METHOD FOR DEVELOPING, TESTING, AND USING ASSOCIATES OF MACROMOLECULES AND COMPLEX AGGREGATES FOR IMPROVED PAYLOAD AND CONTROLLABLE DE/ASSOCIATION RATES

• US 20080311184A1
• Filed: 10/30/2007
• Published: 12/18/2008
• Est. Priority Date: 10/23/1998
• Status: Abandoned Application

• Current Assignee: IDEA AG
• Original Assignee: IDEA AG
• Inventors: Cevc, Gregor
• Application Number:
  US11/929,544
• Publication Number:
  US 20080311184A1
• Time in Patent Office: Days
• US Class Current: 424/450
• 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: 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

This invention describes the principles and procedures suitable for developing, testing, manufacturing, and using combinations of various amphipatic, if necessary modified, macromolecules (such as polypeptides, proteins, etc.) or other chain molecules (such as suitable, e.g. partly hydrophobised, polynucleotides or polysaccharides) with the aggregates which comprise a mixture of polar and/or charged amphipats and form extended surfaces that can be freely suspended or supported. The described methods can be utilised for the optimisation of aggregates that, after association with chain molecules exerting some activity or a useful function, are suitable for the application in vitro or in vivo, for example, in the fields of drug delivery, diagnostics or bio/catalysis. As special examples, mixtures of vesicular droplets consisting of lipids loaded (associated) with insulin, interferon, interleukin, nerve growth factor, calcitonin, and an immunoglobulin, etc., are described.

Claims

1. A pharmaceutical composition comprising:

(i) a bilayer vesicle consisting essentially of;

at least one phosphatidylcholine; and

a nonionic detergent, at least one detergent;

(ii) at least one macromolecule; and

(iii) an aqueous liquid medium, wherein the macromolecule resides on the surface of the vesicle.

2. The composition of claim 1, wherein, prior to association of the macromolecule with the surface of the vesicle, the surface of the vesicle carries a net electric charge and the macromolecule carries a net electric charge, and the net electric charge of the surface of the vesicle and the net electric charge of the macromolecule have the same sign.

3. The composition of claim 2, wherein the surface of the vesicle is negatively charged and wherein the macromolecule is negatively charged.

4. The composition of claim 75, wherein the nonionic detergent is a long-chain fatty acid;

a long-chain fatty alcohol;

an alkyl-N-methylglucamide;

an alkanoyl-N-methylglucamide;

a polyethylene-glycol-octylphenyl ether;

nonaethylenglycol-octylphenyl ether;

a polyethylene-acyl ether;

a nonaethylen-dodecyl ether;

a polyethylenegylcol-isoacyl ether;

an octaethyleneglycol-isotridencyl ether;

a polyethylene-acyl ether;

an octaethylenedodecyl ether;

a polythyleneglycol-sorbitane-acyl ester;

polyethyleneglycol-20-monolaurate;

polyethyleneglycol-20-sorbitan-monooleate;

a polyhydroxyethylene-acyl ether;

a polyhydroxyethylene-lauryl ether;

a polyhydroxyethylenemyristoyl ether;

a polyhydroxyethylene-cetylstearyl ether;

apolyhydroxyethylene-oleoyl ether;

a polyhydroxyethylene-4, or 6, or 8, or 10, or 12-lauryl ether;

a Brij;

Myrj 45;

a polyhydroxyethylene-laurate;

a polyhydroxyethylene-oleate;

polyethoxylated castor oil 40;

a sorbitan-monoalkylate;

sorbitane-monolaurate;

an acyl-N-methylglucaraide;

an alkanoyl-N-methylglucamide;

decanoyl-N-methylglucamide;

dodecanoyl-N-methylglucamide;

or a surface-active polypeptide.

5. The composition of claim 75, wherein the nonionic detergent is a polyethyleneglycol-sorbitan-acyl ester, a Brij, a Myrj, a polyhydroxyethylene-8-stearate, a polyhydroxyethylene lauryl ether, a polyethylene-glycol-octylphenyl ether, a nonaethylene-glycol-octylphenyl ether, Triton, or an —

N-glucamide or a sorbitan monoalkylate nonionic detergent.

6. The composition of claim 1, wherein the macromolecule is a hormone.

7. The composition of claim 1, wherein the macromolecule is human recombinant insulin or humanized insulin.

8. The composition of claim 1, wherein the macromolecule is interleukin suitable for the use in humans or animals and is IL-2, IL-4, IL-8, IL-10, or IL-12.

9. The composition of claim 1, wherein the macromolecule is interferon alpha, beta or gamma.

10. The composition of claim 1, wherein the macromolecule is immunoglobulin (Ig) IgA, IgG, IgE, IgD or IgM.

11. The composition of claim 1, wherein the macromolecule is calcitonin.

13. The composition of claim 1, wherein the phosphatidylcholine is from soy-bean.

14. The composition of claim 75, wherein the nonionic detergent is a polyethyleneglycol-sorbitan-acyl ester.

15. The composition of claim 14, wherein the polyethyleneglycol-sorbitan-acyl ester is polyethyleneglycol-20-sorbitan-monooleate or polyethyleneglycol-20-sorbitan-monolaurate.

