WO2017221314A1 - Procédé pour produire des particules fines organiques. - Google Patents

Procédé pour produire des particules fines organiques. 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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English (en)
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 PCT/JP2016/068312 priority Critical patent/WO2017221314A1/fr
Priority to JP2017537324A priority patent/JPWO2017221314A1/ja
Publication of WO2017221314A1 publication Critical patent/WO2017221314A1/fr

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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

Definitions

  • 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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  • Organic Chemistry (AREA)
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Abstract

L'objectif de la présente invention est de fournir un procédé de production des particules fines organiques, qui est capable de contrôler facilement et de façon stable les diamètres des particules fines organiques lorsque elles sont produites au moyen d'un procédé à faible solvant. Un procédé de production des particules fines organiques, dans lequel un solvant pauvre (A) et un bon solvant (B), dans lesquels une matière organique est dissoute, sont mélangés et des particules fines organiques sont précipitées dans la solution mixte. Dans ce procédé, une solution aqueuse contenant un polymère soluble dans l'eau (A1) qui a au moins un groupe hydroxyle est utilisée comme solvant pauvre (A) et le pH de la solution mélangée est ajusté pour se situer dans la plage de 3,5 à 8,5 pendant la précipitation des particules fines organiques, de sorte que les diamètres de particule des particules fines organiques soit régulés, ce qui permet d'obtenir des particules fines organiques ayant les diamètres de particule désireés.
PCT/JP2016/068312 2016-06-20 2016-06-20 Procédé pour produire des particules fines organiques. WO2017221314A1 (fr)

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JP2017537324A JPWO2017221314A1 (ja) 2016-06-20 2016-06-20 有機物微粒子の製造方法

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009008391A1 (fr) * 2007-07-06 2009-01-15 M.Technique Co., Ltd. Procédé de production de microparticules devant être ingérées dans le corps, microparticules devant être ingérées dans le corps et dispersion et composition médicinales les contenant
JP2015520149A (ja) * 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． 疎水性治療剤の調製物、製造方法およびその使用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009008391A1 (fr) * 2007-07-06 2009-01-15 M.Technique Co., Ltd. Procédé de production de microparticules devant être ingérées dans le corps, microparticules devant être ingérées dans le corps et dispersion et composition médicinales les contenant
JP2015520149A (ja) * 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． 疎水性治療剤の調製物、製造方法およびその使用

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