CN87102758A - 能延续释放的新药物制剂 - Google Patents
能延续释放的新药物制剂 Download PDFInfo
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- CN87102758A CN87102758A CN87102758.5A CN87102758A CN87102758A CN 87102758 A CN87102758 A CN 87102758A CN 87102758 A CN87102758 A CN 87102758A CN 87102758 A CN87102758 A CN 87102758A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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Abstract
一种能延续释放的低溶解度的活性化合物制剂及其制备方法。所说的活性化合物是溶解或分散于半固体或液体的非离子型增溶剂之中，而且增溶剂的重量至少需与活性化合物的重量相等。
Description
本发明是关于一种能延续释放药物的低溶解度活性化合物的制剂，尤其是关于取代的二氢吡啶以及这类制剂的制备方法。
本发明的目的在于取得具有高生物利用度和延读释放的活性化合物的固体制剂。该化合物一般溶解度很低。
水溶性很差的药物，由于其低溶解速率而产生配制问题。它们的功效可能受到严格限制，而且人与人之间对于它们的吸收也可能存在很大的差异。溶解度很低的药物之实例是一些取代的二氢吡啶化合物，诸如硝苯啶（nifedipine）和非洛地平（felodipine）。所述二氢吡啶一般类属钙拮抗剂。这种拮抗剂广泛用于心血管性病症，如局部缺血心脏病和低动脉压的治疗。上述的一种二氢吡啶，即非洛地平，在其水的溶解度仅为0.5毫克/升。其他低溶解度的药物例子是，灰黄霉素、地高辛、去甲羟基安定、苯妥英和环斯坡任（cyclosporine）。
现有文献介绍过增加药物吸收的一些方法。在德意志联邦共和国专利申请公开号3024858中介绍了其中一种方法，该方法为了提高肠中活性化合物的吸收而采用无定形微溶的取代的二氢吡啶、尼卡地平（nicardipine）。在欧洲专利申请号47899中介绍了另一种方法，该方法为使生物利用度提高到某种程度而采用了实际上不溶解的二氢吡啶、硝苯啶的细结晶体。Ed S.H.Yalkowsky在药物和药用科学第12卷中的“药物溶解作用的技术”也介绍了上述那些方法和其他一些方法。该篇介绍与本发明特别有关的是为了提高溶解度很低的药物的生物利用度可采用具表面活性剂的增溶剂。一般认为，吸收性的改进可归于三种方法：（1）提高水分，（2）提高薄膜渗透率和（3）增溶作用。公开文献介绍了若干实施例，并在有关药物溶解技术，尤其是提高低溶解度药物的生物利用度方面作了充分的述评。
由德意志联邦共和国专利申请公开号3400106已知控制释放的制剂，含有一种或多种天然的聚合物、部份合成聚合物或合成聚合物，一种或多种亲脂性溶剂和（或）亲水性溶剂或与一种或多种药用活性化合物在一起的增稠剂。在实施例中说明增溶剂用于活性化合物的适宜重量较1∶1小得多。
在各种疾病的药物治疗中，例如心血管性、肠胃和化学治疗领域里，使所施的药在血液里保持稳定浓度是有利的。因此，药物制剂的延续释放是必要的。
延续释放制剂在整个治疗的剂量间隔中释放出需要的药量以维持足够和平稳的作用，这是很重要的。这一般是指药物必须按恒速释放，使血液中的药有均匀浓度。这对于治疗指数小，即效应浓度与毒性浓度差异小的药物尤其重要。药物的延时释放和恒定释放对于当产生大的局部浓度便有引起肠胃障碍潜在危险的局部刺激药物和半寿期短的药物也是很重要的。就后一种情况来说，与普通剂量型相比，延续释放制剂可以达到投药不太频繁而且因此可以更好地符合病人的需要量（参看Hayes R.B.等人的Clin.Pharm.Ther.（1977），22，第125-130页）。
