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glp-1 derivative particle complex and its preparation method and application

A granular compound, GLP-1 technology, applied in the direction of drug combination, pharmaceutical formula, medical preparations of non-active ingredients, etc., can solve the problems of limiting the breadth and depth of use, reduce the number of injections, avoid side effects, High safety effect

Active Publication Date: 2017-01-18
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Among the drugs already on the market, in order to increase the solubility and stability of the drug, it is often necessary to modify the structure of the drug or use drug excipients, such as Taxol, a paclitaxel injection developed by Bristol-Myers Squibb, in order to improve the water solubility of paclitaxel. CrEL [Huizing M, J ChromatogrB, 1998, 709(1): 161-5], a derivative of polyoxyethylene castor oil, was used, and CrEL was found to have a series of adverse reactions such as acute hypersensitivity, peripheral neurotoxicity, and cytotoxicity. reaction, which limits the breadth and depth of its use [Gao Peng. Pharmacy and Clinical Research, 2010,18(1):61-63]

Method used

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Embodiment 1

[0042] The preparation method of embodiment 1γ-PGA

[0043] (1) Preparation of γ-PGA

[0044] Strain activation: Take the frozen Bacillus licheniformis ATCC 9945a out of the -80°C refrigerator, and after thawing, insert it into the seed medium at 1% inoculum size, and culture it at 37°C and 210r / min for 11 hours. Seed medium (LB liquid medium): peptone 1%, NaCl 0.5%, yeast extract 0.5%.

[0045] Fermentation culture: Add the above seed liquid into the fermentation medium according to the inoculum amount of 5%, and cultivate at 37°C and 210r / min for 12h60-72h until the culture liquid becomes viscous. Fermentation medium: maltose 5%, sodium chloride 1%, yeast powder 1%, sodium glutamate 3%, potassium dihydrogen phosphate 0.5%, magnesium sulfate heptahydrate 0.05%.

[0046] Extraction and purification of γ-PGA: Adjust the pH value of the above fermentation culture liquid to 3.0, centrifuge at 10,000 r / min for 30 min to remove bacteria, obtain supernatant, and adjust the pH valu...

Embodiment 2

[0049] The preparation of embodiment 2γ-PGA-L-PAE

[0050] Weigh 0.1 g of γ-PGA obtained in Example 1 and dissolve it in 50 ml of pure water to prepare a 2% solution, add 2.97 g of EDC.I, shake in a shaker at 37°C and 210 rpm for 15 min, then weigh L- Add 0.96-1.69g of PAE into the reaction system, and continue to react in a shaker at 37°C and 210rpm for 24 hours. A white precipitate was produced in the solution, centrifuged, discarded the supernatant, washed again with ultrapure water, centrifuged and discarded the supernatant, repeated 3 times, and the obtained white precipitate was freeze-dried for 48-72 hours, and the obtained white solid was γ-PGA-L-PAE. For the obtained γ-PGA-L-PAE, carry out proton nuclear magnetic resonance spectrum detection, the solvent is deuterated DMSO, and the spectrum is as follows image 3 As shown, the results show that the characteristic peak of γ-PGA—chemical shift 4.0, and the characteristic peak of L-PAE—chemical shift 8.0 appear in the ...

Embodiment 3

[0051] Preparation and characterization of embodiment 3aGLP-1-NPs

[0052] Preparation method: Dissolve γ-PGA-L-PAE obtained in Example 2 in DMSO to form a 5-40 mg / ml solution. Take 500ul of γ-PGA-L-PAE, slowly add it dropwise to 500ul 0.25~3mg / ml aGLP-1 derivative solution to form a white milky system, centrifuge in a high-speed refrigerated centrifuge at 16000rpm, 4°C for 15min, discard the supernatant , add water again, wash and centrifuge, repeat 3 times, the white precipitate obtained is aGLP-1-NPs, ie aGLP-1-NPs. Wherein, the sequence of aGLP-1 is shown in SEQ ID No:1.

[0053] The aGLP-1-NPs were stained with 1% ammonium molybdate, and the microstructure of the aGLP-1-NPs was observed by transmission electron microscopy, showing a state of round particles with a scale of 100-150nm and uniform distribution, such as Figure 4 Shown; Detected its particle size with a nanometer particle size analyzer, the particle diameter is 140nm, and is a monodisperse system, such as ...

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Abstract

The invention relates to a GLP-1 derivative particle compound and a preparation method thereof, as well as an application thereof in preparation for medicines for treating diabetes and weight-reducing medicines. The compound is a composite system with a core-shell structure, which is formed by entrapping GLP-1 derivative aGLP-1 or mGLP-1 in particles formed by modified polymer gamma-PGA-L-PAE. The particles of the compound disclosed by the invention are capable of stably existing in a solution, and capable of resisting degradation of a PPIV enzyme on the GLP-1 derivative, thus prolonging the systemic circulation time; the particles of the compound have a controlled-release effect for prolonging the internal activity time thereof, so that long-acting blood sugar reduction can be realized, and a weight-reducing effect of controlling body weight growth is further achieved. The invention further discloses a composition for reducing blood sugar and / or reducing body weight. Raw materials involved in the preparation method disclosed by the invention are all free from biotoxicity, high in safety, low in cost, simple in preparation process, and high in entrapment efficiency; the obtained compound is uniform and controllable in particle diameter, good in stability, long in internal activity time, good in body weight control effect, suitable for industrialized mass production, and good in application prospect.

Description

technical field [0001] The invention belongs to the technical field of biopharmaceuticals, and relates to a GLP-1 derivative particle complex, a preparation method and application thereof, and a composition for reducing blood sugar and / or body weight. Background technique [0002] Diabetes is one of the most important chronic non-communicable diseases currently threatening global human health. Diabetic patients in my country have exceeded 100 million, becoming the country with the largest number of diabetic patients in the world. The research and development of new diabetes drugs has always been an important part of medical research and development in recent years, and Glucagon-like peptide 1, or Glucagon-like peptide 1, abbreviated as GLP-1, has become the focus of diabetes drug research and development. GLP-1 is a potent hypoglycemic hormone, and has a glucose-dependent function of stimulating insulin secretion and inhibiting glucagon secretion, reducing the risk of hypog...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K38/26A61K9/16A61K47/34A61P3/04A61P3/10
Inventor 潘盈盈黄静杨芳谭世明严文娟陈亚州吴自荣
Owner EAST CHINA NORMAL UNIV
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