CN110840866A - 一种细辛脑药物组合物及其在防治神经退行性疾病方面的应用 - Google Patents
一种细辛脑药物组合物及其在防治神经退行性疾病方面的应用 Download PDFInfo
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- CN110840866A CN110840866A CN201810946961.XA CN201810946961A CN110840866A CN 110840866 A CN110840866 A CN 110840866A CN 201810946961 A CN201810946961 A CN 201810946961A CN 110840866 A CN110840866 A CN 110840866A
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- Prior art keywords
- sodium
- asarin
- pharmaceutical composition
- bicarbonate
- asarone
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- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 8
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Abstract
本发明技术方案提供了一种细辛脑药物组合物及其在防治神经退行性疾病方面的应用,该组合物是以细辛脑为药理活性成分,加上药学上常用的碱性物质和其他辅料组成。该组合物可通过适宜的药剂学技术制备成片剂、胶囊剂、颗粒剂及干混悬剂等固体制剂,其可增强细辛脑在酸性溶液中的稳定性,进而可显著提高细辛脑的溶出度与口服生物利用度,可用于临床预防和/或治疗包括阿尔茨海默病(Alzheimer′s disease,AD)、帕金森病(Parkinson′s disease,PD)在内的神经退行性疾病,属于生物医药领域。
Description
技术领域
本发明公开了一种含细辛脑(α-细辛脑和/或β-细辛脑)的药物组合物及其在防治神经退行性疾病方面的应用。其特征是该组合物由细辛脑、碱性物质及其他药用辅料组成,该组合物可提高细辛脑在酸性溶液中的稳定性,还可显著改善口服给药制剂的溶出度与生物利用度。本发明药物组合物可用于预防和/或治疗包括阿尔茨海默病(Alzheimer′sdisease,AD)、帕金森病(Parkinson′s disease,PD)在内的神经退行性疾病,属于生物医药领域。
背景技术
细辛脑,化学名为2,4,5-三甲氧基-1-丙烯基苯,系中药石菖蒲的主要有效成分,具有平喘、止咳、祛痰、镇静、解痉、抗惊厥等作用。平喘:本品可对抗组胺、乙酰胆碱,缓解支气管痉挛;止咳:对咳嗽中枢具有较强的抑制作用;祛痰:本品可使气道分泌物增加,稀释痰液;镇静:可显著降低自发活动而无抑制作用;解痉:类似氨茶碱,有松弛支气管平滑肌的作用;抗惊厥:细辛脑能提高大脑皮层的点刺激阈,抑制电刺激的突触传导及痫性放电。对癫痫大发作有显著疗效。细辛脑有两种同分异构体,分别为顺式(β-细辛脑,CAS:5273-86-9)与反式(α-细辛脑,CAS:2883-98-9)构型。
