Controlled release of antihypertensive drug from the interpenetrating network poly(vinyl alcohol)–guar gum hydrogel microspheres

Poly(vinyl alcohol)-guar gum interpenetrating network microspheres were prepared by cross-linking with glutaraldehyde. Nifedipine, an antihypertesive drug, was loaded into these matrices before and after cross-linking to study its release patterns. The extent of cross-linking was analyzed by Fourier transform infrared spectroscopy and differential scanning calorimetry. Furthermore, the microspheres were characterized for drug entrapment efficiency, particle size, transport of water into the matrix and drug release kinetics. Scanning electron microscopic photographs confirmed the spherical nature and surface morphology. The mean particle size of the microspheres was found to be around 300 μm. The molecular transport phenomenon, as studied by the dynamic swelling experiments, indicated that an increase in cross-linking affected the transport mechanism from Fickian to non-Fickian. The in vitro release study indicated that the release from these microspheres is not only dependent upon the extent of cross-linking, but also on the amount of the drug loaded as well as the method of drug loading.     

成骨生长肽壳聚糖-海藻酸钠微球的制备及体外检测

背景：成骨生长肽体外注射可以刺激外周血和骨髓细胞数增加,增加动物的骨量,加速骨折愈合,但因多肽不稳定性及注射应用不方便,限制了其临床应用。 目的：应用乳化交联法制备成骨生长肽壳聚糖-海藻酸钠缓释微球,并对其粒径、载药、体外释药、理化特性进行检测。 方法：以戊二醛作为交联剂,应用乳化交联法制备具有控制释放功能的负载成骨生长肽壳聚糖-海藻酸钠微球,显微镜及扫描电镜观察微球的形态和粒径;利用酶联免疫吸附实验动态检测成骨生长肽壳聚糖-海藻酸钠微球的载药率、包封率和缓释规律。 结果与结论：乳化交联法制备的壳聚糖-海藻酸钠微球,球形良好,球体表面有较多微孔,具有较高的包封率(>72%)。体外药物释放实验表明,成骨生长肽可以从壳聚糖-海藻酸钠微球中缓慢释放,整个释放过程可达49 d,累积释放率>85%。提示应用乳化交联法制备的负载成骨生长肽壳聚糖-海藻酸钠缓释微球,具有很好的控制释放成骨生长肽的能力。     

Rifampicin carrying polyhydroxybutyrate microspheres as a potential chemoembolization agent

In this study, we attempted to prepare microspheres from a microbial biodegradable polyester, i.e. polyhydroxybutyrate (PHB) as a potential chemoembolization agent. The drug loaded PHB microspheres were prepared by a solvent evaporation technique, in which methylene chloride, distilled water, and polyvinyl alcohol were utilized as the solvent, dispersion medium, and emulsifier, respectively. Microspheres were obtained within a size range of 5-100 μm by changing the initial polymer/solvent ratio, emulsifier concentration, stirring rate, and initial drug concentration. It was possible to obtain PHB with very narrow size distributions by applying gravity field-flow fractionation technique. Very high drug loadings of up to 407.6 mg rifampicin/g PHB were achieved. Drug release rates were very rapid. Almost 90% of the drug loaded was released in about 24 h. Both the size and drug content of PHB microspheres were found to be effective in controlling the drug release from these microspheres.     

Therapeutic effect of in vivo sustained estradiol release from poly (lactide-co-glycolide) microspheres on bone mineral density of osteoporosis rats

Poly (lactide-co-glycolide or PLGA) microspheres containing 0.3% (w/w) of estradiol were prepared by a solvent evaporation method. These PLGA microspheres had a wide particle distribution between 0.5 and more than 100 microm. The average size was 76 microm. Physicochemical properties of the microspheres were characterized by X-ray diffraction patterns, FT-IR spectra and DSC. In vitro estradiol release was maintained at a constant rate from these PLGA microspheres for 1 month. The loaded drug was totally recovered in the collection buffer within this time period. In vivo experiments were performed on Wistar rats that had received ovariectomy. These rats were fed with a vitamin D-deficient and Ca-deficient diet. The combination of ovariectomy and diet induced osteoporosis. PLGA microspheres containing either 50, 100, or 200 microg estradiol were injected into these rats. The plasma estradiol in each rat was monitored for 50 days. These in vivo drug release patterns were found to be different from the one obtained from in vitro release. The Ca-AUC was not significant different among various dosages administered. However, bone mineral density for rats after the injection of estradiol loaded microspheres was higher than that obtained for the control. This suggested that all estradiol microspheres administration induced bone generation in osteoporosis rats.     

