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Liposome combined with GLP-1 (Glucagon-Like Peptide-1) analogue and polyethylene glycol and preparation method of liposome

A GLP-1, polyethylene glycol technology, applied in liposome delivery, drug combination, medical preparations containing active ingredients, etc., can solve the problems of short biological half-life, short half-life of protein drugs, low bioavailability, etc. , to achieve good hypoglycemic activity, excellent plasma stability, and avoid side effects.

Inactive Publication Date: 2015-01-21
艾韦特(溧阳)医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

2) The instability of peptide and protein drugs in vivo and in vitro
3) Protein drugs have short half-life, high clearance rate, large molecular weight, easy to be destroyed by enzymes, bacteria and body fluids in the body, and low bioavailability of non-injection administration, generally only a few percent
However, natural GLP-1 has a short biological half-life and is quickly degraded by dipeptidyl peptidase IV (DPP-IV) in the body. metabolism
[0006] So far, in the fields of diabetes and obesity, liposome preparations have been applied to peptide drug GLP-1 analogs to prolong the plasma stability of GLP-1 analogs.

Method used

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  • Liposome combined with GLP-1 (Glucagon-Like Peptide-1) analogue and polyethylene glycol and preparation method of liposome

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] (1) Preparation of liposomes

[0030] To a liposome mixture (4.8 g) consisting of dipalmitoylphosphatidylcholine (DPPC) / cholesterol / mercaptohexanoyl dipalmitoylphosphatidylethanolamine (HS-DPPE) molar ratio of 18 / 10 / 0.5) Add 48mL of 0.3M citric acid buffer (pH4.0), after hydration, freeze and thaw three times with liquid nitrogen and a warm bath at 60°C to make multilayered liposomes. Further adjust the particle size by extrusion method 0.1 micron.

[0031] Liposome mixture ratio:

[0032] The molar ratio of dilauroylphosphatidylcholine (DLPC) / cholesterol / mercaptocaproyl dilauroylphosphatidylethanolamine (HS-DLPE) is 18 / 10 / 0.5;

[0033] The molar ratio of dimyristoylphosphatidylcholine (DMPC) / cholesterol / mercaptocaproyl dimyristoylphosphatidylethanolamine (HS-DMPE) is 18 / 10 / 0.5;

[0034] Distearoylphosphatidylcholine (DSPC) / cholesterol / mercaptocaproyl distearoylphosphatidylethanolamine (HS-DSPE) molar ratio is 18 / 10 / 0.5;

[0035] The molar ratio of dioleoylphosphati...

Embodiment 2

[0061] (1) Plasma stability test

[0062] The prepared compound was mixed with human plasma in triethanolamine-HCl (pH7.8, peptide final concentration 2-20nM) at 37°C

[0063] Incubate for 1-24 hours under conditions. Finally, 10% (V / V) trifluoroacetic acid / water was added to terminate the enzymatic reaction. The hydrolyzed product was analyzed and identified by C-18 reverse-phase HPLC, and the ultraviolet absorption was measured at 214nm.

[0064] (2) Oral glucose tolerance test

[0065] For GLP-1 derivatives combined with PEG liposomes, glucose was administered after 90 minutes of administration of the test compound: 10-week-old male Kunming mice were randomly divided into groups of 10. Water only and no food overnight. One group was injected with normal saline intraperitoneally according to the weight of the mice per kilogram, and the other groups were injected with 25 nmol of liposome solution per kilogram of the body weight of the mice; 90 minutes later, 18 mmol of gl...

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Abstract

The invention belongs to a liposome combined with a GLP-1 (Glucagon-Like Peptide-1) analogue and polyethylene glycol and a preparation method of the liposome. The liposome is prepared by combining a polyethylene glycol part on one part of sulfhydrylated liposome on the tail end of lipid through a disulfide bond and combining with the GLP-1 analogue through a disulfide bond. In the terms of 1 mol of sulfhydrylated lipid in the liposome, the combination quantity of PEG (Polyethylene Glycol) and the combination quantity of the GLP-1 analogue are respectively 15-50mol percent and 0.5-10mol percent. According to the liposome, the bioactivity of a GLP-1 polypeptide is kept, the stability of the GLP-1 analogue in blood is improved, and the half-life period of the GLP-1 analogue in vivo is prolonged.

Description

Technical field: [0001] The invention relates to a liposome, in particular to a liposome combined with GLP-1 analogs and / or polyethylene glycol, which has excellent plasma stability and therapeutic effect, and its preparation technology. Background technique: [0002] As a means of delivering a large amount of drug to a specific site, a method of encapsulating the drug in liposomes and binding antibodies to the surface of the liposomes has been proposed. Especially in the field of cancer treatment, there are many reports on the effectiveness of liposomes in which antitumor drugs are incorporated and bound to antibodies (Konno et al., Cancer Tes., 47, 4471, 1987, JP-A 58-134032 Furthermore, as a method for improving the problems existing in liposomes, that is, the leakage of encapsulated materials, the aggregation of liposomes, and the capture in reticuloendothelial organs, it has been proposed to bind polyethylene glycol to liposomes. Alcohol method (JP-P1-249717, JP-2-1495...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/127A61K47/34A61K47/42A61K38/16A61P3/04A61P3/10
Inventor 曹亮
Owner 艾韦特(溧阳)医药科技有限公司
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