Amphiphilic materials and liposome formulations thereof

• US 6,699,499 B1
• Filed: 06/11/2001
• Issued: 03/02/2004
• Est. Priority Date: 08/14/1996
• Status: Expired due to Term

• Current Assignee: Nutrimed Biotech
• Original Assignee: Nutrimed Biotech
• Inventors: Aneja, Rajindra
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US09/879,368
• Time in Patent Office: 995 Days
• Field of Search: 424/450, 424/1.21, 424/9.321, 424/9.51, 424/417, 424/94.3, 428/402.2, 436/829, 554/76, 554/80, 554/103, 554/227
• US Class Current: 424/450
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 8/14 Liposomes; Vesicles
• CPC Class Codes: A61K 8/72 containing organic macromolecular compounds
• CPC Class Codes: A61K 8/86 Polyethers
• 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 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61Q 19/00 Preparations for care of the skin
• CPC Class Codes: C07F 9/10 Phosphatides, e.g. lecithin
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08G 65/3353 containing oxygen in addition to phosphorus
• CPC Class Codes: C08G 65/337 containing other elements organic compounds containing halogens only as halides of a carboxyl group C08G65/332
• CPC Class Codes: C08L 2203/02 for biomedical use
• CPC Class Codes: C11D 17/0026 Structured liquid compositions, e.g. liquid crystalline phases or network containing non-Newtonian phase
• CPC Class Codes: Y10S 436/829 Liposomes, e.g. encapsulation
• CPC Class Codes: Y10S 977/907 Liposome
• 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 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 molecules;

wherein said kit further comprises a selected agent.

2. A cosmetic formulation comprising, in a cosmetically acceptable base, 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 wherein at least a first and second hydrophobic moiety is separately attached to, or proximal to, said first and second terminus, said first and second hydrophobic moieties extending into the hydrophobic bilayer of the liposome or lipid complex.

3. A medicinal delivery composition comprising, in a pharmaceutically acceptable vehicle, a population of liposomes or lipid complexes comprising a selected agent;

wherein said liposomes or lipid complexes 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 wherein at least a first and second hydrophobic moiety is separately attached to, or proximal to, said first and second terminus, said first and second hydrophobic moieties extending into the hydrophobic bilayer of the liposome or lipid complex.

22. The composition of claim 3, wherein said selected agent is a nutrient or a nutritional supplement.

23. The composition of claim 3, wherein said selected agent is a blood product.

24. The composition of claim 3, wherein said selected agent is an immunological component.

25. The composition of claim 3, wherein said selected agent is a chemotherapeutic agent or cytotoxin.

26. The composition of claim 3, wherein said selected agent is a protein, peptide, enzyme, hormone, growth factor or neurotransmitter.

27. The composition of claim 3, wherein said selected agent is an antibiotic, an anti-viral or a fungicide.

28. The composition of claim 3, wherein said selected agent is an anaesthetic.

29. The composition of claim 3, wherein said selected agent is nucleic acid molecules, a nucleic acid construct or vector, an antisense nucleic acid or a ribozyme.

30. The composition of claim 3, wherein said selected agent is a surfactant.

31. The composition of claim 3, wherein said selected agent is an agent from Table 3A, Table 3B or Table 4.

32. The composition of claim 3, wherein said hydrophilic component of said amphiphilic molecules is a substantially linear, a branched, a pendant or a star hydrophilic component.

33. The composition of claim 3, wherein said hydrophilic component of said amphiphilic molecules is a hydrophilic component from Table 1.

34. The composition of claim 3, wherein at least one of said hydrophobic moieties of said amphiphilic molecules is a hydrophobic moiety from Table 2.

35. The composition of claim 3, 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.

36. The composition of claim 3, 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.

37. The composition of claim 3, 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.

38. The kit of claim 3, wherein said selected agent is a pheromone or an agricultural agent.

44. The composition of claim 23, wherein said selected agent is an oxygen carrier, haemoglobin, a red blood cell or a coagulant.

45. The composition of claim 24, wherein said selected agent is an antigen, an antibody, a cytokine or an anti-inflammatory agent.

4. A method for providing a selected agent to an animal, comprising administering to said animal a medicinal delivery composition comprising, in a pharmaceutically acceptable vehicle, a population of liposomes or lipid complexes comprising said selected agent;

wherein said liposomes or lipid complexes 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 wherein at least a first and second hydrophobic moiety is separately attached to, or proximal to, said first and second terminus, said first and second hydrophobic moieties extending into the hydrophobic bilayer of the liposome or lipid complex.

5. The method of claim 4, wherein said selected agent is a nutrient or a nutritional supplement.

6. The method of claim 4, wherein said selected agent is an oxygen carrier, haemoglobin, a coagulant or a blood product.

7. The method of claim 4, wherein said selected agent is an antigen, an antibody, an immunological component, a cytokine or an anti-inflammatory agent.

8. The method of claim 4, wherein said selected agent is a chemotherapeutic agent or cytotoxin.

9. The method of claim 4, wherein said selected agent is a protein, peptide, enzyme, hormone, growth factor or neurotransmitter.

10. The method of claim 4, wherein said selected agent is an antibiotic, an anti-viral or a fungicide.

11. The method of claim 4, wherein said selected agent is an anaesthetic.

12. The method of claim 4, wherein said selected agent is nucleic acid molecules, a nucleic acid construct or vector, an antisense nucleic acid or a ribozyme.

13. The method of claim 4, wherein said animal is a human subject.

14. 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.

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

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

17. 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.

18. 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.

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

20. The method of claim 4, wherein said selected agent is a surfactant.

21. A method for providing a selected agent to an animal, comprising administering to said animal a medicinal delivery composition comprising, in a pharmaceutically acceptable vehicle, a population of liquid-crystalline multimolecular aggregates comprising said selected agent;

wherein said liquid-crystalline multimolecular aggregates comprising a plurality of amphiphilic molecules that comprise a hydrophilic component having covalently attached, at spatially distant sites, at least two hydrophobic moieties, wherein the mesophases of said liquid-crystalline multimolecular aggregates, as characterized by X-ray diffraction, include the fluid L_α

, gel L_β

, and hexagonal mesophases.

39. A formulation comprising a population of liposomes or lipid complexes, wherein said liposomes or lipid complexes 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 wherein at least a first and second hydrophobic moiety is separately attached to, or proximal to, said first and second terminus, said first and second hydrophobic moieties extending into the hydrophobic bilayer of the liposome or lipid complex, and further comprising a selected agent.

40. The formulation of claim 39, wherein said formulation is a cosmetic formulation.

41. The formulation of claim 39, wherein said formulation is a medicinal delivery formulation.

42. A composition comprising a liquid-crystalline multimolecular aggregate comprising a selected agent;

wherein said liquid-crystalline multimolecular aggregate comprises 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.

43. A composition comprising a liquid-crystalline multimolecular aggregate comprising a selected agent;

wherein said liquid-crystalline multimolecular aggregate comprises a plurality of amphiphilic molecules dispersed in an aqueous solution, said amphiphilic molecules comprising a hydrophilic component having covalently attached, at spatially distant sites, at least two hydrophobic moieties, wherein the mesophases of said liquid-crystalline multimolecular aggregates, as characterized by X-ray diffraction, include the fluid L_α

, gel L_β

, and hexagonal mesophases.