Treating diabetes melitus using insulin injections with less than daily injection frequency

• US 9,603,904 B2
• Filed: 10/29/2009
• Issued: 03/28/2017
• Est. Priority Date: 10/30/2008
• Status: Active Grant

• Current Assignee: Novo Nordisk A/S
• Original Assignee: Novo Nordisk A/S
• Inventors: Johansen, Thue, Michelsen, Birgitte Koch, Edsberg, Berit
• Primary Examiner(s): Cordero Garcia, Marcela M
• Assistant Examiner(s): Mader, Catherine
• Application Number:
  US13/124,750
• Publication Number:
  US 20110230402A1
• Time in Patent Office: 2,707 Days
• Field of Search: 514/6.3
• US Class Current: 1/1
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• 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: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07K 14/575 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695
• CPC Class Codes: C07K 14/62 Insulins

Abstract

The present invention relates to an insulin derivative for the treatment of a condition or disease where administration of insulin will be of benefit, comprising administering, to a patient in need thereof, effective dosages of the insulin derivative, wherein said insulin derivative exhibits a prolonged profile of action and wherein said dosages are administered at intervals longer than 24 hours.

Claims

1. A method of treating a condition or disease where administration of insulin will be of benefit comprising:

administering effective dosages of an insulin derivative to a patient in need thereof, wherein said insulin derivative is administered at intervals of at least 36 hours, wherein the disease or condition is selected from the group consisting of diabetes mellitus or other conditions characterized by hyperglycaemia, pre-diabetes, impaired glucose tolerance, metabolic syndrome, obesity, cachexia, in vivo beta-cell loss/death, excessive appetite, and inflammation, and wherein said derivative has a side chain attached to the α

-amino group of the N-terminal amino acid residue of the B chain or to the ε

-amino group of a Lys residue present in the B chain of the parent insulin, the side chain being of the general formula;

—

W—

X—

Y—

Z

wherein W is;

an α

-amino acid residue having a carboxylic acid group in the side chain which residue forms, with one of its carboxylic acid groups, an amide group together with the α

-amino group of the N-terminal amino acid residue of the B chain or together with the ε

-amino group of a Lys residue present in the B chain of the parent insulin;

a chain composed of two, three or four α

-amino acid residues linked together via amide bonds, which chain—

via an amide bond—

is linked to the α

-amino group of the N-terminal amino acid residue of the B chain or to the ε

-amino group of a Lys residue present in the B chain of the parent insulin, the amino acid residues of W being selected from the group of amino acid residues having a neutral side chain and amino acid residues having a carboxylic acid group in the side chain so that W has at least one amino acid residue which has a carboxylic acid group in the side chain;

or

a covalent bond from X to the α

-amino group of the N-terminal amino acid residue of the B chain or to the ε

-amino group of a Lys residue present in the B chain of the parent insulin;

X is;

—

CO—

;

—

COCH(COOH)CO—

;

—

CON(CH₂COOH)CH₂CO—

;

—

CON(CH₂COOH)CH₂CON(CH₂COOH)CH₂CO—

;

—

CON(CH₂CH₂COOH)CH₂CH₂CO—

;

—

CON(CH₂CH₂COOH)CH₂CH₂CON(CH₂CH₂COOH)CH₂CH₂CO—

;

—

CONHCH(COOH)(CH₂)₄NHCO—

;

—

CON(CH₂CH₂COOH)CH₂CO—

;

or

—

CON(CH₂COOH)CH₂CH₂CO—

that

a) when W is an amino acid residue or a chain of amino acid residues, via a bond from the underscored carbonyl carbon forms an amide bond with an amino group in W, or

b) when W is a covalent bond, via a bond from the underscored carbonyl carbon forms an amide bond with the N-terminal α

-amino group in the B chain or with the ε

-amino group of a Lys residue present in the B chain of the parent insulin;

Y is;

—

(CH₂)_m—

where m is an integer in the range of 6 to 32;

a divalent hydrocarbon chain comprising 1, 2 or 3 —

CH═

CH—

groups and a number of —

CH₂—

groups sufficient to give a total number of carbon atoms in the chain in the range of 10 to 32;

a divalent hydrocarbon chain of the formula —

(CH₂)_vC₆H₄(CH₂)_W—

wherein v and w are integers or one of them is zero so that the sum of v and w is in the range of 6 to 30; and

Z is;

—

COOH;

—

CO-Asp;

—

CO-Glu;

—

CO-Gly;

—

CO-Sar;

—

CH(COOH)₂;

—

N(CH₂COOH)₂;

—

SO₃H;

or

—

PO₃H;

and any Zn²⁺ complexes thereof, provided that when W is a covalent bond and X is —

CO—

, then Z is different from —

COOH.

2. The method of claim 1, wherein said dosages are administered at intervals of at least 42 hours, 48 hours, 72 hours or 96 hours.

