Transdermal insulin

• US 5,597,796 A
• Filed: 09/07/1994
• Issued: 01/28/1997
• Est. Priority Date: 01/22/1991
• Status: Expired due to Fees

• Current Assignee: Novo Nordisk A/S
• Original Assignee: Novo Nordisk A/S
• Inventors: Brange, Jens J. V.
• Primary Examiner(s): Russel, Jeffrey E.
• Application Number:
  US08/301,838
• Time in Patent Office: 874 Days
• Field of Search: 530/303, 514/3, 204/165, 204/180.1, 204/182.6, 204/183.3, 204/450, 204/550, 424/78.02, 424/449, 604/20, 604/21
• US Class Current: 514/6.2
• 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: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/62 Insulins

Abstract

Insulin analogues have been developed which are well suited for transdermal administration by iontophoresis. The insulin analogues have a negative charge at neutral pH and a reduced tendency to association. They are prepared by altering the human insulin molecule by substituting at least two of the amino acid residues of human insulin by Glu and/or Asp at selected positions in the molecule.

Claims

1. An insulin analogue having the general formula III:

##STR4## wherein the amino acid residue designated Xaa in at least one of the positions B9,B10,B16, B26,B28,B1,B2,B18,B20,B28, or A21 and furthermore an amino acid residue designated Xaa in at least one of the positions A5,A15,A18,B3,B4,A12,A14,B22,B29 or B30 is independently substituted by Asp or Glu while any remaining Xaa designated the amino acid residue occurring in human insulin in the pertinent position, the terminal ends of the B-chain optionally being extended by one or two amino acid residues which can be chosen independently among Asp and Glu, with the proviso that it no amino acid residue designated Xaa in position A12,A14,B22,B29 or B30 is substituted, or if the terminal ends of the B-chain have not been extended, then the total number of substitutions is at least five.

2. An insulin analogue according to claim 1 wherein two amino acid residues designated Xaa in positions B9,B10,B16,B28,B1,B2,B18,B20,B27 or A21 and furthermore an amino acid residue designated Xaa in at least one of the positions A5,A15,A18,B3,B4,A12,A14,B22,B29 or B30 independently is substituted by Asp or Glu while any remaining Xaa designates the amino acid residue occurring in human insulin in the pertinent position, the terminal ends of the B-chain optionally being extended by one or two amino acid residues which can be chosen independently among Asp and Glu.

3. An insulin analogue according to claim 1 wherein the total number of substitutions is at least five.

4. An insulin analogue according to claim 1 wherein one amino acid residue designated Xaa in position A12,A14,B22,B29 or B30 is substituted by Asp or Glu.

5. An insulin analogue according to claim 1 wherein two amino acid residues designated Xaa in position A12,A14,B22,B29 or B30 independently are substituted by Asp or Glu.

6. An insulin analogue according to claim 1 wherein three amino acid residues designated Xaa in position A12,A14,B22,B29 or B30 independently are substituted by Asp or Glu.

7. An insulin analogue according to claim 1 wherein one amino acid residue designated Xaa in position A5,A15,A18,B3, or B4 is substituted by Asp or Glu.

8. An insulin analogue according to claim 1 wherein two amino acid residues designated Xaa in position A5,A15,A18, B3, or B4 independently are substituted by Asp or Glu.

9. An insulin analogue according to claim 1 wherein three amino acid residues designated Xaa in position A5,A15,A18,B3, or B4 independently are substituted by Asp or Glu.

10. A pharmaceutical composition comprising an insulin analogue according to claim 1.

11. A method for administering the insulin analogue of claim 1 transdermally which comprises placing an aqueous medium of the insulin in contact with human skin then applying a direct current to said insulin medium and the skin in contact therewith so that at least 5 IU per day of the insulin analogue crosses the skin through iontophoresis.