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Composition for treating diabetes comprising long-acting insulin conjugate and long-acting insulinotropic peptide conjugate

a technology of insulinotropic peptides and conjugates, which is applied in the direction of peptide/protein ingredients, drug compositions, metabolic disorders, etc., can solve the problems of increasing the risk of cardiovascular disease and insulin resistance, aversion to needles, and difficulty in handling injection devices, so as to improve the duration of in-vivo efficacy and stability, improve the effect of diabetes treatment, and stabilize the blood glucose control

Inactive Publication Date: 2019-03-21
HANMI SCI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0013]The long-acting insulin conjugate and the long-acting exendin-4 conjugate of the present invention show excellent therapeutic effects on diabetes, and in particular, the concurrent administration thereof stimulates an insulin receptor and a glucagon like peptide-1 receptor at the same time to improve in-vivo duration of the efficacy and stability thereof, and to remarkably reduce the required doses of the drugs and stably control the blood glucose at a stable level, leading to improvements in hypoglycemia and weight gain. In addition, it inhibits nausea and vomiting and has improved drug compliance as a therapeutic agent for diabetes. In particular, it has remarkably improved stability and in-vivo duration of efficacy allowing a reduction in treatment frequency, which contributes to patient convenience.

Problems solved by technology

However, long-term use of insulin three times a day can lead to disadvantages such as aversion to needles, difficulty in handling the injection device, hypoglycemia, and weight gain.
Weight gain due to long-term use of insulin may increase the risk of cardiovascular disease and insulin resistance.
However, these drug formulations are also disadvantageous in that they must be given once or twice a day.
However, the primary obstacle to the use of GLP-1 as a therapeutic agent is its extremely short half-life of less than 2 minutes in plasma.
However, with the method for increasing the resistance to DPP IV only, the physiological activity is not sufficiently sustained, and for example, in the case of commercially available exendin-4 (exenatide), it needs to be injected to a patient twice a day, and exenatide-treated patients still experience adverse events such as nausea and vomiting.
However, there are still the problems of weight gain, or nausea and vomiting, when insulin or exendin-4 is injected in an amount which maintains a stable blood glucose level.

Method used

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  • Composition for treating diabetes comprising long-acting insulin conjugate and long-acting insulinotropic peptide conjugate
  • Composition for treating diabetes comprising long-acting insulin conjugate and long-acting insulinotropic peptide conjugate
  • Composition for treating diabetes comprising long-acting insulin conjugate and long-acting insulinotropic peptide conjugate

Examples

Experimental program
Comparison scheme
Effect test

example 1

on of Long-Acting Insulin Conjugate

[0091]For PEGylation of the N-terminus of immunoglobulin Fc region with 5K PropionALD(3) PEG (PEG with three propylaldehyde groups, NOF, Japan), the immunoglobulin Fc region and PEG were reacted at a molar ratio of 1:2 with the immunoglobulin Fc concentration of 10 mg / mL at 4° C. for 4.5 h. At this time, the reaction was conducted in a 100 mM potassium phosphate (pH 6.0), and a reducing agent, 20 mM SCB (NaCNBH3) was added thereto. The mono-PEGylated immunoglobulin Fc was purified from the reaction mixture using a SOURCE 15Q (GE Healthcare) purification column.

[0092]In order to prepare an insulin-PEG-immunoglobulin Fc conjugate having 90% or more modification of phenylalanine (B1F) at position 1 of the beta chain of insulin, the mono-PEGylated immunoglobulin Fc and insulin were prepared at a molar ratio of 4:1 and at the total protein concentration of 20 mg / mL, and reacted with each other at 4° C. for 20 h. 100 mM potassium phosphate (pH 6.0) was u...

example 2

on of Long-Acting Exendin-4 Conjugate

[0093]3.4 k PropionALD (2) PEG was reacted with the lysine (Lys) of CAexendin-4 using imidazo-acetyl exendin-4 (CAexendin-4, AP, USA). Among the two Lys isomer peaks, the last isomer peak (positional isomer of Lys27), which has more reaction and which is easily distinguishable from the N-terminal isomer peaks, was used for the coupling reaction.

