LIQUID FORMULATION

• US 20150148335A1
• Filed: 05/17/2013
• Published: 05/28/2015
• Est. Priority Date: 05/18/2012
• Status: Active Grant

• Current Assignee: Luoda Pharma Limited
• Original Assignee: Luoda Pharma Pty Ltd
• Inventors: Bova, Nicholas, Page, Stephen, Pippia, Giuseppe
• Granted Patent: US 9,808,529 B2
• Time in Patent Office: Days
• US Class Current: 514/212.07
• 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 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 15/14 for lactation disorders, e.g. galactorrhoea
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/12 Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

The invention relates to a liquid formulation comprising propylene glycol and an effective amount of an inodilator, an angiotensin converting enzyme inhibitor, or a combination of an inodilator and an angiotensin converting enzyme inhibitor and to use of the formulation for treating cardiac disease and/or hypertension.

Claims

1. A liquid formulation comprising propylene glycol and an effective amount of an inodilator, an angiotensin converting enzyme inhibitor, or a combination of an inodilator and an angiotensin converting enzyme inhibitor.

5. The formulation of any one of claims 1, 2 and 4, wherein the inodilator is selected from the group consisting of pimobendan, levosimendan, aminone, enoximone, milrinone, olprinone, vesnarinone and pharmaceutically or veterinary acceptable salts thereof, or a combination thereof.

6. The formulation of claim 5, wherein the inodilator is pimobendan or a pharmaceutically or veterinary acceptable salt thereof.

7. The formulation of any one of claims 1, 3 and 4, wherein the angiotensin converting enzyme inhibitor is selected from the group consisting of enalapril, benazepril, alacepril, captopril, cilazapril, delapril, fosinopril, imidapril, moexipril, spirapril, temocapril, trandolapril, zofenopril, ramipril, quinapril, perindopril, lisinopril and pharmaceutically and veterinary acceptable salts thereof, or a combination thereof.

8. The formulation of claim 7, wherein the angiotensin converting enzyme inhibitor is selected from the group consisting of enalapril, benazepril and pharmaceutically and veterinary acceptable salts thereof.

9. The liquid formulation of any one of claims 1 to 8, further comprising one or more further active agents.

10. The formulation of claim 9, wherein the further active agent is a diuretic.

11. The formulation of claim 10, wherein the diuretic is selected from the group consisting of furosemide, hydrochlorothiazide, chlorthalidone, bumetanide, ethacrynic acid, torasemide, chlorothiazide, spironolactone, triamterene, amiloride and pharmaceutically or veterinary salts thereof, or a combination thereof.

12. The formulation of claim 11, wherein the diuretic is furosemide or a pharmaceutically or veterinary acceptable salt thereof.

13. The formulation of any one of claims 1, 2 and 4 to 12, wherein the inodilator is present in an amount of about 0.1 wt % to about 50 wt % of the total formulation.

14. The formulation of any one of claims 9 to 13, wherein the further active agent is present in an amount of about 0.1 wt % to about 50 wt % of the total formulation.

15. The formulation of any one of claims 1, 3 to 14, wherein the angiotensin converting enzyme inhibitor is present in an amount of about 0.1 wt % to about 50 wt % of the total formulation.

16. The formulation of any one of claims 1 to 13, wherein the propylene glycol is present in an amount of about 0.1 wt % to about 99 wt % of the total formulation.

17. The formulation of any one of claims 1 to 16, wherein the formulation further comprises one or more pharmaceutically or veterinary acceptable excipient(s).

18. The formulation of claim 17, wherein the pharmaceutically or veterinary acceptable excipient is selected from the group consisting of a surfactant, a viscosity modifier, a flavour enhancer, a preservative, and a solvent or a combination thereof.

19. The formulation of claim 18, wherein the surfactant is selected from the group consisting of acetoglycerides, diethylene glycol esters, diethylene glycol ethers, ethylene glycol esters, glyceryl behenate, glyceryl mono- and di-esters, glyceryl monocaprylocaprate, glyceryl monolinoleate, glyceryl mono-oleate, glyceryl stearates, macrogol cetostearyl ethers, macrogol/glycerol esters, macrogol 6 glyceryl caprylocaprate, macrogol 20 glyceryl monostearate, macrogol 15 hydroxystearate, macrogol laurates, macrogol lauril ethers, macrogol monomethyl ethers, macrogol oleates, macrogol oleyl ethers, macrogol 40 sorbitol heptaoleate, macrogol stearates, macrogolglycerol cocoates, nonoxinols, octoxinols, oleyl oleate, palmitic acid, poloxamers, polyoxyl castor oils, polyoxyl hydrogenated castor oils, polysorbates (e.g. polysorbate 80, polysorbate 60, polysorbate 40, polysorbate 20, etc.), polyvinyl alcohol, propylene glycol caprylates, propylene glycol diacetate, propylene glycol laurates, propylene glycol monopalmitostearate, quillaia, sorbitan esters, sucrose esters, triglycerol diisostearate, and tyloxapol, or a combination thereof.

