Preparation and Pharmacodynamic Evaluation of Liposomes of Indomethacin

The side effects of indomethacin, such as ulceration of the kidney and central nervous system (CNS) toxicity, limit its use as a drug for rheumatoid arthritis. Encapsulation of this drug in liposomes may reduce the toxic effects. The aim of this study was to determine the factors influencing encapsulation of indomethacin in liposomes and to determine anti-inflammatory potential of liposomal indomethacin. A series of liposomal formulations of indomethacin were prepared using various phospholipids. The effects of method of preparation, lipid composition, charge, and cholesterol (CH) on encapsulation of indomethacin in liposomes were investigated. A significant variation in encapsulation of the drug in liposomes was observed when prepared by different methods. With all the methods of preparation tried, the favorable lipid compositn for high encapsulation of this drug was egg phosphatidyl choline:CH:stearlyamine (PC:CH:SA) at a 1:0.5:0.1 molar ratio. Inclusion of cholesterol did not affect the encapsulation efficiency of the drug in liposomes. The drug release profile from the liposomes was biphasic, and the highest percentage drug release was observed with large unilamellar vesicles (LUVs) (100 nm). Inclusion of steary-Ujylamine (PC:CH:SA 1:0.5:0.1) and phosphatidyl glycerol (PG) (PC:CH:PG:1:0.5:0.2) in the liposomes reduced the release of the drug in comparison to the neutral liposomes (PC:CH 1:1). The slow release of the drug from stearylamine-containing liposomes may be explained by the electrostatic interaction between the acid moiety of the drug and the amine moiety of the lipid. It is assumed that the possible hydrogen bonding between –OH groups of phosphatidyl glycerol and the –COOH group of the drug might be the reason for the slow release of the drug from PC:CH:PG (1:0.5:0.2) containing liposomes. Pharmacodynamic evaluation of the liposomes was performed by carrageenan-induced rat paw edema (acute) and adjuvant arthritis (chronic) models. The anti-inflammatory activity was increased from the first to fifth hour PC:CH:PG (1:0.5:0.2) and PC:CH:SA(1:0.5:0.1) liposomes showed the highest percentage inhibition of edema. In both these models, anti-inflammatory activity of liposomal indomethacin was significantly higher than that of free indomethacin (p <. 01). The ulcer index of the free drug was about three times more than the encapsulated drug when administered at the same dose intraperitoneally to arthritic rats consecutively for 21 days.     

Biodistribution of liposomes of terbutaline sulfate in guinea pigs

A series of liposomes was prepared with various lipid (egg phosphatidyl choline [egg PC], phosphatidyl glycerol [PG], dipalmitoyl phosphatidylcholine [DPPC], distearoyl phosphatidyl choline [DSPC], dipalmitoyl phosphatidyl glycerol [DPPG], phosphatidyl ethanolamine [PE], cholesterol [CH], and stearylamine [SA]) compositions, such as egg PC:PG:CH (55:5:40), DPPC:PG:CH (55:5:40), DSPC:DSPG:CH (55:5:40) egg PC:SA:CH (55:5:40), DSPE:DSPG:CH (55:5:40) in molar ratio. Liposomal formulations were administered to guinea pigs intravenously; 3 hr after the treatment, serum samples and various organs (e.g., liver, spleen, lung) were removed and analyzed for drug concentration by a high-performance liquid chromatographic (HPLC) method. Based on the above study, a liposomal preparation with better lung specificity was selected, and the time profile of these liposomes was determined in guinea pigs. Three hours postadministration, a significant difference in blood levels was observed between free terbutaline sulfate and the various liposomal formulations. Localization of the drug in the lungs increased considerably when encapsulated drug was used, and the highest percentage localization was observed with DSPC:DSPG:CH (55:5:40) liposomes. The percentage recovery of the drug in the lungs with egg PC:CH:SA (55:40:5) liposomes did not change significantly when compared with egg PC:CH:PG (55:40:5) liposomes. To establish the time course of disposition of the liposomes, DSPC:SPG:CH (55:5:40) liposomes were selected. Terminal half-life t_1/2 of the drug in blood with free drug solution was about 12 hr, whereas with liposomes, a twofold increase in t_1/2 was observed. The disposition data indicated that the clearance of the drug was delayed by 1.5 times when incorporated into liposomes.     

