Medical glue for treating aneurysm and preparation method thereof

Abstract

The invention provides medical glue for treating aneurysm and a preparation method of the medical glue, and the medical glue comprises the following components in parts by weight: 55-61 parts of n-octyl cyanoacrylate; 4 parts of a polymerization inhibitor; 3.3-5 parts of a first stabilizer; 5-8 parts of a second stabilizer; 15-22 parts of a plasticizer; 2.6 to 4.8 parts of a first thickening agent; 0.2 to 0.3 part of a second thickening agent; 4-5 parts of a bonding strength modifier; the first thickening agent is one or two of polyisobutyl methacrylate or cellulose acetate butyrate, and the second thickening agent is calixarene. The medical glue provided by the invention has the characteristics of high viscosity, high curing speed, good flexibility and long degradation period, and is suitable for blocking aneurysm.

Description

Technical Field

[0001] The present invention relates to the technical field of medical materials, and particularly relates to a medical glue for treating aneurysms and a preparation method thereof. Background Art

[0002] The existing methods for interventional treatment of arterial aneurysms mainly include embolization with coils, implantation of covered stents, and implantation of a dense mesh stent.

[0003] The method of coil embolization has the following disadvantages: the coils are prone to falling off and slipping outside the aneurysm into the normal blood vessels, where the blood flow passing through the coils in the normal blood vessels forms a turbulent flow and results in thrombosis. Moreover, the thrombus formed in the aneurysm will also fall off into the blood flow for circulation. Once the thrombus enters the blood circulation, it will cause serious uncertainties to the patient and may lead to blockage of a certain blood vessel.

[0004] The implantation of covered stents also has the following disadvantages. Similar to all stents, there is a possibility of endoleakage, which is related to the design of the device and also to the operation of the doctor. And if the endoleaked blood continues to enter the aneurysm, the aneurysm will rupture at a certain moment.

[0005] The implantation of a dense mesh stent, which is currently mainly used for treating intracranial aneurysms. This stent will have delayed aneurysm rupture and bleeding in the brain parenchyma at a distant site during treatment, which cannot be completely avoided at present. Although the incidence of delayed bleeding is relatively low, only 1.7% on average, the mortality rate reaches 80%. Therefore, at present, this stent is more often implanted secondarily after coil embolization.

[0006] Currently, medical glue mainly composed of cyanoacrylate is applied in the surgery for closing blood vessels. Because there is a carbon in the structure of the cyanoacrylate monomer connecting a cyano group and an ester group, and these two groups have strong electrophilic ability. This monomer polymerizes through anionic polymerization and only requires very little anionic initiation. There are many anionic polymerization initiators in the blood, so the medical glue can polymerize instantly to achieve the bonding effect and tightly adhere to the aneurysm wall. The polymerization does not require heating or pressurization and can occur at room temperature. This medical glue has problems such as high heat release during curing, poor flexibility, cracking and falling off after curing, short degradation time, and substances generated by metabolism causing inflammation, and does not meet the requirements for long-term embolization treatment of aneurysms. Therefore, it is necessary to develop a cyanoacrylate-based medical glue with low heat release during curing, high flexibility, high bonding strength, not easy to fall off, and good biocompatibility for treating aneurysms. Summary of the Invention

[0007] Based on this, it is necessary to provide a medical glue suitable for treating aneurysms.

[0008] The present invention provides a medical glue for treating aneurysms. Calculated by weight parts, the medical glue comprises: 55-61 parts of n-octyl cyanoacrylate; 4 parts of inhibitor; 3.3-5 parts of first stabilizer; 5-8 parts of second stabilizer; 15-22 parts of plasticizer; 2.6-4.8 parts of first thickener; 0.2-0.3 parts of second thickener; 4-5 parts of bonding strength modifier; the first thickener is one or two of polyisobutyl methacrylate or cellulose acetate butyrate, and the second thickener is calixarene.

[0009] In one embodiment, the inhibitor is one or several of phosphoric acid, hydroquinone, 4-methoxyphenol and p-hydroxyanisole.

[0010] In one embodiment, the first stabilizer is tributyl citrate; the second stabilizer is 6-hydroxyhexyl acrylate.

[0011] In one embodiment, the plasticizer is one or more of triethyl citrate, tributyl acetylcitrate, triethyl phosphate, dioctyl phthalate.

[0012] In one embodiment, the bonding strength modifier is ethylene glycol diacrylate.

[0013] In one embodiment, the medical glue further comprises 4-6 parts of roughness modifier.

