Synthesis and characterization of grafting β‐cyclodextrin with chitosan

Two new adsorbents [β‐cyclodextrin–chitosan (β‐CD–CTS) and β‐cyclodextrin‐6–chitosan (β‐CD‐6‐CTS)] were synthesized by the reaction of β‐cyclodextrin (β‐CD) with epoxy‐activated chitosan (CTS) and the sulfonation of the C‐6 hydroxyl group of β‐cyclodextrin with CTS, respectively. Their structures were confirmed by IR spectral analysis and X‐ray diffraction analysis, and their apparent amount of grafting was determined by ultraviolet spectroscopy. The adsorption properties of β‐CD‐CTS and β‐CD‐6‐CTS for p‐dihydroxybenzene were studied. The experimental results showed that the two new adsorbents exerted adsorption on the carefully chosen target. The highest saturated capacity of p‐dihydroxybenzene of β‐CD‐CTS and β‐CD‐6‐CTS were 51.68 and 46.41 mg/g, respectively. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 94: 860–864, 2004     

β‐cyclodextrin‐conjugated hyaluronan hydrogel as a potential drug sustained delivery carrier for wound healing

In order to develop a potential drug sustained delivery carrier suitable for wound healing, a series of β‐cyclodextrin conjugated hyaluronan hydrogels (β‐CD‐HA) with adjustable crosslink densities were synthesized and characterized, meanwhile the delivery kinetics and mechanism of diclofenac as a model anti‐inflammatory drug from these hydrogels were investigated. By controlling the feeding molar ratio of β‐CD/HA, a β‐CD substitution degree of 4.65% was obtained by ¹H‐NMR analysis. The incorporation of β‐CD modification had little effect on the internal porous structure, water swelling ratio, and rheological property of HA hydrogel, which however were influenced by the crosslink density. Although the crosslink density had an influence on the drug loading and release profile by altering the water swelling property, the interaction between β‐CD and drug was the primary factor for the high loading capacity and long‐term sustained delivery of diclofenac. The semiempirical equation fit showed that the release of diclofenac from HA‐based hydrogels followed a pseudo‐Fickian diffusion mechanism. By the aid of β‐CD and controlled crosslink density, a β‐CD‐HA hydrogel with a diclofenac sustained delivery period of over 28 days and desirable physicochemical properties was achieved, which will be a promising drug sustained delivery carrier for wound healing. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43072.     

Preparation and evaluation of chitosan/β‐cyclodextrin magnetic nanoparticles as a photodegradable and hydrophobic drug delivery carrier

In this study, novel tumor targeting nanocarriers comprised of chitosan (CS)/β‐cyclodextrin (β‐CD) magnetic nanoparticles were prepared to improve the photodegradable stability and bioavailability of hydrophobic drug. Resveratrol (Res) with photodegradable and hydrophobic properties was selected as a model drug. The photodegradation rate of Res in Fe₃O₄ nanoparticles solution was 7.8 times lower than that in the ethanol solution_. In addition, the value of the saturation magnetization of CS/β‐CD nanoparticles was found to be 19.56 emu/g with characteristic of superparamagnetism. Approximately 90% Res was entrapped into the CS/β‐CD magnetic nanoparticles with the size distribution ranging from 200 to 359 nm, and the nanoparticles were spherical in shape with high zeta potentials. Furthermore, the formation of CS/β‐CD nanoparticles showed a sustained release in vitro. These results indicated that the obtained CS/β‐CD magnetic nanoparticles were a promising magnetic targeting carrier for photodegradable and hydrophobic drugs. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 45076.     

Adsorption and drug release based on β‐cyclodextrin‐grafted hydroxyapatite composite

In this study, β‐cyclodextrin (β‐CD) was covalently grafted on hydroxyapatite (HA) using a coupling agent to improve the drug loading capacity and prolong the drug release. The binding of β‐CD on the HA surface was confirmed by Fourier transformation infrared spectroscopy, thermal gravimetric analysis, and X‐ray powder diffraction. The adsorption capacity of ofloxacin on β‐CD‐grafted hydroxyapatite (β‐CD‐g‐HA) composite was found to be 30 mg g^?1 at 37°C and 24 h. The adsorption process is spontaneous, given the negative values of free energy change. Compared with the release of ofloxacin loaded on HA, the release of ofloxacin loaded on β‐CD‐g‐HA was slowed down 28% and 21% in pH 2.0 and pH 7.4 buffer media at 2 h, respectively. Biocompatibility of β‐CD‐g‐HA was assessed by MTT assay, and the result showed that it had no cytotoxicity. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

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.     

