CN117379319A - 一种根管封药peg基温敏水凝胶制剂及制备方法 - Google Patents
一种根管封药peg基温敏水凝胶制剂及制备方法 Download PDFInfo
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Abstract
本发明公开了一种根管封药PEG基温敏水凝胶制剂及制备方法。本发明以PEG基温敏水凝胶为载体,首先利用纳米共沉淀技术制备负载奥替尼定的纳米粒。随后,在凝胶制备过程中,将氧化钙粉末分散至水凝胶溶液中,将氢氧化钙组分引入水凝胶体系,形成OCT/PEG基水凝胶+ALK复合水凝胶。本发明利用PEG基温敏水凝胶的药物储存及输送缓释能力同时负载亲水、疏水两种性质的OCT,同时负载碱性氢氧化钙,形成临床操作性强、抗菌效果优异的新型水凝胶,并将其应用于根管封药,从而同时达到短期及长期抗根管生物膜的效果。
Description
技术领域
本发明涉及水凝胶材料技术领域,特别涉及一种用于根管封药的去除残余根管生物膜、防止根管再感染的碱性可注射温敏水凝胶制剂。
背景技术
根管治疗(Root canal treatment,RCT)是目前治疗牙髓感染及根尖周炎的首选临床治疗方法。RCT的首要目的是彻底清除髓腔内的微生物,通过必要的根管预备和消毒,达到防止再感染的目的。研究报道,导致根管治疗失败最主要的因素为持续存在的细菌感染。造成根管感染的菌群十分复杂,目前多篇研究证明,放线菌、拟杆菌、变形杆菌及梭杆菌等种属细菌在感染根管中的检出率和丰度都远高于其他细菌。其中,粪肠球菌(E.faecalis)的检出率高达77%。因此,如何有效清除感染根管内多样的微生物,使RCT获得良好的预期效果,防止根管治疗失败的发生,始终是临床研究的重点。
感染根管中的活跃菌群主要以生物膜的形式存在,不仅粘附在根内牙本质壁、分支和峡部,也可存在于牙根外表面,有研究证实这种生物膜对标准抗菌剂的抵抗力约为普通浮游细菌的10-1000倍,根管系统解剖结构的复杂性以及根管内细菌生物膜逐渐形成的抗药性,使得仅依靠机械预备以及短时间的根管冲洗并不能完全去除根管内隐蔽的微生物。因此,需要进一步的根管封药去除残留微生物、防止根管再感染。目前临床使用率最高的根管封药材料为氢氧化钙糊剂,其可以在根管中解离为Ca2+和OH-,使根管内呈现高pH的碱性环境,诱导根管内细菌的蛋白质变性、DNA损伤并对细菌细胞质膜产生损害,从而杀死细菌达到根管消毒的目的。但目前研究证明Ca(OH)2对根管内复杂菌群的抗菌效果有限,E.faecalis等细菌可以耐受高碱性环境(pH>11.5)。此外,由于细小根管侧支的存在,加之目前临床所用的氢氧化钙糊剂剂型的影响,Ca(OH)2常在结束封药时难以去除,碎屑残留于根管内,为进一步的根管充填带来不便。因此,寻找抗菌效果更好的、更便于临床操作的封药材料是目前研究根管消毒药物的重要方向。
发明内容
本发明为了解决上述技术问题,提供一种根管封药PEG基温敏水凝胶制剂及制备方法。
第一方面,本发明提供一种根管封药PEG基温敏水凝胶制剂的制备方法,是采用以下技术方案得以实现的。
一种根管封药PEG基温敏水凝胶制剂的制备方法,包括以下步骤:
