维甲酸固体脂质纳米粒冷冻干燥工艺研究

选用不同辅料作为冻干保护剂，制备维甲酸固体脂质纳米粒冻干品，并考察不同制品的外观、粒径、包封率。以冻干品外观、再分散后的粒径和包封率为评价指标，筛选保护剂的优化处方。结果表明，选择蔗糖、蔗糖＋海藻糖、甘露醇＋海藻糖、甘露醇＋蔗糖为冻干保护剂，冻干纳米粒再分散后粒径减小，包封率与冻干前相比有所降低，含海藻糖处方可大大加快纳米粒的再分散速率，4℃和20℃放置3个月稳定性良好。     

两性霉素B长循环脂质体冻干剂的制备工艺研究

目的:对两性霉素B长循环脂质体的冻干工艺进行研究,制备两性霉素B长循环脂质体的冻干剂.方法:采用薄膜-超声法制备了两性霉素B长循环脂质体混悬液.以冻干品再分散后的粒径、包封率为评价指标,考察了不同种类的冻干保护剂和浓度对脂质体冻干品的影响,并对冻干工艺参数进行了优化.结果:选择海藻糖为冻干保护剂,冻干效果较好.制备的冻干剂的平均粒径为(116.8±1.6)nm,药物包封率为(76.0±1.9)%.结论:通过冻干保护剂的筛选和优化冻干工艺参数可以获得最佳的两性霉素B长循环脂质体的冻干品.     

阿霉素脂质体的冻干工艺考察

目的:对阿霉素脂质体冻干工艺进行考察。方法:以外观、再分散性、粒径为指标,对冻干工艺中参数进行优化。结果:优化的冻干工艺为-75℃预冻24h,升温至-25℃保持16h,再升温至20℃持续8h,选择10%海藻糖作为阿霉素脂质体的冻干保护剂。结论:通过优化冻干工艺参数,所得的阿霉素脂质体冻干制品外观平整、质地疏松,加水后能迅速分散均匀。     

聚(2-乙基-2-噁唑啉)修饰超氧化物歧化酶模拟物脂质体冻干制剂的制备

目的:制备聚(2-乙基-2-噁唑啉)(PEOZ)修饰超氧化物歧化酶(SOD)模拟物脂质体的冻干制剂。方法:通过考察预冻方式、预冻时间、真空干燥时间及联合冻干保护剂的种类及比例等优化冻干工艺,并测定所制制剂的水化复溶时间、粒径和包封率。结果:以10%乳糖+1%甘露醇+10%海藻糖作为联合冻干保护剂,并以外加方式加入PEOZ修饰SOD模拟物脂质体中,快速冷冻5h,真空干燥30h,可得到外观光洁、平整的目标冻干制剂;其水化复溶时间为(10±1)s,粒径为(159.3±10.2)nm,包封率为86.25%(RSD=3.26%,n=6)。结论:该优化冻干工艺质量可控,重复性好。     

去氢骆驼蓬碱脂质体冻干剂粉的制备工艺优选

目的:制备含有不同冻干保护剂的N-三甲基壳聚糖(TMC)包衣去氢骆驼蓬碱脂质体(TMC-HM-LP)的冻干粉,并筛选其最佳制备工艺。方法:用"薄膜分散-pH梯度法"制备去氢骆驼蓬碱脂质体,并采用孵育包衣法、低温高速离心法和结合高效液相色谱(HPLC)定量方法测定其包衣脂质体的包封率;以其冻干粉的外观在冻干前和复溶后脂质体的粒径、包封率作为对比指标,优选出最佳的冻干工艺以及冻干保护剂的种类及比例。结果:以葡萄糖-乳糖-甘露醇(2:1:0.5)作为冻干保护剂,通过"分步预冻"的方法和-80℃冷冻干燥技术得到的TMC-HM-LP外观良好,冻干前后粒径和包封率变化较小。结论:采用冷冻干燥技术并结合冻干保护剂的优选,可显著提高包衣脂质体的稳定性。     

