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Folic acid receptor targeted liposome medicine carrier, its preparation and application

A technology targeting liposomes and folic acid receptors, applied in liposome delivery, drug combination, pharmaceutical formulation, etc., can solve problems such as reduced leakage rate, drug leakage, liposome instability, etc.

Active Publication Date: 2005-06-01
ZHEJIANG JIANFENG HANSHENG BIOSCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For other drugs, such as vincristine, the drug exists in the liposome in a soluble state after remote uploading, and the acidic pH condition inside the liposome required by remote uploading aggravates the hydrolysis of the drug and lipid, resulting in liposome unstable
Therefore, the vincristine liposome preparation of current development can only be preserved in the form that blank liposome, drug solution, and buffer are separated, and the administration of the mode of instant preparation before the patient takes has caused great inconvenience to the treatment personnel and the patient. big inconvenience
[0008] Freeze-dried preparations are widely used in the pharmaceutical field to increase the stability of the preparation form, but the main difficulty of liposome freeze-dried preparations is the destruction of lipid bilayers in the process of dehydration and rehydration, resulting in drug leakage, usually seepage Leak rate can reach 40-50%
The cryoprotectants such as sucrose and lactose used in ordinary freeze-dried preparations can partially alleviate the damage to the lipid bilayer during dehydration and rehydration, but still cannot reduce the leakage rate to a pharmaceutically acceptable level

Method used

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  • Folic acid receptor targeted liposome medicine carrier, its preparation and application
  • Folic acid receptor targeted liposome medicine carrier, its preparation and application
  • Folic acid receptor targeted liposome medicine carrier, its preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Synthesis of mPEG-Chol:

[0083] Under stirring with a magnetic stirrer, 2.5 mmol of monomethyl polyethylene glycol dissolved in 10 ml of dichloromethane was added dropwise to a dichloromethane solution containing 2.5 mmol of cholesteryl chloroformate and 3.75 mmol of NaOH aqueous solution (33%) container. The reaction was carried out at room temperature under nitrogen protection and continuous stirring, and the reaction was terminated after 7 days. TLC (RP-18, plate, Merk, ethanol-dichloroethane, 88:12, v / v) and infrared spectroscopy (Perkin-Elmer 782, dissolved in dichloroethane) were used to track the whole reaction process Generation of M-PEG cholesterol derivatives. The sodium chloride in the mixture was removed by filtration, and the dichloroethane was removed by distillation under reduced pressure. The solid residue was resuspended in 3ml of ethyl acetate, and loaded onto the top of a 3*40cm silica gel column. Firstly, ethyl acetate was used to elute the unrea...

Embodiment 2

[0088] Synthesis of F-PEG-Chol:

[0089] A. Synthesis of NHS-F:

[0090] 500 mg of folic acid was dissolved in 10 ml of dimethylsulfoxide (DMSO) together with 1.1 mol excess of N-hydroxysuccinimide (NHS) and then 1.1 mol excess of dicyclohexylcarbodiimide was added. The reaction mixture was then stirred overnight at room temperature in the dark. The insoluble by-product dicyclohexylurea was removed by filtration with lanolin. Store 9.8 ml of the NHS-folate DMSO filtrate at -20°C for future use.

[0091] B. Synthesis of folic acid-polyethylene glycol-amine

[0092] Dissolve 500 mg diaminopolyethylene glycol in 2 ml DMSO. Add to 1.4ml of the previously synthesized folic acid-NHS. The reaction mixture was incubated overnight at room temperature in the dark.

[0093] DMSO and small molecule by-products were removed from the mixture with a Sephadex G-25 gel column equilibrated with deionized water. Diaminopolyethylene glycol containing a small amount of folic acid-polyethyle...

Embodiment 3

[0103] Preparation of Folate Receptor Targeting Liposomes Based on Cholesterol Anchor

[0104] Weighed 10.48 g and 2.75 g of analytically pure HSPC and Chol purchased from Sigma, 2.47 g of mPEG-Chol prepared in Example 1, and 0.31 g of F-PEG-Chol prepared in Example 2, and dissolved them in 1 liter of ethanol.

[0105] After filtering solution I with a 0.22 micron membrane, 1 liter of clear solution was obtained, called solution 1, which was transferred to container 1 (polyester container with a capacity of 5 liters), and heated to 40°C. 4.5 liters of 300 mM citrate buffer with a total concentration of 0.22 micron membrane filtration, called solution II, was transferred to container 2 (a polyester container with a volume of 10 liters). Vessel 2 was likewise heated to 40°C. Use two peristaltic pumps to transport solutions I and II to a microvolume mixer with a magnetic stirrer respectively, the flow rates are 0.4ml / min and 1.8ml / min respectively, and the magnetic stirrer speed...

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Abstract

The present invention discloses one kind of folic acid acceptor targeting liposome as medicine carrier and its preparation process and application. The liposome has components including synthetic phospholipid, cholesterol, folic acid acceptor targeting anchor point and polyglycol hydrating anchor point. The present invention has relatively simple preparation process, and can prepare liposome of size smaller than 200 nm in large scale and prepare freeze dried powder of weak alkali medicine, including leurocristine, etc. carried on the liposome with greatly raised use convenience and stability. The medicine is re-constructed with bacteria-free water or brine before use, and the medicine leakage rate is lower than 10 %.

Description

technical field [0001] The invention relates to a liposome carrier for loading medicine, in particular to a targeting liposome, in particular to a folic acid receptor targeting liposome formulation suitable for the pharmaceutical industry and a manufacturing method thereof. Background technique [0002] Liposome is a promising anticancer drug carrier. American ALZA company trade name is Doxil TM Doxorubicin hydrochloride liposomes, and Nexstar's trade name Daunoxome TM Daunorubicin citrate liposomes and other products have been used clinically. The advantage of liposome preparations is to avoid filtration from the glomerulus, so that the drug in it is gradually released into the blood circulation, thereby reducing the peak plasma drug concentration and reducing toxicity. [0003] Liposomes are phospholipid bilayer microcapsules, which can encapsulate therapeutic drugs in their hydrophilic core. Phospholipids synthesized by high phase transition temperature, such as diste...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K31/519A61K45/00A61K47/10A61K47/24A61P35/00
Inventor 罗伯特·李赵孝斌杨正茂
Owner ZHEJIANG JIANFENG HANSHENG BIOSCI
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