WO2017221314A1 - Method for producing organic fine particles - Google Patents

Method for producing organic fine particles Download PDF

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WO2017221314A1
WO2017221314A1 PCT/JP2016/068312 JP2016068312W WO2017221314A1 WO 2017221314 A1 WO2017221314 A1 WO 2017221314A1 JP 2016068312 W JP2016068312 W JP 2016068312W WO 2017221314 A1 WO2017221314 A1 WO 2017221314A1
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fine particles
organic fine
organic
water
solvent
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PCT/JP2016/068312
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French (fr)
Japanese (ja)
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榎村眞一
荒木加永子
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エム・テクニック株式会社
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Priority to JP2017537324A priority Critical patent/JPWO2017221314A1/en
Priority to PCT/JP2016/068312 priority patent/WO2017221314A1/en
Publication of WO2017221314A1 publication Critical patent/WO2017221314A1/en

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus

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  • the present invention relates to a method for producing organic fine particles.
  • organic substances such as pharmaceuticals, organic pigments, and resins can be made fine particles, new functions can be expressed in their physical properties. Therefore, the technology for making organic substances fine particles has become an important theme throughout the entire industry.
  • the organic substance has the solubility in a solvent as the most different characteristic from the inorganic substance, and the solubility of the organic substance in the poor solvent is higher than that of the inorganic substance.
  • finely divided organic substances often have higher solubility than the generally indicated value, and the finely divided organic substances are dissolved again, and then the particles grow, resulting in coarse particles. Therefore, it has been difficult to control the particle size by the conventional method.
  • organic fine particles change their solubility, dissolution time, absorbency and stability, optical properties, and other functionalities, depending on the particle size, techniques for controlling the particle size are required.
  • a water-soluble polymer has a hydroxyl group, so it has strong adhesion to substances with a hydrophilic surface, and since it has a hydrophilic hydroxyl group and a hydrophobic functional group, it exhibits surface activity. .
  • Water-soluble polymers are often used in processes where organic substances dissolved in a good solvent and poor solvents in which water-soluble polymers are dissolved are mixed to precipitate organic fine particles for the above reasons.
  • water-soluble polymers have the advantage of being used in processes that use temperature changes due to the fact that hydrophilic groups are easily affected by temperature because they are caused by hydrogen bonding between hydrophilic groups and water molecules.
  • organic fine particles become disadvantageous in that they become unstable in the mixed solution.
  • Patent Document 1 also reports a method of controlling the particle size of organic fine particles by changing the molecular weight of the water-soluble polymer in order to control the particle size of the organic fine particles.
  • the disadvantage that the organic fine particles become unstable in the mixed solution due to the temperature change has not been solved, and the applicable organic matter is often limited.
  • the concentration and temperature of the organic matter in the mixed solution change from the start to the completion of mixing the poor solvent and the good solvent in which the organic matter is dissolved.
  • the state of the mixed solution changes every moment.
  • the particle size distribution of the precipitated organic fine particles may have a broad range, and depending on the conditions, coarse particles that do not exhibit the characteristics expected as organic fine particles may be present. May be generated.
  • Patent Document 2 discloses a method in which a drug containing a biocompatible polymer is dissolved in a water-miscible good solvent and dropped into an aqueous solution of polyvinyl alcohol, which is a poor solvent, to precipitate the drug.
  • a drug containing a biocompatible polymer is dissolved in a water-miscible good solvent and dropped into an aqueous solution of polyvinyl alcohol, which is a poor solvent, to precipitate the drug.
  • the concentration, temperature and pH of the organic substance in the mixed solution change from the time when the mixing of the poor solvent and the good solvent in which the organic substance is dissolved until the completion. Therefore, the state of the mixed solution changes every moment, and the distribution of the particle diameter of the deposited organic fine particles sometimes has a spread.
  • Patent Document 2 Although the amount of the drug with respect to polyvinyl alcohol is shown in Patent Document 2, there is a case where aggregation of the precipitated particles may be observed. Due to problems such as adhesion to the precipitation container, the particles are stably added. Sometimes it was difficult to get. In particular, it was difficult to precipitate the drug at a high concentration, and there was a problem that it could only be prepared in a dilute system.
  • Patent Document 3 a method of depositing organic fine particles between relatively rotating processing surfaces that can approach and leave.
  • the biologically ingested fine particles produced by the method described in Patent Document 3 are finer and more uniform than conventional ones, and the number of rotations of the processing surfaces 1 and 2 and the distance between the processing surfaces 1 and 2 are as follows:
  • organic fine particles having a target particle size by changing the flow rate, temperature, raw material concentration, etc. of the thin film fluid.
  • coarse particles may be observed after the organic fine particles are ejected from the processing surface.
  • the present applicant includes a fluid containing a raw material solution in which the substance to be precipitated is dissolved between the relatively rotating processing surfaces that can approach and leave, and a precipitation solvent for precipitating the substance to be precipitated.
  • a fluid containing a raw material solution in which the substance to be precipitated is dissolved between the relatively rotating processing surfaces that can approach and leave
  • a precipitation solvent for precipitating the substance to be precipitated.
  • the present invention solves the demerits due to temperature changes while taking advantage of the emulsification and dispersion power of water-soluble polymers when controlling the particle size of organic fine particles using the poor solvent method.
  • a method for producing organic fine particles in which organic fine particles are precipitated in a mixed liquid obtained by mixing a poor solvent (A) containing molecules and a good solvent (B) in which organic matters are dissolved the particle diameter of the organic fine particles can be controlled easily and It is an object of the present invention to provide a method for producing organic fine particles that can be stably performed.
  • the inventor of the present application stably adjusts the pH of the liquid mixture at the time of precipitation in order to solve the disadvantages due to temperature change while taking advantage of the emulsification / dispersion power of the water-soluble polymer.
  • I can control.
  • the inventor of the present application can easily control the target particle diameter by adjusting the pH of the mixed liquid at the time of precipitation, can produce particles having excellent stability, can simplify the process, and is stable.
  • the present invention has been completed by finding that a suitable formulation can be obtained and optimized.
  • the properties of the desired organic fine particles, the degree of polymerization of the water-soluble polymer used when the organic fine particles are precipitated, the degree of saponification, and the properties of the aqueous phase (poor solvent (A)) as a continuous phase are considered.
  • the inventors have found that organic fine particles having a target particle diameter can be produced by adjusting the pH to an appropriate pH within the range of 3.5 to 8.5, and have reached the present invention.
  • the present invention relates to a method for producing organic fine particles in which organic fine particles are precipitated in a mixed solution in which a poor solvent (A) and a good solvent (B) in which an organic substance is dissolved are mixed.
  • aqueous solution containing the water-soluble polymer (A1) the above (A) and (B) are mixed, and the pH at the time of precipitation is adjusted in the range of 3.5 to 8.5, whereby the above organic fine particles Is a method for producing organic fine particles having a target particle size.
  • a water-miscible organic solvent is preferably used for the good solvent (B).
  • the poor solvent (A) contains a pH adjuster (A2), and the poor solvent (A) and the good solvent (B) in which the organic substance is dissolved are mixed by the pH adjuster (A2) It is preferable to adjust the pH of the mixture at that time.
  • the present invention is preferably carried out by adjusting the pH adjuster (A2) for the organic substance to a weight ratio of 0.001 or more and 1.0 or less.
  • Various water-soluble polymers having a hydroxyl group can be used.
  • polyvinyl alcohol, hydroxypropylcellulose, hydroxypropylmethylcellulose, and the like are preferable. Can do.
  • the present invention is preferably carried out by adjusting the weight ratio of the organic substance to the water-soluble polymer having a hydroxyl group contained in the poor solvent (A) to 0.1 to 3.0. Even when the weight ratio is 3.0 or more, the particle diameter can be made uniform, but the molecular weight is high, which may not be preferable for exhibiting the performance of organic matter.
  • the particle diameter of the organic fine particles of the present invention is preferably 20 to 500 nm from the viewpoint of its functionality.
  • the organic substance has a great effect on ingested living organisms.
  • the production method of the present invention it is possible to produce organic fine particles with a controlled particle diameter that can fully exhibit the original performance of the organic fine particles.
  • a water-soluble polymer having at least a hydroxyl group By using an aqueous solution containing A1), mixing a poor solvent (A) and a good solvent (B) in which an organic substance is dissolved, and adjusting the pH of the mixture at the time of precipitation in the range of 3.5 to 8.5.
  • the present invention can be carried out by a simple method of controlling the particle diameter of the organic fine particles.
  • the applicable range of target organic matter is wide, the obtained organic matter fine particles are stable to temperature change, and various types of organic matter fine particles having a particle size according to the purpose are provided. It became possible to do.
  • organic fine particles having a precisely controlled particle diameter can be stably produced at low cost, and can meet various demands of the industry.
  • FIG. 1 is a molecular structure diagram of curcumin, which is a target organic substance of Examples 1 to 3 of the present invention and Comparative Example 1.
  • FIG. 2 is a molecular structure diagram of probucol, which is a target organic substance of Examples 4 to 10 and Comparative Example 2 of the present invention. It is a TEM photograph of probucol microparticles
  • the present invention provides a method for producing organic fine particles in which organic fine particles are precipitated by mixing a poor solvent (A) and a good solvent (B) in which an organic substance is dissolved.
  • the aqueous solution containing the molecule (A1) is used to mix the poor solvent (A) and the good solvent (B) in which the organic substance is dissolved.
  • the pH at the time of precipitation of this mixed solution is 3.5 to 8.5.
  • This is a method for producing organic fine particles in which the particle diameter of the organic fine particles is controlled by adjusting within a range.
  • the present invention uses an organic substance as a main raw material, a good solvent (B) obtained by dissolving the organic substance as the main raw material in a solvent, and mixes the good solvent (B) with a poor solvent (A). Some organic fine particles are obtained.
  • the organic fine particles are fine particles composed of the organic matter.
  • the average particle diameter of the fine particles is preferably in nm units, but may be in ⁇ m units.
  • the particle diameter of the organic fine particles is more preferably 20 nm to 500 nm.
  • the raw material and the organic substance as the target product are compounds containing carbon. In particular, those mainly formed from carbon and oxygen are included.
  • the origin of the organic material is not particularly limited, and may be artificially synthesized or extracted from a natural product, and is not particularly limited.
  • pharmaceutical compositions for humans and animals biological ingestions such as foods, food additives, health foods, agricultural chemicals, etc., pigment compounds including polymer compounds such as resins and rubbers, dyes and pigments, paints, etc. And fragrances.
  • the in-vivo ingestion is not particularly limited as long as it is intended to be ingested into the living body, but for example, it is intended to be absorbed into the living body like a drug in a pharmaceutical product and to exert an in vivo effect.
  • substances that transport drug components in drug delivery systems, or those that are applied to living skin such as cosmetics, and intermediates between food and the above substances It is done.
  • cosmetics and intermediates between food and the above substances It is done.
  • it refers to organic substances used in medicines, quasi drugs, cosmetics, foods, food additives, health foods, agricultural chemicals and the like.
  • a commercially available product may be used, or it may be synthesized newly.
  • biological intake examples include analgesics, anti-inflammatory drugs, anthelmintic drugs, antiarrhythmic drugs, antibiotics, anticoagulants, antihypertensive drugs, antidiabetic drugs, antiepileptic drugs, antihistamines, antimalignant tumors Drugs, appetite suppressants, antiobesity drugs, antimuscarinic drugs, antimycobacterial drugs, antineoplastic drugs, immunosuppressive drugs, antithyroid drugs, antibacterial drugs, antiviral drugs, anxiolytic drugs, astrinsen, adrenergic ⁇ receptors Blocking agents, blood products, plasma substitutes, myocardial degenerative drugs, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopamine agonists, hemostatic agents, immunologic agents, lipid modulators, Muscle relaxants, parasympathomimetic stimulants, parathyroid calcitonin, biphosphonates, prostaglandins, radiopharmac
  • danazol tacrolimus hydrate, progesterone, indomethacin, curcumin, tranilast, benzbromarone, naproxen, phenytoin, carotenes, pipesulfam, pipesalphan, captothecin, acetominophen, acetylsalicylic acid, amiodarone, colestifol, Cromolyn sodium, albuterol, sucralfate, sulfasalazine, minoxidil, tempazepam, alprazolam, propoxyphene, auranofin, erythromycin, cyclosporine, acyclovir, ganciclovir, etoposide, mephalan, methotrexate, minoxantrone, daunorubicin, doxorubicin , Tamoxifen, Medroxyprogesterone, Nai Statins, terbutaline, amphotericin B, aspirin, ibuprofen
  • Cosmetics include, for example, basic cosmetics such as lotion, milky lotion, beauty liquid, sunscreen cosmetics, makeup cosmetics, hair cosmetics, cleansing cosmetics, lip cosmetics, oral cosmetics, nail cosmetics, eyeliner cosmetics, bath cosmetics, etc. Can be mentioned.
  • foods or food additives include vitamins such as vitamins A, B, C, and E and derivatives thereof, 2 amino acids, carotenoids, fruits, and plant extracts.
  • Examples of health foods include coenzyme Q10, vitamins such as vitamins A, B, C, and E, and derivatives thereof. These may be used singly or in combination of two or more.
  • High molecular compounds include natural waxes such as paraffin wax, honey, carnauba wax, synthetic waxes such as polyethylene wax (LDPE, low density polyethylene and HDPE, high density polyethylene) and propylene wax, semi-synthetic waxes such as amide wax, Resin and rubber are listed.
  • natural waxes such as paraffin wax, honey, carnauba wax
  • synthetic waxes such as polyethylene wax (LDPE, low density polyethylene and HDPE, high density polyethylene) and propylene wax
  • semi-synthetic waxes such as amide wax, Resin and rubber are listed.
  • solvent used for good solvent (B) The solvent used for the good solvent (B) in which the organic substance of the present invention is dissolved must be selected so that it can dissolve the organic substance.
  • various solvents can be used in order to dissolve the raw material of organic fine particles or to precipitate organic fine particles from a good solvent in which organic fine particles are dissolved.
  • these solvents include water (distilled water, pure water, etc.) and organic solvents (alcohol solvents, ketone solvents, nitrile solvents, sulfoxide solvents, amine solvents, ionic solutions, etc.). I can do it.
  • solvents can be carried out by selecting one or more mixed solvents according to the purpose.
  • an acidic substance or a basic substance can be added to various solvents to adjust the pH.
  • a solvent that is miscible with water and is soluble in organic substances is preferably selected as the solvent used for the good solvent (B).
  • the solvent used for the good solvent (B) For example, it is miscible with water such as xylene. Even if it is not a solvent, you may select the solvent which has the solubility with respect to an organic substance as a solvent used for the said good solvent (B).
  • the solvent that is miscible with water and soluble in organic substances include alcohol solvents such as methanol, ethanol, isopropanol, n-propanol, 1-methoxy-2-propanol, tert-butanol, and the like.
  • Examples thereof include polyhydric alcohols such as ethylene glycol and diethylene glycol, propylene glycol monomethyl ether, and the like.
  • Examples of the ketone solvent include acetone.
  • Examples of the ether solvent include tetrahydrofuran.
  • Examples of the nitrile solvent include acetonitrile.
  • Examples of the sulfoxide solvent include dimethyl sulfoxide and diethyl sulfoxide.
  • Examples of the amine solvent include dimethylaminoethanol, ethylenediamine, methylamine, dimethylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, and triethylamine.
  • Examples of the amide solvent include N, N-dimethylformamide and N, N-dimethylacetamide.
  • an aqueous solution containing at least a water-soluble polymer (A1) having a hydroxyl group is used. It is necessary to select at least water as a solvent for preparing this poor solvent.
  • water tap water, ion exchange water, RO water, pure water, distilled water, ultrapure water, or the like can be used.
  • alcohols such as methanol, ethanol, and isopropanol, and water miscible organic solvents such as acetone and tetrahydrofuran are used as the above poor solvents within a range that does not affect the method for producing organic fine particles of the present invention. It may be mixed with.
  • the water-soluble polymer (A1) having a hydroxyl group used for the poor solvent (A) can be selected from a polymer having various hydroxyl groups and water-soluble.
  • Examples of the water-soluble polymer (A1) include polyvinyl alcohol, Mention may be made of hydroxypropylmethylcellulose or hydroxypropylcellulose.
  • the water-soluble polymer (A1) having a hydroxyl group preferably has a weight ratio of 0.1 to 3.0 with respect to the organic substance.
  • the pH of the mixture obtained by mixing the good solvent (B) in which the organic substance is dissolved and the poor solvent (A) containing the water-soluble polymer having a hydroxyl group is in the range of 3.5 to 8.5.
  • the particle size of the organic fine particles as the target is controlled by adjusting the pH.
  • the method for adjusting the pH is not particularly limited, and an example thereof is the use of a pH adjuster (A2).
  • a pH adjuster A2
  • the pH adjusting agent (A2) is added to at least one of the good solvent (B) in which the organic substance is dissolved and the poor solvent (A) containing a water-soluble polymer having a hydroxyl group is shown.
