Claims for Patent: 10,092,557

Summary for Patent: 10,092,557

Title:	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, an organic solvent, an oil, or a cyclodextrin, 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.
Inventor(s):	Kottayil; S. George (West Windsor, NJ), Kumar; Amresh (Plainsboro, NJ), Sunthankar; Prasanna (West Windsor, NJ), Kavuru; Vimal (Holmdel, NJ)
Assignee:	Nortic Holdings Inc. (East Brunswick, NJ)
Application Number:	15/485,813
Patent Claims:	1. A nimodipine injection concentrate formulation, consisting of nimodipine base or a pharmaceutically acceptable nimodipine salt in a concentration from about 0.01 to about 5 mg/ml; an organic solvent; a pharmaceutically acceptable aqueous carrier; an optional preservative; and an effective amount of a single hydrophilic surfactant, such that nimodipine in the injection concentrate formulation is contained in micelles and the formulation is stable and clear. 2. The nimodipine injection concentrate formulation of claim 1, wherein the nimodipine base or a pharmaceutically acceptable nimodipine salt is in a concentration from about 0.5 mg/ml to about 5 mg/ml; the hydrophilic surfactant is from about 1% to about 30% by weight; the organic solvent is from about 30% to about 90% by weight; and the pharmaceutically acceptable aqueous carrier is water for injection, and the water for injection is from about 30% to about 70% by weight of the injection concentrate formulation. 3. The nimodipine injection concentration formulation of claim 1, wherein the total volume of the concentrate formulation is from about 1 ml to about 10 ml. 4. The nimodipine injection concentrate formulation of claim 1, wherein the single hydrophilic surfactant is a polyoxyethylene sorbitan fatty acid ester. 5. The nimodipine injection concentrate formulation of claim 4, wherein the hydrophilic surfactant is polysorbate 80 and the polysorbate 80 is from about 1% to about 15% by weight of the injection concentrate formulation. 6. The nimodipine injection concentrate formulation of claim 4, wherein the hydrophilic surfactant is polysorbate 80 and the polysorbate 80 is from about 6% to about 10% by weight of the injection concentrate formulation. 7. The nimodipine injection concentrate formulation of claim 1, wherein the single hydrophilic surfactant is a nonionic surfactant selected from the group consisting of a polyoxyethylene fatty alcohol ester, a sorbitan fatty acid esters, a polyoxyethylene sorbitan fatty acid ester, a sorbitan ester, a glycerol ester, a sulfosuccinate, an alkyl sulfate, a PEG glyceryl fatty acid ester, a propylene glycol fatty acid ester, and a polyoxethyleneglycerol fatty acid ester. 8. The nimodipine injection concentrate formulation of claim 4, wherein the organic solvent is ethanol. 9. The nimodipine injection concentrate formulation of claim 4, wherein the nimodipine injection concentrate when diluted with a carrier 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) to a concentration as dilute as 0.01 mg/ml nimodipine remains clear displays no precipitation of nimodipine. 10. The nimodipine injection concentrate formulation of claim 1, wherein the nimodipine injection concentrate when diluted with a pharmaceutically acceptable aqueous injection medium allows for administration of a single 250 ml infusion bag or bottle that contains less than 2% w/v alcohol, the diluted injection medium remaining a clear micellar solution that displays no precipitation of nimodipine. 11. The nimodipine injection concentrate formulation of claim 1, wherein the preservative is selected from the group consisting of cresols, mercurial, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride, benzethonium chloride, boric acid p-hydroxybenzoates, phenols, chlorinated phenolic compounds, alcohols, quaternary compounds, mercurial, and mixtures thereof. 12. The nimodipine injection concentrate formulation of claim 4, which is diluted to a volume from about 50 ml to about 1000 ml with a pharmaceutical acceptable carrier for injection such that the nimodipine is present in a concentration from about 0.01mg/ml to about 1.0 mg/ml, and the organic solvent is less than 2% w/v of the formulation, the nimodipine being substantially present in the form of micelles, the diluted formulation remaining clear micellar solution and displaying no crystal precipitation of nimodipine. 13. The nimodipine injection concentrate formulation of claim 1, wherein the median particle size of micelles containing nimodipine ranges from about 0.5 nanometer to about 350 nanometers. 14. The nimodipine injection concentrate formulation of claim 12, wherein the median particle size of micelles containing nimodipine ranges from about 0.5 nanometer to about 350 nanometers. 15. A method for treating a condition in a human patient selected from the group consisting of an aneurysm, 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, comprising administering an intravenous infusion of the nimodipine solution of claim 12 to the patient in need thereof over a period of about three weeks. 16. The method of claim 15, wherein the nimodipine infusion rate is from about 0.05 mg nimodipine per hour to about 5 mg nimodipine per hour. 17. The method of claim 15, wherein the intravenous nimodipine dose is from about 2 to 10 mg administered every five hours. 18. The nimodipine injection concentrate formulation of claim 1, which is prepared by mixing the nimodipine base or a pharmaceutically acceptable nimodipine salt with the organic solvent; adding the hydrophilic surfactant to the mixture of nimodipine and organic solvent; and thereafter adding from about 0.5 ml to about 4 ml of a pharmaceutically acceptable aqueous medium for injection to prepare a nimodipine concentrate formulation wherein nimodipine is contained in micelles. 19. The nimodipine formulation of claim 12, wherein the hydrophilic surfactant is from about 0.01% to about 2.5% w/v of the formulation. 20. The nimodipine formulation of claim 12, wherein the organic solvent is less than 1% w/v of the formulation. 21. The nimodipine formulation of claim 12, which has a pH from about 4.5 to about 8. 22. The nimodipine injection concentrate formulation of claim 1, which is stable when exposed to conditions of 40.degree. C..+-.2.degree. C./ 75%RH.+-.5%RH for at least 3months; or which is stable when exposed to conditions of 25.degree. C..+-.2.degree. C./60%RH.+-.5%RH for at least 12 months. 23. A directly infusible nimodipine formulation suitable for parenteral administration in humans, consisting of nimodipine in a concentration from about 0.01 mg/ml to about 1.0 mg/ml, a pharmaceutically acceptable organic solvent in a concentration of less than 2% w/v, a pharmaceutically acceptable aqueous carrier, an optional preservative, and effective amount of a single hydrophilic surfactant such that the nimodipine is substantially contained in micelles, the formulation is present at a volume from about 50 ml to about 1000 ml and contained in a pharmaceutically acceptable container, the formulation being a stable clear micellar solution and displaying no precipitation of nimodipine. 24. The directly infusible nimodipine formulation of claim 23, wherein the hydrophilic surfactant is from 0.01% to about 2.5% w/v of the formulation. 25. The directly infusible nimodipine formulation of claim 23, wherein the hydrophilic surfactant is a non-ionic hydrophilic surfactant. 26. The directly infusible nimodipine formulation of claim 23, wherein the hydrophilic surfactant is polysorbate 80 and the organic solvent is alcohol. 27. The directly infusible nimodipine formulation of claim 23, wherein the median particle size of micelles containing nimodipine ranges from about 0.5 nanometer to about 350 nanometers. 28. The directly infusible nimodipine formulation of claim 23, which is stable when exposed to conditions of 40.degree. C..+-.2.degree. C. / 75%RH.+-.5%RH for at least 6months; or which is stable when exposed to conditions of 25.degree. C..+-.2.degree. C./60%RH.+-.5%RH for at least 12 months.

Details for Patent 10,092,557

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Merck Sharp & Dohme Corp.	ZOSTAVAX	zoster vaccine live	For Injection	125123	05/25/2006		2039-09-23