WO2012133608A1 - 生分解性粒子、血管塞栓材料及び生分解性粒子の製造方法 - Google Patents
生分解性粒子、血管塞栓材料及び生分解性粒子の製造方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0042—Materials resorbable by the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/148—Materials at least partially resorbable by the body
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
- C08G63/08—Lactones or lactides
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/66—Polyesters containing oxygen in the form of ether groups
- C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/28—Treatment by wave energy or particle radiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2367/00—Characterised by the use of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Derivatives of such polymers
- C08J2367/04—Polyesters derived from hydroxy carboxylic acids, e.g. lactones
Definitions
- the present invention relates to a biodegradable particle, a vascular embolization material, and a method for producing the biodegradable particle.
- Patent Document 1 Blocking of poly (lactic acid / glycolic acid) copolymer (Patent Document 1), polyethylene glycol and polylactic acid, etc. for hemostasis at incision of affected area, blocking of nutrient supply to tumor, maintenance of anticancer drug concentration in tumor A copolymer (Patent Documents 2 to 5) or a multi-block copolymer (Patent Document 6) obtained by copolymerizing lactic acid, polyethylene glycol and polyvalent carboxylic acid is used as polymer particles for embolization of blood vessels and the like.
- Such polymer particles for embolization of blood vessels, etc. are spherical particles that are used to securely embolize blood vessels and the like without gaps, but are transported to a target site such as a blood vessel through a microcatheter or the like. Therefore, the polymer particles themselves have problems such as clogging in the catheter due to lack of flexibility or aggregation, or deformation of the polymer particles until they reach the target site, and the shape cannot be restored. .
- Patent Document 7 the surface of polymer particles is coated with polyethylene glycol to prevent agglomeration and improve catheter passage
- Patent Document 8 the flexibility of polymer particles by blending multiple types of polymers.
- JP-A-5-969 Japanese Patent Publication No. 5-17245 JP 2004-167229 A JP 2005-31623 A JP 2007-291323 A US Patent Application Publication No. 2009/0117033 JP 2007-145826 A JP 2007-146146 A JP 2005-314535 A
- an object of the present invention is to provide a biodegradable vascular embolization material in which aggregation is unlikely to occur, flexibility is improved, and particle shape is restored after passing through a catheter or the like.
- the present invention provides biodegradable particles, vascular embolization materials, and methods for producing the same as described in (1) to (9) below.
- a water-soluble, biodegradable copolymer having a structure consisting of at least hydroxycarboxylic acid a1 and hydroxycarboxylic acid a2, and a functional group selected from the group consisting of a hydroxyl group, an amino group and a carboxylic acid group at both ends A homopolymer comprising a block copolymer obtained by copolymerizing a polymer and a polyvalent compound having two or more functional groups selected from the group consisting of a hydroxyl group, an amino group and a carboxylic acid group, wherein the hydroxycarboxylic acid a1 is homopolymerized.
- the glass transition point of the homopolymer obtained by homopolymerizing the hydroxycarboxylic acid a2 is -40 ° C or less, and the hydroxycarboxylic acid a2 occupies the biodegradable copolymer.
- A represents a block composed of the biodegradable copolymer or a copolymer in which two or more biodegradable copolymers are covalently bonded
- B represents a block composed of the water-soluble polymer
- C represents a single bond. Or the structure which consists of the said polyvalent compound is represented, n represents an integer greater than or equal to 1.
- (3) The (1) or (2) above, wherein the 40% compression load in a saturated water-containing state is 500 mN or less, and the compression recovery rate is 40% or more when the compression rate in the saturated water-containing state is 10%.
- the glass transition point of a homopolymer having at least a hydroxycarboxylic acid a1 and a hydroxycarboxylic acid a2 and homopolymerized with the hydroxycarboxylic acid a1 is 40 ° C. or higher, and the hydroxycarboxylic acid a2 is single.
- the glass transition point of the polymerized homopolymer is ⁇ 40 ° C. or less, and the weight ratio of the structure composed of hydroxycarboxylic acid a2 in the biodegradable copolymer is 30 to 90% by weight.
- the copolymer has, at both ends, a water-soluble polymer having a functional group selected from the group consisting of a hydroxyl group, an amino group and a carboxylic acid group, and two or more functional groups selected from the group consisting of a hydroxyl group, an amino group and a carboxylic acid.
- a block copolymer to obtain a block copolymer by copolymerizing with a polyvalent compound, and the block copolymer And sterilizing comprising: a granulating step for obtaining biodegradable particles; and a radiation irradiation step for obtaining sterilized biodegradable particles by irradiating the biodegradable particles with radiation.
- a method for producing biodegradable particles comprising: a granulating step for obtaining biodegradable particles; and a radiation irradiation step for obtaining sterilized biodegradable particles by irradiating the biodegradable particles with radiation.
- the biodegradable particles of the present invention can be suitably used as a vascular embolization material because the polymer particles do not easily aggregate with each other and can easily reach a target site such as a blood vessel without clogging inside a catheter or the like. Furthermore, since the biodegradable particles of the present invention have an improved resilience of the particle shape after passing through a catheter or the like, the target site can be effectively embolized with the minimum necessary amount.
- the biodegradable particle of the present invention has a structure selected from the group consisting of a biodegradable copolymer having at least a hydroxycarboxylic acid a1 and a hydroxycarboxylic acid a2 and a hydroxyl group, an amino group and a carboxylic acid group at both ends.
- a block copolymer comprising a water-soluble polymer having a group and a polyvalent compound having two or more functional groups selected from the group consisting of a hydroxyl group, an amino group, and a carboxylic acid group, and the hydroxycarboxylic acid described above
- the glass transition point of the homopolymer obtained by homopolymerizing a1 is 40 ° C.
- the glass transition point of the homopolymer obtained by homopolymerizing the hydroxycarboxylic acid a2 is ⁇ 40 ° C. or lower, and the biodegradation described above.
- the weight ratio of the structure comprising hydroxycarboxylic acid a2 in the functional copolymer is 30 to 90% by weight. And butterflies.
- Biodegradable refers to the property that particles or biodegradable copolymers composed of the specific block copolymer described above are decomposed or dissolved, absorbed, or metabolized in vivo, or discharged from the living body to the outside of the living body.
- “Hydroxycarboxylic acid” includes a cyclic compound such as an acid halide of hydroxycarboxylic acid, an acid anhydride of hydroxycarboxylic acid, an ester of hydroxycarboxylic acid, and a cyclic dimer of hydroxycarboxylic acid. Moreover, about the hydroxycarboxylic acid which has an optical isomer like malic acid or tartaric acid, all of D-form, L-form, or those mixtures are contained. Furthermore, a copolymer formed by copolymerizing these hydroxycarboxylic acids is also included.
- Examples of the hydroxycarboxylic acid include glycolic acid, lactic acid, glyceric acid, hydroxybutyric acid, malic acid, tartaric acid, hydroxyvaleric acid, 3-hydroxyhexanoic acid, and 6-hydroxycaproic acid.
