EP0102976A1 - Procede de production d'une preparation d'insuline - Google Patents
Procede de production d'une preparation d'insulineInfo
- Publication number
- EP0102976A1 EP0102976A1 EP19830900834 EP83900834A EP0102976A1 EP 0102976 A1 EP0102976 A1 EP 0102976A1 EP 19830900834 EP19830900834 EP 19830900834 EP 83900834 A EP83900834 A EP 83900834A EP 0102976 A1 EP0102976 A1 EP 0102976A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- insulin
- zinc
- process according
- preparation
- weight
- 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- Withdrawn
Links
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound 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 171
- 102000004877 Insulin Human genes 0.000 title claims abstract description 86
- 108090001061 Insulin Proteins 0.000 title claims abstract description 86
- 229940125396 insulin Drugs 0.000 title claims abstract description 85
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 238000000034 method Methods 0.000 title claims description 18
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 19
- 239000011701 zinc Substances 0.000 claims abstract description 19
- 150000002500 ions Chemical class 0.000 claims abstract description 9
- 239000012736 aqueous medium Substances 0.000 claims abstract description 5
- 150000003752 zinc compounds Chemical class 0.000 claims abstract 6
- -1 sodium ions Chemical class 0.000 claims abstract 2
- 239000000243 solution Substances 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000002609 medium Substances 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 239000000872 buffer Substances 0.000 claims description 6
- 239000012533 medium component Substances 0.000 claims description 5
- 239000003755 preservative agent Substances 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims 2
- 239000008365 aqueous carrier Substances 0.000 claims 1
- 230000007935 neutral effect Effects 0.000 claims 1
- 239000006174 pH buffer Substances 0.000 claims 1
- 238000004220 aggregation Methods 0.000 abstract description 5
- 230000002776 aggregation Effects 0.000 abstract description 5
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 229910001415 sodium ion Inorganic materials 0.000 abstract 1
- 239000012153 distilled water Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 8
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000011592 zinc chloride Substances 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- 238000011146 sterile filtration Methods 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 150000003751 zinc Chemical class 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- GUBGYTABKSRVRQ-WFVLMXAXSA-N DEAE-cellulose Chemical compound OC1C(O)C(O)C(CO)O[C@H]1O[C@@H]1C(CO)OC(O)C(O)C1O GUBGYTABKSRVRQ-WFVLMXAXSA-N 0.000 description 1
- PQFMNVGMJJMLAE-QMMMGPOBSA-N L-tyrosinamide Chemical compound NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 PQFMNVGMJJMLAE-QMMMGPOBSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000004026 insulin derivative Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 108010066090 neutral insulin Proteins 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- 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
Definitions
- the present invention relates to a process for preparing a stable, quick-acting insulin preparation of the type defined in the introductory portion of claim 1.
- the present insulin preparation is suitable for use in insulin delivery devices.
- the previously known insulin preparations are intended for storage at rest at 4oC.
- the insulin preparation is stored in the reservoir of insulin devices for an extended period of time at temperatures between 30 and 37oC, and is moreover subjected to a good deal of motion during this period.
- the previously known dissolved insulin preparations are usually produced from zinc-crystallized insulin and are admixed with the necessary and known medium components, such as preservative, isotonic and buffer to maintain the pH, and the zinc content may optionally be adjusted with a zinc salt.
- the art also comprises insulin preparations which are not produced on the basis of zinc-crystallized insulin.
- the Danish Patent Specifications 127 165, 143 024 and 143 106 teach processes, for preparing and purifying alkali metal and ammonium insulin, i.e. insulin crystallized with lithium, sodium, potassium or ammonium instead of zinc, while the Danish Patent Specification 140 801 concerns a process for preparing insulin preparations with protracted action, in which the crystallization step is omitted because immediately after the purification of crude insulin the purified insulin is passed into the preparation medium comprising an amino group containing a base, and finally the pH and optionally the zinc content are adjusted.
- These methods have been developed to provide better yields and preparations of lower antigenicity, respectively.
- the insulin starting material used for making the preparation must be essentially zinc-free, preferably not zinc crystallized. Useful insulins are stated in claim 2 and the preferred insulin in claim 3.
