Granulation composition, method for producing solid preparation, and granulation apparatus

Abstract

To produce, with high productivity, a granulation composition having core granules composed of a granulating liquid containing an active ingredient or a bioregulatory component or a dried product thereof, and an outer layer composed of multiple solid particles covering the outer surfaces of the core granules, wherein, preferably, the particle size of the granulation composition can be controlled.SOLUTION: A method for producing a granulation composition for a pharmaceutical or a health food, comprises a step for nozzle-spraying a granulating liquid containing an active ingredient or a bioregulatory component onto a group of solid particles comprising a plurality of solid particles accommodated in a fluidized bed and fluidized therein. Preferably, the spraying is performed by means of a two-fluid nozzle.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The present invention relates to a method for producing a granulated composition and a solid preparation, and a granulation device. [Background technology]

[0002] In the fields of pharmaceuticals and health foods, formulations containing "granulated compositions" containing active ingredients and other biofunctional ingredients are known. "Granulation" is the process of processing powdered raw materials consisting of single or multiple components into larger granules; "granulated compositions" refer to granular materials obtained by granulation.

[0003] There are various known granulation methods, typically including dry granulation and wet granulation. Briefly, dry granulation is a method in which powder, either as is or after pretreatment, is made into a particulate material (also called granules) by applying pressure; wet granulation is a method in which water or a solution containing a binder is dripped or sprayed onto a powder to moisten it, and the moisture is then dried to make a particulate material (granules).

[0004] One example of wet granulation is fluidized bed granulation, in which raw material powder particles are fluidized to form a layer (fluidized bed), and then a solution containing water or a binder is added dropwise or sprayed to grow the raw material powder particles into granules by agglomeration or coating. For example, Patent Document 1 describes a method for producing a solid formulation, characterized by blending part or all of a poorly soluble drug with a binder solution and performing fluidized bed granulation. Patent Document 2 describes the preparation of granules by spraying a suspension of an isoxazole derivative dispersed in an aqueous solution of a water-soluble binder onto a mixture of a water-soluble excipient and a disintegrant.

[0005] On the other hand, as a granulation technique completely different from these methods, there is known a technique of forming liquid particles consisting of a solution containing an active ingredient or other biofunctional ingredient to produce granules (granulated composition) containing the active ingredient or biofunctional ingredient (Patent Document 3); or a technique of producing granules (granulated composition) consisting of core particles consisting of a solution containing the active ingredient or other biofunctional ingredient and solid particles covering the core particles (Patent Document 4).Patent Document 5 discloses a granulation method for obtaining such granules, in which droplets of a liquid raw material for granulation containing the active ingredient or biofunctional ingredient are intermittently added, under certain conditions, to a fluidized bed consisting of a flowing particulate coating agent, thereby obtaining powder particles with a sharp particle size distribution.

[0006] It is also known that the granules obtained by this granulation method can be used as granules as they are, filled into capsule shells to make capsules, or mixed with other ingredients (ingredients other than granules) and compressed into tablets (Patent Document 6). [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Japanese Patent Application Laid-Open No. 2003-160474 [Patent Document 2] Japanese Patent Application Laid-Open No. 2004-137272 [Patent Document 3] Japanese Patent Application Laid-Open No. 2017-210415 [Patent Document 4] Japanese Patent Application Publication No. 2019-182856 [Patent Document 5] Japanese Patent Publication No. 2020-090460 [Patent Document 6] International Publication No. 2020 / 213589 Summary of the Invention [Problem to be solved by the invention]

[0008] However, as described in Patent Documents 3 to 5, methods of intermittently adding a granulation liquid dropwise to a fluidized bed containing solid particles have sometimes resulted in insufficient productivity of the granulation composition. That is, these methods have the problem of not being able to sufficiently increase the amount of granulation liquid added (amount supplied per unit time). If the amount of granulation liquid added is increased in order to increase the productivity of the granulation composition, it becomes difficult to control the particle size of the added droplets. As a result, it becomes difficult to control the particle size of the resulting granulation composition (particles), which can lead to problems such as increased variation in particle size.

[0009] For these reasons, there is a need for the development of a granulation method in which a granulation liquid is dropped into a fluidized bed containing solid particles, which is highly productive and allows easy control of particle size. [Means for solving the problem]

[0010] The first aspect of the present invention relates to, for example, a method for producing a granulated composition as shown below. [1] A method for producing a granulated composition for pharmaceuticals or health foods, comprising a step of spraying a granulation liquid containing an active ingredient or a biofunctional ingredient through a nozzle onto a group of solid particles containing a plurality of solid particles that are contained in a fluidized bed and flowing.

[0011] The present invention preferably relates to a method for producing a granulated composition as follows. [2] The manufacturing method according to [1] above, wherein the nozzle is a single-fluid nozzle or a multi-fluid nozzle. [3] The method according to [1] or [2] above, wherein the nozzle is a two-fluid nozzle, and the granulation liquid and the gas are supplied to the two-fluid nozzle. [4] The method according to [3] above, wherein the ratio of the liquid pressure of the granulation liquid to the air pressure of the gas supplied to the two-fluid nozzle (liquid pressure / air pressure) is 0.1 to 2.0. [5] The method according to any one of [1] to [4] above, wherein the spray rate (liquid rate) of the granulation liquid is 5 g / min or more. [6] The method according to any one of [1] to [5] above, wherein the granulation composition comprises a core particle made of the granulation liquid or a dried form thereof, and an outer layer made of the plurality of solid particles attached to the outer surface of the core particle. [7] The method according to any one of [1] to [6] above, wherein the granulation liquid contains a polymeric substance. [8] The method for producing a pharmaceutical composition according to any one of [1] to [7] above, wherein the active ingredient or biofunctional ingredient is a poorly water-soluble ingredient, an ingredient requiring masking, an ingredient requiring targeting, a peptide, a protein, or a nucleic acid.

[0012] The present invention also preferably relates to a method for producing a granulated composition having a specified particle size, as shown below. [9] The method according to any one of [1] to [8] above, wherein the particle size (D50) of the granulated composition is 1000 μm or less.

[10] The method according to any one of [1] to [9] above, wherein the particle size (D90) of the granulated composition is 1600 μm or less.

[11] The method according to [9] above, wherein the particle size (D50) of the granulated composition is 10 to 450 μm.

[12] The method according to

[10] above, wherein the particle size (D90) of the granulated composition is 50 to 850 μm.

[13] The method according to [9] above, wherein the particle size (D50) of the granulated composition is 400 to 1000 μm.

[14] The method according to

[10] above, wherein the particle size (D90) of the granulated composition is 700 to 1600 μm.

[15] The method according to any one of [1] to

[14] above, wherein the value determined by the following formula (1) is less than 1.60: (D90-D10) / D50 ···(1) [In formula (1), D90, D10, and D50 respectively represent the particle size (D90), particle size (D10), and particle size (D50) of the granulated composition.]

[0013] The second aspect of the present invention relates to a method for producing a solid formulation as follows.

[16] A method for producing a solid preparation, which comprises blending a granulated composition produced by the production method according to any one of the above [1] to

[15] .

[17] The method according to

[16] above, wherein the solid preparation is a tablet or a hard capsule.

[0014] The third aspect of the present invention relates to the following granulation apparatus.

