(12) United States Patent (10) Patent No.: US 9,125,833 B2 Babul (45) Date of Patent: *Sep

US009 125833B2

(12) United States Patent (10) Patent No.: US 9,125,833 B2 Babul (45) Date of Patent: *Sep. 8, 2015

(54) MULTIMODAL ABUSE RESISTANT AND A61K 31/13: A61K 31/46; A61K 31/404; EXTENDED RELEASE OPOD A61K 31/443; A61K 31/444; A61K 31/485; FORMULATIONS A61K31/537; A61K31/5375 See application file for complete search history. (75) Inventor: Najib Babul, Blue Bell, PA (US) (73) Assignee: Relmada Therapeutics, Inc., Blue Bell, (56) References Cited PA (US) U.S. PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 2,867,565 A * 1/1959 Wolffe ...... 514/157 U.S.C. 154(b) by 844 days. 3,493,657 A 2f1970 Lewenstein This patent is Subject to a terminal dis (Continued) claimer. FOREIGN PATENT DOCUMENTS (21) Appl. No.: 12/597,702 GB O5 06982.8 4/2005 (22) PCT Fled: Apr. 26, 2008 WO WO 2006/106344 10, 2006 (86) PCT NO.: PCT/US2O08/OOS541 (Continued) S371 (c)(1), OTHER PUBLICATIONS (2), (4) Date: Jun. 4, 2010 PCT Pub. No.: WO2O08/134O71 Banker (Modern Pharmaceutics) Banker, G.S. et al., “Modern (87) Pharmaceutics, 3ed”, Marcel Dekker, New York, 1996, pp. 451 and PCT Pub. Date: Nov. 6, 2008 596. (65) Prior Publication Data (Continued) US 2010/0249045A1 Sep. 30, 2010 Primary Examiner — Lakshmi Channavaljala Related U.S. Application Data (74) Attorney, Agent, or Firm — Dilworth Paxson LLP: Gary (63) Continuation-in-part of application No. 12/216,645, D. Colby filed on Jul. 7, 2008, which is a continuation-in-part of application No. 12/223.987, filed as application No. (57) ABSTRACT PCT/US2006/042962 on Nov. 2, 2006, and a The present invention is in the field of oral, abuse resistant pharmaceutical compositions of opioid agonists, extended (Continued) release pharmaceutical compositions of opioid agonists and (51) Int. C. extended release abuse resistant pharmaceutical composi A6 IK9/42 (2006.01) tions of opioid agonists and the use thereof. The present A6 IK3I/44 (2006.01) invention is also directed to extended release pharmaceutical (Continued) compositions and the use thereof for preventing or minimiz ing the risk of abuse and/or toxicity from either intentional or (52) U.S. C. unintentional tampering. The present invention is further CPC ...... A61K 9/4866 (2013.01); A61 K9/485 directed at a method of preventing or minimizing the risk of (2013.01); A61 K9/4858 (2013.01); A61 K abuse and/or toxicity from either intentional or unintentional 3 1/44 (2013.01) tampering. (58) Field of Classification Search CPC ... A61 K9/2068: A61 K9/4875; A61 K31/00; 20 Claims, 11 Drawing Sheets

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Related U.S. Application Data 2003.0049.317 A1 3/2003 Lindsay 2003.01.18641 A1 6/2003 Maloney continuation-in-part of application No. 12/223,327, 2003/O1241.85 A1 7/2003 Oshlack et al. 2003/0129229 A1 7/2003 KrSek filed as application No. PCT/US2007/002378 on Jan. 2003. O180352 A1 9, 2003 Patel et al. 29, 2007. 2004/0042964 A1 3/2004 Joshi et al. 2004/0058946 A1 3/2004 Buchwald et al. (60) Provisional application No. 60/907.987, filed on Apr. 2004/0101557 A1 5, 2004 Gibson et al. 26, 2007, provisional application No. 60/732,121, 2004/O131552 A1 7/2004 Boehm filed on Nov. 2, 2005, provisional application No. 2004/O131680 A1 7/2004 Goldenheim et al. 60/929,611, filed on Jul. 5, 2008, provisional applica 2004/O132826 A1 7, 2004 Hirsh 2004/0176341 A1 9, 2004 Chou et al. tion No. 60/762,489, filed on Jan. 27, 2006. 20040191323 A1 9, 2004 Asius et al. 2004/0202717 A1 10, 2004 Mehta (51) Int. C. 2004/0228802 A1 1 1/2004 Chang et al. A6 IK9/48 (2006.01) 2005.0020613 A1 1/2005 Boehmet al. A61 K9/20 (2006.01) 2005/0O25832 A1 2/2005 Lam et al. A61 K 9/26 (2006.01) 2005, OO31546 A1 2/2005 Bartholomaus et al. 2005/OO74493 A1 4/2005 Mehta 2005. O152843 A1 7/2005 Bartholomaus et al. (56) References Cited 2005/0208047 A1 9, 2005 Anderson 2005/0238709 A1 10, 2005 Lam et al. U.S. PATENT DOCUMENTS 2005/0281748 A1 12/2005 Hirsh 2006,0002860 A1 1/2006 Bartholomaus et al. 3,773.955 A 11, 1973 Pachter 2006,0003006 A1 1/2006 Remon et al. 3,966,940 A 6, 1976 Pachter 2006.0034872 A1 2, 2006 Woolf 3,980,766 A 9, 1976 Shaw 2006, OO39864 A1 2/2006 Bartholomaus et al. 4,070,494 A 1/1978 Hoffmeister 2006, O110327 A1 5/2006 Emigh et al. 4,457.933 A 7, 1984 Gordon 2006, O188447 A1 8/2006 Arkenau-Maric et al. 4,582,835 A 4, 1986 Lewis 2006, O251721 A1 11, 2006 Cruz et al. 4,713,243 A 12/1987 Schiraldi 2007/0020339 A1 1, 2007 Bear 5,378.474. A 1/1995 Morella et al. 2007/0026.065 A1 2/2007 Benke et al. 5,747,058 A 5/1998 Tipton 2007/0O87977 A1 4/2007 Robbins 5,922,341 A 7, 1999 Smith et al. 2007/O122482 A1 5/2007 Holmet al. 5,958,452 A 9, 1999 OShlack et al. 2007/0231268 A1 10/2007 Emigh et al. 5,968,542 A 10/1999 Tipton 2008.0020032 A1 1/2008 Crowley 5,968,551 A 10, 1999 OShlack 2008 OO698.71 A1 3/2008 Vaughn 6,227,384 B1 5/2001 Saylor 2008.0075768 A1 3/2008 Vaughn 6,228,863 B1 5, 2001 Palermo 2008.007577O A1 3/2008 Vaughn 6,261,599 B1 7/2001 Oshlack 2008.0075771 A1 3/2008 Vaughn 6,266,331 B1 7/2001 Baker 2008/0076789 A1 3/2008 Stinchcomb et al. 6,309.668 B1 10/2001 Bastin 2008. O152595 A1 6/2008 Emigh et al. 6,326,027 B1 12/2001 Miller 2008/O1995.30 A1 8, 2008 Hirsh 6,335,033 B2 1/2002 Oshlack 2008/0280975 A1 11/2008 Badul 6,375,957 B1 4/2002 Kaiko 2009/0082466 A1 3/2009 Babul ...... 514,646 6,475,494 B2 11/2002 Kaiko 2009, O123386 A1 5/2009 Young 6,559,159 B2 5, 2003 Carroll 6,627,635 B2 * 9/2003 Palermo et al...... 514,282 6,638,533 B2 10/2003 Krsek FOREIGN PATENT DOCUMENTS 6,692,771 B2 2/2004 Pather 6,696,066 B2 2/2004 Kaiko WO WO 2007/056142 5/2007 6,696,088 B2 2/2004 OShlack WO WO 2007/087452 8, 2007 6,706,281 B2 3, 2004 OShlack WO WO 2008/033351 3, 2008 6,743,442 B2 6, 2004 OShlack WO WO 2008/134071 11, 2008 7,015,346 B2 3, 2006 Jenkins et al. OTHER PUBLICATIONS 7,083,808 B2 8, 2006 Goldenheim et al. 7,144,587 B2 12/2006 Oshlack et al. West, Anthony R., Solid State Chemistry and its Applications, Wiley, 7,169,752 B2 1, 2007 Mickle 7,172,767 B2 2/2007 Kaiko New York, 1988, pp. 358 & 365.* 7,201.920 B2 4/2007 Kumar et al. Wolff, Manfred E. "Burger's Medicinal Chemistry, 5ed, Part I”, John 7,226,619 B1 6, 2007 Bear Wiley & Sons, 1995, pp.975-977.* 7,399,488 B2 7, 2008 Hirsh Lopez, J. “The Neurobiology of Depression” Cyberounds, 2000, 4 7,419,686 B2 9, 2008 Kaiko pageS. 7,511,054 B2 3/2009 Stinchcomb et al. U.S. Appl. No. 12/223,987, Babul. 7,731,758 B2 6/2010 Asius et al. 2002/0192287 Al 12/2002 Mooney et al. * cited by examiner U.S. Patent Sep. 8, 2015 Sheet 1 of 11 US 9,125,833 B2

Figure 1. WSpectrun of tramadol HCl in water Figure 2. Formulation 05204 dissolution profile

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Figure 3. Formulation 0.520s dissolution prufile Figure 4. Formulation 052,019 dissolution profile, Gelucire 50,02 with Methocei K00M f2 secretary Aeet

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Figures. Formulation 052024 dissolution profile Figure 6, Formulation 0527024 dissolution profile in STF containing pancreatin

Transac in Gelacross2.fuulatian M24 in F8-pincreat rolesaproseaf Tramadol car delucineSat2 Refs224

As of 62 U.S. Patent Sep. 8, 2015 Sheet 2 of 11 US 9,125,833 B2

Figure 7 Dissolution profile of propranolol HCl in Gelucire 50/02 in SIF without pancreatin Figures. Dissolution profile of propranolol HCl in Gelucire 50/02 in SIF containing pancreatin

P Creater SF pa te. Refs Preparescia Gewiresons:Fs Pancretscaps Rev.234

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r 9. Combined averaged dissoluti ?iles of lol HC in Geucire 50/02 in SF with and gure ged A0 E. t 0. s: al Figtre 10, Combined issolution profiles of2ydol XL 150 andromacklSR tablets in SEF Ayernato?phopruwe Kingacruth SF with and without Psncreath adox assarrondesr dissolution insFropancroar Reftslews2954

to s 2 2s so as SaaS2 in an Tristasae Aruam Arumares rean comesR Takemar Rurs rehargewigeon2rdalata

Figure it. Combined dissolution profiles of seven different excipient formulations in SIF Figure 12. Combined dissolution profiles of seven different excipient formulations, extended scale HydrokoteA MC5235- seasons Release Rate of Tramadoles samples Rafas?o. Relas RTraradohc Sangles Rafs2O3. os

to 12 4 6 A 28 22 24 2s 2d 30 33 34 as 28 43 2 4 6 29 22 24 2s 28 3 32 38 38 3 49 42 44 46 4. 7 t of 82 Tine, As a 2 offiz Tin, br. U.S. Patent Sep. 8, 2015 Sheet 3 of 11 US 9,125,833 B2

Figure 13. Combined dissolution profiles oftive base excipients in HPMCinodified formulations Figure 14. Dissolutionprofiles offive capsule samplc of cetyl alcohol formulation with lo'6HPMC Trimdohkreisagroflaweh time, carbingdomulticas pet tissolution of Trumadol harvacetyakoholt fM3 Rafsirst

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gure 15. Dissolution profiles of modified SteratexNFormulation Figure 16, Average dissolution profiles of modified Sterolex NFromulalion Tramme Kinsanbaxwith Heck say insFrancti Razos Awarwelramadoc dissolution profit Mesertex Fort

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Figurg 17.7. Dissolutionprofiles of furthermodified Stcrotex NF formulation Figure 18. Average dissolution profiles of further modified Steviex NFfumulation Tranada ic insterosawth HPhc BAarons propancreat refpsos wergaakkariramadol clineherwth KPMcK15 Aerovicoke,05200

bdi o 7 of S3 A to G2 U.S. Patent Sep. 8, 2015 Sheet 4 of 11 US 9,125,833 B2

Figure 9. Dissolution profiles of tydrokote formulations containing Methccel K 100MerMethocel K 15M Figure 20 Averaged dissolution protes of Hydrokote formulations containing Methocet K100M of MetoceKSM Trunado Hict is hydrokote 112 with KOOLK15MHPIC+Aerosil) in SF C2v62-82 Tremade hid in hydrocote 132 swage plots crxidou K15 HPacissoszos2-182

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gre 2. Dissolution prafles of 256 ring fraruado?hchira 55 ng Steiute x NF based formulation Figureigure 22.22 AAveraged dissolution profiles of 250 mg Tramadolrana HC1 in a 550 mg Scrotex NrbasNF based fouaulation 2sengtrude Hcasterotaxiwirassmgnsrsaries Awrage2songTransdel Heinserotex (noHPwcass0ng insFr20s

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Figure 23, dissolution profiles of75 mg Tramadol FC in beeswax with 20% HPMC based formulation Figure24. Averaged dissolution profiles of 75 mg Tramado HCl in beeswax with 20% HPMC based formulation 75 athsaada HC inbostwar 20%hrie Kisie Aurosk2%)nsfs2Nite Awagators ragtransdal Kosbercwaxwith 20% tracK15kg+ Asrss. CCK842 tn SF Drea

i : t

o Time hrs U.S. Patent Sep. 8, 2015 Sheet 5 of 11 US 9,125,833 B2

Figure25. issolution profiles of 75 mg Tramadol HC in beeswax with 23% PMC based formulation Aweraged dissolution profiles of 75formulation mgranado HClin beeswax with 23%HPMC based strumcotka in beeswax2.3%hracKiss Aeros. 2)ksFost Average for Songbonado C in beeswaxwith 23%. Pick15ki Aerosicok B42Kirstf sword

Figure27. Comparison of averaged dissolution pries of Trainadol HC in beeswaxwith 20% ali.23%HPMC baseballation Figure 28, Combined dissolution profiles of first the Tamadol HCl formulations comprison of average tranadci Hcabeeswax (with 2023& HPCK13N Aerodeo B424) insF52088,0520? 75 mTranskeikistaevax, Gaucasurzandatikcho;5272,05272-2.52G733

Figure 29, Tramadol CLinbeeswax dissolution profile normalised top Cassay data Figure 30, Tramadol FCL in Gelucire 50.02 dissolution profile normalised to HPLCassay tata Truroadskii byeswax (GS27-labortance data terruled with Plcatsy data TrucciolhclugebirgsO2 (5222-2) attertanced twripated with PLCRJayhat

f30 offs U.S. Patent Sep. 8, 2015 Sheet 6 of 11 US 9,125,833 B2

Figure 3. TrattacklhkcLin Gelucire $0/02 repeat dissolution profile nomalised to HPLCassay data Figure 32. Tramadol HC. in cetyl alcohol dissolution profile normalised to HPLC assay data tranudo HCI in Gatteresaeosota-aesartancedtneroused with HPesta Teamsdelic incelynkicholes2G733) absorbancedatasaraised with hPlessay data

s 60

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igure 33 framadol KCL in cetylalcohol repeat dissolution profile nomalised a FEPLCassay data Figure 34 Combined dissolution profiles of second three Tramado Ciformulatios nuradocin Catyakakeltoizots-abseriance dataemised with hPucal sing Trimdohcasterotax NF, caenre gass, hydrokow 12: osafor-4, 952/93-5,352/0744s

Figure 35. Tramadol HCL in Sierulex NF dissolution profile normalised to HPLC assay data Figure 36. Tramadol HCLI seen dispermite to HPLC assay data with extended tarnado Honsterstars273-4 absodhancedasantnalised with Pucata Trumatolic in swiss S20734 absertarredata formalised with her cdrta U.S. Patent Sep. 8, 2015 Sheet 7 of 11 US 9,125,833 B2

Figure 37. Tramadol HCL in Cithrol GMs dissolution profile nomalised to HPLCassay data Figure 58. Tramadol HCinCithrol GMS dissolution profile nomalised to HPLC assay data with extendex timescale Trradshei actrol GMSC527-5 absorbancedstenorruised with HPicarta Transistic in chro Gastaszars-strariac data amused with KPLc data

8.so

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Figure 39 ramadol HClin Hydrokote 2 dissolution protile normalised to HPLCassay data Figure 40. Tramadol HCL in Hydrokote 112 dissolution profile normalised to HPLC assay data with exteaded lime scale andohc in Hydrokote 1252,044 sortuce deaneraised whicata Innachcin Hydrotate 252Mrds absetbarcadurotrasadwahifle dista

19 of S2.

Figure 4i. Tramadol ICL in beeswax dissolution profile normalised to HPI? assay data Figure 42. Abuse resistance esting, Tesi 1. Ethanol extraction on whole dosage units Trunado Hon Bernax (20%. KiteS2O741 absorbetesc dubu nomalised with KPlc sers Awithstast;Exhudraetian,r s fast U.S. Patent Sep. 8, 2015 Sheet 8 of 11 US 9,125,833 B2

Figure 44. Dissolution profile of tramadol HC2 in Sierotex NF formulations Figure i3. Abuse resistance testing, Test la. Ethanol extraction oncut or crushed dosage units Trawdollcruktor Sofokx NFwiki%und 19%kasawax,8327-12 Abts resistancussextraction, Yust (cut in halforskgkactylshadosage urits

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Figure 4S. dissolution profile of tranado Clin Steotex.NF formulations with and without factionated cocoqut oit Figure d6. Abuse resistance testing, Test i. Ethanut extraction on whole dosage units Dissolution Profew travadlothicia BargtaxNF0h actionabad acoristolicerwhelous Airestrealistance:EOthextracka, Test1. Osame-setzas 1,2ss rtacidosage was

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Figure 47. Abuse resistance testing. Test la Bhanol extraction on crushed or cut dosage units Figure 48. Dissolution profile gifstored SterouexNF brmulation Abuse resistance; exh extractor, testt. 7stnado Holin Sant s2 Packism); scapsules, so (Cut in halfo sire crushaftssagewrits

A 47 of 52 48 of2. U.S. Patent Sep. 8, 2015 Sheet 9 of 11 US 9,125,833 B2

Figure 49. Comparison of Dissolution profiles of freshandstored Sterotex NF formulation Figure 50. Dissolution profile of stored SterotexNFormulation with 25% factionated coconut oil Carpakenoidatehalfpeatssoftwharfutured sing Tmadilkata strutakakabekisuyu-ri Tsastnadohc in serote 23x f. coconutola-26s picki5Mk 5 capsules, 0520s-s

est).

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Comparison offissolution profiles offlesh and stored SterotexNF formulation with 25% Figure 52. Dissolution profile of stored Cithral GMS formulation fractionaled coconut oil 75ngTarasdo?hcin citrol Glts; seapsugs, 52073-5 Copravletvolution ww.esothoharwater hull Kicinikah stewashewto,2044; wrv

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Figure 34. Dissolution profile of stored Hydrokote 112 formulation Figure 53. Comparison of Eissolution profiles of fresh and stored Cithrol GMS formulation sing framic hydrokota 25% MPNGESR; capsas, 2044 carris admulationprofit of wharwordsww.Travadkahcekaloids,8934; whd ------

ca U.S. Patent Sep. 8, 2015 Sheet 10 of 11 US 9,125,833 B2

Figure 55. Comparison of Dissolution profiles of fresh and stored Hydrokoke 112 formulation Figure 56. Dissolution pruitle of stored beeswax formulation

camparisonfdomhthaprakeoful and Horod Treat Hirkyakuteihin sntrumdac is beeswax 4.2c tracks; scapsules, 52074-7

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Figure 58. Crushing. Grinding water or vinegar Solubilization and Filtration Figure 37, Comparison of Dissolution profiles of fresh and stored beeswax formulation Capason of Aastated Anokampmeaf Travakanawatu-Y, m 100

d i 6) 50 4) 30 2) 10

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Figure 59. Dissahition Profiles in a Beeswax. Femulation Figure 60. DissolutionProfiles in a Cithrul Fonunulation

layorphandfa?hiatrianghaeswax based formulater larophano Tartrautwmockhrabased formulater &Si33-33songtarger &Siriss-systergrifts 82 I U.S. Patent Sep. 8, 2015 Sheet 11 of 11 US 9,125,833 B2

Figure S. dissolution Profilesia SterotexFormulation Figure 62. Dissolution Profiles in a Hydrokote Formulation

wiptional fartrattorgstre basemata saissassing targetti)

