Dispersion Of Dosage Forms In The Stomach

of in vitro dissolution tests; however this is often not the case. Endoscopy has demonstrated that when multiple tablets are administered, all lie in the same place in the stomach, at the base of the greater curvature. This is a particular problem with formulations which cause gastric irritation or damage, for example non-steroidal anti-inflammatory drugs which can produce focal erosions due to repeated insult to a small area of the mucosa. Iatrogenically-produced ulcers can often be differentiated from those of natural origin, since drug-induced erosions usually occur at the base of the greater curvature, whereas peptic ulcers form on the lesser curvature. Multiple unit dose forms can also cause mucosal damage; for example microencapsulated potassium chloride showed similar gastric mucosal irritation to single units. This was attributed to poor dispersion of the potassium chloride, with clumps of the drug held together with gastric mucus64.

Hard gelatin capsules

Hard gelatin capsules have found a variety of applications in drug formulation. The capsule can be used as a container for powdered drug, multiparticulate systems, a liquid-fill matrix or oily vehicle. The nature of the interior of the fill of the capsule is known to affect the rate of disintegration within the stomach. A hydrophobic interior reduces the rate of disintegration of the capsule compared to that of a water soluble material, and in addition it reduces the dispersion of the released material. When capsules contain components which are insoluble in gastric juice, then their disintegration time is of the order of 30 minutes in fasted volunteers and 100 minutes in fed volunteers65. Changing the fill to a water soluble material decreases the break-up time to 6 minutes.

The dispersion of the capsule fill is limited in fasted subjects, and the material empties from the stomach as a bolus66-68. Dispersion is increased if the capsule is taken with a meal, particularly if the meal has a high liquid content. This is of importance since patients are often instructed to take medications with a meal, but it is unclear whether this means before, during or after food. If capsules are given with 100 ml of water, they will initially float above the gastric folds. Rapidly the ends of the capsule become sticky and can become attached to the gastric wall, which may be another explanation for the poor dispersion of the capsule contents64.

The dispersion of milled resin administered in a hard gelatin capsule in fasted volunteers was greatly reduced when it was milled from 25 pm to 9 pm66 68. It was proposed that this was due to changes in the hydrophobicity of the surfaces, arising from chemical and physical variations in the resin through the bulk of the particle. It is equally likely that milling changes the wettability of the material due to variations in particle surface roughness.

Soft gelatin capsules

There have been relatively fewer studies of the behaviour of soft gelatin capsules in man. Pilot studies indicate that the time of disintegration of soft gelatin capsule formulations is highly variable, particularly if the formulations are given without food. The capsules were predominantly broken up as they entered the pylorus immediately prior to leaving the stomach (unpublished data). Armstrong and co-workers69 have compared the dispersion of oils from soft gelatin capsules in man and rabbits using x-ray techniques and gamma scintigraphy. Soft gelatin capsules were filled with iodinated cotton seed oil (Lipiodol) for x-ray studies, or iodine-123 labelled ethyl oleate for gamma camera studies in humans. In x-ray studies of rabbits, disintegration of the capsule began after 2 to 3 minutes, swelling into a more isometric shape. This behaviour was observable in vitro and was associated with the breakdown of the capsule at the sealing line. Subsequently it was difficult to assess whether the shell had dissolved with the oil as one discrete globule, or whether the oil had emerged from the shell before it had completely dissolved. When a surfactant (1% polysorbate 80) was added to the formulation, the mean disintegration time of the soft gelatin capsule decreased markedly.

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