Liposome formulations of boronic acid compounds

• US 20060159736A1
• Filed: 11/04/2005
• Published: 07/20/2006
• Est. Priority Date: 11/05/2004
• Status: Abandoned Application

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Martin, Francis J., Zalipsky, Samuel
• Application Number:
  US11/267,076
• Publication Number:
  US 20060159736A1
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 31/7024 Esters of saccharides
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A liposome composition comprised of liposomes having the peptide boronic acid proteasome inhibitor compound bortezomib entrapped in the liposomes is described. The boronic acid compound is entrapped in the liposomes in the form of a boronate ester, subsequent to interaction with a liposome-entrapped polyol. In one embodiment, the liposomes have an outer coating of hydrophilic polymer chains and are used to treat a solid tumor in a subject.

Claims

1. A composition, comprising

liposomes formed of a vesicle-forming lipid, and

entrapped in said liposomes, a boronate ester compound prepared from bortezomib and a polyol.

2. The composition of claim 1, wherein said polyol is a compound having a cis 1,2-diol functionality or a 1,3-diol functionality.

3. The composition of claim 1, wherein said polyol is polyvinylalcohol.

4. The composition of claim 1, wherein said polyol is a monosaccharide, a disaccharide, an oligosaccharide, or a polysaccharide.

5. The composition of claim 4, wherein said polyol is a monosaccharide selected from maltose, glucose, ribose, fructose, and sorbitol.

6. The composition of claim 1, wherein said polyol is glycerol or polyglycerol.

7. The composition of claim 1, wherein said polyol is an aminopolyol.

8. The composition of claim 7, wherein said aminopolyol is an aminosorbitol.

9. The composition of claim 7, wherein said aminopolyol is a copolymer of vinyl alcohol and vinyl amine.

10. The composition of claim 1, wherein said liposomes further comprise a higher inside/lower outside ion gradient.

11. The composition of claim 10, wherein said ion gradient is a hydrogen ion gradient.

12. The composition of claim 11, wherein said hydrogen ion gradient provides an inside pH of between about 7.5-8.5 and an outside pH of between about 6-7.

13. The composition of claim 1, wherein said liposomes further comprise between about 1-20 mole percent of a hydrophobic moiety derivatized with a hydrophilic polymer.

14. The composition of claim 13, wherein said hydrophobic moiety derivatized with a hydrophilic polymer is a hydrophobic moiety derivatized with polyethylene glycol.

15. The composition of claim 14, wherein said hydrophobic moiety is a lipid.

16. A treatment method, comprising

preparing a suspension of liposomes having in entrapped form a boronate ester compound prepared from bortezomib and a polyol, and;

administering the suspension of liposomes to a subject.

17. The method of claim 16, wherein said preparing further includes preparing a suspension of liposomes having a higher inside/lower outside ion gradient and adding bortezomib to the suspension to achieve uptake of bortezomib into the liposomes for formation of a peptidyl boronate ester compound.

18. The method of claim 16, wherein said administering is via injection.

19. The method of claim 16, wherein said subject has a hematologic malignancy.

20. A method of selectively destroying tumor tissue in a tumor-bearing subject undergoing radiation therapy, comprising

administering to a tumor-bearing subject, liposomes having in entrapped form (i) a boronate ester compound prepared from bortezomib and a polyol;

and

(ii) an isotope of boron; and

subjecting said subject to radiation therapy.

21. The method of claim 20, wherein said isotope of boron is on bortezomib.

22. The method of claim 20, wherein said isotope of boron is a ¹⁰B.