Poly(ε‐caprolactone) composites containing gentamicin‐loaded β‐tricalcium phosphate/gelatin microspheres as bone tissue supports

In this work, novel antibacterial composites were prepared by using poly(ε‐caprolactone) (PCL) as the main matrix material, and gentamicin‐loaded microspheres composed of β‐tricalcium phosphate (β‐TCP) and gelatin. The purpose is to use this biodegradable material as a support for bone tissue. This composite system is expected to enhance bone regeneration by the presence of β‐TCP and prevent a possible infection that might occur around the defected bone region by the release of gentamicin. The effects of the ratio of the β‐TCP/gelatin microspheres on the morphological, mechanical, and degradation properties of composite films as well as in vitro antibiotic release and antibacterial activities against Escherichia coli and Staphylococcus aureus were investigated. The results showed that the composites of PCL and β‐TCP/gelatin microspheres had antibacterial activities for both bacteria. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Preparation of injectable paclitaxel sustained release microspheres by spray drying for inhibition of glioma in vitro

The major aim of this work was to prepare injectable paclitaxel‐loaded poly(D ,L ‐lactide) microspheres for the inhibition of brain glioma. Paclitaxel‐loaded PLA microspheres were prepared by spray drying method employing ethyl acetate as solvent. And the microspheres were characterized by scanning electron microscopy (SEM) for the morphology and differential scanning calorimetry for thermal analysis. The encapsulation efficiency (EE) and in vitro release profiles of paclitaxel‐loaded microspheres were determined by using ultraviolet spectrophotometer. The results showed that the microspheres possess a narrow size distribution with the average diameter of 4.6 μm. The surface of the microspheres was smooth, and the paclitaxel dispersed in microspheres in amorphous state. The solvent residue was 0.03%, and the EE reaches ～ 90%. The microspheres exhibited a sustained release behavior, and the release period last for at least three months, depending on the EE of the microspheres. The γ irradiation sterilization had little effect on the EE and drug release in vitro. Compared with the commercial formulation, the sustained release microsphere showed a stronger inhibition on the tumor cells, suggesting the potential application of long‐term delivery of paclitaxel‐loaded PLA microspheres in clinic tumor therapy. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

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     

Fabrication and drug release properties of poly(5‐benzyloxy‐trimethylene‐co‐glycolide) microspheres

Poly(5‐benzyloxy‐trimethylene carbonate‐co‐glycolide) random copolymers were synthesized through the ring‐opening polymerization of 5‐benzyloxy‐trimethylene carbonate and glycolide (GA). The copolymers with different compositions, PBG‐1 with 17% GA units and PBG‐2 with 45% GA units, were obtained. Using these copolymers, microsphere drug delivery systems with submicron sizes were fabricated using an “ultrasonic assisted precipitation method.” The in‐vitro drug release from these microspheres was investigated. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Preparation and in vitro characterization of poly(sebacic acid‐co‐ricinoleic acid)‐based tamoxifen citrate‐loaded microparticles for breast cancer

This study was aimed to develop an injectable polymeric drug delivery system for tamoxifen citrate (TC) using poly(sebacic acid‐co‐ricinoleic acid) [poly(SA‐RA) 70 : 30 w/w] as a drug carrier for the treatment of estrogen receptor positive breast cancer. Injectable biodegradable microparticles of TC were produced by solvent displacement technique of microencapsulation and were characterized by surface morphology (scanning electron microscopy), particle size, size distribution, physical and chemical interaction (Fourier transform infrared), nature and physical state of drug [DSC and X‐ray diffraction (XRD)], and in vitro release studies. TC loading over different concentrations was analyzed by high performance liquid chromatography (HPLC) technique. Polyanhydride microparticles obtained after lyophilization were nearly spherical in shape with smooth surface and size less than 2.5 μm. TC was dispersed in the form of amorphous state, and TC remains intact and stable during the process of microencapsulation. In vitro drug release studies demonstrated prolonged controlled release of TC with zero‐order kinetics. Stability studies revealed that the production process of microparticles itself did not affect the chemical stability of the drug and polymer forming the particle matrix. Significant difference in drug release capacity was observed in microparticles with different drug loadings, and the drug release was more sustained in microparticles prepared with high TC. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Synthesis of collagen‐modified polylactide and its application in drug delivery

