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Nintedanib supramolecular co-loaded clathrate compound

A technology of nintedanib and nintedanib ethanesulfonate, which is applied in the directions of drug combinations, organic active ingredients, medical preparations of non-active ingredients, etc., can solve problems such as side effects

Pending Publication Date: 2021-06-04
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main toxic and side effects of nintedanib are intestinal side effects

Method used

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  • Nintedanib supramolecular co-loaded clathrate compound
  • Nintedanib supramolecular co-loaded clathrate compound
  • Nintedanib supramolecular co-loaded clathrate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The preparation of embodiment 1 nintedanib supramolecular clathrate

[0035]

[0036] Weigh HP-β-CD, add appropriate amount of water, stir to dissolve; add nintedanib ethanesulfonate, continue stirring to dissolve nintedanib ethanesulfonate; add NaOH solution to adjust pH 5.0-7.5, add water to Sufficient amount is stirred evenly to prepare nintedanib supramolecular clathrate. Among them, nintedanib ethanesulfonate / hydroxypropyl-β-cyclodextrin (10:200) or more, the inclusion rate is greater than 90%.

Embodiment 2

[0037] Example 2 Preparation of nintedanib / itraconazole co-loaded inclusion compound

[0038]

[0039] Weigh itraconazole, add cyclodextrin derivatives and appropriate amount of water, stir to completely dissolve itraconazole; then add nintedanib ethanesulfonate, continue to stir to completely dissolve; adjust pH with sodium hydroxide solution value to 5.0-7.5, and add water to a sufficient amount to obtain nintedanib / itraconazole co-loaded clathrate solution.

[0040] XRD and infrared images showed that both nintedanib ethanesulfonate and itraconazole existed in the co-carrier molecular clathrate in molecular form.

Embodiment 3

[0041] Example 3 Oral pharmacokinetics of nintedanib inclusion compound combined with itraconazole

[0042] Commercially available itraconazole capsule contents (dose 50mg / kg) rat gavage, give prescription 4 and prescription 6 nintedanib inclusion compound (dose 50mg / kg) preparation in embodiment 1 again by gavage after 30min, Determination of blood concentration. attached image 3 It is the drug-time curve of nintedanib injection after tail vein injection in rats. attached Figure 4The drug-time curves of prescription 4 and prescription 6 nintedanib inclusion compound and commercially available itraconazole capsule content or itraconazole inclusion compound intragastric administration to rats, compared with prescription 6 alone, and nintedanib Cloth solution was compared with the contents of commercially available itraconazole capsules.

[0043] The results show that with Figure 4 In schemes 1#, 2#, 3#, 4# and 5#, the absolute bioavailability of nintedanib was 12.2%, 23...

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Abstract

The invention provides a nintedanib supramolecular co-loaded clathrate compound. The clathrate compound mainly comprises: a medicine A, a medicine B and an auxiliary material; the medicine A is nintedanib or nintedanib ethanesulfonate salt; The medicine B is a P-glycoprotein inhibitor and / or a CYP3A4 enzyme inhibitor; and the auxiliary material is cyclodextrin or a derivative thereof. According to the invention, oral bioavailability of the nintedanib is improved, thus realizing a better synergistic anti-cancer curative effect with a lower administration dosage than that of the existing commercially-available nintedanib preparation and reducing clinical treatment cost.

Description

technical field [0001] The invention relates to a nintedanib supramolecular co-loading clathrate to improve the bioavailability of nintedanib. Background technique [0002] Nintedanib ethanesulfonate is an oral triple angiokinase inhibitor that targets platelet-derived growth factor receptor, fibroblast growth factor receptor, and vascular endothelial growth factor receptor. Nintedanib ethanesulfonate is originally researched by Boehringer Ingelheim, and the only marketed preparation is lipid soft capsules. The trade name is Vegat, which is composed of medium-chain triolein, hard fat and phospholipids. Each capsule contains Nintedanib Nebulb 100mg or 150mg, 30 capsules per bottle, the price is 11,200 yuan, clinically used for the treatment of idiopathic pulmonary fibrosis and non-small cell lung cancer. In addition, nintedanib is used in phase II and III clinical trials of solid tumors such as colorectal cancer, ovarian cancer, liver cancer (hepatocellular carcinoma), mesot...

Claims

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Application Information

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IPC IPC(8): A61K47/69A61K31/496A61K45/06A61P35/00
CPCA61K47/6951A61K45/06A61K31/496A61P35/00
Inventor 熊素彬王建栋
Owner ZHEJIANG UNIV OF TECH
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