Preparation,characterization, and drug‐release properties of pH/temperature‐responsive poly(N‐isopropylacrylamide)/chitosan semi‐IPN hydrogel particles

Novel poly(N‐isopropylacrylamide) (PNIPAAm)/chitosan (CS) semi‐interpenetrating polymer network hydrogel particles were prepared by inverse suspension polymerization. The prepared particles were sensitive to both temperature and pH, and they had good reversibility in solution at different temperatures and pH values. The swelling ratios of PNIPAAm/CS hydrogel particles decreased slightly with the addition of CS, which did not shift the lower critical solution temperature. The drug‐release behavior of the particles was investigated using cyclic adenosine 3′,5′‐monophosphate (cAMP) as a model drug. The release of cAMP from the hydrogel particles was affected by temperature, pH, and the CS content in the particles. These results showed that semi‐IPN hydrogel particles appeared to be of great promise in pH‐ and temperature‐sensitive oral drug release. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Synthesis of chitosan‐graft‐β‐cyclodextrin for improving the loading and release of doxorubicin in the nanopaticles

Chitosan‐graft‐β‐cyclodextrin (CS‐g‐β‐CD) copolymer was synthesized by conjugating β‐cyclodextrins to chitosan molecules through click chemistry. The copolymer structure was characterized by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR). CS‐g‐β‐CD/CMC nanoparticles were prepared by a polyelectrolyte complexation process in aqueous solution between CS‐g‐β‐CD copolymer and carboxymethyl chitosan (CMC), which was used to load anticancer drug (Doxorubicin hydrochloride, DOX·HCl) with hydrophobic group. The particle size, surface charge, zeta potential, and morphology of the nanoparticles were characterized with dynamic light scattering. The drug loading efficiency and in vitro release of DOX·HCl of the nanoparticles were measured by ultraviolet spectrophotometer. The results demonstrated that the size, surface charge and drug loading efficiency of the nanoparticles could be modulated by the fabrication conditions. The drug loading efficiency of CS‐g‐β‐CD/CMC nanoparticles was improved from 52.7% to 88.1% because of the presence of β‐CD moieties with hydrophobic cavities, which can form inclusion complexes with the drug molecules. The in vitro release results showed that the CS‐g‐β‐CD/CMC nanoparticles released DOX·HCl in a controlled manner, importantly overcoming the initial burst effect. These nanoparticles possess much potential to be developed as anticancer drug delivery systems, especially those drugs with hydrophobic group. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 41034.     

Preparation of surface‐modified,micrometer‐sized carboxymethyl chitosan drug‐loaded microspheres

Drug‐loaded microspheres have attracted much attention in embolization therapy for liver cancer in recent years. Carboxymethyl chitosan has obvious advantages for biomedical applications because of its exceptional biocompatibility and biodegradability. In this study, surface‐modified carboxymethyl chitosan microspheres were prepared by the crosslinking reactions of carboxymethyl chitosan in a reverse suspension system with poly(ethylene glycol diglycidyl ether) (PEGDE) as the crosslinking agent; this was followed by the grafting polymerization of 2‐acrylamido‐2‐methyl propane sulfonic acid on the surface of the microspheres. The microspheres showed regular spherical shapes with size distributions ranging from 300 to 600 μm. Ion‐exchange groups (? COOH, ? SO₃H) were introduced into the microspheres; these groups could load doxorubicin with a loading rate as high as 34.6% in 24 h. This was an increase of 49.8% compared to that of the pure carboxymethyl chitosan microspheres. Additionally, the microspheres possessed large network structures because macromolecular PEGDE was used as the crosslinking agent. The drug‐release profile showed that the surface‐modified microspheres displayed a sustained‐release manner compared with the nonmodified microspheres in phosphate‐buffered saline. These microspheres have promising applications as drug‐loaded arterial embolization agents for the interventional treatment of tumors. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 45731.     

PEGylated chitosan microspheres as mucoadhesive drug‐delivery carriers for puerarin

PEGylated chitosans with different degrees of grafting were synthesized, and the application potential of microspheres based on PEGylated chitosan as mucoadhesive drug‐delivery carriers for puerarin was investigated. Compared with chitosan microspheres, PEGylated chitosan microspheres (PCMs) exhibited better physical stability and higher swelling capacity, and the amount of water uptake increased as the content of poly(ethylene glycol) methyl ether in the microspheres increased. PCMs showed obviously improved mucoadhesive behavior on a mucosa‐like surface. Puerarin was incorporated into the microspheres, and the release experiments in vitro showed that the PEGylation of chitosan accelerated puerarin release from the particles and decreased the retention of the drug. The abilities of all of the tested microspheres to open tight junctions and improve the permeability of puerarin were demonstrated with a Caco‐2 cell monolayer as an in vitro model. The amount of puerarin permeating across the Caco‐2 cell monolayer was significantly increased by the incorporation of puerarin into the PCMs. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 42623.     

