甲基纤维素湿敏水凝胶中溶菌酶微球性质的体外评价

Long-terrn injectable microspheres have some inherent disadvantages such as migration of microspheres from the originalsite an.d the burst effect. In order to avoid these problems, microsphere-loaded thermosensitive, hydrogel system was designed and expected to achieve a zero-order release Of biomolecular drugs in relativehigh initial drug loadings. Lysozyme, an antibacterial protein usually used to reduce prosthetic valve endocarditis,was selected as the model drug. Poly （DL-lactide-co-glycolide） （PLGA） microspheres, prepared by solvent evaporation method, were employee to encapsulate lysozyme and dispersed into thermosensitive pre-gel solution containing methylcellulose （MC）, polyethylene glycol （PEG）, sodium citrate （SC）, and sodium alginate （SA）. The mixture could act asadrug reservoir by.performing sol-gel transition rapidly if the temperature was raised from roomtemperature to 37℃. The in vitro release results showed that the burst effect was avoided due to strengthening ofdiffusion resistance in the gel. The formulation was able.to deliver lysozy.me for over.30 daysin a nearly zero-order release profile with a rate of 32.8μg.d^-1 which exhibits its remarkable potential for effective aoolication in long-term drug delivery.     

载5-氟尿嘧啶的pH敏感自组装纳米粒制备及体外释放

In order to improve the cancer-targeting and selective activity of antineoplastic agent [5-fluorouracil （5-FU）], a novel pH-responsive drug delivery system [pullulan acetate/sulfonamide （PA/SDM） conjugate] was synthesized by a diafiltration method. Sulfonamide was grafted to the hydrophobicaUy modified pullulan acetate to enhance the pH sensitivity for better cancer-targeting delivery. 5-FU was loaded into the self-assembled nanoparticles by the same method. The drug-loaded self-assembled nanoparticles were successfully obtained and characterized in terms of particle size, morphology and drug loading and release profile at various pHs. The results showed that the mean diameter of the self-assembled particles was approximately 100nm, with uniform size and good spherical morphology. The nanoparticles showed good stability at pH 7.4, which is equal to that of the normal body fluid, but shrank and aggregated below pH 6.8, which is close to the pH with tumors. The loading efficiency and concentration of released 5-FU was monitored at 269 nm on the UVNis spectrophotometer. The release profile was heavily pH-dependent around phvsiological pH, and the release rate was significantly enhanced under pH of 6.8.     

布洛芬固体脂质微颗粒的制备及其晶体构型研究

An emulsion-congealing technique is used to prepare solid lipid microparticles （SLM） containing ibuprofen with glyceryl behenate, tripalmitin and beewax as excipients. The difference of the solubility parameters between the excipients and ibuprofen are used to analyze their compatibility. Both the solubility parameter analysis and the experimental results show that glyceryl behenate is the best among the three excipients. The solid particles disperse well in aqueous phase when the drug loading reaches 10% （relative to lipid only）. Glycerides exhibit marked polymorphism and their rapid rates of crystallization accelerate the formation of metastable crystal modification. The metastable crystal modification characterizes high drug loading capacity but less stability. Increasing the content of lipophilic drug in a lipid matrix facilitates the transformation of excipients to more stable polymorphic forms.     

