结合雌激素阴道用脂质体温敏凝胶的制备与性质考察

目的 制备结合雌激素阴道用脂质体温敏凝胶,考察其体外释放、流变学及阴道滞留等性质。方法 采用Box-Behnken响应面法优化脂质体处方;冷溶法制备结合雌激素脂质体温敏凝胶;用Franz扩散池考察体外释放性质;用流变仪进行剪切速率扫描、温度扫描、角频率扫描;用荧光成像法考察阴道滞留性。结果 以包封率为指标筛得结合雌激素脂质体最优处方：大豆磷脂与胆固醇用量分别为0.123 6 g与0.030 0 g(4.12∶1.00),脂类与原料药用量分别为0.153 6 g与0.021 6 g(7.11∶1.00),水化介质3.67 mL,包封率为(93.99±0.92)%;48 h累积释放率为(77.82±0.75)%;胶凝温度为(33.0±0.5)℃;胶凝后相变为半固体,流变学性质显著变化;IR820标记的脂质体温敏凝胶在昆明小鼠阴道内具有较高荧光强度且下降速率较慢。结论 结合雌激素脂质体温敏凝胶制备工艺可行,可在体温条件相变并延长在阴道的滞留时间。     

尼古丁二元醇脂质体温敏凝胶的制备及体外评价

目的 制备尼古丁二元醇脂质体温敏凝胶,并对其进行处方筛选,优化药物的经皮转运。方法 选用温敏材料泊洛沙姆407(P407)及泊洛沙姆188(P188)为基质,尼古丁二元醇脂质体温敏凝胶用冷溶法制备,以胶凝温度为考察指标,采用单因素实验对尼古丁二元醇脂质体温敏凝胶进行处方优化;考察尼古丁乙醇溶液、二元醇脂质体及含P407/P188二元醇脂质体温敏凝胶的体外释放性质;Franz扩散池对比尼古丁二元醇脂质体和二元醇脂质体凝胶透皮量及皮内滞留量。结果 制备的温敏凝胶在室温以液体状态存在,在32℃形成凝胶。体外释放实验显示,24 h二元醇脂质体和二元醇脂质体凝胶的释放率分别是(78.60%±0.43%)、(56.36%±0.26%)。与二元醇脂质体相比,二元醇脂质体凝胶有明显的缓释作用。12 h透皮实验表明,二元醇脂质体凝胶可以增大皮内滞留量,而二元醇脂质体可以增加透皮深度。结论 与二元醇脂质体相比,二元醇脂质体温敏凝胶有明显的缓释作用,且显著增加药物的皮内滞留量。     

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...     

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。     

布洛芬二元醇脂质体温敏凝胶的处方筛选与体外释放研究

目的:制备布洛芬二元醇脂质体温敏凝胶,研究其体外释放特性。方法:以泊洛沙姆407(P407)和泊洛沙姆188(P188)为凝胶基质,采用冷溶法制备布洛芬二元醇脂质体温敏凝胶;以胶凝温度为指标,以P407、P188比例(g/100 ml)与布洛芬二元醇脂质体的加入量为因素,采用正交试验对布洛芬二元醇脂质体温敏凝胶处方进行优化;采用Franz扩散池法比较布洛芬乙醇溶液、布洛芬二元醇脂质体、布洛芬P407二元醇脂质体温敏凝胶和优选制备的布洛芬P407/P188二元醇脂质体温敏凝胶的体外释放特性。结果:最优处方为32%P407、3.2%P188及2.5 ml的布洛芬二元醇脂质体,所制温敏凝胶的胶凝温度为(32.1±0.5);体外释放结果显示,与布洛芬乙醇溶液及布洛芬二元醇脂质体比较,优选制备的温敏凝胶具有明显缓释作用,其12 h内累积释放度为(40.9±0.43)%,24 h内累积释放度为(60.76±0.58)%,符合一级释药模型;布洛芬P407二元醇脂质体温敏凝胶和优选制备的温敏凝胶的体外释放特性无明显差异。结论:成功制得具有温敏特性和明显缓释作用的布洛芬二元醇脂质体温敏凝胶。     

