Lyophilized liposome formulations and method

• US 20060110441A1
• Filed: 10/28/2005
• Published: 05/25/2006
• Est. Priority Date: 10/28/2004
• Status: Abandoned Application

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Zhang, Yuanpeng, Wong, Harry, Huang, Anthony Hei-Leung
• Application Number:
  US11/261,983
• Publication Number:
  US 20060110441A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/4706 4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/7012 Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid gluconic acid A61K31/191; ascorbic acid A61K31/375
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00

Abstract

Formulations and methods for preparing a lyophilized composition comprising liposomes comprised of an unsaturated lipid and a hydrophobic drug associated with the liposome, and a cryoprotectant in a solution at a selected concentration. The phase transition temperature of the lipid is greater than the freezing point of the solution at the selected concentration.

Claims

1. A lyophilized composition comprising:

liposomes comprised of an unsaturated lipid and a hydrophobic drug associated with the liposome; and

a cryoprotectant in a solution at a selected concentration;

wherein a phase transition temperature of the lipid is greater than a freezing point of the solution at the selected concentration.

2. The composition of claim 1, wherein the phase transition temperature of the lipid is at least 1°

C. greater than the freezing point of the cryoprotectant in the solution.

3. The composition of claim 1, wherein the lipid is selected from the group consisting of palmitoyl-oleoylphosphatidylcholine, oleoyl-palmitoylphosphatidylcholine, stearoyl-oleoylphosphatidylcholine, oleoyl-stearoylphosphocholine, and egg phosphatidylcholine.

4. The composition of claim 1, wherein the cryoprotectant is a disaccharide selected from the group consisting of sucrose, maltose, trehalose, and lactose.

5. The composition of claim 1, wherein the lipid is palmitoyl-oleoylphosphatidylcholine and the cryoprotectant is sucrose.

6. The composition of claim 1, wherein the cryoprotectant is sucrose with the concentration selected from 5%, 10%, 12%, 15%, 20%, and 25%.

7. The composition of claim 1, wherein the hydrophobic drug is selected from paclitaxel, etoposide, cyclosporin A, docetaxel, cephalomannine, camptothecin, bryostatin-1, plicamycin, fluorouracil, chlorambucil, acetaminophen, antipyrine, betamethasone, carbamazepine, chloroquine, chlorprothixene, corticosterone, and 1(2′

,6′

-difluorobenzoyl)-5-amino-3-(4′

-aminosulfonylanilino)-1,2,4-triazole.

8. The composition of claim 1, wherein the hydrophobic drug has a water solubility of <

100 μ

g/mL.

9. The composition of claim 1, wherein said liposomes are comprised of a lipid mixture that contains at least 10 mol % of at least one unsaturated lipid.

10. A method of preparing a lyophilized liposome composition comprising:

preparing a liposome composition comprised of an unsaturated lipid, a hydrophobic drug associated with the liposome, and a cryoprotectant at a selected concentration, a phase transition temperature of the lipid being greater than a freezing point of the cryoprotectant at the selected concentration; and

lyophilizing the liposome composition.

11. The method of claim 10, wherein said preparing further includes:

selecting a lipid or a lipid mixture; and

selecting a concentration of the cryoprotectant in a solution;

whereby said selecting steps achieve a phase transition temperature of the lipid or the lipid mixture that is at least 1°

C. greater than the freezing point of the cryoprotectant in the solution.

12. The method of claim 10, wherein said lipid is selected from the group consisting of palmitoyl-oleoylphosphatidylcholine, oleoyl-palmitoylphosphatidylcholine, stearoyl-oleoylphosphatidylcholine, oleoyl-stearoylphosphocholine, and egg phosphatidylcholine.

13. The method of claim 10, wherein the cryoprotectant is a disaccharide selected from the group consisting of sucrose, maltose, trehalose, and lactose.

14. The method of claim 10, wherein the lipid is palmitoyl-oleoylphosphatidylcholine and the cryoprotectant is sucrose.

15. The method of claim 10 wherein the cryoprotectant is sucrose with the concentration selected from 5%, 10%, 12%, 15%, 20%, and 25%.

16. The method of claim 10, wherein the hydrophobic drug is selected from paclitaxel, etoposide, cyclosporin A, docetaxel, cephalomannine, camptothecin, bryostatin-1, plicamycin, fluorouracil, chlorambucil, acetaminophen, antipyrine, betamethasone, carbamazepine, chloroquine, chlorprothixene, corticosterone, and 1(2′

,6′

-difluorobenzoyl)-5-amino-3-(4′

-aminosulfonylanilino)-1,2,4-triazole.

17. The method of claim 10, wherein the hydrophobic drug has a water solubility of <

100 μ

g/mL.

18. The method of claim 10, wherein said liposome composition is comprised of a lipid mixture that contains at least 10 mol % of at least one unsaturated lipid.