JP5780507B2 - Biodegradable hollow fine particles and production method thereof - Google Patents

Description

  The present invention relates to hollow fine particles formed of a biodegradable aliphatic polyester resin typified by polylactic acid and a method for producing the same.

  Polylactic acid is generally known as an aliphatic polyester resin having biodegradability, and the development of fine particles (microcapsules) in which a specific functional substance is encapsulated in a coating film is also promoted. ing.

As a method for producing such a microcapsule based on polylactic acid, for example, oil phase solidification from a W / O / W emulsion (Non-Patent Document 1), interfacial polymerization using a polylactic acid macromonomer (Non-patent) Reference 2), preparation of monodispersed polymer capsules using a block copolymer with a fluoroalkyl chain has been reported. Recently, a method for preparing hollow polylactic acid microcapsules using microbubbles has been reported (Patent Document 1). The microcapsules obtained by this method contain only gas and are water-soluble. It is not possible to prepare microcapsules enclosing an aqueous solution in which a functional substance or the like is dissolved.

JP 2008-161817 A

Pharm. Res., 24, 1007-1013 (2007) Colloid Polym. Sci., 284, 513-519 (2006) Colloid Surf. A, 289, 96-104 (2006)

  A method for producing a microcapsule having a biodegradable resin (aliphatic polyester resin) as a coating and having a hollow part capable of storing an aqueous phase such as an aqueous solution therein, as well as the production method An object of the present invention is to provide hollow fine particles encapsulating a desired water-soluble substance.

  The present inventors have made an aliphatic polyester resin (biodegradable resin) in a specific desirable organic solvent by an emulsification process using a specific diblock copolymer having a hydrophilic part and a hydrophobic part as an emulsifier. It was found that by preparing an emulsion containing a dissolved oil phase and distilling off the organic solvent from the emulsion, fine particles with a hollow inside can be formed using the aliphatic polyester resin as a coating. It came to complete.

  That is, according to one aspect of the present invention, the outer shell layer (II) constructed of the aliphatic polyester resin (A) having 2 to 6 carbon atoms of the constituent hydroxycarboxylic acid or dicarboxylic acid, Provided is a hollow fine particle characterized by having a structure comprising a hollow portion (I) formed inside a shell layer (II).

The number average particle diameter of the hollow fine particles is preferably in the range of 0.1 to 500 μm. Further, the coefficient of variation (CV) of the hollow fine particles is preferably in the range of 0.1 to 10%, more preferably in the range of 2 to 5%.

  At least a part of the hollow part (I) of the hollow fine particles may be filled with the water phase (W1) in which the water-soluble encapsulating substance (s) is dissolved, or is filled with air or a gas other than air. Also good.

  The aliphatic polyester resin (A) is preferably at least one aliphatic polyester resin selected from the group consisting of polylactic acid, polyglycolic acid, polycaproic acid, and polybutylene succinate. The aliphatic polyester resin (A) preferably has a number average molecular weight Mn measured by GPC in the range of 100 to 200,000, a weight average molecular weight Mw in the range of 100 to 200,000, and a molecular weight. It is an aliphatic polyester resin having a distribution Mw / Mn in the range of 1.00 to 2.00.

  The water-soluble encapsulating substance (s) is preferably at least one selected from the group consisting of proteins, medicinal ingredients, agricultural chemicals and chelating agents, for example.

In another aspect, the present invention includes the following step (1a) or (1b), step (2), and step (3), and the aqueous phase (W2) in the following step (2) is used as an emulsifier: A diblock copolymer (B) composed of a block derived from an aliphatic polyester resin (B1) having 2 to 6 carbon atoms in the constituent hydroxycarboxylic acid or dicarboxylic acid and a block derived from a hydrophilic polymer (B2) A method for producing hollow microparticles as described above, characterized in that:
[Step 1a] The oil phase (O) containing the aliphatic polyester resin (A) having 2 to 6 carbon atoms of the constituent hydroxycarboxylic acid or dicarboxylic acid and the aqueous phase (W1) are emulsified to give W1 / Preparing an O emulsion;
[Step 1b] An oil phase (O) which contains an aliphatic polyester resin (A) having 2 to 6 carbon atoms of hydroxycarboxylic acid or dicarboxylic acid as a constituent component and may further contain water not exceeding a saturated dissolution amount (O )
[Step 2] A step of emulsifying the preparation obtained through the above step (1a) or (1b) and the aqueous phase (W2) to prepare an emulsion;
[Step 3] The organic solvent (o) contained in the emulsion that has undergone the above step (2) is distilled off, and the aliphatic polyester resin (A) is precipitated to deposit the aliphatic polyester resin (A). A step of forming hollow fine particles having a structure comprising a shell layer (II) and a hollow portion (I) formed in the outer shell layer (II).

