Patent Application
20240131219
The present invention claims the priority of a Chinese prior application No. 202211299465.2 filed on Oct. 21, 2022, the specification, claims and attached drawings of which are incorporated herein as a part of references of the present invention, and the present invention is also a partial continuing application based on the application.
The present invention belongs to the technical field of biomedicine, and relates to radioactive glass microspheres for embolization, a preparation method and an application thereof.
During therapy for liver cancer, as normal hepatic cells have a lower radiation dose to be tolerated and hepatoma carcinoma cells required to be killed have a relatively higher radiation dose, external radiotherapy for the liver cancer has not been widely used in clinical practice.
However, during internal radiotherapy for the liver cancer, a radioactive embolization method can achieve the effects of relatively higher therapeutic effect and relatively fewer side effects. Specifically, radioactive embolization refers to a process of injecting radionuclide microspheres into hepatic arteries. The microspheres can be highly concentrated and retained in micro-blood vessels of the hepatoma carcinoma cells, so as to embolize nourishing blood vessels of tumors and kill surrounding carcinoma cells through radiation.
Radionuclide emitting rays loaded by the microspheres generally include a beta-ray and have an action distance within a few millimeters to tens of millimeters, which can cause the death of surrounding tumor cells and have little damage to normal hepatic cells far from the microspheres.
At present, two kinds of radioactive microspheres have been put into clinical use, including TheraSphere® microspheres developed by NORDION in Canada and SirSpheres® microspheres developed by Sirtex Medical in Australia. The two kinds of microspheres use a beta-ray emitted by yttrium-90 to achieve a therapeutic effect, but have different physical properties and production methods. The TheraSphere® microspheres are glass microspheres containing non-radioactive yttrium-89, and the yttrium-89 contained in the glass microspheres are activated into radioactive yttrium-90 by neutron activation before use (U.S. Pat. Nos. 4,789,501 and 5,011,677). The SirSpheres® microspheres use ion-exchange resin microspheres to adsorb activated yttrium-90 ions and cure the same in a phosphate form at adsorption sites (US20070253898A1). Glass microspheres are loaded with more radionuclides than resin adsorption microspheres. For example, each TheraSphere® glass microsphere has a radiation dose of about 2,500 Bq and a nuclide loading capacity of about 30%, while each SirSpheres® resin microsphere has a radiation dose of about 75 Bq. As for the same therapeutic dose, more resin microspheres are required. However, the glass microspheres have a higher density. The TheraSphere® glass microspheres have a density of 3.6 g/cm3, which is three times higher than the density of blood (1.05 g/cm3). Due to the too high density, the glass microspheres have a too high sedimentation velocity and poor distribution and deposition effects in liver blood vessels. The SirSpheres® microspheres have a density of 1.6 g/cm3, which is similar to the density of blood, thus having good distribution and deposition effects in liver blood vessels. However, such microspheres have a low nuclide loading capacity. According to SIRTEX, a method for preparing low-density radioactive glass microspheres for embolization is disclosed (U.S. Pat. No. 6,998,105), and the density can be as low as 2.2 g/cm3. With respect to such microspheres, the density of the microspheres is decreased by reducing the proportion of a high-density nuclide oxide in a glass matrix (only 2%). Although the density is decreased, the nuclide loading rate is much lower than that of the TheraSphere® microspheres (with a nuclide loading rate of 30%). Apart from glass, resins and other materials, degradable polymers (such as PLGA, PLLA and the like) are also used for preparing radioactive microspheres for embolization with lower density, while the stability and the nuclide loading rate are inferior to glass micropsheres.
According to U.S. Ser. No. 10/940,219B2, radioactive microspheres for radiation therapy are disclosed. Resin glass with nanopores is used for preparation, a solution containing a radionuclide is loaded into the nanopores on the surfaces of microspheres, the solution is evaporated until the radionuclide precipitates onto the surfaces of the nanopores in the microspheres, and then baking at high temperature is performed for fixing to obtain the radioactive microspheres. However, the radioactive microspheres prepared by this method still belong to resin microspheres and still have a low nuclide loading capacity, and as for the same therapeutic dose, more microspheres are required.
At present, radioactive microspheres that have a high nuclide loading capacity and a suitable density to achieve good distribution and deposition effects during injection are not provided.
