Compositions and methods for dosing liposomes of certain sizes to treat or prevent disease

• US 20040009216A1
• Filed: 03/31/2003
• Published: 01/15/2004
• Est. Priority Date: 04/05/2002
• Status: Abandoned Application

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Bisgaier, Charles L., Rodrigueza, Wendi V.
• Application Number:
  US10/403,402
• Publication Number:
  US 20040009216A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• 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 9/06 Antiarrhythmics
• 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

Abstract

The present invention relates to pharmaceutical compositions comprising liposomes and methods of using such liposomes to prevent, treat, or manage a variety of diseases and/or bodily conditions. The liposomes may comprise large unilamellar vesicles (LUVs) alone or in combination with multilamellar vesicles (MLVs), small unilamellar vesicles (SUVs), or other therapeutics. The invention relates to liposomes having certain diameters administered to patients using specific doses and/or dosing regimens.

Claims

1. A method for preventing, treating, or managing a disease or bodily condition comprising administering liposomes between 50 mg/kg and 300 mg/kg in single or divided doses, said liposomes comprising phospholipids and an aqueous layer, said liposomes having an average diameter between about 50 nm and 250 nm.

2. The method of claim 1 , wherein the liposomes are administered in a dose between 50 mg/kg and 300 mg/kg at 4-10 day interval

3. The method of claim 1 wherein the liposomes have an average diameter of between about 50 and 150 nm.

4. The method of claim 1 wherein the liposomes have an average diameter of between about 50 and 200 nm.

5. The method of claim 1 wherein the liposomes have an average diameter of between about 100 and 200 nm.

6. The method of claim 1 wherein the liposomes have an average diameter of between about 100 and 250 nm.

7. The method of claim 1 wherein the liposomes have an average diameter of between about 150 and 200 nm.

8. The method of claim 1 wherein the liposomes have an average diameter of between about 150 and 250 nm.

9. The method of claim 5 wherein the liposomes are administered in combination with other phospholipid vesicles selected from the group consisting of multilamellar vesicles, large unilamellar vesicles, small unilamellar vesicles, and mixtures thereof.

10. The method of claim 1 which does not cause a substantial increase or decrease in the LDL levels of the subject.

11. The method of claim 1 which does cause a substantial increase or decrease in the LDL levels of the subject.

12. The method of claim 1 in which the phospholipid is selected from the group consisting of egg phosphatidylcholine, egg phosphatidylglycerol, distearoylphosphatidylcholine, or distearoylphosphatidylglycerol, phosphatidylcholine, phosphatidylglycerol, lecithin, beta, glycolipids, gamma-dipalmitoyl-alpha-lecithin, sphingomyelin, phosphatidylserine, phosphatidic acid, N-(2,3-di(9-(Z)-octadecenyloxy))-prop-1-yl-N,N,N-trimethylammonium chloride, phosphatidylethanolamine, lysolecithin, lysophosphatidylethanolamine, phosphatidylinositol, cephalin, cardiolipin, cerebrosides, dicetylphosphate, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, dioleoylphosphatidylglycerol, palmitoyl-oleoyl-phosphatidylcholine, di-stearoyl-phosphatidylcholine, stearoyl-palmitoyl-phosphatidylcholine, di-palmitoyl-phosphatidylethanolamine, di-stearoyl-phosphatidylethanolamine, di-myrstoyl-phosphatidylserine, di-oleoyl-phosphatidylcholine, oleoyl-palmitoyl phosphatidylcholine, a lipid which is in a liquid-crystalline phase at 370°

C., and mixtures thereof.

13. The method of claim 1 wherein the phospholipid is palmitoyl-oleoyl phosphatidylcholine.

14. The method of claim 1 wherein the disease or bodily condition is selected from the group consisting of atherosclerosis, phlebosclerosis or any venous condition in which deposits of plaques containing cholesterol or other material are formed within the intima or inner media of veins, acute coronary syndromes, angina including, stable angina, unstable angina, inflammation, vascular inflammation, dermal inflammation, congestive heart failure, coronary heart disease (CHD), ventricular arrythmias, peripheral vascular disease, myocardial infarction, onset of fatal myocardial infarction, non-fatal myocardial infarction, ischemia, cardiovascular ischemia, transient ischemic attacks, ischemia unrelated to cardiovascular disease, ischemia-reperfusion injury, decreased need for revascularization, coagulation disorders, thrombocytopenia, deep vein thrombosis, pancreatitis, non-alcoholic steatohepatitis, diabetic neuropathy, retinopathy, painful diabetic neuropathy, claudication, psoriasis, critical limb ischemia, impotence, hyperlipidemia, hyperlipoproteinemia, hypoalphalipoproteinemia, hypertriglyceridemia, any stenotic condition leading to ischemic pathology, diabetes including both Type I and Type II, ichtyosis, stroke, vulnerable plaques, Alzheimer'"'"'s disease, lower-limb ulceration, severe coronary ischemia, lymphomas, cataracts, endothelial dysfunction, xanthomas, end organ dysfunction, vascular disease, vascular disease that results from smoking and diabetes, carotid and coronary artery disease, regress and shrink established plaques, unstable plaques, vessel intima that is weak, unstable vessel intima, endothelial injury, endothelial damage as a result of surgical procedures, morbidity associated with vascular disease, ulcerations in the arterial lumen, restenosis as a result of balloon angioplasty, and subindications of the foregoing.

