Embolization material and its manufacturing method

Abstract

To provide an embolic material that has X-ray visibility and high filling rate of a hydrophilic drug, and a method for producing the material.SOLUTION: An embolic material has polymers, oily contrast medium, a hydrophilic drug, and amphipathic molecules, and the polymers include hydrophobic polymers.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to an embolic material and a method for producing the same. [Background technology]

[0002] Transarterial chemoembolization (TACE) is an option for cases of hepatocellular carcinoma where treatment by resection or other methods is difficult, such as when there are multiple tumors or the tumors are large. TACE is a method of treating hepatocellular carcinoma by injecting an embolic material loaded with an anticancer drug into the hepatic artery via a catheter, thereby stopping blood flow and causing tumor necrosis, and also by implementing a pharmacological approach using the anticancer drug slowly released from the embolic material. However, the embolic materials currently used in TACE are not visible on X-rays, making it difficult to predict complications due to unintended vascular embolization. Furthermore, the embolic material remains in the blood vessels and continues to embolize even after treatment, posing the risk of serious complications.

[0003] In response to these problems, the inventors' previous research led to the development of a hydrophobic embolic material for TACE that is X-ray visible and biodegradable, containing an oily contrast agent and a biodegradable polymer (Patent Document 1, Non-Patent Document 1). This embolic material exhibited excellent X-ray visibility and biodegradability both in vitro and in vivo, and showed promising results not only in its usefulness as an embolic substance but also in predicting complications and preventing their aggravation when unintended vascular embolism occurs.

[0004] Currently, epirubicin (EPI) and other anticancer drugs are known to be used worldwide in TACE and exhibit strong efficacy. However, EPI is a hydrophilic anticancer drug and is incompatible with the hydrophobic materials used in embolic materials. This has led to the problem that such hydrophilic anticancer drugs cannot be stably loaded into the embolic material, resulting in a low loading rate.

[0005] Furthermore, this decrease in filling rate caused the anticancer drug to be released from the embolic material in a short period of time (i.e., an initial burst), causing the concentration of the anticancer drug in the blood to temporarily exceed the recommended dose, resulting in the problem of significant side effects of the anticancer drug. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Patent Publication No. 2018-130322 [Non-patent literature]

[0007] [Non-Patent Document 1] Okamoto, Y,et al.Polymer Degradation and Stability,2020,175 Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present disclosure is to provide an embolic material that is X-ray visible and has a high loading rate of a hydrophilic drug, and a method for manufacturing the same. [Means for solving the problem]

[0009] One aspect of the present disclosure is an embolic material having a polymer, an oil-based contrast agent, a hydrophilic drug, and an amphiphilic molecule, wherein the polymer includes a hydrophobic polymer. In one embodiment of the present disclosure, the hydrophilic drug and the amphiphilic molecule may form a micelle.

[0010] Additionally, in one embodiment of the present disclosure, the hydrophilic portion of the amphiphilic molecule may be hyaluronic acid. In one embodiment of the present disclosure, the amphiphilic molecule may be hyaluronic acid ceramide.

[0011] In one embodiment of the present disclosure, the polymer may be a biodegradable polymer. In one embodiment of the present disclosure, the hydrophilic drug may be a hydrophilic anti-cancer drug, a hydrophilic anti-inflammatory drug, or a hydrophilic antibacterial / antifungal drug.

[0012] Furthermore, one aspect of the present disclosure is a method for manufacturing an embolic material, comprising the steps of: mixing a mixture containing a hydrophilic drug, an amphipathic molecule, and a first hydrophilic liquid with a solvent containing a polymer and an oil-based contrast agent to obtain a mixture; and dispersing the mixture in a second hydrophilic liquid, wherein the polymer comprises a hydrophobic polymer.

[0013] Additionally, in one embodiment of the present disclosure, micelles may be formed with hydrophilic drugs and amphiphilic molecules. According to this configuration, it is possible to obtain an embolic material that is X-ray visible and has a high filling rate of a hydrophilic drug, and a method for producing the same. [Brief explanation of the drawings]

