Prolonged-release multimicroparticulate oral pharmaceutical form

Abstract

Modified-release multimicroparticulate pharmaceutical form capable of maintaining the modified release of the active principle in an alcoholic solution and of resisting attempts at misuse.

1 .- 69 . (canceled) 
     
     
         70 . A tablet comprising:
 i) coated modified release microparticles comprising at least one active principle (AP), and   ii) a pharmaceutically acceptable compound of which the rate of hydration or of solvation or the ability to hydrate or to solvate is greater in an aqueous medium free of alcohol than in an alcoholic solution, said compound being named agent D,   wherein the agent D is present in a mixture with the coated modified release microparticles of AP or is included in a coating deposited onto the tablet, wherein the coated modified release microparticles of AP comprise a core comprising said AP, said core being coated with at least one coating R,   wherein the coating R represents at least 30% by weight on dry basis, relative to the total weight of the coated modified release microparticles of AP, and comprises by weight relative to the total weight of the coating R:
 60 to 90% of a film-forming (co)polymer A1 which is insoluble in the fluids of the gastrointestinal tract; 
 2 to 40% of a (co)polymer A2 which is soluble in the fluids of the gastrointestinal tract; and 
 1 to 30% of a plasticizer A3. 
   wherein the time for releasing 50% of the AP in an alcoholic solution is not decreased by more than threefold compared to the time for releasing 50% of the AP in an aqueous medium free of alcohol.   
     
     
         71 . The tablet according to  claim 70 , wherein in the event of crushing, the modified release is maintained for at least 40% of the coated modified release microparticles of AP. 
     
     
         72 . The tablet according to  claim 70 , wherein in the event of crushing, the modified release is maintained for at least 60% of the coated modified release microparticles of AP. 
     
     
         73 . The tablet according to  claim 70 , wherein in the event of crushing, the modified release is maintained for at least 80% of the coated modified release microparticles of AP. 
     
     
         74 . The tablet according to  claim 70 , wherein the agent D is chosen from the group consisting of: cellulose derivatives, polyalkylene oxides, polysaccharides, proteins, clays and mixtures thereof. 
     
     
         75 . The tablet according to  claim 74 , wherein the agent D is chosen from the group consisting of:
 methylcelluloses,   (hydroxy)(alkyl)celluloses,   carboxyalkylcelluloses and salts thereof,   celluloses,   crosslinked carboxyalkylcelluloses,   polyethylene oxide,   polypropylene oxide   natural starches,   modified starches,   alginates and salts thereof,   polacrilin potassium,   guar gums,   carrageenans,   pullulans,   pectins,   chitosans and derivatives thereof,   gelatins,   albumins,   caseins,   lactoglobulins,   bentonite,   laponite,   and mixtures thereof.   
     
     
         76 . The tablet according to  claim 75 , wherein the agent D is chosen from the group consisting of:
 hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose;   carboxymethylcellulose and salts thereof;   cellulose powder, cellulose microcrystalline;   crosslinked carboxymethylcelluloses;   starch of maize, starch of wheat, starch of potato;   starches modified with sodium glycolate   sodium alginate   and mixtures thereof.   
     
     
         77 . The tablet according to  claim 76 , wherein the agent D is sodium croscarmellose. 
     
     
         78 . The tablet according to  claim 70 , wherein the agent D is present in a mixture with the coated modified release microparticles of AP and included in the binding phase of granules or pellets including the coated modified release microparticles of AP. 
     
     
         79 . The tablet according to  claim 78 , wherein the granules or pellets are obtained by granulation, extrusion or compression. 
     
     
         80 . The tablet according to  claim 70 , wherein the agent D is present in a proportion of 1% to 30% w/w of the total weight of the tablet. 
     
     
         81 . The tablet according to  claim 70 , wherein the agent D is present in a proportion of 2% to 25% w/w of the total weight of the tablet. 
     
     
         82 . The tablet according to  claim 70 , wherein the agent D is present in a proportion of 2% to 20% w/w, of the total weight of the tablet. 
     
     
         83 . The tablet according to  claim 70 , wherein A1 represents 60% to 80% by weight, relative to the weight of the coating R. 
     
     
         84 . The tablet according to  claim 70 , wherein A2 represents 5% to 40% by weight, relative to the weight of the coating R. 
     
