RU2518460C2 - Производные инсулина - Google Patents
Производные инсулина Download PDFInfo
- Publication number
- RU2518460C2 RU2518460C2 RU2008152033/04A RU2008152033A RU2518460C2 RU 2518460 C2 RU2518460 C2 RU 2518460C2 RU 2008152033/04 A RU2008152033/04 A RU 2008152033/04A RU 2008152033 A RU2008152033 A RU 2008152033A RU 2518460 C2 RU2518460 C2 RU 2518460C2
- Authority
- RU
- Russia
- Prior art keywords
- insulin
- glu
- asp
- hglu
- des
- Prior art date
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical class N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title claims abstract description 420
- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical class C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 claims abstract description 195
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- 235000019698 starch Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 125000000185 sucrose group Chemical group 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- AKFVZALISNAFRA-HNNXBMFYSA-N tert-butyl (2s)-2-amino-6-(phenylmethoxycarbonylamino)hexanoate Chemical compound CC(C)(C)OC(=O)[C@@H](N)CCCCNC(=O)OCC1=CC=CC=C1 AKFVZALISNAFRA-HNNXBMFYSA-N 0.000 description 1
- SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical compound CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000001196 time-of-flight mass spectrum Methods 0.000 description 1
- BMCJATLPEJCACU-UHFFFAOYSA-N tricin Natural products COc1cc(OC)c(O)c(c1)C2=CC(=O)c3c(O)cc(O)cc3O2 BMCJATLPEJCACU-UHFFFAOYSA-N 0.000 description 1
- HHLJUSLZGFYWKW-UHFFFAOYSA-N triethanolamine hydrochloride Chemical compound Cl.OCCN(CCO)CCO HHLJUSLZGFYWKW-UHFFFAOYSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Endocrinology (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
- Toxicology (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200301129 | 2003-08-05 | ||
| DKPA200301129 | 2003-08-05 | ||
| US49545103P | 2003-08-14 | 2003-08-14 | |
| US60/495,451 | 2003-08-14 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2006103280/04A Division RU2352581C2 (ru) | 2003-08-05 | 2004-07-22 | Производные инсулина |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| RU2008152033A RU2008152033A (ru) | 2010-07-10 |
| RU2518460C2 true RU2518460C2 (ru) | 2014-06-10 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2008152033/04A RU2518460C2 (ru) | 2003-08-05 | 2008-12-29 | Производные инсулина |
Country Status (18)
| Country | Link |
|---|---|
| US (3) | US7615532B2 (enExample) |
| EP (3) | EP2107069B1 (enExample) |
| JP (1) | JP4463814B2 (enExample) |
| KR (1) | KR101159559B1 (enExample) |
| AU (2) | AU2004261353B2 (enExample) |
| BE (2) | BE2013C035I2 (enExample) |
| BR (1) | BRPI0413276B8 (enExample) |
| CA (1) | CA2531988C (enExample) |
| CY (5) | CY1113850T1 (enExample) |
| FR (2) | FR13C0035I2 (enExample) |
| HU (1) | HUS1300033I1 (enExample) |
| IL (1) | IL172980A (enExample) |
| LU (2) | LU92213I2 (enExample) |
| MX (1) | MXPA06001283A (enExample) |
| NO (5) | NO340925B1 (enExample) |
| PL (1) | PL2107069T3 (enExample) |
| RU (1) | RU2518460C2 (enExample) |
| WO (1) | WO2005012347A2 (enExample) |
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| AU2004261319B2 (en) * | 2003-07-25 | 2010-12-23 | Conjuchem Biotechnologies Inc. | Long lasting insulin derivatives and methods thereof |
| BRPI0413276B8 (pt) | 2003-08-05 | 2021-05-25 | Novo Nordisk As | derivado de insulina, complexo de zinco do mesmo, e, composição farmacêutica |
