槐定碱/苦参碱二元醇脂质体不同制备方法的比较

目的:以包封率、粒径分布和Zeta电位为指标,探讨槐定碱/苦参碱(sophoridine/matrine,S/M)二元醇脂质体3种不同制备方法的适宜性。方法:用被动载药法(Ⅰ法)、主动载药法(Ⅱ法)和被动加主动载药法(Ⅲ法)分别制备了S/M的二元醇脂质体,并考察了3种方法制备的不同药脂比二元醇脂质体的包封率、粒径分布和Zeta电位。结果:当药脂比为1∶1时,用Ⅰ法制备的S二元醇脂质体包封率最高,用Ⅲ法制备的M二元醇脂质体包封率最高;用Ⅱ法制备时,2种碱的包封率均随药脂比的减小而增大;而采用Ⅰ/Ⅲ法时2种碱的包封率均随药脂比的减小而减小。结论:制备S/M二元醇脂质体时,不同的方法和药脂比对其包封率有显著影响。S二元醇脂质体适宜用Ⅰ法制备,而M二元醇脂质体则适宜用Ⅲ法。     

灯盏花素纳米脂质体包封率测定方法研究

灯盏花素(breviscapine)是菊科植物短葶飞蓬(Erigeron breviscapus(vant.)Hand-Mazz)中提取的黄酮类有效成分。临床多用于治疗脑梗死、脑血栓、脑出血等。将药物制成脂质体,能帮助药物进入脑部,提高治疗指数。灯盏花素水溶性较差,直接溶于注射用水有一定困难,将其制成脂质体可以解决其难溶问题,提高药物稳定性及载药量,同时提高药物的靶向性及疗效。包封率是脂质体质量评定的重要指标,本实验建立了灯盏花素纳米脂质体包封率的测定方法,该法操作简单、可行、准确性较好。     

表面带电脂质体载药及对小鼠体内弓形虫的作用

表面电性是脂质体重要性质之一,本文用1,8-ANS作为探剂,采用荧光法和电泳法测定脂质体的表面电位。离子性药物的包封率及渗漏速度受脂质体表面电性影响,实验表明,脂质体表面电性和药物离子电性相反时,包封率高,渗漏速度慢。以小鼠感染弓形虫做模型,进行体内试验,证明脂质体载药显著优于游离药物的治疗效果。因弓形虫是细胞内寄生的原虫,凡有利于药物入胞的方法,可提高其疗效。此种模型试验简便、准确,其结果对载抗癌药脂质体研究可以借鉴。     

脂质体气雾剂的研究进展

载药脂质体(liposome)是指药物包封于类脂质双分子层内而形成的微型泡囊。由于药物被脂质体包封后具有靶向性、缓释性、细胞亲和性和组织相容性等优点,可以提高药物的疗效,增加稳定性,减少不良反应,所以成为人们探讨研究的热点。目前在脂质体的众多给药途径中,肺部给药由于其刺     

八聚精氨酸修饰的载紫杉醇脂质体的制备工艺研究

目的 研究八聚精氨酸(R8)修饰的载紫杉醇脂质体的制备工艺.方法 采用有机相反应法,将R8修饰到脂质体表面,并以薄膜分散-探头超声法制备载紫杉醇脂质体,以细胞摄取、粒径、PDI、包封率为主要指标对磷脂/胆固醇、药脂比、水化液种类、R8密度、DSPE-PEG2000密度进行筛选,进一步优化处方.结果 最优处方为磷脂-胆固醇2∶1、药脂比1∶40、水化液为PBS(pH6.5)、R8密度5％、DSPE-PEG2000密度3％,所制脂质体的粒径为156 ±2 nm,PDI＝ 0.25,包封率为80.87％±8.9％.结论 成功制备了八聚精氨酸(R8)修饰的载紫杉醇脂质体.     

牛血清白蛋白/壳聚糖双层修饰载肉桂醛脂质体的制备

目的 制备牛血清白蛋白(BSA)/壳聚糖(CTS)双层修饰的载肉桂醛(CA)脂质体(BSA/CTS-Lip-CA),以提高脂质体纳米粒子对药物的缓释效果和储存稳定性.方法 采用薄膜分散法制备载药脂质体(Lip-CA)和空白脂质体(Lip-Blank),然后利用静电吸附作用制备CTS修饰脂质体(CTS-Lip-CA)和B...     