S1.将疏水性奥替尼啶与PEG基温敏水凝胶按照质量比为1:(5-50)的比例溶于三氟乙醇中,随后逐滴滴入水中,搅拌6-24h;将所得溶液离心,弃去沉淀后,得到稳定载药纳米粒溶液,将纳米粒溶液冻干,得到负载疏水性奥替尼啶的纳米粒冻干粉;所得PEG基温敏水凝胶纳米粒冻干粉,疏水性奥替尼啶的载药量为4.5-8.3%,包封率为28-95%;
S2.将步骤S1制备得到的负载疏水性奥替尼啶的纳米粒冻干粉按质量比为10-50wt%的比例分散在水中,并搅拌分散一段时间;向载药纳米粒溶液中加入0-15mg/mL的亲水奥替尼啶盐酸盐,并进行搅拌(磁性搅拌),分散均匀,得到负载双性奥替尼啶的纳米粒分散液;所得负载双性奥替尼啶的纳米粒可以短期内突释,长期缓释奥替尼啶;
S3.向步骤S2制备得到的负载双性奥替尼啶的纳米粒分散液中加入0.5-5mM/mL氧化钙,并在封口状态下进行搅拌溶解,得到根管封药PEG基温敏水凝胶制剂;制备的根管封药PEG基温敏水凝胶制剂,可以在局部长期维持pH>11的碱性微环境。
进一步的,步骤S1中,PEG基温敏水凝胶选用聚乙二醇-聚异丙醇-聚乙二醇、聚ε-己内酯-聚乙二醇-聚ε-己内酯、聚乳酸-羟基乙酸-聚乙二醇-聚乳酸-羟基乙酸、聚乳酸-聚乙二醇-聚乳酸、聚(5-乙二醇缩酮-ε-己内酯-ε-己内酯)-聚乙二醇-聚(5-乙二醇缩酮-ε-己内酯-ε-己内酯)、单甲醚聚乙二醇-聚丙氨酸、单甲醚聚乙二醇-聚缬氨酸中的一种或多种。
进一步的,步骤S1中,含有疏水奥替尼啶的PEG基温敏水凝胶与三氟乙醇的质量比为1:(1-10)。
进一步的,步骤S1中,含有疏水奥替尼啶与PEG基温敏水凝胶的三氟乙醇溶液与双蒸水的体积比为1:(5-50)。
进一步的,步骤S1中,含有疏水奥替尼啶与PEG基温敏水凝胶的三氟乙醇溶液的滴速为100-1000μL/min。
进一步的,步骤S1中,离心条件为1000-10000r/min离心1-15min。
进一步的,步骤S2中,负载疏水奥替尼啶的纳米粒冻干粉分散在水中,采用的搅拌转速为50-500r/min,搅拌时间为30-300min。
进一步的,步骤S2中,加入亲水性奥替尼啶盐酸盐后采用的搅拌转速为50-500r/min,搅拌时间为15-30min。
进一步的,步骤S3中,加入氧化钙后,并在封口状态下搅拌5-30min。
第二方面,本发明提供一种根管封药PEG基温敏水凝胶制剂,是采用以下技术方案得以实现的。
一种上述制备方法制备得到的根管封药PEG基温敏水凝胶制剂。
本申请具有以下有益效果。
引起牙髓、根尖周炎最主要的因素即为细菌感染,多种细菌在根管壁内形成致密结构的多菌种生物膜,在临床机械预备及短暂根管冲洗之后不能完全去除根管内的生物膜,残余生物膜附着于根管细小部位,将本发明OCT/PECT@OCT+ALK水凝胶纳米溶液通过注射器注入根管中,达到根管隐蔽部位,该水凝胶为温敏水凝胶,在体温状态下可迅速转变为凝胶态,在后续长达7-14天的封药过程中持续释放药物并在根管封闭状态下营造碱性环境,达到对多菌种生物膜的持续清除及抑制效果,防止根管再感染的发生。同时该水凝胶可仅通过生理盐水冲洗去除,临床操作简便,为进一步的根管充填提供有利条件。
附图说明
图1是本发明PECT空白水凝胶(a)、OCT/PECT@OCT水凝胶(b)OCT/PECT@OCT+ALK水凝胶(c)的SEM图;
图2是本发明奥替尼啶吸光度曲线图;
图3是本发明各载药凝胶释放曲线图;
