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Mineralized exenatide release system and preparation method and application thereof

A technology of exenatide and system, which is applied in the field of novel exenatide sustained-release preparations, can solve the problems of immune rejection in the body, easy to induce matrix immune response, and influence on the biological activity of exenatide.

Active Publication Date: 2017-12-01
SHANGHAI THERANOSTICS BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Facts have proved that the first way is easy to affect the biological activity of exenatide, for example, the use of polyethylene glycol to modify exenatide will reduce its ability to stimulate cells to produce cAMP
In addition, the introduction of polymer materials can easily trigger the body's immune rejection
Proteins in blood and interstitial fluid are easily adsorbed on the surface of the polymer. With the participation of immune and inflammatory cells, the surface of the polymer is prone to fibrosis, which hinders its long-term effect on the biological system
[0007] In order to overcome the disadvantages of existing exenatide preparations that easily affect its biological activity and easily induce matrix immune responses, and provide long-acting drug therapy, it is necessary to develop a new exenatide sustained-release system

Method used

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  • Mineralized exenatide release system and preparation method and application thereof
  • Mineralized exenatide release system and preparation method and application thereof
  • Mineralized exenatide release system and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1: Preparation of Mineralized Exenatide

[0036] Weigh 2 mg of exenatide and dissolve it in 1 ml of DMEM cell culture medium, and place the solution at 37 degrees Celsius for 24 hours. Weigh 110 mg of calcium chloride solid and dissolve it in 1 ml of ultrapure water to obtain a 1 mol / L calcium chloride solution. Add 10 microliters of calcium chloride solution to 1 milliliter of exenatide DMEM solution, and react at 37 degrees Celsius in a 5% carbon dioxide environment for 24 hours. The obtained solution was centrifuged by ultrafiltration, the molecular weight cut-off was 100k, the centrifugation speed was 6000 rpm, and the centrifugation time was 20 minutes. Obtained mineralized exenatide utilizes the transmission electron microscope to observe the morphology, and it can be known that the mineralized exenatide is a nanoparticle system composed of exenatide at the center and its surrounding biomimetic mineral calcium phosphate (such as figure 1 shown), using a ...

Embodiment 2

[0037] Example 2: In Vitro Release of Exenatide

[0038] The mineralized exenatide particles prepared in Example 1 were dispersed in 1 ml of DMEM solutions containing different calcium ion concentrations (0.9, 2.5 or 5 mmol / L). At the time points of 0, 0.5, 1, 2, 24, 48, 72, 96, 120, 144, 168, and 192 hours, the reaction system was centrifuged by ultrafiltration (100k molecular weight cut-off, 6000 rpm, 20 minutes), The remaining solid was separated from the supernatant. The drug concentration in the supernatant was determined using a commercial exenatide ELISA kit. Finally, the residual particles were reacted in the pH 5 solution environment for 24 hours to dissolve the particles completely, measure the maximum release amount, set it as 100%, and calculate the relative release amount at each time point (such as image 3 shown). The structure of the released exenatide was determined by circular dichroism chromatography and compared with exenatide without any treatment (eg F...

Embodiment 3

[0039] Example 3: In vivo release of exenatide

[0040] Cysteine ​​was connected to position 39 of exenatide to form a new reactive site (side chain of -SH group), which was labeled with near-infrared fluorescent dye IRdye 800CW. The specific operation is as follows: first, N-hydroxysuccinimide-modified IRdye 800CW (25 microliters, 10 mmol / liter) was added to 500 microliters of dimethyl sulfoxide, and then 20 microliters of N-( 2-Aminoethyl) maleimide trifluoroacetate (3 mg / ml dimethyl sulfoxide solution), stirred for 4 hours. Then, 1 mg of exenatide with one cysteine ​​inserted at the C-terminus was added to the above reaction system and reacted overnight (about 12 hours). The resulting product was separated using high performance liquid chromatography, and its structure was characterized using Funky. Thereafter, the near-infrared fluorescent dye-labeled exenatide and its mineralized particles were injected subcutaneously, and the fluorescent signal at the injection point w...

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Abstract

The invention provides a mineralized exenatide release system. The mineralized exenatide release system is composed of, by weight, 15-20% of exenatide in the center position, 75-78% of bionic mineral calcium phosphate around the exenatide and the balance crystal water. The mineralized enexatide release system can efficiently maintain the biological activity of the exenatide, and meanwhile can evade the immune reaction in the body. The invention further provides a preparation method of the mineralized exenatide release system and an application of the mineralized exenatide release system in preparation of drugs for treating II type diabetes.

Description

technical field [0001] The invention relates to the fields of biomedical technology and drug controlled release technology, in particular to a novel exenatide sustained-release preparation, its preparation method and application. Background technique [0002] According to the International Diabetes Federation, as of 2015, there were approximately 415 million diabetics worldwide. also. It is estimated that by 2040, the number of patients will reach 642 million, of which type 2 diabetes patients account for about 90% of the total number of patients, which mainly show the characteristics of decreased insulin sensitivity (insulin resistance) and attenuation of insulin secretion function of pancreatic beta cells. It is worth noting that human glucagon-like peptide-1 (GLP-1) can be used as an effective drug for the treatment of type 2 diabetes, which can stimulate the regeneration of β cells, promote insulin secretion, and inhibit pancreatic hypertrophy. Glucagon secretion, slow...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/22A61K47/02A61P3/10
CPCA61K9/0002A61K38/22A61K47/02
Inventor 陈小元陈伟
Owner SHANGHAI THERANOSTICS BIOTECH CO LTD
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