Semi‐interpenetrating polymer network beads of crosslinked chitosan–glycine for controlled release of chlorphenramine maleate

Spherical, semi‐interpenetrating polymer network beads of chitosan and glycine, crosslinked with different concentrations of glutaraldehyde were prepared for controlled release of drugs. The structural and morphological studies of the beads were carried out with FTIR and SEM techniques. The swelling behavior of the beads at different time intervals was monitored in solutions of different pH. Structural changes of the beads in response to solution pH were put forward using the data obtained from IR/UV spectral analysis. The release experiments were performed in solutions of pH 2.0 and pH 7.4 at 37°C, using chlorphenramine maleate as a model drug. The results indicate that, chitosan might be useful as a vehicle for controlled release of drugs. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 76: 672–683, 2000     

Preparation,characterization and release profiles of pH‐sensitive chitosan beads

Spherical crosslinked beads using chitosan, glycine and glutaraldehyde were prepared for controlled release formulations. Structural investigation of the beads was made with IR analysis. Morphological study of the beads was carried out by scanning electron microscopy. The swelling behaviour of the beads was monitored as a function of time in solutions of different pH. The release experiments were performed using thiamine hydrochloride (Thi‐HCl) as a model drug. These preliminary results suggest the possibility of modifying the formulations to obtain the desired controlled release of drug in an oral sustained delivery system. © 2000 Society of Chemical Industry     

Studies on semi‐interpenetrating polymer network beads of chitosan–poly(ethylene glycol) for the controlled release of drugs

Semi‐interpenetrating polymer network beads of chitosan and poly(ethylene glycol) were prepared and characterized for controlled release of drugs. A viscous solution of chitosan and poly(ethylene glycol) in 2% acetic acid was extruded as droplets with the help of a syringe and crosslinked using glutaraldehyde. The structural studies of the beads were performed by using a Fourier transform infrared spectrophotometer and scanning electron microscope. The swelling behavior, solubility, hydrolytic degradation, and loading capacity of the beads for isoniazid were investigated. The structural changes of the beads at pH 2.0 and 7.4 were put forward using the data obtained by infrared and ultraviolet spectroscopy. The prepared beads showed 82% drug‐loading capacity, which suggested that these semi‐interpenetrating polymer network beads are suitable for controlled release of drugs in an oral sustained delivery system. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 80: 639–649, 2001     

Chitosan–polyelectrolyte complexation for the preparation of gel beads and controlled release of anticancer drug. II. Effect of pH‐dependent ionic crosslinking or interpolymer complex using tripolyphosphate or polyphosphate as reagent

Chitosangel beads were prepared using an in‐liquid curing method by ionotropic crosslinking or interpolymer linkage with tripolyphosphate (TPP) or polyphosphate (PP). The ionic interaction of chitosan with TPP or PP is pH‐dependent due to the transition of “ladder‐loop” complex structures. Chitosan gel beads cured in a pH value lower than 6 of a TPP solution was a controlled homogeneous ionic‐crosslinking reaction, whereas chitosan gel beads cured in a lower pH PP solution was a nonhomogeneous interpolymer complex reaction due to the mass‐transfer resistance for the diffusion of macromolecular PP. According to the results of FTIR and EDS studies, it was suggested that significantly increasing the ionic‐crosslinking density or interpolymer linkage of a chitosan–TPP or chitosan–PP complex could be achieved by transferring the pH value of curing agent, TPP or PP, from basic to acidic. The swelling behavior of various chitosan beads in acid medium appeared to depend on the ionic‐crosslinking density or interpolymer linkage of the chitosan–TPP or chitosan–PP complex, which were deeply affected by the in‐liquid curing mechanism of the chitosan gel beads. By the transition of the in‐liquid curing mechanism, the swelling degree of chitosan–TPP or chitosan–PP beads was depressed and the disintegration of chitosan–TPP or chitosan–PP beads did not occur in strong acid. The drug‐release patterns of the modified chitosan gel beads in simulated intestinal and gastric juices were sustained for 20 h. These results indicate that the sustained release of anticancer drugs could be achieved due to the variation of the reaction mechanism of a chitosan–polyelectrolyte pH‐dependent ionic interaction. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 74: 1093–1107, 1999     

Chitosan–Polyelectrolyte complexation for the preparation of gel beads and controlled release of anticancer drug. I. Effect of phosphorous polyelectrolyte complex and enzymatic hydrolysis of polymer

