CN103550138A - 一种索拉非尼有机凝胶及其制备方法 - Google Patents
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Abstract
本发明提供一种新型索拉非尼有机凝胶及其制备方法。该索拉非尼有机凝胶由有机胶凝剂、有机溶剂、分散稳定剂、活性药物组成，该有机凝胶是热敏型有机凝胶，胶凝温度为40-50℃，高温呈溶液，冷却后呈凝胶，并且遇水能迅速分散成纳米溶液。本发明的有机凝胶具有显著提高索拉非尼体外溶出速率和大鼠口服生物利用度；凝胶中凝胶剂用量较少，安全性好；制备方法简单；用途广，能加工成多种给药途径的制剂等特点，具有良好的应用前景。
Description
技术领域
本发明涉及索拉非尼的一种药物新剂型和新技术，特别是涉及一种有机凝胶及其制备方法。
背景技术
索拉非尼(sorafenib)化学名4-{4-[3-(4-氯-3-三氟甲基-苯基-酰脲]-苯氧基}-吡啶-2-羧酸甲胺，分子式：C21H16ClF3N4O3，分子量464.8g／mol。临床使用的是索拉非尼的甲苯磺酸盐形式，分子结构式如下：
索拉非尼是一种新型多靶点药物，主要通过两种途径发挥抗癌活性。①抑制Raf-1和B-Raf丝氨酸和苏氨酸激酶的活性，从而抑制RAS／RAF／MEK／ERK信号传导通路，抑制肿瘤细胞的增殖。②抑制肿瘤新生血管生成。肿瘤的生长依赖新生血管的形成，索拉非尼通过抑制血管内皮生长因子受体VEGFR和PDGFR的酪氨酸激酶活性阻断肿瘤新生血管的形成和切断肿瘤细胞的营养供应，间接抑制肿瘤细胞的生长。
索拉非尼可显著延长晚期肾癌、原发性肝癌患者的生存期，成为治疗肝癌和肾癌首选化疗药物，同时也可用于非小细胞肺癌、前列腺癌、卵巢癌等治疗。
甲苯磺酸索拉非尼片剂含甲苯磺酸索拉非尼274mg／片，相当于索拉非尼200mg，每日服用2次，总剂量为548mg。一期临床研究表明，单剂400mg给药后的平均最大浓度为1.67-2.13mg／l，，达峰时间为4-8小时，半衰期24-48小时，与口服溶液比较相对生物利用度38-49％，与高脂性食物同食时生物利用度降低至29％。
由此可知该药物片剂吸收慢(达峰时间长)，生物利用度低，这可能是由于索拉非尼溶解性能差(它水中不溶，油中溶解度也较差)的缘故。因此急需研究索拉非尼研究新剂型或新制剂，提高生物利用度(包括增加吸收速度和程度)，减少给药剂量，降低成本。本专利中发明正是通过有机凝胶这一新型制剂技术来达到此目的。
有机凝胶系由低浓度的凝胶剂在有机溶剂中通过物理或化学键相互作用自组装、相互缠绕形成的三维网状结构固定有机溶剂而形成的半固体系统。简言之，有机凝胶系主要由具有自组装有机凝胶剂的三维网络固定有机溶剂组成的半固体体系。其中有机凝胶剂(organogelator)大都是通过低能键物理作用(如氢键和范德华键等)而形成凝胶的，这种物理凝胶一般是可逆凝胶，而少数是通过化学共价键连接获得凝胶的，化学凝胶一般是不可逆的。目前文献报道应用于药剂学领域的有机凝胶用的凝胶剂有卵磷脂、卵磷脂-泊洛沙姆、山梨醇脂肪酸衍生物、脂肪酸衍生物、氨基酸衍生物及聚丙烯酸、甲基丙烯酸-甲基丙烯酸甲酯共聚物等。与使用水作为溶剂的水凝胶不同，有机凝胶不使用水，大多数采用植物油，酯类液体化合物(如十四烷酸异丙酯、司盘)为有机溶剂。令人遗憾的是，仅有为数不多研究描述有机凝胶在给药中的应用，这可能是研究中多数有机凝胶剂可能有潜在的毒性或缺乏毒理学研究。
