Effect of formulation variables on cis-platin loaded chitosan microsphere properties

Chitosan microspheres containing cis-platin were prepared using a w/o emulsion system. Variables important for microsphere properties were investigated: these include; chitosan, cis-platin and glutaraldehyde concentrations, the types of chitosan and oil, the cross-linking process and stirring rate. Chitosan and glutaraldehyde concentrations, the types of oil and chitosan have a significant effect on cis-platin entrapment in chitosan microspheres. In general, incorporation efficiency was high and ranged from 28-99%. The type and concentration of chitosan affected cis-platin release from microspheres. The type of oil was also important for release properties. Cis-platin release from microspheres is characterized by an initial burst effect.     

5-Fluorouracil loaded chitosan microspheres for chemoembolization

In this study, chitosan microspheres were prepared by a suspension crosslinking technique. A petroleum ether/mineral oil mixture was used as the suspension medium which includes an emulsifier, e.g. Tween-80. Glutaraldehyde was used as the cross-linker. 5-Fluorouracil was incorporated in the matrix for the possible use of the microspheres in chemoembolization. The size andsize distributionof thechitosanmicrospheres variedinthesizerangeof 100-200mum, by changing the emulsifier concentration, stirring rate, chitosan/ solvent ratio and drug/chitosan solution ratio. In summary, the size and size distribution of the microspheres decreased when the emulsifier concentration and stirring rate were increased. Smaller microspheres with narrower size distributions were obtained when the chitosan/solvent ratio and drug/chitosan ratiowerelower. Itwas possibletoload thechitosanmicrospheres with 5-FU to a concentration of 10.4mg 5-FU/g chitosan. Around 60%of the loaded drug was released within the first 24h, then the release rate became much slower.     

壳聚糖/聚乙烯醇微球吸附脲酶的特性及其动力学

目的制备壳聚糖/聚乙烯醇(PVA)微球脲酶,探讨其最适温度、最适pH、热稳定性及其动力学。方法用微乳法制备壳聚糖/PVA微球,采用电子扫描电镜表征其形态;用吸附法获得壳聚糖/PVA微球脲酶;运用Berthlot测定其活力。结果壳聚糖/PVA微球脲酶酶活性保持率是原酶的91.93%,最适温度为47℃,最适pH6.5,热稳定性明显高于溶液脲酶;壳聚糖/PVA微球脲酶的动力学参数KM=11.8 mmo.lL-1,Vm ax=37.1μmo.lm in-.1mg-1。结论壳聚糖/PVA微球脲酶可制备成用于尿毒症患者的口服制剂。     

Effect of formulation variables on in vitro drug release and micromeritic properties of modified release ibuprofen microspheres

Modified release microspheres of the non-steroidal anti-inflammatory drug, ibuprofen, were formulated and prepared using the emulsion solvent diffusion technique. The contribution of various dispersed phase and continuous phase formulation factors on in vitro drug release and micromeritic characteristics of microspheres was examined. The results demonstrated that the use of Eudragit RS 100 and Eudragit RL 100 as embedding polymers modified the drug release properties as a function of polymer type and concentration. Eudragit RS 100 retarded ibuprofen release from the microspheres to a greater extent than Eudragit RL 100. The drug/polymer concentration of the dispersed phase influenced the particle size and drug release properties of the formed microspheres. It was found that the presence of emulsifier was essential for microsphere formation. Increasing the concentration of emulsifier, sucrose fatty acid ester F-70, decreased the particle size which contributed to increased drug release properties. Scanning electron microscopy revealed profound distortion in both the shape and surface morphology of the microspheres with the use of magnesium stearate as added emulsifier. The application of an additional Eudragit RS 100 coat onto formed microspheres using fluid bed technology was successful and modulated the drug release properties of the coated microspheres.     

Lipid microsphere formulation containing rifampicin targets alveolar macrophages

The study demonstrated that lipid microspheres (LM) containing rifampicin (LM-RFP) could deliver the drug to alveolar macrophages in vitro and in vivo, and that intranasal administration to animals could achieve preferential accumulation in the lungs with less effect on the liver. The LM-RFP particles had a mean diameter of 247.2 ± 75.7 nm, and their size remained stable when stored at 4°C or 25°C for at least 4 weeks. In vitro uptake of [³H]LM-RFP by alveolar macrophages was over 4 times higher than that of unencapsulated [³H]RFP, whereas the in vivo uptake was 30 times higher. Flow cytometric analysis and confocal laser scanning microscopy confirmed that LM could deliver the encapsulated drug effectively to alveolar macrophages in vitro and in vivo. Intranasal administration of [³H]LM-RFP to normal mice resulted in preferential pulmonary uptake of the drug and lower levels in the blood and liver compared with administration of unencapsulated [³H]RFP. In conclusion, LM-RFP could be a promising preparation for delivery via the respiratory tract to tuberculosis (TB) and TB/HIV patients.     

