Oil core-polymer shell microcapsules prepared by internal phase separation from emulsion droplets. I. Characterization and release rates for microcapsules with polystyrene shells

Microcapsules with an oil core surrounded by a polymeric shell have been prepared by the controlled phase separation of polymer dissolved within the oil droplets of an oil-in-water emulsion. The dispersed oil phase consists of the shell polymer (polystyrene), a good solvent for the polymer (dichloromethane), and a poor solvent for the polymer (typically hexadecane). Removal of the good solvent results in phase separation of the polymer within the oil droplets. If the three interfacial tensions between the core oil, the shell-forming polymer, and the continuous phase are of the required relative magnitudes, a polymer shell forms surrounding the poor solvent. A UV-responsive organic molecule was added to the oil phase, prior to emulsification, to investigate the release of a model active ingredient from the microcapsules. This molecule should be soluble in the organic core but also have some water solubility to provide a driving force for release into the continuous aqueous phase. As the release rate of the active ingredient is a function of the thickness of the polymeric shell, for controlled release applications, it is necessary to control this parameter. For the preparative method described here, the thickness of the shell formed is directly related to the mass of polymer dissolved in the oil phase. The rate of volatile solvent removal influences the porosity of the polymer shell. Rapid evaporation leads to cracks in the shell and a relatively fast release rate of the active ingredient. If a more gentle evaporation method is employed, the porosity of the polymer shell is decreased, resulting in a reduction in release rate. Cross-linking the polymer shell after capsule formation was also found to decrease both the release rate and the yield of the active ingredient. The nature of the oil core also affected the release yield.     

Block Copolymer Capsules with Structure‐Dependent Release Behavior

Although high‐boiling non‐solvent induced macrophase separation in emulsion droplets has been widely applied for the fabrication of polymeric capsules, precise control of their structures remains a great challenge. Herein, block copolymer capsules with tunable shell structures were fabricated by employing a non‐solvent as a liquid template in emulsion droplets. The properties of the non‐solvents dictate the phase separation sequence in the droplets and the capsule formation mechanism. Two different pathways for capsule formation were observed, and could be applied to predict the shell structure. The structured capsules could be transformed into mesoporous capsules, which demonstrated an intriguing structure‐dependent release behavior. Capsules with spherical shell structures displayed the best permeability, while those with lamellar shell structures showed the slowest release, but with a stepwise profile. After loading with an anticancer drug, different capsules induced different apoptosis ratios in cancer cell studies.     

The effect of formulation variables on the characteristics of insulin-loaded poly(lactic-co-glycolic acid) microspheres prepared by a single phase oil in oil solvent evaporation method

Biodegradable polymeric microspheres are ideal vehicles for controlled delivery applications of drugs, peptides and proteins. Amongst them, poly(lactic-co-glycolic acid) (PLGA) has generated enormous interest due to their favorable properties and also has been approved by FDA for drug delivery. Insulin-loaded PLGA microparticles were prepared by our developed single phase oil in oil (o/o) emulsion solvent evaporation technique. Insulin, a model protein, was successfully loaded into microparticles by changing experimental variables such as polymer molecular weight, polymer concentration, surfactant concentration and stirring speed in order to optimize process variables on drug encapsulation efficiency, release rates, size and size distribution. A 2⁴ full factorial design was employed to evaluate systematically the combined effect of variables on responses. Scanning electron microscope (SEM) confirmed spherical shapes, smooth surface morphology and microsphere structure without aggregation. FTIR and DSC results showed drug–polymer interaction. The encapsulation efficiency of insulin was mainly influenced by surfactant concentration. Moreover, polymer concentration and polymer molecular weight affected burst release of drug and size characteristics of microspheres, respectively. It was concluded that using PLGA with higher molecular weight, high surfactant and polymer concentrations led to a more appropriate encapsulation efficiency of insulin with low burst effect and desirable release pattern.     