  • the pH adjusting agent is prepared as a physically separate liquid from the good solvent (B) and the poor solvent (A), and simultaneously with the mixing of the good solvent (B) and the poor solvent (A), or
  • the pH adjusting agent may be added before or after mixing.
  • the pH adjuster (A2) is in the range of 0.001 to 1.0 by weight with respect to the organic substance, and 0.001 to 1.0 by weight with respect to the polymer having a hydroxyl group (A1). A range is preferable.
  • pH adjustment include changing the concentration of organic matter in the good solvent (B) and the solvent used in the good solvent (B), changing the water-soluble polymer having a hydroxyl group contained in the poor solvent (A), Examples thereof include changing the mixing ratio of the poor solvent (A) containing a water-soluble polymer having a hydroxyl group and the good solvent (B) in which an organic substance is dissolved.
  • Examples of the pH adjuster (A2) used in the present invention include carbonates such as sodium hydrogen carbonate and calcium carbonate, inorganic salts such as sodium hydroxide, potassium hydroxide and sodium hydrogen phosphate, amines such as triethanolamine, Ammonia and ammonium salts, inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid and boric acid, organic acids such as acetic acid, citric acid and adipic acid or salts thereof can be used.
  • carbonates such as sodium hydrogen carbonate and calcium carbonate
  • inorganic salts such as sodium hydroxide, potassium hydroxide and sodium hydrogen phosphate
  • amines such as triethanolamine
  • Ammonia and ammonium salts inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid and boric acid
  • organic acids such as acetic acid, citric acid and adipic acid or salts thereof can be used.
  • the organic substance is a biologically ingested substance, it is
  • the particle diameter of the organic fine particles can be controlled by adjusting the pH at the time of precipitation of the organic fine particles in the mixed solution to a range of 3.5 to 8.5.
  • the present inventor considers that the following at least two factors are acting in a complex manner. (First factor) By controlling the pH within the range of 3.5 to 8.5, the interaction between the organic fine particles and the water-soluble polymer containing a hydroxyl group could be strengthened, and the particle size of the organic fine particles can be controlled. This is the first factor.
  • one of the purposes of using a water-soluble polymer having a hydroxyl group is to prevent particle growth on the organic fine particles.
  • the water solubility having a hydroxyl group is more than the interaction between the water soluble polymer having a hydroxyl group and the surface of the organic fine particles.
  • the interaction between the polymer and the organic fine particles with the good solvent or the poor solvent used for the dissolution or the interaction between the water-soluble polymers is stronger.
  • the effect which prevents the particle growth of the organic fine particle expected for the water-soluble polymer containing a hydroxyl group is lowered. That is, the functional group possessed by the organic fine particles, even when the organic fine particles are in a solid state, at least the surface thereof is exposed to a good solvent used for the dissolution and a poor solvent such as water.
  • the functional group of the organic fine particles increases the affinity for the solvent or water.
  • an apparent structural change occurs due to adsorption of an organic solvent to the functional group, desorption or addition of hydrogen ions, and the like. These are presumed to be due to the effect of the hydroxyl groups of the water-soluble polymer forming hydrogen bonds, and as a result, it is considered that the effect expected of the water-soluble polymer was not obtained.
  • These structural changes may be accompanied by temperature changes. However, when organic fine particles are precipitated using only water-soluble polymers using temperature changes, the organic fine particles are aggregated or fused by subsequent temperature changes. In some cases, particle growth occurs.
  • the second factor is considered to be that the solubility of the organic substance can be subtly changed by setting the pH to 3.5 to 8.5.
  • Many organic substances have water-soluble functional groups such as a hydroxyl group, a carboxylic acid group, and an amide group. In addition to the property of being soluble in an organic solvent, they are often soluble in water depending on the property of the functional group.
  • Organic substances having these functional groups often change in solubility due to changes in pH. By controlling the pH with a small amount of pH adjuster, the solubility is controlled, and coarse particles or fine particles far from the average particle diameter are controlled. There is a possibility that the particle diameter can be controlled in a uniform state without almost any visible particles.
  • the particle size of the organic fine particles as the target product is changed by changing the concentration of the water-soluble polymer (A1) having a hydroxyl group contained in the poor solvent (A). Can be further controlled.
  • the good solvent (B) in which the organic matter is dissolved and the poor solvent (A) which is an aqueous solution containing the water-soluble polymer (A1) having at least a hydroxyl group are mixed, and organic fine particles are precipitated from the mixture.
  • the method is not particularly limited, and various methods can be employed. For example, a method of performing a reaction in a dilute system in a batch container or a mixing container, a method of using a reaction apparatus such as a microreactor, etc. can be shown. Can also be implemented. Also, an apparatus and a method proposed by the applicant of the present application and described in Japanese Patent Laid-Open No. 2009-112892 may be used.
  • the apparatus includes at least two processing surfaces that rotate relatively so that the two processing surfaces can relatively approach or separate from each other in the axial direction of the rotation.
  • the one arranged in is used.
  • a gap between the two processing surfaces is maintained at a minute interval, and a poor solvent (A) and a good solvent (B) are introduced between the two processing surfaces maintained at the minute interval.
  • the poor solvent (A) and the good solvent (B) are preferably introduced between the two processing surfaces from different introduction paths, but the poor solvent (A) and the good solvent are introduced immediately before the introduction. (B) may be mixed and introduced from one introduction path.
  • one introduction path is provided at the center of at least one of the two processing surfaces, and the other introduction path includes the center introduction path and the two treatment paths. It can implement as what is provided between the outer periphery of a use surface.
  • a forced thin film is formed between the two processing surfaces by mixing the poor solvent (A) and the good solvent (B), and organic fine particles are deposited in the forced thin film.
  • the pH adjuster (A2) is preliminarily mixed with the poor solvent (A), but a third introduction path is provided on at least one of the two processing surfaces,
  • the poor solvent (A), the good solvent (B), and the pH adjusting agent (A2) may be mixed between the two processing surfaces.
  • a transmission electron microscope, JEM-2100 manufactured by JEOL was used for TEM observation.
  • the acceleration voltage was 80 kV.
  • the particle diameter was evaluated by using an average value of 50 particles using a 25,000 times photograph in TEM observation.
  • the results of particle size evaluation are listed in the “Particle Size” section of Tables 1-3.
  • Example 1 shows conditions using curcumin as the organic substance, acetic acid as the pH adjuster (A2), and hydroxymethylpropylcellulose (hereinafter, HPMC) as the water-soluble polymer (A1) having a hydroxyl group.
  • the molecular structure of curcumin is shown in FIG.
  • curcumin is an organic substance with a benzene ring and an unsaturated hydrocarbon as the basic skeleton, but because it has multiple hydroxyl groups in its structure, it has some affinity for water even though it is an organic substance. It is a substance to show.
  • liquid A The poor solvent (A) (hereinafter referred to as “liquid A”) and the good solvent (B) (hereinafter referred to as “liquid B”) in which organic substances were dissolved were prepared at the following weight ratio.
  • Solution A was prepared in a weight ratio of 0.67 wt% HPMC (Shinetsu Chemical Co., Ltd.) / 0.0009 wt% acetic acid / 993291 wt% pure water.
  • the pH of the liquid A after preparation was 4.81 (18.8 ° C.) (liquid specific gravity: 1.0).
  • Liquid B was prepared at a weight ratio of 3.0 wt% curcumin cocoon / 97.0 wt% ethanol ((liquid specific gravity: 0.8, hereinafter EtOH).
  • Liquid A was a CLEARMIX dissolver (Product) Name: CLM-2.2SD, manufactured by M Technique Co., Ltd. Based on the above formulation, each component of liquid A was prepared using a CLEARMIX dissolver at a preparation temperature of 25 ° C., a rotor speed of 15000 rpm, 30 The mixture was uniformly mixed by stirring for a minute to prepare solution A.
  • Solution B was prepared using CLEARMIX (product name: CLM-2.2S, manufactured by M Technique), which is a high-speed rotary dispersion emulsifier. Mix each component of B liquid with CLEARMIX and mix uniformly by stirring for 30 minutes at a preparation temperature of 25 ° C. and a rotor speed of 15000 rpm. It was manufactured.
  • the prepared liquid A and liquid B were mixed using the fluid processing apparatus of Patent Document 3 by the present applicant.
  • the fluid processing apparatus described in Patent Document 3 is the apparatus described in FIG. 1 of the same publication, and the opening at the center of the processing surface 2 in which the opening d20 of the second introduction part is a ring-shaped disk. Is a concentric ring shape surrounding the circle.
  • the liquid A is introduced from the first introduction part d1 between the processing surfaces 1 and 2, and the processing part 10 is operated at the number of revolutions described in Table 1 while the B
  • the liquid was introduced between the processing surfaces 1 and 2 from the second introduction part d2, and the A liquid and the B liquid were mixed in a thin film fluid, and organic fine particles were deposited between the processing surfaces 1 and 2.
  • organic fine particle dispersion A fluid containing organic fine particles precipitated between the processing surfaces 1 and 2 (hereinafter, organic fine particle dispersion) was discharged from between the processing surfaces 1 and 2 of the fluid processing apparatus.
  • the discharged organic fine particle dispersion was collected in the beaker b through the vessel v.
  • Table 1 shows the conditions under which curcumin fine particles were deposited as organic fine particles using the above apparatus and the particle diameter evaluation results of the obtained organic fine particles.
  • the number of rotations in the table is the number of rotations of the processing unit 10 in Patent Document 3, and the discharge liquid is an organic fine particle dispersion liquid discharged from between the processing surfaces 1 and 2. Since it is substantially difficult to measure the pH when organic fine particles are precipitated, the pH of the discharged liquid collected in the beaker b was measured, and the results are shown in Table 1.
  • the obtained organic fine particle dispersion containing the curcumin fine particles was dropped on the ester support film and dried at room temperature to prepare a sample for TEM observation.
  • the TEM observation result of Example 1 is shown in FIG. As a result of TEM observation, the particle diameter was 71 nm.
  • Example 2 it implemented on the same conditions as Example 1 except having changed the density
  • FIG. 1 The obtained organic fine particle dispersion containing the curcumin fine particles was dropped on the ester support film and dried at room temperature to prepare a sample for TEM observation. The TEM observation results are shown in FIG. As a result of TEM observation, the particle size was 158 nm.
  • Example 3 As shown in Table 1, acetic acid as the pH adjusting agent used in Example 1 was removed, and the other conditions were the same as in Example 1.
  • the obtained organic fine particle dispersion containing the curcumin fine particles was dropped on the ester support film and dried at room temperature to prepare a sample for TEM observation. As a result of TEM observation, the particle diameter was 140 nm.
  • Example 1 As Comparative Example 1, the acetic acid concentration was made higher than that in Example 2, and the pH during precipitation was adjusted to 3.09. Other conditions were the same as in Example 1.
  • the obtained organic fine particle dispersion containing the curcumin fine particles was dropped on the ester support film and dried at room temperature to prepare a sample for TEM observation.
  • the TEM observation result is shown in FIG.
  • the particle diameter was 620 nm, but it was seen that particles of about 50 nm were mixed, and distribution was observed in the particle diameter.
  • Example 1 the ratio of the water-soluble polymer to the organic substance (weight ratio basis) was constant, and the pH was changed by changing the concentration of the pH adjuster.
  • Example 3 organic fine particles having a target particle diameter were obtained, but there were some aggregates of particles in which a plurality of particles were aggregated.
  • Comparative Example 1 in which the pH adjuster in the liquid mixture of the liquid A and the liquid B was set to 1.25 with respect to the organic matter, a distribution was observed in the particle diameter.
  • the amount of the pH adjuster added to the organic substance is very small, about 0.001 to 0.01.
  • Example 4 shows the conditions using probucol as the organic substance, sodium bicarbonate as the pH adjuster (A2), and polyvinyl alcohol (hereinafter referred to as PVA) as the water-soluble polymer (A1) having a hydroxyl group.
  • the molecular structure of probucol is shown in FIG.
  • Probucol is an organic substance having a hydroxyl group in its structure.
  • liquid A The poor solvent (A) (hereinafter referred to as “liquid A”) and the good solvent (B) (hereinafter referred to as “liquid B”) in which organic substances were dissolved were prepared at the following weight ratio.
  • the liquid A was prepared at a weight ratio of 0.125 wt% PVA (EG-05P manufactured by Nippon Gosei Co., Ltd.) / 0.0009 wt% sodium hydrogen carbonate / 99.8741 wt% pure water.
  • the pH of the liquid A after preparation was 7.07 (27.1 ° C.) (liquid specific gravity: 1.0).
  • Liquid B was prepared at a weight ratio of 3.0 wt% probucol /97.0 wt% ethanol ((liquid specific gravity: 0.8, hereinafter EtOH).
  • the conditions for preparing liquids A and B were the same as in Example 1.
  • the prepared liquid A and liquid B are mixed using the fluid processing apparatus used in Example 1 so that the mixed liquid of liquid A and liquid B has the pH described in Table 2, and the processing surface 1 Probucol fine particles, which are organic fine particles, were precipitated between the two.
  • a fluid containing organic fine particles precipitated between the processing surfaces 1 and 2 (hereinafter, organic fine particle dispersion) was discharged from between the processing surfaces 1 and 2 of the fluid processing apparatus.
  • the discharged organic fine particle dispersion was collected in the beaker b through the vessel v.
  • Table 2 shows the conditions under which probucol fine particles were deposited as organic fine particles using the above apparatus and the particle diameter of the obtained organic fine particles.
  • the number of rotations in the table is the number of rotations of the processing unit 10 in Patent Document 3, and the discharge liquid is an organic fine particle dispersion liquid discharged from between the processing surfaces 1 and 2. Since it is substantially difficult to measure the pH at the time of precipitation of the organic fine particles, the pH of the discharged liquid collected in the beaker b was measured, and the results are shown in Table 2.
  • the obtained organic fine particle dispersion containing the probucol fine particles was dropped on the ester support film and dried at room temperature to prepare a sample for TEM observation.
  • the TEM observation result of Example 4 is shown in FIG. As a result of TEM observation, the particle diameter was 380 nm.
  • Example 5 was carried out under the same conditions as in Example 4 except that the mixing ratio of the A liquid and the B liquid in Example 4 was changed, and the aqueous solution having a hydroxyl group with respect to the organic matter in the mixed liquid of the A liquid and the B liquid.
  • the ratio of the functional polymer (weight ratio basis) was increased. From the result of TEM observation, the particle diameter was 226 nm.
  • Examples 6 to 10 and Comparative Example 2 were prepared with formulations using the poor solvent (A) and good solvent (B) described in Table 2.
  • the conditions for preparing the A and B solutions were the same as in Example 1.
  • the prepared liquid A and liquid B were mixed under the conditions described in Table 2 using the fluid treatment apparatus used in Example 1, to precipitate probucol fine particles.
  • a fluid containing organic fine particles precipitated between the processing surfaces 1 and 2 (hereinafter, organic fine particle dispersion) was discharged from between the processing surfaces 1 and 2 of the fluid processing apparatus.
  • the discharged organic fine particle dispersion was collected in the beaker b through the vessel v.
  • Example 5 From the results of TEM observation, in Example 5, the particle size was 123 nm, in Example 6, 68 nm, in Example 7, 102 nm, and in Example 175 nm.
  • the TEM observation result of Example 9 is shown in FIG. Further, in Comparative Example 2 mixed under the condition that the pH was 8.72, the particle diameter was about 378 nm from the TEM observation result, but the particles seemed to be aggregated and fused.
  • FIG. 8 shows a TEM photograph. In Example 10 in which sodium hydrogen carbonate was not added, the result of TEM observation was 480 nm, but there were some aggregates of particles in which a plurality of particles were aggregated.
  • the ratio of the water-soluble polymer to probucol in the liquid mixture of liquid A and liquid B was changed by changing the mixing ratio of liquid A and liquid B. (Weight ratio basis) was changed.
  • Weight ratio basis By changing the ratio of water-soluble polymer to probucol in the liquid mixture of liquid A and liquid B (weight ratio basis), coarse particles and fine particles that are far from the average particle diameter are hardly seen, The particle size changed in a uniform state. Specifically, it was confirmed that the particle size of the organic fine particles was reduced by increasing the ratio of water-soluble polymer to probucol (weight ratio basis) in the liquid mixture of liquid A and liquid B.
  • paraffin wax In Example 11, paraffin wax (manufactured by Nippon Seiwa Co., Ltd., product name FNP-0090, melting point 80 ° C.), ammonia as a pH adjuster (A2), polyvinyl alcohol (hereinafter referred to as a water-soluble polymer having a hydroxyl group) (A1) as Example 11 The conditions using PVA) are shown.
  • liquid A The poor solvent (A) (hereinafter referred to as “liquid A”) and the good solvent (B) (hereinafter referred to as “liquid B”) in which organic substances were dissolved were prepared at the following weight ratio.