| JP4933455B2 (ja) * | 2005-02-02 | 2012-05-16 | ノヴォ ノルディスク アー／エス | 新規のインスリン誘導体 |
| EP2292653B1 (en) * | 2005-02-02 | 2014-05-21 | Novo Nordisk A/S | Novel insulin derivatives |
| PL1969004T3 (pl) * | 2005-12-28 | 2012-01-31 | Novo Nordisk As | Kompozycje zawierające acylowaną insulinę i cynk oraz sposób wytwarzania tych kompozycji |
| DE602007009496D1 (de) | 2006-02-27 | 2010-11-11 | Novo Nordisk As | Insulinderivate |
| WO2007104736A2 (en) * | 2006-03-13 | 2007-09-20 | Novo Nordisk A/S | Acylated single chain insulin |
| EP2015722B1 (en) | 2006-04-28 | 2016-11-16 | Avent, Inc. | Antimicrobial site dressings |
| EP2024390B1 (en) | 2006-05-09 | 2015-08-19 | Novo Nordisk A/S | Insulin derivative |
| EP2386572B1 (en) * | 2006-05-09 | 2015-07-08 | Novo Nordisk A/S | Insulin derivative |
| CN101437849B (zh) * | 2006-05-09 | 2015-09-30 | 诺沃-诺迪斯克有限公司 | 胰岛素衍生物 |
| JP5097900B2 (ja) * | 2006-06-27 | 2012-12-12 | 独立行政法人物質・材料研究機構 | 有機酸又はこれらの誘導体の活性エステル体の製造方法 |
| WO2008015099A2 (en) * | 2006-07-31 | 2008-02-07 | Novo Nordisk A/S | Pegylated, extended insulins |
| 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 |
| EP2497462A1 (en) * | 2007-06-01 | 2012-09-12 | Novo Nordisk A/S | Stable non-aqueous pharmaceutical compositions |
| EP2514406A1 (en) | 2007-06-01 | 2012-10-24 | Novo Nordisk A/S | Spontaneously dispersible preconcentrates including a peptide drug in a solid or semisolid carrier |
| WO2008152106A1 (en) | 2007-06-13 | 2008-12-18 | Novo Nordisk A/S | Pharmaceutical formulation comprising an insulin derivative |
| AU2008288413B2 (en) | 2007-08-15 | 2013-09-26 | Novo Nordisk A/S | Insulin analogues with an acyl and aklylene glycol moiety |
| US8962794B2 (en) | 2007-08-15 | 2015-02-24 | Novo Nordisk A/S | Insulins with an acyl moiety comprising repeating units of alkylene glycol containing amino acids |
| CN101157725B (zh) * | 2007-10-24 | 2012-07-25 | 中国药科大学 | 人胰岛素类似物的制备方法及用途 |
| WO2009060071A1 (en) * | 2007-11-08 | 2009-05-14 | Novo Nordisk A/S | Insulin derivative |
| CA2705821A1 (en) | 2007-11-16 | 2009-05-22 | Novo Nordisk A/S | Pharmaceutical compositions containing insulin and an insulinotropic peptide |
| EP2254905B1 (en) | 2008-03-14 | 2016-12-14 | Novo Nordisk A/S | Protease-stabilized insulin analogues |
| DK2254906T3 (en) | 2008-03-18 | 2017-01-23 | Novo Nordisk As | Protease-stabilized acylated insulin analogues |
| US8637647B2 (en) | 2008-09-12 | 2014-01-28 | Novo Nordisk A/S | Method of acylating a peptide or protein |
| WO2010049488A1 (en) * | 2008-10-30 | 2010-05-06 | Novo Nordisk A/S | Treating diabetes melitus using insulin injections with less than daily injection frequency |
| CN102361647B (zh) | 2009-01-23 | 2018-02-16 | 诺沃-诺迪斯克有限公司 | 具有白蛋白结合剂a‑b‑c‑d‑e‑的fgf21衍生物及其应用 |
| CN102666579A (zh) | 2009-10-30 | 2012-09-12 | 诺沃—诺迪斯克有限公司 | 降钙素基因相关肽的衍生物 |
| CA2786953A1 (en) * | 2010-01-12 | 2011-07-21 | Florian Anders Foeger | Pharmaceutical compositions for oral administration of insulin peptides |
| WO2011101261A2 (en) | 2010-02-16 | 2011-08-25 | Novo Nordisk A/S | Purification method |
| US9234192B2 (en) | 2010-02-16 | 2016-01-12 | Novo Nordisk A/S | Conjugated proteins |
| AU2011252127B2 (en) | 2010-05-10 | 2014-02-20 | Novo Nordisk A/S | Process for the preparation of insulin-zinc complexes |
| US8748570B2 (en) | 2010-05-25 | 2014-06-10 | Syngene Limited | Insulin analogues |
