Preparation of magnetic poly(lactic‐co‐glycolic acid) microspheres featuring monodispersity and controllable particle size using a microchannel device

Poly(lactic‐co‐glycolic acid) (PLGA) microspheres prepared using a traditional solvent evaporation or double emulsification method are usually polydisperse with an uncontrollable particle size distribution, which brings about poor application performance. In our research, monodisperse magnetic PLGA microspheres were prepared using a microchannel device based on a water‐in‐oil‐in‐water composite emulsion. The composite emulsion was formed by injecting a dichloromethane–gelatin water‐in‐oil emulsion into a microchannel together with an external water phase, i.e. poly(vinyl alcohol) (PVA) aqueous solution. Mean particle size control of the microspheres was executed using the osmotic pressure difference between internal and external aqueous phases caused by regulating NaCl concentration in PVA aqueous phase. It is found that monodisperse magnetic PLGA microspheres with high magnetic responsiveness can be successfully prepared combining the microchannel device with composite emulsion method. Mean particle size of the microspheres with coefficient of variation value below 4.72% is controllable from 123 to 203 µm depending on the osmotic pressure. The resulting samples have pyknotic and smooth surfaces, as well as spherical appearance. These monodisperse magnetic PLGA microspheres with good superparamagnetism and magnetic mobility have potential use as drug carriers for uniform release and magnetic targeting hyperthermia in biological fields. © 2015 Society of Chemical Industry     

Chitosan microspheres: modification of polymeric chem‐physical properties of spray‐dried microspheres to control the release of antibiotic drug

Antibiotic drug releasing from chitosan and acylchitosan microspheres was studied. The acylchitosan microspheres were prepared by modifying the microencapsulation process from spray‐drying to spray in‐liquid coagulating process for the improvement of chem‐physical properties of polymer in controlling the release of antibiotic drug. A higher yield of microspheres was recovered by this improved process. Crystallinity, swelling ability, and the morphology of various microspheres were investigated by X‐ray, water adsorption, and scanning electron microscopy studies. Results show that by modifying the microencapsulation process from spray‐drying to spray in‐liquid coagulating process, the chemical properties of the microsphere were varied from a hydrophilic chitosan microsphere to a hydrophobic acylchitosan microsphere, while the physical structure of the microsphere was varied from a porous chitosan microsphere to a dense acylchitosan microsphere. For the reasons, drug release rate of acylchitosan microspheres prepared by the novel spray microencapsulation method were apparently depressed, and the long‐acting release of antibiotic drug was possible to be achieved. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 71: 747–759, 1999     

单分散性PLGA磁性微球制备及其缓释性研究

为获得单分散性PLGA磁性微球,文中以纳米四氧化三铁明胶分散液作为内水相(W1),PLGA（聚乳酸羟基乙酸共聚物）的二氯甲烷溶液作为油相(O),PVA（聚乙烯醇）水溶液作为外水相(W2),利用T型微通道并采用复合乳液法制备PLGA磁性微球,考察流速比和油相与内水相体积比对微球制备的影响。借助FTIR、SEM及VSM（振动样品磁强计）对磁性微球组分、形貌、粒径分布和磁学性能进行表征;并以阿司匹林作为药物模型进行缓释性测试。结果表明：流速比v(W2):v(W1/O)=120:1且体积比V(O):V(W1)=2:1时可均匀成球,其粒径分布系数CV值仅为4.66%,表现出良好单分散性;此时比饱和磁化强度可达1.52emu/g,兼具优异顺磁性。制得的载药微球在60h内表现出阶段性匀速释放,且有较好磁响应性,有望用于磁响应性药物载体。     

Preparation of magnetic poly(lactic‐co‐glycolic acid) microspheres with a controllable particle size based on a composite emulsion and their release properties for curcumin loading

