Calcium alginate microparticles for oral administration: I: Effect of sodium alginate type on drug release and drug entrapment efficiency.

The natural polymers alginate and chitosan were used for the preparation of controlled release nicardipine HCl gel microparticles. The effect of the mannuronic/guluronic acid content and the alginate viscosity on the prolonged action of the microparticles, which were prepared with different types of alginates, were investigated. The mean particle sizes and the swelling ratios of the microparticles were also determined. The in vitro release studies were carried out with a flow-through cell apparatus in different media (pH 1.2, 2.5, 4.5, 7 and 7.5 buffer solutions). The release of nicardipine was extended with the alginate gel microparticles prepared with guluronic acid rich alginate. After the determination of the most appropriate alginate type, the effect of alginate-chitosan complex formation was studied on the release pattern of drug incorporated. It was observed that the alginate-chitosan complex formation reduced the erosion of the alginate-chitosan matrix at pH 7-7.5. The release of drug from the chitosan-alginate gel microparticles took place by both diffusion through the swollen matrix and relaxation of the polymer at pH 1.2-4.5.     

Calcium alginate microparticles for oral administration: II effect of form ulation factors on drug release and drug entrapment efficiency

The release rate of nicardipine HCl from various alginate microparticles was investigated. Manugel A7B618 which has a high guluronic acid content of 70% and a low polymerization degree of 60-400 was used as alginate. A 23 factorial design was utilized for the preparation of the alginate microparticles. The effect of drug:polymer weight ratio, CaCl2 concentration and curing time on parameters such as the time for 50% of the drug to be released (t50%) and the drug entrapment efficiency were evaluated with analysis of variance. The mean particle sizes and the swelling ratios of the microparticles were determined. The in vitro release studies were carried out with a flow-through cell apparatus at different media (pH 1.2, 2.5, 4.5, 7, 7.5 buffer solutions). Drug:polymer weight ratio and the concentration of the crosslinking agent were the influential factors on the release of NC from the alginate microparticles. The release of nicardipine was extended with alginate microparticles prepared in aratio of 1:1 (drug:polymer weight ratio). The release of drug from alginate microparticles took place by both diffusion through the swollen matrix and relaxation of the polymer at pH: 1.2-4.5. However, the release was due to diffusion and erosion mechanisms at pH 7-7.5.     

Calcium alginate microparticles for oral administration: II. Effect of formulation factors on drug release and drug entrapment efficiency.

The release rate of nicardipine HCl from various alginate microparticles was investigated. Manugel A7B618 which has a high guluronic acid content of 70% and a low polymerization degree of 60-400 was used as alginate. A 2(3) factorial design was utilized for the preparation of the alginate microparticles. The effect of drug:polymer weight ratio, CaCl2 concentration and curing time on parameters such as the time for 50% of the drug to be released (t50%) and the drug entrapment efficiency were evaluated with analysis of variance. The mean particle sizes and the swelling ratios of the microparticles were determined. The in vitro release studies were carried out with a flow-through cell apparatus at different media (pH 1.2, 2.5, 4.5, 7, 7.5 buffer solutions). Drug:polymer weight ratio and the concentration of the crosslinking agent were the influential factors on the release of NC from the alginate microparticles. The release of nicardipine was extended with alginate microparticles prepared in a ratio of 1:1 (drug:polymer weight ratio). The release of drug from alginate microparticles took place by both diffusion through the swollen matrix and relaxation of the polymer at pH: 1.2-4.5. However, the release was due to diffusion and erosion mechanisms at pH 7-7.5.     

Sustained release of antineoplastic drugs from chitosan-reinforced alginate microparticle drug delivery systems

Alginate based microparticle drug delivery systems were prepared for the sustained release of antineoplastic drugs. Two drugs, 5-fluorouracil (5-FU) and tegafur, were encapsulated into the microparticles. The drug loaded microparticles were fabricated using a very convenient method under very mild conditions, i.e., directly shredding the drug loaded beads into microparticles in a commercial food processor. The mean sizes of the obtained microparticles were between 100 and 200 μm. To effectively sustain the drug release, alginate microparticles were reinforced by chitosan during gelation. The drug release from the chitosan-reinforced alginate microparticles was obviously slower than that from the unreinforced microparticles. The effect of the reinforcement conditions on the drug release property of the microparticles was studied, and the optimized concentration of chitosan solution for reinforcement was identified. The effects of drug feeding concentration and pH value of the release medium on the drug release were investigated.     

