Methods for treating edema intranasally

Abstract

The present disclosure provides a method of edema in a subject in need thereof. The method includes administering to the subject a pharmaceutical composition comprising bumetanide using a nasal delivery device, wherein the plume generated by the nasal delivery device is characterized by the total volume administered per actuation, the average droplet size, the spray pattern, or the plume geometry.

Description

[0001] PATENT

[0002] ATTORNEY DOCKET NO.: 51378-005WO2

[0003] METHODS FOR TREATING EDEMA INTRANASALLY

[0004] Background of the Invention

[0005] Congestive heart failure (CHF) is a common heart disease. The prevalence of incidents of congestive heart failure has recently increased, and there is considerable morbidity and mortality-associated with its diagnosis. In fact, congestive heart failure is an extremely lethal disease with an estimated five-year mortality for a vast majority of both men and women who encounter the disease. Congestive heart failure results from loss of, or impairment of, normal heart function. This loss or impairment reduces cardiac output. This, in turn, results in a reduction in both blood flow and blood pressure in the kidneys. This reduction in flow and pressure causes a renin-angiotensin response that exacerbates congestive heart failure. Blood volume is increased because angiotensin II stimulates secretion of aldosterone from the adrenal cortex which, in turn, causes an increase in salt and water retention in the kidneys. The increase in blood volume and the corresponding vasoconstriction cause an increase in blood pressure and hence fluid overload on the heart which causes further deterioration of the heart condition.

[0006] To treat CHF, physicians put patients on a strict low sodium diet and their fluid intake is monitored. Some patients are limited to as little as one liter of fluid a day. The most important drugs in the physician’s arsenal to combat fluid overload are the class of drugs called diuretics. Diuretics affect the kidney function in such a way that the reabsorption of fluid is suppressed. As a result, there is more urine output contrary to neurohormonal commands that the kidney is receiving. Physicians can treat the patient with agents that improve the pumping ability of the heart, increase blood pressure, and attempt to reactivate a more normal behavior of the body's control system. In general, this is effective in sustaining life of many heart failure patients. Nevertheless, in hundreds of thousands of patients, treatments with drugs and diet alone fail. When the patient is in an edematous state and is experiencing fluid overload, gastrointestinal absorption can be compromised, thus limiting the effectiveness of oral diuretics. As a result, the patient is often instructed to increase the dosage of oral diuretics putting further strain on the patient’s kidneys. Eventually, oral diuretics become insufficient to remove excess fluid causing the patients to seek intravenous diuretics to bypass absorption by the gastrointestinal system. Consequently, the patients are often repeatedly admitted to the hospital for intensive care and administration of iv diuretics and are at risk (with each event) of over-diuresis once gastrointestinal absorption is restored. Ultimately, the over-diuresis can result in kidney failure. When available treatment can no longer achieve adequate fluid removal with existing kidney function, renal replacement therapies such as hemofiltration or dialysis have been increasingly used as a method of removing fluid in the acute CHF state. Acute heart failure can be treated with the Continuous Renal Replacement Therapy (a.k.a., an artificial kidney or dialysis machine) in the ICU of a hospital.

[0007] Therefore, there remains a need for treatment options for patients with heart failure in acute distress from fluid overload, such as to reduce the risk of hospitalizations and kidney failure.

[0008] Summary of the Invention

[0009] In an aspect, the disclosure provides a method of treating edema in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising bumetanide or a PATENT

[0010] ATTORNEY DOCKET NO.: 51378-005WO2

[0011] pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is administered to the subject using a nasal spray device, wherein the nasal spray device delivers a dosage unit by way of a plume upon actuation, wherein the in the plume is characterized by: (a) total volume deployed upon actuation, wherein the total volume delivered per actuation is between 50 pl and 150 pl (e.g., 50 pl± 10 pl, 60 pl± 10 pl, 70 pl± 10 pl, 80 pl± 10 pl, 90 pl± 10 pl, 100 pl± 10 pl, 110 pl± 10 pl, 120 pl± 10 pl, 130 pl± 10 pl, 140 pl± 10 pl, or 150 pl± 10 pl); (b) droplet size, wherein the droplets have an average diameter of greater than 10 pm; (c) spray pattern, wherein the spray pattern is characterized as having an ovality of from 1 to 2 (e.g., 1±0.2, 1.2±0.2, 1,4±0.2, 1,6±0.2, 1,8±0.2, or 2±0.2); and / or (d) plume geometry, wherein plume geometry is characterized by having an angle of from 54° to 70° (e.g., 54°±2°, 56°±2°, 58°±2°, 60°±2°, 62°±2°, 64°±2°, 66°±2°, 68°±2°, or 70°±2°) when measured at 6 cm above the device or 60° to 78° (e.g., 60°±2°, 62°±2°, 64°±2°, 66°±2°, 68°±2°, 70°±2°, 72°±2°, 74°±2°, 76°±2°, or 78°±2°) when measured at 3 cm above the device. In some embodiments, the droplets have an average diameter ranging from 1 pm to 250 pm (e.g., 1 pm± 1 pm, 2 pm ± 1 pm, 3 pm ± 1 pm, 4 pm ± 1 pm, 5 pm ± 1 pm, 6 pm ± 1 pm, 7 pm ± 1 pm, 8 pm ± 1 pm, 9 pm ± 1 pm, 10 pm ± 1 pm, 15 pm± 5 pm, 20 pm± 5 pm, 25 pm± 5 pm, 30 pm± 5 pm, 35 pm± 5 pm, 40 pm± 10 pm, 50 pm± 10 pm, 60 pm± 10 pm, 70 pm± 10 pm, 80 pm± 10 pm, 90 pm± 10 pm, 100 pm± 20 pm, 120 pm± 20 pm, 140 pm± 20 pm, 160 pm± 20 pm, 180 pm± 20 pm, 200 pm± 20 pm, 220 pm± 20 pm, 240 pm± 20 pm, or 250 pm± 20 pm). For example, the droplets may have an average diameter ranging from 1 pm to 210 pm (e.g., 1 pm± 1 pm, 2 pm ± 1 pm, 3 pm ± 1 pm, 4 pm ± 1 pm, 5 pm ± 1 pm, 6 pm ± 1 pm, 7 pm ± 1 pm, 8 pm ± 1 pm, 9 pm ± 1 pm, 10 pm ± 1 pm, 15 pm± 5 pm, 20 pm± 5 pm, 25 pm± 5 pm, 30 pm± 5 pm, 35 pm± 5 pm, 40 pm± 10 pm, 50 pm± 10 pm, 60 pm± 10 pm, 70 pm± 10 pm, 80 pm± 10 pm, 90 pm± 10 pm, 100 pm± 20 pm, 120 pm± 20 pm, 140 pm± 20 pm, 160 pm± 20 pm, 180 pm± 20 pm, 200 pm± 10 pm, or 210 pm± 10 pm). In some embodiments, the droplets have an average diameter ranging from 50 pm to 150 pm (e.g., 50 pm±10 pm, 60 pm±10 pm, 70 pm±10 pm, 80 pm±10 pm, 90 pm±10 pm, 100 pm±10 pm, 110 pm±10 pm, 120 pm±10 pm, 130 pm±10 pm, 140 pm±10 pm, or 150 pm±10 pm). The droplets may have an average diameter ranging from 15 pm to 50 pm (e.g., 15 pm± 5 pm, 20 pm± 5 pm, 25 pm± 5 pm, 30 pm± 5 pm, 35 pm± 5 pm, 40 pm± 5 pm, 45 pm± 5 pm, or 50 pm± 5 pm).

[0012] In some embodiments, the droplets have a Dv10 of between 10 pm and 16 pm (e.g., 10 pm ± 1 pm, 11 pm ± 1 pm, 12 pm ± 1 pm, 13 pm ± 1 pm, 14 pm ± 1 pm, 15 pm ± 1 pm, or 16 pm ± 1 pm) when measured 3 cm from the device. In some embodiments, the droplets have a Dv10 of between 6 pm and 27 pm when measured 3 cm from the device. In some embodiments, the droplets have a Dv50 of between 26 pm and 35 pm (e.g., 26 pm ± 1 pm, 27 pm ± 1 pm, 28 pm ± 1 pm, 29 pm ± 1 pm, 30 pm ± 1 pm, 31 pm ± 1 pm, 32 pm ± 1 pm, 33 pm ± 1 pm, 34 pm ± 1 pm, or 35 pm ± 1 pm) when measured 3 cm from the device. In some embodiments, the droplets have a Dv50 of between 14 pm and 51 pm when measured 3 cm from the device. In some embodiments, the droplets have a Dv90 of between 70 pm and 280 pm (e.g., 70 pm ± 10 pm, 80 pm ± 10 pm, 90 pm ± 10 pm, 100 pm ± 10 pm, 110 pm ± 10 pm, 120 pm ± 10 pm, 130 pm ± 10 pm, 140 pm ± 10 pm, 150 pm ± 10 pm, 160 pm ± 10 pm, 170 pm ± 10 pm, 180 pm ± 10 pm, 190 pm ± 10 pm, 200 pm ± 10 pm, 210 pm ± 10 pm, 220 pm ± 10 pm, 230 pm ± 10 pm, 240 pm ± 10 pm, 250 pm ± 10 pm, 260 pm ± 10 pm, 270 pm ± 10 pm, or 280 pm ± 10 pm) when measured 3 cm from the device. In some embodiments, the droplets have a Dv90 of between 70 pm and 500 pm PATENT

[0013] ATTORNEY DOCKET NO.: 51378-005WO2

[0014] when measured 3 cm from the device. In some embodiments, the droplets have a Dv90 of less than 500 pm when measured 3 cm from the device. The droplets may have a Dv10 of between 13 pm and 22 pm (e.g., 13 pm ± 1 pm, 14 pm ± 1 pm, 15 pm ± 1 pm, 16 pm ± 1 pm, 17 pm ± 1 pm, 18 pm ± 1 pm, 19 pm ± 1 pm, 20 pm ± 1 pm, 21 pm ± 1 pm, or 22 pm ± 1 pm) when measured 6 cm from the device. In some embodiments, the droplets have a Dv10 of between 6 pm and 27 pm when measured 6 cm from the device. The droplets may have a Dv50 of between 32 pm and 41 pm (e.g., 32 pm ± 1 pm, 33 pm ± 1 pm, 34 pm ± 1 pm, 35 pm ± 1 pm, 36 pm ± 1 pm, 37 pm ± 1 pm, 38 pm ± 1 pm, 39 pm ± 1 pm, 40 pm ± 1 pm, or 41 pm ± 1 pm) when measured 6 cm from the device. In some embodiments, the droplets have a Dv50 of between 14 pm and 51 pm when measured 6 cm from the device. The droplets may have a Dv90 of between 70 pm and 240 pm (e.g., 70 pm ± 5 pm, 75 pm ± 5 pm, 80 pm ± 5 pm, 85 pm ± 10 pm, 95 pm ± 10 pm, 105 pm ± 10 pm, 115 pm ± 10 pm, 125 pm ± 10 pm, 135 pm ± 10 pm, 145 pm ± 10 pm, 155 pm ± 10 pm, 165 pm ± 10 pm, 175 pm ± 10 pm, 185 pm ± 10 pm, 195 pm ± 10 pm, 205 pm ± 10 pm, 210 pm ± 10 pm, 220 pm ± 10 pm, 230 pm ± 10 pm, or 240 pm ± 10 pm) when measured 6 cm from the device. In some embodiments, the droplets have a Dv90 of between 70 pm and 400 pm when measured 6 cm from the device. In some embodiments, the droplets have a Dv90 of less than 400 pm when measured 6 cm from the device.

[0015] In some embodiments, the spray pattern is characterized by its maximum diameter, minimum diameter, or ovality. For example, the spray pattern may be characterized as having a maximum diameter of between 12 mm and 56 mm (e.g., 16 mm ± 4 mm, 18 mm ± 4 mm, 22 mm ± 4 mm, 26 mm ± 4 mm, 30 mm ± 4 mm, 34 mm ± 4 mm, 38 mm ± 4 mm, 42 mm ± 4 mm, 44 mm ± 4 mm, 48 mm ± 4 mm, or 52 mm ± 4 mm) when measured 3 cm from the device. The spray pattern may be characterized as having a maximum diameter of between 18 mm and 44 mm (e.g., 18 mm ± 4 mm, 22 mm ± 4 mm, 26 mm ± 4 mm, 30 mm ± 4 mm, 34 mm ± 4 mm, 38 mm ± 4 mm, 42 mm ± 4 mm, 44 mm ± 4 mm) when measured 3 cm from the device. The spray pattern may be characterized as having a maximum diameter of between 22 mm and 32 mm (e.g., 22 mm ± 1 mm, 23 mm ± 1 mm, 24 mm ± 1 mm, 25 mm ± 1 mm, 26 mm ± 1 mm, 27 mm ± 1 mm, 28 mm ± 1 mm, 29 mm ± 1 mm, 30 mm ± 1 mm, 31 mm ± 1 mm, or 32 mm ± 1 mm) when measured 3 cm from the device. For example, the spray pattern may be characterized as having a maximum diameter of between 32 mm and 44 mm (e.g., 32 mm ± 1 mm, 33 mm ± 1 mm, 34 mm ± 1 mm, 35 mm ± 1 mm, 36 mm ± 1 mm, 37 mm ± 1 mm, 38 mm ± 1 mm, 39 mm ± 1 mm, 40 mm ± 1 mm, 41 mm ± 1 mm, 42 mm ± 1 mm, 43 mm ± 1 mm, or 44 mm ± 1 mm) when measured 3 cm from the device. The spray pattern may be characterized as having a minimum diameter of between 20 mm and 27 mm (e.g., 20 mm ± 1 mm, 21 mm ± 1 mm, 22 mm ± 1 mm, 23 mm ± 1 mm, 24 mm ± 1 mm, 25 mm ± 1 mm, 26 mm ± 1 mm, or 27 mm ± 1 mm) when measured 3 cm from the device. For example, the spray pattern may be characterized as having a minimum diameter of between 21 mm and 23 mm (e.g., 21 mm ± 1 mm, 22 mm ± 1 mm, or 23 mm ± 1 mm) when measured 3 cm from the device. The spray pattern may be characterized as having a maximum diameter of between 19 mm and 135 mm (e.g., 19 mm ± 2 mm, 21 mm ± 2 mm, 23 mm ± 2 mm, 25 mm ± 2 mm, 27 mm ± 2 mm, 29 mm ± 2 mm, 31 mm ± 2 mm, 33 mm ± 2 mm, 35 mm ± 2 mm, 37 mm ± 2 mm, 39 mm ± 2 mm, 41 mm ± 2 mm, 43 mm ± 2 mm, 45 mm ± 2 mm, 47 mm ± 2 mm, 49 mm ± 2 mm, 51 mm ± 2 mm, 53 mm ± 2 mm, 55 mm ± 2 mm, 57 mm ± 2 mm, 59 mm ± 2 mm, 61 mm ± 2 mm, 63 mm ± 2 mm, 65 mm ± 2 mm, 67 mm ± 2 mm, 69 mm ± 2 mm, 71 mm ± 2 mm, 73 mm ± 2 mm, 75 mm ± 2 mm, 77 mm ± 2 mm, 79 mm ± 2 mm, 81 mm ± 2 mm, 83 mm ± 2 mm, 85 mm ± 2 PATENT

[0016] ATTORNEY DOCKET NO.: 51378-005WO2

[0017] mm, 87 mm ± 2 mm, 89 mm ± 2 mm, 91 mm ± 2 mm, 93 mm ± 2 mm, 95 mm ± 2 mm, 97 mm ± 2 mm, 99 mm ± 2 mm, 101 mm ± 2 mm, 103 mm ± 2 mm, 105 mm ± 2 mm, 107 mm ± 2 mm, 109 mm ± 2 mm, 111 mm ± 2 mm, 113 mm ± 2 mm, 115 mm ± 2 mm, 117 mm ± 2 mm, 119 mm ± 2 mm, 121 mm ± 2 mm, 123 mm ± 2 mm, 125 mm ± 2 mm, 127 mm ± 2 mm, 129 mm ± 2 mm, 131 mm ± 2 mm, 133 mm ± 2 mm, or 135 mm ± 2 mm) when measured 6 cm from the device. In some embodiments, the spray pattern is characterized as having a maximum diameter of between 33 mm and 69 mm (e.g., 33 mm ± 2 mm, 35 mm ± 2 mm, 37 mm ± 2 mm, 39 mm ± 2 mm, 41 mm ± 2 mm, 43 mm ± 2 mm, 45 mm ± 2 mm, 47 mm ± 2 mm, 49 mm ± 2 mm, 51 mm ± 2 mm, 53 mm ± 2 mm, 55 mm ± 2 mm, 57 mm ± 2 mm, 59 mm ± 2 mm, 61 mm ± 2 mm, 63 mm ± 2 mm, 65 mm ± 2 mm, 67 mm ± 2 mm, or 69 mm ± 2 mm) when measured 6 cm from the device. The spray pattern may be characterized as having a maximum diameter of between 40 mm and 59 mm (e.g., 40 mm ± 2 mm, 42 mm ± 2 mm, 44 mm ± 2 mm, 46 mm ± 2 mm, 48 mm ± 2 mm, 50 mm ± 2 mm, 52 mm ± 2 mm, 54 mm ± 2 mm, 56 mm ± 2 mm, 58 mm ± 2 mm, or 59 mm ± 2 mm) when measured 6 cm from the device. For example, the spray pattern may be characterized as having a maximum diameter of between 45 mm and 57 mm (e.g., 45 mm ± 1 mm, 46 mm ± 1 mm, 47 mm ± 1 mm, 48 mm ± 1 mm, 49 mm ± 1 mm, 50 mm ± 1 mm, 51 mm ± 1 mm, 52 mm ± 1 mm, 53 mm ± 1 mm, 54 mm ± 1 mm, 55 mm ± 1 mm, 56 mm ± 1 mm, or 57 mm ± 1 mm) when measured 6 cm from the device. In some embodiments, the spray pattern is characterized as having a minimum diameter of between 28 mm and 52 mm (e.g., 28 mm ± 1 mm, 29 mm ± 1 mm, 30 mm ± 1 mm, 31 mm ± 1 mm, 32 mm ± 1 mm, 33 mm ± 1 mm, 34 mm ± 1 mm, 35 mm ± 1 mm, 36 mm ± 1 mm, 37 mm ± 1 mm, 38 mm ± 1 mm, 39 mm ± 1 mm, 40 mm ± 1 mm, 41 mm ± 1 mm, 42 mm ± 1 mm, 43 mm ± 1 mm, 44 mm ± 1 mm, 45 mm ± 1 mm, 46 mm ± 1 mm, 47 mm ± 1 mm, 48 mm ± 1 mm, 49 mm ± 1 mm, 50 mm ± 1 mm, 51 mm ± 1 mm, or 52 mm ± 1 mm) when measured 6 cm from the device. For example, the spray pattern may be characterized as having a minimum diameter of between 36 mm and 44 mm (e.g., 36 mm ± 1 mm, 37 mm ± 1 mm, 38 mm ± 1 mm, 39 mm ± 1 mm, 40 mm ± 1 mm, 41 mm ± 1 mm, 42 mm ± 1 mm, 43 mm ± 1 mm, or 44 mm ± 1 mm) when measured 6 cm from the device.

[0018] The spray pattern may be characterized as having an ovality of from 0.7 to 2.2 (e.g., 0.7±0.1, 0.8±0.1, 0.9±0.1, 1.0±0.1, 1.1 ±0.1, 1.2±0.1, 1.3±0.1, 1.4±0.1, 1.5±0.1, 1.6±0.1, 1.7±0.1, 1.8±0.1, 1.9±0.1, 2.0±0.1, 2.1 ±0.1, or 2.2±0.1 ). The spray pattern may be characterized as having an ovality of from 1 to 1.6 (e.g., 1 ±0.1, 1.1 ±0.1, 1.2±0.1, 1.3±0.1, 1.4±0.1, 1.5±0.1, or 1,6±0.1 ). For example, the spray pattern may be characterized as having an ovality of from 1.1 to 1.4 (e.g., 1.1 ±0.1, 1,2±0.1, 1,3±0.1, or 1,4±0.1 ). In some embodiments, the spray pattern is characterized as having an ovality of about 1.3. The spray pattern may be characterized as having an ovality of between 1.2 and 1.4 (e.g., 1.2 ±0.1, 1.3±0.1, or 1.4 ±0.1 ) when measured 6 cm above the device. In some embodiments, the spray pattern has an ovality of between 0.7 and 2.2 when measured 6 cm above the device. For example, the spray pattern may be characterized as having an ovality of between 1.2 and 1.3 when measured 3 cm above the device. In some embodiments, the spray pattern has an ovality of between 0.7 and 2.2 when measured 3 cm above the device.

[0019] The plume may be characterized by having an angle of from 52° to 76° (e.g., 52°±1 °, 53°±1 °, 54°±1 °, 55°±1 °, 56°±1 °, 57°±1 °, 58°±1 °, 59°±1 °, 60°±1 °, 61 °±1 °, 62°±1 °, 63°±1 °, 64°±1 °, 65°±1 °, 66°±1 °, 67°±1 °, 68°±1 °, 69°±1 °, 70°±1 °, 71 °±1 °, 72°±1 °, 73°±1 °, 74°±1 °, 75°±1 °, or 76°±1 °) when measured at 6 cm above the device. In some embodiments, the plume is characterized by having an angle of from 56° to PATENT

[0020] ATTORNEY DOCKET NO.: 51378-005WO2

[0021] 68° (e.g., 56°±1 °, 57°±1 °, 58°±1 °, 59°±1 60°±1 °, 61 °±1 °, 62°±1 °, 63°±1 °, 64°±1 °, 65°±1 °, 66°±1 °, 67°±1°, or 68°±1°) when measured at 6 cm above the device. For example, the plume may be characterized by having a width of from 58 mm to 92 mm (e.g., 58 mm ± 2 mm, 60 mm ± 2 mm, 62 mm ± 2 mm, 63 mm ± 2 mm, 65 mm ± 2 mm, 67 mm ± 2 mm, 69 mm ± 2 mm, 70 mm ± 2 mm, 72 mm ± 2 mm, 74 mm ± 2 mm, 76 mm ± 2 mm, 78 mm ± 2 mm, 80 mm ± 2 mm, 82 mm ± 2 mm, 84 mm ± 2 mm, 86 mm ± 2 mm, 88 mm ± 2 mm, 90 mm ± 2 mm, or 92 mm ± 2 mm) when measured at 6 cm above the device.

