Drugs contain particles

Abstract

A method for producing drug-containing particles having raw material particles and a coating layer on the outside thereof, with at least one drug contained in the raw material particles and / or the coating layer, the method comprising a granulation step having a stirring function, in which a mixture containing core particles for powder coating, in which raw material particles are coated with a polymer, and a drug and / or a pharmaceutically acceptable additive, is sprayed with a solvent capable of dissolving the polymer.

Description

Technical Field

[0001] The present invention relates to core particles in which raw material particles are coated with a polymer, drug-containing particles using the core particles, and a method for producing the same.

Background Art

[0002] In pharmaceuticals, spherical granules containing a drug are useful from the viewpoints of bitterness masking, dissolution control, and stabilization. For example, if they have the same particle size, spherical granules have a smaller surface area than non-spherical granules, so that coating can be efficiently carried out. Similarly, granules with a sharp particle size distribution can be uniformly coated compared to granules with a broad particle size distribution, thus improving the coating efficiency. Thus, granules having the above characteristics can exhibit a desired effect even when the amount of the coating agent used is reduced, and are extremely useful from the viewpoints of productivity and cost reduction.

[0003] In addition, in preparations using spherical granules with a sharp particle size distribution, granules, dry syrups, etc. have excellent fluidity, so they have the advantages of excellent productivity and easy handling of the product. Furthermore, when used for capsules, tablets, orally disintegrating tablets (OD tablets), etc., spherical granules with a sharp particle size distribution have excellent fluidity, so the productivity during filling and tableting is improved.

[0004] As a method for obtaining spherical granules containing a drug, a method is known in which a commercially available spherical additive is charged into a fluidized bed granulator or a rolling granulator, and a solution or dispersion of the drug is sprayed to coat around the spherical additive. However, this method has a demerit that it takes a long time for coating. Furthermore, since the drug is in a dissolved or dispersed state in water or a solvent for a long time, there is a risk that the crystal form of the drug changes or the drug decomposes.

[0005] Furthermore, a method is known in which additives and drugs are loaded into a rolling granulator in powder form, and a binder solution is sprayed to coat the material (for example, Patent Document 1). However, with this method, the particle size distribution of the granules is not sharp, and there is room for improvement.

[0006] Furthermore, methods for granulation in which smaller powder particles are attached to the surface of core particles using a binder (nucleated granulation method) are also known (for example, Patent Document 2). [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] Japanese Patent Publication No. 2000-128774 [Patent Document 2] Japanese Patent Application Publication No. 6-218266 [Overview of the project] [Problems that the invention aims to solve]

[0008] The present invention aims to provide a method for efficiently producing drug-containing particles that have a sharp particle size distribution, high sphericity, and good fluidity. [Means for solving the problem]

[0009] As a result of diligent research, the inventors of the present invention have discovered that drug-containing particles with a desired particle size and particle size distribution can be produced in a short time by a simple method of granulation, in which raw material particles are coated with a polymer to form core particles, to which drugs and / or pharmaceutically acceptable additives are added in powder form, and then stirred while spraying a solvent that can dissolve the polymer. This has led to the completion of the present invention.

[0010] In other words, the present invention is [1] Core particles for powder coating by wet process, in which raw material particles are coated with polymer, [2] The core particle according to [1], wherein the raw material particle contains at least one selected from the group consisting of D-mannitol, lactose, crystalline cellulose, corn starch, silicon dioxide, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, and drugs. [3] A core particle according to [1] or [2], wherein the polymer comprises at least one selected from the group consisting of hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, pregelatinized starch, ethyl acrylate / methyl methacrylate copolymer, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, and ethyl cellulose. [4] A method for producing drug-containing particles having raw material particles and a coating layer on the outside thereof, wherein at least one drug is contained in the raw material particles and / or the coating layer, the method comprising a granulation step having a stirring function while spraying a solvent capable of dissolving the polymer onto a mixture containing a core particle for powder coating obtained by coating raw material particles with a polymer, and a drug and / or a pharmaceutically acceptable additive. [5] A manufacturing method according to [4], which includes a step of stirring and granulating while heating at 35 to 100°C. [6] A drug-containing particle having a discontinuous layer between the raw material particle and the coating layer, the method of manufacturing according to [4] or [5] [7] A manufacturing method according to any one of [4] to [6], wherein the span of the drug-containing particles is 1.0 or less. [8] A manufacturing method according to any one of [4] to [7], wherein the degree of compression of the drug-containing particles is 14% or less. This relates to drug-containing particles manufactured by the manufacturing method described in any of [9], [4], to [8]. [Effects of the Invention]

[0011] The use of the powder-coating core particles of the present invention makes the powder coating process for core particles, which conventionally required a long time, more efficient. Furthermore, due to its high versatility, it can be used in the manufacture of various solid dosage forms.

