US-20260124186-A1 - Nimodipine Parenteral Administration

Abstract

A method of providing an IV nimodipine infusion regimen using a solubilized nimodipine solution suitable for IV administration is disclosed. The IV nimodipine infusion regimen provides a constant infusion rate over the (entire) 24-hour period supplemented with higher infusions of nimodipine at set intervals to duplicate the 24-hour AUC and Cmax of an oral nimodipine dose.

Inventors

• S. George Kottayil
• Amresh Kumar
• Prasanna Sunthankar
• Kamalkishore Pati
• Vimal Kavuru

Assignees

• ACASTI PHARMA U.S., INC.

Dates

Publication Date

20260507

Application Date

20250813

Claims (20)

1. 1 . A method of treating a condition selected from a 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 in a human, the method comprising intravenously administering over a 24-hour period to the human: (i) a continuous intravenous nimodipine infusion of a nimodipine parenteral solution at a rate of about 0.15 mg/hour, and (ii) intravenous boluses of the nimodipine parenteral solution at about 4-hour intervals, each bolus delivering about 4 mg nimodipine over about 30 minute, thereby providing the 24-hour area under the curve (AUC) and C max of nimodipine that mimic the 24-hour area under the curve (AUC) and C max provided by a 60 mg nimodipine administered orally at 4-hour intervals over the 24-hour period.
2. 2 . The method of claim 1 , wherein the condition is subarachnoid hemorrhage.
3. 3 . The method of claim 2 , wherein the 24-hour area under the curve (AUC) of nimodipine is 491.630 h*ng/mL and the 24-hour C max of nimodipine is 63.086 ng/ml.
4. 4 . The method of claim 2 , wherein 27.6 mg of nimodipine intravenously administered over the 24-hour period provides an equivalent 24-hour plasma nimodipine exposure to 360 mg of oral nimodipine, and a similar pulsatile concentration-time profile.
5. 5 . The method of claim 2 , which is accomplished by using a single programmable infusion pump.
6. 6 . The method of claim 5 , wherein the single programmable infusion pump delivers a bolus nimodipine dose of about 4.15 mg administered over about 30 minutes, and a continuous nimodipine dose of about 0.15 mg/hour for 3.5 hours after the bolus dose.
7. 7 . The method of claim 2 , which is accomplished by using two infusion pumps, one operating continuously at a slow rate, and one turned on at 4-hour intervals for 30 minutes and then turned off, with the 2 pumps delivering their infusates into a common infusion line by means of a 3-way valve.
8. 8 . A method of treating subarachnoid hemorrhage in a human comprising intravenously administering over a 24-hour period to the human: (i) a continuous intravenous nimodipine infusion of a nimodipine parenteral solution, and (ii) intravenous boluses of the nimodipine parenteral solution at a set interval, thereby providing a 24-hour AUC and C max of nimodipine that are equivalent to the 24-hour AUC and C max of a 30 mg or 60 mg oral nimodipine dose administered orally at about 4-hour intervals over the 24-hour period.
9. 9 . The method of claim 8 , wherein the set interval is about 4 hours, the continuous intravenous nimodipine infusion is at a rate of about 0.15 mg/hour, and the intravenous boluses are of about 4 mg nimodipine infused over about 30 minute, such that the administering provides the 24-hour AUC and C max of nimodipine that are equivalent to the 24-hour area under the curve and the 24-hour C max of the 60 mg nimodipine administered orally at about 4-hour intervals over the 24-hour period.
10. 10 . The method of claim 9 , wherein 27.6 mg of nimodipine intravenously administered over the 24-hour period provides an equivalent 24-hour plasma nimodipine exposure to 360 mg of oral nimodipine, and a similar pulsatile concentration-time profile.
11. 11 . The method of claim 9 , wherein the continuous intravenous nimodipine infusion rate is halved to provide a continuous intravenous nimodipine dose of about 0.075 mg/hour, and an intravenous bolus nimodipine dose of about 2 mg is administered over about 30 minutes at about 4-hour intervals, to provide equivalent plasma nimodipine exposures as an oral regimen of 30 mg nimodipine administered orally every 4 hours.
12. 12 . The method of claim 8 , comprising administering an intravenous bolus infusion of about 3.6 mg nimodipine over about 30 minutes, followed by a continuous intravenous nimodipine infusion at a rate of about 1.2 mg/hour for up to 21 days.
13. 13 . The method of claim 8 , wherein the continuous intravenous nimodipine infusion is at a rate from about 0.05 mg/hour to about 1.5 mg/hour.
14. 14 . The method of claim 13 , wherein each intravenous bolus is from about 1 mg to about 8 mg and is administered over a time period from about 20 minutes to about 50 minutes.
15. 15 . A method of treating subarachnoid hemorrhage in a human comprising intravenously administering over a 24-hour period to the human: (i) a continuous intravenous nimodipine infusion of a nimodipine parenteral solution at a rate from about 0.05 mg/hour to about 1.5 mg/hour over the 24-hour period, and (ii) intravenous boluses of the nimodipine parenteral solution at a set interval over the 24-hour period, thereby providing the 24-hour area under the curve (AUC) and C max of nimodipine that mimic the 24-hour area under the curve (AUC) and C max provided by a 60 mg nimodipine administered orally at 4-hour intervals over the 24-hour period.
16. 16 . The method of claim 15 , wherein the set interval is about 4 hours to about 24 hours.
17. 17 . The method of claim 15 , wherein about 27.6 mg of nimodipine is administered intravenously to the human over the 24-hour period, and a similar pulsatile concentration-time profile.
18. 18 . The method of claim 15 , comprising repeating the continuous intravenous nimodipine infusion and the intravenous boluses every 24 hours.
19. 19 . The method of claim 1 , comprising repeating the continuous intravenous nimodipine infusion and the intravenous boluses every 24 hours.
20. 20 . The method of claim 1 , comprising repeating the continuous intravenous nimodipine infusion and the intravenous boluses every 24 hours.

