Preparation, characterization, swelling and in vitro drug release behaviour of poly[N-acryloylglycine-chitosan] interpolymeric pH and thermally-responsive hydrogels

Novel biodegradable pH- and thermal-responsive interpenetrating polymer network (IPN) hydrogels were prepared for controlled drug delivery studies. The IPN hydrogels were obtained in mild aqueous acid media by irradiation of solutions of N-acryloylglycine (NAGly) mixed with chitosan, in the presence of glutaraldehyde as a crosslinking agent and using 2,2-dimethoxy-2-phenyl acetophenone as photoinitiator. These hydrogels were subjected to equilibrium swelling studies at different temperatures (25 °C, 37 °C and 45 °C) in buffer solutions of pH 2.1 and 7.4 (similar to that of gastric and intestinal fluids respectively). 5-Fluorouracil (5-FU) was entrapped in the hydrogels, and drug release studies carried out at 37 °C in buffer solutions at pH 2.1 and 7.4.     

Poly[(N-isopropylacrylamide-co-acrylamide-co-(hydroxyethylmethacrylate))] thermoresponsive microspheres: An accurate method based on solute exclusion technique to determine the volume phase transition temperature

Poly[(N-isopropylacrylamide-co-acrylamide-co-(hydroxyethylmethacrylate))] [poly(NIPAAm-co-AAm-co-HEMA)] copolymer was synthesized as a new thermoresponsive material possessing a lower critical solution temperature (LCST) around 37 °C in phosphate buffer, pH 7.4, at a solution concentration of 1%, w/v. The influence of polymer concentration on LCST was determined by cloud point measurements and by microcalorimetric analysis. The copolymer was transformed in hydrogel microspheres by suspension reticulation of OH groups with glutaraldehyde. The volume phase transition temperature (VPTT) of microspheres was determined by a new approach, which involves measurement of the increase in concentration of a blue dextran (BD) solution at different temperatures in the presence of dry microspheres. The minimum BD concentration that gives reliable and reproducible results was determined to be 1 mg/ml. However, the higher is the concentration of BD in solution the smaller is the error. Contrary to solution of the linear polymer which displays a sharp phase transition temperature, the dependence of water regain of the hydrogel with temperature lasts from 4 °C to 50 °C.     

Preparation of chitosan scaffolds loaded with dexamethasone for tissue engineering applications using supercritical fluid technology

Supercritical fluid impregnation was tested to prepare a new scaffold loaded with a bioactive compound. Dexamethasone is used in osteogenic media to direct the differentiation of stem cells towards the osteogenic lineage. Dexamethasone was impregnated in chitosan scaffolds at different operating conditions, in order to optimize the impregnation process. Pressure and temperature affect the carbon dioxide density and influence the swelling of the polymer and the drug solubility in the fluid phase, therefore these are two important parameters that were studied in this work. Chitosan sponges prepared by freeze drying were impregnated with the active compound at pressures from 8.0 up to 14.0 MPa and temperatures from 35 up to 55 °C. The effect of the impregnation contact time (3 h and 6 h) was also evaluated. From the experiments performed we can conclude that the yield of impregnation is lower when increasing pressure and temperature. The contact time will mainly influence the amount of drug impregnated in the scaffold and for higher contact times the impregnation yield is also higher. Scanning electron microscopy shows particles of dexamethasone in the bulk of the scaffold, which confirms the feasibility of the supercritical fluid impregnation technology for the preparation of delivery devices. The loading capacity of the scaffolds was determined by spectroscopic analysis and the highest loading was achieved for the experiments performed at 8.0 MPa and 35 °C. Furthermore, in vitro drug release studies were carried out and the results show that dexamethasone was sustainably released. Supercritical fluid impregnation proved to be feasible for the preparation of a drug delivery system for bone tissue engineering purposes.     

