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A kind of liraglutide multivesicular liposome and its preparation method and application

A technology of multivesicular liposomes and liraglutide, which is applied in the field of medicine, can solve problems such as inflammatory reactions, decreased activity, and denaturation of polypeptide and protein drugs, and achieve reduction of toxic and side effects, slow release and absorption, and blood drug concentration. stable effect

Active Publication Date: 2022-04-22
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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, PartB: p.486-493.), and long-term residence in the body will produce inflammatory reactions, leading to immune responses ( 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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  • A kind of liraglutide multivesicular liposome and its preparation method and application
  • A kind of liraglutide multivesicular liposome and its preparation method and application
  • A kind of liraglutide multivesicular liposome and its preparation method and application

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Experimental program
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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 medicine, in particular to a liraglutide multivesicular liposome and a preparation method thereof. The liraglutide multivesicular liposome provided by the present invention includes: liraglutide, a membrane material, an osmotic pressure regulator, and a stabilizer. The liraglutide multivesicular liposome prepared by the invention has good stability, high drug encapsulation rate, large drug loading capacity, slow and stable drug release rate, no burst release phenomenon, and significantly improved bioavailability of the drug. Therefore, the curative effect is improved, the dose-related toxic and side effects of the drug are reduced, the drug cost is reduced, and the method has great application value. Experiments show that the liposomes provided by the present invention can release drugs at a constant rate in vitro for nearly 432 hours, and can provide stable blood drug concentrations in vivo. Kinetic characteristics, can provide normal stable blood sugar level, hypoglycemic effect up to 312 hours, and relative bioavailability with injection is 661%.

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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Patent Type & Authority Patents(China)
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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