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WO1992000321A1 - Nouveaux analogues insuliniques a effet prolonge - Google Patents

Nouveaux analogues insuliniques a effet prolonge Download PDF

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Publication number
WO1992000321A1
WO1992000321A1 PCT/DK1991/000167 DK9100167W WO9200321A1 WO 1992000321 A1 WO1992000321 A1 WO 1992000321A1 DK 9100167 W DK9100167 W DK 9100167W WO 9200321 A1 WO9200321 A1 WO 9200321A1
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WO
WIPO (PCT)
Prior art keywords
arg
lys
pro
human insulin
thr
Prior art date
Application number
PCT/DK1991/000167
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English (en)
Inventor
Jan Markussen
Liselotte Langkjaer
Kjeld Norris
Leo Boye Snel
Original Assignee
Novo Nordisk A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Publication of WO1992000321A1 publication Critical patent/WO1992000321A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/62—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to novel insulin analogues with a prolonged insulin action, to a process for the preparation of such insulin analogues and to injectable solutions containing the novel insulin analogues.
  • Insulin analogues with a protracted insulin action have previously been described in EP 0194864A and EP 0254516A.
  • EP 0194864A protracted human insulin analogues wherein the C-terminal carboxyl group of the B-chain is blocked with an amido or ester residue and the amino acid residue in position A4, A17, B13 and B21 may be substituted by Gin are described.
  • EP 0254516A describes human insulin of the same type as in EP 0194486A but further being modified in the A21 position.
  • Some of the above insulin analogues may, however, show a too low biological potency or the level of prolongation may be too low for specific purposes.
  • the present invention is thus related to novel analogues of human insulin wherein at least one of the amino acid residues from B1 to B6 has been replaced by a basic amino acid residue, i.e. a lysine or arginine residue (Lys or Arg).
  • a basic amino acid residue i.e. a lysine or arginine residue (Lys or Arg).
  • asparagine (Asn) in position A21 may furthermore be substituted with another amino acid residue.
  • a further positive charge may be introduced by blocking the C-terminal carboxyl group in position B30 preferably by means of an amido or ester group.
  • the amino group linked to the C-terminal end of the Lys or Arg residue substituent is a proline residue.
  • the invention is also related to a method for the preparation of the novel insulin analogues by which a biosynthetic precursor of the insulin analogue is converted into the insulin analogues by enzymatic and chemical conversion and to insulin solutions containing the novel insulin analogues.
  • insulin analogues as used herein is meant a compound having a molecular structure similar to that of insulin including the disulphide bridges between Cys A7 and Cys B7 , and between Cys A20 and Cys B19 and an internal disulphide bridge between Cys A6 and Cys A11 and with insulin activity.
  • the present insulin analogues may be represented by the following formula I
  • Z is Asn or another naturally occuring amino acid residue
  • X 1 is Phe, Lys or Arg
  • X 2 is Val, Lys or Arg
  • X 3 is Asn, Lys, Arg or Pro
  • X 4 is Gin, Lys, Arg or Pro
  • X 5 is His, Lys, Arg or Pro
  • X 6 is Lys, Arg, Leu or Pro
  • Y is a threonine residue wherein the carboxyl group may be blocked by an ester or amido group, with the proviso that at least one of X 1 , X 2 , X 3 , X 4 , X 5 and X 6 is Lys or Arg.
  • the change in charge is obtained by substituting one or more of the amino acid residues in position B1 to B6 with an arginine or lysine residue.
  • the C-terminal carboxyl group of the B- chain may be blocked by an ester group or amide group.
  • Z is not asparagine it may be a neutral amino acid, for example valine, glutamine, isoleucine, leucine, phenylalanine, tyrosine, methionine or preferably glycine, serine, threonine or alanine.
  • Z may also be an acidic amino acid, viz. glutamic acid or aspartic acid, or a basic amino acid, viz. lysine, arginine or histidine.
  • Z is preferably glycine, alanine or serine.
  • blocking groups of the C-terminal carboxyl group in the B30 amino acid residue (threonine) are ester moities such as lower alkoxy with preferably not more than 8 carbon atoms, preferably less than 5 carbon atoms.
  • Preferred alkoxy groups are methoxy, ethoxy and tertiary butoxy.
  • the blocking group may also be an amido group with the formula -NR 1 R 2 wherein R 1 and R 2 are the same or different and each represents hydrogen or alkyl with preferably up to 8 carbon atoms. R 1 and R 2 are preferably each hydrogen.
