CN1197481C - 用红藤叶萃取物治疗慢性静脉机能不全的方法 - Google Patents
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Abstract
本发明是关于用以预防和缓解因腿部轻微至中度慢性静脉不全所引起不适症的由红藤叶的水萃取物及可接受载体构成的饮食品添加剂。
Description
相关的申请案资料
本申请案要求保护的相当于1999年10月20日提出申请的美国临时申请案第60/160,518号。
技术领域
本发明是关于饮食品添加剂，更具体地说，是关于用以预防及缓解因轻微至中度下部肢体的慢性静脉机能不全所引起不适症的饮食品添加剂。
发明背景
近来，全世界有数以百万计的人罹患轻微至中度下部肢体的慢性静脉机能不全。这种常见疾病的特征为静脉循环由腿部回流至心脏的血量不足。因为缺乏足够的静脉回流而导致静脉血停滞及升高静脉循环内的压力，因而促进水肿及组织内水滞留的发展。
慢性静脉机能不全(CVI)是一种因持续性的静脉回流机能不全所引起的功能性障碍，其临床症状为水肿，皮肤变化及主诉性不适，诸如疲倦，腿部无力，疼痛或刺痛感，这些症状会随着站立与环境温度高而加剧。这种功能失调对于病人可能是一种主要的不舒适应激的原因，因而对病人整体生活幸福及生活质量有极明显的负面冲击。早期(第I级)症状为冠状静脉扩张paraplantaris，筋膜下淤血及水肿；第II级CVI则伴随着低程度的皮肤变化，湿疹及皮脂硬化。如果不加以治疗，第I级及II级症状通常会进展到症状为复发性腿静脉溃疡期(第III级)。这些症状所引起的不舒适应激，甚至在刚开始时相当轻微，以及随后产生并发症的危险都期待在CVI的早期就可以开始进行适当的支持性或预防性措施。
尽管有部分病人在早期时需要手术治疗(硬化治疗及静脉曲张手术)，但是使用弹性袜并用或不用其他物理治疗法仍是最常使用的治疗方式。弹性袜的效果只是机械力的效果，即该方法不能影响或是纠正相关的生物性功能失常(特别是微血管脆化)。此外，以弹性袜治疗常常缺乏顺从性，特别是在夏季因为外观上的考量以及弹性袜整体的不方便性所致。因此就有迫切的需要一种有效的，很耐受的及更方便的替代性治疗方式。
发明概述
意想不到地发现红藤叶的水萃取物可用来制备本发明的饮食品添加剂用以预防及治疗下部肢体的轻微至中度慢性静脉机能不全所引起的不适症。
因此本发明是关于一种预防及/或缓解下肢体的轻微至中度慢性静脉机能不全所引起的不适症的方法，该方法包括给药含有红藤叶的水萃取物的饮食品添加剂。
本发明的另一方面是一种饮食品添加剂组合物，该组合物包含一种可以预防及/或治疗下部肢体轻微至中度慢性静脉机能不全所引起的不适症活性成分，以及一种医药上、外观上或饮食上可接受的载体，其改善在于其中的活性成分主要由红藤叶的水萃取物组成。其中，所述组合物为颗粒剂、片剂、胶囊、滴剂或糖浆剂型。
另一方面，本发明提供了一种适于口服给药形式的组合物在制备用于预防和/或治疗下部肢体的轻微至中度慢性静脉不全引起的不适症的饮食添加剂中的用途，其中所述的组合物含有可以预防或治疗下部肢体的轻微至中度慢性静脉不全所引起不适症的活性成分，以及医药上、外观上或饮食上可接受的载体，其中该活性成分主要由含有2-20％类黄酮的红藤叶的水萃取物所组成，其中该红藤叶水萃取物是由包含下列步骤的方法获得：
(a)在葡萄的采收季节节采收红藤叶子；
(b)干燥并碾碎该叶子；
(c)将叶子切成小片；
(d)在60-80℃的温度下在全渗滤器中以水萃取叶子6至10小时；
(e)任选将所得萃取液浓缩。
优选者，本发明的饮食品添加剂组合物包含衍生于红藤叶的水萃取物(folia vitis viniferae；Extractum Vitis viniferae e folium spissum et siccum)的草药成分以及一种可接受的载剂。该萃取物含有黄酮-苷、黄酮醇-苷、黄酮-葡糖苷酸、黄酮醇-葡糖苷酸及类黄酮，含有五羟黄酮-3-O-β-D-葡糖苷酸及异五羟黄酮(五羟黄酮-3-O-β-葡糖甘)为主要活性成分。这些活性成分的药理活性范围仍未阐明，但是体外试验显示其具有抗氧化及抗发炎作用，抑制血小板凝集与玻璃酸酶，以及可能因为减少微血管渗透而降低水肿。其临床体内试验则显示具有抗发炎及微血管壁增厚效果。
发明详述