[0014] In one embodiment, the roughness modifier is one or more of polylactic acid microspheres, polyvinyl alcohol microspheres, poly(lactic acid-glycolic acid) microspheres, sodium alginate microspheres, ethylene glycol dimethacrylate microspheres; the microsphere diameter of the roughness modifier is 130-150 μm, and the roughness modifier is loaded with antiplatelet aggregation drugs.

[0015] The present invention also provides a preparation method of the above-mentioned medical glue, comprising the following steps:

[0016] 1) Sequentially add the inhibitor, stabilizer, plasticizer and n-octyl cyanoacrylate into a beaker, heat to the first temperature and stir at a rotor speed of 300-400 rpm for 30 min;

[0017] 2) Add the first thickener and the second thickener in small amounts and multiple times, heat to the second temperature and continue stirring for 24 h;

[0018] 3) Turn off the heating, wait until the temperature drops below room temperature, then add the bonding strength modifier and continue stirring for 30 min.

[0019] In one embodiment, the first temperature is 40-50 °C; the second temperature is 60-65 °C.

[0020] In one of the embodiments, the method further includes step 4): adding a roughness modifier and ultrasonically mixing for 30 min at room temperature.

[0021] The medical glue provided by the present invention has n-octyl cyanoacrylate as the main body. The medical glue with n-octyl cyanoacrylate as the main body has better flexibility, lower heat release during curing, and a longer degradation period. Since the medical glue of the present invention needs to exist in the aneurysm for a long time after curing to block the aneurysm, the medical glue of the present invention has high flexibility, which can better avoid the rupture of the aneurysm, and the longer degradation period enables the cured medical glue to be degraded after being endothelialized, ensuring effective occlusion of the aneurysm.

[0022] The medical glue of the present invention uses calixarene as the second thickener, which not only greatly improves the viscosity of the medical glue, but also can increase the curing speed of the medical glue. On the one hand, calixarene has a promoting effect on the curing of n-octyl cyanoacrylate; on the other hand, compared with only using the first thickener, after adding calixarene as the second thickener, the total addition amount of the first thickener and the second specific thickener required to reach the same viscosity is less than the addition amount of only adding the first thickener, that is, the dilution of the main component n-octyl cyanoacrylate is minimized, thereby obtaining a faster curing speed.

[0023] The medical glue of the present invention selects 6-hydroxyhexyl acrylate as a stabilizer, which effectively reduces the degradation speed of the medical glue, solves the problems of embolization failure caused by the degradation of the medical glue and inflammation of patients caused by degradation products, and at the same time, 6-hydroxyhexyl acrylate can increase the flexibility of the medical glue.

[0024] The medical glue of the present invention selects ethylene glycol diacrylate as a bonding strength modifier, which effectively improves the bonding strength of the medical glue and avoids the detachment and displacement of the medical glue after curing.

[0025] The medical glue of the present invention adds a roughness modifier, which improves the surface roughness of the cured medical glue. After the medical glue is cured in the aneurysm, the higher surface roughness is beneficial to accelerating the endothelial crawling speed and further blocking the gap between the medical glue and the inner surface of the aneurysm.

[0026] The preparation method of the medical glue provided by the present invention is to first mix n-octyl cyanoacrylate with an inhibitor, a stabilizer, and a plasticizer, stir and dissolve; then add the thickener in small amounts and at multiple times and raise the temperature and stir, and finally turn off the heating, cool down, and add the bonding strength modifier and stir the solvent. Through the above method, it is possible to avoid incomplete dissolution of some substances or premature polymerization, and obtain a medical glue with uniform quality and viscosity meeting expectations.

[0027] In summary, the medical glue provided by the present invention has the characteristics of high viscosity, fast curing speed, good flexibility, and long degradation period while. After contacting the inner wall of the aneurysm, the medical glue quickly cures, and after curing, it has high stability and flexibility, ensuring effective occlusion of the aneurysm and preventing the aneurysm from being damaged by the cured medical glue. Detailed implementation manners

[0028] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which the present invention belongs. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0030] Embodiment 1

[0031] The raw material composition of the medical glue provided in this embodiment is as follows: 61 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 5 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 4 g of polyisobutyl methacrylate; 0.25 g of calixarene; 5 g of ethylene glycol diacrylate.

