CN115040495B - 一种利用小分子营养物质介导的口服纳米递药系统 - Google Patents
一种利用小分子营养物质介导的口服纳米递药系统 Download PDFInfo
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Abstract
本发明公开了一种基于小分子营养物质介导的，主动靶向肠上皮细胞的口服纳米载体及其制备方法，该纳米粒由核壳两部分组成，其中，内核由生物相容性载体材料与活性成分所组成，外壳为共价连接小分子营养物质配体的亲水材料。本发明提高了口服纳米载体的递药效率，在医药领域具有良好的研究和开发应用前景。
Description
本申请是申请日为2019年11月4日的题为“一种利用小分子营养物质介导的口服纳米递药系统”的中国专利，申请号201911068292.1的分案申请。
技术领域
本发明涉及一种将小分子营养物质修饰在纳米粒表面，主动靶向肠上皮细胞表面受体，以克服肠上皮细胞屏障，提高纳米粒口服吸收的策略，属于药物制剂领域。
背景技术
纳米递药系统能够有效改善难溶性药物的溶解度，提高大分子蛋白多肽类药物的胃肠道稳定性，并能有效控制药物的释放，因而被广泛用于口服递药的研究(ACSNano2015,9,2345-2356)。
为有效递送药物进入血液循环，纳米载体需克服肠上皮细胞吸收屏障(DrugDiscov Today2016,21,1155-1161)。近年来，大量研究致力于在纳米粒表面修饰配体，通过配体与肠上皮细胞表面的受体相互作用，增加纳米粒与细胞膜的亲和力，进而提高细胞摄取(Biomaterials2018,180,78-90)。其中，研究较多的配体为靶向多肽或蛋白，例如RGD、穿膜肽、转铁蛋白等(Adv Drug Deliv Rev 2013,65,822-832)。
然而，值得注意的是，胃肠道复杂的环境与特殊的生理结构，限制了蛋白多肽类配体的靶向效率(Adv Drug Deliv Rev 2013,65,833-844)。一方面，胃肠道复杂多变的pH与酶环境，可能会破坏蛋白多肽的结构(Adv Drug Deliv Rev 2016,101,75-88)；另一方面，蛋白多肽类配体中疏水与正电的区域易与黏液中黏蛋白相互作用，使纳米载体的黏液穿透性降低，从而限制了配体与细胞膜表面受体的相互作用(Eur J Pharm Biopharm 2014,88,518-528)。
肠道是人体最重要的吸收器官，许多小分子营养物质，如糖类、氨基酸等，能够快速大量地被肠上皮细胞吸收，从而保证人体的能量供应(Science 2017,357,1299-1303)。
发明内容
为了解决上述现有研究中主动靶向口服纳米载体存在的问题，本发明人通过创造性的研究将小分子营养物质作为配体，修饰于亲水外壳包裹的纳米粒表面。一方面，小分子营养物质的化学稳定性较高，能够在胃肠道环境中保持结构稳定；另一方面，修饰分子量较小的营养物质，能够保持纳米粒表面的亲水、负电的特征，不影响其黏液穿透性，提高其与上皮细胞表面受体相互作用。
本发明的目的之一是提供，一种提高纳米粒口服吸收的方法，是将小分子营养物质修饰在纳米粒表面，主动靶向肠上皮细胞表面受体。
本发明的目的之一是提供，一种利用小分子营养物质作为配体，制备克服肠道吸收屏障的药物组合物/药物制剂中的应用。
本发明的目的之一是提供，一种克服肠道吸收屏障的纳米粒，所述纳米粒具有亲水外壳与疏水核芯，其中，亲水外壳是由末端共价连接或物理吸附小分子营养物质的亲水聚合物组成；疏水核芯部分是由活性成分与生物相容性载体材料组成。
