US010182992B2 (12 ) United States Patent ( 10) Patent No. : US 10 , 182 , 992 B2 Vamvakas et al. (45 ) Date of Patent: Jan . 22 , 2019 (54 ) ABUSE -DETERRENT CONTROLLED A61K 9 /2846 ; A61K 9 /0004 ; A61K RELEASE FORMULATIONS 9 / 2027 ; A61K 9 /28 ; A61K 31/ 4985 ; A61K 45 / 06 ; A61K 31 / 138 ; A61K (71 ) Applicant: PATHEON SOFTGELS INC . , High 31 /495 ; A61K 31 /724 ; A61K 31 / 485 ; Point, NC (US ) A61K 9 / 485 ; A61K 9 / 4858 ; A61K 9 / 4866 ; A61K 9 /4875 (72 ) Inventors : George Vamvakas, Greensboro , NC See application file for complete search history. (US ) ; Aqeel A Fatmi, High Point, NC (US ) (56 ) References Cited ( 73 ) Assignee : Patheon Softgels Inc ., High Point, NC U . S . PATENT DOCUMENTS (US ) 5 ,146 ,730 A 9 / 1992 Sadek et al. 5 , 459 , 983 A 10 / 1995 Sadek et al . ( * ) Notice : Subject to any disclaimer , the term of this 6 , 482 ,516 B1 11/ 2002 Sadek et al . patent is extended or adjusted under 35 8 ,685 , 445 B2 4 / 2014 Hassan et al. U . S . C . 154 (b ) by 150 days . 2004 / 0052731 A1 3 /2004 Hirsh et al. 2006 /0115527 A1 6 / 2006 Hassan et al . 2006 / 0165778 A1 7 / 2006 Hassan et al . (21 ) Appl. No. : 14 /679 , 062 2007 /0092560 A1 4 / 2007 Sukuru 2009 /0082466 A1 * 3 / 2009 Babul A61K 9 /4858 (22 ) Filed : Apr. 6 , 2015 514 /646 2009/ 0232887 A1 * 9 / 2009 Odidi ...... A61K 9 / 06 (65 ) Prior Publication Data 424 /457 US 2015 /0283087 A1 Oct 8 , 2015 OTHER PUBLICATIONS Related U . S. Application Data International Search Report for PCT / 2015 /024422 , dated Aug. 27 , (60 ) Provisional application No. 61/ 976 ,237 , filed on Apr. 2015. 7 , 2014 , provisional application No . 62/ 101, 431, filed on Jan . 9 , 2015 . * cited by examiner (51 ) Int. Ci. Primary Examiner — Snigdha Maewall A61K 9 /48 ( 2006 . 01 ) (74 ) Attorney , Agent, or Firm — Brinks Gilson & Lione A61K 31/ 137 ( 2006 .01 ) A61K 31 /485 ( 2006 . 01 ) (57 ) ABSTRACT (52 ) U .S . CI. Described herein are abuse deterrent controlled release oral CPC ...... A61K 9 /4866 (2013 . 01 ); A61K 9 /485 pharmaceutical compositions comprising and methods for (2013 .01 ) ; A61K 9 /4858 ( 2013 .01 ) ; A61K making the same. In particular, an abuse deterrent controlled 9 /4875 ( 2013 .01 ) ; A61K 31/ 137 (2013 .01 ) ; release oral pharmaceutical composition comprising a soft A61K 31/ 485 (2013 .01 ) capsule and an abuse deterrent controlled release matrix (58 ) Field of Classification Search comprising an active pharmaceutical ingredient are CPC ...... A61K 2300 /00 ; A61K 31 / 137 ; A61K described . 31/ 135 ; A61K 9 / 2866 ; A61K 9 /2886 ; 4 Claims, 9 Drawing Sheets U . S . Patent Jan . 22, 2019 Sheet 1 of 9 US 10 , 182, 992 B2

FIGURE 1

Physicalmanipulations performed at ambient conditions ( ca . 25 °C ) Tampering Method ????????????????????????????????????Crushing ????????????????????????????????????????????????? ?????????????????????????????Grating ???????????????????????????????? Grinding?????????????????????????? Cutting?????????????????????????????????????

The capsule was The capsule was crushed but the grated with a cheese A razor was used to material released was grater . It released a cut the capsule . The thick , waxy , sticky thick , waxy , sticky The capsule could not thick , waxy , sticky fill material that cannot material that cannot be ground in a coffee material cannot be be easily snorted , be easily snorted , grinder. easily snorted , dispersed , dissolved , dispersed , dissolved , dispersed , dissolved , or extracted for or extracted for or extracted for injection . injection . injection . , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , U . S . Patent Jan . 22, 2019 Sheet 2 of 9 US 10 , 182, 992 B2

FIGURE 2

Physical manipulations performed after storage at 40 °C for 2 hours Method of Tampering Crushing Grating Grinding Cutting

* * * ** * *

22

The capsule behaved The capsule behaved The capsule behaved The capsule behaved in the samemanner as in the samemanner as in the samemanner as in the samemanner as under ambient under ambient under ambient under ambient conditions. conditions. conditions . conditions . U . S . Patent Jan . 22, 2019 Sheet 3 of 9 US 10 , 182, 992 B2

FIGURE 3

Physical manipulationsHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEHEH performed after storage at 0 °C for 2 hours

Method of Tampering . : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : ?????????????????????????????????? Crushing Grating Grinding Coro

VILLEVILEVILEVILLE VILLA The capsule behaved The capsule behaved The capsule behaved The capsule behaved in the same manner as in the same manner as in the same manner as 1 in the same manner as under ambient under ambient under ambient under ambient conditions. conditions. conditions. conditions. U . S . Patent Jan . 22, 2019 Sheet 4 of 9 US 10 , 182, 992 B2

FIGURE 4

PercentRelease

.

0 100 200 300 400 500 600 700 800 Time (min ) U . S . Patent Jan . 22, 2019 Sheet 5 of 9 US 10 ,182 ,992 B2

FIGURE 5

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0 T uusuvussanomaan 0 20 40 60 80 100 120 140 Time (min ) U . S . Patent Jan . 22, 2019 Sheet 6 of 9 US 10 , 182, 992 B2

FIGURE 6

PercentRelease

3 months + 2 months + 1 month 10months

0 100 200 300 400 500 600 700 800 Time (min ) atent Jan . 22 , 2019 Sheet 7 of 9 US 10 , 182, 992 B2

FIGURE 7

PercentRelease

0 months + - 1 month + 2 months - 3 months 0 20 40 60 80 100 120 140 Time (min ) U . S . Patent Jan . 22, 2019 Sheet 8 of 9 US 10 , 182, 992 B2

FIGURE 8

H PercentRelease

20 + RD1147 _ 171 INITIAL + RD1147 _ 171 2wk 30 /65 + RD1147 _ 171 2wk 40 /75 0 100 200 300 400 500 600 700 Time (min ) U . S . Patent Jan . 22, 2019 Sheet 9 of 9 US 10 , 182, 992 B2

FIGURE 9

PercentRelease

+ RD1163 _ 141_ F2 + RD1163 _ 141_ F2 _ ETOH

0 100 200 300 400 500 600 700 Time (min ) US 10 , 182 , 992 B2 ABUSE -DETERRENT CONTROLLED changed into the active form of the drug in the gastrointes RELEASE FORMULATIONS tinal tract. The pharmaceutical industry is utilizing these strategies to develop abuse - deterrent pharmaceutical com CROSS REFERENCE TO RELATED positions in order to reduce the potential for misuse of APPLICATIONS prescription pharmaceutical compositions . Accordingly, there is a need for abuse deterrent pharma This application claimspriority to U . S . Provisional Patent ceutical compositions that have controlled release proper Application Nos . U . S . 61 /976 ,237 , filed on Apr. 7 , 2014 and ties . The matrix formulations described herein minimize the U . S . 62 / 101, 431 , filed on Jan . 9 , 2015, both of which are likelihood of tampering , " dose dumping, ” or the extraction incorporated by reference herein in their entirety . This 10 of active pharmaceutical ingredients from the composition . application is related to International Patent Application No . PCT/ US2015 /24422 filed on Apr. 6 , 2015 , which is incor SUMMARY porated by reference herein in its entirety . This application is also related to U . S . patent application Ser . No . 14 /679 ,233 Described herein are pharmaceutical compositions com and International Patent Application No . PCT/ US2015 / 15 prising abuse deterrent controlled release matrices compris 24464 , both filed on Apr. 6 , 2015 , both of which are ing active pharmaceutical ingredients . The matrix is struc incorporated by reference herein in their entirety . tured to prevent extraction of the active pharmaceutical ingredients . TECHNICAL FIELD One embodiment described herein is an abuse deterrent 20 oral pharmaceutical composition comprising a tamper resis Described herein are abuse deterrent controlled release tant controlled release matrix comprising: (a ) at least one oral pharmaceutical compositions comprising and methods lipid or lipophilic vehicle; ( b ) at least one hydrophilic for making the same. In particular, an abuse deterrent polymer ; (c ) at least one hygroscopic polymer; and ( d ) at controlled release oral pharmaceutical composition compris least one active pharmaceutical ingredient; wherein the ing a soft capsule and an abuse deterrent controlled release 25 matrix is resistant to tampering and is encapsulated in a soft matrix comprising an active pharmaceutical ingredient are capsule shell. described . In one embodiment, the abuse deterrent oral pharmaceu tical compositions described herein further comprises at BACKGROUND least one suspension agent. In one aspect , the suspension 30 agent comprises fumed silica , fumed alumina, or mixtures Increased attention has been drawn to the recreational use thereof. and abuse of prescription pharmaceutical compositions . The I n one aspect , the lipid or lipophilic vehicle comprises abuse , or non -medicinal use , of prescription pharmaceutical about 25 % to about 90 % of the total matrix mass . In another compositions is an increasing problem . Accordingly , pre - aspect , the at least one hygroscopic polymer comprises from venting the abuse of prescription pharmaceuticals through 35 about 1 % to about 10 % of the total matrix mass . In another the development of abuse deterrent pharmaceutical compo - aspect , the at least one hydrophilic polymer comprises about sitions has become a high public health priority for the U . S . 5 % to about 17 % of the total matrix mass . In another aspect , Food and Drug Administration (FDA ) . Prescription phar- the at least one active pharmaceutical ingredient comprises maceutical compositions that are typically misused or about 1 % to about 50 % of the total matrix mass . In another abused fall , primarily , into three groups : ( 1 ) opioids pre - 40 aspect, the ratio of the active pharmaceutical ingredient scribed for pain ; ( 2 ) Central Nervous System (CNS ) depres - percent mass to the matrix percent mass is about 1 : 100 to sants prescribed for anxiety or sleep problems; and ( 3 ) about 1 : 1 . stimulants , prescribed , for example , for attention deficit In one aspect, the lipid or lipophilic vehicle comprises at hyperactivity , narcolepsy, or obesity . least one liquid lipid or lipophilic vehicle and at least one Methods for abusing prescription pharmaceutical compo - 45 semisolid lipid or lipophilic vehicle . In another aspect, the sitions are varied and can include , for example , extraction , liquid lipid or lipophilic vehicle comprises : olive oil , sun melting, volatilization , physical tampering ( e . g ., grinding , flower oil , canola oil , palmitoleic acid , oleic acid , myristo grating , crushing , etc . ) , or direct administration . For pur- leic acid , linoleic acid , arachidonic acid , paraffin oil , or poses of abuse , methods of administering active drug sub - mineral oil. In another aspect , the lipid or lipophilic vehicle stances obtained from prescription pharmaceutical compo - 50 comprises olive oil or soybean oil . In another aspect , the sitions or of the pharmaceutical compositions themselves are semisolid lipid or lipophilic vehicle comprises one or more similarly diverse and include , for example , injection , smok of: polyethylene glycol glyceride ester , paraffin wax , or ing , snorting , swallowing , sublingual or buccal administra - bee ' s wax . In another aspect, the lipid or lipophilic vehicle tion , chewing , or administration as an anal or vaginal comprises soybean oil , a polyethylene glycol glyceride ester, suppository . Alcohol- induced “ dose dumping, " i. e ., the rapid 55 and bee 's wax . In another aspect, the polyethylene glycol release of active pharmaceutical ingredients in the presence glyceride esters comprises glycerol esters of saturated fatty of a solvent such as ethanol, is also an abuse concern and acids of about 8 to about 18 carbon molecules in length . In safety issue . another aspect , the lipid or lipophilic vehicle comprises There are a number of strategies for preventing the abuse about 48 % to about 52 % of the total matrix mass . of pharmaceuticals . Physical and chemical barriers can 60 In one aspect , the hygroscopic polymer comprises one or prevent the extraction of the drug or change the form of the more of: polyvinylpyrrolidone , copovidone, hydroxypropy drug making it less likely to be abused . Combinations of imethylcellulose, hydroxypropylcellulose , ethyl cellulose, agonists and antagonists can be used , wherein the antagonist methylcellulose , or polyethylene oxide . In another aspect , is only released upon product manipulation or tampering the hygroscopic polymer comprises polyvinylpyrrolidone Another strategy is to use aversives, compounds that pro - 65 having a K value from about 70 to about 90 . duce an unpleasant effect when the dosage form is tampered In one aspect , the hydrophilic polymer comprises: poly with . In addition , prodrugs can be used , which are only hydroxylalkylenediamine, dimethylaminoethyl methacry US 10 , 182 , 992 B2 late copolymer , sodium carboxy methylcellulose , ethylene In one embodiment, the abuse deterrent controlled release diamine , sodium alginate , carbomers , poly galacturonic matrix comprises: ( a ) about 30 % to about 40 % olive oil ; (b ) acid , or acrylic methacrylate copolymers . about 7 % to about 15 % Gelucire® 43 /01 ; ( c ) about 1 % to In one aspect, the active pharmaceutical ingredient com about 10 % Pluronic® F127 ; (d ) about 2 % to about 8 % prises at least one of: oxycodone, morphine , morphine 5 Kollidon® 90 F ; (e ) about 1 % to about 6 % Carbopol® 971 analogues , or morphine antagonists , tapentadol, codeine , A ; ( f ) about 2 % to about 8 % EUDRAGIT® EPO ; ( g ) about morphine , methadone, fentanyl and analogs , opioid pain 0 . 5 % to about 6 % N -methyl - D - glucamine ; and (h ) about relievers : oxycodone hydrochloride, hydrocodone bitartrate , 2 . 9 % tapentadol hydrochloride . hydromorphone, oxymorphone, meperidine , propoxyphene, In one embodiment , the soft capsule shell comprises a flunitrazepam , barbiturates, amytal, nembutal, seconal, phe - 10 film forming polymer , a plasticizer, a solvent, optionally , an nobarbital ; benzodiazepines, zolpidem , zaleplon , eszopi- opacifying agent, a coloring agent, or a pharmaceutical clone, amphetamines, methylphenidate , or a combination of excipient. any of the foregoing . In another aspect , the active pharma- In one embodiment, the soft capsule shell comprises: (a ) ceutical ingredient comprises tapentadol. about 25 -50 % of at least one film - forming polymer ; (b ) In one embodiment, the abuse deterrent controlled release 15 about 15 - 25 % of at least one plasticizer; (c ) about 20 - 40 % matrix comprises: ( a ) a liquid lipid vehicle ; ( b ) a semi solid of a solvent ; ( d ) optionally , an opacifying agent , a coloring lipid or lipophilic vehicle ; ( c ) at least one ionic hydrophilic agent, a pharmaceutical excipient, or combination thereof. polymer ; ( d ) at least one hydroscopic polymer; ( e ) a sus . In one embodiment, the soft capsule shell comprises : ( a ) pension agent; and ( f ) at least one active pharmaceutical about 43 % of at least one film - forming polymer; ( b ) about ingredient. 20 20 % of at least one plasticizer ; ( c ) about 37 % of a solvent ; In one embodiment, the abuse deterrent controlled release (d ) optionally , about 0 . 7 % of an opacifying agent ; and (e ) matrix comprises : (a ) soybean oil; ( b ) polyethylene glycol optionally , about 0 . 1 % at least one coloring agent. glyceride ester ; ( c) bee ' s wax ; (d ) polyvinylpyrrolidone or In one embodiment, the soft capsule shell comprises polyethylene oxide; ( e ) hydroxypropylmethylcellulose ; ( f ) gelatin , glycerol, water, titanium oxide , and a coloring agent. carbomer polymer ; ( g ) dimethylaminoethyl methacrylate 25 One embodiment described herein is a method for manu copolymer ; ( h ) fumed silica ; and ( i ) tapentadol. facturing an oral abuse deterrent controlled release con In one embodiment, the abuse deterrent controlled release trolled release soft capsule shell and matrix comprising : ( a ) matrix comprises : ( a ) about 45 % to about 52 % soybean oil ; providing a matrix as described in the embodiments and ( b ) about 1 . 