HK1036217B - Solid, quick dissolving cetirizine formulations - Google Patents

Description

Solid, rapidly disintegrating cetirizine formulations

The present invention relates to solid, rapidly disintegrating effervescent formulations of cetirizine in the form of soluble tablets, dispersible tablets or soluble granules.

EP 058146 describes that cetirizine is a 4- (diphenylmethyl) piperazino alkoxyacetic acid derivative with antiallergic and antispasmodic effects. EP 294993, WO 92/02212 and EP 357369 claim cetirizine formulations in the form of tablets and capsules for achieving controlled or continuous release of cetirizine. WO 94/08551 discloses oral or nasal formulations, for example in the form of cough syrups.

EP 605203 describes cetirizine solutions for ophthalmic and intranasal administration. Oral administration forms coated with at least one layer of a volatile flavour, for example menthol (WO 94/25009) and freeze-dried forms with a taste-masked matrix (EP636365) can also be found in the patent literature.

EP 548356 claims multiparticulate tablets having a disintegration rate in the oral cavity or on the tongue of less than 60 seconds, which tablets contain the active ingredient in the form of coated microcrystals or microgranules, in particular for taste masking.

WO 95/07070 discloses effervescent granules based on calcium carbonate and citric acid for the preparation of pharmaceutical preparations, wherein 5 to 20 parts by weight of citric acid are replaced by at least one other edible acid, such as malic acid.

EP636364 describes a very rapidly dissolving dosage form consisting of active ingredient particles coated with a taste-masking substance, a water-soluble, bindable carbohydrate and a binder. After oral administration, the tablet disintegrates in the mouth within 30 seconds, so that the coated active ingredient particles can be swallowed by the patient before the active ingredient is released. The carbohydrate used is, for example, mannitol, glucose or lactose, and the taste-masking substance used is, for example, cellulose acetate or hydroxypropylmethylcellulose.

EP 525388 claims lozenges or chewable tablets consisting essentially of a tertiary edible organic acid, in particular the dibasic alkali metal and/or alkaline earth metal salt of citric acid, and preferably an edible organic acid which reacts only partially to alkali metal and/or alkaline earth metal salt, in particular malic acid, and further auxiliaries. Thus, the aftertaste of the hitherto known lozenges or chewable tablets is avoided. In particular, the lime taste prevention effect of pastilles or chewable tablets containing inorganic substances is described. However, no reduction in bitterness was observed.

The active ingredient cetirizine hydrochloride has a very bitter taste and is not particularly suitable for rapidly disintegrating solid preparations. Thus, cetirizine effervescent formulations are also unknown in the prior art.

However, for various reasons, there is a need to introduce effervescent pharmaceutical formulations on the market, in particular in the form of soluble and dispersible tablets based on a calcium-containing matrix. On the one hand, especially the elderly may face problems when taking tablets, and on the other hand, there are many patients who have difficulty swallowing.

Certain rapidly disintegrating effervescent formulations additionally have the advantage of being convenient to administer on the way, without the need for fluid intake.

The simultaneous intake of inorganic calcium with antihistamines is highly advantageous in the treatment of allergies.

Masking the bitter taste of cetirizine leads to particular problems. Thus, aqueous solutions of cetirizine hydrochloride have an unpleasant bitter taste. The preparation process becomes more complicated by the addition of suitable taste-masking substances, as described for example in EP636364 or US 5178878. In addition, the dispersibility of the microencapsulated active ingredient is also significantly reduced. A further disadvantage is that, in addition to the actual active ingredient, a large number of auxiliaries are required in the preparation of such a formulation.

Heretofore, film-coated tablets and oral liquids have been marketed. Here, the film layer serves to mask the bitter taste. The solution contained a large amount of sorbitol (450mg sorbitol per 1mg cetirizine).

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

This object is achieved by the present invention which provides a solid, rapidly disintegrating effervescent formulation for oral administration comprising cetirizine or a pharmaceutically acceptable salt thereof and an effervescent base comprising at least one organic food acid and/or salt thereof, an alkali metal and/or alkaline earth metal carbonate or bicarbonate, and where appropriate pharmaceutically acceptable auxiliaries.

By adding water to the soluble or dispersible tablets or soluble granules according to the invention, with CO₂The evolution of gas to form a solution or suspension is extremely easy to administer, even to dysphagia patients.

Surprisingly, the solution already had a pleasant taste. This is particularly the case in the case of calcium-containing effervescent preparations in soluble form.

Rapidly disintegrating tablets may also be administered directly by disintegration in the mouth.

Here, a rapid release of the active ingredient is of particular importance to ensure a rapid onset of action.