[18] A granulation apparatus comprising: a spraying section having a nozzle for spraying a granulation liquid containing an active ingredient or a biofunctional ingredient; and a fluidized bed forming section arranged opposite the nozzle, containing a solid particle mass containing a plurality of solid particles, and fluidizing the solid particle mass; wherein the liquid particles of the granulation liquid sprayed by the spraying section are introduced into the solid particle mass contained in the fluidized bed forming section, adhere to the plurality of solid particles, and solidify.

[19] The granulation device described in

[18] , wherein the nozzle is a two-fluid nozzle that sprays the granulation liquid and the gas, and the ratio of "liquid pressure of the granulation liquid / air pressure of the gas" can be adjusted within the range of 0.1 to 2.0.

[20] The granulation device according to

[18] or

[19] , wherein the nozzle is capable of spraying the granulation liquid at a rate of 5 g / min or more.

[21] The granulating apparatus according to any one of

[18] to

[20] , wherein the inner diameter of the nozzle is in the range of 0.1 to 1.0 mm.

[22] The granulation apparatus according to any one of

[18] to

[21] , wherein the fluidized bed forming unit fluidizes the solid particle mass by centrifugal force generated by the rotation of the fluidized bed itself, or by agitating blades disposed within the fluidized bed. [Effects of the Invention]

[0015] According to the production method of the present invention, it is possible to produce a granulated composition consisting of a granular material containing a core particle and an outer layer consisting of a plurality of solid particles that covers the core particle; the productivity of the granulated composition can be increased, and the particle size of the granulated composition can be easily controlled. [Brief explanation of the drawings]

[0016] [Figure 1]1 is a diagram schematically showing a cross section of a granulated composition produced by the production method of the present invention. [Figure 2] FIG. 1 is a flow diagram showing a manufacturing method of the present invention. [Figure 3] FIG. 1 is a diagram showing an embodiment of a granulation apparatus of the present invention. [Figure 4A] FIG. 2 shows an embodiment of a fluidized bed forming section. [Figure 4B] FIG. 2 shows an embodiment of a fluidized bed forming section. [Figure 5] FIG. 10 is a diagram showing another embodiment of the granulation apparatus of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0017] [1. Granulated composition] One aspect of the present invention relates to a method for producing a granulated composition. A granulated composition 100 produced by the production method of the present invention has 1) a core particle 10 and 2) an outer layer 20 consisting of a plurality of solid particles 21 that covers the outer periphery of the core particle 10, as shown in a cross section schematically in Fig. 1. The outer layer 20 is formed when the plurality of solid particles 21 adhere to the surface of the core particle 10 to form a layer. The outer layer 20 may completely cover the core particle 10, or may cover only a portion of the core particle 10. In a form in which only a portion of the core particle 10 is covered, the portion of the core particle 10 that is not covered by the outer layer 20 will be exposed and form the granulated composition.

[0018] [1-1.Nuclear particle] The core particles in the granulation composition consist of liquid particles of the granulation liquid in the manufacturing method described below, or a dried product thereof. The core particles may be a dried product of liquid particles of the granulation liquid, and therefore may be porous (they become porous when the solvent of the granulation liquid dries). The core particles contain an active ingredient or a biofunctional ingredient as a pharmaceutical composition or health food composition. The active ingredient or biofunctional ingredient contained in the core particles is an ingredient that exerts a biological function as a pharmaceutical or health food. Furthermore, the core particles preferably contain a polymeric substance that functions as an excipient, etc., and may further contain other ingredients as necessary.

[0019] [1-1-1. Active ingredients or biofunctional ingredients] The active ingredient or biofunctional ingredient may be a poorly water-soluble ingredient. These ingredients are often poorly absorbed by the body and generally have low bioavailability. In the granulated composition of the present invention, the core particles can be blended with an ingredient that enhances the absorbability of the active ingredient or biofunctional ingredient, thereby improving the absorbability of the active ingredient or biofunctional ingredient in the body.

[0020] "Poorly water-soluble ingredient" means a drug that is classified as slightly soluble, slightly soluble, slightly soluble, slightly soluble, very slightly soluble, or almost insoluble, among those classified as extremely soluble, soluble, slightly soluble, very slightly soluble, or almost insoluble in the solubility terms used in the 17th edition of the Japanese Pharmacopoeia. Specifically, it may be an ingredient with a solubility in water of 1 mg / mL or less.

[0021] Specific examples of poorly water-soluble components (poorly water-soluble drugs) include clarithromycin, ritonavir, cyclosporine, nifedipine, paclitaxel, phenytoin, carbamazepine, diazepam, clonazepam, indomethacin, ibuprofen, farnersil, cilostazol, itraconazole, rusartan, simvastatin, lansoprazole, olanzapine, omeprazole, furosemide, and fat-soluble vitamins (vitamin A, vitamin D, vitamin E, vitamin K).

[0022] The active ingredient or biofunctional ingredient may be a bitter ingredient. It may be preferable to mask the bitter ingredient (also referred to as bitterness masking) so that a subject who orally ingests it does not easily perceive its taste. The core particles of the granulated composition of the present invention can be formulated with a release-controlling agent having a masking function, along with the active ingredient or biofunctional ingredient. This can reduce the bitterness of the active ingredient or biofunctional ingredient. Furthermore, since the core particles of the present invention are covered with an outer layer consisting of multiple particles, even if the core particles contain a bitter ingredient, a subject who receives them is less likely to perceive the bitterness.

[0023] A bitter ingredient refers to a drug that tastes bitter after approximately 10 mg of the active ingredient is taken orally and spat out. For example, the 14th Revised Japanese Pharmacopoeia describes drugs as having an "extremely bitter taste," "bitter taste," "initial bitter taste," "gradually becoming bitter taste," "slightly bitter taste," "slightly bitter taste," "acrid taste," "tongue-burning taste," or "extremely astringent taste." Specific examples of bitter ingredients include azithromycin, fluvoxamine, rabeprazole, clarithromycin, amoxicillin, oseltamivir, rebamipide, acetaminophen, atenolol, atorvastatin, and ritonavir.

[0024] The active ingredient or biofunctional ingredient may be an ingredient to be absorbed at a specific site (particularly, absorbing a drug at a specific site is also referred to as targeting), particularly an ingredient to be absorbed in the intestine. An example of an ingredient to be absorbed in the intestine is an ingredient that is easily decomposed by acid. If an acid-decomposable ingredient is attempted to be absorbed in the stomach, it will decompose in the acidic environment inside the stomach, preventing the active ingredient or biofunctional ingredient from fully exerting its function. The core particles in the granulated composition of the present invention can be formulated with an enteric ingredient (e.g., an enteric polymer) that does not dissolve under acidic conditions, along with the active ingredient or biofunctional ingredient, so that the active ingredient or biofunctional ingredient can be released and absorbed in the intestine.

[0025] The component to be absorbed in the intestine is not particularly limited, but is preferably one that exerts a therapeutic effect by being absorbed or acting in the small intestine or large intestine. Specific examples of components to be absorbed in the intestine include mesalazine, salazosulfapyridine, prednisolone, azathioprine, tacrolimus, budesonide, 5-aminosalicylic acid, ustekinumab, sulfasalazine, anti-TNF antibodies (adalimumab, golimumab, infliximab, certolizumab pegol), betamethasone, betamethasone phosphate sodium, betamethasone phosphate, azathioprine, 6-mercaptopurine, cyclosporine, natalizumab, dexamethasone, and beclomethasone dipropionate.

