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 13h, and the density of the calcium alginate beads was <1.000gcm(-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.

Effects of the method of preparation on the compression, mechanical, and release properties of khaya gum matrices.

A study has been made of the compression properties of khaya gum matrices and the effects of drug concentration and method of preparation of the material on the compression, mechanical and the drug release characteristics of the matrices. Khaya gum matrix tablets were prepared by direct compression and wet granulation methods. The compression properties of the formulations were assessed using the equations of Heckel and Kawakita. The mechanical properties of the tablets were evaluated using crushing strength and friability of the tablets, whereas the release properties of the tablets were evaluated by using the disintegration and dissolution times. The results obtained show that khaya gum deformed mainly by plastic deformation. The compression properties of the formulations were affected by the concentration of the drug and the method of preparation of the materials for compression. Tablets prepared by wet granulation showed faster onset and higher amount of plastic deformation during compression than those prepared by direct compression. Tablets containing dicalcium phosphate showed higher mechanical strength and disintegration and dissolution times. Wet granulation also increased the mechanical strength of the tablet without significantly affecting the drug release characteristics from the matrix tablets. Thus, the wet granulation method could be useful in the preparation of khaya gum matrix tablet with acceptable mechanical properties and drug release properties.

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.

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.

Formulation and processing factors influencing the adhesion of film coats to tablet cores.

The effect of six factors: spray gun, formulation, inlet temperature, atomizing air pressure, fan air pressure, and gun-bed distance, on the final adhesion of the film coat to the tablet core were assessed. The method used was based on an experimental design, Resolution IV, that allowed the main effects to be free from any two factor interactions. Using a specially designed adhesion tester, values for the maximum force of adhesion, elongation, and area under the curve were obtained. The results obtained show that the effect of all the process parameters on the three adhesive responses measured vary according to which adhesive property is considered. An increase in the fan air pressure decreased the elongation, and increased the area under the curve while the maximum force of adhesion remained unchanged. Both atomizing air and inlet temperature affect the adhesive responses, but they are dependent on the formulation and spray gun used. The gun-bed distance has no influence on the adhesion for the distances used in this study.

In-vitro evaluation of khaya and albizia gums as compression coatings for drug targeting to the colon.

Khaya and albizia gums were evaluated as compression coatings for target drug delivery to the colon using indometacin (a water insoluble drug) and paracetamol (a water soluble drug) as model drugs. The core tablets were compression-coated with 300 and 400 mg of 100% khaya gum, 100% albizia gum and a mixture of khaya and albizia gum (1:1). Drug release studies were carried out in 0.1(M) HCl (pH 1.2) for 2 h, Sorensen's buffer (pH 7.4) for 3 h and then in phosphate-buffered saline (pH 6.8) or in simulated colonic fluid for the rest of the experiment to mimic the physiological conditions from the mouth to colon. The results indicated that khaya and albizia gums were capable of protecting the core tablet in the physiological environment of the stomach and small intestine, with albizia gum showing greater ability than khaya gum. The release from tablets coated with the mixture of khaya and albizia gums was midway between the two individual gums, indicating that there was no interaction between the gums. Studies carried out using rat caecal matter in phosphate-buffered saline at pH 6.8 (simulated colonic fluid) showed that the gums were susceptible to degradation by the colonic bacterial enzymes, leading to release of the drug. The results demonstrate that khaya gum and albizia gum have potential for drug targeting to the colon.

Comparison studies on the percolation thresholds of binary mixture tablets containing excipients of plastic/brittle and plastic/plastic deformation properties.

Percolation theory has been used with great interest in understanding the design and characterization of dosage forms. In this study, work has been carried out to investigate the behavior of binary mixture tablets containing excipients of similar and different deformation properties. The binary mixture tablets were prepared by direct compression using lactose, polyvinyl chloride (PVC), Eudragit RS 100, and microcrystalline cellulose (MCC). The application of percolation theory on the relationships between compactibility, Pmax, or compression susceptibility (compressibility), gamma, and mixture compositions reveals the presence of percolation thresholds even for mixtures of similar deformation properties. The results showed that all mixture compositions exhibited at least one discreet change in the slope, which was referred to as the percolation threshold. The PVC/Eudragit RS100 mixture compositions showed significant percolation threshold at 80% (w/w) PVC loading. Two percolation thresholds were observed from a series of binary mixtures containing similar plastic deformation materials (PVC/MCC). The percolation thresholds were determined at 20% (w/w) and 80% (w/w) PVC loading. These are areas where one of the components percolates throughout the system and the properties of the tablets are expected to experience a sudden change. Experimental results, however, showed that total disruption of the tablet physical properties at the specified percolation thresholds can be observed for PVC/lactose mixtures at 20-30% (w/w) loading while only minor changes in the tablets' strength for PVC/MCC or PVC/Eudragit RS 100 mixtures were observed.

Evaluation of khaya gum as a directly compressible matrix system for controlled release.

