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EP0536245A1 - Nouveaux analogues insuliniques a effet prolonge - Google Patents

Nouveaux analogues insuliniques a effet prolonge

Info

Publication number
EP0536245A1
EP0536245A1 EP91912264A EP91912264A EP0536245A1 EP 0536245 A1 EP0536245 A1 EP 0536245A1 EP 91912264 A EP91912264 A EP 91912264A EP 91912264 A EP91912264 A EP 91912264A EP 0536245 A1 EP0536245 A1 EP 0536245A1
Authority
EP
European Patent Office
Prior art keywords
arg
lys
pro
human insulin
thr
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP91912264A
Other languages
German (de)
English (en)
Inventor
Jan Markussen
Liselotte Langkjaer
Kjeld Norris
Leo Boye Snel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
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 AS filed Critical Novo Nordisk AS
Publication of EP0536245A1 publication Critical patent/EP0536245A1/fr
Withdrawn legal-status Critical Current

Links

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)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Endocrinology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Toxicology (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Diabetes (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Medicinal Preparation (AREA)

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.
EP91912264A 1990-06-28 1991-06-21 Nouveaux analogues insuliniques a effet prolonge Withdrawn EP0536245A1 (fr)

Applications Claiming Priority (2)

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

Publications (1)

Publication Number Publication Date
EP0536245A1 true EP0536245A1 (fr) 1993-04-14

Family

ID=8106031

Family Applications (1)

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EP91912264A Withdrawn EP0536245A1 (fr) 1990-06-28 1991-06-21 Nouveaux analogues insuliniques a effet prolonge

Country Status (10)

Country Link
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)

