JP2017014119A - Oral pharmaceutical composition - Google Patents
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- JP2017014119A JP2017014119A JP2015129299A JP2015129299A JP2017014119A JP 2017014119 A JP2017014119 A JP 2017014119A JP 2015129299 A JP2015129299 A JP 2015129299A JP 2015129299 A JP2015129299 A JP 2015129299A JP 2017014119 A JP2017014119 A JP 2017014119A
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- olanzapine
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- 239000008203 oral pharmaceutical composition Substances 0.000 title claims abstract description 17
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 claims abstract description 38
- 229960005017 olanzapine Drugs 0.000 claims abstract description 37
- 239000000654 additive Substances 0.000 claims abstract description 27
- 230000000996 additive effect Effects 0.000 claims abstract description 20
- 239000006191 orally-disintegrating tablet Substances 0.000 claims abstract description 19
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims abstract description 13
- 239000003826 tablet Substances 0.000 claims abstract description 12
- 239000000347 magnesium hydroxide Substances 0.000 claims abstract description 11
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims abstract description 11
- 239000004475 Arginine Substances 0.000 claims abstract description 5
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims abstract description 5
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 claims abstract description 5
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000395 magnesium oxide Substances 0.000 claims abstract description 5
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims abstract description 5
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229960003194 meglumine Drugs 0.000 claims abstract description 5
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 238000009472 formulation Methods 0.000 abstract description 6
- 238000013329 compounding Methods 0.000 abstract 1
- 239000000126 substance Substances 0.000 description 22
- 239000000843 powder Substances 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 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 8
- 238000004811 liquid chromatography Methods 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- -1 cetyl ester Chemical class 0.000 description 7
- 239000008187 granular material Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000004698 Polyethylene Substances 0.000 description 5
- 229920002678 cellulose Polymers 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 229920000573 polyethylene Polymers 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 229960000913 crospovidone Drugs 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
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- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- 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 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- OMOVVBIIQSXZSZ-UHFFFAOYSA-N [6-(4-acetyloxy-5,9a-dimethyl-2,7-dioxo-4,5a,6,9-tetrahydro-3h-pyrano[3,4-b]oxepin-5-yl)-5-formyloxy-3-(furan-3-yl)-3a-methyl-7-methylidene-1a,2,3,4,5,6-hexahydroindeno[1,7a-b]oxiren-4-yl] 2-hydroxy-3-methylpentanoate Chemical compound CC12C(OC(=O)C(O)C(C)CC)C(OC=O)C(C3(C)C(CC(=O)OC4(C)COC(=O)CC43)OC(C)=O)C(=C)C32OC3CC1C=1C=COC=1 OMOVVBIIQSXZSZ-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 238000002845 discoloration Methods 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 235000010919 Copernicia prunifera Nutrition 0.000 description 1
- 244000180278 Copernicia prunifera Species 0.000 description 1
- 229920003119 EUDRAGIT E PO Polymers 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000010358 acesulfame potassium Nutrition 0.000 description 1
- 229960004998 acesulfame potassium Drugs 0.000 description 1
- 239000000619 acesulfame-K Substances 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 229950008138 carmellose Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000002706 dry binder Substances 0.000 description 1
- XPNLOZNCOBKRNJ-UHFFFAOYSA-N ethyl prop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C=C.COC(=O)C(C)=C XPNLOZNCOBKRNJ-UHFFFAOYSA-N 0.000 description 1
- 238000005562 fading Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 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
- 208000024891 symptom Diseases 0.000 description 1
- 150000003571 thiolactams Chemical class 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、有効成分としてオランザピンを含有する経口医薬組成物に関する。 The present invention relates to an oral pharmaceutical composition containing olanzapine as an active ingredient.
式（Ｉ）で示される２−メチル−４−（４−メチル−１−ピペラジニル）−１０Ｈ−チエノ−［２，３−ｂ］［１，５］ベンゾジアゼピン（以下、オランザピンと称する。）は、統合失調症や双極性障害における躁症状の治療薬として広く用いられている。 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno- [2,3-b] [1,5] benzodiazepine (hereinafter referred to as olanzapine) represented by the formula (I) is: It is widely used as a treatment for manic symptoms in schizophrenia and bipolar disorder.