Biodistribution of Liposomes of Terbutaline Sulfate in Guinea Pigs

A series of liposomes was prepared with various lipid (egg phosphatidyl choline [egg PC], phosphatidyl glycerol [PG], dipalmitoyl phosphatidylcholine [DPPC], distearoyl phosphatidyl choline [DSPC], dipalmitoyl phosphatidyl glycerol [DPPG], phosphatidyl ethanolamine [PE], cholesterol [CH], and stearylamine [SA]) compositions, such as egg PC:PG:CH (55:5:40), DPPC:PG:CH (55:5:40), DSPC:DSPG:CH (55:5:40) egg PC:SA:CH (55:5:40), DSPE:DSPG:CH (55:5:40) in molar ratio. Liposomal formulations were administered to guinea pigs intravenously; 3 hr after the treatment, serum samples and various organs (e.g., liver, spleen, lung) were removed and analyzed for drug concentration by a high-performance liquid chromatographic (HPLC) method. Based on the above study, a liposomal preparation with better lung specificity was selected, and the time profile of these liposomes was determined in guinea pigs. Three hours postadministration, a significant difference in blood levels was observed between free terbutaline sulfate and the various liposomal formulations. Localization of the drug in the lungs increased considerably when encapsulated drug was used, and the highest percentage localization was observed with DSPC:DSPG:CH (55:5:40) liposomes. The percentage recovery of the drug in the lungs with egg PC:CH:SA (55:40:5) liposomes did not change significantly when compared with egg PC:CH:PG (55:40:5) liposomes. To establish the time course of disposition of the liposomes, DSPC:SPG:CH (55:5:40) liposomes were selected. Terminal half-life t_1/2 of the drug in blood with free drug solution was about 12 hr, whereas with liposomes, a twofold increase in t_1/2 was observed. The disposition data indicated that the clearance of the drug was delayed by 1.5 times when incorporated into liposomes.     

Preparation, optimization, and characterization of topotecan loaded PEGylated liposomes using factorial design

This study reports the development of liposomal system for a potent antitumor drug, topotecan. To achieve this goal conventional and PEGylated liposomes were prepared according to a factorial design by hydration method followed by extrusion. Parameters such as type of lipid, percentage of cholesterol, percentage of phosphatidylglycerols, percentage of polyethylene glycol (PEG)-lipids, and drug to lipid molar ratio were considered as important factors for the optimizing the entrapment and retention of topotecan inside the liposomes. The size and zeta-potential of the PEGylated and conventional liposomes were measured by particle size analyzer and zeta-potentiometer, respectively. The stability and release characteristics of PEGylated liposome loaded topotecan were compared with conventional liposomes and free topotecan. The optimized PEGylated [distearoyl phosphatidylcholine (DSPC)/cholesterol/ distearoyl phosphatidylglycerol (DSPG)/ distearoyl phosphatidylethanolamine-PEG(2000) (DSPE-PEG(2000)); 7:7:3:1.28] and related conventional [DSPC/cholesterol/DSPG; 7:7:3] liposomes showed a narrow size distribution with a polydipersity index of 0.15 and 0.10, an average diameter of 103.0 +/- 13.1 and 95.2 +/- 11.10 nm, and with drug loading of 11.44 and 6.21%, respectively. Zeta-potential was -10 +/- 2.3 and -22 +/- 2.8 mV for PEGylated and conventional liposomes, respectively. The results of stability evaluation showed that the lactone ring of topotecan was notably preserved upon liposome encapsulation. PEGylated liposomes containing topotecan showed a significant decrease (P < 0.001) in release rate in comparison with conventional leptosomes. These results indicate the suitability of PEGylated liposomes in controlling topotecan release. The prepared liposomes (especially PEGylated liposomes) as those described here may be clinically useful to stabilize and deliver topotecan for the treatment of cancer.     