[0012] According to the manufacturing method of the present invention, there is no need to prepare a solution or suspension of the main drug or additives, and the powder and the solvent can be used as they are, so the operation is simple, and the manufacturing time can be shortened compared to the conventional nucleated granulation method. Furthermore, even for main drugs and the like that are unstable in water or solvents, they are less affected.

[0013] Also, according to the manufacturing method of the present invention, depending on the composition of the core particles, functions such as release control and bitterness masking can be imparted to the drug-containing particles. Furthermore, it becomes possible to design and manufacture drug-containing particles having a desired particle size and particle size distribution.

Brief Description of the Drawings

[0014] [Figure 1] It is an electron micrograph showing the appearance of the raw material particles (Celluphane CP-102Y). [Figure 2] It is an electron micrograph showing the appearance of the core particles obtained by coating the raw material particles (Celluphane CP-102Y) with a water-soluble polymer (HPC-L). [Figure 3A] It is an electron micrograph showing the appearance of the drug-containing particles of Example 1. [Figure 3B] It is an electron micrograph showing the appearance of the drug-containing particles of Example 1. [Figure 4A] It is an electron micrograph showing the cross-section of the drug-containing particles of Example 1. [Figure 4B] It is an electron micrograph showing the cross-section of the drug-containing particles of Example 1. [Figure 4C] It is an electron micrograph showing the cross-section of the drug-containing particles of Example 1. [Figure 5A] It is an electron micrograph showing the appearance of the drug-containing particles of Comparative Example 1. [Figure 5B] It is an electron micrograph showing the appearance of the drug-containing particles of Comparative Example 1. [Figure 6A] It is an electron micrograph showing the appearance of the drug-containing particles of Comparative Example 2. [[ID=4�]] [Figure 6B] It is an electron micrograph showing the appearance of the drug-containing particles of Comparative Example 2. <00>< / [Figure 7A]It is an electron micrograph showing the appearance of the drug-containing particles of Comparative Example 3. [Figure 7B] It is an electron micrograph showing the appearance of the drug-containing particles of Comparative Example 3. [Figure 8] It is a graph showing the particle size distribution of the drug-containing particles of Example 1. [Figure 9] It is a graph showing the particle size distribution of the drug-containing particles of Comparative Example 1. [Figure 10] It is a graph showing the particle size distribution of the drug-containing particles of Comparative Example 2. [Figure 11] It is a graph showing the particle size distribution of the drug-containing particles of Comparative Example 3. [Figure 12] It is a graph showing the particle size distribution of the raw material particles (Celluia CP-102Y). [Figure 13] It is a graph showing the particle size distribution of the drug-containing particles of Example 2. [Figure 14] It is a graph showing the particle size distribution of the drug-containing particles of Example 3. [Figure 15] It is a graph showing the particle size distribution of the drug-containing particles of Example 4. [Figure 16] It is a graph showing the particle size distribution of the drug-containing particles of Example 5.

Mode for Carrying Out the Invention

[0015] [[ID=The production procedure of the drug-containing particles including the production of the core particles for powder coating, which is one embodiment of the present invention, will be described in detail below. However, the following description is an exemplification for explaining the present invention, and is not intended to limit the technical scope of the present invention only to this description range. In this specification, when indicating a numerical range using "~", it shall include the numerical values at both ends.

[0016]

[0017] ​In this embodiment, the compressibility, which represents the fluidity of the particles, is determined from the specific volume ((loose (mL / g), tap (mL / g)) measured using a 100 mL stainless steel cup) by the following formula. (Compression degree (%)) = ((loose (mL / g)) - (tap (mL / g)) / (loose (mL / g)) × 100

[0018] In this embodiment, Span, which represents the extent of the particle size distribution, is determined by the following formula from the cumulative 90% particle size (D90), cumulative 10% particle size (D10), and cumulative 50% particle size (D50) obtained from mass-based measurements using a commercially available laser diffraction particle size distribution analyzer or ultrasonic vibration sieving analyzer. (Span)=(D90-D10) / D50

[0019] <Powder-coated core particles and method for producing the same> The powder-coated core particles (hereinafter sometimes simply referred to as core particles) according to this embodiment are characterized by being coated with a functional polymer. By using core particles in which the polymer is localized on the surface of raw material particles in this way, spherical drug-containing particles with a sharp particle size distribution can be produced in a short time by a simple method of adding drugs and / or pharmaceutically acceptable additives in powder form and stirring and granulating while spraying a solvent that can dissolve the polymer.

