难溶性药物美洛昔康脂质体温敏凝胶眼用制剂的研究

目的制备美洛昔康脂质体温敏型眼用凝胶剂,考察其包封率、胶凝性质、离体角膜透过性和眼部刺激性。方法采用薄膜旋蒸法制备美洛昔康脂质体,并对其包封率和理化性质等进行了测定;将美洛昔康脂质体制备成温敏型眼用凝胶制剂,通过搅拌子法,考察了其胶凝行为;采用活体成像系统对比了制剂的角膜滞留特性;采用卧式扩散池,考察了其离体角膜透过性;多次给药后裂隙灯显微镜观察角膜组织考察了其眼部刺激性。结果美洛昔康脂质体包封率可达(77.9±3.10)%,zeta电位为+(35.1±3.62)m V,平均粒径为141.9 nm。美洛昔康脂质体凝胶的胶凝温度为31.7℃。活体成像实验结果显示原位凝胶延长了药物的眼部滞留时间。离体角膜透过结果为美洛昔康脂质体凝胶的透过速率最优。眼部刺激性实验多次给药后,观察日本大耳白兔眼角膜无浑浊,虹膜和结膜未见红肿、充血、肿胀等异常现象,提示多次给药对兔眼角膜无刺激。结论采用薄膜旋蒸法制备的美洛昔康脂质体有较高的包封率,且美洛昔康脂质体温敏型眼用制剂在眼部温度下可自发形成凝胶,延长眼部滞留时间,无眼部刺激性。     

利福平脂质体温敏型原位凝胶的制备及其体外释药特征研究

目的 制备利福平脂质体温敏型原位凝胶,并对其体外性质进行研究。方法 采用薄膜分散法制备利福平脂质体,并对利福平脂质体进行表征研究;以泊洛沙姆188、泊洛沙姆407为凝胶基质,制备利福平脂质体温敏型原位凝胶;以无膜溶出模型研究温敏型原位凝胶体外累积溶蚀率;采用透析袋法分析药物体外释放情况。结果 制备的利福平脂质体平均粒径、聚分散指数、Zeta电位、包封率和载药量分别为(149.0±5.67)nm、0.275±0.056、-(29.8±1.59)mv、(79.6±2.67)%,(18.6±0.25)%;利福平脂质体温敏型原位凝胶的胶凝温度为(34.3±0.6)℃。体外溶蚀曲线和体外释药曲线均符合零级动力学特征。结论 利福平脂质体温敏型原位凝胶的制备工艺简单易行,体外释放显示其有很好的缓释作用。     

氟比洛芬脂质体凝胶的制备及质量控制

目的:制备氟比洛芬脂质体凝胶,并建立其质量控制方法。方法:采用乙醇注入法制备脂质体、研和法制备脂质体凝胶;HPLC法测定氟比洛芬含量;离心法测定脂质体的包封率。结果:氟比洛芬含量测定方法的平均回收率为(98.62±2.22)%,脂质体的包封率为(58.44±3.05)%,脂质体凝胶剂的pH值为6.0～7. 0,其稳定性良好。结论:本制备工艺简单,性质稳定,质量可控,适于作为医院制剂开发。     

眼用阿奇霉素脂质体原位凝胶的制备及体外释药行为

目的制备眼用阿奇霉素脂质体原位凝胶,并对其体外释放行为和刺激性进行考察。方法薄膜分散法制备阿奇霉素脂质体,将其分散于泊洛沙姆407(P407)中制备阿奇霉素脂质体凝胶,根据胶凝温度筛选P407浓度,双室法对该制剂的体外释药行为进行考察,荧光示踪法测定制剂眼部滞留时间,同体自身对照观察制剂的眼部刺激性。结果处方中P407最佳浓度为20%,脂质体凝胶中药物的释放明显慢于其他制剂,眼部滞留时间(28.1±5.5)min,明显长于其他三种剂型(P<0.05),且对兔眼无刺激。结论 P407原位脂质体凝胶缓释特性突出、刺激性低,适合作为阿奇霉素眼用给药载体。     

