CN116350572A - 可注射原位凝胶缓释递药系统、载药制剂及其制备方法 - Google Patents
可注射原位凝胶缓释递药系统、载药制剂及其制备方法 Download PDFInfo
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- CN116350572A CN116350572A CN202310055018.0A CN202310055018A CN116350572A CN 116350572 A CN116350572 A CN 116350572A CN 202310055018 A CN202310055018 A CN 202310055018A CN 116350572 A CN116350572 A CN 116350572A
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- injectable
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- glycyrrhizate
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Abstract
本发明一种可注射原位凝胶缓释递药系统、载药制剂及其制备方法,系统包括作为凝胶缓释递药系统核心原料为甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐中的一种或几种,药学上可接受的与水互溶的溶剂,发挥治疗作用的活性成分。制备方法为按照处方量称取甘草酸、甘草次酸及甘草酸盐,加入溶剂中,加热搅拌使体系完全溶解,冷却至室温,再加入活性成分,搅拌溶解,经滤膜过滤除菌,即得可注射原位凝胶缓释递药组合物。该组合物在常温下是溶液,在给药部位或者进入机体后,有机溶剂逐渐扩散,组织液渗入凝胶基质,凝胶基质快速由溶液状态转变成凝胶状态,活性物质被储存于凝胶孔隙中,随后缓慢从凝胶中释放出来,发挥缓释递药作用。
Description
技术领域
本发明属于药物制剂领域,涉及一种可注射原位凝胶缓释递药系统和载药制剂,及其制备方法。
背景技术
原位凝胶又称为在位凝胶,是一种新型递药系统,它与用药部位接触前呈液态,与用药部位接触后立即发生相转变,由液态转化成固态或半固体状。使用前活性药物与凝胶材料可以形成均匀透明溶液,注射后形成凝胶状。原位凝胶剂具有生物相容性好、用药部位滞留时间长、良好的药物缓控释性、制备工艺简单、递药方便等特点。
原位凝胶分为温度敏感型、pH敏感型、离子敏感型和溶剂交换型等。原位凝胶剂作为一种新型的凝胶剂,广泛用于缓释、控释和脉冲释放等新型递药系统中,原位凝胶可以用于皮下、皮肤表面、眼部、鼻腔、口腔、直肠、阴道、关节腔、肌内等多部位多途径递药。
现有原位水凝胶的凝胶物质主要选用泊洛沙姆、壳聚糖、海藻酸钠、聚N-异丙基丙烯酰胺、聚乳酸羟基乙酸共聚物(PLGA)、聚碳酸亚乙酯、醋酸异丁酸蔗糖酯(SAIB)、卡波姆等高分子,有机溶剂常选用N-甲基吡咯烷、二甲基亚砜、三乙酸甘油酯、苯甲酸苄酯、甘油糖醛等。这些原位凝胶使用大量的高分子、交联剂和有机溶剂,在体内降解缓慢且有残留,存在安全性的问题。
甘草酸属于三萜类化合物,提取自甘草根部,纯品甘草酸为白色针状晶体,熔点220℃,其结构中包含一分子甘草次酸和两分子葡萄糖醛酸,分为α和β两种异构体,分子中有三个羧基,可呈单盐、二盐、三盐等三种形式。具有抗炎、保护肝脏等作用,临床常用于各种急慢性肝炎以及肝硬化等疾病。甘草次酸属于肾上腺皮质激素及促肾上腺皮质激素药,可代替去氧皮质酮用于阿狄森病的治疗。甘草酸二钠具有抗炎、保护肝脏、降血脂、增强免疫力,也可作为低热量甜味剂。甘草酸单钾盐属于抗肝炎药。适用于防治病毒性、慢性迁延性肝炎、慢性活动性肝炎、急慢性乙型肝炎、肝中毒、初期肝硬化。甘草酸单铵盐对气管炎、支气管炎、咳嗽、哮喘等呼吸系统疾病有显著疗效,对消化道感染、乙肝、口腔溃疡、胃溃疡等也有效果。
