Integrated intelligent response baicalein metal supramolecular implantation device and preparation method thereof
By forming a supramolecular network layer of baicalin on the surface of the metal matrix, the problems of interface compatibility of intelligent response device materials and baicalin solubility are solved, anti-inflammatory, antibacterial effects and hemostatic functions are achieved, and the device has good stability and circulation. Utilization characteristics, suitable for dynamic monitoring and on-demand drug release.
Patent Information
- Application Number
- CN202411217221.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-02
- Publication Date
- 2024-12-13
AI Technical Summary
Existing intelligent response devices independently form coatings on the device surface, involving complex chemical synthesis and modification, resulting in challenges in material interface compatibility, and baicalin is difficult to dissolve in water to limit its application, making it difficult to prepare stable intelligent response devices.
By forming a baicalin supramolecular network layer on the surface of the metal matrix, the solubility of baicalin is enhanced by using aminoglycoside antibiotics, and the metal supramolecular network layer is formed through ultrasonic dispersion and in-situ reaction, loading antibiotics to achieve functional integration and stability of the device.
It has achieved anti-inflammatory and antibacterial effects. Baicalin is rapidly converted into baicalin in the blood, promoting hemostasis, and the device has good stability and recycling characteristics, reducing costs, and is suitable for dynamic monitoring and on-demand release of drugs.
Smart Images
Figure CN119113232A_ABST
Abstract
Description
Technical Field
[0001] The present application belongs to the technical field of intelligent response devices, and specifically relates to an integrated intelligent response baicalein metal supramolecular implant device and a preparation method thereof. Background Art
[0002] Bacterial infection and persistent bleeding caused by implanted devices can lead to the formation of chronic wounds. At the same time, the inflammatory response caused by chronic wounds will hinder wound healing. Therefore, timely hemostasis, antibacterial and elimination of inflammatory response on the wound after device implantation are of great significance to reduce infection and accelerate wound healing.
[0003] At present, the treatment of chronic wounds mostly adopts exogenous treatment methods, which largely depends on the subjective judgment of doctors, and exogenous drugs will affect the repair of chronic wounds. Therefore, there is an urgent need for a method that can continuously deliver drugs in a non-invasive, continuous and timely manner to promote rapid wound healing. Smart response devices have attracted widespread attention due to their autonomy in treatment methods, but currently, coatings are often formed independently on the surface of the device. The formation of independent coatings involves complex chemical synthesis, modification and purification, and such independent coatings pose great challenges to the interfacial compatibility of materials. Therefore, it is of great significance to reasonably and conveniently manufacture an integrated smart response device that releases antibiotics on demand and has effective anti-inflammatory and hemostatic properties.
[0004] Baicalein is a bioactive flavonoid compound isolated from the traditional Chinese medicine Scutellaria baicalensis. It can be rapidly converted into baicalin in the blood and has significant biological activity. It has obvious effects in antibacterial, anti-inflammatory, anti-thrombotic and hemostatic effects, and can effectively improve and repair liver and kidney damage caused by aminoglycoside antibiotics. However, due to the cross-conjugated system in the baicalein molecule, it is difficult to dissolve in water, which greatly limits the application of baicalein.
[0005] The dynamic chemical bonds of Schiff bases formed by the condensation of active carbonyl groups and amines have been widely used in pharmacology and medicine, especially in the field of intelligent antibacterial drugs. The dynamic chemical properties and pH response characteristics of Schiff bases are increasingly used in intelligent medical devices. It is also due to the dynamic chemical properties of Schiff bases that the stability of materials constructed by a single Schiff base construction method is insufficient, making it difficult to prepare standardized intelligent response devices. Summary of the invention
[0006] The purpose of the present application is to provide an integrated intelligent response baicalein metal supramolecular implant device and a preparation method thereof.