     
         85 . The tablet according to  claim 70 , wherein A2 represents 5% to 25% by weight, relative to the weight of the coating R. 
     
     
         86 . The tablet according to  claim 70 , wherein A3 represents 2% to 20% by weight, relative to the weight of the coating R. 
     
     
         87 . The tablet according to  claim 70 , wherein A3 represents 5% to 15% by weight, relative to the weight of the coating R. 
     
     
         88 . The tablet according to  claim 70 , wherein A1 is selected from the group consisting of: water-insoluble derivatives of cellulose, acrylic polymers, poly(vinyl acetate)s, and mixtures thereof. 
     
     
         89 . The tablet according to  claim 88 , wherein A1 is selected from the group consisting of:
 ethylcellulose and cellulose acetates,   copolymers of (meth)acrylic acid and of alkyl ester and copolymers of an ester of acrylic acid and methacrylic acid bearing at least one quaternary ammonium group, copolymers of alkyl (meth)acrylate and trimethylammonioethyl methacrylate chloride.   
     
     
         90 . The tablet according to  claim 70 , wherein A2 is selected from the group consisting of: nitrogenous (co)polymers, water-soluble derivatives of cellulose, polyvinyl alcohols (PVAs), polyalkylene oxides, polyethylene glycols (PEGs), and mixtures thereof. 
     
     
         91 . The tablet according to  claim 90 , wherein A2 is selected from the group consisting of: polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVPs) and poly-N-vinyllactams. 
     
     
         92 . The tablet according to  claim 70 , wherein A3 is selected from the group consisting of: cetyl alcohol esters, glycerol and esters thereof, phthalates, citrates, sebacates, adipates, azelates, benzoates, plant oils, fumarates, malates, oxalates, succinates, butyrates, malonates, castor oil and mixtures thereof. 
     
     
         93 . The tablet according to  claim 70 , wherein:
 A1 is selected from the group consisting of water-insoluble derivatives of cellulose;   A2 is selected from the group consisting of: nitrogenous(co)polymers, water-soluble derivatives of cellulose, polyethylene glycols (PEGs), and mixtures thereof;   A3 is selected from the group consisting of: triethyl citrate, dibutyl sebacate, plant oils, castor oil and mixtures thereof.   
     
     
         94 . The tablet according to  claim 70 , wherein the coating R further comprises at least one surfactant, lubricant, mineral filler or organic filler A4. 
     
     
         95 . The tablet according to  claim 94 , wherein A4 represents less than or equal to 40% by weight, relative to the weight of the coating R. 
     
     
         96 . The tablet according to  claim 94 , wherein A4 represents less than or equal to 20% by weight, relative to the weight of the coating R. 
     
     
         97 . The tablet according to  claim 94 , wherein A4 is selected from the group consisting of: anionic surfactants, nonionic surfactants, stearates, stearyl fumarates, glycerol behenates, talc, colloidal silica, titanium oxide, magnesium oxide, bentonite, microcrystalline cellulose, kaolin, aluminum silicate, and mixtures thereof. 
     
     
         98 . The tablet according to  claim 97 , wherein A4 is selected from the group consisting of:
 alkali metal and alkaline earth metal salts of fatty acids;   polyoxyethylenated oils; polyoxyethylene/polyoxypropylene copolymers (poloxamer); polyoxyethylenated sorbitan esters; polysorbates and polyoxyethylenated castor oil derivatives;   calcium stearate, magnesium stearate, aluminum stearate and zinc stearate.   
     
     
         99 . The tablet according to  claim 98 , wherein A4 is polyoxyethylenated hydrogenated castor oil. 
     
     
         100 . The tablet according to  claim 70 , wherein the coating R represents 30% to 60% by weight on dry basis, of the total weight of the coated modified release microparticles of AP. 
     
     
         101 . The tablet according to  claim 70 , wherein the coating R represents 40% to 60% by weight on dry basis, of the total weight of the coated modified release microparticles of AP. 
     
     
         102 . The tablet according to  claim 70 , wherein the coating R represents 45% to 55% by weight on dry basis, of the total weight of the coated modified release microparticles of AP. 
     
     
         103 . The tablet according to  claim 70 , wherein the coating R is a single coating layer. 
     