Synthesis, characterization and in vitro degradation of a novel degradable poly((1,2-propanediol-sebacate)-citrate) bioelastomer

Degradable bioelastomers represent a useful class of biomaterials. In this paper, a novel biodegradable network of elastomeric polyesters, poly((1,2-propanediol-sebacate)-citrate) (PPSC), was synthesized by condensation of 1,2-propanediol, sebacic acid and citric acid without any catalyst. An oligomeric diol of 1,2-propanediol-sebacate was first synthesized by carrying out a controlled condensation reaction between 1,2-propanediol and sebacic acid, and then a pre-polymer was synthesized by condensation of the diol and citric acid, whereat the pre-polymer was post-polymerized and simultaneously crosslinked in mold at 120 °C. A series of PPSC polymers were prepared at different post-polymerization times and different monomers' ratio. T_g confirms that PPSC is totally amorphous at 37 °C. The mechanical properties of PPSC testified that the new polymers are typical elastomers with low hardness and large elongation. The different post-polymerization times and monomers' ratio had strong influence on the degradation rates and mechanical performances. The material was expected to be useful for drug controlled delivery, tissue engineering scaffold and other biomedical applications.     

Synthesis, characterization and in vitro degradation study of a novel and rapidly degradable elastomer

Biodegradable elastomers represent a useful class of biomaterials. In this paper, a novel biodegradable elastomer, poly(PEG-co-CA) (PEC), was synthesized by condensation of poly(ethylene glycol) (PEG) and citric acid (CA) under atmospheric pressure without any catalyst. We first synthesized a pre-polymer by carrying out a controlled condensation reaction between PEG and citric acid, and then post-polymerised and simultaneously cross-linked the pre-polymer in the mould at 120 °C. The pre-polymer was characterized by FT-IR, ¹H NMR, ¹³C NMR, GPC and DSC. A series of polymers were prepared at different post-polymerisation time and different monomer ratios. Measurements on the mechanical properties of PEC testified that the new polymers are elastomers with low hardness and big elongation, and hydrolytic degradation of the polymer films in a buffer of pH 7.4 at 37 °C showed that PEC had excellent degradability (all the films show the weight losses more than 60% after 96 h incubation). The different post-polymerisation time and monomer ratio had strong influence on the degradation rates and mechanical performances. The material is expected to be useful for controlled drug delivery and other biomedical applications.     

Evaluation of retention and release processes of two antibiotics from the biocompatible core-shell microparticles

By dropwise addition of a chitosan solution into different non-solvent, such as: 1 N and 2 N NaOH as well as 1 N NaOH: C₂H₅OH mixture (2:1, v/v) at temperature of 25 °C and 50 °C under stirring, the spherical pure chitosan microparticles were performed. As solvents for chitosan was used 0.1 N acetic acid or 0.1 N HCl. The immersion of the pure chitosan microparticles in hyaluronan solution led to complex microparticles, namely chitosan microparticles covered by a hyaluronan layer. For all the microparticles performed the behaviours in the retention process of two antibiotics: chloramphenicol succinate sodium salt and cefotaxime sodium salt were analyzed. Also, the study shows the release behaviour of cefotaxime sodium salt by the microparticles loaded with this drug. Among the microparticles performed a type of complex microparticles can be considered a suitable drug delivery system for cefotaxime. These microparticles were performed by dropwise addition of chitosan solution in 0.1 N acetic acid into the 1 N NaOH: C₂H₅OH (2:1, v/v) non-solvent at 20 °C for 3 h, followed by their washing up to alkalinity loss and the immersion in hyaluronan solution of 10 g/L concentration for 24 h.     

Radiation synthesis of poly[(dimethylaminoethyl methacrylate)-co-(diallyl dimethyl ammonium chloride)] hydrogels and its application as a carrier for notoginsenoside delivery

Novel pH/temperature sensitive hydrogel was synthesized by radiation induced copolymerization and cross-linking of dimethylaminoethyl methacrylate (DMAEMA) and diallyldimethyl ammonium chloride (DADMAC). Reactivity ratio of DADMAC (r₁) and DMAEMA (r₂) was determined as 1.02 and 0.98, which means that poly(DMAEMA-co-DADMAC) is an azeotropic copolymer. Content of DADMAC, i.e., charge density of the hydrogel was found to influence their properties significantly. Compared with polyDMAEMA hydrogel, poly(DMAEMA-co-DADMAC) showed enhanced equilibrium degree of swelling (EDS). Low critical solution temperature (LCST) of the hydrogel increased with the charged density. Content of DADMAC had no effect on the pH dependence of the final gel. Aiming at its application as a carrier for Chinese herb extract delivery system, the embedment and pH/temperature dependence of controlled release were investigated using notoginsenoside as a model drug. The maximum embedment amount of notoginsenoside was obtained in a gel containing 3 mol.% DADMAC. The temperature dependence and pH dependence of notoginsenoside release followed the same trend as that of EDS, for instance, higher ratio of notoginsenoside release occurred at 25 °C and pH 1.7, at which higher EDS was obtained. By these means, the release of notoginsenoside can be controlled by adjusting the pH, ionic strength, temperature of solution as well as the composition and structure of the gel.     