作为具体的实施方案之一，所述纳米粒平均粒径范围约10～1000nm；所述核壳结构的纳米粒是由疏水核芯与亲水聚合物的外壳按重量比1:99～95:5(w/w)制成；所述活性成分含量占纳米粒总重的0.1％～90％(w/w)。
在疏水核芯部分中，生物相容性载体材料包括但不限于：乳酸和羟基乙酸的单聚或共聚物、聚苯乙烯、聚癸二酸、聚乙烯亚胺、丙交酯和乙交酯的单聚或共聚物、无机硅材料、无机碳材料、聚氰基丙烯酸烷基酯、聚氨基酸、胆固醇、脂肪酸、磷脂、鞘脂、蜡质及脂肪酸甘油酯的一种或多种的组合。
本发明的实施例中进一步优选乳酸-羟基乙酸共聚物、磷脂及脂肪酸甘油酯作为生物相容性载体材料与活性成分制备成核芯。
作为优选的实施方案之一，所述活性成分包括蛋白多肽类药物、核酸类药物及化学药物中的至少一种，其含量为纳米粒总重的0.1％～90％(w/w)，优选1％～80％(w/w)；
所述蛋白多肽类药物包括但不限于：胰岛素、奥曲肽醋酸亮丙瑞林、降钙素、胸腺五肽、促黄体生成素释放激素、醋酸替可克肽、布舍瑞林、艾塞那肽、胰高血糖素样肽-1、醋酸曲普瑞林、白细胞生长因子、红细胞生长因子、巨噬细胞生长因子、肿瘤坏死因子、表皮生长因子、白细胞介素、血管生成抑制素、牛血清白蛋白、卵清蛋白、甲状旁腺素、生长激素、生长抑素、干扰素、单克隆抗体和疫苗；
所述核酸类药物包括但不限于小分子干扰核糖核酸和质粒DNA；
所述化学类药物包括但不限于：阿司匹林、对乙酰氨基酚、贝诺酯、布洛芬、萘普生、双氯芬酸钠、吲哚美辛等解热镇痛药及非甾体抗炎药；或苯唑西林钠、四环素、阿莫西林、氨苄西林、甲硝唑、替硝唑、左氧氟沙星、加替沙星、呋喃唑酮、庆大霉素、利福霉素、红霉素、罗红霉素、克拉霉素、阿奇霉素等抗生素及其它抗菌药物；或阿霉素、紫杉醇、顺铂、5-氟尿嘧啶、羟喜树碱、常春碱、吉西他滨、硫酸长春碱等抗肿瘤药；或米索前列醇、雌二醇、己烯雌酚、他莫昔芬、左炔诺孕酮、炔诺酮、米非司酮、氢化可的松、地塞米松等激素类药物；或地西泮、异戊巴比妥、苯妥英钠、卡马西平、丙戊酸钠、氯丙嗪、氟哌啶醇、盐酸哌替啶、左旋多巴等中枢神经系统药物；或氯贝胆碱、溴新斯的明、硫酸阿托品、溴丙胺太林、肾上腺素、盐酸麻黄碱、普鲁卡因、利多卡因等外周神经系统药物；或普萘洛尔、硝苯地平、卡托普利、氯沙坦、地高辛、洛伐他汀、吉非贝齐等循环系统药物；或甲苯磺丁脲、二甲双胍、那格列奈、氢氯噻嗪、螺内酯、呋塞米、依地尼酸等降血糖药及利尿药。
作为本发明具体实施方案之一，优选胰岛素作为活性成分。
本发明所述的纳米粒外壳，是由两亲性嵌段聚合物的亲水端组成，其中亲水端通过共价连接修饰小分子营养物质(配体)，使配体暴露在纳米粒表面。其中，亲水端包括但不限于聚乙二醇、聚氨基酸、N-(2-羟丙基)甲基丙烯酰胺(HPMA)聚合物、两性离子聚合物、透明质酸。
本发明所述小分子营养物质包括但不限于：葡萄糖、果糖、半乳糖、甘露糖、氨基酸、胆固醇、谷甾醇的一种或多种的组合。所述氨基酸包括但不限于谷氨酸、半胱氨酸、组氨酸、赖氨酸、苏氨酸、亮氨酸、异亮氨酸、缬氨酸、蛋氨酸、色氨酸、苯丙氨酸。
作为本发明优选的实施方案之一，本发明优选聚乙二醇和聚氨基酸作为纳米粒亲水外壳。
本发明的目的之一是提供一种制备基于小分子营养物质介导的提高口服纳米递药系统克服肠上皮细胞吸收屏障的方法，包括以下步骤：
(1)将小分子营养物质或其衍生物与两亲性聚合物的亲水端共价相连；
(2)将修饰后的两亲性聚合物、生物相容性载体材料(纳米粒核芯)与活性成分混合，采用药剂学领域的常规方法如微流控技术、纳米沉淀法、高压匀化法、乳化溶剂挥发法、薄膜法、超临界萃取法等，制备纳米粒。
作为具体的实施方案之一，包括以下步骤：
