JP2007146146A - Biodegradable particle and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide biodegradable particles of which material is smoothly decomposed after passing through a specific period and the decomposed components can be finally absorbed or discharged to the outside of a body, capable of being molded without being aggregated or agglomerated among particles, conveyed or injected, in a fine caliber tube of a catheter, needle or syringe of mainly medical or medicinal use or in blood vessel, having a smaller inner diameter than the particle size without causing clogging by their aggregation. <P>SOLUTION: The biodegradable particles are characterized by having ≤10 MPa compressive elasticity modulus under a water-saturated state. Preferably, the biodegradable particles are characterized by consisting of a water-insoluble polymer A having ≥1 and <50 MPa tensile elastic modulus of its film under the water-saturated state and a water-insoluble polymer B having ≥50 MPa tensile elastic modulus of its film under the water-saturated state. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to biodegradable microparticles conveyed through a tube having a small diameter smaller than the particle size of a catheter, needle, syringe, etc., which are mainly medical and medical devices. In particular, after being carried into the living body and demonstrating the function and finishing the role, it is decomposed in the living body after a specific period of time, and finally the decomposed component can be absorbed or discharged from the body. The present invention relates to biodegradable fine particles that can be used as a material that does not remain, and a method for producing the same.

  In the field of medicine, importance is attached to the safety of treatment and the concept of minimally invasive treatment that does not burden the patient. Along with this, technologies for designing and synthesizing safer materials and technologies for administering them into the body have been developed. One of them is a technique for treatment or drug administration through a narrow-bore tube. The narrow diameter of the tube eliminates unnecessary cutting of the patient's body, and the pain associated with the insertion of the tube into the body is greatly reduced. Catheter treatment is a prominent example. The other is technology related to biodegradable and absorbable materials that do not remain in the body. Sutures and orthopedic materials made of polylactic acid, polyglycolic acid, polycaprolactone, etc. are also used in clinical settings, and recently many research results on regenerative medicine using these materials have been reported. Polymer particles that are decomposed and absorbed in the body are also known mainly as drug carriers (see Patent Documents 1 and 2).

  In addition, by injecting an embolic material into a blood vessel prior to incision associated with an operation on an organ such as the liver, hemostasis can be reliably and rapidly stopped, and bleeding can be minimized. Moreover, as a technique and therapy using such embolization material, in addition to the use for preventing bleeding, it is used for arterial embolization to block nutrients for unresectable tumors by hemostasis, and further, anticancer agents and vascular embolization materials Chemoembolization therapy is known in which a high anticancer drug concentration in a tumor is maintained by administering a combination thereof. On the other hand, with the development of the catheter and its operation technique, appropriate carrier fine particles and embolic materials can be selectively and accurately delivered to the local position.

  As vascular embolization materials, gelatin sponge, polyvinyl alcohol, degradable starch particles (DSM), iodinated poppy oil, crosslinked collagen fibers, ethyl cellulose microcapsules, cyanoacrylate, stainless coils, and the like have been used so far. In particular, an embolic material made of polymer particles can be introduced into the body by being injected into the affected area with a microsyringe or the like through a microcatheter placed in a living body in a state of being dispersed in a contrast medium or the like. . Such an embolization material of polymer particles can reach an affected area located deep and can form an embolus.

However, carrier fine particles made of polymer particles and embolic materials have the following problems.
(1) Since the shape is irregular and the particle size distribution is wide, the function may not be exhibited at the target site.
(2) It may clog due to aggregation or increase in viscosity in the tube of a medical device such as a catheter, needle or syringe. In particular, clogging often occurs when particles smaller than the inner diameter of the catheter are passed.
(3) Since it aggregates or becomes highly viscous in normal blood vessels on the way to the affected area, it may not be possible to reach the target site.
(4) When used as an embolization material, the material is hard and does not fit to the cross-sectional shape of the blood vessel, so even if the blood flow can be reduced, it may not be completely embolized.
(5) Furthermore, as a biodegradable material, the degradation rate may vary greatly due to minute differences in the environment in which it is placed, such as where it is in contact with blood and where it is not.
(6) Since the particle size is not appropriate, it may not be placed at the target site.

  Conventionally, as a biodegradable polymer, polylactic acid (hereinafter referred to as PLA) or poly (lactic acid / glycolic acid) copolymer (hereinafter referred to as PLGA) particles (see Non-Patent Document 1), specific drugs There is disclosed a biodegradable material containing (see Patent Document 3), but this has a high hydrophobicity of the base polymer and has the above problems (2) to (5).

  On the other hand, as a block copolymer consisting of polyethylene glycol (hereinafter referred to as PEG) and PLA or PLGA, a drug is mixed with a base polymer having a structure such as PLA-PEG, PLA-PEG-PLA, or PLGA-PEG-PLGA. Application of the technique of sustained release to pharmaceutical and veterinary medicine is disclosed (see Patent Document 4). However, this is difficult to adjust the flexibility of the base polymer and the strength necessary for molding, and has any of the problems (1) to (5).

  Further, a vascular embolization material comprising a water-insoluble PEG copolymer has been disclosed (Patent Document 5). However, it is also difficult to adjust the flexibility of the base polymer and the strength required for molding, and there is a problem of any one of the above (1) to (5).

Particles made of a water-insoluble polymer such as a polyethylene glycol copolymer having a tensile modulus of film of 1500 MPa or less as a technique for improving clogging in a catheter tube when the biodegradable particles are conveyed by injection from a catheter. Is disclosed (Patent Document 6). However, the technique disclosed here is limited to a technique for improving the passage of a catheter having a particle size smaller than the inner diameter of the catheter tube as shown in the examples of the same document, and has a diameter larger than the inner diameter of the catheter tube. The molecular weight range or composition of the copolymer required to prevent clogging in the catheter tube by particles having a diameter larger than the inner diameter of the catheter tube has not been reached. Not found.
Japanese Patent No. 3242118 Japanese Patent No. 3428972 JP-A-5-969 Japanese Patent Publication No. 5-17245 JP 2004-167229 A JP 2004-313759 A Bastian P, Bartowski, et al., “Chemo-embolization of experimental river metastases”, European. Journal of Pharmaceuticals and Biopharmaceutics, 1998, Vol. 43, p243-254.

  The object of the present invention is to form without aggregation or consolidation between particles, and has an inner diameter smaller than the particle size of instruments such as catheters, needles, and syringes, which are mainly used for medical treatment. It can be transported and injected with the necessary strength without causing clogging and clogging in a small-diameter tube or blood vessel, and the material decomposes smoothly after a specified period of time, and finally the decomposition components are absorbed. It is to provide biodegradable particles that can be obtained or discharged out of the body.