Impregnation and release of aspirin from chitosan/poly(acrylic acid) graft copolymer microspheres

The purpose of this study was to produce aspirin-impregnated microspheres of chitosan/poly(acrylic acid) copolymer in order to evaluate the release characteristics as a function of pH, simulating the fluids in the gastrointestinal tract. Chitosan microspheres were obtained by the coacervation-phase separation method, induced by the addition of a non-solvent (NaOH 2.0 M solution). The microspheres were cross-linked with glutaraldehyde, reduced with sodium cianoborohydride and grafted with poly(acrylic acid). The impregnation of aspirin into chitosan/poly(acrylic acid) copolymer microspheres was achieved by the dissolution of the drug in water:ethanol (2:1), which was adsorbed by the microspheres for 24 h at 25 °C. The efficiency of aspirin impregnation was high (~94%). The approach employed herein in the production of aspirin-impregnated microspheres using chitosan/poly(acrylic acid) can be a suitable drug-release control system.     

Encapsulation of immunoglobulin G by solid-in-oil-in-water: Effect of process parameters on microsphere properties

Antibodies (Abs) are prone to a variety of physical and chemical degradation pathways, which require the development of stable formulations and specific delivery strategies. In this study, injectable biodegradable and biocompatible polymeric particles were employed for controlled-release dosage forms and the encapsulation of antibodies into polylactide-co-glycolide (PLGA) based microspheres was explored. In order to avoid stability issues which are commonly described when water-in-oil (w/o) emulsion is used, a solid-in-oil-in-water (s/o/w) method was developed and optimized. The solid phase was made of IgG microparticles and the s/o/w process was evaluated as an encapsulation method using a model Ab molecule (polyclonal bovine immunoglobulin G (IgG)). The methylene chloride (MC) commonly used for an encapsulation process was replaced by ethyl acetate (EtAc), which was considered as a more suitable organic solvent in terms of both environmental and human safety. The effects of several processes and formulation factors were evaluated on IgG:PLGA microsphere properties such as: particle size distribution, drug loading, IgG stability, and encapsulation efficiency (EE%). Several formulations and processing parameters were also statistically identified as critical to get reproducible process (e.g. the PLGA concentration, the volume of the external phase, the emulsification rate, and the quantity of IgG microparticles). The optimized encapsulation method has shown a drug loading of up to 6% (w/w) and an encapsulation efficiency of up to 60% (w/w) while preserving the integrity of the encapsulated antibody. The produced microspheres were characterized by a d(0.9) lower than 110 μm and showed burst effect lower than 50% (w/w).     

Crosslinked chitosan microspheres for encapsulation of diclofenac sodium: effect of crosslinking agent

Microspheres of chitosan crosslinked with three different crosslinking agents viz, glutaraldehyde, sulphuric acid and heat treatment have been prepared to encapsulate diclofenac sodium (DS). Chitosan microspheres are produced in a w/o emulsion followed by crosslinking in the water phase by one of the crosslinking methods. Encapsulation of DS has been carried out by soaking the already swollen crosslinked microspheres in a saturated solution of DS. Microspheres are further characterized by FTIR, x-RD and SEM. The in-vitro release studies are performed in 7.4 pH buffer solution. Microspheres produced are spherical and have smooth surfaces, with sizes ranging between 40-230 #181;m, as evidenced by SEM. The crosslinking of chitosan takes place at the free amino group in all the cases, as evidenced by FTIR. This leads to the formation of imine groups or ionic bonds. Polymer crystallinity increases after crosslinking, as determined by x-RD. The method adopted for drug loading into the microspheres is satisfactory, and up to 28-30% w/w loading is observed for the sulphuric acid-crosslinked microspheres, whereas 23-29 and 15-23% of loadings are obtained for the glutaraldehyde (GA)- and heat-crosslinked microspheres, respectively. Among all the systems studied, the 32% GA crosslinked microspheres have shown the slowest release i.e. 41% at 420 min, and a fastest release of 81% at 500 min is shown by heat crosslinking for 3 h. Drug release from the matrices deviates slightly from the Fickian process.     

