JP5223182B2 - Biodegradable particles and method for producing the same - Google Patents

Description

  The present invention relates to biodegradable microparticles that are mainly conveyed through a micro-caliber tube of a medical device such as a catheter, needle, or syringe. In particular, after being carried into the living body and demonstrating its function, after finishing its role, it is decomposed in the living body after a lapse of a specific period, and finally the decomposed component can be absorbed into the body or discharged from the body. The present invention relates to biodegradable fine particles that can be used as a material that does not remain in a living body, 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.
(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), a specific drug, Although the biodegradable material to contain is disclosed (refer patent document 3), this has the high hydrophobicity of a base polymer, and there existed the problem of said (2)-(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, it is difficult to adjust the flexibility of the base polymer and the strength necessary for molding, and there are problems (1) to (5) described above.
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 are problems (1) to (5) described above.

In addition, a nano fine particle having an average particle diameter of less than 300 nm and accompanying or including a surface modifier is disclosed (Patent Document 6). The patent document discloses particles whose surface has been modified with a polyalkylene glycol such as polyethylene glycol or pluronic. However, since the particles used here have a sufficiently small particle size, there is no problem of clogging the particles when they pass through a tube such as a catheter, needle, or syringe. No means for solving such a problem that occurs when particles having a larger particle diameter are used is also shown. Furthermore, the role of surface modifiers such as polyalkylene glycol is described to improve the suspendability of particles when dispersed in a dispersion medium or when dried, and to prevent aggregation. The purpose of preventing clogging in the pipe is not described at all. Therefore, in the said patent document, the molecular weight range and density | concentration range of polyalkylene glycol suitable for the solution of this subject are not found.
Japanese Patent No. 3242118 Japanese Patent No. 3428972 JP-A-5-969 Japanese Patent Publication No. 5-17245 JP 2004-167229 A Japanese Patent Publication No. 10-511957 Bastian P, Bartowski S et al., “Chemo-embolization of experimental river metastasis”, European. Journal of Pharmaceuticals and Biopharmaceutics, 1998, Vol. 43, p243-254.

  It is an object of the present invention to be able to mold without aggregation or consolidation between particles, and causes aggregation clogging mainly in devices such as catheters, needles, and syringes, which are medical medical devices, or blood vessels. An object of the present invention is to provide biodegradable particles that can be transported and injected without any problems, and the materials are smoothly decomposed after a specific period.

The object of the present invention is achieved by a particle having the following constitution or a production method thereof.
1. A biodegradable particle having a particle diameter of 5 μm or more and coated with polyalkylene glycol or a derivative thereof.
2. 2. The biodegradable particle as described in 1 above, wherein the polyalkylene glycol or derivative thereof has a weight average molecular weight of 1,000 or more and 40,000 or less.
3. 3. The biodegradable particle according to 1 or 2 above, wherein the core portion of the particle contains a water-insoluble polyalkylene glycol copolymer.
4). 4. The biodegradable particle according to any one of the above 1 to 3, wherein the water-insoluble polyalkylene glycol copolymer is a copolymer in which polyalkylene glycol or a derivative thereof and a biodegradable polymer are chemically bonded. .
5. 5. The biodegradable particle as described in any one of 1 to 4 above, wherein the biodegradable polymer contains an α-hydroxy acid unit.
6). 6. The biodegradable particle according to any one of 3 to 5, wherein the water-insoluble polyalkylene glycol copolymer has a weight average molecular weight of 1,000 to 100,000.
7). 7. The biodegradable particle as described in any one of 1 to 6 above, wherein the polyalkylene glycol is polyethylene glycol.
8. The biodegradable particles as described in any one of 1 to 7 above, wherein the remaining weight after immersion in phosphate buffered saline at 37 ° C. is 80% or less of the weight before immersion.
9. The biodegradability as described in any one of 1 to 8 above, wherein the weight average molecular weight after immersion in phosphate buffered saline at 37 ° C. is 80% or less of the weight average molecular weight before immersion. particle.
10. 10. The biodegradable particle as described in any one of 1 to 9 above, which is used for medical treatment.
11. The biodegradable particle according to any one of 1 to 9 above, which is used as an indwelling device.
12 10. The biodegradable particle as described in any one of 1 to 9 above, which is used for embolization treatment.
13. A method for producing biodegradable particles, characterized in that biodegradable particles containing a water-insoluble polyalkylene glycol copolymer and having a particle size of 5 μm or more are brought into contact with an aqueous polyalkylene glycol solution and then dried to obtain particles. .
14 14. The production method as described in 13 above, wherein the polyalkylene glycol concentration in the aqueous polyalkylene glycol solution is 1% by weight or more and 50% by weight or less.
15. 15. The production method as described in 13 or 14 above, wherein the biodegradable particles are brought into contact with the polyalkylene glycol aqueous solution by introducing the polyalkylene glycol aqueous solution into the biodegradable particles on the sieve.
16. 16. The method according to any one of 13 to 15, wherein the polyalkylene glycol aqueous solution is an aqueous solution of polyethylene glycol.

