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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WO
WIPO (PCT)
Prior art keywords
characterized
pharmaceutical composition
composition according
acid
derivatives
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PCT/FR1999/003120
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French (fr)
Inventor
Alain Dufour
Christian Ahond
Original Assignee
Sanofi-Synthelabo
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Priority to FR9816309A priority Critical patent/FR2787715B1/en
Priority to FR98/16309 priority
Application filed by Sanofi-Synthelabo filed Critical Sanofi-Synthelabo
Publication of WO2000038649A1 publication Critical patent/WO2000038649A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/55Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/55131,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/55171,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/55Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/55Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/55131,4-Benzodiazepines, e.g. diazepam or clozapine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0002Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007Effervescent
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056Mouth 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • A61K9/2086Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat

Abstract

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

Description

PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION FOR PREVENTING MISUSE OF USE THE COSTS OF A THIRD

The present invention relates to a pharmaceutical composition for oral administration, intended to prevent creep at the expense of another.

The active ingredients which may be included in the pharmaceutical compositions of the present invention belong to the therapeutic classes at risk of function creep. One can quote in this regard the following classes of active ingredients: analgesics, anxiolytics and hypnotics.

Thus mention may be made from analgesics methadone, among analgesics weak opioids codeine and its derivatives, dextropropoxyphene, tramadol, among analgesics mixed opioid agonist / antagonist opioids such as buprenorphine or pentazocine, morphine and morphine such as phéthidine, dextromoramide, oxycodone, fentanyl and tamgésic.

Among the anxiolytic compounds include diazepam, medazepam, oxazepam, lorazepam, benzodiazepines, eprobamate, the ydroxyzine, buspirone.

One can also cite the antihistamine Phenergan, digitalis such as digoxin and digitalis and vitamin K coumarin.

The hypnotic compounds can belong to all therapeutic classes, both short and long duration of action, for example: - the compounds of the benzodiazepine class recognized for their hypnotic activity such as triazolam, loprazolam, nitrazepam, lormetazepam, temazepam, estazolam, flunitrazepam, brotizolam, the cinolazepam, the haloxazolam, the doxefazepam and the pharmacologically acceptable salts, e.g. mesilate loprazolam, - zopiclone and particularly the (R) -ZOPICLONE therapeutic class cyclopyrrolones,

- zaleplon therapeutic class pyrazolopyrimidine,

- zolpidem and pharmaceutically acceptable salts of the imidazopyridine class of drugs. One of zolpidem preferred salts is the zolpidem hemitartrate.

The object of the present invention is to provide a pharmaceutical composition for oral administration comprising an active ingredient at risk of change of use or a pharmaceutically acceptable salt thereof, capable of both:

- produce a release of active ingredient after regular oral,

- and, if it is introduced into an optionally alcoholic drink, generate visual means on contact with the latter. These visual means then possible to avoid that said beverage is administered to a person without his knowledge.

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

It is preferred in the context of the present invention pharmaceutical compositions with immediate release. These compositions according to the present invention may be in the form of a conventional tablet (monolayer), a multilayer tablet, in particular 2 or 3 layers or in the form of conventional capsules (containing the powder) or comprising microgranules or bags comprising the powder or granules. In the case of a triple layer tablet, two of the layers may contain independently one of the other two different active principles.

Is meant within the scope of the present invention, by visual means, any element indicating the presence of the composition according to the invention in an optionally alcoholic aqueous beverage and may take the form for example, a dye, a floatation of the composition to the surface of the drink, formation of insoluble particles on the surface of the drink, on the edges of the container in the beverage and on the bottom of the container. The possibly alcoholic aqueous beverage may especially consist of coffee, tea, wine, spirits, hot and cold chocolate drinks, hot or cold milk, while soda like Coca Cola ®, any alcoholic soft drink or not, everything cocktail or liquid mixture based on fruit juice, milk or cream, liquor ...

