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Pharmaceutical composition for the prevention or treatment of non-alcoholic fatty liver disease

A non-alcoholic, composition technology, used in the prevention or treatment of non-alcoholic fatty liver disease, the field of pharmaceutical compositions of long-acting insulin-releasing peptide conjugates, to prevent accumulation, prevention and treatment of non-alcoholic fatty liver disease Disease, effect of increasing blood half-life

Inactive Publication Date: 2014-11-19
HANMI SCI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although its blood half-life is longer than that of GLP-1, it also requires daily infusions

Method used

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  • Pharmaceutical composition for the prevention or treatment of non-alcoholic fatty liver disease
  • Pharmaceutical composition for the prevention or treatment of non-alcoholic fatty liver disease
  • Pharmaceutical composition for the prevention or treatment of non-alcoholic fatty liver disease

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0071] In a preferred embodiment, the invention provides a preparation method, which comprises the following steps:

[0072] (1) covalently linking a non-peptidyl polymer having an aldehyde reactive group at its two ends to a lysine residue of exendin-4;

[0073] (2) isolating a conjugate comprising exendin-4 from the reaction mixture of (1), wherein the non-peptidyl polymer is covalently linked to a lysine residue; and

[0074] (3) Covalently linking the immunoglobulin Fc region to the other end of the non-peptidyl polymer of the isolated conjugate, thereby producing a protein conjugate comprising immunoglobulins linked to the respective ends of the non-peptidyl polymer Protein Fc region and exendin-4. More preferably, the non-peptidyl polymer in (1) and the lysine residue of exendin-4 are linked at pH 9.0 or higher.

[0075] The insulinotropic peptide conjugate of the present invention activates major proteins of the insulin signaling pathway via the GLP-1 receptor, and th...

Embodiment 1

[0086] Example 1. Testing the In Vitro Activity of Exendin-4

[0087] Various exendin-4 derivatives used in this experiment were prepared in the same manner as in the present inventor's Korean Patent No. 10-1058315.

[0088]The method for measuring cell viability in vitro was used in order to measure the potency of a depot formulation of exendin-4. In the in vitro activity measurement, RIN-m5F called rat insulinoma cells was used. Because this cell has a GLP-1 receptor, it is often used in methods for measuring the in vitro activity of the GLP-1 family. RIN-m5F was treated with different concentrations of GLP-1, exendin-4 and test materials. EC50 values ​​were determined by measuring the generation of signaling molecule cAMP in cells induced by the test materials, and compared with each other. The results are summarized in Table 1.

[0089] Table 1

[0090] test material

Blood half-life (hr)

In vitro titer (%)

[0091] Exendin-4

0.7...

Embodiment 2

[0095] Example 2. Effect on Fatty Liver Formation in Hypertrophic Animal Model ob / ob Mice

[0096] Grouping of experimental animals

[0097] Female 5-week-old ob / ob mice (C57BL / 6JHamSlc-ob / ob, 24-34 g) were purchased from Slc, Japan. The ob / ob mouse is an animal model commonly used in efficacy testing of anti-obesity and anti-diabetic dosage forms. They had free access to solid feed for experimental animals sterilized by radiation (manufacturer: Picolab Rodent Diet, product name: 5053) and filtered, UV-irradiation-sterilized tap water in drinking water bottles. They were maintained in a GLP compliant crate system requiring a 12 hour dark-light cycle (lights on at 6:00 am and off at 6:00 pm) according to animal care standard guidelines. Thereafter, healthy ob / ob mice were selected and acclimated to laboratory conditions for 1 week. Then, drug administration was performed, and mice were divided into 4 groups and administered as follows.

[0098] Group 1 (negative control)...

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Abstract

The present invention relates to a pharmaceutical composition for the prevention and treatment of non-alcoholic fatty liver disease (NAFLD), including a conjugate prepared by covalently linking an insulinotropic peptide, a non-peptidyl polymer and an immunoglobulin Fc region. The composition of the present invention maintains the in-vivo activity of the peptide at a relatively high level, and remarkably increases the blood half-life, thereby preventing triglyceride accumulation which is a typical feature of non-alcoholic fatty liver disease. Ultimately, it can be desirably employed for the prevention and treatment of non-alcoholic fatty liver disease.

Description

technical field [0001] The present invention relates to a pharmaceutical composition comprising a long-acting insulinotropic peptide conjugate, which can be used for preventing or treating non-alcoholic fatty liver disease. In particular, the present invention relates to insulinotropic peptide conjugates, wherein insulinotropic peptide, non-peptidyl polymer and immunoglobulin Fc region are covalently linked to each other so as to significantly increase blood half-life, effectively prevent triglyceride accumulation, and to Its use in preventing or treating non-alcoholic fatty liver disease. Background technique [0002] Non-alcoholic fatty liver disease refers to a broad spectrum of diseases ranging from simple steatosis without an inflammatory response in patients without excessive alcohol intake to hepatic fibrosis and cirrhosis Cirrhosis results from the progression of pure steatosis and shows hepatocellular inflammation. [0003] Nonalcoholic fatty liver disease can be ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/17A61K38/16A61P1/16
CPCA61K47/48692A61K38/26A61K47/48215A61K47/60A61K47/6883A61P1/16A61P3/06A61P43/00A61P5/50A61P3/10A61K38/16A61K2039/505A61K38/17A61K38/28A61K39/3955C07K14/605C07K16/18C07K2317/41C07K2317/75C07K2317/94
Inventor 林世荣朴晟喜申玲爱崔仁荣权世昌
Owner HANMI SCI CO LTD
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