1. A biodegradable particle characterized in that the compression elastic modulus of the particle in a saturated water-containing state is 10 MPa or less.
2. A water-insoluble polymer A having a tensile elastic modulus of a film of 1 MPa or more and less than 50 MPa in a saturated water-containing state and a water-insoluble polymer B having a tensile elastic modulus of a film of 50 MPa or more in a saturated water-containing state Degradable particles.
3. 3. The biodegradable particle as described in 2 above, wherein the ratio of the water-insoluble polymer B is 20% by weight or more.
4). Biodegradable particles obtained from a water-soluble polymer and a biodegradable polymer, wherein the weight ratio of the water-insoluble polymer C is 50% or more and the weight ratio of the water-soluble polymer is less than 50%. A biodegradable particle characterized by being blended with a water-insoluble polymer D.
5. 5. The biodegradable particle as described in 4 above, wherein the ratio of the water-insoluble polymer D is 20% by weight or more.
6). 6. The biodegradable particle according to any one of 2 to 5, wherein the compression elastic modulus of the particle in a saturated water-containing state is 10 MPa or less.
7). The biodegradable particle as described in any one of 4 to 6 above, wherein the water-soluble polymer is polyalkylene glycol or a derivative thereof.
8). 8. The biodegradable particle as described in any one of 1 to 7 above, which is coated with polyalkylene glycol or a derivative thereof.
9. 9. The biodegradable particle as described in 8 above, wherein the polyalkylene glycol has a weight average molecular weight of 1,000 or more and 40,000 or less.
10. 10. The biodegradable particle as described in 8 or 9 above, wherein the polyalkylene glycol is polyethylene glycol.
11. 11. The biodegradable particle according to any one of 1 to 10 above, wherein the particle is spherical.
12 12. The biodegradable particle according to any one of 2 to 11, wherein at least one of the water-insoluble polymers A to D is a copolymer in which a water-soluble polymer and a biodegradable polymer are bonded.
13. The biodegradable particle as described in any one of 4 to 12 above, wherein the biodegradable polymer contains an α-hydroxy acid unit.
14 14. The biodegradable particle as described in 13 above, wherein the α-hydroxy acid unit is a polylactic acid unit and / or a polyglycolic acid unit.
15. The biodegradable particle according to any one of 3 to 14, wherein the water-insoluble polymer has a weight average molecular weight of 1,000 to 100,000.
16. The ratio of residual weight and / or weight average molecular weight after 28 days of immersion in phosphate buffered saline at 37 ° C. is 80% or less of that before immersion, any of 1 to 15 above The biodegradable particles described.
17. 17. The biodegradable particle according to any one of 16 above, wherein the particle size is 5 to 2000 μm.
18. 18. The biodegradable particle according to any one of 1 to 17 above, which is used for medical treatment.
19. The biodegradable particle according to any one of 1 to 18 above, which is used as an indwelling device.
20. 20. The biodegradable particle as described in 19 above, which is used for embolization treatment.
21. The biodegradable particle according to any one of 18 to 20, wherein the particle size distribution is within ± 60% of the average particle size.
22. A particle is obtained by blending a water-insoluble polymer A having a tensile modulus of a film of 1 MPa or more and less than 50 MPa in a saturated water-containing state and a water-insoluble polymer B having a tensile modulus of a film of 50 MPa or more in a saturated water-containing state. A method for producing biodegradable particles characterized by
23. 23. The method for producing biodegradable particles as described in 22 above, wherein the blend ratio of the water-insoluble polymer B is 20% by weight or more.
24. 24. The method for producing biodegradable particles as described in 22 or 23 above, wherein the particles are formed into a spherical shape.
25. 25. The production method according to any one of the above 22 to 24, wherein the water-insoluble polymers A and B are copolymers in which a water-soluble polymer and a biodegradable polymer are bonded.
26. A method for producing biodegradable particles obtained from a water-insoluble polymer in which a water-soluble polymer and a biodegradable polymer are combined, wherein the water-insoluble polymer has a water-soluble polymer weight ratio of 50% or more. A method for producing biodegradable particles, which is a blend of C and a water-insoluble polymer D having a water-soluble polymer weight ratio of less than 50%.
27. 27. The method according to any one of 25 or 26, wherein the water-soluble polymer is polyalkylene glycol or a derivative thereof.
28. 28. The production method as described in 27 above, wherein the polyalkylene glycol is polyethylene glycol.
29. 29. The method according to 27 or 28, wherein the polyalkylene glycol has a weight average molecular weight of 1,000 or more and 40,000 or less.
30. 30. The production method according to any of 25 to 29, wherein the biodegradable polymer contains an α-hydroxy acid unit.
31. 31. The biodegradable particle as described in 30 above, wherein the α-hydroxy acid unit is a polylactic acid unit and / or a polyglycolic acid unit.
32. 32. The method according to any one of 22 to 31, wherein the water-insoluble polymer has a weight average molecular weight of 1,000 to 100,000.

  The biodegradable particles of the present invention can be formed without agglomerating or consolidating between the particles. Particularly, the inner diameter smaller than the particle size of instruments such as catheters, needles, and syringes that are mainly used for medical and medical purposes. Can reach the target site without causing clogging in the tube or in the blood vessel and maintaining the required strength, and can be smoothly performed in vivo after a specific period regardless of the placement site or placement environment. And eventually the decomposition components can be absorbed or discharged out of the body.

  The biodegradable particles in the present invention are particles that are decomposed by chemical decomposition represented by hydrolysis or by enzymes produced by cells or microorganisms. Those mainly hydrolyzed are preferred. The raw material of the biodegradable particles used is not particularly limited, and may be any of natural polymers and artificially synthesized polymers, such as polyesters, polyethers, polyanhydrides, polypeptides, Poly (α-cyanoacrylate), polyacrylamide, poly (orthoester), polyphosphazene, polyamino acid, biodegradable polyurethane, polycarbonate, polyiminocarbonate, nucleic acid, polysaccharide, etc. Specific representative examples are gelatin , Chitin, chitosan, dextran, gum arabic, alginic acid, starch, polylactic acid (hereinafter referred to as PLA), polyglycolic acid (hereinafter referred to as PGA), polylactic acid glycolic acid copolymer (hereinafter referred to as PLGA), Hydroxy-terminated poly (ε-caprolactone) -polyether, poly Examples thereof include caprolactone, n-butylcyanoacrylic acid, and a copolymer comprising the above polymer.