- aqueous medium does not contain di- or polyvalent ions which would impair the stability, but only monovalent ions.
- the preparation medium is to be admixed with a zinc salt so that the zinc content of the finished preparation constitutes 0.5 to 1.0%, based on the weight of insulin, preferably 0.7 to 0.9%, such as 0.76 to 0.84, the optimum content being around 0.8%.
- the pH of the medium is to be in the range of 6.9 to 8.9, preferably 6.9 to 7.8.
- the optimum range is 7.2 to 7.8, such as 7.4.
- a non-dissociable isotonic such as glycerol, or a nonreducible sugar type may be added.
- a suitable sugar type is mannitol.
- the preservative used may be a phenol or an alkyl- substituted phenol, preferably m-cresol.
- a preparation thus produced usually requires no addition of a buffer, in particular in case of insulin concentrations of 100 to 1500 IU/ml, because the insulin molecule itself exerts an adequate buffer effect.
- common buffers such as sodium acetate, or more special buffers of the amine or amide type, such as tyrosine amide.
- the present process is useful in connection with insulin of different purity, such as repeatedly recrystallized products or the so-called highly purified types which are almost completely freed of antigenic impurities.
- Sodium-crystallized insulin corresponding to 100,000 IU was dissolved in 800 ml of sterile, distilled water. Then 16 g of glycerol and 5 g of phenol were added with stirring. This was followed by addition of a solution of ZnCl 2 containing an amount of zinc corresponding to 0.8% of the insulin amount, determined by Kjeldahl's method, and the solution was topped with sterile, distilled water to 990 ml. Finally, the pH of the solution was adjusted to 7.4 with 0.1 N NaOH and its volume was adjusted to 1000 ml with sterile, distilled water, followed by sterile filtration of the solution.
- Sodium crystallized insulin corresponding to 100,000 IU was dissolved in 200 ml of sterile distilled water, and pH was adjusted to 8.1 with 0.1 N NaOH or 0.1 N HCl. 16 g of glycerol and 3.3 g of m-cresol were dissolved in about 700 ml of sterile distilled water. This was followed by addition of a solution of ZnCl 2 containing an amount of zinc corresponding to 0.8% of the insulin amount, determined by Kjeldahl's method. Then the pH of the medium was adjusted to 6.9 with 0.1 N NaOH and its volume to 790 ml with sterile distilled water. The medium was carefully added to the 200 ml of insulin solution with stirring. Finally, the pH of the solution was adjusted to 7.4 with 0.1 N NaOH, optionally 0.1 N HCl, and its volume to 1000 ml with sterile distilled water, and the solution was sterile filtrated.
- Freeze-dried, essentially zinc-free insulin corresponding to 100,000 IU was dissolved in 800 ml of sterile, distilled water. The pH was adjusted to 7.8 with 0.1 N NaOH. The solution, was admixed, with stirring, with 1 g of NaCl and 3.0 g of m-cresol. This was followed by addition of a solution of ZnCl 2 containing an amount of zinc corresponding to 0.8% of the insulin amount, determined by Kjeldahl's method, and the solution was topped with sterile, distilled water to 990 ml. Finally, the pH of the solution was adjusted to 7.8 with 0.1 N NaOH and its volume was adjusted to 1000 ml with sterile, distilled water, followed by sterile filtration of the solution. EXAMPLE 4
- a column of a diameter of 2.5 cm was packed at room temperature with a 75 cm high layer of Sephadex ® G25 medium swollen in distilled water.
- an insulin solution resulting from ion exchange in a known manner on DEAE cellulose in a 7 molar urea solution there were applied 40 ml containing insulin corresponding to 20,000 IU after concentration and adjustment of the pH of the solution to 8.2. This was followed by elution with distilled water at a rate of 108 ml/h, and the eluate was divided into fractions. The extinction at 280 run was measured, and the fractions containing insulin were collected, followed by determination of the insulin content.
- Part of the resulting insulin solution containing insulin corresponding to 10,000 IU was diluted with sterile, distilled water to 80 ml.
