CN113813395A - 一种缓释膜片及其制备方法 - Google Patents
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Abstract
本发明公开一种缓释膜片及其制备方法，属于缓释膜片制备技术领域。本发明所述方法包括壳聚糖(CTS)的纯化，然后依次制备聚N‑乙烯基己内酰胺(PNVCL)、聚N‑乙烯基己内酰胺接枝壳聚糖(PNVCL‑g‑CS)、聚N‑乙烯基己内酰胺接枝壳聚糖羧基(PNVCL‑g‑CS‑COOH)，聚N‑乙烯基己内酰胺接枝壳聚糖‑紫杉醇(PNVCL‑g‑CS‑PTX)，聚N‑乙烯基己内酰胺接枝壳聚糖‑紫杉醇(PNVCL‑g‑CS‑PTX)缓释膜片；本发明所述方法制备步骤简单、产物可靠，所得到的产品紫杉醇载药量大，并可通过改变水溶液环境的温度进行可控的药物释放量同时，本发明产品合成的原料的蛋白质含量极低，将来可以安全应用于人体。
Description
技术领域
本发明涉及一种缓释膜片及其制备方法，属于缓释膜片制备技术领域。
背景技术
良性胆管狭窄(BBS)是指胆管损伤和复发性胆管炎所致的胆管腔瘢痕性缩窄，可由多种损伤情况引起。受累胆管因反复慢性炎症、胆盐刺激，导致纤维组织增生、管壁变厚、管腔缩窄，进而出现胆道梗阻、感染的病理和临床表现。近年来，随着胆道外科手术的普及、腔镜技术的推广和肝移植的开展，BBS发生率亦有上升趋势。有报道，胆道修复后的再狭窄率高达60％。BBS的临床治疗一直是困扰胆道外科医生的一大难题，一旦发生，不仅使患者身心遭受巨大创伤和痛苦，而且由此带来高昂的治疗费用，加重患者家庭的经济负担。因此对于如何有效防治BBS形成及减少再狭窄率的研究，一直是肝胆胰外科的研究热点和难点，具有重大临床意义。
临床上对良性胆管狭窄的治疗方法众多，外科手术仍是治疗的金标准，但胆道修复术后仍可继发狭窄，引发梗阻性黄疸、胆汁淤积性肝硬化及难以矫治的并发症，最终将威胁患者的生命。目前发现，紫杉醇不仅可用于临床多种肿瘤的治疗，还在支架治疗冠状动脉狭窄、硬皮病及预防青光眼术后疤痕形成等方面有很好的质量效果。但因紫杉醇水溶性差及助溶剂毒副作用等缺点，限制了紫杉醇的临床推广和应用。因此开发新的药物输送系统和改进给药方式，以提高效率、避免不良反应，已成为药物缓释领域的研究热点。因此，本发明制备了一种新的缓释材料，避免使用紫杉醇产生的不良反应。
发明内容
本发明的目的在于提供一种缓释膜片，所述缓释膜片的结构式如下：
本发明的另一目的在于提供所述缓释膜片的制备方法，具体包括以下步骤：
(1)壳聚糖(CTS)的纯化：
将壳聚糖加入到氢氧化钠(NaOH)溶液中，在70℃下搅拌3h以脱色、脱蛋白，反应完毕后用真空泵进行抽滤，固液分离，反复用蒸馏水冲洗固体，中性后冷冻干燥得到纯化后的壳聚糖。
(2)聚N-乙烯基己内酰胺(PNVCL)的制备：
将N-乙烯基己内酰胺(NVCL)试剂放入反应器中在60～70℃减压蒸馏以去除N-乙烯基己内酰胺(NVCL)里面的稳定剂。
将15g去除了稳定剂的N-乙烯基己内酰胺(NVCL)加入反应器中，依次加入0.06g偶氮二异丁腈(AIBN)、0.5g链转移剂，在氮气保护下65℃～70℃油浴锅搅拌反应12-14h，搅拌后变成黄色物质，加入四氢呋喃搅拌溶解后，滴管滴入装有足量石油醚的烧杯中共沉淀，滴入后产生白色絮状沉淀，充分静置，静置的溶液吸去上清液留固体，待溶剂挥干后用水溶解，放入透析袋中透析72h，冷冻干燥制成聚N-乙烯基己内酰胺(PNVCL)。
(3)聚N-乙烯基己内酰胺接枝壳聚糖(PNVCL-g-CS)的制备：
将壳聚糖0.5g溶于100mL的1％醋酸溶液中，搅拌均匀后，加入5mL溶有0.2g聚N-乙烯基己内酰胺接枝壳聚糖(PNVCL-g-CS)的去离子水溶液；将0.4g的1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和0.2g N-羟基琥珀酰亚胺(NHS)溶于5mL去离子水并逐滴加到反应物混合物中，室温搅拌反应24h；反应完毕后透析72h，最后冷冻干燥得到产物。
