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Stable Nimodipine Parenteral Formulation

Inactive Publication Date: 2019-08-22
GRACE THERAPEUTICS LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention aims to provide a stable and easy-to-administer nimodipine infusion injection to resolve solubility issues of previously approved nimodipine dosage forms. The invention also aims to reduce or eliminate ethanol from the formulation and minimize the first-pass metabolism of nimodipine by the liver for improved bioavailability. The nitomodipine injectable formulations have shown consistent levels in the plasma and CSF of the patient, with improved safety and effectiveness. The invention can also provide prophylactic, symptomatic, or palliative treatment of diseases. The formulation remains a clear solution without drug precipitation clinically significant for regulatory purposes.

Problems solved by technology

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.
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.
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.
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.
The amount of alcohol in this medicine may alter the effects of other medicines.
Nimodipine has poor water solubility and is therefore difficult to formulate as an aqueous injectable.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

examples 1-2

[0084]The formulation of Example 1-2 was prepared as follows: nimodipine base was added to ethanol while stirring and mixing until a clear solution is observed. Polysorbate 80 was then added as a surfactant while stirring and mixing for 30 minutes to form stable micelles. Sufficient water for injection (deoxygenated water) was then added to the solution to generate 5 ml of nimodipine injection concentrate. The ethanol is then completely, or almost completely, removed by evaporation in a lyophilizer using vacuum drying cycle at room temperature. After lyophilization, the product is a viscous liquid with little or no alcohol remains. In these examples, the lyophilization process includes a vacuum at about 75-100 millitorr at 25° C. until the final product is obtained (little or no alcohol as per the present invention). The ingredients of Examples 1-2 are set forth in Table 1 below:

TABLE 1Example 1Example 2CompositionQuantity in mgQuantity in mgConcentrate SolutionNimodipine1010Alcohol...

examples 3

[0086]The concentrated formulation of Example 2 with ethanol content about 2 mg / dose was reconstituted with sterile 0.9% sodium chloride solution up to 100 ml volume and filled in the amber color glass bottle. The composition of the formulation is further detailed in Table 3 below:

TABLE 3CompositionQty / doseConcentrated formulation ofEquivalent to 10 mg of Nimodipineexample 20.9% Sodium chlorideQuantity sufficient up to 100 mLTotal100 mL

example 4

[0087]Amber glass bottles were filled with the formulation of Example 2 (Concentrate) and Example 3 (100 mL ready to infuse) with a rubber stopper and flip-off seal and subjected to stability under following conditions:

[0088]ICH accelerated conditions (ACC) at 40° C.±2° C. / 75% RH±5% RH; and

[0089]ICH room temperature conditions (CRT) at 25° C.±2° C. / 60% RH±5% RH

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is a project that brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry.

[0090]Samples were analyzed to measure the Nimodipine assay, impurities and physical stability (drug precipitation during stability). The stability data is provided in Table 4 below.

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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.

Description

FIELD OF THE INVENTION[0001]The present invention provides a stable nimodipine concentrate and parenteral solution suitable for continuous intravenous (IV) administration. The parenteral solution composition consists of an aqueous solution of nimodipine (concentrations ranging from about 0.5 to about 50 mg / ml), a hydrophilic surfactant and an aqueous solvent, wherein the formulation is essentially free of organic solvents.BACKGROUND OF THE INVENTION[0002]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...

Claims

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Application Information

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IPC IPC(8): A61K31/451A61K9/00A61K47/26A61K47/10A61P9/04A61P9/06A61P9/10A61P9/12A61P9/14
CPCA61K31/451A61K9/0019A61K47/26A61K47/10A61P9/04A61P9/06A61P9/10A61P9/12A61P9/14A61K47/02A61K9/19A61K9/107
Inventor KOTTAYIL, S. GEORGEKUMAR, AMRESHSUNTHANKAR, PRASANNAKAVURU, VIMALPATI, KAMALKISHORE
Owner GRACE THERAPEUTICS LLC
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