Liposomal mitigation of drug-induced inhibition of the cardiac ikr channel

• US 10,349,884 B2
• Filed: 01/11/2017
• Issued: 07/16/2019
• Est. Priority Date: 06/03/2011
• Status: Active Grant

• Current Assignee: SignPath Pharma, Inc.
• Original Assignee: SignPath Pharma, Inc.
• Inventors: Helson, Lawrence, Shopp, George M., Bouchard, Annie
• Primary Examiner(s): Roney, Celeste A
• Application Number:
  US15/403,831
• Publication Number:
  US 20170119802A1
• Time in Patent Office: 916 Days
• Field of Search: None
• CPC Class Codes: A61B 2503/42 for laboratory research
• CPC Class Codes: A61B 5/364 Detecting abnormal ECG interval, e.g. extrasystoles, ectopic heartbeats
• CPC Class Codes: A61B 5/4848 Monitoring or testing the effects of treatment, e.g. of medication
• 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 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 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/127 Liposomes

Abstract

Compositions and methods are provided for preventing one or more cardiac channelopathies or conditions resulting from irregularities or alterations in cardiac patterns, or both, in a human or animal subject comprising: one or more pharmacologically active agents that causes at least one of I_Kr channel inhibition or QT prolongation by inhibiting the activity of an ether-a-go-go-related gene (hERG); and one or more liposomes, wherein the liposomes are empty liposomes and administered prior to, concomitantly, or after administration of the pharmacologically active agent.

Claims

1. A composition for treating IKr channel inhibition or QT prolongation caused by a pharmacologically active agent, in a human or animal subject consisting of:

one or more pharmacologically active agents at a therapeutically effective amount that causes the at least one of IKr channel inhibition or QT prolongation by inhibiting the activity of an ether-a-go-go-related gene; and

one or more liposomes, wherein the liposomes are empty liposomes and administered prior to, concomitantly, or after administration of the pharmacologically active agent, wherein the empty liposomes are provided in an amount effective to reduce the at least one of IKr channel inhibition or QT prolongation caused by the therapeutically effective amount of the one or more pharmacologically active agents.

2. The composition of claim 1, wherein the one or more active agents is selected from at least one of crizotinib, nilotinib, terfenadine, astemizole, gripafloxacin, terodilene, droperidole, lidoflazine, levomethadyl, sertindoyle or cisapride.

3. The composition of claim 1, wherein the one or more active agents is selected from at least one of:

Aloxi;

Amiodarone;

Arsenic trioxide;

Astemizole;

Bepridil;

Chloroquine;

Chlorpheniramine;

Chlorpromazine;

Cisapride;

Celaxa;

Citalopram;

Clarithromycin;

Erythromycin;

Curcumin;

Disopyramide;

Dofetilide;

Domperidone;

Doxorubicin;

Dronedarone;

Droperidol;

Grepafloxacin;

Haldol;

Haloperidol;

Halofantrine;

Ibutilide;

Levomethadyl;

Lidoflazine;

Loratidine;

Lovostatin;

Mesoridazone;

Methadone;

Methanesulphonanilide;

Moxifloxacin;

Palonasitron;

Pentamadine;

Pimozide;

Prenylamine;

Probucol;

Procainamide;

Propafenone;

Pyrilamine;

Quinidine;

Terfenidine;

Sertindole;

Sotalol;

Sparfloxacin;

Thioridazine;

or Vandetanib.

4. The composition of claim 1, wherein the composition is adapted for enteral, parenteral, intravenous, intraperitoneal, or oral administration.

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

6. The composition of claim 1, wherein the liposomes comprises 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, 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 composition further comprises a pharmaceutically acceptable dispersion medium, solvent, or vehicle, wherein the active agent, the liposome or both are dissolved, dispersed, or suspended in the medium, the solvent, or the vehicle.

8. The composition of claim 1, wherein the liposomes comprise DMPC (1,2-dimyristoil-sn-glycero-3-phosphocholine) and DMPG (1,2-dimyristoyl-sn-glycero-3-phospho-rac-[1-glycerol]).

9. The composition of claim 1, wherein the liposomes comprise a 9.7:

1 ratio of DMPC (1,2-dimyristoil-sn-glycero-3-phosphocholine) and DMPG (1,2-dimyristoyl-sn-glycero-3-phospho-rac-[1-glycerol]).

19. The composition of claim 1, wherein the ether-a-go-go-related gene is hERG.

10. A composition for treating IKr channel inhibition or QT prolongation arising from administration of a therapeutically active agent or a drug in a human that causes at least one of IKr channel inhibition or QT prolongation by inhibiting the activity of an ether-a-go-go-related gene consisting of:

one or more pharmacologically active agents at a therapeutically effective amount that causes the at least one of IKr channel inhibition or QT prolongation and one or more empty liposomes administered prior to, concomitantly, or after administration of the therapeutically active agent or the drug in an amount effective to reduce the IKr channel inhibition or QT prolongation arising from administration of the therapeutically active agent or drug.

11. The composition of claim 10, wherein the one or more active agents is selected from at least one of crizotinib, nilotinib, terfenadine, astemizole, gripafloxacin, terodilene, droperidole, lidoflazine, levomethadyl, sertindoyle or cisapride.

12. The composition of claim 10, wherein the composition is adapted for enteral, parenteral, intravenous, intraperitoneal, or oral administration.

13. The composition of claim 10, wherein the liposomes comprise anionic, cationic, or neutral liposomes.

14. The composition of claim 10, wherein the liposomes comprises 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, 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.

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

16. The composition of claim 10, wherein the liposomes comprise DMPC (1,2-dimyristoil-sn-glycero-3-phosphocholine) and DMPG (1,2-dimyristoyl-sn-glycero-3-phospho-rac-[1-glycerol]).

17. The composition of claim 10, wherein the liposomes comprise a 9.7:

1 ratio of DMPC (1,2-dimyristoil-sn-glycero-3-phosphocholine) and DMPG (1,2-dimyristoyl-sn-glycero-3-phospho-rac-[1-glycerol]).

18. The composition of claim 10, wherein the one or more active agents is selected from at least one of:

Aloxi;

Amiodarone;

Arsenic trioxide;

Astemizole;

Bepridil;

Chloroquine;

Chlorpheniramine;

Chlorpromazine;

Cisapride;

Celaxa;

Citalopram;

Clarithromycin;

Erythromycin;

Curcumin;

Disopyramide;

Dofetilide;

Domperidone;

Doxorubicin;

Dronedarone;

Droperidol;

Grepafloxacin;

Haldol;

Haloperidol;

Halofantrine;

Ibutilide;

Levomethadyl;

Lidoflazine;

Loratidine;

Lovostatin;

Mesoridazone;

Methadone;

Methanesulphonanilide;

Moxifloxacin;

Palonasitron;

Pentamadine;

Pimozide;

Prenylamine;

Probucol;

Procainamide;

Propafenone;

Pyrilamine;

Quinidine;

Terfenidine;

Sertindole;

Sotalol;

Sparfloxacin;

Thioridazine;

or Vandetanib.

20. The composition of claim 10, wherein the ether-a-go-go-related gene is hERG.