WO1983000288A1 - Preparation therapeutique d'insuline aqueuse stable et son procede de preparation - Google Patents

Preparation therapeutique d'insuline aqueuse stable et son procede de preparation Download PDF

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Publication number
WO1983000288A1
WO1983000288A1 PCT/DK1982/000068 DK8200068W WO8300288A1 WO 1983000288 A1 WO1983000288 A1 WO 1983000288A1 DK 8200068 W DK8200068 W DK 8200068W WO 8300288 A1 WO8300288 A1 WO 8300288A1
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WO
WIPO (PCT)
Prior art keywords
insulin
formula
preparation
compound
medium
Prior art date
Application number
PCT/DK1982/000068
Other languages
English (en)
Inventor
Insulinlaboratorium Nordisk
Original Assignee
Balschmidt, Per
Johansen, Kristian, Betton
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 Balschmidt, Per, Johansen, Kristian, Betton filed Critical Balschmidt, Per
Publication of WO1983000288A1 publication Critical patent/WO1983000288A1/fr
Priority to DK096483A priority Critical patent/DK152409C/da
Priority to FI830871A priority patent/FI830871L/fi

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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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to a novel stable therapeutic insulin preparation in an aqueous medium suitable for use in insulin delivery devices, including portable devices for external as well as internal use.
  • insulin delivery devices which can remedy the above-mentioned problem. If, however, such devices are applied internally or externally to a human, insulin preparations experience far inferior storage conditions in terms of temperature and motion when stored in the reservoir of the device than the injectable preparations.
  • 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.
  • n 2 - 80, preferably 8-45
  • Y represents oxygen or imino
  • R 1 represents hydrogen, methyl or ethyl, where the groups
  • R 1 may be the same or different, with the proviso that methyl or ethyl is present in at least half of the chain links X, and R 2 and R 3 independently represent hydrogen or an organic group, preferably alkyl of 1 to 20 carbon atoms, carboxyalkyl of 2 to 20 carbon atoms or alkylphenyl of 1 to 10 alkyl carbon atoms, with the proviso that when Y represents imino R 2 can only represent alkyl of 1 to 20 carbon atoms.
  • These surfactants "saturate" the interfaces since the hydrophobic groups of the chains bind well to a larger hydrophobic face.
  • the invention relates to a stable aqueous, therapeutic insulin preparation which is particularly useful in insulin delivery devices and is unique in that the aqueous medium has a pH of 6.5 to 9 and contains a polyoxyethylene alkylether of the general formula
  • R represents a straight or branched, saturated or unsaturated C 8 - C 15 alkyl group, and n is an integer from 2 to 25.
  • Preferred compounds are in particular those of formula 4 wherein R represents a C 12 - C 13 alkyl group, preferably lauryl or tridecyl, because they give the best stability.
  • n in the compounds of formula 4 is an integer, preferably from 4 to 23, in particular 6 to 15.
  • These polyoxyethylene alkylethers are active in insulin preparations in an aqueous medium in concentrations down to 2 ppm. The effect for concentrations between 2 and 100 ppm is demonstrated below, but the compounds are also active in higher concentrations, such as 100 to
  • concentration most appropriate in the individual case can be determined by tests and depends e.g. upon the type of the compound, the concentration of insulin and the other components of the medium, as well as upon the mode of application of the preparation.
  • the above-mentioned compounds are comprised by the general formula for a group of non-ionic surfactants which prevent denaturation of insulin and adsorption to interfaces according to the DE Offenlegun ⁇ sschrift 29 17 53.5.
  • the compounds used in accordance with the invention are not described in detail or examined in the examples of that specification/ which are included in the EP 18609 claiming priority from this DE application.
  • the formula of the active compounds is restricted to formula 1 above.
  • Compounds of the type used in accordance with the invention have directly been characterized as having no protective effect during the processing of the EP 18609 by the EPO in connection with a discussion of the DE Auslegeschrift 26 20 483.
  • the solutions have a pH of 2.5 to 4.7 and contain one or more non-ionic surfactants having an HLB value of 9 to 22 and/or polyethylene glycol having a molecular weight of 200 to 7500 as a stabilizer to counteract the ceamidation of the insulin, well-known in the acid pH range, and to improve the shelf-life by counteracting gel formation and precipitations.
  • the content of surfactant usually constitutes 0.1 to 20% by weight, preferably 0.5 to 10% by weight. A content below 0.1% is characterized as being insufficient.
  • R' and n have values corresponding to formula 4, are inactive as stabilizers in shaking tests.
  • the Zn content in the medium can constitute 0 to 5%, preferably 0 to 1%, in particular 0.3 to 1% of the insulin, expressed as weight per cent of anhydrous insulin.
