.

Pharmaceutical Business Intelligence

  • Anticipate P&T budget requirements
  • Evaluate market entry opportunities
  • Find generic sources and suppliers
  • Predict branded drug patent expiration

► Plans and Pricing

Upgrade to enjoy subscriber-only features like email alerts and data export. See the Plans and Pricing

DrugPatentWatch Database Preview

Claims for Patent: 6,011,007

« Back to Dashboard

Claims for Patent: 6,011,007

Title: Acylated insulin
Abstract:The present invention relates to protracted human insulin derivatives in which the A21 and the B3 amino acid residues are, independently, any amino acid residue which can be coded for by the genetic code except Lys, Arg and Cys; Phe.sup.B1 may be deleted; the B30 amino acid residue is (a) a non-codable, lipophilic amino acid having from 10 to 24 carbon atoms, in which case an acyl group of a carboxylic acid with up to 5 carbon atoms is bound to the .epsilon.-amino group of Lys.sup.B29 ; or (b) the B30 amino acid residue is deleted or is any amino acid residue which can be coded for by the genetic code except Lys, Arg and Cys, in any of which cases the .epsilon.-amino group of Lys.sup.B29 has a lipophilic substituent; and any Zn.sup.2+ complexes thereof with the proviso that when B30 is Thr or Ala and A21 and B3 are both Asn, and Phe.sup.B1 is present, then the insulin derivative is always present as a Zn.sup.2+ complex.
Inventor(s): Havelund; Svend (Bagsvaerd, DK), Halstrom; John (Hundested, DK), Jonassen; Ib (Valby, DK), Andersen; Asser Sloth (Frederiksberg, DK), Markussen; Jan (Herlev, DK)
Assignee: Novo Nordisk A/S (Bagsvaerd, DK)
Application Number:08/975,365
Patent Claims: 1. An insulin derivative having the following sequence: ##STR2## wherein (a) Xaa at positions A21 and B3 are, independently, any amino acid residue which can be coded for by the genetic code except Lys, Arg and Cys;

(b) Xaa at position B1 is Phe or is deleted;

(c) Xaa at position B30 is any amino acid residue which can be coded for by the genetic code except Lys, Arg and Cys; and

(d) the .epsilon.-amino group of Lys.sup.B29 is substituted with a lipophilic substituent having at least 10 carbon atoms;

wherein the insulin derivative is a Zn.sup.2+ complex and the Zn.sup.2+ complex of the insulin derivative is more water soluble than the insulin derivative without Zn.sup.2+.

2. The insulin derivative according to claim 1, wherein Xaa at position A21 is Asn.

3. The insulin derivative according to claim 2, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

4. The insulin derivative according to claim 1, wherein Xaa at position A21 is Ala, Asn, Gln, Gly or Ser.

5. The insulin derivative according to claim 4, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

6. The insulin derivative according to claim 1, wherein Xaa at position B1 is deleted.

7. The insulin derivative according to claim 6, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

8. The insulin derivative according to claim 1, wherein Xaa at position B1 is Phe.

9. The insulin derivative according to claim 8, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

10. The insulin derivative according to claim 1, wherein Xaa at position B3 is Asn, Asp, Gln or Thr.

11. The insulin derivative according to claim 10, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

12. The insulin derivative according to claim 1, wherein Xaa at position B30 is Ala or Thr.

13. The insulin derivative according to claim 12, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

14. The insulin derivative according to claim 1, wherein Xaa at position A21 is Ala, Asn, Gln, Gly or Ser, Xaa at position B3 is Asn, Asp, Gln or Thr, and Xaa at position B30 is Ala or Thr.

15. The insulin derivative according to claim 14, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

16. The insulin derivative according to claim 1, wherein Xaa at position A21 is Asn, Xaa at position B3 is Asn, Xaa at position B1 is Phe and Xaa at position B30 is Thr.