  • Solution A was prepared at a weight ratio of 0.02 wt% PVA (EG-05P manufactured by Nippon Synthetic Co., Ltd.) / 0.0008 wt% Ammonia / 19.98 wt% Pure water / 79.9992 wt% isopropyl alcohol (hereinafter, IPA).
  • the pH of the liquid A after preparation was 9.16 (24.2 ° C.) (liquid specific gravity: 0.90).
  • Liquid B was prepared at a weight ratio of 0.02 wt% paraffin wax w / 99.98 wt% m-xylene (liquid specific gravity: 0.86).
  • Liquid A was prepared using a CLEARMIX dissolver (product name: CLM-2.2SD, manufactured by M Technique), which is a high-speed rotary dispersion emulsifier. Based on the above formulation, each component of the A liquid was uniformly mixed by stirring for 30 minutes at a preparation temperature of 25 ° C. and a rotor rotation speed of 15000 rpm using a CLEARMIX dissolver to prepare A liquid.
  • Liquid B was prepared using CLEARMIX (product name: CLM-2.2S, manufactured by M Technique), which is a high-speed rotary dispersion emulsifier. Each component of the B liquid was uniformly mixed by stirring for 30 minutes at a preparation temperature of 90 ° C. and a rotor rotation speed of 15000 rpm using a CLEARMIX to prepare a B liquid.
  • CLEARMIX product name: CLM-2.2S, manufactured by M Technique
  • the prepared liquid A and liquid B were mixed using the fluid processing apparatus used in Example 1 so that the mixed liquid of liquid A and liquid B had the pH described in Table 3, and the processing surface 1 Between the two, paraffin wax fine particles, which are organic fine particles, were deposited.
  • a fluid containing organic fine particles precipitated between the processing surfaces 1 and 2 (hereinafter, organic fine particle dispersion) was discharged from between the processing surfaces 1 and 2 of the fluid processing apparatus.
  • the discharged organic fine particle dispersion was collected in the beaker b through the vessel v.
  • Table 3 shows the conditions under which paraffin wax fine particles were deposited as organic fine particles using the above apparatus and the particle diameter evaluation results of the obtained organic fine particles.
  • the number of rotations in the table is the number of rotations of the processing unit 10 in Patent Document 3, and the discharge liquid is an organic fine particle dispersion liquid discharged from between the processing surfaces 1 and 2. Since it is substantially difficult to measure the pH at the time of precipitation of the organic fine particles, the pH of the discharged liquid collected in the beaker b was measured, and the results are shown in Table 3.
  • Example 11 to 14 in which the pH of the discharge liquid, that is, the mixed liquid of the A liquid and the B liquid was adjusted to the range of 3.5 to 8.5, the particle diameter of the organic fine particles was controlled by the pH of the discharge liquid.
  • Comparative Examples 3 and 4 in which organic fine particles having a target particle size were prepared and the particle size of the organic fine particles changed in a uniform state, but the pH of the discharge liquid was adjusted outside the range of 3.5 to 8.5.
  • Table 3 as a result of the particle size evaluation, the respective particle sizes are described as 879 nm and 671 nm in Table 3. However, many coarse particles of 2 ⁇ m or more were observed, and it was impossible to control the particle size of the organic fine particles.
  • the ratio of the water-soluble polymer to the paraffin wax in the liquid mixture of liquid A and liquid B was changed (weight ratio) by changing the mixing ratio of liquid A and liquid B. Base) was changed.
  • the ratio of the water-soluble polymer to the paraffin wax in the liquid mixture of the liquid A and the liquid B was changed (weight ratio basis)
  • coarse particles and fine particles far from the average particle diameter are not substantially confirmed,
  • the particle size changed in a uniform state.
  • the particle size of the organic fine particles is increased by increasing the ratio of water-soluble polymer to the paraffin wax (weight ratio basis) in the liquid mixture of liquid A and liquid B.
  • the ratio of the water-soluble polymer to the paraffin wax in the liquid mixture of the liquid A and the liquid B was reduced. It was confirmed that the particle size was small.

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Abstract

The objective of the present invention is to provide a method for producing organic fine particles, which is capable of easily and stably controlling the particle diameters of organic fine particles when the organic fine particles are produced by means of a poor solvent process. A method for producing organic fine particles, wherein a poor solvent (A) and a good solvent (B), in which an organic material is dissolved, are mixed and organic fine particles are precipitated in the mixed solution. In this method, an aqueous solution containing a water-soluble polymer (A1) that has at least a hydroxyl group is used as the poor solvent (A) and the pH of the mixed solution is adjusted to be within the range of from 3.5 to 8.5 during the precipitation of organic fine particles, so that the particle diameters of the organic fine particles are controlled, thereby obtaining organic fine particles having desired particle diameters.

Description

有機物微粒子の製造方法Method for producing organic fine particles
本発明は、有機物微粒子の製造方法に関するものである。 The present invention relates to a method for producing organic fine particles.
医薬品や有機顔料、樹脂などの有機物を微粒子化することで、その物性に新たな機能を発現させることが出来るため、有機物の微粒子化技術は産業界全般にわたって重要なテーマとなっている。 Since organic substances such as pharmaceuticals, organic pigments, and resins can be made fine particles, new functions can be expressed in their physical properties. Therefore, the technology for making organic substances fine particles has become an important theme throughout the entire industry.
有機物微粒子として期待された特性を発揮するためには、粒子径の制御が必要である。しかし、有機物は、無機物と最も異なる特性として、溶媒への溶解度があり、有機物の貧溶媒に対する溶解度は無機物に比べて高い。特に微粒子化された有機物は、その溶解度が一般的に示されている値よりも高くなることが多く、微粒子化された有機物が再度溶解し、その後粒子が成長することで結果として粗大な粒子となるため、従来の方法では粒子径を制御することが困難であった。また、有機物微粒子はその粒子径により、特に溶解性や溶解時間、吸収性や安定性、また光学特性やその他の機能性が変化するため、粒子径制御の技術が必要とされている。 In order to exhibit the characteristics expected as organic fine particles, it is necessary to control the particle diameter. However, the organic substance has the solubility in a solvent as the most different characteristic from the inorganic substance, and the solubility of the organic substance in the poor solvent is higher than that of the inorganic substance. In particular, finely divided organic substances often have higher solubility than the generally indicated value, and the finely divided organic substances are dissolved again, and then the particles grow, resulting in coarse particles. Therefore, it has been difficult to control the particle size by the conventional method. In addition, since organic fine particles change their solubility, dissolution time, absorbency and stability, optical properties, and other functionalities, depending on the particle size, techniques for controlling the particle size are required.
水溶性高分子を用いて有機物微粒子を作製する場合においては、その水溶性高分子の重合度が大きく、ケン化度が低い方が小さな粒子を作製できる場合が多いことが知られている。水溶性高分子は水酸基を持っているため親水性の表面を持った物質に対して強い接着力があり、親水性の水酸基と疎水性の官能基を各々持っているため、界面活性能を示す。 In the case of producing organic fine particles using a water-soluble polymer, it is known that in many cases, smaller particles can be produced when the degree of polymerization of the water-soluble polymer is larger and the degree of saponification is lower. A water-soluble polymer has a hydroxyl group, so it has strong adhesion to substances with a hydrophilic surface, and since it has a hydrophilic hydroxyl group and a hydrophobic functional group, it exhibits surface activity. .
水溶性高分子は、上記の理由により良溶媒に溶かした有機物と、水溶性高分子を溶かした貧溶媒に混合し、有機物微粒子を析出させるプロセスに多く使用されている。また、水溶性高分子は、親水基が親水基と水分子との水素結合に起因するために温度の影響を受けやすいという性質から、温度変化を利用したプロセスで用いる利点はあるが、温度変化により有機物微粒子が混合液中で不安定になるなどのデメリットとなることが多い。
また、特許文献１には、有機物微粒子の粒子径を制御するために、水溶性高分子の分子量を変化させて、有機物微粒子の粒子径を制御する方法も報告されている。しかしながら、温度変化により有機物微粒子が混合液中で不安定になるなどのデメリットは解決されておらず、適用できる有機物も限定されてしまうことが多いという問題を抱えている。
さらに、貧溶媒法を用いて有機物微粒子を析出させる場合、貧溶媒と有機物を溶解させた良溶媒との混合を開始した時点から完了するまでの間、混合溶液中の有機物の濃度や温度は変化を伴い、混合溶液の状態は、刻一刻と変化することとなる。特にバッチ式で大量に処理を行う場合には、析出された有機物微粒子の粒子径の分布が広がりを持つ場合があり、条件によっては有機物微粒子として期待された特性を発揮しがたい粗大な粒子が生成する場合がある。 Water-soluble polymers are often used in processes where organic substances dissolved in a good solvent and poor solvents in which water-soluble polymers are dissolved are mixed to precipitate organic fine particles for the above reasons. In addition, water-soluble polymers have the advantage of being used in processes that use temperature changes due to the fact that hydrophilic groups are easily affected by temperature because they are caused by hydrogen bonding between hydrophilic groups and water molecules. In many cases, organic fine particles become disadvantageous in that they become unstable in the mixed solution.
Patent Document 1 also reports a method of controlling the particle size of organic fine particles by changing the molecular weight of the water-soluble polymer in order to control the particle size of the organic fine particles. However, the disadvantage that the organic fine particles become unstable in the mixed solution due to the temperature change has not been solved, and the applicable organic matter is often limited.
Furthermore, when the organic fine particles are deposited using the poor solvent method, the concentration and temperature of the organic matter in the mixed solution change from the start to the completion of mixing the poor solvent and the good solvent in which the organic matter is dissolved. As a result, the state of the mixed solution changes every moment. In particular, when batch processing is performed in large quantities, the particle size distribution of the precipitated organic fine particles may have a broad range, and depending on the conditions, coarse particles that do not exhibit the characteristics expected as organic fine particles may be present. May be generated.
一方、特許文献２には、水混和性の良溶媒で生体適合性高分子を含む薬物を溶解し、貧溶媒であるポリビニルアルコールの水溶液に滴下して薬物を析出させる方法が開示されている。しかし、このような方法で有機物を析出させる場合、貧溶媒と有機物を溶解した良溶媒との混合を開始した時点から完了するまでの間、混合溶液中の有機物の濃度や温度及びｐＨは変化を伴うため、混合溶液の状態は、刻一刻と変化することとなり、析出された有機物微粒子の粒子径の分布が広がりを持つ場合があった。また、特許文献２にはポリビニルアルコールに対する薬物の量については示されているものの、析出させた粒子の凝集が見られる場合があり、析出容器内への付着等の問題から、安定して粒子を得ることが難しい場合があった。特に、薬物を高濃度で析出させることが難しく、希薄系での調製しかできないことなどの問題があった。 On the other hand, Patent Document 2 discloses a method in which a drug containing a biocompatible polymer is dissolved in a water-miscible good solvent and dropped into an aqueous solution of polyvinyl alcohol, which is a poor solvent, to precipitate the drug. However, when the organic substance is precipitated by such a method, the concentration, temperature and pH of the organic substance in the mixed solution change from the time when the mixing of the poor solvent and the good solvent in which the organic substance is dissolved until the completion. Therefore, the state of the mixed solution changes every moment, and the distribution of the particle diameter of the deposited organic fine particles sometimes has a spread. Moreover, although the amount of the drug with respect to polyvinyl alcohol is shown in Patent Document 2, there is a case where aggregation of the precipitated particles may be observed. Due to problems such as adhesion to the precipitation container, the particles are stably added. Sometimes it was difficult to get. In particular, it was difficult to precipitate the drug at a high concentration, and there was a problem that it could only be prepared in a dilute system.
そのような問題を解決するために、本願出願人よって、接近・離反可能な相対的に回転する処理用面間において、有機物微粒子を析出させる方法が提案された（特許文献３）。この特許文献３記載の方法で作製した生体摂取物微粒子は、従来のものに比べて微細かつ均一であり、また、処理用面１、２の回転数や処理用面１、２間の距離、及び、薄膜流体の流速や温度又は原料濃度等を変えることにより、目的とする粒子径の有機物微粒子を得ることが可能になった。しかしながら、有機物微粒子を処理用面から吐出させた後、微粒子の粗大化が見られる場合があるなど、有機物微粒子を安定的に得るには課題が残っていた。 In order to solve such a problem, the applicant of the present application has proposed a method of depositing organic fine particles between relatively rotating processing surfaces that can approach and leave (Patent Document 3). The biologically ingested fine particles produced by the method described in Patent Document 3 are finer and more uniform than conventional ones, and the number of rotations of the processing surfaces 1 and 2 and the distance between the processing surfaces 1 and 2 are as follows: In addition, it has become possible to obtain organic fine particles having a target particle size by changing the flow rate, temperature, raw material concentration, etc. of the thin film fluid. However, there has been a problem in stably obtaining organic fine particles, for example, coarse particles may be observed after the organic fine particles are ejected from the processing surface.
通常、有機物微粒子を含む目的物製造にあたり、最終製品の最適化のため、ｐＨ調整を行う事例は多く存在する。例えば、点眼薬では目への刺激性の問題などから、ｐＨ調整されることが一般的に行われている（特許文献３、特許文献４）。しかしながら、これら従来技術は、水溶性高分子の乳化・分散力の長所を生かしながら、温度変化などのデメリットを解決するかという課題に着目したものではなかった。言い換えれば、従来技術のように最終製品の最適化のためにｐＨ調整を行うのではなく、有機物微粒子の析出時の粒子径や乳化粒子径を直接制御するためにｐＨ調整を行うという技術思想については、今まで提案されたり開示されたりしていなかった。 Usually, there are many cases in which pH adjustment is performed for the purpose of optimizing the final product in the production of an object containing organic fine particles. For example, in the case of eye drops, pH adjustment is generally performed due to the problem of eye irritation (Patent Document 3 and Patent Document 4). However, these conventional techniques have not focused on the problem of solving the disadvantages such as temperature change while taking advantage of the emulsification / dispersion power of the water-soluble polymer. In other words, the technical idea is not to adjust the pH to optimize the final product as in the prior art, but to adjust the pH to directly control the particle size and emulsified particle size at the time of precipitation of organic fine particles. Has never been proposed or disclosed.
また、本願出願人によって、接近・離反可能な相対的に回転する処理用面間において、被析出物質を溶解した原料溶液を含む流体と、この被析出物質を析出させるための析出用溶媒を含む流体とを被処理流動体として混合して被析出物質を析出させる際に、上記処理用面間に導入される上記被処理流動体の粘度を制御することによって、粒子径が制御された微粒子を得る方法が提案された（特許文献５）。しかしながら、特許文献５には、微粒子の粒子径の制御にあたり、微粒子の析出時にｐＨ調整を行うことについては、記載されていなかった。 In addition, the present applicant includes a fluid containing a raw material solution in which the substance to be precipitated is dissolved between the relatively rotating processing surfaces that can approach and leave, and a precipitation solvent for precipitating the substance to be precipitated. When mixing a fluid as a fluid to be treated to precipitate a substance to be precipitated, the viscosity of the fluid to be treated introduced between the processing surfaces is controlled, thereby controlling fine particles having a controlled particle size. A method of obtaining was proposed (Patent Document 5). However, Patent Document 5 does not describe that the pH is adjusted when the fine particles are precipitated in controlling the particle diameter of the fine particles.
特開平１０－２１８９０１号公報Japanese Patent Laid-Open No. 10-218901 特開２００５－２１３７０号公報Japanese Patent Laying-Open No. 2005-21370 特開２０１１－１８９３４８号公報JP 2011-189348 A 特開昭６１－２４６１１７号公報Japanese Patent Laid-Open No. 61-246117 国際公開第２０１２／０１４５３０号パンフレットInternational Publication No. 2012/014530 Pamphlet
本発明は、貧溶媒法を用いて有機物微粒子の粒子径を制御する際に、水溶性高分子の乳化、分散力の長所を生かしながら、温度変化によるデメリットを解決すること、すなわち、水溶性高分子を含む貧溶媒（Ａ）と有機物を溶解した良溶媒（Ｂ）とを混合した混合液中にて有機物微粒子を析出させる有機物微粒子の製造方法において、有機物微粒子の粒子径の制御を簡便にかつ安定的に行える有機物微粒子の製造方法を提供することを課題とする。 The present invention solves the demerits due to temperature changes while taking advantage of the emulsification and dispersion power of water-soluble polymers when controlling the particle size of organic fine particles using the poor solvent method. In a method for producing organic fine particles in which organic fine particles are precipitated in a mixed liquid obtained by mixing a poor solvent (A) containing molecules and a good solvent (B) in which organic matters are dissolved, the particle diameter of the organic fine particles can be controlled easily and It is an object of the present invention to provide a method for producing organic fine particles that can be stably performed.
