Pharmaceutical compositions for subcutaneous administration of levosimendan
Inventors
Randall, Doug • Hay, Douglas • Hecox, Nancy J. M.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11213524-B2
Publication Date
2022-01-04
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 subcutaneous pharmaceutical compositions and methods for treating a subject in need thereof using levosimendan. The pharmaceutical composition comprises an effective amount of levosimendan, a cyclodextrin derivative, and one or more additional pharmaceutically acceptable additives, and is characterized by a pH of about 5 to about 9.
The cyclodextrin derivative is an alpha-cyclodextrin derivative, a beta-cyclodextrin derivative, or a gamma-cyclodextrin derivative, including ether-spacer derivatives with an ether-spacer group. Captisol® is described as sulfobutylether beta-cyclodextrin within the cyclodextrin derivative category, and additional pharmaceutically acceptable additives include non-citrate buffering agents, including phosphate buffer as an example.
The described use includes treatment for health conditions where subcutaneous administration is employed, including chronic or repeated dosing and situations where patients are unable or unwilling for intravenous or oral delivery. Compared with intravenous administration, subcutaneous administration reduces levosimendan peak plasma and delays absorption while maintaining comparable exposure to the levosimendan metabolite OR-1896.
Claims Coverage
The independent claim set centers on a single independent method claim for treating a subject by subcutaneous administration of a levosimendan/cyclodextrin-derivative formulation with a defined pH range. The main inventive features are governed by the formulation components, pH limitation, and treatment scope.
Subcutaneous administration of levosimendan at about pH 5 to about pH 9
A method of treating a subject in need thereof comprising subcutaneously administering to the subject a pharmaceutical composition comprising an effective amount of levosimendan and wherein the composition comprises a pH of about 5 to about 9.
Cyclodextrin derivative formulation component
The pharmaceutical composition comprises a cyclodextrin derivative in addition to the effective amount of levosimendan and one or more additional pharmaceutically acceptable additives.
Cyclodextrin derivative includes a beta-cyclodextrin derivative
The cyclodextrin derivative used in the method is a beta-cyclodextrin derivative.
Non-citrate buffering agent additive
The pharmaceutically acceptable additives include one or more non-citrate buffering agents.
Levosimendan concentration range
Levosimendan is present at an amount of about 0.1 mg/ml to about 100 mg/ml.
Treatment for enumerated health conditions
The method is for a health condition selected from the group including heart failure, pulmonary hypertension, essential hypertension, chronic kidney disease, neurodegenerative disease, stroke, and cardiomyopathy.
Improved tolerance compared with intravenous administration
The method improves tolerance to levosimendan administration compared with intravenous (IV) administration of levosimendan.
Across the provided independent claim and its dependent refinements, claim coverage is focused on subcutaneous delivery of levosimendan formulated with a cyclodextrin derivative at a composition pH of about 5 to about 9, with additional emphasis on non-citrate buffering, specific cyclodextrin subclass selection, and defined formulation ranges. The claimed treatment scope includes enumerated cardiovascular and other health conditions, and the description supports improved tolerance compared with IV administration.
Stated Advantages
Improved aqueous solubility/stability for physiologic pH.
Reduced levosimendan peak plasma (lower Cmax) and delayed absorption versus intravenous administration.
Maintains comparable OR-1896 metabolite exposure versus intravenous administration.
Improved safety/tolerability compared with intravenous administration.
Minimizes injection site pain/irritation.
Documented Applications
Treatment of a subject having a health condition, including heart failure, pulmonary hypertension, essential hypertension, chronic kidney disease, neurodegenerative disease, stroke, and cardiomyopathy, using subcutaneous administration.
Chronic or repeated dosing as supported by the described use-case for subcutaneous administration.
Use when patients are unable or unwilling for intravenous or oral delivery, as described in the provided summary.
Interested in licensing this patent?