Sustained release properties of alginate microspheres and tabletted microspheres of diclofenac sodium

This study focused on the properties of diclofenac sodium (DNa) alginate (alg) microspheres and tabletted DNa alg microspheres using different polymers as additives. DNa alginate microspheres were prepared by the emulsification method and different polymers such as Eudragit (Eud) NE 30 D, Eudragit (Eud) RS 30 D and Aquacoat, which were incorporated into alg gel to control the release rate of drug. The release properties of DNa alg microspheres (1:1) were affected by the size, drug load of microspheres and also by the incorporated polymers, pH and ionic strength of dissolution medium. Tabletting of alg microspheres using carrageenan (carr), alg, pectin, NaCMC, tragacanth (trgh) and HPMC as additives in a (50:50) ratio produced tablets with good physical properties and also better controlled release of DNa. Dissolution studies were carried out in pH 7.2 phosphate buffer and phosphate buffers whose pH values were gradually changed from pH 3 to 7.4. The rank order of DNa release from tablets was carr < alg < pectin < NaCMC < trgh < HPMC which relates to the viscosity and swelling properties of polymers. The drug release was very slow from trgh and HPMC based tablets, but addition of carr or alg in different ratios could adjust the release rate of drug.     

Polymers for sustained release formulations of dipyridamole-alginate microspheres and tabletted microspheres

The preparation of dipyridamole (DIP) alginate (alg) microspheres by different methods or the incorporation of tragacanth (trgh), pectin or Eudragit L-100 55 (Eud) in alg microsphere formulations did not provide a prolonged release of DIP at pH 1.2. Tabletted microsphere formulations containing alg, trgh, pectin, sodium carboxymethyl cellulose (CMC), sodium starch glycolate (SSG), carrageenan (carrg) or Eud as diluents in different ratios, produced tablets with good physical properties which did prolong DIP release. The type, viscosity and the ratio of the diluent polymer, microsphere size and the compression pressure were found to be important factors to produce tablets with desired properties. No advantage of the tablets containing alg microspheres and granulated diluents was observed over the tablets containing powdered diluents.     

Polymers for sustained release formulations of dipyridamole-alginate microspheres and tabletted microspheres.

The preparation of dipyridamole (DIP) alginate (alg) microspheres by different methods or the incorporation of tragacanth (trgh), pectin or Eudragit L-100 55 (Eud) in alg microsphere formulations did not provide a prolonged release of DIP at pH 1.2. Tabletted microsphere formulations containing alg, trgh, pectin, sodium carboxymethyl cellulose (CMC), sodium starch glycolate (SSG), carrageenan (carrg) or Eud as diluents in different ratios, produced tablets with good physical properties which did prolong DIP release. The type, viscosity and the ratio of the diluent polymer, microsphere size and the compression pressure were found to be important factors to produce tablets with desired properties. No advantage of the tablets containing alg microspheres and granulated diluents was observed over the tablets containing powdered diluents.     

Preparation and release characteristics of polymer-coated and blended alginate microspheres

To prevent a rapid drug release from alginate microspheres in simulated intestinal media, alginate microspheres were coated or blended with polymers. Three polymers were selected and evaluated such as HPMC, Eudragit RS 30D and chitosan, as both coating materials and additive polymers for controlling the drug release. This study focused on the release characteristics of polymer-coated and blended alginate microspheres, varying the type of polymer and its concentration. The alginate microspheres were prepared by dropping the mixture of drug and sodium alginate into CaCl(2) solution using a spray-gun. Polymer-coated microspheres were prepared by adding alginate microspheres into polymer solution with mild stirring. Polymer-blended microspheres were prepared by dropping the mixture of drug, sodium alginate and additive polymer with plasticizer into CaCl(2) solution. In vitro release test was carried out to investigate the release profiles in 500 ml of phosphate buffered saline (PBS, pH 7.4). As the amount of polymer in sodium alginate or coating solution increase, the drug release generally decreased. HPMC-blended microspheres swelled but withstood the disintegration, showing an ideal linear release profiles. Chitosan-coated microspheres showed smooth and round surface and extended the release of drug. In comparison with chitosan-coated microspheres, HPMC-blended alginate microspheres can be easily made and used for controlled drug delivery systems due to convenient process and controlled drug release.     

Effect of anionic polymers on the release of propranolol hydrochloride from matrix tablets.

