TWI351957B - Prolonged-release diuretic compositions - Google Patents
Prolonged-release diuretic compositions Download PDFInfo
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- TWI351957B TWI351957B TW094108282A TW94108282A TWI351957B TW I351957 B TWI351957 B TW I351957B TW 094108282 A TW094108282 A TW 094108282A TW 94108282 A TW94108282 A TW 94108282A TW I351957 B TWI351957 B TW I351957B
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- Prior art keywords
- lactose
- tablet
- ratio
- torasemide
- extended release
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- 239000000203 mixture Substances 0.000 title description 23
- 230000001882 diuretic effect Effects 0.000 title description 5
- 239000002934 diuretic Substances 0.000 title description 4
- 230000002035 prolonged effect Effects 0.000 title 1
- NGBFQHCMQULJNZ-UHFFFAOYSA-N Torsemide Chemical compound CC(C)NC(=O)NS(=O)(=O)C1=CN=CC=C1NC1=CC=CC(C)=C1 NGBFQHCMQULJNZ-UHFFFAOYSA-N 0.000 claims description 40
- 229960005461 torasemide Drugs 0.000 claims description 40
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
- 238000013265 extended release Methods 0.000 claims description 15
- 239000003826 tablet Substances 0.000 claims description 14
- 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 claims description 13
- 239000008101 lactose Substances 0.000 claims description 13
- 239000007937 lozenge Substances 0.000 claims description 12
- 235000019359 magnesium stearate Nutrition 0.000 claims description 9
- 229920002261 Corn starch Polymers 0.000 claims description 7
- 239000008120 corn starch Substances 0.000 claims description 7
- 229920002907 Guar gum Polymers 0.000 claims description 5
- 239000000665 guar gum Substances 0.000 claims description 5
- 235000010417 guar gum Nutrition 0.000 claims description 5
- 229960002154 guar gum Drugs 0.000 claims description 5
- 230000036470 plasma concentration Effects 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- 206010027566 Micturition urgency Diseases 0.000 claims 1
- 150000002013 dioxins Chemical class 0.000 claims 1
- 230000003068 static effect Effects 0.000 claims 1
- 238000013268 sustained release Methods 0.000 claims 1
- 239000012730 sustained-release form Substances 0.000 claims 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 12
- 229920000642 polymer Polymers 0.000 description 11
- 229940099112 cornstarch Drugs 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- 206010022998 Irritability Diseases 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 229920001661 Chitosan Polymers 0.000 description 2
