JPH0320215A - Granule with core and its production - Google Patents
Granule with core and its productionInfo
- Publication number
- JPH0320215A JPH0320215A JP1156085A JP15608589A JPH0320215A JP H0320215 A JPH0320215 A JP H0320215A JP 1156085 A JP1156085 A JP 1156085A JP 15608589 A JP15608589 A JP 15608589A JP H0320215 A JPH0320215 A JP H0320215A
- Authority
- JP
- Japan
- Prior art keywords
- agent
- granules
- coating
- coated
- spraying
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000008187 granular material Substances 0.000 title claims abstract description 69
- 238000004519 manufacturing process Methods 0.000 title description 7
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 58
- 238000000576 coating method Methods 0.000 claims abstract description 34
- 239000011248 coating agent Substances 0.000 claims abstract description 32
- 239000000843 powder Substances 0.000 claims abstract description 12
- 238000010410 dusting Methods 0.000 claims abstract description 11
- 239000011230 binding agent Substances 0.000 claims abstract description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 19
- 239000002270 dispersing agent Substances 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 17
- 229940079593 drug Drugs 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 10
- 239000011247 coating layer Substances 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- 239000007921 spray Substances 0.000 claims description 7
- 238000005507 spraying Methods 0.000 abstract description 33
- 239000000203 mixture Substances 0.000 abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 230000002411 adverse Effects 0.000 abstract description 2
- 238000007493 shaping process Methods 0.000 abstract 6
- 238000003892 spreading Methods 0.000 description 17
- 229920002261 Corn starch Polymers 0.000 description 10
- 239000008120 corn starch Substances 0.000 description 10
- 229940099112 cornstarch Drugs 0.000 description 10
- 235000021552 granulated sugar Nutrition 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 9
- 239000002775 capsule Substances 0.000 description 8
- -1 carbamoyloxy Chemical group 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000000454 talc Substances 0.000 description 8
- 229910052623 talc Inorganic materials 0.000 description 8
- 229920002678 cellulose Polymers 0.000 description 7
- 239000001913 cellulose Substances 0.000 description 7
- 239000002702 enteric coating Substances 0.000 description 7
- 238000009505 enteric coating Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- 229940126062 Compound A Drugs 0.000 description 5
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 5
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 5
- 239000007931 coated granule Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 5
- 239000001095 magnesium carbonate Substances 0.000 description 5
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 5
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 5
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 4
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 4
- 229920000053 polysorbate 80 Polymers 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000013268 sustained release Methods 0.000 description 4
- 239000012730 sustained-release form Substances 0.000 description 4
- 229920003138 Eudragit® L 30 D-55 Polymers 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 3
- 150000002431 hydrogen Chemical group 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000004014 plasticizer Substances 0.000 description 3
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920003134 Eudragit® polymer Polymers 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 2
- 229920001218 Pullulan Polymers 0.000 description 2
- 239000004373 Pullulan Substances 0.000 description 2
- 241000978776 Senegalia senegal Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 239000002216 antistatic agent Substances 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 229960003276 erythromycin Drugs 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 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
- 239000000049 pigment Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 235000019423 pullulan Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 1
- 229920002126 Acrylic acid copolymer Polymers 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 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 description 1
- 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 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000005083 alkoxyalkoxy group Chemical group 0.000 description 1
- 125000005079 alkoxycarbonylmethyl group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 125000005242 carbamoyl alkyl group Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 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
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 125000005117 dialkylcarbamoyl group Chemical group 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 239000004083 gastrointestinal agent Substances 0.000 description 1
- 229940127227 gastrointestinal drug Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- POOYFSLWYLDQMD-UHFFFAOYSA-N heptacalcium;zinc Chemical compound [Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Zn+2] POOYFSLWYLDQMD-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 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 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- DOKHEARVIDLSFF-UHFFFAOYSA-N prop-1-en-1-ol Chemical group CC=CO DOKHEARVIDLSFF-UHFFFAOYSA-N 0.000 description 1
- 229950000112 serrapeptase Drugs 0.000 description 1
- 108010038132 serratiopeptidase Proteins 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、顆粒強度が強くしかも主薬の安定性にすぐれ
た有核顆粒およびその製造法に関する。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to cored granules that have strong granule strength and excellent stability of the active ingredient, and a method for producing the same.
近年、薬物放出制御システム（ドラッグデリバリーシス
テム）に関する検討が数多く行われ、特に経口投与剤形
としては、顆粒に各種コーティングを施したいわゆるコ
ーティング顆粒を用いることが多くなり、そのまま顆粒
剤にするか、あるいはカプセルに充填したカプセル剤と
して開発されている。In recent years, many studies have been conducted on drug release control systems (drug delivery systems), and in particular, as oral dosage forms, so-called coated granules, in which granules are coated with various types of coatings, are often used. Alternatively, it has been developed as a capsule filled with capsules.
該理由としては、生物薬剤学的な観点から、錠剤に比べ
て顆粒剤の方が、胃排出速度、吸収性等においても個体
差がみられず、また食事の影響もほとんど受けないこと
が挙げられる。The reason for this is that, from a biopharmaceutical perspective, compared to tablets, granules show no individual differences in gastric emptying rate, absorption, etc., and are hardly affected by meals. It will be done.
該剤形には、均一なコーティングが容易に可能な真球度
が高く、粒度分布の小さい球形顆粒が適しており、近年
、遠心流動型コーティング造粒装置（以下、ＯＦ装置と
省略する。）が多用されている。Spherical granules with high sphericity and small particle size distribution, which can easily be uniformly coated, are suitable for this dosage form. is frequently used.
該顆粒を製造するためには得られた球形顆粒の表面を、
胃溶性、腸溶性、徐放性被膜等でコーティングするが、
該コーティング法として一般的には、流動層コーティン
グが行なわれている。In order to produce the granules, the surface of the obtained spherical granules is
Coated with gastric-soluble, enteric-coated, sustained-release coatings, etc.
Fluidized bed coating is generally used as the coating method.