Anionic polymers, namely Eudragit S, Eudragit L 100-55, and sodium carboxymethylcellulose, were incorporated into hydroxypropylmethylcellulose (HPMC K100M) to modify the drug release from HPMC matrices. The effects of changing the ratio of HPMC to anionic polymers were examined in water and in media with different pH. The dissolution profiles were compared according to release rates. The interaction between propranolol hydrochloride and anionic polymers was confirmed using the UV difference spectra method. The drug release was controlled with the type of anionic polymer and the interaction between propranolol hydrochloride and anionic polymers. The HPMC-anionic polymer ratio also influenced the drug release. The matrix containing HPMC-Eudragit L 100-55 (1:1 ratio) produced pH-independent extended-release tablets in water, 0.1 N HCl, and pH 6.8 phosphate buffer.     

Gastro-resistant microspheres containing ketoprofen.

Ketoprofen gastroresistant microspheres were prepared by spray-drying using common pH dependent polymers, such as Eudragit S and L, CAP, CAT and HPMCP. The long ketoprofen recrystallization time was a serious hindrance to the preparation of microspheres having a drug content higher than 35%. Microspheres were characterized by scanning electron microscopy, differential scanning calorimetry, X-ray diffractometry and in vitro dissolution studies, and used for the preparation of tablets. During this step, the compaction ability of the spray-dried powders was measured. While the compressibility of the microspheres containing the enteric cellulosic derivatives are not acceptable and different from those of the microcrystalline cellulose, the compaction properties of ketoprofen/Eudragit L or S microspheres are comparable to those of the Avicel PH 101. In vitro dissolution studies were performed on the microspheres and the tablets. All microspheres showed a good gastroresistance, but some differences among the five polymers in reducing drug release at low pH values are present. Acrylic polymers (Eudragit L or S) are considerably more effective than the cellulosic derivatives CAP and CAT, while the HPMCP profile is in an intermediate position. These differences are erased by the microspheres compression process. In HCl 0.1 N, the percentage of ketoprofen released from the tablets is always close to zero, independently from the polymer used.     

Effect of tabletting compaction pressure on alginate microspheres

Alginate and alginate-hydroxypropylmethylcellulose (HPMC) microspheres were prepared by the emulsification method. The compaction of microspheres for producing tablet dosage forms raises concerns about possible damage to microsphere walls with subsequent unpredictable dissolution rates. The effect of different compaction pressures on the integrity of the microspheres was investigated. The addition of a diluent, microcrystalline cellulose (MCC), was required to make compacts containing alginate and alginate-HPMC microspheres. Compacts containing alginate-HPMC (7:3) microspheres had the highest crushing strength followed by compacts containing alginate-HPMC (9:1) microspheres and alginate microspheres. However, compact crushing strength did not vary significantly with increased compaction pressures over the range of compaction pressures investigated. Differences in the drug release profiles of the original non-compacted and compacted alginate and alginate HPMC microspheres were slight and not marked. Although dentation and distortion of the microspheres were observed with increasing compaction pressures, the microspheres generally remained intact, with minimal rupture/fracture.     

Insulin encapsulation in reinforced alginate microspheres prepared by internal gelation.

Insulin-loaded alginate microspheres prepared by emulsification/internal gelation were reinforced by blending with polyanionic additive polymers and/or chitosan-coating in order to increase the protection of insulin at simulated gastric pH and obtain a sustained release at simulated intestinal pH. Polyanionic additive polymers blended with alginate were cellulose acetate phtalate (CAP), Eudragit L100 (EL100), sodium carboxymethylcellulose (CMC), polyphosphate (PP), dextran sulfate (DS) and cellulose sulfate (CS). Chitosan-coating was applied by using a one-stage procedure. The influence of additive polymers and chitosan-coating on the size distribution of microspheres, encapsulation efficiency and release profile of insulin in simulated gastrointestinal pH conditions was studied. The mean diameter of blended microspheres ranged from 65 to 106 microm and encapsulation efficiency of insulin varied from 14 to 100%, reaching a maximum value when CS and DS were incorporated in the alginate matrix. Insulin release, at pH 1.2, was almost prevented by the incorporation of PP, DS and CS. When uncoated microspheres were transferred to pH 6.8, a fast dissolution occurred, independently of the additive polymer blended with alginate, and insulin was completely released. Increasing the additive polymer concentration in the alginate matrix and/or chitosan-coating the blended alginate microspheres did not promote a sustained release of insulin from microspheres at pH 6.8.     