已知延续释放型的药物，一般给药途径是通过口服。这类制剂最好是使药物延续和重复释放并有助于重复吸收，该制剂应是无毒性或无刺激性组成物，而且也适合于高剂量药物。通常，延续的释放是由控制剂量型的药物溶解和（或）扩散而获得。若干种材料可作为这种用途，例如腊、脂质材料、聚合物、天然胶、合成胶和半合成胶。在胶之中，羟丙基甲基纤维素（HPMC）成为重要的一类，这是由于它对pH无依赖性和来源于半合成之故。有关供口控释放剂量型的亲水性基质纤维素醚的研突究已示于Alderman D.A.Int.J.Pharm.Tech.& Prod.Mfr（1984）5（3）1-9中。有关HPMC的化学处理产生所需要的组成以及这些特性的应用，在美国3087790、美国4226849、美国4357469和美国4369172中作了公开。而瑞典专利申请号8008646-5介绍了HPMC和羟丙基纤维素的组合物。该组合物用于控制活性化合物的药物释放速度。
当使用亲水性基质时，在片剂暴露于肠胃液或唾液后，可溶性聚合物围绕着片剂构成胶状层。药物释放受到水渗入所构成的胶层的速度以及通过所构成的胶层扩散药物的限制（Bamba等人Int.J.Pharm（1979），2，307）。在系统中胶结构的浸蚀也是药物释放的重要作用过程。为了防止片剂溶解太快，必须使所用的聚合物急速形成水合物（Alderman 1984）。
由肠道进入循环的低溶解度药物其吸收速率接近于溶解速率。由于低溶解速率导致低生物利用度，所以难以降低吸收速率，即增加持续时间，但不会同时降低生物利用度。
本发明的目的在于提供低溶解度药物的制剂。该制剂显示了药物吸收可在一段长期间内延长并接近稳定，同时保持高生物利用度。通过使用作为混合低溶解度药物的增溶剂而达到上述目的。按照本发明的适宜的增溶剂将在下面详细说明。化合物最好溶解或分解在增溶剂中。活性化合物（药物）和增溶剂的混合物可以用水或肠液稀释，稀释后的溶液没有显著的溶解的药物沉淀。在溶液中，药物被包含在增溶剂构成胶粒结构中。以其他一般所用的增溶剂或共溶剂稀释则可能产生药物沉淀。将药物和增溶剂的合剂并入可提供延长释放的药物组成物中。
按本发明，适于作为提供延续释放制剂的药物是一种化合物，其特征为溶解度极低，即在水中少于0.1%（重量）。另外，它们可溶于增溶剂或增溶剂和水的混合溶剂中。按本发明，适宜药物的样品是一些取代的二氢吡啶，如硝苯啶和非洛地平。非洛地平是4-（2，3-二氯苯基）-1，4-二氢-2，6-二甲基-3，5-吡啶二羧酸乙基甲基酯。硝苯啶是1，4-二氢-2，6-二甲基-4-（2-硝基苯）-3，5-吡啶二羧酸二甲酯。非洛地平和硝苯定两者实际上都为不溶性化合物，所以它们都非常适宜于增溶溶解。溶解度极低的药物的其他样品为灰黄霉素、地高辛、去甲羟基安定、苯妥英和环斯玻任。
按本发明，适合于制剂的增溶剂为半固体或液体的非离子型表面活性剂，主要是如含有聚乙二醇的酯类或醚类。它们最好选自聚乙氧基脂肪酸、羟基脂肪酸和脂肪族醇。增溶剂尤其要优先选自一组包括聚乙氧基蓖麻油、聚乙氧基氢化蓖麻油、来源于蓖麻油的聚乙氧基脂肪酸或来源于氢化蓖麻油的聚乙氧基脂肪酸的化合物中。市场上可买到的增溶剂，已知可以采用商品名为Cremophor、Myrj、Polyoxy 40硬脂酸酯、Emerest 2675、Lipal 395和HCO 50。尤其理想的增溶剂是Cremophor
RH 40（西德苯胺烧碱工厂<BASF>）。
混以增溶剂的活性化合物是并入已知的各种释放控制系统中，例如一种亲水的凝胶系统，包上控速薄膜的小圆珠。它们可以是减速扩散包层或分解包层或带有多孔惰性基质的片剂。按本发明，增溶溶解的药物最好与亲水性凝胶结合，即亲水膨胀基质，例如HPMC。这种形式的释放控制机理是控制胶粒中药物和增溶剂释放的一种适宜方法。技术特性良好，在体内的实验也令人满意。在已测定的各种亲水性材料中，HPMC、羟丙基甲基纤维素是最好的凝胶型材料。在亲水性凝胶系统中可使活性化合物释出的其他适宜化合物的样品为果阿胶、汉生胶、羧基聚亚甲基、各种不同的纤维材料（如羧甲基纤维素钠和羧丙基纤维素钠）、乳糖和硅酸铝。
