JP3659801B2 - Tranilast aqueous solution formulation - Google Patents
Tranilast aqueous solution formulation Download PDFInfo
- Publication number
- JP3659801B2 JP3659801B2 JP15051798A JP15051798A JP3659801B2 JP 3659801 B2 JP3659801 B2 JP 3659801B2 JP 15051798 A JP15051798 A JP 15051798A JP 15051798 A JP15051798 A JP 15051798A JP 3659801 B2 JP3659801 B2 JP 3659801B2
- Authority
- JP
- Japan
- Prior art keywords
- tranilast
- aqueous solution
- trometamol
- acid
- preparation
- 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.)
- Expired - Fee Related
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- NZHGWWWHIYHZNX-CSKARUKUSA-N tranilast Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 title claims description 46
- 229960005342 tranilast Drugs 0.000 title claims description 46
- 239000007864 aqueous solution Substances 0.000 title claims description 39
- 239000000203 mixture Substances 0.000 title claims description 14
- 238000009472 formulation Methods 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 claims description 28
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 15
- 229960000281 trometamol Drugs 0.000 claims description 15
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 229960000686 benzalkonium chloride Drugs 0.000 description 10
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 10
- 239000008213 purified water Substances 0.000 description 10
- 230000007794 irritation Effects 0.000 description 9
- 239000002997 ophthalmic solution Substances 0.000 description 9
- 239000003889 eye drop Substances 0.000 description 8
- 229940054534 ophthalmic solution Drugs 0.000 description 8
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 7
- 239000004327 boric acid Substances 0.000 description 7
- 229940012356 eye drops Drugs 0.000 description 7
- 239000002736 nonionic surfactant Substances 0.000 description 7
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 7
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 7
- 229920000053 polysorbate 80 Polymers 0.000 description 7
- 230000003204 osmotic effect Effects 0.000 description 6
- 239000000654 additive Substances 0.000 description 5
- 239000003963 antioxidant agent Substances 0.000 description 5
- 235000006708 antioxidants Nutrition 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 230000003078 antioxidant effect Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229940068968 polysorbate 80 Drugs 0.000 description 4
- 230000002335 preservative effect Effects 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 239000002562 thickening agent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 3