[0032] The preparation method of the medical glue provided in this embodiment includes the following steps:

[0033] Weigh each substance separately, and sequentially add phosphoric acid, tributyl citrate, 6-hydroxyhexyl acrylate, triethyl citrate, and n-octyl cyanoacrylate into a beaker, and stir at 40 °C and a stirrer speed of 400 r / min for 30 min. Then add polyisobutyl methacrylate and calixarene in small amounts multiple times, set the temperature to 60 °C, and keep stirring at the rotation speed for 24 h to achieve uniform mixing. After turning off the heating and waiting for the temperature to drop to room temperature, add ethylene glycol diacrylate and continue stirring for 30 min. Finally, after sterilization, the medical glue of this embodiment can be obtained. The viscosity and curing time and other indicators are detected, and the results are shown in Table 1.

[0034] Embodiment 2

[0035] The raw material composition of the medical glue provided in this embodiment is as follows: 61 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 5 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 4 g of polyisobutyl methacrylate; 0.2 g of calixarene; 5 g of ethylene glycol diacrylate.

[0036] The preparation method of the medical glue provided in this embodiment includes the following steps:

[0037] Weigh each substance separately. Add phosphoric acid, tributyl citrate, 6-hydroxyhexyl acrylate, triethyl citrate, and n-octyl cyanoacrylate to a beaker in sequence. Stir for 30 min under the conditions of 40 °C and a magnetic stirrer speed of 400 r / min. Then add polyisobutyl methacrylate and calixarene in small amounts and multiple times. Set the temperature to 60 °C and keep stirring at this speed for 24 h to achieve uniform mixing. After turning off the heating and waiting for the temperature to drop to room temperature, add ethylene glycol diacrylate and continue stirring for 30 min. Finally, after sterilization, the medical glue of this embodiment can be obtained. Detect indexes such as viscosity and curing time, and the results are shown in Table 1.

[0038] Example 3

[0039] The raw material composition of the medical glue provided in this embodiment is as follows: 61 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 5 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 4 g of polyisobutyl methacrylate; 0.3 g of calixarene; 5 g of ethylene glycol diacrylate.

[0040] The preparation method of the medical glue provided in this embodiment includes the following steps:

[0041] Weigh each substance separately. Add phosphoric acid, tributyl citrate, 6-hydroxyhexyl acrylate, triethyl citrate, and n-octyl cyanoacrylate to a beaker in sequence. Stir for 30 min under the conditions of 40 °C and a magnetic stirrer speed of 400 r / min. Then add polyisobutyl methacrylate and calixarene in small amounts and multiple times. Set the temperature to 60 °C and keep stirring at this speed for 24 h to achieve uniform mixing. After turning off the heating and waiting for the temperature to drop to room temperature, add ethylene glycol diacrylate and continue stirring for 30 min. Finally, after sterilization, the medical glue of this embodiment can be obtained. Detect indexes such as viscosity and curing time, and the results are shown in Table 1.

[0042] Example 4

[0043] The raw material composition of the medical glue provided in this embodiment is as follows: 61 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 5 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 4 g of polyisobutyl methacrylate; 0.6 g of calixarene; 5 g of ethylene glycol diacrylate.

[0044] Weigh each substance separately. In sequence, add phosphoric acid, tributyl citrate, 6-hydroxyhexyl acrylate, triethyl citrate, and n-octyl cyanoacrylate into a beaker. Stir for 30 min under the conditions of 40 °C and a magnetic stirrer speed of 400 r / min. Then, add polyisobutyl methacrylate and calixarene in small portions multiple times. Set the temperature to 60 °C and keep stirring for 24 h to achieve uniform mixing. After turning off the heating and waiting for the temperature to drop to room temperature, add ethylene glycol diacrylate and continue stirring for 30 min. Finally, after sterilization, the medical glue of this example can be obtained. Detect indexes such as viscosity and curing time, and the results are shown in Table 1.

[0045] Example 5

[0046] The raw material composition of the medical glue provided in this example is as follows: 61 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 5 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 4.25 g of polyisobutyl methacrylate; 5 g of ethylene glycol diacrylate.

[0047] Weigh each substance separately. In sequence, add phosphoric acid, tributyl citrate, 6-hydroxyhexyl acrylate, triethyl citrate, and n-octyl cyanoacrylate into a beaker. Stir for 30 min under the conditions of 40 °C and a magnetic stirrer speed of 400 r / min. Then, add polyisobutyl methacrylate in small portions multiple times. Set the temperature to 60 °C and keep stirring for 24 h to achieve uniform mixing. After turning off the heating and waiting for the temperature to drop to room temperature, add ethylene glycol diacrylate and continue stirring for 30 min. Finally, after sterilization, the medical glue of this example can be obtained. Detect indexes such as viscosity and curing time, and the results are shown in Table 1.

