Development of hollow/porous calcium pectinate beads for floating-pulsatile drug delivery.

The purpose of this work was to develop hollow calcium pectinate beads for floating-pulsatile release of diclofenac sodium intended for chronopharmacotherapy. Floating pulsatile concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release. To overcome limitations of various approaches for imparting buoyancy, hollow/porous beads were prepared by simple process of acid-base reaction during ionotropic crosslinking. The floating beads obtained were porous (34% porosity), hollow with bulk density<1 and had Ft50% of 14-24 h. In vivo studies by gamma scintigraphy determined on rabbits showed gastroretention of beads up to 5 h. The floating beads provided expected two-phase release pattern with initial lag time during floating in acidic medium followed by rapid pulse release in phosphate buffer. This approach suggested the use of hollow calcium pectinate microparticles as promising floating-pulsatile drug delivery system for site- and time-specific release of drugs acting as per chronotherapy of diseases.     

Calcium pectinate gel beads for controlled release drug delivery:: I. Preparation and in vitro release studies

Calcium pectinate gel (CPG) beads of indomethacin, a poorly soluble drug, were prepared by dispersing indomethacin in a solution of pectin and then dropping the dispersion into calcium chloride solution. The droplets instantaneously formed gelled spheres by ionotropic gelation. The effect of several factors such as pectin type, the presence of a hardening agent and the drug loading were investigated on the percentage of drug entrapped, size distribution and drug release from the CPG beads. The release characteristics were studied using the rotating basket dissolution method. Strong spherical beads with narrow size distributions, high yields and good entrapment efficiencies could be prepared. All factors investigated have significantly affected the release of indomethacin from CPG beads. The mechanism of drug release from CPG beads followed the diffusion controlled model for an inert porous matrix. Therefore, calcium pectinate gel could be a useful carrier for controlled release drug delivery of poorly soluble drugs.     

Emulsion gel beads of calcium pectinate capable of floating on the gastric fluid: effect of some additives,hardening agent or coating on release behavior of metronidazole

Emulsion gel (EMG) beads of calcium pectinate capable of floating in the gastric condition were developed using an emulsion-gelation method and their release properties were investigated. Attempts to modify the drug release were made by applying some additives into the starting solution prior to bead formation, by hardening with glutaraldehyde, and by coating with polymer. The metronidazole-loaded EMG beads were found to float on simulated gastric fluid. Increasing the drug to pectin ratio in the beads slowed the drug release from the conventional and the EMG beads. However, the drug release from these beads was rapid, i.e., about 80% of drug loading released within 20–80 min. The additives (PEG10000, glyceryl monostearate and Eudragit^® L) had a slight, insignificant, effect on the drug release. Using 2% glutaraldehyde as a hardening agent prolonged the drug release. Coating the beads with Eudragit^® RL significantly sustained the drug release while the beads remained buoyant. The results suggest that EMG beads are suitable as a carrier for intragastric floating drug delivery and that their release behaviour could be modified by hardening with glutaraldehyde or by coating with Eudragit^® RL.     

酮洛芬果胶钙凝胶小球和海藻酸钙凝胶小球的制备及性能比较

目的酮洛芬果胶钙凝胶小球和酮洛芬海藻酸钙凝胶小球的制备及性能比较。方法利用果胶、海藻酸钠及二者不同比例,以酮洛芬为模型药物采用滴制法制备凝胶小球,考察2种多糖物质对药物包封率和释放行为的影响。利用大鼠肠囊外翻实验对凝胶小球的生物黏附性能进行比较,通过对释放机理的探讨和凝胶小球溶胀性的测定进一步证明2种凝胶小球释药行为的不同。结果酮洛芬果胶钙凝胶小球和酮洛芬海藻酸钙凝胶小球均具有良好的生物黏附性能,果胶钙凝胶小球主要通过溶胀作用缓慢释药,而海藻酸钙凝胶小球的释药与凝胶小球慢慢吸水后骨架溶蚀有关。结论酮洛芬果胶钙凝胶小球和酮洛芬海藻酸钙凝胶小球通过与生物黏膜的紧密结合缓慢释药,而二者的释放行为有所不同。     

