WO2010101240A1 - Biodegradable porous hollow particle, and production method and application thereof - Google Patents

Biodegradable porous hollow particle, and production method and application thereof

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Publication number
WO2010101240A1
WO2010101240A1 PCT/JP2010/053626 JP2010053626W WO2010101240A1 WO 2010101240 A1 WO2010101240 A1 WO 2010101240A1 JP 2010053626 W JP2010053626 W JP 2010053626W WO 2010101240 A1 WO2010101240 A1 WO 2010101240A1
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Prior art keywords
copolymer
porous
block
particles
diblock
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PCT/JP2010/053626
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French (fr)
Japanese (ja)
Inventor
努 小野
幸敬 木村
誠 村中
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国立大学法人岡山大学
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    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08GMACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/66Polyesters containing oxygen in the form of ether groups
    • C08G63/664Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G
    • C08J9/00Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
    • C08J9/28Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof by elimination of a liquid phase from a macromolecular composition or article, e.g. drying of coagulum
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G
    • C08J2201/00Foams characterised by the foaming process
    • C08J2201/04Foams characterised by the foaming process characterised by the elimination of a liquid or solid component, e.g. precipitation, leaching out, evaporation
    • C08J2201/048Elimination of a frozen liquid phase
    • C08J2201/0484Elimination of a frozen liquid phase the liquid phase being aqueous
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G
    • C08J2367/00Characterised by the use of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Derivatives of such polymers
    • C08J2367/04Polyesters derived from hydroxy carboxylic acids, e.g. lactones
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G
    • C08J2371/00Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
    • C08J2371/02Polyalkylene oxides

Abstract

Disclosed is a method where pore diameter and other attributes can be easily controlled, and which can produce porous particles with a novel form having a hollow section. Namely, disclosed is a production method for porous particles formed from a diblock copolymer which includes a step where water, an organic solvent, and the abovementioned diblock copolymer comprising a site derived from a particular aliphatic polyester resin (polylactic acid, etc.) and a site derived from a hydrophilic macromolecule (polyethylene glycol, etc.) are emulsified or admixed. Porous particles having a hollow section are obtained by making the quantity of the abovementioned water less than or equal to the quantity to saturate the abovementioned organic solvent. The pore diameter of the porous particles can be made relatively larger by making the length of the hydrophilic macromolecule site in the abovementioned diblock copolymer relatively longer (increasing the hydrophilic-lipophilic balance value). Furthermore, the abovementioned diblock copolymer may also include a mixture of at least two types (e.g. an oil-soluble diblock copolymer and a water-soluble diblock copolymer).

Description

Biodegradable porous hollow particles, their preparation and use

The present invention relates to porous microparticles and a method of manufacturing is formed by the aliphatic polyester-based resin (biodegradable resin).

Porous fine particles that the porosity and micro and have been utilized as, for example, as a base material for pharmaceutical preparations and agricultural chemicals having a sustained release, or a carrier for immobilizing the enzyme or catalyst. In particular, aliphatic polyester resins represented by polylactic acid has biodegradability and because of their excellent biocompatibility, it can be said that the preferred material in the above applications.

Such a method of manufacturing the porous microparticles with an aliphatic polyester resin are known several.
For example, Non-Patent Document 1, a polylactic acid, a lactic acid-glycolic acid copolymer, and a mixture of lactic acid-glycolic acid copolymer and polyethylene glycol, to form a W / O / W emulsion under various conditions , preparation of the porous microparticles is described.

Non-Patent Document 2, polycaprolactone, polyethylene oxide, and preparation of the porous microparticles with triblock copolymer consisting of polylactides is described.
Non-Patent Document 3, preparation of the porous particles by chemical foaming with lactic acid-glycolic acid copolymer is described.

However, the porous fine particles obtained by either method, does not constitute a hollow portion structured as covering the porous capsule membrane. Moreover, not known so far also porous particles formed by diblock copolymer composed of an aliphatic polyester resin block and a hydrophilic polymer block.

Yi-Yan Yung, Tai-Shung Chung, Xin-Lai Bai and Woon-Khion Chan, Effect of preparaition condition on morphology and release profiles of biodegradable polymeric microspheres containing protein fabricated by double-emulsion method, Chemical Engineering Science, 55, 2223- 2236 (2000) Guangming Li, Qing Cai, Jianzhong Bei and Shenguo Wang, Morphology and Levonorgestrel Release Behavior of Polycaprolactone / Poly (ethylene oxide) / Polylactide Tri-component Copolymeric Microssspheres, Polymer for Advanced Technologies, 14, 239-244 (2003) Taek Kyoung Kim, Jun Jin Yoon, Doo Sung Lee and Tae Gwan Park, Gas formed open porous biodegradable polymeric microspheres, Biomaterials, 27, 152-159 (2006)

In conventional manufacturing methods, although it is possible to some extent modify the properties of the pore diameter of the resulting porous particles, difficulties accompanied to be controlled to a desired property. Also, for example, when considering the application as such as pharmaceuticals and pesticides porous carrier particles have a hollow portion that can be holding the drug or the like therein, the structure as the outer layer porous capsule membrane covering particles is considered to be characteristic products having a modified release properties not conventionally have.

That is, the present invention is directed to one object is to provide a method of manufacturing properties and easy to control the porous microparticles of the hole diameter and the like. The present invention is directed to one object is to provide a method for producing a novel form of porous fine particles having a hollow structure.

