Hydrated gel for embolization with adjustable decomposition time and its manufacturing method

Abstract

The present invention relates to an amorphous or spherical hydrated gel for embolization, the decomposition time of which can be precisely adjusted within a blood vessel, and a method for producing the same.

Description

Technical Field

[0001] The present invention claims the benefit of priority based on Korean Patent Application No. 2021-0055086 filed on April 28, 2021, and all the contents disclosed in the documents of the Korean patent application are incorporated herein by reference in their entirety.

[0002] The present invention relates to a hydrating gel for a plug whose decomposition time can be adjusted and a method for manufacturing the same. Specifically, the present invention relates to an amorphous or spherical hydrating gel for a plug whose decomposition time can be precisely adjusted in a blood vessel and a method for manufacturing the same.

Background Art

[0003] Due to the remarkable development of imaging diagnostic technology, it has become possible to accurately detect the location of cancer and the blood vessels supplying blood to the cancer. As a result, various anti-cancer treatments such as radiation therapy, surgical removal, and embolization can be precisely performed.

[0004] Embolization is a treatment method that induces necrosis of a tumor by occluding the blood vessels supplying blood to the tumor. Transcatheter arterial chemoembolization (TACE) is the most commonly performed method among the treatment methods for liver cancer. TACE is a treatment method that simultaneously performs physical embolization of the artery supplying blood to the tumor and chemical treatment with an anti-cancer agent injected through the artery.

[0005] Embolization is also used for the treatment of various indications such as uterine fibroids, prostate cancer, lung cancer, and kidney cancer. Recently, it has been reported that it can also be used for the treatment of arthritis and frozen shoulder.

[0006] Permanently embolizing a blood vessel makes the original blood vessel inoperable for reoperation. Instead, new blood vessels are generated, reducing the effect by half. To treat arthritis, frozen shoulder, etc., it is preferable to embolize the blood vessels that supply nutrients to the nerves that induce pain for a short period of time. Only the nerve cells at the inflammatory site should be necrotized, and the impact on other muscles, etc., should be minimized.

[0007] The embolization used in conventional cancer treatment has a decomposition time that is too long in units of days or weeks, and moreover, the time adjustment is not accurate. To treat arthritis, frozen shoulder, etc., an embolizing agent that can adjust the time more precisely is required. Conventional embolization products include amorphous gelpart (registered trademark), cali-gel (registered trademark), embocube (registered trademark), etc., and spherical embosphere (registered trademark), embozene (registered trademark), bead block (registered trademark), etc. Conventional embolization products not only have a long decomposition time but also cannot be adjusted precisely. On the other hand, there are biodegradable embolizing agents, but they are amorphous and have a decomposition time of more than two weeks, which is not suitable for application to arthritis, frozen shoulder, etc.

[0008] Patent Document 1 is a patent by the applicant of the present invention and relates to microparticles that can be used as hydrated gel microparticles for drug-loaded embolization and a method for manufacturing the same. Patent Document 1 is an embolizing agent for cancer treatment, and the time of decomposition when administered in vivo can be adjusted. However, like conventional embolizing agents, the decomposition time is in units of days, so it cannot present a technique for short-time adjustment for arthritis, frozen shoulder, etc.

[0009] Patent Document 2 relates to gelatin particles having a specific volume swelling ratio in the form of solid spheres rather than porous ones, gelatin particles obtained by dissolving and retaining a physiologically active substance in the gelatin particles, and a device in which the gelatin particles impregnated and retained with the physiologically active substance dissolved together with physiological saline are dispersed and used in a syringe. Similar to Patent Document 1, Patent Document 2 also has a decomposition time in units of days and cannot present a technique for short-term regulation for arthritis, frozen shoulder, etc.

