from the spirit and scope of the invention. Thus, it is intended that the present invention cover modifications and variations that come within the scope of the appended claims and their equivalents.

[0017] definition

[0020] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or combination of compounds described herein that is sufficient to have an effect for the intended use, including but not limited to the treatment of a disease. A therapeutically effective amount may vary depending on the intended use (in vitro or in vivo), the subject and condition to be treated (e.g., the subject's weight, age, and sex), the severity of the condition, the method of administration, and the like, and can be easily determined by one of ordinary skill in the art. The term also applies to a dose that will cause a particular response in target cells (e.g., reduced platelet adhesion and / or reduced cell migration). The specific dose will vary depending on the particular compound selected, the administration 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 through which the compound is delivered.

[0018]

[0021] As used herein, the term "therapeutic benefit" encompasses therapeutic benefit and / or prophylactic benefit. A prophylactic benefit includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0019]

[0022] When ranges are used herein to describe aspects of the invention, such as, for example, dosage ranges, amounts of components of a formulation, etc., it is intended to include all combinations and subcombinations of the ranges and specific embodiments therein. The use of the term "about" when referring to a number or numerical range means that the number or numerical range referred to is an approximation within experimental variation (i.e., within statistical experimental error), and thus, 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 number or numerical range mentioned. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes embodiments such as, for example, any composition of matter, any method, or any process "consisting of" or "consisting essentially of" the described features.

[0020]

[0023] For the avoidance of doubt, it is intended herein that a particular feature (e.g., integer, property, value, use, disease, formula, compound, or group) described in connection with a particular aspect, embodiment, or example of the invention should be understood to be applicable to any other aspect, embodiment, or example described herein, unless inconsistent therewith. Thus, such features may be used where appropriate in connection with any of the definitions, claims, or embodiments defined herein. All of the features disclosed herein (including any accompanying claims, abstract, and figures), and / or all of the method or process steps disclosed therein 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 of the disclosed embodiments. The invention extends to any novel or any novel combination of the features disclosed herein (including any accompanying claims, abstract, and figures), or any novel or any novel combination of the method or process steps disclosed therein.

[0021]

[0024] In accordance with the present invention, in certain embodiments, a dose of gas (e.g., NO) is administered to a patient in pulses during inspiration by the patient. Surprisingly, it has been found that delivery of nitric oxide can be precise and accurate within the first two-thirds of the total respiratory inspiration time, and that the patient benefits from such delivery. Such delivery, which minimizes the risk of pharmaceutical loss and adverse side effects, increases the effectiveness of the pulsed administration, which in turn results in a smaller overall amount of NO that needs to be administered to the patient to be effective. Such delivery is useful for the treatment of various diseases, including, but not limited to, idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), including groups I-V pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and emphysema, and is also useful as an antibacterial agent in the treatment of, for example, pneumonia.

[0022]

[0025] Such precision has the added advantage that only portions of poorly ventilated lung regions are exposed to NO. Hypoxia and hemoglobin disturbances may also be reduced using such pulsed delivery, but exposure to NO2 is also more limited.

[0023] Breathing Patterns, Detection, and Triggering

[0026] Breathing patterns vary based on the individual, time of day, level of activity, and other variables. This makes it difficult to predetermine an individual's breathing pattern. Therefore, a delivery system that delivers therapy to a patient based on breathing patterns should be able to address a range of possible breathing patterns in order to be effective.

[0024]

[0027] In certain embodiments, the patient or individual may be of any age, but in more particular embodiments, the patient is 16 years of age or older.

[0028] In one embodiment of the invention, a breathing pattern, as used herein, includes a measurement of total inspiration time determined for a single breath. However, depending on the context, "total inspiration time" may also refer to the sum of all inspiration times in all breaths detected during therapy. Total inspiration time may be observed or calculated. In another embodiment, total inspiration time is a time verified based on a simulated breathing pattern.

[0025]

[0029] In certain embodiments of the invention, breath detection includes at least one trigger, and in some embodiments includes at least two separate triggers that work together: a breath level trigger and / or a breath slope trigger.

[0026]

[0030] In one embodiment of the invention, a breath level trigger algorithm is used for breath detection. The breath level trigger detects a breath when a threshold level of pressure (eg, a threshold negative pressure) is reached during inspiration.

