CN108785260A - 温敏性非甾体抗炎药固体分散体和速溶片及其制备方法 - Google Patents
温敏性非甾体抗炎药固体分散体和速溶片及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种温敏性非甾体抗炎药固体分散体和速溶片及其制备方法,属于药物剂型领域。该固体分散体含有非甾体抗炎药和温敏性载体;所述非甾体抗炎药与温敏性载体的质量份数之比为1:(1~10)。该分散体采用反溶剂法将药物与载体共沉淀,分离冻干制备。非甾体抗炎药与温敏性载体相互作用强,分散体稳定性好;进入体内与消化液接触后,温敏性载体在水合作用下发生温敏性变化引起体系的相分离,迅速释放药物。此外,该分散体通过辅料调节还可得到微纳级固体分散体粒子,增加体系的流动性和可压性,实现固体分散体的直接粉末压片。本固体分散体可发挥口服速效作用,提高非甾体抗炎药的相对生物利用度。
Description
技术领域
本发明属于药物剂型技术领域,具体涉及一种具有温敏性的可发挥速效作用的非甾体抗炎药固体分散体。
背景技术
目前许多有潜力的药物由于其溶解度低而严重影响了在体内的吸收,导致生物利用度低而被搁置,由此造成极大的浪费。据粗略统计在临床应用前景好的药物中,有近七成左右属难溶性药物。难溶性药物的溶解度、溶出速率直接影响其生物利用度,随着新药的不断开发,提高难溶性药物的溶解度,改善难溶性药物的理化性质是国际药学界研究的热点,也是摆在药剂学研究者面前的艰巨任务。
难溶性药物增溶是制剂研究的一个热点,常用的增溶技术包括溶剂系统、表面活性剂、环糊精的包合物、纳米结晶系统以及无定形态的固体分散体。其中,无定型固体分散是增加难溶性药物吸收最有效的手段。1961年,由Sekiguchi等首先提出固体分散技术的概念,并以尿素为载体,用熔融法制备了磺胺噻唑固体分散体,并显著提高了难溶性药物磺胺噻唑的水溶性和生物利用度。经证实,固体分散体技术是一种能有效改善水难溶性药物的溶解度、溶解速度和生物利用度,减小药物粒径,提高润湿性和孔隙度,使药物从结晶状态转变成无定形状态的方法。
固体分散体除了提高水难溶性药物的溶出度和生物利用度外,还具有诸多优点,比如使药物呈无定形态、减小药物粒径、增加润湿性、提高病人耐受性、制作工艺简单、应用广泛,既可制成速释又可制成缓释药物,还可降低毒副作用和可用于油性药物的固体化等。目前常用于制备固体分散的方法有溶剂法、熔融法、溶剂-熔融法、喷雾(冷冻)干燥、热熔挤出技术及共研磨技术等。现有的固体分散体的工业化制备方法主要是喷雾干燥法和反溶剂共沉淀法,其中,喷雾干燥法的溶剂用量较大,溶剂残留多,且放大化生产后粒子粒径变大,难以实现工业化。而反溶剂共沉淀法可以用水来多次清洗以除去有机溶剂,可控性好,工艺放大容易,成本低。在辅料方面,固体分散体常用的载体主要分为水溶性载体包括PEG类、Poloxamer188、蔗糖等;难溶性载体如乙基纤维素、聚丙烯树脂类等;肠溶性载体如羟丙基甲基纤维素酞酸类(HPMCP)、羧甲基乙基纤维素(CMEC)等。载体的性质与制备工艺将很大程度上决定了固体分散体中药物的溶出速率。