The present inventor has for object the first one, an aliphatic polyester resin (e.g., polylactic acid) derived from the block and a hydrophilic polymer (e.g., polyethylene glycol) consisting of the origin of the block diblock copolymer used Te to produce a porous particle, by varying the ratio of molecular length of both blocks at this time, found that it is possible to adjust the properties related to porosity and average pore diameter.

Further, the relative second challenge, W / O emulsion to an extremely small amount the amount of aqueous phase (W) in the primary emulsification process to form a specific oil phase the amount of water added to the (O ) with less saturated dissolution amount of an organic solvent which forms was found that a novel form of porous fine particles having a hollow structure is obtained.

That is, the present invention provides, in one aspect, the number of carbon atoms of the hydroxy carboxylic acids or dicarboxylic acids constituents is 2-6 aliphatic polyester resin (A) derived from the block and a hydrophilic polymer (B) from the block and formed by diblock copolymer (C) consisting of, providing a porous fine particle having a hollow portion.

A preferred embodiment of the porous fine particles having a hollow portion has an average outer diameter is the 0.05 ~ 500 [mu] m, an average pore diameter of 0.005 ~ 10 [mu] m existing in the entire particles and the average diameter of the hollow portion is 0.01 ~ 450μm.

The di-block copolymer (C) is in the range of number average molecular weight Mn of 500 to 200,000 as measured by GPC, and the range of the weight-average molecular weight Mw of 500 to 200,000, and a molecular weight distribution Mw / Mn is preferably in the range of 1.00 to 2.00.

The aliphatic polyester resin (A) is in the range of number average molecular weight Mn of 100 to 200,000 as measured by GPC, and the range of the weight-average molecular weight Mw of 100 to 200,000, a molecular weight distribution Mw / Mn it is preferably in the range of 1.00 to 2.00.

The hydrophilic polymer (B) is in the range of number average molecular weight Mn of 100 to 200,000 as measured by GPC, and the range of the weight-average molecular weight Mw of 100 to 200,000, a molecular weight distribution Mw / Mn it is preferably in the range of 1.00 to 2.00.

The aliphatic polyester resin (A), polylactic acid, polyglycolic acid, is preferably at least one aliphatic polyester resin selected from the group consisting of Porikapuron acid and polybutylene succinate.

The hydrophilic polymer (B) include polyoxyethylene, polyoxypropylene, polyvinyl alcohol, partially hydrolyzed polyvinyl acetate copolymers, polymethacrylic acid, polyacrylic acid, polyacrylamide, poly-aspartic acid, polysaccharides , poly acrylamide, is preferably at least one hydrophilic polymer selected from the group consisting of sodium polystyrene sulfonate and derivatives thereof.

The diblock copolymer component ratio (C), the degree of polymerization of the hydrophilic polymer (B) derived from the block with respect to the polymerization degree 100 parts of the aliphatic polyester resin (A) derived from the block 0.1 range becomes to 100,000 parts, or diblock copolymers HLB value of (C) is preferably less than 0.4 more than 20.

The di-block copolymer (C), oil-soluble di-block copolymer having an HLB value of 0.4 to 12 and (C1), is less than an HLB value of 8 or more 20 and oil-soluble diblock copolymer HLB value than the polymer (C1) contains a water-soluble di-block copolymer having at least 2 larger value (C2), preferably a mixture composed of at least two diblock copolymer .

The di-block copolymer (C), the oil-soluble di-block copolymer (C1) with respect to 100 parts by weight, the water-soluble di-block copolymer (C2) of 100 to 1,000,000 parts by weight a proportion, is preferably a mixture composed of at least two diblock copolymer.

The invention, in one aspect, (1) the number of carbon atoms of the hydroxy carboxylic acids or dicarboxylic acids component is an aliphatic polyester resin (A) derived from 2 to 6 blocks and hydrophilic polymer (B) from emulsifying step, the mixture of the preparation and water (2) the step (1) for mixing diblock copolymer composed of blocks (C), a good organic solvent also include saturated dissolution amount of water or less step to form an emulsion by, and (3) by distilling off the organic solvent from the emulsion obtained in the above step (2) comprises a step of forming the porous microparticles, the di-block copolymer (C ) to provide a manufacturing method of the porous fine particles having a hollow portion formed by.

Note that the aliphatic polyester resin (A) in this production method, a preferred embodiment of the porous fine particles having a hydrophilic polymer (B) and diblock copolymers (C) and the hollow portion obtained is as described above.

The proportion of water in the mixture in the step (1), by the saturation dissolution amount or less relative to the organic solvent used in the process, can be made to have a hollow portion resulting porous particles.

The organic solvent is an ester of dissolving di-block copolymer (C), ethers, ketones, halogenated hydrocarbons, aromatic compounds, alcohols, mineral oil, at least one selected from the group consisting of silicone oils and ester carbonate it is preferred species of the organic solvent.

Preparation of the porous microparticles, as the di-block copolymer (C), in the step (1), oil-soluble di-block copolymer having an HLB value is 0.4 to 12 a (C1) used, further, in the step (2), an HLB value of less than 8 or more 20 and a water-soluble di-block copolymer oil-soluble di-block copolymer having an HLB value than (C1) has at least two large value ( also preferred are embodiments using C2).

