Effect of Ionic Concentration on Drug Release from Polyelectrolyte Hydrogel Carriers Analyzed via Triphasic Mechanism Model

In different parts of the gastrointestinal tract, the rate of drug release from polyelectrolyte hydrogel tablets is highly affected by variance of ionic concentration. This research aims at revealing clearly how the drug release from a hydrogel matrix is affected by ionic concentration of external solution through the finite element simulation and triphasic mechanism model. The coupled relationship of the motions including the polyelectrolyte hydrogel swelling, the water flow and the ion diffusion, is illustrated in the present work. In order to simulate the drug controlled release from a swollen polyelectrolyte hydrogel carrier, the mathematical model was built on the basis of the multiphasic theory of polyelectrolyte hydrogels. Finally, the reliability of the simulation method was verified qualitatively by experimental results. The results reveal that when the initial concentration of fixed anions of polymer network is higher than the concentration of free anions in the external solution, the drug release rate increases with increasing the ionic concentration of the external solution. The research is helpful for the optimal design of oral drug release in gastrointestinal tract.     

Molecular Imprinting of Cyclodextrin Supramolecular Hydrogels Improves Drug Loading and Delivery

Cyclodextrin‐based controlled delivery materials have previously been developed for controlled release of different therapeutic drugs. In this study, a supramolecular hydrogel made from cyclodextrin‐based macromonomers is subjected to molecular imprinting to investigate the impact on release kinetics and drug loading, when compared with non‐imprinted, or alternately imprinted hydrogels. Mild synthesis conditions are used to molecularly imprint three antibiotics—novobiocin, rifampicin, and vancomycin—and to test two different hydrogel chemistries. The release profile and drug loading of the molecularly imprinted hydrogels are characterized using ultraviolet spectroscopy over a period of 35 days and compared to non‐imprinted, and alternately imprinted hydrogels. While only modest differences are observed in the release rate of the antibiotics tested, a substantial difference is observed in the total drug‐loading amount possible for hydrogels releasing drugs which has been templated by those drugs. Hydrogels releasing drugs which are templated by other drugs do not show improved release or loading. Analysis by FTIR does not show substantial incorporation of drug into the polymer. Lastly, bioactivity assays confirmed long‐term stability and release of incorporated antibiotics.     

Chondroitin/polypyrrole nanocomposite hydrogels for the accurate release of 5-fluorouracil by electrical stimulation

The development of electro-stimulated drug release devices is an innovative approach to attain the drug delivery in accurate doses at target sites in a programmed manner. In this work, novel electroactive nanocomposite hydrogels were prepared by encapsulating green-synthesized polypyrrole (PPy) colloids within chondroitin sulfate (CS) networks during the self-crosslinking of CS via N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide chemistry. The structural and morphological properties of CS/PPy hydrogels were studied by Fourier-transformed infrared spectroscopy, scanning electron microscopy, and swelling kinetic measurements. The chemotherapeutic agent 5-fluorouracil (5-FU) was loaded into CS/PPy samples by hydrogel swelling method, or alternatively, by pre-incubating the drug in polymer mixture before crosslinking. Different electrical stimulations can be used to switch ON and accurately tune the 5-FU delivery from GG/PPy hydrogels. A single pulse potential of 5 V switched on the drug delivery up to 90% from nanocomposite hydrogel, in contrast to the low 5-FU amount released in a passive form (< 20%). PPy electroactive behavior played a determining role as the main driving force in 5-FU release activation. Cytotoxicity of hydrogels with and without 5-FU was examined in normal and cancer cells. Considering the high cytotoxicity of 5-FU, the ON/OFF 5-FU release patterns evidenced the potential of CS/PPy hydrogels for electrically controlled drug delivery in implantable or transdermal drug release devices.     

Polymeric hydrogels with memory effect for immobilization of binary drug combinations

Hydrogels with memory effect (imprinted hydrogels) with respect to a combination of cefotaxime and diclofenac were synthesized from 2-hydroxyethyl methacrylate and functional monomers (acrylic acid and N,N-dimethylacrylamide). The hydrogels obtained show increased ability to sorb cefotaxime and especially diclofenac. Prolonged release of cefotaxime was revealed, becoming more pronounced with an increase in the cefotaxime concentration in the solution from which it is sorbed with the hydrogel. The effect of selective sorption of diclofenac with imprinted hydrogels from the diclofenac-cefotaxime drug combination was discovered.     