[0007] To achieve the above objectives, the present application provides, on the one hand, an integrated intelligent response baicalin metal supramolecular implant device, which includes a metal substrate, a supramolecular network layer formed on the surface of the metal substrate, and an aminoglycoside antibiotic loaded on the supramolecular network layer; wherein the supramolecular network layer is formed by the metal chelation of the catechol structure of baicalin and the metal substrate.
[0008] In some embodiments, the aminoglycoside antibiotic is selected from one or more of tobramycin, gentamicin sulfate, apramycin sulfate, paromomycin sulfate, kanamycin sulfate, neomycin sulfate, and streptomycin sulfate.
[0009] In some embodiments, the metal matrix is selected from a metal implant device, such as a bone screw.
[0010] In some embodiments, the supramolecular network layer has a thickness of 25±10 nm.
[0011] On the other hand, the present application provides a method for preparing the baicalein metal supramolecular implant device, comprising:
[0012] preparing baicalein ethanol solution and aminoglycoside antibiotic aqueous solution respectively;
[0013] The ethanol solution of baicalin and the aqueous solution of aminoglycoside antibiotics are mixed and ultrasonically dispersed;
[0014] The metal substrate is immersed in the mixed solution and placed on a shaker for in-situ reaction for 12 to 96 hours to obtain the baicalein metal supramolecular implant device.
[0015] In some embodiments, the concentration of the ethanol solution of baicalein is 10 mg / mL to 20 mg / mL; and the concentration of the aqueous solution of aminoglycoside antibiotics is 5 mg / mL to 10 mg / mL; and the ethanol solution of baicalein and the aqueous solution of aminoglycoside antibiotics are mixed at a volume ratio of 2:1 to 1:2.
[0016] In some embodiments, the aminoglycoside antibiotic is selected from one or more of tobramycin, gentamicin sulfate, apramycin sulfate, paromomycin sulfate, kanamycin sulfate, neomycin sulfate, and streptomycin sulfate.
[0017] In some embodiments, the metal matrix is a metal implant device, such as a bone screw.
[0018] In the present application, aminoglycoside is used to greatly enhance the solubility of baicalein, and the catechol structure of baicalein directly interacts with the metal matrix through strong hydrogen bonding and metal chelation, forming a multi-angle, strongly bonded metal supramolecular network layer on the surface of the metal matrix. The formed metal supramolecular network layer is integrated with the surface of the metal matrix, and has better stability when implanted in the body.
[0019] The baicalein metal supramolecular implant device prepared in the present application has a metal supramolecular network layer formed on the surface of the metal substrate, which gradually decomposes and releases the drug under acidic conditions, specifically, when the pH is 4.5 to 6.5, it gradually decomposes and releases the drug. When the drug is completely released, the metal substrate body is not destroyed, and the supramolecular network layer can be formed again on the surface of the metal substrate body by the above method.
[0020] Compared with the prior art, this application has the following advantages and beneficial effects:
[0021] (1) This application uses the natural flavonoid baicalin to construct a stable supramolecular network layer on the surface of a metal implant device through a Schiff base chemical bond, and loads an aminoglycoside antibiotic. The resulting baicalin metal supramolecular implant device exhibits good anti-inflammatory and antibacterial effects in vivo; at the same time, baicalin can be rapidly converted into baicalin in the blood, promoting the synergistic treatment and hemostasis of the device. This application realizes the functional integration and intelligent response of the implant device, and also greatly improves the biosafety of the implant device.
[0022] (2) The baicalein metal supramolecular implant device of the present application has the characteristics of recycling, which can effectively reduce the cost of device use; and the baicalein metal supramolecular implant device of the present application also has good pH response ability, and has broad applications in the fields of dynamic monitoring and on-demand release.
[0023] (3) The preparation method of the present application is simple and efficient. The raw materials aminoglycoside antibiotics and baicalein used are common reagents on the market and are easy to obtain. The solvents used are green and environmentally friendly, which can ensure the green and environmental protection of the preparation process. It also has good repeatability and good industrialization prospects.