[0026] The active ingredient or biofunctional ingredient may be unstable in the digestive environment, such as gastric juice, endogenous enzymes, or water, or may be difficult to absorb into the body from the digestive tract. Examples of such ingredients include peptides, proteins, nucleic acids, etc., which have traditionally been administered parenterally. The core particles of the granulated composition of the present invention can be formulated with a release-controlling agent that protects the active ingredient or biofunctional ingredient from gastric juice, etc., or with an absorption enhancer. This can increase the stability of the active ingredient or biofunctional ingredient in the digestive system and enhance its absorption into the body from the digestive tract. As a result, pharmaceutical compositions and health food compositions containing the granulated composition of the present invention can be administered or ingested orally.

[0027] Specific examples of such active ingredients or biofunctional ingredients include insulin, calcitonin, angiotensin, vasopressin, desmopressin, LH-RH (luteinizing hormone-releasing hormone), somatostatin, glucagon, oxytocin, gastrin, cyclosporine, somatomedin, secretin, h-ANP (human atrial natriuretic peptide), ACTH (adrenocorticotropic hormone), MSH (melanophore-stimulating hormone), β-endorphin, muramyl dipeptide, enkephalin, neurotensin, bombesin, VI Examples of such inhibitors include vasoactive intestinal peptide (P), CCK-8 (cholecystokinin-8), PTH (parathyroid hormone), CGRP (calcitonin gene-related peptide), TRH (thyrotropin-releasing hormone), endothelin, hGH (human growth hormone), cytokines such as interleukins, interferons, colony-stimulating factors, and tumor necrosis factors, GLP-1 receptor agonists (semaglutide), cyanocobalamin, Rho kinase inhibitors, endothelin A receptor inhibitors, transmembrane conductance regulator (CFTR) modulators, TRPV1 inhibitors, NK1 receptor inhibitors, purinergic receptor inhibitors, angiotensin receptor inhibitors, peroxisome proliferator-activated receptors, P2Y receptor inhibitors, and VEGF inhibitors.

[0028] [1-1-2. Other components of the nuclear particle] The components constituting the core particles of the granulation composition other than the active ingredient or biofunctional ingredient will be described in detail in [2-1. Granulation liquid] below.

[0029] [1-2.Outer layer] The outer layer of the granulated composition is composed of a plurality of solid particles that cover the outer periphery of the core particle. The outer layer may cover the entire outer periphery of the core particle, or may cover only a part of the outer periphery.

[0030] The outer layer made of solid particles can increase the physical strength of the granulated composition, for example, contributing to maintaining the particle shape of the granulated composition. In addition, by masking the core particles, it is possible to suppress the taste and flavor of the components contained in the core particles.

[0031] The solid particles constituting the outer layer are not particularly limited, but are usually water-insoluble or hydrophobic particles, and are preferably particles that are insoluble or difficult to dissolve in the granulation liquid described below. Specific examples of solid particles include divalent or higher metal salts, inorganic substances, polysaccharides or derivatives thereof, and organic polymers.

[0032] Specific examples of the divalent or higher metal salts include calcium chloride, calcium carbonate, calcium oxide, calcium sulfate, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium stearate, magnesium chloride, magnesium carbonate, magnesium oxide, magnesium silicate, aluminum chloride, aluminum hydroxide, aluminum phosphate, aluminum sulfate, aluminum silicate, potassium alum, iron chloride alum, ammonium alum, ferric sulfate, iron citrate, zinc oxide, zinc sulfate, and hydrates thereof.

[0033] Specific examples of the inorganic substances include silicic anhydride, silicon dioxide, titanium oxide, kaolin, diatomaceous earth, bentonite, zeolite, and talc.

[0034] Specific examples of the polysaccharides or derivatives thereof include corn starch, rice starch, wheat starch, potato starch, powdered agar, crystalline cellulose, ethyl cellulose, croscarmellose sodium, low-substituted sodium carboxymethyl starch, sodium starch glycolate, and the like.

[0035] Specific examples of the organic polymer include crospovidone, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer S, ammonioalkyl methacrylate copolymer, and the like.

[0036] Of these, the solid particles constituting the outer layer preferably contain at least one selected from the group consisting of bentonite, ethyl cellulose, corn starch, rice starch, wheat starch, potato starch, calcium stearate, magnesium carbonate, low-substituted sodium carboxymethyl starch, sodium starch glycolate, silicic anhydride, magnesium silicate, diatomaceous earth, zeolite, silicon dioxide, powdered agar, croscarmellose sodium, crospovidone, and talc, more preferably bentonite and / or corn starch, and even more preferably corn starch. The above-mentioned solid particles may be used alone or in combination of two or more.

[0037] The average particle size of the solid particles is preferably 1 μm or more, more preferably 2 μm or more, and even more preferably 3 μm or more; on the other hand, it is preferably 100 μm or less, more preferably 50 μm or less, and even more preferably 30 μm or less. An average particle size of 1 μm or more is preferable because it can increase the fluidity of the solid particles. On the other hand, an average particle size of 100 μm or less is preferable because it reduces the surface area and can increase the bonding strength between the solid particles and the core particles.

[0038] The upper limit of the solid particle content is preferably 85% by mass or less, more preferably 80% by mass or less, even more preferably 75% by mass or less, and particularly preferably 70% by mass or less, relative to the total mass of the granulated composition. On the other hand, the lower limit of the solid particle content is preferably 10% by mass or more, more preferably 15% by mass or more, and even more preferably 20% by mass or more, relative to the total mass of the granulated composition. A solid particle content of 85% by mass or less relative to the total mass of the granulated composition is preferred because it can improve the shape stability of the granulated composition.

[0039] [1-3. Shape of granulated composition] The granulated composition produced by the production method of the present invention is preferably in the form of particles. The particulate form may be spherical, blocky, plate-like, needle-like, or the like, but is preferably spherical.

[0040] The particle size of the granulated composition is set appropriately depending on its application, but the number-based D50 (median diameter) is preferably 1000 μm or less, and the number-based D90 is preferably 1600 μm or less. When the particle size is below a certain level, the composition is more likely to exhibit its functions (such as bioabsorbability and bioavailability) as a pharmaceutical composition or health food composition. The particle size of the granulated composition can be measured by dry or wet dispersion of the granulated composition and laser diffraction / scattering.

[0041] It is sometimes preferable that the particle size distribution of a granulated composition is relatively sharp. A granulated composition with a sharp particle size distribution can prevent segregation when mixed with other ingredients, resulting in a mixture with excellent mixing uniformity, and can also suppress variation in functionality when used as a pharmaceutical composition or health food composition. For example, the value obtained by dividing the difference between the number-based particle diameters D90 and D10 by D50 (median diameter), as shown in the following formula (1), is preferably equal to or less than a certain value, specifically, preferably less than 1.60, more preferably less than 1.55, and even more preferably less than 1.50. (D90-D10) / D50 ···(1)

[0042] The particle size of the granulated composition can be appropriately set for its formulation. For example, when the granulated composition is filled into a hard capsule shell to form a capsule formulation, the particle size D50 of the granulated composition is preferably 400 μm or more, more preferably 450 μm or more, and even more preferably 500 μm or more; on the other hand, the particle size D50 is preferably 1000 μm or less, more preferably 950 μm or less, and even more preferably 900 μm or less. When forming a capsule formulation, the particle size D90 of the granulated composition is preferably 700 μm or more, more preferably 750 μm or more, and even more preferably 800 μm or more; on the other hand, it is preferably 1600 μm or less, more preferably 1500 μm or less, and even more preferably 1400 μm or less. By setting the particle size of the granulated composition to be used in a capsule formulation within this range, loss is less likely to occur when filling the capsule.