[0022] The plume may be characterized by having an angle of from 63° to 76° (e.g., 63° ± 2°, 65° ± 2°, 67° ± 2°, 69° ± 2°, 70° ± 2°, 72 ° ± 2°, 74° ± 2°, or 76 ° ± 2°) when measured at 3 cm above the device. In some embodiments, the plume is characterized by having an angle of from 60° to 79° (e.g., 60° ± 1°, 61° ± 1 °, 62° ± 1 °, 63° ± 1 °, 64° ± 1 °, 65° ± 1 °, 66° ± 1 °, 67 ° ± 1 °, 68° ± 1 °, 69° ± 1 °, 70° ± 1 °, 71 ° ± 1 °, 72° ± 1 °, 73° ± 1 °, 74° ± 1 °, 75° ± 1 °, 76° ± 1 °, 77° ± 1 °, 78° ± 1°, or 79° ± 1 °) when measured at 3 cm above the device. In some embodiments, the plume is characterized by having a width of from 34 mm to 51 mm (e.g., 34 mm ± 1 mm, 35 mm ± 1 mm, 36 mm ± 1 mm, 37 mm ± 1 mm, 38 mm ± 1 mm, 39 mm ± 1 mm, 40 mm ± 1 mm, 41 mm ± 1 mm, 42 mm ± 1 mm, 43 mm ± 1 mm, 44 mm ± 1 mm, 45 mm ± 1 mm, 46 mm ± 1 mm, 47 mm ± 1 mm, 48 mm ± 1 mm, 49 mm ± 1 mm, 50 mm ± 1 mm, or 51 mm ± 1 mm) when measured at 3 cm above the device.

[0023] In some embodiments, the total volume delivered per actuation is between 80 pl and 120 pl (e.g., 80 pl± 5 pl, 85 pl± 5 pl, 90 pl± 5 pl, 95 pl± 5 pl, 100 pl± 5 pl, 105 pl± 5 pl, 110 pl± 5 pl, 115 pl± 5 pl, or 120 pl± 5 pl). For example, the total volume delivered per actuation may be about 100 pl.

[0024] In some embodiments, the pharmaceutically acceptable salt of bumetanide is potassium bumetanide. The pharmaceutical composition may have a concentration of potassium bumetanide of from 1 mg / mL to 15 mg / mL (e.g., 1 mg / mL ± 1 mg / mL, 2 mg / mL ± 1 mg / mL, 3 mg / mL ± 1 mg / mL, 4 mg / mL ± 1 mg / mL, 5 mg / mL ± 1 mg / mL, 6 mg / mL ± 1 mg / mL, 7 mg / mL ± 1 mg / mL, 8 mg / mL ± 1 mg / mL, 9 mg / mL ± 1 mg / mL, 10 mg / mL ± 1 mg / mL, 11 mg / mL ± 1 mg / mL, 12 mg / mL ± 1 mg / mL, 13 mg / mL ± 1 mg / mL, 14 mg / mL ± 1 mg / mL, or 15 mg / mL ± 1 mg / mL). For example, the pharmaceutical composition may have a concentration of potassium bumetanide of from 2 mg / mL to 10 mg / mL (e.g., 2 mg / mL ± 1 mg / mL, 3 mg / mL ± 1 mg / mL, 4 mg / mL ± 1 mg / mL, 5 mg / mL ± 1 mg / mL, 6 mg / mL ± 1 mg / mL, 7 mg / mL ± 1 mg / mL^ 8 mg / mL ± 1 mg / mL, 9 mg / mL ± 1 mg / mL, or 10 mg / mL ± 1 mg / mL). The pharmaceutical composition may have a concentration of potassium bumetanide of about 5 mg / mL. In some embodiments, the pharmaceutical composition has a concentration of potassium bumetanide of from 5 mg / mL to 6 mg / mL (e.g., 5.1 mg / mL ± 0.1 mg / mL, 5.2 mg / mL ± 0.1 mg / mL, 5.3 mg / mL ± 0.1 mg / mL, 5.4 mg / mL ± 0.1 mg / mL, 5.5 mg / mL ± 0.1 mg / mL, 5.6 mg / mL ± 0.1 mg / mL, 5.7 mg / mL ± 0.1 mg / mL, 5.8 mg / mL ± 0.1 mg / mL, 5.9 mg / mL ± 0.1 mg / mL, and 6.0 mg / mL ± 0.1 mg / mL). In some embodiments, the pharmaceutical composition has a concentration of potassium bumetanide of from 5.5 mg / mL to 5.6 mg / mL (e.g., 5.50 mg / mL ± 0.01 mg / mL, 5.51 mg / mL ± 0.01 mg / mL, 5.52 mg / mL ± 0.01 mg / mL, 5.53 mg / mL ± 0.01 mg / mL, 5.54 mg / mL ± 0.01 mg / mL, 5.55 mg / mL ± 0.01 mg / mL, 5.56 mg / mL ± 0.01 mg / mL, 5.57 mg / mL ± 0.01 mg / mL, 5.58 mg / mL ± 0.01 mg / mL, 5.59 mg / mL ± 0.01 mg / mL, or 5.60 mg / mL ± 0.01 mg / mL). In some embodiments, the pharmaceutical composition has a concentration of potassium bumetanide of about 5.54 mg / mL. In some embodiments, the pharmaceutical composition has a concentration of potassium bumetanide of from 5.26 mg / mL to 5.82 mg / mL (e.g., 5.25 mg / mL ± 0.05 mg / mL, 5.30 mg / mL ± 0.05 mg / mL, 5.35 mg / mL ± 0.05 mg / mL, 5.40 mg / mL ± 0.05 mg / mL, 5.45 mg / mL ± 0.05 mg / mL, 5.50 mg / mL ± PATENT

[0025] ATTORNEY DOCKET NO.: 51378-005WO2

[0026] 0.05 mg / mL, 5.55 mg / mL ± 0.05 mg / mL, 5.60 mg / mL ± 0.05 mg / mL, 5.65 mg / mL ± 0.05 mg / mL, 5.70 mg / mL ± 0.05 mg / mL, 5.75 mg / mL ± 0.05 mg / mL, or 5.80 mg / mL ± 0.05 mg / mL). The pharmaceutical composition may have a pH of between about 5 and about 9 (e.g., pH 5±0.5, 5.5±0.5, 6±0.5, 6.5±0.5, 7±0.5, 7.5±0.5, 8±0.5, 8.5±0.5, or 9±0.5). In some embodiments, the pharmaceutical composition has a pH of between about 6 and about 8.5. For example, the pharmaceutical composition may have a pH of between about 6 and about 8 (e.g., pH 6±0.5, 6.5±0.5, 7±0.5, 7.5±0.5, or 8±0.5). The pharmaceutical composition may have a pH of between 6.6 and 7.8 (e.g., 6.6 ± 0.1, 6.7 ± 0.1, 6.8 ± 0.1, 6.9± 0.1, 7.0± 0.1, 7.1 ± 0.1, 7.2 ± 0.1, 7.3 ± 0.1, 7.4 ± 0.1, 7.5 ± 0.1, 7.6 ± 0.1, 7.7 ± 0.1, and 7.8 ± 0.1). In some embodiments, the pharmaceutical composition has a pH of between about 6 and about 7.8.

[0027] In some embodiments, the one or more pharmaceutically acceptable excipients comprises a buffering agent, a preservative, a viscosity enhancer, or a tonicity agent.

[0028] In some embodiments, the pharmaceutical composition comprises a tonicity agent. The tonicity agent may have a concentration in the pharmaceutical composition of between 1 mg / mL and 100 mg / mL (e.g., 1 mg / mL ± 1 mg / mL, 2 mg / mL ± 1 mg / mL, 3 mg / mL ± 1 mg / mL, 4 mg / mL ± 1 mg / mL, 5 mg / mL ± 1 mg / mL, 6 mg / mL ± 1 mg / mL, 7 mg / mL ± 1 mg / mL, 8 mg / mL ± 1 mg / mL, 9 mg / mL ± 1 mg / mL, 10 mg / mL ± 5 mg / mL, 15 mg / mL ± 5 mg / mL, 20 mg / mL ± 5 mg / mL, 25 mg / mL ± 5 mg / mL, 30 mg / mL ± 5 mg / mL, 35 mg / mL ± 5 mg / mL, 40 mg / mL ± 5 mg / mL, 45 mg / mL ± 5 mg / mL, 50 mg / mL ± 5 mg / mL, 55 mg / mL ± 5 mg / mL, 60 mg / mL ± 5 mg / mL, 65 mg / mL ± 5 mg / mL, 70 mg / mL ± 5 mg / mL, 75 mg / mL ± 5 mg / mL, 80 mg / mL ± 5 mg / mL, 85 mg / mL ± 5 mg / mL, 90 mg / mL ± 5 mg / mL, 95 mg / mL ± 5 mg / mL, or 100 mg / mL ± 5 mg / mL). For example, the tonicity agent may have a concentration in the pharmaceutical composition of about 40 mg / mL. In some embodiments, the tonicity agent comprises mannitol. In some embodiments, the pharmaceutical composition has a mannitol concentration in an amount of from 38 mg / mL to 42 mg / mL. In some embodiments, the pharmaceutical composition has a mannitol concentration of 40 mg / mL.

[0029] The pharmaceutical composition may comprise a preservative. For example, the preservative may comprise benzyl alcohol. In some embodiments, the preservative has a concentration in the pharmaceutical composition of between 1 mg / mL and 10 mg / mL (e.g., 1 mg / mL ± 1 mg / mL, 2 mg / mL ± 1 mg / mL, 3 mg / mL ± 1 mg / mL, 4 mg / mL ± 1 mg / mL, 5 mg / mL ± 1 mg / mL, 6 mg / mL ± 1 mg / mL, 7 mg / mL ± 1 mg / mL, 8 mg / mL ± 1 mg / mL, 9 mg / mL ± 1 mg / mL, or 10 mg / mL ± 1 mg / mL). In some embodiments, the preservative has a concentration in the pharmaceutical composition of about 5 mg / mL. In some embodiments, the pharmaceutical composition has a benzyl alcohol concentration in an amount of from 4.75 mg / mL to 5.25 mg / mL. In some embodiments, the pharmaceutical composition has a benzyl alcohol concentration of 5 mg / mL.

[0030] The pharmaceutical composition may comprise a viscosity enhancer. The viscosity enhancer may comprise sodium carboxymethyl cellulose. For example, the viscosity enhancer may be low viscosity sodium carboxymethyl cellulose. In some embodiments, the viscosity enhancer has a final concentration in the pharmaceutical composition of between 0.1 mg / mL and 2 mg / mL (e.g., 0.1 mg / mL ± 0.1 mg / mL, 0.2 mg / mL ± 0.1 mg / mL, 0.3 mg / mL ± 0.1 mg / mL, 0.4 mg / mL ± 0.1 mg / mL, 0.5 mg / mL ± 0.1 mg / mL, 0.6 mg / mL ± 0.2 mg / mL, 0.8 mg / mL ± 0.2 mg / mL, 1 mg / mL ± 0.2 mg / mL, 1.2 mg / mL ± 0.2 mg / mL, 1.4 mg / mL ± 0.2 mg / mL, 1.6 mg / mL ± 0.2 mg / mL, 1.8 mg / mL ± 0.2 mg / mL, or 2 mg / mL ± 0.2 mg / mL). For example, the viscosity enhancer may have a final concentration in the pharmaceutical composition is about 1 PATENT

[0031] ATTORNEY DOCKET NO.: 51378-005WO2

[0032] mg / mL. In some embodiments, the pharmaceutical composition has a viscosity of 1.3 cPs to 1.6 cPs (e.g., 1.3 cPs±0.1 cPs, 1.4 cPs±0.1 cPs, 1.5 cPs±0.1 cPs, or 1.6 cPs±0.1 cPs). In some embodiments, the pharmaceutical composition has a viscosity of 1.3 mm2 / g to 1.6 mm2 / g (e.g., 1.3 mm2 / g±0.1 mm2 / g, 1.4 mm2 / g±0.1 mm2 / g, 1.5 mm2 / g±0.1 mm2 / g, or 1.6 mm2 / g±0.1 mm2 / g). In some embodiments, the pharmaceutical composition has a viscosity of from 1.2 mm2 / s to 2.0 mm2 / s (e.g., 1.2 mm2 / s±0.1 mm2 / s, 1.3 mm2 / s±0.1 mm2 / s, 1.4 mm2 / s±0.1 mm2 / s, 1.5 mm2 / s±0.1 mm2 / s, 1.6 mm2 / s±0.1 mm2 / s, 1.7 mm2 / s±0.1 mm2 / s, 1.8 mm2 / s±0.1 mm2 / s, 1.9 mm2 / s±0.1 mm2 / s, or 2.0 mm2 / s±0.1 mm2 / s). In some embodiments, the pharmaceutical composition has a viscosity of 1.3 mm2 / s to 1.6 mm2 / s (e.g., 1.3 mm2 / s±0.1 mm2 / s, 1.4 mm2 / s±0.1 mm2 / s, 1.5 mm2 / s±0.1 mm2 / s, or 1.6 mm2 / s±0.1 mm2 / s). The pharmaceutical composition has a sodium carboxymethyl cellulose concentration in the amount of 0.95 mg / mL to 1.05 mg / mL. In some embodiments, the pharmaceutical composition has a sodium carboxymethyl cellulose concentration in the amount of 1 mg / mL.

[0033] The pharmaceutical composition may comprise bumetanide in an amount of 5 mg / mL, a viscosity enhancer in an amount of 1 mg / mL, a preservative in an amount of 5 mg / mL, and a tonicity agent in an amount of 40 mg / mL. The pharmaceutical composition may comprise 5 mg / mL potassium bumetanide, 1 mg / mL sodium carboxymethyl cellulose, 5 mg / mL benzyl alcohol, and 40 mg / mL mannitol. The pharmaceutical composition may be an aqueous solution having a pH between 6 and 8, comprising potassium bumetanide in an amount of from 5.26 mg / mL to 5.82 mg / mL, sodium carboxymethyl cellulose in an amount of from 0.95 mg / mL to 1.05 mg / mL, benzyl alcohol in an amount of from 4.75 mg / mL to 5.25 mg / mL, and mannitol in an amount of from 38 mg / mL to 42 mg / mL. The pharmaceutical composition may comprise potassium bumetanide in an amount of 5.54 mg / mL, sodium carboxymethyl cellulose (low viscosity) having a final concentration of 1 mg / mL, benzyl alcohol having a final concentration of 5 mg / mL, and mannitol in water having a final concentration of 40 mg / mL, wherein the pharmaceutical composition has a pH of between 6.6. and 7.8. In some embodiments, the pharmaceutical composition is a composition consisting of potassium bumetanide in the amount of 5.54 mg / mL, sodium carboxymethyl cellulose in the amount of 1 mg / mL, benzyl alcohol in the amount of 5 mg / mL, and mannitol in the amount of 40 mg / mL.

[0034] The nasal delivery device may comprises a body, a reservoir containing the pharmaceutical composition, a nasal dispensing head comprising a dispensing orifice, and dispensing means for dispensing at least a portion of the pharmaceutical composition through the dispensing orifice upon actuation. The device may further comprise a linear actuating system, wherein the linear actuating system is integral with the nasal dispensing member, wherein the linear actuating system comprises at least one actuating element cooperating with the reservoir. The linear actuating system may be a manual linear actuating system. In some embodiments, the actuating element is movable between a rest position, wherein the dispensing member is not actuated and an actuation arrangement, wherein the dispensing member is actuated. The device may further comprise a surface guide fixed relative the nasal dispensing head and substantially parallel to the axis of movement of the moveable member in the body upon actuation of the nasal dispensing member. The device may be a non-priming device, such that the nasal spray device not require one pump of the device to be sprayed away from the subject prior to administration to the subject. In some embodiments, the subject is suffering from edema refractory to oral PATENT

[0035] ATTORNEY DOCKET NO.: 51378-005WO2

[0036] diuretics. The subject may have congestive heart failure. The subject may be suffering from edema in the lung. The subject may be suffering from edema in the gastro-intestinal tract.

[0037] In some embodiments, the pharmaceutical composition is administered intranasally to the subject in an outpatient setting or the pharmaceutical composition is self-administered. In some embodiments, the subject has failed to achieve diuresis with oral diuretic therapy prior to the administering. The subject may be experiencing swelling of the legs, shortness of breath, difficulty breathing, or chest pain unresolved with oral diuretic therapy prior to the administering. In some embodiments, the subject is experiencing reduced intestinal motility prior to the administering.

[0038] Brief Description of the Drawings

[0039] FIG. 1 A and FIG. 1 B show two schematics of a unit dose sprayer (UDS) nasal delivery device which may be used to deliver the pharmaceutical composition.

[0040] FIG.2A and FIG. 2B show an exemplary spray pattern measured at 3 cm from the origin of the plume (FIG. 2A) and measured at 6 cm from the origin of the plume (FIG. 2B).

[0041] FIG.3A and FIG. 3B show an exemplary plume geometry measured at 3 cm from the origin of the plume (FIG. 3A) and measured at 6 cm from the origin of the plume (FIG. 3B).

[0042] Definitions

[0043] As used herein, the term “about” refers to a value that is within 10% above or below the value being described. For instance, the phrase “about 6 mg / mL” refers to a value between 5.4 and 6.6 mg / mL.

[0044] The term “administration” or “administering” refers to a method of giving a dosage of a pharmaceutical composition to a patient, where the method is systemic, e.g., intranasal. The preferred method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, site of administration, and severity of the symptoms being treated.

[0045] As used herein, the terms "axial" and "radial" refer to the longitudinal axis of the nasal delivery device.

[0046] As used herein, there term “droplet size distribution” refers to the variability of droplet sizes emitted in the plume which may be characterized as in terms of the diameter which 10% of the droplets in the plume have a smaller diameter than (Dv10), the diameter which 50% of the droplets in the plume have a smaller diameter than (Dv50), or the diameter which 90% of the droplets in the plume have a smaller diameter than (Dv90). The droplet size distribution may also be characterized by the span of droplet sizes present in the plume, wherein the span is calculated as (Dv90-Dv10) / Dv50.

[0047] As used herein, the term "effective amount," refers to a quantity of a pharmaceutical composition sufficient to, when administered to the subject, for example a human subject, affect beneficial or desired results, such as clinical results. For example, in the context of edema, described herein, this term refers to an amount of the composition sufficient to achieve a reduction in the symptoms of edema as compared to the response obtained without administration of the composition. The quantity of a given composition described herein that will correspond to such an amount depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the identity of the subject (e.g., age, sex, weight) being treated, and the like. PATENT

[0048] ATTORNEY DOCKET NO.: 51378-005WO2

[0049] As used herein, the terms “edema in the lung” or “pulmonary edema” refer to a condition where the patient has excess fluid in the lungs, which results in difficulty breathing. Edema in lungs may be caused by conditions related to heart failure, pneumonia, trauma, an allergic reaction, or another cause.

[0050] As used herein, the term “edema refractory to oral diuretics” refers to edema that is not responsive to oral diuretic treatment, such that diuresis is not achieved and excessive bodily fluid persists despite treatment with oral diuretics, thus resulting in persistence of the edematous state.

[0051] As used herein, the term “failed to achieve diuresis” refers to a patient’s lack of increased voiding of bodily fluid and consequent persistence of an edematous state despite administration of oral diuretics.

[0052] As used herein, the term “intranasal” or “intranasally” refers to a method of administration of a pharmaceutical composition wherein the composition is delivered by way of the nasal cavity.

[0053] As used herein, the term “loop diuretic” means a drug used in patients with congestive heart failure or renal insufficiency to reduce symptoms of hypertension and edema. A loop diuretic belongs to a class of diuretic agents that reduce reabsorption of sodium and chloride by the kidney leading in an increased secretion of urine.

[0054] As used herein, the term “low viscosity sodium carboxymethyl cellulose” or “low viscosity sodium CMC” refers to sodium carboxymethyl cellulose which has a viscosity of between 30 cP and 50 cP (e.g., 30±1 cP, 31 ±1 cP, 32±1 cP, 33±1 cP, 34±1 cP, 35±1 cP, 36±1 cP, 37±1 cP, 38±1 cP, 39±1 cP, 40±1 cP, 41 ±1 cP, 42±1 cP, 43±1 cP, 44±1 cP, 45±1 cP, 46±1 cP, 47±1 cP, 48±1 cP, 49±1 cP, and 50±1 cP) in 2% aqueous solution at 25 °C or between 50-200 cP in 4% aqueous solution at 25 °C. Low viscosity sodium carboxymethyl cellulose can have a molecular weight of approximately 90 kDa. The viscosity may also be from 30 mm2 / g to 50 mm2 / g (e.g., 30±1 mm2 / g, 31 ±1 mm2 / g, 32±1 mm2 / g, 33±1 mm2 / g, 34±1 mm2 / g, 35±1 mm2 / g, 36±1 mm2 / g, 37±1 mm2 / g, 38±1 mm2 / g, 39±1 mm2 / g, 40±1 mm2 / g, 41 ±1 mm2 / g, 42±1 mm2 / g, 43±1 mm2 / g, 44±1 mm2 / g, 45±1 mm2 / g, 46±1 mm2 / g, 47±1 mm2 / g, 48±1 mm2 / g, 49±1 mm2 / g, and 50±1 mm2 / g). The viscosity may also be from 30 mm2 / s to 45 mm2 / s (e.g., 30±1 mm2 / s, 31 ±1 mm2 / s, 32±1 mm2 / s, 33±1 mm2 / s, 34±1 mm2 / s, 35±1 mm2 / s, 36±1 mm2 / s, 37±1 mm2 / s, 38±1 mm2 / s, 39±1 mm2 / s, 40±1 mm2 / s, 41 ±1 mm2 / s, 42±1 mm2 / s, 43±1 mm2 / s, 44±1 mm2 / s, and 45±1 mm2 / s) in 2% aqueous solution at 25 °C. Sodium carboxymethyl cellulose may also be defined by degree of substitution. For example, the sodium carboxymethyl cellulose of the invention may have a degree of substitution of between 0.65 and 0.90.

[0055] As used herein, the terms “plume ovality” and “ovality” when used in connection with a plume, refers to shape and size of the plume at a distance from its origin. The ovality of the plume is measured as the ratio of the largest diameter of the plume at a particular distance from the origin of the plume to the smallest diameter of the plume at the same particular distance from the origin of the plume.

[0056] As used herein, the term “pharmaceutically acceptable salt,” represents those salts which are suitable for use in the treatment of humans without undue toxicity. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. PH. Stahl and C. G. Wermuth), Wiley-VCH, 2008. The salts can be prepared, for example, in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include, without limitation, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, PATENT

[0057] ATTORNEY DOCKET NO.: 51378-005WO2

[0058] camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include, without limitation, sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, L-a-phosphatidylethanolamine, bis(2-ethylhexyl)amine, soy Lecithin and the like. Representative amino acid salts include lysine, arginine, glycine, histidine, and the like. One of skill in the art will recognize that any mention of a drug compound includes within its scope the pharmaceutically acceptable salts of the indicated drug compound.