Paclitaxel and etoposide-loaded Poly (lactic-co-glycolic acid) microspheres fabricated by coaxial electrospraying for dual drug delivery

Abstract

In this study, we fabricated paclitaxel (PTX) and etoposide (ETP) loaded Poly (lactic-co-glycolic acid) (PLGA) microspheres with core–shell structures and particle sizes ranging from 1 to 4?µm by coaxial electrospraying. The microspheres were analyzed by scanning electron microscopy (SEM), transmission electron microscopy (TEM). The drug loading rate and entrapment efficiency of the microspheres were detected by high performance liquid chromatograph (HPLC). Moreover, the drug release profiles and degradation of drug-loaded PLGA microspheres in vitro were investigated, respectively. The distinct layered structure that existed in the manufactured core–shell microspheres can be observed by TEM. The in vitro release profiles indicated that the PLGA/PTX?+?ETP (PLGA/PE) microspheres exhibited the controlled release of two drugs in a sequential manner. Cell Counting Kit-8 was used to detect the toxic and side effects of the microspheres on bone tumor cells. PTX and ETP for combination drug therapy loaded microspheres had more cytotoxic effect on saos-2 osteosarcoma cells than the individual drugs. In conclusion, core–shell PLGA microspheres by electrospraying for combination drug therapy is promising for medicine applications, the PLGA/PE microspheres have some potential for osteosarcoma treatment.     

Fabrication and characterization of monodisperse PLGA–alginate core–shell microspheres with monodisperse size and homogeneous shells for controlled drug release

Monodisperse PLGA–alginate core–shell microspheres with controlled size and homogeneous shells were first fabricated using capillary microfluidic devices for the purpose of controlling drug release kinetics. Sizes of PLGA cores were readily controlled by the geometries of microfluidic devices and the fluid flow rates. PLGA microspheres with sizes ranging from 15 to 50 μm were fabricated to investigate the influence of the core size on the release kinetics. Rifampicin was loaded into both monodisperse PLGA microspheres and PLGA–alginate core–shell microspheres as a model drug for the release kinetics studies. The in vitro release of rifampicin showed that the PLGA core of all sizes exhibited sigmoid release patterns, although smaller PLGA cores had a higher release rate and a shorter lag phase. The shell could modulate the drug release kinetics as a buffer layer and a near-zero-order release pattern was observed when the drug release rate of the PLGA core was high enough. The biocompatibility of PLGA–alginate core–shell microspheres was assessed by MTT assay on L929 mouse fibroblasts cell line and no obvious cytotoxicity was found. This technique provides a convenient method to control the drug release kinetics of the PLGA microsphere by delicately controlling the microstructures. The obtained monodisperse PLGA–alginate core–shell microspheres with monodisperse size and homogeneous shells could be a promising device for controlled drug release.     

Drug entrapment in silica microspheres through a single step sol-gel process and in vitro release behavior

A single step sol-gel process was used to precipitate silica microspheres containing ibuprofen or naproxen for controlled drug delivery applications. The drug release behavior from these systems was analyzed in vitro. Pure ibuprofen and naproxen exhibited linear release with time, while sol-gel silica entrapped drugs were released with a logarithmic time dependence starting with an initial burst effect followed by a gradual decrease. Microscopic analysis combined with gravimety and infrared spectroscopy indicated that some of the drug is entrapped as large crystals attached to silica microspheres while the rest is encapsulated inside the microspheres. Drug-loaded silica microspheres with no open porosity and with a narrow particle size distribution were obtained. Both erosion of the microspheres and diffusion through them contributed to drug release. Sol-gel precipitation of silica microspheres is a promising method for drug entrapment and controlled release.     