图4是本发明凝胶降解曲线图;
图5是本发明凝胶降解液纳米粒粒径图;
图6是本发明凝胶降解液pH曲线图;
图7是本发明E.faecalis,S.mutans及A.viscous的浮游细菌清除率结果图;
图8是本发明体外抗多菌种生物膜实验结果图(A.根管模型封药7天后,SEM镜下根管面多菌种生物膜的图像(2KX/5KX);B.通过imagej软件分析SEM镜下封药7天的生物膜清除率*P<0.05,**P<0.01,***P<0.001以及ns:无统计学意义);
图9是本发明水凝胶清除效果对比图。
具体实施方式
以下结合实施例对本专利申请进行进一步的说明。
以下制备例和实施例中所使用的实验方法如无特殊说明,均为常规方法;以下制备例和实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
1.根管封药PEG基温敏水凝胶制剂的制备
(1)PEG基温敏水凝胶的选用
本发明选取了几种典型的PEG基温敏水凝胶作为研究对象,材料具体组分与规格如下表所示:
表1 PEG基温敏水凝胶的种类与规格
制备例1
PECT的制备:
①将约300mL的ε-己内酯放入一500ml的烧杯中,然后加入适量CaH2,待其完全溶解后,室温下干燥48h。48h后在94-96℃(5mmHg)的条件下,将已过滤并行减压蒸馏的馏分收集,即获得纯净的ε-己内酯。
②将适量1,4-环己二酮单乙二醇缩酮和二氯甲烷放入广口瓶中,待1,4-环己二酮单乙二醇缩酮完全溶解后,将间氯过氧苯甲酸分次加入其内反应,然后旋干过滤后的二氯甲烷。用乙醚将所得产物进行重结晶三次,最终则得到纯净的5-乙二醇缩酮-ε-己内酯(TOSUO)。
③使用开环聚合法制备PECT,单体为TOSUO和己内酯(CL),引发剂为聚乙二醇(PEG),催化剂为辛酸亚锡。具体步骤如下:将CL、PEG和TOSUO加入到容量为200mL的广口瓶中,130℃环境中,在辛酸亚锡的催化下,将除水后所得的产物反应13小时。然后将粗产物溶于二氯甲烷。待其充分溶解后,使用微量注射泵将所得产物滴加到-20℃的冷乙醚内。一段时间后,将过滤所得沉淀进行真空干燥,最终得到终产物PECT。在磁力搅拌的作用下,使用微量注射泵,将用四氢呋喃溶解的PECT滴加到双蒸水中。然后静置过夜,让四氢呋喃挥发完全。次日继续搅拌6小时,聚合物链段即可在双蒸水内自组装成为核-壳结构纳米粒。将适量PECT空白纳米粒溶液置于冻干机内充分冻干,即获得PECT空白纳米粒冻干粉。
制备例2
PEG-PA的制备:
mPEG-NH2(分子量2000;Sigma-Aldrich,货号:QBD10918)
L-缬氨酸-N-羧基环内酸酐(L-Val NCAs;CAS:24601-74-9)和L-丙氨酸-N-羧基环内酸酐(PA-NCA;CAS:2224-52-4)成都恩来生物科技有限公司。mPEG-NH2为引发剂,通过NCA的开环聚合,制备PEG聚氨基酸。mPEG-NH2(1.0g,0.5mmol)溶解在无水二甲基甲酰胺(15mL)中。然后,将PA-NCA(1.15g,2.5mmol)加入烧瓶中,并在氩气保护下,30℃反应72小时。将获得的聚合物使用截留分子量(MWCO)为1.0kDa的透析袋在双蒸水中透析48小时。冷冻干燥后,得到PEG-PA共聚物的白色粉末,总收率约为73%。
制备例3