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s R. US 9,125,833 B2 1. 2 MULTIMODALABUSE RESISTANT AND ety (2003); Evidence Based Report of the U.S. Agency for EXTENDED RELEASE OPOD Healthcare Research and Quality (AHRQ) on the Manage FORMULATIONS ment of Cancer Pain, Report No.35, AHRQ Publication No. 02-E002, October 2001; Canet al. J Nat Cancer Inst Mono This application is a section 371 filing corresponding to 5 graph 2004; 32:23-31; Agency for Health Care Policy and PCT/US2008/005541, filed 26 Apr. 2008, which is entitled to Research Clinical Practice Guidelines for Cancer Pain Man priority to U.S. provisional application No. 60/907.987, filed agement, Guideline No. 9, AHCPR Publication No. 94-0592, 26 Apr. 2007; the present application is also a continuation March 1994: Agency for Health Care Policy and Research in-part of U.S. patent application Ser. No. 12/216,645 (pend Clinical Practice Guideline for Acute Pain Management, ing), filed 7 Jul. 2008, which is a CIP of U.S. patent applica 10 Guideline No. 1, AHCPR Publication No. 92-0032, February, tion Ser. No. 12/223,987 (pending), filed 2 Nov. 2006, which 1992; Guideline for the Management of Cancer Pain in is a section 371 filing corresponding to PCT/US06/42962 Adults, American Pain Society, 2005: Guideline for the Man (inactive), filed 2 Nov. 2006, which is entitled to priority to agement of Pain in Osteoarthritis, Rheumatoid Arthritis, and U.S. provisional application No. 60/732,121, filed 2 Nov. Juvenile Chronic Arthritis, 2" Ed., American Pain Society, 2005: U.S. patent application Ser. No. 12/216,645 is entitled 15 2002). to priority to U.S. provisional application No. 60/929,611, Conventional (so called “immediate-release”, “rapid filed 5 Jul. 2008; the present application is also a continua release' or 'short acting) opioid analgesics have been dem tion-in part of U.S. patent application Ser. No. 12/223,327 onstrated to provide short-lived plasma levels, thereby requir (pending), which is a section 371 filing corresponding to ing dosing every 4-6 hours in chronic pain. In contrast, PCT/US2007/02378 (inactive), filed Jan. 29, 2007, which is extended release oral opioids are designed to maintain effec entitled to priority to U.S. provisional application no. 60/762, tive plasma levels throughout a 12 or 24-hour dosing interval. 489, filed Jan. 27, 2006; each of the applications identified in Extended release opioid formulations have now become the this paragraph other than U.S. patent application Ser. No. standard of care for the management of chronic pain. Use of 12/223.987 is herein incorporated by reference in its entirety. extended release opioids can result in fewer interruptions in 25 sleep, reduced dependence on caregivers, improved compli FIELD OF THE INVENTION ance, enhanced quality of life outcomes, and increased con trol over the management of their pain. In addition, Such The present invention is in the field of multimodal oral, formulations can provide more constant plasma concentra abuse resistant pharmaceutical compositions of opioid ago tions and clinical effects, less frequent peak to trough fluc nists, extended release pharmaceutical compositions of 30 tuations and fewer side effects, compared with short acting opioid agonists, extended release abuse resistant pharmaceu opioids (Babul et al. Journal of Pain and Symptom Manage tical compositions of opioid agonists and the use thereof. ment 2004; 28:59-71; Matsumoto et al., Pain Medicine 2005; 6:357-66; Dhaliwal et al., Journal of Pain Symptom Manage BACKGROUND OF THE INVENTION ment 1995; 10:612-23; Hays et al., Cancer 1994; 74: 1808-16: 35 Arkinstall et al., Pain 1995; 62: 169-78; Hagen et al., Journal Although the abuse of opioids has been documented over of Clinical Pharmacology 1995:35:38-45; Peloso et al., Jour many centuries, it is largely in the last century that we have nal of Rheumatology 2000: 27:764-71). been confronted by the abuse of pharmaceutical grade opio Several studies have suggested the benefits of extended ids in the form of pharmaceutical dosage forms intended for release over immediate release opioids. Ferrell et al (Oncol therapeutic uses. The abuse of opioids is either due to iatro 40 Nur Forum 1989; 4:521-6) compared 12-hourly controlled genic addiction or willful abuse of the products outside their release morphine and short-acting analgesics in cancer pain intended use or method of use by drug abusers and recre and demonstrated that compliance increased as the required ational drug users. dosing frequency decreased, and noncompliance resulted in Currently, medical practitioners may choose from several Suboptimal pain control and poor quality-of-life outcomes. well-accepted classes of pharmaceutical agents in their 45 Arkinstall et al. (Pain 1995; 62:169-78) demonstrated that attempts to alleviate and prevent pain. Nonlimiting examples around that twice daily administration of controlled release of agents used include nonsteroidal anti-inflammatory agents codeine provided superior to pain control thana PRN regimen (NSAIDs), e.g., aspirin, ibuprofen, ketoprofen, diclofenac; of acetaminophen plus codeine. opioids, e.g., morphine, hydromorphone, hydrocodone, An important drawback with the use of opioids is the risk of levorphanol, oxycodone, tramadol, and codeine; cyclooxyge 50 drug addiction, drug diversion and drug abuse. Although the nase-2 (COX-2) selective NSAIDs, e.g., celecoxib, Valde use of opioids for non-medical purposes has existed through coxib, etoricoxib, lumiracoxib, and rofecoxib; acetami out recorded human history, their abuse has increased signifi nophen and nitroparacetamol, tricyclic antidepressants, e.g., cantly in the past two decades (Drug Abuse Warning Net amitriptyline, desipramine, nortriptyline; non-tricyclic anti work, http://dawninfo.samhsa.gov/; Drug Enforcement depressants, e.g., doxepin, dulloxetine, paroxetine, Venlafax 55 Administration, http://www.deadiversion.usdoj.gov/: ine; antiepileptics, e.g., gabapentin, pregabalin, carbam National Survey on Drug Use & Health, http://www.oas.sa azepine, oXcarbazepine, lamotrigine; Voltage sensitive mhsa.gov/nhsda.htm; American Association of Poison Con N-type calcium channel blockers, e.g., Ziconotide and alpha trol Centers Toxic Exposure Surveillance System, http://ww adrenergic agonists, e.g., clonidine. W.aapcc.org/annual.htm). An important goal of analgesic therapy is to achieve con 60 Our increased understanding of the clinical pharmacology tinuous relief of pain. Regular administration of an analgesic of opioids and data from well controlled clinical trials in is generally required to ensure that the next dose is given chronic non-cancer pain (Peloso et al., Journal of Rheuma before the effects of the previous dose have worn off. Con tology 2000:27:764-71; Caldwell, et al., Journal of Pain and tinuous Suppression of pain through the use of around the Symptom Management 2002; 23:278-91; Matsumoto et al., clock opioid analgesics is now recommended in treatment 65 Pain Medicine 2005; 6:357-66; Arkinstall et al., Pain1995; guidelines (Principles of Analgesic Use in the Treatment of 62: 169-78) and neuropathic pain (Watson and Babul, Neu Acute Pain and Cancer Pain, Fifth Ed., American, Pain Soci rology 1998: 50: 1837-41) have resulted in more widespread US 9,125,833 B2 3 4 use in patients with non-malignant pain (for a review, see Addicts and recreational drug may user extended release Sloan and Babul. Expert Opinion on Drug Delivery 2006; opioids by the parenteral, intranasal or oral route. Opioid 3:489-97). This in turn has led to concerns about the increased abuse can involve physical, mechanical, thermal or chemical non-medical use of opioids through both licit and illicit chan tampering of the dosage form (e.g., crushing, melting, Solvent nels. For instance, unsuspecting clinicians may prescribe extraction and filtration) opioids for pain to individuals with an addiction disorder or Scheduling of opioid drugs has also had the unintentional individuals with pain who divert a portion of their prescribed side-effect of causing physicians, fearful of being accused of dose to other individuals. There have also been documented permitting “opioid overuse', to prescribe suboptimal doses of cases of inappropriate prescribing or dispensing of opioids by opioids to patients in need of them, and to prescribe less 10 effective drugs to patients that are not similarly scheduled. physicians and pharmacists, with its eventual diversion into This phenomenon is described in the literature as “opiopho the non-medical marketplace. Additionally, non-medical Sup bia' or “narcophobia. plies of pharmaceutical grade opioids are often obtained There is a growing recognition in the medical community through prescription forgeries and break-ins into pharmacies. that a large number of patients suffer from the undertreatment Pharmaceutical dosage forms containing opioids may be 15 of pain. Among the reasons frequently cited as causative of ingested whole, crushed and ingested, crushed or vaporized undertreatment are: (1) the failure to prescribe enough drug at and Snorted or injected intravenously after attempted extrac the right dosage interval to reach a steady-state threshold tion of the active pharmaceutical ingredient. commensurate with the pain relief needed; (2) failure of The introduction of extended release morphine (MS Con patients to comply with a given dosage regimen; and (3) the tin R) revolutionized the management of cancer pain. MS reluctance of many physicians to prescribe analgesics catego Contin R. gained widespread acceptance due to its global rized as controlled drugs based on often unfounded concerns availability, significant pharmacokinetic and pharmacody of future addiction and fear of regulatory sanctions. For namic data, and the convenience of an extended-release for example, it has been reported that with respect to cancer pain, mulation. However, the incidence and severity of side effects a large percentage of cancer patients suffer debilitating pain limits the use of morphine in some patients (Hagen and Babul, 25 despite treatment with analgesics (Cleeland et al., New Cancer 1997: 79: 1428-37). In patients with renal impairment, England Journal of Medicine 1994; 330:592-596). morphine’s principal metabolites, morphine-3-glucuronide A number of reported cases of opioid toxicity area result of and morphine-6-glucuronide can accumulate. Morphine-3- inadvertent or unintentional medical use of opioids. It is not glucuronide accumulation has been implicated in hyperalge uncommon for patients who have difficulty Swallowing, to sia, respiratory stimulation, and behavioral excitatory prop 30 crush the contents of tablets or open a capsule, and Swallow erties through nonopioid receptor mechanisms. Morphine-6- the contents with liquids or on soft food. In the case of most glucuronide accumulation has been implicated in increasing immediate release formulations, this generally produces no levels of nausea and sedation in patients with renal impair significant harm, with marginally higher peak concentrations ment (Babul and Darke, Clin Pharm Ther, 1993:54:286-92). (C) and time to peak concentrations (t). However, in the Clinicians treating cancer pain with opioids have reported 35 case of extended release opioid formulations, crushing the significant variability among patients in efficacy and side oral Solid dosage form destroys the controlled-release mecha effects with available opioid analgesics. Patients with poor nism and results in a rapid Surge of drug into the bloodstream, analgesic efficacy or safety outcomes on one opioid fre with the entire 12 or 24-hour drug supply released immedi quently tolerate another opioid well. This clinical observation ately with toxic effects. For this reason, all extended release led to the development of oxycodone ER (OxyContinR). Due 40 formulations available for sale in the United States carry a to the limitations associated with extended release morphine warning to the prescriber and patient not to crush or tamper noted above and the “stigma' associated with its use (i.e., with the oral solid dosage form (see Prescribing Information association with addiction, advanced cancer, dying and for MS Contin R, OxyContin R, AvinzaR) and Kadian(R), Phy death), extended release oxycodone gained rapid acceptance sician’s Desk Reference, 2005, Thompson PDR, Montvale, by patients with chronic non-cancer pain. However, its wide 45 N.J.). spread use for the treatment of chronic non-malignant pain There is therefore a need for a “passive’ abuse deterrent was also associated with its diversion into the non-medical system to protect both medical and non-medical users of Supply for use both by addicts and recreational drug users. opioids from intentional or unintentional opioid toxicity, The popularity of extended release oxycodone among without unnecessary harm to either group from the abuse addicts and recreational drug users was due to a large amount 50 deterrent technology. of drug per tablet (a 12 or 24 hour supply). Commercially Similarly, abuse deterrent pharmaceutical compositions available immediate release opioid tablets and capsules are containing aversive Substances can cause serious harm to usually administered every 4 to 6 hours and they release their Subjects if injected intravenously and the long terms safety of dose into the systemic circulation over one to two hours. New, small amounts of such aversive substances which would be extended release formulations are designed to gradually 55 inevitably released in the gastrointestinal tract is unknown. release their much larger opioid content over a 12 or 24-hour There is also need, therefore, for novel methods of prevent period. Most recreational drug users and addicts have a unit of ing opioid abuse which do not require the incorporation of use which is one tablet or capsule. The 12 or 24-hour supply aversive and potentially unsafe agents into the formulation. of opioid contained in one tablet or capsule, instead of 4 to 6 In 2005, a serious new clinical problem arose with the tablets or capsules means that there is a greater risk that Such 60 therapeutic use of extended release opioids, particularly formulations may be highly sought by drug addicts and rec extended release formulations in capsule dosage forms, when reational drug users alike, for non-medical use. Intentional or co-ingested with alcohol. In this setting, the opioid analgesic inadvertent tampering from extended release formulations was being used for legitimate medical purposes (e.g., to treat will rapidly deliver a massive dose and produce profound a pain) and was being ingested as an untampered or intact variety of serious and life threatening side effects, including 65 formulation. Although subjects with chronic pain are discour respiratory depression and failure, sedation, cardiovascular aged from using opioids with alcohol, the co-ingestion of collapse, coma and death. opioids with alcohol, especially in the setting of intractable US 9,125,833 B2 5 6 pain is widespread. The problem was discovered with a once constant plasma concentrations and clinical effects, less fre a-day extended release formulation of the opioid hydromor quent peak to trough fluctuations and fewer side effects, com phone HCL (Palladone(R) capsules). Palladone(R) capsules pared with short acting or immediate release versions of were introduced in the United States and Canada in 2004. In opioids. 2005, Palladone(R) capsules were withdrawn from the market Toxicity from opioids can result from unintentional or in both countries due to dose-dumping when co-ingested with intentional tampering of the dosage form. It is not uncommon alcohol. In a 24-Subject study, patients consuming 240 mL of for patients who have difficulty swallowing, to crush the 40% ethanol had a 6-fold mean increase in peak plasma contents of tablets or open a capsule, and Swallow the con hydromorphone concentration compared with co-ingestion tents with liquids or on Soft food. In the case of most imme of Palladone(R) capsules with water. One subject experienced 10 diate release dosage forms of opioids, this generally produces a 16-fold increase when the drug was ingested with 40% no significant harm, with marginally higher peak concentra alcohol compared with water. Patients consuming 240 mL of tions (C) and time to peak concentrations (t). However, 20% ethanol had a 2-fold mean increase in peak plasma in the case of extended release dosage forms of opioids, hydromorphone concentration. One Subject in this group crushing the oral Solid dosage form destroys the controlled experienced a 6-fold increase when the drug was ingested 15 release mechanism and results in a rapid Surge of drug into the with 20% alcohol compared with water. In some subjects, 8 bloodstream, with the entire 8, 12 or 24-hour drug supply ounces of 4% alcohol (equivalent to 2/3 of a typical serving of released immediately with toxic effects, or pleasurable beer) resulted in almost twice the peak plasma hydromor effects in the case of a drug abuser. For this reason, all phone concentration than when the drug was ingested with extended release dosage forms available for sale in the United water. In requesting the withdrawal of Palladone(R) capsules, States carry a warning to the prescriber and patient not to FDA noted that the manufacturer of “PalladoneR provided crush or tamper with the oral Solid dosage form. FDA data that showed that drinking alcohol while taking There is a need, therefore, for novel methods and pharma Palladone(R) capsules may cause rapid release of hydromor ceutical compositions of extended release formulations of phone, leading to high drug levels in the body, with poten opioids to provide continuous relief of signs and symptoms tially fatal effects. High drug levels of hydromorphone may 25 amenable to treatment with the abusable drug, without having depress or stop breathing, cause coma, and even cause death. to take frequent doses of opioids. There is a need, therefore, The Agency has concluded that the overall risk versus benefit for novel methods and pharmaceutical compositions of profile of Palladone(R) is unfavorable due to a potentially fatal extended release formulations of opioids that result in fewer interaction with alcohol. Pharmacokinetic data indicate that interruptions in sleep, reduced dependence on caregivers, the co-ingestion of Palladone Rand alcohol results in danger 30 improved compliance, enhanced quality of life outcomes, and ous increases in the peak plasma concentrations of hydromor increased control over the management of their medical con phone. These elevated levels may be lethal, even in opioid dition. There is a need, therefore, for novel methods and tolerant patients.” (Sloan and Babul, Expert Opinion on Drug pharmaceutical compositions of extended release formula Delivery 2006; 3:489-97: http://www.fda.gov/cder/drug/in tions of opioids that result in more constant plasma concen fopage/palladone/default.htm) 35 trations and clinical effects, less frequent peak to trough fluc FDA has since noted that a number of other capsule for tuations and fewer side effects, compared with short acting or mulations of extended release opioids may be similarly Vul immediate release versions of opioids. There is a need for nerable to dose dumping when co-ingested with alcohol. In novel methods and pharmaceutical compositions of extended vitro studies performed by the FDA have demonstrated that release formulations of opioids that achieve the aforemen when Avinza R (once-daily extended release morphine) 30 40 tioned benefits without increasing the risk of toxicity, drug mg was mixed with 900 mL of buffer solutions containing diversion and drug abuse. There is a need for novel methods ethanol, the dose of morphine that was released was alcohol and pharmaceutical compositions of extended release formu concentration-dependent, leading to a more rapid release of lations of opioids that achieve the aforementioned benefits morphine. While the relevance of in vitro lab tests regarding and also provide abuse deterrence. AvinzaR) to the clinical setting remains to be determined, this 45 To date, no extended release formulations of opioids with acceleration of release may correlate with in vivo rapid abuse deterrent technology of any kind have been submitted release of the total morphine dose, which could result in the for Marketing Application (New Drug Application) or been absorption of a potentially fatal dose of morphine. (http:// commercialized anywhere in the world. Indeed if prior drug www.fda.gov/medwatch/SAFETY/2005/AVINZA DHC development history is any guide, most such strategies are P Letter Oct2005.pdf. Sloan and Babul, Expert Opinion on 50 unlikely to be developed or commercialized and the optimal Drug Delivery 2006; 3:489-97) formulation(s) will likely be apparent only through postmar There is therefore also need, therefore, for novel methods keting Surveillance of several formulations with competing of preventing excessive peak concentrations (dose dumping) technologies. In addition, regional differences in patterns of of opioids when they are co-ingested for medical purposes at abuse mean that different abuse deterrence strategies may be prescribed doses with alcohol. 55 useful in different part of the world. Finally, experience with Extended release formulations have become highly pref Substance abuses indicates that those who are habitual abus erable and in Some cases, the standard of care for the man ers, particularly those who inject drugs intravenously, have a agement of a wide variety of conditions, particularly chronic remarkable ability to defeat abuse deterrence strategies conditions. Additionally, extended release formulations can through physical and chemical manipulation of opioids and make otherwise non-viable pharmaceutical agents (e.g., due 60 other drugs of abuse. Such addicts are frequently only one to an exceedingly short duration of effect) into viable formu step behind strategies to deter abuse. With the ready access to lations with clinical and commercial potential. information from their well knit network and more recently, Extended release dosage forms of opioids may result in from websites on how to optimally extract the active agent fewer interruptions in sleep, reduced dependence on caregiv from pharmaceutical dosage forms and maximize euphoriant ers, improved compliance, enhanced quality of life outcomes, 65 effects, the development of abuse deterrent formulations has and increased control over the management of their medical become a major pharmaceutical, clinical, regulatory and law condition. In addition, such dosage forms may provide more enforcement challenge. US 9,125,833 B2 7 8 In view of this, it is not surprising that the Food and Drug A number of strategies have been introduced to minimize Administration’s Division of Anesthetic, Analgesic and the abuse of mood altering drugs. Primary among these Rheumatology Drug Products and the U.S. Drug Enforce schemes is a legal infrastructure that controls the manufac ment Administration have encouraged companies to develop ture, distribution and sale of such drugs. In the United States, wide ranging abuse deterrent strategies for opioids, particu opioids are restricted to dispensing on a prescription-only larly extended release opioids and as “inducement”, offered basis. Most of these drugs are “scheduled as “controlled that such products may include in their prescribing informa drugs, such that distribution of the drug is subject to strict tion data about their products abuse deterrent properties controls and overview. The idea behind scheduling opioids as (FDA Perspectives on Opioid Risk Management. Opioid Risk “controlled' is to ensure that the drugs are dispensed only for Management Meeting, Tufts Healthcare Institute, Boston, 10 the amelioration of legitimate therapeutic maladies, and not Mar. 29, 2005; DEA Perspectives on Opioid Risk Manage for any mood-altering effect “high” or euphoria that may be ment. Opioid Risk Management Meeting, Tufts Healthcare produced by the drug when used in Supra-therapeutic doses or Institute, Boston, Mar. 29, 2005). administered by non-approved routes of administration. Various attempts have been made and are described in prior While the scheduling of opioids as “controlled drugs” has art to develop abuse-deterrent dosage forms. Clearly there is 15 reduced abuse of the drugs, it has not been entirely successful. a need for a delivery system for commonly used oral dosage For example, some persons who are legitimately prescribed formulations of drugs, and in particular analgesics Such as the drugs sometimes divert the drugs to persons seeking their opioid analgesics, for patients seeking drug therapy and procurement for “recreational uses.” These “recreational drug which deters abuse and minimizes or reduces the potential for users' are frequently willing to pay significant Sums of money psychological dependence. In particular, there is a need for for the drugs. In other cases, certain health professionals, formulations that simultaneously provide robust abuse deter unfortunately, have been found to be culprits in the non rence properties and an extended release pharmacokinetic approved distribution of opioid drugs. profile suitable for every 12 or 24 hour oral administration. It is believed that the most widely used diversion tech There is also a need for extended release formulations of niques at the “street level” are “doctor shopping and pre opioids that are stable (i.e., do not dose dump) when used at 25 scription forgeries. In the case of the former, individuals who therapeutic doses for medical purposes in conjunction with may or may not have a legitimate ailment requiring a doctor's alcohol. An ideal formulation will provide a extended release prescription for controlled Substances, visit numerous doc pharmacokinetic profile suitable for every 12 or 24 hour tors, sometimes in several states, to acquire large amounts of release and will be resistant to crushing at room temperature controlled substances they abuse or sell to others. and upon freezing, melting to allow for filtration and/or aspi 30 There is a growing recognition in the medical community ration into a syringe and extraction with recreational Solvents, that a large number of patients suffer from the undertreatment all without doing harm to pain patients or patients with a of their medical condition when the treatment involves the use Substance abuse disorder, through the use of aversive agents of psychoactive drugs, particularly those drugs which tend to or opioid antagonists. diverted and abused. Scheduling of opioids has also had the Pharmaceutical dosage forms containing opioids have 35 unintentional side-effect of causing physicians, fearful of been used for non-medical purposes in a variety of settings: i) being accused of permitting or even promoting drug abuse by patients with a disorder requiring treatment with an abus and drug overuse, to prescribe suboptimal doses of opioids to able drug who have developed an addiction disorder follow patients in need of them, and to prescribe less effective drugs ing initiation of therapy; ii) by patients with said disorder who to patients that are not similarly scheduled. had a pre-existing addiction disorder; iii) by patients with an 40 An additional issue with extended release forms of drugs, addiction disorder seeking opioids for their reinforcing, including opioids is the interaction of the drug, even in an rewarding, euphoriant or other mood altering properties. untampered form, when consumed with alcohol. Under Such Non-medical users of opioids are either recreational drug conditions, a number of drugs have demonstrated an in vitro users who may use Such agents episodically, or individuals and in vivo propensity for significant dose dumping when with an addiction disorder who may require frequent main 45 they are co-ingested for medical purposes at prescribed doses tenance doses. Opioids may be ingested whole, crushed and with alcohol, increasing the potential for drug toxicity and ingested, crushed or vaporized and Snorted or injected intra further exacerbating the intensity of the (abusable) drug-al venously after attempted extraction of the active pharmaceu cohol pharmacodynamic interaction. tical ingredient. The manipulation of pharmaceutical dosage There is therefore also need, therefore, for novel methods forms of opioids has been documented for many decades. For 50 of preventing excessive peak concentrations (dose dumping) instance, pentazocine (Talwin R), a synthetic opioid was of opioids when they are co-ingested for medical purposes at crushed, extracted and injected intravenously by drug addicts. prescribed doses with alcohol. Addicts and recreational drug users commonly use The present invention also involves oral pharmaceutical extended release versions of opioids by a variety of routes of compositions of opioids and methods of use thereof which administration. Commonly used methods include 1) 55 provide reduced variability in rate and extent of absorption parenteral (e.g., intravenous injection), 2) intranasal (e.g., when taken with food, compared with the fasted state. Snorting), and 3) episodic or repeated oral ingestion of intact The present invention also involves oral extended release or crushed tablets or capsules. pharmaceutical compositions of opioids and methods of use One mode of abuse can involve the extraction of the opioid thereof which provide reduced variability in rate and extent of component from the dosage form by first mixing the table or 60 absorption when taken with food, compared with the fasted capsule with a Suitable solvent (e.g., water or alcohol), and State. then filtering and/or extracting the opioid component from Most pharmaceutical companies strive to develop oral the mixture for intravenous injection. Another mode of abuse pharmaceutical products which can be taken without regard of extended release opioids can involve dissolving the drug in to meal intake, i.e., on an empty stomachor with food. Indeed, water, alcohol or another “recreational solvent to hasten its 65 it is now a requirement of both U.S. and E.U regulatory release and to ingest the contents orally, in order to provide guidance's to conduct studies of all new chemical entities to high peak concentrations and maximum euphoriant effects. determine the influence of concurrent food intake on the US 9,125,833 B2 10 bioavailability of products. Concurrent intake of food in so peutic agents, and opioids that provide a extended release called “fed-fasted' human bioavailability studies may pharmacokinetic profile suitable for every 8, 12 or 24 hour increase, decrease or have no effect on the bioavailability of release and will be resistant to crushing at room temperature the pharmaceutical products. Accordingly, the prescribing and upon freezing, melting to allow for filtration and/or aspi information guides both the prescriber and the patient on the ration into a syringe and extraction with recreational Solvents, appropriate use of the pharmaceutical product. all without doing harm to patients or patients with a Substance The issue of food effects on oral bioavailability has par abuse disorder, through the use of aversive agents or antago ticular importance with oral extended release products, due to nists. the possibility of “dose dumping where the is potential that a portion or a substantial portion of the dose intended to be 10 BRIEF DESCRIPTION OF THE DRAWINGS released gradually overtime (e.g., over 8, 12 or 24 hours) may be released instantaneously or rapidly, such that the peak FIG. 1 is a graph which depicts the UV spectrum of trama plasma concentration of the drug (peak exposure) will be dol HCl in water. Substantially increased, resulting in toxicity and the duration FIG. 2 is a graph which depicts a dissolution profile for of effect will be significantly reduced, potentially resulting in 15 formulation 052/014. reduced duration of therapeutic effect. The ability to take the FIG. 3 is a graph which depicts a dissolution profile for drug without regard to food intake and in the case of extended formulation 052/015. release pharmaceutical products, the absence of dose dump FIG. 4 is a graph which depicts a dissolution profile for ing has been found to be a significant patient benefit and a formulation 052/019. competitive marketing advantage. It is not uncommon to see FIG. 5 is a graph which depicts a dissolution profile for pharmaceutical advertising targeted to medical practitioners formulation 052/024. which states “no food effect”, “may be taken on an empty FIG. 6 is a graph which depicts a dissolution profile for stomach or with food” and “may be taken without regard to formulation 0527024 in SIF containing pancreatin. food” and “no change in bioavailability with food. FIG. 7 is a graph which depicts a dissolution profile of The U.S. prescribing information for OxyContinTM (oxy 25 propanolol HCl in Gelucire 50/02 in SIF without pancreatin. codone ER) states “Food has no significant effect on the FIG. 8 is a graph which depicts a dissolution profile of extent of absorption of oxycodone from OxyContin. How propanolol HCl in Gelucire 50/02 in SIF containing pancre ever, the peak plasma concentration of oxycodone increased atin. by 25% when a OxyContin 160 mg Tablet was administered FIG.9 is a graph which depicts average dissolution profiles with a high-fat meal.” 30 of propanolol HCl in Gelucire 50/02 in SIF with and without The U.S. prescribing information for Opana TM ER (oxy pancreatin. morphone ER) states “two studies examined the effect offood FIG. 10 is a graph which depicts dissolution profiles of on the bioavailability of single doses of 20 and 40 mg of Zydol XL 150 and Dromadol SR tablets in SIF. OPANA ER in healthy volunteers. In both studies, after the FIG. 11 is a graph which depicts combined dissolution administration of OPANA ER, the Cmax was increased by 35 profiles of seven different excipient formulations in SIF. approximately 50% in fed subjects compared to fasted sub FIG. 12 is a graph which depicts combined dissolution jects. A similar increase in Cmax was also observed with profiles of seven different excipient formulations, using an oxymorphone solution.” extended scale. In Summary, many opioids in extended release form have a FIG. 13 is a graph which depicts combined dissolution potentially clinically important food effect. 40 profiles of five base excipients in HPMC modified formula There is therefore a need for oral immediate release phar tions. maceutical compositions, and particularly extended release FIG. 14 is a graph which depicts dissolution profiles of five pharmaceutical compositions with consistent bioavailability capsule sample of cetyl alcohol formulation with 10% regardless of administration in the fed or fasted State. HPMC. There is a need for methods and pharmaceutical composi 45 FIG. 15 is a graph which depicts dissolution profiles of tions of pharmaceuticals and therapeutic agents that provide modified Sterotex NF formulation. an extended release profile, preferably suitable for every 8, 12 FIG. 16 is a graph which depicts average dissolution pro or 24 hour oral administration. There is a need for methods files of modified Sterotex NF formulation. and pharmaceutical compositions of opioids that provide an FIG. 17 is a graph which depicts dissolution profiles of extended release profile. There is also a need for methods and 50 further modified Sterotex NF formulation. pharmaceutical compositions of opioids that provide an FIG. 18 is a graph which depicts average dissolution pro abuse deterrent profile. In particular, there is a need for meth files of further modified Sterotex NF formulation. ods and pharmaceutical compositions of opioids that simul FIG. 19 is a graph which depicts dissolution profiles of taneously provide abuse deterrence properties and extended Hydrokote formulations containing Methocel K 100M or release profiles, preferably suitable for every 8, 12 or 24 hour 55 Methocel K 1.5M. oral administration. There is also a need for extended release FIG. 20 is a graph which depicts average dissolution pro formulations of pharmaceuticals and therapeutic agents, and files of Hydrokote formulations containing Methocel K opioids that are stable (i.e., do not dose dump) when used at 1 OOM or Methocel K 1.5M. therapeutic doses for medical purposes in conjunction with FIG. 21 is a graph which depicts dissolution profiles of 250 alcohol. There is also a need for extended release formula 60 mg Tramadol HCl in a 550 mg Sterotex NF based formula tions of pharmaceuticals and therapeutic agents, and opioids tion. that provide a extended release pharmacokinetic profile Suit FIG. 22 is a graph which depicts averaged dissolution able for every 8, 12 or 24 hour release and will be resistant to profiles of 250 mg Tramadol HCL in a 550 mg Sterotex NF crushing at room temperature and upon freezing, melting to based formulation. allow for filtration and/or aspiration into a syringe and extrac 65 FIG. 23 is a graph which depicts dissolution profiles of 75 tion with recreational solvents. There is also a need for mg Tramadol HCl in beeswax with 20% HPMC based for extended release formulations of pharmaceuticals and thera mulation. US 9,125,833 B2 11 12 FIG. 24 is a graph which depicts averaged dissolution FIG. 51 is a graph which depicts comparison of dissolution profiles of 75 mg Tramadol HCL in beeswax with 20% profiles of fresh and stored Sterotex NF formulations with HPMC formulation. 25% fractionated coconut oil. FIG. 25 is a graph which depicts dissolution profiles of 75 FIG. 52 is a graph which depicts dissolution profile of mg Tramadol HCl in beeswax with 23% HPMC based for stored Cithrol GMS formulation. mulation. FIG. 53 is a graph which depicts comparison of dissolution FIG. 26 is a graph which depicts averaged dissolution profiles of fresh and stored Cithrol GMS formulations. profiles of 75 mg Tramadol HCl in beeswax with 23% HPMC FIG. 54 is a graph which depicts dissolution profile of based formulation. stored Hydrokote 112 formulation. FIG.27 is a graph which depicts a comparison of averaged 10 FIG.55 is a graph which depicts comparison of dissolution dissolution profiles of Tramadol HCl in beeswax with 20% profiles of fresh and stored Hydrokote 112 formulations. and 23% HPMC based formulation. FIG. 56 is a graph which depicts dissolution profile of FIG. 28 is a graph which depicts combined dissolution stored beeswax formulation. profiles of first three Tramadol HCl formulations. 15 FIG. 57 is a graph which depicts comparison of dissolution FIG. 29 is a graph which depicts Tramadol HCl in beeswax profiles of fresh and stored beeswax formulations. dissolution profile normalized to HPLC assay data. FIG. 58 is a pair of bar graphs which depict the effects of FIG. 30 is a graph which depicts Tramadol HCL in Gelu crushing, grinding, water or vinegar Solubilization and filtra cire 50/02 dissolution profile normalized to HPLC assay data. tion. FIG.31 is a graph which depicts Tramadol HCl in Gelucire FIG. 59 is a graph which depicts dissolution profiles in a 50/02 repeat dissolution profile normalized to HPLC assay beeswax formulation. data. FIG. 60 is a graph which depicts dissolution profiles in a FIG. 32 is a graph which depicts Tramadol HCl in cetyl Cithrol formulation. alcohol dissolution profile normalized to HPLC assay data. FIG. 61 is a graph which depicts dissolution profiles in a FIG. 33 is a graph which depicts Tramadol HCl in cetyl 25 Sterotex formulation. alcohol repeat dissolution profile normalized to HPLC assay FIG. 62 is a graph which depicts dissolution profiles in a data. Hydrokote formulation. FIG. 34 is a graph which depicts combined dissolution profiles of second three Tramadol HCl formulations. DETAILED DESCRIPTION OF THE INVENTION FIG.35 is a graph which depicts Tramadol HCl in Sterotex 30 NG dissolution profile normalized to HPLC assay data. In some preferred embodiments, the present invention is FIG.36 is a graph which depicts Tramadol HCl in Sterotex directed at pharmaceutical compositions of abusable drugs to NG dissolution profile normalized to HPLC assay data with provide abuse deterrence properties. an extended time scale. In some preferred embodiments, the present invention is FIG. 37 is a graph which depicts Tramadol HCl in Cithrol 35 directed at pharmaceutical compositions of abusable drugs to GMS dissolution profile normalized to HPLC assay data. provide extended release properties. FIG.38 is a graph which depicts Tramadol HCl in Cithrol In some preferred embodiments, the present invention is GMS dissolution profile normalized to HPLC assay data with directed at pharmaceutical compositions of abusable drugs an extended time scale. that provide simultaneous abuse deterrence properties and FIG. 39 is a graph which depicts Tramadol HCl in 40 extended release properties. Hydrokote 112 dissolution profile normalized to HPLC assay In some preferred embodiments, the present invention is data. directed at pharmaceutical compositions of abusable drugs FIG. 40 is a graph which depicts Tramadol HCl in that provide simultaneous abuse deterrence properties and Hydrokote 112 dissolution profile normalized to HPLC assay extended release properties using Substantially the same data with an extended time scale. 45 ingredients to achieve abuse deterrence properties and FIG. 41 is a graph which depicts Tramadol HCl in beeswax extended release. dissolution profile normalized to HPLC assay data. In some preferred embodiments, the present invention is FIG. 42 is a graph which depicts abuse resistance testing, directed at liquid pharmaceutical compositions of abusable specifically ethanol extraction on whole dosage units. drugs that solidify at room temperature to provide abuse FIG. 43 is a graph which depicts abuse resistance testing, 50 deterrence properties. specifically ethanol extraction on cut or crushed dosage units. In some preferred embodiments, the present invention is FIG. 44 is a graph which depicts dissolution profile of directed at liquid pharmaceutical compositions of abusable Tramadol HCl in Sterotex NF formulations. drugs that Solidify at room temperature to provide extended FIG. 45 is a graph which depicts dissolution profile of release properties. Tramadol HCl in Sterotex NF formulations with and without 55 In some preferred embodiments, the present invention is fractionated coconut oil. directed at oral Solid pharmaceutical compositions of abus FIG. 46 is a graph which depicts abuse resistance testing, able drugs that are in the form of a liquid, semisolid, oil or specifically ethanol extraction on whole dosage units. otherwise difficult to granulate. FIG. 47 is a graph which depicts abuse resistance testing, In some preferred embodiments, the present invention is specifically ethanol extraction on crushed or cut dosage units. 60 directed at liquid pharmaceutical compositions of abusable FIG. 48 is a graph which depicts dissolution profile of drugs that Solidify at room temperature to provide simulta stored Sterotex NF formulation. neous abuse deterrence properties and extended release prop FIG. 49 is a graph which depicts comparison of dissolution erties. profiles of fresh and stored Sterotex NF formulation. In some preferred embodiments, the present invention is FIG. 50 is a graph which depicts dissolution profile of 65 directed at liquid pharmaceutical compositions of abusable stored Sterotex NF formulation with 25% fractionated coco drugs that Solidify at room temperature to provide simulta nut oil. neous abuse deterrence properties and extended release prop US 9,125,833 B2 13 14 erties using Substantially the same ingredients to achieve In some preferred embodiments, abusable drug pharma abuse deterrence properties and extended release. ceutical compositions and methods of the present invention In some preferred embodiments, the present invention is provide (i) extended release; and (ii) protection against etha directed at oral abusable drug pharmaceutical compositions nol induced dose dumping, prepared using ADER, using Sub and the use thereof for preventing or minimizing the risk of 5 stantially the same ingredients to effect extended release and abusable drug toxicity from either intentional or uninten protection against ethanol induced dose dumping. tional tampering. In some preferred embodiments, abusable drug pharma In some preferred embodiments, the present invention is ceutical compositions and methods of the present invention directed at oral abusable drug pharmaceutical compositions provide (i) abuse deterrence and extended release; and (ii) and the use thereof for deterring abuse by drug addicts and/or 10 protection against ethanol induced dose dumping, prepared recreational drug users. using ADER. In some preferred embodiments, the present invention is In some preferred embodiments, abusable drug pharma directed at oral abusable drug pharmaceutical compositions ceutical compositions and methods of the present invention that provide extended release delivery of the drug and the use 15 provide (i) abuse deterrence and extended release; and (ii) thereof for the treatment of pain and addiction disorders. protection against ethanol induced dose dumping, prepared For the purposes of the present invention and not with using ADER, using Substantially the same ingredients to standing anything to the contrary, the phrase “abusable effect abuse deterrence and extended release, and protection drugs are limited to one or more “opioid agonists' or “opioid against ethanol induced dose dumping. receptor agonists', as further defined herein. In some preferred embodiments, the present invention is In some preferred embodiments, abusable drugs of the directed to a novel method for reducing the peak concentra present invention can beformulated with the substantially the tion (C) of the abusable drug, said method comprising same ingredients to deter abuse and minimize abusable drug administering the abusable drug and a suitable amount of toxicity on tampering while simultaneously providing an ADER. extended release pharmacokinetic profile suitable for every 4, 25 In some preferred embodiments, the present invention is 6, 8, 12 or 24 hour dosing. directed to a novel method for reducing the early post-dose In some preferred embodiments, abusable drugs of the partial area under the plasma concentration time curve (e.g., present invention can beformulated with the substantially the AUCo., AUC and AUC) of the abusable drug, said same ingredients to deter abuse and minimize abusable drug method comprising administering the abusable drug and a toxicity on tampering while simultaneously providing an 30 extended release pharmacokinetic profile suitable for every 4, suitable amount of ADER. 6, 8, 12 or 24 hour dosing, without the need to include an In some preferred embodiments, the present invention is aversive agent or an antagonist for the abusable drug in the directed to a novel method for reducing the early post-dose formulation. average plasma concentration time (Cave) of the abusable In some preferred embodiments, abusable drug pharma 35 drug, said method comprising administering the abusable ceutical compositions and methods of the present invention drug and a suitable amount of ADER. provide (i) abuse deterrence; (ii) extended release; and (iii) In some preferred embodiments, the present invention is simultaneous abuse deterrence and extended release, pre directed to a novel method for reducing the incidence of pared using one or more ADER compounds. abusable drug toxicity upon tampering of the abusable drug, As used herein, the term “ADER. “ADER material' and 40 said method comprising administering the abusable drug and “ADER agent” refers to one or more compounds selected a suitable amount of ADER. from the group consisting of: (a) hydrogenated Type I or Type In some preferred embodiments, the present invention is II vegetable oils; (b) polyoxyethylene stearates and distear directed to a novel method for reducing the intensity of abus ates; (c) glycerol monostearate; (d) poorly water soluble, high able drug toxicity upon tampering of the abusable drug, said melting point (mp=45 to 100° C.) waxes, and mixtures 45 method comprising administering the abusable drug and a thereof. In some preferred embodiments, ADER is a mixture suitable amount of ADER. of two or more compounds from the forgoing group i.e., (a) In some preferred embodiments, the present invention is to (d). In some preferred embodiments, to qualify as an directed to a novel method for reducing the intensity or fre “ADER requires a mixture of two or more compounds from quency of one or more signs and symptoms of abusable drug the form the foregoing group i.e., (a) to (d). In some par 50 toxicity, including nausea, vomiting, Somnolence, stupor, ticularly preferred embodiments, to qualify as an “ADER coma, respiratory depression, apnea, respiratory arrest, cir requires a mixture of two or more compounds selected from culatory depression, bradycardia, hypotension, shock and at least two categories i.e., (a) to (d). skeletal muscle flaccidity, said method comprising adminis As used herein, the term “ADER. “ADER material' and tering the abusable drug and a suitable amount of ADER. “ADER agent” also includes glyceryl behenate (e.g., Comp 55 In some preferred embodiments, the present invention is tirolTM 888 ATO), glyceryl palmitostearate (e.g., PrecirolTM directed to a novel method for reducing the intensity or fre ATO 5), stearoyl macrogolglycerides (GelucireTM 50/13), quency of one or more signs and symptoms of abusable drug lauroyl macrogolglycerides (LabrafiltMM 2130 CS). toxicity, including tachycardia, mood alteration, euphoria, In some preferred embodiments, abusable drug pharma CNS stimulation, agitation, increased Sweating, psychotomi ceutical compositions and methods of the present invention 60 metic effects, hallucinations, perception alterations, cogni provide simultaneous abuse deterrence and extended release, tive alterations, reinforcing effects and pleasurable effects prepared using ADER, using Substantially the same ingredi said method comprising administering the abusable drug and ents to effect abuse deterrence and extended release. a suitable amount of ADER. In some preferred embodiments, abusable drug pharma In some preferred embodiments, the present invention is ceutical compositions and methods of the present invention 65 directed to a novel method for reducing the intensity or fre provide (i) extended release; and (ii) protection against etha quency of one or more signs and symptoms of abusable drug nol induced dose dumping, prepared using ADER. toxicity, including “high”, “liking, pleasurable, euphoric, US 9,125,833 B2 15 16 alertness, wakefulness, calming, anxiolytic, auditory and (iv) from the group consisting of: (i) hydrogenated Type I or visual perceptual alterations, relaxing, analgesic and reward Type II vegetable oils; (ii) polyoxyethylene Stearates and ing effects. distearates; (iii) glycerol monostearate; (iv) poorly water In some preferred embodiments, the present invention is soluble, high melting point (mp=45 to 100° C.) waxes. directed to novel pharmaceutical compositions for use in 5 In some embodiments, the invention provides an oral phar reducing the peak concentration (C) of the abusable drug, maceutical composition of an abusable oral drug which is: (a) said method comprising administering the abusable drug and abuse resistant; (b) extended release; (c) resistant to dose a suitable amount of ADER. dumping due to alcohol; (d) resistant to significant changes in In some preferred embodiments, the present invention is oral bioavailability due to changes in food intake; and (e) directed to novel pharmaceutical compositions for reducing 10 resistant to intentional or surreptitious adulteration of bever the early post-dose partial area under the plasma concentra ages; or two or more of the above (a) to (e), said composition tion time curve (e.g., AUCo., AUCo. and AUC) of the comprising: (A) an abusable drug or a pharmaceutically abusable drug, said method comprising administering the acceptable salt thereof or a mixture thereof; and (B) One or abusable drug and a suitable amount of ADER. more compounds selected from the categories (i) to (iv) In some preferred embodiments, the present invention is 15 from the group consisting of: (i) hydrogenated Type I or Type directed to novel pharmaceutical compositions for reducing II vegetable oils; (ii) polyoxyethylene Stearates and distear the early post-dose average plasma concentration time (Cave) ates; (iii) glycerol monostearate; (iv) poorly water Soluble, of the abusable drug, said method comprising administering high melting point (mp=45 to 100°C.) waxes; said composi the abusable drug and a suitable amount of ADER. tion (a) to (e) using Substantially the same ingredients. In some preferred embodiments, the present invention is In some embodiments, the invention provides an oral phar directed to novel pharmaceutical compositions for reducing maceutical composition of an abusable oral drug which is: (a) the incidence of abusable drug toxicity, said method compris abuse resistant; (b) extended release; (c) resistant to dose ing administering the abusable drug and a suitable amount of dumping due to alcohol; (d) resistant to significant changes in ADER. oral bioavailability due to changes in food intake; and (e) In some preferred embodiments, the present invention is 25 resistant to intentional or surreptitious adulteration of bever directed to novel pharmaceutical compositions for reducing ages; or two or more of the above (a) to (e), said composition the intensity of abusable drug toxicity, said method compris comprising: (A) an abusable drug or a pharmaceutically ing administering the abusable drug and a suitable amount of acceptable salt thereof or a mixture thereof; and (B) Two or ADER. more compounds selected from the categories (i) to (iv) In some embodiments, the invention provides an oral phar 30 from the group consisting of: (i) hydrogenated Type I or Type maceutical composition of an abusable oral drug which is: (a) II vegetable oils; (ii) polyoxyethylene Stearates and distear abuse resistant; (b) extended release; (c) resistant to dose ates; (iii) glycerol monostearate; (iv) poorly water soluble, dumping due to alcohol; (d) resistant to significant changes in high melting point (mp=45 to 100°C.) waxes; said composi oral bioavailability due to changes in food intake; and (e) tion (a) to (e) using Substantially the same ingredients. resistant to intentional or surreptitious adulteration of bever 35 In some embodiments, the invention provides an oral phar ages; or two or more of the above (a) to (e), said composition maceutical composition of an abusable oral drug which is: (a) comprising: (A) an abusable drug or a pharmaceutically abuse resistant; (b) extended release; (c) resistant to dose acceptable salt thereof or a mixture thereof; and (B) One or dumping due to alcohol; (d) resistant to significant changes in more compounds selected from the categories (i) to (iv) oral bioavailability due to changes in food intake; and (e) from the group consisting of: (i) hydrogenated Type I or Type 40 resistant to intentional or surreptitious adulteration of bever II vegetable oils; (ii) polyoxyethylene Stearates and distear ages; or two or more of the above (a) to (e), said composition ates; (iii) glycerol monostearate; (iv) poorly water Soluble, comprising: (A) an abusable drug or a pharmaceutically high melting point (mp=45 to 100°C.) waxes. acceptable salt thereof or a mixture thereof; and (B) Two or In some embodiments, the invention provides an oral phar more compounds selected from at least two categories (i) to maceutical composition of an abusable oral drug which is: (a) 45 (iv) from the group consisting of: (i) hydrogenated Type I or abuse resistant; (b) extended release; (c) resistant to dose Type II vegetable oils; (ii) polyoxyethylene Stearates and dumping due to alcohol; (d) resistant to significant changes in distearates; (iii) glycerol monostearate; (iv) poorly water oral bioavailability due to changes in food intake; and (e) soluble, high melting point (mp=45 to 100°C.) waxes; said resistant to intentional or surreptitious adulteration of bever composition (a) to (e) using Substantially the same ingredi ages; or two or more of the above (a) to (e), said composition 50 entS. comprising: (A) an abusable drug or a pharmaceutically In some embodiments, compositions and methods of the acceptable salt thereof or a mixture thereof; and (B) Two or present invention include: (i) one or more abusable drugs (i.e., more compounds selected from the categories (i) to (iv) one or more opioid agonists); and (ii) ADER, and (iii) option from the group consisting of: (i) hydrogenated Type I or Type ally, other therapeutic agents in immediate or extended II vegetable oils; (ii) polyoxyethylene Stearates and distear 55 release form; and (iv) optionally one or more excipients or ates; (iii) glycerol monostearate; (iv) poorly water Soluble, auxiliary agents (e.g., glidants, lubricants, disintegrants, anti high melting point (mp=45 to 100°C.) waxes. Static agents, solvents, channel forming agents, coating In some embodiments, the invention provides an oral phar agents, flavorants, preservatives, bulking agents, polymers, maceutical composition of an abusable oral drug which is: (a) etc) and inert carriers; wherein the dosage form provides for abuse resistant; (b) extended release; (c) resistant to dose 60 abuse deterrence of the abusable drugs. dumping due to alcohol; (d) resistant to significant changes in In some embodiments, compositions and methods of the oral bioavailability due to changes in food intake; and (e) present invention include: (i) one or more abusable drugs (i.e., resistant to intentional or surreptitious adulteration of bever one or more opioid agonists); and (ii) ADER, and (iii) option ages; or two or more of the above (a) to (e), said composition ally, other therapeutic agents in immediate or extended comprising: (A) an abusable drug or a pharmaceutically 65 release form; and (iv) optionally one or more excipients or acceptable salt thereof or a mixture thereof; and (B) Two or auxiliary agents (e.g., glidants, lubricants, disintegrants, anti more compounds selected from at least two categories (i) to Static agents, solvents, channel forming agents, coating US 9,125,833 B2 17 18 agents, flavorants, preservatives, bulking agents, polymers, of abusable drug toxicity, including “high”; “liking”; “plea etc) and inert carriers; wherein the dosage form resists, deters Surable'; "euphoric'; “alertness”; “wakefulness”: “calm or prevents crushing, shearing, grinding, chewing, dissolv ing: "anxiolytic'; auditory and visual perceptual alterations; ing, melting, needle aspiration, inhalation, insufflation or Sol “relaxing and “rewarding effects. vent extraction of the abusable drug. In some preferred embodiments, the present invention is In some embodiments, compositions and methods of the directed to a novel method and pharmaceutical compositions present invention include: (i) one or more abusable drugs (i.e., for preventing or minimizing excessive peak concentrations one or more opioid agonists); and (ii) ADER, and (iii) option (dose dumping) of therapeutic doses of extended release ally, other therapeutic agents in immediate or extended abusable drugs used for medical purposes, when they are release form; and (iv) optionally one or more excipients or 10 co-ingested with alcohol. auxiliary agents (e.g., glidants, lubricants, disintegrants, anti In some preferred embodiments, the present invention is Static agents, solvents, channel forming agents, coating directed to a novel method and pharmaceutical compositions agents, flavorants, preservatives, bulking agents, polymers, for reducing the solvent extraction efficiency of the dosage etc) and inert carriers; wherein the dosage form provides form upon tampering. extended release of the abusable drug. 15 In some preferred embodiments, the present invention is In some embodiments, compositions and methods of the directed to a novel method and pharmaceutical compositions present invention include: (i) one or more abusable drugs (i.e., for reducing the filtration efficiency of the dosage form upon one or more opioid agonists); and (ii) ADER, and (iii) option tampering. ally, other therapeutic agents in immediate or extended In some preferred embodiments, the present invention is release form; and (iv) optionally one or more excipients or directed to a novel method and pharmaceutical compositions auxiliary agents (e.g., glidants, lubricants, disintegrants, anti for preventing the Surreptitious adulteration of beverages. Static agents, solvents, channel forming agents, coating In some preferred embodiments, the present invention is agents, flavorants, preservatives, bulking agents, polymers, directed pharmaceutical compositions which include one or etc) and inert carriers; wherein the dosage form provides more abusable drugs alone or in combination with other abuse deterrence and extended release of the abusable drug. 25 therapeutic agents, one or more ADER agents specified In some embodiments, compositions and methods of the herein, and optionally one or more excipients (e.g., glidants, present invention include: (i) one or more abusable drugs (i.e., lubricants, disintegrants, etc) and inert carriers, said compo one or more opioid agonists); and (ii) ADER, and (iii) option sition resisting, deterring, discouraging or preventing crush ally, other therapeutic agents in immediate or extended ing, shearing, grinding, chewing, dissolving, melting, needle release form; and (iv) optionally one or more excipients or 30 aspiration, inhalation, insufflation, solvent extraction and fil auxiliary agents (e.g., glidants, lubricants, disintegrants, anti tration of the abusable drug. Static agents, solvents, channel forming agents, coating In some preferred embodiments, pharmaceutical composi agents, flavorants, preservatives, bulking agents, polymers, tions of the present invention provide a more extended release etc) and inert carriers; wherein the dosage form provides pharmacokinetic profile compared with formulations devoid simultaneous abuse deterrence and extended release of the 35 of ADER. abusable drug. In some preferred embodiments, pharmaceutical composi In some embodiments, compositions and methods of the tions and methods of the present invention can form a viscous present invention include: (i) one or more abusable drugs (i.e., Substance upon contact with a solvent such that the abusable one or more opioid agonists); and (ii) ADER, and (iii) option drug cannot be easily drawn into a Syringe; crushed and ally, other therapeutic agents in immediate or extended 40 powdered to facilitate or enhance nasal delivery (Snorting or release form; and (iv) optionally one or more excipients or nasal insufflation), inhalation or rapid oral delivery of a larger auxiliary agents (e.g., glidants, lubricants, disintegrants, anti than medically intended delivery of the abusable drug; Static agents, solvents, channel forming agents, coating extracted with solvents and filtered. agents, flavorants, preservatives, bulking agents, polymers, In some preferred embodiments, the pharmaceutical com etc) and inert carriers; wherein the dosage form provides 45 position resists the rapid release of all or substantially all of simultaneous abuse deterrence and extended release of the the abusable drug content of the unit dose upon tampering. In abusable drug using Substantially the same ingredients. another preferred embodiment of the invention, the pharma In some preferred embodiments, the present invention is ceutical composition resists the rapid release of a portion of directed to novel pharmaceutical compositions for reducing the abusable drug content of the unit dose upon tampering. In the intensity or frequency of one or more symptoms, includ 50 yet another preferred embodiment of the invention, upon ing nausea, Vomiting. Somnolence, stupor, coma, respiratory tampering, the abusable drug formulated with ADER resists depression, apnea, respiratory arrest, circulatory depression, the release of the abusable drug to a greater extent than when bradycardia, hypotension, shock and skeletal muscle flaccid formulated without ADER. ity, said method comprising administering the abusable drug In some preferred embodiments, the pharmaceutical com and a suitable amount of ADER. 55 position resists the rapid release of all or substantially all of In some preferred embodiments, the present invention is the abusable drug content of the unit dose upon co-adminis directed to novel pharmaceutical compositions for reducing tering with alcohol. In another preferred embodiment of the the intensity or frequency of one or more signs and symptoms invention, the pharmaceutical composition resists the rapid of abusable drug toxicity, including tachycardia, mood alter release of a portion of the abusable drug content of the unit ation, euphoria, CNS stimulation, agitation, increased Sweat 60 dose upon co-administering with alcohol. In yet another pre ing, psychotomimetic effects, hallucinations, perception ferred embodiment of the invention, upon co-administering alterations, cognitive alterations, reinforcing effects and plea with alcohol, the abusable drug formulated with ADER Surable effects said method comprising administering the resists the release of the abusable drug to a greater extent than abusable drug and a suitable amount of ADER. when formulated without ADER. In some preferred embodiments, the present invention is 65 In some preferred embodiment of the abuse deterrent phar directed to a novel pharmaceutical compositions for reducing maceutical composition, the therapeutic pharmaceutical the intensity or frequency of one or more signs and symptoms composition can be filled in a hard gelatin capsule without US 9,125,833 B2 19 20 banding. In some preferred embodiment of the abuse deter stantially reduced variability in rate and extent of absorption rent pharmaceutical composition, the therapeutic pharmaceu when taken with food, compared with the fasted state. tical composition can be filled in a hard gelatin capsule with It is an object of certain preferred embodiments of the security banding. In another preferred embodiment of the present invention to provide bioavailable oral immediate abuse deterrent pharmaceutical composition, the therapeutic release formulations of abusable drugs which provide a sub pharmaceutical composition can be filled in a soft shell cap stantially reduced variability in rate and extent of absorption sules. In another preferred embodiment of the abuse deterrent when taken with alcohol, compared to an alcohol-free state. pharmaceutical composition, the therapeutic pharmaceutical It is an object of certain preferred embodiments of the composition can be prepared as a solid dispersion for direct present invention to provide bioavailable oral extended compression into tablets, for extrusion and pelletization, fol 10 release formulations of abusable drugs which provide a sub lowed by compression into a tablet or filling into a capsule. In stantially reduced variability in rate and extent of absorption another preferred embodiment of the abuse deterrent pharma when taken with food, compared with the fasted state. ceutical composition, the therapeutic pharmaceutical compo It is an object of certain preferred embodiments of the sition can be compressed into tablets. In another preferred 15 present invention to provide bioavailable oral extended embodiment of the abuse deterrent pharmaceutical composi release formulations of abusable drugs which provide a sub tion, the therapeutic pharmaceutical composition can be pre stantially reduced variability in rate and extent of absorption pared into multiparticulate matrices followed by tabletting or when taken with alcohol, compared to an alcohol-free state. capsule filling. It is an object of certain preferred embodiments of the The present invention is directed at oral pharmaceutical present invention to provide bioavailable oral abuse resistant compositions of abusable drugs or their pharmaceutically and abuse deterrent extended release formulations of abus acceptable salts or mixtures thereof. able drugs which provide a substantially reduced variability The present invention also relates to oral abusable drug in rate and extent of absorption when taken with food, com pharmaceutical compositions and methods for the prevention pared with the fasted state. and treatment of pain, musculoskeletal disorders ands other 25 It is an object of certain preferred embodiments of the medical conditions amenable to treatment with the abusable present invention to provide bioavailable oral abuse resistant drug. and abuse deterrent extended release formulations of abus It is an object of certain preferred embodiments of the able drugs which provide a substantially reduced variability present invention to Substantially improve the efficiency and in rate and extent of absorption when taken with alcohol, quality of disease management for: (i) pain; (ii) musculosk 30 compared to an alcohol-free state. eletal disorders; (iii) addiction disorders; and/or (iv) other It is an object of certain preferred embodiments of the medical conditions amenable to treatment with the abusable present invention to provide bioavailable oral extended drug. release formulations of abusable drugs which provide a sub It is an object of certain preferred embodiments of the stantially reduced abuse potential compared with currently present invention to provide bioavailable oral formulations of 35 available extended release formulations. abusable drugs suitable for up to once-daily (e.g., Q4H, Q6H, It is an object of certain preferred embodiments of the Q8H, Q12H, Q24H) administration which substantially present invention to provide bioavailable formulations for improve the efficiency and quality of disease management oral administration Suitable for up to once-a-day administra for: (i) pain; (ii) musculoskeletal disorders; (iii) addiction tion (e.g., Q4H, Q6H, Q8H, Q12H, and Q24H). disorders; and/or (iv) other medical conditions amenable to 40 It is an object of certain preferred embodiments of the treatment with the abusable drug. present invention to provide bioavailable formulations for It is an object of certain preferred embodiments of the oral administration Suitable for up to once-a-day administra present invention to provide bioavailable oral formulations of tion which provide an early onset and Sustained duration of abusable drugs which provide a Substantially increased dura therapeutic effect. tion of effect as compared to immediate release formulations. 45 It is an object of certain preferred embodiments of the It is an object of certain preferred embodiments of the present invention to provide formulations of abusable drugs present invention to provide bioavailable oral formulations of which provide atherapeutic effect for up to about 30 minutes. abusable drugs which provide a substantially reduced abuse In other preferred embodiments, the formulations of abusable potential compared with immediate release formulations of drugs provide atherapeutic effect for up to about 1 hour, or up abusable drugs. 50 to about 2 hours, or up to about 4 hours, or up to about 6 hours, It is an object of certain preferred embodiments of the or up to about 8 hours, or up to about 10 hours, or up to about present invention to provide bioavailable oral formulations of 12 hours, or up to about 16 hours, or up to about 18 hours, or abusable drugs which provide a substantially reduced abuse up to about 24 hours or up to about 36 hours, or up to about 48 potential compared with currently available extended release hours. formulations. 55 It is an object of certain preferred embodiments of the It is an object of certain preferred embodiments of the invention to provide a method and formulations of oral abus present invention to provide bioavailable oral formulations of able drugs for the prevention and treatment of: (i) pain; (ii) abusable drugs which provide a substantially reduced abuse musculoskeletal disorders; (iii) addiction disorders; and/or potential compared with commercially available formula (iv) other medical conditions amenable to treatment with the tions of abusable drugs. 