| AU2011269000C1 (en) * | 2010-06-23 | 2015-10-08 | Novo Nordisk A/S | Insulin derivatives containing additional disulfide bonds |
| 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 (en) | 2010-06-23 | 2013-05-01 | Novo Nordisk A/S | Human insulin containing additional disulfide bonds |
| US20140315797A1 (en) | 2010-10-15 | 2014-10-23 | Peter Madsen | Novel N-Terminally Modified Insulin Derivatives |
| RS59423B1 (sr) * | 2010-10-27 | 2019-11-29 | Novo Nordisk As | Lečenje dijabetesa melitusa korišćenjem insulinskih injekcija davanih u različitim intervalima ubrizgavanja |
| RU2013123515A (ru) * | 2010-10-27 | 2014-12-10 | Ново Нордиск А/С | Лечение сахарного диабета с помощью инъекций инсулина, вводимых с различными интервалами |
| CN103249427A (zh) | 2010-12-14 | 2013-08-14 | 诺沃—诺迪斯克有限公司 | 速效胰岛素联合长效胰岛素 |
| EP2675470A1 (en) | 2011-02-15 | 2013-12-25 | Novo Nordisk A/S | Long-acting il-1 receptor antagonists |
| MX2013011175A (es) * | 2011-03-28 | 2013-11-01 | Novo Nordisk As | Analogos de glucagon novedosos. |
| EP2696847A1 (en) | 2011-04-14 | 2014-02-19 | Novo Nordisk A/S | Fatty acid acylated amino acids for oral peptide delivery |
| JP6058646B2 (ja) | 2011-06-15 | 2017-01-11 | ノヴォ ノルディスク アー／エス | 多置換インスリン |
| WO2013041678A1 (en) * | 2011-09-23 | 2013-03-28 | Novo Nordisk A/S | Novel glucagon analogues |
| KR20140104994A (ko) * | 2011-12-15 | 2014-08-29 | 샹하이 헨그루이 파마수티컬 컴퍼니 리미티드 | 인간 인슐린 유사체 및 이의 아실화 유도체 |
| WO2013093009A1 (en) | 2011-12-21 | 2013-06-27 | Novo Nordisk A/S | N -terminally modified insulin derivatives |
| CA2870313A1 (en) | 2012-04-11 | 2013-10-17 | Novo Nordisk A/S | Insulin formulations |
| US20160031962A1 (en) * | 2012-04-20 | 2016-02-04 | Kleomenis K. Barlos | Solid phase peptide synthesis of insulin using side chain achored lysine |
| EP2844274B1 (en) | 2012-05-01 | 2019-03-20 | Novo Nordisk A/S | Pharmaceutical composition |
| WO2014009316A1 (en) | 2012-07-09 | 2014-01-16 | Novo Nordisk A/S | Novel use of insulin derivatives |
| UA116217C2 (uk) | 2012-10-09 | 2018-02-26 | Санофі | Пептидна сполука як подвійний агоніст рецепторів glp1-1 та глюкагону |
| US20150265710A1 (en) | 2012-10-17 | 2015-09-24 | Novo Nordisk A/S | Fatty Acid Acylated D-Amino Acids for Oral Peptide Delivery |
| PT2934568T (pt) | 2012-12-21 | 2018-01-04 | Sanofi Sa | Agonistas duplos de glp1/gip ou trigonais de glp1/gip/glucagina |
| WO2014147141A1 (en) * | 2013-03-20 | 2014-09-25 | Novo Nordisk A/S | Insulin dosing regimen |
| RU2683039C2 (ru) | 2013-04-18 | 2019-03-26 | Ново Нордиск А/С | Стабильные совместные агонисты рецептора глюкагоноподобного пептида-1/глюкагона пролонгированного действия для медицинского применения |
| WO2014177623A1 (en) | 2013-04-30 | 2014-11-06 | Novo Nordisk A/S | Novel administration regime |
| GB201315335D0 (en) | 2013-08-29 | 2013-10-09 | Of Singapore | Amino diacids containing peptide modifiers |
| AU2014333979B2 (en) | 2013-10-07 | 2018-02-15 | Novo Nordisk A/S | Novel derivative of an insulin analogue |
| FR3013049B1 (fr) | 2013-11-14 | 2015-11-13 | You-Ping Chan | Analogue de l'insuline glargine |
| TW201609796A (zh) | 2013-12-13 | 2016-03-16 | 賽諾菲公司 | 非醯化之艾塞那肽－４（ｅｘｅｎｄｉｎ－４）胜肽類似物 |
| TW201609799A (zh) | 2013-12-13 | 2016-03-16 | 賽諾菲公司 | 雙重ｇｌｐ－１／ｇｉｐ受體促效劑 |
| TW201609797A (zh) | 2013-12-13 | 2016-03-16 | 賽諾菲公司 | 雙重ｇｌｐ－１／升糖素受體促效劑 |
| TW201609795A (zh) | 2013-12-13 | 2016-03-16 | 賽諾菲公司 | 作為雙重ｇｌｐ－１／ｇｉｐ受體促效劑的艾塞那肽－４（ｅｘｅｎｄｉｎ－４）胜肽類似物 |
