Preparation and characterization of chitosan microparticles for oral sustained delivery of gliclazide: in vitro/in vivo evaluation

Chitosan microparticles were prepared with tripolyphosphate (TPP) by ionic cross‐linking with gliclazide (GLZ) as a model drug. The particle sizes of TPP‐chitosan microparticles ranged from 675–887 µm with loading efficiencies of greater than 94%. Chitosan concentration, TPP solution pH, and glutaraldehyde volume solution added to the TPP cross‐linking solution affected drug release characteristics. Pectin interactions with cationic chitosan on the surface of TPP/chitosan microparticles led to the formation of polyelectrolyte complex films that improved drug sustained release performance. In vivo testing of the GLZ‐chitosan microparticles in diabetic albino rabbits demonstrated a significant antidiabetic effect of GLZ/chitosan microparticles after 8 h that lasts for 18 h compared with GLZ powder that produced a maximal hypoglycemic effect at 4 h, suggesting that GLZ/chitosan microparticles represent an improved system for the long‐term delivery of GLZ. Drug Dev Res 72: 235–246, 2011. © 2010 Wiley‐Liss, Inc.     

Design and characterisation of doxorubicin-releasing chitosan microspheres for anti-cancer chemoembolisation

The aims of this study were to design and characterise doxorubicin-loaded chitosan microspheres for anti-cancer chemoembolisation. Doxorubicin-loaded chitosan microspheres were prepared by emulsification and cross-linking methods. Doxorubicin–chitosan solution was initially complexed with tripolyphosphate (TPP) to improve drug loading capabilities. Doxorubicin-loaded chitosan microspheres were highly spherical and had approximately diameters of 130–160?µm in size. Drug loading amount and loading efficiency were in the range 3.7–4.0% and 68.5–85.8%, respectively, and affected by TPP concentration, drug levels and cross-linking time. Doxorubicin release was affected by TPP complexation, cross-linking time and release medium. Especially, lysozyme in release media considerably increased drug release. Synergistic anti-cancer activities of doxorubicin-releasing chitosan microspheres were confirmed to VX2 cells in the rabbit auricle model compared with blank microspheres. Doxorubicin-loaded chitosan microspheres can efficiently be prepared by TPP gelation and cross-linking method and developed as multifunctional anti-cancer embolic material.     

Synthesis and characterization of cross-linked chitosan microspheres for drug delivery applications

The present study deals with the synthesis and characterization of cross-linked chitosan microspheres containing an hydrophilic drug, hydroquinone. The microspheres were prepared by the suspension cross-linking method using glutaraldehyde as the cross-linking agent of the polymer matrix. Perfectly spherical cross-linked hydrogel microspheres loaded with hydroquinone were obtained in the size range of 20–100 μm. The effect of the degree of polymer cross-linking, chitosan molecular weight, chitosan concentration and amount of the encapsulated drug on the hydroquinone release kinetics was extensively investigated. It was found that slower drug release rates were obtained from microspheres prepared by using a higher initial concentration of chitosan, a higher molecular weight of chitosan or/and a lower drug concentration. Most importantly, it was shown that the release rate of hydroquinone was mainly controlled by the polymer cross-linking density and, thus, by the degree of swelling of the hydrogel matrix.     

Encapsulation of vitamin C in tripolyphosphate cross-linked chitosan microspheres by spray drying

This paper describes vitamin C-encapsulated chitosan microspheres cross-linked with tripolyphosphate (TPP) using a new process prepared by spray drying intended for oral delivery of vitamin C. Thus, prepared microspheres were evaluated by loading efficiency, particles size analysis, scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), zeta potential and in vitro release studies. The microspheres so prepared had a good sphericity and shape but varied with the volume of cross-linking agent solution added. They were positively charged. The mean particle size ranged from 6.1–9.0?µm. The size, shape, encapsulation efficiency, zeta potential and release rate were influenced by the volume of cross-linking agent. With the increasing amount of cross-linking agent, both the particle size and release rate were increased. Encapsulation efficiency decreased from 45.05–58.30% with the increasing amount of TPP solution from 10–30?ml. FTIR spectroscopy study showed that the vitamin C was found to be stable after encapsulation. XRD studies revealed that vitamin C is dispersed at the molecular level in the TPP-chitosan matrix. Well-defined change in the surface morphology was observed with the varying volume of TPP. The sphericity of chitosan microspheres was lost at higher volume of cross-linking agent. The release of vitamin C from these microspheres was sustained and affected by the volume of cross-linking agent added. The release of vitamin C from TPP-chitosan microspheres followed Fick's law of diffusion.     