Because of their unique magnetic features and good biocompatibility, magnetic poly(lactic‐co‐glycolic) acid (PLGA) microspheres have great application potential in magnetic targeted drug‐delivery systems. In this research, magnetic PLGA microspheres with controllable particle sizes were successfully prepared from a composite emulsion with a T‐shaped microchannel reactor. A water‐in‐oil‐in‐water composite emulsion was generated by the injection of a dichloromethane/gelatin water‐in‐oil initial emulsion into the microchannel together with a coating aqueous phase, that is, the aqueous solution of glucose and poly(vinyl alcohol). The mean particle size of the microspheres could be controlled by the manipulation of the osmotic pressure difference between the internal and external aqueous phases via changes in the glucose concentration. Curcumin, a drug with an inhibitory effect on tumor cells, was used to exemplify the release properties of the magnetic PLGA microspheres. We found that the mean particle size of the microspheres ranged from 16 to 207 μm with glucose concentrations from 0 to 20 wt %. The resulting microspheres showed a rapid magnetic response, good superparamagnetism, and a considerable magnetocaloric effect, with a maximum magnetic entropy of 0.061 J·kg^?1·K^?1 at 325 K. An encapsulation efficiency of up to 77.9% was achieved at a loading ratio of 3.2% curcumin. A release ratio of 72.4% curcumin from the magnetic PLGA microspheres was achieved within 120 h in a phosphate‐buffered solution. The magnetic PLGA microspheres showed potential to be used as drug carriers for magnetic targeted tumor therapy. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43317.     

Facile preparation of PLGA microspheres with diverse internal structures by modified double‐emulsion method for controlled release

Poly(l ‐lactide‐co‐glycolide) (PLGA) microspheres with diverse internal structures and different release behaviors were prepared via a modified double‐emulsion method by introduction of heparin or carboxymethyl chitosan in the inner aqueous phase and calcium chloride in the outer aqueous phase, respectively. The main factors affecting the microsphere morphology were systematically studied, including compositions in the inner aqueous phase, the oily phase, and the outer aqueous phase. The transmission electron microscope images demonstrated that the microspheres are featured with single core, hollow, and multicore structures when their sizes were less than 200 nm, in the range of 200–700 nm, and greater than 700 nm, respectively. In comparison with hollow PLGA microspheres, the PLGA microspheres with heparin and carboxymethyl chitosan in the inner aqueous phase also showed multicore and single core structures, respectively, and exhibited higher loading efficiencies and slower release rates by using bovine serum albumin as a model for bioactive substances. It was concluded that this study provided a facile method to prepare microspheres with single core, multicore, or hollow feature, and the tunability of the different internal structures and related release profiles enables these systems cater to specific requirements for potential applications in controlled biomolecule delivery for tissue regeneration. POLYM. ENG. SCI., 55:896–906, 2015. © 2014 Society of Plastics Engineers     

Acetylsalicylic acid loading and release studies of the PMMA‐g‐polymeric oils/oily acids micro and nanospheres

Poly(methyl methacrylate) (PMMA) and PMMA copolymers derived from plant oils (Polylinseed oil‐g‐PMMA, Polysoybean oil‐g‐PMMA, Polylinoleic acid‐g‐PMMA (PLina‐g‐PMMA) and Polyhydroxy alkanoate‐ sy‐g‐Polylinoleic acid‐g‐PMMA (PHA‐g‐PLina‐g‐PMMA)) as hydrophobic polymers, a series of hydrophobic microsphere or nanosphere dispersions, were prepared by the emulsion/solvent evaporation method. The diameters of the nanospheres and microspheres were measured by dynamic light scattering with a zetasizer, optically and by scanning electron microscopy. The magnetic quality of the microspheres was determined by the electron spin resonance technique. Acetylsalicylic acid (aspirin, ASA) was used as a model drug and loaded into the microspheres during the preparation process. The effect of the stirring rate over the size and size distribution of the micro/nanospheres was evaluated, and the effects of copolymer types derived from plant oil/oily acids and the copolymer/drug ratios were evaluated. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Influence of Surfactant on the Characteristics of W1/O/W2-Microparticles