| BR112016016321A2 (pt) | 2014-02-18 | 2017-10-03 | Novo Nordisk As | Derivados de análogos de glucagon estáveis, seus usos, e composição farmacêutica |
| AR099569A1 (es) | 2014-02-28 | 2016-08-03 | Novo Nordisk As | Derivados de insulina y los usos médicos de estos |
| TW201625669A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 衍生自艾塞那肽－４（Ｅｘｅｎｄｉｎ－４）之肽類雙重ＧＬＰ－１／升糖素受體促效劑 |
| TW201625670A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 衍生自ｅｘｅｎｄｉｎ－４之雙重ｇｌｐ－１／升糖素受體促效劑 |
| TW201625668A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 作為胜肽性雙重ｇｌｐ－１／昇糖素受體激動劑之艾塞那肽－４衍生物 |
| JP2017525656A (ja) | 2014-06-04 | 2017-09-07 | ノヴォ ノルディスク アー／エス | 医療用のｇｌｐ−１／グルカゴン受容体コアゴニスト |
| US9932381B2 (en) | 2014-06-18 | 2018-04-03 | Sanofi | Exendin-4 derivatives as selective glucagon receptor agonists |
| AR105319A1 (es) | 2015-06-05 | 2017-09-27 | Sanofi Sa | Profármacos que comprenden un conjugado agonista dual de glp-1 / glucagón conector ácido hialurónico |
| TW201706291A (zh) | 2015-07-10 | 2017-02-16 | 賽諾菲公司 | 作為選擇性肽雙重ｇｌｐ－１／升糖素受體促效劑之新毒蜥外泌肽（ｅｘｅｎｄｉｎ－４）衍生物 |
| US20180244743A1 (en) | 2015-08-25 | 2018-08-30 | Novo Nordisk A/S | Novel Insulin Derivatives and the Medical Uses Hereof |
| JP2018531901A (ja) | 2015-08-25 | 2018-11-01 | ノヴォ ノルディスク アー／エス | 新規インスリン誘導体及びその医学的使用 |
| US10815287B2 (en) | 2016-08-02 | 2020-10-27 | Jiangsu Hengrui Medicine Co., Ltd. | Acylated derivative of human insulin or analogue thereof |
| CN110022935A (zh) | 2016-11-28 | 2019-07-16 | 诺和诺德股份有限公司 | 用于心血管病况的德谷胰岛素 |
| WO2018096164A1 (en) | 2016-11-28 | 2018-05-31 | Novo Nordisk A/S | Insulin degludec for treating diabetes |
| WO2018096163A1 (en) | 2016-11-28 | 2018-05-31 | Novo Nordisk A/S | Insulin degludec for improvement of glycaemic control and reduction of acute and long-term diabetes complications |
| HUE060149T2 (hu) | 2016-12-16 | 2023-02-28 | Novo Nordisk As | Inzulint tartalmazó gyógyászati készítmények |
| JOP20190273A1 (ar) * | 2017-05-26 | 2019-11-24 | Lilly Co Eli | مركب إنسولين معالج بأسيل |
| AU2019218315A1 (en) | 2018-02-09 | 2020-07-09 | Jiangsu Hengrui Medicine Co., Ltd. | Codon optimized precursor gene and signal peptide gene of human insulin analogue |
| WO2019223752A1 (zh) | 2018-05-24 | 2019-11-28 | 江苏恒瑞医药股份有限公司 | 一种重组人胰岛素或其类似物的前体的制备方法 |
| EP3815106B1 (en) | 2018-06-26 | 2024-12-25 | Novo Nordisk A/S | System providing dose recommendations for basal insulin titration |
| US10335464B1 (en) | 2018-06-26 | 2019-07-02 | Novo Nordisk A/S | Device for titrating basal insulin |
| KR102666154B1 (ko) | 2018-08-08 | 2024-05-20 | 주식회사 대웅제약 | 지속형 인슐린 아날로그 및 그 복합체 |
| KR20200080748A (ko) | 2018-12-27 | 2020-07-07 | 주식회사 폴루스 | 음이온 교환 크로마토그래피를 이용한 인슐린 전구체의 정제방법 |
| KR20200080747A (ko) | 2018-12-27 | 2020-07-07 | 주식회사 폴루스 | 인슐린 전구체의 인슐린 효소 전환용 조성물 및 이를 이용하여 인슐린 전구체를 인슐린으로 전환하는 방법 |
| JP7518149B2 (ja) | 2019-07-12 | 2024-07-17 | ノヴォ ノルディスク アー／エス | 高濃度インスリン製剤 |
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| EP4299057A1 (en) | 2022-06-30 | 2024-01-03 | Adocia | Solid compositions comprising a peptide or a protein and an acylated amino acid |
| CN118574842A (zh) | 2022-01-28 | 2024-08-30 | 甘李药业股份有限公司 | 酰化胰岛素 |
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| WO2025104600A1 (en) * | 2023-11-15 | 2025-05-22 | Ambio, Inc. | Insulin analogs for the treatment of human metabolic disorder and disease |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998002460A1 (en) * | 1996-07-11 | 1998-01-22 | Novo Nordisk A/S | Selective acylation method |
