WO2019006134A1 - Formulation parentérale stable de nimodipine - Google Patents

Formulation parentérale stable de nimodipine Download PDF

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Publication number
WO2019006134A1
WO2019006134A1 PCT/US2018/040038 US2018040038W WO2019006134A1 WO 2019006134 A1 WO2019006134 A1 WO 2019006134A1 US 2018040038 W US2018040038 W US 2018040038W WO 2019006134 A1 WO2019006134 A1 WO 2019006134A1
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WO
WIPO (PCT)
Prior art keywords
nimodipine
formulation
injection
pharmaceutically acceptable
concentrate formulation
Prior art date
Application number
PCT/US2018/040038
Other languages
English (en)
Inventor
S. George Kottayil
Amresh Kumar
Prasanna SUNTHANKAR
Kavuru VIMAL
Kamalkishore Pati
Original Assignee
Nortic Holdings Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US15/638,901 external-priority patent/US10092553B2/en
Application filed by Nortic Holdings Inc. filed Critical Nortic Holdings Inc.
Publication of WO2019006134A1 publication Critical patent/WO2019006134A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the present invention provides a stable preservative free nimodipine parenteral solution suitable for continuous intravenous (rV) administration.
  • 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.
  • 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).
  • SAH subarachnoid hemorrhage
  • nimodipine treatment of ischemic brain injury is the first-line treatment.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • Intravenous (rV) 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.
  • high concentrations of ethanol may cause pain and irritation at the injection site.
  • IV Nimotop is most often infused continuously 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 rV infusion solution utilizes up to 23.7% of alcohol as a co-solvent to solubilize nimodipine.
  • 114,956 describes parenteral formulations containing nimodipine, that contain 0.01-0.4% by weight of nimodipine, relative to 100 parts by weight of a solvent consisting of 30-70% by weight, preferably 45-70% by weight, of water, 15-40% by weight, preferably 15- 30% by weight, of propylene glycol and/or polyethylene glycol, preferably with a mean molecular weight of 200, 400 and 600, 15-30% by weight, preferably 15-25% by weight, of ethanol, and, where appropriate, customary auxiliaries and/or additives.
  • a solvent consisting of 30-70% by weight, preferably 45-70% by weight, of water, 15-40% by weight, preferably 15- 30% by weight, of propylene glycol and/or polyethylene glycol, preferably with a mean molecular weight of 200, 400 and 600, 15-30% by weight, preferably 15-25% by weight, of ethanol, and, where appropriate, customary auxiliaries and/or additives.
  • the invention is directed in part to a nimodipine concentrate formulation, comprising nimodipine base or a pharmaceutically acceptable salt of nimodipine in a concentration from about 0.01 or from about 0.5 mg/ml to about 5 mg/ml; an organic solvent; an aqueous carrier; and an effective amount of a hydrophilic surfactant, such that nimodipine in the concentrate formulation is contained in micelles.
  • the invention is directed in part to a nimodipine injection concentrate formulation, comprising nimodipine in a concentration from about 0.5 mg/ml to about 5 mg/ml; an organic solvent in an amount greater than 30% to about 90%, w/w; from about 0.005 to about 30%, preferably from about 0.5% or 1% to about 15% of a hydrophilic surfactant, and a pharmaceutically acceptable aqueous carrier for injection comprising from about 30 to about 80% of the concentrate formulation, such that nimodipine in the concentrate is contained in micelles.
  • the formulation is stable and clear.
  • the hydrophilic surfactant is polysorbate 80.
  • the pharmaceutically acceptable carrier is water for injection, and the nimodipine is substantially contained within micelles.
  • the organic solvent comprises or consists of ethanol.
  • a unit dose of the concentrate is diluted to a total volume of 5 ml with water for injection and enclosed within a pharmaceutically acceptable container, e.g., an ampule or vial.
  • the nimodipine injection concentrate further comprises an effective amount of a preservative.
  • the median particle size of micelles or nano-emulsions ranges from about 0.5 nanometer to about 350 nanometers, or from about 0.5 nm to about 200 nm, or from about 5 nm to about 50 nm.
  • the nimodipine concentrate formulation is clear and does not contain a crystal nimodipine precipitate.
  • the nimodipine is substantially contained within micelles as a nano-emulsion.
  • the invention is further directed in part to the nimodipine concentrate formulation of the present invention (e.g., as described above), which is diluted in a suitable injection medium, such that the diluted formulation for injection contains less than about 2% or preferably less than about 1% w/v organic solvent (e.g., alcohol).
  • a suitable injection medium such that the diluted formulation for injection contains less than about 2% or preferably less than about 1% w/v organic solvent (e.g., alcohol).
  • organic solvent e.g., alcohol
  • the solution is predominantly an aqueous medium, the diluted injection medium remaining a clear solution that displays no precipitate of nimodipine.
  • the concentrate when diluted in a suitable injection medium allows for parenteral administration of a single 250 ml infusion bag or bottle to a human patient, the diluted formulation containing less than about 2% or preferably less than about 1% w/v organic solvent (e.g., alcohol).
  • organic solvent e.g., alcohol
  • the concentrate and diluted solution further comprise an effective amount of a pharmaceutically acceptable preservative.
  • substantially all or all of the nimodipine contained in the formulation is contained in micelles.
  • the invention is directed in part to a nimodipine injection concentrate formulation, comprising nimodipine in a concentration from about 0.5 mg/ml to about 5 mg/ml, from about 1% to about 15% of a hydrophilic surfactant, and a pharmaceutically acceptable carrier for injection comprising from about 10% to about 90% of the formulation injection concentrate, the pharmaceutically acceptable carrier forinjection selected from the group consisting of an aqueous solution, an organic solvent, an oil, and 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.
  • the hydrophilic surfactant is polysorbate 80.
  • the pharmaceutically acceptable carrier is water for injection, further comprising from about 0.5% to about 30% of a pharmaceutically acceptable hydrophilic surfactant (alternatively referred to as an emulsifier herein), and the nimodipine is substantially contained within micelles.
  • the pharmaceutically acceptable carrier is an organic solvent, and the concentrate further comprises water for injection.
  • the pharmaceutically acceptable carrier is an oil, further comprising from about 0.005% to about 30%, more preferably from about 0.5 to about 15%, of a pharmaceutically acceptable hydrophilic surfactant, and the nimodipine is substantially contained within micelles.
  • the hydrophilic surfactant is selected from the group consisting of a phospholipid and a polyethylene glycol.
  • a unit dose of the concentrate is diluted to a total volume of 5 ml with water for injection and enclosed within a pharmaceutically acceptable container, e.g., an ampule or vial.
