Derivatives of GLP-1 analogs

• US 20030199672A1
• Filed: 08/19/2002
• Published: 10/23/2003
• Est. Priority Date: 08/30/1996
• Status: Active Grant

• Current Assignee: Freddy Zimmerdahl Pedersen, Helle Birk Olsen, Kjeld Madsen, Liselotte Bjerre Knudsen, Niels C. Kaarsholm, Per Franklin Nielsen, Per Olaf Huusfeldt, Soren Erik Bjorn
• Original Assignee: Freddy Zimmerdahl Pedersen, Helle Birk Olsen, Kjeld Madsen, Liselotte Bjerre Knudsen, Niels C. Kaarsholm, Per Franklin Nielsen, Per Olaf Huusfeldt, Soren Erik Bjorn
• Inventors: Olsen, Helle Birk, Kaarsholm, Niels C., Knudsen, Liselotte Bjerre, Nielsen, Per Franklin, Madsen, Kjeld, Bjorn, Soren Erik, Pedersen, Freddy Zimmerdahl, Huusfeldt, Per Olaf
• Granted Patent: US 7,235,627 B2
• Time in Patent Office: Days
• US Class Current: 530/324
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 38/2264 Obesity-gene products, e.g. leptin
• CPC Class Codes: A61K 38/26 Glucagons
• 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 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: C11D 3/0063 Photo- activating compounds
• CPC Class Codes: C11D 3/168 Organometallic compounds or orgometallic complexes

Abstract

The present invention relates to a pharmaceutical composition comprising a GLP-1 derivative having a lipophilic substituent; and a surfactant.

Claims

1. A pharmaceutical composition comprising a GLP-1 derivative of formula I (SEQ ID NO:

2);

28. The pharmaceutical composition of any of claims 1-27, wherein in the GLP-1 derivative only one Lys is present.

29. The pharmaceutical composition of any of claims 1-28, wherein in the GLP-1 derivative Lys is at the carboxy-terminus.

30. The pharmaceutical composition of any of claims 1-29, wherein in the GLP-1 derivative Glu or Asp is adjacent to Lys.

31. The pharmaceutical composition of any of claims 1-30, wherein the total number of different amino acids between the GLP-1 derivative and the corresponding native form of GLP-1 is five.

32. The pharmaceutical composition of any of claims 1-30, wherein the total number of different amino acids between the GLP-1 derivative and the corresponding native form of GLP-1 is four.

33. The pharmaceutical composition of any of claims 1-30, wherein the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 is three.

34. The pharmaceutical composition of any of claims 1-30, wherein the total number of different amino acids between the GLP-1 derivative and the corresponding native form of GLP-1 is two.

35. The pharmaceutical composition of any of claims 1-30, wherein the total number of different amino acids between the GLP-1 derivative and the corresponding native form of GLP-1 is one.

36. The pharmaceutical composition of claim 1 or any of claims 28-35, wherein in the GLP-1 derivative the amino acids at positions 37-45 are absent.

37. The pharmaceutical composition of claim 1 or any of claims 28-35, wherein in the GLP-1 derivative the amino acids at positions 38-45 are absent.

38. The pharmaceutical composition of claim 1 or any of claims 28-35, wherein in the GLP-1 derivative the amino acids at positions 39-45 are absent.

39. The pharmaceutical composition of claim 1 or any of claims 28-38, wherein in the GLP-1 derivative Xaa at position 8 is Ala, Gly, Ser, Thr, or Val.

40. The pharmaceutical composition of claim 1 or any of claims 28-39, wherein in the GLP-1 derivative Xaa at position 9 is Glu.

41. The pharmaceutical composition of claim 1 or any of claims 28-40, wherein in the GLP-1 derivative Xaa at position 11 is Thr.

42. The pharmaceutical composition of claim 1 or any of claims 28-41, wherein in the GLP-1 derivative Xaa at position 14 is Ser.

43. The pharmaceutical composition of claim 1 or any of claims 28-42, wherein in the GLP-1 derivative Xaa at position 16 is Val.

44. The pharmaceutical composition of claim 1 or any of claims 28-43, wherein in the GLP-1 derivative Xaa at position 17 is Ser.

45. The pharmaceutical composition of claim 1 or any of claims 28-44, wherein in the GLP-1 derivative Xaa at position 18 is Ser, Lys, Glu, or Asp.

46. The pharmaceutical composition of claim 1 or any of claims 28-45, wherein in the GLP-1 derivative Xaa at position 19 is Tyr, Lys, Glu, or Asp.

47. The pharmaceutical composition of claim 1 or any of claims 28-46, wherein in the GLP-1 derivative Xaa at position 20 is Leu, Lys, Glu, or Asp.

48. The pharmaceutical composition of claim 1 or any of claims 28-47, wherein in the GLP-1 derivative Xaa at position 21 is Glu, Lys, or Asp.

49. The pharmaceutical composition of claim 1 or any of claims 28-48, wherein in the GLP-1 derivative Xaa at position 22 is Gly, Glu, Asp, or Lys.

50. The pharmaceutical composition of claim 1 or any of claims 28-49, wherein in the GLP-1 derivative Xaa at position 23 is Gln, Glu, Asp, or Lys.

51. The pharmaceutical composition of claim 1 or any of claims 28-50, wherein in the GLP-1 derivative Xaa at position 24 is Ala, Glu, Asp, or Lys.

52. The pharmaceutical composition of claim 1 or any of claims 28-51, wherein in the GLP-1 derivative Xaa at position 25 is Ala, Glu, Asp, or Lys.

53. The pharmaceutical composition of claim 1 or any of claims 28-52, wherein in the GLP-1 derivative Xaa at position 26 is Lys, Glu, Asp, or Arg.

54. The pharmaceutical composition of claim 1 or any of claims 28-53, wherein in the GLP-1 derivative Xaa at position 27 is Glu, Asp, or Lys.

55. The pharmaceutical composition of claim 1 or any of claims 28-54, wherein in the GLP-1 derivative Xaa at position 30 is Ala, Glu, Asp, or Lys.

56. The pharmaceutical composition of claim 1 or any of claims 28-55, wherein in the GLP-1 derivative Xaa at position 31 is Trp, Glu, Asp, or Lys.

57. The pharmaceutical composition of claim 1 or any of claims 28-56, wherein in the GLP-1 derivative Xaa at position 32 is Leu, Glu, Asp, or Lys.

58. The pharmaceutical composition of claim 1 or any of claims 28-57, wherein in the GLP-1 derivative Xaa at position 33 is Val, Glu, Asp, or Lys.

59. The pharmaceutical composition of claim 1 or any of claims 28-58, wherein in the GLP-1 derivative Xaa at position 34 is Lys, Arg, Glu, or Asp.

60. The pharmaceutical composition of claim 1 or any of claims 28-59, wherein in the GLP-1 derivative Xaa at position 35 is Gly, Glu, Asp, or Lys.

61. The pharmaceutical composition of claim 1 or any of claims 28-60, wherein in the GLP-1 derivative Xaa at position 36 is Arg, Lys, Glu, or Asp.

62. The pharmaceutical composition of claim 1 or any of claims 28-61, wherein in the GLP-1 derivative Xaa at position 37 is Gly, Glu, Asp, or Lys.

