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)
• 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)

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• 1982
  • 1982-07-16 WO PCT/DK1982/000068 patent/WO1983000288A1/en not_active Application Discontinuation
  • 1982-07-16 JP JP57502198A patent/JPS58501125A/ja active Pending
  • 1982-07-16 AU AU87304/82A patent/AU558474B2/en not_active Ceased
  • 1982-07-16 EP EP82902164A patent/EP0083619A1/de not_active Withdrawn
• 1983
  • 1983-03-16 NO NO830933A patent/NO830933L/no unknown

Non-Patent Citations (1)

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