Preparation and characterization of Mitomycin-C loaded chitosan-coated alginate microspheres for chemoembolization

Mitomycin-C loaded and chitosan-coated alginate microspheres were prepared for use in chemoembolization studies. In this respect, first alginate microspheres were prepared by using a spraying method using an extrusion device with a small orifice and following suspension cross-linking in an oil phase. Chitosan-coating onto the alginate microspheres was achieved by polyionic complex formation between alginate and chitosan. CaCl₂ was used as a cross-linker for alginate microspheres. The obtained chitosan-coated alginate microspheres were spherical shaped and ～100–400?µm average size. The microspheres were evaluated based on their swellability and the swelling ratio was changed between 50–280%. CaCl₂ concentration, stirring rate, chitosan molecular weight, chitosan concentration and time for coating with chitosan were selected as the effective parameters on microsphere size and swelling ratio. Equilibrium swellings were achieved in ～30?min. On the other hand, chitosan molecular weight, chitosan concentration and time for coating with chitosan were found as the most effective parameters on both drug loading ratio and release studies. Maximum drug loading ratio of 65% was achieved with high molecular weight (HMW) chitosan, highest chitosan concentration (i.e. 1.0% v/v) and shortest time for coating with chitosan (i.e. 1?h) values.     

Synthesis and characterization of cross-linked chitosan microspheres for drug delivery applications

The present study deals with the synthesis and characterization of cross-linked chitosan microspheres containing an hydrophilic drug, hydroquinone. The microspheres were prepared by the suspension cross-linking method using glutaraldehyde as the cross-linking agent of the polymer matrix. Perfectly spherical cross-linked hydrogel microspheres loaded with hydroquinone were obtained in the size range of 20-100 microm. The effect of the degree of polymer cross-linking, chitosan molecular weight, chitosan concentration and amount of the encapsulated drug on the hydroquinone release kinetics was extensively investigated. It was found that slower drug release rates were obtained from microspheres prepared by using a higher initial concentration of chitosan, a higher molecular weight of chitosan or/and a lower drug concentration. Most importantly, it was shown that the release rate of hydroquinone was mainly controlled by the polymer cross-linking density and, thus, by the degree of swelling of the hydrogel matrix.     

Preparation and characterization of Mitomycin-C loaded chitosan-coated alginate microspheres for chemoembolization

Mitomycin-C loaded and chitosan-coated alginate microspheres were prepared for use in chemoembolization studies. In this respect, first alginate microspheres were prepared by using a spraying method using an extrusion device with a small orifice and following suspension cross-linking in an oil phase. Chitosan-coating onto the alginate microspheres was achieved by polyionic complex formation between alginate and chitosan. CaCl(2) was used as a cross-linker for alginate microspheres. The obtained chitosan-coated alginate microspheres were spherical shaped and approximately 100-400 microm average size. The microspheres were evaluated based on their swellability and the swelling ratio was changed between 50-280%. CaCl(2) concentration, stirring rate, chitosan molecular weight, chitosan concentration and time for coating with chitosan were selected as the effective parameters on microsphere size and swelling ratio. Equilibrium swellings were achieved in approximately 30 min. On the other hand, chitosan molecular weight, chitosan concentration and time for coating with chitosan were found as the most effective parameters on both drug loading ratio and release studies. Maximum drug loading ratio of 65% was achieved with high molecular weight (HMW) chitosan, highest chitosan concentration (i.e. 1.0% v/v) and shortest time for coating with chitosan (i.e. 1 h) values.     

