Hemoglobin-Liposomes as Blood Replacement Fluid

Human hemoglobin is encapsulated in unilamellar liposomes by French press extrusion in order to form hemoglobin liposomes (HBL). The mean diameter of the HBL is 50 nm by TEM. Therefore the preparation can be passed through microbial retentive filters (200 nm). The encapsulation efficiency is 11.5% and the hemoglobin content 0.52 g/100 ml for a 5.75% (v/v) dispersion. The HBL are able to bind 3.8% (v/v) 0₂ (32% (v/v) dispersion) and show the same oxygen dissociation characteristics as the hemoglobin solution. The lipid mixture consists of hydrogenated soy lecithin, which is inexpensive and stable against oxidation, and cholesterol in a molar ratio 1:l. The French press extrusion process is suitable for a scaling up.     

The preparation,characterization of Lupeol PEGylated liposome and its functional evaluation in vitro as well as pharmacokinetics in rats

Objective: The objective of this study was to enhance the solubility and bioavailability of Lupeol.

Methods: Utilizing a thin-film dispersion method, we prepared Lupeol-loaded PEGylated liposomes and Lupeol-loaded liposomes, which was characterized using SEM, mean diameter, PDI, zeta potential, and entrapment efficiency (EE). The EE, in vitro release, and stability of Lupeol-loaded PEGylated liposomes were detected using HPLC. In addition to the safety evaluation, the evaluation was carried out on HepG2 cells in vitro; the pharmacokinetics were carried out after i.v. in the rats.

Results: The size, PDI, zeta potential, and EE of Lupeol-loaded PEGylated liposomes and Lupeol-loaded liposomes were 126.9?nm, 0.246, ?1.97?mV, 87%; 97.23?nm, 0.25, 1.6?mV, 86.2%, respectively. Lupeol-loaded PEGylated liposomes showed the slow-release effect in vitro release experiments. Lupeol-loaded PEGylated liposomes offered significant advantages over other experimental groups in vitro studies, such as the highest inhibition rate and the highest apoptosis rate. We also found that Lupeol-loaded PEGylated liposomes blocked cells in the G₂M phase. The pharmacokinetics result showed that the AUC of Lupeol-loaded PEGylated liposomes group was 3.2 times higher than free Lupeol group after i.v., the MRT and t_1/2 values of Lupeol-loaded PEGylated liposomes (MRT = 6.09?h, t_1/2 =12.94?h) showed improvements of 2.5 and 4.1 times compared to free Lupeol (MRT = 2.43?h, t_1/2 = 3.16?h).

Conclusion: The Lupeol-loaded PEGylated liposomes have successfully solved its poor hydrophilicity, low bioavailability.     

Development and optimization of a new processing approach for manufacturing topical liposomes-in-hydrogel drug formulations by dual asymmetric centrifugation

Objective: The objective of the present study was to utilize dual asymmetric centrifugation (DAC) as a novel processing approach for the production of liposomes-in-hydrogel formulations.

Materials and methods: Lipid films of phosphatidylcholine, with and without chloramphenicol (CAM), were hydrated and homogenized by DAC to produce liposomes in the form of vesicular phospholipid gels with a diameter in the size range of 200?300?nm suitable for drug delivery to the skin. Different homogenization processing parameters were investigated along with the effect of adding propylene glycol (PG) to the formulations prior to homogenization. The produced liposomes were incorporated into a hydrogel made of 2.5% (v/v) soluble β-1,3/1,6-glucan (SBG) and mixed by DAC to achieve a homogenous liposomes-in-hydrogel-formulation suitable for topical application.

Results and discussion: CAM-containing liposomes with a vesicle diameter of 282?±?30?nm and polydispersity index (PI) of 0.13?±?0.02 were successfully produced by DAC after 50?min centrifugation at 3500?rpm, and homogenously (Conclusion: We managed to develop a relatively fast and reproducible new method for the production of liposomes-in-hydrogel formulations by DAC.     

