Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same

• US 20060199759A1
• Filed: 05/04/2006
• Published: 09/07/2006
• Est. Priority Date: 06/04/2001
• Status: Active Grant

• Current Assignee: Amy L. Odenbaugh, Aslam M. Ansari, Balasingam Radhakrishnan, Christopher H. Price, Nnochiri N. Ekwuribe
• Original Assignee: Amy L. Odenbaugh, Aslam M. Ansari, Balasingam Radhakrishnan, Christopher H. Price, Nnochiri N. Ekwuribe
• Inventors: Radhakrishnan, Balasingam, Ekwuribe, Nnochiri N., Odenbaugh, Amy L., Price, Christopher H., Ansari, Aslam M.
• Granted Patent: US 7,470,663 B2
• Time in Patent Office: Days
• US Class Current: 514/6.3
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin

Abstract

A mixture of conjugates in which each conjugate in the mixture comprises an insulin drug coupled to an oligomer that includes a polyalkylene glycol moiety is disclosed. The mixture may exhibit higher in vivo activity than a polydispersed mixture of similar conjugates. The mixture may also be more effective at surviving an in vitro model of intestinal digestion than polydispersed mixtures of similar conjugates. The mixture may also result in less inter-subject variability than polydispersed mixtures of similar conjugates.

Claims

1-33. -33. (canceled)

34. A substantially monodispersed mixture of conjugates each comprising human insulin covalently coupled at Lys^B29 of the human insulin to the carboxylic acid moiety of a carboxylic acid, which is covalently coupled at the end distal to the carboxylic acid moiety to a methyl terminated polyethylene glycol moiety having at least 7 polyethylene glycol subunits.

35. The substantially monodispersed mixture according to claim 34, wherein the conjugates each comprising human insulin covalently coupled at Lys^B29 of the human insulin to the carboxylic acid moiety of hexanoic acid, which is covalently coupled at the end distal to the carboxylic acid moiety to a methyl terminated polyethylene glycol moiety having 7 polyethylene glycol subunits.

36. A substantially monodispersed mixture of conjugates each comprising insulin coupled to an oligomer that comprises a polyethylene glycol moiety, said mixture having an in vivo activity that is greater than the in vivo activity of a polydispersed mixture of insulin drug-oligomer conjugates having the same number average molecular weight as the substantially monodispersed mixture.

37. The mixture according to claim 36, further having an in vitro activity that is greater than the in vitro activity of the polydispersed mixture of insulin-oligomer conjugates.

38. The mixture according to claim 36, further having an increased resistance to degradation by chymotrypsin when compared to the resistance to degradation by chymotrypsin of the polydispersed mixture of insulin-oligomer conjugates.

39. The mixture according to claim 36, further having an inter-subject variability that is less than the inter-subject variability of the polydispersed mixture of insulin-oligomer conjugates.

40. A mixture of conjugates each comprising insulin coupled to an oligomer that comprises a polyethylene glycol moiety, said mixture having a molecular weight distribution with a standard deviation of less than about 22 Daltons.

41-59. -59. (canceled)