Claims for Patent: 10,092,553

Summary for Patent: 10,092,553

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), Pati; Kamalkishore (Old Bridge, NJ)
Assignee:	Nortic Holdings Inc. (East Brunswick, NJ)
Application Number:	15/638,901
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 mg/ml 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 and stored in a container, wherein the formulation has a dissolved oxygen content of about 2 ppm and a head space oxygen content of less than 5%. 2. The nimodipine injection concentrate formulation of claim 1, wherein the nimodipine base or 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 hydrophilic surfactant is selected from the group consisting of a polyoxyethylene fatty alcohol ester, a sorbitan fatty acid ester, 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 polyoxyethylene glycerol 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 100 ml with a pharmaceutical acceptable carrier for injection such that the nimodipine is present in a concentration from about 0.01 mg/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. 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; 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; and storing the formulation with degassing to provide an dissolved oxygen content of about 2.0 ppm and headspace replacement with an inert gas. 16. The nimodipine formulation of claim 12, wherein the hydrophilic surfactant is from about 0.01% to about 2.5% w/v of the formulation. 17. The nimodipine formulation of claim 12, wherein the organic solvent is less than 1% w/v of the formulation. 18. The nimodipine formulation of claim 12, which has a pH from about 4.5 to about 8. 19. 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 3 months; or which is stable when exposed to conditions of 25.degree. C..+-.2.degree. C./60% RH.+-.5% RH for at least 12 months. 20. The nimodipine formulation of claim 12, which is chemically stable for at least 48 hours for continuous infusion.

Details for Patent 10,092,553

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		2036-01-12