CN109010261B - 一种小分子药物原位相变凝胶缓释系统及其制备方法 - Google Patents
一种小分子药物原位相变凝胶缓释系统及其制备方法 Download PDFInfo
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- CN109010261B CN109010261B CN201810909188.XA CN201810909188A CN109010261B CN 109010261 B CN109010261 B CN 109010261B CN 201810909188 A CN201810909188 A CN 201810909188A CN 109010261 B CN109010261 B CN 109010261B
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Abstract
本发明提供一种以磷脂和司盘为基质的小分子药物原位相变凝胶缓释制剂,并提供了该制剂的制备方法,本发明采用简单的方法将磷脂、司盘、药物活性成分、不同浓度的乙醇溶液制备成磷脂司盘缓释制剂,具有生物相容性好、不良反应小、突释抑制能力强、延长释放时间的优点,适用于皮下注射、外部给药等多种给药形式的特点,而且所包载药物的量可方便地根据药物临床用药剂量进行调节,具有广阔的应用前景。
Description
技术领域
本发明涉及一种以磷脂和司盘为基质,乙醇为溶剂,适用于小分子药物的原位相变凝胶缓释系统,属于医药技术领域。
技术背景
小分子药物对人类健康具有突出的、不可替代的重要作用,其具有相对分子量小,物化性质明确,结构简单,稳定性好,价格便宜,无抗原性等优点,但同时也存在一些问题。小分子药物给药后的血药浓度存在明显的峰值和谷值,使其毒副作用较大且药效降低;对于慢性病,需要长期持续给药,加重了患者的身体、心理和经济负担。因此,通过缓释制剂能够使药物缓慢地释放,得到平稳的血药浓度,降低峰谷值是减毒增效,增加患者用药依从性的关键。因此人们希望开发出一种可注射的小分子药物的缓释给药系统。
目前已上市的注射用缓释给药系统主要是PLGA(聚乳酸-羟基乙酸共聚物)微球。在诸多的小分子药物缓释制剂中,注射用利培酮缓释微球是研究最为成功的品种之一。利培酮是治疗精神病的药物之一,长效利培酮微球注射液(long-acting risperidonemicroshere,简称“利培酮微球”),商品名恒德(Consta)由美国杨森公司研发生产,2003年在美国和欧洲相继上市,2006年进入中国市场,可缓释7周。绿叶制药自行研发用于治疗精神分裂症的利培酮缓释微球肌肉注射制剂(LY3004),已在172名美国患者中完成3项关键性的I期临床试验,仅需每两周注射一次,使用方便。尽管PLGA微球具有较好的缓释作用,但是其制备工艺复杂、载药量低、制备过程中使用的有机溶剂在制剂中有残留,另外其降解过程中产生的乳酸和羟基乙酸会引起注射部位pH值的下降,从而可能引起炎症反应。以上的缺点限制了PLGA微球的应用。
囊泡型磷脂凝胶(VPG)是一种半固体的磷脂分散系统,可以包封水溶性、脂溶性、两亲性的药物。专利CN102697741A开发了一种奥沙利铂囊泡型磷脂凝胶注射剂,由奥沙利铂、大豆卵磷脂、胆固醇、PEG和葡萄糖按特定的重量比制备而成,提高了制剂的稳定性,但是,由结果可知,该制剂在延长药物释放时间和抑制突释方面没有明显的优势,释放时间较短。且其在储存过程中易出现的沉降聚集等问题,影响制剂的稳定性,不利于制剂的保存和运输。
本实验室开发了一种以高浓度磷脂为主要基质,并添加小部分植物油的原位相变凝胶缓释制剂(CN102526753A),该磷脂凝胶制剂具有生物相容性好、缓释作用显著、体内降解性好等优点,应用于蛋白多肽类药物具有好的缓释效果,如醋酸奥曲肽在大鼠、兔子和狗体内可以平稳缓释一个月左右,药物突释很少,优于市售的醋酸奥曲肽微球(MX Wang,etal.Pharmacokinetic and pharmacodynamic study of a phospholipid-based phaseseparation gel for once a month administration of octreotide,Journal ofControlled Release 230(2016)45–56);醋酸艾塞那肽磷脂凝胶几乎没有突释,在大鼠体内缓释长达一个月,能够保持20多天稳定的降血糖效果(M Hu,et al.Long-ActingPhospholipid Gel of Exenatide for Long-TermTherapy of Type II Diabetes,PharmRes 33(2016):1318–1326)。