CN117017909A - 和厚朴酚脂质体眼用凝胶及其制备方法和应用 - Google Patents
和厚朴酚脂质体眼用凝胶及其制备方法和应用 Download PDFInfo
- Publication number
- CN117017909A CN117017909A CN202311298067.3A CN202311298067A CN117017909A CN 117017909 A CN117017909 A CN 117017909A CN 202311298067 A CN202311298067 A CN 202311298067A CN 117017909 A CN117017909 A CN 117017909A
- Authority
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- Prior art keywords
- honokiol
- liposome
- carbomer
- ophthalmic gel
- gel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明属于脂质体制剂的制备技术领域,具体涉及和厚朴酚脂质体眼用凝胶及其制备方法和应用。本发明提供了一种和厚朴酚脂质体眼用凝胶,含有重量百分比0.01‑0.45wt%和厚朴酚、0.6‑5wt%磷脂、0.1‑1wt%胆固醇、0.04‑0.2wt%聚乙二醇或聚乙二醇化磷脂、0.4‑2wt%卡波姆、0.4‑2.5wt%三乙醇胺,余量为水,所述眼用凝胶的pH为5~7,所述凝胶具有较好的眼部吸收效果,提高眼前室组织和厚朴酚的药物浓度,并延长脂质体在眼部的滞留时间,使治疗效果持久。
Description
技术领域
本发明属于脂质体制剂的制备技术领域,具体涉及和厚朴酚脂质体眼用凝胶及其制备方法和应用。
背景技术
厚朴为多年生木兰科植物厚朴凹叶厚朴的干燥树皮,是一种临床上常用的中药材,其主要有效成分包括厚朴酚、和厚朴酚、异厚朴酚、四氢厚朴酚、厚朴碱等,其中以厚朴酚、和厚朴酚的含量最高。
研究表明,和厚朴酚具有广泛的药理作用,包括抗菌作用、抗炎作用、抗焦虑作用、抗吗啡戒断反应、抑制儿茶酚胺的分泌、钙调素措抗作用、抗病毒作用、抗肿瘤作用以及抗衰老作用等。因此和厚朴酚在临床上具有较大的应用前景。近年来,和厚朴酚的强效抗菌、抗氧化、抗炎作用使研究者关注其在眼科的应用前景,但和厚朴酚水溶性低、生物利用度低,不利于吸收,限制了其在眼科给药方面的临床应用。
CN114869885A公开了一种和厚朴酚眼用药物的制备及其在真菌性角膜炎治疗中的应用,包括滴眼液,其组成为:L-门冬氨酸钾130μg/mL、6 .5μg/mL的维生素B6、盐酸萘甲唑林0 .39μg/mL、甲基硫酸新斯的明0 .65μg/mL、L-薄荷脑0 .16μg/mL、和厚朴酚8μg/mL;此外,也公开了由和厚朴酚、黄凡士林、羊毛脂、维生素E组成的眼膏。然而,由于眼部特殊的生理结构与诸多屏障的存在,上述传统眼用制剂存在生物利用度低、眼内保留时间短以及刺激性等问题,其治疗效果受到一定影响。
为了促进和厚朴酚的吸收,延长和厚朴酚在眼表的滞留时间,CN105641709A公开了眼部用和厚朴酚磺丁基醚-β-环糊精壳聚糖纳米粒及其制备方法,该载药纳米粒包括和厚朴酚、磺丁基醚-β-环糊精和壳聚糖,由和厚朴酚与磺丁基醚-β-环糊精制备成包合物,再与壳聚糖反应得到。然而,壳聚糖难溶于水和碱性溶液,只能溶于盐酸、醋酸、甲酸等酸性溶液,而眼用制剂中掺入酸性成分将导致较强的刺激性,容易出现灼热感、瘙痒感等不适感,并且,壳聚糖在眼部生理环境下无法以离子状态存在,导致水溶性变差。此外,磺丁基醚-β-环糊精会在基础肾功能不全患者体内蓄积,其长期安全性尚待进一步证实。
脂质体作为一种新型眼用药物载体,具有缓慢释放药物、增强疗效、减低毒性、靶向释放药物等优点。其组成材料为磷脂双分子层膜,易于生物融合,促进药物对生物膜的穿透性。由于它具有良好的生物相容性及无毒、无免疫原性等优点,越来越引起广泛关注。
