CN1146429C - 用作抗动脉粥样硬化剂的原花色素a2的磷脂复合物 - Google Patents
用作抗动脉粥样硬化剂的原花色素a2的磷脂复合物 Download PDFInfo
- Publication number
- CN1146429C CN1146429C CNB998144460A CN99814446A CN1146429C CN 1146429 C CN1146429 C CN 1146429C CN B998144460 A CNB998144460 A CN B998144460A CN 99814446 A CN99814446 A CN 99814446A CN 1146429 C CN1146429 C CN 1146429C
- Authority
- CN
- China
- Prior art keywords
- proanthocyanidin
- complex
- phospholipid
- medicine
- application
- 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
Links
Classifications
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
- A61K47/544—Phospholipids
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biophysics (AREA)
- Obesity (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
用于预防和治疗由动脉粥样硬化引起的病症的原花色素A2的磷脂复合物。
Description
本发明涉及原花色素A2或富含原花色素A2的提取物的磷脂复合物及其在制备用于预防和治疗动脉粥样硬化、心肌梗塞和脑梗塞的药物中的应用。
原花色素A2或式(I)的8，14-桥亚甲基-2H，14H-1-苯并吡喃并[7，8-d][1，3]苯并二氧杂环辛烷-3，5，11，13，15-戊醇-2，8-二(3，4-二羟基苯基)-3，4-二氢[2R-2α，3α，8β，14β，15R]
是从马栗树种子中分离出来的(Tetrahedron Lett.，429，1966)。EP-A-210785(1987年2月4日)公开了原花色素A2作为结瘢剂、细胞保护剂、抗溃疡剂、静脉紧张剂(venotonic)、血管保护剂和抗过氧化剂的治疗应用。
现在已经惊奇地发现，当***给药、优选通过口服途径给药时，原花色素A2的磷脂复合物在动物和人中表现出显著的抗动脉粥样硬化活性。
本发明复合物可由天然或合成磷脂，例如卵磷脂、磷脂酰胆碱、磷脂酰丝氨酸、磷脂酰乙醇胺组成。原花色素A2与磷脂的比例为2∶1-1∶2、优选为约1∶1.5w/w。特别优选的复合物是与大豆磷脂酰胆碱的复合物。
本发明复合物是这样制得的：将磷脂溶液与原花色素A2在合适的溶剂例如丙酮、乙酸乙酯、乙醇中的溶液反应，然后将该反应混合物减压浓缩，获得了浓稠的残余物，可将残余物磨碎。
本发明复合物剂量依赖性地阻止或减轻动脉粥样斑块的形成。该活性在喂高胆固醇食物以在血管水平、特别是主动脉弓、腹主动脉、颈动脉和脑血管水平上诱导出与人类似的动脉粥样损害的兔子中得到了证实。在所述模型中，与未治疗动物相比，上述磷脂复合物改变了宏观和微观的血管状况，使得动脉粥样化斑的数量和严重程度都降低了，带来了令人惊奇的血管组织方面的益处。在关于脑保护的另一动脉粥样硬化模型中，通过手术减小兔子内颈动脉的血管腔，同时施用富含饱和脂肪的高胆固醇血饮食，在施用本发明复合物后，我们观察到，颈动脉堵塞减轻了，血管壁厚度变薄了，并且动物存活率提高了。6个月的治疗后，动脉粥样硬化患者表现出，由于动脉粥样化斑造成的颈动脉堵塞减轻了，并且改善了颈动脉血流(通过多普勒超声波检查法测定的)。
原花色素A2的磷脂复合物可以以合适的口服给药剂型例如片剂、软或硬明胶胶囊剂使用，根据疾病的严重程度，其每天以50到500mg的剂量给药2-3次。可依据常规技术和赋形剂制备药物制剂。
下述实施例更详细地举例说明本发明。
实施例1
制备原花色素A2与磷脂的复合物
在70℃，将1kg原花色素A2在5升丙酮中的溶液加到1577g磷脂酰胆碱在5升乙酸乙酯中的溶液中。
将该混合物在搅拌下回流，然后真空蒸发至干。将所得残余物在50℃真空干燥24小时，然后研磨以获得具有所需粒径的颗粒。
实施例2
将32只新西兰兔子分成4组，每组有8只兔子，并如下所述进行治疗：
组1)：对照组，标准饮食
组2)：高胆固醇血饮食(0.2％w/w胆固醇)
组3)：高胆固醇血饮食+原花色素A2提取物的磷脂复合物(0.2％胆固醇+2％w/w实施例1的复合物)
组4)：高胆固醇血饮食+原花色素A2提取物(0.2％胆固醇+原花色素A2，后者的量相当于在2％w/w实施例1复合物中存在的量)。
8周治疗后，将动物杀死，在治疗期间测定胆固醇、LDL/VLDL、HDL和甘油三酯水平。
测定在胸和腹部主动脉上的动脉粥样损害的数目、大小和分布。
将主动脉条固定，并用苏丹IV染色，以目测检验损害，并通过气相色谱法测定血管胆固醇和氧化胆固醇的含量。
在下表中报告的结果证实了用原花色素A2的磷脂复合物进行治疗使得由高胆固醇血饮食引起的动脉粥样损害以统计学显著的方式减轻。
表
治疗 损害的面积％
组1 0.5％
组2 34％
组3 7.5％*
组4 30％
*与组2相比，p＜0.01。
实施例3
含有500mg原花色素A2的磷脂复合物的胶囊
组成：
原花色素A2与大豆磷脂酰胆碱的复合物 150mg
乳糖 57mg
改性淀粉 40mg
硬脂酸镁 3.0mg
实施例4
胃耐受性片剂
原花色素A2与大豆磷脂酰胆碱的复合物 200mg
微晶纤维素 118mg
沉淀二氧化硅 3mg
硬脂酸镁 4mg
异丁烯酸阴离子聚合物及其酯 12mg
滑石粉 8mg
碳酸镁 8mg
玉米淀粉 5mg
***树胶 159mg
实施例5
软明胶胶囊
原花色素A2与大豆磷脂酰胆碱的复合物 216mg
花生油 209mg
部分氢化植物油 100mg
大豆卵磷脂 5mg
Claims (9)
1.原花色素A2的磷脂复合物。
2.权利要求1的复合物，其中所述磷脂选自卵磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸。
3.权利要求2的复合物，其中所述磷脂是磷脂酰胆碱。
4.权利要求1-3任一项的复合物，其中原花色素A2与磷脂的重量比为2∶1-1∶2。
5.权利要求1的复合物在制备用于预防或治疗动脉粥样硬化、心肌梗塞和脑梗塞的药物中的应用。