  The emulsification in at least one of the steps (1a) or (2) is preferably performed by a microchannel branch emulsification method.

  The water-soluble diblock copolymer (B) is preferably a water-soluble diblock copolymer having an HLB value in the range of 8 or more and less than 20. The composition ratio of the diblock copolymer (B) is preferably such that the degree of polymerization of the block derived from the hydrophilic polymer (B2) is 100 parts of the degree of polymerization of the block derived from the aliphatic polyester resin (B1). It is the range which becomes 0.1-100,000 parts. The water-soluble diblock copolymer (B) preferably has a number average molecular weight Mn measured by GPC in the range of 500 to 200,000 and a weight average molecular weight Mw in the range of 500 to 200,000. And a water-soluble diblock copolymer having a molecular weight distribution Mw / Mn in the range of 1.00 to 2.00.

The aliphatic polyester resin (B1) is preferably at least one aliphatic polyester resin selected from the group consisting of polylactic acid, polyglycolic acid, polycaproic acid, and polybutylene succinate. The aliphatic polyester resin (B1) preferably has a number average molecular weight Mn measured by GPC in the range of 100 to 200,000, a weight average molecular weight Mw in the range of 100 to 200,000, and a molecular weight distribution Mw. / Mn is an aliphatic polyester resin in the range of 1.00 to 2.00.

  The hydrophilic polymer (B2) is preferably polyoxyethylene, polyoxypropylene, polyvinyl alcohol, a partial hydrolyzate of polyvinyl acetate copolymer, polymethacrylic acid, polyacrylic acid, polyacrylamide, polyaspartic acid , At least one hydrophilic polymer selected from the group consisting of polysaccharides, polyisopropylacrylamide, sodium polystyrene sulfonate and derivatives thereof. The hydrophilic polymer (B2) preferably has a number average molecular weight Mn measured by GPC in the range of 100 to 200,000, a weight average molecular weight Mw in the range of 100 to 200,000, and a molecular weight. It is a hydrophilic polymer having a distribution Mw / Mn in the range of 1.00 to 2.00.

  The organic solvent (o) is preferably at least one organic solvent selected from the group consisting of esters, ethers, ketones, aromatic compounds and alcohols, which dissolves the aliphatic polyester resin (A).

  According to the present invention, biodegradation of a mononuclear structure encapsulating an aqueous solution or other solvent by a series of simple manufacturing methods that does not require the synthesis of a complicated nozzle structure for emulsification processing or a special polylactic acid derivative. Microcapsules can be produced. In particular, in the production method of the present invention, an emulsification treatment technique using a microreactor can be adopted, so that monodisperse emulsions and final hollow microparticles with uniform sizes can be easily prepared.

BRIEF DESCRIPTION OF THE DRAWINGS Schematic of the microreactor used for the preparation of the emulsion by a microchannel branch emulsification method in an Example and a reference example. The SEM image of the polylactic acid microparticles | fine-particles prepared in the Example. The SEM image of what can confirm a cross section among the polylactic acid microparticles | fine-particles prepared in the Example. The SEM image of what can confirm a cross section among the polylactic acid microparticles | fine-particles prepared by the reference example.

− Hollow fine particles −
The hollow fine particles of the present invention have a structure comprising an outer shell layer (II) constructed of a specific aliphatic polyester resin (A) and a hollow portion (I) formed inside the outer shell layer (II). Have

  The “hollow part” refers to a part not filled with the aliphatic polyester resin (A), and at least a part (part or all) of the hollow part is made of the water-soluble encapsulating substance (s). It may be filled with a dissolved aqueous phase (W1), or may be filled with air or a gas other than air.

<Particle size>
The size of the hollow fine particles of the present invention is not particularly limited, and can be adjusted by using an appropriate emulsification technique depending on the application. In particular, in the present invention, the production method of the present invention as described later, in particular, the microchannel branch emulsification method can be used. Therefore, the number average particle diameter of the hollow fine particles can be generally adjusted in the range of 0.1 to 10,000 μm, preferably 0.1 to 500 μm, more preferably 0.5 to 500 μm. can do. Further, the variation coefficient (= standard deviation / number average particle diameter) of the particle diameter of the hollow fine particles is preferably 0.1 to 10%, more preferably 2 to 5%. In order to produce such hollow fine particles that satisfy both the number average particle size and the coefficient of variation of the particle size, for example, the production method of the present invention as described later, particularly the microchannel branch emulsification method, may be used. desirable.

