PRE-MIXED, READY-TO-USE IV BOLUS COMPOSITIONS AND METHODS OF USE
Provided herein are ready-to-use premixed bolus injection pharmaceutical compositions of nicardipine or a pharmaceutically acceptable salt and methods for use in treating cardiovascular and cerebrovascular conditions.
1 . A pharmaceutical composition comprising a pharmaceutically acceptable salt of nicardipine in an aqueous carrier, one or more buffering agent(s) and having a pH within the range from about 3.5 to about 5.5, wherein the concentration of the nicardipine in the composition is from 0.25 mg/ml to 5.0 mg/ml, inclusive, the concentration of each buffering agent in the composition is from 0.1 mM to 100 mM wherein the composition is formulated for direct parenteral bolus administration to a human.
2 . The pharmaceutical composition of claim 1 , wherein the nicardipine concentration in the formulation is 0.25 to 1.0 mg/ml, inclusive.
3 . The pharmaceutical composition of claim 1 , wherein the nicardipine concentration is 0.5 mg/ml.
4 . The pharmaceutical composition of claim 1 , wherein the buffering agent is one or more agents selected from the group consisting of salts or acids of acetate, citrate, succinate, and phosphate buffering agents.
5 . The pharmaceutical composition of claim 4 , wherein the buffering agents comprise acetate and citrate buffering agents, acetate and phosphate buffering agents, citrate and phosphate buffering agents, succinate and phosphate buffering agents; acetate and succinate buffering agents; and citrate and succinate buffering agents.
6 . The pharmaceutical composition of claim 4 , wherein buffering agents comprise acetate, phosphate and citrate buffering agents; succinate, citrate and phosphate buffering agents; succinate, acetate, and phosphate buffering agents, and citrate, acetate and succinate buffering agents.
7 . The pharmaceutical composition of claim 1 , further comprising a tonicity adjusting agent.
8 . The pharmaceutical composition of claim 7 , wherein the tonicity adjusting agent comprises one or more of dextrose and sodium chloride.
9 . The pharmaceutical composition of claim 1 , wherein the composition further comprises at least one co-solvent in a concentration of 0.1 to 25% (w/v).
10 . The pharmaceutical composition of claim 9 , wherein concentration of the co-solvent is 0.1 to 10% (w/v).
11 . The pharmaceutical composition of claim 10 , wherein the at least one co-solvent comprises any one or more of ethanol, sorbitol, polyethylene glycol, or propylene glycol.
12 . The pharmaceutical composition of claim 1 , wherein the pH is above a pH of 3.5 and less than a pH of 5.0.
13 . A method of treating a subject for elevated blood pressure, comprising parenterally administering a bolus composition of claim 1 to a human subject.
14 . The method of claim 13 , wherein the subject is volume-restricted.
15 . The method of claim 14 , wherein the subject has edema, renal failure, ascites, cerebral edema, or other fluid overload, congestive heart failure, liver failure, or a CNS injury.
16 . The method of claim 13 , wherein the composition is administered over a time period of less than 30 seconds.
17 . The method of claim 13 , wherein the elevated blood pressure is reduced.
18 . The method of claim 13 , wherein the elevated blood pressure is controlled or prevented.
19 . An inclusion complex of nicardipine or a pharmaceutically acceptable salt thereof and a sulfoalkylated β-cyclodextrin.
20 . The inclusion complex of claim 19 , wherein the sulfoalkylated β-cyclodextrin is sulfobutylated β-cyclodextrin.
21 . The inclusion complex of claim 20 , wherein the sulfobutylated β-cyclodextrin is sulfobutylether β-cyclodextrin.
22 . The inclusion complex of claim 20 , wherein the pharmaceutically acceptable salt of nicardipine is the nicardipine hydrochloride salt.
23 . A pharmaceutical composition comprising an inclusion complex of claim 19 , wherein the composition is formulated for parenteral bolus administration to a human subject
24 . The pharmaceutical composition of claim 23 , wherein the sulfoalkylated β-cyclodextrin is a sulfobutylated β-cyclodextrin having an average of 5 to 8 degrees of sulfobutylation.
25 . The pharmaceutical composition of claim 24 , wherein the sulfobutylated β-cyclodextrin having an average of 5 to 8 degrees of sulfobutylation is sulfobutylether β-cyclodextrin.
