CN1151784C - 快速吸收的液体组合物 - Google Patents
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Abstract
本发明提供对药学上可接受的胺的快速吸收的方法,该方法提供液体形式的与非甾族消炎药混合的药学上可接受的胺,优选的实施例采用假麻黄碱和异丁苯丙酸。
Description
本发明涉及包含止痛/消炎的酸性化合物和具有药理活性的胺的组合药物。在一个优选实施方式中,本发明涉及液体剂量形式的物质的组合。
组合多种药物活性成分的制品在世界各地都可买得到。消费者购买这些药物是因为它们可以同时缓解几种症状。例如以固体形式组合出售的异丁苯丙酸和假麻黄碱,如片剂、胶囊和再组装的粉末剂。异丁苯丙酸是有效的止痛/退热剂,而假麻黄碱是有效的减充血剂。这两种活性成分的组合对缓解鼻窦性头痛和风寒和流感的症状特别有效。美国专利4,552,899揭示了这样的异丁苯丙酸和假麻黄碱组合物。
尽管已知这样的制品是有效力的,但使用它们的消费者仍在寻求更快地缓解症状。因此,继续开发能快速缓解消费者症状的制品仍是一种长期的需求。
已经作了一些努力来提高各种药物活性开始发挥作用的速率,方法是提高它们口服后吸收入血的速率。例如PCT专利申请WO 98/38983揭示了提高止痛药乙酰氨基酚吸收速率的方法,系将它与重碳酸钠以特定的重量比混合装入片剂或胶囊中。Irwin等人[J.Pharm.Sci,58(3),1969年3月]揭示当服用季铵化合物与摩尔数远远过量的三氯乙酸酯的组合物溶液时,季铵化合物的吸收增强。Meyer和Manning[Pharm.Res.15(2),1998]讨论了采用疏水离子对来增强难溶于油脂的蛋白质和肽类药物的生物利用度。
目前,意外地发现,当胺与酸性非甾族消炎药(例如异丁苯丙酸)一起在液体介质中配成制剂时,具有药物活性的胺(例如假麻黄碱)的吸收速率提高。
本发明提供一种提高具有药理活性的胺的吸收的方法,该方法包括提供药学上有效剂量的胺,与有效剂量的非甾族消炎剂一同配制在液体介质中,用来提高胺的生物吸收度。
图1显示了液体剂量形式的异丁苯丙酸的药物动力学曲线。
图2显示了液体剂量形式的假麻黄碱的药物动力学曲线。
图3显示了固体剂量形式的假麻黄碱的药物动力学曲线。
用于本发明中的非甾族消炎药,常常称为NSAISDs,是本行业中众所周知的。它们可以选自丙酸衍生物、乙酸衍生物、灭酸衍生物和二苯基羧酸衍生物。因此,本文所用的NSAID一词可理解为任何非麻醉止痛的非甾族消炎化合物,包括其药学上可接受的属于上述化合物类别中的盐。可接受的盐包括钠、钾、精氨酸、赖氨酸等。
丙酸衍生物的具体例子包括异丁苯丙酸、甲氧萘丙酸、甲氧萘丙酸钠、fenoprefen、酮丙酸等。合适的乙酸衍生物包括茚甲新、毒素、苏灵大等。合适的灭酸衍生物包括甲灭酸和甲氯灭酸钠。合适的二苯基羧酸衍生物包括二氟苯水杨酸和氟苯沙酸。优选的NSAIDs是异丁苯丙酸、酮丙酸和甲氧萘丙酸。可以理解阿斯匹林不包括在用于本发明的NSAIDs定义内。
NSAID的剂量将随具体化合物的效力而变。这些止痛药的治疗剂量在本行业中是众所周知的,而且能够在Physician’Desk Reference(Medical EconomicsCompany,Montvale,新泽西)中找到。NSAID的优选剂量是每4-6小时40-800毫克的异丁苯丙酸。
药学上可接受的胺包括伯、仲、叔胺。药学上可接受的合适的胺包括假麻黄碱、苯基氨基丙醇、美沙芬、氯曲米通、苯海拉明、ioratadine、fexofenadine、citirazine、法莫替丁、甲胺呋硫、甲氰咪呱及其药学上可接受的盐。
胺的剂量随具体化合物的效力而变。这些止痛药的治疗剂量在本行业中是众所周知的,而且能够在Physician’Desk Reference(Medical EconomicsCompany,Montvale,新泽西)中找到。胺的优选剂量是每4-6小时15-60毫克的假麻黄碱,优选的组合物剂量是每5毫升100毫克异丁苯丙酸和15毫克假麻黄碱。
