Light-controlled release of unfractionated heparin ion complex material and preparation method thereof
By preparing a light-controlled release ungraded heparin ion complex material, the problem of overuse of heparin drugs in clinical applications has been solved, and the controlled release of heparin and the light-regulated anticoagulant effect have been achieved, thus enhancing the application potential of heparin materials in the treatment and prevention of thrombosis.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- QINGDAO UNIV OF SCI & TECH
- Filing Date
- 2023-12-06
- Publication Date
- 2026-08-04
AI Technical Summary
Existing heparin drugs pose a risk of overuse in clinical applications, leading to problems such as bleeding, thrombocytopenia, and osteoporosis. Furthermore, smart materials lacking light-controlled release functionality are not widely used in heparin drugs, limiting their controllability in anticoagulation therapy.
A light-controlled release type unfractionated heparin ion complex material was prepared by combining unfractionated heparin sodium salt with a quaternary ammonium salt surfactant containing an azophenyl group to form an ion complex, and the controlled release of heparin was achieved by ultraviolet light stimulation.
It achieves controlled release of heparin, prolongs clotting time, has good biocompatibility and photomodulated anticoagulant function, and reduces the risk of overdose.
Smart Images
Figure HDA0004590384630000011
Abstract
Description
Technical Field
[0001] This invention relates to the fields of biomaterials and stimulus-responsive materials, and mainly to an ungraded heparin ion complex material with photocontrolled release function and its preparation method. Background Technology
[0002] Heparin is one of the most commonly used anticoagulants for treating and preventing thrombosis. Naturally occurring heparin is unfractionated heparin. Unfractionated heparin is currently mainly used clinically for anticoagulation therapy in extracorporeal blood circulation, such as in hemodialysis. However, despite its excellent anticoagulant effect, the risks of overdose still require close monitoring in clinical application. Overuse of heparin can easily cause bleeding, thrombocytopenia, and osteoporosis; therefore, achieving controlled release of heparin is crucial.
[0003] In reported studies, heparin release can be effectively achieved using mesoporous materials, carbon nanocapsules, and thrombin-responsive percutaneous patches. However, to date, the stimulus-response mechanism, widely used in smart materials design, has not been applied to the design and fabrication of heparin drug materials. Developing a heparin drug material that can effectively respond to external stimuli is expected to promote the application of heparin as a smart anticoagulant in the treatment and prevention of thrombosis. Because heparin molecules themselves do not possess functional groups that respond to external stimuli, the fabrication of such materials requires combining heparin molecules with stimulus-responsive functional molecules.
[0004] Azobenzene is one of the most widely used organic photosensitive molecules. Under light stimulation, this type of molecule can change its polarity and spatial conformation through reversible isomerization of the azo moiety. Specifically, ultraviolet light stimulation drives the azobenzene molecule from a planar trans structure to a non-planar cis structure, while visible light drives the molecule back to the trans structure. This cis-trans conformational transition can drive significant changes in material properties, such as altering the phase state and aggregation state of the material. This has led to the development and application of various photostimulation-responsive smart materials. However, the controlled release of heparin-like drugs using azobenzene, and thus the effective photomodulation of blood's anticoagulant function, has not yet been reported. This limits the application of heparin as a smart drug in modulated anticoagulant therapy. Therefore, developing photocontrolled release heparin-like materials to achieve effective photomodulation of anticoagulant therapy is of great significance for expanding the application of heparin in basic research and medicine. Summary of the Invention
[0005] In view of this, the purpose of the present invention is to provide a light-controlled release type ungraded heparin ion complex material and its preparation method.
[0006] The technical solution of the present invention is as follows:
[0007] This invention provides a light-controlled release type unfractionated heparin ion complex material, the raw materials for which include unfractionated heparin sodium salt and a quaternary ammonium salt surfactant containing an azophenyl group.
[0008] In this invention, the ungraded heparin sodium salt is a heparin sodium salt derived from pig intestines, with a molecular weight range of 6000 to 20000 g / mol.
[0009] In this invention, the quaternary ammonium salt surfactant containing an azophenyl group is N,N-dimethyl-N-(4-(4-((4-n-octyloxyphenyl)diazepine)phenoxy)n-butyl)-3,6,9,12-tetraoxatridecylammonium bromide.
