LIPOSOMAL FORMULATIONS COMPRISING AN AMPHIPATHIC WEAK BASE LIKE TEMPAMINE FOR TREATMENT OF NEURODEGENERATIVE CONDITIONS

• US 20110027351A1
• Filed: 10/13/2010
• Published: 02/03/2011
• Est. Priority Date: 09/09/2004
• Status: Abandoned Application

• Current Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem)
• Original Assignee: Hadasit Medical Research Services & Development Ltd (Hadassah, The Women's Zionist Organization of America, Inc.), Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem)
• Inventors: Barenholz, Yechezkel, Ovadia, Haim, Kizelsztein, Pablo
• Application Number:
  US12/903,266
• Publication Number:
  US 20110027351A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 31/45 having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
• 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 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• 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 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Provided is the use of an amphipathic weak base having defined characteristics for the preparation of a pharmaceutical formulation for the treatment or prevention of neurodegenerative conditions. The amphipathic weak base can be encapsulated in a liposome. Also provided are pharmaceutical formulations and methods of use thereof for the treatment or prevention of neurodegenerative conditions. A specific and amphipathic weak base is tempamine (TMN). Further, tempamine can be loaded in sterically stabilized liposomes (SSL-TMN).

Claims

1-51. -51. (canceled)

52. A method of treating a subject having, or in disposition of developing, amyotrophic lateral sclerosis (ALS), the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising an amphipathic weak base, the amount being effective to treat or prevent the development of ALS, wherein said amphipathic weak base has one or more of the following characteristics:

(i) it has pKa below 11.0;

(ii) in an n-octanol/buffer system having a pH of 7.0, it has a partition coefficient in the range between 0.001 and 5.0;

(iii) it exhibits an antioxidative activity; and

(iv) it exhibits a pro-apoptotic activity.

53. The method of claim 52, wherein the amphipathic weak base is characterized by a pKa below 11.0 and a partition coefficient in the range between 0.001 and 5.0.

54. The pharmaceutical formulation of claim 52, wherein the partition coefficient is in the range of between 0.005 and 0.5.

55. The method of claim 52, wherein the formulation comprises a liposome encapsulating the amphipathic weak base.

56. The method of claim 55, wherein the liposome comprises a combination of phospholipid, cholesterol and a lipopolymer.

57. The method of claim 56, wherein the phospholipid is egg phosphatidylcholine (EPC), 1-palmitoyl-2-oleoylphosphatidyl choline (POPC), distearoylphosphatidylcholine (DSPC) or hydrogenated soy phosphatidylcholine (HSPC).

58. The method of claim 56, wherein the combination comprises EPC:

Chol;

²⁰⁰⁰PEG-DSPE or HSPC;

Chol;

²⁰⁰⁰PEG-DSPE at a mole ratio of 54;

41;

5.

59. The method of claim 52, wherein the amphipathic weak base is TMN.

60. The method of claim 52, comprising parenteral administration of the pharmaceutical formulation.

61. The method of claim 60, wherein the parenteral administration comprises administration by injection.

62. A method of treating a subject having, or in disposition of developing amyotrophic lateral sclerosis (ALS), the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising tempamine, the amount being effective to treat or prevent the development of ALS.

63. The method of claim 62, wherein the formulation comprises a liposome encapsulating tempamine.

64. The method of claim 63, wherein the liposome comprises a combination of phospholipid, cholesterol and a lipopolymer.

65. The method of claim 63, wherein the phospholipid is egg phosphatidylcholine (EPC), 1-palmitoyl-2-oleoylphosphatidyl choline (POPC), distearoylphosphatidylcholine (DSPC) or hydrogenated soy phosphatidylcholine (HSPC).

66. The method of claim 65, wherein the combination comprises EPC:

Chol;

²⁰⁰⁰PEG-DSPE or HSPC;

Chol;

²⁰⁰⁰PEG-DSPE at a mole ratio of 54;

41;

5.

67. The method of claim 62, comprising parenteral administration of the pharmaceutical formulation.

68. The method of claim 67, wherein the parenteral administration comprises administration by injection.