PEG-PLV的制备:
mPEG-NH2(1.0g,0.5mmol)溶解在无水二甲基甲酰胺(15mL)中。然后,将L-Val NCA(0.72g,5mmol)加入烧瓶中,并在氩气保护下,30℃反应72小时。将获得的聚合物使用截留分子量(MWCO)为1.0kDa的透析袋在双蒸水中透析48小时。冷冻干燥后,得到PEG-PLV共聚物的白色粉末,总收率约为61%。
(2)PEG基温敏水凝胶纳米粒的制备
采用纳米粒沉淀技术,制备负载疏水性奥替尼啶的PEG基温敏水凝胶纳米粒。以PECT为例,称取质量比为1:20的OCT与PECT,溶于5mL的三氟乙醇,随后逐滴滴入体积比为1:10的双蒸水中,流速200μL/min,继续搅拌12h。所得溶液以3000r/min离心,弃去沉淀后,得到稳定载药纳米粒溶液,得到PECT@OCT水凝胶。
2.实验结果
2.1PEG基水凝胶表征
2.1.1水凝胶纳米粒表征
通过动态光散射测试负载奥替尼啶前后纳米粒的粒径,结果如下表所示:
表2负载奥替尼啶前后纳米粒表征
以以结果表明,PEG基聚合物由于其具有两亲性结构,可以在水中自组装成外壳亲水,内核疏水的纳米粒结构,并将疏水的奥替尼啶负载到疏水内核中。上表数据同样表明,负载前后纳米粒粒径无明显变化,说明奥替尼啶的负载对纳米粒的组装特性没有显著影响。
2.1.2水凝胶药物负载量表征
通过紫外分光光度计表征水凝胶纳米粒的药物负载量及包封率,结果如下表所示:
表3水凝胶纳米粒的药物负载量及包封率
药物负载量(DLC)与包封率(DLE)的计算公式如下:
以上数据说明,PEG基温敏水凝胶对疏水药物奥替尼啶均可以实现较高浓度的药物负载,负载量均大于4wt%。而包封率受疏水内核结晶性影响,其中PEG-PCL具有较高的包封率(大于90%),而疏水性较差的PEG-氨基酸类水凝胶包封率较低(小于50%)。其中PECT温敏水凝胶具有较高的药物负载量(7.1%)以及最高的包封率(95.2%),因此,后续表征均以PECT为例。
2.1.3载药PECT水凝胶的制备
亲水性OCT盐酸盐购自源叶生物(CAS:70775-75-6)、疏水性OCT购自源叶生物(CAS:71251-02-0)。
PECT@OCT:仅负载疏水性OCT,将OCT(20mg)和PECT(250mg)溶解在5m L三氟乙醇中,然后逐渐滴加到100mL双蒸水中。随后,在室温下进一步搅拌12小时,去除三氟乙醇,获得PECT@OCT纳米颗粒。
OCT/PECT:仅负载亲水性OCT;将PECT冻干粉按1:4比例溶解于水中,加入0.5wt%亲水性OCT盐酸盐。经磁性搅拌30min以确保均匀分散后,得到OCT/PECT水凝胶。
OCT/PECT@OCT:负载亲水、疏水两种性质的OCT;将OCT(20mg)和PECT(250mg)溶解在5m L三氟乙醇中,然后逐渐滴加到100mL双蒸水中,滴速为500ul/min。随后,在室温下进一步搅拌12小时,将所得溶液以3000r/min,离心10min去除三氟乙醇,获得PECT@OCT纳米颗粒。接下来,将PECT@OCT纳米颗粒冻干成白色粉末,将PECT@OCT纳米颗粒冻干粉以1:4的比例溶解在水中,然后在混合物中加入0.5wt%亲水性OCT盐酸盐。经磁性搅拌30min以确保均匀分散后,得到OCT/PECT@OCT纳米分散液。