Modification of Dietary Fiber Psyllium with Poly(vinyl pyrrolidone) through Network Formation for Use in Slow Drug Delivery Application

In view of the pharmacological importance of dietary fibre, psyllium, to cure the constipation and diverticulitis, in the present study, an attempt has been made to modify psyllium polysaccharide with PVP to develop the hydrogel meant for slow and controlled drug delivery systems. The polymer was characterized by SEMs, FTIR, XRD, TGA and swelling studies. Swelling of hydrogels and drug (ciprofloxacin) release profile from the drug loaded hydrogels were determined for the evaluation of the swelling/release mechanism. Biomedical properties; biocompatibility and mucoadhesion of the hydrogels, were also studied. Swelling of the hydrogels and release of drugs from drug loaded hydrogels occurred through non-Fickian diffusion mechanism. Here it is pertinent to mention that both psyllium husk polysaccharide and antibiotic drug ciprofloxacin are used for gastrointestinal tract (GIT) problem, especially in case of diverticulitis. Hence, degradation of the polymer matrix and release of drug may exert the synergic effect and the present drug delivery system may act with enhanced potential.     

Three-dimensional porous HPMA-co-DMAEM hydrogels for biomedical application

The aim of this work is to develop a novel biocompatible drug delivery carrier and tissue engineering scaffold with the ability of controlled drug release and also tissue regeneration. We have synthesized N-(2-hydroxypropyl)methacrylamide and 2-(dimethylamino)ethyl methacrylate copolymer-based hydrogels loaded with doxorubicin and tested in vitro. The manifestation of temperature sensitivity is noted with a sharp decrease or increase in hydrogel optical transparency that happens with the temperature exceeding a critical transition value. The drug release profile exhibited pH-sensitive behavior of the hydrogel. The hydrolytic degradation of gel and in vitro studies of polymer–doxorubicin conjugate and doxorubicin release from hydrogel matrix indicated that hydrogels were stable under acidic conditions (in buffers at pH 4.64 and 6.65). In both drug forms, polymer–doxorubicin conjugate and free doxorubicin could be released from the hydrogel scaffold at a rate depending directly on either the rate of drug diffusion from the hydrogel or rate of hydrogel degradation or at rate controlled by a combination of the both processes. In vitro analysis showed homogenous cell attachment and proliferation on synthesized hydrogel matrix. In vivo implantation demonstrated integration of the gel with the surrounding tissue of mice within 2 weeks and prominent neo-angiogenesis observed in the following weeks. This multifunctional hydrogels can easily overcome biological hurdles in the in vivo conditions where the pH range changes drastically and could attain higher site-specific drug delivery improving the efficacy of the treatment in various therapeutical applications, especially in cancer therapy, and could also be used as tissue engineering scaffold due to its porous interconnected and biocompatible behavior.     

Thermosensitive molecularly imprinted hydrogel cross‐linked with N‐malely chitosan for the recognition and separation of BSA

A novel temperature‐sensitive molecularly imprinted hydrogel composed of N‐isopropylacrylamide and acrylamide has been prepared by using free‐radical polymerization and was cross‐linked by modified water‐soluble N‐maley chitosan in aqueous solution. BSA (pI 4.9, MW 66.0 kDa) was used as the template protein. The produced hydrogels were characterized by environmental SEM to reveal the microcosmic morphology. A microporous structure was only found in the imprinted hydrogel, while no obvious microporous structure was found in nonimprinted hydrogels. The lower critical solution temperature of the hydrogels was 34°C, and the optimal binding conditions were tested, namely, the adsorption equilibrium time of 6 h and initial BSA concentration of 1.0 mg/mL. The adsorption capacity Q_max was determined by Langmuir isotherm plots and was 5.72 mg/g for imprinted hydrogel and 1.18 mg/g for nonimprinted hydrogels. A separation factor (β) of 4 was obtained when bovine hemoglobin (pI 6.9, MW 64.0 kDa) was selected as the particular reference protein. Molecular weights and pIs were chosen to investigate the selectivity of the hydrogels. It was shown that the shape memory and the size effect were the major factors for the recognition. This imprinted hydrogel was used to specifically adsorb the BSA from the protein mixture.     

Adsorption and controlled release of Chlortetracycline HCl by using multifunctional polymeric hydrogels

Adsorption and controlled release of Chlortetracycline HCl to and from multifunctional polymeric materials (HEMA/MAA) hydrogels were investigated. P(HEMA/MAA) hydrogels were synthesized by gamma radiation-induced copolymerization of 2-hydroxyethylmethacrylate (HEMA) and methacrylic acid (MAA) in aqueous solution. The influence of copolymer composition and pH value of the surrounding medium on the type of water diffusion into the glassy polymer were discussed. Drug, Chlortetracycline HCl containing hydrogels, with different drug concentration to polymer ratios, was loaded by direct adsorption method. The influence of MAA content in the gel on the adsorption capacities of hydrogel was studied. Chlortetracycline HCl adsorption capacity of hydrogels was found to increase from 8 to 138 mg Chlortetracycline HCl per gram dry gel with increasing amount of MAA in the gel system and drug concentration. The effect of pH on the releasing behavior of Chlortetracycline HCl from gel matrix was investigated. In vitro drug release studies in different buffer solutions show that the basic parameters affecting the drug release behavior of hydrogel are the pH of the solution and MAA content of hydrogel.     

