Stable Nimodipine Parenteral Formulation

Abstract

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 nimodipine concentrate formulation, comprising nimodipine base or a pharmaceutically acceptable salt of nimodipine at a concentration from about 10 mg/ml to about 50 mg/ml in an aqueous carrier, and an effective amount of a hydrophilic surfactant consisting of polysorbate 80, the formulation being lyophilized or vacuum dried such that it contains from about 0 to about 0.5% organic solvent, the nimodipine in the concentrate formulation contained in micelles, the concentrate formulation further comprising an optional preservative and an optional buffering agent, the concentrate formulation being clear, colorless, stable, and without crystalline nimodipine precipitate. 
     
     
         2 . The nimodipine concentrate formulation of  claim 1 , wherein the median particle size of micelles ranges from about 0.5 nm to about 350 nm. 
     
     
         3 . The nimodipine concentration formulation of  claim 1 , wherein the total volume of the concentrate formulation is from about 0.5 ml to about 10 ml. 
     
     
         4 . The nimodipine concentrate formulation of  claim 3 , wherein the polysorbate 80 comprises from about 40% to about 99% of the injection concentrate formulation. 
     
     
         5 . The nimodipine concentration formulation of  claim 1 , which contains from about 0 to about 300 mg organic solvent. 
     
     
         6 . The nimodipine concentrate formulation of  claim 1 , which contains from about 0 to about 100 mg alcohol per dose per 10 mg dose of nimodipine. 
     
     
         7 . The nimodipine concentrate formulation of  claim 5 , wherein the organic solvent is dehydrated alcohol and the aqueous carrier is water for injection. 
     
     
         8 . The nimodipine concentrate formulation of  claim 7 , which contains from about 0 to about 100 mg alcohol per dose per 10 mg dose of nimodipine. 
     
     
         9 . The nimodipine concentrate formulation of  claim 1 , which is stored in a container wherein the dissolved oxygen content is about 2 ppm and the head space oxygen content is less than 5%. 
     
     
         10 . The nimodipine concentrate formulation of  claim 1 , which (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) both (i) and (ii). 
     
     
         11 . The nimodipine concentrate formulation of  claim 1 , which can be diluted in an aqueous carrier to a concentration from about 0. 0.001 mg/ml to about 0.5 mg/ml without crystalline nimodipine precipitate. 
     
     
         12 . A nimodipine formulation, comprising the nimodipine concentrate formulation of  claim 1  diluted in an aqueous carrier to a concentration from about 0.001 mg/ml to about 0.5 mg/ml without crystalline nimodipine precipitate, the nimodipine formulation being stable such that the nimodipine does not phase separate at a temperature from about 15° C. to about 25° C. and at a pH from about 5 to about 8. 
     
     
         13 . The nimodipine formulation of  claim 12 , which (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) both (i) and (ii). 
     
     
         14 . The nimodipine formulation of  claim 13 , wherein the aqueous carrier is selected from the group consisting sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water for injection, dextrose, Lactated Ringers injection, and total parenteral nutrition (TPN). 
     
     
         15 . A method of treatment, comprising administering a therapeutically effective dose of the formulation of  claim 13  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. 
     
     
         16 . A nimodipine infusion formulation, comprising a nimodipine base or a pharmaceutically acceptable salt of nimodipine and an effective amount of a hydrophilic surfactant consisting of polysorbate 80 lyophilized or vacuum dried to a nimodipine concentrate to remove alcohol or other organic solvent, the lyophilized nimodipine concentrate diluted with a pharmaceutically acceptable aqueous carrier for injection such that the nimodipine infusion formulation can be administered at an infusion rate of nimodipine from about 0.5 mg/hr to about 2.5 mg/hr and such that the infusion does not provide alcohol in an amount of more than 6 mg/kg/day when infused into a human patient, the formulation further comprising an optional preservative and an optional buffering agent, the nimodipine infusion formulation being clear, colorless, stable, and without crystalline nimodipine precipitate. 
     
     
         17 . The nimodipine infusion formulation of  claim 16 , wherein the nimodipine in the nimodipine concentrate formulation is contained in micelles at a concentration from about 10 mg/ml to about 50 mg/ml, and wherein the nimodipine in the nimodipine infusion formulation is contained in micelles at a concentration from about 0. 0.001 mg/ml to about 0.5 mg/ml. 
     
     
         18 . The nimodipine infusion formulation of  claim 17 , wherein the polysorbate 80 comprises from about 40% to about 99% of the injection concentrate and the polysorbate 80 comprises less than 1% of the nimodipine infusion formulation. 
     
     
         19 . The nimodipine concentrate formulation of  claim 18 , wherein the organic solvent is dehydrated alcohol and the aqueous carrier is selected from the group consisting sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water for injection, dextrose, Lactated Ringers injection, and total parenteral nutrition (TPN). 
     
     
         20 . A method of treatment, comprising intravenously administering the nimodipine infusion formulation of  claim 19  to a human patient at a nimodipine infusion rate of from about 8 mg/day to about 50 mg/day.