本发明考虑了任何稳定的液体形式的NSAID和胺,包括而不局限于溶液、乳液、分散液、胶状分散液、悬浮液、填充液软凝胶胶囊等。液体将采用在本行业中所熟知的合适的乳化剂、悬浮剂、分散剂,稳定剂或增溶剂和稀释剂。这里所使用的稳定液形式可理解为:该系统在普通的药用包装内,在液体制品的普通分装和储藏期间所遇到的条件下,可保持合格的物理、化学和微生物性能达至少30天、更好至少12个月、最好至少24个月。
NSAID将是溶解的或悬浮的,但优选悬浮的。而胺实际上溶解于液体介质中。本文所用的悬浮液可理解为一个这样的体系:其中小颗粒或多或少地均匀分散在液体介质中。悬浮液将采用本行业中所熟知的合适的悬浮剂和分散剂,例如见美国专利No.5,375,659,其内容在这里引入以供参考。这种悬浮材料的例子包括但不局限于:多糖,如纤维素衍生物、淀粉和淀粉衍生物、黄原胶、carageenan、刺槐豆胶等;湿润剂,如月桂基硫酸钠、和烷基聚氧乙烯硫酸盐;磺酸盐,如季铵化合物;非离子材料,例如聚氧乙烯脂肪醇醚、山梨糖醇脂肪酯和聚氧乙烯山梨糖醇脂肪酸酯。美国专利No.5,374,659所揭示的优选体系包括黄原胶、预凝胶淀粉和单油酸聚氧乙烯酯。另外的加入剂在1975年Osal和Hoover编辑的Remmington′s Pharmaceutical Sciences,第15版中有说明。
悬浮剂的用量约为0.1-5%(重量),更优为0.25-3%(重量),最优为0.5-2%(重量)。尽管可以使用药学上可接受的任何溶剂,但水是优选的溶剂体系。
除了NSAID和胺成分,本发明的组合物也可以包含其他具有药理活性的成分,包括抗组胺剂、减充血剂、止咳药和化痰药。这些具有药理活性的成分一般以已知的有效剂量提供,见美国专利No.4,552,889。
本发明的组合物在服药后的早期,与其他胺组合物相比,具有人体内胺量的增高。早期体内的药量是自吞下药至1或2小时之后(AUC 1H或AUC 2H),由血液、血浆或血清的药物浓度曲线下的面积测得。总药量是外推至无限长时间(AUC无限)的浓度曲线下的面积。对比研究表明,相对于缺乏液体形式的有效量NSAID所获得的早期胺量(AUC 1H和AUC 2H),服用本发明组合物后,早期(体内)胺量有所增高。
给予本发明的组合物后第一小时(AUC 1H)消费者血液内的早期胺量,比给予单组分液体制品所致的早期胺量约高10%、更优约高40%、最优约高80%。此外,给予本发明的组合物后第二小时(AUC 2H)消费者血液内的早期胺量,比给予单组分液体制品所致的早期胺量约高10%、更优约高20%、最优约高40%。
另外,本发明的组合物具有增高的CMAX。CMAX是血液、血浆或血清中的胺的最大浓度,与其他的胺液体组合物相比,它出现得较早。该变化也表明,与不含NSAID的胺相比,服用本发明的组合物后药学上可接受的胺的吸收速率增高或吸收提高。给予本发明组合物后消费者血液内的胺的最大浓度,比给予单组分液体制品所致的胺的最大浓度约高10%、更优约高12.5%、最优约高15%。
另外,本发明组合物提供的总胺量(AUC无限)与不含NSAID的胺制品提供的相等,表明药学上可接受的胺的吸收总量没有下降。
不希望受到任何理论的束缚,据认为本发明制品起作用是由于液体介质中形成了离子对。显然,该离子对在固体剂形中不会形成。离子对使药物胺更有效更快速地传递到血液中,因此与不含NSAID的液体形式胺制品或不含NSAID的固体形式的胺制品相比,提供了体内更高的早期药物量和较早出现更高的最大浓度。因此本发明将向消费者提供药理活性胺更快地发挥活性作用。
提供下面的实施例,来进一步说明本发明的权利要求,但本发明不受下面提供的实施例的限制。本文所用的mg理解为毫克,ng理解为毫微克,kg理解为千克,ml理解为毫升。
实施例1
对18-55岁的24位健康人,10个男人和14个女人进行了研究。他们经过3次治疗,研究期间隔至少1个星期,让药物排出。在每次研究之前晚,报告他们的临床地点,并保持隐居直至服药后14小时收集完最后的血液样品。