市售细辛脑(主要活性成分为α-细辛脑,英文名称α-asarone)剂型有注射剂、片剂和胶囊剂。其中,注射剂用于支气管炎、肺炎、哮喘、慢性阻塞性肺病(COPD)的治疗;片剂的适应证为支气管炎和支气管哮喘;胶囊剂则用于控制癫痫大发作。细辛脑属生物药剂学分类(BCS分类)II类药物,其溶解度低、渗透性强,溶出为吸收的限速步骤。细辛脑片剂与胶囊剂的生物利用度低,仅为3%~5%[1]。为提高细辛脑口服制剂的生物利用度,文献报道采用环糊精进行包合,提高了其溶出速率,但在稳定性研究中发现有晶体析出,形成的包合物不够稳定[2]。对比文献1(专利申请号:200510073286.0一种细辛脑口腔崩解片及其制备方法)采用溶剂溶解主药,进而制粒或直接压片,其技术方案中采用有机溶剂溶解主药,对制剂生产车间的环保与防爆要求严苛,实际应用存在困难;由于细辛脑原料药脂溶性强、溶解度低,直接压片法难以提高溶出度。对比文献2(专利申请号:200910089567.X一种低熔点药物固体分散体的制备方法)采用将所有辅料一次性加入,由于混合物料熔点低,药粒间易发生粘连,压片时易发生粘冲现象,亦难以实现工业化生产。
发明内容
发明人经研究发现,细辛脑在酸性溶液中(pH<3.5)易发生降解,这是导致其生物利用度低的重要原因之一。据此,发明人曾尝试使用肠溶片、肠溶胶囊、肠溶颗粒等技术,以期改善其在酸液中的稳定性,进而提高生物利用度。由于上述肠溶包衣等技术使得药物溶出存在时滞效应,口服给药后难以迅速达到有效血药浓度,不能满足临床需要。据此,我们创造性地设想,如在细辛脑药物组合物中加入碱性物质,其可通过中和胃酸使细辛脑保持稳定;同时药物口服后在胃部即可快速溶出而被吸收,将有助于其迅速发挥药效。
经反复研究证实,在细辛脑药物组合物中加入碱性物质确可达到上述预期目标。据此,我们进一步优选了碱性物质的种类和用量。本发明所述的可增强细辛脑在酸液中稳定性的药物组合物,其中的碱性物质为氢氧化钠、氢氧化钾、氢氧化钙、氢氧化铝、碳酸钠、碳酸氢钠、碳酸氢钾、碳酸氢钙、碳酸钙、碳酸镁、碳酸钾、磷酸氢二钠、硬脂富马酸钠、磷酸氢二钾、磷酸氢钙、醋酸钠、乳酸钠、苹果酸钠、苹果酸钙、精氨酸、赖氨酸、组氨酸、氧化镁、氧化钙、硬脂酸镁、十二烷基硫酸钠、十二烷基磺酸钠、油酸钠、硬脂酸钠、磷酸钠、枸橼酸钠、酒石酸钠、羧甲基纤维素钠、羧甲基淀粉钠中的一种及以上;进一步地,该药物组合物中的碱性物质可优选为碳酸氢钠、碳酸氢钾、碳酸氢钙、碳酸氢镁、碳酸钙、碳酸钠、碳酸镁、碳酸钾中的一种及以上;更进一步地,该药物组合物中的碱性物质可优选为碳酸氢钠、碳酸氢钾、碳酸氢钙、碳酸氢镁中的一种及以上。
在确定上述碱性物质种类的基础上,本发明技术方案的另一目的,是提供了该组合物中碱性物质的用量,其单剂量所含碱性物质的量为1~50毫摩尔(mmol)。当其加入至50ml(模拟人体胃液体积)酸性溶液(0.1mol/L盐酸溶液,pH≈1.0)中,其可使该酸性溶液的pH值上升至少2个单位(pH≥3.0),使细辛脑几无降解而保持稳定。
由于细辛脑的水溶液pH值近中性,碱性物质的加量主要考虑用于中和胃酸。一般人体胃液体积与含酸量按50ml盐酸溶液(0.1mol/L)计(最大体积≈500ml),pH值约为1.0。欲使主药细辛脑在胃液中溶出且保持稳定,应考虑中和胃酸所需加入碱性物质及加量,如加入碱性物质碳酸氢钠:HCl+NaHCO3=H2O+NaCl+CO2,此时加入碳酸氢钠的量,相当于50ml盐酸溶液(0.1mol/L)中所含盐酸的摩尔量,即5mmol;如胃液体积按500ml计,则需要碳酸氢钠量为50mmol;如加入二价碱盐-碳酸钠,则需要碱性物质的摩尔量为5/2=2.5mmol;如加入三价碱盐如氢氧化铝,可以此类推计算得所需碱性物质的摩尔量为5/3=1.67mmol。在此基础上,本发明药物组合物如另加入其他碱性辅料,如润滑剂硬脂酸镁等,则碱性物质加量可减少至1mmol。据此,我们可确定由本发明药物组合物制备的单位制剂中碱性物质的加量应为1mmol~50mmol,优选为5mmol~20mmol。
