CN1252714A - 用于预防再狭窄的制剂 - Google Patents
用于预防再狭窄的制剂 Download PDFInfo
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- CN1252714A CN1252714A CN98804401A CN98804401A CN1252714A CN 1252714 A CN1252714 A CN 1252714A CN 98804401 A CN98804401 A CN 98804401A CN 98804401 A CN98804401 A CN 98804401A CN 1252714 A CN1252714 A CN 1252714A
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Abstract
本发明涉及一种用于冠状干预治疗后预防再狭窄的制剂,其包括一种具下式的作为活性成分的化合物:根据本发明,用于预防再狭窄的制剂对于患有局部缺血心脏病的患者来说,可以提供一种新的冠状干预治疗后预防再狭窄的用途,上述患者患有严重的狭窄或不能进行药物治疗,其中部分患者伴有由冠状动脉狭窄引起的心绞痛发作。
Description
本发明涉及一种用于冠状干预治疗后预防再狭窄的制剂。
冠状干预治疗是一种通过对冠状动脉血液循环进行再造的外科手术治疗方法。该治疗方法可用PTCA治疗作为代表(经皮经腔冠状血管再造术)，其中冠状动脉所显示出来的高强度的器官狭窄借助在血管中插入气球状的导管被物理性的扩大了，还有斯坦特印模(stent)治疗，其中用气球扩大后从内部植入金属支持物斯坦特印模，以及动脉粥样硬化斑切除术治疗，其中的动脉粥样硬化被切除等。最近，除了药物治疗外，人们还积极地对患有局部缺血心脏病的患者(例如心绞痛和心肌梗塞)实施了上述治疗。
从致病病原学的角度而言，再狭窄后新生的内膜(intimal)增厚部位(其在一定程度上可以根据最初的内膜增厚的构造而变化)主要包含转移到合成型的平滑肌细胞，另外还有大噬菌体和新生血管。
更具体讲，通常认为内膜增厚是由于活体血管修复功能所导致的平滑肌细胞异常增高的转移和分化所引起的，或者是由于对细胞程序性死亡(其为平滑肌生长控制机制)的抑制引起的。然而它们的细节至今没有被阐述清楚。
迄今为止，为了开发药物，借助对平滑肌生长的抑制活性的体外筛选，人们进行了许多尝试，但是没有产品被证明对患者来说是有效的，或者能作为药物上市，无论是在日本还是其它国家。
对于冠状干预治疗来说，PTCA是目前最常使用的方法，其可实施于患有局部缺血心脏病的患者，这些患者患有严重的狭窄或不能进行药物治疗，其中部分患者伴有由冠状动脉狭窄引起的心绞痛发作。随着近来技术的改进，接受治疗的病人人数增加。
PTCA的主要问题是再狭窄，其情况是即使PTCA物理性地使血管的狭窄部位进行扩张，但通常在接受治疗后3个月，狭窄将再次发生，程度大约是先前的30-40％。据说再狭窄是由于弹性减弱(其可以发生在PTCA治疗后的早期)，血栓形成，内膜增厚以及冠状动脉的再成型(其可以在治疗后1-3月个内发生)。
在这些问题中，最严重的的问题是由内膜增厚引起的再狭窄，其可以在PTCA治疗后1-3月个内发生。在目前情况下没有药物能抑制内膜增厚。
基于上述问题，本发明用兔子内皮损伤引发的内膜增厚模型进行了筛选实验，结果发现了有效的化合物，在此基础上完成了本发明。
更具体地，本发明涉及一种用于冠状干预治疗后预防再狭窄的制剂，其包括一种具下式的作为活性成分的化合物：
由式(I)表示的化合物(这里称为本发明化合物)在两种兔子皮膜损伤引发的内膜增厚模型中均显示出内膜增厚抑制活性。
正常兔子体内内皮损伤引发的内膜增厚模型是这样一个模型，其中的内膜增厚是由介质平滑肌向平滑肌内膜转移以及通过剥离血管内膜导致的合成型内膜平滑肌的分化引起的，并且是一种众所周知的用于人类PTCA治疗后再狭窄的模型。
一般认为，另一个由变性的低密度脂蛋白(LDL)导致的胆甾醇在内膜中的供应被高血脂WEEL兔子中的内皮损伤所促进的模型，更接近于人类的病理模型。
由于在上述两个模型中，本发明化合物在不改变血清胆甾醇水平的低剂量下可以抑制动脉的内膜增厚，故本发明化合物被认为可以直接作用于动脉壁。
象本发明化合物的内膜增厚抑制机制一样，ACAT抑制活性被认为可以部分地改进动脉壁中的胆甾醇代谢。然而，主要在大噬菌体中ACAT抑制剂显示出改进的胆甾醇代谢活性(Thomas M.A.Bocan等人，Arteriosclerosis and Thrombosis，Vol.11，pp.1830-1843(1991))，并且认为其对大部分平滑肌病灶没有作用。