3. The method of claim 1, wherein the dosages are administered at regular intervals.

4. The method of claim 1, wherein the dosages are administered at fixed weekdays.

7. The method of claim 1, wherein administration of the insulin derivative exhibiting a prolonged profile of action is supplemented with more frequent administrations of a fast-acting naturally occurring insulin or insulin analogue and/or administration of a non-insulin anti-diabetic drug.

8. The method of claim 1, wherein substantially no other naturally occurring insulin, insulin analogue or derivative of naturally occurring insulin or insulin analogue is administered to said patient.

9. The method of claim 1, wherein the insulin derivative is selected from the group consisting of N^ε

B29—

(N^α

—

(HOOC(CH₂)₁₄CO)-γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

—

(HOOC(CH₂)₁₅CO)-γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

—

(HOOC(CH₂)₁₆CO)-γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

—

(HOOC(CH₂)₁₇CO)-γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

—

(HOOC(CH₂)₁₈CO)-γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

—

(HOOC(CH₂)₁₆CO)-γ

-Glu-N-(γ

-Glu)) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

-(Asp-OC(CH₂)₁₆CO)-γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

-(Glu-OC(CH₂)₁₄CO)-γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

-(Glu-OC(CH₂)₁₄CO—

) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

-(Asp-OC(CH₂)₁₆CO—

) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

—

(HOOC(CH₂)₁₆CO)-α

-Glu-N-(β

-Asp)) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

-(Gly-OC(CH₂)₁₃CO)-γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

-(Sar-OC(CH₂)₁₃CO)-γ

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

—

(HOOC(CH₂)₁₃CO)-γ

-Glu) des(B30) human insulin;

(N<sup>ε

B29</sup>—

(N^α

—

(HOOC(CH₂)₁₃CO)-β

-Asp) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

—

(HOOC(CH₂)₁₃CO)-α

-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

—

(HOOC(CH₂)₁₆CO)-γ

-D-Glu) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

—

(HOOC(CH₂)₁₄CO)-β

-D-Asp) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N^α

—

(HOOC(CH₂)₁₄CO)-β

-D-Asp) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N—

HOOC(CH₂)₁₆CO-β

-D-Asp) des(B30) human insulin;

N<sup>ε

B29</sup>—

(N—

HOOC(CH₂)₁₄CO—

IDA) des(B30) human insulin;

N<sup>ε

B29</sup>—

[N—

(HOOC(CH₂)₁₆CO)—

N-(carboxyethyl)-Gly] des(B30) human insulin;

N<sup>ε

B29</sup>—

[N—

(HOOC(CH₂)₁₄CO)—

N-(carboxyethyl)-Gly] des(B30) human insulin; and

N<sup>ε

B29</sup>—

[N—

(HOOC(CH₂)₁₄CO)—

N-(carboxymethyl)-β

-Ala] des(B30) human insulin.

10. The method of claim 1, wherein the insulin derivative is N^ε

B29—

(N^α

—

(HOOC(CH₂)₁₄CO)-γ

-L-Glu) des(B30) human insulin.

11. The method of claim 1, wherein the diabetes mellitus is Type 1 or 2 diabetes.

12. The method of claim 1, wherein the insulin derivative is formulated together with a pharmaceutically acceptable carrier and/or vehicle and/or diluent and/or excipient.

13. The method of claim 1, wherein the condition or disease is selected from the group consisting of diabetes mellitus, hyperglycaemia, pre-diabetes, impaired glucose tolerance, metabolic syndrome, obesity, cachexia, in vivo beta-cell loss/death, excessive appetite, and inflammation, comprising administering the insulin derivative of claim 1.

14. The insulin derivative according to claim 4, wherein the dosages are administered at 3 fixed weekdays.

15. The insulin derivative according to claim 4, wherein the dosages are administered at 2 fixed weekdays.

5. A method of treating a condition or disease where administration of insulin will be of benefit comprising administering an effective amount of an insulin derivative to a patient in need thereof, wherein said insulin derivative is administered at intervals longer than 36 hours, and wherein the dosages are administered at 3 fixed weekdays.

6. A method of treating a condition or disease where administration of insulin will be of benefit comprising administering an effective amount of an insulin derivative to a patient in need thereof, wherein said insulin derivative is administered at intervals longer than 36 hours, and wherein the dosages are administered at 2 fixed weekdays.

16. A method of treating diabetes mellitus, hyperglycaemia, pre-diabetes, impaired glucose tolerance, metabolic syndrome, obesity, cachexia, in vivo beta-cell loss/death, excessive appetite, and inflammation, comprising administering to a subject effective dosages of N^ε

B29—

(N^α

—

(HOOC(CH₂)₁₄CO)-γ

-L-Glu) des(B30) human insulin, wherein said dosages are administered at intervals of at least 36 hours.