Method for preparing filling material for cerebral aneurysm embolization, and use thereof

Abstract

The present invention relates to a method for preparing a filling material for cerebral aneurysm embolization, and use thereof. The filling material for cerebral aneurysm embolization, prepared according to the preparation method of the present invention, and thus can contribute to increasing the success rate of embolization and improving the safety of surgery, thereby being suitable for use in actual cerebral aneurysm embolization procedures.

Description

Method for manufacturing a filling material for cerebral aneurysm embolization and the use thereof

[0001] The present invention relates to a method for manufacturing a photocrosslinked-based filler material for cerebral aneurysm embolization and the use thereof.

[0002] In general, a cerebral aneurysm is a representative cerebrovascular disease in which a blood vessel swells abnormally due to a structural defect in the inner wall of the blood vessel. Cerebral aneurysms are generally asymptomatic before rupture, but if they are large, they can compress the brain parenchyma or cranial nerves, causing neurological symptoms. If a cerebral aneurysm ruptures, it causes subarachnoid hemorrhage, which increases intracranial pressure. This leads to a decline in consciousness or coma, or in severe cases, death, and even if the patient recovers, it leaves serious aftereffects.

[0003] To treat such cerebral aneurysms, surgical methods such as neck ligation and minimally invasive endovascular procedures such as coil embolization are applied. Among these, cerebral aneurysm coil embolization is a method in which a microcatheter is inserted into the cerebral aneurysm and coils, which are embolizing materials (platinum), are thoroughly filled inside the aneurysm to prevent blood flow from entering the aneurysm. Generally, coil embolization, a minimally invasive endovascular procedure, tends to be preferred over neck ligation, which requires craniotomy.

[0004] However, in the case of conventional cerebral aneurysm coil embolization, the filling rate of the coils filling the aneurysm generally does not exceed 30-40%. Consequently, the recurrence rate of the embolized aneurysm reaches 20-30%, and retreatment is required in 50% of these cases. Furthermore, coil embolization requires a long training period to become proficient, which leads to significant variations in outcomes among operators. Additionally, the materials used in coil embolization (coils, support balloons, stents, etc.) are expensive imported materials, which is a reality that places a significant burden on both patients and society. Moreover, taking antiplatelet agents for an extended period after the procedure is also a considerable burden for patients. Therefore, there is a need to develop a new concept of embolization material to overcome the shortcomings of conventional coil embolization, and photocrosslinked semi-solid microfiber embolization materials that can replace metal coils can serve as an alternative.

[0005] Accordingly, in order to solve the limitations of existing embolization materials, the inventors developed a high-strength embolization material for cerebral aneurysm embolization comprising a PEGDA-based photocrosslinkable polymer compound and a liquid contrast agent as an embolization filling material that can be used for the treatment of cerebrovascular diseases (e.g., cerebral aneurysms), and completed the present invention by identifying that it can be stably maintained even in a high arterial pressure environment.

[0006] Accordingly, one objective of the present invention is to provide a method for manufacturing a filling material for cerebral aneurysm embolization.

[0007] In addition, another objective of the present invention is to provide an embolization filler material that can be used in embolization for treating cerebrovascular disease.

[0008] In addition, another objective of the present invention is to provide a composition for cerebral aneurysm embolization.

[0009] In addition, another objective of the present invention is to provide a pharmaceutical composition for the prevention or treatment of cerebrovascular disease comprising a filling material for cerebral aneurysm embolization.

[0010] In addition, another objective of the present invention is to provide a method for treating cerebrovascular disease.

[0011]

[0012] Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention and claims.

[0013] The terms used in this specification are for illustrative purposes only and should not be interpreted as being limiting. Singular expressions include plural expressions unless the context clearly indicates otherwise. In this specification, terms such as "comprising" or "having" are intended to indicate the existence of the features, numbers, steps, actions, components, parts, or combinations thereof described in the specification, and should be understood as not precluding the existence or addition of one or more other features, numbers, steps, actions, components, parts, or combinations thereof.