[0059] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms, which are suitable for contact with the tissues of a subject, such as a mammal (e.g., a human) without excessive toxicity, irritation, allergic response, and other problem complications commensurate with a reasonable benefit / risk ratio.

[0060] As used herein, the term “pharmaceutical composition” refers to a mixture containing a therapeutic agent, optionally in combination with one or more pharmaceutically acceptable excipients, diluents, and / or carriers, to be administered to a subject in order to prevent, treat, or control a particular disease or condition affecting or that may affect the subject.

[0061] As used herein, the term “pharmaceutically acceptable salt,” represents those salts which are suitable for use in the treatment of humans without undue toxicity. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P. H. Stahl and C. G. Wermuth), Wiley-VCH, 2008. The salts can be prepared, for example, in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include, without limitation, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include, without limitation, sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, L-a-phosphatidylethanolamine, bis(2-ethylhexyl)amine, soy Lecithin and the like. Representative amino acid PATENT

[0062] ATTORNEY DOCKET NO.: 51378-005WO2

[0063] salts include lysine, arginine, glycine, histidine, and the like. One of skill in the art will recognize that any mention of a drug compound includes within its scope the pharmaceutically acceptable salts of the indicated drug compound.

[0064] As used herein, the terms “plume geometry” and “geometry” when used in connection with a plume, means the measurement of the angle of the plume at its origin. Plume geometry can be measured at two distances from the origin of the plume, for example, at two side views 90° relative to each other. The plume geometry may be determined by measuring the angle between a first arm of the plume and a longitudinal access and a second arm of the plume that is 180° relative to the first arm in comparison to a longitudinal access, wherein the angle between the first arm of the plume and a longitudinal access and the angle between the second arm of the plume and a longitudinal access measure the total plume angle.

[0065] As used herein, the term “potassium-sparing diuretics” refers to a kind of diuretic drug that does not promote the secretion of potassium into urine, thus increasing fluid voiding. These diuretics can be used alone or in conjunction with loop or thiazide diuretics.

[0066] As used herein, the term “reduced intestinal motility” refers to a slowing of the activity of the gastrointestinal tract in a subject. One effect of the slowed activity can be reduced absorption, thus preventing effective absorption of pharmaceutical compositions. For example, this reduced intestinal motility can be caused by edema (e.g., such as fluid overload resulting from congestive heart failure) and prevents adequate absorption of the oral diuretics necessary for the treatment of the edema.

[0067] As used herein, the term “risk of hospitalization” refers to the potential likelihood that a patient is hospitalized for the treatment of edema, instead of effectively treating the edema without hospitalization by self-administering bumetanide using a method of the invention. A reduced risk of hospitalization is assessed for a given diseased population (e.g., patients suffering from congestive heart failure) of a particular severity comparing hospitalization rates for the treatment of edema in patients selfadministering bumetanide to patients relying solely upon oral diuretics to treat the edema. Using the bumetanide methods of the invention, the hospitalization rates for the treatment of edema in a population of patients can be reduced by at least 10%, 20%, 30%, or 50%, and so the risk of hospitalization in individual patients using bumetanide can be reduced.

[0068] As used herein, the term “spray pattern” refers to the maximum diameter of a plume at a particular distance from the origin, the minimum diameter of a plume at a known distance from the origin, and / or the ovality of the plume at a known distance from the origin.

[0069] As used herein, "treatment" and "treating" refer to therapy for a subject in need of diuresis, such as therapy to ameliorate one or more symptoms of edema in a subject suffering from edema, or prophylactically reducing the risk of one or more symptoms of edema in a subject at risk of from edema.

[0070] As used herein, the term “unit dose” or “dosage” when used in reference to a therapeutic composition refers to physically discrete units suitable as unitary dosage for the subject, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required diluent, i.e., carrier, or vehicle.

[0071] Detailed Description

[0072] The invention features methods of treating edema in a subject in need thereof by administering a pharmaceutical composition of bumetanide intranasally. The pharmaceutical composition described PATENT

[0073] ATTORNEY DOCKET NO.: 51378-005WO2

[0074] herein may be administered intranasally using a nasal delivery device. The nasal delivery device generates a plume comprising the pharmaceutical composition upon actuation of the device. For example, the plume consists of droplets of the pharmaceutical composition comprising bumetanide. The plume may be characterized by the amount of volume it delivers per actuation, the average droplet size of the droplets in the plume, the spray pattern of the plume, and geometry of the plume, one or more of which may impact the bioavailability of the bumetanide in the subject. With greater bioavailability of the bumetanide in the subject, edema may be effectively and quickly treated in the subject.

[0075] Intranasal administration of bumetanide to patients who are experiencing edema refractory to oral diuretics due to their edematous state (e.g., an occurrence found in patients suffering from edema related reduced intestinal motility) can relieve the edema and restore the effectiveness of orally administered diuretics without the need for hospitalization. Subjects may be able to self-administer the pharmaceutical composition using a nasal delivery device based on their symptoms, therefore, preventing the need for hospitalization, or the pharmaceutical composition may be administered by a medical professional (e.g., medical doctor, emergency responder or nurse) when a subject is experiencing acute distress.

[0076] Furthermore, the methods of the invention can reduce the risk of kidney failure in certain patients, such as those suffering from congestive heart failure. When such patients are in an edematous state and experiencing fluid overload, gastrointestinal absorption can be compromised, thus limiting the effectiveness of oral diuretics. As a result, the patient is often instructed to increase the dosage of oral diuretics putting further strain on the patient’s kidneys. Eventually, oral diuretics become insufficient to remove excess fluid causing the patients to be hospitalized to receive intravenous diuretics to bypass the gastrointestinal system. Consequently, the patients are at risk of over-diuresis once gastrointestinal absorption is restored. This over-diuresis can result in kidney failure.

[0077] Methods of Treatment

[0078] The methods and compositions of the invention can be used in patients generally at risk of edema. The edema may be, for example, pedal edema, peripheral edema, edema of the gastrointestinal tract, lung edema (e.g., pulmonary edema). The methods and compositions of the invention may be used where the subject is a mammal. Specifically, the subject may be a dog, where the dog is need of veterinary care. Additionally, the subject may be a human. Subjects that may be treated using the methods described herein are subjects having a diagnosis of congestive heart failure. Congestive heart failure (CHF) is characterized by an inability of the heart to generate sufficient cardiac output to meet the body’s demands. Patients having CHF experience signs and symptoms of intravascular and interstitial volume overload, including shortness of breath, rapid heart rate, fluid in the lungs, and edema, along with indicators of inadequate tissue perfusion, including fatigue and / or poor exercise tolerance. Subjects that may be treated include those that have heart failure diagnosed by the standard and routine diagnostic procedures known in the art (e.g., electrocardiography (ejection fraction), radionuclide imaging, magnetic resonance imaging, computed tomography imaging, cardiac catheterization with angiography, heart muscle biopsy, and / or assessment of atrial natriuretic peptide (ANP) and / or B-type natriuretic peptide levels in the blood (BNP)).

[0079] Subjects that may be treated are currently experiencing symptoms known to be associated with congestive heart failure, such as shortness of breath (e.g. dyspnea), fatigue, weakness, peripheral PATENT

[0080] ATTORNEY DOCKET NO.: 51378-005WO2

[0081] edema, or fluid overload. Subjects may be taking a daily dosage of oral diuretics, such as loop diuretics, potassium-sparing diuretics, or thiazides, to reduce the fluid overload and edema along with any one of the symptoms associated with congestive heart failure.

[0082] Subjects that may be treated using the methods described herein are experiencing symptoms of renal insufficiency caused by a reduction in blood flow, such as decreased urine output, swelling of the legs, ankles, feet, or abdomen, shortness of breath or fatigue caused by fluid overload as a result of the renal insufficiency. Subjects may experience fluid overload to the level wherein intestinal mobility becomes compromised preventing normal absorption of ingested nutrients, leading to inadequate gastrointestinal absorption, making for reduced bioavailability of pharmaceutical compositions administered orally.

[0083] Subjects that may be treated using the methods described herein can be experiencing symptoms of refractory edema as a result of congestive heart failure along with decreased intestinal mobility, thus preventing the subject’s oral diuretics from effectively causing diuresis to remove excess bodily fluid. As a result of the persistence of symptoms of edema such as fatigue, shortness of breath and swollen limbs and abdomen, the subject seeks hospitalization to be administered intravenous diuretics, which then have the potential to put the subject at risk for kidney failure.

[0084] Pharmaceutical Compositions

[0085] The bumetanide formulations described herein can be solutions, suspensions, or emulsions. The formulations can include surfactants, antioxidants, pH adjusting agents (e.g., an acid or a base), buffering agents, preservatives, tonicity agents, viscosity enhancers (e.g., carboxymethylcellulose), surfactants, and / or permeation enhancing agents. The formulations may be administered as an aqueous solution on in the form of an emulsion, including nanoemulsions and microemulsions. The formulations may be provided in a single or multidose form. The formulation may be administered intranasally. The bumetanide described herein may be administered, for example, by means of a metering atomizing spray pump. The metered spray pump may be a single metered spray pump device (e.g., APTAR® Unidose, Unidose®Xtra) or may be a multi-dose metered pump device (e.g., APTAR® Bidose (BDS), MK® pump).

[0086] The pharmaceutical compositions described herein for use in a method of treating a subject suffering from edema includes bumetanide. The pharmaceutical composition may have a concentration of bumetanide of from 1 mg / mL to 15 mg / mL (e.g., 1 ±1 mg / mL, 2±1 mg / mL, 3±1 mg / mL, 4±1 mg / mL, 5±1 mg / mL, 6±1 mg / mL, 7±1 mg / mL, 8±1 mg / mL, 9±1 mg / mL, 10±1 mg / mL, 11 ±1 mg / mL, 12±1 mg / mL, 13±1 mg / mL, 14±1 mg / mL, or 15±1 mg / mL). For example, the bumetanide may be present in the pharmaceutical composition in an amount of from 2 mg / mL to 10 mg / mL (e.g., 2±1 mg / mL, 3±1 mg / mL, 4±1 mg / mL, 5±1 mg / mL, 6±1 mg / mL, 7±1 mg / mL, 8±1 mg / mL, 9±1 mg / mL, or 10±1 mg / mL). In some embodiments, the pharmaceutical composition has a concentration of potassium bumetanide of about 5 mg / mL. In some embodiments, the pharmaceutical composition has a concentration of potassium bumetanide of about 5.54 mg / mL. The bumetanide may be administered as potassium bumetanide. The potassium bumetanide may have a concentration in the pharmaceutical composition of from 1 mg / mL to 15 mg / mL (e.g., 1 ±1 mg / mL, 2±1 mg / mL, 3±1 mg / mL, 4±1 mg / mL, 5±1 mg / mL, 6±1 mg / mL, 7±1 mg / mL, 8±1 mg / mL, 9±1 mg / mL, 10±1 mg / mL, 11 ±1 mg / mL, 12±1 mg / mL, 13±1 mg / mL, 14±1 mg / mL, or 15±1 mg / mL). PATENT

[0087] ATTORNEY DOCKET NO.: 51378-005WO2

[0088] Viscosity Enhancers

[0089] Viscosity enhancers can be used in the pharmaceutical compositions of the invention formulated for nasal administration. Viscosity enhancers that can be used in accordance with the present invention include, without limitation, cellulose derivatives, carbomers (Carbopol), gums, and hyaluronic acids (hyaluronates), dextrans, polyvinyl alcohol, polyacrylic acids, povidone, polyethylene glycol, polyols (e.g., glycerol), propylene glycol and chitosans; where for cellulose derivatives particularly preferred are one or more of carboxymethyl cellulose (" CMC") high molecular weight blend, CMC low molecular weight blend, CMC moderate molecular weight blend, Sodium CMC (low viscosity), methylcellulose, methyl cellulose 4000, hydroxymethyl cellulose, hydroxypropyl cellulose (" HPC"), hydroxypropylmethyl cellulose high molecular weight blend (" HPMC"), hydroxyl propyl methyl cellulose 2906, carboxypropylmethyl cellulose high molecular weight blend (" CPMC"), hydroxyethyl cellulose, or hydroxyethyl cellulose and hyaluronic acid. In particular embodiments, the viscosity enhancer is sodium CMC, preferably in combination with a polyol selected from the group consisting of mannitol, xylitol, sorbitol, isosorbide, erythritol, glycerol, maltitol and combinations thereof. In some embodiments, the viscosity enhancer is sodium carboxymethylcellulose.

[0090] The viscosity of the pharmaceutical composition may be from 1.1 to 1.8 cPs (e.g., 1.1 ±0.1 cPs, 1.2±0.1 cPs, 1.3±0.1 cPs, 1.4±0.1 cPs, 1.5±0.1 cPs, 1.6±0.1 cPs, 1.7±0.1 cPs, or 1,8±0.1 cPs). For example, the viscosity of the pharmaceutical composition may be from 1.3 to 1.6 cPs (e.g., 1.3±0.1 cPs, 1.4±0.1 cPs, 1.5±0.1 cPs, or 1,6±0.1 cPs). The viscosity of the pharmaceutical composition may be from 1.1 mm2 / g to 1.8 mm2 / g (e.g., 1.1 ±0.1 mm2 / g, 1.2±0.1 mm2 / g, 1.3±0.1 mm2 / g, 1.4±0.1 mm2 / g, 1.5±0.1 mm2 / g, 1,6±0.1 mm2 / g, 1,7±0.1 mm2 / g, or 1,8±0.1 mm2 / g). For example, the viscosity of the pharmaceutical composition may be from 1.3 to 1.6 mm2 / g (e.g., 1.3±0.1 mm2 / g, 1,4±0.1 mm2 / g, 1,5±0.1 mm2 / g, or 1,6±0.1 mm2 / g). In some embodiments, the pharmaceutical composition has a viscosity of from 1.2 mm2 / s to 2.0 mm2 / s (e.g., 1.2 mm2 / s±0.1 mm2 / s, 1.3 mm2 / s±0.1 mm2 / s, 1.4 mm2 / s±0.1 mm2 / s, 1.5 mm2 / s±0.1 mm2 / s, 1.6 mm2 / s±0.1 mm2 / s, 1.7 mm2 / s±0.1 mm2 / s, 1.8 mm2 / s±0.1 mm2 / s, 1.9 mm2 / s±0.1 mm2 / s, or 2.0 mm2 / s±0.1 mm2 / s). In another example, the viscosity of the pharmaceutical composition may be from 1.3 to 1.6 mm2 / s (e.g., 1.3±0.1 mm2 / s, 1.4±0.1 mm2 / s, 1.5±0.1 mm2 / s, or 1,6±0.1 mm2 / s). The viscosity enhancer may be present in the pharmaceutical composition in an amount of between 0.1 mg / mL and 2 mg / mL (e.g., 0.1 ±0.1 mg / mL, 0.2±0.1 mg / mL, 0.3±0.1 mg / mL, 0.4±0.1 mg / mL, 0.5±0.1 mg / mL, 0.6±0.2 mg / mL, 0.8±0.2 mg / mL, 1 ±0.2 mg / mL, 1.2±0.2 mg / mL, 1.4±0.2 mg / mL, 1.6±0.2 mg / mL, 1,8±0.2 mg / mL, or 2±0.2 mg / mL). For example, the viscosity enhancer may have a final concentration in the pharmaceutical composition of about 1 mg / mL. In some embodiments, the pharmaceutical composition comprises sodium carboxymethyl cellulose in an amount of from 1 mg / mL to 15 mg / mL (e.g., 1±1 mg / mL, 2±1 mg / mL, 3±1 mg / mL, 4±1 mg / mL, 5±1 mg / mL, 6±1 mg / mL, 7±1 mg / mL, 8±1 mg / mL, 9±1 mg / mL, 10±1 mg / mL, 11 ±1 mg / mL, 12±1 mg / mL, 13±1 mg / mL, 14±1 mg / mL, or 15±1 mg / mL).

[0091] Tonicity Agents

[0092] Tonicity agents can be utilized in the pharmaceutical compositions of the invention to modulate the tonicity of the liquid pharmaceutical composition. Tonicity in general relates to the osmotic pressure of a solution and is typically assessed relative to that of human blood serum. Tonicity agents may be PATENT

[0093] ATTORNEY DOCKET NO.: 51378-005WO2

[0094] included in pharmaceutical compositions (e.g., pharmaceutical dosage forms) to increase osmolality. Nonlimiting examples of tonicity agents include substantially neutral buffering agents (e.g., phosphate buffered saline, tris buffer, or artificial perilymph), dextrose, mannitol, trehalose, sucrose, sorbitol, glycerin (aka glycerol), potassium chloride, and sodium chloride (e.g., as a hypertonic, isotonic, or hypotonic saline) as well amino acids (e.g., arginine, glycine, ornithine, lysine, histidine, glutamic acid, aspartic acid, isoleucine, leucine, alanine, phenylalanine, tyrosine, tryptophan, methionine, serine, and proline). In some embodiments, the tonicity agent is mannitol. Pharmaceutical compositions (e.g., pharmaceutical dosage forms) include sufficient amount of tonicity agents to provide for administration to a subject a hypertonic pharmaceutical dosage form.

[0095] The tonicity agent may be present in the pharmaceutical composition in an amount of from 1 mg / mL to 100 mg / mL (e.g., 1 mg / mL to 80 mg / mL, 1 mg / mL to 60 mg / mL, 1 mg / mL to 40 mg / mL, 1 mg / mL to 20 mg / mL, 20 mg / mL to 100 mg / mL, 40 mg / mL to 100 mg / mL, 60 mg / mL to 100 mg / mL, 80 mg / mL to 100 mg / mL, 5 mg / mL to 50 mg / mL, or 10 mg / mL and 70 mg / mL). For example, the tonicity agent has a concentration in the pharmaceutical composition of about 40 mg / mL. In some embodiments, the pharmaceutical composition includes mannitol as the tonicity enhancer in an amount of from 10 mg / mL to 70 mg / mL (e.g., 10±5 mg / mL, 15±5 mg / mL, 20±5 mg / mL, 25±5 mg / mL, 30±5 mg / mL, 35±5 mg / mL, 40±5 mg / mL, 45±5 mg / mL, 50±5 mg / mL, 55±5 mg / mL, 60±5 mg / mL, 65±5 mg / mL, or 70±5 mg / mL).

[0096] Buffering Agents

[0097] In some embodiments, the pharmaceutical composition includes a buffering agent. A buffering agent may be included in the pharmaceutical composition to increase stability of the composition by maintaining a consistent pH range. A buffering agent may improve the ability of the composition to be absorbed by the subject. Additionally, the buffering agent may act to increase the solubility of the composition. A buffering agent may increase the solubility of the drug by maintaining a high solubility of the drug at a constant pH range, preferably pH 6- 8. The pharmaceutical composition may include a buffering agent such that the pH of the pharmaceutical composition is between about 5 and about 9 (e.g., 5±0.5, 5.5±0.5, 6±0.5, 6.5±0.5, 7±0.5, 7.5±0.5, 8±0.5, 8.5±0.5, or 9±0.5). In some embodiments, the pharmaceutical composition has a pH of between about 6 and about 8.5. For example, the pharmaceutical composition may have a pH of between about 6 and about 8 (e.g., 6±0.2, 6.2±0.2, 6.4±0.2, 6.6±0.2, 6.8±0.2, 7±0.2, 7.2±0.2, 7.4±0.2, 7.6±0.2, 7.8±0.2, or 8±0.2). In some embodiments, the pharmaceutical composition has a pH of between about 6 and about 7.8. The pharmaceutical composition may have a pH of between 6.6. and 7.8.

[0098] The buffering agents that can be used in accordance with the present invention include but are not limited to, potassium hydroxide, arginine, and Lysine. One or more components of the pharmaceutical composition (e.g., potassium hydroxide, arginine, and Lysine) may act as the counter ion species of the buffer in which the bumetanide also functions as a buffering agent. A buffering agent may be added to the pharmaceutical composition depending on if the method of administration requires a specific pH range be maintained. For example, potassium hydroxide may be used as a buffering agent to adjust the pH to a value between 6.6 and 7.8. In a pharmaceutical composition comprising about 5.54 mg / mL potassium bumetanide where potassium hydroxide is used as a buffering agent in combination with bumetanide, the PATENT

[0099] ATTORNEY DOCKET NO.: 51378-005WO2

[0100] amount of potassium ion in the pharmaceutical composition would be from about 0.054 % w / w to about 0.31 % w / w. In some embodiments, the pharmaceutical composition has a potassium ion concentration of about 0.078 % w / w.

[0101] Preservatives

[0102] In some embodiments of the pharmaceutical composition, a preservative is included as part of the pharmaceutical composition in order to increase the stability and / or shelf-life of the pharmaceutical composition. A preservative may be in the form of an antioxidant, an antimicrobial agent, or a chelating agent for example. An antioxidant may be added to the pharmaceutical composition in order to prevent the oxidation of other components in the composition that may be sensitive to oxidation in the presence of oxygen or sunlight. An antimicrobial agent may be included in the pharmaceutical composition in order to inhibit contamination of the pharmaceutical composition by microbes. A chelating agent may be added to the pharmaceutical composition to bind the pharmaceutically active ingredient to protect it from deterioration and increase stability. The preservatives that can be used in accordance with the present invention include, without limitation, benzyl alcohol, benzoic acid, and ethylenediaminetetraacetic acid (EDTA). In some embodiments, the pharmaceutical composition includes benzyl alcohol.

[0103] In some embodiments, the preservative is present in the pharmaceutical composition in an amount of 1 mg / mL to 10 mg / mL (e.g., 1 ±1 mg / mL, 2±1 mg / mL, 3±1 mg / mL, 4±1 mg / mL, 5±1 mg / mL, 6±1 mg / mL, 7±1 mg / mL, 8±1 mg / mL, 9±1 mg / mL, or 10±1 mg / mL). For example, the preservative may have a concentration in the pharmaceutical composition of about 5 mg / mL. The pharmaceutical composition may include the preservative of benzyl alcohol in an amount of 1 mg / mL to 10 mg / mL (e.g., 1 ±1 mg / mL, 2±1 mg / mL, 3±1 mg / mL, 4±1 mg / mL, 5±1 mg / mL, 6±1 mg / mL, 7±1 mg / mL, 8±1 mg / mL, 9±1 mg / mL, or 10±1 mg / mL). In some embodiments, the pharmaceutical composition has a benzyl alcohol concentration of 5 mg / mL.