63. The pharmaceutical composition of claim 1 or any of claims 28-62, wherein in the GLP-1 derivative Xaa at position 38 is Arg or Lys.

64. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at position 26 is Arg, each of Xaa at positions 37-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7-36).

65. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at position 26 is Arg, each of Xaa at positions 38-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7-37).

66. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at position 26 is Arg, each of Xaa at positions 39-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7-38).

67. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at position 34 is Arg, each of Xaa at positions 37-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7-36).

68. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at position 34 is Arg, each of Xaa at positions 38-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7-37).

69. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at position 34 is Arg, each of Xaa at positions 39-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7-38).

70. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at positions 26 and 34 is Arg, Xaa at position 36 is Lys, each of Xaa at positions 37-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7-36).

71. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at positions 26 and 34 is Arg, Xaa at position 36 is Lys, each of Xaa at positions 38-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7-37).

72. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at positions 26 and 34 is Arg, Xaa at position 36 is Lys, each of Xaa at positions 39-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7-38).

73. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at positions 26 and 34 is Arg, Xaa at position 38 is Lys, each of Xaa at positions 39-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7-38).

74. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at position 8 is Thr, Ser, Gly or Val, Xaa at position 37 is Glu or Asp, Xaa at position 36 is Lys, each of Xaa at positions 38-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7).

75. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at position 8 is Thr, Ser, Gly or Val, Xaa at position 37 is Glu or Asp, Xaa at position 36 is Lys, each of Xaa at positions 39-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7-38).

76. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at position 8 is Thr, Ser, Gly or Val, Xaa at position 36,is Lys, each of Xaa at positions 37-45 is deleted. And each of the other Xaa is the amino acid in native GLP-1(7-36).

77. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at position 8 is Thr, Ser, Gly or Val, Xaa at position 36 is Lys, each of Xaa at positions 38-45 is deleted. And each of the other Xaa is the amino acid in native GLP-1(7-37).

78. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at position 8 is Thr, Ser, Gly or Val, Xaa at position 36 is Lys, each of Xaa at positions 39-45 is deleted. And each of the other Xaa is the amino acid in native GLP-1(7-38).

79. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at position 8 is Thr, Ser, Gly or Val, Xaa at position 37 is Glu or Asp, Xaa at position 38 is Lys, each of Xaa at positions 39-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7-38).

80. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at position 18, 23 or 27 is Lys, and Xaa at positions 26 and 34 is Arg, each of Xaa at positions 37-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7-36).

81. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at position 18, 23 or 27 is Lys, and Xaa at positions 26 and 34 is Arg, each of Xaa at positions 38-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7-37).

82. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at position 18, 23 or 27 is Lys, and Xaa at positions 26 and 34 is Arg, each of Xaa at positions 39-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7-38).

83. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at position 8 is Thr, Ser, Gly, or Val, Xaa at position 18, 23 or 27 is Lys, and Xaa at position 26 and 34 is Arg, each of Xaa at positions 37-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7-36).

84. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at position 8 is Thr, Ser, Gly, or Val, Xaa at position 18, 23 or 27 is Lys, and Xaa at position 26 and 34 is Arg, each of Xaa at positions 38-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7-37).

85. The pharmaceutical composition of claim 1, wherein in the GLP-1 derivative Xaa at position 8 is Thr, Ser, Gly, or Val, Xaa at position 18, 23 or 27 is Lys, and Xaa at position 26 and 34 is Arg, each of Xaa at positions 39-45 is deleted, and each of the other Xaa is the amino acid in native GLP-1(7-38).

86. The pharmaceutical composition of any of claims 1-85, wherein in the GLP-1 derivative the lipophilic substituent is attached to the N-terminal amino acid residue.

87. The pharmaceutical composition of any of claims 1-85, wherein in the GLP-1 derivative the lipophilic substituent is attached to the C-terminal amino acid residue.

88. The pharmaceutical composition of any of claims 1-85, wherein in the GLP-1 derivative the lipophilic substituent is attached to an am in o acid residue which is not the N-terminal or C-terminal amino acid residue.

89. The pharmaceutical composition of any of the preceding claims, wherein in the GLP-1 derivative the lipophilic substituent comprises from 4 to 40 carbon atoms, more preferred from 8 to carbon atoms.

90. The pharmaceutical composition of any of the preceding claims, wherein in the GLP-1 derivative a lipophilic substituent is attached to an amino acid residue in such a way that a carboxyl group of the lipophilic substituent forms an amide bond with the ε

-amino group of Lys.

91. The pharmaceutical composition of any of the preceding claims, wherein in the GLP-1 derivative the lipophilic substituent is attached to the parent peptide by means of a spacer.

92. The pharmaceutical composition of claim 91, wherein in the GLP-1 derivative the spacer is an unbranched alkane α

,ω

-dicarboxylic acid group having from 1 to 7 methylene groups, preferably two methylene groups, which form a bridge between an amino group of the parent peptide and an amino group of the lipophilic substituent.

93. The pharmaceutical composition of claim 91, wherein in the GLP-1 derivative the spacer is an amino acid residue except Cys, or a dipeptide such as Gly-Lys.

94. The pharmaceutical composition of claim 93, wherein in the GLP-1 derivative the ε

-amino group of Lys forms an amide bond with a carboxylic group of the amino acid residue or dipeptide spacer, and an amino group of the amino acid residue or dipeptide spacer forms an amide bond with a carboxyl group of the lipophilic substituent.

95. The pharmaceutical composition of claim 93, wherein in the GLP-1 derivative the spacer is N^ε

-γ

-L-glutamyl).

96. The pharmaceutical composition of claim 93, wherein in the GLP-1 derivative the spacer is N^ε

-(β

-L-asparagyl).

97. The pharmaceutical composition of claim 93, wherein in the GLP-1 derivative the spacer is N^ε

-glycyl.

98. The pharmaceutical composition of claim 93, wherein in the GLP-1 derivative the spacer is N^ε

-(α

-(γ

-aminobutanoyl).

99. The pharmaceutical composition of any of the preceding claims, wherein in the GLP-1 derivative the lipophilic substituent comprises a partially or completely hydrogenated cyclopentanophenathrene skeleton.

100. The pharmaceutical composition of any of claims 1-89, wherein in the GLP-1 derivative the lipophilic substituent is an straight-chain or branched alkyl group.

101. The pharmaceutical composition of any of claims 1-89 wherein in the GLP-1 derivative the lipophilic substituent is the acyl group of a straight-chain or branched fatty acid.

102. The pharmaceutical composition of claim 101 wherein in the GLP-1 derivative the acyl group is selected from the group comprising CH₃(CH₂)_nCO—

, wherein n is 4 to 38, preferably CH₃(CH₂)₆CO—

, CH₃(CH₂)₈CO—

, CH₃(CH₂)₁₀CO—

, CH₃(CH₂)₁₂CO—

, CH₃(CH₂)₁₄CO—

, CH₃(CH₂)₁₆CO—

, CH₃(CH₂)₁₈CO—

, CH₃(CH₂)₂₀CO— and

CH₃(CH₂)₂₂CO—

.

103. The pharmaceutical composition of any of claims 1-89 wherein in the GLP-1 derivative the lipophilic substituent is an acyl group of a straight-chain or branched alkane α

,ω

-dicarboxylic acid.