60 abusable drug. It is an object of certain preferred embodiments of the It is an object of certain preferred embodiments of the present invention to provide bioavailable oral immediate invention to provide a method and formulations of oral abus release formulations of abusable drugs which provide a sub able drugs for the prevention and treatment of (i) pain; (ii) stantially reduced abuse potential. musculoskeletal disorders; (iii) addiction disorders; and/or It is an object of certain preferred embodiments of the 65 (iv) other medical conditions amenable to treatment with the present invention to provide bioavailable oral immediate abusable drug; said formulations and methods not having a release formulations of abusable drugs which provide a sub propensity of Substantial drug accumulation. US 9,125,833 B2 21 22 It is an object of certain preferred embodiments of the In some preferred embodiments of the invention, the abus invention to provide a method and formulations of oral abus able drugs are in a matrix that is in the form of pellets or beads. able drugs for the prevention and treatment of (i) pain; (ii) In some preferred embodiments, the dosage form of the musculoskeletal disorders; (iii) addiction disorders; and/or invention comprises a compressed tablet, compressed cap (iv) other medical conditions amenable to treatment with the Sule or uncompressed capsule. In other embodiments, the abusable drug; said formulations having a reduced potential dosage form comprises a liquid fill capsule. for tampering (e.g., mechanical, thermal, chemical or physi In some preferred embodiments, the dosage form of the cal tampering). invention comprises an oral formulation (e.g., tablet or cap It is an object of certain preferred embodiments of the Sule) which is coated to prevent substantial direct contact of invention to provide a method and formulations of oral abus 10 able drugs for the prevention and treatment of (i) pain; (ii) abusable drug with oral cavity (e.g. tongue, oral mucosa), musculoskeletal disorders; (iii) addiction disorders; and/or oropharyngeal mucosal Surface, esophagus or stomach. In (iv) other medical conditions amenable to treatment with the Some preferred embodiments, the dosage form of the inven abusable drug; said formulations in Some embodiments hav tion comprises an oral formulation which is coated with a film ing a reduced potential for drug abuse (e.g., inhalational, 15 or polymer. In some preferred embodiments, the dosage form intranasal, intravenous or oral abuse); said formulations in of the invention comprises abusable drugs in an enteric coat Some embodiments having a reduced potential for drug diver ing. In some preferred embodiments, the dosage form of the sion; said formulations in some embodiments having a invention comprises abusable drugs formulated with pharma reduced intrasubject and intrasubject pharmacokinetic Vari ceutical excipients and auxiliary agents known in the art, Such ability, said formulations in some embodiments having a that the abusable drug is released after a approximately spe reduced intersubject and intrasubject pharmacodynamic Vari cific amount of time, oratan approximately specific anatomic ability, said formulations in some embodiments having a location in the gastrointestinal tract, or when the dosage form reduced peak to trough fluctuation, said formulations in some is in contact with specific gastrointestinal conditions (e.g., pH embodiments having a shorter time to therapeutic concentra range, osmolality, electrolyte content, food content.). tions and a shorter time to steady-state; said formulations in 25 In some preferred embodiments, the in vivo pharmacoki Some embodiments being in extended release dosage form, netic parameters of the specifications and claims are derived and said formulations providing an extended duration of or determined under fed conditions. In other preferred action; said formulations in Some embodiments providing embodiments, the in vivo pharmacokinetic parameters are more than one of the aforementioned properties. derived or determined under fasted conditions. It is an object of certain preferred embodiments of the 30 Some or all of the above objects and other objects herein invention to provide a method and formulations of oral abus able drugs for the prevention and treatment of pain, said are achieved by embodiments of the present invention, which formulations suitable for use in acute pain, including acute is directed in part to a dosage form of oral abusable drugs in postSurgical pain. In other preferred embodiments, the inven abuse deterrent form. tion provides a method and formulations of oral abusable 35 Some or all of the above objects and other objects herein drugs for the prevention and treatment of chronic pain, cancer are achieved by embodiments of the present invention, which pain, neuropathic pain, Somatic pain, visceral pain, idiopathic is directed in part to a dosage form of oral abusable drugs in pain and breakthrough pain of various etiologies, including extended release form. cancer, chronic pain and neuropathic pain. Some or all of the above objects and other objects herein It is an object of certain embodiments of the present inven 40 are achieved by embodiments of the present invention, which tion to provide oral formulations of abusable drugs with both is directed in part to a dosage form of oral abusable drugs in immediate release and controlled release forms. an abuse deterrent and extended release form. It is an object of certain embodiments of the present inven Some or all of the above objects and other objects herein tion to provide oral formulations of abusable drugs in pulsa are achieved by embodiments of the present invention, which tile release form. 45 is directed in part to a dosage form of oral abusable drugs and It is an object of certain embodiments of the present inven ADER. tion to provide abusable drugs for oral administration wherein Some or all of the above objects and other objects herein the abusable drugs are dispersed within a matrix. are achieved by embodiments of the present invention, which In certain preferred embodiments the oral dosage form of is directed in part to a dosage form of oral extended release the present invention comprises a matrix which includes 50 abusable drugs and ADER. ADERandanabusable drug or a pharmaceutically acceptable Some or all of the above objects and other objects herein salt thereof. In certain preferred embodiments, the matrix is are achieved by embodiments of the present invention, which compressed into a tablet and may be optionally overcoated is directed in part to a dosage form of abuse deterrent abusable with a coating that in addition to the Sustained release material drugs and ADER. of the matrix may control the release of the abusable drug or 55 Some or all of the above objects and other objects herein pharmaceutically acceptable salt thereof from the formula are achieved by embodiments of the present invention, which tion, such that blood levels of active ingredient are maintained is directed in part to a dosage form which provides simulta within the therapeutic range over an extended period of time. neous abuse deterrence and extended release through the In certain alternate embodiments, the matrix is encapsulated. inclusion of ADER. In certain preferred embodiments, the sustained release 60 In some preferred embodiments, compositions and meth oral dosage form of the present invention comprises ADER ods of the present invention involve abusable drugs, wherein and a plurality of pharmaceutically acceptable Sustained the abusable drugs are limited to opioid agonists which are release matrices comprising an abusable drug or a pharma scheduled drugs under the United States Controlled Sub ceutically acceptable salt thereof, the dosage form maintain stances Act of 1970, as amended. ing the plasma levels of abusable drug within the therapeutic 65 In some preferred embodiments, compositions and meth range over an extended period of time when administered to ods of the present invention involve abusable drugs, wherein patients. the abusable drugs are limited to prodrugs of abusable drugs. US 9,125,833 B2 23 24 In some preferred embodiments, the dosage form is a cap ADER material to render said dosage form extended release: Sule, said capsule rendered tamper-resistant with a security said dosage form providing at least 60% of the steady state banding seal between the capsule parts. concentration of abusable drug after administration of one In some preferred embodiments, the dosage form is a cap dose at its intended dosing frequency. In other preferred Sule, said capsule rendered liquid tight or leak resistant with a embodiments, the dosage form provides at least about 62.5%, banding seal between the capsule parts. or at least about 65%, or at least about 67.5%, or at least about In another aspect, the invention relates to a method and 70%, or at least about 72.5%, or at least about 75%, or at least pharmaceutical compositions for prevention or treatment of about 77.5%, or at least about 80%, or at least about 82.5%, or (i) pain; (ii) musculoskeletal disorders; (iii) addiction disor at least about 85%, or at least about 87.5%, or at least about ders; or (iv) other medical conditions amenable to treatment 10 90%, or at least about 92.5%, or at least about 95% or at least with the abusable drug; comprising oral administration of a 98% of the steady state therapeutic concentration of abusable dosage form containing an abusable drug or a pharmaceuti drug after administration of one dose at its intended dosing cally acceptable salt of abusable drug or a mixture thereofand frequency. ADER. In some preferred embodiments, the dosage form provides In some preferred embodiments, the dosage form provides 15 an oral pharmaceutical composition comprising a therapeu an oral pharmaceutical composition for the prevention and tically effective amount of abusable drug or a pharmaceuti treatment of (i) pain; (ii) musculoskeletal disorders; (iii) cally acceptable salt of abusable drug or a mixture thereofand addiction disorders; or (iv) other medical conditions ame ADER material to render said dosage form abuse deterrent nable to treatment with the abusable drug; comprising athera and extended release, said dosage form Suitable for up to peutically effective amount of abusable drug or a pharmaceu every 24 hour (once-a-day) administration to a human tically acceptable salt of abusable drug or a mixture thereof patient; said dosage form providing at least 60% of the steady and ADER material to render said dosage form: (a) abuse state concentration of abusable drug after administration of deterrent; and/or (b) extended release; and/or (c) resistant to one dose at its intended dosing frequency. In other preferred significant alcohol dose-dumping; and/or (d) resistant to sig embodiments, the dosage form provides at least about 62.5%, nificant variations in rate and/or extent of absorption based on 25 or at least about 65%, or at least about 67.5%, or at least about a fed or fasted State; and/or (e) resistant to intentional or 70%, or at least about 72.5%, or at least about 75%, or at least unintentional tampering; and/or (f) resistant to abusable drug about 77.5%, or at least about 80%, or at least about 82.5%, or toxicity due to intentional or unintentional tampering; and/or at least about 85%, or at least about 87.5%, or at least about (g) resistant to significant variations in clinical effects when 90%, or at least about 92.5%, or at least about 95% or at least ingested after attempted tampering; and/or (h) resistant to 30 98% of the steady state therapeutic concentration of abusable intentional or Surreptitious adulteration of beverage; and/or drug after administration of one dose at its intended dosing (i) resistant to significant drug-food interaction (i.e., large frequency. changes in rate or extent of absorption when taken with food); In some preferred embodiments, the dosage form provides said rendering by said ADER material achieved in some an oral pharmaceutical composition comprising a therapeu embodiments using substantially the same ADER material; 35 tically effective amount of abusable drug or a pharmaceuti said dosage form in Some embodiments Suitable for admin cally acceptable salt of abusable drug or a mixture thereofand istration up to about every 2 hours, or up to about every 4 ADER material to render said dosage form resistant to alco hours, or up to about every 6 hours, or up to about every 8 hol dose dumping, said dosage form suitable for up to every hours, or up to about every 12 hours, or up to about every 24 24 hour (once-a-day) administration to a human patient, said hours to a human patient, said dosage form in some embodi 40 dosage form providing at least 60% of the steady state con ments having a therapeutic effect of up to about every 1 hour, centration of abusable drug after administration of one dose at or up to about every 4 hours, or up to about every 6 hours, or its intended dosing frequency. In other preferred embodi up to about every 8 hours, or up to about every 12 hours, or up ments, the dosage form provides at least about 62.5%, or at to about every 24 hours upon administration to a human least about 65%, or at least about 67.5%, or at least about patient. 45 70%, or at least about 72.5%, or at least about 75%, or at least In some preferred embodiments, the dosage form provides about 77.5%, or at least about 80%, or at least about 82.5%, or an oral pharmaceutical composition comprising a therapeu at least about 85%, or at least about 87.5%, or at least about tically effective amount of abusable drug or a pharmaceuti 90%, or at least about 92.5%, or at least about 95% or at least cally acceptable salt of abusable drug or a mixture thereofand 98% of the steady state therapeutic concentration of abusable ADER material to render said dosage form abuse deterrent, 50 drug after administration of one dose at its intended dosing said dosage form Suitable for up to every 24 hour (once-a- frequency. day) administration to a human patient, said dosage form In some preferred embodiments, the dosage form provides providing at least 60% of the steady state concentration of an oral pharmaceutical composition comprising a therapeu abusable drug after administration of one dose at its intended tically effective amount of abusable drug or a pharmaceuti dosing frequency. In other preferred embodiments, the dos 55 cally acceptable salt of abusable drug or a mixture thereofand age form provides at least about 62.5%, or at least about 65%, ADER material to render said dosage form resistant to sig or at least about 67.5%, or at least about 70%, or at least about nificant fluctuations in bioavailability when given under fed 72.5%, or at least about 75%, or at least about 77.5%, or at and fasted conditions, said dosage form suitable for up to least about 80%, or at least about 82.5%, or at least about every 24 hour (once-a-day) administration to a human 85%, or at least about 87.5%, or at least about 90%, or at least 60 patient; said dosage form providing at least 60% of the steady about 92.5%, or at least about 95% or at least 98% of the state concentration of abusable drug after administration of steady state therapeutic concentration of abusable drug after one dose at its intended dosing frequency. In other preferred administration of one dose at its intended dosing frequency. embodiments, the dosage form provides at least about 62.5%, In some preferred embodiments, the dosage form provides or at least about 65%, or at least about 67.5%, or at least about an oral pharmaceutical composition comprising a therapeu 65 70%, or at least about 72.5%, or at least about 75%, or at least tically effective amount of abusable drug or a pharmaceuti about 77.5%, or at least about 80%, or at least about 82.5%, or cally acceptable salt of abusable drug or a mixture thereofand at least about 85%, or at least about 87.5%, or at least about US 9,125,833 B2 25 26 90%, or at least about 92.5%, or at least about 95% or at least or about 1 to about 18 hours, or about 1 to about 16 hours, or 98% of the steady state therapeutic concentration of abusable about 1 to about 12 hours, or about 1 to 10 hours, or about 1 drug after administration of one dose at its intended dosing to about 8 hours, or about 1 to about 6 hours, or about 1 to frequency. about 4 hours, about 2 to about 24 hours, or about 3 to 24 In some preferred embodiments, the invention comprises hours, or about 4 to about 24 hours, or about 6 to about 24 an oral pharmaceutical composition comprising a therapeu hours, or about 8 to about 24 hours, about 2 to about 12 hours, tically effective amount of abusable drug or a pharmaceuti or about 3 to 10 hours, or about 3 to about 8 hours, or about 4 cally acceptable salt of abusable drug, or a mixture thereof to about 8 hours, or about 6 to about 10 hours. and ADER to render said dosage form suitable for three times In some preferred embodiments, the invention comprises a day administration (TID) or about every eight hours admin 10 an oral pharmaceutical composition comprising therapeuti istration (Q8H). cally effective amounts of abusable drug or pharmaceutically In some preferred embodiments, the TID or Q8H oral acceptable salts thereof, or mixtures thereof and ADER: said pharmaceutical composition of an abusable drug provides a dosage form providing a systemic exposure as assessed by the therapeutic effect for about 8 hours. mean abusable drug area under the plasma concentration time In some preferred embodiments, the TID or Q8H oral 15 curve (AUC) after first administration which is at least pharmaceutical composition of an abusable drug provides a about 40% of the area under the plasma drug concentration C of abusable drugs at about 1 to about 6 hours. time curve from time Zero to infinity (AUC). In other In some preferred embodiments, the TID or Q8H oral preferred embodiments, the dosage from provides an AUCo., pharmaceutical composition of abusable drugs provide a C, which is at least about 45%, or which is at least about 50%, or of abusable drugs at about 6 to 10 hours. which is at least about 55%, or at least about 60%, or which is In some preferred embodiments, the TID or Q8H oral at least about 65%, or at least about 70%, or which is at least pharmaceutical composition of abusable drugs provide a about 75%, or at least about 80%, or at least about 85%, or at mean abusable drugs C/C ratio of 0.25 to about 0.95. least about 88%, or at least about 90%, or at least about 92%, In some preferred embodiments, the TID or Q8H oral or at least about 94%, or at least about 96% or at least about pharmaceutical composition of abusable drugs provide a per 25 98% of the AUC. cent fluctuation of less than 400%. In some preferred embodiments, the dosage form provides In some preferred embodiments, the TID or Q8H oral an oral pharmaceutical composition comprising a therapeu pharmaceutical composition of an abusable drug provides a tically effective amount of an abusable drug or pharmaceuti Ws of 1.5 to about 6.5 hours. cally acceptable salts thereof or mixtures thereof and ADER: In some preferred embodiments, the TID or Q8H oral 30 said dosage form providing at least 80% of the steady state pharmaceutical composition of an abusable drug provides an therapeutic concentration of abusable drug after administra HVD of 2 to about 7 hours. tion of sthree doses at their intended dosing frequency. In In some preferred embodiments, the TID or Q8H oral other preferred embodiments, said dosage form provides at pharmaceutical composition of an abusable drug provides an least about 60%, or at least about 65%, or at least about 70%, HVD of about 2 to about 7 hours. 35 or at least about 75%, or at least about 85%, or at least about In some preferred embodiments, the TID or Q8H oral 90%, or at least about 92%, or at least about 95%, or at least pharmaceutical composition of an abusable drug an AI of not about 97%, or at least about 99% of the steady state therapeu more that 4.0. tic concentration of abusable drug after administration of In some preferred embodiments, the invention comprises sthree doses at their intended dosing frequency. an oral pharmaceutical composition comprising therapeuti 40 In some preferred embodiments, the dosage form provides cally effective amounts of abusable drug or pharmaceutically an oral pharmaceutical composition comprising a therapeu acceptable salts thereof, or mixtures thereof and ADER: said tically effective amount of abusable drug or pharmaceutically dosage from providing a C of abusable drug occurring acceptable salts thereof or mixtures thereof and ADER: said from a mean of about 0.25 to about 30 hours. In other pre dosage form providing at least 80% of the steady state thera ferred embodiments, the dosage form provides a C of 45 peutic concentration of abusable drug after administration of abusable drug occurring from a mean of about 0.5 to about 30 stwo doses at their intended dosing frequency. In other pre hours, or from a mean of about 1 to about 30 hours, or about ferred embodiments, said dosage form provides at least about 1 to about 26 hours, or about 1 to about 24 hours, or about 1 60%, or at least about 65%, or at least about 70%, or at least to about 20 hours, or about 1 to about 18 hours, or about 1 to about 75%, or at least about 85%, or at least about 90%, or at about 16 hours, or about 1 to about 14 hours, or about 1 to 50 least about 92%, or at least about 95%, or at least about 97%, about 12 hours, or about 1 to about 10 hours, or about 1 to or at least about 99% of the steady state therapeutic concen about 8 hours, or about 1 to about 6 hours, or about 1 to about tration of abusable drug after administration of stwo doses at 4 hours, or about 1 to about 3 hours, or about 2 to about 30 their intended dosing frequency. hours, or about 4 to about 30 hours, or about 4 to about 24 In some preferred embodiments, the dosage form provides hours, or about 6 to about 24 hours, or about 8 to about 24 55 an oral pharmaceutical composition comprising a therapeu hours, or about 10 to about 20 hours, or about 12 to about 24 tically effective amount of abusable drug or pharmaceutically hours, or about 18 to about 24 hours, or about 2 to about 12 acceptable salts thereof or mixtures thereof and ADER: said hours, or about 3 to about 12 hours, or about 3 to about 8 dosage form providing at least 80% of the steady state thera hours, or about 4 to about 10 hours, or about 4 to about 12 peutic concentration of abusable drug after administration of hours, or about 4 to about 9 hours, or about 5 to about 8 hours. 60 one dose at their intended dosing frequency. In other pre In some preferred embodiments, the invention comprises ferred embodiments, said dosage form provides at least about an oral pharmaceutical composition comprising therapeuti 60%, or at least about 65%, or at least about 70%, or at least cally effective amounts of abusable drug or pharmaceutically about 75%, or at least about 85%, or at least about 90%, or at acceptable salts thereof, or mixtures thereof and ADER: said least about 92%, or at least about 95%, or at least about 97%, dosage from providing a C of abusable drug occurring 65 or at least about 99% of the steady state therapeutic concen from a mean of about 0.5 to about 28 hours, or about 1 to about tration of abusable drug after administration of one dose at 28 hours, or about 1 to 24 hours, or about 1 to about 20 hours, their intended dosing frequency. US 9,125,833 B2 27 28 In some preferred embodiments, the dosage form provides abusable drug of not more than about 2.5, or not more than an oral pharmaceutical composition comprising a therapeu about 2, or not more than about 1.75, or not more than about tically effective amount of abusable drug or pharmaceutically 1.5, or not more than about 1.25, or not more than about 1, or acceptable salts thereof or mixtures thereof and ADER: said not more than about 0.75, or not more than about 0.5, or not dosage form after administration to a human patient provid more than about 0.25. ing a C/C ratio of abusable drug of 0.1 to about 1.0. In In some preferred embodiments, the dosage form provides other preferred embodiments, the dosage form provides a an oral pharmaceutical composition comprising a therapeu C/C, ratio of abusable drug of about 0.1 to about 0.9, or tically effective amount of abusable drug or pharmaceutically about 0.1 to about 0.8, or about 0.1 to about 0.7, or about 0.1 acceptable salts thereof or mixtures thereof and ADER to to about 0.6, or about 0.1 to about 0.5, or about 0.1 to about 10 render said dosage form abuse deterrent and/or suitable for 0.4, or about 0.1 to about 0.3, or about 0.2 to about 1.0, or twice-a-day administration to a human patient, said dosage about 0.25 to about 1.0, or about 0.4 to about 1.0, or about 0.5 form providing a C of abusable drug at 2 to about 10 hours; to about 0.9, or about 0.5 to about 0.85, or about 0.5 to about and said dosage form providing a therapeutic effect for at 0.8, or about 0.5 to about 0.75, or about 0.5 to about 1.0, or least about 12 hours. In other preferred embodiments, the about 0.65 to about 1.0, or about 0.75 to about 1.0, or about 15 dosage form provides a C of abusable drug at about 2 to 0.2 to about 0.9, or about 0.3 to about 0.95, or about 0.3 to about 8 hour or about 2 to about 6 hours, or about 2 to about about 0.85, or about 0.3 to about 0.8, or about 03 to about 5 hours, or about 2 to about 7 hours, or about 2 to about 4.5 0.75, or about 0.3 to about 0.7, or about 0.3 to about 0.6, or hours, or about 2 to about 4 hours, or 2 to about 3.5 hours, or about 0.4 to about 0.9, or about 0.4 to about 0.8, or about 0.4 about 2 to about 3 hours, or about 3 to about 10hours, or about to about 0.7, or about 0.4 to about 0.6, or about 0.8 to about 1, 3.5 to about 10 hours, or about 4 to about 10 hours, or about or about 0.8 to about 1.1. 4.5 to about 10 hours, or about 5 to about 10 hours, or 5 to In some preferred embodiments, the dosage form provides about 10 hours, or about 6 to about 10 hours, or about 3 to an oral pharmaceutical composition comprising a therapeu about 8 hours, or about 3 to about 7 hours, or about 3 to about tically effective amount of abusable drug or pharmaceutically 6 hours, or about 4 to about 8 hours, or about 4 to about 6. acceptable salts thereof or mixtures thereof and ADER: said 25 In some preferred embodiments, the dosage form provides dosage form after administration to a human patient provid an oral pharmaceutical composition comprising a therapeu ing a percent fluctuation of abusable drug of less than 400%. tically effective amount of abusable drug or pharmaceutically In other preferred embodiments, the dosage form provides a acceptable salts thereof or mixtures thereof and ADER to percent fluctuation of abusable drug of less than 350%, or less render said dosage form abuse deterrent and/or suitable for than 300%, or less than 250%, or less than 200%, or less than 30 twice-a-day administration to a human patient, said dosage 150%, or less than 100%, or less than 75%, or less than 50%, form providing a C/C ratio of abusable drug of 0.1 to or less than 25%. about 1; and said dosage form providing a therapeutic effect In some preferred embodiments, the dosage form provides for at least about 12 hours. In other preferred embodiments, an oral pharmaceutical composition comprising a therapeu the dosage form provides a C/C ratio of abusable drug of tically effective amount of abusable drug or pharmaceutically 35 about 0.25 to about 0.9, or about 0.25 to about 0.8, or about acceptable salts thereof or mixtures thereof and ADER: said 0.25 to about 0.75, or about 0.25 to about 0.6, or 0.25 to about dosage form after administration to a human patient provid 0.5, or about 0.25 to about 0.4, or about 0.25 to about 0.35, or inga Wso of abusable drug of about 1 to about 6 hours for each about 0.3 to about 0.95, or about 0.4 to about 0.95, or about 6 hour time period of intended dosing frequency and intended 0.5 to about 0.95, or about 0.65 to about 0.95, or about 0.75 to duration of action. In other preferred embodiments, the dos 40 about 0.95, or about 0.3 to about 0.8, or about 0.4 to about age form provides a Wso of abusable drug for each 6 hour time 0.75, or about 0.5 to about 0.75, or about 0.1 to about 0.9, or period of intended dosing frequency and intended duration of about 0.1 to about 0.8, or about 0.1 to about 0.7, or about 0.1 action of about 1 to about 5 hours, or about 1 to about 4 hours, to about 0.6, or about 0.1 to about 0.5, or about 0.1 to about or about 1 to about 3 hours, or about 1 to about 2 hours, or 2 0.4, or about 0.1 to about 0.3, or about 0.2 to about 1.0, or to about 6 hours, or about 3 to about 6 hours, or about 4 to 45 about 0.25 to about 1.0, or about 0.4 to about 1.0, or about 0.5 about 6 hours, or about 2 to about 4 hours. to about 0.9, or about 0.5 to about 0.85, or about 0.5 to about In some preferred embodiments, the dosage form provides 0.8, or about 0.5 to about 0.75, or about 0.5 to about 1.0, or an oral pharmaceutical composition comprising a therapeu about 0.65 to about 1.0, or about 0.75 to about 1.0, or about tically effective amount of abusable drug or pharmaceutically 0.2 to about 0.9, or about 0.3 to about 0.95, or about 0.3 to acceptable salts thereof or mixtures thereof and ADER: said 50 about 0.85, or about 0.3 to about 0.8, or about 03 to about dosage form after administration to a human patient provid 0.75, or about 0.3 to about 0.7, or about 0.3 to about 0.6, or ing an HVD of abusable drug of about 1.5 to about 6 hours for about 0.4 to about 0.9, or about 0.4 to about 0.8, or about 0.4 each 6 hour time period of intended dosing frequency and to about 0.7, or about 0.4 to about 0.6, or about 0.8 to about 1, intended duration of action. In other preferred embodiments, or about 0.8 to about 1.1. the dosage form provides a HVD of abusable drug for each 6 55 In some preferred embodiments, the dosage form provides hour time period of intended dosing frequency and intended an oral pharmaceutical composition comprising a therapeu duration of action of about 1.5 to about 5 hours, or about 1.5 tically effective amount of abusable drug or pharmaceutically to about 4 hours, or about 1.5 to about 3 hours, or about 1.5 to acceptable salts thereof or mixtures thereof and ADER to about 2 hours, or 2 to about 6 hours, or about 3 to about 6 render said dosage form abuse deterrent and/or suitable for hours, or about 4 to about 6 hours, or about 2 to about 4 hours. 60 twice-a-day administration to a human patient, said dosage In some preferred embodiments, the dosage form provides form providing a percent fluctuation of abusable drug of less an oral pharmaceutical composition comprising a therapeu than 400%; and said dosage form providing a therapeutic tically effective amount of abusable drug or pharmaceutically effect for at least about 12 hours. In other preferred embodi acceptable salts thereof or mixtures thereof and ADER: said ments, the dosage form provides a percent fluctuation of dosage form after administration to a human patient provid 65 abusable drug of less than about 375%, or less than about ing an AI of abusable drug of not more than 3.0. In other 350%, or less than about 325%, or less than about 300%, or preferred embodiments, the dosage form provides an AI of less than about 275%, or less than about 250%, or less than US 9,125,833 B2 29 30 about 225%, or less than about 200%, or less than about and 7.2 at 37° C. of from 0% to about 47.5% at 1 hour, from 175%, or less than about 150%, or less than about 125%, or about 10% to about 65% at 2 hours, from about 15% to about less than about 100%, or less than about 75%, or less than 70% at 4 hours, from about 25% to about 77.5% at 6 hours, about 50%, or less than about 25%. from about 35% to about 87.5% at 9 hours, and greater than In some preferred embodiments, the dosage form provides about 65% at 12 hours. In other preferred embodiments, the an oral pharmaceutical composition comprising a therapeu dosage form provides said an in-vitro release rate of from 0% tically effective amount of abusable drug or pharmaceutically to about 40% at 1 hour, from about 5% to about 55% at 2 acceptable salts thereof or mixtures thereof and ADER to hours, from about 10% to about 60% at 4 hours, from about render said dosage form abuse deterrent and/or suitable for 15% to about 70% at 6 hours, from about 25% to about 80% twice-a-day administration to a human patient, said dosage 10 at 9 hours, and greater than about 50% at 12 hours. form after administration to a human patient, providing a Wso In some preferred embodiments, the dosage form provides of abusable drug of 2 to about 11 hours; and said dosage form an oral pharmaceutical composition comprising a therapeu providing a therapeutic effect for at least about 12 hours. In tically effective amount of abusable drug or pharmaceutically other preferred embodiments, the dosage form provides a acceptable salts thereof or mixtures thereof and ADER to Ws of abusable drug of about 2 to about 10 hours, or about 2 15 render said dosage form abuse deterrent and/or suitable for to about 9 hours, or about 2 to about 9 hours, or about 2 to twice-a-day administration to a human patient, said dosage about 8 hours, or 2 to about 7 hours, or about 2 to about 6 form providing an in-vitro release rate by weight of abusable hours, or about 2 to about 5 hours, or about 2 to about 4 hours, drug, when measured by the USP Basket and Paddle Methods or about 3 to about 10 hours, or about 4 to about 10 hours, or at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 about 5 to about 10 hours, or about 6 to about 10 hours, or 7 and 7.2 at 37° C. of from 0% to about 47.5% at 1 hour, from to about 10 hours, or about 3 to about 8 hours, or about 4 to about 10% to about 65% at 2 hours, from about 15% to about about 8 hours, or about 4 to about 7 hours, or about 3 to about 70% at 4 hours, from about 25% to about 77.5% at 6 hours, 6 hours. from about 35% to about 87.5% at 9 hours, and greater than In some preferred embodiments, the dosage form provides about 65% at 12 hours; said dosage form providing a C, an oral pharmaceutical composition comprising a therapeu 25 from a mean of about 2 to about 10 hours after first adminis tically effective amount of abusable drug or pharmaceutically tration or at steady state. acceptable salts thereof or mixtures thereof and ADER to In some preferred embodiments, the dosage form provides render said dosage form abuse deterrent and/or suitable for an oral pharmaceutical composition comprising a therapeu twice-a-day administration to a human patient, said dosage tically effective amount of abusable drug or pharmaceutically form after administration to a human patient, providing a 30 acceptable salts thereof or mixtures thereof and ADER to HVD of abusable drug of 1.5 to about 10 hours; and said render said dosage form abuse deterrent and/or suitable for dosage form providing a therapeutic effect for at least about twice-a-day administration to a human patient; said dosage 12 hours. In other preferred embodiments, the dosage form form providing an in-vitro release rate by weight of abusable provides an HVD of abusable drug of about 1.5 to about 9 drug, when measured by the USP Basket and Paddle Methods hours, or about 1.5 to 8 hours, or about 1.5 to about 7 hours, 35 at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 or about 1.5 to 6 hours, or about 1.5 to about 5 hours, or about and 7.2 at 37° C. of from 0% to about 47.5% at 1 hour, from 1.5 to about 4 hours, or about 2 to about 10 hours, or about 3 about 10% to about 65% at 2 hours, from about 15% to about to 10 hours, or about 4 to about 10 hours, or about 5 to 10 70% at 4 hours, from about 25% to about 77.5% at 6 hours, hours, or about 6 to about 10 hours, or about 8 to 10 hours, from about 35% to about 87.5% at 9 hours, and greater than about 3 to about 8 hours, or about 4 to 8 hours, or about 5 to 40 about 65% at 12 hours; said dosage form providing a C, about 7 hours, or about 3 to 6 hours, or about 3 to about 8 occurring from a mean of about 10 to about 14 hours after first hours, or about 5 to about 8 hours. administration or at steady state. In some preferred embodiments, the dosage form provides In some preferred embodiments, the dosage form provides an oral pharmaceutical composition comprising a therapeu an oral pharmaceutical composition comprising a therapeu tically effective amount of abusable drug or pharmaceutically 45 tically effective amount of abusable drug or pharmaceutically acceptable salts thereof or mixtures thereof and ADER to acceptable salts thereof or mixtures thereof and ADER to render said dosage form abuse deterrent and/or suitable for render said dosage form abuse deterrent and/or suitable for twice-a-day administration to a human patient, said dosage twice-a-day administration to a human patient, said dosage form after administration to a human patient, providing an AI form providing an in-vitro release rate by weight of abusable of abusable drug of not more that 4.0; and said dosage form 50 drug, when measured by the USP Basket and Paddle Methods providing a therapeutic effect for at least about 12 hours. In at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 other preferred embodiments, the dosage form provides an AI and 7.2 at 37° C. of from 0% to about 47.5% at 1 hour, from of abusable drug of not more than about 3.75, or not more than about 10% to about 65% at 2 hours, from about 15% to about about 3.5, or not more than about 3.25, or not more than about 70% at 4 hours, from about 25% to about 77.5% at 6 hours, 3, or not more than about 2.75, or not more than about 2.5, or 55 from about 35% to about 87.5% at 9 hours, and greater than not more than about 2, or not more than about 1.5, not more about 65% at 12 hours; said dosage form providing a mean than about 1.25, or not more than about 1, or not more than abusable drug AUCo/AUCo. ratio after first administration about 0.75. of about 0.4, or about 0.5, or about 0.6, or about 0.7, or about In some preferred embodiments, the dosage form provides 0.75, or about 0.8, or about 0.85, or about 0.88, or about 0.90, an oral pharmaceutical composition comprising a therapeu 60 or about 0.92, or about 0.95, or about 0.97 or about 0.99. tically effective amount of abusable drug or pharmaceutically In some preferred embodiments, the dosage form provides acceptable salts thereof or mixtures thereof and ADER to an oral pharmaceutical composition comprising a therapeu render said dosage form abuse deterrent and/or suitable for tically effective amount of abusable drug or pharmaceutically twice-a-day administration to a human patient, said dosage acceptable salts thereof or mixtures thereof and ADER to form providing an in-vitro release rate by weight of abusable 65 render said dosage form abuse deterrent and/or suitable for drug, when measured by the USP Basket and Paddle Methods twice-a-day administration to a human patient, said dosage at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 form providing an in-vitro release rate by weight of abusable US 9,125,833 B2 31 32 drug, when measured by the USP Basket and Paddle Methods once-a-day administration to a human patient, said dosage at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 form providing a C/C ratio of abusable drug of 0.1 to and 7.2 at 37° C. of from 0% to about 47.5% at 1 hour, from about 1; and said dosage form providing a therapeutic effect about 10% to about 65% at 2 hours, from about 15% to about for at least about 24 hours. In other preferred embodiments, 70% at 4 hours, from about 25% to about 77.5% at 6 hours, the dosage form provides a C/C ratio of abusable drug of from about 35% to about 87.5% at 9 hours, and greater than about 0.25 to about 0.9, or about 0.25 to about 0.8, or about about 65% at 12 hours; said in-vitro release rate being sub 0.25 to about 0.75, or about 0.25 to about 0.6, or 0.25 to about stantially independent of pH in that a difference, at any given 0.5, or about 0.25 to about 0.4, or about 0.25 to about 0.35, or time, between an amount of abusable drug released at one pH about 0.3 to about 0.95, or about 0.4 to about 0.95, or about and an amount released at any other pH, when measured 10 0.5 to about 0.95, or about 0.65 to about 0.95, or about 0.75 to in-vitro using the USP Basket and Paddle Methods of USP about 0.95, or about 0.3 to about 0.8, or about 0.4 to about Drug Release test of U.S. Pharmacopeia (2003) at 100 rpm in 0.75, or about 0.5 to about 0.75, or about 0.1 to about 0.9, or 900 ml aqueous buffer, is no greater than 30%. about 0.1 to about 0.8, or about 0.1 to about 0.7, or about 0.1 In some preferred embodiments, the dosage form provides to about 0.6, or about 0.1 to about 0.5, or about 0.1 to about an oral pharmaceutical composition comprising a therapeu 15 0.4, or about 0.1 to about 0.3, or about 0.2 to about 1.0, or tically effective amount of abusable drug or pharmaceutically about 0.25 to about 1.0, or about 0.4 to about 1.0, or about 0.5 acceptable salts thereof or mixtures thereof and ADER to to about 0.9, or about 0.5 to about 0.85, or about 0.5 to about render said dosage form abuse deterrent and/or suitable for 0.8, or about 0.5 to about 0.75, or about 0.5 to about 1.0, or once-a-day administration to a human patient, said dosage about 0.65 to about 1.0, or about 0.75 to about 1.0, or about form providing a C of abusable drug at about 3 to about 20 0.2 to about 0.9, or about 0.3 to about 0.95, or about 0.3 to hours; and said dosage form providing atherapeutic effect for about 0.85, or about 0.3 to about 0.8, or about 03 to about at least about 24 hours. In some preferred embodiments, the 0.75, or about 0.3 to about 0.7, or about 0.3 to about 0.6, or abusable drugs dosage forms provide a C of abusable drug about 0.4 to about 0.9, or about 0.4 to about 0.8, or about 0.4 at about 3 to about 18 hours, or about 3 to about 15 hours, or to about 0.7, or about 0.4 to about 0.6, or about 0.8 to about 1, about 3 to about 12 hours, or at about 3 to about 10 hours, or 25 or about 0.8 to about 1.1. at about 3 to about 8 hours, or at about 3 to about 7 hours, or In some preferred embodiments, the dosage form provides at about 3 to about 7 hours, or about 4 to about 20 hours, or an oral pharmaceutical composition comprising a therapeu about 5 to about 20 hours, or about 6 to about 20 hours, or at tically effective amount of abusable drug or pharmaceutically about 8 to about 20 hours, or at about 10 to about 20 hours, or acceptable salts thereof or mixtures thereof and ADER to at about 12 to about 20 hours, or at about 14 to about 20 hours, 30 render said dosage form abuse deterrent and/or suitable for or about 18 to about 20 hours, or about 4 to about 18 hours, or once-a-day administration to a human patient, said dosage about 4 to about 16 hours, or at about 4 to about 12 hours, or form providing a percent fluctuation of abusable drug of less at about 4 to about 8 hours, or at about 4 to about 10 hours, or than 400%; and said dosage form providing a therapeutic at about 3 to about 6 hours. effect for at least about 24 hours. In other preferred embodi In some preferred embodiments, the dosage form provides 35 ments, the dosage form provides a percent fluctuation of an oral pharmaceutical composition comprising a therapeu abusable drug of less than about 375%, or less than about tically effective amount of abusable drug or pharmaceutically 350%, or less than about 325%, or less than about 300%, or acceptable salts thereof or mixtures thereof and ADER to less than about 275%, or less than about 250%, or less than render said dosage form abuse deterrent and/or suitable for about 225%, or less than about 200%, or less than about once-a-day administration to a human patient, said dosage 40 175%, or less than about 150%, or less than about 125%, or form providing a C of abusable drug at about 20 to about less than about 100%, or less than about 75%, or less than 28 hours; and said abusable drugs dosage forms providing a about 50%, or less than about 25%. therapeutic effect for at least about 24 hours. In some pre In some preferred embodiments, the dosage form provides ferred embodiments, the abusable drugs dosage forms pro an oral pharmaceutical composition comprising a therapeu vide a C of abusable drug at about 20 to about 26 hours, or 45 tically effective amount of abusable drug or pharmaceutically about 20 to about 27 hours, or about 20 to about 25 hours, or acceptable salts thereof or mixtures thereof and ADER to about 20 to about 24 hours, or about 20 to about 23 hours, or render said dosage form abuse deterrent and/or suitable for about 21 to about 28 hours, or about 22 to about 28 hours, or once-a-day administration to a human patient, said abusable about 23 to about 28 hours, or about 23.5 to about 28 hours, or drugs dosage form after administration to a human patient, about 22 to 26 hours. 50 providing a Wso of abusable drug of 4 to about 22 hours; and In some preferred embodiments, the dosage form provides said dosage form providing a therapeutic effect for at least an oral pharmaceutical composition comprising a therapeu about 24 hours. In other preferred embodiments, the abusable tically effective amount of abusable drug or pharmaceutically drugs dosage from provides a Wso of abusable drug of about acceptable salts thereof or mixtures thereof and ADER: said 4 to about 20 hours, or about 4 to about 19 hours, or about 4 dosage from providing a C of abusable drug from about 55 to about 18 hours, or 4 to about 16 hours, or 4 to about 14 0.25 hours to about 30 hours. hours, or about 4 to about 12 hours, or about 4 to about 10 In some preferred embodiments, the dosage form provides hours, or about 4 to about 8 hours, or about 6 to about 20 an oral pharmaceutical composition comprising a therapeu hours, or about 8 to about 20 hours, or about 10 to about 20 tically effective amount of abusable drug or pharmaceutically hours, or about 12 to about 20 hours, or 14 to about 20 hours, acceptable salts thereof or mixtures thereof and ADER: said 60 or about 6 to about 16 hours, or about 8 to about 16 hours, or dosage from providing a C of abusable drug from about 0.5 about 8 to about 14 hours, or about 6 to about 12 hours. hour to about 30 hours. In some preferred embodiments, the dosage form provides In some preferred embodiments, the dosage form provides an oral pharmaceutical composition comprising a therapeu an oral pharmaceutical composition comprising a therapeu tically effective amount of abusable drug or pharmaceutically tically effective amount of abusable drug or pharmaceutically 65 acceptable salts thereof or mixtures thereof and ADER to acceptable salts thereof or mixtures thereof and ADER to render said dosage form abuse deterrent and/or suitable for render said dosage form abuse deterrent and/or suitable for once-a-day administration to a human patient, said abusable US 9,125,833 B2 33 34 drugs dosage form after administration to a human patient, at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 providing a HVD of abusable drug of 3 to about 20 hours; and and 7.2 at 37° C. of from 0% to about 30% at 1 hour, from said dosage form providing a therapeutic effect for at least about 10% to about 65% at 4 hours, from about 20% to about about 24 hours. In other preferred embodiments, the abusable 70% at 8 hours, from about 25% to about 80% at 12 hours, drugs dosage from provides an HVD of abusable drug of 5 from about 35% to about 95% at 18 hours, and greater than about 3 to about 18 hours, or about 3 to 16 hours, or about 3 about 65% at 24 hours; said dosage form providing a C of to about 14 hours, or about 3 to 12 hours, or about 3 to about abusable drug occurring from a mean of about 20 to about 28 10 hours, or about 3 to about 8 hours, or about 4 to about 20 hours after first administration or at steady state. hours, or about 6 to 20 hours, or about 8 to about 20 hours, or In some preferred embodiments, the dosage form provides about 10 to 20 hours, or about 12 to about 20 hours, or about 10 an oral pharmaceutical composition comprising a therapeu 16 to 20 hours, about 6 to about 16 hours, or about 8 to 16 tically effective amount of abusable drug or pharmaceutically hours, or about 10 to about 14 hours, or about 6 to 12 hours, acceptable salts thereof or mixtures thereof and ADER to or about 6 to about 16 hours, or about 10 to about 16 hours. render said dosage form abuse deterrent and/or suitable for In some preferred embodiments, the dosage form provides once-a-day administration to a human patient, said dosage an oral pharmaceutical composition comprising a therapeu 15 form providing an in-vitro release rate by weight of abusable tically effective amount of abusable drug or pharmaceutically drug, when measured by the USP Basket and Paddle Methods acceptable salts thereof or mixtures thereof and ADER to at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 render said dosage form abuse deterrent and/or suitable for and 7.2 at 37° C. of from 0% to about 30% at 1 hour, from once-a-day administration to a human patient, said dosage about 10% to about 65% at 4 hours, from about 20% to about form after administration to a human patient, providing an AI 70% at 8 hours, from about 25% to about 80% at 12 hours, of abusable drug of not more that 4.0; and said abusable drugs from about 35% to about 95% at 18 hours, and greater than dosage form providing a therapeutic effect for at least about about 65% at 24 hours; said dosage form providing a mean 24 hours. In other preferred embodiments, the abusable drugs abusable drug AUC/AUCo. ratio after first administration dosage from provides an AI of abusable drug of not more than of about 0.4, or about 0.5, or about 0.6, or about 0.7, or about about 3.75, or not more than about 3.5, or not more than about 25 0.75, or about 0.8, or about 0.85, or about 0.88, or about 0.90, 3.25, or not more than about 3, or not more than about 2.75, or or about 0.92, or about 0.95, or about 0.97 or about 0.99. not more than about 2.5, or not more than about 2, or not more In some preferred embodiments, the dosage form provides than about 1.5, not more than about 1.25, or not more than an oral pharmaceutical composition comprising a therapeu about 1, or not more than about 0.75. tically effective amount of abusable drug or pharmaceutically In some preferred embodiments, the dosage form provides 30 acceptable salts thereof or mixtures thereof and ADER to an oral pharmaceutical composition comprising a therapeu render said dosage form abuse deterrent and/or suitable for tically effective amount of abusable drug or pharmaceutically once-a-day administration to a human patient; said dosage acceptable salts thereof or mixtures thereof and ADER to form providing an in-vitro release rate by weight of abusable render said abusable drug dosage form abuse deterrent and/or drug, when measured by the USP Basket and Paddle Methods Suitable for once-a-day administration to a human patient; 35 at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 said abusable drugs dosage form providing an in-vitro release and 7.2 at 37° C. of from 0% to about 30% at 1 hour, from rate by weight of abusable drug, when measured by the USP about 10% to about 65% at 4 hours, from about 20% to about Basket and Paddle Methods at 100 rpm in 900 mL aqueous 70% at 8 hours, from about 25% to about 80% at 12 hours, buffer at a pH of between 1.6 and 7.2 at 37° C. of from 0% to from about 35% to about 95% at 18 hours, and greater than about 30% at 1 hour, from about 10% to about 65% at 4 hours, 40 about 65% at 24 hours; said in-vitro release rate being sub from about 20% to about 70% at 8 hours, from about 25% to stantially independent of pH in that a difference, at any given about 80% at 12 hours, from about 35% to about 95% at 18 time, between an amount of abusable drug released at one pH hours, and greater than about 65% at 24 hours. and an amount released at any other pH, when measured In some preferred embodiments, the dosage form provides in-vitro using the USP Basket and Paddle Methods of USP an oral pharmaceutical composition comprising a therapeu 45 Drug Release test of U.S. Pharmacopeia (2003) at 100 rpm in tically effective amount of abusable drug or pharmaceutically 900 ml aqueous buffer, is no greater than 30%. acceptable salts thereof or mixtures thereof and ADER to In some preferred embodiments, the dosage form provides render said abusable drug dosage form abuse deterrent and/or an oral pharmaceutical composition comprising a therapeu Suitable for once-a-day administration to a human patient; tically effective amount of abusable drug or pharmaceutically said abusable drugs dosage form providing an in-vitro release 50 acceptable salts thereof or mixtures thereof and ADER to rate by weight of abusable drug, when measured by the USP render said dosage form abuse deterrent and/or suitable for Basket and Paddle Methods at 100 rpm in 900 mL aqueous extended release administration to a human patient, said dos buffer at a pH of between 1.6 and 7.2 at 37° C. of from 0% to age form after administration to a human patient providing a about 30% at 1 hour, from about 10% to about 65% at 4 hours, mean abusable drug C, occurring from a mean of about from about 20% to about 70% at 8 hours, from about 25% to 55 0.25 to about 22 hours; said dosage form providing a mean about 80% at 12 hours, from about 35% to about 95% at 18 abusable drug C, occurring from a mean of about 0.5 to hours, and greater than about 65% at 24 hours; said dosage about 28 hours; said dosage form providing a mean abusable form providing a C from a mean of about 3 to about 20 drug HVD of about 1 to about 5 hours for each 6 hour time hours after first administration or at steady state. period of intended dosing frequency and intended duration of In some preferred embodiments, the dosage form provides 60 action; said dosage form providing a mean abusable drug Wso an oral pharmaceutical composition comprising a therapeu of about 1 to about 5.5 hours for each 6 hour time period of tically effective amount of abusable drug or pharmaceutically intended dosing frequency and intended duration of action; acceptable salts thereof or mixtures thereof and ADER to said dosage form providing a mean abusable drug AI of not render said dosage form abuse deterrent and/or suitable for more than 3.0; said dosage form providing a mean abusable once-a-day administration to a human patient, said dosage 65 drug percent fluctuation of less than 400%; said dosage form form providing an in-vitro release rate by weight of abusable providing a mean abusable drug C/C ratio of 0.1 to drug, when measured by the USP Basket and Paddle Methods about 1.0; said dosage form providing at least 80% of the US 9,125,833 B2 35 36 steady state abusable drug therapeutic concentration after 10% to about 50%, or about 5% to about 60%, or about 5% to administration of sthree doses at their intended dosing fre about 70%, or about 5% to about 80%, or about 5% to about quency, said dosage form providing a mean abusable drug 90%, or about 5% to about 100%, or about 10% to about 20%, AUCo. to AUCo. ratio of greater than 0.4; and said dosage or about 10% to about 35%, or about 10% to about 50%, or form providing a mean time to 75% abusable drug C of 5 about 10% to about 60%, or about 10% to about 70%, or about about 100% to about 2000% of the time to 75% mean C. of 10% to about 80%, or about 10% to about 90%, or about 10% an oral immediate release abusable drug Solution or Suspen to about 100%, or about 20% to about 40%, or about 20% to S1O. about 50%, or about 20% to about 60%, or about 20% to about In some preferred embodiments, the dosage form provides 70%, or about 20% to about 80%, or about 20% to about 90%, an oral pharmaceutical composition comprising a therapeu 10 or about 20% to about 100%, or about 30% to about 50%, or tically effective amount of abusable drug or pharmaceutically about 30% to about 60%, or about 30% to about 70%, or about acceptable salts thereof or mixtures thereof and ADER to 30% to about 80%, or about 30% to about 90%, or about 40% render said dosage form abuse deterrent and/or suitable for to about 80%, or about 40% to about 90%, or about 60% to extended release administration to a human patient, said dos about 100%, or greater than about 5%, or greater than about age form after administration to a human patient providing a 15 10%, or greater than about 15%, or greater than about 20%, or mean abusable drug C, which is less than 65% of the C. greater than about 30%, or greater than about 40%, or greater of an equivalent dose of an oral immediate release abusable than about 50%, or greater than about 60%, or greater than drug solution or Suspension; and said dosage form maintain about 80%, or greater than about 90%, or greater than about ing a mean abusable drug plasma concentration within 50% 95%, at one hour, when measured by the USP Basket and of C for about 1 to about 5.5 hours for each 6 hour time Paddle Methods at 100 rpm in 700 ml of Simulated Gastric period of intended dosing frequency and intended duration of Fluid (SGF) at 37° C. action. In some preferred embodiments, the abusable drugs dosage In some preferred embodiments, the dosage form provides form provides a C of abusable drug which is less than 65% an oral pharmaceutical composition comprising a therapeu of the C of an equivalent dose of an oral immediate release tically effective amount of abusable drug or pharmaceutically 25 abusable drug Solution or Suspension. In other preferred acceptable salts thereof or mixtures thereof and ADER to embodiments, said dosage form provides a C, which is less render said dosage form abuse deterrent and/or suitable for than about 85%, or less than about 75%, or less than about extended release administration to a human patient, said dos 60%, or less than about 55%, or less than about 50%, or less age form after administration to a human patient providing a than about 45%, or less than about 40%, or less than about mean abusable drug C, occurring from a mean of about 30 30%, or less than about 20% of the Cofan equivalent dose 0.25 to about 22 hours; said dosage form providing a mean of an oral immediate release abusable drug Solution or Sus abusable drug C, occurring from a mean of about 0.5 to pension. about 28 hours; said dosage form providing a mean abusable In some preferred embodiments, the dosage form provides drug HVD of about 1 to about 5 hours for each 6 hour time a time to 75% mean C. of abusable drug which is about period of intended dosing frequency and intended duration of 35 100% to about 2000% of the time to 75% mean Cofan oral action; said dosage form providing a mean abusable drug Wso immediate release abusable drug solution or Suspension. of about 1 to about 5.5 hours for each 6 hour time period of In some preferred embodiments, the dosage form provides intended dosing frequency and intended duration of action; a time to 30% mean C. of abusable drug which is about said dosage form providing a mean abusable drug AI of not 100% to about 2000% of the time to 30% mean Cofan oral more than 3.0; said dosage form providing a mean abusable 40 immediate release abusable drug solution or Suspension. drug percent fluctuation of less than 400%; said dosage form In some preferred embodiments, the dosage from main providing a mean abusable drug C/C ratio of 0.1 to tains a plasma abusable drug concentration within 50% of about 1.0; said dosage form providing at least 80% of the C for about 1 to about 9 hours during a 12 hour dosing steady state abusable drug therapeutic concentration after interval. In other preferred embodiments, said dosage form administration of sthree doses at their intended dosing fre 45 maintains plasma abusable drug concentration within 50% of quency, said dosage form providing a mean abusable drug C for about 2 to about 9 hours, or about 3 to about 9 hours, AUC to AUCo. ratio of greater than 0.4, said dosage form or about 4 to about 9 hours, or about 5 to about 9 hours, or providing a mean time to 75% abusable drug C of about about 6 to about 9 hours, or about 1 to about 11 hours, or about 100% to about 2000% of the time to 75% mean Cofan oral 2 to about 11 hours, or about 3 to about 11 hours or about 4 to immediate release abusable drug Solution or Suspension; said 50 about 11 hours, or about 5 to about 11 hours, or about 6 to dosage form after administration to a human patient provid about 11 hours, or about 7 to about 11 hours, or about 8 to ing a mean abusable drug C, which is less than 65% of the about 11 hours, or about 1 to about 10 hours, or about 2 to Cofan equivalent dose of an oral immediate release abus about 10 hours, or about 3 to about 10 hours or about 4 to able drug Solution or Suspension; and said dosage form main about 10 hours, or about 5 to about 10 hours, or about 6 to taining a mean abusable drug plasma concentration within 55 about 10 hours, or about 7 to about 10 hours, or about 8 to 50% of C for about 1 to about 5.5 hours for each 6 hour about 10hours, or about 1 to about 7 hours, or about 2 to about time period of intended dosing frequency and intended dura 7 hours, or about 3 to about 7 hours or about 4 to about 7 tion of action. hours, or about 5 to about 7 hours, or about 6 to about 7 hours, In some preferred embodiments, the abusable drugs dosage or about 1 to about 4 hours, or about 1 to about 5 hours, during forms provide an in-vitro release of from 0% to about 50% by 60 a 12 hour dosing interval. weight of the abusable drug or a pharmaceutically acceptable In some preferred embodiments, the dosage from main salt thereoffrom the dosage format one hour when measured tains a plasma abusable drug concentration within 30% of by the USP Basket and Paddle Methods at 100 rpm in 700 ml C for about 1.5 to about 9 hours during a 12 hour dosing of Simulated Gastric Fluid (SGF) at 37°C. In other preferred interval. In other preferred embodiments, said dosage form embodiments, said in-vitro release rate by weight of the abus 65 maintains plasma abusable drug concentration within 30% of able drug or a pharmaceutically acceptable salt thereof from C for about 2 to about 9 hours, or about 3 to about 9 hours, said dosage form is from about 5% to about 45%, or about or about 4 to about 9 hours, or about 5 to about 9 hours, or US 9,125,833 B2 37 38 about 6 to about 9 hours, or about 1 to about 11 hours, or about about 6 to about 18 hours, or about 6 to about 20 hours, or 2 to about 11 hours, or about 3 to about 11 hours or about 4 to about 5 to about 12 hours, or about 5 to about 14 hours, or about 11 hours, or about 5 to about 11 hours, or about 6 to about 3 to about 22 hours, or about 3 to about 9 hours or about about 11 hours, or about 7 to about 11 hours, or about 8 to 3 to about 12 hours, or about 1 to about 6 hours, or about 2 to about 11 hours, or about 1 to about 10 hours, or about 2 to 5 about 8 hours, or about 2 to about 10 hours, or about 3 to about about 10 hours, or about 3 to about 10 hours or about 4 to 16 hours, during a 24 hour dosing interval. about 10 hours, or about 5 to about 10 hours, or about 6 to In some preferred embodiments, the dosage from main about 10 hours, or about 7 to about 10 hours, or about 8 to tains a plasma abusable drug concentration within 65% of about 10 hours, or about 1 to about 7 hours, or about 2 to about C for about 2 to about 22 hours during a 24 hour dosing 7 hours, or about 3 to about 7 hours or about 4 to about 7 10 interval. In other preferred embodiments, said dosage form hours, or about 5 to about 7 hours, or about 6 to about 7 hours, maintains plasma abusable drug concentration within 65% of or about 1 to about 4 hours, or about 1 to about 5 hours, during C for about 1 to about 9 hours, or about 4 to about 9 hours, a 12 hour dosing interval. or about 6 to about 9 hours, or about 1 to about 20 hours, or In some preferred embodiments, the dosage from main about 2 to about 20 hours, or about 3 to about 20 hours, or tains a plasma abusable drug concentration within 65% of 15 about 1 to about 18 hours, or about 1 to about 16 hours or C for about 1 to about 9 hours during a 12 hour dosing about 2 to about 18 hours, or about 2 to about 16 hours, or interval. In other preferred embodiments, said dosage form about 1 to about 14 hours, or about 1 to about 12 hours, or maintains plasma abusable drug concentration within 65% of about 4 to about 16 hours, or about 4 to about 18 hours, or C for about 2 to about 9 hours, or about 3 to about 9 hours, about 4 to about 20 hours, or about 3 to about 15 hours or or about 4 to about 9 hours, or about 5 to about 9 hours, or about 6 to about 15 hours, or about 6 to about 12 hours, or about 6 to about 9 hours, or about 1 to about 11 hours, or about about 6 to about 18 hours, or about 6 to about 20 hours, or 2 to about 11 hours, or about 3 to about 11 hours or about 4 to about 5 to about 12 hours, or about 5 to about 14 hours, or about 11 hours, or about 5 to about 11 hours, or about 6 to about 3 to about 22 hours, or about 3 to about 9 hours or about about 11 hours, or about 7 to about 11 hours, or about 8 to 3 to about 12 hours, or about 1 to about 6 hours, or about 2 to about 11 hours, or about 1 to about 10 hours, or about 2 to 25 about 8 hours, or about 2 to about 10 hours, or about 3 to about about 10 hours, or about 3 to about 10 hours or about 4 to 16 hours, during a 24 hour dosing interval. about 10 hours, or about 5 to about 10 hours, or about 6 to In some preferred embodiments, the dosage form provides about 10 hours, or about 7 to about 10 hours, or about 8 to a T of abusable drug at a time point 1 to 18 times later than about 10 hours, or about 1 to about 7 hours, or about 2 to about the T provided by an equivalent dose of an oral immediate 7 hours, or about 3 to about 7 hours or about 4 to about 7 30 release abusable drug solution or Suspension. In the dosage hours, or about 5 to about 7 hours, or about 6 to about 7 hours, form provides a T at a time point about 1 to 15 times late, or about 1 to about 4 hours, or about 1 to about 5 hours, during or about of 1 to 10 times later, or about of 1 to 7 times later, or a 12 hour dosing interval. about of 1 to 4 times later, or about of 3 to 20 times later, or In some preferred embodiments, the dosage from main about of 3 to 10 times later, or about of 3 to 5 times later, or tains a plasma abusable drug concentration within 55% of 35 about 1.5 to 15 times later, or about of 1.5 to 10 times later, or C for about 3 to about 22 hours during a 24 hour dosing about of 1.5 to 7 times later, or about of 1.5 to 3 times later, or interval. In other preferred embodiments, said dosage form about of 2 to 20 times later, or about of 2 to 10 times later, or maintains plasma abusable drug concentration within 50% of about of 2 to 5 times later, or about of 2 to 3 times later, or C for about 1 to about 9 hours, or about 4 to about 9 hours, about of 2.5 to 20 times later, or about of 2.5 to 8 times later, or about 6 to about 9 hours, or about 1 to about 20 hours, or 40 or about of 2.5 to 5 times later, or about of 2.5 to 4 times later, about 2 to about 20 hours, or about 3 to about 20 hours, or or about of 3 to 20 times later, or about of 3 to 10 times later, about 1 to about 18 hours, or about 1 to about 16 hours or or about of 3 to 5 times later. about 2 to about 18 hours, or about 2 to about 16 hours, or In some preferred embodiments, the dosage form provides about 1 to about 14 hours, or about 1 to about 12 hours, or a meanin vivo extent of absorption of abusable drug from 0 to about 4 to about 16 hours, or about 4 to about 18 hours, or 45 4 hours which is at least 20% of the mean in vivo extent of about 4 to about 20 hours, or about 3 to about 15 hours or absorption from to 0 to 12 hours, wherein the mean in vivo about 6 to about 15 hours, or about 6 to about 12 hours, or extent of absorption is the area under the plasma or serum about 6 to about 18 hours, or about 6 to about 20 hours, or abusable drug concentration time curve from the time of drug about 5 to about 12 hours, or about 5 to about 14 hours, or administration to the specified time point. In other preferred about 3 to about 22 hours, or about 3 to about 9 hours or about 50 embodiments, said in vivo extent of absorption from 0 to 4 3 to about 12 hours, or about 1 to about 6 hours, or about 2 to hours is at least about 5%, or at least about 10%, or at least about 8 hours, or about 2 to about 10 hours, or about 3 to about about 15%, or at least about 25%, or at least about 30%, or at 16 hours, during a 24 hour dosing interval. least about 40%, or at least about 50%, or at least about 60%, In some preferred embodiments, the dosage from main or at least about 70%, or at least about 80%, at least about tains a plasma abusable drug concentration within 30% of 55 90%, or about 100% of the mean in vivo extent of absorption C for about 2 to about 22 hours during a 24 hour dosing from to 0 to 12 hours. interval. In other preferred embodiments, said dosage form In some preferred embodiments, the dosage form provides maintains plasma abusable drug concentration within 30% of a meanin vivo extent of absorption of abusable drug from 0 to C for about 1 to about 9 hours, or about 4 to about 9 hours, 8 hours which is at least 20% of the mean in vivo extent of or about 6 to about 9 hours, or about 1 to about 20 hours, or 60 absorption from to 0 to 24 hours, wherein the mean in vivo about 2 to about 20 hours, or about 3 to about 20 hours, or extent of absorption is the area under the plasma or serum about 1 to about 18 hours, or about 1 to about 16 hours or abusable drug concentration time curve from the time of drug about 2 to about 18 hours, or about 2 to about 16 hours, or administration to the specified time point. In other preferred about 1 to about 14 hours, or about 1 to about 12 hours, or embodiments, said in vivo extent of absorption from 0 to 8 about 4 to about 16 hours, or about 4 to about 18 hours, or 65 hours is at least about 5%, or at least about 10%, or at least about 4 to about 20 hours, or about 3 to about 15 hours or about 15%, or at least about 25%, or at least about 30%, or at about 6 to about 15 hours, or about 6 to about 12 hours, or least about 40%, or at least about 50%, or at least about 60%, US 9,125,833 B2 39 40 or at least about 70%, or at least about 80%, at least about Basket and Paddle Methods at 100 rpm in 900 mL aqueous 90%, or about 100% of the mean in vivo extent of absorption buffer at a pH of between 1.6 and 7.2 at 37° C. of between 5% from to 0 to 24 hours. and about 60% at 1 hour, between about 12.5% and about In some preferred embodiments, the dosage form provides 80% at 2 hours, between about 25% and about 95% at 4 hours, a meanin vivo extent of absorption of abusable drug from 0 to 5 between about 45% and about 100% at 8 hours, greater than 12 hours which is at least 20% of the mean in vivo extent of about 55% at 12 hours, greater than about 65% at 18 hours, absorption from to 0 to 24 hours, wherein the mean in vivo and greater than about 70% at 24 hours. extent of absorption is the area under the plasma or serum In some preferred embodiments, the dosage form provides abusable drug concentration time curve from the time of drug an oral pharmaceutical composition comprising a therapeu administration to the specified time point. In other preferred 10 tically effective amount of abusable drug or pharmaceutically embodiments, said in vivo extent of absorption from 0 to 12 acceptable salts thereof or mixtures thereof and ADER, said hours is at least about 5%, or at least about 10%, or at least abusable drugs dosage form providing an in-vitro release rate about 15%, or at least about 25%, or at least about 30%, or at by weight of abusable drug, when measured by the USP least about 40%, or at least about 50%, or at least about 60%, Basket and Paddle Methods at 100 rpm in 900 mL aqueous or at least about 70%, or at least about 80%, at least about 15 buffer at a pH of between 1.6 and 7.2 at 37° C. of between 0% 90%, or about 100% of the mean in vivo extent of absorption and about 40% at 1 hour, between about 0% and about 70% at from to 0 to 24 hours. 2 hours, between about 5% and about 95% at 4 hours, In some preferred embodiments, the dosage form provides between about 12.5% and about 100% at 8 hours, between a mean in vivo extent of absorption of abusable drug over the about 20% and about 100% at 12 hours, between about 35% dosing interval, AUCo. (e.g., from 0 to 8 hours, or from 0 to and about 100% at 16 hours, between about 55% and about 12 hours or from 0 to 24 hours) which is at least 40% of the 100% at 24 hours, and greater than about 75% at 36 hours. mean in vivo extent of absorption from to 0 to infinity In some preferred embodiments, the dosage form provides (AUC). In other preferred embodiments, said AUC is at an oral pharmaceutical composition comprising a therapeu least about 50%, or at least about 60%, or at least about 70%, tically effective amount of abusable drug or pharmaceutically or at least about 80%, or at least about 90% of the meanin vivo 25 acceptable salts thereof or mixtures thereof and ADER, said extent of absorption from to 0 to infinity (AUC). abusable drugs dosage form providing an in-vitro release rate In some preferred embodiments, the dosage form provides by weight of abusable drug, when measured by the USP an oral pharmaceutical composition comprising a therapeu Basket and Paddle Methods at 100 rpm in 900 mL aqueous tically effective amount of abusable drug or pharmaceutically buffer at a pH of between 1.6 and 7.2 at 37° C. of between 0% acceptable salts thereof or mixtures thereof and ADER, said 30 and about 60% at 1 hour, between about 0% and about 75% at abusable drugs dosage form providing an in-vitro release rate 2 hours, between about 5% and about 95% at 4 hours, by weight of abusable drug, when measured by the USP between about 12.5% and about 100% at 8 hours, between Basket and Paddle Methods at 100 rpm in 900 mL aqueous about 15% and about 100% at 12 hours, between about 25% buffer at a pH of between 1.6 and 7.2 at 37° C. of between 0% to about 100% at 16 hours, between about 30% and about to about 100% at 0.5 hours, and greater than about 60% at 1 35 100% hours at 24 hours and greater than 60% at 36 hours. hour. In some preferred embodiments, the dosage form provides In some preferred embodiments, the dosage form provides an oral pharmaceutical composition comprising a therapeu an oral pharmaceutical composition comprising a therapeu tically effective amount of abusable drug or pharmaceutically tically effective amount of abusable drug or pharmaceutically acceptable salts thereof or mixtures thereof and ADER, said acceptable salts thereof or mixtures thereof and ADER, said 40 abusable drugs dosage form providing an in-vitro release abusable drugs dosage form providing an in-vitro release rate from the dosage format one hour when measured by the USP by weight of abusable drug, when measured by the USP Basket and Paddle Methods at 100 rpm in 700 ml of Simu Basket and Paddle Methods at 100 rpm in 900 mL aqueous lated Gastric Fluid (SGF) at 37° C. of between 0% to about buffer at a pH of between 1.6 and 7.2 at 37° C. of between 0% 50% by weight of the abusable drug. In other preferred to about 40% at 1 hour, from about 5% to about 60% at 2 45 embodiments, said release rate is between 0% to about 1%, or hours, from about 10% to about 75% at 4 hours, from about 0% to about 3%, or 0% to about 5%, or 0% to about 10%, or 20% to about 75% at 6 hours, from about 30% to about 80% 0% to about 15%, or 0% to about 20%, 0% to about 30%, or at 9 hours, and greater than about 70% at 12 hours. 0% to about 40%, or 0% to about 60%, or 0% to about 70%, In some preferred embodiments, the dosage form provides or 0% to about 80%, or 0% to about 90%, 0% to about 100%. an oral pharmaceutical composition comprising a therapeu 50 In some preferred embodiments, the dosage form provides tically effective amount of abusable drug or pharmaceutically an oral pharmaceutical composition comprising a therapeu acceptable salts thereof or mixtures thereof and ADER, said tically effective amount of abusable drug or pharmaceutically abusable drugs dosage form providing an in-vitro release rate acceptable salts thereof or mixtures thereof and ADER, said by weight of abusable drug, when measured by the USP abusable drugs dosage form providing an in-vitro release Basket and Paddle Methods at 100 rpm in 900 mL aqueous 55 from the dosage format one hour when measured by the USP buffer at a pH of between 1.6 and 7.2 at 37° C. of between 1% Basket and Paddle Methods at 100 rpm in 900 mL aqueous and about 45% at 1 hour, between about 5% and about 70% at buffer at a pH of between 1.6 and 7.2 at 37° C. of between 0% 2 hours, between about 10% and about 90% at 4 hours, and about 60% at 1 hour, between about 0% and about 80% at between about 20% and about 90% at 8 hours, greater than 2 hours, between about 3% and about 95% at 4 hours and about 60% at 12 hours, greater than about 80% at 18 hours, 60 between about 10% and about 100% at 8 hours. In other and greater than about 85% at 24 hours. preferred embodiments, said release rate is between 0% and In some preferred embodiments, the dosage form provides about 10% at 1 hour, between about 0% and about 20% at 2 an oral pharmaceutical composition comprising a therapeu hours, between about 2% and about 80% at 4 hours and tically effective amount of abusable drug or pharmaceutically between about 5% and about 100% at 8 hours; or between 0% acceptable salts thereof or mixtures thereof and ADER, said 65 and about 20% at 1 hour, between about 0% and about 40% at abusable drugs dosage form providing an in-vitro release rate 2 hours, between about 0% and about 80% at 4 hours and by weight of abusable drug, when measured by the USP between about 2% and about 100% at 8 hours; or between 0% US 9,125,833 B2 41 42 and about 40% at 1 hour, between about 0% and about 60% at hours, and greater than about 30% at 12 hours; or between 0% 2 hours, between about 5% and about 85% at 4 hours and to about 50% at 1 hour, from about 15% to about 70% at 2 between about 5% and about 90% at 8 hours and greater than hours, from about 20% to about 75% at 4 hours, from about 20% at 12 hours; or between 0% and about 50% at 1 hour, 30% to about 80% at 6 hours, from about 30% to about 90% between about 0% and about 50% at 2 hours, between about at 9 hours, and greater than about 70% at 12 hours; or between 10% and about 90% at 4 hours and between about 15% and 0% to about 60% at 1 hour, from about 15% to about 80% at about 90% at 8 hours and greater than 30% at 12 hours; or 2 hours, from about 25% to about 85% at 4 hours, from about between 0% and about 70% at 1 hour, between about 0% and 35% to about 90% at 6 hours, from about 40% to about 90% about 70% at 2 hours, between about 10% and about 75% at at 9 hours, and greater than about 80% at 12 hours; or between 4 hours and between about 15% and about 90% at 8 hours and 10 0% to about 70% at 1 hour, from about 20% to about 80% at greater than 30% at 12 hours. 