  • a particularly good effect of the polyoxyethylene alkylethers is obtained when the Zn content in the dissolved insulin constitutes between 0.6 and 0.9%.
  • the pH value is, as mentioned, between 6.5 and 9.0, but is preferably 6.5 to 8.0, in particular 7.0 to 8.0.
  • the insulin concen tration may be up to 1500 IU/ml.
  • aqueous insulin preparations for the use described can be prepared by the following general procedure:
  • Human or animal insulin or biologically active derivatives thereof are dissolved in water with addition of e.g. an HCl solution.
  • the Zn content is adjusted by adding a solution of a Zn salt in water.
  • the resulting solution is admixed with a solution that may contain a preservative, such as phenol, m-cresol or p-methylhydroxy benzoate; an isotonic, such as glucose, glycerol or sodium chloride, and - to maintain a specific pH - a buffer such as acetate or sodium phosphate. pH is adjusted to the desired value e.g. with an NaOH solution or an HCl solution.
  • the stabilizing polyoxyethylene alkylether dissolved in water is added.
  • the insulin may be dissolved directly in an aqueous medium containing a buffer, an isotonic, a preservative and the stabilizing compound, and then the Zn content and the pH are adjusted.
  • the order of these steps is arbitrary, it being possible to vary it in different ways; e.g. the stabilizing polymer might be added to the insulin during the purification process of the insulin.
  • the invention also relates to a process for preparing the present insulin preparations which comprises admixing an aqueous medium containing insulin with a polyoxyethylene alkylether of the formula
  • Crystalline pork insulin corresponding to 100,000 IU containing 0.4% Zn was dissolved in 400 ml of water by means of 3.3 ml of IN HCl. 10 ml of a ZnCl 2 solution were added, containing 2.20 mg of ZnCl 2 per ml. Then were added 500 ml of a solution of 3.0 g of m-cresol, 16.0 g of anhydrous glycerol and 2.373 g of Na 2 HPO 4 , 2H 2 O. After mixing, pH was adjusted to 7.3 by means of IN NaOH. Addition of 10 ml of a solution containing 1% polyoxyethylene-23-laurylether (corresponding to a concentration of 100 ppm), was followed by topping with water to 1 litre, and the solution was sterile filtrated.
  • Crystalline pork insulin corresponding to 100,000 IU containing 0.7% Zn was dissolved in 400 ml of water by means of 3,3 ml of IN HCl. Then were added 500 ml of a solution of 3.0 g of m-cresol, 16 g of anhydrous glycerol and 2.373 g of Na 2 HPO 4 , 2H 2 O. After mixing pH was adjusted to 7.3 by means of IN NaOH. Addition of 1 ml of a solution of 1% polyoxyethylene-15-tridecylether (corresponding to a concentration of 10 ppm)was followed by topping with water to 1 litre, and the solution was sterile filtrated.
  • 1% polyoxyethylene-15-tridecylether corresponding to a concentration of 10 ppm
  • Crystalline pork insulin (40,000 ID) having 0.6% by weight of zinc was dissolved in 200 ml ofwater with addition of 3 ml of IN hydrochlorid acid. This solution was admixed with 700 ml of a solution of 1 g of p- hydroxybenzoic acid methylester, 17 g of glycerol, 1.4 g of sodium acetate, 3 H 2 O and 10 mg of linear polypropylene glycol of an average molecular weight of 1.750. The solution was adjusted to a pH of 6.9 to 7.4. Water was topped up to 1-0 litre, and the solutionwas sterile filtrated. Shaking tests like in example 1 demonstrated that the stability only lasted for 200 hours.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La préparation d'insuline, qui convient à l'utilisation dans des dispositifs d'administration d'insuline, se compose d'un milieu aqueux contenant de l'insuline ayant un pH compris entre 6,5 et 9 et un alkyléther de polyoxyéthylène correspondant à la formule générale R-O-(CH2-CH2-O)n-H où R représente un groupe alkyl C8-C15 saturé ou non saturé, droit ou ramifié, et n est un nombre entier compris entre 2 et 25, ainsi qu'éventuellement des additifs communs, tels que des isotoniques, des conservants, des tampons, etc., et éventuellement également un composant provoquant une accélération ou un ralentissement de l'effet de la préparation. La préparation est obtenue en mélangeant un milieu aqueux contenant de l'insuline humaine ou animale ou un dérivé de celle-ci avec un alkyléther de polyoxyéthylène, en ajustant le cas échéant le pH du milieu à une valeur comprise entre 6,5 et 9 et, facultativement, en ajoutant des composants résiduels du milieu et/ou en ajustant la concentration d'insuline pour obtenir le produit fini. Après plus de 500 heures d'agitation constante en présence d'air atmosphérique dans des fioles remplies à trois quarts, disposées horizontalement, à une température de 37oC et avec 80 oscillations à la minute, ces préparations restent claires et ne présentent aucun changement physique ou chimique.
PCT/DK1982/000068 1981-07-17 1982-07-16 Preparation therapeutique d'insuline aqueuse stable et son procede de preparation WO1983000288A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DK096483A DK152409C (da) 1981-07-17 1983-02-28 Fremgangsmaade til fremstilling af et stabilt vandigt terapeutisk insulinpraeparat
FI830871A FI830871L (fi) 1981-07-17 1983-03-16 Ett stabilt vattenhaltigt terapeutiskt insulinpreparat och ett foerfarande foer framstaellning daer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK319881 1981-07-17
DK3198/81810717 1981-07-17

