Starch-based coatings for colon-specific delivery. Part II: physicochemical properties and in vitro drug release from high amylose maize starch films.

This work reports an investigation into free-film properties of a high amylose maize starch-based film coating that has been used in the preparation of formulations for drug delivery to the colon (WO 2008/012573 A1) and relates these properties to in vitro drug release from pellets. Maize starch/ethylcellulose free films were prepared and characterised by scanning electron microscopy (SEM), light microscopy, modulated differential scanning calorimetry (mDSC), Fourier-transform infrared (FT-IR), X-ray and % swelling in aqueous fluids with pH conditions similar to the stomach and small intestine. 5-ASA release from film-coated pellets was tested in enzyme free simulated gastric fluid and phosphate buffer pH 7.2. Selected formulations were further assessed in simulated gastric and intestinal fluids containing pepsin and pancreatin, respectively. The free films prepared were smooth and homogeneous in their appearance. The two polymers are immiscible, and neither mDSC nor FT-IR could detect interactions between them. Films made from high amylose starches were found to have a considerably lower swelling ability than high amylopectin-based films, and they suppressed drug release in the enzyme free media successfully. 5-ASA release from pellets coated with mixtures of high amylose starches (Hylon VII, Hylon V or LAPS) and Surelease in a ratio of 1 to 2 w/w was found to be minimal in simulated gastric and intestinal fluids. This suggests that these mixed films provide starch domains that are resistant to the enzymes present in the upper GI tract and thus can potentially be used in the preparation of colon-specific delivery devices. Starches with a minimum amylose content of 56% such as the starches used in this study (Hylon VII and Hylon V) are preferred, and although pure amylose can also be used this is not essential.

The preparation of pellets containing non-ionic surfactants by extrusion/spheronization.

The aim of the study was to investigate the possibility of incorporating non-ionic surfactants into pellets produced from microcrystalline cellulose by the process of extrusion/spheronization and the properties of the pellets. A hydrophilic surfactant, polysorbate 60 (PS 60), and two hydrophobic surfactants, sorbitan monostearate (S 60) and sorbitan monooleate (S 80), were included in the water used to form the pellets in concentrations ranging from 5 to 95%. The presence of the surfactants influenced the type of the extrusion profile and improved the ability to provide round pellets, and the addition of the surfactants changed the range of liquid levels required to prepare the pellets. At a low level, i.e., 5%, all the surfactants increased the range of water contents possible, compared to the use of water alone. At high surfactant levels, the level of liquid, which could be used, became restricted. The median size of the pellets was dependent on the type of surfactant and the concentration included in the formulation. The range of sizes produced was generally quite narrow and there were many systems with more than 90% of the pellets in the modal fraction. The highest concentration of the surfactant in water that can be used to form pellets ranged from 50% for S 60, to 80% for S 80 and 95% for PS 60. The maximum amount of the surfactant, which could be incorporated into the final pellet, however, was found to be approximately 22.5% for both the hydrophobic surfactants and 32.5% for the hydrophilic surfactant.

The evaluation of modified microcrystalline cellulose for the preparation of pellets with high drug loading by extrusion/spheronization.

The performance of microcrystalline cellulose (MCC) which had been modified by the inclusion of various levels of sodium carboxymethylcellulose (SCMC) in the wet cake prior to drying, in terms of their ability to form pellets by a standardised extrusion/spheronization process has been assessed. Initial screening of the ability of the modified MCCs to form pellets with an 80% level of lactose as a model drug identified two potential products containing 6 or 8% of SCMC (B 6 and B 8). These two products were compared with a standard grade of MCC (Avicel PH101) in terms of their ability to produce pellets with 80% of model drugs of low (ibuprofen), intermediate (lactose) and high (ascorbic acid) water solubility when subjected to a standardised extrusion/spheronization process. Also assessed was their ability to retain water with applied pressure using a pressure membrane technique and their ability to restrict water migration during extrusion with a ram extruder. The two new types of MCC (B 6 and B 8) were able to form good quality pellets with all three model drugs, whereas Avicel PH101 could not form pellets with this high level of ibuprofen. This improved performance was related to the ability of the new types of MCC to hold higher levels of water within their structure and restrict the migration of water in the wet mass when subjected to pressure applied during the process of preparing the pellets. There is evidence to show that the two new types of MCC can function over a wider range of water contents than Avicel PH101 and that they have an improved performance if the extrusion process is rapid and if, after incorporation of the water into the powder, the sample is stored for some time before extrusion.

