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

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

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

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

An anti-inflammatory drug (mefenamic acid) incorporated in biodegradable alginate beads: development and optimization of the process using factorial design

The objective of this study was to prepare and evaluate biodegradable alginate beads as a controlled-release system for a water-insoluble drug, mefenamic acid (MA), using 3 x 2(2) factorial design by ionotropic gelation method. Therefore, the mefenamic acid dispersion in a solution of alginate was dropped into the cross-linking CaCl(2) solution and a fairly high yield (71-89%) of MA-alginate beads were obtained. Their encapsulation efficiencies were in the range of 79.3-98.99%. The effect of drug:polymer ratio, CaCl(2) concentration, and curing time on the time for 50% of the drug to be released (t(50%)), and the drug entrapment efficiency were evaluated with factorial design method. It was found that drug:polymer ratio and interaction of drug:polymer ratio and curing time had an important effect on the drug to be released (t(50%)). The effect of CaCl(2) concentration is also important on the drug release. On the other hand, all factors except CaCl(2) concentration were effective on the drug entrapment efficiency. The swelling properties of beads were also studied. The release mechanism was described and found to be non-Fickian, Case II, and Super Case II transport for the formulations. This study suggested a new mefenamic acid alginate bead formulation for oral delivery of nonsteroidal anti-inflammatory drugs, which cause gastric irritation.     

An Anti-Inflammatory Drug (Mefenamic Acid) Incorporated in Biodegradable Alginate Beads: Development and Optimization of the Process Using Factorial Design

The objective of this study was to prepare and evaluate biodegradable alginate beads as a controlled-release system for a water-insoluble drug, mefenamic acid (MA), using 3 × 2² factorial design by ionotropic gelation method. Therefore, the mefenamic acid dispersion in a solution of alginate was dropped into the cross-linking CaCl₂ solution and a fairly high yield (71–89%) of MA-alginate beads were obtained. Their encapsulation efficiencies were in the range of 79.3–98.99%. The effect of drug:polymer ratio, CaCl₂ concentration, and curing time on the time for 50% of the drug to be released (t_50%), and the drug entrapment efficiency were evaluated with factorial design method. It was found that drug:polymer ratio and interaction of drug:polymer ratio and curing time had an important effect on the drug to be released (t_50%). The effect of CaCl₂ concentration is also important on the drug release. On the other hand, all factors except CaCl₂ concentration were effective on the drug entrapment efficiency. The swelling properties of beads were also studied. The release mechanism was described and found to be non-Fickian, Case II, and Super Case II transport for the formulations. This study suggested a new mefenamic acid alginate bead formulation for oral delivery of nonsteroidal anti-inflammatory drugs, which cause gastric irritation.     

Controlling release of metformin HCl through incorporation into stomach specific floating alginate beads

The aim of present study was to develop stomach specific floating beads of metformin hydrochloride for effective management of type 2 diabetes mellitus. The beads were evaluated for surface morphology, particle size, tapped density, true density, percent porosity, drug entrapment efficiency, percent yield, differential scanning calorimetry, in vitro floating ability and in vitro drug release. Stability studies were performed at 25 and 40 °C up to 45 days. Effectiveness of the formulations was evaluated in vivo by hypoglycemic response in both normal and diabetic albino rats. The beads were grossly spherical in shape, and average particle diameter of beads was found to be in the size range of 861.34 to 991.75 μm. Percent entrapment was found to be in the range of 77.61 to 82.48%. Beads demonstrated favorable in vitro floating ability. All the formulations followed a non-Fickian release mechanism. It was found that there was no significant effect on floating ability of aged beads since it floated up to an 8 h study period. In vivo studies on diabetic rats showed that the hypoglycemic effect induced by the metformin hydrochloride loaded alginate beads was significantly greater (P < 0.05) and more prolonged than that induced by the nonfloating beads. The results clearly demonstrated the ability of the formulation to maintain blood glucose level and improved the patient compliance by enhancing, controlling and prolonging the systemic absorption of metformin hydrochloride.     