(1)将D-果糖炔基化，通过点击化学与二硬脂酰磷脂酰乙醇胺(DSPE)-聚乙二醇(PEG)-叠氮基相连，即得果糖修饰的DSPE-PEG。
(2)将处方量果糖修饰的DSPE-PEG与纳米粒核芯材料混合，溶于二甲基亚砜(DMSO)，缓慢滴入搅拌的水相中，即得。
本发明的目的之一是提供一种制备小分子营养物质修饰的载体材料，其中，小分子营养物质及其衍生物可通过酰胺键、酯键等与载体材料相连。
作为本发明具体的实施方案之一，如称取适量25-羟基胆固醇(25HC)，溶于二氯甲烷，加入丁二酸酐，反应24h，萃取得到丁二酸化的25HC；将其与DSPE-PEG-NH2反应24h，利用透析的方法除去未反应的25HC，冷冻干燥，即得25HC修饰的DSPE-PEG(DSPE-PEG-25HC)。
作为本发明具体的实施方案之一，小分子营养物质修饰的载体材料可采用药剂学领域的常规方法制备纳米粒，如纳米沉淀法、离子交联法、高压乳匀法、乳化溶剂挥发法、薄膜法等。
本发明目的之一是提供一种可用于口服给药的克服肠上皮细胞吸收屏障的纳米粒及其制备方法。
具体地，本发明提供了一种可克服胃肠道吸收屏障的纳米粒制剂，主要是由本发明的纳米粒与药学上可以接受的辅料制备成溶液型液体制剂、高分子溶液剂、乳剂、混悬剂、糖浆剂、滴剂、散剂、颗粒剂、片剂及胶囊剂等口服给药制剂。
有益效果
1.本发明中的活性成分主要位于纳米粒核芯，表面为亲水聚合物形成的外壳，有助于提高纳米粒的胶体稳定性，并能有效减少药物在制备与储存过程中的泄露，以提高药物的稳定性，保持其活性。
2.本发明中纳米粒核芯的载体材料可具备多种性质，而且可通过共价连接或物理吸附作用与药物交联，因此可对具有不同性质的药物进行包封，包括水溶性药物及脂溶性药物。
3.营养物质在肠道具有特定转运体，且能快速吸收。本发明中表面修饰小分子营养物质的纳米载体，能利用上述特性，主动靶向肠上皮细胞表面受体，有效提高细胞摄取与跨膜转运效率。
4.本发明中将小分子营养物质作为配体，与现有的蛋白多肽类配体相比，化学稳定性更高，更利于其在复杂胃肠道环境中发挥作用。
5.本发明中使用小分子营养物质，能避免引入蛋白多肽类配体的疏水和正电区域，且不会增加纳米粒粒径，因此可有效避免与黏蛋白的疏水和静电相互作用，不影响纳米载体的黏液穿透性，有助于纳米粒到达肠上皮细胞表面，进而促进细胞摄取。
6.本发明中的小分子营养物质配体，生物相容性好，与现有合成的多肽类配体相比，能一定程度提高口服纳米载体的安全性。
附图说明
以下，结合附图来详细说明本发明的实施方案，其中：
图1表示果糖修饰的DSPE-PEG的合成路径。
图2表示谷氨酸修饰两亲性分枝状聚赖氨酸的合成路径。
图3表示果糖修饰前后纳米粒的粒径、电位变化图。
图4表示果糖修饰前后纳米粒穿黏液速率图。
图5表示氨基酸修饰前后纳米粒的细胞摄取效果图。
图6表示果糖修饰纳米粒的主动靶向能力研究图。
图7表示果糖修饰后纳米粒的跨膜效率研究图。
图8表示大鼠口服胰岛素原药及果糖修饰前后纳米粒的药效学研究图。
具体实施方式
以下实施例是对本发明的进一步说明，但绝不是对本发明范围的限制。下面参照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果糖修饰的DSPE-PEG的合成
果糖修饰的DSPE-PEG的合成路线如附图1所示。首先，将D-果糖(2g，0.011mol)溶于丙酮(40ml)，室温搅拌，将浓硫酸(4ml)缓慢滴入，直至果糖完全溶解。在0℃条件，将反应液逐滴加入氢氧化钠(NaOH)水溶液(25ml，4.5mol/L)。真空浓缩反应液，用二氯甲烷萃取三次，合并油相，用饱和食盐水洗三次。加入无水硫酸钠，干燥30min，过滤后，用正己烷和乙醚(1:1，v/v)混合溶剂重结晶，干燥后称重，得到化合物1，产率86.5％。
