WO2021060304A1 - 不快な味がマスクされた顆粒剤及びその製造方法 - Google Patents
不快な味がマスクされた顆粒剤及びその製造方法 Download PDFInfo
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- WO2021060304A1 WO2021060304A1 PCT/JP2020/035883 JP2020035883W WO2021060304A1 WO 2021060304 A1 WO2021060304 A1 WO 2021060304A1 JP 2020035883 W JP2020035883 W JP 2020035883W WO 2021060304 A1 WO2021060304 A1 WO 2021060304A1
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- Prior art keywords
- active ingredient
- particles
- unpleasant taste
- core particles
- ethyl cellulose
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- 239000008187 granular material Substances 0.000 title claims abstract description 65
- 235000019640 taste Nutrition 0.000 title claims abstract description 50
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 31
- 239000004480 active ingredient Substances 0.000 claims abstract description 108
- 239000002245 particle Substances 0.000 claims abstract description 48
- 239000001856 Ethyl cellulose Substances 0.000 claims abstract description 37
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims abstract description 37
- 235000019325 ethyl cellulose Nutrition 0.000 claims abstract description 37
- 229920001249 ethyl cellulose Polymers 0.000 claims abstract description 37
- 239000007771 core particle Substances 0.000 claims abstract description 35
- 238000000576 coating method Methods 0.000 claims abstract description 27
- 239000011248 coating agent Substances 0.000 claims abstract description 25
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000004246 zinc acetate Substances 0.000 claims abstract description 15
- 238000010828 elution Methods 0.000 claims description 29
- 239000000725 suspension Substances 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 19
- 239000007884 disintegrant Substances 0.000 claims description 15
- 239000011230 binding agent Substances 0.000 claims description 13
- 239000004014 plasticizer Substances 0.000 claims description 13
- 239000012085 test solution Substances 0.000 claims description 12
- 229920002678 cellulose Polymers 0.000 claims description 8
- 239000001913 cellulose Substances 0.000 claims description 8
- 238000005507 spraying Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 150000001720 carbohydrates Chemical class 0.000 claims description 7
- 239000012798 spherical particle Substances 0.000 claims description 5
- 239000006185 dispersion Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 238000010998 test method Methods 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 2
- 238000010298 pulverizing process Methods 0.000 claims 1
- 238000007873 sieving Methods 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 abstract description 15
- 238000002360 preparation method Methods 0.000 description 11
- 239000003814 drug Substances 0.000 description 10
- 230000000873 masking effect Effects 0.000 description 9
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 6
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 6
- 239000008186 active pharmaceutical agent Substances 0.000 description 5
- 238000007922 dissolution test Methods 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 4
- 229940088679 drug related substance Drugs 0.000 description 4
- -1 for example Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 3
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 230000009747 swallowing Effects 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 239000001069 triethyl citrate Substances 0.000 description 3
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 3
- 235000013769 triethyl citrate Nutrition 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000004683 dihydrates Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 208000002972 Hepatolenticular Degeneration Diseases 0.000 description 1
- 206010021148 Hypozincaemia Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000018839 Wilson disease Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 235000019606 astringent taste Nutrition 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 235000021552 granulated sugar Nutrition 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000013021 overheating Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- DJWUNCQRNNEAKC-UHFFFAOYSA-L zinc acetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O DJWUNCQRNNEAKC-UHFFFAOYSA-L 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/30—Zinc; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
Definitions
- the present invention relates to a granule in which the unpleasant taste of the active ingredient is masked and the quick-release property of the active ingredient is maintained, and a method for producing the same.
- the present invention relates to granules containing zinc acetate as an active ingredient having an unpleasant taste and a method for producing the same.
- the therapeutic agents containing zinc acetate that have been used so far are capsules and film-coated tablets, the problem of the unpleasant taste of the active ingredient when taken has not become apparent.
- zinc acetate preparations are used for patients of a wide range of ages from children to the elderly, granule-form preparations that are easier to take and whose dose can be easily adjusted are desired.