治疗A是服用1剂量测试的悬浮液,由7.5毫克/千克的异丁苯丙酸和1.125毫克/千克按美国专利5,621,005实施例1所公开方法制备的假麻黄碱HCl(表1中提供了成分)组成,加入异丁苯丙酸之后,再加入假麻黄碱HCl。治疗B是服用1剂量的Children′s Motrin异丁苯丙酸悬浮液(McNeil ConsumerHealthcare),由7.5毫克/千克异丁苯丙酸组成。治疗C是服用1剂量的Children′sSudafedNasal Decongestant Liquid(Warner Lambert),由1.125毫克/千克假麻黄碱组成。
表1
治疗A的悬浮液配方
成分 | (%w/v) |
丙三醇USP | 10.0 |
黄原胶N | 0.18 |
预凝胶淀粉 | 1.5 |
蔗糖NF | 35.0 |
着色剂 | 0.0038 |
聚山梨醇酯80NF | 0.05 |
人造香料 | 0.893 |
异丁苯丙酸USP | 2.0 |
假麻黄碱HCl USP | 0.30 |
苯甲酸钠NF | 0.20 |
柠檬酸USP | 0.18 |
纯化水USP | 64.2 |
前一夜禁食后,实验者吞下制品,并立刻喝6盎司液体水。服药前和服药后0.33、0.67、1、1.5、2、2.5、3、4、6、8、10、12和14小时采7毫升血液。从血液样品中分离血浆,并采用两种特殊的高效液相色谱法分别定量分析异丁苯丙酸和假麻黄碱。
采用非间隔密封小室方法测定血浆中异丁苯丙酸和假麻黄碱的以下单剂给药的药学动力学参数:1小时(AUC 1H)以内的早期药物量、2小时以内的早期药物量(AUC 2H),外推至无限长时间(AUC无限)的血浆浓度-时间曲线下的面积,和血浆浓度的峰值(CMAX)。药物吸收的速度或速率由AUC 1H、AUC 2H和CMAX反映出来。
分别分析了异丁苯丙酸和假麻黄碱参数平均值,形成三个期间、两次治疗有交叉。组合制品和单用异丁苯丙酸或单用假麻黄碱的平均值以方差分析(ANOVA)进行比较。ANOVA测得平均值有统计学意义的差异p值低于0.05。
异丁苯丙酸-假麻黄碱组合物悬浮液和Motrin悬浮液的异丁苯丙酸血浆浓度平均值与时间的关系曲线如图1所示。它们的形状相似,实际上是可重叠的,这表明与胺合用时,异丁苯丙酸的吸收速率没有变化。异丁苯丙酸-假麻黄碱组合物悬浮液和Sudafed液体的平均值曲线如图2所示。与市场出售的液体相比,胺以更快的速率从悬浮液组合物中被吸收,这由更陡的斜度和更高的峰值浓度反映出来。该观测结果是出乎意料的,因为假麻黄碱作为盐酸盐溶解于两种制品的液态载体中。
假麻黄碱的数据分析结果总结于表2中,它清楚地显示出胺的吸收速率由于液体剂形内的异丁苯丙酸而得以提高。与单组分液体胺制品相比时,本发明实施例的组合物在第一小时(AUC 1H)期间人体内早期胺量提高了93%,在第二小时(AUC 2H)期间提高了54%。该差异有统计学意义,因为两者的P值都等于0.0001。另外,液体组合物制品中的假麻黄碱血浆平均浓度峰值比Sudafed液体的高18%,而且早1小时出现。后面两种差异都有统计学意义。
表2假麻黄碱(PSE)的研究结果
参数 | SUDAFED液体 | IBU-PSE悬浮液 | 差异百分比 | ANOVA的p值 |
1小时以内的AUC(ng.h/mL) | 83.6 | 161.6 | +93% | 0.0001 |
2小时以内的AUC(ng.h/mL) | 299 | 461 | +54% | 0.0001 |
无限长的AUC(ng.h/mL) | 2633 | 2614 | -1% | NS |
CMAX(ng/mL) | 273 | 322 | +18% | 0.0001 |
NS=不具有统计学意义
对比性实施例2
对18-50岁的24健康男人进行了研究。他们经过4次治疗,研究期间隔最短1个星期,让药物排出。在每次研究之前晚,报告他们的临床地点,并保持隐居直至服药后24小时收集完最后的血液样品。