[0104] Permeation Enhancers

[0105] In some embodiments of the pharmaceutical compositions for nasal administration, a permeation enhancer may be included in the formulation to increase the intranasal bioavailability of the bumetanide. Examples of permeation enhancers that can be used in the pharmaceutical compositions of the invention include alcohol, aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramides, cetylpyridinium chloride, chitosan, cyclodextrins, deoxycholic acid, glycocholic acid, decanoyl, dimethyl sulfoxide, glyceryl monooleate, glycofurol, glycosylated sphingosines, glycyrrhetinic acids, 2-hydroxypropyl-P-cyclodextrin, laureth-9, lauric acid, lauroyl carnitine, sodium lauryl sulfate, lysophosphatidylcholine, menthol, poloxamer 407 or F68, poly-L-arginine, polyoxyethylene-9-lauryl ether, isopropyl myristate, isopropyl palmitate, lanolin, linoleic acid, medium chain triglycerides (MCT) menthol, myristic acid, myristyl alcohol, oleic acid, or salt thereof, oleyl alcohol, palmitic acid, polysorbate 80, propylene glycol, polyoxyethylene alkyl ethers, polyoxylglycerides, pyrrolidone, quillaia saponin, salicylic acid, sodium salt, b-sitosterol b-D-glucoside, sucrose cocoate, taurocholic acid, taurodeoxycholic acid, taurodihydrofusidic acid, thymol, tricaprylin, triolein, and alkylsaccharides, and combinations thereof, including but not limited to dodecyl maltoside, dodecyl-D-maltoside, tetradecyl maltoside, tetradecyl -b-D-maltoside and sucrose dodecanoate. Certain permeation enhancers can also function as surfactants (solubilizers) of bumetanide including, without PATENT

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[0107] limitation, glycerides, alkyl saccharides, ester saccharides, polyglycolized glycerides, and polysorbate surfactants. In particular embodiments, the permeation enhancer used in the pharmaceutical composition of the invention is selected from tetradecyl-β-D-maltoside, soy lecithin, lecithin (E80) distearoyl glycerol-3-phosphatidylamine, and L-a-phosphatidylethanolamine and bis(2-ethylhexyl) amine.

[0108] Plume Characterization

[0109] The plume and its droplets of the pharmaceutical composition comprising bumetanide and one or more pharmaceutically acceptable excipients may be characterized using one or more method characterization. For example, the plume may be characterized according to the total volume that is dispensed upon actuation of the nasal spray device, the average diameter of the droplets in the plume, the maximum diameter of the plume, the minimum diameter of the plume, the ovality of the plume, or the angle of the plume when it is dispensed.

[0110] Volume

[0111] The total volume of the pharmaceutical composition comprising bumetanide and one or more pharmaceutically acceptable excipients that is dispensed upon actuation of the nasal spray device may be characterized. In some embodiments, the total volume delivered per actuation is between 50 pl and 150 pl (e.g., 50±10 pl, 60±10 pl, 70±10 pl, 80±10 pl, 90±10 pl, 100±10 pl, 110±10 pl, 120±10 pl, 130±10 pl, 140±10 pl, or 150±10 pl). For example, the total volume delivered per actuation may be between 80 pl and 120 pl (e.g., 80±2 pl, 82±2 pl, 84±2 pl, 86±2 pl, 88±2 pl, 90±2 pl, 92±2 pl, 94±2 pl, 96±2 pl, 98±2 pl, 100±2 pl, 102±2 pl, 104±2 pl, 106±2 pl, 108±2 pl, 110±2 pl, 112±2 pl, 114±2 pl, 116±2 pl, 118±2 pl, or 120±2 pl). The total volume delivered per actuation may be about 100 pl.

[0112] Droplet Size

[0113] The droplets of the pharmaceutical composition comprising bumetanide and one or more pharmaceutically acceptable excipient that are generated upon actuation of the nasal spray device may be characterized by their size. The resulting droplets from actuation of the nasal spray device may have an average diameter ranging from 1 pm to 300 pm (e.g., 1 pm to 275 pm, 1 pm to 250 pm, 1 pm to 225 pm, 1 pm to 210 pm, 1 pm to 200 pm, 1 pm to 175 pm, 1 pm to 150 pm, 1 pm to 125 pm, 1 pm to 100 pm, 1 pm to 75 pm, 1 pm to 50 pm, 1 pm to 25 pm, 10 pm to 300 pm, 15 pm to 50 pm, 25 pm to 300 pm, 50 pm to 150 pm, 50 pm to 300 pm, 75 pm to 300 pm, 100 pm to 300 pm, 125 pm to 300 pm, 150 pm to 300 pm, 200 pm to 300 pm, 225 pm to 300 pm, 250 pm to 300 pm, or 10 pm to 200 pm). The resulting droplets from actuation of the nasal spray device may have an average diameter ranging from 1 pm to 250 pm (e.g., 1 pm to 210 pm 1 pm to 250 pm, 1 pm to 225 pm, 1 pm to 200 pm, 1 pm to 175 pm, 1 pm to 150 pm, 1 pm to 125 pm, 1 pm to 100 pm, 1 pm to 75 pm, 1 pm to 50 pm, 1 pm to 25 pm, 10±10 pm, 20±10 pm, 30±10 pm, 40±10 pm, 50±10 pm, 60±20 pm, 80±20 pm, 100±25 pm, 125±25 pm, 150±25 pm, 175±25 pm, 200±25 pm, 225±25 pm, or 250±25 pm). The droplets from actuation of the nasal spray device may also have an average diameter ranging from 1 pm to 210 pm (e.g., 1 pm to 210 pm 1 pm to 200 pm, 1 pm to 175 pm, 1 pm to 150 pm, 1 pm to 125 pm, 1 pm to 100 pm, 1 pm to 75 pm, 1 pm to 50 pm, 1 pm to 25 pm, 10±10 pm, 20±10 pm, 30±10 pm, 40±10 pm, 50±10 pm, 60±20 pm, 80±20 pm, 100±25 pm, 125±25 pm, 150±25 pm, 175±25 pm, 200±10 pm, or 210 pm) For example, the droplets may have an PATENT

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[0115] average diameter ranging from 50 gm to 150 gm (e.g., 50±10 gm, 60±10 gm, 70±10 gm, 80±10 gm, 90±10 gm, 100±10 gm, 110±10 gm, 120±10 gm, 130±10 gm, 140±10 gm, or 150±10 gm). In some embodiments, the droplets have an average diameter ranging from 15 gm to 50 gm (e.g., 15±5 gm, 20±5 gm, 25±5 gm, 30±5 gm, 35±5 gm, 40±5 gm, 45±5 gm, or 50±5 gm). The droplets may have an average diameter of greater than 10 pm.

[0116] The droplet size may be characterized by the drop size distribution (DSD). The size distribution may be characterized by the diameter of droplets which encompass 90% of the droplets that are dispersed by the plume (Dv90), 50% of the droplets that are dispensed by the plume (Dv50), or 10% of the droplets that are dispensed by the plume. The Dv90 signifies the point in the size distribution, up to and including, 90% of all the droplets dispersed by the plume are smaller than. For example, if the Dv90 is 80 gm, this indicates that 90% of the droplets in the plume have a diameter of 80 gm or smaller. The definition for Dv50 is the diameter of the droplet below which 50% of the droplets dispensed are smaller. Similarly, the Dv10 is that size below which 10% of the droplets dispensed is smaller. These values may be determined by laser diffraction.

[0117] The droplet size may have a Dv10 of between 10 pm and 16 pm (e.g., 10±1 gm, 11 ±1 gm, 12±1 gm, 13±1 pm, 14±1 gm, 15±1 pm, 16±1 pm, between 11 gm and 15 gm, or between 12 gm and 14 gm) when measured 3 cm above the origin of the plume. In some embodiments, the droplets have a Dv10 of between 6 gm and 27 gm (e.g., 6±1 gm, 7±1 gm, 8±1 gm, 9±1 gm, 10±1 gm, 11 ±1 gm, 12±1 gm, 13±1 gm, 14±1 gm, 15±1 gm, 16±1 pm, 17±1 gm, 18±1 gm, 19±1 gm, 20±1 gm, 21 ±1 gm, 22±1 gm, 23±1 gm, 24±1 gm, 25±1 gm, 226±1 gm, or 27±1 gm) when measured 3 cm from the device. The droplet size may have a Dv50 of between 26 gm and 35 gm (e.g., 26±1 gm, 27±1 gm, 28±1 gm, 29±1 gm, 30±1 gm, 31 ±1 gm, 32±1 gm, 33±1 gm, 34±1 gm, 35±1 gm, between 29 gm and 33 gm, or between 30 gm and 31 gm) when measured 3 cm above the origin of the plume. In some embodiments, the droplets have a Dv50 of between 14 pm and 51 gm (e.g., 14±5 gm, 19±5 gm, 24±5 gm, 28±5 gm, 32±5 gm, 36±5 gm, 40±5 gm, 44±5 gm, or 49±5 gm) when measured 3 cm from the device. The droplet size may have a Dv90 of between 70 gm and 280 gm (e.g., 70±10 gm, 80±10 gm, 90±10 gm, 100±10 gm, 110±10 gm, 120±10 gm, 130±10 gm, 140±10 gm, 150±10 gm, 160±10 gm, 170±10 gm, 180±10 gm, 190±10 gm, 200±10 gm, 210±10 gm, 220±10 gm, 230±10 gm, 240±10 gm, 250±10 gm, 260±10 gm, 270±10 gm, 280±10 gm, between 70 gm and 280 gm, between 80 gm and 250 gm, between 90 gm and 200 gm, between 100 gm and 180 gm, between 120 gm and 150 gm, between 150 gm and 220 gm, or between 102 gm and 209 gm) when measured 3 cm above the origin of the plume. For example, the Dv90 may be between 70 gm and 240 gm (e.g., 70±10 gm, 80±10 gm, 90±10 gm, 100±10 gm, 110±10 pm, 120±10 gm, 130±10 gm, 140±10 gm, 150±10 gm, 160±10 gm, 170±10 gm, 180±10 gm, 190±10 gm, 200±10 gm, 210±10 gm, 220±10 gm, 230±10 gm, 240±10 gm, between 70 gm and 240 gm, between 80 gm and 220 gm, between 90 gm and 200 gm, between 100 gm and 180 gm, between 120 gm and 150 gm, between 150 gm and 220 gm, or between 102 gm and 209 gm). In some embodiments, the droplets have a Dv90 of between 70 gm and 500 gm (e.g., 70±20 gm, 90±20 gm, 110±20 gm, 130±20 gm, 150±20 gm, 170±20 gm, 190±20 gm, 210±20 gm, 230±20 gm, 250±20 gm, 270±20 gm, 290±20 gm, 310±20 gm, 330±20 gm, 350±20 gm, 370±20 gm, 390±20 gm, 410±20 gm, 430±20 gm, 450±20 gm, 470±20 gm, or 490±20 gm) when measured 3 cm from the device. In some embodiments, the droplets have a Dv90 of less than 500 gm when measured 3 cm from the device. PATENT

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[0119] The droplet size may have a Dv10 of between 13 pm and 22 pm (e.g., 13±1 pm, 14±1 pm, 15±1 pm, 16±1 pm, 17±1 pm, 18±1 pm, 19±1 pm, 20±1 pm, 21 ±1 pm, 22±1 pm, between 13 pm and 22 pm, between 14 pm and 21 pm between 16 pm and 19 pm, or between 15 pm and 20 pm) when measured 6 cm above the origin of the plume. In some embodiments, the droplets have a Dv10 of between 6 pm and 27 pm (e.g., 6±1 pm, 7±1 pm, 8±1 pm, 9±1 pm, 10±1 pm, 11 ±1 pm, 12±1 pm, 13±1 pm, 14±1 pm, 15±1 pm, 16±1 pm, 17±1 pm, 18±1 pm, 19±1 pm, 20±1 pm, 21 ±1 pm, 22±1 pm, 23±1 pm, 24±1 pm, 25±1 pm, 226±1 pm, or 27±1 pm) when measured 6 cm from the device. The droplet size may have a Dv50 of between 32 pm and 41 pm (e.g., 32±1 pm, 33±1 pm, 34±1 pm, 35±1 pm, 36±1 pm, 37±1 pm, 38±1 pm, 39±1 pm, 40±1 pm, 41 ±1 pm, between 32 pm and 41 pm, between 33 pm and 40 pm, between 35 pm and 37 pm, or between 34 pm and 38 pm) when measured 6 cm above the origin of the plume. In some embodiments, the droplets have a Dv50 of between 14 pm and 51 pm (e.g., 14±5 pm, 19±5 pm, 24±5 pm, 28±5 pm, 32±5 pm, 36±5 pm, 40±5 pm, 44±5 pm, or 49±5 pm) when measured 6 cm from the device. The droplet size may have a Dv90 of between 70 pm and 280 pm (e.g., 70±10 pm, 80±10 pm, 90±10 pm, 100±10 pm, 110±10 pm, 120±10 pm, 130±10 pm, 140±10 pm, 150±10 pm, 160±10 pm, 170±10 pm, 180±10 pm, 190±10 pm, 200±10 pm, 210±10 pm, 220±10 pm, 230±10 pm, 240±10 pm, 250±10 pm, 260±10 pm, 270±10 pm, 280±10 pm, between 70 pm and 280 pm, between 80 pm and 240 pm, between 90 pm and 200 pm, between 100 pm and 180 pm, between 120 pm and 150 pm, between 150 pm and 220 pm, or between 90 pm and 160 pm) when measured 6 cm above the origin of the plume. For example, the droplet size may have a Dv90 of between 85 pm and 210 pm (e.g., 85±10 pm, 95±10 pm, 105±10 pm, 115±10 pm, 125±10 pm, 135±10 pm, 145±10 pm, 155±10 pm, 165±10 pm, 175±10 pm, 185±10 pm, 195±10 pm, 205±10 pm, between 92 pm and 203 pm, between 95 pm and 190 pm, between 100 pm and 180 pm, between 150 pm and 210 pm, or between 90 pm and 170 pm). In some embodiments, the droplet size has a Dv90 of between 70 pm and 240 pm when measured 6 cm above the origin of the plume. In some embodiments, the droplets have a Dv90 of between 70 pm and 400 pm (e.g., 70±20 pm, 90±20 pm, 110±20 pm, 130±20 pm, 150±20 pm, 170±20 pm, 190±20 pm, 210±20 pm, 230±20 pm, 250±20 pm, 270±20 pm, 290±20 pm, 310±20 pm, 330±20 pm, 350±20 pm, 370±20 pm, or 390±20 pm) when measured 6 cm from the device. In some embodiments, the droplets have a Dv90 of less than 400 pm when measured 6 cm from the device.

[0120] Additionally, the size distribution of the droplets dispensed may be characterized by their span. The span of a volume-based size distribution is defined as span = (Dv90 - Dv10) / Dv50. The span may give an indication of how far the 10 percent and 90 percent points are apart, normalized with the midpoint.

[0121] Spray Pattern

[0122] The pattern of the plume of the pharmaceutical composition comprising bumetanide and one or more pharmaceutically acceptable excipients that is generated upon actuation of the nasal spray device may be characterized by the spray pattern that results. The spray pattern of the plume may not be completely circular and therefore may include some oval character. As a result, the spray pattern may be characterized by its maximum diameter, minimum diameter, and ovality.

[0123] The maximum diameter of the spray pattern is the widest part of the plume when measured at a particular distance from its origin. In some embodiments, the spray pattern has a maximum diameter of between 12 mm and 56 mm (e.g., 16 mm ± 4 mm, 18 mm ± 4 mm, 22 mm ± 4 mm, 26 mm ± 4 mm, 30 PATENT

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[0125] mm ± 4 mm, 34 mm ± 4 mm, 38 mm ± 4 mm, 42 mm ± 4 mm, 44 mm ± 4 mm, 48 mm ± 4 mm, or 52 mm ± 4 mm) when measured 3 cm from the device. In some embodiments, the spray pattern has a maximum diameter of between 18 mm and 44 mm (e.g., 18±1 mm, 19±1 mm, 20±1 mm, 21 ±1 mm, 22±1 mm, 23±1 mm, 24±1 mm, 25±1 mm, 26±1 mm, 27±1 mm, 28±1 mm, 29±1 mm, 30±1 mm, 31 ±1 mm, 32±1 mm, 33±1 mm, 34±1 mm, 35±1 mm, 36±1 mm, 37±1 mm, 38±1 mm, 39±1 mm, 40±1 mm, 41 ±1 mm, 42±1 mm, 43±1 mm, or 44 ±1 mm) when measured 3 cm from its origin. For example, the spray pattern may have a maximum diameter of between 32 mm and 44 mm (e.g., 32±1 mm, 33±1 mm, 34±1 mm, 35±1 mm, 36±1 mm, 37±1 mm, 38±1 mm, 39±1 mm, 40±1 mm, 41 ±1 mm, 42±1 mm, 43±1 mm, or 44 ±1 mm) when measured 3 cm from its origin. In some embodiments, the spray pattern has a maximum diameter of between 22 mm and 32 mm (e.g., 22±1 mm, 23±1 mm, 24±1 mm, 25±1 mm, 26±1 mm, 27±1 mm, 28±1 mm, 29±1 mm, 30±1 mm, 31 ±1 mm, or 32±1 mm) when measured 3 cm from its origin.

[0126] The spray pattern may be characterized as having a maximum diameter of between 19 mm and 135 mm (e.g., 19 mm ± 2 mm, 21 mm ± 2 mm, 23 mm ± 2 mm, 25 mm ± 2 mm, 27 mm ± 2 mm, 29 mm ± 2 mm, 31 mm ± 2 mm, 33 mm ± 2 mm, 35 mm ± 2 mm, 37 mm ± 2 mm, 39 mm ± 2 mm, 41 mm ± 2 mm, 43 mm ± 2 mm, 45 mm ± 2 mm, 47 mm ± 2 mm, 49 mm ± 2 mm, 51 mm ± 2 mm, 53 mm ± 2 mm, 55 mm ± 2 mm, 57 mm ± 2 mm, 59 mm ± 2 mm, 61 mm ± 2 mm, 63 mm ± 2 mm, 65 mm ± 2 mm, 67 mm ± 2 mm, 69 mm ± 2 mm, 71 mm ± 2 mm, 73 mm ± 2 mm, 75 mm ± 2 mm, 77 mm ± 2 mm, 79 mm ± 2 mm, 81 mm ± 2 mm, 83 mm ± 2 mm, 85 mm ± 2 mm, 87 mm ± 2 mm, 89 mm ± 2 mm, 91 mm ± 2 mm, 93 mm ± 2 mm, 95 mm ± 2 mm, 97 mm ± 2 mm, 99 mm ± 2 mm, 101 mm ± 2 mm, 103 mm ± 2 mm, 105 mm ± 2 mm, 107 mm ± 2 mm, 109 mm ± 2 mm, 111 mm ± 2 mm, 113 mm ± 2 mm, 115 mm ± 2 mm, 117 mm ± 2 mm, 119 mm ± 2 mm, 121 mm ± 2 mm, 123 mm ± 2 mm, 125 mm ± 2 mm, 127 mm ± 2 mm, 129 mm ± 2 mm, 131 mm ± 2 mm, 133 mm ± 2 mm, or 135 mm ± 2 mm) when measured 6 cm from the device. The spray pattern may be characterized as having a maximum diameter of between 33 mm and 69 mm (e.g., 33±1 mm, 34±1 mm, 35±1 mm, 36±1 mm, 37±1 mm, 38±1 mm, 39±1 mm, 40±1 mm, 41 ±1 mm, 42±1 mm, 43±1 mm, 44±1 mm, 45±1 mm, 46±1 mm, 47±1 mm, 48±1 mm, 49±1 mm, 50±1 mm, 51 ±1 mm, 52±1 mm, 53±1 mm, 54±1 mm, 55±1 mm, 56±1 mm, 57±1 mm, 58±1 mm, 59±1 mm, 60±1 mm, 61 ±1 mm, 62±1 mm, 63±1 mm, 64±1 mm, 65±1 mm, 66±1 mm, 67±1 mm, 68±1 mm, or 69±1 mm,) when measured 6 cm from the plume’s origin. For example, the maximum diameter may be between 40 mm and 59 mm (e.g., 40±1 mm, 41 ±1 mm, 42±1 mm, 43±1 mm, 44±1 mm, 45±1 mm, 46±1 mm, 47±1 mm, 48±1 mm, 49±1 mm, 50±1 mm, 51 ±1 mm, 52±1 mm, 53±1 mm, 54±1 mm, 55±1 mm, 56±1 mm, 57±1 mm, 58±1 mm, or 59±1 mm,) when measured 6 cm from the plume’s origin. The maximum diameter may be between 45 mm and 57 mm (e.g., 45±1 mm, 46±1 mm, 47±1 mm, 48±1 mm, 49±1 mm, 50±1 mm, 51 ±1 mm, 52±1 mm, 53±1 mm, 54±1 mm, 55±1 mm, 56±1 mm, or 57 ±1 mm) when measured 6 cm from the plume’s origin.

[0127] The minimum diameter of the spray pattern is the narrowest part of the plume when measured at a particular distance from the origin of the plume. In some embodiments, the spray pattern is characterized as having a minimum diameter of between 17 mm and 27 mm (e.g., 17±1 mm, 18±1 mm, 19±1 mm, 20±1 mm, 21 ±1 mm, 22±1 mm, 23±1 mm, 24±1 mm, 25±1 mm, 26±1 mm, or 27±1 mm). The minimum diameter of the spray pattern when measured 3 cm from the origin of the plume may be between 21 mm and 23 mm (e.g., 21 ±1 mm, 22±1 mm, or 23±1 mm). The spray pattern may be characterized as having a minimum diameter of between 28 mm and 52 mm (e.g., 28±1 mm, 29±1 mm, PATENT

[0128] ATTORNEY DOCKET NO.: 51378-005WO2

[0129] 30±1 mm, 31 ±1 mm, 32±1 mm, 33±1 mm, 34±1 mm, 35±1 mm, 36±1 mm, 37±1 mm, 38±1 mm, 39±1 mm, 40±1 mm, 41 ±1 mm, 42±1 mm, 43±1 mm, 44±1 mm, 45±1 mm, 46±1 mm, 47±1 mm, 48±1 mm, 49±1 mm, 50±1 mm, 51 ±1 mm, or 52±1 mm,) when measured 6 cm from the device. For example, when measured 6 cm from the device, the minimum diameter may be between 36 mm and 44 mm (e.g., 36±1 mm, 37±1 mm, 38±1 mm, 39±1 mm, 40±1 mm, 41 ±1 mm, 42±1 mm, 43±1 mm, or 44±1 mm).