但固体分散体技术也存在许多问题,首先,制备过程中可能存在溶剂残留、热不稳定和过饱和溶解后沉淀等问题;其次,固体分散体的粘度较大,流动相差,可压性差,粉碎混合困难,不适宜制备成片剂、胶囊等制剂;最后,制备和储存过程中固体分散体物理稳定性差,会出现相分离、药物重结晶现象等问题,严重影响了固体分散体的应用。因此,开发一种易于储存和工业化,并且稳定的新型固体分散体是一项具有重大意义的研究。
非甾体抗炎药主要通过抑制前列腺素的合成而产生镇痛、抗炎、解热作用。目前,市场上的非甾体抗炎药的Tmax通常在1小时以上,因此,开发吸收速度更快、达峰时间更短、峰浓度高的剂型有着重要的意义。
发明内容
本发明解决了现有技术中非甾体抗炎药释药缓慢和溶解性不佳的技术问题,提供了一种稳定性好的温敏性非甾体抗炎药固体分散体和速溶片及其制备方法。
按照本发明的第一方面,提供了一种温敏性非甾体抗炎药固体分散体,该固体分散体含有非甾体抗炎药和温敏性载体通过氢键和范德华力连接构成的部分;所述非甾体抗炎药与温敏性载体的质量份数之比为1:(1~10)。
优选地,所述温敏性载体为聚(N-异丙基丙烯酰胺)、聚(N,N-二甲基丙烯酰胺)或聚甲基乙烯基醚的均聚物;或所述温敏性载体为聚(N-异丙基丙烯酰胺)、聚(N,N-二甲基丙烯酰胺)、聚甲基乙烯基醚与亲水性单体共聚而成的无规共聚物、嵌段共聚物或接枝共聚物。
优选地,所述聚(N-异丙基丙烯酰胺)的均聚物分子量为3000~10000;所述亲水性单体为葡聚糖、羟乙基纤维素、聚乙二醇、甲基丙烯酸羟乙酯、丙烯酰胺或甲基丙烯酸。
优选地,所述聚(N-异丙基丙烯酰胺)与亲水单体的接枝共聚物为葡聚糖-g-聚(N-异丙基丙烯酰胺);所述聚(N-异丙基丙烯酰胺)与亲水单体的嵌段共聚物为聚乙二醇-b-聚(N-异丙基丙烯酰胺);所述葡聚糖-g-聚(N-异丙基丙烯酰胺)中葡聚糖的分子量为30000~50000;所述聚乙二醇-b-聚(N-异丙基丙烯酰胺)中聚乙二醇的分子量为2000~10000。
优选地,所述非甾体抗炎药为布洛芬、萘普生、双氯芬酸或塞来昔布。
按照本发明的另一方面,提供了一种温敏性非甾体抗炎药固体分散体的制备方法,包含以下步骤:
(1)将非甾体抗炎药和温敏性载体溶解于能与水互溶的有机溶剂中;所述非甾体抗炎药与温敏性载体的质量份数之比为1:(1~10);
(2)若步骤(1)所述的能与水互溶的有机溶剂能自发挥发,那么此步骤为将步骤(1)所得溶液逐滴滴入5倍-10倍体积的水中,使得步骤(1)所述非甾体抗炎药和温敏性载体通过氢键和范德华力连接;若步骤(1)所述的能与水互溶的有机溶剂不能自发挥发,那么此步骤为将步骤(1)所得溶液装入透析袋中以水为外向进行透析,使得步骤(1)所述非甾体抗炎药和温敏性载体通过氢键和范德华力连接;
(3)将步骤(2)所得产物离心后,取上清液,除去未结合的非甾体抗炎药物和未结合的温敏性载体的沉淀物;
(4)将步骤(3)所得上清液冷冻干燥,即得到温敏性非甾体抗炎药固体分散体。
优选地,步骤(2)所述能自发挥发的能与水互溶的有机溶剂为乙醇、丙酮或四氢呋喃;步骤(2)所述不能自发挥发的能与水互溶的有机溶剂为二甲基亚砜或N,N-二甲基甲酰胺;步骤(2)所述透析过程分为两个连续的阶段,第一阶段为每2~4小时换水,换水3~5次;第二阶段为每5~7小时换水,换水5~7次;步骤(4)所述冷冻干燥的过程加入了冻干保护剂;
优选地,所述冻干保护剂为乳糖、蔗糖或甘露糖。
按照本发明的另一方面,提供了一种温敏性非甾体抗炎药固体分散体速释片,该速释片含有所述的温敏性非甾体抗炎药固体分散体,还含有崩解剂和润滑剂。
