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Method for preparing nano micelle formulation of anthracene nucleus antineoplastic antibiotic

A nano-micelle, anti-tumor technology, applied in anti-tumor drugs, pharmaceutical formulations, medical preparations with inactive ingredients, etc. Targeting, improving the effect of drug distribution

Active Publication Date: 2008-12-17
SHANGHAI WHITTLONG PHARMA INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Micellar preparations prepared according to conventional thinking need to be changed into lipophilic and dissolved in organic solvents to be assembled into the hydrophobic core of micelles, while PEG derivatized phospholipids also need to be dissolved in organic solvents (polyethylene glycol derivatized phospholipids entrapped The nano-micelle preparation of anthracycline antitumor antibiotics, publication number CN1840193), the organic solvent introduced in the preparation makes the process complicated, and it is difficult to control in industrial production

Method used

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  • Method for preparing nano micelle formulation of anthracene nucleus antineoplastic antibiotic
  • Method for preparing nano micelle formulation of anthracene nucleus antineoplastic antibiotic
  • Method for preparing nano micelle formulation of anthracene nucleus antineoplastic antibiotic

Examples

Experimental program
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Effect test

Embodiment 1

[0052] Example 1: Encapsulation efficiency of ADM-PEG2000-DSPE (polyethylene glycol derivatized stearoylphosphatidylethanolamine entrapped adriamycin hydrochloride) micelles

[0053] See Table 1 for the prescription:

[0054] Table 1 Example 1: Encapsulation efficiency of ADM-PEG2000-DSPE micelles

[0055]

[0056] Preparation Process:

[0057] Original process: According to the ratio of traditional Chinese medicine in the above prescription, weigh ADM (doxorubicin hydrochloride) and dissolve it in methanol (2mg / ml), and weigh PEG2000-DSPE. (polyethylene glycol derivatized stearoylphosphatidylethanolamine) , dissolved in an appropriate amount of chloroform, placed in a 100ml eggplant-shaped bottle. Set up a rotary evaporator to remove the organic solvent and form a thin and uniform phospholipid film on the surface of the eggplant-shaped bottle. Add the phosphate buffer solution into an eggplant-shaped bottle, shake and hydrate at 30°C for 1 hour, protect with nitrogen, f...

Embodiment 2

[0059] Example 2: In vitro release test of ADM-PEG2000-DSPE micelles.

[0060] The release rate of ADM from PEG2000-DSPE micelles was determined by dissolution method and detected by HPLC.

[0061] Place the prepared ADM-PEG2000-DSPE micelles 1ml (1mg / ml) in the dialysis bag (molecular weight cut-off 1,2000-1,4000), place the fastened dialysis bag in the basket of the drug dissolution apparatus, The external fluid for dialysis was 150ml of PBS buffer, and three samples were prepared in parallel. Run at 37°C and 50 rpm for 24 hours. Samples were taken at 1h, 2h, 4h, 6h, 12h, and 24h. Fresh PBS 0.2ml. Samples taken at fixed points were entered into HPLC, and compared with the standard curve, the release percentage was obtained. see results figure 1 . Among them, when the ratio of lipid to drug is 1:1, the release rate in 24 hours is 29%; when the ratio of lipid to drug is 2:1, the release rate in 24 hours is 16%; there is no burst release phenomenon.

Embodiment 3

[0062] Example 3: In vitro cytotoxicity test of doxorubicin hydrochloride micellar preparation.

[0063] The antitumor effect of the nano-micelle preparation of anthracycline antitumor antibiotic prepared by the present invention is tested by in vitro cytotoxicity test and in vivo tumor growth inhibition test.

[0064] A549 cells (ATCC) according to 8.0*10 3 Inoculate each well into a 96-well plate, culture overnight, wash off the medium, and add 5ul of the following samples with different doxorubicin concentrations: free doxorubicin (C sample), new technology ADM-PEG2000-DSPE solution (A sample ), the new process ADM-PEG2000-DSPE freeze-dried reconstituted sample (B sample), each sample has three replicate holes. Add 100ul culture medium containing 10% fetal calf serum to each well, incubate at 37°C, 5% CO 2 Continue culturing for 48 h in the incubator. Take out the cells at each set time point, add 20ul of MTT (5mg / ml) to each well, and after culturing for another 4 hours...

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Abstract

The invention provides a method for preparing a nano micelle preparation of anthracycline antitumor antibiotics, including the following steps: (1) dissolving anthracycline antitumor antibiotics in water or medicinal buffer salt solution; (2) dissolving polyethylene glycol-phospholipid in water or medicinal buffer salt solution; (3) mixing the solution in step (1) and the solution in step (2) and hydrating the mixture at 25 DEG C to 60 DEG C to obtain the nano micelle of anthracycline antitumor antibiotics. Compared with the prior art, the method of the invention is simple and easy to operate, does not need complex large-scale instruments, and is suitable for industrial production, and the obtained nano micelle preparation does not contain nano organic solvent.

Description

technical field [0001] The invention relates to a preparation method of a nano-micelle preparation of intravenously injectable anthracycline antitumor antibiotics. Background technique [0002] Anthracycline anti-tumor antibiotics are a class of effective broad-spectrum anti-tumor drugs, which are widely used in clinical treatment of various cancers, such as leukemia, lymphoma, breast cancer, lung cancer, liver cancer and many other solid tumors. Such antineoplastic drugs mainly include: Doxorubicin (ADM), Daunorubicin (DNR), Epirubicin (Epirubicin, EPI), Pirarubicin (THP-ADM), Aclacinomycin (ACM). However, like other cytotoxic antineoplastic drugs, it lacks selectivity to tumor tissue and has severe dose-dependent acute toxicity, which is clinically manifested as nausea, vomiting, hair loss, and bone marrow suppression. What's more serious: repeated medication, drug accumulation in the heart tissue leads to serious irreversible heart damage. The toxic and side effects of...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K47/34A61K31/704A61P35/00A61K47/24
Inventor 张春玲杨真威韩晓芬唐宁梁伟
Owner SHANGHAI WHITTLONG PHARMA INST
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