Hydrogel-shelled biodegradable microspheres for sustained release of encapsulants

Biodegradable microparticles are promising for the sustained release of encapsulated lipophilic drugs. In particular, the microparticles with uniform size show excellent linearity of cumulated release over time with minimized initial burst. Here, we encapsulate the biodegradable microparticles with a hydrogel shell to improve the controllability over the sustained release and suspension stability. With a capillary microfluidic device, monodisperse oil-in-water-in-oil (O/W/O) double-emulsion droplets are produced to have a toluene solution of polylactic acid (PLA) in the core and sodium alginate and calcium-ethylenediaminetetraacetic acid (EDTA) complex in the shell, whereas the continuous oil phase contains acetic acid. As the toluene evaporates, PLA consolidates to form a microsphere in the core. At the same time, acetic acid diffuses from the continuous phase to the water layer, which causes the dissociation of the Ca-EDTA complex and the gelation of alginate. The hydrogel-shelled PLA microspheres are transferred from the oil to an aqueous solution of calcium chloride, which further tightens the gel shell. The resulting core-shell microspheres show sustained release of encapsulants for extended periods as the hydrogel shell serves as a diffusion barrier. Moreover, the hydrogel shells prevent interparticle agglomeration and adhesion to the solid walls, securing high suspension stability during the injection.     

Synthesis of cross-linked polymer microspheres in supercritical carbon dioxide

Herein we report the synthesis of highly cross-linked polymers based on divinylbenzene by heterogeneous polymerization in supercritical CO₂ (scCO₂). The polymers were isolated in the form of discrete microspheres (diameter = 1.5–5 μm) in good yields (≥90%), in the absence of any stabilizers. In the presence of a CO₂-soluble polymeric stabilizer, much smaller particles (diameter <0.5 μm) were formed in high yields (≥95%) by emulsion polymerization in scCO₂.     

Fabrication of double-walled microspheres for the sustained release of doxorubicin

Double-walled microspheres with poly(L-lactic acid) shells and poly(DL-lactic-co-glycolic acid) cores were fabricated using solvent evaporation technique which involves the phase separation phenomenon of a binary composite of these two polymers. Doxorubicin, a hydrophilic drug, was entrapped within the core of these double-walled microspheres with different core-shell thicknesses and compositions to investigate the in vitro release on this class of microspheres. Microspheres of different size ranging from 50 to 300 microm were also fabricated to investigate whether this method is suitable for fabricating small particles for intramuscular injection applications, and their phase separation and surface morphology were examined by differential scanning calorimetry, scanning electron microscopy, and optical microscopy.     

Photo cross-linked biodegradable hydrogels for enhanced vancomycin loading and sustained release

A series of biodegradable hydrogels based on dextran and poly（L-glutamic acid） were fabricated for effective vancomycin loading and release. The preparation of hydrogels was simply achieved by photo cross-linking of methacrylated dextran and poly（L-glutamic acid）-g-hydroxyethyl methacrylate （PGH） in the presence of photoinitiator 12959. The structures of hydrogels were characterized by FTIR and SEM. The swelling and enzymatic degradation behaviors of hydrogels were examined to be dependent on the poly（L-glutamic acid） content in the hydrogels. The higher content of poly（L-glutamic acid） in the gel, the higher swelling ratio and quicker degradation were observed. More interestingly, the hydrogel with higher PGH ratio showed higher vancomycin （VCM） loading content, which might be due to the electrostatic interaction between carboxylate groups in hydrogel and ammonium group of VCM. In vitro drug release from the VCM-loaded hydrogels in aqueous solution exhibited sustained release of VCM up to 72 h, while the in vitro antibacterial test based on the VCM-loaded hydrogel showed an efficient Methicillin-Resistant S. aureus （MRSA） inhibition extending out to 7 days. These results demonstrated that the biodegradable hydrogels which formed by in situ photo-cross linking would be promising as scaffolds or coatings for local antibacterial drug release in tissue engineering.     

