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US-12616694-B2 - Pharmaceutical compositions for subcutaneous administration of levosimendan

US12616694B2US 12616694 B2US12616694 B2US 12616694B2US-12616694-B2

Abstract

A composition containing levosimendan, one or more solubilizing and/or stabilizing agents, and one or more additional pharmaceutically acceptable additives. The one or more solubilizing and/or stabilizing agents may be a cyclodextrin or a cyclodextrin derivative. The cyclodextrin derivative may be a derivative of an alpha-cyclodextrin, or beta-cyclodextrin, or a gamma-cyclodextrin. The cyclodextrin derivative may contain a butyl ether spacer group, an alkyl ether space group, or both. The one or more additional pharmaceutically acceptable additives may be a non-citrate buffer. The composition may be used in a method of treating a health condition, such as heart failure, pulmonary hypertension, chronic kidney disease, amyotrophic lateral sclerosis, stroke, in advance of a planned cardiac surgery, or other health conditions for which a minimally invasive or repeated administration of levosimendan may be beneficial. The composition may be administered subcutaneously.

Inventors

  • Doug Randall
  • Douglas Hay
  • Nancy J. M. Hecox

Assignees

  • TENAX THERAPEUTICS, INC.

Dates

Publication Date
20260505
Application Date
20211208

Claims (20)

