Release characteristics of brilliant blue from calcium-alginate beads coated with quaternized chitosan

Calcium-alginate beads coated with quaternized chitosan were prepared in a neutral environment, and morphologies were observed by SEM. Optimum conditions for the encapsulation and retention of a model drug (brilliant blue, BB) in acid were obtained from studies of preparation conditions, including alginate and quaternized chitosan concentration, calcium chloride (CaCl2) concentration in the gelling medium and by comparing one-step and two-step preparation methods. Results showed that very high BB encapsulation efficiency (99%, w/w) and low leakage in acid (8%, w/w) was achieved from dry beads when 2.0% (w/v) alginate was dropped into 1.0% (w/v) CaCl2 containing 0.3% (w/v) quaternized chitosan by a one-step method. The release of BB in 0.9% (w/v) NaCl was modulated by coating calcium-alginate with different weight average molecule weight (Mw) and degree of substitution (DS) of quaternized chitosan. A decreased of Mw accelerated the release of BB and a high DS value significantly decreased the release in 0.9% (w/v) NaCl.     

Release characteristics of chitosan treated alginate beads: II. Sustained release of a low molecular drug from chitosan treated alginate beads

The aim of this paper was to investigate the possible applicability of chitosan treated alginate beads as a controlled release system of small molecular drugs with high solubility. Timolol maleate (mw 432.49) was used as a model drug. The beads were prepared by the ionotropic gelation method and the effect of various factors (alginate, chitosan, drug and calcium chloride concentrations, the volume of external and internal phases and drying methods) on bead properties were also investigated. Spherical beads with 0.78-1.16 mm diameter range and 10.8-66.5% encapsulation efficiencies were produced. Higher encapsulation efficiencies and retarded drug release were obtained with chitosan treated alginate beads. Among the different factors investigated such as alginate, drug, chitosan and CaCl2 concentrations, the volumes of the external and internal phases affected bead properties. The drying technique has an importance on the bead properties also. The release data was kinetically evaluated. It appeared that chitosan treated alginate beads may be used for a potential controlled release system of small molecular drugs with high solubility, instead of alginate beads.     

Novel solvent-based method for preparation of alginate beads with improved roundness and predictable size

Attempts to determine conditions or processes within alginate gel beads often suffer from inaccuracies due to an improper roundness of the analysed beads. Therefore, a novel solvent-based method for the preparation of alginate beads with improved shape was developed: An aqueous solution of 2% (w/v) alginate in water was injected into a solvent layering consisting of hexane, n-butanol, n-butanol with 1% (w/v) CaCl2 and finally 2% (w/v) CaCl2 in water. Beads of up to 3.5 mm in diameter obtained with this method had a roundness which was approximately 5% better than comparable beads prepared by dropping an alginate solution into a CaCl2-hardening bath. This was determined by a software supported quantitative analysis of bead size and shape. Additionally, the novel solvent-based method allows for highly reproducible preparation of alginate beads with exactly predictable sizes. The biggest beads obtained with this method were 9 mm in diameter. Thus, with the solvent-based preparation of alginate beads it is now possible to easily obtain beads of exactly the type needed for a specific analytical purpose.     

Preparation and characterization of Mitomycin-C loaded chitosan-coated alginate microspheres for chemoembolization

Mitomycin-C loaded and chitosan-coated alginate microspheres were prepared for use in chemoembolization studies. In this respect, first alginate microspheres were prepared by using a spraying method using an extrusion device with a small orifice and following suspension cross-linking in an oil phase. Chitosan-coating onto the alginate microspheres was achieved by polyionic complex formation between alginate and chitosan. CaCl(2) was used as a cross-linker for alginate microspheres. The obtained chitosan-coated alginate microspheres were spherical shaped and approximately 100-400 microm average size. The microspheres were evaluated based on their swellability and the swelling ratio was changed between 50-280%. CaCl(2) concentration, stirring rate, chitosan molecular weight, chitosan concentration and time for coating with chitosan were selected as the effective parameters on microsphere size and swelling ratio. Equilibrium swellings were achieved in approximately 30 min. On the other hand, chitosan molecular weight, chitosan concentration and time for coating with chitosan were found as the most effective parameters on both drug loading ratio and release studies. Maximum drug loading ratio of 65% was achieved with high molecular weight (HMW) chitosan, highest chitosan concentration (i.e. 1.0% v/v) and shortest time for coating with chitosan (i.e. 1 h) values.     

