WO2019198612A1 - 造粒組成物 - Google Patents

造粒組成物 Download PDF

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Publication number
WO2019198612A1
WO2019198612A1 PCT/JP2019/014955 JP2019014955W WO2019198612A1 WO 2019198612 A1 WO2019198612 A1 WO 2019198612A1 JP 2019014955 W JP2019014955 W JP 2019014955W WO 2019198612 A1 WO2019198612 A1 WO 2019198612A1
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WIPO (PCT)
Prior art keywords
granulated
particles
binder
core
coated
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/JP2019/014955
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English (en)
French (fr)
Japanese (ja)
Inventor
俊介 清
三寿々 峯田
主税 森実
亙 平澤
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Sunsho Pharmaceutical Co Ltd
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Sunsho Pharmaceutical Co Ltd
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Priority to US17/044,599 priority Critical patent/US12496277B2/en
Publication of WO2019198612A1 publication Critical patent/WO2019198612A1/ja
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1658—Proteins, e.g. albumin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a granulated composition whose surface is coated with a particulate coating agent and the surface is not smooth. More specifically, the present invention is suitable for uniform particles even if the binder is a dilute solution with low gel strength.
  • the present invention relates to a granulated composition which can be granulated and hardly segregates or separates during mixing and storage with different types of powders and easily ensures content uniformity.
  • particles are formed from solutions containing medicinal ingredients and other biofunctional ingredients to produce granules containing the medicinal ingredients or biofunctional ingredients, which are directly used as granules.
  • capsules are filled into capsules, or tablets are produced by tableting the granules.
  • Patent Document 1 As a granulation method for obtaining the granules, a solution containing a medicinal component or a biofunctional component is dropped onto a fluidized bed composed of a flowing coating agent. A method has been proposed in which particles coated with a coating agent are obtained and dried to obtain spherical coated particles.
  • coated particles are granulated, for example, a medicinal component or a biofunctional component is blended in a gelling agent solution (binder) in which a polymer material having a gelling action such as gelatin is dissolved in water.
  • a solution is prepared, and this is dropped onto a fluidized bed of the above-mentioned coating agent so that the coating particle is adhered to the droplet, and the droplet is dried, and a granulated composition having a surface covered with the coating particle is prepared. Getting is done.
  • the gelatin concentration of the gelling agent solution (binder) can be set low to obtain a dilute solution, the size of the spraying device or the discharging device for dropping the granulated solution onto the fluidized bed is reduced. Even when the pressure resistance and performance for ejecting uniform droplets are not provided, the granulation solution can be satisfactorily dropped to obtain a granulation composition.
  • the gelling agent solution (binder) is a dilute solution, the amount that can be dripped in a certain time increases, which is advantageous in terms of the productivity of the granulated composition.
  • “having a gelling effect” means that the polymer solution completely dissolved in a good solvent is visually observed to show no fluidity when allowed to stand at room temperature and open for 10 minutes. It refers to the polymer and its concentration, and “gel strength” refers to the strength of this gelling action or the degree of gelation. Specifically, for example, pork or bovine gelatin having a Bloom number of 200 or more is adjusted when 20 g of a 20% by mass aqueous solution is adjusted to 25 ° C. and left in a 100 mL beaker at room temperature and open for 10 minutes. Since the gelatin aqueous solution does not flow even if it is tilted, it can be determined that it has a gel action.
  • an ethanol solution containing 10% by mass of hydroxypropyl cellulose follows the movement of the container even when 20 g of the solution is adjusted to 25 ° C. and left in a 100 mL beaker at room temperature and open for 10 minutes. Therefore, it can be determined that the solution does not have a gelling action. Moreover, even if the above-mentioned Bloom number of 200 or more porcine or bovine gelatin is below, for example, less than 10% by weight, it does not gel by the above-described method and flows. Therefore, this gelatin concentration aqueous solution exhibits gel strength. It can be determined that the polymer substance solution has a concentration that is so thin that it cannot be obtained.
