An investigation of the disintegration of tablets in biorelevant media.

The purpose of the study was to examine the disintegration of tablets in media designed to simulate conditions pertaining in the stomach. Although many studies have been performed to determine dissolution rates in these media, little work has been undertaken on the preliminary step in dissolution, namely disintegration. Two tablet formulations were prepared. One disintegrated rapidly (under 25 s in water) and the other more slowly (8 min in water). The disintegration times were measured by the BP 2000 test using discs. For the rapidly disintegrating tablets, disintegration times were similar in all media except for whole milk. This media is used to simulate the fed stomach and disintegration times were over five times longer than in the other media (P < 0.05). A similar effect was seen with the poorly disintegrating tablets in milk, and prolonged times were also observed in some of the other media. For these latter media, there was a good correlation between the penetration rate of the fluid into the tablet and the disintegration time. Penetration rates for milk were also slow which may be a reflection of its relatively high viscosity and low surface tension.

The influence of additives on the spreading coefficient and adhesion of a film coating formulation to a model tablet surface.

The surface energies of film coating formulations based on hydroxypropyl methylcellulose and containing microcrystalline cellulose, lactose and Tween 20, respectively, have been assessed. The approach taken allowed the components of the surface energy, in terms of the Lifshitz-van der Waals and the acid-base contributions, to be determined. Spreading coefficients of these coating formulations were determined on a model tablet surface whose surface energy had been similarly characterised. The determined spreading coefficients were high and positive indicating that spreading and wetting would not be a controlling factor in the formation of an adequate film coat. The adhesion of the coats to the core was measured and showed that the inclusion of additives influenced the adhesion of the film. Maximum adhesion was obtained when microcrystalline cellulose was included in the coating formulation that presumably allowed a strong interaction with the same component in the tablet core. Adhesion was enhanced when the tablet cores were made at a higher compaction force. Atomising air pressure had little influence on the adhesion.

Biphasic drug release: the permeability of films containing pectin, chitosan and HPMC.

The permeabilities of mixed films of pectin/chitosan/HPMC have been studied to assess their value in producing a dosage form with biphasic drug release characteristics. The inclusion of chitosan enhanced the properties of the films, rendering them stable at all physiological pH values. Pectin/HPMC films were soluble at pH values above 3.0. All pectin/chitosan/HPMC films were permeable to a model drug, paracetamol. HPMC initially increased the permeability of the films and subsequently reduced it at higher concentrations. The minimum permeability was obtained at pH 3 and at an HPMC level of 5% where the potential for polyelectrolyte complex formation between pectin and chitosan exists. The permeabilities of the films increased when they were exposed to pectinolytic enzymes, a system designed to mimic conditions in the colon. The film formulation thus show the potential for biphasic delivery with an initial, controllable slow phase that can be manipulated by changes in the formulation followed by a faster phase under conditions pertaining in the colon.

Amoxycillin release from a floating dosage form based on alginates.

Floating alginate beads have been prepared from alginate solutions containing either dissolved or suspended amoxycillin. The beads were produced by the dropwise addition of the alginate into calcium chloride solution, followed by removal of the gel beads and freeze drying. Drug release studies showed that beads prepared with the drug in solution provided some sustained release characteristics and that these could be improved by the addition of amylose. In all cases, the drug release was consistent with release of a dissolved solute from a granular or porous matrix. The beads retained their buoyancy when amylose and amoxycillin were incorporated, exhibiting resultant weight values greater than zero after 20 h. Preparation of the beads from alginate solutions containing the drug in suspension allowed higher drug loadings, at the expense of faster release and lower buoyancy.

An in vitro investigation into the potential for bimodal drug release from pectin/chitosan/HPMC-coated tablets.

The influence of disintegrant on the water uptake and subsequent disintegration force developed was investigated in a simple tablet formulation. The results indicated that a reasonable correlation existed between water uptake and disintegration force for the disintegrants screened with cross linked polyvinyl pyrrolidone (PVP XL) showing a proportionally higher disintegration force for the amount of water imbibed. Two tablet formulations, intended to promote accelerated drug release in the colon, were prepared, with and without PVP XL, and film coated with a mixture of pectin, chitosan and HPMC. The two systems showed different drug release rates which were influenced by the pH of the dissolution medium. In the presence of pectinolytic enzyme, drug release was faster when compared to release in buffer alone for both systems although the mechanism differed for each. Drug release in simulated gastrointestinal conditions showed a bimodal profile with the increased drug release rate being triggered by the action of pectinolytic enzymes.