Preparation and Pharmacokinetics in Rabbits of Breviscapine Unilamellar Vesicles

ABSTRACT

The purpose of the study was to prepare the unilamellar liposomal vesicles of breviscapine (Breviscapine-LUVs) and investigate the pharmacokinetics of Breviscapine-LUVs in rabbits. Breviscapine-LUVs were prepared by the film dispersion method and treated further by extrusion. Its size distribution and zeta potential were determined by photon correlation spectroscopy. The encapsulation efficiency (EE) and cumulative release of Breviscapine-LUVs were assayed by the dialysis method. The crossover design (two periods) was used in six rabbits, which were administered Breviscapine-LUVs and reference preparation. Results showed that the particle size of Breviscapine-LUVs was 50.8 nm, and the polydispersity index was 0.287. The zata potential was ?24 mV ± 9 mV(n = 3), and the EE% was 81.1 ± 1.1% (n = 3). The cumulative release of vesicles in 0.9% NaCl was 17.2 ± 0.78%, 26.1 ± 0.68%, and 29.9 ± 0.81% in 2, 8, and 24 h, respectively. The mean concentration-time curves of breviscapine liposomes and reference preparation were both fitted to a two-compartment model with the main pharmacokinetic parameters as follows: t_1/2β of Breviscapine-LUVs and reference preparation were (42.5 ± 28.6) min and (6.01 ± 4.64) min, respectively; CL_(s) were (15.3 ± 9.03) mL × min^?1 and (84.6 ± 40.6) mL × min^?1, respectively; AUC_0–300 were (1267 ± 1083) μg × min × mL^?1 and (196 ± 107) μg × min × mL^?1, respectively. Compared with the reference preparation, breviscapine liposomes had a much higher concentration in plasma and contained characteristic of sustained-release, which ameliorated the pharmacokinetic properties of scutellarin.     

Extrusion modelling of 6061 aluminium alloy and particle reinforced MMCs

Abstract

Extrusion modelling was performed for 6061 aluminium alloy and three particle reinforced MMCs (10%Al₂O₃/6061, 15%SiC/6061, 20%Al₂O₃/6061) using constitutive equations previously obtained from torsion test data. In applying the finite element software DEFORM, suitable heat transfer, friction, and velocity boundary conditions were chosen based on a direct extrusion press. Simulations were run for various extrusion conditions and the outputs for the four materials were compared. The simulation results were validated by comparison with real life extrusions and modelling of other researchers. The results showed that an increase in billet temperature, a reduction in ram speed, or a reduction in extrusion ratio had the effect of reducing the ram load. In consequence, extrusion conditions could be selected so that extrusion of the composite was carried out with the same peak ram load as the alloy.     

Design by optimization and comparative evaluation of vesicular gels of etodolac for transdermal delivery

Aim of the present study was to design vesicular gels of etodolac loaded liposomes and ethosomes for effective transdermal delivery. The physicochemical properties of vesicular gels were compared with 45% v/v ethanolic etodolac solution and commercial product (PROXYM®). The liposomes were prepared by film hydration technique whereas ethosomes were prepared by cold method respectively. Both the systems were characterized for various physicochemical properties. The size range of liposomes shows 186?nm–363?nm whereas for ethosomes 170?nm–261?nm respectively. The zeta potential of optimized liposomes and ethosomes was found to be ?36.5?mV and ?48.3?mV, respectively. The highest %EE of liposomes and ethosomes shows 71.5% and 78.5%, respectively. The permeation of liposomes shows in the range of 67.50%–86.06% whereas ethosomes shows 52.30%–99.49%, respectively. The optimization was done by 3² experimental design. The optimized vesicular dispersions were subjected to gel preparation using carbopol 940 NF. The prepared liposomal gel (ETO-LG) and ethosomal gel (ETO-EG) were optimized and characterized. The vesicular gels showed desirable results compared to other test formulations.     

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.     

Cholesterol derivative-based liposomes for gemcitabine delivery: preparation,in vitro,and in vivo characterization

As an anti-tumor drug, gemcitabine (Gem) is commonly used for the treatment of non-small cell lung cancer and pancreatic cancer. However, there are several clinical drawbacks to using Gem, including its extremely short plasma half-life and side effects. To prolong its half-life and reduce its side effects, we synthesized a derivative of Gem using cholesterol (Chol). This derivative, called gemcitabine-cholesterol (Gem-Chol), was entrapped into liposomes by a thin-film dispersion method. The particle size of the Gem-Chol liposomes was 112.57?±?1.25?nm, the encapsulation efficiency was above 99%, and the drug loading efficiency was about 50%. In vitro studies revealed that the Gem-Chol liposomes showed delayed drug release and long-term stability at 4?°C for up to 2 months. In vivo studies also showed the superiority of the Gem-Chol liposomes, and compared with free Gem, the Gem-Chol liposomes had longer circulation time. Moreover, an anti-tumor study in H₂₂ and S180 tumor models showed that liposomal entrapment of Gem-Chol improved the anti-tumor effect of Gem. This study reports a potential formulation of Gem for clinical application.     

