洛伐他汀自组装前体脂质体的制备及其理化性质的研究

目的:为研究洛伐他汀新剂型,制备洛伐他汀新型前体脂质体,并对其质量进行考察。方法:采用一种新型前体脂质体制备方法将洛伐他汀制成自组装前体脂质体,对水合后脂质体的形态、粒径、Zeta电位、包封率、自组装速度、稳定性等进行考察,验证这种新型前体脂质体制备方法用于制备洛伐他汀脂质体的可行性。结果:所形成的洛伐他汀脂质体包封率为95.4%±6.7%,平均粒径为(327.4±29.6)nm,Zeta电位值为-(22.4±1.5)mV。洛伐他汀自组装前体脂质体可在60 s内自发形成脂质体并达到分散平衡;以人工胃液为稀释介质,洛伐他汀脂质体在12 h内稳定。结论:采用新型前体脂质体制备方法可将洛伐他汀制成洛伐他汀脂质体,形成的脂质体包封率较高且具有良好的稳定性。     

盐酸小檗碱前体脂质体的制备及理化性质研究

目的制备盐酸小檗碱前体脂质体,并对其理化性质进行考察。方法采用薄膜载体沉积法制备盐酸小檗碱前体脂质体,正交实验优选处方;透射电镜观察形态;马尔文激光粒度仪测定粒径;高效液相色谱法测定包封率。结果电镜下观察脂质体形态多为圆形或椭圆形,平均粒径为741nm,包封率为(29.93±1.32)%。结论该方法制备工艺简单,易于工业化生产。     

载基因纳米阳离子脂质体前体制剂的制备及性质研究

目的:制备稳定的载反义寡核苷酸的阳离子脂质体前体制剂。方法:以磷脂-二油酰磷脂酰乙醇胺(dioleoylphophatidylethanolamine,DOPE)-十八胺-胆固醇为类脂成分,采用薄膜超声-挤压制备空白阳离子脂质体,吸附-冷冻干燥法制备载反义寡核苷酸阳离子脂质体前体。激光粒度仪测定冷冻干燥前后脂质体Zeta电位及粒径,透射电镜观察其形态,葡聚糖凝胶柱分离未包封的反义寡核苷酸,紫外法测定冻干前后的载药率。结果:海藻糖与甘露醇及甘氨酸为较好的冻干保护剂,制得的阳离子脂质体前体带正电荷,规则球形,大小较均匀,海藻糖作为保护剂复溶前后平均粒径为175和320 nm左右,复融前后Zeta电位值在+32和+40 mV左右,脂质体的载药率复溶前后分别为87.6%与83.21%。结论:海藻糖作为冻干保护剂,薄膜超声挤压法与冷冻干燥法结合,可成功制备反义寡核苷酸阳离子脂质体前体制剂,稳定性大大改善。     

依托泊苷隐形前体脂质体的构建及家兔体内药动学研究

构建依托泊苷隐形前体脂质体，并考察其在家兔体内的药动学。采用薄膜分散法构建窄白隐形脂质体；硫酸铵梯度法包封依托泊苷；结合真空冷冻干燥技术构建依托泊苷隐形前体脂质体。采用凝胶色谱法测定脂质体包封率；透射电镜观察脂质体的形态；电泳光散射技术测定Zeta电位与粒径分布；以市售依托泊苷注射液和普通脂质体为参比制剂，评价其在家兔体内药动学特点。脂质体平均包封率为83．92％±3．65％，粒径为（124．5±26．9）nm，Zeta电位为（-39．50±1．04）mV，家兔单剂量静脉注射1．5mg／kg依托泊苷制剂后呈二室模型特征，依托泊苷隐形前体脂质体的T1/2β为（19．26±3．16）h，AUC为（26．04±3．53）μg／h／mL；注射液的T1/2β为（0．94±0．21）h，AUC为（0．98±0．26）μg／h／mL；普通脂质体的T1/2β为（7．99±1．36）h,AUC为（11．65±1．70）μg/mL。构建的隐形前体脂质体包封率高，且延长了依托泊苷在血液中的循环时间。     

卡铂前体脂质体的制备及安全性的初步评价

目的：制备卡铂前体脂质体,并对用药安全性进行初步评价.方法：采用薄膜挤压法制备卡铂脂质体,加入冻干支持剂冷冻干燥后得到卡铂前体脂质体.对豚鼠全身用药的过敏性、家兔全身用药的血管刺激性以及溶血性进行考察.结果：制备所得的卡铂前体脂质体水合后的包封率为72.0%,载药量为24.0%,平均粒径为125.1 nm.卡铂前体脂质体不引起豚鼠过敏反应,不引起家兔溶血和红细胞凝集反应,静脉注射对家兔血管无刺激性.结论：制备所得的卡铂前体脂质体有较高的包封率和载药量,水合后粒径均匀,形态圆整,且具有较好的用药安全性.     