[0014] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as generally understood by those skilled in the art to which the embodiments pertain. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and should not be interpreted in an ideal or overly formal sense unless explicitly defined in this application.

[0015]

[0016] The present invention will be described in detail below.

[0017]

[0018] According to one aspect of the present invention, the present invention provides a method for manufacturing a filling material for cerebral aneurysm embolization and a filling material for cerebral aneurysm embolization manufactured according to the following steps:

[0019] (a) a step of preparing an aqueous solution of PEGDA ((poly(ethylene glycol) diacrylate) as a photosensitive polymer material;

[0020] (b) a step of preparing a first mixture by mixing one first contrast agent selected from the group consisting of iopromide, iopamidol, ioversol, iomeprol, iohexol, iobitridol, and iodixanol into the PEGDA aqueous solution of step (a);

[0021] (c) a step of preparing a second mixture by mixing one second contrast agent selected from the group consisting of iopromide, iopamidol, ioversol, iomeprol, iohexol, iobitridol, and iodixanol into the first mixture of step (b) above;

[0022] (d) a step of preparing an embolization material precursor by mixing a photoinitiator into the second mixture of step (c) above; and

[0023] (e) A step of irradiating the embolization material precursor of step (d) with blue light.

[0024] The photocrosslinked-based embolization material of the present invention, suitable for use in cerebral aneurysm embolization, is an embolization material capable of providing stable mechanical properties based on a polymer, and can induce stable embolization by utilizing photoresponsive crosslinking suitable for delivering and crosslinking the embolization material to a cerebral artery model. In particular, it exhibits advantageous benefits in that it can be maintained stably even in an environment where strong pressure, such as actual arterial pressure, is continuously applied, and it also exhibits an contrast effect, thereby contributing to its utilization in cerebral aneurysm embolization.

[0025] In the present invention, the PEGDA is a photocrosslinkable polymer compound, and any PEGDA known in the art can be used as long as the purpose of the present invention is achieved, and preferably, it may be a PEGDA having a molecular weight of 500 to 1000 g / mol, for example, a PEGDA having a molecular weight of 700 g / mol, but is not limited thereto.

[0026] The PEGDA aqueous solution of step (a) above can be prepared with any solvent known in the art and any volume ratio as long as the purpose of the present invention is achieved, but preferably, it is a mixture of PEGDA and distilled water in a volume ratio of 9:1.

[0027] The first mixture of step (b) above can be prepared by mixing in any wt% as long as the purpose of the present invention is achieved, but preferably, the first contrast agent is mixed in 10 to 30 wt% relative to the PEGDA aqueous solution of step (a), and most preferably in 15 wt%.

[0028] The second mixture of step (c) above can be prepared by mixing in any % (v / v) as long as the purpose of the present invention is achieved, but preferably, the second contrast agent is mixed in 10 to 30% (v / v) relative to the first mixture of step (b), and most preferably, in 15% (v / v).

[0029] The photoinitiator of step (d) above may be prepared by mixing in any weight% as long as the purpose of the present invention is achieved, but preferably, it is mixed in an amount of 0.1 to 10 wt% relative to the second mixture of step (c), and preferably 0.4 wt%.

[0030] According to one embodiment of the present invention, the iopromide is Ultravist ® And, the above iopamidol is Pamiray 250 ® used .

[0031] As long as the purpose of the present invention is achieved, any photoinitiator known in the art may be used, and preferably, it may be one or more selected from the group consisting of camphorquinone, ruthenium (Ru(II)), palladium (Pd(II)), copper (Cu(II)), nickel (Ni(II)), manganese (Mn(II)), and iron (Fe(III)), and may be, for example, camphorquinone, but is not limited thereto.

[0032] The filling material for cerebral aneurysm embolization of the present invention, produced according to the method of the present invention, forms a hydrogel by blue light crosslinking, and the hydrogel has an elastic modulus of 1000 to 1500 kPa and has superior mechanical properties and long-term structural stability compared to conventional alginate-based polymer materials.

