JPWO2020218517A5 - - Google Patents

Description

[0029]
It can be carried out by the same method as the measurement of the degree of cohesion of the nuclear particles.
[0087]
Further, it is preferable that the cohesiveness of the pharmaceutical product is improved (lower) than the cohesiveness of the nuclear particles.
[0088]
The particle size of the pharmaceutical product is not particularly limited, but preferably the 50% particle size (D50) based on the volume distribution is 100 to 400 μm, and more preferably 120 to 250 μm. The measurement of the 50% particle size (D50) based on the volume distribution of the pharmaceutical product can be performed by the same method as the measurement of the 50% particle size (D50) based on the volume distribution of the nuclear particle component described above.
[089]
The pharmaceutical preparation of the present invention may be used as it is, or may be used as a preparation having various dosage forms. The dosage form of the preparation is not particularly limited as long as the effect of the present invention is exhibited, and examples thereof include granules, tablets, pills, capsules, powders and the like. Of these, granules, tablets and capsules are preferred. Further, examples of the capsule include a hard capsule.
[0090]
[Manufacturing method of pharmaceutical product]
The method for producing the pharmaceutical preparation of the present invention is not particularly limited, and a known method can be used. The conditions for producing the pharmaceutical product can be appropriately adjusted depending on the types of the nuclear particle component, the non-volatile solvent, the drug, the coating layer component and the like. Specifically, the pharmaceutical product of the present invention can be produced, for example, according to the following procedure. First, a fluidized bed of a first nuclear particle component, which is needle-like and / or substantially columnar crystalline cellulose, and a second nuclear particle component, which is a substantially spherical at least one pharmaceutically acceptable additive. Mix using a granulator (for example, FD-MP-01D, manufactured by Paulek Co., Ltd.) to obtain a nuclear particle mixture. On the other hand, a drug is added to a non-volatile solvent and stirred using a stirrer (NZ-1200, manufactured by Tokyo Rika Kikai Co., Ltd.) to obtain a mixed solution (drug solution) in which the drug is dissolved or suspended. Next, the obtained mixture and the mixed solution are brought into contact with each other using a fluidized bed granulator, and the mixed solution is adhered to the nuclear particle components in the mixture to obtain nuclear particles. Here, the contact between the mixture and the mixture is carried out by, for example, a method of spraying the mixture on the mixture, a method of immersing the mixture in the mixture, or the like. Then, the nuclear particles are needed

0033
[Table 2]

［００９７］
＜核粒子混合物のかさ密度の測定＞
得られたそれぞれの核粒子混合物について、かためかさ密度およびゆるみかさ密度を測定した。具体的には、パウダテスタ（登録商標）ＰＴ－Ｒ（ホソカワミクロン株式会社製）を用いて、第１７改正日本薬局方に記載されている、かさ密度およびタップ密度測定法第３法の測定用容器と同サイズの円筒容器に核粒子混合物を篩いを通して上方から均一に供給し、上面をすり切って秤量することによって疎充填の状態のかさ密度（ゆるみかさ密度）を測定。次いで、この容器の上に補助円筒をはめ、この上縁まで核粒子混合物を加えてタッピングを１８０回行ない、終了後、補助円筒を外して容器の上面で核粒子混合物をすり切って秤量し、タッピング後の密充填した場合のかさ密度（かためかさ密度）を測定した。さらに、各核粒子混合物について、かためかさ密度とゆるみかさ密度の差（かためかさ密度－ゆるみ0034
[0906]
Next, the mixture of each Example and Comparative Example was put into a fluidized bed granulator (FD-MP-01D, manufactured by Paulek Co., Ltd.), and the nuclear particle mixture was mixed under the conditions shown in Table 3 (preheating step).
[Table 3]

[097]
<Measurement of bulk density of nuclear particle mixture>
The bulk density and loose bulk density were measured for each of the obtained nuclear particle mixtures. Specifically, using Powder Tester (registered trademark) PT-R (manufactured by Hosokawa Micron Co., Ltd.), the container for measuring bulk density and tap density measurement method 3 described in the 17th revised Japanese Pharmacopoeia. The bulk density (loose bulk density) in a loosely filled state is measured by uniformly supplying the nuclear particle mixture through a sieve to a cylindrical container of the same size from above and then scraping the upper surface and weighing. Next, an auxiliary cylinder is fitted on the container, the nuclear particle mixture is added up to the upper edge, and tapping is performed 180 times. After the completion, the auxiliary cylinder is removed and the nuclear particle mixture is scraped and weighed on the upper surface of the container. The bulk density (bulk density) in the case of tight packing after tapping was measured. In addition, for each nucleus particle mixture, the difference between bulk density and loose bulk density (bulk density-looseness).

