JP4442302B2 - Biodegradable particles - Google Patents

Description

  The present invention relates to biodegradable particles, and more particularly to biodegradable particles that can be used as an embolization material used to occlude tubular organs in a living body and occlude body fluids such as blood flow.

  More specifically, it is a biodegradable particle having a compressive elastic modulus of 280 MPa or less and a strength at a compression volume of 5% strain of 10 MPa or less in a saturated water-containing state, which occludes the inside of a tubular organ and occludes blood flow. The present invention relates to a biodegradable particle that can be used as an embolization particle that can be used as an embolization material that can be used as an embolization material that can be used as an embolization material that does not remain in vivo.

  Prior to the incision associated with the operation of an organ such as the liver, the embolization material is injected into the blood vessel for the purpose of minimizing bleeding, so that the hemostasis can be surely and rapidly performed. In addition to bleeding prevention, arterial embolization that blocks nutrients by hemostasis for unresectable tumors, and a combination of anticancer drugs and vascular embolization materials to maintain high anticancer drug concentration in the tumor Embolization therapy is known as an effective therapy. Vascular embolization materials are used for the purpose of blocking blood vessels during such bleeding, controlling blood flow, and blocking blood supply to tumors.

  With the development of catheters and their manipulation techniques, appropriate embolic materials can be selectively and accurately delivered to the site to be embolized. As such an intravascular embolization material, polymer particles, polymer gels, and metal coils are known.

  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. The embolic material made of polymer particles can be introduced by being injected toward the affected area with a microsyringe or the like through a microcatheter placed in a living body in a state where it is dispersed in a contrast medium or the like. According to such an embolization material of polymer particles, an embolus can be formed by reaching the affected part located in the deep part.

However, the embolic material made of polymer particles has the following problems.
(1) Since the shape is irregular and the particle size distribution is wide, it may not be occluded at the target site of the blood vessel. (2) The catheter may clog due to aggregation or high viscosity in the catheter.
(3) In some cases, normal blood vessels on the way to the affected area may aggregate or become highly viscous and cannot reach the affected area.
(4) Since the material is hard and does not fit to the cross-sectional shape of the blood vessel, the blood flow rate is reduced, but it may not be completely embolized.
(5) Since the polymer has no contrast, the embolization state and site of the affected area cannot be confirmed under X-ray fluoroscopy. (6) Furthermore, as a biodegradable embolization material, Even if the particles are the same or the same type of particles, the decomposition rate may vary greatly depending on the difference in the microenvironment where they are not.

  As a prior art, a vascular embolization material containing a specific drug made of biodegradable polylactic acid or poly (lactic acid / glycolic acid) copolymer has been disclosed (see Patent Document 1). The hydrophobicity was high, and there were problems (1) to (5) described above.

On the other hand, as block copolymers comprising polyethylene glycol (hereinafter referred to as PEG) and polylactic acid (hereinafter referred to as PLA) or a poly (lactic acid / glycolic acid) copolymer (hereinafter referred to as PLGA), PLA-PEG, PLA-PEG -Application to pharmaceutical / pharmaceutical applications in which a drug is mixed with a base polymer such as PLA, PLGA-PEG-PLGA and sustained release is disclosed (see Patent Document 2). However, this also has a high hydrophobicity of the base polymer, and has the above problems (1) to (5).
JP-A-5-969 Japanese Patent Publication No. 5-17245

  It is an object of the present invention to reliably occlude a target site without causing clogging in a catheter or a non-target tubular organ, and a blood flow occlusion state after a specific period regardless of an embolization site or an embolization environment. Is to provide biodegradable particles in which the material is decomposed in vivo and the degradation components can be metabolized or excreted from the body.