RhBMP-2-loaded Poly(lactic-co-glycolic acid) microspheres fabricated by coaxial electrospraying for protein delivery

In this study, we fabricated recombinant human bone morphogenetic protein-2 (rhBMP-2) loaded Poly(lactic-co-glycolic acid) (PLGA) microspheres with core–shell structures and particle sizes ranging from 2.5 to 8 μm by coaxial electrospraying. The manufacturing process of core–shell microspheres by coaxial electrospraying is simpler than that with other methods, and a smaller diameter can be obtained. The microspheres were analyzed by environmental scanning electron microscopy, transmission electron microscopy (TEM), and laser scanning confocal microscopy (LSCM). Moreover, the drug release profiles and degradation of rhBMP-2-loaded PLGA microspheres in vitro were investigated for 21 days and for 7 weeks, respectively. The rhBMP-2 was stabilized by using bovine serum albumin (BSA) to ensure protein activity in the electrospraying process. Fluorescently labeled protein that was loaded into the core–shell PLGA microspheres was verified by LSCM. The distinct layered structure that existed in the manufactured core–shell microspheres can be observed by TEM. Cell Counting Kit-8 (CCK-8) indicated that the core–shell PLGA microspheres loaded with rhBMP-2 have great potential for the treatment of bone defects, for bone regeneration, and in bone tissue engineering.     

Poly(ethylene glycol)-poly(lactic-co-glycolic acid) core–shell microspheres with enhanced controllability of drug encapsulation and release rate

Poly(lactic-co-glycolic acid) (PLGA) microspheres have been widely used as drug carriers for minimally invasive, local, and sustained drug delivery. However, their use is often plagued by limited controllability of encapsulation efficiency, initial burst, and release rate of drug molecules, which cause unsatisfactory outcomes and several side effects including inflammation. This study presents a new strategy of tuning the encapsulation efficiency and the release rate of protein drugs from a PLGA microsphere by filling the hollow core of the microsphere with poly(ethylene glycol) (PEG) hydrogels of varying cross-linking density. The PEG gel cores were prepared by inducing in situ cross-linking reactions of PEG monoacrylate solution within the PLGA microspheres. The resulting PEG-PLGA core–shell microspheres exhibited (1) increased encapsulation efficiency, (2) decreased initial burst, and (3) a more sustained release of protein drugs, as the cross-linking density of the PEG gel core was increased. In addition, implantation of PEG-PLGA core–shell microspheres encapsulated with vascular endothelial growth factor (VEGF) onto a chicken chorioallantoic membrane resulted in a significant increase in the number of new blood vessels at an implantation site, while minimizing inflammation. Overall, this strategy of introducing PEG gel into PLGA microspheres will be highly useful in tuning release rates and ultimately in improving the therapeutic efficacy of a wide array of protein drugs.     

Fabrication and characterizations of a novel drug delivery device liposomes-in-microsphere (LIM)

In the present work, we developed a novel drug delivery system, liposomes-in-microsphere (LIM) of biodegradable polymers, which is conceived from a combination of the polymer- and the lipid-based delivery systems and can thus integrate the advantages and avoid the drawbacks of the two systems. Liposomes were encapsulated into microspheres of biodegradable polymers by the solvent extraction/evaporation process to form LIMs. The integrity of the liposomes was preserved by modifying the microencapsulation process and coating the liposomes with chitosan. We demonstrated by scanning electron microscopy, laser light scattering and fluorescence spectroscopy that the particle size and surface morphology of the polymeric microspheres did not change significantly with the liposomes encapsulated, the liposomes remained intact within the polymeric matrix of the microspheres, and the encapsulated liposomes could be released from the microspheres in a controlled manner at a nearly constant release rate after an initial off-release period. Decreasing the particle size of liposomes and increasing the pore size of the polymeric matrix shortened the initial off-release period and increased the liposome release rate. In conclusion, a novel drug delivery system, liposomes-in-microsphere, was successfully developed and characterized. The liposome release kinetics could be controlled by the composition and fabrication parameters of the liposomes and polymeric microspheres. Such a novel controlled release system may have potential to be applied for drug delivery and gene therapy.     

