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

Pharmaceutical composition for oral administration designed to prevent misuse at the expense of a third party Download PDF

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Publication number
WO2000038649A1
WO2000038649A1 PCT/FR1999/003120 FR9903120W WO0038649A1 WO 2000038649 A1 WO2000038649 A1 WO 2000038649A1 FR 9903120 W FR9903120 W FR 9903120W WO 0038649 A1 WO0038649 A1 WO 0038649A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
acid
derivatives
chosen
Prior art date
Application number
PCT/FR1999/003120
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French (fr)
Inventor
Alain Dufour
Christian Ahond
Original Assignee
Sanofi-Synthelabo
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Application filed by Sanofi-Synthelabo filed Critical Sanofi-Synthelabo
Priority to AU16639/00A priority Critical patent/AU1663900A/en
Priority to EP99959478A priority patent/EP1140011A1/en
Publication of WO2000038649A1 publication Critical patent/WO2000038649A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • 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.
  • the following classes of active principles may be mentioned: analgesics, anxiolytics or hypnotics.
  • methadone among the weak opioid analgesics codeine and its derivatives, dextropropoxyphene, tramadol
  • the mixed opioid analgesics the morphine agonists / antagonists such as buprenorphine or pentazocine, morphine and morphinomimetics such as phethidine, dextromoramide, oxycodone, fentanyl and tamgesic.
  • anxiolytic compounds mention may be made of diazepam, medazepam, oxazepam, lorazepam, benzodiazepines, eprobamate, ydroxyzine, buspirone.
  • 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,
  • 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:
  • 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.
  • 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.
  • a conventional tablet monolayer
  • a multilayer tablet in particular of 2 or 3 layers
  • conventional capsules containing powder
  • microgranules or sachets comprising powder or granules.
  • two of the layers may contain two different active ingredients independently of each other.
  • 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 ...
  • the present invention is a pharmaceutical composition
  • 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.
  • 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.
  • the viscosity measured according to the method described in point 3.3 of Example 3 can vary from 1500 to 6000 mPa.s.
  • 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 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
  • 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.
  • 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.
  • 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.
  • a pharmaceutical composition for oral administration, immediate release 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.
  • 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.
  • 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 can be chosen so as to be sparingly soluble in alcohol.
  • 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.
  • 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).
  • 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.
  • additives can advantageously supplement the composition of the tablet.
  • 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.
  • 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.
  • - 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.
  • - 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
  • 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.
  • 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.
  • 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:
  • the first 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,
  • tracer layer comprising an effervescence generator and at least one gelable compound.
  • the hydrophilic excipient of the active layer can be chosen from thickening and / or gelling agents and / or binders as described above.
  • suitable hydrophilic excipients mention may be made of cellulose derivatives and in particular carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and methylcellulose.
  • sodium carboxymethylcellulose is preferred.
  • 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.
  • 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.
  • the effervescence generator of the tracer layer may be identical to or different from that of the active layer.
  • 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 tracer layer is obtained by direct mixing before compression, the active layer is obtained by alcoholic granulation.
  • 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
  • Glycerol behenate 2 5.60 5.60 2.20
  • Magnesium stearate 1.20 1.20 0.47 100.00 100.00 39.216
  • active layer 1 (10 mg zolpidem hemitartrate) mg per% mass% compressed mass total layer Zolpidem hemitartrate 10.00 6.67 3.92 Carboxymethylcellulose
  • 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
  • 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).
  • Example 1 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
  • the tablet 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.
  • 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.
  • 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.

Abstract

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

Description

COMPOSITION PHARMACEUTIQUE POUR UNE ADMINISTRATION PAR VOIE ORALE DESTINEE A EVITER LE DETOURNEMENT D'USAGE AU DEPENS D'UN TIERSPHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION TO AVOID MISUSE OF THIRD PARTY AT THE COST OF A THIRD PARTY
La présente invention est relative à une composition pharmaceutique pour l'administration par voie orale, destinée à éviter le détournement d'usage aux dépens d'un tiers .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.
Les principes actifs qui peuvent être compris dans les compositions pharmaceutiques selon la présente invention appartiennent aux classes thérapeutiques exposées au risque du détournement d'usage. On peut citer à ce titre les classes de principes actifs suivantes : les analgésiques, anxiolytiques ou hypnotiques.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.
Ainsi on peut citer parmi les analgésiques la méthadone, parmi les antalgiques opiacés faibles la codéine et ses dérivés, le dextropropoxyphène, le tramadol, parmi les antalgiques opioides mixtes les agonistes/antagonistes morphiniques tels que la buprénorphine ou la pentazocine, la morphine et les morphinomimétiques tels que la phéthidine, la dextromoramide, l'oxycodone, le fentanyl et le tamgésic.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.
Parmi les composés anxiolytiques on peut citer le diazepam, medazepam, oxazepam, le lorazepam, les benzodiazépines, le eprobamate, l' ydroxyzine, la buspirone.Among the anxiolytic compounds, mention may be made of diazepam, medazepam, oxazepam, lorazepam, benzodiazepines, eprobamate, ydroxyzine, buspirone.
On peut également citer l' antihistaminique phénergan, les digitaliques tels que la digoxine et la digitaline et l' anti-vitamine K coumarine.Mention may also be made of the phenergan antihistamine, digitalis such as digoxin and digitalis and the anti-vitamin K coumarin.
Les composés hypnotiques peuvent appartenir à toutes les classes thérapeutiques, qu'ils soient de courte ou de longue durée d'action, à titre d'exemple : - les composés de la classe des benzodiazépines reconnus pour leur activité hypnotique tels que le triazolam, le loprazolam, le nitrazepam, le lormetazepam, le temazepam, l'estazolam, le flunitrazepam, le brotizolam, le cinolazepam, l' haloxazolam, le doxefazepam ainsi que leurs sels pharmacologiquement acceptables, par exemple le mésilate de loprazolam, - la zopiclone et particulièrement la (R) -zopiclone de la classe thérapeutique cyclopyrrolones,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,
- le zaleplon de la classe thérapeutique pyrazolopyrimidines,- the zaleplon of the pyrazolopyrimidines therapeutic class,
- le zolpidem ainsi que ses sels pharmaceutiquement acceptables, de la classe thérapeutique imidazopyridines . L'un des sels de zolpidem particulièrement préféré est l' hémitartrate de zolpidem.- Zolpidem and its pharmaceutically acceptable salts, from the imidazopyridines therapeutic class. One of the particularly preferred zolpidem salts is zolpidem hemitartrate.
L'objet de la présente invention est de fournir une composition pharmaceutique destinée à l'administration par voie orale, comprenant un principe actif exposé au risque du détournement d'usage ou un de ses sels pharmaceutiquement acceptables, capable à la fois :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:
- de produire une libération du principe actif après administration orale régulière,- produce a release of the active ingredient after regular oral administration,
- et, si elle est introduite dans une boisson éventuellement alcoolisée, de générer des moyens visuels au contact de cette dernière. Ces moyens visuels permettent alors d'éviter que ladite boisson soit administrée à une personne, à son insu.- 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.