2 hours, from about 25% to about 80% at 4 hours, from about In some preferred embodiments, the dosage form provides 35% to about 80% at 6 hours, from about 40% to about 80% an oral pharmaceutical composition comprising a therapeu at 9 hours, and greater than about 60% at 12 hours; or between tically effective amount of abusable drug or pharmaceutically 0% to about 75% at 1 hour, from about 30% to about 80% at acceptable salts thereof or mixtures thereof and ADER, said 15 2 hours, from about 35% to about 90% at 4 hours, from about abusable drugs dosage form providing an in-vitro release 50% to about 90% at 6 hours, from about 55% to about 95% from the dosage format one hour when measured by the USP at 9 hours, and greater than about 70% at 12 hours. Basket and Paddle Methods at 100 rpm in 900 mL aqueous In some preferred embodiments, the dosage form provides buffer at a pH of between 1.6 and 7.2 at 37° C. of between an oral pharmaceutical composition comprising a therapeu 10% and about 65% at 1 hour, between about 20% and about tically effective amount of abusable drug or pharmaceutically 75% at 2 hours, between about 30% and about 95% at 4 hours acceptable salts thereof or mixtures thereof and ADER, said and between about 40% and about 100% at 8 hours. In other abusable drugs dosage form providing an in-vitro release rate preferred embodiments, said release rate is between 2% and by weight of the abusable drug, when measured by the USP about 70% at 1 hour, between about 5% and about 80% at 2 Basket and Paddle Methods at 100 rpm in 900 mL aqueous hours, between about 10% and about 90% at 4 hours and 25 buffer at a pH of between 1.6 and 7.2 at 37° C. of between 5% between about 20% and about 100% at 8 hours; or between and about 50% at 1 hour, between about 10% and about 75% 5% and about 60% at 1 hour, between about 10% and about at 2 hours, between about 20% and about 95% at 4 hours, 75% at 2 hours, between about 15% and about 85% at 4 hours between about 40% and about 100% at 8 hours, greater than and between about 30% and about 100% at 8 hours; or about 50% at 12 hours, greater than about 70% at 18 hours, between 20% and about 70% at 1 hour, between about 20% 30 and greater than about 80% at 24 hours. In other preferred and about 75% at 2 hours, between about 20% and about 90% embodiments, said release rate is between 2% and about 50% at 4 hours and between about 40% and about 100% at 8 hours; at 1 hour, between about 5% and about 75% at 2 hours, or between 30% and about 80% at 1 hour, between about 40% between about 15% and about 75% at 4 hours, between about and about 85% at 2 hours, between about 40% and about 90% 30% and about 90% at 8 hours, greater than about 40% at 12 at 4 hours and between about 60% and about 100% at 8 hours; 35 hours, greater than about 60% at 18 hours, and greater than or between 1% and about 20% at 1 hour, between about 5% about 70% at 24 hours; or between 1% and about 40% at 1 and about 20% at 2 hours, between about 10% and about 40% hour, between about 2% and about 60% at 2 hours, between at 4 hours and between about 20% and about 40% at 8 hours about 10% and about 65% at 4 hours, between about 20% and and greater than 40% at 12 hours. about 80% at 8 hours, greater than about 30% at 12 hours, In some preferred embodiments, the dosage form provides 40 greater than about 40% at 18 hours, and greater than about an oral pharmaceutical composition comprising a therapeu 60% at 24 hours; or between 5% and about 60% at 1 hour, tically effective amount of abusable drug or pharmaceutically between about 15% and about 80% at 2 hours, between about acceptable salts thereof or mixtures thereof and ADER, said 25% and about 95% at 4 hours, between about 45% and about abusable drugs dosage form providing an in-vitro release rate 100% at 8 hours, greater than about 60% at 12 hours, greater by weight of the abusable drug, when measured by the USP 45 than about 80% at 18 hours, and greater than about 90% at 24 Basket and Paddle Methods at 100 rpm in 900 mL aqueous hours; or between 10% and about 65% at 1 hour, between buffer at a pH of between 1.6 and 7.2 at 37° C. of between 0% about 20% and about 85% at 2 hours, between about 30% and to about 47.5% at 1 hour, from about 10% to about 65% at 2 about 100% at 4 hours, between about 60% and about 100% hours, from about 15% to about 70% at 4 hours, from about at 8 hours, greater than about 70% at 12 hours, greater than 25% to about 77.5% at 6 hours, from about 35% to about 50 about 90% at 18 hours, and greater than about 95% at 24 87.5% at 9 hours, and greater than about 65% at 12 hours. In hours. other preferred embodiments, said release rate is between 0% In some preferred embodiments, the dosage form provides to about 30% at 1 hour, from about 5% to about 45% at 2 an oral pharmaceutical composition comprising a therapeu hours, from about 10% to about 60% at 4 hours, from about tically effective amount of abusable drug or pharmaceutically 15% to about 70% at 6 hours, from about 25% to about 80% 55 acceptable salts thereof or mixtures thereof and ADER, said at 9 hours, and greater than about 50% at 12 hours; or between abusable drugs dosage form providing an in-vitro release rate 0% to about 20% at 1 hour, from about 2% to about 35% at 2 by weight of the abusable drug, when measured by the USP hours, from about 5% to about 50% at 4 hours, from about Basket and Paddle Methods at 100 rpm in 900 mL aqueous 10% to about 60% at 6 hours, from about 15% to about 70% buffer at a pH of between 1.6 and 7.2 at 37° C. of between 0% at 9 hours, and greater than about 40% at 12 hours; or between 60 to about 30% at 1 hour, from about 10% to about 65% at 4 0% to about 10% at 1 hour, from about 1% to about 30% at 2 hours, from about 20% to about 70% at 8 hours, from about hours, from about 5% to about 40% at 4 hours, from about 25% to about 80% at 12 hours, from about 35% to about 95% 10% to about 60% at 6 hours, from about 15% to about 70% at 18 hours, and greater than about 65% at 24 hours. In other at 9 hours, and greater than about 40% at 12 hours; or between preferred embodiments, said release rate is between 0% to 0% to about 5% at 1 hour, from about 0% to about 10% at 2 65 about 20% at 1 hour, from about 5% to about 50% at 4 hours, hours, from about 2% to about 20% at 4 hours, from about 5% from about 10% to about 60% at 8 hours, from about 15% to to about 30% at 6 hours, from about 10% to about 40% at 9 about 70% at 12 hours, from about 25% to about 90% at 18 US 9,125,833 B2 43 44 hours, and greater than about 55% at 24 hours; or between 0% 100% at 4 hours, between about 30% and about 100% at 8 to about 10% at 1 hour, from about 5% to about 40% at 4 hours, between about 50% and about 100% at 12 hours, hours, from about 8% to about 50% at 8 hours, from about between about 60% and about 100% at 16 hours, between 10% to about 60% at 12 hours, from about 22% to about 80% about 80% and about 100% at 24 hours, and greater than at 18 hours, and greater than about 45% at 24 hours; or about 95% at 36 hours. between 0% to about 35% at 1 hour, from about 15% to about In some preferred embodiments, the dosage form provides 70% at 4 hours, from about 25% to about 75% at 8 hours, from an oral pharmaceutical composition comprising a therapeu about 30% to about 85% at 12 hours, from about 40% to about tically effective amount of abusable drug or pharmaceutically 100% at 18 hours, and greater than about 75% at 24 hours; or acceptable salts thereof or mixtures thereof and ADER, said between 0% to about 40% at 1 hour, from about 20% to about 10 abusable drugs dosage form providing an in-vitro release rate 70% at 4 hours, from about 30% to about 80% at 8 hours, from by weight of the abusable drug, when measured by the USP about 35% to about 90% at 12 hours, from about 45% to about Basket and Paddle Methods at 100 rpm in 900 mL aqueous 100% at 18 hours, and greater than about 80% at 24 hours; or buffer at a pH of between 1.6 and 7.2 at 37° C. of between between 0% to about 45% at 1 hour, from about 25% to about 20% and about 50% at 1 hour, between about 40% and about 75% at 4 hours, from about 35% to about 85% at 8 hours, from 15 75% at 2 hours, between about 60% and about 95% at 4 hours, about 40% to about 90% at 12 hours, from about 50% to about between about 80% and about 100% at 8 hours and between 100% at 18 hours, and greater than about 90% at 24 hours; or about 90% and about 100% at 12 hours. In other preferred between 0% to about 50% at 1 hour, from about 30% to about embodiments, said release rate is between 15% and about 80% at 4 hours, from about 40% to about 90% at 8 hours, from 45% at 1 hour, between about 35% and about 70% at 2 hours, about 45% to about 95% at 12 hours, from about 60% to about between about 55% and about 90% at 4 hours, between about 100% at 18 hours, and greater than about 95% at 24 hours; or 75% and about 90% at 8 hours and between about 80% and between 0% to about 60% at 1 hour, from about 40% to about about 95% at 12 hours; or between 10% and about 40% at 1 80% at 4 hours, from about 45% to about 90% at 8 hours, from hour, between about 30% and about 65% at 2 hours, between about 50% to about 100% at 12 hours, from about 70% to about 50% and about 85% at 4 hours, between about 70% and about 100% at 18 hours, and greater than about 80% at 24 25 about 85% at 8 hours and between about 75% and about 90% hours. at 12 hours; or between 5% and about 35% at 1 hour, between In some preferred embodiments, the dosage form provides about 25% and about 60% at 2 hours, between about 45% and an oral pharmaceutical composition comprising a therapeu about 80% at 4 hours, between about 65% and about 80% at tically effective amount of abusable drug or pharmaceutically 8 hours and between about 70% and about 85% at 12 hours; acceptable salts thereof or mixtures thereof and ADER, said 30 orbetween 25% and about 55% at 1 hour, between about 45% abusable drugs dosage form providing an in-vitro release rate and about 80% at 2 hours, between about 65% and about 95% by weight of the abusable drug, when measured by the USP at 4 hours, between about 85% and about 100% at 8 hours and Basket and Paddle Methods at 100 rpm in 900 mL aqueous between about 95% and about 100% at 12 hours; or between buffer at a pH of between 1.6 and 7.2 at 37° C. of between 0% 30% and about 60% at 1 hour, between about 50% and about and about 50% at 1 hour, between about 0% and about 75% at 35 80% at 2 hours, between about 70% and about 95% at 4 hours, 2 hours, between about 3% and about 95% at 4 hours, between about 90% and about 100% at 8 hours and between between about 10% and about 100% at 8 hours, between about 95% and about 100% at 12 hours; or between 35% and about 25% and about 100% at 12 hours, between about 30% about 60% at 1 hour, between about 50% and about 80% at 2 and about 100% at 16 hours, between about 50% and about hours, between about 80% and about 95% at 4 hours, between 100% at 24 hours, and greater than about 80% at 36 hours. In 40 about 90% and about 100% at 8 hours and between about 95% other preferred embodiments, said release rate is between 0% and about 100% at 12 hours; or between 20% and about 40% and about 40% at 1 hour, between about 0% and about 65% at at 1 hour, between about 40% and about 65% at 2 hours, 2 hours, between about 2% and about 85% at 4 hours, between about 60% and about 85% at 4 hours, between about between about 8% and about 90% at 8 hours, between about 70% and about 90% at 8 hours and between about 80% and 20% and about 95% at 12 hours, between about 25% and 45 about 100% at 12 hours. about 95% at 16 hours, between about 40% and about 90% at In some preferred embodiments, the dosage form provides 24 hours, and greater than about 70% at 36 hours; or between an oral pharmaceutical composition comprising a therapeu 0% and about 30% at 1 hour, between about 0% and about tically effective amount of abusable drug or pharmaceutically 50% at 2 hours, between about 1% and about 75% at 4 hours, acceptable salts thereof or mixtures thereof and ADER, said between about 5% and about 80% at 8 hours, between about 50 abusable drugs dosage form providing an in-vitro release rate 10% and about 85% at 12 hours, between about 15% and by weight of the abusable drug, when measured by the USP about 90% at 16 hours, between about 30% and about 80% at Basket and Paddle Methods at 100 rpm in 900 mL aqueous 24 hours, and greater than about 70% at 36 hours; or between buffer at a pH of between 1.6 and 7.2 at 37° C. of between 0% 0% and about 60% at 1 hour, between about 0% and about and about 50% at 1 hour, between about 0% and about 75% at 80% at 2hours, between about 5% and about 100% at 4 hours, 55 2 hours, between about 10% and about 95% at 4 hours, between about 15% and about 100% at 8 hours, between between about 35% and about 100% at 8 hours, between about 35% and about 100% at 12 hours, between about 40% about 55% and about 100% at 12 hours, between about 70% and about 100% at 16 hours, between about 60% and about to about 100% at 16 hours, and greater than about 90% at 24 100% at 24 hours, and greater than about 85% at 36 hours; or hours. In other preferred embodiments, said release rate is between 0% and about 65% at 1 hour, between about 0% and 60 between 0% and about 40% at 1 hour, between about 0% and about 85% at 2 hours, between about 10% and about 100% at about 65% at 2 hours, between about 8% and about 85% at 4 4 hours, between about 20% and about 100% at 8 hours, hours, between about 30% and about 90% at 8 hours, between between about 40% and about 100% at 12 hours, between about 45% and about 100% at 12 hours, between about 60% about 50% and about 100% at 16 hours, between about 70% to about 100% at 16 hours, and greater than about 80% at 24 and about 100% at 24 hours, and greater than about 90% at 36 65 hours; or between 0% and about 30% at 1 hour, between about hours; or between 0% and about 70% at 1 hour, between about 0% and about 55% at 2 hours, between about 5% and about 0% and about 90% at 2 hours, between about 20% and about 75% at 4 hours, between about 20% and about 80% at 8 hours, US 9,125,833 B2 45 46 between about 35% and about 100% at 12 hours, between hours, between about 55% and about 100% hours at 24 hours about 50% to about 100% at 16 hours, and greater than about and greater than 85% at 36 hours; or between 0% and about 70% at 24 hours; or between 0% and about 20% at 1 hour, 40% at 1 hour, between about 0% and about 55% at 2 hours, between about 0% and about 45% at 2 hours, between about between about 10% and about 65% at 4 hours, between about 5% and about 65% at 4 hours, between about 10% and about 20% and about 75% at 8 hours, between about 30% and about 70% at 8 hours, between about 25% and about 80% at 12 85% at 12 hours, between about 40% to about 100% at 16 hours, between about 40% to about 100% at 16 hours, and hours, between about 55% and about 100% hours at 24 hours greater than about 60% at 24 hours; or between 0% and about and greater than 90% at 36 hours; or between 0% and about 60% at 1 hour, between about 0% and about 80% at 2 hours, 45% at 1 hour, between about 0% and about 60% at 2 hours, between about 15% and about 95% at 4 hours, between about 10 between about 15% and about 70% at 4 hours, between about 40% and about 100% at 8 hours, between about 60% and 25% and about 80% at 8 hours, between about 35% and about about 100% at 12 hours, between about 75% to about 100% at 90% at 12 hours, between about 45% to about 100% at 16 16 hours, and greater than about 90% at 24 hours; or between hours, between about 60% and about 100% hours at 24 hours 0% and about 65% at 1 hour, between about 0% and about and greater than 60% at 36 hours; or between 0% and about 85% at 2hours, between about 20% and about 90% at 4 hours, 15 50% at 1 hour, between about 5% and about 65% at 2 hours, between about 45% and about 100% at 8 hours, between between about 20% and about 75% at 4 hours, between about about 65% and about 100% at 12 hours, between about 80% 30% and about 85% at 8 hours, between about 40% and about to about 100% at 16 hours, and greater than about 90% at 24 95% at 12 hours, between about 50% to about 100% at 16 hours; or between 0% and about 40% at 1 hour, between about hours, between about 70% and about 100% hours at 24 hours 0% and about 50% at 2 hours, between about 10% and about and greater than 70% at 36 hours; or between 0% and about 80% at 4 hours, between about 25% and about 70% at 8 hours, 30% at 1 hour, between about 5% and about 40% at 2 hours, between about 40% and about 80% at 12 hours, between between about 10% and about 60% at 4 hours, between about about 60% to about 100% at 16 hours, and greater than about 20% and about 70% at 8 hours, between about 30% and about 90% at 24 hours. 100% at 12 hours, between about 40% to about 100% at 16 In some preferred embodiments, the dosage form provides 25 hours, between about 60% and about 100% hours at 24 hours an oral pharmaceutical composition comprising a therapeu and greater than 90% at 36 hours; or between 0% and about tically effective amount of abusable drug or pharmaceutically 30% at 1 hour, between about 0% and about 30% at 2 hours, acceptable salts thereof or mixtures thereof and ADER, said between about 0% and about 30% at 4 hours, between about abusable drugs dosage form providing an in-vitro release rate 5% and about 70% at 8 hours, between about 10% and about by weight of the abusable drug, when measured by the USP 30 80% at 12 hours, between about 20% to about 100% at 16 Basket and Paddle Methods at 100 rpm in 900 mL aqueous hours, between about 40% and about 100% hours at 24 hours buffer at a pH of between 1.6 and 7.2 at 37° C. of between 0% and greater than 50% at 36 hours; or between 0% and about and about 30% at 1 hour, between about 0% and about 45% at 20% at 1 hour, between about 0% and about 20% at 2 hours, 2 hours, between about 3% and about 55% at 4 hours, between about 0% and about 20% at 4 hours, between about between about 10% and about 65% at 8 hours, between about 35 0% and about 20% at 8 hours, between about 5% and about 20% and about 75% at 12 hours, between about 30% to about 40% at 12 hours, between about 10% to about 80% at 16 88% at 16 hours, between about 50% and about 100% hours hours, between about 40% and about 100% hours at 24 hours at 24 hours and greater than 80% at 36 hours. In other pre and greater than 60% at 36 hours; or between 0% and about ferred embodiments, said release rate is between 0% and 10% at 1 hour, between about 0% and about 20% at 2 hours, about 25% at 1 hour, between about 0% and about 40% at 2 40 between about 0% and about 40% at 4 hours, between about hours, between about 2% and about 50% at 4 hours, between 5% and about 60% at 8 hours, between about 10% and about about 8% and about 60% at 8 hours, between about 10% and 80% at 12 hours, between about 20% to about 100% at 16 about 70% at 12 hours, between about 25% to about 80% at 16 hours, between about 40% and about 100% hours at 24 hours hours, between about 45% and about 100% hours at 24 hours and greater than 50% at 36 hours. and greater than 75% at 36 hours; or between 0% and about 45 In some preferred embodiments, the dosage form provides 20% at 1 hour, between about 0% and about 35% at 2 hours, an oral pharmaceutical composition comprising a therapeu between about 1% and about 45% at 4 hours, between about tically effective amount of abusable drug or pharmaceutically 5% and about 55% at 8 hours, between about 8% and about acceptable salts thereof or mixtures thereof and ADER, said 65% at 12 hours, between about 20% to about 75% at 16 abusable drugs dosage form providing an in-vitro release rate hours, between about 40% and about 100% hours at 24 hours 50 by weight of the abusable drug, when measured by the USP and greater than 70% at 36 hours; or between 0% and about Basket and Paddle Methods at 100 rpm in 900 mL aqueous 15% at 1 hour, between about 0% and about 30% at 2 hours, buffer at a pH of between 1.6 and 7.2 at 37° C. of between 0% between about 0% and about 40% at 4 hours, between about and about 50% at 1 hour, between about 0% and about 75% at 5% and about 50% at 8 hours, between about 8% and about 2 hours, between about 3% and about 95% at 4 hours, 60% at 12 hours, between about 15% to about 70% at 16 55 between about 10% and about 100% at 8 hours, between hours, between about 35% and about 100% hours at 24 hours about 20% and about 100% at 12 hours, between about 30% and greater than 60% at 36 hours; or between 0% and about to about 100% at 16 hours, between about 50% and about 10% at 1 hour, between about 0% and about 25% at 2 hours, 100% hours at 24 hours and greater than 80% at 36 hours. In between about 0% and about 35% at 4 hours, between about other preferred embodiments, said release rate is between 0% 5% and about 45% at 8 hours, between about 10% and about 60 and about 45% at 1 hour, between about 0% and about 70% at 50% at 12 hours, between about 10% to about 60% at 16 2 hours, between about 3% and about 90% at 4 hours, hours, between about 30% and about 90% hours at 24 hours between about 8% and about 100% at 8 hours, between about and greater than 70% at 36 hours; or between 0% and about 15% and about 100% at 12 hours, between about 25% to 35% at 1 hour, between about 0% and about 50% at 2 hours, about 100% at 16 hours, between about 45% and about 100% between about 5% and about 60% at 4 hours, between about 65 hours at 24 hours and greater than 80% at 36 hours; or 15% and about 70% at 8 hours, between about 25% and about between 0% and about 40% at 1 hour, between about 0% and 80% at 12 hours, between about 35% to about 90% at 16 about 65% at 2 hours, between about 0% and about 80% at 4 US 9,125,833 B2 47 48 hours, between about 5% and about 80% at 8 hours, between In some preferred embodiments, the dosage form provides about 10% and about 90% at 12 hours, between about 20% to an oral pharmaceutical composition comprising a therapeu about 100% at 16 hours, between about 40% and about 100% tically effective amount of abusable drug or pharmaceutically hours at 24 hours and greater than 70% at 36 hours; or acceptable salts thereof or mixtures thereof and ADER, said between 0% and about 35% at 1 hour, between about 0% and in-vitro release rate being substantially independent of pH in about 60% at 2 hours, between about 0% and about 70% at 4 that a difference, at any given time, between an amount of hours, between about 3% and about 70% at 8 hours, between abusable drug released at one pH and an amount released at about 5% and about 80% at 12 hours, between about 15% to any other pH, when measured in-vitro using the USP Basket about 100% at 16 hours, between about 30% and about 100% and Paddle Methods of USP Drug Release test of U.S. Phar 10 macopeia (2003) at 100 rpm in 900 ml aqueous buffer, is no hours at 24 hours and greater than 40% at 36 hours; or greater than 30%. In other preferred embodiments, the differ between 0% and about 60% at 1 hour, between about 0% and ence, at any given time, between an amount of abusable drug about 80% at 2 hours, between about 5% and about 100% at released at one pH and an amount released at any other pH 4 hours, between about 15% and about 100% at 8 hours, using the aforementioned methods is no greater than 50%, or between about 30% and about 100% at 12 hours, between 15 no greater than 40%, or no greater than 35%, or no greater about 40% to about 100% at 16 hours, between about 60% than 25%, or no greater than 20%, or no greater than 15%, or and about 100% hours at 24 hours and greater than 70% at 36 no greater than 10%, or no greater than 5%. hours; or between 0% and about 50% at 1 hour, between about In some preferred embodiments, the dosage form provides 0% and about 75% at 2 hours, between about 5% and about an oral pharmaceutical composition comprising a therapeu 95% at 4 hours, between about 25% and about 80% at 8 hours, tically effective amount of abusable drug or pharmaceutically between about 30% and about 100% at 12 hours, between acceptable salts thereof or mixtures thereof and ADER, said about 40% to about 100% at 16 hours, between about 60% dosage forms of abusable drug providing in-vitro release rates and about 100% hours at 24 hours and greater than 60% at 36 by weight of between 0% to about 50% by weight of the hours; or between 0% and about 60% at 1 hour, between about abusable drug from the dosage form at one hour when mea 0% and about 85% at 2 hours, between about 5% and about 25 sured by the USP Basket and Paddle Methods at 100 rpm in 100% at 4 hours, between about 10% and about 100% at 8 700 ml of Simulated Gastric Fluid (SGF) at 37°C. In other hours, between about 20% and about 100% at 12 hours, preferred embodiments, said release rate at one hour is between about 30% to about 100% at 16 hours, between about between 0% to about 10% by weight, or 0% to about 20% by 50% and about 100% hours at 24 hours and greater than 80% weight, or is between 0% to about 30% by weight, or 0% to at 36 hours. 30 about 40% by weight, or between 0% to about 60% by weight, In some preferred embodiments, the dosage form provides or 0% to about 70% by weight, or 0% to about 80% by weight, an oral pharmaceutical composition comprising a therapeu or 0% to about 90% by weight, or 10% to about 50% by tically effective amount of abusable drug or pharmaceutically weight, or 10% to about 60% by weight, or 10% to about 70% acceptable salts thereof or mixtures thereof and ADER, said by weight, or 10% to about 90% by weight, or 10% to about abusable drugs dosage form providing an in-vitro release rate 35 100% by weight, or 30% to about 100% by weight, or 50% to by weight of the abusable drug, when measured by the USP about 100% by weight. Basket and Paddle Methods at 100 rpm in 900 mL aqueous In some preferred embodiments, the dosage form provides buffer at a pH of between 1.6 and 7.2 at 37° C. of between an oral pharmaceutical composition comprising a therapeu 15% and about 25% at 1 hour, between about 25% and about tically effective amount of abusable drug or pharmaceutically 35% at 2hours, between about 30% and about 45% at 4 hours, 40 acceptable salts thereof or mixtures thereof and ADER, said between about 40% and about 60% at 8 hours, between about dosage forms of abusable drug providing in-vitro release rates 55% and about 70% at 12 hours and between about 60% to by weight of abusable drug, when measured by the USP about 75% at 16 hours. In other preferred embodiments, said Basket and Paddle Methods at 100 rpm in 900 mL aqueous release rate is between 10% and about 20% at 1 hour, between buffer at a pH of between 1.6 and 7.2 at 37° C. of between 0% about 20% and about 30% at 2 hours, between about 25% and 45 to about 80% at 0.5 hours, and greater than about 40% at 1 about 40% at 4 hours, between about 30% and about 50% at hour. In other preferred embodiments, said release rate is 8 hours, between about 50% and about 65% at 12 hours and between 0% to about 40% at 0.5 hours, and greater than about between about 55% to about 65% at 16 hours; or between 5% 60% at 1 hour, or between 0% to about 20% at 0.5 hours, and and about 15% at 1 hour, between about 15% and about 25% greater than about 40% at 1 hour; or between 0% to about at 2 hours, between about 20% and about 35% at 4 hours, 50 20% at 0.5 hours, and greater than about 20% at 1 hour; or between about 25% and about 45% at 8 hours, between about between 0% to about 90% at 0.5 hours, and greater than about 45% and about 60% at 12 hours and between about 50% to 60% at 1 hour; or between 0% to about 100% at 0.5 hours, and about 60% at 16 hours; or between 15% and about 30% at 1 greater than about 60% at 1 hour; or between 0% to about hour, between about 20% and about 40% at 2 hours, between 90% at 1 hour, and greater than about 40% at 2 hours; or about 20% and about 50% at 4 hours, between about 30% and 55 between 0% to about 100% at 1 hour, and greater than about about 70% at 8 hours, between about 60% and about 80% at 60% at 2 hours; or between 0% to about 60% at 1 hour, and 12 hours and between about 70% to about 90% at 16 hours; or greater than about 40% at 2 hours; or between 0% to about between 0% and about 50% at 1 hour, between about 5% and 40% at 1 hour, and greater than about 30% at 2 hours; or about 50% at 2 hours, between about 5% and about 70% at 4 between 0% to about 50% at 1 hour, and greater than about hours, between about 10% and about 80% at 8 hours, between 60 40% at 2 hours; or between 0% to about 30% at 1 hour, and about 20% and about 100% at 12 hours and between about greater than about 20% at 2 hours; or between 0% and about 40% to about 100% at 16 hours; or between 15% and about 50% at 1 hour, between about 0% and about 80% at 2 hours, 40% at 1 hour, between about 15% and about 45% at 2 hours, between about 5% and about 100% at 4 hours and between between about 20% and about 60% at 4 hours, between about about 10% and about 100% at 8 hours; or between 10% and 20% and about 80% at 8 hours, between about 30% and about 65 about 60% at 1 hour, between about 15% and about 75% at 2 90% at 12 hours and between about 40% to about 100% at 16 hours, between about 20% and about 95% at 4 hours and hours. between about 30% and about 100% at 8 hours. US 9,125,833 B2 49 50 In some preferred embodiments, the oral dosage form of or not more than about 4:1, or not more than about 3:1, or not the present invention is directed to an oral dosage form com more thanabout 2:1, or not more than about 1.5:1, or not more prising: (i) an abusable drug and (ii) ADER, such that the ratio than about 1.25:1. of the mean C of the abusable drug after single dose oral In some preferred embodiments, the oral dosage form of administration of the dosage form after tampering to the mean 5 the present invention is directed to an oral dosage form com C of abusable drug after single dose oral administration of prising: (i) an abusable drug and (ii) ADER, such that the ratio an intact dosage form is not more than about 20:1. In other of the mean T of the abusable drug after single dose oral embodiments of the invention, the mean C, ratio using the administration of an immediate release reference product aforementioned test method is not more than about 15:1, or containing an equivalent amount of abusable drug to the mean about 10:1, or about 7.5:1, or about 6:1, or about 5:1, or about 10 T, of abusable drug after single dose oral administration of 4:1, or about 3:1, or about 2:1, or about 1.5:1, or about 1.25:1. an intact dosage form of the invention is at least about 1.25:1. In some preferred embodiments, the oral dosage form of In other embodiments of the invention, the mean T. ratio the present invention is directed to an oral dosage form com using the aforementioned test method is at least about 1.5:1, prising: (i) an abusable drug and (ii) ADER, such that the ratio or at least about 2:1, or at least about 3:1, or at least about 4:1, of the mean C of the abusable drug after single dose oral 15 or at least about 5:1, or at least about 6:1, or at least about administration of an immediate release reference product 10:1, or at least about 15:1 or at least about 20:1. containing an equivalent amount of abusable drug to the mean In some preferred embodiments, the invention is directed C of abusable drug after single dose oral administration of to an oral dosage form comprising (i) an abusable drug and an intact dosage form of the invention is at least about 1.25:1. (ii) ADER, such that less than 70% of the abusable drug is In other embodiments of the invention, the mean C, ratio released from the intact dosage form after 1 hour based on the using the aforementioned test method is at least about 1.5:1, in-vitro dissolution of the dosage form in 900 mL of 40% or about 2:1, or about 3:1, or about 4:1, or about 5:1, or about ethanol in water using the USP Basket and Paddle Methods at 6:1, or about 10:1, or about 15:1 or about 20:1. 50 rpm and 37°C. In other embodiments of the invention, the In some preferred embodiments, the oral dosage form of release rate of the abusable drug from the intact dosage form the present invention is directed to an oral dosage form com 25 by the aforementioned USP basket method at 1 hours is 60% prising: (i) an abusable drug and (ii) ADER, such that the ratio or less, 50% or less, 45% or less, 40% or less, 35% or less, of the mean AUCo. of the abusable drug after single dose oral 33% or less, 30% or less, 25% or less, 20% or less or 15% or administration of the dosage form after tampering to the mean less. AUCo. of abusable drug after single dose oral administration In certain preferred embodiments of the invention, the of an intact dosage form is not more than about 20:1. In other 30 mean ratio of the amount of abusable drug released from the embodiments, the mean AUC ratio using the aforementioned dosage form after mechanical tampering (e.g., after crushing test method is measured from time 0 to up to 1, 2.5, 3, 4, 5 or with a single crush of a spatula or in the case of a capsule 6 hours post dose (i.e., AUCo., AUCos, AUCo., AUCo., containing a solid, cutting into two pieces) to the amount of AUCos and AUCo., respectively). In other embodiments of abusable drug released from the intact dosage form based on the invention, the mean AUCo., AUC, AUCs, AUC. 35 the dissolution at 0.5 hours of the dosage form in 900 mL of AUCo., AUCos and AUCoe ratios using the aforementioned Simulated Gastric Fluid using the USP Basket and Paddle test method are not more than about 15:1, or about 10:1, or Methods at 50 rpm at 37 degrees C. is less than 20:1. In other about 7.5:1, or about 6:1, or about 5:1, or about 4:1, or about embodiments of the invention, the mean ratio by the afore 3:1, or about 2:1 or about 1.5:1. mentioned USP basket method at 0.5 hours is 15:1 or less, In some preferred embodiments, the oral dosage form of 40 10:1 or less, 7.5:1 or less, 5:1 or less. 3:1 or less, 2:1 or less, the present invention is directed to an oral dosage form com 1.5:1 or less. prising: (i) an abusable drug and (ii) ADER, such that the ratio In certain preferred embodiments of the invention, the of the mean AUCo. of the abusable drug after single dose oral mean ratio of the amount of abusable drug released from the administration of an immediate release reference product dosage form after mechanical tampering (e.g., after crushing containing an equivalent amount of abusable drug to the mean 45 with a single crush of a spatula or in the case of a capsule AUCo. of abusable drug after single dose oral administration containing a solid, cutting into two pieces) to the amount of of an intact dosage form of the invention is at least about abusable drug released from the intact dosage form based on 1.25:1. In other embodiments, the mean AUC ratio using the the dissolution at 1 hour of the dosage form in 900 mL of aforementioned test method is measured from time 0 to up to Simulated Gastric Fluid using the USP Basket and Paddle 1, 2.5, 3, 4, 5 or 6 hours post dose (i.e., AUCo., AUCos, 50 Methods at 50 rpm at 37 degrees C. is less than 20:1. In other AUCo., AUCo., AUCs and AUCo., respectively). In other embodiments of the invention, the mean ratio by the afore embodiments of the invention, the mean AUCo., AUCo., mentioned USP basket method at 1 hour is 15:1 or less, 10:1 AUCo-2s, AUCo-s, AUCoa, AUCo-sand AUCo. ratios using or less, 7.5:1 or less, 5:1 or less. 3:1 or less, 2:1 or less, 1.5:1 the aforementioned test method are not more than about 15:1, or less. or about 10:1, or about 7.5:1, or about 6:1, or about or about 55 In certain preferred embodiments of the invention, the 5:1, or about 4:1, or about 3:1, or about 2:1 or about 1.5:1. mean ratio of the amount of abusable drug released from the In some preferred embodiments, the oral dosage form of dosage form after mechanical tampering (e.g., after crushing the present invention is directed to an oral dosage form com with a single crush of a spatula or in the case of a capsule prising: (i) an abusable drug and (ii) ADER, such that the ratio containing a solid, cutting into two pieces) to the amount of of the mean T of the abusable drug after single dose oral 60 abusable drug released from the intact dosage form based on administration of the intact dosage form to the mean T of the dissolution at 2 hours of the dosage form in 900 mL of abusable drug after single dose oral administration of an Simulated Gastric Fluid using the USP Basket and Paddle dosage form after tampering is not more than about 20:1. In Methods at 50 rpm at 37 degrees C. is less than 20:1. In other other embodiments of the invention, the mean T. ratio embodiments of the invention, the mean ratio by the afore using the aforementioned test method is not more than about 65 mentioned USP basket method at 2 hours is 15:1 or less, 10:1 15:1, or not more than about 10:1, or not more than about or less, 7.5:1 or less, 5:1 or less. 3:1 or less, 2:1 or less, 1.5:1 7.5:1, or not more than about 6:1, or not more than about 5:1, or less. US 9,125,833 B2 51 52 In some preferred embodiments, the present invention is about 35%, or less than about 30%, or less than about 27%, or directed to an oral dosage form comprising (i) an abusable less thanabout 25%, or less thanabout 22%, or less thanabout drug and (ii) ADER, such that the ratio of the mean C. of the 20% or less than about 18%, or less than about 15%, or less abusable drug after single dose oral administration of the than about 12%, or less than about 10%, or less than about dosage form after tampering to the mean C of abusable 8%, or less than about 6%, or less than about 5%, or less than drug after single dose oral administration of an intact dosage about 3%. form is less than about 20:1. In other embodiments of the In some embodiments, the abusable drug dosage form of invention, said mean ratio using the aforementioned test the invention is bioequivalent when taken under with and method is less than about 15:1 or less than about 10:1, or less without 30 mL, 60 mL, 90 mL, 120 mL, 180 mL,240 mL,270 than about 7:1, or less than about 5:1, or less than about 4:1, 10 mL, 300 mL of a 40% ethanol solution. or less than about 3:1, or less than 2.5:1, or less than about 2:1, In some embodiments, the abusable drug dosage form of or less than about 1.75:1, or less than about 1.5:1, or less than the invention upon administration provides a mean alcohol to about 1.25:1 or less than about 1.25:1 no alcohol state abusable drug AUC difference of less than In some preferred embodiments, the present invention is about 50%, or less than about 45%, or less than about 40%, or directed to an oral dosage form comprising (i) an abusable 15 less thanabout 35%, or less thanabout 30%, or less thanabout drug and (ii) ADER, such that the ratio of the mean AUC of 27%, or less than about 25%, or less than about 22%, or less the abusable drug after single dose oral administration of an than about 20% or less than about 18%, or less than about immediate release dosage form containing an equivalent 15%, or less than about 12%, or less than about 10%, or less amount of abusable drug to the mean AUCo. of abusable drug than about 8%, or less than about 6%, or less than about 5%, after single dose oral administration of an intact dosage form or less than about 3%, said alcohol state induced by concur of the invention is at least 1.25:1. In other embodiments of the rent ingestion of the abusable drug with about 300 mL or invention, the mean AUCo. ratio using the aforementioned about 270 mL, or about 240 mL, or about 210 mL, or about test method is at least about 1.5:1, or at least about 1.75:1, or 180 mL or about 150 mL, or about 120 mL, or about 90 mL, at least about 2:1, or at least about 2.5:1, or at least about 3:1, or about 60 mL or about 30 mL of a 40% solution of ethanol. or at least about 3.5:1, or at least about 4:1, or at least about 25 In some embodiments, the abusable drug dosage form of 5:1, or at least about 6:1, or at least about 10:1 or at least about the invention upon administration provides a mean alcohol to 15:1 or at least about 20:1. no alcohol state abusable drug C, difference of less than The invention is also directed to methods of preventing about 50%, or less than about 45%, or less than about 40%, or abuse and misuse of an abusable drug utilizing the dosage less thanabout 35%, or less thanabout 30%, or less thanabout forms disclosed herein. The method can comprise providing 30 27%, or less than about 25%, or less than about 22%, or less the abusable drug in an oral dosage form together with ADER, than about 20% or less than about 18%, or less than about wherein the abusable drug is present in a form which is 15%, or less than about 12%, or less than about 10%, or less partially or Substantially resistant to tampering (e.g., crush than about 8%, or less than about 6%, or less than about 5%, ing, shear forces which break up the dosage form, solvent or less than about 3%, said alcohol state induced by concur extraction, etc.). 35 rent ingestion of the abusable drug with about 300 mL or In certain preferred embodiments of the invention, the about 270 mL, or about 240 mL, or about 210 mL, or about release for the abusable drug component of the formulation is 180 mL or about 150 mL, or about 120 mL, or about 90 mL, expressed in terms of a ratio of the release achieved after or about 60 mL or about 30 mL of a 40% solution of ethanol. tampering, relative to the amount released from the intact In some preferred embodiments, the dosage form provides formulation. The ratio is therefore expressed as Crushed/ 40 an oral pharmaceutical composition comprising a therapeu Whole, and it is desired that this ratio have a numerical tically effective amount of abusable drug or pharmaceutically range of not more than 20:1 (crushed release in 1 hour/intact acceptable salts thereof or mixtures thereof, ADER material, release in 1 hour), based on in-vitro dissolution of the dosage and a pharmacologic antagonist to the abusable drug. form in 900 ml of Simulated Gastric Fluid using the USP In some preferred embodiments, the dosage form provides Basket and Paddle Methods at 50 rpm and 37° C. In other 45 an oral pharmaceutical composition comprising a therapeu embodiments of the invention, the mean ratio using the afore tically effective amount of abusable drug or pharmaceutically mentioned test method is less than about 15:1, or less than acceptable salts thereof or mixtures thereof, ADER material, about 10:1, or less than about 7:1, or less than about 5:1, or and a pharmacologic antagonist to a co-abused abusable drug, less than about 3:1, or less than about 2:1, or less than about said co-abused abusable drug not part of the dosage form. 1.5:1, or less than about 1.25:1. 50 In some preferred embodiments, the dosage form provides In some embodiments, the abusable drug dosage form of an oral pharmaceutical composition comprising a therapeu the invention is bioequivalent when taken under fed and tically effective amount of abusable drug or pharmaceutically fasted conditions. acceptable salts thereof or mixtures thereof, ADER material, In some embodiments, the abusable drug dosage form of and a pharmacologic antagonist for both the abusable drug of the invention upon administration provides a mean fed to 55 the dosage form and a co-abused abusable drug, said co fasted abusable drug AUC difference of less than about abused abusable drug not part of the dosage form. 50%, or less than about 45%, or less than about 40%, or less In some preferred embodiments, when the dosage form of than about 35%, or less than about 30%, or less than about the invention comprises a therapeutically effective amount of 27%, or less than about 25%, or less than about 22%, or less abusable drug or pharmaceutically acceptable salt thereof or than about 20% or less than about 18%, or less than about 60 mixture thereof, ADER material, and a pharmacologic 15%, or less than about 12%, or less than about 10%, or less antagonist to the abusable drug (and/or to a co-abused abus than about 8%, or less than about 6%, or less than about 5%, able drug, said co-abused abusable drug not part of the dosage or less than about 3%. form), some or all of the in vitro dissolution rates or in-vitro In some embodiments, the abusable drug dosage form of release rates (e.g., USP Basket and Paddle Methods) referred the invention upon administration provides a mean fed to 65 to in the embodiments and specifications herein and appli fasted abusable drug C, difference of less than about 50%, cable to the abusable drug are also applicable to said antago or less than about 45%, or less than about 40%, or less than nist. In the interest of brevity, such embodiments and speci US 9,125,833 B2 53 54 fications are not repeated here. In some preferred In certain preferred embodiments of the invention, wherein embodiments, the in vitro dissolution rates or in-vitro release the abusable drug is an analgesic, the mean ratio of the time to rates for the abusable drug and the pharmacologic antagonists confirmed perceptible pain relief after administration of the are the same. In other preferred embodiments, the in vitro intact dosage form to the time to confirmed perceptible pain dissolution rates or in-vitro release rates for the abusable drug 5 relief after administration of the tampered dosage form is less and for the pharmacologic antagonists are from different. than 20:1. In other embodiments of the invention, the mean In some preferred embodiments, when the dosage form of ratio using the aforementioned test method is less than about the invention comprises a therapeutically effective amount of 15:1, or less than about 10:1, or less than about 7:1, or less abusable drug or pharmaceutically acceptable salt thereof or than about 5:1, or less than about 3:1, or less than about 2:1, mixture thereof, ADER material, and an aversive agent, some 10 or less than about 1.5:1, or less than about 1.25:1. or all of the in vitro dissolution rates or in-vitro release rates In certain preferred embodiments of the invention, wherein (e.g., USP Basket and Paddle Methods) referred to in the the abusable drug is an analgesic, the mean ratio of the time to embodiments and specifications herein and applicable to the meaningful pain relief after administration of the intact dos abusable drug are also applicable to said aversive agent. In the age form to the time to meaningful pain relief after adminis interest of brevity, such embodiments and specifications are 15 tration of the tampered dosage form is less than 20:1. In other not repeated here. In some preferred embodiments, the in embodiments of the invention, the mean ratio using the afore vitro dissolution rates or in-vitro release rates for the abusable mentioned test method is less than about 15:1, or less than drug and the aversive agent are the same. In other preferred about 10:1, or less than about 7:1, or less than about 5:1, or embodiments, the in vitro dissolution rates or in-vitro release less than about 3:1, or less than about 2:1, or less than about rates for the abusable drug and for the aversive agent are 1.5:1, or less than about 1.25:1. different. In certain preferred embodiments of the invention, wherein In some preferred embodiments, when the dosage form of the abusable drug is an analgesic, the mean ratio of the peak the invention comprises a therapeutically effective amount of pain intensity difference score after administration of the abusable drug or pharmaceutically acceptable salt thereof or tampered dosage form to the peak pain intensity difference mixture thereof, ADER material, and a pharmacologic 25 score after administration of the intact dosage form is less antagonist to the abusable drug (and/or to a co-abused abus than 10:1. In other embodiments of the invention, the mean able drug, said co-abused abusable drug not part of the dosage ratio using the aforementioned test method is less than about form), Some or all of the pharmacokinetic parameters (e.g., 8:1, or less than about 7:1, or less than about 5:1, or less than AUCo-e AUCo., AUCo-s: AUCo-12. AUCo-24. C. Cs. C12. about 3:1, or less than about 2:1, or less than about 1.5:1, or C24 to or T. C. HVD, Wso steady state, percent 30 less than about 1.25:1. fluctuation and AI) referred to in the embodiments and speci In certain preferred embodiments of the invention, wherein fications herein and applicable to the abusable drug are also the abusable drug is an analgesic, the mean ratio of the peak applicable to said antagonist. In the interest of brevity, Such pain relief score after administration of the tampered dosage embodiments and specifications are not repeated here. In form to the peak pain relief score after administration of the Some preferred embodiments, the pharmacokinetic param 35 intact dosage form is less than 10:1. In other embodiments of eters for the abusable drug and the pharmacologic antagonists the invention, the mean ratio using the aforementioned test are the same. In other preferred embodiments, the pharmaco method is less than about 8:1, or less than about 7:1, or less kinetic parameters for the abusable drug and for the pharma than about 5:1, or less than about 3:1, or less than about 2:1, cologic antagonists are different. or less than about 1.5:1, or less than about 1.25:1. In some preferred embodiments, the ADER material pro 40 In certain preferred embodiments of the invention, wherein vides extended release of the abusable drug and the pharma the abusable drug is an analgesic, the mean ratio of change cologic antagonist for the abusable drug, thereby significantly from baseline to two hours post-dose in pain intensity score reducing the risk precipitating signs and symptoms of abus after administration of the tampered dosage form to the able drug withdrawal or an abstinence syndrome in abusable change from baseline to two hours post-dose in pain intensity drug dependent and tolerant individuals, and diminution of 45 score after administration of the intact dosage form is less the intended therapeutic response from the abusable drug. than 20:1. In other embodiments of the invention, the mean When such a dosage form is tampered with, the ADER mate ratio using the aforementioned test method is less than about rial provides one line of defense and the antagonist provides 15:1, or less than about 10:1, or less than about 7:1, or less yet another line of defense against drug abuse. than about 5:1, or less than about 3:1, or less than about 2:1, The amount of pharmacologic antagonist to the abusable 50 or less than about 1.5:1, or less than about 1.25:1. drug in the oral dosage form will vary for a variety of reasons, In certain preferred embodiments of the invention, wherein including the choice of abusable drug, the potency of the the abusable drug is an analgesic, the mean ratio of the num abusable drug, the potency of the antagonist, the oral bioavail ber of patients with pain who need to be treated to obtain ability of the abusable drug and the antagonist, the safety and >50% pain reliefin one patient (i.e., number needed to treator tolerability of the antagonist, the degree of blockade sought to 55 NNT) after administration of the tampered dosage form to the the effects of the abusable drug, the patients prior exposure to NNT after administration of the intact dosage form is less the abusable drug, the nature of the formulation (e.g., imme than 20:1. In other embodiments of the invention, the mean diate release or extended release), the pharmacokinetics, ratio using the aforementioned test method is less than about pharmacodynamics and physicochemical characteristics of 15:1, or less than about 10:1, or less than about 7:1, or less the abusable drug and the antagonist. 60 than about 5:1, or less than about 3:1, or less than about 2:1, In some embodiments, pharmacologic antagonist to the or less than about 1.5:1, or less than about 1.25:1. Preferably, abusable drug is about 0.00001 mg to 1000 mg. or about the aforementioned at NNT is measured at 0.5, 1, 1.5, 2, 3, 4, 0.00001 mg to about 700 mg, or about 0.001 mg to about 500 5 or 6 hours post-dose. mg, or about 0.01 mg to about 400 mg. or about 0.1 mg to In certain preferred embodiments of the invention, wherein about 200 mg. or about 1 mg to about 100 mg. or about 65 the abusable drug is an analgesic, the mean ratio of the num 0.00001 to about 500 mg, or about 0.001 to about 300 mg, or ber needed to harm (referred to hereinafter as “NNH) due to about 0.01 to about 200 mg. moderate or severe nausea in healthy Subjects (naive to said US 9,125,833 B2 55 56 analgesic) after administration of the tampered dosage form or less than about 7:1, or less thanabout 6:1, or less than about to the NNH after administration of the intact dosage form is 5:1, or less than about 4:1, less than about 3:1, or less than less than 20:1. In other embodiments of the invention, the about 2.5:1, or less than about 2:1, less than about 1.75:1, or mean ratio using the aforementioned test method is less than less than about 15:1, or less than about 1.25:1, or less than about 15:1, or less than about 10:1, or less than about 7:1, or 5 about 1.1:1. Preferably, the aforementioned at NNH is mea less than about 5:1, or less than about 3:1, or less than about sured at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose. 2:1, or less than about 1.5:1, or less than about 1.25:1. Pref In certain preferred embodiments of the invention, wherein erably, the aforementioned at NNH is measured at 0.5, 1, 1.5, the abusable drug is produces sedation or drowsiness on 2, 3, 4, 5 or 6 hours post-dose. administration to naive (i.e., abusable drug naive) healthy In certain preferred embodiments of the invention, wherein 10 subjects, the mean ratio of the NNH due to moderate or severe the abusable drug is an analgesic, the mean ratio of the NNH sedation or drowsiness in healthy Subjects who are naive to due to moderate or severe sedation or drowsiness in healthy said abusable drug and who are occasional or light consumers Subjects (naive to said analgesic) after administration of the of alcohol, after administration of the tampered dosage form tampered dosage form to the NNH after administration of the to the NNH after administration of the intact dosage form is intact dosage form is less than 20:1. In other embodiments of 15 less than 20:1, said NNH measured 2.5 to 6 hours after admin the invention, the mean ratio using the aforementioned test istration of the dosage form, said dosage form administration method is less than about 15:1, or less than about 10:1, or less followed about 1.5 hours later by alcohol (ethanol) adminis than about 7:1, or less than about 5:1, or less than about 3:1, tration Sufficient to maintain a blood alcohol concentration of or less than about 2:1, or less than about 1.5:1, or less than 0.04% to 0.08%. In other embodiments of the invention, the about 1.25:1. Preferably, the aforementioned at NNH is mea mean ratio using the aforementioned test method is less than sured at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose. about 18:1, or less than about 16:1, or less than about 15:1, or In certain preferred embodiments of the invention, wherein less than about 14:1, or less than about 12:1, or less than about the abusable drug is an analgesic, the mean ratio of the NNH 11:1, or less than about 10:1, or less than about 9:1, or less due to moderate or severe sedation or drowsiness in healthy than about 8:1, or less than about 7:1, or less than about 6:1, Subjects who are naive to said abusable drug and who are 25 or less than about 5:1, or less than about 4:1, less than about occasional or light consumers of alcohol after administration 3:1, or less than about 2.5:1, or less than about 2:1, less than of the tampered dosage form to the NNH after administration about 1.75:1, or less than about 15:1, or less than about of the intact dosage form is less than 20:1, said NNH mea 1.25:1, or less than about 1.1:1. sured 2.5 to 6 hours after administration of the dosage form, In certain preferred embodiments of the invention, wherein said dosage form administration followed about 1.5 hours 30 the abusable drug is produces nausea on administration to later by alcohol (ethanol) administration sufficient to main naive (i.e., abusable drug naive) healthy Subjects, the mean tain a blood alcohol concentration of 0.04% to 0.08%. In ratio of the NNH due to moderate or severe nausea in naive other embodiments of the invention, the mean ratio using the healthy Subjects after administration of the tampered dosage aforementioned test method is less than about 15:1, or less form to the NNH after administration of the intact dosage than about 10:1, or less than about 7:1, or less than about 5:1, 35 form is less than 20:1. In other embodiments of the invention, or less than about 3:1, or less than about 2:1, or less than about the mean ratio using the aforementioned test method is less 1.5:1, or less than about 1.25:1. than about 18:1, or less than about 16:1, or less than about In certain preferred embodiments of the invention, wherein 15:1, or less than about 14:1, or less than about 12:1, or less patients have the medical condition for which the abusable thanabout 11:1, or less than about 10:1, or less than about 9:1, drug is medically used, the mean ratio of the number of 40 or less than about 8:1, or less thanabout 7:1, or less than about patients who need to be treated (NNT) to obtain a 50% reduc 6:1, or less than about 5:1, or less than about 4:1, less than tion in the cardinal sign or symptom of the medical condition about 3:1, or less than about 2.5:1, or less than about 2:1, less after administration of the tampered dosage form to the NNT than about 1.75:1, or less than about 15:1, or less than about after administration of the intact dosage form is less than 1.25:1, or less than about 1.1:1. Preferably, the aforemen 20:1. In other embodiments of the invention, the mean ratio 45 tioned at NNH is measured at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours using the aforementioned test method is less than about 18:1, post-dose. or less than about 16:1, or less than about 15:1, or less than In certain preferred embodiments of the invention, upon about 14:1, or less than about 12:1, or less than about 11:1, or administration of abusable drug to naive (i.e., abusable drug less than about 10:1, or less than about 9:1, or less than about naive) healthy subjects, the mean ratio of the NNH due to the 8:1, or less than about 7:1, or less than about 6:1, or less than 50 incidence of dizziness in naive healthy Subjects after admin about 5:1, or less than about 4:1, less than about 3:1, or less istration of the tampered dosage form to the NNH after thanabout 2.5:1, or less thanabout 2:1, less than about 1.75:1, administration of the intact dosage form is less than 20:1. In or less than about 15:1, or less than about 1.25:1, or less than other embodiments of the invention, the mean ratio using the about 1.1:1. Preferably, the aforementioned at NNT is mea aforementioned test method is less than about 18:1, or less sured at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose. 55 than about 16:1, or less than about 15:1, or less than about In certain preferred embodiments of the invention, wherein 14:1, or less than about 12:1, or less than about 11:1, or less the abusable drug is produces sedation or drowsiness on than about 10:1, or less than about 9:1, or less than about 8:1, administration to naive (i.e., abusable drug naive) healthy or less than about 7:1, or less thanabout 6:1, or less than about subjects, the mean ratio of the NNH due to moderate or severe 5:1, or less than about 4:1, less than about 3:1, or less than sedation or drowsiness in naive healthy Subjects after admin 60 about 2.5:1, or less than about 2:1, less than about 1.75:1, or istration of the tampered dosage form to the NNH after less than about 15:1, or less than about 1.25:1, or less than administration of the intact dosage form is less than 20:1. In about 1.1:1. Preferably, the aforementioned at NNH is mea other embodiments of the invention, the mean ratio using the sured at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose. aforementioned test method is less than about 18:1, or less In certain preferred embodiments of the invention, upon than about 16:1, or less than about 15:1, or less than about 65 administration of abusable drug to naive (i.e., abusable drug 14:1, or less than about 12:1, or less than about 11:1, or less naive) healthy subjects, the mean ratio of the NNH due to the than about 10:1, or less than about 9:1, or less than about 8:1, incidence of lightheadedness in naive healthy subjects after US 9,125,833 B2 57 58 administration of the tampered dosage form to the NNH after again questionnaire after administration of the tampered administration of the intact dosage form is less than 20:1. In dosage form to the mean ratio of the score on the “take again other embodiments of the invention, the mean ratio using the questionnaire after administration of the intact dosage form is aforementioned test method is less than about 18:1, or less less than 20:1. In other embodiments of the invention, the than about 16:1, or less than about 15:1, or less than about mean ratio using the aforementioned test method is less than 14:1, or less than about 12:1, or less than about 11:1, or less about 18:1, or less than about 16:1, or less than about 15:1, or than about 10:1, or less than about 9:1, or less than about 8:1, less than about 14:1, or less than about 12:1, or less than about or less than about 7:1, or less than about 6:1, or less than about 11:1, or less than about 10:1, or less than about 9:1, or less 5:1, or less than about 4:1, less than about 3:1, or less than than about 8:1, or less than about 7:1, or less than about 6:1, about 2.5:1, or less than about 2:1, less than about 1.75:1, or 10 or less than about 5:1, or less than about 4:1, less than about less than about 15:1, or less than about 1.25:1, or less than 3:1, or less than about 2.5:1, or less than about 2:1, less than about 1.1:1. Preferably, the aforementioned at NNH is mea about 1.75:1, or less than about 15:1, or less than about sured at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose. 1.25:1, or less than about 1.1:1. Preferably, the aforemen In certain preferred embodiments of the invention, upon tioned ratio is measured at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours administration of abusable drug to naive (i.e., abusable drug 15 post-dose. naive) healthy subjects, the mean ratio of the NNH due to the In certain preferred embodiments of the invention, upon incidence of dry mouth in naive healthy subjects after admin administration of abusable drug to drug abusers and recre istration of the tampered dosage form to the NNH after ational drug users, the mean ratio of the score on the “coast administration of the intact dosage form is less than 20:1. In ing questionnaire after administration of the tampered dos other embodiments of the invention, the mean ratio using the age form to the mean ratio of the score on the “coasting aforementioned test method is less than about 18:1, or less questionnaire after administration of the intact dosage form is than about 16:1, or less than about 15:1, or less than about less than 20:1. In other embodiments of the invention, the 14:1, or less than about 12:1, or less than about 11:1, or less mean ratio using the aforementioned test method is less than than about 10:1, or less than about 9:1, or less than about 8:1, about 18:1, or less than about 16:1, or less than about 15:1, or or less than about 7:1, or less than about 6:1, or less than about 25 less than about 14:1, or less than about 12:1, or less than about 5:1, or less than about 4:1, less than about 3:1, or less than 11:1, or less than about 10:1, or less than about 9:1, or less about 2.5:1, or less than about 2:1, less than about 1.75:1, or than about 8:1, or less than about 7:1, or less than about 6:1, less than about 15:1, or less than about 1.25:1, or less than or less than about 5:1, or less than about 4:1, less than about about 1.1:1. Preferably, the aforementioned at NNH is mea 3:1, or less than about 2.5:1, or less than about 2:1, less than sured at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose. 30 about 1.75:1, or less than about 15:1, or less than about In certain preferred embodiments of the invention, upon 1.25:1, or less than about 1.1:1. Preferably, the aforemen administration of abusable drug to drug abusers and recre tioned ratio is measured at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours ational drug users, the mean ratio of the drug liking score after post-dose. administration of the tampered dosage form to the mean ratio In certain preferred embodiments of the invention, wherein of the drug liking score after administration of the intact 35 the abusable drug is produces sedation or drowsiness on dosage form is less than 20:1. In other embodiments of the administration to naive (i.e., abusable drug naive) healthy invention, the mean ratio using the aforementioned test Subjects, the mean ratio of impairment on the "critical track method is less than about 18:1, or less than about 16:1, or less ing task driving skills test in naive healthy subjects after than about 15:1, or less than about 14:1, or less than about administration of the tampered dosage form to the impair 12:1, or less than about 11:1, or less than about 10:1, or less 40 ment after administration of the intact dosage form is less than than about 9:1, or less than about 8:1, or less than about 7:1, 20:1. In other embodiments of the invention, the mean ratio or less than about 6:1, or less than about 5:1, or less than about using the aforementioned test method is less than about 18:1, 4:1, less than about 3:1, or less than about 2.5:1, or less than or less than about 16:1, or less than about 15:1, or less than about 2:1, less than about 1.75:1, or less than about 15:1, or about 14:1, or less than about 12:1, or less than about 11:1, or less than about 1.25:1, or less than about 1.1:1. Preferably, the 45 less than about 10:1, or less than about 9:1, or less than about aforementioned ratio is measured at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 8:1, or less than about 7:1, or less than about 6:1, or less than hours post-dose about 5:1, or less than about 4:1, less than about 3:1, or less In certain preferred embodiments of the invention, upon thanabout 2.5:1, or less thanabout 2:1, less than about 1.75:1, administration of abusable drug to drug abusers and recre or less than about 15:1, or less than about 1.25:1, or less than ational drug users, the mean ratio of the drug effect score after 50 about 1.1:1. Preferably, the aforementioned ratio is measured administration of the tampered dosage form to the mean ratio at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose. of the drug effect score after administration of the intact In certain preferred embodiments of the invention, wherein dosage form is less than 20:1. In other embodiments of the the abusable drug is produces sedation or drowsiness on invention, the mean ratio using the aforementioned test administration to healthy Subjects who are naive to said abus method is less than about 18:1, or less than about 16:1, or less 55 able drug and who are occasional or light consumers of alco than about 15:1, or less than about 14:1, or less than about hol, the mean ratio of impairment on the “critical tracking 12:1, or less than about 11:1, or less than about 10:1, or less task driving skills test score in naive healthy subjects after than about 9:1, or less than about 8:1, or less than about 7:1, administration of the tampered dosage form to the impair or less than about 6:1, or less than about 5:1, or less than about ment after administration of the intact dosage form is less than 4:1, less than about 3:1, or less than about 2.5:1, or less than 60 20:1, said “critical tracking task driving skills test score about 2:1, less than about 1.75:1, or less than about 15:1, or measured 2.5 to 6 hours after administration of the dosage less than about 1.25:1, or less than about 1.1:1. Preferably, the form, said dosage form administration followed about 1.5 aforementioned ratio is measured at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours later by alcohol (ethanol) administration sufficient to hours post-dose. maintainablood alcohol concentration of 0.04% to 0.08%. In In certain preferred embodiments of the invention, upon 65 other embodiments of the invention, the mean ratio using the administration of abusable drug to drug abusers and recre aforementioned test method is less than about 18:1, or less ational drug users, the mean ratio of the score on the “take than about 16:1, or less than about 15:1, or less than about US 9,125,833 B2 59 60 14:1, or less than about 12:1, or less than about 11:1, or less In certain preferred embodiments of the invention, wherein than about 10:1, or less than about 9:1, or less than about 8:1, the abusable drug is produces sedation or drowsiness on or less than about 7:1, or less than about 6:1, or less than about administration to healthy Subjects who are naive to said abus 5:1, or less than about 4:1, less than about 3:1, or less than able drug and who are occasional or light consumers of alco about 2.5:1, or less than about 2:1, less than about 1.75:1, or hol, the mean ratio of impairment on the “Tower of London less than about 15:1, or less than about 1.25:1, or less than driving skills test score in naive healthy Subjects after admin about 1.1:1. istration of the tampered dosage form to the impairment after In certain preferred embodiments of the invention, wherein administration of the intact dosage form is less than 20:1 said the abusable drug is produces sedation or drowsiness on “Tower of London driving skills test score measured 2.5 to 6 administration to naive (i.e., abusable drug naive) healthy 10 hours after administration of the dosage form, said dosage Subjects, the mean ratio of impairment on the “stop signal form administration followed about 1.5 hours later by alcohol (ethanol) administration Sufficient to maintain a blood alco task driving skills test in naive healthy subjects after admin hol concentration of 0.04% to 0.08%. In other embodiments istration of the tampered dosage form to the impairment after of the invention, the mean ratio using the aforementioned test administration of the intact dosage form is less than 20:1. In 15 method is less than about 18:1, or less than about 16:1, or less other embodiments of the invention, the mean ratio using the than about 15:1, or less than about 14:1, or less than about aforementioned test method is less than about 18:1, or less 12:1, or less than about 11:1, or less than about 10:1, or less than about 16:1, or less than about 15:1, or less than about than about 9:1, or less than about 8:1, or less than about 7:1, 14:1, or less than about 12:1, or less than about 11:1, or less or less than about 6:1, or less thanabout 5:1, or less than about than about 10:1, or less than about 9:1, or less than about 8:1, 4:1, less than about 3:1, or less than about 2.5:1, or less than or less than about 7:1, or less than about 6:1, or less than about about 2:1, less than about 1.75:1, or less than about 15:1, or 5:1, or less than about 4:1, less than about 3:1, or less than less than about 1.25:1, or less than about 1.1:1. about 2.5:1, or less than about 2:1, less than about 1.75:1, or The invention is also directed to a method of treating or less than about 15:1, or less than about 1.25:1, or less than preventing diseases and disorders amenable to treatment with about 1.1:1. Preferably, the aforementioned ratio is measured 25 abusable drugs. The method can comprise providing an oral at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours post-dose. dosage form containing an abusable drug and ADER, said In certain preferred embodiments of the invention, wherein dosage form an immediate release formulation, an extended the abusable drug is produces sedation or drowsiness on release formulation or a formulation comprising both imme administration to healthy Subjects who are naive to said abus diate release and extended release. able drug and who are occasional or light consumers of alco 30 The oral dosage form containing an abusable drug in com hol, the mean ratio of impairment on the “stop signal task bination with ADER includes, but is not limited to tablets or driving skills test score in naive healthy subjects after admin capsules. The dosage forms of the present invention may istration of the tampered dosage form to the impairment after include any desired pharmaceutical excipients known to administration of the intact dosage form is less than 20:1, said those skilled in the art. The oral dosage forms may further “stop signal task driving skills test score measured 2.5 to 6 35 provide an immediate release of the abusable drug. In certain hours after administration of the dosage form, said dosage preferred embodiments, the oral dosage forms of the present form administration followed about 1.5 hours later by alcohol invention provide a Sustained release of the abusable drug (ethanol) administration Sufficient to maintain a blood alco contained therein. Oral dosage forms providing Sustained hol concentration of 0.04% to 0.08%. In other embodiments release of the abusable drug may be prepared in accordance of the invention, the mean ratio using the aforementioned test 40 with formulations/methods of manufacture known to those method is less than about 18:1, or less than about 16:1, or less skilled in the art of pharmaceutical formulation. than about 15:1, or less than about 14:1, or less than about In some particularly preferred embodiments, the dosage 12:1, or less than about 11:1, or less than about 10:1, or less form is capsule which is filled with the aid of heat as a liquid than about 9:1, or less than about 8:1, or less than about 7:1, and which upon cooling becomes a solid within said capsule. or less than about 6:1, or less than about 5:1, or less than about 45 The benefits of the abuse-resistant dosage form are espe 4:1, less than about 3:1, or less than about 2.5:1, or less than cially great in connection with oral dosage forms of potent about 2:1, less than about 1.75:1, or less than about 15:1, or abusable drug, which can provide valuable therapeutic ben less than about 1.25:1, or less than about 1.1:1. efits but are prone to being abused. This is particularly true for In certain preferred embodiments of the invention, wherein Sustained release abusable drug products which have a large the abusable drug is produces sedation or drowsiness on 50 dose of a desirable abusable drug intended to be released over administration to naive (i.e., abusable drug naive) healthy a period of time in each dosage unit. Drug abusers take Such subjects, the mean ratio of impairment on the “Tower of Sustained-release product and crush, grind, extract or other London' driving skills test score in naive healthy subjects wise damage the product so that the full contents of the after administration of the tampered dosage form to the dosage form become available for immediate absorption. impairment after administration of the intact dosage form is 55 Since Such tampering of the dosage form of the invention less than 20:1. In other embodiments of the invention, the results in the abusable drug also becoming available for mean ratio using the aforementioned test method is less than absorption, the present invention provides a means for deter about 18:1, or less than about 16:1, or less than about 15:1, or ring Such abuse. In addition, the present invention addresses less than about 14:1, or less than about 12:1, or less than about the risk of overdose to non-abusing patients from “dumping 11:1, or less than about 10:1, or less than about 9:1, or less 60 effect of the full dose of the abusable drug if the product is than about 8:1, or less than about 7:1, or less than about 6:1, accidentally chewed or crushed, co-ingested with a signifi or less than about 5:1, or less than about 4:1, less than about cant amount of alcohol or taken interchangeably in fasted and 3:1, or less than about 2.5:1, or less than about 2:1, less than fed states. about 1.75:1, or less than about 15:1, or less than about In certain preferred embodiments, a combination of two 1.25:1, or less than about 1.1:1. Preferably, the aforemen 65 abusable drug is included in the formulation with the ADER. tioned ratio is measured at 0.5, 1, 1.5, 2, 3, 4, 5 or 6 hours In further embodiments, one or more abusable drug and post-dose. ADER are included and a further non-abusable drug is also US 9,125,833 B2 61 62 included for the treatment of the same medical condition as The term “abuse”, “drug abuse”, “cannabinoid abuse'. the abusable drug or for the treatment of a different medical “stimulant abuse”, “benzodiazepine abuse', or “sedative condition. abuse', in the context of the present invention, when it refers Another embodiment of the invention is directed to a to the effects of abusable drug in causing such, includes method of preventing or treating pain, addiction disorders, intermittent use, recreational use and chronic use of abusable musculoskeletal disorders, and other medical maladies drugs alone or in conjunction with other drugs means use: (i) responsive to treatment with the abusable drugs with the in quantities or by methods and routes of administration that disclosed dosage forms. In certain preferred embodiments, do not conform to standard medical practice; (ii) outside the the method of treating the aforementioned disorders in Scope of specific instructions for use provided by a qualified patients with a dosage form having less abuse potential com 10 medical professional; (iii) outside the Supervision of a quali prises providing an oral dosage form containing an abusable fied medical professional; (iv) outside the approved instruc drug and ADER, and orally administering the dosage form to tions on proper use provided by the drugs legal manufac provide a plasma level of abusable drug greater than the turer, (v) which is not in specifically approved dosage forms minimum therapeutic or minimum effective concentration of for medical use as pharmaceutical agents; (vi) where there is the abusable drug. 15 an intense desire for and efforts to procure same; (vii) com The invention is also directed to methods of preparing the pulsive use; (viii) through acquisition by manipulation of the dosage forms disclosed herein. medical system, including falsification of medical history, The benefits of the abuse-resistant dosage form are espe symptom intensity, disease severity, patient identity, doctor cially greatin connection potent abusable drugs, which would shopping, prescription forgeries; (ix) where there is impaired provide valuable therapeutic benefits but would be prone to control over use; (X) despite harm; (xi) by procurement from being abused. This is particularly true for oral dosage forms, non-medical sources; (xii) by others through sale or diversion including, in Some preferred embodiments, Sustained release by the individual into the non-medical supply chain; (xiii) for dosage forms of abusable drugs which would have a large medically unapproved or unintended mood altering purposes. dose of a desirable drug intended to be released over a period The term “mood altering is defined for purposes of the of time in each dosage unit. Drug abusers may tamper the 25 present invention to mean that the “high”, “liking, pleasur dosage form of the invention so that the full contents of the able, euphoric, alerting, calming, anxiolytic, auditory and dosage form become available for immediate and maximal visual perceptual alterations, relaxing, psychotomimetic, mood altering effects. The dosage form of the present inven rewarding, reinforcing and toxic effects of the abusable drug. tion would reduce the mood altering effects of the abusable The term “abuse resistant”, “abuse deterrent”, “tamper drugs upon tampering and as Such the invention provides 30 resistant”, “deter abuse' and “deter abuse' (as well of the pharmaceutical compositions, dosage forms and methods of words “resist” or “deter' when applied to abusable drugs of deterring misuse, abuse, tampering and diversion of the dos the invention) are used interchangeably in the context of the age form. present invention and include pharmaceutical compositions In some embodiments of the invention, when the dosage and methods that resist, deter, discourage, diminish, delay form of the invention is tampered, the amount of abusable 35 and/or frustrate: (i) the intentional, unintentional or acciden drug released in immediate release form is reduced, which in tal physical or chemical manipulation or tampering of the turn reduces the euphoric, pleasurable, reinforcing, reward dosage form (e.g., crushing, shearing, grinding, chewing. ing, mood altering and toxic effects of the abusable drugs of dissolving, melting, needle aspiration, inhalation, insuffla the dosage form. tion, extraction by mechanical, thermal and chemical means, When the dosage form of the present invention is orally 40 and/or filtration); (ii) the intentional, unintentional or acci administered as intended to humans, the abusable drugs is dental use or misuse of the dosage form outside the scope of released into systemic circulation as intended and is therefore specific instructions for use provided by a qualified medical available for absorption into the body. However, if the dosage professional, outside the Supervision of a qualified medical forms of the present invention is tampered (e.g., chemical, professional and outside the approved instructions on proper solvent, thermal or mechanical extraction, followed by 45 use provided by the drug's legal manufacturer (e.g., intrave administration into the body) the ADER of the invention nous use, intranasal use, inhalational use and oral ingestion to would reduce the amount of abusable drugs available in provide high peak concentrations); (iii) the intentional, unin immediate release form. Additionally, the dosage form of the tentional or accidental conversion of an extended release invention Substantially reduces the efficiency of drug aspira dosage form of the invention into a more immediate release tion into Syringes, drug filtration after Solvent extraction and 50 form; (iv) the intentional and iatrogenic increase in physical drug extraction after attempts at chemical, mechanical or and psychic effects sought by recreational drug users, addicts, thermal extraction from both immediate and sustained release and patients with pain who have an addiction disorder, (v) dosage form of the invention. These characteristic decrease attempts at Surreptitious administration of the dosage form to the potential for abuse or diversion of the abusable drugs in a third party (e.g., in a beverage); (vi) attempts to procure the the dosage form by blocking the mood altering, euphoric, 55 dosage form by manipulation of the medical system and from pleasurable, reinforcing, rewarding or toxic effects of the non-medical sources; (vii) the sale or diversion of the dosage abusable drug. form into the non-medical Supply chain and for medically The term “tampering or “tamper” means any manipula unapproved or unintended mood altering purposes; (viii) the tion by mechanical, thermal and/or chemical means which intentional, unintentional or accidental attempts at otherwise changes the physical or chemical properties of the dosage 60 changing the physical, pharmaceutical, pharmacological and/ form, e.g., to liberate the abusable drugs for immediate or medical properties of the dosage form from what was release if it is in Sustained release form, or to make the intended by the manufacturer. abusable drugs available for inappropriate use Such as admin As used herein, the term “aversive agents”, “aversion pro istration by an alternate route, e.g., parenterally. The tamper ducing agents' and 'aversive compounds’ means to com ing can be, e.g., by means of crushing, shearing, grinding. 