Etherlipid-containing multiple lipid liposomes

• US 6,180,137 B1
• Filed: 09/03/1999
• Issued: 01/30/2001
• Est. Priority Date: 02/16/1996
• Status: Expired due to Fees

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: The Liposome Co., Inc. (Perrigo Company PLC)
• Inventors: Ahmad, Imran, Janoff, Andrew S., Mayhew, Eric, Bhatia, Suresh K.
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US09/390,395
• Time in Patent Office: 515 Days
• Field of Search: 424/450, 424/1.21, 424/9.321, 424/9.51, 424/417, 424/94.3, 428/402.2, 436/829
• US Class Current: 424/450
• CPC Class Codes: A61K 31/685 one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
• 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: 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: Y10T 428/2984 Microcapsule with fluid core [includes liposome]

Abstract

Described herein are liposomes containing etherlipids of the formula:

as well as a phosphatidylcholine, a sterol, and a headgroup-derivatized lipid. These liposomes are useful in a variety of therapeutic regimens, including the treatment of cancers and inflammatory disorders.

Claims

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a liposome, the liposome comprising:

a lipid bilayer which comprises;

(a) a phosphatidylcholine;

(b) a sterol;

(c) a headgroup derivatized lipid comprising a phosphatidylethanolamine linked at the ethanolamine group to a moiety selected from the group consisting of dicarboxylic acids, polyethylene glycols, gangliosides and polyalkyl ethers; and

, (d) an etherlipid having the formula;

wherein;

R₁ is Y₁Y₂, Y₂ is CH₃ or CO₂H, Y₁ is (CH₂)_n1(CH═

CH)_n2(CH₂)_n3(CH═

CH)_n4(CH₂)_n5(CH═

CH)_n6(CH₂)_n7 (CH═

CH)_n8(CH₂)₉, the sum of n₁+2n2+n3+2n4+n5+2n6+n7+2n8+n9 is an integer of from 3 to 23, n1 is equal to zero or is an integer of from 1 to 23, n3 is equal to zero or is an integer of from 1 to 20, n5 is equal to zero or is an integer of from 1 to 17, n7 is equal to zero or is an integer of from 1 to 14, n9 is equal to zero or is n integer of from 1 to 11, and each of n2, n4, n6 and n8 is independently zero or 1;

Z is oxygen or sulfur; and

,

the headgroup-derivatized lipid comprises from about 5 mole percent to about 20 mole percent of the liposome'"'"'s lipid bilayer and the etherlipid comprises from greater than about 10 mole percent to less than about 30 mole percent of the bilayer.

2. A method of treating a mammal afflicted with a cancer selected from the group consisting of lung cancers, brain cancers, colon cancers, ovarian cancers, breast cancers, leukemias, lymphomas, sarcomas and carcinomas, the method comprising administering to the mammal an amount of the pharmaceutical composition of claim 1 which comprises from about 0.1 mg of the etherlipid per kg of body weight of the mammal to about 1000 mg per kg.

3. The method of claim 2, comprising administering to the mammal an additional biologically active agent.

4. The method of claim 3, wherein the additional agent is selected from the group consisting of antineoplastic agents, antimicrobial agents, therapeutic lipids and hematopoietic cell growth stimulating agents.

5. The method of claim 2, wherein the liposome is a unilamellar liposome having a diameter of from about 50 nm to about 200 nm.