[0014] [Figure 1] FIG. 1 is a schematic diagram showing a method for producing HACE / EPI polymer beads by a W / O / W emulsion method. [Figure 2] Figure 1 shows the hydrogen atom spectra of HACE, HACE / EPI polymer beads, and EPI polymer beads measured by nuclear magnetic resonance (NMR). (a) shows the hydrogen atom spectrum of HACE, (b) shows the hydrogen atom spectrum of EPI polymer beads, and (c) shows the hydrogen atom spectrum of HACE / EPI polymer beads. [Figure 3] 1 shows images of HACE / EPI polymer beads and EPI polymer beads observed with a scanning electron microscope (SEM), where (a) shows an image of EPI polymer beads and (b) shows an image of HACE / EPI polymer beads. [Figure 4] This is a calibration curve graph of absorbance for PVA aqueous solutions with various EPI concentrations (20, 10, 5, 2.5, 1.25, and 0.625 μg / mL) measured using an ultraviolet-visible-near-infrared spectrophotometer (UV-Vis-NIR). The horizontal axis represents EPI concentration (μg / mL), and the vertical axis represents absorbance. [Figure 5] 1 is a graph showing the results of measuring the sustained release rate of anticancer drugs from HACE / EPI polymer beads and EPI polymer beads using UV-Vis-NIR. The horizontal axis shows the time (h) elapsed after adding each bead to a phosphate buffer solution and leaving it in a water bath at 37°C, and the vertical axis shows the drug release rate. DETAILED DESCRIPTION OF THE INVENTION

[0015] Hereinafter, exemplary embodiments of the present disclosure will be described with reference to the drawings. 1. Embolization material The embolic material comprises a polymer, an oil-based contrast agent, a hydrophilic drug, and an amphiphilic molecule, and the polymer includes a hydrophobic polymer.

[0016] The embolic material of the present disclosure contains amphipathic molecules, which allows the preparation of an embolic material containing a hydrophilic drug, thereby increasing the loading rate of the hydrophilic drug in the embolic material. Furthermore, the introduction of amphipathic molecules causes the amphipathic molecules and the hydrophilic drug to form micelles, and the hydrophilic drug is encapsulated in the micelles, which reduces the initial burst compared to conventional embolic materials.

[0017] In this disclosure, the term "amphiphilic molecule" refers to a molecule that has both a hydrophilic portion and a hydrophobic portion within the molecule. Examples of the hydrophilic portion of an amphiphilic molecule include a hydroxyl group, a carboxyl group, a sulfone group, an amino group, and a phosphate group.

[0018] The hydrophilic portion of the amphiphilic molecule preferably contains hyaluronic acid (HA). HA specifically binds to the CD44 receptor of hepatocellular carcinoma. Therefore, the inclusion of HA in the embolic material enables effective and selective delivery to tumor sites in the liver.

[0019] Furthermore, HA may be used with its structure modified, but the modification rate is preferably 25% or less to maintain CD44 receptor binding ability. In this disclosure, "modification rate" refers to the ratio (%) of the number of modification groups to the number of disaccharide units (glucuronic acid and N-acetylglucosamine) that are bonded adjacently to form hyaluronic acid, when this unit is defined as one disaccharide unit.

[0020] Furthermore, the HA used in the embolic material of the present disclosure may be HA with a relatively low molecular weight. For example, the HA may have a weight-average molecular weight (Mw) of 4000 to 8000. Furthermore, the degree of polymerization of HA is not particularly limited and can be adjusted as appropriate.

[0021] The hydrophobic portion of the amphiphilic molecule may be, for example, a hydrocarbon group. A specific example of an amphiphilic molecule of the present disclosure is hyaluronic acid ceramide (HACE).

[0022] The presence of amphiphilic molecules allows the formation of micelles in which the hydrophilic portion and hydrophilic drug are located on the inside and the hydrophobic portion on the outside. These micelles can enhance the compatibility of the hydrophilic drug and the hydrophobic embolic material in the embolic material. Therefore, the presence of such amphiphilic molecules in the embolic material improves the loading rate of the hydrophilic drug. Furthermore, the encapsulation of the hydrophilic drug in the micelles can also reduce the initial burst.

[0023] The mass ratio of the amphiphilic molecules to 100 parts by mass of the hydrophilic drug is preferably 50 to 200 parts by weight, more preferably 100 to 150 parts by weight. If the mass ratio of the amphiphilic molecules is too small, micelles of the hydrophilic drug may not be formed, and the loading rate of the hydrophilic drug in the embolic material may decrease, while if the mass ratio of the amphiphilic molecules is too large, the mass ratio of the polymer in the embolic material may decrease.

[0024] The mass ratio of the amphiphilic molecules to 100% by weight of the embolic material is preferably 1 to 10% by mass, more preferably 1.2 to 2.6% by mass. If the mass ratio of the amphiphilic molecules is too small, the loading rate of the hydrophilic drug may decrease, and if the mass ratio of the amphiphilic molecules is too high, the mass ratio of the polymer in the embolic material may decrease.

