Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-10-22
2001-04-24
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S465000, C424S468000, C424S485000, C424S488000, C514S770000, C514S772300, C514S774000, C514S777000, C514S781000, C514S782000, C514S784000, C514S951000
Reexamination Certificate
active
06221393
ABSTRACT:
The present invention relates to pharmaceutical compositions in the form of sustained-release (also called delayed-release) tablets and to a process for their preparation.
The present invention relates more particularly to compositions of the above type where the tablets are based on polysaccharide granules of high molecular weight, and more particularly on granules of xanthan gum.
The pharmaceutical compositions of the above type contain a pharmacologically active principle and are used when it is desired to administer a medicament to a patient over a prolonged period without requiring the patient to take repeat doses at short intervals.
Direct tableting is a pharmaceutical procedure which is of particular interest since it involves a limited number of operations and constituents and, consequently, requires for its implementation facilities which are less expensive than for a wet-granulation tableting procedure. However, not all pharmaceutical compositions can be obtained by this route.
Natural or synthetic hydrophilic gums, which are polysaccharides of high molecular weight, are known as pharmaceutical excipients, but not all gums can be used in sustained-release compositions in dry tableting procedures. These polysaccharides are of either microbial origin, in which case they are obtained by fermentation of a carbohydrate which can be assimilated by an appropriate microorganism (for example, the xanthan gum obtained from
Xanthomonas campestris
), or natural origin, such as guar gum and carob gum, for example.
Xanthan gums are also excipients which are known for their possible use in the pharmaceutical field, especially for constituting matrices which are intended for the preparation of controlled-release forms. However, hydrophilic gums in general, and xanthan gum in particular, are not used in the pregranulated state.
WO-A 87/05212 teaches the preparation of sustained-release tablets comprising a matrix formed from polysaccharides of natural origin including xanthan gum.
EP-A 234 670 likewise teaches the preparation of sustained-release tablets in which the matrix makes up from 7.5 to 28% by weight of the tablet, the said matrix preferably comprising at least 75% by weight of xanthan gum.
However, the use of non-pregranulated xanthan gum, especially with a high content, i.e. generally a content of approximately 30% by weight relative to the total weight of the tablet, to prepare a tablet by direct tableting, leads to a tablet which has numerous defects, such as splits, heterogeneity, poor mechanical properties, etc.
One aim of the present invention is to prepare a sustained-release tablet based on polysaccharide of high molecular weight, in particular based on xanthan gum, which can be prepared without difficulty by direct tableting and has good properties of release of the active principle and good mechanical properties.
This aim and others are achieved by the present invention, which in fact relates to a pharmaceutical composition in the form of delayed-release tablets which are prepared by direct tableting and consist of at least one active principle and a matrix which gives the said composition its delayed-release effect, characterized in that the said matrix consists at least in part of pregranulated polysaccharides of high molecular weight.
The polysaccharides of high molecular weight which can be used in the context of the present invention include hydrophilic gums, which may be synthetic or natural in origin. High molecular weight polysaccharides of synthetic origin are obtained by fermentation of a carbohydrate in the presence of microorganisms.
By way of natural or modified natural polysaccharides it is recommended to use galactomannans, glucomannans, succinoglycans, scleroglucans, alginates, carragheenans, carob gum, guar gum, cassia gum and tara gum, starch, starch derivatives, pectins, chitosan, and their various possible mixtures. Pregranulated forms of a single polysaccharide or of a polysaccharide mixture can be used. Xanthan gum is the preferred polysaccharide. The term modified polysaccharides according to the invention is intended to mean, more particularly, their chemical derivatives, such as hydroxypropyl derivatives or carboxymethyl derivatives of the gums, for example.
More particularly recommended is the xanthan gum whose preparation is described in numerous publications such as U.S. Pat. No. 3,020,206, U.S. Pat. No. 3,391,060 and U.S. Pat. No. 4,154,654.
It is also recommended according to the invention to use another type of polysaccharide having thickening properties and rheology which are adapted to the same types of application as those of the xanthan gum, these other polysaccharides consisting of succinoglycans whose basic unit contains glucose, galactose and a succinyl radical; they are described in European Patent Application EP-A 351 303 and EP-A 40 445, and in Carbohydrate Research, 73 (1979) pp. 159-168 by Clarence A. Knutson; they can be obtained by microbial fermentation of a medium comprising a carbon source by means of a microorganism belonging to the genus Arthrobacter, such as
Arthrobacter stabiles,
in particular the strain
Arthrobacter stabiles
NRRL-B-1973, to the genus Agrobacterium, such as
Agrobacterium tumefaciens, Agrobacterium radiobacter
or
Agrobacterium rhizogenes,
to the genus Rhizobium, in particular
Rhizobium meliloti
and
Rhizobium trifoli,
to the genus Alcaligenes, such as
Alcaligenes faecalis,
especially the variety myxogenes, or to the genus Pseudomonas, especially the strains Pseudomonas ap. NCIB 11264 and NCIB 11592. Among these succinoglycans, particular mention may be made of the Rheozan® gums described in European Patent Application EP-A 351 303 and obtained by fermentation of a carbon-containing source by means of the strain
Agrobacterium tumefaciens
I-736 deposited in the French National Microorganism Culture Collection (CNCM).
Examples which may be mentioned of commercial polysaccharides which can also be used in the context of the present invention are Wellan®, Chamzan®, Gellan®, Dextran®, Pullulan® and Curdlan®.
The preformed granules entering into the pharmaceutical composition according to the invention are advantageously prepared from a polysaccharide powder, preferably xanthan gum having a particle size distribution which is such that 90% of the particles have a size less than 100 &mgr;m, preferably less than 75 &mgr;m.
The mean diameter is advantageously between 30 and 60 &mgr;m. The term mean diameter is understood to refer to a diameter which is such that 50% by weight of the particles have a diameter which is less than or equal to this diameter.
Numerous processes exist, described in the literature, for preparing polysaccharide granules from polysaccharide powder or from a polysaccharide fermentation solution. Within the context of the present invention it is possible to use any granulation process, such as spray drying, fluidized bed, extrusion, rotating-disc granulation, etc., or any combination of these processes.
Among these known processes mention may be made of U.S. Pat. No. 3,551,133, which describes a process for the preparation of cogranulated forms of xanthan gum and carob gum obtained by spraying an aqueous solution of a powder mixture of the two gums onto inclined-plate or disc granulators.
GB-A 2 086 204 describes a process of the same type.
According to EP-A 206 368, a solution of gums is sprayed onto a fluidized bed of gum.
U.S. Pat. No. 4,557,938 describes the fluidized-bed preparation of granules formed from a mixture of a xanthan gum, guar gum or carob gum with starch.
The preferred granulation process according to the invention is that in which polysaccharide powder, preferably xanthan gum, is sprayed in a fluidized bed with the aid of a stream of gas, water optionally containing a surfactant is sprayed onto the powder, and the granules are obtained by drying. A process of this kind is described in detail in FR-A 2 600 267. According to a preferred variant, all of the excipients of the matrix are cogranulated before being tableted.
In order to prepare the pharmaceu
Collaueri Jean-Pierre
Conrath Guillaume
Derian Paul-Joel
Gousset Gabriel
Mauger Frédéric
Rhodia Chimie
Seugnet Jean-Louis
Spear James M.
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