Pharmaceutical agent for the treatment of diabetes mellitus

• US 4,608,364 A
• Filed: 07/20/1984
• Issued: 08/26/1986
• Est. Priority Date: 07/22/1983
• Status: Expired due to Term

• Current Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Original Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Inventors: Grau, Ulrich
• Primary Examiner(s): WADDELL, FREDERICK
• Application Number:
  US06/632,859
• Time in Patent Office: 767 Days
• Field of Search: 514/4, 514/3, 260/112.7
• US Class Current: 514/6.9
• 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
• CPC Class Codes: C07K 14/625 Extraction from natural sources
• CPC Class Codes: Y10S 930/26 Containing cys-cys disulfide bridge between nonadjacent cysteine residues

Abstract

The invention relates to medicaments consisting of a physiologically acceptable excipient and an active compound combination of

(a) an insulin derivative of the formula I ##STR1## in which R¹ denotes H or H--Phe, R³⁰ represents the radical of a neutral L-aminoacid and R³¹ represents a physiologically acceptable organic group of basic character with up to 50 carbon atoms, with an isoelectric point between 5.8 and 8.5, and

(b) an insulin of the formula I in which R¹ denotes H or H--Phe, R³⁰ represents Ala, Thr or Ser and R³¹ denotes OH,

and to its use for the treatment of diabetes mellitus.

Claims

1. A pharmaceutical composition stable on storing and being suitable for the treatment of diabetes mellitus consisting of a physiologically acceptable excipient and an active compound combination, which contains, as the active compound combination,

(a) an insulin derivative of the formula I ##STR5## in which R¹ denotes H or H--Phe

R³⁰ represents the radical of Ala, Thr or Ser and

R³¹ represents a physiologically acceptable organic group of basic character of the formula X_n --S which has up to 50 carbon atoms, in which

n is 0, 1, 2 or 3,

X represents identical or different radicals of naturally occurring neutral or basic α

-amino acids and

S denotes OH or a physiologically acceptable group which blocks the carboxyl group but S being, if n is 0, a positively charged or protonatable basic radical or, if n is greater than 0, S can carry such a radical, or in which, if n is 2 or 3, the C-terminus X--S can also represent the homoserine-lapton radical

and which contains or does not contain a terminal carboxyl function or an ester or an amide thereof,

with an iso electric point between 5.8 and 8.5, and

(b) an insulin of the formula I in which R¹ denotes H or H--Phe, R³⁰ represents Ala, Thr or Ser and R³¹ denotes OH, or

(b2) physiologically acceptable salts thereof, or

(b3) proinsulin or

(b4) C peptide or

(b5) a combination thereof, component (a) being present in an amount of at least 1% by weight.

2. A composition as claimed in claim 1, in which R¹ represents H--Phe in the insulin derivative and in the insulin of the formula I.

3. A composition as claimed in claim 1, in which the amino acid radicals X are in the L-configuration in the insulin derivative of the formula I, mentioned under (1a).

4. A composition as claimed in claim 1, in which S represents OH or (C₁ to C₆)-alkoxy.

5. A composition as claimed in claim 1, in which X denotes Lys or Arg or both, in the insulin derivative of the formula I, mentioned under (1a).

6. A composition as claimed in claim 5, which contains insulin-B31--Arg--OH or insulin-B31--Arg--Arg--OH.

7. A composition as claimed in claim 1, which contains a plurality of (a) different insulin derivatives of the formula I or (b) different insulins of the formula I or of (a) and (b).

8. A composition as claimed in claim 1, which contains proinsulin or a proinsulin analogue or human C peptide or a combination thereof.

9. A composition as claimed in claim 1, which has a pH between 2.5 and 8.5 and is in the form of a solution or suspension, and contains a conventional isotonicity agent and a conventional preservative.

10. A composition as claimed in claim 1, which additionally contains a conventional buffer substance, if the pH value is between 5.0 and 8.5.

11. A composition as claimed in claim 1, wherein the formulation contains a conventional stabilizer which prevents precipitation of protein on exposure to heat or mechanical stress on contact with various materials.

12. A composition as claimed in claim 1, which contains a suitable amount of zinc, which can be between 0 and 100 μ

g/100 units.

13. A composition as claimed in claim 1, in which the insulin or proinsulin or des-Phe^B1 -insulin or C peptide or a combination thereof and insulin derivative of the formula I are used in the form of an alkali metal salt or the ammonium salt.

14. A composition as claimed in claim 1, wherein the content of insulin or proinsulin or des-Phe^B1 -insulin or C-peptide or a combination thereof and the content of insulin derivative of the formula I can in each case be, independently of one another, in dissolved, amorphous or crystalline form or a combination thereof.

15. A composition as claimed in claim 1, in which in each case any desired part of the content of insulin or proinsulin or des-Phe-^B1 -insulin or C-peptide or a combination thereof and of the content of insulin derivative of the formula I is in crystalline form, in each case any other desired part of the content of insulin or proinsulin or des-Phe-insulin or C-peptide or a combination thereof and of the content of the insulin derivative of the formula I is in amorphous form, and in each case the remainder of the content of insulin or proinsulin or des-Phe-insulin or C peptide or a combination thereof and of the content of the insulin derivative of the formula I is in dissolved form.

16. A composition as claimed in claim 1, which contains a conventional auxiliary having a delaying action.

17. A composition as claimed in claim 16, in which this delayed action principle is used in combination with the entire active compound content or with parts thereof.

18. A composition as claimed in claim 16, which contains insulin or proinsulin or des-Phe-insulin or C peptide or a combination thereof and insulin derivative of the formula I in combination with a plurality of different auxiliaries having a delaying action.

19. A method of treating a patient suffering from diabetes mellitus which comprises administering an effective amount of an insulin derivative of the formula I and an insulin of the formula I according to claim 1 or a pharmaceutically acceptable salt thereof.