- Patent Document 1 in the production of a quick-release granular preparation masking an unpleasant taste, ethyl cellulose and hydroxypropyl cellulose are dissolved in hydrous ethanol for a nucleus containing a pharmacologically active substance, and this is dissolved for elementary granules.
- a method of coating 60 to 100% is disclosed.
- Patent Document 2 discloses a method using an aqueous ethyl cellulose suspension as a coating method that does not use an organic solvent.
- Patent Document 2 discloses a method in which a nucleus containing a pharmacologically active substance is coated with an aqueous suspension of ethyl cellulose and then heat-treated under a constant humidity.
- Patent Document 3 as a technique for masking an unpleasant taste and for rapid release, a core containing a pharmacologically active substance is first coated with a water-soluble polymer as an intermediate layer, and then a certain amount is provided.
- a method of coating a 20-40% aqueous suspension of ethyl cellulose containing a plasticizer of the above is disclosed.
- the present invention has been made in view of the above circumstances, and an object of the present invention is to provide a granule in which the unpleasant taste of the active ingredient is masked and the quick-release property of the active ingredient is maintained, and a method for producing the same.
- the present inventors have diligently studied the heat treatment in the coating process with a conventional release system, and surprisingly, this heating process is put into a sealed state contrary to the common general technical knowledge. By doing so, the problem was solved and the present invention was reached. That is, by heat-treating the core particles sprayed with the water-dispersed ethyl cellulose suspension in a closed state, the active ingredient having an unpleasant taste is not released in the mouth after taking the drug, but the active ingredient in the stomach after swallowing. Succeeded in obtaining a granule having a coating having an amount or thickness capable of immediately releasing the substance, and reached the present invention.
- the term core particle is used to mean the particle which becomes the center of each particle which constitutes a granule.
- immediate release is used to mean that the active ingredient is released early in the stomach after swallowing.
- the present invention comprises (1) a step of obtaining core particles containing an active ingredient having an unpleasant taste, (2) a step of coating the surface of the core particles obtained in step (1) with ethyl cellulose, and (3).
- a method for producing granules which comprises a step of heat-treating the particles obtained in the step (2) in a sealed state, in which the unpleasant taste of the active ingredient is masked and the quick-release property of the active ingredient is maintained. ..
- the present invention is a granule obtained by the production method described in the present specification, in which the unpleasant taste of the active ingredient is masked and the quick-release property of the active ingredient is maintained.
- the present invention is effective in masking the unpleasant taste of the active ingredient by coating the core particles containing the active ingredient having an unpleasant taste with a film containing 2 to 12% by weight of ethyl cellulose with respect to the core particles. It is a granule in which the quick-release property of the ingredient is maintained.
- core particles containing an active ingredient having an unpleasant taste are coated with a film containing 2 to 12% by weight of ethyl cellulose with respect to the core particles, and the second method of dissolution test (paddle) of the Japanese Pharmacopoeia. It is a granule having an elution 5-minute value of 80% or less and an elution 15-minute value of 85% or more according to the method, test solution: water, test solution amount: 900 mL, 50 rpm).
- Examples of the active ingredient having an unpleasant taste that can be used in the present invention include various substances having an unpleasant flavor such as bitterness and astringency, but it is difficult to maintain immediate release while masking the conventional taste. It is particularly effective to use it for a highly water-soluble substance, for example, zinc acetate.
- Zinc acetate may be anhydrous or hydrated, more preferably dihydrate.
- the step (1) can be a step of spraying a solution or suspension of the active ingredient onto the core particles of the core particles to coat the particles with the active ingredient.
- the core particle of the core particle is not particularly limited as long as it is a particle whose main component is a substance having disintegration in the body, such as saccharide and / or crystalline cellulose.
- particles containing sucrose and corn starch as main constituents, particles composed of lactose and crystalline cellulose, spherical particles composed of D-mannitol, granulated sugar and the like can be used.
- the shape of the core particles of the core particles is not particularly limited, but preferably substantially spherical particles can be used. The closer the particle shape is to a sphere, the more uniform the coating of the active ingredient and the like, and the more stable the quality.