[0027]

[0031] In one embodiment of the invention, a respiratory slope trigger detects a breath when the slope of the pressure waveform indicates inspiration. A respiratory slope trigger can be more accurate than a threshold trigger in some cases, especially when used to detect short, shallow breaths.

[0028]

[0032] In one embodiment of the present invention, the combination of these two triggers provides a generally more accurate breath detection system, especially when multiple therapeutic gases are being administered to the patient simultaneously.

[0029]

[0033] In one embodiment of the invention, the respiration sensitivity control for detecting respiration level and / or respiration slope is fixed. The respiration sensitivity control for detecting either the respiration level and / or the respiration slope is adjustable or programmable. In one embodiment of the invention, the respiration sensitivity control for detecting the respiration level and / or the respiration slope is adjustable ranging from a minimum sensitivity to a maximum sensitivity, where the maximum sensitivity setting is more sensitive to detecting respiration than the minimum sensitivity setting.

[0030]

[0034] In certain embodiments where at least two triggers are used, the sensitivity of each trigger is set at a different relative level. In one embodiment where at least two triggers are used, one trigger is set to maximum sensitivity and the other trigger is set to less than maximum sensitivity. In one embodiment where at least two triggers are used and one trigger is a breath level trigger, the breath level trigger is set to maximum sensitivity.

[0031]

[0035] Often, not all of a patient's inhalations / breaths are detected and classified as inhalation / breath events for a pulsed administration of gas (e.g., NO). Detection errors can occur, especially when multiple gases are administered to the patient simultaneously, for example, in combination therapy with NO and oxygen.

[0032]

[0036] Embodiments of the present invention, and particularly those that incorporate a respiratory slope trigger, either alone or in combination with another trigger, can maximize correct detection of inspiration events, thereby maximizing the effectiveness and efficiency of therapy while minimizing waste due to misdetection or errors in timing.

[0033]

[0037] In certain embodiments, greater than 50% of the patient's total number of inspirations over a time frame for gas delivery to the patient are detected. In certain embodiments, greater than 75% of the patient's total number of inspirations are detected. In certain embodiments, greater than 90% of the patient's total number of inspirations are detected. In certain embodiments, greater than 95% of the patient's total number of inspirations are detected. In certain embodiments, greater than 98% of the patient's total number of inspirations are detected. In certain embodiments, greater than 99% of the patient's total number of inspirations are detected. In certain embodiments, between 75% and 100% of the patient's total number of inspirations are detected.

[0034] NO Dosage and Administration Regimen

[0038] In certain embodiments of the invention, nitric oxide delivered to a 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 may be administered alone or in combination with an alternative gas therapy. In certain embodiments, oxygen (e.g., concentrated oxygen) may be administered to a patient in combination with NO.

[0035]

[0039] In certain embodiments of the invention, a 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 may be the same over the course of a single session. In some embodiments, the volume of nitric oxide in several pulse doses may vary over the course of a single time frame for delivering gas to a patient. In some embodiments, the volume of nitric oxide in each pulse dose may be adjusted while monitoring breathing patterns over the course of a single time frame for delivering gas to a patient. In certain embodiments of the invention, the amount of nitric oxide (ng) delivered to a patient per pulse ("pulse dose") for purposes of treating or alleviating symptoms of a pulmonary disease is calculated as follows, rounded to the nearest nanogram: Dose ug / kg-IBW / hour x ideal body weight kg (kg-IBW) x ((1 hour / 60 minutes) / (1 minute / respiration rate (bpm))×(1,000ng / ug).

[0036]

[0040] As an example, patient A on a dose of 100ug / kg IBW / hr has an ideal body weight of 75kg and a respiratory rate of 20 breaths per minute (or 1200 breaths per hour): 100ug / kg-IBW / hr x 75kg x (1hr / 1200 breaths) x (1,000ng / ug) = 6250ng per pulse

[0037]

[0041] In certain embodiments, the variable 60 / respiratory rate (min) may be referred to as the administration event time. In another embodiment of the invention, the administration event time is 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, or 10 seconds.