脂质体主动载药及其研究进展

脂质体主动载药法是在制备脂质体的传统方法上引入pH梯度法等而形成的一种新的制备方法，使得制备高包封率脂质体成为可能，较好地改变了难以制备水溶性药物脂质体的局面。本文主要对主动载药法的分类、起源及研究进展作一综述。     

TPGS修饰的紫杉醇pH敏感脂质体处方优化及制剂学性质的考察

目的筛选生育酚聚乙二醇琥珀酸盐(tocopheryl polyethylene glycol 1000 succinate,TPGS)与紫杉醇(paclitaxe,PTX)的质量比例,对TPGS修饰的PTX p H敏感脂质体进行处方优化及制剂学性质的考察。方法采用噻唑蓝(methyl thiazolyl tetrazolium,MTT)法以逆转耐药为指标筛选TPGS与PTX的质量比;采用薄膜分散法制备脂质体,对制剂进行单因素考察,并以包封率、载药量和24 h稳定性(24 h包封率和24 h载药量)为指标,应用星点设计-效应面法对处方及工艺进行优化。测定脂质体的粒径、Zeta电位和体外释药行为。结果 TPGS与PTX的最优质量比例为1:1,制剂的最优处方和工艺确定为m(dioleoyl phosphoethanolamine,DOPE):m(cholesteryl hemisuccinate,CHEMS):m(hydrogenated soybean phospholipids,HSPC)=6:4:2,m(TPGS):m(PTX)=1:1,投药量:1.02 mg,水化时间:12.29 min,水化温度:35℃,超声条件:200 W,5 min。脂质体的包封率为83.54%,载药质量分数为6.52%,24 h包封率和载药质量分数分别为80.03%和5.97%,稳定性良好。脂质体粒径为(115.8±2.03)nm,Zeta电位为(-56.47±1.55)m V。在p H 5.0条件下脂质体释药速率明显增加。结论星点设计成功实现了对处方的优化,且模型预测性良好;最优处方制备的脂质体具有较高的包封率和载药量,粒径较小且分布均匀,体外释放表现出一定的p H敏感性。     

月桂酸二乙醇酰胺修饰利福喷丁脂质体的制备、性质及肺部给药

目的制备表面活性剂修饰利福喷丁(RIF)脂质体，进行该脂质体水化性能、载药量、释药速度和肺部给药研究。方法采用薄膜超声法制备利福喷丁脂质体，比较月桂酸二乙醇酰胺(LDEA)，Tween 80和azone修饰利福喷丁脂质体的形态、包封率、释药速度和离体猪肺膜透过性，通过纤支镜进行肺部给药研究。结果RIF-LDEA脂质体粒径在15～50 nm，包封率为83.0%，表观透膜系数Kp为44.29；LD₅₀为675 mg·kg^-1。结论LDEA修饰使利福喷丁脂质体的载药量增加1倍、释药速度的可调性强及安全性好。经纤支镜介导灌注给药治疗肺内膜结核的效果显著。     

肺靶向吡非尼酮脂质体的制备及体外释药性质研究

目的：研究肺靶向吡非尼酮脂质体的制备方法并考察其体外释药性质。方法：采用薄膜分散法制备吡非尼酮脂质体;用D-甘露糖修饰脂质体并添加适量十八胺调节脂质体表面电荷;用紫外分光光度法测定包封率;用正交实验优化处方,用透析法考察药物体外释放性质。结果：制得的脂质体平均粒径为581.1nm,表面电荷为-20.61mV,包封率为81.1%,稳定性好。药物体外释药符合Weibull方程。结论：采用薄膜分散法,用D-甘露糖修饰并添加十八胺可制得具有较高包封率及稳定性的吡非尼酮脂质体,有助于提高吡非尼酮的肺靶向性。     

Alkylation activity and molecular properties of two antineoplastic agents that utilise indometacin and a conjugate of aspirin with 2-aminonicotinic acid to transport nitrogen mustard groups