[0020] When polymers acting as binders are present randomly, they not only bind drugs and / or pharmaceutically acceptable additives to the raw material particles, but also bind the raw material particles to each other and to each other, making it difficult to sharpen the particle size distribution of the granules. In the powder coating core particles according to this embodiment, the polymers acting as binders are pre-coated to the raw material particles, so they are selectively consumed in binding the raw material particles to the drugs and / or pharmaceutically acceptable additives. Then, by spraying a solvent that dissolves the polymers while stirring, the polymers gradually dissolve, and the drugs and / or pharmaceutically acceptable additives adhere to them, which is thought to lead to efficient spherical granulation.

[0021] (raw material particles) Suitable raw material particles include drugs, pharmaceutically acceptable additives, or mixtures thereof, as well as granules obtained by known granulation methods. These raw material particles may be used individually or in combination of two or more. Furthermore, some components of the raw material particles may overlap with those of the polymers described below. It is essential that the additives do not inhibit the effects of the drug (active ingredient) they are used with, and it is preferable that their inclusion imparts additional functionality to the granules.

[0022] Examples of pharmaceutically acceptable additives include excipients, binders, disintegrants, lubricants, sweeteners, flavorings, coatings, stabilizers, colorants, solubilizers, and fluidizers.

[0023] The excipients are not particularly limited, but examples include D-mannitol, lactose, crystalline cellulose, pregelatinized starch, agar, gelatin, sucrose, corn starch, calcium hydrogen phosphate, silicon dioxide, etc., with D-mannitol, lactose, crystalline cellulose, corn starch, and silicon dioxide being preferred.

[0024] The binder is not particularly limited, but examples include hydroxypropylcellulose, hypromellose (hydroxypropyl methylcellulose), polyvinylpyrrolidone (povidone), and soy lecithin, with hydroxypropylcellulose and hypromellose being preferred.

[0025] The disintegrant is not particularly limited, but examples include low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, crospovidone, and carboxymethyl starch sodium. Preferably, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, and crospovidone are used; more preferably, low-substituted hydroxypropyl cellulose and crospovidone are used.

[0026] The lubricant is not particularly limited, but examples include talc, magnesium stearate, stearic acid, sucrose fatty acid ester, stearyl alcohol, etc., with magnesium stearate being preferred.

[0027] The sweetener is not particularly limited, but examples include aspartame, saccharin, and sucralose, with aspartame being preferred.

[0028] The fragrance is not particularly limited, but examples include peppermint and l-menthol, with peppermint being preferred.

[0029] The coating agent is not particularly limited, but examples include ethyl acrylate / methyl methacrylate copolymer, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, ethyl cellulose, titanium dioxide, etc., with ethyl acrylate / methyl methacrylate copolymer, ethyl cellulose, and titanium dioxide being preferred.

[0030] The coloring agent is not particularly limited, but examples include yellow iron(III) oxide, iron(III) oxide, black iron oxide, etc., with yellow iron(III) oxide and iron(III) oxide being preferred.

[0031] The solubilizer is not particularly limited, but examples include polysorbate and macrogol, with polysorbate being preferred.

[0032] The fluidizing agent is not particularly limited, but examples include light anhydrous silicic acid and hydrated silicon dioxide, with light anhydrous silicic acid being preferred.

[0033] The drugs contained in the drug-containing particles are not particularly limited and can be used regardless of their properties (basic, acidic, amphoteric, neutral, etc.) or solubility. Furthermore, these drugs may be used individually or in combination of two or more.

[0034] Among the above raw material particles, raw material particles containing at least one selected from the group consisting of D-mannitol, lactose, crystalline cellulose, corn starch, silicon dioxide, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, and drugs are preferred; raw material particles containing at least one selected from the group consisting of D-mannitol, lactose, crystalline cellulose, corn starch, silicon dioxide, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, and drugs are more preferred. Furthermore, combinations of at least one selected from the group consisting of D-mannitol, lactose, crystalline cellulose, corn starch, silicon dioxide, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, and drugs with a binder and / or coating agent are also preferred embodiments.

[0035] The average particle size of the raw material particles is arbitrary and can be appropriately designed according to the type of raw material particles, for example, it can be in the ranges of 5-1000 μm, 10-800 μm, 20-600 μm, 30-500 μm, 40-400 μm, or 50-300 μm.

