CN101627969B - 一种姜黄素自乳化给药系统及其制备 - Google Patents
一种姜黄素自乳化给药系统及其制备 Download PDFInfo
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Abstract
本发明公开了一种新型的姜黄素自乳化给药系统及其制备，所述姜黄素自乳化给药系统包括姜黄素、油相、TPGS、聚乙二醇硬脂酸酯15和助乳化剂，各组分含量以重量份数计表示如下：姜黄素0.1～10份，油相4～75份，TPGS 0.1～90份，聚乙二醇硬脂酸酯15 5～90份，助乳化剂0～70份；所述的TPGS即为维生素E琥珀酸聚乙二醇酯。具体制备方法为：先将除姜黄素以外的组分按照重量配比混合，加热溶解使混合均匀，然后加入姜黄素在25～55℃搅拌使其溶解，即得姜黄素自乳化给药系统。本发明通过以TPGS和Solutol HS15为混合乳化剂，将姜黄素制成姜黄素自乳化给药系统，大大提高了姜黄素的吸收和口服生物利用度。
Description
技术领域
本发明涉及一种新型姜黄素自乳化给药系统及其制备。
背景技术
姜黄素(curcumin)是从姜科姜黄属(Curcuma L.)植物姜黄、莪术、郁金等的根茎中提取得到的一种天然有效成分。具有抗炎、抗癌、抗氧化、肾脏保护、抑制肝、肺纤维化等多种药理作用，其毒副作用小，使用安全，临床应用前景好。但姜黄素几乎不溶于水，且胃肠道吸收少，口服生物利用度低，故给药剂量大。
为提高难溶性药物的生物利用度，常用的技术有超微粉碎技术，固体分散技术和纳米技术如脂质体、纳米粒、微乳和自乳化给药系统等。为提高姜黄素的口服生物利用度，国内外已有姜黄素固体分散体[文献1：许东晖.姜黄素固体分散体及制备方法与应用.CN100340238C，2007]、脂质体[文献2：楼红祥，刘安昌，范培红.姜黄素磷脂复合物及制备方法.CN1283237C，2006]、乳剂[文献3：王振华，张雪梅，马福禄，苟海涛，何杰.姜黄素乳剂及其制备方法和用途.CN1736369A，2006]，自乳化给药系统[文献4：翟光喜，楼红祥，崔晶.姜黄素自乳化制剂及其制备方法.CN100352430C.2007]和纳米粒[文献5：Shaikh J.，A.D.D.，Beniwal V.，Singh D.，Ravi KumarM.N.V..Nanoparticle encapsulation improves oral bioavailability ofcurcumin by at least 9-fold when compared to curcumin administeredwith piperine as absorption enhancer.Eur J Pharm Sci，2009，37：223-30] 等的研究报道。这些新技术的应用，均在一定程度上较混悬液提高了生物利用度。大鼠灌胃给予姜黄素固体分散体(PVP K30)和姜黄素混悬液(100，200，400mg/kg)，采用HPLC-UV-VIS法测定血浆中姜黄素，结果混悬液组在0-4h内均未测得姜黄素，固体分散体组(100，200，400mg/kg)的峰浓度依次为74.588±2.287ng/ml，110.174±7.474ng/ml和193.665±10.400ng/ml[文献1]。而脂质体专利大鼠灌胃给予姜黄素混悬液和姜黄素脂质复合物500mg/kg后，采用HPLC-MS测得混悬液的姜黄素峰浓度为2.22±1.33ng/ml，四氢姜黄素为12.22±13.16ng/ml；脂质复合物的姜黄素峰浓度为6.96±1.62ng/ml，四氢姜黄素为18.97±8.65ng/ml[文献2]。Shaikh等大鼠灌胃姜黄素PLGA纳米粒和混悬液，HPLC-UV-VIS法测定，结果姜黄素PLGA纳米粒(100mg/kg)的峰浓度为260.5±26.4ng/ml，姜黄素混悬液(250mg/kg)的峰浓度为90.3±15.5ng/ml[文献5]。但已发表的专利姜黄素自微乳化给药系统只报道了小肠在体肠吸收情况，小肠的吸收量为57.6％±2.3％，原料姜黄素的为32.4％±1.8％，即自乳化给药系统的小肠吸收约为原料的1.8倍[文献4]。
