Porous embolism microsphere, preparation method thereof and drug-loaded embolism microsphere

Abstract

The invention discloses a porous embolism microsphere, a preparation method of the porous embolism microsphere and a drug-loaded embolism microsphere, and relates to the field of medical materials. The porous embolization microsphere comprises a network structure formed by cross-linking polymerization of a polyhydroxy water-soluble polymer, a first cross-linking agent, a second cross-linking agent and an ionic monomer, and the network structure comprises a first pore structure formed by cross-linking of the first cross-linking agent and a second pore structure formed by cross-linking of the second cross-linking agent, the aperture of the first pore structure is greater than that of the second pore structure; wherein the molecular weight of the first cross-linking agent is 1000-20000, and the molecular weight of the second cross-linking agent is less than 500. The microsphere provided by the invention can be used for simultaneously and efficiently loading a small molecule drug and a macromolecular drug, and has excellent drug loading rate and drug loading capacity on the small molecule drug and the macromolecular drug, so that the application scene of the microsphere is expanded. In addition, the invention also has a controllable slow-release effect on the medicine.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medical materials, in particular to a porous embolization microsphere, a preparation method thereof and a drug-loaded embolization microsphere. BACKGROUND

[0002] In clinical treatment, drug-loaded microspheres need to have high loading and controllable release capacity for various drug molecules. These properties are related to the structure of the microspheres, especially the crosslinking degree, which is usually controlled by adjusting the type and amount of crosslinking agent.

[0003] In clinical application, a combination of multiple drugs is often required, including small molecule chemotherapy drugs, liposome drugs or albumin binding drugs, and various target drugs, in order to achieve the best therapeutic effect. Different drug molecules have different requirements for the performance of drug-loaded microspheres due to their different molecular weights and charges.

[0004] Most of the existing microspheres are prepared using a single small molecule crosslinking agent. The pore size of the resulting microspheres is usually inversely proportional to the amount of crosslinking agent. In order to maintain the stability of the microsphere structure and a certain drug loading capacity, the pore structure of the resulting microspheres is relatively simple, and only drug molecules with a certain range of molecular weights can be adsorbed. When the amount of crosslinking agent is high, the resulting microspheres have a relatively dense structure, which is suitable for loading small molecule drugs, but may result in slow drug loading rate. When the amount of crosslinking agent is low, the resulting microspheres have a relatively loose structure, which allows large molecule drug molecules to easily enter the pores, but the binding force between the drug and the microspheres is weak, resulting in low drug loading and fast release. Therefore, it is difficult to obtain a microsphere structure that has fast loading capacity and appropriate release rate for drugs with different molecular weights by adjusting the amount of a single crosslinking agent. SUMMARY

[0005] The present application aims to provide a porous embolization microsphere, a preparation method thereof and a drug-loaded embolization microsphere to solve the above problems.

[0006] To achieve the above object, the following technical solutions are adopted in the present application: A porous embolization microsphere, comprising a network structure crosslinked by a multi-hydroxyl water-soluble polymer, a first crosslinking agent, a second crosslinking agent and an ionic monomer, the network structure comprising a first pore structure crosslinked by the first crosslinking agent and a second pore structure crosslinked by the second crosslinking agent, the pore size of the first pore structure being larger than the pore size of the second pore structure; wherein, The molecular weight of the first crosslinking agent is 1000-20000, and the molecular weight of the second crosslinking agent is <500.

[0007] Compared with the prior art, the present application has the following advantages: This application constructs macroporous and microporous structures within microspheres by introducing a first crosslinking agent with a larger molecular weight and a second crosslinking agent with a smaller molecular weight. These structures can simultaneously and efficiently load both large and small molecule drugs, exhibiting excellent drug loading rates and amounts for both types, thus expanding the application scenarios of microspheres. Specifically, the macroporous channels provide unobstructed pathways for drug delivery, allowing large molecule drugs to directly enter the microsphere interior, reducing resistance and improving the loading rate and amount. The presence of macroporous channels also reduces resistance for small molecule drugs, enhancing the loading effect of the microspheres on small molecule drugs. Furthermore, this application also provides a sustained-release effect; the microporous channels increase the resistance to drug release, enabling controllable sustained-release effects for both large and small molecule drugs. Attached Figure Description

[0008] To more clearly illustrate the technical solutions of the embodiments of this application, the accompanying drawings used in the embodiments will be briefly described below. It should be understood that the following drawings only show some embodiments of this application and should not be regarded as a limitation on the scope of this application.