In order to overcome the defects of the prior art, the present invention provides novel radioactive glass microspheres for embolization. A nuclide oxide and a foaming agent are added into a glass matrix, blended and uniformly mixed for making the foaming agent decomposed and vaporized at a high temperature to generate bubbles, so as to prepare the radioactive glass microspheres for embolization with cavities. The radioactive glass microspheres for embolization have a density of 1.4-2.3 g/cm3, a nuclide loading rate of 15-40 wt % and a higher and more stable radiation dose. It can achieve better distribution and deposition effects in liver blood vessels after injection, and can achieve a better therapeutic effect for liver cancer or hepatocellular carcinoma (HCC).
The cavities in the glass microspheres are formed during machining rather than being etched from the outside, so as to form microchannels communicated the outside. At a high temperature, the glass microspheres are melted into a liquid state, and gases released by decomposition of the foaming agent, such as carbon dioxide emitted from the microspheres, form bubbles in the melted glass microspheres. As the temperature is decreased rapidly, melted glass is cured rapidly, and the internal bubbles form cavities to obtain non-solid microspheres, so that the density of the microspheres is decreased. That is so say, the weight is decreased while the overall volume is unchanged, thereby decreasing the density.
On the one hand, the present invention provides radioactive glass microspheres for embolization. The glass microspheres include glass microsphere bodies and cavities formed in the glass microsphere bodies, and the glass microsphere bodies contain a nuclide oxide; and the glass microspheres have a density of not higher than 2.3 g/cm3.
Further, the nuclide oxide is any one or more of Y2O3, Lu2O3, Ho2O3 or P2O5; and the glass microsphere bodies further contain any one or more of Al2O3, SiO2 and B2O3.
Further, the glass microspheres have a density of 1.4-2.3 g/cm3 and a nuclide loading rate of 15-40 wt %.
Due to a higher density, existing solid glass microspheres are quickly sedimentated to every corner of the bottoms of blood vessels after each injection and are difficult to be accurately located for vascular embolization, thus having a greatly reduced therapeutic effect.
In the present invention, the glass microspheres are prepared by adding a foaming agent into a glass matrix. As the foaming agent is decomposed at a high temperature to generate bubbles, the microspheres are more loose in texture and have more cavities, thus having a lower density. The microspheres are not immediately sedimentated to the bottoms of blood vessels after injection, but can be uniformly distributed on upper sides, lower sides, left sides and right sides of accurate positions in the blood vessels. Therefore, the microspheres have better distribution and deposition effects in liver blood vessels and can accurately accumulate in sites requiring vascular embolization to achieve a better vascular embolization effect.
The glass microspheres prepared by the present invention can achieve a high nuclide loading capacity and a higher radiation dose, is more suitable for being used as radioactive glass microspheres for embolization, and can achieve a better therapeutic effect. It is proven through research that compared with solid stripped microspheres without addition of a foaming agent, the glass microspheres prepared after foaming with a foaming agent are loose in texture and contain more cavities. A nuclide in the glass microspheres prepared therefrom can produce a higher radiation dose after neutron activation. The reason may be that a beta-ray emitted by yttrium-90 is more likely to radiate from a loose glass matrix with cavities and can produce a higher radiation dose and kill surrounding tumor cells more effectively, thereby having a better therapeutic effect.
The radiation dose of the present invention refers to an irradiation effect produced by each glass microsphere on the inside of a quantitative irradiated substance. For example, when an irradiation quantity generated by irradiation of 1 g of the radioactive glass microspheres is 2,500 Bq, the radiation dose is 2,500 Bq. The radiation dose may also be considered as a radiation intensity emitted by the microspheres of a same weight. It may be understood that as for the radiation or irradiation intensity, the irradiation intensity will be decreased or weakened when the microspheres pass through some barriers, such as plastics, steel plates and the like. However, the microspheres of the present invention have many pores, and a beta-ray emitted by a substance (yttrium-90) in the microspheres basically realizes irradiation or radiation directly without barriers and is basically not weakened, so that the irradiation intensity is generally enhanced compared with that of solid microspheres.
Further, the glass microspheres contain, by molar percentage, 0-40% of Al2O3, 20-80% of SiO2, 0-20% of B2O3 and 10-30% of a nuclide oxide, and have a particle size of 10-100 μm.