[0094]The reaction was performed at a molar ratio of peptide:immunoglobulin Fc of 1:8, and a total concentration of proteins of 60 mg / mL at 4° C. for 20 h. The reaction was performed in a solution of 100 mM K-P (pH 6.0), and 20 mM SCB was added as a reducing agent. The coupling reaction solution was purified through two purification columns. First, SOURCE Q (XK 16 mL, Amersham Biosciences) was used to remove a large amount of immunoglobulin Fc which had not participated in the coupling reaction. Using 20 mM Tris (pH 7.5) and 1 M NaCl with salt gradients, the immunoglobulin Fc having relatively weak binding...

example 3

Test on Concurrent Administration of Long-Acting Insulin Conjugate and Long-Acting Exendin-4 Conjugate in STZ (Streptozotocin)-Induced Diabetes

[0101]In order to perform in vivo efficacy test on administration of the compositions including the long-acting insulin conjugate and the long-acting exendin-4 conjugate prepared in Examples 1 and 2 or concurrent administration of the long-acting insulin conjugate and the long-acting exendin-4 conjugate, changes in the blood glucose levels were examined using STZ (Streptozotocin)-induced diabetic mice.

[0102]Diabetes was induced in 7-week old C57BL / 6 mice fasted for 16 h by intraperitoneal injection of STZ (50 mg / kg, 1 mg / mL) in 10 mM citrate buffer (pH 4.5) for 5 consecutive days. After 2 days, 1-2 drops of blood was taken from the tail vein using a 26 G syringe, and the blood glucose was measured using a glucometer (OneTouch Ultra, LifeScan, Inc., USA). Diabetes induction was determined by the measured blood glucose (350-600 mg / dL).

[0103]Dia...

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Abstract

The present invention relates to a composition for the prevention or treatment of diabetes comprising a long-acting insulin conjugate and a long-acting insulinotropic peptide conjugate, and a therapeutic method for the treatment of diabetes, and more particularly, concurrent administration of the long-acting insulin conjugate and the long-acting insulinotropic peptide conjugate inhibits weight gain caused by insulin treatment, and vomiting and nausea caused by insulinotropic peptide treatment, and reduces the required dose of insulin, thereby remarkably improving drug compliance. Moreover, each of the long-acting insulin conjugate and the long-acting insulinotropic peptide conjugate of the present invention is prepared by linking insulin or insulinotropic peptide with an immunoglobulin Fc region via a non-peptidyl linker, thereby showing improved in-vivo duration of efficacy and stability.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a Rule 53 (b) Divisional of U.S. application Ser. No. 14 / 123,355 filed Dec. 2, 2013, which is a National Stage of International Application Non. PCT / KR2012 / 004367 filed Jun. 1, 2012, claiming priority based on Korean Patent Application No. 10-2011-0053488 filed Jun. 2, 2011, the contents of all of which are incorporated herein by reference in their entirety.TECHNICAL FIELD[0002]The present invention relates to a composition for the prevention or treatment of diabetes comprising a long-acting insulin conjugate and a long-acting insulinotropic peptide conjugate, and a method for treating diabetes comprising the step of administering the composition.BACKGROUND ART[0003]Insulin is a peptide secreted by the beta cells of the pancreas, and plays an important role in controlling the blood glucose level in the body. A metabolic disease, diabetes is associated with elevated blood glucose levels caused by an abnormality in the s...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/26A61K47/68A61K38/28
CPCA61K38/26A61K47/6883A61K38/28A61K47/68A61K47/6811A61P3/00A61P43/00A61P3/10A61K47/30
Inventor WOO, YOUNG EUNJANG, MYUNG HYUNPARK, YOUNG JINPARK, YOUNG KYUNGLIM, CHANG KIKWON, SE CHANG
Owner HANMI SCI CO LTD
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