Fabrication and dissolution behavior of hollow hydroxyapatite microspheres intended for controlled drug release

Hollow hydroxyapatite (HA) microspheres were fabricated by a simple spray drying method in this study. Moreover, the dissolution behavior of these hollow HA microspheres after immersion in simulated body fluid (SBF) was also studied. The results indicated that the dissolution of the HA microspheres in SBF is not homogeneous in a layer-by-layer fashion but was preferential at different locations of the particle surface. Generically, dissolution preferentially occurs on the location with looser structure and high porosity of the microspheres. The degradable HA microspheres are expected to have potential applications in bone local drug delivery systems.     

A novel pH- and time-dependent system for colonic drug delivery

A novel pH- and time-dependent delivery system was developed for delivering drugs to the colon. In vitro studies showed that this novel system could release the drug at a predetermined time, which was mainly controlled by the coating layers of the system. The delayed time of the press-coating layer was controlled by its erosion rate, which followed Hixson-Crowell equation. A proper selection of such factors as the viscosity grade of HPMC and tablet hardness, etc., can help reproduce the drug release profile as expected. The transit profiles in two healthy volunteers by gamma scintigraphy demonstrated that the tablets were able to pass through the stomach and small intestine intact and could safely reach the distal end of the small intestine, where the system began to release the drug contained in the core tablet. For both of the volunteers, disintegration of the tablets occurred in the ascending colon, which had highlighted the potential of this system for colonic drug delivery.     

BCP ceramic microspheres as drug delivery carriers: synthesis,characterisation and doxycycline release

Resorbable ceramics such as biphasic calcium phosphates (BCP) are ideal candidates as drug delivery systems. The BCP ceramic is based on the optimum balance of the most stable hydroxyapatite (HA) phase and more soluble tricalcium phosphate phase (TCP). Doxycycline is a broad-spectrum antibiotic used for the local treatment of periodontitis. The development of BCP microspheres and its release kinetics with doxycycline have been studied. The BCP ceramic powder were prepared by microwave processing and characterised by X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR) methods. The BCP microspheres were formed by liquid immiscibility effect using gelatin and paraffin oil. Difference in the morphology of the microspheres as a function of gelatin content has been observed. Scanning electron microscope indicated spherical and porous morphology of the microspheres. Drug incorporation was studied at varying pH and the pH 7 was found to be optimal for drug loading. Release pattern tend to depend on the morphology of BCP microspheres. An optimum release of 80% drug has been observed for BCP microsphere with HA:TCP = 65:35 ratio. The surface area measurement results also correlate with drug release obtained.     

pH-Sensitive and mucoadhesive microspheres for duodenum-specific drug delivery system

Particulate systems that could deliver drug specifically to duodenum have not yet been reported. The aim of this study was to develop a novel duodenum-specific drug delivery system based on thiolated chitosan and hydroxypropyl methylcellulose acetate maleate (HPMCAM) for the duodenal ulcer application. Berberine hydrochloride was used as model drug. Thiolated chitosan was synthesized and further used for the preparation of mucoadhesive microspheres. HPMCAM, which is insoluble below pH 3.0 was synthesized and used for the coating of thiolated chitosan microspheres (TCM). The resulting thiolated chitosan immobilized on chitosan was 268.21?±?18 μmol/g. In vitro mucoadhesion study showed that the mucoadhesion property of TCM was better than that of chitosan microspheres. Morphological observation showed that the HPMCAM coating would maintain its integrity in simulated gastric fluid (SGF) for 2?h and dissolved quickly in simulated pathological duodenal fluid (SPDF; pH 3.3). In vitro drug release studies showed that only 4.75% of the drug was released in SGF for 2?h, while nearly 90% of the drug was released within 6?h after transferring into SPDF.     

pH-sensitive and mucoadhesive microspheres for duodenum-specific drug delivery system

Particulate systems that could deliver drug specifically to duodenum have not yet been reported. The aim of this study was to develop a novel duodenum-specific drug delivery system based on thiolated chitosan and hydroxypropyl methylcellulose acetate maleate (HPMCAM) for the duodenal ulcer application. Berberine hydrochloride was used as model drug. Thiolated chitosan was synthesized and further used for the preparation of mucoadhesive microspheres. HPMCAM, which is insoluble below pH 3.0 was synthesized and used for the coating of thiolated chitosan microspheres (TCM). The resulting thiolated chitosan immobilized on chitosan was 268.21?±?18 μmol/g. In vitro mucoadhesion study showed that the mucoadhesion property of TCM was better than that of chitosan microspheres. Morphological observation showed that the HPMCAM coating would maintain its integrity in simulated gastric fluid (SGF) for 2?h and dissolved quickly in simulated pathological duodenal fluid (SPDF; pH 3.3). In vitro drug release studies showed that only 4.75% of the drug was released in SGF for 2?h, while nearly 90% of the drug was released within 6?h after transferring into SPDF.     