[0009] Figure 1 This is a flowchart of the preparation method of porous embolic microspheres in this application. Detailed Implementation

[0010] As used herein, when an amount, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper and lower preferred values, it should be understood as specifically disclosing all ranges formed by any pair of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually.

[0011] This application discloses a porous embolic microsphere, comprising a network structure formed by crosslinking and polymerization of a multi-hydroxyl water-soluble polymer, a first crosslinking agent, a second crosslinking agent, and an ionic monomer. The network structure includes a first pore structure formed by crosslinking with the first crosslinking agent and a second pore structure formed by crosslinking with the second crosslinking agent, wherein the pore size of the first pore structure is larger than the pore size of the second pore structure; wherein... The molecular weight of the first crosslinking agent is 1000-20000, and the molecular weight of the second crosslinking agent is <500.

[0012] The porous embolic microspheres of this application comprise a network structure constructed from a first crosslinking agent of a specific high molecular weight and a second crosslinking agent of a specific low molecular weight. The network structure simultaneously includes first and second pore structures with different pore sizes. The larger pore size of the first pore structure significantly improves drug loading efficiency and drug capacity, particularly facilitating the rapid entry of large molecule drugs; the smaller pore size of the second pore structure effectively delays the drug release rate, enabling a sustained-release effect.

[0013] In some embodiments, the molecular weight of the first crosslinking agent is 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 11000, 12000, 13000, 14000, 15000, 16000, 17000, 18000, 19000, 20000 or any value between 1000 and 20000, and the molecular weight of the second crosslinking agent is <500, <450, <400, <350, <300, <250, <200, <150, <100 or any value <500.

[0014] According to an embodiment of this application, the first crosslinking agent comprises a polyethylene glycol derivative having 2-8 arms, and the end capping groups of at least two of the arms comprise aldehyde, acetal, or hemiacetal groups. Optionally, the first crosslinking agent includes at least one of aldehyde-modified linear polyethylene glycol, tetra-armed polyethylene glycol, hexa-armed polyethylene glycol, and octa-armed polyethylene glycol.

[0015] According to embodiments of this application, the second crosslinking agent includes N-(2,2-dimethoxy)-2-methylacrylamide, N-(1-hydroxy-2,2-dimethoxyethyl)-2-acrylamide, and N-(2,2-dimethoxy) At least one of 2-acrylamide, N-(1-hydroxy-2,2-dimethoxyethyl)-2-methacrylamide, N-(2,2-dimethoxy)-2-methacrylate, N-(1-hydroxy-2,2-dimethoxyethyl)-2-acrylate, N-(2,2-dimethoxy)-2-acrylate, and N-(1-hydroxy-2,2-dimethoxyethyl)-2-methacrylate; and / or, The multi-hydroxyl water-soluble polymer includes at least one of polyvinyl alcohol, sodium alginate, sodium hyaluronate, water-soluble chitosan, and sodium carboxymethyl cellulose.

[0016] According to embodiments of this application, the ionic monomer includes a water-soluble ionic monomer with polymerizable double bonds and ionic groups, wherein the ionic groups include at least one of anionic groups and cationic groups; by introducing ionic monomers, microspheres can adsorb and load drugs with different charge properties.

[0017] Optionally, the ionic monomer includes at least one of methacryloylethyl sulfobetaine, 2-methacryloyloxyethyl phosphorylcholine, methacryloyloxyethyl carboxybetaine, methacrylic acid sulfobetaine, sodium 2-acrylamide-2-methylpropanesulfonate, sodium allyl sulfonate, and sodium acrylate.