Preparation,Characterization, and Pharmacokinetics of Sterically Stabilized Nimodipine-Containing Liposomes

ABSTRACT

Nimodipine is a dihydropyridine calcium antagonist used in clinical trials in the treatment of ischemic damage in subarachnoid hemorrhage and commercially available as nimotop® intravenous infusion solution and tablets. However, due to its poor solubility in water, intravenous administration depends on the use of the dehydrated alcohol to achieve a clinically relevant concentrated infusion solution while the low bioavailability of the nimotop® tablets were far away from content. We have prepared a well-characterized novel lyophilized liposome-based nimodipine formulation that is sterile and easy-to-use. Of the several formulations examined, nimodipine-liposomes composed of ePC/CHOL 20:3 and co-surfactant poloxamer 188/sodium deoxycholate/ePC/3:0.3:5 were chosen for further studies. This composition was found to give more stable liposomes than other formulations. It gave 89.9% entrapment efficiency and particle size of 200 nm after lyophilization. The pharmacokinetic parameters following orally and intravenously administration to New Zealand rabbits were determined and compared with those of commercial nimodipine formulations. Encapsulation of nimodipine in liposomes produced marked differences over those of commercial preparations with an increased C_max, prolonged elimination half-life, and an increased value for AUC. The obtained values for mean residence time (MRT) indicated that nimodipine remains longer for liposomal formulation. Thus an optimum i.v. liposome formulation for nimodipine can be developed for an alternative to the commercial nimodipine preparations.     

Extrusion characteristics of aluminium alloy/SiCpmetal matrix composites

Abstract

Systematic extrusion studies have been carried out on aluminium alloy 2124/SiC_p metal matrix composites. Effects of various extrusion process parameters, such as die design, ram speed, extrusion ratio, reheat temperature, and lubrication, on the pressure requirement and surface quality of the as extruded circular rods have been investigated. Different volume fractions of SiC particles (10, 15, and 20 vol.-%) were used for the synthesis of metal matrix composite billets. These composites were synthesised using two different techniques, namely, stir casting and powder metallurgy. These billets were then hot extruded on a laboratory scale 500 ton vertical hydraulic press. The significance of specially designed dish shaped dies, avoiding the dead metal zone, has also been highlighted. The results indicated that the best extrusion was possible when powder metallurgical processed billets were extruded. Volume fraction analysis of ceramic reinforcement in the extruded rod (typically 2 m long) and in the extruded discard showed no appreciable backward migration of these particles during extrusion.     

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.     

Formulation design and optimization of novel soft glycerosomes for enhanced topical delivery of celecoxib and cupferron by Box–Behnken statistical design

Background: The present study describes glycerosomes (vesicles composed of phospholipids, glycerol and water) as a novel drug delivery system for topical application of celecoxib (CLX) and cupferron (CUP) compound.

Aim: The goal of this research was to design topical soft innovative vesicles loaded with CLX or CUP for enhancing the efficacy and avoiding systemic toxicity of CLX and CUP.

Methods: CLX and CUP loaded glycerosomes were prepared by hydrating phospholipid-cholesterol films with glycerol aqueous solutions (20–40%, v/v). Box–Behnken design, using Design-Expert® software, was the optimum choice to statistically optimize formulation variables. Three independent variables were evaluated: phospholipid concentration (X₁), glycerol percent (X₂) and tween 80 concentration (X₃). The glycerosomes particle size (Y₁), encapsulation efficiency percent (Y₂: EE %) and drug release (Y₃) were selected as dependent variables. The anti-inflammatory effect of CLX and CUP glycerosomal gel was evaluated by carrageenan-induced rat paw edema method followed by histopathological studies.

