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 alginatechitosan 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.     

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.     

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.     

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.     

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.     

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.     

Comparison of the pharmaceutical properties of sustained-release gel beads prepared by alginate having different molecular size with commercial sustained-release tablet

Spherical alginate gel beads containing pindolol were prepared using three types of sodium alginate with different molecular size. The rate of gelation of sodium alginate in calcium chloride solution was in the range of 1.0 to 1.3 h-1 among the used three alginates, but the amount of water squeezed from the alginate gel beads during gelation increased from 5 to 40% with increasing molecular size of the alginate. The beads prepared were similar in diameter (1.2 mm after drying), weight (0.9 mg/bead), calcium content (27-29 micrograms/bead) and pindolol content (40-45%). Pindolol was rapidly released from all the alginate gel beads at pH 1.2 owing to the high solubility of pindolol, in spite of non-swelling of beads. On the other hand, pindolol release from alginate gel beads at pH 6.8 was dependent on the swelling of the beads and was significantly depressed compared to drug powder. Interestingly, the release rate of pindolol and the swelling rate of beads were markedly slow for gel beads prepared by low molecular size alginate. However, when the alginate gel beads were administered orally to beagle dogs, the serum levels of pindolol showed sustained-release profiles, depending on the molecular size of the alginate. The in vivo absorption of pindolol from alginate gel beads did not reflect their in vitro release profiles, because of a physical strength of beads in the intestinal tract. Furthermore, the in vivo and in vitro release of pindolol from alginate gel beads were compared with a commercial sustained-release tablet, Carvisken showed a rapid release of 50% of content in pH 1.2 fluid and residual 50% of pindolol were easily dissolved at pH 6.8. Although the release characteristics of pindolol from Carvisken and the alginate gel beads were completely different, the serum levels of pindolol in human volunteers were comparable.     

The Controlled Release of Prednisolone Using Alginate Gel

In a release study of alginate gel beads, swelling and erosion of the beads were observed at pH 6.8, whereas no swelling occurred at pH 1.2. The amount of released prednisolone (PL) was greater at pH 6.8 than at pH 1.2. The lower the ratio of mannuronic acid block to guluronic acid block in alginate, the slower the release of PL. An increase in loaded PL in the beads resulted in a slower release of PL. The decrease in bead size caused a rapid release of PL. The addition of sodium alginate propylene glycol ester elevated the extent of PL release. The plasma profile of PL showed sustained-release behavior after the oral administration of the beads to beagles. Furthermore, the correlation between in vitro release and in vivo absorption of PL for various alginate gel beads was evaluated using deconvolution and convolution methods. The in vivo absorption of PL was correlated with the PL release at pH 1.2, and it differed from that at pH 6.8. The release of PL from alginate gel beads in vivo appeared to occur under conditions that cause little swelling.     

Evaluation of sodium alginate as drug release modifier in matrix tablets

Alginates are useful natural polymers suitable for use in the design of pharmaceutical dosage forms. However, the effects of particle size, viscosity and chemical composition of alginates on drug release from alginate matrix tablets are not clearly understood. Hence, 17 grades of sodium alginate with different particle size distributions, viscosities and chemical compositions were used to prepare matrix tablets at various concentrations to screen the factors influencing drug release from such matrices. Particle size was found to have an influence on drug release from these matrices. Sodium alginate was subsequently classified into several size fractions and also cryogenically milled to produce smaller particle size samples. Cryogenic milling could be successfully applied to pulverize coarse alginate particles without changing the quality through degradation or segregation. This study showed the significance of each alginate property in modulating drug release: particle size is important in initial alginic acid gel barrier formation as it affected the extent of burst release; higher alginate viscosity slowed down drug release rate in the buffer phase but enhanced release rate in the acid phase; high M-alginate might be more advantageous than high-G-alginate in sustaining drug release; and, the effect of increasing alginate concentration was greater with larger alginate particles. This can serve as a framework for formulators working with alginates. Furthermore, the results showed that sodium alginate matrices can sustain drug release for at least 8 h, even for a highly water-soluble drug in the presence of a water-soluble excipient.     

Modulating drug release and matrix erosion of alginate matrix capsules by microenvironmental interaction with calcium ion.