  The size of the hollow part (I) formed inside the hollow fine particles can be adjusted according to the use of the hollow fine particles, and is not particularly limited. Specifically, it can be adjusted in the range of 1 to 50 μm, preferably 1 to 20 μm. The ratio of the diameter of the hollow part to the particle diameter of the hollow fine particles (number average value) can be generally adjusted in the range of 10 to 90%, preferably 50 to 90%. The hollow fine particles having the hollow portion (I) of such size are the conditions relating to the oil phase (O) in which the aliphatic polyester resin (A) is dissolved in the organic solvent (o) in the production method of the present invention as described later. It can produce by adjusting the conditions regarding solvent distillation.

  The number average particle size and coefficient of variation (CV) of hollow fine particles and the diameter of the hollow portion (I) are determined by observing a predetermined number (for example, 50) of hollow fine particles using a scanning electron microscope (SEM), for example. By doing this (the diameter of the hollow part can be calculated by targeting the hollow fine particles in which the hollow part is divided and appears).

<Aliphatic polyester resin (A)>
The aliphatic polyester resin (A) used in the present invention is a so-called biodegradable resin, in which the constituent hydroxycarboxylic acid or dicarboxylic acid has 2 to 6 carbon atoms. As such aliphatic polyester resin (A), various known aliphatic polyester resins can be used. For example, polylactic acid, polyglycolic acid, polycaproic acid, polypolypropylene, which are general biodegradable resins, can be used. Butylene succinate and the like are preferred. These resins may be used alone or in combination of two or more.

  The hydroxycarboxylic acid or dicarboxylic acid having 2 to 6 carbon atoms can be selected from those used as raw materials for producing known aliphatic polyester resins. For example, as the hydroxycarboxylic acid having 2 to 6 carbon atoms, glycolic acid (C2), lactic acid (C3), 3-hydroxybutyric acid (C4), 4-hydroxybutyric acid (C4), 4-hydroxyvaleric acid (C5 ), 5-hydroxyvaleric acid (C5), 6-hydroxycaproic acid (C6) and the like. In addition, when aliphatic hydroxycarboxylic acid has an asymmetric carbon, any of a L body, a D body, and its mixture (racemic body) may be sufficient. Examples of the dicarboxylic acid having 2 to 6 carbon atoms include oxalic acid (C2), malonic acid (C3), succinic acid (C4), glutaric acid (C5), adipic acid (C6), and the like. These compounds may be used alone or in combination of two or more.

  On the other hand, the dialcohol that can be copolymerized with the hydroxycarboxylic acid or dicarboxylic acid as described above can also be selected from those used as raw materials for producing known aliphatic polyester resins, such as ethylene glycol. , Diethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, 1,3-butanediol, 1,4-butanediol, 3-methyl-1,5-pentadiol, 1,6-hexanediol, and the like. These compounds may be used alone or in combination of two or more.

Aliphatic polyester resins (A) obtained from the above raw materials include aliphatic hydroxycarboxylic acid homopolymers (eg, polylactic acid, polyglycolic acid) and copolymers (eg, copolymers of lactic acid and glycolic acid); Copolymers of alcohol and aliphatic dicarboxylic acid (eg 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 and It may be any of an aliphatic dialcohol and / or a copolymer with an aliphatic dicarboxylic acid (for example, a block copolymer of polylactic acid and polybutylene succinate), or a mixture thereof.

  The aliphatic polyester resin (A) has a number average molecular weight Mn measured by GPC of preferably 100 to 200,000, a weight average molecular weight Mw of preferably 100 to 200,000, and a molecular weight distribution Mw / Mn of 1.00 to 2. 0.00 is preferred.

<Water-soluble inclusion substance (s)>
The water-soluble encapsulating substance (s) is a substance encapsulated in the hollow part (I) inside the hollow fine particles. The water-soluble encapsulating substance (s) in the present invention is not particularly limited, and an appropriate one can be selected according to the use of the hollow fine particles of the present invention.

  Typical water-soluble encapsulating substances (s) in the present invention include proteins, medicinal ingredients, agricultural chemicals and chelating agents.

  Examples of proteins include enzymes involved in various biological reactions, antigens and antibodies. Medicinal ingredients include those used in pharmaceuticals, cosmetics, (functional) foods, such as contrast agents, anticancer agents, antibacterial agents, anti-inflammatory agents, whitening agents, rough skin prevention agents, anti-aging agents, Examples include hair growth promoters, moisturizers, vitamins, nucleic acids (DNA or RNA sense or antisense strands, plasmids, vectors, mRNA, siRNA, etc.), and particularly those that are expected to be used in DDS. Examples of agricultural chemicals and fertilizers include those that are expected to be used in a sustained release manner. Examples of the chelating agent include those for adsorbing and recovering metal (rare metal). This chelating agent may be polymerized so as to be suitable for encapsulation. In addition, pigments, dyes, pigments, fluorescent pigments and the like used in paints and inks can also be cited as water-soluble encapsulating substances (s).

