Preparation of alginate beads for floating drug delivery system: effects of CO(2) gas-forming agents

Floating beads were prepared from a sodium alginate solution containing CaCO(3) or NaHCO(3) as gas-forming agents. The solution was dropped to 1% CaCl(2) solution containing 10% acetic acid for CO(2) gas and gel formation. The effects of gas-forming agents on bead size and floating properties were investigated. As gas-forming agents increased, the size and floating properties increased. Bead porosity and volume average pore size, as well as the surface and cross-sectional morphology of the beads were examined with Mercury porosimetry and Scanning Electron Microscopy. NaHCO(3) significantly increased porosity and pore diameter than CaCO(3). Incorporation of CaCO(3) into alginate solution resulted in smoother beads than those produced with NaHCO(3). Gel strength analysis indicated that bead strength decreased with increasing gas-forming agent from 9 to 4 N. Beads incorporating CaCO(3) exhibited significantly increased gel strength over control and NaHCO(3)-containing samples. Release characteristics of riboflavin as a model drug were studied in vitro. Release rate of riboflavin increased proportionally with addition of NaHCO(3). However, increasing weight ratios of CaCO(3) did not appreciably accelerate drug release. The results of these studies indicate that CaCO(3) is superior to NaHCO(3) as a gas forming agent in alginate bead preparations. The enhanced buoyancy and sustained release properties of CaCO(3)-containing beads make them an excellent candidate for floating drug dosage systems (FDDS).     

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.     

Formulation and evaluation of floating drug delivery system of famotidine

A multiple unit oral floating drug delivery system of famotidine was developed to prolong gastric residence time, target stomach mucosa and increase drug bioavailability. Drug and polymer compatibility was studied by subjecting physical mixtures of drug and polymers to differential scanning calorimetry. Cod liver oil entrapped calcium alginate beads containing famotidine, capable of floating in the gastric condition were formulated and evaluated. The gel beads were prepared by emulsion gelation method by employing sodium alginate alone and mixture of sodium alginate and hydrophilic copolymers such as carbopol 934P and hydroxypropylmethylcellulose K15M grade in three different ratios. The effect of selected factors, such as percentage of oil and amount of copolymers on floating properties was investigated. The beads were evaluated for percent drug loading, drug entrapment efficiency, buoyancy and in vitro drug release. The in vitro drug release study of the beads was carried out in simulated gastric media employing a modified Rosette-Rice test apparatus. Wherein, the apparatus was further modified by incorporating a water jacket to the apparatus to circulate hot water to maintain 37±2° for throughout the release study. All the oil entrapped calcium alginate beads floated if a sufficient amount of oil was used. Beads formulated employing sodium alginate alone could not sustain the drug release up to 8 h, whereas beads formulated with mixture of sodium alginate and copolymers demonstrated sustained release of famotidine up to 8 h. The results suggested that cod liver oil entrapped calcium alginate beads were promising as a carrier for intragastric floating drug delivery of famotidine.     

Preparation and characterisation of gastroretentive alginate beads for targeting H. pylori

Abstract

There are various obstacles in the eradication of Helicobacter pylori (H. pylori) infections including low drug levels due to short gastric residence times and poor accessibility of the drug at the site of the infection. In this study, calcium alginate beads containing metronidazole were prepared by ionotropic gelation with diameters ranging from 2 to 3?mm and bulk densities ranging from 0.11 to 0.23?g/cm³. These beads failed buoyancy tests and released the drug rapidly. The formulation was modified in order to improve floating and modify their drug release profile through addition of oil and coating with chitosan. Upon modification, buoyancy improved and drug release was sustained. This novel formulation will ensure retention for a longer period in the stomach and control the release of drug, ensuring high local drug concentrations, leading to improved eradication of the bacteria.     

Preparation and evaluation of a novel gastric floating alginate/poloxamer inner-porous beads using foam solution

In the present study, a simple and rapid method was developed to prepare a novel kind of inner-porous floating beads. The beads were prepared by dripping the foam solution into CaCl(2) solution using disposable syringe needle, where the foam solution consisting numerous of microbubbles with poloxamer 188 as foaming agents, alginate as foaming stablizer. Foamability and foam stability of different polymer ratios were evaluated. The SEM cross-section pictures of the beads showed that the beads were inner-porous and composed of bubbles with very thin wall bubbles stacked together. The visual observation result and the resultant-weight method confirmed that the floating beads showed good buoyancy, most beads could float in the stomach for more than 6 h. The floating beads release behavior in vitro showed that drug release from the beads in a sustained-release fashion for 10 h. Gamma scintigraphic images and pharmacokinetic studies in vivo showed that the beads can retained in the stomach for over 6 h and can improve the bioavailability of drug with narrow absorption window.     