目前研究最多的是卵磷脂泊洛沙姆有机凝胶，用于提高难溶性药物生物利用度，但仅用做外用制剂。最近有一些口服有机凝胶的报道，例如布洛芬有机凝胶(IwanagaK.et al.，Int JPharm，388：123-128，2010)是用12-羟基硬脂酸为有机凝胶剂，大豆油为有机溶剂而制成的，该有机凝胶制剂布洛芬口服绝对生物利用度达98％，血药浓度曲线下面积(AUC)是布洛芬大豆油溶液的1.3倍，布洛芬水性混悬剂的1.5倍，但是吸收速度慢，有机凝胶峰浓度(Cmax)<大豆油溶液<水性混悬剂，显示缓释效应。环孢素有机凝胶(Murdan S.et al.，Int J Pharm，300：113-124，2005)是以司盘60为凝胶剂，吐温或与司盘80的混合物为有机溶剂而制备的，最佳有机凝胶处方口服生物利用度的参数(如AUC和Cmax)与上市环孢素制剂均相近。
有机凝胶的制备方法通常采用加热熔融-冷却法，该方法用于载药量较大的制剂时药物存在沉淀致含药量不均的问题，这也是水凝胶制剂在载入水难溶性药物时普遍存在的问题。
至今亲水性和亲脂性都差的索拉非尼的有机凝胶仍处于空白。
发明内容
本发明提供一种索拉非尼有机凝胶及其制备方法。
本发明有机凝胶由活性药物、有机胶凝剂、有机溶剂、稳定剂组成。
本发明有机凝胶中各组分质量百分含量为：
本发明有机凝胶中的活性药物包括索拉非尼及其类似物(如尼罗替尼，舒尼替尼，达沙替尼、拉帕替尼)，或其药学上可接受的盐(如甲苯磺酸盐，苯磺酸盐，乙磺酸盐)，优选索拉非尼或索拉非尼甲苯磺酸盐，其中载药量为10％-35％。
本发明有机胶凝中有机凝胶剂包括泊洛沙姆407，或泊洛沙姆407与同系物(如泊洛沙姆188)组成的混合物，用量小于16％，优选10-15％。
本发明有机胶凝中有机溶剂包括PEG400及其同系物(如PEG300，PEG400，PEG600)，或者PEG400与其他药学上可接受的有机溶剂(如无水乙醇、丙二醇、甘油)的混合物，优选PEG400。
本发明有机胶凝中稳定剂为聚乙烯吡咯烷酮类，如聚乙烯吡咯烷酮K-12、聚乙烯吡咯烷酮K-15、聚乙烯吡咯烷酮K-30和聚乙烯吡咯烷酮K-90中的一种或两种以上混合物，优选聚乙烯吡咯烷酮K-15，用量为3％-10％。
本发明中有机凝胶采用溶剂挥发-冷却法制备，其制备方法是：取处方量聚乙二醇400、泊洛沙姆407、聚乙烯吡咯烷酮、索拉非尼于烧杯中，加入无水乙醇适量，50-70℃加热搅拌溶解，在挥尽乙醇后，4℃冰浴搅拌下得索拉非尼有机凝胶。
本发明特征在于：有机凝胶为热敏性凝胶，胶凝温度为40-50℃，在胶凝温度下为凝胶，温度上升至胶凝温度以上可以缓慢融化成溶胶，且该过程是可逆的(见图1)，该索拉非尼有机凝胶适用于制成口服制剂(如胶囊剂)和外用制剂。
本发明特征在于：索拉非尼有机凝胶在适量的pH4.0-7.0水中经搅拌或振摇，能迅速分散，形成具蓝色乳光的纳米溶液，粒径小于300nm。这种特性使得该有机凝胶适用于加工成注射制剂、外用制剂(如眼用)和口服制剂，在临用前加水给药。
本发明中提供一种新型索拉非尼有机凝胶，大大提高了难溶性药物在制剂中的分散度，加快药物体外溶出的速度，增加药物的生物利用度，索拉非尼有机凝胶大鼠口服给药，与原料药混悬液比较，能使索拉非尼体内血药峰浓度增加6.7倍，体内生物利用度增加9.8倍；该有机凝胶处方中凝胶剂等表面活性剂用量较低(<16％)，大大提高用药安全性；该凝胶制剂载药量高和均匀度好，且稳定性好，与脂质体，微乳，胶束等常见增溶技术比较，无需经过冷冻干燥工艺使制剂稳定；在制备过程中加入低沸点亲水性有机溶剂(如无水乙醇、甲醇、异丙醇等)，采用溶解-挥发-冷却工艺制备有机凝胶，使水溶性差和亲脂性也较差的索拉非尼药物在凝胶中均匀分散，较好地解决了大剂量药物有机凝胶含量不均的问题。
该有机凝胶特点1)处方工艺简单，便于大生产，成本大大降低，2)药物处于凝胶状态，不仅增加药物载药量和分散均匀性，而且体外稳定，3)能增加药物在体内吸收速率和体内生物利用度4)适用于多种给药途径的制剂，如口服制剂和外用制剂，5)遇水能形成纳米溶液，便于注射给药。