  • granule particles are required to have a smooth and spherical shape with few irregularities and to have the same particle size as other mixed particles. That is, when a granule is filled into a capsule to form a capsule, or when the granule is tableted to produce a tablet, the granule is significantly powdered with other excipients, medicinal ingredients or biofunctional ingredients. If they are different from each other, uniform mixing becomes difficult and they are easily separated.
  • the different types of granules to be mixed are made into a smooth spherical shape with few irregularities, or the particle diameter is made uniform within a range of, for example, 200 ⁇ m or less.
  • Patent Document 1 Prior art documents other than the above-mentioned Patent Document 1 include Patent Documents 2 to 5 listed below.
  • the present invention has been made in view of the above circumstances, and a granule body is formed that can hold the shape well without collapsing even if the binder is a dilute solution with low gel strength.
  • An object of the present invention is to provide a granulated composition capable of satisfactorily producing a granulated product of uniform particles that are difficult to segregate by adhering coated particles.
  • the inventors of the present invention dropped droplets of a granulated solution containing a binder and a medicinal component or a biofunctional component onto a fluidized bed of coated particles to form a surface.
  • the droplets can be formed even when the binder has low gel strength.
  • a granulated body capable of holding a particulate form in a fluidized bed can be obtained, and a good granulated product with the coated particles attached thereto can be obtained, and the core particles constituting the granulated body and It is possible to obtain a desired granulated composition by containing a medicinal component or a biofunctional component in the binder, and more surprisingly, unevenness corresponding to the size of the coated particle due to the adhesion of the coated particle. Is formed on the surface of the granulated body Ri, found that segregation is less likely to occur. Thus, as a result of further investigation on the irregularities formed on the particle surface, it has been found that it is preferable to set the development area ratio Sdr of the interface to 100 to 700, and the present invention has been completed.
  • the present invention provides the following granulated composition.
  • a granulated product comprising a core particle, a coated particle, a binder that binds the core particles to each other and the core particle and the coated particle to maintain a granular shape, and is composed of the core particle and the binder.
  • the coated particles are attached to the periphery of the main body, the coated particles are insoluble in the binder, the medicinal component or the biofunctional component is contained in the core particles and / or the binder, and the interface
  • a granulated composition having a development area ratio Sdr of 100 to 700. 2.
  • the granulated composition according to 1, wherein the coated particles have an aspect ratio of 11 or less. 3.
  • the above-mentioned binder is a polymer substance solution or a polymer substance dispersion having a concentration such that the gel strength is so weak that it cannot hold a granular form by itself, or the concentration is so thin that the gel strength cannot be exhibited.
  • the granulation composition according to 2. 4). 4. The granulation composition according to any one of 1 to 3, comprising a particulate medicinal component or a biofunctional component as the core particle. 5. 4. The granulation composition according to any one of 1 to 3, wherein the medicinal component or biofunctional component is dissolved or dispersed in a hydrophobic liquid, and droplets of the hydrophobic liquid are dispersed in the binder. . 6).
  • Hydrophobic liquid is propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol monolaurate, propylene glycol monooleate, benzyl benzoate, octyldecyltriglyceride, oleic acid, triethyl citrate, dimethylpolysiloxane Cinnamaldehyde, medium chain mono / diglyceride, medium chain triglyceride, triacetin, piperonyl butoxide, diethyl phthalate, dibutyl phthalate, butyl phthalyl butyl glycolate, octyldodecyl myristate, ethyl butyrate
  • the granulation composition according to 5, wherein 7).
  • the granulated body is formed of a binder obtained by dissolving a polymer substance having no gelling action in a solvent other than water, and core particles composed of particles of a medicinal component or a biofunctional component insoluble in the solvent. 5.
  • the coated particles are ethyl cellulose, corn starch, rice starch, wheat starch, potato starch, calcium stearate, magnesium carbonate, sodium carboxymethyl starch having a low degree of substitution, sodium starch glycolate, anhydrous silicic acid, magnesium silicate, diatomaceous earth, bentonite.