In the above embodiment, with respect to the oil-soluble di-block copolymer (C1) 100 parts by weight, the water-soluble di-block copolymer (C2) used at a rate of 100 to 1,000,000 parts by weight preferable.

Further, in the above aspects, the organic solvent dissolves the oil-soluble di-block copolymer (C1), esters, ethers, ketones, at least one organic solvent selected from the group consisting of aromatics and alcohol it is preferable that.

The present invention, the porous particles having a hollow portion as described above or using the porous fine particles having a hollow portion obtained by the manufacturing method described above, for sustained release medicament for sustained release pesticide, the immobilized enzyme-, immobilization microbial catalyst, using a porous capsule for or isolation material for animal cell culture, for sustained release medicament for sustained release pesticide, the immobilized enzyme-immobilizing microorganisms, catalysts, animal cells providing a porous carrier for or separation material culture.

According to the present invention, the porous particles having never been hollow structures being conventionally implemented, it is possible to manufacture a relatively easy way at room temperature. Moreover, in the manufacturing method of the porous microparticles of the present invention, by a straightforward way of adjusting the hydrophilic polymer (B) length from the block of the diblock copolymer as a starting material (C), the desired it is possible to manufacture a porous fine particles having a mean pore diameter. The manufacturing method of the present invention, without at all using those having halogen (e.g. halogenated hydrocarbons such as chloroform) as the organic solvent of step (1) dissolving the diblock copolymer (C) porous hollow particles it is possible to produce, such preparation and the resulting porous hollow particles has high safety to a living body and the environment.

Furthermore, since the porous hollow particles of the present invention having good porosity, is suitable for use in various conventional porous fine particles has been used fields of, unlike the conventional porous microparticles, hollow because having a unique morphology (capsule structure) that includes a section with a porous outer layer is expected as to enable the development of products with new properties.

1, Example 1 ([a]: the internal aqueous phase 0 mL), Example 2 ([b]: the internal aqueous phase 0.1 mL), Reference Example 1 ([c]: the internal aqueous phase 1 mL) and Reference Examples 2: whole porous fine particles obtained by ([d] internal aqueous phase 2.5 mL), enlarged view, the surface and the inside is a photograph taken by a scanning electron microscope.

- porous particles -
The present invention provides a porous hollow particles formed from predetermined diblock copolymer (C). In the present invention, the outer layer of the hollow portion and the porous and what is constructed by (capsule membrane) is called "porous hollow particles". If such simply "porous particles" in the present invention, unless otherwise specified, is meant the porous hollow particles.

In the present invention, "average outer diameter" of the porous fine particles is an average value of the diameter of each of the porous particles, the "average pore size", the individual pores having a pore diameter of present throughout the porous microparticles an average value, "average inner diameter" as in the case of porous particles having a hollow portion therein, the average value of the diameter of each of the hollow portion. These averages is an average number either, for example, (by Target porous microparticles hollow portion appeared are split if the average inner diameter) by observation using a scanning electron microscope (SEM) measurement can do.

The present invention in one aspect consists of diblock copolymer (C), providing a porous fine particle having a hollow portion (porous hollow particles).
The average outer diameter of the porous hollow particles is preferably 0.05 ~ 500 [mu] m, more preferably 10 ~ 100 [mu] m. The average pore diameter is preferably 0.005 ~ 10 [mu] m, more preferably 0.1 ~ 1 [mu] m. The average inner diameter is preferably 0.01 ~ 450 [mu] m, more preferably 1 ~ 80 [mu] m. The average of the ratio of the inside diameter to the outside diameter of the porous hollow particles is preferably 5 to 95%.

- di-block copolymer (C) -
In the present invention, as a raw material for the production of porous particles, the number of carbon atoms of the hydroxy carboxylic acids or dicarboxylic acids constituents is 2-6 aliphatic polyester resin (A) derived from the block (building block) and a hydrophilic polymer (B) di-block copolymer of derived blocks (C) is used. Coupling form of the di-block copolymer (C) is a so-called A-B type block derived from an aliphatic polyester resin (A) becomes a site of hydrophobic block is derived from a hydrophilic polymer (B) literally becomes a part of the hydrophilic.

The-aliphatic polyester resin (A) block diblock copolymer (C) one of the configuration is the unit of the raw material aliphatic polyester resin (A), the use of various known aliphatic polyester resin (A) but it is, for example, known conventional polylactic acid as a biodegradable polymer, polyglycolic acid, Porikapuron acid, polybutylene succinate are preferred. These resins may be used in combination of two or more kinds may be used singly.

Dialcohol carbon atoms hydroxycaproic acid or dicarboxylic acid of 2 to 6, or copolymerizable therewith is not limited in particular as long as it can be used as a raw material for producing the aliphatic polyester resin. For example, the hydroxycarboxylic acid having a carbon number of 2-6, glycolic acid (C2), lactic acid (C3), 3- hydroxybutyric acid (C4), 4-hydroxybutyric acid (C4), 4-hydroxy valeric acid (C5 ), 5-hydroxy valeric acid (C5), 6- hydroxycaproic acid (C6), and the like. In the case where an aliphatic hydroxycarboxylic acid having an asymmetric carbon, L body, may be any of D-form, and mixtures thereof (racemates). The dicarboxylic acid having a carbon number of 2 to 4, oxalic acid (C2), malonic acid (C3), succinic acid (C4), glutaric acid (C5), and the like adipic acid (C6). The di-alcohol, ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, 1,3-butanediol, 1,4-butanediol, 3-methyl-1,5-pentanediol, 1,6 such as hexane diol. These compounds may be used in combination of two or more may be used singly.

