WO2000038649A1 - Pharmaceutical composition for oral administration designed to prevent misuse at the expense of a third party - Google Patents

Abstract

The invention concerns a pharmaceutical composition for oral administration to prevent misuse at the expense of a third party.

Description

PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION TO AVOID MISUSE OF THIRD PARTY AT THE COST OF A THIRD PARTY

The present invention relates to a pharmaceutical composition for oral administration, intended to avoid the misuse of use at the expense of a third party.

The active ingredients which can be included in the pharmaceutical compositions according to the present invention belong to the therapeutic classes exposed to the risk of misuse. As such, the following classes of active principles may be mentioned: analgesics, anxiolytics or hypnotics.

Mention may therefore be made, among the analgesics, of methadone, among the weak opioid analgesics codeine and its derivatives, dextropropoxyphene, tramadol, among the mixed opioid analgesics the morphine agonists / antagonists such as buprenorphine or pentazocine, morphine and morphinomimetics such as phethidine, dextromoramide, oxycodone, fentanyl and tamgesic.

Among the anxiolytic compounds, mention may be made of diazepam, medazepam, oxazepam, lorazepam, benzodiazepines, eprobamate, ydroxyzine, buspirone.

Mention may also be made of the phenergan antihistamine, digitalis such as digoxin and digitalis and the anti-vitamin K coumarin.

Hypnotic compounds can belong to all therapeutic classes, whether short or long acting, for example: - compounds of the benzodiazepine class recognized for their hypnotic activity such as triazolam, loprazolam, nitrazepam, lormetazepam, temazepam, estazolam, flunitrazepam, brotizolam, cinolazepam, haloxazolam, doxefazepam and their pharmacologically acceptable salts, for example loprazolam mesilate, - zopiclone and in particular (R) -zopiclone of the therapeutic class cyclopyrrolones,

- the zaleplon of the pyrazolopyrimidines therapeutic class,

- Zolpidem and its pharmaceutically acceptable salts, from the imidazopyridines therapeutic class. One of the particularly preferred zolpidem salts is zolpidem hemitartrate.

The object of the present invention is to provide a pharmaceutical composition intended for oral administration, comprising an active principle exposed to the risk of misuse or a pharmaceutically acceptable salt thereof, capable of both:

- produce a release of the active ingredient after regular oral administration,

- And, if it is introduced into a possibly alcoholic drink, to generate visual means in contact with the latter. These visual means then make it possible to prevent said drink from being administered to a person, without their knowledge.

The pharmaceutical compositions according to the present invention are of acceptable size for conventional oral administration. Thus, compositions with a weight of less than 800 mg will be preferred.

Preferred within the scope of the present invention are the immediate-release pharmaceutical compositions. These compositions according to the present invention can be in the form of a conventional tablet (monolayer), of a multilayer tablet, in particular of 2 or 3 layers or also in the form of conventional capsules (containing powder) or comprising microgranules or sachets comprising powder or granules. In the case of a three-layer tablet, two of the layers may contain two different active ingredients independently of each other.

In the context of the present invention, the term “visual means” means any element indicating the presence of the composition according to the invention in an aqueous alcoholic beverage which may be alcoholic and which may take the form, for example, of a dye, a flotation of the composition on the surface of the drink, of a formation of insoluble particles on the surface of the drink, on the edges of the container, in the drink and on the bottom of the container. The optionally alcoholic aqueous beverage may in particular consist of coffee, tea, wine, spirits, hot or cold chocolate drinks, hot or cold milk, any soda such as Coca Cola ®, any carbonated alcoholic drink or not, any cocktail or liquid mixture based on fruit juice, milk or cream, alcohols ...

More particularly, the present invention is a pharmaceutical composition comprising an active principle exposed to the risk of misuse or one of its salts, characterized in that it is in the form of a tablet intended for administration by the oral and endowed with means. visuals which are put in place after introduction into an optionally alcoholic beverage, consisting either in the flotation of the tablet, or in the formation of insoluble particles or in a combination of these two visual means.

The buoyancy of the tablet can be ensured by an effervescence which can be obtained by means of an effervescence generator, as described below. In addition to this effervescence, the tablet may have viscosity properties appearing in contact with any drink. This last characteristic allows trapping of the gas produced by the effervescence which also results in swelling of the tablet. The drop in density generated then makes it possible to maintain the tablet on the surface of the drink. Such viscosity can be obtained by one or more gelling compounds. Typically, in the context of the present invention, the viscosity, measured according to the method described in point 3.3 of Example 3 can vary from 1500 to 6000 mPa.s.