载药壳聚糖缓释微球的制备及其释放研究

实验采用乳化交联法,使用复合交联剂(先用甲醛交联,再用戊二醛交联),制得盐酸四环素壳聚糖缓释微球,并考察不同分子量的壳聚糖、原料质量比、交联剂用量、复合交联剂用量、搅拌速度对微球的影响,筛选出最佳条件制备出戢药微球,并研究了该微球在扫描电镜和倒置式研究型显微镜下的形态及其在pH=7.4,温度为37℃时的释放规律.结果表明,采用复合交联剂的乳化交联法所制得的微球球形好,粒径分布为5～50μm之间,载药量为26.9%,包封率为56.3%,并且具有良好的缓释效果.     

Development and in vitro characterization of chitosan-coated polymeric nanoparticles for oral delivery and sustained release of the immunosuppressant drug mycophenolate mofetil

Objective: To develop an oral sustained release formulation of mycophenolate mofetil (MMF) for once-daily dosing, using chitosan-coated polylactic acid (PLA) or poly(lactic-co-glycolic) acid (PLGA) nanoparticles. The role of polymer molecular weight (MW) and drug to polymer ratio in encapsulation efficiency (EE) and release from the nanoparticles was explored in vitro.

Methods: Nanoparticles were prepared by a single emulsion solvent evaporation method where MMF was encapsulated with PLGA or PLA at various polymer MW and drug: polymer ratios. Subsequently, chitosan was added to create coated cationic particles, also at several chitosan MW grades and drug: polymer ratios. All the formulations were evaluated for mean diameter and polydispersity, EE as well as in vitro drug release. Differential scanning calorimetry (DSC), surface morphology, and in vitro mucin binding of the nanoparticles were performed for further characterization.

Results: Two lead formulations comprise MMF: high MW, PLA: medium MW chitosan 1:7:7 (w/w/w), and MMF: high MW, PLGA: high MW chitosan 1:7:7 (w/w/w), which had high EE (94.34% and 75.44%, respectively) and sustained drug release over 12?h with a minimal burst phase. DSC experiments revealed an amorphous form of MMF in the nanoparticle formulations. The surface morphology of the MMF NP showed spherical nanoparticles with minimal visible porosity. The potential for mucoadhesiveness was assessed by changes in zeta potential after incubation of the nanoparticles in mucin.

Conclusion: Two chitosan-coated nanoparticles formulations of MMF had high EE and a desirable sustained drug release profile in the effort to design a once-daily dosage form for MMF.     

可生物降解聚合物微球的制备及载药应用

综述了近年来合成生物降解聚合物微球的种类、制备方法及作为药物载体的应用.结果表明,这类聚合物微球具有良好的安全性、生物相容性和生物降解性,在药物缓释、控释和疾病的治疗中具有非常重要的作用和应用前景.     

Cytocompatible chitosan-graft-mPEG-based 5-fluorouracil-loaded polymeric nanoparticles for tumor-targeted drug delivery

Biodegradable materials like chitosan (CH) and methoxy polyethylene glycol (mPEG) are widely being used as drug delivery carriers for various therapeutic applications. In this study, copolymer (CH-g-mPEG) of CH and carboxylic acid terminated mPEG was synthesized by carbodiimide-mediated acid amine reaction. The resultant hydrophilic copolymer was characterized by Fourier transform infrared spectroscopy and ¹H NMR studies, revealing its relevant functional bands and proton peaks, respectively. Blank polymeric nanoparticles (B-PNPs) and 5-fluorouracil loaded polymeric nanoparticles (5-FU-PNPs) were formulated by ionic gelation method. Furthermore, folic acid functionalized FA-PNPs and FA-5-FU-PNPs were prepared for folate receptor-targeted drug delivery. FA-5-FU-PNPs were characterized by particle size, zeta potential, and in vitro drug release studies, resulting in 197.7?nm,?+29.9?mv, and sustained drug release of 88% in 24?h, respectively. Cytotoxicity studies were performed for FA-PNPs and FA-5-FU-PNPs in MCF-7 cell line, which exhibited a cell viability of 80 and 41%, respectively. In vitro internalization studies were carried out for 5-FU-PNPs and FA-5-FU-PNPs which demonstrated increased cellular uptake of FA-5-FU-PNPs by receptor-mediated transport. Significant (p?相似文献   

Strontium-substituted,luminescent and mesoporous hydroxyapatite microspheres for sustained drug release

