CN1183960A - 用于口服的含有活性成分硝苯吡啶的缓释药物组合物 - Google Patents
用于口服的含有活性成分硝苯吡啶的缓释药物组合物 Download PDFInfo
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Abstract
用于口服的硝苯吡啶的药物组合物,其含有硝苯吡啶和聚乙烯吡咯烷酮的无定型共沉淀物以及合适的赋形剂,通过调节所用赋形剂的剂量和类型,其释放被调制到8—24小时。所述组物除了缓释的优点外,还表现有高的溶解度和生物利用度。
Description
硝苯吡啶是研究得最多的以及用得最多的位于血流缓慢的血管中的钙离子通道的抑制剂,这些钙离子通道影响着心肌、静脉平滑肌系统以及窦房结和房室结。
给药硝苯吡啶使增加冠状血流和减小外周静脉阻力得到解决,而对窦房结和房室结无实际妨碍。
因此,几年来都将硝苯吡啶用于高血压样病的治疗,在通常的多因子治疗方案中用于对心绞痛综合症的控制,以及由于这些病的慢性发生而将其用于长期治疗。
硝苯吡啶是一种晶状粉末,不溶于水,溶于丙酮和其他有机溶剂,对包括紫外光在内的不同波长的光敏感。
对硝苯吡啶的吸收呈现出强的个体差异,并且由于其是一个重要的治疗用途的参考药物的问题,所以针对证实物理特征、药物剂型和治疗效果之间的可能的联系,已有一些研究。
晶态硝苯吡啶在水中的溶解度低实际上导致其生物利用度低。
由于以上所述问题,已建议用多种溶剂,但是,这些溶剂表现出有缺限,即产生令人不满意的产物或者产物太复杂。
在欧洲专利0047899中证实了晶体大小对于治疗效果的目的的重要性,其中建议用由极细的、具有0.5-6m2/g的比表面积的硝苯吡啶的晶体获得的制剂。
在欧洲专利0220760B1中,硝苯吡啶的生物利用度与活性要素的微粉化过程有关,该过程是为了达到“非常高的比表面积”。
为克服与晶体大小有关的差异,甚至采用了工艺复杂的溶液,如溶于四氢化呋喃乙醇的衍生物中的硝苯吡啶溶液及随后的软胶囊剂(欧洲专利0143857)。
欧洲专利0315960建议用水溶液或水-醇溶液,以增加生物利用度:当然,克服了与晶体有关的差异,但又引起了诸如稳度性较低和生产复杂度较高的问题。
专利WO 93/13713中描述了由3种成份(硝苯吡啶、聚乙烯吡咯烷酮或衍生物,以及基于丙烯酸的聚合物)的混合物获得的缓解剂,其沉积在可溶于水的载体粒子上,使能获得适宜于每天给药一次的剂型。
专利GB 2166651A涉及称为“pharmasomes”的0.1-125微米的缓释微粒产品,其是通过复杂的工艺而获得的,其中把药物(实施例3中的硝苯吡啶)和适宜的聚合物增溶化,再乳化,然后除去溶剂相以得到被包被而掩盖气味或达到缓释的粉末。
本发明的用于口服的含有活性成份硝苯吡啶的缓释药物组合物克服了现有技术的这些问题。
所述组合物包括:
——硝苯吡啶和聚乙烯吡咯烷酮的无定形共沉淀物;
——一定剂量的纤维素的亲水衍生物,其重量为硝苯吡啶的0.1-6倍;
——一定剂量的羧基聚亚甲基和乳糖,其重量为硝苯吡啶的0.1-5倍;以及
——一种保护性的或缓释性的表面包衣。
所述组合物可以制成释放时间为8-24小时的片剂或胶囊形式。
制备本发明的用于口服的含有活性物质硝苯吡啶的缓释药物组合物,首先是进行硝苯吡啶和聚乙烯吡咯烷酮的无定形共沉淀物的制备,然后将所述共沉淀物用于制备与适宜的赋形剂混合的组合物。
根据以下方法来制备硝苯吡啶和聚乙烯吡咯烷酮的共沉淀物。
在有机溶剂(优选二氯甲烷)中制备硝苯吡啶和聚乙烯吡咯烷酮的溶液,其中硝苯吡啶的浓度为2.5-20%(重量),硝苯吡啶和聚乙烯吡咯烷酮的重量比为1∶1-1∶5。
然后在等于90℃的温度下于喷雾干燥器中处理所得的溶液。
所得的共沉淀物的形态为无定形粉末,以示差扫描量热法(DSC)分析其吸热熔化峰为大约175℃,无硝苯吡啶晶体的特征。
在图1中记录了用以下所述的实施例1中所得的共沉淀物得到的图形,为进行比较,在图2中记录了硝苯吡啶晶体的特性图。通过图4的硝苯吡啶和聚乙烯吡咯烷酮的共沉淀物的X-射线结晶衍射图与图3的硝苯吡啶的结晶衍射图相比较证实了共沉淀物的无定形特征。