- 206010015946 Eye irritation Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- -1 alkali metal salts Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 231100000013 eye irritation Toxicity 0.000 description 3
- 239000007951 isotonicity adjuster Substances 0.000 description 3
- 231100000286 mucous membrane, eye irritation or corrosion testing Toxicity 0.000 description 3
- 229920000136 polysorbate Polymers 0.000 description 3
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- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
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- 238000001556 precipitation Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
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- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 1
- NZHGWWWHIYHZNX-UHFFFAOYSA-N 2-((3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl)amino)benzoic acid Chemical compound C1=C(OC)C(OC)=CC=C1C=CC(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- ALXKXLYYPHLLJL-UHFFFAOYSA-N 3-[2-(3-sulfopropylamino)ethylamino]propane-1-sulfonic acid Chemical compound OS(=O)(=O)CCCNCCNCCCS(O)(=O)=O ALXKXLYYPHLLJL-UHFFFAOYSA-N 0.000 description 1
- PDLPTSJWDUCMKS-UHFFFAOYSA-N 3-[4-(3-sulfopropyl)piperazin-1-yl]propane-1-sulfonic acid Chemical compound OS(=O)(=O)CCCN1CCN(CCCS(O)(=O)=O)CC1 PDLPTSJWDUCMKS-UHFFFAOYSA-N 0.000 description 1
- OBCXLYATNJKYMT-UHFFFAOYSA-N 4-[4-(4-sulfobutyl)piperazin-1-yl]butane-1-sulfonic acid Chemical compound OS(=O)(=O)CCCCN1CCN(CCCCS(O)(=O)=O)CC1 OBCXLYATNJKYMT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-DUZGATOHSA-N D-isoascorbic acid Chemical compound OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 0.000 description 1
- 239000004287 Dehydroacetic acid Substances 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 229960002242 chlorocresol Drugs 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- 235000019258 dehydroacetic acid Nutrition 0.000 description 1
- JEQRBTDTEKWZBW-UHFFFAOYSA-N dehydroacetic acid Chemical compound CC(=O)C1=C(O)OC(C)=CC1=O JEQRBTDTEKWZBW-UHFFFAOYSA-N 0.000 description 1
- 229940061632 dehydroacetic acid Drugs 0.000 description 1
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
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- 235000010350 erythorbic acid Nutrition 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
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- 239000000594 mannitol Substances 0.000 description 1
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- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
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- 230000007935 neutral effect Effects 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は有機アミンを配合したトラニラスト水溶液製剤に関するものである。
【０００２】
更に詳しく述べれば、本発明は顕著な安定性を有し、長期保存性に優れていること及び配合変化を起こさないことなどを特徴とする点眼液、点鼻液或いは注射液などとして有用な前記トラニラスト水溶液製剤に関するものである。