  The biodegradable particle of the present invention has elasticity so that it can easily pass through a tube having a small diameter smaller than the particle size, and has a strength required in a catheter tube, a blood vessel and the like. Since a material that can be maintained is preferable, the compression elastic modulus in a saturated water-containing state is 10 MPa or less, preferably 0.5 MPa or more, 10 MPa or less, more preferably 5 MPa or less, and more preferably 3 MPa or less. More preferably. The saturated water content here means a state in which the water content of the material immersed in pure water at room temperature is constant. Here, the constant water content means that the change in weight of a certain material is within 3% even after several hours. A material having a compression modulus exceeding 10 MPa in a saturated water-containing state is not suitable because it is hard as a material to be administered and used with a microcatheter having a tube having an inner diameter smaller than the particle size of biodegradable particles.

  The elastic property can be evaluated as follows, for example.

[Measurement condition]
Compression tester: MCT-W500; manufactured by Shimadzu Corporation (or as long as the same results can be obtained under the same conditions, there is no problem)
Test room temperature: 25 ° C
Test room humidity: 50%
Upper pressure indenter: Flat type φ500μm
Load speed: 4.462 mN / sec
With respect to the stress-strain curve obtained by this method, the compression modulus can be obtained by the following equation.
Compression modulus (unit: MPa) = (δ2−δ1) / (ε2−ε1)
Here, strain ε1 = 0.0005, strain ε2 = 0.005. δ1 and δ2 are compressive stresses corresponding to ε1 and ε2 that are uniquely determined from the stress-strain curve.

  In the present invention, it is preferable to blend at least two types of water-insoluble polymers having different tensile elastic moduli in order to develop a soft elasticity that can easily pass through a small-diameter tube. Specifically, the water-insoluble polymer constituting the particles has a film-forming ability, and one polymer (polymer A) forming the water-insoluble polymer has a tensile elastic modulus of 1 MPa or more in a saturated water-containing state. The other polymer (polymer B) is 50 MPa or more and preferably 400 MPa or less. Furthermore, in order to maintain the required strength, the ratio of the polymer B is most preferably 20% by weight or more. The elastic modulus of particles produced by such a blend is not obtained by controlling the composition of a single polymer.

  The tensile modulus of the film in the present invention is one of the tensile properties of the film, but the tensile property of the film in the saturated water-containing state in the present invention is a film obtained from a water-insoluble polymer having film-forming ability. It refers to characteristic values such as elastic modulus and elongation obtained by measurement after immersion in pure water at room temperature until the water content becomes constant. Here, the constant water content means that the change in weight of a certain material is within 3% even after several hours.

  The tensile properties of the film can be evaluated, for example, as follows, and any evaluation method can be used as long as the same result can be obtained. The film forming method includes a cast method, a bar coater method, and the like. The tensile modulus in the present invention means a value measured by a film formed by a cast method.

[Measurement condition]
Tensile tester: RTM-100 type; manufactured by Orientec Co. (or no problem as long as the same results can be obtained under the same conditions)
Test room temperature: 25 ° C
Test room humidity: 50%
Specimen shape: Strip type (80mm x 7.5mm)
Test piece thickness: 30 μm ± 10 μm
Distance between chucks: 20mm
Test speed: 10 mm / min In addition to the above-described at least two kinds of polymers having different tensile elastic moduli, other components described later, that is, an oily contrast agent, a medicinal component, and the like are added to the biodegradable particles of the present invention. Also good.

  The shape of the biodegradable particle of the present invention is not particularly limited, but it is preferable to keep the particle shape at 37 ° C., and more preferably a spherical particle, particularly considering pharmaceutical use for the human body. . The term “spherical particle” as used herein means that the ratio of the maximum vertical length to the maximum length of the inner diameter of the circle when the particle is observed as a circle from any one direction is 0.5 or more and 1.0 or less, preferably 0. It means particles that fall within the range of 0.8 or more and 1.0 or less, and includes shapes such as rugby ball ellipsoids and spheroids as well as true spherical shapes. In addition, when the particles of the present invention do not maintain a particle shape such as a liquid or gel at 37 ° C., there is a possibility that the particles cannot be placed at the target site due to low strength. On the other hand, if the particles have a spherical shape, the in-vivo indwelling and the intended function can be more effectively exhibited.

  Particle granulation methods include tumbling granulation method, fluidized bed granulation method, spray bed granulation method, stirring granulation method, crushing granulation method, compression granulation method, extrusion granulation method, droplet solidification A known method such as a granulation method can be employed. For example, in the droplet solidification granulation method, a water-insoluble polymer is dissolved in dichloromethane, chloroform, ethyl acetate or isopropyl ether and dispersed in an aqueous phase containing a surfactant, a protective colloid agent, etc. / Water type (hereinafter referred to as O / W type) or water / oil / water type (hereinafter referred to as W / O / W type) in-liquid drying method or a method similar thereto, spray drying method, etc. It can be manufactured by making it into a shape. The surfactant and protective colloid used here are not particularly limited as long as they can form a stable O / W emulsion. For example, anionic surfactants (sodium oleate, sodium stearate, sodium lauryl sulfate) Etc.), nonionic surfactants (polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, etc.), polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose, lecithin, gelatin and the like. Among these, one type or a plurality may be used in combination. In particular, polyvinyl alcohol, carboxymethyl cellulose, and gelatin are preferable. The concentration of the aqueous solution is selected from 0.01 to 80% by weight, more preferably 0.05 to 60% by weight, and the particle shape and / or particle size can be adjusted by adjusting this concentration. . Further, the particle shape or particle size can be easily adjusted by adjusting the polymer concentration of the water-insoluble polymer solution. The particles produced by the above production method are generally spherical particles, but contain particles of various particle sizes. In order to obtain particles having a target particle size and a target particle size distribution, a plurality of sieves can be used. When a plurality of sieves are stacked in order from the finest and the liquid prepared by dispersing the particles prepared by the above manufacturing method is put into the coarsest uppermost sieve, the particles are placed on a sieve with a mesh size smaller than the particle size. Therefore, the particles can be divided according to particle size. The mesh size of the sieve is not particularly limited, and may be appropriately selected according to the target particle size and particle size distribution.

  The biodegradable particles of the present invention preferably have a particle size of 5 to 2,000 μm, more preferably 10 to 1,500 μm. When using biodegradable particles as carrier fine particles, this range is preferable because it can be placed in the body smoothly via a catheter, needle, syringe, or the like and can function at a target site. Moreover, when using biodegradable particle | grains for embolization use, since the target site | part can be effectively embolized when it is this range, it is preferable. Further, when used in such applications, the particle size distribution is more preferably ± 60% or less of the average particle size, and more preferably ± 50% or less of the average particle size.

  In the present invention, the particle size, average particle size, and particle size distribution refer to those in pure water or physiological saline at 25 ° C. The particle size and particle size distribution of the particles of the present invention can be measured by various commercially available measuring devices, particularly those by the particle size distribution measuring device “Microtrack Series” manufactured by Leeds & Northrup Co., Ltd. Since measurement can be performed in physiological saline, it is preferable in that it can be measured in a state close to blood vessels or internal environment. Or if it is based on the apparatus which can obtain the result equivalent to this, there is no problem. The average particle diameter is calculated from the volume average value, and is displayed as an “MV” value in the “Microtrack Series” regardless of the sphericity of the particles.