新疆紫草提取物脂质体制备工艺的初步筛选

目的:筛选新疆紫草提取物脂质体的制备工艺。方法:分别采用薄膜分散法、逆相蒸发法、乙醇注入法、乙醚注入法和熔融法制备新疆紫草提取物(AEE)脂质体,以包封率、形态、粒径分布等为指标比较5种方法的适用性。结果:薄膜分散法、逆相蒸发法、乙醇注入法与乙醚注入法制得的脂质体形态较完整,大小较均匀;其中乙醇注入法制备的AEE脂质体包封率最高,为(63.53±0.71)%。结论:乙醇注入法适合于AEE脂质体的制备。     

川芎嗪眼用脂质体温敏凝胶的制备及体内外特性评价

目的:制备川芎嗪眼用脂质体温敏凝胶,考察其体内外特性。方法:采用硫酸铵梯度法制备川芎嗪脂质体,以正交试验优化制备工艺,并以泊洛沙姆P407为凝胶基质进一步制成温敏凝胶。采用无膜溶出模型对该凝胶的溶蚀性和体外释药特性进行研究;采用改良Franz扩散池考察其角膜透过性,并进一步测定角膜水化值;采用MTT法评价该凝胶对人角膜上皮细胞HCE-T增殖的影响;采用苏木素-伊红染色法和Draize眼部刺激评分考察该凝胶对家兔角膜的刺激性,并观察其眼部组织学变化。结果:川芎嗪脂质体的最优制备工艺为药脂比1∶10(m/m)、硫酸铵溶液浓度0.2 mol/L、磷脂与胆固醇质量比4∶1、孵育温度45℃;再以23%质量分数的泊洛沙姆P407作为凝胶基质制得川芎嗪眼用脂质体温敏凝胶。该凝胶具有良好的胶凝温度;其溶蚀和体外释药均呈零级动力学特征,且体外释药主要与溶蚀相关(R2=0.9934)。该凝胶6 h内累计透过量为43.3%;角膜水化值为72.98%。低、中质量浓度(1、5 mg/L)的川芎嗪眼用脂质体温敏凝胶对HCE-T细胞无明显增殖毒性,但其在高质量浓度(10 mg/L)时显示出一定的细胞毒性。该凝胶对家兔角膜的Draize眼部刺激平均评分属于无刺激范围,且家兔角膜组织学未见异常变化。结论:所制备的川芎嗪眼用脂质体温敏凝胶具有适宜的胶凝温度,对角膜渗透性好、刺激性小。     

氟比洛芬脂质体的制备及其理化特性

目的:制备氟比洛芬乙醇脂质体并对其理化特性进行评价。方法:采用注入法工艺制备氟比洛芬乙醇脂质体,正交设计法筛 选处方;用粒度分析仪测定粒径大小与分布;用HPLC法测定乙醇脂质体中氟比洛芬的含量及其包封率。结果:制备的脂质体粒径分 布集中,平均粒径为153nm,最大粒径1.3μm,300nm以下占78.1%;包封率为36.28%,25℃条件下贮存3个月,粒径分布无显著变 化,渗漏率小于5%,表明本品稳定性良好。结论:注入法制备乙醇脂质体简便可行,质量控制方法简便、快速、准确、重现性好。     

维生素A棕榈酸酯阳离子脂质体原位凝胶的制备及其兔角膜滞留性考察

摘 要 目的: 以维生素A棕榈酸酯(VAP)为主药,制备阳离子脂质体原位凝胶,并对其兔角膜滞留性进行考察。方法: 采用薄膜分散法制备VAP脂质体(VAPL),并用不同季铵化程度的N-三甲基壳聚糖(TMC)包衣制备VAP阳离子脂质体(TMC-VAPL),再以泊洛沙姆407为基质,制备VAP阳离子脂质体原位凝胶(TMC-VAPL-ISG)。采用荧光示踪法对其兔角膜的滞留时间进行考察。结果:透射电镜显示VAP脂质体粒径分布均匀,未包衣时平均粒径为(62.98±0.078) nm,Zeta电位为(－11.2±0.57) mV,平均包封率为(70.62±0.66)%(n=3);TMC包衣后,脂质体粒径明显增大(P<0.05),平均包封率为(69.49±0.79)%,随着TMC季铵化程度的增大,Zeta电位显著增大(P<0.05)。与未包衣和包衣的VAPL相比,TMC-VAPL-ISG兔角膜的滞留时间延长2倍,且随着TMC季铵化程度的提高,滞留效果逐渐增强(P<0.05)。结论:TMC-VAPL-ISG具有阳离子脂质体和原位凝胶的优势,能明显延长兔角膜滞留时间。     