Les compositions pharmaceutiques selon la présente invention sont de taille acceptable pour l'administration orale classique. Ainsi on préférera les compositions d'un poids inférieur à 800 mg.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.
On préfère dans le cadre de la présente invention les compositions pharmaceutiques à libération immédiate. Ces compositions selon la présente invention peuvent se présenter sous forme d'un comprimé classique (monocouche), d'un comprimé multicouche, notamment de 2 ou 3 couches ou encore sous forme de gélules classiques (contenant de la poudre) ou comprenant des microgranules ou de sachets comprenant de la poudre ou des granulés. Dans le cas d'un comprimé tricouche, deux des couches peuvent contenir indépendamment l'une de l'autre deux principes actifs différents.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.
On entend, dans le cadre de la présente invention, par moyen visuel, tout élément signalant la présence de la composition selon l'invention dans une boisson aqueuse éventuellement alcoolisée et pouvant prendre les formes par exemple, d'un colorant, d'une flottaison de la composition à la surface de la boisson, d'une formation de particules insolubles à la surface de la boisson, sur les bords du récipient, dans la boisson et sur le fond du récipient. La boisson aqueuse éventuellement alcoolisée peut notamment consister en du café, du thé, du vin, des spiritueux, des boissons chocolatées chaudes ou froides, du lait chaud ou froid, tout soda comme le Coca Cola ®, toute boisson gazeuse alcoolisée ou non, tout cocktail ou mélange liquide à base de jus de fruit, de lait ou crème, d'alcools...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 ...
Plus particulièrement, la présente invention est une composition pharmaceutique comprenant un principe actif exposé au risque du détournement d'usage ou un de ses sels, caractérisée en ce qu'elle se présente sous la forme d'un comprimé destiné à l'administration par voie orale et doté de moyens . visuels qui se mettent en place après introduction dans une boisson éventuellement alcoolisée, consistant soit en la flottaison du comprimé, soit en la formation de particules insolubles soit en une combinaison de ces deux moyens visuels.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.
La flottaison du comprimé peut être assurée par une effervescence qui peut être obtenue au moyen d'un générateur d'effervescence, tel que décrit plus loin. En plus de cette effervescence, le comprimé peut présenter des propriétés de viscosité apparaissant au contact de toute boisson. Cette dernière caractéristique permet un piégeage du gaz produit par l'effervescence qui se traduit également par un gonflement du comprimé. La baisse de densité engendrée permet alors d'assurer le maintien du comprimé à la surface de la boisson. Une telle viscosité peut être obtenue grâce à un ou plusieurs composés gélifiables. Typiquement, dans le cadre de la présente invention, la viscosité, mesurée selon la méthode décrite au point 3.3 de l'exemple 3 peut varier de 1500 à 6000 mPa.s.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.
Une liste est dressée plus bas d'excipients hydrophiles qui conviennent à titre de composé gélifiable.A list is given below of hydrophilic excipients which are suitable as a gelable compound.
Les particules peuvent être obtenues par l'association d'un excipient lipophile à un excipient hydrophile utile pour la flottaison, telle que décrite ci-dessus. Une liste d'excipients lipophiles adéquats est dressée plus bas.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.
Le comprimé peut libérer des particules insolubles visibles même si le comprimé ne flotte pas ou pas immédiatement.The tablet may release visible insoluble particles even if the tablet does not float or does not immediately float.
Un mode préféré de réalisation de l'invention est donc une composition pharmaceutique comprenant un principe actif exposé au détournement d'usage ou un de ses sels, caractérisée en ce qu'elle se présente sous la forme d'un comprimé destiné à l'administration par voie orale, capable de flotter et de former des particules insolubles dans tout liquide dans lequel il est introduit et contenant un ou plusieurs générateurs d'effervescence et un ou plusieurs composés gélifiables.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.
Le générateur d'effervescence peut se présenter sous la forme d'un couple effervescent, constitué par un agent générateur de dioxyde de carbone et un composé acide pharmaceutiquement acceptable.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.
L'agent générateur de dioxyde de carbone est habituellement un carbonate ou un bicarbonate d'un métal alcalin, d'un alcalino-terreux ou d'un acide aminé. On peut citer, par exemple, à titre d'agent générateur de dioxyde de carbone le carbonate de calcium, le bicarbonate de sodium, le bicarbonate de potassium, le carbonate de potassium, le carbonate de L-lysine, le carbonate d'arginine ou le sesquicarbonate de sodium. Le composé acide pharmaceutiquement acceptable est un anhydride d'acide, un acide monocarboxylique, un acide polycarboxylique ou un sel partiel d'acide polycarboxylique . On peut choisir plus particulièrement le composé acide pharmaceutiquement acceptable parmi l'acide citrique, l'acide tartrique, l'acide ascorbique, l'acide fumarique, l'acide nicotinique, l'acide acétylsalicylique, l'acide malique, l'acide adipique, l'acide succinique, l'anhydride glutarique, l'anhydride citrique, l'acide maleïque, l'acide malonique, le citrate monosodique et l'anhydride succinique.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.
L'agent générateur de dioxyde de carbone peut être constitué par un mélange de plusieurs agents générateurs de dioxyde de carbone précédemment cités.The carbon dioxide generating agent can consist of a mixture of several carbon dioxide generating agents mentioned above.
Dans le générateur d'effervescence, la teneur en composé acide est généralement choisie de sorte que le rapport entre le nombre de moles en composé acide et le nombre de moles en générateur de dioxyde de carbone soit compris entre 1 et 2.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.
Le composé gélifiable peut être constitué par un ou plusieurs excipients hydrophiles provoquant le gonflement du comprimé et le piegeage du gaz formé par le générateur d' effervescence .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.
Afin d'assurer la formation de particules insolubles et visibles à la surface de la boisson et sur les parois du récipient, on associe à l'excipient hydrophile un ou plusieurs excipients lipophiles.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.
Le comprimé, dans le liquide ou à sa surface, se désagrège sous l'action de l'effervescence. Au cours de cette désagrégation on observe la formation d'agglomérats visqueux qui flottent et se collent aux parois du récipient et se mettent en suspension dans le liquide. Ce processus s'achève avec la fin de l'effervescence et peut par exemple durer de 0,5 à 25 minutes selon le type de liquide ou boisson. Lorsque qu'une composition pharmaceutique pour l'administration orale, à libération immédiate, selon la présente invention contient à la fois un générateur d'effervescence et un composé gélifiable, un autre avantage subséquent de cette composition réside dans l'amélioration des caractéristiques d'absorption de cette dernière. En particulier, on peut observer une diminution de la variabilité interindividuelle de l'absorption par rapport à une formulation à libération immédiate classique. On peut ainsi obtenir une régularisation de la latence d'apparition des concentrations plasmatiques, ainsi qu'une diminution de la variation des concentrations plasmatiques pendant la phase d'absorption.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.
Parmi les excipients lipophiles on peut citer les stéarates, palmitostéarates et béhénates de glycérol ; les huiles végétales hydrogénées et leurs dérivés ; les cires végétales et animales et leurs dérivés ; les huiles de ricin hydrogénées et leurs dérivés et les esters et alcools cétyliques.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.