  • the binder is gelatin, carrageenan, agar, polyethylene glycol, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, ammonioalkyl methacrylate copolymer, ethyl acrylate / methyl methacrylate copolymer, hyprome. 10.
  • Granule composition is gelatin, carrageenan, agar, polyethylene glycol, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, ammonioalkyl methacrylate copolymer,
  • the binder is a dilute solution with low gel strength, it is possible to stably obtain a uniform granulated product whose surface is covered with coated particles and hardly segregated.
  • productivity can be improved without requiring excessive performance in the spraying device or the discharging device for dropping the granulated solution onto the fluidized bed. Improvements can be made.
  • FIG. 6 is a micrograph showing wollastonite (trade name: KGP-H65) used as coated particles in Example 6, and the aspect ratio of the wollastonite was determined based on this photograph.
  • FIG. 3 is a micrograph showing crystalline cellulose (product name: KC Flock W-200G) used as coated particles in Comparative Example 1, and the aspect ratio of the crystalline cellulose was determined based on this photograph.
  • the granulated composition of the present invention has a form in which the coated particles adhere to the periphery of the granulated body composed of the core particles and the binder and have irregularities corresponding to the particle shape of the coated particles.
  • a medicinal component or a functional component is contained in the core particle and / or the binder forming the granule body.
  • the medicinal component or biofunctional component is not particularly limited as long as it can be dispersed or dissolved in a binder described later.
  • the medicinal ingredients include chlorpromazine, thioridazine, olanzapine, quetiapine, risperidone, haloperidol, perphenazine, aripiprazole, paliperidone, amoxapine, fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone, nefazodone, clipramine, petitipramine, Bromocriptine, pergolide, pramipexole, ropinirole, methylphenidate, atomoxetine, pregabalin, lacosamide, carbamazepine, clonazepam, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, valproic acid, divalproex sodium,
  • Biofunctional components are those that are absorbed into the living body and have a predetermined action on the living body, and are used for functional foods such as supplements.
  • coenzyme Q10 lutein, curcuminoids, silymarin , Astaxanthin, zeaxanthin, cryptoxanthin, fucoxanthin, lycopene, sesamin, ⁇ -lipoic acid, fat-soluble vitamins (vitamin A, vitamin D, vitamin E, vitamin K) and derivatives thereof, docosahexaenoic acid (DHA), eicosapentaenoic acid ( EPA), saw palmetto extract (oleic acid, lauric acid, myristic acid, linoleic acid, palmitic acid), St.
  • DHA docosahexaenoic acid
  • EPA eicosapentaenoic acid
  • saw palmetto extract oleic acid, lauric acid, myristic acid, linoleic acid, palmi
  • John's wort hypoicin
  • royal jelly decenoic acid
  • hesperidin nobiletin
  • quercetin kaempferol
  • myricitrin ca Kin
  • a medicinal component or a biofunctional component is not limited to these, Any thing can be used if it is applicable to the granulation composition of this invention.
  • coated particles are acceptable as long as they are acceptable to the living body, especially pharmaceutically or food hygienically acceptable, and insoluble in the binder, and are known as coated particles for pharmaceuticals and functional foods.
  • ethyl cellulose, corn starch, rice starch, wheat starch, potato starch, calcium stearate, magnesium carbonate, sodium carboxymethyl starch with a low degree of substitution, sodium starch glycolate, anhydrous silicic acid, magnesium silicate, diatomaceous earth, bentonite, zeolite examples thereof include silicon dioxide, agar powder, croscarmellose sodium, crospovidone, talc and the like, and one or more of these can be used in combination.
  • the water-absorbing property may be inferior and the water absorption may be insufficient.
  • the particle size is too small, the fluidized bed is likely to be scattered during the granulation operation.
  • the particle diameter of the coated particles may affect the Sdr value described later, and it is preferable to consider so that the Sdr value falls within the scope of the present invention.