[0048] Example 6

[0049] The raw material composition of the medical glue provided in this example is as follows: 61 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 5 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 4 g of polyisobutyl methacrylate, 0.8 g of cellulose acetate butyrate; 5 g of ethylene glycol diacrylate.

[0050] Weigh each substance separately. In sequence, add phosphoric acid, tributyl citrate, 6-hydroxyhexyl acrylate, triethyl citrate, and n-octyl cyanoacrylate into a beaker. Stir for 30 min under the conditions of 40 °C and a magnetic stirrer speed of 400 r / min. Then, add polyisobutyl methacrylate and cellulose acetate butyrate in small portions multiple times. Set the temperature to 60 °C and keep stirring at the same speed for 24 h to achieve uniform mixing. After turning off the heating and waiting for the temperature to drop to room temperature, add ethylene glycol diacrylate and continue stirring for 30 min. Finally, after sterilization, the medical glue of this example can be obtained. Detect indexes such as viscosity and curing time, and the results are shown in Table 1.

[0051] Example 7

[0052] The raw material composition of the medical glue provided in this example is as follows: 61 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 5 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 0.25 g of calixarene; 5 g of ethylene glycol diacrylate.

[0053] Weigh each substance separately. In sequence, add phosphoric acid, tributyl citrate, 6-hydroxyhexyl acrylate, triethyl citrate, and n-octyl cyanoacrylate into a beaker. Stir for 30 min under the conditions of 40 °C and a magnetic stirrer speed of 400 r / min. Then, add calixarene in small portions multiple times. Set the temperature to 60 °C and keep stirring at the same speed for 24 h to achieve uniform mixing. After turning off the heating and waiting for the temperature to drop to room temperature, add ethylene glycol diacrylate and continue stirring for 30 min. Finally, after sterilization, the medical glue of this example can be obtained. Detect indexes such as viscosity and curing time, and the results are shown in Table 1.

[0054] Example 8

[0055] The raw material composition of the medical glue provided in this example is as follows: 61 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 5 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 4 g of cellulose acetate butyrate; 0.25 g of calixarene; 5 g of ethylene glycol diacrylate.

[0056] Weigh each substance separately. In sequence, add phosphoric acid, tributyl citrate, 6-hydroxyhexyl acrylate, triethyl citrate, and n-octyl cyanoacrylate into a beaker. Stir for 30 min under the conditions of 40 °C and a magnetic stirrer speed of 400 r / min. Then, add calixarene and cellulose acetate butyrate in small portions multiple times. Set the temperature to 60 °C and keep stirring at the same speed for 24 h to achieve uniform mixing. After turning off the heating and waiting for the temperature to drop to room temperature, add ethylene glycol diacrylate and continue stirring for 30 min. Finally, after sterilization, the medical glue of this example can be obtained. Detect indexes such as viscosity and curing time, and the results are shown in Table 1.

[0057] Example 9

[0058] The raw material composition of the medical glue provided in this example is as follows: 61 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 20 g of triethyl citrate; 4 g of polyisobutyl methacrylate; 0.25 g of calixarene; 5 g of ethylene glycol diacrylate.

[0059] Weigh each substance separately. In sequence, add phosphoric acid, tributyl citrate, triethyl citrate, and n-octyl cyanoacrylate into a beaker, and stir for 30 min under the conditions of 40°C and a magnetic stirrer speed of 400 r / min. Then, add calixarene and polyisobutyl methacrylate in small amounts and multiple times. Set the temperature to 60°C and keep stirring at the same speed for 24 h to achieve uniform mixing. After turning off the heating and waiting for the temperature to drop to room temperature, add ethylene glycol diacrylate and continue stirring for 30 min. Finally, after sterilization, the medical glue of this example can be obtained. Detect indexes such as viscosity and curing time, and the results are shown in Table 1.

[0060] Example 10

[0061] The raw material composition of the medical glue provided in this example is as follows: 61 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 2 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 4 g of polyisobutyl methacrylate; 0.2 g of calixarene; 5 g of ethylene glycol diacrylate.

[0062] Weigh each substance separately. In sequence, add phosphoric acid, tributyl citrate, 6-hydroxyhexyl acrylate, triethyl citrate, and n-octyl cyanoacrylate into a beaker, and stir for 30 min under the conditions of 40°C and a magnetic stirrer speed of 400 r / min. Then, add calixarene and polyisobutyl methacrylate in small amounts and multiple times. Set the temperature to 60°C and keep stirring at the same speed for 24 h to achieve uniform mixing. After turning off the heating and waiting for the temperature to drop to room temperature, add ethylene glycol diacrylate and continue stirring for 30 min. Finally, after sterilization, the medical glue of this example can be obtained. Detect indexes such as viscosity and curing time, and the results are shown in Table 1.