[0033] The above embolization refers to a procedure intended to intentionally block blood flow by blocking blood vessels for the prevention or treatment of vascular disease, or to block blood vessels at risk of rupture.

[0034] The aforementioned embolization filling material refers to a substance that can alter blood flow by filling blood vessels at risk of rupture during embolization. Conventional embolization has the disadvantage of a very high recurrence rate of over 20% after the procedure due to incomplete occlusion.

[0035] On the other hand, the filling material for cerebral aneurysm embolization according to the present invention has technical features that distinguish it from conventional technology, in that, unlike conventional technology, it not only completely blocks blood vessels at risk of rupture but also maintains its shape for a long period, thereby significantly reducing the possibility of recurrence.

[0036] Furthermore, the filling material for cerebral aneurysm embolization according to the present invention can be crosslinked using a safe blue light crosslinking mechanism without the use of ultraviolet rays harmful to the human body. Therefore, it can resolve the cytotoxicity problems that occur during conventional photocrosslinking using ultraviolet rays.

[0037]

[0038] In addition, according to another aspect of the present invention, the present invention provides a composition for cerebral aneurysm embolization comprising: a first contrast agent selected from the group consisting of iopromide, iopamidol, ioversol, iomeprol, iohexol, iobitridol, and iodixanol; a second contrast agent selected from the group consisting of iopromide, iopamidol, ioversol, iomeprol, iohexol, iobitridol, and iodixanol; an aqueous solution of PEGDA (poly(ethylene glycol) diacrylate) as a photosensitive polymer material; and a photocrosslinking agent.

[0039] The composition of the present invention can create an environment suitable for the desired embolization procedure.

[0040]

[0041] In addition, according to another aspect of the present invention, the present invention provides a pharmaceutical composition for the prevention or treatment of any one of a cerebrovascular disease selected from a cerebral aneurysm, cerebral hemorrhage caused by a cerebral aneurysm, intracerebral hemorrhage, subarachnoid hemorrhage, and cerebral infarction, comprising the aforementioned filling material for cerebral aneurysm embolization.

[0042] The above cerebrovascular disease may preferably be any one selected from cerebral aneurysm, cerebral hemorrhage caused by a cerebral aneurysm, intracerebral hemorrhage, subarachnoid hemorrhage, and cerebral infarction, but is not limited thereto and may be used for any vascular disease requiring embolization.

[0043] In addition to the above-mentioned vascular diseases, the composition of the present invention may also be used for any disease that can be treated using embolization, for example, embolization for liver cancer patients.

[0044] In the present invention, the term "prevention" refers to any act of suppressing cerebrovascular disease or delaying its onset by administering the above composition.

[0045] In the present invention, the term "treatment" refers to all acts of curing cerebrovascular disease by administering the composition in embolization, and is defined as the application or administration of the composition to a subject (human or animal) having the disease, symptoms of the disease, disease or secondary disease of the disease, or predisposition thereto, with the purpose of treating, alleviating, remedying, or improving the disease, symptoms of the disease, disease or secondary disease of the disease, or predisposition thereto.

[0046] The composition containing the above-mentioned embolization filling material may be provided in the form of a suspension, emulsion, solution, or hydrogel, etc., according to conventional methods.

[0047] Additionally, the composition of the present invention may further comprise a pharmaceutically acceptable carrier, excipient, or diluent, wherein "pharmaceutically acceptable" means exhibiting a property that is not toxic to cells or humans exposed to said composition.

[0048] The method of administration of the pharmaceutical composition for the prevention or treatment of cerebrovascular disease according to the present invention is not particularly limited and may be in various oral or parenteral formulations, and may follow methods commonly used in the art. As a non-limiting example of the above method of administration, the composition may be administered directly to the affected area by a parenteral method. Furthermore, the composition for the prevention, improvement, or treatment of cerebrovascular disease according to the present invention may be prepared in various formulations depending on the intended method of administration.