- the solution was admixed, with stirring, with 1.6 g of glycerol, 0.2 g of NaCl and 0.33 g of m-cresol.
- a solution of ZnCl 2 containing an amount of zinc corresponding to 0.8% of the insulin amount, determined by Kjeldahl's method, and the solution was topped with sterile, distilled water to 95 ml.
- the pH of the solution was adjusted, to 7.4 with 0.1 N NaOH, and its volume was adjusted -to 100 ml with sterile, distilled water, followed by sterile filtration of the solution.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Une préparation d'insuline stable et d'action rapide est produite en dissolvant de l'insuline exempte de zinc dans un milieu aqueux contenant des ions monovalents, tels que des ions de sodium, mais pratiquement pas d'ions bivalents ou polyvalents, en réglant le pH entre 6,9 et 8,0, de préférence entre 7,2 et 7,8, et en ajoutant un composé de zinc correspondant à une quantité de 0,5 à 1,0 % de zinc, de préférence de 0,7 à 0,9 % de zinc, en fonction du poids de l'insuline. La préparation est très stable contre l'aggrégation entre 25 et 37oC, et convient donc particulièrement à l'utilisation dans des dispositifs portatifs ou implantables d'administration d'insuline.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK918/82 | 1982-03-03 | ||
| DK91882 | 1982-03-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0102976A1 true EP0102976A1 (fr) | 1984-03-21 |
Family
ID=8099004
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19830900834 Withdrawn EP0102976A1 (fr) | 1982-03-03 | 1983-03-02 | Procede de production d'une preparation d'insuline |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0102976A1 (fr) |
| ES (1) | ES8403723A1 (fr) |
| WO (1) | WO1983003054A1 (fr) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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. |
| US5597893A (en) * | 1994-10-31 | 1997-01-28 | Eli Lilly And Company | Preparation of stable insulin analog crystals |
| AU2002300833B2 (en) * | 1997-08-04 | 2007-05-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Aqueous aerosol preparations containing biologically active macromolecules and method for producing the corresponding aerosols |
| DE19733651A1 (de) * | 1997-08-04 | 1999-02-18 | Boehringer Ingelheim Pharma | Wässrige Aerosolzubereitungen enthaltend biologisch aktive Markomoleküle und Verfahren zur Erzeugung entsprechender Aerosole |
| RU2202365C2 (ru) * | 2001-07-20 | 2003-04-20 | Институт биоорганической химии им. М.М.Шемякина и Ю.А.Овчинникова РАН | Способ приготовления быстродействующего раствора инсулина для инъекций |
| UA46669C2 (uk) * | 2001-12-29 | 2005-12-15 | Товариство З Обмеженою Відповідальністю "Мако" | Спосіб приготування готової лікарської форми інсуліну пролонгованої дії |
| UA46668C2 (en) * | 2001-12-29 | 2006-01-16 | Omakooe Ltd Liability Company | Method for preparing combined dosage form of human insulin |
| UA46666C2 (en) * | 2001-12-29 | 2006-01-16 | Omakooe Ltd Liability Company | Method for preparing dosage form of short-term acting insulin |
| RU2252752C2 (ru) * | 2002-05-15 | 2005-05-27 | Ооо Мако | Готовая лекарственная форма инсулина человека короткого действия |
| RU2251426C1 (ru) * | 2003-09-18 | 2005-05-10 | Цыганков Владимир Владимирович | Способ получения инсулина из природного источника и инсулин |
| RU2281756C2 (ru) * | 2004-11-25 | 2006-08-20 | Институт биоорганичексой химии им. академиков М.М. Шемякина и. Ю.А. Овчинникова Российской Академии Наук | Способ приготовления суспензии фармацевтической композиции на основе субстанции генно-инженерного (рекомбинантного) инсулина человека |