另一方面,由该药物组合物制得的细辛脑固体制剂口服后在胃部即可快速溶出而被吸收,从而迅速发挥药效,进而可显著提高其口服生物利用度。在此基础上,将该组合物口服给药用于阿尔茨海默病(Alzheimer′s Disease,简称AD)模型大鼠的治疗,发现其可显著改善AD 模型大鼠的学习记忆能力;另将该组合物口服给药用于帕金森病(Parkinson′sdisease,简称PD) 大鼠模型,发现其也可显著改善PD模型大鼠的病理行为;表明该药物组合物具有明显的实用性。在本发明提交前,该技术方案尚未见报道。
本发明涉及的药物组合物,为方便临床应用,可采用适宜制剂技术,将其进一步制备成片剂、胶囊剂、颗粒剂及干混悬剂等。显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过具体实施例形式对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
附图1 细辛脑药物组合物片剂与市售片剂的累积溶出曲线
具体实施方式
实施例
本发明涉及的细辛脑药物组合物可以具体表述为以下形式:
实施例1
实施例2
实施例3
本发明药物组合物制备的单位制剂中碱性物质的加量应为1mmol~50mmol,优选为5mmol~20mmol。以上实施例组合物,可以通过适当的制剂学技术,制成需要的片剂、胶囊、颗粒剂及干混悬剂等制剂形式。
通过以下实验例可进一步说明本发明所产生的有益的效果。
实验例1 细辛脑的含量测定
色谱仪:Agilent HP-1100型高效液相色谱仪;色谱柱:Kromasil C18色谱柱(150mm× 4.6mm,5μm),柱温:30℃,流动相:甲醇-水(70∶30),检测波长:258nm,流速:1.0ml/min。
精密量取供试溶液(含细辛脑约2mg)1ml,置50ml量瓶中,加流动相稀释至刻度,摇匀,滤过;精密量取20μl,注入液相色谱仪,记录色谱图;另取细辛脑对照品适量,精密称定,加甲醇适量溶解后,用流动相定量稀释,制成每1ml中含细辛脑40μg的溶液,同法测定。按外标法以峰面积计算,即得。
实验例2 细辛脑在不同pH值溶液中的稳定性
称取细辛脑原料药适量,置于50ml量瓶中,加入含有适量乙醇的水溶液至刻度,摇匀;精密量取10ml至25ml量瓶中,续加入不同pH值溶液(采用不同浓度盐酸溶液配制)至刻度,摇匀;于37℃水浴加热,不同时间点取样,照实验例1项下方法操作,测定溶液中细辛脑的含量,结果见表1。
表1 细辛脑在不同pH值溶液中的稳定性(初始含量按100%计)
由表1可见:在37℃条件下,当细辛脑处于pH值1.0~3.0的溶液中,其在90分钟内降解约为10%~15%,即细辛脑在溶液pH值≤3.0时不稳定;而当溶液pH值≥3.5时稳定性良好 (pH值为3.5时,降解约1.0%,随pH值的升高,稳定性增加)。考虑到人体胃液的pH值<3.0(空腹时),因此普通的细辛脑口服制剂在胃液中溶出后,细辛脑是不稳定的。这可能是导致其生物利用度低的重要原因之一。
实验例3 本发明自制样品与市售制剂加至酸性溶液中的pH值
