Drug release behavior of beads and microgranules of chitosan

Beads and microgranules carriers have important potential applications for the administration of therapeutic molecules. A novel approach for the preparation of chitosan beads and microgranules is presented. The present work is an investigation of the in vitro release kinetics of diclofenac sodium (DFS) from chitosan beads and microgranules. The in vitro release profiles of DFS from chitosan beads and microgranules are monitored using Shimadzu 1601 UV-VIS spectrophotometer. Drug release behavior of beads and microgranules has been compared. The release rate of DFS from the beads has been found to be slower in comparison to the microgranules. It may also be noted that the percent and amount of the drug release were much higher in acidic solution than in basic solution, probably due to the swelling properties of the matrix at acidic pH.     

Physically crosslinked alginate/N,O-carboxymethyl chitosan hydrogels with calcium for oral delivery of protein drugs

In the study, a complex composed of alginate blended with a water-soluble chitosan (N,O-carboxymethyl chitosan, NOCC) was prepared to form microencapsulated beads by dropping aqueous alginate-NOCC into a Ca(2+) solution. These microencapsulated beads were evaluated as a pH-sensitive system for delivery of a model protein drug (bovine serum albumin, BSA). The main advantage of this system is that all procedures used were performed in aqueous medium at neutral environment, which may preserve the bioactivity of protein drugs. The swelling characteristics of these hydrogel beads at distinct compositions as a function of pH values were investigated. It was found that the test beads with an alginate-to-NOCC weight ratio of 1:1 had a better swelling characteristic among all studied groups. With increasing the total concentration of alginate-NOCC, the effective crosslinking density of test beads increased significantly and a greater amount of drug was entrapped in the polymer chains (up to 77%). The swelling ratios of all test groups were approximately the same ( approximately 3.0) at pH 1.2. At pH 7.4, with increasing the total concentration of alginate-NOCC, the swelling ratios of test beads increased significantly (20.0-40.0), due to a larger swelling force created by the electrostatic repulsion between the ionized acid groups (-COO(-)). It was shown that BSA was uniformly distributed in all test beads. At pH 1.2, retention of BSA in hydrogels may be improved by rinsing test beads with acetone (the amount of BSA released was below 15%). At pH 7.4, the amounts of BSA released increased significantly ( approximately 80%) as compared to those released at pH 1.2. With increasing the total concentration of alginate-NOCC, the release of encapsulated proteins was slower. Thus, the calcium-alginate-NOCC beads with distinct total concentrations developed in the study may be used as a potential system for oral delivery of protein drugs to different regions of the intestinal tract.     

pH-responsive swelling behavior of collagen complex materials

This article deals with an natural collagen blended with chitosan, poly(vinyl alcohol)(PVA). We investigated the swelling properties of collagen and collagen complex in the solution with different pH, and the swelling/deswelling behavior of collagen and collagen-chitosan complex when changing the pH of the medium from 5.4 to 1.8 and in the reverse. The results show that the swelling degree of collagen and collagen complex are dependent to pH of the solution, and the swelling behavior of collagen and collagen-chitosan complex are pH-responsive.     

Immobilization of lipase using hydrophilic polymers in the form of hydrogel beads

The purpose of this study was to immobilize lipase (triacylglycerol ester hydrolase, E.C. 3.1.1.3) from Candida rugosa using various polymers in the form of beads, to evaluate enzyme loading, leaching, and activity; and to characterize the beads. Agarose, alginate, and chitosan were the polymers selected to immobilize lipase by entrapment. Agarose beads exhibited undesirable swelling in the leaching and activity medium and the polymer was not used further. Alginate or chitosan beads were prepared by ionic gelation using calcium chloride or sodium tripolyphosphate, respectively, as the cross-linking agent in the gelling solution. Some hatches of beads of each polymer were freeze dried. The results show that alginate beads leached substantially more enzyme than did chitosan beads. Entrapment efficiency, however, was the same for different chitosan levels as well as different alginate levels (43-50%). Activity in alginate was low at 240 +/- 33 and 220 +/- 26, compared to 1,110 +/- 51 and 1,150 +/- 11 units/ml in chitosan, for fresh and freeze-dried beads, respectively. The higher lipase activity in chitosan beads compared to that in alginate beads could be attributed to an alginate-enzyme interaction. It can be concluded that chitosan is a polymer worthy of pursuit to immobilize lipase.     