[0049] When formulating, the preparation is typically made using diluents or excipients such as commonly used fillers, volume expanders, binders, wetting agents, disintegrants, and surfactants. Solid dosage forms for oral administration include capsules, powders, granules, tablets, and pills, and these solid dosage forms are prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose or lactose, or gelatin, with one or more compounds. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid dosage forms for oral administration include suspensions, emulsions, syrups, and aerosols, and may contain various excipients, such as wetting agents, sweeteners, flavoring agents, and preservatives, in addition to commonly used simple diluents like water and liquid paraffin. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized agents, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspension solvents. Witepsol, Macrogol, Tween 61, cocoa paste, laurin paste, glycerogelatin, etc., may be used as bases for suppositories. For parenteral administration, it is preferable to select a method of topical application or intraperitoneal, rectal, intravenous, intramuscular, subcutaneous, intrauterine dura mater, or intracerebrovascular injection.

[0050] The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the level of the effective amount may be determined according to factors including the type and severity of the patient's disease, drug activity, sensitivity to the drug, time of administration, route of administration and elimination rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as a single or multiple doses. It is important to administer an amount that obtains maximum effect with a minimum amount without side effects by taking all of the above-mentioned factors into account, and this can be easily determined by a person skilled in the art.

[0051] The dosage of the composition of the present invention varies depending on the patient's body weight, age, gender, health status, diet, time of administration, method of administration, excretion rate, and severity of the disease. The composition of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modulators.

[0052]

[0053] In addition, according to another aspect of the present invention, the present invention provides a method for treating any one of a cerebrovascular disease selected from a cerebral aneurysm, cerebral hemorrhage caused by a cerebral aneurysm, intracerebral hemorrhage, subarachnoid hemorrhage, and cerebral infarction, comprising the step of administering the above-described filling material for cerebral aneurysm embolization or a composition for cerebral aneurysm embolization to a subject requiring embolization.

[0054] For example, it is used as an embolizing agent for surgery on an aneurysm in a cerebral artery, delivered to the aneurysm through a catheter to fill it.

[0055] Since the method of the present invention utilizes the composition for preventing discoloration of red-meat fish of the present invention described above, the common details between the two are omitted to avoid excessive complexity in this specification.

[0056] The filling material for cerebral aneurysm embolization manufactured according to the method of the present invention exhibits excellent physical properties and structural stability, and thus can contribute to increasing the success rate of embolization and improving surgical safety, making it suitable for use in actual cerebral aneurysm embolization.

[0057] Figure 1 is PEGDA 700 The hydrogel form after photocrosslinking was confirmed.

[0058] Figure 2 is PEGDA 700 The viscosity was confirmed according to the mixing ratio of the contrast agent in the solution.

[0059] Figure 3 is PEGDA 700 The storage modulus according to the mixing ratio of the contrast agent in the hydrogel was confirmed.

[0060] Figure 4 is PEGDA 700 The elastic modulus according to the mixing ratio of the contrast agent in the hydrogel was confirmed.

[0061] Figure 5 is PEGDA 700 This confirms the radiocapacity according to the mixing ratio of contrast agents in the hydrogel.

[0062] Figure 6 is PEGDA 700 It was confirmed that embolic material fibers are formed in the catheter delivery system using -15.

[0063] Figure 7 is PEGDA 700 It was confirmed that embolic material fibers are formed in the phantom model emobilization using a catheter delivery system with -15.

[0064] Figure 8 is PEGDA 700This confirms the change in the embolic material formed at -15 under an arterial pressure environment for two weeks.

[0065] Preferred embodiments are presented below to aid in understanding the present invention. However, the following embodiments are provided merely to facilitate a better understanding of the invention and do not limit the scope of the invention.