按本发明的制剂含有20-80%（重量）的亲水性凝胶系统，最好是含30-50%（重量）。
亲水性凝胶的主要部份的粘度为100厘泊以下。尤其要优先使用羟丙基含量为4-12%（重量），特别是8.5%（重量），而且粘度低于100厘泊，如6、15和（或）50厘泊的HPMC。粘度是用如美国药典（Pharmacopeia ⅩⅪ，1985，第672页）所述的标准方法测量。
最终制剂，例如凝胶片剂型。小心选择充填剂和粘合剂以及形成凝胶的材料以制成商业上可接受的制剂形式，例如在活性化合物的吸收和作期间的延长方面有意想不到的好效果的片剂或包含粒状凝胶的硬胶囊剂。按本发明的制剂，其中活性化合物和增溶剂的比例在1∶1至1∶10范围内变动，最好在1∶2至1∶6范围内。
按本发明，其他类型的控制释放制剂也可以用，例如有多孔惰性基质的片剂、含有减速扩散包层颗粒的胶囊剂或含有分解包层的胶囊剂。
具有多孔惰性基质的片剂是通过药物和增溶剂与水不溶性聚合物或蜡并与充填剂和粘合剂混合而获得的。聚乙酸乙烯酯、聚氯乙烯、乙基纤维素、石蜡和乙酸邻苯二甲酸纤维素可用作适宜的减速扩散聚合物。充填剂和粘合剂是固体的，而载体是粉末的，诸如乳糖、蔗糖、山梨醇、甘露醇、淀粉、支链淀粉、纤维素衍生物、明胶或其他适宜载体。混合物用溶剂，例如用水或乙醇或含有水和共聚物，如聚乙烯吡咯烷酮溶液润湿。也可以加入润滑剂，如硬脂酸镁、硬脂酸钙、硬脂酰富马酸钠、聚乙二醇和蜡。然后把混合物制成片剂。
含具有延续释放特性颗粒的胶囊剂是通过制作一个包含药物和增溶剂连同充填剂的芯材而获得。再将芯材表面包以扩散一减速的水不溶性聚合物或蜡。然后将颗粒装入硬胶囊里。芯材可以通过药物和增溶剂与小心选择的充填剂，如乳酸、山梨醇、淀粉、纤维素衍生物或其他适宜的充填剂相混合而制取。混合物用溶剂，如水或乙醇或含有诸如水和聚合物，如聚乙烯吡咯烷酮的溶液润湿。用挤压法或球化处理把块丸制成颗粒。在所形成的芯材表面包以含溶剂，如氯乙烯和（或）异丙醇和水不溶聚合物，如乙基纤维素的溶液。然后将颗粒装入硬胶囊里。
现以下面的实例来说明本发明：
例1
克
非洛地平 10
Cremophor RH 40 90
磷酸钙 250
羟丙基甲基纤维素2910 6厘泊 250
汉生胶 25
果阿胶 25
硬脂酰富马酸钠 13
按例1的成分可制成每片含10毫克非洛地平的亲水性基质的片剂。该片剂可按下述方法制备：
把非洛地平溶解于Cremophor RH40，将所取得的溶液小心地与载体材料HPMC、汉生胶、果阿胶和磷酸钙混合。用乙醇使混合物粒化并干燥。加入硬脂酰富马酸钠作为润滑剂并以压片机压制成片剂。
例2
克
非洛地平 10
Cremophor RH 60 90
硅酸铝 100
石蜡 80
羟丙基纤维素 7.5
硬脂酰富马酸钠 5.0
按例2的成分可制成每片含10毫克非洛地平的多孔惰性基质的控制释放的片剂。该片剂可按下述方法制备：
把非洛地平溶解于Cremophor RH60，将所取得的溶液小心地与载体材料硅酸铝和石蜡混合。用羟丙基纤维素的乙醇溶液使之粒化并干燥。加入硬脂酰富马酸钠作为润滑剂并以压片机压制成片剂。根据玻璃试管内的结果，取得的非洛地平的控制释放为2小时后释放50%和6小时后释放100%。
例3
克
非洛地平 20
Cremophor RH 40 100
聚乙烯基吡咯烷酮 66.5
微晶纤维素 62
玉米淀粉 29.5
乳酸 157
乙基纤维素 36
羟丙基甲基纤维素2910 6厘泊 12
胶囊
按例3的成分可制成每个胶囊含20毫克非洛地平的控制释放胶囊剂。该胶囊剂可按下述方法制备：
把非洛地平溶解于Cremophor并将所取得的溶液小心地与载体，聚乙烯吡咯烷酮、纤维素、玉米淀粉和乳酸混合。混合物用水润湿并使之粒化。把取得的粒剂进行干燥和过筛，并选用粒径为0.71-1.12毫米的粒剂。芯材用乙基纤维素的氯乙烯和乙醇混合的溶液包层。把包层颗粒装入胶囊里。
例4
克
非洛地平 20
Myrj 51 120
羟丙基甲基纤维素2910 50厘泊 200
微晶纤维素 20
乳糖 167
硬脂酰富马酸钠 10.5
