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A dual-response prodrug containing a polysialic acid group, its synthesis method and its application in pharmaceutical preparations

A polysialic acid, dual-response technology, applied in the field of preparation and modification of microparticle preparations, can solve problems such as decreased activity, achieve the effects of good biocompatibility and biodegradability, good clinical transformation and industrial development prospects

Active Publication Date: 2022-07-29
北京双枝医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies have pointed out that PSA-asparaginase has no immunogenicity, and the activity of asparaginase is hardly affected, but the activity is severely reduced after PEG modification

Method used

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  • A dual-response prodrug containing a polysialic acid group, its synthesis method and its application in pharmaceutical preparations
  • A dual-response prodrug containing a polysialic acid group, its synthesis method and its application in pharmaceutical preparations
  • A dual-response prodrug containing a polysialic acid group, its synthesis method and its application in pharmaceutical preparations

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Example 1 PSA 100 - AE-AE-DOX synthesis

[0084]

[0085] PSA of the present invention 100 -AE-AE-DOX preparation process: first, the feeding ratio is the number of carboxyl groups in polysialic acid (PSA 100 , Y=100) / 2-mercaptoethylamine (AE) / N-hydroxysuccinimide (NHS) / 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) / triethylamine (TEA)=1:1:2:4:4 (molar ratio); an appropriate amount of PSA 100Dissolve in 5 mL of formamide (FA), add EDC / NHS in proportion, activate at 4 °C for 90 min, the system is clear at this time; then add AE dissolved in 2 mL of FA into the reaction system, add TEA, and stir at room temperature for 48 h. , the reaction solution was added to 20 times the volume of 0°C acetone to obtain a light yellow precipitate, which was vacuum dried for 24h to obtain PSA 100 -AE.

[0086] Then, the feeding ratio was doxorubicin (DOX) / AE / TEA=1:5:1.5 (molar ratio); an appropriate amount of DOX was dissolved in 5 mL of formamide (FA), AE and TE...

Embodiment 2

[0093] Example 2 PSA 100 -AP-PEG 2000 -Mit synthesis

[0094]

[0095] PSA of the present invention 100 -AP-PEG 2000 -Mit preparation process: First, the feeding ratio is the number of carboxyl groups in polysialic acid (PSA 100 , Y=100) / 2-mercaptopropylamine (AP) / N-hydroxysuccinimide (NHS) / 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride ( EDC) / triethylamine (TEA)=1:1:2:4:4 (molar ratio); an appropriate amount of PSA 100 Dissolve in 5 mL of formamide (FA), add EDC / NHS in proportion, activate at 4 °C for 90 min, the system is clear at this time; then add AE dissolved in 2 mL of FA into the reaction system, add TEA, and stir at room temperature for 48 h. , the reaction solution was added to 20 times the volume of 0°C acetone to obtain a light yellow precipitate, which was vacuum dried for 24h to obtain PSA 100 -AP.

[0096] Then, the feed ratio is mitoxantrone (Mit) / amino-polyethylene glycol 2000 -Sulfhydryl (NH 2 -PEG 2000 -SH) / TEA=1:5:1.5 (molar ratio); ...

Embodiment 3

[0103] Example 3 PSA 20 -MB-AT-EPI synthesis

[0104]

[0105] PSA of the present invention 20 -MB-AT-EPI preparation process: first, the feeding ratio is the number of carboxyl groups in polysialic acid (PSA 20 , Y=20) / 4-mercapto-1-butylamine (MB) / N-hydroxysuccinimide (NHS) / 1-ethyl-(3-dimethylaminopropyl)carbodiimide Hydrochloride (EDC) / triethylamine (TEA)=1:1:2:4:4 (molar ratio); an appropriate amount of PSA 200 Dissolve in 5 mL of formamide (FA), add EDC / NHS in proportion, activate at 4 °C for 90 min, the system is clear at this time; then add MB dissolved in 2 mL of FA into the reaction system, add TEA, and stir at room temperature for 48 h. , the reaction solution was added to 20 times the volume of 0°C acetone to obtain a light yellow precipitate, which was vacuum dried for 24h to obtain PSA 20 -MB.

[0106] Then, the feeding ratio is epirubicin (EPI) / 5-mercapto-1-pentylamine (AT) / TEA=1:5:1.5 (molar ratio); an appropriate amount of EPI is dissolved in 5 mL of for...

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Abstract

The present invention provides a dual-response prodrug containing a polysialic acid group, a synthesis method thereof, and application thereof in a pharmaceutical preparation, and the dual-response prodrug containing a polysialic acid group has the structure of formula (I): Wherein, R in formula (I) 1 stands for ‑OH, ‑HNCOCH 3 ,‑NHCOCH 2 One of OH; S‑R 2 ‑NH fragment from HS‑R 2 ‑NH 2 , HS‑R 2 ‑NH 2 is a compound containing a primary amine group and a sulfhydryl group; S‑R 3 ‑N fragment from HS‑R 3 ‑NH 2 , HS‑R 3 ‑NH 2 is a compound containing a primary amine group and a sulfhydryl group; R 4 is a drug molecule containing a hydroxyl, amino, carboxyl or carbonyl group; R 4 It is one of single bond and double bond between N and N; X is the number of side chain derivative fragments grafted in the polysialic acid molecule, Y is the number of sialic acid units in the PSA molecule, 1≤X≤500, 2≤Y≤1000, X / Y is 0.5%~50%. The dual-response prodrug of the present invention has good biocompatibility and biodegradability, has amphiphilicity, can be stably modified on the surface of nano-formulations, and has good prospects for clinical transformation and industrial development.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, in particular to a dual-response prodrug containing a polysialic acid group that is dual-responsive to redox and acidity, a synthesis method thereof, and its application in pharmaceutical preparations, in particular to microparticle preparations. Preparation and modification. Background technique [0002] All disease is a process, not a state, in which the immune system is always involved. After the organic combination of immunology and pharmacy, we can transform the strategy of avoiding immune recognition into using the immune system to design a drug delivery system (DDS) to achieve efficient targeting. Therefore, in the future drug delivery system (DDS), nanotechnology will actively "find" immune cells, improve the immune environment, and rely on a strong immune system to cure diseases. [0003] The classical immunology theory points out that the percentages of various white blood c...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/61A61K45/00A61P29/00A61P31/04A61P35/00
CPCA61K47/61A61K45/00A61P35/00A61P29/00A61P31/04
Inventor 骆翔李聪邱秋钧俞燕娜吴梦琦朱柯武沈润溥杜奎席眉扬蔡涛余乐茂
Owner 北京双枝医药科技有限公司