目前尚无和厚朴酚脂质体眼用凝胶的相关报道,因此,如何提供一种和厚朴酚脂质体眼用凝胶,以期能够实现较佳的眼部吸收和持久的眼部滞留时间,达到更好的治疗眼科疾病的目的,成为亟待解决的技术问题。
发明内容
本发明的目的是为了解决上述技术问题,从而提供一种和厚朴酚脂质体眼用凝胶及其制备方法和应用。所述脂质体眼用凝胶能够解决现有的和厚朴酚眼用制剂生物利用度低、眼内保留时间短、刺激性强等问题。
为了实现上述目的,本发明采用的技术方案如下:
本发明提供一种和厚朴酚脂质体眼用凝胶,所述脂质体眼用凝胶含有如下重量百分比的组分:
和厚朴酚 0.01~0.45wt%,
磷脂 0.6~5wt% ,
胆固醇 0.1~1wt%,
聚乙二醇或聚乙二醇化磷脂 0.04-0.2wt%,
卡波姆 0.4~2wt%,
三乙醇胺 0.4~2.5wt%,
余量为水,
所述眼用凝胶的pH为5~7。
进一步,所述磷脂与和厚朴酚的重量比为2.5~60:1。
进一步,所述磷脂与胆固醇的重量比为4~10:1,优选为6.22:1。
本发明所述磷脂,可以为大豆磷脂、氢化大豆卵磷脂、蛋黄卵磷脂、氢化蛋黄卵磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰甘油、磷脂酰丝氨酸、神经鞘磷脂、二肉豆蔻磷脂酰胆碱、二油酰磷脂酰胆碱、二月桂酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱或磷脂酸肌醇中的任意一种或其组合。较佳的为大豆磷脂、蛋黄卵磷脂或磷脂酰胆碱。
本发明所述聚乙二醇或聚乙二醇化磷脂,较佳地,其聚乙二醇的分子量为800~20000 Da,优选为1000~8000 Da。
本发明所述聚乙二醇,较佳地为聚乙二醇1000、聚乙二醇2000、聚乙二醇4000、聚乙二醇8000中的任意一种或其组合,优选为聚乙二醇2000。
本发明所述聚乙二醇化磷脂,较佳地,为磷脂酰胆碱-聚乙二醇2000(PC-PEG2000)、磷脂酰乙醇胺-聚乙二醇2000(PE-PEG2000)、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)、二硬脂酰磷脂酰胆碱-聚乙二醇2000(DSPC-PEG2000)、二棕榈酰磷脂酰胆碱-聚乙二醇2000(DPPC-PEG2000)、二棕榈酰基磷脂酰乙醇胺-聚乙二醇2000(DPPE-PEG2000)中的任意一种或其组合,更优选为磷脂酰胆碱-聚乙二醇2000(PC-PEG2000)、二硬脂酰磷脂酰胆碱-聚乙二醇2000(DSPC-PEG2000)、二棕榈酰磷脂酰胆碱-聚乙二醇2000(DPPC-PEG2000)中的一种。
进一步,所述卡波姆包括卡波姆934P、卡波姆TR1、卡波姆940、卡波姆941、卡波姆980、卡波姆947P、卡波姆974P、卡波姆971P中的任意一种或其组合。
进一步,所述眼用凝胶含有添加剂,所述添加剂选自抗氧剂、渗透促进剂、保湿剂、抑菌剂、渗透压调节剂、助溶剂中的任意一种或其组合。
本发明所述抗氧剂、渗透促进剂、保湿剂、抑菌剂、渗透压调节剂、助溶剂均为现有技术,是本领域在凝胶制剂中常规使用的添加剂,其使用量为本领域常规的用量。
本发明所述抗氧剂,可以为亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、焦亚硫酸钠、抗坏血酸、抗坏血酸棕榈酸酯、没食子酸丙酯、生育酚、叔丁基对羟基茴香醚、二丁基羟基甲苯、依地酸二钠中的任意一种或其组合,但不限于此。
本发明所述渗透促进剂,可以为月桂氮卓酮、丙二醇、乙醇、薄荷醇、薄荷油、水杨酸甲酯、冰片、油酸,油酸酯,桉叶油,DMSO,氮酮,月桂酸中的任意一种或其组合,但不限于此。
本发明所述保湿剂,可以为甘油、丙二醇、透明质酸、1,3-丁二醇、1,2-己二醇、山梨醇、麦芽糖醇的任意一种或其组合,但不限于此。
本发明所述抑菌剂,可以为羟苯乙酯、羟苯甲酯、羟苯丙酯、醋酸苯汞、山梨酸、三氯叔丁醇、硫柳贡、苯扎氯铵、苯扎溴铵、硼酸的任意一种或其组合,但不限于此。
本发明所述渗透压调节剂,可以为氯化钠、甘油、聚乙二醇或丙二醇中的任意一种或其组合,但不限于此。
