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.     

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.     

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.     

Potential of calcium pectinate beads for target specific drug release to colon

A pectin-based colon specific delivery system bearing 5-fluorouracil (5-FU) was developed for effective delivery of drug to the colon. Calcium pectinate gel (CPG) beads were prepared by ionotropic gelation method followed by enteric coating with Eudragit S-100. The CPG beads formed were spherical with smooth surfaces. CPG beads size was found to be in the range of 1.32+/-0 . 12-1.88+/-0.08 mm. The in vitro drug release was investigated using USP dissolution rate test paddle type apparatus in different simulated mediums. Release in PBS (pH 7.4) and simulated gastric fluid showed almost similar pattern and rate, whereas a significant increase in percent cumulative drug release (58.3+/-1.36%) was observed in medium containing rat caecal content, i.e. the amount of the drug released from the formulation was found to be 49.2+/-2.29 and 58.3+/-1.36% of drug with 2 and 4% w/v caecal matter after 24 h whereas in control study 33.2+/-1.19% of drug was released. Moreover, to induce the enzymes that specifically act on pectin, the rats were treated with 1 ml of 1% w/v dispersion of pectin for 2 and 4 days and release rate studies were repeated in SCF in the presence of 2 and 4% w/v of caecal matter. A marked improvement in the drug release was observed in presence of caecal matter obtained after induction when compared to those without induction. The percentage of drug released after 24 h release was observed to be 69.3+/-2.81 and 86.7+/-3.15%, respectively, with 2 and 4% w/v rat caecal matter obtained after 2 days of enzyme induction, and 82.4+/-3.15 and 98.7+/-4.26%, respectively, after 4 days of enzyme induction. In vivo data showed that Eudragit S-100 coated calcium pectinate beads delivered most of its drug load (93.2+/-3.67%) to the colon after 9 h, which reflects its targeting potential to the colon. It is concluded that orally-administered 5-FU loaded Eudragit S-100 coated calcium pectinate beads can be used effectively for the specific delivery of drug to the colon.     

Utilization of ionotropic gelation technique for bioavailability enhancement of cinnarizine: in-vitro optimization and in-vivo performance in human

Gastro retentive drug delivery system techniques were adopted to deliver drugs having narrow absorption window from a particular site in the GIT. Therefore, gastro retentive dosage forms were retained in the stomach, thus improving absorption and bioavailability would be improved consequently. In this study, cinnarizine (CNZ) was employed as the model drug. CNZ is a poorly soluble basic drug, suffering from low and erratic bioavailability. This is attributed to its pH-dependant solubility (highly soluble at pH?<?4). CNZ is characterized by short half-life (3–6?h). Accordingly, floating CNZ emulsion gel calcium pectinate beads were developed. A mixture design was employed to study the effect of the percent of LM pectin (A), the percent of GMO (B) and the percent of Labrafac Lipophile (C) simultaneously on the percent of drug released and loaded. The optimized floating CNZ emulsion gel calcium pectinate beads and Stugeron® (the marketed reference product) were compared through a pharmacokinetic study carried on healthy human volunteers. Fortunately, simple floating CNZ emulsion gel calcium pectinate beads were prepared with zero-order release profile for 12?h. A promising in-vivo CNZ controlled release dosage form with higher bioavailability, when compared to once daily administration of Stugeron® tablets was achieved.     

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.     

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。     

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.     

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.     

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.     

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.     

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.     

Biphasic release of indomethacin from HPMC/pectin/calcium matrix tablet: I. Characterization and mechanistic study.

Calcium-induced crosslinking of pectin acts as the dominating factor controlling drug release from pectin-based matrices. The same interaction was employed to modify indomethacin release from HPMC/pectin/calcium matrix in this study. The aim was to characterize the release profiles, and to study the formulation variables and the underlying mechanisms. The matrix tablet was made up of pectin HM 70, calcium chloride and HPMC K4M, and prepared by the wet granulation method. In vitro release was performed in water and characterized by the power law. Matrix erosion was evaluated by studying the weight loss and pectin release. Biphasic release of indomethacin from the HPMC/pectin/calcium matrix tablet was observed, and extraordinary power law exponent n values of over 1.0 were observed. Increase in calcium amount led to more significant retardation on drug release. The two power law parameters, n and K, correlated to the amount of calcium in the matrix. A lag time of over 4 h can be achieved at HPMC/pectin/calcium chloride amount of 100 mg/100 mg/100 mg. Both matrix weight loss and pectin release were linearly correlated to indomethacin release, indicating erosion-controlled drug release mechanisms. The hybrid matrix showed retarded erosion and hydration rate, which served as the basis for retarded indomethacin release. It is concluded that the pectin/calcium interaction can be employed to modify drug release from HPMC/pectin/calcium matrix tablet with biphasic release patterns for potential timed or site-specific drug delivery.     

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.     

Shape,optimization and in vitro evaluation of colon-specific multi-particulate system based on low-methoxy amidated pectin and polycarbophil

Natural polysaccharides are widely used for development of colon-specific drug delivery systems. The present study was carried out to develop multi-particulate calcium pectinate (Ca-pectinate) formulations for colon-targeted delivery of lornoxicam. The formulations were developed using a combination of polycarbophil and low-methoxy amidated pectin. The beads were prepared using an ionotropic gelation technique. The effects of the polycarbophil and low-methoxy amidated pectin concentrations on the beads characteristics, encapsulation efficiency, swelling study and drug release performance were investigated. The optimized formulation was evaluated for its morphological characteristics. The in vitro drug release of the optimized formulation over a period of 12 h was 96.78 ± 1.35 %. The concentration of the polycarbophil was a decisive factor in sustaining drug release in the colon. The study revealed that optimized Ca-pectinate beads prepared with polycarbophil can efficiently encapsulate lornoxicam. It also showed that these beads can potentially be used for colon-specific delivery of lornoxicam.     