在0℃搅拌条件下，将NaOH(0.87g,0.0218mol)缓慢加入DMF，并将化合物1(2g,0.008mol)加入混合溶液中，搅拌15min，逐滴滴加溴丙炔(1ml,0.012mol)。室温下，向反应液中加入75ml水，用乙醚萃取三次，合并有机相，依次用10％盐酸溶液和饱和NaCl洗涤。无水硫酸钠干燥，真空浓缩反应液，得化合物2(2.0g，87.3％)。
将化合物2(0.5g,0.0017mol)溶于三氟乙酸-水(9:1)，室温搅拌2h，过滤并浓缩反应液。粗产物用甲苯洗涤，采用硅胶柱纯化(流动相为二氯甲烷：甲醇＝15:1，v/v)。得浅黄色油状物(化合物3)，产率为67.6％。
将化合物3(109mg,0.5mmol)和DSPE-PEG-N3(PEG分子量为5kDa)(125mg,0.025mmol)溶于DMF，在60℃搅拌条件下加入硫酸铜溶液(8mg/ml)。在0min、30min、60min时逐滴加入抗坏血酸钠溶液(5ml，40mg/ml)。2h后，将反应液转移至透析袋，乙二胺四乙酸二钠透析一天，超纯水透析两天，冻干透析液得到果糖修饰的DSPE-PEG(化合物4)，产率为91.2％。利用傅里叶变换红外光谱仪对结构进行了确认，化合物4在2101.14cm-1处叠氮基特征峰消失，在3445.65cm-1出现果糖特征峰。
实施例2 25-羟基胆固醇(25HC)修饰的DSPE-PEG的合成
首先，将25羟基胆固醇(25HC)丁二酸化，得到丁二酸衍生的25羟基胆固醇。具体流程为，将反应物溶于二氯甲烷(25HC:丁二酸酐:DMAP＝25:50:25mol％)，25HC终浓度为80mg/ml。恒温30℃，500rpm反应24h。将产物旋干，加入纯水，40℃水解2h，使未反应的丁二酸酐水解为丁二酸。采用二氯甲烷萃取丁二酸化的25HC，采用核磁共振氢谱进行结构确认，发现5.3ppm氢峰变为4.6ppm(C3位)，同时2.5ppm出现了典型的丁二酸的4氢峰，可确证丁二酸的成功连接。
通过酰胺反应将DSPE-PEG-NH2(PEG分子量为2kDa)和25HC-COOH共价连接。首先将25HC-COOH、1-乙基-3(3-二甲基丙胺)碳二亚胺(EDCI)和N-羟基琥珀酰亚胺(NHS)于25℃活化0.5h，再加入DSPE-PEG-NH2，滴加少量三乙胺调节pH。其中，反应物溶于DMSO(DSPE-PEG-NH2:25HC-COOH:EDCI:NHS＝16.7:33.3:25:25mol％)，DSPE-PEG-NH2终浓度为20mg/ml。而后25℃，500rpm反应24h。产物用DMSO快速透析12h(25℃)，再用纯水透析24h，冻干即得产物(DSPE-PEG-25HC)。采用核磁共振氢谱进行结构确认，在低化学位移处(0.5-1.5ppm)能观察到胆固醇峰，证明25HC的成功连接。
实施例3氨基酸修饰两亲性分枝状聚赖氨酸的合成
γ-谷氨酸修饰的两亲性分枝状聚赖氨酸的合成路线如附图2所示，主要分为谷氨酸十二醇酯E(C12)(化合物A)、两亲性分枝状聚赖氨酸(化合物B)和谷氨酸修饰两亲性分枝状聚赖氨酸(化合物D)的合成。
(1)谷氨酸十二醇酯的合成:Fmoc-谷氨酸(3.69g,10mmol)与十二醇(3.72g,20mmol)溶解于二氯甲烷，依次加入EDCI(5.73g,30mmol)与4-二甲氨基吡啶(DMAP)(0.61g,5mmol)，置于室温搅拌4小时。反应液依次用饱和氯化铵水溶液与饱和氯化钠水溶液洗涤，有几层用无水硫酸钠干燥，浓缩，硅胶柱层析分离得产物化合物A，产率为74％。