[0130] The spray pattern may be characterized by the ovality of the plume. The ovality of the plume may be measured by determining the ratio of the maximum diameter of the plume at a particular distance from the plume’s origin to the minimum diameter of the plume at the same particular distance from the plume’s origin. The spray pattern may be characterized as having an ovality of from 0.7 to 2.2 (e.g., 0.7±0.1, 0.8±0.1, 0.9±0.1, 1.0±0.1, 1.1 ±0.1, 1.2±0.1, 1.3±0.1, 1.4±0.1, 1.5±0.1, 1.6±0.1, 1.7±0.1, 1.8±0.1, 1.9±0.1, 2.0±0.1, 2.1 ±0.1, or 2.2±0.1). In some embodiments, the spray pattern is characterized as having an ovality of from 1 to 2 (e.g., 1±0.1, 1.1 ±0.1, 1.2±0.1, 1.3±0.1, 1.4±0.1, 1.5±0.1, 1.6±0.1, 1.7±0.1, 1.8±0.1, 1.9±0.1, or 2±0.1 ). For example, the spray pattern may be characterized as having an ovality of from 1 to 1.6 (e.g., 1 ±0.1, 1.1 ±0.1, 1.2±0.1, 1.3±0.1, 1.4±0.1, 1.5±0.1, or 1,6±0.1). The ovality of the spray pattern may be from 1.1 to 1.4 (e.g., 1.1 ±0.1, 1,2±0.1, 1,3±0.1, or 1,4±0.1), such as an ovality of about 1.3. When the maximum diameter and minimum diameter is measured 6 cm above the device, the spray pattern may have an ovality of between 1.3 and 1.5 (e.g., 1,3±0.1, 1,4±0.1, or 1,5±0.1 ). In some embodiments, the spray pattern has an ovality of between 0.7 and 2.2 when measured 6 cm above the device. In some embodiments, the ovality is measured to be between 1.2 and 1.4 (e.g., 1.2±0.1, 1.3±0.1, or 1,4±0.1) at 6 cm from the origin of the plume. When measured 3 cm above the device, the spray pattern may have an ovality of between 1.2 and 1.3 (e.g., 1.21 ±0.1, 1.22±0.1, 1.23±0.1, 1.24±0.1, 1.25±0.1, 1.26±0.1, 1,27±0.1, 1.28±0.1, 1,29±0.1, or 1,3±0.1 ). In some embodiments, the spray pattern has an ovality of between 0.7 and 2.2 when measured 3 cm above the device.

[0131] Plume Geometry

[0132] The geometry of the plume of the pharmaceutical composition comprising potassium bumetanide and one or more pharmaceutically acceptable excipients that is generated upon actuation of the nasal spray device may be characterized. The resulting plume may be characterized in terms of the arm angle which is formed between the outer edge of the plume and the longitudinal axis at a known distance above the opening of the delivery device which dispenses the plume. Each of the two arm angles of the plume may be characterized. The two arm angles may be added together to identify the angle of the total plume at a determined distance from the tip of the nasal delivery device. For example, when measured at 6 cm above the device, the angle of the total plume may be from 52° to 76° (e.g., 52°±1 °, 53°±1 °, 54°±1 °, 55°±1°, 56°±1°, 57°±1°, 58°±1°, 59°±1°, 60°±1°, 61°±1 °, 62°±1°, 63°±1°, 64°±1°, 65°±1°, 66°±1°, 67°±1°, 68°±1°, 69°±1 °, 70°±1 °, 71 °±1 °, 72°±1 °, 73°±1 °, 74°±1 °, 75°±1 °, or 76°±1 °). In some embodiments, the angle of the total plume is from 56° to 68° (e.g., 56°±1 °, 57°±1 °, 58°±1 °, 59°±1 °, 60°±1 °, 61 °±1°, 62°±1°, 63°±1°, 64°±1 °, 65°±1 °, 66°±1 °, 67°±1 or 68°±1 ) when measured a 6 cm away from the origin of the plume. For example, the plume may have an angle of from 56° to 67° when measured at 6 cm above the device. The total plume may have an angle of from 64° to 68° when measured at 6 cm above the device. The width of the plume may also be measured 6 cm from the origin of the plume. The plume may have a width of 58 mm to 92 mm (e.g., 58±1 mm, 59±1 mm, 60±1 mm, PATENT

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[0134] 61 ±1 mm, 62±1 mm, 63±1 mm, 64±1 mm, 65±1 mm, 66±1 mm, 67±1 mm, 68±1 mm, 69±1 mm, 70±1 mm, 71 ±1 mm, 72±1 mm, 73±1 mm, 74±1 mm, 75±1 mm, 76±1 mm, 77±1 mm, 78±1 mm, 79±1 mm, 80±1 mm, 81 ±1 mm, 82±1 mm, 83±1 mm, 84±1 mm, 85±1 mm, 86±1 mm, 87±1 mm, 88±1 mm, 89±1 mm, 90±1 mm, 91 ±1 mm, or 92±1 mm,) when measured at 6 cm from the origin of the plume.

[0135] In some embodiments, the angle of the total plume is from 60° to 79° (e.g., 60°±1 °, 61 °±1 °, 62°±1°, 63°±1°, 64°±1°, 65°±1°, 66°±1°, 67°±1°, 68°±1°, 69°±1°, 70°±1°, 71°±1°, 72°±1°, 73°±1°, 74°±1°, 75°±1°, 76°±1, 77°±1°, 78°±1°, or 79°±1°) when measured a 3 cm away from the origin of the plume. In another example, when the plume geometry is measured at 3 cm above the device, the total plume may have an angle of from 60° to 78° (e.g., 60°±1 °, 61 °±1 °, 62°±1 °, 63°±1 °, 64°±1 °, 65°±1 °, 66°±1 °, 67°±1 °, 68°±1 °, 69°±1 °, 70°±1 °, 71 °±1 °, 72°±1 °, 73°±1 °, 74°±1 °, 75°±1 °, 76°±1 °, 77°±1 °, or 78°±1 ) when measured at 3 cm above the device. For example, the plume may have an angle of 70° to 74° from vertical when measured at 3 cm above the device. The plume may also have an angle of 63° to 76° from when measured at 3 cm above the device. The width of the plume may also be measured 3 cm from the origin of the plume. The plume may have a width of 34 mm to 51 mm (e.g., 34±1 mm, 35±1 mm, 36±1 mm, 37±1 mm, 38±1 mm, 39±1 mm, 40±1 mm, 41 ±1 mm, 42±1 mm, 43±1 mm, 44±1 mm, 45±1 mm, 46±1 mm, 47±1 mm, 48±1 mm, 49±1 mm, 50±1 mm, or 51 ±1 mm) when measured at 3 cm from the origin of the plume.

[0136] Nasal Delivery Device

[0137] The pharmaceutical compositions described herein comprising bumetanide may be administered to the subject in need thereof using a nasal spray device. The pharmaceutical composition may be administered to the subject, for example, by means of a metering atomizing spray pump. The metered spray pump may be a single metered spray pump device (e.g., APTAR® Unidose (UDS), Unidose®Xtra, or the Silgan Monodose Nasal System) or may be a multi-dose metered pump device (e.g., APTAR® Bidose (BDS), MK® pump).

[0138] The nasal delivery device may include a body, a reservoir containing the pharmaceutical composition, a nasal dispensing head comprising a dispensing orifice where dispensing means for dispensing at least a portion of the pharmaceutical composition through the dispensing orifice upon actuation. In some embodiments, the nasal delivery device includes a fluid dispenser device comprising a body, a reservoir containing fluid, a nasal dispensing head provided with a dispensing orifice, and dispensing means for dispensing at least a portion said fluid product through said dispensing orifice upon actuation, said device having a mouthpiece removably disposed around said nasal dispensing head (nozzle). The nasal delivery device may further include a linear actuating system, wherein the linear actuating system is integral with the nasal dispensing member, wherein the linear actuating system comprises at least one actuating element cooperating with the reservoir (container) The linear actuating system (actuator) may be a manual linear actuating system, such that, for example, the actuation may be performed using one or two fingers and pressing down and / or pushing the container holder parallel to the nasal dispensing head.

[0139] The nasal delivery device may be a single-dose device, in which the entire dose of the pharmaceutical composition is distributed in one actuation. It should be noted that the present invention could also be adapted to other types of devices, such as for example devices of the bi-dose type, PATENT

[0140] ATTORNEY DOCKET NO.: 51378-005WO2

[0141] containing two doses of flu id to be dispensed in two successive actuations of the device. The nasal delivery device may include a body. The body may include a radial flange for the support of the fingers of the user during actuation. A nasal dispensing head may extend axially from the radial flange and the nasal dispensing head may include dispensing orifice oriented axialiy. The dispensing orifice may serve to dispense a dose of pharmaceutical composition from the dispensing head during the actuation of the device by a user. The nasal dispensing head may be made in one piece with the body.

[0142] The body may include a reservoir. The reservoir may be formed by a hollow body and blind, having a single opening closed by a plug and containing a single dose of the pharmaceutical composition to distribute a single actuation of the device. The nasal dispensing head may include passage means which connect, during actuation, the reservoir to the dispensing orifice. These means of passage advantageously may include a hollow needle having a tip adapted to pierce the stopper at the time of actuation. The needle may be fixed relative to the body and in particular with respect to the dispensing orifice. Actuating means are provided to enable actuation of the device. The actuating means may include an actuating body movable relative to the body, said actuating body cooperating with said reservoir to move axialiy relative to the body and therefore with respect to the needle, towards the dispensing orifice. During this movement, the tip of the needle may pierce the stopper, and then slide into the reservoir to expel the pharmaceutical composition through the needle. The stopper may form the distribution means. Alternatively, the actuating means could be formed by the bottom of the tank (tank holder) itself.

[0143] The nasal dispensing head may include a radially protruding radial boss which, in the assembled state of said mouthpiece, cooperates with a radially inner surface of said mouthpiece. The mouthpiece may include an axial opening, in particular circular, which, in the assembled state of the mouthpiece, surrounds the dispensing orifice of the nasal dispensing head, to allow dispensing of the fluid product through the dispensing orifice. The mouthpiece may have a substantially planar axial end surface which includes said axial opening. The axial end surface may be of an oblong shape, with a radially outer edge of oval shape. The radially outer edge of oval shape may have a major axis of 15 to 20 mm, in particular 18 mm, and a small axis of 10 to 15 mm, in particular 13.5 mm, the axial opening having a radius of 2 to 6 mm, in particular 3.5 mm. The mouthpiece may include a radial flange which, in the assembled stale of the mouthpiece, may be in the form of a radial flange of said body.

[0144] In another embodiment, the reservoir may not be formed by a blind hollow body having only one opening, but by a hollow cylinder axially open on both sides. The cylinder would then be closed on the proximal side by a first plug and on the distal side by a second plug, the volume defined between said two plugs containing the fluid to be dispensed. When the user actuates the device, it will as previously described axialiy press the actuating body to slide axiaiiy towards the dispensing orifice. This causes the second plug (container holder) to move the tank (container). Now, the pharmaceutical composition being incompressible, this displacement of the second plug will therefore move the first plug in the direction of the needle, which is fixed. The first plug will thus be pierced by the needle and the contents of the reservoir will be dispensed through said needle through the second plug, which then acts as a piston. In this embodiment, it is the second plug which forms the distribution means.

[0145] In some embodiments, the nasal delivery device includes: a body; a reservoir; a dispenser head incorporating a dispenser orifice; and a dispenser member that is mounted on the reservoir. The dispenser member may include a dispenser-member body and a movable member that moves axially in PATENT

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[0147] said dispenser-member body while said dispenser member is actuated. The nasal delivery device may further comprise a lateral actuator system that is secured to the body of nasal delivery device. The lateral actuator system may include at least one actuator element that co-operates with the reservoir in the nasal delivery device, with the dispenser member, or with an element secured to at least one of the reservoir and to the dispenser member. The at least one actuator element is movable between a rest position in which the dispenser member is not actuated, and an actuated position in which the dispenser member is actuated. The body of the nasal delivery device may include at least one guide surface for guiding the at least one actuator element. The guide surface may be stationary relative to the dispenser head, and substantially parallel to the axial movement of the movable member in the dispenser-member body while the dispenser member is being actuated. The lateral actuator system may include a presser element that is mounted on the body to pivot about a first axis, said at least one actuator element mounted on said presser element to pivot about a second axis.

[0148] In some embodiments, the nasal delivery device includes a dispenser including a medium reservoir, a nose applicator aligned in the direction of a longitudinal axis and including at least one discharge opening at the end of the nose applicator, a finger rest, which can be manually subjected to force, and a pump, having at least two pump parts which are axially movable relative to each other, wherein the applicator, which is configured for introduction into a nostril of a user. The nose applicator may be fixedly connected to the medium reservoir and characterized in that the finger rest is axially movable in the direction of the longitudinal axis in a translatory motion relative to the medium reservoir and the applicator between a first, non-pressed operating end position and a second, pressed operating end position.

[0149] The nasal delivery device may include a reservoir containing the pharmaceutical composition, a dispensing member, such as a pump or a valve, mounted on the reservoir, and a head of distribution mounted on the dispensing member. The dispensing head may include a hollow body, defining a fluid product passage between an inlet orifice connected to the dispensing device, and a spray orifice, characterized in that vibration generating means are arranged in the passage upstream of the spray orifice. The vibration generating means may be actuated during passage of the pharmaceutical composition to finely spray the pharmaceutical composition through said spray port.

[0150] The nasal delivery device may be a single use device including an outlet opening in form of a spray nozzle, at least one closing and opening element located between a reservoir holding the pharmaceutical composition and the outlet opening. The opening element may be spaced inwardly from the outlet opening and an outlet channel located between the reservoir and the spray nozzle. The device may include an actuating unit. The actuating unit may be separable from the dispenser unit. The actuating unit includes functional parts at least contributing to actuation of the dispenser unit. The dispenser unit may include a wall apart from the reservoir that encloses the opening and closing elements to protect the pharmaceutical composition within the dispenser from contamination.

[0151] The nasal delivery device may be a metered delivery device, wherein multiple doses of a specific volume may be administered to the subject. The metered delivery device may include a manually operable Pumpeinrich- device. The Pumpeinrich device comprises a pumping chamber and an inlet valve. The inlet valve may be designed as a slide valve and may be movable in its closed position seal ingly in a PATENT

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[0153] metering via a Dosierhub which defines a metering volume for the pumping chamber. The metering on the inlet side may open into an inlet region.

[0154] The nasal delivery device may include the elements described in International Publication WO 2019 / 220062, U. S. Publication No. 2011 / 0062188; U. S. Publication No. 2010 / 0294807; U. S. Publication No. 2019 / 0111448; U. S. Publication No. 2009 / 0026289; U. S. Publication No. 2017 / 0304568; U. S. Patent No. 6,626,379; U. S. Publication No. 2012 / 0205464; U. S. Patent No. 6,708,846; U. S. Publication No. US 2006 / 0011659, U. S. Publication No. US 2012 / 0199119, U. S. Publication No. US 2005 / 0098175, U. S. Patent No. 7,296,566, U. S. 10, 829,276, and U. S. 11, 22, 536 which are each incorporated herein by reference in their entirety.

[0155] Dosing Regimens

[0156] The dosing regimen used for the treatment methods described herein can vary depending on many factors, e.g., the age, health, and weight of the recipient; the nature and extent of the symptoms of edema; and the frequency and type of concurrent treatment, if any. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds used in the methods described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the individual response. In general, a suitable dose of bumetanide according to the invention will be in the range of between 0.5 and 10 mg (e.g., 0.5, 1.0, 2.0, and 5 mg) of bumetanide in from 1 to 4 doses over a 1 to 4 hour period until the patient is no longer in an edematous state. Four doses of 100 pL per dose of the pharmaceutical composition may be delivered to the subject over a period of less than 1 hour.

[0157] Alternatively, two doses of about 100 pL per dose may delivered to a subject followed by two more doses of about 100 pL each after a period of about 30 to 60 minutes. The bumetanide can be administered to a patient at the onset of symptoms of edema. Aternatively, the bumetanide is administered to a patient after symptoms persist following the failure of previously administered oral diuretics to treat the edema. If oral diuretics have been administered without effect, the patient may be restricted to an initial dose of less than 5 mg of bumetanide for a period of least 1 or 2 hours to further reduce the risk of over-diuresis, which may present as symptoms of dehydration and low blood pressure in the subject suffering from over-diuresis.

[0158] Oral Diuretics

[0159] The disclosure features methods and compositions for the treatment of edema refractory to oral diuretics. Oral diuretics have long been used to relieve fluid retention, a hallmark of congestive heart failure. Aggressive use of diuretics, even in people taking ACE inhibitors, can reduce hospitalizations and improve exercise capacity. Diuretics act on the kidneys to rid the body of excess salt and water. They reduce the accumulation of fluid in the legs, abdomen and lungs, lower blood pressure and improve the efficiency of the circulation. Side effects of diuretics include low blood pressure, dehydration, and kidney dysfunction; they also may trigger gout, increase blood sugar and triglyceride, LDL, and overall cholesterol levels and may deplete the B vitamin thiamin. Although many diuretics are available, they are generally categorized as thiazides and loop diuretics, used with or without potassium-sparing agents. It is important to note that a recent study found an increased incidence of hospitalization in patients who were PATENT

[0160] ATTORNEY DOCKET NO.: 51378-005WO2

[0161] taking nonsteroidal anti-inflammatory drugs (NTHEs) along with diuretics. Common NSAIDS include aspirin, ibuprofen, and naproxen. Thiazides, including hydrochlorothiazide (HydroDIURIL, Esidrix), chlorothiazide (Diuril), metolazone (Zaroxolyn), and chlorthalidone (Hygroton), are usually prescribed for patients with mild heart failure and good kidney function.

[0162] Loop diuretics, such as furosemide (Lasix), bumetanide (BumeX), and ethacrynic acid (Edecrine), are generally used for more severe heart failure, especially when kidney function is impaired. Loop diuretics are used intravenously to treat pulmonary edema and acute congestive heart failure, a thiazide and a loop diuretic may be administered simultaneously. Fluid may persist in the lungs even after standard treatment for congestive failure, limiting the patient’s ability to function normally. One study treated patients with this condition very aggressively with furosemide to further reduce fluids, but no improvement was observed. Another method using a filtration technique was more successful.

[0163] Potassium loss is a major problem with diuretic use. Unless patients are also taking ACE inhibitors, which raise potassium levels, the physician may recommend a potassium supplement or the use of a potassium-sparing diuretic, such as spironolactone (Aldactone), amiloride (Midamor), and triamterene (Dyrenium), along with a thiazide or loop diuretic. All patients receiving diuretics with or without potassium-sparing drugs should have their blood potassium levels checked at regular intervals.

[0164] The methods of the invention can include the bumetanide therapy described herein used in combination with oral diuretics, such as loop diuretics, potassium-sparing diuretics, thiazides, or other oral diuretics, to manage edema in patients. Typically, the intranasally or subcutaneously administered bumetanide is administered to a patient having taken oral diuretics previously, for example, within the past 1 hour, 2 hours, or 4 hours, for edema that is discovered to be refractory to oral diuretics. For example, the patient may be taking oral diuretics, such as high ceiling loop diuretics (e.g., furosemide, ethacrynic acid, torsemide and bumetanide), thiazides (e.g., hydrochlorothiazide acid), carbonic anhydrase inhibitors (e.g., acetazolamide and methazolamide), potassium-sparing diuretics (e.g., aldosterone antagonists: spironolactone, and epithelial sodium channel blockers: amiloride and triamterene), and / or calcium-sparing diuretics. The patient can continue with their regular regimen of oral diuretics following successful treatment of the acute edematous state using the methods of the invention.

[0165] Examples

[0166] The following examples are put forth so as to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used, made, and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure.

[0167] Example 1: Characterization of average droplet size in plume

[0168] The droplet size distribution (DSD) of the droplets contained in the plume upon actuation of the nasal delivery device were characterized.

[0169] Nine nasal delivery Aptar Unidose® devices each containing the same pharmaceutical composition including 5.54 mg / mL potassium bumetanide, 1 mg / mL low viscosity carboxymethyl cellulose, 5 mg / mL benzyl alcohol, 40 mg / mL mannitol in water at a pH of between 6.6 and 7.8 were dispensed to generate a plume of the pharmaceutical composition. The size droplet sizes were measured PATENT

[0170] ATTORNEY DOCKET NO.: 51378-005WO2

[0171] either 3 cm (Tables 1-3 and 7) or 6 cm (Table 4-6 and 8) above the tip of the nasal delivery device. The droplet size distribution was characterized in terms of the diameter which 10% of the particles were smaller than (Dv10), 50% of the particles were smaller than (Dv50), 90% of the particles were smaller than (Dv90), and % of the droplets dispensed that had diameter smaller than 10 pM (Tables 9A-9D) Lastly, the droplet sized distribution was further characterized based on the span of the droplet sizes in the plume using the equation of: span = (Dv90-Dv10) / Dv50. Nine devices stored either upright or inverted from each of three manufacturing batches had their spray pattern characterized after storage at 25 °C and approximately 60% relative humidity for the indicated time. The results are presented in Tables 9A-9D and demonstrate the exceptional consistency of the sprayed droplets irrespective of the storage orientation and length of storage from the time of manufacture. Each cell of Tables 9A-9D presents data corresponding to manufactured batches 1-3, ordered from top to bottom (batch 1 - top, batch 2 - middle, and batch 3 - bottom). In some embodiments, the spray pattern is characterized using measurements collected from 9 different devices. In some embodiments, the spray pattern is calculated as an average of 9 measurements. In some embodiments, the droplet size distribution (e.g. Dv10, Dv50, or Dv90) is calculated as an average of 9 measurements. In some embodiments, the maximum diameter is calculated as an average of 9 measurements. In some embodiments, the minimum diameter is calculated as an average of 9 measurements. In some embodiments, the ovality is calculated as an average of 9 measurements.