104. The pharmaceutical composition of claim 103 wherein in the GLP-1 derivative the acyl group is selected from the group comprising HOOC(CH₂)_mCO—

, wherein m is from 4 to 38, preferably from 4 to 24, more preferred selected from the group comprising HOOC(CH₂)₁₄CO—

, HOOC(CH₂)₁₆CO—

, HOOC(CH₂)₁₈CO—

, HOOC(CH₂)₂₀CO— and

HOOC(CH₂)₂₂CO—

.

105. The pharmaceutical composition of any of claims 1-89, wherein in the GLP-1 derivative the lipophilic substituent is a group of the formula CH₃(CH₂)_p((CH₂)_qCOOH)CHNH—

CO(CH₂)₂CO—

, wherein p and q are integers and p+q is an integer of from 8 to 33, preferably from 12 to 28.

106. The pharmaceutical composition of any of claims 1-89, wherein in the GLP-1 derivative the lipophilic substituent is a group of the formula CH₃(CH₂)_rCO—

NHCH(COOH) (CH₂)₂CO—

, wherein r is an integer of from 10 to 24.

107. The pharmaceutical composition of any of claims 1-89, wherein in the GLP-1 derivative the lipophilic substituent is a group of the formula CH₃(CH₂),CO—

NHCH((CH₂)₂COOH)CO—

, wherein s is an integer of from 8 to 24.

108. The pharmaceutical composition of any of claims 1-89, wherein in the GLP-1 derivative the lipophilic substituent is a group of the formula —

NHCH(COOH)(CH₂)4NH—

CO(CH₂).CH₃, wherein u is an integer of from 8 to 18.

109. The pharmaceutical composition of any of claims 1-89, wherein in the GLP-1 derivative the lipophilic substituent is a group of the formula —

NHCH(COOH)(CH₂)₄NH—

COCH((CH₂)₂COOH)NH—

CO(CH₂)_wCH₃, wherein w is an integer of from 10 to 16.

110. The pharmaceutical composition of any of claims 1-89, wherein in the GLP-1 derivative the lipophilic substituent is a group of the formula —

NHCH(COOH)(CH₂)₄NH—

CO(CH₂)₂CH(COOH)NH—

CO(CH₂)_xCH₃, wherein x is an integer of from 10 to 16.

111. The pharmaceutical composition of any of claims 1-89, wherein in the GLP-1 derivative the lipophilic substituent, is a group of the formula —

NHCH(COOH)(CH₂)₄NH—

CO(CH₂)₂CH(COOH)NH—

CO(CH₂)_yCH_3, wherein y is zero or an integer of from 1 to 22.

112. The pharmaceutical composition of any of claims 1-111 which has insulinotropic, ability to decrease glucagon, ability to suppress gastric motility, ability to restore glucose competency to beta-cells, and/or ability to suppress appetite/reduce weight.

113. The pharmaceutical composition of any of claims 1-111, further comprising another antidiabetic agent.

114. The pharmaceutical composition of claim 113, wherein the antidiabetic agent is an insulin, more preferably human insulin.

115. The pharmaceutical composition of claim 113, wherein the antidiabetic agent is a hypoglaemic agent.

116. The pharmaceutical composition of any of claims 1-111, further comprising another antiobesity agent.

117. A method of treating insulin dependent or non-insulin dependent diabetes mellitus in a patient in need of such a treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of any of claims 1-111.

118. A method of treating obesity in a patient in need of such a treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of any of claims 1-111.

2. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising one or more of the following substitutions:

(a) Ala at position 8 is substituted with Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys,

(b) Glu at position 9 is substituted with Asp or Lys,

(c) Thr at position 11 is substituted with Ala, Gly, Ser, Leu, Ile, Val, Glu, Asp, or Lys,

(d) Ser at position 14 is substituted with Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys,

(e) Val at position 16 is substituted with Val, Ala, Gly, Ser, Thr, Leu, Ile, Tyr, Glu, Asp, or Lys,

Ser at position 17 is substituted with Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys,

(g) Ser at position 18 is substituted with Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys,

(h) Tyr at position 19 is substituted with Tyr, Phe, Trp, Glu, Asp, or Lys,

(i) Leu at position 20 is substituted with Leu, Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys,

(j) Glu at position 21 is substituted with Glu, Asp, or Lys,

(k) Gly at position 22 is substituted with Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys,

(l) Gln at position 23 is substituted with Gln, Asn, Arg, Glu, Asp, or Lys,

(m) Ala at position 24 is substituted with Ala, Gly, Ser, Thr, Leu, Ile, Val, Arg, Glu, Asp, or Lys,

(n) Ala at position 25 is substituted with Ala, Gly, Ser. Thr, Leu, Ile, Val, Glu, Asp, or Lys,

(o) Lys at position 26 is substituted with Arg, Gln, Glu, Asp, or His,

(p) Glu at position 27 is substituted with Asp or Lys,

(q) Ala at position 30 is substituted with Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys,

(r) Trp at position 31 is substituted with Phe, Tyr, Glu, Asp, or Lys,

(s) Leu at position 32 is substituted with Gly, Ala, Ser, Thr, He, Val, Glu, Asp, or Lys,

(t) Val at position 33 is substituted with Gly, Ala, Ser, Thr, Leu, Ile, Glu, Asp, or Lys,

(u) Lys at position 34 is substituted with Arg, Glu, Asp, or His,

(v) Gly at position 35 is substituted with Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys,

(w) Arg at position 36 is substituted with Lys, Glu, Asp, or His,

(x) Gly at position 37 is substituted with Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys,

(y) Arg at position 38 is substituted with Lys, Glu, Asp, or His, and

(z) Arg at position 39 is substituted with Lys, Glu, Asp, or His, or

(a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the ε

-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and

a surfactant.

3. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Ala at position 8 with Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-i-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the ε

-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and

a surfactant.

4. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Ser at position 18 with Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the ε

-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and

a surfactant.

5. A pharmaceutical composition comprising a GLP-1 I derivative of an analog of GLP-1(7-3 6), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Tyr at position 19 with Phe, Trp, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the 6-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six;

and a surfactant.

6. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Leu at position 20 with Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the ε

-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and

a surfactant.

7. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Glu at position 21 with Asp or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the ε

-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and

a surfactant.

8. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Gly at position 22 with Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the ε

-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and

a surfactant.

9. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-3 6), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Gin at position 23 with Asn, Arg, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (1,) amide, C-1 -6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the ε

-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and

a surfactant.

10. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Ala at position 24 with Gly, Ser, Thr, Leu, Ile, Val, Arg, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the ε

-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and

a surfactant.

25. A pharmaceutical composition comprising the GLP-1 derivative of the analog of GLP-1(7-GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39) of any of claims 3-11 and 14-24, further comprising the substitution of Lys at position 26 with Arg;

and a surfactant.

26. A pharmaceutical composition comprising the GLP-1 derivative of the analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39) of any of claims 3-18 and 21-24, further comprising the substitution of Lys at position 34 with Arg;

and a surfactant.

27. A pharmaceutical composition comprising the GLP-1 derivative of the analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39) of any of claims 3-11, 14-18, and 21-24, further comprising the substitution of Lys at positions 26 and 34 with Arg;

and a surfactant.

11. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Ala at position 25 with Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the ε

-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and

a surfactant.