[0018] This application also provides a method for preparing porous embolic microspheres as described above, referencing... Figure 1 The preparation method includes the following steps: A first aqueous phase is obtained by mixing a polyhydroxy water-soluble polymer with a first crosslinking agent and water. The second crosslinking agent, ionic monomer, initiator and water are mixed to obtain the second aqueous phase; The first aqueous phase is added to the oil phase to form a water-in-oil reverse suspension polymerization system; A catalyst is added to the water-in-oil reverse suspension polymerization system to carry out the first crosslinking reaction; The second aqueous phase is added to the reaction system after the first crosslinking reaction is completed to carry out the second crosslinking reaction, thereby obtaining porous embolic microspheres.

[0019] Under the catalysis of a catalyst, a polyhydroxy water-soluble polymer undergoes a first cross-linking reaction with a first cross-linking agent with a large molecular weight and long molecular chain, forming a microsphere framework with a large pore size. The second cross-linking agent and ionic monomer in the second aqueous phase have smaller molecular weights, allowing them to penetrate into the microsphere framework and undergo a second cross-linking reaction with the polyhydroxy water-soluble polymer, forming a microporous structure. The resulting porous embolic microspheres possess both a large-pore first pore structure and a small-pore second pore structure. The large-pore first pore structure can load large molecule drugs, while the small-pore second pore structure can load small molecule drugs. Therefore, the microspheres of this application can simultaneously and efficiently load both small molecule and large molecule drugs.

[0020] In the clinical use of microspheres, drug-loaded microspheres need to be delivered to the target location via catheters. Microspheres require both excellent mechanical properties (resistance to deformation and breakage) and excellent suspension properties (suspension stability). However, traditional microspheres struggle to balance mechanical and suspension properties. When the cross-linking agent content is too high, the microsphere's pores become dense, slowing the contrast agent's penetration and increasing the time it takes for the microsphere to reach suspension. Furthermore, uneven contrast agent distribution may reduce the microsphere's ability to maintain suspension, thus affecting catheter permeability and the uniformity of embolization. When the cross-linking agent content is too low, the microspheres may deform very easily, posing a high risk of breakage.

[0021] According to embodiments of this application, the first crosslinking agent includes at least one of aldehyde-modified linear polyethylene glycol, tetra-armed polyethylene glycol, hexa-armed polyethylene glycol, and octa-armed polyethylene glycol. The first crosslinking agent added in this application can enable the microspheres to form a large-pore structure, which is beneficial for the rapid and uniform penetration of high-viscosity contrast agents into the interior of the microspheres, shortens the time required for the microspheres to reach suspension, and prolongs the time of maintaining suspension, thereby improving the permeability of the microspheres in the catheter and the uniformity of embolization.

[0022] The second crosslinking agent added in this application can cause the intermediate with a macroporous structure to undergo a second crosslinking reaction, increase the local crosslinking density, and form a microporous structure, so that the microspheres have both macroporous and microporous structures. The introduction of the second crosslinking agent can also enhance the mechanical strength of the crosslinking network, further reducing the risk of deformation or breakage of the microspheres during transportation.

[0023] The multi-hydroxyl water-soluble polymer includes at least one of polyvinyl alcohol, sodium alginate, sodium hyaluronate, water-soluble chitosan, and sodium carboxymethyl cellulose. The ionic monomers include at least one of the following: methacryloylethyl sulfobetaine, 2-methacryloyloxyethyl phosphorylcholine, methacryloyloxyethyl carboxybetaine, methacrylic acid sulfobetaine, sodium 2-acrylamide-2-methylpropanesulfonate, sodium allyl sulfonate, and sodium acrylate. The initiator includes at least one of potassium persulfate, ammonium persulfate, and azobisisobutyronitrile; The catalyst includes at least one of hydrochloric acid, sulfuric acid, and nitric acid.

[0024] According to embodiments of this application, the mass of the first crosslinking agent is 0.1%-5% of the mass of the polyhydroxy water-soluble polymer; In some embodiments, the mass of the first crosslinking agent is any value between 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, or 0.1%-5% of the mass of the polyhydroxy water-soluble polymer.

[0025] And / or, the mass of the second crosslinking agent is 0.05%-5% of the mass of the polyhydroxy water-soluble polymer; In some embodiments, the mass of the second crosslinking agent is any value between 0.05%, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% or 0.05%-5% of the mass of the polyhydroxy water-soluble polymer.

