Synthesis and properties of thermo- and pH-sensitive poly(N-isopropylacrylamide)/polyaspartic acid IPN hydrogels

Various interpenetrating polymer network (IPN) hydrogels with sensitivity to temperature and pH were prepared by introducing the pH-sensitive polymer polyaspartic acid (PASP) hydrogel, into the poly(N-isopropylacrylamide) (PNIPAAm) hydrogel system for the purpose of improving its response rate to temperature. The morphologies and thermal behavior of the prepared IPN hydrogels were studied by both scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). The IPN hydrogels showed a large and uneven porous network structure, without showing the common PNIPAAm hydrogel structure. The paper moreover studied their swelling properties, such as temperature dependence of equilibrium swelling ratio, shrinking kinetics, re-swelling kinetics and oscillatory swelling behavior in water. The swelling experiment results revealed that IPN hydrogels exhibited much faster shrinking and re-swelling in function of the composition ratio of the two network components. These fast responsive hydrogels foster potential applications in biomedical and biotechnology fields.     

Preparation and characterization of konjac glucomannan–poly(acrylic acid) IPN hydrogels for controlled release

In this paper, we reported the synthesis and properties of interpenetrating polymer network (IPN) hydrogel systems designed for colon targeted drug delivery. The gels were composed of konjac glucomannan (KGM) and cross-linked poly(acrylic acid) (PAA) by N,N-methylene-bis-(acrylamide) (MBAAm). It was possible to modulate the swelling degree of the gels. And the swelling ratio has sensitive respondence to the environmental pH value variation. The degradation tests show that the hydrogels retain the enzymatic degradation character of KGM. In vitro release of model drug VB₁₂ was studied in the presence of Cellulase E0240 in pH 7.4 phosphate buffer at 37 °C. The accumulative release percent of the model drug reached 85.6% after 48 h and the drug release was controlled by the swelling and the degradation of the hydrogels. The results indicated that the IPN hydrogels can be exploited as potential carriers for colon-specific drug delivery.     

Synthesis and characterization of hydrogels based on grafted chitosan for the controlled drug release

Temperature and pH-responsive hydrogels based on chitosan grafted with poly acrylic acid (PAAc), poly hydroxy propyl methacrylate (PHPMA), poly (vinyl alcohol) (PVA) and gelatin were prepared for controlled drug delivery. These stimuli-responsive hydrogels were synthesized by gamma irradiation technique. The degree of gelation was over 90% and increased as chitosan, AAc and PVA content increased, while the degree of gelation decrease with the increase of gelatin content. The equilibrium swelling studies of hydrogels prepared in various conditions were carried out in an aqueous solution, and the pH sensitivity in the range of 2–9 was investigated. An increase of swelling degree with an increase in the pH was noticed and showed the highest value at pH 9. Also antibiotic drug Oxttetracycline was loaded into the hydrogels and the release studies were carried out at different pH and temperature. The in vitro release profiles of the drug showed that, the release of the drug increased as the time, temperature and pH increased and reached to maximum after 48 h at pH 9. The prepared hydrogels were characterized by using SEM, FTIR, and DSC.     

IPNs based on chitosan with NVP and NVP/HEMA synthesised through photoinitiator-free photopolymerisation technique for biomedical applications

Biocompatible interpenetration polymeric network (IPN) hydrogels based on chitosan with N-vinylpyrrolidinone (NVP) as well as its copolymer with 2-hydroxymethyl methacrylate (HEMA) were synthesised using the photopolymerisation technique without the inclusion of any photoinitiator or crosslinking agent. These hydrogels were characterised using the Fourier-transform infrared spectroscopy (FTIR) technique. Equilibrium swelling of these hydrogels was performed in Milli-Q water and drug release studies were carried out using theophylline as the model drug. These tests showed that the IPN comprised of chitosan and NVP with a very small amount of N-hydroxymethyl maleimide (HMMI) included exhibited higher swelling abilities and fast drug release rates than the IPN which contained chitosan, NVP and HEMA. Kinetic studies of water diffusion into these hydrogels and drug release revealed that with the exception of the IPN with HEMA incorporated, the other hydrogels did not adhere to the Fickian diffusion model. These hydrogels were tested for their biocompatibility with human epidermal keratinocyte cells (HaCaT). A positive cell growth as evidenced by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) cell proliferation assay indicated that these hydrogels are non-toxic to human keratinocytes and can be potentially used as biomaterials for biomedical applications.     