壳聚糖-琼胶复合微球的制备及其药物释放性能

采用小分子离子交联法制备了pH值敏感的壳聚糖-琼胶复合微球,对壳聚糖-琼胶复合微球的粒径、形貌、pH值敏感性等进行了表征.以茶碱为模型药物研究了壳聚糖-琼胶复合微球的药物释放性能,结果发现一定量琼胶的引入有助于改善壳聚糖微球的药物缓释性能.     

A convenient scheme for synthesizing reduction‐sensitive chitosan‐based amphiphilic copolymers for drug delivery

A novel type of reduction‐sensitive graft copolymers, chitosan‐S‐S‐poly(ε‐caprolactone) (CS‐S‐S‐PCL, here ‐S‐S‐ means PCL was conjugated onto chitosan backbone through disulfide linkage), was synthesized through a convenient route using dithiodipropionic anhydride (DTDPA) as a disulfide donor. Reaction of hydroxy‐terminated poly(ε‐caprolactone) (PCL) with DTDPA quantitatively yielded DTDPA functionalized PCL (PCL‐S‐S‐COOH). The disulfide‐containing polyester was regioselectively conjugated onto the hydroxy groups of chitosan under mild and homogeneous conditions, utilizing dodecyl sulfate‐chitosan complexes (SCC) as an intermediate. The self‐assembly and Doxorubicin (Dox) release behavior of the copolymers were investigated. Spherical micelles could be formed through self‐assembly of CS‐S‐S‐PCL in aqueous media. The reduction‐sensitive behavior of CS‐S‐S‐PCL micelles was investigated by using Dithiothreitol (DTT) as a reductive reagent. In the presence of 10 mM DTT, the micelles gradually lost their aggregation stability and were precipitated out after four days. In addition, the Dox release was accelerated when the micelles were treated with DTT. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Effect of proteolytic enzymes in gastrointestinal fluids on drug release from polyelectrolyte complex microspheres based on partially phosphorylated chitosan

This study investigated the effect of proteolytic enzymes on in vitro release of ibuprofen from phosphorylated chitosan (PCS) microspheres in simulated gastric fluid (SGF) (pH 1.4) and simulated intestinal fluid (SIF) (pH 7.4). To reduce the enzymatic degradability and to enhance the sustained release property, polyelectrolyte complex microspheres based on PCS were developed and characterized. The ibuprofen release from PCS microspheres was found to be sustained more effectively than that from CS microspheres in the medium containing proteolytic enzymes. It was concluded that the PCS microspheres can be used more successfully as sustained oral drug‐delivery vehicles than CS microspheres due to their lesser enzymatic degradability. Copyright © 2004 Society of Chemical Industry     

Preparation,characterization, and drug‐release properties of poly(N‐isopropylacrylamide) microspheres having poly(itaconic acid) graft chains

An inverse suspension polymerization method for the preparation of thermoresponsive hydrogel microspheres based on N‐isopropylacrylamide was described in this article. The polymerization reaction was carried out at 200 rpm stirring rate and the microspheres obtained were in the size range of 71–500 μm in the swollen states. The particles were sieved by using ASTM sieves. The selected fraction (180–250 μm) of poly(N‐isopropylacrylamide) (PNIPAAm) microspheres was used for radiation‐induced modification with itaconic acid (IA) to obtain PNIPAAm/poly(itaconic acid) graft copolymer. Viagra and lidocaine were used as model drugs for the investigation of controlled‐release behavior of the microspheres. Incorporation of IA graft chains onto microspheres enhanced significantly the uptake of both drugs and further controlled release at specific pH values. The release studies showed that some of the basic parameters affecting the drug‐loading and ‐release behavior of the microspheres were pH, temperature, particle size, and chemical nature of drug. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 97: 1115–1124, 2005     

Preparation of chitosan microspheres loading of 3,5-dihydroxy-4-i-propylstilbene and in vitro release

3,5-Dihydroxy-4-i-propylstilbene (DHPS) is a compound expected to be developed into effective drugs for many inflammatory and autoimmune diseases. In order to improve the stablity of DHPS, the cross-linked chitosan (CS) microspheres loading of DHPS were prepared and characterized. The optimal conditions for preparing CS-microspheres loading of DHPS were investigated. The results showed that the CS-microspheres loading of DHPS had spherical shape with diameters between 8 and 12 microns. The entrapment of DHPS in the CS-microspheres was more than 36%. The released percentage of CS-microspheres loading of DHPS in pH 3.6 buffer solution was up to 30.9% within 96 h. In transdermal in vitro release, DHPS kept release within 60 h through rat skin and the released percentage could arrive 76.2%. The CS-microspheres loading of DHPS had excellent stability and ability of sustained release.     

