Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-09-28
2003-08-12
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S465000, C424S490000
Reexamination Certificate
active
06605301
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to dispersible tablets containing macrolides as active ingredients, alone or combined with other active ingredients, and their method of preparation.
The present invention relates more particularly to dispersible tablets containing azithromycin, roxithromycin or clarithromycin as active ingredients, alone or combination with other active ingredients.
In therapy, the simplicity of using tablets has always been considered as a major advantage in particular in the context of ambulatory treatments, as demonstrated by the very large number of proprietary medicinal products which are provided in this form.
However, some patients and, in particular, children and the elderly experience deglutition difficulties such that it is difficult and consequently unpleasant for them to ingest tablets, even with a dose combined with liquid.
That is the reason why it is desirable to have available tablets capable of disintegrating in a small volume of liquid, so as to be able to be ingested in the form of solutions or suspensions which can be taken orally.
However, numerous active ingredients are known to exhibit a bitterness which is very difficult to mask, when they are provided in the form of solutions or suspensions to be taken orally.
This is the case in particular with macrolides, whether they are used alone or in combination with other active ingredients. Macrolides have in common the feature of comprising a central lactonic nucleus consisting of 14 to 16 members with few or no double bonds and no nitrogen. One or more amino and/or neutral sugars (desosamine, cladinose, mycarose, mycaminose) are attached by &agr;- or &bgr;-glycosidic bonds to this nucleus, also called aglycone. There may be mentioned as macrolides natural derivatives, erythromycin A to F, oleandomycin, spiramycin, midecamycin and troleandomycin and as semisynthetic macrolides, roxithromycin, dirithromycin, clarithromycin, flurithromycin and rokitamycin. The 15-membered azolides, which possess an endocyclic nitrogen atom, such as azithromycin also form part of the macrolides [A. Bryskier, 1995, in
Le bon usage des macrolides,
page 8, Classification des macrolides (Classification of the macrolides), Ed. Phase 5].
However, this bitterness is marked to a greater or lesser degree depending on the physicochemical characteristics of the macrolide. For example, troleandomycin is practically free of bitterness [
Traité de chimie therapeutique,
1992, vol. 2, Médicaments Antibiotiques (Antibiotic drugs) TEC & DOC Lavoisier, Editions Médicales Internationales], whereas pristinamycin, azithromycin, roxithromycin, clarithromycin and spiramycin have a very pronounced bitterness.
Accordingly, numerous techniques have been proposed for masking the bitterness of these active ingredients and in particular that of roxithromycin, clarithromycin and spiramycin.
In general, these techniques consist either in carrying out a more or less complex coating of the active ingredient (French patent application No. 2 669 533; international application No. WO 97/16174), or simply in trying to mask the taste by the use of a suitable sweetener, most often combined with a large quantity of sucrose (French patent application No. 2 696 346; proprietary medicinal product Rulid® 50 mg, powder for suspension which can be taken orally).
Thus, French patent application No. 2 669 533 describes a method for the manufacture of dispersible granules containing spiramycin and intended to mask the taste of this active ingredient. In this method, the spiramycin encapsulated in albumin by a technique which requires the use of organic solvents such as isooctane and their removal at the end of the method, and then the capsules thus obtained are diluted with a mixture of sugars (lactose+fructose). The technique for the encapsulation of spiramycin, although effective, is very expensive because it only allows the manufacture of small quantities of pharmaceutical composition, and requires long and expensive steps for the recycling of solvents.
That is why international application No. WO 97/16174 provides, for its part, a method which makes it possible to prepare dispersible granules of a macrolide and, for example, of clarithromycin, without the use of organic solvents. In this method, the macrolide is subjected to granulation after mixing with a polymer of branched acrylic acid with high crosslinking power. This granulation is carried out in the presence of water and is optionally followed by a second granulation which, for its part, is carried out in the presence of an aqueous solution of a binding agent such as polyvinylpyrrolidone.
French patent application No. 2 696 346 also proposes preparing spiramycin formulations with enhanced taste and provided in the form of granules to be dissolved or to be dispersed in water. These formulations contain a particular sweetener, namely acesulfame potassium, and sucrose in a high proportion—since the spiramycin/sucrose weight ratio is between 1/1 and 1/9—in order to mask the bitterness of the spiramycin.
However, the latter formulations, just like the formulations obtained by coating as proposed in FR-A-2 669 533 and WO-A-97/16174, exhibit certain disadvantages and, in particular, that of not sufficiently masking the bitterness of the macrolides which they contain. Furthermore, the quantities of sugar(s) present in the formulations described in FR-A-2 669 533 and FR-A-2 696 346 make the administration of these formulations contraindicated in diabetic patients.
Recently, a dispersible tablet, with no coating and free of sugar, has indeed been proposed for josamycin (dispersible JOSACINE®), but the latter is known to have a taste which is a lot less bitter than the other macrolides and to exhibit no technical difficulty for the formulation. In this tablet, the josamycin is present in propionate form, in a quantity corresponding to 50% of the total weight of said tablet.
However, to date, no dispersible tablet free of sugar and having a suitable taste has ever been provided for the most bitter macrolides such as spiramycin, roxithromycin, clarithromycin, pristinamycin and azithromycin.
Consequently, the inventors set themselves the aim of remedying this fault and of developing dispersible tablets which contain active ingredients and, in particular, very bitter macrolides, and which, although free of sugars, lead, when they disintegrate in water, to oral suspensions having a completely acceptable taste so that these suspensions are not unpleasant to swallow.
BRIEF SUMMARY OF THE INVENTION
The subject of the present invention is therefore dispersible tablets which contain a macrolide as active ingredient, alone or in combination with another active ingredient, which tablets are characterized in that the macrolide is chosen from the group consisting of pristinamycin, azithromycin, roxithromycin, clarithromycin and spiramycin, and is present in base form, in proportions of between 20% and 60% of their total weight, and in that they comprise at least one disintegrant, in proportions of between 1% and 25% of their total weight, and at least one sweetener.
For the purposes of the present, the expression “dispersible tablets” is understood to mean tablets capable of completely disintegrating in less than 3 minutes when they are placed in a liquid such as water, and of thus leading to an oral suspension that can easily be made homogeneous by stirring it, for example, using a teaspoon. Such tablets may however be also swallowed directly with a quantity of liquid capable of facilitating their deglutition.
In spite of the absence of sugars and, in particular, of sucrose, the tablets in accordance with the invention surprisingly have a markedly more pleasant taste than that presented by the dispersible powders and granules provided up until now for the bitter macrolides, even when they contain high quantities of macrolide.
A more detailed explanation of the invention is provided in the following description and appended claims.
DETAILED DESCRIPTION OF THE INVENTION
A
Gimet René
Laruelle Claude
Toselli Dominique
Zakarian Noël
CCL Pharma
Page Thurman K.
Tolpin Thomas W.
Welsh & Katz Ltd.
Young Micah Paul
LandOfFree
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