- 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 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- 239000000230 xanthan gum Substances 0.000 description 2
- 229920001285 xanthan gum Polymers 0.000 description 2
- 235000010493 xanthan gum Nutrition 0.000 description 2
- 229940082509 xanthan gum Drugs 0.000 description 2
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- WNTGYJSOUMFZEP-UHFFFAOYSA-N 2-(4-chloro-2-methylphenoxy)propanoic acid Chemical compound OC(=O)C(C)OC1=CC=C(Cl)C=C1C WNTGYJSOUMFZEP-UHFFFAOYSA-N 0.000 description 1
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 1
- 240000001548 Camellia japonica Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000008967 Enuresis Diseases 0.000 description 1
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229920000877 Melamine resin Polymers 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000350158 Prioria balsamifera Species 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 241000270708 Testudinidae Species 0.000 description 1
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 1
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 1
- -1 and eight analogs Substances 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229940045110 chitosan Drugs 0.000 description 1
- 235000018597 common camellia Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 230000003804 effect on potassium Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960004488 linolenic acid Drugs 0.000 description 1
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 1
- 210000000210 loop of henle Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- QXUAFCKBYYPTPQ-ZWKAXHIPSA-L magnesium (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol octadecanoate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O QXUAFCKBYYPTPQ-ZWKAXHIPSA-L 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- JDSHMPZPIAZGSV-UHFFFAOYSA-N melamine Chemical compound NC1=NC(N)=NC(N)=N1 JDSHMPZPIAZGSV-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 208000005346 nocturnal enuresis Diseases 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- 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
- A61K9/20—Pills, tablets, discs, rods
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- 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
- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
