A short-term developing embolizing foam and a method for preparing the same

Abstract

The present application discloses a short-term developed embolism foam and its preparation method, the embolism foam adopts polyurethane shape memory material, has a compressed state suitable for interventional delivery and an opposite expanded state, the foam connects a developing agent on the thin wall surface of the foam material in a surface grafting manner. In the foam preparation process, a certain proportion of isocyanate groups are closed by adding a blocking agent to prevent self-polymerization or reaction consumption by process and moisture in the air. After the foam is prepared, it is immersed in a solution of the developing agent, the blocking agent is unblocked under the action of heating and a catalyst, and the isocyanate groups in the foam are combined with the hydroxyl groups in the molecular structure of the developing agent to form a stable structure. The developing agent is a hydrophilic material, is delivered into a blood vessel, and can be quickly degraded under the action of blood, thereby avoiding late development and causing artifacts in the CT process.

Description

Technical Field

[0001] This application relates to the field of medical embolization materials technology, specifically to a short-term visible shape memory polymer embolization foam and its preparation method. Background Technology

[0002] Postoperative endoleak is a common complication in the treatment of abdominal aortic aneurysms. Therefore, interventional embolization is often chosen as a minimally invasive treatment to reduce the blood flow rate and volume, allowing the aneurysm cavity to be thrombotic smoothly. Commonly used embolization materials include coils, gelatin powder, tissue adhesives, thrombin, and vascular plugs. Although there are clinical examples of these materials, there are still some shortcomings.

[0003] Metal coils are currently the most commonly used material for vascular embolization. They have long-term stability and strong support performance. However, the disadvantage of coils is that after intervention, the stent in the anchoring area cannot completely fit the aortic wall, resulting in poor compaction. This may lead to incomplete embolization and complications such as endoleak. Data shows that the thrombus formation rate of metal coils is between 80% and 92%. Long-term implantation may also cause metal ion precipitation, which may cause allergies, inflammation, etc. Furthermore, after achieving medical function, a second surgery is required to remove the formed thrombus.

[0004] Gelatin and thrombin are mainly used in short-term embolization procedures. Their advantages are rapid thrombus formation, no toxic side effects, and short metabolism time, which minimizes side effects. However, they cannot provide high support strength, and high blood pressure can easily lead to embolism entering the systemic circulation, affecting other tissues or structures. Their degradation rate is too fast and it is difficult to control the embolism function. Therefore, they do not meet the thrombosis conditions of arterial vessels with fast flow and high blood pressure.

[0005] Utilizing shape memory polymers as embolic materials is also a technological development trend. To achieve imaging, commonly used methods include bonding metal ring structures or chemical synthesis. Chemical synthesis involves combining iohexol, 5... amino 2, 4, 6 Iodides such as triiodophthalic acid are incorporated into the molecular structure of polyurethane shape memory foam, specifically through a reaction between the iodide and the NCO groups of the isocyanate. However, the iodide in the embolized foam produced by this method is incorporated into the molecular structure, exhibiting long-term imaging characteristics. After tumor embolization, regular CT scans are required to monitor tumor shrinkage. The contrast agent remains permanently within the foam, forming a high-density white shadow that obscures the tumor and surrounding blood vessels, making it impossible to distinguish between residual tumor and the imaging shadow of the embolization material. Summary of the Invention

[0006] In view of the above problems, this application provides an embolic material that can be self-developed, and the developer can be rapidly degraded with a controllable degradation cycle, as well as a method for preparing the same.

[0007] A method for preparing a short-term developing embolic foam, comprising: Step S100: Mix the isocyanate and the first polyol evenly to obtain the prepolymer; Step S200: Add a capping agent to the prepolymer to obtain the capped prepolymer as component A; Step S300: Mix the second part of polyol, the first catalyst, silicone oil, foaming agent and water evenly to obtain component B; mix component A and component B and foam to obtain polyurethane foam. Step S400: Immerse the polyurethane foam in a developer solution containing a second catalyst to react and obtain the short-term developing plug foam. The mass ratio of isocyanate to polyol is 100:50~90; the polyol includes the first part of polyol and the second part of polyol, wherein the first part of polyol accounts for 30%~80% of the total mass of the polyol, and the remainder is the second part of polyol.