The object of the present invention is achieved by the following configurations.
(1) A biodegradable particle having a compressive elastic modulus of 280 MPa or less in a saturated water-containing state.
(2) A biodegradable particle characterized by a strength of 10 MPa or less when the compression volume is 5% in a saturated water-containing state.
(3) The biodegradable particle according to claim 1, wherein in a saturated water-containing state, the strength when the compression volume is 5% strain is 10 MPa or less.
(4) The biodegradable particle according to any one of (1) to (3), wherein the crushing strength is 700 kPa or more in a saturated water-containing state.
(5) The biodegradable particle according to any one of (1) to (4), wherein the weight in a saturated water-containing state is 105% or more as compared with the weight in a dry state.
(6) The biodegradable particle according to any one of (1) to (5), comprising a polyethylene glycol copolymer.
(7) The biodegradable particle according to any one of (1) to (6), wherein the average particle size is 60 to 2000 μm.
(8) the particle size distribution is characterized by an average particle diameter ± 100 [mu] m (1) ~ (7) Neu biodegradable particles according to any misalignment.
(9) The biodegradable particle according to any one of (1) to (8), wherein the shape is spherical at 37 ° C.
(10) The biodegradation according to any one of (1) to (9), wherein the residual weight after immersion in a phosphate buffered saline solution at 37 ° C. is 80% or less of the weight before immersion. Sex particles.
(11) The biodegradable particle according to any one of (1) to (10), which is used for medical use.
(12) The biodegradable particle according to (11), which is a particle for embolizing a tubular organ in a living body.
(13) The biodegradable particle according to (12), wherein a water-soluble X-ray contrast medium is held in the particle, and an embolized site and an embolized state can be confirmed in X-ray fluoroscopy.

  The biodegradable particles of the present invention can reliably occlude a target site without causing clogging in a catheter or a non-target tubular organ, and after a specific period regardless of the embolization site or embolization environment, The occlusion state is released, the material decomposes in vivo, and the degradation component can be metabolized or excreted from the body.

  The saturated water-containing state in the present invention refers to a state of being immersed in pure water at room temperature (25 ° C .: measurement chamber temperature) until the water content of the particles becomes constant. Here, the constant water content means a state in which the weight change is within 10%. Further, the compression elastic modulus, the strength at the time of 5% compression volume and the compressive strength in the present invention refer to values of the elastic modulus and strength obtained by performing measurement in the compression mode in the saturated state.

  As the vascular embolization material, a material having pressure resistance at the time of vascular embolization, elasticity that easily passes through the catheter, and strength capable of reliably controlling the embolism is preferable. The biodegradable particle of the invention of 1 is required to have a compression elastic modulus of 280 MPa or less in a saturated water-containing state. More preferably, it is 0.001-250 MPa. By having a compressive elastic modulus of 280 MPa or less in a water-containing state, the particles become soft and suitable as a material for use in a microcatheter and blood vessels.

The biodegradable particles of the second invention of the present invention are required to have a compression volume 5% strain strength of 10 MPa or less in a saturated water-containing state. More preferably 10Pa~8MP a. In a water-containing state, particles having a compression volume of 5% or less and a strain strength of 5% do not become hard and are suitable as materials for use in a microcatheter and blood vessels.

In the first to third aspects of the present invention, the crushing strength in a saturated water-containing state is preferably 700 kPa or more. More preferably, it is 1 MPa or more. Since the particles do not become brittle by having a crushing strength of 700 kPa or more in a water-containing state, and the possibility of clogging clogged substances in the microcatheter can be eliminated, it is more suitable as a material used in the microcatheter and blood vessels. Become.

  In addition, biodegradable particles that satisfy both the requirements of the first invention and the requirements of the second invention, that is, the compression elastic modulus and the compression volume 5% strain strength are further preferred embodiments.

  In the present invention, the compression elastic property can be evaluated as follows in accordance with Japanese Industrial Standard Z8841-1993.

[Measurement condition]
Compression testing machine: MCT-W500; Shimadzu Corporation test room temperature: 25 ° C
Test room humidity: 50%
Upper pressure indenter: Flat type φ500μm
Load speed: 207mN / sec
The compression elasticity measurement of the present invention is not particularly limited as long as particles in a saturated water content state can be measured, but when measuring by pulling up the particles from the immersion water, the volume change or / and the weight change of the particles are measured within 10%. I can do it.

  The compression elastic modulus of the present invention can be calculated according to Japanese Industrial Standard K7181-1994. The compression volume 5% strain strength and crushing strength are calculated by the following formula according to Reference 1.

S (5%) = 2.8P / πD2
St = 2.8P / πD2
Here, St (5%): strain 5% strength, P: test force, D: particle diameter, St: crushing strength.

