Aqueous Preparation and Evaluation of Albumin‐Chitosan Microspheres Containing Indomethacin

Controlled‐release egg albumin‐chitosan microspheres containing indomethacin as a model drug were successfully prepared by coacervation method. The proposed method can offer a simple method for microsphere preparation in an aqueous system with the elimination of the use of organic solvents that are usually needed in conventional techniques of microencapsulation. The interaction between negatively charged egg albumin molecules in phosphate buffer, pH 7.2, or sodium hydroxide solution and positively charged chitosan molecules dissolved in diluted acetic acid to form an insoluble precipitate was the principle for the formation of the microspheres. The effects of many process variables, such as amount of formaldehyde as a cross‐linking agent, stirring time, final pH of encapsulation medium, initial drug loading, and albumin concentration or albumin‐to‐chitosan weight ratio, on the properties of the prepared microspheres were investigated. Incorporation efficiencies of the microspheres to the drug were high in most cases and ranged between 63.3 ± 3.6% and 92.39 ± 3.2%, while particle sizes were 435.2 ± 12.6 up to 693.9 ± 34.6 µm for the different tested batches. On the other hand, the values of angles of repose and compressibility indices were in the range of 23.5 ± 0.4 to 32.0 ± 0.7 degrees and 11.1 ± 0.7% to 23.6 ± 0.7% respectively, which indicate overall good free flowing nature of the microspheres of all batches. The maximum required amount of the cross‐linking agent was determined to avoid excessive unnecessary chemicals. It was also noticed that excessive time of stirring and excessive initial drug loading are not recommended as it may lead to microspheres of low properties. The pH of the encapsulation media (pH 3.77 up to pH 4.91) significantly affected the properties of the microspheres. As the pH of the encapsulation media was increased, the incorporation efficiency, particle size, and flowability decreased, along with increase of drug release rate, which could be related to incomplete cross linking of the microspheres matrix. It was also observed that high concentration of albumin solution and accordingly the increase of albumin‐to‐chitosan weight ratio were accompanied with increases in incorporation efficiency and particle size with improved microsphere flowability and slow indomethacin release. Thus, the proposed microspheres showed the ability to control the release of indomethacin, and their properties were highly affected by many process variables that could be controlled to obtain an optimized system.     

磁性高分子微球的制备及应用

本文对新型功能材料磁性高分子微球的组成、制备方法、应用及其发展前景进行了简要介绍     

储能微球的制备

通过悬浮聚合法合成了石蜡聚苯乙烯微球,研究了合成过程中复合介质的配比及用量对微球粒径分布的影响。     

CS/n-HA复合微球的制备与表征

在CS载药微球和n-HA载药的基础上探索新的复合药物载体材料,以戊二醛为交联剂采用乳化交联法制得CS/n-HA复合微球,并采用SEM、XRD、IR及激光粒度测试等手段对复合微球进行分析表征.结果表明,CS/n-HA复合微球球形度较好,微球表面致密;复合微球样品的中位粒径D50为20μm,大部分分布在10～50μm范围内;复合后CS/n-HA微球中的n-HA结晶状态未发生明显变化,而CS的结晶程度有所降低;CS/n-HA复合微球的形成主要是基于CS和戊二醛的Schiff碱反应.     

Development and optimization of chemically stable lipid microspheres containing flunarizine

Aim: The purpose of this study is to develop an appropriate dispersion system containing flunarizine, and most of all, to improve the chemical stability of flunarizine. Method: In this study, a higher incubation temperature (60°C), to induce a faster chemical degradation, was adopted to optimize a better vehicle, an appropriate pH value, and an effective antioxidant system for flunarizine. Results: The chemical stability of flunarizine was improved significantly in lipid microspheres (LMs) compared with the aqueous solution. The optimal formulation of LMs for flunarizine at pH 8.0 is composed of (w/v): flunarizine 0.1%, dl-α-tocopherol 0.1%, medium-chain triglyceride 5%, long-chain triglyceride 5%, soybean lecithin 1.8%, poloxamer 188 0.4 %, Tween-80 0.2%, glycerol 2.5% and l-cysteine 0.05%, Na₂SO₃ 0.15%, and EDTA 0.01%. Conclusions: The long-term stability investigation, stored at 10 ± 2°C and 25 ± 2°C for 6 months, witnessed the better chemical stability of flunarizine in LMs. An intravenous delivery system of LMs for flunarizine focusing on a better chemical stability of flunarizine has been successfully developed and optimized.     