17. The insulin derivative according to claim 16, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

18. The insulin derivative according to claim 1, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

19. The insulin derivative according to claim 1 which is in the form of a hexamer.

20. The insulin derivative according to claim 19, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

21. The insulin derivative according to claim 19, wherein Xaa at position A21 is Asn, Xaa at position B1 is Phe, Xaa at position B3 is Asn, and Xaa at position B30 is Thr.

22. The insulin derivative according to claim 19, wherein two zinc ions bind to the hexamer.

23. The insulin derivative according to claim 22, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

24. The insulin derivative according to claim 19, wherein three zinc ions bind to the hexamer.

25. The insulin derivative according to claim 24, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

26. The insulin derivative according to claim 19, wherein four zinc ions bind to the hexamer.

27. The insulin derivative according to claim 26, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

28. A pharmaceutical composition which is an aqueous solution, comprising (a) an insulin derivative according to claim 1, (b) an isotonic agent, (c) a preservative and (d) a buffer.

29. The pharmaceutical composition according to claim 28, wherein the pH of the aqueous solution is in the range of 6.5-8.5.

30. The pharmaceutical composition according to claim 28, wherein the solubility of the insulin derivative exceeds 600 nmol/ml of the aqueous solution.

31. The pharmaceutical composition according to claim 28, further comprising an insulin or an insulin analogue which has a rapid onset of action.

32. The pharmaceutical composition according to claim 28, wherein Xaa at position A21 is Asn, Xaa at position B3 is Asn, Xaa at position B1 is Phe and Xaa at position B30 is Thr.

33. The pharmaceutical composition according to claim 28, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

34. The pharmaceutical composition according to claim 28, wherein the insulin derivative is in the form of a hexamer.

35. A method of treating diabetes in a patient in need of such a treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to claim 28.

36. The insulin derivative of claim 1, wherein the lipophilic substituent is cyclohexylvaleroyl.

37. The insulin derivative of claim 1, wherein the lipophilic substituent is acyl-glutamyl wherein the acyl is a linear, saturated acyl having 6 to 24 carbon atoms.

38. The insulin derivative of claim 1, wherein the lipophilic substituent is lauroyl.

39. The insulin derivative of claim 1, wherein the lipophilic substituent is myristoyl.

40. The insulin derivative of claim 1, wherein the lipophilic substituent is palmitoyl.

41. The insulin derivative of claim 1, wherein the lipophilic substituent is 2-succinylamido myristic acid.

42. The insulin derivative of claim 1, wherein the lipophilic substituent is 2-succinylamido palmitic acid.

43. The insulin derivative of claim 1, wherein the lipophilic substituent is 2-succinylamidoethyloxy palmitic acid.

44. The insulin derivative of claim 1, wherein the lipophilic substituent is myristoyl-.alpha.-glutamyl.

45. The insulin derivative of claim 1, wherein the lipophilic substituent is myristoyl-.alpha.-glutamyl-glycyl.

46. The insulin derivative of claim 1, wherein the lipophilic substituent is choloyl.

47. The insulin derivative of claim 1, wherein the lipophilic substituent is 7-deoxycholoyl.

48. The insulin derivative of claim 1, wherein the lipophilic substituent is lithocholoyl.

49. The insulin derivative of claim 1, wherein the lipophilic substituent is lithocholoyl-glutamyl.

50. The insulin derivative of claim 1, wherein the lipophilic substituent is 4-benzoyl-phenylalanine.

51. The insulin derivative of claim 1, wherein the lipophilic substituent is L-thyroxyl.

52. The insulin derivative of claim 1, wherein the lipophilic substituent is suberoyl-D-thyroxine.

53. The insulin derivative of claim 1, wherein the lipophilic substituent is 3,3',5,5'-tetraiodothyroacetyl.

54. An insulin derivative having the following sequence: ##STR3## wherein (a) Xaa at positions A21 and B3 are, independently, any amino acid residue which can be coded for by the genetic code except Lys, Arg and Cys;

(b) Xaa at position B1 is Phe or is deleted;

(c) Xaa at position B30 is deleted; and

(d) the .epsilon.-amino group of Lys.sup.B29 is substituted with a lipophilic substituent having at least 10 carbon atoms;

wherein the insulin derivative is a Zn.sup.2+ complex and the Zn.sup.2+ complex of the insulin derivative is more water soluble than the insulin derivative without Zn.sup.2+.