Morphology and buoyancy of oil-entrapped calcium pectinate gel beads

A new emulsion-gelation method to prepare oil-entrapped calcium pectinate gel (CaPG) beads capable of floating in the gastric condition was designed and tested. The gel beads containing edible oil were prepared by either being gently mixed or homogenized an oil phase and a water phase containing pectin, and then extruded into calcium chloride solution with gentle agitation at room temperature. The gel beads formed were then separated, washed with distilled water, and dried at 37 degrees C for 12 hours. A model of the emulsion-gelation process to illustrate the formation of oil-entrapped CaPG beads was proposed. The effect of selected factors, such as type of oil, percentage of oil, and type of pectin on morphology and floating properties was investigated. The oil-entrapped calcium pectinate gel beads floated if a sufficient amount of oil was used. Scanning electron photomicrographs demonstrated very small pores, ranging between 5 and 40 microm, dispersed all over the beads. The type and percentage of oil play an important role in controlling the floating of oil-entrapped CaPG beads. The results suggested that oil-entrapped CaPG beads were promising as a carrier for intragastric floating drug delivery.     

Calcium pectinate gel beads for controlled release drug delivery: II. Effect of form ulation and processing variables on drug release

The effect of four formulation and processing variables, calcium concentration, drying condition, concentration of hardening agent and hardening time on the bead properties and the release characteristics of a model drug from calcium pectinate gel (CPG) beads were studied. A poorly soluble compound, indomethacin, was used as the model drug. The investigated variables affected the bead size, the entrapment efficiency and the release of indomethacin from CPG beads. Drug release was found to be a function of the formulation and processing variables. The slower drug release was achieved from the formulations with higher calcium concentration, higher concentration of hardening agent and longer hardening time. The drying condition, however, did not influence the drug release. The mechanism of indomethacin release from CPG beads followed the diffusion controlled model for an inert porous matrix. All drug release data fitted well to the Higuchi square root time expression.     

Calcium pectinate gel beads for controlled release drug delivery: II. Effect of formulation and processing variables on drug release.

The effect of four formulation and processing variables, calcium concentration, drying condition, concentration of hardening agent and hardening time on the bead properties and the release characteristics of a model drug from calcium pectinate gel (CPG) beads were studied. A poorly soluble compound, indomethacin, was used as the model drug. The investigated variables affected the bead size, the entrapment efficiency and the release of indomethacin from CPG beads. Drug release was found to be a function of the formulation and processing variables. The slower drug release was achieved from the formulations with higher calcium concentration, higher concentration of hardening agent and longer hardening time. The drying condition, however, did not influence the drug release. The mechanism of indomethacin release from CPG beads followed the diffusion controlled model for an inert porous matrix. All drug release data fitted well to the Higuchi square root time expression.     

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.     

Calcium pectinate gel beads for controlled release drug delivery:: I. Preparation and in vitro release studies

Calcium pectinate gel (CPG) beads of indomethacin, a poorly soluble drug, were prepared by dispersing indomethacin in a solution of pectin and then dropping the dispersion into calcium chloride solution. The droplets instantaneously formed gelled spheres by ionotropic gelation. The effect of several factors such as pectin type, the presence of a hardening agent and the drug loading were investigated on the percentage of drug entrapped, size distribution and drug release from the CPG beads. The release characteristics were studied using the rotating basket dissolution method. Strong spherical beads with narrow size distributions, high yields and good entrapment efficiencies could be prepared. All factors investigated have significantly affected the release of indomethacin from CPG beads. The mechanism of drug release from CPG beads followed the diffusion controlled model for an inert porous matrix. Therefore, calcium pectinate gel could be a useful carrier for controlled release drug delivery of poorly soluble drugs.     