Surface modification by deposition of IPA plasma and gellan gum/chitosan hybrid hydrogel onto thermoplastic polyurethane for controlled release of N‐acetylcysteine

A thin film system composed of gellan gum and chitosan was fabricated through a combination of polyelectrolyte blend and hybrid hydrogel gelation for controlled release of drug. In this study, precursor isopropyl alcohol (IPA) was used to plasma deposit on the surface of thermoplastic polyurethane (TPU) to form a hydrophilic film. The features of the thin film were evaluated using water contact angle (WCA) measurement, scanning electron microscopy (SEM), Fourier transform infra‐red (FTIR), UV/Vis spectroscopy, and studies of controlled release of drugs. The hybrid hydrogel, pH‐sensitive, was tested at pH values of 1.2 and 7.4 of buffer solution and at a temperature of 37°C to observe its swelling ratio and drug delivery properties with N‐acetylcysteine as a drug material for controlled release. Furthermore, at pH 7.4, the hybrid hydrogel has an outstanding release ratio of up to about 90% absorption amounts of N‐acetylcysteine after 8 hr. The mechanism of drug release from thin film devices (n = 0.684) is anomalous (non‐Fickian) transport, the value of n lies between 0.43 and 0.85.     

Frontal polymerization synthesis and drug delivery behavior of thermo-responsive poly(N-isopropylacrylamide) hydrogel

Thermo-responsive hydrogels of poly(N-isopropylacrylamide) (PNIPAm) were prepared by fontal polymerization and investigated as a temperature-triggered delivery device for the model drug aspirin. The influence of relative amount of reactant components on the feature of the polymerization front was studied. Furthermore, aspirin was loaded into hydrogels prepared by fontal polymerization method and classical polymerization, respectively, and its release characteristics were determined under different temperature conditions (25 °C and 37 °C). The drug storages and kinetic parameters for two hydrogels indicated that drug-loading capacity and drug release of frontal polymerization (FP) hydrogel were improved as compared with the classical polymerization (CP) one. Scanning electronic microscope and differential scanning calorimetry (DSC) results could account for these improvements in drug delivery for FP hydrogel. The above results indicate that FP can be an alternative method for the preparation of PNIPAm hydrogels used as drug delivery devices with less time consuming and easier protocols.     

Lower critical solution temperature control and swelling behaviour of physically crosslinked thermosensitive copolymers based on N-isopropylacrylamide

In this contribution we have developed thermosensitive polymer matrices based on N-isopropylacrylamide (NIPAAm). Preparation of the hydrogels involved photopolymerisation of a combination of NIPAAm, 1-vinyl-2-pyrrolidinone (NVP) and distilled water, in appropriate amounts and contained a UV-light sensitive initiator called 1-hydroxycyclohexylphenylketone. As NIPAAm monomer could be readily dissolved in mixtures of liquid NVP and distilled water, the use of organic solvents was not required in the polymerisation process. Furthermore, chemical crosslinking agents are not needed in the synthesis. By alternating the feed ratio, hydrogels were synthesised to have lower critical solution temperatures (LCST) in the vicinity of 37 °C. This ability to shift the phase transition temperature of the gels provides excellent flexibility in tailoring transitions for specific uses. The transition temperature of the pseudo gels was established using cloud point measurement and modulated differential scanning calorimetry (MDSC). The chemical structure of the xerogels was characterised by means of Fourier transform infrared spectroscopy (Ftir), while swelling experiments in distilled water indicate that the swelling and dissolution behaviour of the gels is strongly temperature dependent.     