161. A method of treating insulin dependent or non-insulin dependent diabetes mellitus in a patient in need of such a treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of claim 119.

12. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Lys at position 26 with Arg, Gln, His, Glu, or Asp, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the C-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six;

and a surfactant.

13. A pharmaceutical composition comprising a GLP-1 derivative of the preceding claim wherein Lys at position 26 is substituted with Arg;

and a surfactant.

14. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Glu at position 27 with Asp or Lys, wherein the derivative is optionally in the form of (a) a C-1 -6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the ε

-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and

a surfactant.

15. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Ala at position 30 with Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the ε

-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and

a surfactant.

16. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Trp at position 31 with Phe, Tyr, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the ε

-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and

a surfactant.

17. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Leu at position 32 with Gly, Ala, Ser, Thr, Ile, Val, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the 6-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six;

and a surfactant.

18. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Val at position 33 with Gly, Ala, Ser, Thr, Leu, Ile, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six;

and a surfactant.

19. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Lys at position 34 with Arg, Glu, or Asp, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six;

and a surfactant.

20. A pharmaceutical composition comprising a GLP-1 derivative of the preceding claim wherein Lys at position 34 is substituted with Arg;

and a surfactant.

21. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Gly at position 35 with Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1 -6-ester thereof, (b) amide, C-1 -6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the ε

-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and

a surfactant.

22. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Arg at position 36 with His, Lys, Glu, or Asp, wherein the derivative is optionally in the form of (a) a C-1 -6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the ε

-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and

a surfactant.

23. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Gly at position 37 with Ala, Ser. Thr, Leu, Ile, Val, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the ε

-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and

a surfactant.

24. A pharmaceutical composition comprising a GLP-1 derivative of an analog of GLP-1(7-36), GLP-1(7-37), GLP-1(7-38), or GLP-1(7-39), comprising the substitution of Arg at position 38 with His, Glu, Asp, or Lys, wherein the derivative is optionally in the form of (a) a C-1-6-ester thereof, (b) amide, C-1-6-alkylamide, or C-1-6-dialkylamide thereof and/or (c) a pharmaceutically acceptable salt thereof, provided that

(i) the derivative of the GLP-1 analog contains only one or two Lys,

(ii) the ε

-amino group of one or both Lys is substituted with a lipophilic substituent optionally via a spacer, and

(iii) the total number of different amino acids between the derivative of the GLP-1 analog and the corresponding native form of GLP-1 does not exceed six; and

a surfactant.

119. A pharmaceutical composition comprising a GLP-1 derivative wherein at least one amino acid residue of the parent peptide has a lipophilic substituent attached with the proviso that if only one lipophilic substituent is present and this substituent is attached to the N-terminal or to the C-terminal amino acid residue of the parent peptide then this substituent is an alkyl group or a group which has an so-carboxylic acid group;

and a surfactant.

120. The pharmaceutical composition of claim 119, wherein in the GLP-1 derivative only one lipophilic substituent is present.

121. The pharmaceutical composition of claim 120, wherein the lipophilic substituent is attached, to the N-terminal amino acid residue.

122. The pharmaceutical composition of claim 120, wherein the lipophilic substituent is attached to the C-terminal amino acid residue.

123. The pharmaceutical composition of claim 120, wherein the lipophilic substituent is attached to an amino acid residue which is not the N-terminal or C-terminal amino acid residue.

124. The pharmaceutical composition of claim 119, wherein in the GLP-1 derivative two lipophilic substituents are present.

125. The pharmaceutical composition of claim 124, wherein one of the lipophilic substituents is attached to the N-terminal amino acid residue while the other is attached to the C-terminal amino acid residue.

126. The pharmaceutical composition of claim 124, wherein one of the lipophilic substituents is attached to the C-terminal amino acid residue while the other is attached to an amino acid residue which is not the N-terminal or C-terminal amino acid residue.

127. The pharmaceutical composition of claim 124, wherein both lipophilic substituents are attached to amino acid residues which are neither the N-terminal nor the C-terminal amino acid residue.

129. The pharmaceutical composition of claim 119, wherein in the GLP-1 derivative the lipophilic substituent comprises from 4 to 40 carbon atoms, more preferred from 8 to 25 carbon atoms.

130. The pharmaceutical composition of claim 119, wherein in the GLP-1 derivative a lipophilic substituent is attached to an amino acid residue in such a way that a carboxyl group of the lipophilic substituent forms an amide bond with an amino group of the amino acid residue.

131. The pharmaceutical composition of claim 119, wherein in the GLP-1 derivative a lipophilic substituent is attached to an amino acid residue in such a way that an amino group of the lipophilic substituent forms an amide bond with a carboxyl group of the amino acid residue.

132. The pharmaceutical composition of claim 119, wherein in the GLP-1 derivative the lipophilic substituent is attached to the parent peptide by means of a spacer.

133. The pharmaceutical composition of claim 132, wherein the spacer is an unbranched alkane α

,ω

-dicarboxylic acid group having from 1 to 7 methylene groups, preferably two methylene groups, which form a bridge between an amino group of the parent peptide and an amino group of the lipophilic substituent.

134. The pharmaceutical composition of claim 132, wherein the spacer is an amino acid residue except Cys, or a dipeptide such as Gly-Lys.

135. The pharmaceutical composition of claim 134, wherein a carboxyl group of the parent peptide forms an amide bond with an amino group of Lys or a dipeptide containing a Lys residue, and the other amino group of the Lys spacer or a dipeptide spacer containing a Lys residue forms an amide bond with a carboxyl group of the lipophilic substituent.

136. The pharmaceutical composition of claim 134, wherein an amino group of the parent peptide forms an amide bond with a carboxylic group of the amino acid residue or dipeptide spacer, and an amino group of the amino acid residue or dipeptide spacer forms an amide bond with a carboxyl group of the lipophilic substituent.

137. The pharmaceutical composition of claim 134, wherein a carboxyl group of the parent X peptide forms an amide bond with an amino group of the amino acid residue spacer or dipeptide spacer, and a carboxyl group of the amino acid residue spacer or dipeptide spacer forms an amide bond with an amino group of the lipophilic substituent.

138. The pharmaceutical composition of claim 134, wherein a carboxyl group of the parent peptide forms an amide bond with an amino group of a spacer which is Asp or Glu, or a dipeptide spacer containing an Asp or Glu residue, and a carboxyl group of the spacer forms an amide bond with an amino group of the lipophilic substituent.

139. The pharmaceutical composition of claim 119, wherein in the GLP-1 derivative the lipophilic substituent comprises a partially or completely hydrogenated cyclopentanophenathrene skeleton.

140. The pharmaceutical composition of claim 119, wherein in the GLP-1 derivative the lipophilic substituent is an straight-chain or branched alkyl group.

141. The pharmaceutical composition of claim 119, wherein in the GLP-1 derivative the lipophilic substituent is the acyl group of a straight-chain or branched fatty acid.

142. The pharmaceutical composition of claim 141 wherein the acyl group is selected from the group comprising CH₃(CH₂)_nCO—

, wherein n is 4 to 38, preferably CH₃(CH₂)₆CO—

, CH₃(CH₂)₈CO—

, CH₃(CH₂)₁₀CO—

, CH₃(CH₂)₁₂CO—

, CH₃(CH₂)₁₄CO—

, CH₃(CH₂)₁₆CO—

, CH₃(CH₂)₁₈CO—

, CH₃(CH₂)₂₀CO— and

CH₃(CH₂)22CO—

.