Nasal administration of metoclopramide from different dosage forms: in vitro,ex vivo,and in vivo evaluation

Nasal drug delivery is an interesting route of administration for metoclopramide hydrochloride (MTC) in preventing different kind of emesis. Currently, the routes of administration of antiemetics are oral or intravenous, although patient compliance is often impaired by the difficulties associated with acute emesis or invasiveness of parenteral administration. In this perspective, nasal dosage forms (solution, gel, and lyophilized powder) of MTC were prepared by using a mucoadhesive polymer sodium carboxymethylcellulose (NaCMC). In vitro and ex vivo drug release studies were performed in a modified horizontal diffusion chamber with cellulose membrane and excised cattle nasal mucosa as diffusion barriers. The tolerance of nasal mucosa to the formulation and its components were investigated using light microscopy. In vivo studies were carried out for the optimized formulations in sheep and the pharmacokinetics parameters were compared with oral solution and IV dosage form. The release of MTC from solution and powder formulations was found to be higher than gel formulation (p?<?0.05). Histopathological examination did not detect any severe damage. Hydroxypropyl-β-cyclodextrin (HPβCD) used in powder formulations was found to be effective for enhancing the release and absorption of MTC. In contrast to in vitro and ex vivo experiments nasal bioavailability of gel is higher than those of solution and powder (p?<?0.05). In conclusion, the NaCMC gel formulation of MTC with mucoadhesive properties with increased permeation rate is promising for prolonging nasal residence time and thereby nasal absorption.     

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.     

Amoxycillin release from a floating dosage form based on alginates

Floating alginate beads have been prepared from alginate solutions containing either dissolved or suspended amoxycillin. The beads were produced by the dropwise addition of the alginate into calcium chloride solution, followed by removal of the gel beads and freeze drying. Drug release studies showed that beads prepared with the drug in solution provided some sustained release characteristics and that these could be improved by the addition of amylose. In all cases, the drug release was consistent with release of a dissolved solute from a granular or porous matrix. The beads retained their buoyancy when amylose and amoxycillin were incorporated, exhibiting resultant weight values greater than zero after 20 h. Preparation of the beads from alginate solutions containing the drug in suspension allowed higher drug loadings, at the expense of faster release and lower buoyancy.     

Molecular and biopharmaceutical investigation of alginate–inulin synbiotic coencapsulation of probiotic to target the colon

Colon targeting, as a site-specific delivery for oral formulation, remains a major challenge, especially for sensitive bioactive components such as therapeutic forms of phages, live attenuated virus and prebiotics–probiotics association. Synbiotics could be used to protect encapsulated probiotics during the gastrointestinal tract and control their release in the colon. To achieve these goals, effective prebiotics, such as inulin, could be combined with alginate – the most exploited polymer used for probiotic encapsulation – in the form of beads. This work aimed to study the biopharmaceutical behaviour of alginate beads (A) and inulin–alginate beads of different inulin concentrations (5 or 20%) in 2% alginate (AI5, AI20). Beads were loaded with three probiotic strains (Pediococcus acidilactici Ul5, Lactobacillus reuteri and Lactobacillus salivarius). Dissolution of beads was studied by USP4 under conditions simulating the gastrointestinal condition. The survival rates of the bacterial strains were measured by a specific qPCR bacterial count. Mucoadhesiveness of beads was studied by an ex vivo method using intestinal mucosa. To understand the behaviour of each formulation, the ultrastructure of the polymeric network was studied using scanning electron microscopy (SEM). Molecular interactions between alginate and inulin were studied by Fourier transform infra-red spectroscopy (FTIR). Dissolution results suggested that the presence of inulin in beads provided more protection for the tested bacterial strains against the acidic pH. AI5 was the most effective formulation to deliver probiotics to the colon simulation conditions. FTIR and SEM investigations explained the differences in behaviour of each formula. The developed symbiotic form provided a promising matrix for the development of colonic controlled release systems.     

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.     

载葛根素的海藻酸镁胃内滞留释药系统的研究

采用滴制法制备微丸\选取海藻酸钠为载体材料,氯化镁为交联剂,碳酸氢钠为制泡剂,海藻酸钠与镁离子发生交联反应制得胃漂浮微丸,考察微丸的外观、粒径、微观结构、漂浮性以及释药行为.为延长药物在胃靶向释放时长,在单因素实验的基础上,以Eudragit L100和Eudragit RSALO作为载体材料制备载药固体分散体,粉碎过...     