Con-A conjugated mucoadhesive microspheres for the colonic delivery of diloxanide furoate

The aim of the research work was to develop cyst-targeted novel concanavalin-A (Con-A) conjugated mucoadhesive microspheres of diloxanide furoate (DF) for the effective treatment of amoebiasis. Eudragit microspheres of DF were prepared using emulsification-solvent evaporation method. Formulations were characterized for particle size and size distribution, % drug entrapment, surface morphology and in vitro drug release in simulated gastrointestinal (GI) fluids. Eudragit microspheres of DF were conjugated with Con-A. IR spectroscopy and DSC were used to confirm successful conjugation of Con-A to Eudragit microspheres while Con-A conjugated microspheres were further characterized using the parameters of zeta potential, mucoadhesiveness to colonic mucosa and Con-A conjugation efficiency with microspheres. IR studies confirmed the attachment of Con-A with Eudragit microspheres. All the microsphere formulations showed good % drug entrapment (78+/-5%). Zeta potential of Eudragit microspheres and Con-A conjugated Eudragit microspheres were found to be 3.12+/-0.7mV and 16.12+/-0.5mV, respectively. Attachment of lectin to the Eudragit microspheres significantly increases the mucoadhesiveness and also controls the release of DF in simulated GI fluids. Gamma scintigraphy study suggested that Eudragit S100 coated gelatin capsule retarded the release of Con-A conjugated microspheres at low pH and released microspheres slowly at pH 7.4 in the colon.     

Effect of formulation variables on in vitro drug release and micromeritic properties of modified release ibuprofen microspheres

Modified release microspheres of the non-steroidal anti-inflammatory drug, ibuprofen, were formulated and prepared using the emulsion solvent diffusion technique. The contribution of various dispersed phase and continuous phase formulation factors on in vitro drug release and micromeritic characteristics of microspheres was examined. The results demonstrated that the use of Eudragit RS 100 and Eudragit RL 100 as embedding polymers modified the drug release properties as a function of polymer type and concentration. Eudragit RS 100 retarded ibuprofen release from the microspheres to a greater extent than Eudragit RL 100. The drug/polymer concentration of the dispersed phase influenced the particle size and drug release properties of the formed microspheres. It was found that the presence of emulsifier was essential for microsphere formation. Increasing the concentration of emulsifier, sucrose fatty acid ester F-70, decreased the particle size which contributed to increased drug release properties. Scanning electron microscopy revealed profound distortion in both the shape and surface morphology of the microspheres with the use of magnesium stearate as added emulsifier. The application of an additional Eudragit RS 100 coat onto formed microspheres using fluid bed technology was successful and modulated the drug release properties of the coated microspheres.     

Influence of Carbopol 71G-NF on the release of dextromethorphan hydrobromide from extended-release matrix tablets

The objective of this study was to evaluate the potential of Carbopol^® 71G-NF on the release of dextromethorphan hydrobromide (DM) from matrix tablets in comparison with hydroxypropyl methylcellulose (HPMC^® K15M) and Eudragit^® L100-55 polymers. Controlled release DM matrix tablets were prepared using Carbopol 71G-NF, HPMC K15M, and Eudragit L100-55 at different drug to polymer ratios by direct compression technique. The mechanical properties of the tablets as tested by crushing strength and friability tests were improved as the concentration of Carbopol, HPMC, and Eudragit increased. However, Carbopol-based tablets showed a significantly (P?<?0.05) higher crushing strength and a lower friability than HPMC and Eudragit tablets. No significant differences in weight uniformity and thickness values were observed between the different formulations. It was also found that Carbopol significantly (P?<?0.05) delayed the release of DM in comparison with HPMC K15M and Eudragit L100-55. A combination of HPMC K15M and Eudragit L100-55 in a 1:1 ratio at 20 and 30% significantly (P?<?0.05) delayed the release of DM than Eudragit L100-55 alone. Moreover, blends of Carbopol and HPMC at a 1:1 ratio at the 10, 20, and 30% total polymer concentration were investigated. The blend of Carbopol and HPMC at 10% level significantly (P?<?0.05) slowed the release of DM than Carbopol or HPMC alone, whereas blends at 20 and 30% level significantly (P?<?0.05) delayed the release of DM compared with HPMC or Carbopol alone. The results with these polymer blends showed that it was possible to reduce the total amount of polymers when used as a combination in formulation.     