Polyelectrolyte multilayer capsules as vehicles with tunable permeability

This review is devoted to a novel type of polymer micro- and nanocapsules. The shell of the capsule is fabricated by alternate adsorption of oppositely charged polyelectrolytes (PEs) onto the surface of colloidal particles. Cores of different nature (organic or inorganic) with size varied from 0.1 to 10 mum can be used for templating such PE capsules. The shell thickness can be tuned in nanometer range by assembling of defined number of PE layers. The permeability of capsules depends on the pH, ionic strength, solvent, polymer composition, and shell thickness; it can be controlled and varied over wide range of substances regarding their molecular weight and charge. Including functional polymers into capsule wall, such as weak PEs or thermosensitive polymers, makes the capsule permeability sensitive to correspondent external stimuli. Permeability of the capsules is of essential interest in diverse areas related to exploitation of systems with controlled and sustained release properties. The envisaged applications of such capsules/vesicles cover biotechnology, medicine, catalysis, food industry, etc.     

Designer polymer-based microcapsules made using microfluidics

Filled microcapsules made from double emulsion templates in microfluidic devices are attractive delivery systems for a variety of applications. The microfluidic approach allows facile tailoring of the microcapsules through a large number of variables, which in turn makes these systems more challenging to predict. To elucidate these dependencies, we start from earlier theoretical predictions for the size of double emulsions and present quantitative design maps that correlate parameters such as fluid flow rates and device geometry with the size and shell thickness of monodisperse polymer-based capsules produced in microcapillary devices. The microcapsules are obtained through in situ photopolymerization of the middle oil phase of water-in-oil-in-water double emulsions. Using polymers with selected glass transition temperatures as the shell material, we show through single capsule compression testing that hollow capsules can be prepared with tunable mechanical properties ranging from elastomeric to brittle. A quantitative statistical analysis of the load at rupture of brittle capsules is also provided to evaluate the variability of the microfluidic route and assist the design of capsules in applications involving mechanically triggered release. Finally, we demonstrate that the permeability and microstructure of the capsule shell can also be tailored through the addition of cross-linkers and silica nanoparticles in the middle phase of the double emulsion templates.     

聚L-谷氨酸担载胰岛素口服微球的制备与评价

以聚L-谷氨酸为载体材料, 采用无水乳液法制备了口服胰岛素微球, 微球直径在5~20 μm, 载药质量分数为5%~9%. 载药微球具有良好的pH敏感释放行为, 在胃模拟液中2 h释放量约为5%, 在肠道模拟液中2 h释放90%以上. 考察聚合物分子量、溶液浓度、理论投药量及混合材料对微球释放行为的影响.     

Morphology Control in Metallocene Polymerization; Organic Supports vs. Non-aqueous Emulsion Polymerization

Nano-sized latex support in metallocene polymerization is known to be able to avoid fuming or leaching and leads to a powder-like and well-processable polymer. Focus has been put on the fragmentation behaviour of the particles, a key parameter to morphology control. To study the different behaviour of the new systems as classical inorganic supported metallocenes, e.g. SiO₂, a wide range of analytical methods were applied. Fluorescence microscopy, polymerization videomicroscopy, as well as kinetic studies led to a better understanding of the process. The performance of the supports was approved by several phenoxy-imine type catalysts (“FI-Catalyst”), which were combined with a tailored latex support. Ultra high molecular weight polyethylene (UHMWPE) was synthesized without any reactor fouling thereby. A different approach towards the metallocene catalyzed olefin polymerization is also presented. Based on emulsion polymerization, it enables very good control over product morphology. The completely hydrophobic system consists of perfluorinated solvent as a continuous phase and a hydrocarbon solvent as a dispersed phase. In contrast to the already existing water based emulsion polymerization of olefins, very high molecular weights are achieved.     