− Method for producing hollow microparticles −
The method for producing hollow fine particles of the present invention includes the following step (1a) or (1b), step (2) and step (3), and may further include other steps as necessary. And the water phase (W2) in the following process (2) contains the specific diblock copolymer (B) described below as an emulsifier.

  In addition, the aliphatic polyester resin (A) and the water-soluble encapsulating substance (s) used in the following production method are as described above.

-Preparation method of water phase and oil phase As an aqueous solvent constituting the water phase (W1) and (W2), water is basically used, and if necessary, other solvents having high compatibility with water are combined. It may be used.

  On the other hand, as an organic solvent constituting the oil phase (O), for example, esters (ethyl acetate, etc.), ethers, ketones, aromatic compounds (benzene, xylene, etc.), alcohols, etc., are slightly soluble in the aqueous phase. There can be used an aliphatic polyester that can be dissolved and that can be dried in liquid under reduced pressure.

  The addition method of the component to be contained in the water phase (W1 or W2) and the component to be contained in the oil phase (O) is not particularly limited, but a general method according to the emulsification technique employed It may be added according to the procedure.

  For example, the oil phase (O) necessarily includes an aliphatic polyester resin (A) for constructing the outer shell layer (II) in the present invention. Moreover, you may contain the fat-soluble enclosure material for encapsulating in outer shell layer (II) as needed. In this case, an aliphatic polyester resin (A), an organic solvent (o), and a fat-soluble encapsulating substance as necessary are mixed in advance to prepare an oil phase (O), which is then used as an aqueous phase (W1). What is necessary is just to use for an emulsification process.

  On the other hand, the aqueous phase (W1) contains a water-soluble encapsulating substance (s) for inclusion in the hollow part (I) in a typical embodiment of the present invention. Also in this case, the water-soluble encapsulating substance (s) and the aqueous solvent (w1) are mixed in advance to prepare an aqueous phase (W1), which is then subjected to an emulsification treatment with the oil phase (O). .

  Furthermore, the diblock copolymer (B) as an emulsifier (surfactant) is also included in at least the aqueous phase (W2) in the following step (2). That is, when the hollow fine particles of the present invention are produced by the following steps (1a), (2) and (3), the diblock copolymer (B) is a step of preparing at least a W1 / O / W2 emulsion ( It is included in the aqueous phase (W2) in 2), and may or may not be included in the aqueous phase (W1) in the step (1a). On the other hand, when the hollow fine particles of the present invention are produced by the following steps (1b), (2) and (3), the diblock copolymer is added to the aqueous phase (W2) in the step (2) for preparing the O / W2 emulsion. The union (B) must be included. In any case, the aqueous phase may be prepared by mixing the diblock copolymer (B) and the predetermined aqueous solvent prior to the step in which the predetermined aqueous phase is used.

  The concentration of the aliphatic polyester resin (A) in the oil phase (O) is determined by, for example, the thickness of the outer shell layer (II) to be formed and the solubility of the aliphatic polyester resin (A) to be used in the organic solvent (o). Although it can be adjusted while considering, it may be adjusted in the range of usually 0.1 to 20% by weight, preferably 1 to 10% by weight.

  The concentration of the water-soluble encapsulating substance (s) in the aqueous phase (W1) may be adjusted in consideration of the use of the hollow fine particles and the solubility of the water-soluble encapsulating substance (s) to be used in water.

  The concentration of the diblock copolymer (B) in the aqueous phase (W2) can be adjusted to a concentration capable of performing a predetermined function as an emulsifier, but is usually 0.1 to 10% by weight, preferably May be adjusted in the range of 1 to 5% by weight.

<Step (1a): First emulsion preparation step>
Step (1a) in the production method of the present invention is a step of preparing a W1 / O emulsion by emulsifying the oil phase (O) containing the aliphatic polyester resin (A) and the aqueous phase (W1) as described above. is there.

-Emulsification method The method for the emulsification treatment in the production method of the present invention can be selected from various known methods using stirring, ultrasonic waves, a homogenizer, a microreactor, a microchannel, a porous membrane, and the like. In addition, various conditions of these various emulsification techniques can be adjusted by those skilled in the art so that the prepared emulsion satisfies the requirements in the present invention.