Enzymic hydrolyzed chitosan was employed to prepare chitosan–tripolyphosphate and chitosan–polyphosphoric acid gel beads using a polyelectrolyte complexation method for the sustained‐release of anticancer agent, 6‐mercaptopurine (6‐MP). pH responsive swelling ability, drug‐release characteristics, and morphology of the chitosan gel bead depends on polyelectrolyte complexation mechanism and molecular weight of the enzymic hydrolyzed chitosan. The complexation mechanism of chitosan beads gelled in pentasodium tripolyphosphate or polyphosphoric acid solution was ionotropic crosslinking or interpolymer complex, respectively. The drug‐release patterns of all chitosan gel beads in pH 6.8 seemed to be diffusional based, which might be in accordance with the Higuchi model, whereas release profiles of the chitosan–tripolyphosphate gel beads in pH 1.2 medium seemed to be non‐Fickian diffusion controlled due to the swelling or matrix erosion of the beads. The rate of 6‐MP releasing from chitosan–tripolyphosphate or chitosan–polyphosphoric acid gel matrix were significantly increased with the decreased molecular weight of enzymic hydrolyzed chitosan. However, the dissolution rates of 6‐MP entraped in chitosan–tripolyphosphate and chitosan–polyphosphoric acid gel matrix were significantly slower than the dissolution rate of the original drug. These results indicate that the chitosan–polyphosphoric acid gel bead is a better polymer carrier for the sustained release of anticancer drugs in simulated intestinal and gastric juice medium than the chitosan–tripolyphosphate gel beads. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 74: 1868–1879, 1999     

Chitosan‐based interpolymeric pH‐responsive hydrogels for in vitro drug release

Two series of pH‐responsive biodegradable interpolymeric (IPN) hydrogels based on chitosan (Ch) and poly(vinyl alcohol) (PVA) were prepared for controlled drug release investigations. The first series was chemically crosslinked with different concentrations of glutaraldehyde and the second was crosslinked upon γ‐irradiation by different doses. The equilibrium swelling characteristics were investigated for the gels at 37°C in buffer solutions of pH 2.1 and 7.4 as simulated gastric and intestinal fluids, respectively. 5‐Fluorouracil (FU) was entrapped in the hydrogels, as a model therapeutic agent, and the in vitro release profiles of the drug were established at 37°C in pH 2.1 and 7.4. FTIR, SEM, and X‐ray diffraction analyses were used to characterize and investigate the structural changes of the gels with the variation of the blend composition and crosslinker content before and after the drug loading. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 2864–2874, 2007     

Preparation and evaluation of chitosan‐coated polyphosphazene hydrogel beads for drug controlled release

Chitosan‐coated polyphosphazene‐Ca²⁺ hydrogel beads were fabricated by dropping polyphosphazene into CaCl₂/chitosan gelling solution. Polyphosphazene used here was a water‐soluble degradable polyanion (PCPAP), which carried almost two carboxylatophenamino groups on each phosphorus atom of the polymer backbone. Two kinds of turbidimetric titration were applied in this study to reveal the interaction between PCPAP and chitosan within the pH range of 4.57≈7.14. The effect of gelling solution pH on the properties of chitosan‐coated PCPAP beads was especially emphasized. It was found that the PCPAP/chitosan complex prepared at relatively high pH (pH 6.5) dissociated most slowly in pH 7.4 phosphate‐buffered solution (PBS). The erosion of chitosan‐coated beads and the release of model drug (Coomassie brilliant blue and myoglobin) in PBS were both obviously prolonged with the increase of gelling solution pH, exhibiting perfect accordance with the behavior of complex dissociation. In addition, the coating of PCPAP/chitosan complex on the bead surface facilitated the improvement of drug loading efficiency. The higher the gelling solution pH, the more the drug loading efficiency improved. At pH 6.5 (PCPAP 5%, CaCl₂ 7%, chitosan 0.3%), the loading efficiency of myoglobin in beads reached as high as 93.2%. These results indicate that the chitosan‐coated polyphosphazene‐ Ca²⁺ bead is a potential formulation for drug controlled release. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 92: 1993–1999, 2004     

Swelling characteristics and in vitro drug release study with pH‐ and thermally sensitive hydrogels based on modified chitosan

The grafting of a poly(ethylene glycol) diacrylate macromer onto a chitosan backbone was carried out with different macromer concentrations. The grafting was achieved by (NH₄)₂Ce(NO₃)₆‐induced free‐radical poly merization. Biodegradable, pH‐ and thermally responsive hydrogels of poly(ethylene glycol)‐g‐chitosan crosslinked with a lower amount of glutaraldehyde were prepared for controlled drug release studies. Both the graft copolymers and the hydrogels were characterized with Fourier transform infrared, elemental analysis, and scanning electron microscopy. The obtained hydrogels were subjected to equilibrium swelling studies at different temperatures (25, 37, and 45°C) in buffer solutions of pHs 2.1 and 7.4 (similar to those of gastric and intestinal fluids, respectively). 5‐Fluorouracil was entrapped in these hydrogels, and equilibrium swelling studies were carried out for the drug‐entrapped gels at pHs 2.1 and 7.4 and 37°C. The in vitro release profile of the drug was established at 37°C and pHs 2.1 and 7.4. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 102: 977–985, 2006     