该磷脂凝胶制剂应用于包载部分水溶性小分子化学药物时,也有较好的缓释效果和较小的突释,如盐酸阿霉素、盐酸溴泰君磷脂凝胶等能在动物体内持续释放半个多月(JW Luo,et al.A novel injectable phospholipid gel co-loadedwith doxorubicin and bromotetrandrine for resistant breast cancer treatmentby intratumoral injection,Colloids and Surfaces B:Biointerfaces 140(2016)538–547)。但是,我们在研究中也发现,对于不少小分子化学药物采用该类磷脂凝胶制剂包载,效果不够理想,虽然也有一定的缓释作用,但缓释时间只能持续几天,无法维持长时间的有效血药浓度,且突释情况比较严重。尤其对于脂溶性药物,突释很明显,推测原因可能是因为磷脂为脂溶性成分,水溶性强的药物包载其中很难扩散,其释药主要依靠磷脂的表面溶蚀,因此药物释放持续时间与磷脂载体在体内注射部位的消除时间几乎一致。但脂溶性药物与磷脂相容性好,在磷脂载体中容易渗透、扩散而释放,导致释药速率明显加快,缓释时间持续相对较短,突释较多,对一些治疗窗窄的药物,可能会引起安全性问题。
因此,对于小分子药物,需要探寻一种适用范围广、突释较小、缓释时间长的药物载体来解决其注射用长效缓释问题。
发明内容
本发明的目的是克服现有技术存在的缺陷,提供一种适用范围广,不但能使水溶性小分子药物注射后长时间缓释,也能适用于脂溶性小分子药物的原位凝胶缓释系统。该原位凝胶系统能够显著减少小分子药物的突释。
在研究中意外地发现,高浓度的磷脂与司盘的混合物在乙醇中可形成流动的可注射液体,并且澄清透明。当该混合物注入水中时,能够迅速地自发形成半固体的凝胶制剂。根据此性质,发明人设想,将药物溶解或分散在含磷脂和司盘的乙醇溶液中,注入体内后,由于体内水分的含量比较高,磷脂和司盘会在注射部位自发形成半固体的凝胶,同时随着乙醇的渗出,该混合物进一步固化,成为药物释放的载体,有效控制药物的释放。
根据上述的意外发现,发明人由此以2,4-二硝基苯酚为模型药物,制备了含30%司盘80和45%磷脂的乙醇溶液,给大鼠皮下注射0.5ml后,药物可平稳释放10天以上。在相同的给药剂量下,Cmax原药≈54.48μg/mL,Cmax高浓度磷脂凝胶(按照专利CN102526753A制备)≈30.28μg/mL,Cmax司盘磷脂凝胶≈14.86μg/mL,且原药组只能释放24h。毒性实验结果表明,磷脂司盘凝胶能有效降低2,4-二硝基苯酚的毒副作用。因而,对于2,4-二硝基苯酚这类治疗窗窄的药物,该类制剂能有效地降低其毒副作用。
根据上述创造性的研究,我们惊奇地发现磷脂司盘凝胶缓释制剂能够明显地减少小分子药物突释并延长释放时间。我们认为我们制备的新型凝胶缓释系统可减少突释并能缓释更长时间。因此,我们选择达比加群酯和依匹哌唑为模型药物进行了进一步的研究,结果发现达比加群酯和依匹哌唑凝胶制剂一直处于较平稳的释放状态,几乎没有突释现象。
司盘是一种亲水亲油平衡值(HLB值)较低的非离子型表面活性剂,具有较好的疏水性和安全性。发明人发现,在处方中加入部分司盘,该凝胶制剂遇水后,即刻固化。一方面可以缩短磷脂凝胶的固化时间;另一方面,在体内外释放试验中对小分子化学药物具有很好的缓释效果。从而拓展了该类磷脂凝胶制剂的应用,对小分子药物的缓释应用提供了可能。
另外,该类磷脂凝胶对于水溶性小分子药物,仍然具有很好的缓释效果,如盐酸阿霉素。
本发明的目的之一,是提供一种适用于小分子药物的原位凝胶缓释系统。
本发明的目的之一,是提供一种能显著减少脂溶性小分子药物突释的原位凝胶缓释系统。
本发明的目的之一,是提供一种包含磷脂、司盘、乙醇溶液的组合物。