The multifunctional strontium (Sr)-substituted hydroxyapatite microsphere was prepared via hydrothermal method, in which the luminescent and controlled drug release functions can be realized. The structure and morphology of the as-prepared microspheres were studied by using XRD, FTIR, SEM, TEM, HR-TEM, BET method. The optical properties was investigated by using photoluminescence (PL) and XPS measurement. Then, the as-prepared multifunctional microspheres were performed as a drug delivery carrier using vancomycin as a model drug. The experimental results show that the composition, morphology, luminescent properties and drug storage/release behaviour were obviously influenced by the amount of Sr. The microspheres with Sr²⁺/(Ca²⁺ + Sr²⁺) = 0.3 of Sr substitution showed the maximum specific surface area, best pore structure and strongest PL intensity. All the samples presented remarkable sustained drug release kinetics. In addition, the PL intensity of SrHA in the drug delivery system increased with the cumulative release time (amount) of vancomycin, which would make the drug release might be possibly tracked by the change of the luminescent intensity. Our study indicated a potential prospect that the fabricated multifunctional SrHA mesoporous microspheres might be applied in the field of bone regeneration and drug delivery.     

Biocompatibility and characteristics of chitosan/cellulose acetate microspheres for drug delivery

In this work, chitosan/cellulose acetate microspheres (CCAM) were prepared by the method of W/O/W emulsion with no toxic reagents. The microspheres were spherical, free flowing, and non-aggregated, which had a narrow size distribution. More than 90% of the microspheres had the diameter ranging from 200 to 280 μm. The hemolytic analysis indicated that CCAM was safe and had no hemolytic effect. The implanted CCAM did not produce any significant changes in the hematology of Sprague-Dawley (SD) rats, such as white blood cell, red blood cell, platelet, and the volume of hemoglobin. In addition, the levels of serum alanine aminotransferase, blood urea nitrogen, and creatinine had no obvious changes in SD rats implanted with CCAM, surger thread, or normal SD rats without any implantation. Thus, the CCAM had good blood compatibility and had no hepatotoxicity or renal toxicity to SD rats. Furthermore, CCAM with or without the model drug had good tissue compatibility with respect to the inflammatory reaction in SD rats and showed no significant difference from that of SD rats implanted with surgery thread. CCAM shows promise as a long-acting delivery system, which had good biocompatibility and biodegradability.     

Development of pH-sensitive pectinate/alginate microspheres for colon drug delivery

The purposes of this study were to develop and evaluate calcium pectinate/alginate microspheres (PAMs) and to exploit their pH-sensitive properties for colon-targeted delivery of encapsulated cisplatin. PAMs were prepared using an electrospraying method. The PAMs, as cores, were then coated with Eudragit S100 using a polyelectrolyte multilayer coating technique in aqueous solution. The morphology of the microspheres was observed under scanning electron microscopy. In vitro drug release studies were performed in simulated gastrointestinal fluid, and the results indicated that approximately 5 % of the cisplatin was released from the Eudragit S100-coated PAMs, and 51 % of the cisplatin was released from the uncoated PAMs at 1 h. The release of cisplatin from the Eudragit S100-coated PAMs was more sustained in simulated gastric fluid than in simulated intestinal fluid due to the increased solubility of the coating polymer in media with pH >7.0. Drug release from the Eudragit S100-coated PAMs was best described by the Higuchi’s square root model. From these results, it was concluded that Eudragit S100-coated PAMs are a potential carrier for delivery of cisplatin to the colon.     

A novel method for the preparation of biodegradable microspheres for protein drug delivery.

Microspheres are potential candidates for the protein drug delivery. In this work, we prepared polymer-coated starch/bovine serum albumin (BSA) microspheres using co-axial electrohydrodynamic atomization (CEHDA). First, starch solution in dimethyl sulphoxide (DMSO) was prepared and then an aqueous solution of BSA was added to it to make a starch-BSA solution. Subsequently, this solution was made to flow through the inner capillary, while the polymer, polydimethylsiloxane (PDMS), flowed through the outer capillary. On collection, filtration and subsequent drying, near-monodisperse microspheres of 5-6microm in size were obtained. The microspheres were characterized by Fourier-transform infrared (FT-IR) spectroscopy and scanning electron microscopy. Cumulative BSA release was investigated by UV spectroscopy. BSA structure and activity was preserved in the microspheres and its release in 0.01M phosphate buffered saline (PBS) was studied over a period of 8 days. There was an initial burst with 32wt% of total BSA released in 2h. Overall 75wt% of BSA was released over a 7 day period.     

