Flow Focusing: a versatile technology to produce size-controlled and specific-morphology microparticles

The Flow Focusing platform is especially advantageous for micro- and nanoparticle production. This versatile technique is amenable to designing the size, surface treatment and internal topology of the particles; mechanical stresses are minimal-an optimal feature for the manipulation of delicate substances. Multiplexing and high-rate production are readily implemented. Adaptive operational design can lead, in one single step, to finely tuned microcapsules encasing different products within a targeted morphology. This achievement is of great significance for most microcapsule applications in the biosciences (for example, drug delivery, cell encapsulation, and the production of bead arrays).     

光控亲/疏水转换的硅钛核壳型微颗粒制备易清洗防晒霜研究

以简便价廉的溶胶-凝胶法和自组装法制备出一种新型三甲基氯硅烷改性的SiO2-TiO2微颗粒用于防晒霜添加剂。采用透射电镜(TEM)和X射线光电子能谱(XPS)对微颗粒结构和成分进行表征。对纯纳米TiO2和改性前后的SiO2-TiO2复合微颗粒进行紫外吸收测试,结果表明,在190~350nm范围内目标颗粒的紫外吸收能力均显著优于另两种。接触角测试结果表明,目标颗粒在UV光照前为亲油疏水性,UV光照一段时间后转变为亲油亲水性。研究中复合微结构的构建在保证良好紫外屏蔽效果的同时,大大提高了使用的安全性;微颗粒表面UV光控亲/疏水转换能力让使用完毕后的清洗卸妆变得容易,该微颗粒作为防晒霜添加剂具有良好的应用前景。     

壳聚糖复合保鲜膜制备及其拉伸性能研究

将充分溶胀的壳聚糖与三偏磷酸钠交联并与硅溶胶共混,制备出了壳聚糖复合保鲜膜,用万能拉力机测试了其拉伸性能。研究结果表明,交联和共混明显提高了壳聚糖复合保鲜膜的力学性能,并且壳聚糖浓度在1.2×10-4～1.4×10-4 mol/L,三偏磷酸钠的含量在0.08%,mSiO2∶m壳聚糖约为0.15时,保鲜膜综合力学性能最佳。     

Preparation and evaluation of posaconazole-loaded enteric microparticles in rats

Objectives: Posaconazole (POS) is an antifungal compound which has a low oral bioavailability. The aim of this study was to prepare POS enteric microparticles to enhance its oral bioavailability.

Methods: POS enteric microparticles were prepared with hypromellose acetate succinate (HPMCAS) via the spray drying method. The solvent mixtures of acetone and ethanol used in the preparation of the microparticles were optimized to produce the ideal POS enteric microparticles. Multivariate data analysis using a principal component analysis (PCA) was used to find the relationship among the HPMCAS molecular characteristics, particle properties and drug release kinetics from the spray dried microparticles.

Key findings: The optimal spray solvent mixtures were critical to produce the POS microparticles with the defined polymer entanglement index, drug surface enrichment, particle size and drug loading. The HPMCAS molecular characteristics affected the microscopic connectivity and diffusivity of polymer matrix and eventually influenced the drug release behavior, and enhanced the bioavailability of POS.

Conclusions: These studies suggested that the selection of suitable solvent mixtures of acetone and ethanol used in the spray drying of the microparticles was quite important to produce the entangled polymer structures with preferred polymer molecular properties of polymer coiling, overlap concentration and entanglement index. Additional studies on particle size and surface drug enrichment eventually produced HPMCAS-based enteric microparticles to enhance the oral bioavailability of POS.     

Preparation and in vitro characteristics of lactoferrin-loaded chitosan microparticles

In order to achieve the delivery and controlled release of lactoferrin (LF), a biologically multifunctional protein, chitosan microparticles loaded with LF were prepared. Several types of chitosan microparticles containing LF were prepared by the w/o emulsification-solvent evaporation method, and the particle characteristics and release properties in JP 2nd fluid, pH 6.8, were examined. All kinds of microparticles were obtained at a yield of more than 75% (w/w). LF-loaded microparticles prepared by nonsonication and nonaddition of sulfate, named Ch-LF(N), showed high drug content, small particle size and spherical particle shape. Also, for release properties, Ch-LF(N) exhibited gradual drug release over 7 hr with less remaining in the microparticles. Considering the mucoadhesive properties of chitosan microparticles, Ch-LF(N) are suggested to be useful for gradual supply to topical diseased sites or for effective delivery to intestinal areas with abundant LF receptors.     