在一个优选的实施方案中，该饮食品添加剂是一种适合口服的剂型，特别是一种固体剂型，即片剂或是胶囊，其中含有20至60％的红藤叶的水萃取物，其中类黄酮含量为2-15％。另一种优选剂型为含有3-90％萃取物的滴剂。其他适当的给药剂型有包衣片剂，糖浆等等。
由前述可知，本发明的主要目的是提供一种预防及缓解下部肢体的轻微至中度慢性静脉机能不全所引起不适症的饮食品添加剂。
本发明的另一个目的是提供一种用于预防及/或缓解下部肢体的轻微至中度慢性静脉机能不全所引起不适症的含植物成分的饮食品添加剂，其中该饮食品添加剂是遵照控制过程制备以保存植物疗效成分的质量。
本发明的另一个目的是提供一种可有效预防及/或缓解下部肢体的轻微至中度慢性静脉机能不全所引起不适症的含植物成分饮食品添加剂。
本发明的另一个目的是提供一种预防及/或缓解下部肢体的轻微至中度慢性静脉机能不全所引起不适症的含植物成分饮食品添加剂，该饮食品添加剂仅有极少或无副作用，因此可以安全地供内服。
本发明的主要部分是制备含有由干红藤叶制备的水萃取物的供口服饮食品添加剂。该水萃取物的特点为富含2至20％，优选为2至10％的具生物活性类黄酮。在本发明的饮食品添加剂中，该类黄酮的含量是相当于所述组合物总重量1至10％的范围内。
下述的实例是为了使更充分理解本发明。这些实施仅供说明本发明的具体实施方案而不是用来限制本发明的范围。
下述的实例仅为说明用，本领域技术熟练的人员应知道，视各别组合物的需要可以对特定条件作适当的调整。下列试验中所用的材料可视为市售品或是由本领域技术熟练的人员由市售品制得。
所述添加剂的基础是红藤叶(folia vitis viniferae L.)的水萃取物。制备萃取物的起始物质是在类黄酮含量达到最适当时所采收的红藤叶。这通常是葡萄的采收季节。小心将叶子干燥后粉碎。为萃取将叶子切割成约为5至10mm大小的碎片。为得到高含量的类黄酮，萃取通常是在高温下进行，优选的温度为60℃至80℃，萃取时间至少6小时最多到10小时。优选的方法为全渗滤法。
由萃取得到的所谓的液体萃取物可以直接用来制备液体剂型。为了得到较浓的萃取物，最好以适当的蒸发器除去至少一部分的溶剂。这个步骤所得的浓萃取物仍然可以直接用来制备液体剂型。
为了制备固体剂型，该浓萃取物以例如真空干燥箱或是真空干燥输送装置进行干燥。在干燥过程中可以加入载体或是赋形剂以利于萃取物的进一步加工。该载体或赋形剂可以是二氧化硅，麦芽糖糊精，葡萄糖糖浆，纤维素等等。
供口服的添加剂是根据食品工业或制药工业所常用的技术制备。优选的给药剂型为片剂，包括包衣片剂或胶囊。但是也可以选择采用液体剂型，优选滴剂。
为了预防及/或缓解下部肢体的轻微至中度慢性静脉机能不全所引起不适症，该种饮食品添加剂的服用剂量相当于每天80-1000mg的萃取物，优选为300-800mg，特别是350-750mg。一天服用的萃取物总量可以分成1至3个胶囊或药片(或是相当剂量的液体剂型)。每天剂量应该服用一次，时间最好在早上。
连续服用6周后应可以感受到明了的改善。进一步长久服用可以维持最佳效果或是进一步改善。
为了确认本发明饮食品补充品效能，安全性及耐受性，即针对下部肢体有轻微至中度慢性静脉机能不全状的一大群具有代表性的病人进行随机的，安慰剂当对照组的双盲平行试验。该试验是根据赫尔辛基宣言及优良临床试验规范进行。结果如下述：
目的-为了评估每天一次剂量360mg及720mg的红藤叶萃取物(RVLE)与安慰剂比较在第I级与第II级前期慢性静脉不全(CVI)病人的效果及安全性。
设计-一个12周，随机性，双盲，安慰剂当对照组，平行进行，多个中心的试验。
病人-年龄介于25至76岁的患有第I级及第II级CVI的男女门诊病人无显著的营养变化，无另外的明显的医学状况而且未用弹性袜，利尿剂或其他会影响体液平衡的药物治疗。
介入-病人随机以安慰剂，360mg RVLE或720mg RVLE治疗，每天一次共12周，试验前及试验后会分别进行2周单盲安慰剂治疗以建立试验前和试验后的基线。试验标准则在基线下，治疗6周及12周后以及停止服药2周后进行评估。
结果测定-主要结果测定：小腿体积变化，以水取代式体积描记器测定。次要结果测定：与基线比较踝及腓周围的变化；主要症状强度的变化(“疲倦，双腿沉重”，“感觉紧张”，“刺痛感觉”，及“脆弱/疼痛”)。
