Vascular embolization agent, vascular embolization kit, and production method for vascular embolization agent

Abstract

This vascular embolization agent contains solid particles of two or more amino acids having different solubilities as an active ingredient. The solid particles dissolve in physiological saline at 37°C within 6 hours. This production method for a vascular embolization agent includes a step for adjusting the dissolution rate of solid particles of two or more amino acids that have different solubilities and serve as an active ingredient so that the solid particles dissolve in physiological saline at 37°C within 6 hours.

Description

Vascular embolization agent, vascular embolization kit, and method for producing vascular embolization agent

[0001] The present invention relates to a vascular embolic agent, a vascular embolization kit, and a method for producing a vascular embolic agent. This application claims priority based on Japanese Patent Application No. 2024-107744, filed on July 3, 2024, the contents of which are incorporated herein by reference.

[0002] Transcatheter embolization of blood vessels can be used to treat a wide variety of conditions, including hypervascular tumors, vascular malformations, aneurysms, and hemorrhages.

[0003] Vascular embolization materials include metal coils, gelatin sponge, n-butyl-2-cyanoacrylate (NBCA), spherical embolization materials, and imipenem hydrate / cilastatin sodium (IPM / CS). Because IPM / CS exhibits broad-spectrum activity against aerobic, anaerobic, gram-positive, and gram-negative bacteria, it has been approved by the Ministry of Health, Labor, and Welfare as a carbapenem antibiotic. Taking advantage of the mechanism by which IPM / CS particles dissolve quickly within blood vessels, clinical reports have shown its use as a vascular embolization agent, both in hemostatic procedures for gastrointestinal bleeding and more recently in chronic pain.

[0004] As examples of dissolvable or degradable vascular embolic agents other than IPM / CS, for example, Patent Document 1 describes a particulate polymeric substance having a structural unit derived from cellulose that is degraded and absorbed in the body after the embolic effect is exerted. Patent Document 2 describes that a particulate polymeric substance can maintain the effectiveness of a vascular embolic agent for a relatively long period of time. Patent Document 3 describes that a polymeric substance that is particulate at pH 6 or less and non-particulate at pH 8 or more and that has an acid group such as a carboxylic acid group, a sulfonic acid group, or a phosphate group is easily excreted from the body after the embolic effect is exerted.

[0005] JP 2022-103880 A JP 2022-103881 A JP 2022-103882 A

[0006] However, all of the above polymeric substances take a long time to decompose and be excreted in the body, and there is a risk of ischemia in blood vessels other than the target blood vessel.

[0007] The present invention has been made in consideration of the above circumstances, and an object of the present invention is to provide a vascular embolic agent having an embolization rate and dissolution rate equivalent to those of IPM / CS, a vascular embolization kit using the vascular embolic agent, and a method for producing the vascular embolic agent.

[0008] The present invention includes the following aspects. [1] A vascular embolic agent, the active ingredient of which is solid particles of two or more amino acids with different solubilities, the solid particles dissolving in physiological saline at 37°C within 6 hours. [2] The vascular embolic agent according to [1], wherein the amino acids are one or more selected from the group consisting of glycine, arginine, serine, alanine, lysine, threonine, and cysteine, and one or more selected from the group consisting of phenylalanine, asparagine, aspartic acid, glutamic acid, glutamine, histidine, methionine, valine, isoleucine, leucine, proline, tryptophan, and tyrosine. [3] The vascular embolic agent according to [1] or [2], wherein the amino acids are glycine and phenylalanine, or glycine and tyrosine. [4] The vascular embolic agent according to [3], wherein the mass of glycine relative to the total mass of glycine and phenylalanine is 40% by mass to 60% by mass. [5] The vascular embolic agent according to [3], wherein the mass of glycine is 85% to 99% by mass relative to the total mass of glycine and tyrosine. [6] The vascular embolic agent according to any one of [1] to [5], wherein the solid particles are compressed into a cylindrical tablet having a diameter of 3 mm and a thickness of 0.7 mm to 1.5 mm, and the dissolved mass after 5 minutes in physiological saline at 37°C is 15% to 40% by mass relative to the tablet mass. [7] The vascular embolic agent according to [6], wherein the dissolved mass is calculated by a test using a static Franz cell, and the solute in the dissolved mass is the solid particles dissolved from the tablet and passed through a filter paper, and the particle retention capacity of the filter paper is greater than 1 μm. [8] A vascular embolization kit comprising the vascular embolic agent according to any one of [1] to [7] and a contrast agent. [9] The vascular embolization kit according to [8], wherein the contrast agent is a non-ionic iodine-based contrast agent.