[0043] Furthermore, when the granulation composition is mixed with other ingredients and the mixture is compressed to form tablets, the particle size D50 of the granulation composition is preferably 10 μm or more, more preferably 25 μm or more, and even more preferably 50 μm or more; on the other hand, it is preferably 450 μm or less, more preferably 400 μm or less, and even more preferably 350 μm or less. When forming tablets, the particle size D90 of the granulation composition is preferably 50 μm or more, more preferably 75 μm or more, and even more preferably 100 μm or more; on the other hand, it is preferably 850 μm or less, more preferably 750 μm or less, and even more preferably 650 μm or less. By setting the particle size of the granulation composition to be formed into tablets within these ranges, tablets with high hardness can be obtained.

[0044] [2. Manufacturing method of granulated composition] The method for producing a granulated composition of the present invention comprises a step of spraying a granulation liquid through a nozzle onto a mass of solid particles containing a plurality of solid particles contained in a fluidized bed and flowing. The method for producing a granulated composition of the present invention can produce a granulated composition consisting of a granule containing a core particle and an outer layer of a plurality of solid particles covering the core particle. Here, the core particle is composed of a granulation liquid or a dried product thereof. Furthermore, the method for producing a granulated composition of the present invention can typically comprise the steps of: (S1) preparing a granulation liquid; (S2) placing solid particles in a fluidized bed; (S3) granulating; (S4) sieving; and (S5) formulating, as shown in FIG. 2.

[0045] [2-1. Granulation liquid] The granulation liquid contains at least an active ingredient or a biofunctional ingredient, and preferably also contains a polymeric substance. The granulation liquid may further contain other optional ingredients. The viscosity of the granulation liquid is sufficient as long as it can be sprayed through a nozzle.

[0046] [2-1-1. Active ingredients or biofunctional ingredients] The active ingredient or biofunctional ingredient contained in the granulation liquid is an ingredient that exhibits the function of a pharmaceutical or health food. Specifically, it is an ingredient described in the above section [1-1. Core particles], and may be a poorly water-soluble ingredient or an ingredient that is difficult to dissolve, an ingredient that has a bitter taste, an ingredient that is desired to be absorbed in the intestine, or an ingredient that generally has low bioavailability even when administered orally, for example, an ingredient that has poor membrane permeability.

[0047] In the granulation liquid, the active ingredient or biofunctional ingredient may be dissolved or uniformly dispersed.

[0048] [2-1-2. Polymer substances] The granulation liquid preferably contains a polymeric substance. The polymeric substance can increase the viscosity of the granulation liquid. The polymeric substance is also a component that can serve as a base or excipient for the core particles in the resulting granulation composition. The polymeric substance contained in the granulation liquid may be a component that causes the granulation liquid to undergo a sol-gel transition. For example, the polymeric substance may be blended so that the granulation liquid becomes a sol when heated and becomes a gel at room temperature. The granulation liquid that undergoes a sol-gel transition is sprayed from a nozzle in a heated state. The polymeric substance contained in the granulation liquid may be a water-soluble polymer, a hydrophilic polymer, an enteric polymer, or the like.

[0049] Specific examples of polymeric substances include gelatin, carrageenan, agar, polyethylene glycol (PEG), methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, ammonioalkyl methacrylate copolymer, ethyl acrylate-methyl methacrylate copolymer, hypromellose phthalate, hypromellose acetate succinate, cellulose acetate phthalate, polyvinyl acetate phthalate, etc.

[0050] In the granulating liquid, the polymeric substance may be dissolved or uniformly dispersed.

[0051] [2-1-3. Other ingredients] Other components contained in the granulation liquid include A) solubilizers, B) release-controlling agents, C) absorption enhancers, D) solvents, etc., and E) other additives. These are appropriately selected and blended depending on the functions required of the granulation composition and its intended use.

[0052] [2-1-3A. Solubilizers] The solubilizer contained in the granulation liquid has the function of improving the solubility of the active ingredient or biofunctional ingredient. In a preferred embodiment, the solubilizer is used in combination with a poorly water-soluble ingredient in the granulation liquid. Examples of solubilizers include polyethylene glycol derivatives such as polyoxyethylene (POE) lauryl ether, POE(50) hydrogenated castor oil, POE(60) hydrogenated castor oil, POE(80) hydrogenated castor oil, and POE(20) cetyl ether; and higher fatty acid esters such as glyceryl monostearate, sorbitan tristearate, glycerol monodibehenate, and diglyceryl monostearate. In this specification, the term "higher fatty acid" refers to a fatty acid having 6 or more carbon atoms, preferably a fatty acid having 8 to 30 carbon atoms, more preferably a fatty acid having 11 to 24 carbon atoms, and particularly preferably a fatty acid having 14 to 22 carbon atoms.

[0053] [2-1-3B. Controlled release agents] The release-controlling agent contained in the granulation liquid may have functions such as masking the bitterness of the active ingredient, masking the odor of the active ingredient, imparting enteric properties, and imparting sustained release. In a preferred embodiment, the release-controlling agent is used in combination with a bitter ingredient, an ingredient that exhibits a therapeutic effect by absorption or action in the small intestine or large intestine, an ingredient that is decomposed by gastric acid, or an ingredient that is decomposed by enzymes secreted from the digestive tract. Such release-controlling agents are typically used by coating the active ingredient (see, for example, JP 2015-40206 A). However, according to the method for producing a granulation composition of the present invention, the release-controlling agent can be blended with the active ingredient in the granulation liquid, eliminating the need to coat the active ingredient with the release-controlling agent. In this specification, "enteric" refers to small intestinal enteric coating and / or large intestinal enteric coating.

[0054] Examples of controlled-release agents include gastric-soluble controlled-release agents and enteric-soluble controlled-release agents. The gastric-soluble controlled-release agents dissolve in the stomach without dissolving in the oral cavity or esophagus, thereby preventing the active ingredient from dissolving from the tablet in the oral cavity or esophagus. This masks the bitterness, odor, etc. of the active ingredient. Examples of gastric-soluble controlled-release agents include, but are not limited to, aminoalkyl methacrylate copolymer, polyvinyl acetal diethylaminoacetate, acetate monoglyceride, citrate monoglyceride, succinate monoglyceride, diacetyltartarate monoglyceride, and lactate monoglyceride.

[0055] Enteric-coated controlled-release agents do not dissolve in the oral cavity, esophagus, or stomach, but dissolve in the small intestine and / or large intestine, thereby preventing the dissolution of the active ingredient from the tablet in the oral cavity, esophagus, and stomach. This inhibits the degradation of the active ingredient in the oral cavity, esophagus, and stomach, preventing the occurrence of side effects due to the degradation products. Examples of enteric-coated controlled-release agents include small-intestinal enteric-coated controlled-release agents and large-intestinal enteric-coated controlled-release agents. Examples of small-intestinal enteric-coated controlled-release agents include, but are not limited to, methacrylic acid copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinyl acetate phthalate, cellulose acetate phthalate (ceracephate), ethyl acrylate-methyl methacrylate copolymer, carboxymethylethylcellulose (CMEC), cellulose acetate phthalate (CAP), polyvinyl alcohol phthalate (PVAP), and carrageenan. Examples of enteric release-controlling agents for the large intestine include chitosan, chitin, cellulose, hemicellulose, lignin, pullulan, and sodium alginate.