Parmi les excipients hydrophiles on peut citer les dérivés de cellulose, hydroxyéthylcellulose, hydroxypropylcellulose (masse moléculaire de 50 à 1 250 kDa) hydroxypropylméthylcellulose (masse moléculaire de 10 à 1500 kDa) , carboxymethylcellulose et carboxymethycellulose sodique ; les gommes végétales et leurs dérivés ; les dérivés de l'acide alginique ; les polyéthylèneglycols et leurs dérivés ; les amidons et leurs dérivés ; les silices et leurs dérivés ; les polyméthacrylates et les copolymères des acides acrylique et méthacrylique.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.
Un des constituants au moins du composé gélifiable, soit l'excipient hydrophile et/ou l'excipient lipophile, peut être choisi de façon à être peu soluble dans l'alcool. Ainsi le comprimé, peu soluble dans un liquide ou une boisson alcoolisée de degré supérieur à 45, freine voire empêche la dissolution du principe actif et donne au liquide ou à la boisson l'aspect d'une suspension de particules insolubles visqueuses. Enfin, on peut avantageusement ajouter un colorant comme moyen visuel supplémentaire prévenant le détournement d'usage aux dépens d'un tiers.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.
Ce colorant peut colorer le liquide ou les particules ou les deux simultanément.This dye can color the liquid or the particles or both simultaneously.
La coloration des particules est particulièrement avantageuse dans le cas où la boisson dans laquelle le comprimé est introduit est foncée (comme le café, le Coca Cola ® ou les cocktails) .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).
Parmi les colorants utilisables dans le comprimé selon l'invention, on peut citer l' indigotine, le rouge cochenille, le jaune orange S, l'allura red AC, les oxydes de fer, Cucurmine, Riboflavine, Tartrazine, Jaune de quinoléine, Azorubine, Amarante, Carmins,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, Rouge 2G, Bleu patenté V, Bleu brillant FCF, Chlorophylles, Complexes cuivriques de chlorophylles, Vert S, Caramels, Noir brillant BN, Charbon végétal, Brun FK et HT, Carotènes, Extraits d'Annatto, Extraits de Paprika, Lycopène, Lutéine, Canthaxanthine, Rouge de betterave, Anthocyanes, Carbonate de calcium, Dioxide de titane, Aluminium, Argent, Or et Litholrubine BK ou tout autre colorant adéquat à la consommation.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.
D'autres additifs peuvent avantageusement compléter la composition du comprimé.Other additives can advantageously supplement the composition of the tablet.
Ainsi, on peut ajouter un agent délitant tel que le carboxyméthylamidon sodique (masse moléculaire de 500 à 1000 kDa) , comme le produit commercialisé par Avebe sous la marque Primojel® ou la polyvinylpyrrolidone réticulée ou crospovidone, comme le produit commercialisé par BASF sous la marque Kolidon®CL.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.
Enfin, la réalisation technique des comprimés peut également amener à introduire des agents de compression : - agents lubrifiants tels que le stéarate de magnésium, l'acide stéarique, le monostéarate de glycérol, les polyoxyethylèneglycols ayant un poids moléculaire de 400 à 7 000 000, l'huile de ricin hydrogénée, le béhénate de glycérol, les glycérides mono-, bi- ou trisubstitués, - agents d'écoulement, tels que la silice colloïdale ou toute autre silice, par exemple le produit commercialisé par Degussa sous la marque Aerosil^, - liants tels que l'amidon, tampons, absorbants, diluants tel que lactose ainsi que tout autre additif pharmaceutiquement acceptable.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.
Un comprimé selon la présente invention peut être obtenu par toute technologie classique de compression connue par l'homme du métier par mélange de poudres et/ou granulation à l'aide par exemple de presses rotatives.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.
La granulation peut s'effectuer par exemple, selon une technique classique, par mélange des différents composés pour obtenir une poudre homogène, mouillage avec une solution alcoolique, aqueuse ou hydroalcoolique puis séchage jusqu'à l'obtention d'un pourcentage d'humidité résiduelle prédéterminé, dans un lit d'air fluidisé, à des températures comprises entre 25 et 80 °C. La solution alcoolique peut être à base de polyvinylpyrrolidone (masse moléculaire de 28 à 1500 kDa) mais encore d' hydropropylméthylcellulose ou de tout autre liant pharmaceutiquement acceptable.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.
Un comprimé peut prendre une forme cylindrique, lenticulaire, sphéroïdale, ovoïdale ou autre, qui permet une administration et une déglutition faciles.A tablet can take a cylindrical, lenticular, spheroidal, ovoid or other form, which allows for easy administration and swallowing.
Le mélange nécessaire à la compression peut également être obtenu par granulation sèche ou mélange direct des constituants .The mixture necessary for compression can also be obtained by dry granulation or direct mixing of the constituents.
Au comprimé selon l'invention on peut en outre appliquer un pelliculage destiné à la protection du principe actif, notamment vis-à-vis de la lumière.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.
Cette pellicule peut avoir une base constituée d'un matériau polymèrique comme l' éthylcellulose, 1' hydroxypropylcellulose ou l' hydroxypropylméthylcellulose et d'un agent opacifiant tel que le dioxyde de titane. Cette pellicule peut en outre être complétée par tout plastifiant et/ou lubrifiant tel que le polyoxyéthylène glycol 400 et colorée par un colorant er/ou sous forme de laque tel que la laque d' indigotine .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.
Les quantités de principe actif nécessaires sont les mêmes que celles qui sont administrées habituellement.The amounts of active ingredient required are the same as those which are usually administered.
A titre d'exemple, la quantité d' hémitartrate de zolpidem va de 3 à 10 mg.For example, the amount of zolpidem hemitartrate ranges from 3 to 10 mg.
Un mode particulier de réalisation de ce comprimé est par exemple un comprimé bicouche doté des moyens visuels combinés constitués par la flottaison et la formation de particules insolubles :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) la première couche, nommée, dans le cadre de la présente invention "couche active", comprenant un principe actif exposé au risque du détournement d'usage ou un de ses sels, associé à au moins un excipient hydrophile ainsi qu'à un générateur d'effervescence,(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) la deuxième couche, nommée, dans le cadre de la présente invention "couche traçante", comprenant un générateur d'effervescence et au moins un composé gélifiable.(2) the second layer, called, in the context of the present invention "tracer layer", comprising an effervescence generator and at least one gelable compound.
Ce mode particulier de réalisation est également avantageux pour les raisons décrites plus haut, à savoir l'amélioration des caractéristiques d'absorption et notamment la diminution de la variabilité interindividuelle de l'absorption par rapport à une formulation à libération immédiate classique. On peut ainsi obtenir une régularisation de la latence d'apparition des concentrations plasmatiques, ainsi qu'une diminution de la variation des concentrations plasmatiques pendant la phase d'absorption. L'excipient hydrophile de la couche active peut être choisi parmi les agents épaississants et/ou gélifiants et/ou liants tels que décrits plus haut. Parmi les excipients hydrophiles adaptés, on peut citer les dérivés cellulosiques et notamment la carboxymethylcellulose, la carboxymethylcellulose sodique, l' hydroxypropylméthylcellulose, l' hydroxypropylcellulose et la méthylcellulose.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.