Allylic monomers as reactive plasticizers of polyphenylene oxide. Part III – Rheological and mechanical properties

The chemorheology of blends of diallyl ortho-phthalate (DAOP) as reactive plasticizer of polyphenylene oxide (PPO) were monitored during their cure with either dicumyl peroxide (DCP) or tert-butyl hydroperoxide (TBHP), and their mechanical properties and morphology were studied. The steady shear and dynamic rheology behaviour was consistent with chemical gelation of DAOP in blends with low concentrations of PPO but the gelation behaviour at higher PPO concentrations was more complex. Dynamic mechanical thermal analysis of the blends of PPO:DAOP cured with either DCP or TBHP indicated a two phase structure. For PPO:DAOP/DCP, the lowest transition (between 150 °C and 200 °C) was attributed to a DAOP-rich phase and its T_g was higher than that for pure DAOP/DCP due to the presence of PPO in the DAOP-rich phase. The smaller damping shoulder near 250 °C was caused by a PPO-rich phase with a T_g that was lower than pristine PPO due to the presence of unpolymerized or polymerized DAOP. In contrast, the glass transition region of the PPO:DAOP/TBHP system was very broad due to an overlap of the transitions for DAOP-rich and PPO-rich phases caused by higher levels of unpolymerized DAOP. SEM observations of the blends revealed a two phase morphology with PPO-rich particles in a poly-DAOP matrix for blends with ?30 wt% PPO, a co-continuous morphology for blends with 40 wt% PPO, and a phase inverted morphology with more than 50 wt% PPO. These SEM observations agree with studies of the swelling, disintegration or dissolution of matrix of the blends in solvent.     

Novel nano-porous hydrogel as a carrier matrix for oral delivery of tetracycline hydrochloride

A novel nano-porous hydrogel (NPH) was synthesized via graft copolymerization of sodium acrylate (Na-AA) and acrylamide (AAm) onto salep backbones and its application as a carrier matrix for oral delivery of tetracycline hydrochloride (TH) was investigated. The Taguchi method as a strong experimental design tool was used for synthesis optimization. The swelling behavior of optimum hydrogel was measured in various media. The hydrogel formation was confirmed by Fourier transform infrared spectroscopy (FT-IR) and thermogravimetrical analysis (TGA). The study of the surface morphology of the hydrogels using SEM and AFM showed a nanoporous (average pore size: 180 nm) structure for the sample obtained under optimized conditions. The drug delivery results demonstrated that this NPH could successfully deliver a drug to the intestine without losing the drug in the stomach, and could be a good candidate as an orally administrated drug delivery system.     

Synthesis and properties of biodegradable thermo- and pH-sensitive poly[(N-isopropylacrylamide)-co-(methacrylic acid)] hydrogels

Thermo- and pH-sensitive hydrogels were synthesized via the copolymerization of N-isopropylacrylamide (NIPAAm) and methacrylic acid (MAA) crosslinked with a biodegradable PEG-co-PCL macromolecular crosslinker under UV irradiation. Swelling measurements showed that temperature and pH sensitivity of the resultant hydrogels were highly dependent on the composition of the hydrogels as well as temperature and pH of the local medium. The pH and temperature dependence of the hydrogels displayed good reversibility. The hydrolytic degradation studies showed that the degradation rate of the hydrogels increased with the increasing content of MAA introduced in the hydrogels in pH 7.4 PBS solutions at 37 °C. The study on the release of BSA indicated that the release rate of BSA was higher at pH 7.4 than at pH 2.0, and increased with the increase of the MAA content in the hydrogels in pH 7.4 PBS solutions at 37 °C. These hydrogel materials are desirable for potential applications as smart drug delivery systems.     

Immobilization of camptothecin with surfactant into hydrogel for controlled drug release

A new strategy has been developed for the controlled release of a hydrophobic anticancer drug, camptothecin (CPT), which suffers a limited therapeutical utility because of its poor water solubility. CPT was first solubilized in the solution of a cationic surfactant, dodecyltrimethylammonium bromide (DTAB). It has been demonstrated that the presence of DTAB has increased the solubility of CPT significantly. In a 50 mM DTAB solution, the drug’s solubility was enhanced to 85 μM, 22 times of its solubility in pure water. The micellar drug solution of CPT-DTAB was subsequently used to prepare agarose hydrogels, which act as the drug carriers in the release studies. To fully take advantage of the cationic property of DTAB, negatively charged κ-carrageenan was added as a guest polymer in some hydrogel samples. The release of CPT from these hydrogel-surfactant systems was performed at 37 °C and the effects of DTAB and κ-carrageenan on the release of CPT were studied respectively. By fitting to the well-known Fickian diffusion model, the diffusion coefficients of CPT were obtained.     