Khaya gum has been evaluated as a controlled release agent in modified release matrices in comparison with hydroxypropylmethylcellulose (HPMC) using paracetamol (water soluble) and indometacin (water insoluble) as model drugs. Tablets were produced by direct compression and the in-vitro drug release was assessed in conditions mimicking the gastrointestinal system. Khaya gum matrices provided a controlled release of paracetamol for up to 5 h. The release of paracetamol from khaya gum matrices followed time-independent kinetics (n = 1.042) and release rates were dependent on the concentration of the drug present in the matrix. The addition of tablet excipients not only improved the mechanical properties of the tablet, but also altered the dissolution profile, except for dicalcium phosphate where the profile remained unchanged. HPMC could be used to control the drug release rates from khaya gum matrices and a combination of khaya gum and HPMC gave zero-order time-independent release kinetics. Indometacin exhibited a lag time in excess of 2 h, due to its insolubility at low pH, before the zero-order release was observed. Thus khaya gum matrices could be useful in the formulation of sustained release tablets for up to 5 h and the appropriate combination of khaya gum and HPMC could be used to provide a time-independent release for longer periods.

Effect of punch tip geometry and embossment on the punch tip adherence of a model ibuprofen formulation.

The sticking of a model ibuprofen-lactose formulation with respect to compaction force, punch tip geometry and punch tip embossment was assessed. Compaction was performed at 10, 25 or 40 kN using an instrumented single-punch tablet press. Three sets of 'normal' concave punches were used to evaluate the influence of punch curvature and diameter. The punches were 10, 11 and 12 mm in diameter, respectively. The 10-mm punch was embossed with a letter 'A' logo to assess the influence of an embossment on sticking. Flat-faced punches (12.5 mm) were used for comparison with the concave tooling. Surface profiles (Taylor Hobson Talysurf 120) of the upper punch faces were obtained to evaluate the surface quality of the tooling used. Following compaction, ibuprofen attached to the upper punch face was quantified by spectroscopy. Increasing punch curvature from flat-faced punches to concave decreased sticking. Altering punch diameter of the concave punches had no effect on sticking when expressed as microg mm(-2). The embossed letter 'A' logo increased sticking considerably owing to the probable concentration of shear stresses at the lateral faces of the embossed logo.

Effect of lubricant type and concentration on the punch tip adherence of model ibuprofen formulations.

A model formulation, comprising ibuprofen and direct compression lactose (Tablettose 80) was used to assess the influence of two lubricants, magnesium stearate and stearic acid, on punch tip adherence. Lubricant concentrations were varied from 0.25% to 2% w/w. Formulations in the presence and absence of 0.5% w/w colloidal silica (Aerosil 200) were examined, to assess the influence of the glidant on the anti-adherent effects of the lubricants. Differential scanning calorimetry (DSC) was used to examine the effect of the lubricants on the melting temperature of ibuprofen. Tablets were compacted using a single punch tablet press at 10 kN using hard chrome-plated punches or at 40 kN using uncoated steel punches, tooling was 12.5-mm diameter in each case. The upper punch faces were characterized by obtaining Taylor Hobson Talysurf surface profiles. Following compaction, ibuprofen attached to the face was quantified by spectroscopy. At low concentrations of each lubricant, the levels of sticking observed were similar. Whilst sticking increased at magnesium stearate concentrations above 1%, sticking with stearic acid remained relatively constant at all concentrations. DSC revealed that the melting temperature of ibuprofen was lowered by the formation of eutectic mixtures with both lubricants. However, the onset temperature of melting and melting point were lowered to a greater extent with magnesium stearate compared with stearic acid. When using uncoated tooling at 40 kN, the deleterious effects of magnesium stearate on the tensile strength of the tablets also contributed to sticking. When using chrome-plated punches at 10 kN, the tensile strength reduction by the presence of magnesium stearate was less pronounced, as was the level of sticking.

Gamma scintigraphic evaluation of film-coated tablets intended for colonic or biphasic release.

The gastrointestinal transit and in vivo drug release behaviour of a film-coated tablet formulation was investigated in five healthy human subjects using the technique of gamma scintigraphy. The film coating system consisted of a mixture of pectin, chitosan and HPMC in a ratio of 6:1:0.37 applied to 750 mg cores at a coat weight gain of 9%. The estimated mean values of the gastric emptying time (62+/-17 min), small intestinal transit time (219+/-53 min), ileocaecal junction lag time (79+/-30 min) and the colon arrival time (345+/-33 min), were similar to published values for the transit of similar sized tablets in humans. The amount of radioactive tracer released from the labelled tablets was minimal when the tablets were in the stomach and the small intestine. There was increased release of radioactivity when the tablets were in the colon due to increased degradation of the film coatings by pectinolytic enzymes resident in the colon. The pectin/chitosan/HPMC film coating system thus acts as a colonic delivery system.