Physicochemical properties and antioxidant activity of gamma-oryzanol-loaded liposome formulations for topical use

The objective of this study is to prepare the γ-oryzanol-loaded liposomes and investigate their physicochemical properties and antioxidant activity intended for cosmetic applications. Liposomes, Composing phosphatidylCholine (PC) and Cholesterol (Chol), CHAPS or sodium taurocholate (NaTC) were prepared by sonication method. γ-oryzanol-loaded liposomes were prepared by using 3, 5 and 10% γ-oryzanol as an initial concentration. The formulation factors in a particular type and composition of lipid and initial drug loading on the physicochemical properties (i.e., particle size, zeta potential, entrapment efficiency, drug release) and antioxidant activity were studied. The particle sizes of bare liposomes were in nanometer range. The γ-oryzanol-loaded liposomes in formulations of PC/CHAPS and PC/NaTC liposomes were smaller than PC/Chol liposomes. The incorporation efficiency of 10% γ-oryzanol-loaded PC/Chol liposomes was less than γ-oryzanol-loaded PC/CHAPS liposomes and PC/NaTC liposomes allowing higher in vitro release rate due to higher free γ-oryzanol in buffer solution. The antioxidant activity of γ-oryzanol-loaded liposomes was not different from pure γ-oryzanol. Both γ-oryzanol-loaded PC/CHAPS liposomes and PC/NaTC liposomes were showed to enhance the antioxidant activity in NHF cells. γ-oryzanol-loaded PC/Chol liposomes demonstrated the lowest cytotoxicity in NHF cells. It was conceivably concluded that liposomes prepared in this study are suitable for γ-oryzanol incorporation without loss of antioxidant activity.     

Proliposomes for oral delivery of dehydrosilymarin: preparation and evaluation in vitro and in vivo

Aim:

To formulate proliposomes with a polyphase dispersed system composed of soybean phospholipids, cholesterol, isopropyl myristate and sodium cholate to improve the oral bioavailability of dehydrosilymarin, an oxidized form of herbal drug silymarin.

Methods:

Dehydrosilymarin was synthesized from air oxidation of silymarin in the presence of pyridine, and proliposomes were prepared by a film dispersion-freeze drying method. Morphological characterization of proliposomes was observed using a transmission electron microscope. Particle size and encapsulation efficiency of proliposomes were measured. The in vitro release of dehydrosilymarin from suspension and proliposomes was evaluated. The oral bioavailability of dehydrosilymarin suspension and proliposomes was investigated in rabbits.

Results:

The proliposomes prepared under the optimum conditions were spherical and smooth with a mean particle size in the range of 7 to 50 nm. Encapsulation efficiency was 81.59%±0.24%. The in vitro accumulative release percent of dehydrosilymarinloaded proliposomes was stable, which was slow in pH 1.2, and increased continuously in pH 6.8, and finally reached 86.41% at 12 h. After oral administration in rabbits, the relative bioavailability of proliposomes versus suspension in rabbits was 228.85%.

Conclusion:

Proliposomes may be a useful vehicle for oral delivery of dehydrosilymarin, a drug poorly soluble in water.     

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.     

Formulation Development and in vitro Characterization of Proliposomes for Topical Delivery of Aceclofenac

Non-steroidal antiinflammatory drugs are routinely prescribed for the patients with rheumatic disease and such patients are at increased risk of serious gastrointestinal complications, when non-steroidal antiinflammatory drugs administered by oral route. The aim of the present study was to develop and characterized a vesicular drug carrier system (proliposome) for topical delivery of aceclofenac to overcome the problems related with oral route. Aceclofenac proliposome were prepared by the film-deposition on carriers method and characterized for size and surface morphology, drug content in both proliposomes and liposomal system, percent yield, in vitro drug release studies and drug permeation studies. The prepared system was also characterized for drug-excipients interaction by Fourier transform infrared spectrophotometer and stability studies. The size and surface morphology were studied using optical microscopy, scanning electron microscopy and transmission electron microscopy. A spherical shape of reconstituted aceclofenac liposome with an average vesicular size of about 500 nm was observed in photomicrographs. The maximum entrapment efficiency of reconstituted liposomes was 80.31% whereas the drug content in proliposomes was found to be more than 90%. In vitro release of drug was significantly retarded indicating sustained release of aceclofenac from proliposomes. Stability study was performed at various temperatures indicating that aceclofenac proliposomes are stable at lower temperature.     

