CN100376267C - 一种包含含钙包衣和干燥植物提取物的药物制剂 - Google Patents
一种包含含钙包衣和干燥植物提取物的药物制剂 Download PDFInfo
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- CN100376267C CN100376267C CNB028114620A CN02811462A CN100376267C CN 100376267 C CN100376267 C CN 100376267C CN B028114620 A CNB028114620 A CN B028114620A CN 02811462 A CN02811462 A CN 02811462A CN 100376267 C CN100376267 C CN 100376267C
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- calcium
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- plant extract
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Abstract
本发明涉及一种含钙盐和干燥植物提取物的药物制剂,其形式是包衣片剂,其中芯片至少为一种干燥的植物提取物,被至少一层含至少一种钙盐的包衣包覆。芯片的植物提取物选自:穗花牡荆;射干;黑升麻;红三叶;月见草;野生大豆;锯棕果;异株荨麻;南瓜;非洲臀果木;及上述植物提取物的适宜混合物。
Description
本发明涉及一种含钙盐和干燥植物提取物的药物制剂,该药物制剂的用途,以及制备方法。
17β-雌二醇正常形成于卵巢中[也被称作E2],其在人类和动物有机体中一般具有增强生殖的作用。除了能控制雌性经期外,其还具有维持骨代谢体内平衡的作用,以及阻止血管内皮形成动脉粥样斑块的作用。
在更年期期间,由于卵巢功能停止而使雌二醇水平降低。血液中缺乏足够高水平的雌二醇,破骨细胞的活性使骨质降低-所谓的骨质疏松症-控制着骨组织,其伴随着骨折危险的增加。
最近发现由缺乏性激素而引起的骨质疏松症并不限制于女性,而发生在一些老年人中。骨质疏松在男性中也会由于缺乏性激素而形成,尤其是患有前列腺疾病的男性。
典型的预防和治疗女性患者的方法在于通过施用天然和合成的雌激素以替代缺乏的天然雌激素。尤其是出于预防目的,男性和女性每天服用大约1克钙的钙剂量。
然而,施用雌激素,如17β-雌二醇或其化学衍生物会伴随已知严重的对于子宫的副作用,及增加血栓形成的几率,增加体重等副作用。
因此,为了找到既能产生雌激素样作用,又没有不利的副作用或使副作用大大降低的药物,现有技术中已经进行了很多尝试。其中使用了很多植物提取物,这些提取物显示了预防骨质疏松的作用,却不具有对子宫的不利作用。
例如,本申请人的WO99/47149(=EP1064009A1)公开了从iridaceae,尤其是从黑升麻(Cimicifuga racemosa)和射干(Belamcanda chinensis)得到的提取物,其中含有异类黄铜鸢尾黄素(isoflavonoid tectorigenin),对于子宫没有雌激素样作用,而作用于下丘脑-脑垂体轴,心血管系统和骨骼,因此,这些植物提取物可用于预防和治疗骨质疏松症。
将钙制剂用于预防骨质疏松症,这在现有技术中是已知的。最终作为考虑的药物制剂除了注射溶液外,优选为口服泡腾片。例如,泡腾片类可以具有以下组分:
含有500mgCa2+的片剂:1250mg的碳酸钙,2050mg的柠檬酸,其它成份:乳糖1H2O,大分子醇6000,聚乙烯吡咯酮(povidon),甜精钠,糖精钠2H2O,二甲硅油(Dimeticon)350,高分散硅土,硬脂酸大分子醇400,山梨酸,矫味剂。