16. The composition of claim 75, wherein the nonionic detergent is a Brij.

17. The composition of claim 75, wherein the nonionic detergent is a Myrj.

18. The composition of claim 17, wherein the Myrj nonionic detergent is Myrj-45.

19. The composition of claim 1, wherein the macrormolecule is a protein.

20. The composition of claim 1, wherein the macrormolecule is a polynucleotide.

21. The composition of claim 1, wherein the macrormolecule is a polysaccharide.

22. The composition of claim 19, wherein the protein is an enzyme, an interferon, an interleukin, an immunoglobulin, or a hormone.

23. The composition of claim 19, wherein the protein is insulin.

29. The pharmaceutical composition of claim 1, wherein the detergent is sodium cholate.

30. The composition of claim 29, wherein, prior to association of the macromolecule with the surface of the vesicle, the surface of the vesicle carries a net electric charge and wherein the macromolecule carries a net electric charge, and the net electric charge of the surface of the vesicle and the net electric charge of the macromolecule have the same sign.

31. The composition of claim 30, wherein the surface of the vesicle is negatively charged and wherein the macromolecule is negatively charged.

32. The composition of claim 29, wherein the macromolecule is a hormone.

33. The composition of claim 32, wherein the hormone is human recombinant insulin or humanized insulin.

34. The composition of claim 29, wherein the macromolecule is interleukin suitable for the use in humans or animals and is IL-2, IL-4, IL-8, IL-10, or IL-12.

35. The composition of claim 29, wherein the macromolecule is interferon alpha, beta or gamma.

36. The composition of claim 29, wherein the macromolecule is immunoglobulin (Ig) IgA, IgG, IgE, IgD or IgM.

37. The composition of claim 29, wherein the macromolecule is calcitonin.

38. The composition of claim 29, wherein the phosphatidylcholine is from soy-bean.

39. The composition of claim 29, wherein the macromolecule is a protein.

40. The composition of claim 39, wherein the protein is an enzyme, an interferon, an interleukin, an immunoglobulin, or a hormone.

41. The composition of claim 40, wherein the hormone is insulin.

42. The composition of claim 29, wherein the macromolecule is a polynucleotide.

43. The composition of claim 29, wherein the macromolecule is a polysaccharide.

75. The composition of claim 1, wherein the detergent is a nonionic detergent.

76. The composition of claim 1, wherein the detergent is an ionic detergent.

77. The composition of claim 76, wherein the ionic detergent is an alkyl-trimethyl-ammonium salt;

an alkyl-dimethyl-ammonium salt;

an alkylsulfate salt;

a monovalent salt of cholate;

a monovalent salt of deoxycholate;

a monovalent salt of glycocholate;

a monovalent salt of glyeodeoxycholate;

a monovalent salt of taurodeoxycholate;

a monovalent salt of taurocholate;

an acyl-dimethyl-aminoxide;

an alkanoyl-dimethyl-aminoxide;

a dodecyl-dimethylaminoxide;

N-alkyl-N,N-dimethylglycine;

3-(acyldimethylammonio)-alkanesulfonate;

N-acyl-sulfobetaine;

lauryl sulfate;

oleoyl sulfate, sodium deoxycholate;

sodium glyeodeoxycholate;

sodium oleate;

sodium taurate;

a fatty acid salt;

sodium eiaidate;

sodium linoleate;

sodium laurate;

a lysophospholipid;

n-octadecylene-glycerophosphatidic acid;

n-octadecylene-phosphorylglycerol;

n-octadecylene-phosphorylserine;

n-alkyl-glycerophosphatidic acid;

lauryl-glycerophosphatidic acid;

oleoyl-glycerophosphatidic acid;

n-alkyl-phosphorylglycerol;

lauryl-phosphorylglycerol;

oleoyl-phosphorylglycerol;

n-alkyl-phosphorylserine;

lauryl-phosphorylserine;

oleoyl-phosphorylserine;

n-tetradecyl-glycerophosphatidic acid;

n-tetradecyl-phosphorylglycerol;

n-tetradecyl-phosphorylserine;

palmitoeloyl-glycerophosphatidic acid;

palmitoeloyl-phosphorylglycerol;

palmitoeloyl-phosphorylserine;

elaidoyl-glycerophosphatidic acid;

elaidoyl-phosphorylglycerol;

elaidoyl-phosphorylserine;

vaccenyl-glycerophosphatidic acid;

vaccenyl-phosphorylglycerol;

or vaccenyl-phosphorylserine.

78. The composition of claim 2, wherein the surface of the vesicle is positively charged and wherein the macromolecule is positively charged.

79. The composition of claim 30, wherein the surface of the vesicle is positively charged and wherein the macromolecule is positively charged.

12. (canceled)

24-28. -28. (canceled)

44-74. -74. (canceled)