(Reference 1: Yoshio Hiramatsu, Shun Sekiyuki, Hideo Motoyama: Journal of the Japan Mining Association, 81024 (1965))
In the present invention, the biodegradable particles are preferably composed of a biodegradable polymer or a copolymer in which a biodegradable polymer and a water-soluble polymer that can be discharged from the body are chemically bonded. Specifically, the weight average molecular weight of the biodegradable polymer or copolymer is preferably 1000 to 300000, and more preferably 2000 to 200000. If the weight average molecular weight is less than 1000, it is gel-like and may adhere to the catheter or blood vessel during delivery into the blood vessel, and the target site in the blood vessel may not be embolized, while the weight average molecular weight exceeds 300000. The above-mentioned range is preferable because the time required for the decomposition of the particles in the living body may be too long.

  The biodegradable particle is not particularly limited as long as the compression elastic modulus of the particle in a saturated water-containing state is 280 MPa or less, and the strength when the compression volume is 5% strain is 10 MPa or less. For example, α-hydroxy acid (Eg, lactic acid, glycolic acid, 2-hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxycaproic acid, 2-hydroxycapric acid, etc.), cyclic dimers of α-hydroxy acid (eg, lactide, glycolide, etc.) And one or more selected from hydroxycarboxylic acids (for example, malic acid, etc.), trimethylene carbonate which is a cyclic ester, ε-caprolactone, 1,4-dioxanone, 1,4-dioxepan-7-one Examples include the resulting polymer.

  Of the cyclic dimers of α-hydroxy acid, lactide and glycolide are preferable. Of the hydroxydicarboxylic acids, malic acid is preferred. When using 2 or more types of biodegradable polymer raw materials, the combination of lactic acid (or lactide) and glycolic acid (or glycolide) is preferable. Moreover, when using 2 or more types of biodegradable polymer raw materials, the combination of lactic acid (or lactide) and (epsilon) -caprolactone is preferable. Of the above, those having optical activity in the molecule may be any of D-form, L-form, D, and L-form.

  The water-soluble polymer chemically bonded to the biodegradable polymer is not particularly limited, and examples thereof include polyethylene glycol, polyacrylamide, polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, polyitaconic acid, and polyethylene oxide. Of these, polyethylene glycol is useful. Although the weight average molecular weight of a water-soluble polymer is not specifically limited, It is preferable that it is 2000-50000. In the present invention, by adjusting the content ratio of the water-soluble polymer in the copolymer, for example, by adjusting the polyethylene glycol content in the copolymer composed of lactic acid (or lactide) and polyethylene glycol to 80 to 20%, These particles achieve either a compression modulus of 280 MPa or less, a compression volume of 10% or less when the compression volume is 5% strain, and a particle having a crushing strength of 700 kPa or more.

  In the present invention, the biodegradable particles preferably have a plurality of biodegradable polymers or / and water-soluble polymers in an internally dispersed composite structure or a coated composite structure. In the case of a composite material, the compressive elastic modulus in a saturated water-containing state may be any of 280 MPa or less and the strength at the time of 5% compression strain is 10 MPa or less, but a biodegradable polymer having a weight average molecular weight of 300,000 or less, Or / and it is preferable to use a water-soluble polymer having a weight average molecular weight of 50,000 or less. In the present invention, by adjusting the content ratio of biodegradable polymers having different compression elastic properties and / or water-soluble polymers, for example, polylactic acid having a compression modulus of 300 MPa, water-soluble lactic acid / glycolic acid / polyethylene glycol (weight) By containing 80% to 20% of the average molecule 18000), the compression elastic modulus of the particles in a saturated water content state is 280 MPa or less, the compression volume is 5%, and the strength at the time of strain is 10 MPa or less. Particles having a crushing strength of 700 kPa or more can be obtained.

  When the biodegradable particle of the present invention is a copolymer in which a biodegradable polymer and a water-soluble polymer are chemically bonded, the copolymer has a compression elastic modulus of 280 MPa or less in a saturated water-containing state and a compression volume of 5% when strain is applied. However, a copolymer obtained by chemically combining the biodegradable polymer and the water-soluble polymer is preferable. Specifically, an embodiment that is a polyethylene glycol copolymer is preferred.