Microencapsulation of a recombinant aminopeptidase (PepN) from Lactobacillus rhamnosus S93 in chitosan-coated alginate beads

A recombinant aminopeptidase (90 kDa) of Lactobacillus rhamnosus S93 produced by E. coli was encapsulated in alginate or chitosan-treated alginate beads prepared by an extrusion method. This study investigated the effects of alginate, CaCl2, chitosan concentrations, hardening time, pH and alginate/enzyme ratios on the encapsulation efficiency (EE) and the enzyme release (ER). Chitosan in the gelling solution significantly increased the EE from 30.2% (control) to 88.6% (coated). This polycationic polymer retarded the ER from beads during their dissolution in release buffer. An increase in alginate and chitosan concentrations led to greater EE and lesser ER from the beads. The greatest EE was observed in a pH 5.4 solution (chitosan-CaCl2) during bead formation. Increasing the CaCl2 concentration over 0.1 M neither affected the EE nor the ER. Increasing hardening time beyond 10 min led to a decrease in EE and the alginate:enzyme ratio (3 : 1) was optimal to prevent the ER.     

pH-dependent release property of alginate beads containing calcium carbonate particles

Alginate bead containing calcium carbonate particle were prepared by dropping the suspension of alginate/calcium carbonate (4/1, w/w) into aqueous solution of CaCl(2) (0.1 M). The pH-dependent release property of the bead was observed for 12 h using blue dextran as a model drug. The release increased up to 4 h in a saturation manner. When no calcium carbonate was contained, the release exhibited no marked variation with pH and the values were 27-39%. On the other hand, in case calcium carbonate was included in the matrix of alginate beads, intensive release(40-50%) was achieved in acidic and neutral conditions and the degrees of release were suppressed in alkali conditions and the values were approximately 20%. The pH-sensitive release property is possibly because the particles of calcium carbonate embedded in the matrix of beads were leached out in acidic and neutral conditions, leaving cavities in the matrix. The cavities are likely to be main pathways for the release of blue dextran.     

Preparation and in vitro evaluation of mucoadhesive properties of alginate/chitosan microparticles containing prednisolone

This study describes the preparation of mucoadhesive alginate/chitosan microparticles containing prednisolone intended for colon-specific delivery. Two methods have been used for the preparation of the particles: the one-step method is the method in which prednisolone was dispersed within sodium alginate solution and this dispersion was then dropped in a solution containing both calcium chloride and chitosan. The two-step method consisted also of the dispersion of prednisolone in alginate solution and then dropping this dispersion into a solution containing calcium chloride, the particles were then transferred to a chitosan solution. The concentration of sodium alginate solution at 2% (w/v), various concentrations of calcium chloride solution (0.5-1.0%, w/v), chitosan solutions (0.5, 1.0 and 1.5%, w/v) and prednisolone drug load (2, 5, 10 and 15%, w/v) have been used. The results for both preparation methods show that the particle size and drug content were mainly depending on the amount of the drug concentration and not the amount of chitosan and calcium chloride. The in vitro mucoadhesive tests for particles prepared from both methods were carried out using the freshly excised gut of pigs. The particles prepared by the one-step method exhibited excellent mucoadhesive properties after 1h test. Increased chitosan concentrations from 0, 0.5, 1.0 to 1.5% (w/v) resulted in 43, 55, 82 and 88% of the particle remaining attached on the gut surface after 1 h, respectively. However, the particles prepared by the two-step method showed significant less mucoadhesion under the same experimental conditions. At chitosan concentrations of 0, 0.5, 1.0 and 1.5% (w/v) the amount of particles remaining attached to the mucosal surface of the pig gut after 1 h was 43, 3, 11 and 11%, respectively. The prednisolone release at a pH of 6.8 after 4 h was between 63 and 79% for the particles prepared by the one-step method and between 57 and 88% for the particles prepared by the two-step method with a prednisolone drug load of 5 and 10% (w/v), respectively. The results show that depending on the preparation method these chitosan coated alginate particles show different mucoadhesiveness whereas their other properties are not statistically significant different.     

