Anti-misuse microparticulate oral pharmaceutical form

Abstract

The present invention relates to solid microparticulate oral pharmaceutical forms whose composition and structure make it possible to avoid misuse of the pharmaceutical active principle (AP) they contain. The object of the present invention is to prevent solid oral drugs from being misappropriated for any use other than the therapeutic use(s) officially approved by the competent public health authorities. In other words, the object is to avoid the voluntary or involuntary misuse of solid oral drugs. The invention relates to a solid oral pharmaceutical form which is characterized in that it contains anti-misuse means, in that at least part of the AP it comprises is contained in coated microparticles for modified release of the AP, and in that the coated microparticles of AP have a coating layer (Ra) which assures the modified release of the AP and simultaneously imparts crushing resistance to the coated microparticles of AP so as to avoid misuse.

1 . A solid oral pharmaceutical form for preventing misuse, the pharmaceutical form comprising coated microparticles for modified release of at least one active principle (AP), said coated microparticles of active principle being resistant to crushing, wherein:
 each of said coated microparticles comprises at least one core and one coating layer (Ra),   said core comprises said at least one active principle,   said core is a granule formed of a matrix of excipients, comprising said at least one active principle,   said coating layer (Ra) represents a fraction by weight (Tp) greater than 30% by dry weight, based on the total weight of the coated microparticles,   said coating layer (Ra) comprises, in a single coating layer:
 at least one film-forming (co)polymer (A1) insoluble in the gastrointestinal juices, present in a proportion of 60% to 90% by weight on a dry basis, relative to the total weight of the coating layer; 
 at least one (co)polymer (A2) soluble in the gastrointestinal juices, present in a proportion of 5% to 40% by weight on a dry basis, relative to the total weight of the coating layer; 
 at least one plasticizer (A3) present in a proportion of 1% to 30% by weight on a dry basis, relative to the total weight of the coating layer; and 
   said pharmaceutical form comprises at least one viscosifier (Vb).   
     
     
         2 . The pharmaceutical form according to  claim 1 , wherein said pharmaceutical form further comprises at least one sequestering agent (Q) capable of forming a complex with the AP in solution. 
     
     
         3 . The pharmaceutical form according to  claim 1 , wherein in the event of crushing, said coating layer (Ra) allows maintenance of a modified release of the active principle for at least some of the coated microparticles. 
     
     
         4 . The pharmaceutical form according to  claim 3 , wherein in the event of crushing, said coating layer (Ra) allows maintenance of a modified release for at least 40% of the coated microparticles for modified release of the active principle. 
     
     
         6 . The pharmaceutical form according to  claim 1 , wherein the coating layer (Ra) comprises A1, A2 and A3 in the following proportion (in % by weight, based on the total weight of the coating): 
       60≦A1≦80; 
       10≦A2≦40; 
       2≦A3≦20. 
     
     
         7 . The pharmaceutical form according to  claim 1 , wherein (A1) is selected from the group comprising:
 water-insoluble cellulose derivatives,   acrylic polymers,   polyvinyl acetates,   and mixtures thereof.   
     
     
         8 . The pharmaceutical form according to  claim 7 , wherein (A1) is selected from the group comprising: ethyl cellulose, cellulose acetate, cellulose acetate butyrate, copolymers of (meth)acrylic acid and an alkyl ester, copolymers of acrylic acid ester and methacrylic acid esters carrying at least one quaternary ammonium group and mixtures thereof. 
     
     
         9 . The pharmaceutical form according to  claim 1 , wherein (A2) is selected from the group comprising:
 nitrogen-containing (co)polymers, selected from the group consisting of polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP), poly-N-vinyl-lactams, and mixtures thereof,   water-soluble cellulose derivatives,   polyvinyl alcohols (PVA),   polyalkylene oxides,   polyethylene glycols (PEG),   and mixtures thereof.   
     
     
         10 . The pharmaceutical form according to  claim 1 , wherein (A3) is selected from the group comprising:
 cetyl alcohol esters,   glycerol and its esters,   phthalates,   citrates,   sebacates,   adipates,   azelates,   benzoates,   vegetable oils,   fumarates,   malates,   oxalates,   succinates,   butyrates,   triacetin,   malonates,   castor oil,   and mixtures thereof.   
     
     
         11 . The pharmaceutical form according to  claim 1 , wherein the coating layer (Ra) further comprises at least one surfactant, lubricant, mineral or organic filler (A4), present in a proportion of less than or equal to 40% by weight on a dry basis, relative to the total weight of the coating layer. 
     
     
         12 . The pharmaceutical form according to  claim 11 , wherein the surfactant, lubricant, mineral or organic filler (A4) is present in a proportion of less than or equal to 30% by weight on a dry basis, relative to the total weight of the coating. 
     