55. The insulin derivative according to claim 54, wherein Xaa at position A21 is Ala, Asn, Gln, Gly or Ser.

56. The insulin derivative according to claim 55, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

57. The insulin derivative according to claim 54, wherein Xaa at position B1 is deleted.

58. The insulin derivative according to claim 57, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

59. The insulin derivative according to claim 54, wherein Xaa at position B1 is Phe.

60. The insulin derivative according to claim 59, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

61. The insulin derivative according to claim 54, wherein Xaa at position B3 is Asn, Asp, Gln or Thr.

62. The insulin derivative according to claim 61, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

63. The insulin derivative according to claim 54 wherein Xaa at position A21 is Ala, Asn, Gln, Gly or Ser, and Xaa at position B3 is Asn, Asp, Gln or Thr.

64. The insulin derivative according to claim 63, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

65. The insulin derivative according to claim 54, wherein Xaa at position A21 is Asn, Xaa at position B1 is Phe, and Xaa at position B3 is Asn.

66. The insulin derivative according to claim 65, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

67. The insulin derivative according to claim 54, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

68. The insulin derivative according to claim 54 which is in the form of a hexamer.

69. The insulin derivative according to claim 68, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

70. The insulin derivative according to claim 68, wherein Xaa at position A21 is Asn, Xaa at position B3 is Asn, and Xaa at position B1 is Phe.

71. The insulin derivative according to claim 68, wherein two zinc ions bind to the hexamer.

72. The insulin derivative according to claim 71, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

73. The insulin derivative according to claim 68, wherein three zinc ions bind to the hexamer.

74. The insulin derivative according to claim 73, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

75. The insulin derivative according to claim 68, wherein four zinc ions bind to the hexamer.

76. The insulin derivative according to claim 75, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

77. A pharmaceutical composition which is an aqueous solution, comprising (a) an insulin derivative according to claim 54, (b) an isotonic agent, (c) a preservative and (d) a buffer.

78. The pharmaceutical composition according to claim 77, wherein the pH of the aqueous solution is in the range of 6.5-8.5.

79. The pharmaceutical composition according to claim 77, wherein the solubility of the insulin derivative exceeds 600 nmol/ml of the aqueous solution.

80. The pharmaceutical composition according to claim 77, further comprising an insulin or an insulin analogue which has a rapid onset of action.

81. The pharmaceutical composition according to claim 77, wherein the insulin derivative is a Zn.sup.2+ complex.

82. The pharmaceutical composition according to claim 77, wherein Xaa at position A21 is Asn, Xaa at position B3 is Asn, and Xaa at position B1 is Phe.

83. The pharmaceutical composition according to claim 77, wherein the lipophilic substituent has from 12 to 24 carbon atoms.

84. The pharmaceutical composition according to claim 77, wherein the insulin derivative is in the form of a hexamer.

85. A method of treating diabetes in a patient in need of such a treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to claim 77.

86. The insulin derivative of claim 54, wherein the lipophilic substituent is cyclohexylvaleroyl.

87. The insulin derivative of claim 54, wherein the lipophilic substituent is acyl-glutamyl wherein the acyl is a linear, saturated acyl having 6 to 24 carbon atoms.