[0008] The short-term embolic foam provided in this application uses polyurethane shape memory material, possessing a compressible state and a relatively expanded state suitable for interventional delivery. A certain proportion of end-capping agent is added to the polyurethane prepolymer to seal the isocyanate groups and prevent their self-polymerization. After polyurethane foaming, the polyurethane foam is immersed in a contrast agent solution. Under the action of heating and a second catalyst, the end-capping agent is desealed, and the remaining isocyanate groups in the polyurethane foam react chemically with the hydroxyl groups of the contrast agent to form a stable linkage structure, grafting the contrast agent onto the thin-walled surface of the polyurethane foam. The contrast agent is a hydrophilic material that can quickly decompose with the polyurethane foam in a blood environment and be normally metabolized, avoiding artifacts in subsequent CT examinations.

[0009] Several alternative methods are provided below, but they are not intended as additional limitations on the overall solution above. They are merely further additions or optimizations. Provided there are no technical or logical contradictions, each alternative method can be combined individually with respect to the overall solution above, or multiple alternative methods can be combined with each other.

[0010] Optionally, the isocyanate is selected from at least one of hexamethylene diisocyanate (HDI), toluene diisocyanate (TDI), diphenylmethane diisocyanate (MDI), hydrogenated diphenylmethane diisocyanate (HMDI), trimethylhexamethylene diisocyanate (TMDI), and isophorone diisocyanate (IPDI).

[0011] Optionally, the polyol is selected from at least one of N,N,N,N-tetra(2-hydroxypropyl)ethylenediamine (HPED), triethanolamine (TEA), polycaprolactone triol (PCL triol, number average molecular weight range 550-1000), polycaprolactone diol (number average molecular weight range 500-1000), polyethylene glycol (number average molecular weight range 400-1000), polycarbonate diol (number average molecular weight range 800-1000), glycerol, and trimethylolethane.

[0012] Optionally, the polyol is a mixture of N,N,N,N-tetra(2-hydroxypropyl)ethylenediamine (HPED), triethanolamine (TEA), and polycaprolactone triol (PCL triol).

[0013] Optionally, the mass ratio of HPED, TEA and PCL triol in the polyol is 26~32:8~14:50~80.

[0014] Optionally, the mass ratio of HPED, TEA and PCL triol in the polyol is 28:8~14:50~80.

[0015] Optionally, the mass ratio of HPED, TEA and PCL triol in the polyol is 28:10~12:60~65.

[0016] Optionally, the first polyol is HPED, TEA and PCL triol, and the second polyol is HPED and TEA.

[0017] Optionally, the HPED in the first portion of the polyol accounts for 30% to 40% of the total mass of HPED in the polyol.

[0018] Optionally, the TEA in the first portion of the polyol accounts for 30% to 40% of the total mass of TEA in the polyol.

[0019] Optionally, the capping agent is at least one selected from sodium bisulfite, methyl ethyl ketone oxime, ε-caprolactam, 3,5-dimethylpyrazole, ethyl acetoacetate, and diethyl malonate. Preferably, the capping agent is sodium bisulfite.

[0020] Optionally, the mass ratio of the capping agent to isocyanate is 100:20~60. More preferably, the mass ratio of the capping agent to isocyanate is 100:26~52. More preferably, the mass ratio of the capping agent to isocyanate is 100:30~40.

[0021] Optionally, the developer is selected from at least one of iohexol, iodofol, iopamidol, 5-amino-2,4,6-triiodophthalic acid, diatrizoic acid, and triiodophenol.