[0038]

[0042] In one embodiment of the invention, a single pulse dose provides a therapeutic benefit (e.g., a therapeutically effective amount of NO) to a patient. In another embodiment of the invention, the total amount of two or more pulse doses provides a therapeutic benefit (e.g., a therapeutically effective amount of NO) to a patient.

[0039]

[0043] In certain embodiments 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 a patient every hour.

[0040]

[0044] In one embodiment of the invention, the nitric oxide therapy sessions occur over a time frame, in one embodiment, the time frame 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 15 hours, about 16 hours, about 17 hours, about 18 hours, or about 24 hours per day.

[0041]

[0045] In some embodiments of the present invention, nitric oxide therapy is administered during the shortest treatment course time frame. In some embodiments of the present invention, the shortest treatment course 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 some embodiments of the present invention, the shortest treatment course 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 certain embodiments of the invention, the minimum course of treatment 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.

[0042]

[0046] In some embodiments of the invention, nitric oxide therapy sessions are performed one or more times per day. In some embodiments of the invention, nitric oxide therapy sessions may be performed one, two, three, four, five, six, or more than six times per day. In some embodiments of the invention, therapy sessions may be performed monthly, biweekly, weekly, every other day, daily, or multiple times per day.

[0043] NO Pulse Timing

[0047] In one embodiment of the invention, breathing patterns are correlated with an algorithm to calculate the timing of administering a dose of nitric oxide.

[0044]

[0048] The accuracy of detecting inhalation / inhalation events is further maximized by timing the gas (e.g., NO) pulse to administer gas at a specific time window in the total inhalation time of a single detected breath.

[0045]

[0049] In certain embodiments of the invention, at least fifty percent (50%) of the pulse dose of gas is delivered over the first third of the total inspiration time of each breath. In certain embodiments of the invention, at least sixty percent (60%) of the pulse dose of gas is delivered over the first third of the total inspiration time of each breath. In certain embodiments of the invention, at least seventy-five percent (75%) of the pulse dose of gas is delivered over the first third of the total inspiration time of each breath. In certain embodiments of the invention, at least eighty-five percent (85%) of the pulse dose of gas is delivered over the first third of the total inspiration time of each breath. In certain embodiments of the invention, at least ninety percent (90%) of the pulse dose of gas is delivered over the first third of the total inspiration time. In certain embodiments of the invention, at least ninety-two percent (92%) of the pulse dose of gas is delivered over the first third of the total inspiration time. In certain embodiments of the invention, at least ninety-five percent (95%) of the pulse dose of gas is delivered over the first third of the total inspiration time. In some embodiments of the invention, at least ninety-nine percent (99%) of the pulse dose of gas is delivered over the first third of the total inspiration time. In some embodiments of the invention, between 90% and 100% of the pulse dose of gas is delivered over the first third of the total inspiration time.

[0046]

[0050] In certain embodiments of the invention, at least seventy percent (70%) of the pulse dose is delivered to the patient over the first half of the total inspiration time. In yet another embodiment, at least seventy-five percent (75%) of the pulse dose is delivered to the patient over the first half of the total inspiration time. In certain embodiments of the invention, at least eighty percent (80%) of the pulse dose is delivered to the patient over the first half of the total inspiration time. In certain embodiments of the invention, at least ninety percent (90%) of the pulse dose is delivered to the patient over the first half of the total inspiration time. In certain embodiments of the invention, at least ninety-five percent (95%) of the pulse dose is delivered to the patient over the first half of the total inspiration time. In certain embodiments of the invention, 95%-100% of the pulse dose of gas is delivered over the first half of the total inspiration time.

[0047]

[0051] In some embodiments of the invention, at least ninety percent (90%) of the pulse dose is delivered over the first two-thirds of the total inspiration time. In some embodiments of the invention, at least ninety-five percent (95%) of the pulse dose is delivered over the first two-thirds of the total inspiration time. In some embodiments of the invention, 95%-100% of the pulse dose is delivered over the first two-thirds of the total inspiration time.

[0048]

[0052] When counted, administration of multiple pulse doses over a therapy session / time frame may also fall within the above range.For example, when counted, more than 95% of all pulse doses administered during a therapy session are administered over the first two-thirds of the total inspiration time of all detected breaths.In a more accurate embodiment, when counted, more than 95% of all pulse doses administered during a therapy session are administered over the first one-third of the total inspiration time of all detected breaths.