Encapsulation of antihypertensive drugs in cellulose-based matrix microspheres: characterization and release kinetics of microspheres and tableted microspheres

This study is an attempt to prepare microspheres loaded with two anti-hypertensive drugs viz., nifedipine (NFD) and verapamil hydrochloride (VRP) using cellulose-based polymers viz., ethyl cellulose (EC) and cellulose acetate (CA). Emulsification and solvent evaporation methods were optimized using ethyl acetate as a dispersing solvent. The particles are spherical in shape and have smooth surfaces, as evidenced by the scanning electron microscopy. The microspheres were characterized for their particle size and distribution, tapped density and encapsulation efficiency. Smaller sized particles with a narrow size distribution were produced with EC when compared to CA matrices. Molecular level drug distribution in the microspheres was confirmed by differential scanning calorimetry. The microspheres were directly compressed into tablets using different excipients. The drug release from CA was faster than EC microspheres and, also, the VRP release was faster than NFD. The excipients used in tableting showed an effect on the release as well as the physical properties of the tablets.     

Liquid phase coating to produce controlled-release alginate microspheres

This study explored a liquid phase coating technique to produce polymethyl methacrylate (PMMA)-coated alginate microspheres. Alginate microspheres with a mean diameter of 85.6?µm were prepared using an emulsification method. The alginate microspheres, as cores, were then coated with different types of PMMA by a liquid phase coating technique. The release characteristics of these coated microspheres in simulated gastric (SGF) and intestinal (SIF) fluids and the influence of drug load on encapsulation efficiency were studied. The release of paracetamol, as a model hydrophilic drug, from the coated microspheres in SGF and SIF was greatly retarded. Release rates of Eudragit RS100-coated microspheres in SGF and SIF were similar as the rate-controlling polymer coat was insoluble in both media. Drug release from Eudragit S100-coated microspheres was more sustained in SGF than in SIF, due to the greater solubility of the coating polymer in media with pH greater than 7.0. The drug release rate was affected by the core:coat ratio. Drug release from the coated microspheres was best described by the Higuchi's square root model. The liquid phase coating technique developed offers an efficient method of coating small microspheres with markedly reduced drug loss and possible controlled drug release.     

Preparation and in vitro dissolution profile of zidovudine loaded microspheres made of Eudragit RS 100, RL 100 and their combinations

The objective of present investigation was to evaluate the entrapment efficiency of the anti-HIV drug, zidovudine, using two Eudragit polymers of different permeability characteristics and to study the effect of this entrapment on the drug release properties. In order to increase the entrapment efficiency optimum concentration of polymer solutions were prepared in acetone using magnesium stearate as droplet stabilizer. The morphology of the microspheres was evaluated using a scanning electron microscope, which showed a spherical shape with smooth surface. The mean sphere diameter was between 1000-3000 microm and the entrapment efficiencies ranged from 56.4-87.1%. Polymers were used separately and in combination to prepare different microspheres. The prepared microspheres were studied for drug release behavior in phosphate buffer at pH 7.4, because the Eudragit polymers are independent of the pH of the dissolution medium. The release profiles and entrapment efficiencies depended strongly on the structure of the polymers used as wall materials. The release rate of zidovudine from Eudragit RS 100 microspheres was much lower than that from Eudragit RL 100 microspheres. Evaluation of release data reveals that release of zidovudine from Eudragit RL 100 microspheres followed the Higuchi rule, whereas Eudragit RS 100 microspheres exhibited an initial burst release, a lag period for entry of surrounding dissolution medium into polymer matrix and finally, diffusion of drug through the wall material.     

Liquid phase coating to produce controlled-release alginate microspheres

This study explored a liquid phase coating technique to produce polymethyl methacrylate (PMMA)-coated alginate microspheres. Alginate microspheres with a mean diameter of 85.6 microm were prepared using an emulsification method. The alginate microspheres, as cores, were then coated with different types of PMMA by a liquid phase coating technique. The release characteristics of these coated microspheres in simulated gastric (SGF) and intestinal (SIF) fluids and the influence of drug load on encapsulation efficiency were studied. The release of paracetamol, as a model hydrophilic drug, from the coated microspheres in SGF and SIF was greatly retarded. Release rates of Eudragit RS100-coated microspheres in SGF and SIF were similar as the rate-controlling polymer coat was insoluble in both media. Drug release from Eudragit S100-coated microspheres was more sustained in SGF than in SIF, due to the greater solubility of the coating polymer in media with pH greater than 7.0. The drug release rate was affected by the core:coat ratio. Drug release from the coated microspheres was best described by the Higuchi's square root model. The liquid phase coating technique developed offers an efficient method of coating small microspheres with markedly reduced drug loss and possible controlled drug release.     