附图说明
图1泊洛沙姆有机凝胶在胶凝温度上下的可逆转变图。
图2泊洛沙姆有机凝胶与原料药的体外溶出曲线图。
图3大鼠口服索拉非尼原料药、有机凝胶、有机凝胶纳米溶液后体内血药浓度曲线图。
具体实施方式
实施例1索拉非尼有机凝胶制备
处方：
制备方法：称取处方量中各物质和适量无水乙醇于三颈烧瓶中，60℃加热搅拌至溶液澄清后，缓慢挥尽甲醇，4℃冰浴搅拌下成凝胶。
实施例2索拉非尼有机凝胶制备
处方：
制备方法：称取处方中各物质于烧杯和适量无水乙醇于三颈烧瓶中，60℃加热搅拌至溶液澄清后，缓慢挥尽乙醇，4℃冰浴搅拌下成凝胶。
实施例3索拉非尼有机凝胶纳米溶液制备
分别取实施例1和实施例2中凝胶0.07g，加入纯化水1ml，迅速搅拌，均得凝胶完全分散的纳米溶液，粒径小于300nm。
实施例4索拉非尼有机凝胶体外溶出度考察
样品：实施例1索拉非尼有机凝胶和索拉非尼原料药
溶出方法：转蓝法测定，溶出介质为0.1MHCL1％SDS溶液，体积为900ml，转速75r／min，取样时间点设为5，10，15，20，30，45，60，90，120min，原料药与有机凝胶的体外溶出曲线如图2。结果表明索拉非尼有机凝胶体外溶出速率大大提高。
实施例5索拉非尼有机凝胶大鼠体内相对生物利用度研究
1.样品：
原料组：适量索拉非尼用0.5％CMC-Na溶液2ml混悬，即得；有机凝胶组：实施例1有机凝胶；纳米溶液组：适量有机凝胶，加2ml纯净水，搅拌成纳米溶液。
2.实验方法：SD雌性大鼠(186g-200g)，随机分为三组，每组6只，按200mg／kg剂量(指相当于原料药甲苯磺酸索拉非尼的质量)，分别灌胃原料药、有机凝胶和纳米溶液，给药后0.5，1，2，3，4，6，8，12，24，36，48，60，72h眼眶取血，每次0.25ml，离心分离出血浆，测定血药浓度。
3.血药浓度测定：取大鼠血浆100μL，加入10ul醋酸甲地孕酮溶液(40ug／ml)，混匀，加入乙腈300μL，涡旋20s，10000rpm离心6min，取上清液置离心管中，25℃N2吹干，适量甲醇溶解，20ul进样HPLC分析，计算血药浓度。图3是血药浓度经时曲线。统计矩法计算的药动学参数见表1，其中相对生物利用度Fr计算方程是：
Fr％=AUC0-72，有机凝胶或纳米溶液／AUC0-72，原料药
表1索拉非尼原料药、有机凝胶组、有机凝胶纳米溶液的药动学参数
*P<0.05，**P<0.01，***P<0.001vs原料药组
结果表明有机凝胶组和纳米溶液组大大提高索拉非尼口服生物利用度，分别是原料药的9.81倍和6.93倍，且吸收速度也大幅度提高，有机凝胶组和纳米溶液组的Cmax分别是原料药组的6.39倍和9.67倍。
Claims (8)
1.一种索拉非尼有机凝胶，其组成为：
2.如权利1要求的索拉非尼有机凝胶，其特征在于：活性药物索拉非尼包括索拉非尼及其类似物(如尼罗替尼，舒尼替尼，达沙替尼、拉帕替尼)，或其药学上可接受的盐(如甲苯磺酸盐，苯磺酸盐，乙磺酸盐)，优选索拉非尼或索拉非尼苯磺酸盐，其中载药量为10％-35％。
3.如权利1要求的索拉非尼有机凝胶，其特征在于：热敏型有机凝胶剂泊洛沙姆407包括泊洛沙姆407，或泊洛沙姆407与同系物(如泊洛沙姆188)组成的混合物，用量小于16％，优选10-15％。
4.如权利1要求的索拉非尼有机凝胶，其特征在于：有机溶剂聚乙二醇400(PEG400)包括PEG400及其同系物(如PEG300，PEG400，PEG600)，或者PEG400与其他药学上可接受的有机溶剂(如无水乙醇、丙二醇、甘油)的混合物，优选PEG400。