Impact of cross-linker on alginate matrix integrity and drug release

Sodium alginate, a biopolymer, was employed in the formulation of matrix tablets. They cracked or laminated at acidic pH, compromising their dissolution performance. Improved mechanical strength and reduced barrier permeability of calcium alginate gel provided the rationale for cross-linking the alginate matrix to sustain drug release. Studies had suggested that the incorporation of soluble calcium salts in alginate matrix tablets could sustain drug release at near-neutral pH due to in situ cross-linking. However, results from the present study showed otherwise when gastrointestinal pH conditions were simulated. Significant reduction in drug release rate was only observed when an external calcium source was utilized at low concentration. High calcium ion concentrations caused matrix disintegration. In contrast, matrices pre-coated by calcium alginate could sustain drug release at pH 1.2 followed by pH 6.8 for over 12h. The presence of cross-linked barrier impeded matrix lamination and preserved matrix structure, contributing to at least three-fold reduction in drug release at pH 1.2. Zero order release as well as delayed burst release could be achieved by employing appropriate grade of alginate and cross-linking conditions.     

Characterization of alginate/poly-L-lysine particles as antisense oligonucleotide carriers

The gel forming characteristics of alginate in the presence of calcium ions and further crosslinking with poly-L-lysine led to the formation of sponge-like nano- and microparticles. The particle size was varied by adjusting the final concentrations of and proportions between the components. The region for particle formation was from 0.04 to 0.08% (w/v) of alginate in the final formulation, the change from the nm to microm size range occurred at a concentration of approx. 0.055% (w/v). Oligonucleotide-loaded microparticles were prepared by two different methods, either by absorption of the drug into the crosslinked polymeric matrix or by incorporation of an oligonucleotide/poly-L-lysine complex into a calcium alginate pre-gel. The release of oligonucleotide from microparticles prepared by the first method was higher. The addition of increasing amounts of poly-L-lysine resulted in larger particles, higher oligonucleotide loading and slower drug release. An increase in the final solid content of the formulation led to larger particles, especially with high concentrated calcium alginate pre-gels. Microparticles based on alginate and poly-L-lysine are potential carriers for antisense oligonucleotides.     

Use of floating alginate gel beads for stomach-specific drug delivery.

Two types of alginate gel beads capable of floating in the gastric cavity were prepared. The first, alginate gel bead containing vegetable oil (ALGO), is a hydrogel bead and its buoyancy is attributable to vegetable oil held in the alginate gel matrix. The model drug, metronidazole (MZ), contained in ALGO was released gradually into artificial gastric juice, the release rate being inversely related to the percentage of oil. The second, alginate gel bead containing chitosan (ALCS), is a dried gel bead with dispersed chitosan in the matrix. The drug-release profile was not affected by the kind of chitosan contained in ALCS. When ALCS containing MZ was administered orally to guinea pigs, it floated on the gastric juice and released the drug into the stomach. Furthermore, the concentration of MZ at the gastric mucosa after administration of ALCS was higher than that in the solution, though the MZ serum concentration was the same regardless of which type of gel was administered. These release properties of alginate gels are applicable not only for sustained release of drugs but also for targeting the gastric mucosa.     

Preparation and characterization of chitosan-treated alginate microparticles incorporating all-trans retinoic acid

Chitosan treated alginate microparticles were prepared with the purpose of incorporating all-trans retinoic acid (ATRA) using an inexpensive, simple and fast method, enhancing dermal localization and sustaining the release of ATRA into the skin. Microparticles characterization, drug-polymer interaction, release profile and in vitro skin retention were investigated. Microparticles presented spherical shape and drug loading capacity of 47%. The drug content of these microparticles was affected by ATRA concentration and by the solvent used and it was more weakly affected by chitosan concentration. The release of ATRA was also affected by chitosan concentration. Microparticles prepared with 0.4% chitosan (w/w) resulted in drug release with a more sustained profile. The results of in vitro retention studies showed that chitosan treated alginate microparticles decreased the drug retention in the stratum corneum (SC), where occur the skin irritation, but maintained the ATRA concentration in the deeper skin layers, where occur the pathologies treated with ATRA. Then, the microparticles developed in this work can be a good candidate to improve the topical therapy with retinoid.     