0036
[0099]
Further, according to the formulation shown in Table 2, each non-volatile solvent was put into a 500 mL beaker, and the mixture was stirred and mixed at 400 to 900 rpm using a stirrer (NZ-1200, manufactured by Tokyo Rika Kikai Co., Ltd.). After stirring and mixing until uniform, each drug was added, and the mixture was further stirred and mixed to obtain a drug solution. The logP values of each drug are as shown in Table 2.
[0100]
Next, using a fluidized bed granulator (FD-MP-01D, manufactured by Paulek Co., Ltd.), the drug solution was sprayed onto each of the nuclear particle mixtures obtained above, and the nuclei to which the drug solution adhered to the nuclear particle mixture. Particles were obtained (granulation process). The setting conditions of the fluidized bed granulator are as shown in Table 3 above.
[0101]
<Measurement of cohesion of nuclear particles>
The degree of cohesion of the obtained nuclei particles of the pharmaceutical preparations of Examples and Comparative Examples was measured using a powder characterization device (Powder Tester (registered trademark) PT-R, manufactured by Hosokawa Micron Co., Ltd.). The setting conditions of the powder property evaluation device were as follows.
Mesh opening: (upper) 710 μm, (middle) 355 μm, (lower) 250 μm
Sampling volume: 2g or 3g
Vibration time: 119 seconds [0102]
Under the above conditions, the value of each item in the following formula is measured.
X = [mass of powder remaining on the upper sieve] / mass of charged powder x 100
Y = [Mass of powder remaining on the middle sieve] / Mass of charged powder x 100 x 0.6
Z = [Mass of powder remaining on the lower sieve] / Mass of powder charged × 100 × 0.2
The sum of the above three values X, Y, and Z is defined as the degree of cohesion (%). The results are shown in Table 4 above.
[0103]
Further, according to the formulation shown in Table 2, each coating layer component is put into a stainless steel container, and the coating layer solution is prepared by stirring and mixing at 400 to 900 rpm using a stirrer (NZ-1200, manufactured by Tokyo Rika Kikai Co., Ltd.). Obtained.
[0104]
Next, a fluidized bed granulator (FD-MP-01D, manufactured by Paulek Co., Ltd.) was installed.

Claims (48)