[0025] Examples of hydrophilic drugs include hydrophilic anticancer drugs, hydrophilic anti-inflammatory drugs, and hydrophilic antibacterial / antifungal drugs. Examples of hydrophilic anticancer drugs include epirubicin, doxorubicin, vinblastine, vinorelbine, mizoribine, cyclophosphamide, and calcium folinate. Examples of hydrophilic anti-inflammatory drugs include loxoprofen and acetaminophen. Examples of hydrophilic antibacterial / antifungal drugs include isoniazid, levofloxacin, chloramphenicol sodium succinate, clindamycin, and micafungin.

[0026] The mass ratio of the hydrophilic drug to 100% by weight of the embolic material is preferably 1 to 10% by mass, and more preferably 1.8 to 3.9% by mass. If the mass ratio of the hydrophilic drug is too small, there is a risk that the drug will not be contained sufficiently, resulting in a decrease in the efficacy rate, and if the mass ratio of the hydrophilic drug is too high, there is a risk that the moldability of the embolic material will decrease.

[0027] The embolic material may have the ability to release a drug gradually as the embolic material decomposes. The embolic material has at least one polymer, and the polymer includes a hydrophobic polymer. If the embolic material does not include a hydrophobic polymer (i.e., if it includes only a hydrophilic polymer), the embolic material may be prone to losing its shape and may have difficulty maintaining a predetermined shape. By using a hydrophobic polymer, a spherical embolic material can be obtained.

[0028] Examples of hydrophobic polymers include polylactic acid (PLA), polycaprolactone (PCL), polybutylene succinate (PBS), and polydioxanone (PDS).

[0029] The degree of polymerization of the hydrophobic polymer is not particularly limited and can be adjusted appropriately. For example, the degree of polymerization of the hydrophobic polymer may be 50 to 6000. The content of the hydrophobic polymer may be, for example, 10 to 50% by mass or more, preferably 20 to 40% by mass, when the embolic material is taken as 100% by mass. This makes it possible to produce an embolic material that has good moldability and sufficient X-ray visibility.

[0030] The weight-average molecular weight of the hydrophobic polymer is preferably 5,000 to 200,000. For example, in the case of PLA, the weight-average molecular weight is preferably 150,000 or more. This allows the hydrophobic polymer to retain the oily contrast agent and form the embolic agent into a more spherical shape.

[0031] In addition to the hydrophobic polymer, the polymer preferably contains a hydrophilic polymer, such as polylactic-co-glycolic acid (PLGA) or polycaprolactone-co-glycolic acid (PCGA).

[0032] The weight average molecular weight of the hydrophilic polymer may be 5,000 to 200,000. It is preferable that the hydrophilic polymer has a part of the structure of the hydrophobic polymer to increase compatibility with the hydrophobic polymer in the embolic material. For example, it is preferable to use PLGA, a hydrophilic polymer containing LA (lactic acid), for PLA, and PCGA, a hydrophilic polymer containing CL (caprolactone), for PCL.

[0033] When one type of hydrophobic polymer and one type of hydrophilic polymer are used as the polymers, the weight mixing ratio of one polymer to the other may be 3.0 or less, for example.

[0034] The above-mentioned hydrophobic polymers and hydrophobic polymers may be biodegradable polymers (hereinafter referred to as biodegradable polymers). In this disclosure, "biodegradable" means the property of being decomposed by enzymes, microorganisms, etc. present in the body. When a polymer is biodegradable, the polymer is decomposed in the body, and the effects on normal tissue caused by the embolic material remaining in the body can be suppressed. Furthermore, when a polymer is biodegradable, the embolic material is decomposed in the body, allowing the embolic material to be used repeatedly in the same subject.

[0035] Here, it is desirable for the embolic material to lose its function within a specific period (e.g., about one week) after vascular embolization, allowing blood flow to be restored. However, a hydrophobic biodegradable polymer with a large molecular weight may take one to two years to be completely degraded in the body. Therefore, by mixing a hydrophilic biodegradable polymer in addition to the hydrophobic biodegradable polymer in the embolic material, the degradation rate in the body can be made relatively fast. Furthermore, by increasing the ratio of hydrophilic biodegradable polymer to hydrophobic biodegradable polymer, the biodegradation rate can be further accelerated, which is thought to result in earlier recovery of blood flow.

[0036] In the present disclosure, the embolic material may, as an example, contain, as biodegradable polymers, PLA, a hydrophobic polymer, and PLGA, a hydrophilic polymer. PLA and PLGA have a proven track record of use in blood-contacting medical devices such as stents, and are highly biocompatible. When PLA and PLGA are selected as biodegradable polymers, the weight mixing ratio of PLA to PLGA is preferably 1.0 or more, and more preferably 1.0 to 3.0. Generally, PLGA has a faster decomposition rate than PLA, a crystalline polymer. Therefore, the use of these two biodegradable polymers makes it possible to control the decomposition rate of the embolic material. Furthermore, by having a weight mixing ratio of PLA to PLGA of 1.0 to 3.0, an embolic material can be obtained that is easy to mold (i.e., spherical) and exhibits sufficient X-ray visibility.