(2)两亲性分枝状聚赖氨酸的合成:化合物A(706mg,1mmol)溶解于二氯甲烷，滴加两滴DBU，薄层色谱(TLC)检测Fmoc脱除。反应液用饱和氯化铵洗涤，硫酸钠干燥，随后减压蒸馏除去溶剂。所得残余物用二氯甲烷溶解，加入PK-dendron(882mg,1.1mmol；参考文献Adv.Funct.Mater.2015,25,5250–5260方法合成)，1-羟基苯并三唑(HOBT)(135mg,1mmol)，EDCI(287mg,1.5mmol)，N,N-二异丙基乙胺(DIEA)(330μL,2mmol)，反应液用氩气保护，室温搅拌24h。反应液依次用饱和氯化铵与饱和氯化钠溶液洗涤，无水硫酸钠干燥。用乙醚和乙腈重结晶得产物化合物B，产率为62％。化合物B是以C12作为疏水端，以聚赖氨酸作为亲水端。
(3)谷氨酸修饰两亲性分枝状聚赖氨酸的合成:取化合物B(317mg,0.25mmol)溶于3mL二氯甲烷，室温搅拌，滴加三氟乙酸3mL，继续搅拌4h。减压蒸馏除去溶剂与TFA，加入乙醚，于低温-10℃下析出固体。离心除去上清液，固体用二氯甲烷溶解，加入Boc-Glu-OtBu(463mg,1.2mmol)，HOBT(135mg,1mmol)，EDCI(287mg,1.5mmol)，DIEA(330μL,2mmol)，反应液用氩气保护，室温搅拌24h。随后依次用饱和氯化铵与饱和氯化钠水溶液洗涤反应液，无水硫酸钠干燥，减压蒸馏除去溶剂。加入乙腈析出沉淀，过滤，用乙腈洗涤，得化合物C，产率为64％。
所得化合物C用4mL二氯甲烷溶解，室温搅拌，滴加TFA 4mL，继续搅拌6h。减压蒸馏除去溶剂与TFA，加入乙腈析出沉淀，离心分离上清，固体用乙腈和乙醚洗涤，得终产物化合物D，产率为87％。利用核磁共振氢谱对化合物D的合成反应进行分析,证实了产物的成功合成。谱图解析如下：1H NMR(400MHz,DMSO-d6)δ9.71(m,4H),8.06(m,11H),4.30–3.95(m,12H),3.01(m,8H),2.38–2.05(m,16H),1.93(m,10H),1.53(m,10H),1.24(m,44H),0.85(t,J＝6.7Hz,6H)。
对于半胱氨酸、α-谷氨酸修饰两亲性分枝状聚赖氨酸的合成，按照类似的方法，将化合物B分别与半胱氨酸、α-谷氨酸共价连接，得到Cys-B和α-Glu-B。利用核磁共振氢谱进行分析,证实了产物的成功合成。Cys-B谱图解析如下：1H NMR(400MHz,DMSO-d6)δ8.28–7.74(m,11H),4.46–3.87(m,12H),3.13–2.89(m,6H),2.87–2.54(m,8H),2.46–1.91(m,8H),1.87(s,12H),1.73–1.44(m,10H),1.42–1.07(m,48H),0.85(t,J＝6.4Hz,6H)。α-Glu-B谱图解析如下：1H NMR(400MHz,DMSO-d6)δ9.86–9.51(m,4H),8.64–7.70(m,11H),δ4.36–4.14(m,4H),4.06–3.92(m,4H),3.83–3.66(m,4H),3.27–2.76(m,8H),2.44–2.11(m,10H),2.05–1.75(m,10H),1.72–1.39(m,16H),1.31–1.03(m,44H),0.85(t,J＝6.4Hz,6H)。
实施例4果糖修饰的聚乳酸-羟基乙酸共聚物(PLGA)纳米粒的制备