[0036] The span of the raw material particles is preferably 1.0 or less, more preferably 0.9 or less, even more preferably 0.8 or less, and particularly preferably 0.7 or less.

[0037] (Polymers and nuclear particles) The core particles according to this embodiment are produced by coating raw material particles with a polymer such as a water-soluble polymer or a water-insoluble polymer. The polymer may be used alone or in combination of two or more types.

[0038] The water-soluble polymers are not particularly limited, but examples include cellulose derivatives and their salts such as methylcellulose, hydroxypropylcellulose (HPC), hypromellose (hydroxypropylmethylcellulose), hydroxyethylcellulose, hydroxymethylcellulose, and carboxymethylcellulose; water-soluble vinyl derivatives such as polyvinylpyrrolidone (povidone), polyvinyl alcohol, copolividone, polyethylene glycol (macrogol), polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, vinyl acetate / vinylpyrrolidone copolymer, and polyvinyl alcohol / polyethylene glycol / graft copolymer; pregelatinized starch, dextrin, dextran, pullulan, alginic acid, pectin, gelatin, hydrolyzed gelatin, agar, polyvinyl alcohol, polyethylene glycol, pullulan, polysorbate 80, sodium lauryl sulfate, refined sucrose, and sucrose. Preferably, the water-soluble polymers include at least one selected from the group consisting of hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and pregelatinized starch; more preferably, the water-soluble polymers include at least one selected from the group consisting of hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and pregelatinized starch; even more preferably, hydroxypropyl cellulose and / or polyethylene glycol. These water-soluble polymers may be used individually or in combination of two or more.

[0039] Examples of water-insoluble polymers are not particularly limited, but include ethyl acrylate / methyl methacrylate copolymer, aminoalkyl methacrylate copolymer, methacrylate copolymer, ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hypromellose phthalate, partially pregelatinized starch, hydrogenated oil, synthetic wax, carnauba wax, stearyl alcohol, stearic acid, calcium stearate, glycerin fatty acid ester, sucrose fatty acid ester dextrin, and soy lecithin. Preferably, the water-insoluble polymers include at least one selected from the group consisting of ethyl acrylate / methyl methacrylate copolymer, aminoalkyl methacrylate copolymer, methacrylate copolymer, and ethyl cellulose; more preferably, the water-insoluble polymers include at least one selected from the group consisting of ethyl acrylate / methyl methacrylate copolymer, aminoalkyl methacrylate copolymer, methacrylate copolymer, and ethyl cellulose; even more preferably, ethyl cellulose and / or aminoalkyl methacrylate copolymer; and particularly preferably, aminoalkyl methacrylate copolymer. These water-insoluble polymers may be used individually or in combination of two or more.

[0040] The apparatus used for coating raw material particles with polymers is not particularly limited, but fluidized bed granulators, rolling granulators, rolling fluidized bed granulators, high-speed agitated granulators, high-speed mixing and stirring granulators, high-speed agitated mixing apparatuses, continuous direct granulation apparatuses, composite fluidized bed granulators, and dry composite apparatuses are used.

[0041] The coating of raw material particles with polymers can be performed, for example, by loading the raw material particles and a fluidity improving agent such as Aerosil into the above-mentioned composite fluid bed granulator and spraying a liquid containing dissolved polymers.

[0042] The amount of polymer used for coating is preferably 5 to 300 parts by mass, more preferably 10 to 200 parts by mass, even more preferably 15 to 150 parts by mass, and particularly preferably 20 to 100 parts by mass, per 100 parts by mass of raw material particles.

[0043] <Drug-containing particles and methods for producing the same> The drug-containing particles according to this embodiment are characterized by having raw material particles and a coating layer on the outside thereof, and containing at least one drug in the raw material particles and / or the coating layer.

[0044] The drug-containing particles according to this embodiment can be produced by adding a solvent capable of dissolving a polymer coated with raw material particles to a powdery mixture containing the aforementioned core particles and a drug and / or pharmaceutically acceptable additive, for example, by granulating while spraying and drying. In other words, the powder-coated core particles according to this embodiment are suitably used in a wet-process cored granulation method.

[0045] The apparatus used for granulating drug-containing particles can be appropriately selected as long as it has a stirring function. Although not particularly limited, stirring granulators, high-speed stirring granulators, mixing and stirring granulators, high-speed mixing and stirring granulators, high-speed stirring and mixing granulators, tumbling granulators, and tumbling fluidized bed granulators are preferred. Among these, the use of high-speed stirring granulators, mixing and stirring granulators, and tumbling granulators is more preferred.

