pH-sensitive polyelectrolyte complex gel microspheres composed of chitosan/sodium tripolyphosphate/dextran sulfate: swelling kinetics and drug delivery properties

Porous chitosan (CS) polyelectrolyte complex (PEC) hydrogel microspheres were prepared via either wet phase-inversion or ionotropic crosslinking with sodium tripolyphosphate (Na+ - TPP) and dextran sulfate (DS). The resulting microspheres were characterized using scanning electron microscopy (SEM) and elemental analysis (EA). The controlled release behavior of ibuprofen (IBU) from these microspheres was investigated. The PEC microspheres were about 700-950 microm in diameter with large pores and open porous structure. The CS/TPP/DS microspheres resisted hydrolysis in strong acid and biodegradation in enzymatic surroundings. The swelling kinetics for CS microspheres was close to Fickian diffusion, whereas those for CS/TPP and CS/TPP/DS were non-Fickian. Furthermore, the equilibrium water content (EWC) and water diffusion coefficient (D) increased with the pH of the media. The release profiles of IBU from CS/TPP/DS microspheres were slow in simulated gastric fluid (SGF, pH 1.4) over 3 h, but nearly all of the initial drug content was released in simulated intestinal fluid (SIF, pH 6.8) within 6 h after changing media. Overall the results demonstrated that CS/TPP/DS microspheres could successfully deliver a hydrophobic drug to the intestine without losing the drug in the stomach, and hence could be potential candidates as an orally administered drug delivery system.     

Preparation of uniform-sized pH-sensitive quaternized chitosan microsphere by combining membrane emulsification technique and thermal-gelation method

In this study, uniform-sized pH-sensitive quaternized chitosan microsphere was prepared by combining Shirasu porous glass (SPG) membrane emulsification technique and a novel thermal-gelation method. In this preparation process, the mixture of quaternized chitosan solution and alpha-beta-glycerophosphate (alpha-beta-GP) was used as water phase and dispersed in oil phase to form uniform W/O emulsion by SPG membrane emulsification technique. The droplets solidified into microspheres at 37 degrees C by thermal-gelation method. The whole process was simple and mild. The influence of process conditions on the property of prepared microspheres was investigated and the optimized preparation condition was obtained. As a result, the coefficient of variation (C.V.) of obtained microspheres diameters was below 15%. The obtained microsphere had porous structure and showed apparent pH-sensitivity. It dissolved rapidly in acid solution (pH 5) and kept stable in neutral solution (pH 7.4). The pH-sensitivity of microspheres also affected its drug release behavior. Bovine serum albumin (BSA) as a model drug was encapsulated in microspheres, and it was released rapidly in acid solution and slowly in neutral medium. The novel quaternized chitosan microspheres with pH-sensitivity can be used as drug delivery system in the biomedical field, such as tumor-targeted drug carrier.     

Preparation of chitosan microspheres by ionotropic gelation under a high voltage electrostatic field for protein delivery

Biodegradable microspheres have been widely used in drug/protein delivery system. In this paper, a modified ionotropic gelation method combined with a high voltage electrostatic field was developed to prepare protein-loaded chitosan microspheres. Bovine serum albumin (BSA) was chosen as a model protein. The preparation process and major parameters were discussed and optimized. The morphology, particle size, encapsulation efficiency and in vitro release behavior of the prepared microspheres were investigated. The results revealed that the microspheres exhibited good sphericity and dispersity when the mixture of sodium tripolyphosphate (TPP) and ethanol was applied as coagulation solution. Higher encapsulation efficiency (>90%) was achieved for the weight ratio of BSA to chitosan below 5%. 35% of BSA was released from the microspheres cured in 3% coagulation solution, and more than 50% of BSA was released from the microspheres cured in 1% coagulation solution at pH 8.8. However, only 15% of BSA was released from the microspheres cured in 1% coagulation solution at pH 4. The results suggested that ionotropic gelation method combined with a high voltage electrostatic field will be an effective method for fabricating chitosan microspheres for sustained delivery of protein.     

肾上腺髓质素微球复合PLGA/纳米羟基磷灰石支架材料的制备及生物活性评价

利用离子乳化交联法制备了负载肾上腺髓质素的壳聚糖微球,应用热致相分离法制备了乳酸和乙醇酸共聚物/纳米羟基磷灰石(PLGA/nHA)支架材料并在其中包覆载药微球.通过扫描电子显微镜、体外释放行为、材料溶血行为、碱性磷酸酶(ALP)活性的测定、支架材料表面细胞荧光染色和MTT[3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐]比色法等手段综合评价载药支架材料的性能及生物活性.结果表明,微球直径均匀,载药支架孔径大小合适并相互穿通.支架材料的溶血率小于5%,符合医用材料的溶血实验要求.载药支架及支架材料本身对成骨细胞及血管内皮细胞的增殖以及成骨细胞的分化均有一定的促进作用.     