Biodegradable thermoresponsive hydrogels for aqueous encapsulation and controlled release of hydrophilic model drugs

A series of hydrogels with both thermoresponsive and completely biodegradable properties was developed for aqueous encapsulation and controlled release of hydrophilic drugs in response to temperature change. The hydrogels were prepared in phosphate-buffered saline (pH 7.4) through free radical polymerization of N-isopropylacrylamide (NIPAAm) monomer and a dextran macromer containing multiple hydrolytically degradable oligolactate-2-hydroxyethyl methacrylate units (Dex-lactateHEMA). Swelling measurement results demonstrated that four gels with feeding weight ratios of NIPAAm:Dex-lactateHEMA = 7:2, 6:3, 5:4, and 4:5 (w/w) were thermoresponsive by showing a lower critical solution temperature at approximately 32 degrees C. The swelling and degradation of the hydrogels strongly depended on temperature and hydrogel composition. An empirical mathematical model was established to describe the fast water absorption at the early stage and deswelling at the late stage of the hydrogels at 37 degrees C. Two hydrophilic model drugs, methylene blue and bovine serum albumin, were loaded into the hydrogels during the synthesis process. The molecular size of the drugs, the hydrophilicity and degradation of the hydrogels, and temperature played important roles in controlling the drug release.     

Radiation crosslinked psyllium and polyacrylic acid based hydrogels for use in colon specific drug delivery

In order to utilize the psyllium husk, a medicinally important natural polysaccharide, to develop the hydrogels meant for the drug delivery, we have prepared psyllium and polyacrylic acid based polymeric networks by radiation-induced crosslinked copolymerization. Polymeric networks (hydrogels) thus formed were characterized with SEMs, FTIR and swelling studies. Swelling behavior of the hydrogels was studied as a function of monomer concentration in the hydrogels and temperature, pH and [NaCl] of the swelling medium. This paper discusses the swelling kinetics of the hydrogels and release dynamics of anticancer model drug 5-fluorouracil from the hydrogels for the evaluation of swelling and drug release mechanisms. It has been observed from the release dynamics of drug that diffusion exponent ‘n’ have 0.7, 0.8 and 0.7 values and gel characteristics constant ‘k’ have 9.13 × 10⁻³, 6.22 × 10⁻³ and 9.01 × 10⁻³ values for the release of 5-fluorouracil, respectively, in distilled water, pH 2.2 buffer and pH 7.4 buffer. The values of the diffusion exponent show that the release of drug from drug-loaded hydrogels has occurred through Non-Fickian diffusion mechanism. It has also been observed from the swelling and release of drug in the different pH buffer that the polymer matrix is pH responsive and can be exploited for the delivery of anticancer drug to the colon.     

Characterization and in vitro evaluation of starch based hydrogels as carriers for colon specific drug delivery systems

A series of starch/methacrylic acid (MAAc) copolymer hydrogels of different compositions were synthesized using γ-rays induced polymerization and crosslinking. The effects of the preparation conditions such as the feed solution concentration, feed solution composition and irradiation dose on the gelation process of the synthesized copolymer were investigated. The swelling behavior of the starch/methacrylic acid (MAAc) copolymer hydrogels was characterized by studying the effect of the hydrogel composition on the time- and pH-dependent swelling. Swelling kinetics showed that the synthesized hydrogels possessed Fickian diffusion behavior at pH 1 and non-Fickian diffusion at pH 7 which recommend them as good candidate for colon specific drug delivery systems. The synthesized hydrogels were loaded with ketoprofen as a model drug to investigate the release behavior of the synthesized hydrogels. The results showed the ability of the hydrogels to keep the loaded drug at pH 1 and release it at pH 7. The data also showed that the release rate can be controlled by controlling the preparation conditions such as comonomer concentration and composition and irradiation dose.     