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。     

非那沙星眼用温敏凝胶的家兔眼刺激性试验及药效学研究

目的 研究非那沙星眼用温度敏感型原位凝胶(FTGE)对兔眼刺激性及药效学.方法 用Draize兔眼刺激性实验考察FTGE的眼部刺激性;以大肠杆菌及金黄色葡萄球菌感染的兔用FTGE进行局部治疗,观察其经过治疗后的细菌清除率.结果 FTGE无明显刺激性,符合眼用制剂的要求;FTGE的细菌清除率超过80%,药效优于氧氟沙星滴眼液.结论 FTGE在实验中无明显刺激性,且治疗角膜炎临床疗效明显,可供临床使用.     

艾司氟比洛芬凝胶抗炎镇痛作用的药效学研究

目的：观察艾司氟比洛芬凝胶的抗炎镇痛作用。方法：采用二甲苯诱导小鼠耳肿胀,用棉球诱导大鼠肉芽肿,观察艾司氟比洛芬凝胶的抗炎作用；用热板法和扭体法观察艾司氟比洛芬凝胶对小鼠和大鼠的镇痛作用。双氯芬酸乳胶剂(1%)作为阳性对照药,以2%,1.5%和1%的艾司氟比洛芬凝胶分组给药。结果：2%和1.5%艾司氟比洛芬凝胶对二甲苯引起的小鼠耳肿胀有较好的抑制作用(P＜0.01),在给药后30,45 min均能明显提高热板法小鼠的痛阈,改善痛阈提高百分率(P＜0.01,P＜0.05)。2%,1.5%和1%艾司氟比洛芬凝胶对大鼠棉球肉芽肿的形成有一定的抑制作用(P＜0.01)；对1%醋酸引起的大鼠痛反应有较好的抑制作用(P＜0.01)。结论：艾司氟比洛芬凝胶对大鼠及小鼠的炎症及痛反应模型均有抑制作用。     

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。     

氟比洛芬纳米结构脂质载体凝胶剂的物理性质

目的制备氟比洛芬纳米结构脂质载体凝胶剂,并对其物理性质如流变学性质、黏附性和凝胶强度等进行研究。方法分别采用同轴圆筒流变仪和物性分析仪研究氟比洛芬纳米结构脂质载体的流变学性质、黏附性和凝胶强度,并研究了不同贮存温度对上述性质的影响。结果流变学研究结果表明FP-NLC凝胶具有良好的黏弹性,为假塑性流体,高温不利于保持其内部网状结构;物性分析结果表明凝胶剂在低温贮存时能够保持较高的黏附性和凝胶强度。结论氟比洛芬纳米结构脂质载体凝胶剂的流变学性质、黏附性和凝胶强度等物理性质受贮存温度影响较大,将其开发成制剂时需考虑其放置稳定性。     

甲壳素温敏水凝胶止血作用的研究

目的 评价甲壳素温敏水凝胶的止血作用。方法 制作大鼠肝脏损伤出血模型,分为空白对照组、阳性对照组、实验组,空白对照组肝脏出血创面不使用止血材料,阳性对照组、实验组肝脏出血创面分别使用纤维蛋白粘合剂和甲壳素温敏水凝胶止血,记录出血时间和出血量,于术后测定血清中TGF-β1和IL-6的含量,观察肝脏愈合情况,对损伤肝脏进行组织学观察。结果 在手术中使用甲壳素温敏水凝胶能够快速止血,大鼠术后血清中TGF-β1和IL-6含量适中,在愈合过程中炎症反应轻。     

