CN1678524A - 含有硅酸的挤出物的制备方法、所述的挤出物、其应用和含有所述挤出物的药物组合物 - Google Patents
含有硅酸的挤出物的制备方法、所述的挤出物、其应用和含有所述挤出物的药物组合物 Download PDFInfo
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- CN1678524A CN1678524A CNA03820875XA CN03820875A CN1678524A CN 1678524 A CN1678524 A CN 1678524A CN A03820875X A CNA03820875X A CN A03820875XA CN 03820875 A CN03820875 A CN 03820875A CN 1678524 A CN1678524 A CN 1678524A
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Abstract
本发明涉及含有硅酸的挤出物的制备方法,包括下列步骤:i)通过在有稳定剂存在的情况下将硅化合物水解成原硅酸和/或其低聚物形成稳定的硅酸,所述的稳定剂为季铵化合物或氨基酸或氨基酸源或其组合;ii)将稳定的硅酸与达硅酸用载体的载荷容量的用量的载体混合;和iii)挤出所得混合物,由此形成挤出物;本发明涉及使用该方法得到的挤出物、涉及挤出物在生产动物饲料、饲料添加剂、人食品和/或食品添加剂以及在药物制剂或化妆品制剂中的应用和在治疗感染、指甲、毛发、皮肤、牙齿、胶原蛋白、结缔组织、骨、骨质减少、细胞传代和变性(老化)过程中的应用并涉及含有挤出物的药物组合物。
Description
本发明涉及含有硅酸的挤出物的制备方法、所述的挤出物、其特定的应用并涉及含有使用所述方法得到的挤出物的药物组合物。
据报导在诸如硅藻、累积Si的植物、鸟类和哺乳动物的几种生物体中硅(Si)具有重要作用。经证实结缔组织成分以及诸如骨和软骨这类其它更特殊组织的形成依赖于Si的状态。膳食Si缺乏导致骨变形、皮质较薄和骨基质钙化较少(Carlisle,1989,有关硅参见:《营养必需矿物元素手册》(Handbook of Nutritionally Essential MineralElements),ed.B.L.De1l和R.A.Sunde,Marcel Dekker Inc.,NewYork,pp.603-618)。大鼠丧失硅导致骨无机质组成改变且骨特异性磷酸酶活性降低(Seabom等,1994,《微量元素实验药物杂志》(JTraceElem Exp Med),7,11)。在对各种疾病的前期临床和临床研究中报导了硅化合物的治疗应用,诸如骨质疏松症、动脉粥样硬化、神经变性疾病、高血压、皮肤老化、脆性毛发和脆性指甲、真菌感染、免疫缺陷和一般与结缔组织相关的疾病。
硅的生物利用度主要取决于其化学形式。固体膳食硅化合物具有低溶解度且难以在胃肠道中吸收。在诸如水和啤酒这类饮料中发现的可溶性硅化合物易于吸收且将其视为硅的生物适合性来源。存在于这些饮料中的水溶性硅化合物的原硅酸仅在稀释浓度下稳定。描述了原硅酸与诸如季铵化合物和氨基酸这类稳定剂的浓缩复合物(″含有稳定的原硅酸的制剂和生物制剂″-US 5,922,360和EP 0473922B1)。当作为液体浓缩物给药时,发现这些原硅酸的稳定形式与其它在单位和人体内的硅化合物相比具有极高的生物利用度(Calomme等,1998,“在健康受试者中进行的硅补充剂的比较生物利用度研究”-《非肠道和肠道营养学杂志》(Journal of Parenteral and Enteral Nutrition),22,S12和Van Dyck等,1999,“来自食品和食品添加剂的硅的生物利用度”-《分析化学Fresenlus杂志》(Fresenlus Journal of AnalyticalChemistry),363,541-544)。当考虑到重要问题、诸如给药的精确性和依从性时,固体盖仑剂型比液体制剂更为优选。
