Claims for Patent: 6,858,580

Summary for Patent: 6,858,580

Title:	Mixtures of drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same
Abstract:	A non-polydispersed mixture of conjugates in which each conjugate in the mixture comprises a 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 be more effective at surviving an in vitro model of intestinal digestion than polydispersed mixtures of similar conjugates. The mixture may result in less inter-subject variability than polydispersed mixtures of similar conjugates.
Inventor(s):	Ekwuribe; Nnochiri N. (Cary, NC), Price; Christopher H. (Chapel Hill, NC), Ansari; Aslam M. (Rockville, MD), Odenbaugh; Amy L. (Morrisville, NC)
Assignee:	Nobex Corporation (Durham, NC)
Application Number:	09/873,797
Patent Claims:	1. A substantially monodispersed mixture of conjugates, each conjugate comprising a drug coupled to an oligomer that comprises a polypropylene glycol moiety having at least 2 polypropylene glycol subunits. 2. The mixture according to claim 1, wherein the polypropylene glycol moiety has at least 5 polypropylene glycol subunits. 3. The mixture according to claim 1, wherein the polypropylene glycol moiety has at least 7 polypropylene glycol subunits. 4. The mixture according to claim 1, wherein the oligomer is covalently coupled to the drug. 5. The mixture according to claim 1, wherein the oligomer further comprises a lipophilic moiety. 6. The mixture according to claim 1, wherein the polypropylene glycol moiety is uniform. 7. The mixture according to claim 6, wherein the oligomer is devoid of a lipophilic moiety, and wherein the conjugate is amphiphilically balanced such that it is aqueously soluble and able to penetrate biological membranes. 8. The mixture according to claim 1, wherein at least 96 percent of the conjugates in the mixture have the same molecular weight. 9. The mixture according to claim 1, wherein the mixture is a monodispersed mixture. 10. The mixture according to claim 1, wherein the mixture is a substantially purely monodispersed mixture. 11. The mixture according to claim 1, wherein at least 96 percent of the conjugates in the mixture have the same molecular weight and the same molecular structure. 12. The mixture according to claim 1, wherein the mixture is a purely monodispersed mixture. 13. The mixture according to claim 12, wherein the oligomer is covalently coupled to the drug. 14. The mixture according to claim 12, wherein the oligomer further comprises a lipophilic moiety. 15. The mixture according to claim 12, wherein the polypropylene glycol moiety is uniform. 16. The mixture according to claim 15, wherein the oligomer is devoid of a lipophilic moiety, and wherein the conjugate is amphiphilically balanced such that it is aqueously soluble and able to penetrate biological membranes. 17. The mixture according to claim 1, wherein the mixture has an in vivo activity that is greater than the in vivo activity of a polydispersed mixture of drug-oligomer conjugates having the same number average molecular weight as the mixture. 18. The mixture according to claim 1, wherein the mixture has an in vitro activity that is greater than the in vitro activity of a polydispersed mixture of drug-oligomer conjugates having the same number average molecular weight as the mixture. 19. The mixture according to claim 1, wherein the mixture has an increased resistance to degradation by chymotrypsin when compared to the resistance to degradation by chymotrypsin of a polydispersed mixture of drug-oligomer conjugates having the same number average molecular weight as the mixture. 20. The mixture according to claim 1, wherein the mixture has an inter-subject variability that is less than the inter-subject variability of a polydispersed mixture of drug-oligomer conjugates having the same number average molecular weight as the mixture. 21. The mixture according to claim 1, wherein the drug is a polypeptide. 