The rheological properties of modified microcrystalline cellulose containing high levels of model drugs

The rheological properties of different types of microcrystalline cellulose (MCC) mixed with model drugs and water have been evaluated to identify the influence of sodium carboxymethylcellulose (SCMC) added to the cellulose during preparation. A ram extruder was used as a capillary rheometer. The mixtures consisted of 20% spheronizing agent (standard grade MCC or modified types with 6% or 8% of low viscosity grade SCMC) and 80% of ascorbic acid, ibuprofen or lactose monohydrate. The introduction of SCMC changed all rheological parameters assessed. It produced more rigid systems, requiring more stress to induce and maintain flow. Degree of non-Newtonian flow, angle of convergence, extensional viscosity, yield and die land shear stress at zero velocity, and static wall friction were increased, but recoverable shear and compliance were decreased. The presence of SCMC did not remove the influence of the type of drug. The mixture of ibuprofen and standard MCC had the lowest values for shear stress as a function of the rate of shear, extensional viscosity, and angle of convergence, but the highest values for recoverable shear and compliance. The findings indicate that the system has insufficient rigidity to form pellets.     

The gastric emptying of food as measured by gamma-scintigraphy and electrical impedance tomography (EIT) and its influence on the gastric emptying of tablets of different dimensions

A study in human volunteers has been designed to evaluate the influence of different food regimes on the gastric emptying of 3 mm and 10 mm diameter tablets. Dextrose and beef drinks were used as liquid food; a mixture of minced beef and mashed potato (shepherd's pie) was used as a solid meal. The gastric emptying of these foods was monitored simultaneously with electrical impedance tomography (EIT) and gamma-scintigraphy (GS), and was quantified in terms of the time before gastric emptying started, the lag time, the mean gastric residence time (MGRT) and its variance (VGRT), and the time for complete emptying. The gastric emptying time of the tablets was established by monitoring the position of the tablets, which had been labelled with suitable radio isotopes, by GS. The two systems for monitoring gastric emptying of the foods did not provide equivalent results: times obtained with EIT were generally shorter than those obtained with GS for the liquid foods, but were longer for the solid meal. There was only a slight difference in the emptying times of the two liquid foods, whereas values for MGRT, VGRT and the time for complete emptying were considerably longer for the solid meal. In nearly all instances the tablets emptied after the foods had emptied completely from the stomach. Gastric emptying times were longer for the 3 mm tablets than the 10 mm tablets, whatever food they were taken with. The difference between the median emptying times was significant when the meal was either a dextrose solution or a beef drink, but not when the meal was shepherd's pie. The increase in gastric emptying time of tablets induced by solid food was greater than that associated with the differences in tablet size. By providing a protocol that did not allow the administration of further food until after the tablets had emptied from the stomach, no tablet emptying times exceeded 6 h.     

Assessment of the in‐vivo drug release from pellets film‐coated with a dispersion of high amylose starch and ethylcellulose for potential colon delivery

Objectives The aim of this study was to test the ability of a colon targeting system comprising pellets film‐coated with a dispersion of high amylose starch (Hylon VII) and ethylcellulose (Surelease) (1 : 2 w/w) to deliver a model drug (5‐aminosalicylic acid; 5‐ASA) in vivo into the colon of rabbits. An uncoated pellet formulation was used as a control. Methods Six New Zealand female rabbits, approximately 2 kg, were randomly divided into two groups. Pellet formulations containing 50 mg/kg of 5‐ASA were filled into hard gelatin capsules size 4, and were administered orally using a cannula. The rabbits were fasted for 12 h before, and throughout, the study but had free access to water. Blood samples were collected, through a catheter inserted into the marginal vein of the ear, at pre‐determined times and the plasma analysed by a validated HPLC method with fluorescence detection. Results Analysis of the 5‐ASA plasma levels following administration of the uncoated pellets showed a C_max of 2.38 ± 0.49 μg/ml at 2 h post administration confirming that this system released the drug at an unspecific site, most likely in the rabbits' stomach and proximal small intestine. On the other hand, the coated formulation showed a delayed drug absorption (C_max 0.22 ± 0.19 μg/ml and t_max of 8 h), suggesting that the coating is able to prevent drug release in the stomach and small intestine, but allowing drug release in the colon. The coated pellets were retrieved from the rabbits' faeces after the 24‐h study. They had a drug content of < 40%, suggesting that the film‐coating had been digested by the bacterial amylases of the colon and the drug was released specifically in the colon of the rabbits. Conclusions Results from this study showed that the proposed drug delivery system has the potential to deliver drugs specifically into the colon.     

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.     

The influence of model drugs on the preparation of pellets by extrusion/spheronization: II. Spheronization parameters.

Five drug-models, 4-parahydroxybenzoic acid (4HBA), methyl (MBA), propyl (PBA) and butyl (BBA) paraben and propyl gallate (PG), all of similar chemical nature, were mixed in different proportions (50-73.7%) with microcrystalline cellulose (MCC) (26.3-50%) plus various levels of water (26.9-50.0%). The wet powder mass was extruded and spheronized under standard conditions. The pellets produced were evaluated in terms of their median diameter, their modal size range, the % within a given size range (0.7-1.7 mm) and their shape factor. For the majority of formulations, all drug models, except 4HBA, produced pellets. This material only had two combinations of excipients that produced acceptable pellets. For all the model drugs, two combinations of formulations could be identified; (1) a combination, which produced pellets from all the model drugs and (2) a combination, which was too wet to produce pellets with any of the model drugs. Between these two extremes, whether pellets could be made and their quality varied with the model drug. Cluster analysis was able to divide the formulations into 4 clusters. In cluster 1 all the model drugs produced pellets except 4HBA; in cluster 2 all drugs produced pellets except MBA; in cluster3, pellets were produced with PBA, BBA and PG while MBA produced agglomerates and 4HBA was too dry; in cluster 4, MBA and BBA produced pellets, PBA produced agglomerates while 4HBA was too dry to pelletise and PG too dry to extrude. The five drug models showed different relationships between the median pellet size and drug-load and initial water content in the formulation. Cluster analysis indicated that, the level of water and type of model drug were the most significant factors in determining the pellet size. Three clusters could be identified, but the response to water content was drug dependent. It was not possible to identify a relationship between the force required to extrude the wet mass and the ability to produce good pellets nor their median size. All the products, which could be classified as good pellets, when produced, had a shape factor that can be considered to be indicative of a spherical shape. The most consistent material, in terms of spheronization, as represented by median diameter, size range and roundness, was propyl gallate (PG), which throughout all the formulations produced an almost constant value for shape factor and median pellet size, which in the majority of cases fell within a limited pellet size.     

Evaluation of the Adhesion Properties of Salbutamol Sulphate to Inhaler Materials

Pharmaceutical Research -