Drug release properties of pectinate microspheres prepared by emulsification method

This study explored the potential of pectin for use in making microspheres for sustained-release of drugs. The pectin microspheres were prepared by external gelation using an emulsification technique with calcium chloride as the crosslinking agent. The influences of drug core (sulphanilamide, sulphaguanidine and sulphathiazole) and dissolution media (distilled water, USP HCl and phosphate buffers) on the drug release properties of the pectinate microspheres were examined. The morphology and drug content of the microspheres, and the solubility and solution pH of the drugs were also determined. Pectinate microspheres were successfully prepared by the emulsification technique. The rate of drug released from microspheres was highest in USP HCl buffer, followed by USP phosphate buffer and distilled water. Interestingly, the lowest percentage of drug released was produced by microspheres which were smallest in size and therefore largest in specific surface area, and consisting of sulphanilamide, the most water soluble drug. Further investigation showed that the microspheres consisted of both bound and unbound drugs. The percentage of drug released was predominantly determined by the relative contents of bound and unbound drugs embedded in the pectinate matrix.     

阿西美辛海藻酸钙凝胶微丸释药影响因素考察

目的:考察阿西美辛海藻酸钙凝胶微丸的释药机制。方法:采用滴制法制备阿西美辛海藻酸钙微丸,考察海藻酸钠浓度,钙离子浓度,投药量,滴头直径大小对药物释放的影响。结果:海藻酸钠浓度增加,钙离子浓度增加,滴头直径增加,释药速率减慢。结论:在体外释放度实验中,阿西美辛海藻酸钙凝胶微丸具有良好的缓释作用,海藻酸钙凝胶微丸是一种非常有潜力的药物载体。     

Oral delayed-release system based on Zn-pectinate gel (ZPG) microparticles as an alternative carrier to calcium pectinate beads for colonic drug delivery.

A new oral timed-release system was developed for colon-targeted delivery of drugs. The system which consists of ketoprofen-loaded Zn-pectinate gel (ZPG) microparticles together with pectin/dextran mixtures in a tablet form, has been investigated, in vitro, using conditions chosen to simulate the pH and times likely to be encountered during transit to the colon. In order to find the suitable ZPG microparticles, the formulations were prepared by utilizing 2(3) factorial design and the effect of various formulation factors on the release and surface characteristics of the microparticles was studied. The results obtained implied that the release of ketoprofen from ZPG microparticles was greatly extended with the pectinate microparticles, which were prepared with 2.5 or 3% w/v pectin, 2.75% w/v Zn(CH3COO)2 and 2.5% w/v drug. Additionally, the analysis of variance results showed that the release of ketoprofen in simulated intestinal fluid (S.I.F., pH 7.4) was strongly affected by crosslinking agent concentration and initial drug amount, but not particularly affected by the amount of pectin added. The investigated drug concentration factor has significantly increased the drug entrapment efficiency (EE). The optimum colonic drug delivery ZPG/tablet system provided the expected delayed-release sigmoidal patterns with a lag-time of 4.125-4.85 h and t(50%) (the time for 50% of the drug to be released) at 7.45-8.70 h, depending on pectin/dextran ratio employed. The results also demonstrated that the untableted ZPG microparticles exhibited drug release profiles which were able to retard the release of ketoprofen in S.I.F. (pH 7.4) to be 5.28-37.82 times (depending on formulation parameters), lower than the conventional calcium pectinate beads. Therefore, this approach suggests that ZPG microparticles and their modified-release formulations are promising as useful controlled-release carriers for colon-targeted delivery of drugs.     

Methotrexate bearing calcium pectinate microspheres: a platform to achieve colon-specific drug release

In the present work calcium pectinate (Ca-pectinate) microspheres were prepared to deliver methotrexate in the environment of colon. Calcium pectinate microspheres were prepared by modified emulsification method using calcium chloride as cross linker. All the formulations were evaluated for various physicochemical parameters. Particle size of the microspheres was determined using laser diffraction particle size analyzer. Encapsulation efficiency was determined by digesting with enzyme pectinase for 24 hours and swellability by equilibrium swelling in simulated gastrointestinal fluid. The in vitro drug release studies were performed in simulated gastric fluid for 2 hours and simulated intestinal fluid for 3 hours. In vitro release rate studies were also carried out in simulated colonic fluid in presence of rat caecal contents. Moreover, release rate studies were also carried out after enzyme induction by treating the rats with 1 ml of 1% w/v aqueous dispersion of pectin for 7 days. Mean particle size of the microspheres was found to be in the range of 20.82+/-1.34 to 32.26+/-1.59 microm whereas the entrapment efficiency varied from 52.28+/-0.32 to 74.01+/-3.32%. The in vitro drug release studies in simulated gastric fluid and simulated intestinal fluid showed that only 8.15+/-0.49% drug was released in 5 hours whereas most of the loaded drug was released in simulated colonic fluid containing pectinase. In vitro release rate study showed release of 69.94+/-3.46% of drug in presence of 3% rat caecal contents, which was further increased to 94.43+/-4.48% when enzyme induction was carried out for 7 days. Thus, it is concluded that calcium pectinate microspheres can be used to effectively localize the release of drug in the physiological environment of colon.