A pH-sensitive nanocomposite microsphere based on chitosan and montmorillonite with in vitro reduction of the burst release effect

Objective: The aim of this study was to prepare pH-sensitive ofloxacin (OFL)/montmorillonite (MMT)/chitosan (CTS) nanocomposite microspheres that improve the burst release effect of the drug by the solution intercalation technique and emulsification cross-linking techniques. Methods: First, OFL/MMT hybrids were prepared through the solution intercalation technique. Then, OFL/MMT-intercalated OFL/MMT/CTS nanocomposite microspheres were obtained through emulsification cross-linking technology. The intercalated nanocomposite was confirmed by Fourier-transform infrared spectroscopy and X-ray diffraction. Finally, in vitro release of OFL from the microspheres was performed in simulated gastric fluids and simulated intestinal fluids. The effect of MMT content on drug encapsulation efficiency and the drug release of the nanocomposite microspheres were investigated. Results: The results showed that the release rate of OFL from the nanocomposite microspheres at pH 7.4 was higher than that at pH 1.2. Compared with pure CTS microspheres, the incorporation of certain amount of MMT in the nanocomposite microspheres can enhance the drug encapsulation efficiency and reduce the burst release. Conclusion: A sustained release particulate system can be obtained by incorporating MMT into the nanocomposite microspheres and can improve the burst release effect of the drug.     

The Effect of Chitosan Molecular Weight on the Characteristics of Spray-Dried Methotrexate-Loaded Chitosan Microspheres for Nasal Administration

In this article, the effect of the chitosan molecular weight (MW) on the characteristics of methotrexate (MTX)-encapsulated non-cross-linked chitosan microspheres was studied. Microspheres composed of low-molecular-weight (LMW, 40,000 Da), medium-molecular-weight (MMW, 480,000 Da) and high-molecular-weight (HMW, 850,000 Da) chitosan with the same degree of deacetylation (96%) were obtained by a simple spray-drying method. The MW of chitosan had a noticeable influence on the size distribution, encapsulation efficiency, micromeritic properties (angle of repose and bulk density), controlled release behavior, and mucoadhesive properties. The entrapment efficiencies were in the range of 90–99%. Spray-dried microspheres had a D₅₀ value of 3.3–4.9 μm, which was suitable for nasal insufflations. The microspheres with LMW chitosan have the best flowability and highest bulk density but were found to be poor in terms of adhesion and in controlling the release behavior of MTX. The MMW chitosan microspheres exhibited the strongest adhesion to the mucosal surface, and the angle of repose values were between 34 and 47 degrees. They could control the release rate by modifying the drug/polymer ratios. Microspheres with HMW chitosan exhibited a lower adhesion than MMW chitosan and a lower release rate of MTX. The physical state of MTX in the chitosan matrix was studied by differential scanning calorimetry, which indicated the presence of a solid dispersion of the amorphous drug in the chitosan matrix. Nasal ciliotoxity showed only minor cilia irritation due to the microspheres, and consequently, they are suitable for nasal drug delivery.     

Preparation and characterization of spray-dried mucoadhesive microspheres of aceclofenac

Objective: Microencapsulation of the anti-inflammatory drug aceclofenac (ACE) was investigated as a means of controlling drug release and minimizing or eliminating local side effects. Method: Microspheres were prepared by a spray-drying technique using solutions of ACE and three polymers, namely, carbopol, chitosan, and polycarbophil, in different weight ratios. Results: The spray-dried mucoadhesive microspheres were characterized in terms of shape (scanning electron microscope), size (6.60–8.40 μm), production yield (34.10–55.62%), and encapsulation efficiency (58.14–90.57%). In vitro release studies were performed in phosphate buffer (pH 6.8) up to 10 hours. The spray-drying process of solutions of ACE with polymeric blends can give prolonged drug release. The in vitro release data were well fit into Higuchi and Korsmeyer–Peppas model and followed Fickian diffusion mechanism. In vivo data showed that the administration of ACE in polymeric microspheres prevented the gastric side effects. Conclusion: The formulations here described can be proposed for the oral administration of nonsteroidal anti-inflammatory drugs with minimal side effects on gastric mucosa.     

