Oral dosage form comprising an antimisuse system

Abstract

An oral solid dosage form containing one or several active principle(s) having analgesic properties, the composition of said dosage form being such that it prevents the misuse of said dosage form through the liquid extraction of the active principle(s) contained therein, using commonly available solvents. Said oral solid dosage form containing at least one salt of at least one analgesic active principle, and an anti-misuse system comprising at least one quenching agent, said quenching agent being suitable for inducing complexation of said analgesic active principle salt when the analgesic active principle salt is improperly extracted, notably by a drug abuser, in vitro in solution from said oral solid dosage form.

1 . An oral solid dosage form containing at least one salt of at least one analgesic active principle, and an anti-misuse system comprising at least one quenching agent, said quenching agent being suitable for inducing complexation of said analgesic active principle salt when the analgesic active principle salt is improperly extracted, notably by a drug abuser, in vitro in solution from said oral solid dosage form.  
   
   
       2 . The dosage form according to  claim 1 , wherein the desired pharmacological effect of the analgesic active principle is not impaired by the quenching agent when the dosage form is not misused.  
   
   
       3 . The dosage form according to  claim 1  or  2 , wherein the concentration of analgesic active principle remaining in solution is low after extraction.  
   
   
       4 . The dosage form according to any one of the preceding claims, wherein said quenching agent comprises a salt, said salt containing ions which form a complex with said analgesic active principle salt extracted in solution.  
   
   
       5 . The dosage form according to any one of the preceding claims, wherein said quenching agent comprises a salt, said salt containing ions, preferably organic ions, having a polarity opposite to that of the analgesic active principle salt in solution, said ions forming a complex with said analgesic active principle salt extracted in solution.  
   
   
       6 . The dosage form according to  claim 5 , wherein said ion having a polarity opposite to that of the analgesic active principle salt in solution, is an organic anion.  
   
   
       7 . The dosage form according to any one of the preceding claims, wherein the quenching agent comprises a salt selected from the group comprising: 
 organic anionic salts, such as sodium dodecyl sulfate or sodium docusate;    anionic polymers, such as (meth)acrylic copolymers (for instance Eudragit® S et L), crosslinked acrylic polyacids (for instance, Carbopol), cellulose carboxymethycellulose and its derivates, crosslinked carboxymethylcellulose and its derivates and other polysaccharides (for instance, alginate, xanthane or arabic gum), alginate (sulfonate)propylene glycol;    mono- or polyvalent salts, such as glucuronates, citrates, acetates, carbonates, gluconates, succinates, phosphates, glycerophosphates, lactates, trisilicates, fumarates, adipates, benzoates, salicylates, tartrates, sulfonamides, acesulfames;    saponified fatty acids, such as the salts of acetic acid, succinic acid, citric acid, stearic acid, palmitic acid, and self emulsifying glyceryl mono-oleates;    polyamino acid, proteins or peptides, such as albumins, caseins, globulins and enzymes;    and mixtures thereof.    
   
   
       8 . The dosage form according to any one of  claims 1  to  5 , wherein said ion having a polarity opposite to that of the analgesic active principle salt in solution, is a metallic cation, an organic cation, or a mixture thereof.  
   
   
       9 . The dosage form according to  claim 8 , wherein the quenching agent comprises a salt selected from the group comprising: 
 metallic cationic salts for example of Ca, Fe, Mg, Zn, in the form of acesulfames, acetates, adipates, benzoates, carbonates, chlorides, citrates, fluorides, fumarates, gluconates, glucuronates, glycerophosphates, hydroxides, iodates, iodides, lactates, oxides, phosphates, trisilicates, phosphates, salicylates, succinates, sulfonamides, tartrates salt;    organic cationic salts, such as quaternary ammonium salts, in particular trimethyl tetradecyl ammonium bromide or benzethonium chloride;    cationic polymers, such as chitosan and (meth)acrylic copolymers (for instance, Eudragit® RS, RL ou E);    polyamino acid, proteins or peptides;    and mixtures thereof.    
   
   
       10 . The dosage form according to any one of  claims 1  to  7 , wherein the quenching agent is a salt of an anionic exchange resin, the cation of which being H + , a metallic cation and/or NH 4   + .  
   
   
       11 . The dosage form according to any one of the preceding claims, wherein the quenching agent is a salt of an ion exchange resin.  
   
   
       12 . The dosage form according to any one of the preceding claims, wherein the quenching agent is selected from the group consisting of: 
 anionic organic salts, such as sodium dodecyl sulfate or sodium docusate;    cationic organic salts, such as quaternary ammonium salts, in particular trimethyl tetradecyl ammonium bromide or benzethonium chloride;    strong acid cation exchange resins, of strong alcali anion exchange resins, depending on the AP polarity.    
   
   
       13 . The dosage form according to  claim 11  or  12 , wherein said ion exchange resin is a strong acid cation exchange resin where the AP is cationic, or a strong alcali anion exchange resin where the AP is anionic.  
   