Pharmacokinetics and analgesic effect of ketorolac floating delivery system

Abstract

Objectives: The efficacy of ketorolac tromethamine (KT) floating alginate beads as a drug delivery system for better control of KT release was investigated. The formulation with the highest drug loading, entrapment efficiency, swelling, buoyancy, and in vitro release would be selected for further in vivo analgesic effect in the mice and pharmacokinetics study in rats compared to the tablet dosage form.

Methods: KT floating alginate beads were prepared by extrusion congealing technique. KT in plasma samples was analyzed using a UPLC MS/MS assay.

Results: The percentage yield, drug loading and encapsulation efficiency were increased proportionally with the hydroxypropylmethyl cellulose (HPMC) polymer amount in the KT floating beads. A reverse relationship was observed between HPMC amount in the beads and the KT in vitro release rate. F3-floating beads were selected, due to its better in vitro results (continued floating for >8?h) than others. A longer analgesic effect was observed for F3 in fed mice as compared to the tablets. After F3 administration to rats, the C_max (2.2?±?0.3?µg/ml) was achieved at ～2?h and the decline in KT concentration was slower. F3 showed a significant increase in the AUC (1.89 fold) in rats as compared to the tablets.

Conclusion: KT was successfully formulated as floating beads with prolonged in vitro release extended to a better in vivo characteristic with higher bioavailability in rats. KT in floating beads shows a superior analgesic effect over tablets, especially in fed mice.     

Release behaviour of diclofenac sodium dispersed in Gelucire® and encapsulated with alginate beads

Sustained release polymeric particles containing diclofenac sodium dispersed in Gelucire® matrix and encapsulated in calcium alginate shell were prepared with different drug-to-polymer ratios and also with different concentrations of sodium alginate for a fixed drug-to-polymer ratio in an aqueous environment. Spherical particles were formed by dropping an emulsion of diclofenac sodium in Gelucire® matrix, emulsified with sodium alginate, into calcium chloride solution. The gelled beads formed by ionotropic gelation of alginate with calcium ions showed sustained release of the water soluble drug in in-vitro release study. Drug release was a function of square-root of time, suggesting a matrix diffusion release pattern. The rate of release was significantly suppressed with increasing proportions of Gelucire® in the mixture. Sustained and complete release was achieved with Gelucire® of low melting point and low HLB value. No significant drug release occurred in a dissolution medium of pH 1.5, whereas complete release was observed at pH 6.8, consistent with considerable swelling of the alginate gel at this pH.     

Effect of calcium concentration, hardening agent and drying condition on release characteristics of oral proteins from calcium pectinate gel beads.

Pectin has been investigated for its ability to produce solid calcium pectinate gel (CPG) beads containing bovine serum albumin (BSA). Several factors can influence the properties and release characteristics of the CPG beads. In this study, the effect of calcium concentration, hardening agent and drying condition on the encapsulation and release characteristics of BSA from the matrix gel beads made of calcium pectinate were studied. BSA release studies under conditions mimicking mouth to colon transit have shown that calcium pectinate protects the drug from being released completely in the physiological environment of the upper gastrointestinal tract, and is susceptible to the enzymatic action with consequent drug release. In addition, the release of BSA from CPG beads was strongly affected by calcium concentration and drying condition. However, the release was not particularly affected by the presence of hardening agent at the concentration of 1% or lower. Since the release of BSA as a model protein drug could be controlled by the regulation of the preparation conditions of CPG beads, the CPG beads may be used for a potential oral controlled release system for protein drugs.     

Bovine Serum Albumin–Loaded Pectinate Beads as Colonic Peptide Delivery System: Preparation and In Vitro Characterization