5 % to about 5 % Gelucire® 43 /01 ; ( c ) about 1 . 8 % aspects herein ; ( b ) providing a soft capsule gel mass as to about 4 % bee ' s wax ; ( d ) about 2 % to about 8 % Kollidon® 30 described in the embodiments and aspects herein ; ( c ) casting 90 F ; ( e ) about 0 . 5 % to about 4 % Carbopol® 971 A ; ( f ) the soft capsule gel mas into films using heat- controlled about 2 % to about 8 % EUDRAGIT® EPO ; ( g ) about 0 . 5 % drums or surfaces ; and ( d ) forming a soft capsule comprising to about 5 % Aerosil 200 ; and ( h ) about 5 % to about 30 % the matrix composition using rotary die encapsulation tech tapentadol hydrochloride . nology. In one aspect, a soft capsule comprising an abuse In one embodiment, the abuse deterrent controlled release 35 deterrent controlled release matrix is produced by the meth matrix comprises : ( a ) about 45 % to about 52 % soybean oil ; ods of manufacturing described herein . In one aspect, an ( b ) about 1 . 8 % to about 4 % Gelucire® 43 /01 ; ( c ) about 1 . 8 % enteric soft capsule comprising an abuse deterrent controlled to about 4 % bee ' s wax ; (d ) about 5 % to about 15 % poly - release matrix is produced by the methods of manufacturing ethylene oxide ; ( e ) about 0 . 5 % to about 4 % Carbopol® 971 described herein . A ; ( f ) about 2 % to about 8 % EUDRAGIT® EPO ; ( g ) about 40 One embodiment described herein is an abuse deterrent 0 . 5 % to about 5 % Aerosil 200 ; and ( h ) about 5 % to about oral pharmaceutical composition comprising a tamper resis 30 % tapentadol hydrochloride . tant controlled release matrix comprising : ( a ) about 45 % to In one embodiment, the abuse deterrent oral pharmaceu about 52 % soybean oil ; ( b ) about 1 .5 % to about 5 % poly tical compositions described herein further comprise at least ethylene glycol glyceride ester ( e . g ., Gelucire® 43 /01 ) ; ( c ) one non - ionic surfactant; and at least one pH -buffering 45 about 1. 8 % to about 4 % bee 's wax ; (d ) about 2 % to about agent. In one aspect, the non - ionic surfactant comprises 8 % polyvinylpyrrolidone ( e . g . , Kollidon® 90 F ) ; ( e ) about from about 1 % to about 15 % of the total matrix mass . In one 0 . 5 % to about 4 % carbomer ( e . g ., Carbopol® 971 A ) ; ( f ) aspect, the non - ionic surfactant comprises at least one of about 2 % to about 8 % dimethylaminoethyl methacrylate Pluronic® , Tween® 80 , Span® 80 , IGEPAL® , or TritonTM copolymer ( e . g . , EUDRAGIT® EPO ) ; ( g ) about 0 . 5 % to X - 100 . In another aspect, the non - ionic surfactant comprises 50 about 5 % fumed silica ( e . g . , Aerosil 200 ) ; and ( h ) about 5 % from about 4 % to about 7 % of the total mass of the matrix . to about 30 % tapentadol hydrochloride ; wherein the matrix In another aspect, the non - ionic surfactant comprises an is resistant to tampering and has controlled release proper HLB value of about 1 to about 25 and a melting point ties ; the matrix being encapsulated in a soft capsule shell temperature of about 30° C . to about 70° C . In another comprising : ( i ) about 25 -50 % gelatin ; ( j ) about 15 - 25 % aspect , the pH - buffering agent comprises about 0 . 5 % to 55 glycerol ( k ) about 20 - 40 % water ; and ( 1) optionally , an about 8 % of the total matrix mass . In another aspect , the opacifying agent, a coloring agent, a pharmaceutical excipi pH -buffering agent comprises at least one of N -methyl - D - ent, or combination thereof. glucamine , di- isopropanol amine , tri -isopropanol amine , tri- One embodiment described herein is an abuse deterrent ethanolamine , tetrahydroxypropyl ethylenediamine , amino oral pharmaceutical composition comprising a tamper resis methyl propanol, amino acids , or other pharmaceutically 60 tant controlled release matrix comprising: ( a ) about 45 % to acceptable buffering agents . about 52 % soybean oil ; ( b ) about 1 . 8 % to about 4 % poly In one embodiment, the abuse deterrent controlled release ethylene glycol glyceride ester ( e . g . , Gelucire® 43 /01 ) ; ( c ) matrix comprises: ( a ) olive oil; ( b ) a polyethylene glycol about 1 . 8 % to about 4 % bee' s wax ; ( d ) about 5 % to about glyceride ester ; ( c ) a poloxamer non - ionic surfactant; ( d ) a 15 % polyethylene oxide ; ( e ) about 0 . 5 % to about 4 % polyvinylpyrrolidone ; ( e ) a carbomer polymer ; ( f ) dimeth - 65 carbomer ( e . g ., Carbopol® 971 A ) ; ( f ) about 2 % to about 8 % ylaminoethyl methacrylate copolymer ; ( g ) N -methyl - D - glu - dimethylaminoethyl methacrylate copolymer ( e . g ., camine ; and ( h ) tapentadol. EUDRAGIT® EPO ) ; ( g ) about 0 . 5 % to about 5 % fumed US 10 , 182 , 992 B2 silica (e .g ., Aerosil 200 ); and (h ) about 5 % to about 30 % FIG . 2 . Physicalmanipulations of a soft capsule compris tapentadol hydrochloride; wherein the matrix is resistant to ing the composition of Table 6 performed after storage at 40° tampering and has controlled release properties ; the matrix C . for 2 hours. being encapsulated in a soft capsule shell comprising : ( 1 ) FIG . 3 . Physical manipulations of a soft capsule compris about 25 -50 % gelatin ; (j ) about 15 - 25 % glycerol (k ) about 5 in 20 -40 % water ; and (1 ) optionally , an opacifying ( kagent ) about, a 5 ing the composition of Table 6 performed after storage at 0° coloring agent, a pharmaceutical excipient, or a combination C . for 2 hours thereof . FIG . 4 . Release profile of a soft capsule comprising the One embodiment described herein is an abuse deterrent composition of Table 6 in 900 mL of simulated intestinal oral pharmaceutical composition comprising a tamper resis - . fluid at 100 rpm and 37° C . tant controlled release matrix comprising : ( a ) about 30 % to 10 FIG . 5 . Release profile of a soft capsule comprising the about 40 olive oil ; ( b ) about 7 % to about 15 % polyethylene composition of Table 6 in 900 mL of 40 % ethanol, 60 % 0 .1N glycol glyceride ester ( e . g . , Gelucire® 43 /01 ) ; ( c ) about 1 % HC1 (pH 2 . 4 ) at 100 rpm and 37° C . to about 10 % a poloxamer non - ionic surfactant ( e . g ., FIG . 6 . Release profile of a soft capsule comprising the Pluronic® F127 ) ; ( d ) about 2 % to about 8 % polyvinylpyr rolidone ( e . g . , Kollidon® 90 F ); ( e ) about 1 % to about 6 % 15is composition of Table 6 in phosphate buffer ( pH 6 . 8 ) after carbomer ( e . g ., Carbopol® 971 A ) ; ( f ) about 2 % to about 8 % storage at 40° C . , 75 % relative humidity . dimethylaminoethyl methacrylate copolymer ( e . g ., FIG . 7 . Release profile of a soft capsule comprising the EUDRAGIT® EPO ) : ( g ) about 0 . 5 % to about 6 % N -methyl - composition of Table 6 in 40 % ethanol, 60 % 0 . 1N HCl ( pH D - glucamine ; and ( h ) about 30 % tapentadol HCl; wherein 2 . 4 ) after storage at 40° C . , 75 % relative humidity . the matrix is resistant to tampering and has controlled 20 FIG . 8 . Release profile of a soft capsule comprising the release properties ; the matrix being encapsulated in a soft composition of Table 7 in phosphate buffer (pH 6 .8 ) initially, capsule shell comprising : ( i ) about 25 -50 % gelatin ; (j ) about after storage for 2 weeks at 30° C ., 65 % relative humidity , 15 - 25 % glycerol (k ) about 20 - 40 % water ; and ( 1 ) optionally, and after storage for 2 weeks at 40° C ., 75 % relative an opacifying agent, a coloring agent, a pharmaceutical humidity . excipient, or a combination thereof . 25 FIG . 9 . Release profile of a soft capsule comprising the One embodiment described herein is a method for treat ing , reducing the symptoms or onset of, or prophylaxis of composition of Table 8 in 40 % ethanol, 60 % 0 . 1N HCl (pH pain stemming from diabetic neuropathy, chronic arthritis , 2 . 4 ) . osteoarthritis , rheumatoid arthritis , acute tendonitis, bursitis , headaches, migraines , chronic neuropathies , shingles , pre - 20 DETAILED DESCRIPTION menstrual symptoms, sports injuries , malignancy , radicu 30 lopathy, sciatica /sciatic pain , sarcoidosis , necrobiosis , Described herein are abuse deterrent controlled release lipoidica or granuloma annulare comprising administering pharmaceutical compositions. The pharmaceutical compo to a subject in need thereof the pharmaceutical compositions sitions described herein provide abuse deterrent matrices described herein . In one aspect, the pharmaceutical compo and methods for preparation thereof. Also described herein sition comprises the soft capsule described herein . 35 are compositions and methods for manufacturing soft cap One embodiment described herein is a method for reduc sules comprising abuse deterrent controlled release pharma ing the ability of a subject to extract an active pharmaceu ceceutical matrices . In some embodiments described herein , tical ingredient from a pharmaceutical composition though the soft capsule is an enteric soft capsule . crushing , grating, grinding, cutting, or solvating or dissolv - The term " abuse deterrent, ” as used herein , refers to a ing the matrix comprising : providing the abuse deterrent 40 pharmaceutical composition that is resistant to tampering or matrix compositions and abuse deterrent oral pharmaceuti - accessing the active pharmaceutical ingredient for recre cal compositions described herein , wherein the composition ational drug use or drug abuse . is resistant to crushing , grating , grinding , cutting , solvation , The phrase “ recreational drug use , " as used herein , refers or dissolution . In one aspect , the pharmaceutical composi - to the voluntary use of an active pharmacetical agent or drug tion comprises the soft capsule as described herein . 45 for a non -medical purpose to induce an effect , such as One embodiment described herein is a kit for dispensing pleasure , satisfaction , euphoria , dissociation , or to enhance providing the abuse deterrentmatrix compositions and abuse an experience . deterrent oral pharmaceutical compositions described herein The term “ drug abuse ," as use herein , refers to the comprising : ( a ) at least one soft capsule comprising an abuse habitual, compulsive , or recurrent use of an active pharma deterrent controlled release matrix comprising an active 50 ceutical agent or drug , often despite negative consequences . pharmaceutical ingredient; ( b ) at least one receptacle com - The term “ tampering , ” as used herein , refers to any kind prising a tamper evident , moisture proof packaging that of actual or attempted physicalmanipulation or interference reduces the ability of removing the oral pharmaceutical thatmay result in particle size reduction of a pharmaceutical composition comprising blister or strip packs, aluminum composition . Tampering , as used herein also includes any blister , transparent or opaque polymer blister with pouch , 55 actual or attempted dissolution or extraction of active phar polypropylene tubes , colored blister materials, tubes , maceutical ingredients using solvents. Compositions that are bottles , and bottles optionally containing a child - resistant resistant to physical tampering are formulated in such a way feature , optionally comprising a desiccant, such as a molecu - that the composition cannot readily reduced to a form that is lar sieve or silica gel; ( c ) optionally , an insert comprising suitable for abuse, such as, for example , injection or snort instructions or prescribing information for the active phar - 60 ing , because the tablet cannot easily be ground , grated , maceutical ingredient. dissolved , extracted , and the like at any temperature . Examples of physical tampering include , but are not limited BRIEF DESCRIPTION OF THE DRAWINGS to , crushing, grinding , grating, cutting , crisping , and other methods of particle size reduction . Dissolution tampering FIG . 1 . Physical manipulations of a soft capsule compris - 65 includes actual or attempted actions to dissolve or extract ing the composition of Table 6 performed at ambient con active pharmaceutical ingredients using aqueous or organic ditions ( ca . 25° C . ) solvents such as water , ethanol, isopropanol, ethyl acetate , US 10 , 182 , 992 B2 acetone , ether , or the like , at any temperature . Tampering , as 20 hours about 24 hours; or even longer ; specifically over a used herein , includes " dose dumping . ” period of at least 18 hours under physiological conditions or The term " dose dumping ” or “ dumping ” as used herein in an in vitro assay . refers to the rapid release of the entire amount or a signifi - As used herein , the phrase " abuse deterrent controlled cant fraction of an active pharmaceutical ingredient or drug . 5 release ” refers to a pharmaceutical composition comprising Drug abusers often intentionally pursue dumping of a drug components or a formulation that prevents liberation of the from the dosage form . active pharmaceutical ingredient( s ) from the composition The terms “ drug" , " active ingredient, " " active pharma for potential abuse or dose dumping and the composition ceutical ingredient, ” or “ active pharmaceutical agent” as provides controlled release delivery of the active pharma used herein refer to an agent, active ingredient, compound , ceutical ingredient upon ingestion of the composition by a or substance , compositions, or mixtures thereof, that provide subject . a pharmacological, often beneficial , effect . Reference to a The term " Cmax " as used herein refers to the maximum specific active ingredient includes, where appropriate , the observed blood (plasma , serum , or whole blood ) concentra active ingredient and any of its pharmaceutically acceptable 15 tion or the maximum blood concentration calculated or salts or esters . estimated from a concentration to time curve , and is The terms “ dosage” or “ dose ” denote any form of the expressed in units of mg /L or ng /mL , as applicable . active ingredient formulation that contains an amount suf The term " Cmin ” as used herein refers to the minimum ficient to produce a therapeutic effect with a single admin - observed blood ( plasma , serum , or whole blood ) concentra istration . The dosage form used herein is for oral adminis - 20 tion or the minimum blood concentration calculated or tration . The preferred oral dosage forms are soft capsules or estimated from a concentration to time curve , and is enteric soft capsules . expressed in units of mg/ L or ng /mL , as applicable . The terms “ active pharmaceutical ingredient load " or The term “ Cve " as used herein refers to the blood " drug load ” as used herein refers to the quantity (mass ) of (plasma , serum , or whole blood ) concentration of the drug the active pharmaceutical ingredient comprised in a single 25 within the dosing interval, is calculated as AUC /dosing soft capsule fill11 . interval, and is expressed in units of mg/ L or ng /mL , as The term " formulation ” or “ composition ” as used herein applicable . refers to the active pharmaceutical ingredient or drug in The term “ Tmax??? " as used herein refers to the time after combination with pharmaceutically acceptable excipients . administration at which Cmor occurs , and is expressed in This includes orally administrable formulations as well as 330 units of hours (h ) or minutes (min ) , as applicable . The term “ AUCO - > T " as used herein refers to area under formulations administrable by other means . the blood (plasma , serum , or whole blood ) concentration The term “ titration ” as used herein refers to the incre versus time curve from time zero to time tau ( T ) over a mental increase in drug dosage to a level that provides the dosing interval at steady state , where tau is the length of the optimal therapeutic effect. 35 dosing interval, and is expressed in units of h•mg/ L or The term “ controlled release ” as used herein refers to a hòng /mL , as applicable . For example , the term AUC0 -> 12 as composition that does not immediately releases an active used herein refers to the area under the concentration versus ingredient. " Controlledntrolled release ” as used hereinherein encompassesencompasses time curve from 0 to 12 hours .

