1. The first phase consists of an amorphous active ingredient and a water-soluble polymer PVP of low viscosity hydroxypropyl metylcellulose. Surface active substance may be added to increase solubility and control dissolution.
2. This phase contains particles of the first phase plus high viscosity hydroxy-propyl metylcellulose and optional mixtures like mono, di and tri glycerides and other auxiliary substances usually used in the manufacture of solid pharmaceuticals (lactose, talc, magnesium stearate and others).
The first and the second phase make up the core of the tablet.
3. The third phase is a film coating, which consists of one or more layers. The first, inner layer, retards dissolving, and functions as a dissolution retardant and is, either resistant to acids (it dissolves in neutral pH), or is not easily soluble; the dissolution is time constricted and independent of pH. The second, outer layer, is a colored coating (which helps identify the pharmaceutical form and acts as a protection against the light).
a) By controlling the speed by which water penetrates the gel layer, the dissolution of the active ingredients as well as the diffusion of the dissolved active ingredient back through the gel layer to the tablet surroundings.
b) By controlling the speed of gel layer erosion. The low solubility coating dissolves at a certain rate (in half an hour or an hour), irrespective of the position of the tablet at the time. All processes that follow are identical to those of the acid-resistant coatings.
Patents: US 6,042,847; EP 0 872 397 B1
Such a system helps control dissolution rates of release by using a combination of both the erosion and diffusion mechanisms. Other options for controlling the release of the active ingredients are by adding pH modulators, solvents and absorption promoters to the matrix system.
Patent: PCT WO 00/48607
When a capsule containing pellets is swallowed, it disintegrates in the stomach. This disintegration releases the pellets, which spread throughout the stomach. The acid resistant coating prevents the release of the active ingredient in the acidic environment of the stomach. The pellets, which are still intact, move along the gastro-intestinal track (GIT) until they reach the alkaline environment of the small intestine. There the coating dissolves and releases the ingredient from the core of the pellets. The rapid dissolution of the cores is made possible by the manufacturing technology of cores as well as the use of selected excipients, which with the active ingredient, make up the pellet cores. This of course helps speed up the release of the active ingredient, its dissolution, and consequently its absorption into the blood circulation.
This special system developed by Lek, maximizes the active ingredient release while maintaining extreme stability.
The system is especially suitable for active ingredients that are unstable in acidic environments while stable in alkaline environments. The classic pharmaceutical form, where active ingredients are released in the stomach, results in active ingredient degradation without a beneficial therapeutic effect. The trick therefore is, to come up with a pharmaceutical form that releases the ingredient in the alkaline environment of the small intestine, where it is stable, and not earlier.
When developing new pharmaceutical forms it is therefore crucial that we choose appropriate auxiliary substances and suitable manufacturing technology. Only then, may we hope to create a drug that will be entirely "safe" as it passes through the stomach, and yet readily and quickly dissolve its active ingredients in the small intestine.
Patent: PCT WO 99/03453
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