载三氧化二砷的PEG—PLGA隐性纳米粒的制备及体外研究

The aim of this study was to prepare arsenic trioxide （ATO）-loaded stealth PEGylated PLGA nanoparticles （PEG-PLGA-NPs） and to assess the merits of PEG-PLGA-NPs as drug carriers for ATO delivery. PEG-PLGA copolymer was synthesized with methoxypolyethyleneglycol （Mw=5000）, D, L-lactide, and glycolide by the ring-opening polymerization method. Amorphous ATO was transformed into cubic crystal form to increase its solu-bility in the organic solvent. ATO-loaded PEG-PLGA-NPs were prepared by the modified spontaneous emulsification solvent diffusion （SESD） method, and the main experimental factors influencing the characteristics of nanopar- ticles were investigated, to optimize the preparation. To confirm the escape of PEG-PLGA-NPs from phagocytosis by phagocytes, PEG-PLGA-NPs labeled rhodamine B uptake by murine peritoneal macrophages （MPM） were analyzed by flow cytometry. The results showed that the physicochemical characteristics of PEG-PLGA-NPs were affected by the type and concentration of the emulsifiers, polymer concentration, and drug concentration. ATO-loaded PEG-PLGA-NPs, with particle size of 120.8nm, zeta potential of-10.73mV, encapsulation efficiency of 73.6%, and drug loading of 1.36%, were prepared under optimal conditions. The images of transmission electron micros-copy （TEM） indicated that the optimized nanoparticles were near spherical and without aggregation or adhesion. The release experiments in vitro showed the ATO release from PEG-PLGA-NPs exhibited consequently sustained release for more than 26d, which was in accordance with Higuchi equation. The uptake of PEG-PLGA-NPs by MPM was found to decrease markedly compared to PLGA-NPs. The experimental results showed that PEG-PLGA-NPs were potential nano drug delivery carriers for ATO.     

用于控制释放的埃洛石纳米管复合温敏型水凝胶系统(英文)

Halloysite nanotube-composited thermo-responsive hydrogel system has been successfully developed for controlled drug release by copolymerization of N-isopropylacrylamide （NIPAM） with silane-modified halloysite nanotubes （HNT） through thermally initiated free-radical polymerization. With methylene blue as a model drug, thermo-responsive drug release results demonstrate that the drug release from the nanotubes in the composited hy-drogel can~be well controlled by manipulating the environmental temperature. When the hydrogel network is swol- len at temperature below the lower critical solution temperature （LCST）, drug releases steadily from lumens of the embedded nanotubes, whereas the drug release stops when hydrogel shrinks at temperature above the LCST. The release of model drug from the HNT-composited hydrogel matches well with its thermo-responsive volume phasetransition, and shows characteristics of well controlled release. The design strategy and release results of the pro- posed novel HNT-composited thermo-responsive hydrogel system provide valuable guidance for designing respon- s_i_ve nanocomposites for controlled-release of active agents.     

Study on Synthesis and Chloramphenicol Release of Poly（2-hydroxyethylmethacrylate-co-acrylamide） Hydrogels

In this article, poly（2-hydroxyethylmethacrylate-co-acrylamide） hydrogels were synthesized by bulk free-radical copolymerization of 2-hydroxyethylmethacrylate （HEMA） and acrylamide （AAm） for soft contact lens（SCL）-based ophthalmic drug delivery system. The copolymer was characterized with FT-IR and SEM, the swelling property of the hydrogels were studied by gravimetrical method, and chloramphenicol was used as a model drug to investigate drug release profile of the hydrogels. The results showed that poly（2-hydroxyethylmethacrylateco-acrylamide） hydrogels were transparent and useful SCL biomaterial, the water content increased as AAm content increase and pH decrease, and in the same way, hydrogel composition affected chloramphenicol release process too. Migration rate of chloramphenicol increased as the AAm content in the hydrogels increased in the first stage of diffusion process, whereas there was no significant difference thereafter.     

Thermosensitive Poly(N-isopropylacrylamide-co-acrylonitrile) Hydrogels with Rapid Response

Acrylonitrile （AN） was copolymerized with N-isopropylacrylamide （NIPA） to synthesize thermosensitive hydrogels, and the on-off switch behavior of poly（NIPA-co-AN） hydrogels with different fraction of hydrophobic component （AN） was investigated. It is found that the lower critical solution temperature （LCST）, the swelling ratio at certain temperature and the reswelling rate of poly（NIPA-co-AN） hydrogels decreased as AN unit fraction in copolymers increased. In order to improve the responsive rate of poly（NIPA-co-AN） hydrogels, they were further treated by surface crosslinking using N, N′-methylene bisacrylamide （BIS） as a crosslinking agent. The swelling and deswelling behaviors of these copolymers were compared with those of the untreated hydrogels. The results indicated that the responsive rate of poly（NIPA-co-AN） hydrogel was improved by surface crosslinking. The resulting hydrogels bearing cyano groups with fast response have potential applications in the field of drug-controlled release and immobilization of biomolecules.     