A list is given below of hydrophilic excipients which are suitable as a gelable compound.

The particles can be obtained by the combination of a lipophilic excipient with a hydrophilic excipient useful for flotation, as described above. A list of suitable lipophilic excipients is given below.

The tablet may release visible insoluble particles even if the tablet does not float or does not immediately float.

A preferred embodiment of the invention is therefore a pharmaceutical composition comprising an active principle exposed to misuse or a salt thereof, characterized in that it is in the form of a tablet intended for administration orally, capable of floating and forming particles insoluble in any liquid into which it is introduced and containing one or more generators of effervescence and one or more gelling compounds.

The effervescence generator can be in the form of an effervescent couple, consisting of a carbon dioxide generating agent and a pharmaceutically acceptable acid compound.

The carbon dioxide generating agent is usually a carbonate or bicarbonate of an alkali metal, an alkaline earth or an amino acid. Mention may be made, for example, as carbon dioxide generating agent, calcium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate, L-lysine carbonate, arginine carbonate or sodium sesquicarbonate. The pharmaceutically acceptable acid compound is an acid anhydride, a monocarboxylic acid, a polycarboxylic acid or a partial salt of polycarboxylic acid. The pharmaceutically acceptable acid compound can be chosen more particularly from citric acid, tartaric acid, ascorbic acid, fumaric acid, nicotinic acid, acetylsalicylic acid, malic acid, adipic acid. , succinic acid, glutaric anhydride, citric anhydride, maleic acid, malonic acid, monosodium citrate and succinic anhydride.

The carbon dioxide generating agent can consist of a mixture of several carbon dioxide generating agents mentioned above.

In the effervescence generator, the acid compound content is generally chosen so that the ratio between the number of moles in acid compound and the number of moles in carbon dioxide generator is between 1 and 2.

The gelable compound can consist of one or more hydrophilic excipients causing the tablet to swell and trap the gas formed by the effervescence generator.

In order to ensure the formation of insoluble and visible particles on the surface of the drink and on the walls of the container, one or more lipophilic excipients are combined with the hydrophilic excipient.

The tablet, in the liquid or on its surface, disintegrates under the action of effervescence. During this disintegration we observe the formation of viscous agglomerates which float and stick to the walls of the container and are suspended in the liquid. This process ends with the end of the effervescence and can, for example, last from 0.5 to 25 minutes depending on the type of liquid or drink. When a pharmaceutical composition for oral administration, immediate release, according to the present invention contains both an effervescence generator and a gelable compound, another subsequent advantage of this composition lies in the improvement of the characteristics of absorption of the latter. In particular, a decrease in the interindividual variability of absorption can be observed compared to a conventional immediate release formulation. It is thus possible to obtain a regularization of the latency of appearance of the plasma concentrations, as well as a reduction in the variation of the plasma concentrations during the absorption phase.

Among the lipophilic excipients, mention may be made of glycerol stearates, palmitostearates and behenates; hydrogenated vegetable oils and their derivatives; vegetable and animal waxes and their derivatives; hydrogenated castor oils and their derivatives and cetyl esters and alcohols.

Among the hydrophilic excipients, mention may be made of cellulose derivatives, hydroxyethylcellulose, hydroxypropylcellulose (molecular weight from 50 to 1,250 kDa) hydroxypropylmethylcellulose (molecular weight from 10 to 1,500 kDa), carboxymethylcellulose and sodium carboxymethycellulose; vegetable gums and their derivatives; alginic acid derivatives; polyethylene glycols and their derivatives; starches and their derivatives; silicas and their derivatives; polymethacrylates and copolymers of acrylic and methacrylic acids.

At least one of the constituents of the gelable compound, either the hydrophilic excipient and / or the lipophilic excipient, can be chosen so as to be sparingly soluble in alcohol. Thus, the tablet, sparingly soluble in a liquid or an alcoholic drink of a degree greater than 45, slows down or even prevents the dissolution of the active principle and gives the liquid or the drink the appearance of a suspension of viscous insoluble particles. Finally, it is advantageous to add a colorant as an additional visual means preventing the misuse of use at the expense of a third party.

This dye can color the liquid or the particles or both simultaneously.

The coloring of the particles is particularly advantageous in the case where the drink into which the tablet is introduced is dark (such as coffee, Coca Cola® or cocktails).