| US5898067A (en) * | 1997-02-07 | 1999-04-27 | Novo Nordisk A/S | Crystallization of proteins |
| WO1999021888A1 (en) * | 1997-10-24 | 1999-05-06 | Novo Nordisk A/S | Aggregates of human insulin derivatives |
| 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 |
| US6251856B1 (en) * | 1995-03-17 | 2001-06-26 | Novo Nordisk A/S | Insulin derivatives |
| RU2198181C2 (ru) * | 1997-03-20 | 2003-02-10 | Ново Нордиск А/С | Не содержащие цинк кристаллы инсулина для применения в легочных композициях |
| US20030171535A1 (en) * | 1996-02-21 | 2003-09-11 | Lauge Schaffer | Peptide derivatives |
Family Cites Families (88)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1212679B (de) | 1957-08-03 | 1966-03-17 | Novo Terapeutisk Labor As | Verfahren zur Herstellung von Insulinloesungen |
| GB1042194A (en) | 1962-04-30 | 1966-09-14 | Olin Mathieson | Insulin preparations |
| US3528960A (en) | 1968-10-07 | 1970-09-15 | Lilly Co Eli | N-carboxyaroyl insulins |
| US3868358A (en) * | 1971-04-30 | 1975-02-25 | Lilly Co Eli | Protamine-insulin product |
| GB1492997A (en) | 1976-07-21 | 1977-11-23 | Nat Res Dev | Insulin derivatives |
| JPS5767548A (en) | 1980-10-14 | 1982-04-24 | Shionogi & Co Ltd | Insulin analog and its preparation |
| FI78616C (fi) * | 1982-02-05 | 1989-09-11 | Novo Industri As | Foerfarande foer framstaellning av en foer infusionsaendamaol avsedd stabiliserad insulinloesning, som har en foerhoejd zinkhalt. |
| PH25772A (en) | 1985-08-30 | 1991-10-18 | Novo Industri As | Insulin analogues, process for their preparation |
| NZ222907A (en) | 1986-12-16 | 1990-08-28 | Novo Industri As | Preparation for intranasal administration containing a phospholipid absorption enhancing system |
| US5605884A (en) * | 1987-10-29 | 1997-02-25 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Factor VIII formulations in high ionic strength media |
| US4877608A (en) | 1987-11-09 | 1989-10-31 | Rorer Pharmaceutical Corporation | Pharmaceutical plasma protein formulations in low ionic strength media |
| JPH01254699A (ja) | 1988-04-05 | 1989-10-11 | Kodama Kk | インスリン誘導体及びその用途 |
| DE3827533A1 (de) * | 1988-08-13 | 1990-02-15 | Hoechst Ag | Pharmazeutische zubereitung zur behandlung des diabetes mellitus |
| KR910700262A (ko) | 1988-12-23 | 1991-03-14 | 안네 제케르 | 사람 인슐린 유사체 |
| PT93057B (pt) | 1989-02-09 | 1995-12-29 | Lilly Co Eli | Processo para a preparacao de analogos da insulina |
| IT1240314B (it) | 1989-09-28 | 1993-12-07 | Immunobiology Research Institutes, Inc. | Formulazioni acquose stabilizzate di piccoli peptidi. |
| ES2072596T3 (es) | 1989-12-21 | 1995-07-16 | Novo Nordisk As | Preparaciones de insulina que contienen acido nicotinico o nicotinamida. |
| DK45590D0 (enExample) | 1990-02-21 | 1990-02-21 | Novo Nordisk As | |
| JP3193398B2 (ja) | 1991-07-23 | 2001-07-30 | サンデン株式会社 | ショ−ケ−ス |
| ATE227583T1 (de) | 1991-12-20 | 2002-11-15 | Novo Nordisk As | Stabilisierte pharmazeutische formulierung, die wachstumshormon und histidin enthält |
| US6869930B1 (en) * | 1993-09-17 | 2005-03-22 | Novo Nordisk A/S | Acylated insulin |
| US6011007A (en) * | 1993-09-17 | 2000-01-04 | Novo Nordisk A/S | Acylated insulin |
| US5652216A (en) | 1994-05-26 | 1997-07-29 | Novo Nordisk A/S | Pharmaceutical preparation |
| AU3562195A (en) | 1994-10-04 | 1996-04-26 | Novo Nordisk A/S | Preparations containing aspb28 human insulin and nicotinamide |