  • the coated particles preferably have an angle of repose of 60 ° or less, particularly 50 ° or less, thereby improving the fluidity of the obtained granulated composition, Workability and productivity in the next step such as when tableting the granulated composition can be further improved.
  • the coated particles are not particularly limited, but the aspect ratio is preferably 11 or less, particularly 4 or less.
  • the aspect ratio of the coated particles exceeds 11, the Sdr value described later increases, Further, the obtained granulated composition tends to have a large variation in Sdr value, and the Sdr value of the present invention may not be stably achieved. This point will be described later.
  • the aspect ratio can be measured simply by suspending the coated particles uniformly in an inert fluid such as silicone oil, encapsulating them in a slide glass, taking images with a microscope, and selecting them randomly from the captured images. It can be easily obtained as the major axis / minor axis ratio in the microscopic image of the obtained particles.
  • the binder may be acceptable in terms of pharmacological or food hygiene, as long as it can retain the granular shape by binding the core particles to each other and the core particles and the coated particles.
  • Known binders used for granulation operations can be used. Specifically, for example, gelatin, carrageenan, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methacrylic acid copolymer, hypromellose phthalate, hypromellose acetate succinate, cellulose acetate phthalate, polyvinyl acetate phthalate, etc.
  • a material obtained by dissolving one or more of these polymer substances in a solvent such as water or ethanol can be used as the binder.
  • solvent other than water examples include acetic acid, acetone, t-butyl methyl ether, ethyl acetate, 2-propanol, methanol, ammonia, hexane, pyridine, dichloromethane and the like in addition to ethanol.
  • the core particles form a granulated body together with the binder, and become the core of the granulated body. Due to the presence of the core particles, the binder is dilute with low gel strength. Even if it exists, it can hold
  • the core particle if the medicinal component and / or biofunctional component can be present in the form of particles in the binder, the core particle can be used as the core particle.
  • the core particles may be blended separately from the medicinal component and the biofunctional component.
  • the core particles may be any one that is pharmaceutically or food hygienically acceptable, and the coated particles The thing similar to what was illustrated can be illustrated.
  • the granulated composition of the present invention is one in which a medicinal component or a biofunctional component is contained in the core particles and / or binder forming the granulated body.
  • the forms mainly include the three forms shown in FIGS. That is, in FIGS. 1 and 2, for example, the particulate medicinal component m is the core particle 1, and the coated particle 4 is attached around the granulated body 3 formed of this and the binder 2.
  • FIG. 1 uses a binder in which a high molecular substance having a gelling action such as gelatin is dissolved in a solvent such as water, and 1 is attached to the central portion of the binder 2 held in a grain shape.
  • FIG. 2 uses a binder 2 in which a high molecular weight material having no gelling action such as hydroxypropylmethylcellulose (HPMC) is dissolved in a solvent other than water such as ethanol.
  • HPMC hydroxypropylmethylcellulose
  • the agent 2 is not held in a granular form, but the binder 2 binds the core particles 1 (medicinal component m) to each other, and the binder 2 and the core particle 1 (medicinal component m) are granulated.
  • a main body 3 is formed, and a large number of the coated particles 4 adhere to the periphery of the granulated body 3.
  • FIG. 3 shows a case where a binder 2 in which a high molecular weight material having a gelling action such as gelatin is dissolved in a solvent such as water is used. And the medicinal component m is contained in the binder 2 forming the granulated body 3. In this case, the medicinal component m may be dispersed in the binder 2 as shown in FIG. 3 or may be dissolved in the binder 2.
  • the medicinal component and the biofunctional component are dispersed or dissolved in the droplet of the hydrophobic liquid, and the droplet h of the hydrophobic liquid is dispersed in the binder 2.
  • the hydrophobic liquid includes propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol monolaurate, propylene glycol monooleate, benzyl benzoate, octyldecyltriglyceride, oleic acid, citric acid
  • Examples include triethyl, dimethylpolysiloxane, cinnamaldehyde, medium chain mono / diglyceride, medium chain triglyceride, triacetin, piperonyl butoxide, diethyl phthalate, dibutyl phthalate, butyl phthalyl butyl glycolate, octyldodecyl my
  • the granulated composition of the present invention is one in which the coated particles 4 are densely attached around the granulated body 3 as shown in FIGS.
