Evaluation of PLGA microspheres as delivery system for antitumor agent-camptothecin

Camptothecin (CPT) and its analogues are a new class of anticancer agents that have been identified over the past several years. Camptothecin exists in two forms depending on the pH: An active lactone form at pH below 5 and an inactive carboxylate form at basic or physiological neutral pH. Poly(lactide-co-glycolide) (PLGA) microspheres have been considered good delivery vehicles for CPT because of acidic microenvironment formed through PLGA degradation. The objective of this study is to investigate antitumor activity of CPT after it is encapsulated in PLGA microspheres. In this study, PLGA microspheres containing various CPT loadings were prepared and characterized. Cytotoxicity of these microspheres to B16 melanoma cells was then evaluated, and uptake of microspheres by B16 cells was also studied. Analysis of drug stability revealed that CPT is released from the microspheres in its active lactone form over the entire release duration. It was also found that there was no interaction between CPT and PLGA matrix within microspheres through Differential Scanning Calorimetry (DSC) and Fourien Transform Infrared Spectroscopy (FT-IR) and hign performance liquid chromatography (HPLC) studies. Cytotoxicity assay showed that CPT encapsulated in PLGA microspheres still retained its antitumor potency. Uptake study revealed quick uptake of the microspheres by B16 cells, which was desirable. It was concluded that PLGA microspheres were suitable delivery vehicles to stabilize and deliver CPT for the treatment of cancer.     

Development of novel interpenetrating network gellan gum-poly(vinyl alcohol) hydrogel microspheres for the controlled release of carvedilol

Novel interpenetrating polymeric network microspheres of gellan gum and poly(vinyl alcohol) were prepared by the emulsion cross-linking method. Carvedilol, an antihypertensive drug, was successfully loaded into these microspheres prepared by changing the experimental variables such as ratio of gellan gum:poly(vinyl alcohol) and extent of cross-linking in order to optimize the process variables on drug encapsulation efficiency, release rates, size, and morphology of the microspheres. Formation of interpenetrating network and the chemical stability of carvedilol after preparing the microspheres was confirmed by Fourier transform infrared spectroscopy. Differential scanning calorimetry and x-ray diffraction studies were made on the drug-loaded microspheres to investigate the crystalline nature of the drug after encapsulation. Results indicated a crystalline dispersion of carvedilol in the polymer matrix. Scanning electron microscopy confirmed the spherical nature and smooth surface morphology of the microspheres produced. Mean particle size of the microspheres as measured by laser light scattering technique ranged between 230 and 346 µm. Carvedilol was successfully encapsulated up to 87% in the polymeric matrices. In vitro release studies were performed in the simulated gastric fluid or simulated intestinal fluid. The release of carvedilol was continued up to 12 h. Dynamic swelling studies were performed in the simulated gastric fluid or simulated intestinal fluid, and diffusion coefficients were calculated by considering the spherical geometry of the matrices. The release data were fitted to an empirical relation to estimate the transport parameters. The mechanical properties of interpenetrating polymeric networks prepared were investigated. Network parameters such as molar mass between cross-links and cross-linking density for interpenetrating polymeric networks were calculated.     

Properties of Hot-Melt Extruded Theophylline Tablets Containing Poly(Vinyl Acetate)

The objectives of this study were to investigate the properties of poly(vinyl acetate) (PVAc) as a retardant polymer and to study the drug release mechanism of theophylline from matrix tablets prepared by hot-melt extrusion. A physical mixture of drug, polymer, and drug release modifiers was fed into the equipment and heated inside the barrel of the extruder. The cylindrical extrudates were either cut into tablets or ground into granules and compressed with other excipients into tablets. Due to the low glass transition temperature of the PVAc, the melt extrusion process was conducted at approximately 70°C. Theophylline was used as the model drug in this study. Theophylline was present in the extrudate in its crystalline form and was released from the tablets by diffusion. The Higuchi diffusion model and percolation theories were applied to the dissolution data to explain the drug release properties of the matrix systems. The release rate was shown to be dependent on the granule size, drug particle size, and drug loading in the tablets. Water-soluble polymers were demonstrated to be efficient release rate modifiers for this system.     