  • the degree of prolongation can be enhanced and controlled by the addition of zinc ions.
  • Parameters that may control the degree of prolongation of the insulin effect are the concentration of zinc and the choice of the compound of formula I.
  • the range for preferred zinc content extends from 0 to about 2 mg/ml, preferably from 0 to 200 ⁇ g/ml zinc and more preferably from about 20 to 200 ⁇ g/ml in a preparation containing about 240 nmole of a compound of formula I per ml. Using other concentrations of the compound of formula I, the content of zinc is to be adjusted correspondingly.
  • the pH of the injectable solution of this invention should preferably be below the physiological pH, the upper limit being the pH where precipitation occurs. At the physiological pH value, compounds of formula I of this invention have a low solubility. Stable solutions containing about 240 nmole/ml of compounds of formula I per ml have been obtained at pH about 5.5. The upper limit depends upon the constituents of the solution, i.e. isotonikum, preservative and zinc concentration, and upon the choice of compound of formula I. There is no lower pH limit of the solutions and the chemical stability of the compounds of formula I where Z is different from asparagine, is high, even at pH 3.
  • the preferred pH range for the injectable solutions of this invention is from about 2.5 to 8.5, more preferred from about 4.5 to 8. Especially preferred are pH ranges about 2.5 to 5.5, most prefered about 3 to 4.5.
  • a furter aspect of this invention is that it provides improved flexibility for the patients.
  • the patient With two aqueous solutions, one containing a compound of formula I and the other containing a zinc salt, the patient can obtain a desired degree of prolonged action and a desired profile by mixing the two solutions appropriately.
  • the patient has, using two stock solutions, the possibility of choosing one action and profile for the morning injection and another action and profile for the evening injection.
  • the zinc solution of this invention contains between about 2 ⁇ g and 20 mg zinc per ml.
  • both of the stock solutions may contain zinc, either in the same or different concentrations, and/or both the stock solutions may contain a compound of formula I, either the same or different compounds.
  • the injectable solutions of this invention have a strength of between about 60 and 6000 nmole of the compound of formula I per ml.
  • novel insulin analogues according to the present invention may be prepared by altering the proinsulin gene through replacement of codon(s) at the appropriate site in the native human proinsulin gene by codon(s) encoding the desired amino acid residue substitute (s) or by synthesizing the whole DNA-sequence encoding the desired insulin analogue.
  • the gene encoding the desired insulin analogue is then inserted into a suitable expression vector which when transferred to a suitable host organism, e.g. E. coli, Bacillus or yeast, generates the desired product.
  • the expressed product is then isolated from the cells or the culture broth depending on whether the expressed product is secreted from the cells or not.
  • novel insulin analogues may also be prepared by chemical synthesis by methods analogue to the method described by Marki et al. (Hoppe-Seyler's Z. Physiol.Chem., 360 (1979), 1619-1632). They may also be formed from separately in vitro prepared A- and B-chains containing the appropriate amino acid residue substitutions, whereupon the modified A- and B-chains are linked together by establishing disulphide bridges according to known methods (e.g. Chance et al., In: Rick DH, Gross E (eds) Peptides: Synthesis - Structure - Function. Proceedings of the seventh American peptide symposium, Illinois, pp. 721-728).
  • the insulin analogues may furthermore be prepared by a method analogue to the method described in EP 0163529A, the disclosure of which is incorporated by reference hereinto.
  • a method analogue to the method described in EP 0163529A an insulin precursor of human insulin wherein LyS B29 is connected to Gly A1 by means of either a peptide bond or a peptide chain of varying length with correctly positioned disulphide bridges is expressed and secreted by yeast and then converted into human insulin by the so-called transpeptidation reaction.
  • transpeptidation reaction is described in US patent specification No. 4,343,898 (the disclosure of which is incorporated by reference hereinto).
  • this reaction the peptide bond or peptide chain connecting Lys B29 and Gly A1 is exised and a threonine ester or threonine amide group is coupled to the C-terminal end of Lys B29 .