In this article, collagen modified polylactide (CPLA) was synthesized by means of graft modification, and its structure was confirmed by FTIR and FITC‐labeled fluorescence spectra. Subsequently, the performance of CPLA was characterized with hydrophilicity test and degradability test. After that, the aspirin sustained release microspheres of the synthetic copolymers were prepared via the emulsion‐solvent evaporation technique, followed with its measurements of morphology, size, and encapsulation efficiency. Finally, the controlled release properties of the obtained microspheres were investigated. The results showed that the aspirin sustained release microspheres exhibited well‐defined morphology with smooth spherical surface, with average size of 3.990 μm and encapsulation efficiency of 51.83%. Furthermore, compared with aspirin‐loaded PLA microspheres, at the initial 32 h, the drug release was faster for aspirin‐loaded CPLA microspheres favored by its increased hydrophilicity, and then the drug release was slower than that of PLA microspheres because the ? NH₂ group on the introduced collagen inhibited acidic autocatalytic degradation. The results suggested that CPLA showed a great potential as particles for drug delivery. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Fabrication of citric acid crosslinked β‐cyclodextrin/hydroxyethylcellulose hydrogel films for controlled delivery of poorly soluble drugs

β‐cyclodextrin grafted hydroxyethylcellulose (βCD‐g‐HEC) hydrogel films were prepared for the controlled release of poorly soluble model drug (ketoconazole) using citric acid as crosslinking agent. The active βCD and carboxyl content of the hydrogel films were determined by phenolphthalein assay and acid–base titration. The films were characterized by solid state ¹³C NMR, ATR–FTIR, thermogravimetric analysis, and differential scanning calorimetric, and analyzed for tensile strength, swelling ratio, drug loading, release, hemocompatibility, in vitro cytotoxicity, and implantation test. An increase in the concentration of βCD in feed increased the active βCD content of the hydrogel films but reduced their extent of interpolymer crosslinking. The βCD‐g‐HEC hydrogel films with high active βCD content showed maximum drug loading whereas those with high crosslinking density were capable of controlling the drug release for long duration. Hemolysis assay and in vitro cytotoxicity study revealed the biocompatible nature of the hydrogel films whereas implantation test indicated their minimal inflammatory effect. From the overall results, βCD‐g‐HEC hydrogel films were found to be better alternative to the previously reported βCD‐HPMC and βCD‐CMC hydrogel films for enhanced loading and long‐term release, respectively, of the poorly soluble drugs. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46452.     

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     

Controlled release of recombinant human nerve growth factor (rhNGF) from poly[(lactic acid)‐co‐(glycolic acid)] microspheres for the treatment of neurodegenerative disorders

Recombinant human nerve growth factor (rhNGF)/bovine serum albumin‐loaded microspheres were prepared by a water/oil/water emulsion and solvent evaporation technique with some modifications. The microspheres were characterized with respect to encapsulation efficiency, morphological properties and drug release. Using higher protein/polymer ratios in the primary emulsion resulted in higher protein content in the microspheres. The protein encapsulation efficiency increased from 89.1% to 97.5% on adding poly(ethylene glycol) to the inner aqueous phase. The in vitro rhNGF release lasted for more than 5 weeks. The biological activity of released rhNGF was confirmed by PC12 cell culture. The microspheres maintained a sustained release of rhNGF for at least 4 weeks in the basal forebrain as detected by fluorescence‐labeled and indirect immunofluorescent techniques. These results demonstrated the rhNGF‐containing microspheres are an effective means for delivering this molecule into the brain and their use may be a promising strategy in the treatment of neurodegenerative disorders such as Alzheimer's disease. Copyright © 2007 Society of Chemical Industry     

Biodegradable polymeric injectable implants for long‐term delivery of contraceptive drugs

Development of injectable, long‐lasting, contraceptive drug delivery formulations, and implants are highly desired to avoid unplanned pregnancies while improving patient compliance and reducing adverse side effects and treatment costs. The present study reports on the fabrication and characterization of two levonorgestrel (LNG) microsphere injectable formulations. Poly(?‐caprolactone) (PCL) with 12.5% and 24% (w/w) LNG were fabricated into microspheres, measuring 300 ± 125 µm, via the oil‐in‐water (o/w) emulsion solvent evaporation technique. Formulations showed sustained drug release up to 120 days. FTIR, XRD, DSC, and TGA confirmed the absence of LNG chemical interaction with PCL as well as its molecular level distribution. The in vitro release of LNG was calculated to be Fickian diffusion controlled and properly characterized. The inclusion of multiple elevated release temperatures allowed for the application of the Arrhenius model to calculate drug release constants and representative sampling intervals, demonstrating the use of elevated temperatures for accelerated‐time drug release studies. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46068.     