进行几种实验以便配制用诸如氯化胆碱或氨基酸源这类季铵化合物稳定的硅酸的生物适合性固体盖仑制剂。制备这类制剂极为困难,因为原硅酸快速转化成非生物适合性凝胶和沉淀。实际上,添加固体或半固体赋形剂而不添加无毒性的溶剂导致原硅酸聚合或胶凝成大分子,由此降低最终制剂的生物利用度。用胆碱稳定的硅酸的液体基质直接填充胶囊或甲基纤维素胶囊在稳定性试验中温育时使胶囊变形和渗漏。诸如氯化胆碱这类原硅酸的稳定剂极易吸湿且从胶囊周围吸水,最终产生变形胶囊。
本发明解决了这一难题并在第一个方面中提供了制备含有生物适合性硅酸的挤出物的方法,包括下列步骤:
i)通过在有稳定剂存在的情况下将硅化合物水解成原硅酸和/或其低聚物形成稳定的硅酸,所述的稳定剂为季铵化合物或氨基酸或氨基酸源或其组合;和
ii)将稳定的硅酸与达到硅酸用载体的载荷容量的用量的载体混合;和
iii)挤出所得混合物,由此形成挤出物。
本发明在第二个方面中提供了所述的挤出物在生产动物饲料或饲料添加剂、人食品和食品添加剂以及在药物制剂或化妆品制剂中的应用和在治疗感染、指甲、毛发、皮肤、牙齿、胶原蛋白、结缔组织、骨、骨质减少、细胞传代和变性(老化)过程中的应用。
本发明的第三个方面涉及含有所述挤出物的药物组合物。
在本发明优选的实施方案中,使用原硅酸及其低聚物。原硅酸(OSA)的聚合物为由数百或数千称作单体(OSA)的单元形成的大分子,而低聚物为中间大小-远大于单体(OSA)、但小于大分子的分子(Brinker CJ等,《溶胶-凝胶科学:溶胶-凝胶处理的物理和化学》(Sol-Gel Science,The physiscs and Chemistry of Sol-gel processing),Academic Press,Boston,p.5)。一般来说,原硅酸的低聚物含有至多约100个原硅酸单元,诸如2-50、2-40或2-30个原硅酸单元。作为原硅酸的前体,使用可水解的硅化合物,诸如硅卤化物、硅酯类、硅酸盐或烷基硅烷醇化合物,诸如乙氧基硅烷醇。作为稳定剂,可以使用:季铵化合物,诸如氯化胆碱;氨基酸,诸如脯氨酸、丝氨酸、赖氨酸、精氨酸、甘氨酸或其组合物;或氨基酸源,诸如多肽类和蛋白质水解产物,诸如猪胶原蛋白或明胶。本发明特别优选的实施方案是,其中稳定的硅酸及其低聚物含有2.5-3.5%体积的硅含量、65-75%重量的胆碱含量和15-25%重量的水含量。
为了提供稳定的硅酸的生物适合性固体形式,加入可以使用挤出工艺的载体赋形剂。可以用作稳定硅酸载体的典型化合物为纤维素或其衍生物,诸如微晶纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素和羧甲基纤维素钠。其它载体或与纤维素的组合可以选自:糖类,诸如乳糖、果胶和藻酸盐;多糖类和寡糖类,诸如麦芽糖糊精、葡聚糖及其衍生物、淀粉及其衍生物;和天然和半合成纤维;蛋白质和蛋白质水解产物。
在本发明优选的实施方案中,将微晶纤维素用作稳定硅酸的载体。这使得可以挤出塑性团并将其球化成具有所需有限颗粒大小分布的颗粒。在优选的实施方案中,硅酸的载荷容量为<50%,这意味着将最大值为50%重量稳定的硅酸与50%重量的微晶纤维素混合并加入了足以获得必需的颗粒特性的适宜体积的水。更优选的实施方案为使用35%重量的稳定硅酸与65%重量的微晶纤维素。
EP 1 110 909 A1中公开了通过使用溶剂制备的基于硅酸的制剂。
在本发明优选的实施方案中,将挤出的条转入球化器,其中在与旋转的摩擦片接触时,它们即刻被粉碎成颗粒。通过流化床干燥或优选使用70℃最高温度的另一种方法将获得的颗粒干燥成丸粒。优选将干燥后丸粒的最终水含量保持在5%重量以下。优选避免较高的水浓度或高于70℃的干燥温度以限制稳定的硅酸缩聚。筛析获得的丸粒显示在实施优选的方法后,90%以上的丸粒具有800-1200μm大小(参见附图1)。可以将获得的丸粒包囊、压制成片剂或用作药物制剂中的成分或用于制备食品或动物饲料。
