EP0083619A1 - Preparation therapeutique d'insuline aqueuse stable et son procede de preparation - Google Patents

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

Info

Publication number
EP0083619A1
EP0083619A1 EP82902164A EP82902164A EP0083619A1 EP 0083619 A1 EP0083619 A1 EP 0083619A1 EP 82902164 A EP82902164 A EP 82902164A EP 82902164 A EP82902164 A EP 82902164A EP 0083619 A1 EP0083619 A1 EP 0083619A1
Authority
EP
European Patent Office
Prior art keywords
insulin
formula
preparation
compound
aqueous medium
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Withdrawn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
EP82902164A
Other languages
German (de)
English (en)
Inventor
Per Balschmidt
Kristian Betton Johansen
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.)
Nordisk Insulinlaboratorium
Original Assignee
Nordisk Insulinlaboratorium
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 Nordisk Insulinlaboratorium filed Critical Nordisk Insulinlaboratorium
Publication of EP0083619A1 publication Critical patent/EP0083619A1/fr
Withdrawn legal-status Critical Current

Links

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.

Landscapes

  • 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)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (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.
EP82902164A 1981-07-17 1982-07-16 Preparation therapeutique d'insuline aqueuse stable et son procede de preparation Withdrawn EP0083619A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK319881 1981-07-17
DK3198/81 1981-07-17

Publications (1)

Publication Number Publication Date
EP0083619A1 true EP0083619A1 (fr) 1983-07-20

Family

ID=8120177

Family Applications (1)

Application Number Title Priority Date Filing Date
EP82902164A Withdrawn EP0083619A1 (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)

Families Citing this family (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0098110B1 (fr) * 1982-06-24 1989-10-18 NIHON CHEMICAL RESEARCH KABUSHIKI KAISHA also known as JAPAN CHEMICAL RESEARCH CO., LTD Composition à action prolongée
DE3325223A1 (de) * 1983-07-13 1985-01-24 Hoechst Ag, 6230 Frankfurt Gegen denaturierung bestaendige, waessrige proteinloesungen, verfahren zu ihrer herstellung und ihre verwendung
DE3443877A1 (de) * 1984-06-09 1985-12-12 Hoechst Ag Insulinzubereitungen, verfahren zu deren herstellung und deren verwendung
CA1291036C (fr) * 1986-04-23 1991-10-22 Edwin I. Stoltz Administration de medicaments par voie nasale
NL8701143A (nl) * 1986-05-27 1987-12-16 Sandoz Ag Farmaceutische preparaten.
DE19726167B4 (de) 1997-06-20 2008-01-24 Sanofi-Aventis Deutschland Gmbh Insulin, Verfahren zu seiner Herstellung und es enthaltende pharmazeutische Zubereitung
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
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
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
HUE037449T2 (hu) 2008-10-17 2018-08-28 Sanofi Aventis Deutschland Egy inzulin és egy GLP-1 agonista kombinációja
US9060927B2 (en) 2009-03-03 2015-06-23 Biodel Inc. Insulin formulations for rapid uptake
EP2414560B1 (fr) 2009-03-31 2013-10-23 Boehringer Ingelheim International GmbH Procédé de revêtement d'une surface d'un composant
JP5763053B2 (ja) 2009-05-18 2015-08-12 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 アダプタ、吸入器具及びアトマイザ
EP3831402A1 (fr) 2009-11-13 2021-06-09 Sanofi-Aventis Deutschland GmbH Composition pharmaceutique comprenant un agoniste du glp-1, une insuline et de la méthionine
ES2965209T3 (es) 2009-11-13 2024-04-11 Sanofi Aventis Deutschland Composición farmacéutica que comprende desPro36exendina-4(1-39)-Lys6-NH2 y metionina
WO2011064163A1 (fr) 2009-11-25 2011-06-03 Boehringer Ingelheim International Gmbh Nébuliseur
AP3141A (en) 2009-11-25 2015-02-28 Boehringer Ingelheim Int Nebulizer
US10016568B2 (en) 2009-11-25 2018-07-10 Boehringer Ingelheim International Gmbh Nebulizer
WO2011160932A1 (fr) 2010-06-24 2011-12-29 Boehringer Ingelheim International Gmbh Nébuliseur
PT2611458T (pt) 2010-08-30 2016-12-16 Sanofi Aventis Deutschland Utilização de ave0010 para o fabrico de um medicamento para o tratamento da diabetes mellitus tipo 2
WO2012130757A1 (fr) 2011-04-01 2012-10-04 Boehringer Ingelheim International Gmbh Appareil médical pourvu d'un récipient
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
AR087693A1 (es) 2011-08-29 2014-04-09 Sanofi Aventis Deutschland Combinacion farmaceutica para uso en el control glucemico en pacientes con diabetes de tipo 2
AR087744A1 (es) 2011-09-01 2014-04-16 Sanofi Aventis Deutschland Composicion farmaceutica para uso en el tratamiento de una enfermedad neurodegenerativa
WO2013152894A1 (fr) 2012-04-13 2013-10-17 Boehringer Ingelheim International Gmbh Pulvérisateur comprenant des moyens de détrompage
RU2019133674A (ru) 2013-04-03 2020-05-20 Санофи Лечение сахарного диабета с помощью составов инсулинов длительного действия
US9744313B2 (en) 2013-08-09 2017-08-29 Boehringer Ingelheim International Gmbh Nebulizer
EP2835146B1 (fr) 2013-08-09 2020-09-30 Boehringer Ingelheim International GmbH Atomiseur
CN106255554B (zh) 2014-05-07 2021-05-04 勃林格殷格翰国际有限公司 容器、喷雾器及用途
WO2015169430A1 (fr) 2014-05-07 2015-11-12 Boehringer Ingelheim International Gmbh Nébuliseur
MX2016014402A (es) 2014-05-07 2017-01-20 Boehringer Ingelheim Int Nebulizador y recipiente.
DK3229828T5 (da) 2014-12-12 2024-10-14 Sanofi Aventis Deutschland Formulering med fast forhold mellem insulin glargin og lixisenatid
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

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1554157A (en) * 1975-06-13 1979-10-17 Takeda Chemical Industries Ltd Stable insulin preparation for intra nasal administration
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
GB1527605A (en) * 1975-08-20 1978-10-04 Takeda Chemical Industries Ltd Insulin preparation for intranasal administration
GB1563311A (en) * 1975-09-26 1980-03-26 Yamanouchi Pharma Co Ltd Pharmaceutical composition of insulin for rectal use
DE2917535C2 (de) * 1979-04-30 1986-10-30 Hoechst Ag, 6230 Frankfurt Gegen Denaturierung beständige Insulinlösungen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8300288A1 *

Also Published As

Publication number Publication date
WO1983000288A1 (fr) 1983-02-03
AU8730482A (en) 1983-03-17
NO830933L (no) 1983-03-16
AU558474B2 (en) 1987-01-29
JPS58501125A (ja) 1983-07-14

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Inventor name: JOHANSEN, KRISTIAN BETTON

Inventor name: BALSCHMIDT, PER