JP2004231520A - Medicinal composition having excellent preservation stability and elution rate - Google Patents
Medicinal composition having excellent preservation stability and elution rate Download PDFInfo
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- JP2004231520A JP2004231520A JP2003018269A JP2003018269A JP2004231520A JP 2004231520 A JP2004231520 A JP 2004231520A JP 2003018269 A JP2003018269 A JP 2003018269A JP 2003018269 A JP2003018269 A JP 2003018269A JP 2004231520 A JP2004231520 A JP 2004231520A
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- 239000000203 mixture Substances 0.000 title abstract description 10
- 238000010828 elution Methods 0.000 title abstract description 3
- 238000004321 preservation Methods 0.000 title abstract 2
- 239000004480 active ingredient Substances 0.000 claims abstract description 32
- 239000000126 substance Substances 0.000 claims abstract description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229920003176 water-insoluble polymer Polymers 0.000 claims abstract description 22
- 230000008961 swelling Effects 0.000 claims abstract description 19
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000003776 cleavage reaction Methods 0.000 claims abstract description 9
- 229960000381 omeprazole Drugs 0.000 claims abstract description 9
- 230000007017 scission Effects 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- 239000008194 pharmaceutical composition Substances 0.000 claims description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 22
- 239000000377 silicon dioxide Substances 0.000 claims description 11
- 235000012239 silicon dioxide Nutrition 0.000 claims description 11
- 238000009505 enteric coating Methods 0.000 claims description 10
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- 229920002472 Starch Polymers 0.000 claims description 5
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- 239000001856 Ethyl cellulose Substances 0.000 claims description 4
- 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 4
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 4
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- 239000004615 ingredient Substances 0.000 abstract 4
- 239000011229 interlayer Substances 0.000 abstract 3
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- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- -1 benzimidazole compound Chemical class 0.000 description 6
- 239000011777 magnesium Substances 0.000 description 6
- 229910052749 magnesium Inorganic materials 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
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- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 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
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
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- 240000002657 Thymus vulgaris Species 0.000 description 1
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- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 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
