Galenic formulations fast disintegrating in the mouth and...

Details Galenic formulations fast disintegrating in the mouth and... Galenic formulations fast disintegrating in the mouth and...

2001-09-05

2003-12-30

Page, Thurman K. (Department: 1616)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S495000, C424S482000, C424S484000, C424S473000, C424S464000, C424S467000

Reexamination Certificate

active

06669957

ABSTRACT:

The present invention relates to pharmaceutical dosage forms with rapid disintegration in the mouth and to their process of preparation.
In therapeutics, the simplicity of the oral administration of a medicinally active principle has always been regarded as a major advantage, as testified by the great diversity of pharmaceutical dosage forms intended for this administration route (uncoated, coated and effervescent tablets, gelatin capsules, soft capsules, solutions to be dissolved, ready-for-use oral suspensions, and the like).
As regards solid forms, these nonetheless exhibit two disadvantages. First, they require that a liquid capable of facilitating the swallowing thereof be taken in combination. In point of fact, there are numerous situations in which it may be appreciable to be able to take a medicament by the oral route, the ingestion of which does not require the simultaneous absorption of a liquid. Secondly, some patients and in particular children and elderly people experience difficulties in swallowing such that it is difficult and consequently unpleasant for them to ingest a solid pharmaceutical dosage form, even in the presence of a liquid.
As regards liquid forms, they are generally provided in bulky or easily damaged packagings (bottles, glass ampules), which makes them ill suited to outpatient use.
For this reason, numerous studies have been carried out with the aim of developing pharmaceutical dosage forms intended for per os administration which, while being provided in a solid form, are capable, when they are placed in the buccal cavity, of rapidly disintegrating on contact with the saliva to form a suspension which is easy to swallow.
Thus it is that Laboratoires Prographarm have provided, in French Patent Application No. 91 09245, multiparticulate tablets in which the active principle is present in the form of microcrystals coated in ethylcellulose or microgranules and is dispersed in an excipient composed of at least two disintegrating agents of the sodium carboxymethylcellulose or crosslinked polyvinylpyrrolidone type, of one or more swelling agents of the starch, modified starch or microcrystalline cellulose type, and of a direct tableting sugar.
Subsequently, Laboratoires Prographarm, wishing to improve the texture of these tablets as they generate a sandy and pasty feeling in the mouth, developed a technology known under the Flashtab® trade mark which is disclosed in French Patent Application No. 97 09233 and which consists in coating microcrystals of active principle in a polymethacrylate or a cellulose polymer intended to mask the taste thereof and in using, as excipient, a mixture of a disintegrating agent (sodium carboxymethylcellulose, crosslinked polyvinylpyrrolidone) and of a polyol with a short carbonaceous chain, such as mannitol, xylitol or sorbitol, this polyol fulfilling the role of diluting agent with binding properties.
French Patent Application No. 88 15183, on behalf of D. Vacher, discloses tablets intended to facilitate the oral administration of a medicinally active principle mainly, but not exclusively, to children and more particularly to infants and in which the active principle represents at least 60% by weight of the tablets, so as to reduce their size as much as possible, and is dispersed in an excipient composed of a crosslinked cellulose gum and of a swelling agent of the microcrystalline cellulose type or of the starch type.
Having noted that the use of such tablets cannot in practice be envisaged in adults in so far as they can only comprise small doses of active principle, which would imply having to be taken very frequently, D. Vacher has provided, in International Application No. 96/02237, an improvement to these tablets by coating the active principle in a water-dispersible binding agent of the alkylcellulose type to facilitate the wettability of this active principle on contact with the saliva and by dispersing the active principle thus coated in an excipient composed of crosslinked carboxylmethylcellulose, which in this case acts as agent for bursting the tablets, of microcrystalline cellulose, which acts as diluent, and of a water-soluble polyol of the mannitol, xylitol or sorbitol type, which is itself intended to mask the taste of the active principle.
At the same time, some research has been devoted to developing pharmaceutical dosage forms capable of disintegrating in the mouth by a controlled effervescence process.
Thus, for example, International Application No. 91/04757, on behalf of Cima Labs, discloses tablets in which the active principle is dispersed, optionally in a microencapsulated form, in a mixture comprising both an acid of the citric acid, tartaric acid, maleic acid or fumaric acid type and a carbonate, such as sodium bicarbonate, so that this acid and this carbonate react together on contact with the saliva to release carbon dioxide gas and thus to make possible the disintegration of said tablets.
Similarly, French Patent Applications Nos. 94 01457 and 95 03711, on behalf of X. Hesnard, relate to tablets, disintegration of which in the mouth is also obtained by reaction between an acid and a carbonate, the acid in this case being in an amount significantly greater than that of the carbonate, so as to bring about, from the introduction of the tablets into the buccal cavity, a hypersalivation capable of increasing the intrabuccal volume of water, which has the effect of promoting the disintegration of said tablets into a dispersion which can then be imbibed by simple salivary swallowing.
Furthermore, it turns out that the development of a pharmaceutical dosage form capable of rapidly disintegrating in the mouth presents a number of specific problems, in particular because it has to satisfy conditions, some of which conflict with one another. Thus, it has to exhibit a sufficient cohesion and a sufficient hardness not to be detrimentally affected during the various stages of manufacturing, of packaging and of storage, while being capable of disintegrating virtually instantaneously on contact with the saliva. Furthermore, it has to have and to leave in the mouth a pleasant taste, even when the medicinally active principle included therein itself exhibits a pronounced bitterness. Furthermore, it is desirable, although not corresponding to the same requirements as the conventional pharmaceutical dosage forms, for it to be able, however, to be manufactured according to the processes and by means of the same equipment as those used for the manufacture of the latter, so as to render its production cost as satisfactory as possible.
Partial solutions to these problems have been provided in European Patent Applications Nos. 0 553 777, 0 636 364 and 0 745 382.
Thus, European Patent Application No. 0 553 777, on behalf of Takeda Chemicals Industries, discloses a process which consists in mixing the active principle with an excipient mainly comprising one or more carbohydrates of the sucrose, glucose, maltitol, xylitol and erythritol type, in then wetting the resulting mixture with a small amount of water (preferably of between 0.7 and 3%, w/w) and in subjecting it to granulation, and finally, after drying the granules, in tableting the latter. According to this Application, this process would exhibit the two-fold advantage of resulting in the production of tablets possessing a satisfactory hardness and of being able to be put into operation using granulators and tableting machines generally used in the pharmaceutical industry.
European Patent Application No. 0 636 364, on behalf of McNeill-PPC, provides tablets in which an active principle is provided in the form of particles coated with a mixture of cellulose polymers intended to mask the taste thereof and is dispersed in this form in a mixture comprising a compressible carbohydrate capable of disintegrating on contact with water (mannitol, sorbitol, dextrose, sucrose, and the like) and a binder such as cellulose and its derivatives, polyvinylpyrrolidone, starch or microcrystalline cellulose, the purpose of the latter being to confer satisfactory cohesion on the

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