[0037] In addition, an oil-based contrast agent is used to form the embolic material. By using an oil-based contrast agent, in particular, the mixture is dispersed in particulate form in a hydrophilic liquid, as described below, making it possible to manufacture an embolic material that is easy to mold and has high visibility under X-ray fluoroscopy.

[0038] Furthermore, the weight mixing ratio of the oily contrast agent to the polymer in the embolic material is preferably 1.0 to 2.0, more preferably 1.3 to 1.7, and most preferably 1.5. Here, if the weight mixing ratio of the oily contrast agent to the polymer is too small, it may be difficult to manufacture an embolic material that exhibits sufficient X-ray visibility. On the other hand, if the weight mixing ratio of the oily contrast agent to the polymer is too large, the excess oily contrast agent that is not completely miscible with the polymer may cause phase separation, which may reduce the X-ray visibility of the embolic material. Therefore, by keeping the weight mixing ratio of the oily contrast agent to the polymer within the range of 1.0 to 2.0, an embolic material that is easy to mold (i.e., spherical) and exhibits sufficient X-ray visibility can be manufactured.

[0039] It is preferable that the oil-based contrast agent is swollen at the molecular level in the polymer network. Examples of oil-based contrast agents include iodized poppy oil fatty acid ethyl esters. Examples of commercially available iodized poppy oil fatty acid ethyl esters include Lipiodol (LPD) (registered trademark). In the present disclosure, Lipiodol is preferred as the oil-based contrast agent from the viewpoint of high liver tumor accumulation and retention in the tumor local area. Note that the oil-based contrast agent may be one other than iodized poppy oil fatty acid ethyl esters.

[0040] The present disclosure makes it possible to obtain a more uniform particulate embolic agent than conventional methods. The size of the embolic material is not particularly limited and can be adjusted as appropriate. As an example, the size of the embolic material may have an average particle size in the range of 50 to 1000 μm. The average particle size may be the average diameter of a predetermined number of embolic materials photographed using a microscope or the like and measured using analysis software for each image data. The predetermined number may be 20 or more, 50 or more, 100 or more, or 150 or more.

[0041] The embolic material can be used for medical purposes, and may be injected into a blood vessel through a catheter to temporarily stop blood flow and to visualize the embolized area in the blood flow with X-ray irradiation.

[0042] The embolic material may be used to treat subjects, including, but not limited to, mammals, such as primates such as humans and chimpanzees, laboratory animals such as rats, mice, and rabbits, livestock animals such as pigs, cows, horses, and sheep, and pets such as dogs and cats, preferably humans.

[0043] Specifically, the embolic material can be used, for example, in TACE for the treatment of hepatocellular carcinoma. Also, the embolic material can be used, for example, as a drug-eluting embolic material in TACE.

[0044] In addition, embolic materials can be used in, for example, musculoskeletal catheter treatment for chronic inflammation affecting joints and muscles, as well as rheumatoid arthritis, or in bronchial artery embolization (BAE) for the treatment of hemoptysis.

[0045] 2. Manufacturing method of embolization material The embolic material of the present disclosure can be obtained by dispersing a hydrophobic mixture containing a hydrophilic material inside in an aqueous solvent (W / O / W emulsion method).

[0046] Specifically, the method for manufacturing an embolic material disclosed herein includes a first step of mixing a mixture containing a hydrophilic drug, amphipathic molecules, and a first hydrophilic liquid with a solvent containing a polymer and an oily contrast agent to obtain a mixture, and a second step of dispersing the mixture in a second hydrophilic liquid. The polymer includes a hydrophobic polymer. The mixture is supplied to the second hydrophilic liquid, whereby it disperses in particulate form in the second hydrophilic liquid. The particulate mixture gradually evaporates the solvent in the second hydrophilic liquid, eventually solidifying or semi-solidifying.

[0047] The polymer, oily contrast medium, hydrophilic drug, and amphiphilic molecule used in this method may be the same as those described in the above section "1. Embolic material." The manufacturing method of the embolic material of the present disclosure will be described in detail below.

[0048] (1) First step The mixture containing the hydrophilic drug, the amphiphilic molecule, and the first hydrophilic liquid can be obtained by dissolving the hydrophilic drug and the amphiphilic molecule in the first hydrophilic liquid.