     
         13 . The pharmaceutical form according to  claim 11 , wherein (A4) is selected from the group comprising:
 anionic surfactants selected from the subgroup comprising alkali metal, alkaline earth metal salts of fatty acids, stearic acid, oleic acid,   non-ionic surfactants selected from the following subgroup: polyethoxylated oils, polyethoxylated hydrogenated castor oil, polyoxyethylene/polyoxypropylene copolymers, polyethoxylated sorbitan esters, polyethoxylated castor oil derivatives,   calcium stearate, magnesium stearate, aluminium stearate, zinc stearate, stearylfumarates, glycerol behenates, talcum, colloidal silica, titanium oxide, bentonite, microcrystalline cellulose, kaolin, aluminum silicate,   and mixtures thereof.   
     
     
         14 . The pharmaceutical form according to  claim 1 , wherein in that the coating layer (Ra) represents a fraction by weight Tp comprised between 40 and 60% by dry weight, based on the total weight of the coated microparticles. 
     
     
         15 . The pharmaceutical form according to  claim 1 , wherein the coated microparticles of active principle have a mean diameter less than or equal to 1000 μm. 
     
     
         16 . The pharmaceutical form according to  claim 1 , wherein the coated microparticles of active principle have a mean diameter between 50 and 800 μm. 
     
     
         17 . The pharmaceutical form according to  claim 1 , wherein the coated microparticles of active principle have a mean diameter between 100 and 600 μm. 
     
     
         18 . The pharmaceutical form according to  claim 1 , wherein the coated microparticles of active principle have a mean diameter between 100 and 300 μm. 
     
     
         19 . The pharmaceutical form according to  claim 1 , wherein the viscosifier (Vb) is selected from those which are soluble in at least one of the following solvents: water, alcohols, ketones and mixtures thereof, said viscosifier being capable of increasing the viscosity of the extraction liquid so as to thwart misuse, especially by injection. 
     
     
         20 . The pharmaceutical form according to  claim 19 , wherein the viscosifier (Vb) is selected from the following groups of polymers:
 polyacrylic acids and derivatives thereof,   polyalkylene glycols,   polyalkylene oxides,   polyvinylpyrrolidones,   gelatins,   polysaccharides, selected from the subgroup comprising sodium alginate, pectins, guars, xanthans, carrageenans, gellans, hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose,   and mixtures thereof.   
     
     
         21 . The pharmaceutical form according to  claim 19 , wherein the viscosifier (Vb) is a polyoxyethylene with a molecular weight of 1 million g/mol to 8 million g/mol. 
     
     
         22 . The pharmaceutical form according to  claim 1 , wherein the viscosifier (Vb) is included in microparticles distinct from the coated microparticles of active principle. 
     
     
         23 . The pharmaceutical form according to  claim 22 , wherein the coated microparticles of active principle and the microparticles of the viscosifier (Vb) have a similar size distribution, a similar density and are inseparable from the coated or uncoated microparticles of active principle. 
     
     
         24 . The pharmaceutical form according to  claim 1 , wherein the amount of viscosifier (Vb) corresponds to the minimum amount needed to increase the viscosity of the extraction liquid to a value greater than or equal to 100 mPa·s in an extraction volume of 2.5 ml so as to trap the extracted active principle in the viscous medium. 
     
     
         25 . The pharmaceutical form according to  claim 2 , wherein the sequestering agent Q is an organic ion of opposite polarity to that of the active principle in solution, which form a slightly soluble complex with the extracted active principle salt in solution. 
     
     
         26 . The pharmaceutical form according to  claim 25 , wherein the coated microparticles of active principle salt and the microparticles of sequestering agent Q are distinct. 
     
     
         27 . The pharmaceutical form according to  claim 26 , wherein the coated microparticles of active principle salt and the microparticles of sequestering agent Q have a similar size distribution, a similar density and are not separable by sieving. 
     
     
         28 . The pharmaceutical form according to  claim 2 , wherein the sequestering agent Q is selected from:
 anionic organic salts selected from sodium dodecylsulfate or sodium docusate;   organic cationic salts selected from quaternary ammonium salts, trimethyl-tetradecylammonium bromide or benzethonium chloride;   a strongly acidic cation exchange resin when the active principle is cationic, or a strongly basic anion exchange resin when the active principle is anionic;   polyamino acids, proteins or peptides, selected from the subgroup: albumins, caseins, globulins and enzyme;   and mixtures thereof.   
     
     
         29 . The pharmaceutical form according to  claim 28 , wherein the sequestering agent Q is a derivative of a styrene/divinylbenzene copolymer. 
     
     
         30 . The pharmaceutical form according to  claim 28 , wherein the sequestering agent Q is a derivative of a sulfonated styrene/divinylbenzene copolymer. 
     
