L—门冬酰胺酶前体脂质体对小鼠毒性及对实验性肿瘤作用

目的：研究L－门冬酰胺酶（L－Asparaginase,L-A)前体脂质体（Proliposome,PL)[L-APL]iv对小鼠的毒性及对荷瘤小鼠的抗肿瘤活性。方法：以小鼠的急性毒性和外周血中白细胞数及血小板数为指标观察药物对小鼠的毒性及以荷瘤小鼠的瘤重和生命延和工率观察药物的抗肿瘤活性;结果：L－APL iV对小鼠的急性毒性与L－A相比明显降低,L－APL对正常小鼠外周血中白细胞数,血小板数无明显影响,而相同剂量L－A对小鼠外周血中白细胞数,血小板数明显降低。与对照组相比,L－APL和L－Aip可明显延长腹水型小鼠移瘤L1210,P388的存活天数,与同剂量L－A相比,L－APL高剂量有明显延长腹水型小鼠移植瘤的存活天数作用。L－APL及L－A ip对小鼠移植瘤Heps,EC实体型的肿瘤生长具有明显的抑制作用,两者抑瘤作用相近。结论：L－APL对小鼠的毒性明显小于相同剂量的L－A,L－APL不仅保持了L－A的抗肿瘤活性,而且有明显的增效作用。     

齐墩果酸新型前体脂质体大鼠小肠吸收实验研究

目的：考察齐墩果酸新型前体脂质体大鼠小肠吸收情况,探讨制备齐墩果酸新型前体脂质体的可行性。方法：采用新型前体脂质体制备方法制备齐墩果酸前体脂质体,采用大鼠离体外翻肠囊法、高效液相色谱法测定齐墩果酸前体脂质体的大鼠小肠吸收,以齐墩果酸溶液同法考察吸收情况作为对照。结果：齐墩果酸前体脂质体给药后大鼠浆膜侧药物浓度-时间曲线下面积显著大于对照组（P〈0.01）。结论：齐墩果酸前体脂质体可增加齐墩果酸的大鼠小肠吸收,初步表明齐墩果酸前体脂质体这一剂型的可行性。     

喷雾干燥法制备阿霉素前体脂质体的研究

 本文采用喷雾干燥法制备了阿霉素前体脂质体，并对其质量进行了评定。结果表明，这种前体脂质体是由表面附着薄膜的微球组成的具有流动性的粉体，与含阿霉素的水相混合后卯形成类似椭圆状的单室脂质体（阿霉素含量：1mg／ml），算术平均粒径为1．3μm，包封率可达39．9％±4．5％。     

四种前体脂质体制剂的包封率比较及小肠吸收研究

目的:采用一种新型前体脂质体制备方法将4种不同极性的药物分别制成前体脂质体,考察此种制备方法对不同药物的适用性。方法:比较齐墩果酸、水飞蓟素、替加氟、肉苁蓉总苷4种前体脂质体制剂水合后所形成脂质体的包封率,选用齐墩果酸前体脂质体、水飞蓟素前体脂质体水合后进行离体小肠吸收实验,以考察所形成脂质体的吸收情况,从而对体内吸收情况进行预测。结果:4种前体脂质体制剂中,包封率为齐墩果酸>水飞蓟素>替加氟>肉苁蓉总苷;离体小肠吸收实验结果显示:齐墩果酸脂质体、水飞蓟素脂质体与其对照溶液相比,药时曲线下面积增大。结论:前体脂质体制备方法尤其适用于弱极性药物如齐墩果酸,制成的脂质体制剂与对照相比,明显促进了药物的吸收。     

Chitosan‐coated antifungal formulations for nebulisation

Objectives The aim of this study was to produce and characterise amphotericin B (AmB) containing chitosan‐coated liposomes, and to determine their delivery from an air‐jet nebuliser. Methods Soya phosphatidylcholine : AmB (100 : 1) multilamellar vesicles were generated by dispersing ethanol‐based proliposomes with 0.9% sodium chloride or different concentrations of chitosan chloride. These liposomes were compared with vesicles produced by the film hydration method and micelles. AmB loading, particle size, zeta potential and antifungal activity were determined for formulations, which were delivered into a two‐stage impinger using a jet nebuliser. Key findings AmB incorporation was highest for liposomes produced from proliposomes and was greatest (approximately 80% loading) in chitosan‐coated formulations. Following nebulisation, approximately 60% of the AmB was deposited in the lower stage of the two‐stage impinger for liposomal formulations, for which the mean liposome size was reduced. Although AmB loading in deoxycholate micellar formulations was high (99%), a smaller dose of AmB was delivered to the lower stage of the two‐stage impinger compared to chitosan‐coated liposomes generated from proliposomes. Chitosan‐coated and uncoated liposomes loaded with AmB had antifungal activities against Candida albicans and C. tropicalis similar to AmB deoxycholate micelles, with a minimum inhibitory concentration of 0.5 µg/ml. Conclusions This study has demonstrated that chitosan‐coated liposomes, prepared by an ethanol‐based proliposome method, are a promising carrier system for the delivery of AmB using an air‐jet nebuliser, having a high drug‐loading that is likely to be effectively delivered to the peripheral airways for the treatment of pulmonary fungal infections.     