芹菜素壳聚糖微球的制备及体外释药研究

目的以芹菜素为模型药物、脱乙酰壳聚糖为药物载体,制备芹菜素壳聚糖微球,并测定微球中芹菜素的体外释放度。方法采用复乳-乳化化学交联法制备微球,正交试验优化微球制备的工艺,高效液相色谱法检测芹菜素含量。结果最佳工艺制备4批微球,形态良好,微球圆整,平均载药量为8.54%,平均包封率为69.69%,平均粒径为84.33μm。微球在pH 6.8和pH 7.4的磷酸盐缓冲液中释放36 h。结论所选制备工艺稳定,适用于芹菜素壳聚糖微球的制备,体外药物释放结果显示,微球具有良好的缓释效果。     

Modulation of stability and mucoadhesive properties of chitosan microspheres for therapeutic gastric application

Chitosan microspheres have been explored for pharmaceutical applications, namely as a drug delivery systems for Helicobacter pylori gastric infection treatment, due to their mucoadhesive capacity. In this study, a different application of chitosan microspheres is proposed aiming the creation of an H. pylori-binding system where, after oral administration, microspheres will capture and remove these bacteria from infected patients, taking advantage of their muco/bacterial adhesive process. However, mucoadhesion is influenced by the degree of crosslinking necessary to avoid microspheres dissolution in the acidic gastric environment.     

The role of chitosan on oral delivery of peptide-loaded nanoparticle formulation

Therapeutic peptides are conventionally administered via subcutaneous injection. Chitosan-based nanoparticles are gaining increased attention for their ability to serve as a carrier for oral delivery of peptides and vaccination. They offered superior biocompatibiltiy, controlled drug release profile and facilitated gastrointestinal (GI) absorption. The encapsulated peptides can withstand enzymatic degradation and various pH. Chitosan-based nanoparticles can also be modified by ligand conjugation to the surface of nanoparticle for transcellular absorption and specific-targeted delivery of macromolecules to the tissue of interest. Current research suggests that chitosan-based nanoparticles can deliver therapeutic peptide for the treatment of several medical conditions such as diabetes, bacterial infection and cancer. This review summarises the role of chitosan in oral nanoparticle delivery and identifies the clinical application of peptide-loaded chitosan-based nanoparticles.     

Physical properties of chitosan pellets produced by extrusion-spheronisation: influence of formulation variables

Pellets comprising chitosan, cellulose microcrystalline, povidone, filler excipient and diclofenac sodium as model drug were prepared by extrusion-spheronisation. The effects of chitosan load (zero, 0%, low, 4% and high, 16% levels), type of filler (lactose, tribasic calcium phosphate and beta-cyclodextrin) and composition of the binding liquid (ethanol/water mixtures 20 and 50%) on physical characteristics of pellets were evaluated. A three-factor factorial design was employed in the study. Analysis of variance (ANOVA) indicated that single factors had significant effect on the physical characteristics of the pellets. The type of filler followed by polymer load markedly affected the density. The type of binding liquid had negligible effect on the shape and surface roughness of the pellets. Increase in the chitosan load resulted in pellets of lower porosity values. This could be attributed to the binding capacity of chitosan and povidone leading to more compacted structures. Chitosan load and type of filler had significant influence on the surface roughness. The surface of pellets became rougher as the chitosan load increased, however, there was no significant difference between zero and low contents of chitosan. Pellets prepared using tribasic calcium phosphate showed a smoother surface when compared with formulations including lactose or beta-cyclodextrin. Chitosan was useful to provide pellets of acceptable physical characteristics when employing an alcohol/water mixture 50% (v/v) as binding liquid for the extrusion-spheronisation process.     

Cross-linked starch microspheres: Effect of cross-linking condition on the microsphere characteristics

Cross-linked starch microspheres were prepared using different kinds of cross-linking agents. The influence of several parameters on morphology, size, swelling ratio and drug release rate from these microspheres were evaluated. These parameters included cross-linker type, concentration and the duration of cross-linking reaction. Microspheres cross-linked with glutaraldehyde had smooth surface compared with those prepared with epichlorhydrine or formaldehyde. The particle size increased with increasing the cross-linking time and increasing the drug loading. Swelling ratio of the particles was a function of cross-linker type but not the concentration or time of cross-linking. Drug release from starch microspheres was measured in phosphate buffer and also in phosphate buffer containing alpha-amylase. Results showed that microspheres cross-linked with epichlorhydrine released all their drug content in the first 30 minutes. However, cross-linking of the starch microspheres with glutaraldehyde or formaldehyde decreased drug release rate. SEM and drug release studies showed that cross-linked starch microspheres were susceptible to the enzymatic degradation under the influence of alpha-amylase. Changing the enzyme concentration from 5000 to 10,000 IU/L, increased drug release rate but higher concentration of enzyme (20,000 IU/L) caused no more acceleration.     