- Examples of the cyclic compound comprising hydroxycarboxylic acid include glycolide, which is a cyclic dimer of glycolic acid, lactide, which is a cyclic dimer of lactic acid, and ⁇ -caprolactone corresponding to 6-hydroxycaproic acid.
- Examples of the copolymer formed by copolymerizing hydroxycarboxylic acids include a copolymer of lactic acid and glycolic acid or a copolymer of 6-hydroxycaproic acid and glycolic acid.
- examples of the “hydroxycarboxylic acid a1” in which the homopolymerized homopolymer has a glass transition point of 40 ° C. or higher include, for example, lactic acid, a copolymer of lactic acid and glycolic acid, a copolymer of lactic acid and terephthalic acid, and lactic acid and isophthalic acid.
- ком ⁇ онент or less include, for example, 6-hydroxycaproic acid, 6-hydroxycaproic acid and glycolic acid And a copolymer of 6-hydroxycaproic acid and polybutylene succinate (copolymer of 1,4-butanediol and succinic acid).
- lactic acid is preferred as the hydroxycarboxylic acid a1
- 6-hydroxycaproic acid is preferred as the hydroxycarboxylic acid a2.
- “Homopolymer” refers to a polymer formed by polymerization of one kind of monomer, such as polylactic acid formed by polymerization of lactic acid alone, but one kind such as a copolymer of lactic acid and glycolic acid. A polymer obtained by further polymerizing the above copolymer is also included in the “homopolymerized homopolymer” referred to in the present invention.
- a polymer compound having a high glass transition point is hard, has high rigidity, and has low fluidity, so that the mobility of the polymer molecular chain is low.
- the glass transition point of a homopolymer obtained by homopolymerizing the hydroxycarboxylic acid a1 Is preferably 50 ° C. or higher, and more preferably 55 ° C. or higher.
- the glass transition point of the homopolymer obtained by homopolymerizing the hydroxycarboxylic acid a2 is preferably ⁇ 50 ° C. or less, and more preferably ⁇ 55 ° C. or less.
- Biodegradable copolymer refers to a copolymer having biodegradability.
- the copolymer refers to a polymer compound obtained by copolymerizing two or more types of monomers, that is, a copolymer having a structure composed of two or more types of monomers.
- the biodegradable copolymer in the present invention needs to have a structure composed of at least hydroxycarboxylic acid a1 and hydroxycarboxylic acid a2, that is, it must contain hydroxycarboxylic acid a1 and hydroxycarboxylic acid a2 as monomers as raw materials.
- monomers such as glycolic acid or glycolide, ethylene glycol, propylene glycol, trimethylene glycol, diethylene glycol or 1,4-butanediol, oxalic acid, malonic acid, succinic acid, glutaric acid, Dicarboxylic acids such as adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, malic acid, tartaric acid or dodecanedioic acid, or acid halides, acid anhydrides or esters thereof may be mentioned, but glycolic acid or glycolide or poly Butylene succinate monomers are preferred.
- Hydroxycarboxylic acid a1 and hydroxycarboxylic acid a2 may each be a mixture of two or more hydroxycarboxylic acids.
- the monomer a3 may also be a mixture of two or more compounds.
- the weight ratio of the structure composed of hydroxycarboxylic acid a2 in the biodegradable copolymer is required to be 30 to 90% by weight, but the flexibility of the resulting biodegradable particles is moderate. Therefore, the weight ratio is preferably 50 to 85% by weight, and more preferably 70 to 80% by weight.
- the weight ratio of the structure comprising monomer a3 in the biodegradable copolymer is preferably 5% by weight or more in order to further improve biodegradability. It is preferably 10% by weight or more. On the other hand, in order not to lower the solubility in an organic solvent, the weight ratio is preferably 35% by weight or less, and more preferably 30% by weight or less.
- the weight average molecular weight of the biodegradable copolymer is preferably 200 to 100,000, and more preferably 1000 to 80,000.
- the weight average molecular weight of the biodegradable copolymer can be measured by a gel permeation chromatography method (hereinafter referred to as “GPC method”) under the following conditions.
- water-soluble polymer having a functional group selected from the group consisting of a hydroxyl group, an amino group and a carboxylic acid group at both ends examples include polyalkylene glycols such as polyethylene glycol (hereinafter “PEG”) or polypropylene glycol Alternatively, these derivatives or copolymers of alkylene glycol and a large excess of dicarboxylic acid may be mentioned, but water-soluble polymers having hydroxyl groups at both ends are preferred, and PEG is more preferred because of high biocompatibility and biodegradability.
- the carboxylic acid group may be converted to an acid halide structure, an ester structure, or an acid anhydride structure.
- the weight average molecular weight of the water-soluble polymer is preferably 200 to 50000, and more preferably 1000 to 40000 or less.
- the weight average molecular weight of the water-soluble polymer can be measured by a GPC method.
- Examples of the “polyvalent compound having two or more functional groups selected from the group consisting of a hydroxyl group, an amino group and a carboxylic acid group” include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, and suberin.
- dicarboxylic acids such as acid, azelaic acid, sebacic acid, malic acid, tartaric acid or dodecanedioic acid, citric acid, or hyperbranched polymers such as hyperbranched polymers or dendrimers
- it consists of a hydroxyl group, amino group and carboxylic acid group at the branch end
- examples thereof include those having two or more functional groups selected from the group, or acid halides, acid anhydrides or esters thereof. That is, the carboxylic acid group may be converted into an acid halide structure, an ester structure, or an acid anhydride structure.
- Block copolymer refers to a copolymer having a molecular structure in which two or more types of polymers having different properties are connected by covalent bonds to form a long chain. Block refers to “two types of different properties that constitute a block copolymer”. Each of the above-mentioned polymers is said.
- the block copolymer of the present invention is a copolymer obtained by copolymerizing the above biodegradable copolymer, the above water-soluble polymer, and the above polyvalent compound.
- the hydroxyl group or amino group at the terminal of the water-soluble polymer can form a covalent bond with the carboxylic acid group of the polyvalent compound.
- the carboxylic acid group which the water-soluble polymer has at its terminal can form a covalent bond with the hydroxyl group or amino group of the polyvalent compound.
- the carboxylic acid group which each has may be converted into an acid halide structure, an ester structure, or an acid anhydride structure.
- Nb which is the number of moles of the water-soluble polymer
- m which is the number of hydroxyl groups, amino groups and carboxylic acid groups of the polyvalent compound
- Nc which is the number of moles of the polyvalent compound
- Nb Wb / Mwb Equation 2
- Wb Weight of water-soluble polymer used for copolymerization (g)
- Mwb Weight average molecular weight of water-soluble polymer used for copolymerization (g / mol)
- Nc Wc / Mwc Equation 3
- Wc Weight of polyvalent compound used for copolymerization (g)
- Mwc Molecular weight of polyvalent compound used for copolymerization (g / mol)
- the weight average molecular weight of the block copolymer is preferably 3000 to 300000, more preferably 4000 to 200000.