Among the dyes which can be used in the tablet according to the invention, there may be mentioned indigotine, cochineal red, orange yellow S, allura red AC, iron oxides, Cucurmine, Riboflavin, Tartrazine, Quinoline yellow, Azorubine , Amarante, Carmins,

Erythrosine, Red 2G, Patented blue V, Bright blue FCF, Chlorophylls, Cupric complexes of chlorophylls, Green S, Caramels, Bright black BN, Vegetable carbon, Brown FK and HT, Carotenes, Annatto Extracts, Paprika Extracts, Lycopene, Lutein, Canthaxanthin, Beet red, Anthocyanins, Calcium carbonate, Titanium dioxide, Aluminum, Silver, Gold and Litholrubine BK or any other coloring suitable for consumption.

Other additives can advantageously supplement the composition of the tablet.

Thus, one can add a disintegrating agent such as sodium carboxymethyl starch (molecular mass from 500 to 1000 kDa), such as the product marketed by Avebe under the brand Primojel ^® or crosslinked polyvinylpyrrolidone or crospovidone, such as the product marketed by BASF under the brand Kolidon ^® CL.

Finally, the technical production of the tablets can also lead to the introduction of compression agents: - lubricating agents such as magnesium stearate, stearic acid, glycerol monostearate, polyoxyethylene glycols having a molecular weight of 400 to 7,000,000, hydrogenated castor oil, behenate glycerol, mono-, bi- or trisubstituted glycerides, - flow agents, such as colloidal silica or any other silica, for example the product sold by Degussa under the brand Aerosil ^, - binders such as starch, buffers , absorbents, diluents such as lactose and any other pharmaceutically acceptable additive.

A tablet according to the present invention can be obtained by any conventional compression technology known to a person skilled in the art by mixing powders and / or granulation using, for example, rotary presses.

Granulation can be carried out for example, according to a conventional technique, by mixing the various compounds to obtain a homogeneous powder, wetting with an alcoholic, aqueous or hydroalcoholic solution then drying until a percentage of residual moisture is obtained. predetermined, in a fluidized air bed, at temperatures between 25 and 80 ° C. The alcoholic solution can be based on polyvinylpyrrolidone (molecular mass from 28 to 1500 kDa) but also on hydropropylmethylcellulose or any other pharmaceutically acceptable binder.

A tablet can take a cylindrical, lenticular, spheroidal, ovoid or other form, which allows for easy administration and swallowing.

The mixture necessary for compression can also be obtained by dry granulation or direct mixing of the constituents.

To the tablet according to the invention, it is also possible to apply a coating intended for the protection of the active principle, in particular with regard to light.

This film may have a base made of a polymeric material such as ethylcellulose, 1 hydroxypropylcellulose or hydroxypropylmethylcellulose and an opacifying agent such as titanium dioxide. This film can also be supplemented with any plasticizer and / or lubricant such as polyoxyethylene glycol 400 and colored with a dye er / or in the form of a lacquer such as indigotine lacquer.

The amounts of active ingredient required are the same as those which are usually administered.

For example, the amount of zolpidem hemitartrate ranges from 3 to 10 mg.

A particular embodiment of this tablet is, for example, a bilayer tablet provided with combined visual means constituted by flotation and the formation of insoluble particles:

(1) the first layer, called, in the context of the present invention "active layer", comprising an active principle exposed to the risk of misuse or a salt thereof, associated with at least one hydrophilic excipient as well as an effervescence generator,

(2) the second layer, called, in the context of the present invention "tracer layer", comprising an effervescence generator and at least one gelable compound.

This particular embodiment is also advantageous for the reasons described above, namely the improvement in absorption characteristics and in particular the reduction in the interindividual variability of absorption compared to a conventional immediate release formulation. It is thus possible to obtain a regularization of the latency of appearance of the plasma concentrations, as well as a reduction in the variation of the plasma concentrations during the absorption phase. The hydrophilic excipient of the active layer can be chosen from thickening and / or gelling agents and / or binders as described above. Among the suitable hydrophilic excipients, mention may be made of cellulose derivatives and in particular carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and methylcellulose.

As the hydrophilic excipient of the active layer, sodium carboxymethylcellulose is preferred.

As the effervescent generator for the active layer, the effervescent couple composed of calcium carbonate and anhydrous citric acid is preferred.

The function of the tracer layer is to ensure flotation and the formation of insoluble particles making it possible to avoid any misuse of use at the expense of a third party. Thus, the tablet according to the present invention can not be dissolved in a glass of an alcoholic or non-alcoholic drink, without the person for whom the glass is intended to realize that the drink contains a foreign body.

The bilayer tablet, due to the presence in the tracer layer of an effervescence generator and of a gellable compound, floats on the surface of the drink into which it is introduced.