微流体技术制备功能性微型颗粒的研究进展

系统地阐述了近几年来微流体制备微型颗粒的现状并探讨了微流体制备微型颗粒过程中的粒径、形态等的控制工艺。采用微流体技术可以制备有机、聚合物、无机等多种类型的微型颗粒,这些微型颗粒在生物、医学、电子、光学等领域有着广阔的应用前景。     

Preparation and characterization of collagen-modified polylactide microparticles

To improve cytocompatibility of polylactide (PLA) and to obtain an injectable scaffold for tissue engineering, collagen-modified PLA (CPLA) microparticles were prepared. Poly-(α-methacrylic acid)-grafted PLA (PMAA-PLA) was obtained by photooxidization and UV induced polymerization. Suspension of PMAA-PLA microspheres with an average size of 172.8 ± 3.6 nm was prepared with solvent evaporation technique. CPLA microparticles were prepared by adding collagen acetic acid solution into PMAA-PLA microsphere suspension prepared above. FTIR spectrum of PMAA-PLA confirmed that PMAA had been grafted on PLA surface. Analytical results of FTIR, XPS, SEM, hematoxylin and eosin (HE) stained and zeta potential measurement showed that the CPLA microparticles obtained by modifying PMAA-PLA microspheres with collagen molecules uniformly have a microporous structure and a particle size of less than 100 μm. The CPLA microparticles were expected to be used as an injectable scaffold for tissue regeneration.     

Development and characterization of gelatin and ethylcellulose microparticles designed as platforms to delivery fluoride

Purpose: To develop and characterize microparticles containing fluoride sources (FS) from sodium fluoride, sodium monofluorophosphate (MFP) or aminofluoride and evaluate their characteristics as fluoride delivery systems.

Methods: Ethylcellulose microparticles containing fluoride (EM) were prepared by emulsification of ethyl acetate dispersion containing polymer and FS (ethylcellulose:FS ratio of 1:0.25 wt/wt) with aqueous external phase containing polysorbate 80 (0.8% vol/vol) using the volume ratio (organic:aqueous) of 1:5. The organic solvent was evaporated; microparticles were collected by centrifuging, washed with deionized water and freeze-dried. Gelatin microparticles containing FS (GM) was obtained by dispersion of the natural polymer in water, adding FS (6:1 wt/wt) and 20% (wt/wt) of mannitol. The final dispersions were spray-dried. Particle morphology and size were investigated using optical microscopy. The content of fluoride ions in the microparticles was quantified using a potentiometric method. The encapsulation efficiency and in vitro release profile of fluoride was also determined.

Results: Microparticles exhibited polydispersity and mean diameters <145.35 and <124.22 µm for EM and GM, respectively. Considering the entrapment efficiency, the spray-drying technique exhibited greater values than microencapsulation by emulsification and solvent evaporation. The release profile of fluoride ions from microparticles was shown to be modified, fitted first order and guided by Fickian diffusion.

Conclusions: Microparticles prepared with ethylcellulose or gelatin can be used as platform for oral delivery of fluoride, providing a means to increase the local supply of this ion in a controlled manner, providing an increased protection against caries. Moreover, further investigations are needed to demonstrate this property in vivo.     

Preparation and characterization of heparin-loaded polymeric microparticles

Microparticles containing heparin were prepared by a water-in-oil-in-water emulsification and evaporation process with pure or blends of biodegradable (poly-epsilon-caprolactone and poly(D,L-lactic-co-glycolic acid)) and of positively-charged non-biodegradable (Eudragit RS and RL) polymers. The influence of polymers and some excipients (gelatin A and B, NaCl) on the particle size, the morphology, the heparin encapsulation rate as well as the in vitro drug release was investigated. The diameter of the microparticles prepared with the various polymers ranged from 80 to 130 microns and was found to increase significantly with the addition of gelatin A into the internal aqueous phase. Microparticles prepared with Eudragit RS and RL exhibited higher drug entrapment efficiency (49 and 80% respectively) but lower drug release within 24 h (17 and 3.5% respectively) than those prepared with PCL and PLAGA. The use of blends of two polymers in the organic phase was found to modify the drug entrapment as well as the heparin release kinetics compared with microparticles prepared with a single polymer. In addition, microparticles prepared with gelatin A showed higher entrapment efficiency, but a significant initial burst effect was observed during the heparin release. The in vitro biological activity of heparin released from the formulations affording a suitable drug release has been tested by measuring the anti-Xa activity by a colorimetric assay with a chromogenic substrate. The results confirmed that heparin remained unaltered after the entrapment process.     