Swelling studies and in vitro release of verapamil from calcium alginate and calcium alginate-chitosan beads

The aim of the present work was to investigate the swelling behavior and the in vitro release of the antihypertensive drug verapamil hydrochloride from calcium alginate and chitosan treated calcium alginate beads. Calcium-alginate beads, chitosan-coated alginate beads and alginate-chitosan mixed beads were synthesized and their morphology was investigated by scanning electron microscopy. The swelling ability of the beads in different media was found to be dependent on the presence of the polyelectrolyte complex between alginate and chitosan, the pH of the aqueous media and the initial physical state of the beads. The results revealed that the encapsulation of verapamil in both calcium-alginate and calcium alginate-chitosan mixed beads exceeded 80%. Considering the in vitro stability of verapamil encapsulating beads, 70% of the drug released from wet and dry plain calcium alginate beads within 1 and 3h, respectively. The presence of chitosan was found to retard significantly the release from wet beads. However, in the case of dry beads the presence of chitosan had no significant effect on the initial release stage and significantly increased the release on the later stage. The results were analyzed by using a semi-empirical equation and it was found that the drug release mechanisms were either "anomalous transport" or "case-II transport".     

海藻酸钙凝胶微丸作为口服缓释给药载体的研究

将海藻酸钠溶液滴入胶凝剂氯化钙溶液中制备了海藻酸钙凝胶微丸。以胶凝过程中凝胶微丸重量变化 (失水量 )研究了胶凝速率及不同浓度海藻酸钠溶液 ( 1 %～ 4 % )与氯化钙溶液 ( 0 0 5～0 2 0mol/L)对胶凝速率的影响 ,结果是 6h前胶凝速率快 ,随后减慢 ,约 70h胶凝完全 ,氯化钙溶液的浓度≥ 0 1mol/L对胶凝速率无明显影响。干燥的凝胶微丸在不同水性介质中溶胀试验结果表明 :在温度约 37℃时 ,微丸在蒸馏水和 0 1mol/L盐酸 ( pH1 0 )中几乎不溶胀 ,而在磷酸盐缓冲溶液( pH6 8)中1h溶胀 ,溶胀后的微丸直径是干燥前湿微丸直径的 1 80 %。海藻酸钙凝胶微丸这种溶胀的 pH敏感性 ,使它能成为口服药物缓释制剂的载体。以硝苯地平为模型药物制备的海藻酸钙凝胶微丸 ,其体外释放试验结果 ,2h累积释放量为 2 0 %～ 30 % ,6h为 6 0 %～ 80 % ,1 2h时大于85 %。药物从微丸中的释放是以扩散和骨架溶蚀相结合的方式。由此可见 ,硝苯地平的海藻酸钙凝胶微丸具有缓释作用     

Calcium Alginate Beads as Core Carriers of 5-Aminosalicylic Acid

The utilization of calcium alginate beads as core carriers for delayed dissolution followed by burst release as a potential method of intestinal site specific drug delivery was investigated. 5-Aminosalicylic acid was spray-coated on dried calcium alginate beads and then coated with different percentages of enteric coating polymer and/or sustained-release polymer. Beads coated with more than 6% (w/w) methacrylic copolymer plastisized with dibutyl sebacate and triethyl citrate resisted release in 2-hr acid fluid challenge and allowed immediate dissolution upon transfer to simulated intestinal fluid. With 6% (w/w) methacrylic copolymer on top of 4% (w/w) ethylcellulose polymer, the major portion of drug did not release in 2 hr of acid treatment or the next 3 hr of simulated intestinal fluid treatment. This dosage form provides the possibility to deliver drug to the lower intestinal tract with minimal early release, followed by sustained release in the colon.     

Colonic delivery of beta-lactamases does not affect amoxicillin pharmacokinetics in rats

Pectin beads containing beta-lactamases were designed for the hydrolysis of colonic residual antibiotics responsible for the emergence of resistance. Beads were prepared by ionotropic gelation in CaCl2 and stabilized by coating with polyethylenimine (PEI) to resist disintegration in the upper GI tract. Particle characterization showed that dried beads had a diameter around 1 mm independently of the presence of PEI. Seven to ten percent (w/w) of PEI was located on bead surface forming a coating layer as observed by scanning electron microscopy. PEI improved considerably bead stability in simulated intestinal medium while affecting slightly the encapsulation efficiency of active beta-lactamases. Coated beads were able to preserve beta-lactamases from premature leakage in the upper GIT whereas, in simulated colonic medium, pectinases induced matrix degradation and reduction of beta-lactamase content especially in beads coated in a 0.8% PEI solution. Finally, the pharmacokinetics of amoxicillin in rat after oral administration was not modified by the co-administration of beads containing beta-lactamases. In conclusion, PEI-coated beads are stable in the upper GIT but remain sensitive to the action of pectinolytic enzymes allowing release of beta-lactamases in a colonic medium without modification of the absorption of a beta-lactam antibiotic when co-administered with loaded beads.     

