# US 10,765,671 B2 · Stable nimodipine parenteral formulation

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- Number: US 10,765,671 B2
- Document ID: US10765671B2
- Status: Granted
- Kind: B2
- Application number: 16/046,476
- Filed: 2018-07-26
- Published: 2018-11-15
- Granted: 2020-09-08
- Earliest claimed: 2016-04-13
- Assignees: Nortic Holdings Inc.
- Applicants: Nortic Holdings Inc.
- Inventors: S. George Kottayil; Amresh Kumar; Prasanna Sunthankar; Vimal Kavuru
- Web page: https://patentgrep.com/patent/US10765671B2

## CPC

- A61K 31/455: Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/1075: {Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence)}
- A61K 31/4422: 1,4-Dihydropyridines, e.g. nifedipine, nicardipine
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/24: containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 47/44: Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin (synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/06: Antiarrhythmics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

A nimodipine injection concentrate formulation, comprising nimodipine base or a pharmaceutically acceptable nimodipine salt in a concentration from about 0.01 to about 5 mg/ml; an organic solvent consisting of ethanol; a pharmaceutically acceptable aqueous carrier; an optional preservative; and an effective amount of a single hydrophilic surfactant which is polysorbate 80 and the polysorbate 80 is from about 6% to about 10% of the injection concentrate formulation , such that nimodipine in the injection concentrate formulation is contained in micelles and the formulation is stable and clear, wherein the nimodipine injection concentrate formulation does not contain poloxamer, a phospholipid, or polyoxyethylene castor oil derivatives.

### Claim 2 (depends on 1)

The nimodipine injection concentrate formulation of claim 1, comprising nimodipine base or a pharmaceutically acceptable nimodipine salt in a concentration from about 0.5 mg/ml to about 5 mg/ml, from about 1% to about 30% of the single hydrophilic surfactant, from about 30% to about 90% organic solvent; and from about 30 to about 70% of a pharmaceutically acceptable aqueous carrier comprising water for injection.

### Claim 3 (depends on 1)

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.

### Claim 4 (depends on 1)

The nimodipine injection concentrate formulation of claim 1, wherein the single hydrophilic surfactant is polysorbate 80 and the polysorbate 80 is from about 1% to about 15% of the injection concentrate formulation.

### Claim 5 (depends on 1)

The nimodipine injection concentrate formulation of claim 1, wherein the single hydrophilic surfactant is polysorbate 80 and the polysorbate 80 is from about 6% to about 10% of the injection concentrate formulation.

### Claim 6 (depends on 1)

The nimodipine injection concentrate formulation of claim 1, wherein the organic solvent comprises ethanol.

### Claim 7 (depends on 1)

The nimodipine injection concentrate formulation of claim 1, 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 and displays no precipitation of nimodipine.

### Claim 8 (depends on 1)

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.

### Claim 9 (depends on 1)

The nimodipine injection concentrate formulation of claim 1, which includes an effective amount of a preservative selected from the group consisting of cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride, benzethonium chloride, boric acid, p-hydroxybenzoates, phenols, chlorinated phenolic compounds, alcohols, quarternary compounds, mercurials, and mixtures of any of the foregoing.

### Claim 10 (depends on 1)

The nimodipine injection concentrate formulation of claim 1, 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 0.01 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.

### Claim 11 (depends on 1)

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.

### Claim 12 (depends on 10)

The nimodipine injection concentrate formulation of claim 10, wherein the median particle size of micelles containing nimodipine ranges from about 0.5 nanometer to about 350 nanometers.

### Claim 13 (depends on 1)

A method of treating a human patient having a condition 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 continuously infusing in the human patient an intravenous solution comprising the nimodipine injection concentrate formulation of claim 1 over a period of about three weeks.

### Claim 14 (depends on 13)

The method of claim 13, wherein the nimodipine infusion rate is from about 0.05 mg nimodipine per hour to about 5 mg nimodipine per hour.

### Claim 15 (depends on 13)

The method of claim 13, wherein the intravenous nimodipine dose is from about 2 to 10 mg administered every five hours.

### Claim 16 (depends on 1)

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.

### Claim 17 (depends on 10)

The nimodipine formulation of claim 10, wherein the single hydrophilic surfactant is from about 0.01 to about 2.5% of the formulation.

### Claim 18 (depends on 10)

The nimodipine formulation of claim 10, wherein the organic solvent is less than 1% of the formulation.

### Claim 19 (depends on 10)

The nimodipine formulation of claim 10, which has a pH from about 4.5 to about 8.

### Claim 20 (depends on 1)

The nimodipine injection concentrate formulation of claim 1, which is stable when exposed to conditions of 40° ° C.±2° C./75% RH±5% RH for at least 3 months; or which is stable when exposed to conditions of 25° C.±2° C./60% RH±5% RH for at least 12 months.

### Claim 21

A directly infusible nimodipine formulation suitable for parenteral administration in humans, comprising nimodipine in a concentration from about 0.01 mg/ml to about 1.0 mg/ml, a pharmaceutically acceptable organic solventconsisting of ethanol copmrising less than 2% w/v of the formulation, a pharmaceutically acceptable aqueous carrier, and an effective amount of a single hydrophilic surfactant which is polysorbate 80 and is from 0.01% to about 2.5% w/v of the formulation, such that the nimodipine is substantially contained in micelles, the formulation comprising 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, wherein the directly infusible nimodipine injection formulation does not contain poloxamer, a phospholipid, or an oil.

### Claim 22 (depends on 21)

The directly infusible nimodipine formulation of claim 21, wherein the single hydrophilic surfactant is from 0.01% to about 2.5% w/v of the formulation.

### Claim 23 (depends on 21)

The directly infusible nimodipine formulation of claim 21, wherein the single hydrophilic surfactant is polysorbate 80 and the organic solvent comprises ethanol.

### Claim 24 (depends on 21)

The directly infusible nimodipine injection formulation of claim 21, wherein the median particle size of micelles containing nimodipine ranges from about 0.5 nanometer to about 350 nanometers.

### Claim 25 (depends on 21)

The directly infusible nimodipine injection formulation of claim 21, which is stable when exposed to conditions of 40° C.±2° C./75% RH±5% RH for at least 6 months; or which is stable when exposed to conditions of 25° C.±2° C./60% RH±5% RH for at least 12 months.

### Claim 26 (depends on 1)

The nimodipine injection concentrate formulation of claim 1, wherein the single hydrophilic surfactant is a polyoxyethylene sorbitan fatty acid ester.

### Claim 27 (depends on 21)

The directly infusible nimodipine injection formulation of claim 21, wherein the single hydrophilic surfactant is a polyoxyethylene sorbitan fatty acid ester.

### Claim 28 (depends on 1)

The nimodipine injection concentrate formulation of claim 1, wherein the single hydrophilic surfactant is polysorbate 80.

### Claim 29 (depends on 21)

The directly infusible nimodipine injection formulation of claim 21, wherein the single hydrophilic surfactant is polysorbate 80.