Photopolymerization of methacrylated chitosan/PNIPAAm hybrid dual-sensitive hydrogels as carrier for drug delivery

A series of hybrid hydrogels based on glycidyl methacrylated chitosan (CS-GMA) and N-isopropylacrylamide (NIPAAm) were designed and prepared via photopolymerization technology. The hydrogels were characterized by Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC) and optical transmittance. The interior morphology of hydrogels was investigated by scanning electron microscopy (SEM). The swelling experiment results revealed that hybrid hydrogel exhibited combined pH and temperature sensitivities. Acid orange 8 (AO8) and 5-flurouracil (5-Fu) were selected as model drugs for examining their release from hydrogels. The results suggested that hydrogel composition and pH value of buffer solution had great influences on release profiles.     

pH-sensitive cationic guar gum/poly (acrylic acid) polyelectrolyte hydrogels: Swelling and in vitro drug release

Novel polyelectrolyte hydrogels (coded as GA) based on cationic guar gum (CGG) and acrylic acid monomer by photoinitiated free-radical polymerization were synthesized with various feed compositions. Fourier transform infrared spectra (FTIR), scanning electron microscopy (SEM), and differential scanning calorimetry (DSC) confirmed that the formation of the polyelectrolyte hydrogels was attributed to the strong electrostatic interaction between cationic groups in CGG and anionic groups in poly (acrylic acid) (PAA). Swelling experiments provided important information on drug diffusion properties, which indicated the GA hydrogels were highly sensitive to pH environments. Potential applications of the hydrogels matrices in controlled drug delivery were also examined. The ketoprofen-loaded CGG/PAA matrices were prepared by hydrogels and directly compressed tablets, respectively. Release behavior of ketoprofen relied on the preparative methods of matrices, ratios of CGG/AA and pH environments. The release mechanism was studied by fitting experimental data to a model equation and calculating the corresponding parameters. The result showed that the kinetics of drug release from the hydrogels in pH 7.4 buffer solution was mainly non-Fickian diffusion. However, for tablets, the drug release in pH 7.4 buffer solution was mainly affected by polymer erosion. The pH of the dissolution medium appeared to have a strong effect on the drug transport mechanism. At more basic pH values, Case II transport was observed, indicating a drug release mechanism highly influenced by macromolecular chain relaxation. The ketoprofen release is also tested in the conditions chosen to simulate gastrointestinal tract conditions. The results implied that the GA hydrogels can be exploited as potential carriers for colon-specific drug delivery.     

Thermo-sensitive chitosan based semi-IPN hydrogels for high loading and sustained release of anionic drugs

Thermo-sensitive poly(N-isopropyl acrylamide-co-vinyl pyrrolidone)/chitosan [P(NIPAM-co-NVP)/CS] semi-IPN hydrogels with improved loading capacity and sustained release for anionic drugs NAP were prepared by free-radical polymerization. The LCST of hydrogels was adjusted to the vicinity of body temperature by introducing hydrophilic NVP. The presence of CS in semi-IPN networks improves the swelling behavior and provides a high affinity for anionic drug NAP due to the strong interactions between NAP molecules and CS chains. Release of NAP was suppressed at pH 2.2 and 5.0 and accelerated at pH 7.4 due to the deprotonation of amino groups in CS. Increasing temperature above LCST, hydrogels showed a continuous release of NAP without burst diffusion due to the shrinkage of PNIPAM restraining the drug release.     

Synthesis and characterization of pH-sensitive hydrogel composed of carboxymethyl chitosan for colon targeted delivery of ornidazole

