JP2002370968A - Medicament-containing sustained-release granule and tablet containing the same - Google Patents
Medicament-containing sustained-release granule and tablet containing the sameInfo
- Publication number
- JP2002370968A JP2002370968A JP2001176735A JP2001176735A JP2002370968A JP 2002370968 A JP2002370968 A JP 2002370968A JP 2001176735 A JP2001176735 A JP 2001176735A JP 2001176735 A JP2001176735 A JP 2001176735A JP 2002370968 A JP2002370968 A JP 2002370968A
- Authority
- JP
- Japan
- Prior art keywords
- granules
- sustained
- release
- fatty acid
- acid ester
- 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 105
- 238000013268 sustained release Methods 0.000 title claims abstract description 54
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 54
- 239000003814 drug Substances 0.000 title claims abstract description 26
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 26
- 239000000194 fatty acid Substances 0.000 claims abstract description 26
- 229930195729 fatty acid Natural products 0.000 claims abstract description 26
- -1 sucrose fatty acid ester Chemical class 0.000 claims abstract description 26
- 229920002678 cellulose Polymers 0.000 claims abstract description 17
- 239000001913 cellulose Substances 0.000 claims abstract description 17
- 229930006000 Sucrose Natural products 0.000 claims abstract description 14
- 239000005720 sucrose Substances 0.000 claims abstract description 14
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000000576 coating method Methods 0.000 claims abstract description 13
- 239000011248 coating agent Substances 0.000 claims abstract description 12
- 239000011159 matrix material Substances 0.000 claims abstract description 8
- 239000007787 solid Substances 0.000 claims abstract description 5
- 239000003826 tablet Substances 0.000 claims description 32
- 229940079593 drug Drugs 0.000 claims description 20
- 235000010980 cellulose Nutrition 0.000 claims description 16
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims description 14
- 229960001597 nifedipine Drugs 0.000 claims description 14
- 235000011187 glycerol Nutrition 0.000 claims description 11
- 239000001856 Ethyl cellulose Substances 0.000 claims description 9
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical group CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 9
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 9
- 229920001249 ethyl cellulose Polymers 0.000 claims description 9
- 239000000314 lubricant Substances 0.000 claims description 8
- 239000000454 talc Substances 0.000 claims description 7
- 229910052623 talc Inorganic materials 0.000 claims description 7
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 5
- 238000002844 melting Methods 0.000 claims description 5
- 230000008018 melting Effects 0.000 claims description 5
- 239000007939 sustained release tablet Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 239000010410 layer Substances 0.000 description 13
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- 230000002776 aggregation Effects 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000011247 coating layer Substances 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 6
- 239000001993 wax Substances 0.000 description 6
- 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 5
- 238000005054 agglomeration Methods 0.000 description 5
- 238000004220 aggregation Methods 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 3
- 230000002265 prevention Effects 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
- 238000004513 sizing Methods 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000007909 melt granulation Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 102220240796 rs553605556 Human genes 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FWLKKPKZQYVAFR-LVEZLNDCSA-N (e)-but-2-enedioic acid;1-(2-ethoxyethyl)-2-(4-methyl-1,4-diazepan-1-yl)benzimidazole Chemical compound OC(=O)\C=C\C(O)=O.OC(=O)\C=C\C(O)=O.N=1C2=CC=CC=C2N(CCOCC)C=1N1CCCN(C)CC1 FWLKKPKZQYVAFR-LVEZLNDCSA-N 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- ZZIZZTHXZRDOFM-UHFFFAOYSA-N 2-(2-ethoxyphenoxy)ethyl-[1-(4-methoxy-3-sulfamoylphenyl)propan-2-yl]azanium;chloride Chemical compound Cl.CCOC1=CC=CC=C1OCCNC(C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-UHFFFAOYSA-N 0.000 description 1
- FEDJGPQLLNQAIY-UHFFFAOYSA-N 2-[(6-oxo-1h-pyridazin-3-yl)oxy]acetic acid Chemical compound OC(=O)COC=1C=CC(=O)NN=1 FEDJGPQLLNQAIY-UHFFFAOYSA-N 0.000 description 1
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 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
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 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 1
- 229930195725 Mannitol Natural products 0.000 description 1
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 1
- FAIIFDPAEUKBEP-UHFFFAOYSA-N Nilvadipine Chemical compound COC(=O)C1=C(C#N)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC([N+]([O-])=O)=C1 FAIIFDPAEUKBEP-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 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 1
- MUXFZBHBYYYLTH-UHFFFAOYSA-N Zaltoprofen Chemical compound O=C1CC2=CC(C(C(O)=O)C)=CC=C2SC2=CC=CC=C21 MUXFZBHBYYYLTH-UHFFFAOYSA-N 0.000 description 1
- RYVJQEZJUFRANT-UHFFFAOYSA-N [3-[4-(3-ethoxy-2-hydroxypropoxy)anilino]-3-oxopropyl]-dimethylsulfanium;4-methylbenzenesulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.CCOCC(O)COC1=CC=C(NC(=O)CC[S+](C)C)C=C1 RYVJQEZJUFRANT-UHFFFAOYSA-N 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 229960000985 ambroxol hydrochloride Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960004916 benidipine Drugs 0.000 description 1