上記に鑑み本願発明者は、水溶性高分子の乳化・分散力の長所を生かしながら、温度変化によるデメリットなど解決するために、析出時の混合液のｐＨを調整することで安定的に粒子径を制御できることを見出した。詳しくは、本願発明者は、析出時の混合液のｐＨを調整することにより、目的とする粒子径を簡単に制御でき、安定性に優れた粒子を作製でき、プロセスは簡略化でき、安定的な処方を得られ、最適化出来ることを見出し、本発明を完成させたものである。具体的には、目的の有機物微粒子の性質、その有機物微粒子の析出時に使用する水溶性高分子の重合度、ケン化度、そして連続相である水相（貧溶媒（Ａ））の性質を考慮して、ｐＨを３．５～８．５の範囲内で適切なｐＨに調整することで、目的の粒子径を有する有機物微粒子を製造できることを見出し、本発明に至った。 In view of the above, the inventor of the present application stably adjusts the pH of the liquid mixture at the time of precipitation in order to solve the disadvantages due to temperature change while taking advantage of the emulsification / dispersion power of the water-soluble polymer. I found that I can control. Specifically, the inventor of the present application can easily control the target particle diameter by adjusting the pH of the mixed liquid at the time of precipitation, can produce particles having excellent stability, can simplify the process, and is stable. The present invention has been completed by finding that a suitable formulation can be obtained and optimized. Specifically, the properties of the desired organic fine particles, the degree of polymerization of the water-soluble polymer used when the organic fine particles are precipitated, the degree of saponification, and the properties of the aqueous phase (poor solvent (A)) as a continuous phase are considered. Thus, the inventors have found that organic fine particles having a target particle diameter can be produced by adjusting the pH to an appropriate pH within the range of 3.5 to 8.5, and have reached the present invention.
　すなわち本発明は、貧溶媒（Ａ）と有機物を溶解した良溶媒（Ｂ）を混合した混合液中にて有機物微粒子を析出させる有機物微粒子の製造方法において、貧溶媒（Ａ）として、少なくとも水酸基を持つ水溶性高分子（Ａ１）を含む水溶液を用い、上記（Ａ）と（Ｂ）とを混合し、析出時のｐＨを３．５～８．５の範囲で調整することで、上記有機物微粒子の粒子径を制御し、目的の粒子径である有機物微粒子の製造方法である。 That is, the present invention relates to a method for producing organic fine particles in which organic fine particles are precipitated in a mixed solution in which a poor solvent (A) and a good solvent (B) in which an organic substance is dissolved are mixed. Using the aqueous solution containing the water-soluble polymer (A1), the above (A) and (B) are mixed, and the pH at the time of precipitation is adjusted in the range of 3.5 to 8.5, whereby the above organic fine particles Is a method for producing organic fine particles having a target particle size.
また本発明は、前記良溶媒（Ｂ）に水混和性の有機溶媒を用いることが好ましい。また本発明は、上記貧溶媒（Ａ）に含まれる水酸基を持つ水溶性高分子（Ａ１）の濃度を変更することが好ましい。また本発明は、上記貧溶媒（Ａ）に、ｐＨ調整剤（Ａ２）を含み、ｐＨ調整剤（Ａ２）により貧溶媒（Ａ）と有機物を溶解した良溶媒（Ｂ）とを混合し、析出時における混合液のｐＨを調整することが好ましい。また本発明は、上記有機物に対する上記ｐＨ調整剤（Ａ２）を重量比０．００１以上、１.０以下に調製して実施することが好ましい。 In the present invention, a water-miscible organic solvent is preferably used for the good solvent (B). In the present invention, it is preferable to change the concentration of the water-soluble polymer (A1) having a hydroxyl group contained in the poor solvent (A). In the present invention, the poor solvent (A) contains a pH adjuster (A2), and the poor solvent (A) and the good solvent (B) in which the organic substance is dissolved are mixed by the pH adjuster (A2) It is preferable to adjust the pH of the mixture at that time. In addition, the present invention is preferably carried out by adjusting the pH adjuster (A2) for the organic substance to a weight ratio of 0.001 or more and 1.0 or less.
上記水酸基を持つ水溶性高分子としては種々のものを利用することができるが、例えば、ポリビニルアルコール、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースなどが好ましく、これらは単独又は複数種類を適宜選択して用いることができる。 Various water-soluble polymers having a hydroxyl group can be used. For example, polyvinyl alcohol, hydroxypropylcellulose, hydroxypropylmethylcellulose, and the like are preferable. Can do.
また本発明は、上記貧溶媒（Ａ）に含まれる水酸基をもつ水溶性高分子に対する上記有機物の重量比を０．１～３．０に調製して実施することが好ましい。重量比率が３．０以上でも、粒子径は均一なものにすることができるが、高分子量が多く、有機物の性能を発揮するのに好ましくない場合もある。 The present invention is preferably carried out by adjusting the weight ratio of the organic substance to the water-soluble polymer having a hydroxyl group contained in the poor solvent (A) to 0.1 to 3.0. Even when the weight ratio is 3.0 or more, the particle diameter can be made uniform, but the molecular weight is high, which may not be preferable for exhibiting the performance of organic matter.
また本発明の有機物微粒子の粒子径がその機能性面より２０～５００ｎｍであることが好ましい。また本発明は、上記有機物が生体摂取物において効果が大きい。 In addition, the particle diameter of the organic fine particles of the present invention is preferably 20 to 500 nm from the viewpoint of its functionality. In the present invention, the organic substance has a great effect on ingested living organisms.
本発明の製造方法を用いることにより、有機物微粒子本来の性能をいかんなく発揮できる粒子径の制御された有機物微粒子を製造することができる。
また、貧溶媒（Ａ）と有機物を溶解した良溶媒（Ｂ）を混合することにより有機物微粒子を析出させる有機物微粒子の製造方法において、貧溶媒（Ａ）として、少なくとも水酸基を持つ水溶性高分子（Ａ１）を含む水溶液を用い、貧溶媒（Ａ）と有機物を溶解した良溶媒（Ｂ）とを混合し、析出時の混合液のｐＨを３．５～８．５の範囲で調整することで、上記有機物微粒子の粒子径を制御するという簡便な方法で、本発明は実施することができる。そのため、本発明にあっては、対象となる有機物の適応範囲が広く、得られた有機物微粒子は温度変化にも安定であり、目的に応じた粒子径を具備した様々な種類の有機物微粒子を提供することが可能となった。
このように本発明の製造方法によって、粒子径が精密に制御された有機物微粒子を安定して低コストで製造できるようになり、産業界の様々な要請に対応できるようになり得る。 By using the production method of the present invention, it is possible to produce organic fine particles with a controlled particle diameter that can fully exhibit the original performance of the organic fine particles.
In the method for producing organic fine particles in which the organic fine particles are precipitated by mixing the poor solvent (A) and the good solvent (B) in which the organic matter is dissolved, as the poor solvent (A), a water-soluble polymer having at least a hydroxyl group ( By using an aqueous solution containing A1), mixing a poor solvent (A) and a good solvent (B) in which an organic substance is dissolved, and adjusting the pH of the mixture at the time of precipitation in the range of 3.5 to 8.5. The present invention can be carried out by a simple method of controlling the particle diameter of the organic fine particles. Therefore, in the present invention, the applicable range of target organic matter is wide, the obtained organic matter fine particles are stable to temperature change, and various types of organic matter fine particles having a particle size according to the purpose are provided. It became possible to do.
As described above, according to the production method of the present invention, organic fine particles having a precisely controlled particle diameter can be stably produced at low cost, and can meet various demands of the industry.
本発明の実施例１～３及び比較例１の対象有機物であるクルクミンの分子構造図である。1 is a molecular structure diagram of curcumin, which is a target organic substance of Examples 1 to 3 of the present invention and Comparative Example 1. FIG. 本発明の実施例１で得られたクルクミン微粒子のＴＥＭ写真である。It is a TEM photograph of curcumin fine particles obtained in Example 1 of the present invention. 本発明の実施例２で得られたクルクミン微粒子のＴＥＭ写真である。It is a TEM photograph of the curcumin microparticles | fine-particles obtained in Example 2 of this invention. 本発明の比較例１で得られたクルクミン微粒子のＴＥＭ写真である。It is a TEM photograph of the curcumin microparticles | fine-particles obtained by the comparative example 1 of this invention. 本発明の実施例４～１０及び比較例２の対象有機物であるプロブコールの分子構造図である。FIG. 2 is a molecular structure diagram of probucol, which is a target organic substance of Examples 4 to 10 and Comparative Example 2 of the present invention. 本発明の実施例４で得られたプロブコール微粒子のＴＥＭ写真である。It is a TEM photograph of probucol microparticles | fine-particles obtained in Example 4 of this invention. 本発明の実施例９で得られたプロブコール微粒子のＴＥＭ写真である。It is a TEM photograph of probucol microparticles | fine-particles obtained in Example 9 of this invention. 本発明の比較例２で得られたプロブコール微粒子のＴＥＭ写真である。It is a TEM photograph of probucol fine particles obtained in Comparative Example 2 of the present invention.
以下、本発明の実施の形態について詳細に説明する。なお、本発明の様態は以下に記載の実施形態のみに限定するものではない。 Hereinafter, embodiments of the present invention will be described in detail. In addition, the aspect of this invention is not limited only to embodiment described below.
本発明は、貧溶媒（Ａ）と有機物を溶解した良溶媒（Ｂ）を混合することにより有機物微粒子を析出させる有機物微粒子の製造方法において、貧溶媒（Ａ）として、少なくとも水酸基を持つ水溶性高分子（Ａ１）を含む水溶液を用い、貧溶媒（Ａ）と有機物を溶解した良溶媒（Ｂ）とを混合するものであり、この混合液の析出時のｐＨを３．５～８．５の範囲で調整することで、上記有機物微粒子の粒子径を制御する有機物微粒子の製造方法である。 The present invention provides a method for producing organic fine particles in which organic fine particles are precipitated by mixing a poor solvent (A) and a good solvent (B) in which an organic substance is dissolved. The aqueous solution containing the molecule (A1) is used to mix the poor solvent (A) and the good solvent (B) in which the organic substance is dissolved. The pH at the time of precipitation of this mixed solution is 3.5 to 8.5. This is a method for producing organic fine particles in which the particle diameter of the organic fine particles is controlled by adjusting within a range.
（原料物質及び目的物）
本発明は、有機物を主たる原料物質とし、この主たる原料物質である有機物を溶媒に溶解した良溶媒（Ｂ）を用い、この良溶媒（Ｂ）を貧溶媒（Ａ）と混合し、目的物である有機物微粒子を得るものである。
本発明において有機物微粒子とは、この有機物により構成された微粒子である。微粒子の平均粒子径は、ｎｍ単位であることが好ましいが、μｍ単位のものであってもかまわない。有機物微粒子の粒子径が、２０ｎｍ～５００ｎｍであることがより好ましい。
　本発明における原料物質及び目的物としての有機物とは、炭素を含む化合物である。特に、主に炭素と酸素から形成されるものを含む。この有機物の由来は特に制限されるものではなく、人工的に合成されたものでもよく、天然物から抽出されたものでもあってもよく、特に限定されるものではない。例えば、人類用や動物用の医薬組成物や、食品、食品添加物、健康食品、農薬などの生体摂取物や、樹脂、ゴムなどの高分子化合物、染料や顔料、塗料などを含む色素系化合物や香料などが挙げられる。 (Raw material and target)
The present invention uses an organic substance as a main raw material, a good solvent (B) obtained by dissolving the organic substance as the main raw material in a solvent, and mixes the good solvent (B) with a poor solvent (A). Some organic fine particles are obtained.
In the present invention, the organic fine particles are fine particles composed of the organic matter. The average particle diameter of the fine particles is preferably in nm units, but may be in μm units. The particle diameter of the organic fine particles is more preferably 20 nm to 500 nm.
In the present invention, the raw material and the organic substance as the target product are compounds containing carbon. In particular, those mainly formed from carbon and oxygen are included. The origin of the organic material is not particularly limited, and may be artificially synthesized or extracted from a natural product, and is not particularly limited. For example, pharmaceutical compositions for humans and animals, biological ingestions such as foods, food additives, health foods, agricultural chemicals, etc., pigment compounds including polymer compounds such as resins and rubbers, dyes and pigments, paints, etc. And fragrances.
生体摂取物とは、生体に摂取する事を目的とするものであれば特に限定されないが、例えば医薬品における薬物のように生体内に吸収され、生体内での効果を発現させる事を目的とするものや、体内を通過させ、その後に***するものやドラッグデリバリーシステムにおける薬物成分の運搬用物質、または化粧料のように、生体皮膚に塗布するもの、及び食品と上記物質の中間体などが挙げられる。具体的には、医薬、医薬部外品、化粧品、食品、食品添加物、健康食品、農薬などに用いられる有機物をいう。本発明の生体摂取物としては、市販のものを使用してもよいし、新規に合成してもよい。 The in-vivo ingestion is not particularly limited as long as it is intended to be ingested into the living body, but for example, it is intended to be absorbed into the living body like a drug in a pharmaceutical product and to exert an in vivo effect. Such as those that pass through the body and then excreted, substances that transport drug components in drug delivery systems, or those that are applied to living skin, such as cosmetics, and intermediates between food and the above substances It is done. Specifically, it refers to organic substances used in medicines, quasi drugs, cosmetics, foods, food additives, health foods, agricultural chemicals and the like. As the biological ingestion of the present invention, a commercially available product may be used, or it may be synthesized newly.
上記生体摂取物の具体例としては、鎮痛薬、抗炎症薬、駆虫薬、抗不整脈薬、抗生物質、抗凝固薬、抗降圧薬、抗糖尿病薬、抗てんかん薬、抗ヒスタミン薬、抗悪性腫瘍薬、食欲抑制薬、抗肥満薬、抗ムスカリン薬、抗ミコバクテリア薬、抗新生物薬、免疫抑制薬、抗甲状腺薬、抗菌薬、抗ウイルス薬、不安解消薬、アストリンゼン、アドレナリン性β受容体遮断薬、血液製剤、代用血漿、心筋変性力薬、コントラスト媒質、コルチコステロイド、咳抑制薬、診断薬、診断像形成薬、利尿薬、ドーパミン作用薬、止血薬、免疫薬、リピッド調節薬、筋肉弛緩薬、副交感神経刺激興奮薬、副甲状腺カルシトニン、ビホスホネート類、プロスタグランジン、放射性医薬、性ホルモン、抗アレルギー薬、興奮薬、食欲減退物質、交感神経興奮薬、甲状腺薬、血管拡張剤およびキサンチン類、白内障治療剤、副腎皮質ホルモン剤、アレルギー性鼻炎治療薬などの医薬組成物や、栄養薬効物質、食物サプリメント、ビタミン、ミネラル、ハーブなどの食物栄養補助剤、葉酸、脂肪酸、果実および野菜抽出物、ビタミン補給剤、ミネラル補給剤、ホスファチジルセリン、リポ酸、メラトニン、グルコサミン／コンドロイチン、アロエ・ベラ、グッグル、グルタミン、アミノ酸、緑茶、リコピンなどの食品または、食品添加物、ハーブ、植物栄養素、抗酸化剤、果実のフラボノイド成分、またコラーゲンやヒアルロン酸、アミノ酸、ビタミンＣ誘導体、ハイドロキノン類等の美容補助食品等が挙げられるが、これに限定されるものではない。好ましい性状としては、水に低溶解度で経口投与可能なものおよび注射剤として適用可能なものなどが挙げられる。 Specific examples of the above-mentioned biological intake include analgesics, anti-inflammatory drugs, anthelmintic drugs, antiarrhythmic drugs, antibiotics, anticoagulants, antihypertensive drugs, antidiabetic drugs, antiepileptic drugs, antihistamines, antimalignant tumors Drugs, appetite suppressants, antiobesity drugs, antimuscarinic drugs, antimycobacterial drugs, antineoplastic drugs, immunosuppressive drugs, antithyroid drugs, antibacterial drugs, antiviral drugs, anxiolytic drugs, astrinsen, adrenergic β receptors Blocking agents, blood products, plasma substitutes, myocardial degenerative drugs, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopamine agonists, hemostatic agents, immunologic agents, lipid modulators, Muscle relaxants, parasympathomimetic stimulants, parathyroid calcitonin, biphosphonates, prostaglandins, radiopharmaceuticals, sex hormones, antiallergic drugs, stimulants, appetite reducing substances, sympathomimetic drugs Pharmaceutical compositions such as glandular drugs, vasodilators and xanthines, cataract treatments, corticosteroids, allergic rhinitis treatments, dietary supplements such as nutritional medicinal substances, food supplements, vitamins, minerals and herbs, Food or food additives such as folic acid, fatty acids, fruit and vegetable extracts, vitamin supplements, mineral supplements, phosphatidylserine, lipoic acid, melatonin, glucosamine / chondroitin, aloe vera, guggle, glutamine, amino acids, green tea, lycopene Products, herbs, phytonutrients, antioxidants, fruit flavonoid components, and cosmetic supplements such as collagen, hyaluronic acid, amino acids, vitamin C derivatives, hydroquinones, and the like, but are not limited thereto. Preferred properties include those that can be administered orally with low solubility in water and those that can be applied as injections.