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。     

A thermo-sensitive PLGA-PEG-PLGA hydrogel for sustained release of docetaxel

The aim of this study was to investigate the suitability of poly-(d,l-lactic acid-co-glycolic acid) (PLGA)-polyethylene glycol (PEG)-PLGA triblock copolymer as a matrix material for a sustained-release system for docetaxel (DTX). The copolymers were synthesized by ring-opening polymerization reaction and characterized by ¹H-NMR and gel permeation chromatography. The DTX-loaded formulations were prepared, characterized. And the antitumor efficacy and the pharmacokinetics of DTX-loaded copolymer on A-549 lung tumor-bearing BALB/cA mice were investigated. The results showed that DTX-loaded copolymer highly increased the solubility of DTX by more than 3000-fold. And copolymer concentration as well as drug loading level exerted appreciable influence on the drug release behavior. Further, the pharmacokinetic test showed that DTX-loaded copolymer could be with the sustained-release nature for over 3 weeks, which correlated well with the in vitro release. Additionally, one intratumoral injection of the thermo-sensitive hydrogel containing DTX was comparable to three intravenous injections of DTX injection in inhibiting the tumor growth in A-549 lung tumor-bearing BALB/cA mice with a less toxic manner. PLGA-PEG-PLGA could thus provide a promising alternate locally delivered vehicle for DTX to achieve prolonged exposure having greater efficacy in inhibiting tumor growth with lower toxicity.     

阿西美辛脂质体凝胶剂的研制

目的研制阿西美辛脂质体凝胶剂,并进行评价.方法采用不同方法、不同药-脂比处方制备脂质体,然后对其包封率进行比较,从而优选出最佳制备方法与最佳处方,并进一步制备成脂质体凝胶剂;采用HPLC测定制剂中阿西美辛的含量,葡聚糖凝胶柱结合HPLC测定制剂中阿西美辛的包封率;考察了制剂的皮肤刺激性与初步稳定性.结果制剂的含量控制在0.09%～0.110%范围之内;平均包封率为(58.76±12.47)%;无皮肤刺激性;不易高温贮存,对光不稳定.结论经初步评价,所制备的阿西美辛脂质体制备方法可行、简便、质量稳定.     

Novel vehicle based on cubosomes for ophthalmic delivery of flurbiprofen with low irritancy and high bioavailability

Aim:

To develop a novel vehicle based on cubosomes as an ophthalmic drug delivery system for flurbiprofen (FB) to reduce ocular irritancy and improve bioavailability.

Methods:

FB-loaded cubosomes were prepared using hot and high-pressure homogenization. Cubosomes were then characterized by particle size, zeta potential, encapsulation efficiency, particle morphology, inner cubic structure and in vitro release. Corneal permeation was evaluated using modified Franz-type cells. Ocular irritation was then evaluated using both the Draize method and histological examination. The ocular pharmacokinetics of FB was determined using microdialysis.

Results:

The particle size of each cubosome formulation was about 150 nm. A bicontinuous cubic phase of cubic P-type was determined using cryo-transmission electron microscopy (cryo-TEM) observation and small angle X-ray scattering (SAXS) analysis. In vitro corneal permeation study revealed that FB formulated in cubosomes exhibited 2.5-fold (F1) and 2.0-fold (F2) increase in P_app compared with FB PBS. In the ocular irritation test, irritation scores for each group were less than 2, indicating that all formulations exhibited excellent ocular tolerance. Histological examination revealed that neither the structure nor the integrity of the cornea was visibly affected after incubation with FB cubosomes. The AUC of FB administered as FB cubosome F2 was 486.36±38.93 ng·mL⁻¹·min·μg⁻¹, which was significantly higher than that of FB Na eye drops (P<0.01). Compared with FB Na eye drops, the T_max of FB cubosome F2 was about 1.6-fold higher and the MRT was also significantly longer (P<0.001).

Conclusion:

This novel low-irritant vehicle based on cubosomes might be a promising system for effective ocular drug delivery.     

