CN115531349A - 一种治疗细菌性结膜炎的生物粘附性纳米粒搭配peg网络给药系统及其制备方法 - Google Patents
一种治疗细菌性结膜炎的生物粘附性纳米粒搭配peg网络给药系统及其制备方法 Download PDFInfo
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Abstract
本发明属于医药技术领域,具体涉及一种治疗细菌性结膜炎的生物粘附性纳米粒搭配PEG网络给药系统及其制备方法。本发明将用于治疗结膜炎的药物与可生物降解的PLA、PLA‑HPG制备成非生物粘性的可降解纳米粒子‑药物/PPHNP,药物/PPHNP再经高碘酸钠氧化还原后成为具有生物粘性的可降解纳米粒子‑药物/PPHNP‑AL,最后与NH2‑PEG‑NH2网络结合形成PPHNP‑AL‑PEG给药系统,由于制得的生物粘附性纳米粒可以与眼组织蛋白以及NH2‑PEG‑NH2上的氨基连接,从而延长纳米粒在眼部滞留的时间,实现眼部药物的局部给药以及缓慢释放,进而发挥更好的治疗效果,减少给药次数,提升患者依从性。
Description
技术领域
本发明属于医药技术领域,具体涉及一种治疗细菌性结膜炎的生物粘附性纳米粒搭配PEG网络给药系统及其制备方法。
背景技术
在世界范围内,结膜炎是人们到眼科就诊的最常见原因之一。结膜炎可由传染性(如细菌或病毒感染)和非传染性(如过敏)病因引起。其中,细菌性结膜炎是常见的感染性结膜炎,而且与大人相比,儿童更容易患细菌性结膜炎。在婴儿和年龄较大的儿童中,最常见的细菌性结膜炎是由流感嗜血杆菌引起的,其次是由肺炎链球菌和卡他分枝杆菌引起的。病患眼睛会出现异物感、烧灼感、眼睑沉重、发痒、摩擦感等症状。当病变累及角膜时,则出现明显的畏光、流泪并有程度不等的疼痛及视力下降。感染细菌性结膜炎后,由于诊断测试、治疗费用以及患者正常社会活动的中断等原因,可能会产生经济和社会影响。所以对结膜炎的及时治疗以及症状缓解能过改善患者的生活质量。
在眼部疾病的治疗方面,市面上常见的药物主要有滴眼液和眼膏,其中通常首选滴眼液,因为后者会造成视物困难,并且滴眼液在顺应性方面要优于眼膏。眼药水作为眼病的治疗手段,由于使用方便,在眼科领域的份额占70%以上。同时,由于药物滞留会受到泪液冲刷、角膜表面屏障、反射性眨眼和鼻泪管引流的阻碍,导致眼睛大约只能吸收应用剂量的5%。因此,传统滴眼液不能在角膜和结膜组织内提供和维持足够的药物浓度,往往需要频繁滴注才能提供足够的治疗效果。然而,频繁滴注会增加血液中的药物浓度,导致患者依从性差,且容易引发全身副作用。可见,能够有效延长滴眼液在眼部的滞留时间就能改善滴眼液现有的缺点。在细菌性结膜炎的治疗方面,目前主要是使用外用抗生素来治疗细菌结膜炎,外用抗生素可缩短病程、减少不适、防止人际传播并降低再感染率。但在选择外用抗生素时应考虑的其他因素包括成本效益、当地可获得性、当地细菌耐药性数据、患者过敏、患者依从性以及患者的偏好等,因为一些眼药水可能会引起眼睛的刺痛、疼痛或刺激。其中,头孢呋辛酯(CA)是一种半合成广谱头孢菌素抗生素,用于咽炎、扁桃体炎、急性细菌性上颌窦炎等。有研究测试了CA对金黄色葡萄球菌生物膜的效力,得出CA是比万古霉素、妥布霉素和环丙沙星更有效的抗生素。然而,CA存在溶解性差、对生物膜的渗透性差和较高的给药频率等缺陷,从而限制了其对生物膜的应用。