本发明所述助溶剂,可以为甘油、丙二醇、蓖麻油、PEG400、吐温80中的任意一种或其组合,但不限于此。
本发明还提供了一种所述和厚朴酚脂质体眼用凝胶的具体制备方法,包括如下步骤:
(1)制备和厚朴酚脂质体:取磷脂、胆固醇、聚乙二醇或聚乙二醇化磷脂、和厚朴酚,混合均匀,加入有机溶剂充分溶解,蒸发除去有机溶剂,得到一层均匀的磷脂薄膜,抽真空处理除去残余的有机溶剂,向磷脂薄膜中加入处方量50~90wt%的水,搅拌1~1.5 h,所得产物进行均质,得到脂质体溶液;将脂质体溶液在2~10℃用0.22μm滤器过滤,得到和厚朴酚脂质体;
(2)制备和厚朴酚脂质体眼用凝胶:将卡波姆用水充分溶胀,余量水中加入三乙醇胺,搅拌均匀,得到三乙醇胺溶液,在搅拌条件下加入溶胀完全的卡波姆,然后加入步骤(1)得到的脂质体,再加入添加剂,搅拌均匀,得到脂质体眼用凝胶。
进一步,步骤(1)中所述有机溶剂为无水乙醇、氯仿、甲醇、乙醇中的任意一种或其组合。
进一步,步骤(2)卡波姆溶胀后加入1~3wt%的甘油研磨20~40min。
本发明还提供了所述和厚朴酚脂质体眼用凝胶在制备用于预防和或治疗真菌性角膜炎制剂中的应用。
本发明的有益效果如下:
本发明提供的和厚朴酚脂质体眼用凝胶,采用脂质体技术结合凝胶技术,将和厚朴酚脂质体纳入卡波姆基质中,通过控制脂质体制备过程中原辅料的配比,尤其是通过控制胆固醇的用量,以及磷脂和胆固醇的用量配比,实现了较好的眼部吸收效果,提高眼前室组织和厚朴酚的药物浓度,并延长脂质体在眼部的滞留时间,使治疗效果持久。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例对本发明进行具体描述,有必要指出的是,以下实施例仅用于对本发明进行解释和说明,并不用于限定本发明。本领域技术人员根据上述发明内容所做出的一些非本质的改进和调整,仍属于本发明的保护范围。
本发明具体实施方式使用的和厚朴酚纯度≥99%。
实施例1 制备和厚朴酚眼用制剂
1、制备和厚朴酚眼膏剂(Ocul)
(1)处方:
和厚朴酚 1.8g
黄凡士林 340g
羊毛脂 160g
维生素E 5g。
(2)制备方法:
将和厚朴酚溶解于适量氯仿中,将处方量的黄凡士林与羊毛脂混合,50℃水浴完全融化,缓慢滴入和厚朴酚氯仿溶液,持续搅拌至溶液与熔融物混合均匀,将混合物真空干燥去除氯仿,得到和厚朴酚眼膏剂。
2、 制备和厚朴酚脂质体眼用凝胶(Lip-Plo-Gel)
(1)处方:
和厚朴酚 1.6g
蛋黄卵磷脂 5.6g
胆固醇 0.8g
聚乙二醇2000 0.3g
卡波姆940 2.3g
三乙醇胺 2.4g
无菌水 450g。
(2)制备方法:
制备和厚朴酚脂质体:取蛋黄卵磷脂、胆固醇、聚乙二醇2000、和厚朴酚,混合均匀,加入无水乙醇充分溶解,于50℃蒸发除去有机溶剂,得到一层均匀的磷脂薄膜,抽真空处理除去残余的有机溶剂,向磷脂薄膜中加入382g水,于40℃搅拌1 h,所得产物进行均质,得到脂质体溶液;将脂质体溶液在2℃用0.22μm滤膜过滤,得到和厚朴酚脂质体。
经测定,制备的和厚朴酚脂质体平均粒径122.8nm,PDI值0.226,Zeta电位-30.5mV,和厚朴酚包封率大于90%。
制备和厚朴酚脂质体眼用凝胶:将卡波姆用58g水充分溶胀,余量水中加入三乙醇胺,搅拌均匀,得到三乙醇胺溶液,在搅拌条件下加入溶胀完全的卡波姆,然后加入脂质体,搅拌40min,得到脂质体眼用凝胶,测定凝胶pH值为6.4。
3 、 制备和厚朴酚环糊精眼用凝胶 (SBE-β-Gel)
(1)处方:
和厚朴酚 3.7g
磺丁基醚-β-环糊精 60g
泊洛沙姆407 160g
泊洛沙姆188 30g
无菌水 800g。
(2)制备方法:
制备和厚朴酚环糊精包合物:将和厚朴酚以无水乙醇溶解,将磺丁基醚-β-环糊精加至部分无菌水中,搅拌溶解,然后搅拌条件下缓慢加入和厚朴酚乙醇溶液,45℃搅拌3h,真空干燥去除有机溶剂,冷却,过0.45μm微孔滤膜,得到环糊精包合物。
制备和厚朴酚环糊精眼用凝胶:将泊洛沙姆407和泊洛沙姆188加入剩余的无菌水中,溶胀后缓慢加入环糊精包合物,搅拌均匀,得到和厚朴酚环糊精眼用凝胶。
实施例2 不同制剂兔眼药代动力学实验