I351C57 .. i 九、發明說明： 【發明所屬之技術領域】 本發明係關於含有托拉塞米（torasemide)作為活性成分 的延長釋放之利尿組成物。 【先前技術】 托拉塞米（美國專利第4018929號）係一臨床上廣泛使 用之有效利尿劑。托拉塞米主要藉由抑制亨利氏襻上升枝 籲 中納的再吸收而發生作用（Puschett JB and Jordan LL. Mode of action of Torasemide in man. Progress in Pharmacology and Clinical Pharmacology. 1990;8(1):7-13)。托拉塞米干 擾在管腔細胞膜上之Na+2C1-K+泵，並阻止底外側氣傳導 (Greger R. Inhibition of active NaCl reabsorption in the thick ascending limb of the loop of Henle by torasemide. Arzneim Forsch./Drug Res. 1 988;38( 1): 1 5 1 -1 55) 〇 托拉塞米口服後之生物有效性係80-90%，其動力學係 _線性且其排除半衰期為3-4小時。其藥物動力學圖形之特 徵為一於相當短期時間内（tmax :大約一小時）達成的最大血 毁濃度（Cmax)高峰，以及快速的排除（ti,2 :約3-4小 時）（Neugebauer G, Besenfelder H and Mollendorf H. Pharmacokinetics and metabolism of torasemide in man. 尸w/i./Drwg Λα. 1988;38(1):164-166)。托拉塞米 在劑量為2.5至20毫克時，對泌尿體積呈線性的劑量-反 應關係。鈉排泄對鉀的影響極小（Scheen AJ. Dose-response 5 ⑧ 1351957 curve of torasemide in healthy volunteers. Arzneim Forsch./Drug Res. 1988;38(1): 156-1 59; Barr WH ei al. Torasemide dose-proportionality of pharmacokinetics and pharmacodynamics. Progress in Pharmacology and Clinical Pharmacology. 1 990;8(1 ):29-37)。對尿液及電解質排泄的 最大影響在約口服後兩小時觀察到（Lesne M. Comparison of the pharmacokinetics and pharmacodynamics of torasemide and furosemide in healthy volunteers. Arzneim Forsch./Drug 籲 Res 1 988;38(1): 160-163)。所有這些影響因急性多尿與因 尿急和恥骨不適事件，而在臨床上顯而易見。（Lambe R， Kennedy O, Kenny M and Darragh A. Study of tolerance and diuretic properties of torasemide following oral or intravenous administration to healthy volunteers. Eur J Clin Pharmacol 1 986;3 1 (Suppl)；9.14) 因此，托拉塞米組成物之有效性，其可避免由傳統立 即釋放之組成物所造成的棘手尿急，極引人注目。 【發明内容】 發明具體事實 —本么明之具體事實係製備利尿組成物，其可提供更穩 m、拉塞米之血漿水平，以避免最初的高峰。此可提供 /、較少波動與輕> , 平之動力圖形。因此，尿急頻率降 低，其造成需托拉实平仏 ^ + /D療之病患的較大舒適。 6 ⑧
發明摘述 本發明之組成物含有托拉塞米作為活性成分，與選自 形成基質之聚合物（如丙烯酸、纖維素、山窬酸甘油酯、 瓜耳膠、黃原膠、殼聚糖、明膠、聚乙烯醇與其類似物之 聚合物）之賦形劑。每個組成物令可使用單一聚合物或其 2合物。本發明之完整組成物的其他成分，係藥學技術上 常見之賦形劑，包含稀釋劑（例如，乳糖、纖維素、甘露 糖醇、磷酸鈣與其類似物、以及其混合物）、結合_與崩解 '作用劑（例如，艾羅西爾® 200(Aerosil® 200)、澱粉、與 八類似物、及其混合物）、潤滑劑（例如，硬脂酸鎂、滑 石與其類似物 '及其混合物）。大體來說，本發明之組 成物包含所佔比例為0 5至20%之活性成分，與所佔比例 為1至40%的形成基質之聚合物。 本發明之組成物係口服旋劑。 本發明之組成物維持尿多的最大期間為24小時，其前 12小時内較佳；因此，可能的夜間遺尿干擾可避免。因為 其服用後所達到的血漿水平之Cmax極小，所以立即釋放之 組成物所造成的棘手尿急可避免。 【實施方式】 發明詳述 本發明之錠劑含有〇·5至20毫克的活性成分，托拉塞 米。實用上’每錠劑之劑量以5、丨〇與20毫克為佳。形 成基質之聚合物係自下列群組中選出：丨）丙烯酸聚合物， 7 1351957 例如，卡波頗®(carb〇P〇1®)(—種卡波姆（carb〇mer)— 一種 丙烯酸聚合物之聚合物）、E里寇特®(K〇lliec)at(g))( 一甲 基丙烯酸之共聚物）、與其類似物及衍生物；2)纖維素聚 合物，如美多秀®(Meth〇Cel®)(經丙基甲基纖維素）、甲 基纖維素、羧曱基纖維納、那酬索®(Natr〇s〇l@)(羥乙基纖 維素）與它們的相似物及衍生物；3)肯普里投％。零 (山茶酸甘㈣）；4)美普羅給特、eypnjgat@)(瓜耳勝） 與其類似物及衍生物；5)黃原膠；6)殼聚糖；7)明膠；8)聚 籲乙烯醇及其衍生物。 本發明之組成物含有所佔比例為〇5至2〇%之活性成 分，托拉塞米’與所佔比例為i 1 4〇%之形成基質之聚合 物。最適合的形成基質之聚合物係瓜耳膠，以所佔比例為 4%為佳’而’其他形成基質之聚合物亦可用於組成物中； 其所佔比例可於相對寬廣的幅度内作改變。因此，卡波頗⑯ 係以1至20%濃度調配，以1〇%為佳；美多秀^至 馨濃度，以40%為佳；那酬索®與肯普里投@1至4〇%濃度’ 以鳩為佳；寇里寇特至4〇%濃度，以15%為佳^美 普羅給特®1%至4〇%濃度，以4%為佳。 本發明之錠劑係依照藥學技術標準程序直接壓製，或 以濕式製粒，其產生之乾燥顆粒的水分低於1 0%。 本發明之錠劑的體外溶解測試，係使用裝置2/槳攪拌 元件（根據美國藥典）以每分鐘50轉進行。 為得到7C王模擬生理狀況之溶解圖形，該測試在首二 小時以PH 1進行，之後以pH 6 8進行。所得結果呈現於 I351P57 . t» * I 螫 t 圖1及圖2。圖1顯示托拉塞米之釋放（累積值），圖2顯 示托拉塞米之釋放。 本發明藉（但非限定於）以下實施例進一步闡明。 實施例
實施例1 : 5毫克托拉塞米錠劑加上卡波頗®，總重量85毫 克。 托拉塞米 5.0毫克 卡波頗940® 10.0毫克 乳糖 硬脂酸鎂 艾羅西爾® 200 甘露糖醇 48.0毫克 0.3毫克 0.5毫克 使總重量85毫克 實施例2 : 5毫克托拉塞米錠劑加美多秀 克。 總重量100毫