As a biodegradable polymer of the present invention, a method for producing a copolymer comprising a biodegradable polymer and a water-soluble polymer is exemplified. A method for synthesizing the water-insoluble polymer is not particularly limited, and examples thereof include melt polymerization and ring-opening polymerization. For example, in a dry air or dry nitrogen stream, a water-soluble polymer having a predetermined average molecular weight and a biodegradable polymer raw material as raw materials are charged into a polymerization tank equipped with a stirring blade, and the mixture is heated and stirred together with the catalyst. Can be obtained. 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 vented twin-screw kneading extruder or an apparatus having a stirring and feeding function similar thereto, continuously generated water while stirring, mixing, and degassing the biodegradable polymer raw material and catalyst in a molten state Polymerization can also be accomplished by removing the insoluble polymer. Furthermore, dissolve the produced water-insoluble polymer in a good solvent, drop the poor solvent to change the temperature of the white turbid matter after the precipitate is formed, dissolve the precipitate once, and then slowly return to the original temperature again. Thus, the separation accuracy can be increased by generating a 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. Then, by appropriately selecting the type of biodegradable polymer and water-soluble polymer, and further selecting the molecular weight thereof, the compression elastic modulus in a saturated water-containing state is 280 MPa or less, and the strength at the time of 5% compression strain is 10 MPa or less. achieved, it is possible to obtain the biodegradable particle crush strength is that Do or more 700 kPa. For example, when a polylactic acid-polyethylene glycol-polylactic acid copolymer is selected as the biodegradable polymer, the weight average molecular weight of the polylactic acid moiety is in the range of 1,000 to 300,000, and the weight average molecular weight of the polyethylene glycol moiety is in the range of 200 to 50,000. As a result, it is possible to achieve a compression elastic modulus of 280 MPa or less, a strength at a compression volume of 5% strain of 10 MPa or less in a saturated water-containing state, and a crushing strength of 700 kPa or more.

The shape of the biodegradable particle of the present invention is not particularly limited, but is preferably a spherical particle. Shapes of rods, cuboids, cubes, etc. have unclear particle diameters, and the embolization state varies depending on the direction of the particles when embolizing a blood vessel, but spherical particles enable more complete occlusion. As granulation methods, rolling granulation method, fluidized bed granulation method, spray bed granulation method, stirring granulation method, crushing granulation method, compression granulation method, extrusion granulation method, droplet solidification granulation Known methods such as the method can be employed. For example, in the droplet solidification granulation method, a water-insoluble polymer is dissolved in dichloromethane, chloroform, ethyl acetate, isopropyl ether, etc., and this is dispersed in an aqueous phase containing a surfactant, a protective colloid agent, etc. A particulate embolic material can be obtained by a method such as a / W type or W / O / W type submerged drying method or a method equivalent thereto, or a spray drying method. The surfactant and protective colloid used here are not particularly limited as long as they can form a stable oil / water emulsion. For example, anionic surfactants (sodium oleate, sodium stearate, sodium lauryl sulfate, etc.) ), Nonionic surfactants (polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, 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 is selected from 0.01 to 80 wt%, more preferably 0.05 to 60 wt%. By adjusting this concentration, the compression elastic modulus is 280 MPa or less and the compression volume is 5% strain in a saturated water-containing state. intensity when is achieving one of the following 10 MPa, more can be crushing strength is not less than 700 kPa. The particles thus produced are generally spherical particles, but some of them may be mixed with amorphous particles. For the purpose of removing such particles, a plurality of appropriate sieves can be used to obtain particles having a target average particle size and a target particle size distribution.

  In the present invention, the average particle size and particle size distribution refer to those in pure water or physiological saline at 25 ° C. Measurement of the average particle size and particle size distribution of the biodegradable particles of the present invention is possible with various commercially available measuring devices and is not particularly limited. For example, Coulter Multisizer II manufactured by Scientific Instruments Or III can be preferably used (electrical resistance method). Since the apparatus can perform measurement in physiological saline, it can measure in a form close to the environment in the blood vessel. Further, since each particle is measured one by one, the particle diameter of a specifically large particle or a specifically small particle can be measured. As the average particle diameter, a number average value or a volume average value can be calculated. Moreover, about the particle diameter at the time of drying, the value computed from the magnitude | size of an opening and the weight fractionated by the sieve can be measured as an average particle diameter (sieving method). Furthermore, it is also possible to obtain one by one by finding the radius with the outline as a circle under the microscope and averaging the number (direct observation method).