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.     

Taste masked microspheres of ofloxacin: formulation and evaluation of orodispersible tablets

Ofloxacin is a synthetic chemotherapeutic antibiotic used for treatment of a variety of bacterial infections, but therapy suffers from low patients' compliance due to its unpleasant taste. This study was aimed to develop taste masked microspheres of ofloxacin using Eudragit and to prepare orodispersible tablets of the formulated microspheres using natural superdisintegrant. Taste masking Eudragit E100 microspheres were prepared by solvent evaporation technique with an entrapment efficiency ranging from 69.54 ± 1.98 to 86.52 ± 2.25%. DSC revealed no interaction between the drug and polymer. Microspheres prepared at a drug/polymer ratio of 1:4 and 1:5 revealed sufficient flow properties and better taste masking as compared to other ratios. Drug loaded microspheres were formulated as orodispersible tablets using locust bean gum as a natural superdisintegrant offering the advatages of biocompatibility and biodegrad-ability. The wetting time, water absorption ratio and in-vitro disintegration time of the tablets were found to range between 19 ± 2 to 10 ± 3 seconds, 59.11 ± 0.65 to 85.76 ± 0.96 and 22 ± 2 to 10 ± 2 seconds, respectively. The in-vitro ofloxacin release was about 97.25% within 2h. The results obtained from the study suggested the use of eudragit polymer for preparing ofloxacin loaded microspheres with an aim to mask the bitter taste of the drug and furthermore orodispersible tablets could be formulated using locust bean gum as a natural superdisintegrant.     

Preparation of sodium alginate microspheres containing hydrophilic β-lactam antibiotics

Alginate microspheres were prepared by the emulsification process as a drug delivery system of ampicillin sodium (AMP-Na). The preparation parameters such as the concentration of calcium chloride, the stirring time and the amount of AMP-Na were investigated. The alginate microspheres containing hydroxypropylmethylcellulose (HPMC) were found to be generally spherical, discrete and had smoother surfaces when compared to without HPMC. However, there was no significant difference in the release profile of AMP-Na from alginate microspheres prepared with or without HPMC. The concentration of calcium chloride solution and the stirring time in the preparation of alginate microspheres influenced the aggregation of alginate microspheres. The amount of AMP-Na in alginate microspheres influenced the surface morphology and the practical drug content in microspheres.     

Compressed biodegradable matrices of spray-dried PLGA microspheres for the modified release of ketoprofen

A spray-drying technique was used to prepare poly(lactide-co-glycolide) (PLGA) drug loaded microspheres. Ketoprofen was chosen as a model NSAID drug. The microspheres were characterized in terms of morphology, drug content and release behaviour. The spray-dried particles were subject to a direct compression process for the preparation of biodegradable matrix tablets. The spray-dried powders were found to have good compaction properties. Tablets were also prepared from a mixture of microspheres and microcrystalline cellulose, mannitol and hydroxypropylmethylcellulose or sodium alginate. The release of ketoprofen in phosphate buffer (pH 7.4) was significantly sustained, indicating the suitability of using tabletted spray-dried PLGA microspheres for controlled drug delivery. The results show that spray-dried PLGA particles have promising properties as direct compression and release controlling excipients in matrix tablets for oral administration.     

Use of enteric polymers for production of microspheres by extrusion-spheronization

To simplify the manufacture of enteric dosage forms, incorporation of enteric polymers into the matrix of phenylbutazone microspheres produced by extrusion-spheronization was compared to the coating of cores. The effect of different polymers, cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulose phthalate (HPMCP) and Eudragit L100-55 and the amount of granulating liquid were evaluated for the effect of selected physical properties and drug release behavior. Using the enteric polymers in the microsphere cores showed a similar pattern of release to the coated spheres with no notable difference in drug release behavior being observed between the dosage forms. The microspheres with Eudragit L100-55 in the matrix were less friable and disintegration times were much closer to the coated microspheres than formulations including the other polymers. Variation of the amount of Eudragit L100-55 in the cores allowed optimization of disintegration and drug release profiles.