[0026] And / or, the mass of the ionic monomer is 5-30% of the mass of the polyhydroxy water-soluble polymer; In some embodiments, the mass of the ionic monomer is any value between 5%, 10%, 15%, 20%, 25%, 30%, or 5-30% of the mass of the polyhydroxy water-soluble polymer.

[0027] And / or, the initiator is 0.1%-3% of the mass of the polyhydroxy water-soluble polymer.

[0028] In some embodiments, the mass of the initiator is any value between 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, or 0.1%-3% of the mass of the polyhydroxy water-soluble polymer.

[0029] According to an embodiment of this application, the temperature of the first crosslinking reaction is 20-45°C, and the time of the first crosslinking reaction is 0.5-3 h; In some embodiments, the temperature of the first crosslinking reaction is any value between 20°C, 25°C, 30°C, 35°C, 40°C, 45°C or 20-45°C, and the time of the first crosslinking reaction is any value between 0.5h, 1h, 1.5h, 2h, 2.5h, 3h or 0.5-3h.

[0030] And / or, the temperature of the second crosslinking reaction is 40-70°C, and the time of the second crosslinking reaction is 2-8 h.

[0031] For example, the temperature of the second crosslinking reaction is any value between 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, or 40-70°C, and the time of the second crosslinking reaction is any value between 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 5.5 h, 6 h, 6.5 h, 7 h, 7.5 h, 8 h, or 2-8 h.

[0032] According to an embodiment of this application, the method for preparing the oil phase includes: mixing an oil-soluble dispersant with an oily solvent to obtain an oil phase; The oil-soluble dispersant includes at least one of cellulose acetate butyrate and Tween 80; The oily solvent includes at least one of butyl acetate and liquid paraffin; Optionally, the oil-soluble dispersant and the oily solvent are mixed and dissolved at 35~45°C (e.g., any value between 35°C, 40°C, 45°C or 35-45°C) to form the oil phase.

[0033] This application also provides a drug-loaded embolization microsphere, comprising porous embolization microspheres loaded with a molecular drug; wherein, the porous embolization microsphere is the porous embolization microsphere described above or the porous embolization microsphere prepared by the preparation method described above; the molecular drug includes at least one of small molecule drugs and large molecule drugs; The macromolecular drug includes at least one of bevacizumab, pembrolizumab, and nivolumab, and the small molecule drug includes at least one of doxorubicin, epirubicin, pirarubicin, irinotecan, topotecan, gemcitabine, sorafenib, and lenvatinib.

[0034] Irinotecan and bevacizumab can be used in combination for the treatment of metastatic colorectal cancer. Irinotecan is a small molecule drug that primarily exerts cytotoxic effects, while bevacizumab is a large molecule targeted drug with anti-angiogenic effects. When both drugs are simultaneously loaded onto microspheres and released into the tumor, they can work synergistically to block blood vessels, inhibit angiogenesis, and exert cytotoxic effects, thereby achieving better therapeutic outcomes.

[0035] The implementation schemes of this application will be described in detail below with reference to specific embodiments. However, those skilled in the art will understand that the following embodiments are only for illustrating this application and should not be regarded as limiting the scope of this application. Unless otherwise specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments used without specified manufacturers are all conventional products that can be purchased commercially.

[0036] I. Preparation of porous embolic microspheres Example 1 Example 1 provides a porous embolic microsphere, the preparation method of which includes: A reverse suspension polymerization method was used. 60 mL of butyl acetate and 1.2 g of cellulose acetate butyrate were added to a four-necked flask and dissolved in a 40°C constant-temperature water bath with stirring to form a homogeneous oil phase. A 10% (w / w) aqueous solution of polyvinyl alcohol was prepared under a 90°C constant-temperature water bath. 20 mL of the polyvinyl alcohol aqueous solution was taken, and 0.1 g of aldehyde-terminated six-arm polyethylene glycol (molecular weight 2000) was separately weighed and dissolved to form the first aqueous phase solution. 0.5 g of methacrylate sulfobetaine, 0.1 g of N-(2,2-dimethoxy)-2-methylacrylamide, and 0.02 g of potassium persulfate were weighed and dissolved in 5 mL of deionized water, dispersed evenly to form the second aqueous phase solution.