- QZVNQOLPLYWLHQ-ZEQKJWHPSA-N benidipine Chemical compound C1([C@H]2C(=C(C)NC(C)=C2C(=O)OC)C(=O)O[C@H]2CN(CC=3C=CC=CC=3)CCC2)=CC=CC([N+]([O-])=O)=C1 QZVNQOLPLYWLHQ-ZEQKJWHPSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 229920003174 cellulose-based polymer Polymers 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229960001193 diclofenac sodium Drugs 0.000 description 1
- 229960005316 diltiazem hydrochloride Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229960000325 emedastine Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- DPCZALPCMCPHAK-UHFFFAOYSA-N hydron;2-hydroxy-n-[3-[3-(piperidin-1-ylmethyl)phenoxy]propyl]acetamide;chloride Chemical compound Cl.OCC(=O)NCCCOC1=CC=CC(CN2CCCCC2)=C1 DPCZALPCMCPHAK-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 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
- 239000004615 ingredient Substances 0.000 description 1
- 229960002373 loxoprofen Drugs 0.000 description 1
- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 description 1
- 229960003963 manidipine Drugs 0.000 description 1
- ANEBWFXPVPTEET-UHFFFAOYSA-N manidipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ANEBWFXPVPTEET-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001783 nicardipine Drugs 0.000 description 1
- LBHIOVVIQHSOQN-UHFFFAOYSA-N nicorandil Chemical compound [O-][N+](=O)OCCNC(=O)C1=CC=CN=C1 LBHIOVVIQHSOQN-UHFFFAOYSA-N 0.000 description 1
- 229960002497 nicorandil Drugs 0.000 description 1
- 229960005366 nilvadipine Drugs 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229960004811 pemirolast potassium 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
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- NMMVKSMGBDRONO-UHFFFAOYSA-N potassium;9-methyl-3-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound [K+].CC1=CC=CN(C2=O)C1=NC=C2C1=NN=N[N-]1 NMMVKSMGBDRONO-UHFFFAOYSA-N 0.000 description 1
- UAJUXJSXCLUTNU-UHFFFAOYSA-N pranlukast Chemical compound C=1C=C(OCCCCC=2C=CC=CC=2)C=CC=1C(=O)NC(C=1)=CC=C(C(C=2)=O)C=1OC=2C=1N=NNN=1 UAJUXJSXCLUTNU-UHFFFAOYSA-N 0.000 description 1
- 229960004583 pranlukast Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229950011082 suplatast tosilate Drugs 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229960003198 tamsulosin hydrochloride Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 229920003176 water-insoluble polymer Polymers 0.000 description 1
- 229950004227 zaltoprofen Drugs 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【本発明の背景と課題】本発明は、薬物を含有する徐放
性顆粒およびそれを打錠して形成した徐放部を有する持
続性錠剤に関する。BACKGROUND OF THE INVENTION The present invention relates to sustained-release granules containing a drug and sustained-release tablets having a sustained-release portion formed by compressing the granules.
【０００２】ニフェジピン等の薬物を含有する徐放性顆
粒は服用後長時間に亘って消化管内で薬物放出される持
続性錠剤およびカプセル剤の徐放部として使用される。[0002] Sustained-release granules containing a drug such as nifedipine are used as a sustained-release portion of sustained-release tablets and capsules that release a drug in the digestive tract for a long time after ingestion.
【０００３】薬物の放出を遅らせる手段の一つとして、
ワックス様の疎水性物質を使用する方法がある。例えば
特開平９−２０６８６号は薬物と、製剤技術の分野で使
用されるセルロース誘導体と、硬化油の混合物を溶融造
粒する方法を開示し、特許第２８２３６０５号および特
開２０００−１９８７４７号は薬物を含む核を遅延被覆
層の調製に使用される水不溶性重合体を含んでいる脂肪
またはロウのような疎水性物質の層で被覆することを開
示し、特許第２９７８１３号は薬物を含んでいる核顆粒
をパラフィンまたはグリセリン脂肪酸エステルの層を溶
融スプレーによって被覆する方法を開示する。本出願人
の特開２０００−１７８１９３はニフェジピンの持続性
有核錠の外側の徐放部としてニフェジピンと賦形剤を含
む消化管内で経時的に侵食消耗される常温で固体のワッ
クス層を記載する。[0003] As one of means for delaying the release of a drug,
There is a method using a wax-like hydrophobic substance. For example, Japanese Patent Application Laid-Open No. 9-20686 discloses a method for melt-granulating a mixture of a drug, a cellulose derivative used in the field of formulation technology, and a hardened oil, and Japanese Patent No. 2823605 and Japanese Patent Application Laid-Open No. 2000-198747 disclose a method. Discloses coating a nucleus comprising a layer of a hydrophobic substance such as a fat or wax containing a water-insoluble polymer used in the preparation of a delay coating layer, and Patent No. 297813 contains a drug. A method is disclosed for coating the core granules with a layer of paraffin or glycerin fatty acid ester by melt spraying. Japanese Patent Application Laid-Open No. 2000-178193 of the present applicant describes a room temperature solid wax layer which is eroded and consumed with time in a digestive tract containing nifedipine and an excipient as a sustained release portion outside of a nifedipine sustained-release coated tablet. .
【０００４】公知文献に記載されている放出を遅らせる
ための疎水性物質（以後「ワックス類」という。）を顆
粒自体の薬物マトリックとしてまたは被覆層に用いた徐
放性顆粒は、顆粒相互間の凝集および顆粒の他の物体表
面への付着が生じ易い欠点を有する。このため顆粒自体
の整粒、貯蔵を含む取扱い、打錠、カプセル充填、分包
などを困難にする。このため先に引用した特許第２８２
３６０５号ではワックス被覆層中にセルロース系および
アクリルポリマー系の遅延被覆剤（エンテリック剤）を
含ませ、かつ最外層にタルク、ステアリン酸マグネシウ
ム、高分散シリカ（アエロジル）のような接着防止剤を
水溶性結合剤を用いてコーティングすることを教えてい
る。[0004] Sustained-release granules using a hydrophobic substance (hereinafter referred to as "wax") for delaying release, which is described in the known literature, as a drug matrix of the granules themselves or in a coating layer, can be used. It has the disadvantage that agglomeration and granules are likely to adhere to other object surfaces. This makes handling of the granules themselves, including sizing and storage, tableting, capsule filling, and packaging difficult. For this reason, the above-cited Patent No. 282
No. 3605 discloses that a wax coating layer contains a cellulose-based and acrylic polymer-based delay coating agent (enteric agent) and an outermost layer contains an anti-adhesion agent such as talc, magnesium stearate, and highly dispersed silica (Aerosil) in water. Teaches coating with a sexual binder.