On préfère, à titre d'excipient hydrophile de la couche active la carboxymethylcellulose sodique.As the hydrophilic excipient of the active layer, sodium carboxymethylcellulose is preferred.
On préfère, à titre de générateur d'effervescence pour la couche active, le couple effervescent composé du carbonate de calcium et de l'acide citrique anhydre.As the effervescent generator for the active layer, the effervescent couple composed of calcium carbonate and anhydrous citric acid is preferred.
La fonction de la couche traçante est d'assurer la flottaison et la formation de particules insolubles permettant d'éviter tout détournement d'usage aux dépens d'un tiers. Ainsi, le comprimé selon la présente invention, ne peut être dissous dans un verre d'une boisson alcoolisée ou non, sans que la personne à qui le verre est destiné s'aperçoive que la boisson contient un corps étranger.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.
Le comprimé bicouche, du fait de la présence dans la couche traçante d'un générateur d'effervescence et d'un composé gélifiable, flotte à la surface de la boisson dans laquelle il est introduit.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.
Le délai de flottaison dépend du degré alcoolique de la boisson et de sa température. Il varie de 30 secondes à 15 minutes. Dans le cas de boissons fortement alcoolisées (40 à 45%), le délai peut atteindre plusieurs minutes (5 à 25 minutes) .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).
On peut utiliser, à titre de générateurs d'effervescence pour la couche traçante les mêmes que ceux utilisés pour la couche active. Dans un même comprimé, le générateur d'effervescence de la couche traçante peut être identique à ou différent de celui de la couche active. On préfère l'association acide citrique anhydre et bicarbonate de sodium, dont l'effervescence est rapide et fortement visible.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.
Le comprimé bicouche peut aussi avantageusement contenir un colorant, dont des exemples ont été précédemment donnés. On peut placer ce colorant dans la couche active ou dans la couche traçante ou dans les deux couches à la fois. On préfère les comprimés bicouches contenant du colorant dans les deux couches afin d'obtenir à la fois une coloration de la boisson elle-même, mais aussi une coloration des particules insolubles. Ainsi, la coloration est visible en surface de la boisson lors de la désagrégation et après celle-ci .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.
La couche active peut avoir une épaisseur qui varie de 1 à 4 mm, et de préférence de 1,5 à 2,5 mm.The active layer can have a thickness which varies from 1 to 4 mm, and preferably from 1.5 to 2.5 mm.
La couche traçante peut avoir une épaisseur qui varie de 1 à 4 mm, et de préférence de 1,5 à 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.
Le comprimé bicouche selon l'invention comprend de 0,1 à 40% en poids, de préférence de 1 à 5 % de principe actif lorsqu'il s'agit du zolpidem, de 0,5 à 50 % en poids, de préférence de 2 à 10 % d'excipient hydrophile à titre de composé gélifiable dans la couche active, de 5 à 70 % en poids, de préférence de 25 à 50 % de générateur d'effervescence dans la couche active et de 5 à 70 % en poids, de préférence de 15 à 35 % de générateur d'effervescence dans la couche traçante et, à titre de composé gélifiable, de 2 à 20 % en poids, de préférence de 4 à 10 % d'excipient hydrophile dans la couche traçante et de 1 à 20% en poids, de préférence de 1 à 5% d'excipient lipophile dans la couche traçante, les pourcentages étant exprimés par rapport au poids total de la composition.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.
Les exemples suivants illustrent la présente invention. Exemple 1 Comprimés bicouches constitués par une couche traçante et une couche active, éventuellement pelliculeThe following examples illustrate the present invention. EXAMPLE 1 Double-Layer Tablets Comprising a Tracer Layer and an Active Layer, Possibly Film
La couche traçante est obtenue par mélange direct avant compression, la couche active est obtenue par granulation alcoolique .The tracer layer is obtained by direct mixing before compression, the active layer is obtained by alcoholic granulation.
Couche traçanteTracer layer
mg par % masse % masse comprimé couche totalmg per% mass% compressed mass total layer
Hydroxypropylméthylcellulose 22,22 22,22 8,55Hydroxypropylmethylcellulose 22.22 22.22 8.55
Béhénate de glycérol 2 5,60 5,60 2,15 Bicarbonate de sodium 22,22 22,22 8,55 Carbonate de calcium 5,00 5,00 1,92 Acide citrique anhydre 33,26 33,26 12,79Glycerol 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 ou jaune orangé S 0,50 0,50 0,19 Polyvinylpyrrolidone 3 4,50 4,50 1,73 Carboxyméthylamidon sodique 4 4,50 4,50 1,73 Silice colloïdale anhydre 5 1,00 1,00 0,38 Stéarate de magnésium 1,20 1,20 0,46Indigotine 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 38,46100.00 100.00 38.46
1 Méthocel® K100 M Premium commercialisé par Colorcon 1 Methocel ® K100 M Premium marketed by Colorcon
2 Compritol® 888 ATO commercialisé par Gattefossé 3 Kolidon® CL commercialisé par BASF 2 Compritol ® 888 ATO marketed by Gattefossé 3 Kolidon ® CL marketed by BASF
4 Primojel®commercialisé par Avebe 4 Primojel ® marketed by Avebe
5 Aérosil® 200 commercialisée par Degussa 5 Aérosil ® 200 marketed by Degussa
couche active 1 (10 mg d' hémitartrate de zolpidem)active layer 1 (10 mg zolpidem hemitartrate)
mg par % masse % masse comprimé couche totalmg per% mass% compressed mass total layer
Hémitartrate de zolpidem 10,00 6,67 3,85 (zolpidem base) 8,04 5,36 3,09)Zolpidem hemitartrate 10.00 6.67 3.85 (zolpidem base) 8.04 5.36 3.09)
CarboxymethylcelluloseCarboxymethylcellulose
22,50 15,00 8,65 sodique λ 22.50 15.00 8.65 sodium λ