     
         31 . The pharmaceutical form according to  claim 28 , wherein the sequestering agent Q is a derivative of a styrene/divinylbenzene copolymer carrying quaternary ammonium groups. 
     
     
         32 . The pharmaceutical form according to  claim 28 , wherein the sequestering agent is a crosslinked methacrylic acid/divinylbenzene copolymer or one of its salts. 
     
     
         33 . The pharmaceutical form according to  claim 28 , wherein the ion exchange resin is a phenolic polyamine. 
     
     
         34 . The pharmaceutical form according to  claim 2 , wherein the amount of sequestering agent Q is adjusted in terms of ionic charge in order to complex all or part of the dose of active principle contained in said pharmaceutical form. 
     
     
         35 . The pharmaceutical form according to  claim 1 , wherein said pharmaceutical form comprises at least one excipient in the free state neither contained in nor supported by microparticles of AP, said excipient contributing to the crushing resistance of the coated microparticles of AP wherein said excipient in free state is selected from the group comprising:
 calcium stearate;   glycerol palmitostearate;   magnesium oxide;   polyalkylene glycols;   polyvinyl alcohol;   sodium benzoate;   stearic acid;   maize starch;   talcum;   colloidal silica;   zinc stearate, magnesium stearate;   stearylfumarate;   and mixtures thereof.   
     
     
         36 . The pharmaceutical form according to  claim 1 , wherein said pharmaceutical form cannot be converted to a dry form with immediate release of the active principle which can be administered by sniffing. 
     
     
         37 . The pharmaceutical form according to  claim 1 , wherein said pharmaceutical form cannot be converted to an injectable form with immediate release of the AP. 
     
     
         38 . The pharmaceutical form according to  claim 1 , wherein said pharmaceutical form further comprises immediate-release active principle. 
     
     
         39 . The pharmaceutical form according to  claim 1 , wherein extraction of the active principle by chewing or crushing is not effective. 
     
     
         40 . The pharmaceutical form according to  claim 1 , wherein the active principle belongs to at least one of the following families of active substances: amphetamines, anorexigenics, antidepressants, antiepileptics, antiparkinsonism substances, anxiolytics, barbiturates, benzodiazepines, hypnotics, narcotics, neuroleptics, opioids, psychostimulants, psychotropic substances and mixture thereof. 
     
     
         41 . The pharmaceutical form according to  claim 1 , wherein the active principle is selected from the following compounds: alfentanil, buprenorphine, codeine, dextropropoxyphene, difenoxin, dihydrocodeine, dihydromorphine, diphenoxylate, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, propoxyphene, pentazocine, pethidine, remifentanil, tramadol, their pharmacologically acceptable salts, esters, hydrates, polymorphs and isomers, and mixtures thereof. 
     
     
         42 . The pharmaceutical form according to  claim 1 , wherein the active principle is selected from the group comprising oxycodone hydrochloride, morphine sulfate, oxymorphone hydrochloride, hydromorphone hydrochloride, hydrocodone hydrochloride and tramadol hydrochloride. 
     
     
         43 . The pharmaceutical form according to  claim 1  wherein said pharmaceutical form is devoid of active principle antagonist(s). 
     
     
         44 . The pharmaceutical form according to  claim 1 , wherein said pharmaceutical form comprises a plurality of populations of coated microparticles of active principle, said populations being distinguished from one another by their release kinetics. 
     
     
         45 . A method of preparing a pharmaceutical formulation for combating the misuse of active principle (AP), the method comprising:
 preparing granules formed of a matrix comprising excipients and including the active principle;   coating the matrix granules comprising the active principle with at least one coating layer (Ra) to create modified release coated microparticles resistant to crushing;   wherein said at least one coating layer (Ra) represents a fraction by weight (Tp) greater than 30% by dry weight, based on the total weight of the coated microparticles,   whereby said at least one coating layer (Ra) comprises:
 at least one film-forming (co)polymer (A1) insoluble in the gastrointestinal juices present in a proportion of 60% to 90% by weight on a dry basis, relative to the total mass of the coating composition; 
 at least one (co)polymer soluble in the gastrointestinal juices (A2) present in a proportion of 5% to 40% by weight on a dry basis, relative to the total mass of the coating composition; and 
 at least one plasticizer (A3) present in a proportion of 1% to 30% by weight on a dry basis, relative to the total mass of the coating composition; and 
   wherein said formulation further comprises at least one viscosifier (Vb).   
     
     
         46 . A method of preparing a pharmaceutical formulation according to  claim 45 , wherein the pharmaceutical formulation further comprises at least one AP sequestering agent Q, whereby a complex with the active principle is formed in solution.