Through optimization of a formula of the glass microspheres in the present invention, it has found that the glass microspheres with cavities containing B2O3 have a higher nuclide loading rate and an obviously higher radiation dose. After analysis of the microspheres, the reason may be that as the glass microspheres containing B2O3 have better properties, convenience is provided for foaming of the foaming agent to further improve the texture and fix more nuclide oxides, and radiation of a 3-ray is more facilitated to achieve a higher sustained radiation dose under the condition of a same nuclide loading capacity.
On the other hand, the present invention provides a method for preparing radioactive glass microspheres for embolization. The method includes the following steps:
In the present invention, as a foaming agent is added into a glass matrix and the foaming agent is decomposed and vaporized at a high temperature during preparation of the glass microspheres, the glass microspheres are more loose in texture and have an obviously decreased density. Meanwhile, many hollow cavities are generated in the glass microspheres, which can not only further decrease the density, but also increase the nuclide loading rate and the radiation dose of the glass microspheres.
Meanwhile, in the radioactive glass microspheres for embolization provided by the present invention, as a nuclide oxide is directly added into a glass matrix, the nuclide oxide is more uniformly distributed in the glass matrix and has a better fusion effect with other components in the glass matrix during preparation of the microspheres. The microspheres have a high nuclide loading rate, a higher radiation dose in the process of emitting a β-ray to a disease site, and a longer stabilization time.
Further, the glass microsphere bodies further contain any one or more of Al2O3, SiO2 and B2O3, and a nuclide oxide; and the nuclide oxide is any one or more of Y2O3, Lu2O3, Ho2O3 or P2O5.
Further, the foaming agent in step (1) and/or step (b) includes any one or more of a sulfate, a carbonate, an inorganic salt of a gas generated by high-temperature decomposition, and an organic polymer.
In some embodiments, the foaming agent includes any one or more of Na2SO4, MgSO4, Na2CO3, CaSO4, K2CO3, Li2CO3, SrCO3, an inorganic salt of a gas produced by high-temperature decomposition, polyethylene glycol and polyvinyl alcohol.
Further, during the melting by heating in step (1) and/or step (a), the heating is performed at a temperature of 1,000-1,600° C.; and during the melting by heating in step (3) and/or step (c), the heating is performed at a temperature of 1,600-1,800° C.
The heating is performed at a temperature of 1,000-1,600° C. in step (1) and/or step (a), which is lower than the temperature of the foaming agent as much as possible, and the heating is performed to melt components of the glass matrix and promote uniform mixing after melting. In some embodiments, in order to prevent a large quantity of the foaming agent from decomposition in advance, other components may be heated, dissolved and mixed uniformly first, and finally the foaming agent is added, stirred and mixed uniformly.
The melting by heating in step (3) and/or step (c) is performed for decomposing the foaming agent to generate bubbles. Different foaming agents have different foaming temperatures, which generally start to decompose and generate bubbles at a temperature higher than 800° C. or 1,300° C.
Further, the method further includes a step (4) and/or a step (d): screening glass microspheres with a suitable particle size of 10-100 μm and a density of 1.4-2.3 g/cm3.
Further, the method for preparing radioactive glass microspheres for embolization provided by the present invention includes the following steps:
Further, the foaming agent in step (1) includes Na2SO4, CaSO4, MgSO4 and other sulfates, Na2CO3, K2CO3, Li2CO3 and other carbonates, and other inorganic salts of a gas produced by high-temperature decomposition, or polyethylene glycol, polyvinyl alcohol and other organic polymers.
Further, the irregular glass particles in step (2) have a particle size of 10-100 μm.
Further, the suitable particle size in step (5) is 10-100 μm, and the density is required to be 1.4-2.3 g/cm3.
Further, a solvent used for density screening includes electronic fluorinated liquids having different densities (such as 3M™Novec™HFE7100, 3M™Novec™ FC40, 3M™Novec™ FC70 and the like), 1,2-dibromoethane, an iopamidol solution and the like.
On another hand, the present invention provides use of the glass microspheres described above, or glass microspheres prepared by the method described above in preparation of radioactive glass microspheres for embolization that can be uniformly distributed and deposited at an injection site and can increase the radiation dose.
Further, the radioactive glass microspheres for embolization can increase the radiation dose of a β-ray.
Further, the radioactive glass microspheres for embolization contain, by molar percentage, 0-40% of Al2O3, 20-80% of SiO2, 0-20% of B2O3 and 10-30% of a nuclide oxide.
On another hand, the present invention provides use of the radioactive glass microspheres for embolization in preparation of drugs for treatment of tumors.