【０００３】
【従来の技術】
式
【０００４】
【化１】
で表されるトラニラスト〔化学名：Ｎ−（３，４−ジメトキシシンナモイル）アントラニル酸〕はアレルギー反応によるケミカルメディエーター遊離抑制作用を有し、アレルギーに起因する各種疾患の治療剤として有用であることが知られている。
【０００６】
トラニラスト及びそのナトリウム塩或いはカリウム塩などのアルカリ金属塩は水に極めて溶けにくく、通常の方法では安定な水溶液製剤を製造することが困難であった。これまでに、トラニラストに対し４倍量以上、好ましくは６倍量以上のポリビニルピロリドンを溶解補助剤として用い、必要に応じ塩基性物質を加えることにより澄明なトラニラスト水溶液が得られること（特開平１−２９４６２０号）、さらにＨＬＢ１０〜１６の非イオン性界面活性剤又は両性界面活性剤を含有することでさらに溶解性が飛躍的に向上したトラニラスト水溶液が得られること（特開平２−２６４７１６号）が見出され、実用化されている。
【０００７】
しかしながら、溶解補助剤としてポリビニルピロリドンを用いる上記水溶液製剤以外には安定なトラニラスト水溶液製剤は今まで報告されていない。
【０００８】
【発明が解決しようとする課題】
本発明の目的は、溶解補助剤としてポリビニルピロリドンを用いることなく安定で配合変化を起こさない新規なトラニラスト水溶液製剤を提供することである。また、点眼液として好ましい眼に対する刺激性が少ない前記トラニラスト水溶液製剤を提供することである。
【０００９】
【発明の実施の形態】
本発明者らは、特別な溶解補助剤を使用することなく、安定性に優れ、配合変化を起こさないトラニラスト水溶液製剤を見出すために、種々処方検討を行った。その結果、モノエタノールアミンやトロメタモール等の有機アミンを配合することで、安定性に優れ、かつ配合変化を起こさず、更には眼に対する刺激性が少ないトラニラスト水溶液製剤を調製できることを見出した。これまで、有機アミンを配合したトラニラスト水溶液製剤が優れた安定性を有し、水溶液製剤として非常に有用であることは何ら知られておらず、また特別な溶解補助剤を使用しない、より簡便なトラニラスト水溶液製剤の開発が望まれていたが、本発明のトラニラスト水溶液製剤は前記の如く優れた特徴を有し、また簡便に製造することができるものである。
【００１０】
本発明は有機アミンを配合したトラニラストを有効成分とする水溶液製剤を提供するものである。本発明の水溶液製剤において用いられる有機アミンとは、トロメタモール、モノエタノールアミン、ジエタノールアミン、トリエタノールアミン等のアルカノールアミン、ＨＥＰＥＳ、１，４−ビス（２−スルホエチル）ピペラジン、１，４−ビス（３−スルホプロピル）ピペラジン、１，４−ビス（４−スルホブチル）ピペラジン等のスルホアルキルピペラジン、Ｎ，Ｎ’−ビス（３−スルホプロピル）エチレンジアミン等のスルホアルキルアルキレンジアミンなどが好ましく、特にトロメタモールやモノエタノールアミンが好ましい。
【００１１】
有機アミンの使用濃度は適宜選択できるが、トロメタモールやモノエタノールアミンであれば０．１〜１０％、その中でも０．３〜４％が好ましい。
【００１２】
本発明においては、等張化剤、安定化剤、保存剤、抗酸化剤、粘稠剤などの添加剤を使用し、白濁化や結晶析出を起こさず、安定で澄明な水溶液製剤を得るため、ＨＬＢ１０〜１６の非イオン性界面活性剤を配合するのが好ましい。例えば、保存剤として塩化ベンザルコニウムを添加した場合、ポリオキシエチレンソルビタンモノオレエートなどの非イオン性界面活性剤を配合することにより澄明かつ安定性に優れた水溶液製剤を製造することができる。非イオン性界面活性剤としてはポリオキシエチレン硬化ヒマシ油類、ポリオキシエチレンソルビタンモノオレエート、モノパルミテート、モノラウレート等があげられ、その中でもポリオキシエチレンソルビタンモノオレエート（ポリソルベート８０）がもっとも好ましい。これらの界面活性剤は少量の方が好ましく、特に点眼剤に適用する場合、角膜への影響を考慮してできるだけ低濃度にする方がよい。通常、非イオン性界面活性剤の場合０．０２５〜０．０７５％程度の濃度があれば充分である。
【００１３】
本発明の水溶液製剤のｐＨ調整は、有機アミンの添加量を調節することによって行うことができるが、緩衝剤として通常の製剤学上使用される酢酸、リン酸、ホウ酸、酒石酸、クエン酸等を配合することもできる。ただし、本発明においてアルカリ金属を含む塩は望ましくない。点眼液の場合、ｐＨは実施例に示すように点眼時の刺激性の点から７．５〜９．０の範囲が好ましく、特に８．０〜８．５の範囲が好ましい。
【００１４】
本発明の水溶液製剤は、トラニラスト、有機アミン、所望に応じ、非イオン性界面活性剤、必要に応じ、適宜好適な等張化剤、安定化剤、保存剤、抗酸化剤、粘稠剤などの添加剤を含有してなる水溶液製剤であり、極めて安定で且つ澄明であるという特徴を有するものである。添加剤としては、点眼液、点鼻液或いは注射液などを調製する際、通常製剤学上使用されるもので、トラニラストに影響を与えないものであればいかなるものも使用することができる。
【００１５】
等張化剤としては、例えば、ブドウ糖などの糖類、グリセリン、マンニトール、ソルビトール、ポリエチレングリコールなどのアルコール類をあげることができる。
【００１６】
安定化剤としては、例えば、エチレンジアミン四酢酸、リン酸などのキレート剤を挙げることができる。
【００１７】
保存剤としては、例えば、パラオキシ安息香酸エステル類、フェノール、クレゾール、クロロクレゾールなどのフェノール類、クロロブタノール、フェニルエチルアルコール、プロピレングリコールなどのアルコール類、塩化ベンザルコニウム、塩化ベンゼトニウムなどの四級アンモニウム塩、安息香酸、サリチル酸、ソルビン酸、デヒドロ酢酸、亜硫酸などの酸類などを挙げることができる。好ましくは、パラオキシ安息香酸エステル類、塩化ベンザルコニウムをあげることができ、特に好ましくは、塩化ベンザルコニウムをあげることができる。
【００１８】
酸化防止剤としては、例えば、点眼剤の抗酸化剤として用いられるアスコルビン酸、イソアスコルビン酸、塩酸システインなどをあげることができる。
