JP2004519440A5 - - Google Patents
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- Publication number
- JP2004519440A5 JP2004519440A5 JP2002550986A JP2002550986A JP2004519440A5 JP 2004519440 A5 JP2004519440 A5 JP 2004519440A5 JP 2002550986 A JP2002550986 A JP 2002550986A JP 2002550986 A JP2002550986 A JP 2002550986A JP 2004519440 A5 JP2004519440 A5 JP 2004519440A5
- Authority
- JP
- Japan
- Prior art keywords
- core
- benazepril
- pharmaceutically acceptable
- pharmaceutical composition
- amlodipine
- 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.)
- Withdrawn
Links
- 239000008194 pharmaceutical composition Substances 0.000 claims 12
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 claims 11
- 239000011248 coating agent Substances 0.000 claims 10
- 238000000576 coating method Methods 0.000 claims 10
- 150000003839 salts Chemical class 0.000 claims 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims 8
- 238000000034 method Methods 0.000 claims 8
- VPSRQEHTHIMDQM-FKLPMGAJSA-N benazepril hydrochloride Chemical compound Cl.C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 VPSRQEHTHIMDQM-FKLPMGAJSA-N 0.000 claims 7
- 229960003619 benazepril hydrochloride Drugs 0.000 claims 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 7
- 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 6
- 229960000528 amlodipine Drugs 0.000 claims 6
- 229960004530 benazepril Drugs 0.000 claims 6
- 229960004005 amlodipine besylate Drugs 0.000 claims 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 5
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims 5
- 229940068968 polysorbate 80 Drugs 0.000 claims 5
- 229920000053 polysorbate 80 Polymers 0.000 claims 5
- 239000000454 talc Substances 0.000 claims 5
- 229910052623 talc Inorganic materials 0.000 claims 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims 4
- 235000019359 magnesium stearate Nutrition 0.000 claims 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims 4
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims 3
- 229920000881 Modified starch Polymers 0.000 claims 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims 3
- 239000007963 capsule composition Substances 0.000 claims 3
- 229960000913 crospovidone Drugs 0.000 claims 3
- 238000001035 drying Methods 0.000 claims 3
- 239000008187 granular material Substances 0.000 claims 3
- 229960001021 lactose monohydrate Drugs 0.000 claims 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims 3
- 229910004298 SiO 2 Inorganic materials 0.000 claims 2
- JUNWLZAGQLJVLR-UHFFFAOYSA-J calcium diphosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])(=O)OP([O-])([O-])=O JUNWLZAGQLJVLR-UHFFFAOYSA-J 0.000 claims 2
- 235000019821 dicalcium diphosphate Nutrition 0.000 claims 2
- 229910000393 dicalcium diphosphate Inorganic materials 0.000 claims 2
- 239000012458 free base Substances 0.000 claims 2
- 239000000843 powder Substances 0.000 claims 2
- 208000024891 symptom Diseases 0.000 claims 2
- 239000005541 ACE inhibitor Substances 0.000 claims 1
- 206010002383 Angina Pectoris Diseases 0.000 claims 1
- 201000001320 Atherosclerosis Diseases 0.000 claims 1
- 206010007559 Cardiac failure congestive Diseases 0.000 claims 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims 1