【０００５】しかしながらこの顆粒は核と、ワックスを
含む遅延被覆層と、接着防止層とを含み、それぞれの部
分を順次形成するための３工程を必要し、最後にワック
スの融点以上へ加熱することを必要とする。また接着防
止層適用前の遅延被覆層の凝集および付着の防止は十分
でない。However, these granules include a core, a delay coating layer containing a wax, and an anti-adhesion layer, and require three steps for sequentially forming each part, and finally heating to above the melting point of the wax. Need. Further, prevention of aggregation and adhesion of the delay coating layer before application of the adhesion preventing layer is not sufficient.
【０００６】本発明は、簡単な少ない工程で凝集および
付着がその製造工程、取扱いおよび加工工程等において
支障のないように減らされた薬物含有徐放性顆粒を提供
することを目的とする。[0006] An object of the present invention is to provide drug-containing sustained-release granules in which aggregation and adhesion are reduced by simple and few steps so as not to hinder production, handling and processing.
【０００７】[0007]
【本発明の開示】本発明は、薬物と、常温で固体のショ
糖脂肪酸エステルまたはグリセリン脂肪酸エステルのマ
トリックスを少なくとも含んでいる一次顆粒に、水不溶
性セルロース誘導体の被覆を施してなる薬物含有徐放性
顆粒を提供する。DISCLOSURE OF THE INVENTION The present invention relates to a drug-containing sustained-release obtained by coating a primary granule containing at least a matrix of a sucrose fatty acid ester or a glycerin fatty acid ester which is solid at room temperature with a water-insoluble cellulose derivative. Provide granular granules.
【０００８】本発明はまた、本発明の薬物含有徐放性顆
粒の徐放部を有する持続性錠剤にも関する。[0008] The present invention also relates to a sustained-release tablet having a sustained-release portion of the drug-containing sustained-release granules of the present invention.
【０００９】本発明による利益は、徐放性顆粒を２工程
で製造することができ、しかも一次顆粒はその成分の溶
融造粒によって簡単に製造することができることであ
る。他の利益は一次顆粒自体の凝集および他の物質表面
への付着が少ない上に、加えて水不溶性セルロース誘導
体の被覆がさらに凝集および付着防止効果を増強するこ
とである。これにより本発明の徐放性顆粒を打錠する際
に被覆層が破れても打錠機の杵および臼のステイッキン
グおよびキャッピングが防止できる。[0009] An advantage of the present invention is that sustained release granules can be produced in two steps, while primary granules can be easily produced by melt granulation of its components. Another advantage is that the primary granules themselves have less agglomeration and adhesion to other material surfaces, and in addition, the coating of the water-insoluble cellulose derivative further enhances the aggregation and adhesion prevention effects. Thereby, even if the coating layer is broken when the sustained release granules of the present invention are tableted, sticking and capping of punches and dies of a tableting machine can be prevented.
【００１０】[0010]
【詳論】本発明は薬物の徐放性顆粒に常温で固体のショ
糖脂肪酸エステルまたはグリセリン脂肪酸エステルをマ
トリックス物質として使用する。ショ糖脂肪酸エステル
はエステル化度および構成脂肪酸の鎖長の違いにより広
い範囲のＨＬＢ値を示す非イオン界面活性剤として知ら
れ、医薬品工業においては錠剤の滑沢剤としても使用さ
れている。滑沢剤の主な役目は打錠に際し打錠成分が杵
および臼へ固着するのを防止することであるので、マト
リックスとしてショ糖脂肪酸エステルの使用は顆粒の凝
集および付着を防止ないし低減する。グリセリン脂肪酸
エステルにも同様な作用がある。DETAILED DESCRIPTION The present invention uses a sucrose fatty acid ester or glycerin fatty acid ester which is solid at room temperature as a matrix material for sustained-release granules of a drug. Sucrose fatty acid esters are known as nonionic surfactants which exhibit a wide range of HLB values depending on the degree of esterification and the difference in the chain length of the constituent fatty acids, and are also used as tablet lubricants in the pharmaceutical industry. The use of a sucrose fatty acid ester as a matrix prevents or reduces the agglomeration and adhesion of granules, since the main role of the lubricant is to prevent the tableting components from sticking to the punch and die during tableting. Glycerin fatty acid esters have a similar effect.
【００１１】薬物は徐放化を必要または望まれる任意の
薬物でよい。その典型例はニフェジピン、塩酸ジルチア
ゼム、ニカルジピン、ジクロフェナクナトリウム、テオ
フィリン、塩酸ベニジピン、ニルバジピン、塩酸マニジ
ピン、カプトプリル、アスピリン、ザルトプロフェン、
ロキソプロフェンナトリウム、塩酸タムスロシン、塩酸
ロキサチジンアセタート、フマル酸エメダスチン、プラ
ンルカスト、トシル酸スプラタスト、塩酸アンブロキソ
ール、ペミロラストカリウム、ニコランジルなどである
がこれらに限られない。[0011] The drug may be any drug which requires or desires sustained release. Typical examples are nifedipine, diltiazem hydrochloride, nicardipine, diclofenac sodium, theophylline, benidipine hydrochloride, nilvadipine, manidipine hydrochloride, captopril, aspirin, zaltoprofen,
Examples include, but are not limited to, loxoprofen sodium, tamsulosin hydrochloride, roxatidine hydrochloride acetate, emedastine fumarate, pranlukast, suplatast tosilate, ambroxol hydrochloride, pemirolast potassium, nicorandil.
【００１２】マトリックスは慣用の賦形剤を含むことが
でき、例えば乳糖、マンニトール、デンプン、結晶セル
ロースなどである。結晶セルロースのような水不溶性賦
形剤が好ましい。顆粒は賦形剤に加え、任意の慣用の補
助成分を含むことができる。The matrix can contain conventional excipients, such as lactose, mannitol, starch, microcrystalline cellulose and the like. Water-insoluble excipients such as microcrystalline cellulose are preferred. The granules may contain, in addition to the excipients, any conventional auxiliary ingredients.
