Amphiphilic materials and liposome formulations thereof

• US 7,368,129 B1
• Filed: 02/27/2004
• Issued: 05/06/2008
• Est. Priority Date: 08/14/1996
• Status: Expired due to Fees

• Current Assignee: Nutrimed Biotech
• Original Assignee: Nutrimed Biotech
• Inventors: Aneja, Rajindra
• Primary Examiner(s): Kishore; Gollamudi S.
• Application Number:
  US10/788,920
• Time in Patent Office: 1,530 Days
• Field of Search: None
• US Class Current: 424/450
• CPC Class Codes: A61K 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• 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: Y10T 428/2984 Microcapsule with fluid core [includes liposome]

Abstract

Disclosed is a new structural class of amphiphilic molecules which incorporate a hydrophilic material or polymer attached, at spatially distinct sites, to at least two hydrophobic residues. Certain of the amphiphilic molecules comprise a plurality of hydrophobic moieties. All such amphiphilic molecules have a common structural motif and, in contact with water, display surface activity and self-assemble into multimolecular aggregates and liquid crystalline phases. Also disclosed are enhanced stability liposomes that incorporate such amphiphilic molecules via unique interactions, and methods of using such formulations in a variety of applications including drug delivery, nutrition, bio-diagnostics, cosmetics, blood products and related applications.

Claims

1. A liquid-crystalline multimolecular aggregate comprising a plurality of amphiphilic molecules dispersed in an aqueous solution, said amphiphilic molecules comprising a hydrophilic component having at least a first and second terminus and at least a first and second hydrophobic moiety separately attached to, or proximal to, said first and second terminus of said hydrophilic component.

2. A liposome or lipid complex comprising amphiphilic molecules that comprise a hydrophilic component positioned over at least a portion of the outer surface of said liposome or lipid complex;

wherein said hydrophilic component has at least a first and second terminus and at least a first and second hydrophobic moiety separately attached to, or proximal to, said first and second terminus, wherein said first and second hydrophobic moieties extend into the hydrophobic bilayer of said liposome or lipid complex.

3. The liposome or lipid complex of claim 2, wherein said amphiphilic molecules comprise a plurality of hydrophobic moieties that extend into the hydrophobic bilayer of said liposome or lipid complex and wherein said hydrophilic component is positioned over a substantial portion of the outer surface of said liposome or lipid complex.

4. A method of making a liposome or lipid complex comprising admixing, an aqueous solution or phase, a population of lipid components with a population of amphiphilic molecules, the said amphiphilic molecules being taken as such or in a prehydrated state;

wherein said amphiphilic molecules comprise a hydrophilic component having at least a first and second terminus and at least a first and second hydrophobic moiety separately attached to, or proximal to, said first and second terminus; and

optionally a selected agent comprising a chemical or a biological agent or a biological cell; and

wherein said admixing is effective to form said liposome or lipid complex, to encapsulate or trap the said selected agent if provided.

5. The method of claim 4, wherein said amphiphilic molecules are in a prehydrated state.

6. The method of claim 4 further comprising contacting or admixing, in an excess of an aqueous solution or phase, a liposome or lipid complex or biological cell, with an amphiphilic material comprising a population of amphiphilic molecules, preferably prehydrated amphiphilic molecules, that comprise a hydrophilic component having at least a first and second terminus and at least a first and second hydrophobic moiety separately attached to, or proximal to, said first and second terminus;

whereupon said first and second hydrophobic moieties extend into the hydrophobic bilayer of said liposome, lipid complex or biological cell and said hydrophilic component is positioned over at least a portion of the surface of said liposome, lipid complex or biological cell;

thereby forming an amphiphilic material-coated liposome, lipid complex or biological cell.

7. The method of claim 6, wherein said biological cell is a red blood cell.

8. The method of claim 7, wherein said biological cell is a human red blood cell.

9. The method of claim 4, further comprising admixing said liposome or lipid complex with a selected agent, wherein said admixing is effective to cause encapsulation or entrapment of said selected agent in said liposome or lipid complex.

11. The method of claim 9, wherein said selected agent is a blood cell blood product or substitute thereof.

12. The method of claim 9, wherein said selected agent is an immunological component.

13. The method of claim 9, wherein said selected agent is a nutrient or a nutritional supplement.

14. The method of claim 11, wherein said selected agent is an oxygen carrier, haemoglobin or a coagulant.

15. The method of claim 12, wherein said selected agent is an antigen, an antibody, a cytokine or an anti-inflammatory agent.

16. The method of claim 9, wherein said selected agent is a chemotherapeutic agent or cytotoxin.

17. The method of claim 9, wherein said selected agent is a protein, peptide, enzyme, hormone, growth factor or neurotransmitter.

18. The method of claim 9, wherein said selected agent is an antibiotic, an anti-viral or a fungicide.

19. The method of claim 9, wherein said selected agent is an anaesthetic or a surfactant.

20. The method of claim 9, wherein said selected agent is nucleic acid molecules, a nucleic acid construct or vector, an antisense nucleic acid or a ribozyme.