【００１９】
粘稠剤としては、例えば、ヒドロキシエチルセルロース、メチルセルロース、ポリビニルアルコールなどをあげることができる。
【００２０】
このような添加剤は必要に応じ、通常の製剤において使用される範囲内において適宜配合することができる。本発明の水溶液製剤は、有効成分のトラニラストを約０．１〜２％含有させることができ、極めて安定で、液状観察において室温遮光下および５℃遮光下で約１週間保存後も浮遊物、沈殿物、結晶などの析出、白濁化などは全く認められない。
【００２１】
本発明の水溶液製剤の調製は、水溶液製剤の調製に一般的に用いられる方法に従い行うことができる。
【００２２】
例えば、本発明の水溶液製剤は、滅菌精製水にトラニラストを加えた後、有機アミンを加え、所望により、非イオン性界面活性剤を加えて加熱溶解し、次いで必要に応じて等張化剤、安定化剤、保存剤、抗酸化剤、粘稠剤、緩衝剤などの添加剤を適宜加えて完全に溶解させて製造する。
【００２３】
【実施例】
本発明の内容を以下の実験例及び実施例によりさらに詳細に説明する。尚、本発明の水溶液製剤は各実施例に記載された処方に限定されるものではない。また、刺激の程度は以下の記号を用いて表す。
【００２４】
−：刺激を感じない
±：少し刺激を感じる
＋：刺激を感じる
＋＋：強い刺激を感じる
【００２５】
実験例１
溶解性試験
トラニラスト（０．５〜２．０％）の各種水溶液に対する溶解性試験を室温下遮光保存及び５℃下遮光保存にて実施し、製剤の安定性を観察した。その結果は以下の通りであった。
【００２６】
【表１】
トロメタモールを用いて調製した各濃度のトラニラスト水溶液は、室温下遮光保存および５℃下遮光保存共に浮遊物等の発生は全く認められなかったのに対し、塩基性物質としてホウ砂を用いて調製したトラニラスト水溶液は調製直後より白濁が発生した。このことからも，トロメタモールを用いて調製したトラニラスト水溶液は極めて安定であることがわかる。
【００２８】
実験例２
点眼刺激性試験（１）
有機アミンとしてトロメタモールまたはモノエタノールアミンを用いてトラニラスト０．５％の点眼液を調製し点眼刺激性を検討した。結果は以下の通りであった。
【００２９】
【表２】
各製剤ともｐＨおよび浸透圧は点眼液として通常許容できる範囲であった。しかし、結果から明らかなように刺激性については処方によって異なり、ｐＨがアルカリ性になるほど刺激性は弱くなり、ｐＨ８．２付近ではほとんど感じられなくなった。
【００３１】
実験例３
点眼刺激性試験（２）
トラニラスト１．５％水溶液を有機アミンとしてトロメタモールを用いて調製し、ｐＨの変化と点眼刺激性の程度を比較した。結果は以下の通りであった。
【００３２】
【表３】
各製剤ともｐＨおよび浸透圧は点眼液として通常許容できる範囲であった。また、結果から明らかなように、刺激性にはｐＨ依存性が認められ、ｐＨが中性からアルカリ性になるほど刺激性は弱くなり、ｐＨ８．２付近ではほとんど認められなくなった。
【００３４】
実験例４
点眼刺激性試験（３）
ｐＨ８以上の各濃度のトラニラスト水溶液を有機アミンとしてトロメタモールを用いて調製し、点眼刺激性を比較した。また、トラニラストを含有しない基剤溶液についても検討した。結果は以下の通りであった。
【００３５】
【表４】
各製剤ともｐＨおよび浸透圧は点眼液として通常許容できる範囲であった。各製剤の刺激性については、いずれもほとんど刺激はないか比較的弱いものであり、点眼液として好ましいものである。尚、基剤溶液には刺激性は認められなかった。
【００３７】
実施例１
トラニラスト０．５％点眼液
処方
トラニラスト ０．５ ％
トロメタモール ３．８２ ％
ホウ酸 １．６ ％
ポリソルベート８０ ０．０５ ％
塩化ベンザルコニウム ０．００５％
滅菌精製水 適量
【００３８】
トラニラスト０．５ｇ、トロメタモール３．８２ｇ及びポリソルベート８００．０５ｇを滅菌精製水約５０ｍｌに加え、６０〜８０℃で加熱溶解し、これにホウ酸１．６ｇ及び塩化ベンザルコニウム０．００５ｇを加えた後、滅菌精製水を加えて全量を１００ｍｌにし、ｐＨ８．４０、浸透圧２８２ｍＯｓｍのトラニラスト０．５％点眼液を得た。
【００３９】
実施例２
トラニラスト１．０％点眼液
処方
トラニラスト １．０ ％
トロメタモール ３．８２ ％
ホウ酸 １．６ ％
ポリソルベート８０ ０．０５ ％
塩化ベンザルコニウム ０．００５％
滅菌精製水 適量
【００４０】
トラニラスト１．０ｇ、トロメタモール３．８２ｇ及びポリソルベート８００．０５ｇを滅菌精製水約５０ｍｌに加え、６０〜８０℃で加熱溶解し、これにホウ酸１．６ｇ及び塩化ベンザルコニウム０．００５ｇを加えた後、滅菌精製水を加えて全量を１００ｍｌにし、ｐＨ８．３２、浸透圧２８３ｍＯｓｍのトラニラスト１．０％点眼液を得た。
【００４１】
実施例３
トラニラスト２．０％点眼液
処方
トラニラスト ２．０ ％
トロメタモール ４．０４ ％
ホウ酸 １．６ ％
ポリソルベート８０ ０．０５ ％
塩化ベンザルコニウム ０．００５％
滅菌精製水 適量
【００４２】
トラニラスト２．０ｇ、トロメタモール４．０４ｇ及びポリソルベート８００．０５ｇを滅菌精製水約５０ｍｌに加え、６０〜８０℃で加熱溶解し、これにホウ酸１．６ｇ及び塩化ベンザルコニウム０．００５ｇを加えた後、滅菌精製水を加えて全量を１００ｍｌにし、ｐＨ８．１７、浸透圧２９８ｍＯｓｍのトラニラスト２．０％点眼液を得た。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a tranilast aqueous solution preparation containing an organic amine.
[0002]
More specifically, the present invention is useful as an ophthalmic solution, nasal solution or injection solution characterized by having remarkable stability, excellent long-term storage stability and no change in formulation. The present invention relates to a tranilast aqueous solution preparation.