  • the coated particles 4 are insoluble in the binder 2 as described above, the surface does not dissolve and adheres to the granulated body 3 as it is.
  • a clear interface exists between the particles 4.
  • the coated particles 4 cover the surface of the granulated product body 3 without overlapping with no gap, and the width and depth of the gap between the coated particles depend on the shape and size of the coated particles. That is, the surface roughness of the granulated composition of the present invention is determined by the shape and size of the coated particles.
  • the method for evaluating the undulation, roughness, and small unevenness of the object surface is defined in the international standard “ISO 25178 surface properties (surface roughness measurement)”.
  • the “development area ratio Sdr of the interface” is the complete surface area when the unevenness recognized in a specific range (for example, 50 ⁇ m square) is spread and smoothly developed, and there is no unevenness in the range. The degree of increase compared to the smooth surface is expressed as a percentage (%).
  • the developed area ratio Sdr of the interface is obtained by using a white light interference microscope and irradiating the object with white light on the surface and moving the lens in the Z direction to obtain the undulation, roughness and smallness of the object surface. It is possible to obtain and measure the three-dimensional information of the unevenness.
  • the surface roughness of the granulated product has an influence on the slipperiness and entanglement of the surface, which causes segregation, there is a correlation between the degree of segregation and the developed area ratio Sdr of the interface. Further, since the surface roughness of the granulated product is determined by the shape and size of the coated particles, the ratio of the developed area Sdr between the appropriate coated particles and the interface in the granulated composition of the present invention. By selecting, segregation of the granulated product can be prevented more reliably.
  • the developed area ratio Sdr of this interface is set to 100 to 700, preferably 150 to 400. If the Sdr is too large, the granulated product main body and other additives are added. When mixing a form, a medicinal component, or a biofunctional component, segregation may occur due to too strong binding and entanglement between the granulated products, while if Sdr is too small, it is uniform in the mixing operation. As the particles cannot be maintained in a dispersed state, the particles slip and are easily segregated.
  • the development area ratio Sdr of the interface in the granulated composition of the present invention is greatly influenced by the size and shape of the coated particles, and the Sdr value is stabilized by adjusting the size and shape of the coated particles. Can be achieved. Specifically, the Sdr value can be easily achieved stably by adjusting the particle size and aspect ratio of the coated particles to the above ranges. In this case, the size of the coated particles as well as the shape of the coated particles greatly affect the Sdr value. For example, as in Comparative Example 1 described later, columnar or needle-shaped coated particles having an aspect ratio exceeding the above-described preferred range are used.
  • the Sdr value of the obtained granulated particles becomes large, but also the variation of the Sdr value becomes very large, and it is difficult to stably achieve the Sdr value.
  • the developed area ratio Sdr of the interface in the above range is achieved, and it is not limited to the size (particle diameter) or shape (aspect ratio) of the coated particles. .
  • the above-mentioned binder and the above-mentioned medicinal component or biofunctional component are added to water or other
  • the above-mentioned core particles are separately added as necessary to prepare a granulated solution, and the granulated solution is dropped into a fluidized bed in which the coated particles are fluidized.
  • a method of granulating in a granular form can be suitably employed by adhering the coated particles to the surface and allowing the coated particles to absorb water and other solvents.
  • the concentration of the polymer substance constituting the binder can be set low. Even in such a granulated solution having a low gelling agent (polymeric substance) concentration and low gel strength, the presence of the core particles causes the droplets to retain a particulate shape in the fluidized bed. It becomes a granulated product body to be obtained, and a good granulated product with the coated particles adhering to the periphery thereof can be obtained.
  • granulated composition of the present invention known additives can be appropriately blended within the range not departing from the object of the present invention.
