CN1150019A - 含苯酮苯丙酸的药用组合物制剂 - Google Patents
含苯酮苯丙酸的药用组合物制剂 Download PDFInfo
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- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 229960000991 ketoprofen Drugs 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims description 12
- 239000000126 substance Substances 0.000 claims abstract description 3
- 239000003826 tablet Substances 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 22
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 13
- 239000000347 magnesium hydroxide Substances 0.000 claims description 13
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 239000008187 granular material Substances 0.000 claims description 8
- DKYWVDODHFEZIM-LLVKDONJSA-N (2r)-2-(3-benzoylphenyl)propanoic acid Chemical class OC(=O)[C@H](C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-LLVKDONJSA-N 0.000 claims description 6
- 239000002131 composite material Substances 0.000 claims description 6
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 6
- 239000001095 magnesium carbonate Substances 0.000 claims description 6
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 239000000395 magnesium oxide Substances 0.000 claims description 3
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 3
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 2
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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 12
- 239000003795 chemical substances by application Substances 0.000 description 9
- 238000010521 absorption reaction Methods 0.000 description 7
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 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 4
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- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
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- 239000004408 titanium dioxide Substances 0.000 description 3
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- 229920002261 Corn starch Polymers 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
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- 239000002552 dosage form Substances 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
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- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 2
- 229940038773 trisodium citrate Drugs 0.000 description 2
- URLVCROWVOSNPT-XOTOMLERSA-N (2s)-4-[(13r)-13-hydroxy-13-[(2r,5r)-5-[(2r,5r)-5-[(1r)-1-hydroxyundecyl]oxolan-2-yl]oxolan-2-yl]tridecyl]-2-methyl-2h-furan-5-one Chemical compound O1[C@@H]([C@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCCCCC=2C(O[C@@H](C)C=2)=O)CC1 URLVCROWVOSNPT-XOTOMLERSA-N 0.000 description 1
- XBYRMPXUBGMOJC-UHFFFAOYSA-N 1,2-dihydropyrazol-3-one Chemical compound OC=1C=CNN=1 XBYRMPXUBGMOJC-UHFFFAOYSA-N 0.000 description 1