The effect of chitosan molecular weight on the characteristics of spray-dried methotrexate-loaded chitosan microspheres for nasal administration

In this article, the effect of the chitosan molecular weight (MW) on the characteristics of methotrexate (MTX)-encapsulated non-cross-linked chitosan microspheres was studied. Microspheres composed of low-molecular-weight (LMW, 40,000 Da), medium-molecular-weight (MMW, 480,000 Da) and high-molecular-weight (HMW, 850,000 Da) chitosan with the same degree of deacetylation (96%) were obtained by a simple spray-drying method. The MW of chitosan had a noticeable influence on the size distribution, encapsulation efficiency, micromeritic properties (angle of repose and bulk density), controlled release behavior, and mucoadhesive properties. The entrapment efficiencies were in the range of 90-99%. Spray-dried microspheres had a D(50) value of 3.3-4.9 microm, which was suitable for nasal insufflations. The microspheres with LMW chitosan have the best flowability and highest bulk density but were found to be poor in terms of adhesion and in controlling the release behavior of MTX. The MMW chitosan microspheres exhibited the strongest adhesion to the mucosal surface, and the angle of repose values were between 34 and 47 degrees. They could control the release rate by modifying the drug/polymer ratios. Microspheres with HMW chitosan exhibited a lower adhesion than MMW chitosan and a lower release rate of MTX. The physical state of MTX in the chitosan matrix was studied by differential scanning calorimetry, which indicated the presence of a solid dispersion of the amorphous drug in the chitosan matrix. Nasal ciliotoxity showed only minor cilia irritation due to the microspheres, and consequently, they are suitable for nasal drug delivery.     

Development and gamma-scintigraphy study of Hibiscus rosasinensis polysaccharide-based microspheres for nasal drug delivery

Objective: This work describes the application of natural plant polysaccharide as pharmaceutical mucoadhesive excipients in delivery systems to reduce the clearance rate through nasal cavity.

Methods: Novel natural polysaccharide (Hibiscus rosasinensis)-based mucoadhesive microspheres were prepared by using emulsion crosslinking method for the delivery of rizatriptan benzoate (RB) through nasal route. Mucoadhesive microspheres were characterized for different parameters and nasal clearance of technetium-99m (^99mTc)-radiolabeled microspheres was determined by using gamma-scintigraphy.

Results: Their Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) studies showed that the drug was stable during preparation of microspheres. Aerodynamic diameter of microspheres was in the range 13.23?±?1.83–33.57?±?3.69?µm. Change in drug and polysaccharide ratio influenced the mucoadhesion, encapsulation efficiency and in-vitro release property. Scintigraphs taken at regular interval indicate that control solution was cleared rapidly from nasal cavity, whereas microspheres showed slower clearance (p?Conclusion: Natural polysaccharide-based microspheres achieved extended residence by minimizing effect of mucociliary clearance with opportunity of sustained delivery for longer duration.     

Preparation, characterization, and mucoadhesive properties of chitosan-coated microspheres encapsulated with cyclosporine A

The aim of this study was to prepare and characterize chitosan-coated microspheres containing cyclosporine A (CyA). Microspheres encapsulated with CyA were prepared by solvent evaporation-emulsification methods. Microspheres were immersed in chitosan solution (0.5% w/w) to be coated. Morphology, mean size, and encapsulation efficiency of chitosan-coated microspheres were evaluated. To assess the mucoadhesive properties of this drug delivery system, the percent of mucin adsorption to the surface of coated microspheres was determined. Microspheres were spherical in shape. Encapsulation efficiency of different microsphere formulations varied from 78% to 92%. According to the mucin adsorption results, this particulate system showed suitable mucoadhesive properties. It can be concluded that surface modification of microspheres by chitosan coating would increase the prospects of their usefulness as oral drug delivery systems for CyA.     

Preparation,Characterization, and Mucoadhesive Properties of Chitosan-Coated Microspheres Encapsulated with Cyclosporine A

The aim of this study was to prepare and characterize chitosan-coated microspheres containing cyclosporine A (CyA). Microspheres encapsulated with CyA were prepared by solvent evaporation-emulsification methods. Microspheres were immersed in chitosan solution (0.5% w/w) to be coated. Morphology, mean size, and encapsulation efficiency of chitosan-coated microspheres were evaluated. To assess the mucoadhesive properties of this drug delivery system, the percent of mucin adsorption to the surface of coated microspheres was determined. Microspheres were spherical in shape. Encapsulation efficiency of different microsphere formulations varied from 78% to 92%. According to the mucin adsorption results, this particulate system showed suitable mucoadhesive properties. It can be concluded that surface modification of microspheres by chitosan coating would increase the prospects of their usefulness as oral drug delivery systems for CyA.     