ところが、主薬と被膜成分との間に相互作用がある場合
、またはそれがなくても流動層コーティングの初期に球
形顆粒のケズレによる主薬成分の脱離等を防止する目的
で、一般的に主薬層と被膜の間に不活性な賦形剤からな
る中間層を施すことが行なわれている。However, if there is an interaction between the active ingredient and the coating component, or even if there is no interaction, the active ingredient layer is generally used to prevent the active ingredient from detaching from the spherical granules due to shearing during the initial stage of fluidized bed coating. It has been practiced to apply an intermediate layer of an inert excipient between the coating and the coating.
しかし、中間層を施す方法では主薬層と中間層との組成
が異なるため、境界面での結合が不充分となり顆粒強度
が弱くなることが多く、それを被覆するために用いられ
る流動層コーティングにおいては、その初期に球形顆粒
の破壊、ケズレ等の障害がしばしば生じる。該障害は、
顆粒剤において被膜の目的をそこなうのみならず、顆粒
製造時の収率にも大きな影響を及ぼすため顆粒強度が強
く、しかも主薬と被膜が反応しない球形顆粒の製造が要
望されていた。However, in the method of applying an intermediate layer, because the composition of the main drug layer and the intermediate layer are different, the bonding at the interface is insufficient and the strength of the granules is often weakened. In the early stages, problems such as destruction of the spherical granules and chipping often occur. The disorder is
In granules, this not only defeats the purpose of the coating, but also has a significant impact on the yield during granule production, so there has been a desire to produce spherical granules that have strong granule strength and do not react with the active ingredient.
〔課題を解決するための手段〕
本発明者らは、この様な事情に鑑み、ＯＦ装置を用いて
、顆粒強度が強く、しかも主薬と被膜とが直接接触しな
い球形顆粒について鋭意検討した結果、本発明を完成し
た。[Means for Solving the Problems] In view of the above circumstances, the present inventors used an OF device to intensively study spherical granules that have strong granule strength and do not have direct contact between the main drug and the coating. The invention has been completed.
即ち本発明は、
（１）主薬と賦形薬とを配合した粉末散布剤で核が被覆
され、被覆層中の主薬と賦形薬の配合比が内部から被覆
層表面に向けて徐々に変化し、該表筒は実質的に賦形薬
で構成されてなる有核顆粒、および
（２〉 主薬と賦形剤を配合した粉末散布剤で核顆粒
を水性結合剤の噴霧下に被覆し、該粉末散布剤中の主薬
と賦形薬の配合比を被覆の始めから終りに向けて徐々に
変化させ、被覆の終りにおいては該粉末散布剤が実質的
に賦形剤で構成されるようにすることを特徴とする有核
顆粒の製造である。That is, the present invention provides the following features: (1) The core is coated with a powder dusting agent containing a base agent and an excipient, and the blending ratio of the base agent and excipient in the coating layer gradually changes from the inside toward the surface of the coating layer. and (2) the core granules are coated with a powder dusting agent containing a main drug and an excipient under spraying of an aqueous binder; The blending ratio of the main drug and excipient in the powder dusting agent is gradually changed from the beginning to the end of coating so that the powder dusting agent is substantially composed of the excipient at the end of coating. This is the production of nucleated granules characterized by:
本発明における主薬としては、顆粒剤として投与される
ものならば特に限定されず、例えば、消化器系薬物とし
ては後述するベンツイミダゾール系薬物、パンクレアチ
ンなどが、抗生物質とじてはエリスロマイシン、エリス
ロマイシンステアレートなどが、代謝系薬物としてはセ
ラペプターゼなどが挙げられる。The main drug in the present invention is not particularly limited as long as it can be administered in the form of granules; for example, gastrointestinal drugs include benzimidazole drugs and pancreatin, which will be described later, and antibiotics include erythromycin and erythromycin starch. Metabolic drugs include serrapeptase and the like.
上記のベンツイミダゾール系薬物は次の式Ｃ 式中、Ｒ
ｌ ｊ．ｔ水素，アルキル，ハロゲン．シアノ．カルボ
キシ，カルボアルコキシ，カルボアルコキシアルキル，
カルバモイル，カルバモイルアルキル，ヒドロキシ，ア
ルコキシ，ヒドロキシアルキル，トリフルオロメチル，
アシル，カルバモイルオキシ，ニトロ，アシルオキシ，
アリール，アリールオキシ．アルキルテオまたはアルキ
ルスルフィニルを、Ｒ２は水素，アルキル，アシル，カ
ルボアルコキシ，カルバモイル．アルキルカルパモイル
，ジアルキルカルバモイル，アルキルカルボニルメチル
，アルコキシカルボニルメチル，アルキルスルホニルを
、Ｒ５およびＲ５は同一または異って水素，アルキル，
アルコキシまたはアルコキシアルコキシを、Ｒ４は水素
，アルキル，フッ素化されていてもよいアルコキシまた
はアルコキシアルコキシを、ｍは０ないし４の整数をそ
れぞれ示す。〕で表わされ、具体例としては２−（（３
−メチル−４−（２，２．２−トリフルオロエトキシ）
−２−ピリジル〕メチルスルフィニル〕ベンツイミダゾ
ール，５−メトキシ−２−（（４−メトキシ−３，５−
ジメチル−２−ピリジル）メチルスルフィニル〕ペンツ
イミダゾール等が挙げられる（アメリカ特許・第４０４
５５６３号明細書，アメリカ特許第４２５５４３１号明
細書，ヨーロッパ特許第４５２００号公開公報，アメリ
カ特許第４４７２４０９号明細書，ヨーロッパ特許第５
１２９号公開公報，イギリス特許第
２１３４５２３号公開公報．ヨーロッパ特許第１ ７４
７２６号公開公報．ヨーロッパ特許第１７５４６４号公
開公報およびヨーロッパ特許第２０８４５２号公開公報
）。The above benzimidazole drug has the following formula C, where R
lj. tHydrogen, alkyl, halogen. Cyano. Carboxy, carbalkoxy, carbalkoxyalkyl,
Carbamoyl, carbamoylalkyl, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl,
Acyl, carbamoyloxy, nitro, acyloxy,
Aryl, aryloxy. alkyltheo or alkylsulfinyl, R2 is hydrogen, alkyl, acyl, carbalkoxy, carbamoyl. alkylcarpamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, alkylsulfonyl, R5 and R5 are the same or different and hydrogen, alkyl,
R4 represents hydrogen, alkyl, alkoxy or alkoxyalkoxy which may be fluorinated, and m represents an integer of 0 to 4. ], and a specific example is 2-((3
-Methyl-4-(2,2,2-trifluoroethoxy)
-2-pyridyl]methylsulfinyl]benzimidazole, 5-methoxy-2-((4-methoxy-3,5-
Dimethyl-2-pyridyl)methylsulfinyl]penzimidazole, etc. (U.S. Patent No. 404)
5563 specification, US Patent No. 4255431, European Patent No. 45200 publication, US Patent No. 4472409, European Patent No. 5
Publication No. 129, British Patent Publication No. 2134523. European Patent No. 1 74
Publication No. 726. EP 175,464 and EP 208,452).