Gastrointestinal transit of model mini-tablet controlled release oral dosage forms in fasted human volunteers.

The aim of this study was to compare the gastrointestinal transit of multiple unit, small diameter (3.2 mm), non-disintegrating tablets of differing densities with results previously reported in the same volunteers in the fasted state for larger diameter (6.6 and 12.2 mm) tablets. The gastrointestinal transit was observed with gamma-scintigraphy at various intervals over a 9-h period to give an accurate assessment of the transit characteristics. The value for the median emptying time of the first light tablet was significantly shorter than that for the dense tablet, but the total emptying time and the time for the last tablet to empty for both sets of tablets were not statistically different. The value of the median time for initial and final emptying of the small tablets from the stomach was significantly longer than that for the larger diameter tablets. The 9-h time limit of the observations limited the estimation of the time taken to enter the caecum and consequently the small intestine transit times. There was clear evidence that for the dense tablets of all sizes, the value for the small intestine transit time was longer than the 3-4 h reported in the literature. The only tablet system to enter the caecum within the time limit of the study was the normal density 12.2-mm tablets.

The influence of non-disintegrating tablet dimensions and density on their gastric emptying in fasted volunteers.

The aim of this work was to identify the influence of tablet density on their gastric emptying in fasted subjects and to compare the findings with those of a previous study using the same subjects with tablets of a larger diameter. Tablets of 6.6 mm diameter and densities of 1.41 and 2.85 g cm-3 were labelled with 99mTc and 111In. They were coated with ethyl cellulose to ensure that they remained intact within the gastrointestinal tract. Their position within the gastrointestinal tract of fasted healthy subjects was monitored with a double-headed gamma camera at 1-min time intervals. The median gastric emptying time and the interquartile range were derived from the Bernoulli random event distribution. It was found that the dense tablets had a significantly longer gastric emptying time than the light tablets. Comparison with the results from the previous study gave a clear indication that irrespective of tablet density, the 6.6-mm tablets had longer gastric emptying times than the 12.0-mm tablets.

The strength of bilayered tablets.

The tensile strength of model materials (dicalcium phosphate dihydrate, microcrystalline cellulose and pregelatinised starch) compacted to form tablets in the form of beams consisting of two layers of equal thickness has been determined by three-point loading. The values of the tensile strength of the materials were sometimes higher and sometimes lower than the tensile strength of beams of the same thickness composed of a single material. Correction of the values for the tensile strength of the layered beams for the differences in the elasticity of the materials in the layered tablets failed to correct for these differences, as did considering the layered beams as beams of half thickness. For a layered tablet with pregelatinised starch at the bottom and microcrystalline cellulose at the top, the value of the tensile strength recorded appeared to be that of the microcrystalline cellulose as the fracture propagated across the boundary between the layers and into microcrystalline cellulose. What appeared to be the important factor was the way the failure of the beam crossed the interface between the two layers.

The rheological properties of self-emulsifying systems, water and microcrystalline cellulose.