Preparation and characterization novel polymer-coated magnetic nanoparticles as carriers for doxorubicin

The poly(lactide-co-glycolide)-coated magnetic nanoparticles (PLGA MNPs) were prepared as carriers of doxorubicin (PLGA-DOX MNPs) through water-in-oil-in-water (W/O/W) emulsification method. The characteristics of PLGA-DOX MNPs were measured by using transmission electron microscopy (TEM) and vibrating-sampling magnetometry (VSM). It was found that the synthesized nanoparticles were spherical in shape with an average size of 100 ± 20 nm, low aggregation and good magnetic responsivity. Meanwhile, the drug content and encapsulation efficiency of nanoparticles can be achieved by varying the feed weight ratios of PLGA and DOX particles. These PLGA-DOX MNPs also demonstrated sustained release of DOX at 37 °C in buffer solution. Besides, influence of drug-loaded nanoparticles on in vitro cytotoxicity was determined by MTT assay, while cellular apoptosis was detected by Annexin V-FITC apoptosis detection kit. The results showed that PLGA-DOX MNPs retained significant antitumor activities. Therefore, PLGA-DOX MNPs might be considered a promising drug delivery system for cancer chemotherapy.     

Swelling and hydrolytic degradation of poly(d,l-lactic acid) in aqueous solutions

Low molecular weight poly(lactic acid) was synthesized by direct polycondensation of lactic acid. The oligomers were characterized by viscometry, light scattering, and gel permeation chromatography (GPC). The swelling behaviour of tablets made of the above polymer immersed in buffer solutions at 37 °C was studied. In the same experiments, the hydrolytic stability of d,l-PLA was assessed by measuring the weight loss after drying the tablets. In order to inhibit any degradation due to bacteria, formaldehyde was added in the solution as biostatic factor. The effect of an incorporated drug on the swelling behaviour of d,l-PLA tablets was also considered. It was found that the incorporation of drug in d,l-PLA tablets increases their swelling index, probably due to the creation of additional porosity in the specimens or other interaction between drug and polymeric matrix.     

Polyvinylpyrrolidone–polycaprolactone block copolymer micelles as nanocarriers of anti-TB drugs

A range of polyvinylpyrrolidone–polycaprolactone diblock copolymers with varying chain lengths were synthesized by Atom Transfer Radical Polymerisation (ATRP) using bromo-polycaprolactone as macroinitiator and copper(I) bromide/bipyridine catalytic system. The copolymers self-assembled in solution into core–shell micelles with sizes varying from 150 to 205 nm and critical micelle concentration of the order of 10⁻⁵ to 10⁻⁶ M. Front line anti-Tuberculosis drugs Rifampicin (RIF), Pyrazinamide (PZA) and Isoniazid (INH) were successfully encapsulated within the micelle hydrophobic core singly or in dual combination. The effect of length of hydrophobic and hydrophilic segments on drug loading, micelle size and drug release was investigated. Determination of binding constants showed that RIF binds more strongly to the micelle core than PZA and INH, leading to highest drug loading content. All drugs were released in vitro (PBS solution at 37 °C) in a sustained manner with zero-order kinetics and followed the order INH > PZA > RIF.     