   
       14 . The dosage form according to any one of claims  1 I to  13 , wherein said resin is derived from a sulphonated styrene-divinylbenzene copolymer.  
   
   
       15 . The dosage form according to any one of  claims 11  to  13 , wherein said resin is derived from a styrene-divinylbenzene copolymer bearing quaternary ammonium moieties, or salts thereof.  
   
   
       16 . The dosage form according to any one of the preceding claims, wherein it comprises modified release units of said analgesic active principle and of said quenching agent.  
   
   
       17 . The dosage form according to  claim 16 , wherein said modified release units comprise microparticles selected from the group comprising: sustained release microparticles, delayed release microparticles, pulsed release microparticles, and mixtures thereof.  
   
   
       18 . The dosage form according to any one of the preceding claims, wherein said dosage form is a multimicroparticulate dosage form.  
   
   
       19 . The dosage form according to any one of the preceding claims, wherein said dosage form is a monolithic dosage form.  
   
   
       20 . The dosage form according to any one of the preceding claims, comprising microparticles of analgesic active principle and microparticles of quenching agent, said microparticles having the same size distribution, the same density and being not sievable.  
   
   
       21 . The dosage form according to  claim 1 , comprising a further antimisuse agent.  
   
   
       22 . The dosage form according to the preceding claim, wherein said further antimisuse agent comprises an anti-crushing agent.  
   
   
       23 . The dosage form according to claims  21  or  22 , wherein said further antimisuse agent comprises a viscosity agent.  
   
   
       24 . The dosage form according to any one of the preceding claims, wherein the antimisuse agent is located: 
 in microparticles containing said antimisuse agent, and/or    in a matrix containing said analgesic active principle, and/or    in a coating of microparticles containing said analgesic active principle, and/or    in a partial or total overcoating of said dosage form, and/or free from said dosage form.    
   
   
       25 . The dosage form according to  claim 22 , wherein said anti-crushing agent comprises: 
 a protective overcoating on said microparticles, said overcoating having at least one of the following features: 
 viscoelastic properties, to absorb the energy dissipated during crushing;  
 a low cohesivity, to favour breaking of the overcoating rather than breaking of the microparticles during crushing;  
 a low surface energy, to favour gliding of the microparticles one on the other during crushing;  
 an ability to form a paste under high shear,  
   and/or free additives, i.e. additives that are not contained in nor borne over microparticles, said additives being suitable to impair, or even to prevent completely, the crushing of the pharmaceutical dosage form containing said analgesic active principle.    
   
   
       26 . The dosage form according to  claim 25 , wherein said overcoating comprises: 
 (i) at least one film forming polymer insuring the cohesion of the overcoating;    and at least one of the following compounds: 
 (ii) a lubricant/lump agent  
 (iii) a viscoelastic compound  
 (iv) a plasticizer.  
   
   
   
       27 . The dosage form according to  claim 26 , wherein said film-forming polymer (i) is selected from the group comprising cellulose derivatives, acrylic polymers and mixtures thereof.  
   
   
       28 . The dosage form according to  claim 26 , wherein said lubricant/lump agent (ii) is selected from the group comprising: 
 stearic acid, stearates, preferably calcium stearate, zinc stearate or magnesium stearate,    magnesium oxide,    poloxamers,    sodium benzoate,    anionic, cationic or non-ionic surfactants,    starch, preferably corn starch,    talc,    colloïdal silica,    waxes, preferably hydrogenated vegetable oils, and more preferably: cotton hydrogenated oils, soybean hydrogenated oils, palm hydrogenated oils, glycerol behenate, castor hydrogenated oils, tristearines, tripalmitines, trimyristines, yellow wax, white wax, hard fat, dairy anhydrous fat, lanolins, glycerol palmitostearate, glycerol stearates, lauric acid macrogolglycerids, cetyl alcohols, polyglycryle di-isostearate, diethylene glycol monostearate, ethylene monostearate, omega-3 fatty acids, and mixtures thereof,    suppository fatty base, comprising glycerine, triglycerids, theobroma oils, cocoa butter, and mixtures thereof,    mixtures thereof.    
   
   
       29 . The dosage form according to  claim 26 , wherein said viscoeslastic compound (iii) is selected from the group comprising: 
 poly-N-vinylamides,    gums,    fatty alcohols,    poly-N-vinyl-lactams,    polyvinyl alcohols,    polyoxiethylenes,    polyethylene glycols,    polydextroses,    hydrogenated mono-, di- and polysaccharides,    polyvinylpyrrolidones, these being preferred, and mixtures thereof.    
   