Thermosensitive injectable hydrogels from poly(N-isopropylacrylamide)–dextran aqueous solutions: Thermogelation and drug release properties

Novel injectable thermosensitive hydrogel formulations with improved both water retention (WR) and drug release profile were prepared by adding dextran (DXT) to poly(N-isopropylacrylamide) (PNIPAM) aqueous solutions as a remedy against the demixing/syneresis phenomenon. The addition of the hydrophilic polysaccharide improved the WR of the hydrogel at 37°C from about 12% in the absence of DXT to about 40–55% out of the initial amount introduced, depending on both PNIPAM and DXT concentrations. Also, the 5-fluorouracil release experiments showed an appreciably reduced “burst effect” for the DXT-containing hydrogels. The shape of the release profiles revealed the presence of two stages, differing each other from the point of view of the drug release rate.     

Composite Hydrogels for Sustained Release of Therapeutic Agents

The goal of this research is to develop a composite hydrogel system for sustained release of therapeutic agents. The hydrogel composites were prepared by embedding drug‐loaded, biodegradable poly (DL‐lactide‐co‐glycolide) (PLGA) microparticles in semicrystalline hydrogels of polyvinyl alcohol (PVA). The gels were physically cross‐linked by the formation of the crystallites. The presence of the crystallites and the composite nature of the structure were confirmed by using differential scanning calorimetry and ATR‐FTIR spectroscopy. The distribution of microparticles in the hydrogel matrix was evaluated by using confocal laser scanning microscopy with coumarin‐6 as a fluorescence marker. The numbers of particles in the hydrogel matrix increased along the scanning depth, indicating uneven distribution. The release behavior of a model therapeutic agent, hydrocortisone, was evaluated, and the hydrogel composite system provided for better control of release than the microparticles and hydrogels alone. The addition of outer layers of PVA to the original single‐layer composite further reduced the initial burst effect from the microparticles and allowed for a linear release profile for greater than 1 month.     

Molecularly imprinted polymers for 5-fluorouracil release in biological fluids

The aim of this work was to investigate the possibility of employing Molecularly Imprinted Polymers (MIPs) as a controlled release device for 5-fluorouracil (5-FU) in biological fluids, especially gastrointestinal ones, compared to Non Imprinted Polymers (NIPs). MIPs were synthesized using methacrylic acid (MAA) as functional monomer and ethylene glycol dimethacrylate (EGDMA) as crosslinking agent. The capacity of the polymer to recognize and to bind the template selectively in both organic and aqueous media was evaluated. An in vitro release study was performed both in gastrointestinal and in plasma simulating fluids. The imprinted polymers bound much more 5-Fu than the corresponding non-imprinted ones and showed a controlled/sustained drug release, with MIPs release rate being indeed much more sustained than that obtained from NIPs. These polymers represent a potential valid system for drug delivery and this study indicates that the selective binding characteristic of molecularly imprinted polymers is promising for the preparation of novel controlled release drug dosage form.     

Molecular Imprinted Polymers for use as Drug Delivery Devices: Preliminary Evaluation

In view of technological significance of molecular imprinting polymers in drug delivery, the present study is an attempt to synthesize 2‐hydroxyethylmetacrylate (HEMA) and acrylic acid (AAc) based hydrogels imprinted with model drug glucose. Both molecular imprinted polymers (MIPs) and non‐imprinted polymers (NIPs) have been synthesized and have been used to study their binding affinity, swelling and in vitro release dynamics of the drug. It has been observed from this study that the template formed in MIPs has increased the absorption percentage of the drug and has improved the release profile of the drug from these polymers.     

聚乙二醇相对分子质量及用量对温敏型PCL-PEG-PCL水凝胶的制备及释药性研究

采用开环聚合法制备PCL-PEG-PCL共聚物,并将其制成温敏性水凝胶,探究了PEG(聚乙二醇)相对分子质量及质量浓度对水凝胶温敏性的影响.水凝胶的相变温度由翻转小瓶法测定.通过FTIR、热分析仪和SEM等技术对其组成及结构进行表征.以疏水性姜黄素(Cur)为模型药物,制备出载Cur PCL-PEG-PCL水凝胶,并研究其体外释药行为.FTIR结果表明:实验制备的共聚物中含有PCL和PEG的链段.热分析结果表明:在25℃~65℃内水凝胶存在相变过程.SEM结果表明:水凝胶剖面具有疏松多孔.体外释药结果表明:PCL-PEG-PCL水凝胶对Cur具有缓释作用,释药机理符合Higuchi骨架溶蚀模型.     