Novel solvent-based method for preparation of alginate beads with improved roundness and predictable size

Attempts to determine conditions or processes within alginate gel beads often suffer from inaccuracies due to an improper roundness of the analysed beads. Therefore, a novel solvent-based method for the preparation of alginate beads with improved shape was developed: An aqueous solution of 2% (w/v) alginate in water was injected into a solvent layering consisting of hexane, n-butanol, n-butanol with 1% (w/v) CaCl₂ and finally 2% (w/v) CaCl₂ in water. Beads of up to 3.5?mm in diameter obtained with this method had a roundness which was ～5% better than comparable beads prepared by dropping an alginate solution into a CaCl₂-hardening bath. This was determined by a software supported quantitative analysis of bead size and shape. Additionally, the novel solvent-based method allows for highly reproducible preparation of alginate beads with exactly predictable sizes. The biggest beads obtained with this method were 9?mm in diameter. Thus, with the solvent-based preparation of alginate beads it is now possible to easily obtain beads of exactly the type needed for a specific analytical purpose.     

In vitro and in vivo studies of ibuprofen-loaded biodegradable alginate beads

The irritation effects of ibuprofen, a widely used non-steroidal anti-inflammatory drug (NSAID), were evaluated on mouse gastric and duodenal mucosa when suspended in 0.5% (w/v) sodiumcarboxymethylcellulose (NaCMC) solution and loaded in alginate beads. The ionotropic gelation method was used to prepare controlled release alginate beads of ibuprofen. The influence of various formulation factors on the encapsulation efficiency, as in vitro drug release and micromeritic properties, was investigated. Other variables included the alginate concentration, percentage drug loading and stirring speed during the microencapsulation process. Scanning electron micrographs of alginate beads loaded with ibuprofen showed rough surface morphology and particle sizes in the range of 1.15 +/- 0.4 - 3.15 +/- 0.6 mm. The yield of microspheres, as collected after drying, was generally 80-90%. Formulation code H showing t50% value of 3.5 h was chosen for in vivo trials because of the appropriate drug release properties. For in vivo trials, free ibuprofen (100 mg kg(-1)), blank and ibuprofen (100 mg kg(-1)) loaded alginate beads (formulation code H) were suspended in 0.5% (w/v) NaCMC solution and each group was given to six mice orally by gavage. NaCMC solution was used as a control in experimental studies. In vivo data showed that the administration of ibuprofen in alginate beads prevented the gastric lesions.     

Novel pH-sensitive citrate cross-linked chitosan film for drug controlled release

Turbidimetric titration revealed that there were electrostatic attractive interactions between citrate and chitosan in the pH region of 4.3-7.6, depending on their degree of ionization. Citrate cross-linked chitosan film was prepared simply by dipping chitosan film into sodium citrate solution. The swelling ratio of citrate/chitosan film was sensitive to pH, ionic strength etc. Under acidic conditions, citrate/chitosan film swelled and even dissociated in the pH less than 3.5, and the model drugs (brilliant blue and riboflavin) incorporated in the film were released quickly (usually within 2 h released completely in simulated gastric fluid at 37 degrees C) while under neutral conditions the swelling ratio of citrate/chitosan film was less significant and the release rate of brilliant blue and riboflavin was low (less than 40% released in simulated intestinal fluid in 24 h). Sodium chloride weakened the electrostatic interaction between citrate and chitosan, and therefore facilitated the film swelling and accelerated drug release. The parameters of film preparation such as citrate concentration, solution pH etc. influencing the film swelling and drug release profiles were examined. The lower concentration and the higher pH of citrate solution resulted in a larger swelling ratio and quicker riboflavin release. To improve the drug controlled release properties of citrate/chitosan film, heparin, pectin and alginate were further coated on the film surface. Among them only the coating of alginate prolonged riboflavin release noticeably (for 80% of drug released the time was extended from 1.5 to 3.5 h with 0.5% w/v alginate used). The results indicated that the citrate/chitosan film was useful in drug delivery such as for the site-specific drug controlled release in stomach.     