the terms “ modified release ,” “ sustained release, ” “ extended The term “ AUCOU - > 00 " as used herein refers to the area release, " and " delayed release. ” 40 under the blood ( plasma , serum , or whole blood ) concen The term " delayed release ” as used herein refers to a tration versus time curve from time 0 hours to infinity , and composition that releases an active ingredient according to is expressed in units of h ·mg / L or h ·ng /mL , as applicable . a desired profile over an extended period under physiologi - The term “ AUCoverali” as used herein refers to the com cal conditions or in an in vitro test. By “ extended period ” it bined area under the blood (plasma , serum , or whole blood ) is meant a continuous period of time of at least about 20 45 concentration versus time curve , and is expressed in units of minutes , about 30 minutes , about 1 hour ; about 2 hours ; h ·mg / L (or hing /mL ) for at least one or more doses of the about 4 hours ; about 6 hours ; about 8 hours ; about 10 hours ; pharmaceutical compositions described herein . In one about 12 hours ; about 14 hours ; about 16 hours; about 18 aspect, the “ AUCoverall” refers to the combined area under hours ; about 20 hours about 24 hours ; or even longer. the blood concentration versus time curve for at least two The term " modified release ” as used herein refers to a 50 doses of the pharmaceutical compositions described herein . composition that releases an active ingredient at a slower The term “ treating ” refers to administering a therapy in an rate than does an immediate release formulation under amount, manner, or mode effective to improve a condition , physiological conditions or in an in vitro test . symptom , or parameter associated with a disorder. The term “ sustained ” release” as used herein refers to a The term “ prophylaxis ” refers to preventing or reducing composition that releases an active ingredient over an 55 the progression of a disorder , either to a statistically signifi extended period of time, for example minutes , hours , or cant degree or to a degree detectable to one skilled in the art. days, such that less than all the active ingredient is released The term “ substantially ” as used herein means to a great initially . A sustained release rate may provide , for example , or significant extent, but not completely . a release of a certain specified amount of a drug or active The term “ about” as used herein refers to any value that ingredient from a dosage form , over a certain period , under 60 is within a variation of up to - 10 % of the value modified by physiological conditions or in an in vitro test. the term “ about. ” The term " extended release ” as used herein refers to a As used herein , “ a ” or “ an ” means one or more unless composition that releases an active ingredient over an otherwise specified . extended period , such as of at least about 20 minutes , about Terms such as “ include, " " including, " " contain , " " con 30 minutes, about 1 hour, about 2 hours ; about 4 hours ; 65 taining, " " has ,” or “ having, ” and the like , mean " compris about 6 hours ; about 8 hours ; about 10 hours ; about 12 ing . " hours ; about 14 hours ; about 16 hours ; about 18 hours ; about The term “ or” can be conjunctive or disjunctive . US 10 , 182 , 992 B2 10 Described herein are pharmaceutical compositions com philic soft capsule shell to minimize any potential shell - fill prising abuse deterrent controlled release matrices compris interactions , such as when the soft capsules are filled with ing active pharmaceutical ingredients . The matrix is struc hydrophilic materials . In one embodiment described herein tured to prevent extraction of the active pharmaceutical are methods for manufacturing matrix fills comprising an 5 abuse deterrent controlled release matrix comprising an ingredients . active pharmaceutical ingredient in a soft capsule in the In one embodiment , the pharmaceutical composition form of a suspension , where part or all of the active described herein comprises a soft capsule comprising an pharmaceutical ingredient is suspended within thematrix . In abuse deterrent controlled release matrix comprising an one embodiment described herein is a soft capsule having a active pharmaceutical ingredient. In one embodiment, the shell and an abuse deterrent controlled release matrix fill, active pharmaceutical ingredient is an analgesic . In another wherein the matrix includes an active pharmaceutical ingre embodiment , the active pharmaceutical ingredient is an dient suspended as solid particles within the lipophilic opiod analgesic . vehicle . In another embodiment , the soft capsule comprising a In one embodiment described herein , an exemplary abuse matrix can provide controlled release properties. Such con - deterrent controlled release matrix has the composition of trolled release matrix fills are described in International Table 1 , including all possible iterations of the specified Patent Application Publication No . WO 2005 / 009409 and ranges that provide 100 % for the total weight percentage , U . S . Patent Application Publication No. US 2006 /0115527 , including or excluding the optional colorings, flavorings, or both of which are incorporated by reference herein for such excipients . TABLE 1 Exemplary Abuse Deterrent Controlled Release Matrix Composition Composition Component Exemplary Components Range ( % ) Lipid or lipophilic Liquid lipid vehicle (LLV ) and /or Semisolid 31- 92 vehicle ( s ) lipid vehicle (SLV ) : soybean oil, bee 's wax (LLV : 25 -60 /SLV : 6 - 32 ) Non - ionic surfactant (s ) Pluronic ® F127 , poloxamer , Tween ® 80 , 1 - 15 Triton TM X Hygroscopic polymer (s ) Polyvinylpyrrolidone ( copovidone ) , ethyl 1 - 10 cellulose , hydroxyproply methylcellulose , polyethylene oxide Hydrophilic polymer ( s ) Carbopol, Eudragit ® , Ethylenediamine 2 - 20 Suspension agent ( s ) Fumed silica , Aerosil ® 0 . 5 -5 pH buffering agent ( s ) Triethanolamine, N -methyl - D - glucamine, 1 - 8 Tromethamine Active pharmaceutical Oxycodone, Tapentadol, Amytal 5 - 50 ingredient( s ) teachings. In one aspect , the soft capsule and matrix can be In another embodiment, the lipid or lipophilic vehicle can configured to provide controlled release , extended release , to be a liquid lipophilic vehicle , a semisolid lipophilic vehicle , sustained release , delayed release , or combinations thereof. or a mixture thereof . Suitable lipid or lipophilic vehicles In other embodiments , the pharmaceutical composition include mineral oil; light mineral oil; natural oils ( e . g ., described herein comprises abuse deterrent properties . vegetable , corn , canola , sunflower, soybean , olive , coconut , These abuse deterrent properties reduce the likelihood that cocoa , peanut, almond, cottonseed , persic , sesame, squalane , the active pharmaceutical ingredient can be extracted from 45 castor, cod liver , etc ) hydrogenated vegetable oil; partially the composition through mechanisms, including but not hydrogenated oils ; bee' s wax (beeswax ) ; polyethoxylated limited to crushing, grating, grinding, cutting of the matrix , bee ' s wax ; paraffin ; normal waxes ; medium chain medium to permit solvation or extraction of the active pharmaceuti - chain monoglycerides , diglycerides and triglycerides ; higher cal ingredient. In addition , the abuse deterrent properties aliphatic alcohols ; higher aliphatic acids ; long chain fatty reduce the likelihood that the active pharmaceutical ingre - 50 acids ; saturated or unsaturated fatty acids ; hydrogenated dient can be extracted from the composition by dissolving or fatty acids ; fatty acid glycerides ; polyoxyethylated oleic extracting in ethanol solutions of about 1 % to about 50 % , glycerides ; monoglycerides and diglycerides ; mono - , bi- or dissolving in solutions having pH values from about 1 to tri- substituted glycerides ; glycerolmono - oleate esters ; glyc about 12, or dissolving in household chemical compositions, erolmono - caprate ; glyceryl monocaprylate ; propylene gly including water , coffee , vinegar , cola , milk , ethanol, isopro - 55 col dicaprylate ; propylene glycol monolaurate ; glyceryl panol, acetone, ethyl acetate , or other common solvents . palmitostearate ; glyceryl behenate ; diethyleneglycol palmi In other embodiments described herein , the matrix com - tostearate ; polyethyleneglycol stearate ; polyoxyethylenegly prises a lipid or lipophilic vehicle that provides a suspension col palmitostearate ; glyceryl mono palmitostearate ; cetyl of the active pharmaceutical ingredient. In one aspect , a soft palmitate ; polyethyleneglycol palmitostearate; dimethylpo capsule comprising an active pharmaceutical ingredient pro - 60 lysiloxane ; mono - or di- glyceryl behenate ; fatty alcohols vides controlled release of the active pharmaceutical ingre - associated with polyethoxylate fatty alcohols ; cetyl alcohol; dient. octyldodecanol; myristyl alcohol; isopropyl myristate, iso In other embodiments described herein , the pharmaceu propyl palmitate , stearic acid , stearyl alcohol, and others tical composition provides matrix fills for the active phar - known in the art. maceutical ingredient, or derivatives thereof, based on lipids 65 In one embodiment, the lipid or lipophilic vehicle com or lipophilic materials . The matrices described herein have prises a liquid lipophilic vehicle and a semisolid lipophilic a hydrophobic (lipophilic ) surface in contact with a hydro - vehicle . In one embodiment, the liquid lipid or lipophilic US 10 , 182 , 992 B2 vehicle can be olive oil , sunflower oil , canola oil, palmitoleic Adogen® 464 , Alkanol® 6112 , Brij® 52 , Brij® 93 , Brij® acid , oleic acid , myristoleic acid , linoleic acid , arachidonic S2 , Brij® S , Brij® 58 , Brij® C10 , Brij® L4 , Brij® 010 , acid , paraffin oil , or mineral oil. In another embodiment, the Brij® 010 , BRIJ® 020 , Brij® S10 , Brij® S20 , ethylene semi- solid lipophilic vehicle can be a polyethylene glycol diamine tetrakis ( ethoxylate- block -propoxylate ) tetrol, ethyl glyceride ester, paraffin wax , or bee 's wax . In another 5 enediamine tetrakis ( ethoxylate -block -propoxylate ) tetrol , embodiment, the semi- solid lipophilic vehicle is Gelucire ethylenediamine tetrakis ( propoxylate - block - ethoxylate ) tet 33 /01 , Gelucire® 37 /02 , Gelucire® 39 /01 , Gelucire® 43 /01 , rol, IGEPAL® CA - 210 , IGEPAL® CA - 520 , IGEPAL® Gelucire® 44 / 14 , Gelucire® 50 /02 , Gelucire® 50 / 13 , Gelu - CA -720 , IGEPAL® CO -520 , IGEPAL® CO -630 , cire® 53 /10 , or Gelucire® 62 /02 . In one aspect , the liquid IGEPAL® CO -720 , IGEPAL® CO - 890 , IGEPAL® lipid or lipophilic vehicle is olive oil. In another aspect , the 10 DM - 970 , MERPOL® DA , MERPOL® HCS , MERPOL® semisolid lipid or lipophilic vehicle comprises a Gelucire® . OJ, MERPOL® SE , MERPOL® SH , MERPOL® A , Poly In another aspect , the semisolid lipid or lipophilic vehicle ( ethylene glycol) sorbitan tetraoleate , poly ( ethylene glycol) comprises bee ' s wax . In one aspect, theGelucire® semisolid sorbitol hexaoleate , poly ( ethylene glycol) ( 12) , poly ( ethyl lipid vehicle has a HLB value of about 1 and a melting point ene glycol) ( 18 ) , polyethylene- block -poly ( ethylene glycol) , of about 43 . In one aspect, the semisolid lipid or lipophilic 15 sorbitan monopalmitate, 2 , 4 , 7 , 9 - tetramethyl- 5 - decyne - 4 , 7 vehicle is Gelucire® 43 / 01 . diol ethoxylate , NonidetTM P -40 , TritonTM N - 101 , TritonTM In one embodiment , the matrix comprises a hydrophilic X - 100 , TritonTM X - 114 , TritonTM X - 405, TWEEN® 20 , ionic polymer. In one embodiment , the hydrophilic poly - TWEEN® 40 , TWEEN® 60 , TWEEN® 85 , Zonyl® mers comprise polyhydroxylalkylenediamine , dimethylam - FS - 300 , or Zonyl® FSN . In one embodiment, the non -ionic inoethyl methacrylate copolymer, Poly (butyl methacrylate - 20 surfactant comprises Pluronic® F127 , Tween® 80 , Span® CO - ( 2 - dimethylaminoethyl) methacrylate - co - ( 2 - 80 , IGEPAL® , or TritonTM X - 100 . In one aspect, the non dimethylaminoethyl) 1: 2 : 1 (Eudragit® EPO ); sodium ionic surfactant comprises a poloxamer. In one aspect , the carboxy methylcellulose, carboxymethyl cellulose ethylene - non - ionic surfactant comprises Pluronic® F127 . diamine , sodium alginate , alginic acid , pectin , carbomers , In another embodiment, the matrix comprises a hygro Carbopol® copolymers (polyacrylic acid polymers ) , such as 25 scopic polymer. In one embodiment, the hygroscopic poly Carbopol 934 , Carbopol® 940 , Carbopol® 941 or Car - mers include polyvinylpyrrolidone , copovidone , hydroxy bopol® 974P ; a Pemulen® polymer ; polycarbophil poly p ropylmethylcellulose , hydroxypropylcellulose , ethyl galacturonic acid , polyglucoronic acid , chondroitic sulfate , cellulose , methylcellulose , and polyethylene oxide . Suitable carrageenan , and acrylic methacrylate copolymers . In one hygroscopic polymers include polyvinyl alcohol, a copoly aspect, the hydrophilic polymer swells in aqueous media . In 30 mer of polyvinylpyrrolidone and polyvinyl acetate , another aspect , the hydrophilic polymers swell at a pH of hydroxypropyl cellulose , hydroxypropyl methylcellulose , about 4 to about 6 . In another embodiment, one or more hydroxyethyl cellulose , hydroxymethyl cellulose , gelatin , hydrophilic ionic polymers form ionic interactions . In polyethylene oxide , such as POLYOXTM 100 ,000 -600 , 000 another embodiment, the matrix comprises anionic poly - MW , acacia , dextrin , starch , polyhydroxyethylmethacrylate , mers , cationic polymers , or mixtures thereof . In another 35 a water - soluble non - ionic polymethacrylate or copolymer embodiment, a hydrophilic cationic polymer and a hydro - thereof, a modified cellulose , a modified polysaccharide, a philic anionic polymer are combined to form an ionic non - ionic gum , or a non - ionic polysaccharide. In one aspect , polymer complex or network . In one aspect , the hydrophilic the hygroscopic polymer is polyvinylpyrrolidone . In one ionic polymer is Carbopol® 971A . In another aspect, the aspect, the hygroscopic polymer comprises Kollidon® 90 F . hydrophilic ionic polymer is Eudragit® EPO . 40 In one aspect, the hygroscopic polymer comprises a cellu In one embodiment, the matrix comprises a non - ionic lose polymer. In one aspect, the hygroscopic polymer com surfactant . The surfactant can have a hydrophilic / lipophilic prises hydroxypropylmethylcellulose ( e . g ., HPMC 4M ) . In balance (HLB ) value between about 1 and about 25 and a another aspect, the hygroscopic polymer is a polyethylene melting point between about 25° C . and about 70° C . The oxide polymer ( e . g . , POLYOXTM 100 , 000 ) . HLB characteristic of surfactants can be determined in 45 In another embodiment, the matrix comprises a pH buff accordance with “ Physical Pharmacy : Physical Chemical ering agent. Suitable pharmaceutically acceptable buffering Principles in the Pharmaceutical Sciences ,” Fourth Edition , agents comprise arginine , aminomethyl propanol, tetrahy pp . 371 -373 , A . Martin , Ed ., Lippincott Williams & Wilkins, droxypropyl ethylenediamine , triethanolamine, trometh Philadelphia ( 1993 ) . Suitable non -ionic surfactants include : amine , PEG - 15 cocamine , di - isopropanol amine , tri -isopro Pluronic® 10R5, Pluronic® 17R2 , Pluronic® 17R4 , 50 panolamine, N -methyl - D - glucamine, glycine , malate , Pluronic® 25R2, Pluronic® 25R4 , Pluronic® 31R1 , tartarate , lactate, citrate , acetate , sodium bicarbonate , Pluronic® F 108 , Pluronic® F 108 NF, Pluronic® F 108 , sodium phosphate , or other buffering agents , having pK s at Pluronic® F 108NF, Poloxamer 338 , Pluronic® F 127 , any physiologically acceptable pH , generally from about pH Pluronic® F 127 NF , Pluronic® F 127 NF 500 BHT Prill , 4 to about pH 7 . Amino acids or other physiological metabo Pluronic® F 127 NF Prill , Poloxamer 407 , Pluronic® F 38 , 55 lites may be used as buffering agents . A combination of Pluronic® F 38 Pastille , Pluronic® F 68 , Pluronic® F 68 LF buffering agents may also be employed , such as phosphate Pastille , Pluronic® F 68 NF , Pluronic® F 68 NF Prill, and acetate , and the like . In one aspect, the pH buffering Poloxamer 188 , Pluronic® F 68 Pastille , Pluronic® F 77 , agent is N -methyl - D - glucamine ( e . g . , meglumine ) . Pluronic® F 77 Micropastille , Pluronic® F 87 , Pluronic® F In another embodiment, the matrix comprises a neutral 87 NF , Pluronic® F 87 NF Prill , Poloxamer 237 , Pluronic® 60 izing agent. Suitable pharmaceutically acceptable neutraliz F 88 , Pluronic® F 88 Pastille , Pluronic® F 98 , Pluronic®L ing agents comprise HC1, phosphoric acid , carbonic acid , 10 , Pluronic® L 101, Pluronic® L 121 , Pluronic® L 31 , sodium hydroxide , ammonium hydroxide, potassium Pluronic® L 35 , Pluronic® L 43 , Pluronic® L 61, Pluronic? hydroxide , sodium bicarbonate , sodium carbonate , and the L 62 , Pluronic® L 62 LF , Pluronic® L 62D , Pluronic® L 64 , like . Pluronic® L 81, Pluronic® L 92, Pluronic® N3, Pluronic® 65 In another embodiment, the matrix comprises a suspen P 103 , Pluronic® P 104 , Pluronic® P 105 , Pluronic® P 123 s ion agent . Suitable pharmaceutically acceptable suspension Surfactant, Pluronic® P65 , Pluronic® P 84 , Pluronic® P85 , agents comprise fumed silicon dioxide , such as Aerosil® 90 , US 10 , 182 , 992 B2 13 14 Aerosil® 130 , Aerosil® 150 , Aerosil® 200 , Aerosil® 255 , the total lipid or lipophilic vehicle comprises about 50 % to Aerosil® 300 , Aerosil® 380 , Aerosil® OX 50 , Aerosil® TT about 55 % of the total matrix mass including all integers 600 , Aerosil® 200 F , Aerosil® 380 F , Aerosil® 200 Pharma within the specified range . In one aspect , the total lipid or Aerosil® 300 Pharma, Aeropearl® 300 / 30 , or Aeropearl® lipophilic vehicle comprises about 55 % of the total matrix 300 Pharma. In one aspect, the suspension agent comprises 5 mass . In another aspect , the total lipid or lipophilic vehicle Aerosil® 200 . comprises about 53 % of the total matrix mass . In another In another embodiment, the matrix can include a hydro aspect, the total lipid or lipophilic vehicle comprises about philic internal phase and a lipid or lipophilic external phase . 50 % of the total matrix mass . In another aspect, the total The internal phase can also be structured . A " structured ” lipid or lipophilic vehicle comprises about 49 % of the total internal phase , as used herein , means a solid , semisolid , or 10 matrix mass . a gel whose shape is relatively stable and does not usually In another embodiment, one or more liquid lipid or aggregate to form a large globule . A structured internal lipophilic vehicles comprise from about 25 % to about 60 % phase therefore provides controlled drug release and stabi- of the total matrix mass including all integers within the lizes the physical state of the matrix . Without being bound specified range. The one or more lipid or lipophilic vehicles to any theory , it is believed that the structured nature of the 15 comprise about 25 % , about 30 % , about 32 % , about 34 % , matrix impedes solvation and/ or diffusion of the active about 36 % , about 38 % , about 40 % , about 42 % , about 45 % , pharmaceutical ingredient out of the matrix . about 50 % , about 55 % , or about 60 % of the total matrix In another embodiment, the active pharmaceutical ingre - mass . In one embodiment, the total liquid lipid or lipophilic dient can be dispersed in the internal phase as a suspension vehicle comprises from about 38 % to about 52 % of the total form . In another embodiment, the active pharmaceutical 20 matrix mass including all integers within the specified range . ingredient can be dispersed in the internal phase as a solid In one aspect, the total liquid lipid or lipophilic vehicle form . comprises about 38 % ofthe total matrix mass. In one aspect , In one embodiment described herein , the matrix may the total liquid lipid or lipophilic vehicle comprises about comprise one or more lipid or lipophilic vehicles , one or 46 % of the total matrix mass . In one aspect, the total liquid more hydrophilic polymers , one or more hygroscopic poly - 25 lipid or lipophilic vehicle comprises about 50 % of the total mers , one or more suspension agents , optionally , one or matrix mass . more non - ionic surfactants , optionally , one or more pH In another embodiment , one or more semisolid lipid or buffering agent, and one or more active pharmaceutical lipophilic vehicles comprise from about 4 % to about 32 % of ingredients . Without being bound to any theory , it is believed the total matrix mass including all integers within the that the hydrophilic cationic and anionic polymers described 30 specified range . The one or more semisolid lipid or lipo herein combine within the matrix to form polymer networks philic vehicles comprise about 4 % , about 5 % , about 6 % , or complexes comprising ionic interactions. Further , without about 7 % , about 8 % , about 9 % , about 10 % , about 12 % , being bound to any theory , it is believed that the ionic about 15 % , about 18 % , about 20 % , about 22 % , about 25 % , polymer network swells when hydrated with an aqueous about 28 % , about 30 % , or about 32 % of the total matrix solution and the swelling impedes the dissolution and / or 35 mass . In one embodiment, the total semisolid lipid or diffusion of the active pharmaceutical ingredient out of the lipophilic vehicle comprises from about 4 % to about 15 % of matrix . Without being bound by any theory, it is believed the total matrix mass including all integers within the that non - ionic surfactants and hygroscopic polymers facili- specified range . In one aspect , the total semisolid lipid or tate hydration of the hydrophilic ionic polymers described lipophilic vehicle comprises about 14 % of the total matrix herein . Moreover, without being bound to any theory , the 40 mass . In one aspect, the total semisolid lipid or lipophilic lipid or lipophilic vehicle of the matrix further prevents vehicle comprises about 11 % of the total matrix mass . In one diffusion and /or solvation of the active pharmaceutical aspect, the total semisolid lipid or lipophilic vehicle com ingredient. Without being bound to any theory , it is believed prises about 8 % of the total matrix mass . In one aspect, the that the suspension agents prevent precipitation of the active total semisolid lipid or lipophilic vehicle comprises about pharmaceutical ingredient or other matrix components . The 45 6 % of the total matrix mass . In one aspect, the total matrix compositions described herein permit abuse deter- semisolid lipid or lipophilic vehicle comprises about 4 % of rence by preventing liberation of the active ingredient for the total matrix mass. injection or insufflation and prevent solvation , dissolution , In another embodiment, the ratio of the liquid lipid or extraction of the active pharmaceutical ingredient by use vehicle to semisolid lipid ranges from about 2 : 1 to about of aqueous or organic solutions . Furthermore, the matrix 50 14 : 1 , including all iterations of ratios within the specified compositions also provide controlled release delivery of the range . In one embodiment, the ratio of the lipid liquid to active pharmaceutical ingredient after ingestion by a subject. semisolid liquid ranges from about 2 . 