- step (1) can be a step of coating a binder in addition to the active ingredient.
- the binder may be contained in a solution or suspension of the active ingredient and sprayed together with the active ingredient, prepared as a solution separate from the solution or suspension of the active ingredient, and sprayed simultaneously with or individually of the active ingredient. You may. By coating the binder together with the active ingredient, the bond between the active ingredient and the core particles can be strengthened.
- the binder may be any one generally used in the pharmaceutical field, and examples thereof include hydroxypropyl cellulose, polyvinyl alcohol, hydroxypropyl methyl cellulose, methyl cellulose, gum arabic, gelatin, starch and the like, and hydroxypropyl cellulose is preferable.
- the blending amount of the binder may be appropriately set as long as the amount of the core particles and the active ingredient can be sufficiently bonded.
- step (1) can be a step of coating a disintegrant in addition to the active ingredient.
- the disintegrant may be contained in a solution or suspension of the active ingredient and sprayed together with the active ingredient, prepared as a solution separate from the solution or suspension of the active ingredient, and sprayed simultaneously with or individually of the active ingredient. You may.
- the disintegrant may be any one generally used in the pharmaceutical field, and examples thereof include partially pregelatinized starch, carboxymethyl cellulose, croscarmellose sodium, crospovidone and the like, and partially pregelatinized starch is preferable.
- the amount of disintegrant can be appropriately adjusted so as to achieve the desired dissolution rate.
- either one of the binder and the disintegrant may be coated on the particles together with the active ingredient, or these may be simultaneously coated on the particles together with the active ingredient.
- the binder and the disintegrant may be mixed with the solution or suspension of the active ingredient and sprayed together with the active ingredient, and the binder and the disintegrant may be bonded separately from the solution or suspension of the active ingredient. Solutions of agents and disintegrants may be prepared and sprayed simultaneously with or individually of the active ingredient.
- an active ingredient having an unpleasant taste is granulated together with a formulation aid such as an excipient, pulverized, and sieved so as to have a constant particle size. It can be a process.
- excipients examples include sugars such as lactose, sucrose and mannitol, starches such as corn starch and potato starch, and binders such as hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol and polyvinyl alcohol.
- sugars such as lactose, sucrose and mannitol
- starches such as corn starch and potato starch
- binders such as hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol and polyvinyl alcohol.
- step (2) can be a step of spray-coating the aqueous dispersion ethyl cellulose suspension.
- the coating amount of ethyl cellulose is 2 to 12% by weight, preferably 5 to 9% by weight, and more preferably 5 to 7% by weight with respect to the core particles.
- step (2) can be a step of coating a plasticizer together with ethyl cellulose.
- a plasticizer By coating ethyl cellulose with a plasticizer, particles can be formed more completely.
- the plasticizer may be any one generally used in the pharmaceutical field, and examples thereof include triethyl citrate, polyethylene glycol, propylene glycol, and triacetin.
- the amount of plasticizer can be appropriately selected and used. For example, when coating a granule having a particle size of 200 to 1000 ⁇ m, an amount of about 5 to 20% by weight may be used with respect to ethyl cellulose.
- the heat treatment in the step (3) heats the particles in a sealed state so as to prevent the moisture contained in the particles from being released to the outside of the system due to overheating to some extent.
- Heating the particles in a closed state means heating the particles under closed conditions, even if the water contained in the particles can be prevented from being released to the outside of the system to some extent. Just do it.
- it means putting the particles obtained in the step (2) into a closed container and heating them.
- the heating in the step (3) is preferably performed under a so-called airtight condition in which liquid does not enter and exit, and more preferably performed in a so-called closed state under a condition in which water vapor, air and other gases do not enter and exit. ..
- the heating may be performed under conditions sufficient for forming a film with ethyl cellulose coated on the particle surface, for example, the temperature may be 70 to 100 ° C., and the treatment time may be 15 to 180 minutes.