- 208000032781 Diabetic cardiomyopathy Diseases 0.000 claims 1
- 206010019233 Headaches Diseases 0.000 claims 1
- 206010019280 Heart failures Diseases 0.000 claims 1
- 206010020772 Hypertension Diseases 0.000 claims 1
- 208000007177 Left Ventricular Hypertrophy Diseases 0.000 claims 1
- 208000019693 Lung disease Diseases 0.000 claims 1
- 206010033557 Palpitations Diseases 0.000 claims 1
- 208000018262 Peripheral vascular disease Diseases 0.000 claims 1
- 208000001647 Renal Insufficiency Diseases 0.000 claims 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 1
- 229920002472 Starch Polymers 0.000 claims 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims 1
- MADRIHWFJGRSBP-ROUUACIJSA-N benazeprilat Chemical compound C([C@H](N[C@H]1CCC2=CC=CC=C2N(C1=O)CC(=O)O)C(O)=O)CC1=CC=CC=C1 MADRIHWFJGRSBP-ROUUACIJSA-N 0.000 claims 1
- 230000036772 blood pressure Effects 0.000 claims 1
- 208000026106 cerebrovascular disease Diseases 0.000 claims 1
- 208000010877 cognitive disease Diseases 0.000 claims 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims 1
- 230000001934 delay Effects 0.000 claims 1
- 239000002552 dosage form Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 239000000428 dust Substances 0.000 claims 1
- 238000010410 dusting Methods 0.000 claims 1
- 238000005538 encapsulation Methods 0.000 claims 1
- 238000005469 granulation Methods 0.000 claims 1
- 230000003179 granulation Effects 0.000 claims 1
- 238000000227 grinding Methods 0.000 claims 1
- 231100000869 headache Toxicity 0.000 claims 1
- 201000006370 kidney failure Diseases 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 238000003801 milling Methods 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 208000010125 myocardial infarction Diseases 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 208000002815 pulmonary hypertension Diseases 0.000 claims 1
- 229940023144 sodium glycolate Drugs 0.000 claims 1
- 229920003109 sodium starch glycolate Polymers 0.000 claims 1
- 229940079832 sodium starch glycolate Drugs 0.000 claims 1
- 239000008109 sodium starch glycolate Substances 0.000 claims 1
- 229940032147 starch Drugs 0.000 claims 1
- 239000008107 starch Substances 0.000 claims 1
- 235000019698 starch Nutrition 0.000 claims 1
- JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 claims 1
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US2000/034246 WO2002049645A1 (en) | 2000-12-18 | 2000-12-18 | Therapeutic combination of amlodipine and benazepril |
| PCT/US2001/048808 WO2002049646A1 (en) | 2000-12-18 | 2001-12-17 | Therapeutic combination of amlodipine and benazepril/benazeprilat |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2009235225A Division JP2010043111A (ja) | 2000-12-18 | 2009-10-09 | アムロジピンとベナゼプリル／ベナゼプリラートの治療上の組み合せ |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2004519440A JP2004519440A (ja) | 2004-07-02 |
| JP2004519440A5 true JP2004519440A5 (enExample) | 2005-12-22 |
Family
ID=21742073
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2002550985A Pending JP2004516266A (ja) | 2000-12-18 | 2000-12-18 | アムロジピンおよびベナゼブリルの治療的組み合わせ |
| JP2002550986A Withdrawn JP2004519440A (ja) | 2000-12-18 | 2001-12-17 | アムロジピンとベナゼプリル／ベナゼプリラートの治療上の組み合せ |
