US 20160038592A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0038592 A1 Yum et al. (43) Pub. Date: Feb. 11, 2016

(54) COMPOSITIONS WITH A RHEOLOGICAL Publication Classification MODIFIER TO REDUCE DISSOLUTION VARIABILITY (51) Int. Cl. A647/02 (2006.01) (71) Applicant: DURECT CORPORATION, 469/48 (2006.01) Cupertino, CA (US) A647/4 (2006.01) A647/38 (2006.01) (72) Inventors: Su Il Yum, Los Altos, CA (US); Wendy A613 L/485 (2006.01) Chao, San Jose, CA (US); Huey-Ching Su, San Jose, CA (US); Roger Fu, A647/26 (2006.01) Saratoga, CA (US); Michael S. (52) U.S. Cl. Zamloot, Austin, TX (US); Karl Bratin, CPC ...... A61K 47/02 (2013.01); A61 K3I/485 Groton, CT (US); Ravi M. Shanker, (2013.01); A61 K47/26 (2013.01); A61K47/14 Groton, CT (US) (2013.01); A61 K47/38 (2013.01); A61 K9/485 (2013.01); A61 K9/4816 (2013.01) (21) Appl. No.: 14/776,585 57 ABSTRACT (22) PCT Filed: Mar. 14, 2014 (57) The present disclosure provides compositions (e.g., extended (86). PCT No.: PCT/US1.4/29607 release compositions) which exhibit a desirable pharmacoki S371 (c)(1), netic profile of an active agent while providing reduced dis (2) Date: Sep. 14, 2015 Solution sample variability, e.g., in the form of reduced inter capsule variability and/or a reduction in storage-time Related U.S. Application Data dependent change in mean release of the active agent from the (60) Provisional application No. 61/801,110, filed on Mar. composition. Related methods of making and administering 15, 2013. the disclosed compositions are also provided.

Process Flow Chart for Oxycodone Compounded Mass

Charge SAIB to the Ross PVM-40 Mixer Heated SAB For at (Set TCU 50°C) least 4 hr (G) 55-65°C Charge Triacetin to the Ross PVM-40 Mixer (Set TCU 50°C) Charge PM/BHT + IPMrinsing (Set TCU 50°C) Disperser Mixing at 950-1050 Mag EMBHT rpm Anchor speed at 20 rpm Out Induct SiO2 Product Temperature at 57-63°C Emulsifier set at 2500 rpm Following induction, mix at least 15 min

Vacuum mixing 30 min at NLT-14 H Transfer CAB (screened w20 mesh) into the Ross Mixer Emulsifier setting 2800-3200 rpm induction rate <20 min Anchor speed 30 rpm Disperser speed 1750 rpm Induct API at an approximate rate of 20 min into the Ross Mixer Emulsifier setting 2800-3200 rpm Keep emulsifier engaged for additional 2 min

Transfer HEC (screened wi2O mesh) into the Ross Mixer Emulsifier setting 2800-3200 rpm Induction rate-20min Keep emulsifier engaged for additional 2 min Anchor speed 30 rpm Disperser speed 1750 rpm Followed by a 2 hr CAB solvation while Emulsifier setting at 0 rpm Patent Application Publication Feb. 11, 2016 Sheet 1 of 52 US 2016/0038592 A1

-A-T=O -e-T=3M -e-T=6M -HT=9M -O-T=12M --T=15M -e-T=18M --T=22M

4 O

2 O

O 5 1O 15 2O 25 Time (Hour) FIG. 1A

M = MOnths L.S. = Label strength Patent Application Publication Feb. 11, 2016 Sheet 2 of 52 US 2016/0038592 A1

Panel A Formulation A (40 mg) Mean Results

2

O 5 10 15 2O 25 Time (Hour) -e-Initial -(-1M/40 C -a- 3M/25 C - A - 3M/3O C - A - 3M/40 C -N- 6M125C -- 6M/3O C -- 6M/40 C -- 12M/25 C

Panel B Formulation 1 (40 mg) Mean Results

6/30

O 5 10 15 20 25 Time (Hour) -e-Initial -(-1M/40 C -a- 3M/25 C - A 3M/3O C - A 3M/40 C -NH 6M/25 C -- 6M/3O C -- 6M/40 C -- 12M/25 C. FIG. 1B Patent Application Publication Feb. 11, 2016 Sheet 3 of 52 US 2016/0038592 A1

Comparative Plots of Gelatin (Lot #1) and HPMC (Lot #2) Using Type 3 Dissolution

-O-Test 1, Lot #1

-- Test 1, Lot #2

- A Test 2, Lot #1

O 5 10 15 20 25 30 Time (hr) FIG. 1C Patent Application Publication Feb. 11, 2016 Sheet 4 of 52 US 2016/0038592 A1

Variation of Gelatin and HPMC Lots Using Type 3 Dissolution

-K)- Test 1, Lot #1 N -- Test 1, Lot #2 Od \\ - A - Test 2, Lot #1 )V O Test 2, Lot #2

O 5 1O 15 20 25 3O Time (hr) FIG. 1D Patent Application Publication Feb. 11, 2016 Sheet 5 of 52 US 2016/0038592 A1

Process Flow Chart for Oxycodone Compounded Mass

Charge SAIB to the Ross PVM-40 Mixer Heated SAB FOr at (Set TCU 50°C) least 4 hr (G) 55-65°C Charge Triacetin to the Ross PVM-40 Mixer (Set TCU 50°C) Charge PM/BHT + IPMrinsing (Set TCU 50°C) Disperser Mixing at 950-1050 Make IPM/BHT rpm Anchor speed at 20 rpm SOlution Induct SiO2 Product Temperature at 57-63°C Emulsifier set at 2500 rpm Following induction, mix at least 15 min Vacuum mixing 30 min at NLT-14 HC

Transfer CAB (Screened w20 mesh) into the Ross Mixer Emulsifier setting 2800-3200 rpm induction rate <20 min Anchor speed 30 rpm Disperser speed 1750 rpm Induct API at an approximate rate of 20 min into the ROSS Mixer Emulsifier setting 2800-3200 rpm Keep emulsifier engaged for additional 2 min

Transfer HEC (screened wi20 mesh) into the Ross Mixer Emulsifier setting 2800-3200 rpm induction rate-20min Keep emulsifier engaged for additional 2 min Anchor speed 30 rpm Disperser speed 1750 rpm Followed by a 2 hr CAB solvation while Emulsifier setting at 0 rpm

FIG. 2 Patent Application Publication Feb. 11, 2016 Sheet 6 of 52 US 2016/0038592 A1

Process Flow Chart for Encapsulation

Set up LIQFIL Super 80 Encapsulator

Hopper temp 60°C Connect ROSS Mixer Block temp 62°C w/cdischarge valve Heated Once the hopper temp reach to 50°C transfer line to 50C turn the impeller to 15 rpm

PrOCeSS: NOZZe: 1.25 mm Speed: 40,000-80,000 Hopper Temp: 58-82°C Black temp: 62°C

Fill Target weight +5% Sample 28 capsules every Load size #4 Capsules (white opaque 30 min and check individual cap w"KP" black ink weight and physicals

Use Ethanol 108 Proof, USP To Seal the capsules body and cap Sample 10 capsules every Sealer speed 20,000/hr 30 min and Weigh and sort final product check individual Sealing

Set up LEMS30 Capsule Sealer Dump Temp: 42C

FIG. 2 (Cont.) Patent Application Publication Feb. 11, 2016 Sheet 7 of 52 US 2016/0038592 A1

-ie- Ref. Form. A - A - Formulation 1 -e- Formulation 2 -- Formulation 3 -(- SOUtion

0 5 10 15 20 25 30 35' 40 45 Time (hr) FIG. 3 Patent Application Publication Feb. 11, 2016 Sheet 8 of 52 US 2016/0038592 A1

Ref. Form. A, 40 mg Formulation 4 Formulation 5 Formulation 6 Formulation 7 Formulation 5

Nominal Time Post Dose (hours) FIG. 4 Patent Application Publication Feb. 11, 2016 Sheet 9 of 52 US 2016/0038592 A1

-O- Ref. Form. A -H FOrmulation 8 -(- FOrmulation 9

Time (hours)

FIG. 5 Patent Application Publication Feb. 11, 2016 Sheet 10 of 52 US 2016/0038592 A1

Panel A (Reference A - 15% IPM) Type 2 Dissolution 12O

100 -o- Capsule 1 8O -- Capsule 2 60 -a- Capsule 3 40 -- Capsule 4 2O O O 10 2O Time (hr) Panel B (Formulation 10 M 8% IPM) Type 2 Dissolution 12O 100 -o- Capsule 1 8O -- Capsule 2 60 -a- Capsule 3 40 -- Capsule 4 2O O O 10 2O Time (hr) Panel C (Formulation 11, 0% IPM) Type 2 Dissolution 120

100 8O -o- Capsule 1 -- Capsule 2 60 -a- Capsule 3 40 -- Capsule 4 2O O O 10 2O Time (hr) FIG. 6 Patent Application Publication Feb. 11, 2016 Sheet 11 of 52 US 2016/0038592 A1

Panel A (Reference Ar 2% SiO2) O c 120 TVoeyp 2 Dissolution CD St 100 -o- Capsule 1 2 80 -- Capsule 2 SS? 6O -a- Capsule 3 S 40 -- Capsule 4 20

O O O 10 2O 30 Time (hr) Panel B (Formulation 12 - 1% SiO2) 12O Type 2 Dissolution 1OO 8O -o- Capsule 1 6 O -- Capsule 2 -a- Capsule 3 -- Capsule 4

O 10 2O 3O Time (hr) Panel C (Formulation 13, 0% SiO2) O 120 Type 2 Dissolution

100 Y O) 8O -o- Capsule 1 60 -- Capsule 2 o 40 -a- Capsule 3 -- Capsule 4 20 0 O O 10 2O 3O Time (hr) FIG. 7 Patent Application Publication Feb. 11, 2016 Sheet 12 of 52 US 2016/0038592 A1

Panel A Type 2 Dissolution (Effect of IPM)

O 1 2 O - (- Ref. A s 1 O O (15% IPM) : -- Formulation 1 O g 8O (8% IPM) a 60 O - A FOrmulation 11 SS (0% IPM) S 40 E 2O O O 10 2O 30 Time (hr)

Panel B Type 2 Dissolution (Effect of Cab-O-Sil)

120 S; -K). Ref. A 100 (2%SiO2) E. 8O -- FOrmulation 12 o (1%SiO2) g 60 -- FOrmulation 13 (0%SiO2) 2 40

E 20 8 O O 1 O 2O 30 Time (hr) FIG. 8 Patent Application Publication Feb. 11, 2016 Sheet 13 of 52 US 2016/0038592 A1

Effect of SiO2 on Oxycodone Release Profile

O 5 10 15 2O 25 Time (hours)

-O FOrm. 1 -- Form. 14 -0- Form. 15

FIG. 9 Patent Application Publication Feb. 11, 2016 Sheet 14 of 52 US 2016/0038592 A1

Panel A

Formulation 1 1.9% SiO2

Panel B Formulation 14 2.85% SiO,

Formulation 15 3.79% SiO,

Patent Application Publication Feb. 11, 2016 Sheet 15 of 52 US 2016/0038592 A1

Complex Viscosity Profiles 1OOO

v

1 O O

-O- Formulation 1 -O Formulation 14 A Formulation 15

1 1O 1OO 1000 Angular Frequency (11S)

FIG 11 Patent Application Publication Feb. 11, 2016 Sheet 16 of 52 US 2016/0038592 A1

Formulation 1

Time (hours)

-o-t-O -- t-1M/25C -0- t-1M/40C

FIG. 12 Patent Application Publication Feb. 11, 2016 Sheet 17 of 52 US 2016/0038592 A1

Panel A

Formulation 1 (t=0)

Y O)

2 S O 5 1O 15 20 25 SS Hours

Panel B Formulation 1 (t=1 month, 25°C)

O 5 10 15 20 25 Hours

Panel C

FOrmulation 1 (t=1 month, 40°C) Patent Application Publication Feb. 11, 2016 Sheet 18 of 52 US 2016/0038592 A1

Formulation 14 (2.85% SiO2) t=1 month, 25°C

A.# t-1 month, 40°C

O 5 10 15 2O 25 Time (hours)

-0-t-O -- t-1M/25C -0- t1M/40C

FIG. 14 Patent Application Publication Feb. 11, 2016 Sheet 19 of 52 US 2016/0038592 A1

Panel A Formulation 14 (2.85% SiO2) (T=0)

1

6 O

O 5 10 15 20 25 Hours Panel B

Formulation 14 (2.85% SiO2) (T=1 month, 25°C)

O 5 10 15 20 25

Panel C Formulation 14 (2.85% SiO2) (T=1 month, 40°C)

6 O

O 5 10 15 20 25 Hours FIG 15 Patent Application Publication Feb. 11, 2016 Sheet 20 of 52 US 2016/0038592 A1

Formulation 15 (3.79% SiO2)

O 5 10 15 2O 25 Time (hours)

-o- t-O -- t-1M/25C -0- t1M/40C

FIG. 16 Patent Application Publication Feb. 11, 2016 Sheet 21 of 52 US 2016/0038592 A1

Panel A Formulation 15 (3.79% SiO2) (t=0)

O 5 10 15 20 25 Hours Panel B Formulation 15 (3.79% SiO2) (t=1 month, 25°C) -0-1

O 5 10 15 20 25 Hours Panel C

Formulation 15 (3.79% SiO2) (t=1 month, 40°C)

6 O

O 5 10 15 20 25 Hours FIG. 17 Patent Application Publication Feb. 11, 2016 Sheet 22 of 52 US 2016/0038592 A1

FOrmulation 16 7 I /41 2 N FOrmulation 18

O 5 10 15 2O 25 Time (hours)

-o- FOrmulation 16 -- Formulation 17 -0- FOrmulation 18

FIG. 18 Patent Application Publication Feb. 11, 2016 Sheet 23 of 52 US 2016/0038592 A1

Panel A Formulation 16

15 Hours

Panel B Formulation 17 -0-1 c 100 --2 g 80 -a-3 5 60 g 40 -be-4 20 E O --5 O 5 1O 15 20 25 O -O-6 SS Hours Panel C

Formulation 18 Patent Application Publication Feb. 11, 2016 Sheet 24 of 52 US 2016/0038592 A1

Formulation 16 (1.9% SiO2)

2 t=1 month (40°C)

O 5 10 15 2O 25 Time (hours)

-o-t-O -- t-1M125C -0- t-1M/40C

FIG. 20 Patent Application Publication Feb. 11, 2016 Sheet 25 of 52 US 2016/0038592 A1

Panel A Formulation 16 (1.9% SiO2) t-0

3. s is: g SSS O 5 10 15 20 25 Hours

Panel B Formulation 16 (1.9% SiO2) t=1 month, 25°C -o-1 it 3 6: g SS ? O 5 10 15 20 25 Hours

Panel C Formulation 16 (1.9%. SiO2) -0-1

100 t=1 month, 40°C O Sc 3 8 f 39 S ? O 5 1O 15 20 25 Patent Application Publication Feb. 11, 2016 Sheet 26 of 52 US 2016/0038592 A1

Formulation 17 (2.85%. SiO2) -0- t-O --t=1M125C -C-t=1M/40C

1 O O 8 O 25:1 \ t=1 month (40°C) 426 OOO 7,11,..., O O 5 10 15 2O 25 Time (hours) FIG. 22 Patent Application Publication Feb. 11, 2016 Sheet 27 of 52 US 2016/0038592 A1

Panel A Formulation 17 (2.85% SiO2) t-0 -0-1 1 -D-2 -A-3 -- 4 s --5 2 -O-6 O 5 10 15 20 25 HOurS

Panel B Formulation 17 (2.85% SiO2) t=1 month, 25°C 1

O 20 O O 5 10 15 20 25 Hours

Panel C Formulation 17 (2.85% SiO2)

t=1 month, 40°C Patent Application Publication Feb. 11, 2016 Sheet 28 of 52 US 2016/0038592 A1

Formulation 18 (3.79% SiO2) -0-t-O -Hit-1M/25C -C)-t=1M/40C

1. \41.Y month (40°C) O

Y O 5 10 15 2O 25 Time (hours)

FIG. 24 Patent Application Publication Feb. 11, 2016 Sheet 29 of 52 US 2016/0038592 A1

Panel A Formulation 18 (3.79% SiO2) t-0 g; it 3 6: g SSS O 5 10 15 20 25 Hours

Panel B Formulation 18 (3.79% SiO2) t=1 month, 25 °C -o-1 g 100 80 is 60 o 40 Os S 2O O O 5 10 15 20 25 Hours

Panel C Formulation 18 (3.79% SiO2)

t=1 month, 40 °C -0-1 de R 8 E. g SS O 5 10 15 20 25 Patent Application Publication Feb. 11, 2016 Sheet 30 of 52 US 2016/0038592 A1

Formulations with SiO, Level (5 mg API)