  The biodegradable particles of the present invention can be formed without agglomeration or consolidation between particles, and are mainly clogged in devices such as catheters, needles, and syringes, which are medical medical devices, or blood vessels. Can reach the target site without causing any problems, and can be smoothly decomposed in vivo after a specific period regardless of the indwelling site or indwelling environment. Ultimately, the decomposed components can be absorbed into the body or discharged outside the body. Is.

  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. The mode of degradation may be chemical degradation represented by hydrolysis or degradation by enzymes produced by living cells or microorganisms, but those which are primarily hydrolyzed by living organisms or microorganisms are preferred. The raw material of the biodegradable particles to be used is not particularly limited, and any of natural polymers and artificially synthesized polymers may be used. Polyester, polyether, polyanhydride, polypeptide , Poly (α-cyanoacrylate), polyacrylamide, poly (orthoester), polyphosphazene, polyamino acid, biodegradable polyurethane, polycarbonate, polyiminocarbonate, nucleic acid, polysaccharide, etc. Gelatin, chitin, chitosan, dextran, gum arabic, alginic acid, starch, polylactic acid (hereinafter referred to as PLA), polyglycolic acid (hereinafter referred to as PGA), polylactic glycolic acid copolymer (hereinafter referred to as PLGA) Hydroxy-terminated poly (ε-caprolactone) -polyether, poly Examples include licaprolactone, n-butylcyanoacrylic acid, and a copolymer comprising the above polymer.

  The biodegradable particle in the present invention is characterized in that the particle surface is coated with a hydrophilic synthetic polymer.

  By hydrophilic synthetic polymer is meant a synthetic polymer that swells in water or is water-soluble. For indwelling and administration in the body, water-soluble synthetic polymers are preferred because they are preferably dissolved and discharged in body fluids. Polyalkylene glycols such as polyethylene glycol and polypropylene glycol or derivatives thereof, polyhydroxymethyl methacrylate, acrylic acid Examples thereof include methacrylic acid and polyvinyl pyrrolidone. In the present invention, polyalkylene glycol or a derivative thereof is preferable because it can be molded without aggregation and consolidation between particles. In particular, polyethylene glycol (hereinafter referred to as PEG) is most preferable because it has clinical results and has high biocompatibility. In addition, the coating in the present invention includes a state in which the hydrophilic synthetic polymer is attached or adsorbed to such an extent that the particle surface is surface modified. The hydrophilic synthetic polymer provides lubricity to the particle surface. It is not particularly limited as long as it is within a range, and it is preferable even when the particles are included in the polyalkylene glycol or 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. Examples of the method for coating the particle surface include a mechanical coating method, a wet coating method, a spray drying method, a sugar coating method, and a powder coating method. Of these, the wet coating method and the spray drying method are preferably used. In particular, a wet coating method in which particles are stirred in the coating solution and the coating solution is in contact with the particles, or the coating solution is allowed to flow from above by placing the particles on a filter or sieve, and the coating solution is in contact with the particles and rinsed is hydrophilic. Since it is easy to adjust the adhesion amount or adsorption amount of the synthetic polymer, it is most preferably used. The molecular weight of the polyalkylene glycol or its derivative is not particularly limited as long as it can be attached or adsorbed to such an extent that it can be surface-modified, but if the molecular weight is less than 1,000, it can be liquid at low molecular weight and room temperature. Therefore, the particle surface tends to be liquid and difficult to handle. In addition, in the case of use for injecting and administering in vivo, especially in medical and medical applications, if the molecular weight is large, it may not be excreted from the glomeruli of the kidney, so that the polyalkylene glycol having an average molecular weight of 40,000 or less Preference is given to using derivatives. Therefore, a weight average molecular weight of 1000 to 40,000 is most preferable.

  As a wet coating method, a melting method or a solvent dilution method can be preferably used. The solvent used in the solvent dilution method is not particularly limited as long as the polymer used for coating can be uniformly dissolved and finally removed, but water, alcohols such as methanol, ketones such as acetone, dichloromethane, and the like. And halides. In particular, water is preferably used because it is inexpensive and has high safety.