Synthesis and characterization of modified chitosan microspheres: Effect of the grafting ratio on the controlled release of nifedipine through microspheres

The grafting of acrylamide onto a chitosan backbone was carried out at three acrylamide concentrations (polymer/monomer ratio = 1:1, 1:2, and 1:3). The synthesis of the grafted polymer was achieved by K₂S₂O₈‐induced free‐radical polymerization. Microspheres of polyacrylamide‐g‐chitosan crosslinked with glutaraldehyde were prepared to encapsulate nifedipine (NFD), a calcium channel blocker and an antihypertensive drug. The microspheres of polyacrylamide‐g‐chitosan were produced by a water‐in‐oil emulsion technique with three different concentrations of glutaraldehyde as the crosslinking agent. Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) were used to characterize the grafted copolymers, and the microspheres were prepared from them. FTIR and DSC were also used to analyze the extent of crosslinking. The microspheres were characterized by the particle size; the water transport into these microspheres, as well as the equilibrium water uptake, were studied. Scanning electron microscopy confirmed the spherical nature of the particles, which had a mean particle size of 450 μm. Individual particle dynamic swelling experiments suggested that with an increase in crosslinking, the transport became case II. The release of NFD depended on the crosslinking of the network and on the amount of drug loading. Calculating the drug diffusion coefficients with the initial time and later time approximation method further supported this. The drug release in all 27 formulations followed case II transport, and this suggested that the time dependence of the NFD release followed zero‐order kinetics. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 2940–2949, 2003     

Preparation and characterization of novel semi‐interpenetrating 2‐hydroxyethyl methacrylate‐g‐chitosan copolymeric microspheres for sustained release of indomethacin

A novel semi‐interpenetrating (semi‐IPN) graft copolymer of 2‐hydroxyethyl methacrylate (HEMA) with chitosan (CS) has been prepared in the form of microspheres, using water‐in‐oil (W/O) emulsion technique. Microspheres were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X‐ray diffractometry (X‐RD) to confirm the crosslinking and polymorphism of indomethacin (IDM). The X‐RD and DSC techniques indicated a molecular‐level dispersion of IDM in the IPN matrix. Scanning electron micrographs (SEM) taken at the cross section of the microspheres have shown rough surfaces around the microspheres. The sustained release characteristics of the matrices for IDM, an anti‐inflammatory drug, were investigated in pH 7.4 media. Particle size and size distribution of the microspheres were studied by laser light diffraction particle size analyzer. The drug was released in a sustained manner for up to 12 h. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci, 2006     

Preparation and in vitro release behavior of urapidil hydrochloride loading into microspheres based on poly(L‐lactide)

Microencapsulation of the antihypertensive drug urapidil hydrochloride was investigated as a means of controlling drug release and minimizing or eliminating local side effects. Poly(L ‐lactide) (PLLA) microspheres were prepared using an alternative oil‐in‐water (O/W) solvent‐evaporation method such as the O/W cosolvent solvent‐evaporation method and O/W with various electrolytes added to the aqueous phase method. The surface morphology and the size of the microspheres were observed by scanning electron microscope. Meanwhile, the drug loading efficiency of microspheres and the in vitro release of urapidil hydrochloride from microspheres were performed. The release study indicated that the urapidil hydrochloride‐PLLA microspheres exhibited better sustained release capacity, and the kinetics of urapidil hydrochloride‐PLLA microspheres in vitro release could be described by the Higuchi equation. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

阿司匹林壳聚糖纳米缓释微球的制备及体外释放性能的研究

以自制阿司匹林为药物,壳聚糖为载体,采用乳化-化学交联法制备了阿司匹林-壳聚糖载药微球,确定了阿司匹林-壳聚糖载药微球的制备工艺条件,探讨搅拌速度、阿司匹林/壳聚糖质量比、交联剂戊二醛、乳化剂Span-80用量对微球的药物包封率、载药量和释药性能的影响。研究结果表明,室温条件下,以液体石蜡为介质,选用3%的壳聚糖冰醋酸溶液、按阿司匹林∶壳聚糖=1.5∶1、4%的戊二醛为交联剂、Span-80用量为体积比6%、中等搅拌速度制备出的微球药物包封率可达79%,微球粒径最小可达20 nm,制得的载药微球在16 h内对药物有良好的缓释作用,在25 h之内仍存在缓药效果。     