聚乳酸/杆菌肽静电纺丝纤维的体外释药研究

为探讨聚乳酸纤维结构形貌对杆菌肽药物的缓慢释放行为及作用机理,通过静电纺丝法制备了聚乳酸/杆菌肽单轴纤维、聚乳酸/杆菌肽串珠和(聚乳酸/杆菌肽)-聚乳酸同轴核-壳纤维等聚乳酸/杆菌肽药物缓释体系,并采用红外光谱法和差热分析法对其化学结构和热性能进行了表征.利用紫外分光光度计法研究了不同载药体系的体外药物释放行为,并探索了不同降解时期载药纤维的质量和形貌变化规律.研究表明:杆菌肽与聚乳酸主要为物理结合;聚乳酸单轴纤维和串珠对杆菌肽的扩散释放机理,属于纯Fick扩散;采用单轴和同轴静电纺丝技术可以获得两种不同释药特性的载药纤维.单轴纤维和串珠能够将药物快速释放,适合抗生素的治疗;同轴纤维中药物受控释放,更适合长期、小剂量的药物释放.     

聚乳酸-羟基乙酸/改性纳米羟基磷灰石复合多孔支架材料的研制

聚乳酸-羟基乙酸(PLGA)/改性纳米羟基磷灰石(MHA)复合多孔组织工程支架材料的制备主要包含以下步骤:首先通过室温化学共沉淀法制备纳米羟基磷灰石,然后通过L-丙交酯在二甲苯溶液中聚合接枝纳米羟基磷灰石得到改性的纳米羟基磷灰石;最后通过改进的热致相分离两步初化法制备PLGA/MHA复合多孔支架.X射线衍射仪(XRD)显示纳米羟基磷灰石合成成功,透射电子显微镜(TEM)结果显示其为半径为30～50nm的球形,红外光谱显示聚乳酸成功的接枝到纳米羟基磷灰石表面;扫描电子显微镜(SEM)结果表明改进的热致相分离两步初化法制备的PLGA/MHA复合多孔支架的孔径在100～450μm.     

The release of 5-fluorouracil from microspheres of poly(epsilon-caprolactone-co-ethylene oxide)

The purpose of this study was to evaluate the in vitro release of 5-fluorouracil from microspheres prepared using a novel triblock copolymer of ε-caprolactone and ethylene oxide as the encapsulating material. Microspheres of poly(ε-caprolactone-co-ethylene oxide) were prepared by employing the “hot-melt” method of microencapsulation. Microspheres were sized using sieve analysis and scanning electron microscopy (SEM). Release studies were performed using a custom-made rotating paddle dissolution apparatus. Copolymer microspheres, fabricated by the hot melt method were shown by electron microscopy to have smooth, nonporous surfaces. Drug-loaded microspheres were found to have a broad distribution of sizes, which was thought to be a consequence of the wide range of crystal sizes of the encapsulated unmilled drug. Nonlinear release kinetics were observed from microspheres in the size fraction 75-250 μm, with a pronounced “burst release” associated with the presence of drug at the surface of the microspheres. A specific delineation of the drug release mechanism was not possible due to rapid gelation, swelling, and subsequent dissolution of the microspheres that occurred on hydration. This work describes the preparation of microspheres that swell rapidly and coalesce together on hydration, accompanied by rapid drug release and copolymer dissolution over a 2-hr period.     

Effect of hydrophilic–hydrophobic balance on biocompatibility of poly(methyl methacrylate) (PMMA)–hydroxyapatite (HA) composites

The purpose of this study is to put in evidence the correlation between hydrophilic/hydrophobic balance and biocompatibility of PMMA–HA composites, in order to select the best composites for futures clinical applications. For this purpose, PMMA–HA cements with different compositions were prepared and static contact angle measurements, water absorption and gingival fibroblasts cell culture were performed and discussed.     

In Vitro and In Vivo Preparation Evaluations of Bleomycin Implants and Microspheres Prepared with DL-Poly (Lactide-Co-Glycolide)

ABSTRACT

In this investigation, poly(lactide-co-glycolide) (PLGA) gel implants and microspheric depot systems of bleomycin (BLM) were formulated and evaluated in vivo in mice bearing transplantable solid tumor (fibrosarcoma). The pharmacodynamic studies showed that both the formulations retarded tumor growth significantly (p < 0.05) when compared to the control animals (without any drug treatment). Preliminary pharmacokinetic studies illustrated controlled release of the drug into the systemic circulation to elicit the anti-neoplastic action. The gel implants showed better release characteristics and greater pharmacodynamic action when compared to the microspheres, thus demonstrating the feasibility of employing biodegradable depot polymer gel matrix for chronic cancer therapy.     