143. The pharmaceutical composition of claim 119, wherein in the GLP-1 derivative the lipophilic substituent is an acyl group of a straight-chain or branched alkane α

,ω

-dicarboxylic acid.

144. The pharmaceutical composition of claim 143 wherein the acyl group is selected from the group comprising HOOC(CH₂)_mCO—

, wherein m is from 4 to 38, preferably from 4 to 24, more preferred selected from the group comprising HOOC(CH₂)₁₄CO—

, HOOC(CH₂)₁₆CO—

, HOOC(CH₂)18CO—

, HOOC(CH₂)₂₀CO— and

HOOC(CH₂)₂₂CO—

.

145. The pharmaceutical composition of claim 119, wherein in the GLP-1 derivative the lipophilic substituent is a group of the formula CH₃(CH₂)_p((CH₂)_qCOOH)CHNH—

CO(CH₂)₂CO—

, wherein p and q are integers and p+q is an integer of from 8 to 33, preferably from 12 to 28.

146. The pharmaceutical composition of claim 119, wherein in the GLP-1 derivative the lipophilic substituent is a group of the formula CH₃(CH₂)_rCO—

NHCH(COOH)(CH₂)₂CO—

, wherein r is an integer of from 10 to 24.

147. The pharmaceutical composition of claim 119, wherein in the GLP-1 derivative the lipophilic substituent is a group of the formula CH₃(CH₂)_sCO—

NHCH((CH₂)₂COOH)CO—

, wherein is an integer of from 8 to 24.

148. The pharmaceutical composition of claim 119, wherein in the GLP-1 derivative the lipophilic substituent is a group of the formula —

NHCH(COOH) (CH₂)₄NH—

CO(CH₂)_uCH₃, wherein u is an integer of from 8to 18.

149. The pharmaceutical composition of claim 119, wherein in the GLP-1 derivative the lipophilic substituent is a group of the formula —

NHCH(COOH)(CH₂)₄NH—

COCH((CH₂)₂COOH)NH—

CO(CH₂)_wCH₃ wherein w is an integer of from 10 to 16.

150. The pharmaceutical composition of claim 119, wherein in the GLP-1 derivative the lipophilic substituent is a group of the formula —

NHCH(COOH)(CH₂)₄NH—

CO(CH₂)₂CH(COOH)NH—

CO(CH₂)_xCH_3, wherein x is an integer of from 10 to 16.

151. The pharmaceutical composition of claim 119, wherein in the GLP-1 derivative the lipophilic substituent is a group of the formula —

NHCH(COOH)(CH₂)₄NH—

CO(CH₂)₂CH(COOH)NH—

CO(CH₂)_yCH_3, wherein y is zero or an integer of from 1 to 22.

152. The pharmaceutical composition of claim 119, wherein in the GLP-1 derivative the parent peptide is s elected from the group comprising GLP-(145) or an analogue or a fragment thereof.

153. The pharmaceutical composition of claim 119, wherein the GLP-1 derivative is selected from a GLP-1(A-B) derivative wherein A is an integer from 1 to 7 and B is an integer from 38 to 45 or an analogue thereof comprising one lipophilic substituent attached to the C-terminal amino acid residue and, optionally, a second lipophilic substituent attached to one of the other amino acid residues.

154. The pharmaceutical composition of claim 152, wherein the parent peptide is GLP-1(7-35);

GLP-1(7-36);

GLP-1(7-36)amide;

GLP-1(7-37);

GLP-1(7-38);

GLP-1(7-39);

GLP-1(7-40), GLP-1(7-41), or an analogue thereof.

155. The pharmaceutical composition of claim 152, wherein the parent peptide is GLP-1(1-35);

GLP-1(1-36);

GLP-1(1-36)amide;

GLP-1(1-37);

GLP-1(1-38);

GLP-1(1-39);

GLP-1(1-40);

GLP-1(1-41), or an analogue thereof.

156. The pharmaceutical composition of claim 119, wherein the designation analogue comprises derivatives wherein a total of up to fifteen, preferably up to ten amino acid residues have been exchanged with any α

-amino acid residue.

157. The pharmaceutical composition of claim 119, wherein the designation analogue comprises derivatives wherein a total of up to fifteen, preferably up to ten amino acid residues have been exchanged with any a-amino acid residue which can be coded for by the genetic code.

158. The pharmaceutical composition of claim 119, wherein the designation analogue comprises V derivatives wherein a total of up to six amino acid residues have been exchanged with any C-amino acid residue which can be coded for by the genetic code.

159. The pharmaceutical composition of claim 119, wherein the parent peptide is

Arg²⁶-GLP-1(7-37);

Arg³⁴-GLP-1(7-37);

Lys³⁶-GLP-1(7-37);

Arg^26,34Lys³⁶-GLP-1(7-37);

Arg^26,34Lys³⁸GLP-1(7-38);

Arg^26,34Lys³⁹-GLP-1(7-39);

Arg^26,34Lys⁴⁰GLP-1(7-40);

Arg²⁶Lys³⁶-GLP-1(7-37);

Arg³⁴Lys³⁶-GLP-1(7-37);

Arg²⁶Lys³⁹-GLP-1(7-39);

Arg³⁴Lys⁴⁰-GLP-1(7-40);

Arg^26,34Lys^36,39GLP-1(7-39);

Arg^{26 34}Lys^36,40GLP-1(7-40);

Gly⁸Arg²⁶-GLP-1(7-37);

Gly⁸Arg³⁴-GLP-1(7-37);

Gly⁸Lys³⁶-GLP-1(7-37);

Gly⁸Arg^26,34Lys³⁶GLP-1(7-37);

Gly⁸Arg^26,34Lys³⁹GLP-1(7-39);

Gly⁸Arg^26,34Lys⁴⁰GLP-1(7-40);

Gly⁸Arg^26,34Lys³⁶-GLP-1(7-37);

Gly⁸Arg³⁴Lys³⁶-GLP-1(7-37);

Gly⁸Arg²⁶Lys³⁹-GLP-1(7-39);

Gly⁸Arg³⁴Lys⁴⁰-GLP-1(7-40 );

Gly⁸Arg^26,34Lys^36,39GLP-1(7-39);

or

Gly⁸Arg^26,34Lys^36,40-GLP-1(7-40).

