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A liquid formulation of long-acting insulin conjugate

A technology for long-acting insulin and liquid preparations, which can be used in medical preparations without active ingredients, medical preparations containing active ingredients, and drug combinations, etc. It can solve problems such as affecting protein stability and achieve the effect of increasing the duration of the body.

Active Publication Date: 2015-04-15
HANMI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] However, the use of preservatives can affect protein stability

Method used

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  • A liquid formulation of long-acting insulin conjugate
  • A liquid formulation of long-acting insulin conjugate
  • A liquid formulation of long-acting insulin conjugate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] Example 1: Identification of Factors Determining Stability of Long-Acting Insulin Conjugate Liquid Formulations

[0099] Long-acting insulin conjugates have been developed that have an increased half-life in blood without causing low blood sugar levels in the body. Insulin conjugates - in which the immunoglobulin Fc region, non-peptidyl polymer, and insulin are site-specifically bound by covalent bonding - have increased half-life in blood and can significantly reduce hypoglycemia levels danger.

[0100] To confirm the stability of the liquid formulation of the long-acting insulin conjugate, the formulation was prepared with the composition of Table 1 and stored at 40°C for 2 weeks, and its stability was analyzed by ion exchange chromatography (IE-HPLC).

[0101] At this time, the main factors that were compared to determine its effect on the stability of the conjugate were pH, type and concentration of buffer, type of isotonicity agent, concentration of sugar alcoho...

Embodiment 2

[0108] Example 2: Evaluation of long-acting insulin conjugate stability according to isotonicity agent and surfactant concentration

[0109] Based on the liquid formulation confirmed in Example 1 (10 mM sodium acetate at pH 6.0, 10 ㎎ / Sodium chloride, 10% (w / v) mannitol, 0.02% (w / v) polysorbate 20), depending on the concentration of isotonicity and surfactant, the stability of the long-acting insulin conjugates was tested. At this point, the concentrations of isotonicity agent and surfactant are set within the maximum acceptable range recommended by commercial formulations and licensing agencies.

[0110] Liquid formulations of long-acting insulin conjugates were prepared with the composition of Table 3 and stored at 40°C for 4 weeks. Then, stability was checked by IE-HPLC and size exclusion chromatography (SE-HPLC).

[0111] The IE-HPLC (%) and SE-HPLC (%) results in Table 4 represent "area % / initial area %" values, indicating the remaining purity of the long-acting insu...

Embodiment 3

[0118] Example 3: Stability evaluation of long-acting insulin conjugates according to sugar alcohol type

[0119] Examples of sugar alcohols that can be added to the formulation to enhance the storage stability of the long-acting insulin conjugate include monosaccharides such as mannose, glucose, fucose and xylose; and polysaccharides such as lactose, maltose, sucrose, raffinose , and dextran. Among them, the effect of sucrose on the stability of long-acting insulin conjugates was tested, since sucrose was confirmed to have the effect of reducing deamidation (J. of Pharmaceutical Sciences, Vol. 94, 2005). At this point, the sucrose concentration is within the maximum acceptable range recommended by commercial formulations and licensing agencies.

[0120] Liquid formulations of long-acting insulin conjugates were prepared with the composition of Table 5 and stored at 40°C for 4 weeks, and their stability was checked by stability testing using IE-HPLC and SE-HPLC. The IE-HPL...

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Abstract

The present invention relates to a liquid formulation of long-acting insulin conjugate, comprising a pharmaceutically effective amount of a long-acting insulin conjugate, wherein a physiologically active peptide, which is an insulin, is linked to an immunoglobulin Fc region; and an albumin-free stabilizer, wherein the stabilizer comprises a buffer, a sugar alcohol, a non-ionic surfactant, and an isotonic agent, and a method for preparing the formulation. For preventing microbial contamination in multiple uses, a preservative can be added to the formulation. The liquid formulation of the present invention does not comprise a human serum albumin and potentially hazardous factors to body, and thus it has excellent storage stability for insulin conjugate without a risk of viral infection.

Description

【Technical field】 [0001] The present invention relates to a liquid preparation of a long-acting insulin conjugate, comprising a pharmaceutically effective amount of the long-acting insulin conjugate, wherein insulin, as a physiologically active peptide, is linked to an immunoglobulin Fc region; and an albumin-free Stabilizers, wherein the stabilizers include buffers, sugar alcohols, nonionic surfactants, and isotonic agents, and methods of making the formulations. 【Background technique】 [0002] Insulin is a peptide consisting of 51 amino acids with a molecular weight of about 5,800 Da. Insulin is secreted by human pancreatic beta cells and plays a central role in controlling the body's blood sugar levels. If the amount of insulin secreted is lacking or the insulin secreted is not functioning properly in the body, blood sugar levels will rise, leading to a metabolic disease known as diabetes. When insulin is not secreted properly or does not function properly in the body, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/08A61K38/26A61K38/28A61K47/48
CPCA61K38/28A61K47/48369A61K47/68A61P43/00A61P5/50A61P3/10A61K47/50A61K9/08A61K38/26A61K47/10A61K47/12A61K47/26A61K47/02
Inventor 林亨奎金贤煜洪性熙金玟永裴城敏权世昌
Owner HANMI PHARMA
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