US 20200038330A1 IN (19 ) United States ( 12) Patent Application Publication (10 ) Pub . No.: US 2020/0038330 A1 BARTHOLOMÄUS et al. (43 ) Pub . Date : Feb. 6 , 2020 (54 ) ABUSE - PROOFED ORAL DOSAGE FORM Publication Classification (51 ) Int. CI. ( 71) Applicant : GRÜNENTHAL GMBH , Aachen (DE ) A61K 9/20 ( 2006.01) ( 72 ) Inventors : Johannes BARTHOLOMÄUS , Aachen A61K 9/00 (2006.01 ) (DE ) ; Heinrich KUGELMANN , A61K 31/485 ( 2006.01) Aachen ( DE ) ; Elisabeth A61K 9/28 ( 2006.01) ARKENAU -MARIC , Köln (DE ) (52 ) U.S. CI. CPC A61K 9/2031 (2013.01 ) ; A61K 9/2068 (73 ) Assignee : GRÜNENTHAL GMBH , Aachen (DE ) ( 2013.01 ) ; A61K 9/0053 ( 2013.01) ; A61K 9/0002 ( 2013.01 ) ; A61K 31/485 (2013.01 ) ; (21 ) Appl. No.: 16 /542,808 A61K 9/28 (2013.01 ) ; A61K 9/2027 ( 2013.01) ; Aug. 16 , 2019 A61K 9/2893 (2013.01 ) ; A61K 9/2095 ( 22 ) Filed : ( 2013.01) ; A61K 9/2013 ( 2013.01 ) ; A61K Related U.S. Application Data 9/2054 ( 2013.01 ) (63 ) Continuation of application No. 15 /878,524 , filed on Jan. 24 , 2018 , now abandoned , which is a continu ation of application No. 15 /255,534 , filed on Sep. 2 , (57 ) ABSTRACT 2016 , now abandoned , which is a continuation of application No. 15 /059,730 , filed on Mar. 3 , 2016 , now abandoned , which is a continuation of applica The present invention relates to an abuse- proofed , oral tion No. 14 /795,900 , filed on Jul. 10 , 2015 , now dosage form with controlled opioid - release for once daily abandoned , which is a continuation of application No. administration , characterised in that it comprises at least one 13 /897,746 , filed on May 20 , 2013 , now abandoned , opioid with potential for abuse ( A ) , at least one synthetic or which is a continuation of application No. 10/890 , natural polymer ( C ) , optionally delayed - release matrix aux 763 , filed on Jul. 14 , 2004 , now abandoned . iliary substances , physiologically acceptable auxiliary sub stances ( B ), optionally a wax ( D ) and optionally at least one Foreign Application Priority Data delayed - release coating, component ( C ) or ( D ) in each case ( 30 ) exhibiting a breaking strength of at least 500 N , preferably Jul . 1 , 2004 (DE ) 10 2004 032 049.7 of at least 1000 N. US 2020/0038330 A1 Feb. 6 , 2020 1 ABUSE -PROOFED ORAL DOSAGE FORM [ 0007 ] The multilayer tablet disclosed in WO 95/20947 is [ 0001 ] This application is a continuation of U.S. patent based on a similar approach to preventing parenteral abuse , application Ser. No. 15 /878,524 , filed Jan. 24 , 2018, now said tablet containing the opioid with potential for abuse and pending , which is a continuation of U.S. patent application at least one gel former , each in different layers. Ser . No. 15 / 255,534 , filed Sep. 2 , 2016 , now abandoned , [0008 ] WO 03/015531 A2 discloses another approach to which is a continuation of U.S. patent application Ser . No. preventing parenteral abuse . A dosage form containing an 15 /059,730 , filed Mar. 3 , 2016 , now abandoned , which is a analgesic opioid and a dye as an aversive agent is described continuation of U.S. patent application Ser . No. 14 /795,900 , therein . The colour released by tampering with the dosage filed Jul. 10 , 2015 now abandoned , which is a continuation form is intended to discourage the abuser from using the ofU.S. patent application Ser. No. 13 /897,746 , filed May 20 , dosage form which has been tampered with . 2013 , now abandoned , which is a continuation of U.S. patent [ 0009 ] Another known option for complicating abuse application Ser. No. 10 /890,763 , filed on Jul . 14 , 2004 , now involves adding to the dosage form an antagonist to the abandoned , which claims priority of German Patent Appli opioid , such as for example naloxone or naltrexone , or cation No. 10 2004 032 049.7 , filed on Jul. 1 , 2004 , the compounds which cause a physiological defence response , entire contents of which patent applications are incorporated such as for example ipecacuanha ( ipecac ) root, or bitter herein by reference . substances . [ 0002 ] The present invention relates to an abuse -proofed oral dosage form with controlled opioid release for once [ 0010 ] However , since in most cases of abuse of dosage daily administration , comprising at least one opioid with forms with delayed - release of an opioid , it is still necessary potential for abuse ( A ) , at least one synthetic or natural to pulverise the dosage form , it was the object of the present polymer ( C ), optionally delayed -release matrix auxiliary invention to complicate or prevent the pulverisation preced substances, optionally physiologically acceptable auxiliary ing abuse of the dosage form comprising the means con substances (B ), optionally a wax ( D ) and optionally a ventionally available for potential abuse and