A pH-sensitive chitosan-tripolyphosphate hydrogel beads for controlled glipizide delivery

A chitosan(CS)-tripolyphosphate (TPP) hydrogel bead was prepared by the ionic gelation method for the controlled delivery of glipizide. The structure and surface morphology of the beads were characterized by FT-IR and SEM, separately. Factors influencing the swelling behavior of the hydrogel beads were also investigated, such as CS concentration (X(1)), TPP concentration (X(2)), the weight ratio of drug to polymer (X(3)), crosslinking time (X(4)), and the volume ratio of CS to TPP (X(5)). In addition, the swelling property and the delivery behavior of the hydrogel bead was studied as well. With decreasing of pH value, the swelling ratio of the bead was increasing. The swelling ratio of hydrogel bead at pH 1.5 was relatively high, while this value was low at pH 6.8. The amount of glipizide released from the hydrogel bead at pH 1.5 was about 90%, while this value approached 36% at pH 6.8. The results clearly suggested that the CS-TPP hydrogel beads were used as a pH-sensitive controlled release system for the delivery of glipizide.     

Swelling characteristics and drug delivery properties of nifedipine-loaded pH sensitive alginate-chitosan hydrogel beads

The aim of the present work was to investigate the swelling behavior and in vitro release of nifedipine from alginate-chitosan hydrogel beads. Structure and surface morphology of the hydrogel were characterized by FTIR and SEM, respectively. Alginate-chitosan mixed beads and alginate-chitosan coated beads were prepared by ionic gelation method. The swelling ability of the beads and in vitro release of nifedipine in simulated gastric fluid (pH 1.5) and different phosphate buffer solutions (pH 2.5, 5.0, 6.8, 7.4, and 8.0) were found to be dependent on the presence of the polyelectrolyte complex between chitosan and alginate. The amount of nifedipine released from the mixed beads at pH 1.5 was relatively low (42%), whereas this value approached to 99% at pH 6.8. In comparison with the mixed beads, the released nifedipine from the coated beads was minimal at pH 1.5 (18%), whereas approximately 99% nifedipine was released at pH 6.8. The results suggested that the coated beads can hold drug better at low pH than the mixed beads and show excellent pH sensitivity. Therefore, the alginate-chitosan coated beads could be a suitable polymeric carrier for drug delivery in the intestinal tract.     

Preparation and characterization of pH-sensitive hydrogel of chitosan/poly(acrylic acid) co-polymer

A pH-sensitive co-polymer hydrogel of chitosan/poly(acrylic acid) (CS/PAAc) was prepared by irradiating the aqueous solution mixture of chitosan and acrylic acid with 60Co gamma-ray irradiation. The effect of the composition of chitosan and AAc on the properties of the hydrogel, such as swelling ratio and pH-sensitivity, were determined. Fourier Transform Infrared (FT-IR) spectrometry was applied in the attenuated total reflectance (ATR) mode for analyzing the structure change of the hydrogels after the treatment in different pH buffer solutions.     

Fabrication of a pure porous chitosan bead matrix: influences of phase separation on the microstructure

The material properties and the microstructure of the scaffold are important parameters that determine the suitability of a material for tissue growth and controlled drug release. Because of its non-toxic, biocompatible, biodegradable, and antithrombogenic nature, chitosan has generated enormous interest for such applications. Chitosan bead-type scaffolds having various microstructures without any other material introduction were fabricated. For fabricating pure chitosan beads, a modified wet process and an extended thermally induced phase separation (TIPS) process were adapted. In the modified wet process, an acidic chitosan solution was phase-separated by changing its pH using an NaOH solution. The microstructure of the chitosan beads became looser with a decrease in the initial chitosan concentration, an increase in the acetic acid concentration, as well as with the addition of PEG to the dope solution. In contrast, the microstructure densified with an increase in the NaOH concentration in the coagulation bath. Through the modified wet process, porous chitosan beads with a relatively small pore size (0.01-13 microm) and moderate porosity (33-71%) could be prepared. In the extended TIPS process, chitosan solutions cast at different temperatures below 0 degrees C resulted in different microstructures wherein the microstructure densified with an increase in the quenching rate. The chitosan beads fabricated via extended TIPS had large pore sizes (26-120 microm) and high porosity (85-92%). All of these matrices showed good interconnected pores.     