Eudragit coating of chitosan-prednisolone conjugate microspheres and in vitro evaluation of coated microspheres

Chitosan-prednisolone conjugate microspheres (Ch-SP-MS) were prepared, and Eudragit coating was applied in order to efficiently deliver the microspheres and drug to the intestinal disease sites. The Eudragit L100-coated microspheres (Ch-SP-MS/EuL100) were examined for particle characteristics and the release of drug and Ch-SP-MS in different pH media at 37°C. Ch-SP-MS were spherical, with a mean size of 4.5 μm and prednisolone content of 3.3% (w/w). Ch-SP-MS/EuL100 were fairly spherical, with a mean size of 22. 5 μm and drug content of 0.32% (w/w). At pH 1.2, the release extent was less than 5% even at 48 h, and Eudragit coating tended to suppress the release. In contrast, at pH 6.8 and 7.4, Ch-SP-MS/EuL100 tended to show somewhat faster drug release than Ch-SP-MS. Ch-SP-MS/EuL100 displayed a release extent of 23 and 27% at pH 6.8 and 7.4, respectively. Ch-SP-MS aggregated at pH 1.2, but almost kept their initial size and shape at pH 6.8 and 7.4. Ch-SP-MS/EuL100 almost maintained their original shape and size at pH 1.2, and gradually released Ch-SP-MS at pH 6.8 and 7.4 due to dissolution of the Eudragit layer. Eudragit coating is suggested to be useful to efficiently deliver Ch-SP-MS to the intestinal disease sites.     

生物可降解高分子多孔微球制备与应用的研究进展

生物可降解高分子多孔微球可以在体内降解并且无毒副作用,已经被广泛应用于药物控制释放、组织工程等领域,它们的制备及应用是近年来的研究热点。概述了生物可降解高分子多孔微球的几种制备方法及其应用领域,并对生物可降解高分子多孔微球的未来发展前景进行了展望。     

壳聚糖微球的制备及其在药物载体中的应用

壳聚糖因其具有良好的生物学特性而成为药物载体研究的热点。药物经壳聚糖负载后,不仅能够达到缓释控释的目的,还能够改变药物的给药方式,降低药物不良反应,提高药物生物利用度。本文就壳聚糖微球的制备及其在药物载体中的应用作一综述。     

酚醛树脂基碳微球的制备及其电化学性能研究

以间苯二酚和甲醛为前驱体,1,6-己二胺作为交联剂,通过水热法制备出一种球形纳米酚醛树脂基碳微球材料。采用N2吸附、XRD及SEM对材料的结构和形貌表征表明,交联剂的加入可得到球形形貌的碳纳米微球,同时,改变交联剂的量可以控制球形颗粒的大小及结构,但FT-IR表明对表面官能团未有影响。利用循环伏安法、恒流充放电及交流阻抗曲线对碳球材料电化学性能进行评价,在-0.95~0 V电压范围内,碳球材料具有典型的双电层电容和充放电可逆性。当1,6-己二胺与间苯二酚摩尔比为0.4时,在1 A/g的电流密度下测得的比电容为147.37 F/g。对电极进行5000次循环充放电测试,其比容保持率为91.27%。     

分子印迹聚合物微球合成方法研究进展

对近年来发展起来的分子印迹聚合物微球(MIPMs)合成方法的研究进展进行了综述。重点介绍了表面分子印迹聚合物合成法、核-壳型分子印迹聚合物合成法、基于β-环糊精分子印迹聚合物的合成法3种新型MIPMs制备方法。阐述了常用的沉淀聚合法、种子溶胀聚合法、悬浮聚合法合成MIPMs的发展现状。最后对MIPMs的发展趋势提出了展望。     

