Methods and apparatus for creating particle derivatives of HDL with reduced lipid content

• US 7,393,826 B2
• Filed: 10/26/2005
• Issued: 07/01/2008
• Est. Priority Date: 07/03/2003
• Status: Active Grant

• Current Assignee: HDL Therapeutics, LLC, Lipid Sciences, Inc.
• Original Assignee: Lipid Sciences, Inc.
• Inventors: Conner, Adam Paul, Perlman, Timothy Jon, Brewer, H. Bryan Jr., Bellotti, Marc, Akeefe, Hassibullah
• Primary Examiner(s): Mondesi; Robert B.
• Application Number:
  US11/260,861
• Publication Number:
  US 20060172939A1
• Time in Patent Office: 979 Days
• Field of Search: None
• US Class Current: 424/529
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/685 one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 9/1275 Lipoproteins; Chylomicrons; Artificial HDL, LDL, VLDL, protein-free species thereof; Precursors thereof
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• 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: B01D 11/0492 Applications, solvents used
• CPC Class Codes: B01D 15/00 Separating processes involving the treatment of liquids with solid sorbents using liquid sorbents B01D11/00; ion exchange processes or materials, sorbent materials in general B01J, e.g. sorbents for chromatography B01J20/281; for investigating or analysing materials G01N30/00; Apparatus therefor
• CPC Class Codes: B01D 15/426 Specific type of solvent
• CPC Class Codes: C07K 14/775 Apolipopeptides
• CPC Class Codes: G01N 33/92 involving lipids, e.g. cholesterol , lipoproteins, or their receptors steroid hormones G01N33/743

Abstract

The present invention is directed to systems, apparatus and methods for creating derivatives of at least one form of HDL without substantially affecting LDL. These derivatives of HDL are particles with reduced lipid content, particularly reduced cholesterol content. These particles have the capacity to bind cholesterol and are administered to a patient to enhance cellular cholesterol efflux and reduce cholesterol levels in cells, tissues, organs, and blood vessels. The present method is useful for treating atherogenic vascular disease and may be combined with other therapies such as statins, inhibitors of cholesterol absorption, niacin, anti-inflammatories, exercise and dietary restriction.

Claims

1. A selectively delipidated biological fluid comprising a particle derivative of an HDL particle and a substantially unmodified LDL particle as compared to an LDL particle,

wherein the selectively delipidated biological fluid is formed by an extracorporeal selective delipidation process comprising the step of exposing a biological fluid comprising the HDL particle and the LDL particle to a lipid removing agent,

wherein the particle derivative of the HDL particle comprises a lipid bilayer comprising phospholipids and a protein shell comprising apolipoprotein A-1, apolipoprotein A-2, and at least one of apolipoprotein C-III, apolipoprotein D or apolipoprotein E, and

wherein a cholesterol content of the HDL particle derivative is lower than a cholesterol content of the HDL particle.

2. The selectively delipidated biological fluid of claim 1, wherein the cholesterol content of the HDL particle derivative is approximately 65% to 87% lower than the cholesterol content of the HDL particle.

3. The selectively delipidated biological fluid of claim 1, wherein a cholesterol content of the substantially unmodified LDL particle is substantially similar to a cholesterol content of the LDL particle.

4. The selectively delipidated biological fluid of claim 3, wherein the cholesterol content of the substantially unmodified LDL particle is lower by no more than approximately 28% than the cholesterol content of the LDL.

5. The selectively delipidated biological fluid of claim 1, wherein a phospholipid content of the substantially unmodified LDL particle is lower by no more than approximately 700 than a phospholipid content of the LDL particle.

6. The selectively delipidated biological fluid of claim 1, wherein the HDL particle derivative is smaller than the HDL particle.

7. The selectively delipidated biological fluid of claim 1, wherein the substantially unmodified LDL particle is of substantially similar size as the LDL particle.

8. The selectively delipidated biological fluid of claim 1, wherein a catabolic rate of the substantially unmodified LDL particle is substantially similar to a catabolic rate of the LDL particle.

9. The selectively delipidated biological fluid of claim 1, wherein a content of preβ

-HDL in the selectively delipidated biological fluid is increased as compared to a content of preβ

-HDL in the biological fluid.

10. The selectively delipidated biological fluid of claim 9, wherein the content of preβ

-HDL in the selectively delipidated biological fluid is increased by approximately 300% as compared to the content of preβ

-HDL in the biological fluid.

11. The selectively delipidated biological fluid of claim 1, wherein a content of mature α

HDL in the selectively delipidated biological fluid is decreased as compared to a content of mature α

HDL in the biological fluid.

12. selectively delipidated biological fluid of claim 11, wherein the content of mature α

HDL in the selectively delipidated biological fluid is decreased by approximately 41% as compared to the content of mature α

HDL in the biological fluid.

13. The selectively delipidated biological fluid of claim 1, wherein the biological fluid is blood or plasma.

14. The selectively delipidated biological fluid of claim 1, wherein the biological fluid is plasma.

15. The selectively delipidated biological fluid of claim 1, wherein the lipid removing agent comprises an ether.

16. The selectively delipidated biological fluid of claim 15, wherein the ether is a fluorinated ether.

17. The selectively delipidated biological fluid of claim 15, wherein the ether is n-sevoflurane.

18. The selectively delipidated biological fluid of claim 1, wherein the lipid removing agent is a mixture of an alcohol and an ether.

19. The selectively delipidated biological fluid of claim 18, wherein the alcohol is a butanol.

20. The selectively delipidated biological fluid of claim 1, wherein the selective delipidation process does not substantially affect non-HDL components of the biological fluid.

21. The selectively delipidated biological fluid of claim 1, wherein the selective delipidation process further comprises a step of removing the lipid removing agent from the biological fluid after the step of exposing the biological fluid to the lipid removing agent.