The rheological properties of mixtures of equal parts of a range of ratios of a self-emulsifying system (MP) and water (W) added to microcrystalline cellulose (MCC), have been measured by an extrusion capillary rheometer. These measurements allow assessment of both the shear and tension components of flow plus the elastic behaviour of the wet powder masses, although the results for the estimation of shear stress require careful interpretation due to the limitation of the measuring system and the assumptions made in their derivation. The results indicate that there are three regions of behaviour of the systems, which are all significantly different from the mixtures containing only W and MCC. At low MP contents (1.5--23%), the masses increase in their resistance to shear and elongational flow and have lower elasticity. These similarities in behaviour occur in spite of considerable increase in the viscosity of the MPW mixtures and a change to non-Newtonian flow of the fluid. The behaviour of the 46% MP system is intermediate between these systems and the high MP concentrations (69, 80 and 92%). These latter systems show less resistance to shear and elongational flow than the first group of concentrations, but show considerably higher levels of elasticity. As the resistance to shear decreases, so does the impairment of the surface of the extrudate. There is clear evidence of a systematic change in behaviour of the wet powder masses as the values for the angle of entry of the wet mass into the die when plotted against the ratio of the resistance to die entry (upstream pressure loss) to the shear stress within the die, is linear on a log/log scale. Also, the values of compliance of the systems as a function of shear stress fall on a common curve. Changes in the ratio of the MPW to MCC for a system for a single level of MP (46%) resulted in a change in the values of the rheological parameters but not the type of behaviour. As all these wet powder masses had been shown previously to form pellets by the process of extrusion/spheronization, it is clear that systems with a wide range of rheological characteristics can be processed and no single rheological parameter can be used to provide complete characterisation of the processability of such systems.

The application of non-contact laser profilometry to the determination of permanent structural change induced by compaction of pellets II. Pellets dried by different techniques.

Microcrystalline (MCC) pellets of different structural and mechanical properties were produced by the process of extrusion and spheronization from the formula MCC:water:ethanol (5:3:2) using four different drying techniques, namely: freeze-drying, fluid-bed drying, hot air oven drying and desiccation with silica-gel. Six hundred milligrams of these pellets were compacted by 130 MPa to flat-faced tablets and stored for 48 h in ambient temperature and humidity after which their permanent structural change (plastic deformation) was investigated in terms of surface roughness parameters using a non-contact laser profilometer. The results were compared with the deformability values measured as a reciprocal of the slope of the force/displacement curve obtained during diametral compression test of the individual pellets. Based on the different rate of moisture removal, means of heat and mass transfer, and static and dynamic nature of the bed the different drying techniques produced pellets of different porosity, strength and deformability. The increase in deformability of the pellets with the increase of porosity was illustrated by the reduction of the surface roughness parameters. Analysis of variance identified the significant difference in the mean rugosity values of the tablets from the pellets produced by the various drying techniques. The deformability values obtained were reasonably comparable to those plasticity values explained in terms of the inverse of the slope of the force/displacement curves. The laser profilometry technique was able to quantify the permanent structural change of the pellets after compaction in terms of mean rugosity values. The methodology was able to incorporate a wide variety of deformable pellets of the same formulations but produced by different drying techniques. The porous freeze-dried pellets produced the smoothest tablet surface profile, while the other techniques increased the rugosity values in ascending order from fluid-bed drying, desiccation with silica-gel to hot air oven drying technique.

Application of dynamic mechanical analysis (DMA) to the determination of the mechanical properties of coated pellets.

Pellets containing a model drug, paracetamol, and microcrystalline cellulose (MCC) were designed to vary their mechanical properties by the incorporation of lactose, glyceryl monostearate (GMS), ethanol, or glycerol, and were produced by the process of extrusion and spheronization. The pellets were coated with an aqueous dispersion of ethyl cellulose (Surelease) to different levels of weight gain (5, 10, and 20%). The tensile strength, deformability, linear strain, elastic modulus, and shear strength of the coated and uncoated pellets were determined by conventional techniques, which are obtained from diametral compression test of individual pellets and compaction of a bed of pellets. Dynamic Mechanical Analysis (DMA) was performed on single pellets to determine the storage modulus and phase angle of the coated pellets. This work demonstrated that the coating film affected the mechanical properties of the pellets differently depending on the properties of the core pellets. Analysis of variance established a significant increase in the strength of the soft GMS- or glycerol-containing pellets with coating, while the effect of the coating material was not significant with respect to the elastic modulus, storage modulus, and phase angle of such pellets. The effects of the coating material on the elastic modulus, deformability, storage modulus, and phase angle of the rigid lactose-containing pellets were significant. The sinusoidal stress-relaxation cycle of the DMA illustrated the increase in the viscoelasticity of all the pellets after coating. Finally, the work demonstrate the advantages of DMA in determining the reversible or dissipated energy by means of storage modulus or phase angle when compared with the irreversible structural destruction of the pellets by conventional techniques.