治疗A是服用含有200毫克异丁苯丙酸和30毫克假麻黄碱的一种组合物药片。治疗B是服用一种含有200毫克异丁苯丙酸的Nuprin药片(Bristol-Meyers)。治疗D是服用一种含有30毫克假麻黄碱的Sudafed药片(WarnerLambert)。
前一夜禁食后,实验者吞下制品,并立刻喝200毫升水。服药前和服药后0.25、0.5、0.75、1、1.5、2、3、4、6、8、10、12和24小时采集8毫升血液。从血液样品中分离出血浆,并分别采用高效液相色谱法和气相色谱法定量分析异丁苯丙酸和假麻黄碱。
采用非间隔密封小室方法测定血浆中异丁苯丙酸和假麻黄碱的以下单剂给药的药学动力学参数:1小时(AUC 1H)以内的早期药物量、2小时以内的早期药物量(AUC 2H),外推至无限长时间(AUC无限)的血浆浓度-时间曲线下的面积,血浆浓度的峰值(CMAX)。药物吸收的速度或速率由AUC 1H、AUC 2H和CMAX反映出来。
分别分析了异丁苯丙酸和假麻黄碱参数平均值,形成4个期间、3次治疗有交叉。组合制品和单用异丁苯丙酸或单用假麻黄碱的平均值以方差分析(ANOVA)进行比较。ANOVA测得平均值有统计学意义的差异p值低于0.05。
异丁苯丙酸-假麻黄碱组合物片剂的假麻黄碱平均值曲线,Sudafed药片单独服用和与NUPRIN药片一同服用的假麻黄碱平均值曲线如图3所示。它们的形状相似,实际上是可重叠的,这表明以固体剂形配制时,假麻黄碱的吸收速率没有变化。
假麻黄碱的数据分析结果总结于表3和4中,它清楚地显示出当配成药片时,胺的吸收速率不受异丁苯丙酸的影响。在下面的任何平均值之间:AUC1H、AUC 2H、AUC无限和CMAX,都没有统计学上有意义的差异。
表3比较治疗A和B的假麻黄碱(PSE)研究结果
参数 | SUDAFEDTablet(NUPRIN)片剂 | IBU-PSE差异 | p值百分比 | ANOVA |
1小时以内的AUC(ng.h/mL) | 43.8 | 43.2 | -1% | NS |
2小时以内的AUC(ng.h/mL) | 136 | 140 | +4% | NS |
无限长的AUC(ng.h/mL) | 1111 | 1203 | +8% | NS |
CMAX(ng/mL) | 102 | 107 | +5% | NS |
NS=不具有统计学意义
表4比较治疗A和D的假麻黄碱(PSE)研究结果
参数 | SUDAFEDTablet(单独)片剂 | IBU-PSE差异,p值 | 百分比 | ANOVA |
1小时以内的AUC(ng.h/mL) | 40.7 | 43.2 | +6% | NS |
2小时以内的AUC(ng.h/mL) | 134 | 140 | +3% | NS |
无限长的AUC(ng.h/mL) | 1125 | 1203 | +7% | NS |
CMAX(ng/mQ) | 104 | 107 | +3% | NS |
NS=不具有统计学意义
Claims (7)
1.一种组合物,它包括药理有效量的药学上可接受的胺和药理有效量的非甾族消炎药,所述胺和非甾族消炎药以稳定的液态悬浮液形式提供,所述悬浮液含有黄原胶、预凝胶淀粉、聚氧乙烯山梨糖醇单油酸酯;
所述组合物与相应的含有胺但不含非甾族消炎药的组合物相比,人体血液内胺的吸收率有增高。
2.如权利要求1所述的组合物,其中所述的非甾族消炎药是异丁苯丙酸,所述药学上可接受的胺是假麻黄碱。
3.如权利要求2所述的组合物,其中所提供的假麻黄碱每单位剂量为15-60毫克。
4.如权利要求2所述的组合物,其中所提供的异丁苯丙酸每单位剂量为40-800毫克。
5.如权利要求2所述的组合物,其中所述的增高的吸收量由AUC 1H表示,即:比单组分液体制品中同样胺的早期胺量至少高10%。
6.如权利要求2所述的组合物,其中所述的增高的吸收量由AUC 2H表示,即:比单组分液体制品中同样胺的早期胺量至少高10%。
7.如权利要求2所述的组合物,其中所述的增高的吸收量由CMAX表示,即:比单组分液体制品中同样胺的CMAX至少高10%。
