Novo Nordisk A/s

Novo Norkisk A/s

Per Balschmidt

Svend Havelund

Ib Jonassen

Jan Markussen

Finn B Hansen

Ole Hvilsted Olsen

Lars Thim

Hans Holmegaard So Slashedrensen

Michi Egel-Mitani

Ivan Verner Diers

Thomas Hoeg-Jensen

Frantisek Hubalek

Svend Ludvigsen

Thorkild Christensen

Thomas Børglum Kjeldsen

Helle Birk Olsen

Peter Kresten Nielsen

Jens J Brange

Thomas Borglum Kjeldsen

Steen Jensen

Inger Lautrup-Larsen

Lauge Schaffer

Thomas B&oslash;rglum Kjeldsen

Lone Lo Kimer

Niels Christian Kaarsholm

Jakob Brandt

Ulla Ribel-Madsen

Knud Vad

Are Bogsnes

Tine Glendorf

Soren Ostergaard

Per Nørgaard

Christensen Thorkild

Ingun Christiansen

Jean Lesley Whittingham

Ingun Christensen

Signe Ridderberg

Annette Frost Pettersson

Thomas H&oslash;eg-Jensen

Annette Frost Petterson

The present invention relates to novel insulin analogs comprising mutations at position A14 in the A chain and at positions B27, B28, B29 and B30 in the B chain and exhibiting resistance towards protease; a method for the preparation of such insulin analogs; insulin preparations containing the insulin analogs of the invention; and, a method of treating diabetes mellitus using these insulin analogs.

Protease-stabilized insulin analogues

The present invention relates to novel insulin analogues exhibiting resistance towards protease, wherein at least two amino acids are substituted and/or deleted relative to the parent insulin molecule. A method for the preparation of such insulin analogues, insulin preparations containing the insulin analogues of the invention and a method of treating diabetes mellitus using these insulin analogues is also provided.

Protease resistant insulin analogues

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 invention is related to fast acting insulin analogues which can form soluble mix-tures (pre-mixed or self-mixed) with long acting insulin analogues. The fast action is achieved through monomerizing substitutions/deletions in the C-terminus of the B-chain of human insulin and the mixability with long acting insulin analogues is achieved through a substitution of the Zn-binding His in position B10 of human insulin with a Gln amino acid residue. In one embodiment the invention is related to fast acting insulin analogues in which at least one of the natural amino acid residues in position B22-B30 in the human B-chain has been substituted with another amino acid residue having the effect of promoting formation of the monomeric form of insulin, the His amino acid residue in position 10 in the B-chain is substituted with a Gln and wherein further one or more of the amino acid residues in position B22-B30 optionally have been deleted.

Rapid acting insulin analogues

The present invention relates to pharmaceutical formulations comprising insulin, an insulin analog, an insulin derivative, or a combination of any of the foregoing, and a salt of protamine, to methods of preparing such formulations, and to uses of such formulations in the treatment of diseases and conditions for which use of the insulin peptide(s) contained in such formulations is indicated. The present invention further relates to methods for increasing the stability and/or solubility of insulin in insulin-containing formulations at a pH less than 7.0 by adding a salt of protamine to the insulin-containing formulations.

Soluble, stable insulin-containing formulations with a protamine salt

A preferred way of converting insulin precursors into insulin compounds is to perform an enzymatic peptide cleavage in an aqueous medium and, thereafter, without removal of the intermediate product formed, to add an amino acid ester or a peptide ester and an organic solvent so that the desired coupling takes place.

Process for preparing insulin compounds

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 polypeptides expressed and processed in yeast, a DNA construct comprising a DNA sequence encoding such polypeptides, vectors carrying such DNA fragments and yeast cells transformed with the vectors, as well as a process of producing heterologous proteins in yeast.

N-terminally extended proteins expressed in yeast

The present invention relates-to protracted acting, water-soluble aggregates of derivatives of human insulin, derivatives of human insulin capable of forming such aggregates, pharmaceutical compositions containing them, and to the use of such aggregates in the treatment of diabetes.

Aggregates of human insulin derivatives

The present invention relates to derivatives of insulin and insulin analogues wherein the N-terminal amino group of the B-chain and/or the &egr;-amino group of Lys in position B28, B29 or B30 has a substituent of the formula &mdash;CO&mdash;W&mdash;COOH wherein W is a divalent long chain hydrocarbon group having from 12 to 22 carbon atoms and zinc complexes thereof are soluble at physiological pH values and exhibit a long disappearance half-life from the injection site after subcutaneous injection.

Peptide derivatives

The present invention relates to synthetic leader peptide sequences for secreting polypeptides in yeast.

Synthetic leader peptide sequences

Insulin preparations of superior physical stability, comprising dissolved and/or precipitated human insulin or an analogue or derivative thereof, and a water-soluble reduced or non-reducing carbohydrate containing at least 4 carbon atoms in the main carbohydrate structure, or a water-soluble non-reducing ester and/or ether derivative of a carbohydrate or reduced carbohydrate containing at least 4 carbon atoms in the main carbohydrate structure, or mixtures thereof are disclosed.

Methods for producing biphasic insulin formulations

A pharmaceutical formulation comprising a growth hormone pretreated with zinc and optionally lysine or calcium ions shows a very high stability against deamidation, oxidation and cleavage of peptide bonds. The stability of the product allows for the storing and shipment thereof in a lyophilized state or in the form of a dissolved or re-dissolved formulation at ambient temperature.

Pharmaceutical formulation of human-growth hormone pretreated with zinc

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Espergaerde, Denmark

Per Balschmidt