全反式维甲酸-聚酸酐长效缓释剂研制及其可行性

背景：如何提高全反式维甲酸疗效、稳定性和降低毒副作用是临床治疗所面临的最大问题。近年来用可生物降解的聚合物为材料,通过乳化包囊等分散技术将药物制备成微粒分散体系,用作缓释、控释注射剂的研究日益增多。 目的：研制全反式维甲酸-聚酸酐长效缓释微球肿瘤治疗剂,观察其体内外全反式维甲酸经时缓释变化规律。 方法：采用乳剂-扩散溶剂挥发法制备全反式维甲酸-聚酸酐长效缓释微球肿瘤治疗剂,扫描电镜检测微球外观及微球粒径,高效液相色谱法检测微球载药量、包封率及体内外释药量。 结果与结论：所制微球治疗剂光滑圆整,大小均一,平均粒径(154.42±26.76) nm,载药率(16.5±1.45)%,包封率(87.84±4.79)%;体外释放实验证明该微球治疗剂可持续释放全反式维甲酸约50 d,将其肌肉注射到大耳白兔体内,可稳定缓释全反式维甲酸近45 d。结果表明该微球治疗剂载药量及包封率均较高,体内外释药平稳并且具有明显的长效缓释作用。     

紫杉醇聚己内酯／泊洛沙姆188共混载药微球及其抗肿瘤活性

目的本研究首次尝试利用聚己内酯（PCL）与亲水性添加剂泊洛沙姆188（Pluronic F68,F68）共混物作为载体材料与抗癌药物紫杉醇组成微球缓释载药系统。方法采用乳化,溶剂挥发法制备紫杉醇PCL/F68共混微球;考察紫杉醇PCL／F68共混微球的表面形态、平均粒径、包埋率及体外释放性能：利用DSC法分析紫杉醇在PCL／F68共混徽球中的分散状态;考察紫杉醇PCL/F68共混微球在小鼠肝癌H22腹水瘤模型中的抗肿瘤活性。结果表明载体材料中的亲水性添加剂F68可在微球表面形成孔状结构,F68的加入提高了紫杉醇从PCL／F68共混载药微球的释放并获得了接近恒定的释放性能;在小鼠肝癌H22腹水瘤模型中。紫杉醇PCL／F68共混载药微球对肿瘤生长具有抑制作用,荷瘤小鼠生存期明显延长。结论以PCL/F68共混物为载体制备的紫杉醇控释微球具有较高的释放能力和明显的控释效果．     

BSA-PLGA缓释微球的制备及优化条件的探索

目的以牛血清白蛋白(BSA)为模型蛋白、聚乳酸-聚乙二醇酸(PLGA)为包裹材料,探索微球的制备方法并优化制备工艺。方法采用复乳-溶剂挥发法制备BSA-PLGA微球,显微测量微球粒径,以微量BCA法测定微球的蛋白含量并计算包封率,进行体外释放,测定微球的累积释放量。探索BSA投药量、PLGA用量、PVA浓度、超声功率等因素对微球包封率、突释量的影响。结果通过正交实验设计,优化了微球的制备工艺,其优化条件是BSA投药量为10mg、PLGA用量为250mg、PVA浓度为1.5%、超声乳化功率为60周。结论通过控制不同的因素,可以得到较高包封率、较小突释、适当载药量和粒径的BSA-PLGA微球。     

Synthesis, characterization, biodegradation, and drug delivery application of biodegradable lactic/glycolic acid polymers: Part III. Drug delivery application