In the present study, carboxymethyl chitosan was prepared from chitosan, crosslinked with glutaraldehyde and evaluated in vitro as a potential carrier for colon targeted drug delivery of ornidazole. Ornidazole was incorporated at the time of crosslinking of carboxymethyl chitosan. The chitosan was evaluated for its degree of deacetylation (DD) and average molecular weight; which were found to be 84.6% and 3.5×10(4) Da, respectively. The degree of substitution on prepared carboxymethyl chitosan was found to be 0.68. All hydrogel formulations showed more than 85% and 74% yield and drug loading, respectively. The swelling behaviour of prepared hydrogels checked in different pH values, 1.2, 6.8 and 7.4, indicated pH responsive swelling characteristic with very less swelling at pH 1.2 and quick swelling at pH 6.8 followed by linear swelling at pH 7.4 with slight increase. In vitro release profile was carried out at the same conditions as in swelling and drug release was found to be dependant on swelling of hydrogels and showed biphasic release pattern with non-fickian diffusion kinetics at higher pH. The carboxymethylation of chitosan, entrapment of drug and its interaction in prepared hydrogels were checked by FTIR, (1)H NMR, DSC and p-XRD studies, which confirmed formation of carboxymethyl chitosan from chitosan and absence of any significant chemical change in ornidazole after being entrapped in crosslinked hydrogel formulations. The surface morphology of formulation S6 checked before and after dissolution, revealed open channel like pores formation after dissolution.     

Drug loading into and drug release from pH- and temperature-responsive cylindrical hydrogels

Hydrogels that undergo deformation upon appropriate changes in pH or temperature have considerable promise as drug delivery vehicles. Drug uptake in swelling and nonswelling cylindrical hydrogels and drug release from these into a target fluid are investigated here. A mathematical model for hydrogel-solution composite, a composite of a distributed parameter system (cylindrical hydrogel) and a lumped parameter system (surrounding solution), is developed. The polymer network displacement in a swelling/deswelling hydrogel is described by a stress diffusion coupling model. The analytical solution for network displacement is used to predict solvent intake by swelling hydrogels, solvent efflux from deswelling hydrogels, and changes in pressure, porosity, and effective drug diffusivity. These in turn influence drug uptake during and after hydrogel swelling and drug release from hydrogel during and after deswelling. Numerical results illustrate benefits of hydrogel swelling for drug loading and merits of different modes of drug release. Drug uptake and drug release by temperature-responsive hydrogels are compared with those by hydrogels not subject to deformation.     

The swelling behavior and network parameters of guar gum/poly(acrylic acid) semi-interpenetrating polymer network hydrogels

Guar gum/poly(acrylic acid) semi-interpenetrating polymer network (IPN) hydrogels have been prepared via free radical polymerization in the presence of a crosslinker of N,N′-methylene bisacrylamide (MBA). The kinetics of swelling and the water transport mechanism were studied as a function of the composition of the hydrogels and the pH of the swelling medium. Hydrogels showed enormous swelling in aqueous medium and displayed swelling characteristics, which were highly dependent on the chemical composition of the hydrogels and pH of the medium in which hydrogels were immersed (ionic strength I = 0.15 mol/L). The semi-INP hydrogels were characterized by evaluating various network parameters such as average molecular weight between crosslinks (M_c) crosslink density (ρ) and mesh size ξ.     

Synthesis, characterization and swelling studies of pH responsive psyllium and methacrylamide based hydrogels for the use in colon specific drug delivery

In order to utilize the psyllium husk a medicinally important natural polysaccharide and to develop the novel hydrogels meant for the colon specific drug delivery, we have prepared psyllium and methacrylamide based polymeric networks by using N,N′-methylenebisacrylamide (NN-MBAAm) as crosslinker and ammonium persulfate (APS) as initiator. To study various structural aspects of the polymeric networks thus formed psy-cl-poly(MAAm), these were characterized with SEMs, FTIR, TGA and swelling studies. The swelling studies of networks were carried out as a function of time, temperature, pH and [NaCl]. Equilibrium swelling has been observed to depend on both composition of the polymer and nature of swelling medium. Maximum percent swelling 1262 was observed for the polymeric network prepared with 19.45 × 10⁻³ mol/L of [NN-MBAAm] at 40 °C in 0.5 M NaOH solution. This article also discusses the release dynamics of tetracycline hydrochloride from the hydrogels, for the evaluation of the drug release mechanism and diffusion coefficients of drug from the polymer matrix. The effect of pH on the release pattern of tetracycline hydrochloride has been studied by varying the pH of the release medium. It has been observed from the release dynamics of drug from the hydrogels that the diffusion exponent ‘n’ have 0.477, 0.423 and 0.427 values and gel characteristic constant ‘k’ have 5.07 × 10⁻², 6.34 × 10⁻² and 6.38 × 10⁻² values, respectively, in distilled water, pH 2.2 buffer and pH 7.4 buffer solution. The values the ‘n’ indicated that the Fickian type diffusion mechanism occurred for the release of tetracycline hydrochloride from drug loaded psy-cl-poly(MAAm) polymers in different release mediums. In Fickian type diffusion mechanism, the rate of polymer chain relaxation is more as compare to the rate of drug diffusion from these hydrogels and release behavior follows Fick’s law of diffusion. In each release medium, the values of the initial diffusion coefficient ‘D_i’ for the release of tetracycline hydrochloride was higher than the values of late time diffusion coefficient ‘D_L’ indicating that in the start, the diffusion of drug from the polymeric matrix was faster as compare to the latter stages.     