原位凝胶应用于眼部给药系统的研究进展

介绍原位凝胶在眼部给药系统中的研究新方法和新进展,以及原位凝胶的不同胶凝机理,分析胶化过程和眼部应用时的影响因素。原位凝胶滴眼剂可以显著延长药物释放,提高药物生物利用度。原位凝胶滴眼剂作为一种新型眼部药物新剂型,具有良好的应用前景。     

重组人生长激素脂质体的制备及载药研究

目的采用乙醇注入法结合反复冻融技术制备重组人生长激素脂质体,并考察影响包封率的主要因素。方法采用乙醇注入法制备空白脂质体,并通过反复冻融载药,采用葡聚糖凝胶柱分离结合CBB G-250染色法测定游离药物含量,计算包封率;考察孵化时间、孵化温度、冻融次数对包封率的影响;对冻干制品的外观、复溶速度、粒径及分布进行综合评分,优选冻干支持剂。结果孵化时间为40 min、孵化温度为10℃、冻融次数为3次时,能够获得较高包封率的脂质体,包封率为63.59%。海藻糖在脂质体冷冻干燥过程中具有最好的保护作用。结论乙醇注入法结合反复冻融可用于大分子蛋白质类脂质体的制备。     

双氯酚酸钠脂质体的制备及其眼部药代动力学

目的研究双氯酚酸钠脂质体的制备方法并考察其在家兔眼部的药代动力学特征。方法采用逆相蒸发法制备双氯酚酸钠正电荷脂质体。脂质体和滴眼液滴眼后家兔采用高效液相色谱法测定角膜前、角膜和房水中药物浓度。结果制得的脂质体平均粒径为226.5 nm，多分散度为0.214，ζ电位为+18.1 mV，经均匀设计优化处方，包封率可达到63%。0.1%双氯酚酸钠脂质体和滴眼液两种制剂家兔局部滴眼后的药代动力学研究显示，脂质体可延缓药物在角膜前的清除，增加角膜中药物的浓度，药物在房水中半衰期延长，以滴眼液为参比制剂，相对生物利用度为211%。结论双氯酚酸钠正电荷脂质体可以增加药物在角膜前的滞留时间，提高角膜渗透性及药物在眼部的生物利用度，减少滴眼次数。     

Nanostructured lipid carriers for intraocular brimonidine localisation: development,in-vitro and in-vivo evaluation

Brimonidine ocular hypotensive effect can be enhanced by increasing residence time and corneal penetration. The current work aimed to formulate, evaluate and compare nanostructured lipid carriers (NLCs) to solid lipid nanoparticles (SLNs) and commercial eye drops for controlled brimonidine delivery. NLCs prepared by modified high shear homogenisation were spherical with a mean size of 151.97?±?1.98?nm, negative zeta potential (ZP) of ?44.2?±?7.81?mV, % entrapment efficiency (EE) of 83.631?±?0.495% and low crystallinity index (CI) (17.12%), indicating a better drug incorporation. Moreover, they kept stable during storage at 4?°C for 3?months. Permeability coefficient of NLCs was 1.227 folds higher than that of SLNs. Histological examination revealed localisation of NLCs in the anterior ocular chamber. NLCs revealed the most sustained and highest intraocular pressure (IOP) lowering activity (?13.14?±?1.28?mmHg) in rabbits. In conclusion, NLCs is a promising approach for IOP reduction compared to eye drops and SLNs.     

