Title:  Pharmaceutical compositions containing an effervescent acid-base couple

United States Patent:  6,667,056

Issued:  December 23, 2003

Inventors:  Chiesi; Paolo (Parma, IT); Ventura; Paolo (Parma, IT); Mezzadri; Rosa (Parma, IT); Brambilla; Gaetano (Parma, IT); Acerbi; Daniela (Parma, IT)

Assignee:  Chiesi Farmaceutici S.p.A. (Parma, IT)

Appl. No.:  932097

Filed:  August 20, 2001

Abstract

A pharmaceutical formulation in the form of a fast dissolving tablet comprising an active ingredient, sodium glycine carbonate and an acid capable of reacting rapidly with sodium glycine carbonate to release carbon dioxide.

BRIEF SUMMARY OF THE INVENTION

Now it has been found, and this is an object of the present invention, that effervescent tablets can be prepared through simple techniques which have direct-industrial application and which are based on the use of a particular effervescent blend of acids and sodium glycine carbonate, provided in a sufficient amount to rapidly disperse and assist dissolution of the components of the formulation.

In particular, according to a second aspect of the invention, it was found that the use of a blend of certain acids with sodium glycine carbonate allows to prepare effervescent tablets by direct compression in normal thermohygrometric conditions and with standard tabletting equipment.

It has been even more surprisingly found that this technology applies also to active ingredients and/or excipients which cannot be wet-granulated or which contain a residual percentage of hardly eliminable crystallisation water.

According to a further aspect of the invention, it was found that the use of certain acids/sodium glycine carbonate blend is particularly advantageous in the preparation of effervescent tablets which contain a cyclodextrin as the component of an inclusion complex or as an excipient, despite of the fact that cyclodextrins have hydration water and tend to absorb moisture very easily.

DESCRIPTION OF RELATED ART

The characteristics of excipients which can be used in the preparation of effervescent tablets, have been described in Aiache J M, Pharm Acta Helv 49 (5/6), 169-178, 1974 and in Boymond C, Labo-Pharma Probl Tech 25(271), 987-995, 1977.

Anyway, Faguet J P et al. in Labo-Pharma Probl Tech 26(274), 207-210, 1978, after evaluating the effects of moisture on the stability of acids, carbonates and bicarbonates, conclude that when sodium glycine carbonate, which is per se moisture--sensitive, is blended with an acid, specifically citric acid, the resulting carbonate is very moisture--unstable, much more than sodium glycine carbonate alone.

In some patents, sodium glycine carbonate is simply mentioned, among various different excipients, as a possible component of effervescent combinations which can be used in chewable tablets (EP 396335), in formulations which form a suspension when contacted with water (EP 528846), in compositions constituted by separated acidic and alkali granules which can also comprise a moisture scavenger (ZA 9307745), in oral, cold-water soluble formulations of JS-cyclodextrin complexes with non steroidal anti inflammatory drugs like ibuprofen, naproxen or ketoprofen (WO 9504528).

However, none of the above documents teaches the preparation of effervescent tablets using sodium-glycine carbonate as the basic component, nor suggests the possible advantages thereof.

The use of sodium glycine carbonate in effervescent formulations is described in patent applications and scientific literature regarding formulations containing hydrated amoxycillin (PCT WO 9115197), isosorbide-5-mononitrate (DE 4416769) and enzymes (FR 2305194). The acidic component in these formulations is constituted of citric, tartaric, malic or adipic acid and the manufacturing process foresees steps of slugging, milling slugs, blending and compressing or the use of anhydrous excipients or, also, an external lubrication of the machine is performed.

Amela J. et al in the paper "Drug Dev Ind Pharm 22(5), 407-16, 1996" make the analysis of various components which can be used in the preparation of effervescent tablets and they conclude that sodium glycine carbonate is one of the carbonates which do not have favourable compressing characteristics.

The formulations of the invention essentially comprise:

an active ingredient;

sodium glycine carbonate;

an acid capable to react rapidly with sodium glycine carbonate to release carbon dioxide.

One of the preferred acids is fumaric acid which may be present in the form of salt such as mono sodium or potassium fumarate. Certain kinds of formulation take advantage by the lubricant properties of fumaric acid allowing to limit the quantity of lubricant.

Another preferred acid is maleic acid eventually present as a salt.

The choice of the acid is made according to the characteristics of the active ingredient. In some cases mixtures of acids and/or salts are particularly suitable to modulate either the strength of the acid or the lubricant properties.

The use of fumaric acid in effervescent formulations is described in several documents which refer to various formulations, but never in combination with sodium glycine carbonate.

EP 443381, FR 2715849, WO 9300886, WO 9107174, WO 9104757 are examples of patent literature which mention fumaric acid among other acids which are commonly used in the effervescent pharmaceutical forms such as U.S. Pat. Nos. 4,153,678, 4,812,303 and 4,704,269, referred to formulations of particular active ingredients. In other documents (among which for example GB 1178294, Roscheisen G. and Schmidt P C Eur J. Pharm. Biopharm 41(5), 302-308, 1995), fumaric acid is considered as a lubricant.

Maleic acid has been also described as an acidic component of effervescent couples but never in combination with sodium glycine carbonate.

DETAILED DESCRIPTION OF THE INVENTION

In a particular embodiment of the invention the active ingredient of the formulation contains residual percentage of moisture or of crystallization water hardly eliminable. Examples of this kind of active ingredients are complexes of drugs such as the piroxicam-.beta.-cyclodextrin complex, levodopa methyl ester and carbidopa hydrate.

