Long-circulation irinotecan lipidosome composition and preparation method thereof

A technology of irinotecan and Kang lipid, applied in the field of long-circulation irinotecan liposome composition and its preparation

Inactive Publication Date: 2014-06-04
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Although the prescriptions and methods recorded in the above-mentioned patent documents can basically prepare liposomes with better encapsulation efficiency, they all need to adopt the gradient method, or...

Method used

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  • Long-circulation irinotecan lipidosome composition and preparation method thereof
  • Long-circulation irinotecan lipidosome composition and preparation method thereof
  • Long-circulation irinotecan lipidosome composition and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example

[0074]

[0075] Add 60% sodium hydride (130mg, 3.3mmol) to a solution of irinotecan (2.03g, 3mmol) in DMF (20ml) at 0°C, stir at room temperature for 1h, then add 2-chloro-5- Fluoro-pyrimidine (440mg, 3.3mmol), continued stirring at room temperature for 1h. The reaction was monitored by TLC (10% methanol in DCM). The reaction mixture was quenched with cold water and extracted with ethyl acetate. The organic layer was washed with brine solution, washed with Na 2 SO 4 Dried and concentrated. Purification by column chromatography on silica gel (4% methanol in DCM) afforded 353 mg of product.

[0076] 1 H NMR (300MHz, CDCl 3 ):δ1.03(t,J=7.3Hz,3H),1.37-1.49(m,J=7.3Hz,3H),1.49-1.70(m,2H),1.73-1.92(m,8H),2.05- 2.30(m,2H),2.85-3.20(m,7H),3.20-3.48(m,2H),4.39-4.61(m,2H),5.26(s,2H),5.31(d,J=16.4Hz, 1H),5.74(d,J=16.4Hz,1H),7.56(dd,J 1 =9.2Hz,J 2 =2.4Hz,1H)7.63(s,1H),7.82(d,J=2.4Hz,1H)8.21(d,J=9.2Hz,1H),8.35(s,1H),8.36(s,1H);

[0077] Example of efficacy

[0078] 5-fluoropyri...

Embodiment 1

[0087] Prescription: see Table 2

[0088] Table 2

[0089]

[0090] Preparation Process:

[0091] (1) Dissolve the prescribed amount of hydrogenated soybean phosphatidylcholine (HSPC), cholesterol (CHOL), α-tocopherol, and cultured phosphatidylcholine (DSPE-PEG2000) in 10 times the amount (ml / g) of tertiary Butanol: ethanol = (5:1) mixed solvent, freeze-dried to obtain freeze-dried powder.

[0092] The freeze-drying steps include pre-freezing and sublimation drying. During the pre-freezing process, the pre-freezing temperature of the front box of the freeze-dryer is -35 ° C ~ -40 ° C, and the temperature of the back box of the freeze-dryer drops to -40 °C during the heat preservation period. ℃~-50℃; during the sublimation drying process, under the condition of vacuuming, turn on the machine and heat up the sublimation drying at 2℃~5℃ per hour. When the temperature of the product reaches 18℃~25℃, keep it for 2~6 hours to remove the remaining organic matter. solvents and m...

Embodiment 2

[0108] prescription:

[0109]

[0110] Preparation Process:

[0111] Same as Example 1, wherein the selection of irinotecan solution in step (3) is shown in Table 3.

[0112] The different groups of products and their properties are shown in Table 4:

[0113] Table 4

[0114] irinotecan solution

[0115] Aqueous solution, L-Lysine to adjust pH

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Abstract

The invention belongs to the field of medicine preparations, which particularly relates to a long-circulation irinotecan lipidosome composition. The long-circulation irinotecan lipidosome composition is prepared from the following components in parts by weight: 1 part of irinotecan, 2 to 4 parts of hydrogenated soy phosphatidylcholine or distearoyl lecithin, 0.5 to 1.5 parts of cholesterol, 0.4 to 1.2 parts of phosphatidylethanolamine pegol and 0.0104 to 0.051 part of metal-chelator. The invention further discloses a preparation method of the long-circulation irinotecan lipidosome composition and an application of the long-circulation irinotecan lipidosome composition prepared into an irinotecan lipidosome composition injection. According to the irinotecan lipidosome composition and the preparation method thereof, the medicine loading ratio of the irinotecan is greatly improved and the encapsulation efficiency is greater than 99.5%, so that the toxic and side effect of the medicine which is not encapsulated can be obviously reduced; the content of relevant substances is lower than 0.5% and the limit of various toxic impurities is lower than 0.1%, so that the safety of the composition is obviously improved; and the composition is uniform in granularity distribution and good in stability.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a long-circulation irinotecan liposome composition and its preparation method and application. Background technique [0002] Irinotecan Hydrochloride, chemical name: (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyridine Pyro[3',4':6,7]indeno[1,2-b]quinolin-9-yl 1,4'-bipiperidine-1'-carboxylate, the chemical structure is: [0003] [0004] The pharmacological effects of irinotecan show that in vitro experiments, irinotecan or its metabolite SN-38 was not found to be effectively recognized by P-glycoprotein MDR, and it showed resistance to doxorubicin and vinblastine. The cell line is still cytotoxic. In addition, in vivo experiments, irinotecan showed broad-spectrum antitumor activity against murine tumor models (PO3 pancreatic ductal adenocarcinoma, MA-16 / C breast cancer, C38 and C51 colon adenocarcinoma), and had anti-human xenogeneic Viabili...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K31/4745A61K9/19A61P35/00C07D491/22A61K31/506
Inventor 赵俊陈祥峰刘留成金雪锋
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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