  The water-insoluble polymer according to the present invention is preferably composed of a copolymer in which a water-soluble polymer and a biodegradable polymer are chemically bonded. The water-soluble polymer as used herein refers to a polymer that dissolves all of the added amount to give a uniform solution when the polymer is added to water at a saturation concentration or less under normal pressure. The time and temperature required for dissolving the polymer are not particularly limited. A water-insoluble polymer refers to a polymer that deviates from the definition of the water-soluble polymer. By controlling the ratio of the water-soluble polymer and the biodegradable polymer in such a copolymer, the water-insoluble polymer A and the water-insoluble polymer B described above can be prepared respectively, and by blending these, the biodegradability according to the present invention can be achieved. Particles can be obtained. The specific ratio is not particularly limited, but the water-insoluble polymer C in which the weight ratio of the water-soluble polymer in the water-insoluble polymer is 50% or more and the water-insoluble copolymer in which the weight ratio is less than 50%. It is preferable to blend with D. Furthermore, in order to maintain a required strength, it is most preferable that the ratio of the polymer D is 20% by weight or more.

  Moreover, as this water-soluble polymer, what uses polyalkylene glycol is preferable. The water-insoluble copolymer using the water-soluble polymer, that is, the water-insoluble polyalkylene glycol copolymer is a block copolymer containing polyalkylene glycol or a derivative thereof as one component. It may be water insolubilized by physically interacting with polyalkylene glycol or a derivative thereof. Examples of the polyalkylene glycol include PEG and polypropylene glycol, and most preferred is PEG which has biocompatibility and has a proven record in medical and medical applications. In particular, it is preferably composed of a water-insoluble PEG copolymer in which PEG or a PEG derivative and a biodegradable polymer are chemically bonded. Although not particularly limited, the biodegradable polymer is chemically bonded to both ends or one end of PEG. Coated copolymers or copolymers in which PEG and biodegradable polymer are alternately bonded are preferably used.

  Here, the biodegradable polymer refers to a polymer that is degraded by chemical degradation represented by hydrolysis or by enzymes produced by cells or microorganisms. The type of the biodegradable polymer is not particularly limited, and polyesters, polysaccharides, polypeptides and the like are preferable, but those containing an α-hydroxy acid unit are most preferable. Examples of those containing an α-hydroxy acid unit include polylactic acid and polyglycolic acid. The raw material of such a biodegradable polymer that has a property of chemically binding to PEG or a PEG derivative is not particularly limited, but lactic acid, glycolic acid, 2-hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxycaproic acid, 2-hydroxycapric acid, lactide, glycolide, malic acid and the like can be mentioned, and it is preferable to contain any one or more of these, and further 2 It is more preferable to use a combination of two or more types to form a copolymer, and a combination of lactic acid (or lactide) and glycolic acid (or glycolide) is particularly preferable. In this case, the weight ratio of lactic acid to glycolic acid is preferably 100: 0 to 30:70. In addition, among the above, in the case of a compound having optical activity in the molecule such as lactic acid or lactide, any of D-form, L-form, D, L-form, and a mixture of D-form and L-form may be used.

  The biodegradable particles of the present invention contain a water-insoluble copolymer having a weight average molecular weight of 1,000 to 100,000, preferably 2,000 to 90,000, for example, a water-insoluble polyalkylene glycol-based copolymer, in the core part. Preferably it is. If the weight average molecular weight is less than 1,000, it may become a gel and adhere to the surface of the catheter or needle tube, and may not reach the target site, while the weight average molecular weight exceeds 100,000. In some cases, the time required for the particles to decompose in vivo becomes too long.

  The polyalkylene glycol or derivative thereof preferably has a weight average molecular weight of 200 to 40,000. If it is less than 200, the polyalkylene glycol copolymer has low hydrophilicity, and uniform biodegradability may not be obtained. On the other hand, when it is larger than 40,000, polyalkylene glycol produced from a copolymer decomposed in vivo may be difficult to be discharged out of the body. The structure of the polyalkylene glycol derivative is not particularly limited, and a structure including a multi-arm polyalkylene glycol derivative can be preferably used. The weight ratio of the polyalkylene glycol or its derivative to the biodegradable polymer is not particularly limited, but can be more preferably used in the range of 80:20 to 5:95.

  Hereinafter, as a representative example of the method for producing a water-insoluble polymer according to the present invention, a method for producing a water-insoluble polyalkylene glycol copolymer comprising a polyalkylene glycol or a polyalkylene glycol derivative and a biodegradable polymer will be exemplified. A method for synthesizing the water-insoluble polyalkylene glycol copolymer is not particularly limited, and examples thereof include melt polymerization and ring-opening polymerization. For example, a water-soluble polymer (polyalkylene glycol or polyalkylene glycol derivative) having a predetermined average molecular weight as a raw material and a biodegradable polymer raw material (monomer, etc.) in a polymerization tank equipped with a stirring blade in a dry air or dry nitrogen stream ) And the mixture is heated with stirring with the catalyst to obtain a water-insoluble copolymer. The catalyst to be used is not particularly limited as long as it is a catalyst used for normal polyester polymerization. For example, tin halides such as tin chloride, organic acid tins such as tin 2-ethylhexanoate, diethyl zinc, zinc lactate, iron lactate, dimethylaluminum, calcium hydride, organic alkali metal compounds such as butyl lithium and t-butoxy potassium And metal alkoxides such as metal porphyrin complexes and diethylaluminum methoxide. In addition, the biodegradable polymer raw material, polyalkylene glycol or polyalkylene glycol derivative and catalyst are stirred, mixed, and degassed in a molten state using a twin-screw kneading extruder with a vent or an apparatus having a similar stirring and feeding function. However, the polymerization can also be carried out by taking out the continuously produced water-insoluble polymer. Furthermore, after the produced water-insoluble polymer is dissolved in a good solvent and a poor solvent is added dropwise to this to form a precipitate, the temperature of the white turbid matter is changed to dissolve the precipitate again, and then slowly to the original temperature again. Sorting accuracy can also be improved by a re-precipitation operation of returning and regenerating the precipitate. Examples of the good solvent used in the fractional precipitation method include tetrahydrofuran, halogen-based organic solvents (dichloromethane, chloroform), and mixed solvents thereof. As the poor solvent used in the fractional precipitation method, an alcohol-based or hydrocarbon-based organic solvent is preferable. Various types of water-insoluble polyalkylene glycol copolymers can be produced by appropriately selecting the types of biodegradable polymer and water-soluble polymer, and further their molecular weight.