[0063] Example 11

[0064] The raw material composition of the medical glue provided in this example is as follows: 61 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 13 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 4 g of polyisobutyl methacrylate; 0.25 g of calixarene; 5 g of ethylene glycol diacrylate.

[0065] Weigh each substance separately. In sequence, add phosphoric acid, tributyl citrate, 6-hydroxyhexyl acrylate, triethyl citrate, and n-octyl cyanoacrylate into a beaker. Stir for 30 min under the conditions of 40 °C and a magnetic stirrer speed of 400 r / min. Then, add calixarene and poly(isobutyl methacrylate) in small portions multiple times. Set the temperature to 60 °C and keep stirring at this speed for 24 h to achieve uniform mixing. After turning off the heating and waiting for the temperature to drop to room temperature, add ethylene glycol diacrylate and continue stirring for 30 min. Finally, after sterilization, the medical glue of this example can be obtained. Detect indexes such as viscosity and curing time, and the results are shown in Table 1.

[0066] Example 12

[0067] The raw material composition of the medical glue provided in this example is as follows: 61 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 5 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 4 g of poly(isobutyl methacrylate), and 0.25 g of calixarene.

[0068] Weigh each substance separately. In sequence, add phosphoric acid, tributyl citrate, 6-hydroxyhexyl acrylate, triethyl citrate, and n-octyl cyanoacrylate into a beaker. Stir for 30 min under the conditions of 40 °C and a magnetic stirrer speed of 400 r / min. Then, add poly(isobutyl methacrylate) and calixarene in small portions multiple times. Set the temperature to 60 °C and keep stirring at this speed for 24 h to achieve uniform mixing. After sterilization, the medical glue of this example can be obtained. Detect indexes such as viscosity and curing time, and the results are shown in Table 1.

[0069] Example 13

[0070] The raw material composition of the medical glue provided in this example is as follows: 61 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 5 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 4 g of poly(isobutyl methacrylate); 0.25 g of calixarene; and 2 g of ethylene glycol diacrylate.

[0071] Weigh each substance separately. In sequence, add phosphoric acid, tributyl citrate, 6-hydroxyhexyl acrylate, triethyl citrate, and n-octyl cyanoacrylate into a beaker. Stir for 30 min under the conditions of 40 °C and a magnetic stirrer speed of 400 r / min. Then, add calixarene and poly(isobutyl methacrylate) in small portions multiple times. Set the temperature to 60 °C and keep stirring at this speed for 24 h to achieve uniform mixing. After turning off the heating and waiting for the temperature to drop to room temperature, add ethylene glycol diacrylate and continue stirring for 30 min. Finally, after sterilization, the medical glue of this example can be obtained. Detect indexes such as viscosity and curing time, and the results are shown in Table 1.

[0072] Example 14

[0073] The raw material composition of the medical glue provided in this example is as follows: 61 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 5 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 4 g of polyisobutyl methacrylate; 0.25 g of calixarene; 4 g of ethylene glycol diacrylate.

[0074] Weigh each substance separately. In sequence, add phosphoric acid, tributyl citrate, 6-hydroxyhexyl acrylate, triethyl citrate, and n-octyl cyanoacrylate into a beaker, and stir for 30 min under the conditions of 40 °C and a magnetic stirrer speed of 400 r / min. Then, add calixarene and polyisobutyl methacrylate in small amounts and multiple times. Set the temperature to 60 °C and keep stirring at the same speed for 24 h to achieve uniform mixing. After turning off the heating and waiting for the temperature to drop to room temperature, add ethylene glycol diacrylate and continue stirring for 30 min. Finally, after sterilization, the medical glue of this example can be obtained. Test indexes such as viscosity and curing time, and the results are shown in Table 1.

[0075] Example 15

[0076] The raw material composition of the medical glue provided in this example is as follows: 61 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 5 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 1 g of polyisobutyl methacrylate, 0.25 g of calixarene; 5 g of ethylene glycol diacrylate.

[0077] Weigh each substance separately. In sequence, add phosphoric acid, tributyl citrate, 6-hydroxyhexyl acrylate, triethyl citrate, ethylene glycol diacrylate, and n-octyl cyanoacrylate into a beaker, and stir for 30 min under the conditions of 40 °C and a magnetic stirrer speed of 400 r / min. Then, add polyisobutyl methacrylate and calixarene in small amounts and multiple times. Set the temperature to 60 °C and keep stirring at the same speed for 24 h to achieve uniform mixing. Finally, after sterilization, the medical glue of this example can be obtained. Test indexes such as viscosity and curing time, and the results are shown in Table 1.