- a fluidizing agent in the heating step in the step (3), can be added to the particles obtained in the step 2 in advance. By adding the fluidizing agent, it is possible to prevent the particles from adhering to each other and agglomerating in the heating step.
- the fluidizing agent may be any one generally used in the pharmaceutical field, and examples thereof include light anhydrous silicic acid.
- the amount of the fluidizing agent added may be an amount sufficient to disperse the particles, and specifically, it may be used in an amount of about 0.5 to 1% by weight based on the particles.
- the term "the unpleasant taste of the active ingredient was masked and the rapid release of the active ingredient was maintained" is used in the initial stage of administration of the granule (the time during which the granule is present in the mouth). It means that the active ingredient does not elute, and that a sufficient amount of the active ingredient elutes after a certain period of time (early time point after swallowing). For example, when the test was carried out by the second dissolution test method (paddle method, test solution: water, test solution volume: 900 mL, 50 rpm) of the Japanese Pharmacy, the dissolution 5-minute value of the active ingredient was 80% or less, and dissolution.
- the production method according to the present invention comprises step (1): spraying a solution or suspension containing an active ingredient and a binder onto substantially spherical particles containing saccharides and / or crystalline cellulose as a main component. Then, a step of spraying a solution or suspension of a disintegrant, step (2): a step of spraying an aqueous dispersion ethyl cellulose suspension containing a plasticizer, a step (3): adding a fluidizing agent and sealing.
- the step of heating in a state of 70 to 100 ° C. for 15 to 180 minutes can be carried out in sequence.
- One aspect of the granules of the present invention is a granule obtained by a method including the above-mentioned steps (1), (2), and (3).
- one aspect of the granule of the present invention is that the core particles containing the active ingredient having an unpleasant taste are coated with a film containing 2 to 12% by weight of ethyl cellulose with respect to the core particles, which is unpleasant for the active ingredient. It is a granule in which the taste is masked and the quick-release of the active ingredient is maintained.
- Such granules can be produced, for example, by the method described above.
- One aspect of the granules of the present invention is to coat core particles containing an active ingredient having an unpleasant taste with a film containing 2 to 12% by weight of ethyl cellulose with respect to the core particles, and elute from the Japanese Pharmacopoeia.
- Granules having an elution 5-minute value of 80% or less and an elution 15-minute value of 85% or more according to the second test method (paddle method, test solution: water, test solution amount: 900 mL, 50 rpm).
- Such granules can be produced, for example, by the method described above.
- Examples of the active ingredient having an unpleasant taste that can be used in the granules of the present invention include the above-mentioned active ingredients, for example, zinc acetate.
- Zinc acetate may be anhydrous or hydrated, more preferably dihydrate.
- the particle size of the granules of the present invention can be appropriately selected and is not particularly limited, but can be, for example, about 200 to 700 ⁇ m. By using a particle size of this degree, it is possible to obtain a preparation that is easy to take even for children and the elderly.
- Example 1 450 g of a 20% ethyl cellulose suspension containing about 2% triethyl citrate was sprayed onto 1500 g of the obtained API particles, and sieved using an 18-mesh sieve to obtain ethyl cellulose-coated particles. To the obtained ethyl cellulose-coated particles, 0.7% of light anhydrous silicic acid was added, mixed, placed in a closed container, and heated at 80 ° C. for 2 hours (hereinafter, referred to as “sealed condition heated granules”). ..
- the elution 15-minute value was almost 100% for both the closed-condition heated granules and the release-condition heated granules, and no difference was observed between the two. From this result, it was confirmed that both the sealed condition heated granules and the release condition heated granules had sufficient quick-release properties of the active ingredient.
- the elution of the sealed condition heated granules was significantly suppressed as compared with the release condition heated granules. This result indicates that the elution of the active ingredient in the early stage after administration is significantly suppressed and the unpleasant taste is effectively masked by performing the heat treatment under the closed condition.
- the production method of the present invention that is, a production method including performing the heat treatment in the coating step under closed conditions, the unpleasant taste of the active ingredient is masked and the quick release of the active ingredient can be achieved. It was confirmed that the maintained granules could be produced.
