Levosimendan Subcutaneous Composition With Cyclodextrin pH Control
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Solution Overview
Problem
Existing formulations of levosimendan are unsuitable for subcutaneous administration due to low pH and painful excipients, and IV administration is invasive and associated with acute hypotensive events, limiting its use for chronic conditions.
Innovation Solution
A pharmaceutical composition comprising levosimendan with solubilizing and stabilizing agents like cyclodextrin derivatives and non-citrate buffers, formulated for subcutaneous delivery with a pH of 5 to 9, reducing pain and irritation at the injection site.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If existing IV formulations of levosimendan are used for subcutaneous administration, then the formulation can be delivered through a less invasive route, but the low pH and painful excipients (povidone, anhydrous citric acid, anhydrous ethanol) cause increased pain and irritation at the injection site
Solution Approach 1:
The patent changes the pH parameter from acidic (existing IV formulations) to neutral or slightly alkaline (pH 6.0-8.0), and modifies the excipient composition by replacing painful components with less irritating alternatives. This resolves the contradiction by maintaining subcutaneous deliverability while eliminating injection site pain and irritation.
Solution Approach 2:
The patent uses a disposable subcutaneous injection device that eliminates the need for chronic indwelling IV lines. This resolves the contradiction by providing the convenience of less invasive administration while avoiding the pain and complications associated with long-term IV catheters.
2Duration of action of moving object
If existing IV formulations of levosimendan are used for repeated dosing, then the long-acting metabolite OR-1896 provides sustained therapeutic effect, but chronic indwelling IV lines create significant safety issues and patient burden
Solution Approach 1:
The patent employs disposable subcutaneous injection devices that eliminate the need for chronic indwelling IV lines. This resolves the contradiction by maintaining the ability to deliver repeated doses for sustained therapeutic effect while removing the safety risks and patient burden associated with long-term IV access.
3Productivity
If levosimendan is formulated with high concentration to reduce injection volume, then the treatment efficiency is improved, but the low intrinsic water solubility of levosimendan makes it difficult to formulate in water-based parenteral formulations at physiologically acceptable pH
Solution Approach 1:
The patent introduces solubilizing agents as intermediaries that enable high concentrations of levosimendan to be formulated in water-based solutions at physiologically acceptable pH. This resolves the contradiction by maintaining treatment efficiency through concentrated formulations while achieving formulation stability and solubility through the mediating作用 of solubilizing agents.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Subcutaneous administration provides better tolerance, reduces side effects, and maintains therapeutic efficacy through delayed levosimendan absorption, achieving similar OR-1896 plasma levels as IV administration without peak levosimendan concentrations.
Implementation Method 1
the one or more solubilizing and/or stabilizing agents may comprise a cyclodextrin or a cyclodextrin derivative
Data Source
AI summary
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.