Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-08-13
2001-04-03
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S489000, C424S490000
Reexamination Certificate
active
06210711
ABSTRACT:
The present application is a U.S. National Application filed under 35 USC 371 of PCT/FR98/00070, filed Jan. 15, 1998 based upon French application Ser. No. 97/00394 filed Jan. 16, 1997.
The present invention relates to multilayer effervescent microspheres and to a process for preparing such microspheres.
The term “microsphere” will be intended to refer to microgranules formed of a support material consisting of a matrix in which the active principle(s), to which auxiliary substances are optionally added, is (are) dispersed. In accordance with the European Pharmacopea monograph on spheres, microspheres have an average diameter of less than 1.0 mm and greater than or equal to 1.0 &mgr;m. They are generally intended for oral or parenteral administration and are used either as constituents of pharmaceutical form, such as tablets, or in their natural form combined or otherwise with other excipients, and distributed or otherwise in unit doses, such as sachets, gel-capsules or powder for injectable preparation.
The effervescent forms for pharmaceutical use described in the prior art exclusively comprise granules and tablets obtained by compressing these granules.
These effervescent forms are intended to be dispersed in water before absorption. Their breakdown is ensured by a release of carbon dioxide resulting from the action of an acid—generally an organic acid, citric acid being the one most commonly used—on a base—generally a carbonate such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, calcium carbonate, magnesium carbonate or lysine carbonate to avoid the introduction of sodium.
The known effervescent forms also comprise diluent adjuvants (generally sugars), binders, sweeteners and flavorings.
Most of the standard processes for preparing effervescent forms comprise a step of granulating powder, either via a wet route or via a dry route.
Despite the difficulties present therein, wet granulation is the method most commonly used.
According to a first variant described in the “Journal of Pharmaceutical Sciences, 1964, 53, 1524-25”, the acidic and basic substances, the active principle(s) and the adjuvants are mixed together in a fluidized air bed. The granulation is initiated by spraying the powder with distilled water or an aqueous diphosphate solution. The water thus sprayed on initiates an effervescence reaction which allows the creation of bonds between the particles of powder. The water is sprayed on until the granules reach the desired size. The drawback of this method is the lack of reproducibility of the results due to poor control of the effervescence reaction.
Patent application EP 673,644 proposes to control the effervescence reaction of the process described in the above reference, by maintaining the moisture content of the air supplied to the fluidized air bed between 0 and 1 g/m
3
, on the one hand, and by evaporating the nebulized water at the surface of the granules being formed while at the same time continuing the spraying with water, on the other hand. The granules are dried once the desired size has been reached. This application describes the use of water or of an aqueous-alcoholic mixture as wetting liquid.
According to a second variant described in patent EP 369,228, the acidic and basic substances are granulated separately and then mixed together after drying. This process is expensive to implement.
In patent application WO 96/19982 which describes a process for preparing effervescent compositions containing ibuprofen, the granulation step concerns only the alkaline substance. According to this process, the granulated alkaline substance is mixed with pulverulent ibuprofen.
Dry granulation includes two phases: compression of the powder and grinding-screening of the powder tablets. This process is of little interest for the preparation of effervescent forms due to the chemical nature of the products inducing bonding phenomena.
Patent FR 2,552,308 describes a process for preparing an effervescent mixture by a method which does not involve a granulation step.
According to the described process, the effervescent mixture contains at least one crystalline solid organic acid and at least one carbonate releasing CO
2
in the reaction with the organic acid and is characterized in that the acid crystals bear a coating containing calcium carbonate which adheres to the surface of the acid crystals by means of the bonding layer formed by partial react-on of the calcium carbonate of the coating with a surface layer of each acid crystal. The mixture is prepared by heating the organic acid in ethanol and water to about 60° C. in a mixer at a pressure of about 0.1 bar or less and by introducing the calcium carbonate which is left to react until the pressure has risen to about 0.9 bar.
The present invention relates to multilayer effervescent microspheres containing an acidic substance, a basic substance and a water-soluble isolating agent whose dissolution in water leads, after almost immediate effervescence, to a solution or a homogeneous dispersion of active principle.
According to a first variant, the water-soluble isolating agent is dispersed in the entire bulk of each microsphere, the latter having a two-layer structure: a layer of acidic substance in which is dispersed the water-soluble isolating agent and a layer of alkaline substance in which is dispersed the water-soluble isolating agent.
According to a second variant, the water-soluble isolating agent is in the form of a thin film separating the acidic and alkaline substances. In this case, each microsphere has a three-layer structure: a layer of acidic substance and a layer of alkaline substance separated by a layer of water-soluble isolating agent.
Whether the microspheres have a two-layer or three-layer structure, the water-soluble isolating agent serves two purposes; it acts as a binder and as an isolating barrier intended to avoid an effervescence reaction between the alkaline substance and the acidic substance during the preparation process but also during storage of the microspheres, irrespective of the storage conditions.
The water-soluble isolating agent is chosen from polyvinylpyrrolidone, hydroxypropyl cellulose, methyl cellulose, lactose and sucrose.
The present invention also relates to a process for preparing the effervescent microspheres described above using the method of rotary granulation in a fluidized air bed.
The advantage of rotary granulation applied to these effervescent compositions is the continuous linking of the operations in one and the same chamber which, as a result of the components used and certain precautions taken, induces no effervescence. Furthermore, this rotary granulation technique allows the relative proportions of the various compounds to be modified, in particular the relative molar proportions of the acidic and basic fractions.
Specifically, the process according to the invention makes it possible advantageously to obtain effervescent forms whose relative proportion of alkaline and acidic fractions is less than the stoichiometric proportion implemented in the prior art for effervescent tablets manufactured by the granulation method, without the quality of the effervescence being adversely affected.
In particular, the relative proportion of the alkaline and acidic fractions implemented in the context of the process according to the invention is less than 0.6, in particular less than 0.25.
All the steps of the process according to the invention are carried out under atmospheric pressure, without any specific dehydration system or any specific precautions.
The apparatus used to carry out the process for preparing the effervescent microspheres is, for example, apparatus constructed by the company Glatt, onto which a rotor tank is fitted.
Such an item of apparatus is described in patent EP 0,505,319, which we include, by way of reference, in the present application.
A subject of the present invention is, firstly, a process for preparing effervescent microspheres which have a two-layer structure according to the first variant described above.
Said process is p
Aiache Jean-Marc
Bougaret Joel
Gauthier Pascale
Pierre Fabre Medicament
Spear James M.
The Firm of Hueschen and Sage
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