Amidated Pectin Hydrogel Beads for Colonic Drug Delivery-An in vitro Study

Hydrogel beads of amidated pectins have been prepared by allowing individual droplets of the pectin solution to fall into calcium chloride solution. Beads have been produced containing either indomethacin or sulphamethoxazole as model drugs and either dextran or amylose to modify drug release. The beads formed were spherical in shape and had drug loading efficiencies of 80-95% for indomethacin and 60-90% for sulphamethoxazole. Thermal analysis indicated that there was no change in the form of the drugs after incorporation into the beads but that an interaction may have occurred between the pectin and either the dextran or amylose. Swelling of all the beads was similar, with a minimum occurring at pH 3. Drug release was related to the solubility of the compound, with sulphamethoxazole releasing more rapidly than indomethacin at all pH values. Indomethacin release was minimal at pH 3 and 5 but was significant at pH 7.4. However, the inclusion of amylose restricted the release at pH 7.4. When pectinolytic enzymes were included in the dissolution media, release was rapid. The results show that for a relatively insoluble compound, release in the conditions akin to the upper gastrointestinal tract can be minimized by the inclusion of amylose, without affecting the ability of the beads to break down in the presence of pectinolytic enzymes.     

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.     

Adipic acid dihydrazide treated partially oxidized alginate beads for sustained oral delivery of flurbiprofen

In this study, periodate oxidation of sodium alginate was controlled such that the oxidized alginate could form isolatable beads with Ca⁺² ions. The beads of oxidized alginate having a degree of oxidation 1 mol%, entrapped 89% flurbiprofen and released almost all of its content within 1.5 h in pH 7.2 phosphate buffer solution. The beads were covalently crosslinked with adipic dihydrazide (ADH) in addition to ionic crosslinks and were characterized. Scanning electron microscopy revealed that the beads were spherical having smooth surfaces. The drug entrapment efficiency decreased (90–86%) with increasing concentration of ADH (2–6% w/v) in the gelation medium. However, the beads prolonged the drug release in alkaline dissolution medium up to 8 h depending upon the concentration of ADH. The beads prepared with 2% ADH swelled more rapidly and led to faster drug release in either pH 1.2 HCl solution or pH 7.2 phosphate buffer solution. The swelling tendencies were reduced and the drug release became slower with higher concentrations in either fluid. The drug diffusion from the beads followed super case II transport mechanism. FTIR spectroscopy indicated stable nature of flurbiprofen in the beads and therefore had potential as sustained oral delivery system for the drug.     

Evaluation of drug release kinetics and physico-chemical characteristics of metronidazole floating beads based on calcium silicate and gas-forming agents

In the present investigation metronidazole-loaded alginate beads consisting of calcium silicate as a porous carrier or NaHCO₃ as a gas-forming agent were prepared for local eradication of Helicobacter Pylori. Gelation method was used for preparation of conventional sodium alginate beads. Drug entrapment efficiency, drug loading, floating properties, drug release, crystallinity and release kinetic as well as morphology of the prepared beads were assessed. The silicate based beads showed slower release pattern, compared to the gas-forming beads due to network structure strengthening effect of the calcium silicate. Furthermore, the gas-forming-based beads had shorter initial buoyancy lag time, owing to the fact that the NaHCO₃ produced larger pores than those of silicate treated ones. Drug entrapment efficiency ranged between 61.7 and 93.1% for the prepared formulations. The maximum value of drug loading for gas-forming and silicate-based beads were 66.64% and 34.97%, respectively. Kinetically, release pattern of metronidazole in simulated gastric fluid from the beads fitted best to Reciprocal powered time, Weibull and log-probability models with the respect overall mean percentage error values of 4.50, 5.30 and 7.76. By and large, these systems can float in the gastric condition and control the drug release from the beads.     

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.     

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.     