More particularly, the present invention is a pharmaceutical composition comprising an active ingredient at risk of change of use or a salt thereof, characterized in that it is in the form of a tablet for administration by oral and provided with means. visuals that are put in place after insertion into an optionally alcoholic beverage, consisting either of the waterline of the tablet or in the formation of insoluble particles or a combination of both visual means.

The buoyancy of the tablet can be provided by an effervescence which can be obtained by means of a effervescence generator, as described below. In addition to the excitement, the tablet may have viscosity properties appearing on contact with any beverage. This latter feature allows trapping the gas produced by the effervescence which also results in swelling of the tablet. The generated density lower then ensures the maintenance of the tablet to the surface of the beverage. Such a viscosity can be obtained through one or more gellable compounds. Typically, in the context of the present invention, the viscosity, measured according to the method described in section 3.3 of Example 3 can vary from 1,500 to 6,000 mPa.s.

A list is compiled lowest hydrophilic excipients which are suitable as gelling compound.

The particles may be obtained by association of a lipophilic excipient useful hydrophilic excipient to the water as described above. A list of suitable lipophilic excipients is drawn down.

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

A preferred embodiment of the invention therefore is a pharmaceutical composition comprising an active ingredient exposed to creep or a salt thereof, characterized in that it is in the form of a tablet for administration orally, able to float and form insoluble particles in any fluid in which it is introduced and containing one or more effervescence generators and one or more gellable compounds.

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

The carbon dioxide generator agent is normally a carbonate or bicarbonate of an alkali metal, an alkaline earth metal or an amine acid. Mention may be made, for example, as carbon dioxide generator agent calcium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate, carbonate L-lysine, 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. Can be chosen more particularly the pharmaceutically acceptable acid compound selected 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 generator agent may be constituted by a mixture of several formers carbon dioxide mentioned above.

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

The gellable compound may comprise one or more hydrophilic excipients provoking the swelling of the tablet and the trapping of the gas generator formed by the effervescence.

To ensure the formation of insoluble particles and visible on the surface of the beverage and on the vessel walls, is associated with the hydrophilic excipient one or more lipophilic excipients.

Tablet, in the liquid or on its surface, disintegrates under the action of effervescence. During this disintegration is observed viscous agglomerates training that float and stick to the walls of the container and put in suspension in the liquid. This process ends with the end of the effervescence, and can last, for example 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 gelling compound, another subsequent advantage of this composition resides in improving the characteristics of absorption of the latter. In particular, one can observe a decrease in interindividual variability in absorption compared to a conventional immediate release formulation. It is thus possible to obtain a regularization of the latency of onset of plasma concentration and a decrease in the variation of plasma concentrations during the uptake phase.

Among lipophilic excipients include stearates, palmitostearates and behenates glycerol; hydrogenated vegetable oils and their derivatives; vegetable and animal wax and their derivatives; hydrogenated castor oils and their derivatives and the esters and cetyl alcohols.

Among hydrophilic excipients there may be mentioned cellulose derivatives, hydroxyethylcellulose, hydroxypropylcellulose (molecular mass from 50 to 1250 kDa), hydroxypropylmethylcellulose (molecular mass from 10 to 1500 kDa), carboxymethylcellulose and sodium carboxymethylcellulose; vegetable gums and their derivatives; derivatives of alginic acid; polyethyleneglycols and their derivatives; starches and their derivatives; silicas and their derivatives; polymethacrylates and copolymers of acrylic and methacrylic acids.

One of the components at least the gelling compound, either hydrophilic and / or lipophilic excipient excipient may be chosen to be slightly soluble in alcohol. Thus the compressed, slightly soluble in a liquid or an alcoholic beverage of degree greater than 45, slows down or even prevents the dissolution of the active ingredient and gives the liquid or beverage the appearance of a viscous suspension of insoluble particles. Finally, it is advantageous to add a dye as an additional visual means preventing the creep at the expense of another.