称取适量PLGA(50/50,黏度:0.26-0.54dL/g)溶于DMSO，浓度为40mg/ml,将实施例1中的果糖修饰的DSPE-PEG与未修饰的DSPE-PEG分别溶于DMSO,浓度均为20mg/ml。将胰岛素(INS)和磷脂(PC)分别溶于DMSO和甲醇，浓度分别为12mg/ml和96mg/ml，按体积比1:1混合均匀，室温磁力搅拌(500rpm)1h，制备磷脂复合物(IPC)。通过调整两种DSPE-PEG的质量分数，制备不同果糖修饰度的纳米粒。具体方法为，将上述材料按表1比例混合均匀，缓缓滴入2ml水相(700rpm)，继续搅拌5min，超滤法除去DMSO，加入超纯水重新分散后即得。
表1：果糖修饰的纳米粒各材料比例
实施例5 25HC修饰的PLGA纳米粒的制备与细胞摄取
将PLGA、DSPE-PEG-25HC与磷脂分别溶于DMSO，配制储备液(16mg/ml)，另将荧光染料香豆素6溶于DMSO，浓度为2mg/ml。按照体积比PLGA:DSPE-PEG-25HC:磷脂：香豆素6＝4:3:1:0.05，将储备液混合均匀作为有机相。有机相与10-15倍体积去离子水通过微流控设备均匀混合，有机相流速为160μl/min，水相流速为1ml/min，制备25HC修饰的PLGA纳米粒。而后，采用超滤法除去DMSO，即得25HC修饰的PLGA纳米粒。
将Caco-2细胞消化后，按照每孔1×104细胞的密度接种于96孔板，待细胞生长4天出现分化后，移去培养基，用新鲜的PBS润洗细胞。将上述纳米粒与细胞共同孵育3h，移去纳米粒，用新鲜的PBS润洗细胞三次，每孔加0.1ml DMSO破坏细胞和纳米粒，用酶标仪测定DiI荧光值。采用刃天青法对每孔细胞数量进行校正，得到相对细胞摄取的量。我们发现，25HC修饰的PLGA纳米粒细胞摄取为未修饰纳米粒的3.45倍，表明以25HC作为配体能够有效提高纳米粒的细胞膜亲和力。
实施例6果糖修饰前后纳米粒穿黏液能力的考察
按实施例4中方法，制备不同果糖修饰度的载染料DiI的果糖纳米粒。将IPC替换为DiI，DiI溶于DMSO中，储备液浓度为1mg/ml，最终纳米粒分散液中DiI浓度为5μg/ml。采用粒径及zeta电位对各纳米粒进行表征，结果见说明书附图3。
由附图3可见，经过果糖修饰后，纳米粒的粒径未见明显变化，且随着果糖修饰度的增加，纳米粒表面负电荷增加，表面果糖成功修饰于纳米粒表面。
取新鲜猪肠道黏液，将其平铺于Transwell小室中(每孔100μl黏液)，小室的膜面积为0.33cm2，聚碳酸酯半透膜的孔径大小为3μm。取200μl纳米粒分散液，小心滴加于黏液上方，在接收室加入800μl的空白缓冲液，分别于15、30、60及120min，从接收室取样50μl进行荧光分析，并立即向接收室中补充等体积的空白缓冲液。纳米粒的表观渗透系数(Papp)值按下述式计算：Papp＝(dQ/dt)×[1/(A×C0)](dQ/dt表示纳米粒的扩散速度，A为膜面积，C0为药物初始浓度)，结果见说明书附图4。
由附图4可以看出，经过果糖修饰后，黏液穿透型PEG纳米粒的Papp值没有明显变化，表明小分子带负电的果糖不会增加纳米粒与黏蛋白的静电与疏水作用力，从而能保证其黏液穿透速率。
实施例7氨基酸修饰前后纳米粒的细胞摄取效果考察