Effect of calcium gluconate (CG) content on release of dextromethorphan hydrobromide (DMP), model drug, from capsules containing low and medium viscosity grades of sodium alginate (SA) was investigated in different dissolution media. Matrix erosion of the SA matrix capsules in distilled water and pH 7.4 phosphate buffer was compared. Molecular interaction of SA with calcium ion in surface gel layer of the SA matrix capsules was examined using Fourier transform infrared spectroscopy and differential scanning calorimetry. In distilled water and pH 7.4 phosphate buffer, DMP release rate depended on the viscosity grade of SA, whereas a comparable DMP release rate was found in 0.1N HCl. Incorporation of CG into the SA matrix capsules caused a faster drug release in acidic medium because CG acted as a channeling agent in the hydrated insoluble gel matrix of alginic acid. Interaction of calcium ions with carboxyl groups of SA could be formed in surface gel layer of hydrated matrix capsules in distilled water. This led to a more rigid matrix gel structure that caused a slower drug release and matrix erosion. In contrast, the extent of this interaction in pH 7.4 phosphate buffer was less than that in distilled water because the common ion effect and high concentration of sodium ion retarded the hydration of SA and the binding of calcium ions with carboxyl groups of SA. Thus, a small change in drug release and matrix erosion was observed. This finding suggests that microenvironmental interaction between hydrated SA and calcium ion in distilled water could be created in the formulations prepared using low compression force. Moreover, incorporation of CG could moderate drug release and matrix erosion of the SA matrix capsules.     

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.     

海藻酸钠骨架材料中药物释放的影响因素

目的以海藻酸钠为亲水骨架材料，考察药物从海藻酸钠骨架片中释放的体外影响因素。方法以茶碱为模型药物，采用直接压片法制备了茶碱海藻酸钠亲水骨架片，通过对骨架片膨胀性、吸水性以及溶蚀性的考察，研究了影响药物从海藻酸钠骨架材料中释放的体外因素。结果茶碱海藻酸钠骨架片的释药速率和释药机理与骨架片中海藻酸钠粘度、释放介质pH值、离子强度以及转速均有关。结论海藻酸钠能有效地控制骨架片中药物的释放，是一种优良的亲水骨架材料。     

Fabrication of novel core-shell hybrid alginate hydrogel beads

Novel hybrid alginate hydrogel beads with shells of porous CaCO3 microparticles were fabricated by templating water-in-oil emulsion and subsequent in situ gelation. Porous CaCO3 microparticles were self-assembled at interfaces of water-in-oil emulsion. Water droplets containing alginate in the emulsion were subsequently in situ gelated by Ca2+ released from CaCO3 through decreasing pH with slow hydrolysis of d-glucono-delta-lactone (GDL). The resulting hybrid beads with alginate gel cores and shells of porous CaCO3 microparticles were called colloidosomes. The packed density of CaCO3 microparticles in the shell increased with increasing the ratio of the CaCO3 microparticle weight to the water phase volume Mp/Vw and decreased with addition of NaCl into water. The size of the produced colloidosome beads was independent of Mp/Vw. Increasing the volume fraction of water Phi w to 0.5, some colloidosome beads deformed to nonspheral shape and even broken. Brilliant blue (BB) as a drug model was loaded into the colloidosome beads by being dissolved in the alginate aqueous solution before gelation. The BB release from the colloidosome beads was slowed down because of the formation of the shells of CaCO3 microparticles. The colloidosome beads may find applications as delivery vehicles for drugs, cosmetics, food supplements and living cell.     

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.     

长春西汀海藻酸钠骨架片体外释药影响因素研究

目的以海藻酸钠为骨架材料 ,制备长春西汀控释骨架片 ,对影响其体外释放的多种因素进行了考察。方法以海藻酸钠为亲水骨架材料 ,粉末直接压片制备长春西汀控释片 ,采用《中华人民共和国药典》2 0 0 0年版二部收载的溶出度测定方法Ⅱ法 (桨法 ) ,测定药物在不同条件下的体外释放度 ,考察海藻酸钠用量及黏度 ,枸橼酸用量 ,释放介质离子强度和pH值对药物体外释放行为的影响。结果与结论海藻酸钠用量及黏度 ,枸橼酸用量 ,释放介质离子强度和pH值均对药物体外释放行为有显著影响。值得注意的是 ,通过调节处方中枸橼酸用量可以使释药行为达零级 ,这为制备长春西汀控释片提供指导 ,有进一步开发的价值。     

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.