[0049]

[0053] Given the high accuracy of the detection method of the present invention, the pulse dose can be determined by measuring the amount of the blood flow during any given inhalation. The pulse dose may be administered during a particular time window. For example, the pulse dose may be administered in the first third, the middle third, or the last third of the patient's inspiration. Alternatively, the first half or the second half of the inspiration may be targeted for administering the pulse dose. Furthermore, the target for administration may be changed. In one embodiment, the first third of the inspiration time may be targeted for one or a series of inspirations, where the second third or the second half may be targeted for a subsequent inspiration or series of inspirations during the same or a different therapy session. Alternatively, the pulse administration may be scheduled to begin after the first quarter of the inspiration time has elapsed, continue for the middle half (next two quarters), and end at the beginning of the last quarter of the inspiration time. In some embodiments, the pulse may be delayed by 50, 100, or 200 milliseconds (ms), or may be delayed in a range of about 50 to about 200 ms.

[0050]

[0054] Utilizing pulsed dosing during inhalation reduces exposure of poorly ventilated lung regions and alveoli from exposure to pulsed gas, e.g., NO. In one embodiment, less than 5% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 10% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 15% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 20% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 25% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 30% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 50% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 60% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 70% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 80% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO. In one embodiment, less than 90% of the poorly ventilated (a) lung regions or (b) alveoli are exposed to NO.

[0051]

[0055] iNO delivered according to the present invention may be useful in treating a variety of pulmonary conditions, including PAH. Co-administration of iNO with pharmaceutical compositions useful in the treatment of hypertension (such as vasodilators) produces a sustained effect of such pharmaceutical compositions in the patient, but does not cause a synergistic effect such that the patient becomes hypotensive.

[0052] Administration of vasodilators, including PDE-5 inhibitors, for the treatment of pulmonary arterial hypertension

[0056] Vasodilators are usually administered for the treatment of hypertension. Vasodilators include PDE-5 inhibitors and stimulators of soluble guanylate cyclase, such as riociguat. PDE-5 inhibitors, such as sildenafil and tadalafil, have been shown to improve clinical status, exercise capacity, and hemodynamics in PAH patients (Montani, D. et al., Adv. Ther., September 2009:26(9):813-825). Sildenafil is approved for the treatment of PAH (REVATIO®). However, REVATIO® is contraindicated for use with organic nitrates or riociguat due to the risk of hypotension (see contraindications on REVATIO® label / package insert).

[0053]

[0057] Some PAH patients being treated with PDE-5 inhibitors such as REVATIO® will also require a second drug regimen to enhance treatment of the disease. The inventors have demonstrated that inhaled nitric oxide (iNO), when administered in combination with another vasodilator, acts locally in the lung to enhance vasodilation without causing systemic hypotension in the patient.

[0054]

[0058] In one embodiment of the invention, co-administration of iNO according to the invention with a pharmaceutical composition for treating hypertension (i.e., an antihypertensive agent) does not have any additive hemodynamic effect on the patient. In another embodiment, co-administration of iNO with an antihypertensive agent does not have a systemic additive hemodynamic effect on the patient. In yet another embodiment, iNO delivered to the lungs has a protective effect on the patient by preventing hypotension that may result from administration of a systemic vasodilator. In another embodiment of the invention, when iNO is administered to the lungs according to the invention while the patient is undergoing a vasodilator treatment regimen for hypertension, hypotension that may result from administration of a systemic vasodilator is blunted. In another embodiment, when iNO is administered to the lungs while the patient is undergoing a vasodilator treatment regimen for hypertension, no further significant reduction in systolic and / or diastolic blood pressure is shown. In another embodiment, when iNO is administered to the lungs while the patient is undergoing a vasodilator treatment regimen for hypertension, no hypotension or symptoms of hypotension such as fainting or lightheadedness occurs when iNO is administered to the lungs while the patient is undergoing a vasodilator treatment regimen for hypertension. In certain embodiments of the invention, iNO is rapidly taken up by hemoglobin, resulting in low levels of circulating NO metabolites that have no additive hemodynamic effects on blood pressure.