Effect of method of preparation and process variables on controlled release of insoluble drug from chitosan microspheres

An inexpensive and simple method was adopted for the preparation of chitosan microspheres, crosslinked with glutaraldehyde (GA), for the controlled release of an insoluble drug‐ibuprofen, which is a commonly used NSAID (non‐steroidal anti‐inflammatory drug). The chitosan microspheres were prepared by different methods and varying the process conditions such as rate of stirring, concentration of crosslinking agent, and drug:polymer ratio in order to optimize these process variables on microsphere size, size distribution, degree of swelling, drug entrapment efficiency, and release rates. The absence of any chemical interaction between drug, polymer, and the crosslinking agent was confirmed by Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and thermogravimetric analyses (TGA) techniques. The microspheres were characterized by optical microscopy, which indicated that the particles were in the size range of 30–200 µm and scanning electron microscopy (SEM) studies revealed a smooth surface and spherical shape of microspheres. The microsphere size/size distributions were increased with the decreased stirring rates as well as GA concentration in the suspension medium. Decreasing the concentration of crosslinker increased the swelling ratio whereas extended crosslinking exhibited lowered entrapment efficiency. The in vitro drug release was controlled and extended up to 10 hr. Copyright © 2007 John Wiley & Sons, Ltd.     

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.     

Preparation and characterization of biodegradable microspheres containing hepatitis B surface antigen

Poly-DL-lactide-poly(ethylene glycol) (PELA) microspheres containing Hepatitis B surface antigen (HBsAg) were elaborated by a solvent extraction method based on the formation of a double water/oil/water (w/o/w) emulsion. Microspheres were characterized in terms of morphology, size and size distribution, encapsulation efficiency, and the efficiency of microsphere formation (EMF). Transmission electron microscopy (TEM) and polyacrylamide gel electrophoresis (PAGE) were used to investigate the structural integrality of HBsAg encapsulated in PELA microspheres. The release profile was investigated by the measurement of antigen present in the release medium at various intervals. The PELA-10 microspheres displayed the highest antigen encapsulation efficiency (about 80%), and antigen molecules could be stabilized in the PELA-10 microspheres during the preparation process. It suggested that the PELA microspheres had a great potential as a new polymer adjuvant for HBsAg. The release of Hepatitis B surface antigen from poly-DL-lactide-poly(ethylene glycol) microspheres.     

Preparation and properties of ionically cross‐linked chitosan nanoparticles

Chitosan nanoparticles were fabricated by a method of tripolyphosphate (TPP) cross‐linking. The influence of fabrication conditions on the physical properties and drug loading and release properties was investigated by transmission electron microscopy (TEM), dynamic light scattering (DLS), and UV–vis spectroscopy. The nanoparticles could be prepared only within a zone of appropriate chitosan and TPP concentrations. The particle size and surface zeta potential can be manipulated by variation of the fabrication conditions such as chitosan/TPP ratio and concentration, solution pH and salt addition. TEM observation revealed a core–shell structure for the as‐prepared nanoparticles, but a filled structure for the ciprofloxacin (CH) loaded particles. Results show that the chitosan nanoparticles were rather stable and no cytotoxicity of the chitosan nanoparticles was found in an in vitro cell culture experiment. Loading and release of CH can be modulated by the environmental factors such as solution pH and medium quality. Copyright © 2008 John Wiley & Sons, Ltd.     

生物降解聚酯包埋利福平缓释微球的制备及释放行为

以生物可降解乙交酯和丙交酯的无规共聚物(PLGA)为载体,将抗结核病药利福平溶解于PLGA的有机溶液中,采用通常乳化-溶剂挥发方法制备了药物缓释微球.研究了影响微球制备的工艺条件.用电子显微镜观察了微球及降解后的表面形态,测定了微球粒径及载药量,评价了载药微球的体外释放行为.结果表明,以质量分数为1%的明胶为稳定剂,制备的微球形态完整,粒径范围为10～30μm,微球中利福平的平均质量分数为24.3%.体外释药时间可以通过高分子的降解速率来调控,本实验的释药时间可以在42～84d之间调控,药物缓释达到了理想的零级动力学释放.因此,利福平PLGA微球具有显著的长效、恒量药物缓释作用.     