本发明的目的之一,是提供一种包含磷脂、司盘、乙醇溶液制备成的高浓度磷脂司盘缓释制剂,即本发明所述的原位注射相变凝胶缓释系统或原位注射相变凝胶缓释制剂。
本发明的目的之一,是提供一种缓释效果好,有效减少药物突释,高浓度磷脂含量、易于注射的含有生物活性成分的磷脂司盘缓释制剂。
适用于本发明的磷脂司盘缓释制剂中的司盘,包括但不限于司盘80、司盘85、司盘60、司盘40、司盘20中一种或多种的组合。
在具体的实施方案中,本发明优选司盘80。
适用于本发明的高浓度磷脂司盘缓释制剂中的磷脂,包括但不限于天然磷脂、半合成磷脂、合成磷脂中一种或多种的组合。
所述天然磷脂,包括但不限于蛋黄卵磷脂、大豆磷脂或其组合等。
所述半合成磷脂,包括但不限于氢化蛋黄卵磷脂、氢化大豆磷脂或其组合等。
所述合成磷脂,包括但不限于二棕酰磷脂酰乙醇胺、二棕酰磷脂酸、二棕酰磷脂酰甘油、二油酰磷脂酰乙醇胺、二棕酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱中的一种或多种的组合等。
在具体的实施方案中,本发明优选大豆磷脂S100。
在具体的实施方案中,本发明所述的磷脂缓释制剂,基于制剂的总重量计,其中磷脂含量,为约40%~60%(g/g),司盘用量小于40%(g/g)。
适用于制备本发明所述的磷脂缓释制剂的药物活性成分,可以是水溶性分子、脂溶性分子或两亲性分子,包括但不限于抗癌药类、抗炎药类、止痛药类、抗感染药类、抗糖尿病药类、抗免疫力药类、抗高血压药类、抗癫痫类、抗抑郁药类、抗精神病药类、抗肥胖药类、尿路病类、强心药类。
适用于本发明的药物活性成分包括但不限于以下:
2,4-二硝基苯酚、达比加群酯、阿司匹林、利多格雷、噻氯匹定、氯吡格雷、肝素、洛吉肝素、洛莫肝素、华法林、双香豆素、茶碱、氨茶碱、胆茶碱、沙丁胺醇、克伦特罗、特布他林、异丙托溴铵、色氨酸钠、酮替芬、丙戊酸钠、卡马西平、苯妥英钠、乙琥胺、扑米酮、水合氯醛、佐匹克隆、扎来普隆、苯巴比妥、异戊巴比妥、硫喷妥钠、地西泮、奥沙西泮、氯硝西泮、硝西泮、三唑仑、阿普唑仑、艾司唑仑、格列吡嗪、地尔硫卓、曲马多、吗啡、哌替啶、芬太尼、美沙酮、喷他佐辛、丁丙吗啡、可待因、纳洛酮、双氯芬酸、双氯芬酸钠、异丁司特、氨溴索、羟考酮、氯丙嗪、三氟拉嗪、氟奋乃静、氟奋乃静葵酸酯、氟奋乃静庚酸酯、奋乃静庚酸酯、奋乃静、硫利达嗪、氯普噻吨、三氟噻吨癸酸酯、氯哌噻吨、氟哌啶醇、氟哌啶醇葵酸酯、哌普嗪棕榈酸酯、三氟哌啶醇、哌迷清、三氯丙嗪、甲硫达嗪、氟司必林、氟哌利多、氯氮平、洛沙平、氯噻平、奥氮平、喹硫平、舒必利、舒托必利、硫必利、泰必利、五氟利多、利培酮、吗啉酮、氧哌丁、克罗麦克朗、利血平、丙米嗪、阿米替林、马普替林、氯丙咪嗪、米安舍林、舍曲林、氟西汀、氟伏沙明、西酞普兰、吗氯贝胺、曲唑酮、碳酸锂、托特罗定、左旋多巴、齐拉西酮,左乙拉西坦、瑞替加滨、吡仑帕奈、布瓦西坦、艾司利卡西平、奥卡西平、度洛西汀、帕罗西汀、沃替西汀、去甲文拉法辛、艾司西酞普兰、阿戈美拉汀、瑞波西汀、卡利拉嗪、帕利哌酮、普拉克索、雷沙吉兰、罗匹尼罗、奥匹卡朋、沙芬酰胺、阿法骨化醇、艾地骨化醇、依达拉奉、阿立哌唑、依匹哌唑、卡比多巴、苄丝肼、司来吉兰、金刚烷胺、美金刚、溴隐亭、苯海索、加兰他敏、石杉碱甲、卡巴拉汀、占诺美林、胞磷胆碱、吡拉西坦、吡硫醇、文拉法辛、安非他酮、氟伐他汀钠、格列齐特、二甲双胍、阿昔洛韦、苯扎贝特、非诺贝特、吉非罗齐、环丙贝特、烟酸、别嘌醇、丙戊酸镁、长春胺、异丙嗪、苯海拉明、曲吡那敏、氯苯那敏、布克力嗪、苯茚胺、赛庚啶、羟嗪、塞克利嗪、美克利嗪、西替利嗪、氯雷他定、乙氟利嗪、甲硝唑、氯马斯汀、氮唑斯汀、阿伐斯汀、咪唑斯汀、阿司咪唑、非尼拉敏、溴苯那敏、托普帕敏、吡咯他敏、曲谱利啶、奈福泮、吲达帕胺、坦洛新、依美斯汀、奥昔布宁、丁咯地尔、坦索罗辛、普萘洛尔、美托洛尔、纳多洛尔、吲哚洛尔、阿替洛尔、阿普洛尔、醋丁洛尔、比索洛尔、倍他洛尔、拉贝洛尔、卡拉洛尔、哌唑嗪、卡托普利、依那普利、苯那普利、福辛普利、西拉普利、群多普利、阿拉普利、地拉普利、培哚普利、喹那普利、硝苯地平、氨氯地平、左旋氨氯地平、尼莫地平、尼卡地平、非洛地平、西拉地平、尼索地平、伊拉地平、维拉帕米、氯沙坦、缬沙坦、替米沙坦、厄贝沙坦、坎地沙坦、波沙坦、特拉唑嗪、多沙唑嗪、可乐定、莫索尼定、利舍平、胍乙啶、硝