Chitosan/cellulose acetate microspheres preparation and ranitidine release in vitro

New microspheres containing hydrophilic core and hydrophobic coating as a controlled-release system with no toxic reagents were proposed. Water in oil in water (W/O/W) emulsion and solvent evaporation methods were used to make chitosan/ cellulose acetate (CCA) microspheres sized 200 - 400 microm. Ranitidine hydrochloride, as a model drug, was investigated for its release properties in vitro. The loading efficiency and release rate of ranitidine were affected by chitosan concentration and molecular weight. Higher loadings were obtained at lower concentrations in the interval of 1% to 2%. With chitosan at a 2% concentration microspheres could be obtained with more spherical appearance, smaller size, and higher ranitidine loading efficiency microspheres than at other concentrations. Among the different molecular weight chitosan (47, 145, 308, 499, and 1130 KD) microspheres, the high molecular weight chitosan (1130 KD) microspheres had relatively high loading efficiency (10%). Molecular weight and concentration of chitosan as well as the size of microspheres affected the release of ranitidine. Microspheres smaller than 280 microm released the drug faster than did the bigger by about 10%. The optimal condition for the preparation of the microspheres was chitosan concentration 2%, molecular weight 1130 KD. The ranitidine release from the microspheres was 30% during 48 h in phosphate-buffer saline medium.     

Preparation of cross-linked chitosan microspheres by spray drying: Effect of cross-linking agent on the properties of spray dried microspheres

Chitosan microspheres cross-linked with three different cross-linking agents viz, tripolyphosphate (TPP), formaldehyde (FA) and gluteraldehyde (GA) have been prepared by spray drying technique. The influence of these cross-linking agents on the properties of spray dried chitosan microspheres was extensively investigated. The particle size and encapsulation efficiencies of thus prepared chitosan microspheres ranged mainly between 4.1–4.7?µm and 95.12–99.17%, respectively. Surface morphology, % erosion, % water uptake and drug release properties of the spray dried chitosan microspheres was remarkably influenced by the type (chemical or ionic) and extent (1 or 2%?w/w) of cross-linking agents. Spray dried chitosan microspheres cross-linked with TPP exhibited higher swelling capacity, % water uptake, % erosion and drug release rate at both the cross-linking extent (1 and 2%?w/w) when compared to those cross-linked with FA and GA. The sphericity and surface smoothness of the spray dried chitosan microspheres was lost when the cross-linking extent was increased from 1 to 2%?w/w. Release rate of the drug from spray dried chitosan microspheres decreased when the cross-linking extent was increased from 1 to 2%?w/w. The physical state of the drug in chitosan-TPP, chitosan-FA and chitosan-GA matrices was confirmed by the X-ray diffraction (XRD) study and found that the drug remains in a crystalline state even after its encapsulation. Release of the drug from chitosan-TPP, chitosan-FA and chitosan-GA matrices followed Fick's law of diffusion.     

Chitosan-based Floating Microspheres of Trimetazidin Dihydrochloride; Preparation and In vitro Characterization

The aim of present study involves preparation and characterization of floating microspheres using trimetazidin dihydrochloride as a model drug to increase the residence time in the stomach without contact with the mucosa, Floating microspheres were prepared by the capillary extrusion technique using chitosan as polymer and sodium lauryl sulphate as cross linking agent. The surface morphology of the prepared microspheres was characterized by the optical microscopic method. The effect of the stirring rate during preparation, polymer concentration and cross linking concentration on the percent yield, in vitro floating behavior, physical state of the incorporated drug, drug loading and in vitro drug release were studied. The prepared microspheres exhibited prolonged drug release (12 h) and remained buoyant for more than 11 h. The microspheres were found to be regular in shape and highly porous. The trimetazidin dihydrochloride release rate was higher in the case of microspheres prepared at a higher agitation speed and decreased with increasing the polymer and cross linking agent concentration. All formulations demonstrated favorable in vitro floating characteristics. The drug entrapment increased from 65.13 to 85.3% with increasing polymer to drug ratio. Diffusion was found to be the main release mechanism. Thus, the prepared floating microspheres may prove to be potential candidates for multiple-unit delivery devices adaptable to any intragastric conditions.     