  The average particle size of the biodegradable particles of the present invention is preferably 20 to 2000 μm. It is preferable to be in such a range from the diameter of the tubular organ to be embolized. If the average particle size is too large or too small, it will be difficult to embolize the target blood vessel site. Therefore, in actual use, it can be appropriately selected according to the diameter of the tubular organ to be embolized. preferable. The particle size distribution is preferably small for the purpose of more complete embolization. The distribution width is preferably in the range of average particle size ± 100 μm, more preferably average particle size ± 50 μm.

  The biodegradable particles of the present invention can be used for arterial embolization and chemoembolization to prevent the development of new vegetative blood vessels, i.e. after 28 days of immersion in phosphate buffered saline at 37 ° C. The remaining weight is preferably 80% or less of the weight before immersion. Further, the remaining weight after immersion in the phosphate buffer solution at 37 ° C. is 50% or less of the weight before immersion, and the remaining weight after 7 days of immersion in the phosphate buffer solution at 37 ° C. is 50% of the weight before immersion. More preferably, it is% or less.

  The biodegradable particles of the present invention can be used as they are or after being dispersed in a suitable dispersion medium or contrast medium at the time of use. As the water-soluble contrast agent, known ones can be used, and either an ionic contrast agent or a nonionic contrast agent may be used. Specific examples include Iopamylon (manufactured by Schering), Hexabrix (manufactured by Eiken Chemical), Omnipark (manufactured by Daiichi Pharmaceutical), Urografin (manufactured by Schering), and Iomeron (manufactured by Eisai). The biodegradable particles and the contrast agent of the present invention can be mixed before use and then injected into a predetermined site. When the tubular organ embolization material of the present invention is highly water-swellable, it is preferable because a part of the contrast agent is impregnated and held inside the particles together with water to exhibit contrast. 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. The dispersed particles are administered from an appropriate artery to a tumor-dominating artery via a catheter guided to the vicinity of the desired embolization site while monitoring the position of the contrast agent by fluoroscopy. In addition, preservatives, stabilizers, tonicity agents, solubilizers, dispersants, excipients and the like that are usually used for injections may be added to the embolic material.

  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, anticancer drugs (eg, Smanx, mitomycin, adreamycin, vinblastine), angiogenesis inhibitors, steroidal hormone drugs, liver disease drugs, gout treatment drugs, diabetes drugs, cardiovascular drugs, hyperlipidemia drugs, bronchodilators , Antiallergic drugs, digestive tract drugs, antipsychotics, chemotherapeutic agents, antioxidants, peptide drugs, protein drugs (for example, interferon) and the like.

  Next, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

<Example 1>
Under a nitrogen stream, 40.3 g of L-lactide (manufactured by Pyrac) and 17.3 g of polyethylene glycol (manufactured by Wako Pure Chemical Industries, Ltd.) having an average molecular weight of about 20,000 were mixed in a flask and dissolved and mixed at 140 ° C. Then, 8.1 mg of tin dioctanoate (manufactured by Wako Pure Chemical Industries, Ltd.) was added and reacted at 180 ° C. to obtain a polylactic acid-polyethylene glycol-polylactic acid copolymer. This copolymer was dissolved in chloroform and dropped into a large excess of methanol to obtain a white precipitate. The weight average molecular weight by GPC method was about 39000.

  The purified copolymer was dissolved in dichloromethane, and spherical particles were obtained by a drying method in an O / W solution. Fractionation was performed with a nylon mesh, followed by vacuum drying and then classification by sieving. When the particle distribution around 100 particles was measured by a direct observation method using an ultra-deep shape measurement microscope “VK-8500” manufactured by Keyence Corporation, spherical particles having an average particle diameter of 140 μm and a distribution of ± 30 μm were obtained. Obtained. When this fractionated particle was immersed in pure water at room temperature, it became constant in about 3 hours (weight change 170% before water impregnation), and spherical particles having an average particle size of about 185 μm and a distribution of ± 50 μm were obtained. When the particles were subjected to a compression test, the compression elastic modulus was 66 MPa, the strength when the compression volume was 5% strain was 2.3 MPa, and the crushing strength was 115 MPa.