[0049] The first hydrophilic liquid may be, for example, a polyvinyl alcohol (PVA) aqueous solution / dimethyl sulfoxide (DMSO) / methanol solution. DMSO can dissolve hydrophilic drugs and amphiphilic molecules even when the amount of the first hydrophilic liquid is small. Methanol is commonly used as a solvent. However, other solvents may be used instead of methanol.

[0050] When a polyvinyl alcohol (PVA) / dimethyl sulfoxide / methanol solution is used as the first hydrophilic liquid, the blending ratio of each component can be adjusted to any ratio. In this case, by adjusting the blending ratio of methanol, the loading rate of the hydrophilic drug in the embolic material can be improved.

[0051] The solvent may be an organic solvent. The organic solvent is preferably a hydrophobic, volatile solvent with a low boiling point that can dissolve the oil-based contrast agent and the biodegradable polymer. The boiling point of the organic solvent used may be 100°C or less, 20 to 80°C, or 40 to 60°C. For example, halogenated hydrocarbons such as dichloromethane (boiling point 40°C) or chloroform (boiling point 60°C) are used as the organic solvent.

[0052] The above-mentioned mixed solution may be mixed with a solvent containing a polymer and an oily contrast agent by, for example, dropping the mixed solution into the solvent using a syringe, a nozzle, or the like. Alternatively, the mixed solution may be injected into the solvent using a syringe, a nozzle, or the like. The diameter of the opening of the syringe, nozzle, or the like used in this case is preferably within the range of 0.01 to 0.9 mm. The particle size of the embolic material to be produced can be changed by adjusting the diameter of the opening.

[0053] Furthermore, the step of mixing the mixed liquid with a solvent containing the polymer and the oily contrast agent may be carried out by supplying the mixed liquid to the solvent while stirring the solvent. By mixing the mixture with a solvent containing a polymer and an oil-based contrast agent, micelles containing a hydrophilic drug and amphipathic molecules are formed. This increases the compatibility between the hydrophilic drug and the hydrophobic embolic material in the embolic material. This improves the loading rate of the hydrophilic drug. In addition, the initial burst can be reduced by encapsulating the hydrophilic drug in the micelles.

[0054] (2)Second process The second hydrophilic liquid can be, for example, an aqueous solution in which an emulsifier is dissolved. By using an aqueous solution in which an emulsifier is dissolved, the mixture can be maintained in a particulate form in the aqueous solution. Examples of emulsifiers include anionic surfactants such as fatty acid sodium salts, monoalkyl sulfate ester salts, alkyl polyoxyethylene sulfate salts, alkyl benzene sulfonates, and monoalkyl phosphate salts (e.g., sodium lauryl sulfate, etc.); cationic surfactants such as alkyl trimethyl ammonium salts, dialkyl dimethyl ammonium salts, and alkyl benzyl dimethyl ammonium salts (e.g., distearyl dimethyl ammonium chloride, benzalkonium chloride, etc.); amphoteric surfactants such as amine oxides and betaines (e.g., cocamidopropyl betaine, etc.); and nonionic surfactants such as polyoxyethylene alkyl ethers, fatty acid sorbitan esters, alkyl polyglucosides, fatty acid diethanolamides, alkyl monoglyceryl ethers, polyethylene glycol, and PVA. PVA is preferred due to its relatively high biocompatibility. For example, when an aqueous PVA solution is used as the second hydrophilic liquid, the concentration of the aqueous PVA solution may be in the range of 0.1 to 5 w / v %, and preferably 0.4 to 0.6 w / v %.

[0055] The mixture can be supplied into the second hydrophilic liquid using a syringe, a nozzle, or the like, in the same manner as in the above-mentioned method for mixing the mixed liquid into the solvent. The shape of the mixture supplied into the second hydrophilic liquid is not limited and may take various forms, but is preferably spherical.

[0056] The step of dispersing the mixture in the hydrophilic liquid may be carried out by supplying the mixture to the hydrophilic liquid while stirring the second hydrophilic liquid. By supplying the mixture to the second hydrophilic liquid, the mixture is dispersed in particulate form in the second hydrophilic liquid. Stirring may be carried out using, for example, a stirrer (SM-102, manufactured by AS ONE Corporation). Stirring may also be carried out using, for example, a stirrer bar. The shape and size of the stirrer bar can be selected arbitrarily, but it is preferable to carry out stirring using a stirrer bar with a shape that easily increases the shear force of the second hydrophilic liquid by stirring. As an example, a propeller-shaped stirrer with stirring blades having a diameter of 50 mm may be used.