A study on the effect of drying techniques on the mechanical properties of pellets and compacted pellets.

Microcrystalline cellulose (MCC) pellets produced by a standard extrusions/spheronisation process with a 40% ethanol/water mixture as the fluid component, were dried by four different techniques, namely: freeze-drying, fluid-bed drying, hot air oven drying and desiccation with silica-gel to less than 5% (w/w) water content. A 1.0-1.18mm size fraction of the dried pellets were characterised structurally and mechanically in terms of, shape, density/porosity (open and closed), pore volume/pore volume distribution, surface area, surface tensile strength, shear strength, deformability, linear strain and elastic modulus. An amount of 600, 700 and 750mg of the same size fraction of each pellet batch were compacted to the same tablet thickness and the tensile strength and volumetric elastic recovery of the resulted compacts were determined. Analysis of variance was used to assess the significance of the drying process on the property of the pellets and their compacts. The drying process did not influence the shape of the pellets, but all the other properties were affected to some extent. Pellets dried by freeze-drying were more porous, with most of the pores open to the atmosphere and had a higher surface area than pellets dried by the other methods. Pellets dried by desiccation contained the highest proportion of closed pores. The decrease in tensile strength of the pellets, which occurred with the increase in porosity could presumably be due to ease of crack initiation and propagation between the MCC fibres. The weaker pellets broke instantly before they were subjected to appreciable strain. The porous pellets needed a higher compressing pressure and work of compaction to produce tablets of the same mass and dimensions. This reflected their compressibility, i.e. relative decrease in volume of the pellet bed during compression. The strength and volumetric elastic recovery of the compacts increased with the increase of their porosity. The drying techniques, which produced porous, deformable and weak pellets, produced stronger tablets. The value of the volumetric elastic recovery of the compacts was also observed to increase with the value of compaction pressure.

The application of non-contact laser profilometry to the determination of permanent structural changes induced by compaction of pellets. I. Pellets of different composition.

Pellets of different mechanical properties were produced by extrusion and spheronisation process based on various composition (microcrystalline cellulose (MCC), lactose, glyceryl monostearate (GMS), water, ethanol and glycerol). Six hundred milligrams of these pellets were compacted at two different pressures (86.7 and 130MPa) to form flat-faced tablets and stored for 48h in ambient temperature and humidity after which their permanent structural change (plastic deformation) was investigated in terms of surface roughness parameters of both faces of the tablets, using a non-contact laser profilometer. The results were compared with the deformability values obtained from the force/displacement curve as well as the phase angle values obtained from the dynamic scan of a dynamic mechanical analyser. The increase in deformability of the pellets with the increase in porosity, increase in the contents of GMS, lactose or ethanol in the formulations and increase in compaction pressure was illustrated by the reduction of the surface roughness parameters. Analysis of variance identified the significant difference in the mean rugosity values of the tablets from the various formulations, tablet faces and compaction pressures. The deformability values obtained were reasonably comparable to those plasticity values obtained in terms of phase angle from the dynamic scan of the DMA and the force/displacement curves. The laser profilometry technique in conjunction with scanning electro-microscopy (SEM) demonstrated the low and broad based wavelike structure of the pellets after compaction rather than spiky sharp protrusions. This confirms the capability of determining the plastic deformability of the pellets from the surface roughness parameters obtained from non-contact laser profilometry.

Application of dynamic mechanical analysis (DMA) to determine the mechanical properties of pellets.