  • novel insulin analogues may thus be prepared by a method wherein a biosynthetic insulin precursor with the following formula II
  • Q is a peptide chain with q amino acid residues, q is an interger from 0 to 33, T is Lys or Arg, r is 0 or 1 and X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and Z are defined as above, is reacted with a compound of the formula III
  • HY (III) wherein Y is a protected threonine amino acid wherein the carboxyl group is protected with an ester or amido group, using trypsin or trypsin like enzymes as a catalyst in a mixture of water and organic solvent. The ester or amido protecting group may then be cleaved off by acid or basic hydrolysis.
  • Preferred compounds of formula III are Thr-NH 2 , Lys(Boc)-NH 2 , Thr(Bu t )-OBu t and Thr-OBu t .
  • Insulin preparations of this invention are prepared by dissolving a compound of formula I in an aqueous medium at slightly acidic conditions, for example, in a concentration of 240 or 600 nmole/ml.
  • the aqueous medium is made isotonic, for example, with sodium chloride or glycerol.
  • the aqueous medium may contain zinc ions in a concentraion of up to about 30 ⁇ g of Zn ++ per nmol of compound of formula I, buffers such as acetate, citrate and histidine and preservatives such as m-cresol, nipagin or phenol .
  • the pH value of the final insulin preparation depends upon the number of charges that have been changed in the compound of formula I, the concentration of zinc ions, the concentration of the compound of formula I and the compound of formula I selected.
  • the pH value is adjusted to a value convenient for administration such as about 2.5 - 5.5, preventing precipitation.
  • the insulin preparation is made sterile by sterile filtration.
  • the insulin preparations of this invention can be used similarly to the use of the known insulin preparations.
  • amino acids are those stated in J.Biol.Chem. 243 (1968), 3558.
  • the amino acids are in the L configuration. Unless otherwise indicated, the species of insulins stated herein is human.
  • B(l-29) means a shortened B-chain of human insulin from Phe B1 to LysB29 and A(1-21) means the A-chain of human insulin.
  • Arg B2 human insulin means a human insulin analogue wherein Arg has been substituted for Val in position 2 in the B-chain.
  • ArgB2 , B ( 1-29 )-Ala-Ala-Lys-A(1-21) human insulin means a precursor for the forementioned insulin analogue wherein Arg has been substituted for Val in position 2 in the shortened B-chain and wherein the B(1-29) chain and the A(1- 21) chain are connected by the peptide sequence Ala-Ala-Lys.
  • the B(l-29) chain and the A(1-21) chain are connected by disulphide bridges between Cys A7 and Cys B7 and between Cys A20 and Cys B19 , respectively, and that the A-chain contains an internal disulphide bridge between Cys A6 and Cys A1 , as in human insulin.
  • the insulin precursors were recovered from the fermentation broths by adsorption of LiChroprepTM RP-18 as described in Example 7 of EP 0163529A.
  • the precursors were eluted from the column with 0.2 M KCl, 0.001 M HCl in 33% (v/v) ethanol.
  • the insulin precursors were crystallized from the pool by successive additions of water (1 volume per volume of pool), solid trisodium citrate to obtain a molarity of 0.05 M and finally zinc acetate to obtain a molarity of 0.006 M.
  • the pH value was adjusted to 6.8 and the mixture was left overnight at 4°C.
  • the crystals were isolated by centrifugation, washed with water and dried in vacuo.
  • Sterile injectable solutions of the above compounds for testing of the degree of prolonged action were made using 1.6% (w/v) glycerol as the isotonicum, and 0.26% (w/v) phenol as the preservative.
  • the concentration of zinc ions was 8, 80 or 160 ⁇ g/ml.
  • the pH values of the solutions were adjusted sufficiently off the isoelectric point of the analogues to keep the solutions clear upon storage at 4°C.
  • the solutions contained 240 nmole/ml of the tested compounds. The concentration of 240 nmole/ml was verified by HPLC.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Endocrinology (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Diabetes (AREA)
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Abstract

Analogues d'insuline humaine à effet insulinique prolongé dans lesquels au moins l'un des restes d'acide aminé en position B1-B6 est remplacé par un reste de lysine (Lys) ou d'arginine (Arg). On peut remplacer Asn en position A21 par un autre reste d'acide aminé de façon à augmenter la statilité de l'anlogue insulinique dans une solution acide. De plus, on peut bloquer la position B30 à l'aide d'un groupe amido ou ester.