- Example 2 Coating amount of ethyl cellulose
- the amount of the 20% ethyl cellulose suspension containing about 2% of triethyl citrate sprayed on the drug substance-coated elementary particles is adjusted so that the coating amount (the amount of ethyl cellulose coated on the drug substance-coated elementary particles) is 5, 6 and 7% by weight. Except for the adjustment, the same operation as in Example 1 was carried out to prepare sealed condition heated granules, and the elution amount of the active ingredient was confirmed by the same test method as in Example 1. The results are shown in FIG. 2 (relationship between the amount of ethyl cellulose coated and the elution rate of the active ingredient).
- the elution 15-minute value showed a value of 85% or more for all coating amounts of granules. From this result, it was confirmed that the quick-release property of the active ingredient was maintained in all the granules. In addition, the 5-minute elution value was less than 70% for all the coating amounts of the granules, which was a good value. From this result, it was confirmed that the unpleasant taste was masked in all the granules.
- Example 2 The same operation as in Example 1 was carried out except that the amount of the plasticizer to be blended in the ethyl cellulose suspension was adjusted to be 7, 9 and 11% by weight based on ethyl cellulose, and the sealed condition heated granules were prepared. The preparation was carried out, and the elution amount of the active ingredient was confirmed by the same test method as in Example 1. The results are shown in FIG. 3 (relationship between the amount of plasticizer added and the elution rate of the active ingredient).
Abstract
Description
なお、本明細書において、コア粒子といった語は、顆粒剤を構成するそれぞれの粒子の中心となる粒子といった意味で用いられる。また、速放性という語は、嚥下後胃の中で有効成分が早期に放出されるといった意味に用いる。
精製白糖及びコーンスターチからなる粒径355~500μmの球状粒子(製品名:ノンパレル(登録商標)-101、フロイント産業株式会社製)1300gを転動流動装置に仕込み、給気温度65℃の条件で、下記組成の原薬溶解液、崩壊剤懸濁液の順にスプレーし、原薬被覆素粒子を得た。
原薬溶解液:6%ヒドロキシプロピルセルロース溶液1183gに、酢酸亜鉛水和物(C4H6O4Zn・2H2O)338.6gを溶解させた液。
崩壊剤懸濁液:6%ヒドロキシプロピルセルロース溶液352gに、部分α化デンプン41.1gを加えて懸濁させた液。
得られた原薬被覆素粒子1500gに対し、クエン酸トリエチル約2%含有20%エチルセルロース懸濁液450gをスプレーし、18メッシュの篩を用いて篩分し、エチルセルロース被覆粒子を得た。
得られたエチルセルロース被覆粒子に、0.7%相当の軽質無水ケイ酸を加えて混合し、密閉容器に入れて80℃の条件で2時間加熱した(以下、「密閉条件加熱顆粒剤」という)。
比較のため、0.7%相当の軽質無水ケイ酸を混合した上記エチルセルロース被覆粒子を開放した容器に入れ、80℃の条件で2時間加熱した粒子を得た(以下、「開放条件加熱顆粒剤」という)。