Description

This application is a continuation of U.S. patent application Ser. No. 18/195,747, filed May 10, 2023, which claims the benefit of U.S. Provisional Application No. 63/342,204, filed May 16, 2022, the disclosures of which are hereby incorporated by reference herein. FIELD OF THE INVENTION The present invention provides a stable preservative free nimodipine parenteral solution suitable for continuous intravenous (IV) administration via an IV nimodipine infusion pump(s). The parenteral solution composition consists of nimodipine (concentrations ranging from about 0.01 to about 5 mg/ml), a hydrophilic surfactant and a co-solvent, preferably ethanol. The final concentration of ethanol in the administered formulation is preferably less than about 2% w/v. BACKGROUND OF THE INVENTION Nimodipine, a lipid soluble substituted 1,4-dihydropyridine with vasodilatatory properties, is indicated for prophylaxis and treatment of ischemic neurologic deficits caused by cerebral vasospasms after subarachnoid hemorrhage (SAH). Currently, nimodipine treatment of ischemic brain injury is the first-line treatment. In man, nimodipine is rapidly absorbed after oral administration, and peak concentrations are generally attained within one hour. The terminal elimination half-life is approximately 8 to 9 hours but earlier elimination rates are much more rapid, equivalent to a half-life of 1-2 hours; a consequence is the need for frequent (every 4 hours) dosing. Nimodipine is eliminated almost exclusively in the form of metabolites and less than 1% is recovered in the urine as unchanged drug. Numerous metabolites, all of which are either inactive or considerably less active than the parent compound, have been identified. Because of a high first-pass metabolism, the bioavailability of nimodipine averages 13% after oral administration. The bioavailability is significantly increased in patients with hepatic cirrhosis, with Cmax approximately double that in normal, which necessitates lowering the dose in this group of patients. Currently approved products in the US market are oral solid and liquid dosage forms of nimodipine. Nimodipine is marketed in the US as an oral dosage form, NIMOTOP® liquid-filled capsules (Bayer Pharmaceuticals Corp.) and equivalent generics. NIMOTOP® capsules and generic versions of the same each contain 30 mg of nimodipine and are commonly administered in a two-capsule 60 mg dose, and dosed every 4 hours. In the event that a patient is unconscious or unable to swallow, the nimodipine capsule contents are extracted by syringe and administered via an intraoral or an intranasal (e.g., naso-gastric) tube. The medical practitioner administering the dose may either unknowingly or due to improper handling, extract less than the full amount of the liquid dose from the capsule, thus introducing substantial risk of incomplete dosing and placing undue burden on medical professionals. The incomplete dosing is exacerbated by the relatively small dosage volumes involved and high drug concentration of drug in the commercially available capsules. Hence, a practitioner's failure to dose the full amount of the high-concentration, small volume liquid from the commercial capsules could lead to a significant under dose of nimodipine. Also, the FDA has noted in warnings related to oral nimodipine administration via nasogastric tubes that because a standard needle does not fit on an oral syringe, the formulation within a capsule is extracted using an intravenous syringe. The use of intravenous syringes to extract nimodipine formulation from the capsule increases the chance of medication being inadvertently administered intravenously instead of by mouth or nasogastric tube. To quickly and effectively treat or control disease progression following SAH, intravenous administration of nimodipine is usually preferred. Intravenous (IV) Nimodipine is approved in Europe and marketed in Europe by Bayer under the trade name Nimotop®. The current commercially marketed injectable nimodipine (Bayer's Nimotop®) available in Europe and other regulated markets contains large amounts of organic solvent—about 23.7% ethanol and 17% polyethylene glycol 400. The large amount of ethanol in Nimotop is harmful for those suffering from alcoholism or impaired alcohol metabolism and in pregnant or breast feeding women. Also, high concentrations of ethanol may cause pain and irritation at the injection site. IV Nimotop is most often infused continuously for up to three weeks. Due to the high alcohol content in Bayer's IV Nimotop solution, it is diluted by co-infusing saline and dextrose by way of a three-way stopcock. Nimodipine has poor water solubility and is therefore difficult to formulate as an aqueous injectable. That is the reason that Nimotop IV infusion solution utilizes up to 23.7% of alcohol as a co-solvent to solubilize nimodipine. U.S. Pat. No. 5,114,956 describes parenteral formulations containing nimodipine, that contain 0.01-0.4% by weight of nimodipi