Low density multiparticulate system for pulsatile release of meloxicam

A blend of floating and pulsatile principles of drug delivery system would have the advantage that a drug can be released in the upper GI tract after a definite time period of no drug release. A multiparticulate floating-pulsatile drug delivery system was developed using porous calcium silicate (Florite RE) and sodium alginate, for time and site specific drug release of meloxicam. Meloxicam was adsorbed on the Florite RE (FLR) by fast evaporation of solvent from drug solution containing dispersed FLR. Drug adsorbed FLR powder was used to prepare calcium alginate beads by ionotropic gelation method, using 3(2) factorial design. Developed formulations were evaluated for yield, entrapment efficiency, image analysis, surface topography, mechanical strength, apparent density, buoyancy studies and dissolution studies. Entrapment efficiency of different formulations varied from 70% to 94%. Formulations show a lag period ranging from 1.9 to 7.8 h in acidic medium followed by rapid release of meloxicam in simulated intestinal fluid USP, without enzymes (SIF). Complete drug release in SIF occurred in less than 1h from the formulations. The size of beads varied from 2.0 to 2.7 mm for different batches. Prepared beads were spherical with crushing strength ranging from 182 to 1,073 g. Floating time was controlled by density of beads and hydrophobic character of drug. A pulsatile release of meloxicam was demonstrated by a simple drug delivery system which could be useful in chronopharmacotherapy of rheumatoid arthritis.     

Multi-unit floating alginate system: effect of additives on ciprofloxacin release

In an attempt to fabricate floating beads of ciprofloxacin, drugloaded alginate beads were prepared by simultaneous external and internal gelation. The effect of blending of alginate with gellan, hydroxypropyl methylcellulose, starch, and chitosan on the bead properties were evaluated. Beads were spherical with incorporation efficiency in the range of 52.81 +/- 2.64 to 78.95 +/- 1.92%. Beads exhibited buoyancy over a period of 7-24 hr based on the formulation variables. In vitro release of ciprofloxacin from the alginate beads in simulated gastric fluid (SGF) (0.1 N HCl, pH 1.2), was influenced significantly (p < 0.001) by the properties and concentration of additives. Among the polymers incorporated into alginate beads. Hydroxy propyl methylcellulose (HPMC) provided an extended release over 7 hr. The drug release predominately followed Higuchi's square root model.     

Biphasic release characteristics of dual drug-loaded alginate beads

The dual drug-loaded alginate beads simultaneously containing drug in inner and outer layers were prepared by dropping plain (single-layered) alginate beads into CaCl₂ solution. The release characteristics were evaluated in simulated gastric fluid for 2 h followed by intestinal fluids thereafter for 12 h. The surface morphology and cross section of dual drug-loaded alginate beads was also investigated using scanning electron microscope (SEM). The poorly water-soluble ibuprofen was chosen as a model drug. The surface of single-layered and dual drug-loaded alginate beads showed very crude and roughness, showing aggregated particles, surface cracks and rough crystals. The thickness of dual drug-loaded alginate beads surrounded by outer layer was ranged from about 57 to 329μm. The distinct chasm between inner and outer layers was also observed. In case of single-layered alginate beads, the drug was not released in gastric fluid but was largely released in intestinal fluid. However, the release rate decreased as the reinforcing Eudragit^® polymer contents increased. When the plasticizers were added into polymer, the release rate largely decreased. The release rate of dual drug-loaded alginate beads was stable in gastric fluid for 2 h but largely increased when switched in intestinal fluid. The drug linearly released for 4 h followed by another linear release thereafter, showing a distinct biphasic release characteristics. There was a difference in the release profiles between single-layered and dual drug-loaded alginate beads due to their structural shape. However, this biphasic release profiles were modified by varying formulation compositions of inner and outer layer of alginate beads. The release rate of dual drug-loaded alginate beads slightly decreased when the outer layer was reinforced with Eudragit^® RS100 polymers. In case of dual drug-loaded alginate beads with polymer-reinforced outer layer only, the initial amount of drug released was low but the initial release rate (slope) was higher due to more swellable inner cores when compared to polymer-reinforced inner cores. The current dual drug-loaded alginate beads may be used to deliver the drugs in a time dependent manner.     