  • the nimodipine injection concentrate further comprises an effective amount of a preservative.
  • the median particle size of micelles or nano-emulsions ranges from about 0.5 nanometer to about 350 nanometers, or from about 0.5 nm to about 200 nm, or from about 5 nm to about 50 nm.
  • the nimodipine concentrate formulation is clear and does not contain a crystal nimodipine precipitate.
  • the nimodipine concentrate formulation is stable.
  • the nimodipine is substantially contained within micelles as a nano-emulsion.
  • the nimodipine infusion concentrate is introduced into an appropriate infusion bag (e.g., 250 ml bag containing saline, dextrose, etc.) and the nimodipine is infused over a time period of about 12 hours as a continuous infusion.
  • the nimodipine concentrate can be introduced in an volume of, e.g., 10 ml into the 250 ml bag (e.g., two 5 ml vials containing nimodipine infusion concentrate).
  • the invention is further directed in part to a directly infusible nimodipine formulation (without dilution; e.g., 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 carrier (e.g., for injection) selected from the group consisting of an aqueous solution, an organic solvent, an oil, and a cyclodextrin, the formulation comprising a volume from about 50 ml to about 1000 ml and contained in a pharmaceutically acceptable container (e.g., a bag or vial), wherein when present the organic solvent preferably comprises less than 2% w/v or less than 1% w/v of the formulation, an effective amount of a hydrophilic surfactant such that the nimodipine is substantially contained in a diluted injection solution in micelles and the formulation remains a clear solution and displays no precipitation of nimodipine.
  • the hydrophilic surfactant is from 0.01% to about 2.5% w/v of the directly infusible (ready-to-use) formulation.
  • the hydrophilic surfactant is a non-ionic hydrophilic surfactant, in certain embodiments most preferably comprising or consisting of polysorbate 80.
  • the organic solvent comprises or consists of ethanol.
  • the pharmaceutically acceptable aqueous carrier comprises water for injection.
  • the hydrophilic surfactant is included in an amount from about 0.01% to about 2.5% of the directly infusible formulation.
  • the formulation 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.
  • the nimodipine is substantially contained within micelles as a nano- emulsion.
  • the pharmaceutically acceptable carrier is a beta-cyclodextrin, wherein the nimodipine is substantially contained within an inclusion complex.
  • a unit dose of the concentrate is diluted to a total volume of 5 ml with water for injection and enclosed within a pharmaceutically acceptable container, e.g., an ampule or vial.
  • a pharmaceutically acceptable container e.g., an ampule or vial.
  • the organic solvent comprises ethanol.
  • the organic solvent may comprise, e.g, at least 25% of the concentrate, and in certain embodiments at least 40% of the concentrate.
  • the nimodipine concentrate has a volume from about 1 ml to about 10 ml, preferably about 5 ml, and is contained in an ampoule or vial.
  • the nimodipine injection concentrate is diluted with water for injection, saline, dextrose or other commonly available infusion solutions up to a concentration of 0.01 mg/ml remains a clear solution and displays no crystal precipitation of nimodipine.
  • the nimodipine injection concentrate can preferably be diluted with a suitable injection medium that allows for administration of, e.g., a single 100 or preferably 250 ml infusion bag or bottle that contains, e.g., less than 1% w/v alcohol in a predominantly aqueous medium, the diluted injection medium remaining a clear solution that displays no precipitation of nimodipine.
  • the invention is further directed in part to a nimodipine formulation suitable for injection into humans, comprising nimodipine in a concentration from about 0.01 mg/ml to about 1.0 mg/ml, a pharmaceutically acceptable carrier (e.g., for injection) selected from the group consisting of an aqueous solution, an organic solvent, an oil, and a cyclodextrin, the formulation comprising a volume from about 50 ml to about 1000 ml, wherein when present the organic solvent preferably comprises less than 2% w/v of the formulation, an effective amount of a hydrophilic surfactant such that the nimodipine is substantially contained in a diluted injection solution, suspension, emulsion or complex as a micelle or a colloidal particle or an inclusion complex and the formulation remains a clear solution and displays no precipitation of nimodipine.
  • the hydrophilic surfactant is polysorbate 80.
  • the hydrophilic surfactant is polysorbate 80.
  • the pharmaceutically acceptable carrier is an organic solvent, further comprising water for injection.
  • the pharmaceutically acceptable carrier is an oil, further comprising from about 0.005% to about 30%, more preferably from about 0.5 to about 15%, and in certain embodiments from about 0.005% to about 3.0%, of a pharmaceutically acceptable hydrophilic surfactant (alternatively referred to as an emulsifier), and the nimodipine is substantially contained within micelles.
  • the nimodipine is substantially contained within micelles as a nano-emulsion.
  • the emulsifier is selected from the group consisting of:
  • the phospholipid consisting of a phospholipid and a polyethylene glycol.
  • the polyethylene glycol consisting of a phospholipid and a polyethylene glycol.
  • pharmaceutically acceptable carrier is a beta-cyclodextrin, wherein the nimodipine is
  • the nimodipine formulation is contained within a single infusion bag or bottle for continuous intravenous infusion.
  • the median particle size of nimodipine micelles or nano-emulsions or complex ranges from about 0.5 nanometer to about 350 nanometers, or from about 0.5 nm to about 200 nm, or from about 5 nm to about 50 nm.
  • the nimodipine formulation is clear and does not contain a crystal nimodipine precipitate.
  • the nimodipine formulation is stable.
  • nimodipine formulation via injection or infusion allows first pass
  • the nimodipine formulation is diluted with a suitable pharmaceutical carrier for oral or nasal ingestion (e.g., a suitable aqueous solution).
  • a suitable pharmaceutical carrier for oral or nasal ingestion e.g., a suitable aqueous solution.
  • the aqueous carrier is selected from the group consisting of Sodium Chloride
  • Ringers Injection Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose, and Lactated Ringers Injection.
  • the oil is selected from the group consisting of fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil.
  • the nimodipine formulation further comprises one or more preservatives.
  • suitable preservatives include, e.g., phenols or 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.
  • the hydrophilic surfactant comprises from about0.01% to about 2.5% of the formulation, and in certain preferred embodiments the hydrophilic surfactant comprises at least 0.1% in the diluted nimodipine formulation.
  • the organic solvent comprises at least 1% of the formulation (diluted formulation).
  • the pharmaceutically acceptable carrier comprises from about 0.1% to about 15% of the formulation.
  • the nimodipine formulation has a pH from about 3 to about 9, and in certain preferred embodiments, preferably from about 4.5 to about 7.5 or 8.