优选地,所述崩解剂为交联羧甲基纤维素钠、低取代羟丙基纤维素、羧甲基淀粉钠和交联聚维酮中的至少一种;所述润滑剂为硬脂酸镁、微粉硅胶和十二烷基硫酸钠中的至少一种。
按照本发明的另一方面,提供了一种温敏性非甾体抗炎药固体分散体速释片的制备方法,将所述的温敏性非甾体抗炎药固体分散体、崩解剂和润滑剂混合均匀后,进行压片制得。
总体而言,通过本发明所构思的以上技术方案与现有技术相比,主要具备以下的技术优点:
(1)本发明中的温敏性非甾体抗炎药固体分散体,具有温度敏感性,无表面活性剂,可发挥口服速效作用,且稳定性好,非甾体抗炎药的相对生物利用度提高。该分散体采用反溶剂法将药物与载体共沉淀,分离冻干制备。温敏性载体在室温下以固体形式储存时,非甾体抗炎药与温敏性载体相互作用强,分散体稳定性好;进入体内与消化液接触后,温敏性载体在水合作用下发生温敏性变化引起体系的相分离,迅速释放药物。此外,该分散体通过辅料调节(如崩解剂和润滑剂)还可得到微纳级固体分散体粒子,增加体系的流动性和可压性,实现固体分散体的直接粉末压片。
(2)本发明可采用能自发挥发的溶剂如乙醇或丙酮等通过反溶剂共沉淀法来制备固体分散体,可以很容易地除去有机溶剂,分散体中无溶剂残留。
(3)本发明通过添加亲水性辅料,将固体分散体制成微纳级颗粒,通过冻干可得冻干粉剂,流动性、可压性得到大幅提升,易于制成片剂、胶囊等常规剂型,实现真正的市场化。
(4)本发明通过引入安全无毒的温敏性载体,在固态储存时,药物与材料相互作用强,稳定性好,不会出现老化现象,可在室温下长期储存。当固体分散体进入体内与消化液接触后,温度超过温敏性载体的LCST,在水合作用下载体发生温敏性变化,载体与药物之间的氢键断裂,二者发生相分离,药物从分散体中解离。相分离之后,难溶性非甾体抗炎药在胃液的酸性环境中呈分子型,有利于药物的吸收入血,进而发挥其药效作用。
附图说明
图1为聚(N-异丙基丙烯酰胺)(PNIPAM)、葡聚糖-g-聚(N-异丙基丙烯酰胺)(Dex-g-PNIPAM)以及聚乙二醇-b-聚(N-异丙基丙烯酰胺)(PEG-b-PNIPAM)在重水里的核磁氢谱图。
图2为布洛芬和布洛芬固体分散体的X射线衍射(XRD)谱图。
图3为布洛芬和布洛芬固体分散体的示差扫描量热曲线(DSC)。
图4为葡聚糖-g-聚(N-异丙基丙烯酰胺)(Dex-g-PNIPAM)以及布洛芬固体分散体的平均水合粒径随温度的变化。
图5为布洛芬和布洛芬固体分散体的体外释放行为。
图6为布洛芬的血浆浓度随时间的变化。
图7为布洛芬混悬液和固体分散体的药动学参数AUC,t1/2,CL,Cmax的比较。
图8为布洛芬混悬液和固体分散体的药效学结果,用肿胀度来表示炎症消除的快慢。
图9为布洛芬固体分散体加入冻干保护剂后的冻干粉稳定性。
图10(a)为实施例2制得的固体分散体4冻干前的实物图;图10(b)为实施例2制得的固体分散体4冻干粉的实物图;图10(c)为实施例2制得的固体分散体4冻干后6个月的复溶的实物图。
图11为布洛芬固体分散体的溶出度及片剂形貌。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。此外,下面所描述的本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。