Carbonate de calcium 51,00 34,00 19,62 Acide citrique anhydre 51,00 34,00 19, 62Calcium carbonate 51.00 34.00 19.62 Citric acid anhydrous 51.00 34.00 19.62
Lactose anhydre 9,00 6,00 3,46Lactose anhydrous 9.00 6.00 3.46
Carboxyméthylamidon sodique 2 4,00 2, 67 1,54Carboxymethyl starch sodium 2 4.00 2.67 1.54
Indigotine 1,00 0, 67 0,38Indigotine 1.00 0.67 0.38
Stéarate de magnésium 1,50 1,00 0,58Magnesium stearate 1.50 1.00 0.58
150,00 100,00 57,69150.00 100.00 57.69
1 Blanose® 9M31F commercialisé par Aqualon 1 Blanose ® 9M31F marketed by Aqualon
2 Primojel® 2 Primojel ®
couche active 2 (5 mg d' hémitartrate de zolpidem)active layer 2 (5 mg zolpidem hemitartrate)
unitaire g. g. mg par masse masse comprimé couche totalunitary g. g. mg by mass mass tablet total layer
Hémitartrate de zolpidem 5,00 3,33 1,92 (zolpidem base 4,02 2,68 1,55)Zolpidem hemitartrate 5.00 3.33 1.92 (zolpidem base 4.02 2.68 1.55)
CarboxymethylcelluloseCarboxymethylcellulose
11,25 7,50 4,33 sodique11.25 7.50 4.33 sodium
Carbonate de calcium 51,00 34,00 19,62Calcium carbonate 51.00 34.00 19.62
Acide citrique anhydre 51,00 34,00 19,62Anhydrous citric acid 51.00 34.00 19.62
Lactose anhydre 25,25 16,83 9,71Lactose anhydrous 25.25 16.83 9.71
Carboxyméthylamidon sodique 4,00 2,67 1,54Carboxymethyl starch sodium 4.00 2.67 1.54
Indigotine 1,00 0,67 0,38Indigotine 1.00 0.67 0.38
Stéarate de magnésium 1,50 1,00 0,58Magnesium stearate 1.50 1.00 0.58
150,00 100,00 57,69150.00 100.00 57.69
pelliculage (optionnel) mg par % masse % masse comprimé couche totalfilm coating (optional) mg per% mass% compressed mass total layer
Hydroxypropylméthylcelulose 7,20 72,00 2,77 Dioxyde de titane 2,10 21,00 0,81 Polyoxyéthylène glycol 400 0,70 7,00 0,27Hydroxypropylmethylcelulose 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 3,8510.00 100.00 3.85
total comprimé pellicule 260.00 Exemple 2 Comprimés bicouches constitués par une couche traçante et une couche active pelliculetotal film tablet 260.00 Example 2 Bi-Layer Tablets Consisting of a Tracer Layer and an Active Film Layer
Couche traçanteTracer layer
mg par masse masse comprime couche totalmg by mass mass compresses total layer
Hydroxypropylméthylcellulose 1 22,22 22,22 8,71Hydroxypropylmethylcellulose 1 22.22 22.22 8.71
Béhénate de glycérol 2 5,60 5,60 2,20Glycerol behenate 2 5.60 5.60 2.20
Bicarbonate de sodium 27,22 27,22 10,67Sodium bicarbonate 27.22 27.22 10.67
Indigotine 0,50 0,50 0,20 Acide citrique anhydre 33,26 33,26 13,04Indigotine 0.50 0.50 0.20 Anhydrous citric acid 33.26 33.26 13.04
Polyvinylpyrrolidone réticulée3 4,50 4,50 1,76Crosslinked polyvinylpyrrolidone 3 4.50 4.50 1.76
Carboxyméthylamidon sodique 4 4,50 4,50 1,76Sodium carboxymethyl starch 4 4.50 4.50 1.76
Silice colloïdale anhydre 5 1,00 1,00 0,39Colloidal anhydrous silica 5 1.00 1.00 0.39
Stéarate de magnésium 1,20 1,20 0,47 100,00 100,00 39,216Magnesium stearate 1.20 1.20 0.47 100.00 100.00 39.216
1 Méthocel® K100 M Premium commercialisé par Colorcon 1 Methocel ® K100 M Premium marketed by Colorcon
2 Compritol® 888 ATO commercialisé par Gattefossé 2 Compritol ® 888 ATO marketed by Gattefossé
3 Crospovidone Kolidon® CL commercialisé par BASF 4 Primojel® commercialisé par Avebe 3 Crospovidone Kolidon ® CL marketed by BASF 4 Primojel ® marketed by Avebe
5 Aérosil® 200 commercialisée par Degussa 5 Aérosil ® 200 marketed by Degussa
couche active 1 (10 mg d' hémitartrate de zolpidem) mg par % masse % masse comprimé couche total Hémitartrate de zolpidem 10,00 6,67 3,92 Carboxymethylcelluloseactive 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 sodique -1-11.25 7.50 4.41 sodium - 1 -
Carbonate de calcium 51,00 34,00 20,00 Acide citrique anhydre 51,00 34,00 20,00 Lactose anhydre 20,45 13,63 8,02Calcium carbonate 51.00 34.00 20.00 Citric acid anhydrous 51.00 34.00 20.00 Lactose anhydrous 20.45 13.63 8.02
Carboxyméthylamidon sodique 2 4,00 2,67 1,57Sodium carboxymethyl starch 2 4.00 2.67 1.57
Indigotine 0,80 0,53 0,31Indigotine 0.80 0.53 0.31
Stéarate de magnésium 1,50 1,00 0,59Magnesium stearate 1.50 1.00 0.59
150,00 100,00 58,824150.00 100.00 58.824
1 Blanose® 9M31F commercialisé par Aqualon Primoj el ® 1 Blanose ® 9M31F marketed by Aqualon Primoj el ®
couche active 2 (5 mg d' hémitartrate de zolpidem)active layer 2 (5 mg zolpidem hemitartrate)
unitaire mg par masse masse comprimé couche totalunit mg by mass mass tablet total layer
Hémitartrate de zolpidem 5,00 3,33 1,96Zolpidem hemitartrate 5.00 3.33 1.96
CarboxymethylcelluloseCarboxymethylcellulose
11,25 7,50 4,41 sodique11.25 7.50 4.41 sodium
Carbonate de calcium 51,00 34,00 20,00Calcium carbonate 51.00 34.00 20.00
Acide citrique anhydre 51,00 34,00 20,00Citric acid anhydrous 51.00 34.00 20.00
Lactose anhydre 25,45 16,97 9,98Lactose anhydrous 25.45 16.97 9.98
Carboxyméthylamidon sodique 4,00 2,67 1,57Carboxymethyl starch sodium 4.00 2.67 1.57
Indigotine 0,80 0,53 0,31Indigotine 0.80 0.53 0.31
Stéarate de magnésium 1,50 1,00 0,59Magnesium stearate 1.50 1.00 0.59
150,00 100,00 58,824150.00 100.00 58.824
pelliculagelamination
mg par % masse % masse comprimé couche totalmg per% mass% compressed mass total layer
Ethylcellulose 22N1 1,22 24,40 0,48 Hydroxypropylcellulose 1,22 24,40 0,48 Dioxyde de titane 2,44 48,80 0,96 Laque d' indigotine 0,12 2,40 0,05Ethylcellulose 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 1,965.00 100.00 1.96
1 commercialisé par Aqualon 1 marketed by Aqualon
2 Klucel® EF commercialisé par Aqualon 2 Klucel ® EF marketed by Aqualon
total comprimé pellicule 255 , 00 Exemple 3 caractéristiques des comprimés de l'exemple 1 et 2total film tablet 255.00 Example 3 Characteristics of the Tablets of Examples 1 and 2
3.1. dissolution in vi tro La libération de l' hémitartrate de zolpidem est immédiate dans un modèle de dissolution in vi tro .3.1. in vi tro dissolution The release of zolpidem hemitartrate is immediate in an in vi tro dissolution model.