[0172] Table 1. Average droplet size measured at 3 cm above device #1

[0173] Measured at 3 cm above nasal device - Device #1

[0174] Spray Pattern Height: 300 mm

[0175] Average o Min Max

[0176] Trans% 55.1 6.893 48.1 75.2

[0177] Dv(10) (pm) 13.74 3.238 11.3 25.69

[0178] Dv(50) (pm) 31.15 6.585 25.7 54.02

[0179] Dv(90) (pm) 95.61 80.26 57.63 392.3

[0180] %V < 10 (pm) (%) 4.06 1.991 0.8225 7.267

[0181] D[4][3] (pm) 64 13.85 45.96 109.3

[0182] D[3][2] (pm) 24.08 5.446 19.83 43.45

[0183]

[0184] Span 2.628 2.101 1.504 10.28

[0185] Table 2. Average droplet size measured at 3 cm above device #2

[0186] Measured at 3 cm above nasal device - Device #2

[0187] Spray Pattern Height: 300 mm

[0188] Average o Min Max

[0189] Trans% 53.8 3.631 49.9 63.0

[0190] Dv(10) (pm) 13.25 1.92 11.45 18.34

[0191] Dv(50) (pm) 29.81 3.84 26.19 40.97

[0192] Dv(90) (pm) 101.6 64.62 62.54 344.1

[0193] %V < 10 (pm) (%) 4.567 1.698 1.522 7.028

[0194] D[4][3] (pm) 63.11 12.17 43.74 106.4

[0195] D[3][2] (pm) 23.04 3.243 20.04 32.54

[0196]

[0197] Span 2.965 1.608 1.668 8.116

[0198] Table 3. Average droplet size measured at 3 cm above device #3

[0199] | Measured at 3 cm above nasal device - Device #3 PATENT

[0200] ATTORNEY DOCKET NO.: 51378-005WO2

[0201] Spray Pattern Height: 300 mm

[0202] Average o Min Max

[0203] Trans% 47.7 2.842 44.9 55.6

[0204] Dv(10) (pm) 12.84 1.898 10.76 17.62

[0205] Dv(50) (pm) 29.01 4.008 24.53 40.6

[0206] Dv(90) (pm) 155 100 59.06 453.6

[0207] %V < 10 (pm) (%) 4.925 2 1.669 8.254

[0208] D[4][3] (pm) 69.64 16.64 52.14 131.6

[0209] D[3][2] (pm) 22.61 3.474 18.94 32.73

[0210]

[0211] Span 4.899 2.512 1.697 10.74

[0212] Table 4. Average droplet size measured at 6 cm above device #1

[0213] Measured at 6 cm above nasal device - Device #1

[0214] Spray Pattern Height: 600 mm

[0215] Average o Min Max

[0216] Trans% 49.3 7.846 41.5 70.2

[0217] Dv(10) (pm) 18.04 1.083 16.89 22.06

[0218] Dv(50) (pm) 37.01 3.296 33.18 46.05

[0219] Dv(90) (pm) 84.06 74.78 63.94 407.7

[0220] %V < 10 (pm) (%) 2.341 0.3449 1.592 3.073

[0221] D[4][3] (pm) 63.87 13.66 42.02 111

[0222] D[3][2] (pm) 29.24 2.511 26.19 36.45

[0223]

[0224] Span 1.784 1.705 1.39 8.903

[0225] Table 5. Average droplet size measured at 6 cm above device #2

[0226] Measured at 6 cm above nasal device - Device #2

[0227] Spray Pattern Height: 600 mm

[0228] Average o Min Max

[0229] Trans% 43.2 5.966 36.8 58.4

[0230] Dv(10) (pm) 16.37 1.184 14.89 2.87

[0231] Dv(50) (pm) 36.25 3.117 33.55 49.39

[0232] Dv(90) (pm) 92 94.28 68.95 544.3

[0233] %V < 10 (pm) (%) 3.387 0.6351 1.846 4.286

[0234] D[4][3] (pm) 70.33 17.97 46.54 160.7

[0235] D[3][2] (pm) 27.7 2.582 25.82 39.66

[0236]

[0237] Span 2.086 2.016 1.538 10.6

[0238] Table 6. Average droplet size measured at 6 cm above device #3

[0239] Measured at 6 cm above nasal device - Device #3

[0240] Spray Pattern Height: 600 mm

[0241] Average o Min Max

[0242] Trans% 51.2 6.518 43.5 68.2

[0243] Dv(10) (pm) 17.92 1.301 16.66 21.48

[0244] Dv(50) (pm) 36.92 2.859 33.63 45.31

[0245] Dv(90) (pm) 83.71 36.84 68.6 242.7

[0246] %V < 10 (pm) (%) 2.215 0.4363 0.761 3.214

[0247] D[4][3] (pm) 61.47 8.435 48.04 84.17

[0248] D[3][2] (pm) 29.29 2.303 24.36 35.71

[0249]

[0250] Span 1.782 0.8861 1.388 5.727

[0251] Table 7. Droplet size distribution in plume 3 cm above nasal spray device

[0252]

[0253] DSD 3cm PATENT

[0254] ATTORNEY DOCKET NO.: 51378-005WO2

[0255] Didihtteces soreprgv u Droplets < 10 pm Device # Dv10 (pm) Dv50 (pm) Dv90 (pm) Span

[0256] (%)

[0257] 1 13.74 31.15 95.61 2.628 4.06

[0258] 2 14.28 30.95 81.62 2.176 3.45

[0259] 3 14.3 31.17 81.64 2.16 3.397 4 13.25 29.81 101.6 2.965 4.567 5 13.36 29.65 114.9 3.424 4.485 6 13.82 30.74 191.3 5.773 3.844 7 12.84 29.01 155 4.899 4.925 8 13.43 30.17 82.92 2.303 4.397 9 13.15 29.43 92.51 2.697 4.63

[0260]

[0261] Mean (n=9) 14 30 111 3.2 4

[0262] Table 8. Droplet size distribution in plume 6 cm above nasal spray device

[0263] DSD 6cm

[0264] Droplets < 10 pm Device # Dv10 (pm) Dv50 (pm) Dv90 (pm) Span

[0265] (%)

[0266] 1 18.04 37.01 84.06 1.784 2.341 2 19.28 38.45 128.8 2.848 1.737 3 17.49 35.54 78.74 1.723 2.113 4 16.37 36.25 92 2.086 3.387 5 17.6 35.97 77.27 1.659 2.514 6 18.7 36.86 74.17 1.505 2.364 7 17.92 36.92 83.71 1.782 2.215 8 16.58 35.97 204.2 5.216 2.457 9 16.78 35.57 79.85 1.773 2.954

[0267]

[0268] Mean (n=9) 18 37 100 2.3 2

[0269] Table 9A. Percentage of droplets that are smaller than 10 pm after 6 months and 12 months at either 3 cm or 6 cm above the plume origin. The devices were stored either upright or inverted.1

[0270] % of droplets that are less than 10 pm

[0271] measured 3 cm above origin of measured 6 cm above origin of plume plume

[0272] t=0 t=6 t=12 t=0 months t=6 months t=12 months months months months

[0273] Device 1 4.1% 4.1% 5.5% 2.3% 2.6% 3.3%

[0274] 5.1% 4.5% 5.9% 2.2% 2.7% 2.5% 3.4% 4.9% 4.8% 2.1% 3.2% 2.4% Device 2 3.5% 3.9% 4.7% 1.7% 3.5% 3.0%

[0275] 4.4% 5.1% 5.5% 1.9% 2.9% 2.7% 4.1% 4.9% 5.0% 2.0% 2.5% 2.0% Device 3 3.4% 4.5% 4.1% 2.1% 2.6% 2.9%

[0276] 5.1% 4.6% 5.2% 3.2% 3.2% 2.9% 3.9% 4.7% 4.4% 2.7% 3.1% 1.5% Device 4 4.6% 4.4% 4.4% 3.4% 2.7% 3.1%

[0277] 4.2% 4.4% 5.6% 3.2% 2.4% 2.9% 3.5% 6.3% 4.8% 1.9% 1.9% 1.8% Device 5 4.5% 4.8% 4.3% 2.5% 1.9% 3.6%

[0278] 4.7% 5.0% 6.0% 3.1% 3.5% 3.4% 4.6% 6.4% 4.8% 3.5% 2.5% 1.8%

[0279]

[0280] PATENT

[0281] ATTORNEY DOCKET NO.: 51378-005WO2

[0282] Did idtteces sorenerevv Device 6 3.8% 4.5% 5.5% 2.4% 3.4% 2.1% Diecev

[0283] 4.8% 4.1% 4.8% 2.3% 2.3% 3.0% s _ _

[0284] 4.8% 5.7% 3.9% 2.2% 2.7% 2.5% Device 7 4.9% 4.2% 5.5% 2.2% 3.2% 2.7%

[0285] 4.5% 3.9% 4.9% 3.0% 3.3% 2.8% 4.7% 5.8% 5.0% 3.0% 2.6% 2.8% Device 8 4.4% 5.5% 5.1% 2.5% 3.0% 3.2%

[0286] 5.4% 4.5% 5.2% 2.4% 3.3% 3.1% 4.7% 3.8% 5.2% 3.3% 2.5% 2.0% Device 9 4.6% 4.5% 6.6% 3.0% 3.1% 1.5%

[0287] 4.5% 4.5% 5.1% 2.4% 3.2% 2.8% 5.7% 6.1% 4.8% 2.9% 2.6% 2.7% Device 1 4.1% 4.6% 4.4% 2.3% 2.9% 2.8%

[0288] 5.1% 4.5% 4.5% 2.2% 2.1% 3.0% 3.4% 5.5% 4.6% 2.1% 2.9% 2.7% Device 2 3.5% 4.0% 4.7% 1.7% 3.4% 3.1%

[0289] 4.4% 4.1% 3.6% 1.9% 2.3% 1.1% 4.1% 5.6% 4.9% 2.0% 2.2% 3.0% Device 3 3.4% 4.3% 4.7% 2.1% 2.6% 2.5%

[0290] 5.1% 4.1% 3.7% 3.2% 2.2% 3.6% 3.9% 6.1% 4.9% 2.7% 2.8% 2.3% Device 4 4.6% 3.8% 4.9% 3.4% 2.5% 2.4%

[0291] 4.2% 4.3% 3.9% 3.2% 1.8% 2.3% 4.6% 5.4% 3.8% 1.9% 3.6% 2.1% Device 5 4.5% 3.5% 4.7% 2.5% 3.6% 1.9%

[0292] 4.7% 4.3% 2.6% 3.1% 2.0% 2.1% 4.6% 5.3% 5.0% 3.5% 2.5% 2.0%- Device 6 3.8% 3.6% 4.6% 2.4% 2.6% 2.7%

[0293] 4.8% 3.7% 4.0% 2.3% 2.3% 2.2% 4.8% 3.9% 4.2% 2.2% 3.0% 3.5% Device 7 4.9% 3.6% 4.1% 2.2% 2.8% 2.5%

[0294] 4.5% 2.7% 3.7% 3.0% 2.8% 2.1% 4.7% 5.9% 5.2% 3.0% 2.3% 2.8% Device 8 4.4% 3.9% 4.7% 2.5% 3.4% 3.4%

[0295] 5.4% 3.8% 3.6% 2.4% 2.2% 2.1% 4.7% 4.7% 5.0% 3.3% 2.1% 3.7% Device 9 4.6% 4.4% 4.0% 3.0% 3.6% 2.3%

[0296] 4.5% 4.3% 3.7% 2.4% 1.9% 2.2% 5.7% 5.9% 4.9% 2.9% 3.0% 2.5%

[0297]

[0298] 1Data presented in each cell corresponds to manufacturing batches 1-3, ordered from top to bottom.

[0299] Table 9B. Droplet size distribution DV10 in plume after 6, 9, and 12 months.1

[0300] Droplet size distribution (DV10) (pm)

[0301] Measured 3 cm above the nasal device Measured 6 cm above the nasal device plume plume

[0302] Time 0 6 9 12 0 6 9 12 months months months months months months months months Device 13.74 13.5 12.99 12.26 18.04 16.61 16.94 15.8 1 12.71 13.05 13 12.07 16.97 16.15 17.56 17.31 14.06 12.49 14.77 12.75 17.79 16.3 16.02 17.6

[0303]

[0304] PATENT

[0305] ATTORNEY DOCKET NO.: 51378-005WO2

[0306] Device 14.28 13.7 13.03 13.2 19.28 16.71 16.71 16.31 Did idtteces sorenerevv

[0307] 2 13.16 12.65 12.73 12.41 17.74 16.01 16.57 17.3 13.71 12.49 15.26 12.88 17.28 17.2 18.23 17.38

[0308] Device 14.3 13.29 12.54 13.49 17.49 17.94 17.94 16.7 3 12.52 12.97 12.38 12.67 15.67 16.33 16.75 16.83 13.53 12.63 15.69 12.91 17.56 18.3 18.99 18

[0309] Device 13.25 13.05 12.81 13.31 16.37 17.33 17.33 16.25 4 13.31 13.31 12.53 12.37 15.84 16.14 18.02 16.76 14.16 11.75 16.28 13.13 17.79 17.66 20.68 18.97

[0310] Device 13.36 12.96 12.73 13.41 17.6 17.4 17.4 15.51 5 13.01 12.63 12.77 11.97 16.53 15.76 17.7 15.74 13.45 11.73 15.44 13 15.65 17.53 19.51 19

[0311] Device 13.82 12.76 12.61 12.34 18.7 16.53 16.53 17.8 6 12.85 13.1 12.58 12.93 17.07 17.07 15.27 16.44 12.76 12.08 15.09 13.92 17.8 16.41 17.67 17.75 Device 12.84 13.23 12.62 12.36 17.92 16.71 16.71 16.84 7 13.2 13.5 13.03 12.75 16.66 15.94 16.5 16.4 12.87 12.04 14.63 12.81 16.22 16.44 19.41 17.97

[0312] Device 13.43 12.42 12.79 12.76 16.58 16.35 16.35 16.35 8 12.52 13.18 12.82 12.67 16.66 16.06 16.24 16.15 12.88 13.63 14.96 12.67 15.91 17.13 18.15 18.79

[0313] Device 13.15 13.19 13.17 11.61 16.78 16.3 16.3 18.15 9 13.14 13.19 13.19 12.75 16.68 15.8 16.95 16.68 12.24 11.95 15.39 13.25 16.95 16.36 18.79 17.91

[0314] Device 13.74 12.89 13 13.16 18.04 16.14 15.17 16.96 1 12.71 13.01 12.97 13.1 16.97 17.76 18.35 17.12 14.06 12.37 14.69 13.28 17.79 16.08 17.4 16.43 Device 14.28 13.42 13.02 13.07 19.28 15.39 16.11 15.78 2 13.16 13.35 13.39 14.35 17.74 17.41 17.27 20.08 13.71 12.37 14.66 12.96 17.28 18.15 19.68 16.12

[0315] Device 14.3 13.12 12.93 13.23 17.49 15.85 17.13 17.05 3 12.52 13.35 13 13.93 15.67 17.7 18.85 16.34 13.53 11.93 14.79 12.97 17.56 17.2 19.19 16.97 Device 13.25 13.86 12.96 12.88 16.37 16.23 18.45 18.24 4 13.31 13.35 12.76 13.81 15.84 17.84 19.33 17.91 14.16 12.44 15 14.08 17.79 15.73 18.38 18.58 Device 13.36 13.82 13.91 13.13 17.6 15.41 16.55 18.84 5 13.01 13.21 12.77 14.89 16.53 18.65 16.39 17.35 13.45 12.43 14.52 12.93 15.65 19.36 17.5 17.89 Device 13.82 13.9 13.02 13.18 18.7 16.45 17.05 16.76 6 12.85 13.61 13.08 13.5 17.07 18.09 16.81 17.66 12.76 13.25 14.19 13.51 17.8 17.22 17.43 15.97 Device 12.84 13.47 13.51 13.7 17.92 15.79 15.97 17.13 7 13.2 14.52 12.7 14.01 16.66 17.17 16.45 17.66 12.87 12.08 14.37 12.76 16.22 18.03 20.26 16.72

[0316]

[0317] PATENT

[0318] ATTORNEY DOCKET NO.: 51378-005WO2

[0319] Device 13.43 13.56 13.19 13.07 16.58 15.94 16.05 15.99 Didihtteces soreprgv u

[0320] 8 12.52 13.75 12.91 14.18 16.66 17.51 17.2 18.6 12.88 12.71 15.69 12.8 15.91 17.37 19.25 15.01 Device 13.15 13.14 13.16 13.71 16.78 15.58 17.58 17.92 9 13.14 13.3 12.74 14.02 16.68 18.7 17.18 18.03 12.24 12.04 14.52 13 16.95 16.95 20.08 17.02

[0321]

[0322] 1Data presented in each cell corresponds to manufacturing batches 1-3, ordered from top to bottom.

[0323] Table 9C. Droplet size distribution DV50 in plume after 6, 9, and 12 months.1

[0324] Droplet size distribution (DV50)

[0325] Measured 3 cm above the nasal device Measured 6 cm above the nasal device plume plume

[0326] Time 0 6 9 12 0 6 9 12 months months months months months months months months Device 31.15 30.27 29.39 27.14 37.01 35.3 35.33 33.97 1 28.77 29.87 30.13 27.68 34.99 33.85 36.35 35.94 30.55 26.42 33.77 27.96 36.13 35.09 35.05 37.62

[0327] Device 30.95 30.55 29.48 30.7 38.45 34 34.72 35.78 2 29.03 29.21 28.96 28.35 35.2 34.98 36.4 35.45 30.48 26.8 35.73 29.71 34.23 34.39 39.1 35.49

[0328] Device 31.17 30.4 29.11 30.39 35.54 35.51 36.63 35.41 3 27.91 29.83 28.12 29.05 34.12 35.46 34.58 35.05 29.57 26.95 35.04 28.66 35.84 38.53 40.55 36.35

[0329] Device 29.81 28.71 29.13 30.97 36.25 35.86 36.25 35.37 4 29.56 30.98 28.14 28.7 34.81 46.99 35.74 34.98 31.49 26.63 38.33 31.05 35.25 34.71 41.07 37.99

[0330] Device 29.65 28.61 28.27 30.54 35.97 35.77 35.28 33.87 5 29.4 28.72 28.99 27.04 36 35.3 35.91 34.7 31.26 26.39 35.1 30.96 34.82 35.9 39.83 37.53

[0331] Device 30.74 27.39 28.57 27.91 36.86 34.08 35.78 35.93 6 29.43 29.09 28.12 29.44 36.37 36.65 33.51 35.5 28.55 26.85 36.89 32.52 35.48 34.11 38.03 38.54

[0332] Device 29.01 29.27 27.91 28.7 36.92 35.44 36.15 35.5 7 30.28 29.49 29.35 28.09 36.43 33.95 36.95 34.36 27.73 26.7 33.51 30.04 34.13 34.79 39.77 39.44

[0333] Device 30.17 28.68 28.17 29.14 35.97 34.12 35.65 36 8 28.82 30.22 29.41 29.6 34.24 35.19 34.9 35.35 28.07 28.27 34.77 28.93 33.82 35.4 38.77 39

[0334]

[0335] PATENT

[0336] ATTORNEY DOCKET NO.: 51378-005WO2

[0337] Device 29.43 29.71 29.84 26.19 35.57 34.13 35.54 36.32 Did id Ditteces sorenereecevvv

[0338] 9 29.42 30.44 29.78 28.27 34.16 34.43 35.28 34.36 s _ _ 27.08 27.74 35.24 31.38 35.34 33.39 40.27 38.94

[0339] Device 31.15 28.24 29.8 29.39 37.01 35.36 32.73 35.39 1 28.77 28.98 29.03 29.67 34.99 38.03 36.91 35.6 30.55 28.04 35.35 30.58 36.13 33.43 36.36 34.17 Device 30.95 29.53 29.68 30.03 38.45 33.95 33.86 33.96 2 29.03 29.61 31.92 33.3 35.2 36.77 35.15 38.78 30.48 27.47 34.04 30.54 34.23 35.42 40.23 34.57

[0340] Device 31.17 28.97 28.59 31.15 35.54 34.65 34.69 35.31 3 27.91 29.43 30.49 31.37 34.12 37.55 36.29 35.04 29.57 27.28 33.83 30.58 35.84 35.21 38.52 34.64 Device 29.81 31.91 28.99 29.53 36.25 33.53 37.47 37.89 4 29.56 30.46 29.74 31.67 34.81 35.71 37.61 37.22 31.49 28.32 33.61 33.77 35.25 34.01 38.88 36.52

[0341] Device 29.65 30.1 29.7 29.76 35.97 34.54 35.83 37.39 5 29.4 29.11 29.17 32.24 36 38.31 35.52 35.64 31.26 28.07 33.86 30.31 34.82 37.43 36.02 35.85 Device 30.74 31.04 29.77 29.99 36.86 35.77 35.06 36.82 6 29.43 29.74 30.3 29.77 36.37 36.81 35.11 35.81 28.55 28.68 33.24 29.95 35.48 36.17 37.14 34.2 Device 29.01 28.78 30.64 32.85 36.92 33.62 34.47 35.65 7 30.28 31.05 29.36 31.66 36.43 37.11 35.61 36.47 27.73 27.1 33.19 30.31 34.13 36.06 40.09 34.3 Device 30.17 29.48 30.05 30.03 35.97 34.87 34.76 35.33 8 28.82 31.06 30.07 31.41 34.24 35.9 35.55 38.1 28.07 27.32 36.32 28.71 33.82 34.21 39.03 33.24 Device 29.43 29.75 29.78 30.63 35.57 34.74 35.26 36.14 9 29.42 28.8 28.62 31.84 34.16 38.18 35.42 37.3 27.08 27.32 34.27 29.81 35.34 35 39.67 35.32

[0342]

[0343] 1Data presented in each cell corresponds to manufacturing batches 1-3, ordered from top to bottom.

[0344] Table 9D. Droplet size distribution DV90 in plume after 6, 9, and 12 months.1

[0345] Droplet size distribution (DV90)

[0346] Measured 3 cm above the nasal device Measured 6 cm above the nasal device plume plume

[0347] Time 0 6 9 12 0 6 9 12 months months months months months months months months Device 95.61 126.9 101.1 84.75 84.06 118.1 82.61 83.77 1 86.11 255.3 180.8 112.8 83.16 75.32 85.26 80.32 91.04 67.21 165.9 86.95 78.04 94.35 109.5 101.7

[0348]

[0349] PATENT

[0350] ATTORNEY DOCKET NO.: 51378-005WO2

[0351] Device 81.62 155.8 109 96.27 128.8 86.69 75.38 192.2 Did idtteces sorenerevv

[0352] 2 78.25 134.9 127.5 82.97 81.04 228.6 100.1 79.72 90.76 72.76 254 93.55 71.7 68.86 194.5 75.95 Device 81.64 117.8 172.6 82.37 78.74 154.2 77.87 78.53 3 83.34 169.6 84.59 115.6 87.3 91.58 73.68 77.29 76.9 74.29 167.6 84.24 75.1 85.23 292.4 91.11 Device 101.6 86.29 105.3 258.3 92 216.5 88.64 96.27 4 100.4 202.3 76.07 158.9 180.4 224.7 76.05 73.62 89.46 81.82 249.4 100.4 73.59 70.85 145.9 84.8 Device 114.9 88.68 79.78 197.14 77.27 105.3 88.6 84.72 5 89.76 104.5 89.82 80.29 100.6 102.5 93.2 87.78 135.7 82.33 233.4 113.8 101.3 79.26 212.5 80.53 Device 191.3 80.14 97.96 95.85 74.17 93.94 124.1 81.22 6 156.7 167.5 85.58 169 176.9 177.2 98.07 96.52 84.56 74.92 335 130.6 74.16 74.83 168.2 116.1 Device 155 124.9 78.76 187.5 83.71 105 94.63 79.77 7 115.6 88.55 91.18 86.27 94.39 73.73 212.1 75.94 73.94 73.96 195.1 98.52 72.7 211.4 171.8 169.2 Device 82.92 98.78 84.88 91.42 204.2 87.99 92.93 195.1 8 113.8 113.2 96.03 131.6 87.28 148.7 94.29 88.72 84.27 66.08 177.8 76.61 72.03 79.44 160.2 133.4 Device 92.51 173.7 103.4 77.02 79.85 86.3 101.6 100.5 9 93.71 177.9 113.4 133 74.12 95.61 79.19 71.53 65.95 101.3 234.4 109.1 73.24 69.26 191 122.1 Device 95.61 117.6 122.8 95.89 84.06 187.2 71.58 85.41 1 86.11 152.2 101.6 190.1 83.16 284.9 154.5 74.35 91.04 80.19 260.5 96.55 78.04 72.7 158.3 72.55 Device 81.62 120.8 121 95.78 128.8 107.4 74.15 81.69 2 78.25 167.8 259.5 231.8 81.04 175.9 74.48 101.7 90.76 71.39 361.4 106.3 71.7 73.37 210.9 86.18

[0353] Device 81.64 105.1 89.73 123.2 78.74 236.3 77.25 83.68 3 83.34 136.6 148 174 87.3 180.2 75.33 73.99 76.9 99.36 227.2 116.9 75.1 71.15 197.9 80.01 Device 101.6 200.3 157.3 91.59 92 73.62 217.3 89.36 4 100.4 221.6 107.8 216.3 180.4 88.75 77.37 102.5 89.46 109.1 207.1 221 73.59 72.35 220.8 75.33

[0354] Device 114.9 84.07 77.02 92.04 77.27 180.2 78.98 83.66 5 89.76 121.5 106.8 174.6 100.6 174.1 175.1 92.77 135.7 89.08 170.1 91.94 101.3 77.77 82.8 78.41 Device 191.3 206.4 148.1 92.97 74.17 136.5 83.43 187.5 6 156.7 149.7 118.7 173.9 176.9 86.79 78.94 77.24 84.56 84.57 260.5 77.66 74.16 75.01 88.5 72

[0355]

[0356] PATENT

[0357] ATTORNEY DOCKET NO.: 51378-005WO2

[0358] Device 155 99.87 229.6 275.6 83.71 82.24 84.92 98.7 7 115.6 179.3 137 213.3 94.39 144.9 95 88.92 73.94 74.53 211.3 99.93 72.7 73.73 208.5 70.4 Device 82.92 84.05 118.1 92.77 204.2 86.66 94.76 103.3 8 113.8 191.6 212.2 96.6 87.28 93.78 79.22 108 84.27 74.86 276.5 74.14 72.03 70.63 182.8 82.23 Device 92.51 167.6 181.3 83.97 79.85 102.5 71.88 91.2 9 93.71 103.8 85.2 177.6 74.12 185.8 81.42 120.2 65.95 81.04 198.8 82.48 73.24 74.9 134.4 81.06

[0359]

[0360] 1Data presented in each cell corresponds to manufacturing batches 1-3, ordered from top to bottom.

