Modified hydrophobic auxiliary material as well as preparation method and application thereof

A water auxiliary material and modification technology, applied in the field of modified hydrophobic auxiliary material and its preparation, can solve the problems of limited solubility and the like

Active Publication Date: 2020-12-22
ZHEJIANG ZHIDA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many drugs have limited solubility in the very hydrophobic oil phase

Method used

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  • Modified hydrophobic auxiliary material as well as preparation method and application thereof
  • Modified hydrophobic auxiliary material as well as preparation method and application thereof
  • Modified hydrophobic auxiliary material as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] A preparation method of a modified hydrophobic auxiliary material, specifically as follows:

[0091] In a 250ml flask, add 9.34g castor oil (10mmol), 29.5gN-fluorenylmethoxycarbonyl-N'-tert-butoxycarbonyl-L-lysine (60mmol), 366mg4-dimethylaminopyridine (DMAP) ( 3mmol), then add dicyclohexylcarbodiimide (DCC) 12.4g (60mmol) dissolved in 50ml of anhydrous dichloromethane, at room temperature, react for three days under dark conditions, after TLC analysis has reacted completely , filtered to remove the precipitate and then spin-dried. After conventional purification, a slightly yellow transparent viscous oil was obtained. After cooling, it became a glassy transparent solid, and a modified hydrophobic auxiliary material was obtained. The reaction equation is shown below. Castor oil is usually a mixture of triglycerides with different ricinoleic acid content (n=0-3), and its molecular formula cannot be accurately represented. The following reaction equation is used to illus...

Embodiment 2

[0094] A preparation method of a hydrophobic auxiliary material, specifically as follows:

[0095] A-1, castor oil-O-glycine triester is esterified by N-tert-butoxycarbonylglycine, and then deprotects the synthetic route with acidification, specifically as follows:

[0096] In a 250ml flask, add 9.34g castor oil (10mmol), 7.2g N-tert-butoxycarbonylglycine (45mmol), 366mg 4-dimethylaminopyridine (DMAP) (3mmol), and then add 50ml of anhydrous dichloro N, N'-dicyclohexylcarbodiimide (DCC) 12.4g (60mmol) of methane was reacted at room temperature for two days in the dark, after the reaction was complete by TLC analysis, the precipitate was removed by filtration and spin-dried , a colorless transparent viscous oil was obtained after conventional purification, and Intermediate 1 was obtained, which was castor oil-O-(N-tert-butoxycarbonylglycine) triester.

[0097] Dissolve intermediate 1 in 40ml of dichloromethane (DCM), then add 40ml of trifluoroacetic acid (TFA), react at room te...

Embodiment 3

[0112] A preparation method of a hydrophobic auxiliary material, specifically as follows:

[0113] A, the synthesis of hydrogenated castor oil-O-glycine triester, specifically as follows:

[0114] In a 250ml flask, add 9.36g hydrogenated castor oil (10mmol), 7.2g N-tert-butoxycarbonylglycine (45mmol), 366mg4-dimethylaminopyridine (DMAP) (3mmol), dissolve in 100ml of anhydrous dichloromethane (DCM), then add 10.3 g (50 mmol) of dicyclohexylcarbodiimide (DCC) dissolved in 50 ml of anhydrous dichloromethane, reflux at a temperature of 45° C., and react for two days under light-shielding conditions. After the reaction was complete by TLC analysis, filter to remove the precipitate and spin dry. After recrystallization and purification from ethyl acetate, a slightly yellow transparent viscous oil was obtained. After cooling, it became white crystals to obtain Intermediate 1, which is hydrogenated castor oil. -O-(N-tert-butoxycarbonylglycine) triester.

[0115] Dissolve intermediat...

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Abstract

The invention relates to preparation of novel pharmaceutic auxiliary materials and drug-loaded fat emulsions, and provides a hydrophobic auxiliary material, the molecular formula of which is as follows: R is a hydrophobic natural compound or synthetic compound with one to three hydroxyl groups (n= 1-3); R1 is an alpha-amino protecting group, R2 is an amino acid side chain, m is equal to 0, and atthe moment, R reacts with the amino acid derivative with the protecting group through esterification to form a hydrophobic auxiliary material carrying the amino acid derivative with the protecting group; or m is equal to 1, at the moment, an amino acid connecting arm (l being equal to 1, 2, 4, and 6) with different chain lengths is introduced into R through an ester group, then an amino acid derivative with a protective group is introduced, and the hydrophobic auxiliary material carrying the amino acid derivative polypeptide with the protective group is formed. According to the method, the amino acid derivative with the aromatic or alkoxycarbonyl or acyl amino protecting group is introduced to the hydrophobic auxiliary material, so that the solubility of the drug in the hydrophobic auxiliary material is increased, and the stability of the drug-loaded fat emulsion is improved.

Description

technical field [0001] The invention relates to the application field of preparation of pharmaceutical excipients and drug-loaded fat emulsion, more specifically, it relates to a modified hydrophobic excipient, its preparation method and its application. Background technique [0002] Many drugs with poor water solubility need to increase water solubility by chemical or physical methods, and can be used after being prepared into injections. Drugs can be solubilized by chemical bonding with hydrophilic or amphiphilic excipients, and can also be used to form molecular inclusions with cyclodextrins, and to form micelles, nanodispersions, and liposomes with surfactants. The active agent and the oil phase form an emulsion, and formulation processes such as albumin encapsulation achieve solubilization. [0003] Emulsion is a commonly used drug carrier, which is used to increase the solubility of poorly water-soluble drugs, while protecting the drug from rapid degradation, and chan...

Claims

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Application Information

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IPC IPC(8): C07C271/22C07C269/06C07J9/00A61K31/337A61K9/107A61K47/18A61K47/54A61P35/00
CPCC07C271/22C07J9/005A61K31/337A61K47/18A61K9/107A61K47/543A61P35/00C07C2603/18Y02P20/55
Inventor 高翔
Owner ZHEJIANG ZHIDA PHARM CO LTD
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