US 2017007 1862A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0071862 A1 WENING et al. (43) Pub. Date: Mar. 16, 2017 (54) PROTECTING ORAL OVERDOSE WITH Publication Classification ABUSE DETERRENT IMMEDIATE RELEASE (51) Int. Cl. FORMULATIONS A69/20 (2006.01) A6II 3/167 (2006.01) (71) Applicant: GRÜNENTHAL GMBH, Aachen (DE) A63/37 (2006.01) (72) Inventors: KLAUS WENING, Koln (DE): A63L/485 (2006.01) Sebastian Schwier, Aachen (DE); (52) U.S. Cl. Ulrike Bertram, Aachen (DE) CPC .......... A61K 9/2022 (2013.01); A61K 31/485 (2013.01); A61K 31/167 (2013.01); A61 K (73) Assignee: GRUNENTHAL GMBH, Aachen (DE) 31/137 (2013.01) (57) ABSTRACT (21) Appl. No.: 15/260,643 The invention relates to a pharmaceutical dosage form which is particularly useful for the prevention of an over (22) Filed: Sep. 9, 2016 dose of the pharmacologically active ingredient contained therein after accidental or intentional simultaneous admin (30) Foreign Application Priority Data istration of a plurality of the dosage forms containing an overall Supratherapeutic dose of the pharmacologically Sep. 10, 2015 (EP) ..................................... 15184634 active ingredient. Patent Application Publication Mar. 16, 2017. Sheet 1 of 16 US 2017/0071862 A1 Ø · ???????-3x=?ö-- e| Ø Patent Application Publication Mar. 16, 2017. Sheet 2 of 16 US 2017/0071862 A1 -ZZZZZZZZZZZZZZZZZZZZZZZZZZZÌX?- ^ST,·N§ e| =Ø?= :))||ZON Patent Application Publication Mar. 16, 2017. 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Sheet 7 of 16 US 2017/0071862 A1 FIG. 7 Patent Application Publication Mar. 16, 2017. Sheet 8 of 16 US 2017/0071862 A1 OO ---------------------------------------------------------------------- mhm 1 tablet invex. 2 90 an 10 tabletS inv. ex. 2 80 °-x-5 tablets invex. 2 ”ue1" 70 see 10 tabletS COmp. eX. 2 a Stomach emptying O SO 40 O O O 2O 30 AO SO 60 70 Time (min) FIG 9 OO 90 FO 60 SO aho. 1 tablet in W. ex: 2 40 on 10 tabletS inv., ex. 2 30 20 one 10 tablets Comp. ex. 2 O am Stomach emptying 2O 4. 6) 8O O 2 AO is 8C 20) Time (min) Patent Application Publication Mar. 16, 2017. Sheet 9 of 16 US 2017/0071862 A1 FIG 10A OO - 90 80 - 70 80 SO 40 3O 20 O m Stomach emptying fed O 20 AO 60 8. 300 20 40 60 80 200 Time (min) FG, 10B OO e s 90 1. Ouala 1. 70 50 40 as as a stomach emptying fasted 3. i Z am stomach emptying fed 2O O i Z 1. was 10 tablets inv. ex: 2 fed O 4 -1 as the 10 tablets inv. ex: 2 fasted O O SO 100 SO 200 Time (min) Patent Application Publication Mar. 16, 2017. Sheet 10 of 16 US 2017/0071862 A1 FIG 10C OO 90 SO 70 60 50 40 30 - X f / / an a stomach emptying fasted f f / / m Stomach emptying fed 20 ... 10 tablets COmp. ex: 2 fed O - 10 tablets comp. ex: 2 fasted O 20 4. 60 8 13 20 40 60 30 200 Time (min) Patent Application Publication Mar. 16, 2017. Sheet 11 of 16 US 2017/0071862 A1 F.G. 11 O) 90 -- 1 tablet inv. eX. 2 10 tablets inv. eX. 2 80 are 5 tabletS inv. eX. 2 70 - 10 tablets Comp. ex. 2 60 Stomach emptying 40 ae 30 s 20 O O O O 20 3O 40 SO 6 70 Time (min) FG, 12 OO 90 80 70 6 - SO O 1 tablet inv. ex. 2 30 MA.- 10 tablets invex. 2 2O | 4 -// are 10 tablets Comp. eX. 2 O 1 1/ m stomach emptying OO 20 40 60 80 200 Time (min) Patent Application Publication Mar. 16, 2017. Sheet 12 of 16 US 2017/0071862 A1 F.G. 13A OO 90 ea. 80 w O a 7 y 40 f A 7 7 30 1 tablet in V. ex: 2 fasted 2O Y 7 /--- stomach emptying fasted i // / a0a 1 tablet inv. ex: 2 fed O waysay O 20 AO 6. 80 100 120 148 is 80 200 Time (min) FG, 13B O 90 -1.-1.- 80 1 -1 60 are or stomach emptying fasted f Y ame stomach emptying fed 30 If A1 7 7 A / / amme 10 tabletS inv. ex: 2 fed 20 7 - one as 10 tablets inv. ex: 2 fasted e O SO 100 SO 200 Time (min) Patent Application Publication Mar. 16, 2017. Sheet 13 of 16 US 2017/0071862 A1 F.G. 13C 100 9 e O 1. er 30 A 7 - "SO A 7 7 30 f 7 A ... Stomach emptying fasted / / - stomach emptying fed 20 were 10 tablets comp. ex: 2 fed estate 10 tablets comp. ex: 2 fasted O 2 AO SO 30 O 20 AO is 80 20 Time (min) Patent Application Publication Mar. 16, 2017. Sheet 14 of 16 US 2017/0071862 A1 FIG. 14 C -12u 40 4264 1 capsule inv. ex. 3 fasted 3O 10 capsules inv. ex. 3 fasted 7/ 1. 