[0022] Optionally, the mass ratio of the developer to isocyanate is 100:20~60. More preferably, the mass ratio of the developer to isocyanate is 100:29~57. Alternatively, the mass ratio of the developer to isocyanate is 100:30~40.

[0023] Optionally, the developer solution uses water as a solvent, and the concentration of the developer solution is 0.05~0.15 g / mL. More preferably, the developer solution uses water as a solvent, and the concentration of the developer solution is 0.09~0.12 g / mL.

[0024] Optionally, the first catalyst is an organometallic catalyst and an amine catalyst, and the mass ratio of the organometallic catalyst to the amine catalyst in the first catalyst is 6-9:1. More preferably, the mass ratio of the organometallic catalyst to the amine catalyst in the first catalyst is 6.8-8.1:1.

[0025] Optionally, the second catalyst is an organometallic catalyst. It can be the same as or different from the organometallic catalyst in the first catalyst.

[0026] Optionally, the organometallic catalyst is an organotin catalyst or an organobismuth catalyst.

[0027] Optionally, the organotin catalyst is selected from at least one of stannous octoate, dibutyltin dilaurate, dibutyltin diacetate, di(dodecyl)dioctyltin, dibutyldithioisooctyltin, and dibutyltin maleate.

[0028] Optionally, the organic bismuth catalyst is selected from at least one of bismuth isooctanoate, bismuth octanoate, bismuth laurate, and bismuth naphthenate.

[0029] Optionally, the amine catalyst is selected from at least one of triethylenediamine, dimethylcyclohexylamine, dimethylbenzylamine, bis(dimethylaminoethyl) ether, and pentamethyldiethylenetriamine.

[0030] Optionally, the first catalyst is bismuth isooctanoate and triethylenediamine, with a mass ratio of bismuth isooctanoate to triethylenediamine of 6.8 to 8.1:1.

[0031] Optionally, the second catalyst is bismuth caprylate.

[0032] Optionally, the foaming agent is selected from at least one of trifluorochloromethane, dichlorofluoroethane, pentafluoropropane, pentafluorobutane, and dichloromethane.

[0033] Optionally, the content of the second catalyst in the developer solution is 0.002~0.004 g / mL. More preferably, the content of the second catalyst in the developer solution is 0.0021~0.0038 g / mL.

[0034] Optionally, the mass ratio of isocyanate, first catalyst, silicone oil, foaming agent and water is 100:1.2~1.8:1.7~2.3:9~12:2~4.

[0035] Optionally, in step S200, after adding the capping agent, the mixture is reacted at 50~70℃ for 2~5 hours to obtain the capped prepolymer.

[0036] Optionally, in step S300, the reaction temperature is 70~100℃ and the reaction time is 10~30 minutes. After foaming is completed in step S300, the product is cured at 50~70℃ for at least 30 minutes before demolding.

[0037] After the reaction is complete in step S400, the product is demolded after curing at 60~80℃ for at least 8 hours.

[0038] This application also provides a short-term developing embolic foam, which is prepared using the preparation method described above.

[0039] Optionally, the glass transition temperature of the short-term developing embolization foam is 38~42℃, and the degradation cycle of the developer in the short-term developing embolization foam is less than 30 days.

[0040] In the short-term imaging embolization foam provided in this application, the contrast agent is a hydrophilic material that is delivered into the blood vessel and can be rapidly degraded under the action of blood, thereby avoiding artifacts caused by subsequent imaging during CT. Attached Figure Description

[0041] Figure 1 X-ray images of the embolic foams prepared in Examples 1-4 and Comparative Examples 1-3 of this application before and after immersion in PBS. Detailed Implementation

[0042] The following embodiments provide specific experimental methods. First, isocyanate and a first-part polyol are copolymerized to form a prepolymer. Then, a sealing agent is added to seal a portion of the isocyanate groups, resulting in a sealed prepolymer, which is component A. Sealing prevents all isocyanate groups from reacting or self-polymerizing during the foaming process. A second-part polyol, catalyst, silicone oil, foaming agent, and water are mixed uniformly to obtain component B. Component B and component A are then mixed to generate shape memory polyurethane foam.