本発明において、核として用いる顆粒としては、例えば
シヲ糖（７５重量部）をコーンスターチ（２５重量部）
で自体公知の方法によりコーティングしたノンパレル（
Ｎｏｎｐａｒｅｉｌ ）および結晶セルロースを用い
た球形顆粒等が挙げられ、該核顆粒の平均粒度は、一般
に１４〜８０メッシュである。In the present invention, the granules used as cores include, for example, sulfate (75 parts by weight) and cornstarch (25 parts by weight).
Nonpareil (
Nonpareil) and spherical granules using crystalline cellulose, etc., and the average particle size of the core granules is generally 14 to 80 mesh.
また、水性結合剤としては水、エタノール、これらの混
合溶液あるいは、下記の結合剤の水および（または）エ
タノール溶液等が挙げられる。纏液の濃度は一般に０，
１〜８０％（Ｗ／Ｖ）、好ましくは０．５〜７０％（Ｗ
／Ｖ）である。該結合剤としては、例えばグラニュー糖
、ヒドロキシプロビルセルロース、ヒドロキシブロビル
メチルセノレロース、ポリビニールピロリドン、プルラ
ン、アラビアゴム等が挙げられ、これらの二種類以上を
併用してもよい。Examples of the aqueous binder include water, ethanol, a mixed solution thereof, and a solution of the following binder in water and/or ethanol. The concentration of the entangled liquid is generally 0,
1-80% (W/V), preferably 0.5-70% (W/V)
/V). Examples of the binder include granulated sugar, hydroxypropylcellulose, hydroxypropylmethylsenolose, polyvinylpyrrolidone, pullulan, and gum arabic, and two or more of these may be used in combination.
本発明の粉状散布剤に用いられる賦形剤は例えば、乳糖
、コーンスターチ、グラニュー糖、結晶セルロース、低
置換度ヒドロキシプロピルセルロ一ス（Ｌ−ＨＰＣ）、
軽質無水ケイ酸等である。Excipients used in the powdered dusting agent of the present invention include, for example, lactose, cornstarch, granulated sugar, crystalline cellulose, low-substituted hydroxypropylcellulose (L-HPC),
Light anhydrous silicic acid, etc.
さらに粉状の添加剤を配合してもよく、該添加剤として
は、例えば結合剤（例、α化デンブン、メチルセルロー
ス、カルボキシメチルセルロース、ヒドロキシプ口ピル
セルロース、ヒドロキシプロビルメチルセルロース、ポ
リビニルピロリドン、プルラン、デキストリン、アラビ
アゴム等）、崩壊剤（例、カルボキシメチルセルロース
カルシウム、デンプン等）、安定化剤（例、炭酸マグネ
シウム、炭酸カルシウム、Ｌ−システイン等）、着色剤
（例、タルク、ベンガラ、タール系色素等）などが用い
られる。Powdered additives may also be blended, such as binders (e.g., pregelatinized starch, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, etc.). dextrin, gum arabic, etc.), disintegrants (e.g., carboxymethyl cellulose calcium, starch, etc.), stabilizers (e.g., magnesium carbonate, calcium carbonate, L-cysteine, etc.), coloring agents (e.g., talc, red iron, tar-based pigments) etc.) are used.
本発明の有核顆粒の製造においては、該散布剤は主薬単
独あるいは主薬と上記賦形剤を均一に混合した散布剤１
と主薬を含まない上記賦形剤だけからなる散布剤２を用
いるのがよい。In the production of the nucleated granules of the present invention, the dispersing agent is a dispersing agent 1 in which the main agent alone or the main agent and the above-mentioned excipients are uniformly mixed.
It is preferable to use a dispersing agent 2 consisting only of the above-mentioned excipients and no active ingredient.
次に、本発明の有核顆粒の製造法について詳述する。顆
粒の製造はＣＦ装置が望ましいが、バンコーターなどそ
れに代わるものでもよい。核顆粒に水性結合剤を噴霧し
ながら粉状の散布剤１および散布剤２で該顆粒を被覆す
る方法としては、散布機を２台用いて散布剤１および散
布剤２をそれぞれ散布しても、散布剤１台で別々のホツ
パーから供給された散布剤１および散布剤２を混合後に
散布してもよい。水性結合剤と総散布剤量の比率（重量
）は約１＝１〜１：３が適当である。散布剤１と散布剤
２の比率は薬物の種類やその投与量などによって異なる
が約１＝３〜３：１が適当である。散布剤１と散布剤２
の比率の変化はそれぞれ次のいずれでもよいし、または
その組合せでもよいが、これらは本発明を限定するもの
ではない。Next, the method for producing nucleated granules of the present invention will be described in detail. A CF device is preferable for producing the granules, but an alternative device such as a van coater may also be used. As a method of coating the granules with powdered dispersing agent 1 and dispersing agent 2 while spraying an aqueous binder onto the core granules, it is also possible to spray dispersing agent 1 and dispersing agent 2 respectively using two spreaders. , Spraying agent 1 and Spreading agent 2 supplied from separate hoppers may be mixed and then sprayed using one device. The ratio (by weight) of the aqueous binder to the total amount of dispersing agent is suitably about 1=1 to 1:3. The ratio of spraying agent 1 to dispersing agent 2 varies depending on the type of drug and its dosage, but is suitably about 1=3 to 3:1. Spreading agent 1 and spreading agent 2
The change in the ratio may be any of the following or a combination thereof, but these do not limit the present invention.