- the weight average molecular weight of said block copolymer can be measured by GPC method.
- the weight ratio of the block A to the block B is preferably 100 to 600% by weight, and 150 to 550% by weight in order to make the solubility in water or an organic solvent appropriate. More preferably, it is 200 to 500% by weight.
- the weight ratio of the specific structure in the biodegradable copolymer and the weight ratio of the block A to the block B in the multi-block copolymer are determined by proton nuclear magnetic resonance spectroscopy (hereinafter referred to as “ 1 H-NMR”) under the following conditions. ”) Can be calculated from the measurement results.
- 1 H-NMR proton nuclear magnetic resonance spectroscopy
- a hydrogen atom at the ⁇ -position (chemical shift value: about 5.2 ppm) which is a methine group is characteristic.
- the hydroxycarboxylic acid a2 is 6-hydroxycaproic acid
- a hydrogen atom at the ⁇ -position that is a methylene group is characteristic.
- the biodegradable particles of the present invention are characterized in that a 40% compression load in a saturated water-containing state is 500 mN or less, and a compression recovery rate when the compression rate in a saturated water-containing state is 10% is 40% or more. To do.
- “Saturated water content” means that about 20 mg of biodegradable particles are immersed in 10 mL of phosphate buffered saline at 37 ° C. (the test tube as a container is rotated at a rate of 0.5 times / second using a rotator). When the contents are rotated and the contents are shaken), the water content of the biodegradable particles is constant.
- “constant water content” means a state in which the weight of biodegradable particles immersed in a phosphate buffered saline solution at 37 ° C. is measured every 1 minute, and the rate of change with time is within 10%.
- the rate of change over time is a value Rw (%) calculated by the following equation 4.
- 40% compressive load is an index indicating the flexibility of biodegradable particles, and refers to a load required to compress one biodegradable particle to a particle size of 40% of the original particle. If the 40% compressive load is too small, the shape of the biodegradable particles cannot be maintained. On the other hand, if the 40% compressive load is too large, resistance when passing through a catheter or the like increases.
- the 40% compressive load in the saturated water-containing state of the conductive particles is preferably 5 to 500 mN, and more preferably 10 to 450 mN.
- the 40% compressive load of the biodegradable particles of the present invention in a saturated water-containing state can be measured under the following conditions using a micro compression tester. Specifically, a load is applied to the particles up to the following set test force, and a load for compressing the particles to a particle size of 40% of the original particles is measured.
- “Compression recovery rate” indicates the ability of the biodegradable particles released from compression to return to the original particle shape before compression, that is, after passing through a catheter having a small inner diameter, that is, the restoring force of the particle shape. An indicator. If the compression recovery rate is too small, the biodegradable particles will flow further downstream than the target site of the blood vessel to be embolized. Therefore, the compression rate in the saturated water-containing state of the biodegradable particles of the present invention is 10%.
- the compression recovery rate is preferably 40% or more, and more preferably 50% or more.
- the compression recovery rate when the compression rate of the biodegradable particle of the present invention in a saturated water content state is 10% is similarly measured using the micro compression tester under the following conditions, and calculated by the following equations 5 to 7. Value Rr (%). Specifically, for each particle, a load is applied to a set test force when the compression rate obtained by the compression test is 10% (that is, the maximum test force), and then the unloading is performed to the minimum test force.
- the average particle size of the biodegradable particles of the present invention is preferably 5 to 2000 ⁇ m, more preferably 10 to 1500 ⁇ m, considering the diameter of the blood vessel that is the main target site of embolism.
- the particle size of the medical biodegradable particles of the present invention can be measured by a light scattering method.
- the vascular embolization material of the present invention is characterized by comprising the biodegradable particles of the present invention.
- the biodegradable particles of the present invention When used as a vascular embolization material, the biodegradable particles may be used as they are, or may be used after being dispersed in a contrast medium or a dispersion medium.
- the contrast agent include water-soluble contrast agents such as iopamidol injection, oxaglic acid injection or iohexol injection, and oil-based contrast agents such as iodinated poppy oil, but water-soluble contrast agents are preferred.
- the dispersion medium examples include a dispersing agent such as polyoxysorbitan fatty acid ester, a retention agent such as methylparaben, or an isotonic agent such as sodium chloride, an aqueous solution for injection, or vegetable oil such as sesame oil or corn oil.
- a dispersing agent such as polyoxysorbitan fatty acid ester
- a retention agent such as methylparaben
- an isotonic agent such as sodium chloride
- an aqueous solution for injection or vegetable oil such as sesame oil or corn oil.
- medicinal components such as preservatives, stabilizers, solubilizers, excipients or anticancer agents may be added to the vascular embolization material.
- the method for producing a sterilized biodegradable particle according to the present invention comprises the step of copolymerizing the biodegradable copolymer, the water-soluble polymer, and the polyvalent compound to obtain the block copolymer. Polymerization step, granulating the block copolymer to obtain biodegradable particles, granulation step, and irradiation of the biodegradable particles to obtain sterilized biodegradable particles, radiation irradiation And a process.
- the “copolymerization step” is a step of obtaining a block copolymer by copolymerizing the biodegradable copolymer, the water-soluble polymer, and the polyvalent compound.
- a biodegradable copolymer is obtained in advance, and this is further copolymerized with the water-soluble polymer and the polyvalent compound.
- a mixture of hydroxycarboxylic acid a1 and hydroxycarboxylic acid a2 (and monomer a3 as necessary) may be copolymerized simultaneously.
- hydroxycarboxylic acid a1 and the hydroxycarboxylic acid a2 may be copolymerized in advance, and the monomer a3 may be added when this is further copolymerized with the water-soluble polymer and the polyvalent compound.
- the hydroxycarboxylic acid a1 when the hydroxycarboxylic acid a1, the hydroxycarboxylic acid a2 and the monomer a3 are lactic acid, 6-hydroxycaproic acid and glycolic acid, respectively, a condensation polymerization method is preferred.
- the hydroxycarboxylic acid a1 when the hydroxycarboxylic acid a1, the hydroxycarboxylic acid a2 and the monomer a3 are cyclic compounds such as lactide, ⁇ -caprolactone and glycolide, respectively, the ring-opening polymerization method is preferred.
- a good solvent for hydroxycarboxylic acid a1 and hydroxycarboxylic acid a2 (and, if necessary, monomer a3) is used.
- the reaction temperature is preferably set so that the good solvent used is refluxed.
- the reaction pressure may be in a reduced pressure state, but normal pressure is preferable because the operation is easy.
- the reaction time is preferably 2 to 24 hours, more preferably 4 to 20 hours in order to appropriately control the molecular weight of the resulting biodegradable copolymer.