Preparation and antimicrobial activity of gelatin microparticles containing propolis against oral pathogens

Gelatin microparticles containing propolis ethanolic extractive solution were prepared by spray-drying technique. Particles with regular morphology, mean diameter ranging of 2.27 μm to 2.48 μm, and good entrapment efficiency for propolis were obtained. The in vitro antimicrobial activity of microparticles was evaluated against microorganisms of oral importance (Enterococcus faecalis, Streptococcus salivarius, Streptococcus sanguinis, Streptococcus mitis, Streptococcus mutans, Streptococcus sobrinus, Candida albicans, and Lactobacillus casei). The utilized techniques were diffusion in agar and determination of minimum inhibitory concentration. The choice of the method to evaluate the antimicrobial activity of microparticles showed be very important. The microparticles displayed activity against all tested strains of similar way to the propolis, showing greater activity against the strains of E. salivarius, S. sanguinis, S. mitis, and C. albicans.     

Preparation and characterization of enteric microparticles by coacervation

The aim of this study was to produce cinnarizine loaded Eudragit^® L100-55 microparticles by coacervation technique in order to achieve pH responsive drug release using hydroxypropyl methycellulose (HPMC) as stabilizer. The effect of enteric polymer: HPMC ratio on properties of microparticles was investigated with regard to particle size distribution, morphology, yield, encapsulation efficiency, in vitro drug release profiles and interaction between cinnarizine and Eudragit^® L100-55. High drug encapsulation efficiency was seen in all microparticles. Particle diameter increased when the enteric polymer content was higher relative to HPMC. In vitro dissolution studies demonstrated that the drug release from the microparticles was dependent upon enteric polymer: HPMC ratio and particle size distribution. At the ratio of at least 3.75:1 of enteric polymer: HPMC, drug release was suppressed most significantly in low pH (hydrochloric acid as medium) while rapid drug release was observed in pH 7.4.     

聚苯胺水基乳胶微粒的制备与性能研究

采用水溶性高聚物聚乙烯吡咯烷酮(PVP)作为空间稳定剂,利用分散聚合的原理成功地制备出了稳定的聚苯胺水基胶体分散液,聚苯胺复合乳胶粒子尺寸为几十至几百纳米,其粒径大小受PVP浓度、苯胺含量和反应温度等因素的影响.空间稳定剂可以提供胶体成核点.当PVP浓度较低时,聚合反应速率较小,当PVP浓度达到2%(质量分数)以后,聚合反应开始加速.红外光谱结果表明PAn-PVP复合物形成了分子内氢键.随着苯胺浓度的增加,聚苯胺电导率先增大后减少,最大值达到8.74×10-3S/cm,具有较好的应用前景.     

Preparation,characterization and dissolution behavior of artemisinin microparticles

In the present study, a modified 4-fluid nozzle spray drier was used to prepare microparticles of a poorly water soluble drug, artemisinin with the aim of improving its solubility. We also investigated the effect of process variables on the physical properties and dissolution rate of spray dried artemisinin. A full factorial experimentally designed study was performed to investigate the following spray drying variables: inlet temperature and feed concentration. The artemisinin powder and spray dried artemisinin microparticles were characterized by scanning electron microscopy (SEM), differential scanning calorimetric (DSC), X-ray diffraction (XRD) and dissolution. SEM study suggested that the inlet temperature and feed concentration impacted on the particle size of the spray dried particles. The crystallinity of spray dried particles was slightly decreased with increasing inlet temperature and concentration. The dissolution of spray dried particles was markedly improved as compared to commercial artemisinin. A dissolution surface-response model was used to elucidate the significant and direct relationships between drug feed concentration and inlet temperature on one hand and dissolution on the other hand. The best dissolution was found to be 117.00 ± 5.15 μg/mL at the drug feed concentration of 10 g/L and inlet temperature of 140 °C.     