黄体酮凝胶剂的刺激性和子宫内膜转化实验研究

目的：研究黄体酮凝胶剂阴道给药后的刺激性及其对子宫内膜Mcphail指数的影响,初步考察药效,探讨黄体酮凝胶剂的制剂可行性。方法：选取雌性未孕未产普通家兔20只,随机分成空白对照组,空白基质组,低、中、高剂量组,每组各4只。除空白对照组和空白基质组外,其余各组分别给予不同剂量黄体酮凝胶剂,考察黄体酮凝胶剂单次和多次给药后的阴道刺激性。在此基础上,采用子宫内膜转化实验检测黄体酮凝胶剂对家兔子宫的作用。结果：单次或多次给药后,与空白对照组相比,各组家兔均未出现明显的红斑、分泌物渗出。病理切片结果表明,单次或多次给药后,各组病理结果无明显差异。药效学结果表明,经过23 d给药,空白基质组,低、中、高剂量组,阳性对照组的Mcphail分级结果分别为（0.25±0.46）、（1.00±0.61）、（1.75±0.50）、（2.25±0.50）、（3.20±0.27）;子宫病理切片结果显示低、中、高剂量组子宫逐渐由增生期向分泌期转变。结论：黄体酮凝胶剂单次或多次给药后,对家兔阴道和子宫无明显刺激性,Mcphail分级显示黄体酮凝胶剂具有一定的孕激素活性,能促进家兔子宫内膜发育,表明该剂型具有一定的制备可行性。     

Nanodispersion-loaded mucoadhesive polymeric inserts for prolonged treatment of post-operative ocular inflammation

Mucoadhesive polymeric films incorporated with ketorolac tromethamine-loaded nanodispersion aiming the sustained delivery of the drug to the cornea have been developed and characterised for the treatment of post-operative ocular inflammation. Nanodispersions were prepared by ionic gelation method with various concentrations of chitosan and sodium tripolyphosphate. The developed nanodispersions were analysed for morphology, particle size, dispersion homogeneity, zeta potential, entrapment efficiency and drug release. The nanodispersion that showed the smallest particle size and the highest entrapment efficiency was incorporated in optimised HPMC E15 and Eudragit RL100/HPMC K4m films. The formulation with optimum physicomechanical properties was selected to study its ex vivo transcorneal permeation through freshly excised bovine cornea in comparison with the nanodispersion and the marketed eye drops (Acular®). The polymeric ocular film showed greater permeation than aqueous eye drops. Moreover, the ocular film revealed a prolonged anti-inflammatory effect compared to eye drops when applied to inflamed rabbit’s eyes.     

新型载药蒙脱石复合微球滴眼剂的刺激性及角膜前滞留时间的荧光示踪法考察

目的： 将阳离子型药物盐酸倍他洛尔（BH）,与具有离子交换性能的蒙脱石及聚丙烯酸树脂联合使用制备新型盐酸倍他洛尔／蒙脱石聚丙烯酸树脂微球（Mt-BH-MP）新型眼用微纳米混悬剂,考察其刺激性及眼前端滞留能力。方法： 采用油包油乳化-溶剂挥发法制备微球,以BH水溶液和市售贝特舒为对照,分别采用永生化人角膜上皮细胞（iHCECs）构筑角膜前滞留的细胞模型和荧光示踪法评价Mt-BH-MP在细胞模型及兔眼眼表的滞留能力;以MTT法、兔眼眨眼实验及角膜荧光损失来共同评价该新型给药系统的刺激性。结果： iHCECs细胞模型角膜前滞留实验结果表明,Mt-BH-MP的眼部滞留能力明显优于贝特舒组和BH水溶液组;Mt-BH-MP兔眼在体角膜前荧光可维持（46±1） min,亦明显长于BH水溶液和贝特舒滴眼液组（P<0.05）,上述二项实验结果一致。MTT实验结果显示,iHCECs与各制剂接触2 h后,细胞存活率大小顺序为：空白微球>Mt-BH-MP> BH水溶液>贝特舒;兔眼眨眼刺激性及荧光角膜损伤实验结果表明,Mt-BH-MP给药后并无明显异物感及角膜机械损伤。结论： 制备的新型微球眼部递药系统具有良好的眼部滞留能力且刺激性相对较小,具有良好的眼部递药应用前景。     