Synthesis of polymer–inorganic patchy microcapsules with tunable patches

We introduce a facile and versatile approach for the formation of ball-like polymer–inorganic patchy microcapsules with a tunable shell by combining sol–gel chemistry of silica precursor and phase separation between the polymer and the precursor. Firstly, chloroform-in-water emulsion droplets containing poly(methyl methacrylate) (PMMA), silica precursor [tetraethyl orthosilicate (TEOS)] and co-surfactant sodium dioctyl sulfosuccinate (Aerosol OT or AOT) were prepared by shaking the mixture by hand. Due to the added AOT, water molecules diffuse into the chloroform droplets, and the tiny water droplets would coalesce gradually, triggering the formation of double emulsion droplets. Upon further solvent evaporation, the concentration of the polymer and the silica precursor in the oil shell of the double emulsions increases, leading to the phase separation between the polymer and the precursors (and partially formed silica through the hydrolysis and condensation of TEOS). Because of the confined geometry of the oil shell in the double emulsions, polymeric disc-like structures, stabilized by AOT, were dispersed in the silica precursors. Meanwhile, the silica precursor hydrolyzed and condensed when brought in contact with the aqueous solution, ultimately leading to the formation of a mineralized shell around the polymer domains and the hybrid patchy microcapsules. Effect of synthesis conditions, such as the amount of TEOS, AOT, and PMMA used, the pH value, and solvent evaporation rate on interfacial behavior of the solvent/water; and the morphology of the patchy microcapsules were investigated. Patchy microcapsules with tunable patch size and shape can be generated through tailoring the experimental parameters. Our study indicates that the hybrid patchy microcapsules can be formed by taking advantage of the sol–gel chemistry and the phase separation process, and the underlying generality of the synthesis procedure allows for a variety of applications, including drug storage, coatings, delivery, catalysis, and smart building blocks in self-assembling systems.     

Biocompatible microcapsules with a water core templated from single emulsions

We use single emulsions as templates to fabricate monodisperse biocompatible microcapsules with a water core. These microcapsules are fabricated using FDA-approved polymer and non-toxic solvents and are of great use in drugs, cosmetics and foods.     

Simple model for grafted polymer brushes

The first theories of grafted polymer brushes assumed a step profile for the monomer density. Later, the real density profile was obtained from Monte Carlo or molecular dynamics simulations and calculated numerically using a self-consistent field theory. The analytical approximations of the solutions of the self-consistent field equations provided a parabolic dependence of the self-consistent field, which in turn led to a parabolic distribution for the monomer density in neutral brushes. As shown by numerical simulations, this model is not accurate for dense polymer brushes, with highly stretched polymers. In addition, the scaling laws obtained from the analytical approximations of the self-consistent field theory are identical to those derived from the earlier step-profile-approximation and predict a vanishing thickness of the brush at low graft densities, and a thickness exceeding the length of the polymer chains at high graft densities. Here a simple model is suggested to calculate the monomer density and the interaction between surfaces with grafted polymer brushes, based on an approximate calculation of the partition function of the polymer chains. The present model can be employed for both good and poor solvents, is compatible with a parabolic-like profile at moderate graft densities, and leads to an almost steplike density for highly stretched brushes. While the thickness of the brush depends strongly on solvent quality, it is a continuous function in the vicinity of the temperature. In good and moderately poor solvents, the interactions between surfaces with grafted polymer brushes are always repulsive, whereas in poor solvents the interactions are repulsive at small separations and become attractive at intermediate separation distances, in agreement with experiment. At large separations, a very weak repulsion is predicted.     

Polymer solubility in mixed solvents

Modeling results indicate that polymer chains in mixtures of a good with a bad solvent exhibit preferential adsorption of the good solvent. That phenomenon is found to be strongly dependent on molecular weight and it increases with a decrease in chain length. These results have important consequences on polymer solubility. Thus, a low molecular weight chain in a solvent mixture behaves as if it were dissolved in the pure good solvent component, whereas the solubility of a longer chain is controlled by the average mixture composition. As a result, quenching a polydisperse system below the cloud point may induce molecular weight segregation between the two phases: the longer chains, which precipitate out first, tend to populate the polymer rich phase whereas the shorter chains, having greater solubility, remain in the solvent phase. © 1999 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 37: 2782–2787, 1999     