Preparation and characterization of chitosan-treated alginate microparticles incorporating all-trans retinoic acid

Chitosan treated alginate microparticles were prepared with the purpose of incorporating all-trans retinoic acid (ATRA) using an inexpensive, simple and fast method, enhancing dermal localization and sustaining the release of ATRA into the skin. Microparticles characterization, drug–polymer interaction, release profile and in vitro skin retention were investigated. Microparticles presented spherical shape and drug loading capacity of 47%. The drug content of these microparticles was affected by ATRA concentration and by the solvent used and it was more weakly affected by chitosan concentration. The release of ATRA was also affected by chitosan concentration. Microparticles prepared with 0.4% chitosan (w/w) resulted in drug release with a more sustained profile. The results of in vitro retention studies showed that chitosan treated alginate microparticles decreased the drug retention in the stratum corneum (SC), where occur the skin irritation, but maintained the ATRA concentration in the deeper skin layers, where occur the pathologies treated with ATRA. Then, the microparticles developed in this work can be a good candidate to improve the topical therapy with retinoid.     

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".     

Release characteristics of chitosan treated alginate beads: I. Sustained release of a macromolecular drug from chitosan treated alginate beads

Alginate and chitosan treated alginate beads were prepared and compared as an oral controlled release system for macromolecular drugs. Dextran (M.W. 70,000) was used as a model substance. 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 investigated. The addition of chitosan increased the drug loading capacity of the beads, and larger beads were obtained in the presence of chitosan. On the other hand, addition of chitosan in the gel structure reduced the drug release from beads. The erosion of the beads was suppressed by chitosan treatment. The drying method was important to the properties of the chitosan-alginate beads. It is proposed that chitosan treated alginate beads may be used as a potential controlled release system of such macromolecules.     

Spray-Dried Lactose Composite Particles Containing an Ion Complex of Alginate-Chitosan for Designing a Dry-Coated Tablet Having a Time-Controlled Releasing Function

Purpose. The properties of novel spray-dried lactose compositeparticles suitable for the coating filler of a dry-coated tablet having a longinduction period in drug release were investigated. Methods. To prepare spray-dried composite particles containingalginate-chitosan complex (SD(L/AL-CS)), an aqueous solution of lactoseand sodium alginate and the acetic acid solution of chitosan wereconcomitantly fed into the rotary atomizer of a spray-dryer. Theformation of the alginate-chitosan complex was confirmed by measuring theweight of insoluble portion in the mixture of sodium alginate andchitosan solutions. The dissolution properties of the dry-coated tabletwere measured with the JP specified paddle method. Results. The micromeritic properties of SD(L/AL-CS) were comparedto those of the SD composite particles of lactose-sodium alginate,having a good compacting property. The drug release profiles ofdry-coated tablet with SD(L/AL-CS) contained a long induction periodfollowed by a rapid drug release phase in the artificial intestinal fluid.The induction period for drug release to occur was increased with anincrease in the degree of deacetylation of chitosan and in the amountof chitosan in the formulation. The prolongation of induction periodwas attributed to the formation of an insoluble ion complex betweensodium alginate and chitosan in the composite particles, which couldform a rigid gel structure on the tablet surface. Conclusions. A time-controlled release tablet was designed with thecomposite particles of lactose containing the alginate-chitosan ioncomplex. The induction period of the dry-coated tablet could be prolongedin order to deliver the drug to the colon by controlling the type andamount of chitosan formulated in the composite particles.     

Diffusion loading and drug delivery characteristics of alginate gel microparticles produced by a novel impinging aerosols method

Microencapsulation of a hydrophilic active (gentamicin sulphate (GS)) and a hydrophobic non-steroidal anti-inflammatory drug (ibuprofen) in alginate gel microparticles was accomplished by molecular diffusion of the drug species into microparticles produced by impinging aerosols of alginate solution and CaCl₂ cross-linking solution. A mean particle size in the range of 30–50 µm was measured using laser light scattering and high drug loadings of around 35 and 29% weight/dry microparticle weight were obtained for GS and ibuprofen respectively. GS release was similar in simulated intestinal fluid (phosphate buffer saline (PBS), pH 7.4, 37°C) and simulated gastric fluid (SGF) (HCl, pH 1.2, 37°C) but was accelerated in PBS following incubation of microparticles in HCl. Ibuprofen release was restricted in SGF but occurred freely on transfer of microparticles into PBS with almost 100% efficiency. GS released in PBS over 7?h, following incubation of microparticles in HCl for 2?h was found to retain at least 80% activity against Staphylococcus epidermidis while Ibuprofen retained around 50% activity against Candida albicans. The impinging aerosols technique shows potential for producing alginate gel microparticles of utility for protection and controlled delivery of a range of therapeutic molecules.     

