CN1253497A - 含扑热息痛的吞咽片剂 - Google Patents
含扑热息痛的吞咽片剂 Download PDFInfo
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Abstract
本发明描述了一种吞咽片剂或胶囊制剂,其中含有扑热息痛、碳酸氢钠和至少一种药用赋形剂。
Description
本发明涉及含N-乙酰基-对氨基酚的药物组合物，N-乙酰基-对氨基酚的通用名为扑热息痛、对乙酰氨基酚和APAP(以后称为扑热息痛)。具体地讲，本发明涉及吞咽片剂或胶囊形式的、作用迅速的扑热息痛制剂，在患者摄入后，其吸收速率大大改善。
扑热息痛是解热止痛剂，广泛用于处方和非处方药物，经常与其它生物活性化合物合用。已发现以固体形式如片剂或胶囊摄入后，吸收速率及药物活性起效随患者的不同而变化，而且有时非常缓慢。
为改善活性起效的速率已进行了多种尝试，例如，通过制备泡腾制剂来加速片剂的崩解。
英国专利公开GB2103087(Bristol-Myers)描述了一种止痛组合物，其中含有吸收速率加大的扑热息痛。GB2103087参考了文献(J.Wojcicki等，Zbl.Pharm.，118，(1979)，Vol 2-3)，该文献描述了对扑热息痛药代动力学的研究，其中单位口服剂量1000mg的扑热息痛与4000mg抗酸剂碳酸钙一起用药。按照GB2103087中的参考文献，发现与单独给用扑热息痛(1000mg)的吸收速率相比，该联合用药形式降低了扑热息痛的吸收速率。
按照GB2103087，通过共同使用一种治疗药物，其中含有约150mg至2000mg扑热息痛和约60mg至约1200mg的抗酸剂，使吸收速率得到改善。此出版物声明可使用通常用于中和胃酸的任何抗酸剂或其结合形式。GB2103087确定特别有利的抗酸剂为碳酸钙、碳酸镁、碳酸钙和碳酸镁的结合形式、碳酸氢钠和氢氧化镁。GB2103087列举了一些组合物，其中含有扑热息痛与碳酸钙、与碳酸钙和碳酸镁混合物、与碳酸氢钠的组合。
GB2103087的实施例包括两种含有扑热息痛和碳酸氢钠的片剂；一种含有325mg的扑热息痛和225mg的碳酸氢钠，其中碳酸氢钠与扑热息痛的重量比为0.69∶1，第二种制剂含有500mg扑热息痛和225mg碳酸氢钠，其中碳酸氢钠与扑热息痛的重量比为0.4∶1。当用GB2103087中列举的不同制剂对健康自愿者用药时，发现对所有的受试制剂来说，与常规扑热息痛片剂相比，其吸收速率快速升高了7至31％。
现在意外地发现，通过选择碳酸氢钠并将其与扑热息痛在片剂或胶囊中组合，其存在量至少为300mg每片，且碳酸氢盐与扑热息痛的重量比至少为0.74∶1，可制备吞咽片剂或胶囊，其与商购的、不含碳酸氢钠的扑热息痛片剂相比吸收速率方面得到了具有统计学意义的改善。当相当量的其它抗酸剂如碳酸钙与扑热息痛在固体剂型中组合时，没有观察到这种改善。更令人惊奇的是，含扑热息痛和碳酸氢钠的该固体剂型口服后，较市售的含扑热息痛和碳酸氢钠的水溶性产物的水溶液口服后，其吸收速率也有所改善。在本文中，当与其它扑热息痛组合物相比时，吸收速率的升高可以表示为Cmax的升高，其中Cmax是血清中扑热息痛的最大浓度，或者通过测量在给药后头20分钟浓度对时间曲线下的面积(AUC0-20)表示。
本发明提供了吞咽片剂和胶囊，其中含有300mg至600mg的扑热息痛和300mg至1200mg的碳酸氢钠，其中碳酸氢钠与扑热息痛的重量比至少为0.74∶1。
为了避免怀疑，吞咽片剂是用来整个吞咽的片剂，而不是给药前溶解或悬浮于水中的那种，例如含有效量的泡腾对的片剂。
本发明的片剂或胶囊优选含有325mg或500mg的扑热息痛。在该制剂中存在的碳酸氢钠的量优选至少370mg，例如至少400mg或500mg，并适于不超过1000mg，优选不大于800mg并更优选不大于700mg。碳酸氢钠与扑热息痛的重量比有利地至少为0.8∶1，优选至少为1∶1，并优选至少1.25∶1。
本发明的制剂一般含有至少一种片剂和/或胶囊领域常规使用的药物赋形剂。可以掺入的适宜的赋形剂包括润滑剂，如硬脂酸镁和硬脂酸；崩解剂，如纤维素衍生物；淀粉；粘合剂，例如改性淀粉和纤维素衍生物；助流剂，如胶体二氧化硅；压片助剂，如纤维素衍生物；及防腐剂、悬浮剂、湿润剂、芳味剂、填充剂、粘合剂、着色剂、适当形式的甜味剂。
除扑热息痛、碳酸氢钠和药用赋形剂外，本发明的制剂还可含有其它药物活性试剂，例如其它止痛剂、抗炎止痛剂、减充血剂、抗组胺药、镇咳剂等。这些制剂还可含有药用止痛辅剂，例如咖啡因。