[0055]

[0059] In one embodiment of the present invention, the administration of iNO to the lung according to the present invention has only a local vasodilatory effect.In other words, the administration of iNO to the lung according to the present invention does not have a systemic effect on vasodilatory effect.This applies to patients who receive both acute and chronic administration of iNO.This preferential local vasodilatory effect in the lung allows the administration of iNO to be safe and effective even in combination with the administration of antihypertensive drugs such as vasodilators.

[0056]

[0060] In one embodiment of the present invention, the antihypertensive agent is a vasodilator. In one embodiment, the antihypertensive agent is a PDE-5 inhibitor. In one embodiment of the present invention, the PDE-5 inhibitor is sildenafil, tadalafil, vardenafil or their salts. Commercially available examples of each of these PDE-5 inhibitors are REVATIO® (sildenafil), CIALIS® (tadalafil), LEVITRA® (vardenafil) and STAXYN® (vardenafil). In one embodiment of the present invention, the dosage of each of these vasodilator / antihypertensive agents is any one or more of the commercially available dosages. In one embodiment of the present invention, the dose of the PDE-5 inhibitor is about 1 mg to about 200 mg, about 2.5 mg to about 200 mg, about 5 mg to about 200 mg, about 10 mg to about 200 mg, about 15 mg to about 200 mg, about 20 mg to about 200 mg, about 25 mg to about 200 mg, about 50 mg to about 200 mg, about 100 mg to about 200 mg, or 150 mg to about 200 mg. In one embodiment of the present invention, the dose of the PDE-5 inhibitor is 1 mg, 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 100 mg, or 200 mg.

[0057]

[0061] In another embodiment of the present invention, the PDE-5 inhibitor is a non-specific PDE-5 inhibitor. In another embodiment, the non-specific PDE-5 inhibitor is selected from the group consisting of theophylline and dipyridamole. In one embodiment of the present invention, the antihypertensive agent is a stimulator of soluble guanylate cyclase. In another embodiment of the present invention, the antihypertensive agent is riociguat. One example of riociguat is ADEMPAS® sold by Bayer. ADEMPAS® is available in several doses, including 0.5 mg, 1.0 mg, 1.5 mg, 2 mg, and 2.5 mg.

[0058]

[0062] In certain embodiments of the invention, iNO is administered according to the pulsatile regimen discussed herein. In certain embodiments of the invention, iNO is delivered to a patient using an INOpulse® device (Bellerofon Therapeutics). In one embodiment, a patient is administered iNO for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, The patient is administered iNO for a period of at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours per day for a period of at least 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks. In one embodiment, the patient is administered iNO for 8 weeks. In another embodiment, the patient is administered iNO for 16 weeks. In an embodiment of the invention, the nitric oxide therapy sessions occur over a time frame. In one embodiment, the time frame 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.

[0059]

[0063] In some embodiments of the present invention, nitric oxide therapy is administered during the shortest treatment course time frame. In some embodiments of the present invention, the shortest treatment course 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 some embodiments of the present invention, the shortest treatment course 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 certain embodiments of the invention, the minimum course of treatment 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.

[0060]

[0064] In certain embodiments of the invention, iNO is administered at anywhere from 10 mcg / kg ideal body weight (IBW) / hr to 100 mcg / kg IBW / hr or more. In one embodiment, iNO is administered at 25 mcg / kg IBW / hr. In one embodiment, iNO is administered at 30 mcg / kg IBW / kg. In one embodiment, iNO is administered at 35 mcg / kg IBW / kg. In one embodiment, iNO is administered at 40 mcg / kg IBW / kg. In one embodiment, iNO is administered at 45 mcg / kg IBW / kg. In one embodiment, iNO is administered at 50 mcg / kg IBW / kg. In one embodiment, iNO is administered at 55 mcg / kg IBW / kg. In one embodiment, iNO is administered at 60 mcg / kg IBW / kg. In one embodiment, iNO is administered at 65mcg / kg IBW / kg. In one embodiment, iNO is administered at 70mcg / kg IBW / kg. In one embodiment, iNO is administered at 75mcg / kg IBW / kg. In one embodiment, iNO is administered at 80mcg / kg IBW / kg. In one embodiment, iNO is administered at 85mcg / kg IBW / kg. In one embodiment, iNO is administered at 90mcg / kg IBW / kg. In one embodiment, iNO is administered at 95mcg / kg IBW / kg. In one embodiment, iNO is administered at 100mcg / kg IBW / kg.