5 : 1 to about 13: 1 , In another embodiment , the lipid or lipophilic vehicle including all iterations of ratios within the specified range . comprises a liquid lipid or lipophilic vehicle , a semisolid In one aspect , the ratio of the lipid liquid to semisolid liquid lipid or lipophilic vehicle , or a combination thereof. In one 55 is about 13 : 1 . In one aspect, the ratio of the lipid liquid to embodiment, the total lipid or lipophilic vehicle comprises semisolid liquid is about 8 : 1 . In one aspect , the ratio of the one or more liquid lipid vehicles and one or more semi- solid lipid liquid to semisolid liquid is about 7 : 1 . In one aspect, the lipid vehicles. In one embodiment, the total lipid or lipo - ratio of the lipid liquid to semisolid liquid is about 6 : 1 . In philic vehicle comprises about 30 % to about 92 % of the total one aspect, the ratio of the lipid liquid to semisolid liquid is matrix mass including all integers within the specified range . 60 about 5 : 1 . In one aspect, the ratio of the lipid liquid to The total lipid or lipophilic vehicle comprises about 30 % , semisolid liquid is about 4 : 1 . In one aspect, the ratio of the about 35 % , about 40 % , about 45 % , about 50 % , about 55 % , lipid liquid to semisolid liquid is about 3 : 1 . In one aspect, the about 60 % , about 65 % , about 70 % , about 75 % , about 80 % , ratio of the lipid liquid to semisolid liquid is about 2: 1 . about 85 % , or about 90 % of the total matrix mass . In one In another embodiment, the one or more hygroscopic embodiment, the total lipid or lipophilic vehicle comprises 65 polymers comprise from about 1 % to about 25 % of the total about 40 % to about 55 % of the total matrix mass including matrix mass including all integers within the specified range . all integers within the specified range . In one embodiment, The one or more hygroscopic polymers comprise about 1 % , US 10 , 182 , 992 B2 15 16 about 2 % , about 3 % , about 4 % , about 5 % , about 6 % , about In another embodiment, the ratio of lipophilic vehicle to 7 % , about 8 % , about 9 % , about 10 % , about 12 % , about the hygroscopic polymer and non -ionic surfactant ranges 15 % , about 18 % , about 20 % , about 22 % , or about 25 % of from about 2 : 1 to about 20 : 1 , including all iterations of the total matrix mass . In another embodiment , the total ratios within the specified range . In another embodiment, the hygroscopic polymer content comprises from about 5 % to 5 ratio of lipophilic vehicle to the hygroscopic polymer and about 18 % of the total matrix mass including all integers non - ionic surfactant ranges from about 2 : 1 to about 10 : 1 , including all iterations of ratios within the specified range . within the specified range . In another embodiment, the total In one aspect, the ratio of the lipophilic vehicle to the hygroscopic polymer content comprises from about 10 % to hygroscopic polymer and non - ionic surfactant is about 3 : 1 . about 16 % of the total matrix mass including all integersm 10 In one aspect, the ratio of the lipophilic vehicle to the within the specified range . In one aspect, the total hygro hygroscopic polymer and non - ionic surfactant is about 4 : 1 . scopic polymer content comprises about 20 % of the total In one aspect, the ratio of the lipophilic vehicle to the matrix mass. In one aspect , the total hygroscopic polymer hygroscopic polymer and non - ionic surfactant is 4 . 2 : 1 . In content comprises about 18 % of the total matrix mass . In one aspect , the ratio of the lipophilic vehicle to the hygro one aspect, the total hygroscopic polymer content comprises 15 scopic polymer and non - ionic surfactant is 3 . 4 : 1 . about 16 % of the total matrix mass. In one aspect, the total In another embodiment, the matrix comprises a hydro hygroscopic polymer content comprises about 15 % of the philic polymer . In one aspect, the hydrophilic polymer is a total matrix mass . In one aspect , the total hygroscopic non - ionic polymer , an anionic polymer , a cationic polymer , polymer content comprises about 13 % of the total matrix or a combination thereof. In one aspect, the matrix com mass . In one aspect, the total hygroscopic polymer content 20 prises a hydrophilic anionic polymer. In another aspect, the comprises about 12 % of the total matrix mass. In one aspect, matrix comprises a hydrophilic cationic polymer . In another the total hygroscopic polymer content comprises about 11 % aspect , the matrix comprises a hydrophilic anionic polymer of the total matrix mass . In one aspect, the total hygroscopic and hydrophilic cationic polymer. polymer content comprises about 10 % of the total matrix In another embodiment, the hydrophilic polymer com mass . In one aspect, a hygroscopic polymer comprises about 25 prises from about 2 % to about 20 % of the total matrix mass 9 % of the total matrix mass . In one aspect, a hygroscopic including all integers within the specified range . The hydro polymer comprises about 8 % of the totalmatrix mass. In one philic polymer comprises about 2 % , about 3 % , about 4 % , aspect, a hygroscopic polymer comprises about 7 % of the about 5 % , about 6 % , about 7 % , about 8 % , about 9 % , about total matrix mass . In one aspect , a hygroscopic polymer 10 % , about 12 % , about 15 % , about 18 % , or about 20 % of comprises about 6 % of the total matrix mass . In one aspect, 30 the totalmatrix mass . In one aspect, the hydrophilic polymer a hygroscopic polymer comprises about 5 % of the total comprises about 10 % of the totalmatrix mass . In one aspect , matrix mass. In one aspect, a hygroscopic polymer com - the hydrophilic polymer comprises about 9 % of the total prises about 4 % of the total matrix mass . matrix mass . In one aspect, the hydrophilic polymer com In another embodiment, the matrix comprises a non - ionic prises about 8 % of the totalmatrix mass. In one aspect, the surfactant. In another embodiment, the non - ionic surfactant 35 hydrophilic polymer comprises about 7 % of the totalmatrix comprises from about 1 % to about 15 % of the total matrix mass . In one aspect, the hydrophilic polymer comprises mass including all integers within the specified range. In about 6 % of the total matrix mass. In one aspect, the another embodiment, non - ionic surfactant comprises from hydrophilic polymer comprises about 5 % of the totalmatrix about 2 . 5 % to about 10 % of the total matrix mass including mass . In one aspect, the hydrophilic polymer comprises all integers within the specified range . In one aspect, non - 40 about 4 % of the total matrix mass . ionic surfactant comprises about 2 .5 % of the total matrix In one embodiment, the matrix comprises multiple spe mass. In one aspect, the non - ionic surfactant comprises cies of hydrophilic ionic polymers. In another embodiment, about 6 . 5 % of the total matrix mass . In one aspect, the the matrix comprises two species of hydrophilic ionic poly non - ionic surfactant comprises about 8 .5 % of the total mers . In one embodiment, one species of hydrophilic poly matrix mass . 45 mer is one or more anionic polymers and the other species In another embodiment, the total amount of hygroscopic of hydrophilic polymer is one or more cationic polymers . In polymer and non - ionic surfactant ranges from about 4 % to one embodiment, the ratio of one species of hydrophilic about 20 % of the total matrix mass including all integers ionic polymer to a second hydrophilic ionic polymer is about within the specified range . In one aspect, the total amount of 0 . 3 : 1 to about 1 : 1 , including all iterations of ratios within the hygroscopic polymer and non - ionic surfactant comprises 50 specified range . In one aspect, the ratio of one species of about 6 % of the total matrix mass . In one aspect , the total hydrophilic ionic polymer to a second hydrophilic ionic amount of hygroscopic polymer and non - ionic surfactant polymer is about 0 . 8 : 1 . In one aspect, the ratio of one species comprises about 10 % of the total matrix mass . In one aspect, of hydrophilic ionic polymer to a second hydrophilic poly the total amount of hygroscopic polymer and non - ionic mer ionic is about 0 . 7 : 1 . In one aspect, the ratio of one surfactant comprises about 18 % of the total matrix mass . 55 species of hydrophilic ionic polymer to a second hydrophilic In another embodiment, the ratio of the non - ionic surfac - polymer ionic is about 0 . 5 : 1 . In one aspect, the ratio of one tant to the hygroscopic polymer ranges from about 0 . 2 : 1 to species of hydrophilic ionic polymer to a second hydrophilic about 15 : 1 , including all iterations of ratios within the polymer ionic is about 0 .4 : 1 . In one aspect , the ratio of one specified range. In another embodiment, the ratio of the species of hydrophilic ionic polymer to a second hydrophilic non - ionic surfactant to the hygroscopic polymer ranges from 60 polymer ionic is about 0 . 3 : 1 . In one aspect, one hydrophilic about 0 .2 : 1 to about 5 : 1 , including all iterations of ratios polymer species is anionic , and the other hydrophilic poly within the specified range. In one aspect, the ratio of the mer species is cationic . non - ionic surfactant to the hygroscopic polymer is about In another embodiment, the matrix comprises a pH buff 0 . 7 : 1 . In one aspect, the ratio of the non - ionic surfactant to ering agent. In one aspect, the pH buffering agent comprises the hygroscopic polymer is about 1 .5 : 1. In one aspect , the 65 a pK? from about pH 2 . 5 to about pH 12, including all ratio of the non - ionic surfactant to the hygroscopic polymer integers within the specified range . In another aspect, the pH is about 3 . 5 : 1 . buffering agent comprises a pK , from about pH 5 to about US 10 , 182 , 992 B2 17 18 pH 11 . In another aspect, the pH buffering agent has a pK , of the total matrix mass . In another aspect, the suspension of about 7 . 5 to about 10 , including all integers within the agent comprises about 1 . 3 % of the total matrix mass . In specified range . In one aspect, the pH buffering agent has a another aspect, the suspension agent comprises about 1 . 2 % PK , of about 9 . of the total matrix mass. In one aspect , the suspension agent In one embodiment, the pH buffering agent comprises 5 comprises about 1 . 2 % of the total matrix mass . In one about 1 % to about 8 % of the total matrix mass including all aspect, the suspension agent comprises about 1 % of the total integers within the specified range . In one aspect , the pH matrix mass . In one aspect, the suspension agent comprises buffering agent comprises about 2 % of the total matrix mass . about 0 . 9 % of the total matrix mass . In one aspect, the In one aspect , the pH buffering agent comprises about 4 % of suspension agent comprises about 0 . 8 % of the total matrix the total matrix mass . In one aspect, the pH buffering agent 10 mass . comprises about 5 . 5 % of the total matrix mass . In one embodiment, the matrix comprises a lipid or In some embodiments , the ratio of the pH buffering agent lipophilic composition and hydrophilic composition . In one to the ionic hydrophilic polymers is from about 0 . 2 : 1 to embodiment, the lipid or lipophilic composition comprises about 3 : 1 , including all iterations of ratios within the speci - one or more liquid lipid vehicles and one or more semi- solid fied range . In some embodiments , the ratio of the pH 15 lipid vehicles and the hydrophilic composition comprises buffering agent to the ionic hydrophilic polymers is from one or more hygroscopic polymers, one or more hydrophilic about 0 .2 : 1 to about 0 . 5 : 1 , including all iterations of ratios polymers . In another embodiment, the hydrophilic matrix within the specified range . In one aspect , the ratio of the pH composition comprises. In one embodiment, the matrix buffering agent to the ionic hydrophilic polymers is about further comprises a suspension agent. In another embodi 0 . 3 . In one aspect, the ratio of the pH buffering agent to the 20 ment, thematrix further comprises a non - ionic surfactant. In ionic hydrophilic polymers is about 0 . 5 . another embodiment, the matrix further comprises a pH The total hydrophilic composition of the matrix comprises buffering agent. one or more one or more hygroscopic polymers ; one or more In one embodiment, the matrix comprises one or more hydrophilic polymers ; optionally , one or more non -ionic liquid lipid vehicles , one or more semi- solid lipid vehicles, surfactants , and optionally , one or more pH buffering agents . 25 one or more one ormore hygroscopic polymers , one or more In one embodiment, the total hydrophilic composition of the hydrophilic polymers, one or more non - ionic surfactants , matrix comprises about 7 % to about 48 % of the total matrix one or more pH buffering agents , and one or more active mass including all integers within the specified range . In pharmaceutical ingredients . In one embodiment, the matrix another embodiment, the total hydrophilic matrix composi- comprises any one of the compositions of Tables 6 , 13 , or tion comprises about 18 % to about 32 % of the total matrix 30 15 . mass including all integers within the specified range. In one In one embodiment, the matrix comprises one or more embodiment, the total hydrophilic matrix composition com - liquid lipid vehicles , one or more semi- solid lipid vehicles , prises about 18 % to about 22 % of the total matrix mass one or more one ormore hygroscopic polymers , one or more including all integers within the specified range . In one hydrophilic polymers, one or more suspension agents , and aspect , the total hydrophilic matrix composition comprises 35 one or more active pharmaceutical ingredients . In one about 18 % of the total matrix mass. In one aspect, the total embodiment, the matrix comprises any one of the compo hydrophilic matrix composition comprises about 19 % of the sitions of Tables 7, 8, 14 , or 16 . total matrix mass . In one aspect, the total hydrophilic matrix In one embodiment, the matrix comprises one or more composition comprises about 20 % of the total matrix mass . active pharmaceutical ingredients ( API) . In one aspect, the In one aspect , the total hydrophilic matrix composition 40 active pharmaceutical ingredient is useful in treating pain . In comprises about 21 % of the total matrix mass. In one aspect , one aspect , the active pharmaceutical ingredient is tapent the total hydrophilic matrix composition comprises about adol, oxycodone , hydrocodeine, or codeine . In one aspect , 22 % of the total matrix mass . the active pharmaceutical ingredient is tapentadol. In another embodiment, the ratio of the total lipid or In another embodiment, the one or more active pharma lipophilic vehicle to the total hydrophilic matrix composi- 45 ceutical ingredient comprises from about 1 % to about 50 % tion is from about 1 : 1 to about 13 : 1 , including all iterations of the total matrix mass including all integers within the of ratios within the specified range . In another embodiment specified range . In another embodiment , the active pharma the ratio of the lipid or lipophilic vehicle to the hydrophilic ceutical ingredient comprises from about 5 % to about 30 % matrix composition is from about 1 : 1 to about 3 : 1 , including of the total matrix mass including all integers within the all iterations of ratios within the specified range . In one 50 specified range . In one aspect, the active pharmaceutical aspect , the ratio of the lipid or lipophilic vehicle to the ingredient comprises about 5 % of the total matrix mass . In hydrophilic matrix composition is about 1 . 5 : 1 . In one aspect, one aspect , the active pharmaceutical ingredient comprises the ratio of the lipid or lipophilic vehicle to the hydrophilic about 10 % of the total matrix mass . In one aspect, the active matrix composition is about 2 . 5 : 1 . In one aspect , the ratio of pharmaceutical ingredient comprises about 15 % of the total the lipid or lipophilic vehicle to the hydrophilic matrix 55 matrix mass . In one aspect, the active pharmaceutical ingre composition is about 2 . 3 : 1 . In one aspect, the ratio of the dient comprises about 20 % of the totalmatrix mass . In one lipid or lipophilic vehicle to the hydrophilic matrix compo aspect, the active pharmaceutical ingredient comprises about sition is about 2 . 7 : 1 . 25 % of the total matrix mass . In another embodiment, the matrix comprises a suspen In another embodiment, the ratio of the active pharma sion agent. In one embodiment, the suspension agent com - 60 ceutical ingredient to the total hydrophilic composition of prises about 0 . 5 % to about 5 % of the total matrix mass the matrix ranges from about 0 . 1 : 1 to about 2 . 6 : 1 , including including all integers within the specified range . In one all iterations of ratios within the specified range . The ratio of embodiment, the suspension agent comprises about 0 .8 % to the active pharmaceutical ingredient to the total hydrophilic about 2 % of the total matrix mass including all integers composition of the matrix can be 0 . 1 : 1 , 0 . 3 : 1 , 0 . 5 : 1 , 1 : 1 , within the specified range . In one aspect, the suspension 65 1 . 1 : 1 , 1 . 2 : 1 , 1. 3 : 1 , 1 . 4 : 1 , 1 . 8 : 1 , 2 : 1 , 2 .4 : 1 , or 2 . 6 : 1 . In one agent comprises about 2 % of the total matrix mass . In aspect, the ratio of the active pharmaceutical ingredient to another aspect , the suspension agent comprises about 1 . 5 % the total hydrophilic composition of the matrix is about US 10 , 182 , 992 B2 20 0 .5 : 1. In one aspect , the ratio of the active pharmaceutical indometacin , sulindac, tolmetin , zomepirac, diclofenac , ingredient to the total hydrophilic composition of the matrix alclofenac , bumadizone, etodolac, lonazolac , fentiazac , is about 1 . 8 : 1 . In one aspect, the ratio of the active phar - acemetacin , difenpiramide , oxametacin , proglumetacin , maceutical ingredient to the total hydrophilic composition of ketorolac, aceclofenac, bufexamac , oxicam , piroxicam , ten the matrix t is about 1 . 6 : 1 . In one aspect, the ratio of the 5 oxicam , droxicam , lornoxicam , meloxicam , methotrexate , active pharmaceutical ingredient to the total hydrophilic propionic acid derivatives, ibuprofen , naproxen , ketoprofen , composition of the matrix is about 1 . 2 : 1 . In one aspect, the fenoprofen , fenbufen , benoxaprofen , suprofen , pirprofen , ratio of the active pharmaceutical ingredient to the total flurbiprofen , indoprofen , tiaprofenic acid , oxaprozin , ibu hydrophilic composition of the matrix is about 1 . 4 : 1 . proxam , dexibuprofen , flunoxaprofen , alminoprofen , dexke In another embodiment, the ratio of the active pharma - 10 toprofen , fenamates , mefenamic acid , tolfenamic acid , flufe ceutical ingredient to the total lipid or lipophilic composition namic acid , meclofenamic acid , coxibs , celecoxib , of the matrix ranges from about 0 .2 : 1 to about 1 . 8 : 1 , rofecoxib , valdecoxib , parecoxib , etoricoxib , lumiracoxib , including all iterations of ratios within the specified range . nabumetone , niflumic acid , azapropazone , glucosamine , The ratio of the active pharmaceutical ingredient to the total benzydamine , glucosaminoglycan polysulfate , proquazone , lipid or lipophilic composition of the matrix can be 0 . 1 : 1 , 15 orgotein , nimesulide, feprazone, diacerein , morniflumate , 0 . 2 : 1 , 0 . 5 : 1 , 0 . 6 : 1 , 0 . 8 : 1 , 0 . 9 : 1 , 1 : 1 , 1 . 2 : 1 , 1 . 4 : 1 , or 1 . 8 : 1 . In tenidap , oxaceprol, chondroitin sulfate , feprazone , dipyro one aspect , the ratio of the active pharmaceutical ingredient cetyl , acetylsalicylic acid , quinolines, oxycinchophen , gold to the total lipid or lipophilic composition of the matrix is preparations, sodium aurothiomalate , sodium aurotiosulfate , about 1 . 4 : 1 . In one aspect, the ratio of the active pharma- auranofin , aurothioglucose , aurotioprol, penicillamine or ceutical ingredient to the total lipid or lipophilic composition 20 bucillamine. of the matrix is about 1 : 1 . In one aspect, the ratio of the In another embodiment, suitable active pharmaceutical active pharmaceutical ingredient to the total lipid or lipo - ingredients can comprise analgesics, such as, for example : philic composition of the matrix t is about 0 . 8 : 1 . In one opioids, natural opium alkaloids, morphine, opium , hydro aspect, the ratio of the active pharmaceutical ingredient to morphone , nicomorphine , oxycodone , dihydrocodeine , the total lipid or lipophilic composition of the matrix is about 25 diamorphine , tapentadol, papavereturn , codeine, phenylpip 0 .6 : 1 . In one aspect, the ratio of the active pharmaceutical eridine derivatives , ketobemidone, pethidine, fentanyl, ingredient to the total lipid or lipophilic composition of the diphenylpropylamine derivatives, dextromoramide, piritr matrix is about 0 . 5 : 1 . amide , dextropropoxyphene , bezitramide , methadone , ben In another embodiment, the ratio of the active pharma zomorphan derivatives, pentazocine , phenazocine , oripavine ceutical ingredient to the total matrix composition ranges 30 derivatives, buprenorphine, morphinan derivatives , butor from about 0 . 1 : 1 to about 1 : 1 , including all iterations of phanol, nalbuphine , tilidine , tramadol, dezocine , salicylic ratios within the specified range . The ratio of the active acid and derivatives, acetylsalicylic acid , aloxiprin , choline pharmaceutical ingredient to the total matrix composition salicylate , sodium salicylate , salicylamide , salsalate , ethen can be 0 . 1 : 1 , 0 .2 : 1 , 0 . 3 : 1 , 0 .4 : 1 , 0 . 5 : 1 , 0 . 6 :1 , 0 . 7 : 1, 0 . 8 :1 , zamide, morpholine salicylate , dipyrocetyl, benorilate , 0 . 9 : 1 , or 1 : 1 . In another embodiment, the ratio of the active 35 diflunisal, potassium salicylate , guacetisal, carbasalate cal pharmaceutical ingredient to the total matrix composition cium , imidazole salicylate , pyrazolones, phenazone, metam ranges from about 0 . 2 : 1 to about 0 . 5 : 1 , including all itera - izole sodium , aminophenazone, propyphenazone , nifena tions of ratios within the specified range . In another embodi- zone , anilides, paracetamol, phenacetin , bucetin , ment, the ratio of the active pharmaceutical ingredient to the propacetamol, other analgesics and antipyretics, such as, for total matrix composition ranges from about 0 . 2 : 1 to about 40 example : rimazolium , glafenine , floctafenine, viminol, nefo 0 . 4 : 1 , including all iterations of ratios within the specified pam , flupirtine , or ziconotide. range. In one aspect, the ratio of the active pharmaceutical In another embodiment, suitable active pharmaceutical ingredient to the total matrix composition is about 0 . 3 : 1 . In ingredients can comprise anaesthetics , such as , for example : one aspect , the ratio of the active pharmaceutical ingredient ethers , diethyl ether , vinyl ether, halogenated hydrocarbons , to the total matrix composition is about 0 . 