普钠、肼屈嗪、米诺地尔、吡那地尔、尼可地尔、乌拉地尔、吡贝地尔、沙克太宁、依那吉仑、瑞米吉仑、氢氯噻嗪、苄氟噻嗪、氢氟噻嗪、环戊噻嗪、姜黄素、他克林、阿米三嗪、铂类配位物、甲氨蝶呤、氟尿嘧啶、硫嘌呤、硫鸟嘌呤、羟基脲、阿糖胞苷、依维莫司、他克莫司、阿昔莫司、西罗莫司、替加氟、喷司他丁、吉西他滨、环磷酰胺、白消安、卡莫司汀、达卡巴嗪、长春碱、长春新碱、长春瑞滨、长春地辛、紫杉醇、多西他赛、卡巴他赛、喜树碱、羟喜树碱、替尼泊苷、依托泊苷、伊立替康、托普替康、三尖杉酯碱、高三尖杉酯碱、多柔比星、吡柔比星、阿柔比星、伊达比星、表柔比星、柔红霉素、放线菌素D、普卡霉素、克拉霉素、米托蒽醌、布洛芬、对乙酰氨基酚、舒林酸、非诺洛芬、氟比洛芬、酮洛芬、美洛昔康、吡罗昔康、尼美舒利、罗非昔布、塞来昔布、秋水仙碱、丙磺舒、磺吡酮、苯溴马隆、保泰松、甲芬那酸、氯芬那酸、萘普生、吲哚美辛、依托度酸、水杨酸镁、水杨酸胆碱、水杨酰胺、双水杨酯、二氟尼柳、肾上腺皮质激素、雌激素、雄激素、他莫昔芬、雷洛昔芬、氯米芬、甲睾酮、丙酸睾酮、苯乙酸睾酮、甲羟孕酮、甲地孕酮、氯地孕酮、乙酸羟孕酮、氢化可的松、可的松、泼尼松、泼尼松龙、甲泼尼龙、地塞米松、倍他米松、氟他胺、维A酸、伊马替尼、吉非替尼、埃罗替尼、沙利度胺、雷利度胺、丙卡巴肼、苯丁酸氮芥、美法仑或上述药物的药学上可接受的盐的一种或多种组合。优选脂溶性药物。
进一步的,上述化学药物药学上可接受的盐形式包括但不限于盐酸盐、硫酸盐、醋酸盐、水杨酸盐、磺酸盐、枸橼酸盐等多种药学上可用的盐形式。
本发明所述的磷脂司盘缓释制剂,以重量份计,包含药物活性成分0.01~20份,磷脂含量30~60份,司盘含量10~40份、乙醇溶液7~30份。
进一步地,按照重量百分比计,磷脂占所述磷脂司盘缓释制剂含量的40%~60%,司盘占所述磷脂司盘缓释制剂含量小于40%。
其中,所述乙醇溶液包括乙醇-水溶液、乙醇-生理盐水溶液、乙醇-磷酸盐缓冲液溶液、乙醇碳酸盐缓冲溶液、乙醇-琥珀酸盐缓冲溶液、乙醇-枸橼酸盐缓冲溶液、乙醇-乳酸盐缓冲溶液等,其中乙醇的浓度可以是70%~100%(v/v)。
本发明所述的磷脂司盘缓释制剂可加入抗氧化剂、防腐剂、pH调节剂等药剂学上使用的常规赋形剂。
本发明的以磷脂司盘为基质的原位注射相变凝胶缓释系统是一种新颖的剂型,药物活性成分可以溶解在磷脂司盘-乙醇溶液中,成为流动性良好的液体,注入体内后,磷脂和司盘能够立即形成包裹药物活性成分的半固体凝胶,具有良好的缓释效果。
药物活性成分也可以以微粒形式分散在磷脂司盘-乙醇溶液中,只要能保持制剂通针性即可。
可以将药物活性成分和空白的磷脂司盘基质分别保存,临用前溶解或分散均匀后给药。
本发明的另一个目的,提供了一种制备磷脂司盘凝胶缓释系统,即磷脂司盘缓释制剂的方法。
本发明的制备方法,包括下述步骤:
(1)取药物活性成分溶于适量的乙醇溶液中,微孔滤膜过滤除菌,形成药物溶液;
(2)在无菌条件下取注射级磷脂和司盘与步骤(1)的药物溶液混合,搅拌使磷脂完全溶解,静置片刻以除去制剂中的气泡,分装,密封,即得。
由于有些药物活性成分溶解度较差,为得到分散均一的制剂,在另一具体实施方案中,本发明还提供了另一种磷脂司盘缓释制剂的制备方法,包括下述步骤:
(1)在无菌的条件下,取药物活性成分通过药剂学上常见的结晶或粉碎方式,制备药物微粒。
(2)在无菌条件下取处方量磷脂、司盘与乙醇溶液混合,搅拌使完全溶解;
(3)在无菌条件下将步骤(1)的药物微粒与步骤(2)中制备的载体溶液混合均匀,静置片刻以除去制剂中的气泡,分装,密封,即得。
在具体的实施方案中,所述微孔滤膜优选0.22μm微孔滤膜。
本发明所述的原位注射相变凝胶缓释制剂可以用于注射给药,优选皮下给药;也可以用于外用给药等其他给药形式。
本发明所述的原位注射相变凝胶缓释制剂也可以用于修复和扩充软和/或硬组织。
本发明通过创造性的研究,以磷脂司盘和乙醇溶液等作为主要原料,采用小分子化学药物如2,4-二硝基苯酚、达比加群酯、依匹哌唑等为模型药物,通过简单搅拌的方式制备成磷脂司盘缓释制剂。所得制剂流动性良好,容易注射给药,动物体内实验证明其具有良好的缓释效果。通过考察磷脂司盘缓释制剂对注射部位的刺激性,其结果显示该制剂具有较好的生物相容性,对给药部位的刺激性较小。