文献1(游广娇等,甘草酸水凝胶载药体系的构建及其对黄芩素体外属性的影响,中华中医药杂志,2021年,36(7):3977-3981)报道了甘草酸单铵盐自组装行为构建甘草酸单铵盐水凝胶载药体系,制备甘草酸单铵盐水凝胶的最佳浓度为10mg/mL。文献2(王文苹等,甘草酸水溶液的凝胶化特性,中国医院药学杂志,2020年,40(16):1724-1727)报道了当甘草酸水溶液浓度达20mg/mL时经放置后可形成稳定性良好的水凝胶,该凝胶黏度随温度升高而逐渐降低。专利申请CN201911063092.7公开了甘草酸和五环三萜化合物或者四环三萜化合物的混合物为凝胶分子,以磷酸盐缓冲溶液为凝胶溶剂,制备抗菌水凝胶的方法。以上现有技术公开的含有甘草酸或者甘草酸盐的水凝胶均属于体外形成凝胶而非原位形成凝胶,体外形成凝胶的注射性差、浓度偏低、体外凝胶灭菌困难等缺点。
发明内容
本发明的目的是为了克服现有技术存在的缺陷,提供一种可注射原位凝胶缓释递药系统和载药制剂,及其制备方法;本发明通过以甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐中的一种或者几种为凝胶基质,选取合适比例溶剂,一定条件下制备得到可注射原位凝胶缓释递药系统,注射前为溶液,注射进入机体内则原位形成凝胶,该原位凝胶系统可以用于载药。该缓释递药系统原料易得,制备方法简便、制剂便于注射、最大载药量高、缓释效果较好。
本发明所要解决的一个技术问题是提供一种具有可注射、可以原位形成凝胶且具有缓释递药性能的递药系统,以及包括所述递药系统和活性药物成分的载药制剂,该系统和/或制剂在注射前是均匀、澄清溶液,均匀度好,产品质量易于控制。
本发明所要解决的另一个技术问题在于提供一种可注射原位凝胶缓释载药制剂的制备方法,该方法操作简单,条件温和,可以实现工业化生产。
为解决上述技术问题,本发明采用的技术方案如下:
提供一种可注射原位凝胶缓释递药系统,所述可注射原位凝胶缓释递药系统为一种透明澄清液体组合物,其包含甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐中的一种或者几种,和一种溶剂,所述溶剂中包含临床上可用的有机溶剂和水、或者临床上可用的有机溶剂和生理性的水性介质;
本发明所用的甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐中的一种或者几种占组合物溶剂总质量的1%至80%;
可注射原位凝胶缓释递药系统常温下呈现透明澄清液体形态,经注射后在给药部位与体液接触后,发生溶剂交换和相转变,呈凝胶或半凝胶状;
所述甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐中的一种或者几种为主要凝胶基质,所述递药系统进一步包含高分子物质,所述高分子物质优选为乙基纤维素、聚乳酸-羟基乙酸共聚物(PLGA)、聚己内酯(PCL)、泊洛沙姆中的一种或者几种,所述高分子物质优选占溶剂质量5%至40%。
本发明组合物中,溶剂中的水或者生理性的水介质中的水占有机溶剂的质量比例为0%至90%;所述生理性的水性介质选自葡萄糖水溶液、氯化钠水溶液或磷酸盐缓冲溶液;
所述的有机溶剂选自N-甲基吡咯烷酮、二甲基亚砜、乙醇、甘油、丙二醇、甘露醇中的一种或者几种。
本发明递药系统在使用之前为可注射溶液,经注射后在体内原位形成凝胶或者半凝胶状态。
本发明优选方案中,组合物主要包含甘草酸、甘草次酸及其盐自组装形成的超分子。
本发明可注射原位凝胶缓释递药系统,其中:
当水或者生理性的水介质中的水占有机溶剂的质量比例为0%至30% W/W时,甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐占溶剂总质量的1%至80% W/W,优选50%至70%;