结果-在筛选进来并随机编组的260个病人中有219个依据试验方法完成试验。在欲治疗分析中(N＝257)，以安慰剂治疗的病人(N＝87)在治疗6周之后小腿平均(±SD)体积变化比基线增加15.2+90.1g(取代的水质量)，而在治疗12周之后比基线增加33.7±96.1g.然而，在以根据本发明的RVLE治疗的病人中则体积减少，而且经过12周治疗之后，有效成分治疗组与安慰剂对照组在平均小腿体积的差异上，以360-mg RVLE处理的这组(N＝86)为-75.9g(95％CI：-106.1至45.8g)以720-mg RVLE处理的这组(N＝84)为-99.9g(95％CI：-130.3至-69.6g)。腓周围的变化显示相同的趋势；以RVLE处理的病人中，高剂量(720mg)以及低剂量(360mg，减少的程度较低)在使用一段时间后周围均明显的减少，而在以安慰剂处理的病人其周围则大致不变(在12周后相较于安慰剂估计治疗效果的95％CI：360mg RVLE为-1.40至-0.56cm，720mg RVLE则为-1.73至-0.88cm)。对于踝周围的减少则在质量上是类似而数量上并不明显。
在所有的治疗中，第6周时均可见主要CVI症状有改善，但是在第12周则只有服用有效成分的试验组中获得进一步的改善；在第12周时，与基线比较，服用有效成分的两组比安慰剂这组有明显的改变(p＜0.001)、治疗的耐受性均良好。副作用极少且一般轻微。治疗期间安慰剂组有两例AEs导致住院。另有三位病人在服用安慰剂时因AEs而退出试验。
结论-每天一次360mg及720mg剂量的RVLE显然在治疗轻度CVI时安全且有效，可以减少小腿及周围水肿并同时改善主要CVI相关的症状。水肿减少的程度至少与报告的弹性袜及/或其他消水肿药物的效果相当。较高剂量的耐受性与低剂量相当，但是其结果确是可以得到略佳及更持久的改善。
本领域技术熟练的人员将明了对于明显实质做各种变化及改进均不脱本发明的精神，而且认为所有变化及改进均在本发明的范畴内，如权利要求部分所限定的。尽管前述的本发明组合物在此认为是优选的实施方案，人们明了在下述的权利要求的精神及范畴内可以进行修改，因此不应加以限制而是应视为在等效物的范围内。
Claims (11)
1.一种适于口服给药形式的组合物在制备用于预防和/或治疗下部肢体的轻微至中度慢性静脉不全引起的不适症的饮食添加剂中的用途，其中所述的组合物含有可以预防或治疗下部肢体的轻微至中度慢性静脉不全所引起不适症的活性成分，以及医药上、外观上或饮食上可接受的载体，其中该活性成分主要由含有2-20％类黄酮的红藤叶的水萃取物所组成，其中该红藤叶水萃取物是由包含下列步骤的方法获得：
(a)在葡萄的采收季节节采收红藤叶子；
(b)干燥并碾碎该叶子；
(c)将叶子切成小片；
(d)在60-80℃的温度下在全渗滤器中以水萃取叶子6至10小时；
(e)任选将所得萃取液浓缩。
2.根据权利要求1的用途，其中所述组合物含有20-60％红藤叶水萃取物。
3.根据权利要求1或2的用途，其中该红藤叶水萃取物含有2-10％类黄酮。
4.根据权利要求1或2的用途，其中该类黄酮的含量是相当于所述组合物总重量1至10％的范围内。
5.根据权利要求1或2的用途，其中所述组合物含有黄酮-苷、黄酮醇-苷和类黄酮。
6.根据权利要求1或2的用途，其中所述组合物含有黄酮-葡糖苷酸、黄酮醇-葡糖苷酸和类黄酮。
7.根据权利要求1或2的用途，其中所述组合物含有五羟黄酮-3-0-β-D-葡糖苷酸和异五羟黄酮。
8.根据权利要求1或2的用途，其中所述组合物为颗粒剂、片剂、胶囊、滴剂或糖浆剂型。
9.根据权利要求1或2的用途，其中所述组合物包含分成1-3个胶囊的80-1000mg萃取物。
10.根据权利要求9的用途，其中所述组合物包含分成1-3个胶囊的300-800mg萃取物。
11.根据权利要求10的用途，其中所述组合物包含分成1-3个胶囊的350-750mg萃取物。
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| US20040151794A1 (en) * | 2002-12-31 | 2004-08-05 | Boehringer Ingelheim International Gmbh | Method of improvement of blood circulation |
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