超临界流体技术制备聚合物超细微粒

以聚甲基丙烯酸甲酯为模型材料,利用近两年提出的超临界流体膨胀减压过程,成功制备出了粒径在5μm以下的超细微粒,系统分析了混合器压力和温度、溶液浓度及进液速率对微粒形态、粒径及其分布的影响。结果表明,混合器压力、溶液浓度和进液速率均对微粒粒径及其分布有明显的影响,而混合器温度的影响较小。较理想的操作条件为混合器压力为10MPa、温度为60℃、溶液浓度为10mg/mL、进液速度为3mL/min。     

Preparation and characterization of spironolactone-loaded gelucire microparticles using spray-drying technique

The basic objectives of this study were to prepare and characterize solid dispersions of poorly soluble drug spironolactone (SP) using gelucire carriers by spray-drying technique. The properties of the microparticles produced were studied by differential scanning calorimetry (DSC), scanning electron microscopy, saturation solubility, encapsulation efficiency, and dissolution studies. The absence of SP peaks in DSC profiles of microparticles suggests the transformation of crystalline SP into an amorphous form. The in vitro dissolution test showed a significant increase in the dissolution rate of microparticles as compared with pure SP and physical mixtures (PMs) of drug with gelucire carriers. Therefore, the dissolution rate of poorly water-soluble drug SP can be significantly enhanced by the preparation of solid dispersion using spray-drying technique.     

Preparation and characterization of novel sinomenine microcapsules for oral controlled drug delivery

Background: Developing a sustained release drug to cure arthritis is needed. Sinomenine (SIN) is abstracted from sinomenium acutum and widely used in the treatment of various rheumatism and arrhythmia with few side effects. The primary aim of this study is to develop SIN microcapsules with polyelectrolyte multilayers for controlled drug release. Method: SIN microcrystals were encapsulated with chitosan, gelatin, and alginate by layer-by-layer technique, such as (gelatin/alginate)₄ and (chitosan/alginate)₆. The size distribution, zeta-potential, stability, and morphology of the microcapsules were characterized by a particle size analyzer, zetasizer, ultraviolet spectroscopy, and transmission electron microscope, respectively. The in vitro controlled release pattern of SIN was studied using a diffusion cell assembly at physiological pH of 6.8 or 1.4. Results: Light stability of these microcapsules was improved after microencapsulation. Compared with release rate of the SIN microcapsules coated by the poly(dimethyldiallyl ammonium chloride)/alginate and gelatin/alginate multilayers, release rate of the SIN microcapsules coated with chitosan/alginate multilayers was fast. Release rate progressively decreased with the increase of chitosan/alginate bilayer number and the decrease of pH value of release medium. Conclusion: These novel SIN microcapsules may be developed into oral controlled drug delivery for rheumatism and arthritis.     

Preparation and characterization of copolymerized methylsilsesquioxane-benzylsilsesquioxane microparticles for electrophoretic sol-gel deposition

Copolymerized methylsilsesquioxane-benzylsilsesquioxane, (100 – x)MeSiO_3/2·xBnSiO_3/2 (mol%), microparticles of 0.3–0.4 m in average diameter have been prepared by the sol-gel method and applied to the formation of thick films on indium tin oxide (ITO)-coated glass substrates by the electrophoretic deposition. The microparticles obtained were considered to be hybrid containing both methyl and benzyl groups from thermal analyses and structural investigations. The microparticles became fusible at x 80 by a heat treatment. Thick film, ca. 5 m thick, consisting of electrophoretically deposited pure BnO_3/2 microparticles became transparent upon thermal sintering of the particles during heat treatment at temperatures higher than 100°C. On the other hand, the increase in optical transmittance during the heat treatment of the films consisting of 20MeSiO_3/2·80BnSiO_3/2 microparticles was as small as about 20% in visible range even after the heat treatment. The smaller increase in transmittance is probably due to the relatively high viscosity of the 20MeSiO_3/2·80BnSiO_3/2 upon sintering in comparison with pure BnO_3/2 for elimination of the voids in the films.     