Evaluation of ketorolac tromethamine microspheres by chitosan/gelatin B complex coacervation

Microspheres (MS) of Ketorolac Tromethamine (KT) for oral delivery were prepared by complex coacervation (method-1) and simple coacervation (method-2) methods without the use of chemical crossalinking agent (glutaraldehyde) to avoid the toxic reactions and other undesirable effects of the chemical cross-linking agents. Alternatively, ionotropic gelation was employed by using sodium-tripolyphosphate (Na-TPP) as cross linking agent. Chitosan and gelatin B were used as polymer and copolymer respectively. All the prepared microspheres were subjected to various physico-chemical studies, such as drug-polymer compatibility by Thin Layer Chromatography (TLC) and Fourier Transform Infra Red Spectroscopy (FTIR), surface morphology by Scanning Electron Microscopy (SEM), frequency distribution, encapsulation efficiency, in-vitro drug release characteristics and release kinetics. The physical state of drug in the microspheres was determined by Differential Scanning Calorimetry (DSC) and X-ray powder Diffractometry (XRD). TLC and FTIR studies indicated no drug-polymer incompatibility. All the MS showed release of drug by a fickian diffusion mechanism. DSC and XRD analysis indicated that the KT trapped in the microspheres existed in an amorphous or disordered-crystalline status in the polymer matrix. It is possible to design a controlled drug delivery system for the prolonged release of KT, improving therapy by possible reduction of time intervals between administrations.     

Development and evaluation of a novel phytosome-loaded chitosan microsphere system for curcumin delivery

In this study, we developed a novel drug delivery system, curcumin-phytosome-loaded chitosan microspheres (Cur-PS-CMs) by combining polymer- and lipid-based delivery systems. Curcumin exhibits poor water-solubility and is rapidly eliminated from the body. We aimed to use our novel delivery system to improve the bioavailability and prolong the retention time of curcumin in the body. The Cur-PS-CMs were produced by encapsulating curcumin-phytosomes (Cur-PSs) in chitosan microspheres using ionotropic gelation. The final microsphere was spherical, with a mean particle size of 23.21 ± 6.72 μm and drug loading efficiency of 2.67 ± 0.23%. Differential scanning calorimetry and Fourier transform infrared spectroscopy demonstrated that the integrity of the phytosomes was preserved within the polymeric matrix of the microspheres. The in vitro release rate of curcumin from the Cur-PS-CMs was slower than that from curcumin-loaded chitosan microspheres (Cur-CMs) in pH 1.0, 4.0, 6.8, and 7.4. Pharmacokinetic studies in rats dosed with Cur-PS-CMs showed a 1.67- and a 1.07-fold increase in absorption of curcumin compared with Cur-PSs and Cur-CMs, respectively. The half-life of curcumin orally administration of Cur-PS-CMs (3.16 h) was longer than those of Cur-PSs (1.73 h) and Cur-CMs (2.34 h). These results indicated that the new Cur-PS-CMs system combined the advantages of chitosan microspheres and phytosomes, which had better effects of promoting oral absorption and prolonging retention time of curcumin than single Cur-PSs or Cur-CMs. Therefore, the PS-CMs may be used as a sustained delivery system for lipophilic compounds with poor water-solubility and low oral bioavailability.     

Microencapsulated chitosan nanoparticles for lung protein delivery

It has already been demonstrated that spray drying is a very valuable technique for producing dry powders adequate for pulmonary delivery of drugs. We have developed chitosan/tripolyphosphate nanoparticles that promote peptide absorption across mucosal surfaces. The aim of this work was to microencapsulate protein-loaded chitosan nanoparticles using typical aerosol excipients, such as mannitol and lactose, producing microspheres as carriers of protein-loaded nanoparticles to the lung. The results showed that the obtained microspheres are mostly spherical and possess appropriate aerodynamic properties for pulmonary delivery (aerodynamic diameters between 2 and 3 μm, apparent density lower than 0.45 g/cm³). Moreover, microspheres morphology was strongly affected by the content of chitosan nanoparticles. These nanoparticles show a good protein loading capacity (65–80%), providing the release of 75–80% insulin within 15 min, and can be easily recovered from microspheres after contact with an aqueous medium with no significant changes in their size and zeta potential values. Therefore, this work demonstrated that protein-loaded nanoparticles could be successfully incorporated into microspheres with adequate characteristics to reach the deep lung, which after contact with its aqueous environment are expected to be able to release the nanoparticles, and thus, the therapeutic macromolecule.     