A pharmaceutical preparation in the form of granules comprising a nucleus particle and a coating layer covering the nucleus particle.
The nuclear particles comprises a drug, a first nuclear particle component, a second nuclear particle component and a non-volatile solvent.
The first nuclear particle component is at least one crystalline cellulose having a shape selected from needle-like and substantially columnar.
The second nuclear particle component is a substantially spherical at least one pharmaceutically acceptable additive.
The pharmaceutical preparation in which the nuclear particle has a void between the first nuclear particle component and the second nuclear particle component. The pharmaceutical preparation according to claim 1, wherein the coating layer is located adjacent to the nuclear particles. The pharmaceutical preparation according to claim 1 or 2, wherein the drug is attached to the surface of at least one of the first nuclear particle component and the second nuclear particle component. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the drug and the non-volatile solvent are retained in the voids of the nuclear particles. The pharmaceutical preparation according to any one of claims 1 to 4, wherein the average aspect ratio of the first nuclear particle component is 1.8 or more. The pharmaceutical preparation according to claim 5, wherein the average aspect ratio of the first nuclear particle component is 1.8 to 10.0. The pharmaceutical preparation according to any one of claims 1 to 6, wherein the average aspect ratio of the second nuclear particle component is 1.0 to 1.7. The pharmaceutical preparation according to claim 7, wherein the average aspect ratio of the second nuclear particle component is 1.0 to 1.5. The pharmaceutical preparation according to any one of claims 1 to 8, wherein the difference in the average aspect ratio between the first nuclear particle component and the second nuclear particle component is 0.5 or more. The ratio of the 50% particle diameter (D50) of the volume distribution standard of the second nuclear particle component to the 50% particle diameter (D50) of the volume distribution standard of the first nuclear particle component is 1: 1.1 or less. , The pharmaceutical preparation according to any one of claims 1 to 9. The pharmaceutical preparation according to any one of claims 1 to 10, wherein the second nuclear particle component comprises at least two different components. The pharmaceutical preparation according to any one of claims 1 to 11, wherein the mass ratio of the first nuclear particle component to the second nuclear particle component is 1: 1 to 1:10. Any of claims 1 to 12, wherein the mass ratio of the total mass of the first nuclear particle component and the second nuclear particle component to the non-volatile solvent is 1: 0.01 to 1: 0.6. The pharmaceutical preparation according to paragraph 1. The pharmaceutical preparation according to any one of claims 1 to 13, wherein the mass ratio of the non-volatile solvent to the drug is 1: 0.1 to 1:10. Any of claims 1 to 14, wherein the mass ratio of the total mass of the first nuclear particle component and the second nuclear particle component to the mass of the coating layer is 1: 0.05 to 1: 0.3. The pharmaceutical preparation according to item 1. The pharmaceutical preparation according to any one of claims 1 to 15, wherein the second nuclear particle component is at least one pharmaceutically acceptable additive selected from the group consisting of saccharides and inorganic compounds. .. The second nuclear particle component is glucose, fructose, lactose, lactose hydrate, sucrose, sucrose, compressed, etc., refined powdered sugar, ammonium alginate, starch, potato starch, wheat starch, corn starch, rice starch, mannitol. , Sorbitol, Phosphate, Magnesium Carbonate, Magnesium Oxide, Calcium Carbonate, Calcium Sulfate, Dextrose, Dextrin, Dextrose, Polymethacrylate, Glycerin Palmitostearate, Isomalt, Lactitol, Kaolin, Lactitol, Martinol, Maltodextrin, The pharmaceutical preparation according to any one of claims 1 to 16, which is at least one selected from the group consisting of maltose, trehalose, xylitol, pregelatinized starch, modified pregelatinized starch, tapioca starch, and sodium chloride. The pharmaceutical preparation according to any one of claims 1 to 17, wherein the non-volatile solvent contains at least one selected from the group consisting of surfactants, vitamins and fats and oils. The pharmaceutical preparation according to claim 18, wherein the surfactant is a nonionic surfactant. The pharmaceutical preparation according to claim 19, wherein the nonionic surfactant is polysorbate. The pharmaceutical preparation according to claim 18, wherein the fat and oil is a glycerin fatty acid ester. The pharmaceutical preparation according to claim 21, wherein the glycerin fatty acid ester is a medium-chain fatty acid triglyceride. The pharmaceutical preparation according to any one of claims 1 to 22, wherein the logP value of the drug is -2 to 7. The pharmaceutical preparation according to any one of claims 1 to 23, wherein the logP value of the drug is 1.9 to 6.5. The pharmaceutical preparation according to any one of claims 1 to 24, wherein the drug comprises a poorly water-soluble drug. The poorly water-soluble drug is at least one selected from the group consisting of hormonal agents, anticancer agents, antibacterial agents and antiviral agents (excluding N- [5-fluoro-2- (1-piperidinyl) phenyl] isonicotine thioamide). 