【００１３】造粒は薬物と、任意に賦形剤と、ショ糖脂
肪酸エステルまたはグリセリン脂肪酸エステルの混合物
を加温ジャケット式ミキサー（例えば万能攪拌機）に投
入し、均一に混合した後ショ糖脂肪酸エステルまたはグ
リセリン脂肪酸エステルの軟化点もしくは融点以上の温
度へ加温しながら攪拌を続け、顆粒化することによって
行われる。In the granulation, a mixture of a drug, optionally an excipient, and a sucrose fatty acid ester or a glycerin fatty acid ester is charged into a heating jacket type mixer (for example, a universal stirrer) and uniformly mixed. Alternatively, the glycerin fatty acid ester is granulated by continuing stirring while heating to a temperature higher than the softening point or the melting point of the glycerin fatty acid ester.
【００１４】一次顆粒はタルク、ステアリン酸マグネシ
ウム、軽質無水ケイ酸などの溶融造粒時に溶融しない滑
沢剤、特にタルクを含むことができる。これら滑沢剤は
一次顆粒およびそれを水不溶性セルロース誘導体で被覆
した二次顆粒の凝集および付着の防止をさらに増強す
る。これらの滑沢剤も一次顆粒の溶融時に混合物へ添加
される。The primary granules may contain a lubricant which does not melt during melt granulation, such as talc, magnesium stearate, light silicic anhydride, etc., especially talc. These lubricants further enhance the prevention of agglomeration and adhesion of primary granules and secondary granules coated with a water-insoluble cellulose derivative. These lubricants are also added to the mixture during the melting of the primary granules.
【００１５】一次顆粒中のショ糖脂肪酸エステルまたは
グリセリン脂肪酸エステルの割合は少なくともその軟化
もしくは溶融によって顆粒に結合した上、所望の遅延放
出を達成するのに十分な割合でなければならない。一般
に一次顆粒の１０〜９０重量％，好ましくは３０〜８０
重量％の範囲である。[0015] The proportion of sucrose or glycerin fatty acid ester in the primary granule must be at least sufficient to achieve the desired delayed release upon binding to the granule by softening or melting. Generally, 10 to 90% by weight of the primary granules, preferably 30 to 80%
% By weight.
【００１６】造粒した一次顆粒は必要により整粒後、水
不溶性セルロース誘導体により被覆される。被覆物質は
製薬工業において錠剤等を耐水性または腸溶性皮膜で被
覆するために使用されるセルロース誘導体であり、その
例はエチルセルロース、ヒドロキシプロピルセルロース
フタレート、ヒドロキシプロピルメチルセルロース、ア
セテートサクシネート、セルロースアセテートフタレー
トを含む。エチルセルロースが好ましい。被覆法は任意
であり、例えば溶液のスプレー法または流動層コーティ
ング法を採用し得る。エチルセルロースの場合は一次顆
粒にエチルセルロースを混合し、流動層造粒機中でエタ
ノールと乾燥空気を交互に噴射し、一次顆粒表面にエチ
ルセルロースの層を被覆する。セルロース誘導体の被覆
量はエチルセルロースの場合徐放性顆粒全体の５〜２０
重量％、特に８〜１２重量％が適当である。水不溶性セ
ルロース誘導体による被覆は顆粒の凝集および付着に対
する抵抗をさらに増強し、徐放性にも部分的に寄与す
る。The granulated primary granules are coated with a water-insoluble cellulose derivative after sizing if necessary. The coating substance is a cellulose derivative used for coating a tablet or the like with a water-resistant or enteric coating in the pharmaceutical industry, and examples thereof include ethylcellulose, hydroxypropylcellulose phthalate, hydroxypropylmethylcellulose, acetate succinate, and cellulose acetate phthalate. Including. Ethyl cellulose is preferred. The coating method is optional, and for example, a solution spraying method or a fluidized bed coating method can be adopted. In the case of ethyl cellulose, the primary granules are mixed with ethyl cellulose, and ethanol and dry air are alternately jetted in a fluidized bed granulator to coat the primary granule surface with the ethyl cellulose layer. In the case of ethyl cellulose, the coating amount of the cellulose derivative is 5 to 20 of the whole sustained release granules.
% By weight, especially 8 to 12% by weight, is suitable. Coating with the water-insoluble cellulose derivative further enhances the resistance of the granules to aggregation and adhesion, and also partially contributes to sustained release.
【００１７】このようにして得られた本発明の徐放性顆
粒は、対応する速放性製剤と組合わせて持続性の細粒
剤、顆粒剤、カプセル剤の製造に使用することができ
る。特に有益な効果が得られるのは有核錠および多層錠
の徐放部分を打錠によって形成する場合である。これは
本発明の顆粒は凝集性および付着性を殆ど有しないか
ら、打錠機の杵および臼に固着するスティッキングおよ
びキャッピングが殆ど見られず、満足な崩壊性および硬
度を有する錠剤が得られるからである。例えば有核錠
は、常法によって打錠した速放性錠剤を芯とし、本発明
の徐放性顆粒にステアリン酸マグネシウム、軽質無水ケ
イ酸のような滑沢剤を混合して打錠することによって製
造される。反対に本発明の徐放性顆粒を芯とし、速放部
を外層とすることもでき、また多層錠に打錠しても良
い。The sustained release granules of the present invention thus obtained can be used in the production of sustained fine granules, granules and capsules in combination with the corresponding immediate release preparations. A particularly beneficial effect is obtained when the sustained release portion of the dry-coated tablet and the multilayer tablet is formed by tableting. This is because the granules of the present invention have little cohesiveness and adhesiveness, so that little sticking and capping sticking to punches and dies of a tableting machine is observed, and tablets having satisfactory disintegration and hardness are obtained. It is. For example, a dry-coated tablet is prepared by mixing a tablet such as a quick-release tablet compressed by a conventional method with a core, and mixing a sustained-release granule of the present invention with a lubricant such as magnesium stearate and light anhydrous silicic acid. Manufactured by Conversely, the sustained-release granules of the present invention may be used as a core, and the immediate-release portion may be used as an outer layer.