附图1:通过挤压-球化胆碱稳定的硅酸与作为载体的微晶纤维素获得的丸粒的颗粒大小分布。
可以通过口服或任意其它合适的方式给予本发明的硅酸挤出物以预防和治疗:心血管疾病,诸如动脉粥样硬化;肌骨骼病,诸如骨质减少和腱炎;带有粘膜破坏的慢性感染;鼻窦炎和溃疡形式;感染,诸如皮肌炎;神经性疾病;变性(老化)-过程;免疫缺陷;和侵害结缔组织和诸如骨、牙齿、指甲、毛发和皮肤这类特殊组织的疾病。
基于下面的附图和实施例理解本发明提及和其它的特征和优点。这些实施例用于解释目的而不用来限定本发明的范围。
制备实施例A
用干盐酸处理氯化胆碱。向形成的胆碱溶液中加入四氯化硅(IV)(比例SiCl4与氯化胆碱:1mol/1-5mol)。通过加入水(冰/冰水)水解所得溶液,同时在-10℃--30℃温度范围内冷却。通过加入氢氧化钠中和该溶液并将温度维持在低于0℃。最终的pH为1-1.5。在用活性炭纯化后,过滤出沉淀与活性炭。通过在真空中蒸馏减少水含量,直到获得含有2.5-3.5%体积的硅、65-75%重量的胆碱和15-25%重量的水的制剂为止。在连续混合的情况下将35%的稳定硅酸溶液(210g)缓慢加入到65%微晶纤维素(Avicel pH 101或Vivapur 101型,1390g)。加入软化水(约Avicel重量的17%)以获得所需的颗粒特性。使用篮式挤出机(Caleva Model 10,Sturminster Newton,UK)挤压湿团。在2-3分钟过程中以750rpm使挤出物球化(Caleva Model 120球化器,Sturminster Newton,UK)。将所得球干燥至其水含量低于如通过卡尔·费歇尔滴定测定的5%。接触空气的丸粒如表1中所示快速吸水。丸粒的硅含量为0.7-1.2%重量。使用29Si-NMR的结构表征在属于碳(C)结合的硅(Si)的光谱区-30--70ppm内没有显示出信号。光谱在分别属于Q0、Q1、Q2、Q3和Q4类特征的-72、-82、-92、-102和-112周围显示出共振。在具有pH 9.5的1ml缓冲液或人工胃液R(欧洲药典,第4版,p.328)中保温350mg丸粒后,在29Si-NMR光谱中发现了种类Q(原硅酸)的主要信号。
表1:获自胆碱稳定的硅酸的挤出物的丸粒中的水含量。
在室温下接触空气的时间(分钟) | 水含量(%) |
0 | 4.91 |
15 | 5.15 |
180 | 7.95 |
制备实施例B
-溶液A:用干盐酸处理氯化胆碱。向形成的胆碱溶液中加入四氯化硅(IV)(比例SiCl4与氯化胆碱:1mol/1-5mol)。
-溶液B:用水制备猪明胶水解产物的溶液(1-5g明胶水解产物/100ml水)。
混合溶液A和B且此后即刻通过加入水(冰/冰水)水解所得溶液,同时在-10℃--30℃温度范围内冷却。通过加入氢氧化钠中和该溶液并将温度维持在低于0℃。最终的pH为1-1.5。在用活性炭纯化后,过滤出沉淀与活性炭。通过在真空中蒸馏减少水含量。在连续混合的情况下将35%的稳定硅酸溶液(210g)缓慢加入到65%微晶纤维素(Avicel pH101或Vivapur 101型,1390g)。加入软化水(约Avicel重量的17%)以获得所需的颗粒特性。使用篮式挤出机(Caleva Model 10,Sturminster Newton,UK)挤压湿团。在2-3分钟过程中以750rpm使挤出物球化(Caleva Model 120球化器,Sturminster Newton,UK)。将所得球干燥至其水含量低于如通过卡尔·费歇尔滴定测定的5%。接触空气的丸粒如表1中所示快速吸水。丸粒的硅含量为0.2-1.2%重量。
制备实施例C