[10] A method for producing a vascular embolization agent, which comprises using solid particles of two or more amino acids with different solubilities as active ingredients, and adjusting the dissolution rate so that the solid particles dissolve in physiological saline at 37°C within 6 hours.

[0009] According to the present invention, it is possible to provide a vascular embolic agent having an embolization rate and dissolution rate equivalent to those of IPM / CS, a vascular embolization kit using the vascular embolic agent, and a method for producing the vascular embolic agent.

[0010] 1 is a diagram showing the results of measuring the change in dissolved mass over time of Tienam (registered trademark), glycine, glutamic acid, phenylalanine, or tyrosine in physiological saline at 37°C. 2 is a diagram showing the change in dissolved mass over time when glycine and phenylalanine are mixed. In the diagram, Gly represents glycine, and Phe represents phenylalanine. 3 is a diagram showing the change in dissolved mass over time when glycine and tyrosine are mixed. In the diagram, Gly represents glycine, and Tyr represents tyrosine.

[0011] Hereinafter, a mode for carrying out the present invention (hereinafter referred to as "the present embodiment") will be described in detail. The following present embodiment is an example for explaining the present invention, and is not intended to limit the present invention to the following content. The present invention can be modified in various ways without departing from the gist of the present invention.

[0012] In the present invention and this specification, the term "comprising" means that components other than the target component may be included. The term "consisting of" means that components other than the target component are not included. The term "consisting essentially of" means that components other than the target component are not included in a form that exerts a special function (such as a form that completely loses the effect of the invention). In this specification, when "comprising" is used, it includes both an embodiment "consisting of" and an embodiment "essentially consisting of."

[0013] <Vascular Embolic Agent> The vascular embolic agent of this embodiment contains solid particles of two or more amino acids with different solubilities as active ingredients. The solid particles dissolve in physiological saline at 37°C within 6 hours.

[0014] The vascular embolization agent of this embodiment has the above-mentioned constitution and therefore has embolization rate and dissolution rate equivalent to those of IPM / CS, as will be shown in the examples described later.

[0015] <Solid Particles> The solid particles used in the vascular embolization agent of this embodiment are solid particles of two or more types of amino acids with different solubilities.

[0016] The vascular embolic agent of this embodiment is highly safe in vivo because it contains solid particles of amino acids as its active ingredient. By using solid particles of two or more types of amino acids with different solubilities as its active ingredients, it is easy to adjust the dissolution rate of the entire vascular embolic agent within a desired range. Therefore, the vascular embolic agent of this embodiment has embolization and dissolution rates equivalent to those of IPM / CS, and is highly safe in vivo.

[0017] The two or more amino acids with different solubilities used in the vascular embolization agent of this embodiment preferably include one or more amino acids with a fast dissolution rate and one or more amino acids with a slow dissolution rate. By appropriately adjusting the blending ratio of the two, it is easy to adjust the dissolution rate of the entire particle to be equivalent to that of IPM / CS.

[0018] The two or more amino acids with different solubilities used in the vascular embolic agent of this embodiment are preferably one or more selected from the group consisting of glycine, arginine, serine, alanine, lysine, threonine, and cysteine, which have a solubility equal to or greater than that of alanine, and one or more selected from the group consisting of phenylalanine, asparagine, aspartic acid, glutamic acid, glutamine, histidine, methionine, valine, isoleucine, leucine, proline, tryptophan, and tyrosine, which have a solubility less than that of alanine. More preferably, one or more selected from the group consisting of glycine, alanine, and serine and one or more selected from the group consisting of phenylalanine, asparagine, glutamine, histidine, methionine, valine, leucine, proline, tryptophan, and tyrosine. Even more preferably, glycine and phenylalanine, or glycine and tyrosine.