Development of biodegradable co-poly( -lactic/glycolic acid) microspheres for the controlled release of 5-FU by the spray drying method

The water-soluble anti-cancer drug, 5-fluorouracil (5-fluoro-2,4-pyrimidinedione) (5-FU) is encapsulated into biodegradable co-poly ( -lactic/glycolic acid) (PLGA) using the spray drying method for the development of long-lasting controlled release systems. In this study, the effects of both polymeric composition and technological parameters on release profiles of 5-FU were investigated. The degradation of various microspheres was also investigated. The mixture of dichloromethane/chloroform/methanol (1:1:2 v/v) instead of dichloromethane/chloroform (1:1 v/v) resulted in the modification of morphology, while the physical structure of the microsphere varied from a porous PLGA microsphere to a dense PLGA microsphere. The results show that the average diameter was 2 μm and the anti-cancer drug loading of microspheres approached approximately 8% (w/w). In addition, the lactide/glycolide ratio of the polymer is an important parameter for controlling the release profile of the entrapped anticancer drug. Our results indicate that the mixture solvent using the spray drying method was more efficient than emulsification solvent diffusion.     

Effect of preparation temperature in solvent evaporation process on Eudragit RS microsphere properties

Eudragit RS 100 microspheres containing ketoprofen as a model drug were prepared by the solvent evaporation method using an acetone/liquid paraffin solvent system. The influence of various preparation temperatures: 10, 25, 35, and 40 degrees C, on particle size and morphology, drug content and release kinetics, and drug crystal state was evaluated. With increasing temperature, microsphere average size was found to increase and particle size distribution to widen significantly. At 10 degrees C particles of irregular shape are formed, whereas higher temperatures gradually improve the sphericity of microspheres. As can be seen from SEM photographs, particle surface roughness decreases as preparation temperature increases. It was found that temperature had no effect either on ketoprofen microencapsulation efficiency or on its crystal state, but it does influence emulsion-stabilizer incorporation. Ketoprofen forms solid solution in Eudragit matrix and maintains amorphous state for significant period of time. Drug release rates from microspheres correlated with microspheres' surface roughness and to a lesser extent with particle size.     

Chitosan nanoparticles crosslinked by glycidoxypropyltrimethoxysilane for pH triggered release of protein

pH-responsive-chitosan nanoparticles for the control release of protein drug were prepared by combining two-step crosslinking method,in which chitosan was subsequently crosslinked by sodium tripolyphosphate(TPP)and glycidoxypropyltrimethoxysilane (GPTMS).Compared with TPP crosslinked chitosan particles,the two-step crosslinked nanoparticles were not only pH-responsive but also more stable in wide pH range.Fluorescein isothiocyanate(FITC)labeled anti-human-IgG antibody was used as a model protein drug for...     

A DSC and Raman spectroscopic study of microspheres preparedwith polar cosolvents by different techniques

A study was made of the possibilities of gradually decreasing the concentration of the toxic organic solvent in the process of microsphere preparation. Ammonio methacrylate copolymer-based microspheres were prepared by spray drying or conventional solvent evaporation techniques, and compared. The formulations were designed by varying the preparation methods and the concentrations of four polar cosolvents as independent variables. DSC was used to study the relationship between the changes in the independent variables and three of the main thermal events of the microspheres. Raman spectroscopy was used to investigate and confirm the possible interactions between drug and copolymer. Appropriate choice of the independent variables led to the molecularly dispersed drug in the polymer matrix. It was demonstrated that only the nature of the preparation method caused significant variations in the structure and thermal behaviour of the microspheres.     

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.     

Spray dried calcium gelled arabinoxylan microspheres: A novel carrier for extended drug delivery

Arabinoxylan (AX) microspheres were formulated by ionotropic gelation for extended drug delivery. AX from Plantago ovata was tested for gelation with aluminium, barium, calcium, magnesium, and iron(III) chloride. Only calcium was found to lead to weak gelation with AX. The conventional needle extrusion produced fragile AX beads with calcium and hence the spray drying process was adopted for the preparation of metronidazole hydrochloride (MH) loaded AX microspheres. MH loading in AX microspheres was 30.8 mass %, 31.9 mass %, and 29.3 mass % in formulations gelled with 0.05 g, 0.1 g, and 0.15 g of calcium chloride per 100 mL of solution, respectively. Scanning electron microscopy revealed the crystallinity reduction of MH in microspheres. The surface of drug loaded calcium gelled AX microsphere was rougher than that of an ungelled one. Interactions of calcium with AX and the amorphous nature of the drug in the microspheres were evidenced by infrared spectroscopy and X-ray diffraction studies. Calcium-induced gelation can extend the drug release to over 90 min in 0.1 M HCl despite the hydrophilic nature of AX and the high solubility of metronidazole.     