[0066]

[0067] Example 1. PEGDA 700 Manufacturing of cerebral aneurysm embolization precursor solution based on

[0068] The inventors, PEGDA 700 To develop a cerebral aneurysm embolization material (filling material for embolization), the PEGDA substance with Molecular number 700 700 PEGDA 700 : A mixture (Mixture 1) with a total volume of 25.3 ml was prepared by mixing 15 wt% (3.3 g) of Ultravist contrast agent with 22 ml of a solution mixed with distilled water at a volume ratio of 9:1 (20 ml:2 ml). To the prepared mixture, a liquid contrast agent (Pamiray 250) was added at a volume ratio of 5% (PEGDA 700 -5, solution 1ml / liquid contrast agent 0.05ml), 15% (PEGDA 700 -15, solution 1ml / liquid contrast agent 0.15ml), 20% (PEGDA 700 -20, solution 1ml / liquid contrast agent 0.20ml), 25% (PEGDA 700 -25, solution 1ml / liquid contrast agent 0.25ml), 35% (PEGDA 700 -35, 1 ml of solution / 0.35 ml of liquid contrast agent) was mixed (second mixture), and a photocatalyst Camphorquinone (CQ) was mixed at a weight ratio of 0.4 wt% (0.1 mg) to induce a photoreaction of the precursor to prepare the precursor.

[0069]

[0070] Experimental Example 1. PEGDA 700Analysis of the rheological properties of cerebral aneurysm embolization precursors

[0071] The inventors, PEGDA 700 To determine the viscosity according to the liquid contrast agent mixing ratio of the cerebral aneurysm embolization precursor based on PEGDA prepared in Example 1 above 700 -5, PEGDA 700 -15, PEGDA 700 -25, PEGDA 700 The viscosity of the solution was measured according to the change in shear rate using a rheometer at -35.

[0072] As a result, as shown in Fig. 2, PEGDA 700 A tendency for viscosity to increase as the mixing ratio of the liquid contrast agent was higher than -5 was observed, and PEGDA 700 -15, PEGDA 700 -25, PEGDA 700 It was confirmed that -35 exhibited a similar viscosity.

[0073] In addition, the inventors, PEGDA 700 To determine the storage modulus according to the liquid contrast agent mixing ratio of the cerebral aneurysm embolization material precursor based on PEGDA prepared in Example 1 above 700 -5, PEGDA 700 -15, PEGDA 700 -25, PEGDA 700 The storage modulus of the solution was measured according to the change in shear rate using a rheometer at -35.

[0074] As a result, as shown in Figure 3, it was confirmed that the storage modulus decreases as the mixing ratio of the liquid contrast agent increases.

[0075]

[0076] Experimental Example 2. PEGDA 700Analysis of Elastic Modulus According to Liquid Contrast Agent Mixing Ratio of Base Cerebral Aneurysm Embolizing Material Precursor

[0077] The inventors [compare] the embolization material precursor PEGDA prepared in Example 1 above. 700 -5, PEGDA 700 -15, PEGDA 700 -25, PEGDA 700 The elastic modulus of the hydrogel at a strain of 25% was measured using a rheometer at -35.

[0078] As a result, as shown in Figure 4, it was confirmed that the elastic modulus decreases as the mixing ratio of the liquid contrast agent increases.

[0079]

[0080] Experimental Example 3. PEGDA 700 Confirmation of radiopacity according to the mixing ratio of liquid contrast agent in the base cerebral aneurysm embolization material precursor

[0081] The inventors [compare] the embolization material precursor PEGDA prepared in Example 1 above. 700 -0, PEGDA 700 -5, PEGDA 700 -10, PEGDA 700 -15, PEGDA 700 -20,PEGDA 700 The radiopacity of -25 was observed using X-ray observation equipment.

[0082] As a result, as shown in Figure 5, it was confirmed that the most stable radiopacity was achieved when the mixing ratio of the liquid contrast agent was 15% by volume.

[0083] Based on the above results, PEGDA 700 -15 Since it was determined that the precursor solution could provide sufficient radiopacity and physical properties, in the following examples, selected PEGDA 700 The experiment was conducted using -15 precursor solution.