- the hydroxycarboxylic acid a1 the hydroxycarboxylic acid a2, and the monomer a3 are cyclic compounds such as lactide, ⁇ -caprolactone, and glycolide, respectively, that is, when the copolymerization reaction is by a ring-opening polymerization method
- the reaction temperature is preferably set to 100 to 180 ° C, more preferably 110 to 160 ° C.
- the total concentration of hydroxycarboxylic acid a1 and hydroxycarboxylic acid a2 (and monomer a3 as necessary) in the reaction solvent for obtaining the biodegradable copolymer in advance varies depending on the type of hydroxycarboxylic acid used and the like. To 100% by weight is preferable, and 50 to 100% by weight is more preferable. On the other hand, if the catalyst concentration in the reaction solvent is too large, removal after the reaction becomes difficult, while if it is too small, the reaction does not proceed easily. More preferable is 0.3 to 0.3% by weight.
- the biodegradable copolymer obtained in advance may be once purified, but may be subjected to further copolymerization reaction to obtain a block copolymer without purification.
- reaction solvent for a copolymerization reaction by a condensation polymerization method of a biodegradable copolymer obtained in advance with a water-soluble polymer and a polyvalent compound (and, if necessary, monomer a3) a biodegradable copolymer, a water-soluble polymer
- a good solvent for the polyvalent compound (and, if necessary, the monomer a3) is used.
- Examples of such a good solvent include dichloromethane, chloroform, tetrahydrofuran, and a mixed solvent thereof.
- the reaction temperature and reaction pressure are preferably set so that the good solvent used is refluxed. It is also preferable to use diphenyl ether having a high boiling point as a good solvent.
- the reaction temperature when diphenyl ether is used is preferably 150 to 200 ° C., more preferably 160 to 190 ° C. so that the reaction proceeds moderately while removing by-product water, but the diphenyl ether itself does not evaporate. .
- the reaction pressure is preferably 1 to 5 kPa, more preferably 2 to 4 kPa.
- the reaction time is preferably 10 to 30 hours and more preferably 15 to 25 hours in order to appropriately control the molecular weight of the resulting biodegradable copolymer.
- the copolymerization reaction may be performed in an air atmosphere, but is preferably performed in an inert gas atmosphere such as argon, helium, or nitrogen, and more preferably in an inexpensive nitrogen atmosphere.
- the total concentration of the monomers a3) is preferably 30 to 70% by weight and more preferably 40 to 60% by weight in order to appropriately control the copolymerization reaction.
- the catalyst concentration in the reaction solvent is too high, removal after the reaction becomes difficult, while if it is too low, the reaction does not proceed easily. 0.3 weight is more preferred.
- a metal catalyst may be mentioned.
- the metal catalyst include metal alkoxides, metal halides, organic carboxylates, carbonates, sulfates, and oxides of metals such as tin, titanium, lead, zinc, cobalt, iron, lithium, and rare earths.
- a tin compound is preferable from the viewpoint of polymerization reactivity.
- the tin compound include tin powder, tin (II) chloride, tin (IV) chloride, tin (II) bromide, tin (IV) bromide, ethoxy tin (II), t-butoxy tin (IV), and isopropoxy.
- the block copolymer obtained in the copolymerization step can be subjected to a granulation step without purification, but may be purified to remove unreacted substances, solvent and catalyst.
- a purification method include a fractional precipitation method.
- the fractional precipitation method is a method of obtaining a purified block copolymer as a precipitate by dissolving the obtained block polymer in a good solvent and dropping the solution into a poor solvent under stirring.
- “good solvent” means an organic solvent in which both the biodegradable copolymer and the water-soluble polymer are dissolved, and “poor solvent” does not dissolve either the biodegradable polymer or the soluble polymer.
- An organic solvent is an organic solvent in which both the biodegradable copolymer and the water-soluble polymer are dissolved, and “poor solvent” does not dissolve either the biodegradable polymer or the soluble polymer.
- Examples of the good solvent used in the fractional precipitation method include dichloromethane, chloroform, tetrahydrofuran, and a mixed solvent thereof.
- the amount of the good solvent to be used varies depending on the composition of the obtained block copolymer and the like, but the concentration of the dissolved block copolymer is preferably 1 to 50% by weight, and more preferably 10 to 40% by weight.
- Examples of the poor solvent used in the fractional precipitation method include alcohol organic solvents such as methanol or ethanol, ether organic solvents such as dimethyl ether, ethyl methyl ether or diethyl ether, pentane, hexane, heptane or octane.
- a hydrocarbon organic solvent or a mixed solvent thereof may be used.
- the “granulation step” is a step of granulating the block copolymer obtained in the copolymerization step to obtain biodegradable particles.
- the granulation method in the granulation step include a rolling granulation method, a fluidized bed granulation method, a spray bed granulation method, a stirring granulation method, a pulverization granulation method, a compression granulation method, and an extrusion granulation method.
- a droplet solidification granulation method may be mentioned, but the droplet solidification granulation method is preferable in order to effectively control the particle shape, particle diameter, and the like.
- the block copolymer obtained in the copolymerization step is dissolved in an organic solvent incompatible with water and then dispersed in a stirred aqueous layer (including an emulsification aid).
- a stirred aqueous layer including an emulsification aid.
- O / W type submerged drying method or water / oil / water submerged drying method is more preferable.
- Examples of the organic solvent incompatible with water in the granulation step include dichloromethane, chloroform, ethyl acetate, isopropyl ether, or a mixed solvent thereof.
- Examples of the emulsifying aid include anionic surfactants such as sodium oleate, sodium stearate or sodium laurate, and nonionic surfactants such as polyoxyethylene sorbitan fatty acid ester or polyoxyethylene castor oil derivative.
- PVA Polyvinyl alcohol
- polyvinyl pyrrolidone a copolymer of vinyl pyrrolidone and vinyl acetate
- a copolymer of vinyl pyrrolidone and vinyl caprolactam a copolymer of vinyl pyrrolidone and vinyl caprolactam
- carboxycellulose lecithin or gelatin, or a mixture thereof.
- PVA polyvinyl alcohol
- carboxycellulose or gelatin is preferred.
- the concentration of the emulsification aid in the aqueous layer varies depending on the composition ratio of the block copolymer to be granulated, but is preferably 0.01 to 80% by weight in order to appropriately control the particle shape, particle diameter, etc. 05 to 60% by weight is more preferable, and 0.1 to 40% by weight is further preferable.
- a water-soluble organic solvent may be added to the aqueous layer in addition to the emulsification aid.
- water-soluble organic solvents include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butyl alcohol, acetonitrile, ethylene glycol, propylene glycol, glycerin, acetone, methyl ethyl ketone.
- Tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, or dimethylacetamide, methanol, ethanol, or acetone is preferable, and methanol or ethanol is more preferable because it is difficult to remain in particles obtained with high volatility.
- the concentration of the water-soluble organic solvent in the aqueous layer is preferably 0.1 to 80% by weight, and more preferably 1 to 70% by weight in order to maintain the hydrophobic / hydrophilic balance of the aqueous layer. Further, considering production stability, it is preferably 5 to 60% by weight, more preferably 10 to 50% by weight.