[0057] Furthermore, when using the above-mentioned agitator, the rotation speed of the agitator can be set between 100 and 1,000 rpm, but to produce spherical particles, it is preferable that the speed be at least such that the dispersed mixture does not settle. Specifically, the rotation speed is preferably 200 to 500 rpm. The particle size of the embolic material can be adjusted by changing the rotation speed of the agitator. Specifically, increasing the rotation speed increases the shear force of the second hydrophilic liquid, resulting in a smaller particle size of the embolic material. The temperature of the hydrophilic liquid during agitation may be between 0°C and 50°C, but is preferably between 10°C and 30°C, and more preferably room temperature. The agitation time can be set between 0.5 and 48 hours, but is preferably between 15 and 20 hours.

[0058] The embolic material remaining after the solvent has evaporated may be recovered and then freeze-dried. The recovery method may be, for example, vacuum filtration. The drying time may be set to a range of 0.5 to 48 hours, preferably 18 to 36 hours.

[0059] The manufacturing method of the present disclosure can form multiple depressions (dimples) on the surface of the embolic material. Furthermore, the manufacturing method of the present disclosure can form voids inside the embolic material, making the embolic material porous. These depressions or voids can be formed as traces of excess oily contrast agent leaking into the second hydrophilic liquid as the solvent is removed.

[0060] [Example] Example 1: Preparation of HACE HACE was synthesized as previously reported (Cho, HJ et al., Biomaterials. (2011) 32(29):7181-90). HA oligomer (12.21 mmol, 4.80 g, Kewpie Corporation) and tetra-n-butylammonium hydroxide (TBA; 6.51 mL) were added to 60 mL of double-distilled water, stirred for 30 min, and lyophilized to obtain activated HA-TBA. DS-Y30 (ceramide 3B: mainly N-oleoyl-phytosphingosine, Doosan Corporation) (8.59 mmol) in 10 mL of tetrahydrofuran (THF) was mixed with 8.59 mmol of 4-chloromethylbenzoyl in 1.32 mL (=9.45 mmol) of triethylamine, stirred at 60 °C for 6 h, concentrated, and recrystallized to obtain the DS-Y30-containing linker. 8.1 mmol of HA-TBA and 0.41 mmol of the DS-Y30-containing linker were dissolved in a mixture of THF and acetonitrile (4:1, v / v) and stirred at 40°C for 5 hours to synthesize HACE.

[0061] Example 2: Preparation of polymer beads HACE / EPI polymer beads, in which HACE and EPI were loaded into hydrophobic polymer beads, were prepared by the W / O / W emulsion method (see Figure 1). The specific preparation procedure is shown below.

[0062] 1) 0.0375 g of Farmorubicin Injection 10 mg (EPI) (Pfizer) and 0.0375 g of HACE synthesized in Example 1 were weighed into a screw bottle using an electronic balance (product name: GR-60, A&D Co., Ltd.) and mixed with a 2 wt% aqueous solution of PVA (Tokyo Chemical Industry Co., Ltd., molecular weight approximately 70,000) / DMSO (Fujifilm Wako Pure Chemical Industries, Ltd.) / methanol (Fujifilm Wako Pure Chemical Industries, Ltd.) solution (PVA:DMSO:methanol = 1:1:8) to prepare a HACE / EPI solution (see Figure 1(a)).

[0063] 2) 0.2 g of biodegradable polymer (PLA (MW=207,000, manufactured by Nature Works) and 0.3 g of LPD (trade name: Lipiodol 480 Injection 10 mL, manufactured by Guerbet Japan) were weighed into a screw bottle using an electronic balance, and 10 mL of DCM was added. Dissolution was carried out at 35°C and a rotation speed of 500 rpm to obtain a DCM solution.

[0064] 3) Approximately 4 mL of the HACE / EPI solution was mixed into beaker 2 containing the DCM solution prepared in 2) using syringe 1 to form a HACE / EPI polymer emulsion (see Figure 1(b)).

[0065] 4) 500 mg of PVA was weighed out on an electronic balance and added to 1 L of water measured in a measuring cylinder. The mixture was stirred at 50°C and 500 rpm to give a 0.5 w / v% PVA aqueous solution. 5) Using syringe 3 equipped with a 20-gauge needle, the HACE / EPI polymer emulsion prepared in 3) was injected into 500 mL of 0.5 w / v% PVA aqueous solution placed in beaker 4 at room temperature while stirring at 300 rpm using stirrer 5 (AS ONE Corporation, SM-102). The PVA aqueous solution was then stirred at 300 rpm for 18 hours using stirrer 5 to volatilize the DCM, producing HACE / EPI polymer beads (see Figure 1(c)). The stirring blade of stirrer 5 (AS ONE Corporation, tornado stirring blade, 50 mm diameter) was attached to the bottom of beaker 4 and rotated to form a tornado of the PVA aqueous solution in beaker 4.