22. The mixture according to claim 21, wherein the polypeptide is selected from the group consisting of adrenocorticotropic hormone peptides, adrenomedullin peptides, allatostatin peptides, amylin peptides, amyloid beta-protein fragment peptides, angiotensin peptides, antibiotic peptides, antigenic polypeptides, anti-microbial peptides, apoptosis related peptides, atrial natriuretic peptides, bag cell peptides, bombesin peptides, bone GLA peptides, bradykinin peptides, brain natriuretic peptides, C-peptides, C-type natriuretic peptides, calcitonin peptides, calcitonin gene related peptides, CART peptides, casomorphin peptides, chemotactic peptides, cholecystokinin peptides, colony-stimulating factor peptides, corticortropin releasing factor peptides, cortistatin peptides, cytokine peptides, dermorphin peptides, dynorphin peptides, endorphin peptides, endothelin peptides, ETa receptor antagonist peptides, ETb receptor antagonist peptides, enkephalin peptides, fibronectin peptides, galanin peptides, gastrin peptides, glucagon peptides, Gn-RH associated peptides, growth factor peptides, growth hormone peptides, GTP-binding protein fragment peptides, guanylin peptides, inhibin peptides, insulin peptides, interleukin peptides, laminin peptides, leptin peptides, leucokinin peptides, luteinizing hormone-releasing hormone peptides, mastoparan peptides, mast cell degranulating peptides, melanocyte stimulating hormone peptides, morphiceptin peptides, motilin peptides, neuro-peptides, neuropeptide Y peptides, neurotropic factor peptides, orexin peptides, opioid peptides, oxytocin peptides, PACAP peptides, pancreastatin peptides, pancreatic polypeptides, parathyroid hormone peptides, parathyroid hormone-related peptides, peptide T peptides, prolactin-releasing peptides, peptide YY peptides, renin substrate peptides, secretin peptides, somatostatin peptides, substance P peptides, tachykinin peptides, thyrotropin-releasing hormone peptides, toxin peptides, vasoactive intestinal peptides, vasopressin peptides, and virus related peptides. 23. The mixture according to claim 21, wherein the oligomer is covalently coupled to a nucleophilic residue of the polypeptide. 24. The mixture according to claim 1, wherein each conjugate comprises a plurality of oligomers. 25. The mixture according to claim 24, wherein each oligomer in the plurality of oligomers is the same. 26. The mixture according to claim 1, wherein the oligomer comprises a first polypropylene glycol moiety covalently coupled to the drug by a non-hydrolyzable bond and a second polypropylene glycol moiety covalently coupled to the first polypropylene glycol moiety by a hydrolyzable bond. 27. The mixture according to claim 26, wherein the oligomer further comprises a lipophilic moiety covalently coupled to the second polypropylene glycol moiety. 28. A pharmaceutical composition comprising: the mixture according to claim 1; and a pharmaceutically acceptable carrier. 29. A substantially monodispersed mixture of conjugates, each conjugate comprising a drug coupled to an oligomer that comprises a polypropylene glycol moiety and wherein the oligomer is devoid of a lipophilic moiety, and wherein the conjugate is amphiphilically balanced such that it is aqueously soluble and able to penetrate biological membranes. 30. The mixture according to claim 29, wherein the polypropylene glycol moiety is uniform. 31. The mixture according to claim 29, wherein the oligomer is covalently coupled to the drug. 32. The mixture according to claim 29, wherein the polypropylene glycol moiety is uniform. 33. A mixture of conjugates each comprising a drug coupled to an oligomer that comprises a polypropylene glycol moiety, said mixture having a molecular weight distribution with a standard deviation of less than about 22 Daltons. 34. The mixture according to claim 33, wherein the standard deviation of the molecular weight distribution is less than about 14 Daltons. 35. The mixture according to claim 33, wherein the standard deviation of the molecular weight distribution is less than about 11 Daltons. 36. The mixture according to claim 33, wherein the polypropylene glycol moiety has at least 7 polypropylene glycol subunits. 37. The mixture according to claim 33, wherein the oligomer further comprises a lipophilic moiety. 38. The mixture according to claim 33, wherein the polypropylene glycol moiety is uniform. 39. The mixture according to claim 38, wherein the oligomer is devoid of a lipophilic moiety, and wherein the conjugate is amphiphilically balanced such that it is aqueously soluble and able to penetrate biological membranes. 