[0037] Maintaining the temperature at 35℃ and stirring at 300 rpm, a first aqueous phase solution was slowly added dropwise to the oil phase to form a water-in-oil reverse suspension polymerization system. After the addition was complete, 1 mL of hydrochloric acid was added to initiate the first crosslinking reaction. After 0.5 h of reaction, a second aqueous phase solution was added to the reaction system, and the temperature was raised to 60℃ to initiate a free radical polymerization reaction, resulting in a second crosslinking reaction and forming a secondary crosslinked network. After 5 h, the second crosslinking reaction was completed, and the microspheres were separated, washed, and sieved to obtain porous embolic microspheres.

[0038] Example 2 Porous embolic microspheres were prepared according to the method of Example 1. The difference between Example 2 and Example 1 is that the aldehyde-terminated six-arm polyethylene glycol with a molecular weight of 2000 in the first aqueous solution of Example 1 was replaced with aldehyde-terminated six-arm polyethylene glycol with a molecular weight of 4000. The remaining reaction conditions were the same as in Example 1.

[0039] Example 3 Porous embolic microspheres were prepared according to the method of Example 1. The difference between Example 3 and Example 1 is that the aldehyde-terminated six-arm polyethylene glycol with a molecular weight of 2000 in the first aqueous solution of Example 1 was replaced with aldehyde-terminated six-arm polyethylene glycol with a molecular weight of 8000. The remaining reaction conditions were the same as in Example 1.

[0040] Example 4 Porous embolic microspheres were prepared according to the method of Example 1. The difference between Example 4 and Example 1 is that the aldehyde-terminated six-arm polyethylene glycol with a molecular weight of 2000 in the first aqueous solution of Example 1 was replaced with aldehyde-terminated four-arm polyethylene glycol with a molecular weight of 8000. The remaining reaction conditions were the same as in Example 1.

[0041] Comparative Example 1: Secondary cross-linking using two different small molecule cross-linking agents Porous embolic microspheres were prepared according to the method of Example 1. The difference between Comparative Example 1 and Example 1 is that the aldehyde-terminated six-arm polyethylene glycol with a molecular weight of 2000 in the first aqueous solution of Example 1 was replaced with glutaraldehyde. The remaining reaction conditions were the same as in Example 1.

[0042] II. Performance Testing of Porous Embolizing Microspheres The porous embolic microspheres prepared in Examples 1-4 and Comparative Example 1 were subjected to performance tests under the same conditions.

[0043] (1) Suspension performance test Two mL of the porous embolic microspheres prepared in Examples 1-4 and Comparative Example 1 were drawn into a syringe, and an equal volume of contrast agent iohexol was added. After mixing thoroughly for 1 min, the microspheres were observed to see if they reached a suspension state, i.e., the microspheres were uniformly dispersed in the contrast agent and maintained for at least 1 min. If not, mixing was continued for 30 s, and the above operation was repeated. The time required to finally reach a suspension state and the time during which the microspheres could maintain a suspension state were recorded. The test results are shown in Table 1.

[0044] Table 1 Microsphere suspension data

[0045] As shown in Table 1, Comparative Example 1 required the longest time to reach suspension and maintained suspension for the shortest time. This may be because the pores of the microspheres in Comparative Example 1 were formed by secondary cross-linking with a small molecule cross-linking agent, resulting in denser pores. Consequently, the contrast agent took longer to penetrate into the microspheres and reach internal and external equilibrium.

[0046] Compared to Comparative Example 1, the time required for the microspheres in Examples 1-4 to reach suspension was significantly shortened. Furthermore, under the same number of arms, the time required to reach suspension gradually decreased with the increase of the molecular weight of the first crosslinking agent (Examples 1 to 3), meaning that suspension was achieved faster and the suspension time gradually increased. This is because the larger the molecular weight of the first crosslinking agent, the larger the macropore space it forms, allowing the contrast agent to penetrate into the microsphere more quickly, achieving internal and external density balance and thus reaching suspension faster. Simultaneously, with the increase of the molecular weight of the first crosslinking agent, the final microsphere density is relatively low, making the microspheres lighter and thus allowing them to maintain suspension for a longer time. Compared to Example 3, the molecular weight of the first crosslinking agent in Example 4 was the same as in Example 3, but the number of arms was fewer. The single-arm molecular chain in Example 4 was longer, forming larger pores. Therefore, Example 4 also achieved suspension quickly and maintained suspension for a longer time.