Effervescent formulations of various active ingredients and vitamins are known in the art. These effervescent formulations generally comprise a substance capable of releasing CO₂And an agent for inducing CO₂The released agent. Preference is given to using a catalyst which releases CO₂The reagent (b) is an alkali metal carbonate or alkali metal bicarbonate, such as sodium carbonate or sodium bicarbonate. For inducing CO₂The releasing agent is edible organic acid or its acid salt, which exists in solid form and can be formulated into granule or tablet with active ingredient and other adjuvants without releasing CO prematurely₂. Possible edible organic acids are, for example, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, ascorbic acid, maleic acid or citric acid, preferably citric acid.

Pharmaceutically acceptable acid salts are, for example, salts of polyacids which are present in solid form, wherein at least one acid function is also present, for example monosodium or disodium phosphate, or monosodium or disodium citrate.

Surprisingly, it has now been found that the taste of the active ingredient cetirizine can be masked by the use of effervescent systems alone, in particular calcium-based systems.

Said complex coating of the individual crystals of the active ingredient for masking the bitter taste of cetirizine is therefore not necessary. Thus, for the first time, effervescent formulations of cetirizine are provided, the active ingredient being very effective against allergic conditions.

It would not be obvious to one skilled in the art to develop such a solid, rapidly disintegrating cetirizine formulation, since the bitter taste of cetirizine is rather discouraging. Our own studies have shown that, for example, 10mg of cetirizine dissolved in 60ml of water has a bitter taste (fig. 1). If the formulation according to the invention is dissolved in an equal amount of water, the solution has a pleasant taste and is taken by the patient without any problems, thus significantly improving acceptability.

Cetirizine is an organic acid in chemical structure and can stimulate the H2 receptor, thereby increasing gastric secretion. The buffering action of the effervescent formulations according to the invention may help to avoid the resulting side effects.

The present invention preferably provides a cetirizine effervescent formulation having an effervescent base comprising:

a) a mixture of calcium carbonate and an organic edible acid,

b) calcium carbonate, sodium bicarbonate and organic edible acid,

c) sodium bicarbonate, sodium carbonate and organic edible acid.

The cetirizine soluble or dispersible tablet or soluble granule comprises from 5mg to 20mg of cetirizine and from 50 to 5000mg, preferably 500-3000mg of effervescent base.

The effervescent base preferably comprises 100-500mg of calcium ions in the form of calcium carbonate and 20-1500mg of citric acid and/or its salts. In a further preferred embodiment, the effervescent base comprises 50-2000mg of sodium bicarbonate, 20-200mg of sodium carbonate and 20-1500mg of citric acid and/or 20-500mg of tartaric acid. A further preferred effervescent base composition comprises 50-500mg sodium bicarbonate, 20-100mg sodium carbonate, 50-750mg calcium carbonate and 100-1500mg citric acid.

When dispersible cetirizine tablets according to the invention are dispersed, CO is likewise produced₂，CO₂Which in turn promotes the disintegration of the tablet. However, a reduction in effervescent activity is observed here compared to soluble tablets.

Soluble/dispersible tablets may be prepared according to known methods for preparing effervescent matrices. In the separated bed process, the acidic component is granulated, for example, with aqueous citric acid solutions, solutions of polyvinylpyrrolidone in water or ethanol. It is also possible for the calcium component to be mixed directly with the calcium carbonate which can be tabletted. The sodium carbonate/bicarbonate and alkaline earth metal carbonate components may also be granulated separately. Other tabletting aids are added uniformly, and the material is tabletted with proper pressure. However, it is also possible to obtain suitable products according to other methods, such as ethanol granulation of the acidic and basic components with binder solutions such as PVP or sugar alcohols. Other granulation methods, such as topical granulation (Topogranulation), have also been described over and over again.

The cetirizine formulation according to the present invention may additionally contain flavors and sweeteners, as well as known pharmaceutical adjuvants, such as polyethylene glycol, sodium benzoate, adipic acid and silicon dioxide.

The formulations according to the invention are illustrated in detail by way of examples, which do not limit the invention.Example 1mg effervescent tablet cetirizine HCl 10 effervescent base 890 mannitol FG 60Pharmatose DCL 2170 mint flavor10

1040The effervescent base comprises: citric acid 558.5 sodium bicarbonate 200 sodium carbonate 100 sodium citrate 0.5 ascorbic acid 25 sodium saccharin6

890 Example 2Soluble tablet of cetirizine 10 sodium bicarbonate 200 citric acid 443 ascorbic acid 25 sodium carbonate 100 saccharin sodium 6 mannitol 60 lactose70

914 Example 3mg soluble granule cetirizine 10 sodium bicarbonate 200 citric acid 730 calcium carbonate 230 ascorbic acid 25 sodium carbonate 50 saccharin sodium 4 mannitol 60 lactose70

1379 Example 4Soluble tablet of cetirizine 5 sodium bicarbonate mg200 tartaric acid 454 sodium carbonate 100 saccharin sodium 6 mannitol 100 lactose40

905 Example 5mg soluble tablet cetirizine 10 sodium bicarbonate 186 citric acid 491 calcium carbonate 130 aspartame 6 sodium carbonate 35 mannitol120

