A ratriptan compound material with light-controlled release function and a preparation method thereof

Abstract

The present application relates to the technical fields of anticoagulant materials and stimuli-responsive materials, and mainly relates to a light-controlled release function of the complex material of nattexarin and a preparation method thereof.The light-controlled release function of the complex material of nattexarin is obtained by mixing calcium nattexarin and quaternary ammonium salt compound containing azobenzene structure in aqueous solution, and then through the treatment of oscillation, centrifugation, water washing and drying.The light-controlled release function of the complex material of nattexarin prepared by the present application has the characteristics of good biocompatibility and the ability to release nattexarin under light control.Using the light-controlled release function of the complex material of nattexarin, the blood clotting time can be effectively controlled by light.The light-controlled release function of the complex material of nattexarin prepared by the present application can be applied to the field of blood clotting regulation.

Description

Technical Field

[0001] This invention relates to the field of anticoagulant materials and stimulus-responsive materials, and mainly to a natropone complex material with light-controlled release function and its preparation method. Background Technology

[0002] Heparin is classified into two types: unfractionated heparin and low molecular weight heparin (LMWH). LMWH typically has a molecular weight range of 2–9 kDa. Compared to unfractionated heparin, LMWH has a better anticoagulant effect and has become the main anticoagulant drug used clinically to treat and prevent deep vein thrombosis and pulmonary embolism. However, the use of heparin carries risks. Overdose can easily cause side effects such as bleeding, thrombocytopenia, and osteoporosis, while insufficient dosage cannot effectively inhibit blood clotting. Therefore, it is crucial to prepare drug materials capable of controllable release of LMWH and to achieve external regulation of anticoagulation effects.

[0003] While mesoporous materials, carbon nanomaterials, and transdermal patches have been applied in heparin release research, designing and manufacturing heparin-releasing materials with controllable release properties for anticoagulation therapy remains a significant challenge. Compared to existing heparin-releasing materials, those responsive to light stimulation hold promise for broader applications due to the advantages of light as a stimulus source, including spatiotemporal controllability, absence of byproducts, and minimal damage. Light-responsive smart materials have made progress in several materials fields, such as light-responsive smart adhesives, energy storage materials, and self-healing materials. However, no research progress has yet been made on the controllable release of heparin using this light-stimulation-responsive strategy.

[0004] Nadroparin, a member of the small-molecule heparin family, lacks photoresponsive groups and cannot effectively respond to light stimuli. Therefore, the preparation of photoresponsive nadroparin materials requires combining it with photosensitive molecules, utilizing structural changes in these molecules to control the properties of nadroparin. Azobenzene is one of the most widely used photosensitive molecules, capable of converting absorbed light energy into mechanical energy through conformational changes, effectively altering the molecular arrangement within the material and thus changing its properties. Utilizing this property, various photosensitive smart materials have been developed and applied. However, no nadroparin with photoresponsive properties has yet been reported, nor have any other photoresponsive heparin materials been reported. This limits the application of heparin materials as smart drug materials in controlled anticoagulation therapy. Therefore, developing photocontrolled release small-molecule heparin materials is of great significance for expanding the applications of heparin-based materials in basic research and medicine. Summary of the Invention

[0005] In view of this, the purpose of the present invention is to provide a heparin complex material with light-controlled release function and a method for preparing the same.

[0006] The technical solution of the present invention is as follows:

[0007] This invention provides a nadroparin complex material with photocontrolled release function, the raw materials for which include nadroparin calcium and a quaternary ammonium salt compound containing an azobenzene structure.

[0008] In this invention, the molecular weight of the Nagqu heparin calcium ranges from 3600 to 5000 g / mol.

[0009] In this invention, the quaternary ammonium salt compound containing the azobenzene structure is N,N-dimethyl-N-(4-(4-((4-n-octyloxyphenyl)diazeninyl)phenoxy)n-butyl)-2,5-dioxaheptylammonium bromide.

[0010] In this invention, the preparation method of the nadroparin complex material with photocontrolled release function includes:

[0011] An aqueous solution of heparin calcium was mixed with an aqueous solution of a quaternary ammonium salt compound containing an azobenzene structure at room temperature. The mixture was shaken, centrifuged, and the supernatant was discarded. The resulting precipitate was washed three times with water and then freeze-dried to obtain a heparin complex material with photocontrolled release function.

[0012] In the present invention, in the preparation method of the nadroparin complex material with photocontrolled release function, the concentration of the aqueous solution of nadroparin calcium, based on the repeating disaccharide unit in nadroparin calcium, is 10-15 mM, and the concentration of the aqueous solution of the quaternary ammonium salt compound containing the azobenzene structure is 10-15 mM.

[0013] In the present invention, in the preparation method of the nadroparin complex material with light-controlled release function, the nadroparin calcium in the mixture is calculated as a repeating disaccharide unit, and the molar ratio of the nadroparin calcium to the quaternary ammonium salt compound containing an azobenzene structure is 1:4 to 1:12.

[0014] In the preparation method of the heparin complex material with light-controlled release function in this invention, the shaking time of the mixture is 3 to 5 minutes, and the freeze-drying time of the precipitated product is 5 hours.

[0015] This invention provides a nadroparin complex material with light-controlled release function and its preparation method. The nadroparin complex material with light-controlled release function and its preparation method have the following characteristics:

[0016] 1. The nadroparin complex material with photocontrolled release function obtained by the present invention is an ionic complex formed by the electrostatic interaction between nadroparin calcium and a quaternary ammonium salt compound containing an azobenzene structure.