自乳化给药系统(self-emulsifying drug delivery system)是一种由油相，乳化剂和助乳化剂组成的固体或液体制剂，其基本特征是在适宜温度和搅拌下，可自发形成粒径在5μm左右的乳剂，或进一步形成微乳。自乳化给药系统可提高脂溶性或水难溶性药物的溶解度，供口服之用。目前已上市的药物有环孢素A(Sandimmune，Sandimmune Neoral)、利托那韦(Norvir)等。自乳化给药系统对药物的溶解度和生物利用度的提高主要受体系中油相、乳化剂和助乳化剂的种类和组成比例的影响。同一药物，不同的自乳化系统将可能得 到不同的结果。
维生素E聚乙二醇琥珀酸酯(TPGS)是由维生素E琥珀酸酯与聚乙二醇1000经酯化形成的维生素E的水溶性衍生物，包括d-α-维生素E琥珀酸聚乙二醇酯(d-TPGS)和dl-α-维生素E琥珀酸聚乙二醇酯(dl-TPGS)，HLB值为13，具有表面活性剂性质；同时可抑制P-gp的功能而促进药物吸收的作用；并具有抗氧化作用。Solutol HS15是聚乙二醇-12-羟基硬脂酸酯，又名聚乙二醇硬脂酸酯15，HLB值14-16，具有良好的乳化性能。本发明基于TPGS和Solutol HS15为混合乳化剂设计姜黄素的自乳化给药系统。
发明内容
本发明要解决的技术问题是提供一种新型的姜黄素自乳化给药系统，提高了姜黄素的吸收和口服生物利用度。
为解决上述技术问题，本发明采用如下技术方案：
一种姜黄素自乳化给药系统，包括姜黄素、油相、维生素E琥珀酸聚乙二醇酯(TPGS)、聚乙二醇硬脂酸酯15(Solutol HS15)和助乳化剂，各组分含量以重量份数计表示如下：姜黄素0.1～10份，油相4～75份，TPGS 0.1～90份，聚乙二醇硬脂酸酯15 5～90份，助乳化剂0～70％。助乳化剂的含量下限“0”表示可以无限趋近于零，但不为零。
下面对制成姜黄素自乳化给药系统的各组分进行具体说明。
本发明中，姜黄素的重量含量优选为0.1～5份，更优选1～3份。
油相即为分散剂，本发明所述油相可选自下列之一：油酸，亚油酸，山嵛酸甘油酯，玉米油单、双、三甘油酯，中链脂肪酸甘油酯， 花生油，橄榄油，蓖麻油，豆油，油酸乙酯。其重量含量优选为5～35份，更优选5～20份。
本发明中，TPGS和聚乙二醇硬脂酸酯15作为混合乳化剂，其中TPGS的重量含量优选为1～20份，更优选1～15份；聚乙二醇硬脂酸酯15的重量含量优选为35～75份，更优选40～65份。此外本发明还可加入聚氧乙烯(40)氢化蓖麻油，聚山梨酯，月桂酸蔗糖酯，聚氧乙烯40脂肪酸酯，泊洛沙姆188等非离子表面活性剂作为乳化剂。
本发明中在自乳化给药系统中加入助乳化剂，可增加溶解性能，减少乳化剂的用量。本发明使用的助乳化剂可选自下列之一：PEG400，PEG300，无水乙醇，丙二醇，异丙醇。当加入助乳化剂时，其重量含量优选为5～40份，更优选10～40份。
维生素E聚乙二醇琥珀酸酯(TPGS)是由维生素E琥珀酸酯与聚乙二醇1000经酯化形成的维生素E的水溶性衍生物，包括d-α-维生素E琥珀酸聚乙二醇酯(d-TPGS)和dl-α-维生素E琥珀酸聚乙二醇酯(dl-TPGS)，本发明中d-TPGS和dl-TPGS均适用。
除了上述的姜黄素、油相、d-α-维生素E琥珀酸聚乙二醇酯、聚乙二醇硬脂酸酯15和助乳化剂外，本发明还可以根据需要加入其它组分，主要包括稳定剂如抗氧化剂维生素E及衍生物、维生素C及衍生物等，及其它可能的辅料。
本发明的优选方案为：所述姜黄素自乳化给药系统包括姜黄素、油相、TPGS、聚乙二醇硬脂酸酯15和助乳化剂，各组分含量以重量份数计表示如下：姜黄素0.1～5份，油相5～35份，TPGS 1～20份，聚乙二醇硬脂酸酯15 35～75份，助乳化剂5～40份。
进一步优选的方案为：所述姜黄素自乳化给药系统由姜黄素、油相、TPGS、聚乙二醇硬脂酸酯15和助乳化剂制成，各组分含量以重量份数计表示如下：姜黄素0.1～5份，油相5～35份，TPGS 1～20份，聚乙二醇硬脂酸酯15 35～75份，助乳化剂5～40份。