88. The insulin derivative of claim 54, wherein the lipophilic substituent is lauroyl.

89. The insulin derivative of claim 54, wherein the lipophilic substituent is myristoyl.

90. The insulin derivative of claim 54, wherein the lipophilic substituent is palmitoyl.

91. The insulin derivative of claim 54, wherein the lipophilic substituent is 2-succinylamido myristic acid.

92. The insulin derivative of claim 54, wherein the lipophilic substituent is 2-succinylamido palmitic acid.

93. The insulin derivative of claim 54, wherein the lipophilic substituent is 2-succinylamidoethyloxy palmitic acid.

94. The insulin derivative of claim 54, wherein the lipophilic substituent is myristoyl-.alpha.-glutamyl.

95. The insulin derivative of claim 54, wherein the lipophilic substituent is myristoyl-.alpha.-glutamyl-glycyl.

96. The insulin derivative of claim 54, wherein the lipophilic substituent is choloyl.

97. The insulin derivative of claim 54, wherein the lipophilic substituent is 7-deoxycholoyl.

98. The insulin derivative of claim 54, wherein the lipophilic substituent is lithocholoyl.

99. The insulin derivative of claim 54, wherein the lipophilic substituent is lithocholoyl-glutamyl.

100. The insulin derivative of claim 54, wherein the lipophilic substituent is 4-benzoyl-phenylalanine.

101. The insulin derivative of claim 54, wherein the lipophilic substituent is L-thyroxyl.

102. The insulin derivative of claim 54, wherein the lipophilic substituent is suberoyl-D-thyroxine.

103. The insulin derivative of claim 54, wherein the lipophilic substituent is 3,3',5,5'-tetraiodothyroacetyl.

104. An insulin derivative having the following sequence: ##STR4## wherein (a) Xaa at positions A21 and B3 are, independently, any amino acid residue which can be coded for by the genetic code except Lys, Arg and Cys;

(b) Xaa at position B1 is Phe or is deleted;

(c) Xaa at position B30 is any amino acid residue which can be coded for by the genetic code except Lys, Arg and Cys; and

(d) the .epsilon.-amino group of Lys.sup.B29 is substituted with a lipophilic substituent having at least 10 carbon atoms;

wherein the lipophilic substituent is benzoyl, phenylacetyl, cyclohexylacetyl, 3,5-diiodotyrosyl or cyclohexylpropionyl and the insulin derivative is a Zn.sup.2+ complex and the Zn.sup.2+ complex of the insulin derivative is more water soluble than the insulin derivative without Zn.sup.2+.

105. The insulin derivative of claim 104, wherein the lipophilic substituent is benzoyl.

106. The insulin derivative of claim 104, wherein the lipophilic substituent is phenylacetyl.

107. The insulin derivative of claim 104, wherein the lipophilic substituent is cyclohexylacetyl.

108. The insulin derivative of claim 104, wherein the lipophilic substituent is 3,5-diiodotyrosyl.

109. The insulin derivative of claim 104, wherein the lipophilic substituent is cyclohexylpropionyl.

110. An insulin derivative having the following sequence: ##STR5## wherein (a) Xaa at positions A21 and B3 are, independently, any amino acid residue which can be coded for by the genetic code except Lys, Arg and Cys;

(b) Xaa at position B1 is Phe or is deleted;

(c) Xaa at position B30 is deleted; and

(d) the .epsilon.-amino group of Lys.sup.B29 is substituted with a lipophilic substituent having at least 10 carbon atoms;

wherein the lipophilic substituent is benzoyl, phenylacetyl, cyclohexylacetyl, 3,5-diidotyrosyl or cyclohexylpropionyl and the insulin derivative is a Zn.sup.2+ complex and the Zn.sup.2+ complex of the insulin derivative is more water soluble than the insulin derivative without Zn.sup.2+.

111. The insulin derivative of claim 110, wherein the lipophilic substituent is benzoyl.

112. The insulin derivative of claim 110, wherein the lipophilic substituent is phenylacetyl.

113. The insulin derivative of claim 110, wherein the lipophilic substituent is cyclohexylacetyl.

114. The insulin derivative of claim 110, wherein the lipophilic substituent is 3,5-diidotyrosyl.

115. The insulin derivative of claim 110, wherein the lipophilic substituent is cyclohexylpropionyl.
« Back to Dashboard

For more information try a trial or see the database preview and plans and pricing

How are People Using DrugPatentWatch?

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.

`abc