Lactic/glycolic acid polymers (PLGA) are widely used for drug delivery systems. The microsphere formulation is the most interesting dosage form of the PLGA-based controlled release devices. In this study, the previously reported PLGA were used to prepare drug-containing microspheres. Progesterone was used as a model drug. The progesterone microspheres were prepared from PLGA having varied compositions and varied molecular weight. The microscopic characterization shows that the microspheres are spherical, nonaggregated particles. The progesterone-containing PLGA microspheres possess a Gaussian size distribution, having average size from 70-134 microm. A solvent extraction method was employed to prepare the microspheres. The microencapsulation method used in this study has high drug encapsulation efficiency. The progesterone release from the PLGA microspheres and the factors affecting the drug release were studied. The release of progesterone from the PLGA microspheres is affected by the properties of the polymer used. The drug release is more rapid from the microspheres prepared using the PLGA having higher fraction of glycolic acid moiety. The drug release from the microspheres composed of higher molecular weight PLGA is faster. The drug content in microspheres also has an effect on the drug release. Higher progesterone content in microspheres yields a quicker initial burst release of the drug.     

Three-month, zero-order piroxicam release from monodispersed double-walled microspheres of controlled shell thickness

Double-walled microspheres represent an increasingly important class of drug delivery devices that provide enhanced control of drug delivery schedules. Clearly, the overall particle size and shell thickness are important parameters in modulating the drug release rates. Precision particle fabrication technology has been used to fabricate double-walled microspheres of predefined uniform diameters of 40-60 microm exhibiting a poly(D,L-lactide-co-glycolide) (PLG) core and poly(L-lactide) (PL) shell of controllable thickness from approximately 2 to 10 microm. The release of a model small-molecule drug, piroxicam, from uniform microspheres of pure PLG and PL is compared to the release from double-walled microspheres exhibiting different PL shell thicknesses. The presence of the PL shell enveloping a PLG core essentially eliminated the initial "burst" of piroxicam that was observed when the drug was released from pure PLG microspheres. In addition, increasing the PL shell thickness shifted the release profile from a biphasic shape for pure PLG microspheres to zero-order piroxicam release over 3 months for the thickest (approximately 10 microm) PL shell.     

In vitro and in vivo evaluation of biodegradable embolic microspheres with tunable anticancer drug release

Natural polymer-derived materials have attracted increasing interest in the biomedical field. Polysaccharides have obvious advantages over other polymers employed for biomedical applications due to their exceptional biocompatibility and biodegradability. None of the spherical embolic agents used clinically is biodegradable. In the current study, microspheres prepared from chitosan and carboxymethyl cellulose (CMC) were investigated as a biodegradable embolic agent for arterial embolization applications. Aside from the enzymatic degradability of chitosan units, the cross-linking bonds in the matrix, Schiff bases, are susceptible to hydrolytic cleavage in aqueous conditions, which would overcome the possible shortage of enzymes inside the arteries. The size distribution, morphology, water retention capacity and degradability of the microspheres were found to be affected by the modification degree of CMC. An anticancer drug, doxorubicin, was successfully incorporated into these microspheres for local release and thus for killing cancerous cells. These microspheres demonstrated controllable degradation time, variable swelling and tunable drug release profiles. Co-culture with human umbilical vein endothelial cells revealed non-cytotoxic nature of these microspheres compared to monolayer control (P > 0.95). In addition, a preliminary study on the in vivo degradation of the microspheres (100–300 μm) was performed in a rabbit renal embolization model, which demonstrated that the microspheres were compatible with microcatheters for delivery, capable of occluding the arteries, and biodegradable inside arteries. These microspheres with biodegradability would be promising for embolization therapies.     

Novel protein-loaded chondroitin sulfate-chitosan nanoparticles: preparation and characterization

In this study, the potential of chondroitin sulfate (ChS)–chitosan (CS) nanoparticles (NPs) for the delivery of proteins was investigated. ChS–CS NPs were prepared by ionic cross-linking of CS solution with ChS. The aggregation line, particle size and zeta potential were investigated as a function of the pH, weight ratio and concentration. The water content and formation yield of the NPs were measured by gravimetry. Results indicated that ChS–CS NPs showed a higher degree of ionic cross-linking and formation yield than sodium tripolyphosphate–CS NPs. Fluorescein isothiocyanate conjugate bovine serum albumin (FITC–BSA), a model protein drug, was incorporated into the ChS–CS NPs. The encapsulation efficiency was obviously increased with the increase in initial FITC–BSA concentration and was as high as 90%. In vitro release studies of ChS–CS NPs showed a small burst effect following a continued and controlled release. Cytotoxicity tests with Caco-2 cells showed no toxic effects of ChS–CS NPs. The ex vivo cellular uptake studies using Caco-2 and HEK-293 cells indicated that NPs were found to be endocytosed into the cells. In conclusion, ChS–CS NPs are a potential new delivery system for the transport of hydrophilic compounds such as proteins.     