Objective of this study was to prepare a drug delivery system for therapeutic peptides that are degraded in the upper part of the gastrointestinal tract due to degradation activity of the enzymes. Delivering peptide to the colon in which enzymatic activity is low is next hope for absorption of these agents. Pectin, a naturally occurring water soluble polysaccharide, as a matrix for peptide delivery was studied. Degradation of pectin by the colonic enzymes makes it suitable for colon-specific delivery of drugs. Bovine serum albumin (BSA) was used as a model peptide. Calcium pectinate beads were prepared by extruding BSA-loaded pectin solution to an agitating calcium chloride solution, and gelled spheres were formed instantaneously by an ionotropic gelation reaction. The effect of several factors such as concentration of pectin, concentration of calcium chloride, and total drug loading on the pattern of drug release in the dissolution medium was studied. Prepared beads showed good resistance in the release medium. The entrapment efficiency of the beads was high (between 63% and 99%). Entrapment efficiency of BSA was reversely dependent to the amount of the drug loaded in the beads. The amount of BSA loaded on the beads affects pattern of drug release. The concentration of the pectin showed the highest impact on the rate of drug release. Presence of the pectiolytic enzymes facilitated the drug release from the beads.     

Drug release property of chitosan–pectinate beads and its changes under the influence of microwave

The effects of microwave irradiation on the drug release property of pectinate beads loaded internally with chitosan (chitosan–pectinate beads) were investigated against the pectinate beads and beads coacervated with chitosan externally (pectinate–chitosonium beads). These beads were prepared by an extrusion method using sodium diclofenac as the model water-soluble drug. The beads were subjected to microwave irradiation at 80 W for 5, 10, 21 and 40 min. The profiles of drug dissolution, drug content, drug–polymer interaction and polymer–polymer interaction were determined by drug dissolution testing, drug content assay, drug adsorption study, differential scanning calorimetry (DSC) and Fourier transform infra-red spectroscopy (FTIR) techniques. Treatment of pectinate beads by microwave did not lead to a decrease, but an increase in the extent of drug released at 4 h of dissolution owing to reduced pectin–pectin interaction via the CO moiety of polymer. In addition, the extent of drug released from the pectinate beads could not be reduced merely through the coacervation of pectinate matrix with chitosan. The reduction in the extent of drug released from the pectinate–chitosonium beads required the treatment of these beads by microwave, following an increase in drug–polymer and polymer–polymer interaction in the matrix. The extent of drug released from the pectinate beads was reduced through incorporating chitosan directly into the interior of pectinate matrix, owing to drug–chitosan adsorption. Nonetheless, the treatment of chitosan–pectinate matrix by microwave brought about an increase in the extent of drug released unlike those of pectinate–chitosonium beads. Apparently, the loading of chitosan into the interior of pectinate matrix could effectively retard the drug release without subjecting the beads to the treatment of microwave. The microwave was merely essential to reduce the release of drug from pectinate beads when the chitosan was introduced to the pectinate matrix by means of coacervation. Under the influences of microwave, the drug release property of beads made of pectin and chitosan was mainly modulated via the CH, OH and NH moieties of polymers and drug, with CH functional group purported to retard while OH and NH moieties purported to enhance the drug released from the matrix.     

Colon-specific drug delivery: Influence of solution reticulation properties upon pectin beads performance

In this study, pectinate gel beads were produced by ionotropic gelation method with different solutions of cross-linking agents and ketoprofen was entrapped as model drug. The influence of these formulation parameters was investigated upon bead properties and upon their performance to target the colon. Zinc pectinate beads obtained with 10% of counter-ions solution at pH 1.6 exhibited the strongest gel network due to "egg-box" dimmer formation helped by hydrogen bonding. Furthermore the gel network formed at low pH was arranged in a compact three-fold conformation. Thus, this matrix structure in enteric capsules induced the lowest drug release in the upper gastro-intestinal tract (pH 1.2 following by pH 7.4). However ketoprofen release occurred specifically in the colon thanks to the presence of pectinolytic enzymes and the release rate can be modulated by the counter-ion concentration during the reticulation process. Therefore this approach using pectinate beads is very promising as efficient carrier for specific delivery of drug into the colon, after oral administration.     

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.     