In some embodiments, the tumors include hepatocellular carcinoma.
The present invention has the following beneficial effects.
The present invention is described in further detail below in conjunction with examples. It is to be noted that the examples below are intended to facilitate understanding of the present invention, rather than to limit the present invention in any manner. Reagents not specifically identified in the examples are known products and are obtained by purchasing commercially available products.
A method for preparing radioactive glass microspheres for embolization is provided in this example. The method includes the following steps.
Certain quantities of Y2O3, SiO2, Al2O3 and B2O3 were weighed, placed in a quartz grinder (specific proportions are as shown in Table 1) and fully ground for 10 minutes for uniform mixing. A uniformly mixed microsphere raw material powder was transferred to a platinum crucible and heated to 1,000-1,600° C. in a Muffle furnace. 20 minutes later, a melted glass mixture was stirred with a quartz rod and heated again for 10 minutes. A certain quantity of Na2SO4 or K2CO3 was taken, placed in a quartz grinder and fully ground for 10 minutes. The melted glass mixture was poured, stirred with a quartz rod, heated for 5 minutes, then taken out and slowly poured into water for water quenching. Then, a prepared glass material was ground into a glass powder with an irregular shape and a particle size of 1-100 μm with a ball mill. The glass powder was subjected to further particle size sorting through an ultrasonic vibrating screen (vibrating for 20 minutes) equipped with a 10 μm filter screen and a 40 μm filter screen, and a glass powder on the 10 μm filter screen was collected. The glass powder was transferred into a flame spheroidization furnace with nitrogen as a carrier gas and an oxygen-acetylene flame as a spheroidization flame (the flame has a temperature of greater than 3,000° C., and the furnace has a temperature of about 1,600-1,800° C.). The glass powder with an irregular shape was melted in a spherical shape, and a foaming agent inside was decomposed to release gases so as to form cavities. Microspheres were collected with a collector at the bottom of the flame spheroidization furnace. The obtained microspheres were first sieved through an ultrasonic vibrating sieve (vibrating for 20 minutes) equipped with a 20 μm filter and a 50 μm filter, and then microspheres on the 20 μm filter were collected.
The glass transition temperature of 14 kinds of glass microsphere samples in Table 1 was measured by a differential scanning calorimeter (DSC3, Mettler Toledo) in Example 1 of the present invention, and specific results are as shown in Table 2. In addition, the density of the glass microsphere samples in Table 1 was measured, and the results are as shown in Table 2. The signal intensity of corresponding nuclides in the glass microsphere samples-in Table 1 was measured by inductively coupled plasma-mass spectrometry (ICP-quadrupole-MS, Varian 810-MS, USA) and compared with standard curves of the corresponding nuclides to determine the final nuclide content. Nuclide loading rate (%)=mass of nuclide/total mass of microspheres for embolization×100%, and the results are as shown in Table 2. 100 mg of the samples in Example 1 were subjected to neutron irradiation for 6 hours (the neutron flux is about 5×1013 neutrons/cm2·s) respectively, and the radiation dose of each sample was measured by a dose calibrator (Atomlab 100). The S104 and H109 microspheres prepared were suspended in a 0.1% Tween 20 solution and then dropped into a hemocytometer, and optical photographs of the microspheres were taken with a microscope. As shown in
It can be seen from Table 2 that compared with solid glass microspheres (S101-S104), the density of glass microspheres (H101-H111) added with a foaming agent is significantly decreased and is generally about 1.4-2.3 g/cm3, which is much lower than that of the solid microspheres (greater than 3.5 g/cm3). The reason is that after a foaming agent is added, the overall glass microspheres are more loose in texture and have more cavities therein, and the density is greatly decreased in comparison with the solid glass microspheres, which is more similar to the density of blood. Thus, the hollow glass microspheres are more suitable for use as radioactive glass microspheres for embolization. The hollow glass microspheres are not quickly sedimentated in liver blood vessels after injection, but can be uniformly and stably distributed in the liver blood vessels to achieve better distribution and deposition effects and a better embolization effect, thereby significantly improving the therapeutic effect.
Compared with the solid glass microspheres (S101-S104), the glass microspheres (H101-H111) added with a foaming agent have little change in glass transition temperature, a slightly increased nuclide loading rate and an obviously different radiation dose, which is increased from about 2,500 MBq to about 3,600 MBq. The reason may be that the glass microspheres (H101-H111) added with a foaming agent are loose in texture and contain many bubbles and cavities therein. After neutron activation of a nuclide in the glass microspheres, a β-ray emitted by yttrium-90 is more likely to radiate from a loose glass matrix with cavities and can produce a higher radiation dose and kill surrounding tumor cells more effectively.