For the preparation of the W1 / O / W2 emulsion, for example, the microchannel branch emulsification method is suitable. This emulsification technique uses a microreactor equipped with a Y-shaped microchannel, and a dispersed phase (W1 / O emulsion) from one of the channels and a continuous phase (aqueous solvent phase ( The target emulsion (W1 / O / W2 emulsion) can be prepared by flowing W2)) and cutting the flow of the dispersed phase by the continuous phase in the vicinity of the confluence to form droplets. By using the micro-channel branch emulsification method, a monodispersed emulsion having a droplet size in a desired range and an extremely small coefficient of variation (that is, a uniform droplet size) can be obtained, and the inner aqueous phase can be obtained. There is an advantage that a mononuclear (W1) is easily formed.

<Step (1b): Oil phase preparation step>
Step (1b) in the production method of the present invention is a step of preparing an oil phase (O) that contains the aliphatic polyester resin (A) as described above, and may further contain water below the saturated dissolution amount. . That is, in this step (1b), water is not used at all or only an insufficient amount of water is used to form the inner aqueous phase (W1) (such a small amount of water is used as the oil phase (O)). Therefore, the obtained preparation is not an emulsion containing the inner aqueous phase (W1) unlike the step (1a). In the case where water is not used at all, the step (1b) for preparing this oil phase is substantially the same as the step for preparing the oil phase used in the step (1a) for preparing the emulsion described above in advance. The same.

  In this step (1b), an organic solvent (o), an aliphatic polyester resin (A), and, if necessary, water below the saturated dissolution amount of the organic solvent (o) are mixed with a general method (stirring). Etc.) so that the aliphatic polyester resin (A) and water below the saturated dissolution amount are dissolved in the organic solvent (o). The saturated dissolution amount of water in the organic solvent (o) can be determined by known or simple measurement. For example, the saturated dissolution amount of water in 100 mL of ethyl acetate is about 2.5 mL.

<Step (2): Second emulsion preparation step>
Step (2) in the production method of the present invention is a step of preparing an emulsion by emulsifying the preparation obtained through step (1a) or (1b) as described above and the aqueous phase (W2).

  That is, when the W1 / O emulsion as the preparation after the step (1a) is used for emulsification, the step (2) is a state where the W1 / O emulsion is dispersed in the aqueous phase (W2). / W2 emulsion preparation step. On the other hand, when the oil phase (O) as a preparation after the step (1b) is used for emulsification, the step (2) is an O in which the oil phase (O) is dispersed in the water phase (W2). / W Emulsion preparation step.

  As the technique for the emulsification treatment in the step (2), the same technique as the emulsification treatment in the step (1a) described above can be applied, and the microchannel branch emulsification method is particularly suitable.

<Process (3): Solvent distillation process>
In step (3) in the production method of the present invention, the organic solvent (o) contained in the emulsion that has undergone the above step (2) is distilled off to precipitate the aliphatic polyester resin (A), thereby aliphatic polyester resin. This is a step of forming hollow fine particles having a structure comprising the outer shell layer (II) constructed in (A) and the hollow portion (I) formed in the outer shell layer (II).

  Techniques for distilling off the organic solvent (o) are known, and for example, a liquid (in water) drying method in which the emulsion is heated or depressurized while stirring can be used. As the distillation of the organic solvent (o) proceeds by such a technique, the aliphatic polyester resin (A) dissolved in the oil phase (O) in the droplets precipitates and becomes a resin, and eventually the outer shell layer Although (II) is formed, the precipitation does not reach a part of the inside of the droplet, and the hollow portion (I) is also formed.

  Here, regarding the oil phase (O) in which the polyester resin (A) is dissolved, the evaporation rate of the organic solvent (o) is larger than the rate at which the internal concentration tends to be uniform, and the precipitation of the polyester resin (A) When the velocity is high, the hollow portion (I) is formed as described above. Otherwise, the aliphatic polyester resin (A) is deposited on the entire inside of the droplet, and the hollow portion (I) is formed. There is a tendency not to be. For example, as shown in Examples and Reference Examples below using polylactic acid as the aliphatic polyester resin (A), hollow portions are formed when ethyl acetate is used as the organic solvent (o), while hollow portions are formed when chloroform is used. No part is formed, and the resulting fine particles are solid. This is because the time until ethyl acetate is distilled off is relatively short, and all the polylactic acid precipitates quickly and forms an outer shell layer. Due to the difference that the time until it is left is relatively long and polylactic acid precipitates slowly with the decrease in chloroform, the outer shell layer reaches the center and no hollow part is formed. In consideration of such matters, the solvent conditions such as the conditions of the organic solvent (o) and the polyester resin (A) used for the preparation of the oil phase (O), the heating temperature, the reduced pressure width, and the processing time are as described above. You may adjust the conditions regarding the last.