Piroxicam encapsulated in liposomes: characterization and in vivo evaluation of topical anti-inflammatory effect

Liposomes of soya phosphatidylcholine, cholesterol, and stearylamine (molar ratio 6/3/1) and 0.1% alpha-tocopherol were prepared by the extrusion of multilamellar vesicles through 0.2-micron polycarbonate membrane. Liposomes were characterized by electron transmission microscopy, and the mean structure diameter was 278 nm. The encapsulation efficiency obtained was 12.73%. The topical anti-inflammatory effect was evaluated in vivo by the cotton pellet granuloma method. We analyzed free piroxicam at 4 mg/kg, piroxicam encapsulated in liposomes added to 1.5% hydroxyethylcellulose (HEC) gel at 1.6 mg/kg, and piroxicam encapsulated in liposomes added to HEC gel at 4 mg/kg; the inhibition of inflammation obtained was 21.1%, 32.8%, and 47.4%, respectively. These results showed that the encapsulation of piroxicam produced an increase of topical anti-inflammatory effect, suggesting that the inhibition of inflammation can be obtained with lower drug concentrations.     

Piroxicam Encapsulated in Liposomes: Characterization and In Vivo Evaluation of Topical Anti-inflammatory Effect

Liposomes of soya phosphatidylcholine, cholesterol, and stearylamine (molar ratio 6/3/1) and 0.1% α-tocopherol were prepared by the extrusion of multilamellar vesicles through 0.2-μm polycarbonate membrane. Liposomes were characterized by electron transmission microscopy, and the mean structure diameter was 278 nm. The encapsulation efficiency obtained was 12.73%. The topical anti-inflammatory effect was evaluated in vivo by the cotton pellet granuloma method. We analyzed free piroxicam at 4 mg/kg, piroxicam encapsulated in liposomes added to 1.5% hydroxyethylcellulose (HEC) gel at 1.6 mg/kg, and piroxicam encapsulated in liposomes added to HEC gel at 4 mg/kg; the inhibition of inflammation obtained was 21.1%, 32.8%, and 47.4%, respectively. These results showed that the encapsulation of piroxicam produced an increase of topical anti-inflammatory effect, suggesting that the inhibition of inflammation can be obtained with lower drug concentrations.     

In vitro skin permeation and retention of paromomycin from liposomes for topical treatment of the cutaneous leishmaniasis

Paromomycin (PA), a very hydrophilic antibiotic, has been tested as an alternative topical treatment against cutaneous leishmaniasis (CL). Although this treatment has shown promising results, it has not been successful in accelerating the recovery in most cases. This could be attributed to the low skin penetration of PA. Liposomal formulations usually provide sustained and enhanced drug levels in skin. The aim of this study was to prepare liposomal formulations containing PA and to investigate their potential as topical delivery systems of this antileishmanial. Large multilamellar vesicles (MLVs) were prepared by conventional solvent evaporation method. Large unilamellar vesicles (LUVs) were prepared by reverse-phase evaporation method. The lipids used were soybean phosphatidylcholine (PC) and PC:cholesterol (CH) (molar ratio 1:1). The skin permeation experiments across stripped and normal hairless mice skin were performed in modified Franz diffusion cells. The PA entrapment in LUV liposomes (20.4 ± 2.2%) was higher than that observed for MLV liposomes (7.5 ± 0.9%). Drug entrapment was 41.9 ± 6.2% and 27.2 ± 2.4% for PC and PC:CH LUV, respectively. The skin permeation was 1.55 ± 0.31%, 1.29 ± 0.40%, 0.20 ± 0.08%, and 0.50 ± 0.19% for PC LUV, PC:CH LUV, empty LUV + PA and aqueous solution, respectively. Controlled topical delivery, across stripped skin, was observed for PA entrapped in LUV liposomes.     

Preparation,Optimization, and Characterization of Topotecan Loaded PEGylated Liposomes Using Factorial Design

This study reports the development of liposomal system for a potent antitumor drug, topotecan. To achieve this goal conventional and PEGylated liposomes were prepared according to a factorial design by hydration method followed by extrusion. Parameters such as type of lipid, percentage of cholesterol, percentage of phosphatidylglycerols, percentage of polyethylene glycol (PEG)-lipids, and drug to lipid molar ratio were considered as important factors for the optimizing the entrapment and retention of topotecan inside the liposomes. The size and zeta-potential of the PEGylated and conventional liposomes were measured by particle size analyzer and zeta-potentiometer, respectively. The stability and release characteristics of PEGylated liposome loaded topotecan were compared with conventional liposomes and free topotecan.