Through comparison of glass matrix formulas of the two kinds of glass microspheres, it can be seen that in the glass microspheres (H101-H111) added with a foaming agent, when the glass matrix contains B2O3, the nuclide loading rate is high, and the radiation dose is obviously higher. After analysis of the microspheres, the reason may be that as the glass microspheres containing B2O3 have better properties, convenience is provided for foaming of the foaming agent to further improve the texture and fix more nuclide oxides, and radiation of a β-ray is more facilitated.
In addition, two different foaming agents including Na2SO4 or K2CO3 have no obviously different foaming effects in preparation of the glass microspheres. With increase of the-amount of the foaming agent Na2SO4 or K2CO3, the density of the prepared glass microspheres is further decreased, but the nuclide loading rate and the radiation dose are not continuously increased. Therefore, the added amount of Na2SO4 or K2CO3 is preferably 2 molar %.
Therefore, in order to improve comprehensive performance of radioactive glass microspheres for embolization, a foaming agent is required to be added for preparing glass microspheres with cavities. B2O3 is required to be added in a glass matrix formula, and 2 molar % Na2SO4 or K2CO3 can be used as a foaming agent.
In this example, in order to further reduce density differences between microspheres, density screening is performed on the microspheres. The microspheres are placed in a solvent with a specific density for centrifugal separation, a precipitated part includes microspheres with a density greater than that of the solvent, and a supernatant part is the part with a density less than that of the solvent. Specific operations are as follows.
10 g of H102 microspheres (prepared in Example 1) were weighed, added into 40 mL of 1,2-dibromoethane (with a density of 2.17 g/cm3) and shaken for 30 seconds for uniform mixing, followed centrifugation for 10 minutes (at 5,000×g), and 15 mL of an emulsion on the upper layer was collected. Then, the microspheres were added into 35 mL of 1,2-dibromoethane and shaken for 30 seconds for uniform mixing, followed by centrifugation for two times for 10 minutes (at 5,000×g), and 10 mL of an emulsion on the upper layer was collected. The obtained microspheres were placed in an oven for drying at 60° C. for more than 2 hours. The dried microspheres were added into 40 mL of a 3 M fluorinated liquid FC40 (with a density of 1.85 g/cm3) and shaken for 30 seconds for uniform mixing, followed by centrifugation for 10 minutes (at 5,000 g), and 35 mL of a solution on the upper layer was removed. Then, the microspheres were added into 35 mL of a 3 M fluorinated liquid FC40 and shaken for 30 seconds for uniform mixing, followed by centrifugation for 10 minutes (at 5,000×g), and 35 mL of a solution on the upper layer was removed. The microspheres at the bottom were placed in an oven for drying at 60° C. for more than 2 hours to make the residual FC40 completely volatilized. The obtained microspheres are as shown in
In order to evaluate the sedimentation velocity of hollow microspheres, 40 mg of solid microspheres (S101) and hollow microspheres prepared in Example 2 were weighed and added into 5 mL of PBS for uniform mixing, followed by standing for 1 minute, respectively, and natural sedimentation photographs of the microspheres in PBS were taken, as shown in
It can be seen from
Thus, it can be seen that due to a high density, existing solid glass microspheres are quickly sedimentated to every corner of the bottoms of blood vessels after each injection and are difficult to be accurately located for achieving a good vascular embolization effect. However, the glass microspheres with cavities, which are prepared by foaming with a foaming agent and provided by the present invention, are not immediately sedimentated to the bottoms of blood vessels after injection, but can be uniformly distributed on upper sides, lower sides, left sides and right sides of vertical interfaces in the blood vessels and accurately accumulate in sites requiring vascular embolization until vascular embolization is realized, so as to achieve a better therapeutic effect.
