Insulin compounds and compositions

• US 5,430,016 A
• Filed: 03/19/1990
• Issued: 07/04/1995
• Est. Priority Date: 03/20/1989
• Status: Expired due to Fees

• Current Assignee: NOVO Nordisk A/S NOVO ALLE Dk-2880 Bagsvaerd Denmark
• Original Assignee: Novo Nordisk A/S
• Inventors: Hansen, Finn B., Balschmidt, Per
• Primary Examiner(s): Moezie, F. T.
• Application Number:
  US07/495,798
• Time in Patent Office: 1,933 Days
• Field of Search: 530/303, 514/3, 514/4, 435/68.1, 435/69.4
• US Class Current: 514/5.9
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/62 Insulins

Abstract

Novel insulin compounds having a desirably protracted insulin action and/or antigenicity are provided.

The novel insulin compounds are represented by the formula II: ##STR1## wherein E individually represents Glu or a neutral amino acid residue which can be coded for by nucleotide sequences, N represents an amino acid residue which can be coded for by nucleotide sequences,

T represents Thr or Arg,

X represents Thr, Ser, Ala or OH, and

Y represents OR or NR¹ R², where R, R¹ and R² individually represents hydrogen or lower alkyl, but is not present when X represents OH.

Claims

1. A purified insulin compound of formula:

##STR8## wherein E is independently Glu or a neutral amino acid residue which can be coded for by nucleotide sequences;

N is an amino acid residue which can be coded by nucleotide sequences;

T is Thr or Arg;

X is Thr, Set, Ala or OH; and

Y is OR or NR¹ R² wherein R, R¹ and R² independently are hydrogen or C_1-6 -alkyl, provided that Y is not present when X is OH and that at least one of E, N and T is an amino acid residue different from the corresponding residue of human insulin when Y is OH.

2. The purified insulin compound according to claim 1, wherein

E is independently Glu or Gln;

N is Asn, Asp, Ser or Gly;

T is Thr or Arg;

X is Thr; and

Y is NH₂.

3. The purified insulin compound according to claim 2, wherein E is Glu, N is Ash, T is Thr, X is Thr and Y is NH₂.

4. The purified insulin compound according to claim 2, wherein E is Glu, N is Ser, T is Thr, X is Thr and Y is NH₂.

5. The purified insulin compound according to claim 1, wherein E in position B13 is Gln, E in the other positions is Glu, N is Ash, T is Thr, X is Thr and Y is NH₂.

6. The purified insulin compound according to claim 1, wherein E in position A4 is Gln, E in the other positions is Glu, N is Asp, T is Thr, X is Thr and Y is NH₂.

7. The purified insulin compound according to claim 1, wherein E is Glu, N is Asn, T is Arg and X is OH.

14. An insulin preparation comprising a solution of a purified insulin compound according to claim 1 in an aqueous medium which is isoosmotic with blood serum and has a pH between 2 and 5.5.

15. The insulin preparation according to claim 14, further comprising a buffer.

16. The insulin preparation according to claim 14, further comprising a preserving agent.

17. The insulin preparation according to claim 14, further comprising a fast acting insulin.

8. A purified insulin compound which is [Arg^A0 ]-des [Thr^B30 ]-human insulin.

9. A purified insulin compound which is [Arg^A0 ]-human insulin (B30 amide).

10. A purified insulin compound which is [Arg^A0, Ser^A21 ]-human insulin (B30 amide).

11. A purified insulin compound which is [Arg^A0, Gln^B13 ]-human insulin (B30 amide).

12. A purified insulin compound which is [Arg^A0,Gln^A4, Asp^A21 ]-human insulin (B30 amide).

13. A purified insulin compound which is [Arg^A0, Arg^B27 ]-des [Thr^B30 ]-human insulin.

18. An insulin preparation comprising a solution of a purified insulin compound selected from the group consisting of:

[Arg^A0 ]-des [Thr^B30 ]-human insulin

[Arg^A0 ]-human insulin (B30 amide)

[Arg^A0, Ser^A21 ]-human insulin (B30 amide)

[Arg^A0, Gln^B13 ]-human insulin (B30 amide)

[Arg^A0, Gln^A4, Asp^A21 ]-human insulin (B30 amide) and

[Arg^A0, Arg^B27 ]-des [Thr^B30 ]-human insulin.