The optimized PEGylated [distearoyl phosphatidylcholine (DSPC)/cholesterol/ distearoyl phosphatidylglycerol (DSPG)/ distearoyl phosphatidylethanolamine-PEG₂₀₀₀ (DSPE-PEG₂₀₀₀); 7:7:3:1.28] and related conventional [DSPC/cholesterol/DSPG; 7:7:3] liposomes showed a narrow size distribution with a polydipersity index of 0.15 and 0.10, an average diameter of 103.0 ± 13.1 and 95.2 ± 11.10 nm, and with drug loading of 11.44 and 6.21%, respectively. Zeta-potential was ?10 ± 2.3 and ?22 ± 2.8 mV for PEGylated and conventional liposomes, respectively. The results of stability evaluation showed that the lactone ring of topotecan was notably preserved upon liposome encapsulation. PEGylated liposomes containing topotecan showed a significant decrease (P < 0.001) in release rate in comparison with conventional leptosomes. These results indicate the suitability of PEGylated liposomes in controlling topotecan release.

The prepared liposomes (especially PEGylated liposomes) as those described here may be clinically useful to stabilize and deliver topotecan for the treatment of cancer.     

The Effect of Polycation Complexation on Methotrexate Retention in Liposomes

Methotrexate and a methotrexate-DEAE dextran complex were encapsulated in dipalmitoyl phosphatidyl choline liposomes. In all cases, the degree of encapsulation of methotrexate in the methotrexate-DEAE dextran liposomes was higher than in the plain methotrexate liposomes.

The kinetic permeability of methotrexate from both methotrexate and methotrexate-DEAE dextran dipalmitoyl phosphatidyl choline liposomes was studied at 37°C in pH 7.4 acetate buffer. All liposome systems appeared to show a biphasic first order kinetic release of methotrexate. The initial rapid release probably resulted from the desorption of adsorbed methotrexate, and the subsequent slow release was from the diffusion of the entrapped drug. The desorption kinetics were separated from the diffusion process in the first phase by graphing. The methotrexate-DEAE dextran liposome data showed 13% methotrexate bound to the liposome surface compared to 23% methotrexate bound on the plain methotrexate liposome surface.     

Chitosan-based thermosensitive hydrogel containing liposomes for sustained delivery of cytarabine

Sustained release thermosensitive solution containing cytarabine-loaded liposome delivery system offers the possibility of reduced dosing frequency and sustained drug action. Biodegradable and biocompatible chitosan-beta-glycerophosphate (C-GP) thermosensitive solution having the property to gel at body temperature and to maintain its physical integrity for longer period of time was used. The C-GP solution containing cytarabine-loaded liposomes (CGPCLL) was studied, and the results showed that the cytarabine liposomes were capable of high encapsulation efficiency (85.2 +/- 2.58%) with the mean diameter of 220 +/- 6.9 nm of extruded cytarabine-loaded liposome. Furthermore, transmission electron microscopy showed spherical-shaped liposomes after extrusion with smooth surface. In vitro studies of CGPCLL in PBS buffer showed that this system can sustain release of encapsulated drug for more than 60 h compared with drug-loaded liposomal suspension (upto 48 h). Pharmacokinetic studies of CGPCLL resulted in higher t(1/2) (28.86 h) and AUC 2526.88 mug/mL h compared with cytarabine-loaded liposomal suspension (CLLS) and C-GP containing free cytarabine (CGPFC) in rats. CGPCLL was capable of sustaining the cytarabine release for more than 60 h in vivo compared with CLLS and CGPFC which showed maximum amount of drug release within 42 and 10 h, respectively. Thus, these results showed that the CGPCLL gels at body temperature and can sustain the delivery of cytarabine effectively.     

