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Thrombin responsive network polymer and its application

A technology of thrombin and polymers, which is applied in the direction of non-active ingredients of polymer compounds, drug combinations, blood diseases, etc., can solve problems such as adverse reactions and low bioavailability, reduce preparation steps, improve stability, and improve biological The effect of utilization

Active Publication Date: 2022-03-11
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In order to solve the technical problems of low bioavailability and adverse reactions after administration of existing thrombin inhibitors, the present invention provides a thrombin-responsive network polymer, which is used to entrap thrombin inhibitors Agent, which can adaptively release the loaded thrombin inhibitor quickly under the action of high concentration of thrombin and slowly release it at low concentration, and finally used for closed-loop thrombin inhibitor delivery, improving its antithrombotic activity and reducing adverse reactions

Method used

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  • Thrombin responsive network polymer and its application
  • Thrombin responsive network polymer and its application
  • Thrombin responsive network polymer and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Preparation and evaluation of "closed-loop regulation" single-molecule protein nanocapsules

[0054] 1. Preparation of single-molecule protein nanocapsules loaded with peptide or protein-like thrombin inhibitors

[0055] 1. Preparation of single-molecule protein nanocapsules (ctNCs) with thrombus targeting and thrombin responsiveness

[0056] Using solid-phase synthesis (Merrifield, R.B., Solid phase synthesis. Science 1986, 232, 341-348), synthesize thrombin-degradable peptide G(allyl) with N-terminal and C-terminal modification of allylglycine (G(allyl)) -PPRSFL-G(allyl) and the thrombus targeting peptide G(allyl)-CREKA with G(allyl) modified at the N-terminus.

[0057] Dissolve 1 mg of peptide or protein thrombin inhibitors hirudin (HV), lepirudin (Lep), desirudin (Des) and bivalirudin (Biv) in 1 mL of carbonate buffer (5 mM , pH 9.0), N-isopropylacrylamide (40mg), G(allyl)-PPRSFL-G(allyl) (10mg) and G(allyl)-CREKA (5mg) were added sequentially under stirring in an...

Embodiment 2

[0097] Preparation and evaluation of "closed-loop regulation" nanogel

[0098] 1. Preparation of nanogels loaded with thrombin inhibitors

[0099] 1. Preparation of nanogels (ctNGs) with thrombus targeting and thrombin responsiveness

[0100] The thrombus-targeting peptide G(allyl)-GCR(NMe)EKA modified with G(allyl) at the N-terminal and the thrombin-degradable peptide G(allyl)-GGLVPRGSGG modified with G(allyl) at both ends were synthesized by solid-phase synthesis -G (allyl).

[0101] The thrombin inhibitors hirudin (HV), lepirudin (Lep), desirudin (Des), bivalirudin (Biv), dabigatran etexilate (Dab), argatroban ( Arg), d-phenylalanyl-1-prolyl arginine-chloromethyl ketone (PPACK), enoxagatran (Ino), melagatran (Mel), ximelagatran (Xim), or RWJ-671818(RWJ) and acrylamide (AAm), G(allyl)-GCR(NMe)EKA, G(allyl)-GGLVPRGSGG-G(allyl)(60:2:1,mol:mol:mol) and dissolved In 0.5 mL of water, the aqueous phase was obtained. Docusate sodium (356 mg) and laureth (688 mg) were dissolved...

Embodiment 3

[0150] Preparation and evaluation of "closed-loop regulation" hydrogel

[0151] 1. Construction of "closed-loop regulation" hydrogel loaded with thrombin inhibitors

[0152] 1. Preparation of thrombus-targeting and thrombin-responsive hydrogel (ctHG)

[0153] 1 mg thrombin inhibitors hirudin (HV), lepirudin (Lep), desirudin (Des), bivalirudin (Biv), dabigatran etexilate (Dab), argatroban (Arg), d-phenylalanyl-1-prolyl arginine-chloromethyl ketone (PPACK), enoxagatran (Ino), melagatran (Mel), simelagatran (Xim) , RWJ-671818(RWJ) and methacrylamide, thrombin response peptide G(allyl)-TPRSFL-G(allyl), glycoprotein receptor antagonist G(allyl)RGD(60:2:1,mol:mol :mol) were mixed and dissolved in 2 mL of normal saline, then APS (5 mg) and TEMED (10 μL) were added, and left to stand for 5 min to form a hydrogel (ctHG).

[0154] The results show that the hydrogel can carry various thrombin inhibitors, and HV / ctHG, Lep / ctHG, Des / ctHG, Biv / ctHG, Dab / ctHG, Arg / ctHG, PPACK / ctHG, Ino / ct...

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Abstract

The invention discloses a thrombin-responsive network polymer and its application in the delivery of closed-loop thrombin inhibitors, belonging to the technical field of pharmaceutical preparations. The thrombin-responsive network polymer consists of polymer monomers, blood coagulation The enzyme-degradable peptide and the thrombus-targeting ligand are obtained through polymerization. The polymer is used to entrap thrombin inhibitors, which can self-adaptively release the loaded thrombin inhibitors quickly under the action of high concentration of thrombin, and slowly release them at low concentrations, and is finally used for closed-loop thrombin inhibitor delivery. Improve its antithrombotic activity and reduce adverse reactions.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparations, in particular to a thrombin-responsive network polymer and its application in the delivery of closed-loop thrombin inhibitors. Background technique [0002] Thrombus is a solid substance precipitated and formed when blood coagulates, and its main components include red blood cells, activated platelets, and fibrin. Abnormal thrombosis is the underlying cause of many cardiovascular and cerebrovascular diseases, such as pulmonary embolism, myocardial infarction, and ischemic stroke. Thrombosis in the body is a complex physiological process, and various coagulation factors participate in the coagulation cascade reaction. Among them, thrombin is an important coagulation factor that mediates the coagulation cascade reaction and converts fibrinogen into fibrin, thereby forming a stable thrombus clot. [0003] Thrombin inhibitors can specifically bind to thrombin, inhibit its activi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K38/58A61K47/42A61K47/32A61K45/06A61K9/51A61K9/06A61P7/02
CPCA61K47/42A61K47/32A61K45/06A61K38/58A61K9/5138A61K9/5169A61K9/06A61P7/02
Inventor 莫然徐霄黄雪超
Owner CHINA PHARM UNIV
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