本发明利用温敏性材料与非甾体抗炎药制备新型温敏固体分散体,可以改善非甾体抗炎药的溶解性,并可以通过材料的温敏性实现其在体内的速释。
首先合成新型温敏辅料:亲水性药用辅料(如PEG、葡聚糖等)与温敏性关键载体N-异丙基丙烯酰胺NIPAM共聚物的合成、纯化、结构优化,实现对非甾体抗炎药的良好包载和对固体分散体的结构可控;同时保证体系的稳定性和温敏性。
第二步制备布洛芬固体分散体:确定能自发挥发溶剂的种类、分散体处方和制备方法,对该微纳级固体分散体的制备进行优化,对其物理性质进行体外表征,包括X射线衍射(XRD)、示差扫描量热法(DSC)等;
第三部制备布洛芬固体分散体:考虑体系加入的冻干保护剂种类、用量等对冻干粉性质的影响,以及对后续制剂形式(胶囊、片剂等)的影响,确保其室温的稳定和口服后的药物速释。
本发明中,所述的具有温敏性辅料为聚(N-异丙基丙烯酰胺)(PNIPAM),聚乙二醇-聚(N-异丙基丙烯酰胺)嵌段共聚物(PEG-b-PNIPAM)和葡聚糖接枝聚(N-异丙基丙烯酰胺)(Dex-g-PNIPAM),结构如式I所示:
当R为PNIPAM的引发剂端基时,该物质为聚(N-异丙基丙烯酰胺)PNIPAM;当R为PEG时,该物质是聚乙二醇-聚(N-异丙基丙烯酰胺)嵌段共聚物PEG-b-PNIPAM;当R为葡聚糖时,该物质为葡聚糖接枝聚(N-异丙基丙烯酰胺)Dex-g-PNIPAM。
实施例1:温敏性辅料合成与核磁表征
1、聚(N-异丙基丙烯酰胺)的合成与核磁表征
将6g N-异丙基丙烯酰胺(NIPAM)晶体溶于装有50mL的去离子水的三颈瓶中,鼓N230分钟,在磁力搅拌下于60℃恒温水浴中加热稳定后,注入含30mg过硫酸铵的5mL水溶液,反应7h。待反应完毕,反应溶液转入透析袋(MWCO:3500)中透析3天,冷冻干燥后收集产物。将样品溶解在重水中,配成浓度为20mg/mL的溶液,在25℃下恒温10min后测量其核磁共振氢谱,如图1所示,确认PNIPAM合成成功。
2、葡聚糖-g-聚(N-异丙基丙烯酰胺)的合成与核磁表征
将5.0g葡聚糖溶于装有50mL的去离子水的三颈瓶中,置于20℃恒温水浴中。鼓N230分钟后,加入10mL硝酸铈氨盐溶液(1.0M硝酸),搅拌10min后,加入5.0g的N-异丙基丙烯酰胺,反应6h后加入与硝酸等摩尔的1M的NaOH溶液至pH为7。反应溶液转入透析袋(MWCO:10000)中透析7天纯化。溶液冻干后得产物。将样品溶解在重水中,配成浓度为20mg/mL的溶液,在25℃下恒温10min后测量其核磁共振氢谱,如图1所示,确认葡聚糖-g-聚(N-异丙基丙烯酰胺)即Dex-g-PNIPAM合成成功。
3、聚乙二醇-b-聚(N-异丙基丙烯酰胺)的合成与核磁表征
将0.5g氨基端PEG(分子量3350)溶于装有50mL的去离子水的三颈瓶中,置于20℃恒温水浴中。鼓N2 30分钟后,加入10mL硝酸铈氨盐溶液(1.0M硝酸),搅拌10min后,加入5.0g的N-异丙基丙烯酰胺,反应6h后加入与硝酸等摩尔的1M的NaOH溶液至pH为7。反应溶液转入透析袋(MWCO:5000)中透析7天纯化,溶液冻干得产物。将样品溶解在重水中,配成浓度为20mg/mL的溶液,在25℃下恒温10min后测量其核磁共振氢谱,如图1所示,确认聚乙二醇-b-聚(N-异丙基丙烯酰胺)即PEG-b-PNIPAM合成成功。