  In the above, the water-insoluble polyalkylene glycol-based copolymer has been exemplified, but a water-insoluble polymer can be similarly obtained by using polyhydroxymethyl methacrylate, acrylic acid, methacrylic acid, polyvinyl pyrrolidone or the like instead of polyalkylene glycol. it can.

  The biodegradable particles in the present invention may have a particle surface coated with a hydrophilic synthetic polymer. The hydrophilic synthetic polymer means a synthetic polymer that swells in water or is water-soluble, and examples thereof include polyalkylene glycols such as polyethylene glycol and polypropylene glycol, polyhydroxymethyl methacrylate, acrylic acid, methacrylic acid, and polyvinylpyrrolidone. In the present invention, polyalkylene glycol is preferable because it can be molded without aggregation and consolidation between particles. In particular, polyethylene glycol is most preferable because it has clinical results and has high biocompatibility. One aspect of the coating is a state in which the hydrophilic synthetic polymer is attached or adsorbed to such an extent that the particle surface is surface modified. It is not particularly limited, and is preferable regardless of the state in which the particles are included in the polyalkylene glycol or the state in which the polyalkylene glycol is partially attached or adsorbed. However, in order to more reliably impart lubricity, it is preferable that the hydrophilic synthetic polymer is attached or adsorbed on 30% or more, more preferably 40% or more of the surface area of the particle surface.

Since the biodegradable particle of the present invention is desirably a material that decomposes in vivo after a specific period of time and a decomposition component is absorbed or discharged from the body, a 37 ° C. phosphate buffered saline (hereinafter, referred to as a biodegradable particle) (Abbreviated as PBS) It is preferable that the residual weight after immersion for 28 days is 80% or less before immersion. That is, since the molecular weight of biodegradable particles is reduced by decomposition and is easily dissolved in PBS at 37 ° C., it is possible to evaluate biodegradability using such an index. In addition, the weight said here means the weight of the particle | grains in a dry state. Furthermore, the residual weight is preferably 70% or less, and more preferably 60% or less. The weight measurement method after 28 days of PBS immersion is not particularly limited, but can be measured, for example, by the following method.
(Weight measurement method after 28 days in PBS)
20 mg (weight in the dry state) of the particles was precisely weighed, placed in a sterile round bottom 10 ml Spitz tube manufactured by Eiken Equipment Co., Ltd., and diluted 10 times with pure water (Nacalai Tesque, Inc., 10 times concentrated pH 7) .4, Code No. 27575-31) is injected. This was stirred in a constant temperature bath “Laboster LC-110” (manufactured by Tabai Espec Co., Ltd.) set at 37 ° C. by “Tube Rotator TR-350” (manufactured by Inai Seieido Co., Ltd.) at 100 rpm Incubate while. The incubated solution is centrifuged at 3000 rpm every 7 days, and the supernatant is separated and replaced with fresh PBS.

The particles after 28 days of PBS immersion are centrifuged at 3000 rpm, the supernatant is removed, and further washed with 10 ml of pure water. Centrifugation is again performed at 3000 rpm to remove pure water, vacuum drying is performed until the particle weight becomes constant, and the weight of the obtained particles is precisely weighed. Here, the constant particle weight means a state in which the weight change is within 5% even after several hours. The remaining weight ratio (W (%)) is calculated from the weight before PBS immersion (W ₀ (g)) and the weight after 28 days immersion (W ₁ (g)): W (%) = W ₁ / W ₀ × 100 can be calculated.

  The biodegradable particles of the present invention preferably have a characteristic that the weight average molecular weight after 28 days of PBS immersion at 37 ° C. is 80% or less before immersion. Furthermore, the weight average molecular weight is preferably 70% or less, and more preferably 60% or less. Particles that are no longer necessary after use because they have a characteristic that the weight average molecular weight after being immersed in PBS at 37 ° C. is 80% or less after 80 days so that the molecular weight of the particle material can be reduced, dissolved and crushed smoothly in the body. The volume occupied in the body is reduced, and the influence on the human body is reduced.

Although the measuring method of molecular weight is not specifically limited, For example, it can measure with the following method.
(Measurement method of weight average molecular weight)
The precisely weighed 10 mg of particles are dissolved in 2 ml of chloroform and filtered through a gel permeation chromatography (hereinafter abbreviated as GPC) filter “Micless LG13” (MILLIPORE SLLGH13NL). The filtrate was measured under the conditions of two GPC columns (Tosoh TSK-gel-GMH _HR- M), a column temperature of 35 ° C., a mobile phase of chloroform of 1 ml / min, and a sample injection amount of 100 μl, and a differential refractometer. (Detected by Tosoh RI-8010). The column calibration is performed using Tosoh standard polystyrene immediately before the measurement.

  The average molecular weight can be calculated using a calibration curve obtained from the relationship between the molecular weight of standard polystyrene and the column elution time using a workstation for data analysis (“Class-Vp” manufactured by Shimadzu Corporation). .

The ratio (M (%)) of the weight average molecular weight after the PBS immersion for 28 days before the PBS immersion is calculated from the weight average molecular weight (M ₀ ) before the PBS immersion and the weight average molecular weight (M ₁ ) after the 28 day immersion. %) = M ₁ / M ₀ × 100.

  The biodegradable particles of the present invention satisfy both the requirement that the residual weight after 28 days of PBS immersion is 80% or less before immersion, and the requirement that the weight average molecular weight after 28 days of PBS immersion is 80% or less before immersion. Is more preferable. The method for adjusting the biodegradation rate is not particularly limited, but the molecular weight of the biodegradable polymer in the copolymer is adjusted, that is, the molecular weight of the biodegradable polymer chemically bonded using, for example, a multi-arm PEG derivative is adjusted. By adjusting the crystallinity of the biodegradable polymer in the copolymer, for example, by using PLGA as the biodegradable polymer, the particle biodegradation rate can be adjusted more preferably. It is also preferable that the core portion of the biodegradable particle has an internal dispersion type composite structure or a coating type composite structure. Another water-insoluble polymer having a different decomposition rate is internally dispersed in the water-insoluble polymer, or these are made into a multilayer structure. For example, a water-insoluble polymer having a PLA-PEG-PLA structure has a PLGA-PEG-PLGA structure. By internally dispersing the water-insoluble polymer, the biodegradation rate of the biodegradable particles can be adjusted.

  The use of the biodegradable particle of the present invention is not particularly limited, but it is preferably used as a device for indwelling in the body, particularly in medical and medical applications using a catheter or needle.

  A device here means an apparatus having some function related to treatment, diagnosis, or prevention of a disease. The size, shape, material, structure, etc. of the device are not particularly limited. For example, a vascular embolic material, a drug delivery system that gradually releases a drug, and the like can be mentioned.

