Liposomal mitigation of drug-induced long QT syndrome and potassium delayed-rectifier current

• US 9,682,041 B2
• Filed: 05/02/2014
• Issued: 06/20/2017
• Est. Priority Date: 06/03/2011
• Status: Active Grant

• Current Assignee: SignPath Pharma, Inc.
• Original Assignee: SignPath Pharma, Inc.
• Inventors: Helson, Lawrence
• Primary Examiner(s): Roney, Celeste A
• Application Number:
  US14/268,376
• Publication Number:
  US 20140242156A1
• Time in Patent Office: 1,145 Days
• Field of Search: None
• CPC Class Codes: A61K 31/12 Ketones
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: Y10S 977/773 Nanoparticle, i.e. structure having three dimensions of 100 nm or less
• CPC Class Codes: Y10S 977/906 Drug delivery
• CPC Class Codes: Y10S 977/907 Liposome

Abstract

Compositions and methods for the treatment of drug-induced long QT syndrome and other cardiac channelopathies are disclosed herein. The compositions and methods of the present invention comprise binding one or more QT prolonging drugs with a liposome prior to parenteral (intravenous or subcutaneous) administration, or administration of an empty liposome prior to or concomitantly with therapeutic agents known to have a high risk of QT prolongation, or immediately following an envenomation. The results presented show an abrogation of the adverse effects of QT prolonging drugs in a dose-dependent manner by the compositions of the present invention.

Claims

1. A composition for treating or preventing drug induced QT prolongation in a human or animal subject comprising:

a combination of i) one or more pharmacologically active agents that induce QT prolongation in the subject; and

ii)

one or more empty liposomes, wherein the empty liposomes are provided in an amount sufficient to prevent or reduce the QT prolongation caused by the one or more pharmacologically active agents, wherein the combination is dispersed in a pharmaceutically acceptable medium, solvent, or vehicle and wherein said combination of i) and ii) reduces hERG current inhibition as compared to i) alone.

2. The composition of claim 1, wherein the one or more active agents comprise palonosetron HCL, Amiodarone, Arsenic trioxide, Astemizole, Bepridil, Chloroquine-Chlorpheniramine, Chlorpromazine, Cisapride, Celaxa, Clarithromycin, Erythromycin, Curcumin, Disopyramide, Dofetilide, Domperidone, Doxorubicin, Dronedarone, Droperidol, Grepafloxacin, Haldol, Haloperidol, Halofantrine, Ibutilide, Levomethadyl, Lidoflazine, Loratidine, Lovostatin, Mesoridazone, Methadone, Methanesulphonanilide (E-4031), Moxifloxacin, Pentamadine, Pimozide, Prenylamine, Probucol, Procainamide, Propafenone, Pyrilamine, Quinidine, Terfenidine, Sertindole, Sotalol, Sparfloxacin, or Thioridazine.

3. The composition of claim 1, wherein the composition is adapted for parenteral or oral administration.

4. The composition of claim 1, wherein the active agent and the liposomes are bound or conjugated together.

5. The composition of claim 1, wherein the liposomes comprise anionic, cationic, or neutral liposomes.

6. The composition of claim 1, wherein the liposomes comprise a lipid or a phospholipid wall, wherein the lipids or the phospholipids are selected from the group consisting of phosphatidylcholine, lysolecithin, lysophosphatidylethanol-amine, phosphatidylserine, phosphatidylinositol, sphingomyelin, phosphatidylethanolamine (cephalin), cardiolipin, phosphatidic acid, cerebrosides, dicetylphosphate, phosphatidylcholine, and dipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine, hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, hexadecyl sterate, isopropyl myristate, amphoteric acrylic polymers, fatty acid, fatty acid amides, cholesterol, cholesterol ester, diacylglycerol, and diacylglycerolsuccinate.

7. The composition of claim 1, wherein the liposomes are spherical liposomes with a diameter ranging from 10 nm-200 nm.

13. The composition of claim 6, wherein the lipids or the phospholipids selected is lecithin.

8. A composition for preventing or treating QT prolongation caused by administration of a therapeutically active agent or a drug in a human or animal subject comprising:

one or more liposomes in combination with a therapeutically active agent or a drug that causes QT prolongation, wherein the liposomes are empty liposomes in an amount sufficient to prevent or reduce the QT prolongation caused by the therapeutically active agent or the drug; and

a pharmaceutically acceptable dispersion medium, solvent, or vehicle, wherein the active agent or drug, the liposome or both are dissolved, dispersed, or suspended in the medium, the solvent, or the vehicle and wherein said combination reduces hERG current inhibition as compared to said active agent or drug alone.

9. The composition of claim 8, wherein the therapeutically active agent or the drug comprises palonosetron HCl, Amiodarone, Arsenic trioxide, Astemizole, Bepridil, Chloroquine-Chlorpheniramine, Chlorpromazine, Cisapride, Celaxa, Clarithromycin, Erythromycin, Curcumin, Disopyramide, Dofetilide, Domperidone, Doxorubicin, Dronedarone, Droperidol, Grepafloxacin, Haldol, Haloperidol, Halofantrine, Ibutilide, Levomethadyl, Lidoflazine, Loratidine, Lovostatin, Mesoridazone, Methadone, Methanesulphonanilide (E-4031), Moxifloxacin, Pentamadine, Pimozide, Prenylamine, Probucol, Procainamide, Propafenone, Pyrilamine, Quinidine, Terfenidine, Sertindole, Sotalol, Sparfloxacin, or Thioridazine.

10. The composition of claim 8, wherein the composition is adapted for parenteral or oral administration.

11. The composition of claim 8, wherein the liposomes comprise anionic, cationic, or neutral liposomes comprising a lipid or a phospholipid wall, wherein the lipids or the phospholipids are selected from the group consisting of phosphatidylcholine, lysolecithin, lysophosphatidylethanol-amine, phosphatidylserine, phosphatidylinositol, sphingomyelin, phosphatidylethanolamine (cephalin), cardiolipin, phosphatidic acid, cerebrosides, dicetylphosphate, phosphatidylcholine, and dipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine, hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, hexadecyl sterate, isopropyl myristate, amphoteric acrylic polymers, fatty acid, fatty acid amides, cholesterol, cholesterol ester, diacylglycerol, and diacylglycerolsuccinate.

14. The composition of claim 11, wherein the lipids or the phospholipids selected is lecithin.

12. A composition for preventing or treating long QT syndrome (LQTS) arising from administration of Terfenidine, or Methanesulphonanilide (E-4031) in a human or animal subject comprising:

i) one or more liposomes, wherein the liposomes are empty liposomes and ii) Terfenidine, or Methanesulphonanilide (E-4031); and

a pharmaceutically acceptable dispersion medium, solvent, or vehicle, wherein the Terfenidine, or Methanesulphonanilide (E-4031), and the liposome are dissolved, dispersed, or suspended in the medium, the solvent, or the vehicle.