Topical Liposomal local Anesthetics: Design, Optimization and Evaluation of Formulations

To improve the rate of penetration into the skin, and to develop an effective topical anesthetic product, selected local anesthetic agents, benzocaine, lidocaine, dibucaine, etidocaine and tetracaine were encapsulated into liposomes using the solvent evaporation method. After the pilot experiments, tetracaine was selected for further development. Encapsulation efficiency was determined by centrifugation of liposomes and spectrophotometric analysis of liposome pellets and supernatants. Physical stability and organoleptic properties of the various liposomal tetracaine formulas were monitored visually and by microscopy for 1 year. Tetracaine was found to be suitable for the development of a liposomal drug delivery system with high encapsulation efficiency (60-90%) and physical stability. The results showed that encapsulation efficiency of tetracaine into liposomes can be increased by increasing drug concentration and pH, and including negatively charged stearic acid or unsaturated lipids in the formula. Stability of tetracaine increased with higher encapsulation efficiency, however the shelf life of the product was still short (2 months). In-process and finished product quality control parameters are suggested to facilitate the topical liposomal product development in general.     

Development and characterization of liposomal disodium ascorbyl phytostanyl phosphates (FM-VP4)

The specific objectives of this project were (1) to develop liposomal disodium ascorbyl phytostanyl phosphate (FM-VP4) formulations, (2) to develop a liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) assay for quantification of FM-VP4 in liposomal formulations and plasma sample, and (3) to characterize liposomal FM-VP4 formulations by finding optimal drug-to-lipid ratios and determining the degradation of FM-VP4 in liposomes. Section 2 describes an LC/MS/MS assay developed for the identification and quantification of FM-VP4 in liposomal formulations to provide estimates of drug concentrations and encapsulation efficiency. The extra step of removing plasma proteins prior to LC/MS/MS assay yields an analysis of FM-VP4 in plasma samples. Section 3 describes experiments designed to find the optimal drug-to-lipid ratio for liposomal FM-VP4 formulations by comparing encapsulation efficiencies and varying the lipid compositions. Additionally, this section details our degradation studies to determine if liposomes have any protective effects on FM-VP4; these studies tested various lipid compositions at 37°C in rabbit plasma. The mechanism of how FM-VP4 lowers low-density lipoprotein (LDL) cholesterol and total cholesterol levels in various animal models is presently unknown. However, before the mechanism of action could be studied, FM-VP4 first had to be delivered efficiently into plasma or cultured cell. The low systemic bioavailability and cellular uptake of FM-VP4 further suggested the importance of finding an efficient delivery vehicle for this drug. This project proposed a framework for such delivery and paves the way for further investigation into how FM-VP4 works in vivo and in vitro.     

The Effect of Polycation Complexation on Methotrexate Retention in Liposomes

Abstract

Methotrexate and a methotrexate-DEAE dextran complex were encapsulated in dipalmitoyl phosphatidyl choline liposomes. In all cases, the degree of encapsulation of methotrexate in the methotrexate-DEAE dextran liposomes was higher than in the plain methotrexate liposomes.

The kinetic permeability of methotrexate from both methotrexate and methotrexate-DEAE dextran dipalmitoyl phosphatidyl choline liposomes was studied at 37°C in pH 7.4 acetate buffer. All liposome systems appeared to show a biphasic first order kinetic release of methotrexate. The initial rapid release probably resulted from the desorption of adsorbed methotrexate, and the subsequent slow release was from the diffusion of the entrapped drug. The desorption kinetics were separated from the diffusion process in the first phase by graphing. The methotrexate-DEAE dextran liposome data showed 13% methotrexate bound to the liposome surface compared to 23% methotrexate bound on the plain methotrexate liposome surface.     

Topical Liposomal local Anesthetics: Design,Optimization and Evaluation of Formulations

Abstract

To improve the rate of penetration into the skin, and to develop an effective topical anesthetic product, selected local anesthetic agents, benzocaine, lidocaine, dibucaine, etidocaine and tetracaine were encapsulated into liposomes using the solvent evaporation method. After the pilot experiments, tetracaine was selected for further development. Encapsulation efficiency was determined by centrifugation of liposomes and spectrophotometric analysis of liposome pellets and supernatants. Physical stability and organoleptic properties of the various liposomal tetracaine formulas were monitored visually and by microscopy for 1 year. Tetracaine was found to be suitable for the development of a liposomal drug delivery system with high encapsulation efficiency (60–90%) and physical stability. The results showed that encapsulation efficiency of tetracaine into liposomes can be increased by increasing drug concentration and pH, and including negatively charged stearic acid or unsaturated lipids in the formula. Stability of tetracaine increased with higher encapsulation efficiency, however the shelf life of the product was still short (2 months). In-process and finished product quality control parameters are suggested to facilitate the topical liposomal product development in general.     