含松香丙烯酸酯的磁性聚合物微球的制备及表征

以苯乙烯(St)为单体,松香丙烯酸与甲基丙烯酸-2-羟乙酯酯化物(RAH)为交联剂,在油酸改性的Fe3O4存在下,采用悬浮聚合法制备了含松香的磁性聚合物微球[P(St/RAH)/Fe3O4],研究了Fe3O4用量对聚合物微球性能的影响,采用红外光谱、X射线衍射、扫描电镜、透射电镜、X射线光电子能谱、热重和磁强计对磁性聚合物微球进行了分析表征。结果表明,成功制得了P(RAH/St)/Fe3O4;得到的磁性微球球形良好,表面光滑,Fe3O4包埋在聚合物中;微球为超顺磁性,在油酸改性Fe3O4用量为8%(质量分数)时磁性达到饱和,饱和磁化强度为3.13A·m2/kg。     

Controllable preparation of thio-functionalized composite polysilsesquioxane microspheres in a microreaction system

Controllable preparation of monodispersed composite polysilsesquioxane microspheres (CPSQs) with scalability is required but difficult to realize in a conventional stirred batch reactor because of the reactors’ poor mixing performance and scaling-up effects. A new semi-continuous microreaction system integrating a microreactor with a stirred batch reactor was developed for the synthesis of monodispersed thio-functionalized CPSQs by employing a two-step sol–gel method. Methyltrimethoxysilane and (3-mercaptopropyl)trimethoxysilane were used as silicon sources. The effects of the synthesis variables were systematically studied. The particle size could be adjusted between several hundreds of nanometers and several micrometers with a narrow size distribution (the coefficient of variation was <10%), and the sulfhydryl group (SH) concentration reached 14.13 at.%. Compared with the batch reactor, the semi-continuous microreaction system showed higher synthesis reproducibility and higher potential for the large-scale production of CPSQs.     

Development and evaluation of intestinal targeted mucoadhesive microspheres of Bacillus coagulans

Background: Intestinal targeted mucoadhesive microsphere of probiotics may provide numerous associated health benefits.

Aim: To develop mucoadhesive microspheres that will deliver viable probiotic cells into gut protectively against harsh environmental conditions of stomach for extended period.

Materials and methods: Core mucoadhesive microspheres of Bacillus coagulans were prepared using hypromellose, following coacervation and phase separation technique and were then coated with hypromellose phthalate to achieve their site-specific release. Microspheres were evaluated for percent yield, entrapment efficiency, surface morphology, particle size and size distribution, flow property, swelling property, mucoadhesion property by the in vitro wash-off and the ex vivo mucoadhesive strength tests, in vitro release profile and release kinetic, in vivo probiotic activity, and stability. The values for kinetic constant and regression coefficient of model-dependent approaches and the difference factor, the similarity factor, and the Rescigno index of model-independent approaches were determined for accessing and comparing in vitro performance.

Results: Microsphere formulation batches have percent yield value between 56.26% and 69.13% and entrapment efficiency value between 66.95% and 77.89%. Microspheres were coarser with spherical shape having mean particle size from 28.03 to 48.31 μm. In vitro B. coagulans release profile follows zero-order kinetics and depends on the grade of hypromellose and the B. coagulans-to-hypromellose ratio. Experimental microspheres rendered adequate stability to B. coagulans at room temperature.

Conclusion: Microspheres had delivered B. coagulans in simulated intestinal condition following zero-order kinetics, protectively in simulated gastric condition, exhibiting appreciable mucoadhesion in intestinal condition, which could be useful to achieve site-specific delivery for extended period.     