A novel pH-sensitive membrane from chitosan--TEOS IPN; preparation and its drug permeation characteristics

A novel organic-inorganic composite membrane was prepared, using tetra ethyl ortho silicate (TEOS) as an inorganic material and chitosan as an organic compound. Equilibrium and oscillatory swelling studies were conducted to investigate swelling behaviors of the membrane according to the pH of the swelling medium. Drug permeation experiments were also performed in phosphate buffer solution of the pH of 2.5 and 7.5, respectively. Lidocaine HCl, sodium salicylate and 4-acetamidophenol were selected as model drugs to examine the effect of ionic property of drug on the permeation behavior. The effects of membrane composition and the external pH on the swelling and the drug permeation behavior of IPN membrane could be summarized as follows; chitosan incorporated into TEOS IPN swelled at pH 2.5 while shrunk at pH 7.5. This swelling behavior was completely reversible and the membrane responded rapidly to the change in environmental pH condition. According to swelling behavior, an increase in pH from 2.5 to 7.5 yielded an increase in the rate of drug permeation because of the shrinking of the incorporated chitosan in TEOS IPN, while decrease in pH resulted in low permeation rate. The optimal TEOS-chitosan ratio for maximum pH-sensitivity existed and drug permeation was influenced not only with the external pH but also with the ionic interactions between the drug and membrane.     

Molecular weight and degree of deacetylation effects on lipase-loaded chitosan bead characteristics

The effects of the molecular weight (MW) and degree of deacetylation (DD) of chitosan on chitosan hydrogel beads were characterized, and the entrapment efficiency, release of entrapped lipase, and activity of immobilized Candida rugosa lipase were investigated. Fresh and freeze-dried beads were characterized. A solution of lipase was prepared in a 1.5% (w/v) chitosan and 1% (v/v) acetic acid medium, and then dropped into a tripolyphosphate solution to prepare the beads. The release studies were performed over 36 h. The enzyme activity was assayed using the Sigma lipase activity method. Chitosan with high MW and DD resulted in a higher loading. A lower activity was observed for beads produced with high DD chitosan. MW did not have a marked effect on the activity. The release study revealed that enzyme release increased to a maximum when the bead was manufactured with a low MW and a moderate to high DD chitosan sample. Freeze drying did not affect the release or the activity of the lipase. Chitosan with a high MW and DD can thus improve loading and reduce the release of lipase in these beads. The choice of chitosan can affect the activity normalized for lipase loading, and beads with desirable qualities can be produced.     

Effects of preparative parameters on the properties of chitosan hydrogel beads containing Candida rugosa lipase

The influences of the pH, tripolyphosphate (TPP) concentration, and ionic strength of the gelling medium on the entrapment efficiency, release, and activity of lipase in chitosan hydrogel beads were studied. A solution of Candida rugosa lipase was prepared in a 1.5% w/v chitosan and 1% (v/v) acetic acid medium, and dropped into a TPP solution. Release of lipase in pH 7.2 Tris buffer was monitored over 36 h using the micro BCA protein assay. The activity of the entrapped enzyme was assayed using the Sigma lipase activity method. Following preliminary studies, an experimental design was followed to develop mathematical models that describe bead characteristics as functions of the pH and the TPP concentration in the gelling medium. The pH and the TPP concentration each had an effect on the entrapment, retention, and activity of lipase. Entrapped lipase retained a high degree of activity in multiple reactions. The ionic strength, in the range studied, exerted a minimal effect on bead characteristics. Statistical analysis allowed optimization within the factor space with respect to maximizing the enzyme entrapment efficiency and activity, and also minimizing the amount released after 36 h in the Tris buffer.     

Preparation and characterization of pH-sensitive hydrogel of chitosan/poly(acrylic acid) co-polymer

A pH-sensitive co-polymer hydrogel of chitosan/poly(acrylic acid) (CS/PAAc) was prepared by irradiating the aqueous solution mixture of chitosan and acrylic acid with ⁶⁰Co γ-ray irradiation. The effect of the composition of chitosan and AAc on the properties of the hydrogel, such as swelling ratio and pH-sensitivity, were determined. Fourier Transform Infrared (FT-IR) spectrometry was applied in the attenuated total reflectance (ATR) mode for analyzing the structure change of the hydrogels after the treatment in different pH buffer solutions.     

Preparation and swelling behavior of chitosan-based superporous hydrogels for gastric retention application

Chitosan and glycol chitosan hydrogels were prepared, and their swelling behaviors in acidic solution were studied to investigate their application for gastric retention device. The optimum preparation condition of superporous hydrogels was obtained from the gelation and blowing kinetics measured at varying acidic conditions. Both the swelling rate and swelling ratio of glycol chitosan hydrogels were higher than those of chitosan hydrogels. Swelling behaviors were significantly affected by not only foaming/drying methods but also crosslinking density, as the sizes and structures of pores generated were highly dependent on those preparation conditions. The prepared superporous hydrogels were highly sensitive to pH of swelling media, and showed reversible swelling and de-swelling behaviors maintaining their mechanical stability. The degradation kinetics in simulated gastric fluid was also studied.     