实施例2:温敏性布洛芬固体分散体的制备、结构表征
1、聚(N-异丙基丙烯酰胺)-布洛芬固体分散体的制备和表征
PNIPAM-布洛芬固体分散体通过反溶剂共沉淀法制备,具体是采用透析法除去有机溶剂的制备方法。将100mg聚(N-异丙基丙烯酰胺)(PNIPAM)和91mg或182mg布洛芬共同溶于30mL二甲基亚砜(DMSO)中,完全溶解后转入透析袋(MWCO:3500)中在1L pH约为3的去离子水中透析。最初的12h每3h换一次水,接下来的36小时每6h换一次水。透析完后,透析袋内溶液在3000rpm下离心10min,弃去沉淀,溶液冻干后得PNIPAM-布洛芬固体分散体。
布洛芬的含量由紫外分光光度法测定,如表1所示,测得固体分散体1和固体分散体2的包封率分别为86.0%与74.0%,载药量分别为43.9%与57.4%。
表1
固体分散体的结晶性由X射线衍射(XRD)和示差扫描量热法(DSC)检测。从图2可以看到,布洛芬透析前后晶型没有发生变化,均为由外消旋IBU二聚体形成的晶体,这说明IBU结晶能力较强。在固体分散体1和固体分散体2中,未出现布洛芬的结晶衍射峰,说明是布洛芬以无定型形式存在的。利用DSC(图3)对布洛芬固体分散体1和固体分散体2进行研究,结果显示,固体分散体1和固体分散体2只表现出一个宽的熔化峰,没有明显的结晶熔融峰,也证实了布洛芬的无定型状态。
2、葡聚糖-g-聚(N-异丙基丙烯酰胺)-布洛芬固体分散体的制备和表征
Dex-g-PNIPAM-布洛芬固体分散体通过透析法制备。将100mg Dex-g-PNIPAM和50mg/90mg布洛芬共同溶于30mL二甲基亚砜(DMSO)中,完全溶解后转入透析袋(MWCO:3500)中在1L pH约为3的去离子水中透析。最初的12h每3h换一次水,接下来的36小时每6h换一次水。透析完后,透析袋内溶液在3000rpm下离心10min,弃去沉淀,溶液冻干后得所得Dex-g-PNIPAM-布洛芬固体分散体。
表1为温敏辅料和布洛芬所形成溶液的制备与表征。布洛芬的含量由紫外分光光度法测定,如表1所示,测得固体分散体3和固体分散体4的包封率分别为68.0%与66.6%,载药量分别为25.4%与37.5%。
固体分散体的结晶性由X射线衍射(XRD)检测。从图2可以看到,在固体分散体4中,未出现布洛芬的结晶衍射峰,说明是布洛芬以无定型形式存在的。
3、聚乙二醇-b-聚(N-异丙基丙烯酰胺)-布洛芬固体分散体的制备和表征
PEG-b-PNIPAM-布洛芬固体分散体通过共沉淀法制备。将100mg聚乙二醇-b-聚(N-异丙基丙烯酰胺)(PEG-b-PNIPAM)和90mg布洛芬共同溶于30mL丙酮中,完全溶解后缓慢滴加于在500mL pH约为3的去离子水中。溶液在3000rpm下离心10min,弃去沉淀,冻干后得聚乙二醇-b-聚(N-异丙基丙烯酰胺)-布洛芬固体分散体。
布洛芬的含量由紫外分光光度法测定,如表1所示,测得固体分散体5的包封率分别91.2%,载药量为45.1%。
固体分散体的结晶性由X射线衍射(XRD)检测。从图2可以看到,在固体分散体5中,未出现布洛芬的结晶衍射峰,说明是布洛芬以无定型形式存在的。
实施例3:布洛芬固体分散体的温敏性行为研究与体外释放
1、布洛芬固体分散体的平均水合粒径与直观温敏性