γ‐Irradiation preparation of poly(acrylic acid)–chitosan hydrogels for in vitro drug release

Biocompatible and biodegradable pH‐responsive hydrogels based on poly(acrylic acid) and chitosan were prepared for controlled drug delivery. These interpolymeric hydrogels were synthesized by a γ‐irradiation polymerization technique. The degree of gelation was over 96% and increased as the chitosan or acrylic acid (AAc) content increased. The equilibrium swelling studies of hydrogels prepared under various conditions were carried out in an aqueous solution, and the pH sensitivity in a range of pH 1–12 was investigated. The AAc/chitosan hydrogels showed the highest water content when 30 vol % AAc and 0.1 wt % chitosan were irradiated with a 30 kGy dose of radiation. In addition, an increase of the degree of swelling with an increase in the pH was noticed and it had the highest value at pH 12. The drug 5‐fluorouracil was loaded into these hydrogels and the release studies were carried out in simulated gastric and intestinal fluids. The in vitro release profiles of the drugs showed that more than 90% of the loaded drugs were released in the first 1 h at intestinal pH and the rest of the drug was released slowly. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 3270–3277, 2003     

Preparation of poly(acrylic acid)–chitosan hydrogels by gamma irradiation and in vitro drug release

Biocompatible and biodegradable pH‐responsive hydrogels based on poly(acrylic acid) (AAc) and chitosan were prepared for controlled drug delivery. These interpolymeric hydrogels were synthesized by a gamma irradiation polymerization technique. The degree of gelation was over 96% and increased as the chitosan or acrylic acid content increased. 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 pH 1–12 was investigated. The AAc/chitosan hydrogels showed the highest water content when the 30 vol % AAc and 0.1 wt % chitosan were irradiated with a 30‐kGy radiation dose. Also, an increase of swelling degree with an increase in the pH was noticed and showed the highest value at pH 12. The drug, 5‐fluorouracil, was loaded into these hydrogels and the release studies were carried out in simulated gastric and intestinal fluids. The in vitro release profiles of the drugs showed that more than 90% of the loaded drugs were released in the first 1 h at the intestinal pH and the rest of the drug had been released slowly. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 90: 3660–3667, 2003     

Facile fabrication of pH-responsive and swellable slow release microparticles of chlorpheniramine maleate with chitosan-starch matrices and their crosslinks

Abstract

We synthesized chitosan and modified same by blending with starch, crosslinking the matrices with sodium tripolyphosphate (TPP) and encapsulation with the drug chlorpheniramine maleate (CPM). These microparticles were characterized by FTIR, TGA, and SEM techniques. The amounts of CPM released from the microparticles generally decreased for the TPP-crosslinked beads but increased as the starch composition increased. Their release rates were best described by zero-order kinetics while their release mechanisms followed less-Fickian diffusional release. Our findings show that both the uncrosslinked and crosslinked chitosan-starch beads are promising carriers for the slow release of CPM.     

Barium chloride crosslinked carboxymethyl guar gum beads for gastrointestinal drug delivery

A mild method for microencapsulation of sensitive drugs, such as proteins, employing a suitably derivatized carboxymethyl guar gum (CMGG) and multivalent metal ions like Ca⁺⁺ and Ba⁺⁺ is reported. Initially, guar gum is derivatized with carboxymethyl groups so that it forms durable, self‐standing microbeads when its solution is dropped into CaCl₂ or BaCl₂ solutions. The swelling data of Ca⁺⁺ and Ba⁺⁺ crosslinked beads suggest that Ba⁺⁺ crosslinks CMGG much more efficiently than Ca⁺⁺. The drug loading efficiency of these Ba⁺⁺/CMGG beads, as a function of concentration of both metal ion as well as drug, was then determined using Bovine Serum Albumin as a model drug. The ability of these beads to protect the drug from the acidic environment of the stomach was investigated. It was found that a very little amount of the drug is released from the beads when they are suspended in NaCl–HCl buffer of pH 1.2 for 6 h. The beads were also shown to release almost the entire encapsulated drug when exposed to TRIS–HCl buffer of pH 7.4. Thus, the results indicate that Ba⁺⁺ crosslinked carboxymethyl guar gum beads can be used for gastrointestinal drug delivery. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 82: 3084–3090, 2001     