Prior Art Documents

Patent Documents

[0010]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0011] Thus, an object of the present invention is to provide a hydrating gel for a plug capable of adjusting the decomposition time, which can be used for a plug agent that can precisely adjust the decomposition time and that conventional plug agents could not provide. Another object of the present invention is to provide a hydrating gel for a plug capable of adjusting the decomposition time and a method for producing the same, which can be used for a plug agent having a very short decomposition time for arthritis, frozen shoulder, etc. in addition to being able to precisely adjust the decomposition time.

[0012] Also, an object of the present invention is to provide a hydrating gel for a plug having an appropriate decomposition time required for treatment and a method for producing the same without using a crosslinking agent.

Means for Solving the Problems

[0013] In order to solve the above problems, the present invention provides a composition for a plug containing hydrated gel microparticles produced without using a crosslinking agent. The hydrated gel microparticles according to the present invention have their in vivo degradation time adjusted by heat treatment and / or washing. For the washing, a solvent having a δP Polar value of 14 or more can be used.

[0014] In particular, the composition for a plug according to the present invention can be applied to plugging of joint sites.

[0015] The hydrated gel microparticles according to the present invention can be produced by heat denaturation, and non-limiting examples thereof may include at least one selected from the group of biocompatible polymers including gelatin, collagen, gum, rosin, hyaluronic acid, heparin, dextran, alginic acid, albumin, chitosan, polyglycolide, polylactide, polyhydroxyvalerate, and silk fibroin.

[0016] The hydrated gel microparticles may be in the form of an emulsion containing an organic solvent, and the organic solvent may be at least one selected from the group including methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, hexyl acetate, ethyl formate, dimethyl carbonate, diethyl carbonate, 1,3-dioxolane-2-one, cellulose acetate butyrate, MCT (Medium Chain Triglyceride) oil, vegetable oil, wax, and Infused oil. Also, the emulsion may not contain a separate emulsifier.

[0017] The composition for a plug according to the present invention may further contain an additional drug, and by way of non-limiting example, at least one of a local anesthetic, an antibiotic, and a contrast agent may be added.

[0018] Still another aspect of the present invention provides a method for producing hydrated gel microparticles produced by the following step (a) or (b).

[0019] (a) 1) A step of producing an aqueous solution of a biocompatible polymer. 2) A step of adding an organic solvent to the aqueous solution of the biocompatible polymer in step 1) to form an emulsion and form micro-sized particles. 3) A step of washing and drying the micro-sized particles produced in step 2) to obtain micro-sized microparticles. 4) A step of thermally curing the micro-sized microparticles in step 3), and 5) A step of washing, dehydrating, and drying the micro-sized microparticles obtained in step 4).

[0020] (b) 1) A step of producing an aqueous solution of a biocompatible polymer. 2) A step of stirring and / or low-temperature curing the aqueous solution of the biocompatible polymer in step 1) to form bubbles and then freeze-drying. 3) A step of thermally curing the bubble-shaped substance in step 2) to obtain micro-sized microparticles. 4) A step of washing the micro-sized microparticles obtained in step 3) and then freeze-drying, and 5) A step of pulverizing the bubble-shaped substance obtained in step 4) to obtain micro-sized microparticles.

[0021] The biocompatible polymer may be at least one selected from the group consisting of gelatin, collagen, gum, rosin, hyaluronic acid, heparin, dextran, alginic acid, albumin, chitosan, polyglycolide, polylactide, polyhydroxyvalerate, and silk fibroin, and the organic solvent may be at least one selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, hexyl acetate, ethyl formate, dimethyl carbonate, diethyl carbonate, 1,3-dioxolane-2-one, cellulose acetate butyrate, MCT (Medium Chain Triglyceride) oil, vegetable oil, wax, and Infused oil.

[0022] Further, a step of low-temperature curing the micro-sized particles produced in the step 2) below room temperature may be added between the step 2) and the step 3) of the step (a).