- Biodegradable particles obtained in the granulation process by the droplet solidification granulation method are generally spherical particles, that is, spherical particles, but the particle size distribution is wide, and in some cases, other Shaped particles may be included. For this reason, you may select what has a desired particle shape and particle diameter from the biodegradable particle
- An example of such a selection method is a sieving method.
- As a dispersion medium for dispersing biodegradable particles during sieving an organic solvent or water that does not dissolve or swell the biodegradable particles is preferable, and water is more preferable.
- the biodegradable particles obtained in the granulation step may be subjected to a coating step as necessary in order to prevent aggregation of the biodegradable particles.
- the coating step refers to a step of coating the surface of the biodegradable particles obtained in the granulation step with a hydrophilic polymer.
- the coating means a state in which a hydrophilic polymer is attached or adsorbed on the surface of the biodegradable particle.
- Examples of the method for coating the surface of the biodegradable particles with the hydrophilic polymer include a mechanical coating method, a wet coating method, a spray drying method, a sugar coating method, and a powder coating method, and the wet coating method is preferable. Among these, a method of immersing biodegradable particles in a hydrophilic polymer solution in a stirred state is more preferable.
- hydrophilic polymer in the coating step examples include polyalkylene glycols such as PEG or polypropylene glycol or derivatives thereof, polyhydroxyethyl methacrylate, acrylic acid, methacrylic acid, polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, or Examples include biodegradable materials such as a copolymer of vinyl pyrrolidone and vinyl caprolactam. Polyalkylene glycol or a derivative thereof is preferable, and PEG is more preferable because of high biocompatibility.
- Examples of the solvent for obtaining a hydrophilic polymer solution in which a hydrophilic polymer is uniformly dissolved include, for example, water, alcohol-based organic solvents such as methanol, ketone-based organic solvents such as acetone, and halogen-based organic solvents such as dichloromethane or chloroform.
- water is preferable because of its low cost and high safety.
- the concentration of the hydrophilic polymer in the hydrophilic polymer solution described above is preferably 0.1 to 50% by weight, more preferably 1 to 10% by weight, although it varies depending on the type of biodegradable particles.
- the biodegradable particles obtained in the granulation step or the biodegradable particles obtained in the granulation step and subjected to the coating step may be subjected to a drying step as necessary.
- the drying step refers to a step of removing a liquid such as water contained in the biodegradable particles obtained in the granulation step or the like.
- methods for removing liquids such as water include convection heat transfer drying methods such as spray drying, airflow drying or fluidized bed drying, conductive heat transfer drying methods such as vacuum drying or rotary drum drying, radiant heat transfer drying methods, Although a microwave drying method or a supercritical drying method is mentioned, a simple conductive heat transfer drying method is preferable.
- the “radiation irradiation process” is a method in which biodegradable particles obtained in the granulation process or biodegradable particles obtained in the granulation process and subjected to the coating process and / or the drying process are irradiated with radiation and sterilized. This is a step of obtaining the biodegradable particles.
- radiation to be irradiated include ⁇ rays, ⁇ rays, ⁇ rays, X rays, ultraviolet rays, and electron beams.
- the irradiation dose is preferably 5 to 100 kGy, more preferably 10 to 50 kGy, and more preferably 20 to 35 kGy is more preferred.
- PURASORB L manufactured by PURAC
- hydroxycarboxylic acid a2 75.0 g ⁇ -caprolactone manufactured by Wako Pure Chemical Industries, Ltd.
- the glass transition point of the homopolymer obtained by homopolymerization of lactide which is hydroxycarboxylic acid a1 is 58 ° C.
- the glass transition point of the homopolymer obtained by homopolymerization of ⁇ -caprolactone which is hydroxycarboxylic acid a2 is ⁇ 61 ° C. It is.
- the obtained purified block copolymer 1 was dried under reduced pressure, dissolved in dichloromethane to a concentration of 5% by weight, and the solution was collected in a syringe with a 14G injection needle.
- PVA Sigma Aldrich Japan; average molecular weight 9000-10000
- methanol is 30 wt%.
- the purified block copolymer solution collected in a syringe with a syringe needle was added dropwise at a flow rate of 1 mL / min to a 5 ° C. (PVA / methanol) aqueous solution stirred at a rate of 1.3 s ⁇ 1 .
- the stirring speed was set to 1.7 s ⁇ 1 and the mixture was stirred at 25 ° C. or lower for 21 hours and dried in an O / W type liquid to obtain spherical biodegradable particles.
- the obtained spherical biodegradable particles were selected by a screening method to obtain biodegradable particles having an average particle diameter of 550 ⁇ m. More specifically, biodegradable particles that passed through a sieve having an opening of 600 ⁇ m and could not pass through a sieve having an opening of 500 ⁇ m were collected. Furthermore, spherical particles that passed through a sieve having an opening of 500 ⁇ m and could not pass through a sieve having an opening of 350 ⁇ m were collected to obtain biodegradable particles having an average particle diameter of 400 ⁇ m.
- biodegradable particles having an average particle size of 550 ⁇ m and biodegradable particles having an average particle size of 300 ⁇ m were collected and 200 mL of 5 wt% PEG (SUNBRIGHT® DKH- 10H; manufactured by NOF Corporation; average molecular weight 1000), each was immersed in an aqueous solution for 30 hours and dried at 25 ° C. for 24 hours to obtain biodegradable particles whose surfaces were coated with a hydrophilic polymer.
- the surface of the biodegradable particle having an average particle diameter of 550 ⁇ m and the biodegradable particle having an average particle diameter of 400 ⁇ m, which are coated with a hydrophilic polymer, are respectively irradiated with ⁇ -rays of cobalt 60 so that the minimum dose is 25 kGy. Then, sterilized biodegradable particles 1 having respective average particle diameters were obtained.
- Sterilized biodegradable particles 1 having an average particle size of 550 ⁇ m are dissolved in chloroform, passed through a 0.2 ⁇ m syringe filter (Puradisc 13 mm Syringe Filters; manufactured by Whatman), and then measured by the GPC method. Then, the weight average molecular weight of the biodegradable particles 1 was calculated. The results are shown in Table 2.
- Sterilized biodegradable particles 1 having an average particle diameter of 550 ⁇ m were dissolved in deuterated chloroform and measured by 1 H-NMR, and the weight ratio of biodegradable particles 1 was calculated. The results are shown in Table 2.
- a dispersion in which 200 mg of sterilized biodegradable particles 1 (average particle size is 550 ⁇ m) is dispersed in 2 mL of water for injection is transferred from a syringe to a microcatheter (RENEGADE; manufactured by Boston Scientific; total length: about 1500 mm, tip inner diameter: 530 ⁇ m ) It was confirmed whether it could be injected without resistance. Moreover, the presence or absence of the biodegradable particles 1 adhering to the syringe inner wall after the injection and the presence or absence of the biodegradable particles 1 remaining on the inner surface of the microcatheter cut in the longitudinal direction after the injection were visually confirmed. Further, the biodegradable particles 1 before and after passing through the catheter were also visually observed for deformation and collapse.