65 pounds contained within the dosage form that produce an mechanical extraction, Solvent extraction, solvent immer aversive, undesirable, repugnant, distasteful, unpleasant, Sion, combustion, heating or any combination thereof. unacceptable physiologic or unacceptable psychic effects, or US 9,125,833 B2 63 64 that pharmacologically block or reduce one or more of the composition of the invention”, “the dosage form of the inven following effects: mood alterations; euphoria, pleasure; a tion', “the current invention' and embodiments of the inven feeling of high; a feeling of drug liking; anxiolysis; mental tion in the embodiments, claims and specifications refer to stimulation; increased mental arousal; sedation; calmness; a pharmaceutical compositions, dosage forms, methods, pro state of relaxation; psychotomimesis; hallucinations; alter- 5 cesses and other innovations that comprise (i) one or more ations in perception, cognition and mental focus; insomnia; abusable drugs, in unsalified form or their pharmaceutically hypersomnia; increased wakefulness or alertness; memory acceptable salts, prodrugs, esters, analogs, derivatives, Sol improvement; increased sexual gratification; increased Vates, complexes, polymorphs, hydrates and metabolites, as sexual arousal; increased sexual desire and sexual anticipa racemates or an individual diastereoisomers or enantiomeric tion; increased socialization; reduced social anxiety; psycho- 10 isomers thereof or mixtures thereof; (ii) one or more com logically reinforcement; and psychologically rewarding. pounds selected from the group consisting of: (a) hydroge In some embodiments, the intention of the aversive agentis nated Type I or Type II vegetable oils; (b) polyoxyethylene deter or further deter the misuse, abuse, tampering or diver Stearates and distearates; (c) glycerol monostearate; (d) sion of the drug for use by addicts, drug abusers and recre poorly water soluble, high melting point (mp=45 to 100°C.) ational drug users. Preferably the aversive agent produces 15 waxes, and mixtures thereof, said compounds also referred to aversive effects only when the dosage form of the abusable as ADER; and optionally (iii) and/or (iv), (iii) other abus drug of the invention is abused. Preferably the aversive agent able or non-abusable drugs for the treatment of the same or a is contained within the dosage format a dose or in a form that different medical condition; and/or (iv) pharmaceutical does not produce aversive effects when the dosage form of the excipients, adjuvants and auxiliary agents including binders, abusable drug of the invention is taken as medically directed 20 disintegrants, fillers, diluents, anti-adherents or glidants, or in a manner that is consistent with the manufacturers lubricants, stabilizers, wetting agents, pharmaceutically com prescribing information, but which when abused or tampered patible carriers and dissolution rate modifiers, and channel with, produces an aversive effect. For example, in some and pore formers. embodiments, the dosage form of the abusable drug of the In some preferred embodiments, references to the term invention contains one or more aversive agents in a non- 25 “the invention”, “the present invention”, “the pharmaceutical releasable form (i.e., sequestered) form, said aversive agent composition of the invention”, “the dosage form of the inven partially or Substantially released upon tampering the dosage tion', “the current invention' and embodiments of the inven form (e.g., mechanical, thermal, chemical, solvent tamper tion in the embodiments, claims and specifications refer to ing, ingestion in ways not recommended, and the like). For pharmaceutical compositions, dosage forms, methods, pro example, in Some other embodiments, the dosage form of the 30 cesses and other innovations that comprise (i) one or more abusable drug of the invention contains one or more aversive abusable drugs, in unsalified form or their pharmaceutically agents in releasable or partially releasable form, said dosage acceptable salts, prodrugs, esters, analogs, derivatives, sol form not aversive when taken at medically approved doses or Vates, complexes, polymorphs, hydrates and metabolites, as at doses consistent with the manufacturers prescribing infor racemates or an individual diastereoisomers or enantiomeric mation, said dosage form producing an aversive effect when 35 isomers thereof or mixtures thereof; (ii) two or more com taken in excess of medically approved doses or the manufac pounds selected from the group consisting of: (a) hydroge turers prescribing information. For example, in yet other nated Type I or Type II vegetable oils; (b) polyoxyethylene embodiments, the dosage form of the abusable drug of the Stearates and distearates; (c) glycerol monostearate; (d) invention contains one or more aversive agents in a non poorly water soluble, high melting point (mp=45 to 100°C.) releasable form (i.e., sequestered) form, said aversive agent 40 waxes, and mixtures thereof, said compounds also referred to partially or Substantially released upon tampering the dosage as ADER; and optionally (iii) and/or (iv), (iii) other abus form (e.g., mechanical, thermal, chemical, solvent tamper able or non-abusable drugs for the treatment of the same or a ing, ingestion in ways not recommended, and the like), and different medical condition; and/or (iv) pharmaceutical said aversive agent pharmacologically blocking the effects of excipients, adjuvants and auxiliary agents including binders, the abusable drug and/or the effects of a co-abused drug, said 45 disintegrants, fillers, diluents, anti-adherents or glidants, co-abused drug not part of the dosage form of the invention. lubricants, stabilizers, wetting agents, pharmaceutically com As used herein, the term “ADER. “ADER material' and patible carriers and dissolution rate modifiers, and channel “ADER agent” refers to one or more compounds selected and pore formers. from the group consisting of: (a) hydrogenated Type I or Type In some preferred embodiments, the dosage form may II vegetable oils; (b) polyoxyethylene stearates and distear- 50 optionally also contain hydrophobic polymers, hydrophilic ates; (c) glycerol monostearate; (d) poorly water soluble, high polymers, gums, protein derived materials, other waxes, shel melting point (mp=45 to 100° C.) waxes, and mixtures lac, other oils and mixtures thereof. thereof. In some preferred embodiments, ADER is a mixture In some preferred embodiments, the invention is directed at of two or more compounds from the forgoing group i.e., (a) an abusable drug dosage form, said dosage form having flo to (d). In some preferred embodiments, to qualify as an 55 tation capabilities to deter Surreptitious attempts at intoxica “ADER requires a mixture of two or more compounds from tion of another subject (e.g., in an alcoholic or non-alcoholic the form the foregoing group i.e., (a) to (d). In some par beverage). ticularly preferred embodiments, to qualify as an “ADER In some preferred embodiments, the invention is directed at requires a mixture of two or more compounds selected from an abusable drug dosage form, said dosage form having flo at least two categories i.e., (a) to (d). 60 tation capabilities to deter Surreptitious attempts at intoxica As used herein, the term “ADER. “ADER material' and tion of another subject (e.g., in an alcoholic or non-alcoholic “ADER agent” also includes glyceryl behenate (e.g., Comp beverage), said dosage form staying Substantially afloat (i.e., tirolTM 888 ATO), glyceryl palmitostearate (e.g., PrecirolTM floatable or buoyant) on a liquid surface for at least about 3 ATO 5), stearoyl macrogolglycerides (GelucireTM 50/13), minutes. In other preferred embodiments, said dosage form lauroyl macrogolglycerides (LabrafiltMM 2130 CS). 65 stays substantially afloat for at least about 5 minutes, or at In some preferred embodiments, references to the term least about 7 minutes, or at least about 10 minutes, or at least “the invention”, “the present invention”, “the pharmaceutical about 15 minutes, or at least about 20 minutes, or at least US 9,125,833 B2 65 66 about 25 minutes, or at least about 30 minutes, or at least Also disclosed are methods of providing relief in a human about 40 minutes, or at least about 50 minutes, or at least patient Suffering from acute pain comprising a therapeuti about 60 minutes, or at least about 90 minutes, or at least cally effective amount of oral abusable drug which possesses about 120 minutes, or at least about 150 minutes, or at least analgesic properties or pharmaceutically acceptable salts about 180 minutes, or at least about 210 minutes, or at least thereof or mixtures thereof. about 240 minutes, or at least about 270 minutes, or at least All kinds of kits of the present invention are contemplated. about 300 minutes, or at least about 330 minutes, or at least In some preferred embodiments, also provided are kits for about 360 minutes, or at least about 400 minutes. use in treating or preventing the pain with the oral adminis In some preferred embodiments, the invention is directed at tration of an abusable drug or pharmaceutically acceptable an abusable drug dosage form, said dosage form having a 10 salts thereof or mixtures thereof for a subject in need of such non-toxic dye to deter Surreptitious attempts at intoxication of treatment, comprising: (i) a dosage form of the invention; (ii) another subject (e.g., in an alcoholic or non-alcoholic bever a container for the dosage form; and optionally, any of (iii) to age). (vi): (iii) a container for individual units of the dosage form In some preferred embodiments, the invention is directed at (e.g., individual tablets or capsules in blisters); (iv) educa an abusable drug dosage form, said dosage form having a 15 tional instructions in any media about various medical con non-toxic bittering agent to deter Surreptitious attempts at ditions, including without limitation, pain, neurologic disor intoxication of another Subject (e.g., in an alcoholic or non ders and psychiatric disorders, their etiology, alcoholic beverage). pathophysiology, consequences and treatment, including In some preferred embodiments, the invention is directed at information on the potential for abuse and diversion and an abusable drug dosage form, said dosage form having a methods for prevention of same and information on the non-toxic bittering agent to deter oral or nasal ingestion of the proper use and disposal of the medication; (V) containers or dosage form. bags for the safe disposal of any used or remaining unused In some preferred embodiments, the in Vivo pharmacoki dosage form, preferably childproof and flushable; (vi) tamper netic parameters of the specifications and claims are derived evident and child proofpackaging for the kit and its contents. or determined from first administration. In other preferred 25 The amount of abusable drug in the oral dosage form will embodiments, the in vivo pharmacokinetic parameters are vary depending on variety of physiologic, pharmacologic, derived or determined from steady state administration. pharmacokinetic, pharmaceutical and physicochemical fac In some preferred embodiments, the in Vivo pharmacoki tors, including: (i) the choice of abusable drug as the unsali netic parameters of the specifications and claims are derived fied form, pharmaceutically acceptable salt or mixtures or determined under fed conditions. In other preferred 30 therof (ii) the nature of the oral dosage form (e.g., immediate embodiments, the in vivo pharmacokinetic parameters are release or extended release); (iii) the intensity and intracta derived or determined under fasted conditions. bility of the medical condition; (iv) the absorption, metabo In some preferred embodiments, the in Vivo pharmacoki lism, distribution and excretion of orally administered abus netic parameters of the specifications and claims are derived able drug in healthy Subjects and in patients with various or determined from an individual subject. In other preferred 35 diseases and disorders, including renal and hepatic impair embodiments, the in vivo pharmacokinetic parameters are ment, (v) the presence of comorbid pathology; (vi) the derived or determined from a population of subjects. patient’s risk of iatrogenic side effects; (vii) the tolerability of In some preferred embodiments, the in Vivo pharmacoki the dose, including the patient’s propensity for abusable drug netic parameters of the specifications and claims are derived associated side effects; (viii) use of other drugs to treat the or determined in subjects having a Body Mass Index (BMI) 40 same medical condition; (ix) the efficiency of the dosage between 18 and 26 kg/m, inclusive (BMI=|weight in form; (x) the physicochemical properties of the abusable kg/height in mix10,000). In some preferred embodiments, drug, including its solubility and hydrophilicity. the in vivo pharmacokinetic parameters of the specifications The invention is also directed to methods of preparing the and claims are derived or determined in Subjects having a dosage forms disclosed herein. Body Mass Index (BMI)>38 kg/m. 45 In certain preferred embodiments, the abusable drug in the Also disclosed are methods for preventing and treating in dosage form is combined with one or more other drugs for the pain, addiction disorders, musculoskeletal disorders, neuro treatment of the same medical condition as the abusable drug logic disorders, and other medical maladies responsive to or for the treatment of a different medical condition. All treatment with the abusable drugs in a human patient Suffer modes of co-administration are contemplated, including via ing from same, comprising atherapeutically effective amount 50 an oral, Subcutaneous, direct intravenous, slow intravenous of oral abusable drugs or pharmaceutically acceptable salts infusion, continuous intravenous infusion, intravenous or epi thereof or mixtures thereof. dural patient controlled analgesia (PCA and PCEA), intra All pain states are contemplated by this invention, regard muscular, intrathecal, epidural, intracisternal, intramuscular, less of etiology, mechanisms, duration, prior treatment intraperitoneal, transdermal, topical, transmucosal, buccal, response and anatomic location, including acute pain, inflam 55 Sublingual, transmucosal, inhalation, intranasal, epidural, matory pain, chronic pain, cancer pain, visceral pain and intra-atricular, intranasal, rectal or ocular routes. neuropathic pain. The term “first administration' means administration of a Also disclosed are methods of providing relief in a human dose of the present invention at the initiation of therapy to an patient Suffering from neuropathic and chronic pain compris individual patient or a patient population. ing a therapeutically effective amount of oral abusable drug 60 The term “steady state' means that the amount of the drug which possesses analgesic properties or pharmaceutically reaching the system is approximately the same as the amount acceptable salts thereof or mixtures thereof. In some pre of the drug leaving the system. Thus, at 'steady-state', the ferred embodiments, the dosage form of the invention is patient’s body eliminates the drug at approximately the same intended for the treatment of neuropathic pain, peripheral rate that the drug becomes available to the patient’s system neuropathic pain, central neuropathic pain, chronic pain, 65 through absorption into the blood stream. osteoarthritis, back pain, cancer pain, fibromyalgia, and As used herein the terms: (i) “AUC” means area under chronic inflammatory pain. the plasma drug concentration-time curve from time Zero to US 9,125,833 B2 67 68 the “t', where t is the time point of the maximum intended In certain preferred embodiments of the present invention, dosing frequency of the dosage form (e.g., 4 hours, 6 hours, 8 an effective amount of abusable drug in immediate release hours, 12 hours or 24 hours for dosage forms intended to be form is included in the controlled release unit dose abusable administered every 4 hours, every 6 hours, every 8 hours, drug formulation to be administered. The immediate release every 12 hours and every 24 hours, respectively, thereby form of the abusable drug is preferably included in an amount providing an AUC time interval of 0 to 4 hours, 0 to 6 hours, which is effective to shorten the time to C or increase the 0 to 8 hours, 0 to 12 hours and 0 to 24 hours, respectively); (ii) magnitude of the C of the abusable drug in the blood (e.g., “AUC” means area under the plasma drug concentration plasma). In Such embodiments, an effective amount of the time curve from time Zero to infinity; (iii) “AUC” means abusable drug in immediate release form may be coated onto area under the plasma drug concentration-time curve from 10 the substrates of the present invention. For example, where time Zero to 8 hours after dosing; (iv) “AUC” means area the extended release abusable drug from the formulation is under the plasma drug concentration-time curve from time due to a controlled release coating, the immediate release Zero to 12 hours after dosing; (V) “AUC” means area under layer would be overcoated on top of the controlled release the plasma drug concentration-time curve from time Zero to 15 coating. On the other hand, the immediate release layer may 24 hours after dosing; (vi) “C” means the maximum be coated onto the surface of substrates wherein the abusable observed plasma drug concentration; (vii) “Cs” means the drug is incorporated in a controlled release matrix. Where a plasma drug concentration at 8 hours after dosing; (viii) plurality of the Sustained release Substrates comprising an 'C' means the plasma drug concentration at 12 hours after effective unit dose of the abusable drug are incorporated into dosing; (ix)'C' means the plasma drug concentration at 24 a hard gelatin capsule, the immediate release portion of the hours after dosing: (X) “t or “T” means the time of the abusable drug dose may be incorporated into the gelatin cap observed maximum drug concentration (also known as the sule via inclusion of the sufficient amount of immediate time at which C occurs); (xi) “C., means the minimum release abusable drug as a powder or granulate within the observed drug concentration following the maximum plasma capsule. Alternatively, the gelatin capsule itself may be concentration or the concentration at the end of the intended 25 coated with an immediate release layer of the abusable drug. dosing interval; (xii) “time at which C, occurs' means the In some other embodiments, the immediate release abusable time at when the minimum observed drug concentration drug is in liquid form, for example as a capsule within a occurs; (xiii) “half value duration' or “HVD' means the capsule or as a liquid in contact with an extended release duration over the dosing interval during which plasma con dosage form within a capsule. One skilled in the art would centration of drug are greater than or equal to one-half of 30 recognize still other alternative manners of incorporating the C, obtained by calculating the time interval beginning immediate release abusable drug into the unit dose. Such when the interpolated concentration first equals or exceeds alternatives are deemed to be encompassed by the appended one-half of C and ending at the first time point for which claims. By including such an effective amount of immediate the interpolated concentration falls below one-half of C: release abusable drug in the unit dose, they may experience of (xiv). “Ws” means the duration of the dosing interval over 35 relatively higher levels of symptom relief or faster symptom which the plasma concentrations are equal to or greater than relief. 50% of the peak concentration; (XV) “steady state' is a state of In certain preferred embodiments, any one or all of the equilibrium wherein the amount of the drug reaching the above in-vivo parameters are achieved after a first adminis system is approximately the same as the amount of the drug tration (often referred to as “single dose administration') of leaving the system or put another way, the patient’s body 40 the dosage form to a human patient or a population of human eliminates the drug at approximately the same rate that the patients. drug becomes available to the patient’s system through In certain alternative embodiments, any one or all of the absorption into the blood stream, said “time to steady state' above in-vivo parameters are achieved after steady state measured by calculating the C, after each sequential dosing administration of the dosage form to a human patient or a of drug administered at the intended dosing frequency until 45 population of human patients. two consecutive C's are not statistically different at a 10% Perceptible Pain Relief, Confirmed Perceptible Pain Relief significance level (p=0.10); (xvi) “‘percent fluctuation” means and Meaningful Pain Relief are assessed and defined as fol the variation in plasma concentrations of the drug computed lows: At the time of dosing with the study medication, a as: (a) (C-C)/CX100 (for an individual patient) and trained member of study staff starts two stopwatches for each (mean C-mean C)/mean CX100 (for a population); 50 patient. The patient is instructed to stop the first stopwatch at or (b) (C-C)/CX100 (for an individual patient) and the time of perceptible pain relief and the second stopwatch at (mean C-mean C)/mean Cx100 (for a population); the time when they first experience meaningful pain relief. (xvii) “accumulation index' or AI means the ratio of the The usual definitions of the perceptible and meaningful pain plasma concentration of the drug at the end of the intended relief are as follows: Perceptible Pain Relief is when the dosing interval (i.e., 8 hours for a Q8H dosage form, 12 hours 55 patient begins to feel any pain relieving effect from the drug. for a Q12H dosage form, and 24 hours for a Q24H dosage The patient is typically instructed as follows: “I would like form) after administration, determined at steady-state you to stop the first stopwatch when you first feel any pain (C) to the plasma concentration of the drug at the end of relief whatsoever. This does not mean you feel completely the intended dosing interval determined at first administration better, although you might, but when you first feel any differ (i.e., after the first dose). 60 ence in the pain that you have had. Meaningful Pain Relief is Pharmacokinetic parameters of the invention are be com when the patient feels their pain relief is meaningful to them. puted from first administration and steady state pharmacoki The patient is typically instructed as follows: “I would like netic studies conducted in an individual Subject or in a popu you to stop the second stopwatch when you have meaningful lation of subjects in the fasted or fed states. The AI and pain relief. That is, when the relief from the pain is meaning percent of steady state computations requires both single dose 65 ful to you”. Confirmed Perceptible Pain Relief is Perceptible (i.e., first administration) and steady state pharmacokinetic Pain Relief in those patients who go on to also have Mean aSSeSSment. ingful Pain Relief. US 9,125,833 B2 69 70 As used herein, “NNT’ or “the number needed to treat is tory tracking task. The error is displayed as a horizontal the number of patients who need to be treated in order for one deviation of a cursor from the midpoint on a horizontal, linear patient to obtain a 50% reduction in signs or symptoms (e.g., scale. Compensatory joystick movements correct the error by >50% reduction in pain intensity score). returning the cursor to the midpoint. The frequency at which The “NNH or “number needed to harm is a measure that the patient loses the control is the critical frequency. The indicates how many patients would require a specific treat critical tracking task measures the psychomotor control dur ment to cause harm in one patient. As used herein, the “NNH ing a closed loop operation. It is a laboratory analog to on-the or “number needed to harm' is a measure that includes: (i) road tracking performance. how many abusable drug naive healthy subjects would The “stop signal task” measures motor impulsivity, which require treatment to cause moderate or severe sedation (or 10 drowsiness) in one subject, where moderate to severe seda is defined as the inability to inhibit an activated or pre-cued tion or drowsiness is defined as a VAS score of>50 mm on a response leading to errors of commission. The task requires 100 mm scale bounded on the left by “no sedation or drowsi patients to make quick key responses to visual go signals, i.e. ness” and on the right by “extreme sedation or drowsiness'; the letters ABCD presented one at a time in the middle of the (ii) how many abusable drug naive healthy subjects would 15 screen, and to inhibit any response when a visual stop signal, require treatment to cause moderate or severe nausea in one i.e. “*” in one of the four corners of the screen, is presented at subject, where moderate to severe nausea is defined as a VAS predefined delays. The main dependent variable is the stop score of>50 mm on a 100 mm scale bounded on the left by reaction time on stop signal trials that represents the esti “no nausea and on the right by “extreme nausea; (iii) how mated mean time required to inhibit a response. many abusable drug naive healthy Subjects would require The Tower of London (TOL) is a decision-making task that treatment to cause dizziness in one Subject, where dizziness is measures executive function and planning. The task consists defined as unsteadiness, imbalance, lightheadedness, spin of computer generated images of begin- and end-arrange ning sensation or sensation that one is falling; (iv) how many ments of three colored balls on three sticks. The subject's task abusable drug naive healthy Subjects would require treatment is to determine as quickly as possible, whether the end-ar to cause a sensation of dry mouth in one Subject, where dry 25 rangement can be accomplished by “moving the balls in two mouth is defined as abnormal dryness of the mouth associated to five steps from the beginning arrangement by pushing the with decreased secretion of saliva. corresponding number coded button. The total number of The "drug effects’ questionnaire assesses the extent to correct decisions is the main performance measure. which subjects currently felt a drug effect, on a scale of 1 to 5 For the purposes of in vivo testing, unless specified other (1=“I feel no effect from it at all': 2="I think I feel a mild 30 wise, pain intensity is measured on a VAS or categorical scale. effect, but I'm not sure': 3="I feel an effect, but it is not real strong’: 4="I feel a strong effect”; 5="I feel a very strong On the categorical scale, the patient is asked “My pain at this effect”). This questionnaire can be used to examine the over time is: None=0, Mild=1, Moderate=2, Severe=3. On the all drug effects of abusable drugs given intact and upon tam VAS, the patient is asked “My pain at this time is” (with VAS pering, preferably in drug abusers and recreational drug users 35 anchors: “No Pain” and “Extreme Pain'). without the medical condition for which the drug is effective. For the purposes of in vivo testing, unless specified other The "drug liking' questionnaire assesses the extent to wise, pain relief is measured on a categorical scale. The which subjects currently like the effects of the drug on a patient is asked “My relief from starting pain is: None=0. A 100-mm VAS, bounded on the left by “0-dislike a lot', little=1, Some=2. A lot=3, Complete=4. bounded on the right by “100-like a lot. This questionnaire 40 In certain preferred embodiments, the amount of abusable can be used to examine the overall drug liking of abusable drug in the dosage form is about 0.01 ug to 1500 mg. In other drugs given intact and upon tampering, preferably in drug more preferred embodiments, the amount of abusable drug in abusers and recreational drug users without the medical con the dosage form is about 0.1 g to 1000 mg or about 0.1 ug to dition for which the drug is effective. 1500 mg. In most preferred embodiments, the amount of The “take again questionnaire assesses whether Subjects 45 abusable drug in the dosage form is about 0.01 ug to 750 mg. would take the abusable drug again if given the opportunity. or about 0.01 g to about 500 mg. or about 0.01 ug to about The patient is asked “If given an opportunity, would you take 250 mg. or about 0.1 ug to about 500 mg, or 0.1 ug to about this drug again? (circle one: YES or NO). This questionnaire 250, or about 0.1 ug to about 250 mg. or about 1 lug to about can be used to examine the overall desirability of the drug 1500 mg. or 1 ug to about 1000 mg. or about 1 lug to about 100 experience with the abusable drugs taken intact and taken 50 mg, or about 5ug to about 1500 mg, or about 5 ug to about after tampering, preferably in drug abusers and recreational 1000 mg. or about 5ug to about 500 mg. or about 10 ug to drug users without the medical condition for which the drug about 1000 mg, or about 10 ug to about 500 mg. or about 100 is effective. ug to about 1000 mg. or about 1 mg to about 1500 mg. or On the "coasting questionnaire the patient is asked to put about 1 mg to about 1000 mg, or about 1 mg ug to about 800 a mark on a horizontal line that best describes their response 55 mg, or about 1 mg to about 500 mg. to the question: "Do you feel like you are coasting or spaced In certain embodiments, the amount of ADER in the out? The horizontal line is a visual analog scale (VAS) claimed composition may be about 1 mg to 1500 mg. In a bounded on the left by “not at all and on the right by preferred embodiment, the amount of ADER in the claimed “extremely'. This questionnaire can be used to examine the composition may be about 10 mg to 800 mg. In a most degree to which subjects feel like they are coasting or spaced 60 preferred embodiment, the amount of ADER in the claimed out with the abusable drugs taken intact and taken after tam composition may be about 50 mg to 600 mg. pering, preferably in drug abusers and recreational drug users In certain preferred embodiments of the present invention, without the medical condition for which the drug is effective. the ratio of the abusable drug and the ADER is about 1:10,000 Three performance tasks may be employed for measuring to about 10,000:1 by weight, preferably about 1:1000 to about skills related to driving. 65 1000:1 by weight, more preferably 1:250 to 250:1. The “critical tracking task” measures the patients ability The term “USP Basket and Paddle Methods is the Basket to control a displayed error signal in a first-order compensa and Paddle Method described, e.g., in specified in the United US 9,125,833 B2 71 72 States Pharmacopeia, USP-28 NF-23 (2005), published by orally or a solution of abusable drug or a salt thereof may be the United States Pharmacopeial Convention, Inc, and herein prepared for the purpose of in vivo testing requiring immedi incorporated by reference. ate release abusable drug. The term “pH-dependent' for purposes of the present For purposes of the invention, the controlled release for invention is defined as having characteristics (e.g., dissolu mulations disclosed herein and the immediate release control tion) which vary according to environmental pH. formulations are dose proportional. In such formulations, the The term “pH-independent' for purposes of the present pharmacokinetic parameters (e.g., AUC and C) increase invention is defined as having characteristics (e.g., dissolu linearly from one dosage strength to another. Therefore the tion) which are substantially unaffected by pH. pharmacokinetic parameters of a particular dose can be The term “bioavailability” is defined for purposes of the 10 inferred from the parameters of a different dose of the same present invention as the rate and extent to which the drug (e.g., formulation. the abusable drug) is absorbed from the unit dosage forms. The phrase “cardinal sign or symptom' and "cardinal sign As used herein with respect to the abusable drug dosage or symptom of said medical condition' when referring to the forms of the invention, the term “oral”, “oral dosage form'. use of the abusable drug of the present invention means the "oral pharmaceutical dosage form”, “oral administration'. 15 major sign or symptom of the medical condition for which the and "oral route', refer to any method of administration abusable drug is approved or commonly used, said sign or involving contact with the mouth and oral mucosa, including symptom commonly used as the primary endpoint in clinical the ingestion of intact drugs (e.g., capsules, tablets, liquids trials published in peer-review journals and for approval of Swallowed whole), lingual, Sublingual administration, buccal the drug by the U.S. FDA and other major drug regulatory administration and transmucosal administration. Particularly authorities (e.g., the EMEA). preferred embodiments involve oral ingestion of intact drugs The term "agonist’ means a ligand that binds to a receptor (e.g., capsules, tablets, liquids Swallowed whole). and alters the receptor state resulting in a biological response. All oral pharmaceutical dosage forms of the invention are Conventional agonists increase receptor activity, whereas contemplated, including oral Suspensions, tablets, capsules, inverse agonists reduce it (See Neubig et al., IUPHAR Com lozenges, effervescent tablets, effervescent powders, pow 25 mittee on Receptor Nomenclature and Classification, Phar ders, Solutions, powders for reconstitution, transmucosal macol Rev, 2003: Howlett et al., Mol Pharmacol, 1988). films, buccal products, oral mucoretentive products, oral gas The term “opioid agonist’ means a molecule that causes a troretentive tablets and capsules, orally disintegrating tablets, specific physiologic, pathophysiologic or pharmacologic fast dissolving tablets, fast dispersing tablets, fast disintegrat effect after binding to an opioid receptor. ing dosage forms, administered as immediate release, 30 An “antagonist’ is a drug or ligand that reduces the action delayed release, modified release, enteric coated, Sustained of another drug or ligand, generally an agonist. Many antago release, controlled release, pulsatile release and extended nists act at the same receptor macromolecule as the agonist. release dosage form. (See Neubig et al., IUPHAR Committee on Receptor Nomen As used herein, “controlled release' is interchangeable clature and Classification, Pharmacol Rev, 2003: Howlett et with “extended release”, “sustained release”, “modified 35 al., Mol Pharmacol, 1988). release”, “delayed release' and the like. Such products pro The term “receptor” means a molecule within a cell, on a vide a longer duration of action than conventional immediate cell Surface, on a membrane, in tissue, in fluid or otherwise release formulations of the same drugs and are usually admin found in humans that serve as a recognition or binding site to istered every 8, 12 or 24 hours. cause specific physiologic, pathophysiologic or pharmaco Controlled release dosage forms of the present invention 40 logic effects. The term “receptor also means a cellular mac release abusable drug from the oral dosage format slower rate romolecule, or an assembly of macromolecules, that is con than immediate release formulations. In some preferred cerned directly and specifically in chemical signaling embodiments, controlled release dosage forms release abus between and within cells. Combination of a hormone, neu able drug at Such a rate that blood (e.g., plasma) concentra rotransmitter, drug, ligand, or intracellular messenger with its tions (levels) or therapeutic effects are maintained within the 45 receptor(s) initiates a change in cell function (Neubig et al. therapeutic range (above the minimum effective therapeutic IUPHAR Committee on Receptor Nomenclature and Classi concentration) but below toxic levels for intended duration fication, Pharmacol Rev. 2003). (e.g., over a period of 1 to 24 hours, preferably over a period The term “abuse”, “drug abuse”, “opioid abuse”, “opioid of time indicative of Q4, Q6, Q8, Q12 or Q24H administra agonist abuse”, “narcotic abuse', in the context of the present tion). Notwithstanding the foregoing, in Some preferred 50 invention includes intermittent use, recreational use and embodiments, the controlled release formulations of the chronic use of abusable drugs alone or in conjunction with present invention provide therapeutic effects for a duration other drugs: (i) in quantities or by methods and routes of that is longer or Substantially longer than the duration of administration that do not conform to standard medical prac meaningful or detectable plasma concentrations of abusable tice; (ii) outside the scope of specific instructions for use drug. Controlled release dosage forms may be administered 55 provided by a qualified medical professional; (iii) outside the around the clock on a scheduled or time contingent basis, or Supervision of a qualified medical professional; (iv) outside on an as needed or PRN basis, e.g., Q3 PRN, Q4 PRN, Q6 the approved instructions on proper use provided by the PRN, Q8 PRN, Q12 PRN or Q24H PRN administration. drug's legal manufacturer, (v) which is not in specifically The term “immediate release abusable drug for purposes approved dosage forms for medical use as pharmaceutical of the present invention is abusable drug for oral administra 60 agents; (vi) where there is an intense desire for and efforts to tion in a dosage form which formulated to release the active procure same; (vii) with evidence of compulsive use; (viii) drug from the dosage form immediately (i.e., without an through acquisition by manipulation of the medical system, attempt to delay or prolong the release of the active drug from including falsification of medical history, symptom intensity, the dosage form as is the case for extended release dosage disease severity, patient identity, doctor shopping, prescrip forms). In the absence of a commercially available oral imme 65 tion forgeries; (ix) where there is impaired control over use: diate release abusable drug product, an available parenteral (X) despite harm; (xi) by procurement from non-medical formulation of abusable drug or a salt thereof may be used sources; (xii) by others through sale or diversion by the indi US 9,125,833 B2 73 74 vidual into the non-medical Supply chain; (xiii) for medically ceutically acceptable salts, prodrugs, esters, analogs, deriva unapproved or unintended mood altering purposes. tives, Solvates, complexes, polymorphs, hydrates and As used herein, “abusable drugs”, “abusable drug”, “abus metabolites, as racemates or an individual diastereoisomers able pharmaceuticals”, “abusable substances” and “abusable or enantiomeric isomers thereof or mixtures thereof. Opioid dosage forms are: (i) opioid agonists for the prevention or agonists also include drugs that bind to opioid receptors to treatment of diseases and disorders amenable to prevention or exert agonist activity and are listed in the United States Con treatment with opioids. trolled Substances Act of 1970, as amended, and regulations In some preferred embodiments, abusable drugs of the thereof, and drugs listed in the United States Psychotropic invention may be in unsalified form as racemates or an indi Substances Act of 1978, as amended, and regulations thereof. vidual diastereoisomers or enantiomeric isomers thereof or 10 mixture thereof. In other preferred embodiment, abusable In a preferred embodiment, the opioid agonist of the inven drugs of the invention may be pharmaceutically acceptable tion is selected from a group consisting of alfentanil, anileri salts, prodrugs, esters, analogs, derivatives, Solvates, com dine, buprenorphine, brifentanil, butorphanol, carfentanil, plexes, polymorphs, hydrates and metabolites, as racemates codeine, dextromoramide, dezocine, dihydrocodeine, dihy or an individual diastereoisomers or enantiomeric isomers 15 dromorphine, fentanyl, heroin, hydrocodone, hydromor thereof or mixture thereof. In particularly preferred embodi phone, hydroxypethidine, isomethadone, ketobemidone, ment, abusable drugs of the invention may be in unsalified levorphanol, levomethadone, lofentanil, meperidine, form, pharmaceutically acceptable salts, prodrugs, esters or meptazinol, metazocine, methadone, 4-methoxymethylfen with a covalently bound pharmaceutically active moiety or tanyl, 3-methylfentanil, metopon, mirfentanil, morphine, mixtures thereof, as racemates or an individual diastereoiso morphine-6-glucuronide, nalbuphine, norlevorphanol, mers or enantiomeric isomers thereof or mixture thereof. normethadone, ohmefentanyl, opium, oxycodone, oxymor The term “opioid receptor includes mu (LL), delta (ö), phone, pentazocine, phenazocine, propiram, propoxyphene, kappa (K) and/or nociceptin/orphanin FO (N/OFO) peptide remifentanil, Sufentanil, tapentadol, trefentanil, tramadol, (NOP) receptors, their subtypes and splice variants such as L, tilidine, any opioid having agonist activity at an opioid recep LL2, Ö, Ö2, K1, K2 and Ks, etc., regardless of whether they also 25 tor belonging to the phenanthrene, morphinan, benzomor bind to or influence other receptor Systems (e.g., norepineph phan, methadone, phenylpiperidine, propionanilide 4-anili rine reuptake inhibition, serotonin reuptake inhibition, dopiperidine, 4-aryl piperidines, and 4-Heteroarylpiperidines NMDA receptor antagonism). class, any opioid having agonist activity at an opioid receptor For the purposes of this invention, the term “opioid” is having the same pentacyclic nucleus as nalmefene, naltrex interchangeable with the term "opioid agonist, except when 30 one, buprenorphine, levorphanol, meptazinol, pentazocine there is a specific reference to an opioid antagonist. and dezocine, any opioid having agonist activity at an opioid For the purposes of the present invention and not with receptor which is a fentanyl analog, or their pharmaceutically standing anything to the contrary, the phrase “abusable acceptable salts, prodrugs, esters, analogs, derivatives, Sol drugs' in relation to the imparting the claimed properties of Vates, complexes, polymorphs, hydrates and metabolites, as the invention are limited to one or more “opioid agonists’ or 35 racemates or an individual diastereoisomers or enantiomeric “opioid receptor agonists', as further defined herein. isomers thereof or mixtures thereof. Opioid agonists include alfentanil, allylprodine, alphapro Opioid antagonists are known or readily determined by dine, anileridine, apomorphine, apocodeine, benzylmor individuals who practice the art. Preferably, the opioid phine, bezitramide, brifentanil, buprenorphine, butorphanol, antagonists useful for the present invention may be selected carfentanil, clonitaZene, codeine, cyclorphen, cyprenorphine, 40 from the group consisting of naltrexone, methylmaltrexone, desomorphine, dextromoramide, dezocine, diampromide, naloxone, nalmefene, cyclazocine, cyclorphan, oxilorphan dihydrocodeine, dihydromorphine, dimenoxadol, dimephep nalorphine, nalorphine dinicotinate, nalmefene, nadide and tanol, dimethylthiambutene, dioxyaphetyl butyrate, dipi levallorphan. panone, eptazocine, ethoheptazine, ethylmethylthiambutene, The present invention anticipates the use of more than one ethylmorphine, etonitaZene, fentanyl, heroin, hydrocodone, 45 abusable drug in some embodiments, given in the same for hydroxymethylmorphinan, hydromorphone, hydroxypethi mulation or in a different formulation, for use to treat, prevent dine, isomethadone, ketobemidone, levallorphan, levorpha or ameliorate the same disease or a different disease. nol, levophenacylmorphan, lofentanil, meperidine, meptazi In certain preferred embodiments of the present invention, nol, metazocine, methadone, methylmorphine, metopon, the invention allows for the use of lower doses of abusable mirfentanil, morphine, morphine-6-glucuronide, myrophine, 50 drug by virtue of the inclusion or co-administration of an nalbuphine, narceline, nicomorphine, norlevorphanol, additional drug for the prevention or treatment of the same normethadone, nalorphine, nociceptin/orphanin FO medical condition. By using lower amounts of either or both (N/OFO), normorphine, norpipanone, ohmefentanyl, opium, drugs, the side effects associated with treatment in humans oxycodone, oxymorphone, papaveretum, pentazocine, phen are reduced. adoxone, phenomorphan, phenazocine, phenoperidine, phol 55 The term “abusable drug' means an the abusable drug in codine, piminodine, piritramide, propheptazine, promedol, unsalified form, a pharmaceutically acceptable salt, prodrugs, profadol, properidine, propiram, propoxyphene, remifenta esters, analogs, derivatives, Solvates, complexes, polymor nil, Sufentanil, tapentadol, tramadol, trefentanil, tilidine, nal phs, hydrates and metabolites, as racemates or an individual buphine, or any opioid having agonist activity at an opioid diastereoisomers or enantiomeric isomers thereof or mixture receptor belonging to the phenanthrene, morphinan, benzo 60 thereof. morphan, methadone, phenylpiperidine, propionanilide The singular forms “a”, “an and “the include plural ref 4-anilidopiperidine, 4-aryl piperidines, and 4-Heteroarylpip erents unless the context clearly dictates otherwise. Thus, for eridines class, any opioid having agonist activity at an opioid example, reference to ADER includes an ADER compound receptor having the same pentacyclic nucleus as nalmefene, as well as a mixture of two or more different ADER com maltrexone, buprenorphine, levorphanol, meptazinol, penta 65 pounds, reference to “opioid agonists' includes an opioid Zocine and dezocine, any drug having agonist activity at an agonist as well as two or more different opioid agonists in opioid receptor which is a fentanyl analog, or their pharma combination, and the like. US 9,125,833 B2 75 76 As used herein, the term “analgesic’ includes pharmaco back pain, burn pain, burn dressing change pain, migraine logic agents intended for or effective in the prevention and/or pain, tension headache pain, acute musculoskeletal pain, treatment of pain. acute exacerbation or flare of chronic back pain, acute exac In Some embodiments, in addition to preventing or treating erbation or flare of osteoarthritis, acute exacerbation or flare pain, analgesics provide salutary effects on signs and Symp of chronic pain, breakthrough chronic non-cancer pain, toms associated with pain. For example, analgesics, in addi breakthrough cancer pain, acute exacerbation or flare of tion to relieving pain in patients with osteoarthritis, relieve fibromylagia, acute exacerbation or flare of rheumatoid stiffness, improve physical function, sleep and quality of life. arthritis, acute exacerbation or flare of myofacsial pain, acute For example, analgesics, in addition to relieving pain in exacerbation or flare of chronic idiopathic pain, acute exac patients with neuropathic pain, reduce disability. 10 erbation or flare of neuropathic pain, procedure related pain As used herein, the term “pain' includes: (i) peripheral (e.g., arthroscopy, laparoscopy, endoscopy, intubation, bone neuropathic pain, e.g., acute and chronic inflammatory dem marrow biopsy, Soft tissue biopsy, catheterization), and other eyelinating polyradiculopathy, alcoholic polyneuropathy, self-limiting pain states. chemotherapy-induced polyneuropathy, complex regional As used herein, the term “acute pain” refers to self-limiting pain syndrome (CRPS) Type I and Type II, entrapment neu 15 pain that Subsides overtime and usually lasting less that about ropathies (e.g., carpal tunnel syndrome), HIV sensory neur 30 days and more preferably lasting less than about 21 days. opathy, iatrogenic neuralgias (e.g., postthoracotomy pain, Acute pain does not include chronic conditions such as postmastectomy pain), idiopathic sensory neuropathy, pain chronic neuropathy, chronic neuropathic pain and chronic ful diabetic neuropathy, phantom limb pain, postherpetic neu cancer and non-cancer pain. ralgia, trigeminal neuralgia, radiculopathy (e.g., cervical tho As used herein, “neuropathic pain' is pain initiated or racic, lumbosacral), Sciatica, acute herpes Zoster pain, caused by a primary lesion or dysfunction of the nervous temporomandibular joint disorder pain and postradiation system and includes (i) peripheral neuropathic pain and (ii) plexopathy; and (ii) central neuropathic pain, e.g., compres central neuropathic pain. sive myelopathy from spinal Stenosis, HIV myelopathy, mul As used herein, the term "chronic pain' includes all non tiple Sclerosis pain, Parkinson's disease pain, postischemic 25 neuropathic pain lasting more than 30 days, including inflam myelopathy, post postradiation myelopathy, poststroke pain, matory pain, non-inflammatory pain, muscle pain, joint pain, posttraumatic spinal cord injury and Syringomyelia; and (iii) fascia pain, visceral pain, bone pain and idiopathic pain. cancer associated neuropathic pain, e.g., chemotherapy As used herein, “neurologic disorders' are disorders that induced polyneuropathy, neuropathy secondary to tumor affect the central nervous system (brain and spinal cord), the infiltration or nerve compression, phantom breast pain, post 30 peripheral nervous system (peripheral nerves-cranial nerves mastectomy pain, postradiation plexopathy and myelopathy; included), or the autonomic nervous system (parts of which (iv) chronic pain, e.g., back pain, rheumatoid arthritis, are located in both central and peripheral nervous system). osteoarthritis, inflammatory pain, non-inflammatory pain, See Adams & Victor's Principles of Neurology (McGraw myofascial pain, fibromyalgia, cancer pain, visceral pain, Hill Professional; 7 edition, 2000); Merritt's Textbook of Neu Somatic pain, pelvic pain, musculoskeletal pain, post-trau 35 rology (9th ed. Edited by Lewis P. Rowland. Baltimore: Wil matic pain, bone pain and idiopathic pain; (V) acute pain, e.g., liams and Wilkins, 1995); and Guide to Clinical Neurology acute postSurgical pain (including laparoscopic, laparatomy, (Mohr and Gautier, eds, New York, Churchill Livingstone, gynecologic, urologic, cardiothoracic, arthroscopic, gas 1995). trointestinal, neurologic, orthopedic, oncologic, maxillofa The term "psychiatric disorders' and “mental illness” are cial, ophthalmic, otolaryngologic, Soft tissue, plastic, cos 40 used interchangeably. A mental illness is an abnormal mental metic, vascular and podiatric Surgery, including abdominal condition or disorder expressing symptoms that cause signifi Surgery, abdominoplasty, adenoidectomy, amputation, angio cant distress and/or dysfunction. This can involve cognitive, plasty, appendectomy, arthrodesis, arthroplasty, arthroscopy, emotional, behavioral and interpersonal impairments. As bilateral cingulotomy, biopsy, brain Surgery, breast biopsy, used herein, psychiatric disorders are disorders described in cauterization, cesarean section, cholecystectomy, circumci 45 the Diagnostic and Statistical Manual of Mental Disorders Sion, commissurotomy, cordotomy, corneal transplantation, (DSM), 1994, as revised in 2000 (DSM-IV-TR). cricothoracotomy, discectomy, diverticulectomy, episiotomy, The term “analgesic effectiveness” is defined for purposes endarterectomy, endoscopic thoracic sympathectomy, fore of the present invention as a satisfactory prevention, reduction skin restoration, fistulotomy, frenectomy, frontalis lift, fun in or elimination of pain, along with a tolerable level of side dectomy, gastrectomy, grafting, heart transplantation, hemi 50 effects, as determined by the human patient. corporectomy, hemorrhoidectomy, hepatectomy, hernia “Therapeutically effective amount', “therapeutic effec repair, hypnosurgery, hysterectomy, kidney transplantation, tiveness” or “therapeutically-effective' refers to the amount laminectomy, laparoscopy, laparotomy, laryngectomy, lithot of an active agent Sufficient to induce a desired biological ripsy, lobotomy, lumpectomy, lung transplantation, mam result. That result may be alleviation of the signs, symptoms, mectomy, mammoplasty, mastectomy, mastoidectomy, men 55 or causes of a disease, or any other desired alteration of a toplasty, myotomy, mryingotomy, nephrectomy, nissen biological system. fundoplication, oophorectomy, orchidectomy, parathyroidec The term “effective amount’ means the quantity of a com tomy, penectomy, phalloplasty, pneumotomy, pneumonec pound according to the invention necessary to prevent, to tomy, prostatectomy, psychoSurgery, radioSurgery, ritido cure, or at least partially arrest a sign or symptom for which plasty, rotationplasty, sigmoidostomy, sphincterotomy, 60 the compound (e.g., abusable drug) has been prescribed to a splenectomy, stapedectomy, thoracotomy, thrombectomy, Subject. thymectomy, thyroidectomy, tonsillectomy, tracheotomy, tra The term “abuse resistant” and “abuse deterrent are used cheostomy, tubal ligation, ulnar collateral ligament recon interchangeably and include pharmaceutical compositions struction, ureterosigmoidostomy, vaginectomy, vasectomy, and methods to resist intentional, unintentional or accidental Vulvectomy; renal colic; incisional pain; inflammatory inci 65 physical, mechanical, chemical or thermal manipulation or sional pain; nociceptive incisional pain; acute neuropathic tampering of the dosage form (e.g., crushing, shearing, grind incisional pain following Surgery), renal colic, trauma, acute ing, pulverizing, chewing, dissolving, melting, needle aspi US 9,125,833 B2 77 78 ration, Syringe aspiration, Syringe injection, solvent extrac naso-mucosal irritants, oro-mucosal irritants, respiratory irri tion, inhalation, insufflation, extraction by mechanical, tants), tissue irritants, gastrointestinal irritants, drugs that pre thermal and chemical means, and/or filtration). The term cipitate withdrawal effects, tissue dyes, lakes and colorants, “abuse resistant” and “abuse deterrent also includes phar beverage dyes, lakes and colorants, non-tissue staining bev maceutical compositions and methods to resist intentional, erage dyes, lakes and colorants (i.e. that do not stain or dis unintentional or accidental use or misuse of the dosage form: color the skin upon ingestion), fecal discolorants, urine dis (i) in quantities or by methods and routes of administration colorants, malodorous agents, opioid antagonists, that do not conform to standard medical practice; (ii) outside benzodiazepine antagonists (e.g., flumazenil), cannabinoid the scope of specific instructions for use provided by a quali antagonists and pharmacologic antagonists to co-abused fied medical professional; (iii) outside the supervision of a 10 drugs not contained in the dosage form. Such aversive agents qualified medical professional; (iv) outside the approved may be in the dosage form in a releasable, partially releasable instructions on proper use provided by the drugs legal manu or a non-releasable form (i.e., sequestered), the latter being facturer, (v) in unapproved dosage forms; (vi) for compulsive released on tampering the dosage form (e.g., mechanical, use; (vii) through acquisition by manipulation of the medical thermal, chemical, solvent tampering, ingestion in ways not system; (viii) for medically unapproved or unintended mood 15 recommended, and the like). Further, in some embodiments, altering purposes. Such aversive agents may be in the dosage form in an amount “Drug”, “drug substance”, “substance”, “therapeutic that does not produce an aversive effect or aversion in any, agent”, “pharmacological agent”, “pharmaceutical agent'. many or Substantially all patients when taken in accordance and “active agent” are used interchangeably and are intended with the prescribing information or the manufacturers to have their broadest interpretation as to any therapeutically instructions (for example, in Small quantities), but which active Substance which is delivered to a living organism to produce an aversive effect when taken in excess (e.g., higher produce a desired, usually beneficial effect. In general, this dose or more frequently). includes therapeutic agents in all of the major therapeutic In some embodiments, one or more aversive agents may be aaS. added to the formulation in an aversive agent amount of less The term “subject” for purposes of treatment is used inter 25 than about 80% by weight, preferably less than about 60% by changeably with “patient”, “male'. “female', and includes weight, more preferably less than about 40% by weight of the any human Subject. dosage form, even more preferably less than about 20% by As used herein, “bioequivalent and “bioequivalence' weight of the dosage form, and most preferably less than means that the 90% Confidence Interval (CI) of the relative about 10 by weight of the dosage form (e.g., mean C, AUCo. and AUCo. of the drug under test and 30 0.000000000000001% to 1%, or 0.000000001% to 3%, or reference conditions (e.g., generic VS. brand name, or fed 0.0001% to 10%, or 0.001% to 5%, or 1% to 10%, or 0.001% versus fasted, or with and without concurrent alcohol) is to 2%, or 1% or 10%, or 2% to 7%) depending on the par within 80% to 125%, when tested in accordance with U.S. ticular aversive agent used. FDA guidelines (see "Guidance for Industry: Bioavailability In some embodiments, the aversive agent in the dosage and Bioeduivalence Studies for Orally Administered Drug 35 form may be about 0.00000000001 mg to about 2000 mg, or Products-General Considerations'. Department of Health about 0.0000001 mg to about 1500 mg, or about 0.000001 mg and Human Services, Food and Drug Administration, Center to about 1000 mg, or about 0.0001 mg to about 1000 mg. or for Drug Evaluation and Research, July 2002 and "Guidance about 0.001 mg to about 1000 mg. or about 0.01 mg to about for Industry: Food-Effect Bioavailability and Fed Bioeduiva 1000 mg. or about 0.1 mg to about 1500 mg. or 1 mg to about lence Studies: Study Design, Data Analysis and Labeling, 40 800 mg, or about 1 mg to about 500 mg. or about 1 mg to about Department of Health and Human Services, Food and Drug 300 mg. or about 1 mg to about 150 mg. or about 5 mg to about Administration, Center for Drug Evaluation and Research, 400 mg. or about 5 mg to about 200 mg. or about October, 2001, which are hereby incorporated by reference). 0.00000000001 mg to about 200 mg. or about “Pharmaceutically or therapeutically acceptable excipient 0.00000000001 mg to about 100 mg. or about or carrier' or “excipient” refers to a substance which does not 45 0.00000000001 mg to about 50 mg, or about 0.0000001 mg to interfere with the effectiveness or the biological activity of the about 200 mg. or about 0.0000001 mg to about 100 mg. or active ingredients and which is not toxic to the Subject. In about 0.00001 mg to about 400 mg. or about 0.0001 mg to Some preferred embodiments of the present invention, phar about 300 mg. maceutically or therapeutically acceptable excipients or car As described above, the present invention can include one riers may play a role in imparting or optimizing the rate and 50 or more aversive agents, selected from the group including, extent of absorption of the abusable drug or additional drugs without limitation antagonists of abusable drugs, laxatives, in the pharmaceutical composition. In some preferred cutaneous vasodilators headache producing agents, emetics, embodiments of the present invention, pharmaceutically or emetogenic compound, nausea producing compounds, bitter therapeutically acceptable excipients or carriers may play a ing agents, drugs that cause burning on irritation when in role in Stabilizing the abusable drug or additional drugs in the 55 contact with tissue or mucous membranes (e.g., naso-mu pharmaceutical composition. cosal irritants, oro-mucosal irritants, respiratory irritants), In certain preferred embodiments of the present invention, tissue irritants, gastrointestinal irritants, drugs that precipitate the dosage form may include, in addition to abusable drug or withdrawal effects, tissue dyes, lakes and colorants, beverage a pharmaceutically acceptable salt thereof and ADER, other dyes, lakes and colorants, non-tissue staining beverage dyes, abuse deterrent or abuse resistant Substances, process or tech 60 lakes and colorants, fecal discolorants, urine discolorants, nologies known in the art, including one or more aversive malodorous agents, opioid antagonists, benzodiazepine agents. All kinds of aversive agents are contemplated, includ antagonists, cannabinoid antagonists, and pharmacologic ing, without limitation, antagonists of abusable drugs, laxa antagonists to co-abused drugs not contained in the dosage tives, cutaneous vasodilators, headache producing agents, form. Preferably, the aversive agent is a pharmaceutically emetics, emetogenic compound, nausea producing com 65 acceptable agent that produces an aversive effect only when pounds, bittering agents, drugs that cause burning on irrita the dosage form of the invention containing the aversive agent tion when in contact with tissue or mucous membranes (e.g., is abused, for example, when taken in excess of medically US 9,125,833 B2 79 80 approved doses, taken in excess of approved doses in the 50 mg, or about 0.00000001 mg to about 20 mg. or about 0.01 manufacturer's prescribing information, taken after tamper mg to about 20 mg. or about 0.01 mg to about 10 mg, or about ing of the dosage form (e.g., mechanical, thermal, chemical, 0.01 mg to about 5 mg, or about 0.01 mg to about 2 mg, or Solvent tampering), ingestion in ways not medically recom about 0.01 mg to about 1 mg, or about 0.01 mg to about 1 mg, mended, administration by routes not approved for the dosage or about 0.01 mg to about 0.5 mg. or about 0.1 mg to about 20 form (e.g., intranasal, inhalation, intravenous) or in a manner mg, or about 0.1 mg to about 10 mg, or about 0.1 mg to about inconsistent with the manufacturer's prescribing informa 7 mg, or about 0.1 mg to about 5 mg, or about 0.1 mg to about tion. 3 mg, or about 0.1 mg to about 2 mg. In some embodiments, the amount of aversive agent in the In some embodiments, the aversive agent in the dosage dosage form of the present invention can be a fixed ratio in 10 form may be quinine or a pharmaceutically acceptable salt of relation to the amount of abusable drug in the dosage form. By quinine, in a quantity expressed as mg of quinine, of about appropriately selecting the quantity of the aversive agent in 0.00001 mg to about 300 mg. or about 0.00001 mg to about the dosage form, aversive effects can be avoided under con 200 mg. or about 0.00001 mg to about 100 mg. or about ditions of proper medical use (e.g., manufacturers prescribing 0.00001 mg to about 75 mg, or about 0.00001 mg to about 50 directions). However, under some conditions of abuse, for 15 mg, or about 0.00001 mg to about 25 mg. or about 0.00001 example excessive intake of the dosage form of the invention, mg to about 20 mg. or about 0.00001 mg to about 10 mg. or the quantity of aversive agent consumed will exceed the "no about 0.00001 mg to about 5 mg. or about 0.00001 mg to effect” or “minimum effect threshold, thereby producing about 2.5 mg. or about 0.00001 mg to about 1 mg, or about one or more aversive effects, for example, e.g., nausea, eme 0.001 mg to about 300 mg. or about 0.001 mg to about 200 sis, diarrhea, laxation, cutaneous vasodilation, headache, bit mg, or about 0.001 mg to about 100 mg. or about 0.001 mg to tertaste, naso-mucosal irritation, oro-mucosal irritation, pre about 75 mg, or about 0.001 mg to about 50 mg. or about cipitation of abstinence from the abusable drug of the dosage 0.001 mg to about 25 mg. or about 0.001 mg to about 20 mg. form, precipitation of abstinence from a co-abused drug or about 0.001 mg to about 10 mg. or about 0.001 mg to about which is not part of the dosage form, reduction of the plea 5 mg, or about 0.001 mg to about 2.5 mg. or about 0.001 mg Surable, mood altering, rewarding, reinforcing, stimulant, 25 to about 1 mg, or about 1 mg to about 300 mg. or about 1 mg depressant or other psychic and physiologic effects of the to about 200 mg. or about 1 mg to about 100 mg. or about 1 mg abusable drug or a co-abused drug, etc.). to about 75 mg, or about 1 mg to about 50 mg. or about 1 mg In some embodiments, the “no effect” or “minimum to about 25 mg, or about 1 mg to about 20 mg. or about 1 mg effect” threshold amount of aversive agent can be exceeded to about 10 mg. or about 1 mg to about 5 mg, or about 1 mg to when the dosage form of the inventionistaken in excess of the 30 about 2.5 mg. manufacturer's recommendation by a factor of about 1.5, or Various emetic agents can be employed including, for about 2, or about 2.5, or about 3, or about 4, or about 5, or example and without limitation, zinc and pharmaceutically about 6, or about 7, or about 8, or about 10, or more than 10. acceptable salts thereof (e.g., Zinc oxide, Zinc gluconate, Zinc In some embodiments, the production of an aversive effect acetate, Zinc sulfate, Zinc carbonate), dopamine agonists, can reduce or stop further abuse of the dosage form, thereby 35 apomorphine, ipecac, ipecacuanha, emetime, emetine (meth reducing the harm or toxicity of the drug in the Subject who is ylcephaeline), cephaeline, psychotrine, O-methylpsychot tampering, misusing or abusing the dosage form, e.g., rine, ammonium chloride, potassium chloride, magnesium addicts, drug abusers and recreational drug users. Sulfate, ferrous gluconate, ferrous Sulfate, aloin, algarot or Various bittering agents can be employed including, for antimonious oxychloride, antimony trichloride, folate, folic example and without limitation, T2R or TAS2R receptorago 40 acid, niacin (niacin) and nicotinamide. nists, phenylthiourea (phenylthiocarbamide), natural, artifi In some embodiments, the aversive agent in the dosage cial and synthetic flavor oils and flavoring aromatics and/or form may be Zinc in the form of elemental Zinc or a pharma oils, oleoresins and extracts derived from plants, leaves, flow ceutically acceptable salt of Zinc, in a quantity expressed as ers, fruits, and so forth, and combinations thereof. Nonlimit mg of elemental Zinc, of about 1 mg to about 400 mg, or about ing representative flavor oils include spearmint oil, pepper 45 1 mg to about 300 mg. or about 1 mg to about 200 mg, or about mint oil, eucalyptus oil, oil of nutmeg, allspice, mace, oil of 1 mg to about 150 mg, or about 1 mg to about 100 mg. or about bitter almonds, menthol and the like. Also useful bittering 1 mg to about 90 mg. or about 1 mg to about 80 mg, or about agents are artificial, natural and synthetic fruit flavors such as 1 mg to about 70 mg. or about 1 mg to about 60 mg, or about citrus oils including lemon, orange, lime, grapefruit, and fruit 1 mg to about 50 mg. or about 1 mg to about 45 mg, or about essences and so forth. Additional bittering agents include 50 1 mg to about 40 mg. or about 1 mg to about 40 mg, or about Sucrose derivatives (e.g., Sucrose octaacetate), chlorosucrose 1 mg to about 35 mg, or about 1 mg to about 30 mg, or about derivatives, quinine and quinine salts, quinidine and quindine 1 mg to about 25 mg, or about 1 mg to about 20 mg, or about salts and the like. The preferred bittering agent for use in the 1 mg to about 10 mg. or about 1 mg to about 5 mg, or about 5 present invention is denatonium, denatonium benzoate and mg to about 400 mg. or about 5 mg to about 300 mg. or about denatonium saccharide. A dosage form including a bittering 55 5 mg to about 200 mg, or about 5 mg to about 150 mg. or about agent preferably discourages improperusage of the tampered 5 mg to about 100 mg, or about 10 mg to about 150 mg. or dosage form by imparting a disagreeable taste to the tampered about 10 mg to about 100 mg. or about 5 mg to about 80 mg. dosage form. or about 5 mg to about 60 mg. or about 5 mg to about 50 mg. In some embodiments, the aversive agent in the dosage or about 5 mg to about 45 mg, or about 5 mg to about 40 mg. form may be denatonium, denatonium saccharide or denato 60 or about 5 mg to about 40 mg. or about 5 mg to about 35 mg. nium benzoate, in a quantity expressed as mg of denatonium, or about 5 mg to about 30 mg. or about 5 mg to about 25 mg. of about 0.00000001 mg to about 100 mg, or about 0.000001 or about 5 mg to about 20 mg. or about 5 mg to about 10 mg. mg to about 100 mg. or about 0.0001 mg to about 100 mg. or or about 10 mg to about 90 mg. or about 10 mg to about 80 mg. about 0.0001 mg to about 20 mg. or about 0.0001 mg to about or about 10 mg to about 60 mg. or about 10 mg to about 50 mg. 10 mg. or about 0.0001 mg to about 5 mg. or about 0.0001 mg 65 or about 10 mg to about 45 mg, or about 10 mg to about 40 mg. to about 2 mg, or about 0.0001 mg to about 1 mg, about or about 10 mg to about 40 mg. or about 10 mg to about 35 mg. 0.0001 mg to about 50 mg. or about 0.00000001 mg to about or about 10 mg to about 30 mg. or about 10 mg to about 25 mg. US 9,125,833 B2 81 82 or about 10 mg to about 20 mg, or about 20 mg to about 100 or a quantity sufficient to be produce an aversive effect when mg, or about 20 mg to about 90 mg. or about 20 mg to about abused but not under conditions of medically appropriate use. 80 mg. or about 20 mg to about 60 mg, or about 20 mg to about Various tissue dyes, lakes and colorants, beverage dyes, 50 mg. or about 20 mg to about 45 mg, or about 20 mg to about lakes and colorants, non-tissue staining beverage dyes, lakes 40 mg, or about 20 mg to about 35 mg. or about 20 mg to about and colorants, fecal discolorants, urine discolorants can be 30 mg, or about 15 mg to about 50 mg. or about 15 mg to about employed including, for example and without limitation, Cur 40 mg, or about 15 mg to about 35 mg, or a quantity Sufficient cumin, Riboflavin, Tartrazine, Quinoline yellow, Sunset yel to be produce an aversive effect vasodilation when abused but low FCF, Carmine, Carmoisine, Amaranth, Ponceau 4R, not under conditions of medically appropriate use. Erythrosine, Allura red AC, Patent blue V, Indigo carmine, Various irritants can be employed including, for example 10 Brilliant blue FCF, Chlorophylls, Copper complexes of chlo and without limitation transient receptor potential vanilloid 1 rophylls and chlorophyllins, Green S. Caramel, Brilliant (TRPV1 or VR1) agonists (including resiniferanoids, capsai black BN, Vegetable carbon, Carotenoids, Alpha-, beta-, cinoids, phorboid Vanilloids, and terpenoid 1.4-unsaturated gamma-carotene, Capsanthin, Capsorubin, Lycopene, Beta dialdehydes, capsaicin, capsaicin analogs and derivatives, apo-8 carotenal, Ethyl ester of beta-apo-8 carotenoic acid, resiniferatoxin, olvanil, piperine, Zingerone, anandamide, 12 15 Xanthophylls, Lutein, Canthaxanthin, Beetroot red, Antho and 15-(S)-hydroperoxy-eicosatetraenoic acids, 5 and 15 cyanins, Cyanidin, Delphidin, Malvidin, Pelargonidin, (S)-hydroxyeicosatetraenoic acids, phorbol 12-phenylacetate Peonidin, Petunidin, Calcium carbonate, Titanium dioxide, 13-acetate 20-homovanillate, 2 phorbol 12,13-didecanoate Iron oxides and hydroxides, Aluminum, Brilliant blue FCF, 20-homovanillate, leukotriene B(4), tinyatoxin, heptanoyl Indigotine, AlphaZurine FG, Indanthrene blue, Fast green isobutylamide, N-(3-acyloxy-2-benzylpropyl)-N'-dihydrox FCF, Alizarin cyanine green F. Quinizarine green SS, Pyra ytetrahydrobenzazepine, tetrahydroisoquinoline thiourea nine concentrated, Orange II, Dibromofluorescein, Diiodof analogs, heptanoyl guaiacylamide, other isobutylamides or luorescein, Erythrosine yellowish Na, Erythrosine, Ponceau guaiacylamides, dihydrocapsaicin, homoVanillyl octylester SX, Lithol rubin B, Lithol rubin B Ca, Toney red, Tetrabro and nonanoylvanillylamide), acids such as acids with one or mofluorescein, Eosine, Tetrachlorotetrabromofluorescein, more carboxyl moieties (e.g., formic acid, acetic acid, propi 25 Phloxine B, Helindone pink CN, Brilliant lake red R, Acid onic acidy, butyric acid, Valeric acid, caproic acid, caprillic fuchsine, Lake bordeaux B, Flaming red, Alba red, Allura red acid, capric acid, oxalic acid, malonic acid, Succicnic acid, AC, Allura Red AC, Alizurol purple SS, Tartrazine, Sunset glutaric acid, adipic acid, maleic acid, fumaric acid, and citric yellow, FCF, Fluorescein, Naphthol yellow S. Uranine, acid), Sodium lauryl Sulfate, poloxamer, Sorbitan monoesters, Quinoline yellow WS, Quinoline yellow SS, Brilliant blue glyceryl monooleates, niacin, mustard, allyl isothiocyaanate 30 FCF, Indigotine, AlphaZurine FG, Alizurol purple SS, Sunset and p-hydroxybenzyl isothiocyanate, acetylsalicylic acid. yellow FCF, Alumina, Aluminum powder, Annatto extract, Various cutaneous vasodilators can be employed includ Beta-caroteine, Bismuth oxychloride, Bronze powder, Cal ing, for example and without limitation, niacin acid, nicoti cium carbonate, Canthaxanthin, Caramel, Chromium-cobalt nuric acid, beta-hydroxybutyrate and nicotinic receptor (e.g., aluminum oxide, Chromium hydroxide green, Chromium HM74A or GPR109A) agonists. 35 oxide green, Cochineal extract, carmine, Copper powder, In some embodiments, the aversive agent in the dosage Dihydroxyacetone, Ferric ammonium citrate, Ferric ammo form may be niacin, in a quantity of about 1 mg to about 400 nium ferrocyanide, Ferric ferrocyanide, Guanine, Iron oxides mg, or about 1 mg to about 300 mg. or about 1 mg to about 200 synthetic, Logwood extract, Mica, Potassium sodium copper mg, or about 1 mg to about 150 mg, or about 1 mg to about 100 chlorophyllin, Pyrogallol, Pyrophyllite, Talc, Titanium diox mg, or about 1 mg to about 90 mg. or about 1 mg to about 80 40 ide, Zinc oxide, FD&C blue #1, FD&C blue #2, D&C blue #4, mg, or about 1 mg to about 70 mg. or about 1 mg to about 60 D&C blue #9, FD&C green #3, D&C green #5, D&C green mg, or about 1 mg to about 50 mg. or about 1 mg to about 45 #6, D&C green #8, D&C orange #4, D&C orange #5, D&C mg, or about 1 mg to about 40 mg. or about 1 mg to about 40 orange #10, D&C orange #11, FD&C red #3, FD&C red #4, mg, or about 1 mg to about 35 mg. or about 1 mg to about 30 D&C red #6, D&C red #7, D&C red #17, D&C red #21, D&C mg, or about 1 mg to about 25 mg. or about 1 mg to about 20 45 red #22, D&C red #27, D&C red #28, D&C red #30, D&Cred mg, or about 1 mg to about 10 mg, or about 1 mg to about 5 #31, D&C red #33, D&C red #34, D&C red #36, D&C red mg, or about 5 mg to about 400 mg. or about 5 mg to about 300 #39, FD&C red #40, FD&C red #40 lake, D&C violet #2, mg, or about 5 mg to about 200 mg. or about 5 mg to about 150 FD&C yellow #5, FD&C yellow #6, D&C yellow #7, Ext. mg, or about 5 mg to about 100 mg. or about 10 mg to about D&C yellow #7, D&C yellow #8, D&C yellow #10, D&C 150 mg. or about 10 mg to about 100 mg. or about 5 mg to 50 yellow #11, FD&C lakes, D&C lakes, Ext. D&C lakes, about 80 mg. or about 5 mg to about 60 mg, or about 5 mg to FD&C blue #1 lake, FD&C blue #2 lake, D&C blue #4 lake, about 50 mg, or about 5 mg to about 45 mg, or about 5 mg to FD&C green #3 lake, D&C green #5 lake, D&C green #6 about 40 mg, or about 5 mg to about 40 mg. or about 5 mg to lake, D&C orange #4 lake, D&C orange #5 lake, D&C orange about 35 mg, or about 5 mg to about 30 mg, or about 5 mg to #10 lake, D&C orange #11 lake, FD&C red #4 lake, D&C red about 25 mg, or about 5 mg to about 20 mg. or about 5 mg to 55 #6 lake, D&C red #7 lake, D&C red #17 lake, D&C red #21 about 10 mg. or or about 10 mg to about 90 mg, or about 10 lake, D&C red #22 lake, D&C red #27 lake, D&C red #28 mg to about 80 mg. or about 10 mg to about 60 mg, or about lake, D&C red #30 lake, D&C red #31 lake, D&C red #33 10 mg to about 50 mg. or about 10 mg to about 45 mg, or about lake, D&C red #34 lake, D&C red #36 lake, D&C violet #2 10 mg to about 40 mg. or about 10 mg to about 40 mg. or about lake, FD&C yellow #5 lake, FD&C yellow #6 lake, D&C 10 mg to about 35 mg. or about 10 mg to about 30 mg, or about 60 yellow #7 lake, Ext. D&C yellow #7 lake, D&C yellow #8 10 mg to about 25 mg, or about 10 mg to about 20 mg. or about lake, D&C yellow #10 lake, Turmeric, Lactoflavin, 20 mg to about 100 mg. or about 20 mg to about 90 mg. or Cochineal, carminic acid, Indigotine, Magnesium chloro about 20 mg to about 80 mg, or about 20 mg to about 60 mg. phyll, Brilliant green BS, Black PN, Carbo medicinalis veg or about 20 mg to about 50 mg. or about 20 mg to about 45 mg. etabilis, Paprika oleoresin, Paprika oleoresin, Betanin, Beta or about 20 mg to about 40 mg. or about 20 mg to about 35 mg. 65 carotene, indigo carmine, iron oxides, Sunset yellow FCF, or about 20 mg to about 30 mg. or about 15 mg to about 50 mg. titanium dioxide, E100, E101, E102, E104, E110, E120, or about 15 mg to about 40 mg. or about 15 mg to about 35 mg. E122, E123, E124, E127, E129, E131, E132, E133, E140, US 9,125,833 B2 83 84 E 141, E142, E150, E151, E153, E160, E161, E162, E163, acceptable salts of Zinc and niacin may be used for pharma E170, E171, E172, E173 and phenazopyridine. ceutical purposes (e.g., pharmaceutical optimization, drug As used herein, “dyes”, “lakes”, “colorants' and “discolo release and drug stability). rants' are used interchangeably and refer to one or more In one preferred embodiment of the invention, the dosage pharmaceutically acceptable dyes, lakes or colorants which 5 form includes both an immediate release and extended may be: (i) tissue staining; (ii) non-tissue staining; (iii) bev release component. erage staining; (iv) urine discolorant; and/or (V) fecal discolo In one preferred embodiment of the invention, the dosage rant. form includes a capsule within a capsule, each capsule con Various laxatives can be employed including, for example taining a different drug or the same drug intended for treating and without limitation, Bis(p-hydroxyphenyl)pyridyl-2- 10 the same or a different medical condition. In some preferred methane, Bisacodyl, bisoxatin, anthraquinone, embodiments, the outer capsule may be an enteric coated anthraquinone analogs and derivatives (e.g., buckthorn, cas capsule or a capsule containing an immediate release formu anthranol, cascara, hydroxyanthracene, glucofrangulin), lation to provide rapid plasma concentrations or a rapid onset dantron, danthron, docusate (e.g., docusate sodium, docusate 15 of effect or a loading dose and the inner capsule contains an calcium, docusate potassium), gastrointestinal chloride chan extended release formulation. In some preferred embodi nel activators (e.g., chloride channel Subtype 2 activators), ments, up to 3 capsules within a capsule are contemplated as lubiprostone, magenesium salts (e.g., magnesium citrate, part of the invention. In one preferred embodiment of the magnesium hydroxide, magnesium oxide), mannitol, invention, the dosage form involves one or more tablets oxyphenisatine, polyethylene glycol, poly(ethylene oxide) within a capsule, wherein the abusable drug is either in the PEO-1500), sodium phosphate, phenolphthalein, senna, tablet and/or in one of the capsules. Senna constituents and derivatives (e.g., Sennoside A, Senno In one preferred embodiment of the invention, the formu side B) and Sodium picosulfate. lation is ingested orally as a tablet or capsule, preferably as a In some embodiments, the aversive agent in the dosage capsule. In another preferred embodiment of the invention, form may be a laxative in the amount of about 0.001 mg to 25 the formulation is administered bucally. In yet another pre about 300 mg. or about 0.001 mg to about 200 mg. or about ferred embodiment of the invention, the formulation is 0.001 mg to about 100 mg. or about 0.001 mg to about 75 mg. administered Sublingually. or about 0.001 mg to about 50 mg. or about 0.001 mg to about The term “pharmaceutically acceptable salt as used herein 25 mg. or about 0.001 mg to about 20 mg. or about 0.001 mg refers to a salt which is toxicologically safe for human and 30 animal administration. Nonlimiting examples of salts include to about 10 mg. or about 0.001 mg to about 5 mg. or about hydrochlorides, hydrobromides, hydroiodides, sulfates, 0.001 mg to about 2.5 mg. or about 0.001 mg to about 1 mg, bisulfates, nitrates, citrates, tartrates, bitartrates, phosphates, or about 1 mg to about 300 mg. or about 1 mg to about 200 mg. malates, maleates, napsylates, fumarates, succinates, or about 1 mg to about 100 mg. or about 1 mg to about 75 mg. acetates, terephlhalates, pamoates and pectinates. or about 1 mg to about 50 mg. or about 1 mg to about 25 mg. 35 In some embodiments, the abusable drug pharmaceutical or about 1 mg to about 20 mg. or about 1 mg to about 10 mg. composition is a salt or complex of inorganic cation salts, or about 1 mg to about 5 mg. or about 1 mg to about 2.5 mg. organic salts such primary, secondary, tertiary and quaternary Aversive agents may include compounds found on the amines include Substituted amines. In some embodiments, FDA EAFUS database (http://vm.cfsan.fda.gov/~dms/eaf examples of Suitable pharmaceutically acceptable salts of us.html); FDA Food Additives Status List (http://www.cfsan. 