另一方面，由于本发明化合物可以高度抑制内膜增厚(主要是平滑肌的内膜增厚)，无论沉积胆甾醇是否存在，这是与ACTA抑制剂不同的其它的作用机制。
预期本发明化合物具有抗氧化活性，因为其结构式中的硫可以被氧化。据报道抗氧化物质(例如生育酚，普罗希考等)通过抑制白细胞介素-1的分泌活性继发性地抑制平滑肌细胞的分化(Ann L.Akeson等人，Atherosclerosis，Vol.86，pp.261-270(1991))。因此，还有一种可能性，即本发明化合物的抗氧化活性也将具有内膜增厚的抑制活性。在任何情况下，由于从病理组织学的角度可以观察到在内膜增厚的分化期间，本发明化合物可以使平滑肌细胞的数量降低，故明显地，根据某些作用机制，本发明化合物对血管损伤后的平滑肌细胞的异常分化具有抑制活性。
本发明化合物是一个众所周知的化合物，其被公开于U.S专利5,475,130。
作为活性成分的本发明化合物的剂量可以根据情况变化。在口服给药的情况下，成人的每日剂量通常在0.5-120mg/人，可以一天一次给药，也可以每天分成几次给药。
本发明中的预防剂可以制成固体形式后给药，例如片剂、丸剂、胶囊、粒剂、干糖浆等。
在制备固体制剂时，可以使用各种添加剂，例如赋形剂，崩解剂，粘合剂，润滑剂或包衣基质，并可以采用振荡粒化方法，流化床粒化方法或破裂粒化方法。
赋形剂包括例如甘露醇，木糖醇，山梨醇，葡萄糖，蔗糖，乳糖，结晶纤维素，结晶纤维素羧甲基纤维素钠，磷酸氢钙，小麦淀粉，水稻淀粉，玉米淀粉，土豆淀粉，羧甲基淀粉钠，糊精，α-环糊精，β-环糊精，羧乙烯基聚合物，轻质无水硅酸，氧化钛，硅铝酸镁，聚乙二醇，中等链长的脂肪酸甘油三酯。
崩解剂包括低取代的羟丙基纤维素，羟甲基纤维素，羧甲基纤维素钙，羧甲基纤维素钠，交联羧甲纤维素。A型(ACTISOL)，淀粉，结晶纤维素，羟丙基淀粉，部分预明胶化的淀粉等。
粘合剂包括甲基纤维素，羟丙基纤维素，羟丙基甲基纤维素，聚乙烯基吡咯烷酮，明胶，阿拉伯胶，乙基纤维素，聚乙烯基醇，出芽短梗孢糖，预明胶化的淀粉，琼脂，黄耆胶，藻酸钠，藻酸丙二醇酯等。
润滑剂包括硬脂酸，硬脂酸镁，硬脂酸钙，硬脂酸聚烃氧酯，鲸蜡醇，滑石，硬化的油，蔗糖脂肪酸酯，二甲基聚硅氧烷，微晶蜡，蜂蜡，漂白的蜂蜡等。
抗氧化剂包括二丁基羟基甲苯(BHT)，焦性没食子酸丙酯，丁基羟基茴香醚(BHA)，α-生育酚，柠檬酸等。
包衣剂包括羟丙基甲基纤维素，羟丙基纤维素，甲基纤维素，乙基纤维素，邻苯二甲酸羟丙基甲基纤维素，乙酸琥珀酸羟丙基甲基纤维素，羧甲基乙基纤维素，乙酸邻苯二甲酸纤维素，二乙基氨基乙酸聚乙烯醇缩乙酯，氨基烷基异丁烯酸酯共聚体，异烯丁酸酯共聚体，乙酸1，2，4-苯三酸纤维素(CAT)，聚乙酸乙烯酯邻苯二甲酸酯，紫胶片等。
增色剂包括焦油色，氧化钛等。
矫味剂包括柠檬酸，己二酸，抗坏血酸，甲醇等。
表面活性剂包括聚氧乙烯硬化蓖麻油，单硬脂酸甘油酯，单硬脂酸脱水山梨醇酯，单棕榈酸脱水山梨醇酯，单月桂酸脱水山梨醇酯，聚氧乙烯-聚氧丙烯嵌段共聚体，聚山梨酸酯，十二烷基硫酸钠，聚乙二醇，蔗糖脂肪酸酯等。
增塑剂包括柠檬酸三乙酯，三醋精，鲸蜡醇等。
本发明中的预防剂可以任意适合给药的剂型经口服或非肠道途径使用。这些剂型的实例有溶液，乳化剂，栓剂等。
与已知的两种制剂相比，在血管内膜损伤引起的内膜增厚模型中，本发明化合物在极低的剂量下(1/500至1/1000或更少)显示出相等或更高的内膜增厚抑制活性，上述模型是一种用于人类的接受PTCA治疗后再狭窄的动物模型，并且本发明化合物是一种用于预防PTCA治疗后再狭窄的高度有效制剂，这在临床上尚未有解释。
下列实验实施例和实施例将更加充分地解释本发明。实验实施例1[在正常兔子体内血管内皮损伤引起的内膜增厚模型中的抑制活性](实验操作)
用5只两个月大的NZW属的雄性兔子作为实验动物(可以从Kitayama RABES K.K.获得)。给予兔子药物一星期后，在用戊巴比妥麻醉的情况下，将用于除去动脉栓的气球状的导管(FogartyCatheter，E-060-2F，可以从Baxter Co.，Inc.获得)经右侧外部颈动脉插到右侧常用的颈动脉中。使气球膨胀(气球压力为0.5-1.0atm)，使得右侧常用颈动脉被擦伤三次，从而制造一个血管内皮损伤的模型。在内皮损伤后，给药两星期，切除颈动脉，将其固定于10％的中性缓冲的福尔马林中，以制备动脉环形组织的切片。用ElasticVan Gieson(EVG)染色来制备弹性纤维-染色的组织标本。借助图形分析系统(Adobe Photoshop，Unitimage for the Apple Macintosh)来测定内膜面积(I)和介面面积(M)，并用计算这两个值(I/M)的比例，以决定内膜增厚的水平。