6.权利要求5的应用，其中所述药物的单位剂量为50-500mg活性组分。
7.权利要求5或6的应用，其中所述药物是通过口服途径给药的。
8.权利要求7的应用，其中所述药物呈软或硬明胶胶囊剂或片剂形式。
9.含有权利要求1复合物作为活性组分的药物组合物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI98A002732 | 1998-12-18 | ||
| IT1998MI002732A IT1304183B1 (it) | 1998-12-18 | 1998-12-18 | Complessi di proantocianidina a2 con fosfolipidi come agentiantiaterosclerotici. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1330548A CN1330548A (zh) | 2002-01-09 |
| CN1146429C true CN1146429C (zh) | 2004-04-21 |
Family
ID=11381268
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB998144460A Expired - Fee Related CN1146429C (zh) | 1998-12-18 | 1999-12-13 | 用作抗动脉粥样硬化剂的原花色素a2的磷脂复合物 |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US6429202B1 (zh) |
| EP (1) | EP1140115B1 (zh) |
| JP (1) | JP4842436B2 (zh) |
| KR (1) | KR100694907B1 (zh) |
| CN (1) | CN1146429C (zh) |
| AT (1) | ATE238803T1 (zh) |
| AU (1) | AU763907B2 (zh) |
| CA (1) | CA2355776C (zh) |
| CZ (1) | CZ301495B6 (zh) |
| DE (1) | DE69907509T2 (zh) |
| DK (1) | DK1140115T3 (zh) |
| ES (1) | ES2197708T3 (zh) |
| HK (1) | HK1042430B (zh) |
| HU (1) | HU228928B1 (zh) |
| IL (2) | IL143751A0 (zh) |
| IT (1) | IT1304183B1 (zh) |
| NO (1) | NO328733B1 (zh) |
| PL (1) | PL197153B1 (zh) |
| PT (1) | PT1140115E (zh) |
| RU (1) | RU2248798C2 (zh) |
| SK (1) | SK284884B6 (zh) |
| WO (1) | WO2000037062A2 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103120798A (zh) * | 2013-01-10 | 2013-05-29 | 施冬云 | 一种具有抗氧化应激作用的磷脂复合物制备方法及其应用 |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8507018B2 (en) * | 1998-03-12 | 2013-08-13 | Mars, Incorporated | Products containing polyphenol(s) and L-arginine and methods of use thereof |
| AU2003226974A1 (en) * | 2002-02-12 | 2003-09-04 | Hunza Di Pistolesi Elvira And C. S.A.S. | N-acyl-phosphatidyl-ethanolamines and/or mixtures of n-acyl-ethanolamines with phosphatidic acids or lysophosphatidic acids |
| ITMI20020756A1 (it) * | 2002-04-09 | 2003-10-09 | Sinclair Pharma S R L | Composizioni farmaceutiche topiche per il trattamento delle dermatiti |
| GB0321996D0 (en) * | 2003-09-19 | 2003-10-22 | Novartis Nutrition Ag | Organic compounds |
| AU2005209317B2 (en) * | 2004-01-28 | 2011-07-07 | Mars, Incorporated | Compositions and methods of use of A-type procyanidins |
| EP1837030A1 (en) | 2006-03-09 | 2007-09-26 | INDENA S.p.A. | Phospholipid complexes of curcumin having improved bioavailability |
| JP5443015B2 (ja) * | 2008-02-19 | 2014-03-19 | 株式会社岐阜セラツク製造所 | 医薬組成物 |
| IT1398624B1 (it) * | 2009-02-02 | 2013-03-08 | Dermogyn S R L | Uso cosmetico della proantocianidina a2 |
| RU2456674C1 (ru) * | 2011-05-31 | 2012-07-20 | Тагир Уралович Гафаров | Способ моделирования атрофического рубца кожи |
| CN102688501A (zh) * | 2012-06-20 | 2012-09-26 | 浙江萧山医院 | 原花青素b2磷脂复合物及其制备方法和用途 |