用于制备本发明的组合物的共沉淀物的粒度小于100微米。
片剂形式的组合物的制备是根据以下步骤来实现的。
通过流化床技术掺入硝苯吡啶和聚乙烯的吡咯烷酮的共沉淀物、重量为硝苯吡啶的0.1-6倍的剂量的纤维素的亲水衍生物以及重量为硝苯吡啶的0.1-5倍的剂量的羧基聚亚甲基和乳糖制备颗粒。此外,还加入合适的有助于工艺过程的物质滑石、硬脂酸镁和胶态硅酸。
使用纯化后的水制粒。然后将所得的颗粒转变成片剂,该片剂覆盖有保护性的或缓释性表面薄膜。
所述纤维素的亲水衍生物选自羟丙基甲基纤维素、羟乙基纤维素、羟甲基纤维素、羟丙基纤维素、羧甲基纤维素,或上述物质以及纤维素的其他衍生物的混合物。
缓释性表面包衣含有一种物质,其选自丙烯酸聚合物、烷基纤维素、石蜡、硬脂酸、紫胶、氢化植物油或任何比例的前述物质的混合物、以及可能的诸如邻苯二甲酸二乙酯、邻苯二甲酸二丁酯、甘油三乙酯、聚乙二醇的增塑剂。
胶囊样组合物的制备可以用相同的用于片剂的微粒来完成,或者可以通过将硝苯吡啶和聚乙烯吡咯烷酮的共沉淀物施加到蔗糖和淀粉惰性核上,随后用诸如流化床技术以所述缓释性物质包被该胶囊样组合物以获得直径700-1400微米的球形颗粒而进行。
如在现有技术的描述中所述的,以必要的时间延迟方案并且通常与其它药物联合,将硝苯吡啶用于医治诸如原发性高血压和心绞痛的疾病的治疗中。
本发明的组合物允许1天给药1或2次,能有助于患者的剂量方案。
实际上,如实施例所说明的,通过改变纤维素的亲水衍生物羧基聚亚甲基和乳糖的剂量,可将硝苯吡啶从所述组合物的释放调节为8至24小时。
除片剂和胶囊形式之外,还可用崩解剂、球状体等将所述组合物制成其他诸如丸剂、糖膏、单剂或多剂粒剂的形式。
用于剂量单位的硝苯吡啶的含量为0.1-400mg。此外,本发明的组合还有其是用比现有技术更简单和更经济的方法制备的优点。
根据现有技术,如根据胃肠治疗体系(GITS:gastrointestinaltherapeutic system),只有通过用很复杂的方法,才能获得具有与本发明的组合物有类似特征的组合物。在“硝苯吡啶胃肠治疗体系”中描述了GITS技术[1987年12月21日,“美国医学杂志”(The American Journal ofMedicine),第83卷,增补6B]。
为说明本发明,对下述实施例进行了描述。
实施例1制备硝苯吡啶和聚乙烯吡咯烷酮的共沉淀物
于室温下,把1.0kg硝苯吡啶和1.0kg聚乙烯吡咯烷酮溶于18L二氯甲烷中。
于90℃温度下,用双液体喷嘴,并通过外部搅拌,用喷雾干燥器处理该得到的溶液。
得到一种固体共沉淀物,其硝苯吡啶和聚乙烯吡咯烷酮的重量比等于1∶1,且粒度小于100微米。
用示差扫描量热法分析该共沉淀物,得到图形(图1)的吸热熔化峰为大约175℃,无硝苯吡啶晶体的特征(所述作为对比的图2)。
此外,通过将图4的X-射线晶体衍射图(共沉淀物)和图3的晶体衍射图(硝苯吡啶)比较,证实了共沉淀物的无定形特征。
实施例2相当于30mg硝苯吡啶的片剂组成
用1∶1的硝苯吡啶和聚乙烯吡咯烷酮的共沉淀物制备得到如前所述的、粒度小于100微米的片剂组合物。
首先除硝苯吡啶和聚乙烯吡咯烷酮外,在流化床中掺入羟丙甲基纤维素、羧基聚亚甲基和滑石,制备颗粒。用纯化过的水,以得到颗粒;将颗粒与硬脂酸镁和胶态硅酸混合,得到片剂;然后用不透明的保护性薄膜包被片剂。
在下表中描述了有关片剂物质的或包衣物质的百分比组成。
——片剂物质硝苯吡啶 15.96%(重量)聚乙烯吡咯烷酮 15.96%(重量)滑石 30.31%(重量)羟丙甲基纤维素 31.91%(重量)羧基聚亚甲基 1.60%(重量)硬脂酸镁 1.06%(重量)胶态二氧化硅 1.60%(重量)
——包衣物质滑 0.49%(重量)硬脂酸镁 0.24%(重量)二氧化钛 0.37%(重量)氧化铁 0.04%(重量)丙烯酸共聚物 0.37%(重量)聚乙二醇4000 0.08%(重量)
片剂平均重量为188mg,根据美国药典中描述的实验2(Paddle<711>Dissolution)的溶出度方法,分析该片剂。
得到的结果见表1
表1
实施例2 | |