The influence of molecular weight of chitosan on the physical and biological properties of collagen/chitosan scaffolds

Biopolymer blends between collagen and chitosan have the potential to produce cell scaffolds with biocompatible properties. However, the relationship between the molecular weight of chitosan and its effect on physical and biological properties of collagen/chitosan scaffolds has not been elucidated yet. Porous scaffolds were fabricated by freeze-drying the solution of collagen and chitosan, followed by cross-linking by dehydrothermal treatment. Various types of scaffolds were prepared using chitosan with various molecular weights and blending ratios. Fourier transform infrared spectroscopy proved that collagen and chitosan scaffolds at all blending ratios contained mainly electrostatic interactions at the molecular level. The compressive modulus decreased with increasing the concentration of chitosan. Equilibrium swelling ratios of approximately 6-8, determined in phosphate-buffered saline at physiological pH (7.4), were found in case of collagen-dominated scaffolds. The lysozyme biodegradation test demonstrated that the presence of chitosan, especially the high-molecular-weight species, could significantly prolong the biodegradation of collagen/chitosan scaffolds. In vitro culture of L929 mouse connective tissue fibroblast evidenced that low-molecular-weight chitosan was more effective to promote and accelerate cell proliferation, particularly for scaffolds containing 30 wt% chitosan. The results elucidated that the blends of collagen with low-molecular-weight chitosan have a high potential to be applied as new materials for skin-tissue engineering.     

Immobilization of Candida rugosa lipase on chitosan with activation of the hydroxyl groups

A method for immobilization of Candida rugosa lipase to two types of chitosan beads by activating the hydroxyl groups of chitosan using carbodiimide coupling agent has been successfully developed. The ability of carbodiimide to activate the hydroxyl groups of chitosan was confirmed using the electron spectroscopy for chemical analysis (ESCA) technique. The properties of lipase immobilized using dry and wet chitosan beads were also investigated and compared. Immobilization enhanced the enzyme stability against changes of pH and temperature. High storage stability of 30 days and an increased enzyme activity of 2,110% were observed in wet immobilized lipase. Immobilized lipase using dry and wet chitosan beads retained 78% and 85% of its initial activity after 10 batch hydrolytic cycles. The kinetic parameters Km and Vmax were determined for the free and immobilized lipase. The activation energy (Ea) was found to decrease for immobilization of lipase on chitosan beads.     

The influence of molecular weight of chitosan on the physical and biological properties of collagen/chitosan scaffolds

Biopolymer blends between collagen and chitosan have the potential to produce cell scaffolds with biocompatible properties. However, the relationship between the molecular weight of chitosan and its effect on physical and biological properties of collagen/chitosan scaffolds has not been elucidated yet. Porous scaffolds were fabricated by freeze-drying the solution of collagen and chitosan, followed by cross-linking by dehydrothermal treatment. Various types of scaffolds were prepared using chitosan with various molecular weights and blending ratios. Fourier transform infrared spectroscopy proved that collagen and chitosan scaffolds at all blending ratios contained mainly electrostatic interactions at the molecular level. The compressive modulus decreased with increasing the concentration of chitosan. Equilibrium swelling ratios of approximately 6–8, determined in phosphate-buffered saline at physiological pH (7.4), were found in case of collagen-dominated scaffolds. The lysozyme biodegradation test demonstrated that the presence of chitosan, especially the high-molecular-weight species, could significantly prolong the biodegradation of collagen/chitosan scaffolds. In vitro culture of L929 mouse connective tissue fibroblast evidenced that low-molecular-weight chitosan was more effective to promote and accelerate cell proliferation, particularly for scaffolds containing 30 wt% chitosan. The results elucidated that the blends of collagen with low-molecular-weight chitosan have a high potential to be applied as new materials for skin-tissue engineering.     