1、分组
取9只新西兰无眼疾白兔随机分为3组,每组3只(六只眼)。
2、给药及采样
分别给各组兔子双眼结膜囊内涂布实施例1制备的Ocul、Lip-Plo-Gel、SBE-β-Gel(以含和厚朴酚10μg计),将兔子麻醉1h、2h、4h、6h、8h和10h后,用一次性注射器抽取兔子眼中的房水100μL,并将房水在-20℃保存备用。
3、样品处理与检测
房水样品处理:将房水样品(100μl)与吴茱萸碱甲醇溶液(内标溶液:20μl,10μg/mL)漩涡混合5min,混合物中加入1.3mL乙酸乙酯,继续漩涡混合8min, 然后14000rpm离心10min,上清液转移至试管,室温下氮气吹干,添加100μl甲醇旋转搅拌5min,再次离心,取上清液HPLC法测定和厚朴酚药物含量,并用统计软件计算房水中和厚朴酚的药代动力学参数。
4、结果
根据单次点眼后不同时间点的兔眼生物样品中的药物浓度,计算药物达峰的质量比Cmax、达峰时间Tmax、药物浓度-时间曲线下面积AUC。结果见表1。
表1 不同眼用制剂在兔眼房水中的药代动力学参数
组别 | Cmax(ng/mL) | Tmax(h) | AUC0-10h(ng.h/mL) |
Ocul | 121.4±43.6 | 1.00±0.00 | 583.2±61.1 |
Lip-Plo-Gel | 287.6±37.8 | 1.95±0.38 | 1121.7±79.2 |
SBE-β-Gel | 212.3±54.2 | 1.64±0.42 | 866.2±84.3 |
由表1可知,在兔眼房水中,Cmax结果Ocul<SBE-β-Gel<Lip-Plo-Gel,Tmax结果Ocul<SBE-β-Gel<Lip-Plo-Gel,AUC结果Ocul<SBE-β-Gel<Lip-Plo-Gel。和厚朴酚脂质体眼用凝胶在兔眼的药代动力学参数表明其药物在兔眼中吸收率更高,药物作用持续时间更长。
实施例3 不同制剂对小鼠真菌性角膜炎模型的抗菌疗效实验
1、分组及给药
鼠龄8-10周雌性健康SPF级C57BL/6小鼠共50只,随机分为5组,分为正常组、模型组、药物组(Ocul组、SBE-β-Gel组、Lip-Plo-Gel组),每组10只。
正常组不接种真菌,模型组和药物组接种真菌造模,药物组在造模成功后第一天开始,分别球结膜下注射给药实施例1制备的Ocul、SBE-β-Gel、Lip-Plo-Gel(以水稀释后用药),每天1次,每次和厚朴酚含药量2ug,连续3天。正常组以等量磷酸盐缓冲液替代。
2、模型建立
小鼠腹腔内注射8%水合氯醛麻醉,在立体显微镜下固定小鼠,用无菌手术刀片刮除直径约2mm的角膜上皮缺损,刮除深度达角膜浅基质层,再将制备好的活性烟曲霉菌混悬液滴于角膜创伤表面(10μl/眼)后,覆盖软性角膜接触镜于其表面,用5-0缝线缝合眼睑使其闭合。在实验预先设计的时间点,使用异氟烷气体麻醉小鼠后,拆除眼睑缝线并在裂隙灯下拍取角膜照片,对小鼠角膜炎症反应进行临床评分。评分标准见表2,三项观察指标得分之和为小鼠角膜炎炎症评分。
表2 小鼠真菌性角膜炎模型炎症分级
Ⅰ级(1分) | Ⅱ(2分) | Ⅲ(3分) | Ⅳ(4分) | |
溃疡面积 | 1%-25% | 26%-50% | 51%-75% | 76%-100% |
浑浊程度 | 虹膜纹理尚清,瞳孔可见,角膜轻度混浊 | 虹膜可见,角膜较混浊 | 虹膜不见,不均匀混浊 | 角膜均匀,重度混浊 |
溃疡形态 | 轻度不规则 | 轻度水肿不规则 | 重度水肿,龛样溃疡或后弹力层膨出 | 穿孔或后弹力层膨出 |
3、检测及结果
各组小鼠分别在第1和第3天,对小鼠角膜炎症反应进行临床评分。结果见表3。
表3 不同制剂小鼠角膜炎症反应评分
组别 | 第1天 | 第3天 |
正常组 | 0.0±0.0 | 0.0±0.0 |
模型组 | 3.6±0.7 | 7.8±0.9 |
药物组Ocul | 3.1±0.5 | 6.2±1.4 |
药物组SBE-β-Gel | 2.9±1.2 | 5.6±1.2 |
药物组Lip-Plo-Gel | 2.6±0.9 | 4.1±1.3 |
