Methods of preparing pre-mixed, ready-to-use pharmaceutical compositions
Inventors
Duncan, Michelle Renee • Gupta, Supriya • Haas, David Hartley • Stephens, Norma V. • Zamiri, Camellia
Assignees
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Publication Number
US-7659290-B2
Publication Date
2010-02-09
Expiration Date
Abstract
Provided herein are ready-to-use premixed pharmaceutical compositions of nicardipine or a pharmaceutically acceptable salt and methods for use in treating cardiovascular and cerebrovascular conditions.
Core Innovation
The invention relates to ready-to-use pre-mixed aqueous solutions for intravenous administration of nicardipine and/or pharmaceutically acceptable salts thereof. The solutions comprise a tonicity agent, a buffer, and an aqueous active ingredient concentration diluted to a final active ingredient concentration from about 0.1 to 0.4 mg/mL, with the composition pH adjusted to within about 3.6 to 4.7.
The invention further requires that the aqueous solution, when stored in the container for at least one year at room temperature, exhibits less than a 10% decrease in the concentration of nicardipine hydrochloride and a total impurity formation of less than about 3%. In packaged form, the pre-mixed aqueous solutions are configured so that the aqueous solution contained in the pharmaceutically acceptable container does not come into contact with polar polymers.
The disclosure also describes solution components that support stability, including tonicity agent selection and citric acid, with pH adjustment options and optional cosolvent presence. Comparative stability is described involving complexing agents such as cyclodextrin, including CAPTISOL, sulfobutylether-β-cyclodextrin/SBECD, 2-hydroxypropyl-β-cyclodextrin/2HPBCD, and HPCD, and reports that pH and drug concentration drive stability and impurity formation, while bag polymer compatibility affects adsorption and potency loss.
Claims Coverage
The document includes three independent claims. Across these claims, the inventive coverage centers on forming and packaging a pre-mixed nicardipine intravenous aqueous composition with controlled pH, defined concentration ranges, tonicity and buffer components including citric acid in packaging claims, stability requirements after at least one year at room temperature, and a container compatibility constraint preventing contact with polar polymers.
Aqueous composition pH within 3.6 to 4.7
The method provides an aqueous solution for intravenous administration and adjusts the pH of the composition to achieve a pH within the range of from about 3.6 to 4.7.
Tonicity agent and buffer with nicardipine active ingredient
The method provides a solution comprising a tonicity agent, a buffer, and at least one active ingredient selected from nicardipine and/or pharmaceutically acceptable salts thereof.
Dilution to final nicardipine hydrochloride concentration 0.1 to 0.4 mg/mL
The method further dilutes the composition to a final active ingredient concentration from about 0.1 to 0.4 mg/mL.
Packaging pre-mixed composition in pharmaceutically acceptable containers
The method fills pharmaceutically acceptable containers with the pre-mixed composition.
Stability in container: less than 10% nicardipine loss and total impurities less than about 3%
The aqueous solution when stored in the container for at least one year at room temperature exhibits less than a 10% decrease in the concentration of nicardipine hydrochloride and total impurity formation of less than about 3%.
Pre-mixed aqueous solution with defined tonicity, pH, and citric acid packaging without contact with polar polymers
The method packages in a pharmaceutically acceptable container a pre-mixed aqueous solution with a pH from about 3.6 to about 4.7 comprising nicardipine hydrochloride, a tonicity agent selected from dextrose or sodium chloride, and citric acid such that the aqueous solution does not come into contact with polar polymers, and the packaged solution meets the stability criteria after at least one year at room temperature.
Specific packaging concentrations for nicardipine, tonicity, and citric acid
The method packages in a pharmaceutically acceptable container a pre-mixed aqueous solution with a pH from about 3.6 to about 4.7 comprising nicardipine hydrochloride, a tonicity agent selected from dextrose or sodium chloride, and citric acid, such that the aqueous solution does not come into contact with polar polymers and exhibits less than a 10% decrease in nicardipine hydrochloride concentration and total impurity formation of less than about 3% after at least one year at room temperature.
Across the independent claims, the inventive concept is the combination of controlled pH, defined nicardipine hydrochloride concentration, defined tonicity and buffer composition including citric acid in packaging embodiments, packaging in pharmaceutically acceptable containers that prevent contact with polar polymers, and stability for at least one year at room temperature with limited nicardipine concentration decrease and limited total impurity formation.
Stated Advantages
When stored in the container for at least one year at room temperature, exhibits less than a 10% decrease in the concentration of nicardipine hydrochloride.
When stored in the container for at least one year at room temperature, exhibits total impurity formation of less than about 3%.
The packaged aqueous solution is configured such that it does not come into contact with polar polymers.
Documented Applications
Intravenous administration of nicardipine and/or pharmaceutically acceptable salts thereof using ready-to-use pre-mixed aqueous compositions in pharmaceutically acceptable containers.
Use in cardiovascular and cerebrovascular conditions associated with hypertension.
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