尼莫地平鼻用冻干脂质体的制备及大鼠鼻黏膜吸收

采用改良乙醇注入法制备了尼莫地平脂质体，运用均匀设计试验优化了脂质体处方，并考察了冷冻干燥工艺与处方因素对其冻干脂质体性质的影响。在优化冻干工艺条件下，甘露醇和蔗糖合用为冻干保护剂，可得到外观良好、易于重建的冻干脂质体，冻干前后的药物包封率分别为97．1％和96．2％，粒径分别为175．1nm和227．9nm。-20℃及4℃贮存3个月，粒径和包封率无显著变化。采用大鼠在体鼻腔循环灌流法，考察了尼莫地平鼻用脂质体及其冻干重建制剂的鼻黏膜吸收规律。结果表明不同药物浓度脂质体及冻干重建脂质体的鼻黏膜吸收速率常数K无显著性差异，药物吸收呈一级动力学特征。     

冻干保护剂和复水溶液对HB-Ⅰa脂质体包封率的影响

目的:研究不同保护剂种类与浓度、不同复水溶液对HB-Ⅰa脂质体冻干前后包封率的影响.方法:按不同配方进行了18组对比实验,通过比较各组脂质体冻干前后包封率,优选较好的HB-Ⅰa脂质体冻干工艺.结果:在对HB-Ⅰa脂质体包封率的提高与冻干保护方面,蔗糖及甘氨酸所组成的二元保护剂显示了较好的效果;在保护剂使用过程中,过高或过低的蔗糖浓度对提高冻干HB-Ⅰa脂质体的包封率不利;在复水溶液的使用方面,当保护剂蔗糖存在时,冻干后缓冲液复水较纯水复水包封率高.结论:以蔗糖-甘氨酸-卵磷脂-胆固醇-HB-Ⅰa(4:0.8:1:0.5:0.2)的配方配制的HB-Ⅰa脂质体包封率冻干前可达91.1%,冻干后可达85.6%.     

多西他赛脂质体冻干粉的制备及质量评价

采用薄膜分散法结合冷冻干燥工艺制备多西他赛脂质体冻干品.采用正交试验,以包封率为指标优化处方,并考察了形态、粒径、包封率、体外释放和稳定性.结果表明,按优化处方制得的脂质体冻干品复溶后颗粒呈球形,平均粒径为(167.1±71.2)nm,平均包封率为(85.9±0.6)%;24h累积释放70.3%,释放曲线符合Weibull方程.多西他赛脂质体冻干品4℃放置3个月稳定性良好.     

灯盏花素脂质体的制备工艺

目的研究灯盏花素脂质体的制备工艺。方法采用薄膜蒸发-探头超声法和冷冻干燥法制备灯盏花素脂质体,在单因素考察基础上采用正交试验设计。以包封率为评价指标,筛选脂质体制备的最佳工艺条件。冻干品水合后,在电镜下观察灯盏花素脂质体的形态,利用马尔文测定仪测定脂质体的粒径,用RP-HPLC法测定其包封率。结果灯盏花素脂质体的最佳工艺处方为药脂比1∶5,SPC∶CH为2∶1,二氯甲烷用量为10 ml。冻干保护剂蔗糖用量为10%。制备3批脂质体,包封率平均为87.5%,平均粒径为378.3 nm。结论所制脂质体包封率较高,粒径分布较均匀。     

阿苯达唑纳米脂质体冻干粉的制备及性质考察

目的:制备阿苯达唑纳米脂质体冻干粉并对其性质进行考察。方法:利用冷冻干燥法制备阿苯达唑纳米脂质体冻干粉,以粒径、包封率联合外观、再分散性为指标,采用单因素试验联合正交试验筛选冻干处方工艺。考察冻干前、后脂质体的形态学变化、粒径、Zeta电位、水分含量、4℃下12个月的稳定性。结果:采用外加冻干保护剂的总量为10%,其中葡萄糖-海藻糖-甘露醇配比为1.0∶1.0∶3.0,以速冻的方式,于-35℃冰箱预冻18 h,冷冻干燥48 h获得冻干粉。与冻干前比较,冻干后脂质体形态未发生明显变化,可见清晰的磷脂双分子层膜结构;冻干前、后脂质体的粒径分别为(208.63±1.04)、(223.04±2.02)nm,Zeta电位分别为(-15.6±0.04)、(-19.4±0.06)m V,包封率分别为(94.62±0.49)%、(91.10±0.46)%(n=3);与脂质体比较,脂质体冻干粉在4℃下12个月较稳定。结论:成功制得阿苯达唑纳米脂质体冻干粉,其稳定性优于阿苯达唑纳米脂质体,冻干工艺可行。     