-0- Form. 5 (1.9% SiO2) -S- Form. 19 (2.4% SiO2) -(- Form. 20 (3.4% SiO2) -e- Form. 7 (3.9% SiO2) -(e- Form. 9 (2.9% SiO2)

Form. 9 (2.9% SiO2)

)

O 5 10 15 2O 25 Time (hours) FIG. 26 Patent Application Publication Feb. 11, 2016 Sheet 31 of 52 US 2016/0038592 A1

Sample Variation for 5 mg Oxycodone Formulations with increasing SiO,

Panel A Panel B ; Formulation 5 Formulation 19 3 (1.9% SiO2) (2.4% SiO2) dis Z 100 asS 6080 g 40 2 20 O s O 5 10 15 20 25 E O 5 10 15 20 25 Hours 3 Hours S. SS SS Panel C Panel D C C i Formulation 9 Formulation 20 (~2.9% SiO2) (3.4% SiO2) Y 100 Z 100 g 8O g 8O 60 S 60 S. 40 S. 40 20 20 O O 8 O 5 10 15 20 25 E O 5 1 O 15 20 25 3 Hours 3 Hours SS SS

Panel E Formulation 7 (3.9% SiO2) g100 ge a 80 w Ed 60 EZO 40 S. 5, 20 a O O 5 10 15 20 25 FIG. 27 Hours Patent Application Publication Feb. 11, 2016 Sheet 32 of 52 US 2016/0038592 A1

Formulations with SiO, Level (40 mg API)

-- Form. 5 (1.9% SiO2)2 -$- Form. 19 (2.4% SiO2)2 -(- Form. 20 (3.4% SiO2) -()- Form. 7 (3.9% SiO2) -(e- Form. 9 (2.9% SiO2)

Form. 7 (3.9% SiO2)

Form. 19 (2.4% SiO2) 6 O Form. 9 (2.9% SiO2) 4 O Form. 5 (1.9% SiO2) 2 O

O 5 10 15 2O 25 Time (hours) FIG. 28 Patent Application Publication Feb. 11, 2016 Sheet 33 of 52 US 2016/0038592 A1

Sample Variation for 40 mg Oxycodone Formulations with increasing SiO,

Panel A Panel B

Formulation 5 Formulation 19 (~1.9% SiO2) (~2.4% SiO2)

O O 5 10 15 20 25 O 5 10 15 20 25 Hours Hours

Panel C Panel D

Formulation 9 Formulation 20

(~2.9% SiO2) (~3.4% SiO2)

O O 5 10 15 20 25 O 5 10 15 20 25 Hours Hours

Panel E Formulation 7 g100 (-3.9% SiO2) Ais 80 EdV c. 60 On2 40 S. E 20 a O O 5 10 15 20 25 FIG. 29 Hours Patent Application Publication Feb. 11, 2016 Sheet 34 of 52 US 2016/0038592 A1

Temperature Sweep of Blending Formulations

Ref. Formulation A (with BHT) Formulation 5 o A. Formulation 7 Formulation 20 : Formulation 9 g Ref. Formulation B x 100 CD Formulation 19

5 50

ASA assa AAAAAA%.1% 2O 30 40 50 60 7O 80 Temperature (C) FIG. 30 Patent Application Publication Feb. 11, 2016 Sheet 35 of 52 US 2016/0038592 A1

Temperature Sweep of Blending Formulations 35 Ref. Formulation A (with BHT) 30 t Formulation 5 25 YS Formulation 19 Ref. Formulation B 0. FOrmulation 9 Nso- Formulation 7 8 20 A“O. Formulation 20 N. As isr 'k. a. 15 -O- "O.O. B -o-o- "D.Ot. 10 fro- "O.O O --O- s O 5 Osgs

O 50 52 54 56 58 6O 62 64 66 68 70 Temperature (C) FIG. 31 Patent Application Publication Feb. 11, 2016 Sheet 36 of 52 US 2016/0038592 A1

Temperature Sweep of Blending Formulations

Ref. Formulation A (with BHT)

Formulation 20 Ref. Formulation B

Formulation 5 Temperature (C)

FIG. 32 Patent Application Publication Feb. 11, 2016 Sheet 37 of 52 US 2016/0038592 A1

Temperature Sweep of Blending Formulations 250

S. Formulation 5 s s Formulation 19 Si. Formulation 9 Bt sSis Formulation 20 NA SS Formulation 7 A . Ref. Formulation B s A. l A. N re. 3 r f OY, As... -- Or- A-Na- "O. R-O--d AN A- Al-A t".ra.O 50 SR- --O--D- A-sassisA-A-A Ref. Formulation ---g--- A (with BHT) O 50 52 54 56 58 60 62 64 66 68 7O Temperature (C) FIG. 33 Patent Application Publication Feb. 11, 2016 Sheet 38 of 52 US 2016/0038592 A1

Temperature Sweep of Blending Formulations 14 -Form 5 12

5 10 - Form. 19 8 -Form. asg 6 AFA s-Ref. Form. A (BHT) A. al-A-AA Form. 20 S 4: D-D-D-D-D-D-o-o-o-o-o-o-o-o-o-o-o- Form 7 2 O NRef. Form. B 50 52 54 56 58 6O 62 64 66 68 70 Temperature (C) FIG. 34 Patent Application Publication Feb. 11, 2016 Sheet 39 of 52 US 2016/0038592 A1

Panel A Complex Viscosity vs. SiO, Composition at 50-70°C --50.1 y = 9.8175e0.3279x R2 = 0.8608 --55.3 y = 6.3867e0.3446XR2 = 0.8981 -a-60.6 y = 4.1315e0.3684x R2 = 0.9246 -0-65.1 y = 2.8602e0.39x R2 = 0.9384 -e-70.3 y = 1.8763e0.4193x R2 = 0.9526

2 l

O 2.5 3.O 3.5 4.O 4.5 Silicon Dioxide (%, wiv)

Panel B Storage Module vs. SiO Composition at 50-70°C --50.1 y = 7.0000e0.5489x R2 = 0.8946 --55.3 y = 3.0779e0.6386x R2 = 0.9378 -a-60.6 y = 1.3123e0.7533x R2 = 0.9581 -0-65.1 y = 0.6358e0.8642x R2 = 0.9676 -e-70.3 y = 0.3047e0.9843x R2 = 0.9743 7 s O 40

O 2.5 3.O 3.5 4.O Silicon Dioxide (%, ww) FIG. 35 Patent Application Publication Feb. 11, 2016 Sheet 40 of 52 US 2016/0038592 A1

Panel A Loss Module vs. SiO2 Composition at 50-70°C --50.1 y = 62.0145e0.317.4x R2 = 0.8572 --55.3 y = 40.7814e0.3332x R2 = 0.8910 -a-60.6 y = 26.3698e0.3581x R2 = 0.9188 -o-65.1 y = 18.369e0.3781x R2 = 0.9324 -e-70.3 y = 12.091e0.4062x R2 = 0.9463

2.0 2.5 3.O 3.5 4.0 Silicon Dioxide (%, wiw) Panel B Damping Factor vs. SiO Composition at 50-70°C --50.1 y = 8.8295e0.2293x R2 = 0.9402 --55.3 y = 13.1407e-0.3012x R2 = 0.9711 -a-60.6 y = 19.9539e-0.3907x R2 = 0.9789 -o-65.1 y = 28.509e-0479x R2 = 0.9828 -e-70.3 y = 39.194e0-0.57x R2 = 0.9826

4

2.O 2.5 3.O 3.5 4.O Silicon Dioxide (%, wiw) FIG. 36 Patent Application Publication Feb. 11, 2016 Sheet 41 of 52 US 2016/0038592 A1

-0- Initial -- 1M/40C - A 3M/25C -H 3M/40C -- 6M/25C -O- 6M/40C Formulation 5 (40 mg) Mean Results 120 1

20-A

HOurS FIG. 37 Patent Application Publication Feb. 11, 2016 Sheet 42 of 52 US 2016/0038592 A1

-0-initial -H 1 M/40C -A-2M/25C

Formulation 8 (40 mg) Mean Results

Hours FIG 38 Patent Application Publication Feb. 11, 2016 Sheet 43 of 52 US 2016/0038592 A1

-0-initial -H 1 M/40C -A-2M/25C

Formulation 9 (40 mg) Mean Results 100

80

60 40 / 2O

O O 5 10 15 2O 25 Hours FIG. 39 Patent Application Publication Feb. 11, 2016 Sheet 44 of 52 US 2016/0038592 A1

-O-Initial -O-1M/40C

Formulation 7 (40 mg) Mean Results 120

100

Hours FIG. 40 Patent Application Publication Feb. 11, 2016 Sheet 45 of 52 US 2016/0038592 A1

SS 1 O 0. O O

4 O O O

O 5 10 15 2O 25 30 Time, hr FIG. 41 Patent Application Publication Feb. 11, 2016 Sheet 46 of 52 US 2016/0038592 A1

Accumulative Amount of Hydromorphone HCI Released 50.0 34 O0. OO 1-2

Time, hr FIG. 42 Patent Application Publication Feb. 11, 2016 Sheet 47 of 52 US 2016/0038592 A1

600 g SABITA Stock Solution Process Temperature maintained at 55 - 5C

500 rpm Gelucire 44/14 mixing for 20 minutes

mixing for 20 minutes

600 rpm mixing for 20 minutes Homogenizer for 5 minutes mixing for 45 minutes

mixing for 30 minutes

900 rpm 1000 rpm, 100 g Hydromorphone HC mixing for 30 minutes

Homogenizer for 5 minutes

Bulk Formulation Physical evaluation Or active formulation

Capsule Filling Filling Temperature maintained at 55 + 5°C

FIG. 43 Patent Application Publication Feb. 11, 2016 Sheet 48 of 52 US 2016/0038592 A1

Initial Dissolution for Formulation 106 Initial Dissolution for Formulation 107 30 mg capsules in gelatin or HPMC 30 mg capsules in gelatin or HPMC

wax · Gelatin (TO) 38 jo ----- 38%.o. HPMC (TO) 8: : ------HPMC (TO)

2: 3: fire tar

FIG. 44 Patent Application Publication Feb. 11, 2016 Sheet 49 of 52 US 2016/0038592 A1

Dissolution Profile for Formulation 10630 mg in Gelatin Capsules

s * - E if ~3/z. Eitia

axi. 255

28:8 f4

E. : 2. Time (hatars)

FIG. 45 Patent Application Publication Feb. 11, 2016 Sheet 50 of 52 US 2016/0038592 A1

Dissolution Profile for Formulation 106 30 mg in HPMC Capsules

% & w Fitia

x ff25

Time hours

FIG. 46 Patent Application Publication Feb. 11, 2016 Sheet 51 of 52 US 2016/0038592 A1

Dissolution Profile for Formulation 107 60 mg in Gelatin Capsules

t-r xx Eritia st 3- ~5-3DE1.25-i- : ww.25

xx E. E.; 33.

E. 1. 1. 2: s Time hours

FIG. 47 Patent Application Publication Feb. 11, 2016 Sheet 52 of 52 US 2016/0038592 A1

Dissolution Profile for Formulation 107 60 mg in HPMC Capsules

&w 100

. % & E; Etial

wäz Ef 35.

gt 40 axx EFA, 43..

s f E Wax. 3.25. c E --~~~4-~%~

Time hours

FIG. 48 US 2016/0038592 A1 Feb. 11, 2016

COMPOSITIONS WITH A RHEOLOGICAL 0009 FIG. 3 is a graph showing mean plasma oxycodone MODIFIER TO REDUCE DISSOLUTION concentration profiles following administration of Reference VARIABILITY Formulation A (without BHT) and Formulations 1-3. 0010 FIG. 4 is a graph showing mean plasma oxycodone CROSS-REFERENCE TO RELATED concentration profiles following administration of Reference APPLICATIONS Formulation A (without BHT) and Formulations 4-7 and Formulation 5'. 0001. This application claims the benefit of and expressly 0011 FIG. 5 is a graph showing mean plasma oxycodone incorporates by reference herein the entire disclosure of U.S. concentration profiles following administration of Reference Provisional Patent Application No. 61/801,110, filed Mar. 15, Formulation A (without BHT) and Formulations 8 and 9. 2013. 0012 FIG. 6 provides graphs showing the results of in vitro dissolution experiments for Reference Formulation A INTRODUCTION (with BHT) (Panel A) and Formulations 10 (Panel B) and 11 0002 Extended release pharmaceutical compositions, (Panel C). including extended release oxycodone compositions, may 0013 FIG. 7 provides graphs showing the results of in include various pharmaceutically inactive components which vitro dissolution experiments for Reference Formulation A contribute to the desired pharmacokinetic parameters of the (with BHT) (Panel A) and Formulations 12 (Panel B) and 13 active agent in the composition. Such compositions may also (Panel C). include pharmaceutically inactive components which con 0014 FIG. 8 provides graphs showing the effects of IPM tribute to one or more abuse-deterrent characteristics of the (Panel A) and SiO (Panel B) on mean release of oxycodone composition. In some such cases, extended release pharma relative to Reference Formulation A (with BHT). ceutical compositions may be provided which are viscoelas I0015 FIG. 9 is a graph showing the effect of SiO, on an tic in nature with a combination of hydrophilic and hydro oxycodone mean release profile. Results for Formulation 1, phobic components. In addition to solubility of the active and Formulations 14 and 15 are shown. agent in the composition, the release of the active agent may 0016 FIG. 10 provides graphs showing the effect of be controlled, at least in part, by balancing the viscoelastic, increased amounts of SiO on inter-capsule variability during hydrophilic and/or hydrophobic nature of the composition. dissolution. Results for Formulation 1 (Panel A), and Formu However, in Some cases, the Viscoelastic, hydrophilic, and/or lations 14 (Panel B) and 15 (Panel C) are shown. hydrophobic nature of the composition may also contribute to (0017 FIG. 11 is a graph showing the complex viscosity undesirable sample variability during dissolution of the active profiles for Formulations 1, 14 and 15. Increasing SiO, con agent from the composition. This undesirable sample vari centration above about 2% increases complex viscosity ability may be evidenced by inter-capsule variability at a which may lead to decreasing reproducible deformation and particular time point and/or as a storage-time dependent therefore low inter-capsule variability during dissolution test change in mean release of the active agent from the compo 1ng. sition (aging). The present disclosure addresses these issues 0018 FIG. 12 is a graph showing mean release of oxyc and provides related advantages. odone from Formulation 1 following storage for 1 month at 25° C. Or 40° C. SUMMARY 0019 FIG. 13 provides graphs showing inter-capsule vari 0003. The present disclosure provides compositions (e.g., ability during dissolution testing of Formulation 1 following extended release compositions) which exhibit a desirable storage for 1 month at 25°C. or 40°C. pharmacokinetic profile of an active agent while providing 0020 FIG. 14 is a graph showing mean release of oxyc reduced dissolution sample variability, e.g., in the form of odone from Formulation 14 following storage for 1 month at reduced inter-capsule variability and/or a reduction in Stor 25° C. Or 40° C. age-time dependent change in mean release of the active 0021 FIG. 15 provides graphs showing inter-capsule vari agent from the composition. Related methods of making and ability during dissolution testing of Formulation 14 following administering the disclosed compositions are also provided. storage for 1 month at 25°C. or 40°C. 0022 FIG. 16 is a graph showing mean release of oxyc BRIEF DESCRIPTION OF THE DRAWINGS odone from Formulation 15 following storage for 1 month at 25° C. Or 40° C. 0004 FIG. 1A is a graph showing a storage-time depen 0023 FIG. 17 provides graphs showing inter-capsule vari dent change in the release of oxycodone from a reference ability during dissolution testing of Formulation 15 following composition (Reference Formulation A (with BHT)). storage for 1 month at 25°C. or 40°C. 0005 FIG. 1B provides graphs showing the effect of for 0024 FIG. 18 is a graph showing mean release of oxyc mulating Reference Formulation A in gelatin (Panel A) vs. odone from Formulations 16, 17 and 18. HPMC (Panel B) capsules. 0025 FIG. 19 provides graphs showing inter-capsule vari 0006 FIG. 1C provides a graph showing comparative ability during dissolution testing of Formulation 16 (Panel A), plots of Formulation A (without BHT) in gelatin and HPMC Formulation 17 (Panel B) and Formulation 18 (Panel C). capsules. The results of two separate tests are shown. 0026 FIG. 20 is a graph showing mean release of oxyc 0007 FIG. 1D provides a graph showing the variation of odone from Formulation 16 following storage for 1 month at gelatin and HPMC lots using Type 3 dissolution. The results 25° C. Or 40° C. of two separate tests are shown. 0027 FIG.21 provides graphs showing inter-capsule vari 0008 FIG. 2 shows a flow diagram of an exemplary com ability during dissolution testing of Formulation 16 following position preparation and encapsulation method. storage for 1 month at 25°C. or 40°C. US 2016/0038592 A1 Feb. 11, 2016