オランザピンは、単独では、比較的安定な化合物であると考えられている。しかし、オランザピンは、高湿度環境下あるいは溶液中では分解または変色を生じることが知られている。オランザピンの加水分解生成物としては例えば式（ＩＩ）で表わされる類縁物質Ｂ、酸化生成物としては式（ＩＩＩ）で表わされる類縁物質Ｃや類縁物質Ａ、ラクタム体、チオラクタム体が知られている。 Olanzapine is considered to be a relatively stable compound by itself. However, olanzapine is known to cause decomposition or discoloration in a high humidity environment or in a solution. For example, related substance B represented by the formula (II) is known as the hydrolysis product of olanzapine, and related substances C and related substances A, lactams and thiolactams represented by the formula (III) are known as oxidation products. .
そこで、特表平１１−５０２８４８号公報（特許文献１）では、湿気に敏感なオランザピンの褪色傾向に照らして改善された経口製剤が提案されている。特許文献１に記載の固形経口製剤は、賦形剤、結合剤、崩壊剤、粉砕性を与えるための乾燥結合剤、および滑沢剤と十分混合された、オランザピンを含有する固形経口製剤であって、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、メチルヒドロキシエチルセルロース、ナアトリウムカルボキシメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルピロリドン、ジメチルアミノエチルメタクリレートメチルアクリレート酸エステル共重合体、エチルアクリレート−メチルメタクリレート共重合体、メチルセルロース、及びエチルセルロースからなる群から選択されるポリマーでコートされる。
Therefore, Japanese Patent Publication No. 11-502848 (Patent Document 1) proposes an oral preparation improved in light of the fading tendency of olanzapine sensitive to moisture. The solid oral preparation described in
また、特表２００１−５０１２０７号公報（特許文献２）には、望ましくない変色現象を防ぐために、１つまたはそれ以上の製薬的に許容される賦形剤とともに、セチルアルコール、セチルエステル蝋、カルナウバ蝋、セラック、蜜蝋、ステアリン酸マグネシウム、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、メチルヒドロキシエチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルセルロース、ポリビニルピロリドン、ジメチルアミノエチルメタクリレートメチルアクリル酸エステル共重合体、エチルアクリレート−メチルメタクリレート共重合体、メチルセルロースおよびエチルセルロースからなる群から選択される重合体でコーティングされているオランザピンを活性成分として含む固形経口用製剤が記載されている。 JP 2001-501207 (Patent Document 2) discloses cetyl alcohol, cetyl ester wax, carnauba together with one or more pharmaceutically acceptable excipients to prevent undesirable discoloration. Wax, shellac, beeswax, magnesium stearate, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, dimethylaminoethylmethacrylate methyl acrylate copolymer, ethylacrylate-methylmethacrylate Olanzapine coated with a polymer selected from the group consisting of a polymer, methylcellulose and ethylcellulose as an active ingredient Solid oral preparations are described.
特開２０１４−０５８４６１号公報（特許文献３）には、長期間の保存においても類縁物質である４’−Ｎ−オキシド体の増加を抑制することを目的として、オランザピンと、低置換度ヒドロキシプロピルセルロースまたは過酸化物含有量が８０ｐｐｍ未満のクロスポビドンもしくはそれらの混合物と、を含むことを特徴とするオランザピン含有製剤が記載されている。 JP 2014-058461 A (Patent Document 3) describes olanzapine and low-substituted hydroxypropyl for the purpose of suppressing an increase in the 4′-N-oxide compound, which is a related substance, even during long-term storage. An olanzapine-containing formulation characterized in that it comprises cellulose or crospovidone or a mixture thereof having a peroxide content of less than 80 ppm is described.