[0078] Example 16

[0079] The raw material composition of the medical glue provided in this example is as follows: 61 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 5 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 1 g of polyisobutyl methacrylate, 0.25 g of calixarene; 5 g of ethylene glycol diacrylate.

[0080] Weigh each substance separately. In sequence, add phosphoric acid, tributyl citrate, 6-hydroxyhexyl acrylate, triethyl citrate, and n-octyl cyanoacrylate into a beaker. Stir for 30 min under the conditions of 50 °C and a magnetic stirrer speed of 400 r / min. Then add calixarene and poly(isobutyl methacrylate) in small portions multiple times. Set the temperature to 60 °C and keep stirring at the same speed for 24 h to achieve uniform mixing. After turning off the heating and waiting for the temperature to drop to room temperature, add ethylene glycol diacrylate and continue stirring for 30 min. Finally, after sterilization, the medical glue of this example can be obtained. Detect indexes such as viscosity and curing time, and the results are shown in Table 1.

[0081] Example 17

[0082] The raw material composition of the medical glue provided in this example is as follows: 61 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 5 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 4 g of poly(isobutyl methacrylate), 0.25 g of calixarene; 5 g of ethylene glycol diacrylate.

[0083] Weigh each substance separately. In sequence, add phosphoric acid, tributyl citrate, 6-hydroxyhexyl acrylate, triethyl citrate, and n-octyl cyanoacrylate into a beaker. Stir for 30 min under the conditions of 60 °C and a magnetic stirrer speed of 400 r / min. Then add calixarene and poly(isobutyl methacrylate) in small portions multiple times. Set the temperature to 60 °C and keep stirring at the same speed for 24 h to achieve uniform mixing. After turning off the heating and waiting for the temperature to drop to room temperature, add ethylene glycol diacrylate and continue stirring for 30 min. Finally, after sterilization, the medical glue of this example can be obtained. Detect indexes such as viscosity and curing time, and the results are shown in Table 1.

[0084] Example 18

[0085] The raw material composition of the medical glue provided in this example is as follows: 61 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 5 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 4 g of poly(isobutyl methacrylate); 0.25 g of calixarene; 5 g of ethylene glycol diacrylate; 5 g of polylactic acid microspheres (loaded with clopidogrel).

[0086] The preparation method of the medical glue provided in this example includes the following steps:

[0087] Weigh each substance separately. In sequence, add phosphoric acid, tributyl citrate, 6-hydroxyhexyl acrylate, triethyl citrate, and n-octyl cyanoacrylate into a beaker. Stir for 30 min under the conditions of 40 °C and a magnetic stirrer speed of 400 r / min. Then, add polyisobutyl methacrylate and calixarene in small amounts and multiple times. Set the temperature to 60 °C and keep stirring for 24 h to achieve uniform mixing. After turning off the heating and waiting for the temperature to drop to room temperature, add ethylene glycol diacrylate and continue stirring for 30 min. Add polylactic acid microspheres (loaded with clopidogrel) and ultrasonically mix for 30 min at room temperature. Finally, after sterilization, the medical glue of this example can be obtained. Detect indexes such as viscosity and curing time, and the results are shown in Table 1.

[0088] Example 19

[0089] The raw material composition of the medical glue provided in this example is as follows: 55 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 5 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 4 g of polyisobutyl methacrylate; 0.25 g of calixarene; 5 g of ethylene glycol diacrylate; 5 g of polylactic acid microspheres (loaded with clopidogrel).

[0090] The preparation method is the same as that of Example 18.

[0091] Example 20

[0092] The raw material composition of the medical glue provided in this example is as follows: 58 g of n-octyl cyanoacrylate; 4 g of phosphoric acid; 3.3 g of tributyl citrate; 5 g of 6-hydroxyhexyl acrylate; 20 g of triethyl citrate; 4 g of polyisobutyl methacrylate; 0.25 g of calixarene; 5 g of ethylene glycol diacrylate; 5 g of polylactic acid microspheres (loaded with clopidogrel).

[0093] The preparation method is the same as that of Example 18.

[0094] The following test items are carried out on Examples 1-20 of the present invention:

[0095] 1. Curing time:

[0096] Method: Take a petri dish with a diameter of 90 mm, configure 50 ml of 0.3 g / L sodium bicarbonate solution in the petri dish, use a disposable dropper to drop a drop of medical glue at a distance of 5 cm from the liquid surface, record the curing time with a stopwatch, measure three times, and take the median value.