[0046] Granulation of drug-containing particles can also be carried out under heating. For example, it can be done at 35 to 100°C, preferably 40 to 90°C.

[0047] As for the drying method, a known method can be appropriately selected, such as drying in a shelf dryer or a fluidized bed.

[0048] In this embodiment, "solvent" means all solvents permissible in the fields of pharmaceuticals, quasi-drugs, cosmetics, food, etc., and is not particularly limited as long as it can dissolve the polymer coating the raw material particles, but a pharmaceutically acceptable solvent is preferred.

[0049] Examples of solvents usable in this embodiment include water; alcohol-based solvents such as methanol, ethanol, n-propanol, and isopropanol; ketone-based solvents such as acetone and methyl ethyl ketone; ester-based solvents such as ethyl acetate; and mixtures thereof.

[0050] When a water-soluble polymer is used as the polymer coating the raw material particles, water is preferably used, but aqueous ethanol or other solvents may be used to improve workability. When a water-insoluble polymer is used as the polymer coating the core particles, ethanol is preferably used, but other alcohol-based solvents, ketone-based solvents, ester-based solvents, etc. may be used depending on solubility.

[0051] The amount of solvent used varies depending on the type and amount of drug and polymer, but is usually 3 to 100 parts by weight, preferably 5 to 80 parts by weight, more preferably 5 to 60 parts by weight, and even more preferably 10 to 50 parts by weight, per 100 parts by weight of the total amount of each component constituting the drug-containing particles.

[0052] The solvent can be sprayed using a spray gun typically used during granulation. To increase the yield of the granulated material, it is preferable to minimize spraying onto areas other than the powder inside the granulation container, such as the inner wall of the granulation container, while spraying the solvent over as wide an area of ​​powder inside the granulation container as possible.

[0053] The pharmaceutically acceptable additives are not particularly limited, and examples include pharmaceutically acceptable additives that can be used as the raw material particles. Furthermore, even if the additive corresponds to the polymer described above, if it does not dissolve in the solvent used, it can be incorporated as an additive without exhibiting the function of the polymer according to this embodiment.

[0054] The span of the drug-containing particles is preferably 1.0 or less, more preferably 0.9 or less, even more preferably 0.8 or less, and particularly preferably 0.7 or less.

[0055] The average particle size of the core particles is preferably 5 times or more, more preferably 10 times or more, even more preferably 15 times or more, and particularly preferably 20 times or more, compared to the average particle size of the drug and / or pharmaceutically acceptable additive. The granulation of drug-containing particles proceeds efficiently when the average particle size of the drug and / or pharmaceutically acceptable additive is within the above range.

[0056] The drug-containing particles in this experimental configuration have a sharp particle size distribution and are spherical, thus exhibiting good fluidity. Here, "good fluidity" means a compressibility of 14% or less. Preferably, it is 12% or less, and more preferably 10% or less. By applying drug-containing particles exhibiting good fluidity to various dosage forms of pharmaceuticals, quality and manufacturability can be improved.

[0057] Furthermore, in one embodiment, the drug-containing particles according to this embodiment have a discontinuous layer between the raw material particles and the coating layer. This "discontinuous layer" refers to a layered void that exists between the raw material particles located at the center of the particles and the coating layer surrounding the raw material particles, and its presence can be confirmed, for example, with an electron microscope or an optical microscope.

[0058] The drug-containing particles according to this embodiment are useful as pharmaceuticals or pharmaceutical raw materials and can be administered orally or parenterally to humans or animals. The dosage can be appropriately selected depending on the drug used.

[0059] The drug-containing particles according to this embodiment can be made into various dosage forms depending on the intended use. For example, the drug-containing particles according to this embodiment can be used as is as granules, injectable preparations for immediate use, implantable dosage forms, etc. They can also be mixed with any additives and compressed into tablets (including orally disintegrating tablets), or filled into capsules to make capsules. Furthermore, they can be used as suspensions (aqueous suspensions, oily suspensions), emulsions, etc. [Examples]

[0060] The present invention will be described based on examples, but the present invention is not limited to the examples.

[0061] The various chemicals used in the examples and comparative examples are summarized below. Raw material particles: Crystalline cellulose (manufactured by Asahi Kasei Corporation, Cellfia CP-102Y) Water-soluble polymer: Hydroxypropylcellulose (manufactured by Nippon Soda Co., Ltd., HPC-L) Compound A: Levofloxacin 0.5 hydrate (Cas No.: 138199-71-0, jet milled, average particle size: 3.38 μm)

[0062] (Example 1) 525 g of raw material particles were placed in a composite fluidized bed granulator (Multiplex MP-01 / SFP, manufactured by Powrec Co., Ltd.), and a 3% aqueous solution of water-soluble polymer was sprayed at a rate of 2.9 g / mL under conditions of an air supply temperature of 70°C and a rotor rotation speed of 1000 rpm. After spraying 262.5 g of water-soluble polymer, the mixture was dried until the exhaust temperature reached 50°C, and then sieved through a 60-mesh sieve to obtain core particles (average particle size: 170 μm).