OCT/PECT@OCT+ALK:负载两种性质的OCT并加入Ca(OH)2;得到上述OCT/PECT@OCT水凝胶后,将1mM氧化钙粉末加入OCT/PECT@OCT纳米分散液中,并在密封容器中搅拌10min,氧化钙与纳米粒分散液中的水反应产生Ca(OH)2,最终以Ca(OH)2形态存在于凝胶体系中,得到OCT/PECT@OCT+ALK水凝胶。
2.1.4PECT水凝胶载药前后SEM观测
如图1a所示,PECT凝胶表面光滑、均匀。图1b显示加入奥替尼啶后原位凝胶表面仍光滑、均一、连续,而且无结晶状或块状物质析出,镜下见多孔隙结构,为药物的缓慢释放提供通道。图1c显示引入氢氧化钙之后体系也未发生明显改变。
2.1.5药物缓释曲线及降解曲线
如图2所示,经测定奥替尼啶最大吸收波长为282nm,使用该波长测定各载药水凝胶中的药物释放曲线如图3,可见各组水凝胶可缓释药物至最少14d。
OCT/PECT水凝胶中所负载的亲水性OCT在早期3天内呈现短时间的突释,在第1天时释放的OCT浓度约为2mg/ml,在第2天后药物释放曲线迅速下降,第4天时释放基本结束。PECT@OCT水凝胶中负载的疏水性OCT,其释放曲线在14天内基本保持平稳在1mg/ml。OCT/PECT@OCT水凝胶负载亲、疏水两种性质的OCT,在第1天出现药物突释达3.2mg/ml。OCT/PECT@OCT+ALK水凝胶凝胶释放曲线整体趋势与OCT/PECT@OCT水凝胶相似,但其1-3天的OCT释放量均少于未引入氢氧化钙体系的水凝胶,在4天后两条药物释放曲线回归平稳,维持长期缓释,药物浓度均约为1mg/ml。
对比图3及图4,后期药物释放曲线与凝胶降解曲线保持基本一致。图4为OCT/PECT@OCT+ALK及OCT/PECT@OCT水凝胶的降解曲线,可见两条曲线趋势基本保持一致,在14天时,两水凝胶的降解率分别为58.2%及48.3%,加入Ca(OH)2的OCT/PECT@OCT+ALK碱性水凝胶的降解速度低于OCT/PECT@OCT水凝胶。
2.1.4激光粒度电位仪测量溶液中释放纳米粒的粒径
如图5所示,使用激光粒度电位仪测量OCT/PECT@OCT+ALK水凝胶降解过程中上清液中的纳米粒粒径,基本维持在162nm左右,证明OCT释放是以纳米粒的形式释放,纳米粒均匀且形态稳定。
2.1.5水凝胶降解液pH
如图6所示,通过PBS溶液取得水凝胶浸取液并测定其pH,空白水凝胶为中性,负载1mM/ml的氢氧化钙后,水凝胶浸取液可在14d内稳定维持pH在12.5左右。
2.2抗菌实验
(1)OCT/PECT@OCT+ALK、OCT/PECT@OCT凝胶浸取液抗菌实验
将配置完成的水凝胶置于transwell孔板中,按凝胶与PBS溶液1:4的比例在底部孔板中加入无菌PBS溶液并持续7d,每日更新以获得凝胶浸取液。取粪肠球菌、变异链球菌、粘性放线菌培养至对数期,标准化其浓度为1*109CFU/ml,取凝胶浸取液100ul加入900ul菌液中,共培养24h,为具体观察菌落生长状况,将共培养液稀释后接种在BHI琼脂上并在37℃下培养24小时,进行CFU计数。对比空白对照组绘制7d细菌清除率曲线。