他克莫司阳离子微乳凝胶的兔眼刺激性研究及房水药动学研究

目的 研究他克莫司阳离子微乳凝胶对兔眼的刺激性及房水药动学。方法 通过HE染色处理的兔眼组织病理切片观察该制剂的眼部刺激性。采用角膜穿刺术抽取兔眼房水,通过液相色谱-质谱联用仪进行房水药动学研究。结果 他克莫司阳离子微乳凝胶对兔眼无明显刺激性,其房水药动学参数AUC为(128.34±13.09)ng·h/ml,是他克莫司阳离子纳米乳AUC(113.61±12.36)ng·h/ml的1.13倍,是市售他克莫司滴眼液Talymus^?AUC(68.25±10.82) ng·h/ml的1.88倍。结论 他克莫司阳离子微乳凝胶眼部刺激性小、滞留时间长且生物利用度高,具有较好的临床应用前景。     

阿魏酸脂质体的制备及其体外抗氧化活性评价

采用醋酸钙梯度法制备阿魏酸脂质体，考察不同因素对包封率的影响。制备的脂质体包封率可达到(80.2±5.2)%，粒径约150 nm。空白脂质体和载药脂质体的zeta 电位分别为(13.14±1.67)mV和(4.12±0.05)mV。冷冻蚀刻电镜观察结果为单室脂质体。建立了U937细胞株氧化损伤模型，采用MTT法、荧光显微镜及光学显微镜考察了细胞活度、线粒体膜电位及细胞的形态学变化，评价阿魏酸脂质体对U937细胞株氧化损伤的保护作用。结果表明，阿魏酸脂质体组体外抗氧化活性强于阿魏酸溶液。     

Melittin liposomes surface modified with poloxamer 188: in vitro characterization and in vivo evaluation

Melittin liposomes surface modified with poloxamer 188 were developed, and the effect of poloxamer 188 was investigated with regard to anti-cancer effect and vascular stimulation. Melittin liposomes surface modified with poloxamer 188 at different concentrations (0%, 2%, and 5%) were prepared using the adsorption method, followed by in vitro characterization, including entrapment efficiency, zeta potential, particle size, and morphology. Subsequently, the influence of repeated freeze-thawing on the liposomes was investigated, and the effect of poloxamer 188 on the repeated freeze-thawing process was explored. Vascular stimulation effects of MLT, and MLT liposome that surface coated with or without poloxamer were all studied. Pharmacokinetics of the different MLT preparations were determined and the anticancer activity of the MLT formulations was investigated. The particle size of the liposomes gradually increased with increasing poloxamer 188 content, while the entrapment efficiency did not change significantly. After the first freeze-thaw cycle, size and PDI were both markedly reduced, entrapment efficiency rose, and there was no significant change of zeta potential. The vascular irritation caused by MLT could be reduced to an extent by encapsulation in liposome, but not completely eliminated, while liposomes coated with poloxamer 188 can effectively abolish the phenomenon. Melittin liposomes with surface modified by poloxamer exhibit enhanced bioavailability, effective anticancer activity, and reduced side effects compared with melittin solution. Poloxamer plays an important role in melittin liposomes.     

Hyaluronic acid modified chitosan nanoparticles for effective management of glaucoma: development,characterization, and evaluation

In clinical practices, solution of dorzolamide hydrochloride (DH) and timolol maléate (TM) is recommended for the treatment of glaucoma. However, low drug-contact time and poor ocular bioavailability of drugs due to drainage of solution, tear turnover and its dilution or lacrimation limits its uses. In addition, systemic absorption of TM may induce undesirable cardiovascular side effects. Chitosan (CS) is a polycationic biodegradable polymer which provides sustained and local delivery of drugs to the ocular sites. Hyaluronic acid (HA) also provides synergistic effect for mucoadhesion in association with chitosan. In the present study, hyaluronic acid modified chitosan nanoparticles (CS-HA-NPs) loaded with TM and DH were developed and characterized. The CS-HA-NPs were evaluated for size, shape, zeta potential, entrapment efficiency, and mucoadhesive strength. The in vitro release study was also performed in PBS pH 7.4. The ocular irritation potential of CS-HA-NPs was estimated using draize test on albino rabbits. A significant reduction in IOP level was obtained using CS-HA-NPs as compared to plain solution of drug and a comparable higher reduction in IOP level was observed as to CS-NPs. These results suggest that HA potentialy enhance the mucoadhesiveness and efficiency of CS-NPs and may be promising carrier for ocular drug delivery.