尼莫地平前体脂质体的制备及其质量评价

目的制备尼莫地平前体脂质体,并进行质量评价,以期得到高效、低毒和稳定的尼莫地平新剂型。方法采用叔丁醇-水共溶剂冻干法制备尼莫地平前体脂质体,考察了影响药物包封率的因素,并对重建脂质体的药物含量、包封率、粒径、Zeta电位、溶血性及稳定性进行考察。结果磷脂浓度、表面电荷是影响尼莫地平脂质体包封率的主要因素。尼莫地平脂质体包封率大于98%,平均粒径为57 nm,Zeta电位小于-20 mV,无溶血性,稳定性好。结论采用叔丁醇水共溶剂冻干法获得了高包封率、粒径均一、无溶血性、稳定的尼莫地平前体脂质体制剂,可用于静脉注射给药。     

喷雾干燥法制备丹参酮前体脂质体的研究

目的 提高丹参酮（tanshinone)的生物利用度及其脂质体的稳定性。方法 先采用薄膜法将丹参酮制备成脂质体混悬液，然后采用喷雾干燥法将其制备成前体脂质体。结果 丹参酮前体脂质体为干燥的球形粒子，粒度约5μm；前体脂质体水合而重建的脂质体的粒度分布与喷雾干燥前的脂质体无明显差别，脂质体呈球形或椭球形，无明显团聚现象；脂质体中的丹参酮和大豆磷脂在喷雾干燥过程中均较稳定。结论 喷雾干燥法制备丹参酮前体脂质体是可行的。     

Improved oral delivery of resveratrol using proliposomal formulation: investigation of various factors contributing to prolonged absorption of unmetabolized resveratrol

Objectives: The objective of this study was to design lipid-based formulation to enhance the absorption of unmetabolized resveratrol (RSV) over adequate time and investigate various factors that contribute to prolonged absorption of RSV.

Methods: Proliposomal formulations containing distearoyl phosphatidyl choline (DSPC) with or without cholesterol were prepared and evaluated. The liposomes obtained from hydration of proliposomal mixture were evaluated for size, zeta, physical appearance and entrapment. The integrity of liposomes in bile salt solution and solubility of RSV in sodium taurocholate solution in the presence of various concentrations of DSPC were evaluated to assess the stability and in varied gastrointestinal conditions. Finally, oral pharmacokinetic studies of liposomal dispersions in comparison with RSV solution were evaluated.

Results: Results revealed that spontaneous formation of liposomes did not occur upon hydration of RSV: DSPC proliposomes rather showed tendency to form loose cotton-like aggregates. Cholesterol aided in the formation of stable liposomes with large negative zeta potential. Release of RSV from liposomes in the presence of taurocholate was dependent on the amount and type of total lipid. Liposomes without cholesterol showed faster release, and release increased as the amount of DSPC in the formulation increased. Solubility studies indicated that DSPC increases the solubility of RSV in the presence of sodium taurocholate, and corroborates that bilayer assembly is disrupted because of interaction between RSV and DSPC. Mixture of RSV:DSPC:Chol at 1:0.25:0.25 formed stable colloidal dispersion with zeta potential ?22 and released only 20 – 23% of entrapped RSV when incubated with 20 mM sodium taurocholate. Pharmacokinetic profile revealed that AUC and C_max were twofold higher than plain RSV.

Conclusion: The proliposomal formulation optimized by considering various physicochemical factors and simulated in vitro testing result in significant improvement rate and extent of absorption of unmetabolized RSV.     

水飞蓟素前体脂质体的制备和大鼠药代动力学的研究水飞蓟素前体脂质体的制备和大鼠药代动力学的研究

目的为了提高水飞蓟素的口服生物利用度，研制水飞蓟素前体脂质体并对其理化性质进行考察；研究水飞蓟素前体脂质体的大鼠体内生物利用度。方法采用薄膜载体沉积法制备水飞蓟素前体脂质体，通过研究水合后脂质体的包封率、粒径、稳定性来考察其理化性质；将水飞蓟素前体脂质体在体外进行水合，再给予大鼠灌胃，用RP-HPLC法测定不同时间血浆中总的和游离的水飞蓟素的浓度，通过3P97程序计算药代动力学参数。结果用该法制得的前体脂质体包封率可达90%以上，平均粒径为238.8 nm，稳定性较好；药代动力学研究表明水飞蓟素脂质体在体内吸收较快，生物利用度较高。结论采用薄膜载体沉积法制备水飞蓟素前体脂质体，制备工艺简单，易于工业化生产；将水飞蓟素制备成前体脂质体提高了水飞蓟素的生物利用度。     

替加氟新型前体脂质体小肠吸收试验研究

目的　考察替加氟新型前体脂质体的小肠吸收情况。方法　采用大鼠离体小肠吸收法 ,UV法测定黏膜液及浆膜液中替加氟浓度 ,以浓度对时间作图 ,计算曲线下面积。结果　前体脂质体给药后测得的浆膜液吸收曲线下面积大于水溶液给药后测得的曲线下面积。结论　制成前体脂质体可显著增加替加氟的小肠吸收