     
         104 . The tablet according to  claim 70 , wherein the core comprising said AP is:
 a matrix granule containing said AP and other pharmaceutically acceptable excipients; or   a support particle coated with at least one layer comprising said AP.   
     
     
         105 . The tablet according to  claim 104 , wherein the pharmaceutically acceptable excipients of the matrix granule are selected from the group consisting of: binders, surfactants, disintegrating agents, fillers and buffering agent. 
     
     
         106 . The tablet according to  claim 104 , wherein the support particle is a cellulose microsphere or a particle comprising at least one of the compounds selected from the group consisting of: sucrose, saccharose, dextrose, lactose, mixture of sucrose and starch, xanthan gum, guar gum, calcium phosphate and calcium carbonate. 
     
     
         107 . The tablet according to  claim 104 , wherein the mean diameter of the support particles is from 1 to 800 μm. 
     
     
         108 . The tablet according to  claim 104 , wherein the mean diameter of the support particles is from 20 to 500 μm. 
     
     
         109 . The tablet according to  claim 70 , wherein the coated modified release microparticles of AP have a volume-average diameter of less than or equal to 1000 μm. 
     
     
         110 . The tablet according to  claim 70 , wherein the coated modified release microparticles of AP have a volume-average diameter of 50 to 800 μm. 
     
     
         111 . The tablet according to  claim 70 , wherein the coated modified release microparticles of AP have a volume-average diameter of 100 to 600 μm. 
     
     
         112 . The tablet according to  claim 70 , wherein the coated modified release microparticles of AP have a volume-average diameter of 100 to 400 μm. 
     
     
         113 . The tablet according to  claim 70 , further comprising at least one viscosity-modifying agent V. 
     
     
         114 . The tablet according to  claim 113 , wherein the viscosity-modifying agent V is in the form of microparticles distinct from the coated modified release microparticles of AP. 
     
     
         115 . The tablet according to  claim 113 , wherein the viscosity-modifying agent V is chosen from viscosity-modifying agents which are soluble in at least one of the following extraction solvents: water, alcohols, ketones, and mixtures thereof. 
     
     
         116 . The tablet according to  claim 113 , wherein the viscosity-modifying agent V is chosen from the group consisting of: poly(meth)acrylic acid and derivatives thereof, polyalkylene glycols, polyalkylene oxides, polyvinylpyrrolidones, gelatins, polysaccharides and mixtures thereof. 
     
     
         117 . The tablet according to  claim 116 , wherein the viscosity-modifying agent V is chosen from the group consisting of: sodium alginate, pectins, guars, xanthans, carrageenans, gellans, and cellulose derivatives. 
     
     
         118 . The tablet according to  claim 117 , wherein the viscosity-modifying agent V is chosen from the group consisting of: hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose. 
     
     
         119 . The tablet according to  claim 113 , wherein the viscosity-modifying agent V is polyoxyethylene having a molecular weight of 1 million g/mol to 8 million g/mol. 
     
     
         120 . The tablet according to  claim 113 , wherein the amount of viscosity-modifying agent V in the tablet is adjusted so as to render the viscosity of 2.5 ml of the extraction solvent greater than or equal to 100 mPa·s. 
     
     
         121 . The tablet according to  claim 113 , wherein the quantity of viscosity-modifying agent V from 2 to 400 mg. 
     
     
         122 . The tablet according to  claim 113 , wherein the quantity of viscosity-modifying agent V is from 5 to 200 mg. 
     
     
         123 . The tablet according to  claim 113 , wherein the quantity of viscosity-modifying agent V is from 10 to 100 mg. 
     
     
         124 . The tablet according to  claim 70 , further comprising at least one quenching agent Q. 
     
     
         125 . The tablet according to  claim 124 , wherein the quenching agent Q is in the form of microparticles distinct from the coated modified release microparticles of AP. 
     
     
         126 . The tablet according to  claim 124 , wherein the quenching agent Q is in a non-complexed form regarding the AP within the tablet. 
     
     
         127 . The tablet according to  claim 124 , wherein the quenching agent Q comprises a salt, which contains ions capable of forming a complex with salt of AP extracted in solution. 
     
     
         128 . The tablet according to  claim 127 , wherein the ions of the quenching agent Q are organic ions of polarity opposite to that of the AP in solution. 
     