Publications (1)

Publication Number Publication Date
WO1983000288A1 true WO1983000288A1 (fr) 1983-02-03

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ID=8120177

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Application Number Title Priority Date Filing Date
PCT/DK1982/000068 WO1983000288A1 (fr) 1981-07-17 1982-07-16 Preparation therapeutique d'insuline aqueuse stable et son procede de preparation

Country Status (5)

Country Link
EP (1) EP0083619A1 (fr)
JP (1) JPS58501125A (fr)
AU (1) AU558474B2 (fr)
NO (1) NO830933L (fr)
WO (1) WO1983000288A1 (fr)

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0098110A2 (fr) * 1982-06-24 1984-01-11 NIHON CHEMICAL RESEARCH KABUSHIKI KAISHA also known as JAPAN CHEMICAL RESEARCH CO., LTD Composition à action prolongée
EP0131864A2 (fr) * 1983-07-13 1985-01-23 Hoechst Aktiengesellschaft Solutions aqueuses de protéines résistantes à la dénaturation, leur procédé de préparation et leur application
DE3443877A1 (de) * 1984-06-09 1985-12-12 Hoechst Ag Insulinzubereitungen, verfahren zu deren herstellung und deren verwendung
WO1987007149A1 (fr) * 1986-05-27 1987-12-03 Sandoz Ag Compositions pharmaceutiques
US5902789A (en) * 1986-04-23 1999-05-11 Fisons Corporation Nasal administration of drugs
US6221633B1 (en) 1997-06-20 2001-04-24 Aventis Pharma Deutschland Gmbh Insulin derivatives having a rapid onset of action
AU753673B2 (en) * 1997-08-04 2002-10-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Aqueous aerosol preparations containing biologically active macromolecules and method for producing the corresponding aerosols
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
US7476652B2 (en) 2002-06-18 2009-01-13 Sanofi-Aventis Deutschland Gmbh Acidic insulin preparations having improved stability
US7696162B2 (en) 2001-03-23 2010-04-13 Sanofi-Aventis Deutschland Gmbh Zinc-free and low-zinc insulin preparations having improved stability
RU2506945C2 (ru) * 2009-03-03 2014-02-20 Байодел Инк. Лекарственные формы инсулина, обладающие быстрым усвоением
US9364519B2 (en) 2011-09-01 2016-06-14 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition for use in the treatment of a neurodegenerative disease
US9408893B2 (en) 2011-08-29 2016-08-09 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for use in glycemic control in diabetes type 2 patients
US9526764B2 (en) 2008-10-17 2016-12-27 Sanofi-Aventis Deutschland Gmbh Combination of an insulin and a GLP-1-agonist
US9545487B2 (en) 2012-04-13 2017-01-17 Boehringer Ingelheim International Gmbh Dispenser with encoding means
US9682202B2 (en) 2009-05-18 2017-06-20 Boehringer Ingelheim International Gmbh Adapter, inhalation device, and atomizer
US9707176B2 (en) 2009-11-13 2017-07-18 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist and methionine