为了解决这一难题和传统滴眼液的缺点,研究人员开发了新型外用给药配方和眼科给药系统,如纳米悬浮液、纳米结构脂质载体等,纳米技术应用于眼科领域的前景广阔,但是需要进一步改进,以延长药物在泪液中的停留时间,以便为眼病提供有效的治疗。
发明内容
为了克服上述现有技术的不足,本发明提供了一种治疗细菌性结膜炎的生物粘附性纳米粒搭配PEG网络给药系统的制备方法,所制得的包载药物的可降解生物黏性纳米颗粒能够很好的黏附并滞留在眼部组织上,从而在治疗部位停留更长的时间,延长局部剂量,达到更好的治疗效果。
本发明是通过以下技术方案来实现的:
本发明提供了一种治疗细菌性结膜炎的生物粘附性纳米粒搭配PEG网络给药系统的制备方法,该方法包括以下步骤:
S1、HPG的合成:在充满绝水的惰性气体氛围下将1,1,1-三羟甲基丙烷置于90-100℃油浴中直至完全溶解之后加入甲醇钾,并继续抽真空,10-30分钟后再充满惰性气体,然后在反应12个半小时内添加25mL缩水甘油,得到粗HPG,粗HPG经过纯化后得到HPG;
S2、PLA-HPG合成:将PLA和HPG分别溶解在有机溶剂中,合并两溶液,干燥后再加入N,N'-二异丙基碳二酰亚胺和4-二甲氨基吡啶,在室温下搅拌反应4-6天,反应后经沉淀制得;
S3、制备PPHNP:用有机溶剂分别配制PLA溶液、PLA-HPG溶液和药物溶液,所述药物为用于治疗眼部结膜炎的药物,将三个溶液按1:1:1的体积比混合均匀后转移至一定量水中,经三次超声后得到小体积纳米乳,再次将小体积纳米乳转移至处于搅拌状态下的水中,并蒸发至无气泡产生,即得药物/PPHNP粗品,粗品经纯化后得到非生物粘附性纳米粒-药物/PPHNP;
S4、制备PPHNP-AL:将高碘酸钠溶液加至药物/PPHNP中反应2-3min,所述高碘酸钠溶液的浓度为0.1mol/L,所述高碘酸钠溶液与药物/PPHNP的体积比为1-3:1;再加入亚硫酸钠溶液终止反应,最后经纯化制得治疗细菌性结膜炎的生物粘附性纳米粒-药物/PPHNP-AL;
S5、制备PPHNP-AL-PEG:将药物/PPHNP-AL与氨基封端的八臂聚乙二醇NH2-PEG-NH2混合后得到治疗细菌性结膜炎的生物粘附性纳米粒搭配PEG网络给药系统PPHNP-AL-PEG。
本发明在生物粘附性可降解纳米粒子的基础上增加了NH2-PEG-NH2网络这一特性,由于眼组织有粘膜蛋白,而PPHNP-AL(药物/PPHNP-AL)上的醛基能与组织蛋白的氨基反应形成schiff键,从而能够附着在眼组织上,但是由于眼部泪液冲刷和眨眼机制导致可逆的schiff键容易断裂,使纳米粒容易脱落。但添加NH2-PEG-NH2网络后,NH2-PEG-NH2上的氨基可以将眼组织上掉落的PPHNP-AL纳米粒子拦截住,从而增加了载药纳米粒在眼部的滞留时间,再加上纳米粒缓慢释放药物的特点,使得局部药物剂量能够长时间维持高浓度,进而提高了治疗效果,减少给药次数,提高患者的顺应性。
优选地,所述细菌性结膜炎的致病菌包括流血嗜血杆菌。
优选地,所述氨基封端的八臂聚乙二醇NH2-PEG-NH2的分子量为20000。
优选地,所述氨基封端的八臂聚乙二醇NH2-PEG-NH2在使用时先制成90-110mg/mL的水溶液,所述药物/PPHNP-AL与氨基封端的八臂聚乙二醇NH2-PEG-NH2水溶液的体积比为1:1。
优选地,所述用于治疗眼部结膜炎的药物包括头孢呋辛酯CA。