A bioinspired 4D printed hydrogel capsule for smart controlled drug release

With the ever-increasing demands for personalized drugs, disease-specific and condition-dependent drug delivery systems, four-dimensional (4D) printing can be used as a new approach to develop drug capsules that display unique advantages of self-changing drug release behavior according to the actual physiological circumstances. Herein, a plant stomata-inspired smart hydrogel capsule was developed using an extrusion-based 4D printing method, which featured with UV cross-linked poly(N-isopropylacrylamide) (PNIPAM) hydrogel as the capsule shell. The lower critical solution temperature (LCST) of the PNIPAM hydrogels was approximately 34.9 °C and macroporous PNIPAM hydrogels were prepared with higher molecular weight polyethylene glycols (PEGs) as the pore-forming agents. Owing to the LCST-induced shrinking/swelling properties, the prepared PNIPAM hydrogel capsules exhibited temperature-responsive drug release along with the microstructure changes in the PNIPAM hydrogels. The in vitro drug release test confirmed that the PNIPAM hydrogel capsules can autonomously control their drug release behaviors on the basis of ambient temperature changes. Moreover, the increased PEG molecular weights in the macroporous PNIPAM hydrogel capsules caused an obvious improvement of drug release rate, distinctly indicating that the drug release profiles can be well programmed by adjusting the internal pore size of the hydrogel capsules. In vitro biocompatibility studies confirmed that the PNIPAM hydrogel capsules have great potential for biomedical applications. The bioinspired 4D printed hydrogel capsules pioneer the paradigm of smart controlled drug release.     

pH/temperature - sensitive imprinted ionic poly(N-tert-butylacrylamide-co-acrylamide/maleic acid) hydrogels for bovine serum albumin

In this study, we have prepared pH/temperature-sensitive imprinted ionic poly(N-tert-butylacrylamide-co-acrylamide/maleic acid) [P(TBA-co-AAm/MA)] hydrogels for bovine serum albumin (BSA) by using molecular imprinting method. BSA adsorption from aqueous BSA solutions was investigated with two types of hydrogel systems prepared by non-imprinted and imprinted methods. Hydrogels imprinted with BSA showed higher adsorption capacity and specificity for BSA than hydrogels prepared by the usual procedure. At all studied conditions, the highest BSA adsorption was observed in the hydrogel imprinted with 8.63 wt.-% BSA. In addition, the imprinted hydrogels exhibited both for good selectivity BSA and high adsorption rate depending on the number of BSA-sized cavities. Adsorption studies showed that other stimuli, such as pH, temperature and initial BSA concentration also influenced the BSA adsorption capacity of both non-imprinted and imprinted hydrogels.     

Development of Antibacterial,Degradable and pH-Responsive Chitosan/Guar Gum/Polyvinyl Alcohol Blended Hydrogels for Wound Dressing

The present research is based on the fabrication preparation of CS/PVA/GG blended hydrogel with nontoxic tetra orthosilicate (TEOS) for sustained paracetamol release. Different TEOS percentages were used because of their nontoxic behavior to study newly designed hydrogels’ crosslinking and physicochemical properties. These hydrogels were characterized using Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and wetting to determine the functional, surface morphology, hydrophilic, or hydrophobic properties. The swelling analysis in different media, degradation in PBS, and drug release kinetics were conducted to observe their response against corresponding media. The FTIR analysis confirmed the components added and crosslinking between them, and surface morphology confirmed different surface and wetting behavior due to different crosslinking. In various solvents, including water, buffer, and electrolyte solutions, the swelling behaviour of hydrogel was investigated and observed that TEOS amount caused less hydrogel swelling. In acidic pH, hydrogels swell the most, while they swell the least at pH 7 or higher. These hydrogels are pH-sensitive and appropriate for controlled drug release. These hydrogels demonstrated that, as the ionic concentration was increased, swelling decreased due to decreased osmotic pressure in various electrolyte solutions. The antimicrobial analysis revealed that these hydrogels are highly antibacterial against Gram-positive (Staphylococcus aureus and Bacillus cereus) and Gram negative (Pseudomonas aeruginosa and Escherichia coli) bacterial strains. The drug release mechanism was 98% in phosphate buffer saline (PBS) media at pH 7.4 in 140 min. To analyze drug release behaviour, the drug release kinetics was assessed against different mathematical models (such as zero and first order, Higuchi, Baker–Lonsdale, Hixson, and Peppas). It was found that hydrogel (CPG2) follows the Peppas model with the highest value of regression (R² = 0.98509). Hence, from the results, these hydrogels could be a potential biomaterial for wound dressing in biomedical applications.     