BACKGROUND: Nitrogen mustard (N-mustard) compounds are considered important anticancer drugs. Various transporting agents have been utilised to carry N-mustard groups including coumarins, amides, polyaromatic molecules and cycloalkyl structures. N-mustards act as bifunctional alkylating agents that induce cross-linking within DNA strands and cytotoxic activity. Compounds that transport the N-mustard group in vivo can also express drug-likeness that can have advantages in clinical application. This study presents data on two anticancer drugs with N-mustard groups covalently attached to NSAIDs. METHODS: Two alkylating compounds were synthesised by covalently attaching a single N-mustard group to 2-2-acetoxybenzoylaminonicotinic acid (for compound I) and indometacin (for compound II). Molecular properties such as aqueous solubility, 1-octanol/water partitioning coefficient (log Kow), molar volume, polar surface area, 1-octanol/water partitioning at pH values other than human blood (log D) and the dermal permeability coefficient (Kp) were determined. The rate-order of reaction and rate constant of alkylation were determined by reacting compound I and compound II with a target compound having a primary amine group in buffered aqueous solution at blood pH 7.4 and 37 masculineC, and monitoring absorbance at 400nm. RESULTS AND C onclusion: Compounds I and II were stable at room temperature, soluble in water and effectively alkylated a nucleophilic primary amine target at physiological temperature and pH. The water solubility of compound I was considerably greater than that of compound II. Both compounds showed second-order rate order of alkylation and effectively alkylated a nucleophilic target under aqueous physiological conditions of pH 7.4 and 37 masculineC. Kp values for compounds I and II were determined to be 0.000786 cm/h and 0.024 cm/h, respectively. Both compound I and compound II had zero percent ionisation at pH 7.4, and compound I showed zero violations of the Rule of 5. Log P values for compounds I and II were 3.27 and 5.08, respectively. This study describes the benefits of antineoplastic agents with NSAID substituents that provide favourable pharmacological properties.     

Transferrin coupled liposomes as drug delivery carriers for brain targeting of 5-florouracil

Diseases and disorders of the brain are extremely difficult to treat pharmacologically because most drugs are unable to pass across the blood--brain barriers. Complex multi-strand tight junctions between adjacent cerebral endothelial cells and between choroid plexus epithelial cells form a physical barrier and prevent the passage of water soluble drugs from the blood into the brain, whereas the inward passage of lipid soluble drugs is restricted by drug efflux pumps which act as a functional barrier. In the present work, a transferrin-coupled liposomal system for brain delivery of 5-florouracil has been investigated.5-florouracil and (99m)Tc-DTPA bearing non-coupled liposomes were prepared by cast film method, which were coupled with the transferrin by incubating these liposomes with transferrin in the presence of the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride in saline phosphate buffer (pH 7.4). These liposomal systems were characterized for vesicle size, percent drug entrapment, and in vitro drug release. The size of the liposomes was increased on coupling with transferrin while percent drug entrapment reduced. The results of the in vitro release profile demonstrated that non-coupled liposomal formulation releases a comparatively higher percent (i.e. 74.8+/-3.21%) of drug than coupled liposomes. Results of in vivo study suggested a selective uptake of the transferrin-coupled liposomes from the brain capillary endothelial cells. In case of coupled liposomes, the level of radioactivity was 17-fold more as compared to the free radioactive agent and 13 times more with the non-coupled liposomes. Therefore, it could be concluded that using transferrin coupled liposomes the brain uptake of the drug could be enhanced.     

Native and β-cyclodextrin-enclosed curcumin: entrapment within liposomes and their in vitro cytotoxicity in lung and colon cancer

With a view to improving the solubility and delivery characteristics of poorly water-soluble drugs, we prepared β-cyclodextrin-curcumin (βCD-C) inclusion complexes (hydrophilic curcumin) and entrapped both native curcumin (hydrophobic) and the complexes separately into liposomes; these were then assessed for in vitro cytotoxicity in lung and colon cancer cell lines. Optimization of curcumin entrapment within βCD was achieved, with the resultant βCD-C complexes prepared by methanol reflux. Inclusion complexes were confirmed using UV spectroscopy, Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction. The water solubility of βCD-C complexes improved markedly (c.f. native curcumin) and successful entrapment of complexes into liposomes, prepared using a thin-film hydration approach, was also achieved. All the liposomal formulations were characterized for curcumin and βCD-C complex entrapment efficiency, particle size, polydispersity and stability at 2–8°C. Curcumin, βCD-C complex and their optimized liposomal formulations were evaluated for anticancer activity in lung (A-459) and colon (SW-620) cancer cell lines. All curcumin-containing formulations tested were effective in inhibiting cell proliferation, as determined via an MTT assay. The median effective dose (EC₅₀) for all curcumin formulations was found to be in the low µM range for both lung and colon cancer cell lines tested. Our results confirm that βCD inclusion complexes of poorly water soluble drugs, such as curcumin can be entrapped within biocompatible vesicles such as liposomes, and this does not preclude their anticancer activity.     