     
         129 . The tablet according to  claim 124 , wherein the quenching agent Q is a ion exchange resin or comprises a salt selected from the group consisting of: anionic organic salts, anionic polymers, monovalent or polyvalent salts, saponified fatty acids, polyamino acids, proteins, peptides, metal cationic salts, organic cationic salts, cationic polymers, and mixtures thereof. 
     
     
         130 . The tablet according to  claim 129 , wherein the quenching agent Q comprises a salt selected from the group consisting of:
 sodium dodecyl sulfate, sodium docusate;   anionic (meth)acrylic copolymers, crosslinked polyacrylic acids, carboxymethylcellulose and its derivatives, crosslinked carboxymethylcellulose and its derivatives, polysaccharides, alginate (sulfonate) propylene glycol;   salts of glucuronates, citrates, acetates, carbonates, gluconates, succinates, phosphates, glycerophosphates, lactates, trisilicates, fumarates, adipates, benzoates, salicylates, tartrates, sulfonamides, acesulfames;   salts of Ca, Fe, Mg and Zn in the form of chlorides, fluorides, hydroxides, iodates, iodides, oxides;   salts of acetic acid, succinic acid, citric acid, stearic acid, palmitic acid, and self-emulsifying glycerylmonooleates;   trimethyltetradecyl ammonium, bromide or benzethonium chloride;   chitosan and cationic(meth)acrylic copolymers;   anionic and cationic polyamino acids, proteins or peptides; and   mixtures thereof.   
     
     
         131 . The tablet according to  claim 130 , wherein the quenching agent Q selected from the group consisting of: alginate, xanthan gum and gum Arabic. 
     
     
         132 . The tablet according to  claim 124 , wherein the quenching agent Q is chosen from: cation exchange resins or anion exchange resins, depending on the polarity of the AP. 
     
     
         133 . The tablet according to  claim 124 , wherein the quenching agent Q is a derivative of a styrene/divinylbenzene copolymer, a derivative of a sulfonic styrene/divinylbenzene copolymer, a derivative of styrene/divinylbenzene copolymer bearing quaternary ammonium functions, a crosslinked copolymer of methacrylic acid and of divinylbenzene or a salt thereof, a phenolic polyamine, or a mixture thereof. 
     
     
         134 . The tablet according to  claim 124 , wherein the quenching agent Q is chosen from: sodium dodecyl sulfate, sodium docusate, trimethyltetradecyl ammonium, bromide or benzethonium chloride and cation exchange resins or anion exchange resins, depending on the polarity of the AP. 
     
     
         135 . The tablet according to  claim 124 , wherein the amount of quenching agent is adjusted so as to complex all or part of the dose of AP contained in the unit form. 
     
     
         136 . The tablet according to  claim 70 , further comprising at least one pharmaceutically acceptable excipient not contained in or supported by coated modified release microparticles of AP, said excipient contributing to the resistance of crushing of the coated modified release microparticles of AP and selected from the group consisting of: calcium stearate, glyceryl behenate, glyceryl palmitostearate, magnesium oxide, polyalkylene glycols, polyvinyl alcohol, sodium benzoate, stearic acid, corn starch, talc, colloidal silica, zinc stearate, magnesium stearate, stearyl fumarate, and mixtures thereof. 
     
     
         137 . The tablet according to  claim 70 , comprising at least 500 coated modified release microparticles of AP. 
     
     
         138 . The tablet according to  claim 70 , comprising from 1000 to 1 000 000 coated modified release microparticles of AP. 
     
     
         139 . The tablet according to  claim 70 , comprising from 5000 to 500 000 coated modified release microparticles of AP. 
     
     
         140 . The tablet according to  claim 70 , comprising a plurality of populations of coated modified release microparticles of AP, said populations differing from one another by virtue of their release kinetics or by virtue of the AP that they contain. 
     
     
         141 . The tablet according to  claim 70 , comprising coated modified release microparticles of AP and immediate-release microparticles of AP. 
     
     
         142 . The tablet according to  claim 70 , comprising an ion exchange resin, polyoxyethylene and wherein agent D is methylcellulose. 
     
     
         143 . The tablet according to  claim 70  comprising an ion exchange resin, polyoxyethylene and wherein agent D is a mixture of methylcellulose and hydroxyethylcellulose. 
     
     
         144 . The tablet according to  claim 70  comprising an ion exchange resin, polyoxyethylene and wherein agent D is a mixture of methylcellulose and hydroxypropylcellulose. 
     