基于实验例2的结果,发明人采用在细辛脑药物组合物中加入碱性物质的方法,对比研究了其与市售制剂在酸性溶液中的pH值。按实施例1、2中所列配方,通过混合、制粒及压片等操作,将细辛脑药物组合物制成片剂(30mg/片);按实施例3中所列配方,通过混合、制粒及装胶囊等操作,将细辛脑药物组合物制成胶囊剂(30mg/粒)。取自制片剂、胶囊剂与市售细辛脑片剂、胶囊剂各1片或1粒,置于50ml盐酸溶液(pH≈1.0)中,搅拌30分钟,测定溶液的pH值,结果见表2。
表2 自制样品与市售品在酸性介质中混悬后的pH值
样品 | 酸性条件 | 方式 | pH值 |
实施例1片剂 | 50ml、pH1.0盐酸溶液 | 搅拌混悬 | 5.1 |
实施例2片剂 | 50ml、pH1.0盐酸溶液 | 搅拌混悬 | 4.4 |
实施例3胶囊 | 50ml、pH1.0盐酸溶液 | 搅拌混悬 | 4.6 |
市售片剂1 | 50ml、pH1.0盐酸溶液 | 搅拌混悬 | 1.3 |
市售片剂2 | 50ml、pH1.0盐酸溶液 | 搅拌混悬 | 1.3 |
市售胶囊剂1 | 50ml、pH1.0盐酸溶液 | 搅拌混悬 | 1.5 |
市售胶囊剂2 | 50ml、pH1.0盐酸溶液 | 搅拌混悬 | 1.5 |
注:市售片剂:30mg/片,批号:160803 市售胶囊剂:30mg/粒,批号:1705031
由表2可见,加入碱性物质后,自制细辛脑药物组合物制成的片剂、胶囊剂均可使50ml 盐酸溶液(pH≈1.0)的pH值升高至pH≥3.5(实测pH 4.4~5.1),达到主药细辛脑稳定的pH 值范围(见实验例2)。据此,该细辛脑药物组合物可确保主药在胃酸性环境中的稳定性。与此相反,市售片剂、胶囊剂则不能使50ml盐酸溶液(pH≈1.0)的pH值升高至pH≥3.5(实测pH 1.3~1.5),难以确保主药细辛脑在胃酸性环境中的稳定性。
实验例4 细辛脑药用组合物片剂的溶出情况
按本发明技术方案得到的细辛脑药物组合物,将其制备成片剂后,按照溶出度测定方法测定。溶出度测定方法如下:取本品,照溶出度测定法(中国药典2015年版四部通则0931第三法),以盐酸溶液(0.1mol/L盐酸溶液50ml加水稀释至250ml)250ml为溶剂,转速为每分钟75转,依法操作,于预先设定的时间取样,过滤,取续滤液作为供试品溶液;另精密称取细辛脑对照品适量,加甲醇适量溶解后,用流动相定量稀释制成每1ml中约含30μg的溶液,作为对照品溶液。精密量取供试品溶液与对照品溶液各20μl,照实验例1项下方法测定,计算每片累积溶出度。结果见表3~表4。
表3 自制细辛脑片剂不同时间的累积溶出度%(平均溶出量:AS)
表4 市售细辛脑片剂不同时间的累积溶出度%(平均溶出量:AS)
时间(分) | 样1(%) | 样2(%) | 样3(%) | 样4(%) | 样5(%) | 样6(%) | AS(%) |
5 | 10.82 | 10.48 | 9.39 | 12.68 | 10.89 | 11.86 | 11.36±1.97 |
10 | 14.56 | 14.72 | 13.95 | 19.25 | 16.80 | 16.32 | 16.09±2.14 |
15 | 25.00 | 24.13 | 22.03 | 26.11 | 21.87 | 22.78 | 23.31±2.80 |
20 | 28.47 | 28.04 | 27.08 | 29.31 | 24.18 | 26.45 | 26.94±2.76 |
30 | 36.72 | 35.61 | 33.94 | 34.51 | 29.76 | 35.17 | 34.64±4.88 |
45 | 43.80 | 42.47 | 39.49 | 42.78 | 33.51 | 41.45 | 40.93±7.42 |