将PLGA、DSPE-PEG(PEG分子量为2kDa)、实施例3中三种氨基酸修饰的化合物B(α-Glu-B、γ-Glu-B和Cys-B)和疏水染料DiI分别溶于DMSO中，浓度分别为40mg/mL、20mg/mL、20mg/mL和1mg/mL；将磷脂溶于甲醇，浓度为20mg/mL。按照实施例4中方法，将氨基酸修饰的化合物B按一定比例被DSPE-PEG替换，制备一系列氨基酸修饰比例不同的纳米粒。对于100％氨基酸修饰纳米粒，按照体积比PLGA:氨基酸修饰的化合物B:磷脂:DiI＝5:2:2:2，将各材料混合均匀，室温条件下将有机相缓慢滴加到快速搅拌(900rpm)的去离子水中(有机相：水相＝1：20，v/v)，超滤法除去DMSO，加入磷酸盐缓冲液(PBS)(pH＝7.4)重新分散后即得纳米粒分散液。按照实施例5中方法进行细胞摄取实验，我们优选100％α-Glu纳米粒、100％γ-Glu纳米粒和50％Cys纳米粒，与未修饰的PEG纳米粒的细胞摄取进行对比，结果如说明书附图5所示。
图5表明，α-谷氨酸、γ-谷氨酸和半胱氨酸修饰在纳米粒表面，能增加纳米粒与细胞膜亲和力，显著提高纳米粒的细胞摄取。
实施例8果糖修饰纳米粒的主动靶向能力考察
按实施例6中方法，制备载DiI的PEG纳米粒与100％果糖纳米粒。将纳米粒分别与葡萄糖转运体2(GLUT2)和葡萄糖转运体5(GLUT5)的抗体共同孵育，3h后按实施例5中方法测定各组纳米粒的细胞摄取，结果如说明书附图6所示。
图6表明，采用GLUT2和GLUT5抗体对葡萄糖转运体进行特异性封闭，能够显著抑制果糖纳米粒的摄取，且不影响PEG纳米粒的摄取。GLUT2和GLUT5能介导游离果糖的吸收，因此，果糖修饰能够使纳米粒主动靶向至葡萄糖转运体，以增加纳米粒与细胞膜亲和力。
实施例9果糖修饰前后纳米粒的跨膜转运效率考察
将Caco-2细胞消化后，按照每孔3×104的密度接种到Transwell小室中(上室)，接收室(下室)中加入0.6mL的完全培养基。小室的膜面积为0.33cm2，聚碳酸酯半透膜的孔径大小为3μm。前12天，每隔一天换一次培养基，后面每天换一次培养基。同时，从第8天起，每两天用电阻仪测定细胞单层的跨膜电阻值(TEER)，检测细胞的生长情况以及细胞单层的完整性。
取TEER值大于500Ω·cm2的Transwell小室测定纳米粒的跨膜转运。实验前移除上室和下室中的培养基，加入等体积预热的空白培养基平衡30min，而后移除空白培养基。上室中加入200μl分散在空白培养基中的荧光标记纳米粒，下室中加入800μl空白培养基。分别于0、15、30、60、90、150、240及360min，从接收室取样50μl进行荧光分析，并立即向接收室中补充等体积的空白培养基。按照实施例6方法，计算Papp值，结果见附图7。从附图7中可以看出，100％果糖纳米粒的Papp值是PEG纳米粒的5.2倍，说明果糖修饰能通过主动靶向作用，显著提高纳米粒的跨膜转运效率，有助于其克服肠上皮细胞吸收屏障。
实施例10果糖修饰的PLGA纳米粒体内药效学考察
随机取已禁食12小时的SD大鼠(180-220g)15只，随机分为3组，游离INS溶液组、包载INS的PEG纳米粒和果糖纳米粒组各5只(实施例4中制备的纳米粒)。分别灌胃给予INS原药及各组纳米粒2.0ml(含胰岛素50IU/kg)，按预定的时间点(0、1、2、4、6、8及10h)测定大鼠的血糖值，以给药前大鼠的血糖值作为100％，各时间点降血糖百分数按下述公式计算：血糖变化百分数％＝Gt/G0×100(Gt和G0分别表示t时间点的大鼠血糖值和给药前大鼠的血糖值)，以血糖变化百分数％对时间t做曲线得血糖百分数-时间曲线，结果见说明书附图8。
由图8可见果糖纳米粒组在1至6h的降血糖效果明显优于原药组，同时2h的血糖值明显低于PEG纳米粒组，表明果糖修饰能够显著提高纳米粒的口服吸收。
Claims (4)