  When the spherical particle dispersion is injected from a syringe into a CORDIS (Cordis) catheter MASS TRANSIT (mass transit; total length of about 1400 mm, tip length of 180 mm, tip inner diameter of about 680 μm), it can be injected without resistance. It was. 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 above spherical particles were added to phosphate buffered saline (PBS; pH 7.3). After 28 days at 37 ° C., the solid content was removed with a membrane filter having a pore size of about 0.2 μm, dried in a vacuum and then treated. When the remaining weight was determined in comparison with the previous weight, it was 74%.

  Further, by the fractionation with the nylon mesh, a spherical particle dispersion having an average particle diameter of about 90 μm and a distribution of ± 50 μm in physiological saline was obtained. Subsequently, a 24 G indwelling needle was inserted into the femoral vein of a 10-week-old rat anesthetized with Nembutal, and this spherical particle dispersion was injected. Two weeks later, lung appearance was observed and tissue sections were prepared. Four rats were each injected with a spherical particle dispersion, and tissue sections were observed. As a result, lung infarction was observed in all four rats.

<Example 2>
In the same manner as in Example 1, a polylactic acid-polyethylene glycol (manufactured by NOF Corporation, average molecular weight 20000) -polylactic acid copolymer (weight average molecular weight of about 40000) was synthesized. In the same manner as in Example 1, spherical particles having an average particle diameter of 185 μm and a distribution of ± 40 μm were obtained in a saturated water-containing state (weight change 174% before water impregnation). As a result of a compression test of the particles, the compression modulus was 75 MPa, the strength at 5% compression volume strain was 2.4 MPa, and the crushing strength was 3400 MPa.

  This spherical particle dispersion is injected from a syringe into a catheter MASS TRANSIT manufactured by CORDIS (Cordis) (mass transit: total length of about 1400 mm, tip length of 180 mm, tip tip inner diameter of about 680 μm), and can be injected without resistance. It was. Thereafter, the catheter was incised in the longitudinal direction, and when the inside of the catheter was visually observed, no spherical particles were observed.

<Example 3>
Under a nitrogen stream, 26.8 g of L-lactide (Purac), 13.4 g of glycolic acid, and 17.3 g of polyethylene glycol (Nippon Yushi Co., Ltd.) having a dehydrated average molecular weight of 20000 were mixed at 140 ° C. Then, 8.1 mg of tin dioctanoate (manufactured by Wako Pure Chemical Industries, Ltd.) was added and reacted at 180 ° C. in the same manner as in Example 1, and polylactic acid / glycolic acid-polyethylene glycol (average) Molecular weight 20000) -polylactic acid / glycolic acid copolymer (weight average molecular weight of about 27000) was obtained. Subsequently, spherical particles having an average particle diameter of 260 μm and a distribution of ± 50 μm were obtained in a saturated water-containing state (weight change 211% of the ratio before water impregnation) in the same manner as in Example 1. As a result of a compression test of the particles, the compression modulus was 13 MPa, the strength when the compression volume was 5% strain was 0.5 MPa, and the crushing strength was 31 MPa.

  This spherical particle dispersion is injected from a syringe into a catheter MASS TRANSIT manufactured by CORDIS (Cordis) (mass transit: total length of about 1400 mm, tip length of 180 mm, tip tip inner diameter of about 680 μm), and can be injected without resistance. It was. Thereafter, the catheter was incised in the longitudinal direction, and when the inside of the catheter was visually observed, no spherical particles were observed.

<Example 4>
Under a nitrogen stream, 26.8 g of L-lactide (manufactured by Purac), 13.4 g of glycolic acid and 17.3 g of polyethylene glycol having a dehydrated average molecular weight of 20,000 (manufactured by Wako Pure Chemical Industries, Ltd.) were mixed. After dissolving and mixing at ℃, 8.1 mg of tin dioctanoate (manufactured by Wako Pure Chemical Industries, Ltd.) was added and reacted at 180 ℃ in the same manner as in Example 1, and polylactic acid / glycolic acid-polyethylene glycol ( Average molecular weight 20000) -polylactic acid / glycolic acid copolymer (weight average molecular weight about 25000) was obtained. Subsequently, spherical particles having an average particle diameter of 360 μm and a distribution of ± 50 μm were obtained in a saturated water-containing state (weight change 211% of the ratio before water impregnation) in the same manner as in Example 1. As a result of a compression test of the particles, the compression modulus was 11 MPa, the strength when the compression volume was 5% strain was 0.4 MPa, and the crushing strength was 3 MPa.