Pellets of a wide range of mechanical properties were produced by the process of extrusion and spheronisation using various formulation factors. A range of mechanical properties from a simple fracture load to detailed load/displacement curves obtained when pellets were subjected to diametral compression test and a bed of pellets was compacted, were used to provide measure of tensile strength, deformability, linear strain, elastic modulus, yield and shear strength. Such conventional techniques resulted in irreversible damage to the structure of the pellets and were unable to establish the viscoelastic properties of the pellets. The application of the dynamic mechanical analysis (DMA), however, allowed the determination of (1) an accurate Young's modulus of elasticity, which was found to be between 8.4 and 24-fold higher than that determined from the diametral compression test, (2) the presence of a reversible elastic deformation even after the yield point in terms of storage modulus and (3) a change in the values of the phase angle, which illustrates the increase in viscoelasticity of the pellets formed with ethanol, glyceryl monostearate (GMS) or glycerol, while a decrease in viscoelasticity with the incorporation of lactose into the microcrystalline cellulose (MCC) pellets. This work further demonstrated that the only feasible technique for determining the elastic and plastic deformability of the pellets is the one which subjects the specimen to stress/relaxation cycles and can determine the dissipated energy in terms of loss modulus or phase angle, and that is DMA.

The formation of colonic digestible films of amylose and ethylcellulose from aqueous dispersions at temperatures below 37 degrees C.

The film forming properties of a commercial aqueous ethylcellulose dispersion (Surelease) mixed with a range of ratios of an amylose/butanol complex in the presence of a range of concentrations of a plasticiser has been studied by measuring the minimum film forming temperature (MFFT). Contrary to what was to be anticipated from the literature, it was found that an additional 4% of the plasticiser (dibutyl sebacate), normally present in the standard formulation of the ethyl cellulose dispersion, was sufficient to lower the MFFT to allow the formation of films at 35 degrees C. This was confirmed by assessment of the glass transition temperature of free films prepared by casting and drying at 35 degrees C by the application of dynamic mechanical analysis. This technique also demonstrated that the ethylycellulose and the amylose were not miscible. The ability of faecal slurry to digest the films formed at low temperatures was confirmed by the use of a batch fermenter. The extent of digestion was directly related to the amylose content of the films, ensuring the potential to provide films, which could function as colon specific coatings.

Physical properties of chitosan pellets produced by extrusion-spheronisation: influence of formulation variables.

Pellets comprising chitosan, cellulose microcrystalline, povidone, filler excipient and diclofenac sodium as model drug were prepared by extrusion-spheronisation. The effects of chitosan load (zero, 0%, low, 4% and high, 16% levels), type of filler (lactose, tribasic calcium phosphate and beta-cyclodextrin) and composition of the binding liquid (ethanol/water mixtures 20 and 50%) on physical characteristics of pellets were evaluated. A three-factor factorial design was employed in the study. Analysis of variance (ANOVA) indicated that single factors had significant effect on the physical characteristics of the pellets. The type of filler followed by polymer load markedly affected the density. The type of binding liquid had negligible effect on the shape and surface roughness of the pellets. Increase in the chitosan load resulted in pellets of lower porosity values. This could be attributed to the binding capacity of chitosan and povidone leading to more compacted structures. Chitosan load and type of filler had significant influence on the surface roughness. The surface of pellets became rougher as the chitosan load increased, however, there was no significant difference between zero and low contents of chitosan. Pellets prepared using tribasic calcium phosphate showed a smoother surface when compared with formulations including lactose or beta-cyclodextrin. Chitosan was useful to provide pellets of acceptable physical characteristics when employing an alcohol/water mixture 50% (v/v) as binding liquid for the extrusion-spheronisation process.

Characterisation of the mechanical properties of polymer films formed from aqueous polymer dispersions by creep testing.

