Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
1999-03-10
2001-04-24
Lankford, Jr., Leon B. (Department: 1651)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S497000, C424S464000
Reexamination Certificate
active
06221368
ABSTRACT:
The present invention relates to a process for producing solid pharmaceutical forms by mixing at least one pharmacologically acceptable polymeric binder and at least one pharmaceutical active ingredient, with or without conventional pharmaceutical additives, and extruding. the mixture to give the desired pharmaceutical form.
Conventional processes for producing solid pharmaceutical forms especially tablets, are carried out batchwise and comprise a number of stages. In general, the ingredients of the drug form are first conveyed into a suitable container and then mixed with the addition of a solvent to give a kneadable paste. The paste is then granulated, and the granules are dried and shaped to the desired drug form, for example by compressing them into tablets. Processes of this type are described in relevant text books and, for example, in DE-A-41 41 268 and EP-A-590 963. A grave disadvantage of these processes is the large number of stages and items of apparatus required.
A considerably simpler continuous process for producing solid pharmaceutical forms has been known for some time and entails converting a melt of polymeric binder which contains active ingredients and is free from solvents into the required drug form by injection molding or extrusion and subsequent shaping; see, for example, EP-A-240 904, EP-A-240 906 and EP-A-337 256. Such a process comprises energy-intensive melting of the thermoplastic binder, which is usually in powder form. Furthermore, the technical complexity involved in mixing the binder with other components, such as a pharmaceutical active ingredient or conventional pharmaceutical auxiliaries which are generally in solid form, is relatively great. For example, special solids mixers are required if the mixing is to take place in a separate step before the melting. In this case, there is also the risk that the components of the premix which is fed into the extruder separate, and thus that drugs of nonuniform composition will be produced. On the other hand, the coupling of the melting and mixing steps in the extruder requires a relatively long residence time in a zone with high shear in order to bring about sufficient mixing of the components. This may result in local overheating and damage to the product, especially when a shear- and temperature-sensitive active ingredient is being used. A further disadvantage of using powder-form substances is the formation of dust.
Although it is true that the transport of dry polymers in powder form is less expensive, a large number of pharmacologically appropriate polymers which are used as binders for producing solid pharmaceutical forms are produced as a dispersion or solution. For use in the process described above, the polymers are in a further step always isolated as solids and dried. Direct use of a polymer dispersion or solution as binder, like the use of the auxiliaries in liquid form, has not hitherto been considered.
Polymer dispersions have previously been employed in the production of solid pharmaceutical forms only for applying a coating. For instance, EP 088 951 describes a process for coating solid drug forms using a coating composition which is dispersed in water. To do this, an emulsion polymer is spray-dried and redispersed, and the resulting dispersion is applied, as the coating composition, to the ready-prepared drug form.
The present invention relates to a process for producing solid dose forms by mixing at least one polymeric binder, with or without at least one active ingredient and with or without conventional additives, extruding the mixture and shaping, which comprises employing at least some of the components in liquid form.
For the purposes of the invention, dose forms are all forms suitable for use as drugs, plant treatment agents, feedstuffs and foodstuffs. These include, for example, tablets of whatever shape, pellets, granules, but also larger forms, such as cubes, blocks or cylindrical forms, which can be used in particular as feed or foodstuffs.
For the purposes of the invention polymeric binders are not only natural or synthetic polymers but also meltable substances of low molecular mass, such as sugar alcohols, sugars, fats or waxes.
For the purposes of the invention liquid form means that one of the components employed has been taken up, at least in part, in a solvent or is in the form of a melt. If the component has been taken up in a solvent, this can be in the form of a solution, dispersion, emulsion or suspension.
The dose forms obtainable in accordance with the invention generally comprise:
a) from 0 to 100% by weight, in particular from 0.1 to 50% by weight (based on the overall weight of the dose form) of an active ingredient,
b) from 0 to 100% by weight, in particular from 50 to 99.9% by weight, of a polymeric binder, and
c) with or without additives.
If the dose form is employed for food or feed purposes, the active ingredient may be absent; ie. the dose form can embrace up to 100% of the polymeric binder.
Particularly suitable binders are pharmacologically acceptable polymers. These are physiologically tolerated polymers which are able to dissolve or swell in a physiological environment and to release the active ingredient (if present). It is also important that the processing temperature can be chosen so that, on the one hand, the mixture can be shaped but, on the other hand, there is no damage to the components, especially to the active ingredient. This means that the glass transition temperature of the polymeric binder is preferably below the decomposition temperature of all the components present in the mixture.
The polymeric binder is preferably employed in the form of an aqueous or alcoholic dispersion or solution. Polymer dispersions or solutions which are suitable in accordance with the invention can be obtained by emulsion, suspension or solution polymerization. These processes are known to the skilled worker. Any ancillary substances which might be required for carrying out these processes are likewise a constituent of the binder e according to the invention and are described in detail hereinafter.
Polymer dispersions or solutions which are suitable in accordance with the invention can also be obtained by dispersing or dissolving, respectively, a solid polymer in a dispersant or solvent. For example, polymer can be dissolved in an organic solvent and then an aqueous solution with emulsifiers suitable for dispersing the polymer in water can be stirred into the organic solution first obtained. The primary product of this—provided the organic phase is in excess—is a W/O emulsion. If further emulsifier solution is added, there is ultimately a phase inversion to form a finely disperse O/W emulsion. A dispersion, preferably an aqueous dispersion, can be obtained from this emulsion by evaporating the organic solvents. Ancillary substances which may be employed to implement this process are a constituent of the dispersions or solutions which are appropriate in accordance with the invention and are described in detail hereinafter. However, it is preferably the solutions or dispersions obtained in the preparation of the polymer, with or without prior concentration, which are employed.
Both W/O emulsions and O/W emulsions can be employed in the process according to the invention.
The polymers suitable in accordance with the invention are obtainable by polymerizing ethylenically unsaturated monomers. These include both essentially water-insoluble and essentially water-soluble monomers. They can be employed alone or in a mixture. The relative proportion of water-insoluble or water-soluble monomers, respectively, has a considerable influence on the properties of the resulting polymer. The location and timing of the release of active ingredient can therefore be adjusted to match the pharmaceutical requirements by the choice of polymer.
Suitable essentially water-insoluble monomers are, in particular, monoethylenically unsaturated monomers, such as esters of &agr;,&bgr;-monoethylenically unsaturated mono- and dicarboxylic acids having 3 to 6 C atoms, such as acrylic acid
Breitenbach Jorg
Kleinke Andreas
Kothrade Stephan
Rosenberg Joerg
BASF - Aktiengesellschaft
Dergosits & Noah LLP
Lankford , Jr. Leon B.
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