W/O/W 다중유화법을 이용한 젬시타빈 함유 Methoxy Poly(ethylene glycol)-b-Poly(L-lactide) 미립자 제조

Preparation of insulin-loaded PLA/PLGA microcapsules by a novel membrane emulsification method and its release in vitro

The emulsification processes, during which acylglycerols/zinc stearate emulsifier, water, and oil phase formed ternary systems, such as water-in-oil (W/O) emulsions, oil-in-water (O/W) dispersions, and unstable oil-water mixtures, were investigated in order to characterize the progressive transformations of the dispersed systems. The type, structure, and phase transitions of the systems were found to be determined by temperature and water phase content. Crystallization of the emulsifier caused the destabilization and subsequent phase inversion of the emulsions studied, at a temperature of 60-61 degrees C. The observed destabilization was temporary and led, at lower temperature, to W/O emulsions, "O/W + O" systems, or O/W dispersions, depending on the water content. Simultaneous emulsification and cooling of 20-50 wt % water systems resulted in the formation of stable W/O emulsions that contained a number of large water droplets with dispersed oil globules inside them ("W/O + O/W/O"). In water-rich systems (60-80 wt % of water), crystallization of the emulsifier was found to influence the formation of crystalline vesicle structures that coexisted, in the external water phase, with globules of crystallized oil phase. Results of calorimetric, rheological, and light scattering experiments, for the O/W dispersions obtained, indicate the possible transition of a monostearoylglycerol-based alpha-crystalline gel phase to a coagel state, in these multicomponent systems.

Vesicles or liposomes are of great interest as drug delivery system or simple model for cell membranes. In biological environments vesicles are capable of transporting messenger molecules in high concentrations within a cell. For industrial applications, it is necessary to produce vesicles which are unilamellar, monodisperse, easy to adjust in size, and which can be filled with various types of active compounds. Particularly the defined filling of these tiny compartments has not yet been brought to a large scale. Our research project within the DFG-priority program 1273 (Colloid Process Engineering) was focused on a new method, which can easily be used for the continuous production of such colloidal particles. Moreover, the novel approach allows us to use a large variety of incorporated ingredients. The high encapsulation efficiency in addition with the flexible synthesis facilitates the utilization as a drug carrier system. On grounds of the interesting structure, consisting of an unilamellar surfactant shell, which is swollen with oil, and an enclosed aqueous reservoir (core), the produced colloidal particles may alternatively be denoted as a special case of water-in-water-emulsions. The synthesis of these particles occurred in three steps. First, a water phase was covered by an oil phase containing surfactants or lipids. A water-in-oil emulsion or microemulsion was then added to the oil phase. In the third step the phase transfer of aqueous droplets from the oil phase into the underlying water phase was stimulated by sedimentation, flow, electric forces or centrifugation processes. During this phase transition a small amount of the organic solvent was entrapped in the ultra-thin membranes and influenced the properties of the filled, vesicular structures. The thin layer of organic solvents reduced the diffusion processes from the core of the vesicles into the surrounding water phase. This might be of special advantage for the encapsulation of water soluble ingredients as drugs or other interesting compounds. It also offers the opportunity, to store oil soluble substances in the swollen membranes of the vesicles. On the other hand the thin oil layers surrounding the vesicles induced creaming processes and influenced the stability of these aggregates. For all applied experimental techniques we systematically measured the encapsulation capacity, the size of the filled vesicles, the amount of entrapped oil within the membranes and the stability of these aggregates. It turned out, that the jet-stream and the electrospray technique provided the best results concerning long-term stability, vesicle production and encapsulation efficiency. Due to the broad spectrum of different applications, we could use the phase-transfer process for the production of tailor-made, filled and swollen vesicles, which showed interesting properties.

Biodegradable polymer nano‐ and microparticles are of interest as drug carriers due to their capability to modulate drug release. Two different methods, including solvent displacement and spray drying, are used, resulting in the fabrication of Artemisone (ART)‐loaded polymeric nano‐ and microparticles, respectively. Scanning electron microscopy, transmission electron microscopy, dynamic light scattering, and asymmetric flow field flow fractionation (AF4) are employed to evaluate the morphology and size of the particles. The encapsulation and loading efficiency of the drug as well as cumulative release are characterized using high‐performance liquid chromatography (HPLC). HPLC results confirm that the spray drying method provides higher encapsulation efficiencies of about 97%, whereas, in nanoparticles prepared by solvent displacement, the highest encapsulation efficiency is 71%. Using these production methods, round‐shaped particles with homogeneous size distribution are fabricated. Moreover, the preparation procedure is optimized to obtain particles with the highest encapsulation and drug loading efficiency. Using the solvent displacement method, stable dispersions in water are obtained without adding any surfactant, whereas, for spray‐dried microparticles, tween 80 is needed to redisperse particles. The micro‐ and nanoparticles show different release properties, which are of interest for drug delivery application of hydrophobic drugs like ART.