Further, the aliphatic polyester resin (A) may be a homopolymer (e.g. polylactic acid, polyglycolic acid) aliphatic hydroxycarboxylic acids and copolymers (such as copolymers of lactic acid and glycolic acid), aliphatic dialcohol and an aliphatic dicarboxylic acid copolymers of (e.g. polybutylene succinate, polyethylene adipate, copolymers of butanediol and succinic acid and adipic acid, copolymers of ethylene glycol and butanediol and succinic acid), aliphatic hydroxycarboxylic acids with aliphatic dialcohols and / or it may be any of copolymers of aliphatic dicarboxylic acids (e.g., block copolymer of polylactic acid and polybutylene succinate), or a mixture thereof.

The number average molecular weight Mn measured by GPC of the aliphatic polyester resin (A) is preferably from 100 to 200,000. The weight average molecular weight Mw is preferably from 100 to 200,000. Molecular weight distribution Mw / Mn is preferably 1.00 to 2.00.

The Hydrophilic polymer (B) block diblock copolymer (C) of the hydrophilic polymer as the other structural unit of the raw material (B), various capable of binding to the aliphatic polyester resin (A) Block it can be used in the hydrophilic polymer. For example, polyoxyethylene (polyethylene glycol: PEG), polyoxypropylene, polyvinyl alcohol, partially hydrolyzed polyvinyl acetate copolymers, polymethacrylic acid, polyacrylic acid, polyacrylamide, poly-aspartic acid, polysaccharides, poly isopropylacrylamide, sodium polystyrene sulfonate, and derivatives thereof. These hydrophilic polymers may be used in combination of two or more kinds may be used singly.

The number average molecular weight Mn measured by GPC of the hydrophilic polymer (B) is preferably from 100 to 200,000. The weight average molecular weight Mw is preferably from 100 to 200,000. Molecular weight distribution Mw / Mn is preferably 1.00 to 2.00.

In the present invention, varying the diblock copolymer the length of the molecular chains of the aliphatic polyester resin (A) blocks in (C) and a hydrophilic polymer (B) the length of the molecular chain of the block, diblock other words by varying the HLB value of the copolymer (C), it is possible to adjust the pore diameter and the like of the resulting porous particles.

For example, a relatively long hydrophilic polymer (B) the length of the molecular chain of the block, that is the ratio of the Mn of the hydrophilic polymer to Mn of the aliphatic polyester resin used as a synthetic raw material (A) (B) the relatively larger, when a relatively large HLB value of the diblock copolymer (C) in other words, can be relatively large pore size of the porous microparticles. Further, the length of the aliphatic polyester resin (A) block and a hydrophilic polymer (B) block length ratio of (HLB value) are the same, hydrophilic polymer (B) block is the longer , pore size is increased, number of pores is reduced.

Preparation method diblock copolymer (C) may be prepared by combining the aliphatic polyester resin (A) and the hydrophilic polymer (B) according to known methods. Component ratio of the time of the aliphatic polyester resin (A) and the hydrophilic polymer (B), the hydrophilic polymer to the polymerization degree 100 parts of the block derived from an aliphatic polyester resin (A) (B) from the degree of polymerization of the block is preferably in a range such that 0.1 to 100,000 parts. The above degree of polymerization can be adjusted by the addition amount of the aliphatic polyester resin (A) and the hydrophilic polymer (B) at the time of di-block copolymer (C) synthesis.

Further, preferably 0.4 or more and less than 20 as HLB value. Incidentally, HLB value in the present invention is defined by the Griffin method represented by the following formula:
HLB = 20 × (Mn diblock copolymer (C)) (Mn of the hydrophilic polymer (B)) /.

Diblock copolymer number average molecular weight measured by GPC of (C) Mn is preferably 500 to 200,000. The weight average molecular weight Mw is preferably from 500 to 200,000. Molecular weight distribution Mw / Mn is preferably 1.00 to 2.00.

- mixtures porous hollow diblock copolymer used in the preparation of fine particles of the present invention (C), even those comprising one single di-block copolymer, two or more of the diblock copolymer or it may be a mixture of. If diblock copolymer (C) is a di-block copolymer alone, the di-block copolymer is usually used by dissolving in an organic solvent in step (1) of the manufacturing method of the present invention things, usually corresponds to lipophilic diblock copolymer (C1). On the other hand, if a mixture diblock copolymer (C) is composed of two or more diblock copolymers, at least one fat-soluble diblock copolymerization used in step (1) dissolved in an organic solvent a coalescing (C1), at least one is preferably a step (2) in was added to the mixture (typically dissolved in water in advance) using a water-soluble di-block copolymer (C2).

Oil-soluble di-block copolymer (C1) is, for example, refers to a diblock copolymer having an HLB value of 0.4 to 12. On the other hand, the water-soluble di-block copolymer (C2), for example, an HLB value of less than 8 or more 20, and oil-soluble di-block copolymer (C1) at least 2 greater than, preferably at least 4 greater It refers to di-block copolymer having a value.