0028 FIG. 22 is a graph showing mean release of oxyc 0048 FIG. 42 is a graph showing the '% cumulative odone from Formulation 17 following storage for 1 month at amount of hydromorphone HCl released over time under 25° C. Or 40° C. abuse extraction conditions. 0029 FIG.23 provides graphs showing inter-capsule vari 0049 FIG. 43 is a flow chart providing materials and ability during dissolution testing of Formulation 17 following methods for the preparation of selected hydromorphone HCl storage for 1 month at 25°C. or 40°C. compositions. 0030 FIG. 24 is a graph showing mean release of oxyc 0050 FIG. 44 is a graph showing initial dissolution results odone from Formulation 18 following storage for 1 month at (TO) for select formulations in gelatin and HPMC capsules. 25° C. Or 40° C. 0051 FIG. 45 is a graph showing cumulative % drug 0031 FIG.25 provides graphs showing inter-capsule vari release over time for a formulation in hard gelatin capsules ability during dissolution testing of Formulation 18 following with storage conditions of 1 month at 25°C. and 40°C., or 30 storage for 1 month at 25°C. or 40°C. months at 25°C. 0032 FIG. 26 is a graph showing mean release of oxyc 0.052 FIG. 46 is a graph showing cumulative % drug odone from Formulations 5, 7, 9, 19 and 20, with varying release over time for the formulation of FIG. 45 in HPMC levels of SiO, and 5 mg oxycodone. capsules with storage conditions of 1 month at 25°C. and 40° 0033 FIG.27 provides graphs showing inter-capsule vari C., or 30 months at 25°C. ability during dissolution testing of Formulations 5 (Panel A), 0053 FIG. 47 is a graph showing cumulative % drug 7 (Panel E), 9 (Panel C), 19 (Panel B) and 20 (Panel D), with release over time for a formulation in hard gelatin capsules varying levels of SiO, and 5 mg oxycodone. with storage conditions of 1 month at 25°C. and 40°C., or 30 0034 FIG. 28 is a graph showing mean release of oxyc months at 25°C. odone from Formulations 5, 7, 9, 19 and 20, with varying 0054 FIG. 48 is a graph showing cumulative % drug levels of SiO, and 40 mg oxycodone. release over time for the formulation of FIG. 47 in HPMC 0035 FIG.29 provides graphs showing inter-capsule vari capsules with storage conditions of 1 month at 25°C. and 40° ability during dissolution testing of Formulations 5 (Panel A), C., or 30 months at 25°C. 7 (Panel E), 9 (Panel C), 19 (Panel B) and 20 (Panel D), with varying levels of SiO, and 40 mg oxycodone. DEFINITIONS 0036 FIG. 30 is a graph showing complex viscosity as a 0055 As used interchangeably herein, the terms “active function of temperature for Reference Formulation A and agent”, “pharmacologically active agent” and “beneficial Formulations 5, 7, 9, 19 and 20. agent” refer to any substance intended for use in the diagno 0037 FIG.31 is another graph showing complex viscosity sis, cure, mitigation, treatment, or prevention of any disease, as a function oftemperature for Reference Formulation A and disorder, or condition or intended to affect the structure or Formulations 5, 7, 9, 19 and 20. The graph in FIG.31 provides function of the body, other than food. It can include any a different temperature scale than that for FIG. 30. beneficial agent or Substance that is biologically active or 0038 FIG. 32 is a graph showing storage modulus (G') as meant to alter animal physiology. a function of temperature for Reference Formulation A and 0056. As used herein, the term “high viscosity liquid car Formulations 5, 7, 9, 19 and 20. rier material (HVLCM) refers to a non-polymeric, non-wa 0039 FIG.33 is a graph showing loss modulus (G") as a ter soluble liquid material having a viscosity of at least 5000 function of temperature for Reference Formulation A and cP at 37° C. that does not crystallize neat at 25° C. and 1 Formulations 5, 7, 9, 19 and 20. atmosphere. 0040 FIG. 34 is a graph showing damping factor (G"/G') 0057. As used herein, the term “rheology modifier” refers as a function oftemperature for Reference Formulation A and to a Substance that possesses both a hydrophobic and a hydro Formulations 5, 7, 9, 19 and 20. philic moiety. Rheology modifiers suitable for use in the 0041 FIG.35 provides graphs showing complex viscosity disclosed compositions and methods generally have a loga (Panel A) and storage modulus (Panel B) as a function of SiO, rithm of octanol-water partition coefficient (“Log P) of content attemperatures between about 50 and 70° C. based on between about -7 and +15, e.g., between -5 and +10, e.g., the results for Formulations 5, 7, 9, 19 and 20. between -1 and +7. 0042 FIG. 36 provides graphs showing loss modulus 0058 As used herein, the term “network former refers to (Panel A) and damping factor (Panel B) as a function of SiO, a material or compound that forms a network structure when content attemperatures between about 50 and 70° C. based on introduced into a liquid medium (such as a HVLCM). the results for Formulations 5, 7, 9, 19 and 20. 0059. As used herein, the term “hydrophilic agent’ means 0043 FIG.37 is a graph showing mean release for Formu a compound or material having a natural affinity for aqueous lation 5 (40 mg) following storage at 25° C./60% relative systems. A material may be regarded as a hydrophilic agent humidity (RH) and 40° C./75% RH for up to 6 months. for the purposes of this disclosure if the material displays a 0044 FIG.38 is a graph showing mean release for Formu water sorption between about 10 to 100% (w/w). Hydrophilic lation 8 (40 mg) following storage for 1 month at 40°C./75% agents will have a low Log Pvalue, for example, a Log P of RH or 2 months at 25° C. f60% RH. less than +1. 0045 FIG. 39 is a graph showing mean release for Formu 0060. As used herein, the term “hydrophilic solvent lation 9 (40 mg) following storage for 1 month at 40°C./75% means a solvent meeting the definition of a hydrophilic agent RH or 2 months at 25° C. f60% RH. as described above. 0046 FIG. 40 is a graph showing mean release for Formu 0061 The term “solvent, as used herein, refers to any lation 7 (40 mg) following storage for 1 month at 40°C./75% Substance that dissolves another Substance (solute). RH or 3 months at 25° C. f60% RH or 40°C/75% RH. 0062. As used herein, the term “treatment”, “treat” and 0047 FIG. 41 is a graph showing cummulative release of “treating pain refers to eliminating, reducing, Suppressing or hydromorphone HCl for selected formulations over time. ameliorating, either temporarily or permanently, either par US 2016/0038592 A1 Feb. 11, 2016 tially or completely, a clinical symptom, manifestation or “the capsule' includes reference to one or more capsules and progression of pain. In addition, or alternatively, the terms equivalents thereof known to those skilled in the art, and so “treatment”, “treat' and “treating as used herein with respect forth. It is further noted that the claims may be drafted to to the methods as described refer to inhibiting, delaying, exclude any element, e.g., any optional element. As such, this Suppressing, reducing, eliminating or ameliorating, either statement is intended to serve as antecedent basis for use of temporarily or permanently, either partially or completely, such exclusive terminology as “solely,” “only' and the like in pain. In some embodiments the treating is effective to reduce connection with the recitation of claim elements, or use of a a symptom, sign, and/or condition of pain in a subject by at “negative' limitation. least about 10% (e.g., 15%, 20%, 25%, 30%, 35%, 40%, 45%, 0071. To the extent the definition or usage of any term 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or herein conflicts with a definition or usage of a term in an 100%) including, as compared to a baseline measurement of application or reference incorporated by reference herein, the the symptom, sign, and/or condition made prior to the treat instant application shall control. ment. In some embodiments, the treating is effective to 0072 The publications discussed herein are provided improve an assessment used to diagnose pain in a subject solely for their disclosure prior to the filing date of the present including, as compared to a baseline assessment made prior to application. Nothing herein is to be construed as an admission the treatment. Such treating as provided herein need not be that the present invention is not entitled to antedate such absolute to be useful. publication by virtue of prior invention. Further, the dates of 0063. The term “pharmaceutically acceptable salt as publication provided may be different from the actual publi used herein, intends those salts that retain the biological cation dates which may need to be independently confirmed. effectiveness and properties of neutral active agents and are 0073. As will be apparent to those of skill in the art upon not otherwise unacceptable for pharmaceutical use. reading this disclosure, each of the individual embodiments 0064. As used herein, the term “viscosity enhancing described and illustrated herein has discrete components and agent” refers to a compound or material that can be added to features which may be readily separated from or combined an extended release composition in order to increase the with the features of any of the other several embodiments Viscosity of the resulting composition. without departing from the scope or spirit of the present 0065. As used herein, the term “stabilizer” refers to any invention. Any recited method can be carried out in the order Substance used to inhibit or reduce degradation (e.g., chemi of events recited or in any other order which is logically cal) of other substances with which the stabilizer is mixed. possible. This is intended to provide support for all such 0066. The terms “% w/w” and “w %' are used inter combinations. changeably herein to refer to percent weight per weight. 0067. Before the present invention is further described, it DETAILED DESCRIPTION is to be understood that this invention is not limited to par 0074 As discussed previously herein, the viscoelastic, ticular embodiments described, as such may, of course, vary. hydrophilic and/or hydrophobic nature of a pharmaceutical It is also to be understood that the terminology used herein is composition may contribute to undesirable sample variability for the purpose of describing particular embodiments only, during dissolution of the active agent from the composition. and is not intended to be limiting, since the scope of the This undesirable sample variability may be evidenced by present invention will be limited only by the appended claims. inter-capsule variability at a particular time point and/or as a 0068. Where a range of values is provided, it is understood storage-time dependent change in mean release of the active that each intervening value, to the tenth of the unit of the lower agent from the composition. limit unless the context clearly dictates otherwise, between 0075. The present disclosure provides compositions (e.g., the upper and lower limit of that range and any other stated or extended release compositions) which exhibit a desirable intervening value in that stated range, is encompassed within pharmacokinetic profile of an active agent while providing the invention. The upper and lower limits of these smaller reduced dissolution sample variability, e.g., in the form of ranges may independently be included in the Smaller ranges, reduced in vitro inter-capsule variability and/or a reduction in and are also encompassed within the invention, Subject to any storage-time dependent change in mean in vitro release of the specifically excluded limit in the stated range. Where the active agent from the composition. Related methods of mak stated range includes one or both of the limits, ranges exclud ing and administering the disclosed compositions are also ing either or both of those included limits are also included in provided. The compositions of the present disclosure gener the invention. ally include a pharmacologically active agent, a high viscos 0069. Unless defined otherwise, all technical and scien ity liquid carrier material (HVLCM) and a solvent. In some tific terms used herein have the same meaning as commonly embodiments, the compositions also include one or more of a understood by one of ordinary skill in the art to which this rheology modifier, a network former, a hydrophilic agent, a invention belongs. Although any methods and materials simi Viscosity enhancing agent and a stabilizing agent. lar or equivalent to those described herein can also be used in 0076. In some embodiments, the inclusion of a viscosity the practice or testing of the present invention, exemplary enhancing agent, e.g., a mineral particle Such as silicon diox methods and materials are now described. All publications ide, within a specified concentration range in the composition mentioned herein are incorporated herein by reference to Surprisingly provides for decreased variability in the dissolu disclose and describe the methods and/or materials in con tion profile of the active agent from the composition, e.g., as nection with which the publications are cited. evidenced by a relative decrease in inter-capsule dissolution 0070. It must be noted that as used herein and in the profile variability, while maintaining an acceptable level of appended claims, the singular forms “a” “and” and “the rigidity/or viscosity which does not significantly interfere include plural referents unless the context clearly dictates with the processability of the composition. This unexpected, otherwise. Thus, for example, reference to “a composition' beneficial balance between dissolution variability and pro includes a plurality of Such compositions and reference to cessability may be achieved by including the Viscosity US 2016/0038592 A1 Feb. 11, 2016 enhancing agent, e.g., a mineral particle Such as silicon diox drug); propoxyphene (e.g. DarvonTM); hydrocodone (e.g. ide, at from about 2.4 to about 5.4 percent by weight relative VicodinTM); hydromorphone (e.g. DilaudidTM); and meperi to the total weight of the composition. dine (e.g. DemeroITM). 0077. As demonstrated by the present disclosure, the con I0083. In addition to relieving pain, opioids can also pro centration of a rheology modifier, such as isopropyl myristate duce a sensation of euphoria, and when taken in large doses, (IPM), in a pharmaceutical composition may also have a can cause severe respiratory depression which can be fatal. significant effect on Sample variability, e.g., as evidenced by I0084 CNS depressants slow down normal brain function inter-capsule dissolution profile variability. It is an unex by increasing GABA activity, thereby producing a drowsy or pected discovery of the present disclosure that providing a calming effect. In higher doses, some CNS depressants can relatively low concentration range of a rheology modifier become general anesthetics, and in very high doses may cause such as IPM, e.g., at from about 2% to about 10% by weight respiratory failure and death. CNS depressants are frequently based on the total weight of the composition, contributes to a abused, and often the abuse of CNS depressants occurs in desirable pharmacokinetic profile while reducing inter-cap conjunction with the abuse of another Substance or drug, Such sule dissolution profile variability. as alcohol or cocaine. Many deaths occuryearly through Such 0078. The present disclosure also provides improved com drug abuse. CNS depressants can be divided into two groups, positions which exhibit a reduction in a storage-time depen based on their chemistry and pharmacology: (1) Barbiturates, dent change in mean in vitro release of the active agent from such as mephobarbital (e.g. MebaralTM) and pentobarbital the composition. Without intending to be bound by any par sodium (e.g. NembutalTM), which are used to treat anxiety, ticular theory, it is believed that reducing the amount of water tension, and sleep disorders. (2) BenZodiazepines, such as available to the compositions of the present disclosure may diazepam (e.g. ValiumTM), chlordiazepoxide HCl (e.g. Lib minimize these effects. For example, by utilizing HPMC riumTM), and alprazolam (e.g. XanaxTM), which can be pre capsules (~2-6% w/w water, e.g., ~4-6% w/w water) instead scribed to treat anxiety, acute stress reactions, and panic of gelatin capsules (~13-16% w/w water) the amount of water attacks. BenZodiazepines that have a more sedating effect, available to the compositions may be reduced. Accordingly, Such as triazolam (e.g. HalcionTM) and estaZolam (e.g. in Some embodiments, the compositions of the present dis ProSomTM) can be prescribed for short-term treatment of closure are specifically encapsulated within capsules having sleep disorders. lower water content than gelatin capsules. Thus, in some I0085 Stimulants are a class of drugs that enhance brain embodiments a composition according to the present disclo activity—they cause an increase in alertness, attention, and sure is one which has relatively low water content. For energy that is accompanied by increases in blood pressure, example, in Some embodiments, a composition according to heart rate, and respiration. Stimulants are frequently pre the present disclosure does not include more than about 5% scribed for treating narcolepsy, attention-deficit hyperactivity water by weight, based on total weight of the composition. disorder (ADHD), and depression. Stimulants may also be used for short-term treatment of obesity, and for patients with 0079. In addition, the present disclosure demonstrates that asthma. Stimulants such as dextroamphetamine a specified ratio range of the amount of an HVLCM such as (DexedrineTM) and methylphenidate (RitalinTM) have chemi sucrose acetate isobutyrate (SAIB), to a solvent such as tri cal structures that are similar to key brain neurotransmitters acetin, to a rheology modifier Such as IPM in a composition called monoamines, which include norepinephrine and contributes to an improved level of sample variability, e.g., as dopamine. Stimulants increase the levels of these chemicals evidenced by a reduced time-dependent change in an in vitro in the brain and body. This, in turn, increases blood pressure release profile of a composition. Accordingly, in some and heart rate, constricts blood vessels, increases blood glu embodiments the compositions of the present disclosure spe cose, and opens up the pathways of the respiratory system. In cifically include an HVLCM, a solvent, and a rheology modi addition, the increase in dopamine is associated with a sense fier, wherein the HVLCM, the solvent and the rheology modi of euphoria that can accompany the use of these drugs. fier are present in the composition at a ratio of about 1.3:1.0: I0086 Taking high doses of a stimulant can result in an 0.3 to about 10:10:0.05. irregular heartbeat, dangerously high body temperatures, and/or the potential for cardiovascular failure or lethal sei Pharmacologically Active Agent Zures. Taking high doses of Some stimulants repeatedly over 0080. The pharmacologically active agents that may be a short period of time can lead to hostility or feelings of included in the compositions of the present disclosure may paranoia in Some individuals. include any type of biologically active compound or compo I0087. One class of biologically active compounds that sition of matter which, when administered to an organism may be included in the compositions of the present disclosure (human or animal Subject) induces a desired pharmacologic is the opioids class, which includes alfentanil, allylprodine, and/or physiologic effect by local and/or systemic action. alphaprodine, anileridine, apomorphine, apocodeine, benzyl morphine, bezitramide, buprenorphine, butorphanol, clonita 0081 Examples of such biologically active compounds or Zene, codeine, cyclazocine, cyclorphen, cyprenorphine, deso compositions of matter useful in the disclosed compositions morphine, dextromoramide, dextromethorphan, dezocine, include, but are not limited to, opioids, CNS depressants and diampromide, dihydrocodeine, dihydromorphine, dimenoxa stimulants. dol, dimepheptanol, dimethylthiambutene, dioxyaphetyl 0082) Opioids are a class of potent narcotics that includes, butyrate, dipipanone, eptazocine, ethoheptazine, ethylmeth for example, morphine, codeine, oxycodone and fentanyl and ylthiambutene, ethylmorphine, etonitaZene, fentanyl, heroin, related drugs. Morphine is often used to alleviate severe pain. hydrocodone, hydroxymethylmorphinan, hydromorphone, Codeine is used for milder pain. Other examples of opioids hydroxypethidine, isomethadone, ketobemidone, levallor that can be prescribed to alleviate pain include oxycodone phan, levorphanol, levophenacylmorphan, levomethorphan, (e.g. OxyContin R-an oral, controlled release form of the lofentanil, meperidine, meptazinol, metazocine, methadone, US 2016/0038592 A1 Feb. 11, 2016 methylmorphine, metopon, morphine, myrophine, nalbu acetate, triamcinolone, methyltesterone, 17 beta-estradiol. phine, narceline, nicomorphine, norlevorphanol, normetha ethinyl estradiol, ethinyl estradiol 3-methyl ether, predniso done, nalorphine, normorphine, norpipanone, ohmefentanyl. lone, 17-hydroxyprogesterone acetate, 19-nor-progesterone, opium, oxycodone, oxymorphone, papaveretum, pentaZo norgestrel, orethindone, norethiderone, progesterone, norg cine, phenadoxone, phenomorphan, phenazocine, phenope estrone, norethynodrel, aspirin, indomethacin, naproxen, ridine, pholcodine, piminodine, piritramide, propheptazine, fenoprofen, Sulindac, diclofenac, indoprofen, nitroglycerin, promedol, profadol, properidine, propiram, propoxyphene, propranolol, metroprolol, Sodium valproate, valproic acid, remifentanyl, Sufentanyl, tramadol, tilidine, naltrexone, taxanes Such as paclitaxel, camptothecins such as 9-ami naloxone, nalmefene, methylmaltrexone, naloxone methio nocamptothecin, Oxprenolol, timolol, atenolol, alprenolol. dide, nalorphine, naloxonazine, nalide, nalmexone, nalbu phine, nalorphine dinicotinate, naltrindole (NTI), naltrindole cimetidine, clonidine, imipramine, levodopa, chloroprop isothiocyanate (NTII), naltriben (NTB), nor-binaltorphimine mazine, resperine, methyldopa, dihydroxyphenylalanine, (nor-BNI), tapentadol, beta-funaltrexamine (b-FNA), 7-Ben pivaloyloxyethyl ester of C.-methyldopa hydrochloride, theo Zylidenenaltrexone (BNTX), cyprodime, N,N-diallyl-Tyr phylline, calcium gluconate ferrous lactate, ketoprofen, ibu Aib-Aib-Phe-Leu (ICI-174,864), 3-1-(3-hydroxy-3-phenyl profen, cephalexin, haloperiodol, Zomepirac, Vincamine, propyl)-3,4-dimethylpiperidin-4-yl)phenol (LY117413), diazepam, phenoxybenzamine, B-blocking agents, calcium (-)-(1R,5R,9R)-5,9-diethyl-2-(3-furylmethyl)-2'-hydroxy channel blocking drugs such as nifedipine, diltiazen, Vera 6.7-benzomorphan (MR2266), etorphine, D-Ala., NMe pamil, lisinopril, captopril, ramipril, fosimopril, benazepril, Phe, Gly-ol-enkephalin (DAMGO), CTOP (CAS libenZapril, cilaZapril cilaZaprilat, perindopril, Zofenopril, No:103429-31-8), diprenorphine, naloxone benzoylhydra enalapril, indalapril, qumapril, and the like. Zone, bremazocine, ethylketocyclazocine, (U50,488), (U69, 0090 The active agent can be present in the compositions 593), spiradoline, D-Pen’Enkephalin (DPDPE), D-Ala2, of the present disclosure in a neutral form, as a free base form, Glu4 deltorphin, D-Ser, Leu, Thr-enkephalin (DSLET), or in the form of a pharmaceutically acceptable salt. Pharma Met-enkephalin, Leu-enkephalin, B-endorphin, dynorphin A, ceutically acceptable salts include Salts of acidic or basic dynorphin B. a-neoendorphin, or an opioid having the same groups, which groups may be present in the active agents. pentacyclic nucleus as nalmefene, naltrexone, buprenor Those active agents that are basic in nature are capable of phine, levorphanol, meptazinol, pentazocine, dezocine, or forming a wide variety of salts with various inorganic and their pharmacologically effective esters or salts. organic acids. Pharmaceutically acceptable acid addition 0088. In some embodiments, opioids for use in the com salts of basic active agents suitable for use herein are those positions of the present disclosure are selected from mor that form acid addition salts, i.e., salts including pharmaco phine, hydrocodone, oxycodone, codeine, fentanyl (and its logically acceptable anions, such as the hydrochloride, relatives), hydromorphone, meperidine, methadone, oxymor hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phos phone, propoxyphene or tramadol, or mixtures thereof. In phate, acid phosphate, isonicotinate, acetate, lactate, salicy Some embodiments, opioids for use in the compositions of the late, citrate, tartrate, pantothenate, bitartrate, ascorbate, suc present disclosure are selected from oxycodone, oxymor cinate, maleate, gentisinate, fumarate, gluconate, phone, hydrocodone and hydromorphone. In some embodi glucaronate, saccharate, formate, benzoate, glutamate, meth ments, the opioids for use in the compositions of the present anesulfonate, ethanesulfonate, benzenesulfonate, p-toluene disclosure may be micronized. With respect to the opioid Sulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy oxycodone, it may be beneficial to provide compositions that 3-naphthoate)) salts. Active agents that include an amino have a reduced level of peroxide degradation products such as moiety may form pharmaceutically acceptable salts with alpha beta unsaturated ketones (ABUK). In such cases, the various amino acids, in addition to the acids mentioned compositions of the present disclosure can be subjected to above. Suitable base salts can be formed from bases which peroxide contaminant reduction and/or removal techniques in form non-toxic salts, for example, aluminium, calcium, accordance with known methods. lithium, magnesium, potassium, Sodium, Zinc and diethano 0089. Other pharmacologically active compounds or com lamine salts. See, e.g., Berge et al. (1977) J. Pharm. Sci. positions of matter useful in the disclosed compositions 66:1-19, the disclosure of which is incorporated by reference include prochlorperazine edisylate, ferrous Sulfate, aminoca herein. proic acid, potassium chloride, mecamylamine, procaina 0091. In the compositions of the present disclosure, the mide, amphetamine (all forms including dexamphetamine, pharmacologically active agent will be dissolved (fully or dextroamphetamine, d-S-amphetamine, and levoamphet partially) in one or more components of the composition or amine), benzphetamine, isoproternol, methamphetamine, dispersed within one or more components of the composition. dexmethamphetamine, phenmetrazine, bethanechol, meta The phrase “dissolved or dispersed” is intended to encompass choline, pilocarpine, atropine, methascopolamine, isopropa all means of establishing a presence of the active agent in the mide, tridihexethyl, phenformin, methylphenidate (all forms Subject compositions and includes dissolution, dispersion, including dexmethylphenidate, d-threo methylphenidate, and partial dissolution and dispersion, and/or Suspension and the dl-threo methylphenidate), oXprenolol, metroprolol, cimeti like. In addition, in certain embodiments of the present dis dine, diphenidol, meclizine, prochlorperazine, phenoxyben closure wherein the active agent is in a Solid particulate form Zamine, thiethylperazine, anisindone, diphenadione erythri Suspended within one or more other components of the com tyl, digoxin, isoflurophate, reserpine, acetazolamide, position, the active agent particulate may be pre-treated with methazolamide, bendroflumethiazide, chlorpropamide, a micronization process Such as those described in U.S. tolaZamide, chlormadinone, phenaglycodol, allopurinol, alu Application Publication No. 2009/0215808, the disclosure of minum aspirin, methotrexate, acetyl Sulfisoxazole, erythro which is incorporated by reference herein, to provide a par mycin, progestins, estrogenic progrestational, corticoster ticle population having a substantially homogeneous particle oids, hydrocortisone, hydrocorticosterone acetate, cortisone size the bulk of which fall within the micron (Lm) range. US 2016/0038592 A1 Feb. 11, 2016