The effects of lyophilization on the stability of liposomes containing 5-FU

Multilamellar liposomes containing 5-fluorouracil (5-FU) were prepared by modified lipid film hydration method and were lyophilized with or without saccharose as cryoprotectant. The effect of lyophilization on the stability of liposomes was evaluated by comparing the vesicle size, encapsulation efficiency and the drug release rate before and after lyophilization/rehydration. The process of lyophilization, without cryoprotectant, resulted in particle size increase and significant content leakage. By the addition of saccharose, the lipid bilayers become more stable and less permeable to the encapsulated drug, saccharose imparted 5-FU retention of about 80% after lyophilization/rehydration. Freeze-drying did not affect the particle size of liposomes containing saccharose as cryoprotectant. The drug release profiles of rehydrated liposomes followed Higuchi's square root model. Also, the obtained release profiles were all biphasic: a rapid initial drug release phase (burst release of the portion of the drug that leaked out of liposomes during the lyophilization) was followed by a slower, approximately constant drug release phase (zero-order kinetics).     

新藤黄酸脂质体冻干粉的制备及其包封率测定

目的制备新藤黄酸脂质体冻干粉并测定其包封率。方法采用薄膜-超声法结合冷冻干燥法制备新藤黄酸脂质体冻干粉,以冷冻超速离心-高效液相色谱法测定包封率。结果电镜下观察所制备的脂质体形态规整,平均粒径为128.30 nm,包封率为83.74%。结论此法制备了包封率较高的新藤黄酸冻干脂质体。     

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。     

A novel approach to the pulmonary delivery of liposomes in dry powder form to eliminate the deleterious effects of milling

The effect of lyophilization and jet-milling on liposome integrity was investigated as a function of their ability to retain the encapsulated model drug on reconstitution of the dry products. The encapsulation efficiencies of the lyophilized and jet-milled formulations were determined at various concentrations of lactose. Lyophilization resulted in considerable leakage of the model drug at lower concentrations of lactose, and jet-milling further augmented the leakage for all the lyophilized formulations, with optimum retention obtained for formulations containing at least 10:1 molar ratio of lactose/lipid. In an attempt to overcome the deleterious effects of lyophilization and jet-milling, the feasibility of formulating phospholipid-based powders that result in spontaneous formation of liposomes in an aqueous environment has been investigated. Partitioning of three model drugs (viz., ciprofloxacin, CM3 peptide, and salbutamol sulfate) between the aqueous phase and spontaneously formed liposomes was determined in terms of encapsulation efficiency. The effects of several parameters, including lactose concentration, lipid composition, and lipid concentration on the encapsulation efficiency of these model drugs were investigated. The spontaneous formation of liposomes on dispersion of phospholipid-based powder formulations was further evidenced by freeze-fracture scanning electron microscopy. This novel approach for the delivery of liposomes in dry powder form appears promising because lyophilization is not involved and jet-milling of these powder formulations did not impact encapsulation efficiency. Jet-milled phospholipid-based powder formulations showed high encapsulation efficiencies of 96.2 +/- 1.4% for ciprofloxacin, 100% for CM3 peptide, and 45.3 +/- 3.1% for salbutamol sulfate compared with a high amount of leakage (> 50%) observed due to jet-milling of lyophilized liposome formulations encapsulating ciprofloxacin.     

芹菜素囊泡的制备及理化性质考察

目的筛选合适的非离子表面活性剂,制备芹菜素囊泡,并考察其体外理化性质和冻干工艺。方法采用Tween80和Myrij52为成囊材料,建立了乙醇注入法制备芹菜素囊泡的制备工艺;采用微柱离心法测定芹菜素囊泡的包封率,并考察不同处方因素对包封率的影响;经正交设计得到最优处方;对囊泡的粒径、外观、稳定性等理化性质及体外释放行为进行研究,分别以外观、粒径和渗漏率为指标对冻干工艺进行初步考察。结果乙醇注入法获得囊泡包封率为(69.48±2.5)%,平均粒径为(148±5.03)nm,透射电镜下观察显示呈类球形,4℃下密封保存3个月包封率为(54.25±3.7)%、渗漏率为21.9%,在pH值为7.4的磷酸盐缓冲液中体外释药行为符合一级动力学方程。以葡萄糖和甘露醇(质量比1∶1)为冻干保护剂,预冻时间为3 h,干燥时间为30 h。结论该制剂制备方法简单,制备的囊泡包封率较高,粒径较小,体外具有明显的缓释作用,冻干制剂外观饱满,粒径和包封率变化较小,可以明显提高囊泡的体外稳定性。     