| CN103467778B (zh) * | 2013-09-06 | 2015-09-30 | 天津大学 | 细菌纤维素/卵磷脂复合材料及制备和应用 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4698360B1 (en) * | 1985-04-09 | 1997-11-04 | D Investigations Pharmacologiq | Plant extract with a proanthocyanidins content as therapeutic agent having radical scavenger effect and use thereof |
| GB8518289D0 (en) * | 1985-07-19 | 1985-08-29 | Inverni Della Beffa Spa | Obtaining proanthocyanidine a2 |
| IT1201151B (it) * | 1987-01-14 | 1989-01-27 | Indena Spa | Complessi fosfolipidici con estratti da vitis vinifera,procedimento per la loro preparazione e composizioni che li cntengono |
| IT1201149B (it) * | 1987-01-14 | 1989-01-27 | Indena Spa | Complessi di bioflavonoidi con fosfolipidi,loro preparazione,uso e composizioni farmaceutici e cosmetiche |
| IT1265312B1 (it) * | 1993-12-21 | 1996-10-31 | Indena Spa | Formulazioni contenenti carotenoidi e procarotenoidi associati a polifenoli nella prevenzione dei danni da abnorme produzione di |
| US5648377A (en) * | 1993-12-21 | 1997-07-15 | Indena S.P.A. | Formulations containing carotenoids an procarotenoids combined with polyphenols in the prevention of the damages due to an abnormal production of free radicals |
| IT1270999B (it) * | 1994-07-26 | 1997-05-26 | Indena Spa | Formulazioni a base di cumarine e loro uso in campo farmaceutico e cosmetico |
| FI955691A (fi) * | 1994-11-28 | 1996-05-29 | Suntory Ltd | Lipoproteiini(a):ta alentava aine, kolesterolia alentava aine ja näitä aineita sisältävät lääkkeet |
| IT1296920B1 (it) * | 1997-12-04 | 1999-08-03 | Indena Spa | Uso di complessi di estratti vitis vinifera con fosfolipidi come agenti anti-aterosclerotici |
| EP1210785B1 (de) | 1999-09-08 | 2005-11-23 | Siemens Aktiengesellschaft | Anordnung und verfahren für eine optische informationsübertragung |
-
1998
- 1998-12-18 IT IT1998MI002732A patent/IT1304183B1/it active
-
1999
- 1999-12-13 JP JP2000589173A patent/JP4842436B2/ja not_active Expired - Fee Related
- 1999-12-13 CZ CZ20012134A patent/CZ301495B6/cs not_active IP Right Cessation
- 1999-12-13 US US09/857,804 patent/US6429202B1/en not_active Expired - Lifetime
- 1999-12-13 HU HU0104665A patent/HU228928B1/hu not_active IP Right Cessation
- 1999-12-13 PL PL349534A patent/PL197153B1/pl unknown
- 1999-12-13 CN CNB998144460A patent/CN1146429C/zh not_active Expired - Fee Related
- 1999-12-13 KR KR1020017007374A patent/KR100694907B1/ko not_active IP Right Cessation
- 1999-12-13 DK DK99966956T patent/DK1140115T3/da active
- 1999-12-13 AU AU22830/00A patent/AU763907B2/en not_active Ceased
- 1999-12-13 SK SK860-2001A patent/SK284884B6/sk not_active IP Right Cessation
- 1999-12-13 ES ES99966956T patent/ES2197708T3/es not_active Expired - Lifetime
- 1999-12-13 CA CA002355776A patent/CA2355776C/en not_active Expired - Fee Related
- 1999-12-13 DE DE69907509T patent/DE69907509T2/de not_active Expired - Lifetime