| JP2009235225A Pending JP2010043111A (ja) | 2000-12-18 | 2009-10-09 | アムロジピンとベナゼプリル／ベナゼプリラートの治療上の組み合せ |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2002550985A Pending JP2004516266A (ja) | 2000-12-18 | 2000-12-18 | アムロジピンおよびベナゼブリルの治療的組み合わせ |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2009235225A Pending JP2010043111A (ja) | 2000-12-18 | 2009-10-09 | アムロジピンとベナゼプリル／ベナゼプリラートの治療上の組み合せ |
Country Status (26)
| Country | Link |
|---|---|
| EP (3) | EP1365761A1 (enExample) |
| JP (3) | JP2004516266A (enExample) |
| KR (3) | KR20040007420A (enExample) |
| CN (2) | CN1461218A (enExample) |
| AT (1) | ATE338549T1 (enExample) |
| AU (4) | AU2581601A (enExample) |
| BR (2) | BR0017386A (enExample) |
| CA (2) | CA2432638A1 (enExample) |
| CY (1) | CY1106275T1 (enExample) |
| CZ (2) | CZ20031678A3 (enExample) |
| DE (1) | DE60122928T2 (enExample) |
| DK (1) | DK1345607T3 (enExample) |
| EC (1) | ECSP034658A (enExample) |
| ES (1) | ES2272565T3 (enExample) |
| HU (2) | HUP0302455A3 (enExample) |
| IL (4) | IL156136A0 (enExample) |
| MX (2) | MXPA03005462A (enExample) |
| NO (2) | NO20032765L (enExample) |
| NZ (1) | NZ526467A (enExample) |
| PL (2) | PL362252A1 (enExample) |
| PT (1) | PT1345607E (enExample) |
| RU (1) | RU2292206C2 (enExample) |
| SI (1) | SI1345607T1 (enExample) |
| SK (2) | SK7652003A3 (enExample) |
| WO (2) | WO2002049645A1 (enExample) |
| ZA (1) | ZA200304514B (enExample) |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR0214383A (pt) * | 2001-11-23 | 2004-11-03 | Solvay Pharm Gmbh | Tratamento de hipertonia durante a fase aguda do ataque de apoplexia |
| US20040229901A1 (en) * | 2003-02-24 | 2004-11-18 | Lauren Otsuki | Method of treatment of disease using an adenosine A1 receptor antagonist |
| AR044069A1 (es) | 2003-04-25 | 2005-08-24 | Nova Cardia Inc | Un metodo de diuresis mejorada en individuos con funcion renal deteriorada |
| AU2004281541B2 (en) * | 2003-10-20 | 2008-05-01 | Novartis Ag | Tbenazpril and amlodipine for reducing cardiovascular morbidity |
| WO2005074927A1 (en) * | 2004-02-09 | 2005-08-18 | Novartis Ag | Therapeutic combination of amlodipine and benazepril/ benazeprilat for the treatment of hypertension |
| WO2005079772A2 (en) * | 2004-02-18 | 2005-09-01 | Sepracor Inc. | Combination of (s)-amlodipine and an ace inhibitor, and methods for reducing hypertension |
| DE102004011512B4 (de) | 2004-03-08 | 2022-01-13 | Boehringer Ingelheim Vetmedica Gmbh | Pharmazeutische Zubereitung enthaltend Pimobendan |
| US8980894B2 (en) | 2004-03-25 | 2015-03-17 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the treatment of asymptomatic (occult) heart failure |
| EP1579862A1 (en) | 2004-03-25 | 2005-09-28 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure |
| US20080268049A1 (en) * | 2005-02-11 | 2008-10-30 | Dhaliwal Mona | Stable Solid Dosage Forms of Amlodipine and Benazepril |
| WO2006092732A2 (en) * | 2005-03-04 | 2006-09-08 | Aurobindo Pharma Ltd | Stable solid dosage form of antihypertensive agent |
| MX2007011119A (es) | 2005-03-15 | 2007-11-14 | Lupin Ltd | Composiciones farmaceuticas de amlodipino y benazepril. |
