CN1403077A - 缓释制剂 - Google Patents

缓释制剂 Download PDF

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CN1403077A
CN1403077A CN01143869A CN01143869A CN1403077A CN 1403077 A CN1403077 A CN 1403077A CN 01143869 A CN01143869 A CN 01143869A CN 01143869 A CN01143869 A CN 01143869A CN 1403077 A CN1403077 A CN 1403077A
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D·M·舍曼
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Abstract

本发明涉及一种可24小时持续释放的制剂及抗抑郁药—盐酸文拉法星的单位剂型，与每天必须服用2次或更多次的常规片剂组合物相比，它能更好地控制血药浓度并降低恶心、呕吐的发生率。

Description

缓释制剂
本申请是1997年3月14日提交的、发明名称为“缓释制剂”的97109594.9号专利申请的分案申请。
通常，缓释药物制剂是用水凝胶压片技术制成。生产这种缓释片药剂时，常将活性成分与纤维素酯，如甲基纤维素、乙基纤维素或者羟丙甲基纤维素混合在一起，还可以加入或不加其它赋形剂，并将所得混合物压制成片。当把片剂口服给药时，片剂中的纤维素酯与消化系统中的水份发生水合作用而膨胀，从而使活性成分有限地暴露于水分中。当纤维素酯逐渐被水分溶解后，水更深地渗入凝胶基质中，活性成分慢慢溶解并扩散进凝胶中，使其能够被机体吸收。这种缓释剂型的例子可见美国专利4,966,768公开的消炎/镇痛药依托度酸(LodineR)释剂。
当片剂的生产不可行时，药厂的常规作法是制备药物的胶囊剂型，它具有延长或持续释放的特点。这种缓释胶囊的制法是：将药物与一种或多种粘合剂混合成均匀的混合物，然后用水或溶剂，如乙醇，使其湿润形成可挤压的胶质物，之后，挤压出的直径很小，一般为1mm的药物/基质的圆柱形，再切成合适的长度并用常规的制粒设备将圆柱制成球粒。干燥后，给该球粒包裹一层膜使其缓慢溶解。把用膜包裹的球粒以所需量装入明胶胶囊就达到了所预期的治疗效果。可将以不同速率释放药物的球粒混合装入一个明胶胶囊中从而获得预期的释放速率和血药浓度。美国专利4,138,475公开了一种缓释药物组合物，是由一个硬明胶胶囊组成的，其中装有用膜包衣的球粒，该球粒是由萘心安与微晶纤维素组成的，膜层由乙基纤维素并可任选羟丙甲基纤维素和/或增塑剂组成。
文拉法星，1-[2-(二甲氨基)-1-(4-甲氧苯基)乙基]环己醇，在神经药理学上是一种治疗抑郁症的重要药物。美国专利4,535,186公开了文拉法星及其酸加成盐。目前，盐酸文拉法星片剂的成人用药量是75到350mg/天，一天分2到3次分别服用。在把治疗量的盐酸文拉法星片剂给药中，药物迅速溶解导致给药不久后活性成分的血药浓度迅速升高，几个小时后活性化合物被排泄或代谢掉，血药浓度也随之下降，给药后约12小时，血药浓度已逐渐下降到不足以起治疗作用的水平，因此需要增加药物的用量。当每天多次用药时，最常见的副作用是恶心，实验证明，用盐酸文拉法星进行治疗的病人，约45％出现恶心，约17％的病人还发生呕吐。
本发明提供一种以盐酸文拉法星作为活性药物成分的缓释(ER)胶囊制剂，它给药一次的方式即能在24小时内保持治疗性血药浓度。具体地说，本发明提供一种用胶囊包裹的盐酸文拉法星的缓释制剂，它包括一个硬明胶胶囊，该胶囊中装有有效治疗量的球粒，该球粒由盐酸文拉法星、微晶纤维素和羟丙甲基纤维素组成，并用乙基纤维素和羟丙甲基纤维素包衣。
服用本发明的文拉法星制剂可得到较平坦的血药浓度-时间曲线，并且与每日多次给药相比能更好地控制治疗性血药浓度范围。换句话说，本发明提供了一种降低因每日多次服用常规的立即释放的盐酸文拉法星片剂而导致的血药浓度出现尖锐峰值和极小值(波峰与波谷)的方法。事实上，给予本发明的缓释制剂后，在约5小时到约8小时(最佳约6小时)内盐酸文拉法星的血浆浓度升高，然后24小时期间的残余物开始缓慢地几乎线性下降，但在整个24小时之间至少保持了药物临界治疗浓度。与此相反，常规立即释放的盐酸文拉法星片剂在2到4小时内出现血浆峰值。因此，按照本发明的用途方面，本发明提供了一种降低每日多次服用盐酸文拉法星片剂的药物动力学中的多次血浆峰值和谷值的方法，该方法包括在需要盐酸文拉法星治疗时，每天一次给病人服用盐酸文拉法星缓释制剂。