按例4的成分可制成每片含20毫克非洛地平的控制释放片剂。该片剂的制备方法同例1所述。
例5
克
硝苯定 20
Cremophor RH 40 50
羟丙基甲基维维素2910 50厘泊 70
羟丙基甲基纤维素2910 6厘泊 160
微晶纤维素 6
乳糖 56
硅酸铝 94
硬脂酰富马酸钠 10
按例5的成分可制成每片含20毫克硝苯啶的亲水性片剂。该片剂的制备方法同例1所述。
目前例5被认为是本发明的最佳实施方案。
参考例A
以下实例说明用于体内研究的参考片剂。
克
非洛地平 25
乳糖 250
甲基纤维素 0.5
聚乙烯吡咯烷酮 1.5
硬脂酸镁 3
按参考例A的成分可制成每片含25毫克非洛地平的速溶常规片剂。该片剂按下述方法制备：
使非洛地平微粉化并与乳糖和甲基纤维素混合。该混合物用水使之粒化并干燥。加入聚乙烯吡咯烷酮和硬脂酸镁并把块状物压制成片剂。
参考例B
克
非洛地平 66
甲基纤维素 13
甘露醇 870
聚乙烯吡咯烷酮 30
微晶纤维素 40
乙基纤维素N 10 34
聚乙二醇6000 41.8
按参考例B的成分可制成每胶囊含10毫克非洛地平的控制释放胶囊剂。该胶囊剂按下述方法制备：
使非洛地平微粉化并小心地与载体、甘露醇、甲基纤维素、聚乙烯吡咯烷酮和纤维素混合。该混合物用水润湿并进行球化处理。把所获得的颗粒干燥、过筛，并选用粒径为0.71-1.12毫米的粒剂。芯材用乙基纤维素和聚乙二醇的氯乙烯和异丙醇混合的溶液包层。包层的颗粒装入硬胶囊里。
下面是关于生物利用度的研究：
非洛地平
附图1说明按例1、4和参考例A的组合剂的平均血浆值（毫微摩尔/升）。按本发明制备的含20毫克非洛地平控释制剂的单剂量施于6个健康的男性受验者。非洛地平的血浆浓度可与经单剂量（含25毫克非洛地平速溶片剂）给药之后的血浆浓度相比。可以看到，按本发明的制剂，其血浆浓度给出较低峰值而速溶片剂则给出不希望有的高峰值。
时间由0直到无限所对应的血浆浓度曲线下面的面积（AUC）为：
制剂 剂量 毫克 AUC/剂量 毫微摩尔·小时-1·升·毫克-1
参考例A 25 7.2
例1 20 8.8
例4 20 7.4
由此表可以看到非洛地平的生物利用度并不随着控制释放制剂而减少。
附图2说明按例3和参考例B的组合剂的平均血浆值（毫微摩尔/升）。按本发明制备的含20毫克非洛地平的控制释放制剂的单剂量施于5个健康男性受验者。非洛地平的血浆浓度可与经单剂量（含10毫克非洛地平，不含增溶剂的一般控制释放剂）给药之后的血浆浓度相比。可以看到，按本发明的制剂，其血浆浓度给出较低峰值和显著程度的生物利用度，而参考例的血浆浓度则测不出。这清楚地说明，如果需要控制释放制剂效应就必须有增溶剂。
硝苯定
附图3说明按例5的组合剂和含有硝苯定，Adalat
10毫克（Bayer）（参考例C）的参考组合剂的平均血浆值（毫微摩尔/升）。Adalat
是市场销售的快速释放制剂。以单剂量为含20毫克硝苯啶的本发明的控制释放制剂施于6个健康男性受验者。硝苯啶的血浆浓度可与经单剂量（含10毫克硝苯定的参考组合剂）给药后的血浆浓度相比。可以看到，按本发明制剂，其血浆浓度给出较低峰值而参考制剂虽然剂量只为一半却给出不希望有的高峰值。当参考例C与例5相比时，可以看到生物利用度基本上没有降低。
时间从0直到无限时血浆浓度曲线下面的面积为：
制剂 剂量 毫克 AUC/剂量 毫微摩尔·小时-1·升·毫克-1
Adalat
，Bayer 10 46.5
例5 20 36.0
上述实例和附图1、2和3说明按本发明的控制释放制剂比传统的制剂或不含增溶剂的控制释放制剂（各种制剂均含相同的活性化合物）具有更多的优点。用溶解度极低的活性化合物的增溶作用可以获得更为稳定的血浆浓度分布图而没有不希望有的高峰值，而且在时间延续期间也可获得效应。当溶解变极低的药物配制后，通常生物利用度有所降低。但本发明提供的制备溶解度极低的药物的控制释放制剂的技术，它具有上述的优点且生物利用度没有显著的下降。
Claims (17)
