The production of active substance compositions in the form of a

Details The production of active substance compositions in the form of a The production of active substance compositions in the form of a

1996-11-21

1998-04-21

Krass, Frederick

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

424465, 424468, 424469, 424486, 424487, 424488, 424484, 424489, 424499, 424500, 264 6, 264141, 2641761, 26421121, 264211, A61K 920, A61K 914

Patent

active

057415196

DESCRIPTION:

BRIEF SUMMARY
The present invention describes a process for producing active substance compositions in which the active substance is present in a molecular dispersion in a polymer matrix, and active substance compositions produced thereby.
Melt extrusion processes for producing drug forms (tablets, pellets, granules) are described in the literature. The combination of an extrusion step with a subsequent shaping step, in particular, makes this process a very straightforward, because single-stage (and thus cost-saving), method for producing drug forms such as tablets (DE-A-1 766 546 and U.S. Pat. No. 4,880,585). These and other references (EP-A-580 860) mention that the thermal processing during the extrusion cause the active substance, owing to the melting, to be incorporated in the form of a molecular dispersion into the likewise molten polymer melt. This is manifested by the fact that clear transparent melts containing active substances are formed, and these usually do not recrystallize after these compositions have been cooled to room temperature, but on the contrary maintain their molecular dispersion.
These formulations are generally referred to as solid solutions and have been described many times per se in the literature (eg. A. S. Kearny et al.; Int. J. Pharm. 104 (1994), 169-174). However, they have to date been produced by melt extrusion processes in only a few cases. Solid solutions are also often produced by a process in which the components are dissolved in an organic solvent, and the solvent is then stripped off again. This has the disadvantage that organic solvents inevitably have to be employed. In addition, these (multistage) processes cannot be carried out continuously, and the homogeneity achieved is unsatisfactory.
Molecular dispersion of an active substance in a water-soluble polymer is a method which has been described many times for increasing the rate of dissolution of a (sparingly soluble) active substance in aqueous media. It has in many cases emerged, especially with sparingly soluble active substances, that absorption of the latter from the gastrointestinal tract after oral administration was impossible or possible to only a very small extent because the rate of dissolution of the active substance was too slow. However, only an active substance which is dissolved (in the aqueous medium) can be absorbed. It is possible, however, with the aid of a molecular dispersion of the active substance in a water-soluble polymer considerably to speed up this process because individual molecules of active substance are released from these formulations directly in the dissolving process of the (water-soluble) formulation, in contrast to previous preparations which contain crystals of active substance whose kinetics of dissolution are considerably slower. Such solid solutions therefore in many cases lead to a distinct increase in the proportion of active substance which can be absorbed, which in many cases leads to improvements in the bioavailability of a (sparingly soluble) active substance (N. Kondo et al., J. Pharm. Sci. 83 (1994), 566-570).
However, it is not possible to prepare solid solutions of all active substances.
The formation of solid solutions by thermal processes such as extrusion (in contrast to the normally employed processes via organic solvents) is subject to various preconditions which must be met at least in part:
a) the melting point of the active substance must be so low that at the temperatures generally prevailing during the extrusion intensive mixing of the two substances in the melt (active substance and polymer) is possible, and/or
b) the rate of dissolution of a (high-melting) active substance in the polymer melt is so high that it is possible for solid solutions to form despite the relatively short residence time in the extruder.
The latter point in particular is not complied with in most cases of high-melting active substances because the residence time of the composition in the extruder is too short (generally below one minute). An increase in this residence time leads to (therm

REFERENCES:
patent: 4880585 (1989-11-01), Klimesch et al.
patent: 5073379 (1991-12-01), Klimesch et al.
patent: 5456923 (1995-10-01), Nakamichi et al.
Kearney et al., Int. Journal of Pharm., 104, 169-174 (1994).
Kondo et al., Journal of Pharm. Sciences, 83, 566-570 (1994).

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