医薬品としては、ダナゾール、タクロリムス水和物、プロゲステロン、インドメタシン、クルクミン、トラニラスト、ベンズブロマロン、ナプロキセン、フェニトイン、カロテン、ピポサルファム、ピポサルファン、カプトテシン、アセトミノフェン、アセチルサリチル酸、アミオダロン、コレスチフミン、コレスチポール、クロモリンナトリウム、アルブテロール、スクラルフェート、スルファサラジン、ミノキシジル、テンパゼパム、アルプラゾラム、プロポキシフェン、オーラノフィン、エリスロマイシン、サイクロスポリン、アシクロビル、ガンシクロビア、エトポサイド、メファラン、メトトリキセート、ミノキサントロン、ダウノルビシン、ドキソルビシン、メガステロール、タモキシフェン、メドロキシプロゲステロン、ナイスタチン、テルブタリン、アンホテリシンＢ、アスピリン、イブプロフェン、ジクロフェナック、ケトプロフェン、フルビプロフェン、ジフルミサール、ジオスゲニン、シロスタゾール、トルブタミド、ペプチド、クロモグリク酸ナトリウム、ピレノキシン、プロブコールなどが挙げられる。
医薬部外品としては、歯磨き剤、薬用化粧品、育毛剤、口中清涼剤、口臭予防剤などがあげられる。 As pharmaceuticals, danazol, tacrolimus hydrate, progesterone, indomethacin, curcumin, tranilast, benzbromarone, naproxen, phenytoin, carotenes, pipesulfam, pipesalphan, captothecin, acetominophen, acetylsalicylic acid, amiodarone, colestifol, Cromolyn sodium, albuterol, sucralfate, sulfasalazine, minoxidil, tempazepam, alprazolam, propoxyphene, auranofin, erythromycin, cyclosporine, acyclovir, ganciclovir, etoposide, mephalan, methotrexate, minoxantrone, daunorubicin, doxorubicin , Tamoxifen, Medroxyprogesterone, Nai Statins, terbutaline, amphotericin B, aspirin, ibuprofen, diclofenac, ketoprofen, flurbiprofen, Jifurumisaru, diosgenin, cilostazol, tolbutamide, peptides, sodium cromoglycate, pirenoxine, and the like probucol.
Examples of quasi drugs include dentifrices, medicinal cosmetics, hair restorers, mouth fresheners, and bad breath prevention agents.
化粧品としては、例えば、化粧水、乳液、美容液などの基礎化粧品、日焼け止め化粧品、メークアップ化粧品、頭髪化粧品、清浄化粧品、***化粧品、口腔化粧品、爪化粧品、アイライナー化粧品、入浴用化粧品などが挙げられる。 Cosmetics include, for example, basic cosmetics such as lotion, milky lotion, beauty liquid, sunscreen cosmetics, makeup cosmetics, hair cosmetics, cleansing cosmetics, lip cosmetics, oral cosmetics, nail cosmetics, eyeliner cosmetics, bath cosmetics, etc. Can be mentioned.
食品もしくは食品添加物としては、ビタミンＡ・Ｂ・Ｃ・Ｅ等のビタミン類およびその誘導体、２アミノ酸類、カロテノイド、果実および植物抽出物などが挙げられる。 Examples of foods or food additives include vitamins such as vitamins A, B, C, and E and derivatives thereof, 2 amino acids, carotenoids, fruits, and plant extracts.
健康食品としては、コエンザイムＱ１０、ビタミンＡ・Ｂ・Ｃ・Ｅ等のビタミン類およびその誘導体等、をあげることができる。これらは単独で使用してもよく、また２種以上を混合して使用してもよい。 Examples of health foods include coenzyme Q10, vitamins such as vitamins A, B, C, and E, and derivatives thereof. These may be used singly or in combination of two or more.
高分子化合物としては、パラフィンワックスや蜜?、カルナバワックスなどの天然ワックスやポリエチレンワックス（ＬＤＰＥ、低密度ポリエチレンおよびＨＤＰＥ、高密度ポリエチレン）やプロピレンワックスなどの合成ワックス、アマイドワックスなどの半合成ワックス、樹脂やゴムなどが挙げられる。 High molecular compounds include natural waxes such as paraffin wax, honey, carnauba wax, synthetic waxes such as polyethylene wax (LDPE, low density polyethylene and HDPE, high density polyethylene) and propylene wax, semi-synthetic waxes such as amide wax, Resin and rubber are listed.
（良溶媒（Ｂ）に用いる溶媒）
本発明の有機物を溶解した良溶媒（Ｂ）に用いる溶媒は、有機物を溶解できるものを選定する必要がある。本発明の溶媒としては、有機物微粒子の原料を溶解させるためや、有機物微粒子を溶解した良溶媒から有機物微粒子を析出させるために様々なものを用いることが出来る。それらの溶媒の一例としては、水（蒸留水、純水等）や、有機溶媒（アルコール系溶媒、ケトン系溶媒、ニトリル系溶媒、スルホキシド系溶媒、アミン系溶媒、イオン性溶液など）を挙げることが出来る。これらの溶媒は、目的に応じて１種または２種以上の混合溶媒を選択して実施することができる。また、必要に応じて、酸性物質や塩基性物質を各種溶媒に加え、ｐＨを調整することもできる。 (Solvent used for good solvent (B))
The solvent used for the good solvent (B) in which the organic substance of the present invention is dissolved must be selected so that it can dissolve the organic substance. As the solvent of the present invention, various solvents can be used in order to dissolve the raw material of organic fine particles or to precipitate organic fine particles from a good solvent in which organic fine particles are dissolved. Examples of these solvents include water (distilled water, pure water, etc.) and organic solvents (alcohol solvents, ketone solvents, nitrile solvents, sulfoxide solvents, amine solvents, ionic solutions, etc.). I can do it. These solvents can be carried out by selecting one or more mixed solvents according to the purpose. Moreover, if necessary, an acidic substance or a basic substance can be added to various solvents to adjust the pH.
本発明においては、水に混和可能な溶媒で有機物に対して溶解度を持つ溶媒を上記良溶媒（Ｂ）に用いる溶媒として選択することが好ましいが、例えば、キシレンなどのように水に混和可能な溶媒でなくても有機物に対して溶解度を持つ溶媒を上記良溶媒（Ｂ）に用いる溶媒として選択してもかまわない。水に混和可能な溶媒で有機物に対して溶解度を持つ溶媒としては、アルコール系溶媒としては、例えばメタノール、エタノール、イソプロパノール、ｎ－プロパノール、１－メトキシ－２－プロパノール、ｔｅｒｔ－ブタノール等のアルコール、エチレングリコール、ジエチレングリコール等の多価アルコールや、プロピレングリコールモノメチルエーテル等が挙げられる。ケトン系溶媒としては、例えば、アセトンなどが挙げられる。エーテル系溶媒としては、例えばテトラヒドロフランなどが挙げられる。ニトリル系溶媒としては、例えば、アセトニトリルなどが挙げられる。スルホキシド系溶媒としては、例えば、ジメチルスルホキシド、ジエチルスルホキドなどが挙げられる。アミン系溶媒としては、例えば、ジメチルアミノエタノールやエチレンジアミン、メチルアミン、ジメチルアミン、ジメチルアミン、トリメチルアミン、エチルアミン、ジエチルアミン、トリエチルアミンなどが挙げられる。アミド系溶媒としては、例えば、Ｎ,Ｎ-ジメチルホルムアミド、Ｎ,Ｎ-ジメチルアセトアミドなどが挙げられる。 In the present invention, a solvent that is miscible with water and is soluble in organic substances is preferably selected as the solvent used for the good solvent (B). For example, it is miscible with water such as xylene. Even if it is not a solvent, you may select the solvent which has the solubility with respect to an organic substance as a solvent used for the said good solvent (B). Examples of the solvent that is miscible with water and soluble in organic substances include alcohol solvents such as methanol, ethanol, isopropanol, n-propanol, 1-methoxy-2-propanol, tert-butanol, and the like. Examples thereof include polyhydric alcohols such as ethylene glycol and diethylene glycol, propylene glycol monomethyl ether, and the like. Examples of the ketone solvent include acetone. Examples of the ether solvent include tetrahydrofuran. Examples of the nitrile solvent include acetonitrile. Examples of the sulfoxide solvent include dimethyl sulfoxide and diethyl sulfoxide. Examples of the amine solvent include dimethylaminoethanol, ethylenediamine, methylamine, dimethylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, and triethylamine. Examples of the amide solvent include N, N-dimethylformamide and N, N-dimethylacetamide.
（貧溶媒（Ａ）について）
本発明に係る貧溶媒（Ａ）には、少なくとも水酸基を持つ水溶性高分子（Ａ１）を含む水溶液を用いる。
この貧溶媒を調製するための溶媒には少なくとも水を選択する必要がある。水には、水道水やイオン交換水、ＲＯ水や純水、蒸留水や超純水などを用いることができる。また、本発明の有機物微粒子の製造方法に影響を与えない範囲で、上記水以外に、例えば、メタノール、エタノール、イソプロパノールなどのアルコール類やアセトン、テトラヒドロフランなどの水混和性の有機溶媒を上記貧溶媒に混和しても良い。上記水混和性の有機溶媒を上記貧溶媒に混和させることで、上記キシレンなどのように水に混和可能でない良溶媒の少なくとも一部を、水酸基を持つ水溶性高分子を含む水溶液に混和させることが出来る利点がある。 (About poor solvent (A))
For the poor solvent (A) according to the present invention, an aqueous solution containing at least a water-soluble polymer (A1) having a hydroxyl group is used.
It is necessary to select at least water as a solvent for preparing this poor solvent. As the water, tap water, ion exchange water, RO water, pure water, distilled water, ultrapure water, or the like can be used. In addition to the above water, for example, alcohols such as methanol, ethanol, and isopropanol, and water miscible organic solvents such as acetone and tetrahydrofuran are used as the above poor solvents within a range that does not affect the method for producing organic fine particles of the present invention. It may be mixed with. By mixing the water-miscible organic solvent with the poor solvent, at least part of a good solvent that is not miscible with water, such as xylene, is mixed with an aqueous solution containing a water-soluble polymer having a hydroxyl group. There is an advantage that can be.
貧溶媒（Ａ）に用いられる水酸基を持つ水溶性高分子（Ａ１）は、種々の水酸基を有する高分子であって水溶性のものを選択することができるが、その一例としては、ポリビニルアルコール、ヒドロキシプロピルメチルセルロースまたはヒドロキシプロピルセルロースを挙げることができる。水酸基を持つ水溶性高分子（Ａ１）は、有機物に対して重量比０．１～３．０の範囲であることが好ましい。 The water-soluble polymer (A1) having a hydroxyl group used for the poor solvent (A) can be selected from a polymer having various hydroxyl groups and water-soluble. Examples of the water-soluble polymer (A1) include polyvinyl alcohol, Mention may be made of hydroxypropylmethylcellulose or hydroxypropylcellulose. The water-soluble polymer (A1) having a hydroxyl group preferably has a weight ratio of 0.1 to 3.0 with respect to the organic substance.
（ｐＨ調整について）
本発明においては、上記有機物を溶解させた良溶媒（Ｂ）と、上記水酸基を持つ水溶性高分子を含む貧溶媒（Ａ）を混合した混合液のｐＨを３．５～８．５の範囲内に調整し、このｐＨ調整によって目的物である有機物微粒子の粒子径を制御する。 (About pH adjustment)
In the present invention, the pH of the mixture obtained by mixing the good solvent (B) in which the organic substance is dissolved and the poor solvent (A) containing the water-soluble polymer having a hydroxyl group is in the range of 3.5 to 8.5. The particle size of the organic fine particles as the target is controlled by adjusting the pH.
ｐＨ調整の方法は特に問わないが、その一例としてｐＨ調整剤（Ａ２）の利用を挙げることができる。具体的には、上記有機物を溶解した良溶媒（Ｂ）と水酸基を持つ水溶性高分子を含む貧溶媒（Ａ）との少なくとも何れか一方に、ｐＨ調整剤（Ａ２）を添加する例を示すことができるが、良溶媒（Ｂ）と貧溶媒（Ａ）とは物理的に別の液体としてｐＨ調整剤を用意し、良溶媒（Ｂ）と貧溶媒（Ａ）との混合と同時、又は、混合の前或いは後にｐＨ調整剤を付加してもかまわない。有機物の溶解度の点から、水酸基を持つ水溶性高分子を含む貧溶媒（Ａ）にｐＨ調整剤（Ａ２）を配合することが好ましい。上記ｐＨ調整剤（Ａ２）は、上記有機物に対しては重量比０．００１～１．０の範囲、水酸基を持つ高分子（Ａ１）に対しては重量比で０．００１～１．０の範囲であることが好ましい。
その他のｐＨ調整の方法としては、良溶媒（Ｂ）中の有機物の濃度や良溶媒（Ｂ）に用いる溶媒の変更、貧溶媒（Ａ）に含まれる水酸基を持つ水溶性高分子の変更や、水酸基を持つ水溶性高分子を含む貧溶媒（Ａ）と有機物を溶解した良溶媒（Ｂ）との混合比を変更することなどが挙げられる。 The method for adjusting the pH is not particularly limited, and an example thereof is the use of a pH adjuster (A2). Specifically, an example in which the pH adjusting agent (A2) is added to at least one of the good solvent (B) in which the organic substance is dissolved and the poor solvent (A) containing a water-soluble polymer having a hydroxyl group is shown. The pH adjusting agent is prepared as a physically separate liquid from the good solvent (B) and the poor solvent (A), and simultaneously with the mixing of the good solvent (B) and the poor solvent (A), or The pH adjusting agent may be added before or after mixing. From the viewpoint of the solubility of the organic substance, it is preferable to blend the pH adjuster (A2) with the poor solvent (A) containing a water-soluble polymer having a hydroxyl group. The pH adjuster (A2) is in the range of 0.001 to 1.0 by weight with respect to the organic substance, and 0.001 to 1.0 by weight with respect to the polymer having a hydroxyl group (A1). A range is preferable.
Other methods of pH adjustment include changing the concentration of organic matter in the good solvent (B) and the solvent used in the good solvent (B), changing the water-soluble polymer having a hydroxyl group contained in the poor solvent (A), Examples thereof include changing the mixing ratio of the poor solvent (A) containing a water-soluble polymer having a hydroxyl group and the good solvent (B) in which an organic substance is dissolved.
本発明に用いるｐＨ調整剤（Ａ２）としては、炭酸水素ナトリウムや炭酸カルシウムなどの炭酸塩、水酸化ナトリウムや水酸化カリウム、リン酸水素ナトリウムなどの無機塩、トリエタノールアミンのようなアミン類、アンモニアやアンモニウム塩、塩酸、硝酸、リン酸、ホウ酸などの無機酸、酢酸、クエン酸、アジピン酸などの有機酸またはそれらの塩を用いることができる。また、特に限定されるものではないが、有機物が生体摂取物の場合には、生体内に取り込んでも問題ない物質を選定する必要がある。 Examples of the pH adjuster (A2) used in the present invention include carbonates such as sodium hydrogen carbonate and calcium carbonate, inorganic salts such as sodium hydroxide, potassium hydroxide and sodium hydrogen phosphate, amines such as triethanolamine, Ammonia and ammonium salts, inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid and boric acid, organic acids such as acetic acid, citric acid and adipic acid or salts thereof can be used. In addition, although not particularly limited, when the organic substance is a biologically ingested substance, it is necessary to select a substance that can be taken into the living body without any problem.
上記混合液の有機物微粒子の析出時におけるｐＨを３．５～８．５の範囲内に調整することで、当該有機物微粒子の粒子径を制御できることは、本願発明者にとっても驚きであった。詳細には検討中であるが、本願発明者は、次の少なくとも２つの要因が複合的に作用しているものと考えている。
（一点目の要因）
上記ｐＨを３．５～８．５の範囲内とすることで、有機物微粒子と水酸基を含む水溶性高分子との相互作用を強めることができたことが、当該有機物微粒子の粒子径が制御可能になった一点目の要因である。まず、水酸基を持つ水溶性高分子を用いる目的の一つは、当該有機物微粒子に対する粒子成長を妨げることにある。ところが、混合液のｐＨが上記３．５～８．５の範囲外の場合には、上記水酸基を持つ水溶性高分子と、当該有機物微粒子の表面との相互作用よりも、水酸基を持つ水溶性高分子並びに有機物微粒子がそれぞれ、上記溶解に用いた良溶媒または貧溶媒との相互作用や水溶性高分子同士の相互作用の方が強くなる。このため、水酸基を含む水溶性高分子に期待した有機物微粒子の粒子成長を妨げる効果が、下がってしまうと考えらえる。すなわち、有機物微粒子のもつ官能基は、有機物微粒子が固体の状態であっても、少なくともその表面は上記溶解に用いた良溶媒、並びに水などの貧溶媒にさらされており、上記ｐＨ３．５～８．５の範囲外では、有機物微粒子の官能基が上記溶媒または水への親和性を高めることになる。場合によっては上記官能基への有機溶媒の吸着や水素イオンの脱離、付加などによる見かけ上の構造変化が生じる。これらは水溶性高分子の持つ水酸基が水素結合を形成することによる効果と推測しており、結果として、水溶性高分子に期待した効果が得られなかったものと考えられる。これらの構造変化は温度変化によっても伴う場合があるが、水溶性高分子だけで温度変化を利用して有機物微粒子を析出させた場合などには、その後の温度変化により有機物微粒子の凝集や融着、粒子成長などが生じる場合があった。
（二点目の要因）
また、上記ｐＨを３．５～８．５にすることで有機物の溶解度を微妙に変化させることができることを二点目の要因と考えている。有機物には水酸基やカルボン酸基、アミド基などの水溶性官能基を持つものが多く、有機溶媒に溶解可能な性質とともに、上記官能基の性質によって、水にも溶解性を示すことが多い。これらの官能基を持つ有機物はｐＨの変化により溶解度が変化することも多く、微量のｐＨ調整剤によりｐＨを制御することで、溶解度を制御し、平均粒子径とはかけ離れた粗大な粒子や微小な粒子が略見られずに、均一な状態で粒子径を制御できる可能性が考えられる。 It was also surprising to the inventors of the present application that the particle diameter of the organic fine particles can be controlled by adjusting the pH at the time of precipitation of the organic fine particles in the mixed solution to a range of 3.5 to 8.5. Although being examined in detail, the present inventor considers that the following at least two factors are acting in a complex manner.