0092. The pharmacologically active agent, which can about 76, about 77, about 78, about 79, about 80, about 81, include one or more Suitable active agent, may be present in about 82, about 83, about 84, about 85, about 86, about 87, the disclosed compositions in an amount of from about 50 to about 88, about 89, about 90, about 91, about 92, about 93, about 0.1 percent by weight relative to the total weight of the about 94, about 95, about 96, about 97, about 98, about 99, composition (wt %), e.g., in an amount of from about 40 to and about 100 mg. about 0.1 wt %, in an amount of from about 30 to about 0.1 wt 0097. In some embodiments, where the active agent %, in an amount of from about 20 to about 0.1 wt %, in an includes oxycodone free base, the active agent is present in amount of from about 10 to about 0.1 wt %, in an amount of the composition in an amount of from about 50 to about 0.1 from about 9 to about 0.1 wt %, in an amount of from about 8 percent by weight relative to the total weight of the compo to about 0.1 wt %, in an amount of from about 7 to about 0.1 sition (wt %), e.g., in an amount of from about 40 to about 0.1 wt %, in an amount of from about 6 to about 0.1 wt %, in an wt %, in an amount of from about 30 to about 0.1 wt %, in an amount of from about 5 to about 0.1 wt %, in an amount of amount of from about 20 to about 0.1 wt %, in an amount of from about 4 to about 0.1 wt %, in an amount of from about 3 from about 10 to about 0.1 wt %, in an amount of from about to about 0.1 wt %, in an amount of from about 2 to about 0.1 9 to about 0.1 wt %, in an amount of from about 8 to about 0.1 wt %, or in an amount of from about 1 to about 0.1 wt %, wt %, in an amount of from about 7 to about 0.1 wt %, in an depending upon the identity of the active agent, the desired amount of from about 6 to about 0.1 wt %, in an amount of dose required for the dosage form, and the intended use from about 5 to about 0.1 wt %, in an amount of from about 4 thereof. to about 0.1 wt %, in an amount of from about 3 to about 0.1 0093. In some embodiments, the pharmacologically wt %, in an amount of from about 2 to about 0.1 wt %, or in an active agent may be present in the disclosed compositions in amount of from about 1 to about 0.1 wt %. an amount from about 0.1 to about 5 w/6, in an amount from 0098. In some embodiments, where the active agent about 5 to about 10w 96, in an amount from about 10 to about includes oxycodone free base, the active agent may be present 20 w 96, in an amount from about 20 to about 30 w 96, in an in the disclosed compositions in an amount from about 0.1 to amount from about 30 to about 40 w 96, or in an amount from about 5 w 96, in an amount from about 5 to about 10 w 96, in about 40 to about 50 w 96, depending upon the identity of the an amount from about 10 to about 20w 96, in an amount from active agent, the desired dose required for the dosage form, about 20 to about 30 w %, in an amount from about 30 to and the intended use thereof. about 40 w6, or in an amount from about 40 to about 50w 96. 0094. In some embodiments, the active agent is present in 0099. In some embodiments, where the active agent com the composition in an amount of about 1 to about 10 wit'6, and prises oxycodone free base, the active agent is present in the can thus be loaded into a suitable dosage form to provide composition in an amount of about 1 to about 10 wt %, and single dosages ranging from about 0.01 mg to about 1000 mg. can thus be loaded into a suitable dosage form to provide or from about 0.1 mg to about 500 mg. or from about 2 mg to single dosages ranging from about 0.01 mg to about 1000 mg. about 250 mg. or from about 2 mg to about 250 mg. or from or from about 0.1 mg to about 500 mg. or from about 2 mg to about 2 mg to about 150 mg. or from about 5 mg to about 100 about 250 mg. or from about 2 mg to about 250 mg. or from mg, or from about 5 mg to about 80 mg. For example, in some about 2 mg to about 150 mg. or from about 5 mg to about 100 embodiments, the active agentis present in the composition in mg, or from about 5 mg to about 80 mg. For example, in some an amount of from about 2 wt % to about 9 wt %, from about embodiments, where the active agent comprises oxycodone 3 wt % to about 8 wt %, from about 4 wt % to about 7 wt %, free base, the active agent is present in the composition in an or from about 5 wt.% to about 6 wt %. In some embodiments, amount of from about 2 wt % to about 9 wt %, from about 3 the active agent is present in the composition in an amount of wt % to about 8 wt %, from about 4 wt % to about 7 wt %, or about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt %, about from about 5 wt % to about 6 wt %. In some embodiments, 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wit where the active agent comprises oxycodone free base, the %, or about 10 wt %. active agent is present in the composition in an amount of 0095 For some embodiments that include an opioid active about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt %, about agent, exemplary single dosages include, but are not limited 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wit to, about 1, about 2, about 3, about 4, about 5, about 10, about %, or about 10 wt %. 15, about 20, about 25, about 30, about 35, about 40, about 45, 0100 For some embodiments, where the active agent about 50, about 55, about 60, about 65, about 70, about 75, comprises oxycodone free base, exemplary single dosages about 80, about 85, about 90, about 95, about 100, about 110, include, but are not limited to, about 1, about 2, about 3, about about 120, about 130, about 140, about 150 and about 160 mg. 4, about 5, about 10, about 15, about 20, about 25, about 30, 0096. In other embodiments that include a CNS depres about 35, about 40, about 45, about 50, about 55, about 60, Santor CNS Stimulant, exemplary single dosages include, but about 65, about 70, about 75, about 80, about 85, about 90, are not limited to, about 5, about 6, about 7, about 8, about 9, about 95, about 100, about 110, about 120, about 130, about about 10, about 11, about 12, about 13, about 14, about 15, 140, about 150, and about 160 mg. about 16, about 17, about 18, about 19, about 20, about 21, 0101. In some embodiments, where the active agent is about 22, about 23, about 24, about 25, about 26, about 27, oxycodone free base, the active agent is present in the com about 28, about 29, about 30, about 31, about 32, about 33, position in an amount of about 1 to about 10 wt %, and can about 34, about 35, about 36, about 37, about 38, about 39, thus be loaded into a Suitable dosage form to provide single about 40, about 41, about 42, about 43, about 44, about 45, dosages ranging from about 0.01 mg to 1000 mg. or from about 46, about 47, about 48, about 49, about 50, about 51, about 0.1 mg to 500 mg. or from about 2 mg to 250 mg. or about 52, about 53, about 54, about 55, about 56, about 57, from about 2 mg to 250 mg, or from about 2 mg to 150 mg. or about 58, about 59, about 60, about 61, about 62, about 63, from about 5 mg to 100 mg. or from about 5 mg to 80 mg. For about 64, about 65, about 66, about 67, about 68, about 69, example, in Some embodiments, the oxycodone free base is about 70, about 71, about 72, about 73, about 74, about 75, present in the composition in an amount of from about 2 wt % US 2016/0038592 A1 Feb. 11, 2016