因此本发明可以普遍实现小分子药物缓释的同时,很好地解决了现有的小分子药物原位凝胶制剂突释性强的问题,具有良好的应用前景。
本发明的优点
磷脂司盘缓释制剂含有能够与水完全互溶的少量乙醇溶液,注射入体内后,磷脂和司盘混合物能够立即固化,乙醇能够快速地扩散到体液,使凝胶制剂进一步固化,成为药物缓释的载体,控制药物的释放。动物体内实验证明该制剂确实具有良好的缓释效果,突释效应较小甚至没有突释。磷脂司盘缓释制剂具有流动性好、易于注射给药等优点。另外还可以根据所要包载药物的溶解性选择合适的溶剂或溶剂组合来溶解药物,以制得均匀透明的稳定制剂。药物也可以微粒形式均匀分散在制剂当中。此外,磷脂司盘缓释制剂中不含有水分或水分含量较低,且制剂中含有乙醇,可以有效抑制微生物的生长,有利于制剂的储存,从而扩大了磷脂司盘制剂的应用范围。
附图说明
图1为磷脂司盘缓释制剂形成凝胶的过程图。
图2为2,4-二硝基苯酚的磷脂司盘缓释制剂(DNP-LC-gel)的体外释放曲线。
图3为2,4-二硝基苯酚的磷脂司盘缓释制剂、高浓度磷脂缓释制剂和溶液组的药时曲线。
图4为皮下注射2,4-二硝基苯酚的磷脂司盘缓释制剂的药时曲线。
图5为2,4-二硝基苯酚的磷脂司盘缓释制剂的毒性试验。
图6为达比加群酯的磷脂司盘缓释制剂、高浓度磷脂缓释制剂和溶液组的药时曲线。
图7为达比加群酯的磷脂司盘缓释制剂局部刺激性试验。
图8为依匹哌唑的磷脂司盘缓释制剂和F127缓释制剂的药时曲线。
具体实施方式
以下实施例是对本发明的进一步说明,但绝不是本发明范围的限制。下面参考实施例进一步详细阐述本发明,但是本领域技术人员应当理解,本发明并不限于这些实施例以及使用的制备方法。而且,本领域技术人员根据本发明的描述可以对本发明进行等同替换、组合、改良或修饰,但这些都将包括在本发明的范围内。
实施例1
取2,4-二硝基苯酚50mg,溶于2.0g的85%(v/v)乙醇-pH 7.6磷酸缓冲液中,经0.22μm微孔滤膜过滤得到药物溶液,然后在无菌条件下,加入注射级的大豆磷脂S100 4.5g和司盘80 3.5g,无菌条件下磁力搅拌约1h,至S100完全溶解,得到含有大量气泡的液体,静置至气泡完全消失,分装,密封,即得。
实施例2
取达比加群酯200mg,溶于1.0g的无水乙醇中,得到药物溶液,0.22μm微孔滤膜过滤,然后在无菌条件下,加入注射级的蛋黄卵磷脂E80 5.0g、司盘80 4.0g,无菌条件下磁力搅拌约1h,至S100完全溶解,得到含有大量气泡的液体,静置至气泡完全消失,分装,密封,即得。
实施例3
在无菌条件下,取适量的依匹哌唑于研钵中研磨粉碎,得到依匹哌唑粉末。取无水乙醇1.5g,司盘80 4.0g和注射级的大豆磷脂S100 4.5g,无菌条件下磁力搅拌约1h,至S100完全溶解,得到含有大量气泡的乳黄色液体。在无菌条件下取依匹哌唑粉末200mg与上述液体混合均匀,静置至气泡完全消失,分装,密封,即得。
实施例4
取茶碱100mg,溶于3.0g的80%(v/v)乙醇-pH 7.6磷酸缓冲液中,得到药物溶液,0.22μm微孔滤膜过滤,然后在无菌条件下,加入注射级的氢化蛋黄磷脂4.0g、司盘80和司盘20各1.0g,无菌条件下磁力搅拌约1h,至氢化蛋黄磷脂完全溶解,得到含有大量气泡的液体,静置至气泡完全消失,分装,密封,即得。
实施例5
取地塞米松10.0mg,溶于0.7g的无水乙醇中,得到药物溶液,0.22μm微孔滤膜过滤,然后在无菌条件下,加入注射级的二棕酰磷脂酰乙醇胺6.0g、司盘20 2.3g和司盘601.0g,无菌条件下磁力搅拌约1h,至二棕酰磷脂酰乙醇胺完全溶解,得到含有大量气泡的液体,静置至气泡完全消失,分装,密封,即得。
实施例6
取阿司匹林100mg,溶于2.0g的80%(v/v)乙醇-pH 7.6磷酸缓冲液中,得到药物溶液,0.22μm微孔滤膜过滤,然后在无菌条件下,加入注射级的蛋黄卵磷脂E80 4.0g和司盘203.9g,无菌条件下磁力搅拌约1h,至E80完全溶解,得到含有大量气泡的液体,静置至气泡完全消失,分装,密封,即得。
实施例7
取西咪替丁200mg,溶于2.8g的90%(v/v)乙醇-pH7.6磷酸缓冲液中,得到药物溶液,0.22μm微孔滤膜过滤,然后在无菌条件下,加入注射级的大豆磷脂S100 6.0g和司盘201.0g,无菌条件下磁力搅拌约1h,至S100完全溶解,得到含有大量气泡的液体,静置至气泡完全消失,分装,密封,即得。