  The concentration of the PEG solution during wet coating is not particularly limited as long as PEG can be uniformly dissolved, but if the concentration is too low, the surface performance of the particles may not be improved and clogging may occur in the capillary tube. If it is too high, the particles may become highly viscous and the workability may deteriorate. Therefore, the range of 1 wt% to 50 wt% is most preferable.

    Thus, after performing the wet coating which makes a coating solution contact particle | grains, the biodegradable particle | grains of this invention can be obtained by drying particle | grains.

  The shape of the biodegradable particle of the present invention is not particularly limited, but it is preferable to maintain the particle shape at 37 ° C., particularly when considering a pharmaceutical medical use targeting the human body. Preferably there is. If it is liquid or gel at 37 ° C. and does not retain the particle shape, it may not be placed at the target site due to its low strength. On the other hand, if the particle shape is maintained, the indwelling in the body and the intended function can be performed more effectively.

  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 preferably 0.01% by weight or more, more preferably 0.05% by weight or more, and preferably 80% by weight or less, more preferably 60% by weight or less. By adjusting the concentration, the particle shape or particle size, or both can be adjusted. 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 method using a plurality of sieves is effective. When a plurality of sieves are stacked in order from the finest and the liquid prepared by dispersing the particles prepared by the above production method is added to the coarsest uppermost sieve, the particles are sieved with a mesh size smaller than the particle size. Because it stays on top, the particles can be separated by 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 have a particle size of 5 μm or more, preferably 10 μm or more, preferably 2,000 μm or less, more preferably 1,500 μm or less. 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. When used for embolization or the like, 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 addition, in all uses including the said use, use of what contains a particle | grain other than a particle size other than 5-2000 micrometers in part is not excluded.

  In the present invention, the particle diameter is used separately from the particle diameter, but the particle diameter represents the average diameter of a plurality of particles, while the particle diameter is used as the diameter of one particle.

  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, average particle size, and particle size distribution of the particles of the present invention can be measured by various commercially available measuring devices, especially by the particle size distribution measuring device “Microtrack Series” manufactured by Leeds and Northrup. Since a thing can be measured in a physiological saline, it is preferable at the point which can measure in the state close | similar to the blood vessel or the internal environment. Alternatively, there is no problem as long as the apparatus can obtain the same result under the same conditions. The particle diameter is calculated from a volume average value, and is displayed as an “MV” value in the “Microtrack Series” regardless of the sphericity of the particle.

  The biodegradable particles of the present invention preferably contain a water-insoluble polyalkylene glycol copolymer in the core portion. The water-insoluble polyalkylene glycol copolymer is not particularly limited, but is a block copolymer containing a polyalkylene glycol or a polyalkylene glycol derivative represented by PEG, polypropylene glycol, etc. as one component. A substantially water-insoluble one is preferably used. The term “water-insoluble polymer” as used herein refers to a polymer that deviates from the definition of the following water-soluble polymer. The water-soluble polymer 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 concentration below the saturation concentration under normal pressure. The time and temperature required for dissolving the polymer are not particularly limited. The water-insoluble polyalkylene glycol-based copolymer preferably includes polyalkylene glycol, and most preferably includes PEG that is biocompatible and has a proven record in pharmaceutical and medical applications. A block copolymer having PEG or a PEG derivative as one component thereof, which is substantially water-insoluble, may be water-insolubilized by physically interacting with PEG or a derivative thereof. Since PEG is water-soluble, the term “water-insoluble” as used herein means that the entire substance containing PEG is substantially insoluble in water due to the contribution of units other than PEG units.

  The biodegradable particle of the present invention preferably contains a water-insoluble PEG-based copolymer in which PEG or a PEG derivative and a biodegradable polymer are chemically bonded to the core portion, although not particularly limited, Alternatively, a copolymer in which a biodegradable polymer is chemically bonded to one end or a copolymer in which PEG and biodegradable polymer are alternately bonded is preferably used. 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 kind 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. 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 preferably have a weight average molecular weight of 1,000 or more, more preferably 2,000 or more, and preferably 100,000 or less, more preferably 90,000 or less in the core part. It preferably contains an insoluble polyalkylene glycol copolymer. 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 PEG or PEG derivative preferably has a weight average molecular weight of 200 to 50,000. If it is less than 200, the hydrophilicity of the PEG copolymer is low, and uniform biodegradability may not be obtained. On the other hand, if it is larger than 50,000, PEG produced from the copolymer decomposed in vivo may be difficult to be discharged out of the body. The structure of the PEG derivative is not particularly limited, and a structure including a multi-arm PEG derivative can be preferably used. The weight ratio of the biodegradable polymer to PEG or PEG derivative is not particularly limited, but can be more preferably used in the range of 80:20 to 5:95.