[0010] In this invention, the preparation method of the light-controlled release type unfractionated heparin ion complex material includes:
[0011] An aqueous solution of unfractionated heparin sodium salt was mixed with an aqueous solution of a quaternary ammonium salt surfactant containing an azophenyl group at room temperature. The mixture was shaken and centrifuged. The supernatant was discarded, and the remaining precipitate was washed three times with water and then freeze-dried to obtain a light-controlled release type unfractionated heparin ion complex material.
[0012] In the present invention, in the preparation method of the light-controlled release type unfractionated heparin ion complex material, the concentration of the aqueous solution of the unfractionated heparin sodium salt is 10-15 mM based on the repeating disaccharide units in the unfractionated heparin sodium salt, and the concentration of the aqueous solution of the azophenyl group-containing quaternary ammonium salt surfactant is 10-15 mM.
[0013] In the preparation method of the light-controlled release type unfractionated heparin ion complex material of the present invention, in the mixture, the unfractionated heparin sodium salt is calculated as repeating disaccharide units, and the molar ratio of the unfractionated heparin sodium salt to the quaternary ammonium salt surfactant containing azophenyl groups is 1:4 to 1:12.
[0014] In the preparation method of the light-controlled release type ungraded heparin ion complex material of the present invention, the shaking time of the mixed solution is 1 to 3 minutes, and the freeze-drying time of the precipitated product is 5 to 8 hours.
[0015] This invention provides a light-controlled release unfractionated heparin ion complex material and its preparation method, the light-controlled release unfractionated heparin ion complex material and its preparation method having the following characteristics:
[0016] 1. The light-controlled release type unfractionated heparin ion complex material obtained in this invention is an ion complex formed by unfractionated heparin and a quaternary ammonium salt surfactant containing an azophenyl group through electrostatic interaction.
[0017] 2. The light-controlled release type unfractionated heparin ion complex material obtained by the present invention can achieve rapid release of unfractionated heparin molecules under ultraviolet light stimulation in an aqueous solution system.
[0018] 3. The light-controlled release unfractionated heparin ion complex material obtained by this invention has good biocompatibility.
[0019] 4. The light-controlled release type unfractionated heparin ion complex material obtained by the present invention can controllably release unfractionated heparin under physiological conditions through ultraviolet light irradiation, effectively prolonging the blood clotting time. Attached Figure Description
[0020] Figure 1 The concentration changes of unfractionated heparin in an aqueous solution system under ultraviolet light irradiation and no light irradiation conditions are compared for the light-controlled release type unfractionated heparin ion complex material described in Example 1. Detailed Implementation
[0021] This invention provides a light-controlled release type unfractionated heparin ion complex material and its preparation method. Those skilled in the art can refer to the content of this document and appropriately modify the process parameters to achieve the same result. It should be noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The methods and applications of this invention have been described through preferred embodiments. Those skilled in the art can obviously make modifications or appropriate alterations and combinations to the methods and applications described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.
[0022] The present invention will be further illustrated below with reference to the embodiments:
[0023] Example 1:
[0024] 100 μL of a 10 mM aqueous solution of heparin sodium salt derived from porcine intestine (based on repeating disaccharide units in unfractionated heparin sodium salt) and 800 μL of a 10 mM aqueous solution of N,N-dimethyl-N-(4-(4-((4-n-octyloxyphenyl)diazeninyl)phenoxy)n-butyl)-3,6,9,12-tetraoxatridecylammonium bromide were mixed in a centrifuge tube and shaken for 3 minutes. The mixture was then centrifuged at a relative centrifugal force of 6100 g for 5 minutes, and the supernatant was discarded. The remaining precipitate was washed three times with water and then freeze-dried for 8 hours to obtain the light-controlled release type unfractionated heparin ion complex material of the present invention.
[0025] The concentration changes of unfractionated heparin in the prepared light-controlled release unfractionated heparin ion complex material in an aqueous solution system under continuous ultraviolet light irradiation and under no-light conditions are as follows: Figure 1 As shown, according to Figure 1 It was found that the light-controlled release type unfractionated heparin ion complex material can rapidly release unfractionated heparin under ultraviolet light irradiation, so that the concentration of unfractionated heparin in the aqueous solution reaches 90 μg / mL within 50 min. However, under no light irradiation conditions, the light-controlled release type unfractionated heparin ion complex material can only release a small amount of unfractionated heparin within 160 min.
