Pharmaceutical compositions for subcutaneous administration of levosimendan
Inventors
Randall, Doug • Hay, Douglas • Hecox, Nancy J. M.
Assignees
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Publication Number
US-12616694-B2
Publication Date
2026-05-05
Expiration Date
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.
Core Innovation
The invention relates to levosimendan subcutaneous pharmaceutical compositions. The compositions include levosimendan and cyclodextrin, including cyclodextrin derivatives such as Captisol® (sulfobutylether beta-cyclodextrin), used as solubilizing and stabilizing agents. The compositions are described as aqueous and may be provided as lyophilized compositions.
The compositions use non-citrate buffers, including phosphate buffer, and define a formulation pH range. The partial content describes compositional ranges for cyclodextrin and levosimendan and indicates that pH is about 5 to 9, with claims specifying pH of about 6 to about 8. The rationale provided is that subcutaneous formulations can address issues associated with low pH and painful excipients in intravenous formulations.
The partial content describes functional outcomes linked to the cyclodextrin-containing subcutaneous formulation, including improved tolerability and reduced injection-site pain. It further describes nonclinical pharmacokinetic results indicating lower levosimendan Cmax while maintaining comparable OR-1896 metabolite exposure to intravenous dosing.
Nonclinical examples are described to support solubility and stability. The partial content states that Captisol concentration improves levosimendan solubility and that a lyophilized composition shows stability with at least about 98% remaining over up to about 6 months, including stressed storage conditions. It also describes a rat PK study reporting reduced levosimendan Cmax with similar OR-1896 profiles and no injection-site irritation.
Claims Coverage
The partial claims include one independent claim directed to treating specified heart and lung conditions by subcutaneous administration of a levosimendan pharmaceutical composition. The independent-claim coverage is grounded by inventive features focused on the treated condition set and subcutaneous levosimendan administration, with dependent claims refining formulation parameters including dosage, concentration, pH, and cyclodextrin/cyclodextrin-derivative content and type.
Subcutaneous levosimendan treatment for specified pulmonary hypertension and heart failure conditions
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) by subcutaneously administering a pharmaceutical composition comprising levosimendan.
Daily levosimendan dosing range for the subcutaneous method
Administering levosimendan at a dose of about 0.1 mg/day to about 15 mg/day.
Levosimendan concentration in the subcutaneous composition
Providing a composition in which levosimendan is present at about 0.1 mg/ml to about 100 mg/ml.
Formulation pH range for the levosimendan composition
Using a composition having a pH of about 6 to about 8.
Cyclodextrin or cyclodextrin derivative amount in the composition
Having cyclodextrin or cyclodextrin derivative present in an amount of about 1 mg/ml to about 800 mg/ml.
Ether/sulfobutyl ether cyclodextrin derivatives as solubilizing and stabilizing agents
Using a cyclodextrin derivative that includes ether functionalities such as a butyl ether group, a sulfobutyl ether group, and/or a sulfoalkyl ether group, optionally in the form of a sodium sulfonate salt, and specifically including sulfobutylether-beta-cyclodextrin.
Across the independent-claim foundation and its dependent refinements in the provided claim set, the coverage centers on subcutaneous levosimendan administration to subjects with specified pulmonary hypertension and heart failure conditions, with additional claim features specifying levosimendan dose, levosimendan concentration, composition pH, and quantitative and structural selection of cyclodextrin or cyclodextrin derivatives, including sulfobutylether-beta-cyclodextrin.
Stated Advantages
Improved tolerability of the subcutaneous levosimendan formulation.
Reduced injection-site pain.
Lower levosimendan Cmax while maintaining comparable OR-1896 metabolite exposure to intravenous.
Improved levosimendan solubility with Captisol concentration.
Stability of a lyophilized composition, with at least about 98% remaining over up to about 6 months including stressed storage.
No injection-site irritation reported in the rat PK study.
Documented Applications
Treating subjects having a health condition selected from pulmonary hypertension, essential hypertension, secondary hypertension, PH-HFpEF, PH-HFrEF, HFrEF, and HFpEF by subcutaneously administering a levosimendan pharmaceutical composition.
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