用干盐酸处理氯化胆碱。向形成的胆碱溶液中加入四氯化硅(IV)(比例SiCl4与氯化胆碱:1mol/1-5mol)。通过加入水(冰/冰水)水解所得溶液,同时在-10℃--30℃温度范围内冷却。通过加入氢氧化钠中和该溶液并将温度维持在低于0℃。最终的pH为1-1.5。在用活性炭纯化后,过滤出沉淀与活性炭。按照1∶1的比例加入胶原蛋白水解产物在水中的溶液(5%w/v)。通过在真空中蒸馏减少水含量。在连续混合的情况下将35%的稳定硅酸溶液(210g)缓慢加入到65%微晶纤维素(Avicel pH 101或Vivapur 101型,1390g)。加入软化水(约Avicel重量的17%)以获得所需的颗粒特性。使用篮式挤出机(Caleva Model 10,Sturminster Newton,UK)挤压湿团。在2-3分钟过程中以750rpm使挤出物球化(Caleva Model 120球化器,Sturminster Newton,UK)。将所得球干燥至其水含量低于如通过卡尔·费歇尔滴定测定的5%。接触空气的丸粒如表1中所示快速吸水。丸粒的硅含量为0.3-1.2%重量。
制备实施例D
用干盐酸处理氯化胆碱。向形成的胆碱溶液中加入四氯化硅(IV)(比例SiCl4与氯化胆碱:1mol/1-5mol)。通过加入水(冰/冰水)水解所得溶液,同时在-10℃--30℃温度范围内冷却。通过加入氢氧化钠中和该溶液并将温度维持在低于0℃。最终的pH为1-1.5。在用活性炭纯化后,过滤出沉淀与活性炭。通过在真空中蒸馏减少水含量。在连续混合的情况下将35%的稳定硅酸溶液(210g)缓慢加入到65%微晶纤维素(Avicel pH 101或Vivapur 101型,1390g)和15%干胶原水解物中。加入软化水(约Avicel重量的17%)以获得所需的颗粒特性。使用篮式挤出机(Caleva Model 10,Sturminster Newton,UK)挤压湿团。在2-3分钟过程中以750rpm使挤出物球化(Caleva Model 120球化器,Sturminster Newton,UK)。将所得球干燥至其水含量低于如通过卡尔·费歇尔滴定测定的5%。接触空气的丸粒如表1中所示快速吸水。丸粒的硅含量为0.3-1.2%重量。
制剂实施例A
将按照制备实施例制备的丸粒包囊入o号大小的vegecaps。将胶囊压入铝-铝泡罩或包入高密度聚乙烯(polyethelene)(HDPB)瓶并封盖。密封瓶并包封硅胶小药囊。将包入的丸粒在40℃和75%相对湿度下保温6个月。在该保温期后,发现包装材料中的丸粒的水含量与保温前的水含量相差无几(参见表2)。
表2:获自在40℃和75%相对湿度下保温后的胆碱稳定的硅酸挤出物的丸粒的水含量
丸粒水含量(%) | |||
包装材料 | 保温前 | 保温3个月 | 保温6个月 |
铝-铝泡罩 | 7.0 | 7.0 | 6.6 |
HDPE瓶 | 6.5 | 6.9 | 7.3 |
制剂实施例B
将按照制备实施例制备的丸粒包囊入o号大小的vegecaps。每粒胶囊中丸粒的平均重量为503mg,等于每粒胶囊中4.5mg的硅剂量。
包括12位健康受试者(6位男性,6位女性,年龄:23-51岁)签署同意书。无一人在开始研究前的3个月内服用Si补充剂。如下在交叉方案中口服给予每位禁食受试者Si:9mg液体胆碱稳定的原硅酸形式的Si(参见附图2″液体″)且在1周后为2粒丸粒状挤出物的胶囊(参见附图2″挤出物″)。在补充前和partem后1、2、4、6和8小时将血样采集入不含Si的聚丙烯管。在实验过程中给予硅补充剂后的2小时和6小时时消耗相同的膳食。用AAS(Zeeman原子吸收分光计,Perkin ElmerCorp.,参见附图2)测定血清中的Si浓度。使用线性梯形规则计算时间曲线下的面积并用作给予补充剂后8小时期限中总Si吸收(″生物利用度″)的参数(参见附图3)。稳定硅酸的挤出形式的生物利用度可以完全与液体形式相比拟且两种形式在血清中具有相似的动力学分布。
附图2:分别补充液体稳定的原硅酸(″液体″)和挤出的稳定硅酸(″挤出物″)后12位健康受试者中自基线水平的血清硅浓度的增加。在两种情况中补充剂量均为9mg Si。