含有1000mgCa2+的片剂:4954mg的乳糖葡萄糖酸钙,900mg的碳酸钙,其它成份:柠檬酸,甜精钠,糖精钠,甘露醇,大分子醇4000,碳酸氢钠,矫味剂。
为了给患者提供多种用途,也出于降低成本的原因,具有抗骨质疏松作用的、含有干燥植物提取物的高含量钙的联合钙制剂更受到人们的欢迎。
直接将干燥的提取物混合到钙泡腾片是不可行的,一方面是由于干燥的提取物对于水媒介中的酸高度敏感,另一方面是由于干燥的提取物在酸性介质中的水溶性差。而且,对于潮气敏感的泡腾片会由于干燥提取物的强吸湿性而受到破坏。
装入常用的凝胶胶囊的做法也同样被排除,因为这种胶囊一般是不防水汽的,因此会使干燥的植物提取物发生降解和/或聚合,因为生物利用度、释放和/或功效的不确定而使药品质量无法的得到保证。而且,这种凝胶胶囊的稳定性也不能得到保证,在文献中有类似的实例报导,如当植物提取物被装入凝胶胶囊中,提取物与凝胶发生交联,而且干燥的提取物吸水会导致成份的显著变化。
因此,如含有钙和干燥的植物提取物混合物的糖衣片、糖衣丸的制剂为较佳。正如上所述,钙含量为500mgCa2+和更高,加上用于制造糖衣丸所需的较大量的辅助剂,会得到大小、重量都不会被患者接受的大糖衣丸。
已知的固体制剂是钙与维生素D3的联合制剂,其形式是咀嚼片,例如,Sellhopsweg 1,D-22459 Hamburg,Strathmann AG+Co.公司的Ossofortinforte咀嚼片。
用于治疗骨质疏松症的这种咀嚼片具有如下成份:
1500.3mg的碳酸钙(相当于600mgCa++),维生素D3干浓度(100,000I.U./g)400I.U.,其它成份:木糖醇,玉米淀粉,糖精钠,矫味剂,硬脂酸镁。
由于上述原因,截至目前,现有技术中还没有能用于上述预防和/或治疗骨质疏松症的钙制剂与植物提取物的联合制剂。
本发明的一个目的是提供一种药物制剂,其结合了各优势:即,既是钙制剂的替代品,在需要的时候,也是维生素D3的替代品,还具有干燥植物提取物预防和/或治疗上述骨质疏松症的优势。
本发明的目的通过包括至少一种干燥的植物提取物的内部压体,其由至少一层包衣包裹,该包衣至少为一种钙盐的药物制剂而实现。
关于用途目的,通过在治疗多种病因的骨质疏松症中的应用实现。
而方法目的是通过将压体芯片由干燥的植物提取物制备,其中干燥的植物提取物选自下述植物提取物:穗花牡荆;射干;黑升麻;红三叶;月见草;野生大豆;锯棕果;异株荨麻,尤其是其根部;南瓜,尤其是其种子;非洲臀果木;及上述植物提取物的适宜混合物;
所得芯片被传送至到至少含一种钙盐的包衣混合物的第一部分含量上,然后用包衣混合物的第二部分含量进行填充;然后
将芯片和两部分含量的含钙盐的包衣混合物组成的完整配料进行压片,从而制备成药物制剂;
其中钙盐选自:
碳酸钙;碳酸氢钙;卤化钙,尤其是氯化钙和碘化钙;磷酸钙;磷酸氢钙,尤其是磷酸一氢钙;磷酸氢二钙,乳酸钙;乳糖酸钙(calciumlactonate);琥珀酸钙;酒石酸钙;葡糖酸钙;以及适宜的上述盐的混合物而实现。
本发明尤其涉及一种含有钙盐和干燥植物提取物的药物制剂,其中,该药物制剂包括至少一种植物提取物的内部压体(inner pressed body),该压体被至少一层包衣包覆,包衣至少由一种钙盐组成。
本发明的药物制剂可能是首次提供有效抑制骨质疏松症的干燥植物提取物如黑升麻(Cimicifuga racemosa),射干(Belamcanda chinensis),穗花牡荆(Vitex agnus castus)或者异株荨麻根(Urtica dioica radix)及其混合物与钙的联合制剂,该制剂的各含量适宜。该制剂尤其具有的优点是其包衣不是现有技术中常用的由辅料所组成的包衣,而基本上只含有活性物质钙。