The water-in-oil-in water (W₁/O/W₂) double emulsion evaporation technique is widely used when the microencapsulation of soluble agents like naloxone HCl is intended. The present work shows the effect of HLB emulsifiers added to phase O on microsphere morphology, size, release, drug encapsulation efficiency. The addition of sorbitan ester to first emulsion (W₁/O) and the HLB of the surfactant have an important effect on the characteristics of poly-lactide-co-glycolide (PLGA) microparticles (MP). This MP with sorbitan esters added were smaller and released the hydrophilic drug, naloxone, with no-significant difference at pH 5 versus pH 7.5 (phosphate medium). This is an important fact when long-drug release is considered since it is known that PLGA degradation leads to media acidification. The HLB value had an important effect on drug loading. Sorbitan monooleate led to the highest naloxone loading. Because of its low HLB (4.3), it is most suitable for stabilizing the W₁/O emulsion, which is fundamental for the successful entrapment of a hydrophilic compound in MP prepared by double emulsion technique. Finally, drug solubility in the MP matrixes cannot be considered as a predictive parameter for drug encapsulation. Both surfactants increased the naloxone solubility in the polymer PLGA and only sorbitan monooleate increased the drug entrapment.     

Production of double‐walled nanoparticles containing meloxicam

Double‐walled nanospheres, containing meloxicam, were fabricated with poly‐(D,L ‐lactide‐co‐glycolide) (PLGA) and poly(L ‐lactide) (PLLA) using the solvent evaporation technique. This article discusses the effect of formulation variables [sonication power, sonication time, concentration of poly(vinyl alcohol), organic/aqueous volume ratio in the first emulsion] on the production of double‐walled nanospheres. The involved phase separation of these two polymers was investigated using differential scanning calorimetry. Double‐walled microspheres containing meloxicam were also produced to determine the composition of the shell and core polymer, based on different solubilities of polymers in ethyl acetate, and to examine the inner morphology and drug distribution using optical and fluorescence microscopy. The produced microparticles have shown a double‐walled structure with meloxicam solubilized in the PLGA‐rich phase. Therefore, adjusting the selected formulation variables and using a mass ratio of 1:1 PLLA/PLGA, double‐walled nanospheres where meloxicam is dispersed within the core can be produced. POLYM. ENG. SCI., 2013. © 2012 Society of Plastics Engineers     

Preparation and in vitro release behavior of urapidil hydrochloride loading into microspheres based on poly(L‐lactide)

Microencapsulation of the antihypertensive drug urapidil hydrochloride was investigated as a means of controlling drug release and minimizing or eliminating local side effects. Poly(L ‐lactide) (PLLA) microspheres were prepared using an alternative oil‐in‐water (O/W) solvent‐evaporation method such as the O/W cosolvent solvent‐evaporation method and O/W with various electrolytes added to the aqueous phase method. The surface morphology and the size of the microspheres were observed by scanning electron microscope. Meanwhile, the drug loading efficiency of microspheres and the in vitro release of urapidil hydrochloride from microspheres were performed. The release study indicated that the urapidil hydrochloride‐PLLA microspheres exhibited better sustained release capacity, and the kinetics of urapidil hydrochloride‐PLLA microspheres in vitro release could be described by the Higuchi equation. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Comparison of the degradation and release behaviors of poly(lactide‐co‐glycolide)–methoxypoly(ethylene glycol) microspheres prepared with single‐ and double‐emulsion evaporation methods

The purpose of this study was to compare the degradation and release behaviors of poly(lactide‐co‐glycolide) (PLGA)–methoxypoly(ethylene glycol) microspheres fabricated by the single‐emulsion evaporation method (DEEM) and double‐emulsion evaporation methods (DEEM). Vancomycin and mizolastine were used as the hydrophilic and hydrophobic model drugs, and they were encapsulated into microspheres through DEEM and SEEM, respectively. The two types of microspheres were similar in size distribution, but the mizolastine‐loaded microspheres showed a much higher encapsulation efficiency than those loaded with vancomycin. Scanning electron microscopy, size, and molecular weight (Mw) analyses during the degradation revealed that the microspheres fabricated by DEEM underwent a bulk degradation process and showed a faster MW reduction rate during the early degradation period than the microspheres fabricated by SEEM, which exhibited a surface‐to‐bulk degradation process according to the Mw and morphological changes. The mass loss rates of the two types of microspheres were similar, but the mean size decrease rates showed a little difference. The mizolastine‐loaded microspheres exhibited an approximately linear release profile after the initial burst release, whereas the vancomycin‐loaded microspheres showed a more severe burst release, a faster release rate, and thus, a shorter time to full release. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41943.     