(4)聚N-乙烯基己内酰胺接枝壳聚糖羧基(PNVCL-g-CS-COOH)的制备：
将聚N-乙烯基己内酰胺接枝壳聚糖(PNVCL-g-CS)粉末充分溶解于去离子水中得到浓度为0.1g/mL的聚N-乙烯基己内酰胺接枝壳聚糖(PNVCL-g-CS)溶液后倒入反应器中，加入0.2g/mL丁二酸酐的二甲基亚砜(DMSO)溶液，室温搅拌反应24h。反应完毕后透析72h，最后冷冻干燥得到产物。
(5)聚N-乙烯基己内酰胺接枝壳聚糖-紫杉醇(PNVCL-g-CS-PTX)的制备：
将聚N-乙烯基己内酰胺接枝壳聚糖羧基(PNVCL-g-CS-COOH)充分溶解于去离子水中，再加入紫杉醇；搅拌均匀后，向混合液中加入4-二甲氨基吡啶(DMAP)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)，室温搅拌反应48h。反应完毕后透析72h，最后冷冻干燥得到产物。
(6)聚N-乙烯基己内酰胺接枝壳聚糖-紫杉醇(PNVCL-g-CS-PTX)缓释膜片的制备：
将步骤(5)制备的聚N-乙烯基己内酰胺接枝壳聚糖-紫杉醇(PNVCL-g-CS-PTX)充分溶解于蒸馏水中后，将溶液平均分为四份，加入交联剂1,4-丁二醇缩水甘油醚，按照聚N-乙烯基己内酰胺接枝壳聚糖-紫杉醇(PNVCL-g-CS-PTX)：1，4-丁二醇二缩水甘油醚(BDDGE)摩尔比为20:1～80:1加入交联剂1,4-丁二醇缩水甘油醚，室温搅拌反应3h；反应完毕后将上述四组反应液用蒸馏水透析48h，透析完成后将透析液定容至20mL，分别加入1滴丙三醇搅拌30-60min，再将上述液体加入聚四氟乙烯模具中，将模具置于50℃烘箱内烘干成膜；即得药物缓释膜片。
步骤(1)中NaOH溶液的浓度为0.03～0.04g/mL，壳聚糖的加入量为0.2g/mL。
步骤(2)中稀盐酸的质量百分比为1％，氢氧化钠溶液的浓度为1mol/L。
本发明的有益效果：
(1)本发明所述聚N-乙烯基己内酰胺(PNVCL)是具有温敏特性的一类聚合物，当PNVCL放入生理性温度(32-38℃)的水溶液里则会发生相变，PNVCL具有非离子性、可生物降解、无毒和生物相容性好的特点；除此之外，跟大部分聚丙烯酰胺类聚合物不同，PNVCL水解后不会产生具有毒性的小分子胺类化合物，这使PNVCL成为一类适用于生物医学人体内应用的聚合物。
(2)本发明制得一种高分子载体聚N-乙烯基己内酰胺接枝壳聚糖(PNVCL-g-CS)，PNVCL-g-CS可溶于水，具有令人满意的理化性质和生物学特性，如组织相容性佳、水解后的代谢产物对人体无伤害、可完全生物降解、无毒、可被人体吸收、止血、促进组织的修复、抑制结缔组织的增生和减少瘢痕处狭窄形成。
(3)本发明采用疏水性药物紫杉醇(PTX)，通过与改性的高分子载体聚N-乙烯基己内酰胺接枝壳聚糖羧基(PNVCL-g-CS-COOH)，发生酯化共价结合，形成聚N-乙烯基己内酰胺接枝壳聚糖-紫杉醇(PNVCL-g-CS-PTX)高分子药物聚合物，并在聚四氟乙烯模具中干燥成膜。该膜片在体外水溶液中，能明显提高疏水性药物紫杉醇(PTX)的水溶性，保持其药效的稳定性，并当水溶液温度处于32-38℃时能够缓慢、持续、稳定的释放药物紫杉醇(PTX)。
(4)本发明膜片中涉及到的紫杉醇(PTX)局部药物缓释技术，可应用于良性胆管瘢痕狭窄形成处、肺脏、肝脏、胰腺和胃肠道等胸腔和腹腔恶性肿瘤的治疗中，显著降低了紫杉醇(PTX)及其助溶解化合物的全身毒性反应，能够降低因患良性胆管狭窄(BBS)手术后再发狭窄而需再次手术的风险，可以减少晚期癌症化疗的次数和单次剂量，显著减轻患者及其家属的心理和经济压力。