- 239000008116 calcium stearate Substances 0.000 description 1
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- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
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- 230000030136 gastric emptying Effects 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 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
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
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- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
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- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
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- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
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- 229940117841 methacrylic acid copolymer Drugs 0.000 description 1
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- 230000007935 neutral effect Effects 0.000 description 1
- 239000008183 oral pharmaceutical preparation Substances 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
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- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
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- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、オメプラゾール及び生理学的に許容されるそれらの塩からなる群から選ばれる有効成分を含み、保存安定性に優れ、小腸付近で速溶性を有する医薬組成物に関する。
【０００２】
【従来の技術】
オメプラゾール即ち、５−メトキシ−２−［（４−メトキシ−３，５−ジメチル−２−ピリジニル）メチル スルフィニル］−１Ｈ−ベンズイミダゾールなどのベンズイミダゾール系化合物は、プロトンポンプの強い阻害作用を有し、胃酸分泌を制御することにより、胃潰瘍、十二指腸潰瘍などの治療において高い有効性を発揮するが、化学的に非常に不安定であり、特に酸性下では短時間で分解が進行するため、一般的には腸溶性製剤として製剤化されている。
【０００３】
しかしながら、腸溶性基剤は弱酸性化合物であり、腸溶性基剤と有効成分との接触により変色が生じるため、製剤化にあたっては様々な工夫がされている。
例えば、特開昭６２−２５８３２０号公報及び特開平５−２９４８３１号公報にはベンズイミダゾール系化合物を含む核部分にアルカリ化合物を配合し、水溶性ないし水に急速に分解する錠剤の賦形剤、または重合体で水溶性のフィルム形成化合物等により被覆し、さらに、腸溶性皮膜で被覆する経口医薬製剤が開示されている。
しかし、このような水溶性皮膜のコーティングでは溶解速度にバラツキが生じてしまう問題があった。
【０００４】
特開昭６２−２７７３２２号公報、特開平３−１６３０１８号公報、及び特開平１０−３６２９０号公報には、ベンズイミダゾール系化合物にマグネシウム及び／またはカルシウムの塩基性無機塩を配合することを特徴とする安定化された医薬組成物の製法が開示されている。
しかし、このようなマグネシウム及び／又はカルシウムの塩基性無機塩の配合のみでは、まだ安定性が不充分であった。
【０００５】
国際公開ＷＯ００／７８２９３には、水不溶性高分子をコーティング剤として使用する例が開示されているが、これは腸溶製剤ではなく、水不溶性高分子をコーティングすることで胃排泄時間に相当するラグタイムを生じさせるものであり、胃酸に対する耐酸性が得られるものではない。
【０００６】
特表２００１−５２６２１３号公報には、コア部分に水膨潤性物質を加える技術が開示されている。
しかし、コア部分と腸溶性コーティング層との間の分離層等は水透過性及び水不溶性層はないので溶解速度にバラツキがあり、溶解の速度が不充分である。
また、コア部分の安定性も未だ不充分であった。
【０００７】
【特許文献１】
特開昭６２−２５８３２０号公報
【特許文献２】
特開平５−２９４８３１号公報
【特許文献３】
特開昭６２−２７７３２２号公報
【特許文献４】
特開平３−１６３０１８号公報
【特許文献５】
特開平１０−３６２９０号公報
【特許文献６】
国際公開ＷＯ００／７８２９３号パンフレット
【特許文献７】
特表２００１−５２６２１３号公報
【０００８】
【発明が解決しようとする課題】
本発明は、オメプラゾール及び生理学的に許容されるそれらの塩からなる群から選ばれる有効成分を活性成分とした医薬組成物であって、保存安定性に優れ、かつ、ｐＨ５以上好ましくはｐＨ６以上の環境で有効成分の速やかな溶出及び溶出速度が得られる医薬組成物の提供を目的とする。
【０００９】
【課題を解決するための手段】
本発明者らは、従来技術に内在する技術的課題を解決すべく鋭意研究した結果、有効成分を含む核部分と腸溶性皮膜との間に設けられる中間層を水不溶性高分子を用いて実質的に水不溶性かつ水透過性の層として形成することで、腸溶性皮膜から核部分を保護し、水分を吸収することにより膨潤する物質を核部分内に配合することにより該中間層を透過した水分が核部分に吸収させた後、核部分の膨潤により該中間層に速やかに亀裂及び／又は開裂を生じさせ、この結果、核部分から極めて高速に有効成分を溶出させることができたものである。