Families Citing this family (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69428134T2 (de) * 1993-09-17 2002-05-02 Novo Nordisk A/S, Bagsvaerd Acyliertes insulin
US5559094A (en) * 1994-08-02 1996-09-24 Eli Lilly And Company AspB1 insulin analogs
US6251856B1 (en) 1995-03-17 2001-06-26 Novo Nordisk A/S Insulin derivatives
CA2215694A1 (fr) * 1995-03-17 1996-09-26 Novo Nordisk A/S Derives de l'insuline
DE19726167B4 (de) 1997-06-20 2008-01-24 Sanofi-Aventis Deutschland Gmbh Insulin, Verfahren zu seiner Herstellung und es enthaltende pharmazeutische Zubereitung
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
DE10114178A1 (de) 2001-03-23 2002-10-10 Aventis Pharma Gmbh Zinkfreie und zinkarme Insulinzubereitungen mit verbesserter Stabilität
DE10227232A1 (de) * 2002-06-18 2004-01-15 Aventis Pharma Deutschland Gmbh Saure Insulinzubereitungen mit verbesserter Stabilität
CA2552043A1 (fr) 2004-01-21 2005-08-04 Novo Nordisk A/S Conjugaison de peptides induite par la transglutaminase
WO2008015099A2 (fr) 2006-07-31 2008-02-07 Novo Nordisk A/S Insulines pegylées à extensions
ES2601839T3 (es) 2006-09-22 2017-02-16 Novo Nordisk A/S Análogos de insulina resistentes a proteasas
JP5496082B2 (ja) 2007-04-30 2014-05-21 ノボ・ノルデイスク・エー／エス タンパク質組成物を乾燥させる方法、乾燥タンパク質組成物、及び乾燥タンパク質を含有する薬学的組成物
AU2009203809B2 (en) 2008-01-09 2013-07-25 Sanofi-Aventis Deutschland Gmbh Novel insulin derivatives having an extremely delayed time-action profile
EP2254905B1 (fr) 2008-03-14 2016-12-14 Novo Nordisk A/S Analogues de l insuline stabilisés une protéase
DK2254906T3 (en) 2008-03-18 2017-01-23 Novo Nordisk As Protease-stabilized acylated insulin analogues
DE102008053048A1 (de) 2008-10-24 2010-04-29 Sanofi-Aventis Deutschland Gmbh Kombination von einem Insulin und einem GLP-1-Agonisten
HUE068164T2 (hu) 2008-10-17 2024-12-28 Sanofi Aventis Deutschland Egy inzulin és egy GLP-1 agonista kombinációja
DE102008051834A1 (de) 2008-10-17 2010-04-22 Sanofi-Aventis Deutschland Gmbh Kombination von einem Insulin und einem GLP-1-Agonisten
DE102009038210A1 (de) 2009-08-20 2011-03-03 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
US20120232002A1 (en) 2009-07-06 2012-09-13 Sanofi-Aventis Deutschland Gmbh Slow-acting insulin preparations
JP2012532177A (ja) * 2009-07-06 2012-12-13 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 熱及び振動安定性インスリン製剤
WO2011003822A2 (fr) 2009-07-06 2011-01-13 Sanofi-Aventis Deutschland Gmbh Préparations d'insuline contenant de la méthionine
AU2010277559B2 (en) 2009-07-31 2016-08-11 Sanofi-Aventis Deutschland Gmbh Prodrugs comprising an insulin linker conjugate
SG178195A1 (en) 2009-07-31 2012-03-29 Sanofi Aventis Deutschland Long acting insulin composition
SG10201500871TA (en) 2009-11-13 2015-04-29 Sanofi Aventis Deutschland Pharmaceutical composition comprising a glp-1 agonist and methionine
CA2780460C (fr) 2009-11-13 2018-09-04 Sanofi-Aventis Deutschland Gmbh Composition pharmaceutique comprenant un agoniste de glp-1, une insuline et de la methionine
CN102947331B (zh) * 2010-06-23 2016-08-03 诺沃—诺迪斯克有限公司 包含额外的二硫键的胰岛素类似物
EP2585483A1 (fr) 2010-06-23 2013-05-01 Novo Nordisk A/S Insuline humaine contenant des liaisons disulfures supplémentaires
AU2011269000C1 (en) * 2010-06-23 2015-10-08 Novo Nordisk A/S Insulin derivatives containing additional disulfide bonds
RS55378B1 (sr) 2010-08-30 2017-03-31 Sanofi Aventis Deutschland Upotreba ave0010 za proizvodnju leka za tretman diabetes mellitus tipa 2
EP2438930A1 (fr) 2010-09-17 2012-04-11 Sanofi-Aventis Deutschland GmbH Promédicaments comprenant un conjugué de liaison d'exendine
EP2686003A2 (fr) * 2011-03-15 2014-01-22 Novo Nordisk A/S Analogues de l'insuline humaine et dérivés comprenant des substitutions de cystéine
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
BR112014004726A2 (pt) 2011-08-29 2017-04-04 Sanofi Aventis Deutschland combinação farmacêutica para uso no controle glicêmico em pacientes de diabetes tipo 2
TWI559929B (en) 2011-09-01 2016-12-01 Sanofi Aventis Deutschland Pharmaceutical composition for use in the treatment of a neurodegenerative disease
CA2870313A1 (fr) 2012-04-11 2013-10-17 Novo Nordisk A/S Formulations a base d'insuline
US20130315891A1 (en) 2012-05-25 2013-11-28 Matthew Charles Formulations of human tissue kallikrein-1 for parenteral delivery and related methods
CA2880085C (fr) 2012-06-04 2021-09-07 Diamedica Inc. Isoformes de glycosylation de la kallikreine-1 tissulaire d'origine humaine
RU2015129087A (ru) 2012-12-19 2017-02-02 Вокхардт Лимитед Стабильная водная композиция, содержащая инсулин человека или его аналог или производное
CN104870469A (zh) 2012-12-26 2015-08-26 沃克哈特有限公司 药物组合物
TWI641381B (zh) 2013-02-04 2018-11-21 法商賽諾菲公司 胰島素類似物及／或胰島素衍生物之穩定化醫藥調配物
JP2016531847A (ja) 2013-09-30 2016-10-13 ウォックハート リミテッド 医薬組成物
AU2014333979B2 (en) 2013-10-07 2018-02-15 Novo Nordisk A/S Novel derivative of an insulin analogue
SG11201604706TA (en) 2014-01-09 2016-07-28 Sanofi Sa Stabilized pharmaceutical formulations of insulin aspart
WO2015104311A1 (fr) 2014-01-09 2015-07-16 Sanofi Formulations pharmaceutiques stabilisées sans glycérol d'analogues de l'insuline et/ou de dérivés de l'insuline
EP3091995B1 (fr) 2014-01-09 2024-03-20 Sanofi Formulations pharmaceutiques stabilisées d'insuline aspart
WO2016001862A1 (fr) 2014-07-04 2016-01-07 Wockhardt Limited Formulations à libération prolongée d'insulines
TWI758239B (zh) 2014-12-12 2022-03-21 德商賽諾菲阿凡提斯德意志有限公司 甘精胰島素/利司那肽固定比率配製劑
TWI748945B (zh) 2015-03-13 2021-12-11 德商賽諾菲阿凡提斯德意志有限公司 第２型糖尿病病患治療
TW201705975A (zh) 2015-03-18 2017-02-16 賽諾菲阿凡提斯德意志有限公司 第２型糖尿病病患之治療
HUE060149T2 (hu) 2016-12-16 2023-02-28 Novo Nordisk As Inzulint tartalmazó gyógyászati készítmények
EP3592377A4 (fr) 2017-03-09 2021-02-17 Diamedica Inc. Formes posologiques de kallicréine tissulaire 1
BR112020002364A2 (pt) 2017-08-17 2020-09-01 Novo Nordisk A/S derivado de insulina, produto intermediário, uso de um derivado de insulina, e, métodos para o tratamento ou prevenção de diabetes, diabetes do tipo 1, diabetes do tipo 2, tolerância à glicose comprometida, hiperglicemia, dislipidemia, obesidade, síndrome metabólica, hipertensão, distúrbios cognitivos, aterosclerose, infarto do miocárdio, acidente vascular cerebral, distúrbios cardiovasculares, doença cardíaca coronariana, síndrome intestinal inflamatória, dispepsia, hipotensão ou úlceras gástricas, e para determinar a seletividade de um composto de insulina
CN109646396A (zh) * 2018-12-29 2019-04-19 江苏万邦医药科技有限公司 一种稳定的胰岛素类似物注射液及其制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2536040A1 (de) * 1975-08-13 1977-02-24 Hoechst Ag Insulin-analoga mit biologischer wirkung
PH25772A (en) * 1985-08-30 1991-10-18 Novo Industri As Insulin analogues, process for their preparation
DK257988D0 (da) * 1988-05-11 1988-05-11 Novo Industri As Nye peptider
KR910700262A (ko) * 1988-12-23 1991-03-14 안네 제케르 사람 인슐린 유사체

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9200321A1 *

Also Published As

Publication number Publication date
ZA914830B (en) 1992-03-25
IL98596A0 (en) 1992-07-15
WO1992000321A1 (fr) 1992-01-09
JPH05508406A (ja) 1993-11-25
AU8054391A (en) 1992-01-23
PT98124A (pt) 1992-04-30
NZ238718A (en) 1992-06-25
DK155690D0 (da) 1990-06-28
IE912247A1 (en) 1992-01-01

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