[0063] Compound A was added to the obtained core particles according to the amount of charge shown in Table 1, and granulation was carried out for 15 minutes using a high-speed stirring granulator (Earth Technica Co., Ltd., LFS-GS-2J) under the manufacturing conditions shown in Table 2 while spraying with a 50% ethanol aqueous solution (note that the amount of charge in Table 1 is shown based on the amount of compound A charged). The mixture was dried using a fluidized bed granulator (Powrec Co., Ltd., Multiplex MP-01) until the exhaust temperature reached 40°C, and then sieved through a 30-mesh sieve to obtain drug-containing particles.

[0064] (Comparative Example 1) Drug-containing particles were obtained in the same manner as in Example 1, except that the water-soluble polymer was not coated onto the raw material particles, and the water-soluble polymer and compound A were added in powder form to the raw material particles according to the amounts shown in Table 1.

[0065] (Comparative Example 2) Drug-containing particles were obtained in the same manner as in Example 1, except that the water-soluble polymer was not coated onto the raw material particles, compound A was added to the raw material particles in powder form according to the amount shown in Table 1, and the water-soluble polymer was dissolved in a 50% ethanol aqueous solution and sprayed.

[0066] (Comparative Example 3) Except for not using a water-soluble polymer, drug-containing particles were obtained in the same manner as in Example 1, according to the amounts of ingredients shown in Table 1.

[0067] <Measurement of particle size distribution and the measure of the extent of particle size distribution (Span)> The particle size distribution (D10, D50, D90) of the raw material particles was measured by mass using a laser diffraction particle size distribution analyzer (SALD-3000J, Shimadzu Corporation). The particle size distribution (D10, D50, D90) of the obtained drug-containing particles was measured by mass using an ultrasonic vibration sieving analyzer (Robot Shifter PRS-95C, Seishin Corporation). Span was calculated using the following formula. The results are shown in Tables 1 and 3. A smaller Span value indicates a sharper particle size distribution. (Span)=(D90-D10) / D50

[0068] <Appearance and cross-section of particles> The appearance and cross-section of the particles were observed using a scanning electron microscope (VE-7800, manufactured by Keyence Corporation) (Figures 1 to 7B).

[0069] <Measurement of specific volume and compressibility> Specific volume is expressed as the volume per unit weight (mL / g) of the powder. Drug-containing particles were added to a 100 mL stainless steel cup by gravity. After scraping off the sample that rose from the cup with a flat metal plate, the mass of the stainless steel cup containing the sample was measured to calculate loose (mL / g). Next, the same stainless steel cup was vibrated and drug-containing particles were added again, repeating this process until there was no further volume change. After scraping off the sample that rose from the cup with a flat metal plate, the mass of the stainless steel cup containing the sample was measured to calculate tap (mL / g). From the values ​​of loose (mL / g) and tap (mL / g), the compressibility (%) of the powder was calculated using the following formula. The results are shown in Table 1. A lower compressibility indicates better particle fluidity. (Compression degree (%)) = ((loose (mL / g)) - (tap (mL / g)) / (loose (mL / g)) × 100

[0070] [Table 1]

[0071] [Table 2]

[0072] [Table 3]

[0073] The span of the drug-containing particles in Example 1 is 1.0 or less, indicating a sharp particle size distribution. Furthermore, while the particle size distribution of the raw material particles is around 100-150 mesh (106-180 μm) (Figure 12), the drug-containing particles in Example 1 have a peak around 80 mesh (180-250 μm) (Figure 8), indicating particle growth. In contrast, the drug-containing particles in Comparative Examples 1-3 have a peak around 100-150 mesh (106-180 μm) or are broad (Figures 9, 10, and 11), indicating that granulation has not progressed, or if it has, it is not homogeneous.

[0074] Furthermore, observation using an electron microscope revealed that the drug-containing particles of Example 1 exhibited superior sphericity (Figures 3A to 7B) and possessed discontinuous layers. In addition, the drug-containing particles of Example 1 showed low compressibility and improved fluidity.