Polymer‐based nucleation for chemical vapour deposition of diamond

Chemical vapour deposition of diamond on foreign substrates is hindered due to its high surface energy. Therefore, nucleation treatment has to be employed to initialize the formation of diamond crystals. This article deals with diamond growth on silicon substrates coated with three types of polymers: (i) polystyrene (PS), (ii) polylactic‐co‐glycolic acid (PLGA), and (iii) polyvinyl alcohol (PVA) were applied in different forms, i.e., microspheres (PS, PLGA), monolayers (PLGA), multilayers (PLGA, PLGA/PS), and composites with embedded diamond nanoparticles (PLGA, PVA). Thin polymers and microsphere monolayers did not contribute to the diamond nucleation and/or growth. A thicker continuous polymer film (>750 nm) or thin polymer/microsphere layer led to a homogeneous and dense formation of diamond grains. In the case of nucleation using polymer composites, where the thin polymer film serves as a 3D carrier matrix for embedded diamond nanoparticles, a comparable nucleation density to the well‐established ultrasonic seeding method was achieved. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43688.     

PCL/poloxamer 188 blend microsphere for paclitaxel delivery: Influence of poloxamer 188 on morphology and drug release

A novel controlled release system, paclitaxel‐loaded poly (ε‐caprolactone) (PCL)/poloxamer 188 (Pluronic F68, F68) blend microspheres is proposed in the present work. F68 was incorporated into PCL matrices as both a pore‐forming agent and a drug releasing enhancer. Paclitaxel‐loaded PCL/F68 blend microspheres with different amounts of F68 were prepared by the oil‐in water (O/W) emulsion/solvent evaporation method. Characterization of the microspheres followed to examine the particle size, the drug encapsulation efficiency, the surface morphology, and in vitro release behavior. The influences of F68 on microsphere morphology and paclitaxel release are discussed. The porosity of the surface of PCL/F68 blend microspheres and the release rate of paclitaxel from the PCL/F68 blend microspheres increased as the initial amount of blended F68 increased. Faster and controlled release was achieved in comparison with the PCL microspheres. Through this study, the developed microporous PCL/F68 blend microspheres could be used as a drug delivery system to enhance and control drug release in the future. © 2007 Wiley Periodicals, Inc. JAppl Polym Sci 104: 1895–1899, 2007     

The effect of process variables on the morphology and release characteristics of protein‐loaded PLGA particles

Poly(lactide‐co‐glycolide) (PLGA 75 : 25), IV 0.94 dL/g was chosen as the matrix of the microparticles. Bovine serum albumin (BSA) (Fraction V) as the model drug was incorporated in the microparticles by a W/O/W emulsification and solvent evaporation technique. The effect of the various preparation parameters on particle morphology, drug loading efficiency, and drug release profiles of the resultant microparticles were examined. Particle size varied from 5 to 60 μm. The final morphology of the microparticles varied dramatically with preparation variables such as equipment used to produce the primary emulsion (W1/O) and the water‐to‐oil ratio (W1/O) in the primary emulsion. In general, the viscosity of the primary emulsion had a significant effect on the porosity of particles produced. The release of BSA showed a strong relationship with the preparation parameters of microparticles, partly due to the morphological effects. For example, microparticles made from the vortex mixer that was used to disperse inner aqueous phase (W1) to oil phase (O) showed a lower burst effect than that made from the homogenizer because of its better surface morphology. W1/O ratio, speed of dispersing the primary emulsion into W2, PLGA concentration, and different matrix materials also affected the drug release profiles. In all the samples studied here, only diffusion‐controlled release was observed. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 101: 3053–3061, 2006     

Preparation and characterization of hollow microcapsules for use as ultrasound contrast agents