当水或者生理性的水介质中的水占有机溶剂的质量比例为30%至60% W/W时,甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐占有机溶剂和水性介质总质量的1%至50% W/W,优选30%至50%;
当水或者生理性的水介质中的水占有机溶剂的质量比例为60%至90% W/W时,甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐占有机溶剂和水性介质总质量的1%至30% W/W。
本发明进一步提供一种可注射原位凝胶缓释载药制剂,所述制剂包括甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐中的一种或者几种,一种溶剂,以及至少一种治疗有效量的活性物质,所述溶剂中包含临床上可用的有机溶剂和水、或者临床上可用的有机溶剂和生理性的水性介质,所述的甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐中的一种或者几种占溶剂总质量的1%至80%,所述的可注射原位凝胶缓释载药制剂常温下呈现透明澄清液体形态,经注射后在给药部位与体液接触后,发生溶剂交换和相转变,呈凝胶或半凝胶状;
所述的活性物质为水溶性药物或醇溶性药物,活性物质占所述组合物总质量的0.1%至20%;
所述的活性物质包括抗炎药、局麻药、镇痛药、抗精神失常药物、抗焦虑药、镇静催眠药、抗抑郁药、抗高血压药、类固醇激素、抗癫痫药、杀菌剂、抗惊厥药、抗帕金森病药物、中枢神经兴奋药、抗精神病药、抗心律失常药、抗心绞痛药、抗甲状腺药、解毒药、止吐药、降糖药、抗结核病药、抗艾滋病药、抗乙肝药、抗肿瘤药、抗排斥药或其混合物。
所述制剂作为药物储库制剂施用,所述制剂为可注射剂型或者所述制剂可以局部给药;
所述可注射剂型常温下呈现透明澄清液体形态,经注射至给药部位与体液接触后,发生溶剂交换和相转变,呈凝胶或半凝胶状。
本发明提供一种可注射原位凝胶缓释载药制剂的方法,该方法包括以下步骤:
(a)按照水或者生理性的水介质中的水占有机溶剂的质量比例为0%至90% W/W配制溶液,按照甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐中一种或者几种混合物占溶剂总质量的1%至80%加入上述溶剂中;
(b)将步骤(a)得到的混合物加热搅拌,充分溶解,加热温度为40至90摄氏度,优选为50至80摄氏度,加热时间大于等于0.5小时,优选大于1小时;
(c)将步骤(b)中溶液冷却至室温,按照活性物质占药物组合物总质量的0.1%至20%,加入活性物质,室温搅拌充分溶解,得澄清溶液;
(d)将步骤(c)获得的溶液,通过膜过滤除菌,灌装于临床上允许的密闭容器中,得到可注射原位凝胶缓释载药制剂。
本发明的可注射原位凝胶缓释递药组合物和载药制剂在体外是均匀的、澄清透明溶液,进入机体后,有机溶剂逐渐扩散,体内组织液渗入凝胶基质,凝胶基质快速由溶液状态转变成凝胶状态,活性物质被储存于凝胶孔隙中,随后缓慢从凝胶中释放出来。
有益效果
本发明具有如下有益效果:
本发明是由甘草酸、甘草次酸及甘草酸盐自组装形成的超分子体系,使用时它是可注射的溶液状态,注射到机体内,在原位形成凝胶,使用方便;本发明使用的溶剂是医学上允许使用的有机溶剂的水溶液,溶剂毒性低,安全性高,溶剂无污染,成本低廉;
本发明制备可注射原位凝胶缓释载药制剂的方法简便、步骤简洁、制备条件温和,便于放大生产,工业上可行性高,可以工业化生产;
本发明的可注射原位凝胶缓释递药系统组合物和载药制剂是均匀的溶液,便于质量检测,容易控制产品质量;
本发明的可注射原位凝胶缓释载药制剂载药量高,药物释放平稳,具有缓释作用;
本发明的可注射原位凝胶缓释递药系统组合物中的自组装超分子体系可降解,可被机体吸收,既是凝胶基质也是具有药效的药物,具有其本身特有的抗炎、保护肝脏等药理活性。
附图说明
图1是实施例8动物实验前、后、解剖观察和扫描电镜图。
图2是实施例9动物实验前、后、解剖观察和扫描电镜图。
图3是实施例10药物体外释放实验曲线图。