US9724482B2 (en) 2009-11-25 2017-08-08 Boehringer Ingelheim International Gmbh Nebulizer
US9744313B2 (en) 2013-08-09 2017-08-29 Boehringer Ingelheim International Gmbh Nebulizer
US9757750B2 (en) 2011-04-01 2017-09-12 Boehringer Ingelheim International Gmbh Medicinal device with container
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
US9827384B2 (en) 2011-05-23 2017-11-28 Boehringer Ingelheim International Gmbh Nebulizer
US9943654B2 (en) 2010-06-24 2018-04-17 Boehringer Ingelheim International Gmbh Nebulizer
US9950039B2 (en) 2014-12-12 2018-04-24 Sanofi-Aventis Deutschland Gmbh Insulin glargine/lixisenatide fixed ratio formulation
US9981013B2 (en) 2010-08-30 2018-05-29 Sanofi-Aventis Deutschland Gmbh Use of AVE0010 for the treatment of diabetes mellitus type 2
US10004857B2 (en) 2013-08-09 2018-06-26 Boehringer Ingelheim International Gmbh Nebulizer
US10011906B2 (en) 2009-03-31 2018-07-03 Beohringer Ingelheim International Gmbh Method for coating a surface of a component
US10016568B2 (en) 2009-11-25 2018-07-10 Boehringer Ingelheim International Gmbh Nebulizer
US10029011B2 (en) 2009-11-13 2018-07-24 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist, an insulin and methionine
US10092513B2 (en) 2013-04-03 2018-10-09 Sanofi Treatment of diabetes mellitus by long-acting formulations of insulins
US10099022B2 (en) 2014-05-07 2018-10-16 Boehringer Ingelheim International Gmbh Nebulizer
US10124129B2 (en) 2008-01-02 2018-11-13 Boehringer Ingelheim International Gmbh Dispensing device, storage device and method for dispensing a formulation
US10124125B2 (en) 2009-11-25 2018-11-13 Boehringer Ingelheim International Gmbh Nebulizer
US10159713B2 (en) 2015-03-18 2018-12-25 Sanofi-Aventis Deutschland Gmbh Treatment of type 2 diabetes mellitus patients
US10195374B2 (en) 2014-05-07 2019-02-05 Boehringer Ingelheim International Gmbh Container, nebulizer and use
US10434147B2 (en) 2015-03-13 2019-10-08 Sanofi-Aventis Deutschland Gmbh Treatment type 2 diabetes mellitus patients
US10722666B2 (en) 2014-05-07 2020-07-28 Boehringer Ingelheim International Gmbh Nebulizer with axially movable and lockable container and indicator

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DE2620483A1 (de) * 1975-06-13 1976-12-23 Takeda Chemical Industries Ltd Stabile waessrige insulinloesungen
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DE2641819A1 (de) * 1975-09-26 1977-04-07 Yamanouchi Pharma Co Ltd Pharmazeutische zubereitung von insulin zur rektalen verwendung
US4164573A (en) * 1975-06-13 1979-08-14 Galinsky Alvin M Composition and method for making a suppository for introducing a hypoglycemic agent into a mammal
DE2917535A1 (de) * 1979-04-30 1980-11-06 Hoechst Ag Gegen denaturierung bestaendige insulinloesungen, ihre herstellung und verwendung

