JP2006514119A - 溶解率が向上した難溶性薬剤の溶媒系 - Google Patents
溶解率が向上した難溶性薬剤の溶媒系 Download PDFInfo
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- JP2006514119A JP2006514119A JP2005515721A JP2005515721A JP2006514119A JP 2006514119 A JP2006514119 A JP 2006514119A JP 2005515721 A JP2005515721 A JP 2005515721A JP 2005515721 A JP2005515721 A JP 2005515721A JP 2006514119 A JP2006514119 A JP 2006514119A
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- Prior art keywords
- polyoxyethylene
- drug
- solvent system
- polyethylene glycol
- hydrochloride
- Prior art date
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- 229940079593 drug Drugs 0.000 title claims abstract description 108
- 238000004090 dissolution Methods 0.000 title claims abstract description 55
- 239000002904 solvent Substances 0.000 title claims abstract description 44
- 230000001976 improved effect Effects 0.000 title description 17
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- 239000002775 capsule Substances 0.000 claims abstract description 27
- 150000001768 cations Chemical class 0.000 claims abstract description 27
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- 239000002202 Polyethylene glycol Substances 0.000 claims description 36
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 26
- 235000011187 glycerol Nutrition 0.000 claims description 18
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 18
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
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- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 8
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- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 claims description 8
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 claims description 8
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 8
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- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
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- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 claims description 6
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- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 239000004359 castor oil Substances 0.000 claims description 5
- 235000019438 castor oil Nutrition 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 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 claims description 5
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 claims description 5