60 | 49.68 | 48.01 | 46.92 | 46.91 | 38.75 | 47.24 | 46.65±7.90 |
90 | 56.60 | 55.13 | 53.83 | 52.47 | 42.67 | 51.47 | 51.81±9.14 |
120 | 61.33 | 58.09 | 58.43 | 55.88 | 45.32 | 56.28 | 56.05±10.73 |
注:市售片剂:30mg/片,批号:160803
由表3、表4可见,自制细辛脑药物组合物片剂在各相应时间点的累积溶出度均显著高于市售片剂(对比累积溶出曲线见附图1),说明组合物中加入的碱性物质有利于细辛脑的溶出和稳定,使细辛脑的累积溶出度得到显著提升,将有利于提高其口服给药的生物利用度。
实验例5 细辛脑组合物片剂与市售片剂在大鼠体内的药动学参数比较
(1)取SD大鼠12只,雌雄各半,体重180~220g,随机分为两组,给药前禁食12h,自由饮水,两组按100mg/kg剂量(自制细辛脑片剂、市售细辛脑片剂)分别灌胃给药,于给药后5、 10、15、30、60、90、120及240min眼眶取血0.5ml,置0.5%肝素钠溶液处理后的1.5ml EP管中,离心5000r/min×5min,取上清液(血浆)备用。精密吸取大鼠含药血浆100μl于1.5mlEP 管中,加入300μl甲醇,旋涡混合1min,离心12000r/min×10min,取上清液,微孔滤膜精滤,精密量取滤液20μl,照实验例1项下所述条件操作,测定细辛脑色谱峰面积,计算各时间点血药浓度。
(2)实验数据的处理以峰面积计算得细辛脑血药浓度测定结果(见表5),采用DAS2.0 软件进行药代动力学数据分析,选择适宜房室模型,以统计矩法计算药时曲线下面积AUC0--∞,结果见表5。
表5 细辛脑片剂口服灌胃给药后不同时间点的血药浓度及药动学参数
此外,采用本发明细辛脑药物组合物制备的片剂的生物利用度(AUC(0--∞)/mg·minL-1)显著优于市售片(322.26±38.28vs 196.80±27.75),将有助于其更好地发挥药效。据此,本发明细辛脑药物组合物所制备的片剂可快速溶出和吸收,提高了血药浓度,并显著提高了生物利用度,使其经口服给药用于预防或治疗神经退行性疾病成为可能。
实验例6 细辛脑药物组合物用于防治AD的药效学研究
(1)采用三氯化铝(20mg·kg-1,i.g,溶液浓度4g·L-1)联合D-半乳糖(180mg·kg-1, i.p,溶液浓度36g·L-1)给药SD大鼠,雌雄各半,共32只,每日1次,连续给药120d,建立AD模型;另给予8只SD大鼠等量生理盐水(5mL·kg-1,i.p)处理,作为正常组。
(2)采用Morris水迷宫实验法,筛选出AD模型大鼠共24只,将其分为3组(使造模各组之间空间学习记忆能力评分基本一致(p>0.05),与正常组比较具显著差异p<0.05),每组8只大鼠,分别给予细辛脑药物组合物(30mg/kg/d,i.g),阳性对照药物-盐酸多奈哌齐组(治疗AD药物,1.75mg/kg/d,i.g.),以及生理盐水(5.0ml/kg/d,i.g.)。另根据其空间学习记忆能力测评结果选取正常组8只大鼠,每日给予一次生理盐水(5.0ml/kg/d,i.g)。上述4组大鼠连续给药30天,给药结束后进行Morris水迷宫实验,对各组大鼠的空间学习记忆能力再次进行评价。
(3)记录每只大鼠在2min内分别从4个象限放入后穿越原平台位置的次数。穿越次数越多,说明其空间学习记忆能力越强。
(4)实验结果
表6 各组大鼠给药前后穿过平台平均次数(n=8)