附图3:分别补充液体稳定的原硅酸(″液体″,9mg Si)和挤出的稳定硅酸(″挤出物″,9mg Si)后0-8小时期限内血清中硅的总吸收。
制剂实施例C
将按照制备实施例A、B、C或D制备的丸粒包囊入o号大小的vegecaps。每粒胶囊中丸粒的平均重量为324mg,等于每粒胶囊中3mg的硅剂量。
12个月中给记录有髋部中骨质减少的4位女性(T得分等于或小于-1.5,参见表3)补充丸粒状挤出物(每天1粒胶囊,2位患者)或安慰剂(对照组,1粒含324mg微晶纤维素的胶囊,2位患者)。每天给全部患者补充1000mg钙和20微克胆钙化醇。使用DEXA在基线(T0)和补充12个月后(T12)测定髋部中的骨无机质密度(BMD)。
表3:使用颗粒化挤出物补充12个月后髋部骨无机质密度的改变
基线下的T得分 | BMD改变(T12-T0,%) | |
颗粒化挤出物(3mg Si/天) | ||
受试者1 | -2.02 | +0.72 |
受试者2 | -2.06 | +0.87 |
对照组(安慰剂) | ||
受试者3 | -1.87 | -1.40 |
受试者4 | -1.50 | -1.05 |
发现使用颗粒化挤出物补充使骨无机质密度增加,而安慰剂组的BMD下降。
这些结果表明用颗粒化挤出物补充可以用于防止一旦发生的进一步骨丢失。
Claims (14)
1.制备含有硅酸的挤出物的方法,包括下列步骤:
i)通过在有稳定剂存在的情况下将硅化合物水解成原硅酸和/或其低聚物形成稳定的硅酸,所述的稳定剂为季铵化合物或氨基酸或氨基酸源或其组合;
ii)将稳定的硅酸与达到硅酸用载体的载荷容量的用量的载体混合;和
iii)挤出所得混合物,由此形成挤出物。
2.权利要求1的方法,其中硅酸为原硅酸和/或低聚物。
3.权利要求1-2的方法,其中所述的季铵化合物为氯化胆碱。
4.权利要求1-2的方法,其中所述的氨基酸为脯氨酸、丝氨酸、赖氨酸、精氨酸、甘氨酸或其组合。
5.权利要求1-2的方法,其中所述的氨基酸源为多肽或蛋白质水解产物。
6.权利要求1-5的方法,其中稳定的硅酸含有2.5-3.5%体积的硅含量、65-75%重量的胆碱含量和15-25%重量的水含量。
7.权利要求1-6的方法,其中将所述的载体与稳定的硅酸分别按65-50%与35-50%的比例混合。
8.权利要求1-7的方法,其中所述的载体为:纤维素或其衍生物,诸如微晶纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素和羧甲基纤维素钠;和/或选自糖类的其它载体或组合,诸如乳糖、果胶和藻酸盐、多糖类和寡糖类,诸如麦芽糖糊精、葡聚糖及其衍生物、淀粉及其衍生物和天然和半合成纤维、蛋白质和蛋白质水解产物。
9.权利要求1-8的方法,其中所述的载体为微晶纤维素且稳定的硅酸的载荷容量为<50%。
10.权利要求1-9的方法,其中将所述的挤出物球化成颗粒。
11.权利要求1-10的方法,其中干燥所述颗粒,所述颗粒优选具有约800-约1200μm的颗粒大小。
12.使用权利要求1-11所述方法得到的挤出物。
13.权利要求12的挤出物在生产动物饲料、饲料添加剂、人食品和/或食品添加剂以及在药物制剂或化妆品制剂中的应用和在治疗感染、指甲、毛发、皮肤、牙齿、胶原蛋白、结缔组织、骨、骨质减少、细胞传代和变性(老化)过程中的应用。
14.含有权利要求12的挤出物的药物组合物。
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CN102834101A (zh) * | 2010-02-24 | 2012-12-19 | 拜尔创新有限责任公司 | 用于促血管生成疗法的含硅的可生物降解的材料 |