小时 | 溶出度% |
148 | 10.352.095.2 |
实施例3相当于60mg硝苯吡啶的片剂的组成
用实施例2中所述的微粒制备平均重量等于376mg的片剂,并对之进行实施例1中的溶出度实验。于表2中描述得到的结果。
表2
实施例3 | |
小时 | 溶出度% |
14812 | 11.949.883.597.5 |
实施例4适于每天给药1次的相当于30mg硝苯吡啶的片剂的组成
用与实施例2中所述的相类似的方法制备颗粒,将其与压缩赋形剂混合,并转变成含30mg硝苯吡啶的片剂。然后用不透明薄膜包被该片剂。
——片剂物质
硝苯吡啶 17.96%(重量)
聚乙烯吡咯烷酮 17.96%(重量)
滑石 35.93%(重量)
羟丙甲基纤维素 7.19%(重量)
羧基聚亚甲基 7.19%(重量)
硬脂酸镁 1.20%(重量)
胶态硅藻土 1.80%(重量)
乳糖 8.98%(重量)
——包衣物质
丙烯酸共聚物 0.42%(重量)
于表3中描述得到的结果,并将其与由相当剂量的GITS技术得到的市售产品进行比较。
表3
实施例4 | 30mg GITS片剂 | |
小时 | 溶出度% | 溶出度% |
148121624 | 2.614.236.858.475.494.8 | 3.011.233.555.077.299 |
在表3中可注意到本发明的片剂溶出度实际上与GITS片剂相当。
实施例5
适宜于每天给药1次的相当于60mg硝苯吡啶的片剂的组成
用实施例4中所述的颗粒,制备含60mg硝苯吡啶的片剂。
于表4中描述溶出度实验的结果,并比较其与GITS技术得到的相当剂量的市售产品。
表4
实施例5 | 60mg GITS片剂 | |
小时 | 溶出度% | 溶出度% |
148121624 | 2.814.432.550.868.592.8 | 3.714.033.650.969.399 |
实施例6
通过组成差异来改变溶出度分布
根据实施例4中所述的方法,通过将羟丙甲基纤维素含量降低25%,将羧基聚亚甲基含量降低50%,并维持其他成份含量不变,制备一种颗粒。
与实施例4中的溶解相比,得到的片剂有表5中所述的溶出度分布。
表5
实施例6 | 实施例4 | |
小时 | 溶出度% | 溶出度% |
148121624 | 11.326.048.968.187.598.8 | 2.614.236.858.475.494.8 |
实施例7
通过与实施例4中所述的相同的方法,将羟丙基纤维素含量降低25%,将羧基聚亚甲基含量降低75%,并将乳糖含量增加50%,制备微粒。在表6中比较得到的溶出度分布和实施例6中的溶出度分布。
表6
实施例7 | 实施例6 | |
小时 | 溶出度% | 溶出度% |
148121624 | 13.832.155.576.597.8- | 11.326.048.968.186.598.8 |
实施例4、6和7可预见的结果表明可以通过改变羟丙甲基纤维素、羧基聚亚甲基和乳糖含量来改变溶出度分布。
实施例8
适宜每天给药2次的相当于20mg硝苯吡啶的片剂的组成
制备了具适宜于每12小时给药20mg硝苯吡啶的溶出度分布的组合物。
如实施例2中所述,以下面列出的百分比组成制备颗粒:
——片剂物质
硝苯吡啶 18.02%(重量)
聚乙烯吡咯烷酮 18.02%(重量)
微晶纤维素 45.06%(重量)
羟丙甲基纤维素 5.41%(重量)
羧基聚亚甲基 1.60%(重量)
硬脂酸镁 0.87%(重量)
乳糖 9.21%(重量)
——包衣物质
滑石 0.53%(重量)
硬脂酸镁 0.28%(重量)
二氧化钛 0.41%(重量)
氧化铁 0.05%(重量)
异丁烯酸聚合物 0.42%(重量)
聚乙二醇4000 0.09%(重量)
表7
实施例8 | |
小时 | 溶出度% |
148 | 29.368.479.9 |
实施例9
适宜每天给药1次的相当于30mg硝苯吡啶的胶囊组成
使用流化床,把1∶1的硝苯吡啶和聚乙烯吡咯烷酮的共沉淀物、羟丙甲基纤维素和羧基聚亚甲基施加到蔗糖和淀粉的惰性核心上,得到直径为1200微米的球形颗粒(丸)。