[0066] 6) The solution containing the HACE / EPI polymer beads was filtered through a glass filter (GS-25, manufactured by Advantec Toyo Co., Ltd.) to recover the HACE / EPI polymer beads, which were then freeze-dried for 48 hours.

[0067] 7) As a comparative example, an EPI solution was prepared by mixing only EPI in a 2 wt% PVA aqueous solution / DMSO / methanol solution (PVA:DMSO:methanol = 1:1:8) in 1), and EPI polymer beads were prepared using the same procedures as in 2) to 6) above.

[0068] (Example 3) Chemical structure analysis of beads by NMR 1 The hydrogen atom spectra of the HACE synthesized in Example 1, the HACE / EPI polymer beads prepared in Example 2, and the EPI polymer beads were measured using H-NMR (manufactured by JEOL Ltd., product name: JNM-ECA500). The measurement nuclear frequency was 400 MHz, the number of accumulations was 64, and the relaxation time was 5 s. 10 mg of HACE, HACE / EPI polymer beads, and EPI polymer beads were each dissolved in 0.8 mL of deuterated dimethyl sulfoxide and used for the measurement.

[0069] It is known that the chemical shift peaks appear at 1.8 ppm for the N-acetyl acid of hyaluronic acid, 0.9 ppm for the terminal methyl group of the ceramide main chain, and 7.5-8.0 ppm for the aromatic ring of 4-chloromethylbenzoyl chloride (Cho, HJ et al., Biomaterials. (2011) 32(29):7181-90). Therefore, the feasibility of HACE synthesis was determined by examining whether all of these chemical shifts were present. Furthermore, the chemical shift peaks of HACE appeared at 1.8 ppm and 0.9 ppm. Because these HACE peaks overlap with those of PLA and LPD, the presence or absence of the aromatic ring peaks in the 7.5-8.0 ppm range was used to determine whether HACE was encapsulated in polymer beads.

[0070] The synthesized HACE, the prepared EPI polymer beads, and the HACE / EPI polymer beads 1The H-NMR signals are shown in Figure 2. First, for the HACE synthesized in Example 1, peaks at 1.8 ppm, 0.9 ppm, and 7.5 to 8.0 ppm were all confirmed (see Figure 2(a)). This indicated that HACE was synthesized without any problems. Furthermore, regarding the chemical shifts of the HACE / EPI polymer beads and EPI polymer beads, the peak at 7.5 to 8.0 ppm derived from the aromatic ring of HACE was confirmed only for the HACE / EPI polymer beads (see Figures 2(b) and (c)). This indicated that HACE was successfully contained within the polymer beads.

[0071] (Example 4) Shape analysis by SEM The morphology of the obtained HACE / EPI polymer beads and EPI polymer beads was analyzed using a SEM (Thermo Fisher Scientific, product name: Inspect S50). Each bead was previously vapor-deposited with osmium to give it conductivity. The applied voltage during observation was 10 kV, and the magnification was 400x.

[0072] SEM images of the HACE / EPI and EPI polymer beads are shown in Figure 3. The beads obtained were confirmed to be uniformly spherical. The average particle sizes of the HACE / EPI and EPI polymer beads were 163±39 μm and 171±36 μm, respectively.

[0073] (Example 5) Measurement of anticancer drug loading rate using UV-vis-NIR First, using UV-Vis-NIR (Shimadzu Corporation, product name: UV-3600Plus), the absorbance of 0.5 w / v% PVA aqueous solution with EPI concentrations of 20, 10, 5, 2.5, 1.25, and 0.625 μg / mL was measured, and a calibration curve was created. Then, similarly to Example 2, 5), the HACE / EPI polymer emulsion was injected into 500 mL of the PVA aqueous solution placed in beaker 4. Thereafter, the EPI concentration in the supernatant solution of the PVA aqueous solution was measured, and the amount of EPI leaked into the PVA aqueous solution was calculated, and the loading rate of EPI into the HACE / EPI polymer beads was calculated using the following formula (1). Here, EPI trepresents the amount of EPI weighed out in Example 2, 1), and EPI e represents the amount of EPI in the supernatant solution (i.e., the amount of EPI leaked into the PVA aqueous solution).

[0074]

number

[0075] The calibration curves created are shown in Figure 4. The maximum absorption wavelength of EPI is approximately 482 nm. From this, the absorbance of EPI leaked into the supernatant solution was 0.20 and 0.14 for EPI polymer beads and HACE / EPI polymer beads, respectively, and the EPI between EPI polymer beads and HACE / EPI polymer beads was e The EPI values ​​were calculated to be 5.4 mg and 3.8 mg, respectively. t By using 6.05 mg of HACE / EPI polymer beads, the loading rates of HACE / EPI polymer beads and EPI polymer beads were 36.6% and 11.0%, respectively. Therefore, it was shown that the loading rate of EPI was improved by 25.6% by using HACE.