[0097] 2. Curing heat:

[0098] Method: Drop 0.5 mL of the sample into artificial blood. According to the ratio of 1:2:3, use a thermocouple combined with a potentiometer to measure. Read the value E on the potentiometer. The corresponding △t is the heat released during curing.

[0099] 3. Viscosity:

[0100] Use a digital display viscometer for testing and read directly.

[0101] 4. Shore hardness:

[0102] Use a Shore hardness tester (LX-A) to measure the hardness of the cured colloid, take 3 different points for measurement and take the median value.

[0103] 5. Stability:

[0104] Place the cured colloid in artificial blood, keep it at 50 °C in a water bath for 1-year test. During this period, analyze the components and the molecular weight of the colloid every 7 days until the molecular weight of the cured colloid decreases by 0.1% compared with the 0 time point and then end the test.

[0105] 6. Bonding strength:

[0106] Conduct the bonding strength test on the specimen according to the requirements of the test method for the bonding performance of tissue adhesives in YY / T 0729-2009.

[0107] 7. Biocompatibility:

[0108] Conduct according to the standard of biological evaluation of medical devices in GB / T 16886, and conduct biological tests on the specimen for pyrogen, cytotoxicity, sensitization, intracutaneous reaction, and acute systemic toxicity. When the pyrogen is negative, the cytotoxicity < grade 1, the sensitization evaluation is 0 points, the intracutaneous reaction is negative and there is no toxic reaction, then the biocompatibility evaluation is excellent.

[0109] 8. Surface roughness:

[0110] Use a non-contact roughness measuring instrument to measure the cured colloid and read directly.

[0111] All the test results are shown in the following table:

[0112] Table 1. Test results of the examples of the present invention

[0113]

[0114]

[0115] The addition of calixarene accelerated the curing rate, increased the viscosity of the medical glue, and reduced the possibility of the medical glue slipping and escaping under the influence of arterial blood flow. Compared with Example 5 without calixarene, the viscosity of the medical glue in Example 1 increased significantly, reaching 63 MPa·s, and the curing time was greatly reduced to 17.12 s. In Example 4, more calixarene was added compared to Example 1. The acceleration of the curing rate of the medical glue was not significant, but the viscosity of the medical glue showed a downward trend. The curing times of Examples 1-3 were all within 19 s, and the viscosities were all above 60 MPa·s. In Example 8, cellulose acetate butyrate was used to replace polyisobutyl methacrylate in Example 1. The curing rate and viscosity of the medical glue in Example 8 were similar to those of the medical glue in Example 1. Compared with Examples 1 and 8, Examples 5 and 6 did not add calixarene, the curing rate was significantly slowed down, and the viscosity of the medical glue also decreased significantly. It can be seen that adding calixarene together with polyisobutyl methacrylate or cellulose acetate butyrate can simultaneously accelerate the curing rate of the medical glue and increase the viscosity of the medical glue.

[0116] The addition of 6-hydroxyhexyl acrylate increased the stability and bonding strength of the medical glue, and at the same time reduced the glass transition temperature of the medical glue, increasing its flexibility. In Example 9 without 6-hydroxyhexyl acrylate, degradation began after only 6 months; in Example 10, a small amount of 6-hydroxyhexyl acrylate was added to the medical glue, and the stability of the medical glue was improved, and the stable period was extended to 8 months; however, excessive addition would lead to a decrease in stability. In Example 11, an excessive amount of 6-hydroxyhexyl acrylate was added, and the stable period decreased to 10 months; from Example 9 to Example 10, with the addition of 6-hydroxyhexyl acrylate, the bonding strength of the medical glue increased significantly, from 22.1 MPa to 24.5 MPa; from Example 9 to Example 11, with the addition of 6-hydroxyhexyl acrylate, the flexibility of the medical glue was improved, from 18A to 16A.

[0117] The addition of ethylene glycol diacrylate increased the bonding strength of the medical glue. The bonding strength of Example 12 without ethylene glycol diacrylate was only 13.8 MPa, and the bonding strength of Example 13 with a small amount of ethylene glycol diacrylate increased to 16.4 MPa. The bonding strengths of other cases with a sufficient amount of ethylene glycol diacrylate were all greater than 22 MPa. However, compared with other examples, in Example 15, ethylene glycol diacrylate was added in advance and heated and stirred, resulting in partial polymerization of some glue during the production process, and the viscosity of the medical glue was too high, making it difficult to push during the operation. Therefore, closing the heating and cooling before adding ethylene glycol diacrylate is beneficial for the medical glue to obtain an appropriate viscosity.