  Hereinafter, a method for producing a water-insoluble PEG copolymer comprising PEG or a PEG derivative and a biodegradable polymer will be exemplified. A method for synthesizing the water-insoluble PEG copolymer is not particularly limited, and examples thereof include melt polymerization and ring-opening polymerization. For example, a raw water-soluble polymer (PEG or PEG derivative, etc.) and a biodegradable polymer raw material (monomer, etc.) having a predetermined average molecular weight as raw materials are charged into a polymerization tank equipped with a stirring blade in a dry air or dry nitrogen stream. 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, using a twin-screw kneading extruder with a vent or an apparatus having a stirring and feeding function similar thereto, the biodegradable polymer raw material, PEG or PEG derivative and catalyst are stirred, mixed and degassed in a molten state, continuously. Polymerization can also be carried out by removing the water-insoluble copolymer produced in the process. Furthermore, after the produced water-insoluble copolymer 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 substance 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 PEG copolymers can be produced by appropriately selecting the types of the biodegradable polymer and the water-soluble polymer, and further their molecular weights.

Since the biodegradable particle of the present invention is desirably a material that decomposes in vivo after a specific period of time and the decomposition component is absorbed or discharged from the body, a 37 ° C. phosphate buffered saline (hereinafter, (It is abbreviated as PBS) It preferably has a characteristic that the residual weight after 28 days of immersion is 80% or less before immersion. The weight here refers to the weight of the particles 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 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 for 28 days. 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 change in weight is within 5% even if time passes. The residual weight ratio (W (%)) is calculated from W (%) = W1 / W0 × 100 from the weight before PBS immersion (W0 (g)) and the weight after 28 days immersion (W1 (g)). be able to.

  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.

The molecular weight can be measured by, for example, the following method.
(Molecular weight measurement method)
10 mg of the precisely weighed 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-GMHHR-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 with 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 M = M1 / M0 × 100 from the weight average molecular weight (M0) before the PBS immersion and the weight average molecular weight (M1) after the 28 day immersion. Can be calculated.

  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. Internally dispersing another water-insoluble polyalkylene glycol copolymer having a different decomposition rate into the water-insoluble polyalkylene glycol-based copolymer, or making them into a multilayer structure, for example, a water-insoluble polyalkylene having a PLA-PEG-PLA structure The biodegradation rate of the biodegradable particles can be adjusted by internally dispersing a water-insoluble polyalkylene glycol copolymer having a PLGA-PEG-PLGA structure in the glycol copolymer.

  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 “Microtrac Series” manufactured by Leeds & Northrup Co., Ltd., measurement was performed at 25 ° C. in physiological saline. As the particle diameter, a value calculated by volume average displayed as “MV value” was used.
(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) 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. The residual weight ratio (W (%)) is calculated from W (%) = W1 / W0 × 100 from the weight before PBS immersion (W0 (g)) and the weight after 28 days immersion (W1 (g)). be able to.
(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 measured under the conditions of two GPC columns (Tosoh TSK-gel-GMHHR-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 ( It was 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).

The ratio (M) of the weight average molecular weight with respect to the pre-soaked PBS after 28 days of PBS is calculated from the weight average molecular weight (M0) before the soaking of PBS and the weight average molecular weight (M1) after the soaked 28 days of M (%) = M1 / Calculated by M0 × 100.
(Catheter passage)
When the particle dispersion obtained in each example and comparative example is injected from a syringe into a catheter and can be injected without resistance, ○, when resistance is generated, and when injection is impossible, it is set as x. Was evaluated. As the catheter, FasTracker-10 Infusion Catheter (catheter length 150 cm, tip inner diameter 380 μm) manufactured by Boston Scientific was used.
<Example 1>
Under a nitrogen stream, 6.6 g of L-lactide (manufactured by Purac Bio-Chem) and 2.9 g of dehydrated PEG (SUNBRIGHT DKH-20T manufactured by NOF Corporation) are mixed in a flask and dissolved and mixed at 150 ° C. Thereafter, 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 to obtain a copolymer having a PLA-PEG-PLA structure. This copolymer was dissolved in chloroform and dropped into a large excess of diethyl ether / acetone mixture to obtain a white precipitate. The weight average molecular weight by the above-mentioned GPC method was 15,000.

  A spherical particle dispersion is obtained by dissolving 1.0 g of the above purified copolymer in 30 mL of dichloromethane and dropping it into an aqueous solution of 1% by weight polyvinyl alcohol (Aldrich, Cat. No. 360627) and drying in an O / W solution. Got. The supernatant of this dispersion was decanted and replaced with a 10% by weight aqueous PEG (Wako Pure Chemical Industries average molecular weight 600) aqueous solution and stirred for 30 minutes. Subsequently, after wet classification using a nylon sieve, vacuum drying was performed to obtain dry spherical particles free from aggregation or consolidation. The particle surface was gel-like.