[0056] [2-1-3C. Absorption enhancers] The absorption enhancer contained in the granulation liquid has the function of acting on cell membranes, intercellular spaces, etc. in the small intestine, etc. to promote absorption of the active ingredient, or the function of acting on cell membranes to promote mucosal permeability of the active ingredient. In a preferred embodiment, the absorption enhancer is used in combination with an active ingredient that is poorly absorbed by the body (low bioavailability), such as a polymeric active ingredient such as a peptide, protein, or nucleic acid. Generally, absorption enhancers can reduce the hardness or disintegration properties of formulations (e.g., tablets) containing them; however, a granulation composition produced by incorporating an absorption enhancer into the granulation liquid can prevent such effects.

[0057] Examples of absorption enhancers include, but are not limited to, at least one selected from the group consisting of sodium caprate, sodium caprylate, SNAC (salcaprozate sodium, see structural formula below), cell membrane-permeable peptides, C-CPE, Angubindin-1, polyoxyethylene alkyl ethers, sodium lauryl sulfate, saponin, chitosan, cyclodextrin, alkyl saccharides, sucrose fatty acid esters, N-acyl amino acids, N-acyltaurine, glycocholic acid, taurocholic acid, deoxycholic acid, ethylenediaminetetraacetic acid (EDTA), sodium salicylate, sodium laurate, tryptophan, and arginine. [ka]

[0058] "C-CPE" includes the C-terminal fragment of Clostridium perfringens enterotoxin and its mutants, such as C-CPE184-319, C-CPE194-319, and C-CPE Y306W / S313H. "Angubindin-1" is the amino acid region from positions 421 to 644 of the Ib component, one of the two proteins (Ia component and Ib component) that make up the iota toxin produced by Clostridium perfringens.

[0059] Examples of polyoxyethylene alkyl ethers include polyoxyethylene capryl ether, polyoxyethylene lauryl ether, polyoxyethylene myristyl ether, and polyoxyethylene stearyl ether.

[0060] Examples of alkyl saccharides include β-octylglucoside, β-decylglucoside, β-decylgalactoside, β-octylmannoside, β-dodecylmaltoside, β-dodecylisomaltoside, β-dodecylmaltotrioside, β-stearylglucoside, β-stearylgalactoside, β-stearylmannoside, β-stearylmaltoside, β-stearylisomaltoside, decyloligoglucoside, and dodecyloligoglucoside.

[0061] Examples of N-acyl amino acids include amino acids N-acylated with fatty acids having 8 to 30 carbon atoms. The amino acids are not particularly limited, but are preferably glutamic acid, aspartic acid, glycine, or alanine. The fatty acids are not particularly limited, but are preferably caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, or stearic acid, and more preferably lauric acid.

[0062] Examples of sucrose fatty acid esters include those in which the hydroxyl group of sucrose is esterified with a fatty acid having 8 to 30 carbon atoms. The fatty acid is not particularly limited, but is preferably caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, or stearic acid, and more preferably lauric acid. The sucrose fatty acid may be a monoester, diester, triester, tetraester, or a mixture thereof. The hydrophilic-lipophilic balance (HLB) of the sucrose fatty acid ester is preferably 1 to 18, more preferably 3 to 15.

[0063] Preferred absorption enhancers include at least one selected from the group consisting of sodium caprate, sodium caprylate, SNAC, cell membrane-permeable peptide, C-CPE, and Angubindin-1, and even more preferably sodium caprate and / or SNAC.

[0064] [2-1-3D. Solvent] The granulation liquid may contain a solvent, which may be water and / or an organic solvent. The solvent can adjust the dispersibility of the active ingredient or biofunctional ingredient in the granulation liquid. The solvent also has the function of adjusting the hardness of the core particles in the resulting granulation composition. Note that the solvent contained in the granulation liquid may be partially or completely removed (dried) in the granulation composition.

[0065] The organic solvent is not particularly limited, but examples thereof include glycerin, propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol monolaurate, propylene glycol monooleate, benzyl benzoate, octyldecyl triglyceride, oleic acid, triethyl citrate, dimethylpolysiloxane, cinnamaldehyde, medium-chain mono- and diglycerides, medium-chain fatty acid triglycerides, triacetin, piperonyl butoxide, diethyl phthalate, dibutyl phthalate, butylphthalyl butyl glycolate, octyldodecyl myristate, ethyl butyrate, ethanol, and isopropanol.

[0066] [2-1-3E. Other additives] The core particles may further contain other additives. Examples of the additives include a pH adjuster and an antioxidant. These additives may be used alone or in combination of two or more.

[0067] [2-2. Spraying of granulation liquid] The granulation liquid is supplied (or dropped) onto a mass of solid particles containing a plurality of solid particles contained in a fluidized bed by spraying through a nozzle (hereinafter referred to as nozzle spraying). The granulation liquid sprayed through a nozzle may be heated. For example, a highly viscous granulation liquid can be heated and sprayed in a low-viscosity state, or a granulation liquid that undergoes a sol-gel transition depending on the temperature can be heated and sprayed as a sol. The granulation liquid sprayed through a nozzle is preferably in a particle form. Examples of nozzles for spraying include single-fluid nozzles and multi-fluid nozzles. However, multi-fluid nozzles are preferred, and two-fluid nozzles are particularly preferred, as they allow for easy control of the particle size of the resulting granulated composition. The granulation liquid can also be sprayed using a rotary atomizer, but spraying using a rotary atomizer may be undesirable because the granulation liquid may be unintentionally heated.

[0068] In spraying with a two-fluid nozzle, two fluids, a liquid and a pressurized gas (usually, but not limited to, compressed air), are mixed and sprayed. In other words, the liquid and pressurized gas are supplied to the nozzle, and the high-speed gas flow is used to atomize the liquid and spray it. In spraying with a two-fluid nozzle, the mixing of the liquid and gas can be broadly categorized as internal mixing and external mixing. The internal mixing type is a method in which the pressurized gas and liquid are mixed inside the nozzle to form particles. The internal mixing type can be further broadly categorized as internal gas type, external gas type, and premix type. The internal gas type is a type in which the gas and liquid are mixed by flowing pressurized gas in the center and liquid on the periphery inside the nozzle. The external gas type is a type in which the gas and liquid are mixed by flowing liquid in the center and gas on the periphery inside the nozzle. The premix type is a type in which the liquid and gas are mixed inside the nozzle before the nozzle orifice. The external air mixing type refers to a type in which the liquid and the gas are mixed outside the nozzle (outside the nozzle opening). When the granulation liquid of the present invention is sprayed through a two-fluid nozzle, the method of mixing the granulation liquid and the pressurized gas is not particularly limited.

[0069] Liquid supply methods for spraying using a two-fluid nozzle can be broadly divided into a liquid pressurization method and a suction method. The liquid pressurization method is a method in which a pressurized liquid is supplied into the nozzle, while the suction method is a method in which a liquid at normal pressure is sucked up by the force of pressurized gas. When the granulation liquid of the present invention is sprayed using a two-fluid nozzle, it is preferable to adopt a liquid pressurization method in which a pressurized granulation liquid is supplied into the nozzle. The liquid pressurization method makes it easy to control the particle size of the sprayed liquid particles, and as a result, it is easy to control the particle size of the obtained granulation composition. Furthermore, the liquid pressurization method makes it easy to increase the amount of liquid that can be sprayed (amount sprayed per unit time), and as a result, the productivity of the granulation composition can be improved.