The mechanical properties of films formed from an aqueous dispersion of polymethlymethacrylate (Eudragit NE30D) and as mixture with an aqueous dispersion of ethylcellulose (Aquacoat ECD30), have been assessed by applying creep tests at different temperatures, using a dynamic mechanical analyser. In the region of linear creep, the film prepared from 100% Eudragit was far less elastic than when 60% Aquacoat was present. In this region, when the applied stress was doubled, the strain response was doubled. In the non-linear region of behaviour, there is clear evidence that the mixed film is more elastic than the film containing only Eudragit.

Kinetic examination of the mechanical transition of polymethyl methacrylate films prepared from aqueous dispersions.

The activation energy of the phase transition of cast polymethyl methacrylate films produced from an aqueous dispersion (Eudragit NE30D) has been estimated from Dynamic Mechanical Thermal Analysis. The value was found to lie between 170 and 350 kJ mol(-1), the variation arising from the different specimen test geometry and testing conditions. From experiments conducted at a range of frequencies and temperatures it was found possible to utilise the concept of frequency shift to produce a master curve, which could relate viscoelastic properties over the temperature range of 5-55 degrees C and a frequency range of 0.1 to 50 Hz.

The influence of core materials and film coating on the drug release from coated pellets.

The objective of this study was to analyse the influence of the composition of the core of the pellets on the in vitro drug release profile. The different materials (drugs and fillers) were chosen according to their relative solubility. Pellets were prepared by a standardised process of extrusion/spheronisation. A selected fraction size (1-1.4 mm diameter) of pellets of each preparation was coated with Surelease (an aqueous dispersion of ethyl cellulose) to give 5% weight gain. The dissolution studies were performed and data analysed in terms of the Area under the Curve (AUC) of the % dissolved as function of time and Mean Dissolution Time (MDT). ANOVA was applied in order to identify the influence factors and the relationship of cross effects. Canonical analysis and multiple regression were employed to quantify these relationships. The film coat was found to be the major factor controlling the drug release. The results however, show that both drug and filler solubility influenced the drug release profile. Some of the unusual results could only be explained if consideration was given to the physical characteristics of both powder and pellets. In particular, the specific surface area of calcium phosphate compared with other fillers played an important role on the release profile of the model drug.

Dynamic mechanical thermal analysis studies of polymer films prepared from aqueous dispersion.

Dynamic Mechanical Thermal Analysis of cast and sprayed films of an aqueous dispersion of polymethyl methacrylate (Eudragit NE30D) and mixtures with an aqueous dispersion of ethylcellulose (Aquacoat ECD-30) has been undertaken. Such analysis allows the identification of glass transition temperatures and the degree of miscibility of the polymers. It was found that the two polymers formed as cast or sprayed films were not miscible but had an optimal composition of 30% of the ethylcellulose dispersion in the polymethyl methacrylate dispersion.

Factors influencing the physical characteristics of pellets obtained by extrusion-spheronization.

The objective of this work was to analyse the influence of the solubility of the drug and the filler on the physical characteristics of pellets prepared by extrusion/spheronization. Different formulations were prepared according to a statistical plan, using five different drugs and five different fillers selected according to their water solubility. The pellets were then obtained by a standardized extrusion/spheronization process and evaluated in terms of their physical characteristics by measuring the pellet size, density, porosity, mechanical strength, residual moisture after drying and shape. The results were first analysed by the analysis of variance to identify the main factors involved. The results were further assessed by canonical analysis and the significant influence factors were quantified in terms of regression equations. It can be concluded that the solubility of materials used (both drugs and fillers) plays an important role in the quantity of water required to form satisfactory pellets and on the physical characteristics of pellets. Quantitative relationships were identified between (a) the extrusion force required to provide extrudate, which would form pellets and the natural log of the filler solubility; (b) the quantity of the pellets in the size range 1-1.4 and the solubility of both the filler and the drug; (c) the apparent pellet density and both the level of drug and filler plus the solubility of the filler; (d) the pellet porosity and the quantity of drug and the inverse function of the filler solubility; and (e) the mechanical strength of the pellets and the square root of the quantity of drug.