分别用1∶10的A种和B种异丁烯酸铵盐共聚物溶液包被得到的球形颗粒,用甘油三乙酸酯增塑。该过程在同样的流化床中进行,在这一过程中加入作为润滑剂的滑石和抗静电剂。
百分比组成:滑石 12.8羟丙甲基纤维素 2.44聚乙烯吡咯烷酮 12.18羧基聚亚甲基 0.81惰性核心 45.45异丁烯酸铵共聚物 21.10滑石 1.62甘油三乙酸酯 4.22
将得到的球形颗粒定量填充至胶囊中以得到相当30mg硝苯吡啶的单位剂量。
对所述胶囊进行溶出度实验。表8示比较根据本专利获得的组合物与在市面上可购得的通过GITS技术生产和建议用于每天给药1次相当于30mg的硝苯吡啶的片剂。
表8
实施例9 | 30mg/GITS | |
小时 | 溶出度% | 溶出度% |
148121624 | 8.514.442.466.887.7100.0 | 3.011.233.555.077.299 |
实施例10
适宜每天给药1次的60mg硝苯吡啶的胶囊的组成
将如实施例6中所述的得到的丸片定量填充到胶囊中,以达到相当于60mg硝苯吡啶的剂量单位。
表9示与市面上可购得的由GITS技术生产的、定量60mg、用于每天给药1次的片剂相比较的溶出度实验结果。
表9
实施例10 | GITS | |
小时 | 溶出度% | 溶出度% |
148121624 | 8.916.145.469.188.099.2 | 3.714.033.650.969.399.3 |
所述实施例涉及到相当于20、30和60mg的剂量,这些剂量是更常用于治疗的、用于每次给药1次或2次的剂量。明了的是前述实施例的剂量组成也适宜于标量剂量,并且可以以不同的剂量(如10、20、30、40、60、80、90mg/给药剂量以及超出这些剂量之外)来制备片剂或胶囊。
对于给药的如用于制备片剂或胶囊的微粒或球形颗粒的每剂量组成,可以定量为0.1-400mg硝苯吡啶。维持百分比组成,可以重复固定的溶出度分布。
Claims (9)
1.用于口服含有活性物质硝苯吡啶的缓释药物组合物,其特征在于其含有:
硝苯吡啶和聚乙烯吡咯烷酮的无定形共沉淀物;
一定剂量的纤维素的亲水衍生物,其重量为硝苯吡啶的0.1-6倍;
一定剂量的羧基聚亚甲基和乳糖,其重量为硝苯吡啶的0.1-5倍;以及
一种保护性或缓释性表面包衣。
2.如权利要求1的组合物,其特征在于所述共沉淀中硝苯吡啶和聚乙烯吡咯烷酮的重量比为1∶1-1∶5。
3.如权利要求1的组合物,其特征在于硝苯吡啶的释放可被调制为8-24小时。
4.如权利要求1的组合物,其特征在于提供每天给药1次或2次的剂量方案。
5.如权利要求1的组合物,其特征在于每一剂量单位的硝苯吡啶的含量为0.1-400mg。
6.如权利要求1的组合物,其特征在于所述共沉淀物粒度小于100微米。
7.如权利要求1的组合物,其特征在于纤维素的亲水衍生物选自羟丙基甲基纤维素、羟乙基纤维素、羟甲基纤维素、羟丙基纤维素、羧甲基纤维素或其混合物。
8.用于制备如权利要求1中所定义的用于口服、含有活性物质硝苯吡啶的药物组合物的方法,其特征在于:
a)用喷雾干燥器由硝苯吡啶和聚乙烯吡咯烷酮溶于有机溶剂的溶液制备这两种成份的无定形共沉淀物;
b)用流化床技术制备含有所述共沉淀物、纤维素的亲水衍生物、羧基聚亚甲基、乳糖,外加能有助于该工艺过程的活性物质的球形颗粒;
c)将步骤b)中得到的颗粒用于制备由保护性的或缓释性的表面薄膜包被的片剂或其它药物剂型。
9.如权利要求1的组合物,其特征在于所述表面包衣含有选自丙烯酸聚合物、烷基纤维素、石蜡、硬脂酸、紫胶、氢化植物油或前述物质的任何比例的混合物的缓释性材料,以及可能有的选自邻苯二甲酸二乙酯、邻苯二甲酸二丁酯、甘油三乙酸酯以及聚乙二醇的增塑剂。
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DE3033919A1 (de) * | 1980-09-09 | 1982-04-22 | Bayer Ag, 5090 Leverkusen | Feste arzneizubereitungen enthaltend nifedipin und verfahren zu ihrer herstellung |
