Protective effect of DMPC, DMPG, DMPC/DMPG, EGPG, LysoPG and LysoPC against drugs that cause channelopathies

• US 10,258,691 B2
• Filed: 06/03/2015
• Issued: 04/16/2019
• Est. Priority Date: 06/03/2014
• Status: Active Grant

• Current Assignee: Avanti Polar Lipids, Inc. (Croda International PLC), SignPath Pharma, Inc.
• Original Assignee: SignPath Pharma, Inc.
• Inventors: Helson, Lawrence, Shopp, George M., Bouchard, Annie, Majeed, Muhammed, Burgess, Stephen W., Shaw, Walter A.
• Primary Examiner(s): Vu, Jake M
• Application Number:
  US14/729,940
• Publication Number:
  US 20150343063A1
• Time in Patent Office: 1,413 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/20 having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• CPC Class Codes: A61K 31/23 of acids having a carboxyl group bound to a chain of seven or more carbon atoms
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/683 Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
• CPC Class Codes: A61K 31/685 one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: G01N 2800/32 Cardiovascular disorders
• CPC Class Codes: G01N 33/5008 for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
• CPC Class Codes: G01N 33/6872 Intracellular protein regulatory factors and their receptors, e.g. including ion channels
• CPC Class Codes: G01N 33/6887 from muscle, cartilage or connective tissue

Abstract

The present invention includes compositions and methods for preventing one or more cardiac channelopathies or conditions resulting from irregularities or alterations in cardiac patterns caused by an active agent or a drug in a human or animal subject comprising: an amount of a lysophosphatidyl compound adapted for oral administration effective to reduce or prevent one or more cardiac channelopathies or conditions resulting from irregularities or alterations in cardiac patterns caused by the active agent or drug. Such compositions may further comprise a monoglyceride, a free fatty acid or a combination of the foregoing, including, e.g., a eutectic mixture.

Claims

1. A method for preventing or treating at least one of IKr channel inhibition or QT prolongation arising from administration of one or more active agents that causes an active agent-induced channelopathy in a human or animal subject comprising the steps of:

identifying the human or animal subject in need of prevention or treatment of a disease treatable with an active agent that causes a drug-induced channelopathy;

providing an amount of a lysophosphatidyl compound adapted for oral administration effective to reduce or prevent one or more cardiac channelopathies or conditions resulting from irregularities or alterations in cardiac patterns caused by one or more active agents, wherein the lysophosphatidyl compound is selected from at least one of 10;

0 LysoPG, 12;

0 LysoPG, 14;

0 LysoPG, 14;

0 EGPG, 16;

0 LysoPG, or 18;

0 LysoPG, wherein the lysophosphatidyl compound enhances the activity of the active agent; and

administering to the human or animal subject a therapeutically effective amount of an active agent that causes an active agent-induced channelopathy, wherein the oral lysophosphatidyl compound reduces or eliminates the channelopathy induced by the therapeutically active agent.

2. The method of claim 1, wherein the active agent has previously failed a clinical trial due to drug-induced IKr channel inhibition or QT prolongation.

3. The method of claim 1, further comprising the step of identifying a drug in a clinical trial that failed or has limited clinical use due to drug-induced IKr channel inhibition or QT prolongation side-effects.