Transferrin coupled liposomes as drug delivery carriers for brain targeting of 5-florouracil

Diseases and disorders of the brain are extremely difficult to treat pharmacologically because most drugs are unable to pass across the blood–brain barriers. Complex multi-strand tight junctions between adjacent cerebral endothelial cells and between choroid plexus epithelial cells form a physical barrier and prevent the passage of water soluble drugs from the blood into the brain, whereas the inward passage of lipid soluble drugs is restricted by drug efflux pumps which act as a functional barrier. In the present work, a transferrin-coupled liposomal system for brain delivery of 5-florouracil has been investigated.

5-florouracil and ^99mTc-DTPA bearing non-coupled liposomes were prepared by cast film method, which were coupled with the transferrin by incubating these liposomes with transferrin in the presence of the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride in saline phosphate buffer (pH 7.4). These liposomal systems were characterized for vesicle size, percent drug entrapment, and in vitro drug release. The size of the liposomes was increased on coupling with transferrin while percent drug entrapment reduced. The results of the in vitro release profile demonstrated that non-coupled liposomal formulation releases a comparatively higher percent (i.e. 74.8±3.21%) of drug than coupled liposomes. Results of in vivo study suggested a selective uptake of the transferrin-coupled liposomes from the brain capillary endothelial cells. In case of coupled liposomes, the level of radioactivity was 17-fold more as compared to the free radioactive agent and 13 times more with the non-coupled liposomes. Therefore, it could be concluded that using transferrin coupled liposomes the brain uptake of the drug could be enhanced.     

Liposomes with nifedipine and nifedipine-cyclodextrin complex: calorimetrical and plasma stability comparison

Inclusion complexes of nifedipine with 2-hydroxypropyl-ß-cyclodextrin (HPβCD) were formed by the spray- and freeze-drying methods. Nifedipine or its inclusion complexes (Nifedipine-CD complex I and II) were incorporated into liposomes prepared by the ethanol injection method. The highest entrapment value (77.7% of the starting material) was achieved for liposomes with N-CD complex II. The interaction of nifedipine with lipid bilayers was measured calorimetrically. DPPC liposomes mixed with nifedipine or N-CD complex II showed a slight shift of the transition temperature of DPPC towards lower temperatures compared to DPPC liposomes alone or mixed with HPßCD. However, with nifedipine, an additional transition peak was seen at lower temperatures in the second and all subsequent scans which could not be detected for the N-CD complex. Plasma stability studies showed that liposomes containing N-CD complex II are more stable than liposomes containing nifedipine. Encapsulation of drug-cyclodextrin complexes into liposomes can increase the entrapment of the lipophilic drug and reduce its release from the carrier.     

Effects of loading procedures of magnetic nanoparticles on the structure and physicochemical properties of cisplatin magnetic liposomes

The effects of different loading procedures of magnetic nanoparticles (MNs) on the structure and physicochemical properties of cisplatin magnetic liposomes were investigated by X-ray diffraction, infrared spectroscopy, transmission electron microscopy, and fluorescence spectroscopy. 1, 2-Dipalmitoyl-sn-glycero-3-Phosphocholine based cisplatin magnetic liposomes were prepared using two different procedures. In procedure I, MNs were combined with phospholipids during film formation; MNs were embedded in a phospholipid bilayer. In procedure II, MNs were mixed with drugs during hydration and MNs were contained in an interior aqueous compartment. The encapsulation efficiency of cisplain and the content of MN in procedure I liposomes were 33.5%?±?3.3% and 2.34?±?0.09?mg?mL^?1, respectively. It indicated that the deliberate MN loading into the liposome structure was not only successful using procedure I, but also superior over procedure II both in cisplatin encapsulation efficiency and MN content, which can promote the magnetic targeting effect of magnetic liposomes during delivering cisplatin.     

Stability and pharmacokinetic studies of O-palmitoyl amylopectin anchored dipyridamole liposomes