The effect of the hydrophobicity of microchannels and components in water and oil phases on droplet formation in microchannel water-in-oil emulsification

Encapsulation of amino acids in water-in-oil-in-water emulsions stabilized by gum arabic and xanthan gum

In this work, a new kind of multiple drug‐release system, graphene oxide (GO)@polylactic acid (PLA)@hydroxyapatite (HA) composite microcapsule, was constructed through the double Pickering emulsion method. In the preparation of the microcapsules, GO and HA were used as stabilizers for the water‐in‐oil (W1/O) and oil‐in‐water (O/W2) systems, respectively. Furthermore, GO, as the internal water phase (W1), could carry a hydrophilic drug (5‐FU), while PLA, as the oil phase (O), was employed to effectively embed a hydrophobic drug (coumarin). Additionally, the pH‐sensitive HA in an external water phase (W2) could also act as a vector to carry hydrophilic rose bengal, due to its excellent adsorption ability. Dynamic optical experiment results show that the uniform size and complete structure of the GO@PLA@HA composite microcapsules can be obtained at a volume ratio of W1/O/W2 = 3:20:100. The prepared GO@PLA@HA composite microcapsules present good biocompatible, biodegradable, and pH‐sensitive features. The respective drug encapsulation efficiencies of 5‐FU, coumarin, and rose bengal are estimated to be 13.38 %, 48.58 %, and 53.24 %, and their loading efficiencies are 0.15 %, 4.49 %, and 5.3 %, respectively. The controlled release of drugs can be realized by the degradation of HA in the simulated acidic tumoral environment, which illustrates the pH‐triggered drug‐release behavior of HA. More importantly, the above three different drugs, with their hydrophilic or hydrophobic natures, could be loaded into the single W1@O@W2 microcapsule, and they exhibited multistage sustained release in PBS solution at pH 5.0. Thus, the as‐synthesized composite microcapsules, with their multistage drug‐delivery function, may act as a new and promising drug‐delivery system in the medical field.

Efficient encapsulation of proteins in submicro liposomes using a supercritical fluid assisted continuous process

Ionotropic gelation is a low-cost, easy and green microencapsulation technique. However, the encapsulation of highly soluble compounds is challenging because of the wide loss of material into the external water phase by passive diffusion and the consequent low encapsulation efficiency. In this work an important increase of encapsulation efficiency for Thymus vulgaris L. aqueous extract in alginate-based microparticles has been obtained. A formulation with the proper thyme extract/alginate ratio (30:70) was used as reference and then optimized by adding different co-carrier excipients. Microparticles obtained by dropping a solution containing thyme extract and alginate into a chitosan/calcium-chloride/acid acetic solution lead to a high encapsulation efficiency (70.43 ± 5.28 %). After drying, microparticles had a particle size of 1096 ± 72 μm, 20.087 ± 1.487 % of extract content, 6.2 % of residual water, and showed a complete release of thyme extract within one hour. Combining alginate and chitosan as polymeric co-carrier was a valuable option for efficiently encapsulating an aqueous extract by ionotropic gelation.

Particle-stabilized W1/O/W2 emulsion gels were fabricated using a two-step procedure: ( i) a W1/O emulsion was formed containing saccharose (for osmotic stress balance) and gelatin (as a gelling agent) in the aqueous phase and polyglycerol polyricinoleate (a lipophilic surfactant) in the oil phase; ( ii) this W1/O emulsion was then homogenized with another water phase (W2) containing wheat gliadin nanoparticles (hydrophilic emulsifier). The gliadin nanoparticles in the external aqueous phase aggregated at pH 5.5, which led to the formation of particle-stabilized W1/O/W2 emulsion gels with good stability to phase separation. These emulsion gels were then used to coencapsulate a hydrophilic bioactive (epigallocatechin-3-gallate, EGCG) in the internal aqueous phase (encapsulation efficiency = 65.5%) and a hydrophobic bioactive (quercetin) in the oil phase (encapsulation efficiency = 97.2%). The emulsion gels improved EGCG chemical stability and quercetin solubility under simulated gastrointestinal conditions, which led to a 2- and 4-fold increase in their effective bioaccessibility, respectively.

