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Modularly-assembled combined biological drug joint delivery system and application

A delivery system and modular technology, applied in the direction of drug combinations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., can solve problems such as inability to obtain technical inspiration

Inactive Publication Date: 2018-10-23
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The previous patents mainly designed and synthesized click chemistry module molecules that can be used for carrier assembly, which are used to endow the carrier with long-term circulation functions and active targeting functions. It cannot be simply thought from the previous patents that this assembly technology can be used to combine different Co-loading and target-specific release of biopharmaceuticals with specific properties, so the present invention cannot obtain technical inspiration from previous patents

Method used

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  • Modularly-assembled combined biological drug joint delivery system and application
  • Modularly-assembled combined biological drug joint delivery system and application
  • Modularly-assembled combined biological drug joint delivery system and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] Preparation and Characterization of Azadibenzocyclooctyne Modified Reduction Sensitive Blank Cationic Liposomes (ADIBO-CL)

[0102] The reduction-sensitive blank cationic liposomes were prepared by thin film dispersion method. Weigh 25 mg of soybean lecithin, 2-(4-(2-(2-(2-(2-(2,6-diamino-hexylamino)-3-(1 hydrogen-imidazolyl-4-yl) isopropyl Amino)ethyl)dithio)diethylamino)-4-oxobutanone)tetradecyl glutarate (LHSSG2C 14 ) 5mg, azadibenzocyclooctyne (ADIBO) modified cholesterol 6mg and azadibenzocyclooctyne (ADIBO) modified DSPE 4mg, dissolved in chloroform / methanol mixed solvent, evaporated under reduced pressure to form a film, and Dry in vacuo overnight to remove residual organic solvent. Hydrate the lipid film at room temperature, disperse the obtained liposome suspension with an ultrasonic cell pulverizer, and pass through a 0.22 μm microporous membrane to obtain a blank liposome solution. Its particle size and potential properties are shown in Table 1.

[0103] ...

Embodiment 2

[0106] Preparation of Gene Drug Liposomes (AD-RSC) with Different Nitrogen-Phosphorus Ratio in Module 1

[0107] After diluting ADIBO-CL 5-10 times with pH 7.4 buffer, add different N / P (0.5, 1.0, 2.0, 5.0, 10, 15) siRNA (sense strand: 5'-CUUGUGCUCAAACUCGUCCdTdT-3', Sense strand: 3'-dTdTGAACACGAGUUUGAGCAGG-5") mixed and allowed to stand at room temperature for 30min to obtain the gene drug liposome (Module 1, AD-RSC). The loading of cationic liposome on siRNA was investigated by agarose gel electrophoresis ability, the results show that when N / P is greater than 5, cationic liposomes can fully load siRNA see image 3 . The particle size and potential of AD-RSC were measured by dynamic light scattering method. The experimental results showed that with the increase of N / P, the particle size of AD-RSC first increased and then decreased, and its surface potential changed from negative to positive. See Figure 4 .

Embodiment 3

[0109] Modified protein (polypeptide) drug (N 3 -s-TRAIL) preparation

[0110] Using Sulfo-SMCC as the coupling agent between the protein (polypeptide) drug and the sensitive linker, mix 1.0mg / mL, 5mL TRAIL with 1.0mg / mL, 1mL azide-enzyme-sensitive linker or acid-sensitive linker (specifically The structure is as follows) were dissolved in PBS buffer, and then 4.8mg / mL, 500μL Sulfo-SMCC was added and reacted at room temperature for 1h. After the reaction was completed, the reaction solution was dialyzed at room temperature for 3 days to obtain the TRAIL modified with the azide-enzyme-sensitive linker.

[0111] The enzyme-sensitive linker is: N 3 -Pro-Leu-Gly-Leu-Ala-Gly-Cys-SH

[0112] The acid-sensitive linking arm is: N 3 -CH 2 -HN-N=CH-CH 2 -SH

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Abstract

The invention relates to a modularly-assembled combined biological drug joint delivery system and application. The joint delivery system is formed by assembling three modules through moderate chemicalreaction; the module I is liposome entrapped with gene drugs; the module II is protein or a polypeptide drug which contains a specific group and is modified by a sensitive connection arm; the moduleIII is a functional molecule which contains a specific group. The modules are connected with the surface of the liposome entrapped with the gene drugs through moderate chemical reaction, the multifunctionality such as focus targeting, cell membrane penetration, long cycle effect and electronegativity of the liposome can be given. According to the modularly-assembled combined biological drug jointdelivery system and the application disclosed by the invention, through a modular assembly technology, common load and separative target release of the combined biological drugs with different properties can be realized, so that the different effects can be played, the curative effect of combined use of the biological drugs is improved, and the system has the better synergistic treatment effect.

Description

technical field [0001] The invention relates to the field of chemistry and preparation, in particular to a modularly assembled combined biological drug delivery system and its application. Background technique [0002] Biological drugs such as proteins and genes are one of the most promising areas of new drug research and development in the 21st century. Due to the high selectivity and high pharmacological activity of biological drugs and many other advantages, they show broad application prospects in the treatment of clinical diseases. However, biopharmaceuticals also have natural disadvantages, such as their complex molecular structure, poor stability, and short half-life in vivo, which make the druggability of free biopharmaceuticals poor. Even though a small amount of biological drugs are currently used for clinical treatment, the existing preparations and dosage forms still cannot give full play to their therapeutic characteristics and advantages. [0003] In recent y...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K47/24A61K31/7105A61K48/00A61K47/62A61K47/65A61K47/54A61P3/10A61P37/02A61P29/00A61P19/02A61P35/00
CPCA61K9/127A61K31/7105A61K47/24A61K47/545A61K47/62A61K47/65A61P3/10A61P19/02A61P29/00A61P35/00A61P37/02
Inventor 张灿鞠曹云周安维薛玲静谢达平张怡頔田春莉
Owner CHINA PHARM UNIV
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