Drug-oligomer conjugates with polyethylene glycol components

• US 20040223948A1
• Filed: 02/10/2004
• Published: 11/11/2004
• Est. Priority Date: 06/19/1999
• Status: Active Grant

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Biocon Limited (Biocon Incorporated)
• Inventors: Ramaswamy, Muthukamar, Ekwuribe, Nnochiri N., Rajagopalan, Jayanthi
• Granted Patent: US 7,030,084 B2
• Time in Patent Office: Days
• US Class Current: 424/78.38
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol

Abstract

The present invention relates generally to hydrolyzable drug-oligomer conjugates, pharmaceutical compositions comprising such conjugates, and to methods for making and using such conjugates and pharmaceutical compositions. For example, a conjugate of insulin, PEG, and oleic acid can be orally administered.

Claims

1-49. -49. (Canceled)

50. A drug-oligomer conjugate having the formula:

D-H_p

wherein D is a therapeutic drug moiety;

H is a PEG polymer having from 1 to 10 PEG units; and

p is a number from 1 to the maximum number of covalent bonding sites at which -H can form a bond with D.

51. The drug-oligomer conjugate of claim 50, wherein H is a PEG polymer having from 2 to 7 PEG units.

52. The drug-oligomer conjugate of claim 50, wherein H is a PEG polymer having 2, 3, 4 or 5 PEG units.

53. The drug-oligomer conjugate of claim 50, wherein H is a PEG polymer having 3 PEG units.

54. The drug-oligomer conjugate of claim 50, wherein the D-H bonds are non-hydrolyzable.

55. The drug-oligomer conjugate of claim 50, wherein the D-H bonds are selected from the group consisting of carbamate, amide and secondary amine.

56. The drug-oligomer conjugate of claim 50, wherein D is a biologically active polypeptide.

57. The drug-oligomer conjugate of claim 56, wherein the biologically active polypeptide has at least one available moiety for conjugation selected from the group consisting of XNH₂;

—

OH and XSH; and

wherein at least one of the available moieties is conjugated to the H moiety.

58. The drug-oligomer conjugate of claim 50, wherein D is selected from the group consisting of insulin, insulin lispro, and a functional equivalent of insulin.

59. The drug-oligomer conjugate of claim 58, wherein H is a PEG polymer having from 2 to 7 PEG units.

60. The drug-oligomer conjugate of claim 58, wherein H is a PEG polymer having 2, 3, 4 or 5 PEG units.

61. The drug-oligomer conjugate of claim 58, wherein H is a PEG polymer having 3 PEG units.

62. A pharmaceutical composition comprising the drug-oligomer conjugate of claim 50, in association with a pharmaceutical carrier.

63. A pharmaceutical composition comprising the drug-oligomer conjugate of claim 58, in association with a pharmaceutical carrier.

64. A method of delivering a drug-conjugate to a situs of a subject, comprising administering to the subject an effective amount of a drug-oligomer conjugate according to claim 50.

65. A method of delivering a drug-conjugate to a situs of a subject, comprising administering to the subject an effective amount of a drug-oligomer conjugate according to claim 58.

66. A drug-PEG conjugate having the formula:

D-H_p

wherein D is selected from the group consisting of insulin, insulin lispro, and a functional equivalent of insulin;

H is a PEG polymer having from 1 to 10 PEG units; and

p is a number from 1 to the maximum number of covalent bonding sites at which

-H can form a bond with D,

 

wherein the drug-PEG conjugate has enhanced activity in comparison with a corresponding unconjugated insulin molecule, unconjugated insulin lispro molecule or unconjugated functional equivalent thereof.

67. A method of delivering the drug-PEG conjugate of claim 66 to a situs of a subject, comprising administering to the subject an effective amount of the drug-PEG conjugate.

68. A pharmaceutical composition comprising the drug-oligomer conjugate of claim 66, in association with a pharmaceutical carrier.