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Oral dosing hypoglycemic polypeptide as well as preparation method and application thereof

A technology for lowering blood sugar and medicine, applied in the field of medicine and biology, can solve problems such as difficult absorption, and achieve the effect of improving anti-enzymatic hydrolysis ability and good application prospect.

Active Publication Date: 2014-03-26
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the oral administration of polypeptides like Exendin-4 is limited by their own physical and chemical properties, such as: easy to be hydrolyzed by digestive enzymes, difficult to be absorbed through the intestinal tract, etc.

Method used

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  • Oral dosing hypoglycemic polypeptide as well as preparation method and application thereof
  • Oral dosing hypoglycemic polypeptide as well as preparation method and application thereof
  • Oral dosing hypoglycemic polypeptide as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] TSME1-7 polypeptide oral hypoglycemic activity determination:

[0051] The oral hypoglycemic activity of TSME1-7 was evaluated by intraperitoneal glucose tolerance test (IPGTT):

[0052] Step 1: Prepare 1 mg / mL Exendin-4 solution and 1, 0.1, 0.01 mg / mL TSME1-7 solution with PBS solution. Then prepare a solution containing 25% PBS / Exendin-4 / TSME1-7, 25% propylene glycol and 50% NaHCO 3 solution (concentration of 3%) mixture.

[0053] Step 2: 138 male Balb / C mice were selected and randomly divided into 23 groups, 6 in each group. The groups and doses are as follows: blank control group (group 1) (PBS solution); positive control group (group 1) (Exendin-4 prototype molecule 500nmol / kg); TSME1-7 (group 3) in three doses (5nmol / kg). kg, 50nmol / kg, 500nmol / kg).

[0054] Step 3: Fasting the mice for 18 hours. Then blood was taken from the tail vein, and the blood glucose concentration was measured with a blood glucose meter as a 0-point blank blood sample.

[0055] The f...

Embodiment 2

[0058] TSME1 biological activity detection in vivo:

[0059] The hypoglycemic activity of TSME was evaluated by intraperitoneal glucose tolerance test (IPGTT):

[0060] Step 1: Select 30 male Balb / C mice and randomly divide them into 5 groups with 6 mice in each group. The groups and doses are as follows: blank control group (group 1) (PBS solution (20mmol / L)); positive control group (group 1) (Exendin-4 prototype molecule 9nmol / kg); TSME1 (group 3) three doses (3nmol / kg, 9nmol / kg, 27nmol / kg).

[0061] Step 2: Fasting the mice for 18 hours. Then blood was taken from the tail vein, and the blood glucose concentration was measured with a blood glucose meter as a 0-point blank blood sample.

[0062] The third step: intraperitoneal injection to mice in each group (see the first step for the dosage).

[0063] The fourth step: intraperitoneally inject glucose solution 30 minutes after the administration (the dosage is the same as that in Example 1). Then blood was taken from th...

Embodiment 3

[0065] Determination of TSME1 resistance to enzymatic hydrolysis:

[0066] Step 1: Prepare 2mmol / L trypsin solution with PBS solution with pH=6.5. Incubate at 37°C for 30 minutes before use. At the same time, a 200ug / mL solution of Exendin-4 and TSME1 was prepared.

[0067] Step 2: Mix 20uL of Exendin-4 and TSME1 solution with 20uL of enzyme solution, and then stop the reaction with 100uL of 1% TFA solution at predetermined time points (0, 5, 10, 15, 20). After centrifugation at 12000rpm for 5min, the supernatant was detected by RP-HPLC.

[0068] Step 3: Calculate the residual rate. The residual rate of 0 point is 100%. The ratio of the peak area of ​​each point to the peak area of ​​0 point is the residual rate of each point. see attached results image 3 .

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Abstract

Oral hypoglycemic polypeptide is an Exendin-4 analogue and is obtained by replacing twelfth, twentieth and twenty-seventh amino acids in an amino acid sequence of the Exendin-4 with non basic amino acids. Compared with an Exendin-4 archetype, the enzymatic hydrolysis resistance of the oral hypoglycemic polypeptide is remarkably improved, and the hypoglycemic polypeptide can be orally taken and has a good application prospect in treatment of type II diabetes mellitus.

Description

technical field [0001] The present invention relates to the preparation and application of orally administrable hypoglycemic polypeptide derivatives. Specifically, the structural transformation and modification of the active polypeptide with hypoglycemic effect is carried out so that it can be absorbed through the gastrointestinal tract and can be absorbed in the body. The characteristic of achieving an effective therapeutic concentration and using the polypeptide derivative for the treatment of diabetes belongs to the field of medical biotechnology. Background technique [0002] Diabetes is a common endocrine and metabolic disease that seriously endangers human health worldwide. In recent years, the global diabetes prevalence and mortality have shown a gradual upward trend. Diabetes mellitus is a metabolic disorder syndrome characterized by chronic hyperglycemia, which is related to genetic factors and various environmental factors. Diabetes can be divided into two main t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605A61K38/26A61P3/10
CPCA61K38/00C07K14/575
Inventor 姚文兵田浤申庆亮高向东
Owner CHINA PHARM UNIV
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