[0047] (2) Drug loading performance test Drug loading: Prepare 20 mg / mL of irinotecan aqueous solution and 25 mg / mL of bevacizumab solution. First, mix 2 mL of the porous embolic microspheres prepared in Examples 1-4 and Comparative Example 1 with 5 mL of irinotecan aqueous solution. After sufficient adsorption and loading for 10 min, aspirate 1 mL of the supernatant to detect the remaining drug concentration in the solution. After removing the remaining supernatant, add 2 mL of bevacizumab solution, mix thoroughly, and adsorb. Then, aspirate 1 mL of the supernatant to detect the remaining drug concentration in the solution. Analyze the drug molecule concentration in the supernatant using high-performance liquid chromatography (HPLC) to calculate the drug loading rate.

[0048] Drug release: The microspheres loaded with the two drugs were transferred to the drug release device and released at 37°C and 150 rpm using physiological saline as the release medium. Samples were taken periodically to obtain release data.

[0049] Drug loading data for porous embolic microspheres in Examples 1-4 and Comparative Example 1 are shown in Table 2.

[0050] Table 2 Comparison of the effects of microsphere loading of irinotecan and bevacizumab

[0051] As shown in Table 2, the loading amount of irinotecan on the microspheres of Examples 2-4 was greater than that in Example 1, while the loading amount of irinotecan on the microspheres of Comparative Example 1 was the smallest. This is due to the difference in the first crosslinking agent used in Examples 1-4 and Comparative Example 1. As the chain length of the first crosslinking agent increases from Comparative Example 1 to Examples 1-4, the pores become larger, making it easier for small molecules to enter the interior of the microspheres, thus gradually increasing the loading amount of irinotecan. Overall, due to the small molecular weight of irinotecan, the microspheres of Examples 1-4 and Comparative Example 1 all showed relatively good loading effects for irinotecan, with the total loading rate of irinotecan on the microspheres reaching 100%.

[0052] For the macromolecular drug bevacizumab, the loading effect of the microspheres in Examples 1-4 and Comparative Example 1 differed significantly. The total loading rate of bevacizumab by the microspheres in Comparative Example 1 was only 12%. This is because the pore size formed in Comparative Example 1 was too small, preventing the macromolecular drug from entering the microspheres and resulting in only a small amount of adsorption on the surface. The microspheres in Examples 1-4, in addition to showing good loading effects for irinotecan, also exhibited excellent loading effects for the macromolecular drug bevacizumab, indicating that the introduction of the first cross-linking agent with a large molecular weight, as described in this application, can create a macroporous structure inside the microspheres, providing a delivery channel for the macromolecular drug. The microspheres in Example 2 showed the best loading effect for bevacizumab because the pores formed were just large enough for bevacizumab to enter, and the density of the small pores also increased the utilization rate of the inner surface of the microspheres. The macropores in Example 1 were relatively denser, allowing bevacizumab to enter, but the loading amount was slightly lower than in Examples 2-4, and the inner surface utilization rate was moderate, hence the total loading rate was slightly lower than in Example 2. Compared to Example 2, Examples 3-4 show a further increase in macropore space, which facilitates the entry of bevacizumab. However, the pore density decreases, and the internal surface utilization is low, leading to a decrease in loading amount and total loading rate. This demonstrates that introducing a macromolecular first cross-linking agent can effectively increase the loading amount of macromolecular drugs. By adjusting the molecular weight and number of arms of the first cross-linking agent, the pore size and density of the macropores can be further refined, thereby affecting the drug loading rate and loading amount.

[0053] Drug release data for porous embolic microspheres in Examples 1-4 and Comparative Example 1 are shown in Table 3.