Oil-soluble di-block copolymer having a predetermined HLB value of the (C1) and a water-soluble di-block copolymer (C2) is an aliphatic polyester resin used as a raw material (A) and a hydrophilic polymer (B) it can be produced by adjusting the properties and amount. For example, with respect to the degree of polymerization 100 parts of aliphatic polyester resin (A) derived from the block, by degree of polymerization of the block from the hydrophilic polymer (B) is adjusted within a range of from 0.1 to 100 parts, oil-soluble di-block copolymer (C1) can be prepared. Further, the aliphatic polyester resin (A) with respect to degree of polymerization 100 parts from the block, the hydrophilic polymer (B) degree of polymerization of from block 100 (preferably 400, more preferably 1,000) and 100 by adjusting the extent that the ratio of 000 parts of water-soluble di-block copolymer (C2) can be prepared.

In the present invention, "oil soluble" diblock copolymer (C1) and the concept of "water-soluble" diblock copolymer (C2) are relative, selected water phase and oil phase ( solubility relationships and with an organic solvent), the step (di-block copolymer and step (2) the nature of which is compared with the diblock copolymer are more oil-soluble or water-soluble strong to be used in for use in 1) it may also depend on the relationship of how. For example, ethyl acetate is dissolved in a certain order of water, because it may be increased water solubility of the diblock copolymer in ethyl acetate along with it, even HLB is a slightly lower diblock copolymer water it may be handled as a sex diblock copolymer.

Di-block copolymer (C) is a mixture comprising an oil-soluble diblock copolymers (C1) and a water-soluble di-block copolymer (C2), their proportions, an oil-soluble diblock copolymer (C1) with respect to 100 parts by weight of a water-soluble di-block copolymer (C2) is usually 100 to 1,000,000 parts by weight, preferably 100 to 100,000 parts by weight.

- method of manufacturing the porous particles -
The porous microparticles of the present invention can be produced by (other steps may be combined if necessary) comprising the step (1) to (3) described below. This manufacturing method is basically the that according to the production method of known porous microparticles may be carried out using the same production equipment such.

Step (1)
In the first step, di-block copolymer (C), and mixed well with good organic solvent include saturated dissolution amount of water or less. Here, the "saturation dissolution amount or less of water optionally containing an organic solvent be", as described below, the organic solvent of embodiments comprising water in an amount albeit saturated dissolution amount less not 0, water and a completely free (including zero amount of water) aspects of organic solvent.

Although the organic solvent comprises water, when the ratio of water to organic solvent and below the saturation dissolution amount of water to the organic solvent, W / O emulsion (reversed micelles) is not formed, dissolved water in an organic solvent by mixing and thus to. For example, the saturation dissolution amount of water to ethyl acetate 100mL is about 2.5 mL, by the amount of water added with the ratio less, water and di-block copolymer (C) was dissolved in ethyl acetate solution It is obtained. In this case, usually allowed to dissolve by mixing with previously organic solvent diblock copolymer (C), and mixed with the addition of water while stirring the solution, the operation of dissolving is performed. The organic solvent may not contain any water, if the diblock copolymer only (C) is dissolved in an organic solvent is obtained. Using a solution of one embodiment, to form an O / W emulsion in the subsequent secondary emulsification step, further evaporating the organic solvent, the porous fine particles having a hollow portion is obtained.

From using such a good organic solvents include saturated dissolution amount less water in step (1), at the same diblock copolymer mixed (C) is easily dissolved in an organic solvent, as described above it is preferable to use an oil-soluble di-block copolymer (C1).

Incidentally, in this process, when larger than the saturation dissolution amount of water the ratio of water to the organic solvent for the organic solvent, this step is so-called "primary emulsification process" and, W / O (water phase - oil phase) emulsion There is formed. Using this W / O emulsion, to form a W / O / W emulsion in the subsequent secondary emulsification step, further evaporating the organic solvent, the resulting porous particles becomes not usually have a hollow portion.

The organic solvent used in step (1) is, (such as ethyl acetate) ester capable of dissolving the aliphatic polyester resin (A) or di-block copolymer (C), ethers, ketones, (such as chloroform) halogenated hydrocarbons, aromatics (toluene, benzene, xylene, etc.), it can be used alcohols, mineral oil, silicone oil, an appropriate one from among such carbonic esters. In particular, by dissolving the oil-soluble di-block copolymer (C1), esters, ethers, ketones, organic solvents which do have at least one halogen selected from the group consisting of aromatics and alcohols, i.e. halogenated hydrocarbons esters with hydrogen or other halogens, ethers, ketones, aromatic compounds, organic solvent preferably does not contain any compound such as alcohol.

The emulsification method in the step (1), stirring, ultrasound, homogenizer, microreactor microchannels, used a porous membrane, various known emulsifying method may be employed. Further, (For example, if the stirring speed of the stirring blade, etc. stirring time) the operating conditions of these emulsification methods according to primary emulsification process which is used in conventional manufacturing method of porous particles, suitably adjusted do it. The amount of di-block copolymer is added to the organic solvent (C) is also intended to be appropriately adjusted by those skilled in the art, taking into account the amount and the amount of water in step (2) of the organic solvent of step (1) Te, also if further addition of di-block copolymer formed in step (2) the amount even taking into account, may be a suitable emulsion and the final amount of the porous fine particles are formed.