[0061]

[0065] In one embodiment of the invention, the patient is also administered oxygen with iNO and vasodilators. In one embodiment of the invention, oxygen is administered at up to 20 L / min. In one embodiment of the invention, oxygen is administered at up to 1 L / min, 2 L / min, 3 L / min, 4 L / min, 5 L / min, 6 L / min, 7 L / min, 8 L / min, 9 L / min, 10 L / min, 11 L / min, 12 L / min, 13 L / min, 14 L / min, 15 L / min, 16 L / min, 17 L / min, 18 L / min, 19 L / min, or 20 L / min. In one embodiment of the invention, oxygen is administered as prescribed by a physician.

[0062]

[0066] While 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 invention. Various alternatives to the described embodiments of the invention may be employed in practicing the invention. EXAMPLES

[0063]

[0067] The embodiments encompassed herein will now be described with reference to the following examples, which are provided for illustrative purposes only, and the disclosure encompassed herein should in no way be construed as being limited to these examples, but rather as encompassing any and all variations that become evident as a result of the teachings presented herein.

[0064]

[0068] Example 1 Drug-drug interaction study between pulsed inhaled nitric oxide and sildenafil in healthy volunteers

[0069] Inhaled nitric oxide (iNO) has been approved for use in infants with hypoxemic respiratory failure. Nitric oxide is a selective pulmonary vasodilator whose action is mediated by the cyclic guanosine monophosphate (cGMP) pathway. Thus, a study was conducted to evaluate the efficacy and safety of iNO for use in adults with pulmonary arterial hypertension (PAH). Patients with PAH may already be receiving 2-3 medications to treat PAH, such as sildenafil. The aim of this study was to investigate the potential pharmacodynamic interaction between pulsed iNO and sildenafil in healthy volunteers.

[0065]

[0070] Five healthy volunteers received sildenafil for 24 hours before adding iNO. Changes in pharmacodynamic parameters, such as heart rate, blood pressure, and oxygen saturation, after administration of both drugs were assessed for 27 hours and hourly for 4 hours after iNO was discontinued.

[0066]

[0071] Figure 7 shows the protocol design of this study. In summary, on day 1, subjects received sildenafil only. One dose of 20 mg sildenafil was administered every 6 hours on day 1 for a total of three doses on day 1. Vital signs (heart rate, blood pressure, and oxygen saturation) were assessed every 30 minutes starting 1 hour prior to sildenafil administration until 2.5 hours after each dose of sildenafil. Adverse events were also monitored. On days 2-3, the sildenafil regimen was continued as administered on day 1 and supplemented with 27.5 hours of pulsed iNO therapy (INOPulse) at 75 mcg / kg individual body weight (IBW) / hour. Vital signs were assessed every 30 minutes starting 1 hour prior to iNO administration until 2.5 hours after each dose of sildenafil. Upon discontinuation of iNO, vital signs were measured hourly for 4 hours and subjects were monitored for syncope and lightheadedness. Nitric oxide metabolites were measured throughout iNO administration and for 4 hours after iNO was discontinued. Drug and / or iNO therapy was discontinued if the subject's blood pressure fell below 90 / 50 mmHg, and iNO therapy was discontinued if syncope or lightheadedness was observed.

[0067]

[0072] Figures 1-6 show the results of this study. Figures 1-5 show the systolic and diastolic blood pressure results for each of subjects 1-5 at various intervals over the dosing period. A reduction in blood pressure was measured in all five subjects within 2.5 hours after administration of sildenafil alone (all three doses on day 1). A similar reduction in blood pressure was measured in all five subjects after administration of sildenafil on days 2 and 3, respectively. The results showed that there was a significant reduction in blood pressure during co-administration of iNO (sildenafil 4 and 5 doses) and peak levels of nitric oxide metabolites (sildenafil 5 and 6 doses) compared to blood pressure values ​​observed with the first three doses of sildenafil alone. The results show that there was no further reduction in systolic and diastolic blood pressure at the first dose (6 and 7 doses). The results were consistent across all subjects. No synergistic interactions (i.e., the result of an antihypertensive drug-drug interaction) were observed between iNO and sildenafil, even at peak metabolite levels in all volunteers in the study. There were no instances of syncope, lightheadedness, or signs of possible rebound upon discontinuation of iNO, and no other adverse events were identified.