[0084]

[0085] Experimental Example 4. PEGDA in a catheter delivery system 700 -15 Confirmation of microfiber formation in cerebral aneurysm embolization precursor fluid

[0086] The inventors, through Experimental Examples 1, 2, and 3 above, selected PEGDA under optimal conditions 700 We aimed to verify the applicability of a catheter delivery system for the -15 progenitor solution and whether microfibers could be formed through phototherapy using blue light. For the catheter system, an outer catheter with a 4 Fr outer diameter and an inner catheter with a 0.017” inner diameter were used, and an optical fiber providing a blue light source was attached to the inner catheter. The Shealth flow rate was 120 ml / hr, the flow rate of the inner progenitor solution was 5 ml / hr, and the blue light source was irradiated at 1.2 W.

[0087] As a result, as shown in Figure 6, it was confirmed that embolic material microfibers were formed under the corresponding conditions.

[0088]

[0089] Experimental Example 5. PEGDA in an in vitrophantom emobilization model 700 -15 Confirmation of Microfiber Formation and Delivery of Cerebral Aneurysm Embolist Precursor

[0090] The inventors, regarding the catheter-based delivery system identified in Experimental Example 4 and PEGDA 700 -15 precursor solution was used and applied to an in vitrophantom emobilization model.

[0091] As a result, as shown in Figure 7, it was confirmed through an optical camera and X-ray transmission images that the embolizing material was delivered and filled the phantom model under the corresponding conditions.

[0092]

[0093] Experimental Example 6. PEGDA in an in vitrophantom emobilization model 700 -15 Confirmation of the stability of cerebral aneurysm embolization material

[0094] The inventors confirmed the stability of the embolizing material applied to the in vitro phantom emobilization model in Experimental Example 5 for 2 weeks in an environment similar to actual arterial pressure (systolic pressure: 96 mmHg, diastolic pressure: 84 mmHg).

[0095] As a result, as shown in Figure 8, it was confirmed through X-ray transmission images that the embolic material was maintained in the phantom model under the corresponding conditions.

[0096]

[0097] In summary, the present invention is a technology for developing a photocrosslinkable polymer-based embolization material suitable for cerebral aneurysm embolization, and aims to stably deliver an embolus to the aneurysm using PEGDA (polyethylene glycol diacrylate) containing a contrast agent. Conventional photocrosslinkable alginate-based polymer embolization materials had limitations in maintaining long-term stability under actual arterial pressure environments due to low mechanical strength. In particular, biopolymer alginate had difficulty maintaining its shape at arterial pressures of 100 mmHg diastolic and 120 mmHg systolic.

[0098] To solve these problems, the present invention utilizes PEGDA, a photosensitive material. 700By introducing an embolization material based on [the substance] and cross-linking diacrylate groups to polymer chains through a photoreaction using safe blue light, enhanced mechanical and rheological properties are provided. Through this, it was possible to confirm the stable delivery of embolization material in a cerebral aneurysm model and the maintenance of its morphology for an extended period even in environments of high arterial pressure. Furthermore, since the delivery process of the embolization material can be monitored in real-time through contrast imaging, there is significant potential for its application in actual surgical procedures.

[0099] In addition, the present invention can be applied not only to cerebral aneurysms but also to other aneurysm embolization procedures, and is expected to overcome the limitations of existing embolization materials by providing stability in which the embolization material maintains its shape for more than two weeks, particularly in high-pressure environments. Consequently, the present invention can contribute to increasing the success rate of embolization and improving the safety of surgery.

[0100]

[0101] The present invention has been described above through embodiments. A person skilled in the art to which the present invention pertains will understand that the present invention may be implemented in other specific forms without altering its technical concept or essential features. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive. The scope of the present invention is defined by the claims set forth below rather than by the detailed description, and all modifications or variations derived from the meaning and scope of the claims and equivalent concepts should be interpreted as being included within the scope of the present invention.