[0070] The liquid pressure of the granulation liquid supplied to the two-fluid nozzle is preferably 0.12 MPa or more, more preferably 0.15 MPa or more; on the other hand, it is preferably 0.6 MPa or less, more preferably 0.5 MPa or less.

[0071] When a granulation liquid is sprayed using a two-fluid nozzle, the particle size of the granulation composition can be controlled by adjusting the ratio (liquid pressure / air pressure) between the liquid pressure of the granulation liquid supplied to the two-fluid nozzle and the air pressure of the gas. Increasing this ratio (liquid pressure / air pressure) tends to increase the size of the sprayed liquid particles (and, as a result, the particle size of the granulation composition also tends to increase); on the other hand, decreasing this ratio (liquid pressure / air pressure) tends to decrease the size of the sprayed liquid particles (and, as a result, the particle size of the granulation composition also tends to decrease).

[0072] When the granulation liquid is sprayed using a two-fluid nozzle, the lower limit of the ratio (liquid pressure / air pressure) is preferably 0.1, more preferably 0.3, and particularly preferably 0.5, while the upper limit of the ratio (liquid pressure / air pressure) is preferably 2.0, more preferably 1.8, and particularly preferably 1.7. By setting the ratio (liquid pressure / air pressure) within this range, a granulated composition having a particle size suitable for pharmaceuticals or health foods can be produced with high productivity.

[0073] When producing a granulation composition for tablets, the lower limit of the liquid pressure / atmospheric pressure is preferably set in the same manner as above, and the upper limit of the liquid pressure / atmospheric pressure is preferably 1.4, more preferably 1.3, and particularly preferably 1.2. On the other hand, when producing a granulation composition for capsules, the upper limit of the liquid pressure / atmospheric pressure is preferably set in the same manner as above, and the lower limit of the liquid pressure / atmospheric pressure is preferably 1.1, more preferably 1.2, and particularly preferably 1.3.

[0074] When the granulation liquid is sprayed using a two-fluid nozzle, the nozzle diameter (inner diameter of the nozzle opening) is not particularly limited, but is preferably 0.1 to 1.0 mm, more preferably 0.2 to 0.8 mm.

[0075] The spray pattern of the nozzle (preferably a two-fluid nozzle) is not particularly limited. The spray pattern refers to the cross-sectional shape of the spray, and the flow rate distribution (distribution state of the spray amount) is controlled by the spray pattern. Nozzle spray patterns can generally be classified into an open cone type, a full cone type, and a fan shape. The spray pattern of the nozzle (preferably a two-fluid nozzle) in the production method of the present invention can be set to any of these, but can be set to a full cone type so that the granulation liquid is sprayed evenly onto the solid particle group.

[0076] In a method in which the granulation liquid is intermittently added dropwise rather than sprayed through a nozzle to form liquid particles (see Patent Document 5, etc.), the discharge rate of the granulation liquid can be increased to only a few g / min, making it difficult to sufficiently increase the productivity of the granulation composition. In contrast, in the production method of the present invention, the granulation liquid is sprayed through a nozzle, preferably using a two-fluid nozzle, so the discharge rate (spray rate) of the granulation liquid can be increased to, for example, 5 g / min or more, or even 10 g / min or more. There is no particular upper limit to the discharge rate, but if the discharge rate is too high, it becomes difficult to control the particle size of the resulting granulation composition, so it is preferably 100 g / min or less.

[0077] [2-3. Flow of solid particles] The method for producing a granulation composition of the present invention includes a step of spraying a granulation liquid through a nozzle onto a mass of solid particles containing a plurality of solid particles contained in a fluidized bed and flowing. In the granulation composition, the plurality of solid particles coat the periphery of the core particle to form an outer layer. The specific components and sizes of the solid particles are as described above in the section [1-2. Outer Layer], and may be divalent or higher metal salts, inorganic substances, polysaccharides or derivatives thereof, organic polymers, etc.

[0078] The solid particles sprayed with the granulation liquid are contained in a fluidized bed, and the "fluidized bed" can fluidize the solid particles. Modes for fluidizing the solid particles include 1) a mode in which the fluidized bed itself rotates, causing the solid particles to fluidize by the centrifugal force (see Figure 3), and 2) a mode in which stirring blades are placed in the fluidized bed, and the solid particles are fluidized by operating the blades (see Figure 4).

[0079] 3 shows a schematic diagram of a fluidized bed 200, as an example of a fluidized bed, which includes a rotary disk 30 at the bottom inside a granulation apparatus 300 and a container (sometimes referred to as a "pan") 40 placed on the upper surface of the rotary disk 30 and containing solid particle mass 50 containing a plurality of solid particles. Liquid particles 70 of a granulation liquid sprayed from a nozzle 60 are supplied to the solid particle mass 50 containing a plurality of solid particles; the liquid particles 70 adhere to the surfaces of the solid particle mass 50, forming a granulated composition 100.

[0080] In the granulation apparatus 300 shown in Figure 3, when the rotary disk 30 is rotated, the container 40 also rotates in synchronization, and the solid particle mass 50 contained in the container 40 flows by centrifugal force and moves toward the inner wall of the container 40. Although not shown, the solid particles that flow toward the inner wall of the container may be blown upward by the flow of gas, fall to the center of the container, and then flow again and move toward the inner wall. A granulated composition 100 can be obtained by spraying liquid particles 70 of the granulation liquid onto the flowing solid particle mass.

[0081] Figure 4 shows another embodiment of a fluidized bed containing solid particle masses, with Figure 4A being a schematic plan view of vessel 41 and Figure 4B being a schematic cross-sectional view of vessel 41 taken along the arrow line in Figure 4A. In fluidized bed 200 in Figure 3, vessel 40 itself rotates, but vessel 41 of the fluidized bed in Figure 4 has an agitator blade 80 therein. Vessel 41 does not rotate itself, but rather agitator blade 80 rotates around axis 81, causing the solid particle masses contained in vessel 41 to fluidize.

[0082] Generally, a "fluidized bed" also includes a method in which an upward gas flow is generated in a granulator without rotation, thereby suspending solid particles in a fluid. In the production method of the present invention, the solid particles are characterized by being fluidized rather than suspended in the fluidized bed. An example of a fluidized bed capable of fluidizing solid particles in this way is a pan granulator in which coated particles are placed and fluidized.

[0083] [2-4. Coating of core particles with solid particles] The method for producing a granulation composition of the present invention involves spraying a granulation liquid through a nozzle onto a fluidized bed containing a plurality of solid particles (solid particle groups), thereby producing a granulation composition. First, the liquid particles of the granulation liquid sprayed through the nozzle come into contact with the solid particles placed or contained in the fluidized bed, causing the solid particles to adhere to the outer surfaces of the liquid particles. When the solid particles adhere to the liquid particles, some of the liquid components (base, solubilizer, solvent, etc.) in the liquid particles are absorbed by the solid particles, reducing the fluidity of the liquid particles and forming core particles. Furthermore, the solid particles attached to the core particles form a layered structure, forming an outer layer consisting of a plurality of solid particles. This produces a granulation composition.

[0084] When the liquid particles of the granulation liquid are brought into contact with the solid particles, the solid particles are fluidized in the fluidized bed, so that the solid particles that come into contact with the liquid particles tend to form a layer-like film (outer layer) on the outer surface of the liquid particles; and this also prevents or suppresses collisions between the preceding liquid particles and the following liquid particles.