[0023] Further, a step of classifying the micro-sized fine particles by particle size using a sieve after pulverizing the micro-sized fine particles may be further added between the step 4) and the step 5) of the step (a) or after the step 5) of the step (a),

[0024] After the step 5) of the step (b), a step of classifying the micro-sized fine particles by particle size using a sieve may be further added.

[0025] At this time, the size of the particles can be divided, as a non-limiting example, into ranges of 75 μm or more and less than 150 μm, 150 μm or more and less than 350 μm, 350 μm or more and less than 560 μm, 560 μm or more and less than 710 μm, 710 μm or more and less than 1000 μm, 1000 μm or more and less than 1400 μm, and 1400 μm or more and less than 2000 μm.

[0026] The thermosetting may be performed at 100°C to 200°C for 10 minutes to 24 hours, and the washing may be performed at a temperature exceeding 0°C and 40°C or lower. The washing may be performed with a solvent having a δP Polar value of 14 or more.

[0027] The hydrated gel microparticles according to the present invention can adjust the in vivo degradation rate in units of hours and minutes by the heat treatment and / or washing.

[0028] The present invention also provides hydrated gel microparticles produced by the above production method and a composition for a plug containing the microparticles.

[0029] The present invention can also provide any combination of the above solutions to the problems.

Advantages of the Invention

[0030] Thus, the present invention can provide hydrated gel microparticles for a plug with adjustable degradation time and a production method thereof, which can be used for a plug that can precisely adjust the degradation time and that conventional plugs could not provide.

[0031] (1) The hydrated gel microparticles according to the present invention can adjust the biodegradation time to as short as 30 minutes or as long as 30 days or more.

[0032] (2) The hydrated gel microparticles according to the present invention can adjust the biodegradation time in units of about 10 minutes.

[0033] (3) The hydrated gel microparticles according to the present invention are produced from a biocompatible polymer and are excellent in biological safety.

[0034] (4) The embolizing agent containing the hydrated gel microparticles according to the present invention is made only of a biocompatible polymer and does not use any chemical cross-linking agent or additive, so it is very safe.

[0035] (5) The embolizing agent containing the hydrated gel microparticles according to the present invention can be used as an embolizing agent having a very short decomposition time for arthritis, frozen shoulder, etc.

Brief Description of the Drawings

[0036]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Modes for Carrying Out the Invention

[0037] In this application, terms such as "comprising", "having", or "including" are intended to specify the presence of the features, numbers, steps, components, parts, or combinations thereof described in the specification, and should be understood not to preclude the presence or addition of one or more other features, numbers, steps, operations, components, parts, or combinations thereof in advance.

[0038] When it is mentioned that a certain component is "connected to" or "attached to" another component, it should be understood that a certain component may be directly connected to or attached to another component, but there may also be other components in between. On the other hand, when it is mentioned that a certain component is "directly connected to" or "directly attached to" another component, it should be understood that there are no other components in between. Other expressions describing the relationship between components, namely "between ~" and "directly between ~", or "adjacent to ~" and "directly adjacent to ~", should be interpreted in the same way.

[0039] Also, unless otherwise specified, all terms used here, including technical or scientific terms, have the same meaning as commonly understood by those with ordinary knowledge in the technical field to which the present invention belongs. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the related art, and should not be interpreted in an ideal or overly formal sense unless specifically defined in this application.

[0040] <Example 1: Production of Spherical Hydrated Gel Particles>

[0041] 1) Completely dissolve 20 g of gelatin in 100 ml of distilled water at 50 °C. 2) Gradually inject the gelatin solution in step 1) into 400 ml of MCT (Medium-Chain Triglyceride) oil under stirring conditions of 450 rpm to produce an emulsion. 3) The emulsion produced in step 2) is cured at 4°C for 30 minutes, then the supernatant is discarded, and after washing with acetone, vacuum drying is performed. 4) The spherical microparticles obtained in step 3) are heat-treated at 150°C for 4 hours. 5) The microparticles from step 4) are washed with distilled water and then again with acetone, followed by vacuum drying to obtain the final spherical hydrated gel microparticles.