Hydrothermal synthesis of composites of well-crystallized hydroxyapatite and poly(vinyl alcohol) hydrogel

Composites of hydroxyapatite (HAp) and poly(vinyl alcohol) (PVA) hydrogel were fabricated by the hydrothermal treatment of calcium phosphate powder. Alpha-tricalcium phosphate (α-TCP) or beta-tricalcium phosphate (β-TCP) powder was dispersed in PVA hydrogel and exposed to water vapor at 120 °C, 140 °C or 160 °C for 6 h. Low crystallinity HAp was formed in specimens prepared from α-TCP and PVA hydrogel prior to hydrothermal treatment, which was caused by hydrolysis of α-TCP. This allowed specimen shape to be retained after hydrothermal treatment. β-TCP showed less reactivity in forming HAp in the PVA hydrogel, which led to the formation of large rod-shaped crystals approximately 15 μm in length. Specimens from β-TCP and PVA were too soft to retain their shape after hydrothermal treatment. HAp with controlled morphology was prepared using different types of tricalcium phosphate precursor. The application of α-TCP allowed the in situ fabrication of HAp/PVA composites.     

Development of Novel Interpenetrating Network Gellan Gum-Poly(vinyl alcohol) Hydrogel Microspheres for the Controlled Release of Carvedilol

Novel interpenetrating polymeric network microspheres of gellan gum and poly(vinyl alcohol) were prepared by the emulsion cross-linking method. Carvedilol, an antihypertensive drug, was successfully loaded into these microspheres prepared by changing the experimental variables such as ratio of gellan gum:poly(vinyl alcohol) and extent of cross-linking in order to optimize the process variables on drug encapsulation efficiency, release rates, size, and morphology of the microspheres. Formation of interpenetrating network and the chemical stability of carvedilol after preparing the microspheres was confirmed by Fourier transform infrared spectroscopy. Differential scanning calorimetry and x-ray diffraction studies were made on the drug-loaded microspheres to investigate the crystalline nature of the drug after encapsulation. Results indicated a crystalline dispersion of carvedilol in the polymer matrix. Scanning electron microscopy confirmed the spherical nature and smooth surface morphology of the microspheres produced. Mean particle size of the microspheres as measured by laser light scattering technique ranged between 230 and 346 µm. Carvedilol was successfully encapsulated up to 87% in the polymeric matrices. In vitro release studies were performed in the simulated gastric fluid or simulated intestinal fluid. The release of carvedilol was continued up to 12 h. Dynamic swelling studies were performed in the simulated gastric fluid or simulated intestinal fluid, and diffusion coefficients were calculated by considering the spherical geometry of the matrices. The release data were fitted to an empirical relation to estimate the transport parameters. The mechanical properties of interpenetrating polymeric networks prepared were investigated. Network parameters such as molar mass between cross-links and cross-linking density for interpenetrating polymeric networks were calculated.     

Controlled drug delivery systems based on thiolated chitosan microspheres

The aim of the present study was to verify the potential of chitosan-thio-butyl-amidine (TBA) microspheres as carrier systems for controlled drug delivery. In this study microspheres were prepared utilizing water in oil (w/o) emulsification solvent evaporation technique. A concentration of 0.5% of chitosan-TBA conjugate displaying 100 µM thiol groups per gram polymer was used in the aqueous phase of the emulsion in order to prepare microspheres. The obtained non-aggregated free-flowing microspheres were examined with conventional light microscope as well as scanning electron microscopy (SEM). The microscopic images indicated that the prepared chitosan-TBA microspheres were of spherical shape and smooth surface while microparticles obtained from the unmodified chitosan were of porous structure and non-spherical shape. Particle size distribution was determined to be in the range from 1 to 59 µm. The free thiol group content of chitosan-TBA microspheres prepared with an aqueous phase of pH 2, 5, and 6.5 were determined to be 71.4, 49.4, and 8.2 µM/g polymer, respectively. Furthermore, results attained from in vitro release studies with fluorescein isothiocyanate labelled dextran (FITC-dextran) loaded chitosan-TBA microspheres showed a controlled release rate for more than three hours while the control reached the maximum peak level of release already within an hour. According to these results, chitosan-TBA microspheres seem to be a promising tool in transmucosal drug delivery for poorly absorbed therapeutic agents.     

聚丙交酯-乙交酯共混膜与梯度膜的体外降解特性研究

以聚丙交酯-乙交酯(PLGA)50/50与75/25为原料,采用流延法制成薄膜,其中包括PLGA50/50单成分膜、PLGA75/25单成分膜、两者的共混膜以及成分非均匀分布的梯度膜,将4种不同类型的膜浸泡在37℃、PH=7.4的磷酸盐缓冲液中进行体外降解实验.对4种膜降解过程中的分子量、质量损失、吸水率、pH值以及表...     