[0043] Iohexol was dissolved in water to form an iohexol aqueous solution. The aforementioned polyurethane foam was then immersed in the iohexol aqueous solution, and bismuth caprylate (octanoate) was added as a metal catalyst. The unsealing and grafting reactions were then carried out at 80°C. The unsealed isocyanate groups reacted with the hydroxyl groups of iohexol under the action of the metal catalyst, grafting iohexol molecules onto the surface of the polyurethane foam, followed by post-curing. Finally, the foam was cut into predetermined shapes.

[0044] After the foam is delivered to the intended site, it expands naturally within the blood vessel and can be visualized for a short period. As the foam remains in the blood vessel, the iohexol structure grafted onto its surface dissociates from the foam and is metabolized normally.

[0045] The following embodiments provide specific preparation methods and parameter characterization.

[0046] Examples 1-4 The surface grafting method is employed. First, a capping agent is used to seal some of the isocyanate groups in the prepolymer. After the foaming reaction is complete, the foam is immersed in an iohexol aqueous solution. Under heating and with the aid of a metal catalyst, the isocyanates are unsealed and undergo a grafting reaction with iohexol. The specific steps are as follows (see Table 1 below for raw material dosages): 1. Mix HDI with HPED (35% of the amount used in Table 1), TEA (35% of the amount used in Table 1), and all of the PCL triol (number average molecular weight 830) until homogeneous. Prepolymerize at room temperature for 24 hours to form a prepolymer. Slowly add sodium bisulfite dropwise to the prepolymer at 50°C (i.e., the end-capping reaction temperature). React for 3 hours after the addition to obtain the end-capped prepolymer as component A.

[0047] 2. Mix water with the remaining HPED (65% of the amount used in Table 1), TEA (65% of the amount used in Table 1), bismuth isooctanoate, triethylenediamine, silicone oil (Momentive L-580, the same brand of silicone oil was used in the following examples and comparative examples), and dichloromethane to obtain component B.

[0048] 3. Mix component A and component B. Foaming will begin after 40 seconds. After foaming is complete, cure in an oven at 60℃ for 30 minutes before demolding.

[0049] 4. Add an organic bismuth catalyst (bismuth caprylate in Table 1) to the iohexol aqueous solution. Immerse the above foam in the iohexol aqueous solution containing the organic bismuth catalyst, heat to 80℃ (i.e., the unsealing and grafting reaction temperature) to carry out the grafting reaction. After 10 minutes, take out the foam and put it in a 70℃ oven for curing for 12 hours.

[0050] 5. Cut the foam according to the preset shape to obtain plugging foam.

[0051] Comparative Example 1 uses water to dissolve iohexol, which participates in the gelation reaction during the foaming process as a polyol component, thus embedding iohexol into the molecular structure. The specific steps are as follows (see Table 1 below for raw material usage, and Table 2 for test data): 1. Dissolve iohexol in water to prepare an iohexol aqueous solution.

[0052] 2. Copolymerize HDI with a portion of HPED (35% of the amount used in Table 1), TEA (35% of the amount used in Table 1), and all of PCL triol to form a prepolymer as component A.

[0053] 3. Mix the aqueous solution of iohexol with the remaining equivalents of HPED (65% of the amount used in Table 1) and TEA (65% of the amount used in Table 1), and add bismuth isooctanoate, triethylenediamine, silicone oil and dichloromethane to obtain component B.

[0054] 4. Mix component A and component B and foam.

[0055] 5. Demold the foam after it has cured in a 70℃ oven for 12 hours.

[0056] 6. Cut the foam into the appropriate size.

[0057] Comparative Example 2 involved dissolving iohexol in N,N-dimethylformamide (DMF) and then prepolymerizing it with HDI. The specific steps are as follows (see Table 1 below for raw material usage, and Table 2 for test data): 1. Dissolve iohexol in N,N-dimethylformamide.