[0024] (4) The preparation method of the present application is adjustable and controllable. The drug loading amount of the metal supramolecular network layer can be controlled by adjusting the reaction time, and the surface of the prepared baicalein metal supramolecular implant device is regular and uniform. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] Figure 1 Characterization of the antibacterial properties of the samples in Example 1
[0026] Figure 2 Characterization of the antibacterial properties of the samples of Example 2;
[0027] Figure 3 Characterization of the antibacterial properties of the samples of Example 3;
[0028] Figure 4 Characterization of the antibacterial properties of the samples of Example 4;
[0029] Figure 5 Characterization of the antibacterial properties of the samples of Example 5;
[0030] Figure 6 Characterization of the antibacterial properties of the samples of Example 6;
[0031] Figure 7 Characterization of the antibacterial properties of the samples of Example 7;
[0032] Figure 8 The drug loading of samples of Examples 8, 10, 12 and 16 at different time gradients;
[0033] Fig. 9 Atomic force microscope photographs of the samples of Example 1 and Examples 17 to 19. DETAILED DESCRIPTION
[0034] In order to make the purpose, technical solutions and beneficial effects of the present application more clearly understood, the present application is further described in detail below in conjunction with embodiments.
[0035] Example 1
[0036] The steps for preparing the baicalein metal supramolecular implant device of this embodiment are as follows:
[0037] (1) dissolving baicalein in an ethanol solvent and performing ultrasonic dispersion for 5 minutes to obtain a baicalein ethanol solution which is light yellow and transparent; the volume of the obtained baicalein ethanol solution is 10 mL and the concentration is 10 mg / mL;
[0038] (2) dissolving tobramycin in deionized water, performing ultrasonic dispersion for 5 minutes, and then continuing to stir at room temperature for 2 minutes to obtain a tobramycin aqueous solution, which is uniform, colorless and transparent; the volume of the obtained tobramycin aqueous solution is 10 mL, and the concentration is 8 mg / mL;
[0039] (3) adding the aqueous solution of tobramycin to the ethanol solution of baicalein and performing ultrasonic dispersion for 5 minutes to obtain a mixed solution;
[0040] (4) soaking the cleaned bone screw in the mixed solution and placing it on a shaker at room temperature for 24 hours to perform an in-situ reaction to obtain a baicalein metal supramolecular implant device;
[0041] (5) Use deionized water to rinse the baicalein metal supramolecular implant device.
[0042] The preparation methods of baicalein metal supramolecular implant devices in Examples 2 to 7 differ from those in Example 1 only in the type and dosage of aminoglycoside antibiotics. The preparation methods of baicalein metal supramolecular implant devices in Examples 8 to 16 differ from those in Example 1 only in the in-situ reaction time. The preparation methods of baicalein metal supramolecular implant devices in Examples 17 to 19 differ from those in Example 1 only in the volume ratio of the baicalein ethanol solution to the aminoglycoside antibiotic aqueous solution. The preparation process parameters of Examples 2 to 19 are shown in Table 1 below. It should be noted that the volume ratio in Table 1 refers to the volume ratio of the baicalein ethanol solution to the antibiotic aqueous solution.
[0043] Table 1 Process parameters of the preparation methods of various embodiments
[0044]
[0045] The baicalein metal supramolecular implant device prepared in the above example was characterized as follows.
[0046] (1) Characterization of antibacterial properties
[0047] The antibacterial properties of the samples of Examples 1 to 7 and the bone screws without antibacterial treatment were characterized. The samples were placed in a bacterial solution of Staphylococcus aureus (Gram-positive bacteria) and incubated at 37°C for 24 hours. The bacterial solution was diluted by 10 4 Take 100 μL of bacterial solution, pipette it onto LB agar plate, spread it evenly and count. Figures 1 to 7 It can be seen that the baicalein metal supramolecular implant devices prepared with different aminoglycoside antibiotics have significant antibacterial activity. The vertical axes of these figures represent the number of colonies per unit gram weight of the sample.