  • the invention is directed to a method of preparing a nimodipine formulation (concentrate) for intravenous administration, comprising mixing nimodipine in a concentration from about 0.5 mg/ml to about 5 mg/ml with a pharmaceutically acceptable carrier, such that the pharmaceutically acceptable carrier for injection comprises from about 10% to about 90% of the concentrate; thereafter adding from about 1% to about 15% of a hydrophilic surfactant to prepare a concentrated injection solution, suspension, emulsion or complex; and optionally adding from about 0.5 ml to about 4.0 ml of a pharmaceutically acceptable medium for injection to prepare a nimodipine concentrate formulation.
  • the nimodipine concentrate formulation is clear and does not contain a crystal nimodipine precipitate.
  • the method may further comprise diluting the nimodipine concentrate in a pharmaceutically acceptable carrier for injection selected from the group consisting of an aqueous solution, an organic solvent, an oil, and a cyclodextrin to a volume from about 50 ml to about 1000 ml, wherein when present the organic solvent comprises less than 2% w/v of the formulation, and the formulation remains a clear solution and displays no crystalline precipitation of nimodipine.
  • a pharmaceutically acceptable carrier for injection selected from the group consisting of an aqueous solution, an organic solvent, an oil, and a cyclodextrin to a volume from about 50 ml to about 1000 ml, wherein when present the organic solvent comprises less than 2% w/v of the formulation, and the formulation remains a clear solution and displays no crystalline precipitation of nimodipine.
  • the median particle size of nimodipine micelles or nano-emulsions or complex ranges from about 0.5 nanometer to about 350 nanometers, or from about 0.5 nm to about 200 nm, or from about 5 nm to about 50 nm.
  • the invention is further directed to a method of treating human patients having a condition selected from 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 an intravenous nimodipine solution in accordance with the present invention over a period of about three weeks.
  • the nimodipine infusion rate may be, e.g., from about 0.05 mg nimodipine per hour to about 5 mg nimodipine per hour.
  • the intravenous nimodipine dose is from about 2 to 10 mg administered every five hours.
  • the nimodipine formulation is administered via intravenous bolus, intravenous infusion, intra-arterial, intraoral, orintranasal using a naso-gastric tube.
  • the method further comprises further diluting to a 2.5 x 10 "5 mole solution of nimodipine to rinse the exposed arteries after clipping the aneurysm and before an intravenous infusion of nimodipine administered to improve patient outcome.
  • the diluted formulation may be contained within an infusion set and bag.
  • the infusion bag is covered with ultraviolet light (UV) protective bags to further protect the nimodipine from photo-degradation.
  • UV ultraviolet light
  • the nimodipine formulation is administered as a continuous infusion. In methods of the invention, first pass metabolism by the liver is minimized and bioavailability is improved. Consistent levels of nimodipine are therefore maintained in the plasma and CSF of the (e.g., human) patient.
  • the nimodipine infusion concentrate is introduced into an appropriate infusion bag (e.g., 250 ml bag containing saline, dextrose, etc.) and the nimodipine is infused into the human patient over a time period of about 12 hours as a continuous infusion.
  • Bayer's Nimotop ® infusion solution is infused via the central vein (probably because the high alcohol content necessitates co-infusion of dextrose and lactate ringer).
  • the infusion solution of the present invention is formulated to be infused via the peripheral vein (which is much less invasive than via the central vein).
  • the infusion solution of the invention can be infused via the peripheral or central vein.
  • the present invention relates to a novel pharmaceutical composition containing nimodipine base or any acceptable pharmaceutical salt as active for continuous parenteral administration.
  • the present invention available in particular in the form of a solution for parenteral administration that is a sterile preservative free premix ready for infusion with no further dilution required prior to administration.
  • the present invention available in particular in the form of a solution for parenteral administration that is in the form of a concentrated injectable solution which can be diluted down in an appropriate medium (e.g. saline) to a solution for administration by infusion.
  • an appropriate medium e.g. saline
  • unit dose refers to physically discrete units suitable as unitary dosages for mammalian subjects, each unit containing as the active ingredient a predetermined quantity of the nimodipine.
  • suitable unit doses of nimodipine in accordance with the invention include clear solution or micelles or nano-emulsion in suitable containers, e.g., in a ampule or vial.
  • a “therapeutically effective amount” means the amount that, when administered to an animal for treating a disease, is sufficient to effect treatment for that disease.
  • treating includes preventing the disease from occurring in an animal that may be predisposed to the disease but does not yet experience or exhibit symptoms of the disease (prophylactic treatment), inhibiting the disease (slowing or arresting its development), providing relief from the symptoms or side-effects of the disease (including palliative treatment), and relieving the disease (causing regression of the disease).
  • the term “stable” with respect to the concentrate intravenous infusion solution comprising the water- insoluble nimodipine and surfactant(s) means that there is less than about 5% degradation (and preferably less than 4%, or less than 3%, or less than 2%, or less than 1.5%, or less than 1% degradation) of the nimodipine and no observable precipitate after storage for 48 hours; or that the nimodipine micelle structure is thermally stable during a terminal sterilization process by autoclaving at 121°C for 30 minutes, in that the mean diameter of the colloidal structures does not change by more than about 50 nanometer comparing the colloidal structures before and after the terminal sterilization process, or both.
  • parenteral as used herein, includes subcutaneous injections, intravenous, intramuscular, intrasternal
  • Figure 1 is a graphical representation of the nimodipine concentration of the formulation of Example 3 at the tested concentrations (0.2 mg/ml, 0.02 mg/ml and 0.01 mg/ml) in 0.9% sodium chloride solution;
  • Figure 2 is a graphical representation of the nimodipine concentration of the formulation of Example 3 at the tested concentrations (0.2 mg/ml, 0.02 mg/ml and 0.01 mg/ml) in 5% dextrose solution;
  • Figure 3 is a graphical representation of the nimodipine concentration of the formulation of Example 3 at the tested concentrations (0.2 mg/ml, 0.02 mg/ml and 0.01 mg/ml) in Lactated Ringer's solution;
  • Figure 4 is a graphical representation of the concentration of the nimodipine formulation of Example 3 over time, where the formulation is at a nimodipine concentration of 2 mg/ml and contained in an amber colored vial and in a clear glass vial and exposed to UV light;
  • Figure 5 is a graphical representation of the micelle distribution of Example 3 prior to terminal sterilization; and [0045] Figure 6 is a graphical representation of the micelle distribution of Example 3 after terminal sterilization.
  • Figure 7 is a graphical representation of the mean plasma concentration-time profile of nimodipine following reference (oral solution) and intravenous continuous infusion
  • test product (Example 14) in rats.