Preparation and characterization of chitosan microparticles intended for controlled drug delivery

Chitosan microparticles were prepared with tripolyphosphate (TPP) by ionic crosslinking. The particle sizes of TPP-chitosan microparticles were in range from 500 to 710 microm and encapsulation efficiencies of drug were more than 90%. The morphologies of TPP-chitosan microparticles were examined with scanning electron microscopy. As pH of TPP solution decreased and molecular weight (MW) of chitosan increased, microparticles had more spherical shape and smooth surface. Release behaviors of felodipine as a model drug were affected by various preparation processes. Chitosan microparticles prepared with lower pH or higher concentration of TPP solution resulted in slower felodipine release from microparticles. With decreasing MW and concentration of chitosan solution, release behavior was increased. The release of drug from TPP-chitosan microparticles decreased when cross-linking time increased. These results indicate that TPP-chitosan microparticles may become a potential delivery system to control the release of drug.     

Encapsulation of vitamin C in tripolyphosphate cross-linked chitosan microspheres by spray drying

This paper describes vitamin C-encapsulated chitosan microspheres cross-linked with tripolyphosphate (TPP) using a new process prepared by spray drying intended for oral delivery of vitamin C. Thus, prepared microspheres were evaluated by loading efficiency, particles size analysis, scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), zeta potential and in vitro release studies. The microspheres so prepared had a good sphericity and shape but varied with the volume of cross-linking agent solution added. They were positively charged. The mean particle size ranged from 6.1-9.0 microm. The size, shape, encapsulation efficiency, zeta potential and release rate were influenced by the volume of cross-linking agent. With the increasing amount of cross-linking agent, both the particle size and release rate were increased. Encapsulation efficiency decreased from 45.05-58.30% with the increasing amount of TPP solution from 10-30 ml. FTIR spectroscopy study showed that the vitamin C was found to be stable after encapsulation. XRD studies revealed that vitamin C is dispersed at the molecular level in the TPP-chitosan matrix. Well-defined change in the surface morphology was observed with the varying volume of TPP. The sphericity of chitosan microspheres was lost at higher volume of cross-linking agent. The release of vitamin C from these microspheres was sustained and affected by the volume of cross-linking agent added. The release of vitamin C from TPP-chitosan microspheres followed Fick's law of diffusion.     

Pectin‐based microspheres for colon‐specific delivery of vancomycin

Objectives The aim of this study was to describe a colon‐specific delivery system based on pectin hydrogels formed by complexation with chitosan. Methods Hydrogels were prepared at different weight ratios (4: 1, 7: 1, 10: 1; pectin/chitosan), loaded with vancomycin hydrochloride (2: 1, 4: 1; polymer/drug weight ratio) and collected by spray‐drying. The microspheres obtained were characterized in terms of morphology, swelling behaviour, mucoadhesive properties and drug loading efficiency. The influence of different pectin/chitosan hydrogels on the release behaviour of microspheres at pH 2.0, 5.5 and 7.4 were evaluated in vitro with and without pectinolytic enzyme. Key findings The results showed that water uptake was increased by raising the environmental pH (from 2.0 to 7.4) and the pectin/chitosan weight ratio, while drug availability was increased by raising the environmental pH (from 2.0 to 7.4) and decreased by raising the pectin/chitosan weight ratio. In the presence of pectinase, the glycoside bonds of pectin were degraded and a considerable amount of drug was released in a short time. Conclusions This study suggested that pectin/chitosan microspheres were able to limit the release of vancomycin under acidic conditions and release it under simulated colonic conditions, confirming their potential for a colon‐specific drug delivery system.     