使用本发明的每天仅给药一次的盐酸文拉法星制剂通过调节减少了每日多次给药引起的恶心程度和呕吐的发生率。在盐酸文拉法星缓释剂的临床试验中，恶心的发生率在第一周后大大下降。在2个8周和一个12周的临床研究中，文拉法星缓释剂显示出了较常规盐酸文拉法星片剂的显著优越性。因此，按照本发明的用法，提供了一种降低服用盐酸文拉法星产生恶心的程度和呕吐发生率的方法，该方法包括在需要用盐酸文拉法星治疗时给病人每日一次服用有效治疗量的盐酸文拉法星缓释制剂。
1-[2-(二甲氨基)-1-(4-甲氧苯基)乙基]环己醇盐酸化物是多晶型的。根据目前的分离及特性形式来看，把I型认为是结晶的动态产物，当加热结晶溶剂时它可转变为II型。I型和II型无法用熔点区分开，但在它们的红外光谱和X-射线衍射照片中确实显示出某些不同。任何一种多晶型，如I型或II型，均可用于本发明的组合物。
本发明的缓释制剂由1-[2-(二甲氨基)-1-(4-甲氧苯基)乙基]环己醇盐酸化物与微晶纤维素和羟丙甲基纤维素混合而成。把所形成珠状或球状的含有药物的制剂用乙基纤维素和羟丙甲基纤维素的混合物包衣来提供所需的包衣程度，一般为成品的约2％到约12％(W/W)，优选约5％到10％(W/W)，最好是约6％到约8％(W/W)。更准确地说，本发明的缓释球状制剂由约30％到40％(W/W)的盐酸文拉法星、约50％到约70％(W/W)的微晶纤维素，NF，约0.25％到约1％(W/W)的羟丙甲基纤维素，USP，和约5％到约10％(W/W)的膜层组成。球状制剂优选含有约35％的盐酸文拉法星，约55％到60％的微晶纤维素NF(AvicelR pH101)，约0.5％的羟丙甲基纤维素2208USP(K3，Dow，2％水溶液的粘度为3cps，甲氧基含量为19-24％，羟丙氧基含量为4-13％)，和约6％到8％的膜层。
在本发明制剂的优选方案中，其中的球粒按重量计约37.3％的盐酸文拉法星、按重量计约0.5％的羟丙甲基纤维素2208和按重量计约62.17％的微晶纤维素组成。本发明制剂中的包衣膜优选由占总重量4.81％的乙基纤维素和占总重量0.85％的羟丙甲基纤维素组成，或由占总重量4.04％的乙基纤维素和占总重量0.714％的羟丙甲基纤维素组成，或由占总重量2.48％的乙基纤维素和占总重量0.437％的羟丙甲基纤维素组成。
膜层由80％到90％(W/W)的乙基纤维素NF和10％到20％(W/W)的羟丙甲基纤维素(2910)，USP组成。优选乙基纤维素的乙氧基含量为44.0-51％，5％水溶液的粘度为50cps，羟丙甲基纤维素(2910)USP的2％水溶液的粘度为6cps，甲氧基含量为28-30％，羟丙氧基含量为7-12％。本文所用的乙基纤维素为AqualonHG2834。
本发明进一步提供一种每天给药一次的盐酸文拉法星缓释制剂，该制剂包含含有37.3％文拉法星、62.17％微晶纤维素和0.5％羟丙甲基纤维素2208的球粒，该球粒用一定量的由85％乙基纤维素HG2834和15％羟丙甲基纤维素2910组成的混合物包衣，该混合物的量足以使被包衣的球粒在24小时期间内以预期的释放速率溶解。
在不违背本发明构思的条件下，制剂中所用的羟丙甲基纤维素2208和2910USP及乙基纤维素N F可用前面所述的专利产品中与它们具有相同物理化学性质的等效物替代。
正因为文拉法星的盐酸化物极易溶于水，所以人们完全没有预料到可将盐酸文拉法星制成缓释制剂。由于压成的片剂的稳定性差(可压缩性差或易剥离)且溶解太迅速，所以利用水凝胶工艺技术制备缓释片剂的大量试验都不成功。通常，水凝胶缓释组合物制备的片剂2小时溶解40-50％，4小时溶解60-70％，8小时则溶解85-100％。
利用不同级别的微晶纤维素和羟丙甲基纤维素、不同比率的盐酸文拉法星和填充剂、不同的粘合剂如聚乙烯吡咯烷酮、甲基纤维素、水和不同分子量范围的聚乙二醇可制成大量的球状制剂从而可找出可压制的制粒混合物的合适配比。在挤压过程中产生的热使被挤出物过分干燥而难以转变为球粒。将羟丙甲基纤维素2208加入到盐酸文拉法星-微晶纤维素混合物中可使得球粒生产得以实施。
下面的实施例详细说明了申请人对本发明的缓释药物制剂制备过程中所遇到问题的解决方法。实施例1  盐酸文拉法星缓释胶囊
将44.8份(88.4％游离碱)盐酸文拉法星、74.6份微晶纤维素NF，和0.60份羟丙甲基纤维素2208，USP，的混合物用41.0份水调均，所得胶质团通过挤压、团成球状并干燥，得到含有药物的未被包衣的球粒。
在二氯甲烷和无水甲醇1∶1V/V混合物中搅拌38.25份乙基纤维素，NF，HG2834和6.75份羟丙甲基纤维素2910，USP，直到形成包衣材料的溶液。
向每份未包衣的球粒的流化床中加入0.667份包衣溶液，得到缓释的、包衣球粒，包衣程度为3％。
把该包衣球粒过筛得到颗粒直径在0.85mm到1.76mm内的包衣球粒，再将这些经过筛选的包衣球粒装入常规的硬明胶胶囊中。
实施例2