散布剤１および２の散布法についてさらに詳述する。す
なわち、
（１）散布剤１を徐々に減少させ、散布剤２を徐々に増
加させる。この減少と増加の速度は、直線的でも曲線的
でも階段状でもよく、またはその組合せでもよい。The method of dispersing Spreading Agents 1 and 2 will be explained in further detail. That is, (1) Gradually reduce the amount of spray agent 1 and gradually increase the amount of spray agent 2. This rate of decrease and increase may be linear, curved, stepwise, or a combination thereof.
（２〉 散布剤１をしばらく一定速度で散布した後、
減少させてもよい。あるいは散布剤２をしばらく一定速
度で散布した後、増加させてもよく、またはその組合せ
でもよい。(2> After spraying spray agent 1 at a constant speed for a while,
May be decreased. Alternatively, the spraying agent 2 may be sprayed at a constant rate for a while and then increased, or a combination thereof may be used.
（３）散布剤１を途中で増加させた後、減少させてもよ
い。あるいは散布剤２を途中で減少させた後、増加させ
てもよく、またはその組合せでもよい。(3) The amount of spraying agent 1 may be increased during the process and then decreased. Alternatively, the amount of the dispersing agent 2 may be decreased midway and then increased, or a combination thereof may be used.
こうして、徐々に散布剤１の比率を低下させ最終的には
散布剤２だけを散布することによって境界面がなく顆粒
表面には主薬がなく実質的に賦形薬で表画が構成される
球形有核顆粒が製造できる。In this way, by gradually reducing the ratio of spraying agent 1 and finally spraying only spraying agent 2, the granule has a spherical shape with no boundary surfaces, no active ingredient on the surface of the granules, and a surface area consisting essentially of excipients. Nucleated granules can be produced.
製造温度は特に調整する必要はなく、一般に室温（１〜
３０℃）でよい。また、乾燥後篩過することにより粒度
のそろった球形の有核顆粒が得られる。用いられる篩と
しては例えば１２〜３２メッシュの丸篩が挙げられ、１
２メッシュを通過し、５２メッシュを通過しない顆粒を
選別すればよい。There is no need to particularly adjust the manufacturing temperature, and it is generally room temperature (1~
30℃) is sufficient. Further, by sieving after drying, spherical nucleated granules with uniform particle size can be obtained. Examples of the sieves used include round sieves with a mesh size of 12 to 32.
Granules that pass through 2 meshes and do not pass through 52 meshes may be selected.
かくして得られた顆粒強度の強い有核顆粒を、自体公知
の方法により胃溶性、腸溶性あるいは徐放性被膜で被覆
して安定な顆粒が製造できる。またそれぞれの膜を組合
せたものでもよい。さらに、自体公知の方法でカプセル
につめてカプセル剤としてもよいし、賦形剤を加え打錠
し錠剤としてもよい。また、被膜を施さない場合もこの
方法を適用することで表面からの主薬のケズレ等が防止
できる。Stable granules can be produced by coating the thus obtained cored granules with strong granule strength with a gastric-soluble, enteric-coated, or sustained-release coating by a method known per se. Alternatively, a combination of the respective films may be used. Furthermore, it may be filled into a capsule by a method known per se to form a capsule, or it may be formed into a tablet by adding an excipient and compressing it into a tablet. Further, even when no coating is applied, by applying this method, it is possible to prevent the main agent from peeling off from the surface.
該胃溶性被膜剤としてはヒドロキシプ口ピルメチルセル
ロース、ヒドロキシブロビルセルロース、ポリビニルア
セタールジエチルアミノアセテートなどが挙げられ、添
加剤として可塑剤（ヒマシ油、ツイーン８０など）、着
色剤（タルク、酸化チタン、ベンガラ、タール系色素な
ど）などを配合しても良い。Examples of the gastric soluble coating agent include hydroxybubutyl methylcellulose, hydroxybrobyl cellulose, polyvinyl acetal diethylaminoacetate, etc., and additives include plasticizers (castor oil, Tween 80, etc.), colorants (talc, titanium oxide, red iron oxide, etc.). , tar-based pigments, etc.) may also be blended.
該腸溶性被膜剤としてはセルロースアセテートフタレー
ト、ヒドロキシプロビルメチルセルロースフタレート、
ヒドロキシプロビルメチルセルロースアセテートサクシ
ネート、オイドラギット（ローム社製、西ドイツ、アク
リル酸系共重合物）などが挙げられ、同様に可塑剤、着
色剤などを配合しても良い。The enteric coating agent includes cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate,
Examples include hydroxypropyl methylcellulose acetate succinate, Eudragit (manufactured by Rohm, West Germany, acrylic acid copolymer), and plasticizers, colorants, etc. may also be blended.
該徐放性被膜剤としてはエチルセルロース、アミノアル
キルメタアクリレートコポリマー、ワックス類などが挙
げられ、同様に可塑剤、着色剤などを配合しても良い。Examples of the sustained-release coating agent include ethyl cellulose, aminoalkyl methacrylate copolymers, waxes, etc., and plasticizers, colorants, etc. may also be blended.
本発明において、核は粉末散布剤による被覆層形成を支
持し、主薬は被覆層内に含有されると共にその濃度が徐
々に変化するので主薬と賦形剤との間の境界面の形成が
抑制されて全体的に強度を保ち、また被覆層表面は実質
的に賦形薬で構成されるので主薬は被膜内部に安全に保
護されると共に主薬が被膜表面に存在することによる種
々の悪影響が防止される。In the present invention, the core supports the formation of the coating layer by the powder dispersing agent, and the main drug is contained in the coating layer and its concentration gradually changes, thereby suppressing the formation of an interface between the main drug and the excipient. In addition, since the surface of the coating layer is substantially composed of excipients, the active ingredient is safely protected inside the coating, and various adverse effects caused by the presence of the active ingredient on the coating surface are prevented. be done.
以下に実施例および実験例を挙げて本発明をさらに詳細
に説明するが、これらは本発明を限定するものではない
。The present invention will be explained in more detail below with reference to Examples and Experimental Examples, but these are not intended to limit the present invention.