  • sweeteners, colorants, preservatives can be used as necessary.
  • Thickeners, stabilizers, antioxidants, fragrances, acidulants, seasonings, pH adjusters, and the like can be blended in the granulated body.
  • Example 1 10 mg of butyl paraoxybenzoate was added to 40 g of purified water, and heated on a 95 ° C. water bath to dissolve butyl paraoxybenzoate. After cooling to room temperature, 5 g of gelatin was added and heated to 55-65 ° C. to obtain an aqueous gelatin solution (binder).
  • This granulation solution was a solution in which methotrexate was uniformly dispersed in an aqueous gelatin solution in which butyl paraoxybenzoate was completely dissolved.
  • the granulated solution is injected from the liquid quantity dispensing device toward the fluidized bed of corn starch powder under the above conditions, and the droplets of the granulated solution are put into the fluidized bed of coated particles made of the corn starch powder. did.
  • the corn starch powder as a coating agent was recovered and passed through a sieve having an opening of 91 ⁇ m to classify 49.7 g of granulated particles and 492 g of ungranulated corn starch.
  • This granulated particle is similar to the schematic diagram of FIG. 1 except that a plurality of methotrexate crystal core particles 1 (m) are placed outside the granulated body 3 in the center of the binder 2 grains.
  • the starch was powdered as coated particles 4. It was 11.3% when the water
  • the granulated particles were obtained by drying the granulated solution discharge droplets from about 80% to about 11% moisture in corn starch. It is inferred that corn starch having absorbed water up to about 11% by adsorbing water from the discharged droplets of the granulated solution adheres as coated particles, and these are composed of a mass ratio of approximately 1: 4. It was done.
  • the average particle size was d 50 of 343 ⁇ m, d 10 was 190 ⁇ m, d 90 was 452 ⁇ m, and the particle size was uniform. It was highly probable. Thus, even if the gelatin concentration of the binder is dilute and the gel strength is low, a uniform granulated composition can be obtained by using the medicinal component particles as core particles.
  • the expansion area ratio Sdr of the interface of the obtained granulated particle was measured by the following method, it was the first measurement: 350, the second measurement: 322, and the average value: 336.
  • Example 2 4 g of gelatin was added to 35 g of purified water and heated to 55 to 65 ° C. to obtain an aqueous gelatin solution (binder). On the other hand, 1 g of cyclosporine (medicinal ingredient) and 10 mg of butyl paraoxybenzoate were added to 3 g of triethyl citrate, and heated to 55 to 65 ° C. to dissolve cyclosporine and butyl paraoxybenzoate to obtain a medicinal ingredient solution.
  • This granulation solution is a dilute solution that cannot exhibit gel strength because the gelatin concentration is 8.5% at the maximum, and the droplets of triethyl citrate in which cyclosporine and butyl paraoxybenzoate are completely dissolved Corn starch particles (core particles) were uniformly dispersed in an aqueous gelatin solution (binder).
  • this granulated particle is a dried product (binder) of an aqueous gelatin solution in which corn starch is used as the core particle 1, and droplets of triethyl citrate containing cyclosporin (medicinal component) m are dispersed.
  • the corn starch (coated particles) 4 was powdered on the surface of the granulated body 3 composed of 2. An appearance photograph of the granulated particles is shown in FIG. As in Example 1, the granulated particles were presumed to be composed of a dried granulated solution and water-absorbed corn starch in a mass ratio of approximately 1: 4.
  • the average particle size was d 50 of 299 ⁇ m, d 10 of 159 ⁇ m, and d 90 of It was 379 ⁇ m, and the uniformity of the particle size was high.
  • the composition of the uniform particles can be obtained by using the corn starch particles as the core particles and containing the medicinal ingredients in the binder. You can get things.
  • a granulation solution was prepared in the same manner as in Example 2 except that triethyl citrate and cyclosporine were not blended and the blend amount of corn starch as a core particle was reduced to 1 g.