Pharmacokinetic and pharmacodynamic evaluation of floating microspheres of metformin hydrochloride

Metformin hydrochloride (MH), a biguanide antidiabetic, is the drug of choice in obese patients. It is well absorbed from the upper part of gastrointestinal tract and has oral bioavailability of 50% to 60%. The objective of this study was to formulate MH into floating microspheres in order to increase its residence time at the site of absorption and thus improve its bioavailability; and to extend the duration of action along with possibilities of dose reduction. Microspheres were prepared by emulsion solvent evaporation method and evaluated for particle size, entrapment efficiency, buoyancy, and in vitro release; and further characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, and differential scanning calorimetry. The pharmacokinetic and pharmacodynamic evaluation of selected formulation was carried out in male Wistar diabetic rats. The data was statistically analyzed by unpaired t-test. A 3.5-fold increase in relative bioavailability was observed. The prolongation of half-life (t_1/2) from 4.5 ± 2.41 h to 14.12 ± 4.81 h indicated extended duration of action. Oral glucose tolerance test (OGTT) was analyzed by one-way analysis of variance followed by Dunnet multiple comparison test, a significant decrease (p < 0.05) in the blood glucose levels was observed when formulations were compared with control rats. Hence, MH floating microspheres were tested at 50 mg/kg and 100 mg/kg body weight, OGTT data showed nonsignificant difference (p >0.05). In conclusion, an effective oral antidiabetics treatment can be achieved by formulating MH into floating microspheres which results in increase in bioavailability along with extended duration of action resulting in possible reduction in dose.     

SiO2微球的制备与应用

综述了致密和多孔SiO2微球的制备方法．重点描述了近年来SiO2微球的一些新应用。     

Development and in vitro evaluation of floating rosiglitazone maleate microspheres

Background: Various approaches have been used to retain the dosage form in stomach as a way of increasing the gastric residence time, including floatation systems; high-density systems; mucoadhesive systems; magnetic systems; unfoldable, extensible, or swellable systems; and superporous hydrogel systems. Aim?: The objective of this study was to prepare and evaluate floating microspheres of rosiglitazone maleate for the prolongation of gastric residence time. Method: The microspheres were prepared by solvent diffusion–evaporation method using ethyl cellulose and hydroxypropylmethylcellulose. A full factorial design was applied to optimize the formulation. Results: Preliminary studies revealed that the polymer:drug ratio, concentration of polymer, and stirring speed significantly affected the characteristics of microspheres. The optimum batch exhibited a prolonged drug release, remained buoyant for >12 hours, high entrapment efficiency, and particle size in the order of 350 μm. Conclusion: The results of 32 full factorial design revealed that the concentration of ethylcellulose 7 cps (X₁) and stirring speed (X₂) significantly affected drug entrapment efficiency, percentage release after 8 h and particle size of microspheres.     

Development of hollow microspheres as floating controlled-release systems for cardiovascular drugs: preparation and release characteristics

Hollow microspheres of cellulose acetate loaded with four cardiovascular drugs (nifedipine [NFD], nicardapine hydrochloride [NCD], verapamil hydrochloride [VRP], and dipyridamole [DIP]) were prepared by a novel solvent diffusion-evaporation method. The oil-in-water emulsion prepared in an aqueous solution of 0.05% poly(vinyl alcohol) medium with ethyl acetate, a water-soluble and less toxic solvent, was used as the dispersing solvent. The yield of the microspheres was up to 80%. The microspheres had smooth surfaces, with free-flowing and good-packing properties. Scanning electron microscopy (SEM) confirmed their hollow structures, with sizes in the range 489-350 μm. The microspheres tended to float over the gastric media for more than 12 h. The drug loaded in hollow microspheres was in an amorphous state, as confirmed by differential scanning microscopy (DSC). The release of the drugs was controlled for more than 8 h. The release kinetics followed different transport mechanisms depending on the nature of the drug molecules.     