【００１８】[0018]
【実施例】以下に薬物としてニフェジピンを使用し、徐
放性顆粒および有核錠の製造に関する実施例および比較
例を記載するが、本発明の原理はニフェジピン以外の薬
物にも適用できることは当業者には自明であろう。EXAMPLES Examples and comparative examples for the production of sustained-release granules and dry coated tablets using nifedipine as a drug are described below. It is understood by those skilled in the art that the principle of the present invention can be applied to drugs other than nifedipine. Would be self-evident.
【００１９】実施例１（徐放性顆粒） ジャケット付きミキサーに、ニフェジピン１２５ｇ、シ
ョ糖脂肪酸エステル２２１５ｇ、および結晶セルロース
３００ｇを入れ、均一に混合した後、ジャケット温度を
５０℃にセットし、加温しながら攪拌を続け造粒し、冷
後パワーミルにて整粒して一次顆粒を得た。次に一次顆
粒２６４０ｇにエチルセルロース粉末３００ｇを加え、
流動層造粒機にて均一に混合し、９５％エタノールを結
合液として噴霧、乾燥、整粒して徐放性二次顆粒を得
た。Example 1 (Sustained Release Granules) In a mixer equipped with a jacket, 125 g of nifedipine, 2215 g of sucrose fatty acid ester and 300 g of crystalline cellulose were mixed uniformly, and then the jacket temperature was set to 50 ° C. and heated. While stirring, the mixture was granulated, cooled, and then sized with a power mill to obtain primary granules. Next, 300 g of ethyl cellulose powder was added to 2640 g of the primary granules,
The mixture was uniformly mixed in a fluidized bed granulator, and sprayed, dried and sized using 95% ethanol as a binder to obtain sustained-release secondary granules.
【００２０】実施例２（徐放性顆粒） 一次顆粒の処方をニフェジピン１２５ｇ、ショ糖脂肪酸
エステル２０００ｇ、結晶セルロース３００ｇ、タルク
２１５ｇに変更し、実施例１と同じ操作によって徐放性
二次顆粒を製造した。Example 2 (Slow release granules) The formulation of the primary granules was changed to 125 g of nifedipine, 2000 g of sucrose fatty acid ester, 300 g of crystalline cellulose, and 215 g of talc. Manufactured.
【００２１】実施例３（徐放性顆粒） 一次顆粒の処方をニフェジピン１２５ｇ、ショ糖脂肪酸
エステル１０００ｇ、結晶セルロース３００ｇ、タルク
１２１５ｇに変更し、実施例１と同じ操作によって徐放
性二次顆粒を製造した。Example 3 (Sustained Release Granules) The formulation of the primary granules was changed to 125 g of nifedipine, 1000 g of sucrose fatty acid ester, 300 g of crystalline cellulose and 1215 g of talc. Manufactured.
【００２２】実施例４（徐放性顆粒） ジャケット付きミキサーに、ニフェジピン１２５ｇ、グ
リセリン脂肪酸エステル（モノステアリン酸ジグリセラ
イドとモノステアリン酸ヘキサグリセライドを約５：３
の割合で含む混合物）８００ｇ、乳糖８５０ｇ、結晶セ
ルロース３００ｇ、およびタルク５６５ｇを入れ、均一
に混合した後、ジャケット温度を６０℃にセットし、加
温しながら攪拌を続け造粒し、冷却パワーミルにて整粒
して一次顆粒を得た。得られた一次顆粒２６４０ｇにエ
チルセルロース粉末３００ｇを加え、流動層造粒機にて
均一に混合し、９５％エタノールを結合液として噴霧、
乾燥、整粒して徐放性二次顆粒を得た。Example 4 (Slow release granules) In a mixer equipped with a jacket, 125 g of nifedipine and glycerin fatty acid ester (monoglyceride monostearate and hexaglyceride monostearate were mixed in a ratio of about 5: 3).
800 g, lactose 850 g, crystalline cellulose 300 g, and talc 565 g, and uniformly mixed. Then, the jacket temperature was set to 60 ° C., stirring was continued while heating, and granulation was performed. To obtain a primary granule. 300 g of ethylcellulose powder was added to 2640 g of the obtained primary granules, and the mixture was uniformly mixed with a fluid bed granulator, and sprayed with 95% ethanol as a binding liquid.
It was dried and sized to obtain sustained-release secondary granules.
【００２３】比較例１ ジャケット付きミキサーに、ニフェジピン１２５ｇ、乳
糖１２１５ｇ、ショ糖脂肪酸エステル１０００ｇ、およ
び結晶セルロース３００ｇを入れ、均一に混合した後、
ジャケット温度を５０℃にセットし、加温しながら攪拌
を続け造粒し、冷後パワーミルにて整粒して一次顆粒を
得た。次に一次顆粒２６４０ｇを流動層造粒機に仕込
み、ステアリルアルコール１５０ｇと硬化油１５０ｇを
９５％エタノール５Ｌに７０℃に加温して溶解した溶液
を噴霧、乾燥、整粒して徐放性二次顆粒を得た。Comparative Example 1 125 g of nifedipine, 1215 g of lactose, 1000 g of sucrose fatty acid ester, and 300 g of crystalline cellulose were put in a jacketed mixer and mixed uniformly.
The jacket temperature was set to 50 ° C., stirring was continued while heating, and granulation was performed. After cooling, the granules were sized with a power mill to obtain primary granules. Next, 2640 g of the primary granules were charged into a fluidized bed granulator, and a solution obtained by heating 150 g of stearyl alcohol and 150 g of hardened oil in 5 L of 95% ethanol at 70 ° C. was sprayed, dried and sized to obtain a sustained release granule. The following granules were obtained.