优选地,所述PPHNP-AL-PEG的使用方法为:先将PPHNP-AL加入眼部,再加入NH2-PEG-NH2与之混合。
优选地,步骤S3中,所述PLA溶液的浓度为50-70mg/mL,PLA-HPG溶液的浓度为20-40mg/mL,药物溶液的浓度为1-20mg/mL。
优选地,步骤S3中,混合溶液与第一次转移时的用水量、第二次转移时的用水量的体积比为0.6:1-2:2-3。
优选地,步骤S3和S4中的纯化均为离心一次,水洗1-2次,总共重复离心三次,每次离心的温度为4℃,转速为4500rpm,时间为10min。
本发明还提供了采用上述制备方法制备得到的治疗细菌性结膜炎的生物粘附性纳米粒搭配PEG网络给药系统。
采用本发明方法制得的生物粘附性纳米粒PPHNP-AL可以与眼组织的蛋白连接,从而能够黏附在眼组织上,而氨基封端的NH2-PEG-NH2能够将从眼部粘蛋白脱落下来的PPHNP-AL截留住,从而延长纳米粒在眼部滞留的时间,实现眼部药物的局部给药以及缓慢释放,进而发挥更好的治疗效果,减少给药次数,提升患者依从性。此外,通过本发明方法还可以制备用于治疗其他眼组织类疾病的药物递送纳米粒。
与现有技术相比,本发明的有益效果是:
本发明公开了一种治疗细菌性结膜炎的生物粘附性纳米粒搭配PEG网络给药系统PPHNP-AL-PEG的制备方法,首先将用于治疗细菌性结膜炎的药物与可生物降解的PLA、PLA-HPG制备成非生物粘性的可降解纳米粒子-药物/PPHNP,药物/PPHNP再经高碘酸钠氧化还原后成为具有生物粘性的可降解纳米粒子-药物/PPHNP-AL,最后与NH2-PEG-NH2网络结合形成PPHNP-AL-PEG给药系统,由于所制得的生物粘附性纳米粒(药物/PPHNP-AL)可以与眼组织蛋白以及NH2-PEG-NH2上的氨基连接,使得在泪液冲刷作用下从眼部粘膜蛋白上掉落的纳米粒子被NH2-PEG-NH2网络拦截住,从而能够长时间滞留在眼部,缓慢释放药物,实现眼部药物的靶向性释放,进而发挥更好的治疗效果,减少给药次数,提高患者的顺应性。此外,本发明制备的给药系统不会对眼部正常视物造成影响,并且所用材料均具有良好的生物相容性以及安全性,是良好的眼部给药的递药平台。
附图说明
图1为各给药系统在不同波长下的吸光度(a-e用于区分不同的给药系统);
图2为纳米粒包载染料的给药系统PPHNP-AL-PEG在眼部的滞留和分布荧光图;
图3为纳米粒包载染料的给药系统PPHNP-AL-PEG在眼部滞留的荧光强度百分比分析图;
图4为纳米粒包载头孢呋辛酯的给药系统PPHNP-AL-PEG在眼部组织上24h内不同时间点的残留量图;
图5为运用纳米粒包载头孢呋辛酯的给药系统PPHNP-AL-PEG治疗过程中结膜炎症状的评分图;
图6为运用纳米粒包载头孢呋辛酯的给药系统PPHNP-AL-PEG在治疗结膜炎过程中眼部菌量的测定图;
图7为纳米粒包载头孢呋辛酯的给药系统PPHNP-AL-PEG对3T3细胞系的细胞毒性实验结果。
具体实施方式
下面对本发明的具体实施方式作进一步说明。在此需要说明的是,对于这些实施方式的说明用于帮助理解本发明,但并不构成对本发明的限定。此外,下面所描述的本发明各个实施方式中所涉及的技术特征只要彼此之间未构成冲突就可以相互组合。
下述实施例中的实验方法,如无特殊说明,均为常规方法,下述实施例中所用的试验材料,如无特殊说明,均为可通过常规的商业途径购买得到。