国際公開ＷＯ２０１４／０８０７８４号（特許文献４）には、溶液中あるいは高湿度下で加水分解されるオランザピンの特性に照らして、オランザピンと水を含み、調整時のｐＨが７〜１０の範囲内であることを特徴とする水性医薬製剤が記載されている。 In the international publication WO2014 / 080784 (patent document 4), in the light of the characteristics of olanzapine hydrolyzed in solution or under high humidity, olanzapine and water are included, and the pH at the time of adjustment is within the range of 7-10. An aqueous pharmaceutical formulation characterized in that is described.
オランザピン経口製剤の検討において、従来の特許文献１〜４の製剤では、オランザピンの加水分解生成物として上の式（ＩＩ）で表わされる類縁物質Ｂ、及び酸化生成物として上の式（ＩＩＩ）で表される類縁物質Ｃの生成は十分に抑制されていなかった。
In the study of oral preparations of olanzapine, in the preparations of the
すなわち、本発明は、オランザピン経口組成物において、塩基性添加剤を配合することで類縁物質の生成を抑制し、安定性を改善することを目的とする。 That is, an object of the present invention is to suppress the formation of related substances and improve the stability by blending a basic additive in the olanzapine oral composition.
本発明者らは、鋭意研究の結果、オランザピン経口製剤において塩基性添加剤を用いることで、類縁物質Ｂ及びＣの生成を抑制することができることを見出した。 As a result of intensive studies, the present inventors have found that the production of related substances B and C can be suppressed by using a basic additive in an olanzapine oral preparation.
以上の知見に基づいて、本願発明は次の構成を備える。すなわち、本願発明に従った経口医薬組成物は、オランザピンと塩基性添加剤とを含むことを特徴とする。 Based on the above knowledge, the present invention has the following configuration. That is, the oral pharmaceutical composition according to the present invention includes olanzapine and a basic additive.
また、本発明に従った経口医薬組成物においては、塩基性添加剤は、水酸化マグネシウム、酸化マグネシウム、アミノアルキルメタクリレートコポリマーＥ、メグルミン、及びアルギニンからなる群から選ばれる少なくとも１つであることが好ましい。 In the oral pharmaceutical composition according to the present invention, the basic additive may be at least one selected from the group consisting of magnesium hydroxide, magnesium oxide, aminoalkyl methacrylate copolymer E, meglumine, and arginine. preferable.
さらに、本発明に従った経口医薬組成物においては、塩基性添加剤の配合割合は、１〜５重量％の範囲内であることが好ましい。 Furthermore, in the oral pharmaceutical composition according to the present invention, the blending ratio of the basic additive is preferably in the range of 1 to 5% by weight.
本発明に従った経口医薬組成物は、錠または口腔内崩壊錠であることが好ましい。 The oral pharmaceutical composition according to the present invention is preferably a tablet or an orally disintegrating tablet.
本発明は、オランザピン経口組成物において、塩基性添加剤を配合することで類縁物質の生成を抑制し、安定性を改善する。 In the oral composition of olanzapine, the present invention suppresses the formation of related substances and improves the stability by adding a basic additive.
本発明に従った経口医薬組成物は、オランザピンと塩基性添加剤とを含む。 The oral pharmaceutical composition according to the present invention comprises olanzapine and a basic additive.
塩基性添加剤としては、水酸化マグネシウム、酸化マグネシウム、アミノアルキルメタクリレートコポリマーＥ（オイドラギッドＥＰＯ（登録商標））、メグルミン、アルギニンがあげられる。また、塩基性添加剤としては、水酸化マグネシウムであることが好ましい。 Examples of the basic additive include magnesium hydroxide, magnesium oxide, aminoalkyl methacrylate copolymer E (Eudragid EPO (registered trademark)), meglumine, and arginine. Further, the basic additive is preferably magnesium hydroxide.
また、本発明に従った経口医薬組成物は、塩基性添加剤を１〜５重量％含むことが好ましい。 Moreover, it is preferable that the oral pharmaceutical composition according to this invention contains 1-5 weight% of basic additives.
また、本発明に従った経口医薬組成物は、錠または口腔内崩壊錠であることが好ましい。 The oral pharmaceutical composition according to the present invention is preferably a tablet or an orally disintegrating tablet.