由表3可知,与正常组相比,模型组角膜炎症反应评分显著上调,药物组不同程度降低了炎症反应评分,Lip-Plo-Gel效果优于SBE-β-Gel,SBE-β-Gel效果优于Ocul。
实施例4 Lip-Plo-Gel中胆固醇用量对房水药物浓度的影响
以表4处方,按实施例1中Lip-Plo-Gel的制备方法制备脂质体眼用凝胶,在步骤(1)制备脂质体之后,取样测定脂质体的粒径和包封率,然后以处方1-6制备的凝胶按下述方法进行房水药物浓度测定实验。
表4 不同胆固醇含量的Lip-Plo-Gel处方
组别 | 处方1 | 处方2 | 处方3 | 处方4 | 处方5 | 处方6 |
重量g | 重量g | 重量g | 重量g | 重量g | 重量g | |
和厚朴酚 | 1.6 | 1.6 | 1.6 | 1.6 | 1.6 | 1.6 |
蛋黄卵磷脂 | 5.6 | 5.6 | 5.6 | 5.6 | 5.6 | 5.6 |
胆固醇 | 0.4 | 0.6 | 0.9 | 1.2 | 1.4 | 1.6 |
聚乙二醇2000 | 0.3 | 0.3 | 0.3 | 0.3 | 0.3 | 0.3 |
卡波姆940 | 2.3 | 2.3 | 2.3 | 2.3 | 2.3 | 2.3 |
三乙醇胺 | 2.4 | 2.4 | 2.4 | 2.4 | 2.4 | 2.4 |
无菌水 | 450 | 450 | 450 | 450 | 450 | 450 |
处方1-处方6在步骤(1)制备脂质体之后,测定脂质体的粒径为108~134.8nm,包封率为90.3~96.6%,PDI值0.218~0.333,Zeta电位-35.4~22.8mV,表明制备的脂质体粒径小,并且粒径均一,包封率高,体系稳定。
1、分组
取24只新西兰无眼疾白兔随机分为6组,每组4只,每组动物随机分为2个时间组,每个时间组分别为2只兔子(四只眼)。
2、给药及采样
分别给各组兔子双眼结膜囊内涂布处方1-6制备的Lip-Plo-Gel(以含和厚朴酚10ug计),按照实施例2所述给药及采样方法,于涂布后第0.5h、1h后,从兔子眼睛中抽取房水。
3、样品处理及检测
按照实施例2所述房水样品处理方法,取上清液,HPLC测定和厚朴酚药物含量,计算样品药物浓度。
4、结果
单次点眼后0.5h、1h时间点的兔眼房水样品中的药物浓度结果见表5。
表5不同处方采样点房水的和厚朴酚药物浓度(μg/L)
组别 | 处方1 | 处方2 | 处方3 | 处方4 | 处方5 | 处方6 |
0.5h | 63.25 | 105.83 | 136.4 | 114.4 | 102.5 | 88.61 |
1h | 89.83 | 161.7 | 195.3 | 179.8 | 172.9 | 118.6 |
由表5结果可知,脂质体眼用凝胶中胆固醇的含量影响和厚朴酚在眼内的吸收,当胆固醇含量高于0.1wt%时,房水中药物浓度更高;脂质体眼用凝胶中磷脂与胆固醇重量比6.22:1时,房水中药物浓度最高。
实施例5 眼部滞留时间考察
以表6处方,按实施例1中Lip-Plo-Gel的制备方法制备脂质体眼用凝胶。并以处方3以及处方7-13制备的凝胶按下述方法进行眼部滞留时间实验。
表6 处方7-13的Lip-Plo-Gel处方
组别 | 处方7 | 处方8 | 处方9 | 处方10 | 处方11 | 处方12 | 处方13 |
重量g | 重量g | 重量g | 重量g | 重量g | 重量g | 重量g | |
和厚朴酚 | 1.6 | 1.6 | 1.6 | 1.6 | 1.6 | 1.6 | 1.6 |
蛋黄卵磷脂 | 5.6 | 5.6 | 5.6 | 5.6 | 5.6 | 5.6 | 5.6 |
胆固醇 | 0.9 | 0.9 | 0.9 | 0.9 | 0.9 | 0.9 | 0.9 |
PEG 4000 | 0.3 | / | / | / | / | / | / |
PEG 8000 | / | 0.3 | / | / | / | / | / |
PC-PEG2000 | / | / | 0.3 | / | / | / | / |
