Compositions of nicardipine and sulfoalkylated β-cyclodextrin
Inventors
Gupta, Supriya • Mi, Yanli • Zamiri, Camellia
Assignees
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Publication Number
US-9549994-B2
Publication Date
2017-01-24
Expiration Date
Abstract
Compositions of an inclusion complex of nicardipine or a pharmaceutically acceptable salt thereof and a sulfoalkylated β-cyclodextrin. The compositions being formulated for parenteral bolus administration to a human subject. The compositions being useful in the treatment of cardiovascular and cerebrovascular disorders.
Core Innovation
The invention relates to a pharmaceutical composition comprising an aqueous solution containing an inclusion complex of nicardipine or a pharmaceutically acceptable salt and a sulfoalkylated β-cyclodextrin, together with a buffering agent. The composition is formulated as a premixed, low-volume injectable unit dose intended for direct parenteral bolus administration for immediate use without dilution. The solution is defined by a pH of 4.5 to 5.5.
The composition is further characterized by a defined unit dose volume of from 0.5 to 20 mL and a nicardipine concentration of 0.5 mg/mL. The sulfoalkylated β-cyclodextrin is present in an amount of 2% to 5% (w/v), and the sulfoalkylated β-cyclodextrin is specifically a sulfobutylated β-cyclodextrin having an average of 5 to 8 degrees of sulfobutylation.
The problem described is the avoidance of dilution-dependent instability and precipitation of nicardipine in ampules by enabling immediate-use bolus formulations. The document further supports that sulfoalkylated β-cyclodextrin inclusion complexation is used together with buffering and pH constraints to improve stability and reduce precipitation-related issues and potency loss/impurity formation at elevated pH.
Claims Coverage
The document provides one independent claim covering a premixed aqueous unit-dose nicardipine inclusion-complex composition for immediate parenteral bolus administration without dilution. The claim is supported by dependent claims that refine specific salt identity, buffering agent species and concentrations, cyclodextrin structure specificity, and optional co-solvent inclusion; the independent claim itself includes five main inventive constraint groups.
Premixed nicardipine inclusion-complex aqueous formulation
A pharmaceutical composition comprising an aqueous solution comprising an inclusion complex of nicardipine or a pharmaceutically acceptable salt thereof, a buffering agent and a sulfoalkylated β-cyclodextrin.
Immediate-use direct parenteral bolus without dilution
The composition is premixed and is formulated for direct parenteral bolus administration for immediate use without dilution to a human subject.
Defined pH window 4.5 to 5.5
A pH of the composition is 4.5 to 5.5.
Unit dose volume 0.5 to 20 mL and nicardipine concentration 0.5 mg/mL
The composition is in unit dose format and the unit dose contains the formulation in a volume of from 0.5 to 20 ml, wherein the nicardipine concentration is 0.5 mg/ml.
Sulfoalkylated β-cyclodextrin as sulfobutylated β-cyclodextrin (2% to 5% w/v; 5 to 8 degrees sulfobutylation)
The sulfoalkylated β-cyclodextrin in the pharmaceutical composition is from 2% to 5% (w/v) wherein the sulfoalkylated β-cyclodextrin is a sulfobutylated β-cyclodextrin having an average of 5 to 8 degrees of sulfobutylation.
Buffering-agent concentration range (0.1 mM to 100 mM)
The composition includes a buffering agent present at a concentration of 0.1 mM to 100 mM.
Nicardipine provided as nicardipine hydrochloride
The nicardipine is provided as the pharmaceutically acceptable salt nicardipine hydrochloride salt.
Buffering agent selected from acetate, citrate, succinate, phosphate
The buffering agent is made from at least one selected among acetate, citrate, succinate, and phosphate.
Cyclodextrin specified as sulfobutylether β-cyclodextrin
The sulfoalkylated β-cyclodextrin is sulfobutylether β-cyclodextrin.
Optional co-solvent at 0.1 to 25% (w/v)
The composition further includes at least one co-solvent at a concentration of 0.1 to 25% (w/v).
Overall, claim coverage centers on an aqueous premixed nicardipine or salt inclusion-complex composition using a buffering agent and a sulfoalkylated β-cyclodextrin, constrained to a pH of 4.5 to 5.5, unit-dose volumes of 0.5 to 20 mL, and a nicardipine concentration of 0.5 mg/mL, with sulfoalkylated β-cyclodextrin present at 2% to 5% (w/v) as a sulfobutylated β-cyclodextrin averaging 5 to 8 degrees of sulfobutylation, plus dependent refinements for salt identity, buffering agent species and concentration, specific sulfobutylether structure, and optional co-solvent.
Stated Advantages
Avoiding dilution-dependent instability and precipitation of nicardipine in ampules by enabling immediate-use bolus formulations.
Improving stability and reducing potency loss/impurity formation at elevated pH.
Reducing in vitro precipitation opacity in static and dynamic precipitation models.
Documented Applications
Direct parenteral bolus administration for immediate use without dilution to a human subject.
Unit dose injectable formulations for acute elevations of blood pressure and for cardiovascular disorders, including cerebrovascular disorders.
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