25. The pharmaceutical formulation according to claim 25, comprising the seed. The pharmaceutical preparation according to any one of claims 1 to 26, wherein the coating layer contains a water-soluble coating agent. The pharmaceutical preparation according to claim 27, wherein the water-soluble coating agent contains at least one component selected from the group consisting of polyalkylene glycols, polysaccharides, and derivatives thereof. The water-soluble coating agent is polyethylene glycol, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methacrylic acid copolymer, vinyl pyridine copolymer, alkyl vinyl pyridine copolymer, amino cellulose derivative, diethyl aminoethyl methacrylate, polyvinyl acetal diethyl amino acetate, Dimethylaminoethyl methacrylate-methacrylate copolymer, cellulose acetate-N, N-di-n-butyl hydroxylpropyl ether, copolymer of vinylpyridine and acrylic acid-based free acid, copolymer of alkylvinylpyridine and acrylic acid-based free acid, vinyl Copolymer of pyridine and acrylic acid-based free acid and vinyl monomer, copolymer of alkylvinyl pyridine and acrylic acid-based free acid and vinyl monomer, 2-methyl-5-vinylpyridine-methacrylic acid copolymer, poly-2- (vinylphenyl) ) A group consisting of glycine, morpholino-N-β-ethylacrylate-methacrylic acid copolymer, shelac, cellulose acetate phthalate, methyl acrylate-methacrylic acid copolymer, methyl methacrylate-methacrylic acid copolymer, zein, hydroxypropyl methyl cellulose phthalate and aminoalkyl methacrylate copolymer. The pharmaceutical formulation according to claim 27 or 28, which is at least one selected from. The pharmaceutical preparation according to any one of claims 1 to 29, wherein the pharmaceutical preparation has a degree of cohesion of 70% or less. The pharmaceutical preparation according to any one of claims 1 to 30, wherein the degree of cohesion of the pharmaceutical preparation is lower than the degree of cohesion of the nuclear particles. The pharmaceutical product according to any one of claims 1 to 31, wherein the 50% particle size (D50) of the pharmaceutical product based on the volume distribution is 100 to 400 μm. A preparation comprising the pharmaceutical preparation according to any one of claims 1 to 32 and having a dosage form selected from the group consisting of granules, tablets, capsules, powders and pills. A method for producing a pharmaceutical preparation in the form of granules comprising nuclear particles and a coating layer covering the nuclear particles.
(A) A step of mixing a first nuclear particle component and a second nuclear particle component to obtain a nuclear particle mixture.
(B) A step of dissolving or suspending a drug in a non-volatile solvent to obtain a mixed solution.
(C) The nuclear particle mixture obtained in step (a) and the mixed solution obtained in step (b) are brought into contact with each other to bring the first nuclear particle component, the second nuclear particle component, the drug and the non-volatile solvent. The process of obtaining nuclear particles containing
(D) A step of coating the nuclear particles obtained in the step (c) to obtain a pharmaceutical preparation is included.
The first nuclear particle component is at least one crystalline cellulose having a shape selected from needle-like and substantially columnar.
The second nuclear particle component is a substantially spherical at least one pharmaceutically acceptable additive.
The production method, wherein the nuclear particles have a void between the first nuclear particle component and the second nuclear particle component. 34. The method of claim 34, wherein the coating layer is located adjacent to the nuclear particles. 34. The method of claim 34 or 35, wherein the drug is attached to the surface of at least one of the first nuclear particle component and the second nuclear particle component. The production method according to any one of claims 34 to 36, wherein the drug and the non-volatile solvent are retained in the voids of the nuclear particles. The production method according to any one of claims 34 to 37, wherein the average aspect ratio of the first nuclear particle component is 1.8 or more. The production method according to claim 38, wherein the average aspect ratio of the first nuclear particle component is 1.8 to 10.0. The production method according to any one of claims 34 to 39, wherein the average aspect ratio of the second nuclear particle component is 1.0 to 1.7. The production method according to claim 40, wherein the average aspect ratio of the second nuclear particle component is 1.0 to 1.5. The ratio of the 50% particle diameter (D50) of the volume distribution standard of the second nuclear particle component to the 50% particle diameter (D50) of the volume distribution standard of the first nuclear particle component is 1: 1.1 or less. , The manufacturing method according to any one of claims 34 to 41. The production method according to any one of claims 34 to 42, wherein the second nuclear particle component comprises at least two different components. The production method according to any one of claims 34 to 43, wherein the non-volatile solvent contains at least one selected from the group consisting of surfactants, vitamins and fats and oils. (E) Any one of claims 34 to 44, further comprising a step of adding a pharmaceutically acceptable additive to the pharmaceutical preparation obtained in step (d) and granulating the product to obtain a granular preparation. The manufacturing method described in the section. (E') Any of claims 34 to 44, further comprising the step of encapsulating the pharmaceutical preparation obtained in step (d) in a film made of gelatin or a plant-derived raw material to obtain a capsule-shaped preparation. The manufacturing method according to paragraph 1. A method for producing a tablet, comprising a step of tableting and molding the pharmaceutical preparation according to any one of claims 1 to 32 to obtain a tablet. A method for producing a capsule, comprising the step of encapsulating the pharmaceutical preparation according to any one of claims 1 to 32.