| US5646242A (en) | 1994-11-17 | 1997-07-08 | Eli Lilly And Company | Selective acylation of epsilon-amino groups |
| US5830999A (en) * | 1995-01-26 | 1998-11-03 | Regents Of The University Of California | Stabilization of insulin through ligand binding interations |
| CA2215694A1 (en) | 1995-03-17 | 1996-09-26 | Novo Nordisk A/S | Insulin derivatives |
| MX9800684A (es) | 1995-07-27 | 1998-04-30 | Genentech Inc | Formulacion de proteinas liofilizadas isotonicas estables. |
| US5898267A (en) * | 1996-04-10 | 1999-04-27 | Mcdermott; Kevin | Parabolic axial lighting device |
| US5866538A (en) * | 1996-06-20 | 1999-02-02 | Novo Nordisk A/S | Insulin preparations containing NaCl |
| US5905140A (en) * | 1996-07-11 | 1999-05-18 | Novo Nordisk A/S, Novo Alle | Selective acylation method |
| US5763401A (en) | 1996-07-12 | 1998-06-09 | Bayer Corporation | Stabilized albumin-free recombinant factor VIII preparation having a low sugar content |
| EP0821006B1 (de) * | 1996-07-26 | 2004-04-21 | Aventis Pharma Deutschland GmbH | Insulinderivate mit erhöhter Zinkbindung |
| IL119029A0 (en) | 1996-08-07 | 1996-11-14 | Yeda Res & Dev | Long-acting drugs and pharamaceutical compositions comprising them |
| EP0971729B1 (en) | 1997-03-20 | 2002-07-03 | Novo Nordisk A/S | Therapeutic powder formulation for pulmonary administration, containing crystalline insulin |
| ATE220555T1 (de) | 1997-03-20 | 2002-08-15 | Novo Nordisk As | Verfahren zur herstellung eines therapeutischen puders durch copräzipitation von insulin und einem absorptionsverstärker |
| US7097845B2 (en) | 1997-04-23 | 2006-08-29 | Jacob Sten Petersen | Combinations of antigen and mucosal binding component for inducing specific immunological tolerance |
| SI0884053T1 (en) | 1997-06-13 | 2003-02-28 | Eli Lilly And Company | Stable insulin formulations |
| TR200001050T2 (tr) | 1997-10-24 | 2000-08-21 | Eli Lilly And Company | Çözünmez insülin bileşimleri |
| US6451762B1 (en) * | 1997-10-24 | 2002-09-17 | Novo Nordisk A/S | Aggregates of human insulin derivatives |
| US20020155994A1 (en) * | 1997-10-24 | 2002-10-24 | Svend Havelund | Aggregates of human insulin derivatives |
| ZA989744B (en) * | 1997-10-31 | 2000-04-26 | Lilly Co Eli | Method for administering acylated insulin. |
| CO4970787A1 (es) * | 1997-12-23 | 2000-11-07 | Lilly Co Eli | Composiciones insolubles de insulina y derivados de insulina que controlan la glucosa sanguinea |
| DE69924232D1 (de) * | 1998-01-09 | 2005-04-21 | Novo Nordisk As | Stabilisierte insulin-zubereitungen |
| PL197504B1 (pl) | 1998-10-16 | 2008-04-30 | Novo Nordisk As | Trwałe stężone preparaty insulinowe do podawania do płuc |
| US6211144B1 (en) * | 1998-10-16 | 2001-04-03 | Novo Nordisk A/S | Stable concentrated insulin preparations for pulmonary delivery |
| ES2435141T3 (es) * | 1999-02-22 | 2013-12-18 | University Of Connecticut | Nuevas formulaciones de factor VIII libres de albúmina |
| JP2002543092A (ja) | 1999-04-27 | 2002-12-17 | イーライ・リリー・アンド・カンパニー | 肺投与用インスリン結晶 |
| GB9930882D0 (en) | 1999-12-30 | 2000-02-23 | Nps Allelix Corp | GLP-2 formulations |
| DE10022092A1 (de) | 2000-05-08 | 2001-11-15 | Aventis Behring Gmbh | Stabilisiertes Protein-Präparat und Verfahren zu seiner Herstellung |
| US6652886B2 (en) * | 2001-02-16 | 2003-11-25 | Expression Genetics | Biodegradable cationic copolymers of poly (alkylenimine) and poly (ethylene glycol) for the delivery of bioactive agents |