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

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

Among the dyes used in the tablet of the invention include the indigo carmine, cochineal red, yellow orange S, allura the red AC, iron oxides, Cucurmine, riboflavin, tartrazine, quinoline yellow, Azorubine Amarante, Carmines,

Erythrosine, Red 2G, Patent Blue V, brilliant blue FCF, chlorophylls, Copper complexes of chlorophylls, green S, Caramel, Black BN Bright, Vegetable carbon, Brown FK and HT, carotenes, annatto extracts of Paprika extract, lycopene, lutein, canthaxanthin, Red beet, anthocyanins, calcium carbonate, titanium Dioxide, Aluminum, Silver, Gold and Lithol Rubine BK or any other suitable dye consumption.

Other additives may advantageously improve the composition of the tablet.

Thus, one can add a disintegrating agent such as sodium carboxymethyl starch (molecular weight of 500 to 1000 kDa) such as the product sold by Avebe under the name Primojel ® or crosslinked polyvinylpyrrolidone or crospovidone, for instance the product sold by BASF under the trademark Kolidon ® CL.

Finally, the technical realization of the tablets can also lead to the introduction tableting agents: - lubricating agents such as magnesium stearate, stearic acid, glyceryl monostearate, polyoxyethylene glycols having a molecular weight of 400 to 7,000,000, hydrogenated castor oil, glyceryl behenate, mono- glycerides, bi- or tri - glidants, such as colloidal silica or any other silica, e.g. the product marketed by Degussa under the trademark Aerosil ^ - binders such as starch, buffers, absorbents, diluents such as lactose as well as any other pharmaceutically acceptable additive.

A tablet according to the present invention may be obtained by any known conventional technology of compression by the skilled person by mixing powders and / or granulation aid e.g. presses.

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

A tablet may take a cylindrical, lenticular, spheroidal, oval or other, which allows easy administration and swallowing.

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

The tablet according to the invention a coating for protection of the active principle can be further applied, in particular vis-à-vis light.

This film may have a base made of a polymeric material such as ethylcellulose, one hydroxypropylcellulose or hydroxypropylmethylcellulose and an opacifying agent such as titanium dioxide. This film may be further supplemented by any plasticizer and / or lubricant such as polyoxyethylene glycol 400 and colored by a dye er / or as a lacquer such that lacquer of indigotin.

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

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

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

(1) the first layer, called in the context of this invention "active layer", comprising an active ingredient at risk of change of use or a salt thereof, combined with at least one hydrophilic excipient, as well as a effervescence generator,

(2) the second layer, named, in the context of the present invention "plotter layer", comprising an effervescence generator and at least one gellable compound.

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

It is preferred, by way of hydrophilic excipient of the active layer sodium carboxymethylcellulose.

It is preferred, as the effervescence generator for the active layer, the effervescent couple consisting of calcium carbonate and citric acid anhydrous.

The function of the tracing layer is to ensure the water and the formation of insoluble particles to prevent creep at the expense of another. Thus, the tablet of the present invention, can be dissolved in a glass of soft drink or not, without the person to whom the glass is intended realizes that the beverage contains a foreign body.

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

The flotation time depends on the alcohol content of the beverage and its temperature. It ranges from 30 seconds to 15 minutes. In the case of strong alcoholic beverages (40 to 45%), the time can be several minutes (5 to 25 minutes).

May be used as effervescence generators for plotter layer the same as those used for the active layer. In one tablet, the effervescence generator plotter layer may be identical to or different from that of the active layer. Preferred is anhydrous citric acid and sodium bicarbonate combination whose effervescence is fast and highly visible.

The bilayer tablet may also advantageously contain a dye, examples of which were given above. This dye can be placed in the active layer or the plotter layer or in both layers at a time. Preferred are bilayer tablets containing dye in both layers in order to obtain both a color of the drink itself, but also a coloring insoluble particles. Thus, the coloration is visible on the surface of the beverage during the disintegration and after thereof.