Step (2)
In the second step, emulsifying the preparation according to the step (1), and water, a mixture of additional diblock copolymer optionally (C). Typically, operation of emulsified with the addition of the preparation according to the step (1) in water and dissolved further diblock copolymer (C) optionally is performed.

When producing the porous hollow particles, the preparation according to step (1), as described above, (including 0) diblock copolymer (C) and a saturated dissolution amount less water and are dissolved organic a solvent solution by emulsifying the mixture of step (2) in the solution and water, O / W (oil phase - the aqueous phase) emulsion is formed.

In the case the preparation according to the step (1) for the addition of more water than the saturation dissolution amount is W / O emulsion instead of a solution, step (2) is next to the so-called "secondary emulsification step", W / O by emulsifying a mixture of an emulsion and water, W / O / W (aqueous phase - an oil phase - the aqueous phase) emulsion is formed.

Also in step (2), can be employed various known emulsion methods as described above, and (rotational speed of the stirring blade is the case of the example stirring and stirring time) the operating conditions therefor are also conventional porous are used in the manufacturing method of quality microparticles according to (secondary) emulsification process may be appropriately adjusted.

Step (2) In the diblock copolymer used in step (1) (in particular oil-soluble di-block copolymer (C1)) identical or different diblock copolymer (especially a water-soluble diblock copolymer polymer (C2)), may also be emulsified and added to the mixture. That is, in the production method of the present invention, it is possible to form a porous particles of step (1) in the diblock copolymer alone present invention was added to the organic solvent, identical or different optionally di was added further a block copolymer in the step (2), it may be formed of porous microparticles of the present invention in both of those diblock copolymers.

For example, process oil-soluble di-block copolymer (1) in the (C1) previously dissolved in an organic solvent, step (2), the aliphatic polyester resin (A) hydrophilic polymer for the block from (B) the ratio of the length the oil-soluble di-block copolymer of blocks from greater than (C1) (i.e. greater than the HLB value), it is preferable to use a water-soluble di-block copolymer (C2). By using those of at least two different properties as diblock copolymers, the properties of the resulting porous particles (pore size, etc. capillary number) the more finely, also possible and can be adjusted to even more preferred Become.

When used in the step (2) water-soluble di-block copolymer (C2), usually to keep dissolved in advance in water to be added preparation step (1) (solution). The amount of water-soluble di-block copolymer used in step (2) (C2), the relationship between the amount of oil-soluble di-block copolymer used in step (1) (C1) is, as described above as the may be such as to satisfy the ratio of the Do mixture.

Step (3)
In a third step, to form a porous microparticle by distilling off the organic solvent from the emulsion prepared in the step (2) (usually O / W emulsion is the case of producing a porous hollow particles). For example, in the liquid for heating or reduced pressure with stirring emulsion (water) when distilling off the organic solvent by using a drying method, the aliphatic polyester resin (A) or di-block copolymer (C) is precipitated resins However, the porous microparticles are formed. The heating temperature in this step, pressure decrease, the processing time, and other operating conditions, according to the liquid drying method used in the conventional method of manufacturing a conventional porous fine particles may be appropriately adjusted.

- of the porous particles applications -
There is no particular limitation porous microparticles applications of the present invention, extended release pharmaceutical conventionally used porous particles, sustained release pesticide, the immobilized enzyme-immobilized microorganisms (bioreactors), chemical reactions, in various fields such as animal cell culture, medicine, agricultural chemicals, enzymes, microorganisms, catalysts, etc. for holding the animal cells, or for the isolation material it can be used as a carrier or capsule.

For example, long while the porous hollow microparticles possess a hollow portion serving as a reservoir of drug therein, because it can be said that with an outer layer portion of the porous capable of sustained release of the agent class, than conventional possible sustained release of drugs, (releasing example drug at once broken particles after a certain time has elapsed from the start sustained) timed to sustained release behavior is changed like, used as drug carriers or capsules having unique properties be able to.

Incidentally, diblock copolymer The hollow portion hydrophilic sites are oriented in (C), it can be encapsulated hydrophilic compounds, while the outer layer portion which hydrophobic portion is oriented (internal micropores) it can be held hydrophobic compound is. Further, for example, polylactic acid and polyethylene glycol (PEG) diblock copolymers obtained by synthesizing the safety in vivo is high, biocompatibility without antigenicity because the surface is covered with PEG because of its excellent, such porous particles formed by diblock copolymers are particularly suitable for use as a pharmaceutical agent to be administered into the body.

The porous hollow particles, since a structure having a capsule film and a hollow portion of the porous believed exchange inside the capsule solution is also large very fast and capacity. Therefore, not only it is suitable as a carrier for immobilizing enzymes or catalysts for chemical reactions by utilizing the high specific surface area, it can be applied to various types of treatment with the enzyme reaction or chemical reaction as efficiently performed (bio) reactor. Since the solution in a sealed volume per mass of porous hollow particles is larger than the conventional non-hollow porous particles is also suitable as a concentrated material for rare resources from solution. Further, the porous hollow particles of the present invention is formed by a biocompatible material, the hollow portion is for a relatively large space is also useful, such as microorganisms or animal cells proliferation.