11 10 tablets comp. ex. 3 fasted Z 121 - stomach emptying fasted 7222 OT O 2O 30 AO 5) 60 7) Time (min) FG 15 OO 2m 2 a 70 SO -------------------------------------------------------------------------------A1 SO ZA 40 17 1 capsule inv. eX. 3 fed 30 10 capsules inv. ex. 3 fed 2O 17 10 tablets comp. ex. 3 fed 10. 12 m Stomach emptying fed O 427 SO O 5) OO Time (min) Patent Application Publication Mar. 16, 2017. Sheet 15 of 16 US 2017/0071862 A1 FIG. 16A 100 70 1. 21 60 SO AO A A 7/7 rt 1 capsule inv. ex. 3 fed in stomach emptying fed 2 // ---. 1 CapSule inv. eX. 3 fasted Stomach emptying fasted O 1 / O 21-1 O 50 100 15 200 Time (min) FIG. 16B OO e 90 FO - 1 60 SO a. 40 f /7 10 capsules inv. ex. 3 fed 3O ZZ e stomach emptying fed 2O A 1/ 10 capsules inv. ex. 3 fasted O E21 stomach emptying fasted is a O 50 O) SO 2O Time (min) Patent Application Publication Mar. 16, 2017. Sheet 16 of 16 US 2017/0071862 A1 FG, 16C 4. the 10 tablets comp. ex. 3 fed 30 f A / D. stomach emptying fed 2 - 10 tablets comp. ex. 3 fasted if A / ran stomach emptying fasted O SO OO 150 200 fine (min) FG, 17 OO 90 c.so-------- 3. E-5-1 O so60 1 1 -1 1 1 -1 30 / 1. ce pellets of 1 capsule inv. ex. 3 fasted -- pellets of 10 Capsules inv. ex. 3 fasted 2C Z 1 1 O 7 1-1 Stomach emptying fasted O O O O 30 4) 50 60 70 Time (min) US 2017/007 1862 A1 Mar. 16, 2017 PROTECTING ORAL OVERDOSE WITH WO 2005/016314, WO 2005/063214, WO 2005/102286, ABUSE DETERRENT IMMEDIATE RELEASE WO 2006/002883, WO 2006/002884, WO 2006/002886, FORMULATIONS WO 2006/082097, WO 2006/082099, WO 2008/107149, 0001. This application claims priority of European patent WO 2009/092601, WO 2011/009603, WO 2011/009602, application no. 15 184634.2 that was filed on Sep. 10, 2015. WO 2009/135680, WO 2011/095314, WO 2012/028317, 0002 The invention relates to a pharmaceutical dosage WO 2012/028318, WO 2012/028319, WO 2011/009604, form which is particularly useful for the prevention of an WO 2013/017242, WO 2013/017234, WO 2013/050539, overdose of the pharmacologically active ingredient con WO 2013/127830, WO 2013/072395, WO 2013/127831, tained therein after accidental or intentional simultaneous WO 2013/156453, WO 2013/167735, WO 2015/004245, administration of a plurality of the dosage forms containing WO 2014/191396, and WO 2014/191397. an overall Supratherapeutic dose of the pharmacologically 0007 Still another concept to prevent abuse relies on the active ingredient. presence of auxiliary Substances that increase the Viscosity 0003) A large number of drugs have a potential for being of the resultant composition when the dosage forms are abused or misused, i.e. they can be used to produce effects tampered with, e.g. when they are subjected to liquids in which are not consistent with their intended use. Examples order to prepare formulations for parenteral administration, of commonly abused drugs include psychoactive drugs, e.g. intravenous injection. Said auxiliary Substances increase anxiolytics, sedative hypnotics, stimulants, depressants, and the viscosity of the resultant compositions to Such an extent analgesics such as narcotic analgesics, among others. In that the liquids cannot be drawn-up in Syringes. While it may particular, drugs which have a psychotropic effect, e.g. be possible to extract the drug from the dosage form at least opioids, morphine derivatives, barbiturates, amphetamines, to a certain extent, the extract is not useful for Subsequent ketamine, and other drugs, are abused to induce euphoric abuse. states similar to being intoxicated, and can cause psycho logical or physical dependence.