5.如权利1要求的索拉非尼有机凝胶，其特征在于：聚乙烯吡咯烷酮包括聚乙烯吡咯烷酮K-12、聚乙烯吡咯烷酮K-15、聚乙烯吡咯烷酮K-30、聚乙烯吡咯烷酮K-90中一种或两种以上混合物，优选聚乙烯吡咯烷酮K-15。
6.如权利1要求的索拉非尼有机凝胶，其制备方法是：取处方量聚乙二醇400、泊洛沙姆407、聚乙烯吡咯烷酮、索拉非尼于烧杯中，加入无水乙醇适量，搅拌加热溶解，挥尽乙醇后，4℃冰浴搅拌下得索拉非尼有机凝胶。
7.如权利1要求的索拉非尼有机凝胶，其特征在于：所述的有机凝胶适用于口服制剂(如口服胶囊剂)和外用制剂。
8.如权利1要求的索拉非尼有机凝胶，其特征在于：该有机凝胶在pH4.0-7.0水中可搅拌或振摇迅速分散，得粒径小于300nm的纳米溶液，便于注射给药。
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| CN116159018A (zh) * | 2023-03-01 | 2023-05-26 | 中国药科大学 | 一种新型外用溴莫尼定凝胶剂 |
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Effective date of registration: 20230413 Address after: Room 201-0806, Building 2, Jinghu Dianjin Business Plaza, No. 101 Nanjiao Shuyuan Road, Chengxiang Town, Taicang City, Suzhou City, Jiangsu Province, 215413 Patentee after: Suzhou New Aidi Pharmaceutical Technology Co.,Ltd. Address before: Room 12011211-1212, block B, phase I, Zhongdan Ecological Life Science Industrial Park, no.3-1, xinjinhu Road, Jiangbei new district, Nanjing, Jiangsu, 211161 Patentee before: Nanjing Puhui Pharmaceutical Technology Co.,Ltd. |
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Effective date of registration: 20231107 Address after: Room 12011211-1212, block B, phase I, Zhongdan Ecological Life Science Industrial Park, no.3-1, xinjinhu Road, Jiangbei new district, Nanjing, Jiangsu, 211161 Patentee after: Nanjing Puhui Pharmaceutical Technology Co.,Ltd. Address before: Room 201-0806, Building 2, Jinghu Dianjin Business Plaza, No. 101 Nanjiao Shuyuan Road, Chengxiang Town, Taicang City, Suzhou City, Jiangsu Province, 215413 Patentee before: Suzhou New Aidi Pharmaceutical Technology Co.,Ltd. |