Methods of treatment with 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-8455524-B2
Publication Date
2013-06-04
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 provides a pre-mixed aqueous solution containing nicardipine or a pharmaceutically acceptable salt thereof, formulated with a tonicity agent and a buffer, for parenteral administration. The aqueous solution requires no dilution before administration and has an acidic pH from about 3.6 to about 4.7. The solution is contained in a pharmaceutically acceptable container so that it is in contact with non-polar polymers.
The core technical concept is maintaining nicardipine concentration and controlling impurity formation during storage in the container in contact with non-polar polymers. When stored for at least three months at room temperature, the aqueous solution exhibits less than a 10% decrease in the concentration of nicardipine or the pharmaceutically acceptable salt and a total impurity formation of less than about 3%.
The described approach addresses stability and plastic container effects by using specified container contact conditions and formulation parameters to reduce concentration loss and total impurity formation. Dependent formulations refine the non-polar polymers and extend storage performance to at least one year while maintaining the same concentration decrease and impurity limits.
Claims Coverage
The independent claims define four related methods: treating acute elevations of blood pressure and inducing hypotension in a human subject, using a pre-mixed aqueous nicardipine solution that requires no dilution, has a pH of about 3.6 to about 4.7, and maintains specified potency and impurity limits after room-temperature storage in contact with non-polar polymers. Across the independent claims, the inventive concept is expressed through a small set of repeated requirements: composition, administration form, pH window, and container-contact stability, with four inventive features in total.
Treating acute elevations of blood pressure with a pre-mixed, non-dilution nicardipine aqueous solution
Parenterally administering a pre-mixed aqueous solution comprising from about 0.1 to 0.4 mg/mL nicardipine or a pharmaceutically acceptable salt thereof; a tonicity agent; and a buffer, wherein the aqueous solution requires no dilution before administration and has a pH from about 3.6 to about 4.7, with the aqueous solution stored in a container in contact with non-polar polymers, exhibiting less than a 10% decrease in nicardipine concentration and total impurity formation of less than about 3% after at least three months at room temperature.
Inducing hypotension with a pre-mixed, non-dilution nicardipine aqueous solution
Parenterally administering a pre-mixed aqueous solution comprising from about 0.1 to 0.4 mg/mL nicardipine or a pharmaceutically acceptable salt thereof; a tonicity agent; and a buffer, wherein the aqueous solution requires no dilution before administration and has a pH from about 3.6 to about 4.7, with the aqueous solution stored in a container in contact with non-polar polymers, exhibiting less than a 10% decrease in nicardipine concentration and total impurity formation of less than about 3% after at least three months at room temperature.
Treating acute elevations of blood pressure using nicardipine hydrochloride with bounded dextrose or sodium chloride tonicity
Parenterally administering to a subject a pre-mixed aqueous solution with a pH from about 3.6 to about 4.7 comprising from about 0.1 to 0.4 mg/mL nicardipine hydrochloride; a tonicity agent selected from (i) about 4.5% to about 5% dextrose or (ii) about 0.8% to about 0.9% sodium chloride; and a buffer, wherein the aqueous solution is contained in a pharmaceutically acceptable container in contact with non-polar polymers and stored for at least three months at room temperature with less than a 10% decrease in nicardipine concentration and total impurity formation of less than about 3%.
Inducing hypotension using nicardipine hydrochloride with bounded dextrose or sodium chloride tonicity
Parenterally administering to a subject a pre-mixed aqueous solution with a pH from about 3.6 to about 4.7 comprising from about 0.1 to 0.4 mg/mL nicardipine hydrochloride; a tonicity agent selected from (i) about 4.5% to about 5% dextrose or (ii) about 0.8% to about 0.9% sodium chloride; and a buffer, wherein the aqueous solution is contained in a pharmaceutically acceptable container in contact with non-polar polymers and stored for at least three months at room temperature with less than a 10% decrease in nicardipine concentration and total impurity formation of less than about 3%.
Across the independent claims, the claimed coverage consistently centers on pre-mixed, non-dilution nicardipine aqueous solutions with an acidic pH window, formulated with a tonicity agent and buffer, and stored in containers contacting non-polar polymers such that, after room-temperature storage, the solution maintains potency and impurity formation limits. The scope distinguishes treatment purpose and, in two claims, narrows the composition to nicardipine hydrochloride with bounded dextrose or sodium chloride tonicity-agent ranges.
Stated Advantages
Less than a 10% decrease in the concentration of nicardipine or a pharmaceutically acceptable salt after at least three months at room temperature.
Total impurity formation of less than about 3% after at least three months at room temperature.
Avoids dilution before administration by providing a pre-mixed aqueous solution.
Stability can be extended such that, after storage for at least one year at room temperature, the aqueous solution exhibits less than a 10% decrease in nicardipine concentration and total impurity formation of less than about 3%.
Documented Applications
Treating acute elevations of blood pressure in a human subject in need thereof by parenterally administering the specified pre-mixed nicardipine aqueous solution.
Inducing hypotension in a human subject in need thereof by parenterally administering the specified pre-mixed nicardipine aqueous solution.
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