【００１０】
即ち、本発明は、オメプラゾール及び生理学的に許容されるそれらの塩からなる群から選ばれる有効成分を含む経口投与用の医薬組成物であって、
（ａ）該有効成分と塩基性物質と膨潤物質とで核部分を形成し、
（ｂ）該核部分の表面全体を被覆する中間層、及び
（ｃ）該中間層の表面全体を被覆する腸溶皮膜
から構成され、該中間層が水不溶性高分子のみからなる水不溶性かつ水透過性の層であり、該中間層を透過した水分が該核部分に吸収されると、該核部分が膨潤し、該中間層に亀裂及び／又は開裂が生じるようにしたものである。
【００１１】
本発明の好ましい態様によれば、核部分に含まれる塩基性物質が含水二酸化ケイ素が良く、さらには核部分に含まれる該含水二酸化ケイ素の重量が有効成分の重量に対して５０重量％以上であり、該含水二酸化ケイ素のｐＨが１０〜１１であるのが好ましい。
【００１２】
膨潤物質は、カルボキシメチルスターチナトリウムが好ましく、水不溶性高分子はアミノアルキルメタアクリレートコポリマーＲＳ及び／又はエチルセルロースが好ましい。
水不溶性高分子からなる中間層を形成する際には、６０〜７０重量％のエタノール／水混合液にこの水不溶性高分子を溶解するのが好ましい。
【００１３】
【発明の実施の形態】
本発明の医薬組成物においては、有効成分であるオメプラゾールとして遊離形態の化合物のほか、塩基付加塩を用いてもよい。
例えば、オメプラゾールのマグネシウム塩などを用いることができる。
核部分に含まれる塩基性物質としては、例えばマグネシウムやカルシウムなどの塩基性無機塩（炭酸マグネシウム、酸化マグネシウム、水酸化マグネシウム、メタケイ酸アルミン酸マグネシウム、ケイ酸アルミン酸マグネシウム、ケイ酸マグネシウム、アルミン酸マグネシウム、沈降炭酸カルシウム、水酸化カルシウムなど）、あるいは、含水二酸化ケイ素などを用いることができる。
これらのうち、含水二酸化ケイ素が好ましい。含水二酸化ケイ素の種類は特に限定されないが、高ｐＨであることが望ましく、ｐＨが１０〜１１であることがより望ましい。
塩基性物質の配合量は、有効成分の重量に対して５０重量％以上であることが望ましい。
塩基性物質は２種以上を組み合わせて用いてもよい。
【００１４】
核部分に含まれる膨潤物質は、水分を吸収することにより急速に膨潤する性質を有している。
膨潤物質としては、医薬用添加物として一般的には崩壊剤に分類される物質を用いることができるが、なかでもカルボキシメチルスターチナトリウムが好ましい。
膨潤物質は２種以上組み合わせて用いてもよい。
核部分内における膨潤物質の配置は特に限定されず、有効成分と均一に混合されていてもよく、あるいは一箇所又は数カ所に局在するか、核部分を実質的にコーティングするような形態であってもよい。
【００１５】
核部分には上記の成分以外に、製剤用添加物として通常用いられる賦形剤、結合剤、滑沢剤、可溶化剤などを適宜配合することができる。
例えば賦形剤として、乳糖、トウモロコシデンプンなどのデンプン類、結晶セルロースなどが挙げられる。結合剤としては、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、部分アルファー化デンプンなどが挙げられる。
滑沢剤としては、ステアリン酸マグネシウム、ステアリン酸カルシウム、ショ糖脂肪酸エステルなどが挙げられる。
可溶化剤としては、ラウリル硫酸ナトリウム、ポリソルベート８０などが挙げられる。
これら各種添加剤は、核部分の成形性や膨潤性などに応じて適宜の配合量を決定することができる。
なお、核部分の形状は特に限定されず、素錠の形状や粒状など適宜の形状を選択できるが、例えば医薬組成物が錠剤の形態である場合は、錠剤の形態を採用することができる。
【００１６】
中間層は核部分の表面を完全に被覆するように配置される。
この中間層は水不溶性高分子のみからなり、実質的に水不溶性かつ水透過性の層として形成される。
この中間層は、酸性、中性、又は塩基性のいずれの液性においても実質的に水不溶性である。
特に、本発明においては実質的にこの水不溶性高分子のみにて中間層を形成した点に特徴がある。
なお、実質的に水不溶性高分子のみであるとは、製剤時に使用した溶媒等が残留している場合も含まれることを言う。
また、この中間層は層を透過した水分が核部分に吸収された後、核部分の膨潤により速やかに亀裂及び／又は開裂を生じるように形成される。
本発明において、亀裂及び／又は開裂とは、中間層が実質的に水に溶解することなく核部分を被覆する中間層皮膜に大きな亀裂が入り、及び／又は中間層皮膜が２個ないし数個の部分に開裂し、核部分が露出した後にも中間層皮膜が大きな残骸として検出可能な状態を意味している。
従って、中間層は溶解により徐々に薄いフラグメントとなって核部分から剥離することはなく、あるいは細かなフラグメントとなって水中に崩壊する過程を経ることがない。
このような剥離過程や崩壊過程を伴う製剤では、中間層の剥離や崩壊の速度にばらつきが生じたり、あるいは中間層の溶解により生じる濃厚溶解が核部分の表面に部分的あるいは全体に存在してしまうため、核部分への水分の浸透が困難になったり核部分からの有効成分の溶出速度が低下する。
一方、本発明の医薬組成物では中間層が実質的に溶解あるいは崩壊することなく、中間層に大きな亀裂及び／又は開裂を生じ、その結果として大量の水分が核部分に短時間に供給される。
従って、本発明の医薬組成物では、水に溶解可能な中間層を用いた場合に比べて、有効成分をより急速にしかも安定して溶出させることが可能になる。
【００１７】
中間層に用いられる水不溶性高分子としては、例えばアミノアルキルメタアクリレートコポリマーＲＳ、エチルセルロースを好ましく用いることができる。
水不溶性高分子を２種以上組み合わせてもよい。
なお、中間層の膜厚は特に限定されないが、核部分と腸溶皮膜を隔てることにより医薬組成物の保存安定性を担保するのに十分な厚さであって、かつ中間層を透過した水分により生じる核部分の膨潤により中間層に十分な亀裂及び／又は開裂を生じるように選択され、一般的には中間層を形成する部材、及び形成される中間層の水透過性などの要素を考慮しつつ、適宜選択することができる。
中間層の膜厚は、通常は３０μｍ以下であり、好ましくは１０〜２５μｍ程度である。
【００１８】
腸溶皮膜を形成するための腸溶性基剤としては、ｐＨ５以上好ましくはｐＨ６以上で溶解する性質を有するものが望ましい。
具体的には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、ヒドロキシプロピルメチルセルロースフタレート、メタアクリル酸コポリマー、カルボキシメチルエチルセルロース、酢酸フタル酸セルロースなどが挙げられる。
また、腸溶コーティング層中には、上記腸溶性基剤以外に所望に応じて製剤用添加剤を配合することができる。
例えば、タルク、酸化チタン、クエン酸トリエチル、グリセリン脂肪酸エステルなどが挙げられる。
