Liposomal Compositions of Glucocorticoid and Glucocorticoid Derivatives

• US 20080058294A1
• Filed: 09/11/2005
• Published: 03/06/2008
• Est. Priority Date: 09/09/2004
• Status: Active Grant

• Current Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem)
• Original Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem)
• Inventors: Gabizon, Alberto, Barenholz, Yechezkel, Avnir, Yuval
• Granted Patent: US 8,932,627 B2
• Time in Patent Office: Days
• US Class Current: 514/169
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/18 of the parathyroid hormones
• CPC Class Codes: A61P 5/38 : of the suprarenal hormones
• CPC Class Codes: A61P 5/44 : Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics

Abstract

The present invention provides pharmaceutical compositions comprising a glucocorticoid or glucocorticoid derivative stably encapsulated in a liposome. The glucocorticoid or glucocorticoid derivative is selected from an amphipathic weak base glucocorticoid or glucocorticoid derivative having a pKa equal or below 11 and a logD at pH 7 in the range between −2.5 and 1.5; or an amphipathic weak acid GC or GC derivative having a pKa above 3.5 and a logD at pH 7 in the range between −2.5 and 1.5. The therapeutic effect of the pharmaceutical composition of the invention was exhibited in vivo with appropriate models of multiple sclerosis and cancer.

Claims

1-36. -36. (canceled)

37. A pharmaceutical composition comprising a glucocorticoid (GC) or GC derivative encapsulated in a liposome, wherein said GC or GC derivative is essentially retained in said liposome for 6 months, the GC or GC derivative being selected from:

i) an amphipathic weak base GC or GC derivative having a pKa equal or below 11 and a logD at pH 7 in the range between −

2.5 and 1.5;

ii) an amphipathic weak acid GC or GC derivative having a pKa above 3 and a logD at pH 7 in the range between −

2.5 and 1.5.

38. The pharmaceutical composition of claim 37, wherein said GC or GC derivative is selected from an amphipathic weak base having a pKa equal or below 11 and a logD at pH 7 in the range between −

1.5 and 1.0;

or an amphipathic weak acid GC or GC derivative having a pKa above 3.5 and a logD at pH 7 in the range between −

1.5 and 1.0.

39. The pharmaceutical composition of claim 37, wherein said GC derivative is a pro-drug which is converted to an active GC upon release thereof from said liposome into a body fluid.

40. The pharmaceutical composition of claim 37, wherein said GC derivative is an acidic glucocorticoid.

41. The pharmaceutical composition of claim 40, wherein said acidic GC is selected from methylprednisolone sodium hemisuccinate (MPS), hydrocortisone sodium hemisuccinate (HYD), Dexamethasone hemisuccinate, Prednisolone hemisuccinate.

42. The pharmaceutical composition of claim 37, wherein said liposome comprises a phospholipid.

43. The pharmaceutical composition of claim 42, wherein said liposome comprises a combination of a phospholipid, a lipopolymer and cholesterol.

44. The pharmaceutical composition of claim 43, wherein said liposome comprises a combination hydrogenated soybean phosphatidylcholine (HSPC), polyethylene glycol coated distearoyl phosphatidyl ethanolamine (PEG-DSPE) and cholesterol.

45. The pharmaceutical composition of claim 37, wherein the liposome is a sterically stabilized liposome (SSL).

46. The pharmaceutical composition of claim 42, comprising a mole ratio between said GC or GC derivative and said phospholipid of between 0.01 and 2.0.

47. The pharmaceutical composition of claim 46, wherein the mole ratio between said GC or GC derivative and said phospholipid is between 0.04 and 0.25.

48. The pharmaceutical composition of claim 37, for the treatment of neurodegenerative disorders.

49. The pharmaceutical composition of claim 48, for the treatment of multiple sclerosis.

50. The pharmaceutical composition of claim 37, for the treatment of cancer.

51. A method for delivery of a glucocorticoid (GC) to a target site within a body comprising chemically modifying said GC to an amphipathic weak acid derivative or amphipathic weak based derivative thereof, and loading said amphipathic weak acid derivative or amphipathic weak base derivative into a liposome, wherein the GC or GC derivative being selected from:

i) an amphipathic weak base GC or GC derivative having a pKa equal or below 11 and a logD at pH 7 in the range between −

2.5 and 1.5;

ii) an amphipathic weak acid GC or GC derivative having a pKa above 3 and a logD at pH 7 in the range between −

2.5 and 1.5.

52. The method of claim 51, wherein said GC is a water immiscible GC.

53. The method of claim 51, wherein said liposome is a sterically stabilized liposome.

54. The method of claim 51, wherein said GC derivative is loaded into the liposome by the formation of an ion or pH gradient across the liposome membrane.

55. A method for treatment of a disease or disorder comprising administration to a subject in need of said treatment a pharmaceutical composition comprising a glucocorticoid (GC) or GC derivative encapsulated in a liposome, wherein said GC or GC derivative is essentially retained in said liposome for 6 months, the GC or GC derivative being selected from:

i) an amphipathic weak base GC or GC derivative having a pKa equal or below 11 and a logD at pH 7 in the range between −

2.5 and 1.5;

ii) an amphipathic weak acid GC or GC derivative having a pKa above 3 and a logD at pH 7 in the range between −

2.5 and 1.5.

56. The method of claim 55, for the treatment of neurodegenerative disorder.

57. The method of claim 55, for the treatment of multiple sclerosis.

58. The method of claim 55, for the treatment or cancer.