- the sterilized biodegradable particles 1 having an average particle diameter of 400 ⁇ m were brought into a saturated water-containing state, and then the compression recovery rate when the 40% compression load and the compression rate were 10% were measured. The results are shown in Table 2.
- the 40% compression load of the biodegradable particles 1 was low, and the compression recovery rate was high when the compression rate was 10%.
- the biodegradable particles 1 had good catheter permeability.
- Example 2 Unpurified biodegradable copolymer 2 was obtained in the same manner as in Example 1 except that the weight was changed to 37.5 g of lactide and 112.5 g of ⁇ -caprolactone, respectively.
- a purified block copolymer 2 was obtained in the same manner as in Example 1 except that the unpurified biodegradable copolymer 1 was changed to the unpurified biodegradable copolymer 2. Further, the purified block copolymer 2 was subjected to the same operation as in Example 1 to obtain sterilized biodegradable particles 2 having respective average particle diameters. Table 2 shows the results of evaluation similar to Example 1 for the purified block copolymer 2 and the biodegradable particles 2.
- the 40% compression load of biodegradable particles 2 was low, and the compression recovery rate was high when the compression rate was 10%.
- the biodegradable particles 2 had good catheter permeability.
- Example 3 Unpurified biodegradable copolymer 3 was obtained in the same manner as in Example 1, except that the weight was changed to 25.0 g of lactide and 125.0 g of ⁇ -caprolactone, respectively.
- a purified block copolymer 3 was obtained in the same manner as in Example 1 except that the unpurified biodegradable copolymer 1 was changed to the unpurified biodegradable copolymer 3. Further, the purified block copolymer 3 was subjected to the same operation as in Example 1 to obtain sterilized biodegradable particles 3 having respective average particle diameters. Table 2 shows the results of evaluation similar to Example 1 for the purified block copolymer 3 and the biodegradable particles 3.
- the 40% compression load of the biodegradable particles 3 was low, and the compression recovery rate was high when the compression rate was 10%. Further, the biodegradable particles 3 had good catheter permeability.
- Example 4 8.0 g of unpurified biodegradable copolymer 1 was changed to 9.0 g of unpurified biodegradable copolymer 2, and PEG was changed to 3.0 g and dodecanedioic acid was changed to 0.035 g, respectively.
- the same operation as in Example 1 was performed to obtain a purified block copolymer 4.
- the purified block copolymer 4 was subjected to the same operation as in Example 1 to obtain sterilized biodegradable particles 4 having respective average particle diameters.
- Table 2 shows the results of evaluation similar to Example 1 for the purified block copolymer 4 and the biodegradable particles 4.
- the 40% compression load of the biodegradable particles 4 was low, and the compression recovery rate was high when the compression rate was 10%.
- the biodegradable particles 4 had good catheter permeability.
- Example 5 The same procedure as in Example 1 was carried out except that the weight was changed to 37.5 g of lactide and 112.5 g of ⁇ -caprolactone, respectively, and the copolymerization reaction was carried out at normal pressure for 16 hours. Copolymer 5 was obtained.
- Example 1 8.0 g of unpurified biodegradable copolymer 1 was changed to 9.0 g of unpurified biodegradable copolymer 5, and the weight was further changed to 3.0 g of PEG and 0.035 g of dodecanedioic acid. The same operation as in Example 1 was performed to obtain a purified block copolymer 5. Further, the purified block copolymer 5 was subjected to the same operation as in Example 1 to obtain sterilized biodegradable particles 5 having respective average particle diameters. Table 2 shows the results of evaluation similar to Example 1 for the purified block copolymer 5 and the biodegradable particles 5.
- the 40% compression load of the biodegradable particles 5 was low, and the compression recovery rate was high when the compression rate was 10%.
- the biodegradable particles 5 had good catheter permeability.
- Example 6 The same as Example 1 except that the weight was changed to 30.0 g of lactide, 90.0 g of ⁇ -caprolactone, and 30.0 g of glycolide (PURASORB G; manufactured by PURAC) as monomer a3 was added. Thus, an unpurified biodegradable copolymer 6 was obtained.
- the glass transition point of a homopolymer obtained by homopolymerizing glycolide as the monomer a3 is 36 ° C.
- Example 1 Except for changing 8.0 g of unpurified biodegradable copolymer 1 to 9.0 g of unpurified biodegradable copolymer 6, further changing the weight of PEG to 3.0 g and dodecanedioic acid to 0.035 g, respectively.
- the same operation as in Example 1 was performed to obtain a purified block copolymer 6.
- the purified block copolymer 6 was subjected to the same operation as in Example 1 to obtain sterilized biodegradable particles 6 having respective average particle diameters.
- Table 2 shows the results of evaluation similar to Example 1 for the purified block copolymer 3 and the biodegradable particles 6.
- the 40% compression load of the biodegradable particles 6 was low, and the compression recovery rate was high when the compression rate was 10%.
- the biodegradable particles 6 had good catheter permeability.
- Example 7 0.046 g dodecanedioic acid was changed to 0.059 g octacarboxylic acid, 8.0 g crude biodegradable copolymer 1 was changed to 9.0 g crude biodegradable copolymer 2, and PEG was changed to 3 A purified block copolymer 7 was obtained in the same manner as in Example 1 except that the weight was changed to 0.0 g. The purified block copolymer 7 was subjected to the same operation as in Example 1 to obtain sterilized biodegradable particles 7 having respective average particle diameters. Table 2 shows the results of evaluation similar to Example 1 for the purified block copolymer 7 and the biodegradable particles 7.
- the 40% compression load of the biodegradable particles 7 was low, and the compression recovery rate was high when the compression rate was 10%.
- the biodegradable particles 7 had good catheter permeability.
- a purified block copolymer W was obtained in the same manner as in Example 1, except that the unpurified biodegradable copolymer 1 was changed to the unpurified biodegradable copolymer W. Further, the purified block copolymer W was subjected to the same operation as in Example 1 to obtain sterilized biodegradable particles W having respective average particle diameters. Table 2 shows the results of evaluation similar to Example 1 for these purified block copolymer W and biodegradable particles W.
- the 40% compression load of the biodegradable particles W was high, and the compression recovery rate when the compression rate was 10% was low. Further, the biodegradable particles W are not flexible enough to pass through the catheter, and the biodegradable particles W after passing through the catheter cannot maintain a spherical shape and are deformed.
- Example 2 A purified block copolymer X was obtained in the same manner as in Example 1 except that the crude biodegradable copolymer 1 was changed to ⁇ -caprolactone. Further, the purified block copolymer X was subjected to the same operation as in Example 1 to obtain sterilized biodegradable particles X having respective average particle diameters. Table 2 shows the results of evaluation similar to Example 1 for these purified block copolymer X and biodegradable particle X.