A pH‐sensitive water‐soluble N‐carboxyethyl chitosan/poly(hydroxyethyl methacrylate) hydrogel as a potential drug sustained release matrix prepared by photopolymerization technique

Biocompatible pH‐sensitive semi‐interpenetration polymeric network hydrogels (semi‐IPN) based on water‐soluble N‐carboxyethyl chitosan (CECS) and 2‐hydroxyethyl methacrylate (HEMA) were synthesized by the photopolymerization technique. pH‐sensitivity, cytotoxicity, morphology, mechanical property, and water state of hydrogel were investigated by a swelling test, methylthiazolydiphenyl‐tetrazolium bromide (MTT) assay, scanning electron microscopy (SEM), universal testing machine, and differential scanning calorimetry (DSC), respectively. The drug release studies were carried out using 5‐Flurouracil as the model drug. The results indicated that the hydrogels were sensitive to pH of the medium and its wet state had good mechanical properties. The results of cytotoxicity and prolonged drug release characteristics revealed the suitability of the hydrogels as drug delivery matrices. The release kinetics was evaluated by fitting the experimental data to standard release equations, and the best fit was obtained with the Higuchi model of the hydrogel. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis and Characterization of Sterculia Gum Based pH Responsive Drug Delivery System for Use in Colon Cancer

The present study deals with the modification of sterculia gum to develop the novel colon specific delivery system for use in colon cancer. The sterculia and acrylic acid based hydrogels were synthesized and characterized with FTIR, SEMs, TGA and swelling behavior. Swelling studies of the hydrogels were carried out as a function of reaction parameters such as monomer concentration, initiator concentration, amount of sterculia gum and crosslinker concentration and nature of swelling mediums. Swelling kinetics of the hydrogels and in vitro release dynamics of anticancer model drug methotrexate from the hydrogels were studied to evaluate the swelling mechanism and drug release mechanism from the drug-loaded hydrogels. The values of diffusion exponent for the release of drug were 0.883, 0.910 and 0.787 in distilled water, pH 2.2 buffer and pH 7.4 buffer, respectively. The release of drug from the polymer matrix occurred through a non -Fickian type diffusion mechanism.     

Polymer hydrogels with the memory effect for immobilization of drugs

Hydrogels with the memory effect are synthesized from crosslinked copolymers of 2-hydroxyethyl methacrylate and functional monomers (acrylic acid or dimethylaminoethyl methacrylate) via the method of template synthesis with the use of the drug cephazoline as a matrix. It is shown that the hydrogels show an increased sorption activity against the target drug and a slow rate of drug release from the hydrogel (the memory effect) under certain conditions. In combination with cephazoline, these hydrogels may be regarded as a new prolonged-drug-release system for the treatment of infectious diseases.     

Controlling drug release from imprinted hydrogels by modifying the characteristics of the imprinted cavities

The aim of this study was to analyse the influence of the template/functional monomer proportion on the achievement of molecularly imprinted hydrogels with cavities with a high enough affinity for the drug to sustain drug release. Imprinted hydrogels were prepared from N,N-dimethylacrylamide and tris(trimethylsiloxy)sililpropyl methacrylate (DMAA and TRIS; main components), methacrylic acid (MAA; functional monomer), ethylene glycol dimethacrylate (EGDMA; cross-linker), and timolol (template drug). Photo-polymerization of the monomer solutions was carried out in poly(propylene) molds (0.3 mm thickness) to obtain contact lens-like devices. Non-imprinted control hydrogels were also prepared in the same way but without the addition of timolol. The imprinted hydrogels showed a higher affinity for timolol and a slower release rate than the non-imprinted hydrogels. The release rate decreased by increasing the MAA/timolol ratio in the gel recipe. Hydrogels prepared with 400 x 10(-3) M MAA, 600 x 10(-3) M EGDMA, and a timolol/MAA mole ratio of 1:16-1:32 had drug diffusion coefficients two orders of magnitude below those of non-imprinted hydrogels. The results obtained clearly indicate that the timolol release rate is critically affected by the conditions under which the hydrogels were synthesized. These effects are discussed on the basis of the influence of drug proportion on the conformation of the imprinted cavities.