Immobilization of aloin encapsulated into liposomes in Layer-by-layer films for transdermal drug delivery

Layer-by-layer (LbL) films have been exploited in drug delivery systems that may be used in the form of patches, but the encapsulation of poor water soluble drugs and their release with a controlled rate are still major challenges to be faced. In this paper, we demonstrate the controlled release of aloin (barbaloin), an important component of the widely used Aloe vera, encapsulated into liposomes and immobilized in LbL films with a polyelectrolyte. With a systematic study using fluorescence spectroscopy of aloin release from solutions and from LbL films with different phospholipid liposomes, we inferred that optimized release was achieved with aloin incorporated into palmitoyl oleyl phosphatidyl glycerol (POPG) or dipalmitoyl phosphatidyl glycerol (DPPG) liposomes immobilized in LbL films. Significantly, with this optimized system aloin was almost completely released within 30 h, with a small release rate at the end, which followed a sharp release in the first 5 h. Upon comparing the rates of the distinct systems, we conclude that the main factors controlling the release are the electrostatic interactions involving the negatively charged phospholipids. Because these interactions can be tuned in LbL films, the approach used here opens the way for new drug delivery systems to be developed with fine control of the drug release.     

Evaluation of in vitro stability of large unilamellar liposomes coated with a modified polysaccharide (O-palmitoylpullulan)

Aiming at encapsulation of a hydrosoluble drug, large unilamellar liposomes (LUV) of egg phosphatidylcholine (PC) were coated with a natural polysaccharide derivative, O-palmitoylpullulan (OPP), and its in vitro stability evaluated using fluorescent probes. This coating (in OPP/PC weight ratio of 3) improved significantly the in vitro stability of LUV by decreasing both the permeability and fluidity of the liposomal membrane.This paper was accepted for publication after the 1995 Conference of the European Society of Biomaterials, Oporto, Portugal, 10–13 September.     

Chitosan-Based Thermosensitive Hydrogel Containing Liposomes for Sustained Delivery of Cytarabine

Sustained release thermosensitive solution containing cytarabine-loaded liposome delivery system offers the possibility of reduced dosing frequency and sustained drug action. Biodegradable and biocompatible chitosan-beta-glycerophosphate (C-GP) thermosensitive solution having the property to gel at body temperature and to maintain its physical integrity for longer period of time was used. The C-GP solution containing cytarabine-loaded liposomes (CGPCLL) was studied, and the results showed that the cytarabine liposomes were capable of high encapsulation efficiency (85.2?±?2.58%) with the mean diameter of 220?±?6.9 nm of extruded cytarabine-loaded liposome. Furthermore, transmission electron microscopy showed spherical-shaped liposomes after extrusion with smooth surface. In vitro studies of CGPCLL in PBS buffer showed that this system can sustain release of encapsulated drug for more than 60 h compared with drug-loaded liposomal suspension (upto 48 h). Pharmacokinetic studies of CGPCLL resulted in higher t_1/2 (28.86 h) and AUC 2526.88 μg/mL h compared with cytarabine-loaded liposomal suspension (CLLS) and C-GP containing free cytarabine (CGPFC) in rats. CGPCLL was capable of sustaining the cytarabine release for more than 60 h in vivo compared with CLLS and CGPFC which showed maximum amount of drug release within 42 and 10 h, respectively. Thus, these results showed that the CGPCLL gels at body temperature and can sustain the delivery of cytarabine effectively.     