Results: The optimized formulations (CLX2* and CUP1*) showed spherical morphology under transmission electron microscopy, optimum particle size of 195.4?±?3.67?nm, 301.2?±?1.75?nm, high EE of 89.66?±?1.73%, 93.56?±?2.87%, high drug release of 47.08?±?3.37%, 37.60?±?1.89% and high cumulative amount of drug permeated in 8?h of 900.18?±?50.24, 527.99?±?34.90?µg.cm^?2 through hairless rat skin, respectively. They also achieved significant remarkable paw edema inhibition in comparison with the control group (p? Conclusion: Finally, the administration of CLX2* and CUP1* loaded glycerosomal gel onto the skin resulted in marked reduction of edema, congestive capillary and inflammatory cells and this approach may be of value in the treatment of different inflammatory disorders.     

Influence of small vanadium and cobalt additions on microstructure and properties of ductile iron

Abstract

Ductile irons containing additions of up to 0·44% Vand 0·48%Co have been prepared and tested in the as cast state and after aferritising heat treatment. In the heat treated condition the microstructure of the alloyed irons consists of graphite nodules in aferrite matrix that contains afine dispersion (20–80 nm in dia.) of V₄C₃ particles. These carbide particles produce dispersion strengthening and refine the grain size of the ferrite, resulting in an iron of intermediate strength and high ductility.

MST/3079     

Billet quenching extrusion process as efficient and reliable replacement for conventional extrusion of Al–Cu alloys

Abstract

In order to eliminate the separate solution soaking treatment used for Al–Cu extrudates, the influence of billet heat treatments before the extrusion process on a precipitation hardenable AlCu6PbBi (AA2011) alloy was studied. The hot deformation behaviour of the alloy was studied using compression tests. A comparison of the conventional extrusion process, press quenching and billet quenching (BQ) before extrusion was made in production on a 35 MN press. The transformation kinetics was studied by heat treating homogenised samples in salt baths. The mechanical testing, using tensile tests and the Brinell hardness test, and a microstructural investigation, using light and TEM microscopy, revealed that extrusion using the billet quenching process results in the formation of extrudates with similar mechanical properties, hardness and microstructures as those produced using conventional technology. In the extrudates produced by BQ a supersaturated solid solution is formed directly after cooling in a standing water wave, which makes BQ an efficient and reliable substitute for the conventional extrusion process.     

Part II: Bioavailability in Beagle Dogs of Nimodipine Solid Dispersions Prepared by Hot-Melt Extrusion

ABSTRACT

The aim of the present work was to investigate the in vitro dissolution properties and oral bioavailability of three solid dispersions of nimodipine. The solid dispersions were compared with pure nimodipine, their physical mixtures, and the marketed drug product Nimotop®. Nimodipine solid dispersions were prepared by a hot-melt extrusion process with hydroxypropyl methylcellulose (HPMC, Methocel E5), polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA, Plasdone S630®), and ethyl acrylate, methyl methacrylate polymer (Eudragit® EPO). Previous studies of XRPD and DSC data showed that the crystallinity was not observed in hot-melt extrudates, two T_gs were observed in the 30% and 50% NMD-HPMC samples, indicating phase separation. The weakening and shift of the N–H stretching vibration of the secondary amine groups of nimodipine as determined by FT-IR proved hydrogen bonding between the drug and polymers in the solid dispersion. The dissolution profiles of the three dispersion systems showed that the release was improved compared with the unmanipulated drug. Drug plasma concentrations were determined by HPLC, and pharmacokinetic parameters were calculated after orally administering each preparation containing 60 mg of nimodipine. The mean bioavailability of nimodipine was comparable after administration of the Eudragit® EPO solid dispersion and Nimotop®, but the HPMC and PVP/VA dispersions exhibited much lower bioavailability. However, the AUC_{0–12 hr} values of all three solid dispersions were significantly higher than physical mixtures with the same carriers and nimodipine powder.     

Press quenching of aluminium alloys

Abstract

The literature concerning press quenching is reviewed and the relevant precipitation kinetics are presented. Such kinetics may be presented on either continuous cooling curve or time–temperature–property diagrams. The homogenisation and subsequent reheating necessary are discussed in terms of microstructure and composition. Thermal considerations include heat transfer occurring both during the extrusion process and cooling after leaving the die. The interaction of extrudability and press quenching is discussed and it is shown that the ultimate solution must be one of compromise. The press effect is shown to be important and some results concerning the press quenching of 2000 series alloys are presented.