[0075] (Example 2) 500g of raw material particles were placed in a composite fluidized bed granulator (Multiplex MP-01 / SFP, manufactured by Powrec Co., Ltd.), and a 3% aqueous solution of water-soluble polymer was sprayed at a rate of 2.9g / mL under conditions of an air supply temperature of 70°C and a rotor rotation speed of 1000rpm. After spraying 150g of water-soluble polymer, the mixture was dried until the exhaust temperature reached 50°C, and then sieved through a 60-mesh (250μm) sieve to obtain core particles (average particle size: 170μm).

[0076] Compound A was added to the obtained core particles according to the charge amounts shown in Table 4, and granulation was carried out for 32 minutes using a high-speed stirring mixer (EL-1, manufactured by Nippon Eirich Co., Ltd.) under the manufacturing conditions shown in Table 5, while spraying with a 50% ethanol aqueous solution (note that the charge amounts in Table 4 are based on the amount of compound A charged). The mixture was dried using a fluidized bed granulator (Multiplex MP-01, manufactured by Powrec Co., Ltd.) until the exhaust temperature reached 40°C to obtain drug-containing particles.

[0077] [Table 4]

[0078] [Table 5]

[0079] In the granulation of drug-containing particles, even when a high-speed stirring and mixing device was used instead of a high-speed stirring and granulating device, drug-containing particles with a sharp particle size distribution and good fluidity were obtained in a short time.

[0080] (Example 3) 594 g of crospovidone (ISP, Polyplasdone INF-10) and 6 g of water-soluble polymer were mixed for 1 minute using a stirring granulator (Powrec Co., Ltd., Vertical Granulator FM-VG-05), and then 613 g of 15% ethanol aqueous solution was sprayed onto the mixture to obtain a paste. The obtained paste was extruded and granulated using a wet extrusion granulator Multi-Gran (DALTON, MG-55-2) equipped with a 0.3 mm screen, then sized using a spherical granulator Marmelizer (DALTON, QJ-230T-2), and finally dried using a fluidized bed granulator until the exhaust temperature reached 45°C. The obtained dried material was sieved through 42 mesh (355 μm) and 60 mesh (250 μm) sieves, with the material that passed through the 42 mesh and remained on the 60 mesh being considered the disintegration nuclei (average particle size: 298 μm).

[0081] 175 g of the aforementioned decay nuclei were placed in a composite fluidized bed granulator (Multiplex MP-01 / SFP, manufactured by Powrec Co., Ltd.), and a 3% aqueous solution of water-soluble polymer was sprayed at a rate of 2.9 g / mL under conditions of an air supply temperature of 70°C and a rotor rotation speed of 1000 rpm. After spraying 52.5 g of water-soluble polymer, the mixture was dried until the exhaust temperature reached 50°C, then passed through a 42-mesh filter, and the particles remaining on the 60-mesh filter were used as nucleus particles (average particle size: 295 μm).

[0082] Compound A was added to the obtained core particles according to the charge amounts shown in Table 6, and granulation was carried out for 60 minutes using a high-speed stirring mixer (EL-1, manufactured by Nippon Eirich Co., Ltd.) under the manufacturing conditions shown in Table 7, while spraying with a 50% ethanol aqueous solution (note that the charge amounts in Table 6 are based on the amount of compound A charged). The mixture was dried using a fluidized bed granulator (Multiplex MP-01, manufactured by Powrec Co., Ltd.) until the exhaust temperature reached 40°C to obtain drug-containing particles.

[0083] [Table 6]

[0084] [Table 7]

[0085] Even when using a disintegrant (crospovidone) instead of an excipient (crystalline cellulose) as the raw material particles, granulated using a standard method, drug-containing particles with a sharp particle size distribution and good fluidity were obtained in a short time.

[0086] (Example 4) A suspension of cilostazol was prepared by adding 600 g of cilostazol and 150 g of water-soluble polymer to 2500 g of purified water. Cilostazol was granulated by spraying the suspension using a continuous direct granulation apparatus (CTS-SGR, manufactured by Powrec Co., Ltd.). The resulting granules were then sized using 83 mesh (180 μm) and 140 mesh (106 μm) granules. The granules that passed through the 83 mesh and remained on the 140 mesh were designated as drug nuclei (average particle size: 137 μm).

[0087] 280 g of the aforementioned drug nuclei were placed in a composite fluidized bed granulator (Multiplex MP-01 / SFP, manufactured by Powrec Co., Ltd.), and a 3% aqueous solution of water-soluble polymer was sprayed at a rate of 2.3 g / mL under conditions of an air supply temperature of 75°C and a rotor rotation speed of 1000 rpm. After spraying 84 g of water-soluble polymer, the mixture was dried until the exhaust temperature reached 50°C, and then sieved through 83 mesh and 140 mesh to obtain nuclei particles (average particle size: 141 μm).