Selective drug delivery to the colon using pectin:chitosan:hydroxypropyl methylcellulose film coated tablets.

A study has been carried out to assess the potential of pectin:chitosan:hydroxypropyl methylcellulose (HPMC) (P:C:H) films for colonic drug delivery. Radiolabelled (99mTc) tablets were coated with a 3:1:1, P:C:H film and administered to human volunteers. The gastro-intestinal transit of the tablets was assessed by gamma scintigraphy. The results showed that in all cases (n=4), the tablets were able to pass through the stomach and small intestine intact. Break up of the tablets commenced once they were in the colon, due to degradation of the coat by colonic bacteria. The study has highlighted the potential of this coating system for colonic drug delivery.

The potential use of mixed films of pectin, chitosan and HPMC for bimodal drug release.

Polyelectrolyte complex (PEC) formation between pectin USP and chitosan was investigated by examining the viscosities of supernatant solutions after removal of the precipitated complex. The amount of pectin, relative to chitosan, required for optimal PEC formation increased as the pH of the solution was reduced. At pH values of less than 1.3, there was no evidence for the formation of the PEC. Swelling studies conducted on pectin/chitosan films, showed minimal swelling occurring when the pectin:chitosan weight ratio was optimal for PEC formation, suggesting the formation of the PEC in situ. The permeability of the films to paracetamol as a model compound was dependent on film composition and was markedly increased after exposure to pectinolytic enzymes, used to mimic conditions in the colon. It may be implied from the results that similar formulations, applied as a film coat to tablets, could be used to achieve bimodal drug release with colonic conditions acting as a trigger for an increased rate of release.

Floating dosage forms: an in vivo study demonstrating prolonged gastric retention.

Gastroretentive dosage forms have potential for use as controlled-release drug delivery systems. The use of floating dosage forms (FDFs) is one method to achieve prolonged gastric residence times (GRTs), providing opportunity for both local and systemic drug action. Multiple-unit systems avoid the 'all-or-nothing' gastric emptying nature of single-unit systems. A freeze-dried calcium alginate multiple-unit FDF has been developed which demonstrated favourable in vitro floating characteristics. The aim of this study was to investigate the in vivo behaviour of this system compared to a multiple-unit non-floating dosage form manufactured from identical material. The study was performed in seven healthy volunteers, who swallowed the radiolabelled formulations after a standard breakfast. Transit was monitored by gamma-scintigraphy and subjects were maintained in the fed state. Prolonged GRTs of over 5.5 h were achieved in all subjects for the floating formulations, which remained high up in the stomach for the whole of the test period. In contrast, the non-floating beads displayed short GRTs, with a mean onset emptying time of 1 h. The results of this study suggest that, in the fed state, this FDF has potential for sustained drug delivery for either local or systemic purposes.

In vivo behavior of hydrogel beads based on amidated pectins.

Radio-labeled hydrogel beads, based on amidated pectin, have been produced by adding droplets of an amidated pectin solution to calcium chloride. Incorporation of model drugs into the beads and measurement of the dissolution rate showed that the properties of the beads were unaffected by the incorporation of the radiolabel. The labeled beads were used to carry out an in vivo study of their behavior in the gastrointestinal tract using human volunteers. The volunteers were given the beads after an overnight fast and images were obtained at frequent intervals during transit through the upper gastrointestinal tract and the colon. The beads exhibited rapid gastric emptying and proceeded to pass through the small intestine individually before regrouping at the ileo-caecal junction. Once in the colon, the beads again proceeded as individuals and evidence of the degradation of the beads was observed.

Targeting of drugs and delivery systems to specific sites in the gastrointestinal tract.

Particle uptake and translocation occur at specific sites in the gastrointestinal tract. Several drugs are also absorbed from solution only through narrow "windows' in the small intestine. In these circumstances, optimum therapeutic benefit would be obtained if the active agent was targeted to the appropriate site in the gastrointestinal tract. Targeting relies on exploiting a unique feature of the intended site and protecting the active agent until it reaches that site. This minireview highlights the problems in achieving site specificity in the gastrointestinal tract and examines possible solutions to the problem for 2 regions, the stomach and the colon.