Ainsi, la dissolution de l' hémitartrate de zolpidem est supérieure ou égale à 80% en 15 minutes. On utilise l'appareil à palette tournante de la Pharmacopée européenne avec dans chaque bol 900 ml d'acide chlorhydrique 0,01 N dégazé à une température de 37°C plus ou moins 0,5°C (le comprimé étant lesté pour éviter sa flottaison) .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. flottaison après introduction dans un liquide On introduit un des comprimés de l'exemple 1 dans 10 à 20 cl des différentes boissons suivantes : vin rouge, vin blanc, café chaud, jus d'orange et chocolat chaud, alcool fort. On observe après 5 à 10 secondes dans les boissons à la température ambiante une flottaison, un dégagement gazeux3.2. 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) et une libération de particules et d'un gel visqueux en surface et dans le liquide ainsi qu'une coloration en surface et dans le liquide. On observe après 2 à 5 secondes dans le café ou le thé ou toute autre boisson chaude une flottaison, un dégagement gazeux rapide pouvant prendre l'aspect d'une mousse visqueuse et une libération de couleur, de particules en surface du liquide et d'un gel. 5 à 20 secondes suffisent pour donner une coloration différente de la coloration initiale à la boisson chaude.(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.
Dans les boissons froides, le délai d'obtention de la flottaison et de l'apparition des particules est plus long, en raison d'un dégagement gazeux plus lent. La flottaison est obtenue en 3 minutes maximum dans les boissons à température ambiante, non alcoolisées et les particules ainsi que le gel sont visibles en surface pendant et après la désagrégation.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.
Dans les boissons alcoolisées la flottaison est très retardée en raison du faible dégagement gazeux. Dans une boisson fortement alcoolisée (40 à 45%), la flottaison n'apparaît qu'après 25 minutes. Pendant ce délai la désagrégation en particules se produit, les particules se déposent sur les parois du récipient, au fond de celui-ci et se dispersent en suspension dans la boisson. La désagrégation n'est pas totale, même après agitation.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.
Dans tous les cas, si on agite la boisson, les particules et le gel formé se collent sur le récipient. Ils restent visibles après la fin de l'effervescence et sont impossibles à éliminer.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.
Si le comprimé est écrasé puis introduit dans une boisson alcoolisée ou non, quelque soit sa température, il provoque une suspension et flottaison instantanée des fragments. Il y a formation d'une mousse gélifiante autour des fragments et apparition immédiate et intense de la coloration des particules visqueuses qui adhèrent aux parois du récipient en cas d'agitation.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.
Les compositions de l'invention permettent donc par la flottaison et par le dégagement de particules dans les boissons d'éviter l'ingestion par une personne, à son insu.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. mesure de la viscosité des agglomérats visqueux Méthode :3.3. viscosity measurement of viscous agglomerates Method:
On introduit 2 comprimés dans 20 ml d'eau. Après la fin de l'effervescence, on prélève la partie visqueuse à l'aide d'une spatule et d'une toile métallique (en évitant de prendre de l'eau et des grains non solubilisés).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).
Avec environ 1 cm3 d'agglomérats visqueux, on effectue une mesure sur un rhéomètre Rheostress RS 100 avec une géométrie de type cône plan C 60/2° à 20°C, sous un cisaillement de 10 s-1 avec une durée de mesure de 300 s. On obtient une viscosité comprise entre 1500 à 6000 mPa.s. Cette méthode est dérivée de la méthode de mesure de la viscosité de l'excipient Méthocel K 100 M. 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

Revendications claims
1. Composition pharmaceutique pour l'administration par voie orale, comprenant un principe actif exposé au risque du détournement d'usage ou un de ses sels pharmaceutiquement acceptables, caractérisée en ce qu'elle comprend des constituants qui, si elle est introduite dans une boisson aqueuse éventuellement alcoolisée, génèrent des moyens visuels au contact de cette dernière.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. Composition pharmaceutique pour l'administration par voie orale selon la revendication 1, caractérisée en ce que la libération du principe actif est immédiate.2. Pharmaceutical composition for oral administration according to claim 1, characterized in that the release of the active principle is immediate.
3. Composition pharmaceutique selon la revendication 1 ou 2, caractérisée en ce qu'elle se présente sous la forme d'un comprimé destiné à l'administration par voie orale, doté de moyens visuels qui se mettent en place après introduction dans une boisson éventuellement alcoolisée, consistant soit en la flottaison dudit comprimé, soit en la formation de particules insolubles soit en une combinaison de ces deux moyens visuels.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. Composition pharmaceutique selon l'une quelconque des revendications 1 à 3, caractérisée en ce qu'elle contient au moins un générateur d'effervescence.4. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that it contains at least one effervescence generator.
5. Composition selon la revendication 4, caractérisée en ce que le générateur d' effervescence est un couple effervescent constitué par :5. Composition according to claim 4, characterized in that the effervescence generator is an effervescent couple constituted by:
- un générateur de dioxyde de carbone choisi parmi un carbonate ou un bicarbonate d'un métal alcalin, d'un alcalino-terreux ou d'un acide aminé tel que le carbonate de calcium, le bicarbonate de sodium, le bicarbonate de potassium, le carbonate de potassium, le carbonate dea 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, le carbonate d'arginine ou le sesquicarbonate de sodium et,L-lysine, arginine carbonate or sodium sesquicarbonate and,
- un acide choisi parmi un anhydride d'acide, un acide monocarboxylique, un acide polycarboxylique ou un sel partiel d'acide polycarboxylique tel que l'acide citrique, l'acide tartrique, l'acide ascorbique, l'acide fumarique, l'acide nicotinique, l'acide acétylsalicylique, l'acide malique, l'acide adipique, l'acide succinique, l'anhydride glutarique, l'anhydride citrique, l'acide maleïque, l'acide malonique, le citrate monosodique ou l'anhydride succinique.- 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. Composition pharmaceutique selon l'une quelconque des revendications 1 à 5, caractérisée en ce qu'elle comprend au moins un composé gélifiable.6. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that it comprises at least one gellable compound.
7. Composition pharmaceutique selon la revendication 6, caractérisée en ce que le composé gélifiable est un excipient hydrophile choisi parmi les dérivés de cellulose, hydroxyéthylcellulose, hydroxypropylcellulose, hydroxypropylméthylcellulose et carboxymethylcellulose ; les gommes végétales et leurs dérivés ; les dérivés de l'acide alginique ; les polyéthylèneglycols et leurs dérivés ; les amidons et leurs dérivés ; les silices et leurs dérivés ; les polyméthacrylates et les copolymères des acides acrylique et méthacrylique.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. Composition pharmaceutique selon l'un quelconque des revendications 1 à 7 comportant les deux moyens visuels consistant en la flottaison et la formation de particules insolubles après introduction dans une boisson éventuellement alcoolisée, caractérisée en ce qu'elle comprend un excipient lipophile choisi parmi les stéarates, palmitostéarates et béhénates de glycérol ; les huiles végétales hydrogénées et leurs dérivés ; les cires végétales et animales et leurs dérivés ; les huiles de ricin hydrogénées et leurs dérivés et les esters et alcools cétyliques .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. Composition pharmaceutique selon l'une quelconque des revendications 1 à 8, caractérisée en ce qu'elle comprend un colorant. 9. Pharmaceutical composition according to any one of claims 1 to 8, characterized in that it comprises a dye.