to about 9 wt %, from about 3 wt % to about 8 wt %, from about 42% by weight to about 45% by weight, from about about 4 wt % to about 7 wt %, or from about 5 wt % to about 43% by weight to about 45% by weight, or from about 44% by 6 wt %. weight to about 45% by weight relative to the total weight of In some embodiments, the oxycodone free base is present in the composition. In some embodiments, the HVLCM may be the composition in an amount of about 1 wt %, about 2 wt %, present in the composition at from about 35% by weight to about 3 wt %, about 4 wt %, about 5 wt %, about 6 wt %, about about 37% by weight, from about 37% by weight to about 7 wt %, about 8 wt %, about 9 wt %, or about 10 wt %. 39% by weight, from about 39% by weight to about 41% by 0102 The precise amount of active agent desired can be weight, from about 41% by weight to about 43% by weight, or determined by routine methods well known to pharmacologi from about 43% by weight to about 45% by weight relative to cal arts, and will depend on the type of agent, and the phar the total weight of the composition. In some embodiments, macokinetics and pharmacodynamics of that agent. the HVLCM may be present in the composition at about 35% by weight, about 36% by weight, about 37% by weight, about High Viscosity Liquid Carrier Material (HVLCM) 38% by weight, about 39% by weight, about 40% by weight, 0103) An HVLCM is a non-polymeric, non-water soluble about 41% by weight, about 42% by weight, about 43% by liquid material having a viscosity of at least 5000 cp at 37°C. weight, about 44% by weight, or about 45% by weight rela that does not crystallize neat at 25°C. and 1 atmosphere. The tive to the total weight of the composition. term “non-water soluble” refers to a material that is soluble in 0105. In some embodiments, the amount of the HVLCM water to a degree of less than one percent by weight at 25°C. present in the composition is provided relative to the amount and 1 atmosphere. The term “non-polymeric' refers to esters of the solvent present in the composition. For example, the or mixed esters having essentially no repeating units in the HVLCM and the solvent may be provided in the composition acid moiety of the ester, as well as esters or mixed esters ataratio of about 1.3:1 to about 1:1, e.g., about 1.20:1 to about having acid moieties wherein functional units in the acid 1:1, about 1.15:1 to about 1:1, about 1.10:1 to about 1:1, or moiety are repeated a small number of times (i.e., oligomers). about 1:1. For example, in some embodiments, the HVLCM Generally, materials having more than five identical and adja and the solvent may be provided in the composition at a ratio cent repeating units or mers in the acid moiety of the ester are of about 1.30:1.0, about 1.25:1.0, about 1.20:1.0, about 1.15: excluded by the term “non-polymeric' as used herein, but 1.0, or about 1.0:1.0. In some embodiments, the HVLCM and materials containing dimers, trimers, tetramers, or pentamers the solvent may be provided in the composition at a ratio of are included within the scope of this term. When the ester is about 0.6:1 to about 1.6:1, e.g., about 0.8:1 to about 1.5:1, or formed from hydroxy-containing carboxylic acid moieties about 0.9:1 to about 1.5:1. For example, in some embodi that can further esterify. Such as lactic acid or glycolic acid, ments, the HVLCM and the solvent (e.g., triacetin) may be the number of repeat units is calculated based upon the num provided in the composition at a ratio of about 0.6:1.0, about ber of lactide or glycolide moieties, rather than upon the 0.7:1.0, about 0.8:1.0, about 0.9:1.0, about 1.0:1.0, about number of lactic acid or glycolic acid moieties, where a 1.1:1.0, about 1.2:1.0, about 1.3:1.0, about 1.4:1.0, about lactide repeat unit contains two lactic acid moieties esterified 1.5:1.0, or about 1.6:1.0. by their respective hydroxy and carboxy moieties, and where 0106. In some embodiments. Sucrose Acetate Isobutyrate a glycolide repeat unit contains two glycolic acid moieties (“SAIB) may be included in the composition as the HVLCM esterified by their respective hydroxy and carboxy moieties. or the HVLCM may include SAIB. SAIB is a non-polymeric Esters having 1 to about 20 etherified polyols in the alcohol highly viscous liquid attemperatures ranging from -80°C. to moiety thereof, or 1 to about 10 glycerol moieties in the over 100° C., it is a fully esterified sucrose derivative, at a alcohol moiety thereof, are considered non-polymeric as that nominal ratio of six isobutyrates to two acetates. The chemi term is used herein. HVLCMs may be carbohydrate-based, cal structure of SAIB is provided in U.S. Application Publi and may include one or more cyclic carbohydrates chemically cation No. 2009/0215808, the disclosure of which is incor combined with one or more carboxylic acids. HVLCMs also porated by reference herein. The SAIB material is available include non-polymeric esters or mixed esters of one or more from a variety of commercial Sources including Eastman carboxylic acids, having a viscosity of at least 5,000 cp at 37° Chemical Company, where it is available as a mixed ester that C., that do not crystallize neat at 25° C. and 1 atmosphere, does not crystallize but exists as a very highly viscous liquid. wherein when the ester contains an alcohol moiety (e.g., It is a hydrophobic, non-crystalline, low molecular weight glycerol). The ester may, for example include from about 2 to molecule that is water insoluble and has a viscosity that varies about 20 hydroxy acid moieties. Various HVLCMs, which with temperature. For example, pure SAIB exhibits a viscos may be used be included in disclosed compositions are ity of approximately 2,000,000 centipoise (cP) at ambient described in U.S. Pat. Nos. 5,747,058; 5,968,542; and 6,413, temperature (RT) and approximately 600 cp at 80°C. The 536; the disclosures of each of which are incorporated by SAIB material has unique solution-viscosity relationship in reference herein. The presently disclosed compositions may that a SAIB solution established in a number of organic employ any HVLCM described in these patents but is not Solvents has a significantly lower viscosity value than the pure limited to any specifically described materials. SAIB material, and therefore the SAIB-organic solvent solu 0104. The HVLCM may be present in the composition at tions render themselves capable of processing using conven from about 35% by weight to about 45% by weight, based on tional equipment such as mixers, liquid pumps and capsule total weight of the composition. For example, the HVLCM production machines. SAIB also has applications in drug may be present in the composition at from about 36% by formulation and delivery, for example as described in U.S. weight to about 45% by weight, from about 37% by weight to Pat. Nos. 5,747,058; 5,968,542; 6,413,536; and 6,498,153, about 45% by weight, from about 38% by weight to about the disclosure of which are incorporated by reference herein. 45% by weight, from about 39% by weight to about 45% by 0107. In the compositions of the present disclosure, SAIB weight, from about 40% by weight to about 45% by weight, may be used as the HVLCM or the HVLCM may include from about 41% by weight to about 45% by weight, from SAIB at from about 35% by weight to about 45% by weight, US 2016/0038592 A1 Feb. 11, 2016

based on total weight of the composition. For example, the ate and dimethyl carbonate; fatty acids such as acetic acid, SAIB may be present in the composition at from about 36% lactic acid and heptanoic acid; alkyl esters of mono-, di-, and by weight to about 45% by weight, from about 37% by weight tricarboxylic acids such as 2-ethyoxyethyl acetate, ethyl to about 45% by weight, from about 38% by weight to about acetate, methyl acetate, ethyl lactate, ethylbutyrate, diethyl 45% by weight, from about 39% by weight to about 45% by malonate, diethylglutonate, tributyl citrate, diethyl Succinate, weight, from about 40% by weight to about 45% by weight, tributyrin, dimethyl adipate, dimethyl succinate, dimethyl from about 41% by weight to about 45% by weight, from oxalate, dimethyl citrate, triethyl citrate, acetyl tributyl cit about 42% by weight to about 45% by weight, from about rate, glyceryl triacetate; alkyl ketones such as acetone and 43% by weight to about 45% by weight, or from about 44% by methyl ethyl ketone; ether alcohols such as 2-ethoxyethanol, weight to about 45% by weight relative to the total weight of ethylene glycol dimethyl ether, glycofurol and glycerol for the composition. In some embodiments, the SAIB may be present in the composition at from about 35% by weight to mal; alcohols such as benzyl alcohol, ethanol and propanol: about 37% by weight, from about 37% by weight to about polyhydroxy alcohols such as propylene glycol, polyethylene 39% by weight, from about 39% by weight to about 41% by glycol (PEG), glycerin (glycerol), 1,3-butyleneglycol, and weight, from about 41% by weight to about 43% by weight, or isopropylidene glycol (2,2-dimethyl-1,3-dioxolone-4- from about 43% by weight to about 45% by weight relative to methanol); Solketal; dialkylamides such as dimethylforma the total weight of the composition. In some embodiments, mide, dimethylacetamide; dimethylsulfoxide (DMSO) and the SAIB may be present in the composition at about 35% by dimethylsulfone; tetrahydrofuran; lactones Such as 8-capro weight, about 36% by weight, about 37% by weight, about lactone and butyrolactone; cyclic alkyl amides Such as capro 38% by weight, about 39% by weight, about 40% by weight, lactam, aromatic amides Such as N,N-dimethyl-m-toluamide, about 41% by weight, about 42% by weight, about 43% by and 1-dodecylazacycloheptan-2-one; and the like; and mix weight, about 44% by weight, or about 45% by weight rela tures and combinations thereof. tive to the total weight of the composition. 0108. In some embodiments, the amount of SAIB present 0111. In some embodiments, the solvent includes or is in the composition is provided relative to the amount of the selected from triacetin, N-methyl-2-pyrrolidone, 2-pyrroli Solvent (e.g., triacetin) present in the composition. For done, dimethylsulfoxide, ethyl lactate, propylene carbonate, example, the SAIB and the solvent may be provided in the and glycofurol. In some embodiments, the solvent is triacetin composition at a ratio of about 1.3:1 to about 1:1, e.g., about which is a hydrophilic solvent. In some embodiments, the 1.20:1 to about 1:1, about 1.15:1 to about 1:1, about 1.10:1 to hydrophilic triacetin solvent can be combined with a hydro about 1:1, or about 1:1. For example, in some embodiments, phobic solvent to provide a hydrophobic/hydrophilic solvent the SAIB and the solvent may be provided in the composition system within the composition. at a ratio of about 1.30:1.0, about 1.25:1.0, about 1.20:1.0, 0.112. The solvent, which can include one or more suitable about 1.15:1.0, or about 1.0:1.0. In some embodiments, the Solvent materials, can be present in the compositions at from SAIB and the solvent may be provided in the composition at about 31% by weight to about 45% by weight, based on total a ratio of about 0.6:1 to about 1.6:1, e.g., about 0.8:1 to about weight of the composition. For example, the Solvent may be 1.5:1, or about 0.9:1 to about 1.5:1. For example, in some present in the composition at from about 32% by weight to embodiments, the SAIB and the solvent (e.g., triacetin) may about 45% by weight, at from about 33% by weight to about be provided in the composition at a ratio of about 0.6:1.0, 45% by weight, at from about 34% by weight to about 45% by about 0.7:1.0, about 0.8:1.0, about 0.9:1.0, about 1.0:1.0, weight, at from about 35% by weight to about 45% by weight, about 1.1:1.0, about 1.2:1.0, about 1.3:1.0, about 1.4:1.0, at from about 36% by weight to about 45% by weight, at from about 1.5:1.0, or about 1.6:1.0. about 37% by weight to about 45% by weight, at from about 0109. In some embodiments, it may be beneficial to pro 38% by weight to about 45% by weight, at from about 39% by vide a SAIB carrier material having a lower peroxide level to weight to about 45% by weight, at from about 40% by weight avoid peroxide-based degradation of various components of to about 45% by weight, at from about 41% by weight to the composition and/or active agent. See, e.g., U.S. Patent about 45% by weight, at from about 42% by weight to about Application Publication Number US 2007/0027105. “Perox 45% by weight, at from about 43% by weight to about 45% by ide Removal From Drug Delivery Vehicle', the disclosure of weight, or at from about 44% by weight to about 45% by which is incorporated by reference herein. weight relative to the total weight of the composition. In some embodiments, the solvent may be present in the composition Solvents at from about 31% by weight to about 33% by weight, at from 0110 Solvents may be used in the compositions of the about 33% by weight to about 35% by weight, at from about present disclosure to dissolve one or more of the following 35% by weight to about 37% by weight, at from about 37% by constituents: HVCLMs; active agents; network formers; rhe weight to about 39% by weight, at from about 39% by weight ology modifiers; Viscosity enhancing agents; hydrophilic to about 41% by weight, at from about 41% by weight to agents; and stabilizing agents. In some embodiments, the about 43% by weight, or at from about 43% by weight to solvent can dissolve both the HVLCM and the network about 45% by weight relative to the total weight of the com former. In some embodiments of the compositions of the position. In some embodiments, the solvent may be present in present disclosure, a composition may include both a hydro the composition at about 31% by weight, about 32% by philic Solvent and a hydrophobic solvent. Organic solvents weight, about 33% by weight, about 34% by weight about suitable for use with the compositions of the present disclo 35% by weight, about 36% by weight, about 37% by weight, sure include, but are not limited to: substituted heterocyclic about 38% by weight, about 39% by weight, about 40% by compounds such as N-methyl-2-pyrrolidone (NMP) and weight, about 41% by weight, about 42% by weight, about 2-pyrrolidone (2-pyrol); triacetin; esters of carbonic acid and 43% by weight, about 44% by weight, or about 45% by alkyl alcohols such as propylene carbonate, ethylene carbon weight relative to the total weight of the composition. US 2016/0038592 A1 Feb. 11, 2016