- MFSJSVNVUDQHLV-UHFFFAOYSA-N 2-(3-benzoylphenyl)propanoic acid Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1.OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 MFSJSVNVUDQHLV-UHFFFAOYSA-N 0.000 description 1
- UJVBZCCNLAAMOV-UHFFFAOYSA-N 2h-1,2-benzothiazine Chemical class C1=CC=C2C=CNSC2=C1 UJVBZCCNLAAMOV-UHFFFAOYSA-N 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- QUHYUSAHBDACNG-UHFFFAOYSA-N acerogenin 3 Natural products C1=CC(O)=CC=C1CCCCC(=O)CCC1=CC=C(O)C=C1 QUHYUSAHBDACNG-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical class NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 1
- 230000001458 anti-acid effect Effects 0.000 description 1
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- URLVCROWVOSNPT-QTTMQESMSA-N desacetyluvaricin Natural products O=C1C(CCCCCCCCCCCC[C@@H](O)[C@H]2O[C@@H]([C@@H]3O[C@@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 URLVCROWVOSNPT-QTTMQESMSA-N 0.000 description 1
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- 239000011777 magnesium Substances 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
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- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
- A61K33/08—Oxides; Hydroxides
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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
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
- A61K33/10—Carbonates; Bicarbonates
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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
- A61K9/20—Pills, tablets, discs, rods
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及苯酮苯丙酸与具有提高疗效的特定的无机碱性物质组合后的用途。
Description
本发明涉及苯酮苯丙酸(ketoprofen)与具有提高疗效的特定的无机碱性物质组合后的用途。
已知象氢氧化镁、氧化镁和碳酸氢钠或它们的混合物这样的碱性物质可以影响某些活性化合物的吸收，例如影响邻氨基苯甲酸衍生物、丙酸衍生物、乙酸衍生物、水杨酸衍生物或它们的盐，或吡唑醇(pyrazolol)或苯并噻嗪衍生物的吸收(参见Neuvonen WO89/07439)。在该专利申请中，也将苯酮苯丙酸作为丙酸衍生物的一个例子。
专家也知道某些添加剂的调节吸收的作用不可能适用于所有的活性化合物(参见D’Arcy等人，Drug Intelligence and ClinicalPharmacy，21，607(1987))。上述Neuvonen的PCT申请中得到授权的权利要求被局限于特定的活性化合物邻甲氯灭酸、甲灭酸和布洛芬，并且只有氢氧化镁和氧化镁被要求作为其组合物中的碱性组合成分。这证实了D’Arcy等人发表的看法即碱性物质如抗酸剂对于活性化合物的吸收性质的作用无法预测。由Neuvonen随后发表在Br.J.Clin.Pharmac.31，263(1991)上的文章也表明：借助于双交叉研究显示加入氢氧化镁可以获得较高血药浓度只有在布洛芬的情况下发生。而对于苯酮苯丙酸则既未观察到其吸收速率的明显增加也未观察到吸收程度上的增加。
现有技术认为无法预测将以外消旋形式和以S(+)和R(-)对映体形式的苯酮苯丙酸与碱性辅料例如氢氧化镁和碳酸镁组合后，与不含缓冲剂的片剂相比，最高血药浓度达到更快和更高。可见图1和图2所示。
根据表1中Cmax/AUC之比可看出氢氧化镁和碳酸镁的促进吸收作用。
此外，与不含缓冲剂的片剂相比，根据本发明的组合物的含缓冲剂的片剂其Tmax区开始得较早，且显示出较小的发散性。比较研究还显示与不含缓冲剂的片剂相比，根据本发明的含缓冲剂的组合物片剂在个体血药浓度上个体差异较小。
据观察三种不同片剂的最高血药浓度(Cmax)存在显著差异。尤其用氢氧化镁缓冲的苯酮苯丙酸片比相应不含缓冲剂片更早达到较高的苯酮苯丙酸血药浓度。所以，尤其在疼痛症状下，建议使用比不含缓冲剂片剂作用更迅速的含缓冲剂片剂。
本发明的创造性不仅在于克服了文献中已知的偏见即碱性物质不能对苯酮苯丙酸的吸收产生正面影响，而且也通过发明人自己的体外试验而证实。苯酮苯丙酸片(25mg)体外释放研究表明苯酮苯丙酸和氢氧化镁的组合物制剂释放最慢，可见图3所示。从这些体外试验的阴性结果，并不能预期尤其苯酮苯丙酸+氢氧化镁的组合物在体内具有这样有利的吸收性质。
按照本发明的确定的组合物是非常重要的，它们是片剂、泡腾片剂、胶囊剂、颗粒剂、粉末混合物、混悬剂、乳剂和滴剂形式的组合物，它们最好含1重量份的苯酮苯丙酸外消旋体或S(+)-苯酮苯丙酸或R(-)-苯酮苯丙酸的纯品或它们的按重量比1∶99～99∶1的混合物，并含1～25重量份的碱性缓冲添加剂，尤其是氢氧化镁。
按照本发明已述剂型的组合物中的碱性组分的缓冲能力优选至少3毫克当量(meq).