利用动态光散射分别测定了布洛芬固体分散体3、固体分散体4在其相变温度以下(室温)及以上(37℃)的水合直径,如图4所示,温敏载体葡聚糖-g-聚(N-异丙基丙烯酰胺)(Dex-g-PNIPAM)在室温时粒径为20nm左右,当温度升到37℃后,溶液形成100nm的胶束。药物包载后,室温下体系就表现为乳液状,温度升高后,粒径从260nm降低为140nm左右,而且其粒径转变可逆。由此说明,当温度低于温敏载体葡聚糖-g-聚(N-异丙基丙烯酰胺)Dex-g-PNIPAM的低临界溶解温度(LCST),即在室温时,载体溶液为亲水性,粒径为20nm左右,当温度升到37℃后,载体溶液由亲水性变为疏水性,形成100nm的胶束,验证了载体葡聚糖-g-聚(N-异丙基丙烯酰胺)Dex-g-PNIPAM的温敏性。
当用温敏载体葡聚糖-g-聚(N-异丙基丙烯酰胺)(Dex-g-PNIPAM)包载药物后,室温下载体与药物通过氢键作用缔合,体系就表现为乳液状,粒径为260nm,温度升高后,氢键断裂,粒径降低为140nm左右,而且其粒径转变可逆,说明药物与温敏辅料的相容性很好,相互作用强。
2、布洛芬固体分散体的体外释放
布洛芬固体分散体的体外释放通过透析法测定:用紫外法测定药物在37℃下的体外释放。将一定体积的布洛芬固体分散体3、固体分散体4溶液转移到透析袋(MWCO 3500)中,再将透析袋放入在装有200mL去离子水的广口瓶中(预先恒温37℃),用紫外法测定一定时间间隔下布洛芬在释放介质的浓度。结果如图5所示。可以看到,布洛芬固体分散体的药物释放速度要远高于布洛芬的释放速度,1小时内释放量超过40%,5小时即达到释放平衡。
实施例4:布洛芬固体分散体的药物代谢动力学研究
1、血浆中布洛芬含量测定方法研究
色谱条件:色谱柱为Hypersil ODS-3C18column(5μm,150mm×4.6mm,Agilent);柱温:25℃;流速:1mL/min;紫外检测波长:263nm;进样量:20μL;流动相:醋酸钠缓冲液(pH2.5):乙腈(40/60v/v)。
标准曲线:配制成浓度为100μg/mL的布洛芬溶液,精密称取布洛芬5mg于50mL容量瓶中,用甲醇稀释到刻度线。根据配好的溶液,用甲醇稀释,依次配制浓度为50、25、10、5、2.5、1、0.5、0.25、0.1、0.05μg/mL的标准溶液,用于标准曲线的测定。
血浆标准曲线:再取10份大鼠空白血浆100μL,分别加入以上配制的标准溶液100μL,涡旋3min,变性蛋白,再加入1mL甲基叔丁基醚,涡旋3min,萃取布洛芬,随后混合液以10000r离心5min破乳,吸取上层800μL甲基叔丁基醚层,氮气吹干,-80℃保存备用。进样前,样本以80μL色谱甲醇复溶,10000r离心5min,取上清50μL进液相色谱检测。
方法学实验:
A、色谱分离条件:本研究比较了血浆空白样品、布洛芬血浆标准液,根据以上血液样品处理方法,采用HPLC,进样分析得出色谱图,考察所选色谱分离条件的的合理性。
B、制备血浆标准曲线:如血浆样品的制备方法,分别以血浆药物浓度依次为50、25、10、5、2.5、1、0.5、0.25、0.1、0.05μg/mL的样品建立标准曲线,样品处理后进样分析,以血浆中布洛芬的浓度(X)为横坐标,布洛芬峰面积(Y)为纵坐标。
2、大鼠药代动力学研究