[0017] 2. The nadroparin complex material with light-controlled release function obtained by the present invention can rapidly release nadroparin under ultraviolet light stimulation under physiological conditions.

[0018] 3. The heparin complex material with light-controlled release function obtained by the present invention has good biocompatibility after cytotoxicity and hemolytic toxicity tests.

[0019] 4. The nadroparin complex material with photocontrolled release function obtained by the present invention can controllably release nadroparin under physiological conditions through ultraviolet light irradiation, effectively regulating the blood clotting time. Attached Figure Description

[0020] Figure 1 To compare the clotting time of blood under ultraviolet light irradiation and no light irradiation conditions with the clotting time without drug use using the natroparin complex material with light-controlled release function described in Example 1. Detailed Implementation

[0021] This invention provides a nadroparin complex material with photocontrolled release function 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] 200 μL of 15 mM (based on the repeating disaccharide unit in nadroparin calcium) aqueous solution of nadroparin calcium and 1.2 mL of 15 mM N,N-dimethyl-N-(4-(4-((4-n-octyloxyphenyl)diazeninyl)phenoxy)n-butyl)-2,5-dioxaheptaylammonium bromide aqueous solution were mixed in a centrifuge tube and shaken for 5 minutes. The mixture was then centrifuged for 5 minutes at a relative centrifugal force of 6124 g. The supernatant was discarded, and the remaining precipitate was washed three times with water and then freeze-dried for 5 hours to obtain the nadroparin complex material with photocontrolled release function described in this invention.

[0025] The prepared nadroparin complex material with photocontrolled release function was tested and found to have low cytotoxicity and hemolytic toxicity, and good biocompatibility.

[0026] Using the prepared nadroparin complex material with photocontrolled release function, the coagulation time of blood under ultraviolet light irradiation and no light irradiation conditions was compared with the coagulation time without drug use. Figure 1 As shown, according to Figure 1 The results show that the nadroparin complex material with photocontrolled release function, under ultraviolet light irradiation, can controllably release nadroparin in vivo. Compared with the absence of medication, the nadroparin complex material with photocontrolled release function can prolong clotting time by more than 3 times, and compared with the absence of light using the nadroparin complex material with photocontrolled release function, it prolongs clotting time by more than 2 times. The nadroparin complex material with photocontrolled release function possesses excellent photoregulated anticoagulant function.

[0027] Comparative Example 1:

[0028] 200 μL of 15 mM aqueous solution of naquheparin calcium (based on repeating disaccharide units in naquheparin calcium) and 400 μL of 15 mM aqueous solution of N,N-dimethyl-N-(4-(4-((4-n-octyloxyphenyl)diazeninyl)phenoxy)n-butyl)-2,5-dioxaheptaylammonium bromide were mixed in a centrifuge tube and shaken for 5 minutes. The mixture was then centrifuged at a relative centrifugal force of 6124 g for 5 minutes. The supernatant was discarded, and 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 5 hours to obtain the naquheparin ion complex material.

[0029] The heparin ion complex material prepared in Comparative Example 1 could not achieve effective photo-controlled anticoagulation function in vivo, according to the test results.

[0030] 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 nadroparin complex material with light-controlled release function, characterized in that, Its synthetic raw materials include naduzheparin calcium and a quaternary ammonium salt compound containing an azobenzene structure. The molecular weight of the naduzheparin calcium ranges from 3600 to 5000 g / mol, and the quaternary ammonium salt compound containing the azobenzene structure is... N,N -dimethyl- N -(4-(4-((4-n-octyloxyphenyl)diazeninyl)phenoxy)n-butyl)-2,5-dioxaheptaylammonium bromide, wherein the preparation method of the nadroparin complex material with light-controlled release function includes mixing an aqueous solution of nadroparin calcium with an aqueous solution of a quaternary ammonium salt compound containing an azobenzene structure at room temperature, shaking the mixture, centrifuging and discarding the supernatant, washing the obtained precipitate three times with water and then freeze-drying it to obtain the nadroparin complex material with light-controlled release function, wherein in the mixture, the nadroparin calcium is calculated as a repeating disaccharide unit, and the molar ratio of the nadroparin calcium to the quaternary ammonium salt compound containing an azobenzene structure is 1:4 to 1:

12.

2. The method for preparing the nadroparin complex material with photocontrolled release function according to claim 1, characterized in that, include: An aqueous solution of nadroparin calcium was mixed with an aqueous solution of a quaternary ammonium salt compound containing an azobenzene structure at room temperature. The mixture was shaken, centrifuged, and the supernatant was discarded. The resulting precipitate was washed three times with water and then freeze-dried to obtain a nadroparin complex material with photocontrolled release function. In the mixture, the nadroparin calcium was calculated as a repeating disaccharide unit, and the molar ratio of nadroparin calcium to the quaternary ammonium salt compound containing an azobenzene structure was 1:4 to 1:

12.

3. The method for preparing the nadroparin complex material with photocontrolled release function according to claim 2, characterized in that, The aqueous solution of Nagqu heparin calcium has a concentration of 10-15 mM, calculated based on the repeating disaccharide units in Nagqu heparin calcium, and the aqueous solution of the quaternary ammonium salt compound containing the azobenzene structure has a concentration of 10-15 mM.

4. The method for preparing the natroparin complex material with photocontrolled release function according to claim 2, characterized in that, The mixing liquid is shaken for 3 to 5 minutes, and the precipitated product is freeze-dried for 5 hours.

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