| DE10114178A1 (de) | 2001-03-23 | 2002-10-10 | Aventis Pharma Gmbh | Zinkfreie und zinkarme Insulinzubereitungen mit verbesserter Stabilität |
| DK1412384T3 (da) | 2001-06-28 | 2008-04-28 | Novo Nordisk As | Stabil formulering af modificeret GLP-1 |
| EP1545460A4 (en) | 2001-12-20 | 2005-11-16 | Lilly Co Eli | INSULIN MOLECULE WITH TEMPORARY EFFECT |
| US8003605B2 (en) * | 2002-03-13 | 2011-08-23 | Novo Nordisk A/S | Minimising body weight gain in insulin treatment |
| ATE496064T1 (de) * | 2002-05-07 | 2011-02-15 | Novo Nordisk As | Lösliche formulierungen, die monomeres insulin und acyliertes insulin enthalten |
| US20050232899A1 (en) * | 2002-05-31 | 2005-10-20 | Aradigm Corporation | Compositions methods and systems for pulmonary delivery of recombinant human interferon alpha-2b |
| US20040002451A1 (en) * | 2002-06-20 | 2004-01-01 | Bruce Kerwin | Compositions of pegylated soluble tumor necrosis factor receptors and methods of preparing |
| KR100615389B1 (ko) | 2002-08-23 | 2006-08-25 | (주)헬릭서 | 다래 추출물을 함유하는 알러지성 질환 및 비알러지성염증 질환의 예방 및 개선용 건강 기능 식품 |
| KR20050083841A (ko) | 2002-10-29 | 2005-08-26 | 알자 코포레이션 | 안정화된 고체상태 폴리펩타이드 입자 |
| US20040138099A1 (en) * | 2002-11-29 | 2004-07-15 | Draeger Eberhard Kurt | Insulin administration regimens for the treatment of subjects with diabetes |
| EP1595544A4 (en) | 2003-02-07 | 2009-05-06 | Ajinomoto Kk | MEANS FOR THE TREATMENT OF DIABETES |
| ES2349128T3 (es) | 2003-02-19 | 2010-12-28 | Novartis Ag | Antigeno de glucoproteina sima 135 expresado en celulas de tumor humanas metastasicas. |
| KR20060015469A (ko) | 2003-03-04 | 2006-02-17 | 더 테크놀로지 디벨로프먼트 컴퍼니 리미티드 | 경구용 인슐린 조성물 및 그 제조방법 및 사용방법 |
| JP4658041B2 (ja) | 2003-06-25 | 2011-03-23 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | Ｖｉｉ因子ポリペプチドの液体組成物 |
| US20050054818A1 (en) * | 2003-07-02 | 2005-03-10 | Brader Mark Laurence | Crystalline compositions for controlling blood glucose |
| BRPI0413276B8 (pt) | 2003-08-05 | 2021-05-25 | Novo Nordisk As | derivado de insulina, complexo de zinco do mesmo, e, composição farmacêutica |
| CN1829738B (zh) | 2003-08-05 | 2012-07-04 | 诺沃挪第克公司 | 新型胰岛素衍生物 |
| RU2388460C2 (ru) | 2003-08-14 | 2010-05-10 | Ново Нордиск Хелс Кеа Аг | Жидкая водная фармацевтическая композиция, содержащая полипептид фактора vii |
| JP5518282B2 (ja) | 2003-09-01 | 2014-06-11 | ノヴォ ノルディスク アー／エス | 安定なペプチドの製剤 |
| ES2229931B1 (es) * | 2003-10-03 | 2006-01-16 | Grifols, S.A. | Composicion liquida bilogicamente estable de fviii, de fvw o del complejo fviii/fvw humanos. |
| EP1687428A1 (en) * | 2003-11-14 | 2006-08-09 | Novo Nordisk A/S | Processes for making acylated insulin |
| JP4845741B2 (ja) | 2003-12-23 | 2011-12-28 | ファルマシア コーポレーション | 安定な成長ホルモン液体製剤 |
| PL1740154T3 (pl) | 2004-03-12 | 2009-11-30 | Biodel Inc | Kompozycje insuliny o ulepszonym wchłanianiu |
| EP1750750B1 (en) | 2004-06-01 | 2012-02-01 | Ares Trading S.A. | Method of stabilizing proteins |
| DE602005022895D1 (de) | 2004-08-12 | 2010-09-23 | Schering Corp | Stabile pegylierte interferon-formulierung |
| PL1778723T3 (pl) | 2004-08-17 | 2013-03-29 | Regeneron Pharma | Preparaty antagonisty IL-1 |
| JP5248113B2 (ja) | 2004-11-12 | 2013-07-31 | ノヴォ ノルディスク アー／エス | ペプチドの安定な処方 |
| CN101060856B (zh) | 2004-11-22 | 2011-01-19 | 诺和诺德公司 | 可溶、稳定的含胰岛素制剂 |