实施例1生物粘附性纳米粒搭配PEG网络给药系统的制备
采用乳液法制备PPHNP-AL,具体包括以下步骤:
(1)HPG(超支化聚缩水甘油醚)的合成:
在氩气保护下将4.67mmol 1,1,1-三羟甲基丙烷(TMP)加入到95℃油浴的烧瓶中,完全溶解后,添加1.4mmol KOCH3(甲醇钾),将烧瓶连接至真空泵,并将烧饼抽至真空状态,10分钟后再充氩气,并一直充满整个烧瓶,然后通过微量注射器泵在12个半小时内添加25mL缩水甘油,得到粗HPG。将粗HPG溶解在甲醇中,并用丙酮沉淀,重复此过程两次或三次来纯化HPG;然后通过透析袋(500-1000D)在超纯水中透析HPG,以去除一些小分子量的HPG,每5小时更换两次水;最后,加丙酮再次沉淀HPG,并将HPG置于真空下在85℃下干燥8-10h即得。
(2)PLA-HPG合成:
将5g PLA(聚乳酸)溶解在DCM(二氯甲烷,用量为能够溶解PLA的最小体积)中,并将2.3g HPG溶解在23mL DMF(N,N-二甲基甲酰胺)中,合并两溶液,然后加入3A分子筛(经高温活化后使用)使其干燥;干燥后转移至反应瓶中,并往反应瓶中加入0.08mL N,N'-二异丙基碳二酰亚胺(DIC)和13.5mg 4-二甲氨基吡啶(DMAP),在室温下搅拌反应5天;反应后往反应瓶中加入冷乙醚进行沉淀,并通过离心收集沉淀物,所得沉淀重新溶解在DCM中,并用冷乙醚再次沉淀,最后在真空下干燥2天即得。
(3)PLA-Cy7.5合成:
将1.95g PLA溶解在DCM(用量为能够溶解PLA的最小体积)中,再加入15mg Cy7.5和0.02mL DIC,在室温下搅拌反应一天,然后加入冷乙醚进行沉淀,并通过离心收集沉淀物,所得沉淀在真空下干燥2天即得。
(4)PPHNP合成:
用DCM(二氯甲烷)分别配制浓度为60mg/mL的PLA溶液,浓度为30mg/mL的PLA-HPG溶液和浓度为15mg/mL的PLA-Cy7.5溶液;然后加入0.2mL的PLA溶液,0.2mL的PLA-HPG溶液、0.2mL的PLA-Cy7.5溶液,涡旋混合均匀后将总计0.6mL的混合溶液转移至1mL超纯水中,随后边涡旋边转移至超声破碎仪中,超声三次(设置功率为65W,每次超声时间10s,每次超声完毕应立即置于冰上冷却)后得到小体积纳米乳。然后将小体积纳米乳转移至2mL处于搅拌状态下的超纯水中,搅拌两分钟;搅拌后将全部溶液转移至圆底烧瓶内,室温下减压旋蒸至无气泡产生,得到包载染料的PPHNP粗品。
(5)将粗产品转移至50mL离心管中,置于离心机中离心一次(4℃,4500rpm,10min),弃去上清,超纯水重悬一次,总共重复三次,最后一次用1mL超纯水重悬得到包载染料的非粘附性纳米粒PPHNP。
(6)采用氧化还原法制备包载染料的生物粘附性纳米粒PPHNP-AL:将一体积(1mL)的高碘酸钠溶液(0.1mol/L)加至一体积(1m L)包载染料的PPHNP中,上下颠倒振摇,反应2min;再加入一体积(1m L)的亚硫酸钠溶液(0.2mol/L)终止反应;转移至超滤管中离心一次(4℃,4500rpm,10min),弃去上清,超纯水重悬一次,总共重复三次,最后一次用1m L超纯水重悬,即得包载染料的生物粘附性纳米粒PPHNP-AL(Cy7.5/PPHNP-AL)。