DSPC-PEG2000 | / | / | / | 0.3 | / | / | / |
DPPC-PEG2000 | / | / | / | / | 0.3 | / | / |
DOPE-PEG2000 | / | / | / | / | / | 0.3 | / |
HSPE-PEG2000 | / | / | / | / | / | / | 0.3 |
卡波姆940 | 2.3 | 2.3 | 2.3 | 2.3 | 2.3 | 2.3 | 2.3 |
三乙醇胺 | 2.4 | 2.4 | 2.4 | 2.4 | 2.4 | 2.4 | 2.4 |
无菌水 | 450 | 450 | 450 | 450 | 450 | 450 | 450 |
取眼用凝胶,分别加入2%的荧光素钠,混合均匀,选择24只新西兰无眼疾白兔随机分为8组,每组3只,分别给各组兔子双眼结膜囊内涂布处方3、处方7-13制备的Lip-Plo-Gel(以含和厚朴酚0.5ug计),闭合眼睑约10s,将紫外灯调制365nm波长处,每隔10min观察眼角膜表面的连续荧光层的强弱,连续荧光层在角膜表面消失的时间规定为眼部滞留时间,结果见表7。
表7 不同处方凝胶的眼部滞留时间结果
组别 | 眼部滞留时间(min) |
处方3 | 180 |
处方7 | 140 |
处方8 | 150 |
处方9 | 200 |
处方10 | 190 |
处方11 | 180 |
处方12 | 100 |
处方13 | 120 |
由表7可知,Lip-Plo-Gel在眼部的滞留时间均较长,达到100min以上,其中处方3、处方9、处方10、处方11的滞留时间达到180min以上,Lip-Plo-Gel能够在眼前段滞留较长时间并维持有效药物浓度,提高药物的生物利用度。
实施例6 稳定性实验
将处方1-13制备的眼用凝胶,于12℃±2%,湿度60%±10%、避光条件下放置6个月,并于0月、6月末取样,稀释样品后测定脂质体粒径大小、表面电荷、包封率和总杂质含量,结果见表8-9。
表8 处方1-13凝胶稳定性试验-0月结果
组别 | 平均粒径(nm) | PDI | 包封率 | 总杂含量 |
处方1 | 132.3 | 0.325 | 90.2% | 0.19% |
处方2 | 125.6 | 0.264 | 92.7% | 0.08% |
处方3 | 131.5 | 0.258 | 99.8% | 0.13% |
处方4 | 122.8 | 0.224 | 95.2% | 0.16% |
处方5 | 132.7 | 0.231 | 96.8% | 0.09% |
处方6 | 133.5 | 0.311 | 90.4% | 0.15% |
处方7 | 118.9 | 0.250 | 93.2% | 0.13% |
处方8 | 120.5 | 0.261 | 93.5% | 0.09% |
处方9 | 123.7 | 0.238 | 94.7% | 0.17% |
处方10 | 126.8 | 0.244 | 93.9% | 0.16% |
处方11 | 131.0 | 0.206 | 98.8% | 0.12% |
处方12 | 124.3 | 0.216 | 96.6% | 0.10% |
处方13 | 126.6 | 0.272 | 94.6% | 0.19% |
表9 处方1-13凝胶稳定性试验-6月结果
组别 | 平均粒径(nm) | PDI | 包封率 | 总杂含量 |
处方1 | 127.4 | 0.362 | 83.2% | 0.34% |
处方2 | 133.2 | 0.271 | 91.6% | 0.10% |
处方3 | 135.6 | 0.261 | 98.6% | 0.16% |
处方4 | 127.5 | 0.234 | 94.3% | 0.22% |
处方5 | 123.9 | 0.239 | 96.0% | 0.13% |
处方6 | 118.9 | 0.328 | 90.3% | 0.19% |
处方7 | 119.6 | 0.269 | 93.4% | 0.16% |
处方8 | 123.4 | 0.294 | 92.6% | 0.10% |