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NL9400189A (nl) * | 1994-02-07 | 1995-09-01 | Bio Pharma Sciences Bv | Gestabiliseerd orthosiliciumzuur bevattend preparaat, een werkwijze voor het bereiden daarvan en een biologisch preparaat. |
FR2799758B1 (fr) | 1999-10-15 | 2002-05-17 | Exsymol Sa | Complexe a base d'acide orthosilicique biologiquement assimilable, se presentant sous forme solide, stable et concentree, et procede de preparation |
EP1110909A1 (en) * | 1999-12-24 | 2001-06-27 | Bio Minerals N.V. | Method for preparing ortho silicic acid, ortho silicic acid as obtained, and its use |
EP1391426A1 (en) | 2002-08-12 | 2004-02-25 | Bio Minerals N.V. | Method for the preparation of a silicic acid comprising extrudate, said extrudate, its use and a pharmaceutical composition comprising the said extrudate |
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CN102256502A (zh) * | 2008-12-23 | 2011-11-23 | 阿格拉集团公司 | 啤酒及啤酒基饮料及调节这些饮料中多酚和硅含量的方法 |
CN102834101A (zh) * | 2010-02-24 | 2012-12-19 | 拜尔创新有限责任公司 | 用于促血管生成疗法的含硅的可生物降解的材料 |
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CN107988292A (zh) * | 2018-01-18 | 2018-05-04 | 江苏江山聚源生物技术有限公司 | 提高重组人源胶原蛋白稳定性的发酵工艺 |
CN107988292B (zh) * | 2018-01-18 | 2023-12-26 | 江苏江山聚源生物技术有限公司 | 提高重组人源胶原蛋白稳定性的发酵工艺 |
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CN101829143A (zh) | 2010-09-15 |
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DE60327231D1 (de) | 2009-05-28 |
CY1109228T1 (el) | 2014-07-02 |
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US8771757B2 (en) | 2014-07-08 |
CA2494165C (en) | 2009-05-26 |
PT1551763E (pt) | 2009-07-07 |
DK1551763T3 (da) | 2009-07-20 |
SI1551763T1 (sl) | 2009-10-31 |
JP4727227B2 (ja) | 2011-07-20 |
IL166779A (en) | 2010-05-17 |
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