  In addition, the hollow fine particles obtained through the solvent distillation step as described above are usually those in which the hollow portion (I) is filled with water. When preparing a product in which at least a part of the hollow part is filled with air or a gas other than air, the hollow fine particles are collected, washed as necessary, and then the water in the hollow part (I) is evaporated. What is necessary is just to perform the drying process for making it. Such a drying process may be carried out using a general drying method while heating, blowing, etc., if necessary, and various conditions can be adjusted appropriately. If performed in an atmosphere of a gas other than air, the hollow portion (I) can be filled with a gas other than air.

<Diblock copolymer (B)>
In the method for producing hollow fine particles of the present invention, the block derived from the aliphatic polyester resin (B1) having 2 to 6 carbon atoms of the constituent hydroxycarboxylic acid or dicarboxylic acid as the emulsifier added to the aqueous phase and hydrophilicity A diblock copolymer (B) comprising a block derived from the polymer (B2) is used. The block derived from the aliphatic polyester resin (B1) is hydrophobic, and the block derived from the hydrophilic polymer (B2) is literally hydrophilic. The diblock copolymer (B) in a form in which these blocks are connected is mainly dissolved in the aqueous phase and oriented near the interface with the oil phase in which the aliphatic polyester resin (A) is dissolved, and functions as an emulsifier. Can be fulfilled.

  The diblock copolymer (B) as an emulsifier may be a single diblock copolymer or a mixture of two or more diblock copolymers.

-HLB value In the production method of the present invention, the diblock copolymer (B) used as an emulsifier is basically hydrophilic as a whole and soluble in water (or an aqueous solvent). The degree of hydrophilicity of the diblock copolymer (B) can be represented by an HLB value. In the present invention, the HLB value is defined by the Griffin method represented by the following formula. As can be seen from the following equation, the closer the HLB value is to 20, the higher the degree of hydrophilicity.
HLB = 20 × (Mn of hydrophilic polymer (B2)) / (Mn of diblock copolymer (B))
In the present invention, the water-soluble diblock copolymer (B) as an emulsifier generally has an HLB value of 8 or more and less than 20, preferably 15 or more and less than 20. Since the function of the diblock copolymer (B) as an emulsifier may vary depending on the HLB value, the property of the aliphatic polyester resin (A) forming the outer shell layer (II) or the property of the component used as the raw material thereof It is appropriate to adjust the HLB value of the diblock copolymer (B) to be used in consideration of the above.

  Whether the diblock copolymer (B) is soluble in the aqueous phase (W1 to W2) used for preparing the emulsion may vary depending on the presence of other solvents that may be used in combination with water. . For example, since ethyl acetate is dissolved in water to some extent and the solubility of the diblock copolymer (B) in ethyl acetate in water may increase accordingly, the diblock copolymer having a lower HLB than the above range. However, it may be handled as a water-soluble diblock copolymer (B).

  The HLB value is the length of the molecular chain of the aliphatic polyester resin (B1) block which is a hydrophobic portion in the diblock copolymer (B) and the hydrophilic polymer (B2) block which is a hydrophilic portion. The molecular chain length ratio can be adjusted. Generally, when the molecular chain of the hydrophilic polymer (B2) block is lengthened, for example, when the diblock copolymer (B) is synthesized, the hydrophilic polymer (M1) of the aliphatic polyester resin (B1) with respect to Mn When the ratio of Mn in B2) is relatively large, the HLB value of the diblock copolymer (B) increases. More specifically, the degree of polymerization of the block derived from the hydrophilic polymer (B2) is 100 (preferably 400, more preferably 1) with respect to 100 parts of the degree of polymerization of the block derived from the aliphatic polyester resin (B1). , 000) to 100,000 parts, the water-soluble diblock copolymer (B) having an HLB value of 8 or more and less than 20 can be produced.

-Aliphatic polyester resin (B1) block About the aliphatic polyester resin (B1) which comprises one block of a diblock copolymer (B), the same thing as the aliphatic polyester resin (A) mentioned above is applicable. Therefore, the description here is omitted. If only the main points are described, as the aliphatic polyester resin (B1), for example, polylactic acid, polyglycolic acid, polycaproic acid, polybutylene succinate and the like, which are general biodegradable resins, are suitable. Moreover, the number average molecular weight Mn measured by GPC of the aliphatic polyester resin (B1) is also preferably 100 to 200,000, the weight average molecular weight Mw is also preferably 100 to 200,000, and the molecular weight distribution Mw / Mn is also 1.00. ~ 2.00 is preferred.