  1. 1 . A method of treating a subject having a health condition selected from the group consisting of pulmonary hypertension, essential hypertension, secondary hypertension, pulmonary hypertension with heart failure with preserved ejection fraction (PH-HFpEF), pulmonary hypertension with heart failure with reduced ejection fraction (PH-HFrEF), heart failure with reduced ejection fraction (HFrEF), and heart failure with preserved ejection fraction (HFpEF), the method comprising subcutaneously administering a pharmaceutical composition comprising levosimendan.
  2. 2 . The method of claim 1 , wherein the levosimendan is administered in an amount of about 0.1 mg/day to about 15 mg/day.
  3. 3 . The method of claim 1 , wherein the health condition is pulmonary hypertension with heart: failure with preserved ejection fraction (PH-HFpEF).
  4. 4 . The method of claim 1 , wherein the health condition is pulmonary hypertension with heart failure with reduced ejection fraction (PH-HFrEF).
  5. 5 . The method of claim 1 , wherein the health condition is heart failure with reduced ejection fraction (HFrEF).
  6. 6 . The method of claim 1 , wherein the health condition is heart failure with preserved ejection fraction (HFpEF).
  7. 7 . The method of claim 1 , wherein the levosimendan is administered in an amount of about 0.1 mg/week to about 100 mg/week.
  8. 8 . The method of claim 1 , wherein the pharmaceutical composition comprising levosimendan is administered chronically or repeatedly.
  9. 9 . The method of claim 1 , wherein the composition also comprises one or more solubilizing and/or stabilizing agents, and one or more additional pharmaceutically acceptable additives.
  10. 10 . The method of claim 9 , wherein the one or more solubilizing and/or stabilizing agents comprise a cyclodextrin or cyclodextrin derivative.
  11. 11 . The method of claim 9 , wherein the pharmaceutically acceptable additive is a solubilizer, an emulsifier, a sweetener, a flavoring agent, a suspending agent, a thickening agent, a color, a viscosity regulator, a stabilizer, and/or an osmo-regulator.
  12. 12 . The method of claim 10 , wherein the cyclodextrin or cyclodextrin derivative is in an amount of about 1 mg/ml to about 800 mg/ml.
  13. 13 . The method of claim 10 , wherein the cyclodextrin is an alpha-cyclodextrin, beta-cyclodextrin, or gamma-cyclodextrin, or wherein the cyclodextrin derivative is a derivative of alpha-cyclodextrin, beta-cyclodextrin, or gamma-cyclodextrin.
  14. 14 . The method of claim 10 , wherein the cyclodextrin derivative comprises an ether group, a butyl ether group, a sulfobutyl ether group, a sulfoalkyl ether group, and/or a sodium sulfonate salt, or wherein the cyclodextrin derivative is a sulfobutylether-beta-cyclodextrin.
  15. 15 . The method of claim 10 , wherein the one or more additional pharmaceutically acceptable additives comprise one or more buffering agents, one or more pH-modifying agents, one or more tonicity-adjusting reagents, one or more preservatives, one or more antioxidants, one or more carriers, or a combination thereof.
  16. 16 . The method of claim 1 , wherein the composition comprises a pH of about 6 to about 8.
  17. 17 . The method of claim 1 , wherein the levosimendan is present in the composition in an amount of about 0.1 mg/ml to about 100 mg/ml.
  18. 18 . The method of claim 1 , wherein the composition comprises a non-citrate buffering agent.
  19. 19 . The method of claim 1 , wherein the composition is aqueous.
  20. 20 . The method of claim 1 , wherein the composition is lyophilized, wherein the composition is free or substantially free of alcohol; and/or wherein the composition is preservative-free.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisional of U.S. application Ser. No. 16/544,098, filed Aug. 19, 2019, now allowed, claiming the benefit of U.S. Provisional Application No. 62/720,260, filed on Aug. 21, 2018, the contents of each of which are hereby incorporated by reference into the application. FIELD OF THE INVENTION The present invention is in the field of compositions and treatments for health conditions that require repeated or chronic dosing of levosimendan, and/or where alternative delivery routes for levosimendan such as intravenous (IV) and oral administration are not practical or preferred. In particular, the present invention generally relates to compositions comprising levosimendan for subcutaneous administration to subjects having such health conditions. BACKGROUND OF THE INVENTION Levosimendan is an inotropic agent that has been used as a treatment for heart failure and studied as a preventative measure of low cardiac output syndrome after cardiac surgery. Levosimendan increases cardiac contractility mediated by calcium sensitization of troponin C, as well as induces vasodilation based on the opening of K+ channels in the vasculature and cardioprotection due to the opening of mitochondrial K+ channels in the cardiomyocytes. In contrast to beta-adrenergic-receptor-stimulating agents and phosphodiesterase inhibitors, which are both known treatments for heart failure, levosimendan increases the sensitivity of the heart to calcium, which can elevate the strength of contraction without a rise in intracellular calcium. The potential benefits of repeated doses of levosimendan, which is currently formulated for IV administration, have been investigated for the treatment of chronic heart failure patients. Studies have shown that it is feasible to treat chronic heart failure patients with repeated IV infusions of levosimendan due in large part to a long-acting metabolite of levosimendan, OR-1896, that has a half-life in the range of 70 to 80 hours. While the results of these studies have been generally positive, the commercial feasibility of such use is limited by the significant safety issues created by having chronic indwelling IV lines and the need for repeated and cumbersome IV infusions. In addition, IV administration of levosimendan is absorbed rapidly, which in some patients can lead to acute hypotensive events. Yet, no other route of administration for levosimendan has been approved. And while other routes of delivery such as subcutaneous administration may address some of these issues associated with IV administration, no known formulations for subcutaneous delivery have been described or investigated. Existing IV formulations of levosimendan are not suitable for other delivery routes such as subcutaneous administration, due to the formulations' low pH. Also, the existing IV formulations rely on excipients such as povidone, anhydrous citric acid, and anhydrous ethanol, which are inherently painful if administered via subcutaneous injection. Further, due to levosimendan's low intrinsic water solubility, it is difficult to formulate levosimendan in water-based parenteral formulations that are sufficiently concentrated and stable in the presence of a physiologically acceptable pH. Thus, there is a need in the art to develop a formulation of levosimendan that can be delivered through a less invasive, more convenient, and better tolerated route of administration than IV and that is more ideal for treating health conditions that require repeated dosing, such as heart failure, pulmonary hypertension, chronic kidney disease, amyotrophic lateral sclerosis (ALS), and stroke. In addition, some patients may have difficulty swallowing (e.g., patients with ALS, stroke, etc.), and in instances where oral administration is not possible or practical, a different route of administration may be preferred. SUMMARY OF THE INVENTION One aspect of the present invention relates to a pharmaceutical composition comprising levosimendan for treatment in subjects in need thereof. The composition may also comprise one or more solubilizing and/or stabilizing agents, and one or more additional pharmaceutically acceptable additives. In embodiments of the invention, the one or more solubilizing and/or stabilizing agents may comprise a cyclodextrin or a cyclodextrin derivative. In some embodiments, the composition may comprise a cyclodextrin derivative, such as an alpha-cyclodextrin derivative, a beta-cyclodextrin derivative, or a gamma-cyclodextrin derivative. In certain embodiments, the cyclodextrin derivative may comprise a beta-cyclodextrin derivative. In particular embodiments, the cyclodextrin derivative comprises a butyl ether spacer group, an alkyl ether space group, or a combination thereof. In some embodiments, the cyclodextrin or the cyclodextrin derivative may be present in the composition in an amount of about 1 mg/ml to about 800 mg/ml. In certain embodiments, the cyclodextrin or the