Self‐assembling chitosan hydrogel: A drug‐delivery device enabling the sustained release of proteins

The development of a self‐assembling hydrogel, prepared from maleimide‐modified and thiolated chitosan (CS), is described. Under mild reaction conditions, the natural CS polymer was coupled with either maleimide or sulfhydryl moieties in a one‐step synthesis. Subsequently, these CS polymers spontaneously formed a covalently crosslinked CS hydrogel when mixed. The three‐dimensional network structure was visualized with scanning electron microscopy. The swelling and degradation behavior was evaluated, and viscosity measurements were conducted. The gel was loaded with the model protein albumin, and prolonged release was achieved. These properties were preserved after lyophilization and rehydration. This makes the hydrogel a promising scaffold for biological wound dressings for the treatment of chronic wounds. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 45638.     

Preparation,characterization, and salicylic acid release behavior of chitosan/poly(vinyl alcohol) blend microspheres

Blend microspheres of chitosan (CS) with poly(vinyl alcohol) (PVA) were prepared as candidates for oral delivery system. CS/PVA microspheres containing salicylic acid (SA), as a model drug, were obtained using the coacervation‐phase separation method, induced by addition of a nonsolvent (sodium hydroxide solution) and then crosslinked with glutaraldehyde (GA) as a crosslinking agent. The microspheres were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC), and scanning electron microscopy. Percentage entrapment efficiency, particle size, and equilibrium swelling degree of the microsphere formulations were determined. The results indicated that these parameters were changed by preparation conditions of the microspheres. Effects of variables such as CS/PVA ratio, pH, crosslinker concentration, and drug/polymer (d/p) ratio on the release of SA were studied at three different pH values (1.2, 6.8, and 7.4) at 37°C. It was observed that SA release from the microspheres increased with decreasing CS/PVA ratio and d/p ratio whereas it decreased with the increase in the extent of crosslinking. It may also be noted that drug release was much higher at pH 1.2 than that of at pH 6.8 and 7.4. The highest SA release percentage was obtained as 100% for the microspheres prepared with PVA/CS ratio of 1/2, d/p ratio of 1/2, exposure time to GA of 5 min, and concentration of GA 1.5% at the end of 6 h. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Drug‐release behavior of chitosan‐g‐poly(vinyl alcohol) copolymer matrix

Chitosan‐g‐poly(vinyl alcohol) (PVA) copolymers with different grafting percent were prepared by grafting water‐soluble PVA onto chitosan. The drug‐release behavior was studied using the chitosan‐g‐PVA copolymer matrix containing prednisolone in a drug‐delivery system under various conditions. The relationship between the amount of the released drug and the square root of time was linear. From this result, the drug‐release behavior through the chitosan‐g‐PVA copolymer matrix is shown to be consistent with Higuchi's diffusion model. The drug‐release apparent constant (K_H) was slightly decreased at pH 1.2, but increased at pH 7.4 and 10 according to the increasing PVA grafting percent. Also, K_H was decreased by heat treatment and crosslinking. The drug release behavior of the chitosan‐g‐PVA copolymer matrix was able to be controlled by the PVA grafting percent, heat treatment, or crosslinking and was also less affected by the pH values than was the chitosan matrix. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 74: 458–464, 1999     

Preparation and release behavior of carboxymethylated chitosan/alginate microspheres encapsulating bovine serum albumin

Microspheres were prepared from carboxymethylated chitosan (CM‐chitosan) and alginate by emulsion phase separation. Their structure and morphology were characterized with IR spectroscopy and scanning electron microscopy. Bovine serum albumin (BSA) was encapsulated in the microspheres to test the release behavior. The swelling behavior, encapsulation efficiency, and release behavior of BSA from the microspheres at different pHs and with a pH‐gradient condition were investigated. The BSA encapsulation efficiency was calculated to be 80%. The degree of swelling of the microspheres without BSA loaded at pH 7.2 was much higher than that at pH 1.0. The encapsulated BSA was quickly released in a Tris–HCl buffer (pH 7.2), whereas a small amount of BSA was released under acid conditions (pH 1.0) because of the strong electrostatic interaction between ? NH₂ groups of CM‐chitosan and ? COOH groups of alginic acid and a dense structure caused by a Ca²⁺ crosslinked bridge. For the simulation of the processing of the drug under the conditions of the intestine, the microspheres were tested in a pH‐gradient medium, in which an acceleration of the release occurred at pH 7.4 after a lag time at a low pH (5.8–6.8). At pH 7.4, a large amount of BSA was released from the microspheres in a short time because of the rapid swelling of the microspheres. However, the release only depended on the diffusion of BSA at relatively low pHs, this resulted in a relatively low release. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 92: 878–882, 2004     