Mucoadhesive microspheres for nasal administration of an antiemetic drug, metoclopramide: in-vitro/ex-vivo studies

Microparticulate delivery systems designed for the nasal administration of an antiemetic drug, metoclopramide hydrochloride, were prepared. Microspheres composed of sodium alginate, chitosan hydrochloride, or both, were obtained using a spray-drying method; some batches of drug-free microparticles were prepared as a comparison. The morphology, in-vitro swelling behaviour, mucoadhesive properties and drug release from microparticles were evaluated. Ex-vivo drug permeation tests were carried out using sheep nasal mucosa; permeation test of the drug solution was performed as comparison. During ex-vivo permeation tests, transmission electron microscopy (TEM) analyses were carried out on the nasal mucosa to study the morphological changes of epithelial cells and tight junctions, while the change in microsphere morphology was examined using photostereo microscopy (PM). Spray-dried microparticles had a mean diameter (d(vs)) in the range of about 3-10 microm. They showed good in-vitro mucoadhesive properties. In-vitro release profiles and swelling behaviour depended on their composition: the drug release occurred in 1-3 h. Ex-vivo studies showed that drug permeation through the mucosa from microparticles based on chitosan was higher than from those consisting of alginate alone. This can be related to the penetration enhancing properties of chitosan. Complexation of chitosan with alginate led to a control of the drug release. Microscopy observation of microspheres during the permeation tests revealed that microparticles swelled and gelled, maintaining their shape. TEM analyses of the mucosa after exposure to the microparticles consisting of alginate/chitosan showed opened tight junctions. This preliminary study shows that alginate/chitosan spray-dried microspheres have promising properties for use as mucoadhesive nasal carriers of an antiemetic drug.     

Development of polysaccharide gel-coated pellets for oral administration. 2. Calcium alginate.

Calcium alginate gel-coated pellets were developed by forming an insoluble gel coat on extruded-spheronized pellets by interfacial complexation. Experiments were designed to investigate the effect of pellet size, alginate type, alginate concentration, and dissolution medium on swelling and drug release behavior. Low swelling in acidic media was related to proton-calcium ion exchange forming insoluble acid gels. In contrast, partial formation of soluble sodium alginate in 0.1M NaCl induced water uptake, resulting in greater swelling. Drug release from coated pellets showed a lag time when the gel coat hydrated and swelled, followed by a zero-order release. Significantly slower release was observed when either the pellet size or the alginate concentration was increased. Alginate with high guluronic acid content gave the slowest release. Different types of alginate with high mannuronic acid content showed different release behaviors that are probably due to the different monomer sequences and botanical sources. The faster drug release in acidic media and 0.1M NaCl compared to water is probably due to reduced calcium cross-linking in the gel. These results suggest that the pellet size, alginate type and concentration and dissolution medium influenced the swelling and drug release behavior of calcium alginate gel-coated pellets.     

Bile salt-reinforced alginate-chitosan beads

A polymeric delayed release protein delivery system was investigated with albumin as the model drug. The polysaccharide chitosan was reacted with sodium alginate in the presence of calcium chloride to form beads with a polyelectrolyte. In this study, attempts were made to extend albumin release in the phosphate buffer at pH 6.8 from the alginate-chitosan beads by reinforcing the matrix with bile salts. Sodium taurocholate was able to prevent albumin release at pH 1.2, protecting the protein from the acidic environment and extending the total albumin release at pH 6.8. This effect was explained by an interaction between the permanent negatively charged sulfonic acid of sodium taurocholate with the amino groups of chitosan. Mild formulation conditions, high bovine serum albumin (BSA) entrapment efficiency, and resistance to gastrointestinal release seem to be synergic and promising factors toward the development of an oral protein delivery form.     