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2620483A1 (de) * 1975-06-13 1976-12-23 Takeda Chemical Industries Ltd Stabile waessrige insulinloesungen
US4164573A (en) * 1975-06-13 1979-08-14 Galinsky Alvin M Composition and method for making a suppository for introducing a hypoglycemic agent into a mammal
DE2620446A1 (de) * 1975-08-20 1977-03-03 Takeda Chemical Industries Ltd Waessriges insulinpraeparat
DE2641819A1 (de) * 1975-09-26 1977-04-07 Yamanouchi Pharma Co Ltd Pharmazeutische zubereitung von insulin zur rektalen verwendung
DE2917535A1 (de) * 1979-04-30 1980-11-06 Hoechst Ag Gegen denaturierung bestaendige insulinloesungen, ihre herstellung und verwendung

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Title
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International Journal of Pharmaceutics, Vol 9, No 2, issued August 1981 (Elsevier/North-Holland Biomedical Press, Amsterdam), S Hirai et al, "Effect of surfactants on the nasal absorption of insulin in rats", see pages 165-172, especially page 168 and page 165, lines 8-4 from the bottom. *
International Journal of Pharmaceutics, Vol 9, No 2, issued August 1981 (Elsevier/North-Holland Biomedical Press, Amsterdam), S Hirai et al, "Mechanisms for the enhancement of the nasal absorption of insulin by surfactants", see pages 173-184, especially pages 178-179 and 173, lines 9-5 from the bottom. *
Journal of Pharmacy and Pharmacology, Vol 32, issued 1980 (London), K Ichikawa et al, "Rectal absorption of insulin suppositories in rabbits", see pages 314-318. *
Journal of Pharmacy and Pharmacology, Vol 33, No 11, issued November 1981 (London), M S Mesiha & H I EL-Bitar, "Hypoglycaemic effect of oral insulin preparations containing Brij 35, 52, 58 or 92 and stearic acid", see pages 733-734. *