壳聚糖/乙基纤维素微胶囊的制备及特性

In this work a system which consists of chitosan microcores entrapped in ethylcellulose is presented.Vitamin D2 was eficiently entrapped in chitosan microcores with spray-drying method and was microencapsulated by coating of ethylcellulose.The average size of chitosan microspheres was 6.06μm.The morphology and release properties of microcapsules were tested.The results of release in vitro showed that the microcapsule could realize sustained release for 12h in artificial intestinal juice.     

Controlled release and enhanced antibacterial activity of salicylic acid by hydrogen bonding with chitosan☆

Microcapsules of salicylic acid(SA)with chitosan were prepared by spray drying method.Various analytical methods were used to characterize the nature of microcapsules.Fourier-transform infrared spectroscopy(FTIR)confirmed the presence of intermolecular interactions between chitosan and SA.Particle size analysis showed that the average size of microcapsules ranged from 2 to 20 μm.Scanning electron microscopy(SEM)studies indicated that the microspheres were spherical and had a relatively smooth surface.Microbiological assay of antibacterial activity for SA and its microcapsules was measured using different bacterial strains.It was found that the antibacterial activity of SA was improved after the formation of microcapsules.The in vitro release profile showed that the microcapsules could control SA release from 1 h to 4 h.Kinetic studies revealed that the release pattern follows Korsmeyer–Peppas mechanism.Enhanced antibacterial activity of the SA microcapsules was attributed to the synergistic effects of intermolecular hydrogen-bonding interactions N–H?O and O–H?O_C between SA and chitosan.It was also confirmed by quantum chemical calculation.     

MATHEMATICAL ANALYSIS OF DRUG RELEASE FROM PLANAR MATRIX WHEN DRUG IS LOADED UNDER THE SOLUBILITY

1 INTRODUCTIONThe release of a drug from a diffusional matrix has been investigated by variousresearchers for different conditions [1-4].The drug loading in the matrix may beabove or below its solubility limit.If it is beyond,the release boundary is generated bythe dissolution of drug,and the concentration in the released region may be propor-tional to the distance and kept at saturation in the unreleased region.Otherwise,the     

Preparation and properties of a novel thermosensitive <Emphasis Type="Italic">N</Emphasis>-trimethyl chitosan hydrogel

A novel injectable thermosensitive hydrogel system composed of N-trimethyl chitosan chloride (TMC) and β-glycerophosphate (β-GP), coded as TMC/β-GP, was designed. The morphology and rheological behavior of hydrogels were characterized by scanning electron microscopy and rheometer, respectively. Their swelling properties were carefully studied. The results revealed that the TMC/β-GP system was liquid with low viscosity at low temperature, which allowed it to be an ideal injectable material for biomedical applications. It was interesting that the system kept in liquid status for a long time near 4 °C and transformed rapidly to gel status within 1 min upon heating to 37 °C. The hydrogel could be dissolved at acid pH, while it absorbed water at neutral and basic conditions. The release of BSA from TMC/β-GP gels was slow at neutral pH. The TMC/β-GP hydrogel is a promising vehicle for the drug release, tissue repairing and regeneration.     

