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Mitoxantrone targeting sustained-release long-circulating nanometer liposome and preparation method

A long-circulating liposome, mitoxantrone technology, applied in the field of medicine, can solve the problems of easy fusion aggregation, poor physical and chemical stability, low gene transfection efficiency in storage and application, and achieve increased bioavailability and biological efficiency. Compatibility, adjustable sustained release time, and short preparation period

Active Publication Date: 2012-07-11
南通药享科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its extensive use often causes severe myelosuppression and cardiopulmonary systemic toxicity, which greatly limits its clinical application.
[0003] Liposomes are currently one of the common means of preparations to reduce drug toxicity, but conventional liposomes prepared from traditional lecithin and cholesterol are mostly swallowed by the reticuloendothelial system (RES) in the body and reside in the blood circulation. Stay for a short time
Moreover, its physical and chemical stability is poor, and it is prone to fusion and aggregation during storage and application, and the encapsulated drug is easy to leak; there are few functional groups, it is difficult to carry out surface modification, no targeting, and single function; the gene transfection efficiency is still significantly lower than that of viral vectors, etc.

Method used

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  • Mitoxantrone targeting sustained-release long-circulating nanometer liposome and preparation method
  • Mitoxantrone targeting sustained-release long-circulating nanometer liposome and preparation method
  • Mitoxantrone targeting sustained-release long-circulating nanometer liposome and preparation method

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preparation example Construction

[0031] d. Preparation of PEG-OQCMC: Dissolve the above-mentioned NHS-PEG in 100-150mL DMSO; dissolve the OQCMC prepared in the laboratory in 100-150mL water; -14,000 dialysis bags were dialyzed for one week, and finally filtered and freeze-dried to obtain the product.

[0032] In the preparation process of the FA-OQCMC, the contents of each component are: folic acid 3-10g; triethylamine 1.8-5ml; NHS 1.56-3g; NHS-FA 2.0-5.0g; OQCMC 15-30mg. The preparation process is as follows: dissolving folic acid in 60-100ml of DMSO solution, adding triethylamine to it, dissolving NHS with a certain amount of DMSO, adding it to the above reaction system and reacting in the dark for more than 12-20 hours. The product was filtered to obtain NHS-FA active lipid as a yellow solid. Dissolve NHS-FA active fat in 50-80ml DMSO, and add OQCMC. Adjust the pH of the reaction system to 10 with Na2HPO4 and NaOH buffer solution, and react for 1-1.5 h. The final product was dialyzed for 24 hours and fr...

Embodiment 1

[0034] The experimental process of PEG modified OQCMC:

[0035] a.Carboxylation of PEG: Dissolve 5.0g of PEG (2000Da) in 40mL of anhydrous toluene; then weigh 4.3g of maleic anhydride, add it to a four-necked flask under nitrogen protection, and heat it to 70°C for 48 , the process continued to stir. After the reaction, the organic solvent was distilled off under reduced pressure to obtain the preliminary product; diethyl ether was added for extraction, and then distilled under reduced pressure to obtain the product carboxylated PEG.

[0036]b.Activation of PEG: Weigh 0.75g of NHS and 0.3g of DCC for later use; weigh 2.8g of carboxylated PEG and NHS and dissolve in 40mL of chloroform, add DCC under the conditions of ice bath, magnetic stirring and nitrogen protection, React for 1 hour, then remove the ice bath, and react for 24 hours at room temperature; after the reaction, filter.

[0037] c. Purification of PEG: add the above filtered filtrate into 50 mL of acetone, place ...

Embodiment 2

[0042] The experimental process of PEG modified OQCMC:

[0043] a.Carboxylation of PEG: Dissolve 7.0g of PEG (2000Da) in 60mL of anhydrous toluene; weigh 7.2g of maleic anhydride, add it to a four-necked flask under nitrogen protection, and heat to 70°C for 50h , the process continued to stir. After the reaction, the organic solvent was distilled off under reduced pressure to obtain the preliminary product; diethyl ether was added for extraction, and then distilled under reduced pressure to obtain the product carboxylated PEG.

[0044] b. PEG activation: Weigh 0.8g of NHS and 0.4g of DCC for later use; weigh 3.5g of carboxylated PEG and NHS and dissolve them in 50mL of chloroform, add DCC under the conditions of ice bath, magnetic stirring and nitrogen protection, After reacting for 1.2h, remove the ice bath, and react at room temperature for 28h; after the reaction, filter.

[0045] c. Purification of PEG: add the filtered filtrate to 60 mL of acetone, place at 4°C for 2 ho...

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Abstract

The invention relates to a mitoxantrone targeting sustained-release long-circulating nanometer liposome and a preparation method. The particle diameter of the liposome is between 90nm and 120nm, the particle diameter is uniform, and the surface is rich in folic acid. The ratio of the compositions of the raw materials is as follows: the mass part ratio of PEG-modified O-quaternized carboxymethyl chitosan tofolic acid-modified O-quaternized carboxymethyl chitosan: O-quaternized carboxymethyl chitosan to mitoxantrone is 1:1-2:2-4:0.5-1; and the mass ratio of O-quaternized carboxymethyl chitosan to cholesterol is 4-2:1. The inverse emulsion polymerization or film dispersion method is used to prepare the liposome, and the whole preparation process is simple and quick, the preparation period isshort, the entrapment efficiency of the prepared polymer liposome for drugs is more than 90% and the drug loading rate is up to 9.0%; and through the modification of surface PEG, the polymer liposomeis not easy to be captured by the reticuloendothelial system of human body, the in vivo circulation time is prolonged, and simultaneously the bioavailability and biocompatibility of the polymer liposome are increased.

Description

technical field [0001] The invention relates to a mitoxantrone nano-targeted sustained-release long-circulation liposome and a preparation method thereof, belonging to the technical field of medicines. Background technique [0002] Mitoxantrone was first synthesized by Zee-Cheng in 1978 and by Murdock in 1979. It is a second-generation anthracycline antineoplastic drug and is mostly used clinically to treat leukemia, breast cancer, and malignant lymphoma. Its mechanism of action is to insert into the DNA of cells to inhibit the synthesis of nucleic acid in cancer cells to exert an anti-cancer effect, but it has a severe myelosuppressive effect, and most of the free drugs (more than 95%) bind to plasma proteins after entering the blood. However, its extensive use often causes severe myelosuppression and heart, liver and lung systemic toxicity, which greatly limits its clinical application. [0003] Liposomes are currently one of the common means of preparations to reduce dru...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/127A61K31/136A61K47/36A61P35/00A61P35/02
Inventor 常津苏文雅王汉杰康世胤胡秀凤
Owner 南通药享科技有限公司
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