  • Figure 8 is a graphical representation of the mean CSF concentrations of
  • nimodipine in rats treated with nimodipine intravenous continuous infusion formulation was treated with nimodipine intravenous continuous infusion formulation.
  • Figure 9 is a graphical representation of the plasma concentrations standard deviation (SD) of nimodipine in rats when treated with nimodipine intravenous continuous infusion and reference oral solution.
  • SD standard deviation
  • Nimodipine is a dihydropyridine calcium antagonist.
  • Nimodipine is isopropyl2 - methoxyethyl 1, 4 - dihydro - 2, 6 - dimethyl - 4 - (m-nitrophenyl) - 3, 5 - pyridinedicarboxylate. It has a molecular weight of 418.5 and a molecular formula of C21H26N207.
  • Nimodipine inhibits calcium ion transfer into these cells and thus inhibits contractions of vascular smooth muscle. The contractile processes of smooth muscle cells are dependent upon calcium ions, which enter these cells during depolarization as slow ionic transmembrane currents.
  • nimodipine had a greater effect on cerebral arteries than on arteries elsewhere in the body perhaps because it is highly lipophilic, allowing it to cross the blood-brain barrier; concentrations of nimodipine as high as 12.5 ng/mL have been detected in the cerebrospinal fluid of nimodipine- treated subarachnoid hemorrhage (SAH) patients.
  • SAH subarachnoid hemorrhage
  • Nimodipine as a pale yellow crystalline powder almost insoluble in water(2.5 ⁇ g/ml, 25°
  • the present invention aims to resolve solubility deficiencies of previously approved nimodipine dosage forms by the development of a robust, stable, and easy to administer nimodipine infusion injection.
  • Another objective of the present invention is to provide the composition and preparation of the nimodipine infusion solution and its administration.
  • excipients include organic solvents, surfactants, triglycerides, cyclodextrins and phospholipids.
  • nimodipine formulation in Europe includes 23.7% ethanol.
  • the intravenous nimodipine formulation of the present invention is a solution comprising nimodipine, a hydrophilic
  • nimodipine is dissolved in a small amount of organic solvent by mixing and further this nimodipine solution is combined with a hydrophilic surfactant to form micelles of nimodipine in a clear solution.
  • One aspect of the present invention is directed to a nimodipine injection concentrate.
  • the nimodipine is mixed with a pharmaceutically acceptable carrier to prepare a concentrated injection solution, suspension, emulsion or complex. Thereafter, an
  • a hydrophilic surfactant is added.
  • a pharmaceutically acceptable medium for injection is added in a relatively small quantity (e.g., 5 ml) in order to prepare the final nimodipine concentrate formulation.
  • the concentrate may be prepared by dissolving the nimodipine in a small amount of organic solvent, e.g., by mixing. Thereafter, in certain preferred embodiments, the resulting nimodipine solution is combined with an effective amount of a hydrophilic surfactant to form micelles of nimodipine in a clear solution. Thereafter, a
  • suitable pharmaceutical medium for injection e.g., water for injection
  • the organic solvent may be, e.g., ethanol 95%
  • the hydrophilic surfactant may be polysorbate 80.
  • the resultant formulation includes stable micelles comprising nimodipine.
  • the concentrate may be prepared by admixing a suitable amount of nimodipine to an organic solvent and the hydrophilic surfactant together for a sufficient period of time to form stable micelles. Thereafter, a suitable pharmaceutical medium for injection (e.g., water for injection) is added to prepare the final nimodipine concentrate.
  • a suitable pharmaceutical medium for injection e.g., water for injection
  • the organic solvent may be, e.g., polyethylene glycol, and the hydrophilic surfactant may be polysorbate 80.
  • the organic solvent comprises at least 25% (and at least 40% in certain embodiments) of the formulation in injection concentrate and at least 1% in final diluted injection solution.
  • the solvent comprises from about 10 to about 90 %, and preferably from greater than 30% to about 90% by weight in injection concentrate and from about 0.1 to about 4 % in final diluted injection solution.
  • the concentrate may be prepared by admixing a suitable amount of nimodipine to a pharmaceutically acceptable oil carrier and a hydrophilic surfactant until a clear solution is obtained, and adding at least one pharmaceutically acceptable emulsifier to make a nano-emulsion and/or a self-emulsifying concentrate formulation.
  • the self- emulsifying formulation forms a nano-emulsion once diluted with water for injection or any commonly available intravenous infusion solutions.
  • the nimodipine is preferably in the oil phase preferably soybean oil, medium chain glycerides, oleic acid, ethyl oleate with other pharmaceutical acceptable excipients either alone or in combination with emulsifiers and water for injection.
  • the emulsifier may be, e.g., phospholipid Lipoid 80 and/or PEG 400.
  • the median particle size of micelles or nano-emulsions ranges from about 0.5 nanometer to about 350 nanometers.
  • the oil carrier comprises from about 1% to about 30% of the formulation in injection concentrate and from about 0.005 % to about 3% of the final diluted injection solution.
  • the oil comprises from about 5% to about 20% of the formulation, by weight in injection concentrate and from about 0.025% to about 2% in final diluted injection solution.
  • the amount of emulsifier may comprise from about 1% to about 30% of the formulation in the injection concentrate and from about 0.005% to about 3% of the final diluted injection solution.
  • a suitable amount of nimodipine together with the hydrophilic surfactant is admixed into a suitable amount of a cyclodextrin (e.g., beta- cyclodextrin) in water for a sufficient period of time to form a stable nimodipine inclusion complex.
  • a cyclodextrin e.g., beta- cyclodextrin
  • the cyclodextrin preferably comprises from about 5% to about 45% of the formulation in injection concentrate and from about 0.025% to about 4.5% of the final diluted injection solution.
  • the hydrophilic surfactant is selected from the hydrophilic surfactant
  • the hydrophilic surfactant comprises at least about 8% of the formulation in the injection concentrate and at least 0.1% in the final diluted injection solution.
  • the hydrophilic surfactant comprises from about 1% to about 15% of the formulation, by weight of the injection
  • the hydrophilic surfactant comprises a
  • non-ionic surfactant is preferably included in an amount sufficient to inhibit precipitation of drug substance from the
  • Non- ionic surfactants form stable micelles with drug substance, can solubilize the drug and may impart additional photo stability to the drug.
  • hydrophilic surfactants are considered those compounds having an HLB value greater than 10 particularly from 12 to 17.
  • the hydrophilic non-ionic surfactant is more soluble in water than in oil (having HLB higher than 10).