Rheology Modifier ronic R (nonionic triblock copolymer), EudragitR) (poly methacrylate), CarbomerTM (polyacrylic acid), hydroxyl pro 0113 Rheology refers to the property of deformation and/ pyl methyl cellulose, other cellulose acetates such as or flow of a liquid, and rheology modifiers are used to modify cellulose triacetate, Poly(methyl methacrylate) (PMMA), as Viscosity and flow of a liquid composition. Rheology modi well as any other material capable of associating, aligning or fiers, which may be used in the compositions of the present disclosure include, for example, caprylic/capric triglyceride congealing to form three-dimensional networks in an aque (e.g., Miglyol(R) 810 or Miglyol(R) 812), isopropyl myristate ous environment. (IM or IPM), ethyl oleate, triethylcitrate, dimethyl phthalate, 0117. In some embodiments, the network former used in the compositions of the present disclosure is or includes a and benzyl benzoate. CAB having a number average molecular weight ranging 0114. In some embodiments, the rheology modifier is or from about 50,000 Daltons to about 100,000 Daltons, e.g., includes IPM. The rheology modifier, which can include one from about 60,000 Daltons to about 100,000 Daltons, from or more Suitable rheology modifier materials, can be present about 70,000 Daltons to about 100,000 Daltons, from about in the compositions at from about 2 to about 10 percent by 80,000 Daltons to about 100,000 Daltons, or from about weight relative to the total weight of the composition (wt %), 90,000 Daltons to about 100,000 Daltons. In some embodi e.g., at from about 2 to about 8 wt %, at from about 2 to about ments, the network former used in the compositions of the 6 wt %, or at from about 2 to about 4 wt.%. In some embodi present disclosure is or includes a CAB having a number ments, the rheology modifier is preset in the compositions at average molecular weight ranging from about 60,000 Daltons from about 2 to about 4 wt %, at from about 4 to about 6 wt %, to about 90,000 Daltons, or from about 70,000 Daltons to at from about 6 to about 8 wt %, or at from about 8 to about 10 about 80,000 Daltons. In some embodiments, the network wt %. For example, in Some embodiments, the rheology former used in the compositions of the present disclosure is or modifier, e.g., IPM, is present in the composition at about 2 wt includes a CAB having a number average molecular weight %, about 3 wt %, about 4 wt %, about 5 wt %, about 6 wt %, of about 50,000 Daltons, about 55,000 Daltons, about 60,000 about 7 wt %, about 8 wt %, about 9 wt %, or about 10 wt %. Daltons, about 65,000 Daltons, about 70,000 Daltons, about 0115. In some embodiments, the rheology modifier is 75,000 Daltons, about 80,000 Daltons, about 85,000 Daltons, present in the compositions of the present disclosure in an about 90,000 Daltons, about 95,000 Daltons, or about 100, amount relative to the amount of solvent in the compositions. 000 Daltons. For example, in some embodiments the solvent and the rhe 0118. In some embodiments, the network former used in ology modifier are present in the compositions at a ratio of the compositions of the present disclosure is or includes a about 1:0.3 to about 1.0:0.05, e.g., about 1:0.2 to about 1:0.06, CAB having at least one feature selected from a butyryl about 1:0.1 to about 1:0.07, or about 1:0.09 to about 1:0.08. content ranging from about 17% to about 41%, an acetyl For example, in some embodiments, the solvent and the rhe content ranging from about 13% to about 30%, and a ology modifier are present in the compositions at a ratio of hydroxyl content ranging from about 0.5% to about 1.7%. In about 1.0:0.3, about 1.0:0.2, about 1.0:0.1, about 10:009, some further embodiments, the network former used in the about 1.0:0.08, about 1.0:0.07, about 10:006, or about 1.0: compositions of the present disclosure is or includes a CAB 0.05. In some embodiments, where the solventistriacetin and comprising at least two of a butyryl content ranging from the rheology modifier is IPM, the solvent and the rheology about 17% to about 41%, an acetyl content ranging from modifier are present in the compositions at a ratio of about about 13% to about 30%, and a hydroxyl content ranging 1.0:0.3, about 1.0:0.2, about 1.0.0.1, about 1.0:0.09, about from about 0.5% to about 1.7%. In still further embodiments, 1.0:0.08, about 1.0:0.07, about 1.0:0.06, or about 10:005. the network former used in the compositions of the present disclosure is or includes a CAB comprising all three of a Network Former butyryl content ranging from about 17% to about 41%, an 0116. Network formers may be added to a composition acetyl content ranging from about 13% to about 30%, and a Such that, upon exposure to an aqueous environment, they hydroxyl content ranging from about 0.5% to about 1.7%. form a three dimensional network within the composition. 0119. Accordingly, in some embodiments, the network While not intending to be bound by any particular theory, it is former used in the compositions of the present disclosure is or believed that the network former allows the formation of a includes a CAB having abutyryl content ranging from about micro-network within the composition upon exposure to an 17% to about 41%. In some embodiments, the network aqueous environment. This micro-network formation appears former used in the compositions of the present disclosure is or to be due, at least in part, to a phase inversion (e.g., a change includes a CAB having an acetyl content ranging from about in glass transition temperature, T) of the network former. 13% to about 30%. In some embodiments, the network The result is believed to be a skin or surface layer of precipi former used in the compositions of the present disclosure is or tated network former at the interface between the composi includes a CAB having a hydroxyl content ranging from tion and the aqueous environment of the GI tract, as well as about 0.5% to about 1.7%. In some embodiments, the net the formation of a three-dimensional micro-network of pre work former used in the compositions of the present disclo cipitated network former within the composition. The net Sure is or includes a CAB having a butyryl content ranging work former is selected so as to have good solubility in the from about 17% to about 41% and an acetyl content ranging selected solvent used in the compositions, for example a from about 13% to about 30%. In some embodiments, the solubility of between about 0.1 and 20 wt %. Additionally, network former used in the compositions of the present dis good network formers will typically have a Log P between closure is or includes a CAB having abutyryl content ranging about -1 to 7. Suitable network formers include, for example, from about 17% to about 41% and a hydroxyl content ranging cellulose acetate butyrate ("CAB), carbohydrate polymers, from about 0.5% to about 1.7%. In some embodiments, the organic acids of carbohydrate polymers and other polymers, network former used in the compositions of the present dis hydrogels, cellulose acetate phthalate, ethyl cellulose, Plu closure is or includes a CAB having an acetyl content ranging US 2016/0038592 A1 Feb. 11, 2016 from about 13% to about 30% and a hydroxyl content ranging embodiments, a network former is present in the composi from about 0.5% to about 1.7%. In still other embodiments, tions of the present disclosure at about 0.1 wt %, about 0.5 wt the network former used in the compositions of the present %, about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt %, disclosure is or includes a CAB having a butyryl content about 5 wt %, about 6 wt %, about 7 wt %, about 8wt %, about ranging from about 17% to about 41%, an acetyl content 9 wt %, about 10 wt %, about 11 wt %, about 12 wt %, about ranging from about 13% to about 30%, and a hydroxyl con 13 wt %, about 14 wt %, about 15 wt %, about 16 wt %, about tent ranging from about 0.5% to about 1.7%. In further 17 wt %, about 18 wt %, about 19 wt %, or about 20 wt %. embodiments, in addition to one of the above features of butyryl content, acetyl content and/or hydroxyl content, the Hydrophilic Agent CAB also has a number average molecular weight ranging from about 50,000 Daltons to about 100,000 Daltons, e.g., 0.124 Materials that can be used as “hydrophilic agents' in from about 60,000 Daltons to about 100,000 Daltons, from the compositions of the present disclosure include those that about 70,000 Daltons to about 100,000 Daltons, from about have natural affinity for aqueous systems. A material may be 80,000 Daltons to about 100,000 Daltons, or from about regarded as a hydrophilic agent for the purposes of this dis 90,000 Daltons to about 100,000 Daltons. In further embodi closure if the material displays a water sorption between ments, in addition to one of the above features of butyryl about 10 to about 100% (w/w). Hydrophilic agents will have content, acetyl content and/or hydroxyl content, the CAB also a low Log P value, for example, a Log P of less than +1. As has a number average molecular weight ranging from about discussed herein above, there are a number of constituents 60,000 Daltons to about 90,000 Daltons, or from about which may be used to produce the compositions of the present 70,000 Daltons to about 80,000 Daltons. In further embodi disclosure that can be classed as a hydrophilic material (e.g., ments, in addition to one of the above features of butyryl a hydrophilic solvent), or at least a material having a hydro content, acetyl content and/or hydroxyl content, the CAB also philic portion (e.g., a rheology modifier). Since the HVLCM has a number average molecular weight of about 50,000 material used in the compositions is hydrophobic, it may be Daltons, about 55,000 Daltons, about 60,000 Daltons, about useful to include other materials in the composition that are 65,000 Daltons, about 70,000 Daltons, about 75,000 Daltons, hydrophilic in order to provide a carrier system that is bal about 80,000 Daltons, about 85,000 Daltons, about 90,000 anced to have both hydrophobic and hydrophilic characteris Daltons, about 95,000 Daltons, or about 100,000 Daltons. tics. For example, it is believed that the inclusion of one or 0120 In some embodiments, the network former used in more hydrophilic agents in the compositions of the present the compositions of the present disclosure is or includes cel disclosure may participate in the control of active agent dif lulose acetate butyrate grade 381-20BP (“CAB 381-20BP” fusion from the compositions. Accordingly, Suitable hydro available from Eastman Chemicals). In some embodiments, philic agents include, but are not limited to, Sugars Such as the network former used in the compositions of the present Sorbitol, lactose, mannitol, fructose. Sucrose and dextrose, disclosure is or includes a CAB, wherein the CAB is a non salts such as Sodium chloride and Sodium carbonate, starches, biodegradable polymer material that has the following chemi hyaluronic acid, glycine, fibrin, collagen, polymers such as cal and physical characteristics: butyryl content of about 36 hydroxylpropylcellulose (“HPC), carboxymethylcellulose, wt %, acetyl content of about 15.5 wt %, hydroxyl content of hydroxyethyl cellulose (“HEC); polyethylene glycol and about 0.8%, a melting point of from about 185-196° C., a polyvinylpyrrolidone, and the like. In some embodiments, a glass transition temperature of about 128°C., and a number controlled release carrier system is provided that includes average of from about 66,000 to 83,000, e.g., about 70,000. In HEC as a hydrophilic agent or a component of a hydrophilic Some embodiments, if a CAB material is used in the compo agent. sition, it may be subjected to an ethanol washing step (and 0.125. The hydrophilic agent, which can include one or Subsequent drying step) prior to addition to the composition more Suitable hydrophilic agent materials, e.g., HEC, can be in order to remove potential contaminants therefrom. present in the compositions at from about 0.1 to about 10 percent by weight relative to the total weight of the compo 0121. In some embodiments, the network former of the sition (wt %), e.g., from about 1 to about 8 wt %, from about present disclosure specifically excludes a network former 2 to about 7 wt %, from about 3 to about 6 wt %, or from about having an acetyl content of about 2.0%, abutyryl content of 4 to about 5 wt.%. In some embodiments, a hydrophilic agent about 46.0%, a hydroxyl content of 4.8%, a melting point of is present in the compositions of the present disclosure at from about 150-160° C., a glass transition temperature of about 0.1 wt % to about 0.5 wt %, about 0.5 wt % to about 1 about 136° C., and a number average molecular weight of wt %, about 1 wt % to about 5 wt %, or about 5 wt % to about about 20,000, e.g., CAB-553-0.4 available from Eastman 10 wt %. In some embodiments, a hydrophilic agentis present Chemicals). in the compositions of the present disclosure at about 0.1 wt 0122. In some embodiments, the network former of the %, about 0.5 wt %, about 1 wt %, about 2 wt %, about 3 wt %, present disclosure specifically excludes a network former, about 4 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about e.g., a CAB, which is soluble in ethanol. 8 wt %, about 9 wt %, or about 10 wt %. 0123. The network former, which can include one or more Suitable network former materials, can be present in the com Viscosity Enhancing Agent positions at from about 0.1 to about 20 percent by weight relative to the total weight of the composition (wt %), e.g., at 0.126 Viscosity enhancing agents can be selected to have from about 1 to about 18wt %, from about 2 to about 10 wt %, good hydrogen bonding capability. Such as a bonding capa from about 4 to about 6 wt %, or at about 5 wt %. In some bility greater than or equal to one per molecule. In certain embodiments, a network former is present in the composi cases, the Viscosity enhancing agent has very low to no sig tions of the present disclosure at from about 0.1 to about 1 wt nificant solubility in the composition. If the agent is soluble, %, about 1 to about 5 wt %, about 5 to about 10 wt %, about then, in some embodiments, the solubility is less than 50 wt 10 to about 15 wt %, or about 15 to about 20 wt %. In some %. For inorganic or mineral Viscosity enhancing agents, it is US 2016/0038592 A1 Feb. 11, 2016

preferable if the material has a specific Surface area greater from about 2.6 wt % to about 2.8 wt %, at from about 2.8 wit than or equal to about 100 m/g. Suitable viscosity enhancing % to about 3.0 wt %, at from about 3.0 wt % to about 3.2 wit agents include biodegradable and non-biodegradable poly %, at from about 3.2 wt % to about 3.4 wt %, at from about 3.4 mer materials. Non-limiting examples of suitable biodegrad wt % to about 3.6 wt %, at from about 3.6 wt % to about 3.8 able polymers and oligomers include: poly(lactide), poly(lac wt %, at from about 3.8 wt % to about 4.0 wt %, at from about tide-co-glycolide), poly(glycolide), poly(caprolactone), polyamides, polyanhydrides, polyamino acids, polyorthoe 4.0 wt % to about 4.2 wt %, at from about 4.2 wt % to about sters, polycyanoacrylates, poly(phosphazines), poly(phos 4.4 wt %, at from about 4.4 wt % to about 4.6 wt %, at from phoesters), polyesteramides, polydioxanones, polyacetals, about 4.6 wt % to about 4.8 wt %, at from about 4.8 wt % to polyketals, polycarbonates, polyorthocarbonates, degradable about 5.0 wt %, at from about 5.0 wt % to about 5.2 wt %, at polyurethanes, polyhydroxybutyrates, polyhydroxyvaler from about 5.2 wt % to about 5.4 wt %, at from about 5.4 wt ates, polyalkylene oxalates, polyalkylene Succinates, poly % to about 5.6 wt %, at from about 5.6 wt % to about 5.8 wit (malic acid), chitin, chitosan, and copolymers, terpolymers, %, or at from about 5.8 wt % to about 6.0 wt %. oxidized cellulose, hydroxyethyl cellulose, or combinations 0.130. In some embodiments, a composition according to or mixtures of the above materials. Suitable non-biodegrad the present disclosure includes a viscosity enhancing agent, able polymers include: polyacrylates, ethylene-vinyl acetate e.g., mineral particle (e.g., silicon dioxide) at about 2.4 wt %, polymers, cellulose and cellulose derivatives, acyl substituted about 2.5 wt %, about 2.6 wt %, about 2.7 wt %, about 2.8wt cellulose acetates and derivatives thereof including cellulose %, about 2.9 wt %, about 3.0 wt %, about 3.1 wt %, about 3.2 acetate butyrate (CAB), which is also used herein as a net work former, non-erodible polyurethanes, polystyrenes, wt %, about 3.3 wt %, about 3.4 wt %, about 3.5 wt %, about polyvinyl chloride, polyvinyl fluoride, polyvinyl (imidazole), 3.6 wt %, about 3.7 wt %, about 3.8 wt %, about 3.9 wt %, chlorosulphonated polyolefins, polyethylene oxide, and about 4.0 wt %, 4.1 wt %, 4.2 wt %, 4.3 wt %, 4.4 wt %, 4.5 polyethylene. wt %, 4.6 wt %, 4.7 wt %, 4.8 wt %, 4.9 wt %, 5.0 wt %, 5.1 0127. Other suitable viscosity enhancing materials wt %, 5.2 wt %, 5.3 wt %, 5.4 wt %, 5.5 wt %, 5.6 wt %, 5.7 include mineral particles Such as clay compounds, including, wt %, 5.8 wt %, 5.9 wt %, or 6.0 wt %. talc, bentonite and kaolin; metal oxides including silicon I0131. As discussed in the Examples below, providing a dioxide, Zinc oxide, magnesium oxide, titanium oxide, and Viscosity enhancing agent, e.g., a mineral particle Such as calcium oxide; and fumed silica, reagent grade sand, precipi silicon dioxide, in an amount outside of one or more of the tated silica, amorphous silica, colloidal silicon dioxide, fused ranges specified above may result in undesirable composition silica, silica gel, and quartz. In some embodiments of the characteristics. For example, variability in a dissolution pro present disclosure, a colloidal silicon dioxide, e.g., Cab-O- file of the active agent from the composition, e.g., as evi Sil(R) M-5P (untreated fumed silica that complies with the denced by increased inter-capsule variability, may be seen at pharmacopeia monograph “Colloidal Silicon Dioxide in the relatively low silicon dioxide levels. On the other hand, U.S. Pharmacopeia/National Formulary), is used in the com reduced processability may be seen at relatively high silicon positions as a viscosity enhancing agent. dioxide levels due to an increase in the rigidity and/or viscos 0128. The Viscosity enhancing agent, e.g., mineral par ity of the composition. Accordingly, in some embodiments, ticle, which can include one or more Suitable viscosity the compositions of the present disclosure specifically enhancing materials, can be present in the compositions at exclude Viscosity enhancing agents, e.g., mineral particles, in from about 2.4 to about 6.0 percent by weight relative to the an amount outside of one or more of the ranges specified total weight of the composition (wt %), e.g., at from about 2.5 above. to about 6.0 wt %, at from about 2.6 to about 6.0 wt %, at from 0.132. In some embodiments an unexpected, beneficial about 2.7 to about 6.0 wt %, at from about 2.8 to about 6.0 wt balance between dissolution variability and processability %, at from about 2.9 to about 6.0 wt %, at from about 3.0 to may be achieved by including the Viscosity enhancing agent, about 6.0 wt %, at from about 3.1 to about 6.0 wt %, at from e.g., mineral particle Such as silicon dioxide, at from about 2.4 about 3.2 to about 6.0 wt %, at from about 3.3 to about 6.0 wt to about 5.4 percent by weight relative to the total weight of %, at from about 3.4 to about 6.0 wt %, at from about 3.5 to the composition (wt %), e.g., at from about 2.4 to about 2.6 wit about 6.0 wt %, at from about 3.6 to about 6.0 wt %, at from %, at from about 2.6 to about 2.8 wt %, at from about 2.8 to about 3.7 to about 6.0 wt %, at from about 3.8 to about 6.0 wt about 3.0 wt %, at from about 3.0 to about 3.2 wt %, at from %, at from about 3.9 to about 6.0 wt %, at from about 4.0 to about 3.2 to about 3.4 wt %, at from about 3.4 to about 3.6 wt about 6.0 wt %, at from about 4.1 to about 6.0 wt %, at from %, at from about 3.6 to about 3.8 wt %, at from about 3.8 to about 4.2 to about 6.0 wt %, at from about 4.3 to about 6.0 wt about 4.0 wt %, at from about 4.0 to about 4.2 wt %, at from %, at from about 4.4 to about 6.0 wt %, at from about 4.5 to about 4.2 to about 4.4 wt %, at from about 4.4 to about 4.6 wt about 6.0 wt %, at from about 4.6 to about 6.0 wt %, at from %, at from about 4.6 to about 4.8 wt %, at from about 4.8 to about 4.7 to about 6.0 wt %, at from about 4.8 to about 6.0 wt about 5.0 wt %, at from about 5.0 to about 5.2 wt %, or at from %, at from about 4.9 to about 6.0 wt %, at from about 5.0 to about 5.2 to about 5.4 wt %. Similarly, a beneficial balance about 6.0 wt %, at from about 5.1 to about 6.0 wt %, at from between dissolution variability and processability may be about 5.2 to about 6.0 wt %, at from about 5.3 to about 6.0 wt achieved by including the Viscosity enhancing agent, e.g., %, at from about 5.4 to about 6.0 wt %, at from about 5.5 to mineral particle Such as silicon dioxide, at from about 2.6 to about 6.0 wt %, at from about 5.6 to about 6.0 wt %, at from about 5.4 wt %, e.g., at from about 2.8 to about 5.4 wt %, at about 5.7 to about 6.0 wt %, at from about 5.8 to about 6.0 wt from about 3.0 to about 5.4 wt %, at from about 3.2 to about %, or at from about 5.9 to about 6.0 wt %. 5.4 wt %, at from about 3.4 to about 5.4 wt %, at from about 0129. In some embodiments, a composition according to 3.6 to about 5.4 wt %, at from about 3.8 to about 5.4 wt %, at the present disclosure includes a viscosity enhancing agent, from about 4.0 to about 5.4 wt %, at from about 4.2 to about e.g., mineral particle, at from about 2.4 to about 2.6 wt %, at 5.4 wt %, at from about 4.4 to about 5.4 wt %, at from about US 2016/0038592 A1 Feb. 11, 2016