注:a与给药前正常组比较,P<0.05;b与给药后模型组比较,P<0.05
研究结果表明:以造模后穿过原平台位置的平均次数为评价指标,正常组与模型组之间均具有显著差异(P<0.05),表明AD模型大鼠建立成功。在造模成功后,按研究方案分别持续给药30天,正常组、细辛脑药物组合物组与盐酸多奈哌齐组均和模型组有显著差异 (P<0.05);细辛脑药物组合物组与正常组相比无显著差异(P>0.05)。由表6可知,本发明细辛脑药物组合物可用于治疗(和/或预防)AD。
实验例7 细辛脑药物组合物用于防治帕金森病(PD)的药效学研究
PD模型采用定向注射微量6-羟基多巴胺法制备PD模型大鼠。腹腔注射4%水合氯醛 (40mg/kg)将大鼠麻醉后,固定。常规消毒后,切开头皮,剥离骨膜,参照Paxinos等所著《大鼠脑立体定位图谱》,确定左侧MFB坐标,前颅后4.4mm,矢状体左侧1.2mm,硬脑膜下7.8mm。按确定坐标,钻透颅骨,微量注射针垂直入颅,缓慢进针到预定深度,用10μl 微量注射器注入6μl浓度为2μg/μl的6-羟基多巴胺(0.2mg/ml维生素C注射液溶解,速度 0.4μl/min),注射完毕后留针10min,缓慢退针,全层缝合头皮。造模前后观察大鼠旋转行为,观察指标:旋转行为检测,术后一周,腹腔注射阿朴吗啡(0.5mg/kg)诱发大鼠产生向右旋转,记录阿朴吗啡注入后30分钟的旋转圈数。恒定向右旋转,转速≥210r/30min定为成功的PD模型。
分组及给药将合格的PD模型大鼠随机分为3组:模型组、细辛脑药物组合物组和阳性药物组(美多巴组),另设假手术组作为对照组。每组10只,雌雄各半,体重180~220g。细辛脑组合物组口服细辛脑药物组合物(30mg/kg/d,i.g),阳性对照组口服美多巴(75mg/kg/d, i.g),模型组与假手术组给予等体积生理盐水(5.0ml/kg,i.g)。
自主活动计数给药前后在安静、光线较暗的环境中进行检测,采用大鼠自主活动仪来测定大鼠自主活动的变化。大鼠适应环境10min后,计数5min内大鼠移动的格子数和站立的次数,连续测定5次,取平均值。
滚轴试验考察大鼠的平衡能力,大鼠需在滚轴上连续运动并保持平衡,是广泛采用的检测运动协调性试验。滚轴直径6cm,转速20r/min,适应5次后检测,每次检测间隔1min,连续测定5次,取平均值。
表7 各组对6-OHDA帕金森大鼠的行为学影响(n=10)
组别 | 移动格子数 | 站立次数 | 滚轴试验 |
假手术组 | 123±5<sup>a</sup> | 27±8<sup>a</sup> | 35±6<sup>a</sup> |
模型组 | 77±6<sup>b</sup> | 10±5<sup>b</sup> | 12±8<sup>b</sup> |
细辛脑药物组合物组 | 106±2<sup>a</sup> | 25±4<sup>a</sup> | 30±3<sup>a</sup> |
阳性对照组 | 108±4<sup>a</sup> | 24±7<sup>a</sup> | 23±7<sup>a</sup> |
注:a与模型组比较,P<0.05;b与假手术比较,P<0.05。
由表7可见,与假手术组比较,模型组大鼠的自主活动计数、站立次数和平衡能力明显降低(P<0.05)。PD模型大鼠给予本发明药物组合物后,大鼠行为学移动格子数、站立次数和滚轴试验计数升高,与模型组比较有显著差异(P<0.05),且与阳性对照组和假手术组数据比较,无明显差异(P>0.05)。表明用本发明药物组合物后行为学有较好的改善。