如图7所示,通过初期7天浸取液抗菌试验可知,OCT/PECT@OCT+ALK及OCT/PECT@OCT水凝胶浸取液对E.faecalis,S.mutans及A.viscous浮游细菌的杀菌率均可达到98%以上,PECT+ALK水凝胶浸取液对E.faecalis及S.mutans的抗菌效果与CHX凝胶基本保持一致,两者对E.faecalis的抗菌率基本维持在60%以上(图8A),对S.mutans的抗菌率维持在85%以上(图8B)。面对A.viscous,PECT+ALK水凝胶及CHX水凝胶抗菌效果呈现较为明显的差异,CHX水凝胶浸取液的浮游菌杀菌率在75%-95%之间,而PECT+ALK水凝胶浸取液的杀菌效果约在50%-75%之间。
本发明将OCT/PECT@OCT+ALK及OCT/PECT@OCT载药温敏水凝胶的浸取液作用于三种牙髓、根尖周病中常见菌群,证明两种水凝胶具有抗根管致病菌效果且优于目前临床用CHX水凝胶。
2.3体外抗多菌种生物膜实验
2.3.1根管模型的制备
选取因正畸治疗拔除的单根管前磨牙,选择没有根管弯曲或折裂的单根管牙,根管形状尽量为圆形。将单根管牙用超声洁牙器清洗,清除牙根外表面的骨质、结石和软组织。121℃高压灭菌20min,然后将牙齿保存在0.9%的生理盐水中。
取根中三分之一,将牙齿切割成6mm长、至少4mm宽的标准根块。使用Protaper机用镍钛系统机械预备每个根管至2506#,使样本标准化。用车针沿牙根长轴形成两个平行的浅槽以获得根管模型。
使用次氯酸钠(5.25%NaOCl)和17%的EDTA溶液进行交替超声冲洗各3min,并用无菌盐水溶液充分冲洗根管后,用无菌蒸馏水彻底清洗,121℃高压灭菌20min后浸泡于无菌生理盐水中4℃备用。
2.3.2根管生物膜的建立
选取根尖周炎的代表性菌群,E.faecalis,S.mutans及A.viscous作为多菌种生物膜的建立菌群。将三种菌培养至对数期后,按1:1:1比例先后加入根管模型中,共培养21d。
2.3.3抗生物膜效果评估
将各组根管封药制剂封入多菌种生物膜根管模型中,在封药第7天进行观测,在扫描电镜(×2kV.×5kV)下评估其生物膜清除率。
多菌种生物膜建立成功后,进行为期7天的封药。如图8A所示,SEM下0.9%生理盐水组及空白PECT组无显著变化,生物膜完整且致密。其余组经过7天封药后对多菌种生物膜均有明显的清除破坏效果。通过图8B中Imagej数据分析可知,OCT/PECT@OCT+ALK组在7天封药结束后,根管模型内侧面仅有少量细菌残留,其生物膜清除率显著优于其他组(P<0.001,其中对比OCT/PECT@OCT凝胶组P<0.05)。同时,OCT/PECT@OCT凝胶组的生物膜清除率也显著优于除实验组外的其他对照组(P<0.05),表明OCT/PECT凝胶体系具有优异抗菌效果,并在引入碱性环境之后得到明显提升。
封药结果证实,本发明的OCT/PECT@OCT及OCT/PECT@OCT+ALK水凝胶均具有比目前临床常用根管封药材料(CHX水凝胶、Ca(OH)2糊剂)更优异的抗菌效果。
2.3.4水凝胶清除效果对比
如图9所示,将OCT/PECT@OCT+ALK水凝胶、Ca(OH)2糊剂及生理盐水空白组,根管封药7d后,无菌生理盐水冲洗1min去除根管封药材料,并将根管模型沿预备凹槽纵劈,暴露根管面,模拟临床显微镜操作,在×20倍镜下观察可见根管面无明显药物碎屑残留,酒精梯度脱水后使用扫描电镜高倍×5000镜下观察,可见氢氧化钙糊剂封药组表面有明显碎屑,PECT水凝胶组可清晰观察到牙本质小管面,无明显水凝胶残留与空白对照组基本相似。