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.     

5-Fluorouracil encapsulated HA/PLGA composite microspheres for cancer therapy

5-Fluorouracil (5FU) was successfully entrapped within poly(lactide-co-glycolide) (PLGA) and hydroyapatite (HA) composite microspheres using the emulsification/solvent extraction technique. The effects of HA to PLGA ratio, solvent ratio as well as polymer inherent viscosity (IV) on encapsulation efficiency were investigated. The degradation and drug release rates of the microspheres were studied for 5?weeks in vitro in phosphate buffered solution of pH 7.4 at 37?°C. The drug release profile followed a biphasic pattern with a small initial burst followed by a zero-order release for up to 35?days. The initial burst release decreased with increasing HA content. The potential of HA in limiting the initial burst release makes the incorporation of HA into PLGA microspheres advantageous since it reduces the risk of drug overdose from high initial bursts. The linear sustained drug release profile over the course of 5?weeks makes these 5-FU-loaded HA/PLGA composite microparticles a promising delivery system for the controlled release of chemotherapy drugs in the treatment of cancer.     

Preparation and Evaluation of Methotrexate-Loaded Biodegradable Polyanhydride Microspheres

Methotrexate-loaded biodegradable polyanhydride microspheres were prepared by modified hot-melt technique and aqueous solvent evaporation technique. The effect of particle size, drug loading and microencapsulation technique on the in vitro drug release was studied. The in vitro release of methotrexate was evaluated using an automated flow-through cell system. The release profile consisted of burst release and sustained release phases. The burst release from the microspheres prepared by the modified technique was lower than that from the aqueous solvent evaporation technique. In addition, the microspheres with lower loadings released smaller amounts during the burst release phase. For a given loading and processing technique, the amount released by burst decreased with an increase in particle size. The microspheres prepared by the modified hot-melt technique with 10% loading and 177-250 μm size fraction gave desirable prolonged release. This formulation was tested in vivo in rats by subcutaneous implantation. The peak serum level of methotrexate was reached between 15-18 hours compared to that between 0-3 hours observed following the administration of an equivalent dose of methotrexate solution. No microspheres were found at the site of implantation at 48 hours post-implantation.     

Preparation and characteristics of erythromycin microspheres for lung targeting

Background: If erythromycin is micronized into microspheres with suitable particle size, it can improve pulmonary drug concentration to maximize its effectiveness and minimize the adverse side effects. Aim: In this study, erythromycin gelatin microspheres (EM-GMS) were prepared and some characteristics of EM‐GMS were investigated. The drug-targeting index (DTI) of EM-GMS was evaluated to predict their potential as a targeted delivery system. Method: Erythromycin was microencapsulated with gelatin by a double emulsion solvent evaporation method. Some characteristics of EM-GMS, including morphology, particle size, in vitro release, and safety were researched. Results: EM-GMS had a spherical shape and smooth surface morphology. The drug loading and encapsulation efficiency of EM-GMS were 13.56 ± 0.25% and 55.82 ± 2.23%, respectively. The release of erythromycin from EM-GMS showed an initial burst and following a sustained release, with an accumulate release of 80% at 4 hours. The EM-GMS was safe since there was no vein irritation and no hemolysis on the erythrocyte of rabbit at 3.5 mg/mL and a LD50 of 173.07 mg/kg. After administering EM-GMS to rabbits, the concentration of erythromycin in lung was 15.92 times higher than that in plasma and the DTI of EM-GMS in lung was 6.65 as compared with erythromycin lactobionate. Conclusions: The preparation technology of EM-GMS for lung targeting was successful and the quality of microspheres was good.     

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.     

Screening of ionically crosslinked chitosan-tripolyphosphate microspheres using Plackett–Burman factorial design for the treatment of intrapocket infections

Objective: Application of Plackett–Burman factorial design to investigate the effect of processing factors in the fabrication of ionically crosslinked chitosan-tripolyphosphate (CS-TPP) microspheres.

Significance: Microspheres were screened and optimized to provide maximum process yield (PY), encapsulation efficiency (EE), and time for 80% drug release (T_80%) and minimum burst and particles size (PS), for successful application in periodontitis.