21. The method of claim 9, wherein said selected agent is an agent from Table 3A, Table 3B or Table 4.

22. The method of claim 9, wherein said selected agent is a pheromone or an agricultural agent.

23. The method of claim 4, wherein said hydrophilic component of said amphiphilic molecules is a substantially linear, a branched, a pendant or a star hydrophilic component.

24. The method of claim 4, wherein said hydrophilic component of said amphiphilic molecules is a hydrophilic component from Table 1.

25. The method of claim 4, wherein at least one of said hydrophobic moieties of said amphiphilic molecules is a hydrophobic moiety from Table 2.

26. The method of claim 25, wherein at least one of said hydrophobic moieties of said amphiphilic molecules is a deoxy-amino, deoxy-N-methylamino, deoxy-N,N dimethylamino, deoxy-N,N-dimethyl-N-alkylammonium or deoxy-N,N,N trialkylammonium analogue of a glyceride, wherein said glyceride is a glycerol fattyacid ester/ether, a monoglyceride (mono-fattyacylglycerol), monoalkylglycerol, diglyceride (difattyacylglycerol) or monoalkyl-monofattyacylglycerol.

27. The method of claim 4, wherein said amphiphilic molecules are bipodal amphiphilic molecules comprising a substantially linear hydrophilic component that has a first and second terminus, and wherein a first and second hydrophobic moiety are separately attached at, or substantially at, said first and second terminus.

28. The method of claim 4, wherein said amphiphilic molecules are oligopodal or polypodal amphiphilic molecules comprising a branched or star hydrophilic component that has a plurality of termini and a plurality of hydrophobic moieties separately attached to each terminus or proximal thereto.

29. The method of claim 28, wherein said amphiphilic molecules comprise a plurality of hydrophobic moieties that extend into the hydrophobic bilayer of said liposome or lipid complex and wherein said hydrophilic component is positioned over a substantial portion of the outer surface of said liposome or lipid complex.

30. The method of claim 4, wherein said liposome or lipid complex comprises between 1% and 99% of said amphiphilic molecules.

31. The method of claim 4, wherein said liposome or lipid complex comprises about 100% of said amphiphilic molecules.

32. The method of claim 4, wherein said amphiphilic molecules are non-ionic species.

33. The method of claim 4, wherein said amphiphilic molecules are charge neutral zwitterionic species.

34. The method of claim 4, wherein said amphiphilic molecules are (poly)anionic species.

35. The method of claim 4, wherein said amphiphilic molecules are (poly)cationic species.

36. The method of claim 4, wherein said amphiphilic molecules comprise branching points or functional groups.

37. The method of claim 36, wherein said branching points or functional groups are provided by glycerol, pentaerythritol, polyols, hydroxy, amino acids or peptides.

38. The method of claim 36, wherein said branching points or functional groups are attached to lipid residues.

39. The method of claim 38, wherein said branching points or functional groups are attached to said lipid residues via linkers or spacer residues.

40. The method of claim 36, wherein said branching points or functional groups are attached to antigens, antibodies or pendant ligands.

41. The method of claim 40, wherein said branching points or functional groups are attached to fluorescent, spin, biotin or thio-gold labels or to chelators.

42. The method of claim 40, wherein said branching points or functional groups are attached to antigens, antibodies or pendant ligands via linkers or spacer residues.

43. A method of claim 4, further comprising:

(a) providing a population of liposomes or lipid complexes that comprise amphiphilic molecules that comprise a hydrophilic component positioned over at least a portion of the outer surface of the liposome or lipid complex;

wherein said hydrophilic component has at least a first and second terminus and at least a first and second hydrophobic moiety separately attached to, or proximal to, said first and second terminus, wherein said first and second hydrophobic moieties extend into the hydrophobic bilayer of the liposome or lipid complex; and

(b) admixing a selected agent comprising a chemical agent or a biological agent or a biological cell with said population of liposomes or lipid complexes, wherein said admixing is effective to cause encapsulation or entrapment of said selected agent in said liposome or lipid complex.

44. A liquid-crystalline multimolecular aggregate comprising a plurality of amphiphilic molecules dispersed in an aqueous solution, said amphiphilic molecules comprising a hydrophilic component having at least a first and second terminus and at least a first and second hydrophobic moiety separately attached to, or proximal to, said first and second terminus of said hydrophilic component, prepared by the method of claim 4.

45. A liposome or lipid complex comprising amphiphilic molecules that comprise a hydrophilic component positioned over at least a portion of the outer surface of said liposome or lipid complex;

wherein said hydrophilic component has at least a first and second terminus and at least a first and second hydrophobic moiety separately attached to, or proximal to, said first and second terminus, wherein said first and second hydrophobic moieties extend into the hydrophobic bilayer of said liposome or lipid complex, prepared by the method of claim 4.

46. A kit comprising, in a suitable container, amphiphilic molecules comprising a hydrophilic component having at least a first and second terminus and at least a first and second hydrophobic moiety separately attached to, or proximal to, said first and second terminus;

or a liposomal formulation comprising said amphiphilic molecule prepared by the method of claim 4.

10. A kit comprising, in a suitable container, amphiphilic molecules comprising a hydrophilic component having at least a first and second terminus and at least a first and second hydrophobic moiety separately attached to, or proximal to, said first and second terminus;

or a liposomal formulation comprising said amphiphilic molecule.