160. The pharmaceutical composition of claim 119, wherein the parent peptide is

Arg^26,34Lys³⁸GLP-1(7-38);

Arg^26,34Lys³⁹GLP-1(7-39);

Arg^26,34Lys⁴⁰GLP-1(7-40);

Arg^26,34Lys⁴¹GLP-1(7-41);

Arg^26,34Lys⁴²GLP-1(7-42);

Arg^26,34Lys⁴³GLP-1(7-43);

Arg^26,34Lys⁴⁴GLP-1(7-44);

Arg^26,34Lys⁴⁵GLP-1(7-45);

Arg^26,34Lys³⁸GLP-1(1-38);

Arg^26,34Lys³⁹GLP-1(1-39);

Arg^26,34Lys⁴⁰GLP-1(1-40);

Arg^26,34Lys⁴¹GLP-1(1-41);

Arg^26,34Lys⁴²GLP-1(1-42);

Arg^26,34Lys⁴³GLP-1(1-43);

Arg^26,34Lys⁴⁴GLP-1(1-44);

Arg^26,34Lys⁴⁵GLP-1(1-45);

Arg^26,34Lys³⁸GLP-1(2-38);

Arg^26,34Lys³⁹GLP-1(2-39);

Arg^26,34Lys⁴⁰GLP-1(2-40);

Arg^26,34Lys⁴¹GLP-1(2-41);

Arg^26,34Lys⁴²GLP-1(2-42);

Arg^26,34Lys⁴³GLP-1(2-43);

Arg^26,34Lys⁴⁴GLP-1(2-44);

Arg^26,34Lys⁴⁵GLP-1(2-45);

Arg^26,34Lys³⁸GLP-1(3-38);

Arg^26,34Lys³⁹GLP-1(3-39);

Arg^26,34Lys⁴⁰GLP-1(3-40);

Arg^26,34Lys⁴¹GLP-1(3-41);

Arg^26,34Lys⁴²GLP-1(3-42);

Arg^26,34Lys⁴³GLP-1(3-43);

Arg^26,34Lys⁴⁴GLP-1(3-44);

Arg^26,34Lys⁴⁵GLP-1(3-45);

Arg^26,34Lys³⁸GLP-1(4-38);

Arg^26,34Lys³⁹GLP-1(4-39);

Arg^26,34Lys⁴⁰GLP-1(4-40);

Arg^26,34Lys⁴¹GLP-1(4-41);

Arg^26,34Lys⁴²GLP-1(4-42);

Arg^26,34Lys⁴³GLP-1(4-43);

Arg^26,34Lys⁴⁴GLP-1(4-44);

Arg^26,34Lys⁴⁵GLP-1(4-45);

Arg^26,34Lys³⁸GLP-1(5-38);

Arg^26,34Lys³⁹GLP-1(5-39);

Arg^26,34Lys⁴⁰GLP-1(5-40);

Arg^26,34Lys⁴¹GLP-1(5-41);

Arg^26,34Lys⁴²GLP-1(5-42);

Arg^26,34Lys⁴³GLP-1(5-43);

Arg^26,34Lys⁴⁴GLP-1(5-44);

Arg^26,34Lys⁴⁵GLP-1(5-45);

Arg^26,34Lys³⁸GLP-1(6-38);

Arg^26,34Lys³⁹GLP-1(6-39);

Arg^26,34Lys⁴⁰GLP-1(6-40);

Arg^26,34Lys⁴¹GLP-1(6-41);

Arg^26,34Lys⁴²GLP-1(6-42);

Arg^26,34Lys⁴³GLP-1(6-43);

Arg^26,34Lys⁴⁴GLP-1(6-44);

Arg^26,34Lys⁴⁵GLP-1(6-45);

Arg^26,34Lys³⁸GLP-1(1-38);

Arg^26,34Lys³⁸GLP-1(1-38);

Arg^26,34Lys^36,38GLP-1(1-38);

Arg^26,34Lys³⁸GLP-1(7-38);

Arg^26,34Lys³⁸GLP-1(7-38);

Arg^26,34Lys^36,38GLP-1(7-38);

Arg^26,34Lys³⁸GLP-1(7-38);

Arg^26,34Lys³⁹GLP-1(1-39);

Arg^26,34Lys³⁹GLP-1(1-39);

Arg^26,34Lys^36,39GLP-1(1-39);

Arg^26,34Lys³⁹GLP-1(7-39);

Arg^26,34Lys³⁹GLP-1(7-39) or

Arg^26,34Lys^36,39GLP-1(7-39).

128. A pharmaceutical composition comprising a derivative of GLP-1(7-C), wherein C is selected from the group comprising 38, 39, 40, 41, 42, 43, 44 and 45 which derivative has just one lipophilic substituent which is attached to the C-terminal amino acid residue;

and a surfactant.

162. A pharmaceutical composition comprising a derivative of GLP-1(A-B) wherein A is an integer from 1 to 7 and B is an integer from 38 to 45 or an analogue thereof comprising one ²lipophilic substituent attached to the C-terminal amino acid residue and a second lipophilic substituent attached to one of the other amino acid residues;

and a surfactant.

163. A pharmaceutical composition comprising a GLP-1 derivative of formula II A-GLP-1(19-B) X (11) wherein

A is a peptide having the amino acid residues of GLP-1(8-18) or a fragment thereof;

B is an integer in the range of 35-45; and

X is OH, —

NH₂, or a C_1-6 alkyl amide or Cl-₆ dialkyl amide group;

or an analogue thereof; and

wherein a lipophilic substituent (optionally via a spacer) is attached to at least one amino acid residue; and

a surfactant.

164. The pharmaceutical composition of claim 163, wherein A is a peptide selected from the group consisting of GLP-1(8-18), GLP-1(9-18), GLP-1(10-18), GLP-1(11-18), GLP-1(12-18), GLP-1(13-18), GLP-1(14-18), GLP-1(15-18), GLP-1(16-18), GLP-1(17-18) and GLP-1(18).

165. The pharmaceutical composition of claim 164, wherein A is a peptide selected from the group consisting of GLP-1(8-18), GLP-1(9-18), GLP-1(10-18), GLP-1(11-18) and GLP-1(12-18).

166. The pharmaceutical composition of claim 165, wherein A is GLP-1(8-18).

167. The pharmaceutical composition of any of claims 163-166, wherein B is 35, 36, 37, 38, 39, 40, 41, 42, 43 or 44.

168. The pharmaceutical composition of claim 167, wherein B is 36.

169. The pharmaceutical composition of claim 167, wherein B is 37.

170. The pharmaceutical composition of claim 167, wherein B is 38.

171. The pharmaceutical composition of any of claims 163-170, wherein up to fifteen, preferably up to ten amino acid residues have been exchanged with any x-amino acid residue.

172. The pharmaceutical composition of any of claims 163-170, wherein up to fifteen, preferably up to ten amino acid residues have been exchanged with any α

-amino acid residue which can be coded for by the genetic code.

173. The pharmaceutical composition of any of claims 163-170, wherein up to six amino acid residues have been exchanged with any α

-amino acid residue which can be coded for by the genetic code.

174. The pharmaceutical composition of any of claims 163-173, wherein

(a) A is selected from the group consisting of GLP-1(8-18), GLP-1(9-18) and GLP-0(10-1 8);

and

(b) B is 36, and the parent peptide comprises one or more amino acid substitutions selected from the group consisting of Arg, Arg and Lys

B is 37, and the parent peptide comprises one or more amino acid substitutions selected from the group consisting of Arg²⁶, Arg³⁴, Lys³⁶ and Lys³⁷;

or B is 38, and the parent peptide comprises one or more amino acid substitutions selected from the group consisting of Arg²⁶, Arg³⁴, Lys³⁶ and Lys³⁸.

175. The pharmaceutical composition of claim 163 which is of formula m (SEQ ID NO:

2)

178. The pharmaceutical composition of claim 175 or 176 which is a derivative of a native form of GLP-1.

179. The pharmaceutical composition of any of claims 175-177, wherein up to fifteen, preferably up to ten amino acid residues have been exchanged with any α

-amino acid residue.