Use of back-scattered electron imaging as a tool for examining matrix structure of calcium pectinate

The internal structure of pharmaceutical solid dosage forms is commonly revealed by secondary electron imaging using standard scanning electron microscopy (SEM) technique. In this work we propose a back-scattered electron imaging (BEI) as a new tool for examining the matrix structure of calcium pectinate beads. Imaging samples with back-scattered electrons in the SEM is based on material or atomic number contrast. High atomic number elements, such as calcium, reflect more electrons and appear bright on electron micrographs. The BEI-SEM images of calcium pectinate matrix beads clearly showed net-like structure of calcium pectinate and uniform distribution of drug particles. The matrix compositions were confirmed by energy dispersive analyzer. The result demonstrates the advantageous of BEI for examining the matrix structure of calcium pectinate.     

Effect of core and surface cross-linking on the entrapment of metronidazole in pectin beads

The purpose of this study was to improve the entrapment efficiency of the water-soluble drug metronidazole using internal cross-linking agents. Calcium pectinate beads containing metronidazole were prepared by dropping a drug-pectin solution in 1% and 5% (m/V) calcium chloride for surface cross-linked beads. For the core cross-linked beads calcium carbonate was dispersed in the drug-pectin solution. The beads were characterized by particle size, swelling ratio, SEM, DSC, and in vitro drug release. It was found that the beads obtained by core cross-linking produced more drug entrapped beads than the surface cross-linked beads. Beads obtained using 1% (m/V) calcium chloride showed more drug entrapment than these obtained using 5% calcium chloride. The core cross-linking of pectin beads reduced drug loss by about 10-20%. The water lodging capacity of beads depended upon gel strength which is a function of the internal gelling agent and pectin concentration. Complete drug release was observed within 30-60 min in the acidic dissolution medium. This work has showed that the core cross-linking agent increases the water-soluble drug entrapment in calcium pectinate beads.     

Development of mucoadhesive floating hollow beads of acyclovir with gastroretentive properties

Abstract

This study aimed at improving the oral bioavailability of acyclovir (ACV) through incorporating it into gastroretentive dosage form based on floating hollow chitosan beads. Hollow chitosan beads were prepared using a solvent free, ionotropic gelation method. The effect of formulation parameters, including chitosan molecular weight and drug concentration, on bead characteristics was studied. The drug containing formulations had yields >70.5?±?0.31%. The entrapment efficiencies for the medium molecular weight chitosan formulations (56.29?±?0.94%–62.75?±?0.86%) was greater than the high molecular weight chitosan formulation (29.21?±?0.89%). The density of all formulations was below that of gastric fluid, the greatest density observed was 0.60?±?0.01?g?cm^?3. Unsurprisingly, the formulations were immediate bouyant to different degrees in both pH 1.2 and pH 6.8 media. In addition, the chitosan beads were all seen to swell in pH 1.2 media and demonstrated mucoadhesive properties. A sustained release profile was observed from the chitosan beads, the developed formulations released drug at slower rates than a marketed ACV oral tablet. The developed system has the dual advantages of being gastroretentive, to increase oral bioavailability and releasing drug in a controlled manner, to reduce the required frequency of administration thereby promoting patient adherence.     

Citric acid prolongs the gastro-retention of a floating dosage form and increases bioavailability of riboflavin in the fasted state

A floating dosage form based on calcium alginate beads has been developed. Riboflavin, was selected as the model drug and successfully incorporated into calcium alginate beads. The aims of the current study were to: (a) assess the influence of prolonged gastro-retention on the bioavailability of riboflavin from freeze dried calcium alginate beads administered under varying conditions of food intake and (b) to investigate the potential of citric acid to delay the gastric emptying of the calcium alginate beads. Gamma scintigraphy was selected as the method to monitor the movement of the calcium alginate beads in vivo. Riboflavin concentrations in the urine were analysed by HPLC. Prolonged gastro-retention can be achieved, in the fasted state, when citric acid solution is used as an administering vehicle. However, prolonged gastro-retention is not achieved to the same extent when the gastric emptying times are compared to those obtained in the fed state. The bioavailability of riboflavin improved when calcium alginate beads were administered in the fasted state with citric acid solution, compared to the bioavailability obtained when the calcium alginate beads were administered in the absence of citric acid.