图4是实施例11药物体外释放实验曲线图。
图5是实施例12布比卡因和原位载药凝胶血药浓度变化曲线图。
具体实施方式
通过以下实施例详细说明本发明,应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被理解为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明保护的范围内,凡基于本发明核心物质为主成分的组合物均在本发明保护范围内。
除非特殊说明,以下实施例中所使用的原料和试剂均为市售商品,或者通过已知方法制备。
实施例1
按照表1配置溶剂,按照表中比例(质量比)配置甘草酸和甘草次酸混合物,取一定量的溶剂加入圆底烧瓶中,按照甘草酸和甘草次酸占溶剂总质量的1%至80%也加入到上述圆底烧瓶中,加冷凝回流装置,将混合物在40℃下加热搅拌1小时,待完全溶解后停止加热,冷却至室温。
表1.实施例处方比例
表中处方各组分含量经过探索实验,在加热状态下完全溶解,冷却后仍为溶液状态,没有析出固体,没有变成凝胶,放置48小时溶液仍然稳定存在,始终呈现均匀溶液状态。取1mL制剂,装入透析袋中,然后放入100mL磷酸盐缓冲液中,模拟体内形成凝胶过程,30分钟后观察,变成水凝胶状态,符合实验预期,由表中数据可见,随着溶剂中水含量的增加,其溶解能力逐渐下降,对应溶质的含量逐渐减少。实验发现,溶质含量越高,其溶液粘度略微增加,但是常温下仍然具有非常好的可注射性。
实施例2
按照表2配置溶剂,配置甘草酸单铵盐和甘草酸的比例(质量比),取一定量的溶剂,按照甘草酸单铵盐和甘草酸占溶剂总质量的2%至80%加入上述溶剂中,将上述混合物置于圆底烧瓶中,加冷凝管,将混合物在50℃下加热搅拌1小时,待完全溶解后停止加热,冷却至室温。
表2.实施例处方比例
表中处方比例配置溶液,搅拌加热后能够完全溶解,冷却至室温后仍为溶液状态,取1mL溶液制剂,装入透析袋中,然后放入100mL磷酸盐缓冲液中,模拟体内形成凝胶过程,30分钟后观察成胶状态,均可以形成凝胶,有机溶剂含量越高,可以溶解的溶质越多,溶液浓度就越高,形成的凝胶硬度就越大。
实施例3
按照表3配置溶剂,配置甘草酸单铵盐、甘草酸和甘草酸二钠的比例(质量比),取一定量的溶剂加入圆底烧瓶中,按照甘草酸单铵盐、甘草酸和甘草酸二钠占溶剂总质量的3%至50%加入上述溶剂中,圆底烧瓶上方加冷凝管,将混合物在60℃下加热搅拌1小时,待完全溶解停止加热,冷却至室温。
取1mL制剂,装入透析袋中,然后放入100mL磷酸盐缓冲液中,模拟体内形成凝胶过程,30分钟后观察成胶状态。
实施例中比例配置,加热条件下均可以溶解,冷却后无固体析出,静置一段时间后仍然呈溶液状态,有机溶剂和水的比例会影响形成凝胶时间,有机溶剂量越高,形成凝胶所需要的时间越长。
表3.实施例处方比例
实施例4
按照表4配置溶剂,配置甘草酸、甘草酸单钾和甘草酸二钠的比例(质量比),取一定量的溶剂,按照甘草酸、甘草酸单钾和甘草酸二钠占溶剂总质量的5%至80%加入上述溶剂中,将上述混合物置于圆底烧瓶中,加冷凝管。将混合物在70℃下加热搅拌0.5小时,待完全溶解停止加热,冷却至室温。
取1mL制剂,装入透析袋中,然后放入100mL磷酸盐缓冲液中,模拟体内形成凝胶过程,30分钟后观察成胶状态。
表4.实施例处方比例
采用透析袋模拟体内环境成胶过程时,经过一定时间实施例都能发生凝胶化,本研究的原位注射凝胶属于溶剂交换型凝胶,其形成凝胶的机理是有机溶剂扩散后,甘草酸及甘草酸盐处于水性环境中,自组装成网状交联的水凝胶状态。
实施例5
按照表5配置溶剂,配置甘草酸单铵、甘草酸和甘草次酸的比例(质量比),取一定量的溶剂,按照甘草酸单铵、甘草酸和甘草次酸占溶剂总质量的3%至80%加入上述溶剂中,将上述混合物置于圆底烧瓶中,加冷凝管。将混合物在70℃下加热搅拌0.5小时,待完全溶解停止加热,冷却至室温。
取1mL制剂,装入透析袋中,然后放入100mL磷酸盐缓冲液中,模拟体内形成凝胶过程,30分钟后观察成胶状态。