4 : 1 . In one aspect, 45 halothane , chloroform , methoxyflurane, enflurane , trichlo the ratio of the active pharmaceutical ingredient to the total roethylene , isoflurane , desflurane, sevoflurane , barbiturates , matrix composition is about 0 . 5 : 1 . methohexital, hexobarbital, thiopental, narcobarbital, opioid In one embodiment, the matrix contains an active phar - anaesthetics , fentanyl, alfentanil , sufentanil, phenoperidine , maceutical ingredient in a suspended , form , soluble form , anileridine , remifentanil , other general anaesthetics , such as , insoluble form , or combinations thereof . In another embodi - 50 for example : droperidol, ketamine, propanidid , alfaxalone , ment, the matrix contains an active pharmaceutical ingredi- etomidate , propofol , hydroxybutyric acid , nitrous oxide , ent useful for the treatment of pain . In one embodiment, the esketamine, xenon , esters of aminobenzoic acid , metabu active pharmaceutical ingredient includes tapentadol, oxy - tethamine, procaine , tetracaine , chloroprocaine , benzocaine , codone , morphine, morphine analogues , or morphine amides, bupivacaine , lidocaine , mepivacaine , prilocaine , antagonists , codeine , morphine, methadone, fentanyl and 55 butanilicaine , cinchocaine , etidocaine , articaine , ropiva analogs, opioid pain relievers : oxycodone hydrochloride , caine , levobupivacaine , esters of benzoic acid , cocaine , hydrocodone bitartrate hydromorphone , oxymorphone , other local anaesthetics, such as, for example : ethyl chloride , meperidine, propoxyphene , flunitrazepam , barbiturates , dyclonine , phenol, or capsaicin . amytal, nembutal , seconal, phenobarbital; benzodiazepines, In another embodiment, suitable active pharmaceutical zolpidem , zaleplon , eszopiclone, amphetamines , or methyl- 60 ingredients can comprise antimigraine active drug sub phenidate . stances, such as , for example : ergot alkaloids, dihydroergot Examples of specific active drug substances suitable for amine, ergotamine, methysergide , lisuride, corticosteroid use in the pharmaceutical compositions provided herein derivatives, flumedroxone , selective serotonin (5HT !) ago include : anti - inflammatory and antirheumatic active drug nists , sumatriptan , naratriptan , zolmitriptan , rizatriptan , substances, such as , for example : butylpyrazolidine, phe - 65 almotriptan , eletriptan , frovatriptan , other antimigraine nylbutazone , mofebutazone , oxyphenbutazone , clofezone , preparations, pizotifen , clonidine , iprazochrome, dimetoti kebuzone, acetic acid derivatives and related substances , azine , or oxetorone . US 10 , 182 , 992 B2 21 22 In another embodiment, suitable active pharmaceutical octadiene derivatives, benzoctamine , azaspirodecanedione ingredients can comprise antiepileptic active drug sub derivatives , buspirone, other anxiolytics , such as , for stances , such as , for example : barbiturates and derivatives , example : mephenoxalone , gedocarnil , or etifoxine . methylphenobarbital, phenobarbital, primidone , barbexa In another embodiment, suitable active pharmaceutical clone , metharbital , hydantoin derivatives , ethotoin , pheny - 5 ingredients can comprise hypnotic and sedative active drug toin , amino (diphenylhydantoin ) valeric acid , mephenytoin , substances, such as , for example : barbiturates, pentobarbital, fosphenytoin , oxazolidine derivatives, paramethadione , amobarbital , butobarbital, barbital, aprobarbital , secobarbi trimethadione , ethadione , succinimide derivatives, ethosuxi tal, talbutal, vinylbital , vinbarbital, cyclobarbital, heptabar mide , phensuximide , mesuximide, benzodiazepine deriva bital, reposal, methohexital, hexobarbital, thiopental, ethal tives, clonazepam , carboxamide derivatives , carbam - 10 lobarbital, allobarbital, proxibarbal, aldehydes and azepine, oxcarbazepine , rufinamide, fatty acid derivatives, derivatives , chloral hydrate , chloralodol, acetylglycinamide valproic acid , valpromide , aminobutyric acid , vigabatrin , chloral hydrate , dichloralphenazone , paraldehyde , benzodi progabide , tiagabine , other antiepileptics , such as , for a zepine emepronium derivatives , flurazepam , nitrazepam , example : sultiame, phenacemide, lamotrigine , felbamate , flunitrazepam , estazolam , triazolam , lormetazepam , temaze topiramate , gabapentin , pheneturide , levetiracetam , zonis - 15 pam , midazolam , brotizolam , quazepam , loprazolam , dox amide, pregabalin , stiripentol, lacosamide , or beclamide . efazepam , cinolazepam , piperidinedione derivatives , glute In another embodiment, suitable active pharmaceutical thimide, methyprylon , pyrithyldione , benzodiazepine ingredients can comprise anticholinergic active drug sub - related drugs , zopiclone , zolpidem , zaleplon , ramelteon , stances, such as , for example: tertiary amines , trihexy - other hypnotics and sedatives, such as , for example : meth phenidyl, biperiden , metixene , procyclidine , profenamine , 20 aqualone , clomethiazole , bromisoval , carbromal, scopol dexetimide , phenglutarimide , mazaticol, bornaprine , tro amine, propiomazine , triclofos , ethchlorvynol, valerian , patepine, ethers chemically close to antihistamines , etanau hexapropymate , bromides , apronal, valnoctamide , methyl tine, orphenadrine ( chloride ), ethers of tropine or tropine pentynol, niaprazine ,melatonin , dexmedetomidine, or dip derivatives , benzatropine , or etybenzatropine . iperonylaminoethanol. In another embodiment, suitable active pharmaceutical 25 In another embodiment, suitable active pharmaceutical ingredients can comprise dopaminergic active drug sub - ingredients can comprise antidepressant active drug sub stances , such as, for example : dopa and dopa derivatives , stances , such as , for example : non -selective monoamine levodopa , melevodopa , etilevodopa , adamantane deriva reuptake inhibitors , desipramine , imipramine , imipramine tives , amantadine , dopamine agonists , bromocriptine, per - oxide , clomipramine , opipramol, trimipramine, lofepramine , golide , dihydroergocryptine mesylate , ropinirole , pramipex - 30 dibenzepin , amitriptyline , nortriptyline , protriptyline , dox ole , cabergoline , apomorphine, piribedil , rotigotine , epin , iprindole , melitracen , butriptyline , dosulepin , amox monoamine , oxidase B inhibitors , selegiline, rasagiline , apine , dimetacrine, amineptine, maprotiline , quinupramine , other dopaminergic agents , such as , for example : tolcapone , selective serotonin reuptake inhibitors , zimeldine, fluox entacapone, or budipine . etine , citalopram , paroxetine , sertraline , alaproclate , fluvox In another embodiment , suitable active pharmaceutical 35 amine , etoperidone , escitalopram , monoamine oxidase ingredients can comprise antipsychotic active drug sub - inhibitors , isocarboxazid , nialamide , phenelzine , tranylcy stances , such as , for example : phenothiazines with aliphatic promine, iproniazide, iproclozide, monoamine oxidase A side - chain , chlorpromazine, levomepromazine , promazine, inhibitors, moclobemide, toloxatone , other antidepressants , acepromazine , triflupromazine , cyamemazine, chlorproeth such as, for example: oxitriptan , tryptophan , mianserin , azine , phenothiazines with piperazine structure , dixyrazine , 40 nomifensine , trazodone , nefazodone , minaprine , bife fluphenazine , perphenazine, prochlorperazine, thiopro - melane , viloxazine, oxaflozane , mirtazapine ,medifoxamine , pazate , trifluoperazine, acetophenazine , thioproperazine , tianeptine , pivagabine , venlafaxine , milnacipran , rebox butaperazine , perazine , phenothiazines with piperidine etine , gepirone , duloxetine , agomelatine , desvenlafaxine , structure , periciazine, thioridazine, mesoridazine , pipotiaz - centrally acting sympathomimetics, such as, for example : ine , butyrophenone derivatives, haloperidol, trifluperidol, 45 amfetamine , dexamfetamine , lisdexamfetamine , metamfet melperone , moperone , pipamperone , bromperidol, benperi- amine , methylphenidate , dexmethylphenidate , pemoline , dol, droperidol, fluanisone , indole derivatives, oxypertine , fencamfamin , modafinil , fenozolone , atomoxetine , fenetyl molindone , sertindole , ziprasidone, thioxanthene deriva - line , xanthine derivatives, caffeine, propentofylline, other tives , flupentixol, clopenthixol, chlorprothixene , tiotixene , psychostimulants and nootropics , such as , for example zuclopenthixol, diphenylbutylpiperidine derivatives , fluspir - 50 meclofenoxate , pyritinol, piracetam , deanol, fipexide, citi ilene, pimozide, penfluridol, diazepines , oxazepines, thiaz coline, oxiracetam , pirisudanol, linopirdine , nizofenone , epines , loxapine, clozapine , olanzapine , quetiapine , neuro aniracetam , acetylcarnitine, idebenone , prolintane , pip leptics , tetrabenazine , benzamides, sulpiride , sultopride , radrol, pramiracetam , adrafinil, or vinpocetine . tiapride , remoxipride , amisulpride , veralipride , levo In another embodiment, suitable active pharmaceutical sulpiride , lithium , other antipsychotics, such as, for example 55 ingredients can comprise anti -dementia active drug sub prothipendyl, risperidone, clotiapine , mosapramine , stances, such as , for example : anticholinesterases, tacrine , zotepine, aripiprazole , or paliperidone . donepezil, rivastigmine , galantamine , other anti -dementia In another embodiment , suitable active pharmaceutical drugs, memantine , or ginkgo biloba . ingredients can comprise anxiolytic active drug substances , In another embodiment, suitable active pharmaceutical such as, for example : benzodiazepine derivatives , diazepam , 60 ingredients can comprise other nervous system active drug chlordiazepoxide , medazepam , oxazepam , potassium clora substances , such as, for example : parasympathomimetics, zepate , lorazepam , adinazolam , bromazepam , clobazam , anticholinesterases, neostigmine, pyridostigmine , distig ketazolam , prazepam , alprazolam , halazepam , pinazepam , mine , ambenonium , choline esters, carbachol, bethanechol, camazepam , nordazepam , fludiazepam , ethyl loflazepate , and other parasympathomimetics , such as, for example , etizolam , clotiazepam , cloxazolam , tofisopam , diphenyl- 65 pilocarpine , or choline alfoscerate . methane derivatives, hydroxyzine, captodiame, carbamates , Active drug substances used in addictive disorders, such meprobamate , emylcamate , mebutamate , dibenzo -bicyclo - as, for example : nicotine, bupropion , varenicline , disulfiram , US 10 , 182 , 992 B2 23 24 calcium carbimide, acamprosate , naltrexone , buprenor- isoquinoline alkaloid , codeine methylbromide , codeine- N phine, methadone , levacetylmethadol, lofexidine, betahis oxide , codoxime, cyclobarbital (hexemal NFN ) , cyprenor tine, cinnarizine , flunarizine, acetylleucine, gangliosides and phine , dehydrochlormethyltestosterone , delorazepam , deso ganglioside derivatives, tirilazad , riluzole , xaliproden , morphine, dexamfetamine , dexfenfluramine , hydroxybutyric acid , or amifampridine . dexmethylphenidate , dextromoramide , dextropropoxy In another embodiment, suitable active pharmaceutical phene , diacetylmorphine , diampromide , diazepam , dichlo ingredients can comprise opium alkaloids and derivatives , ralphenazone, diethylpropion , diethylthiambutene , diethyl such as, for example : ethylmorphine, hydrocodone , codeine, tryptamine , difenoxin , dihydrocodeine , dihydroetorphine , opium alkaloids with morphine, normethadone , noscapine , dihydromorphine , dihydrotestosterone , dimenoxadol, pholcodine, dextromethorphan , thebacon , dimemorfan , 10 dimepheptanol , dimethylthiambutene , dimethyltryptamine , acetyldihydrocodeine , benzonatate , benproperine, clobuti - dioxaphetyl butyrate , diphenoxylate , dipipanone , diprenor nol, isoaminile , pentoxyverine , oxolamine , oxeladin , clofe - phine , dronabinol, drostanolone , drotebanol, ecgonine , esta danol , pipazetate , bibenzonium bromide, butamirate , fedri zolam , ethchlorvynol, ethinamate, ethyl loflazepate , ethyl late , zipeprol, dibunate , droxypropine , prenoxdiazine , estrenol, ethylmethylthiambutene, ethylmorphine, dropropizine, cloperastine, meprotixol, piperidione, tipepi- 15 ethylmorphine , eticyclidine, etilamfetamine, etonitazene , dine , morclofone , nepinalone , levodropropizine , or dime- etorphine, etoxeridine, etryptamine , fencamfamin , fenethyl thoxanate . line , fenetylline , fenfluramine , fenproporex , fentanyl, fludi In another embodiment, the active pharmaceutical ingre - azepam , flunitrazepam , fluoxymesterone, flurazepam , dient may be a substance with abuse potential that presents formebolone, fungi and spores of the species psilocybe a safety risk . Such active drug substance may include : 20 semilanceata , furethidine , gamma hydroxybutyric acid , glu 1 - ( 1 -phenylcyclohexyl )pyrrolidine , 1 - ( 2 - phenylethyl) - 4 - tethimide, halazepam , haloxazolam , heroine, hydrocodone , phenyl- 4 - acetoxypiperidine , 1 - [ 1 - ( 2 - thienyl) - cyclohexylpi- hydrocodone & isoquinoline alkaloid , hydromorphinol, peridine , 1 -[ 1 -( 2 - thienyl) cyclohexyl ] pyrrolidine , 1- methyl - hydromorphone , hydroxypethidine, ibogaine , isobutyl 4 -phenyl - 4 - propionoxy -piperidine , nitrite , isomethadone, ketamine , ketazolam , ketobemidone , 1 -phenylcyclohexylamine , 1 -piperidinocyclohexanecarbo - 25 levamfetamine, levo -alphacetylmethadol , levo -metham nitrile , 2 , 5 - dimethoxy - 4 - ethylamphetamine, 2 , 5 - dime phetamine , levomethorphan , levomoramide , levophenacyl thoxyamphetamine , 2C = B - (4 -bromo -2 ,5 -dimethoxypen morphan , levorphanol, lisdexamfetamine, loprazolam , lora ethylamine ), 2C - D ( 2 , 5 -dimethoxy - 4 zepam , lormetazepam , lysergic acid , lysergic acid amide, methylphenethylamine ) , 2C - I (4 - iodo - 2 , 5 - dimethoxy lysergic acid diethylamide , marijuana , mazindol, MBDN phenethylamine ), 2C - T - 2 (2 , 5 - dimethoxy - 4 - 30 (N -methyl - 1 -( 3 ,4 -methylenedioxyphenyl ) -2 -butanamine ), ethylthiophenethylamine ), 2C - T- 4 (2 , 5 -dimethoxy -4 - mCPP (1 -( 3 - chlorphenyl) piperazine ), mebutamate , meclo isopropyl thiophenethylamine ), 2C - T - 7 (2 , 5 - dimethoxy - 4 qualone , medazepam , mefenorex , MeOPP ( 1 -( 4 -methoxy ( n ) - propylthiophenethylamine ) , 3 , 4 -methylene phenyl) piperazine ), meperidine , meperidine intermediate , dioxymethamphetamine , 3 , 4 , 5 - trimethoxyamphetamine , meprobamate , mescaline , mesocarb , mesterolone , metamfe 3 ,4 -methylenedioxyamphetamine , 3 , 4 -methylenedioxy - N - 35 tamine , metazocine , methadone , methadone intermediate , ethylamphetamine , 3 -methylfentanyl , 3 -methylthiofentanyl , methamphetamine, methandienone , methandrolone , meth 4 - brorno - 2 , 5 - dimethoxyamphetamine , 4 -bromo - 2 , 5 - dime- andriol, methandrostenolone , methaqualone , methcathi thoxyphenethylamine , 4 -methoxyamphetamine , 4 -methyl - 2 , none, methenolone, methohexital, methyldesorphine , meth 5 - dimethoxyamphetamine , 4 -methylaminorex ( cis isomer ), yldihydromorphine , methylphenidate , methylphenobarbital 5 -MeO -DIPT ( 5 -methoxy - N , N - diisopropyltryptamine) , 40 (mephobarbital ) , methyltestosterone, methyprylone, meto 5 -MeO -DMT ( 5 -methoxy - N , N -dimethyltryptamine ), pone , mibolerone, midazolam , modafinil , moramide - inter 5 -methoxy - 3 , 4 -methylenedioxyamphetamine , acetorphine , mediate , morpheridine , morphine , morphine methylbro acetorphine, acetyl- alpha- methylfentanyl , acetyl- alpha - mide , morphine methylsulfonate , morphine - N -oxide , methylfentanyl, acetyldihydrocodeine , acetylmethadol, myrophine , N , N -dimethylamphetamine , nabilone , nalor acetylmethadol, alfentanil , allobarbital , allylprodine , 45 phine , nandrolone, N - ethyl- 1 -phenylcyclohexylamine , alphacetylmethadol except levo -alphacetylmethadol , alpha - N -ethyl - 3 -piperidyl benzilate , N - ethylamphetamine , N -hy ethyltryptamine , alphameprodine , alphamethadol , alphame droxy - 3 , 4 -methylenedioxyamphetamine , nicocodeine , thadol, alpha -methylfentanyl , alpha -methylthiofentanyl , nicocodine , nicodicodine , nicomorphine , nimetazepam , alphaprodine, alprazolam , amfepramon , amfetaminil , nitrazepam , N -methyl - 3 -piperidyl benzilate , noracymeth amineptin , aminorex , amobarbital, amphetamine , dextroam - 50 adol, norcodeine , nordiazepam , norethandrolone , norlevor phetamine, amilnitrite ( all isomers of the amyl group ) , phanol, normethadone , normorphine, norpipanone , norpi anabolic steroids, anileridine , aprobarbital, barbital, barbi panone, opium , oxandrolone , oxazepam , oxazolam , turic acid derivative , BDB ( 3 ,4 -methylenedioxyphenyl ) - 2 oxycodone , oxymesterone, oxymetholone, oxymorphone , butanamine ), benzethidin , benzethidine , benzoylecgonine , para - fluorofentanyl, parahexyl, paraldehyde , pemoline, pen benzphetamine , benzphetamine , benzylmethylcetone, ben - 55 tazocine , pentobarbital , petrichloral, peyote , phenadoxone , zylmorphine , betacetylmethadol, beta - hydroxy - 3 -methyl phenampromide, phenazocine , phencyclidine, phendimetra fentanyl, beta -hydroxyfentanyl , betameprodine, betame zine, phenmetrazine , phenobarbital, phenomorphan , pheno prodine, betamethadol, betaprodine , bezitramide , peridine, phentermine , phenylacetone, pholcodine , pimino bezitramide, boldenone , brolamfetamine, bromazepam , bro - dine , pinazepam , pipradrole , piritramide, PMMA tizolam , bufotenine , buprenorphine , butabarbital, butalbital, 60 (paramethyxymethyl amphetamine ), prazepam , prohep butobarbital, butorphanol, BZP (A2 ) ( 1 -benzylpiperazin ), tazine, properidine, propiram , psilocybine , psilocine , pyrov camazepam , cannabis , carfentanil , catha edulis , cathine, alerone , quazepam , racemethorphane, racemoramide , rac cathinone , chloral betaine, chloral hydrate , chlordiazepox emorphane, remifentanil , salvia divinorum , salvinorin A , ide , chlorhexadol , chlorotestosterone ( same as clostebol ) , secobarbital, secobarbital, sibutramine , SPA , stanolone , chlorphentermine , clobazam , clonazepam , clonitazene, clo - 65 stanozolol, sufentanil, sulfondiethylmethane , sulfonethyl nitazene , clorazepate , clortermine , clostebol , clotiazepam , methane , sulfonmethane , talbutal, temazepam , tenamfet cloxazolam , coca leaves , cocaine , codeine , codeine and amine , testolactone , testosterone, tetrahydrocannabinols , US 10 , 182 , 992 B2 25 26 tetrazepam , TFMPP ( 1 - ( 3 -triflourmethylphenyl ) piperazine ), phenazocine , oripavine derivatives, buprenorphine , morph thebacon , thebaine , thiamylal, thiofentanyl , thiopental, tile inan derivatives , butorphanol, nalbuphine, tilidine , trama tamine and zolazepam in combination , tilidine, trenbolone , dol, dezocine, salicylic acid and derivatives, acetylsalicylic triazolam , trimeperidine , vinbarbital, zaleplon , zipeprol, acid , aloxiprin , choline salicylate , sodium salicylate , salicy zolpidem , or zopiclone . 5 lamide , salsalate , ethenzamide , morpholine salicylate , dipy Other suitable examples of active drug substances suitable rocetyl, benorilate , diflunisal, potassium salicylate , guaceti for use in the pharmaceutical compositions described herein sal, carbasalate calcium , imidazole salicylate , pyrazolones, include, for example , alfentanil, allylprodine , alphaprodine , phenazone, metamizole sodium , aminophenazone, propy anileridine, benzylmorphine, bezitramide , buprenorphine , phenazone , nifenazone , anilides , paracetamol, phenacetin , butorphanol, clonitazene, codeine , cyclazocine , desomor- 10 bucetin , propacetamol, other analgesics and antipyretics phine , dextromoramide , dezocine , diampromide, dihydroco - such as, for example , rimazolium , glafenine , floctafenine , deine , dihydromorphine , dimenoxadol, dimepheptanol, dim - viminol, nefopam , flupirtine , or ziconotide. ethylthiambutene , dioxaphetyl butyrate , dipipanone, In another embodiment , the active drug substance is an eptazocine , ethoheptazine, ethylmethylthiambutene , ethyl- opioid . Where an opioid is included as an active drug morphine , etonitazene , fentanyl, heroin , hydrocodone , 15 substance , the opioid may comprise naturally occurring hydromorphone , hydroxypethidine , isomethadone , dextro - opioids , synthetic opioids , or semisynthetic opioids . propoxyphene, ketobemidone , levallorphan , levorphanol, In other embodiment, the active drug substance comprises levophenacylmorphan , lofentanil , meperidine, meptazinol, amfetamine, dexamfetamine , lisdexamfetamine , metamfet metazocine , methadone , metopon , morphine, morphine amine, methylphenidate , dexmethylphenidate , or combina 6 - glucuronide , morphine 3 - glucuronide , myrophine, nalbu - 20 tions thereof . phine, narcine , nicomorphine , norlevorphanol, normetha In another embodiment , the pharmaceutical compositions done , nalorphine, normorphine , norpipanone , opium , oxy - disclosed herein includes an opioid , the opioid is selected codone, oxycodeine , oxymorphone , papavereturn , from buprenorphine , codeine , dextromoramide , dihydroco pentazocine , phenadoxone, phenomorphan , phenazocine , deine , fentanyl, hydrocodone , hydromorphone, morphine , phenoperidine, piminodine , piritramide , propheptazine , 25 pentazocine, oxycodeine , oxycodone, oxymorphone , norhy promedol, properidine , propiram , propoxyphene , sufentanil, drocodone , noroxycodone , morphine - 6 - glucuronode , trama tilidine , tramadol, thebaine , levo - alphacetylmethadol dol, tapentadol, or dihydromorphine . (LAAM ) , remifentanil , carfentanyl, ohmefentanyl, MPPP, Where an opioid is used as an active drug substance , the prodine , PEPAP, levomethorphan , etorphine, lefetamine , opioid may be present in any of its crystalline, polymor loperamide, diphenoxylate , or pethidine . 30 phous , semi- crystalline , and amorphous or polyamorphous Other examples of active drug substances suitable for use forms. Furthermore, in another embodiment, an opioid used in the pharmaceutical compositions described herein include as an active drug substance may be present in one or more anabolic steroids , cannabis , cocaine , or diazepam . forms selected from its crystalline , polymorphous , semi In another embodiment, the active drug substance com crystalline, or amorphous or polyamorphous forms. prises the therapeutic classes including non -steroidal anti - 35 Some embodiments of the pharmaceutical compositions inflammatory substances or antirheumatic active drug sub - disclosed herein include an opioid as an active drug sub stances . stance, the active drug substance is selected from morphine , In other embodiments , the active drug substance com oxycodone , hydrocodone , hydromorphone , norhydroco prises analgesics, opioids, antipyretics, anaesthetics , antimi done , oxymorphone , noroxycodone , morphine - 6 - glu graine agents , antiepileptics , anti -parkinson agents , dop - 40 curonode and pharmaceutically acceptable salts thereof, aminergic agents , antipsychotics, anxiolytics, sedatives , including oxycodone hydrochloride, hydrocodone bitartrate , antidepressants , psychostimulants agents , dopamine , nora - hydromorphone hydrochloride or morphine sulphate penta drenaline, nicotinic , alfa - adrenergic , serotonin , H3 antago - hydrate . nists used for ADHD or nootropics agents used in addictive In other embodiments , the pharmaceutical compositions disorders. 