978 Example 6mg soluble granule cetirizine 10 calcium carbonate 750 citric acid 805 microcrystalline cellulose 42 mannitol 625 maltodextrin 15 aspartame 3 flavor 20

2270 Example 7mg dispersible tablet cetirizine 5 calcium carbonate 500 polyvinylpyrrolidone 20 citric acid 270 microcrystalline cellulose 20 maltodextrin 18 xylitol 500 aspartame 2 saccharin sodium 1 flavor 15 corn starch60

1411 Example 8mg dispersible tablet cetirizine 10 calcium carbonate 500 polyvinylpyrrolidone 17 citric acid 160 microcrystalline cellulose 15 mannitol 430 maltodextrin 18 aspartame 2 flavor 15

1167 Example 9mg dispersible tablet cetirizine 10 calcium carbonate 300 citric acid 32 microcrystalline cellulose 17 mannitol 250 maltodextrin 6 aspartame 1 hydrogenated castor oil 21 flavor8

645 Example 10mg chewable dispersible tablet cetirizine 5 calcium carbonate 750 ethylcellulose 37A highly dispersed silica gel (Aerosil) 100 mannitol 1130 citric acid 123 maltodextrin 23 microcrystalline cellulose 87 aspartame 5 mint flavor 8 Citrus flavor70

2338 Example 11mg chewable dispersible tablet cetirizine 10 calcium carbonate 750 ethylcellulose 37A highly dispersed silica gel (Aerosil) 100 mannitol 1130 citric acid 123 maltodextrin 23 microcrystalline cellulose 87 aspartame 5 mint flavor 8 Citrus flavor70

2343 Example 12mg chewable dispersible tablet cetirizine 5 calcium carbonate 750 gastric soluble acrylic resin E (Eudragit E) 37A highly dispersed silica gel (Aerosil) 100 mannitol 1130 citric acid 123 maltodextrin 23 microcrystalline cellulose 87 Aspartame 5 mint flavor 8 Citrus flavor 8 orange flavor 70

2338 Example 13mg chewable dispersible tablet cetirizine 10 calcium carbonate 750 ethylcellulose 37A highly dispersed silica gel (Aerosil) 100 mannitol 1130 citric acid 123 maltodextrin 23 microcrystalline cellulose 87 aspartame 5 mint flavor 8 Citrus flavor70

2343

Claims (14)

1. Solid, rapidly disintegrating effervescent preparation for oral administration, comprising cetirizine or a pharmaceutically acceptable salt thereof, an effervescent base consisting of at least one organic food acid and/or salt thereof, sodium and/or calcium carbonate or bicarbonate, and where appropriate pharmaceutically acceptable auxiliaries.

2. An effervescent formulation according to claim 1 in the form of a soluble tablet, dispersible tablet or soluble granules.

3. An effervescent formulation according to claim 1 or 2 comprising from 5mg to 20mg cetirizine or a pharmaceutically effective salt thereof and from 50 to 5000mg effervescent base.

4. An effervescent formulation as claimed in claim 3, comprising from 5mg to 20mg cetirizine or a pharmaceutically effective salt thereof and 500-3000mg effervescent base.

5. Effervescent preparation according to claim 1 or 2, characterized in that the effervescent base consists of a mixture of sodium bicarbonate, sodium carbonate and an organic food acid.

6. Effervescent preparation according to claim 5, characterized in that the effervescent base consists of 50-2000mg of sodium bicarbonate, 20-200mg of sodium carbonate and 20-1500mg of citric acid and/or 20-500mg of tartaric acid.

7. An effervescent formulation according to claim 1 or 2 characterised in that the effervescent base comprises a mixture of calcium carbonate and an organic food acid.

8. Effervescent preparation according to claim 7, characterized in that the effervescent base comprises 100-500mg of calcium ions in the form of calcium carbonate and 20-1500mg of citric acid and/or its salts.

9. Effervescent preparation according to claim 1 or 2, characterized in that the effervescent base consists of calcium carbonate, sodium bicarbonate, a mixture of sodium carbonate and an organic food acid.

10. Effervescent preparation according to claim 9, characterized in that the effervescent base comprises 50 to 500mg of sodium bicarbonate, 20 to 100mg of sodium carbonate, 50 to 750mg of calcium carbonate and 100 to 1500mg of citric acid and/or salts thereof.

11. Effervescent preparation according to claim 1, characterized in that the organic food acid used is tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, ascorbic acid, maleic acid or citric acid.

12. Effervescent preparation according to claim 11, characterized in that the organic food acid used is citric acid.

13. Effervescent preparation according to claim 1, characterized in that the preparation can additionally comprise flavors and sweeteners as well as known pharmaceutical auxiliaries.

14. An effervescent formulation according to claim 13 characterised in that the pharmaceutical adjuvants are polyethylene glycol, sodium benzoate, adipic acid, silicon dioxide.