   
       30 . The dosage form according to  claim 26 , wherein said plasticizer (iv) is selected from the group comprising: 
 glycerol, glycerol esters, preferably acetylated glycerides, glycerylmonostearates, glyceryltriacetate, glyceryltributyrate,    phtalates, preferably: dibutylphthalate, diethylphthalate, dimethylphthalate, dioctylphthalate,    citrates, preferably: acetyltributylcitrate, acetyltriethylcitrate, tributylcitrate, triethylcitrate,    sebaçates, preferably: diethylsebaçate, dibutylsebaçate,    adipates,    azelates,    benzoates,    vegetable oils, preferably: cotton oils, soybean oils, palm oils, castor oils, and mixtures thereof,    fumarates, preferably: diethylfumarate,    malates, preferably: diethylmalate,    oxalates, preferably: diethyloxalate,    succinates; preferably: dibutylsuccinate,    butyrates,    cetyl alcohol esters,    triacetine,    malonates, preferably: diethylmalonate,    and mixtures thereof.    
   
   
       31 . The dosage form according to  claim 25 , wherein said additive is selected from the group comprising: 
 compression agents, and/or    inert microbeads, and/or    gums, and/or    viscoelastic compound as defined in  claim 29 .    
   
   
       32 . The dosage form according to  claim 23 , further comprising viscosity agents which are suitable to increase the viscosity of a liquid extract prepared from said dosage form, so as to impair misuse of said dosage form.  
   
   
       33 . The dosage form according to  claim 32 , wherein said viscosity agent is selected from the group comprising: 
 acrylic polyacids and derivatives thereof, and/or    polyoxyethylenes, and/or    polyvinyl alcohol, and/or    polyvinylpyrrolidones, and/or    gelatins    cellulose derivatives, for instance hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, and/or    polysaccharides, preferably from the group comprising sodium alginate, pectins, guar, xanthanes, carraghenanes, gellanes, and/or    mixtures thereof.    
   
   
       34 . The dosage form according to  claim 1 , wherein said dosage form comprises a plurality of microparticles for the modified release of said analgesic active principle, each microparticles individually comprising a core and a coating on said core, wherein the core comprises at least one analgesic active principle and wherein the coating controls the modified release of said active principle, said microparticles having a mean diameter lower than or equal to 1,000 μm.  
   
   
       35 . The dosage form according to any one of the preceding claims, wherein said analgesic active principle comprises an opioid active principle in the form of a salt.  
   
   
       36 . The dosage form according to  claim 35 , wherein said opioid active principle is selected from the group comprising: anileridine, acetorphine, acetylalphamethylfentanyl, acetyldihydrocodeine, acetylmethadol, alfentanil, allylprodine, alphacetylmethadol, alphameprodine, alphaprodine, alphamethadol, alphamethylfentanyl, alpha-methylthiofentanyl, alphaprodine, anileridine, atropine, butorphanol, benzethidine, benzylmorphine, beta-hydroxyfentanyl, beta-hydroxy-methyl-3-fentanyl, betacetylmethadol, betameprodine, betamethadol, betaprodine, bezitramide, buprenorphine, butyrate de dioxaphetyl, clonitazene, cyclazocine, cannabis, cetobemidone, clonitazene, codeine, coca, cocaine, codoxime, dezocine, dimenoxadol, dioxaphetylbutyrate, dipipanone, desomorphine, dextromoramide, dextropropoxyphene, diampromide, diethyl-thiambutene, difenoxine, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, diphenoxylate, dipipanone, drotebanol, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, ecgonine, ephedrine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, etoxeridine, fentanyl, furethidine, heroine, hydrocodone, hydromorphinol, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphane, lofentanil, levomethorphane, levomoramide, levophenacylmorphane, levorphanol, meptazinol, meperidine, metazocine, methadone, methyldesorphine, methyldihydro-morphine, methylphenidate, methyl-3-thiofentanyl, methyl-3-fentanyl, metopon, moramide, morpheridine, morphine, mppp, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, nicocodine, nicodicodine, nicomorphine, noracymethadol, norcodeine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papavereturn, phenadoxone, phenoperidine, promedol, properidine, propiram, propoxyphene para-fluorofentanyl, pepap, pentazocine, pethidine, phenampromide, phenazocine, phenomorphane, phenoperidine, pholcodine, piminodine, piritramide, proheptazine, propanolol, properidine, propiram, racemethorphane, racemoramide, racemorphane, remifentanil, sufentanil, thebacone, thebaine, thiofentanyl, tilidine, trimeperidine, tramodol, pharmacologically acceptable salts thereof and their mixtures.  
   
   
       37 . The dosage form according to any one of the preceding claims, comprising at least one non-analgesic active principle selected from the group comprising: anti-depressants, amphetamines, anorectics, pain killers, antiepileptics, anitmigraines, antiparkinson agents, antitussives, anxiolytics, barbiturics, benzodiazepines, hypnotics, laxatives, neuroleptics, psychostimulants, psychotropes, sedatives, stimulants, anti-inflammatory agents, the pharmacologically acceptable salts thereof, and their mixtures.  
   
   
       38 . The dosage form according to  claim 1 , which is in the form of tablets, powders, sachets, or capsules.