(First factor)
By controlling the pH within the range of 3.5 to 8.5, the interaction between the organic fine particles and the water-soluble polymer containing a hydroxyl group could be strengthened, and the particle size of the organic fine particles can be controlled. This is the first factor. First, one of the purposes of using a water-soluble polymer having a hydroxyl group is to prevent particle growth on the organic fine particles. However, when the pH of the mixed solution is outside the above range of 3.5 to 8.5, the water solubility having a hydroxyl group is more than the interaction between the water soluble polymer having a hydroxyl group and the surface of the organic fine particles. The interaction between the polymer and the organic fine particles with the good solvent or the poor solvent used for the dissolution or the interaction between the water-soluble polymers is stronger. For this reason, it is thought that the effect which prevents the particle growth of the organic fine particle expected for the water-soluble polymer containing a hydroxyl group is lowered. That is, the functional group possessed by the organic fine particles, even when the organic fine particles are in a solid state, at least the surface thereof is exposed to a good solvent used for the dissolution and a poor solvent such as water. Outside the range of 8.5, the functional group of the organic fine particles increases the affinity for the solvent or water. In some cases, an apparent structural change occurs due to adsorption of an organic solvent to the functional group, desorption or addition of hydrogen ions, and the like. These are presumed to be due to the effect of the hydroxyl groups of the water-soluble polymer forming hydrogen bonds, and as a result, it is considered that the effect expected of the water-soluble polymer was not obtained. These structural changes may be accompanied by temperature changes. However, when organic fine particles are precipitated using only water-soluble polymers using temperature changes, the organic fine particles are aggregated or fused by subsequent temperature changes. In some cases, particle growth occurs.
(Second factor)
Further, the second factor is considered to be that the solubility of the organic substance can be subtly changed by setting the pH to 3.5 to 8.5. Many organic substances have water-soluble functional groups such as a hydroxyl group, a carboxylic acid group, and an amide group. In addition to the property of being soluble in an organic solvent, they are often soluble in water depending on the property of the functional group. Organic substances having these functional groups often change in solubility due to changes in pH. By controlling the pH with a small amount of pH adjuster, the solubility is controlled, and coarse particles or fine particles far from the average particle diameter are controlled. There is a possibility that the particle diameter can be controlled in a uniform state without almost any visible particles.
混合液の有機物微粒子の析出時におけるｐＨ調整に加えて、貧溶媒（Ａ）に含まれる水酸基を持つ水溶性高分子（Ａ１）の濃度を変更することによって、目的物である有機物微粒子の粒子径をさらに制御することができる。 In addition to pH adjustment at the time of precipitation of the organic fine particles in the mixed solution, the particle size of the organic fine particles as the target product is changed by changing the concentration of the water-soluble polymer (A1) having a hydroxyl group contained in the poor solvent (A). Can be further controlled.
（混合と析出について）
本発明における上記有機物を溶解した良溶媒（Ｂ）と、少なくとも水酸基を持つ水溶性高分子（Ａ１）を含む水溶液である貧溶媒（Ａ）とを混合させ、その混合液から有機物微粒子を析出させる方法としては、特に限定はなく、種々の方法を採用することができる。例えば、希薄系での反応をバッチ容器や混合容器内で行うなどの方法や、マイクロリアクターのような反応装置を用いる方法などを示すことができ、バッチ式であってもよく連続式であっても実施することが出来る。また本願出願人によって提案された、特開２００９－１１２８９２号公報にて記載されたような装置並びに方法を用いても良い。本発明においては、特許文献３に記載の流体処理装置と同様の原理の装置を用いて有機物微粒子を作製することが好ましい。具体的には、相対的に回転する少なくとも２つの処理用面を備えた装置であって、上記２つの処理用面同士が上記回転の軸方向において相対的に接近し又は離反することができるように配置されたものを用いる。上記２つの処理用面同士の間を微小間隔に維持し、この微小間隔に維持された上記２つの処理用面間に、貧溶媒（Ａ）と良溶媒（Ｂ）とを導入する。この導入に際しては、貧溶媒（Ａ）と良溶媒（Ｂ）とを別々の導入路から、上記２つの処理用面間に導入することが好ましいが、導入直前に貧溶媒（Ａ）と良溶媒（Ｂ）とを混合して一つの導入路から導入してもかまわない。また、２つの導入路を用いる場合には、一方の導入路は、上記２つの処理用面のうちの少なくとも一方の中央に設け、他方の導入路は、上記中央の導入路と上記２つの処理用面の外周との間に設けるものとして実施することができる。これによって、貧溶媒（Ａ）と良溶媒（Ｂ）とを混合した混合液による強制薄膜を上記２つの処理用面間で形成し、この強制薄膜中において有機物微粒子の析出を行うものである。その際、ｐＨ調整剤（Ａ２）は、貧溶媒（Ａ）と予め混合させておくことが適当であるが、第３の導入路を上記２つの処理用面のうちの少なくとも一方に設けて、貧溶媒（Ａ）と良溶媒（Ｂ）とｐＨ調整剤（Ａ２）とを、上記２つの処理用面の間で混合するようにしてもかまわない。 (About mixing and precipitation)
In the present invention, the good solvent (B) in which the organic matter is dissolved and the poor solvent (A) which is an aqueous solution containing the water-soluble polymer (A1) having at least a hydroxyl group are mixed, and organic fine particles are precipitated from the mixture. The method is not particularly limited, and various methods can be employed. For example, a method of performing a reaction in a dilute system in a batch container or a mixing container, a method of using a reaction apparatus such as a microreactor, etc. can be shown. Can also be implemented. Also, an apparatus and a method proposed by the applicant of the present application and described in Japanese Patent Laid-Open No. 2009-112892 may be used. In the present invention, it is preferable to produce organic fine particles using an apparatus having the same principle as the fluid processing apparatus described in Patent Document 3. Specifically, the apparatus includes at least two processing surfaces that rotate relatively so that the two processing surfaces can relatively approach or separate from each other in the axial direction of the rotation. The one arranged in is used. A gap between the two processing surfaces is maintained at a minute interval, and a poor solvent (A) and a good solvent (B) are introduced between the two processing surfaces maintained at the minute interval. In this introduction, the poor solvent (A) and the good solvent (B) are preferably introduced between the two processing surfaces from different introduction paths, but the poor solvent (A) and the good solvent are introduced immediately before the introduction. (B) may be mixed and introduced from one introduction path. When two introduction paths are used, one introduction path is provided at the center of at least one of the two processing surfaces, and the other introduction path includes the center introduction path and the two treatment paths. It can implement as what is provided between the outer periphery of a use surface. As a result, a forced thin film is formed between the two processing surfaces by mixing the poor solvent (A) and the good solvent (B), and organic fine particles are deposited in the forced thin film. At that time, it is appropriate that the pH adjuster (A2) is preliminarily mixed with the poor solvent (A), but a third introduction path is provided on at least one of the two processing surfaces, The poor solvent (A), the good solvent (B), and the pH adjusting agent (A2) may be mixed between the two processing surfaces.
（実施例）
以下、実施例を挙げて本発明をさらに具体的に説明する。しかし、本発明は下記の実施例に限定されるものではない。以下の実施例においては、本願出願人によって特許文献３に示された流体処理装置と同様の装置を用いて有機物微粒子を作製した。ただし本願発明の有機物微粒子の製造については、上記装置を使用することに限定されるものではない。 (Example)
Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples. In the following examples, organic fine particles were produced using an apparatus similar to the fluid treatment apparatus disclosed in Patent Document 3 by the applicant of the present application. However, the production of the organic fine particles of the present invention is not limited to the use of the above apparatus.
本発明の実施例において、ＴＥＭ観察には、透過型電子顕微鏡、ＪＥＭ－２１００（ＪＥＯＬ製）を用いた。観察条件としては、加速電圧を８０ｋＶとした。 In the examples of the present invention, a transmission electron microscope, JEM-2100 (manufactured by JEOL) was used for TEM observation. As an observation condition, the acceleration voltage was 80 kV.
粒子径評価は、ＴＥＭ観察において２５０００倍の写真を用い、粒子５０個の平均値を用いた。粒子径評価の結果を、表１～３の「粒子径」の項目に記載した。 The particle diameter was evaluated by using an average value of 50 particles using a 25,000 times photograph in TEM observation. The results of particle size evaluation are listed in the “Particle Size” section of Tables 1-3.
（クルクミン）
　実施例１として有機物にクルクミン、ｐＨ調製剤（Ａ２）に酢酸、水酸基を持つ水溶性高分子（Ａ１）にヒドロキシメチルプロピルセルロース（以下、ＨＰＭＣ）を用いた条件を示す。クルクミンの分子構造を図１に示す。図１に見られるように、クルクミンはベンゼン環と不飽和の炭化水素を基本骨格とする有機物であるが、構造に複数の水酸基を持つため、有機物でありながら、水にも一部親和性を示す物質である。ｐＨが酸性側の場合には、上記クルクミン分子の水酸基に水素陽イオンが接近し、見かけ上（－ＯＨ２ ＋）のような状態を取ろうとし、塩基性側の場合には、液中に含まれる水酸基との相互作用によって、クルクミンに結合している水酸基の水素原子が酸素原子から離れようとし、見かけ上（－Ｏ－）のような状態を取ろうとする可能性がある。 (Curcumin)
Example 1 shows conditions using curcumin as the organic substance, acetic acid as the pH adjuster (A2), and hydroxymethylpropylcellulose (hereinafter, HPMC) as the water-soluble polymer (A1) having a hydroxyl group. The molecular structure of curcumin is shown in FIG. As seen in Figure 1, curcumin is an organic substance with a benzene ring and an unsaturated hydrocarbon as the basic skeleton, but because it has multiple hydroxyl groups in its structure, it has some affinity for water even though it is an organic substance. It is a substance to show. When the pH is on the acidic side, the hydrogen cation approaches the hydroxyl group of the curcumin molecule and apparently tries to take a state like (—OH 2 + ). Due to the interaction with the hydroxyl group contained, the hydrogen atom of the hydroxyl group bonded to curcumin tends to be separated from the oxygen atom, and there is a possibility that an apparent state (—O—) is attempted.
貧溶媒（Ａ）（以下、Ａ液）並びに有機物を溶解した良溶媒（Ｂ）（以下、Ｂ液）は、以下の重量比にて調製した。Ａ液は、０．６７ｗｔ％ ＨＰＭＣ（信越化学製メトローズ） /０．０００９ｗｔ％ 酢酸 / ９９.３２９１ｗｔ％ 純水の重量比にて調製した。調製後のＡ液のｐＨは４．８１（１８．８℃）であった（液比重：１．０）。Ｂ液は３．０ｗｔ％ クルクミン / ９７．０ｗｔ％ エタノール（（液比重：０．８、以下ＥｔＯＨ）の重量比で調製した。Ａ液は、高速回転式分散乳化装置であるクレアミックスディゾルバー（製品名：ＣＬＭ－２．２ＳＤ、エム・テクニック製）を用いて調製した。上記処方に基づいて、Ａ液の各成分をクレアミックスディゾルバーを用いて、調製温度２５℃、ローター回転数を１５０００ｒｐｍ、３０分間撹拌することにより均一に混合し、Ａ液を調製した。Ｂ液は、高速回転式分散乳化装置であるクレアミックス（製品名：ＣＬＭ－２．２Ｓ、エム・テクニック製）を用いて調製した。Ｂ液の各成分をクレアミックス用いて、調製温度２５℃、ローター回転数を１５０００ｒｐｍ、３０分間撹拌することにより均一に混合し、Ｂ液を調製した。 The poor solvent (A) (hereinafter referred to as “liquid A”) and the good solvent (B) (hereinafter referred to as “liquid B”) in which organic substances were dissolved were prepared at the following weight ratio. Solution A was prepared in a weight ratio of 0.67 wt% HPMC (Shinetsu Chemical Co., Ltd.) / 0.0009 wt% acetic acid / 993291 wt% pure water. The pH of the liquid A after preparation was 4.81 (18.8 ° C.) (liquid specific gravity: 1.0). Liquid B was prepared at a weight ratio of 3.0 wt% curcumin cocoon / 97.0 wt% ethanol ((liquid specific gravity: 0.8, hereinafter EtOH). Liquid A was a CLEARMIX dissolver (Product) Name: CLM-2.2SD, manufactured by M Technique Co., Ltd. Based on the above formulation, each component of liquid A was prepared using a CLEARMIX dissolver at a preparation temperature of 25 ° C., a rotor speed of 15000 rpm, 30 The mixture was uniformly mixed by stirring for a minute to prepare solution A. Solution B was prepared using CLEARMIX (product name: CLM-2.2S, manufactured by M Technique), which is a high-speed rotary dispersion emulsifier. Mix each component of B liquid with CLEARMIX and mix uniformly by stirring for 30 minutes at a preparation temperature of 25 ° C. and a rotor speed of 15000 rpm. It was manufactured.
次に調製したＡ液並びにＢ液を本願出願人による特許文献３の流体処理装置を用いて混合した。ここで、特許文献３に記載の流体処理装置とは、同公報の図１に記載の装置であって、第２導入部の開口部ｄ２０がリング状ディスクである処理用面２の中央の開口を取り巻く同心円状の円環形状であるものである。具体的には、上記Ａ液を第１導入部ｄ１から処理用面１、２間に導入し、処理用部１０を表１に記載の各実施例毎の回転数で運転しながら、上記Ｂ液を第２導入部ｄ２から処理用面１、２間に導入して、上記Ａ液とＢ液とを薄膜流体中で混合し、処理用面１、２間において有機物微粒子を析出させた。処理用面１、２間おいて析出させた有機物微粒子を含む流体（以下、有機物微粒子分散液）を流体処理装置の処理用面１、２間から吐出させた。吐出させた有機物微粒子分散液をベッセルｖを介してビーカーｂに回収した。 Next, the prepared liquid A and liquid B were mixed using the fluid processing apparatus of Patent Document 3 by the present applicant. Here, the fluid processing apparatus described in Patent Document 3 is the apparatus described in FIG. 1 of the same publication, and the opening at the center of the processing surface 2 in which the opening d20 of the second introduction part is a ring-shaped disk. Is a concentric ring shape surrounding the circle. Specifically, the liquid A is introduced from the first introduction part d1 between the processing surfaces 1 and 2, and the processing part 10 is operated at the number of revolutions described in Table 1 while the B The liquid was introduced between the processing surfaces 1 and 2 from the second introduction part d2, and the A liquid and the B liquid were mixed in a thin film fluid, and organic fine particles were deposited between the processing surfaces 1 and 2. A fluid containing organic fine particles precipitated between the processing surfaces 1 and 2 (hereinafter, organic fine particle dispersion) was discharged from between the processing surfaces 1 and 2 of the fluid processing apparatus. The discharged organic fine particle dispersion was collected in the beaker b through the vessel v.
上記装置を用いて有機物微粒子としてクルクミン微粒子を析出させた条件と得られた有機物微粒子の粒子径評価の結果を表１に示す。なお、表中における回転数は、特許文献３における処理用部１０の回転数であり、吐出液とは、処理用面１、２間から吐出させた有機物微粒子分散液である。有機物微粒子の析出時のｐＨの測定は実質的に困難であるため、ビーカーｂに回収した吐出液のｐＨを測定し、その結果を表１に記載した。 Table 1 shows the conditions under which curcumin fine particles were deposited as organic fine particles using the above apparatus and the particle diameter evaluation results of the obtained organic fine particles. The number of rotations in the table is the number of rotations of the processing unit 10 in Patent Document 3, and the discharge liquid is an organic fine particle dispersion liquid discharged from between the processing surfaces 1 and 2. Since it is substantially difficult to measure the pH when organic fine particles are precipitated, the pH of the discharged liquid collected in the beaker b was measured, and the results are shown in Table 1.