  When 40 mg of these particles were dispersed in 1 mL of PBS and the particle size distribution was measured, the average particle size was 125 μm and the distribution was ± 60 μm. More than 90% of the particles were included in this range. When this particle dispersion was injected from a syringe into a catheter and its permeability was evaluated, it could be injected without resistance. Thereafter, the catheter was incised in the longitudinal direction and the inside was visually observed, and spherical particles were not observed.

  When the degradability of the particles after 28 days of PBS immersion was evaluated, the proportion of the remaining weight was 69% and the proportion of the weight average molecular weight was 31% as compared with before immersion.

In addition, after wet classification using a nylon sieve, particles obtained by vacuum drying were immersed in physiological saline to obtain a particle dispersion. Next, after inserting a 24 G indwelling needle into the femoral vein of two 10-week-old rats anesthetized with Nembutal, the spherical particle dispersion was injected through the catheter. After 28 days, the lung appearance was observed, and the tissue section was prepared and the spherical particle dispersion was injected, and then the tissue section was observed. As a result, pulmonary infarction was observed in both animals, and particle decomposition could be confirmed. It was.
<Example 2>
The dispersion of spherical particles having a PLA-PEG-PLA structure obtained by drying in O / W liquid in Example 1 was subjected to wet classification with a nylon sieve, and then 10% by weight of PEG (average manufactured by Wako Pure Chemical Industries, Ltd.). (Molecular weight 600) Rinse with about 200 mL of an aqueous solution and vacuum dry to obtain dry spherical particles free from aggregation or consolidation. The particle surface was gel-like.

  When 40 mg of the particles were dispersed in 1 mL of PBS and the particle size distribution was measured, the average particle size was 220 μm and the distribution was ± 50 μm. More than 90% of the particles were included in this range. When this particle dispersion was injected from a syringe into a catheter and its permeability was evaluated, it could be injected without resistance. Thereafter, the catheter was incised in the longitudinal direction and the inside was visually observed, and spherical particles were not observed.

Further, when the degradability of the particles after 28 days of PBS immersion was evaluated, the ratio of the remaining weight was 68% and the ratio of the weight average molecular weight was 31% compared to before the immersion.
<Example 3>
The dispersion of spherical particles having a PLA-PEG-PLA structure obtained by drying in an O / W solution in Example 1 was wet-classified with a nylon sieve and then 1% by weight of PEG (average manufactured by Wako Pure Chemical Industries, Ltd.). After rinsing with about 200 mL of an aqueous solution having a molecular weight of 1,000), vacuum drying was performed to obtain dry spherical particles free from aggregation or consolidation. The particle surface was dry and smooth.

  When 40 mg of these particles were dispersed in 1 mL of PBS and the particle size distribution was measured, the average particle size was 125 μm and the distribution was ± 60 μm. More than 90% of the particles were included in this range. When this particle dispersion was injected from a syringe into a catheter and its permeability was evaluated, it could be injected without resistance. Thereafter, the catheter was incised in the longitudinal direction and the inside was visually observed, and spherical particles were not observed.

Further, when the degradability of the particles after 28 days of PBS immersion was evaluated, the ratio of the remaining weight was 68% and the ratio of the weight average molecular weight was 31% compared to before the immersion.
<Example 4>
The dispersion of spherical particles having a PLA-PEG-PLA structure obtained by drying in an O / W solution in Example 1 was wet-classified with a nylon sieve and then 1% by weight of PEG (average manufactured by Wako Pure Chemical Industries, Ltd.). After rinsing with about 200 mL of an aqueous solution having a molecular weight of 1,000), vacuum drying was performed to obtain dry spherical particles free from aggregation or consolidation. The particle surface was dry and smooth.

When 40 mg of the particles were dispersed in 1 mL of PBS and the particle size distribution was measured, the average particle size was 220 μm and the distribution was ± 50 μm. More than 90% of the particles were included in this range. When this particle dispersion was injected from a syringe into a catheter and its permeability was evaluated, it could be injected without resistance. Thereafter, the catheter was incised in the longitudinal direction and the inside was visually observed, and spherical particles were not observed.
Further, when the degradability of the particles after 28 days of PBS immersion was evaluated, the ratio of the remaining weight was 67% and the ratio of the weight average molecular weight was 31% as compared with before the immersion.
<Example 5>
The dispersion of spherical particles having a PLA-PEG-PLA structure obtained by drying in an O / W solution in Example 1 was wet-classified with a nylon sieve and then 3% by weight of PEG (average manufactured by Wako Pure Chemical Industries, Ltd.) After rinsing with about 200 mL of an aqueous solution having a molecular weight of 1,000), vacuum drying was performed to obtain dry spherical particles free from aggregation or consolidation. The particle surface was dry and smooth.