N-mPEG-O-季铵化壳聚糖微球的制备及其载药性能

将聚乙二醇单甲醚（mPEG）醛化改性后,通过西佛碱反应接枝到自制的O-季铵化壳聚糖的NH2上,硼氢化钠还原制得N-mPEG接枝O-季铵化壳聚糖（QACS-mPEG）,反相悬浮法制备二乙烯基砜交联QACS-mPEG微球。用FTIR、1 H NMR、EA和SEM对产物进行表征,并且以酮洛芬为模型药物研究微球的载药性能及释放行为。结果表明,mPEG和季铵盐基团的引入提高了N-mPEG-O-季铵化壳聚糖微球的载药量,为4.31mg/mg;载药N-mPEG-O-季铵化壳聚糖微球在模拟肠液的缓释效果优于胃液,微球释药具有pH响应性。     

Facile preparation of PLGA microspheres with diverse internal structures by modified double‐emulsion method for controlled release

Poly(l ‐lactide‐co‐glycolide) (PLGA) microspheres with diverse internal structures and different release behaviors were prepared via a modified double‐emulsion method by introduction of heparin or carboxymethyl chitosan in the inner aqueous phase and calcium chloride in the outer aqueous phase, respectively. The main factors affecting the microsphere morphology were systematically studied, including compositions in the inner aqueous phase, the oily phase, and the outer aqueous phase. The transmission electron microscope images demonstrated that the microspheres are featured with single core, hollow, and multicore structures when their sizes were less than 200 nm, in the range of 200–700 nm, and greater than 700 nm, respectively. In comparison with hollow PLGA microspheres, the PLGA microspheres with heparin and carboxymethyl chitosan in the inner aqueous phase also showed multicore and single core structures, respectively, and exhibited higher loading efficiencies and slower release rates by using bovine serum albumin as a model for bioactive substances. It was concluded that this study provided a facile method to prepare microspheres with single core, multicore, or hollow feature, and the tunability of the different internal structures and related release profiles enables these systems cater to specific requirements for potential applications in controlled biomolecule delivery for tissue regeneration. POLYM. ENG. SCI., 55:896–906, 2015. © 2014 Society of Plastics Engineers     

Synthesis,characterization, and drug‐release behavior of amphiphilic quaternary ammonium chitosan derivatives

A new type of amphiphilic quaternary ammonium chitosan derivative, 2‐N‐carboxymethyl‐6‐O‐diethylaminoethyl chitosan (DEAE–CMC), was synthesized through a two‐step Schiff base reaction process and applied to drug delivery. In the first step, benzaldehyde was used as a protective agent for the incorporation of diethylaminoethyl groups to form the intermediate (6‐O‐diethylaminoethyl chitosan). On the other hand, NaBH₄ was used as a reducing agent to reduce the Schiff base, which was generated by glyoxylic acid, for the further incorporation of carboxymethyl groups to produce DEAE–CMC. The structure, thermal properties, surface morphology, and diameter distribution of the resulting chitosan graft copolymers were characterized by Fourier transform infrared spectroscopy, ¹H‐NMR, thermogravimetric analysis, differential scanning calorimetry, X‐ray powder diffraction, scanning electron microscopy, and laser particle size analysis. Benefiting from the amphiphilic structure, DEAE–CMC was able to be formed into microspheres in aqueous solution with an average diameter of 4.52 ± 1.21 μm. An in vitro evaluation of these microspheres demonstrated their efficient controlled release behavior of a drug. The accumulated release ratio of vitamin B₁₂ loaded DEAE–CMC microspheres were up to 93%, and the duration was up to 15 h. The grafted polymers of DEAE–CMC were found to be blood‐compatible, and no cytotoxic effect was shown in human SiHa cells in an MTT [3‐(4, 5‐dimethyl‐thiazol‐2‐yl)‐2, 5‐diphenyltetrazolium bromide] cytotoxicity assay. These results indicate that the DEAE–CMC microspheres could be used as safe, promising drug‐delivery systems. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 39890.