4.6 to about 5.4 wt %, at from about 4.8 to about 5.4 wt %, at includes one or more GelucireRS (saturated polyglycolized from about 5.0 to about 5.4 wt %, or at from about 5.2 to about glycerides). Suitable Gelucire Rs include, e.g., GelucireR) 5.4 wt %. 44/14 (lauroyl polyoxylglycerides) and Gelucire R 50/13 0133 AS discussed above, a Viscosity enhancing agent, (Stearoyl polyoxylglycerides). Accordingly, in Some embodi e.g., mineral particle. Such as silicon dioxide, when included ments, a Gelucire(R), e.g., GelucireR 44/14, Gelucire R 50/13, at specific concentration ranges in the compositions of the or a combination thereof, is present the compositions of the present disclosure, may reduce dissolution variability of the present disclosure at from about 0.01 to about 5 percent by composition, e.g., inter-capsule dissolution variability as weight relative to the total weight of the composition (wt %), determined using a USP Apparatus 2 dissolution tester and e.g., at from about 0.1 to about 5 wt %, or at from about 0.1 to method as described below in the Examples. See also, USP about 3 wt %. In some embodiments, a Gelucire(R), e.g., NF, Dissolution <711 >. Rockville, Md. US Pharmacopeial Gelucire R44/14, Gelucire R 50/13, or a combination thereof, Convention; 2008, the disclosure of which is incorporated by is present in the compositions of the present disclosure at reference herein. about 0.1 wt %, about 0.5 wt %, about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt %, or about 5 wt %. Stabilizing Agent Exemplary Compositions 0134) Materials that can be used as stabilizing agents in the compositions of the present disclosure include any mate 0.137 With reference to the various components discussed rial or Substance that can inhibit or reduce degradation (e.g., above, exemplary compositions are now described. by chemical reactions) of other substances or Substances in 0.138. In some embodiments a composition is provided the composition with which the stabilizer is mixed. Exem which includes a pharmacologically active agent; about 35% plary stabilizers typically are antioxidants that prevent oxi by weight to about 45% by weight, based on total weight of dative damage and degradation, e.g., sodium citrate, ascorbyl the composition, of a high viscosity liquid carrier material palmitate, vitamin A, and propyl gallate and/or reducing (HVLCM) having a viscosity of at least 5000 cF at 37° C. that agents. Other examples include ascorbic acid, vitamin E, does not crystallize neat at 25° C. and 1 atmosphere; about sodium bisulfite, butylhydroxyl toluene (BHT), BHA, acetyl 31% by weight to about 45% by weight, based on total weight cysteine, monothioglycerol, phenyl-alpha-nathylamine, leci of the composition, of a solvent; about 2% by weight to about thin, and EDTA. These stabilizing materials, which can 10% by weight, based on total weight of the composition, of include one or more of such Suitable materials, can be present a rheology modifier, and a cellulose acetate butyrate. Option in the compositions at from about 0.001 to about 2 percent by ally, the composition may be provided within a capsule hav weight relative to the total weight of the composition (wt %), ing a water content of less than about 10% by weight, e.g., an e.g., at from about 0.01 to about 0.1 wt %, or at from about HPMC capsule having a water content of less than about 10% 0.01 to about 0.02 wt %. In some embodiments, the compo by weight, e.g., less than about 5% by weight. sitions of the present disclosure specifically exclude a stabi 0.139. In some embodiments, a composition is provided lizing agent, such as those listed above. which includes a pharmacologically active agent; about 35% by weight to about 45% by weight, based on total weight of Surfactants the composition, of sucrose acetate isobutyrate (SAIB); about 31% by weight to about 45% by weight, based on total weight 0135) In some embodiments, a composition according to of the composition, of triacetin; about 2% by weight to about the present disclosure may include one or more surfactants. 10% by weight, based on total weight of the composition, of Materials that can be used as surfactants in the practice of the isopropyl myristate (IPM); and about 4% to about 6% of a present disclosure include neutral and/or anionic/cationic cellulose acetate butyrate (CAB), based on total weight of the excipients. Accordingly, Suitable charged lipids include, composition. Optionally, the composition may be provided without limitation, phosphatidylcholines (lecithin), and the within a capsule having a water content of less than about like. Detergents will typically be a nonionic, anionic, cationic 10% by weight, e.g., an HPMC capsule having a water con or amphoteric Surfactant. Examples of Suitable Surfactants tent of less than about 10% by weight, e.g., less than about 5% include, for example, Tergitol(R) and Triton R surfactants by weight. (Union Carbide Chemicals and Plastics); polyoxyethylene 0140. In some embodiments, a composition is provided sorbitans, e.g., TWEENR) surfactants (Atlas Chemical Indus which includes a pharmacologically active agent; a high vis tries); polysorbates; polyoxyethylene ethers, e.g. Brij; phar cosity liquid carrier material (HVLCM) having a viscosity of maceutically acceptable fatty acid esters, e.g., lauryl Sulfate at least 5000 cPat 37° C. that does not crystallize neat at 25° and salts thereof ampiphilic Surfactants (glycerides, etc.); C. and 1 atmosphere; a solvent; about 2% by weight to about GelucireRS (saturated polyglycolized glyceride (e.g., Gatte 10% by weight, based on total weight of the composition, of fosse brand)); and like materials. Surfactants, which can a rheology modifier; and a cellulose acetate butyrate (CAB), include one or more Suitable Surfactant material, can be wherein the HVLCM and the solvent are present in the com present in the compositions of the present disclosure at from position at a ratio of about 1.3:1 to about 1:1. Optionally, the about 0.01 to about 5 percent by weight relative to the total composition may be provided within a capsule having a water weight of the composition (wt %), e.g., at from about 0.1 to content of less than about 10% by weight, e.g., an HPMC about 5 wt %, or at from about 0.1 to about 3 wt %. In some capsule having a water content of less than about 10% by embodiments, a Surfactant is present in the compositions of weight, e.g., less than about 5% by weight. the present disclosure at about 0.1 wt %, about 0.5 wt %, 0.141. In some embodiments, a composition is provided about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt %, or which includes a pharmacologically active agent; a high vis about 5 wt %. cosity liquid carrier material (HVLCM) having a viscosity of 0136. In some embodiments, a suitable surfactant for at least 5000 cPat 37° C. that does not crystallize neat at 25° incorporation into the compositions of the present disclosure C. and 1 atmosphere; a solvent; a rheology modifier; and a US 2016/0038592 A1 Feb. 11, 2016

cellulose acetate butyrate (CAB), wherein the HVLCM, the modified to include a 20 mesh screen hanging basket to hold Solvent and the rheology modifier are present in the compo the testarticle is utilized with dissolution medium containing sition at a ratio of about 1.3:1.0:0.3 to about 1.0:1.0:0.05. 1000 ml 0.1 NHCl with 0.5% (w/w) SDS. The dissolution Optionally, the composition may be provided within a cap medium is maintained at 37° C. with stirring with 100 rpm sule having a water content of less than about 10% by weight, paddle speed over the course of a 24 hour dissolution test. e.g., an HPMC capsule having a water content of less than Standard sampling time points of 0.5, 2, 3, 6, 12 and 24 hours about 10% by weight, e.g., less than about 5% by weight. are utilized. A 1 mL sample is taken at each time point and 0142. In some embodiments, compositions are provided assayed using reverse-phase HPLC at 240 nm wavelength which provide specific advantages relative to a reference with a mobile phase including 0.35% (w/v) SDS/0.7% (v/v) composition, e.g., Reference Formulation A as described in acetic acid/44% (v/v) acetonitrile in water. Where the disso Example 1 below. Accordingly, in some embodiments a com lution test is used to determining a time-dependent change in position is provided which includes a pharmacologically an in vitro release profile of a composition, the composition active agent; a high viscosity liquid carrier material (HV may be stored for a Suitable period of time prior to testing, LCM) having a viscosity of at least 5000 cB at 37° C. that does e.g., the composition may be stored at 25°C./60% relative not crystallize neat at 25°C. and 1 atmosphere; a solvent; a humidity (RH) for from 1 to 6 months or at 40°C./75% RHfor rheology modifier; and a cellulose acetate butyrate (CAB), from 1 to 6 months. A Suitable number of capsules per com wherein the HVLCM, the solvent and the rheology modifier position tested may be, e.g., 12 capsules. are present in the composition at a ratio Sufficient to increase 0147 For compositions including amphetamine, the fol reproducibility of release relative to Reference Formulation A lowing dissolution testing protocol may be utilized: 2-phase when assayed in a USP Apparatus 2 dissolution tester modi dissolution medium is utilized in a USP Apparatus 2. Cap fied to have a 20-mesh basket for containing the composition. sules are placed in stainless steel (316SS) wire spiral capsule Optionally, the composition may be provided within a cap sinkers for dissolution testing. The dissolution parameters are sule having a water content of less than about 10% by weight, as follows: Dissolution medium: 750 ml 0.1N HCl for the first e.g., an HPMC capsule having a water content of less than 2 hours, with the addition of 200 ml 0.19M phosphate buffer about 10% by weight, e.g., less than about 5% by weight. to achieve a final pH of 6.0; Paddle speed: 50 rpm; Vessel 0143. In some embodiments, an increase in the reproduc temperature: 37°C. Sampling time points: 0.25, 0.5, 1, 1.5, 2. ibility of release may refer to a reduction or decrease in a 3, 6, 9, 12 and 24 hours. Sampling volume: 1 mL. Suitable storage time-dependent change in an in vitro release profile of HPLC parameters are as follows: Mobile phase A: 5 mM a composition. In such embodiments, the reproducibility of 1-Decanesulfonic acid, sodium salt, 5 mM sodium phosphate release for the composition may be determined relative to monobasic, pH 2.5: Mobile phase B: 100% acetonitrile; Reference Formulation A, which exhibits more than 10% Mobile phase: 67% Mobile phase A and 33% Mobile phase B; mean drug release decline, a similarity factor (f) of less than 210 nm wavelength. A Suitable number of capsules per com 50, when stored at 40° C./75% RH for a one month period of position tested may be, e.g., 6 capsules. time relative to its initial release profile. 0.148. For compositions including methylphenidate, the 0144) “Similarity factor' (f) as used herein refers to a following dissolution testing protocol may be utilized: logarithmic reciprocal square root transformation of one plus 2-phase dissolution medium is utilized in a USP Apparatus 2. the mean squared (the average sum of squares) differences of Capsules are placed in stainless steel (316SS) wire spiral drug percent dissolved between the test and the reference capsule sinkers for dissolution testing. The dissolution products. In other words, the similarity factor (f) is a loga parameters are as follows: Dissolution medium: 750 ml 0.1N rithmic transformation of the sum-squared error of differ HCl for the first 2 hours, with the addition of 200 ml 0.19M ences between the test T, and reference products R, over all phosphate buffer to achieve a final pH of 6.0; Paddle speed: 50 time points. It represents the closeness of two comparative rpm; Vessel temperature: 37° C. Sampling time points: 0.25, compositions. Generally similarity factor in the range of 0.5, 1, 1.5,2,3,6, 9, 12 and 24 hours. Sampling volume: 1 mL. 50-100 is acceptable according to the US FDA. f. may be Suitable HPLC parameters are as follows: Mobile phase A: 5 calculated as follows: f. 50*log {1+(1/n)X,*n(R-T)'' mM 1-Decanesulfonic acid, sodium salt, 5 mM sodium phos 5*100, where R, and T, are the cumulative percentage dis phate monobasic, pH 2.5: Mobile phase B: 100% acetonitrile; solved at each of the selected n time points of the reference Mobile phase: 71% Mobile phase A and 29% Mobile phase B; and test product respectively. 210 nm wavelength. 0145. In some embodiments, an increase in the reproduc 0149. In some embodiments, a composition is provided ibility of release may refer to a reduction or decrease in which includes: a pharmacologically active agent; a high inter-capsule variability at a particular time point. In Such viscosity liquid carrier material (HVLCM) having a viscosity embodiments, a decrease in inter-capsule variability may be of at least 5000 cB at 37° C. that does not crystallize neat at evidenced by a % RSD of less than about 15%, e.g., less than 25°C. and 1 atmosphere; a solvent; a rheology modifier; and about 10%, or less than about 5% at the particular time point, a cellulose acetate butyrate, wherein the composition is e.g., t 2 hr or t=3 hr. 96 RSD may be calculated as follows: % encapsulated within a hydroxypropylmethylcellulose cap RSD-((SD/mean)x100). In some embodiments, a decrease Sule, and wherein the composition within the capsule includes in inter-capsule variability may be evidenced by a % RSD of less than 5% water by weight, based on total weight of the from about 15% to about 1%, e.g., from about 10% to about composition within the capsule. 1%, or from about 5% to about 1%. 0150. In some embodiments, a composition is provided 0146 Suitable in vitro dissolution test conditions for which includes: a pharmacologically active agent; and means determining a time-dependent change in an in vitro release for reducing a storage time-dependent change in an in vitro profile of a composition or inter-capsule variability of a com release profile of a composition relative to Reference Formu position, e.g., an oxycodone or hydrocodone containing com lation A. Optionally, the composition may be provided within position are as follows: a USP Apparatus 2 dissolution tester a capsule having a water content of less than about 10% by US 2016/0038592 A1 Feb. 11, 2016 weight, e.g., an HPMC capsule having a water content of less position; and about 2.5% by weight to about 3.2% by weight than about 10% by weight, e.g., less than about 5% by weight. of silicon dioxide relative to the total weight of the composi 0151. In some embodiments, a composition is provided tion. Optionally, the composition may be provided within a which includes: oxycodone at about 5% by weight relative to capsule having a water content of less than about 10% by the total weight of the composition; and means for reducing a weight, e.g., an HPMC capsule having a water content of less storage time-dependent change in an in vitro release profile of than about 10% by weight, e.g., less than about 5% by weight. the composition Relative to Ref. Formulation A. Optionally, 0156. In some embodiments, a composition is provided the composition may be provided within a capsule having a which includes: about 5% by weight of oxycodone relative to water content of less than about 10% by weight, e.g., an the total weight of the composition; about 39% by weight to HPMC capsule having a water content of less than about 10% about 41% sucrose acetate isobutyrate (SAIB) relative to the by weight, e.g., less than about 5% by weight. total weight of the composition; about 38% by weight to 0152. In some embodiments, a composition is provided about 41% of triacetin relative to the total weight of the which includes: a pharmacologically active agent; a high composition; about 2% by weight to about 3% by weight of viscosity liquid carrier material (HVLCM) having a viscosity isopropyl myristate (IPM) relative to the total weight of the of at least 5000 cF at 37° C. that does not crystallize neat at composition; about 4% to about 6% by weight of cellulose 25°C. and 1 atmosphere; a solvent; a network former; and a acetate butyrate (CAB) relative to the total weight of the mineral particle, wherein the mineral particle is present in the composition; about 5% by weight to about 6% by weight of composition in an amount from about 2.4% by weight to hydroxyethyl cellulose (HEC) relative to the total weight of about 5.4% by weight relative to the total weight of the the composition; and about 2.5% by weight to about 3.2% by composition. Optionally, the composition may be provided weight of silicon dioxide relative to the total weight of the within a capsule having a water content of less than about composition. Optionally, the composition may be provided 10% by weight, e.g., an HPMC capsule having a water con within a capsule having a water content of less than about tent of less than about 10% by weight, e.g., less than about 5% 10% by weight, e.g., an HPMC capsule having a water con by weight. tent of less than about 10% by weight, e.g., less than about 5% 0153. In some embodiments, a composition is provided by weight. which includes: an opioid; Sucrose acetate isobutyrate 0157. In some embodiments, a composition is provided (SAIB); triacetin; isopropyl myristate (IPM); cellulose which includes: oxycodone at about 5% by weight relative to acetate butyrate (CAB); hydroxyethyl cellulose (HEC); and the total weight of the composition; Sucrose acetate isobu silicon dioxide, wherein the silicon dioxide is present in the tyrate (SAIB) at about 40% by weight relative to the total composition in an amount from about 2.4% by weight to weight of the composition; triacetin at about 39% by weight about 5.4% by weight relative to the total weight of the relative to the total weight of the composition; isopropyl composition. Optionally, the composition may be provided myristate (IPM) at about 2.5% by weight relative to the total within a capsule having a water content of less than about weight of the composition; cellulose acetate butyrate (CAB) 10% by weight, e.g., an HPMC capsule having a water con at about 4.5% by weight relative to the total weight of the tent of less than about 10% by weight, e.g., less than about 5% composition; hydroxyethyl cellulose (HEC) at about 5.5% by by weight. weight relative to the total weight of the composition; and 0154) In some embodiments, a composition is provided silicon dioxide at about 2.9% by weight relative to the total which includes: oxycodone; about 35% by weight to about weight of the composition. Optionally, the composition may 45% sucrose acetate isobutyrate (SAIB) relative to the total be provided within a capsule having a water content of less weight of the composition; about 31% by weight to about than about 10% by weight, e.g., an HPMC capsule having a 45% of triacetin relative to the total weight of the composi water content of less than about 10% by weight, e.g., less than tion; about 2% by weight to about 10% by weight ofisopropyl about 5% by weight. myristate (IPM) relative to the total weight of the composi 0158. In some embodiments, a composition is provided tion; about 4% to about 6% by weight of cellulose acetate which includes: oxycodone at about 5% by weight relative to butyrate (CAB) relative to the total weight of the composi the total weight of the composition; Sucrose acetate isobu tion; about 5% by weight to about 6% by weight of hydroxy tyrate (SAIB) at about 40% by weight relative to the total ethyl cellulose (HEC) relative to the total weight of the com weight of the composition; triacetin at about 39% by weight position; and about 2.4% by weight to about 5.4% by weight relative to the total weight of the composition; isopropyl of silicon dioxide relative to the total weight of the composi myristate (IPM) at about 2.5% by weight relative to the total tion. Optionally, the composition may be provided within a weight of the composition; cellulose acetate butyrate (CAB) capsule having a water content of less than about 10% by at about 4.5% by weight relative to the total weight of the weight, e.g., an HPMC capsule having a water content of less composition; hydroxyethyl cellulose (HEC) at about 5.5% by than about 10% by weight, e.g., less than about 5% by weight. weight relative to the total weight of the composition; and 0155. In some embodiments, a composition is provided silicon dioxide at about 2.9% by weight relative to the total which includes: oxycodone; about 39% by weight to about weight of the composition, wherein the composition is encap 41% sucrose acetate isobutyrate (SAIB) relative to the total sulated within a hydroxypropylmethylcellulose (HPMC) weight of the composition; about 38% by weight to about capsule. 41% of triacetin relative to the total weight of the composi 0159. In some embodiments, a composition is provided tion; about 2% by weight to about 3% by weight of isopropyl which includes: a pharmacologically active agent; a high myristate (IPM) relative to the total weight of the composi viscosity liquid carrier material (HVLCM) having a viscosity tion; about 4% to about 6% by weight of cellulose acetate of at least 5000 cB at 37° C. that does not crystallize neat at butyrate (CAB) relative to the total weight of the composi 25° C. and 1 atmosphere; a solvent; a network former; and a tion; about 5% by weight to about 6% by weight of hydroxy mineral particle, wherein the HVLCM, the solvent, the net ethyl cellulose (HEC) relative to the total weight of the com work former, and the mineral particle are present in a ratio US 2016/0038592 A1 Feb. 11, 2016