  The aliphatic polyester resin (B1) used for the diblock copolymer (B) as an emulsifier and the aliphatic polyester resin (A) used for the construction of the outer shell layer (II) are the same. Something is not required and may be different.

-Hydrophilic polymer (B2) block As the hydrophilic polymer (B2) constituting the other block of the diblock copolymer (B), various hydrophilic substances that can be bonded to the aliphatic polyester resin (B1) block. Can be used. For example, polyoxyethylene (polyethylene glycol: PEG), polyoxypropylene, polyvinyl alcohol, polyvinyl acetate copolymer partial hydrolysates, polymethacrylic acid, polyacrylic acid, polyacrylamide, polyaspartic acid, polysaccharides, poly Examples include isopropyl acrylamide, sodium polystyrene sulfonate, and derivatives thereof. These hydrophilic polymers may be used alone or in combination of two or more.

  The number average molecular weight Mn measured by GPC of the hydrophilic polymer (B2) is preferably 100 to 200,000. The weight average molecular weight Mw is preferably 100 to 200,000. The molecular weight distribution Mw / Mn is preferably 1.00 to 2.00.

-Preparation method The diblock copolymer (B) can be prepared by synthesizing the aliphatic polyester resin (B1) and the hydrophilic polymer (B2) according to a known method.

  Typically, as shown in the examples of the present invention, a hydrophilic polymer (B2) having a functional group for introducing a block composed of an aliphatic polyester resin (B1) at the terminal is prepared in advance. Then, the block derived from the aliphatic polyester resin (B1) and the block derived from the hydrophilic polymer (B2) are linked by advancing the polymerization reaction of the aliphatic polyester resin (B1) based on the functional group. The diblock copolymer (B) can be synthesized.

  The diblock copolymer (C) obtained by such a preparation method has a number average molecular weight Mn measured by GPC of preferably 500 to 200,000, a weight average molecular weight Mw of preferably 500 to 200,000, and a molecular weight distribution. Mw / Mn is preferably 1.00 to 2.00.

− Use of hollow fine particles −
The hollow fine particles of the present invention have a variety of uses. In particular, an aqueous solution of a water-soluble encapsulating substance can be enclosed in the interior (hollow part) that can ensure a certain volume, and the coating (outer shell layer) is biodegradable. A characteristic of being formed of a resin (aliphatic polyester resin) and capable of encapsulating a fat-soluble encapsulating substance in the coating can be utilized if desired. Examples of applications of such hollow fine particles include sustained-release agrochemicals, DDS, immobilized enzymes, catalyst carriers, separation materials, heat insulating materials, heat storage materials, contrast agents, cosmetics, cosmetics, paints, inks, and the like. . In addition, what is necessary is just to fill a hollow part with gas, when using hollow microparticles as a heat storage material or a contrast agent.

Example [1] Synthesis of Diblock Copolymer (B) As the diblock copolymer (B) in the present invention, water-soluble polylactic acid (PLA) and polyethylene glycol (PEG) chains are connected in two blocks. A diblock copolymer (PLE, below) was synthesized according to the following procedure. PLA chains are difficult to dissolve in water and act as hydrophobic groups. Conversely, PEG chains are readily soluble in water and act as hydrophilic groups, so PLE can be used as an emulsifier.

A diblock copolymer was synthesized by ring-opening polymerization of D, L-lactide using MeO-PEG (Mn = 4,000, Mw / Mn = 1.06) as an initiator. At this time, the polymerization was carried out at a scale of 10 g charged with a MeO-PEG concentration of 15 mol%. The polymerization catalyst is Tin (II) 2-ethylhexanoate / toluene (
50 μL of the solution having a concentration of 0.4 g / 5 mL) was used. The polymerization was carried out in an oil bath at 130 ° C. for 24 hours. The resulting product was dissolved in chloroform and reprecipitated in hexane to remove the catalyst from the product. Moreover, the unreacted monomer was removed by reprecipitation in 2-propanol, and then the product was recovered by centrifugation (15,000 rpm, 5 min). The recovered product was dried under reduced pressure overnight to obtain a diblock copolymer (Mn = 4,400 (PEG 4,000 + PLA 400), Mw / Mn = 1.05, HLB = 18.2). The yield was 73.3 wt%.

[2] Preparation of O / W Emulsion PLE prepared in the above step as the diblock copolymer (B) in the present invention is dissolved in water (1 wt%) to form an aqueous phase (W), while the fat in the present invention Group polyester resin (A)
As an oil phase (O), 1 wt% of D, L-polylactic acid homopolymer (Mw: 3,200, Mn: 3,000, Mw / Mn: 1.05) was dissolved in ethyl acetate. Then, an oil-in-water (O / W) emulsion was prepared by emulsification using a microreactor (FIG. 1).