[0054] Table 3 Comparison of the release effects of microspheres on irinotecan and bevacizumab

[0055] As shown in Table 3, the release rate of the microspheres for the small molecule drug irinotecan in Examples 1-4 and Comparative Example 1 was 100%. The release time of the microspheres for irinotecan in Examples 1-4 was longer than that in Comparative Example 1. The release rate of irinotecan decreased with the introduction of the macromolecular first cross-linking agent. This is because the macromolecular drug bevacizumab has a certain occupancy effect, which creates some resistance to the release pathway of the small molecule drug irinotecan. The shorter the single arm of the cross-linking agent, the denser the pores, and the greater the resistance. Therefore, the release rate of irinotecan in Examples 4-1 became slower and slower, and the release time of the microspheres for irinotecan gradually increased, but 100% release could still be achieved. For the macromolecular drug bevacizumab, release of more than 95% could generally be achieved, showing a similar trend to the release of the small molecule drug irinotecan. The shorter the single arm of the cross-linking agent, the longer the release time. Because the bevacizumab molecule is relatively large, the presence of small pores creates some resistance, so the overall release time of bevacizumab is longer than that of irinotecan, showing a good sustained-release effect.

[0056] The above demonstrates that the introduction of the first cross-linking agent of macromolecules can effectively control the release rate of both small and large molecule drugs, resulting in a sustained-release effect and potentially leading to better clinical outcomes.

[0057] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.

[0058] Furthermore, those skilled in the art will understand that although some embodiments herein include certain features included in other embodiments but not others, combinations of features from different embodiments are intended to be within the scope of this application and form different embodiments. For example, in the foregoing claims, any of the claimed embodiments can be used in any combination. The information disclosed in this background section is intended only to enhance the understanding of the general background of this application and should not be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

Claims

1. A porous embolizing microsphere, characterized by, The porous embolization microspheres comprise a network structure formed by cross-linking of a multi-hydroxyl water-soluble polymer, a first cross-linking agent, a second cross-linking agent and an ionic monomer, the network structure comprises a first pore structure formed by cross-linking of the first cross-linking agent, and a second pore structure formed by cross-linking of the second cross-linking agent, the pore size of the first pore structure is larger than the pore size of the second pore structure; wherein, The molecular weight of the first cross-linking agent is 1000-20000, and the molecular weight of the second cross-linking agent is <500.

2. The porous embolic microspheres of claim 1, wherein, The first cross-linking agent comprises a polyethylene glycol derivative with 2-8 arms, and the end capping groups of at least two of the arms comprise aldehyde groups, acetal groups or hemiacetal groups. Optionally, the first cross-linking agent comprises at least one of an aldehyde group modified linear polyethylene glycol, a four-arm polyethylene glycol, a six-arm polyethylene glycol and an eight-arm polyethylene glycol.

3. The porous embolic microspheres of claim 1, wherein, The second crosslinking agent includes N-(2,2-dimethoxy)-2-methylacrylamide, N-(1-hydroxy-2,2-dimethoxyethyl)-2-acrylamide, and N-(2,2-dimethoxy) At least one of 2-acrylamide, N-(1-hydroxy-2,2-dimethoxyethyl)-2-methacrylamide, N-(2,2-dimethoxy)-2-methacrylate, N-(1-hydroxy-2,2-dimethoxyethyl)-2-acrylate, N-(2,2-dimethoxy)-2-acrylate, and N-(1-hydroxy-2,2-dimethoxyethyl)-2-methacrylate; and / or, The multi-hydroxyl water-soluble polymer comprises at least one of polyvinyl alcohol, sodium alginate, sodium hyaluronate, water-soluble chitosan and sodium carboxymethyl cellulose.

4. The porous embolic microspheres of claim 1, wherein, The ionic monomer comprises a water-soluble ionic monomer with a polymerizable double bond and an ionic group, the ionic group comprises at least one of an anionic group and a cationic group; Optionally, the ionic monomer comprises at least one of methacryloyl ethyl sulfobetaine, 2-methacryloyloxyethyl phosphorylcholine, methacryloyloxyethyl carboxybetaine, methacrylic acid sulfobetaine, 2-acrylamide-2-methylpropane sulfonic acid sodium, allyl sulfonic acid sodium and acrylic acid sodium.