(7)将包载染料的生物粘附性纳米粒PPHNP-AL与氨基封端的且八臂20000分子量聚乙二醇(氨基-八聚乙二醇-氨基,NH2-PEG-NH2)水溶液(100mg/mL)等体积混合,得到生物粘附性纳米粒搭配PEG网络给药系统PPHNP-AL-PEG(即PEG网络搭配载荧光染料生物粘性纳米粒给药系统)。
实验例1PEG网络搭配载荧光染料生物粘性纳米粒给药系统对正常视物的影响
在本实施例中,PPHNP是指包载染料的非生物粘附性纳米颗粒,PPHNP-AL是指包载染料的生物粘附性纳米颗粒,PPHNP-AL-PEG是指NH2-PEG-NH2与PPHNP-AL的混合溶液,Artificial tears是指配制的人工泪液。
分别在400nm、500nm、600nm和700nm的可见光波段处测量NH2-PEG-NH2,PPHNP,PPHNP-AL,PPHNP-AL-PEG组的吸光度,并以人工泪液作对照。如图1,NH2-PEG-NH2,PPHNP,PPHNP-AL,PPHNP-AL-PEG的吸光度均无明显差异,且吸光度均小于人工泪液。
实验例2PEG网络搭配载荧光染料生物粘性纳米粒给药系统在大鼠眼部的滞留时间考察
在本实施例中,PPHNP是指包载染料的非生物粘附性纳米颗粒,PPHNP-AL是指包载染料的生物粘附性纳米颗粒,PPHNP-AL-PEG是指PEG网络搭配载荧光染料生物粘性纳米粒的给药系统,即NH2-PEG-NH2与PPHNP-AL的混合溶液。
为评估纳米粒在眼部的滞留和分布情况,分别将1mL浓度为2mg/mL的包载染料的PPHNP、PPHNP-AL和PPHNP-AL-PEG滴入到雌性Wistar大鼠(购自红萝卜生物技术有限公司,饲养3-5周至30g左右大小)的结膜囊内,并分别在不同时间点(0,4,8,12,16,24h),用小动物活体成像仪(Perkin Elmer小动物活体成像系统,型号为Lumina XR SeriesⅢ)观察眼部纳米粒子的残留情况。在小动物活体成像仪下拍照后,根据荧光区域对应的ROI数值对其进行荧光定量分析。此外,还通过小动物活体成像处理软件(成像仪配套软件)对不同时间点(0,4,8,12,16,24h)下纳米粒子在眼部的荧光强度进行分析。
如图2、图3所示,与PPHNP和PPHNP-AL相比,PPHNP-AL-PEG在24h内于大鼠眼部的保留度更高。由图3可以看出,PPHNP-AL-PEG对眼部的粘附性更好,8h时,PPHNP和PPHNP-AL纳米粒只有不足20%能够保留在眼部,而PPHNP-AL-PEG的保留率超过50%。在16小时,PPHNP与PPHNP-AL的荧光强度已经完全消失,而PPHNP-AL-PEG组在24h时仍然有20%的纳米粒保留率。可见,生物粘性纳米粒PPHNP-AL搭配NH2-PEG-NH2网络能够在大鼠眼部滞留更长的时间。
实验例3PEG网络搭配载头孢呋辛酯生物粘性纳米粒给药系统的药物体内释放情况
载头孢呋辛酯生物粘性纳米粒给药系统CA/PPHNP-AL(载药纳米粒,简称CA/PPHNP-AL)的制备方法同Cy7.5/PPHNP-AL,不同点在于:将PLA-Cy7.5替换为药物CA(头孢呋辛酯)。
在大鼠的结膜囊分别滴入5uL浓度为1.5mg/mL的CA/PPHNP、CA/PPHNP-AL、CA/PPHNP-AL-PEG,随后分别在0、1、2、4、6、10、24小时后收集泪液10uL,加90uL乙腈,混合均匀。将样本以3000转/分钟的速度离心10分钟,随后收集80μL上清,最后对每个过滤样品进行HPLC分析。