Alginate/carboxymethyl chitosan composite gel beads for oral drug delivery

This paper reports the synthesis of pH-sensitive gel beads derived from alginate (SA) and carboxymethyl chitosan (CMCS) for drug delivery. The composite SA/CMCS gel beads were prepared by dual ionic gelation: one ionic gelation between SA and Ca²⁺ and another one between CMCS and β-Sodium glycerophosphate (β-GP). The structure properties of hydrogel beads were characterized by SEM, IR and TG technique. The influence of the polymer composition and cross-linkers on the gel swelling property was investigated. When the concentration of CMCS and SA were 3 % and the volume ratio was 1:2, the swelling rate of gel beads crosslinked by β-GP and CaCl₂ solution can increase up to 31.2 and the swelling time can reach 10.5 h. In the drug release study, bovine serum albumin (BSA) was chosen as model drugs. The results indicated that BSA released slowly from the gel beads at pH 1.2 and the release ratio was about 10 %. At pH 7.4, the amounts of BSA released increased significantly as compared to those released at pH 1.2 and the total release time was extended to 11 h. The composite gel system demonstrates sustained release profile and pH sensitivity, which can be considered as good candidates for oral drug delivery systems.     

载5-氟尿嘧啶壳聚糖/明胶微粒的制备及药物释放性能

壳聚糖及明胶是生物相容性良好的高分子药物载体,制备载5-氟尿嘧啶壳聚糖/明胶微粒,并进行体外释药研究。以石蜡油为外相,壳聚糖/明胶为内相,用乳化交联法制备微粒,以吸附药量为指标,采用正交设计实验优化获得最佳制备条件,用红外光谱、SEM对最佳条件下制备的微粒进行表征。结果表明壳聚糖/明胶微粒的最佳制备条件如下:水油比1:7,壳聚糖/明胶浓度比1:3,乳化剂100.7mmol/L,乳化5min,乳化温度60℃,交联剂戊二醛用量5.5mmol/L,交联时间1h。在此条件下,载药微粒的载药量为34.93%,包封率为38.36%。红外光谱图表明壳聚糖/明胶微粒已负载5-氟尿嘧啶,SEM表明微粒成球状,表面较光滑。模拟胃肠释放表明,微粒具有一定的缓释性能。采用乳化交联法制备载5-氟尿嘧啶壳聚糖/明胶微粒方法简单,重现性好,且其体外释放实验显示出明显的缓释作用。     

Microparticles based on hydrophobically modified chitosan as drug carriers

In this work, a hydrophobically modified (HM) chitosan derivative was prepared by covalent linkage of C₁₂ groups to the chitosan backbone. HM‐chitosan microparticles were prepared according to an emulsification‐solvent evaporation method and naltrexone (NTX) was used as a model drug. For comparison, unmodified chitosan and poly lactic‐co‐glycolic acid (PLGA) microparticles were also tested as carriers for NTX. HM‐chitosan formed viscous semi‐dilute solutions, suggesting a high level of chain entanglements and hydrophobic associations. HM‐chitosan microparticles generally showed higher production yield and encapsulation efficiency, as compared with chitosan and PLGA. The burst release shown by chitosan microparticles was significantly reduced when using the HM‐chitosan derivative. An enhanced control of drug release was observed over at least 50 days. PLGA particles demonstrated inferior controlled release properties as compared to HM‐chitosan subsequent to the initial release stage. These results revealed the potential of hydrophobic modification of chitosan as a means to improve the stability and sustained delivery properties of the polymer. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40055.     

Bioadhesive hydrophobic chitosan microparticles for oral delivery of insulin: In vitro characterization and in vivo uptake studies