[0026] The prepared light-controlled release unfractionated heparin ion complex material, after testing, exhibits low biotoxicity and good biocompatibility.
[0027] The prepared photocontrolled release unfractionated heparin ion complex material, after testing, showed that under ultraviolet light irradiation, it could controllably release unfractionated heparin in vivo, prolonging coagulation time by more than 2 times, and possessing good photoregulated anticoagulation function.
[0028] Comparative Example 1:
[0029] 100 μL of a 10 mM aqueous solution of heparin sodium salt derived from porcine intestine (based on repeating disaccharide units in unfractionated heparin sodium salt) and 200 μL of a 10 mM aqueous solution of N,N-dimethyl-N-(4-(4-((4-n-octyloxyphenyl)diazepine)phenoxy)n-butyl)-3,6,9,12-tetraoxatridecylammonium bromide were mixed in a centrifuge tube and shaken for 3 minutes. The mixture was then centrifuged at a relative centrifugal force of 6100 g for 5 minutes, and the supernatant was discarded. Only a small amount of precipitate was obtained at the bottom of the sample tube. The precipitate was washed three times with water and then freeze-dried for 8 hours to obtain the ion complex material of unfractionated heparin.
[0030] The unfractionated heparin ion complex material prepared in Comparative Example 1 could not achieve rapid release of unfractionated heparin in aqueous solution by ultraviolet light irradiation, nor could it achieve effective photocontrolled anticoagulation function in vivo.
[0031] The above are merely preferred embodiments of the present invention. It should be noted that those skilled in the art can make several improvements without departing from the principle of the present invention, and these improvements should also be considered within the scope of protection of the present invention.
Claims
1. A light-controlled release type unfractionated heparin ion complex material, characterized in that, Its synthetic raw materials include unfractionated heparin sodium salt and a quaternary ammonium salt surfactant containing azophenyl groups. The unfractionated heparin sodium salt is derived from porcine intestines and has a molecular weight range of 6000~20000 g / mol. The azophenyl-containing quaternary ammonium salt surfactant is... N,N -dimethyl- N -(4-(4-((4-n-octyloxyphenyl)diazeninyl)phenoxy)n-butyl)-3,6,9,12-tetraoxatridecylammonium bromide, wherein the method for preparing the light-controlled release type unfractionated heparin ion complex material includes mixing an aqueous solution of unfractionated heparin sodium salt with an aqueous solution of a quaternary ammonium salt surfactant containing an azophenyl group at room temperature, centrifuging the mixture after shaking, discarding the supernatant, washing the remaining precipitate three times with water, and then freeze-drying to obtain the light-controlled release type unfractionated heparin ion complex material, wherein in the mixture, the unfractionated heparin sodium salt is calculated as repeating disaccharide units, and the molar ratio of the unfractionated heparin sodium salt to the quaternary ammonium salt surfactant containing an azophenyl group is 1:4 to 1:
12.
2. The method for preparing the light-controlled release type unfractionated heparin ion complex material according to claim 1, characterized in that, include: An aqueous solution of unfractionated heparin sodium salt and an aqueous solution of a quaternary ammonium salt surfactant containing an azophenyl group were mixed at room temperature. The mixture was shaken and centrifuged, the supernatant was discarded, and the remaining precipitate was washed three times with water and then freeze-dried to obtain a light-controlled release type unfractionated heparin ion complex material. In the mixture, the unfractionated heparin sodium salt was calculated as repeating disaccharide units, and the molar ratio of the unfractionated heparin sodium salt to the quaternary ammonium salt surfactant containing an azophenyl group was 1:4 to 1:
12.
3. The method for preparing the light-controlled release type unfractionated heparin ion complex material according to claim 2, characterized in that, The concentration of the aqueous solution of the unfractionated heparin sodium salt, calculated based on the repeating disaccharide units in the unfractionated heparin sodium salt, is 10-15 mM, and the concentration of the aqueous solution of the azophenyl-containing quaternary ammonium salt surfactant is 10-15 mM.
4. The method for preparing the light-controlled release type unfractionated heparin ion complex material according to claim 2, characterized in that, The mixing liquid is shaken for 1 to 3 minutes, and the precipitated product is freeze-dried for 5 to 8 hours.