[0003]
[Prior art]
Formula
[Chemical 1]
Tranilast [chemical name: N- (3,4-dimethoxycinnamoyl) anthranilic acid] represented by the formula has a chemical mediator release inhibitory action due to allergic reaction, and is useful as a therapeutic agent for various diseases caused by allergy It has been known.
[0006]
Tranilast and alkali metal salts such as sodium salt or potassium salt thereof are extremely insoluble in water, and it is difficult to produce a stable aqueous solution preparation by a usual method. Up to now, a clear aqueous solution of tranilast can be obtained by using 4 times or more, preferably 6 times or more of polyvinylpyrrolidone as a solubilizing agent with respect to tranilast and adding a basic substance as required (Japanese Patent Laid-Open No. 1). No. -294620), and further by containing a nonionic surfactant or an amphoteric surfactant of HLB 10-16, a tranilast aqueous solution with significantly improved solubility can be obtained (JP-A-2-264716). Found and put into practical use.
[0007]
However, no stable tranilast aqueous solution formulation has been reported so far other than the above aqueous solution formulation using polyvinylpyrrolidone as a solubilizing agent.
[0008]
[Problems to be solved by the invention]
An object of the present invention is to provide a novel aqueous solution of tranilast which is stable and does not cause a change in composition without using polyvinylpyrrolidone as a solubilizing agent. Moreover, it is providing the said tranilast aqueous solution formulation with little irritation with respect to an eye preferable as an eye drop.
[0009]
DETAILED DESCRIPTION OF THE INVENTION
The present inventors have conducted various prescription studies in order to find a tranilast aqueous solution preparation that is excellent in stability and does not cause a change in composition without using a special solubilizing agent. As a result, it has been found that by adding an organic amine such as monoethanolamine or trometamol, a tranilast aqueous solution preparation which is excellent in stability, does not cause a change in the composition, and is less irritating to the eyes can be prepared. So far, tranilast aqueous solution formulation containing organic amine has excellent stability, it is not known at all that it is very useful as an aqueous solution formulation, and it is easier to use without using a special solubilizing agent. Development of a tranilast aqueous solution preparation has been desired, but the tranilast aqueous solution preparation of the present invention has excellent characteristics as described above and can be easily produced.