10. Composition pharmaceutique selon la revendication 9, caractérisée en ce que le colorant est choisi parmi l' indigotine, le rouge cochenille, le jaune orange S, les oxydes de fer, l'allura red AC, Cucurmine, Riboflavine, Tartrazine, Jaune de quinoléine, Azorubine, Amarante, Carmins, Erythrosine, Rouge 2G, Bleu patenté V, Bleu brillant FCF, Chlorophylles, Complexes cuivriques de chlorophylles, Vert S, Caramels, Noir brillant BN, Charbon végétal, Brun FK et HT, Carotènes, Extraits d'Annatto, Extraits de Paprika, Lycopène, Lutéine, Canthaxanthine, Rouge de betterave, Anthocyanes, Carbonate de calcium, Dioxide de titane, Aluminium, Argent, Or ou Litholrubine BK.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. Composition pharmaceutique selon l'un quelconque des revendications précédentes, caractérisée en se quelle se présente sous la forme d'un comprimé bicouche doté des moyens visuels combinés constitués par la flottaison et la formation de particules insolubles : (1) la première couche comprenant le principe actif ou un de ses sels, associé à au moins un excipient hydrophile ainsi qu'à un générateur d'effervescence, (2) la deuxième couche comprenant un générateur d'effervescence et au moins un composé gélifiable.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. Composition pharmaceutique selon la revendication 11, caractérisée en ce que l'excipient hydrophile de la couche active est choisi parmi les dérivés cellulosiques notamment la carboxymethylcellulose, l' hydroxypropylméthylcellulose, l' hydroxypropylcellulose et la méthylcellulose .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. Composition pharmaceutique selon la revendication 11 ou 12 caractérisée en ce que le générateur d'effervescence de la première couche est une association de carbonate de calcium et d'acide citrique anhydre.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. Composition pharmaceutique selon l'une quelconque des revendications 11 à 13 caractérisée en ce que le générateur d'effervescence de la deuxième couche est une association bicarbonate de sodium et acide citrique anhydre.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. Composition pharmaceutique selon l'une quelconque des revendications 11 à 14, caractérisée en ce que le composé gélifiable est l'association d'un excipient hydrophile et d'un excipient lipophile.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. Composition pharmaceutique selon la revendication 15, caractérisée en ce que l'excipient hydrophile est tel que défini dans la revendication 7 et l'excipient lipophile est tel que défini dans la revendication 8.16. 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. Composition pharmaceutique selon la revendication 16, caractérisée en ce que l'excipient hydrophile est 1' hydroxypropylméthylcellulose et l'excipient lipophile est le béhénate de glycérol.17. Pharmaceutical composition according to claim 16, characterized in that the hydrophilic excipient is hydroxypropylmethylcellulose and the lipophilic excipient is glycerol behenate.
18. Composition pharmaceutique selon l'une quelconque des revendications 1 à 17, caractérisée en ce que le principe actif appartient à l'une des classes thérapeutiques suivantes : hypnotiques, anxiolytiques ou analgésiques.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. Composition pharmaceutique selon la revendication 18, caractérisée en ce que le principe actif est un composé hypnotique.19. Pharmaceutical composition according to claim 18, characterized in that the active principle is a hypnotic compound.
20. Composition pharmaceutique selon la revendication 19, caractérisée en ce que le composé hypnotique appartient à la classe des benzodiazépines, des cyclopyrrolones, des pyrazolopyrimidines ou des imidazopyridines .20. Pharmaceutical composition according to claim 19, characterized in that the hypnotic compound belongs to the class of benzodiazepines, cyclopyrrolones, pyrazolopyrimidines or imidazopyridines.
21. Composition pharmaceutique selon la revendication 20, caractérisée en ce que le composé hypnotique est choisi parmi le triazolam, le loprazolam, le nitrazepam, le lormetazepam, le temazepam, l'estazolam, le flunitrazepam, le brotizolam, le cinolazepam, l' haloxazolam, le doxefazepam, la zopiclone, la (R) -zopiclone, le zaleplon ou le zolpidem ainsi que leurs sels pharmacologiquement acceptables . 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. Composition pharmaceutique selon la revendication 21, caractérisée en ce que le composé hypnotique est le zolpidem ou un de ses sels pharmaceutiquement acceptables.22. Pharmaceutical composition according to claim 21, characterized in that the hypnotic compound is zolpidem or one of its pharmaceutically acceptable salts.
23. Composition pharmaceutique selon la revendication 22, caractérisée en ce que le sel de zolpidem est 1' hémitartrate de zolpidem.23. Pharmaceutical composition according to claim 22, characterized in that the zolpidem salt is 1 zolpidem hemitartrate.
24. Composition pharmaceutique selon la revendication 18, caractérisée en ce que le principe actif est un analgésique .24. Pharmaceutical composition according to claim 18, characterized in that the active principle is an analgesic.
25. Composition pharmaceutique selon la revendication 24, caractérisée en ce que le principe actif est choisi parmi : la méthadone, la codéine et ses dérivés, le dextropropoxyphène, le tramadol, la buprénorphine, la pentazocine, la morphine, la phéthidine, la dextromoramide, l'oxycodone, le fentanyl et le tamgésic.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. Composition pharmaceutique selon la revendication 18, caractérisée en ce que le principe actif est un anxiolytique.26. Pharmaceutical composition according to claim 18, characterized in that the active principle is an anxiolytic.
27. Composition pharmaceutique selon la revendication 26, caractérisée en ce que le principe actif est choisi parmi : diazepam, medazepam, oxazepam, le lorazepam, les benzodiazépines, le meprobamate, l' hydroxyzine et la buspirone.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. Composition pharmaceutique selon l'une quelconque des revendications 1 à 17, caractérisée en ce que le principe actif est choisi parmi : phénergan, digoxine, digitaline et coumarine. REVENDICATIONS MODIFIEES28. 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
[reçues par le Bureau International le 09 Mai 2000 (09.05.00); revendications 1-28 remplacées par les nouvelles revendications 1-21 (5 pages)][received by the International Bureau on May 09, 2000 (09.05.00); claims 1-28 replaced by new claims 1-21 (5 pages)]
1. Composition pharmaceutique pour l'administration par voie orale, comprenant un composé hypnotique ou un de ses sels pharmaceutiquement acceptables, caractérisée en ce qu'elle comprend des constituants qui, si elle est introduite dans une boisson aqueuse éventuellement alcoolisée, génèrent des moyens visuels au contact de cette dernière .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. Composition pharmaceutique pour l'administration par voie orale selon la revendication 1, caractérisée en ce que la libération du composé hypnotique ou un de ses sels pharmaceutiquement acceptables est immédiate.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. Composition pharmaceutique selon la revendication 1 ou 2 , caractérisée en ce qu'elle se présente sous la forme d'un comprimé destiné à l'administration par voie orale, doté de moyens visuels qui se mettent en place après introduction dans une boisson éventuellement alcoolisée, consistant soit en la flottaison dudit comprimé, soit en la formation de particules insolubles soit en une combinaison de ces deux moyens visuels.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. Composition pharmaceutique selon l'une quelconque des revendications 1 à 3, caractérisée en ce qu'elle contient au moins un générateur d'effervescence.4. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that it contains at least one effervescence generator.