40 abusable drugs include any of the inorganic cation salts such fla.gov/~dms/opa-appa.html); FDAGRAS list and database: as Sodium, potassium, lithium, magnesium, calcium, cesium, FDA Color Additive Status List (http://www.cfsan.fda. ammonia, ferrous, Zinc, manganous, aluminum, ferric, and gov/~dmS/opa-appe.html); FDA Inactive Ingredients Data manganic; organic salts with primary, secondary, tertiary and base (http://www.accessdata.fda.gov/scripts/cder/iig/index. quaternary amines, or mixtures thereof. Examples of Such cfm); Rowe, Sheskey and Owen, Handbook of Pharmaceuti 45 primary, secondary, tertiary and quaternary amines include cal Excipients, APhA Publications; 5th edition (2006); Good Substituted amines including but not limited to naturally man & Gilman's The Pharmacological Basis of Therapeutics occurring Substituted amines, cyclic amines, basic ion (Brunton, Lazo and Parker, eds, 11th ed., McGraw Hill exchange resins, and mixtures thereof. More specifically, (2005); Remington: The Science and Practice of Pharmacy, suitable amines include but are not limited to tromethamine, 21st ed., Lippincott Williams & Wilkins (2005); Martindale: 50 triethylamine, tripropylamine, dropopizine, 2-dimethylami The Complete Drug Reference, 35th Edition, Pharmaceutical noethanol, 2-diethylaminoethanol, lysine, arginine, orni Press (2007); United States Pharmacopeia-National Formu thine, histidine, caffeine, procaine, N-ethylpiperidine, hydra lary (USP-NF), (USP 30-NF 25, 2007), the International bamine, choline, betaine, ethylenediamine, glucosamine, Programme on Chemical Safety (http://www.inchem.org/) tris-(hydroxymethyl)aminomethane, N-methylglucamine, and Health Canada's List of Acceptable Non-medicinal 55 methylglycamine, theobromine, piperazine, piperidine, Ingredients (http://www.hc-sc.gc.ca/dhp-mps/prodnatur/leg polyamine resins and the like, and mixtures thereof. islation/docs/nmi-imn list1 e.html), all hereby incorporated In some embodiments, examples of suitable pharmaceuti by reference in their entirety. cally acceptable salts of abusable drugs include aminoalco It should be noted that the above mentioned aversive agents hols chosen from the group consisting of ethanolamine, may, in some embodiments be used in the dosage form of the 60 3-amino-1-propanol, (R)-1-amino-2-propanol, (S)-1-amino invention for purposes other than as aversive agents, or for 2-propanol, 2-amino-1,3-propandiol, N-(2-hydroxyethyl) both aversive and non-aversive purposes. Such non-aversive pyrrolidine, D-glucamine and L-prolinol, D-glucosamine, uses can include, without limitation, pharmaceutical pur and N-methylglucosamine. poses and pharmacologic purposes. For example, in some In some embodiments, examples of suitable pharmaceuti embodiments, the laxative agent may be used to counteract 65 cally acceptable salts of abusable drugs include alkali and the constipating effects of the abusable dosage form of the alkaline earth metals and salts of an organic nature. Such as invention. In some embodiments, Zinc and pharmaceutically the salts of basic amino acids. US 9,125,833 B2 85 86 It is contemplated that the present invention may be used Stearates and distearates; (c) glycerol monostearate; (d) alone or in combination with other drugs to provide additive, poorly water soluble, high melting point (mp=45 to 100°C.) complementary, or synergistic therapeutic effects or for the waxes, and mixtures thereof. treatment of entirely different medical conditions. In some preferred embodiments, the ADER agent of the Other pharmaceutically active ingredients from various invention is selected from among hydrogenated Type I or therapeutic classes may also be used in combination with the Type II vegetable oils. present invention. They include, but are not limited to decon In some preferred embodiments, the ADER agent of the gestants, analgesics, analgesic adjuvants, antidepressants, invention is selected from among polyoxyethylene Stearates. antipsychotics, anxiolytics, hypnotics, sedatives, anti-ADHD In some preferred embodiments, the ADER agent of the drugs, psychoStimulants, drugs to treaturinary incontinence, 10 invention is selected from among polyoxyethylene distear ates. antihistamines, expectorants, antitussives, diuretics, anti-in In some preferred embodiments, the ADER agent of the flammatory agents, antipyretics, antirheumatics, antioxi invention is selected from among polyoxyethylene Stearates dants, laxatives, local anesthetics, proton pump inhibitors, or distearates. motility modifying agents, vasodilators, inotropes, beta 15 In some preferred embodiments, the ADER agent of the blockers, beta adrenergic agonists, drugs to treat asthma and invention is selected from among poorly water Soluble, high COPD, antiinfectives, anti-migraine agents, antihyperten melting point (mp=45 to 100° C.) waxes. Sives, antianginal agents, gastric acid reducing agents, anti In some preferred embodiments, the ADER agent of the ulcer agents, anticoagulants, lipid and cholesterol lowering invention is selected from among hydrogenated Type I or drugs, anti-diabetic drugs, anti-epileptics, hormones, Smooth Type II vegetable oils; said invention also including an aver muscle relaxants, skeletal muscle relaxants, bronchodilators, sive agent. Vitamins, trace minerals, amino acids, biological peptides and In some preferred embodiments, the ADER agent of the drugs to treat various infectious, immunologic disorders, car invention is selected from among polyoxyethylene Stearates; diovascular, pulmonary, gastrointestinal, hepatic, biliary, said invention also including an aversive agent. nutritional, metabolic, endocrine, hematologic, oncologic, 25 In some preferred embodiments, the ADER agent of the musculoskeletal, neurologic, psychiatric, genitourinary, invention is selected from among polyoxyethylene distear gynecologic, obstetric, pediatric, otolaryngogologic, oph ates; said invention also including an aversive agent. thalmic, dermatologic, dental, oral, and genetic disorders, In some preferred embodiments, the ADER agent of the diseases and maladies. The drug being used in combination invention is selected from among polyoxyethylene Stearates therapy with the present invention can be administered by any 30 or distearates; said invention also including an aversive agent. route, including parenterally, orally, topically, transdermally, In some preferred embodiments, the ADER agent of the invention is selected from among poorly water soluble, high Sublingually, and the like. melting point (mp=45 to 100°C.) waxes; said invention also The terms “medical condition”, “malady”, “disease”, "dis including an aversive agent. order and “pathological states' are used interchangeably and 35 In some preferred embodiments, the ADER agent of the are intended to have their broadest interpretation to refer to invention excludes hydrogenated Type I vegetable oils. any physiologic, pathologic or pathophysiologic state in a In some preferred embodiments, the ADER agent of the human that can be prevented, treated, managed or altered to invention excludes hydrogenated Type II vegetable oils. produce a desired, usually beneficial effect. In some preferred embodiments, the ADER agent of the In some preferred embodiments, the oral abusable drug is 40 invention excludes hydrogenated Type I or Type II vegetable intended to prevent or treat pain. A co-administered drug (in oils. the same or different dosage form, by any route of adminis In some preferred embodiments, the ADER agent of the tration) may be used to provide additive, complementary, invention excludes polyoxyethylene Stearates. Superadditive or synergistic therapeutic analgesic effects, In some preferred embodiments, the ADER agent of the including other NSAIDs, NO-NSAIDs, COX-2 selective 45 invention excludes polyoxyethylene distearates. inhibitors, acetaminophen, nitroparacetamol, nitric oxide In some preferred embodiments, the ADER agent of the donors, tramadol, beta adrenergic agonists, alpha-2 agonists, invention excludes polyoxyethylene Stearates or distearates. selective prostanoid receptor antagonists, NO-opioid recep In some preferred embodiments, the ADER agent of the toragonists, local anesthetics, purinergic P2 receptor antago invention excludes poorly water Soluble, high melting point nists, NMDA receptor antagonists, gabapentin, pregabalin, 50 (mp=45 to 100° C.) waxes. gabapentinoids, ligands of alpha(2)delta Subunits of Voltage In some preferred embodiments, the ADER agent of the gated calcium channels, neuronal nicotinic receptoragonists, invention excludes poorly water Soluble, high melting point calcium channel antagonists, sodium channel blockers, (mp=50 to 100° C.) waxes. superoxide dismutase mimetics, p38 MAP kinase inhibitors, In some preferred embodiments, the ADER agent of the TRPV1 agonists, dextromethorphan, dextrorphan, ketamine, 55 invention excludes poorly water Soluble, high melting point glycine receptor antagonists, antidepressants, corticoster (mp=60 to 100° C.) waxes. oids, and antiepileptics, and any other drugs that can be In some preferred embodiments, the ADER agent of the shown by a person proficient in the art to prevent or treat pain. invention excludes poorly water Soluble, high melting point Compositions and methods of the present invention pro (mp=70 to 85°C.) waxes. vide: (i) abuse deterrence; (ii) extended release; and/or (iii) 60 In some preferred embodiments, the ADER agent of the protection against alcohol dose dumping; and/or (iv) protec invention excludes poorly water Soluble, high melting point tion against significant changes in bioavailability due to fedor (mp=75 to 90° C.) waxes. fasted States; and/or (V) simultaneously providing more than In some preferred embodiments, the ADER agent of the one of foregoing (i) to (iv) abuse deterrence and extended invention excludes poorly water Soluble, high melting point release; wherein the dosage form is prepared using com 65 (mp=70 to 100° C.) waxes. pounds selected from the group consisting of: (a) hydroge Inaparticularly preferred embodiment of the invention, the nated Type I or Type II vegetable oils; (b) polyoxyethylene dosage form includes two or more compounds selected from US 9,125,833 B2 87 88 the categories (i) to (iv) from the group consisting of: (i) than about 275 mg, or less than about 250 mg. or less than hydrogenated Type I or Type II vegetable oils; (ii) polyoxy about 225 mg, or less than about 200 mg. or less than about ethylene Stearates and distearates; (iii) glycerol monostear 175 mg, or less than about 150 mg. or less than about 125 mg, ate; (iv) poorly water Soluble, high melting point (mp 45 to or less than about 100 mg. or less than about 90 mg. or less 100° C.) waxes. than about 80 mg, or less than about 70 mg. or less than about In a most preferred embodiment of the invention, the dos 60 mg. or less than about 50 mg. or less than about 40 mg. or age form includes two or more compounds selected from at less than about 30 mg, or less than about 20 mg, or less than least two categories (i) to (iv) from the group consisting of about 10 mg. (i) hydrogenated Type I or Type II vegetable oils; (ii) poly In some preferred embodiments, the dosage form includes oxyethylene Stearates and distearates; (iii) glycerol 10 glycerol monostearate in an amount that is less than about monostearate; (iv) poorly water soluble, high melting point 1200 mg. or less than about 100 mg, or less than about 900 (mp=45 to 100° C.) waxes. mg, or less than about 800 mg. or less than about 700 mg. or In some preferred embodiments, the dosage form includes less than about 600 mg. or less than about 550 mg. or less than hydrogenated Type I or Type II vegetable oils in an amount about 500 mg, or less than about 400 mg. or less than about that is less than about 1200 mg. or less than about 100 mg. or 15 375 mg. or less than about 350 mg, or less than about 325 mg. less than about 900 mg. or less than about 800 mg. or less than or less than about 300 mg. or less than about 275 mg, or less about 700 mg, or less than about 600 mg. or less than about than about 250 mg. or less than about 225 mg, or less than 550 mg. or less than about 500 mg. or less than about 400 mg. about 200 mg, or less than about 175 mg. or less than about or less than about 375 mg. or less than about 350 mg. or less 150 mg. or less than about 125 mg. or less than about 100 mg. than about 325 mg, or less than about 300 mg. or less than or less than about 90 mg. or less than about 80 mg. or less than about 275 mg, or less than about 250 mg. or less than about about 70 mg. or less than about 60 mg, or less than about 50 225 mg. or less than about 200 mg, or less than about 175 mg. mg, or less than about 40 mg. or less than about 30 mg, or less or less than about 150 mg. or less than about 125 mg, or less than about 20 mg, or less than about 10 mg. than about 100 mg. or less than about 90 mg. or less than about In some preferred embodiments, the dosage form includes 80 mg. or less than about 70 mg. or less than about 60 mg. or 25 poorly water soluble, high melting point (mp=45 to 100°C.) less than about 50 mg, or less than about 40 mg, or less than waxes in an amount that is less than about 1200 mg, or less about 30 mg. or less than about 20 mg, or less than about 10 than about 100 mg. or less than about 900 mg. or less than ng. about 800 mg, or less than about 700 mg. or less than about In some preferred embodiments, the dosage form includes 600 mg. or less than about 550 mg. or less than about 500 mg. polyoxyethylene Stearates in an amount that is less than about 30 or less than about 400 mg. or less than about 375 mg, or less 1200 mg. or less than about 100 mg, or less than about 900 than about 350 mg. or less than about 325 mg. or less than mg, or less than about 800 mg. or less than about 700 mg. or about 300 mg, or less than about 275 mg. or less than about less than about 600 mg. or less than about 550 mg. or less than 250 mg. or less than about 225 mg, or less than about 200 mg. about 500 mg, or less than about 400 mg. or less than about or less than about 175 mg. or less than about 150 mg. or less 375 mg. or less than about 350 mg, or less than about 325 mg. 35 than about 125 mg, or less than about 100 mg. or less than or less than about 300 mg. or less than about 275 mg, or less about 90 mg. or less than about 80 mg, or less than about 70 than about 250 mg. or less than about 225 mg, or less than mg, or less than about 60 mg. or less than about 50 mg, or less about 200 mg, or less than about 175 mg. or less than about than about 40 mg, or less than about 30 mg, or less than about 150 mg. or less than about 125 mg. or less than about 100 mg. 20 mg. or less than about 10 mg. or less than about 90 mg. or less than about 80 mg. or less than 40 In some preferred embodiments, the dosage form includes about 70 mg. or less than about 60 mg, or less than about 50 two or more compounds selected from the categories (i) to mg, or less than about 40 mg. or less than about 30 mg, or less (iv) from the group consisting of: (i) hydrogenated Type I or than about 20 mg, or less than about 10 mg. Type II vegetable oils; (ii) polyoxyethylene Stearates and In some preferred embodiments, the dosage form includes distearates; (iii) glycerol monostearate; (iv) poorly water polyoxyethylene distearates in an amount that is less than 45 soluble, high melting point (mp=45 to 100°C.) waxes in total about 1200 mg, or less than about 100 mg. or less than about (i.e. cumulative) amount that is less than about 1200 mg. or 900 mg. or less than about 800 mg. or less than about 700 mg. less than about 100 mg. or less than about 900 mg. or less than or less than about 600 mg. or less than about 550 mg. or less about 800 mg, or less than about 700 mg. or less than about than about 500 mg. or less than about 400 mg. or less than 600 mg. or less than about 550 mg. or less than about 500 mg. about 375 mg, or less than about 350 mg. or less than about 50 or less than about 400 mg. or less than about 375 mg, or less 325 mg. or less than about 300 mg, or less than about 275 mg. than about 350 mg. or less than about 325 mg. or less than or less than about 250 mg. or less than about 225 mg, or less about 300 mg, or less than about 275 mg. or less than about than about 200 mg. or less than about 175 mg. or less than 250 mg. or less than about 225 mg, or less than about 200 mg. about 150 mg, or less than about 125 mg. or less than about or less than about 175 mg. or less than about 150 mg. or less 100 mg. or less than about 90 mg. or less than about 80 mg. or 55 than about 125 mg, or less than about 100 mg. or less than less than about 70 mg, or less than about 60 mg, or less than about 90 mg. or less than about 80 mg, or less than about 70 about 50 mg. or less than about 40 mg, or less than about 30 mg, or less than about 60 mg. or less than about 50 mg, or less mg, or less than about 20 mg. or less than about 10 mg. than about 40 mg, or less than about 30 mg, or less than about In some preferred embodiments, the dosage form includes 20 mg. or less than about 10 mg. glyceryl behenate, glyceryl palmitostearate, Stearoyl mac 60 In some preferred embodiments, the dosage form includes rogolglycerides and/or lauroyl macrogolglycerides in an the dosage form includes two or more compounds selected amount that is less than about 1200 mg. or less than about 100 from the categories (i) to (iv) from the group consisting of mg, or less than about 900 mg. or less than about 800 mg. or (i) hydrogenated Type I or Type II vegetable oils; (ii) poly less than about 700 mg. or less than about 600 mg. or less than oxyethylene Stearates and distearates; (iii) glycerol about 550 mg, or less than about 500 mg. or less than about 65 monostearate; (iv) poorly water Soluble, high melting point 400 mg. or less than about 375 mg, or less than about 350 mg. (mp=45 to 100° C.) waxes in total (i.e. cumulative) amount or less than about 325 mg. or less than about 300 mg. or less that is less than about 1200 mg. or less than about 100 mg. or US 9,125,833 B2 89 90 less than about 900 mg. or less than about 800 mg. or less than devoid of vegetable waxes. In other embodiments, the dosage about 700 mg, or less than about 600 mg. or less than about form is devoid of mineral waxes. In other embodiments, the 550 mg. or less than about 500 mg. or less than about 400 mg. dosage form is devoid of petroleum waxes. In other embodi or less than about 375 mg. or less than about 350 mg. or less ments, the dosage form is devoid of synthetic waxes. In other than about 325 mg, or less than about 300 mg. or less than embodiments, the dosage form is devoid of nonionic emulsi about 275 mg, or less than about 250 mg. or less than about fying waxes or cetomacrogol emulsifying wax. In other 225 mg. or less than about 200 mg, or less than about 175 mg. embodiments, the dosage form is devoid of anionic emulsi or less than about 150 mg. or less than about 125 mg, or less fying wax. In other embodiments, the dosage form is devoid than about 100 mg. or less than about 90 mg. or less than about of carnauba wax. In other embodiments, the dosage form is 80 mg. or less than about 70 mg. or less than about 60 mg. or 10 less than about 50 mg, or less than about 40 mg, or less than devoid of microcrystalline wax. In other embodiments, the about 30 mg. or less than about 20 mg, or less than about 10 dosage form is devoid of yellow wax. In other embodiments, ng. the dosage form is devoid of white wax. In other embodi Representative examples of hydrogenated vegetable oils of ments, the dosage form is devoid of cetyl esters wax. In other the present invention include, without limitation, hydroge 15 embodiments, the dosage form is devoid of hydrogenated nated cottonseed oil (e.g., Akofine?R); Lubritab(R); SteroteXCR) castor oil. In other embodiments, the dosage form is devoid of NF), hydrogenated palm oil (Dynasan RP60; Softisan.R. 154), lanolin alcohols. In other embodiments, the dosage form is hydrogenated soybean oil (Hydrocote(R); Lipovol HS-KR); devoid of lanolin. In other embodiments, the dosage form is Sterotex(R) HM) and hydrogenated palm kernel oil (e.g., devoid of glyceryl palmitostearate. In other embodiments, the Hydrokote(R) 112). dosage form is devoid of cetostearyl alcohol. In other embodi Representative examples of polyoxyethylene Stearates and ments, the dosage form is devoid of beeswax. distearates of the present invention include, without limita In one preferred embodiment of the present invention, the tion, Polyoxyl 2, 4, 6, 8, 12, 20, 30, 40, 50, 100 and 150 abusable drug is combined with beeswax, hydroxypropyl stearates (e.g., Hodag R DGS: PEG-2 stearate; Acconon(R) methyl cellulose (e.g., HPMC K15M), silicon dioxide (alone 200-MS; HodagR 20-S; PEG-4 stearate; CerasyntR 616: 25 or in combination with Al-O; e.g., Aerosil R), Aerosil R. 200, KesscoR PEG 300 Monostearate; Acconon R 400-MS: Cera Aerosil R. COK84). syntR 660; CithrolR4MS; Hodag R 60-S; Kessco R. PEG 600 In one preferred embodiment of the present invention, the Monostearate; Cerasynt(R) 840; Hodag 100-S: MyrjR 51: abusable drug is combined with hydrogenated cottonseed oil PEG-30 stearate; polyoxyethylene (30) stearate; Crodet(R) (e.g., Sterotex(R) NF), hydroxypropyl methyl cellulose (e.g. S40; E431; Emerest(R2672: Atlas G-2153; Crodet(R) S50) and 30 HPMC K15M), fractionated coconut oil and silicon dioxide polyoxyl 4, 8, 12, 32 and 150 distearates (e.g., Lipo-PEG(R) (alone or in combination with Al-O; e.g., Aerosil R. Aerosil(R) 100-S: MyrjR59; HodagR 600-S: Ritox(R59; Hodag R22-S: 200, Aerosil R. COK84). PEG-4 distearate; HodagR 42-S; Kessco(R) PEG 400 DS: In another preferred embodiment of the present invention, HodagR 62-S; Kessco(R) PEG 600 Distearate; HodagR 154 the abusable drug is combined with glycerol monostearate S; Kessco R. PEG 1540 Distearate; Lipo-PEG(R) 6000-DS: 35 (e.g., CithrolR GMS), hydroxypropyl methyl cellulose (e.g. Protamate R 6000-DS). HPMC K10OM) and silicon dioxide (alone or in combination Representative examples of poorly water soluble, high with Al-O; e.g., Aerosil R, Aerosil(R) 200, Aerosil R. COK84). melting point (mp=45 to 100°C.) waxes of the present inven In yet another preferred embodiment of the present inven tion include, without limitation: (i) animal waxes; (ii) insect tion, the abusable drug is combined with hydrogenated palm waxes; (iii) Vegetable waxes; (iv) mineral waxes, (v) petro 40 kernel oil (e.g., Hydrokote(R) 112), hydroxypropyl methyl leum waxes; (vi) synthetic waxes; (vi) nonionic emulsifying cellulose (e.g., HPMC K15M) and silicon dioxide (alone or in waxes or cetomacrogol emulsifying wax (e.g., Colone NITM: combination with Al-O; e.g., Aerosil(R), Aerosil R. 200, Aero Crodex NTM; Emulgade 1000NITM; Permulgin DTM; Pola sil R. COK84). waxTM; Ritachol 2000; T-WaxTM); (vii) anionic emulsifying In one preferred embodiment of the present invention, wax (e.g., Colone HVTM; Crodex ATM: Cyclonette wax. Lan 45 release rate modifiers may be incorporated. Release rate ette wax SXTMBP); (viii) carnauba wax (also known as Brazil modifiers can also have additional useful properties that opti wax; caranda wax: E903); (ix) microcrystalline wax (also mize the formulation. known as amorphous wax: E907; petroleum ceresin: petro In one preferred embodiment of the present invention, also leum wax (microcrystalline)); (x) yellow wax (e.g., yellow included are cellulose and cellulose derivatives including, beeswax: ApifilTM; E901; refined wax: (xi) white wax 50 without limitation cellulose acetate, microcrystalline cellu (bleached wax: E901); (xii) cetyl esters wax (e.g., cera cetyla; lose, powdered cellulose, cellulose acetate phthalate, Crodamol SSTM; Cutina CPTM; Liponate SPSTM; Protachem hydroxyethyl cellulose, silicified microcrystalline cellulose, MSTTM; RitacetiTM; Ritachol SSTM; spermaceti wax replace hydroxypropyl cellulose, hydroxyethylmethyl cellulose, ment; Starfol wax CGTM: Synaceti 116TM; synthetic sper low-substituted hydroxypropyl cellulose, carboxymethylcel maceti), (xiii) hydrogenated castor oil (e.g., CastorwaxTM; 55 lulose, carboxymethylcellulose calcium, hypromellose Castorwax MP 70TM: Castorwax MP 80TM; CroduretTM; acetate Succinate, hypromellosephthalate and ethylcellulose. Cutina HRTM; FancolTM; Simulsol 1293TM); (xiv) lanolin In one preferred embodiment of the present invention, also alcohols (e.g., Cholesterol; lanolin; lanolin, hydrous; petro included are coconut oil products, including without limita latum and lanolin alcohols; mineral oils); (XV) lanolin (e.g., tion, coconut oil, fractionated coconut oil, cetyl alcohol, lau ceralanae; E913; lanolina; lanolin anhydrous; Protalan anhy 60 ric acid and medium chain triglycerides (e.g., Bergabest; drous; purified lanolin; refined wool fat); (xvi) glyceryl caprylic/capric triglyceride; Captex 300; Captex 355; palmitostearate; (Xvii) cetostearyl alcohol (e.g., cetearyl alco Crodamol GTC/C; glyceryl tricaprylate/caprate; Labrafac hol; Crodacol CS90TM; Lanette OTM, Tego Alkanol 1618TM; CC; MCT oil; Miglyol 810TM; Miglyol 812TM; Myritol; Tego Alkanol 6855TM); (xviii) beeswax. Neobee M5TM; NesatolTM; oleum neutrale; oleum vegetable In some embodiments, the dosage form is devoid of animal 65 tenue; thin vegetable oil; Waglinol 3/9280TM). In a most pre waxes. In other embodiments, the dosage form is devoid of ferred embodiment, the coconut oil is fractionated coconut insect waxes. In other embodiments, the dosage form is oil. US 9,125,833 B2 91 92 In one preferred embodiment of the present invention, oil; (ii) a hydrogenated Type II vegetable oil; (iii) a polyoxy hydroxypropyl methyl cellulose (e.g., HPMC K15M) may be ethylene Stearate; (iv) a polyoxyethylene distearate; (V) a incorporated. glycerol monostearate; and (vi) a wax. A variety of agents may be incorporated into the ADER In some particularly preferred embodiments, the abuse invention as thixotropes (e.g., fumed silicon dioxides, Aero deterrent, extended release, resistance against alcohol dose sil R, Aerosil R. COK84, Aerosil R. 200, etc.). Thixotropes dumping when formulated as extended release, and/or abuse enhance the pharmaceutical formulations of the invention by deterrent plus extended release dosage form of the invention increasing the Viscosity of solutions during attempted extrac comprises at least two ADER agents, selected from at least tion, complementing the action of HPMCs. They may also two groups, comprising: (i) a hydrogenated Type I vegetable provide a tamper resistance by helping to retain the structure 10 oil; (ii) a hydrogenated Type II vegetable oil; (iii) a polyoxy of dosage units that have been heated to temperatures greater ethylene Stearate; (iv) a polyoxyethylene distearate; (V) a than the melting point of the base excipient (Aerosils are glycerol monostearate; and (vi) a wax, said dosage form unaffected by heat). having a melting point >50° C., or >55° C., or >60° C., or As described above, the present invention can include one >65° C., or >70° C., or >75° C., or >80° C., or >85°C., or or more ADER agents. Any amount of ADER may be used. In 15 >90° C., or between 50 and 60°C., or between 55 and 65°C., some embodiments, the total amount of ADER agent is about or between 60 and 70° C., or between 65 and 75° C., or 5 to about 98 percent, preferably 7 to 90 percent and more between 70 and 80°C., or between 75 and 85°C., or between preferably 10 to 85 percent on a dry weight basis of the 80 and 90° C., or between 90 and 100° C., or between 50 and composition. 100° C., or between 60 and 100° C., or between 70 and 100° In one preferred embodiment, the ADER can prevent less C., or between 80 and 100° C., or between 60 and 80°C., or than or equal to about 98%, 90%, 80% 75%, 60%, 50%, 45%, between 60 and 90° C., or between 65 and 85°C., or between 40%, 33%, 30%, 25%, 15%, 10%, 8%, 5%, or 2% of the total 7O and 90° C. amount of drug in a dosage form from being recovered from In other particularly preferred embodiments, the abuse a solvent in contact with a dosage form of the present inven deterrent, extended release, resistance against alcohol dose tion. 25 dumping when formulated as extended release, and/or abuse In Some preferred embodiments, the dosage form is devoid deterrent plus extended release dosage form of the invention of hydrogenated Type I vegetable oils. In other embodiments, comprises at least two ADER agents, selected from at least the dosage form is devoid of hydrogenated Type II vegetable two groups, comprising: (i) hydrogenated Type I or Type II oils. In other embodiments, the dosage form is devoid of Vegetable oil; (ii) polyoxyethylene Stearate or distearate; (iii) polyoxyethylene Stearates. In other embodiments, the dosage 30 a glycerol monostearate; and (iv) a wax. form is substantially of polyoxyethylene distearates; in other In other particularly preferred embodiments, the abuse embodiments, the dosage form is substantially of glycerol deterrent, extended release, resistance against alcohol dose monostearate. In other embodiments, the dosage form is Sub dumping when formulated as extended release, and/or abuse stantially of poorly water Soluble, high melting point (mp-45 deterrent plus extended release dosage form of the invention to 100° C.) waxes. 35 comprises at least two ADER agents, selected from at least In preferred embodiments, the abuse deterrent, extended two groups, comprising: (i) hydrogenated Type I or Type II release, alcohol dose dumping protective and/or abuse deter Vegetable oil; (ii) polyoxyethylene Stearate or distearate; (iii) rent plus extended release dosage form of the invention com a glycerol monoStearate; and (iv) a wax, said dosage form prises at least two ADER agents, each a hydrogenated Type I having a melting point >50° C., or >55° C., or >60° C., or vegetable oil. In other embodiments, the abuse deterrent, 40 >65° C., or >70° C., or >75° C., or >80° C., or >85°C., or extended release and/or abuse deterrent plus extended release >90° C., or between 50 and 60°C., or between 55 and 65°C., dosage form of the invention comprises at least two ADER or between 60 and 70° C., or between 65 and 75° C., or agents, each a hydrogenated Type II vegetable oil. In other between 70 and 80°C., or between 75 and 85°C., or between embodiments, the abuse deterrent, extended release and/or 80 and 90° C., or between 90 and 100° C., or between 50 and abuse deterrent plus extended release dosage form of the 45 100° C., or between 60 and 100° C., or between 70 and 100° invention comprises at least two ADER agents, each a hydro C., or between 80 and 100° C., or between 60 and 80°C., or genated Type I or Type II vegetable oil. In other embodiments, between 60 and 90° C., or between 65 and 85°C., or between the abuse deterrent, extended release and/or abuse deterrent 7O and 90° C. plus extended release dosage form of the invention comprises The present invention can also optionally include other at least two ADER agents, each a polyoxyethylene Stearate. In 50 ingredients to enhance dosage form manufacture from a phar other embodiments, the abuse deterrent, extended release maceutical composition of the present invention and/or alter and/or abuse deterrent plus extended release dosage form of the release profile of a dosage form including a pharmaceu the invention comprises at least two ADER agents, each a tical composition of the present invention. polyoxyethylene distearate. In other embodiments, the abuse Some embodiments of the present invention include one or deterrent, extended release and/or abuse deterrent plus 55 more pharmaceutically acceptable fillers, diluents, glidants extended release dosage form of the invention comprises at and lubricants of various particle sizes and molecular least two ADER agents, each a glycerol monostearate. In weights. other embodiments, the abuse deterrent, extended release The dosage form according to the invention may also com and/or abuse deterrent plus extended release dosage form of prise a coating which is resistant to gastric juices and dis the invention comprises at least two ADER agents, each a 60 solves as a function of the pH value of the release environ Wax. ment. By means of this coating, it is possible to ensure that, In some particularly preferred embodiments, the abuse when correctly administered, the dosage form according to deterrent, extended release, resistance against alcohol dose the invention passes through the stomach undissolved and the dumping when formulated as extended release, and/or abuse active ingredient is only released in the intestines. deterrent plus extended release dosage form of the invention 65 In some preferred embodiments, the dosage form may comprises at least two ADER agents, selected from at least include a Surfactantingredient to impart Suitable formulation two groups, comprising: (i) a hydrogenated Type I vegetable characteristics to the composition. Surfactants may be hydro US 9,125,833 B2 93 94 philic preferably selected from the group consisting of non lyceride, isopropyl myristate, ethyl oleate, triethyl citrate, ionic hydrophilic Surfactants and anionic hydrophilic Surfac dimethyl phthalate, and benzyl benzoate. tants or the Surfactant may have hydrophobic properties. The pharmaceutical compositions and dosage form of the Examples of non-ionic hydrophilic Surfactants are polyoxy invention may further contain one or more pharmaceutically ethylene Sorbitan esters, cremophores and poloxamers. acceptable excipients. When used in the present invention, Examples of anionic Surfactants are sodium lauryl sarcosi pharmaceutically acceptable excipients can play a small or nate, docusate and pharmaceutically acceptable docusate significant role in the behavior of the dosage form, depending salts. Also a mixture of these Surfactants can be used. on the choice of excipient, quantity of excipient and interac The formulation optionally comprises auxiliary materials. tion with other constituents of the dosage form and the gas Examples of these auxiliary materials (or pharmaceutically 10 acceptable excipients) are (i) Binders such as acacia, alginic trointestinal tract. Pharmaceutically acceptable excipients are acid and salts thereof, cellulose derivatives, methylcellulose, well known in the art and include, without limitation, excipi hydroxyethyl cellulose, hydroxypropyl cellulose, magne ents referenced in the FDA EAFUS database (http://vm.cf. sium aluminum silicate, polyethylene glycol, gums, polysac san.fda.gov/-dims/eafus.html); FDA Food Additives Status charide acids, bentonites, hydroxypropyl methylcellulose, 15 List (http://www.cfsan.fda.gov/~dmS/opa-appa.html); FDA gelatin, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl GRAS list and database; FDA Color Additive Status List acetate copolymer, crospovidone, povidone, polymethacry (http://www.cfsan.fda.gov/~dmS/opa-appc.html); FDA Inac lates, hydroxypropylmethylcellulose, hydroxypropylcellu tive Ingredients Database (http://www.accessdata.fda.gov/ lose, starch, pregelatinized starch, ethylcellulose, tragacanth, scripts/cder/iig/index.cfm); Rowe. Sheskey and Owen, dextrin, microcrystalline cellulose. Sucrose, or glucose, and Handbook of Pharmaceutical Excipients, APhA Publica the like; (ii) Disintegrants such as starches, pregelatinized tions; 5th edition (2006); Remington: The Science and Prac corn starch, pregelatinized Starch, celluloses, cross-linked tice of Pharmacy, 21st ed., Lippincott Williams & Wilkins carboxymethylcellulose, crospovidone, cross-linked polyvi (2005); United States Pharmacopeia-National Formulary nylpyrrolidone, a calcium or a sodium alginate complex, (USP-NF), (USP 30-NF 25, 2007), the International Pro clays, alginates, gums, or Sodium starch glycolate, and any 25 gramme on Chemical Safety (http://www.inchem.org/) and disintegration agents used in tablet preparations; (iii) Filling Health Canada's List of Acceptable Non-medicinal Ingredi agents such as lactose, calcium carbonate, calcium phos ents (http://www.hc-sc.gc.ca/dhp-mps/prodnatur/legislation/ phate, dibasic calcium phosphate, calcium sulfate, microc docs/nmi-imn list1 e.html), all hereby incorporated by ref rystalline cellulose, cellulose powder, dextrose, dextrates, erence in their entirety. dextran, starches, pregelatinized starch, Sucrose, Xylitol, lac 30 titol, mannitol, Sorbitol, Sodium chloride, polyethylene gly The dosage form according to the invention may also com col, and the like; (iv) Stabilizers such as any antioxidation prise a coating which is resistant to gastric juices and dis agents, reducing agents, buffers, or acids, sodium citrate, solves as a function of the pH value of the release environ ascorbyl palmitate, propyl gallate, ascorbic acid, vitamin E, ment. sodium bisulfite, butylhydroxyl toluene, BHA, acetylcys 35 By means of this coating, it is possible to ensure that, when teine, monothioglycerol, phenyl-alpha-nathylamine, lecithin, correctly administered, the dosage form according to the EDTA, and the like: (v) Lubricants such as magnesium Stear invention passes through the stomach undissolved and the ate, calcium hydroxide, talc, colloidal silicon dioxide, sodium active ingredient is only released in the intestines. Stearyl fumarate, hydrogenated vegetable oil, Stearic acid, In one preferred embodiment of the invention, the formu glyceryl behenate, magnesium, calcium and sodium Stear 40 lation is ingested orally as a tablet or capsule, preferably as a ates, Stearic acid, talc, waxes, Stearowet, boric acid, sodium capsule. In another preferred embodiment of the invention, benzoate, Sodium acetate, sodium chloride, DL-leucine, the formulation is administered bucally. In yet another pre polyethylene glycols, sodium oleate, or sodium lauryl Sulfate, ferred embodiment of the invention, the formulation is and the like; (vi) Wetting agents such as oleic acid, glyceryl administered Sublingually. monostearate, Sorbitan monooleate, Sorbitan monolaurate, 45 In one preferred embodiment, the invention provides for triethanolamine oleate, polyoxyethylene Sorbitan methods and pharmaceutical compositions to prevent or monooleate, polyoxyethylene Sorbitan monolaurate, sodium minimizing excessive peak concentrations (dose dumping) of oleate, or sodium lauryl sulfate, and the like: (vii) Diluents therapeutic doses of extended release abusable drugs for Such lactose, starch, mannitol, Sorbitol, dextrose, microcrys medical purposes, when they are co-ingested with alcohol. talline cellulose, dibasic calcium phosphate. Sucrose-based 50 In one preferred embodiment, the invention provides for diluents, confectioner's Sugar, monobasic calcium Sulfate methods and pharmaceutical compositions to achieve an monohydrate, calcium Sulfate dihydrate, calcium lactate tri extended release formulation of abusable drugs. hydrate, dextrates, inositol, hydrolyzed cereal Solids, amy In one preferred embodiment, the invention provides for lose, powdered cellulose, calcium carbonate, glycine, or ben methods and pharmaceutical compositions to achieve an tonite, and the like; (viii) Anti-adherents or glidants such as 55 talc, corn starch, DL-leucine, Sodium lauryl Sulfate, and mag abuse deterrent formulation of abusable drugs. nesium, calcium, or sodium Stearates, and the like; (ix) Phar In one preferred embodiment, the invention provides for maceutically compatible carriers such as acacia, gelatin, col methods and pharmaceutical compositions to simultaneously loidal silicon dioxide, calcium glycerophosphate, calcium achieve an extended release and abuse deterrence for abus lactate, maltodextrin, glycerin, magnesium silicate, sodium 60 able drugs. caseinate, soy lecithin, Sodium chloride, tricalcium phos In one preferred embodiment, the invention provides for phate, dipotassium phosphate, sodium Stearoyl lactylate, car methods and pharmaceutical compositions to simultaneously rageenan, monoglyceride, diglyceride, or pregelatinized achieve an extended release and abuse deterrence for abus starch, and the like: (X) Other pharmaceutical excipients able drugs, using Substantially the same excipients. including polymers, hydrogels, silicon dioxide, ion exchange 65 In one preferred embodiment, the invention provides for resins, cellulose acetate butyrate, carbohydrate polymers, methods and pharmaceutical compositions to achieve abuse organic acids of carbohydrate polymers caprylic/capric trig deterrence, without the use of aversive agents. US 9,125,833 B2 95 96 In one preferred embodiment, the invention provides for and/or (iv) resistance against alcohol dose dumping when methods and pharmaceutical compositions to simultaneously formulated as extended release; and/or (v) more than one of achieve extended release and abuse deterrence, without the the foregoing (i) to (iv) properties; said invention compris use of aversive agents. ing one or more abusable drugs and one or more ADER In one preferred embodiment, the invention provides for agents; said invention using Substantially the same ADER methods and pharmaceutical compositions to simultaneously agents to achieve the foregoing (i) to (V). achieve an extended release formulation and an abuse deter In one preferred embodiment, the invention provides for rence formulation, using substantially the same ADER methods and pharmaceutical compositions to achieve the fol agents. lowing properties: (i) abuse deterrence; and/or (ii) extended In one preferred embodiment, the invention provides for 10 release; and/or (iii) resistance against alcohol dose dumping; methods and pharmaceutical compositions to achieve one or and/or (iv) resistance against alcohol dose dumping when more of the following properties: (a) abuse resistance; (b) formulated as extended release; and/or (v) more than one of extended release; (c) resistant to dose dumping due to alco the foregoing (i) to (iv) properties; said invention compris hol; (d) resistant to significant changes in oral bioavailability ing one or more abusable drugs and one or more ADER due to changes in food intake; (e) resistant to intentional or 15 agents; said invention using Substantially the same ADER Surreptitious adulteration of beverages. agents to achieve the foregoing (i) to (V); said invention pro In one preferred embodiment, the invention provides for viding abuse deterrence without the use of aversive agents. methods and pharmaceutical compositions to achieve two ore In one preferred embodiment, the invention provides for more of the following properties: (a) abuse resistance; (b) methods and pharmaceutical compositions to achieve the fol extended release; (c) resistant to dose dumping due to alco lowing properties: (i) abuse deterrence; and/or (ii) extended hol; (d) resistant to significant changes in oral bioavailability release; and/or (iii) resistance against alcohol dose dumping; due to changes in food intake; (e) resistant to intentional or and/or (iv) resistance against alcohol dose dumping when Surreptitious adulteration of beverages. formulated as extended release; and/or (v) more than one of In one preferred embodiment, the invention provides for the foregoing (i) to (iv) properties; said invention compris methods and pharmaceutical compositions to achieve three or 25 ing one or more abusable drugs and at least two ADER agents. more of the following properties: (a) abuse resistance; (b) In one preferred embodiment, the invention provides for extended release; (c) resistant to dose dumping due to alco methods and pharmaceutical compositions to achieve the fol hol; (d) resistant to significant changes in oral bioavailability lowing properties: (i) abuse deterrence; and/or (ii) extended due to changes in food intake; (e) resistant to intentional or release; and/or (iii) resistance against alcohol dose dumping; Surreptitious adulteration of beverages. 30 and/or (iv) resistance against alcohol dose dumping when In one preferred embodiment, the invention provides for formulated as extended release; and/or (v) more than one of methods and pharmaceutical compositions to achieve four or the foregoing (i) to (iv) properties; said invention compris more of the following properties: (a) abuse resistance; (b) ing one or more abusable drugs and at least two ADER agents; extended release; (c) resistant to dose dumping due to alco said invention providing abuse deterrence without the use of hol; (d) resistant to significant changes in oral bioavailability 35 aversive agents. due to changes in food intake; (e) resistant to intentional or In one preferred embodiment, the invention provides for Surreptitious adulteration of beverages. methods and pharmaceutical compositions to achieve the fol In one preferred embodiment, the invention provides for lowing properties: (i) abuse deterrence; and/or (ii) extended methods and pharmaceutical compositions to achieve the fol release; and/or (iii) resistance against alcohol dose dumping; lowing properties: (a) abuse resistance; (b) extended release; 40 and/or (iv) resistance against alcohol dose dumping when (c) resistant to dose dumping due to alcohol; (d) resistant to formulated as extended release; and/or (v) more than one of significant changes in oral bioavailability due to changes in the foregoing (i) to (iv) properties; said invention compris food intake; (e) resistant to intentional or Surreptitious adul ing one or more abusable drugs and at least two ADER agents; teration of beverages. said invention using Substantially the same ADER agents to In one preferred embodiment, the invention provides for 45 achieve the foregoing (i) to (V). methods and pharmaceutical compositions to achieve the fol In one preferred embodiment, the invention provides for lowing properties: (i) abuse deterrence; and/or (ii) extended methods and pharmaceutical compositions to simultaneously release; and/or (iii) resistance against alcohol dose dumping; achieve an extended release formulation and an abuse deter and/or (iv) resistance against alcohol dose dumping when rence formulation, using Substantially the same ADER agents formulated as extended release; and/or (v) more than one of 50 without the use of aversive agents. the foregoing (i) to (iv) properties; said invention compris It is understood that each of the various embodiments of ing one or more abusable drugs and one or more ADER methods and pharmaceutical compositions described herein agents. may be used alone or in conjunction with one or more or all of In one preferred embodiment, the invention provides for the various embodiments described herein. methods and pharmaceutical compositions to achieve the fol 55 Additionally, it is understood that each of the various lowing properties: (i) abuse deterrence; and/or (ii) extended embodiments of the pharmaceutical compositions described release; and/or (iii) resistance against alcohol dose dumping; herein may be used with each of the various embodiments of and/or (iv) resistance against alcohol dose dumping when the described method of the present invention as described formulated as extended release; and/or (v) more than one of herein. the foregoing (i) to (iv) properties; said invention compris 60 Determination of Biologic Effects in Humans ing one or more abusable drugs and one or more ADER The pharmacologic effects of the pharmaceutical compo agents; said invention providing abuse deterrence without the sitions of the present invention can be evaluated using meth use of aversive agents. ods well established in the art. The choice of method will In one preferred embodiment, the invention provides for depend, among other things, on: (i) the abusable drug and (ii) methods and pharmaceutical compositions to achieve the fol 65 the therapeutic use to which the abusable drug is applied (i.e., lowing properties: (i) abuse deterrence; and/or (ii) extended the disease, disorder, or symptom(s) being treated with the release; and/or (iii) resistance against alcohol dose dumping; abusable drug). Opioid analgesics, while primarily used for US 9,125,833 B2 97 98 the treatment of pain have multiple therapeutic applications. ments. Both single and multiple (repeated) dose studies may Additionally, certain evaluations may be conducted in be conducted. Patients are encouraged to wait at least 60 healthy Subjects, recreational drug users or drug addicts. A minutes before requesting remedication for pain. At the wide variety of clinical states and study designs may be used completion of the single-dose phase (8 hours) or at first to evaluate the therapeutic effects of intact and tampered request for remedication (whichever is earlier), patients enter dosage forms of the invention. This invention therefore con into a multiple-dose phase lasting approximately 72 hours. templates the use of test methods other than those specifically During the multiple dose phase patients receive study medi disclosed herein, including those which may hereafter cation or placebo at a fixed dose interval (e.g., every 8, 12 or become known to the art to be capable of performing the 24 hours). Once the multiple dose phase of the study has necessary functions. Sample sizes in the studies are sufficient 10 begun, patients experiencing pain between scheduled doses to demonstrate the objectives of the testing. A non-limiting of study medication are provided access to Supplemental list of methods to evaluate the analgesic and other effects of open-label (rescue) analgesia. Patients whose pain cannot be the invention is provided below: adequately managed on a combination of study medication Third Molar Extraction Model and rescue medication or who develop unacceptable side Male and female patients with acute postSurgical pain fol 15 effects during the study are discontinued from further study lowing the removal of one or more bony impacted third participation and their pain managed conventionally. molars are participants. Within 4 to 6 hours after completion Pain intensity (VAS and categorical), pain relief (categori of Surgery, patients who are experiencing moderate or severe cal) and whether pain is half-gone is recorded by the patient pain, as measured by a visual analog pain intensity scale under the Supervision of the investigator study coordinator at (VAS250 mm) and by a categorical pain intensity Scale (mod representative time points, e.g., Baseline (pain intensity erate or severe pain descriptor), and who meet all other inclu only), 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7 and 8 sion/exclusion criteria are admitted to the study. Patients are hours after administration of study medication and immedi randomly assigned to receive the dosage form of the invention ately prior to the first remedication. Sedation and nausea may given intact or placebo, in some preferred embodiments, and be evaluated using VAS or categorical scales. Time to onset of the dosage form of the invention given intact or dosage form 25 perceptible and meaningful pain relief is evaluated using the of the invention given in tampered form in other embodi double-stopwatch method. Patients complete a global evalu ments. Both single and multiple (repeated) dose studies may ation of study medication at the completion of the 8-hour be conducted. Pain intensity (VAS and categorical), pain assessment or just prior to the first remedication. Following relief (categorical) and whether pain is half-gone is recorded completion of the single-dose phase (8 hours or just prior to by the patient under the Supervision of the investigator study 30 first remedication, if s8 hours), patients begin the multiple coordinator at the various time points: Baseline (0hour pain dose phase of the study. During the multiple dose phase, intensity only), 15, 30 and 45 minutes, and at 1, 1.5, 2, 3, 4, 5, patients record their overall pain intensity since the previous 6, 7, 8 and 12 hours after administration of study medication, scheduled dose, their current pain intensity and a patient and immediately prior to the first rescue dose. Sedation and global, immediately prior to each scheduled dose of study nausea may be evaluated using VAS or categorical scales. 35 medication and at early termination. Time to onset of perceptible and meaningful pain relief is Measures of efficacy in the single-dose phase include Sum evaluated using the two stopwatch method. Patients record of Pain Intensity Difference (SPID), Total Pain Relief (TOT their global evaluation of study medication at the completion PAR), Sum of Pain Relief Intensity Difference (SPRID), of the 8-hour assessment or at the time of first rescue medi Time to First Remedication, Time Specific Pain Intensity cation use. Efficacy endpoints include Total Pain Relief 40 Difference (PID), Time Specific Pain Relief (PR), Peak Pain (TOTPAR), Sum of Pain Intensity Difference (SPID) and Intensity Difference (PPID), Peak Pain Relief (PPR), Time to Sum of Pain Relief Intensity Difference (SPRID) at various Confirmed Perceptible Pain Relief (stopwatch), Time to time points, Time to First Rescue, Time Specific Pain Inten Meaningful Pain Relief (stopwatch), Patient Global Evalua sity Difference (PID), Time Specific Pain Relief (PR), Peak tion, Time to Change in Categorical PID-1, Percent Change Pain Intensity Difference (PPID), Peak Pain Relief (PPR), 45 in Pain Intensity Score from Baseline, Mean Change in Pain Time to Confirmed Perceptible Pain Relief (stopwatch), Time Intensity Score From Baseline, Percent Change in Pain Relief to Meaningful Pain Relief (stopwatch), Patient Global Evalu Score from Baseline. Mean Change in Pain Relief Score ation, Time to Change in Categorical PID-1, Percent Change From Baseline, Percent of Responders, Number of Patients in Pain Intensity Score from Baseline. Mean Change in Pain Needed to Treat to Obtain One Patient with >50% Response Intensity Score From Baseline, Percent Change in Pain Relief 50 (NNT). Score from Baseline, Mean Change in Pain Relief Score Measures of efficacy in the multiple-dose phase include the From Baseline, Percent of Responders, Number of Patients time specific overall pain intensity, current pain intensity and Needed to Treat to Obtain One Patient with >50% Response patient global at the time of scheduled remedication, the (NNT). average of overall pain intensity, current pain intensity and Bunionectomy Surgery 55 patient global over 0-24, 24-48 and 48-72 and number of Male or female patients requiring primary unilateral first doses of rescue analgesic over 0-24, 24-48 and 48-72 and metatarsal bunionectomy Surgery alone or with ipsilateral 0-72 hours. hammertoe repair (without additional collateral procedures) Chronic Pain of Osteoarthritis under regional anesthesia (Mayo block) are participants. The analgesic efficacy of the invention may be demon Patients who experience moderate or severe pain on a 60 strated in single or repeated dose randomized double-blind, categorical scale (moderate or severe descriptor) and on a controlled studies. Patients are randomized to receive the visual analog pain intensity scale (VAS; >50 mm) within 6 dosage form of the invention given intact or placebo, in some hours following completion of bunionectomy Surgery are preferred embodiments, and the dosage form of the invention randomly assigned to receive the dosage form of the invention given intact or dosage form of the invention given in tampered given intact or placebo In some preferred embodiments, and 65 form in other embodiments. In repeated dose studies, typi the dosage form of the invention given intact or dosage form cally, patients who meet the American College of Rheuma of the invention given in tampered form in other embodi tology criteria for knee and/or hip OA are washed off their US 9,125,833 B2 99 100 analgesics for 2 to 7 days to allow for pain of moderate to neuralgia >3 months and pain of at least moderate intensity severe intensity to return. Once a stable baseline pain score is are enrolled in the study. Patients with hypersensitivity to established, patients are randomized to treatment, usually for study medications, a history of drug or alcohol abuse and a period of 1 to 12 weeks. Pain, joint stiffness and physical significant pain of alternate etiology are generally excluded. function can be measured with a multidimensional instru Patients meeting study eligibility criteria are “washed off ment, such as the WOMAC, quality of life with the SF-12 or their analgesics in some embodiments, generally for 2 to 7 SF-36 and adverse events with a non-directed questionnaire days to allow for pain of moderate to severe intensity to at baseline and at post-baseline return visits. Response to return. Once a stable baseline pain score is established, pain, stiffness, physical function, quality of life and adverse patients are randomized to treatment, usually for a period of 4 events are calculated as change from baseline and compared 10 to 12 weeks. Pain intensity is assessed one to several times a between treatments. Sedation and nausea may be evaluated day and in some cases only once weekly using VAS, categori using VAS or categorical scales. cal or numerical rating scales. Various dimensions of neuro Migraine pathic pain may be assessed, including steady pain (ongoing The analgesic efficacy of the invention may be demon pain), brief pain (paroxysmal pain) and skin pain (allodynia). strated in single or repeated dose randomized double-blind, 15 Pain may also be assessed at Scheduled clinic study visits. controlled studies. Patients are randomized to receive the Pain may also be assessed using standardized pain scales Such dosage form of the invention given intact or placebo, in some as the Neuropathic Pain Scale (Galer et al., Neurology 1997: preferred embodiments, and the dosage form of the invention 48:332-8), the Neuropathic Pain Symptom Inventory (Bou given intact or dosage form of the invention given in tampered hassira et al., Pain 2004: 108:248-57), interference measures form in other embodiments. Patients with migraine head of the Brief Pain Inventory (Cleeland, CRC Press, 1991: aches are typically evaluated in prospective, randomized, 293–305 and Ann Acad Med Singapore 1994; 23:129-38) or double-blind, parallel group, single-dose studies. Crossover the McGill Pain Questionnaire Short-Form (Melzack, Pain studies are also possible. The study population consists of 1987:30:191-7). Patient global assessment may be measured male and non-pregnant female Subjects, 18 to 65 years of age using a number of available tools, for example Patient Global with a primary headache diagnosis of either migraine attack 25 Impression of Change (Farrar et al., Pain 2001; 94:149-580). without aura or migraine attack with aura, as diagnosed Quality of life may similarly be assessed using number of according to the International Classification of Headache available tools, for example the SF-36, SF-12 or SF-8. Disorders-2 criteria. To qualify, the subject must typically Examples of randomized, placebo or active studies conducted have a history, on average, of at least one migraine attack per in postherpetic neuralgia are known in the art (e.g., Watson month, but an average of no more than 6 migraine attacks each 30 and Babul, Neurology 1998: 50:1837-41; Sabatowski et al., month during the past year. Using a headache diary Subjects Pain. 2004; 109:26-35; Rowbotham et al., JAMA. 1998; 280: are instructed to treat and evaluate the headache pain and 1837-42). Adverse events may be assessed using a non-di symptoms associated with one eligible migraine attack, with rected questionnaire, a symptom checklist or specific queries or without aura, with at least moderate headache pain inten on adverse signs and symptoms. Response to pain, function, sity. Eligible subjects are randomly assigned to receive the 35 quality of life and adverse events are calculated as change drug to treat one migraine attack, with or without aura, with from baseline and compared between treatments. Sedation headache pain of at least moderate pain intensity as deter and nausea may be evaluated using VAS or categorical scales. mined by them migraine questionnaire they are asked to take Evaluating Effects Fed and Fasted State on Oral Bioavailabil a single dose of study drug, according to their randomized ity treatment assignment. Headache pain intensity, nausea, pho 40 The effects of fed and fasted state of the invention, and in tophobia, phonophobia, Vomiting, and ability to function are particular, their effects on C, AUCo., and AUCo., can be assessed at baseline, 0.25, 0.5,0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 16 evaluated using methods well know in the art. More specifi and 24 hours post-dose. In addition, the recurrence of pain cally, the invention relies on the methods contained in the and use of any rescue mediation is documented. Primary document entitled: "Guidance for Industry: Food-Effect Bio efficacy variables typically consist of the percent of subjects 45 availability and Fed Bioeduivalence Studies: Study Design, who are without: (i) pain; (ii) nausea; (iii) photophobia and, Data Analysis and Labeling. Department of Health and (iv) phonophobia, each at 2 hours post-dosing. Secondary Human Services, Food and Drug Administration, Center for efficacy variables typically consist of headache pain intensity Drug Evaluation and Research, October, 2001, which is here and associated symptoms at each evaluation time point, inci incorporated by reference. Additional guidance on the con dence of Vomiting, patient function, Sum of pain intensity 50 duct of bioavailability studies is found in "Guidance for difference at each evaluation time (SPID), percent of subjects Industry: Bioavailability and Bioeduivalence Studies for who experience headache recurrence up to 24 hours, and the Orally Administered Drug Products-General Consider median time to recurrence. Sedation may be evaluated using ations'. Department of Health and Human Services, Food VAS or categorical scales. Recurrence is defined as the reduc and Drug Administration, Center for Drug Evaluation and tion in pain from moderate or severe pain to none at 2 hours 55 Research, July 2002, which is here incorporated by reference. after taking study drug, followed by: (i) an increase to mild, Alcohol induced dose dumping may be evaluated using the moderate or severe pain within 24 hours after taking the study above methods, where the test drug is co-administered with drug, or (ii) consuming a rescue medication within 24 hours and without a specified amount of ethanol. after taking the study drug. Tamper Resistance and Tamper Deterrence Testing Postherpetic Neuralgia 60 The popularity of immediate release formulations of abus The analgesic efficacy of the invention may be demon able drugs among drug addicts and recreational drug users is strated in repeated dose randomized double-blind, controlled in part due to the mood altering and reinforcing effects of the studies. Patients are randomized to receive the dosage form of drug. The popularity of extended release formulations of the invention given intact or placebo, in Some preferred abusable drugs among drug addicts and recreational drug embodiments, and the dosage form of the invention given 65 users is in part due to the pharmacologic properties of the drug intact or dosage form of the invention given in tampered form therein (e.g., mood altering and reinforcing effects) and in in other embodiments. Patients with a history of postherpetic part due to the large amount of drug per tablet or capsule (e.g., US 9,125,833 B2 101 102 a 12 or 24 hour Supply). For example commercially available Freeze and Crush immediate release abusable drugs tablets and capsules are Method: Freeze the dosage unit in a domestic freezer for 24 usually administered every 4 to 6 hours and they release their hr, then grind with a mortar and pestle for five minutes. Sieve through a suitable sieve (ca 600 micron) and, by weighing, dose into the systemic circulation over one to two hours. New, measure the percentage passing the sieve. extended release formulations are designed to gradually Taste of Base Excipient Mix (Organoleptic Test) release their much larger abusable drugs content over a 12 or Method: Chew a placebo mix for five minutes and rate the 24-hour period. Most recreational drug users and addicts have taste on a 0-10 scale with 0 as bland to repulsive at 10. This a unit of use which is one tablet or capsule. The 12 or 24-hour method is relevant only to dosage units containing taste modi Supply of an abusable drugs typically contained in one fiers. extended release tablet or capsule, instead of in 4 to 6 tablets 10 Extraction into Acid or capsules means that there is a greater risk that such formu Method: Crush with a mortar and pestle and heat to boiling lations may be highly sought by drug addicts and recreational in 5 mL of vinegar. The resulting Suspension is filtered drug users alike, for non-medical use. Intentional or inadvert through a 0.45 micron filter into a flask and diluted to 50 mL with water. Quantify drug concentration by HPLC. ent tampering from extended release formulations will rap 15 Application of Heat (Melting Temperature>50° C. Or 55° C.) idly deliver a massive dose and produce profound pharmaco Method: Heat the squashed contents of a dosage unit on a logic effects. hot plate until melted. Determine the temperature of melting Addicts and recreational drug users commonly use abus and test whether the mix becomes sufficiently fluid to be able drugs by a variety of routes of administration. Com drawn up into a syringe via a 1.2 mm needle then expelled. monly used methods include 1) parenteral (e.g., intravenous injection, where the drug is crushed and extracted or melted EXAMPLES and the contents of a dosage unit then injected), 2) intranasal (e.g., Snorting, where the drug is inhaled as powdered dosage Non-limiting examples for preparing the dosage form are unit), and 3) episodic or repeated oral ingestion of crushed set forth below. product, where the drug is chewed to increase the Surface area 25 and permit rapid release of drug Substance. All of these strat Detailed Description of the Preferred Embodiments egies are intended to more efficiently get the abusable drug into the CNS, both in terms of total amount of drug, peak The following examples illustrate various aspects of the concentration of drug and time to peak concentration of drug. present invention. They are not to be construed to limit the One mode of abuse involves the extraction of the drug 30 claims in any manner whatsoever. component from the dosage form by first mixing the tablet or A wide variety of methods known in the art for the prepa capsule with a suitable solvent (e.g., water or alcohol), and ration of immediate release and controlled release dosage then filtering and/or extracting the drug component from the forms may be incorporated into the invention. mixture for intravenous injection. Another mode of abuse of Other suitable abusable drugs as defined in this invention extended release drugs involves dissolving the drug in water, 35 may also be prepared by modification of the examples herein alcohol or another “recreational solvent to hasten its release and by use of material other than those specifically disclosed and to ingest the contents orally, in order to provide high peak herein, including those which may hereafter become known concentrations and maximum euphoriant effects. to the art to be capable of performing the necessary functions. It is necessary to be able to measure resistance or deter Other suitable modifications and adaptations of the variety of rence to the likely routes of abuse in a meaningful and rel 40 conditions and parameters normally encountered and obvious evant way. The in vitro tests below are provided for illustra to those skilled in the art are within the spirit and scope of the tion of Some testing methods and are intended to be non invention. limiting examples. This invention therefore contemplates the More than abusable drug may be included in the dosage use of test methods other than those specifically disclosed form either in an immediate release or extended release form herein, including those which may hereafter become known 45 The ingredients used for the preparation of the dosage form to the art to be capable of performing the necessary functions. may be modified depending on the selection of dose and Extraction With Alcohol on Whole Dosage Unit desired duration of effect of the abusable drug and any Method: Place a whole dosage unit in 18 mL of 0.1N HCl included aversive agent, pharmacologic antagonist or other in a 60 mLamber bottle and shake at 240 rpm on an orbital non-abusable therapeutic agent. In some embodiments, a shaker for 30 min. After 30 min add 12 mL of ethanol (95 50 change in the dose or amount of abusable drug does not 96%) to each bottle. Swirl by hand and remove a 1 mL sample require a change in amount of other ingredients. In other from each bottle (T). Place the solutions back in the orbital embodiments, a proportional change in the amount of other shaker for further shaking at 240 rpm. Take 1 mL samples ingredients is required to maintain the desired properties. In after 10, 20, 30, 40, 60 and 180 minoffurther shaking for each yet other embodiments, a change in the dose or amount of bottle. Analyze and graph the results on a linear scale of 55 abusable drug necessitates a change in the nature and/or cumulative release (%) vs. time (min). amount of ingredients to provide the required characteristics Extraction with Alcohol on a Crushed or Cut Dosage Unit of the abusable drug (e.g., immediate release, Sustained Extension of the above test. Method: Place a tablet (after release, duration of effect, rate and extent of absorption, crushing with a single crush with a spatula) or a capsule (cut therapeutic concentrations and effect, abuse deterrence prop in half) in 18 mL of 0.1N HCl in a 60 mL amber bottle and 60 erties, protection against alcohol dose dumping; and/or pro shake at 240 rpm on an orbital shaker for 30 min. Continue the tection against significant changes in bioavailability due to test as in 1) above. fed or fasted states etc.) Extraction into Water Optionally, aversive agents may be included selected from Method: Crush with a mortar and pestle and grind in 5 mL the group comprising (i) laxatives; (ii) cutaneous vasodila of water for 5 minutes. The resulting suspension is filtered 65 tors; (iii) headache producing agents; (iv) emetics, emetoge through a 0.45 micron filter into a flask and diluted to 50 mL nic and nausea producing compounds; (iv) bittering agents with water. Quantify drug concentration by HPLC. (V) mucosal, naso-mucosal, oro-mucosal, respiratory, tissue US 9,125,833 B2 103 104 and gastrointestinal irritants; (vi) tissue staining, non-tissue invention, in some embodiments, further comprising an staining and beverage staining dyes, lakes and colorants; (vii) immediate release form of the abusable drug; said invention, fecal and urine discolorants; (viii) malodorous agents; (ix) in some embodiments, further comprising an immediate opioid antagonists; and (X) and (X) benzodiazepine antago release form of the abusable drug in Solution, said invention, nists (e.g., flumazenil), and mixtures thereof. 5 in some embodiments, simultaneously providing more than The preparation of oral immediate release dosage forms is one of foregoing (i) to (V); said invention, in Some embodi well known in the art—see Remington: the science of Phar ments, simultaneously providing more than one of foregoing macy Practice, 21 Edition, 2006, Lippincott, Williams & (i) to (V) using Substantially the same ADER agents. Wilkins, Baltimore, Md., Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selec- 10 In some embodiments, the ADER material does not include tion to Commercial Dosage Form. Gibson, M (ed). CRC compounds selected from the group consisting of: (a) hydro Press, 2001; Niazi, S. Handbook of Pharmaceutical Manu genated Type I or Type II vegetable oils; (b) polyoxyethylene facturing Formulations: Uncompressed Solid Products (Vol Stearates and distearates; (c) glycerol monostearate; (d) ume 2 of 6), CRC Press, 2004; Niazi, S. Handbook of Phar poorly water soluble, high melting point (mp=45 to 100°C.) maceutical Manufacturing Formulations: Compressed Solid 15 waxes, and mixtures thereof. Instead, other ADER material of Products (Volume 1 of 6), CRC Press, 2004: Mollet, H, the invention described herein is utilized to achieve some or Grubenmann A. Payne H. Formulation Technology: Emul all of the objectives of the invention. sions, Suspensions, Solid Forms, Wiley-VCH, 2001; Niazi S Example 1 to 33 may be prepared as follows: (i) Dispense and Niazi SK, Pharmaceutical Capsules, 2" Ed., Podczeck, the hydrogenated Type I vegetable oil, hydrogenated Type II F and Jones B E (eds), Pharmaceutical Press, 2004, London 20 (all of which are hereby incorporated by reference). A major Vegetable oil, polyoxyethylene Stearates, polyoxyethylene ity of oral dosage forms commercially available world wide distearates, glycerol monostearate, poorly water soluble, high are formulated as immediate release products. melting point (mp=45 to 100°C.) waxes and/or other ADER Manufacturing methods described herein are utilized for material of the invention (e.g., glyceryl behenate, glyceryl the preparation of the abusable drugs as shown in the 25 palmitostearate, Stearoyl macrogolglycerides or lauroyl mac examples below. Variations to the methods may be employed, rogolglycerides) into a mixer; (ii) Heat until fully melted; (iii) in Some embodiments, depending on the specific chemical, dispense the hydroxypropyl methyl cellulose (HPMC) into physicochemical, pharmaceutical and pharmacologic prop the mixer; (iv) Mix until dispersed; (v) Dispense the Aerosil erties of the abusable drug, excipients and their interaction into the same vessel; (vi) Mix until dispersed; (vii) Dispense and other factors. Compositions and methods of the present 30 the desired abusable drug or mixture of abusable drugs into invention provide: (i) abuse deterrence; (ii) extended release: the same vessel; (viii) Stir thoroughly with a high shear and/or (iii) protection against alcohol dose dumping; and/or mixer: (ix) Transfer the mix into a liquid filling machine; (x) (iv) protection against significant changes in bioavailability Fill into hard gelatin (or HPMC) capsule; (xi) Optionally, due to fed or fasted states; and/or (v) simultaneously provid transfer the capsules to a banding machine and band the ing more than one of foregoing (i) to (iv); wherein the dosage 35 capsules. form is prepared using compounds selected from the group consisting of: (a) hydrogenated Type I or Type II vegetable oils; (b) polyoxyethylene Stearates and distearates; (c) glyc Example 1 erol monostearate; (d) poorly water soluble, high melting point (mp=45 to 100°C.) waxes, and mixtures thereof. 40 As shown in further examples below, any abusable drug of the invention may be prepared to provide (i) abuse deterrence; Ingredients Quantity (mg), Dose or (ii) extended release; or (iii) resistance againstalcohol dose dumping; or (iv) resistance against alcohol dose dumping Sterotex (R) NF 2OO when formulated as extended release; or (v) protection 45 Fractionated coconut oil 70 against significant changes in bioavailability due to fed or Methocel(R) K15M 81 fasted States; or (vi) more than one of the foregoing (i) to (v) properties; said invention comprising one or more abusable Aerosil (R) COK 84 4 drugs and one or more ADER agents; said invention, in some Oxycodone 2O embodiments, providing further abuse deterrence through the 50 use of aversive agents; said invention, in Some embodiments, Capsule fill weight 375 using Substantially the same ADER agents to achieve the foregoing (i) to (V); said invention, in some embodiments, providing more than one of the foregoing (i) to (v) proper ties; said invention, in Some embodiments, comprising one or 55 Example 2 more abusable drugs and at least two ADER agents; said invention, in Some embodiments, comprising at least two ADER agents selected from the group consisting of: (a) hydrogenated Type I or Type II vegetable oils; (b) polyoxy Ingredients Quantity (mg), Dose ethylene Stearates and distearates; (c) glycerol monostearate; 60 Sterotex (R) NF 135 (d) poorly water soluble, high melting point (mp=45 to 100° Fractionated coconut oil 50 C.) waxes; said invention, in some embodiments, comprising Methocel(R) K15M 60 at least two ADER agents selected from at least two catego Aerosil (R) COK 84 3 ries (a) to (d) from the group consisting of: (a) hydrogenated Levorphanol 2 Type I or Type II vegetable oils; (b) polyoxyethylene stearates 65 Capsule fill weight 250 and distearates; (c) glycerol monostearate; (d) poorly water soluble, high melting point (mp=45 to 100°C.) waxes; said US 9,125,833 B2 Example 3 Example 8

