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

• US 7,375,191 B2
• Filed: 03/08/2004
• Issued: 05/20/2008
• Est. Priority Date: 07/03/2003
• Status: Active Grant

• Current Assignee: HDL Therapeutics, LLC, Lipid Sciences, Inc.
• Original Assignee: Lipid Sciences, Inc.
• Inventors: Perlman, Timothy Jon, Brewer, H. Bryan Jr., Conner, Adam Paul, Bellotti, Marc, Akeefe, Hassibullah
• Primary Examiner(s): Mondesi; Robert B.
• Application Number:
  US10/796,691
• Publication Number:
  US 20050004004A1
• Time in Patent Office: 1,534 Days
• Field of Search: 514/2, 514/171, 514/266.3, 514/266.2, 514/365, 514/374, 514/397, 514/217.11, 514/423, 514/12
• US Class Current: 530/359
• 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 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 25/00 Drugs for disorders of the nervous system
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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 9/12 Antihypertensives
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• 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 composition comprising substantially unmodified low density lipoprotein particles and a particle derivative of high density lipoprotein particles comprising lipids, apolipoprotein A-1 and at least one of apolipoprotein C-III, apolipoprotein D or apolipoprotein E,

wherein the lipids include phospholipids,

wherein the composition is formed by an extracorporeal process comprising exposing a biological fluid comprising low density lipoprotein particles and high density lipoprotein particles to a lipid removing agent,

wherein the substantially unmodified low density lipoprotein particles are substantially unmodified as compared to the low density lipoprotein particles in the biological fluid prior to exposure of the biological fluid to the lipid removing agent,

and wherein the particle derivative of the high density lipoprotein particles has a lower content of at least one of the phospholipids or cholesterol than the high density lipoprotein particles in the biological fluid prior to exposure of the biological fluid to the lipid removing agent.

3. The composition of claim 1, wherein the lipids include at least one of triglycerides or fatty acids.

4. The composition of claim 1, wherein the particle derivative of the high density lipoprotein particles has a lower content of cholesterol than the high density lipoprotein particles in the biological fluid prior to exposure of the biological fluid to the lipid removing agent.

5. The composition of claim 1, wherein the lipid removing agent is an ether or a combination of an alcohol and an ether.

6. The composition of claim 5, wherein the ether is di-isopropyl ether.

7. The composition of claim 5, wherein the alcohol is n-butanol.

8. The composition of claim 1, wherein the lipid removing agent is a mixture of sevoflurane and n-butanol.

9. The composition of claim 1, wherein the exposure is achieved by an exposure process comprising the steps of:

a. mixing the lipid removing agent with the biological fluid comprising the high density lipoprotein particles and the low density lipoprotein particles, to create a mixture comprising the particle derivative, the substantially unmodified low density lipoprotein particles, removed lipids, and the lipid removing agent;

b. separating the lipid removing agent and the removed lipids from the mixture; and

,

c. collecting the composition.

10. The composition of claim 9, wherein the lipid removing agent comprises a mixture of sevoflurane and n-butanol.

11. The composition of claim 9, wherein the mixing is performed using a static mixer.

12. The composition of claim 9, wherein the separation is performed using a charcoal column.

13. The composition of the high density lipoprotein particles of claim 1, wherein the biological fluid comprising low density lipoprotein particles and high density lipoprotein particles is obtained by a process comprising the steps of:

a. connecting a patient to a device for withdrawing blood;

b. withdrawing the blood containing blood cells from the patient;

c. separating the blood cells from the blood to yield the biological fluid comprising the high density lipoprotein particles and the low density lipoprotein particles.

2. A composition comprising substantially unmodified low density lipoprotein particles and a particle derivative of high density lipoprotein particles comprising lipids, apolipoprotein A-1 and at least one of apolipoprotein C-III, apolipoprotein D or apolipoprotein E,

wherein the lipids include phospholipids and at least one of triglycerides or fatty acids,

wherein the composition is formed by an extracorporeal process comprising exposing a biological fluid comprising low density lipoprotein particles and high density lipoprotein particles to a lipid removing agent,

wherein the substantially unmodified low density lipoprotein particles are substantially unmodified as compared to the low density lipoprotein particles in the biological fluid prior to exposure of the biological fluid to the lipid removing agent,

and wherein the particle derivative of the high density lipoprotein particles has a lower content of at least one of the phospholipids or cholesterol than the high density lipoprotein particles in the biological fluid prior to exposure of the biological fluid to the lipid removing agent.

14. The composition of claim 2, wherein the particle derivative of the high density lipoprotein particles has a lower content of cholesterol than the high density lipoprotein particles in the biological fluid prior to exposure of the biological fluid to the lipid removing agent.

15. The composition of claim 2, wherein the lipid removing agent is an ether or a combination of an alcohol and an ether.

16. The composition of claim 15, wherein the ether is di-isopropyl ether.

17. The composition of claim 15, wherein the alcohol is n-butanol.

18. The composition of claim 2, wherein the lipid removing agent is a mixture of sevoflurane and n-butanol.

19. The composition of claim 2, wherein the exposure is achieved by an exposure process comprising the steps of:

a. mixing the lipid removing agent with the biological fluid comprising the high density lipoprotein particles and the low density lipoprotein particles, to create a mixture comprising the particle derivative, the substantially unmodified low density lipoprotein particles, removed lipids, and the lipid removing agent;

b. separating the lipid removing agent and the removed lipids from the mixture; and

,

c. collecting the composition.

20. The composition of claim 19, wherein the lipid removing agent comprises a mixture of sevoflurane and n-butanol.

21. The composition of claim 19, wherein the mixing is performed using a static mixer.

22. The composition of claim 19, wherein the separation of the lipid removing agent and the removed lipids is performed using a charcoal column.

23. The composition of claim 2, wherein the biological fluid comprising low density biological particles and high density biological particles is obtained by an exposure process comprising the steps of:

a. connecting a patient to a device for withdrawing blood;

b. withdrawing the blood containing blood cells from the patient;

c. separating the blood cells from the blood to yield the biological fluid comprising the high density lipoprotein particles and the low density lipoprotein particles.