PCT/DK1991/000167 1990-06-28 1991-06-21 Nouveaux analogues insuliniques a effet prolonge WO1992000321A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK1556/90 1990-06-28
DK155690A DK155690D0 (da) 1990-06-28 1990-06-28 Nye peptider

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EP (1) EP0536245A1 (fr)
JP (1) JPH05508406A (fr)
AU (1) AU8054391A (fr)
DK (1) DK155690D0 (fr)
IE (1) IE912247A1 (fr)
IL (1) IL98596A0 (fr)
NZ (1) NZ238718A (fr)
PT (1) PT98124A (fr)
WO (1) WO1992000321A1 (fr)
ZA (1) ZA914830B (fr)

Cited By (56)

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WO1996029344A1 (fr) * 1995-03-17 1996-09-26 Novo Nordisk A/S Derives de l'insuline
RU2164520C2 (ru) * 1993-09-17 2001-03-27 Ново Нордиск А/С Производное инсулина, растворимая пролонгированная фармацевтическая композиция, способ пролонгирования гипогликемического действия при лечении диабета
US6221633B1 (en) 1997-06-20 2001-04-24 Aventis Pharma Deutschland Gmbh Insulin derivatives having a rapid onset of action
US6251856B1 (en) 1995-03-17 2001-06-26 Novo Nordisk A/S Insulin derivatives
EP0781295A4 (fr) * 1994-08-02 2001-08-29 Lilly Co Eli Analogues d'insuline asp b1
WO2003105888A1 (fr) * 2002-06-18 2003-12-24 Aventis Pharma Deutschland Gmbh Preparations acides d'insuline ayant une meilleure stabilite
US7202059B2 (en) 2001-02-20 2007-04-10 Sanofi-Aventis Deutschland Gmbh Fusion proteins capable of being secreted into a fermentation medium
US7205276B2 (en) 2001-03-23 2007-04-17 Sanofi-Aventis Deutschland Gmb Zinc-free and low-zinc insulin preparations having improved stability
EP2033662A1 (fr) 2004-01-21 2009-03-11 Novo Nordisk Health Care AG Conjugaison au moyen de transglutaminase de peptides
US7638618B2 (en) 2001-02-20 2009-12-29 Sanofi-Aventis Deutschland Gmbh Nucleic acids encoding a hirudin and pro-insulin as superscretable peptides and for parallel improvement of the exported forms of one or more polypeptides of interest
DE102008051834A1 (de) 2008-10-17 2010-04-22 Sanofi-Aventis Deutschland Gmbh Kombination von einem Insulin und einem GLP-1-Agonisten
DE102008053048A1 (de) 2008-10-24 2010-04-29 Sanofi-Aventis Deutschland Gmbh Kombination von einem Insulin und einem GLP-1-Agonisten
DE102008064270A1 (de) * 2008-12-20 2010-07-01 Voith Patent Gmbh Verfahren und Vorrichtung zur Flotation einer wässrigen Faserstoffsuspension
WO2011003823A1 (fr) 2009-07-06 2011-01-13 Sanofi-Aventis Deutschland Gmbh Préparations d'insuline à effet retard
WO2011003822A2 (fr) 2009-07-06 2011-01-13 Sanofi-Aventis Deutschland Gmbh Préparations d'insuline contenant de la méthionine
WO2011003820A1 (fr) 2009-07-06 2011-01-13 Sanofi-Aventis Deutschland Gmbh Préparations d'insuline stables à la chaleur et aux agitations
DE102009038210A1 (de) 2009-08-20 2011-03-03 Sanofi-Aventis Deutschland Gmbh Kombination von einem Insulin und einem GLP-1-Agonisten
WO2011058083A1 (fr) 2009-11-13 2011-05-19 Sanofi-Aventis Deutschland Gmbh Composition pharmaceutique comprenant un agoniste de glp-1, une insuline et de la méthionine
WO2011161083A1 (fr) * 2010-06-23 2011-12-29 Novo Nordisk A/S Insuline humaine contenant des liaisons disulfures supplémentaires
WO2011161125A1 (fr) * 2010-06-23 2011-12-29 Novo Nordisk A/S Dérivés d'insuline contenant des liaisons disulfure supplémentaires
WO2011161124A1 (fr) * 2010-06-23 2011-12-29 Novo Nordisk A/S Analogues de l'insuline contenant des liaisons disulfures supplémentaires
WO2012035139A1 (fr) 2010-09-17 2012-03-22 Sanofi-Aventis Deutschland Gmbh Promédicaments comprenant un conjugué exendine-lieur
WO2012123519A3 (fr) * 2011-03-15 2012-11-15 Novo Nordisk A/S Analogues de l'insuline humaine et dérivés comprenant des substitutions de cystéine