45 as described herein are suitable for use for water soluble as In other embodiments , the active drug substance com - well as slightly soluble or insoluble active drug substances . prises therapeutic classes including anaesthetics, centrally In another embodiment, all of the above mentioned active acting analgesics , sedative -hypnotics , anxiolytics , appetite drug substances may also be in the form of pharmaceutically suppressants , decongestants , antitussives , antihistamines , acceptable salts , uncharged or charged molecules , molecular antiemetics , antidiarrheals , and drugs used to treat narco - 50 complexes , solvates , or anhydrates thereof, and , if relevant , lepsy , or attention deficit hyperactivity disorder . single isomers , enantiomers, racemic mixtures , or mixtures In another embodiment, the active drug substance is thereof . associated with abuse syndromes and the active drug sub - In another embodiment, the pharmaceutical compositions stance may , for example , be selected from opioids, CNS described herein may comprise pharmaceutically acceptable depressants , CNS stimulants , cannabinoids, nicotine - like 55 salts of any of the above mentioned active drug substances. compounds, glutamate antagonists , or N -methyl - D -aspartate In another embodiment, the active pharmaceutical ingre (NMDA ) antagonists. dient is tapentadol or a pharmaceutically acceptable salt In another embodiment, the active drug substance is an form . Pharmaceutically acceptable salts forms are those analgesic . Examples of analgesics suitable for use in the formed by contacting tapentadol free base with a suitable pharmaceutical compositions described herein include, for 60 acid in a suitable solvent under suitable conditions that will example , opioids , natural opium alkaloids , morphine , form a form of tapentadol acid addition salt. Suitable acids opium , hydromorphone, nicomorphine , oxycodone, dihy - include hydrochloric acid , camphorsulfonic acid , hydrobro drocodeine , diamorphine , tapentadol, papavereturnmon , mic acid , sulfuric acid , methanesulfonic acid , formic acid , codeine, phenylpiperidine derivatives , ketobemidone , pethi- acetic acid , oxalic acid , succinic acid , tartaric acid , mandelic dine , fentanyl, diphenylpropylamine derivatives , dextromor - 65 acid , malic acid , salicylic acid , fumaric acid , lactic acid , amide , piritramide , dextropropoxyphene, bezitramide , citric acid , glutamic acid , and/ or aspartic acid . In another methadone , benzomorphan derivatives, pentazocine, embodiment, the suitable tapentadol salt may include : tapen US 10 , 182 , 992 B2 27 28 tadol hydrochloride , tapentadol L - ( - ) - camphorsulfonate, TABLE 3 tapentadol dibenzoyl- ( L )- tartrate , tapentadol dibenzoyl -( D ) tartrate , tapentadol malate , or tapentadol maleate . Exemplary Soft Capsule Shell Composition The term “ pharmaceutically acceptable salts ” of an active Component Percent weight ( % ) drug substance includes alkali metal salts such as, for 5 Gelatin 43 example , sodium or potassium salts , alkaline earth metal Glycerol 20 salts such as , for example , calcium and magnesium salts, and Titanium dioxide ( optional ) 0 . 7 salts with organic or inorganic acid such as, for example , Coloring agent (optional ) 0 . 1 hydrochloric acid , hydrobromic acid , nitric acid , sulfuric Water 36 . 2 acid , phosphoric acid , citric acid , formic acid , maleic acid , TOTAL 100 % succinic acid , tartaric acid , methanesulphonic acid , toluene Final pH - 4 - 7 sulphonic acid etc . In another embodiment, pharmaceuti Ratio total plasticizer to gelatin 20 : 43 (0 .46 : 1 ) cally acceptable opioid salts can comprise sulphate salts , Water content in dried soft capsule shell : 8 - 15 % hydrochloride salts , and bitartrate salts . In another embodiment, the active pharmaceutical ingre 15 In one embodiment described herein , the soft capsule dient may be in any of its crystalline , polymorphous, semi comprises about 43 % of at least one film - forming polymer ; crystalline , amorphous or polyamorphous forms or mixtures about 20 % of at least one plasticizer; about 36 % water ; thereof. optionally , about 0 .7 % titanium dioxide ; and optionally , The concentration of the active drug substance in the 20 about 0 . 1 % of at least one coloring agent. pharmaceutical composition for use according to the disclo In one embodiment, the weight percentage range of sure depends on the specific active drug substance , the film - forming polymer of the soft capsule described herein is disease to be treated , the condition of the patient, the age, about 35 % to about 45 % , including all integers within the and gender of the patient, etc . The above- mentioned active specified range . In one aspect , the film - forming polymer drug substances may be known active drug substances and 25 weight percentage is about 38 % . In another aspect , the a person skilled in the art will be able to find information as film - forming 1 polymer weight percentage is about 42 % . In to the dosage of each active drug substance and, accordingly , another aspect , the film - forming polymer weight percentage will know how to determine the amount of each active drug is about 44 % . substance in the pharmaceutical composition . In one embodiment, the weight percentage range of The active pharmaceutical ingredient may be a new 30 plasticizer is about 15 % to about 22 % , including all itera chemical entity for which the amount of information is tions of integers with the specified range . In one aspect , the limited . In such cases , the dosage has to be evaluated based plasticizer weight percentage is about 17 % . In another on available preclinical and /or clinical data . aspect , the plasticizer weight percentage is about 18 . 5 % . In In one embodiment described herein , the pharmaceutical another aspect , the plasticizer weight percentage is about composition comprises soft capsule shell comprising a 35 20 % . matrix comprising an active pharmaceutical ingredient. In one embodiment, the weight percentage ratio range of In one embodiment described herein , the soft capsule plasticizer to film - forming polymer is about 0 .33 : 1 to about shell has the composition of Table 2 , including all possible 0 . 56 : 1 , including all iterations of iterations of ratios with the iterations of the specified ranges that provide 100 % for the specified range . In one embodiment, the weight percentage total weight percentage, including or excluding the optional 40 ratio range of plasticizer to film - forming polymer is about colorings, flavorings, or excipients . 0 . 38 : 1 . In one embodiment, the weight percentage ratio range of plasticizer to film -forming polymer is about 0 .42 : 1 . TABLE 2 In one embodiment, the weight percentage ratio range of plasticizer to film - forming polymer is about 0 .46 : 1 . In one Exemplary soft gelatin capsule composition · 45 embodiment, the weight percentage ratio range of plasticizer Component Exemplary Component Weight Percentage ( % ) to film - forming polymer is about 0 .52 : 1 . In one aspect, soft capsules are made using a rotary die Film - forming polymer Gelatin 25 - 50 apparatus as described in U . S . Pat. Nos. 5 , 459 , 983 ; 5 , 146 , Plasticizer Glycerol 15 - 25 Solvent Water 20 - 40 730 ; and 6 ,482 , 516 , each of which are incorporated by Opacifier (optional ) Titanium dioxide 0 . 5 - 1 . 5 50 reference herein for such teachings . Coloring agent (optional ) Various 0 . 05 - 0 . 1 Another embodiment described herein includes a process ofmanufacturing soft capsules comprising the pharmaceu TOTAL 100 % tical composition as described herein . The process includes preparing a gel mass composition comprising a film - form Film - former polymers that are useful for creating soft 55 ing , water -soluble polymer, an appropriate plasticizer, and capsules as described herein are gelatin or hydroxypropyl- solvent; casting the gel mass into films or ribbons using methylcellulose (HPMC ) . In one aspect , the film - forming heat - controlled drums or surfaces , and manufacturing a soft polymer is gelatin . capsule comprising a matrix fill using rotary die technology. Plasticizers that are useful for creating soft capsules as The thickness of the films or ribbons that form the soft described herein are glycerol, sorbitol, polyethylene glycols , 60 capsule shell is from about 0 .010 inches ( ~ 0 . 254 mm ) to or combinations thereof. The weight ratio between the about 0 .050 inches ( ~ 21 .27 mm ), including all integers film - forming polymer, plasticizer , and solvent is adjusted so within the specified range . The shell thickness can be about that the gel mass is flowable and not too viscous, and can be 0 .010 inch ( 20 .254 mm ), about 0 .015 inch ( - 0 .381 mm ) , made into soft capsules using rotary die encapsulation about 0 . 02 in ( - 0 . 508 mm ), about 0 .03 in ( ~ 0 .762 mm ), methods . 65 about 0 . 04 in ( ~ 21. 02 mm ), or about 0 .05 in ( ~ 1 .27 mm ) . In In one embodiment, the enteric soft capsule shell has the one embodiment, the thickness is about 0 .02 inches ( ~ 0 . 508 exemplary composition shown in Table 3 . mm ) to about 0 .040 inches ( ~ 21 .02 mm ) . In one embodi US 10 , 182 , 992 B2 29 30 ment, the shell thickness is about 0 . 028 inches ( ~ 0 .711 mm ) . EUDRAGIT® RS 30 D ; EUDRAGIT® RS 12 . 5 ; In another embodiment, the shell thickness is about 0 .033 EUDRAGIT® NE 30 D ; EUDRAGIT® NE 40 D ; inches ( ~ 0 .838 mm ). In another embodiment, the shell EUDRAGIT® NM 30 D ; or other poly (meth )acrylate poly thickness is about 0 .038 inches ( ~ 0 . 965 mm ). mers. In one aspect, the enteric polymer is EUDRAGIT® L In one embodiment described herein , the soft capsule 5 100 , a methacrylic acid copolymer, Type A . Acid - insoluble shell described herein , encapsulates a matrix fill as described polymer specifications are detailed in the United States herein . In another embodiment described herein , the soft Pharmacopoeia and in various monographs. capsule shell and encapsulated matrix fill comprises a outer Plasticizers that are useful for creating enteric soft cap dimension from about 2 oval to about 30 oval including all sules as described herein are glycerol, sorbitol, polyethylene iterations of capsule size within the specified range ( e . g . , 2 10 glycol, citric acid , citric acid esters , such as tri - ethyl citrate , oval , 3 oval , 4 oval , 5 oval , 6 oval , 7 oval, 8 oval, 10 oval, or combinations thereof. The weight ratio between the 12 oval, 16 oval, 20 , or 30 oval) . In another embodiment film - forming polymer, the enteric acid -insoluble polymer , described herein , the soft capsule shell and encapsulated and plasticizer is adjusted so that the gel mass is flowable matrix fill comprises a outer dimension from about 2 round and not too viscous, and can bemade into soft capsules using to about 28 round including all iterations of capsule size 15 rotary die encapsulation methods. within the specified range ( e . g ., 2 round , 3 round , 4 round , In one embodiment, enteric soft capsule shell composi 5 round , 6 round , 7 round , 8 round , 10 round , 12 round , 16 tions can be made by dissolving the enteric acid - insoluble round , 20 round or 28 round ) . In another embodiment polymer in an aqueous solution of an alkali neutralizing described herein , the soft capsule shell and encapsulated agent such as ammonia , sodium hydroxide , potassium matrix fill comprises a outer dimension from about 2 oblong 20 hydroxide, or liquid amines such as tri- ethanol amine or ethylene diamine . The amount of alkali is adjusted to give a to about 22 oblong including all iterations of capsule size final pH value of the gel mass less than or equal to about pH within the specified range ( e . g . , 2 oblong, 3 oblong , 4 9 .0 . In one embodiment, the final pH does not exceed 8 . 5 . oblong, 5 oblong , 6 oblong , 7 oblong , 8 oblong , 10 oblong , The volatile alkali neutralizing agent, ammonia is preferred . 11 , oblong , 12 oblong , 14 oblong , 16 oblong , 20 oblong , or The film - forming polymer can then be combined with the 22 oblong ) . Dimension specifications of soft capsules and 25 plasticizer and solvent and then blended with the acid tablets are known to those skilled in the art . See Remington ' s insoluble gel to make a final homogeneous mix in a heat Essentials of Pharmaceutics , Pharmaceutical Press Publish controlled vessel and can be degassed by using vacuum . The ing Company, London , UK , 1st Edition , 2013, which is fugitive ammonia evaporates during degassing . Using the incorporated by reference herein for such teachings . foregoing process , the alkali concentrations do not require In another embodiment described herein , the pharmaceu - 30 an additional step such as heating or neutralizing with acid tical composition comprises an enteric soft capsule shell in order to neutralize the gel mass . comprising a matrix fill comprising an active pharmaceutical In another embodiment described herein , an enteric soft ingredient. capsule shell can be made by using an aqueous dispersion of Enteric soft capsules are described in International Patent the acid - insoluble polymer by adding alkaline materials such Application Publication No . WO 2004 / 030658 ; U . S . Patent 35 as ammonium , sodium , or potassium hydroxides , other Application Publication No. US 2006 / 0165778 ; and U . S . alkalis , or a combination thereof that will cause the enteric Pat. No. 8 ,685 ,445 , each of which is incorporated by refer - acid - insoluble polymer to dissolve. The plasticizer- wetted , ence herein for such teachings . The enteric soft capsule shell film - forming polymer can then be mixed with the solution of may comprise one or more film forming polymers , one or the acid - insoluble polymer. In one embodiment, enteric astia 40 acid - insoluble polymers in the form of salts of the above more enteric acid -insoluble polymers, one or more plasti - 40 mentioneda bases or alkalis can be dissolved directly in water cizers , one or more alkali- neutralizing agents , one or more and mixed with the plasticizer- wetted , film - forming poly solvents , optionally one or more colorants , and optionally mer. one or more flavorings or other conventionally accepted In one embodiment, an enteric soft capsule shell has the pharmaceutical excipients or additives . composition of Table 4 , including all possible iterations of Film - former polymers that are useful for creating enteric 45 the specified ranges that provide 100 % for the total weight soft capsules are gelatin or hydroxypropylmethylcellulose percentage, including or excluding the optional, excipients , ( HPMC ) . In one aspect of the enteric soft capsule shell opacifiers, colorants , and flavorings. described herein , the film - forming polymer is gelatin . Examples of enteric , acid - insoluble polymers are acrylic TABLE 4 and methacrylate acid copolymers , cellulose acetate phtha - 50 late (CAP ) , cellulose acetate butyrate , hydroxypropylmeth Exemplary Enteric Soft Capsule Shell Composition ylcellulose phthalate ( HPMCP ) , algenic acid salts such as Composition sodium or potassium alginate , or shellac . Poly (methacylic Component Exemplary Component Range ( % ) acid - co -methyl methacrylate ) anionic copolymers based on Film - forming polymer Gelatin 20 - 36 methacrylic acid and methyl methacrylate are particularly 55 Enteric , acid insoluble Methacrylic Acid 8 - 20 stable and are preferred in some embodiments . Poly (meth ) polymer Copolymer acrylates (methacrylic acid copolymer ), available under the Plasticizer Glycerol , Triethyl 15 - 22 trade name EUDRAGIT® (Evonik Industries AG , Essen , citrate Germany ) , are provided as powder or aqueous dispersions. Alkali neutralizing NH ,OH ( 30 % ) , 1 -5 agents NaOH In one aspect, the methacrylic acid copolymer can be 60 Solvent Water 20 - 40 EUDRAGIT® L 30 D - 55 ; EUDRAGIT® L 100 - 55 ; Opacifier Titanium Dioxide 1 - 7 . 5 EUDRAGIT® L 100 ; EUDRAGIT® L 12 . 5 ; EUDRAGIT® Colorant (optional ) Various 0 . 05 - 1 S 100 ; EUDRAGIT? S 12 . 5 ; EUDRAGIT® FS 30 D ; Flavoring ( optional ) Various 0 .05 - 2 EUDRAGIT® E 100 ; EUDRAGIT® E 12 . 5 ; EUDRAGIT® Excipients (optional ) Various 1 - 5 E PO ; EUDRAGIT® RL 100 ; EUDRAGIT® RL PO ; 65 EUDRAGIT® RL 30 D ; EUDRAGIT® RL 12 . 5 ; In one embodiment, an enteric soft capsule shell com EUDRAGIT® RS 100 ; EUDRAGIT® RS PO ; prises a composition of about 30 % film forming polymer; US 10 , 182 ,992 B2 31 32 about 10 % enteric , acid insoluble polymer ; about 20 % In one embodiment, the weight ratio range of total plas plasticizer ; about 1 % alkali neutralizing agent; and about ticizer to total polymer ( film forming and enteric acid 37 % solvent. insoluble polymer ) is about 18 :45 to about 20 : 40 In one embodiment, the weight percentage range of total ( i . e . , 24 . 40 - 0 . 5 ) , including all iterations of ratios within the polymer content ( i. e ., film forming polymer and enteric 5 specified range . In one aspect, the weight ratio range of total acid - insoluble polymer ) of the enteric soft capsule described plasticizer to total polymer is about 18 :45 ( 20 .40 ) . In another aspect, the weight ratio range of total plasticizer to herein is about 30 % to about 45 % , including all integers total polymer is about 19 :40 ( - 0 .475 ). In another aspect, the within the specified range . In one aspect, the total polymer weight ratio range of total plasticizer to total polymer is weight percentage is about 40 % . In another aspect, the total about 20 : 40 ( - 0 . 5 ) . In another aspect, the weight ratio range polymer weight percentage is about 42 % . In another aspect, 10 of total plasticizer to total polymer is about 19 . 3 : 40 . 4 the total polymer weight percentage is about 45 % . In another ( - 0 .477 ) . aspect , the total polymer weight percentage is about 38 % . In one embodiment, the solvent comprises about 20 % to In one embodiment, the weight percentage range of total about 40 % of the enteric soft capsule composition , including plasticizer is about 15 % to about 22 % , including all itera all integers within the specified range . In one embodiment, tions of integers with the specified range . In one aspect, the 15 |the solvent is water . The quantity ofwater in the composition total plasticizer weight percentage is about 19 % . In another varies depending on the quantities of the other ingredients. aspect , the total plasticizer weight percentage is about For example , the quantity of opacifier, colorant, flavoring , or 17 . 7 % . In another aspect, the total plasticizer weight per other excipients can change the percentage of water present centage is about 18 . 9 % . In another aspect , the total plasti the composition . In one embodiment, the weight percentage cizer weight percentage is about 19 .3 % . 2020 of water is as much as suffices to bring the total weight In one embodiment , the alkali neutralizing - agent is percentage to 100 % ( i . e . , quantum sufficiat ; q . s . ) . In another ammonia (ammonium hydroxide ; 30 % w / v ) that is added to embodiment, the water comprises about 20 % , about 25 % , comprise a weight percentage of about 1 to about 5 % of the about 30 % , about 35 % , or about 40 % of the enteric soft total enteric soft capsule composition . In one aspect, 30 % capsule composition . In another embodiment, water com w / v ammonia is added to comprise a weight percentage of 25 prises about 35 % to about 40 % of the enteric soft capsule about 2 % . In another aspect, 30 % w / v ammonia is added to a weight percentage of about 1 . 7 % . In one aspect, ammonia composition . In one embodiment, water comprises about is added to provide a final pH of about 9 in the enteric soft 37 % of the composition . capsule composition . In another aspect, ammonia is added to In one embodiment, the final moisture ( water ) content of provide a final pH of about 8 . 5 in the enteric soft capsule 30 the enteric soft capsule is from about 8 % to about 15 % , composition . In another aspect, after the capsules are filled including all integers within the specified range . In another and dried , the ammonia concentration is substantially embodiment, the moisture content is about 8 % to about reduced , owing to the fugitive nature of the volatile alkali. 12 % , including all integers within the specified range . In one In one aspect, practically all of the ammonia is evaporated aspect, the final moisture content is about 8 % . In one aspect , except for ammonium ions comprising salts with other 35 thefin final moisture content is about 9 % . In one aspect, the moieties in the composition . final moisture content is about 10 % . In one aspect , the final In one embodiment, the weight ratio range of film forming moisture content is about 11 % . In another aspect, the final polymer to enteric acid insoluble polymer ( film forming: moisture content is about 12 % . enteric ) is about 25 : 75 ( - 0 . 33 ) to about 40 :60 ( - 0 .67 ) ( i. e ., In one embodiment, the enteric soft capsule shell has the ~ 0 . 33 - 0 .67 ) , including all iterations of ratios within the 40 exemplarycm composition shown in Table 5 . specified range . In one aspect, the ratio of film forming polymer to enteric acid insoluble polymer is about 30 : 70 TABLE 5 ( 20 .43 ) . In another aspect, the ratio of film forming polymer Exemplary Enteric Soft Capsule Shell Composition to enteric acid insoluble polymer is about 28 : 72 ( - 0 .38 ) . In one embodiment, the weight ratio of total plasticizer to 45 Component Percent weight film forming polymer is about 20 : 40 to 21 : 30 ( i. e ., - 4 . 5 - 0 . 7 ) , Gelatin 29 . 2 including all iterations of ratios within the specified range . Methacrylic Acid Copolymer (EUDRAGIT® L 100 ) 11 . 2 Glycerol 18 . 0 In one aspect , the weight ratio of total plasticizer to film Triethyl citrate 1 . 3 forming polymer is about 20 : 40 ( 24. 5 ) . In another aspect, Ammonium hydroxide 1 . 7 the weight ratio of total plasticizer to film forming polymer 50 Titanium dioxide 1 . 5 is about 21: 30 ( ~ 4 .7 ) . In another aspect , the weight ratio of Water 37 . 1 total plasticizer to film forming polymer is about 19 : 29 TOTAL 100 % ( - 0 .65 ) . In another aspect, the weight ratio of total plastic Final pH - 4 - 9 cizer to film forming polymer is about 19 . 3 : 29 . 2 (20 .66 ) . Total polymer % weight (gelatin + enteric ) 40 . 4 % In one embodiment, the weight ratio of total plasticizer to 55 Gelatin % wt of total polymer (gelatin + enteric ) 72. 4 % Enteric % wt of total polymer ( gelatin + enteric ) 27 . 6 % enteric acid insoluble polymer is about 1 : 1 to about 2 : 1 Ratio of Enteric to Gelatin 11. 2 : 29 . 2 ( 0 . 38 ) ( ~ 1 - 2 ) , including all iterations of ratios within the specified Total plasticizer % weight ( glycerol + triethyl citrate ) 19 . 