(Synthesis of the diblock copolymer having an HLB value of 10)
MeO-PEG (Mn = 4,000, Mw / Mn = 1.06) was conducted D to the initiator, the synthesis of di-block copolymer at the ring-opening polymerization of L-lactide. At this time, as 3 mol% of MeO-PEG concentration, polymerization was carried out on the scale of the charged amount 10 g. As a catalyst for polymerization, Tin (II) 2-ethylhexanoate / toluene (concentration 0.4 g / 5 mL) solution was used 50 [mu] L. Polymerization, 130 ° C. in an oil bath, was carried out for 24 hours. The resulting product was dissolved in chloroform, the catalyst was removed from the product by reprecipitated in hexane. In addition, by re-precipitation in 2-propanol, to remove unreacted monomers, then the product was recovered by centrifugation (15,000 rpm, 5 min). The product after recovery be to overnight drying under reduced pressure, to give di-block copolymer (Mn = 8,000, Mw / Mn = 1.08). The yield was 68.9 wt%.

(Synthesis of the diblock copolymer HLB value 18.2)
MeO-PEG (Mn = 4,000, Mw / Mn = 1.06) was conducted D to the initiator, the synthesis of di-block copolymer at the ring-opening polymerization of L-lactide. At this time, the MeO-PEG concentration as 15 mol%, polymerization was carried out on the scale of the charged amount 10 g. As the catalyst for polymerization Tin (II) 2-ethylhexanoate / toluene (concentration 0.4 g / 5 mL) solution was used 50 [mu] L. Polymerization, 130 ° C. in an oil bath, was carried out for 24 hours. The resulting product was dissolved in chloroform, the catalyst was removed from the product by reprecipitated in hexane. In addition, by re-precipitation in 2-propanol, to remove unreacted monomers, then the product was recovered by centrifugation (15,000 rpm, 5 min). The recovery of the product after it to overnight drying under reduced pressure, to give di-block copolymer (Mn = 4,400, Mw / Mn = 1.05). The yield was 73.3 wt%.

Example 1 (Preparation of in O / W emulsion)
Diblock copolymers having an HLB value of 10 to ethyl acetate (Mn = 8,000, Mw / Mn = 1.08) solution was used as the oil phase solution prepared by dissolving such that 1 wt%. The solution 8 mL, diblock copolymers having an HLB value of 18.2 (Mn = 4,400, Mw / Mn = 1.05) of 1 wt% and so as to dissolved the neck that contains the ethyl saturated aqueous acetate 300 mL It poured into a flask (the time external aqueous phase is stirred at 250 rpm by a stirring blade, three-neck flask with an external aqueous phase was kept at 50 ° C. in a water bath).

After preparing the O / W emulsion, and distilling off the ethyl acetate by performing 4 hours it was dried under reduced pressure to prepare microparticles. After solvent evaporation, by centrifugation (11,000 rpm, 3 min), the solid was collected, it was further washed three times with ultrapure water. The resulting solid is dispersed in a small amount of ultrapure water was frozen with liquid nitrogen. As by drying overnight in a lyophilizer to give the porous hollow particles (see FIG. 1 [a]).

Example 2 (Preparation for W / O / W emulsion)
Diblock copolymers having an HLB value of 10 to ethyl acetate (Mn = 8,000, Mw / Mn = 1.08) solution was used as the oil phase solution prepared by dissolving such that 1 wt%. The solution 8 mL in ultrapure water was added 0.1 mL, to prepare a W / O emulsion by emulsifying 2 minutes (8,000 rpm, 2 min) with a homogenizer. The emulsion, containing the previously prepared diblock copolymers having an HLB value of 18.2 had been (Mn = 4,400, Mw / Mn = 1.05) of 1 dissolved ethyl acetate such that the wt% saturated aqueous 300 mL It poured necked flask there (at that time the outer aqueous phase is stirred at 250 rpm by a stirring blade, three-neck flask with an external aqueous phase was kept at 50 ° C. in a water bath).

After preparing the W / O / W emulsion, under vacuum, by performing the 4-hour liquid drying, the ethyl acetate was distilled off to prepare fine particles. After solvent evaporation, by centrifugation (11,000 rpm, 3 min), the solid was collected, it was further washed three times with ultrapure water. The resulting solid is dispersed in a small amount of ultrapure water was frozen by liquid nitrogen. As by drying overnight in a lyophilizer to give the porous hollow particles (see FIG. 1 [b]).

Reference Example 1
In preparing the W / O emulsion, except that ultrapure water to the oil phase solution 8 mL was added 1 mL more than the amount saturation solubility was prepared porous particles in the same manner as in Example 2 (FIG. 1 [c ]reference). The resulting porous particles were those having no hollow portion.

Reference Example 2
In preparing the W / O emulsion, except that ultrapure water to the oil phase solution 8 mL was added more 2.5 mL than the amount saturation solubility was prepared porous particles in the same manner as in Example 2 (FIG. 1 [d ]reference). The resulting porous particles were those having no hollow portion.