[0010]
The present invention provides an aqueous solution preparation containing tranilast containing an organic amine as an active ingredient. The organic amine used in the aqueous solution preparation of the present invention is alkanolamine such as trometamol, monoethanolamine, diethanolamine, triethanolamine, HEPES, 1,4-bis (2-sulfoethyl) piperazine, 1,4-bis (3 -Sulfopropyl) piperazine, sulfoalkylpiperazines such as 1,4-bis (4-sulfobutyl) piperazine, and sulfoalkylalkylenediamines such as N, N'-bis (3-sulfopropyl) ethylenediamine are preferred. Ethanolamine is preferred.
[0011]
Although the use concentration of the organic amine can be selected as appropriate, it is 0.1 to 10%, preferably 0.3 to 4% among trometamol and monoethanolamine.
[0012]
In the present invention, an additive such as a tonicity agent, a stabilizer, a preservative, an antioxidant, and a thickener is used to obtain a stable and clear aqueous solution preparation without causing clouding or crystal precipitation. , HLB 10-16 nonionic surfactant is preferably blended. For example, when benzalkonium chloride is added as a preservative, a clear and stable aqueous solution preparation can be produced by blending a nonionic surfactant such as polyoxyethylene sorbitan monooleate. Nonionic surfactants include polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monooleate, monopalmitate, monolaurate, etc. Among them, polyoxyethylene sorbitan monooleate (polysorbate 80) is used. Most preferred. A small amount of these surfactants is preferable, and when applied to eye drops, it is better to make the concentration as low as possible in consideration of the effect on the cornea. Usually, in the case of a nonionic surfactant, a concentration of about 0.025 to 0.075% is sufficient.
[0013]
The pH of the aqueous solution preparation of the present invention can be adjusted by adjusting the amount of organic amine added, but acetic acid, phosphoric acid, boric acid, tartaric acid, citric acid, etc., which are commonly used as a buffering agent for pharmaceutical preparations. Can also be blended. However, in the present invention, a salt containing an alkali metal is not desirable. In the case of ophthalmic solutions, the pH is preferably in the range of 7.5 to 9.0, particularly preferably in the range of 8.0 to 8.5, from the viewpoint of irritation at the time of instillation, as shown in the Examples.
[0014]
The aqueous solution preparation of the present invention comprises tranilast, organic amine, if desired, nonionic surfactant, if necessary, appropriate isotonic agent, stabilizer, preservative, antioxidant, thickener, etc. It is an aqueous solution preparation containing the additive, and is characterized by being extremely stable and clear. Any additive can be used as long as it does not affect tranilast and is usually used in pharmacology when preparing eye drops, nasal drops or injections.
[0015]
Examples of the isotonic agent include sugars such as glucose, and alcohols such as glycerin, mannitol, sorbitol, and polyethylene glycol.
[0016]
Examples of the stabilizer include chelating agents such as ethylenediaminetetraacetic acid and phosphoric acid.
[0017]
Examples of the preservative include paraoxybenzoates, phenols such as phenol, cresol, and chlorocresol, alcohols such as chlorobutanol, phenylethyl alcohol, and propylene glycol, and quaternary ammonium such as benzalkonium chloride and benzethonium chloride. Examples thereof include salts, acids such as benzoic acid, salicylic acid, sorbic acid, dehydroacetic acid and sulfurous acid. Preferable examples include paraoxybenzoates and benzalkonium chloride, and particularly preferable examples include benzalkonium chloride.
[0018]
Examples of the antioxidant include ascorbic acid, isoascorbic acid, cysteine hydrochloride and the like used as an antioxidant for eye drops.
[0019]
Examples of the thickener include hydroxyethyl cellulose, methyl cellulose, polyvinyl alcohol and the like.
[0020]
Such additives can be appropriately blended as necessary within the range used in ordinary preparations. The aqueous solution preparation of the present invention can contain about 0.1 to 2% of the active ingredient tranilast, is extremely stable, and is suspended in the liquid state after being stored for about one week under light shielding at room temperature and light shielding at 5 ° C., Precipitation and precipitation of crystals and clouding are not observed at all.
[0021]
The aqueous solution preparation of the present invention can be prepared according to a method generally used for preparing an aqueous solution preparation.