实施例8
取盐酸多奈哌齐40mg,溶于2.5g的70%(v/v)乙醇-水中,得到药物溶液,0.22μm微孔滤膜过滤,然后在无菌条件下,加入注射级的大豆磷脂S100 6.0g、司盘80 1.0g和司盘400.5g,无菌条件下磁力搅拌约0.5h,至S100完全溶解,得到含有大量气泡的液体,静置至气泡完全消失,分装,密封,即得。
实施例9
在无菌条件下,取适量的利培酮于研钵中研磨粉碎,得到利培酮粉末。取无水乙醇溶液2.0g和司盘20 3.5g,大豆磷脂S100 4.5g,无菌条件下磁力搅拌约0.5h,至S100完全溶解,得到含有大量气泡的乳黄色液体。在无菌条件下取利培酮粉末150mg与上述液体混合均匀,静置至气泡完全消失,分装,密封,即得。
实施例10
取卡托普利200mg,溶于1.5g 90%(v/v)乙醇-水溶液中,得到药物溶液,经0.22μm微孔滤膜过滤,在无菌条件下加入注射级蛋黄卵磷脂E80 5.5g和司盘85 3.0g,无菌条件下磁力搅拌约0.5h,至E80完全溶解,得到含有大量气泡的乳黄色液体,静置至气泡完全消失,分装,密封,即得。
实施例11
取地西泮100mg,溶于2.0g的75%(v/v)乙醇-水中,得到药物溶液,经0.22μm微孔滤膜过滤,在无菌条件下加入注射级蛋黄卵磷脂E80 5.5g和司盘20 2.5g,无菌条件下磁力搅拌约0.5h,至E80完全溶解,得到含有大量气泡的乳黄色液体,静止至气泡完全消失,分装,密封,即得。
实施例12
取异丙嗪80mg,溶于2.0g的70%(v/v)乙醇-水中,得到药物溶液,0.22μm微孔滤膜过滤,在无菌条件下加入大豆磷脂S100 5.5g和司盘80 3.5g,无菌条件下磁力搅拌约0.5h,至S100完全溶解,得到含有大量气泡的乳黄色液体,静止至气泡完全消失,分装,密封,即得。
实施例13
取阿柔比星70mg,溶于2.0g的80%(v/v)乙醇-水中,得到药物溶液,0.22μm微孔滤膜过滤,在无菌条件下加入蛋黄卵磷脂E80 5.5g和司盘80 2.5g,无菌条件下磁力搅拌约0.5h,至E80完全溶解,得到含有大量气泡的乳黄色液体,静止至气泡完全消失,分装,密封,即得。
实施例14
取卡莫司汀90mg,溶于2.5g的80%(v/v)乙醇-水中,得到药物溶液,0.22μm微孔滤膜过滤,在无菌条件下加入大豆磷脂S100 5.5g和司盘80 2.0g,无菌条件下磁力搅拌约0.5h,至S100完全溶解,得到含有大量气泡的乳黄色液体,静止至气泡完全消失,分装,密封,即得。
实验例1
按照实施例1的制备方法进行下列试验,将实施例1处方中的司盘换成二油酸甘油酯(试验例1),吐温(试验例2)和乙酸异丁酸蔗糖酯(试验例3)。同时设计原药溶液组(试验例4,将50mg药物溶解于10mL磷酸盐缓冲液(pH=7.6),制备与实施例1相同浓度的溶液)。
将200~220g的SD大鼠随机分为五组,每组6只,按照2,4-二硝基苯酚12.5mg/kg的剂量皮下注射给药(实施例1,试验例1,试验例2,试验例3和试验例4),在预定的时间点,通过大鼠眼眶取血,置于肝素钠抗凝的试管中,样品经处理后,LC-MS/MS进样检测血药浓度,结果如下表所示:
结果:从上表中可以看出,磷脂凝胶中加入司盘优于其他表面活性剂,可以有效地抑制2,4-二硝基苯酚的突释作用。
实验例2
按照实施例1的制备方法进行下列试验,将实施例1处方中的乙醇换成丙二醇(试验例1)和甘油(试验例2)。考察制剂的外观并通过黏度仪测定黏度。
结果如下表:
结果:由于乙醇对磷脂溶解量最大,其他两种溶剂溶解度不高,过夜搅拌不能溶解,制得制剂黏度大于300cp,甚至呈半固体,无法注射。可见,在相同的溶剂用量条件下,乙醇具有优于其他溶剂的溶解性能,能较好地溶解配方中的组分,易于注射给药。
实验例3
制备不同比例的磷脂司盘80缓释制剂,进行局部刺激性实验,考察无水乙醇的用量对注射部位的刺激性,包括红肿、溃烂等现象。
结果如下表:
结果:当制剂中无水乙醇的含量低于30%时,制剂对给药部位的刺激性较小。理论上用含有一定量水分的乙醇溶液代替无水乙醇,其毒性应该更低。
实验例4
(1)磷脂司盘凝胶相变过程
将实施例1的产品注入水中,结果见图1,磷脂司盘凝胶从乳黄色透明液体变成球状半固体状态,说明磷脂司盘凝胶乙醇扩散后会发生相变过程。