The use of citric acid to prolong the in vivo gastro-retention of a floating dosage form in the fasted state

Gastro-retentive dosage forms have the potential to improve local therapy and decrease the variation in bioavailability that is observed with a number of commercially available immediate and modified release preparations. In this study, a dosage form has been developed, utilising freeze-dried calcium alginate beads, designed to float on the surface of the stomach contents thus prolonging the retention time. The aim of the study was to also assess the in vivo behaviour of the radio-labelled calcium alginate beads when they were administered under fasting conditions with either water or an aqueous solution of citric acid, a potential gut transit delaying substance. The study was performed in healthy male volunteers who swallowed the radio-labelled calcium alginate beads after a 10h overnight fast. Gamma scintigraphy was selected as the method to monitor the movement of the calcium alginate beads. The volunteers consumed no further food or drink until gastric emptying of the calcium alginate beads was complete. The results indicated that prolonged gastric retention was achieved when the dosage form was administered with the citric acid solution when compared to retention in the absence of citric acid. Citric acid, therefore, has the potential to delay the gastric emptying of the calcium alginate beads when administered to fasted volunteers.     

Polyethyleneimine-modified pectin beads for colon-specific drug delivery: in vitro and in vivo implications

Calcium-pectinate (Ca-pectinate) beads have shown immense potential as colon-specific drug carrier. However, Ca-pectinate itself is unable to prevent its swelling/degradation in the upper gastro-intestinal (GI) conditions. Hence, polyethyleneimine (PEI) was added in the cross-linking solution to strengthen the Ca-pectinate network. Resveratrol was used as a model drug due to its promising therapeutic activity towards several colonic diseases. Beads were prepared by varying cross-linking solution pH and other formulation variables. The effects of these formulation variables were investigated on the bead's characteristics. Furthermore, surface morphology, drug-polymer interaction, stability, and in vivo pharmacokinetic study of the optimized formulation were performed. The optimized PEI-modified beads prevented drug release in the upper GI conditions, while released the drug in simulated colonic fluid. Furthermore, in vivo pharmacokinetics studies in rats demonstrated delayed appearance of drug in blood after oral administration. The optimized Ca-pectinate beads demonstrated both in vitro and in vivo colon-specific drug release.     

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.     

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.     

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.     

5-Fluorouracil encapsulated alginate beads for the treatment of breast cancer

Alginate beads containing 5-fluorouracil (5-FU) were prepared by the gelation of alginate with calcium cations. Alginate beads loaded with 5-FU were prepared at 1.0 and 2.0% (w/v) polymers. The effect of polymer concentration and the drug loading (1.0, 5.0 and 10%) on the release profile of 5-FU was investigated. As the drug load increased, larger beads were obtained in which the resultant beads contained higher 5-FU content. The encapsulation efficiencies obtained for 5-FU loads of 1.0, 5.0 and 10% (w/v) were 3.5, 7.4 and 10%, respectively. Scanning electron microscopy (SEM) and particle size analysis revealed differences between the formulations as to their appearance and size distribution. The amount of 5-FU released from the alginate beads increased with decreasing alginate concentrations.     

Novel tamarind seed polysaccharide-alginate mucoadhesive microspheres for oral gliclazide delivery: in vitro-in vivo evaluation

Novel tamarind seed polysaccharide (TSP)-alginate mucoadhesive microspheres were prepared using TSP and alginate as blend in different ratios with different calcium chloride (CaCl(2)) concentration as a cross linker by ionotropic gelation. The prepared microspheres were of spherical shape having rough surfaces, and average particle sizes within the range of 752.12 ± 6.42 to 948.49 ± 20.92 μm. The drug entrapment efficiency of these microspheres were within the range between 58.12 ± 2.42 to 82.78 ± 3.43% w/w. Fourier transform infrared (FTIR) studies indicated that there were no reactions between gliclazide, and polymers (TSP, and sodium alginate) used. Different formulations of gliclazide loaded TSP-alginate microspheres showed prolonged in vitro release profiles of gliclazide over 12 hours in both stomach pH (pH 1.2), and intestinal pH (pH 7.4). It was found that the gliclazide release in gastric pH was comparatively slow and sustained than intestinal pH. These TSP-alginate microspheres also exhibited good mucoadhesivity. The in vivo studies on alloxan-induced diabetic rats (Animal Ethical Committee registration number: IFTM/837ac/0160) demonstrated the significant hypoglycemic effect of selected formulation of TSP-alginate mucoadhesive microspheres containing gliclazide on oral administration. This developed gliclazide loaded new TSP-alginate mucoadhesive microspheres may be very much useful for prolonged systemic absorption of gliclazide for proper maintaining blood glucose level and advanced patient compliance.     

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.