本发明还提供了制备本发明片剂或胶囊的方法，该方法包括将扑热息痛和碳酸氢钠与任何药用赋形剂、其它药用活性试剂或辅剂一起混合。因此，扑热息痛和碳酸氢钠可以与一种或多种粘合剂一起混合并用水制粒。然后将所得颗粒干燥、过筛并与其它赋形剂如润滑剂和崩解剂在压片前混合。或者，在制粒步骤中可不加碳酸氢钠，并随后与其它赋形剂一起加入。在另一种方法中，用直接压片级的扑热息痛可制备片剂，该扑热息痛包括不需要制粒步骤的商购形式。还可通过其它本领域已知的方法制备片剂，例如通过将挤出混合物成形。对于胶囊的制备，可如片剂的制备，将扑热息痛和碳酸氢钠混合并制粒，并将需要的量填充入适当型号的胶囊壳中。
如上所述，与其它扑热息痛组合物相比，本发明的制剂具有升高的Cmax，其中Cmax是血清中扑热息痛的最大浓度。对比试验表明，与只含扑热息痛或扑热息痛加碳酸钙的吞咽片剂，或与专卖的水溶性扑热息痛制剂相比，Cmax都升高。此外，本发明的该制剂具有升高的(AUC0-20)，这表明与常规扑热息痛吞咽片剂相比时，其扑热息痛的吸收速率升高。
确实，本发明的扑热息痛制剂的血浆性质与扑热息痛静脉给药的效果相当。(Seymor R A，欧洲临床药理学杂志(European J.Clin.Pharmacol.)，20，215-218，(1981)，证明1000mg扑热息痛静脉给药后血浆浓度为23.7mg/升)。为了达到通过口服给药不能达到的最大治疗作用，通常建议静脉给药。但是，静脉给药疼痛且不便。此外，因为如扑热息痛这样的药物溶解性差，一般不提供静脉制剂，本发明提供了相当实用的效益。
此外，以本发明的重量比加入碳酸氢钠可能具有其它附加优点，即可降低患者发生扑热息痛过量使用而产生副作用的可能性，此副作用可能产生致命的后果，至少会导致不可逆的肝损伤。摄入含500mg扑热息痛的扑热息痛片剂约40片通常引起严重的肝损伤，有时是致命的。对于大多数患者来说，在吞咽本发明的片剂后，恰在扑热息痛达到致命浓度前，会达到碳酸氢钠的催吐剂量。
本发明制剂的另一个潜在的优点存在于偏头痛的治疗中。减轻偏头痛的含有扑热息痛的专卖产品，还含有如metaclopramide等组分，该组分用来克服伴随偏头痛的胃郁积并为了增加扑热息痛的血浆浓度而加速胃排空。这些组分可导致不需要的副作用。本发明的制剂具有意外升高的吸收速率，并因此排除了其它组分带来的副作用，因此它具有明显的优点。
下列实施例(1至10)是对本发明的举例说明。对比实施例A不在本发明的范围内，但是用来进一步说明本发明的优点。
实施例1
由下列组分制备适于压片的颗粒。组分 mg/片 批量(g)1.扑热息痛(细粉) 500.00 9000.002.碳酸氢钠(细粉) 630.00 11340.003.淀粉(玉米) 11.40 205.204.淀粉(预凝胶化) 50.00 900.005.聚维酮K25 2.00 36.006.山梨酸钾 0.60 10.80
将组分1-6用16号筛筛入适宜的混合器中，并用适量的去离子水制粒成中/重颗粒。在适宜的烘箱中在45将此颗粒干燥，至含水量＜1％。然后将所得干燥颗粒通过12号筛，得到白色颗粒(产量20.250kg)。
实施例2
用下列组分制备片剂：组分 mg/片 批量(g)1.实施例1的颗粒 1194.00 19104.00g2.淀粉(玉米) 10.00 160.003.滑石 15.00 240.004.硬脂酸 5.00 80.005.内交联羧甲基纤维素钠 36.70 587.20总量 1260.70 20171.20
将组分1-5通过16号筛筛入适宜的混合器中，并混合。然后用适宜的胶囊形状的工具将所得混合物压片得到胶囊形状的片剂(目标重量1260.7mg)，此最终片剂组成如下：组分 mg/片1.扑热息痛(细粉) 500.002.碳酸氢钠(细粉) 630.003.淀粉(玉米) 21.404.淀粉(预凝胶化) 50.005.聚维酮K25 2.006.山梨酸钾 0.607.滑石 15.008.硬脂酸 5.009.内交联羧甲基纤维素钠 36.70总量 1260.70
每片含有扑热息痛500mg和碳酸氢钠630mg，其中碳酸氢钠∶扑热息痛的比例为1.26∶1。
实施例3
按照与实施例1和2相似的方法，使用不同重量各组分制备片剂(目标重量1023.82mg)，其最终组成如下：组分 mg/片1.扑热息痛(细粉) 500.002.碳酸氢钠(细粉) 400.003.淀粉(玉米) 21.404.淀粉(预凝胶化) 50.005.聚维酮K25 2.006.山梨酸钾 0.607.滑石 15.008.硬脂酸 5.009.内交联羧甲基纤维素钠 29.82总量 1023.82
每片含有扑热息痛500mg和碳酸氢钠400mg，其中碳酸氢钠∶扑热息痛的比例为0.8∶1。
实施例4