40. The mixture according to claim 33, wherein the drug is a polypeptide selected from the group consisting of adrenocorticotropic hormone peptides, adrenomedullin peptides, allatostatin peptides, amylin peptides, amyloid beta-protein fragment peptides, angiotensin peptides, antibiotic peptides, antigenic polypeptides, anti-microbial peptides, apoptosis related peptides, atrial natriuretic peptides, bag cell peptides, bombesin peptides, bone GLA peptides, bradykinin peptides, brain natriuretic peptides, C-peptides, C-type natriuretic peptides, calcitonin peptides, calcitonin gene related peptides, CART peptides, casomorphin peptides, chemotactic peptides, cholecystokinin peptides, colony-stimulating factor peptides, corticortropin releasing factor peptides, cortistatin peptides, cytokine peptides, dermorphin peptides, dynorphin peptides, endorphin peptides, endothelin peptides, ETa receptor antagonist peptides, ETb receptor antagonist peptides, enkephalin peptides, fibronectin peptides, galanin peptides, gastrin peptides, glucagon peptides, Gn-RH associated peptides, growth factor peptides, growth hormone peptides, GTP-binding protein fragment peptides, guanylin peptides, inhibin peptides, insulin peptides, interleukin peptides, laminin peptides, leptin peptides, leucokinin peptides, luteinizing hormone-releasing hormone peptides, mastoparan peptides, mast cell degranulating peptides, melanocyte stimulating hormone peptides, morphiceptin peptides, motilin peptides, neuro-peptides, neuropeptide Y peptides, neurotropic factor peptides, orexin peptides, opioid peptides, oxytocin peptides, PACAP peptides, pancreastatin peptides, pancreatic polypeptides, parathyroid hormone peptides, parathyroid hormone-related peptides, peptide T peptides, prolactin-releasing peptides, peptide YY peptides, renin substrate peptides, secretin peptides, somatostatin peptides, substance P peptides, tachykinin peptides, thyrotropin-releasing hormone peptides, toxin peptides, vasoactive intestinal peptides, vasopressin peptides, and virus related peptides. 41. A mixture of conjugates each comprising a drug coupled to a polymer comprising a polypropylene glycol moiety, wherein the mixture has a dispersity coefficient (DC) greater than 10,000 where ##EQU4## wherein: n is the number of different molecules in the sample; N.sub.i is the number of i.sup.th molecules in the sample; and M.sub.i is the mass of the i.sup.th molecule. 42. The mixture according to claim 41, wherein the dispersity coefficient is greater than 100,000. 43. The mixture according to claim 41, wherein the dispersity coefficient is greater than 500,000. 44. The mixture according to claim 41, wherein the polypropylene glycol moiety has at least 7 polypropylene glycol subunits. 45. The mixture according to claim 41, wherein the polymer further comprises a lipophilic moiety. 46. The mixture according to claim 41, wherein the polypropylene glycol moiety is uniform. 47. The mixture according to claim 46, wherein the polymer is devoid of a lipophilic moiety, and wherein the conjugate is amphiphilically balanced such that it is aqueously soluble and able to penetrate biological membranes. 48. The mixture according to claim 41, wherein the drug is a polypeptide selected from the group consisting of adrenocorticotropic hormone peptides, adrenomedullin peptides, allatostatin peptides, amylin peptides, amyloid beta-protein fragment peptides, angiotensin peptides, antibiotic peptides, antigenic polypeptides, anti-microbial peptides, apoptosis related peptides, atrial natriuretic peptides, bag cell peptides, bombesin peptides, bone GLA peptides, bradykinin peptides, brain natriuretic peptides, C-peptides, C-type natriuretic peptides, calcitonin peptides, calcitonin gene related peptides, CART peptides, casomorphin peptides, chemotactic peptides, cholecystokinin peptides, colony-stimulating factor peptides, corticortropin releasing factor peptides, cortistatin peptides, cytokine peptides, dermorphin peptides, dynorphin peptides, endorphin peptides, endothelin peptides, ETa receptor antagonist peptides, ETb receptor antagonist peptides, enkephalin peptides, fibronectin peptides, galanin peptides, gastrin peptides, glucagon peptides, Gn-RH associated peptides, growth factor peptides, growth hormone peptides, GTP-binding protein fragment peptides, guanylin peptides, inhibin peptides, insulin peptides, interleukin peptides, laminin peptides, leptin peptides, leucokinin peptides, luteinizing hormone-releasing hormone peptides, mastoparan peptides, mast cell degranulating peptides, melanocyte stimulating hormone peptides, morphiceptin peptides, motilin peptides, neuro-peptides, neuropeptide Y peptides, neurotropic factor peptides, orexin peptides, opioid peptides, oxytocin peptides, PACAP peptides, pancreastatin peptides, pancreatic polypeptides, parathyroid hormone peptides, parathyroid hormone-related peptides, peptide T peptides, prolactin-releasing peptides, peptide YY peptides, renin substrate peptides, secretin peptides, somatostatin peptides, substance P peptides, tachykinin peptides, thyrotropin-releasing hormone peptides, toxin peptides, vasoactive intestinal peptides, vasopressin peptides, and virus related peptides. 