[0048] (2) Characterization of drug loading performance
[0049] The release behavior of samples in Examples 8, 10, 12, and 16 was evaluated using the well-established derivatization method of ninhydrin to characterize the drug loading of the samples. The derivatization reagent was prepared by dissolving 85 mg of ninhydrin and 15 mg of reduced ninhydrin in 10 mL of ethylene glycol methyl ether, and the derivatization reagent was freshly prepared before measurement. The fully released solution sample (500 μL) was thoroughly mixed with 500 μL of the derivatization reagent and 500 μL of sodium acetate buffer (pH = 5.4). The mixture was then heated to 100°C for 15 minutes and then cooled to room temperature. During this process, the color of the reaction system will change from brown-yellow to blue-purple. The absorbance of the sample at 570 nm was recorded for colorimetric analysis and the drug loading was calculated. Each sample was repeated three times, and the drug loading at different time gradients is shown in Table 1. Figure 8 shown.
[0050] (3) Morphology and thickness characterization
[0051] The samples of Examples 1 and 17 to 19 were observed under a desktop scanning electron microscope, and the thickness was counted by atomic force microscopy. Fig. 9 , Fig. 9 The thickness distribution of the baicalein metal supramolecular network on the surface of the implanted device is shown, indicating the good uniformity and interfacial compatibility of the sample.
[0052] The above embodiments are only for the purpose of clearly illustrating the embodiments, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above descriptions. It is not necessary and impossible to list all the implementation methods here, so the obvious changes or modifications derived are still within the protection scope of the invention.
Claims
1. An integrated intelligent response baicalein metal supramolecular implant device, Its characteristics are: The invention comprises a metal matrix, a supramolecular network layer formed on the surface of the metal matrix, and an aminoglycoside antibiotic loaded on the supramolecular network layer; the supramolecular network layer is formed by the chelation of the catechol structure of baicalein and the metal of the metal matrix.
2. The integrated intelligent response baicalein metal supramolecular implant device as claimed in claim 1, Its characteristics are: The metal matrix is selected from metal implant devices.
3. The integrated intelligent response baicalein metal supramolecular implant device as claimed in claim 1, Its characteristics are: The thickness of the supramolecular network layer is 25±10 nm.
4. The integrated intelligent responsive baicalein metal supramolecular implant device as claimed in claim 1, Its characteristics are: The aminoglycoside antibiotic is selected from one or more of tobramycin, gentamicin sulfate, apramycin sulfate, paromomycin sulfate, kanamycin sulfate, neomycin sulfate, and streptomycin sulfate.
5. A method for preparing an integrated intelligent response baicalein metal supramolecular implant device, Its characteristics include: preparing baicalein ethanol solution and aminoglycoside antibiotic aqueous solution respectively; The ethanol solution of baicalein and the aqueous solution of aminoglycoside antibiotics are mixed and ultrasonically dispersed; The metal substrate is immersed in the mixed solution and placed on a shaker for in-situ reaction for 12 to 96 hours to obtain the baicalein metal supramolecular implant device.
6. The preparation method according to claim 5, Its characteristics are: The concentration of the baicalein ethanol solution is 10 mg / mL to 20 mg / mL; the concentration of the aminoglycoside antibiotic aqueous solution is 5 mg / mL to 10 mg / mL; and the baicalein ethanol solution and the aminoglycoside antibiotic aqueous solution are mixed at a volume ratio of 3:1 to 1:
2.
7. The preparation method according to claim 5, Its characteristics are: The aminoglycoside antibiotic is selected from one or more of tobramycin, gentamicin sulfate, apramycin sulfate, paromomycin sulfate, kanamycin sulfate, neomycin sulfate, and streptomycin sulfate.
8. The preparation method according to claim 5, Its characteristics are: The metal matrix is selected from metal implant devices.