- 1999-12-13 AT AT99966956T patent/ATE238803T1/de active
- 1999-12-13 WO PCT/EP1999/009854 patent/WO2000037062A2/en active IP Right Grant
- 1999-12-13 RU RU2001116085/15A patent/RU2248798C2/ru not_active IP Right Cessation
- 1999-12-13 PT PT99966956T patent/PT1140115E/pt unknown
- 1999-12-13 EP EP99966956A patent/EP1140115B1/en not_active Expired - Lifetime
- 1999-12-13 IL IL14375199A patent/IL143751A0/xx active IP Right Grant
-
2001
- 2001-06-13 IL IL143751A patent/IL143751A/en not_active IP Right Cessation
- 2001-06-14 NO NO20012944A patent/NO328733B1/no not_active IP Right Cessation
-
2002
- 2002-04-30 HK HK02103200.8A patent/HK1042430B/zh not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103120798A (zh) * | 2013-01-10 | 2013-05-29 | 施冬云 | 一种具有抗氧化应激作用的磷脂复合物制备方法及其应用 |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1146429C (zh) | 用作抗动脉粥样硬化剂的原花色素a2的磷脂复合物 | |
| JPH02304084A (ja) | 抗ウイルス性薬剤 | |
| CA2664935A1 (en) | Compositions for the treatment of hepatitis c and methods for using compositions for the treatment of hepatitis c | |
| US4910224A (en) | Method of modifying the lipid structure and function of cell membranes and pharmaceutical compositions for use therein | |
| CZ295567B6 (cs) | Tetrahydrolipstatin pro výrobu orálního farmaceutického prostředku pro ošetřování typu II diabetes mellitus | |
| CN1126564C (zh) | 葡萄提取物的膦脂复合物作为抗动脉粥样硬化剂的应用 | |
| JP2002534379A (ja) | 新規なブレチリウム組成物およびキットならびに心血管症状の予防および治療におけるそれらの使用 | |
| KR0133555B1 (ko) | 5-플루오로우라실계 화합물에 기인한 염증의 발생을 억제할 수 있는 비-주사제 형태의 항암조성물 | |
| CN110038002B (zh) | 丹酚酸a防治肌肉萎缩、肌病及肌肉骨骼并发症的用途 | |
| CA2123780A1 (en) | Amphotericin b composition with enhanced antifungal activity | |
| US6998422B2 (en) | Lipid peroxide-lowering compositions | |
| CN109260214A (zh) | 芍药苷类化合物在制备治疗脓毒症药物中的应用 | |
| KR20010040413A (ko) | 스피카마이신 또는 이것의 유도체를 사용하여 동통을감소시키거나 예방하는 방법 | |
| CN112891362B (zh) | 一种用于治疗脓毒症的药物组合物及其应用 | |
| US20030143282A1 (en) | Adenosine A3 receptor agonist | |
| CN101574339A (zh) | β-脱水淫羊藿素在制备防治心脑血管疾病药物中的应用 | |
| CN1718566A (zh) | 作为预防和治疗老年痴呆药物的阿魏酸及其钠盐 | |
| AU604226B2 (en) | Method of modifying the lipid structure function and expression of cell membranes and pharmaceutical compositions for use therein | |
| US3803319A (en) | Treating hyperlipemia with isatin | |
| CN1177587C (zh) | 利鲁唑和α-生育酚联合制剂 | |
| KR100485936B1 (ko) | 진세노사이드 Rh2 및 Rg3 항암 조성물 | |
| Upadhyaya et al. | Role of an indigenous drug Geriforte on blood levels of biogenic amines and its significance in the treatment of anxiety neurosis | |
| CN1679914A (zh) | 还原型谷胱甘肽和依布硒啉的组合药物 | |
| CN1245970C (zh) | 丹参酮iia用于制备预防和治疗动脉粥样硬化的药物 | |
| WO2009072688A1 (en) | Composition for inhibition of trasplant rejection containing the cordyceps mycellia extract as an active ingredient |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20040421 Termination date: 20161213 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |