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 CaCl₂ (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 ～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.     

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.     

Floating dosage forms to prolong gastro-retention--the characterisation of calcium alginate beads

Floating calcium alginate beads, designed to improve drug bioavailability from oral preparations compared with that from many commercially available and modified release products, have been investigated as a possible gastro-retentive dosage form. A model drug, riboflavin, was also incorporated into the formula.

The aims of the current work were (a) to obtain information regarding the structure, floating ability and changes that occurred when the dosage form was placed in aqueous media, (b) to investigate riboflavin release from the calcium alginate beads in physiologically relevant media prior to in vivo investigations.

Physical properties of the calcium alginate beads were investigated. Using SEM and ESEM, externally the calcium alginate beads were spherical in shape, and internally, air filled cavities were present thereby enabling floatation of the beads. The calcium alginate beads remained buoyant for times in excess of 13 h, and the density of the calcium alginate beads was <1.000 g cm⁻³. Riboflavin release from the calcium alginate beads showed that riboflavin release was slow in acidic media, whilst in more alkali media, riboflavin release was more rapid.

The characterisation studies showed that the calcium alginate beads could be considered as a potential gastro-retentive dosage form.     

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 release behavior of brilliant blue from calcium-alginate gel beads coated by chitosan: the preparation method effect.

The aim of this study is to reveal how the release behavior of a model drug (brilliant blue, BB) from chitosan coating calcium-alginate gel beads (CCAGB) was influenced by the preparation methods. The CCAGB were prepared by dropping alginate solution into CaCl(2)/chitosan solution (method 1(a)), or into chitosan solution then gelled by CaCl(2) (method 1(b)), or into CaCl(2) solution then coated by chitosan (method 2). Scanning electron microscopy was used for morphology observation, and elemental analysis was applied to determine the chitosan content bound on calcium-alginate gel beads (CAGB). Compared to CAGB, the dried CCAGB had poorer shape and rougher surface morphology especially in methods 1(a) and (b); moreover, CCAGB was found to be more instable in 0.9% NaCl and serious burst of beads occurred when high concentration of alginate (3.0 and 5.0% w/v) was used. The influence on BB release from the beads by chitosan coating was not only related to the chitosan density on bead surface, but also preparation method and other factors. Under un-dried bead state in method 1(a), the increase of chitosan content prolonged BB release in 0.9% (w/v) NaCl; while in method 2, the increase of chitosan concentration over 0.1% (w/v) (3.0% (w/v) alginate concentration was used) resulted in more serious burst of beads and hence facilitated BB release. Furthermore, in both methods 1(a) and 2, the increase of alginate from 1.5 to 3.0 or 5.0% (w/v) usually resulted in the significant burst of beads and accelerated BB release when 0.3 or 0.5% (w/v) chitosan was used for coating. Drying process greatly influenced BB release profile due to the destroying of alginate-chitosan film. The acceleration of BB release from CCAGB by drying process was more significant in the case of method 1 than of method 2.     

Development and evaluation of polyethyleneimine-treated calcium alginate beads for sustained release of diltiazem

The objective of this investigation is to develop a multi-unit sustained release dosage form of a water soluble drug from a completely aqueous environment avoiding the use of any organic solvent. The drug was complexed with resin and calcium alginate or polyethyleneimine-treated calcium alginate beads loaded with the resinate were prepared by a ionic/polyelectrolyte complexation method. The effect of different formulation variables on the characteristics of the beads was investigated. Although the drug release from spherical and smooth-surfaced calcium alginate beads in both acidic and alkaline dissolution media were slower than those obtained from plain resinate, none of the variables were found to prolong the drug release considerably due to rapid swelling and disintegration of calcium alginate beads in alkaline medium. On the other hand, drug release from polyethyleneimine-treated calcium alginate beads in acidic medium did not increase appreciably following a burst release. However, in alkaline medium, the drug release was found to increase gradually and extend over a different period of time depending on the intensity of polyethyleneimine treatment. Scanning electron micrographs revealed the formation of a dense membrane around the resinate-loaded calcium alginate matrix. The membrane appeared to be responsible for reduced swelling and protracted disintegration of the beads resulting in slow release of the drug. The results indicate that sustained release of a water soluble drug from polyethyleneimine-treated calcium alginate beads could be achieved by adjusting the formulation variables.     

Development and evaluation of polyethyleneimine-treated calcium alginate beads for sustained release of diltiazem

The objective of this investigation is to develop a multi-unit sustained release dosage form of a water soluble drug from a completely aqueous environment avoiding the use of any organic solvent. The drug was complexed with resin and calcium alginate or polyethyleneimine-treated calcium alginate beads loaded with the resinate were prepared by a ionic/polyelectrolyte complexation method. The effect of different formulation variables on the characteristics of the beads was investigated. Although the drug release from spherical and smooth-surfaced calcium alginate beads in both acidic and alkaline dissolution media were slower than those obtained from plain resinate, none of the variables were found to prolong the drug release considerably due to rapid swelling and disintegration of calcium alginate beads in alkaline medium. On the other hand, drug release from polyethyleneimine-treated calcium alginate beads in acidic medium did not increase appreciably following a burst release. However, in alkaline medium, the drug release was found to increase gradually and extend over a different period of time depending on the intensity of polyethyleneimine treatment. Scanning electron micrographs revealed the formation of a dense membrane around the resinate-loaded calcium alginate matrix. The membrane appeared to be responsible for reduced swelling and protracted disintegration of the beads resulting in slow release of the drug. The results indicate that sustained release of a water soluble drug from polyethyleneimine-treated calcium alginate beads could be achieved by adjusting the formulation variables.     

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     

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.     

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 0.78-1.16mm diameter range and 10.8-66.5% encapsulation efficiencies were produced. Higher encapsulation efficiencies and retarded drug release were obtained with chitosan treated alginatebeads. Amongthedifferentfactors investigatedsuchas 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.     

Controlled release tamsulosin hydrochloride from alginate beads with waxy materials

The objective of this study was to develop oral controlled release delivery systems for tamsulosin hydrochloride (TSH) using alginate beads with various waxy materials, such as Compritol 888 ATO, Precirol ATO 5 and Gelucires. The beads were prepared from sodium alginate-waxy material-TSH slurry dropped onto calcium chloride to form spherical beads. The effects of the addition of various waxy materials to alginate beads on the drug encapsulation efficiency, bead size and morphology were investigated. The drug encapsulation efficiency significantly increased with the addition of waxy materials. The TSH-loaded alginate beads with and without waxy materials were almost spherical particles with an average diameter of 1.44 and 1.22 mm, respectively. In dissolution study, the TSH-loaded alginate beads with waxy materials exhibited controlled release behaviour over a 6-h period, while beads without waxy materials showed release of 100% TSH within 2 h. These results may be attributed to the formation of a more rigid alginate matrix structure due to incorporated waxy materials. From the Dunnett's t-test and the f2 factor, the release of TSH from alginate beads, a similar dissolution pattern to that of the marketed product (Harunal capsules) could be achieved by adding Gelucire 50/13 into TSH-loaded alginate beads. From these results, oral controlled release of TSH could be achieved with loading in alginate beads with waxy materials, such as Compritol 888 ATO, Precirol ATO 5 and Gelucires.     

Encapsulation of RIN-m5F cells within Ba2+ cross-linked alginate beads affects proliferation and insulin secretion

The viability, proliferation and insulin production of RIN-m5F cells when loaded into alginate beads to form a 3D culture system has been investigated. The mechanism of alginate cross-linking (calcium ions vs barium ions), the addition of poly(L-lysine) (PLL) and poly(L-ornithine (PLO) and presence of different extra-cellular matrix proteins (ECM) influence the RIN-m5F cell behaviour. Cells in calcium alginate beads (CAB) proliferated and produced more insulin per cell than monolayer culture, but the physical properties of the beads were poor and they ruptured within a few days of culture. Barium alginate beads (BABs) provided a stable encapsulation method. Addition of PLL and PLO at concentrations above 0.1% w/v with the culture medium increased cell proliferation. With the addition of ECMs after bead formation there was a further increase in cell proliferation for certain combinations of ECM and PLO. It was concluded that RIN-m5F-loaded Ba-alginate beads (BABs), when incorporated with varying concentrations of poly (L) lysine (PLL), poly (L) ornithine (PLO) in the presence of extra-cellular matrix proteins (ECMs) were superior to both tissue culture and RIN-m5F-loaded Ca-alginate beads (CABs) in terms of physical stability, cell proliferation and insulin production.     

Hydrocolloid carriers with filler inclusion for diltiazem hydrochloride release

Hydrocolloid beads based on agarose, alginate (both 3%, w/w), or gellan (2%, w/w) were produced to study their potential as drug carriers. The beads included various fillers: talc, kaolin, calcium carbonate, potato, or corn starch (10%, w/w). After gelation, the carriers were subjected to either freeze- or vacuum-drying. The dried carriers were spheroids. The diameters of freeze- and vacuum-dried carriers ranged from 2.4 to 4.1 mm and 1.5 to 2.8 mm, respectively. The porosity values of the freeze-dried carriers were significantly higher than those of their vacuum-dried counterparts. Scanning electron microscopy (SEM) revealed that all dried carriers included internal voids that were partially occupied by the filler particles. Upon their introduction into simulated gastric fluid (3 h), followed by 6 h in intestinal fluid, all carriers were stable and underwent swelling. Release profiles of diltiazem hydrochloride from different carriers were obtained during immersion in dissolution medium. Filler inclusion (but not the type of filler) contributed to the stability of the carriers and prolonged the time of drug release (6.5-8.5 h) relative to the faster drug release from carriers that contained no filler (3.5 h). In summary, alginate, agar, and gellan beads with filler inclusion may be useful for slow drug release.     