表5.实施例处方比例
实施例6
按照表6配置溶剂,按照比例(质量比)配置甘草酸和甘草酸单铵的混合物,根据表中比例(质量比)配置乙基纤维素与PLGA的混合物,取一定量的溶剂加入圆底烧瓶中,按照甘草酸和甘草酸单铵占溶剂总质量的5%至70%加入上述溶剂中,按照乙基纤维素与PLGA混合物占溶剂总质量的5%至40%加入上述溶剂中,圆底烧瓶加装冷凝管。将混合物在90℃下加热搅拌0.5小时,待完全溶解停止加热,冷却至室温。取1mL制剂,装入透析袋中,然后放入100mL磷酸盐缓冲液中,模拟体内形成凝胶过程,30分钟后观察成胶状态。
本实施例,研究了增加适量高分子物质之后的配方比例,加入适量高分子物质,加热搅拌、冷却后依然可以得到透明溶液,模拟成胶过程类似,都可以30分钟内成凝胶状。
表6.含有适量高分子物质实施例处方比例
实施例7
按照表7配置溶剂,按照比例(质量比)配置甘草酸、甘草酸单铵和甘草酸二钠的混合物,按照比例(质量比)配置聚己内酯与泊洛沙姆的混合物,取一定量的溶剂加入圆底烧瓶中,按照甘草酸、甘草酸单铵和甘草酸二钠占溶剂总质量的5%至70%加入上述溶剂中,按照聚己内酯与泊洛沙姆混合物占溶剂总质量的5%至40%加入上述溶剂中,在圆底烧瓶上装冷凝管,将混合物在80℃下加热搅拌1小时,待完全溶解停止加热,冷却至室温。
按照表中配方组分,加热搅拌、冷却后依然可以得到透明溶液,取1mL制剂,装入透析袋中,然后放入100mL磷酸盐缓冲液中,模拟体内形成凝胶过程,30分钟后观察成胶状态。实验发现,在模拟成胶过程,可以30分钟内成凝胶状。
表7.含有适量高分物质实施例处方比例
实施例8
配置30%丙二醇水溶液,配置甘草酸单铵盐:甘草酸:甘草酸二钠质量比2:2:1混合物,按照混合物占溶剂总质量25%,加入圆底烧瓶中,加热,充分搅拌,完全溶解后冷却,得到可注射凝胶组合物,进行原位凝胶在动物体内成胶情况研究,采用SD大鼠,7%水合氯醛麻醉,大鼠背部实验区域剃毛,暴露皮肤,注射1mL凝胶溶液,20分钟后,解剖,剥离皮下凝胶,观察成胶情况。实验发现,注射后皮肤隆起,触摸为硬块,说明在体内很快成胶,解剖后,发现呈现白色蜡状凝胶。取出凝胶组织,液氮速冻,再低温冷冻干燥,保持其形貌,取少许冻干后块状固体,置于电镜载样台,导电胶粘合固定,喷金,钨灯丝扫描电镜观察形貌。具体结果见图1,注射前为澄清、透明均匀溶液,动物皮下注射后可见明显隆起,触摸呈块状,解剖后得到凝胶状固体,扫描电镜下观察其形貌,呈蜂窝状,具有载药空隙。
实施例9
配置30%乙醇水溶液,配置甘草酸:甘草次酸质量比3:1混合物,按照混合物占溶剂总量15%,加入圆底烧瓶中,加热搅拌,完全溶解后冷却,得到可注射凝胶组合物,进行原位凝胶在动物体内成胶情况研究,采用SD大鼠,7%水合氯醛麻醉,大鼠背部实验区域剃毛,暴露皮肤,注射1mL凝胶溶液,20分钟后,解剖,剥离皮下凝胶,观察成胶情况。实验发现,注射后皮肤隆起,触摸为硬块,说明在体内很快成胶,解剖后,发现呈现白色蜡状凝胶。取出凝胶组织,液氮速冻,再低温冷冻干燥,保持其形貌,取少许冻干后块状固体,置于电镜载样台,导电胶粘合固定,喷金,钨灯丝扫描电镜观察形貌。具体结果见图2,注射前为澄清、透明均匀溶液,动物皮下注射后可见明显隆起,触摸呈块状,解剖后得到凝胶状固体,扫描电镜下观察其形貌,呈蜂窝状,具有载药空隙。
实施例10
凝胶载药体外模拟药物释放实验,30%乙醇水溶液,配置甘草酸:甘草次酸质量比3:1混合物,按照混合物占溶剂总量35%,将上述混合物置于圆底烧瓶中。将混合物在70℃下加热搅拌1小时,待完全溶解停止加热。冷却至室温,加入盐酸布比卡因占药物制剂总质量的10%,折算载药浓度为100mg/g,室温搅拌充分溶解,得澄清溶液制剂。通过0.22μm滤膜过滤除菌备用。采用药典中的浆法进行药物释放实验,取1mL制剂,装入透析袋中,封口,再放入900mL水中,水温37℃,搅拌桨转速恒定。每隔一定时间,取样少量样品,采用高效液相色谱分析药物浓度,计算药物释放百分比,绘制药物释放曲线,如图3所示,药物在模拟体液中缓慢释放,随着时间延续,累积释放百分比逐渐达到最大值,可见药物释放平稳,具有缓释效果。