将药物与兔子的饲料RC-49(可从Oriental Kobo K.K.获得)混合给予兔子，药物的浓度为0.0003％，剂量可根据食入的饲料量和体重计算得到。采用促进瘢痕瘤愈合的试剂曲尼司特(已知其具有内膜增厚抑制活性)与RC-4混合作为对照，浓度为0.167％(结果)表1[用于正常兔子体内血管内皮损伤的内膜增厚模型中的抑制活性]
内膜增厚的水平 抑制率
N mg/kg I/M (％)对照 9 -- 0.251±0.030 -本发明化合物 9 0.2 0.126±0.028* 49.8曲尼司特 9 100 0.184±0.051 26.6
平均值±S.E.
*p＜0.05vs.对照
I/M＝内膜面积/介面面积
实验实施例2[在WEEL兔子体内血管内皮损伤引起的内膜增厚模型中的抑制活性](实验操作)
用4只两个月大的纯合子遗传的高血脂WEEL属的雄性兔子作为实验动物(可以从Kitayama RABES K.K.获得)。在用戊巴比妥麻醉的情况下，将用于除去动脉栓子的气球状的导管(Fogarty Catheter，E-060-2F，可以从Baxter Co.，Inc.获得)经右侧外部颈动脉插到右侧常用的颈动脉中。使气球膨胀(气球压力为0.5-1.0atm)，使得右侧常用颈动脉被擦伤三次，从而制造一个血管内皮损伤的模型。在内皮损伤后，给药四星期，切除颈动脉，将其固定于10％的中性缓冲的福尔马林中，以制备动脉环形组织的切片。用Elastic Van Gieson(EVG)染色来制备弹性纤维-染色的组织标本。借助图形分析系统(Adobe Photoshop，Unitimage for the Apple Macintosh)来测定内膜面积(I)和介面面积(M)，并用计算这两个值(I/M)的比例，以决定内膜增厚的水平。根据酶方法(Autosera CHO-2，Daiichi KagakuYakuhin K.K.)，采用自动分析仪(Hitachi 7150型)测定血中总胆甾醇的水平。
将药物与兔子的饲料RC-49(可从Oriental Kobo K.K.获得)混合给予兔子，药物的浓度为0.0003％和0.003％，剂量可根据食入的饲料量和体重计算得到。采用抗高血脂的制剂，普罗布考(已知其在高血脂模型中具有内膜增厚抑制活性)与RC-4混合作为对照，浓度为0.35％。(结果)表2[用于WEEL兔子体内血管内皮损伤的内膜增厚模型中的抑制活性]
总血胆甾醇 内膜增厚的水平 抑制率
mg/kg mg/dl I/M (％)对照 - 841±44 1.00±0.23 -本发明化合物 0.2 861±83 0.45±0.19* 55.0本发明化合物 2.0 907±48 0.38±0.05* 62.0曲尼司特 190 723±44* 0.43±0.08* 57.0平均值±S.E.*p＜0.05vs.对照I/M＝内膜面积/介面面积实施例1
将50g本发明化合物溶于945g中等链长的脂肪酸甘油三酯和5g聚山梨酯80中，制备用于包囊的溶液。实施例2
将100g本发明化合物溶于895g中等链长的脂肪酸甘油三酯和5g聚山梨酯80中，制备用于包囊的溶液。实施例3
将10g本发明化合物溶于985g大豆油和5g聚山梨酯80中，制备用于包囊的溶液。实施例4
将50g本发明化合物溶于945g中等链长的脂肪酸甘油三酯和5g聚山梨酯中。用20g硅酸钙和40g磷酸氢钙的预混合物吸收10g生成的溶液，然后加入29g甘露糖醇制备粉末状混合物。再加入1g硬脂酸镁制备粉末。实施例5
将50g本发明化合物溶于945g中等链长的脂肪酸甘油三酯和5g聚山梨酯中。用20g硅酸钙和40g磷酸氢钙的预混合物吸收10g生成的溶液，然后加入24g乳糖制备粉末状混合物。再加入1g硬脂酸镁和5g滑石，使混合物均匀混合，填充到胶囊中制备胶囊。实施例6
将50g本发明化合物溶于945g中等链长的脂肪酸甘油三酯和5g聚山梨酯中。用20g硅酸钙和40g磷酸氢钙的预混合物吸收10g生成的溶液，然后加入24g结晶纤维素和10g交联羧甲纤维素制备粉末状混合物。再加入1g硬脂酸镁和5g滑石，使混合物均匀混合，用压片机进行压片。实施例7配方(每个胶囊)
本发明化合物 30mg
油酸 268.65mg
聚山梨酯80 1.35mg
总量 300mg
将本发明化合物溶于油酸和聚山梨酯80中，制备用于包囊的溶液。
Claims (1)
1、用于冠状干预治疗后预防再狭窄的制剂，其包括一种具下式的作为活性成分的化合物：
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP82649/1997 | 1997-04-01 | ||