腸溶皮膜の膜厚は特に限定されないが、十分な耐酸性を確保できる膜厚として一般的には約５０μｍ以上とすることが望ましい。
【００１９】
耐酸性試験は日局溶出試験法第２法（パドル法）により実施した。
試験液に日局崩壊試験法第１液（ｐＨ１．２）９００ｍｌを用い、毎分５０回転で２時間試験を行い、２時間後の試験液中の活性成分量を測定することで耐酸性の合否が確認できる。耐酸性が確認できていれば、活性成分はほとんど溶出されていない。また、耐酸性が確保できていない場合は、活性成分が溶出するとともに、分解が生じ、試験液は紫色に変色する。
【００２０】
本発明の医薬組成物は経口投与に適した形態で調製される。
例えば、錠剤、顆粒剤、カプセル剤などの形態が好適である。
本発明の医薬組成物の製造方法は特に限定されないが、錠剤の場合、一般的には、まず、オメプラゾール及び生理学的に許容されるそれらの塩からなる群から選ばれる有効成分、塩基性物質、及び膨潤物質を含む造粒物を製造する。
造粒の方法は特に限定されないが、湿式造粒の場合、結合剤及び可溶化剤など製剤用添加剤を溶解した精製水を上記の成分を含む混合物にスプレー又は注加し、市販の装置にて造粒して乾燥すればよい。
その後、上記造粒物を所望の粒度となるよう市販の粉砕機等を用いて粉砕することが望ましいが、粒度は概ね５０〜１０００μｍが適当である。
このようにして得られた粉砕物を必要に応じてさらに整粒し、打錠工程を経て核部分を製造する。
【００２１】
その後、水不溶性高分子を溶媒に溶解させ、コーティング液を調製し、これを上記核部分にスプレーしながら中間層をコーティングした組成物を得ることができる。
本工程で使用する溶媒は、エタノール・精製水の混合液が挙げられる。
水不溶性高分子を溶解させる溶媒の混合比率は、本発明の医薬品組成物の安定性に重要であり、エタノールと水の混合比率は６０：４０又は７０：３０が望ましい。溶媒中のエタノール含量が８０％以上では、スプレー中に核部分の有効成分の一部が溶解し、その一部が中間層に混入する。
その中間層表面に腸溶基材を被覆することで、中間層中の有効成分と腸溶基材が接触し、表面が変色してしまう。
一方、エタノール含量が６０％未満では、水不溶性高分子が溶媒に溶解せず、被覆工程のトラブルの原因となる。中間層のコーティングでは市販の錠剤コーティング装置を用いることで容易に製造することができる。
さらに、腸溶性高分子を溶媒に溶解・分散させた腸溶性コーティング液を調製し、これを上記中間層コーティング錠にスプレーしながら腸溶コーティング錠を得る。
この工程で用いることができる溶媒の種類は特に限定されないが、エタノール、エタノール・精製水混合液、エタノール・塩化メチレン混合液、水が挙げられる。
腸溶コーティングは、市販の錠剤コーティング装置を用いることで容易に製造することができる。
【００２２】
顆粒剤の製造においても、錠剤同様に有効成分、塩基性物質、及び膨潤物質を含む造粒物を核部分として調製できる。また、ノンパレルなど芯物質を用いる場合には、その表面に有効成分、塩基性物質、及び膨潤物質、及び必要に応じて各種添加剤を修飾造粒し核部分を製造することも可能である。
その後、これら核顆粒に、錠剤と同様に中間層及び腸溶層をコーティングし顆粒剤を得ることができる。
また、この顆粒を硬カプセルに充填し、カプセル剤とすることもできるし、この顆粒を打錠して錠剤とすることもできる。
【００２３】
【実施例】
以下、本発明を実施例によりさらに具体的に説明するが、本発明の範囲は下記の実施例に限定されることはない。
実施例１
表１に示した配合処方に従って公知の方法により核錠を製造した。さらに、表２に示した中間層及び腸溶層をコーティングした（表中の単位はｍｇである）。
【００２４】
【表１】
【表２】
表３に製した各錠剤の製造直後及びアルミニウム袋に入れた後、４０℃、７５％相対湿度下１ヶ月保存した時の外観の様子を示した。結果を表３に示す。
この結果より、核部分中に塩基性物質として含水二酸化ケイ素を配合して水不溶性かつ水透過性の中間層を、エタノールと水の混合比６：４の溶媒に溶解させてコーティングした腸溶錠は、製造直後及び保存１ヶ月後も外観の変化は認められなかった。
一方、中間層を施さない場合や、中間層をエタノール単独あるいはエタノールと水の混合比８：２の溶媒に溶解させてコーティングした腸溶錠は、製造直後に錠剤外観は褐色に変化する。
また、核錠中に含水二酸化ケイ素を配合しない場合は、中間層を施しても１ヶ月保存時に薄い褐色に変化した。
以上の結果より、本発明の医薬組成物における水不溶性かつ水透過性の中間層は安定性に効果があることが認められた。
【００２７】
【表３】
表４には、各腸溶錠の崩壊時間を示した。
【００２９】
【表４】
表４には、各腸溶錠について中間層の亀裂及び／又は開裂による核部分の露出状況を確認した結果を示す。試験は日本薬局方崩壊試験法の腸溶性の操作方法に従って行った。
試験液は第２液（ｐＨ６．８）を用いた。この結果、核部分に膨潤性物質としてカルボキシメチルスターチナトリウムを含有し、（核部分処方▲１▼又は▲２▼）、中間層の水不溶性高分子（エチルセルロース）をエタノールと水の混合比６：４の溶媒に溶解させコーティングした（中間層処方Ａ及びＢ）場合には、核部分の露出は極めて速やかに生じた。
一方、比較例（処方Ｄ）では、核部分の露出に時間を要した。
これらの結果から、本発明の医薬組成物では、錠剤の安定性と速溶性を兼ね備えたものであることが明らかになった。
【００３１】
【発明の効果】
本発明の医薬組成物は優れた保存安定性を有しており、しかも腸管内に移行した後に有効成分が極めて短時間に溶出するという特徴を有している。
特に本発明においては、核部分と腸溶皮膜の間を形成する中間層として、実質的に水不溶性高分子皮膜を介在させたので、有効成分の安定性に優れ、かつ、腸溶皮膜溶解後はこの水不溶性高分子からなる中間層に微細孔等が形成された水透過性を有するので、この透過水が核部分の膨潤物質に吸収されると中間層に亀裂及び／又は開裂が生じ、極めて速やかに、しかも安定して有効成分が溶出する。
従って、従来の医薬組成物の中間層が溶出性を有していたので、その中間層の溶出をまたなければ有効成分が溶速しなかったのに比較して、本発明に係る医薬組成物は、極めて速やかに溶出することになる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising an active ingredient selected from the group consisting of omeprazole and a physiologically acceptable salt thereof, having excellent storage stability, and having rapid solubility near the small intestine.
[0002]
[Prior art]
Omeprazole, a benzimidazole compound such as 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole has a strong proton pump inhibitory action. By controlling gastric acid secretion, it exerts high efficacy in the treatment of gastric ulcer, duodenal ulcer, etc., but it is very unstable chemically, especially under acidic conditions, because decomposition progresses in a short time, Are formulated as enteric-coated preparations.
[0003]
However, the enteric base is a weakly acidic compound, and discoloration occurs when the enteric base and the active ingredient come into contact with each other.
For example, JP-A-62-258320 and JP-A-5-294831 disclose an excipient for a tablet which is prepared by mixing an alkali compound into a core containing a benzimidazole compound and dissolving rapidly in water or water. Or, an oral pharmaceutical preparation which is coated with a water-soluble film-forming compound or the like with a polymer and further coated with an enteric coating is disclosed.
However, such a water-soluble coating has a problem that the dissolution rate varies.
[0004]
JP-A-62-277322, JP-A-3-163018 and JP-A-10-36290 are characterized in that a benzimidazole compound is blended with a basic inorganic salt of magnesium and / or calcium. A method of making a stabilized pharmaceutical composition is disclosed.
However, the stability was still insufficient with only such a basic inorganic salt of magnesium and / or calcium.
[0005]
International Publication WO00 / 78293 discloses an example in which a water-insoluble polymer is used as a coating agent, but this is not an enteric preparation, but a lag equivalent to gastric emptying time by coating with a water-insoluble polymer. It causes thyme and does not provide acid resistance to gastric acid.
[0006]
JP-T-2001-526213 discloses a technique of adding a water-swellable substance to a core portion.
However, since there is no water-permeable and water-insoluble layer in the separation layer between the core portion and the enteric coating layer, the dissolution rate varies, and the dissolution rate is insufficient.
Further, the stability of the core portion was still insufficient.
[0007]
[Patent Document 1]
JP-A-62-258320 [Patent Document 2]
JP-A-5-294831 [Patent Document 3]
JP-A-62-277322 [Patent Document 4]
JP-A-3-163018 [Patent Document 5]
JP-A-10-36290 [Patent Document 6]
International Publication WO00 / 78293 pamphlet [Patent Document 7]
JP 2001-526213 A
[Problems to be solved by the invention]
The present invention relates to a pharmaceutical composition comprising an active ingredient selected from the group consisting of omeprazole and a physiologically acceptable salt thereof as an active ingredient, having excellent storage stability and having a pH of 5 or more, preferably pH 6 or more. It is an object of the present invention to provide a pharmaceutical composition capable of rapidly dissolving an active ingredient and a dissolution rate in an environment.
[0009]
[Means for Solving the Problems]
The present inventors have conducted intensive studies to solve the technical problems inherent in the prior art, and as a result, an intermediate layer provided between a core portion containing an active ingredient and an enteric coating was substantially formed using a water-insoluble polymer. By forming a water-insoluble and water-permeable layer, the core portion is protected from the enteric film, and a substance that swells by absorbing moisture is incorporated into the core portion to allow the intermediate layer to permeate. After the water is absorbed by the core, the intermediate layer is rapidly cracked and / or cleaved by the swelling of the core, and as a result, the active ingredient can be eluted from the core at a very high speed. is there.
[0010]
That is, the present invention is a pharmaceutical composition for oral administration comprising an active ingredient selected from the group consisting of omeprazole and physiologically acceptable salts thereof,
(A) forming a core with the active ingredient, the basic substance, and the swelling substance;
(B) an intermediate layer covering the entire surface of the core portion, and (c) an enteric coating covering the entire surface of the intermediate layer, wherein the intermediate layer is composed of only a water-insoluble polymer and is water-insoluble and water-soluble. The permeable layer is such that when moisture transmitted through the intermediate layer is absorbed by the core portion, the core portion swells and cracks and / or cleavage occur in the intermediate layer.
[0011]
According to a preferred embodiment of the present invention, the basic substance contained in the core portion is preferably water-containing silicon dioxide, and more preferably, the weight of the water-containing silicon dioxide contained in the core portion is 50% by weight or more based on the weight of the active ingredient. The pH of the hydrous silicon dioxide is preferably 10 to 11.