Methods: Processing factors viz. method of preparation (MOP), CS, TPP, crosslinking time (CT), agitation (AS), and drying technique (DT) were selected. Solid state characterization was performed by Fourier-Transform infrared (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and scanning electron microscopy (SEM). Mucoadhesion, cytocompatibility, and stability of microspheres were also evaluated.

Results: Pareto analysis and analysis of variance, screened most significantly (p?Staphylococcus aureus and Escherichia coli, cytocompatibility for L929 cells, and long-term stability.

Conclusions: Therefore, CS-TPP microspheres were found mucoadhesive, safe, stable and provided controlled and prolonged release of drugs. These properties confirmed its high potential and applicability in chronic periodontitis.     

Sustained release optimized formulation of anastrozole-loaded chitosan microspheres: in vitro and in vivo evaluation

The purpose of this study was to develop sustained release formulation of anastrozole-loaded chitosan microspheres for treatment of breast cancer. Chitosan microspheres cross-linked with two different cross-linking agents viz, tripolyphosphate (TPP) and glutaraldehyde (GA) were prepared using single emulsion (w/o) method. A reverse phase HPLC method was developed and used for quantification of drug in microspheres and rat plasma. Influence of cross-linking agents on the properties of chitosan microspheres was extensively investigated. Formulations were characterized for encapsulation efficiency (EE), compatibility of drug with excipients, particle size, surface morphology, swelling capacity, erosion and drug release profile in phosphate buffer pH 7.4. EE varied from 30.4 ± 1.2 to 69.2 ± 3.2% and mean particle size distribution ranged from 72.5 ± 0.5 to 157.9 ± 1.5 μm. SEM analysis revealed smooth and spherical nature of microspheres. TPP microspheres exhibited higher swelling capacity, percentage erosion and drug release compared to GA microspheres. Release of anastrozole (ANS) was rapid up to 4 h followed by slow release status. FTIR analysis revealed no chemical interaction between drug and polymer. DSC analysis indicated ANS trapped in the microspheres existed in amorphous form in polymer matrix. The highest correlation coefficients (R ²) were obtained for Higuchi model, suggesting a diffusion controlled mechanism. There was significant difference in the pharmacokinetic parameters (AUC_0−∞, Kel and t_1/2) when ANS was formulated in the form of microspheres compared to pure drug. This may be attributed to slow release rate of ANS from chitosan microspheres and was detectable in rat plasma up to 48 h which correlates well with the in vitro release data.     

Sustained Release Microspheres of Diclofenac Sodium Using PEGylated Rosin Derivatives

The PEGylated derivatives of rosin-PD-1 and PD-2 synthesized and characterized earlier () were investigated as potential materials for sustained release microsphere prepared by emulsion solvent evaporation method using diclofenac sodium (DCS) as model drug. All the microspheres exhibited smooth surfaces intercepted by pores; their sizes (d₉₀) ranged between 11–24 μm. The entrapment efficiency (< 80%) of the microspheres increased proportionally with derivative concentration. Presence of solvent like isopropyl alcohol or dichloromethane rendered the microspheres with large sizes but with reduced drug entrapment. Microspheres with small size were obtained at an optimum viscosity of liquid paraffin; any change lead to increase in the particle size. Magnesium stearate was found to be most suitable detackifier in the present system. The drug release was directly related to the particle size—small sized microspheres released drug at a faster rate. The dissolution data complied with Higuchi equation while the mechanism of drug release was Fickian diffusion (n ～ 0.5). Controlled inhibition of edema, as tested by hind paw edema method, was observed for 10 h when the microspheres were administered intraperitoneally. The present study found the derivatives as promising materials for preparing microspheres for sustained delivery of DCS.     

Preparation of embolic NEMs loading capecitabine

The nanoparticles-embedded microcapsules (NEMs) with smooth surface, good sphericity, excellent dispersivity and uniform particle size distribution were prepared by emulsification combined with electrospraying to extend the sustained release performance of the embolic microcapsules loading capecitabine (CAP). The sodium alginate and chitosan with good biocompatibility were used as the materials and CAP as a small-molecule model drug. The drug loading, encapsulation efficiency and drug release of CAP in the NEMs were investigated. The results showed that the drug-loading and encapsulation efficiency both increased with the increment of chitosan and CAP concentration. The maximum values of drug loading and encapsulation efficiency were 1.97 and 18.01 % respectively when initial CAP concentration was 5.0 g/L and chitosan molecular weight 100 kDa. The cumulative release rate of CAP released from the NEMs was lower than 30 % in 0.5 h, which indicated that there was no obvious initial burst release behavior. In the subsequent 240 h, the release results confirmed that the NEMs had better sustained release properties compared to pure microcapsules, and it might be a new anticancer drug delivery system in the future studies.     