[0118] Example 17 Compared with other examples, after adding an inhibitor and a stabilizer to n-octyl cyanoacrylate, the temperature was directly raised to 60 °C for stirring. Since the n-octyl cyanoacrylate was not evenly mixed with the inhibitor and the stabilizer, partial polymerization was likely to occur under high-temperature conditions, resulting in too high viscosity of the medical glue and making it difficult to push during the operation. Therefore, during the mixing stage of n-octyl cyanoacrylate with the inhibitor, the stabilizer, and the plasticizer, the temperature should be appropriately raised to ensure uniform mixing. After the n-octyl cyanoacrylate was evenly mixed with the inhibitor and the stabilizer, a thickener was added and the temperature was further raised to 60 °C to facilitate faster dissolution of the thickener, thereby making the medical glue more evenly mixed.

[0119] Examples 18 - 20 Compared with other examples, polylactic acid microspheres (loaded with clopidogrel) were added to the medical glue. The addition of a small amount of polylactic acid microspheres increased the surface roughness of the cured medical glue and did not affect the stability of the medical glue. After the medical glue was cured in the aneurysm, the higher surface roughness was beneficial to accelerating the endothelial crawling speed and further sealing the gap between the medical glue and the inner surface of the aneurysm. At the same time, the polylactic acid microspheres were loaded with clopidogrel for antiplatelet aggregation to avoid unnecessary thrombus caused by the shed polylactic acid microspheres.

[0120] The medical glue of the present invention has the characteristics of high curing rate, low heat release, high viscosity, good flexibility, high stability, and excellent biocompatibility. When the medical glue of the present invention is injected into the aneurysm, it quickly cures when it contacts the inner wall of the aneurysm, forming a solid substance with high toughness and difficult migration, quickly and effectively sealing the aneurysm.

[0121] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope described in this specification.

[0122] The above-described embodiments only represent several implementation manners of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the present invention patent should be subject to the appended claims.

Claims

1. A medical glue for treating aneurysms, characterized in that, Calculated by weight parts, the medical glue includes: 55-61 parts of n-octyl cyanoacrylate; 4 parts of inhibitor; 3.3-5 parts of the first stabilizer; 5-8 parts of the second stabilizer; 15-22 parts of plasticizer; 2.6-4.8 parts of the first thickener; 0.2-0.3 parts of the second thickener; 4-5 parts of bonding strength modifier; the first thickener is one or both of polyisobutyl methacrylate or cellulose acetate butyrate, and the second thickener is calixarene.

2. The medical glue for treating aneurysms according to claim 1, wherein the inhibitor is one or several of phosphoric acid, hydroquinone, 4-methoxyphenol and p-hydroxyanisole.

3. The medical glue for treating aneurysms according to claim 1, wherein The first stabilizer is tributyl citrate; the second stabilizer is 6-hydroxyhexyl acrylate.

4. The medical glue for treating aneurysms according to claim 1, wherein the plasticizer is one or more of triethyl citrate, tributyl acetylcitrate, triethyl phosphate, dioctyl phthalate.

5. The medical glue for treating aneurysms according to claim 1, wherein The bonding strength modifier is ethylene glycol diacrylate.

6. The medical glue for treating aneurysms according to claim 1, wherein The medical glue further includes 4-6 parts of roughness modifier.

7. The medical glue for treating aneurysms according to claim 6, wherein the roughness modifier is one or more of polylactic acid microspheres, polyvinyl alcohol microspheres, poly(lactic-co-glycolic) acid microspheres, sodium alginate microspheres, ethylene glycol dimethacrylate microspheres; the microsphere particle size of the roughness modifier is 130-150 μm, and the roughness modifier is loaded with antiplatelet aggregation drugs.

8. A method for preparing the medical glue according to claim 6, characterized in that, Including the following steps: 1) Sequentially add the inhibitor, stabilizer, plasticizer and n-octyl cyanoacrylate into a beaker, heat to the first temperature and stir at a rotor speed of 300-400 rpm for 30 min; 2) Add the first thickener and the second thickener in small amounts and multiple times, heat to the second temperature and continue stirring for 24 h; 3) Turn off the heating, wait for the temperature to drop below room temperature, then add the bonding strength modifier and continue stirring for 30 min.

9. The preparation method of the medical glue according to claim 8, wherein the first temperature is 40-50 °C; the second temperature is 60-65 °C.

10. The preparation method of the medical glue according to claim 8, wherein the method further includes step 4): add the roughness modifier and ultrasonically mix at room temperature for 30 min.

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