Physico-chemical characteristics of methotrexate-entrapped oleic acid-containing deformable liposomes for in vitro transepidermal delivery targeting psoriasis treatment

This study aimed to investigate the physico-chemical characteristics and in vitro permeability of methotrexate (MTX)-entrapped deformable liposomes prepared from phosphatidylcholine (PC) and oleic acid (OA), comparing with those of MTX-entrapped conventional liposomes prepared from PC and cholesterol (CH). Two formulations of MTX-entrapped PC2:CH1 and PC9:CH1 liposomes and one formulation of MTX-entrapped PC2.5:OA1 liposomes were prepared. The size, size distribution, zeta potential, thermal properties, entrapment efficiency, stability, and in vitro permeability across a porcine skin of the MTX-entrapped liposomes were evaluated. All liposome formulations showed a narrow size distribution with the size range of 80-140 nm which is appropriate for the skin permeability. The percentage of MTX loading, entrapment efficiency and the stability of MTX-entrapped PC2:CH1 and PC9:CH1 liposomes were slightly higher than those of MTX-entrapped PC2.5:OA1 liposomes. However, the MTX-entrapped PC2.5:OA1 liposomes enhanced the skin permeability characterized by the higher concentration and flux of MTX diffused across or accumulated in the epidermis and dermis layers of porcine skin. The enhanced permeability of MTX-entrapped PC2.5:OA1 liposomes was explained by 2 mechanisms: (1) the deformable and elasticity characteristics of OA-containing liposomes and (2) a property as a skin penetration enhancer of OA. This suggested that the PC2.5:OA1 deformable liposome was one of promising candidates to enhance the permeability of MTX for the treatment of psoriasis.     

Elastic liposomes containing benzophenone-3 for sun protection factor enhancement

This work was focused on the loading of benzophenone-3 in elastic liposomes composed of egg phosphatidylcholine and cholesterol, prepared by the Bangham method. Samples were characterized in terms of particle size, polydispersity index (PI), zeta potential, encapsulation efficiency and in vitro photoprotection properties. The extrusion of liposomes loading benzophenone-3 produced reduced-size (100?nm) elastic liposomes with a PI of 0.2. The active was loaded with a concentration of 20.34% (m/m) revealing changes in the ultraviolet properties after loading. On the basis of these results, it can be anticipated that liposomes are able to improve sun protector factor in vitro compared the free active.     

Factors influencing the tissue distribution of coenzyme Q10 intravenously administered in an emulsion to rats: emulsifying agents and lipoprotein lipase activity

The tissue distribution of coenzyme Q10 (CoQ10) administered intravenously in an emulsion prepared with egg yolk phosphatidylcholine (PC), egg yolk sphingomyelin (SPM) or a combination of PC and a polyoxyethylene derivative of hydrogenated castor oil (HCO-60) (PC + HCO-60) was investigated. The disappearance from the plasma of CoQ10 administered in three different emulsions of lipid particle size less than 0.5 micron varied with the particular emulsifier. Its disappearance occurred most rapidly from the PC emulsion; with the addition of HCO-60, its disappearance was much slower. In the reticuloendothelial system, the concentration of CoQ10 was higher in the spleen, for both the SPM and PC + HCO-60 emulsions than for the PC emulsion. HCO-60 reduced the CoQ10 distribution in the liver from the PC emulsion. Differences in disappearance rates from the plasma are thus considered to be due to the extent of CoQ10 distribution in the liver. CoQ10 concentration in the heart, a target organ, was greatest with the PC emulsion. Its distribution was related to lipoprotein lipase (LPL) activity in this organ. The effects caused by HCO-60, however, could not be explained by LPL activity alone. CoQ10 distribution in the adrenal gland and kidney can be explained partly by LPL activity but in the presence of HCO-60, the distribution mechanism apparently involves other factors.     

Elastic liposomes containing benzophenone-3 for sun protection factor enhancement

This work was focused on the loading of benzophenone-3 in elastic liposomes composed of egg phosphatidylcholine and cholesterol, prepared by the Bangham method. Samples were characterized in terms of particle size, polydispersity index (PI), zeta potential, encapsulation efficiency and in vitro photoprotection properties. The extrusion of liposomes loading benzophenone-3 produced reduced-size (100?nm) elastic liposomes with a PI of 0.2. The active was loaded with a concentration of 20.34% (m/m) revealing changes in the ultraviolet properties after loading. On the basis of these results, it can be anticipated that liposomes are able to improve sun protector factor in vitro compared the free active.     

