Value of a provocation test with diprafenone in patients with bifascicular block]

The significance of provocative tests in patients with bifascicular block is not established. We studied 14 patients with bifascicular block, syncope and documented episodes of high degree AV-block. 1.5 mg/kg Diprafenon was given after a period of at last 12 hours 1:1 AV-conduction. Electrophysiologic evaluation was performed before and after diprafenon. AV-block III could be provoked in 1 of 14 patients with Diprafenon. Therefore a total AV block occurred in 7% of patients. The low sensitivity of provocative test with Diprafenon even in patients with documented high degree AV-block prevents its application in clinical practice.     

Investigations into the use of pregelatinised starch to develop powder-filled hard capsules

The use of pregelatinised starch in tamp filling of hard capsules with powder formulations containing a low-solubility drug (theophylline anhydrous) with very poor powder flow and stickiness to metal surfaces was investigated. Twenty-one mixtures containing the drug, pregelatinised starch, lactose monohydrate and magnesium stearate were produced, with their quantitative composition based on a central composite design. These mixtures were filled into hard capsules using an instrumented tamp-filling machine. Seven different compression settings ranging from "no" to "firm" compression were employed, and the tamping force was recorded on stations 3 and 4. It was found that the use of pregelatinised starch as an excipient in the manufacture of powder-filled hard capsules could be beneficial in terms of reducing the coefficient of fill weight variability. To improve drug dissolution of poorly soluble drugs, larger amounts of this excipient were required, and the maximum capsule fill weight that could be achieved was slightly reduced at the same time.     

The evaluation of formulations for the preparation of pellets with high drug loading by extrusion/spheronization

A capillary rheometer was used to evaluate rheological properties and the fluid mobility of mixtures with a high drug loading (80%) of three model drugs (ibuprofen, lactose, and ascorbic acid) when extruded. These drugs have a range of solubility in water, with 20% microcrystalline cellulose (MCC) as the spheronization aid, and water, pH 2.0, and pH 10.0 buffer as the binder liquid. The results were compared with the ability of the systems to form spherical pellets by the process of extrusion/spheronization. It was found possible to produce round pellets with a narrow size distribution by the process of extrusion/spheronization for formulations containing 80% of either lactose or ascorbic acid with MCC as the spheronization aid. It was not, however, possible to form pellets containing the same level of ibuprofen. This appears to be associated with the high level of fluid mobility observed when the wet masses were extruded in a ram extruder. A range of rheological characteristics in terms of shear stress, die entry pressure, angles of convergence, extensional flow, and elasticity were determined, but the variations in the values of these, which were observed, did not give an indication of the ability of the wet mass to form spherical pellets when subjected to the spheronization process. This could be associated with the fact that the selection of the conditions necessary to provide a valid quantification of the extrusion process did not truly represent the stability of the systems in terms of the mobility of the fluid when the wet mass was processed. The formulation of a wet mass with limited fluid mobility appears to be the first priority of formulations used in extrusion/spheronization.     

The relationship between granule growth mechanism,amount of liquid binder added and properties of the wet powder mass determined using a split bed shear tester

The Peschl-split bed shear tester was utilised to study the formation of different liquid states during wet massing for granulation. Using lactose monohydrate as a model bulking agent the threshold between pendular and funicular state was found to be at about 6% (w/w) of liquid binder added to the wet mass, here a 5% colloidal solution of HPMC in water. The upper limit of the funicular state appeared to be at approximately 15% (w/w) of liquid binder. The threshold values obtained from the shear cell measurements did correlate with values obtained from dried granule characteristics such as granule density and compressive Young's modulus determined by Dynamic Mechanical Analysis. The compressive Young's modulus increased with an increasing density of the wet mass during the shear experiments and decreased with an increase in the angle of internal friction. The results suggest that stiffer granules were a result of densification, not the strength of liquid bridge bond formation.     

Angina pectoris anamnesis in patients with their first myocardial infarct

In 650 consecutive patients with first acute myocardial infarction the time interval between the first anginal attack and the acute infarction as well as the time interval between onset of symptoms suggestive for acute myocardial infarction and hospitalization were evaluated. Our results demonstrate that in 25% of patients the history of angina was less than 24 hours, in 50% of all patients less than three days; furthermore, the time interval from onset of symptoms of acute myocardial infarction to hospitalization correlated with the history of angina; the depression of left ventricular function after myocardial infarction was independent of a previous history of angina; in patients with a very short history of angina there was a significantly higher incidence of single vessel disease. Thus, prevention of acute myocardial infarction would have been possible only in about half of the patients with impending myocardial infarction due to the short duration of preceding angina.     

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.     

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.     

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.     

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.     

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.