Evaluating chitosan/β‐tricalcium phosphate/poly(methyl methacrylate) cement composites as bone‐repairing materials

This study related to the preparation of chitosan microspheres by means of reacting chitosan with β‐tricalcium phosphate (β‐TCP) and glutaraldehyde by crosslinking reaction in the oil phase, followed by de‐oil and purification processes to get the product. Three cement composites, Pure P, C1P1, and C2P1, were prepared by the polymerization of poly(methyl methacrylate) (PMMA) bone cement in the presence of 0, 50, and 66.7% chitosan/β‐TCP microspheres, respectively. The result revealed the chitosan/β‐TCP microspheres obtained was in the size range of 50–150 μm. The presence of chitosan/β‐TCP microspheres in the prepared composites decreased the ultimate tensile strength, whereas the modulus remained the same as compared with the commercial PMMA bone cement. Addition of chitosan/β‐TCP microspheres into commercial PMMA cement significantly improved the handling property of the cement paste—that is, the increased setting time and less stickiness behavior of this paste was beneficial, in manipulation, to the operation and easier fittings to the shape and gap of the bony defect and interface. The decreased curing temperature was also less harmful to the surrounding tissues. From scanning electron micrograph observations, chitosan/β‐TCP microspheres can completely mix with bone cement powder and the prepared composites could provide scaffold for osteoblast cells growth and thus improve defects of commercial PMMA bone cement. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 3897–3904, 2003     

Investigation on preparation and protein release of biodegradable polymer microspheres as drug‐delivery system

Among the different approaches to achieve protein delivery, the use of polymers, especially biodegraded, holds great promise. This work aimed to study the preparation and protein release of a novel drug‐delivery system based on human serum albumin (HSA) encapsulated into biodegradable polymer microspheres. The microspheres containing HSA were elaborated by the solvent‐extraction method based on the formation of multiple w/o/w emulsion. The encapsulation efficiency (E.E.) of HSA was determined by the CBB method. Alginate/alginate and calcium chloride was added into an internal aqueous phase to investigate the protein loading efficiency, protein stability, and in vitro release profiles. Microspheres were characterized in terms of their morphology, size distribution, loading efficiency, and in vitro protein release. SDS–PAGE results showed that HSA kept its structural integrity during the encapsulation and release procedure. In vitro studies indicated that the microspheres with alginate added in the internal aqueous phase had a smaller extent of burst release. In conclusion, the work presents a new approach for macromolecular drugs (such as protein drugs, vaccines, and peptide drugs) delivery. © 2002 John Wiley & Sons, Inc. J Appl Polym Sci 84: 778–784, 2002; DOI 10.1002/app.10327     

Preparation of novel amphiphilic copolymer microspheres and their drug‐release and glucose‐sensitive properties

A novel amphiphilic copolymer was prepared by the copolymerization of N‐acryloyl‐3‐aminophenylboronic acid with β‐cyclodextrin containing maleic anhydride. The copolymer was fully characterized with ¹³C‐NMR, ¹H‐NMR, IR, and scanning electron microscopy. The self‐assembling mechanism of the copolymer in H₂O–CH₃OH cosolvents was studied. Gliclazide as a model drug was loaded inside the copolymer microspheres, and the drug‐release behavior of the microspheres was studied. The results of in vitro oscillating release tests indicated that the microspheres responded to glucose rapidly in 30 min, and the microspheres exhibited self‐regulated on–off release behavior four to six times in 6 h between the solution with 3 g/L glucose and the medium without glucose; this met the clinical requirements of multidrug delivery. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

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     

Novel thermo‐responsive semi‐interpenetrating network microspheres of gellan gum‐poly(N‐isopropylacrylamide) for controlled release of atenolol

Thermoresponsive microspheres of gellan gum‐poly(N‐isopropylacrylamide), i.e., GG‐P(NIPAAm) semi‐interpenetrating polymer networks (semi‐IPNs) have been prepared by ionic crosslinking and used to study the controlled release (CR) of atenolol (ATL), an antihypertensive drug. Interaction of the drug with polymers was studied by Fourier transform infrared (FTIR) spectroscopy. Differential scanning calorimetry (DSC) was used to confirm the polymorphism and molecular level dispersion of ATL. Scanning electron microscopy (SEM) indicated spherical nature and smooth surfaces of the microspheres with some debris attached on their surfaces. Mean particle size measured by laser light diffraction ranged between 34 and 76 μm. Equilibrium swelling performed at 25°C and 37°C in pH 7.4 phosphate buffer exhibited thermoresponsive nature of the polymers. In vitro drug release performed at 25°C and 37°C indicated temperature‐dependency of ATL release, which was extended up to 12 h. In vitro release profiles at both the temperatures confirmed thermoresponsive nature of the polymers giving pulsatile trends. The % cumulative release data have been fitted to an empirical equation to estimate transport parameters and to understand the nature of drug release. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010