从图4可以看出,CA/PPHNP-AL-PEG中的CA在大鼠眼部滞留更久,说明本实施例制备的装载药物的生物粘性纳米粒搭配NH2-PEG-NH2网络能够黏附在眼部组织上,可以使药物得到缓慢的释放,从而提高药物的利用率,发挥更好的治疗效果,改善患者的顺应性。
实验例4PEG网络搭配载头孢呋辛酯生物粘性纳米粒给药系统对大鼠细菌性结膜炎的治疗效果
将体重约30克的雌性Wistar大鼠用10%的水合氯醛麻醉,用微量注射器在结膜部位注射5uL 1×108CFU的流感嗜血杆菌,然后划伤睑结膜部位致出血。同时,假手术组的大鼠也接受了生理盐水代替细菌溶液的手术。手术1天后,分别将5uL的PBS,CA/PPHNP,CA/PPHNP-AL,游离CA,CA/PPHNP-AL-PEG和Blank-PPHNP-AL对造模的大鼠进行眼部给药两天,造模后,在七天内记录每只大鼠的结膜炎症状,并对其进行评分。造模后每天取10uL泪液,稀释后涂板,置于培养箱孵育16h后记录菌落数量,观察泪液菌量变化情况。
如图5、图6所示,各组给药两天后,就能明显看出CA/PPHNP-AL-PEG组炎症消退最明显,菌落数量最少,是治疗效果最好的一组。
实验例5给药系统的安全性
将3T3细胞以每孔10000个细胞的密度接种在96孔板中,用DMEM(含10%血清和1%双抗)孵育24小时后,将培养基替换为含有以下不同配方的新鲜培养基:对照(正常细胞培养液)、Blank-PPHNP、Blank-PPHNP-AL、CA/PPHNP,CA/PPHNP-AL和CA/PPHNP-AL-PEG溶液。孵育12h后,采用CCK8法测定3T3细胞的活力。加入CCK8测定液10μL,37℃再孵育4h。然后,用酶标仪(ThermoFisher Scientific,USA)在450nm处测量每个孔的吸光度。
如图7所示,各组与对照组相比,细胞存活率没有明显的差别,说明PPHNP-AL-PEG给药系统没有明显的细胞毒性。
综上所述,本发明将用于治疗结膜炎的药物与可生物降解的PLA、PLA-HPG制备成非生物粘性的可降解纳米粒子-药物/PPHNP,药物/PPHNP再经高碘酸钠氧化还原后成为具有生物粘性的可降解纳米粒子-药物/PPHNP-AL,最后与NH2-PEG-NH2网络结合形成PPHNP-AL-PEG给药系统,由于所制得的生物粘附性纳米粒PPHNP-AL可以与眼组织的蛋白连接,从而能够黏附在眼组织上,而氨基封端的NH2-PEG-NH2能够将从眼部粘蛋白脱落下来的PPHNP-AL截留住,从而延长纳米粒在眼部滞留的时间,实现眼部药物的局部给药以及缓慢释放,进而发挥更好的治疗效果,减少给药次数,提升患者依从性。
以上对本发明的实施方式作了详细说明,但本发明不限于所描述的实施方式。对于本领域的技术人员而言,在不脱离本发明原理和精神的情况下,对这些实施方式进行多种变化、修改、替换和变型,仍落入本发明的保护范围内。
Claims (10)
1.一种治疗细菌性结膜炎的生物粘附性纳米粒搭配PEG网络给药系统的制备方法,其特征在于,包括以下步骤:
S1、HPG的合成:在充满绝水的惰性气体氛围下将1,1,1-三羟甲基丙烷置于90-100℃油浴中直至完全溶解之后加入甲醇钾,并继续抽真空,10-30分钟后再充满惰性气体,然后在反应12个半小时内添加25mL缩水甘油,得到粗HPG,粗HPG经过纯化后得到HPG;