[0088] To the obtained core particles, talc (Victorilite SK-C, average particle size: 3.23 μm, manufactured by Katsumitsuyama Mining Co., Ltd.) was added according to the amount of charge shown in Table 8, and granulation was carried out for 80 minutes using a high-speed stirring and mixing device (EL-1, manufactured by Nippon Eirich Co., Ltd.) while spraying with a 50% ethanol aqueous solution under the manufacturing conditions shown in Table 9 (note that the amount of charge in Table 8 is shown based on the amount of talc charged). The mixture was dried using a fluidized bed granulator (Multiplex MP-01, manufactured by Powrec Co., Ltd.) until the exhaust temperature reached 40°C to obtain drug-containing particles.

[0089] [Table 8]

[0090] [Table 9]

[0091] Even when using granulated drug particles (cilostazol) instead of excipient (crystalline cellulose) as raw material particles, drug-containing particles with a sharp particle size distribution and good fluidity were obtained in a short time.

[0092] (Example 5) Using a dry compounding apparatus (Nobilta Mini, manufactured by Hosokawa Micron Corporation), the raw material particles and polyethylene glycol (Macrogol 6000, manufactured by Sanyo Chemical Industries, Ltd.) were mixed for 1 minute. Then, the mixture was dry compounded under jacket temperature conditions of 40°C while adjusting the rotor speed to achieve a motor load of approximately 100W. The resulting composite particles were sieved through 83 mesh (180 μm) and 140 mesh (106 μm). The particles that passed through the 83 mesh and remained on the 140 mesh were used as nuclei particles (average particle size: 130 μm).

[0093] Compound A was added to the obtained core particles according to the charge amounts shown in Table 10, and granulation was carried out for 30 minutes using a high-speed stirring granulator (Earth Technica Co., Ltd., LFS-GS-2J) under the manufacturing conditions shown in Table 11 while spraying with a 50% ethanol aqueous solution (note that the charge amounts in Table 10 are based on the amount of compound A charged). The mixture was dried using a fluidized bed granulator (Powrec Co., Ltd., Multiplex MP-01) until the exhaust temperature reached 40°C, and then sieved through a 42-mesh (355 μm) sieve to obtain drug-containing particles.

[0094] [Table 10]

[0095] [Table 11]

[0096] Even when polyethylene glycol was used instead of hydroxypropyl cellulose as the water-soluble polymer, drug-containing particles with a sharp particle size distribution and good fluidity were obtained in a short time. [Industrial applicability]

[0097] According to the present invention, drug-containing particles with a sharp particle size distribution, high sphericity, and good fluidity can be efficiently produced, making them suitable for use in the manufacture of various solid dosage forms.

Claims

1. A core particle for powder coating by a wet method, wherein raw material particles are coated with a water-soluble polymer, and the water-soluble polymer is localized on the surface of the raw material particles, and the amount of water-soluble polymer used for coating is 15 to 300 parts by mass per 100 parts by mass of raw material particles. The raw material particles include at least one selected from the group consisting of D-mannitol, lactose, crystalline cellulose, corn starch, silicon dioxide, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, and drugs. The aforementioned wet method is a method of stirring while spraying a solvent capable of dissolving the water-soluble polymer. The aforementioned nuclear particle.

2. A method for producing drug-containing particles having raw material particles and a coating layer on the outside thereof, wherein at least one drug is contained in the raw material particles and / or the coating layer, comprising a granulation step having a stirring function while spraying a solvent capable of dissolving the water-soluble polymer into a mixture containing the powder coating core particles described in claim 1 and a drug and / or a pharmaceutically acceptable additive (provided that the drug and / or pharmaceutically acceptable additive is in powder form), wherein the sprayed solvent does not contain dissolved polymers or drugs.

3. The manufacturing method according to claim 2, comprising the step of granulating while stirring at a temperature of 35 to 100°C.

4. The manufacturing method according to claim 2 or 3, wherein the drug-containing particles have a discontinuous layer between the raw material particles and the coating layer.

5. The manufacturing method according to any one of claims 2 to 4, wherein the Span of the drug-containing particles is 1.0 or less.

6. The manufacturing method according to any one of claims 2 to 5, wherein the degree of compressibility of the drug-containing particles is 14% or less.

7. Drug-containing particles produced by the manufacturing method described in any one of claims 2 to 6.

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