The active layer may have a thickness ranging from 1 to 4 mm, and preferably 1.5 to 2.5 mm.

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

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

The following examples illustrate the present invention. Example 1 Tablets bilayer constituted by a plotter layer and an active layer, optionally film

Plotter layer is obtained by direct mixing prior to compression, the active layer is obtained by alcoholic granulation.

fescue layer

mg% weight% total tablet mass layer

Hydroxypropylmethylcellulose 22.22 22.22 8.55

Glyceryl behenate 2 5.60 5.60 2.15 Sodium Bicarbonate 22.22 22.22 8.55 Calcium Carbonate 5.00 5.00 1.92 Citric acid anhydrous 33,26 33,26 12,79

Indigo or Sunset Yellow 0.50 0.50 0.19 4.50 4.50 Polyvinylpyrrolidone 3 Sodium starch glycollate 1.73 4 4.50 4.50 1.73 Silica, colloidal anhydrous 1.00 1.00 0.38 5 magnesium stearate 1.20 1.20 0.46

100.00 100.00 38.46

1 Methocel ® K100 M Premium commercially available from Colorcon

2 Compritol ® 888 ATO sold by Gattefossé 3 Kolidon ® CL sold by BASF

4 Primojel ® marketed by Avebe

5 Aerosil ® 200 marketed by Degussa

active layer 1 (10 mg zolpidem hemitartrate)

mg% weight% total tablet mass layer

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

carboxymethylcellulose

22.50 15.00 Sodium 8.65 λ

calcium carbonate 51,00 34,00 19,62 Citric acid anhydrous 51,00 34,00 19, 62

Lactose anhydrous 9.00 6.00 3.46

Sodium starch 2 4.00 2 67 1.54

Indigo 0 1.00 67 0.38

magnesium stearate 1.50 1.00 0.58

150.00 100.00 57.69

1 Blanose ® marketed by Aqualon 9M31F

2 Primojel ®

active layer 2 (5 mg of zolpidem hemitartrate)

gg mg unitary weight total tablet mass layer

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

carboxymethylcellulose

11.25 7.50 4.33 Sodium

Calcium carbonate 51,00 34,00 19,62

Citric acid anhydrous 51,00 34,00 19,62

Lactose anhydrous 25.25 16.83 9.71

Sodium starch 4.00 2.67 1.54

Indigo 1.00 0.67 0.38

magnesium stearate 1.50 1.00 0.58

150.00 100.00 57.69

coating (optional) mg% weight% total tablet mass layer

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

10.00 100.00 3.85

Total film tablet 260.00 Example 2 Tablets bilayer constituted by a plotter layer and an active layer film

fescue layer

mg total mass compresses mass layer

Hydroxypropylmethylcellulose 1 22.22 22.22 8.71

Glyceryl behenate 2 5.60 5.60 2.20

Sodium bicarbonate 27.22 27.22 10.67

Indigotine 0.50 0.50 0.20 Citric acid anhydrous 33,26 33,26 13,04

Crosslinked polyvinylpyrrolidone 3 4.50 4.50 1.76

Sodium starch 4 4.50 4.50 1.76

Colloidal anhydrous silica 1.00 1.00 0.39 5

magnesium stearate 1.20 1.20 0.47 100.00 100.00 39.216

1 Methocel ® K100 M Premium commercially available from Colorcon

2 Compritol ® 888 ATO sold by Gattefossé

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

5 Aerosil ® 200 marketed by Degussa

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

11.25 7.50 4.41 sodium - 1 -

calcium carbonate 51,00 34,00 20,00 Citric acid anhydrous 51,00 34,00 20,00 20,45 13,63 8,02 Anhydrous lactose