Molecularly imprinted polymer nanocarriers for recognition and sustained release of diclofenac

In this study, a series of imprinted poly(methacrylic acid‐co‐ethylene glycol dimethacrylate) nanocarriers for diclofenac and corresponding nonimprinted polymer nanocarriers have been synthesized in 4 different types of solvents by precipitation polymerization. The products were characterized by Fourier transform infrared, scanning electron microscopy, dynamic light scattering, and Brunauer‐Emmett‐Teller measurement. Results showed that uniformly sized molecularly imprinted polymer (MIP) nanospheres with relatively good porosity could only be obtained in acetonitrile. The effects of solvents on the recognition and release properties of polymer particles were also carefully investigated. The binding experiments indicated that MIPs prepared in acetonitrile displayed much higher binding capacity than other MIPs with a maximum binding capacity of 65.18 mg g⁻¹. The Scatchard analysis showed that synthetic MIPs have special recognition sites for diclofenac, while nonimprinted polymers have not. The Sips model could provide a best fit to the equilibrium data of nanocarriers over whole concentrations. The experimental data of an adsorption kinetic study were well fitted to the pseudo–second‐order kinetic model, indicating the chemisorption mechanism between diclofenac and MIPs in the process of adsorption. The drug release of diclofenac from MIPs could well be described by the Ritger‐Peppas model, suggesting a non‐Fickian diffusion mechanism. In addition, we successfully used MIPs to extract diclofenac at low levels from fetal bovine serum.     

Cyclodextrin/polyethylenimine-based supramolecular nanoparticles for loading and sustained release of ATP

A new supramolecular nanoparticle PEI/SCD was successfully constructed, showing the loading/sustained release abilities towards ATP.     

Enhanced gentamicin loading and release of PLGA and PLHMGA microspheres by varying the formulation parameters

The purpose of this study was to develop a suitable formulation for gentamicin sulfate (GS) that gives a sustained release of the drug. Therefore this drug was loaded into poly(D,L-lactide-co-glycolide) (PLGA) and poly(lactic-co-hydroxymethyl glycolic acid) (PLHMGA) microspheres. The effects of various formulation parameters (ethanol, surfactant, osmotic value of the external phase, polymer type and concentration) on particle characteristics (size, loading and release) were investigated. The GS loaded microspheres were prepared using a double emulsion evaporation technique. The results demonstrate that neither ethanol nor surfactants had beneficial effects on the drug loading efficiency (around 4-10%). However, an increase in buffer concentration (and thus osmotic pressure) of the external phase resulted in a substantial increase of GS-loading (from 10 to 28%). Further, an increase of concentration of PLGA in DCM from 10% to 15/20% caused a 4-time increase of the drug loading. The best formulation identified in this study had a loading efficiency of around 70% resulting in PLGA microspheres with a 6% (w/w) loading. The particles showed a burst release of the drug depending on their porosity, followed by a phase of 35 days where hardly any release occurred. The drug was then slowly released for around 25 days likely due to degradation of the microspheres. The drug loading efficiency of GS in PLHMGA was not significantly different from PLGA microspheres (64%). The release of GS from PLHMGA microspheres was faster than that of PLGA because the degradation rate of PLHMGA is more rapid than PLGA. This study shows that prolonged release of gentamicin can be obtained by loading this drug into microspheres made of biodegradable aliphatic polyesters.     

Carbon dioxide and methane adsorption at high pressure on activated carbon materials

Granular and monolith carbon materials were prepared from African palm shell by chemical activation with H₃PO₄, ZnCl₂ and CaCl₂ aqueous solutions of different concentrations. Adsorption capacity of carbon dioxide and methane were measured at 298 K and 4,500 kPa, and also of CO₂ at 273 K and 100 kPa, in a volumetric adsorption equipment. Correlations between the textural properties of the materials and the adsorption capacity for both gases were obtained from the experimental data. The results obtained show that the adsorption capacity of CO₂ and CH₄ increases with surface area, total pore volume and micropore volume of the activated carbons. Maximum adsorption values were: 5.77 mmol CO₂ g^?1 at 273 K and 100 kPa, and 17.44 mmol CO₂ g^?1 and 7.61 mmol CH₄ g^?1 both at 298 K and 4,500 kPa.     