本発明に従った経口医薬組成物には、上記成分以外にも、薬学的に許容される添加物を必要に応じて適宜配合することができる。具体的な添加物としては、乳糖水和物やＤ−マンニトールのような賦形剤、低置換度ヒドロキシプロピルセルロースやカルメロースのような崩壊剤、アスパルテームやアセスルファムカリウムのような甘味剤、黄色三二酸化鉄のような着色剤、ステアリン酸マグネシウムやステアリン酸カルシウムのような滑沢剤等を配合することができる。 In the oral pharmaceutical composition according to the present invention, in addition to the above components, pharmaceutically acceptable additives can be appropriately blended as necessary. Specific additives include excipients such as lactose hydrate and D-mannitol, disintegrants such as low-substituted hydroxypropylcellulose and carmellose, sweeteners such as aspartame and acesulfame potassium, yellow sesquioxide Coloring agents such as iron, lubricants such as magnesium stearate and calcium stearate, and the like can be blended.
本発明に従った経口医薬組成物の製造方法としては、公知の方法を使用することができる。例えば、上記の各成分を混合した後、錠剤または口腔内崩壊錠として成形する方法等がある。 As a method for producing an oral pharmaceutical composition according to the present invention, a known method can be used. For example, after mixing each of the above components, there is a method of forming a tablet or an orally disintegrating tablet.
具体的には、以下に示す方法によってオランザピン口腔内崩壊錠を製造することができる。崩壊剤、賦形剤等を含む成分を用い、公知の造粒方法によって造粒し、その後整粒することで整粒末を得る。次いで、その整粒末と原薬であるオランザピンと塩基性添加剤を含むその他の添加物とを混合した後、滑沢剤を加えて打錠末を得る。その後、打錠末は、公知の方法で口腔内崩壊錠に打錠される。 Specifically, an olanzapine orally disintegrating tablet can be manufactured by the method shown below. A granulated powder is obtained by granulating by a known granulation method using components including a disintegrant, an excipient, and the like, and then sizing. Next, the sized powder, olanzapine as the drug substance, and other additives including a basic additive are mixed, and then a lubricant is added to obtain a tableting powder. Thereafter, the tableting powder is compressed into an orally disintegrating tablet by a known method.
以下、実施例等により本発明を詳細に説明するが、本発明はこれに限定されるものではない。 Hereinafter, although an example etc. explain the present invention in detail, the present invention is not limited to this.
（安定性試験１）
実施例１−ａのオランザピン口腔内崩壊錠とコントロールａのオランザピン口腔内崩壊錠の処方を表１に示す。
(Stability test 1)
Table 1 shows the formulations of the olanzapine orally disintegrating tablet of Example 1-a and the olanzapine orally disintegrating tablet of Control a.
実施例１−ａとコントロールａの口腔内崩壊錠は、表１の処方で、以下の製造方法に従って製造された。すなわち、Ｄ−マンニトール、セルロース化合物、デンプン及びクロスポビドンからなる顆粒成分を用いて、流動層造粒法により顆粒を得た後、得られた顆粒を、整粒機を用いて整粒し整粒末を得た。次いで、この整粒末、オランザピン、塩基性添加剤として水酸化マグネシウム、セルロース化合物、軽質無水ケイ酸、甘味剤とをポリエチレン袋にて混合後、ステアリン酸マグネシウムを投入し混合することで打錠末を得た。そして、打錠末を打錠機（株式会社菊水製作所製、ＶＥＬＡ５）で打錠し、目的の口腔内崩壊錠を得た。 The orally disintegrating tablets of Example 1-a and Control a were prepared according to the following production method with the formulation shown in Table 1. That is, after using the granule component which consists of D-mannitol, a cellulose compound, starch, and crospovidone, the granule was obtained by the fluidized-bed granulation method, and the obtained granule was sized using a granulator and sized. I got the end. Next, after mixing this sized powder, olanzapine, and basic additives such as magnesium hydroxide, cellulose compound, light anhydrous silicic acid and sweetener in a polyethylene bag, magnesium stearate is added and mixed to form a tableting powder. Got. The tableting powder was tableted with a tableting machine (VELA5, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain the desired orally disintegrating tablet.