Alginate-diltiazem hydrochloride beads: optimization of formulation factors,in vitro and in vivo availability

Alginate beads containing diltiazem hydrochloride (DTZ) were prepared by the ionotropic gelation method. The effects of various factors (alginate concentration, additives type, calcium chloride concentration and curing time) on the efficiency of drug loading were investigated. The formulation containing a mixture of 0.8% methylcellulose (MC) and 4% alginate cured in 2% calcium chloride for 6 h was chosen as the best formula regarding the loading efficiency. The release rate of DTZ from various beads formulations was investigated. The release of drug from alginate beads followed two mechanisms; by diffusion and relaxation of the polymer at pH 1.2, whilst diffusion and erosion are at pH 6.8. The in vitro release of DTZ from MC-alginate beads showed an extended release pattern which was compared with that from commercially available sustained-release (Dilzem SR) and fast release tablets (Dilzem). Thermal analysis revealed that the drug was molecularly dispersed in the beads matrix. Although the release characteristics of DTZ from Dilzem SR and MC-alginate beads were completely different, the bioavailability of DTZ in dogs was comparable as measured by AUC, MRT and relative bioavailability. The absolute bioavailability of MC-alginate beads and Dilzem SR was 88 and 93%, respectively.     

Literature Alerts

In an attempt to fabricate floating beads of ciprofloxacin, drugloaded alginate beads were prepared by simultaneous external and internal gelation. The effect of blending of alginate with gellan, hydroxypropyl methylcellulose, starch, and chitosan on the bead properties were evaluated. Beads were spherical with incorporation efficiency in the range of 52.81 ± 2.64 to 78.95 ± 1.92%. Beads exhibited buoyancy over a period of 7–24 hr based on the formulation variables. In vitro release of ciprofloxacin from the alginate beads in simulated gastric fluid (SGF) (0.1 N HCl, pH 1.2), was influenced significantly (p < 0.001) by the properties and concentration of additives. Among the polymers incorporated into alginate beads. Hydroxy propyl methylcellulose (HPMC) provided an extended release over 7 hr. The drug release predominately followed Higuchi's square root model.     

Sodium lauryl sulfate impedes drug release from zinc-crosslinked alginate beads: switching from enteric coating release into biphasic profiles

The aim of this research is to investigate the effects of sodium lauryl sulfate (SLS) on ionotropically cross-linked alginate beads. Different levels of SLS were mixed with sodium alginate and chlorpheniramine maleate (as loaded model drug). The resulting viscous solutions were dropped onto aqueous solutions of zinc or calcium ions for ionotropic curing. The generated beads were assessed by their drug releasing profiles, infrared and differential scanning colorimetery (DSC) traits.

SLS was found to exert profound concentration-dependent impacts on the characteristics of zinc-crosslinked alginate beads such that moderate modifications in the levels of SLS switched drug release from enteric coating-like behavior to a biphasic release modifiable to sustained-release by the addition of minute amounts of xanthan gum.

Calcium cross-linking failed to reproduce the same behavior, probably due to the mainly ionic nature of calcium–carboxylate bonds compared to the coordinate character of their zinc–carboxylate counterparts. Apparently, moderate levels of SLS repel water penetration into the beads, and therefore minimize chlorpheniramine release. However, higher SLS levels seem to discourage polymeric cross-linking and therefore allow biphasic drug release.     

Alternate polyelectrolyte coating of chitosan beads for extending drug release

In the present study, we addressed the factors modifying ciprofloxacin release from multiple coated beads. Beads were prepared by simple ionic cross-linking with sodium tripolyphoshate and coated with alginate and/or chitosan to prepare single, double, or multilayered beads. The water uptake capacity depended on the nature of beads (coated or uncoated) and pH of test medium. The number of coatings given to the beads influenced ciprofloxacin release rate. The coating significantly decreased the drug release from the beads in comparison to uncoated beads (p < 0.001). When the beads were given three coatings, viz., alginate, chitosan, and again alginate, the drug release appeared to follow the pattern exhibited by colon-targeted drug delivery systems with time dependent release behavior. The increase in coating formed a barrier for easy ingress of dissolution medium into the bead matrix, reducing the diffusion of drug.     

Preparation of alginate gel beads containing chitosan nicotinic acid salt and the functions.

Calcium-induced alginate gel beads containing chitosan salt (Alg-CS) was prepared using nicotinic acid (NA), a drug for hyperlipidemia, and investigated its two functions in gastrointestinal tract, (a) NA release from Alg-CS, (b) uptake of bile acids into Alg-CS. The amount of NA incorporated in Alg-CS increased according to increment of CS content. NA was rapidly released from Alg-CS in diluted HCl solution (pH 1.2) or physiological saline without disintegration of the beads. When Alg-CS was placed in bile acid solution it took bile acid into itself. About 80% of taurocholic acid dissolved in the medium was taken into Alg-CS. According to increment of bile acid concentration, the uptake amount increased and an approximately linear relationship existed among them.     

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.