CN1682701A - 姜黄素自微乳化制剂及其制备方法 - Google Patents
姜黄素自微乳化制剂及其制备方法 Download PDFInfo
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- CN1682701A CN1682701A CN 200510042547 CN200510042547A CN1682701A CN 1682701 A CN1682701 A CN 1682701A CN 200510042547 CN200510042547 CN 200510042547 CN 200510042547 A CN200510042547 A CN 200510042547A CN 1682701 A CN1682701 A CN 1682701A
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Abstract
一种姜黄素自微乳化制剂及其制备工艺。该制剂由姜黄素、表面活性剂、助表面活性剂、油相以及固体吸附剂组成，可制成胶囊或颗粒剂用于口服给药，进入体内后在胃肠液的作用下可自微乳化形成100nm以下纳米粒径的液滴，可以增大姜黄素的溶解度、促进其在胃肠道的吸收、提高生物利用度。
Description
(一)技术领域
本发明涉及一种姜黄素自微乳化制剂及其制备方法。
(二)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的一种天然有效成分，分子式为C21H20O6。药理实验表明姜黄素除具有抗炎、抗癌、抗氧化作用外，还具有保护肾脏、抑制肺纤维化、抑制肝纤维化、帮助肌肉损伤修复、治疗白内障、抗寄生虫病等多种药理作用，且毒副作用小，使用安全，有良好的临床应用前景。但姜黄素几乎不溶于水，在多种油中的溶解度也不理想，因此经胃肠道吸收少，口服生物利用度低，而注射给药使用不方便，病人不能自主给药，顺应性差。因此目前改善姜黄素的口服吸收是扩大姜黄素临床应用、使其进一步规模化生产的瓶颈。
微乳就是由水、油和两性分子组成的光学上均一、热力学上稳定、液滴粒径在10～100nm之间的液态体系，作为口服药物载体，微乳可以增加疏水性药物的溶解度，提高生物利用度，制备简单，不需要外力作用，只需轻微搅拌使组分混合均匀即可形成；而且稳定性好，放置、离心均不分层。自微乳化体系是由油、表面活性剂形成的微乳浓缩液，或在浓缩液基础上加入固体吸附剂形成固体分散物，置于水中或胃肠液中可自发形成微乳；与微乳相比，自微乳体系体积小、便于携带、并且可以进一步提高药物的稳定性。
(三)发明内容
本发明针对现有技术的不足，提供一种姜黄素自微乳化制剂及其制备方法。
本发明的姜黄素自微乳化制剂，以姜黄素作为原料药，采用表面活性剂、助表面活性剂、油相和固体吸附剂组成的混合物作为药物载体，各组份重量份如下：
姜黄素100份，表面活性剂1500～8000份，助表面活性剂1500～8000份，油相300～6000份，固体吸附剂3000～8000份。
上述的表面活性剂选自下列之一或它们的组合：月桂酸蔗糖酯，棕榈酸蔗糖酯，硬脂酸蔗糖酯，脂肪酸山梨坦，聚山梨酯，聚氧乙烯40硬脂酸酯，苄泽30、苄泽35，聚氧乙烯蓖麻油甘油醚(氧乙烯单位为35～40)，泊洛沙姆188，氢化蓖麻油，卵磷脂，十二烷基硫酸钠，十八烷基硫酸钠，阿洛索-OT或十二烷基苯磺酸钠。
上述的脂肪酸山梨坦选自下列之一或它们的组合：脂肪酸山梨坦20、脂肪酸山梨坦40、脂肪酸山梨坦60、脂肪酸山梨坦65、脂肪酸山梨坦80或脂肪酸山梨坦85。
上述聚山梨酯选自下列之一或它们的组合：聚山梨酯20、聚山梨酯40、聚山梨酯60、聚山梨酯65、聚山梨酯80或聚山梨酯85。
上述的助表面活性剂选自下列之一或它们的组合：乙醇、异丙醇、1，2-丙二醇、正丁醇、正辛醇、正庚醇、聚氧乙烯(400)单月桂酸酯、聚氧乙烯(400)单硬脂酸酯或聚乙二醇400。