  This spherical particle dispersion is injected from a syringe into a catheter MASS TRANSIT manufactured by CORDIS (Cordis) (mass transit: total length of about 1400 mm, tip length of 180 mm, tip tip inner diameter of about 680 μm), and can be injected without resistance. It was. Thereafter, the catheter was incised in the longitudinal direction, and when the inside of the catheter was visually observed, no spherical particles were observed.

<Example 5>
Polylactic acid-polyethylene glycol (manufactured by NOF Corporation, average molecular weight 20000) -polylactic acid copolymer (weight average molecular weight of about 40000) and polylactic acid (weight average molecular weight of about 70000) were mixed in a weight ratio of 3 to 7, In the same manner as in Example 1, spherical particles having an average particle diameter of 185 μm and a distribution of ± 50 μm were obtained in a saturated water-containing state (weight change 107% of the ratio before water impregnation). As a result of a compression test of the particles, the compression modulus was 255 MPa, the strength when the compression volume was 5% strain was 10.1 MPa, and the crushing strength was 5500 MPa.

  This spherical particle dispersion is injected from a syringe into a catheter MASS TRANSIT manufactured by CORDIS (Cordis) (mass transit: total length of about 1400 mm, tip length of 180 mm, tip tip inner diameter of about 680 μm), and can be injected without resistance. It was. Thereafter, the catheter was incised in the longitudinal direction, and when the inside of the catheter was visually observed, no spherical particles were observed.

<Example 6>
Polylactic acid (weight average molecular weight of about 70,000) was averaged in a 40% polyvinyl alcohol (weight average molecular weight 50000) aqueous solution in a saturated water-containing state (weight change 104% of water pre-impregnation ratio) in the same manner as in Example 1. Spherical particles having a diameter of 260 μm and a distribution of ± 60 μm were obtained. When the particles were subjected to a compression test, the compression elastic modulus was 276 MPa, the strength when the compression volume was 5% strain was 10.3 MPa, and the crushing strength was 26000 MPa or more.

  This spherical particle dispersion is injected from a syringe into a catheter MASS TRANSIT manufactured by CORDIS (Cordis) (mass transit: total length of about 1400 mm, tip length of 180 mm, tip tip inner diameter of about 680 μm), and can be injected without resistance. It was. Thereafter, the catheter was incised in the longitudinal direction, and when the inside of the catheter was visually observed, no spherical particles were observed.

<Example 7>
Example 1 A polylactic acid / glycolic acid-polyethylene glycol having a weight average molecular weight of about 30000 (Nippon Yushi Co., Ltd., average molecular weight 20000) and polylactic acid (weight average molecular weight of about 70000) were mixed in a weight ratio of 2 to 8. In the same manner, spherical particles having an average particle diameter of 185 μm and a distribution of ± 50 μm were obtained in a saturated water-containing state (weight change 108% of the ratio before water impregnation). As a result of a compression test of the particles, the compression modulus was 290 MPa, the strength when the compression volume was 5% strain was 6.5 MPa, and the crushing strength was 26000 MPa or more.

  This spherical particle dispersion is injected from a syringe into a catheter MASS TRANSIT manufactured by CORDIS (Cordis) (mass transit: total length of about 1400 mm, tip length of 180 mm, tip tip inner diameter of about 680 μm), and can be injected without resistance. It was. Thereafter, the catheter was incised in the longitudinal direction, and when the inside of the catheter was visually observed, no spherical particles were observed.

  From the above, particles having a low compressive modulus or / and 5% compressive volume strain strength could easily pass through without clogging in the catheter.

<Example 8>
Using a polylactic acid / glycolic acid-polyethylene glycol having a weight average molecular weight of about 30,000 (Nippon Yushi Co., Ltd., average molecular weight 20000) in the same manner as in Example 1, saturated water content (weight change in water pre-impregnation ratio) Spherical particles having an average particle size of 260 μm and a distribution of ± 100 μm were obtained. As a result of a compression test of the particles, the compression modulus was 0.1 MPa or less, the strength at 5% compression volume strain was 0.001 MPa or less, and the crushing strength was less than 0.7 MPa.