与实施例1相同，只是每份未包覆的球粒改用1.11份包衣溶液，最终得到的包衣程度为5％。
实施例3
与实施例1相同，只是改用1.33份包衣溶液，最终包衣程度为6％。
实施例4
与实施例1相同，只是改用1.55份包衣溶液，最终包衣程度为7％。
包衣程度的可接受性可通过分析装囊前的包衣球粒的溶解速率来决定。溶解过程按照美国药典注解1(basket)的方法，在37℃蒸馏水中以100rpm进行。表1中所给出的溶解速率的一致提供了本发明缓释胶囊中的药物组分在24小时内的治疗性血药浓度。当某批量包衣球粒释放药物太慢而不能达到预期的溶解速率时，可向其中加入部分未包衣的球粒或包衣程度低的球粒，充分混合，从而达到血药浓度迅速升高的填充剂量。而当某批包衣球粒的释药速度太快时，也可添加包衣材料以得到预期的溶解速率。
            表1  可接受的包衣球粒的溶解速率
时间(小时)            盐酸文拉法星释放的平均百分比
   2                        ＜30
   4                        30-55
   8                        55-80
   12                       65-90
   24                       ＞80
以能达到预期单位剂量浓度所需的量，将具有表1中所列溶解速率的含盐酸文拉法星的包衣球粒装入硬明胶胶囊中。目前所使用的标准单位剂量立即释放(IR)的片剂所提供的盐酸文拉法星的量为25mg、37.5mg、50mg、75mg和100mg文拉法星。填充的本发明的胶囊能够提供与目前所用片剂所提供的等量的盐酸文拉法星，并且也能达到约150mg的量。
按照美国药典(USP)注解1中所述的方法，在0.9L水中以100rpm测定盐酸文拉法星缓释胶囊的溶解。在特定时间取过滤后的溶解基质样品在抗溶液基质的240到450nm间测定澄清溶液的吸收系数。基线A从450nm，经400nm一直描绘到240nm。根据该基线测定到了最大吸收波长(约274nm)处的吸收系数。向六个硬明胶胶囊中装入理论治疗量的盐酸文拉法星球粒并测定其溶解。标准样品由盐酸文拉法星标准溶液以及明胶胶囊校正溶液组成。文拉法星释放的百分比按照下述公式得到：其中As为样品的吸收系数，Wr为对照标准品的质量，mg；S为标准对照品的浓度，小数；V1是用来溶解药物的溶剂的体积，mL；0.884是游离碱百分数；Ar是标准品的吸收系数，V2是标准对照液的体积，mL；C是以mg限定的球粒量。
表2为文拉法星的血药浓度与时间的比值，一组人每12小时服用一片75mg的常规快速释放(IR)片剂，一组人每24小时同时服用二片75mg的缓释(ER)胶囊，还有一组人每24小时服用一片150mg的缓释(ER)胶囊，被测者为男性。由于被测者已按照实验时原始记录的剂量服用了盐酸文拉法星，所以当血药浓度为0时，给药剂量不为0。
        表2  文拉法星血药浓度(ng/mL)随时间的变化及
             常规片剂(非缓释的)与缓释胶囊的对比时间(小时)    75mg         2×75mg(ER)胶囊     1×150mg
          (IR)片剂                         (ER)胶囊
          (q12h)        (q24hr)            (q24h)0             62.3           55.0               55.80.5           76.31             135.6          53.3               53.22             212.1          69.8               70.94             162.0          138.6              133.36             114.6          149.0              143.58             86.7           129.3              129.510                           118.4              114.412            51.9           105.1              105.812.5          74.713            127.514            161.3          90.5               91.316            134.6          78.2               78.518            106.220            83.6           62.7               63.324            57.6           56.0               57.3