Xanthan-alginate composite gel beads: molecular interaction and in vitro characterization

Xanthan gum (XG), a trisaccharide branched polymer, was applied to reinforce calcium alginate beads in this study. Composite beads consisting of XG and sodium alginate (SA) were prepared using ionotropic gelation method. Diclofenac calcium-alginate (DCA) beads incorporated with different amounts of XG were produced as well. Molecular interaction between SA and XG in the composite beads and the XG-DCA beads was investigated using FTIR spectroscopy. Physical properties of the XG-DCA beads such as entrapment efficiency of diclofenac sodium (DS), thermal property, water uptake, swelling and DS release in various media were examined. XG could form intermolecular hydrogen bonding with SA in the composite beads with or without DS. Differential scanning calorimetric study indicated that XG did not affect thermal property of the DCA beads. The DS entrapment efficiency of the DCA beads increased with increasing amount of XG added. The XG-DCA beads showed higher water uptake and swelling in pH 6.8 phosphate buffer and distilled water than the DCA beads. A longer lag time and a higher DS release rate of the XG-DCA beads in pH 6.8 phosphate buffer were found. In contrast, the 0.3%XG-DCA beads could retard the drug release in distilled water because interaction between XG and SA gave higher tortuosity of the bead matrix. However, higher content of XG in the DCA beads increased the release rate of DS. This can be attributed to erosion of small aggregates of XG on the surface of the DCA beads. This finding suggested that XG could modulate physicochemical properties and drug release of the DCA beads, which based on the existence of molecular interaction between XG and SA.     

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.     

Sulindac loaded alginate beads for a mucoprotective and controlled drug release

Ionotropic gelation was used to entrap sulindac into calcium alginate beads as a potential drug carrier for the oral delivery of this anti-inflammatory drug. Beads were investigated in vitro for a possible sustained drug release and their use in vivo as a gastroprotective system for sulindac. Process parameters such as the polymer concentration, polymer/drug ratio, and different needle diameter were analysed for their influences on the bead properties. Size augmented with increasing needle diameter (0.9 mm needle: 1.28 to 1.44 mm; 0.45 mm needle: 1.04 to 1.07 mm) due to changes in droplet size as well as droplet viscosity. Yields varied between 87% and 98% while sulindac encapsulation efficiencies of about 88% and 94% were slightly increasing with higher alginate concentrations. Drug release profiles exhibited a complete release for all formulations within 4 hours with a faster release for smaller beads. Sulindac loaded alginate beads led to a significant reduction of macroscopic histological damage in the stomach and duodenum in mice. Similarly, microscopic analyses of the mucosal damage demonstrated a significant mucoprotective effect of all bead formulation compared to the free drug. The present alginate formulations exhibit promising properties of a controlled release form for sulindac; meanwhile they provide a distinct tissue protection in the stomach and duodenum.     

A novel approach to prepare tripolyphosphate/chitosan complex beads for controlled release drug delivery

A novel approach was developed to improve the mechanical strength of tripolyphosphate (TPP)/chitosan beads prepared under coagulation condition at 4 degrees C in the presence of gelatin. Cross-sectional analysis indicated that the beads had a homogeneous crosslinked structure, as a result the beads were strengthened greatly (the mechanical strength increased more than ten times). Furthermore sodium alginate (a polyanion) can interact with cationic chitosan on the surface of these TPP/chitosan beads to form polyelectrolyte complex film for the improvement of the drug sustained release performances. The loading efficiency of model drugs (brilliant blue and FITC-dextran) in these beads was very high (more than 90%). Crosslinking time, TPP solution pH and other preparation factors had an effect on the drug release performance of beads. The release period of brilliant blue (a poor water soluble dye) was more than 2-months at a fairly constant rate in 0.9% NaCl, 10 mM PBS pH 7.4. However, for FITC-dextran (a water soluble polysaccharide) only 1-2 days in the same conditions. It seems that TPP/chitosan bead prepared by the novel method is a promising formulation for drug delivery.     

Encapsulation of RIN-m5F cells within Ba2+ cross-linked alginate beads affects proliferation and insulin secretion

The viability, proliferation and insulin production of RIN-m5F cells when loaded into alginate beads to form a 3D culture system has been investigated. The mechanism of alginate cross-linking (calcium ions vs barium ions), the addition of poly(L-lysine) (PLL) and poly(L-ornithine (PLO) and presence of different extra-cellular matrix proteins (ECM) influence the RIN-m5F cell behaviour. Cells in calcium alginate beads (CAB) proliferated and produced more insulin per cell than monolayer culture, but the physical properties of the beads were poor and they ruptured within a few days of culture. Barium alginate beads (BABs) provided a stable encapsulation method. Addition of PLL and PLO at concentrations above 0.1% w/v with the culture medium increased cell proliferation. With the addition of ECMs after bead formation there was a further increase in cell proliferation for certain combinations of ECM and PLO. It was concluded that RIN-m5F-loaded Ba-alginate beads (BABs), when incorporated with varying concentrations of poly (L) lysine (PLL), poly (L) ornithine (PLO) in the presence of extra-cellular matrix proteins (ECMs) were superior to both tissue culture and RIN-m5F-loaded Ca-alginate beads (CABs) in terms of physical stability, cell proliferation and insulin production.     

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.     

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.