Preparation of lipid particles

• US 20050175683A1
• Filed: 10/22/2004
• Published: 08/11/2005
• Est. Priority Date: 10/24/2003
• Status: Abandoned Application

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Zhang, Yuanpeng
• Application Number:
  US10/970,861
• Publication Number:
  US 20050175683A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 9/127 Liposomes
• 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 9/1277 Processes for preparing; Proliposomes
• CPC Class Codes: A61P 31/04 Antibacterial agents

Abstract

A method for preparing lipid particles comprising producing discrete droplets of vesicle-forming lipids in a solvent, where the droplets have a diameter and a volume, introducing the discrete droplets into an aqueous solution to form lipid particles suitable for in vivo administration. The droplet may further contain any one or more of oils, surfactants, targeting ligands, markers, or therapeutic and diagnostic agents. The droplets may be generated by a system selected from a nebulizer, an atomizer, a venturi mist generator, a focused acoustic ejector, and an electrospray device. This method can be used to select or regulate the size and/or size distribution of the lipid particles.

Claims

1. A method for preparing lipid particles, comprising:

producing discrete droplets of vesicle-forming lipids in a solvent, said droplets having a diameter and a volume;

introducing said droplets into an aqueous solution; and

forming lipid particles suitable for in vivo administration.

2. The method of claim 1, wherein said lipid particle is a liposome.

3. The method of claim 1, wherein the lipid is selected from the group consisting of distearoyl phosphatidyl choline, distearoyl phosphatidyl ethanolamine, and hydrogenated soy phosphatidyl choline.

4. The method of claim 1, further comprising:

including a therapeutic agent in at least one of the solvent or the aqueous solution.

5. The method of claim 4, wherein said therapeutic agent is an anthracycline antibiotic.

6. The method of claim 5, wherein said anthracycline antibiotic is selected from the group consisting of daunorubicin, doxorubicin, mitoxantrone, and bisantrene.

7. The method of claim 1, further comprising:

including a lipopolymer in said droplet.

8. The method of claim 7, wherein said lipopolymer is selected from the group consisting of polyvinylpyrrolidone, polyvinylmethylether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, polyhydroxypropylmethacrylate, polyhydroxyethylacrylate, hydroxymethylcellulose, hydroxyethylcellulose, polyethyleneglycol, and polyaspartamide.

9. The method of claim 8, wherein said lipopolymer is polyethylene glycol chains having a molecular weight of between about 500 Daltons and about 10,000 Daltons.

10. The method of claim 7, further comprising a ligand attached to the distal end of at least a portion of said lipopolymers.

11. The method of claim 1, further comprising a ligand attached the polar head group of at least a portion of the vesicle-forming lipids.

12. The method of claim 1, wherein the concentration of lipid in each droplet is between about 0.1 mg/mL and about 1 g/mL.

13. The method of claim 1, wherein the concentration of lipid in each droplet is between about 1 mg/mL and about 100 mg/mL.

14. The method of claim 1, wherein the droplet volume is between about 10⁻

4 fL and about 1 nL.

15. The method of claim 1, wherein the droplet volume is between about 10⁻

2 fL and about 10 pL.

16. The method of claim 1, further comprising:

including at least one of a cationic lipid, an anionic lipid, a surfactant, a marker, an oil, or a pharmaceutical excipient in said solvent.

17. The method of claim 1, further comprising:

applying a focused acoustic radiation at a focal point near a surface of the solution prior to and/or during said introducing.

18. The method of claim 1, said introducing step further comprising:

providing a plurality of ejectors such that a plurality of droplets can be ejected from a plurality of solvent reservoirs containing said lipids and solvent.

19. The method of claim 1, wherein said discrete droplets are produced as a mist and said introducing step comprises:

directing the mist of droplets into contact with the aqueous solution.

20. The method of claim 19, wherein the mist of droplets is generated by a system selected from the group consisting of a nebulizer, an atomizer, a venturi mist generator, a focused acoustic ejector, and an electrospray device.