180. The pharmaceutical composition of any of claims 175-178, wherein up to fifteen, preferably up to ten amino acid residues have been exchanged with any α

-amino acid residue which can be coded for by the genetic code.

181. The pharmaceutical composition of any of claims 175-179, wherein up to six amino acid residues have been exchanged with any α

-amino acid residue which can be coded for by the genetic code.

182. The pharmaceutical composition of any of claims 175-180, wherein B is 36, and the parent peptide comprises one or more amino acid substitutions selected from the group consisting of Arg²⁶, Arg³⁴ and Lys³⁶;

B is 37, and the parent peptide comprises one or more amino acid substitutions selected from the group consisting of Arg²⁶, Arg³⁴, Lys³⁶ and Lys³⁷;

or B is 38, and the parent peptide comprises one or more amino acid substitutions selected from the group consisting of Arg²⁶, Arg³⁴, Lys³⁶ and Lys³⁸.

183. The pharmaceutical composition of claim 175 which is of formula III (SEQ ID NO:

2)

184. The pharmaceutical composition of any of claims 175-183, wherein A is selected from

185. The pharmaceutical composition of any of claims 163-184 wherein the GLP-1 derivative contains three lipophilic substituents.

186. The pharmaceutical composition of any of claims 163-184 wherein the GLP-1 derivative contains two lipophilic substituents.

187. The pharmaceutical composition of any of claims 163-184 wherein the GLP-1 derivative contains one lipophilic substituent.

188. The pharmaceutical composition of any of claims 163-187, wherein a lipophilic substituent is attached to the amino group of the N-terminal amino acid residue of the parent GLP-1 peptide.

189. The pharmaceutical composition of any of claims 163-188, wherein a lipophilic substituent is attached to the carboxy group of the C-terminal amino acid residue of the parent GLP-1 peptide.

190. The pharmaceutical composition of any of claims 163-189, wherein a lipophilic substituent is attached to the carboxy group which is part of the R group of Asp or Glu of the parent GLP-1 peptide.

191. The pharmaceutical composition of any of claims 163-190, wherein a lipophilic substituent is attached to an ε

-amino group of Lys of the parent GLP-1 peptide.

192. The pharmaceutical composition of any of claims 163-191, wherein the lipophilic substituent comprises from 4 to 40 carbon atoms, more preferably from 8 to 25 carbon atoms, most preferably 12 to 18 carbon atoms.

193. The pharmaceutical composition of any of claims 163-192, wherein a lipophilic substituent is attached to an amino acid residue in such a way that a carboxyl group of the lipophilic substituent forms an amide bond with the ε

-amino group of Lys of the parent GLP-1 peptide.

194. The pharmaceutical composition of any of claims 163-193, wherein the lipophilic substituent is attached to the parent peptide by means of a spacer.

195. The pharmaceutical composition of claim 194, wherein the spacer is an unbranched alkane (ω

-dicarboxylic acid group having from 1 to 7 methylene groups, preferably two methylene groups, which forms an amide bond with an amino group of the parent GLP-1 peptide and an amide bond with an amino group of the lipophilic substituent.

196. The pharmaceutical composition of claim 194, wherein the spacer is an amino acid residue except Cys or Met, or a dipeptide such as Gly-Lys.

197. The pharmaceutical composition of claim 196, wherein the α

-amino group of Lys forms an amide bond with a carboxylic group of the amino acid residue or dipeptide spacer, and an amino group of the amino acid residue or dipeptide spacer forms an amide bond with a carboxyl group of the lipophilic substituent.

198. The pharmaceutical composition of any of claims 194-197, wherein the spacer is γ

-L-glutamyl.

199. The pharmaceutical composition of any of claims 194-197, wherein the spacer is β

-L-asparagyl.

200. The pharmaceutical composition of any of claims 194-197, wherein the spacer is β

-alanyl.

201. The pharmaceutical composition of any of claims 194-197, wherein the spacer is glycyl.

202. The pharmaceutical composition of any of claims 194-197, wherein the spacer is α

-(γ

-aminobutanoyl).

203. The pharmaceutical composition of any of claims 163-202, wherein the lipophilic substituent comprises a partially or completely hydrogenated cyclopentanophenathrene skeleton.

204. The pharmaceutical composition of any of claims 163-203, wherein the lipophilic substituent is a straight-chain or branched alkyl group.

205. The pharmaceutical composition of any of claims 163-204, wherein the lipophilic substituent is an acyl group of a straight-chain or branched fatty acid, preferably an acyl group of a straight-chain fatty acid.

206. The pharmaceutical composition of claim 205, wherein the acyl group is selected from the group comprising CH₃(CH₂)_nCO—

, wherein n is 10 to 38, preferably CH₃(CH₂)₁₀CO—

, —

CH₃(CH₂)₁₂CO—

, CH₃(CH₂)₁₄CO—

, CH₃(CH₂)₁₆CO—

, CH₃(CH₂)₁₈CO—

, CH₃(CH₂)₂₀CO— and

CH₃(CH₂)₂₂CO—

.

207. The pharmaceutical composition of claim 205, wherein the acyl group is tetradecanoyl.

208. The pharmaceutical composition of claim 205, wherein the acyl group is hexadecanoyl.

209. The pharmaceutical composition of any of claims 163-208 wherein the lipophilic substituent is an acyl group of a straight-chain or branched alkane α

,ω

-dicarboxylic acid.

210. The pharmaceutical composition of claim 209, wherein the acyl group is selected from the group comprising HOOC(CH₂)_mCO—

, wherein m is from 4 to 38, preferably from 4 to 24, more preferably selected from the group comprising HOOC(CH₂)₁₄CO—

, HOOC(CH₂)₁₆CO—

, HOOC(CH₂)₁₈CO—

, HOOC(CH₂)₂₀CO— and

HOOC(CH₂)₂₂CO—

.

211. The pharmaceutical composition of any of claims 163-210, wherein the lipophilic substituent with the attached spacer is a group of the formula CH₃(CH₂)_pNH—

CO(CH₂)₂CO—

, wherein p is an integer of from 8 to 33, preferably from 12 to 28.

212. The pharmaceutical composition of any of claims 163-211, wherein the lipophilic substituent with the attached spacer is a group of the formula CH₃(CH₂)_rCO NHCH(COOH)(CH₂)2CO—

, wherein r is an integer of from 10 to 24.

213. The pharmaceutical composition of any of claims 163-212, wherein the lipophilic substituent with the attached spacer is a group of the formula CH₃(CH₂),CO-NHCH((CH₂)2COOH)CO—

, wherein s is an integer of from 8 to 24.

214. The pharmaceutical composition of any of claims 163-213, wherein the lipophilic substituent with the attached spacer is a group of the formula —

NHCH(COOH)(CH₂)₄NH—

CO(CH₂)_uCH_3, wherein u is an integer of from 8 to 18.

215. The pharmaceutical composition of any of claims 163-214, wherein the lipophilic substituent with the attached spacer is a group of the formula —

NHCH(COOH)(CH₂)₄NH—

COCH((CH₂)₂COOH)NH—

CO(CH₂)_wCH₃, wherein w is an integer of from 10 to 16.