Chitosan microspheres of aceclofenac: In vitro and in vivo evaluation

The objective of this investigation was to achieve controlled drug release of Aceclofenac (ACE) microspheres and to minimize local side-effects in the gastrointestinal tract (GIT). Sustained release chitosan microspheres containing ACE were prepared using double-emulsion solvent evaporation method (O/W/O). Chitosan microspheres were prepared by varying drug to polymer ratio (1:3, 1:4, 1:5 and 1:6). Microspheres were characterized for morphology, swelling behavior, mucoadhesive properties, FTIR and DSC study, drug loading efficiency, in vitro release, release kinetics, and in vivo study was performed on rat model. ACE-loaded microspheres were successfully prepared having production yield, 57–70% w/w. Drug encapsulation efficiency was ranging from 53–72% w/w, Scanning electron microscopy (SEM) revealed particle size of microspheres was between 39 and 55 μm. FTIR spectra and DSC thermograms demonstrated no interaction between drug and polymer. The in vitro release profiles of drug from chitosan microspheres showed sustained-release pattern of the drug in phosphate buffer, pH 6.8. In vitro release data showed correlation (r² > 0.98), good fit with Higuchi/Korsmeyer-Peppas models, and exhibited Fickian diffusion. ACE microspheres demonstrated controlled delivery of aceclofenac and apparently, no G.I.T. erosion was noticed.     

Effect of manufacturing parameters on the characteristics of vitamin C encapsulated tripolyphosphate-chitosan microspheres prepared by spray-drying

To prepare the sustained release vitamin C carriers, vitamin C was successfully encapsulated in tripolyphosphate (TPP) cross-linked chitosan (TPP-chitosan) microspheres by the spray-drying method at different manufacturing conditions. Manufacturing parameters (inlet temperature, liquid flow rate, chitosan concentration and volume of 1% w/v TPP solution) had a significant influence on the characteristics of thus prepared microspheres. The optimum spray-drying conditions such as inlet temperature, liquid flow rate and compressed air flow rate for the encapsulation of vitamin C in TPP-chitosan microspheres was found to be 170 degrees C, 2 ml min(-1) and 101 min(-1), respectively. The size and yield of the TPP-chitosan microspheres ranged from 3.9-7.3 microm and 54.5-67.5%, respectively. The encapsulation efficiency of TPP-chitosan microspheres ranged from 45.72-68.7% and it decreased with the increasing volume of 1% w/v TPP solution. At the same cross-linking extent, the encapsulation efficiency of TPP-chitosan microspheres increased when the concentration of chitosan was increased from 0.5-1% w/v. Effect of volume of 1% w/v TPP solution on the surface morphology of chitosan microspheres was examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). These studies revealed that chitosan solution (250 ml) cross-linked with 15 ml 1% w/v TPP solution produced more porous microspheres than that cross-linked with 5 and 10 ml TPP solution. The release rate of vitamin C from TPP-chitosan microspheres decreased when the concentration of chitosan was increased from 0.5-1.0% w/v. Vitamin C release rate was also modulated by varying the volume of 1% w/v TPP solution. The release rate of vitamin C from TPP-chitosan microspheres decreased with increasing volume (5-15 ml) of 1% w/v TPP solution.     

Preparation and investigation the release behaviour of wax microspheres loaded with salicylic acid

Salicylic acid-beeswax microspheres were prepared by melt dispersion technique. The effects of formulation parameters on the microscopic characteristic, drug loading and cumulative amount of released drug were investigated by experimental design. Results showed that all of the microparticles were spherical with porous surfaces. The average size of microspheres was 24–48 µm, the drug content was in the range of 22–45% and the encapsulation efficiency was 46–93%. Drug loading was influenced by emulsification speed as a main factor. All the microspheres had a burst release initially. The emulsifier concentration did not have a significant effect on drug release. The release behaviour of microspheres conformed best to Korsmeyer-Peppas semi-empirical model and the release of SA from beeswax microspheres was Fickian (n < 0.45).     

Cross-linked chitosan microspheres: preparation and evaluation as a matrix for the controlled release of pharmaceuticals.

Chitosan microspheres having good spherical geometry and a smooth surface were prepared by the glutaraldehyde cross-linking of an aqueous acetic acid dispersion of chitosan in paraffin oil using dioctyl sulphosuccinate as the stabilizing agent. Microspheres having different degrees of swelling were made by varying the cross-linking density. Microspheres were prepared by incorporating theophylline, aspirin or griseofulvin. Drug incorporation efficiencies exceeding 80% could be achieved for these drugs. In-vitro release studies of these drugs were carried out in simulated gastric and intestinal fluids at 37 degrees C. It was observed that the drug release rates were influenced by the cross-linking density, particle size and initial drug loading in the microspheres.     