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US09/329,900 | 1999-06-10 | ||
US09/329,900 US6211246B1 (en) | 1999-06-10 | 1999-06-10 | Rapidly absorbed liquid compositions |
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EP (1) | EP1059084B1 (zh) |
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CA (1) | CA2311039A1 (zh) |
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- 2000-06-07 AR ARP000102833A patent/AR024314A1/es not_active Application Discontinuation
- 2000-06-08 ZA ZA200002892A patent/ZA200002892B/xx unknown
- 2000-06-09 ES ES00304912T patent/ES2397262T3/es not_active Expired - Lifetime
- 2000-06-09 JP JP2000174301A patent/JP2001019638A/ja active Pending
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- 2003-06-26 US US10/608,170 patent/US7060730B2/en not_active Expired - Lifetime
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Publication number | Publication date |
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CN1277841A (zh) | 2000-12-27 |
KR20010007332A (ko) | 2001-01-26 |
CO5160329A1 (es) | 2002-05-30 |
AU3794300A (en) | 2000-12-14 |
US6211246B1 (en) | 2001-04-03 |
ZA200002892B (en) | 2001-12-10 |
ES2397262T3 (es) | 2013-03-05 |
US20030083379A1 (en) | 2003-05-01 |
US20040091508A1 (en) | 2004-05-13 |
AR024314A1 (es) | 2002-09-25 |
CA2311039A1 (en) | 2000-12-10 |
US20010005729A1 (en) | 2001-06-28 |
US20060128809A1 (en) | 2006-06-15 |
EP1059084B1 (en) | 2012-11-07 |
US20040091507A1 (en) | 2004-05-13 |
NZ504944A (en) | 2002-03-28 |
JP2001019638A (ja) | 2001-01-23 |
SA00210280B1 (ar) | 2005-12-26 |
US7060730B2 (en) | 2006-06-13 |
EP1059084A3 (en) | 2002-11-06 |
BR0002607A (pt) | 2001-01-02 |
EP1059084A2 (en) | 2000-12-13 |
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