- a purified block copolymer Y was obtained in the same manner as in Example 1 except that the unpurified biodegradable copolymer 1 was changed to the unpurified biodegradable copolymer Y. Further, the purified block copolymer Y was subjected to the same operation as in Example 1 to obtain sterilized biodegradable particles having respective average particle diameters. Table 2 shows the results of evaluation similar to Example 1 for these purified block copolymer Y and biodegradable particle Y.
- the 40% compression load of the biodegradable particles Y was high, and the compression recovery rate when the compression rate was 10% was low.
- the biodegradable particles Y are not flexible enough to pass through the catheter, and the biodegradable particles Y after passing through the catheter cannot maintain a spherical shape and are deformed.
- Example 4 An unpurified biodegradable copolymer Z was obtained in the same manner as in Example 1 except that ⁇ -caprolactone was changed to 3-hydroxybutyric acid and lactide was changed to 37.5 g in weight.
- the glass transition point of a homopolymer obtained by homopolymerizing 3-hydroxybutyric acid which is hydroxycarboxylic acid a2 is 15 ° C.
- a purified block copolymer Z was obtained in the same manner as in Example 1 except that the unpurified biodegradable copolymer 1 was changed to the unpurified biodegradable copolymer Z. Further, the purified block copolymer Z was subjected to the same operation as in Example 1 to obtain sterilized biodegradable particles Z having respective average particle diameters. Table 2 shows the results of evaluation similar to Example 1 for these purified block copolymer Z and biodegradable particle Z.
- the 40% compression load of the biodegradable particles Z was high, and the compression recovery rate when the compression rate was 10% was low.
- the biodegradable particle Z is not flexible enough to pass through the catheter, and the biodegradable particle Z after passing through the catheter cannot maintain a spherical shape and is deformed.
- the biodegradable particles of the present invention can be used for embolizing blood vessels in the medical field.
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Abstract
Description
(1) 少なくともヒドロキシカルボン酸a1及びヒドロキシカルボン酸a2からなる構造を有する、生分解性コポリマーと、両末端に、水酸基、アミノ基及びカルボン酸基からなる群から選ばれる官能基を有する、水溶性ポリマーと、水酸基、アミノ基及びカルボン酸基からなる群から選ばれる官能基を2以上有する、多価化合物と、が共重合した、ブロックコポリマーからなり、上記ヒドロキシカルボン酸a1が単独重合したホモポリマーのガラス転移点は、40℃以上であり、上記ヒドロキシカルボン酸a2が単独重合したホモポリマーのガラス転移点は、-40℃以下であり、かつ、上記生分解性コポリマーに占める、ヒドロキシカルボン酸a2からなる構造の重量比率は、30~90重量%である、生分解性粒子。
(2) 上記ブロックコポリマーは、下記の一般式(I)で示される繰り返し単位を有するマルチブロックコポリマーである、上記の(1)に記載の生分解性粒子。
(3) 飽和含水状態における40%圧縮荷重が500mN以下であり、かつ、飽和含水状態における圧縮率が10%のときの圧縮復元率が40%以上である、上記の(1)又は(2)に記載の生分解性粒子。
(4) 上記ブロックコポリマーの重量平均分子量は、3000~300000である、上記の(1)~(3)のいずれかに記載の生分解性粒子。
(5) 上記水溶性ポリマーの重量平均分子量は、200~50000である、上記の(1)~(4)のいずれかに記載の生分解性粒子。
(6) 上記ヒドロキシカルボン酸a1は、乳酸である、上記の(1)~(5)のいずれかに記載の生分解性粒子。
(7) 上記ヒドロキシカルボン酸a2は、6-ヒドロキシカプロン酸である、上記の(1)~(6)のいずれかに記載の生分解性粒子。
(8) 上記の(1)~(7)のいずれかに記載の生分解性粒子からなる、血管塞栓材料。
(9) 少なくともヒドロキシカルボン酸a1及びヒドロキシカルボン酸a2からなる構造を有し、上記ヒドロキシカルボン酸a1が単独重合したホモポリマーのガラス転移点は、40℃以上であり、上記ヒドロキシカルボン酸a2が単独重合したホモポリマーのガラス転移点は、-40℃以下であり、かつ、上記生分解性コポリマーに占める、ヒドロキシカルボン酸a2からなる構造の重量比率は、30~90重量%である、生分解性コポリマーと、両末端に、水酸基、アミノ基及びカルボン酸基からなる群から選ばれる官能基を有する、水溶性ポリマーと、水酸基、アミノ基及びカルボン酸からなる群から選ばれる官能基を2以上有する、多価化合物と、を共重合させてブロックコポリマーを得る、共重合工程と、上記ブロックコポリマーを造粒して、生分解性粒子を得る、造粒工程と、上記生分解性粒子に放射線を照射して滅菌された生分解性粒子を得る、放射線照射工程と、を備える、滅菌された生分解性粒子の製造方法。
[測定条件]
装置(カラム) :TSKgel GMHHR-M
(東ソー株式会社製、内径7.8mm、
長さ30cmを2本直列)
溶離液 :クロロホルム
カラム温度 :35℃
流速 :1.0mL/min
検出方法 :屈折率
検量線 :ポリスチレン標準サンプルを用いて作成