更进一步优选的方案为：所述姜黄素自乳化给药系统由姜黄素、油相、TPGS、聚乙二醇硬脂酸酯15和助乳化剂制成，各组分含量以重量分数计表示如下：姜黄素1～3份，油相5～20份，TPGS 1～15份，聚乙二醇硬脂酸酯15 40～65份，助乳化剂10～40份。
本发明具体推荐如下技术方案：所述的姜黄素自乳化给药系统由姜黄素、油相、TPGS、聚乙二醇硬脂酸酯15和助乳化剂制成，各组分含量以重量份数计表示如下：姜黄素1～3份，油相5～20份，TPGS1～15份，聚乙二醇硬脂酸酯15 40～65份，助乳化剂10～40份；所述的油相为油酸、山嵛酸甘油酯或中链脂肪酸甘油酯；所述的助乳化剂为PEG400或无水乙醇。
本发明所述的姜黄素自乳化给药系统可通过如下方法制备：先将除姜黄素以外的原料按照重量配比混合，加热溶解使混合均匀，然后加入姜黄素在25～55℃搅拌使其溶解，即得姜黄素自乳化给药系统。
本发明所述的姜黄素自乳化给药系统，得到的药液可制成不同的剂型，如口服液、胶囊剂、颗粒剂或其他可能的剂型。
与现有技术相比，本发明的有益效果在于：本发明通过以TPGS和Solutol HS15为混合乳化剂，将姜黄素制成姜黄素自乳化给药系统，大大提高了姜黄素的吸收和口服生物利用度。
附图说明
图1为实施例4得到的姜黄素的血药浓度与时间曲线图，其中◆为本发明的姜黄素自乳化系统，■为姜黄素混悬液。
具体实施方式
下面以具体实施例对本发明的技术方案做进一步说明，但本发明的保护范围不限于此：
实施例1姜黄素自乳化给药系统I
| 处方 | mg |
| 姜黄素 | 2mg |
| 油酸 | 10mg |
| Solutol HS15 | 45mg |
| d-TPGS | 5mg |
| PEG400 | 30mg |
制备：将油酸，Solutol HS15，d-TPGS和PEG400加热溶解混合均匀，再加入姜黄素40℃磁力搅拌使其溶解即得。37℃水中分散后测得平均粒径58.4±41.9nm。
实施例2姜黄素自乳化给药系统II
| 处方 | mg |
| 姜黄素 | 2mg |
| 山嵛酸甘油酯 | 15mg |
| Solutol HS15 | 60mg |
| d-TPGS | 10mg |
| PEG400 | 15mg |
制备：将山嵛酸甘油酯，Solutol HS15，d-TPGS和PEG400加热溶解混合均匀，再加入姜黄素40℃磁力搅拌使其溶解即得。37℃水中分散后测得平均粒径70.5±32.8nm。
实施例3姜黄素自乳化给药系统III
| 处方 | mg |
| 姜黄素 | 2mg |
| 中链脂肪酸三甘油酯 | 20mg |
| Solutol HS15 | 65mg |
| d-TPGS | 5mg |
| 无水乙醇 | 10mg |
制备：将中链脂肪酸三甘油酯，Solutol HS15，d-TPGS和无水乙醇加热溶解混合均匀，再加入姜黄素40℃磁力搅拌使其溶解即得。37℃水中分散后测得平均粒径78.5±43.9nm。
实施例4：姜黄素自乳化给药系统与混悬液的药动学比较
昆明种小鼠36只，雄性，体重18-20g，，姜黄素自乳化给药系统(实施例1)和姜黄素混悬液各6组，每组3只。分别灌胃给予相同剂量的自乳化给药系统和姜黄素混悬液(600mg/kg)，于给药后15min，30min，60min，90min，120min，180min，眼眶取血于肝素钠处理的离心管中，3500rpm离心分离得血浆。取血浆100μL，加内标Arg 1 μg/mL 10μL和水100μL，漩涡混合均匀。加乙酸乙酯1mL，室温振荡1h，14000rpm离心10min，取上层乙酸乙酯，氮气挥干除尽乙酸乙酯。残渣加流动相100μL溶解作供试品。采用HPLC-MS/MS测定姜黄素和内标Arg，色谱条件如下：流动相乙腈：0.1％甲酸(50/50，v/v)，流速：0.2ml/min，色谱柱：betabasic 8，50mm×2.1mm×5μm，进样20μL。结果两制剂的血药浓度时间曲线见图1。从图1可见，自乳化给药系统血药峰浓度约为混悬液的10倍，且血药浓度维持时间延长。
Claims (8)
1.一种姜黄素自乳化给药系统，包括姜黄素、油相、TPGS、聚乙二醇硬脂酸酯15和助乳化剂，各组分含量以重量份数计表示如下：姜黄素0.1～10份，油相4～75份，TPGS 0.1～90份，聚乙二醇硬脂酸酯155～90份，助乳化剂5～40份；所述的TPGS即为维生素E琥珀酸聚乙二醇酯。