Background/Objectives: Nanoemulsions (NEs) possess properties that enhance the solubility, bioavailability and therapeutic efficacy of drugs. Chalcones are compounds known for their antifungal properties. In this study, we evaluated different emulsification techniques to create alginate nanoemulsions containing chalcone (1E,4E)-1,5-bis (4-methoxyphenyl) penta-1,4-dien-3-one (DB4OCH3). Our goal was to develop an antifungal formulation targeting Candida albicans strains. Methods: Ultrasound and ultrasound combined with high-speed homogenization techniques were used to prepare alginate-stabilized nanoemulsions. Particle size, zeta potential and encapsulation efficiency were evaluated. Additionally, in vitro release studies were conducted. Results: The combined emulsification technique produced stable nanoparticles with high encapsulation efficiency and antifungal activity, with a minimum inhibitory concentration of 8.75 μg/mL for the nanoemulsions compared to 312 µg/mL for free DB4OCH3. NEs' effectiveness can be attributed to their ability to form nanodroplets efficiently, facilitating the solubilization of the chalcone in the oily phase. The particle size varied between 195.70 ± 2.69 and 243.40 ± 4.49 nm, with an increase in chalcone concentration leading to larger particle sizes. The zeta potential showed values from -91.77 ± 5.58 to -76.90 ± 4.44 mV. The UHS-7 sample exhibited an encapsulation efficiency of 92.10% ± 0.77, with a controlled in vitro release of 83% after 34 h. Molecular docking simulations showed that the aromatic nature of DB4OCH3 resulted in the formation of apolar interactions with aromatic residues located in the active site of the TMK, as observed in their respective co-crystallized inhibitors, within an affinity energy range that enables optimum specificity of the ligand for these two pathways. Pharmacokinetic analyses indicated high passive cell permeability and low hepatic clearance, and phase I metabolism reduces its oral bioavailability and metabolic stability, suggesting a promising active ingredient as an oral drug with control of the daily oral dose administered. Conclusions: The combined nanoemulsification technique led to the formation of finely dispersed nanodroplets that favored the solubilization of the chalcone in the oil phase, which led to a better performance in the antifungal properties. DB4OCH3 shows promise as an oral drug with controlled dosing.

The mobility of Winsor III microemulsions, which can form in reservoirs when a surfactant formulation contacts oil, has become a critical parameter for feasibility evaluations of surfactant flooding EOR. The reason is that these bicontinous phases with low mobility are likely to impair the sweep efficiency of the remobilized oil. The common procedures to evaluate microemulsion's mobility are based on viscosity measurements. As they involve rheometers, namely pure shear flows, and conditions where microemulsions are separated from the water and oil phases they should remain equilibrated with, they are not satisfactory. We present a new method to directly determine the mobility of microemulsions at equilibrium and in-situ, namely when flowing in porous media. The method consists in preforming the Winsor III microemulsion in a buffer cell and then injecting it in a small sized core plug. The bicontinous phase stays at equilibrium because the oil and water phases, present in the buffer cell, remain in contact with it. The mobility is assessed through the resistance factor (or mobility reduction factor), relative to the water phase injected first. This observable accounts for both viscosity and potential permeability impairment effect. As it directly represents the reduction of the mobility of the water phase, it is representative of phenomena taking place in the reservoir. During a typical experiment, the same microemulsion is also injected in a capillary tube, in order to determine its viscosity in a pure shear flow. Winsor III microemulsions were injected in sandstone plugs of three different permeabilities (1700 to 45 mD), and in a 170 mD carbonate plug. The first outcomes are that the resistance factors in the porous media and capillary relative viscosities have a marked shear-thinning behavior but are always of the same order of magnitude. This indicates that the flow of microemulsions entails no or little permeability impairment. Based on the experimental determination of the porous media's shape factors, the resistance factors and capillary viscosity data were also plotted against the equivalent wall shear rate. For the highest permeability sandstone, the capillary and porous medium data scaled almost perfectly, showing that, in this case, the microemulsion's transport properties are that of an ideal non-Newtonian fluid. However, increasing deviations were observed when decreasing the sandstone permeability as well as for the carbonate porous medium. This suggests that microemulsions are strongly affected by the composite deformations taking place in complex microscopic pore structures. These outcomes show the importance of determining the microemulsion-induced resistance factor in representative conditions in order to forecast for the impact of microemulsion's mobility in reservoirs. Furthermore, the method proposed can be applied to investigate close to optimum conditions as well as to study the propagation of microemulsions.

The impact of connate water saturation and salinity on oil recovery and CO2 storage capacity during carbonated water injection in carbonate rock

Oxalate particles of rare-earth-metal elements were prepared by using an emulsion liquid membrane (ELM, water-in-oil-in-water (W/O/W) emulsion) system, consisting of Span 83 (sorbitan sesquioleate) as a surfactant and bis(1,1,3,3-tetramethylbutyl)phosphinic acid as an extractant (cation carrier). Rare-earth-metal ions were extracted from the external water phase and stripped into the internal water phase to make oxalate particles. Well-defined spherical oxalate particles, smaller than 0.5 μm in diameter, were obtained for lighter and heavier rare-earth-metals such as Pr, Sm, Eu, Gd, Dy, Y, and Yb, following the formation of primary particles of about 20 nm in size. The present result differs from that obtained using EHPNA (2-ethylhexylphosphonic acid mono-2-ethylhexyl ester) as an extractant, where no submicrometer-sized spherical particles are obtained for the heavier rare-earth metals such as Dy, Y, and Yb. The smaller extracting ability of alkylphosphinic acid eases the stripping of rare-earth-metal ions by oxalic acid into the internal phase. Effects of the internal water droplet size, the rare-earth-metal ion concentration in the external water phase, and the volume ratio of organic membrane phase to internal water phase of the W/O emulsion (O/A ratio), on the size of spherical particles, were investigated. The control of the particle size was found to be feasible by control of the feed rare-earth-metal concentration and the size of the internal water droplets.

Preparation of polystyrene/sodium monofluorophosphate microcapsules by W/O/W solvent evaporation method