A laboratory-scale method of producing micron-sized hollow microscapsules from a biodegradable polymer such as 50/50 poly(D, L-lactide-co-glycolide) (PLGA), for use as a diagnostic ultrasound contrast agent, was developed. The technique involved microencapsulation of a volatile solid core material, and subsequent sublimation of the core to leave a hollow microsphere. A core material, such as ammonium carbonate, was ground to a suitable size distribution and encapsulated by a modified solvent evaporation or coacervation technique. This study investigated process parameters to produce diagnostically viable microscapsules by these two en-capsulation methods, such as polymer molecular weight (from 10,000 to 50,000), initial polymer concentration, agitation method, and stabilizer type. Polymer solution viscosity, polydispersity, and agitation rates significantly controlled the mean size of the microcapsules. Stabilizers were essential in solvent evaporation, but corrupted the morphology of spheres made by coacervation. Zeta potential values of microsphere dispersions revealed differences in surface characteristics between both encapsulation methods. Incubation of microcapsules with serum improved their dispersion in aqueous media. Preliminary in vivo ultrasound studies with the New Zealand white rabbit model, using color Doppler, showed that the microcapsules gave significant contrast in the right kidney.     

可降解聚乳酸多孔微球的制备探究

以聚乳酸为壁材,碳酸氢铵为致孔剂,采用双乳液溶剂挥发法,制备出具有孔状的聚乳酸微球,探讨制备条件对聚乳酸微球的影响.结果表明,在内外水相体积比1∶7.5,初乳化搅拌速度1 000 r/min下制得的PLA多孔微球的球形和孔结构较好.     

Effects of the process parameters on the initial burst release of poly(lactide‐co‐glycolide) microspheres containing bovine serum albumin by the double‐emulsion solvent evaporation/extraction method

The effects of fabrication parameters on the morphology, drug loading, and initial burst release of poly(lactide‐co‐glycolide) microspheres loaded with bovine serum albumin were investigated to establish an optimal process and system for the in vivo delivery of therapeutic proteins. Through the addition of salts or sugars to induce an osmotic pressure in the external water phase, large microspheres were seen to have their morphology, drug loading, and initial burst release significantly affected. However, the effect was not observed for compact microspheres less than 10 μm in diameter. The presence of poly(vinyl alcohol), Pluronic F127, and Tween 80 in the internal water phase had detrimental effects on the drug loading because of the depressed stability of the primary emulsion and competitive interactions of surface‐active substances with the polymer. However, the simultaneous addition of salts to the external water phase resulted in enhanced drug loading and decreased initial burst. The polymer concentration and volume of the internal water phase were important factors influencing the characteristics of the microspheres. These parameters were optimized for achieving the maximal drug loading and a low initial burst. The solvent extraction method yielded microspheres with a higher drug loading and a lower initial burst in comparison with the solvent evaporation method. Different ranges of protein encapsulation efficiencies were obtained with blends of poly(lactide‐co‐glycolide) and poly(ethylene glycol), depending on the molecular weight and content of poly(ethylene glycol). © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Liposome Microencapsulation for the Surface Modification and Improved Entrapment of Cytochrome c for Targeted Delivery

In this study, we established a procedure based on the microencapsulation vesicle (MCV) method for preparing surface‐modified liposomes, using polyethylene glycol (PEG) and a site‐directed ligand, with high entrapment efficiency of cytochrome c (Cyt c). For preparing a water‐in‐oil (W/O) emulsion, egg phosphatidylcholine and cholesterol were dissolved in organic solvents (O phase) and emulsified by sonication with aqueous solution of Cyt c (W₁). Although the dispersion stability of the W₁/O emulsion was low when n‐hexane was used to dissolve the lipids in the O phase, it was substantially improved by using mixed solvents consisting of n‐hexane and other organic solvents, such as ethanol and dichloromethane (DCM). The W₁/O emulsion was then added to another water phase (W₂) to prepare the W₁/O/W₂ emulsion. PEG‐ and/or ligand‐modified lipids were introduced into the W₂ phase as external emulsifiers not only for stabilizing the W₁/O/W₂ emulsion but also for modifying the surface of liposomes obtained later. After solvent evaporation and extrusion for downsizing the liposomes, approximately 50% of Cyt c was encapsulated in the liposomes when the mixed solvent consisting of n‐hexane and DCM at a volume ratio of 75/25 was used in the O phase. Finally, the fluorescence‐labeled liposomes, with a peptide ligand having affinity to the vasculature in adipose tissue, were prepared by the MCV method and intravenously injected into mice. Confocal microscopy showed the substantial accumulation of these liposomes in the adipose tissue vessels. Taken together, the MCV technique, along with solvent optimization, could be useful for generating surface‐modified liposomes with high drug entrapment efficiency for targeted delivery.     