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- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 claims description 4
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 claims description 4
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 claims description 4
- PJJGZPJJTHBVMX-UHFFFAOYSA-N 5,7-Dihydroxyisoflavone Chemical compound C=1C(O)=CC(O)=C(C2=O)C=1OC=C2C1=CC=CC=C1 PJJGZPJJTHBVMX-UHFFFAOYSA-N 0.000 claims description 4
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 claims description 4
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- 239000002947 C09CA04 - Irbesartan Substances 0.000 claims description 4
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 claims description 4
- KBAUFVUYFNWQFM-UHFFFAOYSA-N Doxylamine succinate Chemical compound OC(=O)CCC(O)=O.C=1C=CC=NC=1C(C)(OCCN(C)C)C1=CC=CC=C1 KBAUFVUYFNWQFM-UHFFFAOYSA-N 0.000 claims description 4
- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical compound COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 claims description 4
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
Description
即ち,ポリオキシエチレングリコール化の天然または水素化植物性オイル類,例えば,ポリオキシエチレングリコール化の天然または水素化ヒマシ油,例えば,商品名クレモフォア(Cremophor)RH40,クレモフォアRH60,クレモフォアEL,ニッコール(Nikkol)HCO−40,ニッコール(Nikkol)HCO−60等があり,特に,クレモフォアRH40とクレモフォアELが望ましい。
例えば,ポリオキシエチレンソルビタン脂肪酸のモノ−及びトリ−ラウリル,パルミチル,ステアリル及びオレイルエステル類であり,商品名ツイン(Tween)20,21,40,61,65,80,81,85,120を用いることができ,ツイン20,ツイン60及びツイン80が望ましい。
例えば,商品名ラブラフィル(Labrafil)として市販中の界面活性剤類,例えば,商品名ラブラフィルM2125CS,ラブラフィルM1944CS,または商品名ラブラファク(Labrafac),ラブラファクCC,ラブラファクPG,ラブラゾール(Labrasol)が望ましい。
例えば,商品名ポリオキシエチレン(8)ステアレート(商品名:Myrj 45),ポリオキシエチレン(30)モノラウレート(商品名:Tagat L),ポリオキシエチレン(20)ステアレート(商品名:Marlosol 1820),ポリオキシエチレン(15)オレート(商品名:Marlosol OL 15),セチオールHE(Cetiol HE)がある。また,ポリオキシエチレンステアリン酸エステル類,例えば,ポリオキシエチレン−ポリオキシプロピレン共重合体類,例えば,商品名プルロニック(Pluronic)とエムカリクス(Emkalyx)がある。また,ポリオキシエチレン−ポリオキシプロピレンブロック共重合体類,例えば,商品名ポロキサマー(Poloxamer),具体的にポロキサマー188,124,237,338,407,モノ−,ジ−及びモノ/ジ−グリセリド,特にカプリル酸またはカプリンとグリセロールとのエステル化反応生成物,主にカプリル酸/カプリン酸モノ−及びジ−グリセリドからなる界面活性剤,例えば,商品名であるイムビトール(Imbitor)がある。
例えば,ソルビタンモノラウレート,ソルビタンモノパルミテート,ソルビタンモノステアレート,ソルビタントリステアレート,ソルビタンモノオレート,ソルビタントリオレートなどがあり,例えば,商品名スパン(Span)がある。また,ポリエチレングリコール脂肪酸エステル類があり,結合脂肪酸によりステアレート,ラウレート,オレートに分けられ,特にポリエチレングリコールモノオレートが望ましく,その例としては商品名ミオ(MYO)として市販中のミオ−2,ミオ−6,ミオ−10等がある。