49. A mixture of conjugates in which each conjugate: comprises a drug coupled to an oligomer; and has the same number of polypropylene glycol subunits. 50. The mixture according to claim 49, wherein the polypropylene glycol moiety has at least 7 polypropylene glycol subunits. 51. The mixture according to claim 49, wherein the oligomer further comprises a lipophilic moiety. 52. The mixture according to claim 49, wherein the polypropylene glycol moiety is uniform. 53. The mixture according to claim 52, wherein the oligomer is devoid of a lipophilic moiety, and wherein the conjugate is amphiphilically balanced such that it is aqueously soluble and able to penetrate biological membranes. 54. The mixture according to claim 49, wherein the drug is a polypeptide selected from the group consisting of adrenocorticotropic hormone peptides, adrenomedullin peptides, allatostatin peptides, amylin peptides, amyloid beta-protein fragment peptides, angiotensin peptides, antibiotic peptides, antigenic polypeptides, anti-microbial peptides, apoptosis related peptides, atrial natriuretic peptides, bag cell peptides, bombesin peptides, bone GLA peptides, bradykinin peptides, brain natriuretic peptides, C-peptides, C-type natriuretic peptides, calcitonin peptides, calcitonin gene related peptides, CART peptides, casomorphin peptides, chemotactic peptides, cholecystokinin peptides, colony-stimulating factor peptides, corticortropin releasing factor peptides, cortistatin peptides, cytokine peptides, dermorphin peptides, dynorphin peptides, endorphin peptides, endothelin peptides, ETa receptor antagonist peptides, ETb receptor antagonist peptides, enkephalin peptides, fibronectin peptides, galanin peptides, gastrin peptides, glucagon peptides, Gn-RH associated peptides, growth factor peptides, growth hormone peptides, GTP-binding protein fragment peptides, guanylin peptides, inhibin peptides, insulin peptides, interleukin peptides, laminin peptides, leptin peptides, leucokinin peptides, luteinizing hormone-releasing hormone peptides, mastoparan peptides, mast cell degranulating peptides, melanocyte stimulating hormone peptides, morphiceptin peptides, motilin peptides, neuro-peptides, neuropeptide Y peptides, neurotropic factor peptides, orexin peptides, opioid peptides, oxytocin peptides, PACAP peptides, pancreastatin peptides, pancreatic polypeptides, parathyroid hormone peptides, parathyroid hormone-related peptides, peptide T peptides, prolactin-releasing peptides, peptide YY peptides, renin substrate peptides, secretin peptides, somatostatin peptides, substance P peptides, tachykinin peptides, thyrotropin-releasing hormone peptides, toxin peptides, vasoactive intestinal peptides, vasopressin peptides, and virus related peptides. 55. A mixture of conjugates in which each conjugate has the same molecular weight and has the formula: ##STR17## wherein: B is a bonding moiety; L is a linker moiety; G, G' and G" are individually selected spacer moieties; R is a lipophilic moiety and R' is a polypropylene glycol moiety, or R' is a lipophilic moiety and R is a polypropylene glycol moiety; T is a terminating moiety; h, i, j, k, m and n are individually 0 or 1, with the proviso that when R is a polypropylene glycol moiety, m is 1; and when R' is a polypropylene glycol moiety, n is 1; and p is an integer from 1 to the number of nucleophilic residues on the drug. 56. The mixture according to claim 55, wherein the polypropylene glycol moiety has at least 7 polypropylene glycol subunits. 57. The mixture according to claim 55, wherein: R is the polypropylene glycol moiety; R' is a lipophilic moiety; n and m are 1; and i, j and k are 0. 58. The mixture according to claim 55, wherein: R is a lipophilic moiety; R' is the polypropylene glycol moiety; n and m are 1; and i, j and k are each 0. 59. The mixture according to claim 55, wherein the polypropylene glycol moiety is uniform. 60. The mixture according to claim 59, wherein: R is the polypropylene glycol moiety; m is 1; i, j, k and n are each 0; and each conjugate in the mixture is amphiphilically balanced such that each conjugate is aqueously soluble and able to penetrate biological membranes. 