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.     

pH Sensitive graft copolymers for zero order drug release: a mechanistic analysis

Aliphatic polyesters containing pendent unsaturation were synthesized by the polycondensation of a diol, dicarboxylic acid and glycidyl methacrylate. Grafting methacrylic acid (MAA) resulted in graft copolymers containing polyester backbone and MAA grafts. Depending on composition, the polymers swelled extensively and eroded or dissolved at near neutral pH but remained in collapsed state at acidic pH. Three representative drugs differing in solubility, viz., Diltiazem hydrochloride (DH), Indomethacin (IM) and Verapamil hydrochloride (VH) were released at constant rate from tablets made by compressing spray-dried microparticles. The release of DH at constant rate has been attributed to increase in diffusion coefficient of the drug from the swollen layer of matrix. The release of IM and VH at constant rate was governed by erosion and was enhanced in matrices which undergo dissolution. The release rate was enhanced with increasing MAA content and the frequency of grafts along the polyester backbone. Once a day dosage forms for drugs differing in solubility have been developed using a single polymer matrix which is easy to manufacture.     

Beclomethasone-loaded lipidic nanocarriers for pulmonary drug delivery: preparation, characterization and in vitro drug release

The purpose of this research paper was the development of lipid nanoparticles (LN) formulation suitable for beclomethasone dipropionate (BDP) administration via the pulmonary route. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) were prepared by high-shear homogenization method; the effects of process and formulation parameters on nanoparticles characteristics were investigated. LN were characterized in terms of morphology, size, encapsulation efficiency, in vitro drug release and aerosol aerodynamic properties. Nano-sized BDP-loaded LN with high entrapment efficiency values reaching 99% were successfully obtained. Application of in vitro drug release data to the Higuchi kinetic equation indicated a diffusion-controlled release from the lipidic matrix. Aerosolisation and subsequent cascade impaction measurements proved that SLN and NLC were efficiently nebulized yielding aerosols of a suitable particle size for BDP deep lung delivery. Results demonstrate that LN are promising nebulized carriers for BDP opening the way for lipophilic drug-targeting strategies by nebulization.     

Dithiocarbamate chitosan as a potential polymeric matrix for controlled drug release

Objective: To develop a polymer matrix for controlled release of drugs, chitosan, a linear aminopolysaccharide, was chemically modified to dithiocarbamate chitosan (DTCC) to afford a matrix where metal–drug complexes could be attached and released in a controlled manner depending on the binding nature between the drugs and the metals.

Materials and methods: DTCC was treated with metal-tetracycline (Tc) complexes to prepare DTCC–Ca(II)–Tc, DTCC–Mg(II)–Tc, DTCC–Cu(II)–Tc and DTCC–Zn(II)–Tc.

Results: The binding amount of Tc was in the order of DTCC–Zn(II)–Tc?≈?DTCC–Mg(II)–Tc?≈ DTCC–Ca(II)–Tc?>?DTCC–Cu(II)–Tc. The biphasic binding profiles, where Tc binding increased initially and then decreased, were shown for DTCC–Cu(II)–Tc and DTCC–Zn(II)–Tc. In a flow method, Tc was released slowly from DTCC–metal–Tc complexes except for DTCC–Cu(II)–Tc compared with Tc release from DTCC–Tc. In parallel with the results of the release experiment, DTCC–metal–Tc complexes except for DTCC–Cu(II)–Tc presented a prolonged antibacterial activity in an antibacterial test. The antibacterial activity of DTCC–Ca(II)–, –Mg(II)– and –Zn(II)–Tc complexes lasted for 28–44 days, while free Tc and DTCC–Tc lasted for 7–12 days.

Discussion and conclusion: Taken together, our data suggest that DTCC could be used for a polymeric matrix for controlled release of drugs such as Tc, which possess functional groups for ionic and/or coordinate bond with metals.     

Dual-pH-sensitive mesoporous silica nanoparticle-based drug delivery system for tumor-triggered intracellular drug release

Reducing the side effects and improving the drug utilization are important work in anti-cancer drug delivery. In this paper, a novel dual-pH-sensitive drug delivery system was reported. Mesoporous silica nanoparticle (MSN) was applied to load anti-cancer drug doxorubicin hydrochloride (DOX) and was covered by mono-6-deoxy-6-EDA-β-cyclodextrine (β-CD-NH₂) to block the pores through pH-sensitive boronate ester bond. And the carriers were then coated with methoxy poly(ethylene glycol) (mPEG) through another pH-sensitive benzoic imine bond. mPEG leaving studies, in vitro cellular uptake studies and the flow cytometry analysis, proved that carriers was “stealthy” at pH 7.4, but could be “activated” for cytophagy by cancer cells in weakly acidic tumor tissues (pH 6.5) due to the departure of mPEG. β-CD-NH₂ leaving studies, the in vitro drug release studies and the in vitro cytotoxicity studies proved that boronate ester bond linking MSN and β-CD-NH₂ was stable at both pH 7.4 and 6.5, but could be hydrolyzed intracellular to release DOX for cellular apoptosis due to the lower pH (5.0). In summary, the novel dual-pH-sensitive drug delivery system fabricated with a dynamic protection strategy should have great application potential in anti-cancer drug delivery fields.