Mucoadhesive and floating chitosan-coated alginate beads for the controlled gastric release of amoxicillin

This work focused on the development of mucoadhesive and floating chitosan-coated alginate beads as a gastroretensive delivery vehicle for amoxicillin, towards the effective eradication of Helicobacter pylori, a major causative agent of peptic ulcers. Alginate was used as the core bead core polymer and chitosan as the mucoadhesive polymer coating. Amoxicillin-loaded alginate beads coated with 0.5% (w/v) chitosan (ALG/0.5%CHI) exhibited excellent floating ability, high encapsulation efficiency, high drug loading capacity, and a strong in vitro mucoadhesion to the gastric mucosal layer. In vitro, amoxicillin was released faster in simulated gastric fluid (pH 1.2, HCl) than in simulated intestinal fluid (phosphate buffer, pH 7.4). ALG/0.5%CHI could be prepared with a > 90% drug encapsulation efficiency and exhibited more than 90% muco-adhesiveness, 100% floating ability, and achieved sustained release of amoxicillin for over six hours in SGF.     

A Comparative Histological Study of Alginate Beads as a Promising Controlled Release Delivery for Mefenamic Acid

The new mefenamic acid-alginate bead formulation prepared by ionotropic gelation method using 3 × 2² factorial design has shown adequate controlled release properties in vitro. In the present study, the irritation effects of mefenamic acid (MA), a prominent non-steroidal anti-inflammatory (NSAI) drug, were evaluated on rat gastric and duodenal mucosa when suspended in 0.5% (w/v) sodiumcarboxymethylcellulose (NaCMC) solution and loaded in alginate beads. Wistar albino rats weighing 200 ± 50 g were used during in vivo animal studies. In this work, biodegradable controlled release MA beads and free MA were evaluated according to the degree of gastric or duodenal damage following oral administration in rats. The gastric and duodenal mucosa was examined for any haemorrhagic changes. Formulation code A10 showing both Case II transport and zero order drug release and t₅₀ % value of 5.22 h was chosen for in vivo animal studies. For in vivo trials, free MA (100 mgkg^?1), blank and MA (100 mgkg^?1) loaded alginate beads (formulation code A10) were suspended in 0.5% (w/v) NaCMC solution and each group was given to six rats orally by gavage. NaCMC solution was used as a control in experimental studies. In vivo data showed that the administration of MA in alginate beads prevented the gastric lesions.     

A comparative histological study of alginate beads as a promising controlled release delivery for mefenamic acid

The new mefenamic acid-alginate bead formulation prepared by ionotropic gelation method using 3 x 2(2) factorial design has shown adequate controlled release properties in vitro. In the present study, the irritation effects of mefenamic acid (MA), a prominent non-steroidal anti-inflammatory (NSAI) drug, were evaluated on rat gastric and duodenal mucosa when suspended in 0.5% (w/v) sodiumcarboxymethylcellulose (NaCMC) solution and loaded in alginate beads. Wistar albino rats weighing 200 +/- 50 g were used during in vivo animal studies. In this work, biodegradable controlled release MA beads and free MA were evaluated according to the degree of gastric or duodenal damage following oral administration in rats. The gastric and duodenal mucosa was examined for any haemorrhagic changes. Formulation code A10 showing both Case II transport and zero order drug release and t(50) % value of 5.22 h was chosen for in vivo animal studies. For in vivo trials, free MA (100 mgkg(-1)), blank and MA (100 mgkg(-1)) loaded alginate beads (formulation code A10) were suspended in 0.5% (w/v) NaCMC solution and each group was given to six rats orally by gavage. NaCMC solution was used as a control in experimental studies. In vivo data showed that the administration of MA in alginate beads prevented the gastric lesions.     