  • Non-ionic surfactants useful in the formulations of the present invention include but are not limited to, for example, polyoxyethylene compounds, ethoxylated alcohols, ethoxylated esters, ethoxylated amides, polyoxypropylene compounds, propoxylated alcohols, ethoxylated/propoxylated block polymers, and propoxylated esters, alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols, ethylene glycol esters, diethylene glycol esters, propylene glycol esters, glyceryl esters, polyglyceryl fatty acid esters, sorbitan esters, sucrose esters, and glucose (dextrose) esters.
  • reaction products of a natural or polyethoxylated castor oil and ethylene oxide may have an ethylene oxide content of 25 to 100 moles ethylene oxide per molecule, preferably 35 to 60 moles ethylene oxide per molecule.
  • the natural or polyethoxylated castor oil may be reacted with ethylene oxide in a molar ratio of from about 1:35 to about 1:60, with optional removal of the polyethoxylated component from the products.
  • Non-ionic hydrophilic surfactants useful in the present invention further include alkylgluceosides; alkylmaltosides; alkylthioglucosides; lauryl macro golglycenides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty (mono- and di-) acid esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglyceryl fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols and analogues thereof; polyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member selected from the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, in sterols; sugar esters, sugar ethers; sucroglycerides; fatty acid salts, bile salts
  • the nonionic surfactant may comprise, for example, polyoxyethylene fatty alcohol esters, sorbitan fatty acid esters (Spans), polyoxyethylene sorbitan fatty acid esters (e.g., polyoxyethylene (20) sorbitan monooleate (Tween 80), polyoxyethylene (20) sorbitan monostearate (Tween 60), polyoxyethylene (20) sorbitan monolaurate (Tween 20) and other Tweens, sorbitan esters, glycerol esters, e.g., Myrj and glycerol triacetate (triacetin), polyethylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, polysorbate 80, poloxamers, poloxamines, polyoxyethylene castor oil derivatives (e.g., Cremophor® RH40, Cremphor A25, Cremphor A20, Cremophor® EL) and other Cremophors, sulfos,
  • PEG polyethylene glycol
  • esters of lauric acid, oleic acid, and stearic acid are most useful.
  • Examples of the same include PEG-8 laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG- 10 laurate, PEG- 10 oleate, PEG- 12 laurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 laurate and PEG-20 oleate.
  • Polyethylene glycol fatty acid esters are also suitable for use as surfactants in the compositions of the present invention, such as PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG- 30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate.
  • the hydrophilic surfactant may further comprise mixtures of any of the foregoing.
  • Polysorbate 80 an especially preferred hydrophilic non-ionic surfactant in the formulations of the present invention, is a surfactant commonly used in protein parenteral formulations to minimize denaturation at the air-water interface. Polysorbate 80 is also sometimes used in injectable solution formulations of small molecules for the purpose of solubility enhancement due to micelle formation. Polysorbates are nonionic surfactants of sorbitan esters. Polysorbates useful in the present invention include, but are not limited to polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (Tween 80) and any combinations or mixtures thereof. Other suitable preferred surfactants includes poloxamer, poloxamer 407, transcutol.
  • the surfactant can be any surfactant suitable for use in pharmaceutical compositions. Suitable surfactants can also be ionic hydrophilic surfactants or hydrophobic surfactants. Suitable hydrophilic surfactants can be anionic, cationic, zwitterionic or non-ionic, although non-ionic hydrophilic surfactants are presently preferred.
  • the nimodipine formulations of the invention include at least one non-ionic hydrophilic surfactant.
  • the nimodipine formulations may include mixtures of two or more non-ionic hydrophilic surfactants, as well as mixtures containing at least one non- ionic hydrophilic surfactant and at least one hydrophobic surfactant.
  • the surfactant can be one or more of the surfactants described in U.S. Patent No. 6,363,471, hereby incorporated byreference.
  • the organic solvent is an alcohol (e.g., ethanol) and the solubilizer is polysorbate.
  • the nimodipine is solubilized using surface active agents as solubilizers via the formation of colloidal particles called micelles and stabilized by using co-solvents and/or appropriate substrates in the aqueous formulation.
  • the liquid formulations are suitable for use as parenteral, nasal or oral administration.
  • Water- miscible surfactant molecules like polysorbate consists of both hydrophobic and hydrophilic portions that can solubilize select poorly water-soluble drugs.
  • Surfactants can also self-assemble to form micelles once the surfactant monomer concentration reaches the critical micelle concentration. Thus, surfactants can solubilize drug molecules by either a direct co- solvent effect or by uptake into micelles.
  • the non-ionic surfactants in commercially available solubilized oral and injectable formulations include polyoxyl 35 castor oil (CremophorEL), polyoxyl 40
  • Span 80 polyoxyl 40 stearate
  • various polyglycolyzed glycerides including Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14, and Softigen 767.
  • nimodipine formulation preferably forms colloidal structures (micelles) about 10 nm in diameter.
  • the mean diameter of the colloidal structures varies from about 0.5 nm to about 200 nm and more preferably about 5 nm to about 50 nm.
  • the nimodipine micelle structure is thermally stable during a terminal sterilization process by autoclaving at 121°C for 30minutes.
  • the formulation may include, forexample, an oil carrier sin the form of commercially available emulsions including Intralipid (10-20% soybean oil), Liposyn (10-20% safflower oil), and Lipofundid MCT/TCL (5-10% soybean oil and medium-chain triglycerides).
  • an oil carrier sin the form of commercially available emulsions including Intralipid (10-20% soybean oil), Liposyn (10-20% safflower oil), and Lipofundid MCT/TCL (5-10% soybean oil and medium-chain triglycerides).
  • the nimodipine is oil-soluble, and can be formulated for intravenous administration in an oil-in-water emulsion because the nimodipine partitions into the oil phase.
  • the nimodipine injectable formulation is a cyclodextrin inclusion complex.
  • Suitable cyclodextrins include but are not limited to a ⁇ - cyclodextrin such as hydroxy-propyl-P-cyclodextrin and a ⁇ -cyclodextrin comprising one or more hydroxybutyl sulfonate moieties such as sulfobutyl-ether-P-cyclodextrin, alpha- cyclodextrins, gamma-cyclodextrins, and cyclodextrins as described in U.S. Pat. No. 6,610,671 or U.S. Pat. No.
  • the nimodipine injectable formulation comprises a beta-cyclodextrin inclusion complex formed by the continuous mixing of nimodipine, hydrophilic surfactant and beta-cyclodextrin for 48 to 78 hours with occasional heating at about 60 degrees in a water bath to increase complex formation.
