Reduction of liposome-induced adverse physiological reactions

• US 5,662,930 A
• Filed: 05/04/1995
• Issued: 09/02/1997
• Est. Priority Date: 05/21/1993
• Status: Expired due to Term

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: The Liposome Co., Inc. (Perrigo Company PLC)
• Inventors: Ahl, Patrick L., Janoff, Andrew S., Bhatia, Suresh K., Minchey, Sharma R.
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US08/433,665
• Time in Patent Office: 852 Days
• Field of Search: 424/450, 424/1.21, 436/829
• US Class Current: 424/450
• 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 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: Y10T 428/2984 Microcapsule with fluid core [includes liposome]

Abstract

Provided herein is a method of administering a liposome composition to an animal, the method involving adminstering to the animal a liposome composition containing an adverse physiological reaction-reducing effective amount of a liposome which has, in addition to a bioactive agent, a lipid bilayer containing a lipid and a surface agent-modified molecule. An adverse physiological reaction which may be experienced by the animal upon administration of a liposome composition is reduced by way of the presence of the surface agent-modified molecule in the liposome'"'"'s lipid bilayer.

Claims

1. A method of reducing a blood pressure decrease associated with the administration of a liposome to an animal which comprises incorporating a surface agent-modifying lipid comprising a phosphatidylethanolamine conjugated to a dicarboxylic acid into a liposome such that the surface agent-modifying lipid comprises at least about 2 mole percent of the lipid component of the liposome'"'"'s bilayer and then administering the liposome to the animal wherein an anti-inflammatory agent is administered to the animal prior to administration of the liposome composition and wherein the liposome has an average diameter of from at least about 200 nm to about 5000 nm.

2. The method of claim 1, wherein the anti-inflammatory agent is a steroid.

3. The method of claim 1, wherein the anti-inflammatory agent is a nonsteroidal anti-inflammatory agent.

4. The method of claim 3, wherein the nonsteroidal anti-inflammatory agent is indomethacin.

5. The method of claim 1, wherein the agent is administered to the animal by intravenous or intra-arterial administration.

6. The method of claim 1, wherein the anti-inflammatory agent is administered at most about 30 minutes prior to administration or the liposome composition.

7. The method of claim 1, wherein the liposome has an average diameter of from about 400 nm to about 1000 nm.

8. The method of claim 1, wherein the liposome is unilamellar.

9. The method of claim 1, wherein the concentration of surface agent modified molecule in the bilayer is at least about 10 mole percent.

10. The method of claim 1, wherein the dicarboxyclic acid is succinic acid, glutaric acid, adipic acid, bimelic acid, tartaric acid, mucic acid, tetrafluorosuccinic acid, or hexafluoroglutaric acid.

11. The method of claim 10, wherein the dicarboxylic acid is glutaric acid.

12. The method of claim 1, wherein the phosphatidylethanoramine is dipalmitoyl phosphatidylethanolamine.

13. The method of claim 1, wherein the surface agent-modifying lipid further comprises a functional group capable of attaching to the glycerol backbone of the phosphatidylethanolamine and a functional group capable of attaching to the phosphate group of the phosphatidyethanolamine.

14. The method of claim 12, wherein the functional group is an hydroxyl, thiol epoxide or amine group.

15. The method of claim 1, wherein the liposome comprises a bioactive agent.

16. The method of claim 15, wherein the bioactive agent is a contrast agent, antibacterial agent, antiviral agent, antifungal agent, anti-parasitic agent, tumoricidal agent, anti-metabolite, carbohydrate, polypeptide, peptide, protein, toxin, enzyme, hormone, neurotransmitter, glycoprotein, lipoprotein, immunoglobulin, immunomodulator, vasodilator, dye, radiolabel, radio-opaque compound, fluorescent compound, receptor binding molecule, anti-inflammatory agent, mydriatic compound, local anesthetic, narcotic, vitamin, nucleic acid, polynucleofide, nucleoside, nucleotide, MRI, radio or a water soluble iodinated contrast agent.

17. The method of claim 1, wherein the bioactive agent is a water-soluble iodinated contrast agent selected from the group consisting of iohexol iopamidol, ioxoglate, iotrolan, ioversol, iothalamate, iodimide, iodipamide, iopromide, metrizamide, iopentol, iodixanol, diatrizoate, or iotroxic acid.