1.一种用于克服肠道吸收屏障的口服给药制剂，其特征在于，由纳米粒与药学上可以接受的辅料制备成，所述纳米粒具有亲水外壳和疏水核芯结构，其中亲水外壳为两亲性聚合物的亲水端及与亲水端共价连接的谷氨酸构成，核芯为两亲性聚合物的疏水端、活性成分以及生物相容性载体材料组成，其中两亲性聚合物亲水端与谷氨酸共价连接形成γ-谷氨酸修饰的两亲性分枝状聚赖氨酸，生物相容性载体材料为乳酸和羟基乙酸的单聚或共聚物和磷脂，所述活性成分为胰岛素，所述γ-谷氨酸修饰的两亲性分枝状聚赖氨酸的结构式为：
2.根据权利要求1所述的制剂，其特征在于，所述γ-谷氨酸修饰的两亲性分枝状聚赖氨酸的制备方法为：(1)谷氨酸十二醇酯的合成：Fmoc-谷氨酸3.69g，10mmol与十二醇3.72g，20mmol溶解于二氯甲烷，依次加入EDCI 5.73g，30mmol与4-二甲氨基吡啶0.61g，5mmol，置于室温搅拌4h，反应液依次用饱和氯化铵水溶液与饱和氯化钠水溶液洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析分离得产物化合物A，产率为74％，(2)两亲性分枝状聚赖氨酸的合成：化合物A706mg，1mmol溶解于二氯甲烷，滴加两滴DBU，薄层色谱(TLC)检测Fmoc脱除，反应液用饱和氯化铵洗涤，硫酸钠干燥，随后减压蒸馏除去溶剂，所得残余物用二氯甲烷溶解，加入PK-dendron 882mg，1.1mmol，1-羟基苯并三唑135mg，1mmol，EDCI 287mg，1.5mmol，N,N-二异丙基乙胺330μL，2mmol，反应液用氩气保护，室温搅拌24h，反应液依次用饱和氯化铵与饱和氯化钠溶液洗涤，无水硫酸钠干燥，用乙醚和乙腈重结晶得产物化合物B，产率为62％，化合物B是以C12作为疏水端，以聚赖氨酸作为亲水端，(3)谷氨酸修饰两亲性分枝状聚赖氨酸的合成：取化合物B317mg，0.25mmol溶于3mL二氯甲烷，室温搅拌，滴加三氟乙酸3mL，继续搅拌4h，减压蒸馏除去溶剂与TFA，加入乙醚，于低温-10℃下析出固体，离心除去上清液，固体用二氯甲烷溶解，加入Boc-Glu-OtBu 463mg，1.2mmol，HOBT 135mg，1mmol，EDCI 287mg，1.5mmol，DIEA330μL，2mmol，反应液用氩气保护，室温搅拌24h，随后依次用饱和氯化铵与饱和氯化钠水溶液洗涤反应液，无水硫酸钠干燥，减压蒸馏除去溶剂，加入乙腈析出沉淀，过滤，用乙腈洗涤，得化合物C，产率为64％，所得化合物C用4mL二氯甲烷溶解，室温搅拌，滴加TFA 4mL，继续搅拌6h，减压蒸馏除去溶剂与TFA，加入乙腈析出沉淀，离心分离上清，固体用乙腈和乙醚洗涤，得终产物化合物D谷氨酸修饰的两亲性分枝状聚赖氨酸，产率为87％。
3.根据权利要求1所述的制剂，其特征在于，所述纳米粒是由疏水核芯与亲水外壳按质量比1:99～95:5制成；所述活性成分质量占纳米粒总重的0.1％～90％。
4.权利要求1-3任一项所述的制剂在制备用于克服肠道吸收屏障的制剂中的用途。
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| CN112755005B (zh) | 2022-05-13 |
| CN115192542A (zh) | 2022-10-18 |
| CN112755005A (zh) | 2021-05-07 |
| CN115040495A (zh) | 2022-09-13 |
| CN115192542B (zh) | 2023-09-08 |
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