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-9370586-B2
Publication Date
2016-06-21
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 a method for making a pharmaceutical composition for intravenous administration by preparing a pre-mixed aqueous solution and filling a pharmaceutically acceptable container with the aqueous solution for drug contact with non-polar polymers. The pre-mixed aqueous solution has a pH from about 3.6 to about 4.4 and comprises a tonicity agent, a buffer, and from about 0.1 mg/mL to about 0.4 mg/mL nicardipine hydrochloride. The approach is directed to maintaining nicardipine hydrochloride stability during storage.
A central aspect is selecting formulation conditions and container compatibility such that, when stored in the container for at least three months at room temperature, the aqueous solution exhibits less than a 10% decrease in the concentration of nicardipine hydrochloride and a total impurity formation of less than about 3%. The claimed compositions include a pre-mixed aqueous solution packaged in a pharmaceutically acceptable container such that the aqueous solution is in contact with non-polar polymers.
The disclosure further emphasizes specific component selections and container-material interactions tied to stability outcomes. The description states that stability is linked to pH, drug concentration, and container material compatibility, including incompatibility with PVC and EVA as non-polar polymer contact is used instead. The formulations may include tonicity agents such as dextrose or sodium chloride and may include cosolvents/complexing agents such as sorbitol and cyclodextrins including CAPTISOL®, SBECD, and HPBCD, with stability reported over extended periods under room temperature storage.
Claims Coverage
The document includes three independent claims, each centered on preparing and packaging a pre-mixed aqueous intravenous nicardipine hydrochloride composition at a defined pH, tonicity agent, and drug concentration, with stability maintained during room-temperature storage under defined concentration-decrease and total impurity thresholds while the solution is in contact with non-polar polymers.
Pre-mixed acidic aqueous nicardipine hydrochloride with tonicity agent and buffer
Preparing a pre-mixed aqueous solution with a pH from about 3.6 to about 4.4 comprising a tonicity agent, a buffer, and from about 0.1 mg/mL to about 0.4 mg/mL nicardipine hydrochloride.
Container contact with non-polar polymers for storage stability
Filling a pharmaceutically acceptable container with the aqueous solution such that the aqueous solution is in contact with non-polar polymers, wherein after at least three months at room temperature the aqueous solution exhibits less than a 10% decrease in the concentration of nicardipine or pharmaceutically acceptable salt thereof and a total impurity formation of less than about 3%.
Packaging pre-mixed aqueous solution with defined pH, drug, and selected tonicity agents
Packaging in a pharmaceutically acceptable container a pre-mixed aqueous solution with a pH from about 3.6 to about 4.4 comprising from about 0.1 mg/mL to about 0.4 mg/mL nicardipine hydrochloride, a tonicity agent selected from about 4.5% to about 5% dextrose or about 0.8% to about 0.9% sodium chloride, and a buffer.
Room-temperature stability while in contact with non-polar polymers
The aqueous solution contained in the pharmaceutically acceptable container is in contact with non-polar polymers, and when stored in the container for at least three months at room temperature exhibits less than a 10% decrease in the concentration of the nicardipine hydrochloride and a total impurity formation of less than about 3%.
Defined drug and tonicity ranges with non-polar polymer contact stability
Packaging in a pharmaceutically acceptable container a pre-mixed aqueous solution with a pH from about 3.6 to about 4.4 comprising from about 0.1 mg/mL to about 0.2 mg/mL nicardipine hydrochloride, a tonicity agent selected from about 46 mg/mL to about 50 mg/mL dextrose or about 8.3 mg/mL to about 9 mg/mL sodium chloride, and a buffer, such that the aqueous solution is in contact with non-polar polymers.
Three-month room-temperature stability limits
The aqueous solution when stored in the container for at least three months at room temperature exhibits less than a 10% decrease in the concentration of the nicardipine hydrochloride and a total impurity formation of less than about 3%.
Across the independent claims, the inventive subject matter is directed to pre-mixed acidic aqueous nicardipine hydrochloride solutions at a defined pH with defined tonicity agent and buffer, packaged in a pharmaceutically acceptable container configured for contact with non-polar polymers, and achieving defined stability at room temperature for at least three months with less than a 10% decrease in nicardipine concentration and less than about 3% total impurity formation.
Stated Advantages
Less than a 10% decrease in the concentration of nicardipine hydrochloride after at least three months at room temperature.
Total impurity formation of less than about 3% after at least three months at room temperature.
Improved container compatibility by maintaining stability with the aqueous solution in contact with non-polar polymers.
Documented Applications
Preparation and packaging of a pharmaceutical composition for intravenous administration of nicardipine hydrochloride.
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