[0361] Example 2: Characterization of spray pattern of the plume

[0362] The spray pattern of the plume upon actuation of the nasal delivery device were characterized. Nine nasal delivery Aptar Unidose® devices each containing the same pharmaceutical composition including 5.54 mg / mL potassium bumetanide, 1 mg / mL low viscosity carboxymethyl cellulose, 5 mg / mL benzyl alcohol, 40 mg / mL mannitol in water at a pH of between 6.6 to 7.8 were dispensed to generate a plume of the pharmaceutical composition. The spray pattern of the plumes were measured either 3 cm (Table 10) or 6 cm (Table 11) above the tip of the nasal delivery device. The spray pattern was characterized in terms of minimum diameter (Dmin), the maximum diameter (Dmax), the ovality of the pattern, the perimeter of the pattern, the area of the pattern, the ellipticity of the pattern, the inclusion of the pattern, and the inclination of the pattern. Exemplary spray patterns are shown in FIG. 2A and FIG. 2B. The spray pattern was assessed again after 6, 9, and 12 months of storage to characterize the stability of the spray pattern. Nine devices stored either upright or inverted from each of three manufacturing batches had their spray pattern characterized after storage at 25 °C and approximately 60% relative humidity for the indicated time. The results are presented in Tables 12A-12C, and demonstrate the exceptional stability of the spray pattern irrespective of the storage orientation and length of storage from the time of manufacture. Each cell of Tables 12A-12C presents data corresponding to manufactured batches 1-3, ordered from top to bottom (batch 1 - top, batch 2 - middle, and batch 3 -bottom).

[0363] Table 10. Characterization of spray pattern measured at 3 cm above the nasal delivery device Measured at 3 cm above Device #1 Device #2 Device #3 nasal device

[0364] Spray Pattern 30.0 Dmin 23.05 mm 23.74 mm 19.36 Height:

[0365] Evacuation 20000 Dmax 28.49 mm 29.42 mm 25.51 Time ms

[0366] Settling Time: 10000 Ovality 1.236 1.239 1.318

[0367] ms

[0368] Perimeter 86.69 mm 94.04 mm 73.56 mm Area 505.2 mm2564.8 mm2387.0 mm2Area 7.6% 8.4% 5.8% Percent

[0369] Major 26.77 mm 28.14 mm 23.93 mm

[0370]

[0371] Minor 23.70 mm 25.39 mm 20.16 mm PATENT

[0372] ATTORNEY DOCKET NO.: 51378-005WO2

[0373] Ellipticity 1.130 1.109 1.187 Didihttevces sore uprg Inclusion 0.086 0.149 0.089

[0374]

[0375] Inclination 113.9 deg 58.2 deg 37.6 deg

[0376] Table 11. Characterization of spray pattern measured at 6 cm above the nasal delivery device Measured at 6 cm above Device #1 Device #2 Device #3 nasal device

[0377] Spray Pattern 60.0 Dmin 44.47 mm 35.88 mm 41.45 mm Height:

[0378] Evacuation 20000 Dmax 56.01 mm 46.76 mm 51.99 mm Time ms

[0379] Settling Time: 10000 Ovality 1.259 1.303 1.254

[0380] ms

[0381] Perimeter 179.09 mm 147.98 mm 157.56 mm Area 1981.7 mm21426.9 mm21659.7 mm2Area 11.5% 8.3% 9.6% Percent

[0382] Major 52.48 mm 44.06 mm 49.36 mm Minor 48.05 mm 40.70 mm 42.18 mm Ellipticity 1.092 1.083 1.170 Inclusion 0.121 0.115 0.061

[0383]

[0384] Inclination 32.7 deg 88.8 deg 53.0 deg Could add here the 6 month stability data of spray pattern for 3 registration lots

[0385] Table 12A. Characterization Dmin of spray pattern stability after 6, 9 and 12 months at room temperature.1_

[0386] Spray Pattern Dmin (mm)

[0387] Measured 3 cm above the nasal device Measured 6 cm above the nasal device plume plume

[0388] Time 0 6 9 12 0 6 9 12 months months months months months months months months Device 23.05 17.22 20.85 22.08 44.47 30.24 34.79 43.57 1 22.52 22.23 18.32 18.08 47.26 45.21 35.51 27.86 22.05 18.42 17.85 21.75 38.47 29.85 34.41 36.84 Device 23.32 20.28 20.29 22.27 42.55 35.38 32.03 57.85 2 21.83 24.53 21.36 22.96 46.23 42.10 42.62 39.51 21.75 19.57 22.65 18.19 34.98 39.16 37.70 39.80 Device 21.94 19.26 22.45 23.18 33.48 38.15 37.88 37.35 3 21.08 21.04 19.65 18.09 36.97 39.46 36.33 35.89 22.21 18.59 18.59 18.81 32.80 38.77 33.39 31.01 Device 23.74 19.16 25.38 19.22 35.88 33.13 35.20 37.78 4 22.17 20.95 19.67 18.31 45.57 44.41 51.91 37.56 19.81 20.00 20.00 20.25 37.77 35.85 38.82 47.98 Device 19.49 17.90 22.05 22.38 33.54 41.60 41.64 38.92 5 24.68 19.69 21.95 20.34 43.44 51.79 35.66 39.14 19.25 23.29 23.29 21.20 43.48 34.03 36.53 38.97 Device 21.83 17.18 20.74 23.26 34.41 31.76 28.23 46.07 6 22.53 22.21 20.92 21.49 42.41 43.57 35.25 30.98 22.32 19.15 19.15 21.25 47.08 42.46 31.21 38.84 Device 19.36 19.11 23.45 19.06 41.45 37.49 37.02 44.62 7 20.52 20.24 17.00 20.47 45.89 49.64 33.32 30.25 22.29 19.42 19.42 22.20 43.25 35.43 30.88 36.93 Device 22.54 18.16 19.28 22.56 35.26 28.50 39.08 37.84 8 21.49 23.09 21.46 19.49 46.82 37.11 42.36 40.57

[0389]

[0390] 21.12 17.53 17.53 19.46 36.80 43.99 37.61 36.80 PATENT

[0391] ATTORNEY DOCKET NO.: 51378-005WO2

[0392] Didihttevces sore uprg Device 23.45 19.53 19.46 21.13 33.70 34.10 34.03 36.58 Did idttevces sorenvere 9 22.81 21.19 19.20 21.54 45.23 44.33 40.73 40.93

[0393] 22.88 19.91 19.91 19.04 35.94 45.75 35.36 33.60 Device 23.05 18.59 21.34 21.94 44.47 31.44 33.95 44.91

[0394] 1 22.52 24.02 21.51 19.97 47.26 44.34 47.59 40.27

[0395] 22.05 19.61 20.10 17.50 38.47 35.71 41.65 38.69 Device 23.32 20.41 20.04 20.11 42.55 34.71 38.53 45.28 2 21.83 22.01 22.59 21.16 46.23 51.26 39.04 33.41

[0396] 21.75 20.23 20.23 20.48 34.98 36.42 37.55 33.03 Device 21.94 20.56 23.55 23.38 33.48 30.77 33.30 44.18 3 21.08 22.19 20.51 19.37 36.97 50.08 44.27 45.12

[0397] 22.21 20.76 23.18 21.86 32.80 46.40 44.71 37.66 Device 23.74 19.58 22.39 22.60 35.88 32.63 38.86 44.76 4 22.17 21.69 19.80 20.68 45.57 41.65 39.54 40.50

[0398] 19.81 21.16 18.62 19.41 37.77 40.56 39.24 32.09 Device 19.49 18.48 23.54 21.67 33.54 33.97 32.29 47.01 5 24.68 22.01 20.19 20.21 43.44 45.76 39.72 38.52

[0399] 19.25 22.42 18.28 17.43 43.48 39.35 30.97 40.56 Device 21.83 18.66 19.90 18.95 34.41 36.50 35.14 45.99 6 22.53 20.04 22.82 20.75 42.41 46.86 40.55 27.34

[0400] 22.32 19.84 22.67 21.47 47.08 37.28 38.26 31.72 Device 19.36 20.50 21.28 23.85 41.45 34.56 35.61 42.81 7 20.52 22.41 21.72 19.76 45.89 34.85 37.70 37.14

[0401] 22.29 20.44 21.16 17.99 43.25 43.26 37.70 38.51 Device 22.54 19.18 18.53 22.63 35.26 34.39 33.34 37.23 8 21.49 20.36 19.15 22.13 46.82 44.34 40.06 34.34

[0402] 21.12 18.26 19.11 20.76 36.80 35.69 46.83 29.10 Device 23.45 18.19 21.51 23.39 33.70 34.10 35.92 44.49 9 22.81 22.37 23.91 22.16 45.23 36.18 42.27 34.14

[0403] 22.88 20.44 19.11 20.13 35.94 35.55 41.47 35.73

[0404]

[0405] 1Data presented in each cell corresponds to manufacturing batches 1-3, ordered from top to bottom.

[0406] Table 12B. Characterization Dmax of spray pattern stability after 6, 9 and 12 months at room temperature.1_

[0407] Spray Pattern Dmax (mm)

[0408] Measured 3 cm above the nasal device Measured 6 cm above the nasal device plume plume

[0409] Time 0 6 9 12 0 6 9 12 months months months months months months months months Device 28.49 22.62 23.36 28.16 56.01 39.69 44.75 54.02 1 29.09 26.90 25.94 27.45 62.48 56.70 55.10 34.60 28.25 25.10 23.76 24.97 54.37 47.64 45.11 53.19 Device 29.39 22.17 28.87 25.30 49.88 45.81 44.64 68.82 2 26.60 28.32 24.77 29.09 57.66 51.29 53.52 50.06 26.77 25.45 30.54 26.09 46.64 55.55 53.29 52.56 Device 23.98 21.88 26.30 25.83 46.05 48.13 52.64 44.48 3 29.27 28.38 25.94 26.48 48.39 55.81 46.29 47.09 33.41 31.83 25.22 24.86 49.30 57.32 46.74 45.90 Device 29.42 23.05 30.59 23.64 46.76 45.75 51.00 49.95 4 29.90 24.60 25.87 26.81 54.16 58.04 64.90 47.02 27.12 28.18 22.26 26.48 49.87 55.50 68.48 62.16 Device 25.16 22.07 25.99 26.03 45.54 49.39 52.96 52.52 5 32.26 28.67 26.51 26.22 58.64 67.13 52.96 48.66 29.54 30.78 27.20 25.71 58.55 43.77 44.38 50.61 Device 26.07 22.21 25.27 28.43 45.73 39.00 42.26 56.70 6 29.37 25.14 24.78 27.54 49.64 55.42 40.61 39.00

[0410]

[0411] 30.16 25.28 23.34 26.60 62.19 52.37 41.32 56.50 PATENT

[0412] ATTORNEY DOCKET NO.: 51378-005WO2

[0413] Did id Didihttttevces sorenvereevces sore uprg Device 25.51 22.02 27.40 25.48 51.99 52.33 49.52 54.86

[0414] 7 26.70 23.86 33.22 27.14 58.82 62.52 38.97 39.59 27.01 26.91 33.91 35.31 61.16 42.93 57.64 48.45 Device 26.22 21.64 24.58 25.75 47.45 40.12 51.46 43.99 8 26.74 28.85 25.72 22.60 57.49 46.69 54.17 55.82 28.15 24.52 28.06 25.04 45.50 53.69 51.44 44.23 Device 29.41 23.12 24.18 25.95 43.82 42.23 41.16 43.89 9 28.90 31.30 23.66 29.52 59.61 57.42 52.66 50.50 30.54 22.52 26.59 22.86 52.49 56.64 45.55 53.11 Device 28.49 24.47 25.31 27.42 56.01 47.70 42.13 57.45 1 29.09 27.42 24.67 26.71 62.48 62.17 59.21 51.86 28.25 25.94 31.57 21.62 54.37 56.60 57.81 51.34 Device 29.39 23.15 25.68 27.56 49.88 43.67 49.91 54.09 2 26.60 23.72 25.77 24.28 57.66 66.19 47.56 43.07 26.77 23.63 30.94 27.06 46.64 49.70 49.90 40.85 Device 23.98 23.71 28.26 29.23 46.05 41.24 41.67 56.03 3 29.27 24.96 27.76 24.28 48.39 61.16 58.06 54.92 33.41 23.31 27.81 24.95 49.30 57.39 57.08 50.32 Device 29.42 22.17 25.54 29.00 46.76 41.41 49.55 57.55 4 29.90 25.51 25.67 26.00 54.16 54.19 52.57 50.43 27.12 25.85 29.00 24.31 49.87 51.23 50.49 43.74 Device 25.16 27.46 26.84 26.61 45.54 38.92 41.64 63.68 5 32.26 27.51 23.07 27.58 58.64 58.75 49.76 48.20 29.54 31.22 23.73 23.36 58.55 48.70 44.09 58.17 Device 26.07 22.36 30.28 28.35 45.73 42.14 43.36 60.89 6 29.37 27.13 25.68 27.76 49.64 61.23 51.70 38.08 30.16 26.75 39.04 28.06 62.19 48.20 63.38 43.75 Device 25.51 29.12 30.08 28.59 51.99 43.99 45.31 53.41 7 26.70 26.82 26.14 26.42 58.82 64.65 46.05 46.91 27.01 25.07 31.99 23.87 61.16 59.77 52.38 53.56 Device 26.22 25.05 27.64 28.58 47.45 46.31 43.77 60.04 8 26.74 27.20 24.41 27.79 57.49 64.90 50.25 45.52 28.15 24.51 27.18 28.92 45.50 54.71 64.09 36.63 Device 29.41 21.23 25.70 28.89 43.82 44.85 42.21 56.08 9 28.90 27.66 20.75 25.44 59.61 47.76 54.23 43.79 30.54 27.53 23.14 26.32 52.49 49.06 52.41 45.86

[0415]

[0416] 1Data presented in each cell corresponds to manufacturing batches 1-3, ordered from top to bottom.

[0417] Table 12C. Characterization ovality of spray pattern stability after 6, 9 and 12 months at room temperature.1_

[0418] Spray Pattern Ovality

[0419] Measured 3 cm above the nasal device Measured 6 cm above the nasal device plume plume

[0420] Time 0 6 9 12 0 6 9 12 months months months months months months months months

[0421] Device 1.236 1.313 1.121 1.276 1.259 1.312 1.286 1.240 1 1.291 1.210 1.416 1.518 1.322 1.254 1.552 1.242 1.281 1.363 1.331 1.148 1.413 1.593 1.311 1.444 Device 1.260 1.093 1.423 1.136 1.172 1.295 1.394 1.190 2 1.218 1.155 1.160 1.267 1.247 1.218 1.256 1.267 1.231 1.300 1.349 1.434 1.333 1.419 1.414 1.321 Device 1.093 1.136 1.171 1.115 1.376 1.262 1.390 1.191 3 1.388 1.349 1.320 1.464 1.309 1.414 1.274 1.312 1.504 1.712 1.193 1.321 1.503 1.478 1.400 1.480

[0422]

[0423] PATENT

[0424] ATTORNEY DOCKET NO.: 51378-005WO2

[0425] Did idttevces sorenvere Device 1.239 1.203 1.205 1.230 1.303 1.381 1.449 1.322

[0426] 4 1.348 1.174 1.315 1.464 1.233 1.307 1.250 1.252 1.369 1.409 1.214 1.308 1.320 1.548 1.764 1.296 Device 1.291 1.233 1.178 1.163 1.358 1.187 1.272 1.349 5 1.307 1.457 1.208 1.289 1.350 1.296 1.485 1.243 1.534 1.322 1.181 1.213 1.347 1.286 1.215 1.299 Device 1.194 1.293 1.219 1.222 1.329 1.228 1.497 1.231 6 1.304 1.132 1.184 1.281 1.170 1.272 1.152 1.259 1.351 1.320 1.318 1.252 1.321 1.233 1.324 1.455 Device 1.318 1.152 1.169 1.336 1.254 1.396 1.338 1.230 7 1.301 1.179 1.954 1.326 1.282 1.259 1.169 1.308 1.212 1.385 1.619 1.591 1.414 1.212 1.866 1.312 Device 1.163 1.192 1.275 1.142 1.346 1.408 1.317 1.163 8 1.245 1.249 1.198 1.159 1.228 1.258 1.279 1.376 1.333 1.399 1.468 1.289 1.236 1.221 1.368 1.202 Device 1.254 1.184 1.242 1.228 1.300 1.238 1.210 1.200 9 1.267 1.477 1.232 1.371 1.318 1.295 1.293 1.234 1.335 1.131 1.230 1.201 1.461 1.238 1.288 1.581 Device 1.236 1.317 1.186 1.249 1.259 1.517 1.241 1.279 1 1.291 1.141 1.145 1.337 1.322 1.402 1.244 1.288 1.281 1.323 1.570 1.236 1.413 1.585 1.388 1.327 Device 1.260 1.134 1.281 1.371 1.172 1.258 1.295 1.195 2 1.218 1.078 1.141 1.148 1.247 1.291 1.218 1.289 1.231 1.168 1.508 1.322 1.333 1.365 1.329 1.237 Device 1.093 1.153 1.200 1.250 1.376 1.340 1.251 1.268 3 1.388 1.125 1.351 1.254 1.309 1.221 1.312 1.217 1.504 1.123 1.200 1.142 1.503 1.237 1.277 1.336 Device 1.239 1.133 1.141 1.283 1.303 1.269 1.275 1.286 4 1.348 1.176 1.297 1.257 1.233 1.301 1.330 1.245 1.369 1.222 1.558 1.252 1.320 1.263 1.287 1.363 Device 1.291 1.486 1.140 1.228 1.358 1.146 1.289 1.354 5 1.307 1.250 1.143 1.364 1.350 1.284 1.240 1.251 1.534 1.392 1.298 1.340 1.347 1.238 1.424 1.434 Device 1.194 1.198 1.521 1.496 1.329 1.155 1.234 1.324 6 1.304 1.353 1.125 1.338 1.170 1.307 1.275 1.393 1.351 1.348 1.281 1.307 1.321 1.293 1.656 1.379 Device 1.318 1.421 1.414 1.199 1.254 1.273 1.273 1.248 7 1.301 1.197 1.204 1.337 1.282 1.855 1.222 1.263 1.212 1.227 1.511 1.327 1.414 1.382 1.390 1.391 Device 1.163 1.306 1.491 1.263 1.346 1.347 1.313 1.612 8 1.245 1.336 1.275 1.256 1.228 1.464 1.254 1.325 1.333 1.343 1.422 1.393 1.236 1.533 1.369 1.259 Device 1.254 1.167 1.195 1.235 1.300 1.315 1.175 1.260 9 1.267 1.236 1.286 1.148 1.318 1.320 1.283 1.283 1.335 1.347 1.211 1.307 1.461 1.380 1.264 1.284

[0427]

[0428] 1Data presented in each cell corresponds to manufacturing batches 1-3, ordered from top to bottom.

[0429] Example 3: Characterization of plume geometry

[0430] The plume geometry of the plume upon actuation of the nasal delivery device was characterized. Nine nasal delivery individual Aptar Unidose® devices each containing the identical pharmaceutical composition including 5.54 mg / mL potassium bumetanide, 1 mg / mL low viscosity carboxymethyl cellulose, 5 mg / mL benzyl alcohol, 40 mg / mL mannitol in water at a pH of between 6.6 and 7.8 were dispensed to generate a plume of the pharmaceutical composition. The plume geometry was measured either 3 cm (Table 14) or 6 cm (Table 13) above the tip of the nasal delivery device. The plume geometry was characterized in terms of the angle created between arm 1 of the plume and a longitudinal PATENT

[0431] ATTORNEY DOCKET NO.: 51378-005WO2

[0432] line, the angle created between arm 2 of the plume and a longitudinal line, the total angle created by the Didihtteces soreprgv u

[0433] plume, and the width of the plume. Exemplary spray patterns are shown in FIG. 3A and FIG. 3B.

[0434] Furthermore, the stability of the plume geometry was assessed again after 6, 9, and 12 months of storage (Tables 15A and 14B). Nine devices stored either upright or inverted from each of three manufacturing batches had their spray pattern characterized after storage at 25 °C and approximately 60% relative humidity for the indicated time. The results are presented in Tables 15A-15B, and demonstrate the exceptional stability of the plume geometry irrespective of the storage orientation and length of storage from the time of manufacture. Each cell of Table 15A or 15B presents data corresponding to manufactured batches 1-3, ordered from top to bottom (batch 1 - top, batch 2 - middle, and batch 3 -bottom).

[0435] Table 13. Characterization of plume geometry measured at 6 cm above the nasal delivery device Measured at 6 cm above nasal Device #1 Device #2 Device #3 device

[0436] Spray Pattern 60.0 mm Arm 1 29.6 deg 28.1 deg 32.8 deg Height:

[0437] Evacuation Time 20000 ms Arm 2 31.7 deg 34.5 deg 36.1 mm Settling Time: 10000 ms Angle 61.3 deg 62.6 deg 68.9 deg Width 71.09 mm 73.18 mm 82.38 mm

[0438]

[0439] Time 200 ms 198 ms 202 ms

[0440] Table 14. Characterization of plume geometry measured at 3 cm above the nasal delivery device Measured at 3 cm above nasal Device #1 Device #2 Device #3 device

[0441] Spray Pattern 60.0 mm Arm 1 36.2 deg 32.4 deg 32.1 deg Height:

[0442] Evacuation Time 20000 ms Arm 2 36.2 deg 35.1 deg 36.5 deg Settling Time: 10000 ms Angle 72.4 deg 67.5 deg 68.6 deg Width 43.91 mm 40.15 mm 40.98 mm

[0443]

[0444] Time 202 ms 200 ms 198 ms

[0445] Table 15A. Characterization of plume width stability after 6, 9 and 12 months.1

[0446]

[0447] Plume width (mm)

[0448] Measured 3 cm above the nasal device Measured 6 cm above the nasal device plume plume

[0449] Time 0 6 9 12 0 6 9 12 months months months months months months months months Device 43.91 45.49 41.93 50.19 82.38 78.04 68.34 91.18 1 37.61 41.01 45.23 44.73 61.11 67.79 80.41 79.33 45.96 45.68 38.89 44.04 74.78 76.27 75.27 74.10 Device 42.24 43.82 40.25 46.01 75.69 77.21 69.60 81.14 2 34.62 41.43 40.62 45.99 58.55 65.28 76.64 83.13 43.03 41.07 42.65 43.19 74.78 71.66 75.27 68.60 Device 44.33 43.82 39.83 47.68 76.11 72.20 70.85 87.00 3 35.90 46.45 38.95 46.42 64.10 81.80 69.52 75.53 42.20 42.74 42.23 42.35 72.28 77.10 72.34 72.83 Device 40.15 46.32 41.93 44.75 71.09 81.38 72.53 81.56 4 37.61 43.52 38.53 44.31 63.25 71.97 67.43 78.49

[0450]

[0451] 45.54 45.68 41.82 41.50 83.14 75.01 67.32 70.29 PATENT

[0452] ATTORNEY DOCKET NO.: 51378-005WO2

[0453] Device 43.49 47.58 39.83 49.77 78.62 77.21 73.79 91.18 Did id Didihtttteces sorenereeces soreprgvvv u

[0454] 5 35.04 42.68 43.98 46.84 62.39 74.06 81.25 79.75 46.79 40.65 42.23 43.19 73.11 67.47 75.27 72.41 Device 43.07 44.24 42.35 50.61 72.76 72.20 75.47 90.34 6 36.33 44.35 41.04 45.15 64.96 76.16 74.13 79.75 48.88 43.58 39.73 37.69 92.33 71.24 60.63 65.63 Device 40.98 47.58 40.67 48.10 73.18 77.21 71.69 82.40 7 35.04 43.10 45.23 43.88 63.25 67.37 78.74 78.49 43.03 41.90 44.33 41.50 83.97 62.02 74.85 69.87 Device 39.31 45.91 44.44 45.59 70.67 73.87 75.05 81.14 8 37.18 41.43 46.49 41.77 65.81 66.95 75.81 71.31 45.96 42.32 40.98 41.50 86.48 75.43 66.91 71.56 Device 40.56 45.07 42.35 43.50 75.27 77.62 73.79 75.29 9 40.60 44.35 42.30 45.57 65.39 71.13 72.87 84.81 48.88 44.42 42.65 40.23 78.54 74.59 72.76 66.48 Device 43.91 45.91 44.02 46.01 82.38 80.55 73.79 81.98 1 37.61 46.87 44.39 47.23 61.11 73.65 76.22 78.06 45.96 46.51 43.49 41.07 74.78 76.27 68.16 63.94 Device 42.24 44.65 40.67 46.01 75.69 75.54 71.69 76.12 2 34.62 43.52 43.56 45.57 58.55 71.97 78.74 84.81 43.03 44.84 42.23 44.04 74.78 77.94 76.94 75.37 Device 44.33 47.16 41.93 46.43 76.11 77.21 77.98 81.14 3 35.90 46.03 43.14 43.88 64.10 84.11 76.64 80.17 42.20 42.32 47.25 45.73 72.28 76.27 80.71 77.49 Device 40.15 47.58 41.93 46.84 71.09 78.46 73.37 80.72 4 37.61 42.68 43.98 47.26 63.25 71.55 77.90 79.75 45.54 44.84 41.82 44.46 83.14 80.87 73.18 76.64 Device 43.49 43.40 41.51 42.24 78.62 73.45 70.85 74.87 5 35.04 45.61 39.79 46.84 62.39 79.08 73.71 80.17 46.79 49.45 44.74 43.19 73.11 81.29 81.54 78.34 Device 43.07 47.16 39.83 46.01 72.76 83.47 70.85 81.56 6 36.33 43.94 43.14 43.46 64.96 80.34 80.41 82.28 48.88 44.42 44.33 41.92 92.33 79.62 75.27 64.36 Device 40.98 45.07 40.67 47.68 73.18 79.71 67.92 84.07 7 35.04 44.35 45.65 46.42 63.25 68.21 82.09 82.28 43.03 43.16 45.16 44.04 83.97 74.17 76.11 71.56 Device 39.31 44.65 44.44 46.84 70.67 78.04 74.21 79.89 8 37.18 46.45 43.14 45.15 65.81 79.08 81.25 86.50 45.96 43.16 42.23 41.50 86.48 73.33 76.11 79.61 Device 40.56 48.41 39.41 43.50 75.27 81.38 67.08 74.87 9 40.60 47.28 39.37 47.26 65.39 70.78 70.78 79.75

[0455]

[0456] 48.88 45.26 41.40 38.11 78.54 80.87 74.02 68.181Data presented in each cell corresponds to manufacturing batches 1-3, ordered from top to bottom.

[0457] Table 15B. Characterization of plume angle stability after 6, 9 and 12 months.1

[0458] Plume angle (deg)

[0459] Measured 3 cm above the nasal device Measured 6 cm above the nasal device plume plume

[0460] Time 0 6 9 12 0 6 9 12 months months months months months months months months Device 72.4 74.3 69.9 79.7 68.9 66.0 59.3 74.3 1 64.1 68.7 74.1 73.4 53.9 59.0 67.7 66.9 74.4 74.5 65.9 72.5 63.5 64.8 64.2 63.4 Device 70.2 72.2 67.7 74.9 64.4 65.5 60.2 68.1 2 60.0 69.2 68.1 74.9 52.0 57.1 65.1 69.3 71.3 68.7 70.7 71.5 63.8 61.7 64.1 59.6 Device 72.8 72.2 67.1 77.0 64.7 62.0 61.1 71.8 3 61.8 75.4 65.9 75.4 56.2 68.2 60.1 64.3 70.2 70.9 70.3 70.2 62.1 65.3 62.1 62.3 Device 67.5 75.3 69.9 73.4 61.3 68.3 62.3 68.4 4 64.1 71.9 65.4 72.8 55.6 61.9 58.5 66.3

[0461]

[0462] 74.3 74.6 69.7 69.2 69.4 64.0 58.6 60.7 PATENT

[0463] ATTORNEY DOCKET NO.: 51378-005WO2

[0464] Device 71.9 76.6 67.1 79.3 66.4 65.5 63.1 74.2 Did idtteces sorenerevv

[0465] 5 60.6 70.8 72.4 75.9 54.9 63.3 68.1 67.2 75.8 68.2 70.2 71.5 62.7 58.7 64.2 62.2 Device 71.3 72.8 70.3 80.3 62.4 62.1 64.3 73.8 6 62.4 72.9 68.8 73.9 56.8 64.7 63.2 67.1 78.3 72.0 67.0 64.3 75.1 61.4 53.5 57.4 Device 68.6 76.8 68.2 77.4 62.6 65.6 61.7 68.9 7 60.5 71.4 74.0 72.2 55.5 58.7 66.4 66.4 71.3 69.9 72.9 69.4 69.8 54.6 63.9 60.4 Device 66.5 74.8 73.1 74.5 61.0 63.2 64.1 68.1 8 63.6 69.3 75.4 69.7 57.5 58.4 64.5 61.4 74.6 70.4 68.7 69.4 71.3 64.3 58.1 61.7 Device 68.1 73.9 70.4 71.8 64.2 65.8 63.1 64.2 9 68.1 72.9 70.4 74.4 57.2 61.3 62.4 70.5 78.4 73.0 70.8 67.5 66.4 63.7 62.5 57.9 Device 72.4 74.9 72.4 75.0 68.9 67.7 63.2 68.6 1 64.1 75.9 73.0 76.4 53.9 63.0 64.8 66.1 74.4 75.5 71.7 68.6 63.5 64.9 59.1 56.1 Device 70.2 73.3 68.2 75.0 64.4 64.4 61.6 64.8 2 60.0 71.9 71.9 74.4 52.0 61.5 66.6 70.3 71.3 73.5 70.2 72.5 63.8 66.0 65.3 64.3 Device 72.8 76.3 69.8 75.5 64.7 65.5 66.0 68.1 3 61.8 74.9 71.4 72.2 56.2 70.1 65.1 67.5 70.2 70.3 76.5 74.6 62.1 64.8 67.8 65.7 Device 67.5 76.8 69.9 75.8 61.3 66.4 62.9 67.9 4 64.1 70.9 72.4 76.4 55.6 61.7 65.9 67.2 74.3 73.5 69.7 73.0 69.4 68.0 62.8 65.1 Device 71.9 71.8 69.3 70.3 66.4 62.9 61.1 63.9 5 60.6 74.4 67.0 75.9 54.9 66.6 63.0 67.4 75.8 78.8 73.4 71.5 62.7 67.9 68.4 66.4 Device 71.3 76.3 67.1 74.9 62.4 69.6 61.0 68.4 6 62.4 72.4 71.3 71.8 56.8 67.6 67.5 68.9 78.3 73.1 72.9 69.9 75.1 67.1 64.2 56.4 Device 68.6 73.8 68.3 76.9 62.6 67.2 59.0 70.0 7 60.5 72.9 74.5 75.4 55.5 59.1 68.7 67.8 71.3 71.4 74.0 72.4 69.8 63.5 64.8 61.5 Device 66.5 73.2 73.0 75.9 61.0 66.0 63.3 67.2 8 63.6 75.4 71.3 73.8 57.5 66.8 68.2 71.5 74.6 71.4 70.2 69.4 71.3 62.8 64.7 67.1 Device 68.1 77.7 66.5 71.8 64.2 68.3 58.4 63.8 9 68.1 76.4 66.5 76.4 57.2 65.8 60.9 67.2

[0466]

[0467] 78.4 74.1 69.1 64.8 66.4 68.0 63.3 59.21Data presented in each cell corresponds to manufacturing batches 1-3, ordered from top to bottom.

Claims

PATENTATTORNEY DOCKET NO.: 51378-005WO2What is claimed:

1. A method of treating edema in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising bumetanide or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is administered to the subject using a nasal spray device, wherein the nasal spray device delivers a dosage unit by way of a plume upon actuation, wherein the in the plume is characterized by:a) total volume deployed upon actuation, wherein the total volume delivered per actuation is between 50 pl and 150 pl;b) droplet size, wherein the droplets have an average diameter of greater than 10 m; c) spray pattern, wherein the spray pattern is characterized as having an ovality of from 1 to 2; and / ord) plume geometry, wherein plume geometry is characterized by having an angle of from 56° to 67° when measured at 6 cm above the device or 63° to 76° when measured at 3 cm above the device.

2. The method of claim 1, wherein the droplets have an average diameter ranging from 1 pm to 210 pm.

3. The method of claim 2, wherein the droplets have an average diameter ranging from 50 pm to 150 pm.

4. The method of claim 2, wherein the droplets have an average diameter ranging from 15 pm to 50 pm.

5. The method of any one of claims 1-4, wherein the droplets have a Dv10 of between 6 pm and 27 pm when measured 3 cm from the device.

6. The method of any one of claims 1-5, wherein the droplets have a Dv50 of between 14 pm and 51 pm when measured 3 cm from the device.

7. The method of any one of claims 1-6, wherein the droplets have a Dv90 of less than 500 pm when measured 3 cm from the device.

8. The method of any one of claims 1-7, wherein the droplets have a Dv90 of between 70 pm and 500 pm when measured 3 cm from the device.

9. The method of any one of claims 1-8, wherein the droplets have a Dv10 of between 6 pm and 27 pm when measured 6 cm from the device.

10. The method of any one of claims 1-9, wherein the droplets have a Dv50 of between 14 pm and 51 pm when measured 6 cm from the device.PATENTATTORNEY DOCKET NO.: 51378-005WO211. The method of any one of claims 1 -10, wherein the droplets have a Dv90 of less than 400 pm when measured 6 cm from the device.

12. The method of any one of claims 1-11, wherein the droplets have a Dv90 of between 70 pm and 400 pm when measured 6 cm from the device.

13. The method of any one of claims 1-12, wherein the spray pattern is characterized by its maximum diameter, minimum diameter, or ovality.

14. The method of claim 13, wherein the spray pattern is characterized as having a maximum diameter of between 12 mm and 56 mm when measured 3 cm from the device.

15. The method of claim 14, wherein the spray pattern is characterized as having a maximum diameter of between 18 mm and 44 mm when measured 3 cm from the device.

16. The method of claim 14, wherein the spray pattern is characterized as having a maximum diameter of between 22 mm and 32 mm when measured 3 cm from the device.

17. The method of claim 14, wherein the spray pattern is characterized as having a maximum diameter of between 32 mm and 44 mm when measured 3 cm from the device.

18. The method of claim 14, wherein the spray pattern is characterized as having a minimum diameter of between 17 mm and 27 mm when measured 3 cm from the device.

19. The method of claim 18, wherein the spray pattern is characterized as having a minimum diameter of between 21 mm and 23 mm when measured 3 cm from the device.

20. The method of any one of claims 13-19, wherein the spray pattern is characterized as having a maximum diameter of between 19 mm and 135 mm when measured 6 cm from the device.

21. The method of claim 20, wherein the spray pattern is characterized as having a maximum diameter of between 33 mm and 69 mm when measured 6 cm from the device.

22. The method of claim 20, wherein the spray pattern is characterized as having a maximum diameter of between 40 mm and 59 mm when measured 6 cm from the device.

23. The method of claim 20, wherein the spray pattern is characterized as having a maximum diameter of between 45 mm and 57 mm when measured 6 cm from the device.

24. The method of claim 20, wherein the spray pattern is characterized as having a minimum diameter of between 28 mm and 52 mm when measured 6 cm from the device.PATENTATTORNEY DOCKET NO.: 51378-005WO225. The method of claim 20, wherein the spray pattern is characterized as having a minimum diameter of between 36 mm and 44 mm when measured 6 cm from the device.

26. The method of any one of claims 1-25, wherein the spray pattern is characterized as having an ovality of from 0.7 to 2.2.

27. The method of claim 26, wherein the spray pattern is characterized as having an ovality of from 1 to 1.6.

28. The method of claim 27, wherein the spray pattern is characterized as having an ovality of from 1.1 to 1.4.

29. The method of claim 28, wherein the spray pattern is characterized as having an ovality of about 1.3.

30. The method of any one of claims 1-25, wherein the spray pattern is characterized as having an ovality of between 1.2 and 1.4 when measured 6 cm above the device.

31. The method of any one of claims 1-25, wherein the spray pattern is characterized as having an ovality of between 1.2 and 1.3 when measured 3 cm above the device.

32. The method of any one of claims 1 -31, wherein the plume is characterized by having an angle of from 52° to 76° when measured at 6 cm above the device.

33. The method of any one of claims 1 -31, wherein the plume is characterized by having a width of from 58 mm to 92 mm when measured at 6 cm above the device.

34. The method of any one of claims 1 -33, wherein the plume is characterized by having an angle of from 60° to 79° when measured at 3 cm above the device.

35. The method of any one of claims 1 -34, wherein the plume is characterized by having a width of from 34 mm to 51 mm when measured at 3 cm above the device.

36. The method of any one of claims 1-35, wherein the total volume delivered per actuation is between 80 pl and 120 pl.

37. The method of claim 36, wherein the total volume delivered per actuation is about 100 pl.

38. The method of any one of claims 1-37, wherein the pharmaceutically acceptable salt of bumetanide is potassium bumetanide.PATENTATTORNEY DOCKET NO.: 51378-005WO239. The method of claim 38, wherein the pharmaceutical composition has a concentration of potassium bumetanide of from 1 mg / mLto 15 mg / mL.

40. The method of claim 39, wherein the pharmaceutical composition has a concentration of potassium bumetanide of from 2 mg / mL to 10 mg / mL.

41. The method of claim 40, wherein the pharmaceutical composition has a concentration of potassium bumetanide of about 5.54 mg / mL.

42. The method of any one of claims 1 -41, wherein pharmaceutical composition has a pH of between about 5 and about 9.

43. The method of claim 42, wherein the pharmaceutical composition has a pH of between about 6 and about 8.5.

44. The method of claim 43, wherein the pharmaceutical composition has a pH of between about 6 and about 7.8.

45. The method of any one of claims 1-44, wherein the one or more pharmaceutically acceptable excipients comprises a buffering agent, a preservative, a viscosity enhancer, or a tonicity agent.

46. The method of claim 45, wherein the pharmaceutical composition comprises a tonicity agent.

47. The method of claim 45 or 46, wherein the tonicity agent has a concentration in the pharmaceutical composition of between 1 mg / mL and 100 mg / mL.

48. The method of claim 47, wherein the tonicity agent has a concentration in the pharmaceutical composition of about 40 mg / mL.

49. The method of any one of claims 46-48, wherein the tonicity agent comprises mannitol.

50. The method of any one of claims 45-49, wherein pharmaceutical composition comprises a preservative.

51. The method of claim 50, wherein the preservative comprises benzyl alcohol.

52. The method of claim 50 or 51, wherein the preservative has a concentration in the pharmaceutical composition of between 1 mg / mL and 10 mg / mL.

53. The method of claim 52, wherein the preservative has a concentration in the pharmaceutical composition of about 5 mg / mL.PATENTATTORNEY DOCKET NO.: 51378-005WO254. The method of any one of claims 45-53, wherein the pharmaceutical composition comprises a viscosity enhancer.

55. The method of claim 54, wherein the viscosity enhancer comprises sodium carboxymethyl cellulose.

56. The method of claim 54 or 55, wherein the viscosity enhancer has a final concentration in the pharmaceutical composition of between 0.1 mg / mL and 2 mg / mL.

57. The method of claim 56, wherein the viscosity enhancer has a final concentration in the pharmaceutical composition is about 1 mg / mL.

58. The method of any one of claims 1 -57, wherein the pharmaceutical composition has a viscosity of 1.3 to 1.6 cPs.

59. The method of any one of claims 1 -57, wherein the pharmaceutical composition has a viscosity of 1.3 to 1.6 mm2 / g.

60. The method of any one of claims 1 -57, wherein the pharmaceutical composition has a viscosity of from 1.2 mm2 / s to 2.0 mm2 / s.

61. The method of claim 1, wherein the pharmaceutical composition comprises bumetanide in an amount of 5 mg / mL, a viscosity enhancer in an amount of 1 mg / mL, a preservative in an amount of 5 mg / mL, and a tonicity agent in an amount of 40 mg / mL.

62. The method of claim 1, wherein the pharmaceutical composition comprises 5.54 mg / mL potassium bumetanide, 1 mg / mL sodium carboxymethyl cellulose, 5 mg / mL benzyl alcohol, and 40 mg / mL mannitol.

63. The method of any one of claims 1-62, wherein the nasal delivery device comprises a body, a reservoir containing the pharmaceutical composition, a nasal dispensing head comprising a dispensing orifice, and dispensing means for dispensing at least a portion of the pharmaceutical composition through the dispensing orifice upon actuation.

64. The method of claim 63, wherein the device further comprises a linear actuating system, wherein the linear actuating system is integral with the nasal dispensing member, wherein the linear actuating system comprises at least one actuating element cooperating with the reservoir.

65. The method of claim 63 or 64, wherein the linear actuating system is a manual linear actuating system.PATENTATTORNEY DOCKET NO.: 51378-005WO266. The method of claim 64 or claim 65, wherein the actuating element is movable between a rest position, wherein the dispensing member is not actuated and an actuation arrangement, wherein the dispensing member is actuated.

67. The method of any one of claims 64-66, wherein the device further comprises a surface guide fixed relative the nasal dispensing head and substantially parallel to the axis of movement of the moveable member in the body upon actuation of the nasal dispensing member.

68. The method of any one of claims 64-66, wherein the device is non-priming spray device.

69. The method of any one of claims 1-68, wherein the subject is suffering from edema refractory to oral diuretics.

70. The method of any one of claims 1 -69, wherein the subject has congestive heart failure.

71. The method of any one of claims 1 -70, wherein the subject is suffering from edema in the lung.

72. The method of any one of claims 1-70, wherein the subject is suffering from edema in the gastrointestinal tract.

73. The method of any one of claims 1-72, wherein the pharmaceutical composition is administered intranasally to the subject in an outpatient setting or the pharmaceutical composition is self-administered.

74. The method of any one of claims 1 -73, wherein the subject has failed to achieve diuresis with oral diuretic therapy prior to the administering.

75. The method of any one of claims 1 -74, wherein the subject is experiencing swelling of the legs, shortness of breath, difficulty breathing, or chest pain unresolved with oral diuretic therapy prior to the administering.

76. The method of any one of claims 1-75, wherein the subject is experiencing reduced intestinal motility prior to the administering.

77. A pharmaceutical composition comprising an aqueous solution having a pH between 6 and 8, comprising potassium bumetanide in an amount of from 5.26 mg / mL to 5.82 mg / mL, sodium carboxymethyl cellulose in an amount of from 0.95 mg / mL to 1.05 mg / mL, benzyl alcohol in an amount of from 4.75 mg / mL to 5.25 mg / mL, and mannitol in an amount of from 38 mg / mL to 42 mg / mL.

78. The pharmaceutical composition of claim 77, consisting of potassium bumetanide in the amount of 5.54 mg / mL, sodium carboxymethyl cellulose in the amount of 1 mg / mL, benzyl alcohol in the amount of 5 mg / mL, and mannitol in the amount of 40 mg / mL.

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