Formation of Concentric Multilayers in a Chitosan Hydrogel Inspired by Liesegang Ring Phenomena

Liesegang rings, periodical bands or ring patterns formed by inorganic precipitation in polymer gel medium, have attracted lots of interest of researchers aiming to construct ordered structures. Inspired by the Liesegang ring phenomena, chitosan, instead of inorganic species, was used as building block to construct a chitosan hydrogel with concentric multilayers in a protonated chitosan/NaOH reaction system by alternate soaking in NaOH solution and water. The morphology of concentric multilayers structure was characterized by environmental scanning electron microscopy. The upload and release behavior of isoniazid was also investigated. The quantitive rules of the concentric layer position/the square root of reaction time and the position of the consecutive concentric layer coincide with the time law and space law of the classical Liesegang ring phenomena, respectively. The chitosan solution converts into a hydrogel accompanied by remarkable volume shrinkage due to hydrogen bonds reconstruction and electrostatic repulsion disappearance. The separated concentric multilayers can be formed due to the fluctuation of hydroxide ions concentration when the neutralization is interrupted by alternate soaking in NaOH solution and water. The major difference of the concentric multilayers in chitosan hydrogel from the classical Liesegang ring phenomena occurring in inorganic precipitation systems is that chitosan not only plays the role of reactant in chitosan hydrogel formation, but also acts as supporting reaction medium to control the diffusion behavior of hydroxide ions. The porosity and equilibrium swelling ratio of the chitosan xerogel are 63% and 1100%, respectively, which is feasible for drug uploading through diffusion or absorption. The isoniazid release kinetics are dominated by the diffusion–erosion model. The chitosan hydrogel with concentric multilayers structure loaded with isoniazid will have wide applications in treatment of bone tuberculosis.     

Adsorption of bovine serum albumin onto surface-modified polyhydroxyethyl methacrylate beads

The adsorption of bovine serum albumin (BSA) onto poly(2-hydroxyethyl methacrylate) (PHEMA) beads modified by using the pair of hexamethylene diisocyonate-suberic acidbis-N-hydroxy succinimide has been studied as a function of protein concentration and adsorption time. The adsorption studies were carried out in phosphate buffer solution (PBS) at pH = 7.4. The isotherm data have been analysed using the Langmuir model and the adsorption parameters Q0 and b were calculated. It is determined that the adsorbed amount of BSA increases by the increase of the adsorption time and BSA concentration until a certain value. PHEMA beads were characterized by using FTIR spectra and SEM analysis. The adsorption of BSA onto PHEMA beads were clearly observed from SEM micrographs. The swelling tests of the beads were performed at 37 degrees C in PBS.     

Polyacrylamide-Grafted-Alginate-Based pH-Sensitive Hydrogel Beads for Delivery of Ketoprofen to the Intestine: in Vitro and in Vivo Evaluation

A pH-sensitive graft co-polymer of polyacrylamide (PAAm) and sodium alginate (SA) was synthesized by free radical polymerization under a nitrogen atmosphere followed by alkaline hydrolysis. The co-polymer was characterized by Fourier transform infrared (FT-IR) spectroscopy, elemental analysis and thermogravimetric analysis (TGA). Ketoprofen-loaded graft co-polymer beads were prepared by ionotropic gelation/covalent cross-linking. The beads were characterized by swelling studies, differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). A pulsatile swelling study indicated that the co-polymer exhibits considerable pH-sensitive behavior. Release of ketoprofen was significantly increased when the pH of the medium was changed from acidic to alkaline. Stomach histopathology of albino rats indicated that the beads were able to retard the release of the drug in the stomach, and gastric side-effects like ulceration, hemorrhage and erosion of gastric mucosa were diminished when the drug was entrapped into PAAm-g-SA-based pH-sensitive hydrogel beads.     

Magnetic/pH-sensitive κ-carrageenan/sodium alginate hydrogel nanocomposite beads: preparation,swelling behavior,and drug delivery

This work describes the preparation of magnetic and pH-sensitive beads based on κ-carrageenan and sodium alginate for use as drug-targeting carriers. Physical cross-linking using K⁺/Ca²⁺ ions was applied to obtain ionic cross-linked magnetic hydrogel beads. The produced magnetite beads were thoroughly characterized by TEM, SEM/EDS, XRD, FTIR, and VSM techniques. While the water absorbency (WA) of magnetic beads was enhanced by increasing the weight ratio of κ-carrageenan, introducing magnetic nanoparticles caused a decrease in WA capacity from 15.4 to 6.3 g/g. Investigation on the swelling of the hydrogel beads in NaCl, KCl, and CaCl₂ solutions revealed the disintegration of beads depending on the composition of hydrogel beads and the type of metal cations in swelling media. The swelling ratio of beads indicated pH-dependent properties with maximum water absorbing at pH 7.4. Also, it was found that the strength of pH-sensitivity of magnetic beads was low for beads with the high content of carrageenan component. The in vitro drug release studies from hydrogels exhibited significant behaviors on the subject of physiological-simulated pH values and external magnetic fields. The maximum cumulative releases obtained were 98 and 43% at pH values 7.4 and 1.2, respectively. The Introducing magnetite nanoparticles influenced the cumulative release of drug.