牛血清白蛋白阳离子微球的制备及体外评价

目的制备牛血清白蛋白（BSA）口服阳离子微球,考察天然阳离子物质壳聚糖（CHS）的加入对蛋白微球的粒径、电动电势、包封率、载药量及体外释放情况的影响。方法以乳酸／羟基乙酸共聚物（PLGA）和壳聚糖（CHS）为载体材料,采用W／O／W复乳-溶剂挥发法制备牛血清白蛋白乳酸／羟基乙酸共聚物-壳聚糖（PLGA／CHS）阳离子微球。通过正交设计优化制备工艺,确定最佳处方。建立准确而简便的蛋白含量测定方法,并对微球进行体外评价。结果最佳处方为：BSA浓度为150g·L^-1、PLGA浓度为8％、外水相体积为80mL、壳聚糖浓度为0．2％。制得的微球形态圆整,平均粒径为（6．9±5．5）μm,为表面荷正电的阳离子微球[ζ电势=00．0±0．6）mV],包封率为（75．4±4．6）％,载药量为（9．3±0．2）％。体外释放结果表明,在模拟胃液和模拟肠液中,壳聚糖的加入均能减少突释,延缓药物的释放。结论与PLGA微球相比,制得的PLGA／CHS阳离子微球表面带正电,具有较高的包封率和载药量,可以延缓药物释放,同时减少突释现象。     

Preparation and characterization of 5‐fluorouracil‐loaded poly(ϵ‐caprolactone) microspheres for drug administration

Microspheres of 5‐fluorouracil‐loaded poly(?‐caprolactone) (PCL) were prepared by spray‐drying procedure. The degradation characteristics and 5‐fluorouracil release in vitro as well as in vivo were investigated. The average molecular weight, weight loss, crystallinity, and morphology of microspheres were determined using GPC, DSC, and SEM, at different times during the in vitro degradation process. The size distribution of the microspheres indicated that most of the particles were smaller than 3 µm. A 30% weight loss as well as an increase of crystallinity were observed on day 330 of incubation. The percentage of entrapment efficiency of 5‐FU was 49% (44 µg of drug/mg of microspheres). The in vitro total release of 5‐FU took place in 8 days. Determination of plasma 5‐FU concentration in vivo using s.c. injection of 5‐FU‐loaded microspheres in Wistar rats by HPLC with analysis of data using a non‐compartmental model showed drug in plasma 18 days after administration with a maximum drug concentration of 1.5 µg/ml at 96 h. Pharmacokineticallly, a significant increase of AUC and MRT of 5‐FU with regard to the administration of the drug in solution. Scanning electron microscopy and histological studies indicated that the microspheres were surrounded by connective tissue and inflammatory processes were not evident. As a result of these characteristics, the 5‐FU‐loaded PCL microspheres could be used for drug delivery. Drug Dev Res 63:41–53, 2004. © 2004 Wiley‐Liss, Inc.     

利福平丝素蛋白载药微球的制备及性能研究

目的通过测定利福平丝素蛋白微球的载药量、包封率及释放度,考察乳化转速、有机溶剂与丝素蛋白溶液比例,对微球的制备方法进行优化,筛选微球的最佳制备方法。方法采用乳化法制备利福平丝素蛋白微球,以不同转速、有机溶剂与丝素蛋白溶液不同比例分别制备利福平丝素蛋白微球,采用扫描电镜观察微球的形态,用紫外分光光度法测定微球的载药量、包封率及释放度,以形态、载药量、包封率及释放度为指标,筛选微球的最佳制备方法。在此基础上,采用最佳处方制备3批利福平丝素蛋白微球,对微球的形态、粒径、包封率、载药量和释放度进行考察。结果有机溶剂与丝素蛋白溶液体积比为4∶1、转速为200 r·min^-1时所得利福平丝素微球形态均匀,近似球形,载药量和包封率较高,所得载药微球有较好的缓释作用。以最佳处方制得微球载药量为66.1%±0.87%,包封率为87.80%±2.23%。结论有机溶剂与丝素蛋白溶液体积比为4∶1、转速为200 r·min^-1时载药量、包封率和释放度较好,故选择此处方为利福平丝素蛋白微球的最佳制备处方。