喷雾干燥法制备眼用壳聚糖/明胶复合微球**

背景：普通滴眼液由于泪液冲刷与鼻泪管吸收等因素,在眼表停留时间短,生物利用度低。 目的：以壳聚糖、明胶为载体材料,左氧氟沙星为模型药物,制备应用于眼表的缓控释微球并考察其理化性质与体外释放。 方法：采用喷雾干燥法制备左氧氟沙星壳聚糖/明胶微球,通过扫描电镜观察微球的表面形态,激光粒度仪测量微球粒径分布与zeta电位,高效液相色谱法检测微球的载药率与包封率,动态透析法研究微球体外药物释放情况。 结果与结论：所得微球形态良好,粒径分布窄,平均粒径为(1 267.4±115.3) nm,zeta电位为+(32.19±0.85) mV,载药量为(18.31±0.22)%,包封率为(91.53±1.12)%。载药微球体外释放符合一级释药方程Ln(1-Q)=-0.699 1t-0.086 4,r2=0.945 1。说明壳聚糖/明胶载药微球对左氧氟沙星具有缓释作用。实验采用喷雾干燥法成功制备了粒径及分布适宜、释放周期较理想、药物稳定性好的载左氧氟沙星壳聚糖明胶缓释微球。      

Development of chondroitin sulfate encapsulated PLGA microsphere delivery systems with controllable multiple burst releases for treating osteoarthritis

The purpose of the study was to design and develop unique drug delivery systems with controllable multiple burst releases of drugs for treating osteoarthritis. Chondroitin sulfate (CS) was encapsulated into four types of PLGA materials, that is, PLGA 50:50, PLGA 65:35, PLGA 75:25, and PLGA 85:15. The effects of microsphere size and various combinations of blend PLGA microspheres on CS release were investigated. The cytotoxicity of the CS-encapsulated microspheres was investigated according to the ISO 10993 guideline. Our study showed that the encapsulation efficiency of CS into PLGA 50:50 microspheres varied with the size of microspheres; however, the encapsulation efficiencies of CS into PLGA microspheres were independent of the types of PLGA materials. The size of PLGA microspheres was shown to affect the rate of CS release. With the increase of microsphere size from 75-150 μm to 300-355 μm, the initial CS release decreased. Further increase in microsphere size led to an increase in the initial CS release. In addition, combination of different types of PLGA microspheres was shown to be capable of achieving multiple burst CS releases. Moreover, the CS encapsulated PLGA microspheres were shown to be non-cytotoxic. This study proved the concept of multiple burst drug releases that were achieved by encapsulating CS into different types of PLGA microspheres and delivering CS from systems consisting of mixed types of PLGA microspheres, which may be applied to treat osteoarthritis by mimicking multiple intra-joint injection of therapeutic agents.     

Microspheres of corn protein, zein, for an ivermectin drug delivery system

A novel microsphere drug delivery system of ivermectin (IVM) using hydrophobic protein zein was prepared by the phase separation method and characterized by a scanning electron microscope and laser light scattering particle size analyzer. Releases of model drug IVM from zein microspheres, tabletted microspheres and pepsin degradation of tabletted microspheres were also performed in vitro to investigate the mechanism of model drug release. The results show that the zein microspheres and tabletted microspheres are suitable for use as a sustained-release form of IVM. The microspheres may also be useful in drug targeting system since the diameter of the microspheres is appropriate for phagocytosis by macrophages. Moreover, the release of IVM from enzymatic degraded tabletted microspheres shows a zero-order release, implying a potential application in tissue engineering for preparing scaffold, which is composed of microspheres encapsulating bioactive components for stimulating cell differentiation and proliferation.