実施例１
ノンパレル（２０〜２８メッシ：Ｌ）１６５０ｆをａｙ
装置（ＣｊＰ−５ ６ ０，フロイント社製、日本）に
入れ、ロータ一回転数を２ ０ Ｏ ｒｐｍとし、室温
でヒドロキシプロビルセルロース水溶液（２％（Ｗ／Ｖ
） ） １ ２ ５ ０ｍｌを５５ａｌ／ｍで噴霧し
ながらあらかじめ混和して得られた下記組成の散布剤１
と散布剤２の割合を１０：０から０：１Ｇに３０分間で
連続的にかつ直線的に変化させながら散布速度９５ｆ／
ＩＩｊｘで散布コーティングした後、４０℃、１６時間
真空乾燥し、丸篩を用いて１２から３２メッシュの球形
顆粒を得た。Example 1 Nonpareil (20-28 mesh: L) 1650f ay
A hydroxypropyl cellulose aqueous solution (2% (W/V)
) ) Spraying agent 1 with the following composition obtained by pre-mixing 1250ml while spraying at 55al/m
While continuously and linearly changing the ratio of spraying agent 2 and spraying agent 2 from 10:0 to 0:1G over 30 minutes, the spraying speed was 95f/.
After spray coating with IIjx, vacuum drying was performed at 40° C. for 16 hours, and spherical granules of 12 to 32 mesh were obtained using a round sieve.
〔散布剤１〕１
化合物Ａ ４５０Ｆ炭酸マ
グネシウム ３３６Ｆグラニュー糖
７９７１コーンスターチ
４５４ｇ〔散布剤２〕
グラニュー糖 ４９２ｇコーンス
ターチ ３００Ｆ化合物Ａ：２−
（（ｊ−メチル−４−（２．２．２−トリフルオロエト
キシ）一２−ピ
リジル〕メチルスルフィニル〕ベン
ツイミダゾール
実施例２
実施例１で得た顆粒１５００Ｆを流動層コーティング機
（大河原社製、日本）に入れ、送風６０゜Ｃ、品温４０
’Ｃにコントロールし下記組成の腸溶性フィルム液を２
５＋ｗ／／一で噴霧して腸溶性コーティングをおこない
、腸溶性有核顆粒を得た。[Spreading agent 1] 1 Compound A 450F magnesium carbonate 336F granulated sugar
7971 Cornstarch
454g [Spreading agent 2] Granulated sugar 492g Cornstarch 300F Compound A: 2-
((j-Methyl-4-(2.2.2-trifluoroethoxy)-2-pyridyl]methylsulfinyl]benzimidazole Example 2 The granules 1500F obtained in Example 1 were coated in a fluidized bed coating machine (manufactured by Okawara Co., Ltd., Japan), blowing air at 60°C, and keeping the product temperature at 40°C.
'C and control the enteric film solution with the following composition.
Enteric coating was performed by spraying with 5+w//1 to obtain enteric coated nucleated granules.
オイドラギット Ｌ３０Ｄ−５５ ７４５ｆ（固形
物として２ ２ ３ ｆ）
タルク ６７ｆポリ
エチレングリコール６Ｇ００ ２２ｇ酸化チタン
２２９ツイーン８０
１ ０９水
１５３６ｇ／実施例３
実施例２で得られた腸溶性顆粒１４７５．２ｇを下記の
静電気防止剤と混合した後、カプセル充填機（ハークデ
ービス社製、米国）を用いて１カプセル当り３７０１ｑ
を１号カプセルに充填したカプセル剤を製造した。Eudragit L30D-55 745f (223f as solid) Talc 67f Polyethylene glycol 6G00 22g Titanium oxide 229 Tween 80
1 09 Wednesday
1536g/Example 3 After mixing 1475.2g of the enteric-coated granules obtained in Example 2 with the antistatic agent described below, 3701q per capsule was prepared using a capsule filling machine (Hark Davis, USA).
Capsules were prepared by filling No. 1 capsules with the following.
タルク ２。４ｇエア
ロジル ２．４１実施例４
実施例１で得た顆粒１ ５００Ｆを流動層コーティング
機（大河原社製、日本）に入れ、送風５５℃、品温４０
゜Ｃにコントロールし下記組成の腸溶性フィルム液を４
０ｗｌ／ｍで噴霧して腸溶性コーティングをおこない、
腸溶性有核顆粒を得た。Talc 2.4g Aerosil 2.41 Example 4 The granules 1 500F obtained in Example 1 were placed in a fluidized bed coating machine (manufactured by Okawara Co., Ltd., Japan), and the air was blown at 55°C and the product temperature was 40°C.
Controlled at °C, an enteric film solution with the following composition was added to 4
Enteric coating is performed by spraying at 0 wl/m,
Enteric coated nucleated granules were obtained.
ヒドロキシプロビルメチル ３００ｆセルロー
スフタレート
ヒマシ油 ３０ｆタルク
６ｇアセトン
３０００＊／実施例５
ノンパレル（２０〜２８メッシュ）１６６０ｆをＯＦ装
置（ＯＦ−１６０．フロイント社製、日本）に入れ、ロ
ータ一回転数を２ ０ Ｏ ｒｐｍとし、室温でヒドロ
キシブロビルセルロース水溶液（２％ （Ｗ／Ｖ ）
） １ ２ ５ ０ｗｌを３５ｇ／／ｍで噴霧しながら
あらかじめ混和して得られた下記組成の散布剤１の半量
を９５ｆ／ｍで散布コーティングし、その後、残った散
布剤１と散布剤２の割合を１０：０からＯ：１０に２０
分間で連続的にかつ直線的に変化させながら散布速度９
５ｇ／廁で散布コーティングした後、４０’０１１６時
間真空乾燥し、丸篩を用いて１２から３２メッシュの球
形顆粒を得た。Hydroxyprobyl methyl 300f cellulose phthalate castor oil 30f talc 6g acetone
3000*/Example 5 Nonpareil (20 to 28 mesh) 1660f was placed in an OF device (OF-160. Freund, Japan), the rotor rotation speed was set to 20 O rpm, and a hydroxybrobyl cellulose aqueous solution ( 2% (W/V)
) 1 2 5 0 wl was mixed in advance while spraying at 35 g//m, and half of the spraying agent 1 having the following composition was sprayed and coated at 95 f/m, and then the remaining spraying agent 1 and spreading agent 2 were mixed. Increase the ratio from 10:0 to O:10 by 20
Spraying rate 9 while changing continuously and linearly in minutes
After spray coating at 5 g/mu, it was vacuum dried for 40'0116 hours and spherical granules with a size of 12 to 32 mesh were obtained using a round sieve.