4. The method of claim 1, wherein the one or more active agents are selected from Albuterol (salbutamol), Alfuzosin, Amantadine, Amiodarone, Amisulpride, Amitriptyline, Amoxapine, Amphetamine, Anagrelide, Apomorphine, Arformoterol, Aripiprazole, Arsenic trioxide, Astemizole, Atazanavir, Atomoxetine, Azithromycin, Bedaquiline, Bepridil, Bortezomib, Bosutinib, Chloral hydrate, Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride, Citalopram, Clarithromycin, Clomipramine, Clozapine, Cocaine, Crizotinib, Dabrafenib, Dasatinib, Desipramine, Dexmedetomidine, Dexmethylphenidate, Dextroamphetamine (d-Amphetamine), Dihydroartemisinin and piperaquine, Diphenhydramine, Disopyramide, Dobutamine, Dofetilide, Dolasetron, Domperidone, Dopamine, Doxepin, Dronedarone, Droperidol, Ephedrine, Epinephrine (Adrenaline), Eribulin, Erythromycin, Escitalopram, Famotidine, Felbamate, Fenfluramine, Fingolimod, Flecainide, Fluconazole, Fluoxetine, Formoterol, Foscarnet, Fosphenytoin, Furosemide (Frusemide), Galantamine, Gatifloxacin, Gemifloxacin, Granisetron, Gripafloxacin, Halofantrine, Haloperidol, Hydrochlorothiazide, Ibutilide, Iloperidone, Imipramine (melipramine), Indapamide, Isoproterenol, Isradipine, Itraconazole, Ivabradine, Ketoconazole, Lapatinib, Levalbuterol (levsalbutamol), Levofloxacin, Levomethadyl, Lidoflazine, Lisdexamfetamine, Lithium, Mesoridazine, Metaproterenol, Methadone, Methamphetamine (methamfetamine), Methylphenidate, Midodrine, Mifepristone, Mirabegron, Mirtazapine, Moexipril/HCTZ, Moxifloxacin, Nelfinavir, Nicardipine, Nilotinib, Norepinephrine (noradrenaline), Norfloxacin, Nortriptyline, Ofloxacin, Olanzapine, Ondansetron, Oxytocin, Paliperidone, Paroxetine, Pasireotide, Pazopanib, Pentamidine, Perflutren lipid microspheres, Phentermine, Phenylephrine, Phenylpropanolamine, Pimozide, Posaconazole, Probucol, Procainamide, Promethazine, Protriptyline, Pseudoephedrine, Quetiapine, Quinidine, Quinine sulfate, Ranolazine, Rilpivirine, Risperidone, Ritodrine, Ritonavir, Roxithromycin, Salmeterol, Saquinavir, Sertindole, Sertraline, Sevoflurane, Sibutramine, Solifenacin, Sorafenib, Sotalol, Sparfloxacin, Sulpiride, Sunitinib, Tacrolimus, Tamoxifen, Telaprevir, Telavancin, Telithromycin, Terbutaline, Terfenadine, Terodilene, Tetrabenazine, Thioridazine, Tizanidine, Tolterodine, Toremifene, Trazodone, Trimethoprim-Sulfa, Trimipramine, Vandetanib, Vardenafil, Vemurafenib, Venlafaxine, Voriconazole, Vorinostat, or Ziprasidone.

5. The method of claim 1, further comprising the step of forming a eutectic mixture with the lysophosphatidyl compound.

6. The method of claim 5, wherein the eutectic mixture comprises a free fatty acid and monoglyceride that comprise from about 70 mole to 99 mole percent of the eutectic mixture, with the lysophosphatidyl compound comprising from about 30 mole percent to 1 mole percent of the eutectic mixture.

7. The method of claim 6, wherein the ratios of the components of the eutectic mixture are 1:

4;

2, a 1;

3;

3, a 2;

4;

2, or a 1;

2;

4 mole percent lysophosphatidyl compound;

monoglyceride;

free fatty acid.

8. The method of claim 1, further comprising the step of forming a eutectic mixture with the lysophosphatidyl compound, wherein the eutectic mixture comprises LysoPG:

myristoyl monoglyceride;

myristic fatty.

9. The method of claim 1, wherein a ratio of the lysophosphatidyl compound to active agent is 3:

1, 1;

1, 0.3;

1, and 0.1;

1.

10. A method for preventing or treating at least one of IKr channel inhibition or QT prolongation arising from administration of one or more active agents that causes an active agent-induced channelopathy in a human or animal subject comprising the steps of:

identifying the human or animal subject in need of prevention or treatment of a disease treatable with the one or more active agent that causes a drug-induced channelopathy;

providing an amount of a lysophosphatidyl compound adapted for oral administration effective to reduce or prevent one or more cardiac channelopathies or conditions resulting from irregularities or alterations in cardiac patterns caused by one or more active agents, wherein the lysophosphatidyl compound is selected from at least one of 10;

0 LysoPG, 12;

0 LysoPG, 14;

0 LysoPG, 14;

0 EGPG, 16;

0 LysoPG, 18;

0 LysoPG, or a eutectic thereof, wherein the lysophosphatidyl compound enhances the activity of the active agent; and

administering to the human or animal subject a therapeutically effective amount of an active agent that causes an active agent-induced channelopathy, wherein the oral lysophosphatidyl compound reduces or eliminates the channelopathy induced by the therapeutically active agent.