Ingredients Quantity (mg), Dose 5 Ingredients Quantity (mg), Dose Sterotex (R) NF 170 Hydrokote 112 250 Fractionated coconut oil 1OO HPMC, K15M 60 Methocel (R) K15M 70 Aerosil COK 84 10 Aerosil (R) COK 84 4.5 Oxycodone HCI 30 Hydromorphone 5.5 mg 10 Capsule fill weight 350 C apsulele fillIlli weightwe1g 350

Example 4 15 Example 9

Ingredients Quantity (mg), Dose Ingredients Quantity (mg), Dose Sterotex (R) NF 2OO 2O Beeswax 200 Fractionated coconut oil 90 HPMC, Pharmacoat 62.5 Methocel (R) K15M 8O 606 Aerosil (R) COK 84 5 Aerosil COK 84 7.5 Morphine HCl 25 Oxymorphone HCI 30 Capsule fill weight 400 mg 25 Capsule fill weight 300

Example 5 Example 10 30

Ingredients Quantity (mg), Dose Ingredients Quantity (mg), Dose Beeswax 200 Gelucire 5002 190 HPMC, K15M 8O 35 Methocel K10OM 35 Aerosil COK 84 8 Aerosil COK 84 10 Levorphanol 12 Hydromorphone HCl 15 Capsule fill weight 300 Capsule fill weight 250

Examplep 6 Example 11

45 Ingredientgredients Quantityti (mg),AD Dose Ingredients Quantity (mg), Dose Sterotex NF 150 HPMC, K1SM 75 Cetyl alcohol 28O Coconut oil 75 Methocel K10OM 50 Aerosil COK 84 5 50 Aerosil COK 84 10 Hydrocodone bitartrate 2O Morphine HCl 10 Capsule fill weight 325 Capsule fill weight 350

55 Example 7 Example 12

Ingredients Quantity (mg), Dose 60 Ingredients Quantity (mg), Dose Cithrol GMS 275 Sterotex NF 32O HPMC, K10OM 40 Methocel K. 15M 60 Aerosil COK 84 10 Aerosil COK 84 10 Morphine Sulfate 25 Hydromorphone HCl 10 Capsule fill weight 350 65 Capsule fill weight 400 US 9,125,833 B2 107 Example 13 -continued

Ingredients Quantity (mg), Dose

Ingredients Quantity (mg), Dose 5 Aerosil (R) COK 84 5 Morphine Sulfate 60 Cithrol GMS 320 Methocel K10OM Capsule fill weight 515 mg Aerosil COK 84 Levorphanol Tartrate 10 Capsule fill weight 400 10 Example 18 Example 14 15 Ingredients Quantity (mg), Dose Beeswax 150 Ingredients Quantity (mg), Dose HPMC, K15M 8O Aerosil COK 84 10 Sterotex (R) NF 100 Cith rol 150 Fractionated coconut oil 18 2O Oxymorphone HCI 2O Beeswax Methocel (R) K15M s Capsule fill weight 410 Aerosil (R) COK 84 Oxycodone HCI 2O

Capsule fill weight 375 25 Example 19 Example 15 30 Ingredients Quantity (mg), Dose Beeswax 150 Ingredients Quantity (mg), Dose HPMC, K15M 8O Aerosil COK 84 15 Sterotex (R) NF 135 Hydrokote 112 75 Fractionated coconut oil 50 Codeine Sulfate 60 Beeswax 52 35 Methocel (R) K15M s Capsule fill weight 380 Aerosil (R) COK 84 Morphine Sulfate 50

Capsule fill weight 350 40 Example 20 Example 16 Ingredients Quantity (mg), Dose 45 Sterotex NF 150 Ingredients Quantity (mg), Dose HPMC, K15M 75 Coconut oil 75 Sterotex (R) NF 130 Aerosil COK 84 5 Fractionated coconut oil 100 Oxymorphone HCI 2O Beeswax 70 Hydrokote 112 75 HPMC, K15M 2O.S 50 Methocel (R) K15M 70 Capsule fill weight 400 Aerosil (R) COK 84 4.5 Hydrocodone bitartrate 15 Capsule fill weight 410 55 Example 21

Example 17 Ingredients Quantity (mg), Dose 60 Cithro GMS 275 Ingredients Quantity (mg), Dose HPMC, K10OM 50 Aerosil COK 84 15 Sterotex (R) NF 150 Hydrokote 112 1OO Fractionated coconut oil 8O Methadone HCI 60 Cithro GMS 120 HPMC, K10OM 2O 65 Capsule fill weight 500 Methocel (R) K15M 8O US 9,125,833 B2 Example 22 Example 27

Ingredients Quantity (mg), Dose 5 Ingredients Quantity (mg), Dose Cithrol GMS 275 glyceryl behenate 135 HPMC, K10OM 60 Fractionated coconut oil 50 Aerosil COK 84 15 Methocel(R) K15M 60 Gelucire 50,02 100 Aerosil (R) COK 84 3 Methadone HCI 25 10 Levorphanol 2 Capsule fill weight 475 Capsule fill weight 250

Example 23 15 Example 28 Ingredients Quantity (mg), Dose Gelucire 5002 140 Ingredients Quantity (mg), Dose Methocel K10OM 35 Aerosil COK 84 15 2O Sterotex (R) NF 170 Sterotex (R) NF 75 glyceryl behenate 1OO Fractionated coconut oil 45 Methocel (R) K15M 70 Methadone HCI 15 Aerosil (R) COK 84 4.5 Levorphanol Tartrate 5.5 mg Capsule fill weight 325 25 Capsule fill weight 350

Example 24 Example 29

30 Ingredients Quantity (mg)/Dose Ingredients Quantity (mg), Dose Gelucire 50,02 100 glyceryl behenate 2OO Methocel K10OM 28 Fractionated coconut oil 90 Aerosil COK 84 12 35 Methocel(R) K15M 8O Beeswax 125 Aerosil (R) COK 84 5 HPMC, K15M 65 Oxycodone HCI 25 Propiram HCl 30 Capsule fill weight 370 Capsule fill weight 400 mg

40 Example 25 Example 30

Ingredients Quantity (mg), Dose 45 Ingredients Quantity (mg), Dose Gelucire 50,02 200 glyceryl behenate 2OO Methocel K10OM 60 HPMC, K15M 8O Aerosil COK 84 2O Aerosil COK 84 8 Cithrol GMS 140 Hydromorphone HCl 12 Propiram HCl 8O 50 Capsule fill weight 3OO Capsule fill weight 500

Example 31 Example 26 55

Ingredients Quantity (mg), Dose Ingredients Quantity (mg), Dose Glyceryl 150 Sterotex (R) NF 200 60 palmitostearate Fractionated coconut oil 70 HPMC, K15M 75 Methocel (R) K15M 81 Coconut oil 75 Aerosil (R) COK 84 4 Aerosil COK 84 5 Dihydrocodeine 2O Morphine Sulfate 2O Capsule fill weight 375 65 Capsule fill weight 325 US 9,125,833 B2 112 Example 32 canol), Lot AO19258301, ex Acros Organics, CithrolR GMS 04.00, Lot 6483-0103, ex Croda, Fractionated coconut oil, Lot Ingredients Quantity (mg), Dose 165544, ex A E Connock GelucireR 44/14, Lot 22009, ex Glyceryl 275 Gattefosse, GelucireR 50/02, Lot 19255, ex Gattefosse, palmitostearate Gelucire R 50/13, Lot 20529, ex Gattefosse, Hydrokote 112 HPMC, K10OM 40 Lot 048M3, ex Abitech Corp., Hydrokote APS, Lot 340J1, ex Aerosil COK 84 10 Abitech Corp., Hydrokote M. Lot 126.J2, ex Abitech Corp. Methadone HCI 25 Methocel(R) AM4, Lot Q101012N01, ex Colorcon, Metho Capsule fill weight 350 cel(R) K10OM, Lot QA15012N01, ex Colorcon, Methocel(R) 10 K15M, Lot QK02012N11, ex Colorcon, Paraffin wax, Lot P/0680/90, ex Fisher Scientific, PEG 400, Lot 310354, ex NOF Corp., Pluriol E6005 (PEG 6000), Lot 97193, ex BASF, Example 33 Pharmacoat 606 (hypromellose USP), Lot 308522, ex Shin Etsu Chemical Co Ltd., Poloxamer 124 (Pluronic L44), Lot 15 WPWV-645E, ex BASF, Poloxamer 188 (Lutrol F68), Lot 0306043523, ex BASF, Propoylene glycol, Lot 09521HO, ex Ingredients Quantity (mg), Dose Aldrich, Propranolol HCl, Lot 044K1219, ex Sigma, Shellac, Lot 4.0102465 2056, ex Syntapharm, Size 1 clear/clear gela Glyceryl 250 palmitostearate tin capsules, Lot C14893, ex Capsugel, Starch 1500, Lot IN HPMC, K15M 60 500578, ex Colorcon, Sterotex(R) NF, Lot 324M2, ex Abitech Aerosil COK 84 10 Corp., Tramadol HCl, Lot 3TRMDNOD105 & Oxymorphone HCI 30 3TRMDNOE056, ex Chemagis Ltd, Zein (Paroxite), Lot 5041C, ex Variati & Co. Capsule fill weight 350 Equipment in the series of experiments below included the 25 following: Caleva 9ST dissolution apparatus with ERWEKA Example 34 to 66 may be prepared as using the formula of P thermostatically controlled water heater, Copley ZT54 dis Examples 1 to 33, respectively with the following modifica integration apparatus, Haake DC5 water bath, Heidolph tion: (i) Dispense the hydrogenated Type I vegetable oil, bench mixer. HiBarbench filling machine, Qualiseal bench hydrogenated Type II vegetable oil, polyoxyethylene Stear banding machine, Silverson SL2 bench high shear mixer, ates, polyoxyethylene distearates, glycerol monostearate, 30 Thermo Electron Vision uV/visible spectrometry data acqui poorly water soluble, high melting point (mp=45 to 100° C.) sition program with Vision Security, Unicam UV2-400 spec waxes and/or and/or other ADER material of the invention trophotometer, Watson Marlow 205U peristaltic pump 650L (e.g., glyceryl behenate, glyceryl palmitostearate, Stearoyl nominal S/s Laboratory test sieve, 600LL S/s certified Labora macrogolglycerides or lauroyl macrogolglycerides) into a tory testsieve from Endecotts Ltd, London, Whatman 25 mm mixer; (ii) Heat until fully melted; (iii) dispense the hydrox 35 45u filters used in combination with a 5 ml Luer lock syringe. ypropyl methyl cellulose (HPMC) into the mixer; (iv) Mix until dispersed; (v) Dispense the Aerosil into the same vessel; Example 1 (vi) Mix until dispersed; (vii) Dispense the desired abusable drug or mixture of abusable drugs into the same vessel; (viii) Binary Mix Compatibility Trials Stirthoroughly with a high shear mixer: (ix) Feed the blended 40 material continuously into a twin screw extruder and collect Binary mixes were prepared of tramadol HCL in potential the resultant strands on a conveyor and allow to cool (the excipients (in Some instances a third material, fractionated conveyor is set to provide extrudate diameter of 0.5 mm or 1 coconut oil was used to bring two non melting materials into mm and the pelletizer is set to provide pellets of approxi intimate contact). The mixes were stored in sealed amber mately 0.5 or 1 mm length); (x) Screen the pellets so formed 45 glass bottles under conditions of 40° C./75% RH for four through a sieve and collect the desired particle size (sieve weeks then examined by HPLC for signs of interaction or portion); (xi) Fill pellets into capsules or blend the pellets degradation. Excipients were chosen from materials consid with talc and magnesium Stearate and compress into tablets. ered to potentially cover the range of material properties that These and other embodiments of the present invention will were likely to be required by this project. Materials were readily occur to those of ordinary skill in the art in view of the 50 chosen for properties such as dissolution rate i.e. from mate disclosure herein. rials that are relatively soluble in aqueous media to totally The included examples are illustrative but not limiting of insoluble materials; their potential as Viscosity/release rate the methods and composition of the present invention. Other modifiers, including such materials as different HPMC (vis Suitable modifications and adaptations of the variety of con cosity) grades and Aerosils for contributing thixotropic prop ditions and parameters normally encountered and obvious to 55 erties. Mixes containing 25% w/w tramadol HCL were pre those skilled in the art are within the spirit and scope of the pared for each excipient. Samples were prepared by mixing invention. tramadol HCl with the melted excipient or for non melting A wide variety of materials can be used for preparing the excipients materials were placed in contact by blending with dosage form according to this invention. This invention there a 50/50 mix of excipient and fractionated coconut oil. fore contemplates the use of materials other than those spe 60 Samples of each excipient were also stored in sealed amber cifically disclosed herein, including those which may hereaf glass bottles at 40° C./75% RH as control samples. The ter become known to the art to be capable of performing the project objective describes a target of 15 binary mixes; how necessary functions. ever, 25 different mixes were made during this trial to maxi Materials in the series of experiments below included the mize the range of excipients available for formulation. following: Aerosil R. 200, Lot 1412033, ex Degussa Huls, 65 Dissolution Testing Aerosil R. COK84, Lot 2258, ex Degussa Huls, Beeswax, Lot Initially two test formulations were prepared as noted A018035701, ex Acros Organics, Cetyl alcohol (1-hexade below. The capsules for this and all other small scale capsule US 9,125,833 B2 113 114 preparations were manufactured by the melting and mixing of Potentially useful formulations could be modified further first the ingredients in a water bath or on a hot plate then hand before going on to six capsule sample dissolution testing. filling capsules to the target weight. All capsules used were Tramadol HCl in aqueous Solution shows an absorbance size 1 gelatin capsules. maximum between 240 nm and 290 nm with the maximum at 271 nm. It starts to show increasingly strong absorbance below the minimum at 240 nm to 200 nm (the limit of the instrument) however absorbance in this area is shown by Formulation 052014 many compounds so observation in the more definitive region Material % ww Quantity per cap mg of 240 nm to 290 was selected with 270-272 nm chosen as the preferential wavelength of observation. A plot of the UV Poloxamer 188 62.8 282.7 10 HPMC K10OM 17.9 80.3 spectrum of tramadol HCl in water is shown in FIG. 1. Aerosol COK 84 2.7 12.0 Dissolution testing was carried out using the USP paddle Tramadol HCI 16.6 74.9 method on a Caleva 9ST dissolution apparatus with an ERWEKAP, thermostatically controlled, water heater. Each Capsule fill weight 450 Solution was continuously cycled through a Unicam UV2 15 400 spectrophotometer using a Watson Marlow 205U peri staltic pump and the solution absorbance in a 1 cm silica cell, at 271 nm, recorded against the absorbance of a placebo or Formulation 052015 SIF blank with the data captured by Thermo Electron Vision UV/visible spectrometry data acquisition software protected Material % ww Quantity per cap mg by Vision Security. The spectrophotometer was fitted with a Gelucire 5002 58.3 233.3 six cell autochanger permitting continuous automatic record HPMC Pharmacoat 606 19.9 79.8 ing of cell Solution absorbances. The capsules were weighed Aerosil (R) COK 84 3.0 12.0 down with 316 stainless steel sinking wire, wrapped round Tramadol HCI 18.7 74.9 each capsule. Each Solution passed through a filter as it was 25 Capsule fill weight 400 pumped from the dissolution bath. Except where otherwise specified, the dissolution medium was 600 ml of Simulated Intestinal Fluid (SIF) USP without the inclusion of enzyme. The target fill weight was set as 400 mg for a size 1 capsule. This dissolution set up was selected to give a final absorbance Formulation 052/014 was initially targeted on a 400 mg fill, value, with full release of tramadol HCl, of not more than 1.5 however, the mix proved too viscous to fill. Additional polox 30 absorbance units (au). Typically, the final absorbance of a test amer 188 had to be added to reduce the mix viscosity to a level solution did not exceed 1.0 au. A placebo blank was used in that could be encapsulated. The addition of extra poloxamer the reference cell. This comprised of a capsule containing the 188 required that the fill weight be increased to 450 mg. This same proportion and quantity of each material used in the quantity could be hand filled into a capsule and would meet active test capsules but without the tramadol HC1. This the requirements of this preliminary trial; however, Such a 35 ensured that the reference Solution contained the same quan quantity would be excessive for machine filling into a size 1 tity (and thus gave the same background absorbance) as the capsule. excipients in the active capsules. The tramadol HCl dissolution release profile was deter Binary Mix Compatibility Study mined, for each formulation. Full dissolution testing is car 25 Different materials were tested for compatibility with ried out using six individual capsule sets. Preliminary screen 40 Tramadol HC1. The results of storage in sealed amber glass ing trials used between two and six capsules per test. This bottles under conditions of 40° C./75% RH for four weeks permitted several candidate formulations to be screened at then subsequent analysis by HPLC for degradants or impuri once and clearly unsuitable formulations eliminated quickly. ties are as below.

Peaks Impurities from Degradants Assay stressed % area Material % excipient normalized Comments

Gelucire 4414 127.9 none Ole Gelucire 4414 71.2 none Ole Mean 2 samples 99.5% REPEAT SAMPLE Gelucire 5013 106.3 none Ole Gelucire 4301 Not available Poloxamer 188 101.9 none Ole Poloxamer 124 98.6 none Ole Separated Suspension (Pluronic L44) re-mixed before sampling PEG 6000 96.6 none Ole PEG 400 100.7 none Ole Propylene glycol 96.5 none Ole Beeswax 2.1 none Ole Material insoluble in (refined yellow) sample diluent 10 Starch 1500 97.3 none Ole Separated Suspension (+ Miglyol) re-mixed before sampling 11 Cetyl alcohol 4.5 none Ole Solution produced was a thick 1-hexadecanol slime. Very hard to take HPLC sample 12 Paraffin wax 15.0 none Ole Material insoluble in sample diluent US 9,125,833 B2 115 116 -continued

Peaks Impurities from Degradants Assay stressed % area Material % excipient normalized Comments 13 Miglyol (fractionated 102.3 none Ole Separated Suspension coconut oil) re-mixed before sampling 14 HPMC Methoce (RK1SMP 104.0 none Ole (+ Miglyol) 15 HPMC Methoce (RK10OMP 98.9 none Ole Separated of components (+ Miglyol) re-mixed before sampling 16 Methocel (RA (+ Miglyol) 101.1 none Ole 17 Hydrokote 112 104.2 None None 18 Hydrokote AP5 101.2 None None 19 Hydrokote M 102.8 None Ole 2O Shellac (+ Miglyol) 99.8 Peaks at RT5.057 = 0.1% - Yellow semisolid 5.065, 10.702 excipient Excipient insoluble in diluent and 12.491 RT 10.436 = O.1% minutes RT 10.704 = 0.5% - excipient RT 12.488 = 0.3% - excipient RT 15.043 = 0.1% RT 15.4O2 = 0.1% Shellac UNSTRESSED N/A Main peaks: NA Conclude: peaks present in 5.035, stressed Shellac were present 10.393, before stress test 10.656, 12455 Several small peaks in time Zone 14 to 18 minutes 21 Zein 100.5 Peak at 7.083 RT 7.080 = 0.1% - Yellow semisolid (+ Miglyol) minutes excipient 22 Aerosil (R) COK 84 (+ Miglyol) 100.2 none None 23 Aerosil (R) 200 (+ Miglyol) 101.9 none Ol 24 Cithrol (R) GMS 99.3 Not available none Solution produced Control a viscous mix sample 96.4% assay 25 Sterotex (R) 62.9 none Ole Solution produced a viscous mix 25 Sterotex (R) 32.7 none Ole Mean 2 samples 47.8% REPEAT SAMPLE 26 Gelucire 5002 104.1 none Ole Solution produced a viscous mix

The results above show that none of the excipients tested show any detectable signs of degradation or interaction after Formulation 052015 one month storage under conditions of 40°C./75% RH. It was 45 therefore possible to use any of these materials as formulation Material % Wiw Quantity per cap mg ingredients. Initial Test Formulation Dissolution Testing Gelucire 5002 58.3 233.3 Preliminary test formulations were prepared based on 50 HPMC Pharmacoat 606 19.9 79.8 poloxamer 188 and Gelucire 50/02. The formulation compo Aerosil (R) COK 84 3.0 12.0 sitions are as below. Tramadol HCI 18.7 74.9

Capsule fill weight 400 Formulation 052014 55

Material % ww Quantity per cap mg

Placebo for 052014 Poloxamer 188 62.8 282.7 60 HPMC K10OM 17.9 80.3 Material % Wiw Quantity per cap mg Aerosol (R) COK 84 2.7 12.0 Poloxamer 188 75.4 282.4 Tramadol HCI 16.6 74.9 HPMC K10OM 21.4 80.0 Aerosol COK 84 3.2 12.O

Capsule fill weight 450 65 Capsule fill weight 374.4 US 9,125,833 B2

Placebo for 052015 Placebo for 052,019 Material % Wiw Quantity per cap mg Material % ww Quantity per cap mg Gelucire 5002 71.6 232.8 HPMC Pharmacoat 606 24.6 79.8 Gelucire 5002 71.5 232.2 Aerosil (R) COK 84 3.8 12.4 HPMC Pharmacoat 606 24.8 80.6 Capsule fill weight 325 Aerosil (R) COK 84 3.7 12.1 10 The dissolution rate had been slowed down slightly com Capsule fill weight 325 pared with 052/015 from 10-12 hr to approximately 15-18 hr. however, this mix was a thick cream and was probably too Viscous to machine fill as this exact formulation. The release profiles, determined from dissolution testing in 15 SIF are shown in FIGS. 2 and 3. Some HPMC gel remained at Example 3 the end of the trial in sample 052/014 (poloxamer 188 based) but all poloxamer 188 and tramadol HCl had dissolved very Dissolution Testing of Tramadol HCl in Gelucire quickly. Plot 2 shows that release took place over a 2-5 hr time 50/02 without Additional Excipients span. This release rate is too fast to be useable in this project Initial dissolution trials on formulations were performed as so the use of poloxamer 188 as a base excipient was dis sighting trials to give some idea of the range of profiles carded. The material of formulation 052/015 remained as a possible for 75 mg of tramadol HCl in a matrix made up to 400 plug at the end of dissolution testing. It appears that the mg. The two major excipients used poloxamer 188 and Gelu tramadol HCl and HPMC dissolved and migrates out through 25 cire 50/02 are at opposite ends of the water solubility/dispers the Gelucire 50/02 over a period of 10-12 hr. This is shorter ibility Scale so would give a good indication of the range of than the project targeted release time of 18-24 hr but Gelucire release rates potentially available. Poloxamer 188 is readily 50/02 was retained as a material worth testing further. water soluble while Gelucire 50/02 is highly lipophilic and only very slowly dispersible in water. The Gelucire 50/02 Example 2 30 formulation 052/019 dissolution release rate, shown in FIG. 5, is close to that desired for this project. This formulation does incorporate materials which would modify (increase) Dissolution Testing of a Modified Gelucire 50/02 the release rate so samples were prepared containing only Formulation tramadol HCl and Gelucire 50/02 to determine the slowest 35 release rate that could be achieved with Gelucire 50/02. Methocel(R) Ki OOM, a very high viscosity HPMC, was Samples were prepared according to the formulation below substituted for Pharmacoat 606, a very low viscosity HPMC, and their release rate determined. to investigate whether this substitution using a much higher viscosity HPMC would significantly slow the release rate of Formulation 0527024 tramadol HCl from the formulation. The active and reference 40 placebo capsules formulations are shown in FIG. 4. It should Material % Wiw Quantity per cap mg be noted that the relative viscosity of HPMC is based on the Gelucire 5002 81.2 32SO viscosity of a 2% aqueous solution at 20° C. measured in Tramadol HCI 18.8 75.0 mPas (millipascal Seconds). The numbers and letters in the 45 HPMC's designation indicate (different manufacturers use Capsule fill weight 400 slightly different conventions) the HPMC's 2% viscosity in mPas (1 mPas=1 centipoise (cps)), e.g. Pharmacoat 606 (Pharmacoat 6 is the HPMC type with the final 6 referring to Placebo for 052,024 the 2% viscosity) has a viscosity of 6 mPas (6 centipoise) as 50 a 2% solution while Methocel(R) K100M (Methocel(R) Kis the Material % Wiw Quantity per cap mg HPMC type and 100M is the 2% viscosity using the letter M as the convention for a multiplication factor of 1000) has a Gelucire 5002 1OO 325 viscosity of 100,000 mPas (100 Pascal Seconds) as a 2% Solution. 55 A single capsule was initially tested then a further five capsules were also tested. All the data has been incorporated into the single plot shown below. The profile with the Formulation 052019 extended time scale is that of the first capsule tested. These experiments indicate that full release takes place in Material % ww Quantity per cap mg 60 the order of 30 hr. The outlying profiles was considered to be Gelucire 5002 58.2 232.9 potentially due to uneven distribution of tramadol HCl in Methocel (R) K10OM 19.9 79.4 these hand mixed preparations but it was not deemed worth Aerosil (R) COK 84 3.0 12.0 while to investigate this further at this stage. Gelucire 50/02 Tramadol HCI 18.7 75.0 melts over a range centered on 50° C. and is hard enough to be Capsule fill weight 400 65 crumbled into a powder. This makes formulations susceptible to abuse (by powdering, extraction, dose dumping, Snorting etc) and it would be essential to include abuse deterrent mate US 9,125,833 B2 119 120 rials such as HPMC and Aerosils in the final formulation. The the tramadol HCl absorbance in the monitored 290 nm region. release rate indicated by these profiles fall within the accept An alternative model compound was found in propranolol able range of release rates worthy of further consideration at HCl, as a substitute for the tramadol HC1. Propranolol HCl this stage of the project, however, as only two materials had has similar solubility and similar UV specific absorbance to tramadol HCl but has its UV absorbance maximum at 319 nm, been examined (with one rejected) by this stage it was 5 just outside the absorbance window of pancreatin. This decided to investigate other materials before narrowing the allowed the testing of the propranolol HCl analogue of the selection of potential formulations. above formulation, 052/024, to be tested in the presence of pancreatin with reduced interference. Example 4 The propranolol HCl analogue was subjected to dissolu 10 tion testing in 600 ml of SIF, with and without (full strength) Dissolution Testing of Tramadol HCl in Gelucire pancreatin. Six capsule samples were tested in each case. 50/02 in SIF Containing Pancreatin FIGS. 7 and 8 shows data for dissolution with and without pancreatin while FIG.9 shows the combined averaged data of The Gelucire range of materials is described as polygly dissolution in the absence and presence of pancreatin. colized glycerides consisting of mono-, di- and triglycerides 15 The pancreatin in suspension caused difficulties with filter and of mono- and di-fatty acid esters of polyethylene glycol blockage in both test and reference vessels leading to irregu (PEG) with a range of HLB (hydrophilic lipophilic balance) larities appearing in the data for propranolol HCl in SIF in the values from 1 to 14. A material with a value of 14 is at the presence of pancreatin. Overall, despite the irregularities in hydrophilic end of the scale where the material is easily water the data, it is concluded that there is no difference detected in dispersible; 1 or 2 is at the other end of the scale and the 20 the overall rate of release for Gelucire 50/02 between disso material is extremely slowly water dispersible, at best. lution in SIF in the absence or presence of pancreatin. This Gelucire 50/02 (the 02 suffix shows the HLB value to be 2) Supports the conclusion reached for the similar experiment is highly lipophilic and only disperses very slowly in aqueous carried out using tramadol HCl in Gelucire 50/02. media. These materials are potentially digestible so it is pos sible that a formulation that shows very slow release in vitro, 25 Example 6 in purely aqueous media Such as SIF, could show dramatically faster release due to digestion, as opposed to dispersion, in Dissolution Testing of Current Tramadol HCl Vivo in the presence of enzymes. Extended Release Products An experiment was performed to look for any indications that the presence of an enzyme, pancreatin, modified the so Tramadol HCl is available in commercial extended release release rate of tramadol HCl in Gelucire 50/02. This experi products. These products contain different doses of tramadol ment encountered difficulties as pancreatin in Solution HCl, typically 150 mg, from the dosage unit under develop absorbs strongly over a range exceeding that of tramadol ment in this project but it was considered useful to broaden HC1's 240 nm to 290 nm band and pancreatin in suspension our knowledge of Such products and to obtain a dissolution tended to block the solution filters. release profile using our current conditions. It was also The dissolution profile of capsules containing formulation 35 intended that proprietary products such as these were used 0527024 was recorded using UV absorbance determination. later in this project as comparators during product tampering The pancreatin level was reduced to one fifth of that specified and extraction tests. in the USP method so that solution absorbance values did not Zydol R XL 150 from Pfizer for once a day administration significantly exceed 1 au. The results shown below were very and Dromadol(R) SR by IVAX for twice a day administration erratic, however, as this was intended as no more than a check 40 are two proprietary products which both contain 150 mg of on whether this family of materials (atypical of future excipi tramadol HCl in an extended release formulation. Two tablets ents) was susceptible to acceleration of release rate by diges of each product had their dissolution profile determined in tion it was decided not to divert the project into the develop 600 ml of SIF without added enzyme with UV monitoring at ment of an HPLC assay for tramadol HCL in the presence of 271 nm according to the standard method used in this devel pancreatin at this stage. 45 opment project. The combined release profiles are shown in The profile (FIG. 6) shows an initial dip due to suspended/ FIG. 10. All tablets were substantially whole at the end of the dissolved pancreatin affecting the reference cell. The absor test period. The release profiles match so closely that it is not bance of the mix appears to stop increasing after approxi possible to distinguish visually one tablet type from the other. mately 30 hr which does indicate that the tramadol HCl is Under the above conditions full release takes of the order of fully released after this time. This corresponds well with the so 40hr and, as the tablets contain double the dose of the experi release time of tramadol HCl in this excipient tested in SIF in mental formulations, the final absorbance is approximately the absence of pancreatin (FIG. 5). This suggests that, at the double that shown in earlier plots. The slight dip in the plot level of pancreatin used, no major variation in dissolution about 17 hr is considered to be an artifact of the method. release rate is observed in the presence of pancreatin. The Gelucire 50/02 units were allowed to be stirred in this Example 7 medium for a further two days. The units maintained their 55 shape and size for the entire period adding some confirmatory Indicative Dissolution Testing of Potential Dosage evidence that the Gelucire 50/02 content remained substan Unit Base Excipients tially unchanged (undigested). Previous trials demonstrated that the hard fats and slowly Example 5 60 dissolving materials were the best choice of base material (a base excipient is the predominant excipient in a dosage unit) Dissolution Testing of Propranolol HCl in Gelucire for a 75 mg tramadol HCl extended release dosage unit. This 50/02 in SIF Containing Pancreatin identified seven other materials, from those tested in the com patibility trial, as potential base excipients. Six of these were The above trial using Gelucire 50/02, as the base excipient, 65 formulated as binary mixtures with tramadol HCl and filled in SIF containing pancreatin suffered from the pancreatin UV into capsules to a fill weight of 400 mg containing 75 mg absorbance overlapping and being of greater intensity than tramadol HCl as had been carried out previously. The final US 9,125,833 B2 121 material, beeswax, was formulated with the additional pres ence of HPMC as an unmodified formulation was unlikely to Formulation 052,035-7 show any significant release due to the known insolubility of beeswax in aqueous media. All formulations had their disso Material % Wiw Quantity per cap mg lution profiles determined using single capsule samples for 5 Beeswax 61.2 244.8 initial Screening. The materials and formulations used are as Methocel(R) K10OM 20.1 8O.S below. The reference cell contained 600 mL of SIF. Tramadol HCI 18.7 74.7 Capsule fill weight 400

Formulation 052,034-1 10 The above tests were carried out using only filtered SIF in Material % Wiw Quantity per cap mg the reference cell. Absorbance values obtained may be com posed of two components, namely, absorbance due to trama Cetyl alcohol 81.2 325.0 dol HCl and absorbance due to dissolved excipient. 75 mg of Tramadol HCI 18.8 75.O 15 Tramadol HCl in SIF gives an absorbance of 0.74 autherefore the absorbance must reach 0.7au (allowing for inter capsule Capsule fill weight 400 variation) before it is possible for all the tramadol HCl to have been dissolved. Absorbances significantly in excess of 0.7 au will have some contribution from excipient dissolution. FIGS. 11 and 12 show that Hydrokote and Hydrokote AP5 Formulation 052,035-2 dissolve rapidly and release their tramadol HCl in approxi mately 2 hours. This is too fast a release rate for the require Material % Wiw Quantity per cap mg ments of this project so these excipients were not able to be Hydrokote 112 81.2 324.8 used as base excipients. Tramadol HCI 18.8 75.2 25 The other excipients were in two groups. CithrolR GMS, Cetyl alcohol and the beeswax/HPMC combination showed Capsule fill weight 400 release rates that were slightly slower than the target of total release in 18-24 hr while the Hydrokote 112 and SteroteXCR) NF were significantly slower. One of the requirements of this 30 project is to develop dosage units with demonstrable deter Formulation 052,035-3 rence to physical or solvent based tampering. Materials were to be incorporated into formulations to enhance abuse resis Material % Wiw Quantity per cap mg tance. As it was likely that these materials would accelerate Hydrokote AP5 813 325.2 release then all of the materials mentioned in this paragraph Tramadol HCI 18.7 74.8 35 were suitable for further consideration. Capsule fill weight 400 Example 8 Dissolution Testing of Modified Tramadol HCl 40 Formulations Formulation 052,035-4 The base excipients CithrolR GMS, Hydrokote 112, Cetyl Material % Wiw Quantity per cap mg alcohol, Sterotex RNF and beeswax showed potential as for Hydrokote M 813 325.4 mulation base excipients in the trial above. These materials, in Tramadol HCI 18.7 74.6 45 binary combination (beeswax as a ternary combination), gave Capsule fill weight 400 dissolution release rates slower than the 18-24 hr target. In this trial HPMCs were incorporated into the formula tions to accelerate release and provide a level of tamper deter rence. Up to this point formulations contained tramadol HCl, Formulation 052,035-5 50 a water soluble material, with a water insoluble base excipient which could make separation by extraction relatively easy. Material % Wiw Quantity per cap mg HPMC has been chosen as a material which might enhance Cithrol (R) GMS 81.6 326.2 tamper resistance as it has the property of being water soluble Tramadol HCI 18.4 73.8 and thus would follow tramadol HCl during attempted aque 55 ous extraction, making separation of the tramadol HCl more Capsule fill weight 400 difficult. HPMC comes in high viscosity grades which can imparta Viscous nature to aqueous extracts of dosage units i.e. if anyone tries to extract the tramadol HCl with a small amount of water in a small spoon then, at best, they will Formulation 052,035-6 60 produce an unpleasant mixture with a gummy’ appearance Material % Wiw Quantity per cap mg which will tend to block attempts at filtration. Additionally, HPMC behaves in an unusual manner in aqueous solution. Sterotex (R) NF 81.2 324.9 Most water soluble materials increase in solubility as the Tramadol HCI 18.8 75.1 water temperature rises. HPMC is most soluble in cold water, Capsule fill weight 400 65 becoming less soluble with temperature increase until, at about 40° C., it becomes totally insoluble. Solutions of HPMC that are heated to 40°C. or above turn into solid gels. US 9,125,833 B2 123 124 This means that although an HPMC may be added to increase Suspending in the dissolution media may increase the release rates from a dosage unit, it can actively deter abuse by recorded absorbance significantly above 0.7 as is clearly seen extraction. If an individual tries to extract tramadol HCl with above for the Sterotex(R) NF plot. FIG. 13 shows that all warm or hot water then the HPMC will become completely formulations release all/almost all tramadol HCl within insoluble and actively resist the diffusion of tramadol HCl approximately 17-27 hr. This is satisfactory at this stage in the through the relatively impermeable base excipient. project. An example of the data and scatter for a five capsule Several formulations were produced incorporating a high dissolution set of results produced using one of the formula viscosity HPMC, Methocel(R) K 100M, into the matrix. The tions used in the combined plot above (cetyl alcohol 052/039 formulations tested and the release profiles obtained are shown below. 10 1) is shown in FIG. 14. Example 9 Formulation 052O39-1 Material % ww Quantity per cap mg 15 Dissolution Testing of Modified Tramadol HCl in Cetyl alcohol 71.2 284.9 Sterotex(R) NF Formulations Methocel (R) K10OM 1O.O 40.O Tramadol HCI 18.8 75.1 The future processing of formulations at manufacturing Capsule fill weight 400 scale required to be considered at this stage. Some formula tions had too low a viscosity, as a melt, to maintain insoluble excipients in Suspension and others were so viscous that, although they could be hand filled for the purposes of these Formulation 052O39-2 trials, they were so viscous that they would cause great diffi culty during manufacture on full scale machinery. Formula Material % ww Quantity per cap mg 25 tions, unstable due to low viscosity, could have their viscosity Hydrokote 112 57.0 227.9 increased using low levels of thixotrope but formulations of Methocel (R) K10OM 24.5 97.9 excessive viscosity required that excipients were reduced or Tramadol HCI 18.6 74.2 substituted. Capsule fill weight 400 30 An Aerosil R) was chosen as both a thixotrope and contribu torto abuse deterrence. Aerosil R is the commercial name for fumed silicon dioxide manufactured by Degussa Hills. They produce a range of Aerosils with differing properties. These Formulation 052040-5 include different particle size, hydrophobic or hydrophilic 35 characteristics or blended with additional materials such as Material %Wiw Quantity per cap mg aluminum oxide for specific purposes. Aerosil(R) COK84 was Hydrokote 112 66.1 264.4 chosen as the Aerosil R) of choice for this project. Aerosil R. Methocel (R) K10OM 15.1 60.3 COK 84 is a mixture of fumed silicon dioxide and highly Tramadol HCI 18.8 75.3 dispersed aluminum oxide in a 5:1 ratio. This material effec Capsule fill weight 400 40 tively thickens aqueous systems and other polar liquids. In this project Aerosil R. COK 84 will increase viscosity in a formulation, however, if attempts are made to add a small quantity of water to produce a solution (e.g. for injection) the Aerosil R. COK 84 will contribute to increase the viscosity of Formulation 052O39-3 45 any solution produced as it is specifically designed to thicken Material % ww Quantity per cap mg aqueous systems. Silicon dioxide and aluminum oxide, addi Cithrol (R) GMS 71.O 284.0 tionally, do not melt below 100° C. (or even 1000°C.) and are Methocel (R) K10OM 10.2 40.8 insoluble. The thickening effect of this Aerosil R is unaffected Tramadol HCI 18.8 75.2 by heat thus an abuser attempting to melt a dosage unit will 50 find that the structure and shape of the dosage unit tends to Capsule fill weight 400 remain unchanged when Sufficient Aerosil R is incorporated even though the melting point of all other excipients has been exceeded

55 Formulations were modified by having Aerosil R. COK 84 Formulation 052040-4 added in Some instances to improve process characteristics Material % ww Quantity per cap mg and enhance abuse resistance while others had the HPMC grade substituted to bring the dissolution release rate towards Sterotex (R) NF 56.5 225.8 Methocel (R) K10OM 25.1 100.4 the target range or to adjust the formulation properties to that Tramadol HCI 18.4 73.8 60 required for commercial production. The Sterotex(R) NF formulation above, 052/040-4, con Capsule fill weight 400 tained 25% of a very high viscosity HPMC which produced a mix that could be hand filled but was excessively viscous for FIG. 13 is based on using only SIF in the reference cell. As machine encapsulation. This formulation was modified with a described previously, the flattening of the curve, having 65 lower quantity of a lower viscosity grade HPMC with the aim reached an absorbance of at least 0.7au, indicates full release of producing a machine fillable formulation of similar release of tramadol HCl from the dosage unit. Materials dissolving or rate US 9,125,833 B2 126 Example 11 Formulation 052058 Material % ww Quantity per cap mg Dissolution Testing of Tramadol HCl in Hydrokote 112 with HPMC and Aerosil R. COK 84 Sterotex (R) NF 66.2 264.9 Methocel (R) K15M 1S.O 6O.O FIG. 13 shows the plot for a formulation based on Tramadol HCI 18.8 75.0 Hydrokote 112 containing 15% Methocel(R) K100M, formu Capsule fill weight 400 lation 052/040-5. Trials indicated that Aerosil(R) COK 84 could be incorporated at 1.5% w/w to produce a flowing light 10 cream. The above formulation was modified to contain 1.5% Aerosil R. COK 84 and to compare release profiles for formu Placebo for 052058 lations containing equal quantities of Methocel(R) K 15M or Material % ww Quantity per cap mg the much higher viscosity grade Methocel(R) K 100M. For 15 mulations were prepared as below. Sterotex (R) NF 81.5 26S Methocel (R) K15M 18.5 6O.O Formulation 052,062-1 Capsule fill weight 325 Material % Wiw Quantity per cap mg The dissolution profile of a four capsule sample is shown in Hydrokote 112 64.7 258.7 Methocel(R) K10OM 1S.O 60.1 FIGS. 15 and 16. The above profiles indicate release in 25-30 Aerosil (R) COK 84 2.1 8.6 hr. (Later data will demonstrate that full release of 75 mg Tramadol HCI 1.6 6.3 tramadol HCl from SteroteXCRNF results in an absorbance of Capsule fill weight 400 approximately 0.8 au under the above conditions). This for 25 mulation was quite thin with fast separation of the insoluble ingredients and required an increase in viscosity. This undoubtedly contributed to the variation between individual Formulation 052,062-2 profiles. The dosage unit was Swollen after dissolution testing but retained its original shape and was tough to breakup. This 30 Material % Wiw Quantity per cap mg demonstrated that the tramadol HCl has diffused out from the Hydrokote 112 64.7 258.6 Methocel (R) K15M 15.0 60.2 dosage unit rather than released after dosage unit dissolution Aerosil (R) COK 84 2.1 8.6 or disintegration. Tramadol HCI 1.5 6.2 Capsule fill weight 400 35 Example 10 Three capsule samples of each formulation had their dis solution absorbance profiles measured in 600 mL of SIF, Dissolution Testing of Further Modified Tramadol without enzyme at 271 nm, using the USP paddle apparatus, HCl in Sterotex(R) NF Formulations 40 at 75 rpm, as carried out previously. The combined individual and averaged profiles are shown in FIGS. 19 and 20. Both Aerosil R. COK 84 was added to the tramadol HCl in Ste dosage units were soft and crumbling at the end of dissolution roteXR NF formulations. Formulations containing quantities testing. Both gave acceptable release times for the tramadol of Aerosil R. COK 84 in excess of 2% w/w were too viscous HCl of 25-30 hr. As would be expected, the lower viscosity for machine filling so formulation 052/058 was modified to 45 grade dissolution was slightly faster than that of the formu contain 2% Aerosil R. COK 84 and subjected to dissolution lation containing the higher viscosity grade. testing against a placebo without tramadol HCl but which contained the same quantities of all other ingredients. Example 12 50 Dissolution Testing of a Formulation Containing 250 Formulation 052060 mg Tramadol HCl in Sterotex(R) NF Material % ww Quantity per cap mg A dosage unit containing 250 mg of tramadol HCl was Sterotex (R) NF 63.9 255.4 considered as a future possibility for this type of slow release Methocel (R) K15M 15.2 61.O 55 dosage form so a preliminary investigation was carried out to Aerosil (R) COK 84 2.1 8.6 estimate the likelihood of this being achievable. Tramadol HCI 18.9 75.5 Tramadol HCl is highly water soluble. This can lead to Capsule fill weight 400 difficulty in producing a slow release formulation as, with the preferred largest capsule size as a size 0, the largest quantity 60 of formulated material that can be filled as a liquid fill is The dosage units had expanded and were soft and easily approximately 550 mg. This means that the formulation will broken up after dissolution testing. The average release pro contain approximately 45% as the very soluble tramadol HC1. file was not significantly different from that of formulation The objective of this exercise was to determine whether 052/058, with release in approximately 25-30 hr, however, 250 mg tramadol HCl could be formulated to 500-550 mg in there was less variation between individual samples indicat 65 a mix, with the properties to enable machine filling, and ing that low viscosity of 052/058 was a major contributor to having a release rate that delivered the tramadol HCl into individual sample variation (FIGS. 17 and 18). solution over at least 18-24 hr. If the formulation released US 9,125,833 B2 127 tramadol at a much slower rate then this was completely acceptable as the release rate could be accelerated by the Formulation 052,068 incorporation of materials such as HPMC. Difficulties would Material % Wiw Quantity per cap mg arise if the releaserate could not achieve 18-24 hr release with only the base excipient. 5 Beeswax 59.4 237.6 Methocel(R) K15M 19.9 79.5 Sterotex RNF was chosen as the base excipient for this trial Aerosil (R) COK 84 2.O 8.2 as, at the 18.8% w/w tramadol HCl level (FIG. 12), it was the Tramadol HCI 18.7 74.7 slowest of the excipients under examination and able to Capsule fill weight 400 deliver extremely slow release. A formulation targeted on 500 10 mg dosage was too viscous to be filled. Diluting to a total mass of 550 mg and the addition of a small quantity of Aerosil R. COK 84 gave a flowing cream that could be Formulation 052070 machine filled. Material % Wiw Quantity per cap mg 15 Beeswax 56.3 22SO Formulation 052066 Methocel(R) K15M 23.0 92.0 Aerosil (R) COK 84 2.O 8.0 Material % ww Quantity per cap mg Tramadol HCI 18.7 75.0 Capsule fill weight 400 Sterotex (R) NF 52.8 29O.S Aerosil (R) COK 84 1.8 1O.O Tramadol HCI 45.4 249.6 The dissolution profiles of both formulations were Capsule fill weight 550 obtained using 600 mL of SIF and the USP paddle method with monitoring at 271 nm, unchanged from previous disso lution trials. Placebos containing all materials in identical The dissolution profile of a six capsule set was obtained in 25 the previous manner. The only difference from previous con quantities without tramadol HCl were used as the reference in ditions was that the dissolution medium volume had been each case. The dissolution profiles obtained shown in FIGS. increased to 1 liter. At this level, total release of the 250 mg of 23, 24, 25, 26 and 27. tramadol HCl would give an absorbance of at least 1.5 au. A Tramadol HCl was released over approximately 40 hr in 30 both cases. The dissolution of 052/070, containing 23% placebo containing all materials in identical quantities with Methocel(R) K 15M, was allowed to continue running for 95 hr out tramadol HCl was used as the reference. to confirm the final absorbance achieved. It would have been The individual plots (FIGS. 21 and 22) showed some atypi expected that formulation 052/070, containing slightly more cal behavior due to bubble generation in the flow through soluble matter, would have shown the faster release. It cells. Despite this, the clear observation is that this formula 35 appears that there is little real difference in release rates at this tion released less than a quarter of its tramadol HC1 content level of HPMC content so the formulation containing 20% over the 38 hr period of the dissolution trial. This release time Methocel(R) K 15M was selected for use. and the percentage released comfortably exceeds the mini mum requirement of release of all tramadol HCl in not less Example 14 than 18-24hr. This trial demonstrates that it should be feasible 40 to produce a similar slow release, liquid filled dosage unit to HPLC Analysis of Tramadol HCl During Dissolution the objective of this project, containing up to 250 mg tramadol Testing HCl in a total formulated mass of up to 550 mg. Tramadol HCl release during dissolution testing had been 45 monitored to this point using the absorbance of the dissolu Example 13 tion media at 271 nm (absorbance maximum for tramadol HCl at longest wavelength) as a function of the quantity of Dissolution Testing of Tramadol HCl in Beeswax tramadol HCl released into solution. This approach was rea Based Formulations sonable as the excipients used in formulations were either 50 almost insoluble or had negligible absorbance at this wave length. It was considered that tramadol HCl was fully Previous beeswax based formulations (052/035-7), con released when the absorbance of the solution became con taining 20% Methocel(R) K 100M released in a period of stant. For 75 mg tramadol formulations and the system used, approximately 40 hr. This exceeded the 18-24 hr target range this meant that the absorbance would be in excess of 0.7 au. of the study, however, it was considered useful to include a 55 The absorbance profile would be composed of absorbance slightly slower, in vitro, formulation to broaden the range of from tramadol HCl plus a small contribution from absor formulations that would eventually be subject to an in vivo bance/scattering from the other excipients. trial. This trial subjected all of the formulations under consider Two other beeswax formulations were prepared to com ation, at this point, to dissolution testing of two capsule pare the quantity and type of HPMC that should be incorpo 60 samples (or twox two) with concurrent sampling and HPLC rated and the effect of Aerosil R. COK 84 inclusion. It was analysis for tramadol HCL. Sufficient samples for HPLC found that up to 2% Aerosil R. COK 84 could be included and analysis were taken over the course of a dissolution run to the material remained as a potentially machine fillable mix. allow a plot of absorbance profile versus quantity of tramadol 25% HPMC was found to produce an excessively viscous HCl released to be constructed. This permitted the assump mix. Two formulas were tested containing 20 and 23% w/w of 65 tions on absorbance profile versus release profile to be tested. the lower viscosity Methocel(R) K 15M HPMC. The formula The formulations tested are detailed below. FIG.28 shows the tions subjected to dissolution testing were as below. combined absorbance profiles for three formulation followed US 9,125,833 B2 129 by individual plots combining the percentage (of 75 mg) released into solution as determined by HPLC with the initial Formulation 052,074-6 absorbance plot overlaid and normalized on the first or near est position to 100% tramadol HCl release by HPLC (FIGS. Material % Wiw Quantity per cap mg 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 and 41). This Hydrokote 112 63.2 252.7 Methocel(R) K15M 15.1 6O2 allows comparison of the quantity of tramadol HCl released Aerosil (R) COK 84 3.0 12.2 and the quantity that would have been estimated from the Tramadol HCI 18.7 74.9 absorbance plot as having been released. Note: The formula Capsule fill weight 400 tion reference details the exact quantities used in a particular set of samples. The same basic formula e.g. 55% of X plus 10 20% of Y plus 18% of Z, may appear as different formulation references as the quantities in a particular set vary slightly due Formulation 052,074-7 to weighing variations. Material % Wiw Quantity per cap mg 15 Beeswax 59.2 236.9 Formulation 052072-1 Methocel(R) K15M 2O.O 80.1 Aerosil (R) COK 84 2.O 8.1 Material % ww Quantity per cap mg Tramadol HCI 18.7 74.9 Capsule fill weight 400 Beeswax 59.3 237.0 HPMC Pharmacoat 606 2O.O 79.8 Aerosil (R) COK 84 2.0 8.0 Tramadol HCI 18.8 75.1 Capsule fill weight 400 TABLE 2 Formulation Release Data Summary from HPLC 25 100% release after approx Formulation 052,072-2 (Same as 052,019 Formula Base excipient HPMC and % wiw (ex HPLC data) Material % Wiw Quantity per cap mg OS2,072-1 Beeswax 20% Pharmacoat 606 70-75% in 45 hr OS2,072-2 Gelucire 50.02 10% Methocel(R) K10OM 15 hr Gelucire 5002 68.2 272.6 30 052,073-3 Cetyl alcohol 10% Methocel(R) K10OM 15 hr Methocel(R) K10OM 1O.O 40.1 OS2,073-4 Sterotex (R) NF 15% Methocel(R) K15M 38 hr Aerosil (RCOK 84 3.0 12.1 052,073-5 Cthro (R) GMS 10% Methoce (R) K10OM 20hr Tramadol HCI 18.7 74.8 OS2,074-6 Hydrokote 112 15% Methocel(R) K 15M 40 hr Capsule fill weight 400 052,074-7 Beeswax 20% Methocel(R) K 15M 25 hr

35 Overall the HPLC data correlated well with absorbance data confirming that the modification of formulations based Formulation 052O73-3 on their absorbance profiles, minimizing delays that HPLC Material % ww Quantity per cap mg analysis would cause if applied to every sample, was a viable 40 and acceptable approach. The above formulations cover a Cetyl alcohol 67.9 271.5 Methocel (R) K10OM 9.8 39.2 broad range of release profiles exceeding the 18-24 hr guide Aerosil (R) COK 84 3.9 15.8 value for this project. At the present stage only the first bees Tramadol HCI 18.4 73.6 wax formulation (52/072-1) is to be discontinued. Further Capsule fill weight 400 modifications may arise during tamper resistance testing. 45 Example 15

Formulation 052,073-4 (Similar to 052,060 Formulations 052/074-7,052/093-3, 052/073-5 and 052/ 074-6 were remanufactured with Aerosil R. COK 84 replaced Material % Wiw Quantity per cap mg 50 in each with Aerosil R. 200. The change in Aerosil(R) did not Sterotex (R) NF 642 256.8 modify the dissolution profile or the tamper deterrence of the Methocel(R) K15M 1S.O 60.1 drug. Aerosil (R) COK 84 2.O 7.9 Tramadol HCI 18.8 75.2 Tamper Resistance Testing Capsule fill weight 400 55 The popularity of extended release oxycodone among addicts and recreational drug users is due to a large amount of drug per tablet (12 hour supply). Commercially available Formulation 052O73-5 immediate release opioid tablets and capsules are usually 60 administered every 4 to 6 hours and they release their dose Material % ww Quantity per cap mg into the systemic circulation over one to two hours. New, Cithrol (R) GMS 68.3 273.0 extended release formulations are designed to gradually Methocel (R) K10OM 1O.O 40.1 Aerosil (R) COK 84 3.0 12.0 release their much larger opioid content over a 12 or 24-hour Tramadol HCI 18.7 74.9 period. Capsule fill weight 400 65 Most recreational drug users and addicts have a unit of use which is one tablet or capsule. The 12 or 24-hour supply of opioid contained in one tablet or capsule, instead of 4 to 6 US 9,125,833 B2 131 132 tablets or capsules means that there is a greater risk that Such Freeze and Crush formulations may be highly sought by drug addicts and rec reational drug users alike, for non-medical use. Intentional or Method: Freeze the dosage unit in a domestic freezer for 24 inadvertent tampering from extended release formulations hr, then grind with a mortar and pestle for five minutes. Sieve will rapidly deliver a massive dose and produce profound a through a suitable sieve (ca 600 micron) and, by weighing, variety of serious and life threatening side effects, including measure the percentage passing the sieve. respiratory depression and failure, sedation, cardiovascular collapse, coma and death. Taste of Base Excipient Mix (Organoleptic Test) Addicts and recreational drug users commonly use extended release opioids by a variety of routes of administra 10 Method: Chew a placebo mix for five minutes and rate the tion. Commonly used methods include 1) parenteral (e.g., taste on a 0-10 scale with 0 as bland to repulsive at 10. This intravenous injection, where the drug is crushed and extracted method is relevant only to dosage units containing taste modi or melted and the contents of a dosage unit then injected), 2) fiers. intranasal (e.g., Snorting, where the drug is inhaled as pow dered dosage unit), and 3) episodic or repeated oral ingestion 15 Extraction into Acid of crushed product, where the drug is chewed to increase the Method: Crush with a mortar and pestle and heat to boiling Surface area and permit rapid release of drug Substance. All of in 5 mL of vinegar. The resulting Suspension is filtered these strategies are intended to more efficiently get the opioid through a 0.45 micron filter into a flask and diluted to 50 mL into the CNS, both in terms of total amount of drug, peak with water. Quantify tramadol HC1 concentration by HPLC. concentration of drug and time to peak concentration of drug. One mode of abuse involves the extraction of the opioid Application of Heat component from the dosage form by first mixing the table or capsule with a Suitable solvent (e.g., water or alcohol), and Melting Temperature >50° C. or 55° C. then filtering and/or extracting the opioid component from 25 the mixture for intravenous injection. Another mode of abuse Method: Heat the squashed contents of a dosage unit on a of extended release opioids involves dissolving the drug in hot plate until melted. Determine the temperature of melting water, alcohol or another “recreational solvent to hasten its and test whether the mix becomes sufficiently fluid to be release and to ingest the contents orally, in order to provide drawn up into a syringe via a 1.2 mm needle then expelled. high peak concentrations and maximum euphoriant effects. 30 The formulations tested were the last six of those listed in It is necessary to be able to measure resistance to the likely Table 2 (omits the first sample 052/072-1). Dromadol R. SR routes of abuse in a meaningful and relevant way. No standard tablets were included into the testing for to allow comparison set of tests exist with companies, interested in abuse resis of the liquid filled dosage units with a commercial tramadol tance, generating their own particular set of tests. The series HCl prolonged release preparation. The results of testing are of tests chosen to evaluate abuse resistance and the source of 35 presented below. the test were: Example 16 Extraction with Alcohol on Whole Dosage Unit Extraction with Alcohol on Whole Dosage Unit This method is based on US patent application 2004/ 40 0161382 A1 (P11, 0122). Method: Place a whole dosage The results of this test are shown in FIG. 42. unit in 18 mL of 0.1N HCl in a 60 mLamber bottle and shake at 240 rpm on an orbital shaker for 30 min. After 30 min add Example 17 12 mL of ethanol (95-96%) to each bottle. Swirl by hand and remove a 1 mL sample from each bottle (T). Place the solu 45 Extraction with Alcohol on Cut or Crushed Dosage tions back in the orbital shaker for further shaking at 240 rpm. Unit Take 1 mL samples after 10, 20, 30, 40, 60 and 180 min of further shaking for each bottle. Analyze and graph the results The samples under test were reduced to four formulations on a linear scale of cumulative release (%) vs. time (min). plus the Dromadol R. SR comparator at this point. The Cetyl 50 alcohol based formulation (052/073-3) and Gelucire 50/02 Extraction with Alcohol on a Crushed or Cut Dosage (052/072-2) were deselected due to their dissolution release Unit time of approx 15 hr to 100% release and their high extract able fraction, as seen in FIG. 42. Formulations showing a Extension of test in above patent. Method: Place a tablet slower than target in vitro release profile may possibly show (after crushing with a single crush with a spatula) or a capsule 55 more rapid release in vivo due to the presence of digestion (cutinhalf) in 18 mL of 0.1NHClin a 60 mLamber bottle and materials but is seems unlikely that formulations showing a shake at 240 rpm on an orbital shaker for 30 min. Continue the faster than desirable in vitro dissolution rate will show a test as in 1) above. retarded rate in vivo. The above two tests demonstrate that whole dosage units Extraction into Water 60 release their contents into alcohol relatively slowly but once crushed or cut the waxy liquid fill dosage unit is much harder This method is based on US patent application 2004/ to extract than the tablet. One single crush turns the Droma 0161382 A1 (P12,0130). Method: Crush with a mortar and dol R tablet into an easily extractable powder. This feature pestle and grind in 5 mL of water for 5 minutes. The resulting would apply to any tablet. It should be noted that the apparent suspension is filtered through a 0.45 micron filter into a flask 65 high quantity released at To is due to the conditions specified and diluted to 50 mL with water. Quantify Tramadol HCl in the method. The method requires an initial 30 min of concentration by HPLC. shaking in 18 mL of 0.1N HCl before the addition of ethanol. US 9,125,833 B2 133 134 The time is defined in the method as starting from the addition Example 19 of ethanol. The tramadol HCl, shown as released at To has dissolved during the 30 min pre ethanol addition sample Extraction into Acid Water Via Crushing and preparation. This test demonstrates that the liquid fill formu Grinding in Dilute Acetic Acid lations are clearly Superior in abuse resistance by ethanol extraction to an extended release tablet (FIG. 43). Dilute acetic acid (6% w/w glacial acetic in water) was used to simulate the vinegar that drug abusers may use when extracting dosage units for injection. Dosage units were Example 18 crushed forcibly 2-3 times in a mortar and pestle then trans 10 ferred to a small beaker where 5 mL of the above dilute acetic acid was added. The mix was heated to boiling on a hotplate Extraction into Water Via Crushing and Grinding in and held boiling for 5-10 s. The mix was allowed to cool to Water room temperature, the resulting Solution filtered through a 45u filter, as above, the solution diluted to volume and the The four formulations continuing under test plus Droma 15 content of tramadol HCl determined by HPLC. The assay dol(R) SR tablets were crushed and ground for 5 minutes in 5 results are shown below expressed as a percentage of the mL of water to simulate extraction in preparation for Swal contents released into Solution. lowing or injection. The material was then filtered (by pres Surizing a 45u filter using an attached syringe) and diluted TABLE 5 before quantifying by HPLC. The results are presented in Percentage release on extraction into dilute acid. Table 3 and 4 below with comments on the mix produced after grinding given below. Base excipient Formulation % released on extraction Dromadol (R) SR na 83.9 TABLE 3 tablets 25 Sterotex (R) NF OS2O73-4 29.3 Product Observations Cithrol (R) GMS O52O73-5 41.7 Hydrokote 112 OS2O74-6 30.2 Dromadol (R) Ground easily and formed a mobile Beeswax O52O74-7 17.6 SR tablet easily filtered solution. Sterotex (R) Difficult to grind, forms a light NF formulation paste that filtered slowly. 30 Tramadol HCl was easily extracted from the tablet. All OS2,073-4 Cithrol (R) Difficult to grind, forms a light liquid fill formulations showed appreciably better resistance GMS formulation paste that filtered very slowly. to extraction. The waxy mass of the four test formulations O52O73-5 coalesced on melting and floated as a mass on the Surface. The Hydrokote Difficult to grind, forms a light HPMC content of the mass is insoluble above 40° C. so, 112 formulation paste that filtered very slowly. instead of its normal property of assisting release at room OS2,074-6 35 temperature, it actively prevents release at this temperature by Beeswax formulation Difficult to grind, forms a light paste helping to hold the molten mass together. The tramadol HCl O52O74-7 that filtered relatively easily migrates relatively slowly to the Surface when boiling agitates the mass while the powdered tablet releases most of its con The Dromadol(R) SR tablet crushed easily and produced a tent instantly. It is easily understood why the formulated solution that filtered in a matter of seconds while the beeswax 40 capsule dosages give Superior extraction resistance to that of formed a light paste, with difficulty, which took approxi tablets. mately five minutes to filter. This difficulty of preparation was common to the other capsule samples with filtration time Example 20 graduating from the five minutes of the beeswax sample to over 60 minutes for the Cithrol R. GMS sample. All liquid fill 45 Effect of Heat on Dosage Units samples gave much greater difficulty in grinding and filtering Tablets can be crushed and extracted easily while soft gel than the tablet sample. contents have been known to be liquefied by slight warming TABLE 4 (to about 40°C.) and the contents injected directly. This test 50 records the temperature at which the meltable excipients in a Percentage release on extraction into water. formulation have liquefied and tests whether this material can be sucked into a syringe and ejected as would take place Base excipient Formulation % released on extraction during an injection. Formulated material was placed in a Dromadol (R) SR na 84.O beaker then slowly warmed in a water bath. The mix tempera tablets 55 ture was recorded with a calibrated thermocouple. The results Sterotex (R) NF OS2O73-4 38.7 are listed in Table 5 below. Cithrol (R) GMS O52O73-5 17.1 Hydrokote 112 OS2O74-6 24.5 Beeswax O52O74-7 30.1 TABLE 6