[0012]
The swelling substance is preferably sodium carboxymethyl starch, and the water-insoluble polymer is preferably an aminoalkyl methacrylate copolymer RS and / or ethyl cellulose.
When forming the intermediate layer composed of the water-insoluble polymer, it is preferable to dissolve the water-insoluble polymer in a 60 to 70% by weight ethanol / water mixture.
[0013]
BEST MODE FOR CARRYING OUT THE INVENTION
In the pharmaceutical composition of the present invention, a base addition salt may be used in addition to a compound in a free form as omeprazole as an active ingredient.
For example, a magnesium salt of omeprazole or the like can be used.
Examples of the basic substance contained in the core portion include basic inorganic salts such as magnesium and calcium (magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium aluminate magnesium, magnesium silicate, aluminate Magnesium, precipitated calcium carbonate, calcium hydroxide, etc.) or hydrated silicon dioxide.
Of these, hydrous silicon dioxide is preferred. The type of hydrous silicon dioxide is not particularly limited, but preferably has a high pH, and more preferably has a pH of 10 to 11.
The amount of the basic substance is desirably 50% by weight or more based on the weight of the active ingredient.
Two or more basic substances may be used in combination.
[0014]
The swelling substance contained in the core has a property of rapidly swelling by absorbing moisture.
As the swelling substance, a substance generally classified as a disintegrant as a pharmaceutical additive can be used, and among them, sodium carboxymethyl starch is preferable.
Two or more swelling substances may be used in combination.
The arrangement of the swelling substance in the core is not particularly limited, and may be uniformly mixed with the active ingredient, or may be localized at one or several places or substantially coat the core. You may.
[0015]
In addition to the above components, excipients, binders, lubricants, solubilizers, and the like that are usually used as pharmaceutical additives can be appropriately added to the core.
For example, excipients include lactose, starches such as corn starch, crystalline cellulose, and the like. Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, partially pregelatinized starch, and the like.
Lubricants include magnesium stearate, calcium stearate, sucrose fatty acid esters and the like.
Solubilizing agents include sodium lauryl sulfate, polysorbate 80, and the like.
The appropriate blending amounts of these various additives can be determined according to the moldability and swellability of the core.
The shape of the core portion is not particularly limited, and an appropriate shape such as the shape of an uncoated tablet or a granular shape can be selected. For example, when the pharmaceutical composition is in the form of a tablet, the form of a tablet can be adopted.
[0016]
The intermediate layer is arranged to completely cover the surface of the core.
This intermediate layer is composed of only a water-insoluble polymer, and is formed as a substantially water-insoluble and water-permeable layer.
This intermediate layer is substantially water-insoluble in any of acidic, neutral and basic liquids.
In particular, the present invention is characterized in that the intermediate layer is formed substantially only of the water-insoluble polymer.
It should be noted that being substantially only a water-insoluble polymer means that the case where the solvent or the like used at the time of preparation remains remains.
Further, the intermediate layer is formed such that, after moisture permeating through the layer is absorbed by the core portion, cracks and / or cleavage are quickly caused by swelling of the core portion.
In the present invention, cracking and / or cleavage means that a large crack is formed in an intermediate layer coating that coats a core portion without substantially dissolving the intermediate layer in water, and / or two to several intermediate layer coatings. And the intermediate layer film can be detected as a large debris even after the core portion is exposed.
Therefore, the intermediate layer does not gradually become thin fragments due to dissolution and does not peel off from the core portion, or does not undergo a process of disintegrating into water as fine fragments.
In preparations that involve such exfoliation and disintegration processes, the rate of exfoliation and disintegration of the intermediate layer varies, or concentrated dissolution caused by dissolution of the intermediate layer exists partially or entirely on the core surface. As a result, it becomes difficult for water to penetrate into the core portion, and the rate of elution of the active ingredient from the core portion decreases.
On the other hand, in the pharmaceutical composition of the present invention, a large crack and / or cleavage is generated in the intermediate layer without substantially dissolving or disintegrating the intermediate layer, and as a result, a large amount of water is supplied to the core in a short time. .
Therefore, in the pharmaceutical composition of the present invention, the active ingredient can be more rapidly and stably eluted as compared with the case where the intermediate layer soluble in water is used.
[0017]
As the water-insoluble polymer used for the intermediate layer, for example, aminoalkyl methacrylate copolymer RS and ethyl cellulose can be preferably used.
Two or more water-insoluble polymers may be combined.
The thickness of the intermediate layer is not particularly limited, but is sufficient to ensure the storage stability of the pharmaceutical composition by separating the core portion and the enteric coating, and the moisture permeating the intermediate layer. Is selected so as to cause sufficient cracking and / or cleavage in the intermediate layer due to the swelling of the core portion caused by the above, and generally takes into account factors such as the members forming the intermediate layer and the water permeability of the formed intermediate layer. In addition, it can be appropriately selected.
The thickness of the intermediate layer is usually 30 μm or less, preferably about 10 to 25 μm.