Sodium starch 2 4.00 2.67 1.57

Indigo 0.80 0.53 0.31

magnesium stearate 1.50 1.00 0.59

150,00 100,00 58.824

1 Blanose ® marketed by Aqualon 9M31F Primoj el ®

active layer 2 (5 mg of zolpidem hemitartrate)

mg unitary weight total tablet mass layer

Zolpidem hemitartrate 5.00 3.33 1.96

carboxymethylcellulose

11.25 7.50 4.41 Sodium

Calcium carbonate 51,00 34,00 20,00

Citric acid anhydrous 51,00 34,00 20,00

Lactose anhydrous 25.45 16.97 9.98

Sodium starch 4.00 2.67 1.57

Indigo 0.80 0.53 0.31

magnesium stearate 1.50 1.00 0.59

150,00 100,00 58.824

filming

mg% weight% total tablet mass layer

Ethylcellulose 22N 1 1.22 0.48 24.40 24.40 Hydroxypropylcellulose 1.22 0.48 Titanium dioxide 2.44 0.96 48.80 Lacquer of Indigotine 0.12 2.40 0.05

5.00 100.00 1.96

1 marketed by Aqualon

2 Klucel EF ® marketed by Aqualon

total tablet film 255, 00 Example 3 characteristics of the tablets of Example 1 and 2

3.1. dissolution in vitro The release of zolpidem hemitartrate is immediate in a model of in vitro dissolution.

Thus, the dissolution of the zolpidem hemitartrate is greater than or equal to 80% in 15 minutes. apparatus is used for rotating pallet of the European Pharmacopoeia in each bowl with 900 ml of 0.01 N hydrochloric acid degassed at a temperature of 37 ° C plus or minus 0.5 ° C (the tablet being weighted to prevent it flotation).

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

(Effervescence) and a release particles and a viscous gel on the surface and in the liquid and a surface coloring and in the liquid. after 2 to 5 seconds is observed in the coffee or tea or other hot drinks flotation, rapid gas evolution which may take the appearance of a viscous foam and color release particles the surface of the liquid and a gel. 5 to 20 seconds to give a different color from the initial color to the hot drink.

In cold drinks, the time to reach the water and the occurrence of particles is longer, due to a slower release of gas. The flotation is obtained in 3 minutes maximum in beverages at room temperature, and soft particles and the gel are visible on the surface during and after the disintegration.

In alcoholic beverages the water is delayed due to the low gas emission. In a highly alcoholic beverage (40 to 45%), the water appears only after 25 minutes. During this period the particulate disintegration occurs, the particles are deposited on the walls of the container at the bottom thereof and disperse suspended in the beverage. The disintegration is not complete, even after stirring.

In any case, if the beverage is stirred, the particles and the formed gel will stick to the container. They remain visible after the end of the effervescence and are impossible to remove.

If the tablet is crushed and then introduced into an alcoholic drink or not, whatever its temperature, it causes instant suspension and floating fragments. There is formation of a gel-forming foam around fragments and immediate and intense color development of the viscous particles adhere to the walls of the container if stirring.

The compositions of the invention allow for the water and the release of particles in beverages to avoid ingestion by a person, without his knowledge.

3.3. measuring the viscosity of the viscous agglomerates Method:

2 tablets are introduced in 20 ml of water. After completion of the effervescence, it picks up the viscous component using a spatula and a metal wire (avoiding taking water and non-solubilized grains).

With about 1 cm 3 of viscous agglomerates, a measurement is made on a rheometer Rheostress RS 100 with a cone geometry type plane C 60/2 ° to 20 ° C, under a shear of 10 s -1 with a measurement time 300 s. This gives a viscosity of between 1,500 to 6,000 mPa.s. This method is derived from the method of measuring the viscosity of the excipient Methocel K 100 M.