| ES2303198T3 (es) * | 2005-09-28 | 2008-08-01 | Teva Pharmaceutical Industries Ltd. | Combinaciones estables de besilato de amlodipina e hidrocloruro de benazeprilo. |
| AU2005336956A1 (en) * | 2005-09-28 | 2007-04-12 | Teva Pharmaceutical Industries Ltd. | Stable combinations of amlodipine besylate and benazepril hydrochloride |
| US8158146B2 (en) | 2005-09-28 | 2012-04-17 | Teva Pharmaceutical Industries Ltd. | Stable combinations of amlodipine besylate and benazepril hydrochloride |
| EP1920785A1 (en) | 2006-11-07 | 2008-05-14 | Boehringer Ingelheim Vetmedica Gmbh | Liquid preparation comprising a complex of pimobendan and cyclodextrin |
| IT1398168B1 (it) * | 2010-02-16 | 2013-02-14 | Chiesi Farma Spa | Uso di ingredienti attivi in combinazione per il trattamento delle complicanze del diabete. |
| WO2011161223A2 (en) | 2010-06-23 | 2011-12-29 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Pharmaceutical oral dosage forms comprising lercanidipine and enalapril and their pharmaceutically acceptable salts |
| CN102389431A (zh) * | 2011-09-28 | 2012-03-28 | 济南龙华医药技术有限公司 | 一种含有盐酸贝尼地平和盐酸贝那普利的复方制剂及其应用 |
| RS54475B1 (sr) | 2011-12-21 | 2016-06-30 | Novartis Tiergesundheit Ag | Nova kombinacija |
| ES2924478T3 (es) | 2012-03-15 | 2022-10-07 | Boehringer Ingelheim Vetmedica Gmbh | Formulación de comprimidos farmacéuticos para el sector médico veterinario, método de producción y uso de los mismos |
| US20150218103A1 (en) * | 2012-08-25 | 2015-08-06 | The Johns Hopkins University | Gapdh cascade inhibitor compounds and methods of use and treatment of stress induced disorders including mental illness |
| JP6272475B2 (ja) | 2013-07-19 | 2018-01-31 | ベーリンガー インゲルハイム フェトメディカ ゲーエムベーハーＢｏｅｈｒｉｎｇｅｒ Ｉｎｇｅｌｈｅｉｍ Ｖｅｔｍｅｄｉｃａ ＧｍｂＨ | 防腐エーテル化シクロデキストリン誘導体含有液体水性医薬組成物 |
| CN110721164B (zh) | 2013-12-04 | 2024-09-17 | 勃林格殷格翰动物保健有限公司 | 匹莫苯的改善的药物组合物 |
| CN108778334A (zh) * | 2016-03-24 | 2018-11-09 | 第三共株式会社 | 用于治疗肾脏疾病的药物 |
| US10537570B2 (en) | 2016-04-06 | 2020-01-21 | Boehringer Ingelheim Vetmedica Gmbh | Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease |
| CN110290791A (zh) | 2016-11-16 | 2019-09-27 | 灵北拉荷亚研究中心公司 | 药物制剂 |
| ES2966939T3 (es) | 2016-11-16 | 2024-04-25 | H Lundbeck As | Una forma cristalina de un inhibidor de MAGL |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6162802A (en) * | 1992-03-10 | 2000-12-19 | Papa; Joseph | Synergistic combination therapy using benazepril and amlodipine for the treatment of cardiovascular disorders and compositions therefor |
| MX9706957A (es) * | 1995-03-16 | 1997-11-29 | Pfizer | Composicion que contiene amlodipina, o una sal, o felodipina y un inhibidor de enzima convertidora de angiotensina. |
| KR19980703647A (ko) * | 1995-04-07 | 1998-12-05 | 베르너발데크 | 베나제프릴 또는 베나제프릴라트 및 발사르탄을 함유하는조성물 |
| EP0795327A1 (en) * | 1996-03-13 | 1997-09-17 | Pfizer Inc. | Use of Amlodipine for the treatment and prophylaxis of congestive cardiac failure of non-ischaemic origin |
-
2000
- 2000-12-18 WO PCT/US2000/034246 patent/WO2002049645A1/en not_active Ceased
- 2000-12-18 CA CA002432638A patent/CA2432638A1/en not_active Abandoned
- 2000-12-18 JP JP2002550985A patent/JP2004516266A/ja active Pending
- 2000-12-18 HU HU0302455A patent/HUP0302455A3/hu unknown