[0018]
As an enteric base for forming an enteric film, one having a property of dissolving at a pH of 5 or more, preferably at a pH of 6 or more is desirable.
Specific examples include hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer, carboxymethylethylcellulose, cellulose acetate phthalate and the like.
In addition, in the enteric coating layer, a pharmaceutical additive can be compounded, if desired, in addition to the enteric base.
For example, talc, titanium oxide, triethyl citrate, glycerin fatty acid ester and the like can be mentioned.
Although the thickness of the enteric coating is not particularly limited, it is generally desirable that the thickness be about 50 μm or more as a thickness capable of securing sufficient acid resistance.
[0019]
The acid resistance test was carried out according to the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method).
Using 900 ml of the first solution (pH 1.2) of the Japanese Pharmacopoeia Disintegration Test Method for 2 hours at 50 revolutions per minute for 2 hours, and measuring the amount of active ingredient in the test solution after 2 hours, the acid resistance of the test solution was measured. Pass / fail can be confirmed. If acid resistance is confirmed, the active ingredient is hardly eluted. If the acid resistance is not ensured, the active ingredient is eluted and decomposed, and the test solution turns purple.
[0020]
The pharmaceutical composition of the present invention is prepared in a form suitable for oral administration.
For example, forms such as tablets, granules and capsules are suitable.
The method for producing the pharmaceutical composition of the present invention is not particularly limited, but in the case of tablets, generally, first, an active ingredient selected from the group consisting of omeprazole and a physiologically acceptable salt thereof, a basic substance, And a granulated material containing a swelling substance.
The method of granulation is not particularly limited, but in the case of wet granulation, spray or pour purified water in which a pharmaceutical additive such as a binder and a solubilizer has been dissolved into a mixture containing the above components, and then use a commercially available device. Granulation and drying.
Thereafter, it is desirable to pulverize the above-mentioned granulated product using a commercially available pulverizer or the like so as to have a desired particle size, but the particle size is preferably approximately 50 to 1000 μm.
The pulverized material thus obtained is further sized if necessary, and a core portion is produced through a tableting step.
[0021]
Thereafter, the water-insoluble polymer is dissolved in a solvent to prepare a coating solution, and the composition is coated with the intermediate layer while spraying the coating solution on the core.
The solvent used in this step includes a mixture of ethanol and purified water.
The mixing ratio of the solvent that dissolves the water-insoluble polymer is important for the stability of the pharmaceutical composition of the present invention, and the mixing ratio of ethanol and water is preferably 60:40 or 70:30. When the content of ethanol in the solvent is 80% or more, a part of the core active ingredient is dissolved during spraying, and a part of the active ingredient is mixed into the intermediate layer.
By coating the surface of the intermediate layer with the enteric substrate, the active ingredient in the intermediate layer comes into contact with the enteric substrate, and the surface is discolored.
On the other hand, when the ethanol content is less than 60%, the water-insoluble polymer does not dissolve in the solvent, causing a trouble in the coating step. The intermediate layer can be easily manufactured by using a commercially available tablet coating apparatus.
Further, an enteric coating solution prepared by dissolving and dispersing an enteric polymer in a solvent is prepared, and the enteric coated tablet is obtained by spraying the solution onto the intermediate layer coated tablet.
The type of solvent that can be used in this step is not particularly limited, and examples thereof include ethanol, a mixed solution of ethanol and purified water, a mixed solution of ethanol and methylene chloride, and water.
Enteric coatings can be easily produced using commercially available tablet coating equipment.
[0022]
Also in the production of granules, a granulated product containing an active ingredient, a basic substance, and a swelling substance can be prepared as a core similarly to a tablet. When a core material such as non-pareil is used, a core portion can be produced by modifying and granulating the surface with an active ingredient, a basic substance, a swelling substance, and, if necessary, various additives.
Thereafter, the core granules can be coated with an intermediate layer and an enteric layer in the same manner as tablets, to obtain granules.
Further, the granules can be filled into hard capsules to form capsules, or the granules can be tabletted to form tablets.
[0023]
【Example】
Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples.
Example 1
According to the formulation shown in Table 1, a core tablet was produced by a known method. Further, the intermediate layer and the enteric layer shown in Table 2 were coated (the unit in the table is mg).
[0024]
[Table 1]
[Table 2]
Table 3 shows the appearance of each tablet immediately after production and after storage in an aluminum bag for one month at 40 ° C. and 75% relative humidity. Table 3 shows the results.
From these results, enteric coated tablets coated with a water-insoluble and water-permeable intermediate layer dissolved in a solvent having a mixing ratio of ethanol and water of 6: 4 by mixing hydrous silicon dioxide as a basic substance in the core portion. No change in appearance was observed immediately after production and one month after storage.
On the other hand, in the case where the intermediate layer is not applied, or in the case of an enteric coated tablet coated with the intermediate layer dissolved in ethanol alone or a solvent having a mixing ratio of ethanol and water of 8: 2, the tablet appearance changes to brown immediately after production.