[0022]
For example, in the aqueous solution preparation of the present invention, after adding tranilast to sterilized purified water, an organic amine is added, and if desired, a nonionic surfactant is added and dissolved by heating, and then an isotonic agent, if necessary, It is manufactured by adding additives such as stabilizers, preservatives, antioxidants, thickeners, and buffering agents as appropriate and completely dissolving them.
[0023]
【Example】
The contents of the present invention will be described in more detail by the following experimental examples and examples. In addition, the aqueous solution preparation of this invention is not limited to the prescription described in each Example. The degree of stimulation is expressed using the following symbols.
[0024]
-: I do not feel stimulation ±: I feel a little stimulation +: I feel stimulation ++: I feel a strong stimulation [0025]
Experimental example 1
Solubility test Solubility test for various aqueous solutions of tranilast (0.5-2.0%) was carried out at room temperature protected from light and at 5 ° C. protected from light, and the stability of the preparation was observed. The results were as follows.
[0026]
[Table 1]
The aqueous solution of tranilast of each concentration prepared using trometamol was prepared using borax as a basic substance, while no occurrence of suspended matter was observed in both light-shielding storage at room temperature and light-shielding storage at 5 ° C. The aqueous solution of tranilast was clouded immediately after preparation. This also shows that the aqueous solution of tranilast prepared using trometamol is extremely stable.
[0028]
Experimental example 2
Eye irritation test (1)
An ophthalmic solution containing 0.5% tranilast was prepared using trometamol or monoethanolamine as the organic amine, and the eye irritation was examined. The results were as follows.
[0029]
[Table 2]
In each preparation, the pH and osmotic pressure were within the ranges generally acceptable as eye drops. However, as is apparent from the results, the irritation varies depending on the formulation, and the irritation becomes weaker as the pH becomes alkaline, and it is hardly felt around pH 8.2.
[0031]
Experimental example 3
Eye irritation test (2)
A 1.5% aqueous solution of tranilast was prepared using trometamol as an organic amine, and the change in pH and the degree of eye irritation were compared. The results were as follows.
[0032]
[Table 3]
In each preparation, the pH and osmotic pressure were within the ranges generally acceptable as eye drops. Further, as is apparent from the results, irritation was pH-dependent, and the irritation became weaker as the pH became neutral to alkaline, and was hardly observed near pH 8.2.
[0034]
Experimental Example 4
Eye irritation test (3)
The aqueous solution of tranilast having a pH of 8 or more was prepared using trometamol as an organic amine, and the eye irritation was compared. A base solution containing no tranilast was also examined. The results were as follows.
[0035]
[Table 4]
In each preparation, the pH and osmotic pressure were within the ranges generally acceptable as eye drops. As for the irritation of each preparation, all of them are hardly irritation or relatively weak and are preferable as eye drops. In addition, irritation was not recognized by the base solution.
[0037]
Example 1
Tranilast 0.5% ophthalmic solution prescription tranilast 0.5%
Trometa Mall 3.82%
Boric acid 1.6%
Polysorbate 80 0.05%
Benzalkonium chloride 0.005%
Sterilized purified water appropriate amount [0038]
0.5 g of tranilast, 3.82 g of trometamol and 800.05 g of polysorbate were added to about 50 ml of sterilized purified water and dissolved by heating at 60 to 80 ° C., and 1.6 g of boric acid and 0.005 g of benzalkonium chloride were added thereto. Thereafter, sterilized purified water was added to bring the total amount to 100 ml, and tranilast 0.5% ophthalmic solution having a pH of 8.40 and an osmotic pressure of 282 mOsm was obtained.
[0039]
Example 2
Tranilast 1.0% ophthalmic solution prescription tranilast 1.0%
Trometa Mall 3.82%
Boric acid 1.6%
Polysorbate 80 0.05%
Benzalkonium chloride 0.005%
Sterilized purified water appropriate amount [0040]
1.0 g of tranilast, 3.82 g of trometamol and 800.05 g of polysorbate were added to about 50 ml of sterilized purified water and dissolved by heating at 60 to 80 ° C., and 1.6 g of boric acid and 0.005 g of benzalkonium chloride were added thereto. Thereafter, sterilized purified water was added to make up a total volume of 100 ml to obtain tranilast 1.0% ophthalmic solution having a pH of 8.32 and an osmotic pressure of 283 mOsm.
