Novo Nordisk A/s

Ib Jonassen

Svend Havelund

Thomas Hoeg-Jensen

Jan Markussen

Peter Madsen

Patrick William Garibay

Per Hertz Hansen

Peter Kurtzhals

Janos Tibor Kodra

Per Balschmidt

Tina Møller Tagmose

Niels Christian Kaarsholm

Asser Sloth Andersen

Jakob Brandt

Ulla Ribel-Madsen

Allan Svendsen

Palle Jakobsen

Ib Groth Clausen

Frantisek Hubalek

Ivan Verner Diers

Michi Egel-Mitani

Thomas Borglum Kjeldsen

John Halstro Slashedm

John Halstrom

Tina Moeller Tagmose

Thomas Børglum Kjeldsen

Helle Birk Olsen

Ejner Bech Jensen

János Tibor Kodra

Soren Ostergaard

Lauge Schaffer

Charlotte Harkjaer Fynbo

Anne Plum

Thomas H&oslash;eg-Jensen

Signe Ridderberg

Einer B Jensen

John B Halstrøm

Charlotte Harkjær Fynbo

Thomas Berglum Kjeldsen

The invention is related to insulin compositions with a high content of zinc atoms per six molecules of acylated insulin. The insulin is an acylated insulin and may be mixed with a further insulin analogue such as the rapid acting insulin Asp B28 human insulin.

Insulin compositions and method of making a composition

The present invention relates to insulin derivatives having a side chain attached either to the &#x3b1;-amino group of the N-terminal amino acid residue of the B chain or to the &#x3b5;-amino group of a Lys residue present in the B chain of the parent insulin via an amide bond which side chain comprises at least one aromatic group; at least one free carboxylic acid group or a group which is negatively charged at neutral pH, a fatty acid moiety with 4 to 22 carbon atoms in the carbon chain; and possible linkers which link the individual components in the side chain together via amide bonds.

Insulin derivatives

The present invention relates to novel human insulin derivatives which are soluble at physiological pH values and have a prolonged profile of action. The invention also relates to methods of providing such derivatives, to pharmaceutical compositions containing them, to methods of treating diabetes and hyperglycaemia using the insulin derivatives of the invention and to the use of such insulin derivatives in the treatment of diabetes and hyperglycaemia.

Insulin derivative

The present invention is related to insulin derivatives having a side chain attached either to the &#x3b1;-amino group of the N-terminal amino acid residue of B chain or to an &#x3b5;-amino group of a Lys residue present in the B chain of the parent insulin molecule via an amide bond which side chain comprises one or more residues of ethyleneglycol, propyleneglycol and/or butyleneglycol containing independently at each termini a group selected from &#x2014;NHand &#x2014;COOH; a fatty diacid moiety with 4 to 22 carbon atoms, at least one free carboxylic acid group or a group which is negatively charged at neutral pH; and possible linkers which link the individual components in the side chain together via amide or ether bonds, said linkers optionally comprising a free carboxylic acid group.

The present invention related to a method of producing polypeptides in transformed host cells by expressing a precursor molecule of the desired polypeptide which are to be acylated in a subsequent in vitro step. The invention is also related to DNA-sequences, vectors and transformed host cells for use in the claimed method. Further, the present invention is related to certain precursors of the desired polypeptides and certain acylation methods. The invention provides a method for making polypeptides being preferentially acylated in certain lysine &#x3b5;-amino groups.

Method for making acylated polypeptides

The present invention relates to insulin derivatives which are naturally occurring insulins or analogues thereof which have a side chain attached either to the &#x3b1;-amino group of the N-terminal amino acid residue of the B chain or to the &#x3b5;-amino group of a Lys residue present in the B chain of the parent insulin, the side chain being of the general formula:&#x2014;W&#x2014;X&#x2014;Y&#x2014;Zwherein W, X, Y and Z are as defined in the disclosure.

Novel human insulin derivatives are described which are soluble at physiological pH values and have a prolonged profile of action.

The present invention is related to insulin derivatives having a side chain attached to an &#x3b5;-amino group of a Lys residue present in the A-chain or to an &#x3b5;-amino group of a Lys residue in the B-chain.

The present invention relates to insulin derivatives which are naturally occurring insulins or analogues thereof which have a side chain attached either to the &#x3b1;-amino group of the N-terminal amino acid residue of the B chain or to the &#x3b5;-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&#x2014;Y-Zwherein W, X, Y and Z are as defined in the disclosure.

A pharmacologically active peptide hormone derivative in which the parent peptide hormone has been modified by introducing either a lipophilic substituent, W, in the N-terminal amino acid or a lipophilic substituent, Z, in the C-terminal amino acid of the parent peptide hormone or an analogue thereof, said lipophilic substituent having from 8 to 40 carbon atoms, has a protracted profile of action.

Peptide derivatives

Insulin derivatives having a built-in glucose sensor, capable of delivering insulin from a depot as a function of the glucose concentration in the surrounding medium (e.g. tissue), such that the rate of insulin release from the depot increases with an increased glucose concentration and decreases with a decreased glucose concentration.

Glucose dependent release of insulin from glucose sensing insulin derivatives

The present invention relates to insulin derivatives in which a lipophilic group having from 12 to 40 carbon atoms is attached to the &#x3b1;-amino group of the N-terminal amino acid in the B-chain or to the carboxy group of the C-terminal amino acid in the B-chain have a protracted profile of action.

The present invention relates to protracted human insulin derivatives in which the A21 and the B3 amino acid residues are, independently, any amino acid residue which can be coded for by the genetic code except Lys, Arg and Cys; Phemay be deleted; the B30 amino acid residue is (a) a non-codable, lipophilic amino acid having from 10 to 24 carbon atoms, in which case an acyl group of a carboxylic acid with up to 5 carbon atoms is bound to the &#x3b5;-amino group of Lys; or (b) the B30 amino acid residue is deleted or is any amino acid residue which can be coded for by the genetic code except Lys, Arg and Cys, in any of which cases the &#x3b5;-amino group of Lyshas a lipophilic substituent; and any Zncomplexes thereof with the proviso that when B30 is Thr or Ala and A21 and B3 are both Asn, and Pheis present, then the insulin derivative is always present as a Zncomplex.

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Valby, Denmark

Ib Jonassen