Effects of surface roughness and chrome plating of punch tips on the sticking tendencies of model ibuprofen formulations.

The sticking of three model ibuprofen-lactose formulations with respect to compaction force and the surface quality of the upper punch were assessed. Compaction was performed at 10, 25 or 40 kN using an instrumented single-punch tablet press. Two sets of 12.5-mm flat-faced punches were used to evaluate the influence of surface quality. A third set of chrome-plated tooling was also used. Surface profiles (Taylor Hobson Talysurf 120) of the normal tooling upper punches indicated a large difference in quality. The punches were subsequently classified as old (Ra = 0.33 microm) or new (Ra = 0.04 microm) where Ra is the mean of all positive deviations from zero. Surface profiles of sample tablets were also obtained. Following compaction, ibuprofen attached to the face was quantified by spectroscopy. Punch surface roughness, compaction force and the blend composition were all significant factors contributing to sticking. Chrome plating of punch faces increased sticking at a low compaction force but decreased sticking at higher forces. Surface roughness of the tablets did not correlate with the corresponding data for sticking, indicating that this is not a suitable method of quantifying sticking.

Mixing efficiency in side-vented coating equipment.

The purpose of this study was to evaluate tablet mixing within side-vented coating equipment by assessing the development of color uniformity during coating. A colorimetric method was used to evaluate the time for uniform coating for different mixing baffle systems at different scales of equipment. The influence of tablet size was also determined. The inclusion of rabbit ear baffles in the small-scale equipment reduced the time to achieve color uniformity by 20 minutes. The design of baffle influenced the time for uniform color with a mixing efficiency rank order of tubular > ploughshare > rabbit ear. Upon scale-up, the efficiency of mixing seen at development scale remained equivalent in terms of the influence of baffle design. The study into the influence of tablet size revealed the importance that the total batch surface area has on the time taken to achieve color uniformity, with 7-mm diameter tablets having a higher surface area for an equivalent volume of product and taking 15 to 20 minutes longer to achieve color uniformity than 16-mm diameter tablets.

Biphasic drug release from film-coated tablets.

A study was carried out into the biphasic drug release properties of film-coated paracetamol tablets. The tablet cores were formulated without a disintegrant and film-coated with a coating formulation consisting of pectin, chitosan and hydroxypropylmethylcellulose in a ratio of 6:1:0.37. The tablet cores and the film-coated tablets with coat weight gains (CWGs) of 6, 9 and 13% were evaluated for their water absorption (swelling) and drug release properties. All the tablets absorbed water from pH 6.0 Sorensen's phosphate buffer and the amount of water absorbed increased with an increase in tablet CWG. The addition of 100 microl/50 ml pectinolytic enzymes to the medium resulted in at least a 40% reduction in the amount of water absorption by the tablets, as compared to the medium without enzymes. When the enzyme concentration was increased to 200 microl/50 ml, there was a further reduction ( approximately 8% w/w) in the amount of water absorbed by the tablets. Drug release was controlled in upper gastrointestinal fluids and decreased with an increase in tablet CWG. Drug release was, however, accelerated in the presence of pectinolytic enzymes, consistent with the entry of the tablets in the colon. An evaluation of the drug release data by the Korsmeyer-Peppas equation showed the involvement of molecular diffusion and other factors such as film/tablet erosion and drug dissolution in drug release.

Leaching of pectin from mixed films containing pectin, chitosan and HPMC intended for biphasic drug delivery.

Mixed films containing pectin, chitosan and HPMC, prepared by solvent casting from 0.1 M HCl (pH 1.5) and 0.1 M acetic acid (pH 2.9) were evaluated for their morphological and leaching properties. Films cast at pH 1.5 were uniform with smooth surfaces while films cast at pH 2.9 showed particle aggregation and had rough surfaces due to polyelectrolyte complex (PEC) formation between pectin and chitosan in the medium. The leaching of pectin was higher from films at cast pH 1.5 due to the absence of PEC formation. Pectin leaching was controlled in simulated upper gastrointestinal conditions but was accelerated in the presence of pectinolytic enzymes. The leaching of pectin from the mixed films was a function of the pH of the film casting solvent, pH of the incubation medium, PEC formation and HPMC content.

Tensile strength and bonding in compacts: a comparison of diametral compression and three-point bending for plastically deforming materials.

The tensile strength of tablets is frequently used as a measure of the bonding achieved during compaction. Tablets from two plastically deforming materials and one brittle material have been subjected to tensile strength testing using diametral compression and three-point bending. The plastically deforming materials exhibited marked inhomogeneities, with the surfaces of the tablets considerably more compact than the inner material. The results from the two tests were different, with the three-point bending test giving higher results for tensile strength. The rate of change of tensile strength with overall tablet porosity was, however, the same for the two tests. Diametral compression would thus appear to give a reasonable estimate of bonding despite the non-homogenous nature of tablets prepared from plastically deforming materials.