Modified polysaccharides have been used widely to increase physico-chemical stability of liposomes. However, the stability and pharmacokinetic studies on the polysaccharides modified anchored liposomes containing hydrophobic drugs which exist in lipid bilayer membranes were insufficient as compared with the liposomes carrying hydrophilic or ionic drugs in inner aqueous phase. In the present study, a hydrophobic drug, dipyridamole (DIP), was entrapped into liposomes through film hydration. Amylopectin was palmitoylated and anchored on the surface of plain DIP liposomes. Subsequently, the stabilities of DIP ethanol solution, plain DIP liposomes (PDL) and anchored DIP liposomes (ODL) against irradiation, disperse medium, biofluid, long-term storage were determined and compared. The concentrations of DIP in plasma of rats and its pharmacokinetic behaviors after intravenous administration of DIP injection, PDL and ODL were studied by RP-HPLC. The pharmacokinetic parameters were computed by software 3p97 programme. The results showed that ODL could increase stabilities more of DIP in vitro as compared with PDL. The plasma concentration-time curves of DIP after intravenous administration of DIP injection, PDL and ODL were all in accordance with open two-compartment model. Pharmacokinetic parameters of DIP injection, PDL and ODL in rats were significantly different. The present findings suggest that anchored liposomes could increase stabilities of DIP in vitro as compared with plain liposomes. Furthermore, the difference of pharmacokinetic profiles was due to the targetability of anchored liposomes.     

Novel O-palmitoylscleroglucan-coated liposomes as drug carriers: development, characterization and interaction with leuprolide

Polysaccharide-coated liposomes have been studied for their potential use for peptide drug delivery by the oral route because they are able to minimize the disruptive influences on peptide drugs of gastrointestinal fluids. The aim of this work was to synthesize and characterize a modified polysaccharide, O-palmitoylscleroglucan (PSCG), and to coat unilamellar liposomes for oral delivery of peptide drugs. To better evaluate the coating efficiency of PSCG, also scleroglucan (SCG)-coated liposomes were prepared. We studied the surface modification of liposomes and the SCG- and PSCG-coated liposomes were characterized in terms of size, shape, zeta potential, influence of polymer coating on bilayer fluidity, stability in serum, in simulated gastric and intestinal fluids and against sodium cholate and pancreatin. Leuprolide, a synthetic superpotent agonist of luteinizing hormone releasing hormone (LHRH) receptor, was chosen as a model peptide drug. After polymer coating the vesicle dimensions increased and the zeta potential shifted to less negative values. These results indicate that both SCG- and PSCG-coated liposomes surface and DSC results showed that PSCG was anchored on the liposomal surface. The stability of coated-liposomes in SGF, sodium cholate solution and pancreatin solution was increased. From this preliminary in vitro studies, it seems that PSCG-coated liposomes could be considered as a potential carrier for oral administration.     

Transfer of lipophilic drugs between liposomal membranes and biological interfaces: consequences for drug delivery.

This review paper describes the present knowledge on the interaction of lipophilic, poorly water soluble, drugs with liposomal membranes and the reversibility of this interaction. This interaction is discussed in the context of equilibrium and spontaneous transfer kinetics of the drug, when the liposomes are brought in co-dispersion with other artificial or natural phospholipid membranes in an aqueous medium. The focus is on drugs, which have the potential to partition (dissolve) in a lipid membrane but do not perturb membranes. The degree of interaction is described as solubility of a drug in phospholipid membranes and the kinetics of transfer of a lipophilic drug between membranes. Finally, the consequences of these two factors on the design of lipid based carriers for oral, as well as parenteral use, for lipophilic drugs and lead selection of oral lipophilic drugs is described. Since liposomes serve as model-membranes for natural membranes, the assessment of lipid solubility and transfer kinetics of lipophilic drug using liposome formulations may additionally have predictive value for bioavailability and biodistribution and the pharmacokinetics of lipophilic drugs after parenteral as well as oral administration.     

Characterisation and in vitro evaluation of bioadhesive liposome gels for local therapy of vaginitis

The purpose of this study was to design and evaluate a new vaginal delivery system for the local treatment of vaginitis. Liposomes containing two commonly applied drugs in the treatment of vaginal infections, namely clotrimazole and metronidazole, were prepared by the proliposome and the polyol dilution methods. Both types of liposomes were characterised and compared for particle size, polydispersity, entrapment efficiency, and tested for in vitro stability in media that mimic human vaginal conditions (buffer, pH 4.5, and vaginal fluid simulant). To achieve application viscosity and to further improve their stability, liposomes containing drugs were incorporated in a bioadhesive gel made of Carbopol 974P NF resin. In vitro release studies have demonstrated that even after 24 h of incubation in vaginal fluid simulant (at 37 degrees C) more than 30% of the originally entrapped clotrimazole (or 50% of metronidazole) was still retained in the gel. Storage stability studies have proved the ability of Carbopol 974P NF gel to preserve original size distributions of incorporated liposomes. All the performed experiments confirm the applicability of bioadhesive liposome gels as a novel delivery system for local therapy of vaginal infections.