Hydrophobically modified polymeric matrices for drug delivery were developed by N‐acylation of chitosan with long(C₁₈) and medium chain(C₈) fatty acid chlorides like octanoyl and oleoyl chloride. Chemical modifications of chitosan were confirmed by IR spectra and trinitrobenzenesulphonic acid assay. Modified chitosan particles were prepared by ionotropic gelation with sodium tripolyphosphate. Hydrophobic modification was confirmed by contact angle measurements. Scanning electron micrographs showed the presence of compact microparticles. Swelling studies showed that oleoyl chitosan exhibited low swelling profile than octanoyl chitosan at acidic pH. In vitro release profile at pH 7.4 showed that about 90% of insulin was released by 5th hour. ELISA studies proved that the microparticles were capable of maintaining biological activity of insulin. Mucoadhesion studies proved that oleoyl derivative was more mucoadhesive than octanoyl derivative. In vivo uptake studies of fluorescent‐labeled microparticles on rat intestinal sections showed that oleoyl chitosan microparticles exhibited significant uptake than octanoyl chitosan. These results suggests that oleoyl moiety would resist degradation by the gastric enzymes and will enhance mucoadhesivity through hydrophobic interactions and also the permeability by loosening the tight junctions, thus making it a useful carrier for oral peptide delivery applications. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

静电喷射技术制备可酸致突释给药的壳聚糖微颗粒

利用静电喷射技术,以西咪替丁作为模型药物,混有药物的壳聚糖水溶液作为喷射液,甲苯/正己醇的混合溶液作为接收液,成功制备得到可在酸性条件下溶解并突释给药的壳聚糖载药微颗粒。系统考察了交联剂含量对壳聚糖微颗粒的药物包封率以及载药量的影响,并研究了壳聚糖微颗粒在酸性条件下的溶解特性以及在体外的突释给药效果。结果表明,当交联剂质量分数为2%时,壳聚糖微颗粒的包封率及载药量最大,分别为80%和3.8%。由于对苯二甲醛与壳聚糖交联形成的Schiff-base结构,使得壳聚糖微颗粒能够在中性条件下保持结构完整,而在酸性条件下由于Schiff-base结构的不稳定性致使微颗粒迅速溶解。因此,体外释药实验结果显示,在pH = 2、37℃的模拟胃酸溶液中,1min内壳聚糖微颗粒即可达到最大释药效果,而在pH = 6.4、37℃的水溶液中,壳聚糖微颗粒可以较长时间保持稳定,药物释放缓慢。这种具有酸致突释释药性能的壳聚糖微粒载体在胃部给药系统方面有良好的应用前景。     

Preparation and evaluation of floating‐bioadhesive microparticles containing clarithromycin for the eradication of Helicobacter pylori

The development of a gastric floating‐bioadhesive drug delivery system to increase the efficacy of clarithromycin against Helicobacter pylori is described. Floating‐bioadhesive microparticles containing clarithromycin were prepared by a combined method of emulsification/evaporation and internal/ion gelation for the treatment of H. pylori infection. Ethylcellulose microspheres (EMs) were prepared by the dispersion of clarithromycin, ethylcellulose, and chitosan in dichloromethane and subsequent solvent evaporation. EMs were coated with alginate by the internal gelation process to obtain alginate–ethylcellulose microparticles (AEMs); then, AEMs were dispersed in a chitosan solution, and chitosan–alginate–ethylcellulose microparticles (CAEMs) were obtained by ion gelation to enhance the bioadhesive properties. The morphologies of EMs and CAEMs were investigated under optical and scanning electron microscopes. In vitro buoyancy and drug‐release testing confirmed the good floating and sustained‐release properties of CAEMs. About 74% of the CAEMs floated in an acetate buffer solution for 8 h, and 90% of the clarithromycin contained in the CAEMs was released within 8 h in a sustained manner. In vivo mucoadhesive testing showed that 61% of the CAEMs could be retained in the stomach for 4 h. Under a pretreatment with omeprazole, the clarithromycin concentration in gastric mucosa of the CAEM group was higher than that of the clarithromycin solution group. These results suggest that CAEMs might be a promising drug delivery system for the treatment of H. pylori infection. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 102: 2226–2232, 2006     

