Combination Therapy

• US 20080058274A1
• Filed: 11/15/2005
• Published: 03/06/2008
• Est. Priority Date: 11/15/2004
• Status: Abandoned Application

• 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: Khazanov, Elena, Barenholz, Yechezkel
• Application Number:
  US11/667,671
• Publication Number:
  US 20080058274A1
• Time in Patent Office: Days
• US Class Current: 514/34
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61K 9/1273 Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances polymers grafted or coated on phosphatidyl liposomes A61K9/1271, on non-phosphatidyl liposomes A61K9/1272
• CPC Class Codes: A61K 9/1278 Post-loading, e.g. by ion or pH gradient
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention concerns a new medical treatment involving the combination of two active entities, as well as pharmaceutical compositions comprising the two active entities. Specifically, the invention provides a pharmaceutical composition comprising a stable lipid assembly comprising as a first active entity an apoptosis-affecting lipid which does not self-aggregate in a polar environment to form liposomes and a lipopolymer. The pharmaceutical composition further comprises, as the second active entity, a cytotoxic amphipathic weak base drug carried by the lipid assembly or by a different liposome. According to one embodiment, the apoptotic-affecting lipid is a pro-apoptotic lipid. A preferred pro-apoptotic lipid is ceramide, preferably C6-ceramide. The cytotoxic amphipathic weak base drug is preferably doxorubicin or a biologically active, anthracyline-based doxorubicin analog thereof.

Claims

1-75. -75. (canceled)

76. A pharmaceutical composition comprising a short chain ceramide selected from C₂, C₄, C₆ or C₈-ceramide, and a lipopolymer forming part of a liposome'"'"'s membrane, the liposome encapsulating a cytotoxic, amphipathic weak base drug.

77. The pharmaceutical composition of claim 76, wherein said short chain ceramide has a hydrophobic region and a polar headgroup, the atomic mass ratio between the headgroup and hydrophobic region being less than 0.3.

78. The pharmaceutical composition of claim 76, wherein said cytotoxic drug is an anthracycline-based drug.

79. The pharmaceutical composition of claim 78, wherein the cytotoxic, amphipathic weak base drug is doxorubicin.

80. The pharmaceutical composition of claim 76, wherein said lipopolymer has a hydrophobic lipid region and a polymer headgroup, wherein the atomic mass ratio between the headgroup and hydrophobic region is at least 1.5.

81. The pharmaceutical composition of claim 76, wherein said lipopolymer has a level of water, tightly bound to its headgroup, of at least about 0.60 molecules of water per lipopolymer headgroup.

82. The pharmaceutical composition of claim 81, wherein said polymer headgroup is polyethylene glycol (PEG).

83. The pharmaceutical composition of claim 82, wherein said PEG has an atomic mass of 2,000 Da (^2kPEG).

84. The pharmaceutical composition of claim 76, wherein said liposome membrane comprises a phospholipid.

85. The pharmaceutical composition of claim 84, wherein said phospholipid is a glycerophospholipid.

86. The pharmaceutical composition of claim 85, wherein said glycerophospholipid is hydrogenated soybean phosphatidylcholine (HSPC).

87. The pharmaceutical composition of claim 76, wherein said ceramide is C₆ ceramide.

88. The pharmaceutical composition of claim 87, wherein said C₆ ceramide is present in said membrane at a molar % of 11.5% of total lipid.

89. The pharmaceutical composition of claim 88, wherein said liposome is stable for at least 6 months when incubated with serum or plasma at 37°

C. with respect to size.

90. The pharmaceutical composition of claim 76, wherein said liposome comprises cholesterol at a mole % which is equal or less than 5%.

92. The pharmaceutical composition of claim 90, wherein the cytotoxic, amphipathic weak base drug is doxorubicin.

93. The pharmaceutical composition of claim 90, wherein said lipopolymer has a hydrophobic lipid region and a polymer headgroup, wherein the atomic mass ratio between the headgroup and hydrophobic region is at least 1.5.

94. The pharmaceutical composition of claim 93, wherein said polymer headgroup is polyethylene glycol (PEG).

95. The pharmaceutical composition of claim 94, wherein said PEG has an atomic mass of 2,000 Da (^2kPEG).

96. The pharmaceutical composition of claim 90, wherein said liposome membrane comprises a phospholipid.

97. The pharmaceutical composition of claim 96, wherein said phospholipid is a glycerophospholipid.

98. The pharmaceutical composition of claim 97, wherein said glycerophospholipid is hydrogenated soybean phosphatidylcholine (HSPC).

99. The pharmaceutical composition of claim 90, wherein said ceramide is C₆ ceramide.

100. The pharmaceutical composition of claim 99, wherein said C₆ ceramide is present in said membrane at a molar % of 11.5% of total lipid.

101. The pharmaceutical composition of claim 90, wherein said liposome comprises cholesterol at a mole % which is equal or less than 5%.

102. A method for the treatment of a disease or disorder comprising administering to a subject in need of said treatment a composition according to claim 76.

103. The method of claim 102, wherein said ceramide is C₆ ceramide, said lipopolymer is PEG and said cytotoxic amphipathic weak base drug is doxorubicin.

104. A method for the treatment of a disease or disorder comprising administering to a subject in need of said treatment a composition according to claim 90.

105. The method of claim 104, wherein said ceramide is C₆ ceramide, said lipopolymer is PEG and said cytotoxic amphipathic weak base drug is doxorubicin.

91. A pharmaceutical composition comprising a short N-acyl chain ceramide or a pro-apoptotic lipid selected from ceramines, sphinganines, sphinganine-1-phosphate, di- or tri-alkylshpingosines and their structural analogs, and a lipopolymer forming part of the liposome'"'"'s membrane, the liposome encapsulating cytotoxic, amphipathic weak base drug.