Claims (16)

  1. Diblock copolymer in which the number of carbon atoms is composed of an aliphatic polyester resin (A) derived from the block and a hydrophilic polymer (B) derived from the block from 2 to 6 hydroxy carboxylic acids or dicarboxylic acids of component (C formed by), porous fine particles having a hollow portion.
  2. The average outer diameter of the porous fine particles having a hollow portion is the 0.05 ~ 500 [mu] m, an average pore diameter of 0.005 ~ 10 [mu] m existing in the entire particles and the average diameter of the hollow portion is 0.01 to it is 450 [mu] m, the porous microparticles according to claim 1.
  3. In the range number-average molecular weight Mn of 500 to 200,000 as measured by GPC of the di-block copolymer (C), the range of weight average molecular weight Mw of 500 to 200,000, and a molecular weight distribution Mw / Mn there is in the range 1.00 and 2.00 porous microparticles according to claim 1 or 2.
  4. In the range number-average molecular weight Mn of 100 to 200,000 as measured by GPC of the aliphatic polyester resin (A), the in the range of the weight-average molecular weight Mw of 100 to 200,000, a molecular weight distribution Mw / Mn 1 in the range of .00 to 2.00, the porous microparticles according to any of claims 1-3.
  5. Number average molecular weight Mn measured by GPC of the hydrophilic polymer (B) is in the range of 100 to 200,000, in the range of the weight-average molecular weight Mw of 100 to 200,000, a molecular weight distribution Mw / Mn 1 in the range of .00 to 2.00, it is derived from the hydrophilic polymer (B), the porous microparticles according to any of claims 1-4.
  6. The aliphatic polyester resin (A) is polylactic acid, polyglycolic acid, at least one aliphatic polyester resin selected from the group consisting of Porikapuron acid and polybutylene succinate, any one of claims 1 to 5, the porous fine particles according to.
  7. The hydrophilic polymer (B) is selected from the group consisting of polyoxyethylene, polyoxypropylene, polyvinyl alcohol, partially hydrolyzed polyvinyl acetate copolymers, polymethacrylic acid, polyacrylic acid, polyacrylamide, poly-aspartic acid, polysaccharides , polyisopropylacrylamide, at least one hydrophilic polymer selected from the group consisting of sodium polystyrene sulfonate and derivatives thereof, the porous microparticles according to any of claims 1-6.
  8. The diblock copolymer component ratio (C), the degree of polymerization of the hydrophilic polymer (B) derived from the block with respect to the polymerization degree 100 parts of the aliphatic polyester resin (A) derived from the block 0.1 range becomes to 100,000 parts, or diblock copolymers HLB value of (C) is less than 0.4 or more 20, the porous microparticles according to any of claims 1 to 7.
  9. The di-block copolymer (C) is oil-soluble di-block copolymer having an HLB value of 0.4 to 12 and (C1), is less than an HLB value of 8 or more 20 and oil-soluble diblock copolymer HLB value than the polymer (C1) contains a water-soluble di-block copolymer having at least two large value (C2), a mixture composed of at least two diblock copolymer according to claim 1 the porous particles according to any one of 1 to 8.
  10. The di-block copolymer (C) is, the oil-soluble di-block copolymer (C1) with respect to 100 parts by weight, the water-soluble di-block copolymer (C2) of 100 to 1,000,000 parts by weight a proportion of a mixture composed of at least two diblock copolymer, porous microparticles according to any of claims 1-9.
  11. (1) components of hydroxycarboxylic acids or dicarboxylic acid and an aliphatic polyester resin carbon atoms is 2 ~ 6 (A) derived from the block and a hydrophilic polymer (B) consists of from block diblock copolymer (C) a step of mixing also a good organic solvent include saturated dissolution amount of water or less,
    (2) Step of forming an emulsion by emulsifying a mixture of a preparation and water of the step (1), and (3) by distilling off the organic solvent from the emulsion obtained in the above step (2) comprising the step of forming the porous fine particles, production methods of the porous fine particles having a hollow portion formed by the di-block copolymer (C).
  12. At least the organic solvent, dissolving the diblock copolymer (C), esters, ethers, ketones, halogenated hydrocarbons, aromatic compounds, selected alcohol, mineral oil, from the group consisting of silicone oils and ester carbonate it is a kind of organic solvent, the preparation of the porous microparticles according to claim 11.
  13. As the di-block copolymer (C), in the step (1), oil-soluble di-block copolymer having an HLB value is 0.4 to 12 a (C1) used in a further step (2), water-soluble di-block copolymer having an HLB value than the HLB value is less than 8 or more 20 and oil-soluble di-block copolymer (C1) has at least two large value using the (C2), according to claim 11 or 12 preparation of the porous microparticles according to.
  14. With respect to the oil-soluble di-block copolymer (C1) 100 parts by weight, the used water-soluble di-block copolymer (C2) at a rate of 100 to 1,000,000 parts by weight, according to claim 13 process for the preparation of porous particles.
  15. The organic solvent to dissolve the oil-soluble di-block copolymer (C1), esters, ethers, ketones, at least one organic solvent selected from the group consisting of aromatics and alcohols, claim 13 or preparation of the porous microparticles according to 14.
  16. Porous microparticles or claim 11 using a porous fine particle having a hollow portion obtained by the method according to any one of 1 to 15, sustained release, having a hollow portion according to any one of claims 1 to 10 pharmaceutical, for sustained release pesticide, porous capsules immobilized enzyme-immobilizing microorganisms, catalysts, for animal cell culture or separation materials.
PCT/JP2010/053626 2009-03-06 2010-03-05 Biodegradable porous hollow particle, and production method and application thereof WO2010101240A1 (en)

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WO2014085151A1 (en) * 2012-11-28 2014-06-05 Eastman Kodak Company Porous particles and methods of making them
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