  When the spherical dispersion of polylactic acid was injected from a syringe into a catheter MASS TRANSIT manufactured by CORDIS (total length: about 1400 mm, tip length: 180 mm, tip inner diameter: about 680 μm). The deformed particles passed through the catheter without resistance.

  From the above, particles having a low compressive modulus or / and a compressive volume 5% strain strength and a small crushing strength were able to pass through the catheter without clogging even when a collapsed material was generated in the catheter.

<Comparative Example 1>
Using polylactic acid (weight average molecular weight of about 70,000), spherical particles having an average particle diameter of 185 μm and a distribution of ± 30 μm are obtained in the saturated water-containing state (weight change 102% of the ratio before water impregnation) in the same manner as in Example 1. It was. When the particles were subjected to a compression test, the compression elastic modulus was 300 MPa, the strength at 5% compression volume strain was 10.9 MPa, and the crushing strength was 26000 MPa or more.

  The spherical dispersion of polylactic acid was injected from a syringe into a CORDIS catheter MASS TRANSIT (total length: about 1400 mm, tip length: 180 mm, tip inner diameter: about 680 μm). Spherical particles aggregated and became impossible to inject with strong resistance.

  From the above, the compression elastic modulus or the compression volume 5% strain strength was large, and hard particles were easily clogged in the catheter and could not pass through the catheter.

<Comparative example 2>
A powder of polylactic acid (weight average molecular weight of about 70,000) is put into a tableting mold having a diameter of 350 μm, and the upper and lower molds are compressed to have an average particle diameter of 350 μm in a saturated water-containing state (weight change of 102% before water impregnation). Spherical particles with a distribution of ± 30 μm were obtained. When the particle was subjected to a compression test, the compression modulus was 281 MPa, the material was crushed before being compressed by 5%, and the crushing strength was less than 0.7 MPa.

  The spherical dispersion of polylactic acid was injected from a syringe into a CORDIS catheter MASS TRANSIT (total length: about 1400 mm, tip length: 180 mm, tip inner diameter: about 680 μm). Spherical particles agglomerated and showed strong resistance together with the crushing material, making injection impossible.

  From the above, the particles having a large compressive elasticity modulus and fragile particles were easily clogged in the catheter, and could not pass through the catheter.

Claims (11)

Strength at the time of 5% compression volume in a saturated water-containing state is 10.3 MPa or less,
The compression elastic modulus in a saturated water-containing state is 280 MPa or less,
alpha-hydroxy acids, alpha-cyclic dimer of hydroxy acid, 1 or more and a polymer of monomers selected from the group consisting of hydroxycarboxylic acids and cyclic esters, or copolymers over the water-soluble polymer is chemically bonded Biodegradable particles composed of The biodegradable particle according to claim 1, wherein the water-soluble polymer is selected from the group consisting of polyethylene glycol, polyacrylamide, polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, polyitaconic acid and polyethylene oxide. The biodegradable particles according to claim 1 or 2 , wherein the crushing strength in a saturated water-containing state is 700 kPa or more. The biodegradable particle according to any one of claims 1 to 3 , wherein the water content is 104% or more. The biodegradable particles according to any one of claims 1 to 4 , wherein the average particle size is 60 to 2000 µm. The biodegradable particles according to any one of claims 1 to 5 , wherein the particle size distribution is an average particle size ± 100 µm. The biodegradable particle according to any one of claims 1 to 6 , which is spherical at 37 ° C. The biodegradable particles according to any one of claims 1 to 7 , wherein the residual weight on the 28th day after being immersed in a phosphate buffered physiological saline at 37 ° C is 80% or less of the weight before the immersion. The biodegradable particle according to any one of claims 1 to 8 , which is used for medical use. The biodegradable particle according to claim 9 , which embodies a tubular organ in a living body. The biodegradable particle according to claim 10 , wherein a water-soluble X-ray contrast agent is held in the particle, and an embolized site and an embolized state can be confirmed in X-ray fluoroscopy.