Preparation and properties of a pH/temperature-responsive carboxymethyl chitosan/poly(N-isopropylacrylamide)semi-IPN hydrogel for oral delivery of drugs

Thermo- and pH-responsive semi-IPN polyampholyte hydrogels were prepared by using carboxymethylchitosan and poly(N-isopropylacrylamide) with N,N'-methylenebisacrylamide (BIS) as the crosslinking agent. The swelling characteristics of these hydrogels at distinct compositions as a function of pH and temperature were investigated. It was found that the semi-IPN hydrogels demonstrated the pH- and temperature-responsive nature of the materials, and it also showed good reversibility. The study on the release of coenzyme A (CoA) showed that within 24h the cumulative release ratio of CoA was 22.6% in pH 2.1 solution and 89.1% in pH 7.4 solution at 37 degrees C, respectively. The release rate of CoA was higher at 37 degrees C than 25 degrees C in a pH 7.4 buffer solution. An increased release rate of CoA was observed with the content of carboxymethylchitosan increasing in the hydrogel at 25 degrees C in pH 7.4 solution. These results show that semi-IPN hydrogel seems to be of great promise in pH-temperature oral drug delivery systems.     

Electrical behavior of polymer hydrogel composed of poly(vinyl alcohol)-hyaluronic acid in solution

Interpenetrating polymer networks (IPN), as polymer hydrogels composed of poly(vinyl alcohol) (PVA) and hyaluronic acid (HA), which exhibited electrical sensitive behavior were prepared. The swelling behavior of the IPN/HA IPN was studied by immersing the gel in various concentrations of aqueous NaCl solutions and various pH buffer solutions. The response of the PVA/HA IPN to electric fields stimuli was also investigated. When swollen IPN was placed between a pair of electrodes, and an electric field applied, it exhibited bending behavior. The PVA/HA IPN also displayed stepwise bending behavior, depending on the magnitude of the electric stimulus. Also, for use in biosensors application, their bending behavior was studied in Hank's solution at pH 7.4.     

Novel interpenetrating polymer network microspheres of chitosan and methylcellulose for controlled release of theophylline

Interpenetrating polymer network (IPN) microspheres of chitosan (CS) and methylcellulose (MC) were prepared by emulsion-crosslinking in the presence of glutaraldehyde (GA) as a crosslinker. Theophylline (THP), an antiasthmatic drug was encapsulated into IPN microspheres under varying ratios of MC and CS, % drug loading and amount of GA added. IPNs have shown better mechanical properties than pure CS. Cross-link density of the matrices was significantly affected by the amount of GA and MC. Microspheres were characterized by Fourier transform infrared (FTIR) spectroscopy to assess the formation of IPN structure and to confirm the absence of chemical interactions between drug, polymer and crosslinking agent. Particle size was measured by laser light scattering technique. Microspheres with the average particle sizes ranging from 119 to 318 μm were produced. Differential scanning calorimetry (DSC) and X-ray diffraction (X-RD) studies were performed to understand the crystalline nature of drug after encapsulation into IPN microspheres. Theophylline encapsulation of up to 82% was achieved as measured by UV spectrometer. Equilibrium swelling was performed in distilled water. In vitro release studies were performed in both 0.1 N HCl and pH 7.4 buffer solutions. These data indicated a dependence of drug release on the extent of crosslinking and amount of MC added during the preparation of microspheres. The release was extended up to 12 h and release rates were fitted to an empirical equation to compute the diffusional parameters, which indicated a slight deviation from the Fickian trend for the release of theophylline.     