含氟聚苯乙烯微球的制备及其疏水性能研究

以苯乙烯(St)和含氟单体(G04)为原料、聚乙烯吡咯烷酮(PVP)为分散剂和乙醇/水为混合溶剂,采用分散聚合法制备出PS-F(含氟聚苯乙烯)微球;然后以苯丙乳液提供的附着力、PS-F微球提供的疏水性能,制备PS-F疏水涂层。结果表明:制备PS-F微球的最佳工艺条件是m(总单体)=m(St+含氟单体)=20 g且m(St):m(含氟单体)=18:2、w(AIBN)=1.5%、w(PVP)=7.5%、V(乙醇)=108 mL、V(H_2O)=72mL、反应温度70℃和反应时间10 h,此时PS-F微球的粒径为0.4～1.0μm;当w(PS-F微球)=60%时,疏水涂层的水接触角为130。左右;含氟单体含量和苯丙乳液含量对水接触角的影响不大,涂层疏水性能主要与PS-F微球大小、涂层表面粗糙度有关。     

Controlled release of recombinant human nerve growth factor (rhNGF) from poly[(lactic acid)‐co‐(glycolic acid)] microspheres for the treatment of neurodegenerative disorders

Recombinant human nerve growth factor (rhNGF)/bovine serum albumin‐loaded microspheres were prepared by a water/oil/water emulsion and solvent evaporation technique with some modifications. The microspheres were characterized with respect to encapsulation efficiency, morphological properties and drug release. Using higher protein/polymer ratios in the primary emulsion resulted in higher protein content in the microspheres. The protein encapsulation efficiency increased from 89.1% to 97.5% on adding poly(ethylene glycol) to the inner aqueous phase. The in vitro rhNGF release lasted for more than 5 weeks. The biological activity of released rhNGF was confirmed by PC12 cell culture. The microspheres maintained a sustained release of rhNGF for at least 4 weeks in the basal forebrain as detected by fluorescence‐labeled and indirect immunofluorescent techniques. These results demonstrated the rhNGF‐containing microspheres are an effective means for delivering this molecule into the brain and their use may be a promising strategy in the treatment of neurodegenerative disorders such as Alzheimer's disease. Copyright © 2007 Society of Chemical Industry     

Intrinsic factor and vitamin B12 complex‐loaded poly[lactic‐co‐(glycolic acid)] microspheres: preparation,characterization and drug release

BACKGROUND: Vitamin B12 is an essential vitamin required by all mammals. Absorption of vitamin B12 is facilitated by binding of intrinsic factor–vitamin B₁₂ complex to specific receptors in the ileum. In humans a deficiency of this vitamin or a lack of intrinsic factor leads to pernicious anaemia. The major objective of the present study was to prepare intrinsic factor–vitamin B12 complex‐loaded poly[lactic‐co‐(glycolic acid)] (PLGA)‐based microparticles and to investigate their release kinetics. RESULTS: PLGA copolymer was synthesized by the ring‐opening polymerization method and characterized using gel permeation chromatography, Fourier transform infrared spectroscopy and ¹H NMR. The glass transition temperature measurement showed a single T_g at 40 °C. The intrinsic factor–vitamin B12 complex‐loaded PLGA microspheres were prepared by a water‐in‐oil‐in‐water double emulsion solvent extraction/evaporation technique. An environmental scanning electron microscopy investigation demonstrated that the PLGA particles had a mean particle diameter of 38 µm. Interestingly, different drug release patterns (bi‐ and triphasic ones) were observed for vitamin B12‐loaded and intrinsic factor–vitamin B12 complex‐loaded microspheres. In contrast to the rapid release of vitamin B12 by itself, in vitro release tests showed that intrinsic factor and vitamin B12 in the complex were released from PLGA microspheres in a sustained manner over 15 days. CONCLUSION: PLGA microspheres can be an effective carrier for the intrinsic factor–vitamin B12 complex. Copyright © 2007 Society of Chemical Industry