【００２４】比較例２（徐放性顆粒） ジャケット付きミキサーに、ニフェジピン１２５ｇ、乳
糖１３６５ｇ、ショ糖脂肪酸エステル１０００ｇ、およ
び結晶性セルロース１５０ｇを入れ、均一に混合した
後、ジャケット温度を５０℃にセットし、加温しながら
攪拌を続け造粒し、冷後パワーミルにて整粒して一次顆
粒を得た。次に一次顆粒２６４０ｇを流動層造粒機に仕
込み、ステアリルアルコール３００ｇを９５％エタノー
ル５Ｌに５０℃に加温して溶解した溶液を噴霧、乾燥、
整粒して徐放性二次顆粒を得た。Comparative Example 2 (Sustained Release Granules) In a mixer equipped with a jacket, 125 g of nifedipine, 1365 g of lactose, 1000 g of sucrose fatty acid ester, and 150 g of crystalline cellulose were mixed, uniformly mixed, and the jacket temperature was set to 50 ° C. The mixture was stirred and granulated while being heated, cooled, and then sized using a power mill to obtain primary granules. Next, 2640 g of the primary granules were charged into a fluidized bed granulator, and a solution obtained by heating and dissolving 300 g of stearyl alcohol in 5 L of 95% ethanol at 50 ° C. was sprayed and dried.
The granules were sized to obtain sustained-release secondary granules.
【００２５】比較例３（徐放性顆粒） 比較例２において一次顆粒のステアリルアルコールによ
る被覆を行わなかった。Comparative Example 3 (Sustained Release Granules) In Comparative Example 2, the primary granules were not coated with stearyl alcohol.
【００２６】実施例５（有核錠） その１．芯部速放錠の製造 ニフェジピン結晶（平均粒子径Ｄ50＝５μｍ）３７５
ｇ、乳糖８００ｇ、結晶セルロース１００ｇ、およびヒ
ドロキシプロピルセルロース６８５ｇを流動層造粒機に
入れ、均一に混合した後、９５％エタノール２．５Ｌに
溶かしたポリビニルピロリドン５００ｇの溶液を結合液
とし、流動層造粒し、乾燥後パワーミルにて整粒した。
得られた顆粒２４６０ｇにステアリン酸マグネシウム４
０ｇを混合し、常法によって打錠し、直径５ｍｍ、重さ
５０ｍｇの芯部錠剤を得た。 その２．有核錠の製造 実施例１の徐放性二次顆粒２９４０ｇに軽質無水ケイ酸
２０ｇ、ステアリン酸マグネシウム４０ｇを混合し、上
で得た速放性錠剤を核として有核打錠機を用いて直径９
ｍｍ、重さ３５０ｍｇの有核錠を製造した。Example 5 (Nucleated Tablets) Manufacture of core immediate release tablet Nifedipine crystal (average particle diameter D 50 = 5 μm) 375
g, lactose 800 g, microcrystalline cellulose 100 g, and hydroxypropyl cellulose 685 g were placed in a fluidized bed granulator, mixed uniformly, and then a solution of polyvinylpyrrolidone 500 g dissolved in 2.5 L of 95% ethanol was used as a binding solution. After granulation, drying and sizing with a power mill.
Magnesium stearate 4 was added to 2460 g of the obtained granules.
0 g were mixed and tableted by a conventional method to obtain a core tablet having a diameter of 5 mm and a weight of 50 mg. Part 2. Production of dry-coated tablets 20 g of light anhydrous silicic acid and 40 g of magnesium stearate were mixed with 2940 g of the sustained-release secondary granules of Example 1, and the quick-release tablets obtained above were used as cores, using a dry-pressed tableting machine. Diameter 9
A dry coated tablet having a size of 350 mm and a weight of 350 mg was produced.
【００２７】実施例６（有核錠） 外層の徐放性顆粒を実施例２の徐放性顆粒に変更し、実
施例５と同じ操作に従って有核錠を得た。Example 6 (Nucleated Tablets) The sustained release granules in the outer layer were changed to the sustained release granules of Example 2, and a dry coated tablet was obtained in the same manner as in Example 5.
【００２８】実施例７（有核錠） 外層の徐放性顆粒を実施例３の徐放性顆粒に変更し、実
施例５と同じ操作に従って有核錠を得た。Example 7 (Nucleated Tablets) The sustained release granules in the outer layer were changed to the sustained release granules of Example 3, and a dry coated tablet was obtained in the same manner as in Example 5.
【００２９】実施例８（有核錠） 外層の徐放部を実施例４の徐放性二次顆粒２９４０ｇに
軽質無水ケイ酸２０ｇ、ステアリン酸マグネシウム４０
ｇを混合し、実施例５において製造した速放性錠剤を核
として有核打錠機を用いて直径９ｍｍ、重さ３５０ｍｇ
の有核錠を製造した。Example 8 (Nucleated Tablets) The sustained release portion of the outer layer was added to 2940 g of the sustained release secondary granules of Example 4 by adding 20 g of light anhydrous silicic acid and 40 g of magnesium stearate.
g, and mixed with the immediate-release tablet produced in Example 5 as a core using a nucleated tableting machine with a diameter of 9 mm and a weight of 350 mg.
Was manufactured.
【００３０】比較例４ 外層の徐放性顆粒を比較例１の徐放性顆粒に変更し、実
施例５と同じ操作に従って有核錠を得た。Comparative Example 4 The sustained release granules of the outer layer were changed to the sustained release granules of Comparative Example 1, and a dry coated tablet was obtained in the same manner as in Example 5.
【００３１】比較例５ 外層の徐放性顆粒を比較例２の徐放性顆粒に変更し、実
施例５と同じ操作に従って有核錠を得た。Comparative Example 5 The sustained release granules in the outer layer were changed to the sustained release granules of Comparative Example 2, and a dry coated tablet was obtained in the same manner as in Example 5.
【００３２】比較例６ 比較例３の顆粒を用いて実施例５と同じ操作に従って有
核錠に打錠しようとしたが、打錠できなかった。Comparative Example 6 Using the granules of Comparative Example 3 in accordance with the same operation as in Example 5, tableting was attempted.
【００３３】[0033]
【評価】実施例１〜４および比較例１〜３の徐放性顆粒
について凝固性および付着率を以下の方法によって評価
した。[Evaluation] The coagulability and adhesion rate of the sustained release granules of Examples 1 to 4 and Comparative Examples 1 to 3 were evaluated by the following methods.