表2显示了服用两片75mg/粒的盐酸文拉法星缓释胶囊与服用一片150mg/粒的盐酸文拉法星缓释胶囊所达到的血药浓度非常接近。该数据也表明服用两种缓释剂型和间隔12小时服用一片立即释放的75mg的盐酸文拉法星片剂的病人在24小时后的血药浓度也非常接近。
进一步说，缓释制剂没有提高每隔12小时给药的迅速释放的常规片剂所达到的文拉法星的血浆峰值。当对目前正用盐酸文拉法星(IR)片剂进行治疗的病人服用特定剂量的缓释剂后，在约6小时，正负2小时的时间达到文拉法星血浓峰值，一般低于150ng/ml。而继续服用(IR)片剂的病人则在2小时达到文拉法星血浓峰值，一般高于200ng/ml，并从此之后迅速下降。
表3始血药浓度为0的男性患者的文拉法星血浆浓度。结果再次表明，在把表中所示量的盐酸文拉法星缓释胶囊给药后约6小时达到文拉法星血浆浓度峰值。而仅服用1粒50mg迅速释放的片剂的患者约4小时就达到了血浓峰值。为了更好地进行对比，可以将服用常规片剂的患者的文拉法星血浆浓度乘以系数3来近似表示服用1粒150mg常规片剂达到的血药浓度。
           表3初始血浓为0的男性的文拉法星血浆浓度时间(小时)    1×50mg       2×75mg      1×150mg
          IR片剂        ER胶囊       ER胶囊
0         0             0            0
1         27.87         1.3          0
1.5       44.12         6.0          2.2
2         54.83         20.6         12.8
4         66.38         77.0         81.0
6         49.36         96.5         94.4
8         30.06         93.3         86.9
10        21.84         73.2         72.8
12        15.91         61.3         61.4
14        13.73         52.9         51.9
16        10.67         47.5         41.1
20        5.52          35.2         34.0
24        3.56          29.3         28.5
28        2.53          23.4         22.9
36        1.44          11.9         13.5
48        0.66          5.8          5.2
按照下列步骤测定文拉法星的血药浓度。将从被测者身上采集的血样放入肝素化的真空血液试管中并将试管慢慢倒转几次，再尽快将试管以2500rpm的速度离心15分钟。用滴管将血浆吸取到塑料试管中并在-20℃下保存直到分析测定完成。
向塑料试管中的每份1ml血样中加入150μL常用内标液(150μg/ml)。再向每个试管中加入饱和四硼酸钠溶液(0.2ml)并进行旋转。再向每个试管中加入5mL乙醚，然后盖上盖并高速振荡10分钟，再以3000rpm的速度离心5分钟。将水层用干冰冷冻，有机层转移到清洁的螺旋帽试管中。再向每个试管中加入0.3mL的0.01N HCl溶液并高速振荡10分钟。将水层冷冻，有机层丢弃。再加入50μL流动相(23∶77乙腈：0.1M单碱式磷酸铵缓冲液，pH4.4)，旋转，将50μL样品注入到一个Supelco Supelcoil LC-8-DB，5cm×4.6mm，5μ柱中，用带有Waters Lambda Max481检测器或其他等效检测器的高效液相色谱仪在229nm处进行测定。用不同浓度的盐酸文拉法星溶液作为标准品。
因此，本发明的包衣球粒组合物使得盐酸文拉法星的缓释剂型达到了预期的溶解速率，而这是水凝胶片剂生产技术所无法做到的。

Claims (1)

1.一种膜包衣组合物，它是由占总重量85％的乙氧基含量为44.0-51.0％的乙基纤维素和占总重量15％的甲氧基含量为28.0-30.0％、羟丙氧基含量为7.0-12.0％的羟丙甲基纤维素组成。
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