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Liraglutide multivesicular liposome and preparation method and application thereof

A polyvesicular liposome and liraglutide technology, which is applied in the field of medicine, can solve the problems of denaturation, inflammatory response, and activity decline of polypeptide and protein drugs, and achieve stable drug release rate, prolong circulation time, and high encapsulation. rate effect

Active Publication Date: 2019-10-18
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The long-acting dosage forms in the research stage are mainly microsphere preparations of synthetic polymers such as liraglutide and PLGA, PLA (CN102085355A, CN104382860A), however, polymer microsphere preparations generally have a burst release effect (Sheikh Hasan, A., et al., Reduction of the in vivo burst release of insulin-loaded microparticles. Journal of Drug Delivery Science and Technology, 2015.30, Part B: p.486-493.), and long-term residence in the body will produce an inflammatory response, leading to the body's immune response ( Anderson, J.M.andM.S.Shive, Biodegradation and biocompatibility of PLA and PLGAmicrospheres.Advanced Drug Delivery Reviews,2012.64,Supplement(0):p.72-82.), in addition, the acidic environment generated by polymer degradation will promote the degradation of polypeptide proteins Drug-like denaturation and decreased activity (Jiskoot, W., et al., Protein Instability and Immunogenicity: Roadblocks to Clinical Application of Injectable Protein Delivery Systems for Sustained Release. Journal of Pharmaceutical Sciences, 2012.101(3): p.946-954)

Method used

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  • Liraglutide multivesicular liposome and preparation method and application thereof
  • Liraglutide multivesicular liposome and preparation method and application thereof
  • Liraglutide multivesicular liposome and preparation method and application thereof

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Effect test

Embodiment 1

[0142]Precisely weigh 10.0mg of liraglutide and dissolve it in 2ml aqueous solution containing 0.8% human serum albumin and 7% sucrose to form an inner water phase; precisely weigh 201.1mg of soybean lecithin, 90.2mg of cholesterol, and 125.0mg of triolein , dissolved in 5ml ether to form an oil phase, add the above-mentioned internal water phase to the oil phase, and vortex for 3 minutes to form a W / O emulsion. Drop this emulsion into 7ml of 7% sucrose aqueous solution of 6mg / ml lysine, and keep stirring at 40°C for 5 minutes to form a W / O / W type double emulsion. Afterwards, it was moved to a rotary evaporator to remove residual organic solvents, and the liraglutide sustained-release multivesicular liposomes were obtained. The measured encapsulation efficiency was 87.5%, the drug loading was 2.3%, and the average particle size was 12.7 μm ( figure 1 ).

Embodiment 2

[0144] Accurately weigh 10.0mg of liraglutide and dissolve it in 2ml of 1% human serum albumin and 7% sucrose aqueous solution to form an inner water phase; accurately weigh 203.0mg of hydrogenated soybean lecithin, 96.6mg of cholesterol, triolein 121.0mg, dissolved in 5ml of chloroform to form an oil phase, add the above internal water phase to the oil phase, vortex to form a W / O emulsion. Drop this emulsion into 7ml of 7% sucrose aqueous solution containing 6mg / ml lysine, and continue to stir at 40°C for 10 minutes to form a W / O / W type double emulsion. , move it to rotary evaporator to remove residual organic solvent to obtain liraglutide sustained-release multivesicular liposomes, the measured encapsulation efficiency is 74.4%, the drug loading is 2.3%, and the average particle diameter is 22.0 μm ( figure 2 ).

Embodiment 3

[0146] Accurately weigh 10.0mg of liraglutide and dissolve it in 2ml of aqueous solution containing 0.9% human serum albumin and 7% sucrose to form an inner water phase; accurately weigh 196.8mg of dioleoylphosphatidylcholine, 99.4mg of cholesterol, three oil Glyceride 126.1 mg, dissolved in 6 ml of chloroform to form an oil phase, the above-mentioned internal water phase was added to the oil phase, vortexed for 5 min to form a W / O emulsion. Under stirring at 1000r / min, drop the emulsion into 20ml of 8% sucrose aqueous solution containing 5mg / ml lysine, stir continuously at 40°C for 10min to form a W / O / W type double emulsion, and blow in nitrogen to make the organic solvent naturally Volatilize, and when sedimentation occurs, move it to a rotary evaporator to remove residual organic solvents to obtain liraglutide sustained-release multivesicular liposomes. The measured encapsulation efficiency is 88.0%, and the drug loading is 2.4%. The particle size is 11.6 μm.

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Abstract

The invention relates to the field of medicines, and particularly relates to a liraglutide multivesicular liposome and a preparation method and an application thereof. The liraglutide multivesicular liposome provided by the invention comprises liraglutide, a membrane material, an osmotic pressure regulator and a stabilizer. The liraglutide multivesicular liposome prepared by the invention has goodstability, high drug encapsulation rate, large drug loading capacity, slow and steady drug release rate and no burst release phenomenon, significantly improves the bioavailability of the drug, thereby improving the curative effect, reduces dose-related side effects of the drug and medication cost and has a higher application value. Experiments shows that the liposome provided by the present invention can continuously release the drug in vitro for about 432 hours, and provide a stable blood concentration in vivo, significantly prolongs in-vivo retention time compared to other injections, showsobvious pharmacokinetic characteristics of a sustained release preparation, can provide a normal steady blood glucose level, plays hypoglycemic effect for 312 hours, and has the relative bioavailability of 661% to injections.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a liraglutide multivesicular liposome and its preparation method and application. Background technique [0002] Diabetes has become the third largest killer of human life and is a global epidemic disease. According to WHO estimates, by 2050, the number of diabetic patients in the world will reach 300 million. Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia caused by defects in insulin secretion and / or insulin action. The chronic hyperglycemia state of diabetes is significantly related to long-term complications, that is, the damage, dysfunction and failure of many organs, especially the kidneys, eyes, nerves, heart and blood vessels. In severe cases, it can cause water, electrolyte disorders and acid-base Acute complications such as balance disorders ketoacidosis and hyperosmolar coma. Therefore, the research and development of efficient and long-actin...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K38/26A61K47/24A61K47/28A61K47/14A61P3/10
CPCA61K9/127A61K9/1277A61K47/24A61K47/28A61K47/14A61K38/26
Inventor 杨丽丁蕾张莉雪
Owner SHENYANG PHARMA UNIVERSITY
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