壳聚糖止血敷料用于永久性心脏起搏器植入术后的效果观察

目的探讨永久性心脏起搏器植入术后应用壳聚糖止血敷料促进伤口愈合的效果。方法选择航天中心医院行永久性心脏起搏器植入术的患者200例,完全随机分为试验组和对照组,各100例。术后当日及后续隔日换药时试验组和对照组分别使用壳聚糖止血敷料涂抹及传统消毒换药方法,评估手术切口愈合情况。结果试验组及对照组甲级愈合率分别为98％和82％（P=0．001）,其余均为乙级愈合。对照组有1例术后切口出血,1例囊袋血肿,试验组无手术并发症。多元回归分析显示,试验组手术切口甲级愈合情况与年龄、体重指数、平均血压、血小板计数、国际标准化比值、糖化血红蛋白均元明显关系（r=0．23,P=0．534;r=0．12,P=0．299;r=0．35,P=0．635;r=0．29,P=0．612;r=0．22,P=0．134;r=0．38,P=0．527）,对照组甲级愈合情况与糖化血红蛋白比值正相关（r=0．72,P=0．044）。结论壳聚糖止血敷料可以明显促进起搏器切口愈合,减少手术并发症。     

Reacetylated chitosan microspheres for controlled delivery of anti-microbial agents to the gastric mucosa

The high aqueous solubility of chitosan restricts the utility of chitosan microspheres for gastric drug delivery. This paper describes the preparation of reacetylated chitosan microspheres with suitable properties for the controlled release of active anti-microbial agents, such as amoxycillin and metronidazole, in the gastric cavity. Two different microencapsulation approaches were developed and optimized in order to encapsulate hydrophilic (amoxycillin) and hydrophobic (metronidazole) compounds efficiently. The reacetylated chitosan microspheres exhibited a controlled water swelling capacity and gelified at acidic pH, resulting in prolonged release of the encapsulated antibiotics. The reacetylation time was found to be a key factor that affects not only drug release, but also encapsulation efficiency and anti-microbial activity of the encapsulated compound. The last two parameters were also dependent on drug solubility in the reacetylating agent. Using short reacetylation time periods, it was possible to efficiently control the release of both hydrophilic and lipophilic antibiotics while maintaining their activity against different bacteria. Consequently, reacetylated chitosan microspheres are promising vehicles for the controlled delivery of anti-microbial agents to the gastric cavity and, hence, for the eradication of Helicobacter pylori, a pathogen strongly associated with gastric ulcers and possibly gastric carcinoma.     

Microspheres containing lipid/chitosan nanoparticles complexes for pulmonary delivery of therapeutic proteins

Chitosan/tripolyphosphate nanoparticles have already been demonstrated to promote peptide absorption through several mucosal surfaces. We have recently developed a new drug delivery system consisting of complexes formed between preformed chitosan/tripolyphosphate nanoparticles and phospholipids, named as lipid/chitosan nanoparticles (L/CS-NP) complexes. The aim of this work was to microencapsulate these protein-loaded L/CS-NP complexes by spray-drying, using mannitol as excipient to produce microspheres with adequate properties for pulmonary delivery. Results show that the obtained microspheres are spherical and present appropriate aerodynamic characteristics for lung delivery (aerodynamic diameters around 2–3 μm and low apparent tap density of 0.4–0.5 g/cm³). The physicochemical properties of the L/CS-NP complexes are affected by the phospholipids composition. Phospholipids provide a controlled release of the encapsulated protein (insulin), which was successfully associated to the system (68%). The complexes can be easily recovered from the mannitol microspheres upon incubation in aqueous medium, maintaining their morphology and physicochemical characteristics. Therefore, this work demonstrates that protein-loaded L/CS-NP complexes can be efficiently microencapsulated, resulting in microspheres with adequate properties to provide a deep inhalation pattern. Furthermore, they are expected to release their payload (the complexes and, consequently, the encapsulated macromolecule) after contacting with the lung aqueous environment.     

难溶性中药姜黄素自乳化微球的制备及性质考察

目的：制备姜黄素自乳化微球,以提高姜黄素的水溶性,进而提高其生物利用度。方法利用溶解度实验和伪三元相图的方法筛选自乳化处方,利用单纯型网格法进行处方优化,并对制备的自乳化微球进行体外性质考察。结果制备的自乳化微球的最大载药量为71.32mg/g,包封率为44.31%,平均粒径为11.33μm,在3种递质中的释放量均超过80%。结论所制备的姜黄素自乳化微球载药量高,包封率、粒径符合要求,能够显著提高姜黄素的释放度。