处方9 | 138.3 | 0.254 | 93.2% | 0.21% |
处方10 | 127.7 | 0.262 | 92.3% | 0.19% |
处方11 | 132.7 | 0.227 | 96.3% | 0.15% |
处方12 | 128.4 | 0.238 | 95.0% | 0.13% |
处方13 | 122.2 | 0.281 | 93.7% | 0.22% |
结果表明,处方2-13眼用凝胶在放置6个月后,粒径、PDI、包封率和总杂含量无明显变化,制剂稳定。
实施例7
按以下处方和制备方法制备和厚朴酚脂质体眼用凝胶
(1)处方:
和厚朴酚 1.8g
大豆卵磷脂 20g
胆固醇 4g
聚乙二醇1000 0.8g
卡波姆934P 1.6g
三乙醇胺 1.65g
无菌水 370g。
(2)制备方法:
制备和厚朴酚脂质体:取大豆卵磷脂、胆固醇、聚乙二醇1000、和厚朴酚,混合均匀,加入无水乙醇充分溶解,于40℃蒸发除去有机溶剂,得到一层均匀的磷脂薄膜,抽真空处理除去残余的有机溶剂,向磷脂薄膜中加入320g水,于40℃搅拌1 h,所得产物进行均质,得到脂质体溶液;将脂质体溶液在2℃用0.22μm滤膜过滤,得到和厚朴酚脂质体;
制备和厚朴酚脂质体眼用凝胶:将卡波姆用40g水充分溶胀,余量水中加入三乙醇胺,搅拌均匀,得到三乙醇胺溶液,在搅拌条件下溶胀完全的卡波姆,然后加入脂质体,搅拌40min,得到脂质体眼用凝胶,测定凝胶pH值在5~7范围内。
实施例8
按以下处方和制备方法制备和厚朴酚脂质体眼用凝胶
(1)处方:
和厚朴酚 0.04g
二肉豆蔻磷脂酰胆碱 2.4g
胆固醇 0.6g
DPPE-PEG2000 0.16g
卡波姆TR1 8g
三乙醇胺 10g
甘油 2.96g
无菌水 370g。
(2)制备方法:
制备和厚朴酚脂质体:取二肉豆蔻磷脂酰胆碱、和厚朴酚、胆固醇、DPPE-PEG-2000,混合均匀,加入无水乙醇,25℃超声条件下匀速缓慢注入到185g水中,减压旋转蒸发除去乙醇后得到和厚朴酚脂质体溶液;
制备和厚朴酚脂质体眼用凝胶:将卡波姆用170g水充分溶胀,加入甘油研磨25min,余量水中加入三乙醇胺,搅拌均匀,得到三乙醇胺溶液,在搅拌条件下加入研磨后的卡波姆,然后加入脂质体,搅拌40min,得到脂质体眼用凝胶,测定凝胶pH值在5~7范围内。
实施例9
按以下处方和制备方法制备和厚朴酚脂质体眼用凝胶
(1)处方:
和厚朴酚 1g
磷脂酸肌醇 10g
胆固醇 2g
PE-PEG2000 0.4g
卡波姆941 2.2g
三乙醇胺 3g
甘油 2g
甘露醇 5g
甲基吡咯烷酮 0.4g
依地酸二钠 0.04g
尼泊金甲酯 0.04g
无菌水 370g。
(2)制备方法:
制备和厚朴酚脂质体:取磷脂酸肌醇、和厚朴酚、胆固醇、PE-PEG-2000,混合均匀,加入无水乙醇,25℃超声条件下匀速缓慢注入到305g水中,减压旋转蒸发除去乙醇后得到和厚朴酚脂质体溶液;
制备和厚朴酚脂质体眼用凝胶:将卡波姆用55g水充分溶胀,加入甘油后研磨30min,将三乙醇胺用余量水溶解,得到三乙醇胺溶液,在搅拌条件下加入研磨后的卡波姆,然后加入脂质体和添加剂,搅拌40min,得到脂质体眼用凝胶,测定凝胶pH值在5~7范围内。
实施例10
按以下处方和制备方法制备和厚朴酚脂质体眼用凝胶
(1)处方:
和厚朴酚 1.5g
磷脂酰甘油 8.5g
胆固醇 2g
PC-PEG2000 0.5g
卡波姆980 4g
三乙醇胺 4.6g
苯扎溴安 0.04g
α-生育酚 0.04g
甲基纤维素 0.2g
吐温80 0.5g
无菌水 450g。
(2)制备方法:
制备和厚朴酚脂质体:取磷脂酰甘油、胆固醇、PC-PEG2000、和厚朴酚,混合均匀,加入无水乙醇充分溶解,于40℃蒸发除去有机溶剂,得到一层均匀的磷脂薄膜,抽真空处理除去残余的有机溶剂,向磷脂薄膜中加入320g水,于40℃搅拌1 h,所得产物进行均质,得到脂质体溶液;将脂质体溶液在2℃用0.22μm滤膜过滤,得到和厚朴酚脂质体;