槲皮素前体脂质体的质量考察

目的制备液体型槲皮素前体脂质体,并对制剂质量进行考察。方法采用一种新型前体脂质体制备方法制备液体型槲皮素前体脂质体,将脂质体膜材和药物等以一定比例溶于分散介质中,形成一种无水的澄明溶液。考察其水合后粒子形态、粒径、电位、包封率及自组装速度等理化性质,并评价其体外释药性质。结果槲皮素前体脂质体遇水即可快速自组装成纳米级含药脂质体混悬液,水合后形态多为类球形,平均粒径为228.7nm,Zeta电位为21.2 mV,包封率可达90%以上,体外释药符合Higuchi方程。结论槲皮素口服前体脂质体制备工艺简单可行,包封率高,具有一定的缓释效果。     

粒径和质量浓度对辅酶Q_(10)脂质体光解动力学的影响

目的为辅酶Q10脂质体的进一步研究提供参考。方法制备不同粒径和不同质量浓度的辅酶Q10脂质体,进行光照加速试验,考察脂质体中辅酶Q10的光解规律。结果辅酶Q10脂质体的光解符合一级降解动力学。平均粒径为309.4、125.9、64.8 nm的1.0 g.L-1辅酶Q10脂质体的光解半衰期分别为55.4、45.3、34.3 h;药物质量浓度为1.0、0.5、0.1 g.L-1辅酶Q10脂质体(309.4 nm)的光解半衰期分别为55.4、31.1、19.3 h。结论辅酶Q10脂质体的光解具有一定的粒径和质量浓度依赖性,粒径越大,起始质量浓度越高,光解半衰期越长,光保护效果越明显。     

新型前体脂质体载药及影响因素考察

Aim A new proliposomal technology was used to trap several drugs, such as tegafur, silymarin, cistanosides, oleanolic acid. And then these proliposomal characters were studied. Methods These proliposomes formed liposomes after mixing with water. And then the liposomal morphology was determined by electron microscope, and the liposomal particle size determined by particle sizes instrument. The trap efficiency was determined by the column chromatography, and then the influence factors on the trap efficiency were investigated. Results The liposomes looked round, some with multiply layers, the particle was small, and the ξ potential was about -30 mV. The trap efficiency changed with the partition coefficient and pH. When the partition coefficient and pH increased, the trap efficiency increased. Furthermore, the trap efficiency was not influenced by the molecular weight. Conclusion This kind of liposomal technology trapped the drugs efficiently, and the lipophilic drugs were trapped more easily. Some Chinese traditional drugs could be trapped too.     

盐酸利多卡因多囊脂质体的制备和质量评价

目的:制备具有缓释特性的盐酸利多卡因多囊脂质体,考察其理化性质。方法:以卵磷脂和胆固醇为膜材,采用复乳法制备盐酸利多卡因多囊脂质体,用透射电镜观察其外观形态,用激光粒度分析仪测定粒径,检测包封率和体外释药特性。结果:盐酸利多卡因多囊脂质体的外观形态圆整、规则,粒径分布在300～700nm及1～6μm两区域,包封率为(27.10±0.66)%。多囊脂质体在pH 7.4的磷酸盐缓冲液中,24h的累积释药百分率为(92.7±3.6)%。结论:盐酸利多卡因多囊脂质体具有一定的缓释特性。     

A novel method to prepare liposomes containing amikacin.

This work describes a novel method to prepare liposomal amikacin composed of soyabean lecithin and cholesterol; these were also prepared using two other methods (cast film method and proliposome method). Encapsulation efficiency was evaluated. Liposomes prepared by the new method, which combines the method of preparing proliposomes with freeze-drying, had the highest encapsulation efficiency. The influence of drug to lipid ratio on the encapsulation efficiency was investigated. The in vitro efflux of amikacin from liposomes with different lecithin: cholesterol ratios was also investigated.     

Solid dispersion and effervescent techniques used to prepare docetaxel liposomes for lung-targeted delivery system: in vitro and in vivo evaluation

A lung-targeting liposomal docetaxel was developed to improve therapeutic index and to reduce side effects. Docetaxel proliposomes composed of docetaxel/Tween-80/Phospholipon 90H/cholesterol/citric acid at molar ratio of 0.18:0.09:3.78:3.78:91.17 were prepared by solid dispersion technique, and then were hydrated with NaHCO₃ solution to obtain docetaxel liposomes by effervescent technique. The stability of proliposomes containing docetaxel, characterization and evaluation of lung-targeting effect of docetaxel liposomes in rabbit were studied. Docetaxel proliposomes were stable at 6?±?2°C for at least 12 months. The particle size, zeta-potential, and entrapment efficiency of the resulted liposomes were 1011?±?22?nm, ?23.7?±?0.26?mv, and 90.12?±?0.36%, respectively. As far as the targeting parameters are concerned, the relative intake rate (R_e) and the ratio of peak concentration (C_e) of lung were 28.91 and 74.28, respectively. Compared with liver, spleen, and kidney, the ratios of targeting efficacy (T_e)_liposomes to (T_e)_injection of lung were increased by a factor of 3.16, 23.00, and 27.83, respectively. In conclusion, the negatively charged docetaxel liposomes with diameter of about 1 µm described in this study have favorable lung-targeting effect and are a promising lung-targeting carrier.     

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。