(5)本发明聚焦于良性胆管狭窄(BBS)这一业内热点且棘手的胆道外科问题，采用有机化学合成的办法，发明了一种实用型新型高分子疏水药物缓释膜片聚N-乙烯基己内酰胺接枝壳聚糖-紫杉醇(PNVCL-g-CS-PTX)缓释膜片，其体外释放性能良好。当前，关于疏水性药物紫杉醇(PTX)与改性的温敏性壳聚糖衍生物聚N-乙烯基己内酰胺接枝壳聚糖羧基(PNVCL-g-CS-COOH)酯化反应后形成的高分子药物聚合物，并干燥成膜片，该局部药物缓释系统可以预防良性胆管狭窄(BBS)的形成，为临床防治良性胆管狭窄(BBS)提供一个新的治疗方法和一定的理论基础。
(6)本发明制备步骤简单、产物可靠，所得到的产品紫杉醇载药量大，并可通过改变水溶液环境的温度进行可控的药物释放量同时，本发明产品合成的原料的蛋白质含量极低，将来可以安全应用于人体。
附图说明
图1为PNVCL-CS-PTX的合成路线。
具体实施方式
下面结合具体实施例本发明作进一步的详细说明，但本发明的保护范围并不限于所述内容。
本发明实施例中所用实验试剂为：(壳聚糖(CS粘度100-200mpa·s)、2-溴乙醇、N-乙烯基己内酰胺(NVCL)、聚N-乙烯基己内酰胺(PNVCL)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC)、4-二甲氨基吡啶(DMAP)、琥珀酸酐、偶氮二异丁腈(AIBN)、紫杉醇(PTX)、异丙醇、氢氧化钠、氢氧化钾、盐酸)。除特殊说明外，本发明所用试剂均为市售分析纯。
实施例1
本实施例所述缓释膜片的制备方法，具体包括以下步骤：
(1)壳聚糖(CTS)的纯化：
将壳聚糖加入到NaOH溶液中，在70℃下搅拌3h以脱色、脱蛋白，反应完毕后用真空泵进行抽滤，固液分离，反复用蒸馏水冲洗固体，中性后冷冻干燥得到纯化后的壳聚糖；
(2)聚N-乙烯基己内酰胺(PNVCL)的制备：
将NVCL(N-乙烯基己内酰胺)试剂放入烧瓶中在70℃减压蒸馏以去除NVCL里面的稳定剂。
将15g去除了稳定剂的NVCL加入烧瓶中，依次加入0.06g AIBN、0.5g链转移剂，在氮气保护下70℃油浴锅搅拌反应12h，搅拌后变成黄色物质，加入四氢呋喃搅拌溶解后，滴管滴入装有足量石油醚的烧杯中共沉淀，滴入后产生白色絮状沉淀，充分静置，静置的溶液吸去上清液留固体，待溶剂挥干后用水溶解，放入透析袋中透析372h，冷冻干燥制成PNVCL；
(3)聚N-乙烯基己内酰胺接枝壳聚糖(PNVCL-g-CS)的制备：
将壳聚糖0.5g溶于100mL1％的醋酸溶液中，搅拌均匀后，加入5mL溶有0.2gPNVCL的去离子水溶液；将0.4g EDC和0.2g NHS溶于5mL去离子水并逐滴加到反应物混合物中，室温搅拌反应24h。反应完毕后透析72h，最后冷冻干燥得到产物。
(4)聚N-乙烯基己内酰胺接枝壳聚糖羧基(PNVCL-g-CS-COOH)的制备：
将PNVCL-g-CS粉末充分溶解于去离子水中得到浓度为0.1g/mL的PNVCL-g-CS溶液后倒入烧瓶中，加入0.2g/mL丁二酸酐的DMSO溶液，室温搅拌反应24h。反应完毕后透析72h，最后冷冻干燥得到产物。
(5)聚N-乙烯基己内酰胺接枝壳聚糖-紫杉醇(PNVCL-g-CS-PTX)的制备：
将PNVCL-g-CS-COOH充分溶解于去离子水中，再加入紫杉醇。搅拌均匀后，向混合液中加入DMAP和EDC，室温搅拌反应48h。反应完毕后透析72h，最后冷冻干燥得到产物。
(6)聚N-乙烯基己内酰胺接枝壳聚糖-紫杉醇(PNVCL-g-CS-PTX)缓释膜片的制备：