〔散布剤１〕
化合物Ａ ４５０１炭酸マ
グネシウム ３３６ｆグラニュー糖
７９７ｇコーンスターチ
４５４ｇ〔散布剤２〕
グラニュー糖 ４９２ｆコーンス
ターチ ３００ｇ実施例６
実施例５で得た顆粒１ ５００Ｆを流動層コーティング
機（大河原社製、日本）に入れ、送風６０゜Ｃ１品温４
０゜Ｃにコントロールし下記組成の腸溶性フィルム液を
２５ｇ／／一で噴霧して腸溶性コーティングをおこない
、腸溶性有核顆粒を得た。[Spreading agent 1] Compound A 4501 magnesium carbonate 336f granulated sugar
797g cornstarch
454g [Spreading agent 2] Granulated sugar 492f Cornstarch 300g Example 6 Granules 1 500F obtained in Example 5 were placed in a fluidized bed coating machine (manufactured by Okawara Co., Ltd., Japan), and the air was blown at 60°C, product temperature 4
Controlling the temperature at 0°C, enteric coating was carried out by spraying 25 g of an enteric film solution having the following composition to obtain enteric coated cored granules.
オイドラギット Ｌ５０Ｄ−５６ １４５１（固形
物として２ ２ ３ Ｆ）
タルク ６７Ｆポリエ
チレングリコール６０００ ２２Ｆ酸化チタン
２２９ツイーン８０
１０９水
１５３６薦ｌ実施例７
ノンパレル（２０〜２８メッシュ）１６５０Ｆをａｙ装
置（ＯＦ−３ ６ ０，フロイント社製、日本）に入れ
、ロータ一回転数を２ ０ Ｏ ｒｐｍとし、室温でヒ
ドロキシブロビルセルロース水溶液（２％（Ｗ／Ｖ ）
） １ ２ ５ ｒＪｘｌを３５ｍｌ／ｍで噴霧しな
がらあらかじめ混和して得られた下記組成の散布剤１と
散布剤２の割合を１０：０から０：１０に３０分間で連
続的にかつ直線的に変化させながら散布速度９５ｆ／ｓ
ｍで散布コーティングした後、４０℃、１６時間真空乾
燥し、丸篩を用いて１２から５２メッシュの球形顆粒を
得た。Eudragit L50D-56 1451 (2 2 3 F as solid) Talc 67F polyethylene glycol 6000 22F titanium oxide
229 Tween 80
109 water
1536 Recommendation Example 7 Nonpareil (20-28 mesh) 1650F was placed in an ay apparatus (OF-360, manufactured by Freund, Japan), the rotor rotation speed was set to 20 O rpm, and hydroxybrobyl cellulose was heated at room temperature. Aqueous solution (2% (W/V)
) 1 2 5 rJxl was mixed in advance while spraying at 35 ml/m, and the ratio of Spreading Agent 1 and Spreading Agent 2 with the following composition was changed from 10:0 to 0:10 continuously and linearly in 30 minutes. Spraying speed 95f/s while changing
After spray coating with m, vacuum drying was carried out at 40° C. for 16 hours, and spherical granules of 12 to 52 mesh were obtained using a round sieve.
〔散布剤１〕
化合物Ａ ４５０１炭酸マ
グネシウム ３３６ｇグラニュー糖
５９７９コーンスターチ
３００ｇＬ−ＨＰ（：！
５５４９〔散布剤２〕
グラニュー糖 ３００１１’コー
ンスターチ ２４６ｇＬ−ＨＰＯ
２４Ｇ！実施例８
実施例７で得た顆粒１５０Ｌｆを流動層コーティング機
（大河原社製、日本）に入れ、送風６０℃、品温４０℃
にコントロールし下記組成の腸溶性フィルム液を２５＊
ｌ／ｍで噴霧して腸溶性コーティングをおこない、腸溶
性有核顆粒を得た。[Spreading agent 1] Compound A 4501 Magnesium carbonate 336g Granulated sugar
5979 Cornstarch
300gL-HP (:!
5549 [Spreading agent 2] Granulated sugar 30011' Cornstarch 246gL-HPO
24G! Example 8 150Lf of the granules obtained in Example 7 were placed in a fluidized bed coating machine (manufactured by Okawara Co., Ltd., Japan), and the air was blown at 60°C and the product temperature was 40°C.
The enteric film solution with the following composition was controlled to 25*
Enteric coating was carried out by spraying at l/m to obtain enteric coated nucleated granules.
オイドラギット Ｌ３０Ｄ−５５ ７４５９（固形
物として２ ２ ３ ｆ）
タルク ６７Ｆポリエ
チレングリコール６０００ ２２Ｆ酸化チタン
２２ｆツイーン８０
１ ０ｆ水
１５３６＋ｗ／実施例９
ノンパレル（２０〜２８メッシュ）１６５０ＦをＣＦ装
置（（：！Ｆ−３６０．フロイント社製、日本）に入れ
、ロータ一回転数を２ ０ ０ ｒｐｍとし、室温でヒ
ドロキシプ口ピルセルロース水溶液（２％（Ｗ／Ｖ ）
） １ ２ ５ ０ｘｌを５５ｘｌ／一で噴霧しなが
らあらかじめ混和して得られた下記組成の散布剤１の半
量を９６ｆ／＋ｗで散布コーティングし、その後、残っ
た散布剤１と散布剤２の割合を１０：Ｏから０：１０に
２０分間で連続的にかつ直線的に変化させながら散布速
度９５ｆ／−で散布コーティングした後、４０゜Ｃ１１
６時間真空乾燥し、丸篩を用いて１２から３２メッシュ
の球形顆粒を得た。Eudragit L30D-55 7459 (2 2 3 f as solid) Talc 67F polyethylene glycol 6000 22F titanium oxide
22f twin 80
1 0f water
1536+w/Example 9 Nonpareil (20 to 28 mesh) 1650F was placed in a CF device ((:!F-360. Freund, Japan), the rotor rotation speed was set to 200 rpm, and hydroxypropylene was added at room temperature. Cellulose aqueous solution (2% (W/V)
) 1 2 5 0xl was mixed in advance while spraying at 55xl/1, and half of the spraying agent 1 with the following composition was spray coated at 96f/+w, and then the ratio of the remaining spreading agent 1 and spreading agent 2 was After spray coating at a spray rate of 95 f/- while changing continuously and linearly from 10:0 to 0:10 in 20 minutes, 40°C11
After vacuum drying for 6 hours, spherical granules of 12 to 32 mesh were obtained using a round sieve.