60 Melting point range and potential for direct injection The HPLC data shows that tramadol HCl was easily Form extracted from the tablet, as would be expected as a tablet Base Excipient Form- ulation crushes easily to give a large Surface area from which extrac excipient mp ulation melted Comment tion can take place. Extraction from the liquid fill formulation Sterotex (R) NF 61-66° C. 052/073-4 65° C. Light cream, can't suck was reduced considerably due to the waxy nature of the base 65 into Syringe, sets excipients and the inclusion of HPMC which caused the instantly in needle tip liquid extracts to turn into a filtration resistant light paste. US 9,125,833 B2 135 TABLE 6-continued -continued Melting point range and potential for direct iniection Formulation 052,087-2 Form Base Excipient Form- ulation excipient mp ulation melted Comment Material % Wiw Quantity per cap mg Cithrol (R) 55-60° C. 052/073-5 58° C. Light cream, can't suck GMS into Syringe, sets Aerosil (R) COK 84 1.O 4.0 instantly in needle tip Beeswax S.O 2O.O Hydrokote 43-46 C. 052,074-6 45° C. Viscous paste, can Suck 10 112 and eject about 5 mm of Tramadol HCI 18.8 75.0 material from needle Capsule fill weight 400 Beeswax 61-66° C. 052/074-7 66° C. Viscous paste, can't Suck into Syringe, sets instantly in needle tip 15 All of the mixes melted around the melting points of the Formulation 052,087-3 base excipients and, due to this elevated melting point, none could be effectively introduced into a syringe nor could be Material % Wiw Quantity per cap mg ejected (or injected). Sterotex (R) NF S.O.3 2012 Methocel(R) K 15 M 2O.O 79.9 Example 21 Aerosil (R) COK 84 1.O 4.0 Beeswax 1O.O 40.O Tramadol HCI 18.8 74.9 Modification to Increase Resistance to Powdering Capsule fill weight 400 25 It was observed during this trial that the Sterotex NF for mulation can be powdered with careful crushing. This occurs The SteroteXCR) formulation without beeswax showed con to a lesser extent with the CithrolR GMS and Hydrokote 112 siderable variability. The addition of 5% or 10% beeswax formulations. It was desirable to decrease the ease with which significantly increased the rate of release to an approximate this formulation could be powdered. Both the SteroteXR NF 30 time for full release of 25 hr. There was no meaningful dif and Hydrokote 112 formulations gave full release of tramadol ference in release rate between either formulation containing HCl in 38-40hr during dissolution testing. It would therefore added beeswax so the formulation containing 10% beeswax be acceptable to add modifiers that decrease the ease of crum (052/087-3) was selected for inclusion in subsequent trials. bling formulated material into a powder even if these accel erated release. Several materials were tested including small 35 levels of beeswax, adding hydrophilic liquids such as maltitol Example 22 or glucose syrup or adding Surfactants such as Crillet 4. The addition of hydrophilic liquids or Surfactants immediately Ease of Powdering and Percentage of Resultant turned the mix into a lumpy unfillable mass by binding the Particles of 650 Micron or Less powder content together. The use of these liquids was discon 40 tinued. Formulations containing SteroteXR NF with increased Capsules were initially powdered at room temperature as level of HPMC to accelerate dissolution plus 0,5% and 10% an indicative guide and for comparison with Subsequent fro beeswax were produced for examination of any change in Zen samples. The contents were removed from the capsules resistance to powdering. The dissolution profiles of each for 45 and ground until the finest powder achievable had been mulation were recorded as the absorbance curve via UV formed. The stated period of five minutes was not normally monitoring at 271 nm as previously. The formulas used are required and it was observed that excessive grinding could show below. The dissolution results are show in FIG. 44. cause the particles to start to coalesce. The data obtained is shown in Table 7. 50 Formulation 052,087-1 TABLE 7 Material % ww Quantity per cap mg Powder generation by grinding of formulated material at RT Sterotex (R) NF 60.3 241.0 Methocel (R) K 15 M 2O.O 8O.O Base Excipient Formulation Comment % as 650 L or less 55 Aerosil (R) COK 84 1.O 4.0 Dromadol (R) SR 64.2% Beeswax O.O O.O tablet Tramadol HCI 18.8 75.0 Dromadol (R) SR Repeat sample 79.9% Capsule fill weight 400 tablet Sterotex (R) NF OS2,087-1 0% beeswax 84.7% 60 Sterotex (R) NF OS2,087-3 Plus 10% beeswax 84.8% Cithrol (R) GMS 052,073-5 86.9% Hydrokote 112 OS2,074-6 2.1% Formulation 052,087-2 Beeswax 052,074-7 1.9% Material % ww Quantity per cap mg

Sterotex (R) NF 55.3 221.0 65 The test was repeated using capsules that had been cooled Methocel (R) K 15 M 2O.O 8O.O in a domestic freezer. The results of this trial are shown in Table 8. US 9,125,833 B2 137 138 TABLE 8 Example 24 Powder generation by grinding of formulated material cooled The test to quantify the ease of powdering, Test 3, was to domestic freezer temperatures repeated using capsules that had been cooled in a domestic Base Excipient Formulation Comment % as 650 L or less 5 freezer. The results of this trial are shown in table 8 below. Dromadol (R) SR 70.6% tablet TABLE 9 Sterotex (R) NF OS2,073-4 78.8% Sterotex (R) NF OS2,087-3 Plus 10% beeswax 82.1% Powder generation from Sterotex (R) NF formulations Cithrol (R) GMS 052,073-5 85.7% 10 containing fractionated coconut oil by grinding Hydrokote 112 OS2,074-6 5.5% of formulated material cooled to domestic freezer temperatures Beeswax 052,074-7 1.5% Base Excipient Formulation Comment % as 650 or less Sterotex (R) NF 052O73-4 Data from Table 6 78.8% There was little significant difference, within experimental Sterotex (R) NF 052,093-1 Plus 15% fractionated 49.7% variation, between the results obtained at room temperature 15 coconut oil and that obtained from dosage units frozen to domestic Sterotex (R) NF 052,093-2 Plus 20% fractionated 33.7% freezer temperature (-20° C.). The Dromadol R. SR tablet coconut oil ground to a fine powder relatively easily. The SteroteXR NF Sterotex (R) NF 052,094-4 Plus 25% fractionated 8.3% and CithrolR GMS formulations also produced similar coconut oil amounts of fine powder. The incorporation of 10% beeswax in one of the SteroteXCR NF formulations made to detectable The addition of fractionated coconut oil produced the difference. The beeswax and Hydrokote 112 formulations desired effect in decreasing the ability to grind cooled formu provided excellent resistance against powdering. lated mix into a powder. The hot mix remained a machine filable light cream. The melting point of the 25% mix had Example 23 25 decreased from the 65° C. melting point of a SteroteXR NF mix with Zero added fractionated coconut oil to an acceptable SteroteXR NF Formulation Modification to Enhance 62° C. for the mix containing 25%. Resistance to Powdering Example 25 Further modifications were made to the SteroteXCR NF 30 based formulation, using fractionated coconut oil, to improve resistance to powdering. Samples were prepared substituting Abuse Resistance Testing 15, 20 and 25% of Sterotex(RNF for fractionated coconut oil. The formulations used were as listed below. Re-Evaluation of Modified Sterotex(R) NF Combinations 35 Formulation 052,093-1 Further testing was required, after revising the SteroteXCR) NF formulation by substituting part of the Sterotex(R) NF for Material % ww Quantity per cap mg fractionated coconut oil, to determine how this change had Sterotex (R) NF 45.2 180.8 40 affected the other parameters. Fractionated coconut oil 1S.O 59.9 Methocel(R) K 15 M 2O.O 80.1 Dissolution testing was carried out, in the same manner as Aerosil (R) COK 84 1.O 4.1 previously; using the USP paddle method to obtain the dis Tramadol HCI 18.8 75.1 solution profiles of the SteroteXR NF formulations with and Capsule fill weight 400 without additional fractionated coconut oil. This plot is 45 shown below in FIG. 45 Formulation 052,093-2 Example 26 Material % ww Quantity per cap mg Tests for ethanol extraction of whole and crushed or cut Sterotex (R) NF 40.2 1608 50 dosage units were also repeated. SteroteXR NF with 25% Fractionated coconut oil 2O.O 79.9 Methocel(R) K 15 M 2O.O 79.9 fractionated coconut oil (052/094-3) was tested alongside the Aerosil (R) COK 84 1.O 4.2 fractionated coconut oil free analogue (052/087-1). The Tramadol HCI 18.8 75.1 opportunity was taken to test some additional relevant Capsule fill weight 400 samples. The three previously tested formulations based on 55 Cithrol. R. GMS (052/073-5), Hydrokote 112 (052/074-6) and the beeswax formulation (052/074-7) were retested. Zydol R. XL 150 tablets were substituted for the previously used Dro Formulation 052,094-3 madol R. SR tablets. Both of these are slow release formula tions containing 150 mg of tramadol HC1. OxyContinR) Material %Wiw Quantity per cap mg 60 extended release 80 mg tablets were included for comparison Sterotex (R) NF 35.3 1410 purposes as Oxycodone extended release tablets are the Sub Fractionated coconut oil 2SO 1OOO ject of current concerns over tablet abuse and they provide Methocel (R) K 15 M 19.9 79.8 another tablet comparator containing a similar quantity of Aerosil (R) COK 84 1.O 4.1 Tramadol HCI 18.8 75.0 water soluble active in a slow release formula. The results of Capsule fill weight 400 65 ethanol extraction of whole dosage units and cut/crushed dosage units are shown below in FIGS. 46 and 47, respec tively. US 9,125,833 B2 139 140 The SteroteXR NF formulation containing 25% fraction formulations were significantly Superior to any of the three ated coconut oil did show increased susceptibility to ethanol commercial tablets formulations. extraction compared with the formulation without fraction ated coconut oil however this was demonstrably much better Example 29 than the tablets or the Cithrol. R. GMS formulation so was considered as acceptable. The quantities extracted were broadly in line with that determined in the earlier ethanol Ease of Powdering and Percentage of Resultant extraction tests, shown in FIGS. 42 and 43. The Zydol R XL Particles of 600 Micron or Less 150 tablets showed comparable release to the Dromadol RSR 10 tablets in the earlier test. The OxyContin R tablets showed Initial powdering tests were carried out using a laboratory much greater and faster release than any of the dosage units in stainless steel sieve of nominal 650 micron size. The sieve either of these sets of tests. size used had been qualitatively determined as a size that Example 27 could differentiate between the powders generated. Initially 15 much finer sieves had been tested but were found to be too fine The abuse resistance test involving extraction into water by e.g. a 45 micron sieve was tested but this was too fine resulting grinding a dosage unit in a mortar and pestle with Subsequent in almost Zero powder passing through the sieve from any filtration was repeated. All of the samples included in the samples. As result of the initial tests, a certified sieve was above ethanol extraction tests were included. Table 10 shows obtained of 600 micron size for further trials. All of the above the results of HPLC analysis of the filtrate expressed as the samples were subjected to the powdering test. The results are percentage of drug Substance released. The results are also shown in Table 12. depicted in Left Panel of FIG. 58 (the bars from left to right are Formulation 052/094-3, Formulation 052/073-5, Formu TABLE 12 lation 052/074-7, Formulation 052/074-6, Zydol XL(R) 150 mg and OxyContinR 80 mg, respectively). 25 Powder generation of formulations and comparator tablets by grinding of dosage units cooled to domestic freezer temperatures TABLE 10 Percentage release on extraction into water. % as 600 % as 600. 30 or less. or less. Base excipient Formulation % released on extraction Base Excipient Formulation Comment Sample 1 Sample 2 Zydol (R) XL 150 na 87.4 Dromadol (R) SR na 48.1% 51.9% OxyContin (R) 80 mg na 90.0 Zydol (R) XL 150 na 52.6% 41.2% Sterotex (R) NF OS2,087-1 28.1 OxyContin (R) 80 na 66.6% Not tested Sterotex (R) NF with OS2,094-3 11.6 35 ng 25% fr. coconut oil Cithrol (R) GMS O52O73-5 15.3 Sterotex (R) NF OS2,094-3 With 25% 2.2% O.6% Hydrokote 112 OS2O74-6 23.1 with 25% fr. fractionated Beeswax O52O74-7 18.6 coconut oil coconut oil Cithrol (R) GMS 052,073-5 40.3% 72.4% 40 Hydrokote 112 OS2,074-6 7.3% 2.6% Example 28 Beeswax 052,074-7 O.7% O.6% The abuse resistance test involving extraction into dilute acetic acid by heating to boiling was repeated. The same It should be noted that the lower results found in this trial samples as immediately above were tested and the results of 45 than those reported previously are due to a slightly finer sieve HPLC analysis of the resulting filtrates are shown in Table 11. size being used. The tablets all powdered relatively easily The results are also depicted in Right Panel of FIG. 58 (the while the Sterotex(R) NF, Hydrokote 112 and beeswax were bars from left to right are Formulation 052/094-3. Formula very resistant to powdering. The CithrolR GMS gave a high tion 052/074-6, Formulation 052/074-7, Formulation 052/ quantity of powder. The same approach of adding a room 073-5, Zydol XLR 150 mg and OxyContinR 80 mg, respec 50 temperature oil could be used on the CithrolR GMS as used tively) on Sterotex(R) NF however, with the CithrolR GMS formula tion showing a release rate of approximately 20 hr, on the fast TABLE 11 size of the target 24 hr, it was decided not to amend it at this Stage. Percentage release on extraction into dilute acid. 55 Base excipient Formulation % released on extraction Example 30 Zydol (R) XL 150 na 87.4 OxyContin (R) 80 mg na 82.2 Sterotex (R) NF OS2,087-1 10.8 Dissolution Testing of Stored Samples Sterotex (R) NF with OS2,094-3 7.0 60 25% fr. coconut oil Cithrol (R) GMS O52O73-5 34.9 Samples of the above formulations were stored for a period Hydrokote 112 OS2O74-6 11.1 of at least four weeks at room temperature (in some cases Beeswax O52O74-7 14.5 much longer) after which their dissolution release profile was 65 redetermined. This was carried out to find out if there were Both sets of results gave similar results for comparable any short term changes in the release rate. The tested formu formulations in this and the earlier set of tests. All liquid fill lations are shown in Table 13 and FIGS. 48 to 57. US 9,125,833 B2 141 142 TABLE 13 invention, in some embodiments, simultaneously providing more than one of foregoing (i) to (V) using Substantially the Formulations used for dissolution testing same ADER agents. after a minimum of 4 weeks storage. Storage Example 31 period Base Excipient Formulation days Comment Sterotex (R) N OS2,087-1 75 20% HPMC Sterotex (R) NF with OS2,094-3 71 Ingredients Quantity (mg), Dose 25% fr. coconut oil 10 Cithrol (R) GMS 052,073-5 95 Sterotex (R) NF 2OO Hydrokote 112 OS2,074-6 98 Fractionated coconut oil 70 Methocel (R) K15M 81 Beeswax 052,074-7 83 Aerosil (R) COK 84 4 Hydromorphone HCl 2O Capsule fill weight 375 Manufacturing methods described above and others are 15 utilized for the preparation of other abusable drugs as shown in the prophetic examples below. Variations to the methods may be employed, in some embodiments, depending on the Example 32 specific chemical, physicochemical, pharmaceutical and pharmacologic properties of the abusable drug, excipients and their interaction and other factors. Compositions and Ingredients Quantity (mg), Dose methods of the present invention provide: (i) abuse deter Sterotex (R) NF 135 rence; (ii) extended release; and/or (iii) protection against Fractionated coconut oil 50 alcohol dose dumping; and/or (iv) protection against signifi 25 Methocel (R) K15M 60 cant changes in bioavailability due to fed or fasted States; Aerosil (R) COK 84 3 and/or (V) simultaneously providing more than one of fore Fentanyl HCl 2 going (i) to (iv); wherein the dosage form is prepared using Capsule fill weight 250 compounds selected from the group consisting of: (a) hydro genated Type I or Type II vegetable oils; (b) polyoxyethylene 30 Stearates and distearates; (c) glycerol monostearate; (d) Example 33 poorly water soluble, high melting point (mp=45 to 100° C.) waxes, and mixtures thereof. As shown in further examples below, any abusable drug of Ingredients Quantity (mg), Dose the invention may be prepared to provide (i) abuse deterrence; 35 Sterotex (R) NF 170 or (ii) extended release; or (iii) resistance againstalcohol dose Fractionated coconut oil 100 dumping; or (iv) resistance against alcohol dose dumping Methocel(R) K15M 70 when formulated as extended release; or (v) protection Aerosil (R) COK 84 4.5 Levorphanol 5.5 mg against significant changes in bioavailability due to fed or 40 fasted States; or (vi) more than one of the foregoing proper Capsule fill weight 350 ties; said invention comprising one or more abusable drugs and one or more ADER agents; said invention, in some embodiments, providing further abuse deterrence through the Example 34 use of aversive agents; said invention, in Some embodiments, 45 using Substantially the same ADER agents to achieve the foregoing (i) to (V); said invention, in some embodiments, providing more than one of the foregoing properties; said Ingredients Quantity (mg), Dose invention, in some embodiments, comprising one or more Sterotex (R) NF 2OO 50 Fractionated coconut oil 90 abusable drugs and at least two ADER agents; said invention, Methocel(R) K15M 8O in some embodiments, comprising at least two ADER agents Aerosil (R) COK 84 5 selected from the group consisting of: (a) hydrogenated Type Hydrocodone 25 I or Type II vegetable oils; (b) polyoxyethylene stearates and Capsule fill weight 400 mg distearates; (c) glycerol monostearate; (d) poorly water soluble, high melting point (mp=45 to 100°C.) waxes; said 55 invention, in Some embodiments, comprising at least two Example 35 ADER agents selected from at least two categories from the group consisting of: (a) hydrogenated Type I or Type II Veg etable oils; (b) polyoxyethylene Stearates and distearates; (c) 60 glycerol monostearate; (d) poorly water Soluble, high melting Ingredients Quantity (mg), Dose point (mp=45 to 100° C.) waxes; said invention, in some Beeswax 2OO embodiments, further comprising an immediate release form HPMC, K15M 8O Aerosil COK 84 8 of the abusable drug; said invention, in Some embodiments, Levorphanol Tartrate 12 further comprising an immediate release form of the abusable 65 Capsule fill weight 3OO drug in solution; said invention, in some embodiments, simul taneously providing more than one of foregoing (i) to (V); said US 9,125,833 B2

Example 36 -continued Ingredients Quantity (mg), Dose Aerosil COK 84 10 Ingredients Quantity (mg), Dose 5 Levorphanol 10 Sterotex NF 150 Capsule fill weight 350 HPMC, K15M 75 Coconut oil 75 Aerosil COK 84 5 Oxymorphone 2O 10 Capsule fill weight 325 Example 42 Ingredients Quantity (mg), Dose Example 37 Sterotex NF 32O Methocel K. 15M 60 15 Aerosil COK 84 10 Oxycodone 10 Capsule fill weight 400 Ingredients Quantity (mg), Dose Cithrol GMS 275 HPMC, K10OM 40 2O Aerosil COK 84 10 Example 43 Methadone 25 Capsule fill weight 350

25 Ingredients Quantity (mg), Dose Example 38 Cithro GMS 32O Methocel K10OM 55 Aerosil COK 84 15 Oxymorphone 10 Ingredients Quantity (mg), Dose 30 Capsule fill weight 400 Hydrokote 112 250 HPMC, K15M 60 Aerosil COK 84 10 Example 44 Morphine 30 Capsule fill weight 350 35 Ingredients Quantity (mg), Dose Example 39 Hydrokote 112 225 Methocel K. 15M 50 40 Aerosil COK 84 10 Hydrocodone 15 Ingredients Quantity (mg), Dose Capsule fill weight 3OO Beeswax 200 HPMC, Pharmacoat 606 62.5 Aerosil COK 84 7.5 45 Example 45 Hydrocodone 30 Capsule fill weight 300

Ingredients Quantity (mg), Dose Example 40 50 Beeswax 225 Methocel K. 15M 75 Aerosil COK 84 10 Dihydrocodeine 15 Ingredients Quantity (mg), Dose Capsule fill weight 325 Gelucire 50,02 190 55 Methocel K10OM 35 Aerosil COK 84 10 Example 46 Hydromorphone HCI 15 Capsule fill weight 250

60 Ingredients Quantity (mg), Dose Example 41 Beeswax 10 HPMC, K15M 8O Ingredients Quantity (mg), Dose Aerosil COK 84 8 Remifentanil 2 Cetyl alcohol 28O 65 Capsule fill weight 3OO Methocel K10OM 50 US 9,125,833 B2

Example 47 -continued Ingredients Quantity (mg), Dose Aerosil COK 84 10 Ingredients Quantity (mg), Dose 5 Hydrocodone 50 Sterotex NF 166 Capsule fill weight 400 HPMC, K15M 75 Coconut oil 75 Aerosil COK 84 5 Sufentani 4 10 Capsule fill weight 325 Example 53 Ingredients Quantity (mg), Dose Example 48 Sterotex NF 32O Methocel K. 15M 60 15 Aerosil COK 84 10 Oxymorphone 40 Capsule fill weight 430 Ingredients Quantity (mg), Dose Cithrol GMS 285 HPMC, K10OM 49 2O Aerosil COK 84 10 Example 54 Alfentani 6 Capsule fill weight 350

25 Ingredients Quantity (mg), Dose Example 49 Cithro GMS 32O Methocel K10OM 68 Aerosil COK 84 12 Oxycodone 60 Ingredients Quantity (mg), Dose 30 Capsule fill weight 460 Hydrokote 112 240 HPMC, K15M 50 Aerosil COK 84 10 Example 55 Propiram HCl 100 Capsule fill weight 400 35

Ingredients Quantity (mg), Dose Example 50 Hydrokote 112 225 Methocel K. 15M 50 40 Aerosil COK 84 10 Methadone 40 Ingredients Quantity (mg), Dose Capsule fill weight 325 Beeswax 195 HPMC, Pharmacoat 606 45 Aerosil COK 84 10 45 Example 56 Propiram 150 Capsule fill weight 400

Ingredients Quantity (mg), Dose Example 51 50 Beeswax 235 Methocel K. 15M 75 Aerosil COK 84 14 Codeine SO 150 Ingredients Quantity (mg), Dose Capsule fill weight 474 Gelucire 50,02 190 55 Methocel K10OM 30 Aerosil COK 84 10 Example 57 Hydromorphone HCI 2O Capsule fill weight 250

60 Ingredients Quantity (mg), Dose Example 52 Beeswax 2OO HPMC, K15M 90 Ingredients Quantity (mg), Dose Aerosil COK 84 10 Pentazocine 1OO Cetyl alcohol 290 65 Capsule fill weight 40 Methocel K10OM 50 US 9,125,833 B2 Example 58 Example 63

Ingredients Quantity (mg), Dose 5 Ingredients Quantity (mg), Dose Cetyl alcohol 270 Methocel K10OM 50 Sterotex NF 150 Aerosil COK 84 10 HPMC, K15M 75 Buprenorphine 2O Coconut oil 8O 10 Capsule fill weight 350 Aerosil COK 84 10 Anleridine 100 Example 64 Capsule fill weight 415 15 Ingredients Quantity (mg), Dose Sterotex NF 293 Methocel K. 15M 45 Example 59 Aerosil COK 84 10 Sufentani 2 2O Capsule fill weight 350

Ingredients Quantity (mg), Dose Cithrol GMS 290 Example 65 HPMC, K10OM 48 25 Aerosil COK 84 12 Lofentanil O.1 Capsule fill weight 3SO.1 Ingredients Quantity (mg), Dose Cithro GMS 325 30 Methocel K10OM 55 Aerosil COK 84 15 Example 60 Fentanyl 5 Capsule fill weight 400

Ingredients Quantity (mg), Dose 35 Example 66 Hydrokote 112 270 HPMC, K15M 65 Aerosil COK 84 15 Carfentani O.2 Capsule fill weight 350.2 40 Ingredients Quantity (mg), Dose Hydrokote 112 225 Methocel K. 15M 50 Aerosil COK 84 10 Example 61 Hydrocodone 15 Capsule fill weight 3OO 45

Ingredients Quantity (mg), Dose Example 67 Beeswax 177 HPMC, Pharmacoat 606 60 50 Aerosil COK 84 10 Fentanyl 3 Ingredients Quantity (mg), Dose Capsule fill weight 250 Beeswax 225 Methocel K. 15M 75 55 Aerosil COK 84 10 Racemorphan 2O Example 62 Capsule fill weight 330

60 Example 68 Ingredients Quantity (mg), Dose Gelucire 50,02 190 Methocel K10OM 40 Aerosil COK 84 10 Ingredients Quantity (mg), Dose Alfentani 10 Capsule fill weight 250 65 Sterotex (R) NF 1OO Fractionated coconut oil 70 US 9,125,833 B2

-continued Example 73 Ingredients Quantity (mg), Dose Beeswax 100 Methocel (R) K15M 81 Ingredients Quantity (mg), Dose Aerosil (R) COK 84 4 Beeswax 150 Hydromorphone HCl 2O HPMC, K15M 8O Capsule fill weight 375 Aerosil COK 84 15 Hydrokote 112 75 Morphine Sulfate 60 10 Capsule fill weight 380 Example 69

Example 74 15 Ingredients Quantity (mg), Dose Sterotex (R) NF 135 Fractionated coconut oil 50 Ingredients Quantity (mg), Dose Beeswax 50 Methocel (R) K15M 60 Sterotex NF 150 Aerosil (R) COK 84 3 HPMC, K15M 75 Fentanyl HCl 2 Coconut oil 75 Capsule fill weight 300 Aerosil COK 84 5 Oxymorphone 2O Hydrokote 112 75 Capsule fill weight 400 25 Example 70

Example 75

Ingredients Quantity (mg), Dose 30 Sterotex (R) NF 130 Fractionated coconut oil 100 Ingredients Quantity (mg), Dose Beeswax 70 HPMC, K15M 2O Cithro GMS 275 Methocel (R) K15M 70 35 HPMC, K10OM 50 Aerosil (R) COK 84 4.5 Aerosil COK 84 15 Levorphanol 5.5 mg Hydrokote 112 1OO Capsule fill weight 400 Methadone 60 Capsule fill weight 500

40 Example 71 Example 76

Ingredients Quantity (mg), Dose 45 Ingredients Quantity (mg), Dose Sterotex (R) NF 150 Fractionated coconut oil 8O Cithro GMS 275 Cithrol GMS 120 HPMC, K10OM 60 HPMC, K10OM 2O Aerosil COK 84 15 Methocel (R) K1SM 8O Gelucire 5002 1OO Aerosil (R) COK 84 5 50 Methadone 25 Methadone 60 Capsule fill weight 475 Capsule fill weight 515 mg

55 Example 77 Example 72

Ingredients Quantity (mg), Dose Ingredients Quantity (mg), Dose 60 Gelucire 5002 140 Beeswax 150 Methocel K10OM 35 HPMC, K15M 8O Aerosil COK 84 15 Aerosil COK 84 10 Sterotex (R) NF 75 Cith rol 150 Fractionated coconut oil 45 Levorphanol Tartrate 2O Hydromorphone HCl 15 Capsule fill weight 410 65 Capsule fill weight 325 US 9,125,833 B2 Example 78 Example 83

Ingredients Quantity (mg), Dose 5 Ingredients Quantity (mg), Dose Gelucire 50,02 100 Methocel K100M 28 Sterotex (R) NF 2OO Aerosil COK 84 12 Beeswax 125 Fractionated coconut oil 90 HPMC, K15M 65 10 Methocel (R) K15M 8O Levorphanol Tartrate 30 il Capsule fill weight 370 Aerosil (R) COK 84 5 Cannabinoid Agonist 25 Capsule fill weight 400 mg Example 79 15 Example 84 Ingredients Quantity (mg), Dose 2O Gelucire 50,02 200 Methocel K10OM 60 Ingredients Quantity (mg), Dose Aerosil COK 84 2O Cithrol GMS 140 Beeswax 2OO Oxycodone HCI 8O HPMC, K15M 8O Capsule fill weight 500 25 Aerosil COK 84 8 Dronabinol 12 Capsule fill weight 3OO Example 80 30 Example 85

Ingredients Quantity (mg), Dose Sterotex (R) NF 200 Ingredients Quantity (mg), Dose Fractionated coconut oil 70 35 Methocel (R) K1SM 81 Sterotex NF 150 Aerosil (R) COK 84 4 HPMC, K15M 75 Dronabinol 2O Coconut oil 75 Capsule fill weight 375 Aerosil COK 84 5 Dronabinol 2O 40 Capsule fill weight 325 Example 81 Example 86 45 Ingredients Quantity (mg), Dose Sterotex (R) NF 135 Ingredients Quantity (mg), Dose Fractionated coconut oil 50 Methocel (R) K1SM 60 Cithro GMS 275 Aerosil (R) COK 84 3 50 HPMC, K10OM 40 Nabilone 2 Aerosil COK 84 10 Capsule fill weight 250 Dronabinol 25 Capsule fill weight 350

Example 82 55 Example 87

Ingredients Quantity (mg), Dose 60 Ingredients Quantity (mg), Dose Sterotex (R) NF 170 Fractionated coconut oil 100 Hydrokote 112 250 Methocel (R) K1SM 70 HPMC, K15M 60 Aerosil (R) COK 84 4.5 Aerosil COK 84 10 THC 5.5 mg Dronabinol 30 Capsule fill weight 350 65 Capsule fill weight 350 US 9,125,833 B2 Example 88 Example 93

Ingredients Quantity (mg), Dose 5 Ingredients Quantity (mg), Dose Hydrokote 112 225 Beeswax 200 Methocel K1SM 50 Aerosil COK 84 10 HPMC, Pharmacoat 606 62.5 Dronabinol 15 Aerosil COK 84 7.5 10 Capsule fill weight 3OO Dronabinol 30 Capsule fill weight 300

15 Example 94 Example 89 Ingredients Quantity (mg), Dose 2O Beeswax 225 Ingredients Quantity (mg), Dose Methocel K. 15M 75 Aerosil COK 84 10 Gelucire 50,02 190 Dronabinol 15 Methocel K10OM 35 Aerosil COK 84 10 Capsule fill weight 325 Dronabinol 15 25 Capsule fill weight 250

Example 95 Example 90 30

Ingredients Quantity (mg), Dose Ingredients Quantity (mg), Dose Beeswax 210 HPMC, K15M 8O Cetyl alcohol 28O 35 Aerosil COK 84 8 Methocel K10OM 50 Nabilone 2 Aerosil COK 84 10 Dronabinol 10 Capsule fill weight 3OO Capsule fill weight 350

40 Example 96 Example 91

45 Ingredients Quantity (mg), Dose Ingredients Quantity (mg), Dose Sterotex NF 166 Sterotex NF 320 HPMC, K15M 75 Methocel K. 15M 60 Coconut oil 75 Aerosil COK 84 10 Aerosil COK 84 5 Dronabinol 10 50 Nabilone 4 Capsule fill weight 400 Capsule fill weight 325

Example 92 55 Example 97

Ingredients Quantity (mg), Dose 60 Ingredients Quantity (mg), Dose Cithrol GMS 320 Cithro GMS 285 Methocel K10OM 55 HPMC, K10OM 49 Aerosil COK 84 15 Aerosil COK 84 10 Dronabinol 10 Nabilone 6 Capsule fill weight 400 65 Capsule fill weight 350 US 9,125,833 B2 156 Example 98 Example 103

Ingredients Quantity (mg), Dose 5 Ingredients Quantity (mg), Dose

Hydrokote 112 239 Cithro GMS 32O etc. 3. s Methocel K10OM 63 eros Aerosil COK 84 12 Nabilone 1 10 Nabilone 5 Capsule fill weight 300 Capsule fill weight 400

Example 99 15 Example 104

Ingredients Quantity (mg), Dose 2O Ingredients Quantity (mg), Dose Beeswax 195 HPMC, Pharmacoat 606 45 Hydrokote 112 225 Aerosil COK 84 7.5 Methocel K. 15M 50 Nabilone 2.5 Aerosil COK 84 10 Nabilone 15 Capsule fill weight 250 25 Capsule fill weight

Example 100 30 Example 105

Ingredients Quantity (mg), Dose Ingredients Quantity (mg), Dose Gelucire 50,02 190 Methocel K10OM 30 35 Beeswax 235 Aerosil COK 84 10 Methocel K. 15M 75 Nabilone 2O Aerosil COK 84 14 Nabilone 1 Capsule fill weight 250 Capsule fill weight 325 40

Example 101 Example 106

45 Ingredients Quantity (mg), Dose Ingredients Quantity (mg), Dose Cetyl alcohol 28O Methocel K10OM 50 Beeswax 2OO Aerosil COK 84 10 HPMC, K15M 8O Nabilone 10 50 Aerosil COK 84 10 THC 10 Capsule fill weight 350 Capsule fill weight 3OO

55 Example 102 Example 107

Ingredients Quantity (mg), Dose 60 Ingredients Quantity (mg), Dose Sterotex NF 320 Sterotex NF 150 Methocel K. 15M 60 HPMC, K15M 75 Aerosil COK 84 10 Coconut oil 8O Nabilone 10 Aerosil COK 84 10 THC 5 Capsule fill weight 400 65 Capsule fill weight 325 US 9,125,833 B2 157 158 Example 108 -continued Ingredients Quantity (mg), Dose

Ingredigredients Quantity (mg),AD Dose 5 AerosilTHC COK 84 102 Cithrol GMS 275 Capsule fill weight 350 HPMC, K10OM 48 Aerosil COK 84 12 THC 15 Capsule fill weight 350 10 Example 114

Example 109 Ingredients Quantity (mg), Dose Cithro GMS 325 Ingredientsgr Quantity ty (mg)(mg). Dose 15 Methocel K10OM 55 Hydrokote 112 26S Aerosil COK 84 15 HPMC, K15M 65 THC 5 Aerosil COK 84 15 Capsule fill weight 400 THC 5 Capsule fill weight 350 2O Example 115

Example 110 25 Ingredients Quantity (mg), Dose Hydrokote 112 225 Methocel K. 15M 50 Ingredients Quantity (mg), Dose Aerosil COK 84 10 Beeswax 177 Suleil weight s HPMC, Pharmacoat 606 60 30 p 9. Aerosil COK 84 10 THC 3 C apsulele fillIlli weightwe1g 250 Example 116

35 Example 111 Ingredients Quantity (mg), Dose Beeswax 225 Methocel K. 15M 75 Ingredients Quantity (mg), Dose 40 Aerosil COK 84 10 THC 5 Gelucire 50,02 190 Capsule fill weight 315 Methocel K10OM 35 Aerosil COK 84 10 THC 15 Capsule fill weight 250 45 Example 117 This formulation of the strong opioid levorphanol was Example 112 prepared in accordance with the procedure described in the above similar examples for Tramadol. The formulation pro 50 vided robust dissolution characteristics consistent with an extended release formulation (see FIG. 59). Ingredients Quantity (mg), Dose Cetyl alcohol 28O Ingredients Quantity (mg), Dose Methocel K10OM 50 Aerosil COK 84 10 55 Beeswax 237 THC 10 HPMC, K15M 8O Capsule fill weight 350 Aerosil COK 84 8 Levorphanol Tartrate 10 Capsule fill weight 335 Example 113 60 Example 118 Ingredient ti AD This formulation of the strong opioid levorphanol was gredients Quantity (mg), Dose prepared in accordance with the procedure described in the Sterotex NF 293 65 above similar examples for Tramadol. The formulation pro Methocel K. 15M 45 vided robust dissolution characteristics consistent with an extended release formulation (see FIG. 60). US 9,125,833 B2 159 160 tetrazepam, triazolam, Zaleplone, Zolpidem and Zopiclone; Ingredients Quantity (mg), Dose said inventions comprising one or more abusable drugs and Cithrol GMS 273 one or more ADER agents; said invention, in Some embodi HPMC, K10OM 40 ments, providing further abuse deterrence through the use of Aerosil COK 84 12 aversive agents; said invention, in Some embodiments, using Levorphanol Tartrate 10 Substantially the same ADER agents to achieve the foregoing Capsule fill weight 335 (i) to (V); said invention, in Some embodiments, providing more than one of the foregoing properties; said invention, in Some embodiments, comprising one or more abusable drugs Example 119 10 and at least two ADER agents; said invention, in some embodiments, comprising at least two ADER agents selected This formulation of the strong opioid levorphanol was from the group consisting of: (a) hydrogenated Type I or Type prepared in accordance with the procedure described in the II vegetable oils; (b) polyoxyethylene stearates and distear above similar examples for Tramadol. The formulation pro ates; (c) glycerol monostearate; (d) poorly water soluble, high vided robust dissolution characteristics consistent with an 15 melting point (mp=45 to 100° C.) waxes; said invention, in extended release formulation (see FIG. 61). Some embodiments, comprising at least two ADER agents selected from at least two categories from the group consist ing of: (a) hydrogenated Type I or Type II vegetable oils; (b) Ingredients Quantity (mg), Dose polyoxyethylene Stearates and distearates; (c) glycerol monostearate; (d) poorly water Soluble, high melting point Sterotex NF 141 Methocel K. 15M 8O (mp=45 to 100° C.) waxes; said invention, in some embodi Fractionated Coconut oil 100 ments, further comprising an immediate release form of the Aerosil 200 4 abusable drug; said invention, in some embodiments, further Levorphanol Tartrate 10 comprising an immediate release form of the abusable drug in Capsule fill weight 335 25 Solution; said invention, in Some embodiments, simulta neously providing more than one of foregoing (i) to (V); said invention, in some embodiments, simultaneously providing Example 120 more than one of foregoing (i) to (V) using Substantially the same ADER agents. This formulation of the strong opioid levorphanol was 30 prepared in accordance with the procedure described in the Example 122 above similar examples for Tramadol. The formulation pro vided robust dissolution characteristics consistent with an Compositions and methods of the present invention can be extended release formulation (see FIG. 62). prepared in accordance with the present invention to provide: 35 (i) abuse deterrence; or (ii) extended release; or (iii) protec tion against alcohol dose dumping; or (iv) protection against Ingredients Quantity (mg), Dose significant changes in bioavailability due to fed or fasted Hydrokote 112 253 states; or (v) protection against significant changes in bio HPMC, K15M 60 availability due to fedor fasted states; or (vi) more than one of Aerosil COK 84 12 40 the foregoing properties; wherein the dosage form is pre Levorphanol Tartrate 10 pared: (I) using compounds selected from the group consist Capsule fill weight 335 ing of: (a) hydrogenated Type I or Type II vegetable oils; (b) polyoxyethylene Stearates and distearates; (c) glycerol monostearate; (d) poorly water Soluble, high melting point Example 121 45 (mp=45 to 100° C.) waxes, and mixtures thereof; and (II) non-benzodiazepine hypnotics and CNS depressants selected Compositions and methods of the present invention can be from the group comprising Sodium oxybate, diphenhy prepared in accordance with the present invention to provide: dramine, chlorpheniramine, traZadone, amitriptyline, (i) abuse deterrence; or (ii) extended release; or (iii) protec cyclobenzaprine, methocarbamol, carisoprodol and ramelt tion against alcohol dose dumping; or (iv) protection against 50 eon, said inventions comprising one or more abusable drugs significant changes in bioavailability due to fed or fasted and one or more ADER agents; said invention, in some states; or (V) protection against significant changes in bio embodiments, providing further abuse deterrence through the availability due to fedorfasted states; or (vi) more than one of use of aversive agents; said invention, in Some embodiments, the foregoing properties; wherein the dosage form is pre using Substantially the same ADER agents to achieve the pared: (I) using compounds selected from the group consist 55 foregoing (i) to (V); said invention, in Some embodiments, ing of: (a) hydrogenated Type I or Type II vegetable oils; (b) providing more than one of the foregoing properties; said polyoxyethylene Stearates and distearates; (c) glycerol invention, in some embodiments, comprising one or more monostearate; (d) poorly water Soluble, high melting point abusable drugs and at least two ADER agents; said invention, (mp=45 to 100° C.) waxes, and mixtures thereof; and (II) in some embodiments, comprising at least two ADER agents benzodiazepine agonist selected from the group consisting of 60 selected from the group consisting of: (a) hydrogenated Type alprazolam, bromazepam, brotizolam, camazepam, chlor I or Type II vegetable oils; (b) polyoxyethylene stearates and diazepoxide, cinolazepam, clobazam, clonazepam, cloraZe distearates; (c) glycerol monostearate; (d) poorly water pate, desalkylflurazepam, diazepam, estazolam, fluni soluble, high melting point (mp=45 to 100°C.) waxes; said trazepam, flurazepam, halazepam, ketazolam, loprazolam, invention, in some embodiments, comprising at least two lorazepam, lormetazepam, medazepam, metaclazepam, 65 ADER agents selected from at least two categories from the midazolam, nitrazepam, nordazepam, OXaZepam, group consisting of: (a) hydrogenated Type I or Type II Veg phenazepam, pinazepam, prazepam, quaZepam, temazepam, etable oils; (b) polyoxyethylene Stearates and distearates; (c) US 9,125,833 B2 161 162 glycerol monostearate; (d) poorly water Soluble, high melting (i) abuse deterrence; or (ii) extended release; or (iii) protec point (mp=45 to 100° C.) waxes; said invention, in some tion against alcohol dose dumping; or (iv) protection against embodiments, further comprising an immediate release form significant changes in bioavailability due to fed or fasted of the abusable drug; said invention, in Some embodiments, states; or (v) protection against significant changes in bio further comprising an immediate release form of the abusable availability due to fedor fasted states; or (vi) more than one of drug in solution; said invention, in some embodiments, simul taneously providing more than one of foregoing (i) to (V); said the foregoing properties; wherein the dosage form is pre invention, in some embodiments, simultaneously providing pared: (I) using compounds selected from the group consist more than one of foregoing (i) to (V) using Substantially the ing of: (a) hydrogenated Type I or Type II vegetable oils; (b) same ADER agents. polyoxyethylene Stearates and distearates; (c) glycerol 10 monostearate; (d) poorly water Soluble, high melting point Example 123 (mp=45 to 100° C.) waxes, and mixtures thereof; and (II) CNS-Stimulants, psychoStimulants, alkylxanthine, and Compositions and methods of the present invention can be anorectic compounds selected from the group comprising prepared in accordance with the present invention to provide: adrafanil, alkyXanthine derivatives, almitrine, amfetaminil, (i) abuse deterrence; or (ii) extended release; or (iii) protec 15 aminophylline, amiphenazole, ammonium camphocarbon tion against alcohol dose dumping; or (iv) protection against ate, amphetamine, bamifylline, benzfetamine, brolamfe significant changes in bioavailability due to fed or fasted tamine, caffeine, cathine (+)-norpseudoephedrine, cathi states; or (V) protection against significant changes in bio none, celastrin, chlorphentermine, clonobenzorex, availability due to fedorfasted states; or (vi) more than one of cropropamide, crotetamide, deanol, dextroamphetamine, the foregoing properties; wherein the dosage form is pre diethylaminoethanol, diethylpropion, dimfline, doxapram, pared: (I) using compounds selected from the group consist doxofylline, diprophylline, dyphylline, etamivan, etofylline, ing of: (a) hydrogenated Type I or Type II vegetable oils; (b) emprophylline, etamiphylline, methylphenidate, dexmeth polyoxyethylene Stearates and distearates; (c) glycerol ylphenidate, fencamfamin, fenetyline, fenozolone, fenpro monostearate; (d) poorly water Soluble, high melting point porex, lisdexamfetamine, lisdexamfetamine dimeSylate, (mp=45 to 100° C.) waxes, and mixtures thereof; and (II) 25 lisofylline, lobeline, mazindol, mefenorex, mepixanox, cannabinoid agonists selected from the group comprising methamphetamine, methylenedioxymethamphetamine, THC, nabilone, dronabinol, cannabidiol, 9-THC propyl ana log, cannabidiol, cannabidiol propyl analog, cannabinol, can modafinil, nicotine, nikethamide, oxtriphylline, pemoline, nabichromene, cannabichromene propyl analog, cannabig pentetraZol, phedimetrazine, phenmetrazine, phentermine, erol, cannabinoid terpenoids, cannabinoid flavonoids, pentoxifylline, phenylpropanolamine, pipradrol, prethcam endocannabinoids, anandamide and 2-arachidonoylglycerol, 30 ide, prolintane, propylhexedrine, propentofylline, pentifyl THC-like ABC tricyclic cannabinoid analogues, exemplified line, pseudoephedrine, pyridophylline, proxyphylline, by HU210 and desacetyllevonantradol; synthetic AC bicyclic Sibutramine, tenamfetamine (methylenedioxeamphetamine), and ACD tricyclic cannabinoid analogues, exemplified by theophylline, theobromine; said inventions comprising one or CP55940, and CP55244 and aminoalkylindole compounds, more abusable drugs and one or more ADER agents; said exemplified by WIN55212-2; said inventions comprising one 35 invention, in Some embodiments, providing further abuse or more abusable drugs and one or more ADER agents; said deterrence through the use of aversive agents; said invention, invention, in some embodiments, providing further abuse in some embodiments, using Substantially the same ADER deterrence through the use of aversive agents; said invention, agents to achieve the foregoing (i) to (V); said invention, in in Some embodiments, using Substantially the same ADER Some embodiments, providing more than one of the foregoing agents to achieve the foregoing (i) to (V); said invention, in 40 properties; said invention, in Some embodiments, comprising Some embodiments, providing more than one of the foregoing one or more abusable drugs and at least two ADER agents; properties; said invention, in some embodiments, comprising said invention, in Some embodiments, comprising at least two one or more abusable drugs and at least two ADER agents; ADER agents selected from the group consisting of: (a) said invention, in some embodiments, comprising at least two hydrogenated Type I or Type II vegetable oils; (b) polyoxy ADER agents selected from the group consisting of: (a) 45 ethylene Stearates and distearates; (c) glycerol monostearate; hydrogenated Type I or Type II vegetable oils; (b) polyoxy (d) poorly water soluble, high melting point (mp=45 to 100° ethylene Stearates and distearates; (c) glycerol monostearate; C.) waxes; said invention, in Some embodiments, comprising (d) poorly water soluble, high melting point (mp=45 to 100° at least two ADER agents selected from at least two catego C.) waxes; said invention, in some embodiments, comprising ries from the group consisting of: (a) hydrogenated Type I or at least two ADER agents selected from at least two catego 50 Type II vegetable oils; (b) polyoxyethylene stearates and ries from the group consisting of: (a) hydrogenated Type I or distearates; (c) glycerol monostearate; (d) poorly water Type II vegetable oils; (b) polyoxyethylene stearates and soluble, high melting point (mp=45 to 100°C.) waxes; said distearates; (c) glycerol monostearate; (d) poorly water invention, in some embodiments, further comprising an soluble, high melting point (mp=45 to 100°C.) waxes; said immediate release form of the abusable drug; said invention, invention, in Some embodiments, further comprising an 55 in some embodiments, further comprising an immediate immediate release form of the abusable drug; said invention, release form of the abusable drug in Solution, said invention, in some embodiments, further comprising an immediate in some embodiments, simultaneously providing more than release form of the abusable drug in Solution, said invention, one of foregoing (i) to (V); said invention, in Some embodi in some embodiments, simultaneously providing more than ments, simultaneously providing more than one of foregoing one of foregoing (i) to (V); said invention, in Some embodi 60 (i) to (V) using Substantially the same ADER agents. ments, simultaneously providing more than one of foregoing (i) to (V) using Substantially the same ADER agents. Example 125 Example 124 Compositions and methods of the present invention can be 65 prepared in accordance with the present invention to provide: Compositions and methods of the present invention can be (i) abuse deterrence; or (ii) extended release; or (iii) protec prepared in accordance with the present invention to provide: tion against alcohol dose dumping; or (iv) protection against US 9,125,833 B2 163 164 significant changes in bioavailability due to fed or fasted ments, simultaneously providing more than one of foregoing states; or (V) protection against significant changes in bio (i) to (V) using Substantially the same ADER agents. availability due to fedorfasted states; or (vi) more than one of Having now fully described the invention, it will be under the foregoing properties; wherein the dosage form is pre stood to those of ordinary skill in the art that the same can be pared: (I) using compounds selected from the group consist performed within a wide and equivalent range of conditions, ing of: (a) hydrogenated Type I or Type II vegetable oils; (b) formulations, and other parameters without affecting the polyoxyethylene Stearates and distearates; (c) glycerol scope of the invention or any embodiment thereof. All patents monostearate; (d) poorly water Soluble, high melting point and publications cited herein are fully incorporated by refer ence herein in their entirety. (mp=45 to 100° C.) waxes, and mixtures thereof; and (II) 10 opioid agonists selected from the group comprising alfenta What is claimed is: nil, allylprodine, alphaprodine, anilleridine, apomorphine, 1. A dosage form for administration via the oral cavity, the apocodeine, benzylmorphine, bezitramide, brifentanil, dosage form comprising buprenorphine, butorphanol, carfentanil, clonitaZene, codeine, cyclorphen, cyprenorphine, desomorphine, dextro a) a drug, being an opioid agonist, combined with 15 b) at least two abuse deterrent extended release (ADER) moramide, dezocine, diampromide, dihydrocodeine, dihy ingredients including a hydrogenated vegetable oil and a dromorphine, dimenoxadol, dimepheptanol, dimethylthiam fractionated coconut oil, butene, dioxyaphetyl butyrate, diplpanone, eptazocine, wherein the ADER ingredients are selected and are present ethoheptazine, ethylmethylthiambutene, ethylmorphine, eto in amounts sufficient to reduce the amount of drug nitaZene, fentanyl, heroin, hydrocodone, hydroxymethylmor released from the dosage form at one hour in the USP phinan, hydromorphone, hydroxypethidine, isomethadone, Basket and Paddle Method at 100 revolutions perminute ketobemidone, levallorphan, levorphanol, levophenacylmor in 700 milliliters of simulated gastric fluid at 37 degrees phan, lofentanil, meperidine, meptazinol, metazocine, Celsius, relative to the same dosage form lacking the methadone, methylmorphine, metopon, mirfentanil, mor ADER ingredients, and phine, morphine-6-glucuronide, myrophine, nalbuphine, nar 25 wherein the fractionated coconut oil is present in an ceine, nicomorphine, norlevorphanol, normethadone, nalor amount Sufficient to enhance by at least a third resistance phine, nociceptin/orphanin FO (N/OFO), normorphine, to powdering of the dosage form to particle sizes of 650 norpipanone, ohmefentanyl, opium, oxycodone, oxymor micrometers or less, relative to an otherwise identical phone, papaveretum, pentazocine, phenadoxone, phenomor dosage form having the hydrogenated vegetable oil Sub phan, phenazocine, phenoperidine, pholcodine, piminodine, 30 stituted in place of the fractionated coconut oil. piritramide, propheptazine, promedol, profadol, properidine, 2. The dosage form of claim 1, wherein the drug is in a form propiram, propoxyphene, remifentanil, sufentanil, tapenta selected from the group consisting of a pharmaceutically dol, tramadol, trefentanil, tilidine, nalbuphine, or any opioid acceptable salt of the drug, an ester of the drug, and combi having agonist activity at an opioid receptor belonging to the nations of these. phenanthrene, morphinan, benzomorphan, methadone, phe 35 3. The dosage form of claim 1, wherein the hydrogenated nylpiperidine, propionanilide 4-anilidopiperidine, 4-aryl pip Vegetable oil is hydrogenated cottonseed oil. eridines, and 4-Heteroarylpiperidines class, any opioid hav 4. The dosage form of claim 1, wherein the ADER ingre ing agonist activity at an opioid receptor having the same dients are present in an amount effective to reduce the rate of pentacyclic nucleus as nalmefene, naltrexone, buprenor release of the drug, relative to the dosage form lacking the phine, levorphanol, meptazinol, pentazocine and dezocine, 40 ADER ingredients, when administered to a human. any drug having agonist activity at an opioid receptor which 5. The dosage form of claim 1, wherein the drug is an is a fentanyl analog; said inventions comprising one or more opioid agonist selected from the group consisting of alfenta abusable drugs and one or more ADER agents; said invention, nil, allylprodine, alphaprodine, anilleridine, apomorphine, in Some embodiments, providing further abuse deterrence apocodeine, benzylmorphine, bezitramide, brifentanil, through the use of aversive agents; said invention, in some 45 buprenorphine, butorphanol, carfentanil, clonitaZene, embodiments, using Substantially the same ADER agents to codeine, cyclorphen, cyprenorphine, desomorphine, dextro achieve the foregoing (i) to (V); said invention, in some moramide, dezocine, diampromide, dihydrocodeine, dihy embodiments, providing more than one of the foregoing dromorphine, dimenoxadol, dimepheptanol, dimethylthiam properties; said invention, in some embodiments, comprising butene, dioxyaphetyl butyrate, dipipanone, eptazocine, one or more abusable drugs and at least two ADER agents; 50 ethoheptazine, ethylmethylthiambutene, ethylmorphine, eto said invention, in some embodiments, comprising at least two nitaZene, fentanyl, heroin, hydrocodone, hydroxymethylmor ADER agents selected from the group consisting of: (a) phinan, hydromorphone, hydroxypethidine, isomethadone, hydrogenated Type I or Type II vegetable oils; (b) polyoxy ketobemidone, levallorphan, levorphanol, levophenacylmor ethylene Stearates and distearates; (c) glycerol monostearate; phan, lofentanil, meperidine, meptazinol, metazocine, (d) poorly water soluble, high melting point (mp=45 to 100° 55 methadone, methylmorphine, metopon, mirfentanil, mor C.) waxes; said invention, in some embodiments, comprising phine, morphine-6-glucuronide, myrophine, nalbuphine, nar at least two ADER agents selected from at least two catego ceine, nicomorphine, norlevorphanol, normethadone, nalor ries from the group consisting of: (a) hydrogenated Type I or phine, nociceptin/orphanin FQ (N/OFO), normorphine, Type II vegetable oils; (b) polyoxyethylene stearates and norpipanone, ohmefentanyl, opium, oxycodone, oxymor distearates; (c) glycerol monostearate; (d) poorly water 60 phone, papaveretum, pentazocine, phenadoxone, phenomor soluble, high melting point (mp=45 to 100°C.) waxes; said phan, phenazocine, phenoperidine, pholcodine, piminodine, invention, in Some embodiments, further comprising an piritramide, propheptazine, promedol, profadol, properidine, immediate release form of the abusable drug; said invention, propiram, propoxyphene, remifentanil, Sufentanil, tapenta in some embodiments, further comprising an immediate dol, tramadol, trefentanil, tilidine, nalbuphine, pharmaceuti release form of the abusable drug in Solution, said invention, 65 cally acceptable salts thereof and mixtures thereof. in some embodiments, simultaneously providing more than 6. The dosage form of claim 1, further comprising an one of foregoing (i) to (V); said invention, in Some embodi aversive agent. US 9,125,833 B2 165 166 7. A method of treating a medical condition amenable to phenanthrene, morphinan, benzomorphan, methadone, phe treatment with an opioid agonist, the method comprising nylpiperidine, propionanilide 4-anilidopiperidine, 4-aryl pip administering to the oral cavity of a human patient afflicted eridines, and 4-Heteroarylpiperidines classes. with the condition an effective amount of the dosage form of 15. The dosage form of claim 1, wherein the drug is an claim 1. 5 opioid agonist selected from the group consisting of opioids 8. The dosage form of claim 1, further comprising a third having agonist activity at an opioid receptor having the same ADER ingredient selected from the group consisting of pentacyclic nucleus as any of nalmefene, naltrexone, hydroxypropyl methyl celluloses and thixotropes. buprenorphine, levorphanol, meptazinol, pentazocine and 9. The dosage form of claim 8, comprising both a hydrox dezocine. ypropyl methyl cellulose and a thixotrope. 10 16. The dosage form of claim 1, wherein the dosage form 10. The dosage form of claim 9, wherein the thixotrope is comprises the fractionated coconut oil in an amount from 15 a fumed silicon dioxide. to 30% w/w. 11. The dosage form of claim 1, wherein the opioid agonist 17. The dosage form of claim 1, wherein the dosage form is is levorphanol. a capsule and comprises the fractionated coconut oil in an 12. The dosage form of claim 11, wherein the levorphanol 15 amount from 15 to 30% w/w of the capsule contents. is present in the form of levorphanol tartrate. 18. The dosage form of claim 1, wherein the weight ratio of 13. The dosage form of claim 12, comprising four ADER hydrogenated vegetable oil:fractionated coconut oil is from ingredients, being hydrogenated cottonseed oil, fractionated 7:5 to 3. coconut oil, hydroxypropyl methyl cellulose, and fumed sili 19. The dosage form of claim 1, wherein the opioid agonist con dioxide. is butorphanol. 14. The dosage form of claim 1, wherein the drug is an 20. The dosage form of claim 1, wherein the opioid agonist opioid agonist selected from the group consisting of opioids is buprenorphine. having agonist activity at an opioid receptor belonging to the