[0019] In particular, the mass of glycine relative to the total mass of glycine and phenylalanine is preferably 40% by mass to 60% by mass, more preferably 42% by mass to 58% by mass, even more preferably 45% by mass to 55% by mass, and particularly preferably 47% by mass to 53% by mass, from the viewpoint of closer approximation to the dissolution rate of IPM / CS.

[0020] In particular, the mass of glycine relative to the total mass of glycine and tyrosine is preferably 85% by mass to 99% by mass, more preferably 86% by mass to 98% by mass, even more preferably 87% by mass to 97% by mass, and particularly preferably 88% by mass to 96% by mass, from the viewpoint of closer approximation to the dissolution rate of IPM / CS.

[0021] A specific example of IPM / CS is "Tienam (registered trademark) for intravenous infusion 0.5 g (trade name), manufactured by MSD Co., Ltd."

[0022] The amino acids used in the vascular embolization agent of this embodiment may be L-amino acids or D-amino acids, with L-amino acids being preferred.

[0023] The average particle size of the solid particles used in the vascular embolic agent of this embodiment is calculated from the particle size distribution by a laser diffraction / scattering method and is expressed as the average particle size, which is the diameter at which the volume-based integrated value is 50%. The average particle size of the solid particles is not particularly limited, but is preferably less than 100 μm. When the average particle size is less than 100 μm, it becomes possible to apply the agent to the therapeutic application to the terminal portion of blood vessels. Even if the average particle size is less than 100 μm, it is possible that blood vessels with a diameter of about 300 μm can be embolized by aggregation of the solid particles.

[0024] The solid particles used in the vascular embolic agent of this embodiment dissolve within 6 hours in physiological saline at 37°C. The short dissolution time of the solid particles allows for embolization of the target blood vessel while suppressing damage to blood vessels other than the target blood vessel. Dissolution within 4 hours is preferred, within 3 hours is more preferred, and within 1.5 hours is even more preferred. The lower limit of the dissolution rate of the solid particles used in the vascular embolic agent of this embodiment in physiological saline at 37°C is not particularly limited, as long as it is possible to embolize the target blood vessel for a time sufficient to cause ischemia in the target blood vessel. The lower limit is, for example, preferably 10 minutes or more, more preferably 30 minutes or more, and even more preferably 1 hour or more.

[0025] In the embolic agent of this embodiment, the solid particles are compressed into a cylindrical tablet having a diameter of 3 mm and a thickness of 0.7 mm to 1.5 mm, and the dissolution mass after 5 minutes in physiological saline at 37°C is preferably 15% to 40% by mass, more preferably 17% to 35% by mass, even more preferably 18% to 30% by mass, and particularly preferably 20% to 28% by mass, relative to the tablet mass. By having the dissolution mass within the above numerical range, it is possible to obtain a embolic agent having a dissolution rate closer to that of IPM / CS.

[0026] Solid particles with a dissolution rate equivalent to that of IPM / CS can be found by the following calculation formula, assuming that the dissolution process is diffusion-controlled: dC / dt is the dissolution rate, K is the apparent dissolution rate constant, S is the surface area of ​​the solid particle, Cs is the solubility of the solid particle in the solvent, and C is the concentration of the solid particle in the internal solution after time t has passed. The internal solution represents the layer of solution where the solid particles are not saturated: dC / dt = K S (Cs - C)

[0027] In the above calculation formula, the influence of the surface area S between solid particles can be eliminated by forming the solid particles into tablets with a constant surface area. Since K depends on the solvent, temperature, and stirring conditions, K can be made constant by keeping the solvent, temperature, and stirring conditions constant. Therefore, the above calculation formula can be used to find a formulation that will result in a dissolution rate equivalent to that of IPM / CS.

[0028] More specifically, it is preferable to use the dissolution mass of a tablet obtained by compressing solid particles into a cylindrical shape with a diameter of 3 mm and a thickness of 0.7 mm to 1.5 mm after 5 minutes in physiological saline at 37° C. as a standard, and to find a formulation that will give a dissolution mass equivalent to that of IPM / CS from the dissolution mass. The evaluation of the dissolution mass is based on the premise that the dissolution process is diffusion-controlled.