X = (2×Nb)/(m×Nc) ・・・式1
ここで、Nb及びNcは、以下の式2及び式3によりそれぞれ算出される。
Nb = Wb/Mwb ・・・式2
Wb : 共重合に用いた水溶性ポリマーの重量(g)
Mwb : 共重合に用いた水溶性ポリマーの
重量平均分子量(g/mol)
Nc = Wc/Mwc ・・・式3
Wc : 共重合に用いた多価化合物の重量(g)
Mwc : 共重合に用いた多価化合物の分子量(g/mol)
[測定条件]
装置 :JNM-EX270(JEOL社製、270MHz)
溶媒 :重クロロホルム
(内部標準TMS0.05体積%含有)
測定温度 :20℃
Rw = {W(t)-W(t-1)}/W(t)×100 ・・・式4
W(t) : 水に浸漬した生分解性粒子のt分後の重量(g)
W(t-1) : 水に浸漬した生分解性粒子の
(t-1)分後の重量(g)
[測定条件]
試験名 :圧縮試験
装置 :MCT-510(株式会社島津製作所製)
設定試験力 :4903mN
負荷速度 :207mN/s
負荷保持時間 :0s
上部加圧因子 :平面500μm(直径)
[測定条件]
試験名 :負荷・除荷試験
装置 :MCT-510(株式会社島津製作所製)
設定試験力 :圧縮試験で得られた各粒子の圧縮率が
10%のときの試験力
負荷速度 :4.5mN/s
負荷保持時間 :2s
上部加圧因子 :平面直径500μm(直径)
L1 = L1b-L1a ・・・式5
L1a : 最小試験力を負荷した時の粒径変位(μm)
L1b : 最大試験力を負荷した時の粒径変位(μm)
L2 = L2b-L1a ・・・式6
L2b : 最大試験力を負荷した後に最小試験力まで除荷した時の
粒径変位(μm)
Rr = {(L1-L2)/L1}×100 ・・・式7
Cr = (L1/d)×100 ・・・式8
d : 生分解性粒子の平均粒子径(μm)
ヒドロキシカルボン酸a1である75.0gのラクチド(PURASORB L;PURAC社製)と、ヒドロキシカルボン酸a2である75.0gのε-カプロラクトン(和光純薬工業株式会社製)とを、ナスフラスコに採取した。これらを窒素雰囲気下120℃で溶融混合してから、触媒である0.34gのオクチル酸スズ(II)(シグマアルドリッチ社製)を添加し、常圧で4時間共重合反応させて、未精製生分解性コポリマー1を得た。なお、ヒドロキシカルボン酸a1であるラクチドが単独重合したホモポリマーのガラス転移点は、58℃であり、ヒドロキシカルボン酸a2であるε-カプロラクトンが単独重合したホモポリマーのガラス転移点は、-61℃である。
ラクチドを37.5gに、ε-カプロラクトンを112.5gに、それぞれ重量変更した以外は、実施例1と同様の操作を行い、未精製生分解性コポリマー2を得た。
ラクチドを25.0gに、ε-カプロラクトンを125.0gに、それぞれ重量変更した以外は、実施例1と同様の操作を行い、未精製生分解性コポリマー3を得た。
8.0gの未精製生分解性コポリマー1を9.0gの未精製生分解性コポリマー2に変更し、さらにPEGを3.0gに、ドデカン二酸を0.035gに、それぞれ重量変更した以外は、実施例1と同様の操作を行い、精製ブロックコポリマー4を得た。また、精製ブロックコポリマー4について、実施例1と同様の操作を行い、各平均粒子径の滅菌された生分解性粒子4を得た。これら精製ブロックコポリマー4及び生分解性粒子4について、実施例1と同様の評価をした結果を表2に示す。
ラクチドを37.5gに、ε-カプロラクトンを112.5gに、それぞれ重量変更し、さらに常圧で16時間共重合反応させた以外は、実施例1と同様の操作を行い、未精製生分解性コポリマー5を得た。
ラクチドを30.0gに、ε-カプロラクトンを90.0gに、それぞれ重量変更し、さらにモノマーa3である30.0gのグリコリド(PURASORB G;PURAC社製)を追加した以外は、実施例1と同様の操作を行い、未精製生分解性コポリマー6を得た。なお、モノマーa3であるグリコリドが単独重合したホモポリマーのガラス転移点は、36℃である。
0.046gのドデカン二酸を0.059gのオクタカルボン酸に変更し、8.0gの未精製生分解性コポリマー1を9.0gの未精製生分解性コポリマー2に変更し、さらにPEGを3.0gに重量変更した以外は、実施例1と同様の操作を行い、精製ブロックコポリマー7を得た。また、精製ブロックコポリマー7について、実施例1と同様の操作を行い、各平均粒子径の滅菌された生分解性粒子7を得た。これら精製ブロックコポリマー7及び生分解性粒子7について、実施例1と同様の評価をした結果を表2に示す。
ヒドロキシカルボン酸a1であるラクチドのみを30.0g、ナスフラスコに採取して、窒素雰囲気下160℃で加熱してから、表1に示す圧力プログラムにて4時間重合反応させて、未精製生分解性コポリマーWを得た。
未精製生分解性コポリマー1をε-カプロラクトンに変更した以外は、実施例1と同様の操作を行い、精製ブロックコポリマーXを得た。また、精製ブロックコポリマーXについて、実施例1と同様の操作を行い、各平均粒子径の滅菌された生分解性粒子Xを得た。これら精製ブロックコポリマーX及び生分解性粒子Xについて、実施例1と同様の評価をした結果を表2に示す。
ラクチドを112.5gに、ε-カプロラクトンを37.5gに、それぞれ重量変更した以外は、実施例1と同様の操作を行い、未精製生分解性コポリマーYを得た。
ε-カプロラクトンを3-ヒドロキシ酪酸に変更し、さらにラクチドを37.5gに重量変更した以外は、実施例1と同様の操作を行い、未精製生分解性コポリマーZを得た。なお、ヒドロキシカルボン酸a2である3-ヒドロキシ酪酸が単独重合したホモポリマーのガラス転移点は、15℃である。
Claims (9)
- 単独重合したホモポリマーのガラス転移点が40℃以上であるヒドロキシカルボン酸a1と、単独重合したホモポリマーのガラス転移点が-40℃以下であるヒドロキシカルボン酸a2と、からなる構造を有する生分解性コポリマーと、
水酸基、アミノ基及びカルボン酸基からなる群から選択される官能基を両末端に有する水溶性ポリマーと、
水酸基、アミノ基及びカルボン酸基からなる群から選択される官能基を2以上有する多価化合物と、
が共重合したブロックコポリマーからなり、
前記生分解性コポリマーの質量に対する前記ヒドロキシカルボン酸a2からなる構造の質量の割合が30~90質量%である、生分解性粒子。 - 飽和含水状態における40%圧縮荷重が500mN以下であり、かつ、飽和含水状態における圧縮率が10%のときの圧縮復元率が40%以上である、請求項1又は2記載の生分解性粒子。
- 前記ブロックコポリマーの重量平均分子量は、3000~300000である、請求項1~3のいずれか一項記載の生分解性粒子。
- 前記水溶性ポリマーの重量平均分子量は、200~50000である、請求項1~4のいずれか一項記載の生分解性粒子。
- 前記ヒドロキシカルボン酸a1は、乳酸である、請求項1~5のいずれか一項記載の生分解性粒子。
- 前記ヒドロキシカルボン酸a2は、6-ヒドロキシカプロン酸である、請求項1~6のいずれか一項記載の生分解性粒子。
- 請求項1~7のいずれか一項記載の生分解性粒子からなる、血管塞栓材料。
- 単独重合したホモポリマーのガラス転移点が40℃以上であるヒドロキシカルボン酸a1と、単独重合したホモポリマーのガラス転移点が-40℃以下であるヒドロキシカルボン酸a2と、からなる構造を有する生分解性コポリマーであり、かつ、該生分解性コポリマーの質量に対する前記ヒドロキシカルボン酸a2からなる構造の質量の割合が30~90質量%である、生分解性コポリマーと、
水酸基、アミノ基及びカルボン酸基からなる群から選択される官能基を両末端に有する水溶性ポリマーと、
水酸基、アミノ基及びカルボン酸からなる群から選択される官能基を2以上有する多価化合物と、
を共重合させてブロックコポリマーを得る共重合工程と、
前記ブロックコポリマーを造粒して、生分解性粒子を得る造粒工程と、
前記生分解性粒子に放射線を照射して滅菌された生分解性粒子を得る放射線照射工程と、
を備える、滅菌された生分解性粒子の製造方法。
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