本具体实施方式的实施例均为本发明的较佳实施例,并非依此限制本发明的保护范围,故:凡依本发明的结构、形状、原理所做的等效变化,均应涵盖于本发明的保护范围之内。
Claims (10)
1.一种根管封药PEG基温敏水凝胶制剂的制备方法,其特征在于:包括以下步骤:
S1.将疏水性奥替尼啶与PEG基温敏水凝胶按照质量比为1:(5-50)的比例溶于三氟乙醇中,随后逐滴滴入水中,搅拌6-24h;将所得溶液离心,弃去沉淀后,得到稳定载药纳米粒溶液,将纳米粒溶液冻干,得到负载疏水性奥替尼啶的纳米粒冻干粉;
S2.将步骤S1制备得到的负载疏水性奥替尼啶的纳米粒冻干粉按质量比为10-50wt%的比例分散在水中,并搅拌分散一段时间;向载药纳米粒溶液中加入0-15mg/mL的亲水奥替尼啶盐酸盐,并进行搅拌,分散均匀,得到负载双性奥替尼啶的纳米粒分散液;
S3.向步骤S2制备得到的负载双性奥替尼啶的纳米粒分散液中加入0.5-5mM/mL氧化钙,并在封口状态下进行搅拌溶解,得到根管封药PEG基温敏水凝胶制剂。
2.根据权利要求1所述的一种根管封药PEG基温敏水凝胶制剂的制备方法,其特征在于:步骤S1中,PEG基温敏水凝胶选用聚乙二醇-聚异丙醇-聚乙二醇、聚ε-己内酯-聚乙二醇-聚ε-己内酯、聚乳酸-羟基乙酸-聚乙二醇-聚乳酸-羟基乙酸、聚乳酸-聚乙二醇-聚乳酸、聚(5-乙二醇缩酮-ε-己内酯-ε-己内酯)-聚乙二醇-聚(5-乙二醇缩酮-ε-己内酯-ε-己内酯)、单甲醚聚乙二醇-聚丙氨酸、单甲醚聚乙二醇-聚缬氨酸中的一种或多种。
3.根据权利要求1所述的一种根管封药PEG基温敏水凝胶制剂的制备方法,其特征在于:步骤S1中,含有疏水奥替尼啶的PEG基温敏水凝胶与三氟乙醇的质量比为1:(1-10)。
4.根据权利要求1所述的一种根管封药PEG基温敏水凝胶制剂的制备方法,其特征在于:步骤S1中,含有疏水奥替尼啶与PEG基温敏水凝胶的三氟乙醇溶液与双蒸水的体积比为1:(5-50)。
5.根据权利要求1所述的一种根管封药PEG基温敏水凝胶制剂的制备方法,其特征在于:步骤S1中,含有疏水奥替尼啶与PEG基温敏水凝胶的三氟乙醇溶液的滴速为100-1000μL/min。
6.根据权利要求1所述的一种根管封药PEG基温敏水凝胶制剂的制备方法,其特征在于:步骤S1中,离心条件为1000-10000r/min离心1-15min。
7.根据权利要求1所述的一种根管封药PEG基温敏水凝胶制剂的制备方法,其特征在于:步骤S2中,负载疏水奥替尼啶的纳米粒冻干粉分散在水中,采用的搅拌转速为50-500r/min,搅拌时间为30-300min。
8.根据权利要求1所述的一种根管封药PEG基温敏水凝胶制剂的制备方法,其特征在于:步骤S2中,加入亲水性奥替尼啶盐酸盐后采用的搅拌转速为50-500r/min,搅拌时间为15-30min。
9.根据权利要求1所述的一种根管封药PEG基温敏水凝胶制剂的制备方法,其特征在于:步骤S3中,加入氧化钙后,并在封口状态下搅拌5-30min。
10.一种权利要求1-9任一所述制备方法制备得到的根管封药PEG基温敏水凝胶制剂。
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