5. A method of producing porous embolic microspheres as claimed in any one of claims 1 to 4, characterized in that, The method comprises the following steps: Mixing the multi-hydroxyl water-soluble polymer with the first cross-linking agent and water to obtain a first aqueous phase; Mixing the second cross-linking agent, the ionic monomer, the initiator and water to obtain a second aqueous phase; Adding the first aqueous phase to the oil phase to form a water-in-oil reverse phase suspension polymerization system; Adding a catalyst to the water-in-oil reverse phase suspension polymerization system to perform a first cross-linking reaction; Adding the second aqueous phase to the reaction system in which the first cross-linking reaction is completed to perform a second cross-linking reaction, thereby obtaining the porous embolization microspheres.

6. The method of claim 5, wherein the porous embolic microspheres are prepared by the steps of: The first cross-linking agent comprises at least one of an aldehyde group modified linear polyethylene glycol, a four-arm polyethylene glycol, a six-arm polyethylene glycol and an eight-arm polyethylene glycol; and / or, The second crosslinking agent includes N-(2,2-dimethoxy)-2-methylacrylamide, N-(1-hydroxy-2,2-dimethoxyethyl)-2-acrylamide, and N-(2,2-dimethoxy) At least one of 2-acrylamide, N-(1-hydroxy-2,2-dimethoxyethyl)-2-methacrylamide, N-(2,2-dimethoxy)-2-methacrylate, N-(1-hydroxy-2,2-dimethoxyethyl)-2-acrylate, N-(2,2-dimethoxy)-2-acrylate, and N-(1-hydroxy-2,2-dimethoxyethyl)-2-methacrylate; and / or, The multi-hydroxyl water-soluble polymer comprises at least one of polyvinyl alcohol, sodium alginate, sodium hyaluronate, water-soluble chitosan and sodium carboxymethyl cellulose; and / or, The ionic monomer comprises at least one of methacryloyl ethyl sulfobetaine, 2-methacryloyloxyethyl phosphorylcholine, methacryloyloxyethyl carboxybetaine, methacrylic acid sulfobetaine, 2-acrylamide-2-methylpropane sulfonic acid sodium, allyl sulfonic acid sodium and acrylic acid sodium; and / or, The initiator comprises at least one of potassium persulfate, ammonium persulfate and azobisisobutyronitrile; and / or, The catalyst comprises at least one of hydrochloric acid, sulfuric acid and nitric acid.

7. The method of claim 6, wherein the porous embolic microspheres are prepared by the steps of: The mass of the first cross-linking agent is 0.1%-5% of the mass of the multi-hydroxyl water-soluble polymer; And / or, the mass of the second cross-linking agent is 0.05%-5% of the mass of the multi-hydroxyl water-soluble polymer; And / or, the mass of the ionic monomer is 5-30% of the mass of the polyhydroxyl water-soluble polymer; And / or, the mass of the initiator is 0.1-3% of the mass of the polyhydroxyl water-soluble polymer.

8. The method for preparing porous embolic microspheres according to claim 6, characterized in that, The temperature of the first cross-linking reaction is 20-45℃, and the time of the first cross-linking reaction is 0.5-3 h; And / or, the temperature of the second cross-linking reaction is 40-70℃, and the time of the second cross-linking reaction is 2-8 h.

9. The method of claim 5-8, wherein the porous embolic microspheres are prepared by, The preparation method of the oil phase comprises: mixing an oil-soluble dispersant with an oily solvent to obtain the oil phase; The oil-soluble dispersant comprises at least one of cellulose acetate butyrate and Tween 80; The oily solvent comprises at least one of butyl acetate and liquid paraffin; Optionally, the oil-soluble dispersant and the oily solvent are mixed and dissolved at 35-45℃ to form the oil phase.

10. A drug-loaded embolizing microsphere, characterized by, The porous embolization microspheres load a molecular drug; wherein, the porous embolization microspheres are the porous embolization microspheres of any one of claims 1-5 or are prepared by the preparation method of any one of claims 6-8; the molecular drug comprises at least one of a small molecule drug and a large molecule drug; The large molecule drug comprises at least one of bevacizumab, pembrolizumab, and nivolumab, and the small molecule drug comprises at least one of doxorubicin, epirubicin, pirarubicin, irinotecan, topotecan, gemcitabine, sorafenib, and lenvatinib.

Images