例えば,プロピレングリコールジカプリレート,例えば,商品名ミグリオール(MIGLYOL)840がある。また,プロピレングリコールジラウレート,プロピレングリコールヒドロキシステアレート,プロピレングリコールイソステアレート,プロピレングリコールラウレート,プロピレングリコールリシンオレエート,プロピレングリコールステアレート等があり,例えば,セフソール(Sefsol)218及びカプリオール(Capryol)90,カプリオール(Capryol)PGMC,ラウログリコール(Lauroglycol)FCCまたはラウログリコール(Lauroglycol)90がある。また,マイシン(MAISINE)35−1(グリセリルモノリノレート),ペセオール(PECEOL)(グリセリルモノオレート),ゲルシル(GELUCIRE)44/14(ラウロイルポリオキシル−32 グリセリド)及びゲルシル(GELUCIRE)33/01(脂肪酸のグリセロールエステル)がある。
例えば,商品名トランスキュトール(Transcutol)(ジエチレングリコールモノエチルエーテル)がある。
例えば,ポリオキシエチレン(10)オレイルエーテル(商品名:Brij 96),ポリオキシエチレン(15)オレイルエーテル(商品名:Volpo 015),ポリオキシエチレン(30)オレインエーテル(商品名:Marlower OA30),ポリオキシエチレン(20)C12〜C14脂肪酸エーテル)を用いることができる。
例えば,シペロニック(Syperonic)PE L44,シペロニック(Syperonic)F127を用いることができる。
ゼラチン塊体の維持温度:58〜62℃
乾燥温度:22〜24℃
乾燥湿度:22〜24%RH(30%RH以下)
代表的な難溶性物質であるデキシブプロフェン(Dexibuprofen)とナプロキセン(Naproxen)に,以下の賦形剤を用いて溶解度を測定し,その結果を以下の表2に示した。
充填内容物に対する補助成分(賦形剤)として下記表3に記載された界面活性剤を選択して,ナプロキセンの溶解度を測定した。
実施例2の溶解度試験結果に基づいて下記表4a,4bに記載された製薬学的剤形を製造し,これらの特性を後述する方法を用いて調べた。各成分の含量単位はmgである。
下記具体的実施例の組成に示した酸性薬剤を,ポリエチレングリコールに完全に湿潤状態の内容物を作った後,水酸化物溶液をゆっくり滴加した。次いで,内容物が完全に澄んだ状態の溶液で形成されたことを確認した後,内容物の気泡を除去した。初期内容物の活性薬物が,湿潤状態で水酸化物溶液を滴加すると溶液が澄んだ状態になる現象は,酸性薬物,即ち,カルボン酸の水酸基の水素が取れて水酸化物のアルカリ金属元素との塩が生成され,薬剤がイオン化されたためである。この平衡状態は,薬剤が内容物中に存在する状態では維持される。しかし,水と会うと,安定化を維持するために再び本来の活性薬物のカルボン酸の形態を取る。従って,処方された内容物の溶液状態は清澄で透明な状態を維持したが,崩壊試験時に水中でカプセルの開口が起きるようになれば,水中で再び還元されて塩の状態ではなくなってしまう。
本発明による処方内容物を含有する軟質カプセルと,比較用として対照薬である錠剤と溶解率を試験した。本発明による処方内容物は実施例4−11の剤形を用い,カプセル被膜はゼラチン43.2%,エシトール及びソルビタン類24.8%及び水32%を含有する組成を用いて成形した。比較用剤形(対照薬)としては大韓薬典の薬効同等性の規定により市販中のナクセン錠(製造元:鐘根堂,ナクセン錠,製造番号DA005)と水における溶解率比較試験した結果を図2に示した。図2のグラフから分かるように共融媒介体の賦形剤を用いた本発明の処方は対照薬として選定された錠剤に比べて溶解率が最大12%の向上した結果を示した。
実施例5で使われた方法に準じて本発明の処方(実験薬)と大韓民国特許公告第1994−0006270号の実施例IVに開示された処方(対照薬)によりそれぞれ軟質カプセル剤形に成形した後,薬効同等性試験の項目における各pH別の溶解液で溶解率を比較し,その結果を表7及び図4,5,6及び7にそれぞれ示した。
実施例5で使われた方法に準じて本発明の実施例4−13によるデキシブプロフェンの処方(実験薬)と大韓薬典の薬効同等性の指針により対照薬(製造元:バイネクス,ダクスペン錠,製造番号:0203002)を比較用処方に対して水及びpH(6.8)による溶解率を比較し,その結果を表8と図8及び9にそれぞれ示した。
実施例5で使われた方法に準じて本発明の実施例4−30によるデキシブプロフェンの処方(実験薬)と大韓薬典の薬効同等性の指針による対照薬(製造元:バイネクス,ダクスペン錠,製造番号:0203002)とのpH1.2における溶解率を比較し,その結果を表9及び図10に示した。
実施例5で使われたものと同様の試験製剤を対象として崩壊試験を行った。崩壊試験法は大韓薬典の一般試験法に収録されている方法に準じた。その結果を以下の表10に示した。
実施例4−11による,被膜にグリセリンが添加されていない処方をカプセル化し,加速6ケ月間実験して内容物の被膜移行を観察した。その結果を以下の表11に示した。
Claims (13)
- 難溶性の酸性薬物及び前記難溶性の酸性薬物に対する溶媒系を含み;
前記溶媒系は製薬学的に許容されるカチオンアクセプタンス,ポリエチレングリコール10〜90重量%,水0.1〜15重量%及びHLB値が3〜40である溶解率を向上させるための界面活性剤0.1〜50重量%を含有し;
前記製薬学的に許容されるカチオンアクセプタンスは,難溶性の酸性薬物を部分イオン化させ,前記薬物が遊離酸とカチオン塩の両者形態で存在することにより薬物の溶解度を増加させる機能を有し;