Development and characterization of coated-microparticles based on whey protein/alginate using the Encapsulator device

The aim of this study is to prepare whey protein (WP)-based microparticles (MP) using the Encapsulator^® device. The viscosity dependence of the extrusion device required to mix WP with a food-grade and less viscous polymer. Mixed WP/ALG MP were obtained with the optimized WP/alginate (ALG) ratio (62/38). These particles were further coated with WP or ALG using non-traumatic and solvent-free coating process developed in this study. Size and morphology of coated and uncoated MP were determined. Then, swelling and degradation (WP release) of formulations were investigated in pH 1.2 and 7.5 buffers and in simulated gastric and intestinal fluids (SGF, SIF) and compared to pure ALG and pure WP particle behaviours. At pH 1.2, pure ALG shrank and pure WP swelled, whereas the sizes of mixed WP/ALG matrix were stable. In SGF, WP/ALG MP resisted to pepsin degradation compare to pure WP particles due to ALG shrinkage which limited pepsin diffusion within particles. Coating addition with WP or ALG slowed down pepsin degradation. At pH 7.5, WP/ALG particles were rapidly degraded due to ALG sensitivity but the addition of a WP coating limited effectively the swelling and the degradation of MP. In SIF, pancreatin accelerated MP degradation but ALG-coated MP exhibited interesting robustness. These results confirmed the interest and the feasibility to produce coated WP-based MP which could be a potential orally controlled release drug delivery system.     

Preparation and in vivo evaluation of spray dried matrix type controlled-release microparticles of tamsulosin hydrochloride for orally disintegrating tablet

The objective of this study was to achieve an optimal formulation of spray dried matrix type controlled-release (MTCR) microparticles containing tamsulosin hydrochloride for orally disintegrating tablet. To control the release rate of tamsulosin hydrochloride, Acrylate-methacrylate copolymer (Eudragit^® L-100 or Eudragit^® S-100) and ethylcellulose were employed on the composition of MTCR microparticles. Physicochemical properties of MTCR microparticles such as particle size and SEM were characterized. Pharmacokinetic parameters of tamsulosin hydrochloride were evaluated in the rats after oral administration. MTCR microparticles were spherical microparticles of around 10 µm diameter with a corrugated surface. ODTs containing MTCR microparticles were disintegrated within 30 s and MTCR microparticles were able to control the release rate of tamsulosin hydrochloride following Fickian diffusion mechanism. The in vitro release rates of tamsulosin hydrochloride from MTCR microparticles were proportional to the ratio of Acrylate-methacrylate copolymer to ethylcellulose. Moreover, MTCR microparticles retarded the in vivo release rate of tamsulosin hydrochloride without reducing the bioavailability. Our results suggest that MTCR microparticles may be potential oral dosage forms to control the release and to improve the bioavailability of tamsulosin hydrochloride.     

Synthesis and characterization of poly(N-vinylcaprolactam)-based spray-dried microparticles exhibiting temperature and pH-sensitive properties for controlled release of ketoprofen

Poly(N-vinylcaprolactam) (PNVCL) and poly(N-vinylcaprolactam-co-acrylic acid) (poly(NVCL-co-AA)) were synthesized by solution-free radical polymerization and displayed thermo-responsive behavior, with lower critical solution temperatures (LCSTs) of 35?°C and 39?°C, respectively. The incorporation of AA unities made the poly(NVCL-co-AA) sensitive to both pH and temperature. They were exploited in this work in preparing microparticles loaded with ketoprofen via spray-drying to modulate the drug release rate by changing pH or temperature. The interaction between polymer and drug was studied using X-ray diffractometry, Raman spectrometry and scanning electron microscopy (SEM). The biocompatibility of pure polymers, free ketoprofen as well as the spray-dried particles was demonstrated in vitro by low cytotoxicity and a lack of nitric oxide production in macrophages at concentrations as high as 100?µg/ml. The release profile of ketoprofen was evaluated by in vitro assays at different temperatures and pH values. Drug diffusion out of PNVCL’s hydrated polymer network is increased at temperatures below the LCST. However, when poly(NVCL-co-AA) was used as the matrix, the release of ketoprofen was primarily controlled by the pH of the medium. These results indicated that PNVCL and the novel poly(NVCL-co-AA) could be promising candidates for pH and temperature-responsive drug delivery systems.