关于干燥植物提取物的制备,本申请人的PCT申请WO99/47149在此作为参考而全文引用。除其中所述溶剂外,还有可能用有机-水溶剂的混合物,仅用水,或用超临界CO2(如,提取锯棕果(Serenoa repens)时)的方法提取植物。
本发明的药物制剂通过将例如结合水的辅料添加至糖衣丸或膜衣片剂中的方法制备了强吸水的植物提取物制剂,植物提取物制剂质量低、体积小,被包裹在惰性包衣内,该包衣为钙盐形式并具有防止潮气的作用。
结果,干燥植物提取物与钙、辅料的最佳比例即可获得,有时甚至除少量的润滑剂外,可能完全没有辅料。
因此,本发明可能是首次提供干燥植物提取物,钙盐以及在需要时可能还有维生素D3的联合制剂,其含有的钙含量约为每天1000mg Ca2+离子,该含量是无需施用其它钙制剂即可达到预防和/或治疗的所需量。
本发明的优选实施方案的特征在于在含钙的包衣中和/或在内部干燥的植物提取物压体(pressed body)中还含有胆骨化醇类(cholecalciferols),尤其是胆骨化醇(Colecalciferol(维生素D3))。
此外,药物制剂中含有至少一种氟化盐,尤其是氟化钠,氟化钠优选存在于内部压体中。
优选的药物制剂的特征在于,干燥的植物提取物选自下列植物的提取物:穗花牡荆(Vitex agnus castus(chaste tree));射干(Belamcandachinensis(leopard lily/blackberry lily));黑升麻(Cimicifuga racemosa(black cohosh));红三叶(Triifolium pratenseL.(purple trefoil));月见草(Oenothera biennis hom.(樱花草));野生大豆(Glycine soja(大豆));锯棕果(Serenoa repens(saw-palmetto));异株荨麻(Urtica dioica(stingingnettle)),尤其是其根部;南瓜(Cucurbita pepo(pumpkin)),尤其是其种子;非洲臀果木(Pygeum africanum);及上述植物的适宜混合物。
本发明的药物制剂的优选实施方案在于钙盐选自:碳酸钙;碳酸氢钙;卤化钙,尤其是氯化钙、碘化钙;磷酸钙;磷酸氢钙,尤其是磷酸一氢钙;磷酸氢二钙,乳酸钙;乳糖酸钙(calcium lactonate);琥珀酸钙;酒石酸钙;葡糖酸钙;其它钙盐;以及适宜的上述盐的混合物。
本发明优选的药物制剂是包衣片剂,其中,包衣是至少一种钙盐的压体,芯片是至少一种上述干燥植物提取物的压体,芯片也可以含有维生素D3。
然而,药物制剂也可以是dot片剂(牛眼片剂(bull-eye tablet)),尽管其芯片仍完全被包衣包覆,但无须在包衣内的中央。
本发明的药物制剂还可能由多个含钙层构成包衣,其中优选每一层含有不同的钙盐。
优选的药物制剂具有的含量,如每个包衣片中钙含量约为50-1000mg,干燥的植物提取物含量约为0.5-100mg。因此,可通过每天服用一至三次即可完全达到建议患者每天服用的约1000mgCa2+的Ca2+离子剂量,及同时服用的具有抗骨质疏松症作用的必要植物提取物和维生素D3的剂量。
一种优选的药物制剂可用聚合物薄膜作为最外层包衣(externalenvelope aufweisen),以改进吞咽特性和在食道滑行的特性,而且,该聚合物薄膜还可阻止灰尘磨损及潮气进入包衣层。然而,这种聚合物外衣不是通常制备中所必需的。
本发明的药物制剂需要很少的辅料或甚至不含辅料。然而,如果需要,也可以使用常用的制剂辅料,如崩解剂,尤其是基于淀粉和/或其衍生物类;粘合剂,尤其是微晶纤维素,阿拉伯胶;润滑剂,尤其是硬脂酸和/或硬脂酸镁;以及增滑剂,尤其是聚乙二醇及类似物。
本发明优选的药物制剂适用作治疗多种病因的骨质疏松的药物,尤其优选用于预防和/或治疗女性和男性老年人中由于缺乏性激素而导致的骨质疏松症。
本发明的药物制剂的制备按如下原则进行:
首先利用干燥的植物提取物制备压体芯片,其中,干燥的植物提取物选自:穗花牡荆;射干;黑升麻;红三叶;月见草;野生大豆;锯棕果;异株荨麻,尤其是其根部;南瓜,尤其是其种子;非洲臀果木;及上述植物的适宜混合物。
该芯片被传送到至少含一种钙盐的包衣混合物的第一部分含量上,然后用包衣混合物的第二部分含量进行填充;将得到的由芯片和两部分含量的含钙盐的包衣混合物组成的完整配料进行压片,从而制备成药物制剂。钙盐选自:
碳酸钙;碳酸氢钙;卤化钙,尤其是氯化钙和碘化钙;磷酸钙;磷酸氢钙,尤其是磷酸一氢钙;磷酸氢二钙,乳酸钙;乳糖酸钙(calciumlactonate);琥珀酸钙;酒石酸钙;葡糖酸钙;其它钙盐;以及适宜的上述盐的混合物。
优选的芯片是在包衣混合物的第一部分含量的中央,从而得到所谓的包衣片。然而,也可以制备所谓的牛眼片剂(bull-eye-片(dot片)),其芯片虽被包覆,但不在包衣内的中央。
可使用商业途径可获得的压片机进行压片,如FETTE,KORSCH和KILIAN公司的产品。尤其适用的是诸如MANESTY公司的能同时运行的双层旋转压片机。使用双层旋转压片机时,在旋转压片机上的一层压制芯片,再由中间传送装置传送至旋转压片机第二层的中央位置,然后压制包衣。
本发明的药物制剂也可以用两个旋转压片机进行压片,在其中一个压片机上压制芯片,而在第二个压片机上压制包衣。
用双层旋转压片机制造本发明药物制剂的包衣片剂的优点是可在压片机的第一层预先压制芯片,因此所得芯片比较软。在双层旋转压片机的第二层最终压制时,则干燥的植物提取物芯片和钙包衣能很好地粘合起来。
例如,用这种方法制备的包衣片剂具有以下组成:
包衣:CaCO3 1250mg(相当于500mg的Ca2+)
维生素D3 200I.U.
芯片:黑升麻 20mg
(干燥的提取物)
辅料:硬脂酸镁 8mg
硬脂酸 4mg
微晶纤维素 40mg
阿拉伯胶 50mg
包衣片剂实例具有的优点是既可为口服钙和维生素D3的替代品,又具有黑升麻干燥提取物的必需剂量。通过每天口服不超过2片的剂量即可达到预防和/或治疗骨质疏松症的推荐剂量,即每天1000mg的Ca2+,或400I.U.的维生素D3以及同时所需的40mg的黑升麻干燥提取物。
当然,根据一系列适应症,也可以制备其它种类植物的干燥提取物或不同种提取物混合物的芯片。例如,如适用于治疗前列腺疾病的本发明的包衣片剂的芯片可以包含锯棕果的提取物。
Claims (26)
1.含钙盐和干燥植物提取物的药物制剂,其特征在于,该药物制剂包括至少一种干燥的植物提取物的内层压体,其由至少一种含钙包衣包覆,其中该药物制剂每片包衣片的钙含量为50-1000mg,干燥的植物提取物含量为0.5-100mg,且所述干燥的植物提取物选自下述植物提取物:穗花牡荆;射干;黑升麻;红三叶;月见草;野生大豆;锯棕果;异株荨麻;南瓜;非洲臀果木;及上述植物提取物的适宜混合物。
2.根据权利要求1所述的药物制剂,其特征在于,所述异株荨麻为其根部;所述南瓜为其种子。
3.根据权利要求1或2所述的药物制剂,其特征在于,所述钙盐选自:碳酸钙;碳酸氢钙;卤化钙;磷酸钙;磷酸氢钙;乳酸钙;乳糖酸钙;琥珀酸钙;酒石酸钙;葡糖酸钙;以及适宜的上述盐的混合物。
4.根据权利要求3所述的药物制剂,其特征在于,所述卤化钙为氯化钙和碘化钙。
5.根据权利要求1所述的药物制剂,其特征在于,该药物制剂是包衣片剂,其中包衣是至少一种钙盐的压体,芯片是至少一种干燥的植物提取物的压体。
6.根据权利要求1所述的药物制剂,其特征在于,该药物制剂是dot片剂。
7.根据权利要求1所述的药物制剂,其特征在于,所述包衣包括多个钙层。
8.根据权利要求7所述的药物制剂,其特征在于,所述多个钙层中的每一层含有不同的钙盐。
9.根据权利要求1所述的药物制剂,其特征在于,该药物制剂还具有聚合物薄膜作为外层包膜。