〔散布剤１〕
化合物Ａ ４５０９炭酸マ
グネシウム ３３６ｇグラニュー糖
５９７ｆコーンスターチ
３００ｆＬ−ＨＰＣ
３５４ｆ／〔散布剤２〕
グラニュー糖 ３００ｆコーンス
ターチ ２４６ｆＬ−ｆ｛Ｐ（：
！ ２４６ｆ実施例１０
実施例７で得た顆粒１ ５００ｇを流動層コーティング
機（大河原社製、日本）に入れ、送風６０゜Ｃ１品温４
０゜Ｃにコントロールし下記組成の腸溶性フィルム液を
２５Ｍｌ／ＭｉＪｉで噴霧して腸溶性コーティングをお
こない、腸溶性有核顆粒を得た。[Spreading agent 1] Compound A 4509 Magnesium carbonate 336g Granulated sugar
597f cornstarch
300fL-HPC
354f/[Spreading agent 2] Granulated sugar 300f Cornstarch 246fL-f{P(:
! 246f Example 10 500 g of the granules 1 obtained in Example 7 were placed in a fluidized bed coating machine (manufactured by Okawara Co., Ltd., Japan), and the air was blown at 60°C, product temperature 4.
Controlling the temperature at 0°C, enteric coating was performed by spraying an enteric film solution having the following composition at 25 Ml/MiJi to obtain enteric coated cored granules.
オイドラギット Ｌ３０Ｄ−５５ ７４３ｇ（固形
物として２ ２ ３ ｆ）
タルク ６７ｆポリエ
チレングリコール６０００ ２２ｆ酸化チタン
２２１ツイーン８０
１ ０ｆ水
１５３６ｇ／実験例
実施例１の方法で製造した有核顆粒Ａ，実施例５の方法
で製造した有核顆粒Ｂ１および対照として実施例１の散
布剤１でコーティングした後散布剤２でコーティングし
た有核顆粒ｃ１実施例１の散布剤１と散布剤２を混和し
た散布剤でコーティングした有核顆粒Ｄを製造した。得
られた該有核顆粒Ａ，ＢおよびＣ（１２〜３２メッシュ
品）のそれぞれ５Ｆを、５０ｇ／のステンレスシリンダ
ー（５０ｇ／容、直径５ ２ｆｌｌ）に入れ、粉砕機（
スペックス社製、スペソクスミル）で３０分間振盪した
のち３２メッシュの丸篩で篩過し篩上の量を測定して残
存率を求め顆粒強度を求めた。結果を第１表に示す。Eudragit L30D-55 743g (223f as solid) Talc 67f polyethylene glycol 6000 22f titanium oxide
221 Tween 80
1 0f water
1536 g/experimental example Nucleated granules A produced by the method of Example 1, nucleated granules B1 produced by the method of Example 5, and a control coated with the dispersant 1 of Example 1 and then coated with the dispersant 2. Nucleated Granules c1 Nucleated granules D coated with a dispersing agent obtained by mixing the dispersing agents 1 and 2 of Example 1 were produced. 5F of each of the obtained nucleated granules A, B and C (12 to 32 mesh products) were placed in a 50 g/volume stainless steel cylinder (50 g/volume, diameter 52 fl.
After shaking for 30 minutes using a Spex Mill (manufactured by Spex Corporation), the mixture was sieved through a 32-mesh round sieve, and the amount on the sieve was measured to determine the residual rate and the granule strength. The results are shown in Table 1.
さらに該有核顆粒ＡおよびＢを実施例２の腸溶性フィル
ム液でコーティングした腸溶性顆粒ＡおよびＢを製造し
た。また対照として有核顆粒Ｄを実施例２の腸溶性フィ
ルム液でコーティングした腸溶性顆粒Ｄを製造した。得
られた該腸溶性顆粒を５０℃、１５％ＲＨの条件下で１
週間保存した後の外観変化を観察した。結果を第２表に
示す。Furthermore, enteric-coated granules A and B were prepared by coating the cored granules A and B with the enteric-coated film liquid of Example 2. In addition, as a control, enteric-coated granules D were prepared by coating the cored granules D with the enteric-coated film liquid of Example 2. The obtained enteric-coated granules were heated at 50°C and 15% RH for 1
Changes in appearance were observed after storage for a week. The results are shown in Table 2.
第１ 表 有核顆粒の強度
以上の結果、本発明の有核顆粒は顆粒強度が強いため均
一な腸溶性コーティングをする事が可能で、かつ安定性
も優れている。Table 1 Strength of Nucleated Granules As a result, the cored granules of the present invention have a strong granule strength that enables uniform enteric coating and excellent stability.
本発明によれば、胃溶性、腸溶性、徐放性被膜などのコ
ーティングに適した強度に優れかつ主薬と上記被膜との
反応を防止できる顆粒が提供される。According to the present invention, granules are provided that have excellent strength and are suitable for coating with gastric-soluble, enteric-coated, sustained-release coatings, etc., and can prevent reaction between the main drug and the coating.