按照与实施例1和2相似的方法，使用不同重量各组分制备片剂(目标重量993.82mg)，其最终组成如下：组分 mg/片1.扑热息痛(细粉) 500.002.碳酸氢钠(细粉) 370.003.淀粉(玉米) 21.404.淀粉(预凝胶化) 50.005.聚维酮K25 2.006.山梨酸钾 0.607.滑石 15.008.硬脂酸 5.009.内交联羧甲基纤维素钠 29.82总量 993.82
每片含有扑热息痛500mg和碳酸氢钠370mg，其中碳酸氢钠∶扑热息痛的比例为0.74∶1。
实施例5
按照与实施例1和2相似的方法，使用不同重量各组分制备片剂(目标重量1430.7mg)，其最终组成如下：组分 mg/片1.扑热息痛(细粉) 500.002.碳酸氢钠(细粉) 800.003.淀粉(玉米) 21.404.淀粉(预凝胶化) 50.005.聚维酮K25 2.006.山梨酸钾 0.607.滑石 15.008.硬脂酸 5.009.内交联羧甲基纤维素钠 36.70总量 1430.70
每片含有扑热息痛500mg和碳酸氢钠800mg，其中碳酸氢钠∶扑热息痛的比例为1.6∶1。
实施例6
按照与实施例1和2相似的方法，使用不同重量各组分制备片剂(目标重量923.82mg)，其最终组成如下：组分 mg/片1.扑热息痛(细粉) 400.002.碳酸氢钠(细粉) 400.003.淀粉(玉米) 21.404.淀粉(预凝胶化) 50.005.聚维酮K25 2.006.山梨酸钾 0.607.滑石 15.008.硬脂酸 5.009.内交联羧甲基纤维素钠 29.82总量 923.82
每片含有扑热息痛400mg和碳酸氢钠400mg，其中碳酸氢钠∶扑热息痛的比例为1∶1。
实施例7
按照与实施例1和2相似的方法，使用不同重量各组分制备片剂(目标重量1223.82mg)，其最终组成如下：组分 mg/片1.扑热息痛(细粉) 600.002.碳酸氢钠(细粉) 500.003.淀粉(玉米) 21.404.淀粉(预凝胶化) 50.005.聚维酮K25 2.006.山梨酸钾 0.607.滑石 15.008.硬脂酸 5.009.内交联羧甲基纤维素钠 29.82总量 1223.82
每片含有扑热息痛600mg和碳酸氢钠500mg，其中碳酸氢钠∶扑热息痛的比例为0.83∶1。
实施例8
按照与实施例1和2相似的方法，使用不同重量各组分制备片剂(目标重量819.46mg)，其最终组成如下：组分 mg/片1.扑热息痛(细粉) 325.002.碳酸氢钠(细粉) 409.503.淀粉(玉米) 13.914.淀粉(预凝胶化) 32.505.聚维酮K25 1.306.山梨酸钾 0.397.滑石 9.758.硬脂酸 3.259.内交联羧甲基纤维素钠 23.86总量 819.46
每片含有扑热息痛325mg和碳酸氢钠409.5mg，其中碳酸氢钠∶扑热息痛的比例为1.26∶1。
实施例9
将组分1至7混合并用适宜的压片机压制，制备了片剂(目标重量1291.56mg)：组分 mg/片1.直接压片级扑热息痛(90％) 555.562.碳酸氢钠 630.003.微晶纤维素 50.004.Explotab(淀粉甘醇酸钠) 25.005.交联聚维酮XL 10 25.006.十二烷基硫酸钠 3.007.硬脂酸镁 3.00总量 1291.56
每片含有扑热息痛500mg和碳酸氢钠630mg，其中碳酸氢钠∶扑热息痛的比例为1.26∶1。
实施例10
胶囊制备如下：
重复实施例1和2的制粒、过筛和混合步骤。将所得粉末填入明胶胶囊，目标填入重量为819.46mg，于是最后组成如下：
组分 mg/片
1.扑热息痛(细粉) 325.00
2.碳酸氢钠(细粉) 409.50
3.淀粉(玉米) 13.91
4.淀粉(预凝胶化) 32.50
5.聚维酮K25 1.30
6.山梨酸钾 0.39
7.滑石 9.75
8.硬脂酸 3.25
9.内交联羧甲基纤维素钠 23.86
总量 819.46
每胶囊含有扑热息痛325mg和碳酸氢钠409.5mg，其中碳酸氢钠∶扑热息痛的比例为1.26∶1。
对比实施例A
按照与实施例1和2相似的方法，使用不同重量各组分制备片剂(目标重量988.23mg)，并用碳酸钙代替碳酸氢钠，其最终组成如下：
组分 mg/片
1.扑热息痛(细粉) 500.00
2.碳酸钙 375.00
3.淀粉(玉米) 21.40
4.淀粉(预凝胶化) 50.00
5.聚维酮K25 2.00
6.山梨酸钾 0.60
7.滑石 15.00
8.硬脂酸 5.00
9.内交联羧甲基纤维素钠 19.23
总量 988.23
每片含有扑热息痛500mg和碳酸钙375mg，其中碳酸钙∶扑热息痛的比例为0.75∶1。
生物研究
用15位禁食的健康人自愿者以5种形式进行交叉药代动力学比较研究下述产物：
试验制剂A 实施例2的片剂
试验制剂B 实施例3的片剂
试验制剂C 对比实施例A的片剂
试验制剂D 商购吞咽片剂，其中含有扑热息痛
(500mg)，不含碳酸氢钠