Preparation and characterization of theophylline loaded chitosan/β-cyclodextrin microspheres

The purpose of this project was to develop sustained release chitosan/β-cyclodextrin microspheres of theophylline (TH) prepared by spray drying method. The effect of several formulation variables on the characteristics of microspheres was studied. The B microspheres had a narrower particle size distribution with the diameter between l and 10 μm. SEM showed spherical microspheres with smooth or slightly wrinkled surfaces. FT-IR spectroscopy revealed that hydrogen bonds were formed between TH and chitosan or β-cyclodextrin. The drug entrapments significantly increased from 13.33 to 35.70% with an increase of the ratio of drug/polymer. The encapsulation efficiencies were from 85.16 to 91.40%. The in vitro release of TH from microspheres was related to the pH of the medium, swelling ability, especially in the ratio of drug/polymer. The B microspheres had a prolonged release pattern with the release rate of 60.20% (pH 6.8) within 8 h.     

Physicochemical characteristics and in vitro release from oil-based vehicles of peptidomimetics: parenteral depots for intra-articular administration

Results: Basic physicochemical properties including their apparent solubility in aqueous buffer and vegetable oils of a series of 11 peptidomimetics varying with respect to chain length and degree of N-methylation were estimated. It was observed that the compounds in contact with water transformed into sticky, slowly dissolving semisolid materials. Based on these observations, the in vitro release behavior of selected peptide derivatives from oil solutions and in situ formed precipitates was investigated using a validated in vitro release model. Conclusion: The results of this investigation suggest that both types of oil-based drug delivery systems might constitute alternative sustained release formulation principles of such amorphous peptide derivatives for the intra-articular route of administration.     

Tracking the effect of microspheres size on the drug release from a microsphere/sucrose acetate isobutyrate (SAIB) hybrid depot in vitro and in vivo

The effects of particle size of microspheres on the drug release from a microsphere/sucrose acetate isobutyrate (SAIB) hybrid depot (m-SAIB) was investigated to develop a long-term sustained release drug delivery system with low burst release both in vitro and in vivo. A model drug, risperidone, was first encapsulated into PLGA microspheres with different particle sizes using conventional emulsification and membrane emulsification methods. The m-SAIB was prepared by dispersing the risperidone-microspheres in the SAIB depot. The drug release from m-SAIB was double controlled by the drug diffusion from the microspheres into SAIB matrix and the drug diffusion from the SAIB matrix into the medium. Large microspheres (18.95?±?18.88?µm) prepared by the conventional homogenization method exhibited porous interior structure, which contributed to the increased drug diffusion rate from microspheres into SAIB matrix. Consequently, m-SAIB containing such microspheres showed rapid initial drug release (C_max?=_?110.1?±54.2?ng/ml) and subsequent slow drug release (C_s(4–54d)=?2.7?±?0.8?ng/ml) in vivo. Small microspheres (5.91?±?2.24?µm) showed dense interior structure with a decreased drug diffusion rate from microspheres into SAIB matrix. The initial drug release from the corresponding m-SAIB was significantly decreased (C_max?=_?40.9?±?13.7?ng/ml), whereas the drug release rate from 4 to 54 d was increased (C_s(4–54d)=4.1?±?1.0?ng/ml). By further decreasing the size of microspheres to 3.38?±?0.70?µm, the drug diffusion surface area was increased, which subsequently increased the drug release from the m-SAIB. These results demonstrate that drug release from the m-SAIB can be tailored by varying the size of microspheres to reduce the in vivo burst release of SAIB system alone.     

氧化海藻酸钠交联壳聚糖载药复合体系的制备及其药物缓释初步研究

为获得一种新型的药物释放复合体系,本实验首先通过乳化交联法制备壳聚糖(CS)包载四环素(TC)微球,然后利用氧化海藻酸钠交联聚磷酸钙/壳聚糖(CPP/CS)复合材料,用冷冻干燥法制备了载药微球复合体系.并用傅立叶红外光谱仪(IR)、扫描电镜(SEM)及药物的体外释放等方法对该载药微球复合体系进行分析和表征.结果显示,经...