MST/742     

Application of hot melt extrusion for improving bioavailability of artemisinin a thermolabile drug

Hot melt extrusion has been used to produce a solid dispersion of the thermolabile drug artemisinin. Formulation and process conditions were optimized prior to evaluation of dissolution and biopharmaceutical performance. Soluplus^®, a low T_g amphiphilic polymer especially designed for solid dispersions enabled melt extrusion at 110?°C although some drug-polymer incompatibility was observed. Addition of 5% citric acid as a pH modifier was found to suppress the degradation. The area under plasma concentration time curve (AUC_0–24h) and peak plasma concentration (C_max) were four times higher for the modified solid dispersion compared to that of pure artemisinin.     

Application of 99mTc Labeling for Fast Comparative Screening of Preformed Liposomes in vivo

Abstract

Labeling of preformed liposomes with ^99mTc is a simple, quick, and highly versatile method, and its potential in the comparative screening of preformed liposomes with regard to their early biodistribution properties, such as the BLOOD/RES ratios at 2 and 30 min postadministration, was investigated. Liposomes differing in lipid composition and size were prepared and labeled under optimum conditions with ^99mTc using a slight modijication of a previously described method (1). The amount of SnCl₂ used to reduce pertechnetate affected liposome biodistribution. The labeling method employed was capable of detecting anticipated changes in liposome biodistribution caused by alterations in liposome composition or size. It could also reveal the effect of a relative immiscibility of monosialganglioside GM₁ with di-myristoy1-phosphatidyl-choline:di-myristoyl-phosphatidyl-glycerol (DMPC:DMPG) on the biodistribution of DMPC:DMPG:GM, liposomes. It is proposed that ^99mTc labeling of liposomes provides a tool for fast comparative screening of preformed liposomal preparations according to their early biodistribution.     

Characterization of Poly(Ethylene Oxide) as a Drug Carrier in Hot-Melt Extrusion

ABSTRACT

Poly(ethylene oxide) (PEO) as a drug carrier in hot-melt extrusion was studied by using a model drug, nifedipine, in a twin-screw extruder. Binary mixtures of PEO and nifedipine have been shown to be amenable to hot-melting at a temperature as low as 70°C, well below nifedipine's melting point (172°C). Hot-stage microscopy provided visual evidence that nifedipine can form a miscible dispersion with PEO at 120°C. Complete loss of nifedipine crystallinity when extrudated at and above 120°C with a drug loading of 20% (w/w) was further confirmed by differential scanning calorimetry (DSC) and X-ray diffraction. Cross-sectional imaging of the extrudates using scanning electron microscopy indicated homogeneous drug distribution inside PEO when the processing temperature was above 120°C. Raman spectroscopy confirmed drug-PEO interactions at a molecular level. Cryo-milled extrudates showed significant improvement in dissolution rate compared to either pure nifedipine or the physical mixture of PEO and nifedipine. A state of supersaturation was achieved after 10-minute release in pH 6.8 phosphate buffer. Finally, stability study demonstrated that the solid dispersion system is chemically stable for at least 3 months under the conditions of both 25°C/60% RH and 40°C/75% RH. Overall, PEO appears to be a promising aid/carrier to solublize poorly soluble drugs through the formation of solid dispersion via hot-melt extrusion, thereby improving dissolution and absorption.     

Investigation on photogenerated radicals of some carboxylates in solution and in aqueous dispersions of AgBr

Abstract

The photogenerated free radicals from formate, oxalate and acetate in aqueous solutions without and with dispered AgBr grains under illuminations of 355 nm laser light, natural light and monochromatic red, green or blue light were detected by electron spin resonance with spin-trap DMPO. The results showed that: (a) ·CO₂^? radicals were produced in the formate solution by all of these illuminations; (b) the signals of ·CO₂^? radicals were greatly intensified when an AgBr dispersion was present in the formate solution; (c) the signals of ·CO₂^? radicals in the oxalate solution were also detected and intensified when an AgBr dispersion was present, but only after illumination by the 355 nm laser; (d) ·CH₃ radicals, instead of ·CO₂^?, were weakly detected in the acetate solution, but only in the presence of AgBr under illumination by the 355 nm laser. The photochemical behaviour of these carboxylates, particularly formate and oxalate, perhaps implies their capability for trapping photogenerated holes and their potential for acting as a hole converter to an effective electron carrier.