三磷酸腺苷脂质体鼻用凝胶制备及其抗缺氧作用

制备三磷酸腺苷(adenosine triphosphate, ATP)脂质体,评价其对缺氧性脑损伤的治疗作用。采用离子对薄膜分散法制备ATP脂质体,其最优处方:三磷酸腺苷二钠、十六烷基三甲基溴化铵、大豆磷脂、胆固醇的质量比为1∶1.98∶8∶3,此时ATP脂质体包封率为(81.50±0.82)%,载药量为(6.79±0.07)%。通过体外释放实验与流变学测定分别考察ATP脂质体与空白凝胶的理化性质;将ATP脂质体、ATP水溶液分别加入甲基纤维素凝胶中,以甲基纤维素凝胶为阴性对照,进行小鼠鼻腔给药。动物实验获得军事医学研究院伦理委员会批准。连续给药9天后,与空白凝胶或ATP水凝胶相比, ATP脂质体水凝胶显著提高了血中红细胞与血红蛋白数值(P<0.01);连续给药13天后,在常压密闭缺氧实验中,与ATP水凝胶或空白凝胶相比, ATP脂质体鼻用凝胶能显著提高小鼠标准缺氧耐受时间(P<0.05)。小鼠海马促凋亡基因p53免疫组化染色显示, ATP脂质体对脑组织有明显保护作用。结果表明, ATP脂质体鼻用凝胶预防给药能明显提高小鼠耐缺氧能力,是一种前景广阔的抗缺氧制剂。     

MDP-阿霉素脂质体交联物治疗大鼠成骨肉瘤的药效学研究

目的：制备出MDP－阿霉素脂质体交联物（MDP－LADM），观察MDP－LADM治疗大鼠成骨肉瘤UMR106模型伯疗效，并与游离阿霉素（ADM）及阿霉素脂质体（LADM）作比较。方法：建立SD大鼠UMR106成骨肉瘤模型，将磷脂修饰后用1，4，－二异氰基甲苯酯（TDD与MDP交联，用改良的逆向蒸发将其制备成阿霉素脂质体－MDP交联物。将荷瘤大鼠随机分为五组，即生理盐水组，ADM组，游离ADM＋空白脂质体组，LADM组及MDP－LADM组，观察它们对大鼠的抑瘤作用。用高效液相色谱测定阿霉素在骨组织及其它器官中的含量。结果：MDP－阿霉素脂质体交联物对阿霉素包裹率为92．3％，MDP交联率为70．2％，对SD大鼠UMR106成骨肉瘤模型的抑瘤作用明显高于阿霉素（P＜0．01）和阿霉素脂质体（P＜0．05），治疗后大鼠生存期明显延长（P＜0．01），阿霉素在骨组织中的含量明显增加。结论：MDP－阿霉素脂质体交联物可明显提高阿霉素脂质体对骨肿瘤的治疗作用，降低其不良反应。     

溴吡斯的明阳离子脂质体体外释放和大鼠离体肠吸收

目的:制备溴吡斯的明脂质体,考察其体外释药性质及各肠段的吸收情况。方法:采用逆向蒸发法制备溴吡斯的明阳离子脂质体;透析法测定阳离子脂质体体外释放情况;并采用外翻肠囊法考察脂质体肠道吸收行为。结果:阳离子脂质体72 h累积释放(97.2±3.3)%;能增加药物在各肠段的吸收量,各肠段表观渗透系数(Papp)增加。结论:制备的阳离子脂质体具有一定的缓释效果;阳离子脂质体能够增加药物渗透性。     

Development and evaluation of fast forming nano-composite hydrogel for ocular delivery of diclofenac

In this paper, a fast forming nano-composite hydrogel was developed for potential application in ocular drug delivery. The optical transmission (OT) as well as rheological properties of nano-composite hydrogel was characterized. The developed nano-composite hydrogel given a high diclofenac micelles loading and provided a sustained release manner of diclofenac within 6 h. The developed nano-composite hydrogel formulation was administrated into the eye as flowable solution, quickly forming a hydrogel that is able to resist of the blinking and flushing of tear, yet resulting in the prolonged residence time of pre-corneal. In vivo eye irritation test suggested that the developed nano-composite hydrogel was none-eye irritation might be suitable for various ocular applications. In vivo pharmacokinetic study indicated that the developed nano-composite hydrogel could significantly increase the bioavailability of diclofenac and maintain the concentration of diclofenac in aqueous humor above MEC at least 24 h after administration as compared with that of the commercial diclofenac sodium eye drops, which might be able to reduce the frequency of administration for patients.