Claims

Revendications1. A pharmaceutical composition for oral administration comprising an active ingredient at risk of change of use or a pharmaceutically acceptable salt thereof, characterized in that it comprises constituents which, if it is introduced into an aqueous drink optionally alcoholic, generate visual means on contact with this dernière.2. A pharmaceutical composition for oral administration according to claim 1, characterized in that the release of the active principle is immédiate.3. A pharmaceutical composition according to claim 1 or 2, characterized in that it is in the form of a tablet for oral administration, with visual means which are set up after introduction in an optionally alcoholic beverage, consisting either of the waterline of said compressed, either by the formation of insoluble particles or a combination of these two visuels.4 means. A pharmaceutical composition according to any one of claims 1 to 3, characterized in that it contains at least one effervescence.5 generator. Composition according to claim 4, characterized in that the generator effervescence is an effervescent couple consisting of: - a carbon dioxide generator selected from a carbonate or a bicarbonate of an alkali metal, an alkaline earth or an amino acid such as calcium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate, ofL-lysine carbonate, arginine carbonate or sodium sesquicarbonate, and - an acid selected from 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 succinique.6 anhydride. A pharmaceutical composition according to any one of claims 1 to 5, characterized in that it comprises at least one compound gélifiable.7. A pharmaceutical composition according to claim 6, characterized in that the gelling compound is a hydrophilic excipient selected from cellulose derivatives, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and carboxymethylcellulose; vegetable gums and their derivatives; derivatives of alginic acid; polyethyleneglycols and their derivatives; starches and their derivatives; silicas and their derivatives; polymethacrylates and copolymers of acrylic acids and méthacrylique.8. Pharmaceutical composition according to any of claims 1 to 7 comprising both visual means consisting of the water and the formation of insoluble particles upon introduction into an optionally alcoholic beverage, characterized in that it comprises a lipophilic excipient selected from stearates, palmitostearates and glycerol behenate; hydrogenated vegetable oils and their derivatives; vegetable and animal wax and their derivatives; hydrogenated castor oils and their derivatives and cetyl esters and alcohols .9. A pharmaceutical composition according to any one of claims 1 to 8, characterized in that it comprises a colorant. 10. A pharmaceutical composition according to claim 9, characterized in that the dye is selected from the indigotine, cochineal red, yellow orange S iron oxides, Allura red AC, Cucurmine, Riboflavin, Tartrazine, Yellow quinoline Azorubine, Amarante, Carmines, Erythrosine, Red 2G, Patent Blue V, brilliant blue FCF, chlorophylls, Copper complexes of chlorophylls, green S, Caramel, Black shiny BN, vegetable charcoal, brown FK and HT, carotenes, Excerpts from annatto, paprika extracts, lycopene, lutein, canthaxanthin, beetroot red, anthocyanins, calcium carbonate, titanium Dioxide, Aluminum, Silver, Gold or Lithol Rubine BK.11. A pharmaceutical composition according to any one of the preceding claims, characterized by what is presented in the form of a bilayer tablet with combined visual means constituted by the water and the formation of insoluble particles: (1) the first layer comprising the principle active or a salt thereof, combined with at least one hydrophilic excipient as well as an effervescence generator, (2) the second layer comprising an effervescence generator and at least one compound gélifiable.12. A pharmaceutical composition according to claim 11, characterized in that the hydrophilic excipient in the active layer is selected from cellulose derivatives include carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and methylcellulose .13. A pharmaceutical composition according to claim 11 or 12 characterized in that the effervescence generator of the first layer is a calcium carbonate of association and anhydre.14 citric acid. A 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 citric acid anhydre.15. A pharmaceutical composition according to any one of claims 11 to 14, characterized in that the gelling compound is a combination of a hydrophilic excipient