Title:  Solid, rapidly disintegrating cetirizine formulations

United States Patent:  6,245,353

Assignee:  ASTA Medica AG (DE)

Filed:  March 26, 1999

Foreign Application Priority Data:  Mar 31, 1998[DE] (198 14 256)

The present invention relates to a solid, effervescent, rapidly dissolving dosage form for oral administration, of (a) cetirizine or a pharmaceutically acceptable salt thereof, (b) an effervescent base comprising (i) at least one of (1) an organic edible acid and (2) a salt thereof, (ii) at least one of an alkali metal and an alkaline earth metal carbonate and bicarbonate, and (c) optionally a pharmaceutically acceptable auxiliary ingredient.

BRIEF DESCRIPTION OF THE INVENTION

It is the object of the present invention to provide novel and therapeutically advantageous solid, rapidly disintegrating effervescent formulations of cetirizine.

The present invention is a solid, effervescent, rapidly dissolving dosage form for oral administration, of (a) cetirizine or a pharmaceutically acceptable salt thereof, (b) an effervescent base comprising at least one of (i) at least one of (1) an organic edible acid and (2) a salt thereof, (ii) at least one of an alkali metal and an alkaline earth metal carbonate and bicarbonate, and (c) optionally a pharmaceutically acceptable auxiliary ingredient.

The development of the present invention, of a solid, rapidly disintegrating cetirizine formulation was unexpected in view of the bitter taste of cetirizine. Our own investigations have shown, for example, that 10 mg of cetirizine, dissolved in 60 ml of water, has a bitter taste (FIG. 1). If the formulation according to the present invention is dissolved in the same amount of water, the solution has a pleasant taste and can be taken by the patient without any problems, thus considerably improving compliance.

A solution or suspension is formed by adding water to the soluble or dispersible tablets or soluble granules, with evolution of CO₂ gas. The resulting effervescent solution or suspension can be taken very easily, even by patients who have difficulties swallowing. Surprisingly, this solution already has a pleasant taste. This becomes evident particularly in the case of calcium-containing effervescent preparations in soluble form.

The rapidly disintegrating tablet can also be administered so that it directly disintegrates in the mouth. A rapid release of the active ingredient is of particular importance here, to ensure a rapid onset of action.

Effervescent agents capable of releasing CO₂ which are suitably employed in connection with the present invention include alkali metal carbonates or alkali metal bicarbonates, such as sodium carbonate or sodium bicarbonate. Agents for inducing CO₂ release which are suitably employed are edible organic acids, or their acidic salts, which are present in solid form and which can be formulated with the cetirizine active ingredient and the other auxiliary ingredients to provide granules or tablets, without premature evolution of CO₂. Edible organic acids which can be so used include for example, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, ascorbic acid, maleic acid or citric acid. Pharmaceutically acceptable acidic salts include, for example, salts of polybasic acids which are present in solid form and in which at least one acid function is still present, such as sodium dihydrogen or disodium hydrogen phosphate or monosodium or disodium citrate.

It has now been surprisingly found that the sole use of an effervescent system, in particular a system based on calcium, leads to a masking of the otherwise bitter taste of the active ingredient cetirizine.

No complicated coating of the individual crystals of the active ingredient for masking the bitter taste of cetirizine is necessary when using the present invention. Thus, it is possible, for the first time, to provide effervescent preparations of cetirizine, which is very effective for allergic disorders.

Cetirizine is an organic acid which can lead to stimulation of the H₂ receptors and consequently to an increase in the secretion of gastric juices. The buffer action of the effervescent formulation according to the invention can contribute to avoiding any side-effects.

The invention thus suitably provides effervescent cetirizine formulations having an effervescent base comprising (a) a mixture of calcium carbonate with an organic edible acid; (b) a mixture of calcium carbonate, sodium carbonate, sodium bicarbonate and an organic edible acid; or (c) a mixture of sodium bicarbonates, sodium carbonate and an organic edible acid.

The soluble or dispersible cetirizine tablet or the soluble granules comprises from about 5 mg to about 20 mg cetirizine and from about 50 mg to about 5000 mg, suitably from about 500 mg to about 3000 mg of an effervescent base.

The effervescent base suitably comprises from about 100 mg to about 500 mg calcium ions as calcium carbonate, and from about 20 mg to about 1500 mg citric acid and/or its salts. In a further suitable embodiment, the effervescent base comprises from about 50 mg to about 2000 mg sodium bicarbonate, from about 20 mg to about 200 mg of sodium carbonate and from about 20 mg to about 1500 mg citric acid and/or from about 20 mg to about 500 mg tartaric acid.

A further suitable composition of the effervescent base comprises from about 50 mg to about 500 mg sodium bicarbonate, from about 20 mg to about 100 mg sodium carbonate, and from about 50 mg to about 750 mg calcium carbonate and from about 100 mg to about 1500 mg of citric acid.

When dispersing the dispersible cetirizine tablet of the invention in water, there is also a formation of CO₂ which accelerates the disintegration of the tablet even to a greater extent. However, a reduced effervescent activity is observed here, compared to the soluble tablet.

The soluble/dispersible tablet can be prepared by known processes for preparing effervescent bases. In the segregated-bed process, the acidic components are granulated with a solution of, for example, citric acid in water or polyvinylpyrrolidone in water or alcohol. It is also possible to admix directly tablettable calcium carbonate for the calcium component. Sodium carbonate/bicarbonate and alkaline earth metal carbonate components can also be granulated separately. The other tabletting auxiliaries are incorporated homogeneously and the material is tabletted using an appropriate press.

However, it is also possible to obtain the appropriate product by other processes, such as alcoholic granulation of acidic and alkaline components with binder solutions, for example PVP or sugar alcohols. Other granulation processes, such as, for example, topogranulation can also be used.

The cetirizine formulations according to the present invention can additionally include aromas and sweeteners and also conventional pharmaceutical auxiliary ingredients, such as polyethylene glycol, sodium benzoate, adipic acid and silica.

Claim 1 of 16 Claims

We claim:

1. A solid, effervescent, rapidly dissolving dosage form for oral administration, which comprises

(a) cetirizine or a pharmaceutically acceptable salt thereof,

(b) an effervescent base comprising

(i) at least one of (1) an organic edible acid and (2) a salt thereof,

(ii) at least one of an alkali metal and an alkaline earth metal carbonate and bicarbonate, and

(c) optionally a pharmaceutically acceptable auxiliary ingredient.

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