10.根据权利要求1所述的药物制剂,其特征在于,该药物制剂的包衣片剂的包衣含有相当于500mg Ca2+的1250mg碳酸钙和200I.U.的维生素D3,包衣片剂的芯片含20mg的黑升麻的干燥提取物。
11.根据权利要求1所述的药物制剂,其特征在于,该含钙的包衣和/或干燥植物提取物的内部压体中还含有胆骨化醇类。
12.根据权利要求11所述的药物制剂,其特征在于,所述胆骨化醇类包括胆骨化醇。
13.根据权利要求1所述的药物制剂,其特征在于,该药物制剂还包含至少一种氟化盐。
14.根据权利要求13所述的药物制剂,其特征在于,所述氟化盐为氟化钠。
15.根据权利要求1所述的药物制剂,其特征在于,氟化盐存在于内部压体中。
16.根据权利要求1所述的药物制剂,其特征在于,该药物制剂的辅料包括崩解剂;粘合剂;润滑剂;以及增滑剂。
17.根据权利要求16所述的药物制剂,其特征在于,所述崩解剂为淀粉和/或其衍生物类;所述粘合剂为微晶纤维素、阿拉伯胶;所述润滑剂为硬脂酸和/或硬脂酸镁;所述增滑剂为聚乙二醇。
18.权利要求1-17中任意一项的药物制剂作为药物在治疗多种病因的骨质疏松症中的应用。
19.根据权利要求18的应用,其特征在于所述药物制剂被用作治疗由缺乏性激素而引起的骨质疏松症,用于预防和治疗激素相关的老年病,和相伴随的心血管疾病以及脂代谢紊乱,和相伴随的钙缺乏病症。
20.根据权利要求19所述的应用,其特征在于,所述激素相关的老年病为更年期疾病和前列腺疾病。
21.制备权利要求1-17中任意一项的药物制剂的方法,其特征在于:
压体芯片由干燥的植物提取物制备,其中干燥的植物提取物选自下述植物提取物:穗花牡荆;射干;黑升麻;红三叶;月见草;野生大豆;锯棕果;异株荨麻;南瓜;非洲臀果木;及上述植物提取物的适宜混合物;
所得芯片被传送至到至少含一种钙盐的包衣混合物的第一部分含量上,然后用包衣混合物的第二部分含量进行填充;然后
将芯片和两部分含量的含钙盐的包衣混合物组成的完整配料进行压片,从而制备成药物制剂;
其中钙盐选自:
碳酸钙;碳酸氢钙;卤化钙;磷酸钙;磷酸氢钙;乳酸钙;乳糖酸钙;琥珀酸钙;酒石酸钙;葡糖酸钙;以及适宜的上述盐的混合物。
22.根据权利要求21所述的方法,其特征在于,所述异株荨麻为其根部;所述南瓜为其种子。
23.根据权利要求21所述的方法,其特征在于,所述卤化钙为氯化钙和碘化钙。
24.根据权利要求21-23任意一项所述的方法,其特征在于,芯片在包衣混合物的第一部分含量的中央。
25.根据权利要求21所述的方法,其特征在于,所用辅料是崩解剂;粘合剂;润滑剂;以及增滑剂。
26.根据权利要求25所述的方法,其特征在于,所述崩解剂为淀粉和/或其衍生物类;所述粘合剂为微晶纤维素、阿拉伯胶;所述润滑剂为硬脂酸和/或硬脂酸镁;所述增滑剂为聚乙二醇。
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- 2002-04-10 DK DK02747268T patent/DK1392337T4/da active
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2003
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2004
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1179972A (zh) * | 1997-09-29 | 1998-04-29 | 杨成玉 | 多能口洁泡腾片 |
KR100267576B1 (ko) * | 1998-07-25 | 2000-11-01 | 허계성 | 활성성분을 분리함유한 츄잉 연질정제 및 그의 제조방법 |
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