试验制剂E 商购溶解性片剂，其中含有扑热息痛
(500mg)和碳酸氢钠(1342mg)
每个自愿者吞咽2片上述一种制剂，随后在至少48小时内分5个时间间隔分别饮用共100ml水。对于试验制剂E，吞咽前将2片溶解于100ml水中。在给药后5、10、15、20、25、30、35、40、45、50、60、75、90、120、180、240、360、480和720分钟采集血样。
用HPLC测定扑热息痛的血清浓度，并给每个自愿者做出扑热息痛血清浓度对时间曲线。任何制剂的血清浓度对时间曲线下的面积(AUC0-∞)无显著性差异。
给药后血清中扑热息痛的最大浓度(Cmax)如下：
试验制剂A 30mg/L
试验制剂B 26mg/L
试验制剂C 15mg/L
试验制剂D 17mg/L
试验制剂E 20mg/L
制剂A的Cmax显著高于制剂C(p＜0.0002)、D(p＜0.002)和E(p＜0.02)。制剂A和B的Cmax之间无显著性差异。制剂B的Cmax显著高于制剂C(p＜0.01)和制剂D(p＜0.02)。
计算出给药后0至20分钟血清浓度对时间曲线下的平均面积(AUC0-20)，结果如下：
试验制剂A 245mg.min/L
试验制剂B 177mg.min/L
试验制剂C 76.0mg.min/L
试验制剂D 69.7mg.min/L
试验制剂E 199mg.min/L
制剂A的(AUC0-20)比制剂D的大3.5倍，制剂B(AUC0-20)比制剂D的大2.5倍，这些差异具有统计学显著性，说明本发明的扑热息痛的吸收比常规吞咽片剂最多升高了250％倍。
Claims (7)
1.一种吞咽片剂或胶囊制剂，其中含有300mg至600mg的扑热息痛和300mg至1200mg的碳酸氢钠及至少一种药用赋形剂，其中碳酸氢钠与扑热息痛的重量比至少为0.74∶1。
2.权利要求1所述的制剂，其中含有至少370mg的碳酸氢钠。
3.权利要求1或2所述的制剂，其中含有不超过1000mg的碳酸氢钠。
4.权利要求1至3任一项所述的制剂，其中含有500mg的扑热息痛。
5.权利要求1至3任一项所述的制剂，其中含有325mg的扑热息痛。
6.权利要求1至5任一项所述的制剂，其中碳酸氢钠与扑热息痛的重量比至少为0.8∶1。
7.制备权利要求1至6任一项所述的吞咽片剂或胶囊制剂的方法，该方法包括将扑热息痛和碳酸氢钠与任何药用赋形剂、其它药用活性试剂或辅剂一起混合。
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| US9060950B2 (en) * | 2005-06-13 | 2015-06-23 | Paul H. Rosenberg, Proximate Concepts, LLC. | Emetic embedded capsule |
| KR100702069B1 (ko) * | 2005-10-31 | 2007-03-30 | (주)이엘티사이언스 | 파라세타몰 경구용 수용산제 복합조성물 및 그 제조방법 |
| EP3449928A1 (en) | 2005-11-28 | 2019-03-06 | Imaginot Pty Ltd. | Oral therapeutic compound delivery system |
| GB0607085D0 (en) * | 2006-04-07 | 2006-05-17 | Smithkline Beecham Corp | Novel compositions |
| WO2008008120A1 (en) * | 2006-07-14 | 2008-01-17 | Fmc Corporation | Solid form |
| US20080311162A1 (en) * | 2007-05-16 | 2008-12-18 | Olivia Darmuzey | Solid form |
| AU2008285244B2 (en) * | 2007-08-07 | 2015-02-19 | Stellenbosch University | A medicament |
| KR101687580B1 (ko) | 2016-07-19 | 2016-12-20 | 주식회사 씨.월드 | 의자 등받이부와 프레임부 조립구조 |
| MX2021005691A (es) | 2018-11-19 | 2021-07-07 | Jazz Pharmaceuticals Ireland Ltd | Formulaciones de farmacos resistentes al alcohol. |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1182049A (en) | 1981-07-13 | 1985-02-05 | Francis J. Sterbenz | Apap antacid composition |