[0058] 2. Copolymerize HDI with a portion of HPED (35% of the amount used in Table 1), TEA (35% of the amount used in Table 1), all of PCL triol, and iohexol N,N-dimethylformamide solution, and then heat to evaporate N,N-dimethylformamide to form a prepolymer, which is used as component A.

[0059] 3. Mix water with the remaining equivalents of HPED (65% of the amount used in Table 1), TEA (65% of the amount used in Table 1), bismuth isooctanoate, triethylenediamine, silicone oil, and dichloromethane to obtain component B.

[0060] 4. Mix component A and component B in the specified proportions and then foam.

[0061] 5. Demold the foam after it has cured in a 70℃ oven for 12 hours.

[0062] 6. Cut the foam into the appropriate size.

[0063] Comparative Example 3: Embolizing foam was immersed in an isocyanate solution to graft isocyanate groups, and then the isocyanate groups were covalently modified onto the surface of embolizing microspheres. The specific steps are as follows (see Table 1 below for raw material usage, and Table 2 for test data): 1. Copolymerize HDI with a portion of HPED (35% of the amount used in Table 1), TEA (35% of the amount used in Table 1), and all of PCL triol as component A.

[0064] 2. Mix water with the remaining equivalents of HPED (65% of the amount used in Table 1), TEA (65% of the amount used in Table 1), bismuth isooctanoate, triethylenediamine, silicone oil, and dichloromethane to obtain component B.

[0065] 3. Mix component A and component B in the specified ratio and foam. Cut into the predetermined size.

[0066] 4. Immerse the above foam in 50 mL of HDI (excluding this portion of HDI in Table 1) and treat at 60°C for 1 h to carry out the grafting reaction.

[0067] 5. Subsequently, the embolic foam was removed and placed in an iohexol solution of N,N-dimethylformamide, using bismuth caprylate as a catalyst, and treated at 40°C for 2 hours. After the reaction was completed, it was removed and rinsed three times with pure water.

[0068] 6. The foam was cured in a 70℃ oven for 12 hours. This yielded a thrombus foam grafted with iohexol.

[0069] Table 1. Amounts of components used in each example and comparative example (unit: g)

[0070] Table 2 Performance indicators of each embodiment and comparative example product

[0071] In Comparative Examples 1-2, the iohexol developer, because it reacts simultaneously with the foaming reaction, occupies a portion of the polyol content. Its cyclic structure and six polyol functional groups result in excessive cross-linking, leading to a higher foam Tg and affecting its expansion effect in vivo. This method requires the addition of a large amount of DMF solvent to increase the amount of iohexol. After prepolymerization, the solvent is difficult to completely remove, and residual solvent can affect the product's biocompatibility and tear resistance.

[0072] In Comparative Example 3, the foam after foaming was soaked and grafted with HDI, and then iohexol was grafted onto the isocyanate groups of HDI. The development effect was very poor (see...). Figure 1 The main reason is that during the soaking of HDI in foam, both of the two isocyanate groups of HDI are highly reactive and will participate in the cross-linking reaction to form a network structure, making it difficult to form independent isocyanate end groups. As a result, the proportion of iohexol that can be grafted later is relatively small.

[0073] The above embodiments compared foams with different HDI contents. Based on the requirement of 100g HDI for the foaming reaction, the excess HDI in Examples 1 to 4 gradually increased from 20g, 30g, 40g, and 50g. The amount of developer added to the iohexol aqueous solution gradually increased from 35g to 85g, resulting in enhanced development. However, excess HDI of 40g and 50g had a certain impact on the structure of the SMP foam, causing uneven foam structure and lower foam tear strength. It is hypothesized that the excess HDI exists in a branched form, reducing the crosslinking density. Therefore, Example 2 is the preferred embodiment.