  • Any suitable pharmaceutically acceptable water- miscible organic solvent can be used in the present invention. Selection of a suitable organic solvent will depend in part upon the solubility of the active material (nimodipine) in the solvent, the degree to which the solvent is miscible in water, and the tolerability of the solvent.
  • the solvent should be physiologically acceptable. Examples of solvents that may be used in the present invention include, but are not limited to, various alcohols such as ethanol, glycols, glycerin, propylene glycol, and various polyethylene glycols and dimethyl isosorbide (DMI).
  • various alcohols such as ethanol, glycols, glycerin, propylene glycol, and various polyethylene glycols and dimethyl isosorbide (DMI).
  • Additional useful alcohols include but are not limited to methanol (methyl alcohol), ethanol, (ethyl alcohol), 1-propanol (n-propyl alcohol), 2-propanol (isopropyl alcohol), 1-butanol (n-butyl alcohol), 2-butanol (sec -butyl alcohol), 2- methyl- 1-propanol (isobutyl alcohol), 2-methyl-2-propanol (t-butyl alcohol), 1-pentanol (n- pentyl alcohol), 3 -methyl- 1-butanol (isopentyl alcohol), 2,2-dimethyl- 1-propanol (neopentyl alcohol), cyclopentanol (cyclopentyl alcohol), 1-hexanol (n-hexanol), cyclohexanol (cyclohexyl alcohol), 1- heptanol (n-heptyl alcohol), 1-octanol (n-octyl alcohol), 1-nonanol (n
  • diphenylmethanol diphenylmethanol (diphenylcarbinol), triphenylmethanol (triphenylcarbinol), glycerin, phenol, 2- methoxyethanol, 2-ethoxyethanol, 3-ethoxy-l,2-propanediol, Di(ethylene glycol) methyl ether,
  • the emulsifier may be a pharmaceutically acceptable polyethylene glycol.
  • Polyethylene glycol is available in many different grades having varying molecular weights.
  • polyethylene glycol is available as PEG 200; PEG 300; PEG 400; PEG 540 (blend); PEG 600; PEG 900; PEG 1000; PEG 1450; PEG 1540; PEG 2000; PEG 3000; PEG 3350; PEG 4000; PEG 4600 and PEG 8000.
  • the polyethylene glycol used to prepare the nimodipine concentrate is preferably PEG 400.
  • nimodipine concentrates of the invention may be contained in any pharmaceutically acceptable container (e.g., ampules, vials) in a unit dose for later dilution (e.g., at the site and time of administration to a human patient).
  • any pharmaceutically acceptable container e.g., ampules, vials
  • a unit dose for later dilution e.g., at the site and time of administration to a human patient.
  • the injectable nimodipine formulations of the invention are preferably clear and contain the nimodipine in micelles or inclusion complexes, etc. which can be diluted with a pharmaceutically acceptable carrier for injection (e.g., water for injection) to produce a pharmaceutically acceptable carrier for injection (e.g., water for injection) to produce a pharmaceutically acceptable carrier for injection (e.g., water for injection) to produce a pharmaceutically acceptable carrier for injection (e.g., water for injection) to produce a pharmaceutically acceptable carrier for injection (e.g., water for injection) to produce a pharmaceutically acceptable carrier for injection (e.g., water for injection) to produce a pharmaceutically acceptable carrier for injection (e.g., water for injection) to produce a pharmaceutically acceptable carrier for injection (e.g., water for injection) to produce a pharmaceutically acceptable carrier for injection (e.g., water for injection) to produce a pharmaceutically acceptable carrier for injection (e.g., water for injection) to produce a pharmaceutically acceptable carrier for injection (e
  • the diluted nimodipine formulation is stable, i.e., the nimodipine does not phase separate across a broad range of temperatures at a wide range of water hardness and a wide range of pH.
  • the nimodipine injection is stable, i.e., the nimodipine does not phase separate across a broad range of temperatures at a wide range of water hardness and a wide range of pH.
  • the nimodipine formulation allows for administration of a single 250 ml infusion bag or bottle that contains rV nimodipine comprising, e.g., less than 2% or less than 1% w/v alcohol in a predominantly aqueous medium, a distinct improvement over rV Nimotop.
  • rV nimodipine comprising, e.g., less than 2% or less than 1% w/v alcohol in a predominantly aqueous medium, a distinct improvement over rV Nimotop.
  • This lower alcohol content in the formulation provides many advantages known to those skilled in the art, for example, making the inventive nimodipine formulation amenable for administration to patients suffering from alcoholism, impaired alcohol metabolism and those who are pregnant and breast feeding.
  • the present invention is a micellar formulation of nimodipine that provides for greatly enhanced aqueous solubility and stability including photo- stability. Nimodipine does not
  • the nimodipine injection concentrate is diluted in an infusion bag containing water for injection or any commonly available intravenous infusion solution.
  • Infusion volumes can range from about 50 ml to about 1000 ml.
  • the current invention provides for dilution of formulation in a single infusion bag and infused over a specific period unlike Bayer's Nimotop intravenous injection which requires a three-way stopcock auxiliary to infuse Nimotop solution along with two other co-infusion solutions to prevent any drug precipitation.
  • the current invention provides for a single infusion solution that does not precipitate upon dilution and/or administration thus improving safety and efficacy.
  • the nimodipine injection can be further diluted to a 2.5x 10 "5 mole solution of nimodipine to rinse the exposed arteries after clipping the aneurysm and before an intravenous infusion of nimodipine administered to improve patient outcome.
  • the novel solvent free (e.g., less than l%w/v organic solvent such as ethanol) nimodipine formulation can be administered intravenous bolus, intravenous infusion, intra-arterial, intraoral, intranasal using a naso-gastrictube.
  • organic solvent such as ethanol
  • the infusion set and bag can be covered with ultraviolet light (UV) protective bags to further protect it from photo-degradation.
  • UV ultraviolet light
  • the compounds of the invention may be administered parenterally in formulations eventually containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired.
  • Injectable preparations for example sterile injectable aqueous or oleaginous suspensions may be formulated according to known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • the acceptable vehicles and solvents are water, Ringer's solution and isotonic sodium chloride.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono or diglycerides, in addition fatty acids such as oleic acid find use in the preparation of injectables.
  • Suitable carriers for intravenous administration include physiological saline or phosphate buffered saline (PBS), and solutions containing solubilizing agents, such as glucose, polyethylene glycol, and
  • the formulation may include an aqueous vehicle.
  • Aqueous vehicles include, byway of example and without limitation, Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose, and Lactated Ringers Injection.
  • Nonaqueous parenteral vehicles include, by way of example and without limitation, fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil.
  • Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple dose containers which include phenols or 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, mixtures of the foregoing and the like.