and a lipophile.16 excipient. A 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. A pharmaceutical composition according to claim 16, characterized in that the hydrophilic excipient is one hydroxypropylmethylcellulose and lipophilic excipient is behenate glycérol.18. A pharmaceutical composition according to any one of claims 1 to 17, characterized in that the active substance belongs to one of the following therapeutic classes: hypnotics, anxiolytics or analgésiques.19. A pharmaceutical composition according to claim 18, characterized in that the active principle is a compound hypnotique.20. A pharmaceutical composition according to claim 19, characterized in that the hypnotic compound belongs to the class of benzodiazepines, cyclopyrrolones, pyrazolopyrimidines or .21 imidazopyridines. A pharmaceutical composition according to claim 20, characterized in that the hypnotic compound is chosen among triazolam, loprazolam, nitrazepam, lormetazepam, temazepam, estazolam, flunitrazepam, brotizolam, the cinolazepam, the haloxazolam, the doxefazepam, zopiclone, (R) -ZOPICLONE, zaleplon and zolpidem and their pharmacologically acceptable salts. 22. A pharmaceutical composition according to claim 21, characterized in that the compound hypnotic is zolpidem or a pharmaceutically acceptables.23 salts. A pharmaceutical composition according to claim 22, characterized in that the salt of zolpidem is 1 'hemitartrate zolpidem.24. A pharmaceutical composition according to claim 18, characterized in that the active ingredient is an analgesic .25. Pharmaceutical composition according to Claim 24, characterized in that the active principle is selected from: methadone, codeine and its derivatives, dextropropoxyphene, tramadol, buprenorphine, pentazocine, morphine, phéthidine, dextromoramide, the oxycodone, fentanyl and tamgésic.26. A pharmaceutical composition according to claim 18, characterized in that the active principle is a anxiolytique.27. Pharmaceutical composition according to Claim 26, characterized in that the active principle is selected from diazepam, medazepam, oxazepam, lorazepam, benzodiazepines, meprobamate, hydroxyzine and buspirone.28. A pharmaceutical composition according to any one of claims 1 to 17, characterized in that the active principle is selected from: phenergan, digoxin, digitalis and coumarin. AMENDED CLAIMS [received by the International Bureau May 9, 2000 (09.05.00); Claims 1-28 replaced by new claims 1-21 (5 pages)]
1. A pharmaceutical composition for oral administration comprising a hypnotic compound or a pharmaceutically acceptable salt thereof, characterized in that it comprises constituents which, if it is introduced into an optionally alcoholic aqueous beverage, generate visual means in contact with it.
2. A pharmaceutical composition for oral administration according to claim 1, characterized in that the release of the hypnotic compound or a pharmaceutically acceptable salt thereof is immediate.
3. A pharmaceutical composition according to claim 1 or 2, characterized in that it is in the form of a tablet for oral administration, with visual means which snap into place after insertion into a beverage optionally alcoholic, consisting either of the waterline of said compressed, either by the formation of insoluble particles or a combination of both visual means.
4. A pharmaceutical composition according to any one of claims 1 to 3, characterized in that it contains at least one effervescence generator.
5. Composition according to claim 4, characterized in that the effervescence generator is an effervescent couple consisting of:
- a carbon dioxide generator selected 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, L-lysine, carbonate of arginine or sodium sesquicarbonate, and
- an acid selected 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. A pharmaceutical composition according to any one of claims 1 to 5, characterized in that it comprises at least one gellable compound.
7. A pharmaceutical composition according to claim 6, characterized in that the gelling compound is a hydrophilic excipient selected from cellulose derivatives, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and carboxymethylcellulose; vegetable gums and their derivatives; derivatives of alginic acid; polyethyleneglycols and their derivatives; starches and their derivatives; silicas and their derivatives; polymethacrylates and copolymers of acrylic and methacrylic acids.