优选具有低的血药浓度个体发散性(individual scatter of theplasma concentration)、提高的吸收速率和较高的最大血药浓度的口服剂型。
按照本发明的确定的组合物是按照常规方法制备的，例如通过混合、随后压片或通过将各成分溶解来制备。
实施例1
将实施例1的成分加工成在体外可以适中的速率释放苯酮苯丙酸的片剂。
素片(Non-lacqueredtablet)
苯酮苯丙酸(外消旋体) 25.0mg
氢氧化镁 150.4mg
胶体硅酸 12.0mg
羧甲基淀粉钠 7.0mg
柠檬酸三钠 50.0mg
硬脂酸镁 0.6mg
包衣层
HPM纤维素 1.2mg
聚乙二醇4000 0.4mg
二氧化钛 0.4mg
总重 147.0mg
将苯酮苯丙酸、氢氧化镁、羧甲基淀粉钠和柠檬酸三钠加水制成颗粒，然后干燥。
将剩余成分(胶体硅酸、硬脂酸镁)与以上颗粒混合，将该混合物在合适的压片机上压成直径为8mm的片剂。
实施例1a和实施例1b
按类似方法制备含S(+)-和R(-)-苯酮苯丙酸的片剂。
实施例2
将实施例2的成分加工成在体外迅速释放苯酮苯丙酸的片剂。
素片
苯酮苯丙酸(外消旋体) 25.0mg
碱式碳酸镁 258.0mg
羧甲基淀粉钠 10.0mg
聚乙烯吡咯烷酮25 7.4mg
胶体硅酸 2.0mg
硬脂酸镁 0.6mg
包衣层
HPM纤维素 1.8mg
聚乙二醇4000 0.6mg
二氧化钛 0.6mg
总重 306.0mg
将苯酮苯丙酸、碳酸镁、羧甲基淀粉钠和PVP加水制成颗粒，然后干燥。
将剩余成分(胶体硅酸、硬脂酸镁)加至该颗粒中，将该混合物在合适的压片机上压成直径为9mm的片剂。
比较实施例3(不含缓冲剂)
将实施例3中的成分加工成在体外迅速释放苯酮苯丙酸的片剂。该片剂不含缓冲添加剂。
苯酮苯丙酸(外消旋体) 25.0mg
玉米淀粉 48.0mg
Avicel 30.0mg
乳糖 32.0mg
羧甲基纤维素钠(Ac-Di-Sol) 4.3mg
硬脂酸镁 0.7mg
包衣层
HPM纤维素 0.6mg
聚乙二醇4000 0.2mg
二氧化钛 0.2mg
总重 141.0mg
将苯酮苯丙酸、玉米淀粉、Avicel、乳糖和Ac-Di-Sol加水制成颗粒，然后干燥。
将该颗粒与硬脂酸镁混合，在合适的压片机上压成直径为7mm的片剂。
表1
| 不含缓冲剂片剂 | 含缓冲剂片剂(Mg(OH)2) | 含缓冲剂片剂(MgCO3) | ||||
| 参数 | R(-)-苯酮苯丙酸 | S(+)-苯酮苯丙酸 | R(-)-苯酮苯丙酸 | S(+)-苯酮苯丙酸 | R(-)-苯酮苯丙酸 | S(+)-苯酮苯丙酸 |
| Cmax/AUC(1h) | 0.60 | 0.61 | 0.84 | 0.87 | 0.74 | 0.75 |
Claims (6)
1.提高了疗效的苯酮苯丙酸制剂，含由1重量份的苯酮苯丙酸和1～25重量份的无机碱性缓冲物质组成的组合物。
2.按照权利要求1的组合物制剂，其特征在于它含氢氧化镁、氧化镁或碳酸镁作为所述无机碱性缓冲物质。
3.按照权利要求1的组合物制剂，其特征在于该活性化合物是以S(+)-或R(-)-苯酮苯丙酸对映体纯品形式或以比例为1∶99～99∶1的混合物形式的苯酮苯丙酸。
4.按照权利要求1的组合物制剂，其特征在于它含苯酮苯丙酸和氢氧化镁。
5.按照权利要求1的组合物制剂，为片剂、胶囊剂、颗粒剂、粉末混合物或混悬剂形式。
6.制备按照权利要求1的组合物制剂的方法，其特征在于将1重量份的苯酮苯丙酸和1～25重量份的无机碱性物质混合，并将该混合物制成合适的给药形式。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19533162A DE19533162A1 (de) | 1995-09-08 | 1995-09-08 | Pharmazeutisches Kombinationspräparat mit Ketoprofen |
| DE19533162.1 | 1995-09-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1150019A true CN1150019A (zh) | 1997-05-21 |
Family
ID=7771571
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96112907A Pending CN1150019A (zh) | 1995-09-08 | 1996-09-06 | 含苯酮苯丙酸的药用组合物制剂 |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US5776505A (zh) |
| EP (1) | EP0761234A3 (zh) |
| JP (1) | JPH09110723A (zh) |
| CN (1) | CN1150019A (zh) |
| AR (1) | AR003990A1 (zh) |
| AU (1) | AU705931B2 (zh) |
| BR (1) | BR9603673A (zh) |
| CA (1) | CA2184887A1 (zh) |
| CZ (1) | CZ261696A3 (zh) |
| DE (1) | DE19533162A1 (zh) |
| HU (1) | HUP9602447A3 (zh) |
| IL (1) | IL119208A (zh) |
| NZ (1) | NZ299304A (zh) |
| PL (1) | PL315965A1 (zh) |
| SK (1) | SK114596A3 (zh) |
| ZA (1) | ZA967542B (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7090859B2 (en) * | 2002-12-13 | 2006-08-15 | Ronald Thomas Haas | Ketoprofen compositions and methods of making them |