托拉塞米 美多秀 K 15 M® 乳糖 玉米澱粉 預明膠化澱粉 艾羅西爾® 200 5.0毫克 40.0毫克 18.0毫克 36.2毫克 0.3毫克 0.5毫克 實施例3 : 5毫克托拉塞米錠劑加那酬索®，總重量85毫克。 1351557 .. I 擎 I 托拉塞米 那酬索 HX® 硬脂酸鎂 艾羅西爾® 200 微晶纖維素 5.0毫克 20.0毫克 0.3毫克 0.5毫克 使總重量85毫克 實施例4 : 5毫克托拉塞米錠劑加肯普里投®，總 重量100 毫克。 # 托拉塞米 5.0毫克 肯普里投 888® 20.0毫克 乳糖 38.0毫克 玉米澱粉 36.2毫克 硬脂酸鎂 0.3毫克 滑石 0.5毫克 實施例5 : 10毫克托拉塞米錠劑加寇里寇特®， 鲁毫克。 托拉塞米 1 0.0毫克 寇里寇特® SR 30 D 30·0毫克 硬脂酸鎂 0.6毫克 滑石 1.0毫克 麟酸#5 使總重量8 5毫克 重量85 實施例6 : 5毫克托拉塞米錠劑加美普羅給特®，總 重量100 10 ⑧ 1351957 ·*. ·
毫克 〇 托拉 塞 米 5.0毫克 美普 羅 給特 ® 90 4.0毫克 乳糖 54.0毫克 玉米 澱粉 36.2毫克 硬脂 酸 鎂 0.3毫克 艾羅 西 爾® 200 0.5毫克 實施例 7 ： 5毫克托拉塞米錠劑 毫克 0 托拉 塞 米 5.0毫克 美普 羅 給特 ® 9〇 3.4毫克 玉米 澱 粉 30.77毫克 艾羅 西 爾® 200 0.42毫克 硬脂 酸 鎂 0.25毫克 乳糖 45.16毫克 實施例 8 : 1 〇毫克托拉塞米錠 170 ·' 6克。 托拉 塞 米 10.0毫克 美普 羅 給特 ® 90 6.8毫克 玉米 澱 粉 61.54毫克 艾羅 西 爾® ： 200 0.85毫克 硬脂 酸鎂 0.51毫克 乳糖 90.30毫克 .1351957 總重量 實施例9: 20毫克托拉塞米鍵劑加美普羅給特 340毫克。 托拉塞米 20.0毫克 美普羅給特®90 13.6毫克 玉米澱粉 123.08毫克 艾羅西爾® 200 1.7〇毫克 硬脂酸鎂 1.02毫克 鲁乳糖 18 0.6毫克 實施例10:人體内托拉塞米之藥物動力學 隨機臨床試驗在1〇位健康自願者之群组中進_ 者交又服用H)毫克延長釋放之托拉塞米錠劑與^毫2 面可購得的立即釋放之托拉塞米錢劑（蘇崔爾> Novag，西班牙）^服用每一錠劑的間隔為一週。延長釋 放之托拉塞米組成物’表現出較緩達到且較低的血 漿水平（Cmax)高峰，其水平較穩定且波動較少(圖3)。延 長釋放之組成物與立即釋放之組成物相比，產生急性尿多 事件之頻率較低（圖4)。 這些數據顯示本發明托拉塞米之組成物與立即釋放之 組成物相比，產生較低的血漿水平高峰，且波動較少。此 外’在使用延長釋放之托拉塞米組成物後尿急事件數量也 較少。 12 【圖式簡單說明】 圖！顯示比較立即釋放(IR)鍵劑與依實施例8之延長 釋放（PR)鍵劑’托拉塞米活體外釋放率（累積值）的曲線。 圖2顯示比較立即釋放(IR)錠劑與依實施例8之延長 釋放（PR)鍵劑，托拉塞米活體外釋放率的曲線。 圖3顯示比較服用立即釋放（IR)錠劑與服用依實施例8 之延長釋放（PR)叙劑之技拉塞米後’人體内之血漿濃度曲 線。 圖4顯示比較服用立即釋放（ir)旋劑與服用依照實施 例8之延長釋放（PR)錠劑之托拉塞米後，人尿急次數對時 間的曲線。 【主要元件符號說明】 無
(D
13
Claims (1)
- I35L957 \十、申請專利範圍：100年4月8曰修正替換頁 1·一種口服用延長釋放鍵劑，其包含： ⑴含量為2.5至40毫克的托拉塞米（t〇rasemide); (11)相對於錠劑總重量，比例為40至6〇%的乳糖； (⑴）相對於乳糖重量，比例為5至1〇%的瓜耳膠； (iv)相對於錠劑總重量，比例為〇 2〇至〇 4〇%的硬脂 酸鎂； (v) 相對於錠劑總重量，比例為〇·25至1%的煙狀二氧 φ 化矽；及 (vi) 含量至高達總共ι〇〇%的澱粉產品。 2 ·根據申請專利範圍第1項之口服用延長釋放錠劑，其 中托拉塞米（torasemide)含量為5至2〇毫克。 3.根據申請專利範圍第丨項之口服用延長釋放錠劑，其 中乳糖相對於錠劑總重量的比例為45至55%。 一 4.根據申請專利範圍第2項之口服用延長釋放錠劑，其 中乳糖相對於錠劑總重量的比例為45至55%。 根據申„月專利範圍第1至4項任一項之口服用延長釋 放錠劑’其中瓜耳膠相對於乳糖重量的比例為6至9%。 6. 根據中請專利範圍第5項之口服用延長釋放鍵劑，其 中瓜耳膠相對於乳糖重量的比例為7至8%。 7. 根據中請專利範圍第！至4項任—項之口服用延長釋 放錠劑，其中澱粉產品為玉米澱粉。 1351057 · _ I r 100年4月8日修正替換頁 十一、圓式： 如次頁15 I35L957 本丨 φ 0 mlο·*ηΙ 5·ει 0.CN1ιηοί—I0·σ\ζ.Γ~ο.νο「寸 ο.Γη「一 0.0 (盤七)酲盤 mmm) mmm ⑧ 资 1957 藥物釋放率> 戀 1957 血漿濃度（ng/ml) Hf 殛(/>BS圏3 • · 靜 1957 尿急次數 0 丨P5P5-1 1-1.5 1.5-2 2 丨 2.5 B#£slsi (令潘)
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| WO2015050570A1 (en) * | 2013-10-06 | 2015-04-09 | Shah Salim | Controlled-release formulations comprising torsemide |
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| DE3305935C2 (de) * | 1983-02-21 | 1985-05-30 | Medice Chem.-Pharm. Fabrik Pütter GmbH & Co KG, 5860 Iserlohn | Kaliumneutrales Saluretikum mit antihypertensiver Wirkung |