【００３４】凝集性：顆粒１００ｇを蓋付き広口ガラス
びんに入れ、室温で７日間保存し、取り出して目視によ
り凝集の有無を観察した。Agglomeration: 100 g of the granules were placed in a wide-mouthed glass bottle with a lid, stored at room temperature for 7 days, taken out, and visually observed for aggregation.
【００３５】付着率：顆粒１０ｇをポリエチレン袋（１
４０ｍｍ×１００ｍｍ）に正確に秤取し、２分間振り混
ぜた後取り出し、バッグに付着して残っている顆粒の重
量を測定して付着率（％）を計算した。結果を表１に示
す。Adhesion rate: 10 g of granules were placed in a polyethylene bag (1
(40 mm x 100 mm), shaken for 2 minutes, taken out, measured the weight of the granules remaining on the bag, and calculated the adhesion rate (%). Table 1 shows the results.
【００３６】 表１ 顆粒 凝集性（目視） 付着率（％） ────────── ──────────── ─────────── 実施例１（二次顆粒） なし ０．７ 実施例２（一次顆粒） なし １．３ 同 （二次顆粒） なし ０．５ 実施例３（一次顆粒） なし ０．８ 同 （二次顆粒） なし ０．６ 実施例４（一次顆粒） なし ０．９ 同 （二次顆粒） なし ０．６ 比較例１（二次顆粒） あり ５．４ 比較例２（二次顆粒） ややあり ２．５ 比較例３（一次顆粒） ややあり ５．０ ───────────────────────────────────Table 1 Granules Cohesiveness (visual) Adhesion rate (%) ────────── ──────────── 実 施Example 1 (secondary granules) None 0.7 Example 2 (primary granules) None 1.3 Same (secondary granules) None 0.5 Example 3 (primary granules) None 0.8 Same (secondary granules) None 0.6 Example 4 (primary granules) No 0.9 Same (Secondary granules) No 0.6 Comparative Example 1 (Secondary granules) Yes 5.4 Comparative Example 2 (Secondary granules) Somewhat 2.5 Example 3 (primary granules) Slightly 5.0
【００３７】有核錠：実施例５〜８および比較例４，５
の有核錠について打錠時のスティッキングおよびキャッ
ピングの有無および錠剤硬度を評価し、表２に示す結果
を得た。Dry-coated tablets: Examples 5-8 and Comparative Examples 4,5
The presence / absence of sticking and capping at the time of tableting and the tablet hardness of the dry coated tablet were evaluated, and the results shown in Table 2 were obtained.
【００３８】 表２ 有核錠 徐放部顆粒 スティッキング／ 硬度（ｋｇ） キャッピング ────── ───────── ────────── ─────── 実施例５ 実施例１ なし ５．４ 実施例６ 実施例２ なし ４．６ 実施例７ 実施例３ なし ９．２ 実施例８ 実施例４ なし ７．２ 比較例４ 比較例１ あり ４．２ 比較例５ 比較例２ あり ４．７ ───────────────────────────────────Table 2 Dry coated tablets Sustained release granules Sticking / Hardness (kg) Capping ────── ────── ────────── ────── ５ Example 5 Example 1 None 5.4 Example 6 Example 2 None 4.6 Example 7 Example 3 None 9.2 Example 8 Example 4 None 7.2 Comparative Example 4 Comparative Example 1 Yes 4. 2 Comparative Example 5 Comparative Example 2 Yes 4.7───────────────────────────────────
【００３９】有核錠の溶出プロファイル：上の有核錠に
ついて溶出性を以下の条件で試験した。 （１）試験液 １％ポリソルベート水溶液、液量９００ｍｌ （２）試験法 パドル法（ハンギングシンカー法）、回転数１００ｒｐ
ｍ、温度３７℃ 溶出プロファイルは、試験した有核錠すべてについて２
４０〜３００分で１００％溶出率まで上昇した。Dissolution Profile of Nucleated Tablets: The above-mentioned hydrated tablets were tested for dissolution under the following conditions. (1) Test solution 1% polysorbate aqueous solution, liquid volume 900 ml (2) Test method Paddle method (hanging sinker method), rotation speed 100 rpm
m, temperature 37 ° C. The dissolution profile was 2 for all of the tested dry coated tablets.
It increased to 100% elution rate in 40 to 300 minutes.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ テーマコート゛(参考） Ａ６１Ｋ 47/14 Ａ６１Ｋ 47/14 47/36 47/36 47/38 47/38 Ａ６１Ｐ 9/12 Ａ６１Ｐ 9/12 // Ｃ０７Ｄ 211/90 Ｃ０７Ｄ 211/90 (72)発明者 松永 伸子 大阪府門真市一番町26−７ 東和薬品株式 会社中央研究所内 Ｆターム(参考） 4C054 AA07 BB03 CC01 DD04 DD08 EE33 FF05 FF16 4C076 AA31 AA41 AA67 BB01 CC11 CC13 DD08 DD28C DD41 EE31 EE32 FF09 FF31 FF43 GG13 GG14 4C086 AA01 AA02 BC25 MA03 MA05 MA35 MA41 MA52 NA12 ZA36 ZA42 ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 7 Identification symbol FI theme coat ゛ (Reference) A61K 47/14 A61K 47/14 47/36 47/36 47/38 47/38 A61P 9/12 A61P 9 / 12 // C07D 211/90 C07D 211/90 (72) Inventor Nobuko Matsunaga 26-7 Ichibancho, Kadoma-shi, Osaka F-term in Central Research Laboratories of Towa Pharmaceutical Co., Ltd. 4C054 AA07 BB03 CC01 DD04 DD08 EE33 FF05 FF16 4C076 AA31 AA41 AA67 BB01 CC11 CC13 DD08 DD28C DD41 EE31 EE32 FF09 FF31 FF43 GG13 GG14 4C086 AA01 AA02 BC25 MA03 MA05 MA35 MA41 MA52 NA12 ZA36 ZA42
Claims (6)
ルまたはグリセリン脂肪酸エステルのマトリックスを少
なくとも含んでいる一次顆粒に、水不溶性セルロース誘
導体の被覆を施してなる薬物含有徐放性顆粒。1. A drug-containing sustained-release granule obtained by coating a primary granule containing at least a matrix of a sucrose fatty acid ester or a glycerin fatty acid ester solid at room temperature with a drug and a water-insoluble cellulose derivative.