  • the average particle size was d 50 of 230 ⁇ m, d 10 of 166 ⁇ m, and d 90 of 294 ⁇ m, and the particle size was highly uniform. Further, the development area ratio Sdr at the interface of the obtained granulated particles was determined in the same manner as in Example 1. As a result, the first measurement was 268, the second measurement was 328, and the average value was 298.
  • the average particle size was d 50 of 248 ⁇ m, d 10 of 202 ⁇ m, and d 90 of 300 ⁇ m, and the particle size was highly uniform.
  • the developed area ratio Sdr at the interface of the obtained granulated particles was determined in the same manner as in Example 1, the first measurement was 186, the second measurement was 240, and the average value was 213.
  • Example 2 A granulation solution was obtained in the same manner as in Example 2 except that corn starch was not added as a core particle to the granulation solution. Since the gelatin concentration of this granulated solution was 9.3%, the solution was so dilute that it could not exhibit gel strength.
  • 40 g of this granulated solution was injected into a fluidized bed of corn starch powder in the same manner as in Example 2, the cornstarch powders in the fluidized bed began to bind to each other, and innumerable masses of about 1 cm in size having various shapes were formed. It was. This was inferred that the ejected droplets were indefinite because they had no substantial particle strength, and the fluidized corn starch powder was simply wetted and bound together.
  • the ejected droplets have a substantial particle strength and become a granulated main body capable of holding a granular shape. It is necessary to adhere insoluble powder that does not dissolve in gelatin aqueous solution as coated particles, and when a polymer solution that is so thin that it is difficult to show substantial particle strength is ejected as droplets, It was revealed that it was necessary to make insoluble particles exist as core particles.
  • HPC ethanol solution binder
  • the obtained granulated particles are composed of corn starch on the outer side of the granulated body 3 in which a plurality of methotrexate crystal core particles 1 (m) are bound by the binder 2.
  • the binder 2 was coated as coated particles 4.
  • the average particle size was d 50 of 176 ⁇ m, d 10 of 131 ⁇ m, and d 90 of 223 ⁇ m. It was highly probable. Thus, even when a high molecular substance (HPC) having no gelling action and a solvent (ethanol) other than water are used, core particles that are not soluble in the solvent (in this example, methotrexate particles that are medicinal components) are used. This confirmed that uniform coated particles could be obtained. Moreover, when the developed area ratio Sdr at the interface of the obtained granulated particles was determined in the same manner as in Example 1, the first measurement was 408, the second measurement was 334, and the average value was 371.
  • HPC high molecular substance having no gelling action and a solvent (ethanol) other than water
  • the granulated composition of the present invention whose surface is coated with a particulate coating agent and whose Sdr value is optimized is less likely to cause segregation or separation during mixing with different powders or storage. was confirmed.
  • the Sdr value of the granulated particles whose shape (aspect ratio) is obtained with the size of the coated particles has a relatively large effect, and when the aspect ratio of the coated particles increases, the Sdr value varies. Is observed to be large.
  • An orally disintegrating tablet having the composition shown in Table 3 was produced by the following method using the granulated particles obtained in the above Reference Example. About the obtained orally disintegrating tablet, sensory evaluation was conducted by five panelists on the touch when disintegrated in the oral cavity without taking water, and whether the granulated particles of the present invention cause an unpleasant rough feeling. Judged. In any panelist, the orally disintegrating tablet disintegrated in the oral cavity after about 50 to 65 seconds, and neither the middle nor the disintegration felt the feeling of hard particles or an unpleasant rough feeling in the oral cavity.