The flotation time depends on the alcoholic degree of the drink and its temperature. It varies from 30 seconds to 15 minutes. In the case of highly alcoholic beverages (40 to 45%), the delay can reach several minutes (5 to 25 minutes).

The same as those used for the active layer can be used as effervescence generators for the tracer layer. In the same tablet, the effervescence generator of the tracer layer may be identical to or different from that of the active layer. The combination of anhydrous citric acid and sodium bicarbonate, whose effervescence is rapid and highly visible.

The bilayer tablet may also advantageously contain a dye, examples of which have been given previously. This dye can be placed in the active layer or in the tracer layer or in the two layers at the same time. The two-layer tablets containing dye in the two layers are preferred in order to obtain both a coloration of the drink itself, but also a coloration of the insoluble particles. Thus, the coloration is visible on the surface of the drink during and after disintegration.

The active layer can have a thickness which varies from 1 to 4 mm, and preferably from 1.5 to 2.5 mm.

The tracer layer may have a thickness which varies from 1 to 4 mm, and preferably from 1.5 to 2.5 mm.

The bilayer tablet according to the invention comprises from 0.1 to 40% by weight, preferably from 1 to 5% of active principle when it is zolpidem, from 0.5 to 50% by weight, preferably from 2 to 10% of hydrophilic excipient as gelable compound in the active layer, from 5 to 70% by weight, preferably from 25 to 50% of effervescence generator in the active layer and from 5 to 70% by weight , preferably from 15 to 35% of effervescence generator in the tracer layer and, as gelling compound, from 2 to 20% by weight, preferably from 4 to 10% of hydrophilic excipient in the tracer layer and 1 to 20% by weight, preferably from 1 to 5% of lipophilic excipient in the tracer layer, the percentages being expressed relative to the total weight of the composition.

The following examples illustrate the present invention. EXAMPLE 1 Double-Layer Tablets Comprising a Tracer Layer and an Active Layer, Possibly Film

The tracer layer is obtained by direct mixing before compression, the active layer is obtained by alcoholic granulation.

Tracer layer

mg per% mass% compressed mass total layer

Hydroxypropylmethylcellulose 22.22 22.22 8.55

Glycerol behenate ² 5.60 5.60 2.15 Sodium bicarbonate 22.22 22.22 8.55 Calcium carbonate 5.00 5.00 1.92 Anhydrous citric acid 33.26 33.26 12.79

Indigotine or orange-yellow S 0.50 0.50 0.19 Polyvinylpyrrolidone ³ 4.50 4.50 1.73 Carboxymethyl starch sodium ⁴ 4.50 4.50 1.73 Anhydrous colloidal silica ⁵ 1.00 1.00 0.38 Magnesium stearate 1.20 1.20 0.46

100.00 100.00 38.46

¹ Methocel ^® K100 M Premium marketed by Colorcon

² Compritol ^® 888 ATO marketed by Gattefossé ³ Kolidon ^® CL marketed by BASF

⁴ Primojel ^® marketed by Avebe

⁵ Aérosil ^® 200 marketed by Degussa

active layer 1 (10 mg zolpidem hemitartrate)

mg per% mass% compressed mass total layer

Zolpidem hemitartrate 10.00 6.67 3.85 (zolpidem base) 8.04 5.36 3.09)

Carboxymethylcellulose

22.50 15.00 8.65 sodium ^λ

Calcium carbonate 51.00 34.00 19.62 Citric acid anhydrous 51.00 34.00 19.62

Lactose anhydrous 9.00 6.00 3.46

Carboxymethyl starch sodium ² 4.00 2.67 1.54

Indigotine 1.00 0.67 0.38

Magnesium stearate 1.50 1.00 0.58

150.00 100.00 57.69

¹ Blanose ^® 9M31F marketed by Aqualon

² Primojel ^®

active layer 2 (5 mg zolpidem hemitartrate)

unitary g. g. mg by mass mass tablet total layer

Zolpidem hemitartrate 5.00 3.33 1.92 (zolpidem base 4.02 2.68 1.55)

Carboxymethylcellulose

11.25 7.50 4.33 sodium

Calcium carbonate 51.00 34.00 19.62

Anhydrous citric acid 51.00 34.00 19.62

Lactose anhydrous 25.25 16.83 9.71

Carboxymethyl starch sodium 4.00 2.67 1.54

Indigotine 1.00 0.67 0.38

Magnesium stearate 1.50 1.00 0.58

150.00 100.00 57.69

film coating (optional) mg per% mass% compressed mass total layer

Hydroxypropylmethylcelulose 7.20 72.00 2.77 Titanium dioxide 2.10 21.00 0.81 Polyoxyethylene glycol 400 0.70 7.00 0.27