Studies on preparation and swelling properties of the N-isopropylacrylamide/chitosan semi-IPN and IPN hydrogels

Semi-interpenetrating network (semi-IPN) polymer gels and interpenetrating network (IPN) polymer gels with thermosensitivity were prepared by introducing a biodegradable polymer, chitosan, into the N-isopropyacrylamide (PNIPAAm) gel system. The swelling behavior, temperature sensitivity, pH sensitivity, gel strength, and drug-release behavior of PNIPAAm/chitosan semi-IPN and IPN hydrogels were investigated. The results indicated that the NIPAAm/chitosan semi-IPN and IPN hydrogels exhibited pH and temperature-sensitivity behavior and could slow drug release and diffusion from the gels. From the stress–strain curves of the hydrogels, the compression moduli of IPN gels containing crosslinked chitosan were higher than those of semi-IPN gels. This is because IPN gels have a more compact structure. The morphology of PNIPAAm/chitosan hydrogels was also investigated. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 82: 2487–2496, 2001     

Calcium‐carboxymethyl chitosan hydrogel beads for protein drug delivery system

In this study, carboxymethyl chitosan (CMC) hydrogel beads were prepared by crosslinking with Ca²⁺. The pH‐sensitive characteristics of the beads were investigated by simulating gastrointestinal pH conditions. As a potential protein drug delivery system, the beads were loaded with a model protein (bovine serum albumin, BSA). To improve the entrapment efficiency of BSA, the beads were further coated with a chitosan/CMC polyelectrolyte complex (PEC) membrane by extruding a CMC/BSA solution into a CaCl₂/chitosan gelation medium. Finally, the release studies of BSA‐loaded beads were conducted. We found that, the maximum swelling ratios of the beads at pH 7.4 (17–21) were much higher than those at pH 1.2 (2–2.5). Higher entrapment efficiency (73.2%) was achieved in the chitosan‐coated calcium‐CMC beads, compared with that (44.4%) in the bare calcium‐CMC beads. The PEC membrane limited the BSA release, while the final disintegration of beads at pH 7.4 still leaded to a full BSA release. Therefore, the chitosan‐coated calcium‐CMC hydrogel beads with higher entrapment efficiency and proper protein release properties were a promising protein drug carrier for the site‐specific release in the intestine. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 3164–3168, 2007     

Glutaraldehyde‐crosslinked chitosan beads for controlled release of diclofenac sodium

An inexpensive and simple method was adopted for the preparation of chitosan beads, crosslinked with glutaraldehyde (GA), for the controlled release of diclofenac sodium (DS). The beads were prepared by varying the experimental conditions such as pH, temperature, and extent of crosslinking. The absence of any chemical interaction among drug, polymer, and the crosslinking agent was confirmed by FTIR and thermal analysis. The beads were characterized by microscopy, which indicated that the particles were in the size range of 500–700 μm and SEM studies revealed smooth surface and spherical shape of beads. The beads produced at higher temperature and extended exposure to GA exhibited lower drug content, whereas increased drug loading resulted in enhanced drug release. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 211–217, 2007     

Preparation and Swelling Study of a pH-Dependent Interpolymeric Hydrogel Based on Chitosan for Controlled Drug Release

Novel pH-dependent, biodegradable interpolymeric network (IPN) hydrogels were prepared for controlled drug release investigations. The IPN hydrogels were prepared by irradiation of solutions of N-acryloyglycine (NAGly), polyethylene glycol diacrylate (PEGDA) mixed with chitosan, in the presence of a lower amount of glutaraldehyde as the crosslinker and using 2,2-dimethoxy-2-phenyl acetophenone as the photo-initiator. The equilibrium swelling studies were carried out for the gels at 37°C in buffer solutions of pH 2.1 and 7.4 (simulated gastric and intestinal fluids, respectively). 5-Fluorouracil (5-FU) was entrapped, as a model therapeutic agent, in the hydrogels and equilibrium-swelling studies were carried out for the drug-entrapped gels at 37°C. The in-vitro release profiles of the drug were established at 37°C in pH 2.1 and 7.4.     