Preparation of polymer microspheres from solutions

Polymer microspheres are obtained by the dropwise addition of a precipitant, containing a polymeric stabilizer, into a polymer solution, containing a polymeric stabilizer. The polymer and stabilizer concentrations, the stirring speed, and the precipitation temperature determine the size and size uniformity of the microspheres. Seven polymer microspheres of polyimide, poly(ether imide), poly(ether ketone), poly(phenylene oxide), polysulfone, poly(vinylidene fluoride), and cellulose diacetate have been prepared with dimethylacetamide as the solvent, with water as the precipitant, and with poly(vinyl alcohol) as the stabilizer. The size and size uniformity of the obtained microspheres are d = 2.3–25.7 μm and ? = 0.15–0.50, respectively (? = σ/d, where ? is the dispersion coefficient, d is the average diameter, and σ is the standard deviation of the diameter). © 2002 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 41: 159–165, 2003     

Mechanical properties of emulsion polymer blends

Polymer blend technology has been one of the most investigated areas in polymer science in the past 3 decades. The one area of polymer blends that has been virtually ignored involves simple emulsion blends, although several articles have recently appeared that address film formation and mechanical characteristics. In this study, we investigated the mechanical property behavior of emulsion blends composed of low/high‐glass‐transition‐temperature polymers (where low and high mean below and above the test temperature, respectively). The emulsions chosen for this study had similar particle sizes, and the mixtures were rheologically stable. Two conditions were chosen, a binary combination of polymers that were thermodynamically immiscible and another system that was thermodynamically miscible. The mechanical property results over the entire composition range were compared with the predictions of the equivalent box model (EBM) with the universal parameters predicted by percolation theory. An array of randomly mixed and equal‐size particles of differing moduli was expected to show excellent agreement with theory, and the emulsion blends provided an excellent experimental basis for testing the theory. For the immiscible blend, the EBM prediction for the modulus showed excellent agreement with experimental results. With tensile strength, the agreement between the modulus and theory was good if the yield strength for the higher glass‐transition‐temperature polymer was employed in comparison with the actual tensile strength. The phase inversion point (where both phases were equally continuous) was at a 0.50 volume fraction of each component (based on an analysis employing Kerner's equation), just as expected for a random mixture of equal‐size particles. © 2001 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 39: 1093–1106, 2001     

In vitro evaluation of sustained release of risperidone‐loaded microspheres fabricated from different viscosity of PLGA polymers

The aim of this study was to fabricate different risperidone (RIS)–loaded poly(lactic‐co‐glycolic acid) microspheres (PLGA MS) with various viscosity of PLGA polymers and investigate the RIS release profiles. Risperidone‐loaded PLGA MS were fabricated via an oil/water–type emulsion solvent evaporation method, using ethyl acetate and benzil alcohol as the dispersed solvents. The PLGA (75:25) with the viscosity of 0.82, 0.93, and 1.10 dL/g was used in the fabrication. The morphology and the degradation of the RIS‐PLGA MS were investigated with a scanning electron microscope. The distribution states of RIS in the PLGA MS were studied with differential scanning calorimetry. The residual of ethyl acetate and benzil alcohol in the resulting MS was monitored with gas chromatography. The in vitro release profiles of RIS from PLGA MS were also studied. Scanning electron microscope photographs illustrated that the obtained PLGA MS were monodisperse spheres with an average diameter of 100 μm. Gas chromatography results suggested that no residual ethyl acetate was left in the final RIS‐PLGA MS, and the residue amount of benzil alcohol was about 1%. In vitro drug release profiles from the microsphere showed a substantially sigmoidal pattern of negligible initial burst up to 24 hours and minimal release (time lag) for 14 days. After the lag phase, slow release took a place up to 30 days, and then rapid release occurred sharply for about 2 weeks. The RIS release reached equilibrium around day 50. All release profiles showed the similar trend, and no significant difference was observed among these release profiles (P > .05). This phenomenon indicated that RIS‐loaded PLGA MS with the viscosity of 0.82 to 0.93 dL/g showed the optimal release behavior. However, no obvious differences were found among the MS obtained from the viscosity of 0.82 to 1.10 dL/g. These studies provided basis for the quality control in the industrial production of PLGA MS.     