Interpenetrating polymer network (IPN) hydrogel microspheres for oral controlled release application

Interpenetrating polymer network (IPN) hydrogel microspheres of sodium carboxymethyl cellulose (NaCMC) and poly(vinyl alcohol) (PVA) were prepared by water-in-oil (w/o) emulsion crosslinking method for oral controlled release delivery of a non-steroidal anti-inflammatory drug, diclofenac sodium (DS). The microspheres were prepared with various ratios of NaCMC to PVA, % drug loading and extent of crosslinking density at a fixed polymer weight. The prepared microspheres with loose and rigid surfaces were evidenced by scanning electron microscope (SEM). Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) analysis confirmed the IPN formation. Differential scanning calorimetry (DSC) study was performed to understand the dispersion nature of drug after encapsulation. The in vitro drug release study was extensively evaluated depending on the process variables in both acid and alkaline media. All the formulations exhibited satisfactory physicochemical and in vitro release characteristics. Release data indicated a non-Fickian trend of drug release from the formulations. Based on the results of this study suggest that DS loaded IPN microspheres were suitable for oral controlled release application.     

Poly(ethylene glycol) methacrylate/dimethacrylate hydrogels for controlled release of hydrophobic drugs

Hydrogels have been successfully used to entrap hydrophilic drugs and release them in a controlled fashion; however, the entrapment and release of hydrophobic drugs has not been well studied. We report on the release characteristics of a model hydrophobic drug, the steroid hormone estradiol, entrapped in low (MW 360/MW 550) and high (MW 526/MW 1000) molecular weight poly(ethylene glycol) methacrylate (PEG-MA)/dimethacrylate (PEG-DMA) hydrogels. The cross-linking ratio, temperature, and pH ranged from 10:1 to 10:3, from 33 to 41 degrees C, and from 2 to 12, respectively. The gelation of the PEG-MA/PEG-DMA hydrogel was initiated with UV irradiation. The absence of poly(glutamic acid) in the hydrogel formulation resulted in a loss of pH sensitivity in the acidic range, which was displayed by the hydrogels' similarities in swelling ratios in the pH buffers of pH 2, 4, and 7. Use of high molecular weight polymers resulted in a higher hydrogel swelling (300%) in comparison to the low molecular weight polymers. Drug size was found to be a significant factor. In comparison to 100% estradiol (MW 272) release, the fractional release of insulin (MW 5733) was 12 and 24% in low and high molecular weight gels at pH 2, respectively, and 17% in low molecular weight gels at pH 7. On the release kinetics of the estradiol drug, the hydrogels displayed a non-Fickian diffusion mechanism, which indicated that the media penetration rate is in the same range as the drug diffusion. The synthesis, entrapment, and release of estradiol by the PEG-MA/PEG-DMA hydrogels proved to be successful, but the use of ethanol in the buffers to promote the hydrophobic release of the estradiol in the in vitro environment caused complications, attributed to the process of transesterification.     

New route for synthesizing poly(ethylene glycol)-acrylic acid hydrogels using γ-irradiation for drug delivery carriers

Biocompatible and pH-responsive poly(ethylene glycol) (PEG)-acrylic acid (AAc) hydrogels were prepared by new technique using γ-irradiation for controlled oral drug delivery. The gel fraction was over 80% and the equal amounts of PEG and AAc blended hydrogel had efficient insulin loading using equilibrium swelling. These hydrogels exhibited unique pH-responsive characteristics in which interpolymer complexes were formed in acidic media and dissociated in neutral or basic environments. The insulin release from the gel was significantly retarded in acidic media while rapid release occurred under neutral/basic conditions. At the high pH solution, the gels swelled rapidly and over 70% of the insulin loaded was released over a period of 10 h. Within 2 h of administration of the insulin-containing gels, significant blood glucose reduction effects were observed in diabetic rats. The blood glucose reduction lasted for up to 10 h following administration.