[0074] In the comparative and example examples above, the X-ray imaging effects of the foams were compared after soaking in PBS solution for one month. The example foam showed almost no development, while the comparative examples showed no significant change in development. This is because the comparative examples used a developer as a monomer block to the molecular chain, meaning the developer molecules could only gradually break down as the foam degraded, a process that was very long. In the example examples, the developer was grafted onto the foam surface, allowing the developer molecules to fully contact the water in the PBS solution and dissolve first due to chain breakage.

[0075] Examples 5-9 Following the preparation process of Example 1, different capping agents were used, as detailed in Table 3, and the test data are shown in Table 4. Table 3. Amounts of components used in each example and comparative example (unit: g)

[0076] Table 4 Performance indicators of each embodiment and comparative example product

[0077] The above embodiments compared the performance of embolic foams prepared with different end-capping agents. Different end-capping agents were used with corresponding end-capping and decapping temperatures to ensure more thorough end-capping and decapping reactions. In contrast, the foams in Examples 5-9 all shrank and had higher densities. Example 7 showed significant shrinkage, which was caused by excessively high temperatures during the decapping reaction, leading to shrinkage and deformation of the foam material.

[0078] Compared with the above embodiments, Example 2, which uses sodium bisulfite as the sealing agent, has a lower sealing and unsealing temperature and will not affect the performance of the foam material, making it a preferred embodiment.

[0079] The embodiments described above are merely illustrative of several implementation methods of this application, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the scope of protection of this application. Therefore, the patent protection scope of this application should be determined by the appended claims.

Claims

1. A method for preparing a short-term developing embolic foam, characterized in that, include: Step S100: Mix the isocyanate and the first polyol evenly to obtain the prepolymer; Step S200: Add a capping agent to the prepolymer to obtain the capped prepolymer as component A; Step S300: Mix the second part of polyol, the first catalyst, silicone oil, foaming agent and water evenly to obtain component B; mix component A and component B and foam to obtain polyurethane foam. Step S400: Immerse the polyurethane foam in a developer solution containing a second catalyst to react and obtain the short-term developing plug foam. The mass ratio of isocyanate to polyol is 100:50-90; the polyol includes the first part of polyol and the second part of polyol, wherein the first part of polyol accounts for 30% to 80% of the total mass of the polyol, and the remainder is the second part of polyol.

2. The method for preparing short-term developing embolic foam as described in claim 1, characterized in that, The capping agent is at least one of sodium bisulfite, methyl ethyl ketone oxime, ε-caprolactam, 3,5-dimethylpyrazole, ethyl acetoacetate, and diethyl malonate.

3. The method for preparing short-term developing embolic foam as described in claim 1, characterized in that, The mass ratio of the capping agent to isocyanate is 100:20~60.

4. The method for preparing short-term developing embolic foam as described in claim 1, characterized in that, The mass ratio of the developer to the isocyanate is 100:20~60.

5. The method for preparing short-term developing embolic foam as described in claim 1, characterized in that, The developer solution uses water as a solvent, and the concentration of the developer solution is 0.05~0.15g / mL.

6. The method for preparing short-term developing embolic foam as described in claim 1, characterized in that, The content of the second catalyst in the developer solution is 0.002~0.004 g / mL.

7. The method for preparing short-term developing embolic foam as described in claim 1, characterized in that, In step S200, after adding the capping agent, the mixture is reacted at 50~70℃ for 2~5 hours to obtain the capped prepolymer.

8. The method for preparing short-term developing embolic foam as described in claim 1, characterized in that, In step S300, the reaction temperature is 70~100℃ and the reaction time is 10~30 minutes.

9. A short-term developing embolic foam, characterized in that, It is prepared by the preparation method described in any one of claims 1 to 8.

10. The short-term developing embolic foam as described in claim 9, characterized in that, The glass transition temperature of the short-term developing embolization foam is 38~42℃, and the degradation cycle of the developer in the short-term developing embolization foam is less than 30 days.

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