实施例11
凝胶载药体外模拟药物释放实验,30%丙二醇水溶液,配置甘草酸单铵盐:甘草酸:甘草酸二钠质量比4:4:2混合物,按照混合物占溶剂总量45%称取,将上述混合物置于圆底烧瓶中。将混合物在70℃下加热搅拌1小时,待完全溶解停止加热。冷却至室温,加入盐酸布比卡因占药物制剂总质量的6%,折算载药浓度为60mg/g,室温搅拌充分溶解,得澄清溶液制剂。通过0.22μm滤膜过滤除菌备用。采用药典中的浆法进行药物释放实验,取1mL制剂,装入透析袋中,封口,再放入900mL水中,水温37℃,搅拌桨转速恒定。每隔一定时间,取样少量样品,采用高效液相色谱分析药物浓度,计算药物释放百分比,绘制药物释放曲线,如图4所示,药物在模拟体液中缓慢释放,随着时间延续,累积释放百分比逐渐达到最大值,可见药物释放平稳,具有缓释效果。
由实施例10和11药物释放实验结果可见,制剂载药量主要取决于药物在溶剂中的溶解度,溶解度越大,载药量越大。同时发现,凝胶具有药物缓释效果,通常前5个小时能够释放总药量的30%,12个小时左右,释放总药量的50%,40个小时可以释放药量90%以上,说明具有较好的缓释效果,可以应用于药物缓慢释放。
实施例12
可注射原位凝胶制剂载药体内药物代谢实验,30% N-甲基吡咯烷酮(NMP)水溶液,按照溶剂总质量的40%称取甘草酸单铵盐和甘草酸(质量比1:1),将其置于圆底烧瓶中,在80℃下加热搅拌1小时,待完全溶解停止加热。冷却至室温,加入盐酸布比卡因占药物制剂总质量的0.2%,折算载药浓度为2mg/g,室温搅拌充分溶解,得澄清溶液制剂。通过0.22μm滤膜过滤除菌备用。
取SD大鼠(n=3),皮下注射1g制剂,每隔一定时间,尾静脉采血0.3mL,离心取上清,加入适量溶剂萃取,蒸干,加入流动相定容,采用高效液相色谱法测定含量。取SD大鼠(n=3),皮下注射与制剂等量的盐酸布比卡因,每隔一定时间,尾静脉采血0.3mL,离心取上清,加入适量溶剂萃取,蒸干,加入流动相定容,采用高效液相色谱法测定含量。绘制药物浓度与时间曲线,如图5所示,随着时间延续,布比卡因很快达到血药浓度最高峰,而载药凝胶则缓慢释放药物,具有缓释作用。
由实验结果可见,载药凝胶可以缓慢释放盐酸布比卡因,具有缓释效果,说明可注射组合物可以作为缓释载药系统,具有应用价值。
实施例13-14
按照与实施例10-11相同的药物释放实验条件,仅将活性成分盐酸布比卡替换为等质量的利培酮,结果表明,凝胶具有相近的药物缓释效果,可以应用于不同药物的缓慢释放。
以上实施例,对本发明示例性的实施方式进行了说明。但是,本发明的保护范围不限定于上述实施方式。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种可注射原位凝胶缓释递药系统,其特征在于:所述可注射原位凝胶缓释递药系统为一种透明澄清液体组合物,其包含甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐中的一种或者几种,和一种溶剂,所述溶剂中包含临床上可用的有机溶剂和水、或者临床上可用的有机溶剂和生理性的水性介质,所述甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐中的一种或者几种占溶剂总质量的1%至80%,所述的可注射原位凝胶缓释递药系统常温下呈现透明澄清液体形态,经注射后在给药部位与体液接触后,发生溶剂交换和相转变,呈凝胶或半凝胶状。
2.根据权利要求1所述的可注射原位凝胶缓释递药系统,其特征在于:所述溶剂中的水或者生理性的水介质中的水占有机溶剂的质量比例为0%至90%;所述生理性的水性介质选自葡萄糖水溶液、氯化钠水溶液或磷酸盐缓冲溶液;所述的有机溶剂选自N-甲基吡咯烷酮、二甲基亚砜、乙醇、甘油、丙二醇、甘露醇中的一种或者几种。