US8710001B2 (en) 2006-07-31 2014-04-29 Novo Nordisk A/S PEGylated, extended insulins
WO2014096985A2 (fr) 2012-12-19 2014-06-26 Wockhardt Limited Composition aqueuse stable comprenant de l'insuline humaine ou un analogue ou un dérivé de celle-ci
WO2014102623A1 (fr) 2012-12-26 2014-07-03 Wockhardt Limited Composition pharmaceutique
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US9018161B2 (en) 2006-09-22 2015-04-28 Novo Nordisk A/S Protease resistant insulin analogues
US9138462B2 (en) 2009-07-31 2015-09-22 Sanofi-Aventis Deutschland Gmbh Prodrugs comprising an insulin linker conjugate
WO2016001862A1 (fr) 2014-07-04 2016-01-07 Wockhardt Limited Formulations à libération prolongée d'insulines
US9260502B2 (en) 2008-03-14 2016-02-16 Novo Nordisk A/S Protease-stabilized insulin analogues
US9265723B2 (en) 2009-07-31 2016-02-23 Sanofi-Aventis Deutschland Gmbh Long acting insulin composition
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US9408893B2 (en) 2011-08-29 2016-08-09 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for use in glycemic control in diabetes type 2 patients
US9481721B2 (en) 2012-04-11 2016-11-01 Novo Nordisk A/S Insulin formulations
US9526764B2 (en) 2008-10-17 2016-12-27 Sanofi-Aventis Deutschland Gmbh Combination of an insulin and a GLP-1-agonist
US9616015B2 (en) 2012-05-25 2017-04-11 Diamedica Inc. Formulations of human tissue kallikrein-1 for parenteral delivery and related methods
US9644017B2 (en) 2008-01-09 2017-05-09 Sanofi-Aventis Deutschland Gmbh Insulin derivatives having an extremely delayed time-action profile
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US9707176B2 (en) 2009-11-13 2017-07-18 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist and methionine
US9821032B2 (en) 2011-05-13 2017-11-21 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin
US9839692B2 (en) 2014-01-09 2017-12-12 Sanofi Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives
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US10919949B2 (en) 2017-08-17 2021-02-16 Novo Nordisk A/S Acylated insulin analogues and uses thereof
US11857608B2 (en) 2017-03-09 2024-01-02 Diamedica Inc. Dosage forms of tissue kallikrein 1
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Cited By (97)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2164520C2 (ru) * 1993-09-17 2001-03-27 Ново Нордиск А/С Производное инсулина, растворимая пролонгированная фармацевтическая композиция, способ пролонгирования гипогликемического действия при лечении диабета
EP0781295A4 (fr) * 1994-08-02 2001-08-29 Lilly Co Eli Analogues d'insuline asp b1
WO1996029344A1 (fr) * 1995-03-17 1996-09-26 Novo Nordisk A/S Derives de l'insuline
US6251856B1 (en) 1995-03-17 2001-06-26 Novo Nordisk A/S Insulin derivatives
US6620780B2 (en) 1995-03-17 2003-09-16 Novo Nordisk A/S Insulin derivatives
US7229964B2 (en) 1995-03-17 2007-06-12 Novo Nordisk A/S Insulin derivatives
US6221633B1 (en) 1997-06-20 2001-04-24 Aventis Pharma Deutschland Gmbh Insulin derivatives having a rapid onset of action
US7638618B2 (en) 2001-02-20 2009-12-29 Sanofi-Aventis Deutschland Gmbh Nucleic acids encoding a hirudin and pro-insulin as superscretable peptides and for parallel improvement of the exported forms of one or more polypeptides of interest
US7202059B2 (en) 2001-02-20 2007-04-10 Sanofi-Aventis Deutschland Gmbh Fusion proteins capable of being secreted into a fermentation medium
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ZA914830B (en) 1992-03-25
NZ238718A (en) 1992-06-25
IL98596A0 (en) 1992-07-15
PT98124A (pt) 1992-04-30
IE912247A1 (en) 1992-01-01
EP0536245A1 (fr) 1993-04-14
AU8054391A (en) 1992-01-23
DK155690D0 (da) 1990-06-28
JPH05508406A (ja) 1993-11-25

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