| CN115607509B (zh) * | 2022-10-11 | 2024-01-30 | 南京正科医药股份有限公司 | 一种右旋酮洛芬氨丁三醇注射液及其制备工艺 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4344929A (en) * | 1980-04-25 | 1982-08-17 | Alza Corporation | Method of delivering drug with aid of effervescent activity generated in environment of use |
| FI89004C (fi) * | 1988-02-16 | 1993-08-10 | Pertti J Neuvonen | Anvaendning av tillsatsmedel foer oekning av absorptionshastigheten av laekemedel i orala laekemedelspreparat |
| US4942039A (en) * | 1989-05-09 | 1990-07-17 | Miles Inc. | Effervescent analgesic antacid composition having reduced sodium content |
| KR920002148A (ko) * | 1990-07-03 | 1992-02-28 | 안드레아 엘. 콜비 | 비스테로이드계 소염제에 의해 유발된 위장 증상을 완화시키기 위한 약제 조성물 및 이를 완화시키는 방법 |
| IT1251153B (it) * | 1991-08-06 | 1995-05-04 | Vectorpharma Int | Composizioni farmaceutiche solide per somministrazione orale aventi proungata residenza gastrica |
-
1995
- 1995-09-08 DE DE19533162A patent/DE19533162A1/de not_active Withdrawn
-
1996
- 1996-08-27 EP EP96113676A patent/EP0761234A3/de not_active Ceased
- 1996-08-30 JP JP8246827A patent/JPH09110723A/ja active Pending
- 1996-08-30 US US08/708,024 patent/US5776505A/en not_active Expired - Fee Related
- 1996-09-03 AU AU64437/96A patent/AU705931B2/en not_active Ceased
- 1996-09-04 AR ARP960104232A patent/AR003990A1/es unknown
- 1996-09-05 IL IL11920896A patent/IL119208A/en active IP Right Grant
- 1996-09-05 NZ NZ299304A patent/NZ299304A/en unknown
- 1996-09-05 CA CA002184887A patent/CA2184887A1/en not_active Abandoned
- 1996-09-06 CN CN96112907A patent/CN1150019A/zh active Pending
- 1996-09-06 PL PL96315965A patent/PL315965A1/xx unknown
- 1996-09-06 HU HU9602447A patent/HUP9602447A3/hu unknown
- 1996-09-06 ZA ZA967542A patent/ZA967542B/xx unknown
- 1996-09-06 SK SK1145-96A patent/SK114596A3/sk unknown
- 1996-09-06 BR BR9603673A patent/BR9603673A/pt active Search and Examination
- 1996-09-06 CZ CZ962616A patent/CZ261696A3/cs unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SK114596A3 (en) | 1997-07-09 |
| US5776505A (en) | 1998-07-07 |
| ZA967542B (en) | 1997-03-20 |
| BR9603673A (pt) | 1998-05-19 |
| MX9603809A (es) | 1997-07-31 |
| DE19533162A1 (de) | 1997-03-13 |
| HUP9602447A2 (en) | 1997-05-28 |
| IL119208A0 (en) | 1996-12-05 |
| AU6443796A (en) | 1997-03-13 |
| NZ299304A (en) | 1997-09-22 |
| JPH09110723A (ja) | 1997-04-28 |
| PL315965A1 (en) | 1997-03-17 |
| HU9602447D0 (en) | 1996-10-28 |
| AR003990A1 (es) | 1998-09-30 |
| EP0761234A3 (de) | 1997-07-30 |
| CA2184887A1 (en) | 1997-03-09 |
| IL119208A (en) | 2001-04-30 |
| EP0761234A2 (de) | 1997-03-12 |
| HUP9602447A3 (en) | 1997-11-28 |
| CZ261696A3 (en) | 1997-03-12 |
| AU705931B2 (en) | 1999-06-03 |
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