磁性壳聚糖-聚丙烯酸载药微球的释放性能研究

对合成的壳聚糖-聚丙烯酸及磁性壳聚糖-聚丙烯酸微球用扫描电镜进行形貌观察,并测定了磁性壳聚糖-聚丙烯酸微球的热稳定性。以牛血清白蛋白(BSA)为模拟蛋白药物,研究了载有BSA的磁性壳聚糖-聚丙烯酸微球的释放性能。结果表明,壳聚糖-聚丙烯酸共聚物外形呈片层状;而磁性壳聚糖-聚丙烯酸微球为致密微球,粒径约在100～400 nm之间,具有较好的分散性,磁性壳聚糖-聚丙烯酸微球在温度区间(0～135℃)内具有良好的热稳定性。载有BSA的磁性微球在模拟肠液中刚开始时有一个突释过程,之后缓慢释放,在6h左右达到了平衡,最终释放率可达到80．5%;而在模拟胃液中几乎没有释放,平衡释放率只有5．8%。     

中空层状羟基磷灰石微球对溶菌酶的吸附与缓释研究

利用锂钙硼玻璃在磷酸盐溶液中的原位转化反应制备表面多孔且具有中空层状结构的羟基磷灰石(HA)微球,以溶菌酶为蛋白的药物模型,研究了中空层状结构的羟基磷灰石微球对溶菌酶的吸附及缓释特性,结果显示,中空微球对不同浓度的溶菌酶溶液,具有不同的吸附机理,当溶菌酶溶液的浓度低于0.8mg/mL时,溶菌酶的吸附主要发生在微球的外表面,符合Langmuir模型,释放速率较快,48h内基本释放完全;当溶菌酶溶液的浓度高于0.8mg/mL时,溶菌酶扩散进入微球内部及球壁的微孔中,使得吸附量显著增加,满足Henry吸附模型,溶菌酶的释放周期明显增加,可持续释放800h,微球对蛋白具有很好的缓释效果。     

Properties of hot-melt extruded theophylline tablets containing poly(vinyl acetate)

The objectives of this study were to investigate the properties of poly(vinyl acetate) (PVAc) as a retardant polymer and to study the drug release mechanism of theophylline from matrix tablets prepared by hot-melt extrusion. A physical mixture of drug, polymer, and drug release modifiers was fed into the equipment and heated inside the barrel of the extruder. The cylindrical extrudates were either cut into tablets or ground into granules and compressed with other excipients into tablets. Due to the low glass transition temperature of the PVAc, the melt extrusion process was conducted at approximately 70°C. Theophylline was used as the model drug in this study. Theophylline was present in the extrudate in its crystalline form and was released from the tablets by diffusion. The Higuchi diffusion model and percolation theories were applied to the dissolution data to explain the drug release properties of the matrix systems. The release rate was shown to be dependent on the granule size, drug particle size, and drug loading in the tablets. Water-soluble polymers were demonstrated to be efficient release rate modifiers for this system.     

磁性壳聚糖-聚丙烯酸载药微球的释放性能研究

对合成的壳聚糖-聚丙烯酸及磁性壳聚糖-聚丙烯酸微球用扫描电镜进行形貌观察,并测定了磁性壳聚糖-聚丙烯酸微球的热稳定性.以牛血清白蛋白(BSA)为模拟蛋白药物,研究了载有BSA的磁性壳聚糖-聚丙烯酸微球的释放性能.结果表明,壳聚糖-聚丙烯酸共聚物外形呈片层状;而磁性壳聚糖-聚丙烯酸微球为致密微球,粒径约在100～400nm之间,具有较好的分散性,磁性壳聚糖-聚丙烯酸微球在温度区间(0～135℃)内具有良好的热稳定性.载有BSA的磁性微球在模拟肠液中刚开始时有一个突释过程,之后缓慢释放,在6h左右达到了平衡,最终释放率可达到80.5%;而在模拟胃液中几乎没有释放,平衡释放率只有5.8%.     

Fibrous growth of strontium substituted hydroxyapatite and its drug release

The effect of strontium on the crystallization of helical ribbon of hydroxyapatite (HAp) was investigated by single diffusion technique in silica gel matrix at 27 °C and physiological pH. Fibers of HAp were obtained on addition of strontium. The length of the HAp fibers, were found to decrease as the strontium substitution increases. The presence of strontium ion increased the crystallinity as well as crystallite size of HAp. The strontium substituted HAp (Sr-HAp) has similar stoichiometry to that of biological apatite. Sr-HAp was found to have increased surface area (35%) compared to control. Further, strontium substitution leads to an enhancement of in vitro bioactivity. The cumulative in-vitro amoxicillin drug release in phosphate buffer solution (PBS, pH 7.2) showed a prolonged release profile for Sr-HAp.     