10.00 100.00 3.85

total film tablet 260.00 Example 2 Bi-Layer Tablets Consisting of a Tracer Layer and an Active Film Layer

Tracer layer

mg by mass mass compresses total layer

Hydroxypropylmethylcellulose ¹ 22.22 22.22 8.71

Glycerol behenate ² 5.60 5.60 2.20

Sodium bicarbonate 27.22 27.22 10.67

Indigotine 0.50 0.50 0.20 Anhydrous citric acid 33.26 33.26 13.04

Crosslinked polyvinylpyrrolidone ³ 4.50 4.50 1.76

Sodium carboxymethyl starch ⁴ 4.50 4.50 1.76

Colloidal anhydrous silica ⁵ 1.00 1.00 0.39

Magnesium stearate 1.20 1.20 0.47 100.00 100.00 39.216

¹ Methocel ^® K100 M Premium marketed by Colorcon

² Compritol ^® 888 ATO marketed by Gattefossé

³ Crospovidone Kolidon ^® CL marketed by BASF ⁴ Primojel ^® marketed by Avebe

⁵ Aérosil ^® 200 marketed by Degussa

active layer 1 (10 mg zolpidem hemitartrate) mg per% mass% compressed mass total layer Zolpidem hemitartrate 10.00 6.67 3.92 Carboxymethylcellulose

11.25 7.50 4.41 sodium - ¹ -

Calcium carbonate 51.00 34.00 20.00 Citric acid anhydrous 51.00 34.00 20.00 Lactose anhydrous 20.45 13.63 8.02

Sodium carboxymethyl starch ² 4.00 2.67 1.57

Indigotine 0.80 0.53 0.31

Magnesium stearate 1.50 1.00 0.59

150.00 100.00 58.824

¹ Blanose ^® 9M31F marketed by Aqualon Primoj el ®

active layer 2 (5 mg zolpidem hemitartrate)

unit mg by mass mass tablet total layer

Zolpidem hemitartrate 5.00 3.33 1.96

Carboxymethylcellulose

11.25 7.50 4.41 sodium

Calcium carbonate 51.00 34.00 20.00

Citric acid anhydrous 51.00 34.00 20.00

Lactose anhydrous 25.45 16.97 9.98

Carboxymethyl starch sodium 4.00 2.67 1.57

Indigotine 0.80 0.53 0.31

Magnesium stearate 1.50 1.00 0.59

150.00 100.00 58.824

lamination

mg per% mass% compressed mass total layer

Ethylcellulose 22N ¹ 1.22 24.40 0.48 Hydroxypropylcellulose 1.22 24.40 0.48 Titanium dioxide 2.44 48.80 0.96 Indigot lacquer 0.12 2.40 0.05

5.00 100.00 1.96

¹ marketed by Aqualon

² Klucel ^® EF marketed by Aqualon

total film tablet 255.00 Example 3 Characteristics of the Tablets of Examples 1 and 2

3.1. in vi tro dissolution The release of zolpidem hemitartrate is immediate in an in vi tro dissolution model.

Thus, the dissolution of zolpidem hemitartrate is greater than or equal to 80% in 15 minutes. The rotary vane apparatus of the European Pharmacopoeia is used with in each bowl 900 ml of 0.01 N hydrochloric acid degassed at a temperature of 37 ° C more or less 0.5 ° C (the tablet being ballasted to avoid its flotation).

3.2. flotation after introduction into a liquid One of the tablets of Example 1 is introduced into 10 to 20 cl of the following different drinks: red wine, white wine, hot coffee, orange juice and hot chocolate, strong alcohol. Floating, gassing is observed after 5 to 10 seconds in drinks at room temperature

(effervescence) and a release of particles and a viscous gel on the surface and in the liquid as well as a coloring on the surface and in the liquid. We observe after 2 to 5 seconds in coffee or tea or any other hot drink a flotation, a rapid gas evolution which can take the appearance of a viscous foam and a release of color, of particles on the surface of the liquid and of a gel. 5 to 20 seconds are enough to give a different color from the initial color to the hot drink.

In cold drinks, the delay in obtaining flotation and the appearance of particles is longer, due to slower gassing. Flotation is obtained in 3 minutes maximum in non-alcoholic room temperature drinks and the particles and the gel are visible on the surface during and after disintegration.