3.根据权利要求1所述的可注射原位凝胶缓释递药系统,其特征在于:所述递药系统在使用之前为可注射溶液,经注射后在体内原位形成凝胶或者半凝胶状态。
4.根据权利要求1-3中任意一项所述的可注射原位凝胶缓释递药系统,其中:
当水或者生理性的水介质中的水占有机溶剂的质量比例为0%至30%W/W时,甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐占溶剂总质量的1%至80%W/W,优选50%至70%;
当水或者生理性的水介质中的水占有机溶剂的质量比例为30%至60%W/W时,甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐占有机溶剂和水性介质总质量的1%至50%W/W,优选30%至50%;
当水或者生理性的水介质中的水占有机溶剂的质量比例为60%至90%W/W时,甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐占有机溶剂和水性介质总质量的1%至30%W/W。
5.根据权利要求1-3中任意一项所述的可注射原位凝胶缓释递药系统,其特征在于,所述甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐中的一种或者几种为主要凝胶基质,所述递药系统进一步包含高分子物质,所述高分子物质优选为乙基纤维素、聚乳酸-羟基乙酸共聚物(PLGA)、聚己内酯(PCL)、泊洛沙姆中的一种或者几种,所述高分子物质优选占溶剂质量的5%至40%。
6.一种可注射原位凝胶缓释载药制剂,其特征在于,所述制剂包括甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐中的一种或者几种,一种溶剂,以及至少一种治疗有效量的活性物质,所述溶剂中包含临床上可用的有机溶剂和水、或者临床上可用的有机溶剂和生理性的水性介质,所述的甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐中的一种或者几种占溶剂总质量的1%至80%,所述的可注射原位凝胶缓释载药制剂常温下呈现透明澄清液体形态,经注射后在给药部位与体液接触后,发生溶剂交换和相转变,呈凝胶或半凝胶状。
7.根据权利要求6所述的可注射原位凝胶缓释载药制剂,其特征在于所述的活性物质为水溶性药物或醇溶性药物,活性物质占所述组合物总质量的0.1%至20%。
8.根据权利要求6或7所述的可注射原位凝胶缓释载药制剂,其特征在于所述的活性物质包括抗炎药、局麻药、镇痛药、抗精神失常药物、抗焦虑药、镇静催眠药、抗抑郁药、抗高血压药、类固醇激素、抗癫痫药、杀菌剂、抗惊厥药、抗帕金森病药物、中枢神经兴奋药、抗精神病药、抗心律失常药、抗心绞痛药、抗甲状腺药、解毒药、止吐药、降糖药、抗结核病药、抗艾滋病药、抗乙肝药、抗肿瘤药、抗排斥药或其混合物。
9.根据权利要求6至8任意一项所述的可注射原位凝胶缓释载药制剂,其特征在于,所述制剂作为药物储库制剂施用,所述制剂为可注射剂型或者所述制剂可以局部给药。
10.一种制备权利要求6-9任意一项所述可注射原位凝胶缓释载药制剂的方法,其特征在于该方法包括以下步骤:
(a)按照水或者生理性的水介质中的水占有机溶剂的质量比例为0%至90%W/W配制溶液,按照甘草酸、甘草次酸、甘草酸二钠、甘草酸单钾盐、甘草酸单铵盐中一种或者几种混合物占溶剂总质量的1%至80%加入上述溶剂中;
(b)将步骤(a)得到的混合物加热搅拌,充分溶解,加热温度为40至90摄氏度,优选为50至80摄氏度,加热时间大于等于0.5小时,优选大于1小时;
(c)将步骤(b)中溶液冷却至室温,按照活性物质占药物组合物总质量的0.1%至20%,加入活性物质,室温搅拌充分溶解,得澄清溶液;
(d)将步骤(c)获得的溶液,通过膜过滤除菌,灌装于临床上允许的密闭容器中,得到可注射原位凝胶缓释载药制剂。
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