  • Isotonic agents include, by way of example and without limitation, sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride.
  • Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose and
  • Emulsifying agents include Polysorbate 80 (TWEEN® 80) [A
  • nimodipine formulations of the invention may additionally include physiologically acceptable components such as sodium chloride and like materials conventionally used to achieve isotonicity with typical body fluids, pH buffers to establish a physiologically compatible pH range and to enhance the solubility of the nimodipine, preservatives, stabilizers and antioxidants and the like.
  • the injectable formulations after dilution with water for injection and other commonly available intravenous infusion solutions will be from about 3 to about 9, and in certain preferred embodiments from about 4.5 to about 8.
  • the pH is adjusted using a pharmaceutically acceptable buffer or alkalizing agent, with suitable alkalizing agents and buffers including but not limited to NaOH, KOH, triethylamine, meglumine, L-Arginine, sodium phosphate buffer (either sodium phosphate tribasic, sodium phosphate dibasic, sodium phosphate monobasic, or o-phosphoric acid), sodium bicarbonate, and mixtures of any of the foregoing.
  • the formulation may be made isotonic via the addition of a tonicity agent, such as but not limited to any pharmaceutically acceptable sugar, salt or any combinations or mixtures thereof, such as, but not limited to dextrose and sodium chloride.
  • a tonicity agent such as but not limited to any pharmaceutically acceptable sugar, salt or any combinations or mixtures thereof, such as, but not limited to dextrose and sodium chloride.
  • the tonicity agents may be present in an amount from about lOOmOsm/kg to about 500mOsm/kg, or from about 200mOsm/kg to about 400mOsm/kg, or from about 280mOsm/kg to about
  • Drug stability is the ability of the pharmaceutical dosage form to maintain its physical, chemical, therapeutic and microbial properties during the time of storage and usage by the patient.
  • Drug dosage can not be used after known and unknown impurity levels exceed the limit, per guidelines set by ICH.
  • some products of drug degradation are toxic and harmful to patients.
  • oxidative degradation is one major factor. This oxidative degradation rate is directly proportional to the amount of oxygen available to drug, in the formulation. Temperature increases oxidative degradation.
  • oxidative degradation rate is directly proportional to the amount of oxygen available to drug, in the formulation. Temperature increases oxidative degradation.
  • Our experimental studies indicate that a lower concentration of over head space and dissolved oxygen provides additional stability to thenimodipine IV formulation.
  • Deaerated WFI for formulation preparation and inert gas blanketing (purging with an inert gas) while processing and during the filling process provide a robust stable nimodipine IV drug formulation.
  • the dissolved oxygen content should be about 2.0 ppm in the nimodipine formulation and head space oxygen content should be less than 5 %.
  • the nimodipine formulations of the invention are preferably chemically stable up to at least 48 hours for continuous infusion.
  • intravenous nimodipine solution can treat conditions such as, but not limited to, aneurysms, 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.
  • conditions such as, but not limited to, aneurysms, 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.
  • Nimodipine is indicated for the treatment of ischaemic neurological deficits following aneurysmal subarachnoid haemorrhage.
  • Nimotop ® 0.02% solution for infusion the recommended treatment is as follows: for the first two hours of treatment 1 mg of nimodipine, i.e. , 5 ml Nimotop solution, (about 15 ⁇ g/kg bw/h), should be infused each hour via a central catheter. If it is well tolerated, the dose should be increased after two hours to 2 mg nimodipine, i.e. 10 ml Nimotop solution per hour (about 30 ⁇ g/kg bw/h), providing no severe decrease in blood pressure is observed.
  • Nimotop capsules are also available in the U.S. for oral administration, each one containing 30 mg of nimodipine in a vehicle of glycerin, peppermint oil, purified water and polyethylene glycol 400.
  • the oral dose is 60 mg every 4 hours for 21 consecutive days, preferably not less than one hour before or two hours after meals.
  • the IV nimodipine solution can be continuously infused over a period of about 3 weeks.
  • the rate of infusion can be titrated based on patient tolerance and avoiding a decrease in blood pressure.
  • the preferred infusion rate is from about 0.05 mg nimodipine per hour to about 5 mg nimodipine per hour. A dose titration is not possible with currently US FDA approved oral do sage forms.
  • the IV nimodipine dose is reduced to about 2 to 10 mg every five hours compared to the current approved oral dose of 60 mg every four hours without reduction in drug product efficacy and safety.
  • the current US FDA approved oral nimodipine drug product has high first-pass metabolism resulting in numerous metabolites, all of which are either inactive or considerably less active than the parent compound. The bioavailability of nimodipine averages 13% after oral administration. The first-pass metabolism is avoided via intravenous administration, and intra-subject (patient) variability associated with current approved oral dosage forms is reduced.
  • the single bag and or bottle continuous intravenous infusion of the nimodipine formulations of the invention is a convenient way to administer the effective concentration of nimodipine to unconscious patient and to patient having difficulty in swallowing oral dosage forms.
  • Examples 1 - 4 were prepared as follows: nimodipine 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. The volume was then increased to 5 ml with water for injection to prepare nimodipine injection concentrate formulations. The nimodipine injection concentrates can be diluted with any quantity of commonly used intravenous infusion solutions.
  • Table 1 The ingredients of Examples 1 - 4 are set forth in Table 1 below: Table 1
  • Example 3 The nimodipine formulation of Example 3 was tested in dilution studies performed with different commonly used intravenous infusion solutions (0.9% sodium chloride, 5% dextrose, and Lactated Ringer's solution) to understand the chemical interaction and to observe if nimodipine crystals precipitate after dilution. Nimodipine crystal precipitation was not observed following dilution of this formulation with these three different IV infusion solutions, as indicated in the Table 2 below.
  • Figure 1 is a graphical representation of the nimodipine concentration of the formulation of Example 3 at the tested concentrations (0.2 mg/ml, 0.02 mg/ml and 0.01 mg/ml) in
  • Figure 2 is a graphical representation of the nimodipine concentration of the formulation of Example 3 at the tested concentrations (0.2 mg/ml, 0.02 mg/ml and 0.01 mg/ml) in 5% dextrose solution.
  • Figure 3 is a graphical representation of the nimodipine concentration of the formulation of Example 3 at the tested concentrations (0.2 mg/ml, 0.02 mg/ml and 0.01 mg/ml) in Lactated Ringer's solution.
  • Example 3 The concentrate formulation of Example 3 was also exposed to UV light under controlled UV camber for 48 hours to understand the photo degradation of this novel nimodipine formulation.