1、一种能延续释放的低溶解度活性化合物的固体制剂，其特征在于它所含的活性化合物是溶解或分散于半固体或液体的非离子型增溶剂中，而增溶剂的重量至少需与活性化合物的重量相等。
2、按照权利要求1的制剂，其中的非离子型增溶剂是选自聚乙二醇的酯类和（或）醚类。
3、按照权利要求1和2中的一项或多项的制剂，其中非离子型增溶剂是选自聚乙氧基脂肪酸、羟基脂肪酸或脂肪族醇。
4、按照权利要求1和3中的一项或多项的制剂，其中非离子型增溶剂是选自聚乙氧基蓖麻油、聚乙氧基氢化蓖麻油、来自蓖麻油的聚乙氧基脂肪酸或来自氢化蓖麻油的聚乙氧基脂肪酸。
5、按照权利要求4的制剂，其中非离子型增溶剂是氢化蓖麻油脂肪酸与氧乙烯甘油形成的酯类，尤其是Cremophor
RH 40（BASF）。
6、按照权利要求1的制剂，其中活性化合物和增溶剂之间的比例在1∶1至1∶10的范围内变动，最好在1∶2至1∶6的范围内。
7、按照权利要求1-6中的一项或多项的制剂，其中活性化合物在水中的溶解度为1∶1000或小于1∶1000（重量）并可溶于非离子型增溶剂或溶于水和非离子型增溶剂混合的溶剂中。
8、按照权利要求1-7中的一项或多项的制剂，其中活性化合物包含一种或多种取代的二氢吡啶。
9、按照权利要求8的制剂，其中取代的二氢吡啶是硝苯啶。
10、按照权利要求8的制剂，其中取代的二氢吡啶是非洛地平。
11、按照权利要求1-10中任何一项的制剂，其中所说的释放是由多孔惰性基质、扩散减速包层或分解包层控制。
12、按照权利要求1-10中任何一项的制剂，其中所说的释放是由亲水性凝胶系统控制。
13、按照权利要求12的制剂，其中亲水性成胶组分占制剂20-80%（重量）之间。
14、按照权利要求12和13的制剂，其中亲水性凝胶系统包括羟丙基甲基纤维素。
15、按照权利要求14的制剂，其中羟丙基甲基纤维素的羟丙基含量为4-12%（重量）。
16、按照权利要求12-14中的一项或多项的制剂，其中亲水性凝胶系统包含羧基聚亚甲基。
17、一种能延续释放的低溶解度活性化合物的固体制剂的制备方法，其特征在于活性化合物在溶解或分散于重量至少与活性化合物相等的半固体或液体的非离子型增溶剂之后，按已知方法把混合物并入适宜的释放控制系统中而配制成含药物剂量的单个制剂。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8601624-3 | 1986-04-11 | ||
| SE8601624A SE8601624D0 (sv) | 1986-04-11 | 1986-04-11 | New pharmaceutical preparations |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN87102758A true CN87102758A (zh) | 1987-10-21 |
| CN1025150C CN1025150C (zh) | 1994-06-29 |
Family
ID=20364135
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN87102758A Expired - Lifetime CN1025150C (zh) | 1986-04-11 | 1987-04-10 | 能延续释放的新药物制剂的制备方法 |
Country Status (34)
| Country | Link |
|---|---|
| US (1) | US4803081A (zh) |
| EP (1) | EP0249587B1 (zh) |
| JP (1) | JPH0778016B2 (zh) |
| KR (2) | KR870009720A (zh) |
| CN (1) | CN1025150C (zh) |
| AT (1) | ATE76288T1 (zh) |
| AU (1) | AU602677B2 (zh) |
| CA (1) | CA1304294C (zh) |
| CS (1) | CS270560B2 (zh) |