  The biodegradable particles of the present invention can be used as they are, or can be used after being dispersed in a suitable contrast agent or dispersion medium at the time of use. The contrast agent is preferably water-soluble, a known one can be used, and may be either ionic or nonionic. Specifically, “Iopamiron” (manufactured by Schering), “Hexabrix” (Eiken Chemical), “Omni Park” (manufactured by Daiichi Pharmaceutical), “Uroglafin” (manufactured by Schering), “Iomeron” (manufactured by Eisai) ) And the like. In this case, the particles and the contrast agent can be mixed before use and then injected into a predetermined site. It is more preferable that the water content of the particles is high because a part of the contrast agent is impregnated and held inside the particles together with water, and the contrast is efficiently expressed. As a dispersion medium, a dispersant (for example, polyoxysorbitan fatty acid ester, carboxymethylcellulose, etc.), a preservative (for example, methylparaben, propylparaben, etc.), an isotonic agent (for example, sodium chloride, mannitol, glucose, etc.) for injection Examples include those dissolved in distilled water, or vegetable oils such as sesame oil and corn oil. When the dispersed particles are used in a catheter, administration is performed while monitoring the position of the contrast agent by fluoroscopy from an appropriate artery to a tumor-controlling artery via a catheter whose tip is guided to the vicinity of a desired location in the body.

  In addition, preservatives, stabilizers, tonicity agents, solubilizers, dispersants, excipients and the like used in ordinary injections may be added to the biodegradable particles.

  The biodegradable particles of the present invention may be used in combination with iodinated poppy oil (lipiodol / ultrafluid), which is an oily contrast agent. In addition, iodinated poppy oil and an anticancer agent (e.g., Smanx, neocarinostatin, mitomycin C, adreamycin, irinotecan hydrochloride, fluorouracil, epirubicin hydrochloride, cisplatin, paclitaxel, leucovorin calcium, vinblastine, altretamine, bleomycin, doxorubicin hydrochloride, picibanil, Krestin, lentinan, cyclophosphamide, thiotepa, tegafur, vinblastine sulfate, pirarubicin hydrochloride) and the like may be used in combination.

  The biodegradable particles of the present invention can achieve the object of the present invention even without containing a medicinal component, but it is also preferable to contain a medicinal component for the purpose of imparting further effects. The medicinal component is not particularly limited as long as the medicinal effect is known, but the above-mentioned anticancer agent, angiogenesis inhibitor, steroid hormone agent, liver disease drug, gout treatment drug, diabetes drug, cardiovascular drug , Hyperlipidemic drugs, bronchodilators, antiallergic drugs, drugs for digestive organs, antipsychotics, chemotherapeutic agents, antioxidants, peptide drugs, protein drugs (for example, interferon) and the like.

  The biodegradable particles of the present invention can be used for various applications, but are most preferably used in the fields of medicine and medicine because of high safety that they are biodegraded and do not remain in the body. Among medical and medical uses, it is preferable to use it as a carrier that carries drugs, cells, and the like into the living body. Further, it is most preferably used for so-called embolization treatment in which a tumor blood vessel is occluded and the tumor is attacked.

Hereinafter, the present invention will be described in more detail by showing the results of experiments conducted on particles through the catheter in the examples. However, the scope of the present invention is not limited to these examples. Hereinafter, the measuring method in an Example is shown.
(Average particle size, particle size distribution)
Using a particle size distribution measuring device “Microtrack Series” manufactured by Leeds & Northrup Co., Ltd., the measurement was performed at 25 ° C. in physiological saline. The average particle diameter is calculated from the volume average value, and is displayed as an “MV” value in the “Microtrack Series” regardless of the sphericity of the particles.
(Compressive modulus)
Evaluation was performed under the following conditions using MCT-W500; manufactured by Shimadzu Corporation as a compression tester.
Test room temperature: 25 ° C
Test room humidity: 50%
Upper pressure indenter: Flat type φ500μm
Load speed: 4.462 mN / sec
The compression elastic modulus was calculated | required using the following formula | equation with respect to the stress-strain curve obtained by this method.
Compression modulus (unit: MPa) = (δ2−δ1) / (ε2−ε1)
Here, strain ε1 = 0.0005, strain ε2 = 0.005, δ1, δ2 are compressive stresses corresponding to ε1, ε2, which are uniquely determined from the stress-strain curve.
(Tensile modulus of film)
The film formed by the casting method was immersed in pure water at room temperature for 3 hours to obtain a saturated water-containing state, and then, using a RTM-100 type tensile tester manufactured by Orientec Co., Ltd. under the following conditions, tensile elasticity Rate was evaluated.
Test room temperature: 25 ° C
Test room humidity: 50%
Specimen shape: Strip type (80mm x 7.5mm)
Test piece thickness: 30 μm ± 10 μm
Distance between chucks: 20mm
Test speed: 10 mm / min (weight measuring method after 28 days of PBS immersion)
20 mg (weight in the dry state) of the particles was precisely weighed, placed in a sterile round bottom 10 ml Spitz tube manufactured by Eiken Equipment Co., Ltd., and diluted 10 times with pure water (Nacalai Tesque, Inc., 10 times concentrated pH 7) .4, Code No. 27575-31) was injected. This was stirred in a constant temperature bath “Laboster LC-110” (manufactured by Tabai Espec Co., Ltd.) set at 37 ° C. by “Tube Rotator TR-350” (manufactured by Inai Seieido Co., Ltd.) at 100 rpm. However, it was incubated for 28 days. The incubated solution was centrifuged at 3000 rpm every 7 days, and the supernatant was separated and replaced with fresh PBS.

After centrifuging the particles after 28 days in PBS at 3000 rpm, the supernatant was removed, washed with 10 ml of pure water, and centrifuged again at 3000 rpm to remove the pure water. Then, vacuum drying was performed until the particle weight became constant, and the weight of the obtained particles was precisely weighed. Here, the constant particle weight means a state in which the weight change is within 5% even after several hours. The remaining weight ratio (W (%)) is calculated from the weight before PBS immersion (W ₀ (g)) and the weight after 28 days immersion (W ₁ (g)): W (%) = W ₁ / W ₀ × 100.
(Measurement method of weight average molecular weight)
The precisely weighed 10 mg of particles were dissolved in 2 ml of chloroform and filtered through a gel permeation chromatography (hereinafter abbreviated as GPC) filter “Micless LG13” (MILLIPORE SLLGH13NL). The filtrate was analyzed under the conditions of two GPC columns (Tosoh TSK-gel-GMH _HR- M), a column temperature of 35 ° C., a mobile phase of chloroform of 1 ml / min, and a sample injection amount of 100 μl, and a differential refractometer. (Measured with Tosoh RI-8010). The column was calibrated using Tosoh standard polystyrene immediately before the measurement.