3 % range . In one aspect , the weight ratio of total plasticizer to Ratio of total plasticizer to total polymer 19 . 3 : 40 . 4 ( 0 . 48 ) enteric acid insoluble polymer is about 11 : 10 ( ~ 1 . 1 ) . In Ratio total plasticizer to gelatin 19 . 3 : 29 . 2 (0 .66 ) another aspect, the weight ratio of total plasticizer to enteric 60 Ratio total plasticizer to enteric 19 . 3 : 11 . 2 ( 1 . 73 ) acid insoluble polymer is about 14 : 10 ( ~ 1 . 4 ) . In another Water content in dried enteric soft capsule : 8 - 15 % aspect , the weight ratio of total plasticizer to enteric acid insoluble polymer is about 17 : 10 ( ~ 1 . 7 ) . In another aspect , In one embodiment, the enteric soft capsule shell com the weight ratio of total plasticizer to enteric acid insoluble prises about 30 % gelatin ; about 10 % poly (methyl ) acrylate polymer is about 20 : 10 ( ~ 2 ). In another aspect, the weight 65 copolymer ; about 18 % glycerol ; about 1 % triethyl citrate ; ratio of total plasticizer to enteric acid insoluble polymer is about 1 . 5 % ammonia ; about 37 % water ; and about 1 . 5 % about 19 . 3 : 11 . 2 ( ~ 21 .73 ) . titanium dioxide . US 10 , 182 ,992 B2 33 34 One embodiment described herein provides an enteric all iterations of capsule size within the specified range ( e . g ., acid - insoluble polymer dispersed within the film - forming 2 round , 3 round, 4 round , 5 round , 6 round , 7 round, 8 polymer gelmass that provides the total soft gel composition round , 10 round , 12 round , 16 round , 20 round or 28 round ). with enteric acid - insoluble properties, at relatively low con In another embodiment described herein , the enteric soft centrations of the enteric acid - insoluble polymer ( e . g ., from 5 capsule shell and encapsulated matrix fill comprises a outer about 8 % to about 20 % of the total wet gel mass composi - dimension from about 2 oblong to about 22 oblong including tion ) and without the need of excessive amounts of alkali , all iterations of capsule size within the specified range ( e. g ., thus avoiding denaturation or degradation of the film - form - 2 oblong , 3 oblong , 4 oblong, 5 oblong , 6 oblong , 7 oblong , ing polymer that can weaken the integrity of the enteric soft 8 oblong , 10 oblong , 11, oblong , 12 oblong , 14 oblong , 16 capsule shell. 10 oblong , 20 oblong, or 22 oblong ). Dimension specifications In some embodiments , the enteric soft capsule shell does of soft capsules and tablets are known to those skilled in the not dissolve or disintegrate in acids, such as 0 . 1N hydro - art . See Remington ' s Essentials of Pharmaceutics, Pharma chloric acid or simulated gastric fluid (ca . pH 1 .2 ), despite ceutical Press Publishing Company, London , UK , 1st Edi the fact that the majority of the shell ingredients ( i .e . , greater tion , 2013 , which is incorporated by reference herein for than 50 % normally dissolve in , or are miscible with , acids . 15 such teachings . In some embodiments , the enteric soft capsules made using The pharmaceutical composition described herein can the compositions described herein remain intact in hydro - comprise a soft capsule comprising a matrix fill that is chloric acid or simulated gastric fluid for at least two hours liquid , semi- solid , or solid . Capsules prepared as described and the capsules readily release their contents upon shifting herein can contain a hydrophobic solution or suspension , the pH of the solution to ca. 6 . 8 , such as that of simulated 20 such as vegetable oils or shortening, or waxes , or combina intestinal fluid . In one aspect, the enteric soft capsule is t ions thereof . The matrix can be formulated to prevent resistant to dissolution at about pH 1 . 2 for at least about 2 interaction with the capsule shell components and release hours . In another aspect, the enteric soft capsule begins the pharmaceutical composition at a specified rate . dissolution at pH of about 6 . 8 within about 10 min . One embodiment described herein , is a pharmaceutical In another embodiment, the final enteric capsule compo - 25 composition comprising a matrix fill formulation compris sition provides films of increased strength without substan - ing any of the formulations shown in the Tables or Examples tially compromising film elasticity . Moreover, films made described herein . Any of the components of the formulations from the enteric soft capsule compositions as described shown in the Tables or Examples can be increased , herein can be sealed at normal temperature range typically decreased , combined , recombined , switched , or removed to used for making traditional soft gel capsules . In one aspect, 30 provide for a formulation comprising about 100 % by enteric soft capsules are made using a rotary die apparatus weight. as described in U . S . Pat. Nos . 5 ,459 ,983 ; 5 , 146 ,730 ; and In another embodiment, the abuse deterrent pharmaceu 6 ,482 ,516 , each of which are incorporated by reference tical composition described herein provides a dosage of an herein for such teachings. active pharmaceutical ingredient described herein for Another embodiment described herein includes a process 35 administration to a subject. The dosage form can be admin of manufacturing enteric soft capsules comprising the phar - istered , for example , to a subject, or a subject in need maceutical composition as described herein . The process thereof. In one aspect, the subject is a mammal, or a mammal includes preparing a gel mass composition comprising a in need thereof. In one aspect, the subject is a human , or film - forming , water - soluble polymer and an enteric acid human in need thereof. In one aspect, the human or human insoluble polymer and mixing with appropriate plasticizers 40 in need thereof is a medical patient. In one aspect, the human and solvent; casting the gel mass into films or ribbons using subject is a child ( - 0 - 9 years old ) or an adolescent ( - 10 - 17 heat - controlled drums or surfaces ; and manufacturing a soft years old ) . In one aspect , the subject is from 0 to 9 years of capsule comprising a matrix fill using rotary die technology . age . In another aspect , the human subject is from 10 to 17 The thickness of the films or ribbons that form the enteric years of age . In another aspect , the human subject is over 17 capsule shell is from about 0 .010 inches ( ~ 0 . 254 mm ) to 45 years of age . In another aspect, the human subject is an adult about 0 .050 inches ( ~ 21. 27 mm ), including all integers (218 years of age ). within the specified range . The shell thickness can be about I n one embodiment, the dosage may be administered to a 0 .010 inch (20 .254 mm ) , about 0 .015 inch ( - 0 . 381 mm ) , human in need of management of moderate to severe about 0 . 02 in (- 0 .508 mm ), about 0 .03 in ( - 0 .762 mm ) , chronic pain and neuropathic pain associated with diabetic about 0 .04 in ( - 21. 02 mm ) , or about 0 .05 in ( ~ 21 .27 mm ) . 50 peripheral neuropathy (DPN ) , when a continuous, persistent In one embodiment, the thickness is about 0 .02 inches ( around - the - clock ) opioid analgesic is needed for an ( ~ 0 .508 mm ) to about 0 .040 inches ( ~ 21. 02 mm ). In one extended period of time. embodiment, the shell thickness is about 0 .028 inches The dosage form can be administered , for example , 1x , ( + 0 .711 mm ) . In another embodiment, the shell thickness is 2x , 3x , 4x , 5x , 6x , or even more times per day . One or more about 0 .033 inches ( ~ 0 . 838 mm ). In another embodiment , 55 dosage form can be administered , for example, for 1, 2 , 3 , the shell thickness is about 0 .038 inches ( ~ 0 . 965 mm ) . 4 , 5 , 6 , 7 days , or even longer. One or more dosage forms can In one embodiment described herein , the enteric soft be administered , for example , for 1 , 2 , 3 , 4 weeks , or even capsule shell described herein , encapsulates a matrix fill as longer. One or more dosage forms can be administered , for described herein . In another embodiment described herein , example , for 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 months , 1 year, the enteric soft capsule shell and encapsulated matrix fill 60 2 , years, 3 years, 4 years, 5 years, over 5 years , a decade , comprises a outer dimension from about 2 oval to about 30 multiple decades , or even longer. One or more dosage forms oval including all iterations of capsule size within the can be administered at a regular interval until the subject or specified range ( e . g ., 2 oval, 3 oval, 4 oval, 5 oval, 6 oval , subject in need thereof, does not require treatment, prophy 7 oval, 8 oval , 10 oval, 12 oval, 16 oval , 20 , or 30 oval ) . In laxis , or amelioration of any disease or condition including another embodiment described herein , the enteric soft cap - 65 but not limited to , pain . sule shell and encapsulated matrix fill comprises a outer In one embodiment, the pharmaceutical composition dimension from about 2 round to about 28 round including described herein is administered in multiple dosages simul US 10 , 182 , 992 B2 35 36 taneously . For example , two or more identical dosages are 28 % . In one aspect , the drug load is about 32 % . In one administered at one time. In another embodiment, two or aspect, the drug load is about 44 % . In one embodiment , the more different dosages are administered at one time. Such drug load is about 48 % . dual or different simultaneous doses can be used to provide In one embodiment, the active pharmaceutical ingredient an effective amount of the pharmaceutical composition to a 5 is tapentadol, or a salt, ether, ester , variant, or derivative subject in need thereof. thereof . In one embodiment, the active pharmaceutical In one embodiment , the abuse deterrent oral composition ingredient is tapentadol hydrochloride ( tapentadol. HCI ) . See described herein , comprises an active pharmaceutical ingre Prescribing Information for Nucynta® 09 / 2013 and dient in an amount of about 10 mg, about 20 mg , about 30 Nucynta® ER 04 / 2014 ( Jansen Pharmaceuticals Inc . ; avail mg, about 40 mg, about 50 mg , about 60 mg, about 70 mg, 10 able at: www .nucynta . com ) , which are incorporated by about 80 mg , about 90 mg , about 100 mg , about 110 mg, reference herein for such teachings . about 120 mg, about 130 mg, about 140 mg, about 150 mg, In one aspect, the dose of tapentadol is 20 mg. In another about 160 mg, about 170 mg, about 180 mg, about 190 mg, aspect, the dose of tapentadol is 25 mg. In another aspect, the about 200 mg, about 210 mg, about 220 mg, about 230 mg , dose of tapentadol is 50 mg. In another aspect, the dose of about 240 mg, about 250 mg, about 260 mg, about 270 mg , is 100 mg. In another aspect , the dose of tapentadol is 150 about 280 mg, about 290 mg, about 300 mg, about 310 mg, mg. In another aspect, the dose of tapentadol is 200 mg. In about 320 mg, about 330 mg, about 340 mg, about 350 mg, another aspect, the dose of tapentadol is 250 mg. In another about 360 mg, about 370 mg, about 380 mg, about 390 mg, aspect, the dose of tapentadol is 300 mg. In another aspect, about 400 mg, about 410 mg, about 420 mg, about 430 mg, 20 the dose of tapentadol is 350 mg. In another aspect , the dose about 440 mg, about 450 mg, about 460 mg, about 470 mg, of tapentadol is 400 mg. In another aspect , the dose of about 480 mg, about 490 mg, about 500 mg, or even more. tapentadol is 450 mg. In another aspect, the dose of tapen In another embodiment, the abuse deterrent oral compo tadol is 500 mg. sition described herein , comprises an active pharmaceutical In another embodiment, the total dosage of tapentadol ingredient in the range of about 20 mg to about 250 mg , 25 administered in a 24 -hour period is about 20 mg to about 600 about 30 mg to about 250 mg, about 40 mg to about 250 mg, mg per 24 -hour period . In one aspect , the total dosage of about 50 mg to about 250 mg, about 60 mg to about 250 mg , tapentadol administered in a 24 -hour period is about 50 mg to about 250 mg per 24 -hour period . The dosage can contain about 70 mg to about 250 mg, about 80 mg to about 250 mg, a total amount of tapentadol effective for treatment, ame about 90 mg to about 250 mg, about 100 mg to abouthout 250 30 lioration , prophylaxis , or reducing the onset of or symptoms mg, about 110 mg to about 250 mg, about 120 mg to about of pain . 250 mg, about 130 mg to about 250 mg, about 140 mg to In one embodiment, the recommended dosage is based about 250 mg, about 150 mg to about 250 mg, about 160 mg upon the condition of the subject in need thereof. The subject to about 250 mg, about 170 mg to about 250 mg, about 180 can comprise a human or mammal in need thereof. In one mg to about 250 mg, about 190 mg to about 250 memg , about 3835 aspect, the need is defined as a painful condition or percep 200 mg to about 250 mg, about 210 mg to about 250 mg, tion of pain . In one embodiment, the perception of pain is about 220 mg to about 250 mg, about 230 mg to about 250 described as a numerical scale . In one aspect , this numerical mg, about 240 mg to about 250 mg; about 250 mg to about scale indicates O for no pain , 1 - 3 suggestive of mild pain ; 500 mg, about 260 mg to about 500 mg, about 270 mg to annoying or nagging pain that does not affect the activities about 500 mg, about 280 mg to about 500 mg, about 290 mg 40 of daily life , 4 -6 for moderate pain that interferes signifi to about 500 mg, about 300 mg to about 500 mg, about 310 cantly with the activities of daily life, and 7 - 10 for severe mg to about 500 mg, about 320 mg to about 500 mg, about pain that is disabling for which the activities of daily life are 330 mg to about 500 mg, about 340 mg to about 500 mg, not possible . Another aspect described herein comprises about 350 mg to about 500 mg, about 360 mg to about 500 orally administering a maximal dosage of about 50 mg to mg, about 370 mg to about 500 mg, about 380 mg to about 45 about 100 mg of tapentadol every 24 hours for humans or 500 mg, about 390 mg to about 500 mg, about 400 mg to mammals with a pain of 1 - 3 . Another aspect described about 500 mg, about 410 mg to about 500 mg, about 420 mg herein comprises orally administering a maximal dosage of to about 500 mg, about 430 mg to about 500 mg, about 440 about 100 mg to about 400 mg of tapentadol every 24 hours mg to about 500 mg , about 450 mg to about 500 mg, about for humans or mammals with a pain of 4 - 6 . Another aspect 460 mg to about 500 mg , about 470 mg to about 500 mg, 50 described herein comprises orally administering a maximal about 480 mg to about 500 mg, or about 490 mg to about 500 dosage of 400 mg to about 600 mg of tapentadol every 24 mg. hours for humans or mammals with a pain of 7 - 10 . In one In one embodiment described herein , the abuse deterrent aspect, the level of pain is assessed by observing the human oral composition described herein may comprise an active or mammal . pharmaceutical ingredient load ( e . g . , drug load ) of about 1 % 55 Another aspect described herein comprises orally admin to about 90 % , including each integer within the specified istering an additional dosage of about 50 mg to about 100 range . In one embodiment, the drug load can comprise about mg of tapentadol after 1 hour from the administration of a 1 % , about 2 % , about 2. 5 % , about 5 % , about 10 % , about first dose if pain of any type is not ameliorated in the human 15 % , about 20 % , about 25 % , about 30 % , about 35 % , about or mammal in need thereof. Another aspect described herein 40 % , about 45 % , about 50 % , about 55 % , about 60 % , about 60 comprises orally administering additional dosages of about 65 % , about 70 % , about 75 % , about 80 % , about 85 % , about 50 mg to about 100 mg of tapentadol every 4 to 6 hours if 90 % , or even higher. In one aspect, the drug load is about pain of any type is not ameliorated in the human or mammal 20 % . In one aspect, the drug load is about 25 % . In one in need thereof. aspect , the drug load is about 30 % . In one aspect , the drug Another aspect described herein comprises orally admin load is about 35 % . In one aspect , the drug load is about 40 % . 65 istering a delayed release dosage of about 50 mg of an active In one aspect, the drug load is about 50 % . In one aspect , the pharmaceutical ingredient every 12 hours for a human or drug load is about 60 % . In one aspect , the drug load is about mammal with a pain of 1- 3 . Another aspect described herein US 10 , 182 ,992 B2 37 38 comprises orally administering a delayed release dosage of 50 % after about 13 hours , about 50 % after about 14 hours , about 150 mg of tapentadol every 12 hours for a human or about 50 % after about 15 hours , about 50 % after about 16 mammal with a pain of 4 - 6 . Another aspect described herein hours , about 50 % after about 17 hours, or about 50 % after comprises orally administering a delayed release dosage of about 18 hours. 5 . In another embodiment , the abuse deterrent pharmaceu about 250 mg of tapentadol every 12 hours for a human or 5 tical composition as described herein has an in vitro disso mammal with a pain of 7 - 10 . Another aspect described lution rate at pH 2 .4 of about 50 % after about 240 to about herein comprises increasing the delayed release dosage of 480 minutes . In another aspect, the in vitro dissolution rate tapentadol by 50 mg increments every 24 hours to a maximal at pH 2 . 4 is about 50 % after about 300 to about 480 minutes . daily dosage of600 mg if pain of any type is not ameliorated In another aspect, the in vitro dissolution rate at pH 2 . 4 is in the human or mammal in need thereof. Another aspect about 50 % after about 320 to about 420 minutes . In another described herein comprises decreasing the dosage of tapen aspect, the in vitro dissolution rate at pH 2 . 4 is about 50 % tadol as needed every 24 hours if pain of any type has after about 300 to about 400 minutes. In another aspect , the decreased or has been ameliorated in the human or mammal in vitro dissolution rate at pH 2 . 4 is about 50 % after about in need thereof. 320 minutes . In another aspect , the in vitro dissolution rate Additional pain that the abuse deterrent pharmaceutical at pH 2 . 4 is about 50 % after about 340 minutes . In another composition described herein may be useful for the treat aspect, the in vitro dissolution rate at pH 2 . 4 is about 50 % ment of pain stemming from including , but not limited to , after about 360 minutes. In another aspect, the in vitro chronic arthritis , osteoarthritis , rheumatoid arthritis , acute dissolution rate at pH 2 . 4 is about 50 % after about 380 tendonitis , bursitis , headaches , migraines, chronic neuropa - minutes. In another aspect, the in vitro dissolution rate at pH thies , shingles, premenstrual symptoms, sports injuries , 2 . 4 is about 50 % after about 400 minutes . In another aspect , malignancy , radiculopathy, sciatica / sciatic pain , sarcoidosis , ththe in vitro dissolution rate at pH 2 . 4 is about 50 % after necrobiosis , lipoidica , or granuloma annulare. about 420 minutes . In another aspect, the in vitro dissolution Another embodiment described herein is an abuse deter rate at pH 2 . 4 is about 50 % after about 440 minutes . In rent pharmaceutical composition as described herein for another aspect , the in vitro dissolution rate at PH 2 . 4 is about administration to a subject having pain , comprising a thera - - - 50 % after about 480 minutes . In another aspect , the in vitro peutically effective amount of one or more active pharma - dissolution rate at pH 2 . 4 is about 50 % after about 500 ceutical ingredients , wherein the subject achieves a reduc minutes. tion of pain relative to baseline without substantially Another embodiment described herein is an abuse deter experiencing one or more side effects including, but not rent pharmaceutical composition as described herein com limited to , headache , vertigo , somnolence , nausea , consti - prising a therapeutically effective amount of one or more pation , vomiting , xerostomia , fatigue , pruritus , eructation , active pharmaceutical ingredients for administration to a heartburn , abdominal discomfort, or loss of appetite . subject having pain , exhibiting an vitro dissolution rate at Another embodiment described herein is an abuse deter - pH 2 . 4 , of about 50 % after about 240 to about 480 minutes . rent pharmaceutical composition as described herein for Another embodiment described herein is an abuse deter administration to a subject having pain , comprising a thera - * rent pharmaceutical composition as described herein com peutically effective amount of one or more active pharma- prising a therapeutically effective amount of one or more ceutical ingredients exhibiting an in vitro dissolution rate at active pharmaceutical ingredients for administration to a PH 2 . 4 comprising about 20 % to about 80 % dissolution after subject having pain , exhibiting an in vitro dissolution rate at about 60 minutes to about 720 minutes including each pH 2 .4 , as described herein in any one of Drawings 4 - 9 . integer within the specified ranges of dissolution and time . Another embodiment described herein is a method for In another aspect , the in vitro dissolution rate at pH 2 . 4 is orally administering a dosage form of an abuse deterrent about 50 % after about 280 minutes to about 720 minutes, pharmaceutical composition comprising an active pharma including each integer with in the specified time range . In ceutical ingredient described herein for the treatment, ame one aspect , the in vitro dissolution rate at pH 2 . 4 about 50 % lioration , prophylaxis , or reducing the onset of or symptoms after about 60 min , about 50 % after about 70 min , about 45 of pain . 50 % after about 30 min , about 50 % after about 90 min , Another embodiment described herein is a method for about 50 % after about 120 min , about 50 % after about 150 treating , retarding the progression of, delaying the onset of , min , about 50 % after about 180 min , about 50 % after about prophylaxis of , amelioration of, or reducing the symptoms 210 min , about 50 % after about 240 min , about 50 % after of pain , comprising administering to a subject in need about 300 min , is about 50 % after about 330 min , about 50 % - thereof an oral pharmaceutical composition as described after about 360 min , is about 50 % after about 390 min , about herein comprising a therapeutically effective amount of one 50 % after about 420 min , about 50 % after about 480 min , ormore active pharmaceutical ingredients for administration about 50 % after about 540 min , about 50 % after about 600 to a subject having pain , wherein the pharmaceutical com min , about 50 % after about 660 min , about 50 % after about position exhibits about a 50 % in vitro dissolution rate at pH 720 min , about 50 % after about 780 min , about 50 % after 2. 4 , comprising about 40 % to about 60 % dissolution after about 840 min , about 50 % after about 900 min , about 50 % about 240 minutes to about 480 minutes . after about 960 min , or about 50 % after 1080 min . Another embodiment described herein is a method for In another embodiment, the abuse deterrent pharmaceu - treating , retarding the progression of, delaying the onset of, tical composition as described herein has an in vitro disso - prophylaxis of, amelioration of, or reducing the symptoms lution rate at pH 2 . 