Claims

1. A method for manufacturing a filling material for cerebral aneurysm embolization, comprising the following steps: (a) a step of preparing an aqueous solution of PEGDA ((poly(ethylene glycol) diacrylate) as a photosensitive polymer material; (b) a step of preparing a first mixture by mixing one first contrast agent selected from the group consisting of iopromide, iopamidol, ioversol, iomeprol, iohexol, iobitridol, and iodixanol into the PEGDA aqueous solution of step (a); (c) a step of preparing a second mixture by mixing one second contrast agent selected from the group consisting of iopromide, iopamidol, ioversol, iomeprol, iohexol, iobitridol, and iodixanol into the first mixture of step (b) above; (d) a step of preparing an embolization material precursor by mixing a photoinitiator into the second mixture of step (c) above; and (e) A step of irradiating the embolization material precursor of step (d) with blue light.

2. In Paragraph 1, A method characterized in that the molecular weight of the PEGDA is 500 to 1000 g / mol.

3. In Paragraph 1, A method characterized in that the PEGDA aqueous solution of step (a) above is a mixture of PEGDA and distilled water in a volume ratio of 9:

1.

4. In Paragraph 1, A method characterized in that the first mixture of step (b) above is a mixture of the first contrast agent at a concentration of 10 to 30 wt% relative to the PEGDA aqueous solution of step (a) above.

5. In Paragraph 1, A method characterized in that the second mixture of step (c) above is mixed with a second contrast agent at a ratio of 10 to 30% (v / v) relative to the first mixture of step (b) above.

6. In Paragraph 1, A method characterized in that the photoinitiator of step (d) is mixed in an amount of 0.1 to 10 wt% relative to the second mixture of step (c).

7. In Paragraph 1, The above iopromide is Ultravist ® And, the above iopamidol is Pamiray 250 ® A method characterized by being.

8. In Paragraph 1, A method characterized in that the above photoinitiator is one or more selected from the group consisting of camphorquinone, ruthenium (Ru(II)), palladium (Pd(II)), copper (Cu(II)), nickel (Ni(II)), manganese (Mn(II)), and iron (Fe(III)).

9. In Paragraph 1, A method characterized in that the filling material for cerebral aneurysm embolization above forms a hydrogel by blue light crosslinking.

10. In Paragraph 9, A method characterized in that the above hydrogel has an elastic modulus of 1000 to 1500 KPa.

11. A filling material for cerebral aneurysm embolization manufactured according to the manufacturing method of claim 1.

12. One first contrast agent selected from the group consisting of iopromide, iopamidol, ioversol, iomeprol, iohexol, iobitridol, and iodixanol; One second contrast agent selected from the group consisting of iopromide, iopamidol, ioversol, iomeprol, iohexol, iobitridol, and iodixanol; As a photosensitive polymer material, an aqueous solution of PEGDA ((poly(ethylene glycol) diacrylate); and A composition for cerebral aneurysm embolization comprising a photocrosslinking agent.

13. In Paragraph 12, The above composition is characterized by forming a hydrogel by blue light crosslinking.

14. A pharmaceutical composition for the prevention or treatment of any one of a cerebrovascular disease selected from a cerebral aneurysm, cerebral hemorrhage caused by a cerebral aneurysm, intracerebral hemorrhage, subarachnoid hemorrhage, and cerebral infarction, comprising the filling material for cerebral aneurysm embolization of claim 11.

15. In Paragraph 14, A pharmaceutical composition for the prevention or treatment of cerebrovascular disease, characterized in that the above composition further comprises a pharmaceutically acceptable carrier, excipient, or diluent.

16. A method for treating any one of a cerebrovascular disease selected from a cerebral aneurysm, cerebral hemorrhage caused by a cerebral aneurysm, intracerebral hemorrhage, subarachnoid hemorrhage, and cerebral infarction, comprising the step of administering the filling material for cerebral aneurysm embolization of claim 11; or the composition for cerebral aneurysm embolization of claim 12 to a subject requiring embolization.

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