  • the nimodipine formulation was kept in amber color and clear glass vial under the same condition. As shown in Table 3 below, no photo degradation was observed in both amber and clear glass vials. This result supports the conclusion that the concentrate (micelle) formulation of Example 3 provides photo-stability to nimodipine.
  • Figure 4 is a graphical representation of the duration of UV light exposure of the nimodipine formulation of Example 3 where the formulation is at a nimodipine concentration of 2 mg/ml and contained in an amber colored vial and in a clear glass vial. The plot shows the nimodipine concentration over time.
  • a nimodipine concentrate is prepared as follows: Add nimodipine to polysorbate 80 and polyethylene glycol 400 while stirring and mix for 30 minutes to form stable micelles and make the volume up to 5 ml with water for injection. Benzyl alcohol added as preservative. This nimodipine injection concentrate can be diluted with any quantity of commonly used intravenous infusion solutions.
  • Table 4 The formulations of Examples 6-8 are set forth in more detail in Table 4 below:
  • a nimodipine concentrate is prepared as follows: Add nimodipine to polysorbate 80 and soybean oil while stirring and mix till clear solution is observed and
  • Phospholipid Lipoid 80 and PEG 400 as emulsifiers to make a nano-emulsion and/or self emulsifying formulation.
  • This nimodipine injection concentrate can be diluted with any quantity of commonly used intravenous infusion solution to form nano-emulsions.
  • the formulations of Examples 9-11 are set forth in more detail in Table 5 below:
  • Example 12 a nimodipine concentrate is prepared as follows: Add beta- cyclodextrin to water for injection while stirring and mix for 15 minutes and add nimodipine and polysorbate 80 while stirring to above dispersion and mix for 48 hours to get clear solution.
  • Heating was applied using a water bath heated up to 60 degrees to increase the rate of inclusion complex.
  • Example 12 The formulation of Example 12 is set forth in more detail in Table 6 below:
  • Example 13 the nimodipine concentrate of Example 3 is subjected to a terminal sterilization process by autoclaving at 121°C for 30 minutes.
  • Figure 5 is a graph showing micelle size distribution of Example 3 before terminal sterilization with a peak at a particle size diameter of approximately 10 nm. The size distribution was measured using a Malvern Zetasizer Nano ZS at a temperature of 25 °C.
  • Figure 6 is a graph showing micelle size distribution of Example 3 after terminal sterilization (autoclaved at 121°C for 30 minutes) with a peak at a particle size diameter of approximately 10 nm. Size distribution was measured using a Malvern Zetasizer Nano ZS at a temperature of 25°C. Based on these results, the formulation of Example 3 is considered to be stable.
  • Example 14
  • Example 14 The formulation of Example 14 was prepared as follows: nimodipine 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 was then added to the solution to generate 5 ml of nimodipine injection concentrate. The nimodipine injection concentrate can be further diluted with any amount of commonly used intravenous infusion solutions.
  • the ingredients of Examples 14 are set forth in Table 7 below:
  • Example 3 100 mL ready to infuse
  • Example 14 5 mL
  • test formulation was a single 0.73 mg dose (concentration of 0.182mg/ml after dilution with D5W infusion solution) of nimodipine administered as a continuous intravenous infusion at a controlled rate over a period of 4 hours (continuous infusion).
  • the reference product was a nimodipine 5.5 mg oral solution Nymalize (the oral bioavailability of nimodipine averages 13% and hence oral dose was adjusted
  • Blood samples were collected at 15 minutes, 30 minutes, and at 1, 2, 4, 6, 8, 12 and 24 hours post-dose.
  • CSF samples were collected at 1, 2, 4, and 24 hours post-dose. All samples were analyzed using a validated analytical LC-MS method.
  • Table 14 Plasma and CSF concentrations of nimodipine in rats treated with the nimodipine
  • nimodipine Consistent levels of nimodipine was observed in the CSF over the duration of infusion of a single dose of 0.73 mg administered over 4 hours. The range of nimodipine CSF levels was measured at 1.26 - 1.56 ng/ml. Consistent nimodipine CSF concentrations were achieved within 1 hour of infusion. The CSF/Plasma ratio was found to be consistent up to 4 hours of infusion with ranges between 0.0064 - 0.0075. Plasma and CSF concentrations of nimodipine in rats treated with nimodipine intravenous continuous infusion formulation are reported in Table 14 and Figure 8.
  • micellar nimodipine formulation of the invention is administered as a continuous intravenous infusion, first pass metabolism by the liver is minimized and resulting in improved bioavailability. Consistent levels of nimodipine are therefore maintained in plasma and CSF.
  • nimodipine concentrate and diluted formulations may be made using different but equivalent methods, and that these formulations may use other surfactants, carriers and emulsifiers beyond those specifically mentioned herein. Such obvious modifications are considered to be within the scope of the appended claims.

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Abstract

La présente invention concerne un concentré d'injection de nimodipine et une formulation diluée comprenant de la nimodipine (base ou sel), une quantité efficace d'un tensioactif hydrophile, un excipient pharmaceutiquement acceptable pour injection qui est une solution aqueuse, un solvant organique, une huile ou une cyclodextrine, de telle sorte que la nimodipine soit sensiblement contenue dans une solution, suspension, émulsion ou complexe d'injection concentré sous forme de micelle, de particule colloïdale ou de complexe d'inclusion et que la formulation soit stable et claire. Dans certains modes de réalisation, le tensioactif hydrophile est du polysorbate 80.
PCT/US2018/040038 2017-06-30 2018-06-28 Formulation parentérale stable de nimodipine WO2019006134A1 (fr)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
US4879308A (en) * 1987-08-11 1989-11-07 Lyphomed, Inc. Aqueous nitroglycerin injection and manufacturing process
US20040180005A1 (en) * 2001-05-21 2004-09-16 Jurgens Kai Christian Method for the production of nanodispersions
CN101129366A (zh) * 2007-08-23 2008-02-27 沈阳万爱普利德医药科技有限公司 一种尼莫地平药物组合物及其制备方法
US20090253722A1 (en) * 2008-04-08 2009-10-08 Arpida Ag Aqueous pharmaceutical formulation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4879308A (en) * 1987-08-11 1989-11-07 Lyphomed, Inc. Aqueous nitroglycerin injection and manufacturing process
US20040180005A1 (en) * 2001-05-21 2004-09-16 Jurgens Kai Christian Method for the production of nanodispersions
CN101129366A (zh) * 2007-08-23 2008-02-27 沈阳万爱普利德医药科技有限公司 一种尼莫地平药物组合物及其制备方法
US20090253722A1 (en) * 2008-04-08 2009-10-08 Arpida Ag Aqueous pharmaceutical formulation

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