Injectable nimodipine-loaded nanoliposomes: preparation, lyophilization and characteristics

The main purpose of this study was to prepare nimodipine-loaded nanoliposomes for injection and evaluate their characteristics after lyophilization. Nimodipine-loaded nanoliposomes were prepared by the emulsion-ultrasonic method with sodium cholesterol sulfate (SCS) as the regulator and then lyophilized by adding different cryoprotectants. SCS was used as a blender of regulator and surfactant and helped to prepare smaller liposomes due to the steric hindrance of the sulfate group. The results showed that nimodipine-loaded nanoliposomes with a 20:1 of egg yolk lecithin PL-100M vs. SCS ratio had a particle size of 86.8±42.007 nm, a zeta potential of -13.94 mV and an entrapment efficiency (EE) of 94.34% and could be stored for 12 days at 25°C. Because of the good bulking effect of mannitol and the preservative effect of trehalose, they were used to obtain suitable lyophilized nanoliposomes. The lyophiles containing 10% mannitol and 20% trehalose had a good appearance and a slightly altered particle size after rehydration. In addition, the lyophilized products were characterized by differential scanning calorimetry, X-ray diffraction and scanning electron microscopy, which confirmed the morphous state of trehalose, mannitol and the mixture. Trehalose could inhibit mannitol crystallization to some extent. The drug release from nanoliposomes before and after lyophilization in pH 7.4 phosphate buffer containing 30% ethanol was also examined and both profiles were found to fit the Viswanathan equation. This means that the drug release was controlled by the pore diffusion resistance.     

5-氟尿嘧啶壳聚糖纳米粒冻干粉的制备

目的 为研究5-氟尿嘧啶壳聚糖纳米粒冻干粉的制备工艺,提高5-氟尿嘧啶壳聚糖纳米粒的稳定性。方法 首先制备5-氟尿嘧啶壳聚糖纳米粒,并以外观和再分散性为指标,进行单因素考察并利用正交实验优化工艺。结果 5-氟尿嘧啶壳聚糖纳米粒冻干粉的最佳制备工艺为预冻时间24 h、冻干保护剂为甘露醇、用量为80 mg、浓度为10%。冻干前后包封率差异无统计学意义（P>0.05）,冻干后的粒径和冻干前相比有一定增大。结论 5-氟尿嘧啶壳聚糖纳米粒冻干粉有望成为新剂型。     

米非司酮脂质体的制备及性质考察

目的研制米非司酮脂质体。方法采用薄膜分散法制备米非司酮脂质体,应用葡聚糖凝胶法测定包封率,并考察该脂质体的形态、粒径、稳定性和体外释放特性。结果所制备的米非司酮脂质体包封率达85．2％,平均粒径为112．7nm,4℃冷藏保存3个月稳定性良好,具有体外缓释作用。结论米非司酮脂质体制备工艺简单可行,脂质体制剂学性质稳定。     

盐酸5-氨基酮戊酸脂质体的制备与表征

目的 研究盐酸5-氨基酮戊酸(5-ALA)脂质体处方组成及制备工艺. 方法 采用薄膜分散 pH梯度法制备5-ALA脂质体,以包封率为评价指标进行正交实验筛选出最佳处方,采用高效液相色谱(HPLC)法测定其包封率. 并对其粒径、电位等理化性质进行研究. 结果最佳处方工艺为：卵磷脂与胆固醇的质量比为6：1,卵磷脂与5-ALA质量比为6：1,孵育温度为60 ℃. 所制脂质体为乳白色,平均粒径为100 nm,Zeta电位为-40 mV,平均包封率为65.0%. 结论 该制备方法 得到的5-ALA脂质体处方合理,工艺可行,包封率较高.