将步骤(5)制备的PNVCL-CS-PTX充分溶解于蒸馏水中后，将溶液平均分为四份，加入交联剂1,4-丁二醇缩水甘油醚，按照PNVCL-CS-PTX：BDDGE摩尔比为20:1、40:1、80:1加入，剩余一组为无交联组，室温搅拌反应3h；反应完毕后将上述四组反应液用蒸馏水透析48h，透析完成后将透析液定容至20mL，分别加入1滴丙三醇搅拌30min，再将上述四份液体以每份5mL加入有16小格自制的聚四氟乙烯模具中，将模具置于50℃烘箱内烘干成膜；即得无交联、80:1、40:1、20:1、交联的四种药物缓释膜片各4片。
Claims (4)
1.一种缓释膜片，其特征在于：所述缓释膜片的结构式如下：
2.权利要求1所述缓释膜片的制备方法，其特征在于，具体包括以下步骤：
(1)壳聚糖的纯化：
将壳聚糖加入到氢氧化钠溶液中，在70℃下搅拌3h以脱色、脱蛋白，反应完毕后用真空泵进行抽滤，固液分离，反复用蒸馏水冲洗固体，中性后冷冻干燥得到纯化后的壳聚糖；
(2)聚N-乙烯基己内酰胺的制备：
将N-乙烯基己内酰胺试剂放入反应器中在60～70℃减压蒸馏以去除N-乙烯基己内酰胺里面的稳定剂；
将15g去除了稳定剂的N-乙烯基己内酰胺加入反应器中，依次加入0.06g偶氮二异丁腈、0.5g链转移剂，在氮气保护下65℃～70℃油浴锅搅拌反应12-14h，搅拌后变成黄色物质，加入四氢呋喃搅拌溶解后，滴管滴入装有足量石油醚的烧杯中共沉淀，滴入后产生白色絮状沉淀，充分静置，静置的溶液吸去上清液留固体，待溶剂挥干后用水溶解，放入透析袋中透析72h，冷冻干燥制成聚N-乙烯基己内酰胺(PNVCL)；
(3)聚N-乙烯基己内酰胺接枝壳聚糖的制备：
将壳聚糖0.5g溶于100mL的1％醋酸溶液中，搅拌均匀后，加入5mL溶有0.2g聚N-乙烯基己内酰胺接枝壳聚糖的去离子水溶液；将0.4g的1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和0.2g N-羟基琥珀酰亚胺溶于5mL去离子水并逐滴加到反应物混合物中，室温搅拌反应24h；反应完毕后透析72h，最后冷冻干燥得到产物；
(4)聚N-乙烯基己内酰胺接枝壳聚糖羧基的制备：
将聚N-乙烯基己内酰胺接枝壳聚糖粉末充分溶解于去离子水中得到浓度为0.1g/mL的聚N-乙烯基己内酰胺接枝壳聚糖溶液后倒入反应器中，加入0.2g/mL丁二酸酐的二甲基亚砜溶液，室温搅拌反应24h，反应完毕后透析72h，最后冷冻干燥得到产物；
(5)聚N-乙烯基己内酰胺接枝壳聚糖-紫杉醇的制备：
将聚N-乙烯基己内酰胺接枝壳聚糖羧基充分溶解于去离子水中，再加入紫杉醇；搅拌均匀后，向混合液中加入4-二甲氨基吡啶和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，室温搅拌反应48h；反应完毕后透析72h，最后冷冻干燥得到产物；
(6)聚N-乙烯基己内酰胺接枝壳聚糖-紫杉醇缓释膜片的制备：
将步骤(5)制备的聚N-乙烯基己内酰胺接枝壳聚糖-紫杉醇充分溶解于蒸馏水中后，加入交联剂1,4-丁二醇缩水甘油醚，按照聚N-乙烯基己内酰胺接枝壳聚糖-紫杉醇：1，4-丁二醇二缩水甘油醚摩尔比为20:1～80:1加入交联剂1,4-丁二醇缩水甘油醚，室温搅拌反应3h；反应完毕后将上述四组反应液用蒸馏水透析48h，透析完成后将透析液定容至20mL，分别加入1滴丙三醇搅拌30-60min，再将上述液体加入聚四氟乙烯模具中，将模具置于50℃烘箱内烘干成膜；即得无交联药物缓释膜片。
3.根据权利要求2所述的缓释膜片的制备方法，其特征在于：步骤(1)中氢氧化钠溶液的浓度为0.03～0.04g/mL，壳聚糖的加入量为0.2g/mL。
4.根据权利要求2所述的缓释膜片的制备方法，其特征在于：步骤(2)中稀盐酸的质量百分比为1％，氢氧化钠溶液的浓度为1mol/L。
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Application publication date: 20211221 |