EP0078430B2 (de) * | 1981-10-29 | 1993-02-10 | Bayer Ag | Verfahren zur Herstellung von festen, schnellfreisetzenden Arzneizubereitungen mit Dihydropyridinen |
DE3376198D1 (en) * | 1983-11-30 | 1988-05-11 | Siegfried Ag | Therapeutic coronary composition in the form of soft gelatine capsules |
JPS6136213A (ja) * | 1984-07-27 | 1986-02-20 | Rooto Seiyaku Kk | 口腔用組成物 |
IE58110B1 (en) * | 1984-10-30 | 1993-07-14 | Elan Corp Plc | Controlled release powder and process for its preparation |
IT1187751B (it) * | 1985-10-15 | 1987-12-23 | Eurand Spa | Procedimento per la preparazione di formulazioni solidi di nifedipina ad elevata biodisponibilita' e ad effetto prolungato e formulazioni cosi' ottenute |
DE3738236A1 (de) * | 1987-11-11 | 1989-05-24 | Euro Celtique Sa | Beisskapsel |
GB8903328D0 (en) * | 1989-02-14 | 1989-04-05 | Ethical Pharma Ltd | Nifedipine-containing pharmaceutical compositions and process for the preparation thereof |
US5209933A (en) * | 1990-01-10 | 1993-05-11 | Syntex (U.S.A.) Inc. | Long acting calcium channel blocker composition |
GB9200607D0 (en) * | 1992-01-13 | 1992-03-11 | Ethical Pharma Ltd | Pharmaceutical compositions containing nifedipine and process for the preparation thereof |
CN1120435A (zh) * | 1994-01-04 | 1996-04-17 | 贵州泰康中医保健技术有限公司 | 硝苯吡啶缓释胶囊 |
CN1129103A (zh) * | 1995-02-14 | 1996-08-21 | 永信药品工业股份有限公司 | 硝苯吡啶剂型的开发 |
DE19515972A1 (de) * | 1995-05-02 | 1996-11-07 | Bayer Ag | Arzneizubereitungen mit kontrollierter Freisetzung und Verfahren zu ihrer Herstellung |
SI9500173B (sl) * | 1995-05-19 | 2002-02-28 | Lek, | Trofazna farmacevtska oblika s konstantnim in kontroliranim sproščanjem amorfne učinkovine za enkrat dnevno aplikacijo |
-
1996