  When 40 mg of the particles were dispersed in 1 mL of PBS and the particle size distribution was measured, the average particle size was 220 μm and the distribution was ± 50 μm. More than 90% of the particles were included in this range. When this particle dispersion was injected from a syringe into a catheter and its permeability was evaluated, it could be injected without resistance. Thereafter, the catheter was incised in the longitudinal direction and the inside was visually observed, and spherical particles were not observed.

Further, when the degradability of the particles after 28 days of PBS immersion was evaluated, the ratio of the remaining weight was 67% and the ratio of the weight average molecular weight was 31% as compared with before the immersion.
<Example 6>
The dispersion of spherical particles having a PLA-PEG-PLA structure obtained by drying in an O / W solution in Example 1 was wet-classified with a nylon sieve and then 3% by weight of PEG (average manufactured by Wako Pure Chemical Industries, Ltd.) After rinsing with about 200 mL of an aqueous solution having a molecular weight of 1,000), vacuum drying was performed to obtain dry spherical particles free from aggregation or consolidation. The particle surface was dry and smooth.

  When 40 mg of these particles were dispersed in 1 mL of PBS and the particle size distribution was measured, the average particle size was 310 μm and the distribution was ± 50 μm. More than 90% of the particles were included in this range. When this particle dispersion was injected from a syringe into a catheter and its permeability was evaluated, it could be injected without resistance. Thereafter, the catheter was incised in the longitudinal direction and the inside was visually observed, and spherical particles were not observed.

Further, when the degradability of the particles after 28 days of PBS immersion was evaluated, the ratio of the remaining weight was 72% and the ratio of the weight average molecular weight was 33% compared to before the immersion.
<Example 7>
The dispersion of spherical particles having a PLA-PEG-PLA structure obtained by drying in O / W liquid in Example 1 was subjected to wet classification with a nylon sieve, and then 20% by weight of PEG (average manufactured by Wako Pure Chemical Industries, Ltd.). After rinsing with about 200 mL of an aqueous solution having a molecular weight of 1,000), vacuum drying was performed to obtain dry spherical particles free from aggregation or consolidation. The particle surface was dry and smooth.

  When 40 mg of the particles were dispersed in 1 mL of PBS and the particle size distribution was measured, the average particle size was 450 μm and the distribution was ± 90 μm. More than 90% of the particles were included in this range. When this particle dispersion was injected from a syringe into a catheter and its permeability was evaluated, it could be injected without resistance. Thereafter, the catheter was incised in the longitudinal direction and the inside was visually observed, and spherical particles were not observed.

Moreover, when the degradability of the particles after 28 days of PBS immersion was evaluated, the proportion of the remaining weight was 80% and the proportion of the weight average molecular weight was 35% as compared with before immersion.
<Example 8>
The spherical particle dispersion having the PLA-PEG-PLA structure obtained by drying in the O / W solution in Example 1 was subjected to wet classification with a nylon sieve, and then 5% by weight of PEG (average manufactured by Wako Pure Chemical Industries, Ltd.). After rinsing with about 200 mL of an aqueous solution having a molecular weight of 4,000), vacuum drying was performed to obtain dry spherical particles free from aggregation or consolidation. The particle surface was dry and smooth.

  When 40 mg of the particles were dispersed in 1 mL of PBS and the particle size distribution was measured, the average particle size was 220 μm and the distribution was ± 50 μm. More than 90% of the particles were included in this range. When this particle dispersion was injected from a syringe into a catheter and its permeability was evaluated, it could be injected without resistance. Thereafter, the catheter was incised in the longitudinal direction and the inside was visually observed, and spherical particles were not observed.

Further, when the degradability of the particles after 28 days of PBS immersion was evaluated, the residual weight ratio was 69% and the weight average molecular weight ratio was 32% as compared to before the immersion.
<Example 9>
Under a nitrogen stream, 5.0 g of L-lactide (manufactured by Pyrac Biochem), 1.7 g of glycolide (manufactured by Boehringer Ingelheim) and dehydrated PEG (SUNBRIGHT DKH-20T, manufactured by NOF Corporation) 2 0.9 g was dissolved and mixed at 150 ° C., and then 490 μL of a toluene solution in which dioctanoic acid tin (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved to a concentration of 0.1 mol / L was added and reacted. -A copolymer having a PEG-PLGA structure was obtained. This copolymer was dissolved in chloroform and dropped into a large excess of diethyl ether / acetone mixture to obtain a white precipitate. The weight average molecular weight by GPC method was 22,000.