卵磷脂/果胶锌复合凝胶球的制备及性能

采用滴制法, 以吲哚美辛(IDM)为模型药物, 皂化高甲氧化苹果果胶为骨架材料, 氯化锌为交联剂, 并复合卵磷脂(PC)制成吲哚美辛卵磷脂/果胶锌复合凝胶球。针对工艺参数对复合凝胶球粒径、粒重、载药量与包封率以及体外释药性能的影响进行了讨论。凝胶球均成均匀球形, 粒径1.13~1.42 mm, 粒重1.13~2.32 mg, 包封率范围70.72%~94.76%, 载药量范围5.84%~13.54%。同时实验结果表明, 卵磷脂的加入比例、药胶比(吲哚美辛与果胶的质量比)和皂化用NaOH浓度对复合凝胶球的形态、载药及释药性能均有明显影响。其中, 卵磷脂的加入使复合凝胶球载药性能和在模拟肠液中的缓释性能明显提高, 当卵磷脂与果胶的质量比为5:4, 皂化用NaOH浓度为30 g/L, 药胶质量比1:4时, 复合凝胶球在肠模拟液中8 h累计释药率为8.93%。稳定性实验结果表明, 在高温和光照的条件下放置, 卵磷脂/果胶锌复合凝胶球比原药及果胶锌凝胶球具有更好的稳定性, 显示出卵磷脂对果胶锌复合凝胶球在结肠定位给药系统的明显改善作用。     

Preparation and pharmaceutical/pharmacodynamic evaluation of topical brucine-loaded liposomal hydrogel

To reduce the toxicity and enhance the therapeutic efficacy of brucine, a traditional Chinese medicine for relieving arthritic and traumatic pain, in this study, a novel brucine-loaded liposomal hydrogel (BLH) formulation, suitable for topical application, was developed. Spherical liposomes composed of lecithin and cholesterol, with brucine, was prepared by a modified ethanol-dripping method. High percentage (over 80%) of encapsulated brucine in liposomes was obtained. Topical liposomal hydrogel formulations were prepared by further incorporation of the prepared liposomes into structured carbopol 940 hydrogels with the concentration of carbopol 1.0%, the ratio of glycerol to carbopol 8:1 and the brucine content 0.1%. The liposomal hydrogel formulations provided an obvious promotion for skin permeation of bruicne while for the free brucine in hydrogels (BH), there was no detectable drug permeation through the skin. The safety evaluation showed that the prepared BLH were no irritation to both the broken and integrity skin. Pharmacodynamic evaluation revealed that the BLH showed a better therapeutic efficacy than that of the BH. So, it can be concluded that the BLH developed here could represent a safe, effective and promising transdermal formulation for local treatment of analgesic and anti-inflammatory disease.     

Chemoprophylaxis of Schistosomiasis Using Liposome Encapsulated Oxamniquine

Abstract

Oxamniquine liposomes with different compositions and surface charges were prepared by the chloroform-film method. The amount of oxamniquine entrapped was estimated and found to range from 1 to 23.09% of the initial amount of drug used for preparation of the liposomes depending on the suvace charge of liposomal vesicles. Negatively charged liposomes exhibited the highest percentage entrapment viz., 23.09%. The maximum oxamniquine entrapment was achieved in liposomes prepared from phospholipids molar ratio (7:4.1). The liposome formulations were characterized by her light scattering technique, particle size analysis and rheological characterization. In vitro release kinetics of oxainquine liposomes reveal that the percentage drug release is suvace charge dependent and irrelevant to the molar ratio. The results of organ, liver and spleen, targetting of oxamniquine liposomes in mice reveal that after 7 days of (S.C.) injection the amount of oxamniquine retain more than three times (7:4:1) more than two times (7:6) and nearly double (7:6:1) the amount of drug retained by injection of the free drug. Afrer 14 days of (S.C.) injection of oxamniquine liposomes, negatively charged liposomes of the highest cholesterol content exhibit better drug retention than neutral liposomes and no free drug detected in these organs, after this period of time. The chemoprophylactic eflect of free and oxamniquine liposome formulations was estimated using female Swiss mice injected 7, 15, 30, and 60 days before larval infection. for 7 days chemoprophylactic study liposomes encapsulation show more eficient prophylaxis. In the 15 days study the percentage worm count reduction is in the following order: 7:4:1 (-ve) (68.8%) > 7:2:1 (-ve) (66%) > 7:2 (34.4%) > free oxamniquine (0.00%). for the 30 day study the negatively charged liposome 7:4:1 exhibited a signifcant reduction of worm burden. for the 60 days, the liposomes 7:6 produced better chemoprophyhis than 7:6:1 (-ve). The results of T-cell and B-cell responses against soluble adult warm proteins reveal that oxamniquine, when encapsulated in liposomes, stimulate the immune system of mice against the worms of S. mansoni.