上述のようにして調製されたオランザピン口腔内崩壊錠の安定性を以下のようにして確認した。
まず、各錠から採取した検体を液体クロマトグラフィーにより試験を行い、類縁物質量を測定した。検体を乾燥剤入りのポリエチレン瓶に収容し、４０℃７５％ＲＨで所定の期間保存した後、液体クロマトグラフィーにより類縁物質量を測定した。
The stability of the olanzapine orally disintegrating tablet prepared as described above was confirmed as follows.
First, specimens collected from each tablet were tested by liquid chromatography, and the amount of related substances was measured. The specimen was placed in a polyethylene bottle containing a desiccant and stored at 40 ° C. and 75% RH for a predetermined period, and the amount of related substances was measured by liquid chromatography.
液体クロマトグラフィーの条件は次の通りであった。
検出器：紫外吸光光度計 （測定波長：２２０ｎｍ）
カラム：内径４．６ｍｍ、長さ２５ｃｍのステンレス管に５ｍｍの液体クロマトグラフィー用オクチルシリル化シリカゲルを充填した。
カラム温度：３０℃付近の一定温度
移動相流量：毎分１．２ｍＬ
サンプル注入量：１０ｍＬ
移動相：溶液Ａ及びＢから構成された。
溶液Ａ：水１０００ｍＬにリン酸二水素ナトリウム二水和物３．１ｇを加えて溶かし、薄めたリン酸を加えてｐＨ ２．５に調整する。この液７００ｍＬにアセトニトリル３００ｍＬを加えて混和し、ラウリル硫酸ナトリウム２．０ｇを加えた。
溶液Ｂ：水１０００ｍＬにリン酸二水素ナトリウム二水和物３．１ｇを加えて溶かし、薄めたリン酸を加えてｐＨ ２．５に調整する。この液３００ｍＬにアセトニトリル７００ｍＬを加えて混和し、ラウリル硫酸ナトリウム２．０ｇを加えた。
The conditions for liquid chromatography were as follows.
Detector: UV absorptiometer (measurement wavelength: 220 nm)
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 25 cm was packed with octylsilylated silica gel for liquid chromatography having a thickness of 5 mm.
Column temperature: constant temperature around 30 ° C Mobile phase flow rate: 1.2 mL / min
Sample injection volume: 10 mL
Mobile phase: composed of solutions A and B.
Solution A: 3.1 g of sodium dihydrogen phosphate dihydrate is added to 1000 mL of water to dissolve, and diluted phosphoric acid is added to adjust to pH 2.5. To 700 mL of this solution, 300 mL of acetonitrile was added and mixed, and 2.0 g of sodium lauryl sulfate was added.
Solution B: 3.1 g of sodium dihydrogen phosphate dihydrate is added to 1000 mL of water to dissolve, and diluted phosphoric acid is added to adjust to pH 2.5. To 300 mL of this solution, 700 mL of acetonitrile was added and mixed, and 2.0 g of sodium lauryl sulfate was added.
各検体のピーク面積を自動積分法により算出し、面積百分率法により各検体に含まれる類縁物質量を求めた。結果を図１（（Ａ）実施例１−ａ、（Ｂ）コントロールａ）に示す。 The peak area of each specimen was calculated by the automatic integration method, and the amount of related substances contained in each specimen was determined by the area percentage method. The results are shown in FIG. 1 ((A) Example 1-a, (B) Control a).
図１に示すように、塩基性添加剤として水酸化マグネシウムを添加したことで、類縁物質Ｂ及びＣの増加が大幅に抑制された。 As shown in FIG. 1, the addition of magnesium hydroxide as a basic additive significantly suppressed the increase in related substances B and C.