| US4942039A (en) * | 1989-05-09 | 1990-07-17 | Miles Inc. | Effervescent analgesic antacid composition having reduced sodium content |
| ES2060736T3 (es) | 1989-01-12 | 1994-12-01 | Bayer Ag | Composicion antiacida analgesica efervescente con un contenido en sodio reducido. |
| US5348745A (en) * | 1989-05-09 | 1994-09-20 | Miles Inc. | Aqueous granulation solution and a method of tablet granulation |
| CA2021548A1 (en) * | 1989-09-01 | 1991-03-02 | Ronald Nash Duvall | Effervescent cold or sinus allergy medicine composition having reduced sodium content |
| DE19502789A1 (de) | 1995-01-28 | 1996-08-01 | Dirk Krischenowski | Arzneimittel |
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1997
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1998
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- 1998-02-27 AU AU68282/98A patent/AU721851B2/en not_active Expired
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Address after: Ireland Waterford Patentee after: GlaxoSmithKline consumer health investment company (Ireland) No. two Address before: Ireland Waterford Patentee before: GlaxoSmithKline consumer health Investments Ltd. (Ireland) No two Address after: The British England Middlesex County Patentee after: Smith Klein Beecham LLC Address before: The British England Middlesex County Patentee before: Smithkline Beecham PLC |
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Effective date of registration: 20140929 Address after: Ireland Waterford Patentee after: GlaxoSmithKline consumer health Investments Ltd. (Ireland) No two Address before: Ireland Waterford Patentee before: GlaxoSmithKline Deng Gavin LLC Effective date of registration: 20140929 Address after: Ireland Waterford Patentee after: GlaxoSmithKline Deng Gavin LLC Address before: The British England Middlesex County Patentee before: Smith Klein Beecham LLC |
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