[0042] Washing method of Example 1

[0043] The washing method is affected by the ratio of the microparticles to the washing solution, the washing intensity, and the washing time.

[0044] After mixing 50 g of the microparticles according to Example 1 with 1.5 L of distilled water at 15°C, washing was performed by stirring at 200 rpm for 30 minutes. After 30 minutes, the swollen microparticles were completely precipitated, and all the supernatant was discarded. Then, 1.5 L of distilled water at 15°C was added and washing was performed again by stirring at 200 rpm for 30 minutes. The washing process was carried out until the supernatant became completely clear. In Example 1, it was carried out a total of 3 times.

[0045] Hereinafter, the washing performed in other examples or comparative examples was carried out in the same manner as described above.

[0046] As a result of checking the washing solution, it was confirmed that the microparticles swell in a solvent with a δP Polar value of 14 or more.

[0047]

Table 1

[0048] <Comparative Example 1> It is the same as Example 1 except that the final step 5) is not performed in the production steps of Example 1.

[0049] <Examples 2 - 5: Production of Spherical Hydrated Gel Microparticles>

[0050] In Example 1, the heat treatment temperature and time in step 4) were changed to 120°C and 3 hours. After the heat treatment was completed, the microparticles were divided into four equal parts and washed with distilled water at 4°C (Example 2), 10°C (Example 3), 20°C (Example 4), and 27°C (Example 5), respectively. After washing the microparticles with distilled water, they were washed with acetone and then vacuum dried to obtain the final spherical hydrated gel microparticles (micro-particles).

[0051] <Examples 6 - 12: Production of Spherical Hydrated Gel Microparticles>

[0052] In Example 1, the heat treatment temperature and time in step 4) were changed as shown in Table 4 below.

[0053] <Example 13: Production of Amorphous Hydrated Gel Microparticles>

[0054] 1) Dissolve 10 g of gelatin completely in 100 ml of distilled water at 50°C. 2) Stir the gelatin solution in step 1) at 14,000 rpm for 30 minutes to form sufficient bubbles, then perform freeze-drying after curing in a -50°C environment for 2 hours. 3) Heat-treat the sponge-shaped gelatin after freeze-drying in step 2) at 150°C for 5 hours. 4) Wash the sponge-shaped gelatin in step 3) with distilled water, then perform freeze-drying again after curing in a -50°C environment for 2 hours. 5) After the freeze-drying in step 4) is completed, crush the obtained sponge to obtain the final amorphous sponge particles.

[0055] <Experiment 1: Microscopic Observation>

[0056] The spherical hydrated gel microparticles produced in Example 1 and the amorphous hydrated gel microparticles produced in Example 13 were observed under a microscope (see Figures 1 and 7, respectively).

[0057] In addition, the spherical hydrated gel microparticles produced in Example 1 and the amorphous hydrated gel microparticles produced in Example 13 were immersed in distilled water for 20 minutes to swell them, and then observed under a microscope (see FIGS. 2 and 8, respectively).

[0058] As can be seen from FIGS. 1 and 2, the hydrated gel microparticles produced in Example 1 are spherical both before and after swelling.

[0059] As can be seen from FIGS. 7 and 8, the amorphous hydrated gel microparticles produced in Example 13 are amorphous both before and after swelling.

[0060] <Experiment 2: Particle Size Distribution Measurement>

[0061] The particle size distribution of the spherical hydrated gel microparticles produced in Example 1 was measured using a particle size analyzer device.

[0062] FIG. 3 shows the measurement results of the particle size distribution of the spherical hydrated gel microparticles according to Example 1 of the present invention. The x-axis represents the particle size in μm, and the y-axis represents the volume (%) occupied by the particle size.