上述的油相选自下列之一或它们的组合：花生油、豆油、蓖麻油、橄榄油、亚油酸乙酯、油酸乙酯、中等链长(C8～18)的甘油三酯、月桂酸异丙酯、肉豆蔻酸异丙酯、丙烯乙二醇单辛酸酯、丙烯乙二醇双辛酸酯或甘油单辛酸酯。
上述的固体吸附材料选自下列之一或它们的组合：乙基纤维素、聚乙二醇(分子量1000～20000)、聚维酮(分子量1000～360000)、草酸、乳糖、甘露醇、山梨醇、醋酸纤维素酞酸酯、羟丙甲纤维素酞酸酯、聚丙烯酸树脂(E、RS、RL)、微粉硅胶或羧甲乙纤维素。以聚乙二醇4000、聚乙二醇6000和微粉硅胶为佳。
上述姜黄素自微乳化制剂为颗粒剂或胶囊剂。
本发明的姜黄素自微乳化制剂的制备方法如下：
将表面活性剂与助表面活性剂混合均匀后，加入油相，用搅拌、振荡、超声或涡旋方式混匀，形成空白微乳浓缩液，加入姜黄素，充分溶解得姜黄素微乳浓缩液。再用固体吸附剂做载体制成颗粒，即得姜黄素自微乳化制剂。
上述制成颗粒的方法可用溶融法、溶剂挥发法、冷冻干燥法或直接造粒等现有技术。
将上述制成的颗粒分装到铝塑袋中得颗粒剂。
将上述制成的颗粒分装入胶囊壳中得胶囊剂。
为提高姜黄素的口服吸收以及形成制剂的稳定性，本发明选择自微乳化体系作为药物载体。本发明所选择的表面活性剂、助表面活性剂和油相为药剂学上广泛应用的药用辅料，具有无毒、无刺激性的特性。通过处方筛选和优化，当三者配比适当时，该混合物在水性条件下可自微乳化形成微乳。
姜黄素在水中的溶解度很低(远小于0.7μg/ml)，本发明所选择的表面活性剂、助表面活性剂和油相，均可提高姜黄素的溶解度，制剂在水中自微乳化形成O/W型微乳液后，姜黄素在水中的溶解度提高到10～15mg/ml，增大1000倍以上。本发明所制成的自微乳化制剂口服进入体内后可自微乳化形成粒径在10～100nm之间的微乳液，由于粒径100nm以下的微粒极易在胃肠道吸收，且O/W型微乳与胃肠道有良好的粘附性，故可有效增加药物的吸收，提高生物利用度。
大鼠在体小肠吸收试验：将50ml供试液加入循环装置的烧杯中，供试液(1)：Krobs-Ringer试液配制的姜黄素表面活性剂胶束溶液(含姜黄素100mg)100ml+2mg酚红，供试液(2)：Krobs-Ringer试液配制的姜黄素微乳液(含姜黄素100mg)100ml+2mg酚红。将禁食一夜的雄性大鼠麻醉后，打开腹腔，自十二指肠上部及回肠下部各插入直径0.5cm的玻璃管，清洗肠道后，打开蠕动泵，使供试液在肠道中进行循环，定时取样并补加酚红溶液(每ml Krobs-Ringer试液含酚红20μg)。测定样液中姜黄素的含量，计算姜黄素的吸收量。结果表明：姜黄素乳化剂OP胶束溶液小肠吸收量为(32.4±1.8)％，姜黄素微乳(处方如实施例1)小肠吸收量为(57.6±2.3)％，微乳吸收明显优于胶束溶液。
姜黄素自微乳化制剂制备简单，采用搅拌、振荡、超声、涡旋等方式将各组分混匀，将药物充分溶解，即可得姜黄素微乳浓缩液。将该浓缩液与适宜的固体吸收剂通过熔融法、溶剂法、冷冻干燥法或直接混合制备颗粒等方法，可使浓缩液在载体材料中均匀分散，可以更好地促进药物的溶解和吸收，且具有提高药物稳定性的作用。
(四)附图说明
图1是本发明实施例5姜黄素微乳电镜照片，放大72000倍。
(五)具体实施方式
实施例1：
称取乳化剂-OP(聚氧乙烯壬烷基酚醚，G34H62O11，分子量648.85)100g，加姜黄素2.5g，搅拌，使药物完全溶解，加入聚乙二醇400 35g，油酸乙酯10g，高速搅拌使混合均匀，得姜黄素自微乳化浓缩液。取过100目筛的微粉硅胶60g和甘露醇20g，与上述浓缩液混合均匀后，过20目筛，制得颗粒，装硬胶囊400粒。
实施例2：
称取吐温-80 100g，加姜黄素3g，加热到40℃，使药物完全溶解，加入甘油100g，油酸乙酯10g，高速搅拌，混合均匀，得姜黄素自微乳化浓缩液。取聚乙二醇4000 200g，水浴加热到70℃熔融，将上述浓缩液迅速倒入聚乙二醇4000中混合均匀后，放入冰水浴中迅速冷却固化。将所得固体粉碎，过18目筛，制得颗粒，干燥后，装入铝塑包装袋得颗粒剂400包。
实施例3：