| DE3529529A1 (de) * | 1985-08-17 | 1987-02-19 | Boehringer Mannheim Gmbh | Verfahren zur herstellung einer stabilen modifikation von torasemid |
| GB8601204D0 (en) * | 1986-01-18 | 1986-02-19 | Boots Co Plc | Therapeutic agents |
| JP3586471B2 (ja) * | 1991-06-25 | 2004-11-10 | 三菱ウェルファーマ株式会社 | トラセミド含有医薬組成物 |
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| DE10013289A1 (de) * | 2000-03-17 | 2001-09-20 | Knoll Ag | Torasemid enthaltende pharmazeutische Zubereitungen |
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| US6863901B2 (en) * | 2001-11-30 | 2005-03-08 | Collegium Pharmaceutical, Inc. | Pharmaceutical composition for compressed annular tablet with molded triturate tablet for both intraoral and oral administration |
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| MXPA06006677A (es) * | 2003-12-12 | 2006-08-31 | Penwest Pharmaceuticals Co | Formas de dosis de torasemida de liberacion sostenida. |
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- 2005-03-23 EP EP05717133.2A patent/EP1732517B1/en active Active
- 2005-03-23 KR KR1020067021596A patent/KR101203763B1/ko active IP Right Grant
- 2005-03-23 MX MXPA06010833A patent/MXPA06010833A/es active IP Right Grant
- 2005-03-23 PT PT57171332T patent/PT1732517T/pt unknown
- 2005-03-24 PA PA20058627401A patent/PA8627401A1/es unknown
-
2006
- 2006-10-24 NO NO20064834A patent/NO336582B1/no not_active IP Right Cessation
-
2010
- 2010-11-03 RU RU2010145009/15A patent/RU2449778C1/ru active
Also Published As
| Publication number | Publication date |
|---|---|
| NO20064834L (no) | 2006-12-07 |
| US20080187585A1 (en) | 2008-08-07 |
| ES2244324B1 (es) | 2006-11-16 |
| NO336582B1 (no) | 2015-09-28 |
| ES2632354T3 (es) | 2017-09-12 |
| WO2005092291A1 (en) | 2005-10-06 |
| EP1732517A1 (en) | 2006-12-20 |
| KR101203763B1 (ko) | 2012-11-23 |
| PA8627401A1 (es) | 2005-11-25 |
| UY28809A1 (es) | 2005-07-29 |
| RU2006137671A (ru) | 2008-04-27 |
| AU2005227095A1 (en) | 2005-10-06 |
| ES2244324A1 (es) | 2005-12-01 |
| BRPI0509165A (pt) | 2007-09-11 |
| EP1732517B1 (en) | 2017-05-03 |
| AR048432A1 (es) | 2006-04-26 |
| CN1946379A (zh) | 2007-04-11 |
| PL1732517T3 (pl) | 2017-09-29 |
| AU2005227095B2 (en) | 2010-10-28 |
| CA2562142A1 (en) | 2005-10-06 |
| RU2449778C1 (ru) | 2012-05-10 |
| CN1946379B (zh) | 2012-05-16 |
| KR20060130756A (ko) | 2006-12-19 |
| JP2007530510A (ja) | 2007-11-01 |
| JP4871258B2 (ja) | 2012-02-08 |
| MXPA06010833A (es) | 2006-12-15 |
| PE20060015A1 (es) | 2006-02-02 |
| PT1732517T (pt) | 2017-08-03 |
| TW200531693A (en) | 2005-10-01 |
| CA2562142C (en) | 2012-06-05 |
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