酸性薬物の酸性基1モル当り0.1〜2モル当量で含まれることを特徴とする,製薬学的製剤。 - 上記難溶性の酸性薬物が,ナプロキセン(C14H14O3,M.W.230.26,Naproxen),イブプロフェン(R,S−Ibuprofen,C13H18O2,M.W.206.28),デキシブプロフェン(Dexibuprofen(S−Ibuprofen),C13H18O2,M.W.206.28),インドメタシン(Indomethacin,C19H16ClNO4,M.W.357.79),アセトアミノフェン(Acetaminophen,M.W.151.17),メフェナム酸(Mefenamic acid,C15H15NO2,M.W.241.29),クロロシンナジン塩酸塩(Chlorocinnazine 2HCl,C26H27N2Cl 2HCl,M.W.475.88),ロキソプロフェン(Loxoprofen,C15H18O3,M.W.246.31),フェノプロフェン(Fenoprofen,C15H14O3,M.W.242.27),ケトプロフェン(Ketoprofen,C16H14O3,M.W.254.29),プラノプロフェン(Pranoprofen,C15H13NO3,M.W.255.27),メクロフェナム酸(Meclofenamic acid,C14H11Cl2NO2,M.W.296.15)及びこれらの塩類,スリンダク(Sulindac,C20H17FO3S,M.W.356.42),ピロキシカム(Piroxicam,C15H13N3O4S,M.W.331.35),メロキシカム(Meloxicam,C14H13N3O4S2,M.W.351.41),テノキシカム(Tenoxicam,C13H11N3O4S2,M.W.337.38),ジクロフェナク(Diclofenac,C14H11Cl2NO2,M.W.296.15),アセクロフェナク(Aceclofenac,C16H13Cl2NO4,M.W.354.19),レバミピド(Rebamipide,C19H15ClN2O4,M.W.370.79),マレイン酸エナラプリル(Enalapril maleate),カプトプリル(Captopril,C9H15NO3S,M.W.217.29),ラミプリル(Ramipril,C23H32N2O5,M.W.416.52),ホシノプリル(Fosinopril,C30H46NO7P,M.W.563.67),ベナゼプリル(Benazepril,C24H28N2O5,M.W.424.50),塩酸キナプリル(Quinapril HCl,C25H30N2O5,M.W.474.99),テモカプリル(Temocapril,C23H28N2O5S2,M.W.476.62),シラザプリル(Cilazapril,C22H31N3O5,M.W.417.51),リシノプリル(Lisinopril,C21H31N3O5,M.W.405.50),バルサルタン(Valsartan,C24H29N5O3,M.W.435.53),ロサルタンカリウム(Losartan potassium,C22H22ClKN6O,M.W.461.01),イルベサルタン(Irbesartan,C25H28N6O,M.W.428.54),塩酸セチリジン(Cetirizine,C21H25ClN2O3,M.W.388.90),塩酸ジフェンヒドラミン(Diphenhydramine hydrochloride,C17H21NO HCl,M.W.291.82),フェキソフェナジン(Fexofenadine,C32H39NO4,M.W.501.67),塩酸プソイドエフェドリン(Pseudoephedrine hydrochloride,C10H15NO HCl,M.W.201.70),塩酸メチルエフェドリン(Methylephedrine hydrochloride,C11H17NO HCl,M.W.215.72),臭化水素酸デキストロメトルファン,(Dextromethorphan,C18H25NO HBr H2O,M.W.370.33),グアイフェネシン(Guaifenesin,C10H14O4,M.W.198.22),ノスカピン(Noscapine,C22H23NO7,M.W.413.43),塩酸トリメトキノール(Trimetoquinol hydrochloride,C19H23NO5 HCl,M.W.399.87),コハク酸ドキシラミン(Doxylamine succinate,C17H22N2O C4H6O4,M.W.388.5),アンブロキソール(ambroxol,C13H18Br2N2O,M.W.378.11),レトステイン(Letostein,C10H17NO4S2,M.W.279.37),ソブレロール(Sobrerol,C10H18O2,M.W.170.25),塩酸ブロムヘキシン(Bromhexine hydrochloride,C14H20Br2N2 HCl,M.W.412.59),マレイン酸クロルフェニラミン(Chlorpheniramine Maleate,C16H19ClN2 C4H4O4,M.W.390.87)及びこれらの光学異性体からなる群より選択されるものである,請求項1に記載の製薬学的製剤。
- 前記カチオンアクセプタンスは,カチオンとアニオンに解離される特性を有するか,あるいは,水素イオンを受け取ることができる特性を有する,製薬学的に使用可能な塩基化合物,弱酸の金属塩,アミン類及びこれらの混合物からなる群より選択されるものである,請求項1に記載の製薬学的製剤。
- 前記カチオンアクセプタンスは,水酸化カリウム(KOH),水酸化ナトリウム(NaOH),酢酸ナトリウム,酢酸カリウム,クエン酸カリウム,クエン酸ナトリウム,プロラミン,ジエタノールアミン,モノエタノールアミン,トリエタノールアミン,リシン,メチルグルカミン及びこれらの混合物からなる群より選択されるものである,請求項1に記載の製薬学的製剤。
- 前記カチオンアクセプタンスの重量に対して50%以上の水を含有するものである,請求項1に記載の製薬学的製剤。
