Title:  Dispersible macrolide compounds and method for production thereof

United States Patent:  6,605,301

Issued:  August 12, 2003

Inventors:  Zakarian; Noel (Marseille, FR); Gimet; Rene (Valbonne, FR); Laruelle; Claude (Villeneuve-Loubet, FR); Toselli; Dominique (Nice, FR)

Assignee:  CCL Pharma (FR)

Appl. No.:  966669

Filed:  September 28, 2001

Abstract

The invention relates to dispersible tablets containing macrolides as active ingredients either on their own or associated with other active ingredients, in addition to a method for the production thereof. The dispersible tablets are characterized in that the macrolide is chosen from a group that is made up of pristinamycin, azithromycin, roxithromycin, clarithromycin and spiramycin, and is present in a basic form in proportions ranging from 20-60% of the total weight of said tablets. The dispersible tablets are also characterized in that they contain at least one disintegrator in proportions ranging from 1-25% of the total weight of said tablets in addition to at least one sweetening agent.

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 dispersible tablet and its composition and uses according to the preferred embodiments of the present invention will now be explained.

According to a first advantageous feature of the invention, the macrolide used is chosen from the group consisting of azithromycin, roxithromycin and clarithromycin.

The disintegrant is the agent which allows the tablets to disintegrate completely in the presence of a liquid, this being in a relatively short time since less than 3 minutes, and the active ingredient(s) to be released into this liquid; its choice is therefore particularly important.

Accordingly, according to another advantageous feature of the invention, the disintegrant is chosen from the group consisting of polyvinylpyrrolidone, croscarmellose sodium and mixtures thereof.

According to a particularly preferred feature of the invention, polyvinylpyrrolidone is used in proportions of between 1% and 16% of the total weight of the tablets, or croscarmellose sodium in proportions of between 1% and 15% of the total weight of the tablets or alternatively the mixture of both in a ratio of between 1:1 and 4:1.

According to yet another advantageous feature of the invention, the sweetener is chosen from the group consisting of aspartame, saccharin sodium, acesulfame potassium, ammonium glycerinate and mixtures thereof.

According to a preferred embodiment of the invention, a mixture of two sweeteners is used in a ratio of between 1:1 and 2:1, said mixture representing, by weight, between 1 and 20% of the total weight of the tablets.

According to another preferred embodiment of the invention, the macrolide is combined with a nitroimidazole derivative. By way of examples of such derivatives there may be mentioned metronidazole, tinidazole or ornidazole.

In this case, the macrolide is preferably spiramycin while the nitroimidazole derivative is preferably metronidazole.

In addition to a macrolide, a disintegrant and a sweetener, the tablets according to the invention contain other excipients, in proportions which are chosen according to the physicochemical properties of the macrolide which they contain.

These excipients are chosen from the group consisting of diluents, surfactants, lubricants and glidants.

The tablets contain, in addition, at least one flavoring which contributes to give them a taste which is acceptable to the patient.

The diluents facilitate the compressing operations necessary for producing tablets and give sufficient hardness to the latter.

According to the invention, the diluent(s) may be chosen in particular from the group consisting of microcrystalline cellulose, lactose, hydroxypropyl methyl cellulose (HPC) and pregelatinized starch. Preferably, microcrystalline cellulose is used in proportions of between 5% and 50% of the total weight of the tablets.

The tablets according to the invention also contain one or more surfactants, for example polysorbates or sodium lauryl sulfate, in proportions of between 0.1% and 3% of their total weight.

They also contain one or more lubricants such as magnesium stearate and calcium stearate. These lubricants, whose role is to reduce friction during the compressing operations, are advantageously present in proportions of between 0.5 and 5% of the total weight of the tablet.

Among the glidants which can be included in the tablets according to the invention, there may be mentioned in particular colloidal silica, talc, stearic acid and magnesium stearate; these glidants, which prevent the components of the tablets from forming aggregates during the preparation of these tablets and which also reduce friction during the compressing operations, are present of proportions of between 0.1% and 3% of the total weight of the tablets.

The flavoring(s) are chosen according to the age of the patients (adults or children) for whom the tablets are intended and are present in proportions of between 0.5% and 15% of the total weight of these tablets.

Among the flavorings which can be used, there may be mentioned mint, chocolate, caramel, vanilla, strawberry and licorice flavors and mixtures thereof.

The mint and vanilla/caramel flavors are particularly preferred. The mint flavor is generally present in proportions of between 1% and 7% of the total weight of the tablets, while the vanilla/caramel flavor is, for its part, present in proportions of between 1% and 10% of the total weight of said tablets.

The dispersible tablets according to the invention offer the following advantages:

ease of use in ambulatory treatment,

accuracy of the unit dosage,

ease of dispersion in a liquid,

pleasant taste,

ease of deglutition in case of direct ingestion, that is to say without prior dispersion in a liquid,

absence of sugars and, in particular, of sucrose, making them particularly suitable for the treatment of diabetic patients.

The subject of the invention is also a method for preparing dispersible tablets as defined above, which method is characterized in that it comprises:

the mixing of the active ingredient(s) with 30% to 60% of the quantity of disintegrant(s) intended to be present in the tablets,

the wet granulation of the resulting mixture in the presence of a wetting liquid containing water and at least one surfactant,

the drying of the granules thus obtained,

the dry addition of the remaining 40 to 70% of the disintegrant(s), of the sweetener or sweeteners, of the diluent(s), lubricants, glidants and flavoring(s), and

the compression of the resulting mixture.

Claim 1 of 16 Claims

What is claimed is:

1. A dispersible tablet containing a macrolide as active ingredient, alone or in combination with another active ingredient, characterized in that the macrolide is not coated, is present in base form and is chosen from the group consisting of pristinamycin, azithromycin and clarithromycin, in proportions of between 20% and 60% of the total weight of the tablet; roxithromycin in proportions of between 15% and 60% of the total weight of the tablet and spiramycin in proportions of between 19% and 60% of the total weight of the tablet; and in that it comprises, as disintegrant, a mixture of polyvinylpyrrolidone and croscarmelose sodium in proportions of between 1% and 25% of the total weight of said tablet, and at least one sweetener.

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