In alcoholic drinks the flotation is very delayed due to the low gas evolution. In highly alcoholic drink (40 to 45%), the flotation only appears after 25 minutes. During this period, particle disintegration occurs, the particles are deposited on the walls of the container, at the bottom of the latter and are dispersed in suspension in the drink. The disintegration is not complete, even after agitation.

In all cases, if the drink is stirred, the particles and the gel formed will stick to the container. They remain visible after the end of the effervescence and are impossible to eliminate.

If the tablet is crushed and then introduced into an alcoholic drink or not, whatever its temperature, it causes an instant suspension and flotation of the fragments. There is formation of a gelling foam around the fragments and immediate and intense appearance of the coloring of the viscous particles which adhere to the walls of the container in the event of agitation.

The compositions of the invention therefore make it possible, by flotation and by the release of particles in drinks, to avoid ingestion by a person, without their knowledge.

3.3. viscosity measurement of viscous agglomerates Method:

2 tablets are introduced into 20 ml of water. After the end of the effervescence, the viscous part is removed using a spatula and a wire cloth (avoiding taking water and non-solubilized grains).

With approximately 1 cm ³ of viscous agglomerates, a measurement is carried out on a Rheostress RS 100 rheometer with a geometry of the plane cone type C 60/2 ° at 20 ° C, under a shear of 10 s ^-1 with a measurement duration. 300 s. A viscosity of between 1500 and 6000 mPa.s is obtained. This method is derived from the method for measuring the viscosity of the methocel K 100 M excipient.