[0029] The method for molding the compressed tablets into a cylindrical shape is not particularly limited as long as it can be compressed into a cylindrical shape with a diameter of 3 mm and a thickness of 0.7 mm to 1.5 mm, but from the viewpoint of further improving measurement accuracy, it is preferable to perform compression molding at a molding pressure of 5 kN to 15 kN. As a machine for obtaining compressed tablets, for example, a compression molding machine can be used as shown in the examples described below.

[0030] From the viewpoint of higher measurement accuracy, it is preferable that the dissolved mass is calculated by a test using a static Franz cell. The solute in the dissolved mass calculated by the test is solid particles dissolved from the tablet that have passed through a filter paper, and the particle retention capacity of the filter paper is greater than 1 μm.

[0031] The dissolved mass of solid particles is evaluated, for example, in the following order: (1) The receptor tank of a Franz cell containing the rotor of a magnetic stirrer is filled with receptor liquid (physiological saline) and stirring is initiated. (2) Filter paper (particle retention capacity: greater than 1 μm) is placed in the joint of the Franz cell and the inside of the jacket of the Franz cell is maintained at 37°C. (3) The above tablet is placed in a donor tank filled with physiological saline and evaluation of the dissolved mass is initiated. (4) The receptor liquid is sampled over time and the dissolved mass of each receptor liquid is determined.

[0032] The filter paper used can be type 5C (for fine precipitation) as specified in JIS P3801 (Filter paper (for chemical analysis)). The top and bottom of the filter paper are continuously filled with physiological saline, and the tablet is always submerged in the physiological saline above the filter paper (donor tank).

[0033] The calculation of the dissolved mass is not particularly limited as long as it can calculate the dissolved mass of amino acids, and can be quantified using a known method. For example, as shown in the Examples below, quantification can be performed using a spectrophotometer. Alternatively, two or more amino acids can be separated and purified by liquid chromatography (LC) or gas chromatography (GC) and then quantified.

[0034] The type and composition ratio of amino acids in the embolic agent of this embodiment may be adjusted appropriately depending on the type and severity of pain. The embolic agent of this embodiment may contain various drugs, additives, and the like.

[0035] As the additive, various substances commonly used as additives for pharmaceuticals can be used as long as they do not impair the effects of the invention, such as sodium bicarbonate.

[0036] <Method for Producing Vascular Embolic Agent> The method for producing a vascular embolic agent of this embodiment includes a step of adjusting the dissolution rate of solid particles of two or more amino acids with different solubilities as active ingredients so that the solid particles dissolve within 6 hours in physiological saline at 37° C. Specifically, it is preferable to adjust the compounding ratio of one or more amino acids with a solubility equal to or greater than that of alanine and one or more amino acids with a solubility less than that of alanine so that the solid particles dissolve within 6 hours in physiological saline at 37° C.

[0037] The solid particles of two or more amino acids with different solubilities may be the same as those described above. In the method for producing a vascular embolic agent of this embodiment, the dissolution rate is adjusted so that the solid particles dissolve in physiological saline at 37°C within 4 hours, more preferably within 3 hours, even more preferably within 1.5 hours, and particularly preferably within 1 hour.

[0038] Other Steps The method for producing a vascular embolic agent of this embodiment can be produced using known methods for producing vascular embolic agents, except for the step of adjusting the dissolution rate. For example, the method may include steps such as sizing, mixing, drying, or granulation of solid particles of two or more amino acids with different solubilities. The sizing step is not particularly limited, but includes crushing sizing, oscillator sizing, etc., and known sizing machines can be used. The mixing step is not particularly limited, but includes stirring mixing, container rotary mixing, etc., and known mixers can be used. The drying step is not particularly limited, but includes box-type shelf drying, conveyor drying, fluidized bed drying, vacuum drying, stirring drying, airflow drying, spray drying, etc., and known dryers can be used. The granulation step is not particularly limited, but includes extrusion granulation, stirring granulation, fluidized bed granulation, slug granulation, dry granulation, etc., and known granulators can be used.