216. The pharmaceutical composition of any of claims 163-215, wherein the lipophilic substituent with the attached spacer is a group of the formula —

NHCH(COOH)(CH₂)₄NH—

CO(CH₂)₂CH(COOH)NH—

CO(CH₂)_xCH₃, wherein x is an integer of from 10 to 16.

217. The pharmaceutical composition of any of claims 163-216, wherein the lipophilic substituent with the attached spacer is a group of the formula —

NHCH(COOH)(CH₂)₄NH—

CO(CH₂)₂CH(COOH)NH—

CO (CH₂)_yCH₃, wherein y is zero or an integer of from 1 to 22.

218. The pharmaceutical composition of any of claims 163-217 which has insulinotropic activity, ability to decrease glucagon, ability to suppress gastric motility, ability to restore glucose competency to beta-cells, and/or ability to suppress appetite/reduce weight.

219. The pharmaceutical composition of claim 218, further comprising another antidiabetic agent.

220. The pharmaceutical composition of claim 219, wherein the antidiabetic agent is an insulin, more preferably human insulin.

221. The pharmaceutical composition of claim 219, wherein the antidiabetic agent is a hypoglycaemic agent.

222. The pharmaceutical composition of claim 218, further comprising another antiobesity agent.

223. The pharmaceutical composition of claim 222, wherein the antiobesity agent is selected from the group consisting of leptin, amphetamin, dexfenfluramine, sibutramine, orlistat, CART agonists, NPY antagonists, orexin antagonists, H3-antagonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β

3 agonists, MSH agonists, CCK agonists, serotonin re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, glucagon, TRH agonists, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (Bromocriptin, Doprexin), lipase/amylase inhibitors, PPAR modulators, PXR modulators and TR β

agonists.

176. A pharmaceutical composition comprising a GLP-1 derivative of formula II

A—

HN—

GLP-1(8-B)—

X  

 

(II)

A is;

wherein R¹, R² and R³ are independently H, lower alkyl, optionally substituted phenyl, NH₂, NH—

CO-(lower alkyl), —

OH, lower alkoxy, halogen, SO₂-(lower alkyl) or CF₃, wherein said phenyl is optionally substituted with at least one group selected from NH₂, —

OH, lower alkyl, lower alkoxy, halogen, SO₂-(lower alkyl), NH—

CO-(lower alkyl) or CF₃, or R¹ and R² may together form a bond; and

Y is a five or six membered ring system selected from the group consisting of

Z is N, O or S, and said ring system is optionally substituted with one or more functional groups selected from the group consisting of NH₂, NO₂, OH, lower alkyl, lower alkoxy, halogen, CF₃ and aryl, provided that A is not histidine;

B is an integer in the range of 35-45; and

X is —

OH, —

NH₂, or a C₁-₆ alkyl amide or C₁-₆ dialkyl amide group;

or an analogue thereof;

wherein a lipophilic substituent (optionally via a spacer) is attached to at least one amino acid residue provided that when the lipophilic substituent is an acyl group and no spacer is present then the acyl group contains at least 12 carbon atoms; and

a surfactant.

177. The pharmaceutical composition of claim 176, wherein B is 36, 37 or 38.

224. The pharmaceutical composition of any one of the preceding composition claims wherein the surfactant is selected from a detergent, ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, such as 188 and 407, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives such as alkylated and alkoxylated derivatives (tweens, e.g. Tween-20), monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, glycerol, cholic acid or derivatives thereof, lecithins, alcohols and phospholipids, glycerophospholipids (lecithins, kephalins, phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS (docusate sodium, CAS registry no 577-11-7), docusate calcium, CAS registry no 128-49-4), docusate potassium, CAS registry no 7491-09-0), SDS (sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate, bile acids and salts thereof and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N^α

-Hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate, anionic (alkyl-aryl-sulphonates) monovalent surfactants, palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g. 1 -acyl-sn-glycero-3-phosphate esters of ethanolamine, choline, serine or threonine), alkyl, alkoxyl (alkyl ester), alkoxy (alkyl ether)-derivatives of lysophosphatidyl and phosphatidylcholines, e.g. lauroyl and myristoyl derivatives of lysophosphatidylcholine, dipalmitoylphosphatidylcholine, and modifications of the polar head group, that is cholines, ethanolamines, phosphatidic acid, serines, threonines, glycerol, inositol, and the postively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine, zwitterionic surfactants (e.g. N-alkyl-N,N-dimethylammonio-1-propanesulfonates 3-cholamido-1 -propyldimethylammonio-1 -propanesulfonate, dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egg lysolecithin), cationic surfactants (quarternary ammonium bases) (e.g. cetyl-trimethylammonium bromide, cetylpyridinium chloride), non-ionic surfactants, polyethyleneoxide/polypropyleneoxide block copolymers (Pluronics/Tetronics, Triton X-100, Dodecyl β

-D-glucopyranoside) or polymeric surfactants (Tween-40, Tween-80, Brij-35). Other preferred surfactants include fusidic acid derivatives-(e.g. sodium tauro-dihydrofusidate etc.), long-chain fatty acids and salts thereof C6-C12(eg. oleic acid and caprylic acid), acylcamitines and derivatives, N^α

-acylated derivatives of lysine, arginine or histidine, or side-chain acylated derivatives of lysine or arginine, N^α

-acylated derivatives of dipeptides comprising any combination of lysine, arginine or histidine and a neutral or acidic amino acid, N^α

-acylated derivative of a tripeptide comprising any combination of a neutral amino acid and two charged amino acids, or the surfactant may be selected from the group of imidazoline derivatives.

224-1. Use of a pharmaceutical composition of any one of the preceding composition claims which has a protracted profile of action relative to GLP-1(7-37).

225. The pharmaceutical composition of any one of the preceding composition claims further comprising an isotonic agent, preferably sodium chloride, mannitol and glycerol.

225-2. Use of a pharmaceutical composition of any one of the preceding composition claims with a protracted profile of action for the treatment of non-insulin dependent diabetes mellitus.

226. The pharmaceutical composition of claim 225 wherein the isotonic agent is present in an amount of about 19-50 mg/ml.

226-3. Use of a pharmaceutical composition of any one of the preceding composition claims with a protracted profile of action for the treatment of insulin dependent diabetes mellitus.

227. The pharmaceutical composition of any one of the preceding composition claims further comprising a preservative, preferably phenol, m-cresol, methyl p-hydroxybenzoate and benzyl alcohol.

227-4. Use of a pharmaceutical composition of any one of the preceding composition claims for treating insulin resistance.

228. The pharmaceutical composition of claim 227 wherein the preservative is present in an amount of about 2.5-18 mg/ml.

228-5. Use of a pharmaceutical composition of any one of the preceding composition claims with a protracted profile of action for the treatment of obesity.

229. The pharmaceutical composition of any one of the preceding composition claims further comprising a buffer, preferably sodium acetate and sodium phosphate.

229-6. A method of treating insulin dependent or non-insulin dependent diabetes mellitus in a patient in need of such a treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of any one of the preceding composition claims together with a pharmaceutically acceptable carrier.

230. The pharmaceutical composition of any one of the preceding composition claims further comprising zinc.

230-7. A method of treating obesity in a patient in need of such a treatment, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of any one of the preceding composition claims.

231. The pharmaceutical composition of any one of the preceding composition claims wherein said composition is suitable for administration by injection.