Double-walled microspheres loaded with meglumine antimoniate: preparation,characterization and in vitro release study

Objective: The objective of this study was to fabricate double-walled poly(lactide-co-glycolide) (PLGA) microspheres to increase encapsulation efficiency and avoid rapid release of hydrophilic drugs such as meglumine antimoniate.

Methods: In this study, double-walled and one-layered microspheres of PLGA were prepared using the emulsion solvent evaporation technique to better control the release of a hydrophilic drug, meglumine antimoniate (Glucantime®), which is the first choice treatment of cutaneous leishmaniasis. The effect of hydrophobic coating on microspheres' size, morphology, encapsulation efficiency and drug release characteristics was evaluated. Furthermore, the presence of antimony in meglumine antimoniate made it possible to observe the drug distribution within the microspheres' cross section by means of energy dispersive X-ray spectroscopy.

Results: Drug distribution images confirmed accumulation of the drug within the inner core of double-walled microspheres. In addition, these microspheres encapsulated the drug more efficiently up to 87% and demonstrated reduced initial burst and prolonged release compared to one-layered microspheres. These superiorities make double-walled microspheres an optimum candidate for sustained delivery of hydrophilic drugs.

Conclusion: Double-walled microspheres provide some advantages over traditional microspheres overcoming most of their limitations. Double-walled microspheres were found to be more efficient than their corresponding one-layered microspheres in terms of encapsulation efficiencies and release characteristics.     

Dual cross-linked chitosan microspheres formulated with spray-drying technique for the sustained release of levofloxacin

Objective: This study was aimed to develop sustained drug release from levofloxacin (LF)-loaded chitosan (CS) microspheres for treating ophthalmic infections.

Significance: Dual cross-linked CS microspheres developed by the spray-drying technique displays significantly higher level of sustained drug release compared with non-cross-linked CS microspheres.

Methods: LF-loaded CS microspheres were prepared using the spray-drying technique, and then solidified with tripolyphosphate and glutaraldehyde as dual cross-linking agents. The microspheres were characterized by surface morphology, size distribution, zeta potential, encapsulation efficiency, and drug release profiles in vitro. The drug quantification was verified and analyzed by high-performance liquid chromatography (HPLC). The structural interactions of the CS with LF were studied with Fourier transform infrared spectroscopy. The effect of various influencing excipients in the formulation of the dual cross-linked CS microspheres on drug encapsulation efficiency and the drug release profiles were extensively investigated.

Result: The microspheres demonstrated high encapsulation efficiency (72.4?～?98.55%) and were uniformly spherical with wrinkled surface. The mean particle size was between 1020.7?±?101.9 and 2381.2?±?101.6?nm. All microspheres were positively charged (zeta potential ranged from 31.1?±?1.32 to 42.81?±?1.55?mV). The in vitro release profiles showed a sustained release of the drug and it was remarkably influenced by the cross-linking process.

Conclusion: This novel spray-drying technique we have developed is suitable for manufacturing LF-loaded CS microspheres, and thus could serve as a potential platform for sustained drug release for effective therapeutic application in ocular infections.     

Paclitaxel-loaded poly(lactide-co-glycolide)/poly(ethylene vinyl acetate) composite for stent coating by ultrasonic atomizing spray

The mixture of poly(lactide-co-glycolide) (PLGA) and poly(ethylene vinyl acetate) (PEVA) forms a homogeneous liquid in an organic solvent such as tetrahydrofuran, and a phase-separated PLGA/PEVA composite can be prepared from it by evaporating the organic solvent. Exploiting this phenomenon, we designed a novel method of preparing a drug-loaded PLGA/PEVA composite and used it for coating drug-eluting stents (DESs). Paclitaxel (PTX), an anticancer drug, was chosen as a model drug. PLGA acts as a microdepot for PTX, and PEVA provides mechanical strength to the coating material. The presence of PLGA in the PLGA/PEVA composite suppressed PTX crystallization in the coating material, and PTX showed a sustained release rate over more than 30 days. The mechanical strength of the PLGA/PEVA composite was better than that of PEVA used as a control. After coating the stent with a PLGA/PEVA composite using ultrasonic atomizing spray, the morphology of the coated material was observed by scanning electron microscopy, and the release pattern of PTX was measured by high-performance liquid chromatography.