Biodegradable PLGA microspheres as a sustained release system for a new luteinizing hormone-releasing hormone (LHRH) antagonist

A sustained release poly(DL-lactide-co-glycolide) (PLGA) microsphere delivery system to treat prostate cancer for a luteinizing hormone-releasing hormone (LHRH) antagonists, LXT-101 was prepared and evaluated in the paper. LXT-101 microspheres were prepared from PLGA by three methods: (1) double-emulsion solvent extraction/evaporation technique, (2) single-emulsion solvent extraction/evaporation technique, and (3) S/O/O (solid-in-oil-in-oil) method. The microspheres were investigated on drug loading, particle size, surface morphology and in vitro release profiles. An accelerated release approach was also established in order to expedite the evaluation periods. The in vivo evaluation of the microspheres was made by monitoring testosterone levels after subcutaneous administration to rats. The LXT-101 PLGA microspheres showed smooth and round surfaces according to a scanning electron microscopic investigation, and average particle size of ca. 30 mum according to laser diffractometry. The drug encapsulation efficiency of microspheres was influenced by LA/GA ratio of PLGA, salt concentrations, solvent mixture and preparation methods. Moreover, LA/GA ratio of PLGA, different preparation methods and different peptide stabilizers affected in vitro release of drugs. In vivo study, the testosterone levels were suppressed to castration up to 42 d as for the 7.5 mg/kg dose. And in vivo performance of LXT-101 microspheres was dose-dependent. The weights of rat sexual organs decreased and histopathological appearance of testes had little changes after 4-month microspheres therapy. This also testified that LXT-101 sustained release microspheres could exert the efficacy to suppress the testosterone level to castration with little toxicity. In conclusion, the PLGA microspheres could be a well sustained release system for LXT-101.     

Conducting polymer/gold nanoparticle hybrid materials: A step toward electroactive plasmonic devices

We have combined metal nanoparticles (NPs) exhibiting strong localised surface plasmon resonance (LSPR) in the visible with conducting polymers. Two different configurations have been used. In the first one, gold NPs are simply absorbed onto the surface of a thin polyaniline (PANI) film. In this case, electrochemical switching of the PANI layer yields to progressive aggregation of the NPs. In the second one, a sandwich structure is built and NPs are completely surrounded by PANI thanks to the electrochemical deposition of a second PANI layer. In this latter case, reversible and potential dependant modulation and damping of the LSPR, upon PANI switching from its reduced to its oxidized state, is observed.     

Quantifying the release of polymer additives from single-use materials by respiration activity monitoring

Single-use technologies, and thereby polymer materials, are increasingly applied in laboratory and large-scale fermentations. However, little is known about how leaching of polymer additives may affect the culture and compromise GMP regulations. The aim of this study is to introduce a standardized analytical device to test the biocompatibility of such polymer materials. The breathing behavior of various microorganisms was determined with the Respiration Activity MOnitoring Systems (RAMOS) as a function of the added amount of polymer commonly applied in biotechnology. Nylon and polyamide 12, used in cable ties and tubing, respectively, were found to delay and inhibit microbial growth. This is caused by leaching of the plasticizer N-butylbenzenesulfonamide and monomer 1,8-diazacyclotetradecane-2,7-dione, respectively, from the polymers. A metabolic activity inhibition threshold concentration between 4–10 g/L was determined for polyamide 12 tubing. In conclusion, RAMOS is a sensitive and time-effective device to qualify materials before they are applied in cultures.     