[0041]
Example 3
Tranilast 2.0% ophthalmic solution prescription tranilast 2.0%
Trometamol 4.04%
Boric acid 1.6%
Polysorbate 80 0.05%
Benzalkonium chloride 0.005%
Sterilized purified water appropriate amount [0042]
2.0 g of tranilast, 4.04 g of trometamol and 800.05 g of polysorbate were added to about 50 ml of sterilized purified water and dissolved by heating at 60 to 80 ° C., and 1.6 g of boric acid and 0.005 g of benzalkonium chloride were added thereto. Thereafter, sterilized purified water was added to bring the total amount to 100 ml to obtain tranilast 2.0% ophthalmic solution having a pH of 8.17 and an osmotic pressure of 298 mOsm.
Claims (5)
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|---|---|---|---|
| JP15051798A JP3659801B2 (en) | 1998-04-21 | 1998-04-21 | Tranilast aqueous solution formulation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15051798A JP3659801B2 (en) | 1998-04-21 | 1998-04-21 | Tranilast aqueous solution formulation |
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| JPH11302162A JPH11302162A (en) | 1999-11-02 |
| JP3659801B2 true JP3659801B2 (en) | 2005-06-15 |
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| JP15051798A Expired - Fee Related JP3659801B2 (en) | 1998-04-21 | 1998-04-21 | Tranilast aqueous solution formulation |
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| Country | Link |
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| JP (1) | JP3659801B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011195559A (en) * | 2010-02-24 | 2011-10-06 | Rohto Pharmaceutical Co Ltd | Tranilast-containing aqueous composition |
| JP2018115160A (en) * | 2017-01-17 | 2018-07-26 | ロート製薬株式会社 | Ophthalmic composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2001158750A (en) * | 1999-12-02 | 2001-06-12 | Lion Corp | Method for improving sustainability of ophthalmic composition and anti-allergic medicine |
| JP2011225626A (en) * | 2001-02-01 | 2011-11-10 | Rohto Pharmaceutical Co Ltd | Eye lotion |
| JP2002234837A (en) * | 2001-02-08 | 2002-08-23 | Nippon Tenganyaku Kenkyusho:Kk | Aqueous topical formulation containing tranilast |
| TW200304812A (en) * | 2002-03-08 | 2003-10-16 | Sankyo Co | An eye drop containing a tetrazole derivative |
| JP2006306765A (en) * | 2005-04-27 | 2006-11-09 | Nippon Tenganyaku Kenkyusho:Kk | Aqueous solution of tranilast for eye lotion |
| JP2007051089A (en) * | 2005-08-18 | 2007-03-01 | Medorekkusu:Kk | Preparation for external use |
| EP2269575A1 (en) | 2009-06-30 | 2011-01-05 | Santen Pharmaceutical Co., Ltd | Method for improving bioavailability of latanoprost |
| JP6732441B2 (en) * | 2015-12-11 | 2020-07-29 | ロート製薬株式会社 | Aqueous composition for topical mucosa application |
| JP6913792B2 (en) * | 2015-12-11 | 2021-08-04 | ロート製薬株式会社 | Topical mucosal application aqueous composition |
| EP4265252A4 (en) * | 2020-12-18 | 2024-11-27 | FUJIFILM Toyama Chemical Co., Ltd. | PHARMACEUTICAL COMPOSITION |
-
1998
- 1998-04-21 JP JP15051798A patent/JP3659801B2/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011195559A (en) * | 2010-02-24 | 2011-10-06 | Rohto Pharmaceutical Co Ltd | Tranilast-containing aqueous composition |
| JP2018115160A (en) * | 2017-01-17 | 2018-07-26 | ロート製薬株式会社 | Ophthalmic composition |
| JP7191515B2 (en) | 2017-01-17 | 2022-12-19 | ロート製薬株式会社 | ophthalmic composition |
| JP7644075B2 (en) | 2017-01-17 | 2025-03-11 | ロート製薬株式会社 | Ophthalmic Composition |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH11302162A (en) | 1999-11-02 |
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