Maleic acid pixantrone liposomal and preparing method thereof

A technology of picentan maleate and liposome, applied in the field of medicine, can solve the problems of inability to prepare samples, low encapsulation rate, drug leakage, etc., and achieves a solution with reduced toxicity, excellent anti-tumor effect, and reliable safety. Effect

Active Publication Date: 2016-05-25
北京博恩特药业有限公司
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  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the patent CN103479578A, the encapsulation efficiency of the liposomes prepared by the pH gradient method is high, but due to the introduction of new buffer salt particles, the risk of clinical drug use is increased; at the same time, the ammonium sulfate gradient method studied in this patent cannot be prepared to meet clinical needs. For samples, the encapsulation efficiency is lower than 10%
Another patent CN1382039A adopts the method of passive drug loading, directly adds picantron solution to the phospholipid membrane for hydration, and the encapsulation efficiency is only 85%, and the drug is easy to leak from the liposome, which has not reached the goal of reducing the toxic reaction of picantron injection. Purpose

Method used

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  • Maleic acid pixantrone liposomal and preparing method thereof
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  • Maleic acid pixantrone liposomal and preparing method thereof

Examples

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experiment example

[0030] The encapsulation efficiency of the pizent agar liposomes prepared by the different methods of Examples 1-9 of the present invention is shown in Table 1. In Example 5, the dialysis method was used to remove the ammonium sulfate solution in the outer water phase. Although the encapsulation rate reached 89.6%, it was not suitable for industrial production. In Examples 7 and 8, the pH value was adjusted with buffer, and the liposome encapsulation efficiency was only 4%. Embodiment 9 adopts the high pressure homogenizer-extruder to prepare the particle size of picanthane maleate liposome is 87.29nm, the particle size distribution is uniform, the distribution width is 40.15, the potential-9.06mV, the result sees figure 1 and figure 2 .

[0031] The encapsulation efficiency of the pizent agar liposome prepared in the embodiment of table 1

[0032]

Embodiment 1

[0034] (1) Film formation: Weigh DSPC300.2mg, CHO100.2mg, DSPE-PEG200099.8mg, dissolve in 10mL chloroform, heat to dissolve, evaporate under reduced pressure at 55°C on a rotary evaporator to remove chloroform to obtain lipids film;

[0035] (2) Hydration: add 26 mL of 0.2 mol / L ammonium sulfate solution to the lipid film, and hydrate at 55°C for 30 min to obtain a blank liposome first product;

[0036] (3) Granulation: ultrasonically disperse the blank liposomes on an ultrasonic disperser for 4 minutes, power 600-800w, filter 3 times with a 0.45-micron microporous membrane after granulation, and filter once with a 0.22-micron microporous membrane , to obtain 24 mL of blank liposomes;

[0037] (4) Making a transmembrane gradient inside and outside the liposome: using an ultrafiltration method, replace the ammonium sulfate solution in the outside water phase of the blank liposome with a 9% sucrose solution, and replace it 7 times to obtain 20 mL of the blank liposome;

[0038...

Embodiment 2

[0041] (1) Oil phase: Weigh DSPC450.6mg, CHO150.3mg, DSPE-PEG2000149.9mg, dissolve in 3.9mL absolute ethanol, heat to dissolve and keep at 55°C for 30min;

[0042] (2) Aqueous phase: prepare 39 mL of 0.2 mol / L ammonium sulfate aqueous solution, and keep it at 55°C for 30 min;

[0043] (3) Emulsification: inject the oil phase into the water phase at 55°C, and continuously stir with a magnetic stirrer until the absolute ethanol is completely volatilized to obtain 37 mL of blank liposomes;

[0044](4) Granulation: ultrasonically disperse the first blank liposomes on an ultrasonic disperser for 4 minutes, with a power of 600-800w, and filter 3 times with a 0.45-micron microporous membrane and a 0.22-micron microporous membrane after granulation. Filter once to obtain 35 mL of blank liposomes;

[0045] (5) Manufacture of liposome transmembrane gradient: adopt ultrafiltration method, replace the ammonium sulfate solution in the outer water phase of blank liposome with 9% sucrose so...

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Abstract

The invention discloses a maleic acid pixantrone liposomal and a preparing method thereof. Pixantrone common injection is prepared into the liposomal so that the toxic and side effects can be relieved, and the medicinal effect can be better performed. The problem that the encapsulation efficiency is low when liposomal is prepared through an ammonium sulfate gradient method is solved. The particle size of the hollow liposomal can be better controlled through a high pressure homogenizing-extruding machine, and particles are evenly distributed. It is verified for a long time that the method for preparing the liposomal through the ammonium sulfate gradient method is good in safety, the preparing technology is simple, the encapsulation efficiency of the liposomal is high, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to a picante maleate liposome and a preparation method thereof, belonging to the technical field of medicine. Background technique [0002] Pixantronedimaleate is a cytotoxic azathanedione, weak topoisomerase II inhibitor, approved by the European Union in 2012 for the treatment of adults with relapsed or refractory aggressive non-Hodgkin B-cell lymphoma. The trade name is Pixuvri. The parent nucleus of picantrone is mitoxantrone. Years of clinical application show that mitoxantrone has obvious toxic side effects, especially those related to bone marrow suppression and cardiotoxicity. It has measurable cardiotoxicity, less cytotoxicity and myelosuppression, and has obvious antitumor activity in different tumor models, especially in leukemia and lymphoma models, which is consistently superior to mitoxantrone and doxorubicin. The free form of picentane is unstable, so it is synthesized in the form of the dimaleate salt, which main...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K31/473A61P35/00
CPCA61K9/1271A61K31/473
Inventor 郭光明佟志远王海燕
Owner 北京博恩特药业有限公司
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