[0039] <Vascular Embolization Kit> The vascular embolization kit of this embodiment includes the above-mentioned vascular embolization agent and a contrast agent. The contrast agent is not particularly limited as long as it is one that is typically used in vascular embolization kits, and examples thereof include non-ionic iodine-based contrast agents.

[0040] <<Application Method>> The vascular embolization kit of this embodiment is applied by a known method of administering it into a blood vessel. Specifically, a microcatheter with a diameter of, for example, 0.1 mm to 2 mm is inserted into a target blood vessel, for example, from the groin or wrist, and the vascular embolization agent and contrast agent (vascular embolization kit) are administered. Alternatively, the vascular embolization agent and contrast agent (vascular embolization kit) of this embodiment can be administered by injection into the target blood vessel.

[0041] Other Embodiments One aspect of the present invention provides a method for treating a disease, comprising administering a therapeutically effective amount of the embolic agent to a patient in need of vascular embolization treatment. Diseases that can be treated by vascular embolization include hypervascular tumors, vascular malformations, aneurysms, hemorrhage, and chronic pain.

[0042] One aspect of the present invention provides use of the above-mentioned vascular embolization agent for producing a vascular embolization kit for therapeutic embolization of a blood vessel.

[0043] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0044] [Evaluation of Dissolution Rate] (Solid Particles) In this example, the solid particles of each amino acid (L-amino acid) used were glycine, L(-)-phenylalanine, L-glutamic acid, and L-tyrosine (special reagent grade) purchased from Fujifilm Wako Pure Chemical Industries, Ltd. In this example, "Tienam (registered trademark) for intravenous infusion 0.5 g (trade name) (hereinafter also referred to as "Tienam (registered trademark)"), manufactured by MSD K.K." was used as the IPM / CS.

[0045] (Tablets) In evaluating the dissolution rate of the solid particles used in this example, the solid particles were made into tablets with a constant surface area to eliminate the effect of the surface area of ​​the solid particles on the dissolution rate. Specifically, amino acid solid particles were dissolved in water at a specified mass ratio and freeze-dried. The dried product (15 mg) obtained by freeze-drying was compressed at a molding pressure of 5 kN to 15 kN using a compression molding machine (vacuum heating press IMC-181A (trade name), manufactured by Imoto Machinery Co., Ltd.) equipped with a mold having the desired diameter (diameter 3 mm) to obtain cylindrical tablets. When evaluating the dissolution rate of Tienam (registered trademark) or solid particles of one type of amino acid, tablets were obtained from each solid particle in the same manner as above.

[0046] (Static Franz Cell) In this example, a static Franz cell (effective diffusion membrane area: approximately 1.77 cm ２ The dissolution rate of each solid particle was evaluated using a Franz cell. The receptor tank (volume: approximately 9 mL) of a Franz cell containing a magnetic stirrer rotor was filled with receptor liquid (physiological saline). Filter paper (particle retention capacity: greater than 1 μm, No. 5C, 21 mmφ, manufactured by Kiriyama Seisakusho Co., Ltd.) was set in the joint of the Franz cell, and the inside of the jacket of the Franz cell was maintained at 37°C. The above tablet was placed in a donor tank (volume: approximately 2 mL) filled with physiological saline, and the evaluation of the dissolution rate was started.

[0047] (Dissolution Rate) The receptor solution was sampled over time, and the absorbance was measured using a spectrophotometer (DU730, manufactured by Beckman Coulter) to determine the change over time in the solute mass relative to the tablet mass in physiological saline at 37° C. The absorbance was measured at a wavelength of 298 nm when the solute was Tienam (registered trademark), 220 nm when the solute was glycine, 202 nm when the solute was glutamic acid, 257 nm when the solute was phenylalanine or a mixture of glycine and phenylalanine, and 275 nm when the solute was tyrosine or a mixture of glycine and tyrosine.

[0048] Reference Example 1: Evaluation of Solubility (Single Substance) The solubility of Tienam (registered trademark), glycine, glutamic acid, phenylalanine, or tyrosine in saline at 37°C was determined. Specifically, an excess amount of each solid particle was added to 2 mL to 4 mL of saline at 37°C and stirred in a 37°C incubator for 15 to 30 minutes. The stirred solution was then sampled and passed through a sample pretreatment filter (GL Chromatodisc 13N 0.45 μm, manufactured by GL Sciences). The mass of the solution after the filter was measured, along with the mass of the solid matter obtained by freeze-drying the solution after the filter. The solubility (g / 100 mL) of each solid particle is shown in Table 1.