     
         145 . The tablet according to  claim 70  comprising an ion exchange resin, polyoxyethylene and wherein agent D is hydroxypropyl methylcellulose. 
     
     
         146 . The tablet according to  claim 70  comprising 2 to 400 mg of a viscosity-modifying agent V contained in microparticles distinct from the coated modified release microparticles of AP and at least one quenching agent Q contained in microparticles distinct from the coated modified release microparticles of AP and from the viscosity agent microparticles. 
     
     
         147 . The tablet according to  claim 146 , wherein:
 A1 is selected from the group consisting of water-insoluble derivatives of cellulose;   A2 is selected from the group consisting of: nitrogenous (co)polymers, water-soluble derivatives of cellulose, polyethylene glycols (PEGs), and mixtures thereof;   A3 selected from the group consisting of: triethyl citrate, dibutyl sebacate, plant oils, castor oil, and mixtures thereof;   the agent D is selected from the group consisting of: hydroxyalkylcelluloses, methylcellulose, carboxy(alkyl)celluloses, and salts thereof, guar gums, carrageenans and mixtures thereof;   the viscosity-modifying agent V is chosen from: polyalkylene oxides, xanthans, cellulose derivatives and mixtures thereof;   the quenching agent Q is selected from the group consisting of: dodecyl sulfate, sodium docusate, trimethyltetradecyl anmmonium bromide, benzethonium chloride and ion exchange resins.   
     
     
         148 . The tablet according to  claim 70 , wherein the active principle AP is selected from the group consisting of: opiates, anxiolytics, benzodiazepines, anorexigens, antidepressants, antiepileptics, antiparkinsonian agents, barbiturates, hypnotics, neuroleptics, psychostimulants, psychotropic agents, amphetamines and mixtures thereof. 
     
     
         149 . The tablet according to  claim 70 , wherein the AP is chosen from the group consisting of: acetorphine, acetyl-alpha-methylfentanyl, acetyldihydrocodeine, acetylmethadol, alfentanil, allylprodine, alpha-cetylmethadol, alphameprodine, alphaprodine, alphamethadol, alpha-methylfentanyl, alphamethylthiofentanyl, anileridine, butorphanol, benzethidine, benzylmorphine, beta-hydroxyfentanyl, beta-hydroxymethyl-3-fentanyl, beta-cetylmethadol, betameprodine, betamethadol, betaprodine, bezitramide, buprenorphine, dioxaphetyl butyrate, clonitazene, cyclazocine, cannabis, codeine, coca, cocaine, codoxime, dezocine, dimenoxadol, dipipanone, desomorphine, dextromoramide, dextropropoxyphene, diampromide, diethylthiambutene, difenoxin, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, diphenoxylate, dipipanone, drotebanol, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, ethylmethylthiambutene, ethylmorphine, etorphine, etoxeridine, fentanyl, furethidine, heroin, hydrocodone, hydromorphinol, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, lofentanil, levomethorphan, levomoramide, levophenacylmorphan, levorphanol, meptazinol, meperidine, metazocine, methadone, methyldesorphine, methyldihydromorphine, methylphenidate, methyl-3-thiofentanyl, methyl-3-fentanyl, metopon, moramide, morpheridine, morphine, myrophine, nalbuphine, narceine, norlevorphanol, normethadone, nalorphine, normorphine, nicocodine, nicodicodine, nicomorphine, noracymethadol, norcodeine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, phenadoxone, phenoperidine, promedol, properidine, propiram, propoxyphene, parafluorofentanyl, pentazocine, pethidine, phenampromide, phenazocine, phenomorphan, phenoperidine, pholcodine, piminodine, piritramide, proheptazine, racemethorphan, racemoramide, racemorphan, remifentanil, sufentanil, thebacone, thebaine, thiofentanyl, tilidine, trimeperidine, tramadol, and the pharmacologically acceptable salts, esters, hydrates, polymorphs and isomers thereof, and mixtures thereof. 
     
     
         150 . The tablet according to  claim 70 , wherein the AP is selected from the group consisting of: oxycodone hydrochloride, morphine sulfate, oxymorphone hydrochloride, hydromorphone hydrochloride, hydrocodone hydrochloride and tramadol hydrochloride.