Ionic gelation controlled drug delivery systems for gastric-mucoadhesive microcapsules of captopril

A new oral drug delivery system was developed utilizing both the concepts of controlled release and mucoadhesiveness, in order to obtain a unique drug delivery system which could remain in stomach and control the drug release for longer period of time. Captopril microcapsules were prepared with a coat consisting of alginate and a mucoadhesive polymer such as hydroxy propyl methyl cellulose, carbopol 934p, chitosan and cellulose acetate phthalate using emulsification ionic gelation process. The resulting microcapsules were discrete, large, spherical and free flowing. Microencapsulation efficiency was 41.7-89.7% and high percentage efficiency was observed with (9:1) alginate-chitosan microcapsules. All alginate-carbopol 934p microcapsules exhibited good mucoadhesive property in the in vitro wash off test. Drug release pattern for all formulation in 0.1 N HCl (pH 1.2) was diffusion controlled, gradually over 8 h and followed zero order kinetics.     

Modifying matrix micro-environmental pH to achieve sustained drug release from highly laminating alginate matrices

Lamination of alginate matrix tablet at acidic pH can compromise its function as a sustained release carrier. This phenomenon is associated with the conversion of sodium alginate to alginic acid. An innovative approach for controlling the release of a highly water-soluble drug from such matrices is presented in this paper. Inclusion of pH-modifiers was employed to raise the micro-environmental pH within matrices undergoing dissolution at gastric pH. The changes in micro-environmental pH of hydrating alginate matrices were visualized with the aid of a pH-indicator and subsequently quantified using image analysis. Transient elevation in micro-environmental pH impeded alginate protonation and minimized or prevented matrix lamination, contributing to preservation of drug diffusion barrier. Significant reduction in the rate of drug release at pH 1.2 was achieved in the presence of such additives. The action of pH-modifiers was synergistically enhanced in the presence of a carbon dioxide barrier formed by effervescing sodium bicarbonate, reducing drug release in the acidic medium from 60 to 20%. Further insight into the influence of lamination on drug release from alginate compacts was given.     

Multilayer alginate/protamine microsized capsules: encapsulation of alpha-chymotrypsin and controlled release study

Stable polyelectrolyte microcapsules with size 6.5 microm were produced by means of the layer-by-layer adsorption of sodium alginate and protamine to surface of melamine formaldehyde microparticles. Core decomposition at low pH leads to formation of polyelectrolyte multilayered capsules filled with alginate gel. A proteolytic enzyme, alpha-chymotrypsin, was loaded into these microcapsules by embedding in alginate gel with high efficacy. The protein in the capsules was found to retain a high physiological activity of about 70% showed with fluorescent product. The protein was found to keep inside the microcapsules in water and acid (HCl solution, pH 1.7) during 24 and 4 h, respectively, while 75-85% of protein can be revealed in supernatant after 6 h incubation at pH 8.0 (0.05 M Tris buffer) in the presence of 2.5% w/v of sodium deoxycholate. The release rate of enzyme from multilayer alginate/protamine microcapsules can be regulated by additional adsorption of polyelectrolytes onto the microcapsules with encapsulated protein. Such protein-loaded capsules can be proposed as a drug delivery system with controllable release properties.     

Application of mathematical modelling to alginate chitosan polyelectrolyte complexes for the prediction of system behavior with Venlafaxine HCl as a model charged drug

PurposeThis work aimed to develop and analyze the performance of chitosan/alginate polyelectrolyte complex (PEC). Multiple regression and Lab fit curve fitting were applied to derive empirical models for the prediction of zeta potential of plain systems as a function of alginate chitosan ratio. Venlafaxine-HCl was loaded as a model charged drug and empirical models for prediction of its release as a function of time were also derived.MethodsCoacervation method was used for the preparation of green PECs. Preliminary studies were conducted to optimize the preparation method. Pre-adjustment of the pH of alginate and chitosan sols enabled the formation of PECs at alginate/chitosan ratios starting from 1:9 to 9:1. On mixing of alginate and chitosan sols, equal volume dilution method produced spherical particles, while direct mixing method gave fibrous particles. Twenty-seven PECs nanoparticle formulae were prepared using nine alginate/chitosan ratios and three levels of total polymer concentrations.ResultsStatistical analysis showed that Zeta potential of the nanoparticle was significantly dependent on alginate/chitosan ratio, while particle size was a function of total polymer concentration. Nine fiber formulae were prepared and evaluated for their appearance and zeta potential. Venlafaxine-HCl release followed anomalous transport mechanism. FT-IR and DSC studies confirmed complexation at the carboxylate and amine site at alginate and chitosan respectively.ConclusionChitosan/alginate PECs were successfully obtained without a cross-linker and empirical equations were obtained to help finding the best composition for loading charged drugs and to predict their release profiles.