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020213589A1 (ja) * 2019-04-15 2020-10-22 三生医薬株式会社 錠剤及び錠剤の製造方法

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JPWO2025037595A1 (enExample) * 2023-08-14 2025-02-20

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07258072A (ja) * 1994-03-17 1995-10-09 Kyowa Yakuhin Kogyo Kk 徐放性細粒剤およびその製造方法
JP2003160474A (ja) * 2001-11-28 2003-06-03 Taisho Pharmaceut Co Ltd 難溶性薬物含有固形製剤の製造方法
JP2004137272A (ja) * 2002-09-26 2004-05-13 Sumitomo Pharmaceut Co Ltd 溶出性の良好なイソキサゾール誘導体経口製剤
WO2007135470A1 (en) * 2006-05-19 2007-11-29 EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság Process for the preparation and surface coating of pellets
JP2009107944A (ja) * 2007-10-26 2009-05-21 Takeda Chem Ind Ltd 医薬組成物
JP2012001460A (ja) * 2010-06-15 2012-01-05 Ohara Yakuhin Kogyo Kk 光過敏性薬物の安定化法

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63188621A (ja) 1987-01-30 1988-08-04 Taisho Pharmaceut Co Ltd 矯味経口製剤
JPH05309314A (ja) 1992-05-07 1993-11-22 Sumitomo Pharmaceut Co Ltd コーティング方法
JP2987813B2 (ja) 1993-07-12 1999-12-06 住友製薬株式会社 ワックス被覆製剤およびその製法
JP2000128774A (ja) * 1998-10-26 2000-05-09 Tanabe Seiyaku Co Ltd 薬物を含有する球形微粒子の製法
JP4974419B2 (ja) 2001-06-12 2012-07-11 東和薬品株式会社 薬物含有徐放性顆粒およびそれを含む錠剤
JP2003292437A (ja) 2002-01-31 2003-10-15 Sumitomo Chem Co Ltd 脂溶性ビタミン及び／またはカロチノイド含有粒状体の製造方法
JP2004250367A (ja) 2003-02-19 2004-09-09 Sumitomo Chem Co Ltd 親油性化合物を含有する粒子の製造方法および製造装置
JP4578124B2 (ja) 2003-03-12 2010-11-10 武田薬品工業株式会社 高濃度に活性成分を球形核に付着させた医薬組成物
JP4065902B2 (ja) * 2006-04-28 2008-03-26 ライオン株式会社 造粒粒子、錠剤、及び造粒粒子の製造方法
WO2009048073A1 (ja) 2007-10-09 2009-04-16 Takeda Pharmaceutical Company Limited 顆粒の被覆方法
JP2013011026A (ja) 2011-06-28 2013-01-17 Daicel Corp セルロースナノファイバーを主成分とする高強度材料及びその製造方法
JP6138635B2 (ja) 2013-08-30 2017-05-31 旭化成株式会社 セルロース系核粒子及びその製造方法
JP6700084B2 (ja) 2016-03-30 2020-05-27 株式会社ファンケル コーティング顆粒
JP2022188621A (ja) 2021-06-09 2022-12-21 パナソニックＩｐマネジメント株式会社 設定システム、蓄電制御システム、蓄電池システム、設定方法、及びプログラム

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07258072A (ja) * 1994-03-17 1995-10-09 Kyowa Yakuhin Kogyo Kk 徐放性細粒剤およびその製造方法
JP2003160474A (ja) * 2001-11-28 2003-06-03 Taisho Pharmaceut Co Ltd 難溶性薬物含有固形製剤の製造方法
JP2004137272A (ja) * 2002-09-26 2004-05-13 Sumitomo Pharmaceut Co Ltd 溶出性の良好なイソキサゾール誘導体経口製剤
WO2007135470A1 (en) * 2006-05-19 2007-11-29 EGIS GYÓGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság Process for the preparation and surface coating of pellets
JP2009107944A (ja) * 2007-10-26 2009-05-21 Takeda Chem Ind Ltd 医薬組成物
JP2012001460A (ja) * 2010-06-15 2012-01-05 Ohara Yakuhin Kogyo Kk 光過敏性薬物の安定化法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020213589A1 (ja) * 2019-04-15 2020-10-22 三生医薬株式会社 錠剤及び錠剤の製造方法
US12582606B2 (en) 2019-04-15 2026-03-24 Sunsho Pharmaceutical Co., Ltd. Tablet and method for producing tablet

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