- 1996-09-27 IT IT96MI001983A patent/IT1284604B1/it active IP Right Grant
-
1997
- 1997-09-09 ZA ZA9708099A patent/ZA978099B/xx unknown
- 1997-09-09 US US08/925,966 patent/US5871775A/en not_active Expired - Fee Related
- 1997-09-12 AU AU37567/97A patent/AU719075B2/en not_active Ceased
- 1997-09-17 ES ES97116153T patent/ES2202528T3/es not_active Expired - Lifetime
- 1997-09-17 EP EP97116153A patent/EP0838218B1/en not_active Expired - Lifetime
- 1997-09-17 DE DE69723024T patent/DE69723024T2/de not_active Expired - Fee Related
- 1997-09-17 AT AT97116153T patent/ATE243499T1/de not_active IP Right Cessation
- 1997-09-18 NZ NZ328783A patent/NZ328783A/en unknown
- 1997-09-22 CA CA002216277A patent/CA2216277C/en not_active Expired - Fee Related
- 1997-09-26 BR BR9706214A patent/BR9706214A/pt active Search and Examination
- 1997-09-26 CN CN97119609A patent/CN1110304C/zh not_active Expired - Fee Related
- 1997-09-29 JP JP9263279A patent/JPH10152440A/ja active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109730967A (zh) * | 2019-02-19 | 2019-05-10 | 广东工业大学 | 一种硝苯地平固体分散体及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
CN1110304C (zh) | 2003-06-04 |
AU3756797A (en) | 1998-04-02 |
ZA978099B (en) | 1998-03-27 |
IT1284604B1 (it) | 1998-05-21 |
ITMI961983A1 (it) | 1998-03-27 |
ES2202528T3 (es) | 2004-04-01 |
CA2216277C (en) | 2003-06-10 |
EP0838218B1 (en) | 2003-06-25 |
CA2216277A1 (en) | 1998-03-27 |
AU719075B2 (en) | 2000-05-04 |
BR9706214A (pt) | 1999-05-04 |
US5871775A (en) | 1999-02-16 |
NZ328783A (en) | 1998-02-26 |
ATE243499T1 (de) | 2003-07-15 |
JPH10152440A (ja) | 1998-06-09 |
DE69723024T2 (de) | 2004-04-29 |
EP0838218A1 (en) | 1998-04-29 |
DE69723024D1 (de) | 2003-07-31 |
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