61. The mixture according to claim 55, wherein the drug is a polypeptide selected from the group consisting of adrenocorticotropic hormone peptides, adrenomedullin peptides, allatostatin peptides, amylin peptides, amyloid beta-protein fragment peptides, angiotensin peptides, antibiotic peptides, antigenic polypeptides, anti-microbial peptides, apoptosis related peptides, atrial natriuretic peptides, bag cell peptides, bombesin peptides, bone GLA peptides, bradykinin peptides, brain natriuretic peptides, C-peptides, C-type natriuretic peptides, calcitonin peptides, calcitonin gene related peptides, CART peptides, casomorphin peptides, chemotactic peptides, cholecystokinin peptides, colony-stimulating factor peptides, corticortropin releasing factor peptides, cortistatin peptides, cytokine peptides, dermorphin peptides, dynorphin peptides, endorphin peptides, endothelin peptides, ETa receptor antagonist peptides, ETb receptor antagonist peptides, enkephalin peptides, fibronectin peptides, galanin peptides, gastrin peptides, glucagon peptides, Gn-RH associated peptides, growth factor peptides, growth hormone peptides, GTP-binding protein fragment peptides, guanylin peptides, inhibin peptides, insulin peptides, interleukin peptides, laminin peptides, leptin peptides, leucokinin peptides, luteinizing hormone-releasing hormone peptides, mastoparan peptides, mast cell degranulating peptides, melanocyte stimulating hormone peptides, morphiceptin peptides, motilin peptides, neuro-peptides, neuropeptide Y peptides, neurotropic factor peptides, orexin peptides, opioid peptides, oxytocin peptides, PACAP peptides, pancreastatin peptides, pancreatic polypeptides, parathyroid hormone peptides, parathyroid hormone-related peptides, peptide T peptides, prolactin-releasing peptides, peptide YY peptides, renin substrate peptides, secretin peptides, somatostatin peptides, substance P peptides, tachykinin peptides, thyrotropin-releasing hormone peptides, toxin peptides, vasoactive intestinal peptides, vasopressin peptides, and virus related peptides. 62. A pharmaceutical composition comprising: the mixture according to claim 12; and pharmaceutically acceptable carrier. 63. A pharmaceutical composition comprising: the mixture according to claim 29; and a pharmaceutically acceptable carrier. 64. A pharmaceutical composition comprising; the mixture according to claim 33; and a pharmaceutically acceptable carrier. 65. A pharmaceutical composition comprising: the mixture according to claim 41; and a pharmaceutically acceptable carrier. 66. A pharmaceutical composition comprising: the mixture according to claim 49; and a pharmaceutically acceptable carrier. 67. A pharmaceutical composition comprising: the mixture according to claim 55; and a pharmaceutically acceptable carrier. 68. A process for synthesizing a substantially monodispersed mixture of conjugates each conjugate comprising a drug coupled to an oligomer that comprises a polyethylene glycol moiety, said process comprising: reacting a substantially monodispersed mixture comprising compounds having the structure of Formula I: 69. The process according to claim 68, wherein the fatty acid moiety or the ester of a fatty acid moiety comprises an alkyl moiety at least 5 carbon atoms in length. 70. The process according to claim 68, wherein R.sup.1 is a methyl group. 71. The process according to claim 68, further comprising: reacting a substantially monodispersed mixture comprising compounds having the structure of Formula V: 72. A process for synthesizing a substantially monodispersed mixture of conjugates each conjugate comprising a drug coupled to an oligomer that comprises a polyethylene glycol moiety, said process comprising: reacting a substantially monodispersed mixture comprising compounds having the structure of Formula VI: 73. The process according to claim 68, further comprising: reacting a substantially monodispersed mixture comprising compounds having the structure of Formula IV: 74. The process according to claim 68, wherein the activating of the substantially monodispersed mixture comprises reacting the substantially monodispersed mixture of polymers of Formula III with N-hydroxy succinimide to provide an activated polymer capable of reacting with a drug. 75. The process according to claim 68, wherein the drug is a polypeptide, and wherein the reacting of the substantially monodispersed mixture of activated polymers with a substantially monodispersed mixture of polypeptides comprises: reacting the substantially monodispersed mixture of activated polymers with one or more amino functionalities of the polypeptide to provide a substantially monodispersed mixture of conjugates each comprising the polypeptide coupled to an oligomer that comprises a polyethylene glycol moiety with m+n subunits.

Details for Patent 6,858,580

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2039-02-26