accordingly to delayed - release coating, component ( C ) or ( D ) in each case provide a dosage form with controlled release of opioids exhibiting a breaking strength of at least 500 N , preferably with potential for abuse which ensures the desired therapeu of 1000 N. tic effect when correctly administered once daily , but from [ 0003] The name opioids is taken according to the inven which the opioids cannot be converted into a form suitable tion to mean compounds which interact with at least one for abuse simply by pulverisation . opioid receptor. In particular , with the exception of ( 1R2R ) [ 0011 ] This object was achieved by the preparation of the 3-( 3 -dimethylamino - 1 - ethyl- 2 -methyl - propyl ) phenol, the abuse -proofed oral dosage form , according to the invention , physiologically acceptable salts or derivatives thereof, opi with controlled release of at least one opioid for once daily oids are taken to mean those compounds which exhibit a administration , which dosage form comprises, in addition to potential for abuse . at least one opioid and / or at least one of the physiologically [ 0004 ] Preferably , opioids are used for combatting pain . acceptable compounds thereof , preferably salts or deriva To this end , analgesics are frequently used in long -term tives, preferably esters or ethers , with potential for abuse treatment, for example in the case of chronic pain or pain ( A ) , at least one synthetic or natural polymer ( C ) , optionally caused by tumours . In long - term treatment, in particular , it delayed - release matrix auxiliary substances , optionally is important to enable the patient to enjoy a good quality of physiologically acceptable auxiliary substances ( B ) , option life . The measures which improve the quality of life of a ally a wax (D ) , and optionally at least one delayed -release patient include dosage forms which allow once daily admin coating , component ( C ) or (D ) in each case exhibiting a istration . However, because of the relatively large quantity breaking strength of at least 500 N , preferably of 1000 N. of opioid , such dosage forms, which provide delayed release [0012 ] By using components ( C ) and optionally (D ) with of the active ingredient, are particularly attractive to the the stated minimum breaking strength , preferably in such abuser who wishes to induce the desired state of narcosis or quantities that the dosage form also exhibits such a mini euphoria as quickly as possible . mum breaking strength , pulverisation of the dosage form [0005 ] Since , however , delayed - release dosage forms con with conventional means and thus subsequent abuse , pref taining opioids with potential for abuse do not usually give erably nasal or parenteral abuse , may be complicated con rise to the kick desired by the abuser when taken orally even siderably or prevented . in abusively high quantities, these dosage forms for example in the form of tablets or capsules are also comminuted , e.g. [ 0013 ] Preferably , the components ( C ) and optionally ( D ) ground , and sniffed by the abuser for the purpose of abuse are present in such quantities that the dosage form exhibits or the active ingredients are extracted from the powder a breaking strength of at least 500 N , preferably of at least obtained in this way by means of an aqueous liquid and the 1000 N. resultant solution is administered parenterally , in particular [0014 ] Without sufficient comminution of the dosage intravenously , optionally after filtration through cotton wool form , non -hazardous parenteral, in particular intravenous or or cellulose wadding . This type of administration produces nasal administration is impossible or extraction of the active even more accelerated increase in opioid levels than with ingredient takes the abuser too long , or no or an inadequate oral or nasal abuse , with the result desired by the abuser, kick is obtained on abusive oral administration , since spon namely the “ kick ” or “ rush ” . taneous release does not occur. [ 0006 ] U.S. Pat . No. 4,070,494 proposed adding a [ 0015 ] According to the invention , comminution is taken swellable agent to the dosage form in order to prevent abuse . to mean pulverisation of the dosage form with conventional When water is added to extract the opioid , this agent swells means which are available to an abuser, such as for example and ensures that the filtrate separated from the gel contains a pestle and mortar, a hammer, a mallet or other usual means only a small quantity of active ingredient. for pulverisation by application of force . US 2020/0038330 A1 Feb. 6 , 2020 2 [0016 ] The dosage form according to the invention is thus ecarboxylate ) (pethidine ), phenadoxone, phenomorphane , suitable for preventing parenteral , nasal and/