[0063] It can be seen that the spherical hydrated gel microparticles according to Example 1 of the present invention have an average size of about 300 μm and a very narrow particle distribution. Also, the particle size distribution is a preferable size for plugs.

[0064] <Experiment 3: Elution Test>

[0065] The eluates were observed for Example 1 and Comparative Example 1.

[0066] For the elution test, 30 ml of 1x PBS solution was added to 2 g of the microparticles and allowed to swell sufficiently, and then elution was carried out in a shaking water bath at 37°C for 24 hours.

[0067] Figure 4 shows the elution test results of Example 1 and Comparative Example 1. In Figure 4, the left side shows the results of Comparative Example 1, and the right side shows the results of Example 1. It can be confirmed that Comparative Example 1 has more eluates than Example 1.

[0068] <Experiment 4: Toxicity Test>

[0069] Cytotoxicity tests (ISO10993-5), endotoxin tests (ISO10993-11), and pyrogen tests (ISO10993-11) were conducted on Example 1 and Comparative Example 1 respectively.

[0070] Table 1 and Figure 5 show the cytotoxicity test results, Table 2 shows the endotoxin test results, and Table 3 shows the pyrogen test results. The following Negative Control, Positive Control, and Blank all comply with the ISO standards.

[0071] In Table 1 below, a cell viability of 80% or more is considered compliant. In Table 2, it must be 20 EU / device or more to be compliant. In Table 3, it is non-compliant if the temperature rises by 0.5°C or more.

[0072] In all three toxicity tests, Comparative Example 1 failed in all cases, while Example 1 passed in all cases.

[0073]

Table 2

[0074]

Table 3

[0075]

Table 4

[0076] <Experiment 5: Observation of Degradation Time by Washing Temperature>

[0077] The microparticles of Examples 2 to 5 were each collected using a sieve to have a size of only 100 to 300 μm, and then placed in 1x PBS (Phosphate-buffered saline), and the decomposition time was observed in a constant temperature water bath at 37 °C similar to the human body temperature. The results for the decomposition time are shown in Fig. 6. As can be seen from Examples 2 to 5, it can be understood that by changing only the temperature of the final distilled water washing step in the production method according to the present invention, the decomposition time can be adjusted at intervals of about 10 minutes. Also, it can be understood that the microparticles according to the present invention can all be decomposed within a relatively very short 1 hour.

[0078] <Experiment 6: Observation of decomposition time according to heat treatment temperature>

[0079] The microparticles of Examples 6 to 12 were each collected using a sieve to have a size of only 100 to 300 μm, and then placed in 1x PBS (Phosphate-buffered saline), and the decomposition time was observed in a constant temperature water bath at 37 °C similar to the human body temperature. The results for the decomposition time are shown in Table 4. It was found in Experiment 5 that by changing the washing temperature after performing the same heat treatment, the decomposition time can be finely adjusted. From Experiment 6, it is clearly understood that by changing the heat treatment temperature and heat treatment time, the decomposition time of a large unit of the microparticles can be adjusted.

[0080]

Table 5

[0081] From Experiments 5 and 6, it can be understood that when designing the decomposition time of the microparticles, first, the decomposition time of a large unit (day or hour) can be set by adjusting the heat treatment temperature and time, and the time of a minute unit can be adjusted by adjusting the washing temperature.

Claims

1. A composition for embolization comprising hydrated gel microparticles for embolization not containing a structure derived from a crosslinking agent, The hydrated gel particles are configured so that they can be thermally denatured to produce particles, and The washing after the thermal denaturation adjusts the in vivo decomposition time of the hydrated gel particles, and The hydrated gel particles are swollen in a solvent having a δP Polar value of 14 or more by washing after the thermal denaturation, and The embolic composition, wherein the washing is carried out using a solvent having a δP Polar value of 14 or more.

2. The embolization composition described in claim 1, wherein the in vivo decomposition time of the hydrated gel microparticles is also regulated by the thermal denaturation.