(2)体外释放结果
将实施例1的产品和溶液组(实验例1中试验例4)分别装在透析袋中,然后放置在50ml PBS缓冲溶液中(pH=7.4),在恒温振荡器(37℃,100rmp)中进行体外释放试验。在设定时间点取出5ml的缓冲液,并加入等体积的新鲜PBS缓冲液,计算2,4-二硝基苯酚的累计释放率。结果见图2,磷脂司盘凝胶组具有抑制突释的特性。
(3)体内药动学结果
将实施例1的产品注射到雄性SD大鼠皮下,定时取血,采用高效液相色谱-质谱法(LC-MS/MS)测定血浆中2,4-二硝基苯酚的含量,考察其缓释效果。
将200~220g的SD大鼠随机分为三组,溶液组(实验例1中试验例4)、磷脂司盘凝胶组(实施例1)、高浓度磷脂凝胶组(按照专利CN102526753A制备),每组6只,按照12.5mg/kg的剂量皮下注射给药,在预定的时间点,通过大鼠眼眶取血,置于肝素钠抗凝的试管中,样品经处理后,LC-MS/MS进样检测血药浓度,
高浓度磷脂凝胶缓释制剂(专利CN102526753A)的处方如下:
各组制剂的药动学参数如下:
结果显示,磷脂司盘凝胶的缓释能力明显高于高浓度磷脂凝胶和溶液,主要表现为Cmax降低,t1/2延长。如图3和图4所示:包载小分子药物DNP的高浓度磷脂原位相变凝胶缓释制剂突释较为严重,缓释效果不好,而本发明的磷脂司盘凝胶制剂能够明显地改善小分子药物的突释情况,缓释效果较好。
(3)毒性结果
将不同药物剂量实施例1的产品(B)和溶液组(实验例1中试验例4)的药物溶液(A)注射到雄性SD大鼠皮下,观察并记录大鼠的死亡情况。结果如图5所示,该类凝胶制剂能够明显地降低其副作用,这是由于该制剂具有很好的缓释和抑制突释的能力,与溶液组相比,该制剂能够明显地降低DNP在体内的血药浓度,从而提高其安全性。
实验例5
(1)体内药动学结果
将实施例2的产品注射到雄性SD大鼠皮下,定时取血,采用高效液相色谱-质谱法(LC-MS/MS)测定血浆中达比加群酯的含量,考察其缓释效果。
将200~220g的SD大鼠随机分为三组,每组6只,按照溶液组(11.4mg/kg,将200mg达比加群酯溶解于10mL磷酸盐缓冲液(pH=7.6),制备与实施例2相同浓度的溶液)、磷脂司盘80凝胶组(80mg/kg)(实施例2)、高浓度磷脂凝胶组(80mg/kg,按照专利CN102526753A制备,将实验例4中高浓度磷脂凝胶组的DNP换成200mg达比加群酯)的剂量皮下注射给药,在预定的时间点,通过大鼠眼眶取血,置于肝素钠抗凝的试管中,样品经处理后,LC-MS/MS进样检测血药浓度,结果显示,磷脂司盘80凝胶组的缓释能力明显高于高浓度磷脂凝胶和溶液组,主要表现为t1/2延长,达比加群酯能维持较高的有效血药浓度。如图6示:包载小分子药物达比加群酯的高浓度磷脂原位相变凝胶缓释效果不好,而本发明的磷脂司盘凝胶制剂能够明显的改善小分子药物的突释情况,缓释效果较好。
各组制剂的药动学参数如下:
(2)局部刺激性实验
将实施例2的产品注射到雄性SD大鼠皮下,在第1天、14天和21天时,处死大鼠,取皮肤组织做HE染色。图7结果表明该凝胶制剂刺激性小,生物相容性好。
实验例6
将实施例3的产品注射到雄性SD大鼠皮下,定时取血,采用高效液相色谱-质谱法(LC-MS/MS)测定血浆中依匹哌唑的含量,与文献报道有显著缓释效果的F127温敏凝胶(LinZ,,et al.Novel thermo-sensitive hydrogel system with paclitaxel nanocrystals:High drug-loading,sustained drug release and extended local retentionguaranteeing better efficacy and lower toxicity,Journal of Controlled Release28(2014)161–70)进行比较。
F127温敏凝胶的处方如下:
将200~220g的SD大鼠随机分为两组,每组6只,按照磷脂司盘80凝胶组(50mg/kg)和20%F127温敏凝胶(50mg/kg)的剂量皮下注射给药,在预定的时间点,通过大鼠眼眶取血,置于肝素钠抗凝的试管中,样品经处理后,LC-MS/MS进样检测血药浓度,结果显示,磷脂司盘80凝胶组的缓释能力明显高于F127温敏凝胶,主要表现为t1/2延长,依匹哌唑能维持较高的有效血药浓度。如图8所示,虽然F127温敏凝胶可以持续缓释100余小时,但很快代谢,突释较明显;而本发明的磷脂司盘凝胶制剂几乎没有药物的突释,缓释效果较好,可以持续缓释25天。
