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.

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• 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)

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Cited By (26)

Citations (8)

• 1983
  • 1983-03-02 ES ES520249A patent/ES8403723A1/es not_active Expired
  • 1983-03-02 EP EP19830900834 patent/EP0102976A1/en not_active Withdrawn
  • 1983-03-02 WO PCT/DK1983/000024 patent/WO1983003054A1/en not_active Ceased

Patent Citations (8)

Non-Patent Citations (2)

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