3. 2. The embolization composition according to claim 1, wherein the hydrated gel microparticles contain at least one selected from the group consisting of biocompatible polymers consisting of gelatin, collagen, gum, rosin, hyaluronic acid, heparin, dextran, alginic acid, albumin, chitosan, polyhydroxyvalerate, and silk fibroin.

4. The embolic composition according to claim 1 , wherein the hydrated gel particles are particles in the form of an emulsion containing an organic solvent.

5. The organic solvent may be methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, hexyl acetate, ethyl formate, dimethyl carbonate, diethyl carbonate, 1,3-dioxolidin-2-one, cellulose acetate butyrate, MCT (Medium Chain Triglyceride), or the like.

5. The embolization composition according to claim 4, which is at least one selected from the group consisting of triglyceride oil, medium chain triglyceride oil, vegetable oil, wax, and infused oil.

6. The embolic composition of claim 4 , wherein the emulsion does not contain a separate emulsifier.

7. The embolic composition according to claim 1 , further comprising at least one of a local anesthetic, an antibiotic, and a contrast agent.

8. A method for producing the hydrated gel microparticles for embolization defined in claim 1 by the following steps (a) or (b): (a) 1) preparing an aqueous solution of a biocompatible polymer; 2) adding an organic solvent to the aqueous biocompatible polymer solution of step 1) to form micro-sized particles; 3) washing and drying the micro-sized particles produced in step 2) to obtain micro-sized fine particles; 4) thermally curing the micro-sized particles of step 3); and 5) washing, dehydrating and drying the micro-sized particles obtained in step 4); (b) 1) preparing an aqueous solution of a biocompatible polymer; 2) stirring the aqueous biocompatible polymer solution of step 1) to form a foam, and then freeze-drying the foam; 3) subjecting the foam-form material obtained in step 2) to thermal curing; 4) washing the hardened foam-form material obtained in step 3) and then freeze-drying it; and 5) pulverizing the foam-form material obtained in step 4) to obtain micro-sized particles; Where: The hydrated gel particles are configured so that they can be thermally denatured to produce particles, and The washing after the heat curing adjusts the in vivo decomposition time of the hydrated gel microparticles, and The hydrated gel particles are swollen in a solvent having a δP Polar value of 14 or more by washing after the heat curing, and The method of claim 1, wherein the washing is carried out using a solvent having a δP Polar value of 14 or more.

9. The method for producing hydrated gel microparticles according to claim 8, wherein the biocompatible polymer is at least one selected from the group including gelatin, collagen, gum, rosin, hyaluronic acid, heparin, dextran, alginic acid, albumin, chitosan, polyhydroxyvalerate, and silk fibroin.

10. The organic solvent may be methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, hexyl acetate, ethyl formate, dimethyl carbonate, diethyl carbonate, 1,3-dioxolidin-2-one, cellulose acetate butyrate, MCT (Medium Chain Triglyceride), or the like.

9. The method for producing hydrated gel microparticles according to claim 8, wherein the oil is at least one selected from the group consisting of triglyceride oil, medium chain triglyceride oil, vegetable oil, wax, and infused oil.

11. 9. The method for producing hydrated gel particles according to claim 8, further comprising a step of hardening the micro-sized particles produced in step 2) at room temperature or below between step (a) 2) and step (a) 3).

12. Between step (a) 4) and step (a) 5) or after step (a) 5), a step of sieving the micro-sized particles according to particle size after pulverization is further added; The method for producing hydrated gel particles according to claim 8, further comprising the step of separating the micro-sized particles by particle size using a sieve after step (b) 5).

13. The method for producing hydrated gel particles according to claim 8, wherein the heat curing is carried out at 100° C. to 200° C. for 10 minutes to 24 hours.

14. The method for producing hydrated gel particles according to claim 8, wherein the washing is carried out at a temperature above 0° C. and not higher than 40° C.

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