Lipopolymer conjugates

• US 20060079486A1
• Filed: 10/07/2005
• Published: 04/13/2006
• Est. Priority Date: 10/08/2004
• Status: Abandoned Application

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Zalipsky, Samuel
• Application Number:
  US11/245,673
• Publication Number:
  US 20060079486A1
• Time in Patent Office: Days
• US Class Current: 514/78
• CPC Class Codes: A61K 47/544 Phospholipids
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: C07F 9/10 Phosphatides, e.g. lecithin
• CPC Class Codes: C07F 9/1411 with hydroxyalkyl compounds with further substituents on alkyl
• CPC Class Codes: C07F 9/2408 of hydroxyalkyl compounds
• CPC Class Codes: C07F 9/2458 of aliphatic amines
• CPC Class Codes: C07F 9/5537 the heteroring containing the structure -C(=O)-N-C(=O)- (both carbon atoms belong to the heteroring)
• CPC Class Codes: C07F 9/65522 condensed with carbocyclic rings or carbocyclic ring systems

Abstract

Conjugates of formula I, below, are useful in biomedicinal applications such as delivery of drugs or labeling moieties or as components of liposomes or micelles. In formula I, A is a hydrophilic polymer, each of L and L′ is independently a linker group, B is a lipid moiety; and Z is a diagnostic ligand, a biologically relevant ligand, or a reactive linking moiety, which is generally linked to the phosphorus atom of the conjugate via a nitrogen, oxygen or sulfur atom in Z.

Claims

1. A compound of the formula:

where

A is a hydrophilic polymer;

each of L and L′

is independently a linker group;

B is a lipid moiety; and

Z is selected from the group consisting of a diagnostic ligand, a biologically relevant ligand, and a reactive linking moiety, wherein said reactive linking moiety is not hydroxy (—

OH), oxide (—

O⁻

), or 2-aminoethoxy.

2. The compound of claim 1, wherein B is selected from a fatty acid, a sterol, a diether lipid, and a diacyl lipid.

3. The compound of claim 2, where B is a diacyl lipid, said compound having the formula:

where each of R¹ and R² is independently alkyl or alkenyl having 4-24 carbon atoms.

4. The compound of claim 3, wherein each of R¹ and R² is C₁₇H₃₅.

5. The compound of claim 1, wherein Z is linked to P via a nitrogen, oxygen or sulfur atom in Z.

6. The compound of claim 1, wherein Z is linked to P via a nitrogen atom in Z.

7. The compound of claim 6, wherein Z is a reactive linking moiety of the form —

NH—

(CH₂)_n—

X, where n is 2 to 8 and X is selected from amino, mercapto, hydroxy, disulfide, aldehyde, ketone, maleimide, hydrazide, an activated ester, other carboxylic acid derivative, and a leaving group.

8. The compound of claim 6, where n is 3 and X is —

NH₂.

9. The compound of claim 6, where n is 3 and X is a succinimidyl ester.

10. The compound of claim 1, wherein Z is a diagnostic ligand.

11. The compound of claim 1, wherein Z is a biologically relevant ligand selected from a polypeptide, a protein, a polynucleotide, and a small molecule compound.

12. The compound of claim 1, wherein A is a polyethylene glycol having 2 to 120 repeating ethylene glycol units.

13. The compound of claim 1, wherein each of L and L′

is independently an alkyl, aryl, or aralkyl moiety, which may be flanked on one or both sides by a group Y, where Y is (i)-W—

(C═

O)-Q-, (ii)-W—

(C═

O)—

, (iii)-W—

, and (iv) disulfide, where W and Q are independently selected from oxygen, NH, and a direct bond.

14. The compound of claim 1, wherein at least one of L and L′

is cleavable in vivo.

15. A liposome comprising a compound according to claim 1.

16. The liposome of claim 15, comprising a compound according to claim 3.

17. The liposome of claim 15, comprising from 1 to about 50 mole percent of the compound according to claim 1.

18. A method of tailoring the hydrophilic-lipophilic balance of a carrier for a drug, comprising

providing a carrier of the formula

where

A is a hydrophilic polymer,

each of L and L′

is independently a linker group;

B is a lipid moiety; and

Z is said drug or a reactive moiety effective to be conjugated to said drug, wherein said reactive moiety is not hydroxy (—

OH), oxide (—

O⁻

), or 2-aminoethoxy;

and wherein the relative size of A and B is effective to give a desired HLB for said carrier.

19. The method of claim 18, where B is a diacyl lipid, said compound having the formula:

where each of R¹ and R² is independently alkyl or alkenyl having 4-24 carbon atoms.

20. The method of claim 19, wherein A is a polyethylene glycol.

21. A method for oral delivery of a therapeutic agent, comprising

administering orally to a subject a conjugate of the formula I:

where

A is a hydrophilic polymer;

each of L and L′

is independently a linker group;

B is a lipid moiety; and

Z comprises said therapeutic agent.

22. The method of claim 21, wherein Z further comprises a linkage to the phosphorus atom of formula I which is cleavable in vivo.

23. The method of claim 21, wherein B is a diacyl lipid, such that the conjugate has the formula II:

where each of R¹ and R² is independently alkyl or alkenyl having 4-24 carbon atoms.

24. The method of claim 23, wherein A is a polyethylene glycol.