制备和厚朴酚脂质体眼用凝胶:将卡波姆用用100g水充分溶胀,将三乙醇胺用余量水溶解,得到三乙醇胺溶液,在搅拌条件下加入溶胀的卡波姆,然后加入脂质体和添加剂,搅拌40min,得到脂质体眼用凝胶,测定凝胶pH值在5~7范围内。
实施例11
按以下处方和制备方法制备和厚朴酚脂质体眼用凝胶
(1)处方:
和厚朴酚 1.8g
磷脂酰丝氨酸 10g
胆固醇 2g
PEG8000 0.6g
卡波姆947P 4.2g
三乙醇胺 4.8g
无菌水 500g。
(2)制备方法:
制备和厚朴酚脂质体:取磷脂酰丝氨酸、胆固醇、PEG8000、和厚朴酚,混合均匀,加入无水乙醇充分溶解,于40℃蒸发除去有机溶剂,得到一层均匀的磷脂薄膜,抽真空处理除去残余的有机溶剂,向磷脂薄膜中加入350g水,于40℃搅拌1 h,所得产物进行均质,得到脂质体溶液;将脂质体溶液在2℃用0.22μm滤膜过滤,得到和厚朴酚脂质体;
制备和厚朴酚脂质体眼用凝胶:将卡波姆用120g水充分溶胀,将三乙醇胺用余量水溶解,得到三乙醇胺溶液,在搅拌条件下加入溶胀的卡波姆,然后加入脂质体和添加剂,搅拌40min,得到脂质体眼用凝胶,测定凝胶pH值在5~7范围内。
本发明实施例7-11为较为优选的实施方案,经测定,其对小鼠真菌性角膜炎模型均具有良好的抗菌疗效,能够显著改善炎症评分,并且在本发明稳定性实验条件下放置6个月,产品性质稳定。本发明所述各组实施例仅为示例性的,并不代表以任何方式限制本发明的范畴。
Claims (10)
1.一种和厚朴酚脂质体眼用凝胶,其特征在于,所述脂质体眼用凝胶含有如下重量百分比的组分:
和厚朴酚 0.01~0.45wt%,
磷脂 0.6~5wt% ,
胆固醇 0.1~1wt%,
聚乙二醇或聚乙二醇化磷脂 0.04-0.2wt%,
卡波姆 0.4~2wt%,
三乙醇胺 0.4~2.5wt%,
余量为水,
所述眼用凝胶的pH为5~7。
2.根据权利要求1所述的和厚朴酚脂质体眼用凝胶,其特征在于,所述磷脂与和厚朴酚的重量比为2.5~60:1。
3.根据权利要求1所述的和厚朴酚脂质体眼用凝胶,其特征在于,所述磷脂与胆固醇的重量比为4~10:1。
4.根据权利要求1所述的和厚朴酚脂质体眼用凝胶,其特征在于,所述聚乙二醇为聚乙二醇2000,所述聚乙二醇化磷脂为磷脂酰胆碱-聚乙二醇2000、二硬脂酰磷脂酰胆碱-聚乙二醇2000、二棕榈酰磷脂酰胆碱-聚乙二醇2000中的一种。
5.根据权利要求1所述的和厚朴酚脂质体眼用凝胶,其特征在于,所述卡波姆包括卡波姆934P、卡波姆TR1、卡波姆940、卡波姆941、卡波姆 980、卡波姆947P、卡波姆974P、卡波姆971P中的任意一种或其组合。
6.根据权利要求1所述的和厚朴酚脂质体眼用凝胶,其特征在于,所述眼用凝胶含有添加剂,所述添加剂选自抗氧剂、渗透促进剂、保湿剂、抑菌剂、渗透压调节剂、助溶剂中的任意一种或其组合。
7.根据权利要求1-6任一项所述的和厚朴酚脂质体眼用凝胶的制备方法,其特征在于,包括如下步骤:
(1)制备和厚朴酚脂质体:取磷脂、胆固醇、聚乙二醇或聚乙二醇化磷脂、和厚朴酚,混合均匀,加入有机溶剂充分溶解,蒸发除去有机溶剂,得到一层均匀的磷脂薄膜,抽真空处理除去残余的有机溶剂,向磷脂薄膜中加入处方量50~90wt%的水,搅拌1~1.5 h,所得产物进行均质,得到脂质体溶液;将脂质体溶液在2~10℃用0.22μm滤器过滤,得到和厚朴酚脂质体;
(2)制备和厚朴酚脂质体眼用凝胶:将卡波姆用水充分溶胀,余量水中加入三乙醇胺,搅拌均匀,得到三乙醇胺溶液,在搅拌条件下加入溶胀完全的卡波姆,然后加入步骤(1)得到的脂质体,再加入添加剂,搅拌均匀,得到脂质体眼用凝胶。
8.根据权利要求7所述的和厚朴酚脂质体眼用凝胶的制备方法,其特征在于,步骤(1)中所述有机溶剂为无水乙醇、氯仿、甲醇、乙醇中的任意一种或其组合。
9.根据权利要求7所述的和厚朴酚脂质体眼用凝胶的制备方法,其特征在于,步骤(2)卡波姆溶胀后加入1~3wt%的甘油研磨20~40min。
10.权利要求1-6任一项所述的和厚朴酚脂质体眼用凝胶在制备用于预防和或治疗真菌性角膜炎制剂中的应用。
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