| AU2006206272A1 (en) | 2005-01-21 | 2006-07-27 | Alza Corporation | Therapeutic peptide formulations for coating microneedles with improved stabitity containing at least one counterion |
| JP4933455B2 (ja) * | 2005-02-02 | 2012-05-16 | ノヴォ ノルディスク アー／エス | 新規のインスリン誘導体 |
| PL1969004T3 (pl) | 2005-12-28 | 2012-01-31 | Novo Nordisk As | Kompozycje zawierające acylowaną insulinę i cynk oraz sposób wytwarzania tych kompozycji |
| DE602007009496D1 (de) * | 2006-02-27 | 2010-11-11 | Novo Nordisk As | Insulinderivate |
| AU2007238114B2 (en) | 2006-04-12 | 2010-10-14 | Biodel, Inc. | Rapid acting and long acting insulin combination formulations |
| EP2386572B1 (en) * | 2006-05-09 | 2015-07-08 | Novo Nordisk A/S | Insulin derivative |
| WO2008152106A1 (en) * | 2007-06-13 | 2008-12-18 | Novo Nordisk A/S | Pharmaceutical formulation comprising an insulin derivative |
| CA2705821A1 (en) * | 2007-11-16 | 2009-05-22 | Novo Nordisk A/S | Pharmaceutical compositions containing insulin and an insulinotropic peptide |
| TWI451876B (zh) * | 2008-06-13 | 2014-09-11 | Lilly Co Eli | 聚乙二醇化之離脯胰島素化合物 |
-
2004
- 2004-07-22 BR BRPI0413276A patent/BRPI0413276B8/pt active IP Right Grant
- 2004-07-22 WO PCT/DK2004/000511 patent/WO2005012347A2/en not_active Ceased
- 2004-07-22 EP EP09165072A patent/EP2107069B1/en not_active Expired - Lifetime
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- 2004-07-22 KR KR1020067002551A patent/KR101159559B1/ko not_active Expired - Lifetime
- 2004-07-22 EP EP04739008A patent/EP1660531A2/en not_active Withdrawn
- 2004-07-22 CA CA2531988A patent/CA2531988C/en not_active Expired - Fee Related
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- 2004-07-22 EP EP10174490.2A patent/EP2264065B1/en not_active Expired - Lifetime
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-
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- 2006-01-05 IL IL172980A patent/IL172980A/en active Protection Beyond IP Right Term
- 2006-01-30 US US11/343,005 patent/US7615532B2/en active Active
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- 2014-08-06 US US14/453,276 patent/US20140349925A1/en not_active Abandoned
-
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- 2018-01-11 NO NO2018002C patent/NO2018002I2/no unknown
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-
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- 2023-12-28 CY CY2013029C patent/CY2013029I2/el unknown
-
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- 2024-01-16 NO NO2024004C patent/NO2024004I1/no unknown
- 2024-01-16 NO NO2024003C patent/NO2024003I1/no unknown
- 2024-01-31 CY CY2013027C patent/CY2013027I2/el unknown
Patent Citations (7)
| 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 |
| US6251856B1 (en) * | 1995-03-17 | 2001-06-26 | Novo Nordisk A/S | Insulin derivatives |
| US20030171535A1 (en) * | 1996-02-21 | 2003-09-11 | Lauge Schaffer | Peptide derivatives |
| WO1998002460A1 (en) * | 1996-07-11 | 1998-01-22 | Novo Nordisk A/S | Selective acylation method |
| US5898067A (en) * | 1997-02-07 | 1999-04-27 | Novo Nordisk A/S | Crystallization of proteins |
| RU2198181C2 (ru) * | 1997-03-20 | 2003-02-10 | Ново Нордиск А/С | Не содержащие цинк кристаллы инсулина для применения в легочных композициях |
| WO1999021888A1 (en) * | 1997-10-24 | 1999-05-06 | Novo Nordisk A/S | Aggregates of human insulin derivatives |
Non-Patent Citations (1)
| Title |
|---|
| A1. * |
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