[0068]

[0073] Example 2 Drug-drug interactions between pulsed inhaled nitric oxide and riociguat in healthy volunteers.

[0074] Ten healthy volunteers are recruited to investigate potential pharmacodynamic interactions between riociguat and pulsed iNO. Subjects receive 2.5 mg riociguat three times per day for 5 days to achieve steady state. Vital signs (heart rate, blood pressure, and oxygen saturation) are assessed every 30 minutes starting 1 hour before the first dose of riociguat until 2.5 hours after each dose of riociguat. Adverse events are also monitored. On day 6, the riociguat regimen is continued as administered the previous day, except that pulsed iNO therapy is initiated 1 hour before the first dose of riociguat. Pulsed iNO therapy is continued for 27.5 hours at 75 mcg / kg individual body weight (IBW) / hour (INOPulse). Vital signs are assessed every 30 minutes starting 1 hour before iNO administration until 2.5 hours after each dose of sildenafil. Upon discontinuation of iNO, vital signs were measured hourly for 4 hours and subjects were monitored for syncope and lightheadedness. Nitric oxide metabolites were measured throughout the administration of iNO and for 4 hours after discontinuation of iNO. If the subject's blood pressure falls below 100 / 50 mmHg, drug therapy and / or iNO therapy is discontinued and if syncope or lightheadedness is observed, iNO therapy is discontinued.

Claims

1. A method for preventing additive hemodynamic effects when treating a patient with a therapeutically effective amount of a pharmaceutical composition for the treatment of hypertension, comprising co-administering a therapeutically effective amount of inhaled nitric oxide with said pharmaceutical composition.

2. The nitric oxide is a. detecting a breathing pattern in the patient, the breathing pattern including a total inspiration time; b. correlating said breathing pattern with an algorithm for calculating when to administer a dose of nitric oxide; c. delivering the nitric oxide to the patient in a pulsed manner for a portion of the total inspiration time; 2. The method of claim 1, wherein the therapeutic agent is delivered in a pulsatile manner by

3. The method of claim 1, wherein the pharmaceutical composition is a PDE-5 inhibitor.

4. 4. The method of claim 3, wherein the PDE-5 inhibitor is sildenafil.

5. 4. The method of claim 3, wherein the PDE-5 inhibitor is tadalafil.

6. 4. The method of claim 3, wherein the PDE-5 inhibitor is vardenafil.

7. The method of claim 3, wherein the PDE-5 inhibitor is a non-specific PDE-5 inhibitor.

8. 8. The method of claim 7, wherein the non-specific PDE-5 inhibitor is selected from dipyridamole and theophylline.

9. The method of claim 1 , wherein the pharmaceutical composition is riociguat.

10. 10. The method of claim 1, wherein delivery of the dose of nitric oxide occurs within the first half of the total inspiration time.

11. 10. The method of claim 1, wherein the nitric oxide is delivered in a series of pulses over a period of time.

12. 1. A method for preventing additive systemic decreases in blood pressure in a patient being treated for hypertension while improving overall treatment of said hypertension, comprising co-administering a PDE-5 inhibitor and inhaled nitric oxide.

13. The nitric oxide is a. detecting a breathing pattern in the patient, the breathing pattern having a total inspiration time and a total expiration time; b. correlating said breathing pattern with an algorithm for calculating when to administer a dose of nitric oxide; c. delivering said dose of nitric oxide to said patient in a pulsed manner for a portion of said total inspiration time necessary to deliver a therapeutically effective amount of nitric oxide to said patient; The method of claim 12, wherein the pharmaceutical composition is delivered by

14. 13. The method of claim 12, wherein the PDE-5 inhibitor is sildenafil.

15. 13. The method of claim 12, wherein the PDE-5 inhibitor is tadalafil.

16. 13. The method of claim 12, wherein the PDE-5 inhibitor is vardenafil.

17. The method of claim 12, wherein the PDE-5 inhibitor is a non-specific PDE-5 inhibitor.

18. 18. The method of claim 17, wherein the non-specific PDE-5 inhibitor is selected from dipyridamole and theophylline.

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