8. Pharmaceutical composition according to any of claims 1 to 7 comprising both visual means consisting of the water and the formation of insoluble particles upon introduction into an optionally alcoholic beverage, characterized in that it comprises a lipophilic base selected from stearates, palmitostearates and behenates glycerol; hydrogenated vegetable oils and their derivatives; vegetable and animal wax and their derivatives; hydrogenated castor oils and their derivatives and the esters and cetyl alcohols.
9. A pharmaceutical composition according to any one of claims 1 to 8, characterized in that it comprises a colorant.
10. A pharmaceutical composition according to claim 9, characterized in that the dye is selected from 1 indigotine, cochineal red, yellow orange S iron oxides, Allura red AC, Cucurmine, Riboflavin, Tartrazine, Yellow quinoline Azorubine, Amarante, Carmines, Erythrosine, Red 2G, Patent Blue V, brilliant blue FCF, chlorophylls, Copper complexes of chlorophylls, green S, Caramel, Black shiny BN, vegetable charcoal, brown FK and HT, carotenes, Excerpts from annatto, paprika extracts, lycopene, lutein, canthaxanthin, beetroot red, anthocyanins, calcium carbonate, titanium Dioxide, Aluminum, Silver, Gold or Lithol Rubine BK.
11. A pharmaceutical composition according to any one of the preceding claims, characterized by what is presented in the form of a bilayer tablet with combined visual means constituted by the water and the formation of insoluble particles: (1) the first layer comprising hypnotic compound or a salt thereof, combined with at least one hydrophilic excipient as well as a generator of effervescence, (2) the second layer comprising an effervescence generator and at least one gellable compound.
12. A pharmaceutical composition according to claim 11, characterized in that the hydrophilic excipient in the active layer is selected from cellulose derivatives including carboxymethylcellulose, 1 'hydroxypropylmethylcellulose, hydroxypropylcellulose and methylcellulose.
13. A pharmaceutical composition according to claim 11 or 12 characterized in that the effervescence generator of the first layer is a calcium carbonate of association and anhydrous citric acid.
14. A 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 citric acid anhydrous.
15. A pharmaceutical composition according to any one of claims 11 to 14, characterized in that the gelling compound is a combination of a hydrophilic excipient and a lipophilic excipient.
16. A pharmaceutical composition according to claim 15, characterized in that the lipophilic excipient excipient is as defined in claim 8.
17. A pharmaceutical composition according to claim 16, characterized in that the hydrophilic carrier is hydroxypropyl methylcellulose and the lipophilic excipient is glyceryl behenate.
18. A 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. A pharmaceutical composition according to claim 18, characterized in that the hypnotic compound is chosen among triazolam, loprazolam, nitrazepam, lormetazepam, temazepam, estazolam, flunitrazepam, brotizolam, the cinolazepam, 1 'haloxazolam the doxefazepam, zopiclone, (R) -ZOPICLONE, zaleplon and zolpidem and their pharmacologically acceptable salts.
20. A pharmaceutical composition according to claim 19, characterized in that the compound hypnotic is zolpidem or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition according to claim 20, characterized in that the salt of zolpidem is the 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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EP2590632B1 (en) * 2010-07-06 2019-04-17 Ethypharm Pharmaceutical form for combating chemical submission of a medicament
WO2012080399A1 (en) 2010-12-16 2012-06-21 Sanofi Zolpidem-based orodispersible pharmaceutical tablet
WO2012080408A1 (en) 2010-12-16 2012-06-21 Sanofi Pharmaceutical composition for oral administration intended to prevent misuse
FR2968995A1 (en) * 2010-12-16 2012-06-22 Sanofi Aventis pharmaceutioue composition for oral administration to prevent misuse
JP2014501739A (en) * 2010-12-16 2014-01-23 サノフイ Zolpidem base orally disintegrating pharmaceutical tablet
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GB2518475A (en) * 2013-09-23 2015-03-25 Howard Buckley Composition for the oral delivery of compounds
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form

Also Published As

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AR021981A1 (en) 2002-09-04
FR2787715B1 (en) 2002-05-10
FR2787715A1 (en) 2000-06-30
CO5150153A1 (en) 2002-04-29
EP1140011A1 (en) 2001-10-10
AU1663900A (en) 2000-07-31

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