由实验例6、7可知,本发明的药物组合物,能够使AD、PD模型大鼠的行为学得到明显改善,预示本发明细辛脑药物组合物可用来预防或治疗AD、PD。
发明的实用性与获益
据流行病学统计,60岁以上的老年痴呆病(AD)患者人数约为5%~7%。目前全球大约有4600万AD患者,预计到2050年AD患者将达到1.15亿。我国目前已有近1000万AD患者,约占全球总病例的1/4。AD现已成为导致老年人死亡的第5位病因,其不仅给患者带来巨大痛苦,还给患者家庭和社会带来了沉重的精神压力和医疗负担。
帕金森病(Parkinson’s disease,PD)是一种常见的神经系统变性疾病,临床表现为运动迟缓、静止震癫、痴呆等,老年人多见,平均发病年龄为60岁左右。我国65岁以上人群P D的患病率大约是1.7%,目前国内帕金森病患者已经超过250万。目前对PD的治疗仍是以控制症状为主,尚无有效治疗药物。
本发明首次提供了一种细辛脑药物组合物,其特征是配方中含有碱性物质,由其制备的片剂、胶囊剂等口服固体制剂,可显著增加细辛脑在酸液中的稳定性与溶出度,进而显著提高其口服给药的生物利用度,使该组合物用于治疗或预防神经退行性疾病(包括AD、PD) 成为可能,为此类神经退行性疾病患者提供了新的治疗选择。本发明技术方案先进合理,具有创造性、新颖性和实用性,预期将产生巨大的社会和经济效益。
参考文献
[1]吴闯.α-细辛脑的研究进展.中国药学杂志,1997,32(3):129~132.
[2]鲁统洁.α-细辛脑速释片的研究,北京化工大学学位论文.2008.06。
Claims (5)
1.一种细辛脑药物组合物及其在防治神经退行性疾病方面的应用,其技术特征是以细辛脑为药理活性成分,加上药学上常用的碱性物质和其他辅料组成,由该组合物制备的含有细辛脑的片剂、胶囊剂及颗粒剂等固体制剂可增强细辛脑在酸性溶液中的稳定性,进而可显著提高辛脑的口服生物利用度,可用于治疗和/或预防包括阿尔茨海默病(Alzheimer′s disease,AD)、帕金森病(Parkinson′s disease,PD)在内的神经退行性疾病。
2.如权利要求1所述的细辛脑药物组合物,其中的碱性物质由至少一种药学上可接受的碱性化合物组成。
3.如权利要求1所述的细辛脑药物组合物,其可通过适宜药剂学技术进一步制成片剂、胶囊、颗粒剂及干混悬剂等,由其制备的单位片剂、胶囊剂、颗粒剂等及干混悬剂中含有碱性物质的量至少为1毫摩尔(1mmol),其置于50ml浓度为0.1M的盐酸溶液中溶解和/或分散均匀后,可使该溶液pH值不小于3.0。
4.如权利要求1所述的细辛脑药物组合物,其中的碱性物质可以是下列化合物中的至少一种:氢氧化钠、氢氧化钾、氢氧化钙、氢氧化铝、碳酸钠、碳酸氢钠、碳酸氢钾、碳酸氢钙、碳酸钙、碳酸镁、碳酸钾、磷酸氢二钠、硬脂富马酸钠、磷酸氢二钾、磷酸氢钙、醋酸钠、乳酸钠、苹果酸钠、苹果酸钙、精氨酸、赖氨酸、组氨酸、氧化镁、氧化钙、硬脂酸镁、十二烷基硫酸钠、十二烷基磺酸钠、油酸钠、硬脂酸钠、磷酸钠、枸橼酸钠、酒石酸钠、羧甲基纤维素钠、羧甲基淀粉钠等;进一步地,该药物组合物中的碱性物质可优选为碳酸氢钠、碳酸氢钾、碳酸氢钙、碳酸氢镁、碳酸钙、碳酸钠、碳酸镁、碳酸钾中的至少一种组成;更进一步地,该药物组合物中的碱性物质可优选为由碳酸氢钠、碳酸氢钾、碳酸氢钙、碳酸氢镁中的至少一种组成。
5.如权利要求1所述的细辛脑药物组合物,如权利要求3所述的细辛脑药物组合物,其单位制剂中碱性物质的含量为1mmol~50mmol,优选为5mmol~20mmol。
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