Novel spray-dried PHA microparticles for antitumor drug release

The production of poly-3-hydroxybutyrate (P3HB) and poly-3-hydroxybutyrate/polyethylene glycol (PEG)-based microparticles, loaded with antitumor drugs paclitaxel (PTX) and 5-Fluorouracil (5-FU) by spray-drying technique, was investigated. The average diameter of microparticles was found to be 3.4?±?0.5?µm and zeta potential was about ?44?mV. The addition of surfactant PEG did not show any effect on the morphological characteristics of the particles. But the chemical structure of drug influenced on the properties. Microparticles had heterogeneous pores on the surface when the hydrophobic PTX was encapsulated. It was established that the addition of surfactant positively influenced on the properties of particles and led to the loading of 5-FU directly into the matrix. This is confirmed by the results of electron microscopy and dynamics of drug release in vitro. As a whole, the release profiles of PTX and 5-FU from composite P3HB/PEG microparticles were less than from P3HB microparticles. The results of the morphological evaluation of Hela cells demonstrated that the use of cytostatic drugs loaded in P3HB microparticles induces morphological changes associated with apoptosis (chromatin condensation, core fragmentation, margination of nucleus). Thus, the obtained results can serve as the basis for the development of new antitumor drugs of prolonged action, intended for various modes of administration.     

Preparation and characterization of a novel thermosensitive hydrogel based on chitosan and gelatin blends

In this study, a novel injectable in situ gelling thermosensitive hydrogel system based on chitosan and gelatin blends was designed and investigated. The addition of gelatin provides the correct buffering and other physicochemical conditions including control of hydrophobic interactions and hydrogen bonding, which are necessary to retain chitosan in solution at neutral pH near 4°C and furthermore to allow gel formation upon heating to body temperature. The chitosan/gelatin hydrogels were studied by FTIR, swelling, and rheological analysis. The rheological analysis evidenced the endothermic gelation of chitosan/gelatin solutions, which indicated their gelation temperatures and reflected the effect of gelatin concentration on the thermosensitive properties of gels. The morphology of this system was examined with laser scanning confocal microscopy and scanning electron microscopy. The images indicated that the gels were quite heterogeneous and porous. The investigation of these gels as vehicles for delivering bovine serum albumin as a model drug of protein showed that the system could sustain the release of the protein drug. These results show that chitosan/gelatin solutions can form gels rapidly at body temperature and have promising perspective for their use in local and sustained delivery of protein drug. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Biodegradable Nanoparticles-Loaded PLGA Microcapsule for the Enhanced Encapsulation Efficiency and Controlled Release of Hydrophilic Drug

Recently, nano- and micro-particulate systems have been widely utilized to deliver pharmaceutical compounds to achieve enhanced therapeutic effects and reduced side effects. Poly (DL-lactide-co-glycolide) (PLGA), as one of the biodegradable polyesters, has been widely used to fabricate particulate systems because of advantages including controlled and sustained release, biodegradability, and biocompatibility. However, PLGA is known for low encapsulation efficiency (%) and insufficient controlled release of water-soluble drugs. It would result in fluctuation in the plasma levels and unexpected side effects of drugs. Therefore, the purpose of this work was to develop microcapsules loaded with alginate-coated chitosan that can increase the encapsulation efficiency of the hydrophilic drug while exhibiting a controlled and sustained release profile with reduced initial burst release. The encapsulation of nanoparticles in PLGA microcapsules was done by the emulsion solvent evaporation method. The encapsulation of nanoparticles in PLGA microcapsules was confirmed by scanning electron microscopy and confocal microscopy. The release profile of hydrophilic drugs can further be altered by the chitosan coating. The chitosan coating onto alginate exhibited a less initial burst release and sustained release of the hydrophilic drug. In addition, the encapsulation of alginate nanoparticles and alginate nanoparticles coated with chitosan in PLGA microcapsules was shown to enhance the encapsulation efficiency of a hydrophilic drug. Based on the results, this delivery system could be a promising platform for the high encapsulation efficiency and sustained release with reduced initial burst release of the hydrophilic drug.