性顆粒。2. The sustained release granule according to claim 1, wherein the drug is nifedipine.
ースである請求項１の徐放性顆粒。3. The sustained-release granule according to claim 1, wherein the water-insoluble cellulose derivative is ethyl cellulose.
リセリン脂肪酸エステルの溶融温度において溶融しない
滑沢剤をさらに含んでいる請求項１の徐放性顆粒。4. The sustained release granule according to claim 1, wherein the primary granule further contains a lubricant which does not melt at the melting temperature of the sucrose fatty acid ester or glycerin fatty acid ester.
粒。5. The sustained-release granule according to claim 4, wherein the lubricant is talc.
いし５の徐放性顆粒よりなる徐放部を打錠によって形成
してなる持続性錠剤。6. A sustained-release tablet comprising a tablet and an immediate-release part containing the same drug and a sustained-release part comprising the sustained-release granules according to claims 1 to 5.
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| JP2001176735A JP4974419B2 (en) | 2001-06-12 | 2001-06-12 | Drug-containing sustained release granules and tablets containing the same |
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| JP2001176735A JP4974419B2 (en) | 2001-06-12 | 2001-06-12 | Drug-containing sustained release granules and tablets containing the same |
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| JP4974419B2 JP4974419B2 (en) | 2012-07-11 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006516969A (en) * | 2003-01-23 | 2006-07-13 | アモレパシフィック コーポレーション | Sustained release preparation and method for producing the same |
| JP2011251959A (en) * | 2010-05-06 | 2011-12-15 | Taisho Pharmaceutical Co Ltd | Ambroxol-containing preparation particle |
| JP2020510000A (en) * | 2017-03-08 | 2020-04-02 | シンリックス ファーマ、エルエルシー | Pharmaceutical preparations of florgurucinol and trimethylphloroglucinol |
| JP2020063202A (en) * | 2018-10-16 | 2020-04-23 | 佐藤薬品工業株式会社 | Pharmaceutical compositions comprising caffeine and hyoscyamine and production methods thereof |
| JP2020532548A (en) * | 2017-08-29 | 2020-11-12 | コンリグ ファーマ エーピーエス | Compositions Containing Splatast Tosylate |
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| JPH02223533A (en) * | 1988-11-08 | 1990-09-05 | Takeda Chem Ind Ltd | Agent with release-controlled matrix |
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| WO1997003656A1 (en) * | 1995-07-21 | 1997-02-06 | Daiichi Pharmaceutical Co., Ltd. | Granular preparation and process for producing the same |
| JPH10218761A (en) * | 1997-02-07 | 1998-08-18 | Taisho Pharmaceut Co Ltd | Multiple unit type sustained release tablet |
| JP2000178193A (en) * | 1998-12-16 | 2000-06-27 | Towa Yakuhin Kk | Nifedipine slow-releasing preparation |
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| JPS618A (en) * | 1984-06-09 | 1986-01-06 | Sawai Seiyaku Kk | Nifedipin-containing drug preparation |
| JPS61148114A (en) * | 1984-11-15 | 1986-07-05 | Teijin Ltd | Nifedipine granule |
| JPH02223533A (en) * | 1988-11-08 | 1990-09-05 | Takeda Chem Ind Ltd | Agent with release-controlled matrix |
| JPH05237A (en) * | 1990-04-28 | 1993-01-08 | Takeda Chem Ind Ltd | Granulated matter and production thereof |
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| JPH08143450A (en) * | 1994-11-14 | 1996-06-04 | Taiyo Yakuhin Kogyo Kk | Sustained release preparation |
| WO1997003656A1 (en) * | 1995-07-21 | 1997-02-06 | Daiichi Pharmaceutical Co., Ltd. | Granular preparation and process for producing the same |
| JPH10218761A (en) * | 1997-02-07 | 1998-08-18 | Taisho Pharmaceut Co Ltd | Multiple unit type sustained release tablet |
| JP2000178193A (en) * | 1998-12-16 | 2000-06-27 | Towa Yakuhin Kk | Nifedipine slow-releasing preparation |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006516969A (en) * | 2003-01-23 | 2006-07-13 | アモレパシフィック コーポレーション | Sustained release preparation and method for producing the same |
| JP2011251959A (en) * | 2010-05-06 | 2011-12-15 | Taisho Pharmaceutical Co Ltd | Ambroxol-containing preparation particle |
| JP2020510000A (en) * | 2017-03-08 | 2020-04-02 | シンリックス ファーマ、エルエルシー | Pharmaceutical preparations of florgurucinol and trimethylphloroglucinol |
| JP7323451B2 (en) | 2017-03-08 | 2023-08-08 | シンリックス ファーマ、エルエルシー | Pharmaceutical preparations of phloroglucinol and trimethylphloroglucinol |
| JP2020532548A (en) * | 2017-08-29 | 2020-11-12 | コンリグ ファーマ エーピーエス | Compositions Containing Splatast Tosylate |
| JP7330948B2 (en) | 2017-08-29 | 2023-08-22 | コンリグ ファーマ エーピーエス | Compositions containing suplatast tosylate |
| AU2018322756B2 (en) * | 2017-08-29 | 2023-10-19 | Conrig Pharma Aps | Composition comprising suplatast tosilate |
| US11819482B2 (en) | 2017-08-29 | 2023-11-21 | Conrig Pharma Aps | Composition comprising suplatast tosilate |
| JP2020063202A (en) * | 2018-10-16 | 2020-04-23 | 佐藤薬品工業株式会社 | Pharmaceutical compositions comprising caffeine and hyoscyamine and production methods thereof |
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