（安定性試験２）
塩基性添加剤として、さらに水酸化マグネシウム１重量％（実施例２）、水酸化マグネシウム５重量％（実施例３）を用いた。総重量は実施例１−ａと同じく１３５ｍｇとし、全体量は顆粒成分で調整した。それぞれの錠剤は、水酸化マグネシウムの配合量を変化させた他は、上記実施例中に記載の製造方法に従って製造された。
(Stability test 2)
As basic additives, 1% by weight of magnesium hydroxide (Example 2) and 5% by weight of magnesium hydroxide (Example 3) were further used. The total weight was 135 mg as in Example 1-a, and the total amount was adjusted with the granule components. Each tablet was produced according to the production method described in the above examples except that the amount of magnesium hydroxide was changed.
上述のようにして調製されたオランザピン口腔内崩壊錠の安定性を以下のようにして確認した。
まず、各錠から採取した検体を液体クロマトグラフィーにより試験を行い、類縁物質量を測定した。検体をポリエチレン瓶に収容し、６０℃で２１日間保存した後、液体クロマトグラフィーにより類縁物質量を測定した。結果を図２に示す。
The stability of the olanzapine orally disintegrating tablet prepared as described above was confirmed as follows.
First, specimens collected from each tablet were tested by liquid chromatography, and the amount of related substances was measured. The specimen was stored in a polyethylene bottle and stored at 60 ° C. for 21 days, and then the amount of related substances was measured by liquid chromatography. The results are shown in FIG.
図２に示すように、塩基性添加剤の配合量を変化させたとしても、類縁物質Ｂ及びＣの増加が十分に抑制された。 As shown in FIG. 2, even when the blending amount of the basic additive was changed, the increase in the related substances B and C was sufficiently suppressed.
（安定性試験３）
実施例１−ｂ，４〜７のオランザピン口腔内崩壊錠とコントロールｂのオランザピン口腔内崩壊錠の処方を表２に示す。
(Stability test 3)
Table 2 shows the formulations of the olanzapine orally disintegrating tablets of Examples 1-b and 4-7 and the olanzapine orally disintegrating tablet of Control b.
実施例１−ｂ，４〜７とコントロールｂの口腔内崩壊錠は、表２に示す処方で、以下の製造方法に従って製造された。すなわち、Ｄ−マンニトール、セルロース化合物、デンプン及びクロスポビドンからなる顆粒成分を用いて、流動層造粒法により顆粒を得た後、得られた顆粒を、整粒機を用いて整粒し整粒末を得た。次いで、この整粒末、オランザピン、Ｄ−マンニトール、塩基性添加剤、セルロース化合物、軽質無水ケイ酸、甘味剤とをポリエチレン袋にて混合後、ステアリン酸マグネシウムを投入し混合することで打錠末を得た。そして、打錠末を打錠機（株式会社菊水製作所製、ＶＥＬＡ ５）で打錠し、目的の口腔内崩壊錠を得た。
The orally disintegrating tablets of Examples 1-b and 4-7 and Control b were prepared according to the following production method with the formulation shown in Table 2. That is, after using the granule component which consists of D-mannitol, a cellulose compound, starch, and crospovidone, the granule was obtained by the fluidized-bed granulation method, and the obtained granule was sized using a granulator and sized. I got the end. Next, after mixing this sized powder, olanzapine, D-mannitol, basic additive, cellulose compound, light anhydrous silicic acid and sweetener in a polyethylene bag, magnesium stearate is added and mixed to form a tableting powder. Got. Then, the tableting powder was tableted with a tableting machine (
塩基性添加剤としては、水酸化マグネシウム（実施例１−ｂ）、酸化マグネシウム（実施例４）、アミノアルキルメタクリレートコポリマーＥ（オイドラギットＥＰＯ（登録商標））（実施例５）、メグルミン（実施例６）、アルギニン（実施例７）を用いた。 As basic additives, magnesium hydroxide (Example 1-b), magnesium oxide (Example 4), aminoalkyl methacrylate copolymer E (Eudragit EPO®) (Example 5), meglumine (Example 6) ), Arginine (Example 7) was used.