[0085] It is preferable that the fluidized bed contains an excess amount of solid particles compared to the amount of solid particles necessary to obtain a granulated composition. For example, it is preferable that the fluidized bed contains at least two times, or even five times, the weight ratio of solid particles necessary to obtain a predetermined granulated composition. By containing excess solid particles, the solid particles quickly adhere to the liquid particles of the granulation liquid, allowing the predetermined granulated composition to be produced with high productivity.

[0086] The rotation speed imparted to the solid particle group in the fluidized bed (for example, the rotation of the vessel 40 in FIG. 3 or the rotation of the stirring blade 80 in FIG. 4) is not particularly limited, but is preferably 50 to 480 rpm, and more preferably 60 to 200 rpm. A rotation speed of 50 rpm or more is preferable because it can prevent or suppress collisions between leading and trailing liquid particles. On the other hand, a rotation speed of 480 rpm or less is preferable because it can suppress deviation of the solid particles due to centrifugal force.

[0087] When the granulation liquid sprayed from the nozzle is heated, the liquid particles of the granulation liquid that come into contact with the solid particle mass are cooled. The viscosity of the cooled liquid particles of the granulation liquid increases, making it easier to form core particles of the desired shape, and as a result, it is easier to produce a granulated composition of a predetermined shape. For example, when a heated sol-like granulation liquid is sprayed, it becomes gel-like liquid particles on contact with the solid particle mass, making it easier to form the desired core particles.

[0088] [2-5. Sieving process] The manufacturing method of the present invention preferably includes a step of sieving the granulated composition produced in the granulation apparatus. The granulated composition produced in the granulation apparatus is often obtained as a mixture with remaining solid particles that do not adhere to the core particles. Therefore, the granulated composition can be sieved to remove the remaining solid particles. Furthermore, the obtained granulated composition can be sieved and classified to obtain only granulated compositions having a predetermined size.

[0089] [2-6. Formulation process] The produced granulated composition can be formulated by any method. The granulated composition may be made into a granule formulation, or may be filled into a hard capsule shell to make a capsule formulation, or may be mixed with other ingredients and then compressed into tablets.

[0090] Tablets are obtained by 1) mixing the granulation composition with other ingredients and then 2) tableting the mixture. These other ingredients may include excipients, disintegrants, binders, and lubricants. Examples of excipients include, but are not limited to, crystalline cellulose, lactose, dextrin, glucose, sugar alcohols, hydroxypropyl cellulose, modified starch, resistant dextrin, and resistant starch, and one or more of these may be used. Examples of disintegrants include, but are not limited to, agar, carboxymethylcellulose calcium, carboxymethylcellulose sodium, and starch, and one or more of these may be used. Examples of binders include, but are not limited to, gum arabic, gelatin, sodium alginate, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, starch, modified starch, carboxymethylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol, and one or more of these may be used. The lubricant is not particularly limited, and examples thereof include calcium stearate, magnesium stearate, sucrose fatty acid ester, fine silicon dioxide, talc, hydrogenated vegetable oil, macrogol, silicone oil, etc., and one or more of these can be suitably used.

[0091] Tableting to obtain tablets can be carried out by a conventionally known method, and a rotary continuous tableting machine, an eccentric tableting machine, or the like can be used.

[0092] [3. Granulation equipment] The granulation apparatus of the present invention comprises 1) a spraying unit having a nozzle for spraying a granulation liquid containing an active ingredient or a biofunctional ingredient, and 2) a fluidized bed forming unit arranged opposite the nozzle, containing a solid particle mass containing a plurality of solid particles, and fluidizing the solid particle mass. The granulation apparatus of the present invention can produce a granulated composition by introducing the liquid particles of the granulation liquid sprayed by the spraying unit into the solid particle mass contained in the fluidized bed forming unit and adhering them to the plurality of solid particles to solidify them.

[0093] The nozzle provided in the spraying section can be a single-fluid nozzle or a multi-fluid nozzle, but is preferably a multi-fluid nozzle, particularly a two-fluid nozzle. That is, it is preferable to spray the granulation liquid and gas (typically air) using a two-fluid nozzle. As described above in the section [2-2. Spraying of Granulation Liquid], the granulation device of the present invention is capable of adjusting the ratio of "liquid pressure of granulation liquid / air pressure" in the two-fluid nozzle, and preferably, the ratio can be adjusted within a range of at least 0.1 to 2.0.

[0094] The granulation device of the present invention sprays the granulation liquid from the spray unit, and the spray rate is adjustable to 5 g / min or more. The nozzle of the spray unit is replaceable with a nozzle having a different inner diameter, and for example, nozzles having different inner diameters in the range of 0.1 to 10 mm can be detachably attached to the granulation device of the present invention.

[0095] The fluidized bed forming section is as described above in the section [2-3. Fluidization of solid particles], has the function of fluidizing the solid particle group, and may be, for example, a fluidized bed having the configuration shown in Figures 3 and 4. The container of the fluidized bed can accommodate a larger amount of solid particles than the amount of solid particles required to produce the granulated composition, and preferably can accommodate at least twice as much solid particles.

[0096] The granulation apparatus of the present invention may be equipped with a sieve. By sieving the granulation composition formed in the fluidized bed forming section, it is possible to remove remaining solid particles that have not adhered to the core particles and to classify the granulation composition.

[0097] A second embodiment of the granulation apparatus of the present invention is shown in Fig. 5. The granulation apparatus 310 shown in Fig. 5 is provided with a nozzle 60 constituting a spray section, and a vessel 41 and an agitator blade 80 constituting a fluidized bed formation section disposed opposite the nozzle 60, in a space defined by a jacket 90. In other words, the fluidized bed formation section of the granulation apparatus 310 has a configuration similar to that of the fluidized bed formation section shown in Fig. 4. The jacket 90 is also integrated with the vessel 41 and the agitator blade 80 constituting the fluidized bed formation section. In the granulation apparatus 310, the granulation liquid 70 sprayed from the nozzle 60 passes through the space surrounded by the jacket 90 and is introduced into a mass of solid particles (not shown) contained in the vessel 41. At this time, the mass of solid particles contained in the vessel 41 is fluidized by the agitator blade 80 rotating about an axis 81. The granulation device 310 is equipped with a jacket 90, which maintains a clean environment and effectively prevents solid particles from scattering, thereby significantly improving the workability of the granulation operation and increasing productivity. [Example]

[0098] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0099] [Example 1] A. Preparation of granulation liquid A granulation liquid was prepared by mixing the ingredients shown in Table 1 below. The viscosity of the prepared granulation liquid measured at 55°C was 109 mPa·s.

[0100] [Table 1] In Table 1, the components are as follows: Riken E Oil 1000: Vitamin E Lauromacrogol 100: Polyoxyethylene lauryl ether

[0101] B. Arrangement of solid particle groups A two-fluid nozzle (nozzle inner diameter: 0.7 mm) and an open-pan granulator (pan (container) opening diameter: 300 mm) were installed 70 cm below the two-fluid nozzle. Solid particles, a mixture of 99% by mass of corn starch (average particle size: 20 μm) and 1% by mass of silicon dioxide powder (Adsolider 101), were placed in the pan of the open-pan granulator. The amount of solid particles placed was 6.8 times the weight of the sprayed granulation liquid. The pan of the open-pan granulator was orbitally vibrated at 100 rpm to form a fluidized bed in which the solid particles flowed.