The piroxicam-.beta.-cyclodextrin complex has been described in EP 153998, wherein also an effervescent tablet formulation is exemplified. In this case citric acid-sodium glycine carbonate represented the effervescent blend. However, tablets corresponding to the formulation exemplified in EP 153998, have unfavourable characteristics like the opacity of the produced solution, high dimension and weight and low flowability of the pondered blend to be compressed. Moreover, the presence of saccharose as diluent, and of sweetening agents, compromises the stability of the same formulation, as it has been afterwards ascertained.

The formulation may comprise other excipients like:

a lubricant selected from PEG higher than 4000 and preferably PEG 6000 sodium benzoate, sodium and potassium fumarate, leucine, alanine;

a sweetening agent selected from aspartame, saccharin, cyclamate, sugars, preferably aspartame;

a diluent selected from lactose, mannitol, sorbitol or mixtures thereof and preferably spray-dried (SD) lactose and optionally aromatizing agents, ligands, preservatives or others.

As a diluent SD lactose is particularly preferred in that it facilitates the blend flowability so improving compressibility and machinability of the formulation.

The particular effervescent blend of the invention, together with the above-mentioned additives, allows highly soluble, stable and small-sized effervescent tablets to be prepared by direct compressing the component mixture which can be worked at the standard thermo-hygrometric conditions of normal pharmaceutical production facilities, using standard to compressing machines with normal punches and dies. Also the subsequent processing, storage and packaging of the tablets can be performed at normal temperature and moisture conditions.

The effervescent compositions of the invention solubilize on contact with water and produce a clear solution for oral administration. Solutions are favoured over suspensions for oral administration, since drugs in solution are more rapidly absorbed. Solutions are also often more acceptable to patients, in terms of palatability. Nevertheless in some cases the active ingredient does not dissolve and the composition does not result in a clear solution, but a suspension. For this kind of active ingredient the possibility to prepare a tablet by direct compression and obtain a rapid disintegration anyway represents a remarkable formulation improvement.

Other advantages of the composition are the low content of sodium ions, due to the employ of sodium glycine carbonate, with respect to other sodium carbonates and the less fizzy effervescence, more pleasant to the patient.

Moreover the composition of the invention, because of its small size, light effervescence and rapid disintegration, can also be prepared as fast dissolving or sucking in the mouth. In fact, as introduced in the mouth, when in contact with saliva, the tablet disintegrates and rapidly forms a solution or an aqueous dispersion easily swallowable.

The following examples further illustrate the invention.

EXAMPLE 1

Piroxicam-.beta.-cyclodextrin, lactose SD, sodium glycine carbonate, lemon flavour, aspartame and PEG 6000 are sieved and pre-mixed. Fumaric acid is added and the components are mixed until an homogeneous blend is obtained. Then the blend is compressed in a standard rotary tabletting machine equipped with round chromium plated punches. The process is carried out at room temperature and with a relative humidity not higher than 55-60%. The dimensions of the produced tablets are about 13 mm diameter, 5 mm thickness and the weight is about 900 mg.

EXAMPLE 2

Active ingredient solution test

The analysis of the tablets prepared according to the example 1 was carried out in order to determine the percentage of the dissolved active ingredient at the end of the effervescence. The maximum dissolution time with effervescence is 1.5 min. The experimental conditions simulated the intake of the effervescent tablets by the patient.

The effervescent tablet was dissolved in three kinds of water. At the end of the effervescence (1.5 min) the amount of piroxicam-.beta.-cyclodextrin was determined in the solution. The data obtained, which are reported in table 1, demonstrate that the active ingredient concentration in the solution is always higher than 70% of the nominal content per tablet.

EXAMPLE 3

Dissolution rate of effervescent tablets containing the piroxicam-.beta.-cyclodextrin complex in comparison with standard tablets. The dissolution rate of effervescent tablets prepared in Example 1 was compared with that of standard piroxicam-.beta.-cyclodextrin tablets using USP Apparatus 2 (paddles) in distilled water at a temperature of 37^oC.

EXAMPLE 4

The oral absorption profile of piroxicam released from effervescent tablets of piroxicam-.beta.-cyclodextrin complex (B-CD) prepared according to the present invention was compared to that of piroxicam-.beta.CD commercially available standard tablets. The test was carried out after single oral dose administration of the two formulations, equivalent to 20 mg piroxicam, in sixteen healthy volunteers according to a randomized two--way crossover design.

The results, reported in table 2, confirmed the behaviour of the two compositions in the dissolution test showing a more rapid absorption of the active ingredient after administration of the effervescent formulation of the invention. Compared to the standard formulation, the effervescent tablet gives remarkably higher plasma concentrations (Cp of 1.93 .mu.g/ml vs 0.77 .mu.g/ml, respectively) 15 min after the administration, as well as a higher drug exposure during the first hour after the administration, as it is shown by the AUC data (AUC=Area Under the Curve, i.e. the area under the plasma concentration vs time curve) collected after 1 hour.

Claim 1 of 13 Claims

What is claimed:

1. A pharmaceutical composition in form of effervescent or fast-dissolving tablet of a water-soluble blend comprising an active ingredient and an effervescent couple, the couple comprising an acidic component and an alkaline component, wherein the active ingredient is selected from the group consisting of piroxicam-.beta.-cyclodextrin complex, ambroxol hydrochloride, piroxicam combined with a cyclodextrin as an excipient, and apomorphine hydrochloride, the acidic component is selected from the group consisting of fumaric acid, maleic acid and their salts and the alkaline component is sodium glycine carbonate.

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