日本薬局方の溶出試験第2法(パドル法、試験液:水、試験液量:900mL、50rpm)に従い、調製した顆粒剤(密閉条件加熱顆粒剤及び開放条件加熱顆粒剤)について、有効成分の溶出5分値、溶出15分値及び溶出30分値を測定した。定量は、紫外可視吸光光度計(検出試薬:1-(2-ヒドロキシカルボニルフェニル)-5-(2-ヒドロキシ-5-スルフォフェニル)-3-フェニルホルマザン、測定波長:620nm)を用いた。結果を、図1(密閉条件加熱製剤と解放条件加熱製剤における有効成分溶出率の比較)及び表1(溶出試験の結果)に示す。
Claims (19)
- (1)不快な味を有する有効成分を含むコア粒子を得る工程、
(2)工程(1)により得られたコア粒子の表面に、エチルセルロースを被覆する工程、及び
(3)工程(2)により得られた粒子を、密閉状態で加熱処理する工程、
を含む、有効成分の不快な味がマスクされ、かつ有効成分の速放性が維持された顆粒剤の製造方法。 - 工程(1)が、糖類及び/又は結晶セルロースを主成分とする粒子に、有効成分を被覆する工程である、請求項1に記載の製造方法。
- 工程(1)が、糖類及び/又は結晶セルロースを主成分とする粒子に、結合剤及び/又は崩壊剤を、有効成分と共に被覆する工程である、請求項1又は2に記載の製造方法。
- 工程(1)が、糖類及び/又は結晶セルロースを主成分とする粒子に、有効成分含有溶液又は有効成分含有懸濁液を噴霧して前記粒子を有効成分で被覆する工程である、請求項1~3のいずれか一項に記載の製造方法。
- 工程(1)が、糖類及び/又は結晶セルロースを主成分とする粒子に、結合剤を含む有効成分含有溶液又は有効成分含有懸濁液を噴霧して前記粒子を有効成分で被覆し、さらに
得られた粒子に、崩壊剤を含む溶液又は懸濁液を噴霧して、前記得られた粒子を崩壊剤で被覆する工程である、請求項1~4のいずれか一項に記載の製造方法。 - 糖類及び/又は結晶セルロースを主成分とする粒子が、略球状の粒子である、請求項2~5のいずれか一項に記載の製造方法。
- 工程(1)が、不快な味を有する有効成分を製剤助剤と共に造粒したものを粉砕し、一定の粒径となる様に篩分する工程である、請求項1に記載の製造方法。
- 工程(2)が、工程(1)で得られたコア粒子の表面に、水分散エチルセルロース懸濁液を噴霧コーティングする工程である、請求項1~7のいずれか一項に記載の製造方法。
- 工程(2)が、工程(1)で得られたコア粒子の表面に、エチルセルロースと共に可塑剤を被覆する工程である、請求項1~8のいずれか一項に記載の製造方法。
- 工程(2)が、工程(1)で得られたコア粒子に、可塑剤を含む水分散エチルセルロース懸濁液を噴霧コーティングする工程である、請求項1~9のいずれか一項に記載の製造方法。
- 工程(2)におけるエチルセルロースのコーティング量が、コア粒子に対して5~9重量%である、請求項1~10のいずれか一項に記載の製造方法。
- 工程(2)におけるエチルセルロースのコーティング量が、コア粒子に対して5~7重量%である、請求項11に記載の製造方法。
- 工程(3)が、工程(2)により得られた粒子を、密閉状態かつ70~100℃の条件で、15~180分間加熱処理する工程である、請求項1~12のいずれか一項に記載の製造方法。
- 不快な味を有する有効成分が、酢酸亜鉛である、請求項1~13のいずれか一項に記載の製造方法。
- 得られた顆粒剤の日本薬局方の溶出試験第2法(パドル法、試験液:水、試験液量:900mL、50rpm)による有効成分の溶出5分値が80%以下であり、かつ溶出15分値が85%以上である、請求項1~14のいずれか一項に記載の製造方法。
- 請求項1~15のいずれか一項に記載の方法により得られた、有効成分の不快な味がマスクされ、かつ有効成分の速放性が維持された顆粒剤。
- 不快な味を有する有効成分を含むコア粒子を、前記コア粒子に対して2~12重量%のエチルセルロースを含む被膜で被覆した、有効成分の不快な味がマスクされ、かつ有効成分の速放性が維持された顆粒剤。
- 不快な味を有する有効成分を含むコア粒子を、前記コア粒子に対して2~12重量%のエチルセルロースを含む被膜で被覆し、かつ
日本薬局方の溶出試験第2法(パドル法、試験液:水、試験液量:900mL、50rpm)による有効成分の溶出5分値が80%以下で、溶出15分値が85%以上である顆粒剤。 - 不快な味を有する有効成分が酢酸亜鉛である、請求項17又は18に記載の顆粒剤。
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CA3153004A CA3153004A1 (en) | 2019-09-25 | 2020-09-24 | Granule having masked unpleasant taste and method for producing same |
AU2020352037A AU2020352037A1 (en) | 2019-09-25 | 2020-09-24 | Granule having masked unpleasant taste and method for producing same |
US17/642,107 US20230016901A1 (en) | 2019-09-25 | 2020-09-24 | Granule in which unpleasant taste is masked and method for producing granule |