CS/TPP纳米微胶囊的制备及其载药性能

利用离子凝胶法, 以三聚磷酸钠(TPP)为交联剂, 由壳聚糖(CS)制备了CS/TPP纳米微胶囊. 用红外光谱仪、扫描电镜和粒径分析仪进行了表征, 并以牛血清蛋白(BSA)作为模型药物, 考察了所制备的CS/TPP纳米微胶囊的包载和缓释性能. 结果表明, CS/TPP纳米微胶囊的红外光谱相对于CS和TPP的红外光谱发生了很大变化, 说明CS和TPP通过正负电荷吸引聚合成囊; 粒径分析表明, 离子凝胶法可以得到粒径约430 nm的均匀分散的壳聚糖纳米微胶囊, 经冷冻干燥后粒径变为300 nm左右; 微胶囊包封率最高可达79.74%, 模型药物的持续释放时间可达7 d以上.     

聚乳酸载药微球制备及释药性能研究最新进展

对可生物降解材料聚乳酸作为药物载体制备微球制剂的研究状况进行了综述。针对目前限制聚乳酸微球制剂临床应用存在的问题,重点介绍了降低药物突释,提高药物包封率,改善多肽和蛋白药物微球释药性能等方面研究的最新进展。聚乳酸载药微球在药物传输中有着广阔的研究和应用前景。     

离子凝聚法制备负载流感疫苗的壳聚糖微球

采用三聚磷酸钠(TPP)作为离子交联剂, 应用离子凝聚法制备负载流感疫苗的壳聚糖微球. 筛选出壳聚糖起始质量分数为1%. TPP的浓度对壳聚糖微球的制备影响较大, 采用低浓度的TPP(200 μg/mL)制备的微球放置过夜均出现沉淀现象, 高浓度的TPP(800 μg/mL)在制备过程中出现絮状沉淀. 固化比影响微球的释放行为, 固化比为1∶1的微球爆炸式释放率达到90％, 固化比为1∶3的微球6 h后逐步释放, 12 h后释放率达到95％. 固化比为1∶5的微球6 h后没有明显的释放行为. 壳聚糖溶液的pH对微球的制备和释放没有显著的影响. 通过对负载流感疫苗的壳聚糖微球的制备条件和释放行为的研究结果表明, pH=5.6的壳聚糖溶液, 固化比为1∶3, TPP的质量浓度为400 μg/mL是较理想的流感疫苗壳聚糖微球的制备条件.     

Chondroitin Sulfate Fluorescence Biosensor Based on Graphere Quantum Dots Aggregating on CMC/CS Polyelectrolyte Microspheres

Here, we report an efficient fluorescence biosensor for chondroitin sulfate(CHS) based on polyelectrolyte microspheres of carboxymethyl cellulose(CMC) and chitosan(CS) composites inducing the aggregation of graphene quantum dots(GQDs), calling CMC/CS-GQDs. The polyelectrolyte microspheres(CMC/CS microspheres) were fabricated by using anioniccationic electrostatic attraction between CMC and CS by high voltage electrostatic spray technology. The aggregating process of GQDs was based on the anionic-cationic electrostatic attraction as well. After combing with the polyelectrolyte microspheres, the fluorescence of GQDs disappeared. CHS, which widely consists in the cell surface of human beings and animals, carries a large number of negative charges on the surface. The addition of CHS enabled CHS and GQDs to compete with each other to composite with the CMC/CS microshpheres. As a result of the higher surface charge density of CHS, CMC/CS-CHS formed accompanied by the release of GQDs, and the fluorescence of the system recovered. The CHS content was detected by analyzing the system's fluorescence recovery, which suggested that the obtained fluorescence biosensor can accurately detect the concentration of CHS. The test results showed that the linear range of the fluorescence recovery for this biosensor with respect to CHS was 0~12.00 mg/mL, and the detection limit was 10-8 M. Besides, to test the stability of the biosensor, the CMC/CS-GQDs micropsheres persisted for one month, with a low fluorescence quenching of 9.48%. These results suggested that CMC/CS-GQDs can be utilized as efficient fluorescence biosensor for the detection of CHS. Moreover, the detection method was simple and efficient, and could be widely popularized.     

阿司匹林-蒙脱土-壳聚糖缓释微球的制备及其体外释放性能

利用溶液法预先制备壳聚糖(Cs)-蒙脱土(MMT)复合材料(Cs-MMT),以Cs-MMT、Cs为原料,采用反相悬浮聚合法制得一种新型药物缓释体系阿司匹林-蒙脱土-壳聚糖载药微球(Asp-MMT-Cs)。采用FT-IR、SEM表征了Cs-MMT和Asp-MMT-Cs载药微球的结构及形态;设计正交实验优化了Asp-MMT-Cs载药微球的制备工艺;通过体外释放实验探讨了载药微球在不同模拟释放液中的释药规律。结果表明:所得微球球形度好,粒径分布较均匀;最优工艺制得的载药微球平均粒径为81.20μm,载药量为9.61%,包封率为76.78%。该缓释体系具有pH敏感性,更倾向于在pH较高的磷酸盐缓冲溶液中释放。