Pectin/ethylcellulose film coating formulations for colonic drug delivery.

PURPOSE: The purpose of the study was to investigate the potential of pectin, ethylcellulose combinations as a practical film coating for colonic delivery. METHODS: Combinations of pectin and ethylcellulose, in the form of an aqueous dispersion, were used as coating formulations. Paracetamol cores were used as the substrate. The coatings were assessed by a flow through dissolution system simulating in vivo conditions by changes in pH and residence time. Pectinolytic enzymes were used to simulate the bacterial flora of the colon. RESULTS: Drug release was controlled by the ratio of ethylcellulose to pectin in the film coat. Increasing the proportion of ethylcellulose and increasing the coat weight reduced drug release in pH1 and pH7.4 media. The addition of pectinolytic enzymes to pH6 media increased the release of drug. CONCLUSIONS: Combinations of ethylcellulose and pectin can provide protection to a drug in the upper g.i. tract while allowing enzymatic breakdown and drug release in the colon.

Targeting drugs to the colon: delivery systems for oral administration.

The oral delivery of drugs to the colon has applications in a variety of therapeutic areas. This review is concerned with the approaches taken to achieve a universal system for delivery. The design of such a system requires the identification and exploitation of a unique feature of the colonic environment. The use of transit times, pH and bacterial enzymes are critically assessed. In addition, the system must provide protection for the drug during transit to the colon. Upper gastro-intestinal physiology and the transit of pharmaceuticals through these regions are reviewed with reference to their relevance in achieving site specificity.

Studies on long-acting aryl carboxylic acid esters of testosterone.

A series of aryl carboxylic acid esters of testosterone have been synthesized as possible agents for long-acting steroid therapy. The solubilities, partition coefficients and hydrolysis rate constants of the compounds have been determined. The results show that the partition coefficients increase with increasing chain length and are in keeping with calculated values. The hydrolysis rates decrease with increasing chain length except for the first member of the series (benzoate ester) which exhibits the slowest rate, possibly due to the hydrolytic attack being hindered by steric and electronic effects.

Assessment of gastric emptying using gamma scintigraphy.

Gamma scintigraphy was used to measure the gastric emptying rates of three test meals in human volunteers. Emptying rates were determined for solid and liquid materials alone, and for liquid in the presence of solid material. It was shown that the emptying of solids from the stomach was significantly slower than that of liquid, whether liquid alone or liquid in the presence of solid material. It was concluded from these results that, in the case of a solid test meal from which radio-label could be eluted, the free label would empty considerably faster than the remaining solid material. The emptying rate observed scintigraphically would not, therefore, be a true estimate of the solid emptying rate.

Representation of the path of a non-disintegrating capsule in the gastrointestinal tract using external scintigraphy and computer graphics.

The intestinal transit rate of a single non-disintegrating object has been measured using gamma scintigraphy. Using computer graphics, a three-dimensional visualization of the data has been developed. The display enables viewing from any angle and should be of value in assessing the effect of variables on the transit of pharmaceuticals and other materials.

Studies on the Dissolution of Drugs from Tablets using Perturbed Angular Correlation.

The perturbed angular correlation (P.A.C.) technique was used to assess the dissolution of drugs coprecipitated with [(111)In]indium chloride in tablets in vitro. The amount of drug in solution was monitored simultaneously with the amount of radioactivity in solution and these were correlated to the anisotropy values obtained by P.A.C. measurements. The results indicated that the rate of drug dissolution paralleled the change in measured anisotropy of the system. Thus, the measurement of anisotropic changes in drug-indium complexes by P.A.C. is a reliable indicator of drug dissolution and can provide meaningful dissolution data for noninvasive in vivo studies.

Effect of stress on the gastric emptying of capsules.

During a series of experiments on the gastric emptying of capsules, certain subjects were exposed to stress in the form of high noise levels. In the non-fasting condition, these subjects showed a significantly faster gastric emptying than those who were not exposed to the stress.

Simultaneous measurement of gastric emptying of the soluble and insoluble components of a formulation using a dual isotope, gamma scintigraphic technique.

The gastric emptying of a soluble and an insoluble component of a capsule formulation has been monitored by gamma scintigraphy using a dual isotope technique. There was no significant difference between the emptying rates for the two components or between fasting and non-fasting conditions (P greater than 0.01).