4 of about 50 % after about 1 hour, about of pain , comprising administering to a subject in need 50 % after about 2 hours , about 50 % after about 3 hours , thereof an oral pharmaceutical composition as described about 50 % after about 4 hours , about 50 % after about 5 herein comprising a therapeutically effective amount of one hours , about 50 % after about 6 hours , about 50 % after about or more active pharmaceutical ingredients for administration 7 hours , about 50 % after about 8 hours, about 50 % after to a subject having pain , exhibiting an in vitro dissolution about 9 hours , about 50 % after about 10 hours , about 50 % rate at pH 2 . 4 , as described herein in any one of Drawings after about 11 hours , about 50 % after about 12 hours, about 4 - 9 . US 10 , 182 , 992 B2 39 40 Another embodiment described herein is a method for treating, retarding the progression of, prophylaxis of, delay TABLE 6 -continued ing the onset of, ameliorating , or reducing the symptoms of Exemplary Abuse Deterrent Controlled pain comprising the administration of a therapeutically Release Matrix Composition effective amount of one or more abuse deterrent pharma Ingredient Percentage ( % ) ceutical compositions described herein to a subject with Carbopol ® 971 A 3 . 1 pain , wherein the administration is sufficient to achieve a Meglumine 2 . 4 reduction pain relative to baseline in the subject without EUDRAGIT ® EPO 4 . 61 substantially inducing one or more side effects including , but Tapentadol HCI 29 . 2 not limited to , headache , vertigo , somnolence , nausea , con - 10 stipation , vomiting , xerostomia , fatigue , pruritus , eructation , TOTAL 100 heartburn , abdominal discomfort , or loss of appetite . In another embodiment , the abuse deterrent pharmaceu tical composition described herein is contained and dis Example 2 pensed from a tamper evident packaging . The term “ tamper 15 evident” or “ tamper resistant” refers to a packaging of any further abuse deterrent matrices as described herein were kind that readily displays or allows for an individual to prepared using the compositions shown in Table 7 and Table observe any physical interference or manipulation of said 8 . The compositions were prepared and encapsulated in a packaging . The tamper evident packaging provides reason - soft capsule shell. able evidence to consumers that tampering has occurred . 20 The tamper evident packaging additionally contains appro TABLE 7 priate labelling statements describing the features and evi dences of the tamper evident packaging . In one aspect, the Exemplary Abuse Deterrent Controlled tamper evident packaging comprises: bottles, film wrappers , Release Matrix Composition blister or strip packs, bubble packs, heat shrink bands or 25 Ingredients Mass ( g ) Percentage ( % ) wrappers , foil, paper , or plastic pouches , container mouth Soybean Oil 32 . 0 46 . 82 inner seals, tape seals , breakable caps, sealed metal tubes or Aerosil ® 0 . 9 1 . 32 plastic heat - sealed tubes , sealed cartons, aerosol containers , Gelucire ® 43 /01 2 . 0 2 . 93 cans including metal and composite materials , or any com Bee ' s wax 2 .0 2 .93 bination thereof. The packaging may also contain appropri- 30 HPMC 4M 4 . 0 5 .85 Kollidon ® 90 F 4 . 5 6 . 58 ate instructions for prescribing , instructions for use , warn Carbopol ® 971 A 1 . 25 1 . 83 ings, or other appropriate information . EUDRAGIT ® EPO 3 . 5 5 . 12 It will be readily apparent to one of ordinary skill in the Tapentadol HCI 18 . 2 26 .63 relevant arts that suitable modifications and adaptations to the compositions , methods , and applications described 35 TOTAL 68 . 35 100 .00 herein can be made without departing from the scope of any embodiments or aspects thereof. The compositions and methods provided are exemplary and are not intended to TABLE 8 limit the scope of the specified embodiments . All of the various embodiments , aspects , and options disclosed herein 40 Exemplary Abuse Deterrent Controlled can be combined in all variations. The scope of the com Release Matrix Composition positions, formulations, methods, and processes described Ingredients Mass ( g ) Percentage ( % ) herein include all actual or potential combinations of Soybean Oil 50 .53 50 .53 embodiments , aspects , options, examples, and preferences Aerosil ® 0 . 89 0 . 89 herein described . All patents and publications cited herein 45 Gelucire ® 43 / 01 2 . 04 2 . 04 are incorporated by reference herein for the specific teach Bee ' s wax 1 . 77 1 . 77 ings thereof . HPMC 4M 6 . 45 6 . 45 PEO (N10 ; 100 ,000 ) 9 .68 9 . 68 Carbopol ® 971 A 0 .89 0 . 89 EXAMPLES EUDRAGIT ® EPO 2 . 94 2 .94 50 Tapentadol HCl 24 . 87 24 . 87 Example 1 TOTAL 100 100 .00 Abuse deterrent matrices as described herein were pre pared using the composition shown in Table 6 . The compo sition was prepared according to the method of Example 3 55 Example 3 and encapsulated in a soft capsule shell . An exemplary abuse deterrent controlled release matrix TABLE 6 composition as described herein comprises a liquid lipo philic vehicle , a semisolid lipophilic vehicle , a non - ionic Exemplary Abuse Deterrent Controlled 60 surfactant, a hygroscopic polymer, one or more pH buffering Release Matrix Composition agents , one or more hydrophilic polymers , and an active Ingredient Percentage ( % ) pharmaceutical ingredient. The abuse deterrent matrices Olive Oil 38 . 3 described herein comprise one or more semi- solid lipophilic Gelucire ® 43 /01 11 . 3 vehicles, one or more hygroscopic polymers , one or more Pluronic ® F127 6 . 5 65 hydrophilic polymers , a suspension agent, and an active Kollidon ® 90 F 4 . 7 pharmaceutical ingredient. The process for preparing an abuse deterrent controlled release matrix includes preparing US 10 , 182 ,992 B2 41 42 a composition of one or more lipid or lipophilic vehicles , from the matrix was assessed at 9 time points over a time one or more hygroscopic polymers , one or more hydrophilic period of 800 minutes as shown in FIG . 4 . polymers , optionally one or more non - ionic surfactant, Next, the abuse deterrent controlled release oral compo optionally one or more pH buffering agent( s ) , optionally one sition described herein was shown to not immediately or more suspension agents , and one or more active pharmaa - s 5 release tapentadol when placed in alcohol as shown in FIG . 5 . These studies were performed by suspending the abuse ceutical ingredient by heating said mixture from between deterrent oral composition described herein was suspended 45° C . and 80° C . with stirring or agitation in a suitable in a 900 mL solution of 40 % ethanol and 60 % 0 . 1N HC1and vessel . The process further comprises decreasing the matrix agitated with paddles at 100 RPM at 37° C . for 120 minutes . mixture temperature to between about 25° C . and about 45° The percentage of tapentadol released from the matrix was C . followed by a homogenization step , wherein the matrix is assessed at 9 - time points over a time period of 120 minutes . homogenized to be substantially flowable . Prior to encap - Further testing showed that the abuse deterrent oral com sulation in a soft gel capsule described herein , the matrix is position described herein retained its controlled release deaerated at a temperature of about 25° C . to about 45° C . properties after being stored at 40° C . at a relative humidity The process for manufacturing a soft capsule comprising (RH ) for up to three months as shown in FIG . 6 . Samples 15 were taken after 1 month , 2 months, and 3 months of time the pharmaceutical composition as described herein includes and the percentage of tapentadol released from the matrix preparing a gel mass for a soft capsule ; casting the gel mass was assessed at 9 - time points over a time period of 800 into films or ribbons using heat- controlled drums or sur minutes . faces ; and manufacturing a soft capsule comprising a matrix As shown in FIG . 7 , the abuse deterrent oral composition fill using rotary die technology . During this process, the 20 described herein , did not release tapentadol immediately in abuse deterrent controlled release matrix is injected in to the ethanol after prolonged storage for up to 3 months at 40° C . lumen as the soft capsule is formed by rotary die encapsu at a RH of 75 % . The effects of long term storage of the abuse lation . The soft capsule can be a typical soft capsule (“ soft deterrent oral composition described herein on its suscepti bility to ethanol extraction was assessed by suspending the gel” ) or an enteric soft capsule . 25 abuse deterrent oral composition described herein , in a 900 Example 4 mL solution of 40 % ethanol and 60 % 0 . 1N HC1 followed by agitation with paddles at 100 RPM at 37° C . for 120 minutes . The abuse deterrent controlled release matrix composition The percentage of tapentadol released from the abuse deter shown in Table 6 , generated by themethods described herein rent controlled release matrix described herein was assessed and encapsulated in a soft gel capsule as described herein , 30 aat 9 - time points over a time period of 120 minutes . was tested on its resistance to physical tampering and its Example 5 stability in various conditions. The abuse deterrent controlled release oral composition The abuse deterrent controlled release matrix composi described herein , was further tested for its resistance to tions shown in Table 7 , generated by the methods described physical tampering by chewing / crushing , grating , grinding , 35 herein and encapsulated in a soft gel capsule as described and cutting . For chewing / crushing studies, the abuse deter - herein , were tested on their respective stability and disso rent oral composition described herein was placed in a lution kinetics . mortar and was crushed by using a pestle under ambient As shown in FIG . 8 , the abuse deterrent oral composition conditions . Physical observations after crushing were used of Table 7 retained its controlled release properties after to make conclusions about the chewability and physical 40 being stored at 30° C . at a relative humidity (RH ) of65 % or strength of the composition . For grating studies , the abuse at 40° C . at a relative humidity (RH ) of 75 % for up to two deterrent controlled release oral composition described weeks . Samples were taken at 0 weeks or at two weeks for herein was hand - grated across a common cheese grater the above noted conditions and the percentage of tapentadol under ambient conditions . For grinding studies, the abuse released from the matrix was assessed at 9 -time points over deterrent oral composition described herein was placed in a 45 a time period of 12 hours (720 min ) during agitation in coffee grinder under ambient conditions and ground . For phosphate buffer , pH 6 . 8 , at 37° C . with paddles at 100 cutting studies , the abuse deterrent controlled release oral RPM . composition described herein was cut with a knife or a lab cutter. These experiments were fully carried out as described Example 6 under ambient conditions (25° C . ) , heated conditions, 50 wherein the abuse deterrent oral composition described The abuse deterrent controlled release matrix composi herein was heated for two hours (40° C . ) , and refrigerated tions shown in Table 8 generated by the methods described conditions , wherein the abuse deterrent controlled release herein and encapsulated in a soft gel capsule as described oral composition described herein was frozen for two hours herein , were tested on their respective dissolution kinetics (0° C . ) . As shown in FIGS . 1 - 3 , the abuse deterrent oral 55 and abuse deterrence in ethanol . composition described herein , was resistant to being dis As shown in FIG . 9 , the abuse deterrent oral composition persed , dissolved , or extracted in the studies utilizing the of Table 8 retained its controlled release properties in a methods described above . dissolution buffer or an ethanol buffer. Samples were taken The abuse deterrent controlled release oral composition and the percentage of tapentadol released from the matrix described herein was subjected to a series of stability 60 was assessed over a time period of 12 hours (720 min ) in a experiments. In these experiments , the abuse deterrent con - solution of 40 % ethanol and 60 % 0 . 1N HC1, pH 2 . 4 , during trolled release oral composition described herein was cut in agitation with paddles at 100 RPM at 37° C . half with a razor blade . The first experiment was a non enzymatic dissolution study, wherein the abuse deterrent Example 7 controlled release oral composition described herein was 65 suspended in 900 mL of simulated intestinal fluid ( SIF ) at a Examples of abuse deterrent controlled release properties temperature of 37° C . The percentage of tapentadol released of the abuse deterrent controlled release matrix described US 10 , 182 , 992 B2 43 44 herein to prevent tapentadol release in different solvents , TABLE 11 including water , coffee , vinegar , cola , milk , and isopropanol are shown in Table 9 . These tests were conducted by placing Tapentadol HCl Release in Ethanol Solutions the soft gel capsule containing the abuse deterrent controlled at 37° C . , rpm ( n = 3 ) . release matrix in a transparent beaker with 100 mL of the 5 Percent Released ( % ) 250 mg soft gel capsule indicated solvent and shaking the beaker at 75 RPM and 37° C . for 2 hours . The percentage of tapentadol released was Ethanol ( % ) v /v 5 min 20 min 60 min 120 min assessed after 5, 20 , 60 , and 120 -minute time points . HPLC 0 % Ethanol 2 % 1 % 9 % 9 % 5 % Ethanol 0 % 0 % 2 % 6 % was used to detect the released tapentadol. 10 20 % Ethanol 0 % 0 % 1 % 3 % 40 % Ethanol 0 % 1 % 4 % TABLE 9 0 % Tapentadol•HCl Release in Solvents at 37° C . 75 rpm ( n = 3 ) Example 10 Percent Released ( % ) 250 mg soft gel capsule 15 Solvent 5 min 20 min 60 min 120 min Examples of abuse deterrent controlled release properties of the abuse deterrent controlled release matrix described Water 2 % 1 % 9 % 9 % herein to prevent tapentadol release in different concentra Coffee 0 % 0 % 16 % 21 % Vinegar 0 % 0 % 0 % 10 % tions of different solvents , including 95 % ethanol, methanol , Cola 0 % 0 % 0 % 21 % 20 acetone, ethyl acetate , paint thinner, mineral spirits , bleach , Milk of Magnesia 0 % 0 % 6 % 21 % 0 . 1N HC1, 0 . 1N acetic acid , 0 . 1N NaOH , and 0 . 1N NaHCO , Milk 0 % 1% 3 % 9 % are shown in Table 12 . These tests are conducted after Isopropanol (97 .7 % ) 0 % 0 % 0 % 0 % cutting the soft gel capsule and placing it in a transparent beaker with 100 mL of the indicated ethanol solution and shaking the beaker at 75 RPM and 37° C . for 2 hours . The percentage of tapentadol released is assessed after 5 , 20 , 60 , Example 8 and 120 -minute time points . Examples of abuse deterrent controlled release properties TABLE 12 of the abuse deterrent controlled release matrix described 30 herein to prevent tapentadol release in buffers of different pH Tapentadol•HCl Release in Solvents at 37° C . values are shown in Table 10 . These tests were conducted by Amount Released from 250 mg soft gel capsule placing the soft gel capsule containing the abuse deterrent Solvent 5 min 20 min 60 min 120 min controlled release matrix in a transparent beaker with 100 35z mL of the indicated pH solvent and shaking the beaker at 75 Ethanol , 95 % pass pass pass pass Methanol pass pass pass pass RPM and 37° C . for 2 hours . The percentage of tapentadol Isopropanol pass pass pass pass released was assessed after 5 , 20 , 60 , and 120 -minute time Acetone pass pass pass pass points . Ethyl acetate pass pass pass pass Paint Thinner pass pass pass pass 40 Mineral Spirits pass pass pass pass TABLE 10 Bleach (NaClO ) pass pass pass pass 0 . 1N HCI pass pass pass pass Tapentadol•HCl release in Different pH Values 0 . 1N acetic acid pass pass pass pass at 37° C ., 100 rpm ( n = 3 ) 0 . 1N NaOH pass pass pass pass 0 . 1N NaHCO3 pass pass pass pass Percent Released ( % ) 250 mg soft gel capsule 45 " pass ” indicates an insignificant amount is released . pH 5 min 20 min 60 min 120 min pH 1 0 % 0 % 3 % 6 % pH 4 0 % 0 % 2 % 6 % Example 11 pH 6 0 % 0 % 2 % 6 % pH 8 0 % 0 % 5 % 50 Additional exemplary gel mass compositions useful for pH 12 0 % 0 % 4 % producing abuse deterrent controlled release soft gel cap sules as described herein are shown in Tables 13 - 16 . Com position components are set forth by weight percentage of the total weight of the gel mass composition . Such compo Example 9 55 sitions may be encapsulated in soft capsules or enteric soft capsules . Examples of abuse deterrent controlled release properties of the abuse deterrent controlled release matrix described TABLE 13 herein to prevent tapentadol release indifferent concentra - 60 Exemplary Abuse Deterrent Controlled tions of ethanol are shown in Table 11 . These tests were Release Matrix Compositions conducted by placing the soft gel capsule containing the Weight Percentage ( % ) abuse deterrent controlled release matrix in a transparent beaker with 100 mL of the indicated ethanol solution and Ingredient EX 1 EX2 EX3 EX 4 EX 5 EX 6 shaking the beaker at 75 RPM and 37° C . for 2 hours . The 65 Total Lipophilic 58 . 0 92 . 0 38. 0 50 . 0 31. 0 47 . 0 percentage of tapentadol released was assessed after 5 , 20 , Vehicle ( TLV ) 60 , and 120 -minute time points . US 10 , 182 , 992 B2 45 46 TABLE 13 - continued TABLE 15 Exemplary Abuse Deterrent Controlled y Abuse Deterrent Controlled Release Matrix Compositions Release Matrix Compositions Non - ionic Surfactant 15. 0 5 3 . 7 .0 6 .0 1 .0 11. 0 5 Weight Percentage ( % ) (NIS ) Hygroscopic Polymer 1. 0 1. 0 10 .0 4. 7 5. 0 9. 0 Ingredient EX 1 EX2 EX3 EX 4 EX 5 EX 6 (HP ) Total Hydrophilic 42 . 0 60 . 0 31. 0 36 . 0 25 . 0 35 . 0 Polymer ( THP ) 12. 0 2. 0 7. 3 7. 7 10. 0 20 .0 GelucireOlive Oil ® 16 . 0 32 . 0 7 . 0 14 . 0 6 . 0 12 . 0 pH Buffering Agent 4 .0 0 .5 2. 8 2. 4 3. 0 8. 0 10 Poloxamer 15 . 0 3 . 5 7 .0 6 . 0 1 . 0 11 . 0 (BA ) Polyvinylpyrrolidone 1 . 0 10 10 4 . 7 5 . 0 9 . 0 Active Pharmaceut . 10 . 0 1. 0 35 . 0 29 . 2 50 . 0 5 . 0 Carbopol ® 971 A 5 .0 1 . 0 3 . 0 3. 1 4 . 0 8 . 0 Meglumine 4 .0 0 . 5 2 . 8 2 . 4 3 . 0 8 . 0 Ingredient ( API) EUDRAGIT ® EPO 7 . 0 1 . 0 4 . 3 4 .6 6 .0 12 . 0 TOTAL 100 100 100 100 100 100 Active Pharmaceut . 10 . 0 1 . 0 35 . 0 29 . 2 50 . 0 5 . 0 Components and Relational Ratios 15 Ingredient (API ) TOTAL 100 100 100 100 100 100 EX 1 EX 2 EX 3 EX 4 EX 5 EX 6 Hydrophilic Matrix 32 .0 7. 0 27 .0 20. 8 19. 0 48. 0 Comp . ( HMC ) TABLE 16 Total Matrix Mass 90 . 0 99 . 0 65 . 0 70 . 8 50 . 0 95 . 0 20 Ratio Liquid to 2 . 6 1 . 9 4 . 4 2 . 6 4 . 2 2 . 9 Exemplary Abuse Deterrent Controlled Semisolid Lipid Release Matrix Compositions Ratio NIS to HP 15 . 0 3 . 5 0 .7 1 . 3 0 . 2 1 . 2 Ratio of Anionic 0 . 7 1 . 0 0 . 7 0 . 7 0 . 7 Weight Percentage ( % ) Pol. : Cationic Pol . Ratio of TLV to HP + 3 . 6 20 . 4 2. 2 NIS 4. 7 5. 2 2. 4 25 Ingredient EX 1 EX 2 EX3 EX 4 EX 5 EX 6 Ratio of BA to THP 0 .3 0 .3 0 .4 0 .3 0 .3 0 .4 Soybean Oil 53 . 0 55 . 0 31 . 0 36 . 0 25 . 0 28 . 0 Ratio of TLV to HMC 1 . 8 13. 1 1 . 4 2 . 4 1 . 6 1. 0 Gelucire ® 10 . 0 5 . 0 3 . 0 9 . 0 1 . 0 2 . 0 Ratio of API to HMC 0 . 3 0 . 1 1 . 3 1 . 4 0 . 1 Bee ' s wax 4 . 5 5 . 0 10 . 0 5 .0 3 . 0 2 . 0 Ratio of API to TLV 0 . 2 0 .01 0 . 9 0 .6 1 .6 0 . 1 Polyvinylpyrrolidone 6 .0 1 . 0 10 . 0 5 .0 - Ratio API to Total 0. 1 0 .01 0 .5 0. 4 1. 0 0 . 1 30 HPMC 4M 4 . 0 7 . 0 3 . 0 8 . 0 — 8 . 0 Matrix Polyethylene oxide 15 . 0 5 . 0 6 . 5 10 . 0 Carbopol ® 971 A 4 . 5 2 . 0 3 . 0 1. 0 3 .0 1 . 0 Aerosil ® 2 . 0 5 . 0 1 . 0 2 . 2 0 . 5 0 . 6 EUDRAGIT ® EPO 6 . 0 4 . 0 4 . 0 4 . 6 6 . 0 3 . 4 TABLE 14 Active Pharmaceut. 10 . 0 1 . 0 35 . 0 29 . 2 50 . 0 45 . 0 35 Exemplary Abuse Deterrent Controlled Ingredient ( API) Release Matrix Compositions TOTAL 100 100 100 100 100 100 Weight Percentage ( % ) What is claimed is : Ingredient EX 1 EX 2 EX 3 EX 4 EX 5 EX 6 40 1 . An abuse deterrent tamper resistant oral pharmaceutical Total Lipophilic 67 .5 65. 0 44 . 0 50 . 0 29. 0 32 . 0 dosage form comprising a soft capsule shell encapsulating a Vehicle ( TLV ) tamper resistant matrix comprising : Hygroscopic Polymer 10. 0 23. 0 13 .0 13. 0 11. 5 18. 0 (HP ) (a ) about 45 % to about 52 % by mass soybean oil ; Total Hydrophilic ( b ) about 1 .8 % to about 4 % by mass polyethylene glycol Polymer ( THP ) 10. 5 6. 0 7. 0 5. 6 9 .0 4. 4 45 glyceride ester ; Stabilizing agent 2. 0 5. 0 1. 0 2. 2 0. 5 0. 6 (c ) about 1. 8 % to about 4 % by mass bee 's wax ; (SA ) ( d ) about 5 % to about 15 % by mass of a polyethylene Active Pharmaceut . 10 . 0 1. 0 35 .0 29 . 2 50. 0 45. 0 oxide having a molecular weight of about 100 ,000 ; Ingredient ( API) ( e ) about 0 .5 % to about 4 % by mass carboxypolymeth TOTAL 100 100 100 100 100 100 50 ylene ; ( f) about 2 % to about 8 % by mass dimethylaminoethyl Components and Relational Ratios methacrylate copolymer; EX 1 EX 2 EX 3 EX 4 EX 5 EX 6 ( g ) about 0 . 5 % to about 5 % by mass fumed silica ; and ( h ) about 5 % to about 30 % by mass tapentadol hydro Hydrophilic Matrix 20 .5 29 .0 20. 0 18 .6 20. 5 22. 4 55 Comp. (HMC ) chloride . Total Matrix Mass 90 . 0 99 . 0 65 . 0 70 . 8 50 . 0 55 . 0 2 . An abuse deterrent oral pharmaceutical dosage form Ratio Liquid to 3 . 7 5 .5 2 . 4 2 . 6 6 . 3 7 .0 comprising a soft capsule shell encapsulating a tamper Semisolid Lipid resistant matrix comprising : Ratio of Anionic ( a ) about 45 % to about 52 % by mass soybean oil ; Pol. :Cationic Pol. 0. 8 0. 5 0 .8 0. 2 0. 5 0 .3 Ratio of TLV to HP 6 . 8 2. 8 3 .4 3 . 8 2 . 5 1. 8 60 (b ) about 1 .5 % to about 5 % by mass polyethylene glycol Ratio of SA to THP 5 . 3 1 . 2 7 . 0 2 .6 18 .0 7 . 3 glyceride ester ; Ratio of TLV to HMC 3 ??????. 3 2 . 2 2. 2 2 . 7 1. 4 1. 4 ( c ) about 1 . 8 % to about 4 % by mass bee ' s wax ; Ratio of API to HMC 0 . 03 1 . 8 1 . 6 2. 0 Ratio of API to TLV 0 . 02 0 . 8 0. 6 1. 7 1. 4 (d ) about 2 % to about 8 % by mass polyvinylpyrrolidone Ratio API to Total 0 . 1 0 .01 0 . 5 0 . 4 1 .0 0 . 8 90 ; Matrix ( e ) about 0 . 5 % to about 4 % by mass carbomer polymer ; ( f ) about 2 % to about 8 % by mass dimethylaminoethyl methacrylate copolymer; US 10 , 182 , 992 B2 47 48 ( g ) about 0 . 5 % to about 5 % by mass fumed silica ; and (h ) about 5 % to about 30 % by mass tapentadol hydro chloride . 3 . The composition of claim 1 , wherein the soft capsule shell comprises: 5 ( a ) about 25 -50 % by mass of at least one film - forming polymer ; ( b ) about 15 -25 % by mass of at least one plasticizer; and (c ) about 20 - 40 % by mass of a solvent. 4 . The composition of claim 2 , wherein the soft capsule 10 shell comprises: ( a ) about 25 -50 % by mass of at least one film - forming polymer ; ( b ) about 15 - 25 % by mass of at least one plasticizer; and ( c ) about 20 -40 % by mass of a solvent. 15 * * * * *