Preparation and in vitro evaluation of new pH‐sensitive hydrogel beads for oral delivery of protein drugs

New biodegradable pH‐responsive hydrogel beads based on chemically modified chitosan and sodium alginate were prepared and characterized for the controlled release study of protein drugs in the small intestine. The ionotropic gelation reaction was carried out under mild aqueous conditions, which should be appropriate for the retention of the biological activity of an uploaded protein drug. The equilibrium swelling studies were carried out for the hydrogel beads at 37°C in simulated gastric (SGF) and simulated intestinal (SIF) fluids. Bovine serum albumin (BSA), a model for protein drugs was entrapped in the hydrogels and the in vitro drug release profiles were established at 37°C in SGF and SIF. The preliminary investigation of the hydrogel beads prepared in this study showed high entrapment efficiency (up to 97%) and promising release profiles of BSA. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Release of vitamin B12 from poly(N‐vinyl‐2‐pyrrolidone)‐crosslinked polyacrylamide hydrogels: A kinetic study

Hydrogels, composed of poly(N‐vinyl‐2‐pyrrolidone) and crosslinked polyacrylamide, were synthesized and the release of vitamin B₁₂ from these hydrogels was studied as a function of the degree of crosslinking and pH of the external swelling media. The three drug‐loaded hydrogel samples synthesized with different crosslinking ratios of 0.3, 0.7, and 1.2 (in mol %) follow different drug‐release mechanisms, that is, chain relaxation with zero‐order, non‐Fickian and Fickian, or diffusion‐controlled mechanisms. To establish a correlation between their swelling behavior and drug‐release mechanism, the former was studied by the weight‐gain method and, at the same time, the concentration of the drug released was studied colorimetrically. Various swelling parameters such as the swelling exponent n, gel‐characteristic constant k, penetration velocity v, and diffusion coefficient D were evaluated to reflect the quantitative aspect of the swelling behavior of these hydrogels. Finally, the drug‐release behavior of the hydrogels was explained by proposing the swelling‐dependent mechanism. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 76: 1706–1714, 2000     

Delivery of bupivacaine included in poly(acrylamide‐co‐monomethyl itaconate) hydrogels as a function of the pH swelling medium

Copolymeric hydrogels of poly(acrylamide‐co‐monomethyl itaconate) (A/MMI) crosslinked with N,N′‐methylenbisacrylamide (NBA) were synthesized as devices for the controlled release of bupivacaine (Bp). Two compositions of the copolymer, 60A/40MMI and 75A/25MMI, were studied. A local anesthetic was included in the feed mixture of polymerization (2–8 mg Bp/tablet) and by immersion of the copolymeric tablets in an aqueous solution of the drug. A very large amount of Bp (36–38 mg Bp/tablet) was included in the gels by sorption due to interactions between the drug and the side groups of the hydrogels. Swelling and drug release were in accordance with the second Fick's law at the first stages of the processes. The swelling behavior of these copolymers depended on the pH of the medium. The equilibrium swelling degree (W_∞) was larger at pH 7.5 (W_∞ ≈ 90 wt %) than at pH 1.5 (W_∞ ≈ 52–64 wt %) due to the ionization of the side groups of the copolymer. Release of the drug also depended on the pH of the swelling medium; at pH 7.5, about 60% of the included drug was released, and at pH 1.5, about 80% was released. Bp release was controlled by the comonomer composition of the gels, their drug‐load, and the pH of the swelling medium. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 86: 327–334, 2002     

pH-/temperature-sensitive carboxymethyl chitosan/poly(N-isopropylacrylamide-co-methacrylic acid) IPN: preparation,characterization and sustained release of riboflavin

Dual crosslinked pH-/temperature-sensitive interpenetrating polymer networks (IPN) were prepared by free-radical copolymerization of N-isopropylacrylamide and methylacrylic acid (MAA) using N,N′-methylenebisacrylamide as a crosslinker in carboxymethyl chitosan (which was crosslinked by Ca²⁺) aqueous solution. Scanning electron microscopy was used to observe the morphologies of the IPN at different pH values and temperatures. The effects of MAA content and environmental pH on the “pH-/temperature-induced” phase transition behavior of the IPN hydrogels were investigated. The phase transition temperature was adjusted to 37 °C by changing the MAA content. The effects of drug-loaded content, crosslinking density, environmental pH, and temperature on the drug release behavior of the drug-loaded IPN hydrogel were also explored. Based on results, the hydrogel possessed pH/temperature sensitivity. The swelling ratio and phase translation temperature of the hydrogel were lower at lower pH. These values were lowest at pH 3.0. The release behavior of riboflavin was dependent on preparation condition, environmental pH, and temperature. Drug cumulative release was only 6 % at pH 1.8 for 2 h. The drug cumulative release was 13 % before the drug-loaded hydrogel reached the position with pH 6.8. The drug release rate was higher at lower temperature. Therefore, dual-crosslinked hydrogel holds much potential as a drug site-specific carrier.