5. Composition selon la revendication 4, caractérisée en ce que le générateur d'effervescence est un couple effervescent constitué par :5. Composition according to claim 4, characterized in that the effervescence generator is an effervescent couple constituted by:
- un générateur de dioxyde de carbone choisi parmi un carbonate ou un bicarbonate d'un métal alcalin, d'un alcalino-terreux ou d'un acide aminé tel que le carbonate de calcium, le bicarbonate de sodium, le bicarbonate de potassium, le carbonate de potassium, le carbonate de L-lysine, le carbonate d'arginine ou le sesquicarbonate de sodium et ,- 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,
- un acide choisi parmi un anhydride d'acide, un acide monocarboxylique, un acide polycarboxylique ou un sel partiel d'acide polycarboxylique tel que l'acide citrique, l'acide tartrique, l'acide ascorbique, l'acide fumarique, l'acide nicotinique, l'acide acétylsalicylique, l'acide malique, l'acide adipique, l'acide succinique, l'anhydride glutarique, l'anhydride citrique, l'acide maleïque, l'acide malonique, le citrate monosodique ou l'anhydride succinique.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. Composition pharmaceutique selon l'une quelconque des revendications 1 à 5, caractérisée en ce qu'elle comprend au moins un composé gélifiable.6. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that it comprises at least one gellable compound.
7. Composition pharmaceutique selon la revendication 6, caractérisée en ce que le composé gélifiable est un excipient hydrophile choisi parmi les dérivés de cellulose, hydroxyéthylcellulose, hydroxypropylcellulose, hydroxypropylméthylcellulose et carboxymethylcellulose ; les gommes végétales et leurs dérivés ; les dérivés de l'acide alginique ; les polyéthylèneglycols et leurs dérivés ; les amidons et leurs dérivés ; les silices et leurs dérivés ; les polyméthacrylates et les copolymères des acides acrylique et méthacrylique .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. Composition pharmaceutique selon l'un quelconque des revendications 1 à 7 comportant les deux moyens visuels consistant en la flottaison et la formation de particules insolubles après introduction dans une boisson éventuellement alcoolisée, caractérisée en ce qu'elle comprend un excipient lipophile choisi parmi les stéarates, palmitostéarates et béhénates de glycérol ; les huiles végétales hydrogénées et leurs dérivés ; les cires végétales et animales et leurs dérivés ; les huiles de ricin hydrogénées et leurs dérivés et les esters et alcools cétyliques.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. Composition pharmaceutique selon l'une quelconque des revendications 1 à 8, caractérisée en ce qu'elle comprend un colorant .9. Pharmaceutical composition according to any one of claims 1 to 8, characterized in that it comprises a dye.
10. Composition pharmaceutique selon la revendication 9, caractérisée en ce que le colorant est choisi parmi 1 ' indigotine, le rouge cochenille, le jaune orange S, les oxydes de fer, l'allura red AC, Cucurmine, Riboflavine, Tartrazine, Jaune de quinoléine, Azorubine, Amarante, Carmins, Erythrosine, Rouge 2G, Bleu patenté V, Bleu brillant FCF, Chlorophylles, Complexes cuivriques de chlorophylles, Vert S, Caramels, Noir brillant BN, Charbon végétal, Brun FK et HT, Carotènes, Extraits d'Annatto, Extraits de Paprika, Lycopène, Lutéine, Canthaxanthine, Rouge de betterave, Anthocyanes, Carbonate de calcium, Dioxide de titane, Aluminium, Argent, Or ou Litholrubine BK.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. Composition pharmaceutique selon l'un quelconque des revendications précédentes, caractérisée en se quelle se présente sous la forme d'un comprimé bicouche doté des moyens visuels combinés constitués par la flottaison et la formation de particules insolubles : (1) la première couche comprenant le composé hypnotique ou un de ses sels, associé à au moins un excipient hydrophile ainsi qu'à un générateur d' effervescence, (2) la deuxième couche comprenant un générateur d'effervescence et au moins un composé gélifiable.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. Composition pharmaceutique selon la revendication 11, caractérisée en ce que l'excipient hydrophile de la couche active est choisi parmi les dérivés cellulosiques notamment la carboxymethylcellulose, 1 ' hydroxypropylméthylcellulose, l'hydroxypropylcellulose et la méthylcellulose .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. Composition pharmaceutique selon la revendication 11 ou 12 caractérisée en ce que le générateur d'effervescence de la première couche est une association de carbonate de calcium et d'acide citrique anhydre .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. Composition pharmaceutique selon l'une quelconque des revendications 11 à 13 caractérisée en ce que le générateur d'effervescence de la deuxième couche est une association bicarbonate de sodium et acide citrique anhydre .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. Composition pharmaceutique selon l'une quelconque des revendications 11 à 14, caractérisée en ce que le composé gélifiable est l'association d'un excipient hydrophile et d'un excipient lipophile.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. Composition pharmaceutique selon la revendication 15, caractérisée en ce que l'excipient l'excipient lipophile est tel que défini dans la revendication 8.16. Pharmaceutical composition according to claim 15, characterized in that the excipient the lipophilic excipient is as defined in claim 8.
17. Composition pharmaceutique selon la revendication 16, caractérisée en ce que l'excipient hydrophile est l' hydroxypropylméthylcellulose et l'excipient lipophile est le béhénate de glycérol .17. Pharmaceutical composition according to claim 16, characterized in that the hydrophilic excipient is hydroxypropylmethylcellulose and the lipophilic excipient is glycerol behenate.
18. Composition pharmaceutique selon l'une quelconque des revendications 1 à 17, caractérisée en ce que le composé hypnotique appartient à la classe des benzodiazépines, des cyclopyrrolones, des pyrazolopyrimidines ou des imidazopyridines .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. Composition pharmaceutique selon la revendication 18, caractérisée en ce que le composé hypnotique est choisi parmi le triazolam, le loprazolam, le nitrazepam, le lormetazepam, le temazepam, l'estazolam, le flunitrazepam, le brotizolam, le cinolazepam, 1 'haloxazolam, le doxefazepam, la zopiclone, la (R) -zopiclone, le zaleplon ou le zolpidem ainsi que leurs sels pharmacologiquement acceptables.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. Composition pharmaceutique selon la revendication 19, caractérisée en ce que le composé hypnotique est le zolpidem ou un de ses sels pharmaceutiquement acceptables.20. Pharmaceutical composition according to claim 19, characterized in that the hypnotic compound is zolpidem or one of its pharmaceutically acceptable salts.
21. Composition pharmaceutique selon la revendication 20, caractérisée en ce que le sel de zolpidem est l' hémitartrate de zolpidem. 21. Pharmaceutical composition according to claim 20, characterized in that the zolpidem salt is zolpidem hemitartrate.
PCT/FR1999/003120 1998-12-23 1999-12-14 Pharmaceutical composition for oral administration designed to prevent misuse at the expense of a third party WO2000038649A1 (en)

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