Crush-resistant tablets intended to prevent accidental misuse and unlawful diversion

Abstract

Water-insoluble matrix tablets which are capable of prolonged release of active principles liable to be diverted for drug addiction purposes, the said active principles being dispersed within a tabletting matrix composed of at least one excipient selected from the group consisting of pH-independent, water-insoluble delay polymers, inorganic excipients and mixtures thereof, and exhibiting a crush resistance of at least 4 MPa.

1 .- 26 . (canceled) 
     
     
         27 . A water-insoluble, matrix tablets capable of releasing one or more active ingredients selected from the group consisting of psychotropics, neuroleptics, tranquilizers, hypnotics, analgesics, and anxiolytics into the body over an extended time period comprising at least one active ingredient dispersed within a compression matrix, said matrix comprising a mixture of microcrystalline cellulose and polyvinyl acetate/polyvinylpyrrolidone (80:20) at a proportion of (1:1) wherein said compression matrix represents 50 to 98 weight % of the total weight of said tablet. 
     
     
         28 . The matrix tablets according to  claim 27 , wherein said compression matrix represents 85 to 95 weight % of the total weight of said tablet. 
     
     
         29 . The matrix tablets according to  claim 27 , wherein said active ingredients are selected from the group consisting of morphine, oxycodone, hydrocodone, hydromorphone, oxymorphone, tramadol, methadone, codeine, fentanyl and buprenorphine, their salts and their pharmaceutically acceptable derivatives. 
     
     
         30 . The matrix tablets according to  claim 27 , wherein said compression matrix also contains at least one pharmaceutically acceptable excipient selected from the group consisting of anti-adherent agents, agents capable of improving tablet cohesion on compressing, fillers, lubricants, plasticizers, bulking agents, sweeteners and colouring agents. 
     
     
         31 . The matrix tablets according to  claim 27 , wherein said compression matrix also contains at least one or more of the following substances (a) to (f) or a mixture thereof:
 a) a substance which irritates the nasal and/or pharyngeal tracts,   b) a viscosity-increasing agent, leading to formation of a gel when the tablet is dissolved in a minimum amount of water,   c) an emetic substance,   d) an aversive colouring agent,   e) a bittering substance,
 an antagonist of the active ingredient(s) which may be the subject of drug abuse. 
   
     
     
         32 . The matrix tablets according to  claim 31 , wherein the antagonist agent of said active ingredient(s) which may be the subject of drug abuse is naloxone or naltrexone or one of their pharmaceutically acceptable salts. 
     
     
         33 . The matrix tablets according to  claim 27 , further comprising an outer coating. 
     
     
         34 . The matrix tablets according to  claim 33 , wherein said outer coating comprises at least one sustained-release polymer selected from the group consisting of ethylcellulose derivatives and methacrylic polymers. 
     
     
         35 . The matrix tablets according to  claim 27 , wherein said matrix consists of a mixture of microcrystalline cellulose and polyvinyl acetate/polyvinylpyrrolidone (80:20) to the proportion of (1:1), and wherein said active ingredient is an analgesic. 
     
     
         36 . The matrix tablets according to  claim 35 , further comprising an outer coating consisting of ethylcellulose. 
     
     
         37 . The matrix tablets according to  claim 27 , wherein said matrix tablets are capable of releasing the active ingredient which may be subject to drug abuse over a period of more than 12 hours. 
     
     
         38 . The matrix tablets according to  claim 27 , wherein said matrix tablets are capable of releasing the active ingredient which may be subject to drug abuse over a period of more than 20 hours. 
     
     
         39 . The matrix tablets containing oxycodone according to  claim 35 , wherein said matrix tablets have a plasma profile after once-a-day administration in a human, such that the ratio of the Cmax observed after administration of said tablets to the Cmax value observed after administration of OxyContin® extended release tablets containing the same dose, does not exceed 0.7. 
     
     
         40 . The matrix tablets according to  claim 27 , further comprising oxycodone, wherein the plasma profile of the matrix tablets after once-a-day administration in a human is such that the ratio of AUC∞ observed for said tablets to the AUC∞ value observed with OxyContin® extended release tablets containing the same dose, is between 80 to 125%. 
     
     
         41 . Tablets according to  claim 27 , wherein said tablets can be administered once a day. 
     
     
         42 . Method to produce matrix tablets according to  claim 27 , wherein it comprises the following steps:
 mixing the active ingredient(s) with the excipient(s) of the compression matrix,   optional granulation, and   compressing said mixture under conditions chosen so that said tablet has a crush resistance of at least 4 MPa, advantageously at least 6 MPa.   
     
     
         43 . The method according to  claim 42 , wherein the compression step is conducted without the compression mixture or the compression tooling being subjected to a heating step either before or during the actual compression step. 
     
     
         44 . The method according to  claim 42 , further comprising coating said matrix tablet. 
     
     
         45 . The method according to  claim 43 , further comprising coating said matrix tablet. 
     
     
         46 . Method according to  claim 44 , further comprising curing said outer coating. 
     
     
         47 . A method comprising administering a pharmaceutical composition in the form of tablets according to  claim 27 , for the sustained delivery of active ingredients which may be the subject of the drug abuse, intended to prevent the accidental misuse and/or to deter drug abuse of these active ingredients.