Claims

claims 1. Pharmaceutical composition for oral administration, comprising an active principle exposed to the risk of misuse or one of its pharmaceutically acceptable salts, characterized in that it comprises constituents which, if introduced into a drink possibly alcoholic aqueous, generate visual means in contact with the latter. 2. Pharmaceutical composition for oral administration according to claim 1, characterized in that the release of the active principle is immediate. 3. Pharmaceutical composition according to claim 1 or 2, characterized in that it is in the form of a tablet intended for oral administration, provided with visual means which are put in place after introduction into a drink optionally alcoholic, consisting either in the flotation of said tablet, or in the formation of insoluble particles or in a combination of these two visual means. 4. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that it contains at least one effervescence generator. 5. Composition according to claim 4, characterized in that the effervescence generator is an effervescent couple constituted by: a carbon dioxide generator chosen from a carbonate or a bicarbonate of an alkali metal, an alkaline earth metal or an amino acid such as calcium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate, carbonate L-lysine, arginine carbonate or sodium sesquicarbonate and, - an acid chosen from an acid anhydride, a monocarboxylic acid, a polycarboxylic acid or a salt partial polycarboxylic acid such as citric acid, tartaric acid, ascorbic acid, fumaric acid, nicotinic acid, acetylsalicylic acid, malic acid, adipic acid, acid succinic, glutaric anhydride, citric anhydride, maleic acid, malonic acid, sodium citrate or succinic anhydride. 6. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that it comprises at least one gellable compound. 7. Pharmaceutical composition according to claim 6, characterized in that the gelable compound is a hydrophilic excipient chosen from cellulose derivatives, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and carboxymethylcellulose; vegetable gums and their derivatives; alginic acid derivatives; polyethylene glycols and their derivatives; starches and their derivatives; silicas and their derivatives; polymethacrylates and copolymers of acrylic and methacrylic acids. 8. Pharmaceutical composition according to any one of claims 1 to 7 comprising the two visual means consisting in flotation and the formation of insoluble particles after introduction into an optionally alcoholic beverage, characterized in that it comprises a lipophilic excipient chosen from glycerol stearates, palmitostearates and behenates; hydrogenated vegetable oils and their derivatives; vegetable and animal waxes and their derivatives; hydrogenated castor oils and their derivatives and cetyl esters and alcohols. 9. Pharmaceutical composition according to any one of claims 1 to 8, characterized in that it comprises a dye. 10. Pharmaceutical composition according to claim 9, characterized in that the dye is chosen from indigotine, cochineal red, orange yellow S, iron oxides, allura red AC, Cucurmine, Riboflavin, Tartrazine, Yellow of quinoline, Azorubin, Amaranth, Carmines, Erythrosine, Red 2G, Patent blue V, Bright blue FCF, Chlorophylls, Cupric complexes of chlorophylls, Green S, Caramels, Bright black BN, Vegetable charcoal, Brown FK and HT, Carotenes, Extracts of Annatto, Paprika Extracts, Lycopene, Lutein, Canthaxanthin, Beet Red, Anthocyanins, Calcium Carbonate, Titanium Dioxide, Aluminum, Silver, Gold or Litholrubine BK. 11. Pharmaceutical composition according to any one of the preceding claims, characterized in that it is in the form of a bilayer tablet provided with combined visual means constituted by the flotation and the formation of insoluble particles: (1) the first layer comprising the active principle or one of its salts, associated with at least one hydrophilic excipient as well as with an effervescence generator, (2) the second layer comprising an effervescence generator and at least one gellable compound. 12. Pharmaceutical composition according to claim 11, characterized in that the hydrophilic excipient of the active layer is chosen from cellulose derivatives, in particular carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and methylcellulose. 13. Pharmaceutical composition according to claim 11 or 12 characterized in that the effervescence generator of the first layer is a combination of calcium carbonate and anhydrous citric acid. 14. Pharmaceutical composition according to any one of claims 11 to 13 characterized in that the effervescence generator of the second layer is a combination sodium bicarbonate and anhydrous citric acid. 15. Pharmaceutical composition according to any one of claims 11 to 14, characterized in that the gelable compound is the combination of a hydrophilic excipient and a lipophilic excipient. 16. Pharmaceutical composition according to claim 15, characterized in that the hydrophilic excipient is as defined in claim 7 and the lipophilic excipient is as defined in claim 8. 17. Pharmaceutical composition according to claim 16, characterized in that the hydrophilic excipient is hydroxypropylmethylcellulose and the lipophilic excipient is glycerol behenate. 18. Pharmaceutical composition according to any one of claims 1 to 17, characterized in that the active principle belongs to one of the following therapeutic classes: hypnotics, anxiolytics or analgesics. 19. Pharmaceutical composition according to claim 18, characterized in that the active principle is a hypnotic compound. 20. Pharmaceutical composition according to claim 19, characterized in that the hypnotic compound belongs to the class of benzodiazepines, cyclopyrrolones, pyrazolopyrimidines or imidazopyridines. 21. Pharmaceutical composition according to claim 20, characterized in that the hypnotic compound is chosen from triazolam, loprazolam, nitrazepam, lormetazepam, temazepam, estazolam, flunitrazepam, brotizolam, cinolazepam, haloxazolam , doxefazepam, zopiclone, (R) -zopiclone, zaleplon or zolpidem and their pharmacologically acceptable salts. 22. Pharmaceutical composition according to claim 21, characterized in that the hypnotic compound is zolpidem or one of its pharmaceutically acceptable salts. 23. Pharmaceutical composition according to claim 22, characterized in that the zolpidem salt is 1 zolpidem hemitartrate. 24. Pharmaceutical composition according to claim 18, characterized in that the active principle is an analgesic. 25. Pharmaceutical composition according to claim 24, characterized in that the active principle is chosen from: methadone, codeine and its derivatives, dextropropoxyphene, tramadol, buprenorphine, pentazocine, morphine, phethidine, dextromoramide, oxycodone, fentanyl and tamgesic. 