Molecularly imprinted polymer microspheres prepared by Pickering emulsion polymerization for selective solid-phase extraction of eight bisphenols from human urine samples

The bisphenol A (BPA) imprinted polymer microspheres were prepared by simple Pickering emulsion polymerization. Compared to traditional bulk polymerization, both high yields of polymer and good control of particle sizes were achieved. The characterization results of scanning electron microscopy and nitrogen adsorption–desorption measurements showed that the obtained molecularly imprinted polymer microsphere (MIPMS) particles possessed regular spherical shape, narrow diameter distribution (30–60 μm), a specific surface area (S_BET) of 281.26 m² g⁻¹ and a total pore volume (V_t) of 0.459 cm³ g⁻¹. Good specific adsorption capacity for BPA was obtained in the sorption experiment and good class selectivity for BPA and its seven structural analogs (bisphenol F, bisphenol B, bisphenol E, bisphenol AF, bisphenol S, bisphenol AP and bisphenol Z) was demonstrated by the chromatographic evaluation experiment. The MIPMS as solid-phase extraction (SPE) packing material was then evaluated for extraction and clean-up of these bisphenols (BPs) from human urine samples. An accurate and sensitive analytical method based on the MIPMS-SPE coupled with HPLC-DAD has been successfully established for simultaneous determination of eight BPs from human urine samples with detection limits of 1.2–2.2 ng mL⁻¹. The recoveries of BPs for urine samples at two spiking levels (100 and 500 ng mL⁻¹ for each BP) were in the range of 81.3–106.7% with RSD values below 8.3%.     

Sonochemical fabrication of fluorinated mesoporous titanium dioxide microspheres

A sonochemical-hydrothermal method for preparing fluorinated mesoporous TiO₂ microspheres was developed. Formation of mesoporous TiO₂ and doping of fluorine was achieved by sonication and then hydrothermal treatment of a solution containing titanium isopropoxide, template, and sodium fluoride. The as-synthesized TiO₂ microspheres were characterized by X-ray diffraction (XRD), Fourier translation infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray (EDX) spectroscopy, photoluminescence spectroscopy (PL), and BET surface areas. The P123 template was removed completely during the hydrothermal and washing steps, which was different from the conventional calcination treatment. The as- synthesized TiO₂ microspheres had good crystallinity and high stability. Results from the photocatalytic degradation of methylene blue (MB) showed that fluorination could remarkably improve the photocatalytic activity of titanium dioxide.     

Exact determination of phagocytic activity of alveolar macrophages toward polymer microspheres by elimination of those attached to the macrophage membrane

A method for exact determination of phagocytic activity of alveolar macrophage (M) cells toward synthetic microspheres (MS) by optical microscopy was developed. We examined the effectiveness of the treatment of M samples with trypsin, acid or xylene to remove the polystyrene latex microspheres (PSL MS) attached to M cell membranes during their phagocytosis by M cells. We found that centrifugation, which was employed to collect M samples after incubation with MS, affected significantly the efficiency of the various treatments. Of the three treatments, xylene treatment without centrifugation was the most effective to determine the phagocytic activity of M cells, as xylene dissolved the PSL MS on the cell surface almost completely. This treatment was also effective in the case of poly(lactic-co-glycolic acid) MS (PLGA MS), which have been commonly used as an efficient vehicle for drug delivery system.     

Caffeine loading into micro- and nanoparticles of mesoporous silicate materials: in vitro release kinetics

Caffeine was loaded into microparticles and nanoparticles of MCM-41 and MCM-48 to study its release into simulated body fluid at pH 7.4 and 37°C. The silicate systems were characterized by X-Rar Diffraction (XRD), scanning electron microscopy, and nitrogen adsorption/desorption isotherms. Loading of caffeine was confirmed by thermal gravimetric analysis and FTIR and the loading capacity was determined by high performance liquid chromatography (HPLC). The loading capacities for the microparticles are higher than that for the nanoparticles for both silicate systems, with the highest (56.8%) for the microparticles of MCM-48. However, for each system, the release from nanoparticle is faster than from microparticles. For all systems, diffusion is the major dissolution mechanism.