10 mg of the microspheres obtained in Example 2 were taken, suspended in 500 μL of a 0.1% Tween 20 solution and dropped into a hemocytometer, and an optical photograph of the microspheres was taken with a microscope. The microspheres have one or more cavity structures. The particle size of the microspheres was analyzed and measured by image processing software Image J. The microspheres have an average diameter of 26.8 μm. The nuclide loading rate of the microspheres for embolization was measured by inductively coupled plasma-mass spectrometry. 5 mg of the microspheres for embolization prepared in Example 2 were weighed, and the signal strength of corresponding nuclides was measured by inductively coupled plasma-mass spectrometry (ICP-quadrupole-MS, Varian 810-MS, USA) and compared with standard curves of the corresponding nuclides to determine the final nuclide content. Nuclide loading rate (%)=mass of nuclides/total mass of microspheres for embolization×100%. Through calculation and analysis, the nuclide loading rate is 34.8%. Test results are as shown in Table 3.
It can be seen from Table 3 that compared with TheraSphere® glass microspheres, the hollow glass microspheres for embolization of the present invention have the advantages that as cavities are formed on the glass microspheres, the density of the glass microspheres for embolization is effectively decreased, and the hollow glass microspheres have good distribution and deposition effects during injection. Moreover, it can also be ensured that the glass microspheres provided by the present invention have a high nuclide loading rate.
A Sumianxin II injection for animals, pentobarbital sodium, an animal fixing frame, an animal dissection plate, a 1 mL syringe, a 5 mL syringe, a 10 mL syringe, an animal shaver, a surgical blade, surgical vessel forceps, surgical scissors, a surgical suture needle, tweezers, a needle holder, a 4-0 surgical suture, an arterial puncture needle, a 0.038 inch radifocus guide wire, a 2% lidocaine injection, a 1.7F Ev3 microcatheter with a guide wire, microspheres for embolization (hollow microspheres prepared by the present invention and solid microspheres on the market: TheraSphere® glass microspheres), ioversol, a disposable surgical drape, iodophor, sterile surgical gloves, heparin sodium and normal saline were used.
A rabbit was fixed onto an animal fixing frame, 0.2 mL of a Sumianxin II injection for animals was intramuscularly injected into a leg, and then 0.8 mL/kg of a 3% pentobarbital solution was intravenously injected into the margin of an ear.
The radifocus guide wire was removed, and a 1.7F Ev3 microcatheter and a micro-guide wire were sent. An abdominal artery near a T12 centrum was found, and an ioversol contrast agent diluted with normal saline containing heparin sodium at a ratio of 1:1 was injected to develop a common hepatic artery and a proper hepatic artery. After the 1.7F Ev3 microcatheter was cannulated into the common hepatic artery, digital subtraction angiography was performed to fully display blood supply conditions of hepatic arteries.
In the case of angiography, equal quantities of solid microspheres and hollow microspheres for embolization were fully suspended in diluted ioversol and slowly injected into a target artery for embolization. Flowing conditions of the contrast agent in the artery branch were carefully observed, and embolization was stopped when reverse flowing occurred. Hepatic arteriography was performed again to determine embolization conditions of blood vessels.
The microcatheter and the micro-guide wire were pulled out, the cannula sheath was removed, the proximal end of the femoral artery was quickly ligated, the muscle layer and the epidermal layer of the thigh of the rabbit were sutured layer by layer with a disposable suture needle and a suture and disinfected, and surgery was completed.
In contrast, when the hollow glass microspheres of the present invention are used for vascular embolization in an embolization area, basically all blood vessels are filled with the hollow glass microspheres. Through comparison between
All patents and publications referred to in the specification of the present invention indicate that these patents and publications are open technologies in the art and can be used in the present invention. All the patents and publications cited herein are also listed in references as each publication is specifically cited separately. The present invention described herein may be realized under the conditions of absence of any one or more elements and presence of one or more limitations, and the limitations are not specified herein. For example, in each instance, the terms “contain”, “substantially composed of . . . ” and “composed of . . . ” can be replaced by either one of the remaining 2 terms. The so-called “one” herein only means “one” and can also mean 2 or above without excluding the meaning of only including one. The terms and expressions used herein are description manners, and the present invention is not limited thereto. Any intentions indicating that the terms and interpretations described herein exclude any equivalent features are also unavailable herein. However, it is to be understood that any suitable changes or modifications can be made within the scope of the present invention and the claims. It is to be understood that the examples described in the present invention are preferred examples and characteristics, some alternations and changes can be made by any person of general skill in the art according to the essence of descriptions of the present invention, and all these alternations and changes are also considered as falling within the scope of the present invention and the scope limited by the independent claims and the dependent claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2022112994652 | Oct 2022 | CN | national |