In addition, when hydrous silicon dioxide was not added to the core tablet, the color changed to light brown after storage for one month even when the intermediate layer was applied.
From the above results, it was confirmed that the water-insoluble and water-permeable intermediate layer in the pharmaceutical composition of the present invention had an effect on stability.
[0027]
[Table 3]
Table 4 shows the disintegration time of each enteric coated tablet.
[0029]
[Table 4]
Table 4 shows the results of confirming the state of exposure of the core portion due to cracking and / or cleavage of the intermediate layer for each enteric coated tablet. The test was conducted in accordance with the enteric operation method of the Japanese Pharmacopoeia Disintegration Test.
The test solution used was the second solution (pH 6.8). As a result, the core portion contains sodium carboxymethyl starch as a swelling substance (core portion formulation (1) or (2)), and the water-insoluble polymer (ethyl cellulose) in the intermediate layer is mixed with ethanol and water at a mixing ratio of 6: When dissolved in the solvent of No. 4 and coated (intermediate layer formulations A and B), the exposure of the core portion occurred very quickly.
On the other hand, in the comparative example (Formulation D), it took time to expose the core.
From these results, it has been clarified that the pharmaceutical composition of the present invention has both tablet stability and rapid solubility.
[0031]
【The invention's effect】
The pharmaceutical composition of the present invention has excellent storage stability, and has a feature that the active ingredient elutes in a very short time after being transferred into the intestinal tract.
In particular, in the present invention, a substantially water-insoluble polymer film is interposed as an intermediate layer formed between the core portion and the enteric film, so that the stability of the active ingredient is excellent, and after the enteric film is dissolved. Has water permeability in which micropores and the like are formed in the intermediate layer made of the water-insoluble polymer, so that when the permeated water is absorbed by the swelling substance in the core portion, cracks and / or cleavages occur in the intermediate layer, The active ingredient elutes very quickly and stably.
Therefore, since the intermediate layer of the conventional pharmaceutical composition had dissolution properties, the pharmaceutical composition according to the present invention was compared with the case where the active ingredient did not dissolve unless the intermediate layer was dissolved. Will elute very quickly.
Claims (6)
（ａ）該有効成分と塩基性物質と膨潤物質とで核部分を形成し、
（ｂ）該核部分の表面全体を被覆する中間層、及び
（ｃ）該中間層の表面全体を被覆する腸溶皮膜
から構成され、該中間層が水不溶性高分子のみからなる水不溶性かつ水透過性の層であり、該中間層を透過した水分が該核部分に吸収されると、該核部分が膨潤し、該中間層に亀裂及び／又は開裂が生じるようにしたことを特徴とする医薬組成物。A pharmaceutical composition for oral administration comprising an active ingredient selected from the group consisting of omeprazole and a physiologically acceptable salt thereof,
(A) forming a core with the active ingredient, the basic substance, and the swelling substance;
(B) an intermediate layer covering the entire surface of the core portion, and (c) an enteric coating covering the entire surface of the intermediate layer, wherein the intermediate layer is composed of only a water-insoluble polymer and is water-insoluble and water-soluble. A permeable layer, wherein when the moisture permeating through the intermediate layer is absorbed by the core portion, the core portion swells, and cracks and / or cleavage occur in the intermediate layer. Pharmaceutical composition.
Priority Applications (1)
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| JP2003018269A JP2004231520A (en) | 2003-01-28 | 2003-01-28 | Medicinal composition having excellent preservation stability and elution rate |
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| JP2003018269A JP2004231520A (en) | 2003-01-28 | 2003-01-28 | Medicinal composition having excellent preservation stability and elution rate |
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| JP2004231520A true JP2004231520A (en) | 2004-08-19 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011241181A (en) * | 2010-05-19 | 2011-12-01 | Takada Seiyaku Kk | Quetiapine fumarate containing oral tablet |
| WO2017146053A1 (en) * | 2016-02-23 | 2017-08-31 | ニプロ株式会社 | Pharmaceutical composition particles and orally disintegrating preparation including same |
| WO2019039420A1 (en) * | 2017-08-21 | 2019-02-28 | ニプロ株式会社 | Pharmaceutical composition particles, orally disintegrating preparation containing same, and method for producing pharmaceutical composition particles |
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| JP2011241181A (en) * | 2010-05-19 | 2011-12-01 | Takada Seiyaku Kk | Quetiapine fumarate containing oral tablet |
| WO2017146053A1 (en) * | 2016-02-23 | 2017-08-31 | ニプロ株式会社 | Pharmaceutical composition particles and orally disintegrating preparation including same |
| JPWO2017146053A1 (en) * | 2016-02-23 | 2018-12-20 | ニプロ株式会社 | Pharmaceutical composition particles and orally disintegrating preparations containing the same |
| WO2019039420A1 (en) * | 2017-08-21 | 2019-02-28 | ニプロ株式会社 | Pharmaceutical composition particles, orally disintegrating preparation containing same, and method for producing pharmaceutical composition particles |
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