实验例7
磷脂司盘缓释制剂对其他小分子药物的缓释特性。
采用动物体内实验考察其他小分子药物抑制突释的效果。将下表中药物按照实施例1处方量及制备方法制备制剂,得到的其他小分子药物的磷脂司盘缓释制剂和原药溶液(每种药物视具体溶解性而定,用注射用水、乙醇或DMSO配置)注射到雄性SD大鼠皮下,定时取血,采用高效液相色谱-质谱法(LC-MS/MS)测定血浆中各其他小分子药物的Cmax,考察其抑制突释的效果。结果如下表所示
结果表明,本发明的磷脂司盘凝胶制剂能够明显地改善小分子药物的突释情况。
综上所述,磷脂司盘原位相变凝胶可以显著地抑制小分子药物突释,延长缓释时间,降低小分子药物的毒性,并且具有良好的生物相容性。
Claims (4)
1.一种原位凝胶制剂,其特征在于,由磷脂、司盘、药物活性成分和乙醇溶液组成,其中所述的药物活性成分为利培酮;以重量份计,所述制剂由利培酮0.01~20份、磷脂30~60份、司盘10~40份、乙醇溶液7~30份组成;其中所述乙醇溶液的浓度范围为70~100%(v/v);其中,所述磷脂选自大豆磷脂、蛋黄卵磷脂、氢化蛋黄磷脂和二棕酰磷脂酰乙醇胺;其中,所述司盘为司盘80。
2.根据权利要求1所述的原位凝胶制剂,其特征在于,所述乙醇溶液选自无水乙醇、乙醇-水溶液、乙醇-生理盐水溶液、乙醇-磷酸盐缓冲液溶液、乙醇碳酸盐缓冲溶液、乙醇-琥珀酸盐缓冲溶液、乙醇-枸橼酸盐缓冲溶液、乙醇-乳酸盐缓冲溶液。
3.根据权利要求1所述的原位凝胶制剂,其特征在于,所述磷脂为大豆磷脂,所述乙醇溶液为无水乙醇。
4.权利要求1所述原位凝胶制剂的制备方法,其特征在于包括以下步骤:
(1)在无菌的条件下,取利培酮粉碎成为粉末;
(2)在无菌条件下取磷脂、司盘与乙醇溶液混合,搅拌使完全溶解,制得载体溶液;
(3)在无菌条件下将步骤(1)的利培酮粉末与步骤(2)中制备的载体溶液混合均匀,静置至气泡完全消失,分装,密封,即得。
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- 2017-06-22 CN CN201810910942.1A patent/CN108771657B/zh active Active
- 2017-06-22 CN CN201710480564.3A patent/CN107049932B/zh active Active
- 2017-06-22 CN CN201810909188.XA patent/CN109010261B/zh active Active
- 2017-10-11 US US16/489,353 patent/US20200069583A1/en not_active Abandoned
- 2017-10-11 WO PCT/CN2017/105682 patent/WO2018233148A1/zh unknown
- 2017-10-11 EP EP17914339.1A patent/EP3643298A4/en active Pending
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WO2018233148A1 (zh) | 2018-12-27 |
CN109010261A (zh) | 2018-12-18 |
CN107049932B (zh) | 2020-11-06 |
CN108771657A (zh) | 2018-11-09 |
EP3643298A4 (en) | 2021-03-24 |
CN108771657B (zh) | 2020-11-06 |
CN107049932A (zh) | 2017-08-18 |
US20200069583A1 (en) | 2020-03-05 |
EP3643298A1 (en) | 2020-04-29 |
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