EP20867214.7A EP4035733A4 (en) | 2019-09-25 | 2020-09-24 | GRANULE HAVING HIDDEN UNPLEASANT TASTE AND METHOD FOR PRODUCING SAME |
JP2021503619A JP6905781B1 (ja) | 2019-09-25 | 2020-09-24 | 不快な味がマスクされた顆粒剤及びその製造方法 |
CN202080059661.5A CN114340601A (zh) | 2019-09-25 | 2020-09-24 | 掩盖了令人不快的味道的颗粒剂及其制造方法 |
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH09194347A (ja) | 1996-01-18 | 1997-07-29 | Asahi Chem Ind Co Ltd | フィルムコーティング粒剤の製造方法 |
JP2000053563A (ja) | 1998-08-07 | 2000-02-22 | Bayer Yakuhin Ltd | 苦味がマスクされた速放性細粒剤 |
JP2007031292A (ja) * | 2005-07-22 | 2007-02-08 | Hamari Chemicals Ltd | 亜鉛化合物含有組成物およびその製造方法 |
WO2008013197A1 (en) * | 2006-07-26 | 2008-01-31 | Asahi Kasei Chemicals Corporation | Spherical crude granule and method for production thereof |
JP2008081448A (ja) | 2006-09-28 | 2008-04-10 | Kowa Pharmaceutical Co Ltd | 酒石酸ゾルピデムの苦味マスキング速放性粒子 |
WO2011043370A1 (ja) * | 2009-10-09 | 2011-04-14 | 旭化成ケミカルズ株式会社 | コーティングフィルム、及びそれを用いた顆粒、錠剤 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005039538A1 (ja) * | 2003-10-29 | 2005-05-06 | Shionogi & Co., Ltd. | 不快味を改善した被覆製剤の製造方法 |
CN103096880B (zh) * | 2010-09-13 | 2016-08-24 | 大鹏药品工业株式会社 | 不愉快味道被掩蔽的含药膜包覆的颗粒 |
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH09194347A (ja) | 1996-01-18 | 1997-07-29 | Asahi Chem Ind Co Ltd | フィルムコーティング粒剤の製造方法 |
JP2000053563A (ja) | 1998-08-07 | 2000-02-22 | Bayer Yakuhin Ltd | 苦味がマスクされた速放性細粒剤 |
JP2007031292A (ja) * | 2005-07-22 | 2007-02-08 | Hamari Chemicals Ltd | 亜鉛化合物含有組成物およびその製造方法 |
WO2008013197A1 (en) * | 2006-07-26 | 2008-01-31 | Asahi Kasei Chemicals Corporation | Spherical crude granule and method for production thereof |
JP2008081448A (ja) | 2006-09-28 | 2008-04-10 | Kowa Pharmaceutical Co Ltd | 酒石酸ゾルピデムの苦味マスキング速放性粒子 |
WO2011043370A1 (ja) * | 2009-10-09 | 2011-04-14 | 旭化成ケミカルズ株式会社 | コーティングフィルム、及びそれを用いた顆粒、錠剤 |
Non-Patent Citations (2)
Title |
---|
"Handbook of Pharmaceutical Excipients", 28 February 2007, YAKUJI NIPPO, LIMITED, JP , ISBN: 978-4-8408-0968-9, article "Zinc acetate", pages: 340 - 341, XP009533810 * |
See also references of EP4035733A4 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024005767A1 (en) * | 2022-07-01 | 2024-01-04 | Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi | A taste masked solid composition of zinc active |
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