得られたクルクミン微粒子を含む有機物微粒子分散液をエステル支持膜に滴下し、室温で乾燥してＴＥＭ観察用の試料を作製した。実施例１のＴＥＭ観察結果を図２に示す。ＴＥＭ観察の結果、粒子径は７１ｎｍであった。 The obtained organic fine particle dispersion containing the curcumin fine particles was dropped on the ester support film and dried at room temperature to prepare a sample for TEM observation. The TEM observation result of Example 1 is shown in FIG. As a result of TEM observation, the particle diameter was 71 nm.
実施例２については、実施例１のＡ液中のｐＨ調整剤の濃度を表１に示すように変更した他は、実施例１と同条件にて実施した。得られたクルクミン微粒子を含む有機物微粒子分散液をエステル支持膜に滴下し、室温で乾燥してＴＥＭ観察用の試料を作製した。ＴＥＭ観察結果を図３に示す。ＴＥＭ観察の結果、粒子径は１５８ｎｍであった。 About Example 2, it implemented on the same conditions as Example 1 except having changed the density | concentration of the pH adjuster in A liquid of Example 1 as shown in Table 1. FIG. The obtained organic fine particle dispersion containing the curcumin fine particles was dropped on the ester support film and dried at room temperature to prepare a sample for TEM observation. The TEM observation results are shown in FIG. As a result of TEM observation, the particle size was 158 nm.
実施例３として、表１に示す様に、実施例１で用いたｐＨ調製剤である酢酸を抜き、その他の条件については実施例１と同条件にて実施した。得られたクルクミン微粒子を含む有機物微粒子分散液をエステル支持膜に滴下し、室温で乾燥してＴＥＭ観察用の試料を作製した。ＴＥＭ観察の結果、粒子径は１４０ｎｍであった。 As Example 3, as shown in Table 1, acetic acid as the pH adjusting agent used in Example 1 was removed, and the other conditions were the same as in Example 1. The obtained organic fine particle dispersion containing the curcumin fine particles was dropped on the ester support film and dried at room temperature to prepare a sample for TEM observation. As a result of TEM observation, the particle diameter was 140 nm.
比較例１として、実施例２よりも酢酸濃度を高くし、析出時のｐＨを３．０９に調整した。その他の条件については実施例1と同条件にて実施した。得られたクルクミン微粒子を含む有機物微粒子分散液をエステル支持膜に滴下し、室温で乾燥してＴＥＭ観察用の試料を作製した。ＴＥＭ観察結果を図４に示す。ＴＥＭ観察の結果、粒子径は６２０ｎｍであったが５０ｎｍ程度の粒子が混在しているようにみられ、粒子径に分布が見られた。 As Comparative Example 1, the acetic acid concentration was made higher than that in Example 2, and the pH during precipitation was adjusted to 3.09. Other conditions were the same as in Example 1. The obtained organic fine particle dispersion containing the curcumin fine particles was dropped on the ester support film and dried at room temperature to prepare a sample for TEM observation. The TEM observation result is shown in FIG. As a result of TEM observation, the particle diameter was 620 nm, but it was seen that particles of about 50 nm were mixed, and distribution was observed in the particle diameter.
[規則26に基づく補充 04.07.2016]　
Figure WO-DOC-TABLE-1
実施例１、２では、有機物に対する水溶性高分子の割合（重量比ベース）を一定とし、ｐＨ調整剤の濃度を変化させることによりｐＨを変更した。ｐＨ調整剤を入れていない実施例３では、目的の粒子径を有する有機物微粒子が得られたが、複数個の粒子が凝集した粒子の凝集体が一部存在した。Ａ液とＢ液との混合液中のｐＨ調整剤を有機物に対して１．２５とした比較例１では粒子径に分布が見られた。有機物に対してｐＨ調整剤の添加量は０．００１～０．０１程度と極微量であり、ｐＨ調製剤を僅かに添加して、クルクミンと水溶性高分子の親和性を制御することで粒子径の制御が可能となる。よって、ｐＨの制御が重要となっていることがみてとれる。また、実施例１について同じ実験を５回繰り返し行った。ＴＥＭ観察結果より粒子径は、７５ｎｍ、８０ｎｍ、７２ｎｍ、６８ｎｍとなり、繰り返し再現性についても問題ないことを確認した。また、実施例１～３と比較例１それぞれの吐出液を５℃から５０℃の範囲で温度変化を与えた後、具体的には、５、１５、２５、４０、５０℃にて３０分間保持した後の粒子の状態をＴＥＭ観察したところ、温度変化を与える前と与えた後の粒子径に変化がないことから、５℃から５０℃の温度変化による粒子の安定性も確認出来た。[Supplement under rule 26 04.07.2016]
Figure WO-DOC-TABLE-1
 In Examples 1 and 2, the ratio of the water-soluble polymer to the organic substance (weight ratio basis) was constant, and the pH was changed by changing the concentration of the pH adjuster. In Example 3 in which no pH adjuster was added, organic fine particles having a target particle diameter were obtained, but there were some aggregates of particles in which a plurality of particles were aggregated. In Comparative Example 1 in which the pH adjuster in the liquid mixture of the liquid A and the liquid B was set to 1.25 with respect to the organic matter, a distribution was observed in the particle diameter. The amount of the pH adjuster added to the organic substance is very small, about 0.001 to 0.01. By adding a slight amount of the pH adjuster, the affinity between curcumin and the water-soluble polymer is controlled. The diameter can be controlled. Therefore, it can be seen that pH control is important. Moreover, the same experiment was repeated about Example 1 5 times. From the TEM observation results, the particle diameters were 75 nm, 80 nm, 72 nm, and 68 nm, and it was confirmed that there was no problem with reproducibility. Further, after changing the temperature of each of the discharged liquids of Examples 1 to 3 and Comparative Example 1 in the range of 5 ° C. to 50 ° C., specifically, 30 minutes at 5, 15, 25, 40 and 50 ° C. When the state of the particles after being held was observed with a TEM, there was no change in the particle diameter before and after the temperature change, and thus the stability of the particles due to the temperature change from 5 ° C. to 50 ° C. could be confirmed.
（プロブコール）
実施例４として有機物にプロブコール、ｐＨ調製剤（Ａ２）に炭酸水素ナトリウム、水酸基を持つ水溶性高分子（Ａ１）にポリビニルアルコール（以下、ＰＶＡと称す）を用いた条件を示す。プロブコールの分子構造を図５に示す。プロブコールは、その構造に水酸基を持つ有機物である。 (Probucol)
Example 4 shows the conditions using probucol as the organic substance, sodium bicarbonate as the pH adjuster (A2), and polyvinyl alcohol (hereinafter referred to as PVA) as the water-soluble polymer (A1) having a hydroxyl group. The molecular structure of probucol is shown in FIG. Probucol is an organic substance having a hydroxyl group in its structure.
貧溶媒（Ａ）（以下、Ａ液）並びに有機物を溶解した良溶媒（Ｂ）（以下、Ｂ液）は、以下の重量比にて調製した。Ａ液は、０．１２５wt% ＰＶＡ(日本合成製ＥＧ-０５Ｐ） /０．０００９ｗｔ％ 炭酸水素ナトリウム / ９９．８７４１ｗｔ％ 純水の重量比にて調製した。調製後のＡ液のｐＨは７．０７（２７．１℃）であった（液比重：１．０）。Ｂ液は３．０ｗｔ％ プロブコール /９７．０ｗｔ％エタノール（（液比重：０．８、以下ＥｔＯＨ）の重量比で調製した。Ａ・Ｂ液の調製条件は、実施例１と同じとした。 The poor solvent (A) (hereinafter referred to as “liquid A”) and the good solvent (B) (hereinafter referred to as “liquid B”) in which organic substances were dissolved were prepared at the following weight ratio. The liquid A was prepared at a weight ratio of 0.125 wt% PVA (EG-05P manufactured by Nippon Gosei Co., Ltd.) / 0.0009 wt% sodium hydrogen carbonate / 99.8741 wt% pure water. The pH of the liquid A after preparation was 7.07 (27.1 ° C.) (liquid specific gravity: 1.0). Liquid B was prepared at a weight ratio of 3.0 wt% probucol /97.0 wt% ethanol ((liquid specific gravity: 0.8, hereinafter EtOH). The conditions for preparing liquids A and B were the same as in Example 1.
上記Ａ液とＢ液との混合液を表２記載のｐＨとなるように、調製したＡ液並びにＢ液を、実施例１で用いた流体処理装置を用いて混合し、処理用面１、２間において有機物微粒子であるプロブコール微粒子を析出させた。処理用面１、２間おいて析出させた有機物微粒子を含む流体（以下、有機物微粒子分散液）を流体処理装置の処理用面１、２間から吐出させた。吐出させた有機物微粒子分散液をベッセルｖを介してビーカーｂに回収した。
上記装置を用いて有機物微粒子としてプロブコール微粒子を析出させた条件と得られた有機物微粒子の粒子径を表２に示す。なお、表中における回転数は、特許文献３における処理用部１０の回転数であり、吐出液とは、処理用面１、２間から吐出させた有機物微粒子分散液である。有機物微粒子の析出時のｐＨの測定は実質的に困難であるため、ビーカーｂに回収した吐出液のｐＨを測定し、その結果を表２に記載した。 The prepared liquid A and liquid B are mixed using the fluid processing apparatus used in Example 1 so that the mixed liquid of liquid A and liquid B has the pH described in Table 2, and the processing surface 1 Probucol fine particles, which are organic fine particles, were precipitated between the two. A fluid containing organic fine particles precipitated between the processing surfaces 1 and 2 (hereinafter, organic fine particle dispersion) was discharged from between the processing surfaces 1 and 2 of the fluid processing apparatus. The discharged organic fine particle dispersion was collected in the beaker b through the vessel v.
Table 2 shows the conditions under which probucol fine particles were deposited as organic fine particles using the above apparatus and the particle diameter of the obtained organic fine particles. The number of rotations in the table is the number of rotations of the processing unit 10 in Patent Document 3, and the discharge liquid is an organic fine particle dispersion liquid discharged from between the processing surfaces 1 and 2. Since it is substantially difficult to measure the pH at the time of precipitation of the organic fine particles, the pH of the discharged liquid collected in the beaker b was measured, and the results are shown in Table 2.
得られたプロブコール微粒子を含む有機物微粒子分散液をエステル支持膜に滴下し、室温で乾燥してＴＥＭ観察用の試料を作製した。実施例４のＴＥＭ観察結果を図６に示す。ＴＥＭ観察の結果、粒子径は３８０ｎｍであった。 The obtained organic fine particle dispersion containing the probucol fine particles was dropped on the ester support film and dried at room temperature to prepare a sample for TEM observation. The TEM observation result of Example 4 is shown in FIG. As a result of TEM observation, the particle diameter was 380 nm.
実施例５では実施例４におけるＡ液とＢ液との混合比を変更した他は実施例４と同条件にて実施し、Ａ液とＢ液との混合液中の有機物に対する水酸基を持つ水溶性高分子の割合（重量比ベース）を増加させた。ＴＥＭ観察の結果から、粒子径は２２６ｎｍとなった。 Example 5 was carried out under the same conditions as in Example 4 except that the mixing ratio of the A liquid and the B liquid in Example 4 was changed, and the aqueous solution having a hydroxyl group with respect to the organic matter in the mixed liquid of the A liquid and the B liquid. The ratio of the functional polymer (weight ratio basis) was increased. From the result of TEM observation, the particle diameter was 226 nm.
実施例６～１０と比較例２は表２に記載した貧溶媒（Ａ）と良溶媒（Ｂ）を用いた処方で調製を行った。なお、Ａ・Ｂ液の調製条件は、実施例１と同じとした。調製したＡ液とＢ液とを実施例１で用いた流体処理装置を用いて表２記載の条件で混合し、プロブコール微粒子を析出させた。処理用面１、２間おいて析出させた有機物微粒子を含む流体（以下、有機物微粒子分散液）を流体処理装置の処理用面１、２間から吐出させた。吐出させた有機物微粒子分散液をベッセルｖを介してビーカーｂに回収した。ＴＥＭ観察結果より、実施例５では、粒子径は１２３ｎｍ、実施例６では６８ｎｍ、実施例７では１０２ｎｍ、実施例８では１７５ｎｍとなった。実施例９のＴＥＭ観察結果を図７に示す。また、ｐＨが８．７２となる条件で混合した比較例２では、ＴＥＭ観察結果より粒子径は３７８ｎｍ程度となったが粒子が凝集し融着しているように見られた。図８にＴＥＭ写真を示す。また、炭酸水素ナトリウムを添加しなかった実施例１０では、ＴＥＭ観察結果より４８０ｎｍとなったが、複数個の粒子が凝集した粒子の凝集体が一部存在した。 Examples 6 to 10 and Comparative Example 2 were prepared with formulations using the poor solvent (A) and good solvent (B) described in Table 2. The conditions for preparing the A and B solutions were the same as in Example 1. The prepared liquid A and liquid B were mixed under the conditions described in Table 2 using the fluid treatment apparatus used in Example 1, to precipitate probucol fine particles. A fluid containing organic fine particles precipitated between the processing surfaces 1 and 2 (hereinafter, organic fine particle dispersion) was discharged from between the processing surfaces 1 and 2 of the fluid processing apparatus. The discharged organic fine particle dispersion was collected in the beaker b through the vessel v. From the results of TEM observation, in Example 5, the particle size was 123 nm, in Example 6, 68 nm, in Example 7, 102 nm, and in Example 175 nm. The TEM observation result of Example 9 is shown in FIG. Further, in Comparative Example 2 mixed under the condition that the pH was 8.72, the particle diameter was about 378 nm from the TEM observation result, but the particles seemed to be aggregated and fused. FIG. 8 shows a TEM photograph. In Example 10 in which sodium hydrogen carbonate was not added, the result of TEM observation was 480 nm, but there were some aggregates of particles in which a plurality of particles were aggregated.
[規則26に基づく補充 04.07.2016]　
Figure WO-DOC-TABLE-2
 [Supplement under rule 26 04.07.2016]
Figure WO-DOC-TABLE-2
まず、Ａ液とＢ液との混合液のｐＨを３．５～８．５の範囲内に調整することにより有機物微粒子の粒子径の変化が見られ、目的の粒子径を有する有機物微粒子が得られた。特に実施例４～９では、平均粒子径とはかけ離れた粗大な粒子や微小な粒子は略見られず、均一な状態で粒子径が変化した。ｐＨ調整剤を入れていない実施例１０では、目的の粒子径を有する有機物微粒子が得られたが、複数個の粒子が凝集した粒子の凝集体が一部存在した。ｐＨ調整剤を有機物に対して１．５とした比較例２では、複数個の粒子が凝集し融着した粒子の凝集体が多く存在した。次に、実施例４と５、実施例６と７については、Ａ液とＢ液との混合比を変更して、Ａ液とＢ液との混合液中のプロブコールに対する水溶性高分子の割合（重量比ベース）を変更した。Ａ液とＢ液との混合液中のプロブコールに対する水溶性高分子の割合（重量比ベース）を変化させることにより、平均粒子径とはかけ離れた粗大な粒子や微小な粒子は略見られず、均一な状態で粒子径が変化した。具体的には、Ａ液とＢ液との混合液中のプロブコールに対する水溶性高分子の割合（重量比ベース）を増加させた方が、有機物微粒子の粒子径が小さくなることを確認した。また、実施例４～１０と比較例２それぞれの吐出液を５℃から５０℃の範囲で温度変化を与えた後、具体的には、５、１５、２５、４０、５０℃にて３０分間保持した後の粒子の状態をＴＥＭ観察したところ、温度変化を与える前と与えた後の粒子径に変化が略見られなかったことから、５℃から５０℃の温度変化による粒子の安定性も確認出来た。これら実施例の結果より、Ａ液とＢ液との混合液のｐＨを３．５～８．５に調整することで有機物微粒子の粒子径を制御し、目的の粒子径を有する有機物微粒子が作製できていること、特に、ｐＨ調整剤の貧溶媒（Ａ）への配合により、均一な有機物微粒子が作製できていることが分かる。 First, by adjusting the pH of the liquid mixture of the liquid A and the liquid B within the range of 3.5 to 8.5, a change in the particle diameter of the organic fine particles is observed, and organic fine particles having a target particle diameter are obtained. It was. In particular, in Examples 4 to 9, coarse particles and minute particles far from the average particle size were hardly seen, and the particle size changed in a uniform state. In Example 10 in which no pH adjuster was added, organic fine particles having a target particle diameter were obtained, but there were some aggregates of particles in which a plurality of particles were aggregated. In Comparative Example 2 in which the pH adjusting agent was 1.5 with respect to the organic substance, there were many aggregates of particles in which a plurality of particles were aggregated and fused. Next, for Examples 4 and 5, and Examples 6 and 7, the ratio of the water-soluble polymer to probucol in the liquid mixture of liquid A and liquid B was changed by changing the mixing ratio of liquid A and liquid B. (Weight ratio basis) was changed. By changing the ratio of water-soluble polymer to probucol in the liquid mixture of liquid A and liquid B (weight ratio basis), coarse particles and fine particles that are far from the average particle diameter are hardly seen, The particle size changed in a uniform state. Specifically, it was confirmed that the particle size of the organic fine particles was reduced by increasing the ratio of water-soluble polymer to probucol (weight ratio basis) in the liquid mixture of liquid A and liquid B. Further, after changing the temperature of each of the discharge liquids of Examples 4 to 10 and Comparative Example 2 in the range of 5 ° C. to 50 ° C., specifically, at 15, 15, 25, 40, and 50 ° C. for 30 minutes. When the state of the particles after being held was observed with a TEM, almost no change was observed in the particle size before and after the temperature change, so the stability of the particles due to the temperature change from 5 ° C. to 50 ° C. was also observed. I was able to confirm. From the results of these examples, the particle diameter of the organic fine particles is controlled by adjusting the pH of the liquid mixture of the liquid A and the liquid B to 3.5 to 8.5, and organic fine particles having a target particle diameter are produced. It can be seen that uniform organic fine particles can be produced by the addition of the pH adjuster to the poor solvent (A).