Preparation and release characteristics of polymer-coated and blended alginate microspheres

To prevent a rapid drug release from alginate microspheres in simulated intestinal media, alginate microspheres were coated or blended with polymers. Three polymers were selected and evaluated such as HPMC, Eudragit RS 30D and chitosan, as both coating materials and additive polymers for controlling the drug release. This study focused on the release characteristics of polymer-coated and blended alginate microspheres, varying the type of polymer and its concentration. The alginate microspheres were prepared by dropping the mixture of drug and sodium alginate into CaCl(2) solution using a spray-gun. Polymer-coated microspheres were prepared by adding alginate microspheres into polymer solution with mild stirring. Polymer-blended microspheres were prepared by dropping the mixture of drug, sodium alginate and additive polymer with plasticizer into CaCl(2) solution. In vitro release test was carried out to investigate the release profiles in 500 ml of phosphate buffered saline (PBS, pH 7.4). As the amount of polymer in sodium alginate or coating solution increase, the drug release generally decreased. HPMC-blended microspheres swelled but withstood the disintegration, showing an ideal linear release profiles. Chitosan-coated microspheres showed smooth and round surface and extended the release of drug. In comparison with chitosan-coated microspheres, HPMC-blended alginate microspheres can be easily made and used for controlled drug delivery systems due to convenient process and controlled drug release.     

Preparation and characterization of Mitomycin-C loaded chitosan-coated alginate microspheres for chemoembolization

Mitomycin-C loaded and chitosan-coated alginate microspheres were prepared for use in chemoembolization studies. In this respect, first alginate microspheres were prepared by using a spraying method using an extrusion device with a small orifice and following suspension cross-linking in an oil phase. Chitosan-coating onto the alginate microspheres was achieved by polyionic complex formation between alginate and chitosan. CaCl₂ was used as a cross-linker for alginate microspheres. The obtained chitosan-coated alginate microspheres were spherical shaped and ～100–400?µm average size. The microspheres were evaluated based on their swellability and the swelling ratio was changed between 50–280%. CaCl₂ concentration, stirring rate, chitosan molecular weight, chitosan concentration and time for coating with chitosan were selected as the effective parameters on microsphere size and swelling ratio. Equilibrium swellings were achieved in ～30?min. On the other hand, chitosan molecular weight, chitosan concentration and time for coating with chitosan were found as the most effective parameters on both drug loading ratio and release studies. Maximum drug loading ratio of 65% was achieved with high molecular weight (HMW) chitosan, highest chitosan concentration (i.e. 1.0% v/v) and shortest time for coating with chitosan (i.e. 1?h) values.     

Effect of manufacturing parameters on the characteristics of vitamin C encapsulated tripolyphosphate-chitosan microspheres prepared by spray-drying

To prepare the sustained release vitamin C carriers, vitamin C was successfully encapsulated in tripolyphosphate (TPP) cross-linked chitosan (TPP-chitosan) microspheres by the spray-drying method at different manufacturing conditions. Manufacturing parameters (inlet temperature, liquid flow rate, chitosan concentration and volume of 1% w/v TPP solution) had a significant influence on the characteristics of thus prepared microspheres. The optimum spray-drying conditions such as inlet temperature, liquid flow rate and compressed air flow rate for the encapsulation of vitamin C in TPP-chitosan microspheres was found to be 170 degrees C, 2 ml min(-1) and 101 min(-1), respectively. The size and yield of the TPP-chitosan microspheres ranged from 3.9-7.3 microm and 54.5-67.5%, respectively. The encapsulation efficiency of TPP-chitosan microspheres ranged from 45.72-68.7% and it decreased with the increasing volume of 1% w/v TPP solution. At the same cross-linking extent, the encapsulation efficiency of TPP-chitosan microspheres increased when the concentration of chitosan was increased from 0.5-1% w/v. Effect of volume of 1% w/v TPP solution on the surface morphology of chitosan microspheres was examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). These studies revealed that chitosan solution (250 ml) cross-linked with 15 ml 1% w/v TPP solution produced more porous microspheres than that cross-linked with 5 and 10 ml TPP solution. The release rate of vitamin C from TPP-chitosan microspheres decreased when the concentration of chitosan was increased from 0.5-1.0% w/v. Vitamin C release rate was also modulated by varying the volume of 1% w/v TPP solution. The release rate of vitamin C from TPP-chitosan microspheres decreased with increasing volume (5-15 ml) of 1% w/v TPP solution.