分组与给药方案:9只SD雄鼠(200±10g)随机分为3组,每组3只。分别为布洛芬混悬液组;布洛芬固体分散体1给药组;布洛芬固体分散体2给药组。
给药剂量:10mg/kg。
给药方法:口服灌胃给药。
大鼠口服灌胃给药后于15min、30min、1h、2h、3h、4h、8h、12h、24h取血样。首先将EP管用肝素进行处理,取约0.25mL血浆,在1h内将血样进行离心处理后取上清,将得到的血清置于-20℃冰箱储存,等待后续处理。
血样测定:按照上述建立的HPLC分析体内布洛芬的方法,用来测定口服灌胃给予不同布洛芬制剂后血浆中布洛芬的浓度。每批样品分析时建立标准曲线。得出不同时间的血药浓度,并根据时间和浓度的关系绘制出药时曲线。得出的药动学数据,采用药动学软件DAS 2.1.1处理血浆中药物浓度,并得出拟合后的参数,对其进行比较。得出静脉给药后的AUC(0-t)(药时曲线下面积)、t1/2(消除半衰期)、Cmax(达峰浓度)、CL(清除率)等参数值。
参见图6,布洛芬固体分散体1的实验组中的大鼠血药浓度明显高于布洛芬混悬液组。表2为布洛芬混悬液和固体分散体的口服药动学参数。布洛芬不同给药组的口服药动学参数具体见表2。进一步可以从图7中的动力学参数可以分析得出,与布洛芬混悬液相比,布洛芬固体分散体1表现出了更长的血液滞留时间,具有13.2倍的曲线下面积(AUC0–72)、13.3倍的达峰浓度(Cmax)和10.9倍的清除率。
表2
实施例5:布洛芬固体分散体的药效学研究
分组与给药方案:9只SD雄鼠(200±10g)随机分为3组,每组3只。分别为布洛芬混悬液组;布洛芬固体分散体1给药组;布洛芬固体分散体2给药组。
足部急性炎症模型:每只大鼠在足部皮下注射0.2mL角叉菜胶(2‰),足部肿胀。
给药剂量:5mg/kg。
给药方法:口服灌胃给药。
大鼠口服灌胃给药后于1h、2h、3h、4h、6h、8h、12h、24h利用排水法测足部肿胀体积,以质量为计量单位。参见图8,布洛芬固体分散体1和2的实验组中的大鼠足部肿胀度明显低于布洛芬混悬液组与空白组。说明其抗炎效果更显著,该足部急性炎症模型验证了布洛芬固体分散体的速效抗炎作用。
实施例6:布洛芬固体分散体的储存稳定性
在所制得的布洛芬固体分散体4溶液中,分别加入与辅料等质量的乳糖100mg做为冻干保护剂,冻干后在室温条件下保存,且分别在第0、1、3、6个月加水复溶,测量粒径变化,如图9所示。结果表明冻干粉在6个月内都能保持形状稳定。图10为冻干粉的实物图,分别为冻干前、冻干后的粉末以及冻干后6个月的复溶的实物图,可看出冻干复溶后仍然能维持好的乳光,说明固体分散体性状未受到破环。
实施例7:布洛芬固体分散体速释片处方
处方:
混合后直接粉末压片(图11),按中国药典片剂溶出度测试方法(1法)测定其溶出度(图11)。结果表明,速释片可在1小时内完全释放出药物。
本领域的技术人员容易理解,以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种温敏性非甾体抗炎药固体分散体,其特征在于,该固体分散体含有非甾体抗炎药和温敏性载体通过氢键和范德华力连接构成的部分;所述非甾体抗炎药与温敏性载体的质量份数之比为1:(1~10)。