26. Pharmaceutical composition according to claim 18, characterized in that the active principle is an anxiolytic. 27. Pharmaceutical composition according to claim 26, characterized in that the active principle is chosen from: diazepam, medazepam, oxazepam, lorazepam, benzodiazepines, meprobamate, hydroxyzine and buspirone. 28. Pharmaceutical composition according to any one of claims 1 to 17, characterized in that the active principle is chosen from: phenergan, digoxin, digitalis and coumarin. AMENDED CLAIMS [received by the International Bureau on May 09, 2000 (09.05.00); claims 1-28 replaced by new claims 1-21 (5 pages)] 1. Pharmaceutical composition for oral administration, comprising a hypnotic compound or one of its pharmaceutically acceptable salts, characterized in that it comprises constituents which, if introduced into an aqueous alcoholic beverage, optionally alcoholic, generate visual means in contact with the latter. 2. Pharmaceutical composition for oral administration according to claim 1, characterized in that the release of the hypnotic compound or one of its pharmaceutically acceptable salts is immediate. 3. Pharmaceutical composition according to claim 1 or 2, characterized in that it is in the form of a tablet intended for oral administration, provided with visual means which are put in place after introduction into a drink optionally alcoholic, consisting either in the flotation of said tablet, or in the formation of insoluble particles or in a combination of these two visual means. 4. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that it contains at least one effervescence generator. 5. Composition according to claim 4, characterized in that the effervescence generator is an effervescent couple constituted by: - a carbon dioxide generator chosen from a carbonate or a bicarbonate of an alkali metal, a alkaline earth or an amino acid such as calcium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate, L-lysine carbonate, arginine carbonate or sodium sesquicarbonate and, an acid chosen from an acid anhydride, a monocarboxylic acid, a polycarboxylic acid or a partial salt of polycarboxylic acid such as citric acid, tartaric acid, ascorbic acid, fumaric acid, nicotinic acid, acetylsalicylic acid, malic acid, adipic acid, succinic acid, glutaric anhydride, citric anhydride, maleic acid, malonic acid, monosodium citrate or anhydride succinic. 6. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that it comprises at least one gellable compound. 7. Pharmaceutical composition according to claim 6, characterized in that the gelable compound is a hydrophilic excipient chosen from cellulose derivatives, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and carboxymethylcellulose; vegetable gums and their derivatives; alginic acid derivatives; polyethylene glycols and their derivatives; starches and their derivatives; silicas and their derivatives; polymethacrylates and copolymers of acrylic and methacrylic acids. 8. Pharmaceutical composition according to any one of claims 1 to 7 comprising the two visual means consisting in the flotation and the formation of insoluble particles after introduction into an optionally alcoholic beverage, characterized in that it comprises a lipophilic excipient chosen from glycerol stearates, palmitostearates and behenates; hydrogenated vegetable oils and their derivatives; vegetable and animal waxes and their derivatives; hydrogenated castor oils and their derivatives and cetyl esters and alcohols. 9. Pharmaceutical composition according to any one of claims 1 to 8, characterized in that it comprises a dye. 10. Pharmaceutical composition according to claim 9, characterized in that the dye is chosen from 1 indigotine, cochineal red, orange yellow S, iron oxides, allura red AC, Cucurmine, Riboflavin, Tartrazine, Yellow of quinoline, Azorubin, Amaranth, Carmines, Erythrosine, Red 2G, Patent blue V, Bright blue FCF, Chlorophylls, Cupric complexes of chlorophylls, Green S, Caramels, Bright black BN, Vegetable charcoal, Brown FK and HT, Carotenes, Extracts of Annatto, Paprika Extracts, Lycopene, Lutein, Canthaxanthin, Beet Red, Anthocyanins, Calcium Carbonate, Titanium Dioxide, Aluminum, Silver, Gold or Litholrubine BK. 11. Pharmaceutical composition according to any one of the preceding claims, characterized in that it is in the form of a bilayer tablet provided with combined visual means constituted by the flotation and the formation of insoluble particles: (1) the first layer comprising the hypnotic compound or one of its salts, associated with at least one hydrophilic excipient as well as with an effervescence generator, (2) the second layer comprising an effervescence generator and at least one compound gellable. 12. Pharmaceutical composition according to claim 11, characterized in that the hydrophilic excipient of the active layer is chosen from cellulose derivatives, in particular carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and methylcellulose. 13. Pharmaceutical composition according to claim 11 or 12 characterized in that the effervescence generator of the first layer is a combination of calcium carbonate and anhydrous citric acid. 14. Pharmaceutical composition according to any one of claims 11 to 13 characterized in that the effervescence generator of the second layer is a combination of sodium bicarbonate and anhydrous citric acid. 15. Pharmaceutical composition according to any one of claims 11 to 14, characterized in that the gelable compound is the combination of a hydrophilic excipient and a lipophilic excipient. 16. Pharmaceutical composition according to claim 15, characterized in that the excipient the lipophilic excipient is as defined in claim 8. 17. Pharmaceutical composition according to claim 16, characterized in that the hydrophilic excipient is hydroxypropylmethylcellulose and the lipophilic excipient is glycerol behenate. 18. Pharmaceutical composition according to any one of claims 1 to 17, characterized in that the hypnotic compound belongs to the class of benzodiazepines, cyclopyrrolones, pyrazolopyrimidines or imidazopyridines. 19. Pharmaceutical composition according to claim 18, characterized in that the hypnotic compound is chosen from triazolam, loprazolam, nitrazepam, lormetazepam, temazepam, estazolam, flunitrazepam, brotizolam, cinolazepam, 1 'haloxazolam , doxefazepam, zopiclone, (R) -zopiclone, zaleplon or zolpidem and their pharmacologically acceptable salts. 20. Pharmaceutical composition according to claim 19, characterized in that the hypnotic compound is zolpidem or one of its pharmaceutically acceptable salts. 21. Pharmaceutical composition according to claim 20, characterized in that the zolpidem salt is zolpidem hemitartrate.