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Fotemustine solid lipid nanoparticle and preparation method thereof

A technology of solid lipid nanometer and formustine, which is applied in the field of pharmacy, can solve the problems of difficult industrial production of instruments and equipment, poor product stability, and limited continuous application, so as to improve the chemical stability and curative effect of the drug, with low cost, The effect of improving bioavailability

Inactive Publication Date: 2011-05-11
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to literature reports, although the drug has a good effect of passing through the blood-brain barrier and can effectively inhibit tumor growth, its more obvious gastrointestinal reactions and delayed bone marrow suppression limit its further continuous application.
[0003] Because formustine is insoluble in water, there are certain difficulties in the preparation of formulations
The currently marketed formustine is freeze-dried powder produced by Servier Pharmaceuticals in France. Due to the poor water solubility of the drug, organic solvents are needed to increase the solubility of formustine, which has special requirements for freeze-drying equipment, and The product has poor stability and can only be stored for 9 months at 2-8°C
In order to solve the above problems, the Chinese patent literature (patent number: ZL 200410024870.9) adopts the solvent crystallization method to prepare sterile powder for injection, so that the stability of the drug is improved; another patent literature (application number: 200710126506.7) has reported that formos for injection The preparation method of statin freeze-dried powder injection has problems such as special requirements for instruments and equipment and difficulties in industrial production in the above preparations. Therefore, it is necessary to find an effective preparation that can improve the stability, solubility and anti-tumor effect of the drug, reduce Toxic and side effects, enhance the clinical applicability of formustine

Method used

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  • Fotemustine solid lipid nanoparticle and preparation method thereof
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  • Fotemustine solid lipid nanoparticle and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0033] Take by weighing 208mg formustine, 1200mg stearic acid and 1000mg lecithin and dissolve in 20ml of methylene chloride, evaporate to dryness under reduced pressure at 40°C to form a lipid film, add 4ml of Tween-80 (2.5%) , ultrasonically dispersed for 30 minutes (ultrasonic power 600w), and the solid lipid nanoparticle suspension was obtained, which was stored at 2°C for later use. Its average particle size is 210nm, all particles are below 500nm, and the particle size distribution is narrow, showing that the size of solid lipid nanoparticles is relatively uniform; the solid lipid nanoparticle suspension can be stable for several days at room temperature and can Stable for 12 months, no precipitation was observed during storage.

Embodiment 2

[0035] Weigh 624mg of formustine, 6240mg of glyceryl monostearate and 3000mg of soybean lecithin into a 50ml conical flask with a stopper, add 10ml of ethanol: acetone (1:1) mixed solvent, ultrasonically dissolve it fully and heat to 60 °C, forming the organic phase. Another 500mg of Poloxamer-188 was dissolved in 30ml of double distilled water to form the water phase. Use a syringe to slowly inject the organic phase into the 60°C aqueous phase stirred at 1000r / min, and continue stirring until a translucent system is formed. The organic solvent was evaporated under reduced pressure at 40° C., the system was concentrated to 12 ml, and cooled to room temperature to obtain a solid lipid nanoparticle suspension.

Embodiment 3

[0037] Dissolve 0.624g of formustine, 12.48g of tripalmitin, 1.2g of stearyl alcohol, and 6.24g of dipalmitoylphosphatidylcholine in 20ml of ethanol, ultrasonically dissolve and heat to (50±2)°C to form an organic phase . Another 1g of myrj 53 was added into 40ml of double-distilled water, and ultrasonically dissolved to form an aqueous phase. Slowly inject the organic phase into the constant temperature water phase of (50±2)°C stirred at 1000r / min to form colostrum, and continue to stir for about 2-3 hours to completely evaporate the organic solvent and concentrate the system to about 2ml. Quickly mix the obtained translucent emulsion into another 10ml ice-water phase stirred at 1000r / min at 0-2°C, continue to stir for 2 hours, and then homogenize 5 times in a high-pressure homogenizer (homogeneous pressure is 15000psi) , to obtain solid lipid nanoparticle suspension.

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Abstract

The invention provides a fotemustine solid lipid nanoparticle for injection and oral administration. The nanoparticle is characterized in that a lipid material and an emulsifier are used to encapsulate the fotemustine to prepare the fotemustine solid lipid nanoparticle with small particle diameter, high encapsulation rate, good stability and low toxicity. The prepared fotemustine solid lipid nanoparticle improves the solubility and the stability of the fotemustine, reduces vascular stimulation of the fotemustine, and prolongs the circulating time of the medicament in blood, thereby improving the curative effect of medicaments, and ensuring that preparations made of the solid lipid nanoparticle have the characteristics of low toxicity, low fotemustine solid lipid nanoparticle with low stimulation and high efficiency. The invention also relates to a method for preparing the fotemustine solid lipid nanoparticle, which has simple preparation process and low cost, and is applicable to industrial production.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to solid lipid nanoparticles containing formustine, an antitumor active ingredient, and a preparation method thereof. Background technique [0002] Malignant glioma is a common brain tumor, and the main treatment methods are surgery and postoperative radiotherapy. Surgery itself is difficult to completely remove all tumors, and the survival period of malignant glioma treated with surgery alone is about 4 months. Combined treatment of radiotherapy and chemotherapy can prolong the survival time of patients with malignant glioma by about 9 to 12 months. Chemotherapy, as a supplement to surgery and radiotherapy for malignant glioma, may be the most important treatment method, especially for some recurrent or radiotherapy cases, and has gradually attracted the attention of clinical and research workers. Formustine is a nitrosourea antineoplastic drug developed by the French company ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/127A61K9/14A61K31/662A61K47/24A61P35/00
Inventor 李亚平陈伶俐顾王文
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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