20. The formulation of claim 18 or claim 19, wherein the surfactant is present in an amount of about 1 wt % to about 99 wt % of the total formulation.

21. The formulation of any one of claims 18 to 20, wherein the viscosity modifier is selected from the group consisting of polyethylene glycol, polypropylene glycol, microcrystalline cellulose, polyvinyl pyrrolidine and hydroxypropyl cellulose, or a combination thereof.

22. The formulation of any one of claims 18 to 21, wherein the viscosity modifier is present in an amount of about 0.05 wt % to about 50 wt % of the total formulation.

23. The formulation of any one of claims 18 to 22, wherein the preservative is selected from the group consisting of benzoic acid, sodium benzoate, sodium propionate, sorbic acid, benzyl alcohol, bronopol, chlorbutol, phenoxyethanol, o-phenoxyethanol, chlorhexidine salts, hydroxybenzoate derivatives, phenylmercuric salts, thiomersal, chlorocresol, cresol, phenol, benzalkonium chloride, cetrimide, alpha-tocopherol, ascorbic acid, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene and sodium metabisulfite, or a combination thereof.

24. The formulation of any one of claims 18 to 23, wherein the preservative is present in an amount of about 0.001 wt % to 10 wt % of the total formulation.

25. The formulation of any one of claims 18 to 24, wherein the flavour enhancer is selected from the group consisting of acesulfame potassium, alitame, aspartame, acesulfame, benzaldehyde, caramel, cyclamic acid, denatonium benzoate, dibutyl sebacate, erythritol, ethyl acetate, ethyl cinnamate, ethyl maltol, ethyl vanillin, maltol, monosodium glutamate, neohesperidin dihydrochalcone, neotame, raspberry, red cherry, saccharin, saffron, stevioside, sucrose octa-acetate, thaumatin, theobroma, tributyl acetylcitrate, vanilla, vanillin, xylitol, dextrose, sucrose or glucose, or a combination thereof.

26. The formulation of any one of claims 18 to 25, wherein the flavour enhancer is present in an amount of about 0.1 wt % to about 40 wt % of the total formulation.

27. The formulation of any one of claims 18 to 26, wherein the solvent is selected from the group consisting of glycerol, ethanol, propenol, butanol, amyl acetate, amylene hydrate, butylenes glycol, glycerol formol, hexylene glycol, polyethylene glycol, PEG300, glycofurol, pyrrolidone, propylene glycol diacetate, canola oil, olive oil, castor oil and peanut oil, or a combination thereof.

28. The formulation of any one of claims 18 to 27, wherein the solvent is present in an amount of about 1 wt % to about 99.94 wt %.

29. The formulation of any one of claims 1 to 28, wherein the formulation is suitable for oral administration.

30. The formulation of any one of claims 1 to 28, wherein the formulation is suitable for parenteral administration.

31. The formulation of any one of claims 1 to 30 which is a veterinary or a human pharmaceutical formulation.

32. The formulation of claim 31 which is a veterinary formulation.

33. The formulation of any one of claims 1 to 32, wherein the formulation is diluted with water.

34. A method of treating cardiac disease and/or hypertension, comprising administering the liquid formulation of any one of claims 1 to 33 to a subject in need thereof.

35. The method of claim 34, wherein cardiac disease is a primary heart disease selected from the group consisting of congestive heart failure (CHF), acute CHF, chronic CHF, decompensated endocardiosis (DCE), dilated cardiomyopathy (DCM), asymptomatic (occult) CHF, asymptomatic DCM, and chronic valvular heart disease, or a combination thereof.

36. The method of claim 34, wherein cardiac disease is a secondary heart disease is selected from the group consisting of cardiovascular dysfunction and impaired renal perfusion during anaesthesia, shock, gastric dilation, volvulus, myocardial ischaemia, and renal ischaemia, or a combination thereof.

37. The method of any one of claims 34 to 36, wherein the subject is a companion animal.

38. The method of claim 37, wherein the subject is a dog or a cat.

39. The method of any one of claims 34 to 38, wherein the administration is oral administration.

40. The method of any one of claims 34 to 38, wherein the administration is parenteral administration.

41. A process for the preparation of the formulation of any one of claims 1 to 33 which comprises mixing an effective amount of an inodilator or an angiotensin converting enzyme inhibitor with propylene glycol.

2. A liquid formulation comprising an effective amount of an inodilator and propylene glycol.

3. A liquid formulation comprising an effective amount of an angiotensin converting enzyme inhibitor and propylene glycol.

4. A liquid formulation comprising propylene glycol and an effective amount of a combination of an inodilator and an angiotensin converting enzyme inhibitor.

42. A kit comprising a first formulation comprising an effective amount of an inodilator, and a second formulation comprising an effective amount of an angiotensin converting enzyme inhibitor, wherein the first and second formulations are held separately and at least one of the first and the second formulations comprises propylene glycol.

43. A kit comprising a first formulation comprising an effective amount of an inodilator or an angiotensin converting enzyme inhibitor and a second formulation comprising a further active agent, wherein the first and second formulations are held separately and at least one of the first and the second formulations comprises propylene glycol.