  In the same manner as in Example 1, 0.5 mg of the purified copolymer was dissolved in 19 mL of dichloromethane, dropped into a 1% by weight aqueous polyvinyl alcohol solution, and dried in an O / W solution to obtain a spherical particle dispersion. The dispersion was wet-classified with a nylon sieve, rinsed with about 200 mL of a 5 wt% aqueous PEG (average molecular weight 1,000, manufactured by Wako Pure Chemical Industries), vacuum-dried, and agglomerated or consolidated into a uniform shape. Dry spherical particles without water were obtained. The particle surface was dry and smooth.

  When 40 mg of the particles were dispersed in 1 mL of PBS and the particle size distribution was measured, the average particle size was 110 μm and the distribution was ± 105 μm. More than 90% of the particles were included in this range. When this particle dispersion was injected from a syringe into a catheter and its permeability was evaluated, it could be injected without resistance. Thereafter, the catheter was incised in the longitudinal direction and the inside was visually observed, and spherical particles were not observed.

  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 62% compared to before the immersion.

Further, the particles were wet classified with a nylon sieve and then vacuum-dried, and the obtained particles were immersed in physiological saline to obtain a particle dispersion. Next, after inserting a 24 G indwelling needle into the femoral vein of two 10-week-old rats anesthetized with Nembutal, the spherical particle dispersion was injected through the catheter. After 28 days, the lung appearance was observed, and the tissue section was prepared and the spherical particle dispersion was injected, and then the tissue section was observed. As a result, pulmonary infarction was observed in both animals, and particle decomposition could be confirmed. It was.
<Example 10>
The dispersion of spherical particles having a PLGA-PEG-PLGA structure obtained by drying in an O / W solution in Example 9 was wet-classified with a nylon sieve and then 5% by weight of PEG (average manufactured by Wako Pure Chemical Industries, Ltd.). After rinsing with about 200 mL of an aqueous solution having a molecular weight of 1,000), vacuum drying was performed to obtain dry spherical particles having a uniform shape and no aggregation or consolidation. The particle surface was dry and smooth.

  When 40 mg of these particles were dispersed in 1 mL of PBS and the particle size distribution was measured, the average particle size was 310 μm and the distribution was ± 50 μm. More than 90% of the particles were included in this range. When this particle dispersion was injected from a syringe into a catheter and its permeability was evaluated, it could be injected without resistance. Thereafter, the catheter was incised in the longitudinal direction and the inside was visually observed, and spherical particles were not observed.

  Further, when the degradability of the particles after 28 days of PBS immersion was evaluated, the ratio of the remaining weight was 32% and the ratio of the weight average molecular weight was 64% compared to before the immersion.

From the above, it has been found that particles whose particle surfaces are coated with PEG can be molded without aggregation or consolidation between the particles, and can pass without causing resistance and clogging when passing through the microcatheter.
<Comparative Example 1>
The dispersion of spherical particles having the PLA-PEG-PLA structure obtained by drying in the O / W liquid in Example 1 was subjected to wet classification with a nylon sieve, followed by vacuum drying, and drying without aggregation or consolidation Spherical particles were obtained.

When 40 mg of the particles were dispersed in 1 mL of PBS and the particle size distribution was measured, the average particle size was 220 μm and the distribution was ± 50 μm. More than 90% of the particles were included in this range. The particle dispersion was injected from a syringe into a catheter and its permeability was evaluated. After the injection was started, spherical particles aggregated at the connector at the catheter inlet, resulting in strong resistance and impossibility of injection.
<Comparative example 2>
The dispersion of spherical particles having the PLA-PEG-PLA structure obtained by drying in the O / W liquid in Example 1 was subjected to wet classification with a nylon sieve, followed by vacuum drying, and drying without aggregation or consolidation Spherical particles were obtained.

When 40 mg of these particles were dispersed in 1 mL of PBS, 10 mg of PEG (average molecular weight 1000 manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved / stirred in this dispersion, and particle size distribution measurement was performed. The average particle size was 220 μm and the distribution was ± 50 μm. . More than 90% of the particles were included in this range. This particle dispersion was injected from a syringe into a catheter and its passability was evaluated. After injection started, spherical particles aggregated at the connector at the catheter inlet, resulting in strong resistance and inability to injection <Comparative Example 3 >
The dispersion of spherical particles having the PLA-PEG-PLA structure obtained by drying in the O / W liquid in Example 1 was subjected to wet classification with a nylon sieve, followed by vacuum drying, and drying without aggregation or consolidation Spherical particles were obtained.