称取吐温-80 200g，PEG400 50g，花生油25g，高速搅拌混合均匀，加入姜黄素2.5g，搅拌使药物完全溶解，得姜黄素自微乳化浓缩液，加入适量蒸馏水，使形成姜黄素微乳液1000ml。取过80目筛的乳糖200g与PVPk15 200g，与上述微乳液混合均匀后，冷冻干燥后过20目筛，制得颗粒。将颗粒分装，即得颗粒剂。
实施例4：
称取乳化剂OP 100g，加入姜黄素3g，超声使药物溶解，加入正辛醇150g，橄榄油25g，高速搅拌混合均匀，得姜黄素自微乳化浓缩液。取聚乙二醇6000 400g，乙基纤维素100g，与上述浓缩液混合均匀后，过18目筛，制得颗粒。
实施例5：
称取吐温-80 300g，无水乙醇45g，葵花油25g，高速搅拌混合均匀，加入姜黄素3g，搅拌使药物完全溶解，得姜黄素自微乳化浓缩液。取聚乙二醇6000 400g，取过100目筛的微粉硅胶60g和聚乙二醇4000 15g，与上述浓缩液混合均匀后，过18目筛，制得颗粒。
取上述颗粒适量加人工肠液适量，使主药姜黄素含量约为3mg/ml，轻微振荡使其自微乳化形成澄清透明的微乳液。将姜黄素微乳滴在铜网上，用2％的磷钨酸(pH4.47)负染色，自然干燥后电镜观察。在电镜下微乳呈圆球形，内部为油相。平均粒径在50nm左右，绝大多数在100nm以下。根据乳剂分散相液滴的大小，该乳剂为微乳。
Claims (9)
1.一种姜黄素自微乳化制剂，其特征在于：以姜黄素作为原料药，采用表面活性剂、助表面活性剂、油相以及固体吸附剂组成的混合物作为药物载体，各组份重量份如下：
姜黄素100份，表面活性剂1500～8000份，助表面活性剂1500～8000份，油相300～6000份，固体吸附剂3000～8000份。
2.如权利要求1所述的姜黄素自微乳化制剂，其特征在于所述的表面活性剂选自下列之一或它们的组合：
月桂酸蔗糖酯，棕榈酸蔗糖酯，硬脂酸蔗糖酯，脂肪酸山梨坦，聚山梨酯，聚氧乙烯40硬脂酸酯，苄泽30、35，聚氧乙烯蓖麻油甘油醚(氧乙烯单位为35～40)，泊洛沙姆188，氢化蓖麻油，卵磷脂，十二烷基硫酸钠，十八烷基硫酸钠，阿洛索-OT或十二烷基苯磺酸钠。
3.如权利要求1所述的姜黄素自微乳化制剂，其特征在于所述的助表面活性剂选自下列之一或它们的组合：乙醇、异丙醇、1，2-丙二醇、正丁醇、正辛醇、正庚醇、聚氧乙烯脂肪酸酯或聚乙二醇400。
4.如权利要求1所述的姜黄素自微乳化制剂，其特征在于所述的油相选自下列之一或它们的组合：花生油、豆油、蓖麻油、橄榄油、亚油酸乙酯、油酸乙酯、中等链长的甘油三酯、月桂酸异丙酯、肉豆蔻酸异丙酯、丙烯乙二醇单/双辛酸酯或甘油单辛酸酯。
5.如权利要求1所述的姜黄素自微乳化制剂，其特征在于所述的固体吸附材料选自下列之一或它们的组合：聚乙二醇、聚维酮、草酸、乳糖、甘露醇、山梨醇、醋酸纤维素酞酸酯、羟丙甲纤维素酞酸酯、聚丙烯酸树脂、微粉硅胶或羧甲基纤维素。
6.如权利要求1所述的姜黄素自微乳化制剂，其特征在于该制剂为颗粒剂或胶囊剂。
7.权利要求1所述的姜黄素自微乳化制剂的制备方法，将表面活性剂与助表面活性剂混合均匀后，加入油相，用搅拌、振荡、超声或涡旋方式混匀，形成空白微乳浓缩液，加入姜黄素，充分溶解得姜黄素微乳浓缩液，再加入固体吸附剂做载体制成颗粒。
8.如权利要求7所述的姜黄素自微乳化制剂的制备方法，其特征在于将制成的颗粒分装到铝塑袋中得颗粒剂。
9.如权利要求7所述的姜黄素自微乳化制剂的制备方法，其特征在于将制成的颗粒分装入胶囊壳中得胶囊剂。
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| CN114557965A (zh) * | 2022-02-09 | 2022-05-31 | 汕头大学 | 一种提高姜黄素稳定性和生物可及性的磷脂复合物纳米粒及制备方法 |
| CN115176989A (zh) * | 2022-07-12 | 2022-10-14 | 河南中大恒源生物科技股份有限公司 | 一种透明姜黄素油溶液及其制备方法和应用 |
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