2.如权利要求1所述的姜黄素自乳化给药系统，其特征在于所述的姜黄素自乳化给药系统包括姜黄素、油相、TPGS、聚乙二醇硬脂酸酯15和助乳化剂，各组分含量以重量份数计表示如下：姜黄素0.1～5份，油相5～35份，TPGS 1～20份，聚乙二醇硬脂酸酯1535～75份，助乳化剂5～40份。
3.如权利要求2所述的姜黄素自乳化给药系统，其特征在于所述的姜黄素自乳化给药系统由姜黄素、油相、TPGS、聚乙二醇硬脂酸酯15和助乳化剂制成，各组分含量以重量份数计表示如下：姜黄素0.1～5份，油相5～35份，TPGS 1～20份，聚乙二醇硬脂酸酯1535～75份，助乳化剂5～40份。
4.如权利要求3所述的姜黄素自乳化给药系统，其特征在于所述的姜黄素自乳化给药系统由姜黄素、油相、TPGS、聚乙二醇硬脂酸酯15和助乳化剂制成，各组分含量以重量份数计表示如下：姜黄素1～3份，油相5～20份，TPGS 1～15份，聚乙二醇硬脂酸酯1540～65份，助乳化剂10～40份。
5.如权利要求1～4之一所述的姜黄素自乳化给药系统，其特征在于所述油相选自下列之一：油酸，亚油酸，山嵛酸甘油酯，玉米油单、双、三甘油酯，中链脂肪酸甘油酯，花生油，橄榄油，蓖麻油，豆油，油酸乙酯。
6.如权利要求1～4之一所述的姜黄素自乳化给药系统，其特征在于所述助乳化剂选自下列之一：PEG400，PEG300，无水乙醇，丙二醇，异丙醇。
7.如权利要求1所述的姜黄素自乳化给药系统，其特征在于所述的姜黄素自乳化给药系统由姜黄素、油相、TPGS、聚乙二醇硬脂酸酯15和助乳化剂制成，各组分含量以重量份数计表示如下：姜黄素1～3份，油相5～20份，TPGS 1～15份，聚乙二醇硬脂酸酯1540～65份，助乳化剂10～40份；所述的油相为油酸、山嵛酸甘油酯或中链脂肪酸甘油酯；所述的助乳化剂为PEG400或无水乙醇。
8.一种如权利要求1所述的姜黄素自乳化给药系统的制备方法，其特征在于所述的姜黄素自乳化给药系统包括姜黄素、油相、TPGS、聚乙二醇硬脂酸酯15和助乳化剂，各组分含量以重量份数计表示如下：姜黄素0.1～10份，油相4～75份，TPGS 0.1～90份，聚乙二醇硬脂酸酯155～90份，助乳化剂5～40份；具体制备如下：先将除姜黄素以外的组分按照重量配比混合，加热溶解使混合均匀，然后加入姜黄素在25～55℃搅拌使其溶解，即得姜黄素自乳化给药系统。
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| CN1626068A (zh) * | 2003-12-11 | 2005-06-15 | 中国科学院生物物理研究所 | 用于改善姜黄素溶出度和生物利用度的药物组合物及其制备方法 |
| CN1682701A (zh) * | 2005-03-09 | 2005-10-19 | 山东大学 | 姜黄素自微乳化制剂及其制备方法 |
| CN1736369A (zh) * | 2004-08-12 | 2006-02-22 | 山东绿叶天然药物研究开发有限公司 | 姜黄素乳剂及其制备方法和用途 |
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2009
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1626068A (zh) * | 2003-12-11 | 2005-06-15 | 中国科学院生物物理研究所 | 用于改善姜黄素溶出度和生物利用度的药物组合物及其制备方法 |
| CN1736369A (zh) * | 2004-08-12 | 2006-02-22 | 山东绿叶天然药物研究开发有限公司 | 姜黄素乳剂及其制备方法和用途 |
| CN1682701A (zh) * | 2005-03-09 | 2005-10-19 | 山东大学 | 姜黄素自微乳化制剂及其制备方法 |
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