  When 40 mg of these particles were dispersed in 1 mL of PBS and the particle size distribution was measured, the average particle size was 310 μm and the distribution was ± 50 μm. More than 90% of the particles were included in this range. The particle dispersion was injected from a syringe into a catheter and its permeability was evaluated. After the injection was started, spherical particles aggregated at the connector at the catheter inlet, resulting in strong resistance and impossibility of injection.

<Comparative example 4>
The dispersion of spherical particles having the PLA-PEG-PLA structure obtained by drying in the O / W liquid in Example 1 was subjected to wet classification with a nylon sieve, followed by vacuum drying, and drying without aggregation or consolidation Spherical particles were obtained.

  When 40 mg of the particles were dispersed in 1 mL of PBS and the particle size distribution was measured, the average particle size was 450 μm and the distribution was ± 90 μm. More than 90% of the particles were included in this range. The particle dispersion was injected from a syringe into a catheter and its permeability was evaluated. After the injection was started, spherical particles aggregated at the connector at the catheter inlet, resulting in strong resistance and impossibility of injection.

<Comparative Example 5>
The dispersion of spherical particles having a PLGA-PEG-PLGA structure obtained by drying in O / W liquid in Example 9 was wet-classified with a nylon sieve and then vacuum-dried. Dry particles in which the consolidated ones were mixed were obtained.

  From the dried particles, 40 mg of particles having a particle size of about 300 μm, in which the particles were not aggregated or consolidated, was selected and dispersed in 1 mL of PBS, and the particle size distribution was measured. The average particle size was 310 μm and the distribution was ± 50 μm. More than 90% of the particles were included in this range. The particle dispersion was injected from a syringe into a catheter and its permeability was evaluated. After the injection was started, spherical particles aggregated at the connector at the catheter inlet, resulting in strong resistance and impossibility of injection.

  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 include moisturizing materials for keeping the wound part dry and scaffolds / carriers for transporting and culturing cells to regenerate tissues. 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 (13)

  A water-insoluble polyalkylene glycol having a particle size of 5 μm or more, wherein the core portion of the particle is chemically bonded to a polyalkylene glycol or a derivative thereof and a biodegradable polymer containing an α-hydroxy acid unit. A biodegradable particle comprising a copolymer and having a polyalkylene glycol or a derivative thereof attached or adsorbed on the surface of the core portion. 2. The biodegradable particle according to claim 1, wherein a weight average molecular weight of the polyalkylene glycol or a derivative thereof attached or adsorbed on the surface of the core portion is 1,000 or more and 40,000 or less. .   The biodegradable particle according to claim 1 or 2, wherein the water-insoluble polyalkylene glycol copolymer has a weight average molecular weight of 1,000 to 100,000.   The biodegradable particle according to any one of claims 1 to 3, wherein the polyalkylene glycol is polyethylene glycol.   The biodegradable particle according to any one of claims 1 to 4, wherein the residual weight after immersion in 37 ° C phosphate buffered saline is 80% or less of the weight before immersion.   The biodegradable particle according to any one of claims 1 to 5, wherein the weight average molecular weight after immersion in a 37 ° C phosphate buffered saline solution is 80% or less of the weight average molecular weight before immersion. .   The biodegradable particle according to any one of claims 1 to 6, wherein the biodegradable particle is used for medical treatment.   The biodegradable particle according to any one of claims 1 to 6, wherein the biodegradable particle is used as an indwelling device.   The biodegradable particle according to any one of claims 1 to 6, wherein the biodegradable particle is used for embolization treatment.   A biodegradable particle having a particle size of 5 μm or more, comprising a water-insoluble polyalkylene glycol copolymer in which polyalkylene glycol or a derivative thereof and a biodegradable polymer containing an α-hydroxy acid unit are chemically bonded; A method for producing biodegradable particles, wherein the particles are dried to obtain particles after contacting with an aqueous polyalkylene glycol solution.   The production method according to claim 10, wherein the concentration of the polyalkylene glycol in the aqueous polyalkylene glycol solution is 1% by weight or more and 50% by weight or less.   The method according to claim 10 or 11, wherein the biodegradable particles are brought into contact with the polyalkylene glycol aqueous solution by introducing the polyalkylene glycol aqueous solution into the biodegradable particles on the sieve. The method according to any one of claims 10 to 12, wherein the aqueous polyalkylene glycol solution is an aqueous solution of polyethylene glycol.