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

Uniform-sized biodegradable PLA/PLGA microcapsules loading recombinant human insulin (rhI) were successfully prepared by combining a Shirasu Porous Glass (SPG) membrane emulsification technique and a double emulsion-evaporation method. An aqueous phase containing rhI was used as the inner water phase (w1), and PLA/PLGA and Arlacel 83 were dissolved in a mixture solvent of dichloromethane (DCM) and toluene, which was used as the oil phase (o). These two solutions were emulsified by a homogenizer to form a w1/o primary emulsion. The primary emulsion was permeated through the uniform pores of a SPG membrane into an outer water phase by the pressure of nitrogen gas to form the uniform w1/o/w2 droplets. The solid polymer microcapsules were obtained by simply evaporating solvent from droplets. Various factors of the preparation process influencing the drug encapsulation efficiency and the drug cumulative release were investigated systemically. The results indicated that the drug encapsulation efficiency and the cumulative release were affected by the PLA/PLGA ratio, NaCl concentration in outer water phase, the inner water phase volume, rhI-loading amount, pH-value in outer water phase and the size of microcapsules. By optimizing the preparation process, the drug encapsulation efficiency was high up to 91.82%. The unique advantage of preparing drug-loaded microcapsules by membrane emulsification technique is that the size of microcapsules can be controlled accurately, and thus the drug cumulative release profile can be adjusted just by changing the size of microcapsules. Moreover, much higher encapsulation efficiency can be obtained when compared with the conventional mechanical stirring method.     

Preparation of PLGA microspheres with different porous morphologies

Poly(D,L-lactide-co-glycolide)(PLGA) microspheres were prepared by emulsion solvent evaporation method. The influences of inner aqueous phase, organic solvent, PLGA concentration on the morphology of microspheres were studied. The results showed that addition of porogen or surfactants to the inner aqueous phase, types of organic solvents and polymer concentration affected greatly the microsphere morphology. When dichloromethane was adopted as organic solvent, microspheres with porous structure were produced. When ethyl acetate served as organic solvent, two different morphologies were obtained. One was hollow microspheres with thin porous shell under a lower PLGA concentration, another was erythrocyte-like microspheres under a higher PLGA concentration. Three types of microspheres including porous, hollow core with thin porous shell(denoted by hollow in brief) and solid structures were finally selected for in vitro drug release tests. Bovine serum albumin(BSA) was chosen as model drug and encapsulated within the microspheres. The BSA encapsulation efficiency of porous, hollow and solid microspheres was respectively 90.4%, 79.8% and 0. And the ultimate accumulative release was respectively 74.5%, 58.9% and 0. The release rate of porous microspheres was much slower than that of hollow microspheres. The experiment results indicated that microspheres with different porous structures showed great potentials in controlling drug release behavior.     

DEMULSIFICATION OF WATER IN OIL EMULSIONS USING WATER SOLUBLE DEMULSIFIERS

The possibility of using a water soluble,as opposed to the conventional oil soluble demulsifier, to destabilize a w/o emulsion in crude oil has been explored. It was found experimentally that a surfactant soluble in the water (dispersed) phase could destabilize the emulsion. Polymer molecules with varying HLB's and molecular weights and structure were synthesized and these compounds were added to the water phase to destabilize the water/crude oil emulsions. Molecules with a high percentage of hydrophilic groups and low molecular weights showed very good demulsifying abilities.     

Controlled Release of Encapsulated Bioactive Volatiles by Rupture of the Capsule Wall through the Light‐Induced Generation of a Gas

The encapsulation of photolabile 2‐oxoacetates in core–shell microcapsules allows the light‐induced, controlled release of bioactive compounds. On irradiation with UVA light these compounds degrade to generate an overpressure of gas inside the capsules, which expands or breaks the capsule wall. Headspace measurements confirmed the light‐induced formation of CO and CO₂ and the successful release of the bioactive compound, while optical microscopy demonstrated the formation of gas bubbles, the cleavage of the capsule wall, and the leakage of the oil phase out of the capsule. The efficiency of the delivery system depends on the structure of the 2‐oxoacetate, the quantity used with respect to the thickness of the capsule wall, and the intensity of the irradiating UVA light.     

A Model for the Emulsion Polymerization of Vinyl Chloride

Phenomena of emulsion polymerization of vinyl chloride have been analyzed on the molecular scale. A quantitative model is developed in which the polymerization is assumed to occur in a shell surrounding the dead core of the particles. The shell has the same composition as the entire particle, but it is assumed that the active species generated in the aqueous phase are not able to diffuse to the center of the particles and rather remain in a zone of limited thickness. Kinetic and geometric parameters are determined by fitting calculated values of rates and molecular weights to experimental data at 50°C.     