- 前記界面活性剤は,天然または水素化植物性オイルとエチレングリコールとの反応生成物,ポリオキシエチレンソルビタン脂肪酸エステル類,天然植物性オイルトリグリセリドとポリアルキレンポリオールとのエステル基伝達反応生成物,ポリオキシエチレン脂肪酸エステル類,ソルビタン脂肪酸エステル類,プロピレングリコールモノ−及びジ−脂肪酸エステル,製薬学的に許容されるC1−5のアルキルまたは低分子量のモノ−もしくはポリオキシ−アルカンジオールのテトラヒドロフルフリルジ−もしくは部分エーテル,ポリオキシエチレン脂肪酸エーテル類,およびポリオキシエチレン−ポリオキシプロピレンコポリマー類からなる群より選択された一つまたは二つ以上の混合物であるものである,請求項1に記載の製薬学的製剤。
- 上記界面活性剤が,クレモフォア RH40(ポリオキシル40硬化ヒマシ油),クレモフォア EL(ポリオキシル 35ヒマシ油),ラブラゾール(ポリエチレングリコールカプリレート/カプリレート),及びトランスキュトール(ジエチレングリコールモノエチルエーテル),ツイン(ポリソルベート20,21,40,61,65,80,81,85,120),ポロキサマー(124,188,237,338,407)(ポリオキシエチレン-ポリオキシプロピレン),ニッコールHCO−40(ポリオキシエチレングリコール化の天然または水素化ヒマシ油),ミルズ(Myrj)45(ポリオキシエチレン(8)ステアレート),タガト(Tagat)L(ポリオキシエチレン(30)モノラウレート),マルロソール(Marlosol)1820(ポリオキシエチレン(20)ステアレート),マルロソール(Marlosol)OL 15(ポリオキシエチレン(15)オレート),ブリズ(Brjj)96(ポリオキシエチレン(10)オレイルエーテル),ボルポ(Volpo)015(ポリオキシエチレン(15)オレイルエーテル),マルロベット(Marlowet)OA30(ポリオキシエチレン(30)オレインエーテル),マルロベット(Marlowet)LMA 20(ポリオキシエチレン(20)オレインエーテル),シペロニック(Syperonic)PE L44(ポリオキシエチレン−ポリオキシプロピレンコポリマー),シペロニック(Syperonic)F127(ポリオキシエチレン−ポリオキシプロピレンコポリマー),ラブラフィルM 2125 CS(リノレオルマクロゴールグリセリド),ラブラファックPG(プロピレングリコールジカプリロカプレート),イムビトール(カプリル酸/カプリン酸モノ−及びジ−グリセリド),ソルビタンモノステアレート,ソルビタントリステアレート,ソルビタンモノオレート,ポリエチレングリコールモノオレート,ミグリオール(MIGLYOL)840(プロピレングリコールジカプリレート),ゲルシル 44/14(ラウロイルポリオキシル−32 グリセリド)及びこれらの混合物からなる群より選択されるものである,請求項6に記載の製薬学的製剤。
- 前記ポリエチレングリコールは,200〜800の平均分子量を有するものである,請求項2に記載の製薬学的製剤。
- 前記ポリエチレングリコールの代わりに,テトラグリコール(Tetraglycol),アルコール類のポリエチレングリコールエーテル(Polyethyleneglycolether),及びポリエチレングリコール(Polyethyleneglycol)の共重合体からなる群より選択されたポリエチレングリコール類似体を含むものである,請求項2に記載の製薬学的製剤。
- 溶媒系のpHが2.0〜8.0に維持されるものである,請求項1に記載の製薬学的製剤。
- 請求項1による製薬学的製剤及び乾燥被膜の重量を基準として,ゼラチン30〜65%,エシトール及びソルビタン類10〜40%,水1〜15%及び必要に応じて保存剤,着色剤,着香剤,遮光剤,芳香剤,崩壊改善剤,コハク酸ゼラチン(succinated gelatin)を含有する被膜組成物を含むことを特徴とする,軟質カプセル。
- さらにグリセリン,プロピレングリコール,プロピルカルボネート,ポリビニルピロリドン,酸化防止剤からなる群より選択された補助成分を含むことを特徴とする,請求項11に記載の軟質カプセル。
- 請求項1による製薬学的製剤の溶媒系を含有する,ツーピースカプセルまたは錠剤。
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PCT/KR2003/001833 WO2004071490A1 (en) | 2003-02-12 | 2003-09-05 | Solvent system of hardly soluble drug with improved elution rate |
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CN116115563B (zh) * | 2023-03-30 | 2023-08-29 | 石家庄四药有限公司 | 一种氟比洛芬混悬注射液及其制备方法 |
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NL6607516A (ja) * | 1966-05-31 | 1967-12-01 | ||
US4002718A (en) * | 1974-10-16 | 1977-01-11 | Arnar-Stone Laboratories, Inc. | Gelatin-encapsulated digoxin solutions and method of preparing the same |
US5071643A (en) * | 1986-10-17 | 1991-12-10 | R. P. Scherer Corporation | Solvent system enhancing the solubility of pharmaceuticals for encapsulation |