The average molecular weight was calculated using a calibration curve obtained from the relationship between the molecular weight of standard polystyrene and the column elution time using a workstation for data analysis (“Class-Vp” manufactured by Shimadzu Corporation).
(Catheter passage)
The particle dispersion obtained in each example and comparative example was injected from a syringe into a catheter. As the catheter, FasTracker-10 Infusion Catheter (both catheter length 1,550 mm, tip inner diameter 380 μm) manufactured by Boston Scientific was used.

<Production Example 1>
Under a nitrogen stream, 4.96 g of L-lactide (manufactured by Pulac Bio-Chem), 1.66 g of glycolide (manufactured by Boehringer Ingelheim) and dehydrated PEG (SUNBRIGHT DKH-20T manufactured by Nippon Oil & Fats Industries) 2 .88 g was mixed and dissolved and mixed at 150 ° C., and then 460 μL of a toluene solution in which tin dioctanoate (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved to a concentration of 0.1 mol / L was added and reacted. A water-insoluble polymer having a PLGA-PEG-PLGA structure and a water-soluble polymer weight ratio of 30.3% was obtained. This water-insoluble polymer was dissolved in chloroform and dropped into a large excess of diethyl ether / acetone mixed solution to obtain a white precipitate. The weight average molecular weight by the above-mentioned GPC method was 22,000.

The obtained purified polymer was dissolved in dichloromethane to a concentration of 30% by weight. The solution was poured into a petri dish having an inner diameter of 85 mm and left at 20 ° C. for one day, and the film was formed by evaporating dichloromethane to obtain a film having a thickness of 20 μm. When this was immersed in pure water at room temperature, the water content became constant in about 3 hours. When a tensile test in a saturated wet state was performed, the tensile elastic modulus was 57 MPa.
<Production Example 2>
Under a nitrogen stream, 1.92 g of L-lactide (manufactured by Pyrac Biochem), 0.96 g of glycolide (manufactured by Boehringer Ingelheim) and dehydrated PEG (SUNBRIGHT MEH-20T, manufactured by NOF Corporation) 2 .88 g was mixed, dissolved, mixed and reacted in the same manner as in Production Example 1 to obtain a water-insoluble polymer having a PLGA-PEG structure and a water-soluble polymer weight ratio of 50.0%. A white precipitate was obtained from this water-insoluble polymer by the same method as in Production Example 1. The weight average molecular weight by the above-mentioned GPC method was 14,000.

  Using the obtained purified polymer, a film was formed in the same manner as in Production Example 1 to obtain a film having a thickness of 20 μm. When this was immersed in pure water at room temperature, the weight became constant in about 3 hours. When a tensile test was performed in a wet state, the tensile elastic modulus was 2.1 MPa.

<Example 1>
The water-insoluble polymer obtained in Production Example 1 and the water-insoluble copolymer obtained in Production Example 2 were mixed at a weight ratio of 70:30 and dissolved in dichloromethane. This was dropped into a 1% by weight polyvinyl alcohol (Aldrich, Cat. No. 360627) aqueous solution and dried in an O / W solution to obtain a spherical particle dispersion.

  Subsequently, after wet classification with a nylon sieve (cut-off particle size: 65 μm, 185 μm, 260 μm, 360 μm, 540 μm), vacuum drying was performed to obtain dry spherical particles free from aggregation and consolidation. Each 40 mg of particles recovered from 4 types of sieves excluding 540 μm of the above cut-off particle size was dispersed in 1 mL of PBS, and the average particle size and particle size distribution were measured. Each of the particles recovered from the 4 types of sieves was measured. Were 125 ± 60 μm, 220 ± 40 μm, 310 ± 50 μm, and 450 ± 90 μm.

  When the catheter dispersion of the above particle dispersion was evaluated, particles having an average particle diameter of 125 μm and 220 μm can be injected without resistance, and particles having an average particle diameter of 310 μm and 450 μm also show some resistance, but the catheter tube I was able to pass. Thereafter, the catheter was incised in the longitudinal direction, and when the inside of the catheter was visually observed, no spherical particles were observed.

  The particles having an average particle diameter of 310 μm were measured for compression elastic modulus with a compression tester MCT-W500 manufactured by Shimadzu Corporation, and found to be 1.4 ± 0.3 MPa.

When the degradability of the particles after 28 days of PBS immersion was evaluated, the residual weight ratio was 30% and the weight average molecular weight ratio was 70% compared to before the immersion.
<Example 2>
A spherical particle dispersion was obtained in the same manner as in Example 1 except that the water-insoluble polymer obtained in Production Example 1 and the water-insoluble polymer obtained in Production Example 2 were mixed at a weight ratio of 50:50.

  Next, after wet classification in the same manner as in Example 1, vacuum drying was performed to obtain dry spherical particles free from aggregation and consolidation. The average particle size and particle size distribution of the particles were measured and found to be 125 ± 60 μm, 220 ± 40 μm, 310 ± 50 μm, and 450 ± 90 μm for each of the four types of sieves recovered.

  When the particle dispersion liquid was injected from the syringe into the same catheter as in Example 1, all particles having an average particle diameter could pass through the catheter tube without resistance. Thereafter, the catheter was incised in the longitudinal direction, and when the inside of the catheter was visually observed, no spherical particles were observed.

  The compression modulus of the particles having an average particle diameter of 310 μm was measured and found to be 2.0 ± 0.5 MPa.

When the degradability of the particles after 28 days of PBS immersion was evaluated, the proportion of the remaining weight was 30% and the proportion of the weight average molecular weight was 70% as compared with before immersion.
<Example 3>
A spherical particle dispersion was obtained in the same manner as in Example 1 except that the water-insoluble polymer obtained in Production Example 1 and the water-insoluble polymer obtained in Production Example 2 were mixed at a weight ratio of 70:30.

  Next, after wet classification by the same method as in Example 1, rinse with about 200 mL of a 5 wt% aqueous PEG (average molecular weight 4,000, manufactured by Wako Pure Chemical Industries), vacuum dry, and dry spheres without aggregation or consolidation Particles were obtained. The average particle size and particle size distribution of the particles were measured and found to be 125 ± 60 μm, 220 ± 40 μm, 310 ± 50 μm, and 450 ± 90 μm for each of the four types of sieves recovered.

  When the particle dispersion was injected from the syringe into the same catheter as in Example 1, particles having an average particle size of 125 μm and 220 μm could be injected without resistance, and particles having an average particle size of 310 μm and 450 μm also showed some resistance. However, it was able to pass through the catheter tube. Thereafter, the catheter was incised in the longitudinal direction, and when the inside of the catheter was visually observed, no spherical particles were observed.