Dissipative Particle Dynamics Simulation of Onion Phase in Star-block Copolymer

A dissipative particle dynamics simulation technique was used to investigate the effect of molecular architecture of star-block copolymer on the patterned structure in a nanodroplet. With increasing the ratio of solvophilic to block length to solvophobic block length(R_H/T), solvophobic sphere, ordered hexagonal phase, onion phase, perforated onion phase and flocculent phase are formed, respectively. Since onion phase has potential application in controlled drug release, it has received wide attention experimentally and theoretically. Our simulation indicates onion phase forms at a certain R_H/T(close to but less than 1). A star-block copolymer molecule has two conformations in onion phase: either fully located in a shell or shared by two neighboring shells. Central structure affects onion's final shape. The molecular number of the copolymer in each shell is a quadratic function of the shell's radius. The arm number of star-block copolymer has little influence on onion's structure, but slightly affects the solvent content. Additionally, we studied the influence of arm length on onion's structure.     

Formation of Pickering emulsions stabilized via interaction between nanoparticles dispersed in aqueous phase and polymer end groups dissolved in oil phase

The influence of end groups of a polymer dissolved in an oil phase on the formation of a Pickering-type hydroxyapatite (HAp) nanoparticle-stabilized emulsion and on the morphology of HAp nanoparticle-coated microspheres prepared by evaporating solvent from the emulsion was investigated. Polystyrene (PS) molecules with varying end groups and molecular weights were used as model polymers. Although HAp nanoparticles alone could not function as a particulate emulsifier for stabilizing dichloromethane (oil) droplets, oil droplets could be stabilized with the aid of carboxyl end groups of the polymers dissolved in the oil phase. Lower-molecular-weight PS molecules containing carboxyl end groups formed small droplets and deflated microspheres, due to the higher concentration of carboxyl groups on the droplet/microsphere surface and hence stronger adsorption of the nanoparticles at the water/oil interface. In addition, Pickering-type suspension polymerization of styrene droplets stabilized by PS molecules containing carboxyl end groups successfully led to the formation of spherical HAp-coated microspheres.     

Preparation of poly(N-isopropylacrylamide) emulsion gels and their drug release behaviors

Stimuli-sensitive drug delivery systems (DDSs) have attracted considerable attention in medical and pharmaceutical fields; thermosensitive DDS dealing with poly(N-isopropylacrylamide) (poly(NIPA)) have been widely studied. Novel NIPA emulsion gels, i.e., NIPA hydrogels containing distributed oil (oleyl alcohol) microdroplets, were synthesized by means of an emulsion-gelation method in which the polymerization of hydrogels in an aqueous phase in an oil-in-water (O/W) emulsion and the loading of a lipophilic drug (indomethacin) dissolved in an oil phase were accomplished simultaneously. The pulsatile (on-off) drug release from the NIPA emulsion gel loading indomethacin to a phosphate buffered saline (PBS) solution was successfully controlled by a temperature swing between 25 degrees C (release off) and 40 degrees C (release on). The mechanism of the pulsatile drug release was discussed in relation to the diffusion rate, distribution ratio, solvent exchange of NIPA hydrogels, and drug release from an NIPA organogel. The mechanism was as follows: the solvent exchange occurred within the NIPA emulsion gel (the NIPA gel-network absorbed oleyl alcohol with indomethacin) at temperatures above the LCST, and the diffusion rate of indomethacin through the solvent-exchanged gel was higher at 40 degrees C than at 25 degrees C.     

The Soret effect in dilute polymer solutions: influence of chain length, chain stiffness, and solvent quality

Thermal diffusion in dilute polymer solutions is studied by reverse nonequilibrium molecular dynamics. The polymers are represented by a generic bead-spring model. The influence of the solvent quality on the Soret coefficient is investigated. At constant temperature and monomer fraction, a better solvent quality causes a higher affinity for the polymer to the cold region. This may even go to thermal-diffusion-induced phase separation. The sign of the Soret coefficient changes in a symmetric nonideal binary Lennard-Jones solution when the solvent quality switches from good to poor. The known independence of the thermal diffusion coefficients of the molecular weight is reproduced for three groups of polymers with different chain stiffnesses. The thermal diffusion coefficients reach constant values at chain lengths of around two to three times the persistence length. Moreover, rigid polymers have higher Soret coefficients and thermal diffusion coefficients than more flexible polymers.