[0102] C. Spraying of granulation liquid The granulation liquid (liquid pressure: 0.3 MPa) and air (atmospheric pressure: 0.4 MPa), both kept at 55°C, were each supplied to a two-fluid nozzle, and the liquid particles of the granulation liquid were sprayed onto the fluidized bed. The spray rate of the granulation liquid was 12 g / min. Solid particles of corn starch adhered to the surfaces of the sprayed liquid particles, producing a granulated composition having core particles derived from the granulation liquid and an outer layer consisting of solid particles of corn starch.

[0103] D. Sieving the Granulation Composition The granulated composition produced in the open pan granulator and the remaining solid particles (corn starch) were separated by passing them through a sieve (mesh opening: 75 μm).

[0104] Based on the weight of the resulting granulation composition and the charged weight of the granulation liquid, it was found that the resulting granulation composition was composed of 37.0% by mass of core particles and 63.0% by mass of solid particles. Next, the particle diameters D50 (median diameter), D90, and D10 of the granulation composition were each measured by a laser diffraction / scattering method (LS13320, manufactured by Beckman Coulter, Inc.). The particle size distribution "(D90-D10) / D50" was calculated from the measured particle diameters. The results are shown in Example 1 of Table 2.

[0105] [Table 2]

[0106] [Examples 2 to 5 and Comparative Example 1] In Examples 2 to 5, granulated compositions were produced in the same manner as in Example 1, except that the liquid pressure and air pressure supplied to the two-fluid nozzle were changed as shown in Table 2. In Comparative Example 1, a granulated composition was produced by intermittently adding the same granulation liquid as used in Example 1 dropwise to a fluidized bed under the same conditions as in Example 1, using a droplet discharge device (nozzle inner diameter: 0.3 mm) described in JP 2023-48022 A. The particle size distribution of the obtained granulated composition was measured using the same method as in Example 1, and the results are shown in Table 2.

[0107] As can be seen from a comparison between Examples 1 to 5 and Comparative Example 1, the granulation liquid flow rate (amount of granulation liquid supplied per unit time) was 3.3 g / min in Comparative Example 1, whereas the granulation liquid flow rate was much higher (12 g / min or higher) in Examples 1 to 5; however, the particle size distribution "(D90-D10) / D50" of the granulation compositions produced in Examples 1 to 5 was less than 1.60, showing a sharper distribution than the granulation composition of Comparative Example 1. Thus, according to the production method of the present invention, a granulation composition with controlled particle size (a granulation composition consisting of a core particle and an outer layer) can be produced with good productivity.

[0108] Furthermore, as can be seen from the results of Examples 1 to 5, the particle size of the granulated composition can be controlled by adjusting the ratio of liquid pressure to air pressure (liquid pressure / air pressure) in two-fluid nozzle spraying, and specifically, the particle size can be increased by increasing the ratio (liquid pressure / air pressure). Thus, according to the production method of the present invention, a granulated composition having a desired particle size (a granulated composition consisting of a core particle and an outer layer) can be simply produced. [Industrial Applicability]

[0109] According to the production method of the present invention, it is possible to efficiently produce a granulated composition having a core particle made of a granulation liquid or a dried form thereof containing an active ingredient or a biofunctional ingredient, and an outer layer made of a plurality of solid particles covering the outer surface of the core particle; moreover, the particle size distribution of the obtained granulated composition can be made sharp, and the particle size can be easily adjusted. Therefore, the granulated composition obtained by the production method of the present invention can be used for various purposes such as a pharmaceutical composition or a health food composition. [Explanation of symbols]

[0110] 10 nuclear particles 20 outer layer 21 Solid particles 30 rotating discs 40,41 container 50 solid particles 60 nozzles 70 liquid particles 80 stirring blade 81 axes 90 Jacket 100 Granulation composition 200 fluidized bed 300,310 Granulation equipment

Claims

1. A method for producing a granulated composition for pharmaceuticals or health foods, comprising a step of spraying a granulation liquid containing an active ingredient or a biofunctional ingredient through a nozzle onto a group of solid particles containing a plurality of solid particles that are contained and flowing in a fluidized bed.

2. The manufacturing method according to claim 1 , wherein the nozzle is a single-fluid nozzle or a multi-fluid nozzle.

3. The method according to claim 1 or 2, wherein the nozzle is a two-fluid nozzle, and the granulation liquid and the gas are supplied to the two-fluid nozzle.

4. 4. The method according to claim 3, wherein a ratio of the liquid pressure of the granulation liquid to the air pressure of the gas supplied to the two-fluid nozzle (liquid pressure / air pressure) is 0.1 to 2.

0.

5. The method according to claim 1 or 2, wherein the spray rate of the granulation liquid is 5 g / min or more.

6. 3. The method according to claim 1, wherein the granulation composition comprises a core particle made of the granulation liquid or a dried form thereof, and an outer layer made of the plurality of solid particles attached to the outer peripheral surface of the core particle.

7. The method of claim 1 or 2, wherein the granulating liquid comprises a polymeric substance.

8. The method according to claim 1 or 2, wherein the active ingredient or biofunctional ingredient is a poorly water-soluble ingredient, an ingredient requiring masking, an ingredient requiring targeting, a peptide, a protein, or a nucleic acid.

9. The method according to claim 1 or 2, wherein the particle size (D50) of the granulated composition is 1000 μm or less.

10. The method according to claim 1 or 2, wherein the particle size (D90) of the granulated composition is 1600 μm or less.

11. The method according to claim 9, wherein the particle size (D50) of the granulated composition is 10 to 450 μm.

12. The method according to claim 10, wherein the particle size (D90) of the granulated composition is 50 to 850 μm.

13. The method according to claim 9, wherein the particle size (D50) of the granulated composition is 400 to 1000 μm.

14. The method according to claim 10, wherein the particle size (D90) of the granulated composition is 700 to 1600 μm.

15. The method according to claim 1 or 2, wherein the value calculated by the following formula (1) is less than 1.60: (D90-D10) / D50...(1) [In formula (1), D90, D10, and D50 mean the particle size (D90), particle size (D10), and particle size (D50) of the granulated composition, respectively.]

16. A method for producing a solid preparation, which comprises blending a granulated composition produced by the method according to claim 1 or 2.

17. The method according to claim 16, wherein the solid formulation is a tablet or a hard capsule.

18. A granulation device comprising: a spraying section having a nozzle for spraying a granulation liquid containing an active ingredient or a biofunctional ingredient; and a fluidized bed forming section disposed opposite the nozzle, accommodating a solid particle mass containing a plurality of solid particles, and fluidizing the solid particle mass, The liquid particles of the granulation liquid sprayed by the spraying unit are introduced into the group of solid particles contained in the fluidized bed forming unit, and adhere to the plurality of solid particles to solidify.

19. The granulating apparatus according to claim 18, wherein the nozzle is a two-fluid nozzle that sprays the granulating liquid and the gas, and the ratio of "liquid pressure of the granulating liquid / air pressure of the gas" is adjustable within a range of 0.1 to 2.

0.

20. 20. The granulating apparatus according to claim 18 or 19, wherein the nozzle is capable of spraying the granulating liquid at a rate of 5 g / min or more.

21. The granulating apparatus according to claim 18 or 19, wherein the inner diameter of the nozzle is in the range of 0.1 to 1.0 mm.

22. 20. The granulating apparatus according to claim 18 or 19, wherein the fluidized bed forming unit fluidizes the solid particle mass by centrifugal force generated by rotation of the fluidized bed itself, or by a stirring blade disposed in the fluidized bed.

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