[0076] (Example 6) Measurement of sustained release rate of anticancer drug by UV-vis-NIR 50 mg of HACE / EPI polymer beads and EPI polymer beads were each added to 2 mL of phosphate buffer solution (PBS, pH = 7.4) and allowed to stand in a water bath at 37°C. After standing, 2 mL of the solution was removed every 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, and 48 hours, and 2 mL of new PBS was added, and this process was repeated. Using the same method as in Example 5, the amount of EPI in the removed solution was calculated, and the sustained release rate relative to the amount of anticancer drug loaded was calculated using the following formula (2). Here, EPI e,n is the cumulative amount of EPI in the solution over n hours.

[0077]

number

[0078] Figure 5 shows the results of the controlled release rate of anticancer drugs from HACE / EPI polymer beads and EPI polymer beads. After 12 hours of standing, the controlled release rate of anticancer drugs decreased from 17.7% to 10.2%, indicating a 7.5% reduction in the initial burst. The controlled release behavior of biodegradable polymer beads is generally thought to be as follows: first, an initial burst occurs in which the drug concentrated near the bead surface is released; then, the drug is released from the interior of the beads by diffusion; and finally, drug release occurs as the beads decompose (Siepmann, JG et al., Advanced Drug Delivery Reviews. (2001) 48(2-3):229-247). Therefore, for HACE / EPI polymer beads and EPI polymer beads, it is believed that the EPI near the bead surface was released by 12 hours after standing, and that the remaining EPI within the beads will also be released over time.

[0079] According to the examples described above, the presence of amphipathic molecules in the embolic material allows the formation of micelles in which the hydrophilic portion and hydrophilic drug are located on the inside and the hydrophobic portion is located on the outside. These micelles can then increase the compatibility between the hydrophilic drug and the hydrophobic embolic material in the embolic material. This allows the loading rate of the hydrophilic drug in the embolic material to be improved.

[0080] In addition, the initial burst can be reduced by encapsulating a hydrophilic drug in the micelles.

[0081] [Other embodiments] Although the embodiments of the present disclosure have been described above, the present disclosure is not limited to the above-described embodiments and can be implemented in various modified forms.

[0082] The function of one component in each of the above embodiments may be shared among multiple components, or the functions of multiple components may be performed by one component. Also, part of the configuration of each of the above embodiments may be omitted. Also, at least part of the configuration of each of the above embodiments may be added to or substituted for the configuration of another of the above embodiments. All aspects included in the technical idea identified by the wording of the claims are embodiments of the present disclosure.

Claims

1. An embolic material comprising a polymer, a contrast agent, a hydrophilic drug, and an amphiphilic molecule, wherein the polymer includes a hydrophobic polymer, the mass ratio of the amphiphilic molecule to 100 parts by mass of the hydrophilic drug is 50 to 200 parts by weight, and the amphiphilic molecule is hyaluronic acid ceramide; The embolic material comprises one type of contrast agent, and the contrast agent is an oil-based contrast agent.

2. The embolic material according to claim 1 , wherein the hydrophilic drug and the amphiphilic molecule form a micelle.

3. The embolic material according to claim 1 or 2, wherein the polymer is a biodegradable polymer.

4. The embolic material according to any one of claims 1 to 3, wherein the hydrophilic drug is a hydrophilic anti-cancer drug, a hydrophilic anti-inflammatory drug, or a hydrophilic antibacterial / anti-fungal drug.

5. An embolic material described in any one of claims 1 to 4, wherein the weight mixing ratio of the oily contrast agent to the polymer in the embolic material is 1.0 to 2.

0.

6. mixing a mixture comprising a hydrophilic drug, an amphipathic molecule, and a first hydrophilic liquid with a solvent comprising a polymer and a contrast agent to obtain a mixture, wherein the contrast agent is an oil-based contrast agent; dispersing the mixture in a second hydrophilic liquid; wherein the polymer comprises a hydrophobic polymer, the mass ratio of the amphiphilic molecule to 100 parts by mass of the hydrophilic drug is 50 to 200 parts by weight, and the amphiphilic molecule is hyaluronic acid ceramide.

7. The method for producing an embolic material according to claim 6 , further comprising forming micelles containing the hydrophilic drug and the amphiphilic molecule.

8. A method for manufacturing an embolic material described in claim 6 or claim 7, wherein the weight mixing ratio of the oily contrast agent to the polymer in the embolic material is 1.0 to 2.0.

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