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Insulin compositions and method of making a composition

a technology of compositions and compositions, applied in the field of pharmaceutical compositions of acylated insulin, can solve the problems of delayed insulin injection action and inflammation of the tissue at the injection si

Inactive Publication Date: 2009-03-19
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0267]5. Pharmaceutical composition according to any of the preceding paragraphs, wherein at least 85% of the acylated insulin is present as complexes which are acylated insulin dodecamers or complexes with a higher molecular weight than acylated insulin dodecamer.
[0268]6. Pharmaceutical composition according to any of the preceding paragraphs, wherein at least 92% of the acylated insulin is present as complexes which are acylated insulin dodecamers or complexes with a higher molecular weight than acylated insulin dodecam...

Problems solved by technology

Certain drawbacks are associated with the use of insulin suspensions.
A drawback with these solutions is that the particle size distribution of the precipitate formed in the tissue on injection, and thus the release profile of the medication, depends on the blood flow at the injection site and other parameters in a somewhat unpredictable manner.
A further drawback is that the solid particles of the insulin may act as a local irritant causing inflammation of the tissue at the site of injection.
In this form, however, the action of injected insulin is delayed while the hexamers diffuse through the subcutis and dissociate into dimers and monomers.

Method used

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  • Insulin compositions and method of making a composition
  • Insulin compositions and method of making a composition
  • Insulin compositions and method of making a composition

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0701]A: Insulin aspart 600 μM, 3 Zn / 6 insulin, 1.6% glycerol, 16 mM phenol and 16 mM m-cresol, 7 mM trishydroxymethylaminomethan, 10 mM NaCl, pH 7.5 and volume of 8 mL:

31 mg insulin aspart was suspended in 2 ml water and 30 μL 1 N HCl added to obtain a solution. 240 μL 10 mM Zn(AcO)2 was then added followed by 3200 μL 4% glycerol, 400 μL 0.32 M phenol, 800 μL m-cresol, 560 μL 0.1 M trishydroxymethylaminomethan, 160 μL 0.5 M NaCl and pH was then adjusted to 7.5 by 1N NaOH and finally the volume to adjusted to 8 mL by water. The solution was filtered through a 0.22 μm sterile filter.

B: LysB29Nε-hexadecandioyl-γ-Glu desB30 human insulin 1200 μM, 3 Zn / 6ins, 1.6% glycerol, 16 mM phenol and 16 mM m-cresol, 7 mM trishydroxymethylaminomethan, 10 mM NaCl, pH 7.5 and volume of 7 mL:

58 mg LysB29Nε-hexadecandioyl-γ-Glu desB30 human insulin was suspended and dissolved in 2 mL water and subsequent added 420 μL 10 mM Zn(AcO)2, 2800 μL 4% glycerol, 350 μL 0.32 M phenol, 700 μL m-cresol, 490 μL 0.1...

example 2

2A: 3 Zn / 6 Acylated Insulin Added Before Phenol and m-cresol

[0709]LysB29Nε-hexadecandioyl-γ-Glu desB30 human insulin 600 μM, 3 Zn / 6insulin, 1.6% glycerol, 16 mM phenol and 16 mM m-cresol, 20 mM NaCl, 7 mM phosphate, pH 7.5, 1.5 μCi 125I-TyrA14-LysB29Nε-hexadecandioyl-γ-Glu desB30 human insulin tracer, and volume of 2 mL.

[0710]8.2 mg LysB29Nε-hexadecandioyl-γ-Glu desB30 human insulin was dissolved in 400 μL water and 3 μCi 125I-TyrA14-LysB29Nε-hexadecandioyl-γ-Glu desB30 human insulin tracer was added, followed by 800 μL 4% glycerol and treated for 10-15 min in a vacuum centrifuge to remove added ethanol included in the tracer solution. 60 μL 10 mM Zn(AcO)2 was added and with 2 minutes interval followed by 100 μL 0.32 M phenol, 200 μL 0.16 M m-cresol, 80 μL 0.5 M NaCl, and 140 μL 0.1 M sodium phosphate and pH adjusted to pH 7.5 mM and a total volume of 2 mL. The solution was filtered through a sterile 0.22 μm filter and used for a disappearance study after subcutaneous injection in p...

example 3

Isolation of LysB29Nε-hexadecandioyl-γ-Glu desB30 Human Insulin by Crystallisation

[0717]LysB29Nε-hexadecandioyl-γ-Glu desB30 human insulin can be crystallized as a hexamer with a zinc content of 2-6 mol zinc per 6 mol insulin and an excess of a phenol-like molecule (preferred phenol). As precipitants, ionic salts are used with NaCl being preferred. Furthermore crystallisation can be enhanced by adding small amounts of organic solvents (ethanol).

Preparation of a Protein Solution (Solution A):

[0718]40.5 mg freeze-dried LysB29Nε-hexadecandioyl-γ-Glu desB30 human insulin is suspended in 4 ml 0.02 mol / l trishydroxymethylaminomethan buffer (adjusted to pH 7.0 with HCl).

[0719]To 1.8 ml of this LysB29Nε-hexadecandioyl-γ-Glu desB30 human insulin solution is added 69.5 μl of a solution containing 0.010 mol / l Zn(OAc)2 in water, and 18 μl of a solution containing 2 mol / l Phenol in ethanol.

Preparation of the Precipitant Solution (Solution B):

[0720]To a 5 ml of a solution containing 0.1M trishydr...

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Abstract

The invention is related to insulin compositions with a high content of zinc atoms per six molecules of acylated insulin. The insulin is an acylated insulin and may be mixed with a further insulin analogue such as the rapid acting insulin Asp B28 human insulin.

Description

FIELD OF THE INVENTION[0001]The present invention relates to pharmaceutical compositions of acylated insulin with a prolonged action profile and high zinc content. Further the invention relates to a method for producing a composition with a prolonged action profile and high zinc content and a method for manufacturing a composition for the treatment of diabetes.BACKGROUND OF THE INVENTION[0002]Currently, the treatment of diabetes, both type 1 diabetes and type 2 diabetes, relies to an increasing extent on the so-called intensive insulin treatment. According to this regimen, the patients are treated with multiple daily insulin injections comprising one or two daily injections of a long acting insulin to cover the basal insulin requirement supplemented by bolus injections of a rapid acting insulin to cover the insulin requirement related to meals.[0003]Long acting insulin compositions are well known in the art. Thus, one main type of long acting insulin compositions comprises injectabl...

Claims

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Application Information

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IPC IPC(8): A61K33/30A61P3/10
CPCA61K38/28A61K47/48015C07K14/62A61K47/52A61P3/10
Inventor HAVELUND, SVENDHUBALEK, FRANTISEKOLSEN, HELLE BIRKJONASSEN, IBHOEG-JENSEN, THOMASPLUM, ANNERIBEL-MADSEN, ULLA
Owner NOVO NORDISK AS
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