  The compression modulus of the particles having an average particle size of 310 μm was measured and found to be 1.3 ± 0.3 MPa.

  When the degradability of the particles after 28 days of PBS immersion was evaluated, the residual weight ratio was 30% and the weight average molecular weight ratio was 70% compared to before the immersion.

As described above, it has been shown that spherical particles made of a blend of a water-insoluble polymer and a water-insoluble polymer can pass through a catheter tube having an inner diameter smaller than the particle size.
<Comparative Example 1>
A spherical particle dispersion was obtained in the same manner as in Example 1 except that only the water-insoluble polymer obtained in Production Example 1 was used.

  Next, after wet classification in the same manner as in Example 1, vacuum drying was performed to obtain dry spherical particles free from aggregation and consolidation. The average particle size and particle size distribution of the particles were measured and found to be 125 ± 60 μm, 220 ± 40 μm, 310 ± 50 μm, and 450 ± 90 μm for each of the four types of sieves recovered.

  When the above particle dispersion was injected from the syringe into the same catheter as in Example 1, particles having an average particle diameter of 125 μm and 220 μm could be injected without resistance, but particles having an average particle diameter of 310 μm and 450 μm were injected into the catheter tube. Could not pass. Thereafter, the catheter was incised in the longitudinal direction, and when the inside of the catheter was visually observed, spherical particles were observed.

  The compression modulus of the particles having an average particle diameter of 310 μm was measured and found to be 14.4 ± 2.9 MPa.

  When the degradability of the particles after 28 days of PBS immersion was evaluated, the proportion of the remaining weight was 28% and the proportion of the weight average molecular weight was 63% as compared to before the immersion.

  As an application field of the present invention, embolization materials, in particular, embolization materials used to occlude tubular organs in vivo and occlusion of body fluids such as blood flow, carriers used for transporting and sustained release of drugs, wounds, etc. Examples thereof include a moisturizing material for keeping the wound part dry and a scaffold / carrier for transporting and culturing cells to regenerate the tissue. Particles used in the above-mentioned fields are transported, administered and injected through a micro-caliber tube, and easily reach the target site in the body without flocculation or increase in viscosity, and exhibit functions.

Claims (32)

A biodegradable particle characterized in that the compression elastic modulus of the particle in a saturated water-containing state is 10 MPa or less. A water-insoluble polymer A having a tensile elastic modulus of a film of 1 MPa or more and less than 50 MPa in a saturated water-containing state and a water-insoluble polymer B having a tensile elastic modulus of a film of 50 MPa or more in a saturated water-containing state Degradable particles. The biodegradable particle according to claim 2, wherein the ratio of the water-insoluble polymer B is 20% by weight or more. Biodegradable particles obtained from a water-soluble polymer and a biodegradable polymer, wherein the weight ratio of the water-insoluble polymer C is 50% or more and the weight ratio of the water-soluble polymer is less than 50%. A biodegradable particle characterized by being blended with a water-insoluble polymer D. The biodegradable particle according to claim 4, wherein the ratio of the water-insoluble polymer D is 20% by weight or more. The biodegradable particle according to any one of claims 2 to 5, wherein the compression elastic modulus of the particle in a saturated water-containing state is 10 MPa or less. The biodegradable particle according to any one of claims 4 to 6, wherein the water-soluble polymer is polyalkylene glycol or a derivative thereof. The biodegradable particle according to any one of claims 1 to 7, which is coated with polyalkylene glycol or a derivative thereof. The biodegradable particle according to claim 8, wherein the polyalkylene glycol has a weight average molecular weight of 1,000 or more and 40,000 or less. The biodegradable particle according to claim 8 or 9, wherein the polyalkylene glycol is polyethylene glycol. The biodegradable particle according to any one of claims 1 to 10, wherein the particle is spherical. The biodegradable particle according to any one of claims 2 to 11, wherein at least one of the water-insoluble polymers A to D is a copolymer in which a water-soluble polymer and a biodegradable polymer are combined. The biodegradable particle according to any one of claims 4 to 12, wherein the biodegradable polymer contains an α-hydroxy acid unit. The biodegradable particle according to claim 13, wherein the α-hydroxy acid unit is a polylactic acid unit and / or a polyglycolic acid unit. The biodegradable particle according to any one of claims 3 to 14, wherein the water-insoluble polymer has a weight average molecular weight of 1,000 to 100,000. The ratio of the residual weight and / or weight average molecular weight after 28 days of immersion in a phosphate buffered saline solution at 37 ° C is 80% or less with respect to that before the immersion. Biodegradable particles. The biodegradable particle according to claim 16, wherein the particle size is 5 to 2000 μm. The biodegradable particle according to any one of claims 1 to 17, wherein the biodegradable particle is used for medical treatment. The biodegradable particle according to any one of claims 1 to 18, wherein the biodegradable particle is used as an indwelling device. The biodegradable particle according to claim 19, which is used for embolization treatment. The biodegradable particles according to any one of claims 18 to 20, wherein the particle size distribution is within ± 60% of the average particle size. A particle is obtained by blending a water-insoluble polymer A having a tensile modulus of a film of 1 MPa or more and less than 50 MPa in a saturated water-containing state and a water-insoluble polymer B having a tensile modulus of a film of 50 MPa or more in a saturated water-containing state. A method for producing biodegradable particles characterized by The method for producing biodegradable particles according to claim 22, wherein the ratio of the water-insoluble polymer B blend is 20% by weight or more. The method for producing biodegradable particles according to claim 22 or 23, wherein the particles are obtained by forming the particles into a spherical shape. The production method according to any one of claims 22 to 24, wherein the water-insoluble polymers A and B are copolymers in which a water-soluble polymer and a biodegradable polymer are combined. A method for producing biodegradable particles obtained from a water-insoluble polymer in which a water-soluble polymer and a biodegradable polymer are combined, wherein the water-insoluble polymer has a water-soluble polymer weight ratio of 50% or more. A method for producing biodegradable particles, which is a blend of C and a water-insoluble polymer D having a water-soluble polymer weight ratio of less than 50%. 27. The production method according to claim 25, wherein the water-soluble polymer is polyalkylene glycol or a derivative thereof. The production method according to claim 27, wherein the polyalkylene glycol is polyethylene glycol. The production method according to claim 27 or 28, wherein the polyalkylene glycol has a weight average molecular weight of 1,000 or more and 40,000 or less. The method according to any one of claims 25 to 29, wherein the biodegradable polymer contains an α-hydroxy acid unit. The biodegradable particle according to claim 30, wherein the α-hydroxy acid unit is a polylactic acid unit and / or a polyglycolic acid unit. The production method according to any one of claims 22 to 31, wherein the water-insoluble polymer has a weight average molecular weight of 1,000 to 100,000.