2.如权利要求1所述的温敏性非甾体抗炎药固体分散体,其特征在于,所述温敏性载体为聚(N-异丙基丙烯酰胺)、聚(N,N-二甲基丙烯酰胺)或聚甲基乙烯基醚的均聚物;或所述温敏性载体为聚(N-异丙基丙烯酰胺)、聚(N,N-二甲基丙烯酰胺)或聚甲基乙烯基醚与亲水性单体共聚而成的无规共聚物、嵌段共聚物或接枝共聚物。
3.如权利要求2所述的温敏性非甾体抗炎药固体分散体,其特征在于,所述聚(N-异丙基丙烯酰胺)的均聚物分子量为3000~10000;所述亲水性单体为葡聚糖、羟乙基纤维素、聚乙二醇、甲基丙烯酸羟乙酯、丙烯酰胺或甲基丙烯酸。
4.如权利要求2所述的温敏性非甾体抗炎药固体分散体,其特征在于,所述聚(N-异丙基丙烯酰胺)与亲水单体的接枝共聚物为葡聚糖-g-聚(N-异丙基丙烯酰胺);所述聚(N-异丙基丙烯酰胺)与亲水单体的嵌段共聚物为聚乙二醇-b-聚(N-异丙基丙烯酰胺);所述葡聚糖-g-聚(N-异丙基丙烯酰胺)中葡聚糖的分子量为30000~50000;所述聚乙二醇-b-聚(N-异丙基丙烯酰胺)中聚乙二醇的分子量为2000~10000。
5.如权利要求1所述的温敏性非甾体抗炎药固体分散体,其特征在于,所述非甾体抗炎药为布洛芬、萘普生、双氯芬酸或塞来昔布。
6.一种温敏性非甾体抗炎药固体分散体的制备方法,其特征在于,包含以下步骤:
(1)将非甾体抗炎药和温敏性载体溶解于能与水互溶的有机溶剂中;所述非甾体抗炎药与温敏性载体的质量份数之比为1:(1~10);
(2)若步骤(1)所述的能与水互溶的有机溶剂能自发挥发,那么此步骤为将步骤(1)所得溶液逐滴滴入5倍-10倍体积的水中,使得步骤(1)所述非甾体抗炎药和温敏性载体通过氢键和范德华力连接;若步骤(1)所述的能与水互溶的有机溶剂不能自发挥发,那么此步骤为将步骤(1)所得溶液装入透析袋中以水为外向进行透析,使得步骤(1)所述非甾体抗炎药和温敏性载体通过氢键和范德华力连接;
(3)将步骤(2)所得产物离心后,取上清液,除去未结合的非甾体抗炎药物和未结合的温敏性载体的沉淀物;
(4)将步骤(3)所得上清液冷冻干燥,即得到温敏性非甾体抗炎药固体分散体。
7.如权利要求6所述的温敏性非甾体抗炎药固体分散体的制备方法,其特征子在于,步骤(2)所述能自发挥发的能与水互溶的有机溶剂为乙醇、丙酮或四氢呋喃;步骤(2)所述不能自发挥发的能与水互溶的有机溶剂为二甲基亚砜或N,N-二甲基甲酰胺;步骤(2)所述透析过程分为两个连续的阶段,第一阶段为每2~4小时换水,换水3~5次;第二阶段为每5~7小时换水,换水5~7次;步骤(4)所述冷冻干燥的过程加入了冻干保护剂;
优选地,所述冻干保护剂为乳糖、蔗糖或甘露糖。
8.一种温敏性非甾体抗炎药固体分散体速释片,其特征在于,该速释片含有权利要求1-5任一所述的温敏性非甾体抗炎药固体分散体,还含有崩解剂和润滑剂。
9.如权利要求8所述的温敏性非甾体抗炎药固体分散体速释片,其特征在于,所述崩解剂为交联羧甲基纤维素钠、低取代羟丙基纤维素、羧甲基淀粉钠和交联聚维酮中的至少一种;所述润滑剂为硬脂酸镁、微粉硅胶和十二烷基硫酸钠中的至少一种。
10.一种温敏性非甾体抗炎药固体分散体速释片的制备方法,其特征在于,将权利要求1-5任一所述的温敏性非甾体抗炎药固体分散体、崩解剂和润滑剂混合均匀后,进行压片制得。
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