15. The method of claim 1 wherein the treatment strengthens the vessel wall intima, stimulates efflux of extracellular cholesterol for transport to the liver, modulates immune responses, mobilizes cholesterol from atherosclerotic plaques, aids in wound healing, modifies any bodily membrane, cell, tissue, organ, extracellular region, or structure.

16. The method of claim 1 wherein the liposomes are administered in combination with or are adjunctively bound to compounds selected from the group consisting of peptides, paraoxonase, lipoprotein lipase, Apo A-I and mimetics, variants of A-I, and combinations thereof.

17. The method of claim 1 wherein the liposomes are administered in combination with small molecules or drugs that affect cholesterol levels.

18. The method of claim 17 wherein the small molecule is a statin, reconstituted HDL, small HDL, or synthetic mimetic HDL lipoprotein particle.

19. The method of claim 1 wherein the liposomes are administered in combination with one or more cardiovascular agents, anti-diabetic agents, or other therapeutic substances.

20. The method of claim 19 wherein the cardiovascular agent is selected from the group consisting of small molecules, statins, aspirin, beta-blockers including clopidodrel, calcium blockers, heparin including low molecular weight heparin, glucose lowering agents, nitrates, IIb/IIIa inhibitors, ACE inhibitors, fibrates, and bile acid sequestrants.

21. The method of claim 1 wherein the liposomes are administered in a dose of about 50 mg/kg about every 7 days.

22. The method of claim 1 wherein the liposomes are administered in a dose of about 100 mg/kg about every 7 days.

23. The method of claim 1 wherein the liposomes are administered in a dose of about 150 mg/kg about every 7 days.

24. The method of claim 1 wherein the liposomes are administered in a dose of about 200 mg/kg about every 7 days.

25. The method of claim 1 wherein the liposomes are administered in a dose of about 250 mg/kg every 7 days.

26. The method of claim 1 wherein the liposomes are administered in a dose of about 300 mg/kg every 7 days.

27. The method of claim 1 wherein the liposomes are administered once.

28. The method of claim 1 wherein the liposomes are administered twice at 4-7 day intervals.

29. The method of claim 1 wherein the liposomes are administered three times at 4-7 day intervals.

30. The method of claim 1 wherein the liposomes are administered four times at 4-7 day intervals.

31. The method of claim 1 wherein the liposomes are administered five times at 4-7 day intervals.

32. The method of claim 1 wherein the liposomes are administered six times at 4-7 day intervals.

33. The method of claim 1 wherein the liposomes are administered seven times at 4-7 day intervals.

34. The method of claim 1 wherein the liposomes are administered eight times at 4-7 day intervals.

35. The method of claim 1 wherein the liposomes are administered nine times at 4-7 day intervals.

36. The method of claim 1 wherein the liposomes are administered ten times at 4-7 day intervals.

37. The method of claim 1 wherein the liposomes are administered eleven times at 4-7 day intervals.

38. The method of claim 1 wherein the liposomes are administered twelve times at 4-7 day intervals.

39. The method of claim 1 wherein the liposomes are administered thirteen times at 4-7 day intervals.

40. The method of claim 1 wherein the liposomes are administered fourteen times at 4-7 day intervals.

41. The method of claim 1 wherein the liposomes are administered 2-14 times at weekly intervals.

42. The method of claim 1 wherein the liposomes are administered 2-14 times at two week intervals.

43. The method of claim 1 wherein the liposomes are administered 2-14 times at monthly intervals.

44. The method of claim 1 wherein the liposomes are administered 2-14 times at 2 month intervals.

45. The method of claim 1 wherein the liposomes are administered 2-14 times at 3 month intervals.

46. The method of claim 1 wherein the liposomes are administered 2-14 times at 4 month intervals.

47. The method of claim 1 wherein the liposomes are administered 2-14 times at 5 month intervals.

48. The method of claim 1 wherein the liposomes are administered 2-14 times at 6 month intervals.

49. The method of claim 1 wherein the liposomes are administered 2-14 times at 7 month intervals.

50. The method of claim 1 wherein the liposomes are administered 2-14 times at 8 month intervals.

51. The method of claim 1 wherein the liposomes are administered 2-14 times at 9 month intervals.

52. The method of claim 1 wherein the liposomes are administered 2-14 times at 10 month intervals.

53. The method of claim 1 wherein the liposomes are administered 2-14 times at 11 month intervals.

54. The method of claim 1 wherein the liposomes are administered 2-14 times at 3 year intervals.

55. The method of claim 1 wherein the liposomes are administered 2-14 times at 4 year intervals.

56. A method of reducing cholesterol in peripheral tissue while reducing or avoiding adverse effects associated with liposome therapy which comprises administering to a patient in need thereof a dose of between 100 mg/kg to 200 mg/kg of liposomes having an average particle size between 50 nm and 250 nm.

58. The method of claim 56 wherein the administration is made once every 7 days.

59. The method of claim 56 wherein the administration is made 6 to 14 times.

61. The method of claim 59 further comprising administering said liposomes in combination with one or more cardiovascular agents, antidiabetic and/or glycemic control agents, and/or other therapeutic agents.

57. A method of preventing or treating a disease or disorder associated with abnormal cholesterol levels which comprises administering to a patient in need thereof doses from 100 mg/kg to 200 mg/kg of liposomes, said administration being made in a single or multiple dose every 7 or more days.

60. A method of reducing cholesterol in a diseased human which comprises administering to said human liposomes in a dose of 100 mg/kg to 200 mg/kg every 4 or more days, said liposomes having an average diameter of between 50 nm and 250 nm.