（パラフィンワックス）
実施例１１として有機物にパラフィンワックス（日本精蝋製、製品名ＦＮＰ－００９０、融点８０℃）、ｐＨ調製剤（Ａ２）にアンモニア、水酸基を持つ水溶性高分子（Ａ１）にポリビニルアルコール（以下、ＰＶＡと称す）を用いた条件を示す。 (Paraffin wax)
In Example 11, paraffin wax (manufactured by Nippon Seiwa Co., Ltd., product name FNP-0090, melting point 80 ° C.), ammonia as a pH adjuster (A2), polyvinyl alcohol (hereinafter referred to as a water-soluble polymer having a hydroxyl group) (A1) as Example 11 The conditions using PVA) are shown.
貧溶媒（Ａ）（以下、Ａ液）並びに有機物を溶解した良溶媒（Ｂ）（以下、Ｂ液）は、以下の重量比にて調製した。Ａ液は、０．０２ｗｔ% ＰＶＡ(日本合成製ＥＧ-０５Ｐ） /０．０００８ｗｔ％ アンモニア / １９．９８ｗｔ％ 純水 / ７９．９９９２ｗｔ％イソプロピルアルコール（以下、ＩＰＡ）の重量比にて調製した。調製後のＡ液のｐＨは９．１６（２４．２℃）であった（液比重：０．９０）。Ｂ液は０．０２ｗｔ％ パラフィンワックス / ９９．９８ｗｔ％ｍ－キシレン（液比重：０．８６）の重量比で調製した。Ａ液は、高速回転式分散乳化装置であるクレアミックスディゾルバー（製品名：ＣＬＭ－２．２ＳＤ、エム・テクニック製）を用いて調製した。上記処方に基づいて、Ａ液の各成分をクレアミックスディゾルバーを用いて、調製温度２５℃、ローター回転数を１５０００ｒｐｍ、３０分間撹拌することにより均一に混合し、Ａ液を調製した。Ｂ液は、高速回転式分散乳化装置であるクレアミックス（製品名：ＣＬＭ－２．２Ｓ、エム・テクニック製）を用いて調製した。Ｂ液の各成分をクレアミックス用いて、調製温度９０℃、ローター回転数を１５０００ｒｐｍ、３０分間撹拌することにより均一に混合し、Ｂ液を調製した。 The poor solvent (A) (hereinafter referred to as “liquid A”) and the good solvent (B) (hereinafter referred to as “liquid B”) in which organic substances were dissolved were prepared at the following weight ratio. Solution A was prepared at a weight ratio of 0.02 wt% PVA (EG-05P manufactured by Nippon Synthetic Co., Ltd.) / 0.0008 wt% Ammonia / 19.98 wt% Pure water / 79.9992 wt% isopropyl alcohol (hereinafter, IPA). The pH of the liquid A after preparation was 9.16 (24.2 ° C.) (liquid specific gravity: 0.90). Liquid B was prepared at a weight ratio of 0.02 wt% paraffin wax w / 99.98 wt% m-xylene (liquid specific gravity: 0.86). Liquid A was prepared using a CLEARMIX dissolver (product name: CLM-2.2SD, manufactured by M Technique), which is a high-speed rotary dispersion emulsifier. Based on the above formulation, each component of the A liquid was uniformly mixed by stirring for 30 minutes at a preparation temperature of 25 ° C. and a rotor rotation speed of 15000 rpm using a CLEARMIX dissolver to prepare A liquid. Liquid B was prepared using CLEARMIX (product name: CLM-2.2S, manufactured by M Technique), which is a high-speed rotary dispersion emulsifier. Each component of the B liquid was uniformly mixed by stirring for 30 minutes at a preparation temperature of 90 ° C. and a rotor rotation speed of 15000 rpm using a CLEARMIX to prepare a B liquid.
上記Ａ液とＢ液との混合液を表３に記載のｐＨとなるように、調製したＡ液並びにＢ液を、実施例１で用いた流体処理装置を用いて混合し、処理用面１、２間において有機物微粒子であるパラフィンワックス微粒子を析出させた。処理用面１、２間おいて析出させた有機物微粒子を含む流体（以下、有機物微粒子分散液）を流体処理装置の処理用面１、２間から吐出させた。吐出させた有機物微粒子分散液をベッセルｖを介してビーカーｂに回収した。
上記装置を用いて有機物微粒子としてパラフィンワックス微粒子を析出させた条件と得られた有機物微粒子の粒子径評価の結果を表３に示す。なお、表中における回転数は、特許文献３における処理用部１０の回転数であり、吐出液とは、処理用面１、２間から吐出させた有機物微粒子分散液である。有機物微粒子の析出時のｐＨの測定は実質的に困難であるため、ビーカーｂに回収した吐出液のｐＨを測定し、その結果を表３に記載した。 The prepared liquid A and liquid B were mixed using the fluid processing apparatus used in Example 1 so that the mixed liquid of liquid A and liquid B had the pH described in Table 3, and the processing surface 1 Between the two, paraffin wax fine particles, which are organic fine particles, were deposited. A fluid containing organic fine particles precipitated between the processing surfaces 1 and 2 (hereinafter, organic fine particle dispersion) was discharged from between the processing surfaces 1 and 2 of the fluid processing apparatus. The discharged organic fine particle dispersion was collected in the beaker b through the vessel v.
Table 3 shows the conditions under which paraffin wax fine particles were deposited as organic fine particles using the above apparatus and the particle diameter evaluation results of the obtained organic fine particles. The number of rotations in the table is the number of rotations of the processing unit 10 in Patent Document 3, and the discharge liquid is an organic fine particle dispersion liquid discharged from between the processing surfaces 1 and 2. Since it is substantially difficult to measure the pH at the time of precipitation of the organic fine particles, the pH of the discharged liquid collected in the beaker b was measured, and the results are shown in Table 3.
得られたパラフィンワックス微粒子を含む有機物微粒子分散液をエステル支持膜に滴下し、室温で乾燥してＴＥＭ観察用の試料を作製した。実施例１２～１４では、実施例１１におけるＡ液とＢ液との混合比を変更した他は実施例１１と同条件にてパラフィンワックス微粒子を作製した。 The obtained organic fine particle dispersion containing paraffin wax fine particles was dropped on an ester support film and dried at room temperature to prepare a sample for TEM observation. In Examples 12 to 14, paraffin wax microparticles were produced under the same conditions as in Example 11 except that the mixing ratio of Liquid A and Liquid B in Example 11 was changed.
[規則26に基づく補充 04.07.2016]　
Figure WO-DOC-TABLE-3
 [Supplement under rule 26 04.07.2016]
Figure WO-DOC-TABLE-3
吐出液、すなわちＡ液とＢ液との混合液のｐＨを３．５～８．５の範囲に調整した実施例１１～１４においては、吐出液のｐＨによって、有機物微粒子の粒子径が制御され、目的の粒子径を有する有機物微粒子が作製され、有機物微粒子の粒子径は均一な状態で変化したが、吐出液のｐＨを３．５～８．５の範囲以外に調整した比較例３、４では、粒子径評価の結果として表３にそれぞれの粒子径を８７９ｎｍ、６７１ｎｍと記載したが、２μｍ以上の粗大な粒子も多数観察され、有機物微粒子の粒子径の制御は不可能であった。実施例１１と１２、実施１３と１４については、Ａ液とＢ液との混合比を変更して、Ａ液とＢ液との混合液中のパラフィンワックスに対する水溶性高分子の割合（重量比ベース）を変更した。Ａ液とＢ液との混合液中のパラフィンワックスに対する水溶性高分子の割合（重量比ベース）を変化させることにより、平均粒子径とかけ離れた粗大な粒子や微小な粒子は略確認されず、均一な状態で粒子径が変化した。具体的には、実施例１１と１２について、Ａ液とＢ液との混合液中のパラフィンワックスに対する水溶性高分子の割合（重量比ベース）を増加させた方が、有機物微粒子の粒子径が小さくなることを確認し、実施例１３と１４については、Ａ液とＢ液との混合液中のパラフィンワックスに対する水溶性高分子の割合（重量比ベース）を減少させた方が、有機物微粒子の粒子径が小さくなることを確認した。 In Examples 11 to 14 in which the pH of the discharge liquid, that is, the mixed liquid of the A liquid and the B liquid was adjusted to the range of 3.5 to 8.5, the particle diameter of the organic fine particles was controlled by the pH of the discharge liquid. Comparative Examples 3 and 4 in which organic fine particles having a target particle size were prepared and the particle size of the organic fine particles changed in a uniform state, but the pH of the discharge liquid was adjusted outside the range of 3.5 to 8.5. In Table 3, as a result of the particle size evaluation, the respective particle sizes are described as 879 nm and 671 nm in Table 3. However, many coarse particles of 2 μm or more were observed, and it was impossible to control the particle size of the organic fine particles. For Examples 11 and 12, and Examples 13 and 14, the ratio of the water-soluble polymer to the paraffin wax in the liquid mixture of liquid A and liquid B was changed (weight ratio) by changing the mixing ratio of liquid A and liquid B. Base) was changed. By changing the ratio of the water-soluble polymer to the paraffin wax in the liquid mixture of the liquid A and the liquid B (weight ratio basis), coarse particles and fine particles far from the average particle diameter are not substantially confirmed, The particle size changed in a uniform state. Specifically, in Examples 11 and 12, the particle size of the organic fine particles is increased by increasing the ratio of water-soluble polymer to the paraffin wax (weight ratio basis) in the liquid mixture of liquid A and liquid B. In Examples 13 and 14, it was confirmed that the ratio of the water-soluble polymer to the paraffin wax in the liquid mixture of the liquid A and the liquid B (based on weight ratio) was reduced. It was confirmed that the particle size was small.

Claims (10)

  1. 貧溶媒（Ａ）と有機物を溶解した良溶媒（Ｂ）とを混合し、その混合液中にて有機物微粒子を析出させる有機物微粒子の製造方法において、
    上記貧溶媒（Ａ）として、少なくとも水酸基を持つ水溶性高分子（Ａ１）を含む水溶液を用い、上記有機物微粒子の析出時における上記混合液のｐＨを３．５～８．５の範囲内において調整することで、
    上記有機物微粒子の粒子径を制御し、目的の粒子径である上記有機物微粒子を得ることを特徴とする、有機物微粒子の製造方法。     In the method for producing organic fine particles in which the poor solvent (A) and the good solvent (B) in which the organic matter is dissolved are mixed, and the organic fine particles are precipitated in the mixed solution.
    As the poor solvent (A), an aqueous solution containing a water-soluble polymer (A1) having at least a hydroxyl group is used, and the pH of the mixed solution at the time of precipitation of the organic fine particles is adjusted within the range of 3.5 to 8.5. by doing,
    A method for producing organic fine particles, comprising controlling the particle size of the organic fine particles to obtain the organic fine particles having a target particle size.
  2. 上記良溶媒（Ｂ）に水混和性の有機溶媒を用いることを特徴とする、請求項１に記載の有機物微粒子の製造方法。 The method for producing organic fine particles according to claim 1, wherein a water-miscible organic solvent is used for the good solvent (B).
  3. 上記貧溶媒（Ａ）にｐＨ調整剤（Ａ２）を配合し、上記ｐＨ調整剤（Ａ２）により、上記有機物微粒子の析出時における上記混合液のｐＨを調整することを特徴とする、請求項１または２の何れかに記載の有機物微粒子の製造方法。 The pH adjuster (A2) is blended with the poor solvent (A), and the pH of the mixed solution at the time of precipitation of the organic fine particles is adjusted with the pH adjuster (A2). 3. The method for producing organic fine particles according to any one of 2 above.
  4. 上記有機物に対する上記ｐＨ調整剤（Ａ２）を重量比０．００１以上、１.０以下に調製することを特徴とする、請求項３に記載の有機物微粒子の製造方法。 The method for producing organic fine particles according to claim 3, wherein the pH adjusting agent (A2) for the organic matter is prepared in a weight ratio of 0.001 or more and 1.0 or less.
  5. 上記貧溶媒（Ａ）に含まれる上記水溶性高分子（Ａ１）の濃度を変更することで、
    上記有機物微粒子の上記粒子径を制御することを特徴とする、請求項１～４の何れかに記載の有機物微粒子の製造方法。     By changing the concentration of the water-soluble polymer (A1) contained in the poor solvent (A),
    5. The method for producing organic fine particles according to claim 1, wherein the particle diameter of the organic fine particles is controlled.
  6. 上記水溶性高分子（Ａ１）が、ポリビニルアルコール、ヒドロキシプロピルセルロース及びヒドロキシプロピルメチルセルロースから選択された少なくとも１種であることを特徴とする、請求項１～５の何れかに記載の有機物微粒子の製造方法 6. The production of organic fine particles according to claim 1, wherein the water-soluble polymer (A1) is at least one selected from polyvinyl alcohol, hydroxypropylcellulose and hydroxypropylmethylcellulose. Method
  7. 上記有機物に対する上記水溶性高分子（Ａ１）の重量比を０．１～３．０に調製することを特徴とする、請求項１～６の何れかに記載の有機物微粒子の製造方法。 7. The method for producing organic fine particles according to claim 1, wherein a weight ratio of the water-soluble polymer (A1) to the organic substance is adjusted to 0.1 to 3.0.
  8. 上記有機物微粒子の粒子径が２０ｎｍ～５００ｎｍであることを特徴とする、請求項１～７の何れかに記載の有機物微粒子の製造方法。 8. The method for producing organic fine particles according to claim 1, wherein the organic fine particles have a particle size of 20 nm to 500 nm.
  9. 上記有機物が生体摂取物であることを特徴とする、請求項１～８の何れかに記載の有機物微粒子の製造方法。 The method for producing organic fine particles according to any one of claims 1 to 8, wherein the organic substance is a biologically ingested substance.
  10. 接近・離反可能な相対的に回転する２つの処理用面間を微小間隔に維持し、この微小間隔に維持された上記２つの処理用面間を上記貧溶媒（Ａ）と上記良溶媒（Ｂ）との流路とすることによって、上記貧溶媒（Ａ）と上記良溶媒（Ｂ）とを混合した上記混合液による強制薄膜を形成し、この強制薄膜中において上記有機物微粒子の析出を行うことを特徴とする、請求項１～９の何れかに記載の有機物微粒子の製造方法。 A distance between two relatively rotating processing surfaces that can be moved toward and away from each other is maintained at a minute interval, and the two solvent processing surfaces maintained at the minute interval are separated from each other by the poor solvent (A) and the good solvent (B ) To form a forced thin film by the mixed liquid in which the poor solvent (A) and the good solvent (B) are mixed, and the organic fine particles are deposited in the forced thin film. The method for producing organic fine particles according to any one of claims 1 to 9, wherein:
PCT/JP2016/068312 2016-06-20 2016-06-20 Method for producing organic fine particles WO2017221314A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009008391A1 (en) * 2007-07-06 2009-01-15 M.Technique Co., Ltd. Method of producing microparticles to be ingested into the body, microparticles to be ingested into the body and dispersion and medicinal composition containing the same
JP2015520149A (en) * 2012-05-08 2015-07-16 アシエクス セラピューティクス インコーポレイテッドＡｃｉｅｘ Ｔｈｅｒａｐｅｕｔｉｃｓ， Ｉｎｃ． Hydrophobic therapeutic agent preparation, manufacturing method and use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009008391A1 (en) * 2007-07-06 2009-01-15 M.Technique Co., Ltd. Method of producing microparticles to be ingested into the body, microparticles to be ingested into the body and dispersion and medicinal composition containing the same
JP2015520149A (en) * 2012-05-08 2015-07-16 アシエクス セラピューティクス インコーポレイテッドＡｃｉｅｘ Ｔｈｅｒａｐｅｕｔｉｃｓ， Ｉｎｃ． Hydrophobic therapeutic agent preparation, manufacturing method and use thereof

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