Preparation and evaluation of mucin-gelatin mucoadhesive microspheres for rectal delivery of ceftriaxone sodium

Soluble mucin (S-mucin) processed from the small intestines (ileal region) of freshly slaughtered pigs via homogenization, dialysis, centrifugation and lyophilization and its admixtures with type A gelatin were dispersed in an aqueous medium and used to formulate ceftriaxone sodium-loaded mucoadhesive microspheres by the emulsification cross-linking method using arachis oil as the continuous phase. The release profile of ceftriaxone sodium from the microspheres was evaluated in both simulated gastric fluid (SGF) without pepsin (pH 1.2) and simulated intestinal fluid (SIF) without pancreatin (pH 7.4). The microspheres were further evaluated as possible novel delivery system for rectal delivery of ceftriaxone sodium in rats. Release of ceftriaxone sodium from the microspheres in both release media was found to occur predominantly by diffusion following non-Fickian transport mechanism and was higher and more rapid in SIF than in SGF. The results obtained from this study may indicate that ceftriaxone sodium could be successfully delivered rectally when embedded in microspheres formulated with either type A gelatin alone or its admixtures with porcine mucin; hence providing a therapeutically viable alternative route for the delivery of this acid-labile third generation cephalosporin.     

In situ preparation and protein delivery of silicate–alginate composite microspheres with core-shell structure

The efficient loading and sustained release of proteins from bioactive microspheres remain a significant challenge. In this study, we have developed bioactive microspheres which can be loaded with protein and then have a controlled rate of protein release into a surrounding medium. This was achieved by preparing a bioactive microsphere system with core-shell structure, combining a calcium silicate (CS) shell with an alginate (A) core by a one-step in situ method. The result was to improve the microspheres'' protein adsorption and release, which yielded a highly bioactive material with potential uses in bone repair applications. The composition and the core-shell structure, as well as the formation mechanism of the obtained CS–A microspheres, were investigated by X-ray diffraction, optical microscopy, scanning electron microscopy, energy dispersive spectrometer dot and line-scanning analysis. The protein loading efficiency reached 75 per cent in CS–A microspheres with a core-shell structure by the in situ method. This is significantly higher than that of pure A or CS–A microspheres prepared by non-in situ method, which lack a core-shell structure. CS–A microspheres with a core-shell structure showed a significant decrease in the burst release of proteins, maintaining sustained release profile in phosphate-buffered saline (PBS) at both pH 7.4 and 4.3, compared with the controls. The protein release from CS–A microspheres is predominantly controlled by a Fickian diffusion mechanism. The CS–A microspheres with a core-shell structure were shown to have improved apatite-mineralization in simulated body fluids compared with the controls, most probably owing to the existence of bioactive CS shell on the surface of the microspheres. Our results indicate that the core-shell structure of CS–A microspheres play an important role in enhancing protein delivery and mineralization, which makes these composite materials promising candidates for application in bone tissue regeneration.     

Preparation and characterization of composite microspheres for brachytherapy and hyperthermia treatment of cancer

Composite microspheres were prepared by coating yttrium-aluminum-silicate (YAS) glass microspheres (20-30 μm) with a layer of Fe₃O₄ nanoparticles and evaluated for potential use in brachytherapy and hyperthermia treatment of cancer. After neutron activation to form the β-emitting ⁹⁰Y radionuclide, the composite microspheres can be injected into a patient to destroy cancerous tumors; at the same time, the composite microspheres can generate heat upon application of a magnetic field to also destroy the tumors. The results showed that the composite microspheres were chemically durable when immersed in a simulated body fluid (SBF), with ~ 0.25% weight loss and ~ 3.2% yttrium dissolved into the SBF after 30 days at 37 °C. The composite microspheres also showed ferromagnetic properties as a result of the Fe₃O₄ coating; when immersed in water at 20 °C (20 mg in 1 mL of water), the application of an alternating magnetic field produced a temperature increase from 20 °C to 38−46 °C depending on the thickness of the Fe₃O₄ coating. The results indicate that these composite microspheres have promising potential in combined brachytherapy and hyperthermia treatment of cancerous tumors.