Stable nimodipine parenteral formulation
A nimodipine injection concentrate and diluted formulation comprises nimodipine (base or salt), an effective amount of a hydrophilic surfactant, and a pharmaceutically acceptable carrier for injection which is an aqueous solution substantially free of organic solvent, such that the nimodipine is substantially contained in a concentrated injection solution, suspension, emulsion or complex as a micelle or a colloidal particle or an inclusion complex and the formulation is stable and clear. In certain embodiments, the hydrophilic surfactant is polysorbate 80.
1. A method of treatment, comprising administering a therapeutically effective dose of a nimodipine concentrate formulation to a human patient suffering from a condition selected from the group consisting of aneurysms, subarachnoid hemorrhage, vasospastic angina, Prinzmetal angina, stable angina, acute myocardial infarction, myocardial arrest, arrhythmia, systemic hypertension, pulmonary hypertension, congestive heart failure, coronary artery surgery and hypertrophic cardiomyopathy,
wherein the nimodipine concentrate formulation consists of:
(a) an aqueous carrier,
(b) nimodipine base or a pharmaceutically acceptable salt of nimodipine at a concentration from about 10 mg/ml to about 50 mg/ml in the aqueous carrier,
(c) an effective amount of a hydrophilic surfactant consisting of polysorbate 80,
(d) from about 0 to about 0.5% organic solvent,
(e) an optional preservative, and
(f) an optional buffering agent,
and wherein the nimodipine concentrate formulation is clear, colorless, stable, and without crystalline nimodipine precipitate.
2. The method of claim 1 , wherein the nimodipine in the nimodipine concentrate formulation is contained in micelles, and the micelles have a median particle size that ranges from about 0.5 nm to about 350 nm.
3. The method of claim 1 , wherein from about 0.5 ml to about 10 ml of the nimodipine concentrate formulation is administered to the human patient.
4. The method of claim 1 , wherein the polysorbate 80 comprises from about 40% to about 99% of the nimodipine concentrate formulation.
5. The method of claim 1 , wherein the nimodipine concentrate formulation contains from about 0 to about 300 mg of the organic solvent.
6. The method of claim 1 , wherein the nimodipine concentrate formulation contains from about 0 to about 100 mg of the organic solvent per dose per 10 mg dose of nimodipine, and the organic solvent is alcohol.
7. The method of claim 1 , wherein the organic solvent is dehydrated alcohol, and the aqueous carrier is water for injection.
8. The method of claim 7 , wherein the nimodipine concentrate formulation contains from about 0 to about 100 mg of the dehydrated alcohol per dose per 10 mg dose of nimodipine.
9. The method of claim 1 , wherein the nimodipine concentrate formulation (i) is stable for at least 3 months when stored under ICH accelerated conditions (ACC) at 40° C.±2° C./75% RH±5% RH, or (ii) is stable for at least 6 months when stored under ICH room temperature conditions (CRT) at 25° C.±2° C./60% RH±5% RH, or (iii) is stable for at least 3 months when stored under ICH accelerated conditions (ACC) at 40° C.±2° C./75% RH±5% RH and is stable for at least 6 months when stored under ICH room temperature conditions (CRT) at 25° C.±2° C./60% RH±5% RH.
10. The method of claim 1 , wherein, prior to the administration, the nimodipine concentrate formulation is diluted in an aqueous carrier to a concentration from about 0.001 mg/ml to about 0.5 mg/ml.
11. The method of claim 1 , wherein the nimodipine concentrate formulation consists of the nimodipine base or the pharmaceutically acceptable salt of nimodipine, the hydrophilic surfactant consisting of polysorbate 80, the aqueous carrier and the organic solvent, wherein the organic solvent is an alcohol.