| JP8264997 | 1997-04-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1252714A true CN1252714A (zh) | 2000-05-10 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98804401A Pending CN1252714A (zh) | 1997-04-01 | 1998-03-31 | 用于预防再狭窄的制剂 |
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| Country | Link |
|---|---|
| EP (1) | EP0983763A4 (zh) |
| KR (1) | KR20010005844A (zh) |
| CN (1) | CN1252714A (zh) |
| AU (1) | AU721632B2 (zh) |
| CA (1) | CA2285374A1 (zh) |
| WO (1) | WO1998043626A1 (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU721698B2 (en) * | 1997-04-01 | 2000-07-13 | Taisho Pharmaceutical Co., Ltd. | Agent for preventing ischemic heart diseases |
| JP2002348235A (ja) * | 2001-03-23 | 2002-12-04 | Clinical Supply:Kk | 再狭窄予防剤 |
| JP4781169B2 (ja) * | 2006-05-31 | 2011-09-28 | 積水メディカル株式会社 | 再狭窄の発症リスクを判定する方法 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992007825A1 (en) * | 1990-11-05 | 1992-05-14 | Taisho Pharmaceutical Co., Ltd. | Phenol derivative |
| KR0169501B1 (ko) * | 1990-11-26 | 1999-03-20 | 우에하라 아키라 | 아닐리드 유도체 |
| EP0619312A4 (en) * | 1991-12-25 | 1995-07-19 | Taisho Pharmaceutical Co Ltd | ANILIDE DERIVATIVE. |
-
1998
- 1998-03-31 CA CA002285374A patent/CA2285374A1/en not_active Abandoned
- 1998-03-31 CN CN98804401A patent/CN1252714A/zh active Pending
- 1998-03-31 EP EP98911141A patent/EP0983763A4/en not_active Withdrawn
- 1998-03-31 AU AU65211/98A patent/AU721632B2/en not_active Ceased
- 1998-03-31 KR KR1019997008918A patent/KR20010005844A/ko not_active Application Discontinuation
- 1998-03-31 WO PCT/JP1998/001486 patent/WO1998043626A1/ja not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0983763A1 (en) | 2000-03-08 |
| EP0983763A4 (en) | 2003-03-19 |
| AU6521198A (en) | 1998-10-22 |
| WO1998043626A1 (fr) | 1998-10-08 |
| AU721632B2 (en) | 2000-07-13 |
| KR20010005844A (ko) | 2001-01-15 |
| CA2285374A1 (en) | 1998-10-08 |
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