JP-2026076167-A - Method and composition for treating edema unresponsive to oral diuretics

Abstract

[Problem] To provide a composition for treating edema that is unresponsive to oral diuretics. [Solution] A pharmaceutical composition is provided comprising (i) an aqueous solution having a pH of about 5 to about 9, (ii) a bumetanide potassium salt in an amount of about 4 mg/mL to about 20 mg/mL, and (iii) one or more pharmaceutically acceptable excipients. [Selection Diagram] None

Inventors

• ラダクリシュナン，バラシンガム
• エスケ，ベン
• リン，ウェイ
• チェン，アンドリュー，シャン

Assignees

• レスク ファーマシューティカルズ エルエルシー

Dates

Publication Date

20260511

Application Date

20251225

Priority Date

20191204

Claims (20)

1. A pharmaceutical composition comprising: (i) an aqueous solution having a pH of approximately 5 to approximately 9; (ii) a bumetanide potassium salt in a concentration of approximately 4 mg/mL to approximately 20 mg/mL; and (iii) one or more pharmaceutically acceptable excipients.
2. (i) an aqueous solution containing approximately 5 mg/mL to approximately 10 mg/mL of bumetanide potassium salt, (ii) one or more pharmaceutically acceptable excipients, and (iii) the aqueous solution having a pH of approximately 6 to approximately 8, according to claim 1.
3. A pharmaceutical composition comprising an aqueous solution of bumetanide arginine salt and one or more pharmaceutically acceptable excipients.
4. The pharmaceutical composition according to claim 3, wherein the aqueous solution contains approximately 4 mg/mL to approximately 15.0 mg/mL of the bumetanide arginine salt, and the aqueous solution has a pH of approximately 5 to approximately 9.
5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutically acceptable excipient comprises a surfactant or a permeation enhancer.
6. The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition comprises a permeation enhancer present in the aqueous emulsion.
7. The pharmaceutical composition according to claim 6, wherein the aqueous solution does not contain any buffering agents other than the buffer formed by bumetanide free acid combined with potassium hydroxide.
8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition is formulated for intranasal administration.
9. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition is formulated for sublingual administration.
10. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition is formulated for subcutaneous administration.
11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the aqueous solution has a pH of approximately 6 to approximately 8.
12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the one or more pharmaceutically acceptable excipients comprises low-viscosity carboxymethylcellulose sodium or a pharmaceutically acceptable salt thereof.
13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the one or more pharmaceutically acceptable excipients include a buffering agent, a preservative, a viscosity improver, or an isotonic agent.
14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the pharmaceutical composition comprises an emulsion, and the one or more pharmaceutically acceptable excipients comprises a polysorbate surfactant, a triglyceride, or lecithin.
15. A method for transmucosal administration of the potassium salt of bumetanide, wherein the potassium salt of bumetanide is administered intranasally or sublingually.
16. The method according to claim 15, wherein the potassium salt of bumetanide is the pharmaceutical composition according to any one of claims 1, 2, or 5 to 14.
17. A method for treating edema in a subject requiring such treatment, comprising administering an effective amount of the pharmaceutical composition described in any one of claims 1 to 14 to the subject.
18. The method according to claim 16 or 17, wherein the administration comprises delivering a dose of 25 μl to 250 μl of the pharmaceutical composition into the nasal cavity of the target.
19. The method according to claim 16 or 17, wherein the administration comprises delivering a dose of 25 μl to 250 μl of the pharmaceutical composition sublingually to the target.
20. The method according to claim 17, wherein the administration comprises delivering a dose of 25 μl to 250 μl of the pharmaceutical composition subcutaneously to the target.

Description

This disclosure features a method and composition for treating edema unresponsive to oral diuretics. Congestive heart failure (CHF) is a common heart disease. The incidence of congestive heart failure has increased in recent years, and its diagnosis is associated with significant morbidity and mortality. In fact, congestive heart failure is an extremely fatal disease, with the vast majority of affected individuals, both male and female, estimated to die within five years. Congestive heart failure arises from the loss or impairment of normal cardiac function. This loss or impairment reduces cardiac output. This results in a decrease in both blood flow to the kidneys and blood pressure. This reduction in blood flow and blood pressure triggers the renin-angiotensin response, which exacerbates congestive heart failure. Angiotensin II stimulates the secretion of aldosterone from the adrenal cortex, resulting in increased salt and water retention in the kidneys, thus increasing blood volume. The increased blood volume and corresponding vasoconstriction lead to increased blood pressure and, consequently, fluid overload on the heart, further worsening the heart's condition. To treat CHF, physicians administer a strict low-sodium diet to patients and monitor their fluid intake. Some patients are restricted to just one liter of fluid per day. The most important medications physicians use to counteract fluid overload are a type of drug called diuretics. Diuretics affect kidney function in a way that inhibits fluid reabsorption. As a result, urine output increases, contrary to the neurohormonal signals the kidneys receive. Physicians may also treat patients with medications that improve the heart's pumping capacity, raise blood pressure, and attempt to reactivate the body's control systems to a more normal function. This is generally effective in keeping many heart failure patients alive. However, in hundreds of thousands of patients, treatment with medication and diet alone is ineffective. When patients are edematous and experiencing fluid overload, gastrointestinal absorption is impaired, and therefore the effectiveness of oral diuretics may be limited. As a result, patients are often instructed to increase their oral diuretic dosage, further burdening their kidneys. Eventually, oral diuretics become insufficient to remove excess fluid, and patients seek intravenous diuretics to avoid gastrointestinal absorption. As a result, patients are frequently hospitalized for intensive care and IV diuretic administration, and are at risk of excessive diuresis (with each event) once gastrointestinal absorption recovers. Ultimately, excessive diuresis can lead to renal failure. When available treatments are no longer sufficient to remove fluid by existing renal function, renal replacement therapies such as hemoperfusion or dialysis are increasingly used to remove fluid in acute CHF conditions. Acute heart failure may be treated in the hospital ICU with continuous renal replacement therapy (also known as an artificial kidney or dialysis machine). Therefore, patients with heart failure experiencing acute distress due to fluid overload still require treatment options that reduce the risk of hospitalization and renal failure. This invention features a composition and method for treating edema unresponsive to oral diuretics. In a first embodiment, the present invention features a pharmaceutical composition comprising (i) an aqueous solution having a pH of about 5 to about 9 (e.g., pH 5±1, 6±1, 7±1, 8±1, or 9±1), (ii) a potassium bumetanide salt in a concentration of about 4 mg/mL to about 20 mg/mL (e.g., 4±1, 5±1, 6±1, 7±1, 8±1, 9±1, 10±1, 11±1, 12±1, 13±1, 14±1, 15±1, 16±1, 17±1, 18±1, 19±1, or 20±1 mg/mL), and (iii) one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises an aqueous solution containing a bumetanide potassium salt in a concentration of about 5 mg/mL to about 10 mg/mL (e.g., 5±1, 6±1, 7±1, 8±1, 9±1, 10±1, 11±1, 11.5±1, 12±1, 13±1, or 14±1 mg/mL), one or more pharmaceutically acceptable excipients, wherein the aqueous solution has a pH of about 6 to about 8 (e.g., pH 6±1, 7±1, 8±1). In a related embodiment, the present invention features a pharmaceutical composition comprising an aqueous solution of bumetanidearginine salt and one or more pharmaceutically acceptable excipients. The aqueous solution may contain bumetanidearginine salt in a concentration of about 4 mg/mL to about 15 mg/mL (e.g., 4–12, 5–10, 5±1, 6±1, 7±1, 8±1, 9±1, 10±1, 11±1, 11.5±1, 12±1, 13±1, or 14±1 mg/mL), the aqueous solution may have a pH of about 5 to about 9 (e.g., a pH of 5±1, 6±1, 7±1, 8±1, or 9±1), and one or more pharmaceutically acceptable excipients. In any one embodiment of the above pharmaceutical composition, the pharmaceutically acceptable excipients include a surfactant or a permeation enhancer. In some embodiments, the pharmaceutical composition includes a permeation enhancer