US5527545A (en) * | 1989-09-18 | 1996-06-18 | Recordati S.A. Chemical And Pharmaceutical Company | Liquid-suspension controlled-release pharmaceutical composition |
JP3121080B2 (ja) * | 1991-12-19 | 2000-12-25 | アール・ピー・シーラー コーポレイション | カプセル封入用溶液 |
US5376688A (en) * | 1992-12-18 | 1994-12-27 | R. P. Scherer Corporation | Enhanced solubility pharmaceutical solutions |
US20020099067A1 (en) * | 1993-07-08 | 2002-07-25 | Ulrich Posanski | Pharmaceutical compositions for sparingly soluble therapeutic agents |
US6383471B1 (en) * | 1999-04-06 | 2002-05-07 | Lipocine, Inc. | Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents |
ITMI20010645A1 (it) * | 2001-03-27 | 2002-09-27 | Acraf | Soluzione acquosa concentrata di ibuprofene facilmente dosabile sottoforma di gocce |
KR100425900B1 (ko) * | 2001-05-04 | 2004-04-03 | 대원제약주식회사 | 고농도 투명액상 이부프로펜 용액을 함유하는 속효성연질캅셀제 |
-
2003
- 2003-09-05 EP EP03815868A patent/EP1605916A4/en not_active Withdrawn
- 2003-09-05 AU AU2003261633A patent/AU2003261633A1/en not_active Abandoned
- 2003-09-05 JP JP2005515721A patent/JP2006514119A/ja active Pending
- 2003-09-05 WO PCT/KR2003/001833 patent/WO2004071490A1/en active Application Filing
- 2003-10-14 US US10/682,989 patent/US20040157928A1/en not_active Abandoned
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013517304A (ja) * | 2010-01-19 | 2013-05-16 | アキュキャップス・インダストリーズ・リミテッド | ソフトゲルカプセル化のためのナプロキセンの医薬処方およびその組合せ |
JP2016094462A (ja) * | 2010-01-19 | 2016-05-26 | アキュキャップス・インダストリーズ・リミテッド | ソフトゲルカプセル化のためのナプロキセンの医薬処方およびその組合せ |
JP2014513710A (ja) * | 2011-05-20 | 2014-06-05 | アバンテイス・フアルマ・エス・アー | ケトプロフェンを含む医薬組成物 |
JP2015516441A (ja) * | 2012-05-18 | 2015-06-11 | ルオダ ファーマ ピーティーワイ リミテッド | 液体配合剤 |
US9808529B2 (en) | 2012-05-18 | 2017-11-07 | Luoda Pharma Pty Ltd | Liquid formulation |
US10413610B2 (en) | 2012-05-18 | 2019-09-17 | Luoda Pharma Limited | Liquid formulation |
US11357855B2 (en) | 2012-05-18 | 2022-06-14 | Luoda Pharma Limited | Liquid formulation |
JP2018076310A (ja) * | 2016-10-31 | 2018-05-17 | エスエス製薬株式会社 | 経口固形組成物 |
JP7163015B2 (ja) | 2016-10-31 | 2022-10-31 | エスエス製薬株式会社 | 経口固形組成物 |
Also Published As
Publication number | Publication date |
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WO2004071490A1 (en) | 2004-08-26 |
US20040157928A1 (en) | 2004-08-12 |
EP1605916A1 (en) | 2005-12-21 |
AU2003261633A1 (en) | 2004-09-06 |
EP1605916A4 (en) | 2012-02-22 |
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