上述のようにして調製されたオランザピン口腔内崩壊錠の安定性を以下のようにして確認した。まず、各錠から採取した検体を液体クロマトグラフィーにより試験を行い、類縁物質量を測定した。結果を図３（Ａ）に示す。検体をポリエチレン瓶に収容し、７０℃で９日間保存した後、液体クロマトグラフィーにより類縁物質量を測定した。結果を図５（Ｂ）に示す。 The stability of the olanzapine orally disintegrating tablet prepared as described above was confirmed as follows. First, specimens collected from each tablet were tested by liquid chromatography, and the amount of related substances was measured. The results are shown in FIG. The specimen was stored in a polyethylene bottle and stored at 70 ° C. for 9 days, and the amount of related substances was measured by liquid chromatography. The results are shown in FIG.
図３に示すように、塩基性添加剤の種類を変更したとしても、類縁物質の増加が十分に抑制された。 As shown in FIG. 3, even if the type of the basic additive was changed, the increase in the related substances was sufficiently suppressed.
以上に開示された実施の形態と実施例はすべての点で例示であって制限的なものではないと考慮されるべきである。本発明の範囲は、以上の説明ではなく、特許請求の範囲によって示され、特許請求の範囲と均等の意味および範囲内でのすべての変形を含むものである。 It should be considered that the embodiments and examples disclosed above are illustrative and non-restrictive in every respect. The scope of the present invention is defined by the terms of the claims, rather than the description above, and includes all modifications within the scope and meaning equivalent to the terms of the claims.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008531681A (en) * | 2005-03-02 | 2008-08-14 | アクタヴィス・グループ・エイチエフ | Fast disintegrating preparation containing magnesium carbonate heavy |
| JP2011509283A (en) * | 2008-01-11 | 2011-03-24 | シプラ・リミテッド | Solid pharmaceutical dosage form |
| KR20120019200A (en) * | 2010-08-25 | 2012-03-06 | 한미약품 주식회사 | Oral pharmaceutical composition comprising olanzapine |
| JP2012046446A (en) * | 2010-08-26 | 2012-03-08 | Sawai Pharmaceutical Co Ltd | Method for producing intraorally disintegrating tablet containing zolpidem tartrate |
| JP2013532651A (en) * | 2010-07-23 | 2013-08-19 | ラティオファルム ゲー・エム・ベー・ハー | Pharmaceuticals for oral administration containing a mixture of silodosin and basic copolymer |
| JP2014058461A (en) * | 2012-09-14 | 2014-04-03 | Sawai Pharmaceutical Co Ltd | Formulation containing olanzapine |
| JP2014218472A (en) * | 2013-05-10 | 2014-11-20 | エルメッド エーザイ株式会社 | Tablet containing olanzapine or salt thereof |
| JP2015098467A (en) * | 2013-10-15 | 2015-05-28 | Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 | Formulation with improved stability |
-
2015
- 2015-06-26 JP JP2015129299A patent/JP2017014119A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008531681A (en) * | 2005-03-02 | 2008-08-14 | アクタヴィス・グループ・エイチエフ | Fast disintegrating preparation containing magnesium carbonate heavy |
| JP2011509283A (en) * | 2008-01-11 | 2011-03-24 | シプラ・リミテッド | Solid pharmaceutical dosage form |
| JP2013532651A (en) * | 2010-07-23 | 2013-08-19 | ラティオファルム ゲー・エム・ベー・ハー | Pharmaceuticals for oral administration containing a mixture of silodosin and basic copolymer |
| KR20120019200A (en) * | 2010-08-25 | 2012-03-06 | 한미약품 주식회사 | Oral pharmaceutical composition comprising olanzapine |
| JP2012046446A (en) * | 2010-08-26 | 2012-03-08 | Sawai Pharmaceutical Co Ltd | Method for producing intraorally disintegrating tablet containing zolpidem tartrate |
| JP2014058461A (en) * | 2012-09-14 | 2014-04-03 | Sawai Pharmaceutical Co Ltd | Formulation containing olanzapine |
| JP2014218472A (en) * | 2013-05-10 | 2014-11-20 | エルメッド エーザイ株式会社 | Tablet containing olanzapine or salt thereof |
| JP2015098467A (en) * | 2013-10-15 | 2015-05-28 | Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 | Formulation with improved stability |
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