EP0083619A1 - Preparation therapeutique d'insuline aqueuse stable et son procede de preparation - Google Patents
Preparation therapeutique d'insuline aqueuse stable et son procede de preparationInfo
- 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- Withdrawn
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 134
- 102000004877 Insulin Human genes 0.000 title claims abstract description 67
- 108090001061 Insulin Proteins 0.000 title claims abstract description 67
- 229940125396 insulin Drugs 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 230000001225 therapeutic effect Effects 0.000 title claims description 5
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- -1 polyoxyethylene Polymers 0.000 claims abstract description 17
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 14
- 150000005215 alkyl ethers Chemical class 0.000 claims abstract description 13
- 239000012736 aqueous medium Substances 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 239000002609 medium Substances 0.000 claims abstract description 8
- 241001465754 Metazoa Species 0.000 claims abstract description 4
- 239000000872 buffer Substances 0.000 claims abstract description 4
- 230000000694 effects Effects 0.000 claims abstract description 4
- 239000003755 preservative agent Substances 0.000 claims abstract description 4
- 239000000654 additive Substances 0.000 claims abstract description 3
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 9
- 239000000126 substance Substances 0.000 abstract description 4
- 238000002156 mixing Methods 0.000 abstract description 3
- 230000010355 oscillation Effects 0.000 abstract description 3
- 230000001133 acceleration Effects 0.000 abstract 1
- 238000003756 stirring Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 26
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000011701 zinc Substances 0.000 description 8
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000004220 aggregation Methods 0.000 description 5
- 230000002776 aggregation Effects 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 230000002209 hydrophobic effect Effects 0.000 description 5
- 230000000087 stabilizing effect Effects 0.000 description 5
- 238000003860 storage Methods 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- 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 3
- 239000002253 acid Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000004925 denaturation Methods 0.000 description 3
- 230000036425 denaturation Effects 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 239000002736 nonionic surfactant Substances 0.000 description 3
- 229940119528 pork insulin Drugs 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 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 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 239000012460 protein solution Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 208000029152 Small face Diseases 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
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000005037 alkyl phenyl group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 150000008040 ionic compounds Chemical class 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 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
-
- 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)
- 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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK3198/81 | 1981-07-17 | ||
| DK319881 | 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)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4609546A (en) * | 1982-06-24 | 1986-09-02 | Japan Chemical Research Co., Ltd. | Long-acting composition |
| 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 |
| HU198626B (en) * | 1986-05-27 | 1989-11-28 | Sandoz Ag | Process for producing pharmaceutical compositions comprising somatostatin analogues as active ingredient |
| DE19726167B4 (de) | 1997-06-20 | 2008-01-24 | Sanofi-Aventis Deutschland Gmbh | Insulin, Verfahren zu seiner Herstellung und es enthaltende pharmazeutische Zubereitung |
| DE19733651A1 (de) * | 1997-08-04 | 1999-02-18 | Boehringer Ingelheim Pharma | Wässrige Aerosolzubereitungen enthaltend biologisch aktive Markomoleküle und Verfahren zur Erzeugung entsprechender Aerosole |
| 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 |
| 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 |
| HUE068164T2 (hu) | 2008-10-17 | 2024-12-28 | 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 |
| US10011906B2 (en) | 2009-03-31 | 2018-07-03 | Beohringer Ingelheim International Gmbh | Method for coating a surface of a component |
| US9265910B2 (en) | 2009-05-18 | 2016-02-23 | Boehringer Ingelheim International Gmbh | Adapter, inhalation device, and nebulizer |
| SG10201500871TA (en) | 2009-11-13 | 2015-04-29 | Sanofi Aventis Deutschland | Pharmaceutical composition comprising a glp-1 agonist and methionine |
| CA2780460C (fr) | 2009-11-13 | 2018-09-04 | Sanofi-Aventis Deutschland Gmbh | Composition pharmaceutique comprenant un agoniste de glp-1, une insuline et de la methionine |
| AP3141A (en) | 2009-11-25 | 2015-02-28 | Boehringer Ingelheim Int | Nebulizer |
| WO2011064163A1 (fr) | 2009-11-25 | 2011-06-03 | Boehringer Ingelheim International Gmbh | Nébuliseur |
| US10016568B2 (en) | 2009-11-25 | 2018-07-10 | Boehringer Ingelheim International Gmbh | Nebulizer |
| US9943654B2 (en) | 2010-06-24 | 2018-04-17 | Boehringer Ingelheim International Gmbh | Nebulizer |
| RS55378B1 (sr) | 2010-08-30 | 2017-03-31 | Sanofi Aventis Deutschland | Upotreba ave0010 za proizvodnju leka za tretman diabetes mellitus tipa 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 |
| BR112014004726A2 (pt) | 2011-08-29 | 2017-04-04 | Sanofi Aventis Deutschland | combinação farmacêutica para uso no controle glicêmico em pacientes de diabetes tipo 2 |
| TWI559929B (en) | 2011-09-01 | 2016-12-01 | Sanofi Aventis Deutschland | Pharmaceutical composition for use in the treatment of a neurodegenerative disease |
| WO2013152894A1 (fr) | 2012-04-13 | 2013-10-17 | Boehringer Ingelheim International Gmbh | Pulvérisateur comprenant des moyens de détrompage |
| ES2709339T3 (es) | 2013-04-03 | 2019-04-16 | Sanofi Sa | Tratamiento de la diabetes mellitus mediante formulaciones de insulinas de acción prolongada |
| 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 |
| CN106456913B (zh) | 2014-05-07 | 2019-08-30 | 勃林格殷格翰国际有限公司 | 喷雾器和容器 |
| EP3139984B1 (fr) | 2014-05-07 | 2021-04-28 | Boehringer Ingelheim International GmbH | Nébuliseur |
| DK3139979T3 (da) | 2014-05-07 | 2023-10-09 | Boehringer Ingelheim Int | Enhed, forstøver og fremgangsmåde |
| TWI758239B (zh) | 2014-12-12 | 2022-03-21 | 德商賽諾菲阿凡提斯德意志有限公司 | 甘精胰島素/利司那肽固定比率配製劑 |
| TWI748945B (zh) | 2015-03-13 | 2021-12-11 | 德商賽諾菲阿凡提斯德意志有限公司 | 第２型糖尿病病患治療 |
| TW201705975A (zh) | 2015-03-18 | 2017-02-16 | 賽諾菲阿凡提斯德意志有限公司 | 第２型糖尿病病患之治療 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| GB1554157A (en) * | 1975-06-13 | 1979-10-17 | Takeda Chemical Industries Ltd | Stable insulin preparation for intra nasal administration |
| 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 |
-
1982
- 1982-07-16 JP JP57502198A patent/JPS58501125A/ja active Pending
- 1982-07-16 EP EP82902164A patent/EP0083619A1/fr not_active Withdrawn
- 1982-07-16 AU AU87304/82A patent/AU558474B2/en not_active Ceased
- 1982-07-16 WO PCT/DK1982/000068 patent/WO1983000288A1/fr not_active Ceased
-
1983
- 1983-03-16 NO NO830933A patent/NO830933L/no unknown
Non-Patent Citations (1)
| Title |
|---|
| See references of WO8300288A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1983000288A1 (fr) | 1983-02-03 |
| AU558474B2 (en) | 1987-01-29 |
| NO830933L (no) | 1983-03-16 |
| JPS58501125A (ja) | 1983-07-14 |
| AU8730482A (en) | 1983-03-17 |
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