26 . The pharmaceutical composition of claim 23 , comprising a pharmaceutically acceptable salt of nicardipine in an parenterally injectable aqueous carrier containing one or more buffering agents and having a pH within the range from about 3.5 to about 7.5, wherein the concentration of the nicardipine in the composition is from 0.25 mg/ml to 5 mg/ml, inclusive, the concentration of the sulfoalkylated β-cyclodextrin in the composition is from 0.1% to 25% (w/v) inclusive, the concentration of each buffering agent in the composition is 0.1 mM to 100 mM.
27 . The pharmaceutical composition of claim 26 , wherein the sulfoalkylated β-cyclodextrin is a sulfobutylated β-cyclodextrin having an average of 5 to 8 degrees of sulfobutylation.
28 . The pharmaceutical composition of claim 27 , wherein the sulfobutylated β-cyclodextrin having an average of 5 to 8 degrees of sulfobutylation is sulfobutylether β-cyclodextrin.
29 . The pharmaceutical composition of claim 26 , wherein the nicardipine is in a concentration of from 0.25 to 1 mg/ml.
30 . The pharmaceutical composition of claim 26 , wherein the nicardipine concentration is about 0.5 mg/ml.
31 . The pharmaceutical composition of claim 27 , wherein the sulfobutylated β-cyclodextrin concentration is from 0.5 to 10% (w/v).
32 . The pharmaceutical composition of claim 27 , wherein the sulfobutylated β-cyclodextrin concentration is from 0.1 to 0.5% (w/v).
33 . The pharmaceutical composition of claim 26 , wherein the composition is in unit dose format and the unit dose contains the formulation in a volume of from 0.5 to 20 ml, inclusive.
34 . The pharmaceutical composition of claim 26 , wherein the nicardipine concentration in the aqueous formulation is from 0.3 mg/ml to 0.7 mg/ml, inclusive.
35 . The pharmaceutical composition of claim 26 , wherein the nicardipine concentration of the aqueous formulation is about 0.5 mg/ml.
36 . The pharmaceutical composition of claim 26 , wherein the buffering agent is one or more agents selected from the group consisting of acetate, citrate, succinate, and phosphate buffering agents.
37 . The pharmaceutical composition of claim 36 , wherein the buffering agents comprise acetate and citrate buffering agents, acetate and phosphate buffering agents, citrate and phosphate buffering agents, succinate and phosphate buffering agents; acetate and succinate buffering agents; and citrate and succinate buffering agents.
38 . The pharmaceutical composition of claim 36 , wherein buffering agents comprise acetate, phosphate and citrate buffering agents; succinate, citrate and phosphate buffering agents; succinate, acetate, and phosphate buffering agents, and citrate, acetate and succinate buffering agents.
39 . The pharmaceutical composition of claim 26 , further comprising a tonicity adjusting agent.
40 . The pharmaceutical composition of 39 , wherein the tonicity adjusting agent comprises one or more of dextrose and sodium chloride.
41 . The pharmaceutical composition of claim 26 , wherein the composition further comprises at least one co-solvent in a concentration of 0.1 to 25% (w/v).
42 . The pharmaceutical composition of claim 41 , wherein concentration of at least one co-solvent is 0.1 to 10% (w/v).
43 . The pharmaceutical composition of claim 41 , wherein at least one co-solvent comprises any one or more of ethanol, sorbitol, polyethylene glycol, or propylene glycol.
44 . The pharmaceutical composition of claim 26 , wherein the pH is above a pH of 3.5 and equal to or less than a pH of 5.5.
45 . A method for treating acute elevations of blood pressure in a human subject in need thereof, said method comprising administering an parenteral bolus composition of claim 26 .
46 . The method of claim 45 , wherein the subject is volume-restricted.
47 . The method of claim 46 , wherein the subject has edema, renal failure, ascites, cerebral edema, or other fluid overload, congestive heart failure, liver failure, or a CNS injury.
48 . The method of claim 45 , wherein the composition is administered over a time period of less than 30 seconds.
49 . The method of claim 45 , wherein the elevated blood pressure is reduced.
50 . A method for preventing acute elevations of blood pressure in a human subject in need thereof, said method comprising administering an parenteral bolus composition of claim 26 .
51 . A method for inducing hypotension in a human subject in need thereof, said method comprising administering a parenteral bolus composition of claim 26.