| EP2077132A1 (fr) | 2008-01-02 | 2009-07-08 | Boehringer Ingelheim Pharma GmbH & Co. KG | Dispositif distributeur, dispositif de stockage et procédé pour la distribution d'une formulation |
| EP2414560B1 (fr) | 2009-03-31 | 2013-10-23 | Boehringer Ingelheim International GmbH | Procédé de revêtement d'une surface d'un composant |
| EP2432531B1 (fr) | 2009-05-18 | 2019-03-06 | Boehringer Ingelheim International GmbH | Adaptateur, dispositif d'inhalation et pulvérisateur |
| US10016568B2 (en) | 2009-11-25 | 2018-07-10 | Boehringer Ingelheim International Gmbh | Nebulizer |
| MX2012005961A (es) | 2009-11-25 | 2012-06-14 | Boehringer Ingelheim Int | Nebulizador. |
| WO2011064163A1 (fr) | 2009-11-25 | 2011-06-03 | Boehringer Ingelheim International Gmbh | Nébuliseur |
| EP2585151B1 (fr) | 2010-06-24 | 2018-04-04 | Boehringer Ingelheim International GmbH | Nébuliseur |
| WO2012130757A1 (fr) | 2011-04-01 | 2012-10-04 | Boehringer Ingelheim International Gmbh | Appareil médical pourvu d'un récipient |
| US9827384B2 (en) | 2011-05-23 | 2017-11-28 | Boehringer Ingelheim International Gmbh | Nebulizer |
| WO2013152894A1 (fr) | 2012-04-13 | 2013-10-17 | Boehringer Ingelheim International Gmbh | Pulvérisateur comprenant des moyens de détrompage |
| JP6643231B2 (ja) | 2013-08-09 | 2020-02-12 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ネブライザ |
| EP2835146B1 (fr) | 2013-08-09 | 2020-09-30 | Boehringer Ingelheim International GmbH | Atomiseur |
| HUE058904T2 (hu) | 2014-05-07 | 2022-09-28 | Boehringer Ingelheim Int | Porlasztókészülék |
| US10722666B2 (en) | 2014-05-07 | 2020-07-28 | Boehringer Ingelheim International Gmbh | Nebulizer with axially movable and lockable container and indicator |
| CA2948071C (fr) | 2014-05-07 | 2022-08-30 | Boehringer Ingelheim International Gmbh | Contenant, nebuliseur et utilisation |
Family Cites Families (8)
| 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 |
| US3091573A (en) * | 1958-05-12 | 1963-05-28 | Novo Terapeutisk Labor As | Quick acting insulin preparation |
| DK116527B (da) * | 1967-03-01 | 1970-01-19 | Nordisk Insulinlab | Fremgangsmåde til fremstilling af en hurtigtvirkende, holdbar, neutral opløsning af rent krystallinsk okseinsulin eller okseinsulin, der ved tilsætning af Zn er krystalliserbart i vand, eller blandinger af okseinsulin og insulin af anden oprindelse. |
| US3657425A (en) * | 1969-03-12 | 1972-04-18 | Burroughs Wellcome Co | Beef insulin preparations |
| US3719655A (en) * | 1969-12-05 | 1973-03-06 | Lilly Co Eli | Process for the crystallization of the ammonium and alkali metal salts in insulin |
| US3876623A (en) * | 1973-05-09 | 1975-04-08 | Lilly Co Eli | Process for purifying insulin |
| US3878186A (en) * | 1973-05-09 | 1975-04-15 | Lilly Co Eli | Process for purifying insulin |
| DK80781A (da) * | 1980-02-29 | 1981-08-30 | Hospital For Sick Children | Oploesninger af polypeptider |
-
1983
- 1983-03-02 EP EP19830900834 patent/EP0102976A1/fr not_active Withdrawn
- 1983-03-02 WO PCT/DK1983/000024 patent/WO1983003054A1/fr not_active Ceased
- 1983-03-02 ES ES520249A patent/ES8403723A1/es not_active Expired
Non-Patent Citations (1)
| Title |
|---|
| See references of WO8303054A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1983003054A1 (fr) | 1983-09-15 |
| ES520249A0 (es) | 1984-04-16 |
| ES8403723A1 (es) | 1984-04-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 19831021 |
|
| AK | Designated contracting states |
Designated state(s): AT BE CH DE FR GB LI LU NL SE |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
| 18D | Application deemed to be withdrawn |
Effective date: 19850802 |
|
| RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: JOHANSEN, KRISTIAN BETTON |