[0049]

[0050] Reference Example 2: Evaluation of dissolution rate (single substance) The dissolved mass of Tienam (registered trademark), glycine, glutamic acid, phenylalanine, or tyrosine in physiological saline at 37° C. was evaluated over time. The results are shown in FIG.

[0051] As shown in Table 1 and Figure 1, it was confirmed that the dissolution rate of each solid particle was in almost the same order as the solubility.

[0052] Example 1: Evaluation of dissolution rate (glycine and phenylalanine) Glycine and phenylalanine were used as the two or more amino acids with different solubilities. Glycine and phenylalanine were mixed so that the mass of glycine relative to the total mass of glycine and phenylalanine was 0 mass%, 50 mass%, or 100 mass%, and the change in the mass dissolved in physiological saline at 37°C over time was evaluated. The results are shown in Figure 2. In Figure 2, Gly represents glycine and Phe represents phenylalanine.

[0053] Example 2: Evaluation of dissolution rate (glycine and tyrosine) Glycine and tyrosine were used as the two or more amino acids with different solubilities. Glycine and tyrosine were mixed so that the mass of glycine relative to the total mass of glycine and tyrosine was 0 mass%, 50 mass%, 70 mass%, 90 mass%, or 100 mass%, and the change in the mass dissolved in physiological saline at 37°C over time was evaluated. The results are shown in Figure 3. In Figure 3, Gly represents glycine and Tyr represents tyrosine.

[0054] As shown in Figures 2 and 3, it was revealed that by using solid particles of two types of amino acids with different solubilities as the active ingredient, the dissolution rate can be adjusted to the same level as that of IPM / CS.

[0055] According to the present invention, it is possible to provide a vascular embolic agent having an embolization rate and dissolution rate equivalent to those of IPM / CS, a method for producing said vascular embolic agent, and a vascular embolization kit using said vascular embolic agent.

Claims

1. A vascular embolization agent containing solid particles of two or more amino acids with different solubilities as active ingredients, said solid particles dissolving within 6 hours in physiological saline at 37°C.

2. The vascular embolization agent according to claim 1, wherein the amino acids are one or more selected from the group consisting of glycine, arginine, serine, alanine, lysine, threonine, and cysteine, and one or more selected from the group consisting of phenylalanine, asparagine, aspartic acid, glutamic acid, glutamine, histidine, methionine, valine, isoleucine, leucine, proline, tryptophan, and tyrosine.

3. The vascular embolization agent according to claim 1, wherein the amino acids are glycine and phenylalanine, or glycine and tyrosine.

4. The vascular embolization agent according to claim 3, wherein the mass of said glycine is 40% by mass to 60% by mass relative to the total mass of said glycine and phenylalanine.

5. The vascular embolization agent according to claim 3, wherein the mass of glycine relative to the total mass of glycine and tyrosine is 85% by mass to 99% by mass.

6. The vascular embolization agent according to claim 1, wherein the solid particles are compressed into a cylindrical tablet having a diameter of 3 mm and a thickness of 0.7 mm to 1.5 mm, and the dissolved mass of the tablet after 5 minutes in physiological saline at 37°C is 15% by mass to 40% by mass of the tablet mass.

7. The vascular embolization agent according to claim 6, wherein the dissolved mass is calculated by a test using a static Franz cell, the solutes in the dissolved mass are the solid particles dissolved from the tablet that have passed through a filter paper, and the particle retention capacity of the filter paper is greater than 1 μm.

8. A kit for vascular embolization comprising the vascular embolization agent according to claim 1 and a contrast agent.

9. The vascular embolization kit according to claim 8, wherein the contrast agent is a non-ionic iodine-based contrast agent.

10. A method for producing a vascular embolization agent, which uses solid particles of two or more amino acids with different solubilities as active ingredients, and includes a step of adjusting the dissolution rate so that the solid particles dissolve in physiological saline at 37°C within 6 hours.

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