Cited By (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0098110A3 (en) * 1982-06-24 1986-03-05 Nihon Chemical Research Kabushiki Kaisha Also Known As Japan Chemical Research Co., Ltd Long-acting composition
EP0098110A2 (fr) * 1982-06-24 1984-01-11 NIHON CHEMICAL RESEARCH KABUSHIKI KAISHA also known as JAPAN CHEMICAL RESEARCH CO., LTD Composition à action prolongée
EP0131864A2 (fr) * 1983-07-13 1985-01-23 Hoechst Aktiengesellschaft Solutions aqueuses de protéines résistantes à la dénaturation, leur procédé de préparation et leur application
EP0131864A3 (en) * 1983-07-13 1987-08-26 Hoechst Aktiengesellschaft Denaturation-resistant aqueous solutions of proteins, process for preparing them and their use
DE3443877A1 (de) * 1984-06-09 1985-12-12 Hoechst Ag Insulinzubereitungen, verfahren zu deren herstellung und deren verwendung
US5902789A (en) * 1986-04-23 1999-05-11 Fisons Corporation Nasal administration of drugs
DE3716437A1 (de) * 1986-05-27 1987-12-03 Sandoz Ag Pharmazeutische zusammensetzung
FR2599254A1 (fr) * 1986-05-27 1987-12-04 Sandoz Sa Compositions pharmaceutiques de polypeptides adaptees a la resorption gastro-intestinale.
BE1000722A4 (fr) * 1986-05-27 1989-03-21 Sandoz Sa Compositions pharmaceutiques de polypeptides adaptees a la resorption gastro-intestinale.
GB2190838B (en) * 1986-05-27 1990-12-12 Sandoz Ltd Pharmaceutical compositions
WO1987007149A1 (fr) * 1986-05-27 1987-12-03 Sandoz Ag Compositions pharmaceutiques
US6221633B1 (en) 1997-06-20 2001-04-24 Aventis Pharma Deutschland Gmbh Insulin derivatives having a rapid onset of action
AU753673B2 (en) * 1997-08-04 2002-10-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Aqueous aerosol preparations containing biologically active macromolecules and method for producing the corresponding aerosols
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
US7696162B2 (en) 2001-03-23 2010-04-13 Sanofi-Aventis Deutschland Gmbh Zinc-free and low-zinc insulin preparations having improved stability
US7713930B2 (en) 2002-06-18 2010-05-11 Sanofi-Aventis Deutschland Gmbh Acidic insulin preparations having improved stability
US7476652B2 (en) 2002-06-18 2009-01-13 Sanofi-Aventis Deutschland Gmbh Acidic insulin preparations having improved stability
US10124129B2 (en) 2008-01-02 2018-11-13 Boehringer Ingelheim International Gmbh Dispensing device, storage device and method for dispensing a formulation
US9526764B2 (en) 2008-10-17 2016-12-27 Sanofi-Aventis Deutschland Gmbh Combination of an insulin and a GLP-1-agonist
US10117909B2 (en) 2008-10-17 2018-11-06 Sanofi-Aventis Deutschland Gmbh Combination of an insulin and a GLP-1 agonist
RU2506945C2 (ru) * 2009-03-03 2014-02-20 Байодел Инк. Лекарственные формы инсулина, обладающие быстрым усвоением
US9060927B2 (en) 2009-03-03 2015-06-23 Biodel Inc. Insulin formulations for rapid uptake
US10011906B2 (en) 2009-03-31 2018-07-03 Beohringer Ingelheim International Gmbh Method for coating a surface of a component
US9682202B2 (en) 2009-05-18 2017-06-20 Boehringer Ingelheim International Gmbh Adapter, inhalation device, and atomizer
US9707176B2 (en) 2009-11-13 2017-07-18 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist and methionine
US10028910B2 (en) 2009-11-13 2018-07-24 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1-agonist and methionine
US10029011B2 (en) 2009-11-13 2018-07-24 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist, an insulin and methionine
US9724482B2 (en) 2009-11-25 2017-08-08 Boehringer Ingelheim International Gmbh Nebulizer
US10016568B2 (en) 2009-11-25 2018-07-10 Boehringer Ingelheim International Gmbh Nebulizer
US10124125B2 (en) 2009-11-25 2018-11-13 Boehringer Ingelheim International Gmbh Nebulizer
US9943654B2 (en) 2010-06-24 2018-04-17 Boehringer Ingelheim International Gmbh Nebulizer
US9981013B2 (en) 2010-08-30 2018-05-29 Sanofi-Aventis Deutschland Gmbh Use of AVE0010 for the treatment of diabetes mellitus type 2
US9757750B2 (en) 2011-04-01 2017-09-12 Boehringer Ingelheim International Gmbh Medicinal device with container
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
US9827384B2 (en) 2011-05-23 2017-11-28 Boehringer Ingelheim International Gmbh Nebulizer
US9408893B2 (en) 2011-08-29 2016-08-09 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for use in glycemic control in diabetes type 2 patients
US9987332B2 (en) 2011-09-01 2018-06-05 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition for use in the treatment of a neurodegenerative disease
US9364519B2 (en) 2011-09-01 2016-06-14 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition for use in the treatment of a neurodegenerative disease
US10220163B2 (en) 2012-04-13 2019-03-05 Boehringer Ingelheim International Gmbh Nebuliser with coding means
US9545487B2 (en) 2012-04-13 2017-01-17 Boehringer Ingelheim International Gmbh Dispenser with encoding means
US11191722B2 (en) 2013-04-03 2021-12-07 Sanofi Treatment of diabetes mellitus by long-acting formulations of insulins
US10092513B2 (en) 2013-04-03 2018-10-09 Sanofi Treatment of diabetes mellitus by long-acting formulations of insulins
US9744313B2 (en) 2013-08-09 2017-08-29 Boehringer Ingelheim International Gmbh Nebulizer
US10894134B2 (en) 2013-08-09 2021-01-19 Boehringer Ingelheim International Gmbh Nebulizer
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NO830933L (no) 1983-03-16
EP0083619A1 (fr) 1983-07-20
JPS58501125A (ja) 1983-07-14
AU558474B2 (en) 1987-01-29
AU8730482A (en) 1983-03-17

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