Sustained release drug delivery using supramolecular hydrogels of the triblock copolymer PCL–PEG–PCL and α-cyclodextrin

Supramolecular hydrogels (SMGel) have attracted much attention as a drug and gene delivery system in recent years. In this study, SMGels based on the tri-block copolymer of poly-ε-caprolactone–polyethylene glycol–poly-ε-caprolactone (PCL–PEG–PCL) and α-cyclodextrin (α-CD) were prepared and evaluated for the delivery of two model drugs, naltrexone hydrochloride and vitamin B₁₂. Tri-block copolymers were synthesized easily in 15 min by ring-opening polymerization using the microwave irradiation technique, and their structures were determined by gel permeation chromatography and nuclear magnetic resonance methods. SMGels composed of various concentrations of the copolymer and α-CD were prepared and characterized for their rheological behaviour, their gel formation time and in vitro drug release profile. The results indicated that copolymers with a PCL to PEG ratio of 1:4 are suitable for SMGel preparation. The most viscose system with good syringeability was prepared by mixing 12 % wt α-CD and 10 % wt of copolymer. The gelation was found to occur within a minute after mixing. The viscosity of the hydrogel systems was determined as a function of shear rate. Finally, in vitro B₁₂ release through the hydrogel systems was studied. Up to 80 % of Vitamin B₁₂ was released through this system during a period of 20 days. Rheological evaluation revealed that the hydrogel has shear thinning properties, and the system regained its ground rheological state in a time dependent manner. Polymer concentration did not affect the drug release profiles. Finally, it was concluded that such systems are appropriate drug delivery systems due to their ability to provide a controlled drug release profile and their shear thinning thixotropic behaviour, which makes them syringeable and injectable.     

Enthalpies of mixing of liquid alloys in the In-Pd-Sn system and the limiting binary systems

The partial and integral enthalpies of mixing of molten binary In-Pd (up to about 29 at.% Pd), In-Sn (entire compositional range) and Pd-Sn (up to about 53 at.% Pd) alloys were determined at 900 °C. A Calvet-type microcalorimeter was used for the measurements employing a drop calorimetric technique. Additionally, five sections in the ternary In-Pd-Sn system (compositions up to about 40 at.% Pd) were investigated at 900 °C. The ternary interaction parameters were fitted using the Redlich-Kister-Muggiano model for substitutional solutions. The isoenthalpy curves for In-Pd-Sn at 900 °C were constructed for the integral molar enthalpy of mixing. Furthermore, the experimental results in the ternary system were compared with calculated values obtained by employing different binary extrapolation models.     

The Research on Intelligent Controlled DDS of Polymer Carrier

The intelligent controlled drug delivery systems (DDS) are a series of the preparations including microcapsules or nanocapsules composed of intelligent polymers and medication. The properties of preparations can change with the external stimuli, such as pH value, temperature,chemical substance, light, electricity and magnetism etc. According to this properties, the DDS can be intelligently controlled. This paper has reviemed research on syntheses and applications of intelligent controlled DDS of polymer carriers.Drug delivery system with pH stimuliThe volume of polymer hydrogel can change with the pH value of external environment. The sensitive polymer hydrogels to pH are often as carriers. The polymer hydrogel carrying medicine is especially suitable for taking orally. In order to protect medicine from losing activation, we enwrapped medicine into polymer hydrogel with acidic group. In the acidic environment of stomach,the volume of polymer hydrogel contracts because of the hydrogen bond. The medicine in the polymer hydrogel cannot disperse out. When it goes to the intestine of basic environment, the hydrogen bond will be broken, and the medicine can release.Drug delivery system with temperatureTemperature sensitive polymer hydrogel can change its volume with changing of environmental temperature. This kind of polymer hydrogel can be also used as a carrier of medicine. At a low temperature, the polymer chains form hydrogen bond with water to swell to let medicine disperse out from the hydrogel. On the other hand, the hydrogen bond will be broken and polymer chain will lose water to contract with temperature's increasing. And the medicine will not disperse out. For example,the poly(N-isopropylacrylamide)(PNIPAAm) is the hydrogel that is swelled at lower temperature and contracted at higher temperature. PNIPAAm has the lower critical solution temperature(LCST).We can adjust its LCST to control PNIPAAm hydrogel's swelling or contraction to let medicine release or not.Drug delivery system with other stimuliThe polymer carrier drug delivery system can be intelligently controlled with the stimuli of pH value and temperature. In addition, there are still some other stimuli for DDS. For example, DDS with light; DDS with electricity(or electric field); DDS with magnetism(magnetic field); DDS with chemical substance; etc. The characteristic of intelligent polymer carrier is based on P.J.Flory's gel-swelling theory. Intelligent polymer carrier DDS will be widely used in biological and medical fields.