[3] Solvent evaporation The O / W emulsion prepared by the above process was recovered, and ethyl acetate used as the oil phase was distilled off under reduced pressure (695 mmHg). D, L-polylactic acid fine particles having a true spherical dense film were obtained by depositing PLA in the oil phase and converting it into a resin. In particular, since emulsification was performed by the microchannel branch emulsification method using a microreactor in this example, the monodispersity was excellent (number average particle size = about 23 μm, coefficient of variation CV = about 4%) D, L-polylactic acid fine particles could be obtained (FIG. 2).

  In addition, when the cross-sectional shape of the polylactic acid fine particles prepared by the same procedure as described above except that the emulsion was prepared not by a microreactor but by a stirring blade, when using ethyl acetate as an oil phase solvent, It was found to have a mononuclear hollow structure as shown in FIG.

Reference Example Polylactic acid fine particles were prepared by the same procedure as in Example 1 except that chloroform was used as the oil phase solvent. When the cross-sectional shape of the obtained polylactic acid microparticles | fine-particles was confirmed, as shown in FIG. 4, it turned out that this particle | grain has a structure which does not have a hollow part.

Claims (9)

Including the following step (1b), step (2), and step (3), and
In the following step (2), the aqueous phase (W2) is a block derived from an aliphatic polyester resin (B1) having 2 to 6 carbon atoms in the constituent hydroxycarboxylic acid or dicarboxylic acid as an emulsifier and a hydrophilic polymer. (B2) Diblock copolymer (B
) Characterized in that it comprises a process for producing a middle empty particles:
[Step 1b] Water containing an aliphatic polyester resin (A) having 2 to 6 carbon atoms of the constituent hydroxycarboxylic acid or dicarboxylic acid and an organic solvent (o) being ethyl acetate , and having a saturated dissolution amount or less Preparing an oil phase (O) which may comprise:
[Step 2] A step of emulsifying the preparation obtained through the above step (1b) and the aqueous phase (W2) to prepare an emulsion;
[Step 3] The organic solvent (o) contained in the emulsion that has undergone the above step (2) is distilled off, and the aliphatic polyester resin (A) is precipitated to deposit the aliphatic polyester resin (A). A step of forming hollow fine particles having a structure comprising a shell layer (II) and a hollow portion (I) formed in the outer shell layer (II). The production method according to claim 1 , wherein the emulsification in the step (2) is performed by a micro-channel branch emulsification method. The manufacturing method according to claim 1 or 2 , wherein the water-soluble diblock copolymer (B) is a water-soluble diblock copolymer having an HLB value in the range of 8 or more and less than 20. The composition ratio of the diblock copolymer (B) is such that the degree of polymerization of the block derived from the hydrophilic polymer (B2) is 0.1 with respect to 100 parts of the degree of polymerization of the block derived from the aliphatic polyester resin (B1). a range of a 100,000 parts, the manufacturing method according to any one of claims 1 to 3. The water-soluble diblock copolymer (B) has a number average molecular weight Mn measured by GPC in the range of 500 to 200,000, a weight average molecular weight Mw in the range of 500 to 200,000, and a molecular weight distribution. Mw / Mn is a water-soluble di-block copolymer in the range of 1.00 to 2.00, the method according to any one of claims 1 to 4. The aliphatic polyester resin (B1) 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 manufacturing method as described in. The aliphatic polyester resin (B1) has a number average molecular weight Mn measured by GPC in the range of 100 to 200,000, a weight average molecular weight Mw in the range of 100 to 200,000, and a molecular weight distribution Mw / Mn. an aliphatic polyester resin in the range of 1.00 to 2.00, the method according to any one of claims 1 to 6. The hydrophilic polymer (B2) is polyoxyethylene, polyoxypropylene, polyvinyl alcohol, polyvinyl acetate copolymer partial hydrolyzate, polymethacrylic acid, polyacrylic acid, polyacrylamide, polyaspartic acid, polysaccharides The production method according to any one of claims 1 to 7 , which is at least one hydrophilic polymer selected from the group consisting of polyisopropylacrylamide, sodium polystyrenesulfonate, and derivatives thereof. The hydrophilic polymer (B2) has a number average molecular weight Mn measured by GPC in the range of 100 to 200,000, a weight average molecular weight Mw in the range of 100 to 200,000, and a molecular weight distribution Mw / Mn. a hydrophilic polymer in the range of 1.00 to 2.00, the method according to any one of claims 1-8.