S2、PLA-HPG合成:将PLA和HPG分别溶解在有机溶剂中,合并两溶液,干燥后再加入N,N'-二异丙基碳二酰亚胺和4-二甲氨基吡啶,在室温下搅拌反应4-6天,反应后经沉淀制得;
S3、制备PPHNP:用有机溶剂分别配制PLA溶液、PLA-HPG溶液和药物溶液,所述药物为用于治疗眼部结膜炎的药物,将三个溶液按1:1:1的体积比混合均匀后转移至一定量水中,经三次超声后得到小体积纳米乳,再次将小体积纳米乳转移至处于搅拌状态下的水中,并蒸发至无气泡产生,即得药物/PPHNP粗品,粗品经纯化后得到非生物粘附性纳米粒-药物/PPHNP;
S4、制备PPHNP-AL:将高碘酸钠溶液加至药物/PPHNP中反应2-3min,所述高碘酸钠溶液的浓度为0.1mol/L,所述高碘酸钠溶液与药物/PPHNP的体积比为1-3:1;再加入亚硫酸钠溶液终止反应,最后经纯化制得治疗细菌性结膜炎的生物粘附性纳米粒-药物/PPHNP-AL;
S5、制备PPHNP-AL-PEG:将药物/PPHNP-AL与氨基封端的八臂聚乙二醇NH2-PEG-NH2混合后得到治疗细菌性结膜炎的生物粘附性纳米粒搭配PEG网络给药系统PPHNP-AL-PEG。
2.根据权利要求1所述的一种治疗细菌性结膜炎的生物粘附性纳米粒搭配PEG网络给药系统的制备方法,其特征在于,所述细菌性结膜炎的致病菌包括流血嗜血杆菌。
3.根据权利要求1所述的一种治疗细菌性结膜炎的生物粘附性纳米粒搭配PEG网络给药系统的制备方法,其特征在于,所述氨基封端的八臂聚乙二醇NH2-PEG-NH2的分子量为20000。
4.根据权利要求1所述的一种治疗细菌性结膜炎的生物粘附性纳米粒搭配PEG网络给药系统的制备方法,其特征在于,所述氨基封端的八臂聚乙二醇NH2-PEG-NH2在使用时先制成90-110mg/mL的水溶液,所述药物/PPHNP-AL与氨基封端的八臂聚乙二醇NH2-PEG-NH2水溶液的体积比为1:1。
5.根据权利要求1所述的一种治疗细菌性结膜炎的生物粘附性纳米粒搭配PEG网络给药系统的制备方法,其特征在于,所述用于治疗眼部结膜炎的药物包括头孢呋辛酯CA。
6.根据权利要求1所述的一种治疗细菌性结膜炎的生物粘附性纳米粒搭配PEG网络给药系统的制备方法,其特征在于,所述PPHNP-AL-PEG的使用方法为:先将PPHNP-AL加入眼部,再加入NH2-PEG-NH2与之混合。
7.根据权利要求1所述的一种治疗细菌性结膜炎的生物粘附性纳米粒搭配PEG网络给药系统的制备方法,其特征在于,步骤S3中,所述PLA溶液的浓度为50-70mg/mL,PLA-HPG溶液的浓度为20-40mg/mL,药物溶液的浓度为1-20mg/mL。
8.根据权利要求1所述的一种治疗细菌性结膜炎的生物粘附性纳米粒搭配PEG网络给药系统的制备方法,其特征在于,步骤S3中,混合溶液与第一次转移时的用水量、第二次转移时的用水量的体积比为0.6:1-2:2-3。
9.根据权利要求1所述的一种治疗细菌性结膜炎的生物粘附性纳米粒搭配PEG网络给药系统的制备方法,其特征在于,步骤S3和S4中的纯化均为离心一次,水洗1-2次,总共重复离心三次,每次离心的温度为4℃,转速为4500rpm,时间为10min。
10.采用权利要求1-9任一项所述的制备方法制备得到的治疗细菌性结膜炎的生物粘附性纳米粒搭配PEG网络给药系统。
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