| CY (1) | CY1826A (zh) |
| DD (1) | DD263231A5 (zh) |
| DE (1) | DE3779183D1 (zh) |
| DK (1) | DK173033B1 (zh) |
| DZ (1) | DZ1067A1 (zh) |
| EG (1) | EG18265A (zh) |
| ES (1) | ES2031929T3 (zh) |
| FI (1) | FI91826C (zh) |
| GR (1) | GR3005286T3 (zh) |
| HK (1) | HK26795A (zh) |
| HU (1) | HU204699B (zh) |
| IE (1) | IE59419B1 (zh) |
| IS (1) | IS1553B (zh) |
| MY (1) | MY101553A (zh) |
| NO (1) | NO174795B (zh) |
| NZ (1) | NZ219633A (zh) |
| PH (1) | PH22494A (zh) |
| PL (1) | PL265078A1 (zh) |
| PT (1) | PT84663B (zh) |
| SE (1) | SE8601624D0 (zh) |
| SG (1) | SG4295G (zh) |
| SU (1) | SU1743332A3 (zh) |
| UA (1) | UA12336A (zh) |
| YU (1) | YU47258B (zh) |
| ZA (1) | ZA871911B (zh) |
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- 1987-04-10 SU SU874202349A patent/SU1743332A3/ru active
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- 1987-04-10 CS CS872587A patent/CS270560B2/cs not_active IP Right Cessation
- 1987-04-10 CN CN87102758A patent/CN1025150C/zh not_active Expired - Lifetime
- 1987-04-10 JP JP62087250A patent/JPH0778016B2/ja not_active Expired - Lifetime
- 1987-04-10 FI FI871585A patent/FI91826C/fi not_active IP Right Cessation
- 1987-04-10 UA UA4202349A patent/UA12336A/uk unknown
- 1987-04-10 PT PT84663A patent/PT84663B/pt unknown
- 1987-04-10 KR KR870003416A patent/KR870009720A/ko not_active Application Discontinuation
- 1987-04-10 IS IS3214A patent/IS1553B/is unknown
- 1987-07-06 KR KR1019870007169A patent/KR950002147B1/ko not_active IP Right Cessation
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1992
- 1992-07-29 GR GR920401616T patent/GR3005286T3/el unknown
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1995
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