Claims (1)
、被覆層中の主薬と賦形薬の配合比が内部から被覆層表
面に向けて徐々に変化し、該表面は実質的に賦形薬で構
成されてなる有枝顆粒。 ２主薬と賦形剤を配合した粉末散布剤で核顆粒を水性結
合剤の噴霧下に被覆し、該粉末散布剤中の主薬と賦形薬
の配合比を被覆の始めから終りに向けて徐々に変化させ
、被覆の終りにおいては該粉末散布剤が実質的に賦形剤
で構成されるようにすることを特徴とする有核顆粒の製
造法。[Scope of Claims] 1. The core is coated with a powder dusting agent containing a main drug and an excipient, and the blending ratio of the main drug and excipient in the coating layer gradually changes from the inside toward the surface of the coating layer. , branched granules whose surface consists essentially of excipient. 2. The core granules are coated under the spray of an aqueous binder with a powder dispersing agent containing a main drug and an excipient, and the blending ratio of the main drug and excipient in the powder dispersing agent is gradually adjusted from the beginning to the end of coating. A process for producing nucleated granules, characterized in that at the end of coating the powder dusting agent is essentially composed of excipients.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1156085A JP2813809B2 (en) | 1989-06-19 | 1989-06-19 | Nucleated granule preparation and production method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1156085A JP2813809B2 (en) | 1989-06-19 | 1989-06-19 | Nucleated granule preparation and production method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0320215A true JPH0320215A (en) | 1991-01-29 |
| JP2813809B2 JP2813809B2 (en) | 1998-10-22 |
Family
ID=15619974
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1156085A Expired - Lifetime JP2813809B2 (en) | 1989-06-19 | 1989-06-19 | Nucleated granule preparation and production method thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2813809B2 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0592918A (en) * | 1991-03-07 | 1993-04-16 | Takeda Chem Ind Ltd | Nucleated powder and its production |
| US5433959A (en) * | 1986-02-13 | 1995-07-18 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
| US6749864B2 (en) | 1986-02-13 | 2004-06-15 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
| WO2004080439A1 (en) * | 2003-03-12 | 2004-09-23 | Takeda Pharmaceutical Company Limited | Drug composition having active ingredient adhered at high concentration to spherical core |
| JP2006515852A (en) * | 2002-12-20 | 2006-06-08 | レーム ゲゼルシャフト ミツト ベシュレンクテル ハフツング ウント コンパニー コマンディートゲゼルシャフト | Coated pharmaceutical form having a concentration gradient in the coating and method for producing a food supplement |
| WO2006090845A1 (en) * | 2005-02-25 | 2006-08-31 | Takeda Pharmaceutical Company Limited | Method for producing granules |
| JP2008509193A (en) * | 2004-08-13 | 2008-03-27 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Sustained release pellet preparation containing pramipexole or a pharmaceutically acceptable salt thereof, its production method and use |
| US7520034B2 (en) | 2004-03-09 | 2009-04-21 | Ashimori Industry Co., Ltd. | Seat belt device |
| JP2017535521A (en) * | 2014-10-08 | 2017-11-30 | シンセティック・バイオロジクス・インコーポレイテッド | Beta-lactamase formulations and uses thereof |
| KR20180120634A (en) * | 2011-10-14 | 2018-11-06 | 지엘팜텍주식회사 | Delayed release enzyme preparations and the preparation method for the same |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5283921A (en) * | 1975-11-17 | 1977-07-13 | Haessle Ab | Production of preparation having controlled relasing speed of active component |
| JPS63301816A (en) * | 1987-01-29 | 1988-12-08 | Takeda Chem Ind Ltd | Core-containing granule and production thereof |
-
1989
- 1989-06-19 JP JP1156085A patent/JP2813809B2/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5283921A (en) * | 1975-11-17 | 1977-07-13 | Haessle Ab | Production of preparation having controlled relasing speed of active component |
| JPS63301816A (en) * | 1987-01-29 | 1988-12-08 | Takeda Chem Ind Ltd | Core-containing granule and production thereof |
Cited By (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5433959A (en) * | 1986-02-13 | 1995-07-18 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
| US5639478A (en) * | 1986-02-13 | 1997-06-17 | Takeda Chemical Industries, Ltd. | Method to stabilize a pharmaceutical composition and its production |
| US5879708A (en) * | 1986-02-13 | 1999-03-09 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
| US6017560A (en) * | 1986-02-13 | 2000-01-25 | Takeda Chemical Industries, Ltd. | Process for producing stabilized pharmaceutical composition |
| US6123962A (en) * | 1986-02-13 | 2000-09-26 | Takeda Chemical Industries, Inc. | Process for producing stabilized pharmaceutical composition |
| US6296875B1 (en) | 1986-02-13 | 2001-10-02 | Takeda Chemical Industries, Ltd. | Method for producing a granule |
| US6380234B1 (en) | 1986-02-13 | 2002-04-30 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition and its production |
| US6521256B2 (en) | 1986-02-13 | 2003-02-18 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
| US6749864B2 (en) | 1986-02-13 | 2004-06-15 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
| JPH0592918A (en) * | 1991-03-07 | 1993-04-16 | Takeda Chem Ind Ltd | Nucleated powder and its production |
| JP2006515852A (en) * | 2002-12-20 | 2006-06-08 | レーム ゲゼルシャフト ミツト ベシュレンクテル ハフツング ウント コンパニー コマンディートゲゼルシャフト | Coated pharmaceutical form having a concentration gradient in the coating and method for producing a food supplement |
| WO2004080439A1 (en) * | 2003-03-12 | 2004-09-23 | Takeda Pharmaceutical Company Limited | Drug composition having active ingredient adhered at high concentration to spherical core |
| US8449911B2 (en) | 2003-03-12 | 2013-05-28 | Takeda Pharmaceutical Company Limited | Drug composition having active ingredient adhered at high concentration to spherical core |
| US7520034B2 (en) | 2004-03-09 | 2009-04-21 | Ashimori Industry Co., Ltd. | Seat belt device |
| JP2008509193A (en) * | 2004-08-13 | 2008-03-27 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Sustained release pellet preparation containing pramipexole or a pharmaceutically acceptable salt thereof, its production method and use |
| WO2006090845A1 (en) * | 2005-02-25 | 2006-08-31 | Takeda Pharmaceutical Company Limited | Method for producing granules |
| US8871273B2 (en) | 2005-02-25 | 2014-10-28 | Takeda Pharmaceutical Company Limited | Method for producing granules |
| US9011926B2 (en) | 2005-02-25 | 2015-04-21 | Takeda Pharmaceutical Company Limited | Method for producing granules |
| KR20180120634A (en) * | 2011-10-14 | 2018-11-06 | 지엘팜텍주식회사 | Delayed release enzyme preparations and the preparation method for the same |
| JP2017535521A (en) * | 2014-10-08 | 2017-11-30 | シンセティック・バイオロジクス・インコーポレイテッド | Beta-lactamase formulations and uses thereof |
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| Publication number | Publication date |
|---|---|
| JP2813809B2 (en) | 1998-10-22 |
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