- 2000-12-18 MX MXPA03005462A patent/MXPA03005462A/es not_active Application Discontinuation
- 2000-12-18 AU AU2581601A patent/AU2581601A/xx active Pending
- 2000-12-18 CN CN00820080A patent/CN1461218A/zh active Pending
- 2000-12-18 BR BR0017386-0A patent/BR0017386A/pt not_active Application Discontinuation
- 2000-12-18 KR KR10-2003-7007578A patent/KR20040007420A/ko not_active Withdrawn
- 2000-12-18 CZ CZ20031678A patent/CZ20031678A3/cs unknown
- 2000-12-18 AU AU2001225816A patent/AU2001225816B2/en not_active Ceased
- 2000-12-18 EP EP00989288A patent/EP1365761A1/en not_active Withdrawn
- 2000-12-18 IL IL15613600A patent/IL156136A0/xx unknown
- 2000-12-18 PL PL00362252A patent/PL362252A1/xx not_active Application Discontinuation
- 2000-12-18 SK SK765-2003A patent/SK7652003A3/sk not_active Application Discontinuation
-
2001
- 2001-12-17 PL PL01360989A patent/PL360989A1/xx not_active Application Discontinuation
- 2001-12-17 JP JP2002550986A patent/JP2004519440A/ja not_active Withdrawn
- 2001-12-17 ES ES01992150T patent/ES2272565T3/es not_active Expired - Lifetime
- 2001-12-17 AU AU2002232620A patent/AU2002232620B9/en not_active Ceased
- 2001-12-17 DK DK01992150T patent/DK1345607T3/da active
- 2001-12-17 DE DE60122928T patent/DE60122928T2/de not_active Revoked
- 2001-12-17 AT AT01992150T patent/ATE338549T1/de active
- 2001-12-17 CZ CZ20031677A patent/CZ301424B6/cs not_active IP Right Cessation
- 2001-12-17 KR KR1020097004242A patent/KR20090033914A/ko not_active Ceased
- 2001-12-17 CA CA002432282A patent/CA2432282A1/en not_active Abandoned
- 2001-12-17 HU HU0302456A patent/HUP0302456A3/hu unknown
- 2001-12-17 IL IL15626701A patent/IL156267A0/xx unknown
- 2001-12-17 MX MXPA03005463A patent/MXPA03005463A/es active IP Right Grant
- 2001-12-17 BR BR0116228-4A patent/BR0116228A/pt not_active IP Right Cessation
- 2001-12-17 SK SK764-2003A patent/SK7642003A3/sk not_active Application Discontinuation
- 2001-12-17 EP EP01992150A patent/EP1345607B1/en not_active Revoked
- 2001-12-17 RU RU2003121019/15A patent/RU2292206C2/ru not_active IP Right Cessation
- 2001-12-17 KR KR10-2003-7007754A patent/KR20030061840A/ko not_active Ceased
- 2001-12-17 EP EP06003150A patent/EP1674099A1/en not_active Withdrawn
- 2001-12-17 AU AU3262002A patent/AU3262002A/xx active Pending
- 2001-12-17 CN CNA018208398A patent/CN1481241A/zh active Pending
- 2001-12-17 NZ NZ526467A patent/NZ526467A/en unknown
- 2001-12-17 WO PCT/US2001/048808 patent/WO2002049646A1/en not_active Ceased
- 2001-12-17 PT PT01992150T patent/PT1345607E/pt unknown
- 2001-12-17 SI SI200130662T patent/SI1345607T1/sl unknown
-
2003
- 2003-06-10 ZA ZA200304514A patent/ZA200304514B/xx unknown
- 2003-06-17 NO NO20032765A patent/NO20032765L/no not_active Application Discontinuation
- 2003-06-17 NO NO20032766A patent/NO20032766L/no not_active Application Discontinuation
- 2003-06-17 EC EC2003004658A patent/ECSP034658A/es unknown
-
2006
- 2006-11-30 CY CY20061101728T patent/CY1106275T1/el unknown
-
2008
- 2008-04-10 IL IL190802A patent/IL190802A0/en unknown
- 2008-04-10 IL IL190801A patent/IL190801A0/en unknown
-
2009
- 2009-10-09 JP JP2009235225A patent/JP2010043111A/ja active Pending
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