Irinotecan-cholesterol succinic acid simple lipid ion pair, liposome and preparation method and application thereof

A technology of cholesterol succinic acid monoester and succinic acid monoester, which is applied in the field of irinotecan-cholesterol succinic acid monoester ion pair and liposome and preparation, which can solve problems such as instability, low encapsulation efficiency, and complicated preparation process

Active Publication Date: 2018-09-28
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] Therefore, it can be understood that although irinotecan liposomes have great development prospects, there are still two problems: the first, irinotecan itself has poor water solubility, is unstable, and often exists in the form of hydrochloride trihydrate Although irinotecan hydrochloride has good water solubility, it needs to actively load drug by ion gradient method when preparing irinotecan liposome; the preparation process is relatively complicated, wh

Method used

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  • Irinotecan-cholesterol succinic acid simple lipid ion pair, liposome and preparation method and application thereof
  • Irinotecan-cholesterol succinic acid simple lipid ion pair, liposome and preparation method and application thereof
  • Irinotecan-cholesterol succinic acid simple lipid ion pair, liposome and preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0046] Preparation of ion pair of irinotecan-cholesterol succinate monoester

[0047] Weigh irinotecan hydrochloride, add appropriate amount of ultrapure water, stir to form a slurry, add 1mol / L NaHCO drop by drop 3 Solution, wherein, the irinotecan hydrochloride and NaHCO that take by weighing are equimolar ratio; Continue to stir until reaction is complete. Centrifuge, discard the supernatant, wash the precipitate with ultrapure water 2 to 3 times, and collect the precipitate. Vacuum dry at 40°C for 2h. The finally obtained off-white powder is irinotecan free base, which is stored in a vial and kept in a refrigerator at 4°C in the dark for future use. Add an appropriate amount of chloroform solution to dissolve irinotecan free base and cholesterol succinate monoester in an equimolar ratio, stir in an ice bath for 1.5 hours, add the anti-solvent methyl tert-butyl ether drop by drop, the solution becomes cloudy and stops, and place it in a fume hood The solvent was evaporat...

Embodiment 2

[0049] Hydrogen-NMR Spectroscopy Research

[0050] Weigh about 5 mg of samples of irinotecan hydrochloride, irinotecan base, cholesterol succinate monoester and irinotecan-cholesterol succinate monoester ion pair, add an appropriate amount of DMSO-d6 to dissolve, and ultrasonicate for 5 minutes until the solution is completely clear , transferred to an NMR sample tube, sealed, and allowed to stand at 20°C for a period of time. Bruker Advance-400MHz equipment was used for detection, and TMS was used as an internal standard substance for chemical shift (δ) determination. Measurement results such as figure 2 As shown, the occurrence of hydrogen proton transfer will be observed more intuitively. In the NMR spectrum of irinotecan base, there is no active hydrogen in the low field region. In the downfield region of cholesterol succinate monoester and irinotecan-cholesterol succinate monoester ion pair, there are obvious active hydrogen peaks. The hydroxyl hydrogen of cholestero...

Embodiment 3

[0052] Determination of Solubility and Apparent Oil-Water Partition Coefficient

[0053] According to Chinese Pharmacopoeia (2010 edition) two appendix solubility determination method, take excessive irinotecan hydrochloride crude drug powder, irinotecan free base powder, irinotecan-cholesterol succinic acid monoglyceride ion pair powder is placed in water for injection respectively , and then placed in a constant temperature oscillator at 37°C, shaken at 100rpm for 72h, after standing at room temperature for a period of time, centrifuge to take the supernatant, filter it with a 0.22μm microporous membrane, take the subsequent filtrate and dilute it properly, and measure its drug concentration by HPLC , and the solubility results of each saturated solution are shown in Table 1.

[0054] Table 1 Solubility of irinotecan and irinotecan-cholesterol succinate monoester ion pair

[0055]

[0056] According to the provisions of the Chinese Pharmacopoeia, the oil-water partition ...

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Abstract

The invention discloses an irinotecan-cholesterol succinic acid simple lipid ion pair, a liposome and a preparation method and application thereof. The cholesterol succinic acid simple lipid is used as a counter-ionic agent, and the active proton of carboxyl in the cholesterol succinic acid simple lipid structure transfers to the nitrogen of irinotecan amino group, a coordination bond is formed, an ion pair is formed with irinotecan, so that the lipid solubility of irinotecan is improved, and the simple preparation method is easily used for packaging the drug on a phospholipid layer of the liposome, and the drug loading and packaging efficiency are improved. According to the irinotecan-cholesterol succinic acid simple lipid ion pair, the liposome and the preparation method and applicationthereof, the hydrophobic ion pair technology is combined with the nano drug delivery system, the lipid solubility of the insoluble drugs is improved, nano-preparations are developed, the complexity ofthe preparation process is simplified, and the irinotecan-cholesterol succinic acid simple lipid ion pair, the liposome and the preparation method and application thereof is conducive to expanding the industrial production. In addition, irinotecan ion pair and the liposome releases faster in the meta-acid environment, certain pH sensitivity is achieved, good antitumor effect and safety are achieved, and good application is achieved.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to an irinotecan-cholesterol succinate monoester ion pair, a liposome, a preparation method and an application. Background technique: [0002] Irinotecan (Irinotecan, CPT-11), chemical name 7-ethyl-10[4-(1-piperidinyl)-1-piperidinyl] carboxyoxycamptothecin, molecular formula C 33 h 38 N 4 o 6 , the relative molecular mass is 586.69. CPT-11 was first developed by Daiichi Seiyaku Company and Yakult Honsha Company in Japan. It was first launched in Japan in 1994 as a specific drug for the treatment of metastatic colorectal cancer. Listed in many countries, it is mainly used for the treatment of adult metastatic colorectal cancer and advanced (metastatic) pancreatic cancer. In addition, various indications such as gastric cancer, esophageal cancer, breast cancer, and extensive-stage small cell lung cancer are also under continuous development. [0003] Irinot...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K47/54A61K31/4745A61P35/00A61P35/04
CPCA61K9/1271A61K31/4745A61K47/541A61P35/00A61P35/04
Inventor 俞磊范明雪王昊耿思聪骆声根闫志强
Owner EAST CHINA NORMAL UNIV
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