Sufficient to reduce a storage time-dependent change in an in assayed in a USP Apparatus 2 dissolution tester modified to vitro release profile of a composition relative to Reference have a 20-mesh basket for containing the composition. Formulation A. Optionally, the composition may be provided Optionally, the composition may be provided within a cap within a capsule having a water content of less than about sule having a water content of less than about 10% by weight, 10% by weight, e.g., an HPMC capsule having a water con e.g., an HPMC capsule having a water content of less than tent of less than about 10% by weight, e.g., less than about 5% about 10% by weight, e.g., less than about 5% by weight. by weight. 0164. In some embodiments, a composition is provided 0160. In some embodiments, a composition is provided which includes: oxycodone at about 5% by weight relative to which includes: a pharmacologically active agent; a high the total weight of the composition; Sucrose acetate isobu viscosity liquid carrier material (HVLCM) having a viscosity tyrate (SAIB); triacetin; isopropyl myristate (IPM); cellulose of at least 5000 cF at 37° C. that does not crystallize neat at acetate butyrate (CAB); hydroxyethyl cellulose (HEC); and 25°C. and 1 atmosphere; a solvent; a network former; and a silicon dioxide, wherein the Sucrose acetate isobutyrate mineral particle, wherein the HVLCM, the solvent, the net (SAIB), triacetin, isopropyl myristate (IPM), cellulose work former, and the mineral particle are present in a ratio acetate butyrate (CAB), hydroxyethyl cellulose (HEC), and sufficient to reduce inter-capsule variability in an in vitro silicon dioxide, are present in a ratio Sufficient to provide an release profile of the composition relative to Reference For in vitro release profile characterized by an inter-capsule Vari mulation A, when assayed in a USP Apparatus 2 dissolution ability having a % RSD of less than 10% at t=2 hr as deter tester modified to have a 20-mesh basket for containing the mined by an in vitro dissolution assay using a USP Apparatus composition. Optionally, the composition may be provided 2 dissolution tester modified to have a 20-mesh basket for within a capsule having a water content of less than about containing the composition. Optionally, the composition may 10% by weight, e.g., an HPMC capsule having a water con be provided within a capsule having a water content of less tent of less than about 10% by weight, e.g., less than about 5% than about 10% by weight, e.g., an HPMC capsule having a by weight. water content of less than about 10% by weight, e.g., less than 0161 In some embodiments, a composition is provided about 5% by weight. which includes: a pharmacologically active agent; a high 0.165. In some embodiments, a composition is provided viscosity liquid carrier material (HVLCM) having a viscosity which includes: a pharmacologically active agent; and com of at least 5000 cF at 37° C. that does not crystallize neat at bined amounts of a high viscosity liquid carrier material 25°C. and 1 atmosphere; a solvent; a network former; and a (HVLCM) having a viscosity of at least 5000 cF at 37° C. that mineral particle, wherein the HVLCM, the solvent, the net does not crystallize neat at 25°C. and 1 atmosphere, a solvent, work former, and the mineral particle are present in a ratio a rheology modifier, silicon dioxide, and a cellulose acetate sufficient to provide an in vitro release profile characterized butyrate, wherein the combined amounts are sufficient to by an inter-capsule variability having a 96 RSD of less than or increase reproducibility of release with respect to inter-cap equal to 10% at t=2 hr as determined by an in vitro dissolution sule variability relative to Reference Formulation A when assay using a USPApparatus 2 dissolution tester modified to assayed in a USP Apparatus 2 dissolution tester modified to have a 20-mesh basket for containing the composition. have a 20-mesh basket for containing the composition. Optionally, the composition may be provided within a cap Optionally, the composition may be provided within a cap sule having a water content of less than about 10% by weight, sule having a water content of less than about 10% by weight, e.g., an HPMC capsule having a water content of less than e.g., an HPMC capsule having a water content of less than about 10% by weight, e.g., less than about 5% by weight. about 10% by weight, e.g., less than about 5% by weight. 0162. In some embodiments, a composition is provided 0166 In some embodiments, a composition is provided which includes: oxycodone at about 5% by weight relative to which includes: a pharmacologically active agent; and com the total weight of the composition; Sucrose acetate isobu bined amounts of a high viscosity liquid carrier material tyrate (SAIB); triacetin; isopropyl myristate (IPM); cellulose (HVLCM) having a viscosity of at least 5000 cF at 37° C. that acetate butyrate (CAB); hydroxyethyl cellulose (HEC); and does not crystallize neat at 25°C. and 1 atmosphere, a solvent, silicon dioxide, wherein the Sucrose acetate isobutyrate a rheology modifier, silicon dioxide, and a cellulose acetate (SAIB), triacetin, isopropyl myristate (IPM), cellulose butyrate, wherein the combined amounts are sufficient to acetate butyrate (CAB), hydroxyethyl cellulose (HEC), and provide an in vitro release profile characterized by an inter silicon dioxide, are present in a ratio Sufficient to reduce a capsule variability having a '% RSD of less than 10% at t=2 hr storage time-dependent change in an in vitro release profile of as determined by an in vitro dissolution assay using a USP the composition relative to Reference Formulation A. Option Apparatus 2 dissolution tester modified to have a 20-mesh ally, the composition may be provided within a capsule hav basket for containing the composition. Optionally, the com ing a water content of less than about 10% by weight, e.g., an position may be provided within a capsule having a water HPMC capsule having a water content of less than about 10% content of less than about 10% by weight, e.g., an HPMC by weight, e.g., less than about 5% by weight. capsule having a water content of less than about 10% by 0163. In some embodiments, a composition is provided weight, e.g., less than about 5% by weight. which includes: oxycodone at about 5% by weight relative to 0167. In some embodiments, a composition is provided the total weight of the composition; Sucrose acetate isobu which includes: a pharmacologically active agent; and com tyrate (SAIB); triacetin; isopropyl myristate (IPM); cellulose bined amounts of a high viscosity liquid carrier material acetate butyrate (CAB); hydroxyethyl cellulose (HEC); and (HVLCM) having a viscosity of at least 5000 cF at 37° C. that silicon dioxide, wherein the Sucrose acetate isobutyrate does not crystallize neat at 25°C. and 1 atmosphere, a solvent, (SAIB), triacetin, isopropyl myristate (IPM), cellulose a rheology modifier, silicon dioxide, and a cellulose acetate acetate butyrate (CAB), hydroxyethyl cellulose (HEC), and butyrate, wherein the combined amounts are sufficient to silicon dioxide, are present in a ratio Sufficient to reduce increase reproducibility of release with respect to storage inter-capsule variability relative to Formulation A when time relative to Reference Formulation A when assayed in a US 2016/0038592 A1 Feb. 11, 2016

USP Apparatus 2 dissolution tester modified to have a 0171 Suitable capsules which may be utilized in connec 20-mesh basket for containing the composition. Optionally, tion with the disclosed compositions include, but are not the composition may be provided within a capsule having a limited to hard-shelled capsules, soft-shelled capsules, and water content of less than about 10% by weight, e.g., an interlocking capsules. HPMC capsule having a water content of less than about 10% 0172. In some embodiments a suitable capsule includes by weight, e.g., less than about 5% by weight. gelatin or synthetic polymers such as hydroxyl ethylcellulose and/or hydroxyl propylmethyl cellulose. Gelcaps can be of Methods of Making, Encapsulating and Administering the hard or soft variety, including, for example, polysaccha 0168 Once constituents have been selected to produce a ride or hypromellose acetate Succinate based caps (e.g., Vegi composition (e.g., an extended release composition) in accor caps brand, available from Catalent). The capsule can also be dance with the present disclosure, a liquid pharmaceutical coated with an enteric coating material Such as AQIAT (Shin composition can be prepared by simply mixing, for example Etsu) to delay release. a HVLCM, a rheology modifier, a network former, the active 0173 As discussed in the Examples below, certain time agent, a solvent and any additional additives. The composi dependent changes in drug release performance have been tions of the present disclosure are produced as liquid mix observed for Reference Formulation A. Without intending to tures, and have a number of excipient ingredients that are in be bound by any particular theory, it is believed that reducing Solution, Suspension, or in partial solution within the final the amount of water available to the compositions of the composition. Suitable methods for compounding or manu present disclosure may minimize these effects. For example, facturing the compositions make use of typical pharmaceuti by utilizing HPMC capsules (-2-6% w/w water, e.g., 4-6% cal/chemical mixing and handling apparatus and techniques. w/w water) instead of gelatin capsules (~13-16% w/w water) Since the liquid compositions of the present disclosure are the amount of water available to the compositions may be formed from a number of highly viscous liquids and Solids, reduced. Accordingly, in some embodiments, the composi they may have high final viscosities. Accordingly, the specific tions of the present disclosure are specifically encapsulated equipment and techniques employed in the manufacture of within capsules having lower water content than gelatin cap Such compositions may be selected so as to accommodate Sules, e.g., water content of less than about 15% w/w, less than Such material demands. In particular, various excipients. Such about 14% w/w, less than about 13% w/w, less than about as network formers, may be added to the composition mixture 12% w/w, less than about 11% w/w, less than 10% w/w, less in the Solid or semi-solid State, and as such they may be than about 9% w/w, less than about 8% w/w, less than about screened or otherwise size-reduced prior to addition to a 7% w/w, less than about 6% w/w, less than about 5% w/w, less composition mixing apparatus. Other solid excipients may than about 4% w/w, less than about 3% w/w, less than about require melting prior to addition to the liquid mixture. The 2% w/w, or less than about 1% w/w. In some embodiments, HVLCM materials are very high viscosity liquid materials, the compositions of the present disclosure are encapsulated however they tend to exhibit a dramatic reduction in viscosity within capsules having a water content of from about 1% w/w with increases in heat, and as such the mixing apparatus may to about 10% w/w, e.g., from about 1% w/w to about 9% w/w, beheated to accommodate the addition of the HVLCM mate from about 1% w/w to about 8%w/w, from about 1% w/w to rial or other similar materials. However, the mixing and pro about 7% w/w, from about 1% w/w to about 6% w/w, from cessing conditions should take into account the final integrity about 1% w/w to about 5% w/w, from about 1% w/w to about of the composition and accordingly the mixing conditions 4% w/w, from about 1% w/w to about 3% w/w, or from about may be selected so as to have a low-sheer effect on the 1% w/w to about 2% w/w. In some embodiments, the com composition, and/or to avoid any extended or pronounced positions of the present disclosure are encapsulated in cap excursions into high or low heat conditions. Once the com sules having a water content less than about 1% w/w includ position has been properly combined, an appropriate amount ing, for example, from about 0.1% w/w to about 1% w/w, of the resulting liquid mixture can be placed into a suitable from about 0.2% w/w to about 0.8% w/w, from about 0.4% capsule. Such as a gelatin or HPMC capsule to provide an oral wfw to about 0.8% w/w, or from about 0.6% w/w to about pharmaceutical dosage form. Alternative liquid compositions 0.8% w/w. Suitable HPMC capsules may include, for may include emulsifying the mixture in water, and introduc example, V-CapsTM, V-caps PlusTM, Quali-VTM, VegiCapsTM, ing this emulsion into a capsule. Embo Caps-VgTM, and HMPC capsules provided by Baotou 0169. An additional, exemplary composition preparation Capstech Co., Ltd, and Zhejiang LinFeng Capsules Co. Ltd. and encapsulation scheme is provided in FIG. 2. 0.174. The water content of a capsule, composition, or 0170 In some embodiments, an oral dosage form is pro composition in combination with a capsule, when provided vided which is composed of a liquid composition containing within a capsule as described in the present disclosure, may the active agent and any additional components within an be determined by Karl Fischer titration method as set forth in enclosure or capsule, e.g., a biodegradable enclosure or cap USP <921 > Method 1C.. In some embodiments, an AquaStar Sule. Such as a capsule or a gelatin capsule ('gelcap), C3000 Karl Fischer Coulometric Titrator may be used in wherein the capsule is made of a Substance that degrades or connection with the disclosed titration method. otherwise dissociates when exposed to conditions present in 0.175. In some embodiments, a composition according to the gastro-intestinal tract of a mammal. Capsules and gelcaps the present disclosure is one which has relatively low water are well known in drug delivery technology and one of skill content. For example, in some embodiments, a composition could select such a capsule as appropriate for delivery of a according to the present disclosure does not include more particular active agent. Once the capsule has dissolved or than about 5% water by weight, based on total weight of the dissociated from the composition, the disclosed compositions composition. For example, the composition may include generally remains intact, especially for hydrophobic compo water at less than about 5% by weight, less than about 4% by sitions, and passes through the GI tract without emulsification weight, less than about 3% by weight, or less than about 2% or fragmentation. by weight, based on the total weight of the composition. In US 2016/0038592 A1 Feb. 11, 2016

Some embodiments, a composition according to the present tion, of a solvent, about 2% by weight to about 10% by disclosure includes water at from about 1.0 to about 5.0% by weight, based on total weight of the composition, of a rheol weight, based on total weight of the composition, e.g., at from ogy modifier, and a cellulose acetate butyrate; and orally about 1.0 to about 4.5% by weight, at from about 1.0 to about administering the composition. Optionally, the composition 3.0% by weight, at from about 1.0 to about 2.5% by weight, at may be provided within a capsule having a water content of from about 1.0 to about 2.0% by weight, or at from about 1.0 less than about 10% by weight, e.g., an HPMC capsule having to about 1.5% by weight, based on total weight of the com a water content of less than about 10% by weight, e.g., less position. In some embodiments, a composition according to than about 5% by weight. the present disclosure includes water at about 1.0% by 0179. In some embodiments, the present disclosure pro weight, about 1.5% by weight, about 2% by weight, about vides a method of reducing a time-dependent change in an in 2.5% by weight, about 3% by weight, about 3.5% by weight, vitro release profile of a pharmacologically active agent from about 4% by weight, about 4.5% by weight, or about 5% by a composition, wherein the method includes formulating the weight, based on the total weight of the composition. In the pharmacologically active agent with (a) a high viscosity liq above embodiments, each of the above compositions may be uid carrier material (HVLCM) having a viscosity of at least a composition which has been encapsulated within a capsule 5000 cB at 37 C that does not crystallize neat at 25 C and 1 having a water content of less than about 15% W/w (e.g., less atmosphere, (b) a solvent, (c) a rheology modifier and (d) than about 10% w/w or less than about 5% w/w), e.g., an cellulose acetate butyrate, such that the composition includes HPMC capsule, and stored for a period of time, e.g., 1, 2, 3, 4, about 35% by weight to about 45% by weight, based on total 5, 6, 7, 8, 9, 10, 11 or 12 months, at 25°C. and 60% relative weight of the composition, of the high viscosity liquid carrier humidity (RH), 30° C. and 65% RH, or 40° C. and 75% RH. material (HVLCM) having a viscosity of at least 5000 cp at 0176 The water content of a composition as described in 37 C that does not crystallize neat at 25C and 1 atmosphere, the present disclosure may be determined by Karl Fischer about 31% by weight to about 45% by weight, based on total titration method as set forth in USP <921 > Method 1C.. In weight of the composition, of the solvent, about 2% by weight some embodiments, an AquaStar C3000 Karl Fischer Coulo to about 10% by weight, based on total weight of the compo metric Titrator may be used in connection with the disclosed sition, of the rheology modifier, and the cellulose acetate titration method. butyrate. Optionally, the composition may be provided within 0177. In some embodiments, the water content of the com a capsule having a water content of less than about 10% by position and the capsule combined is less than about 5% by weight, e.g., an HPMC capsule having a water content of less weight based on the total weight of the composition and the than about 10% by weight, e.g., less than about 5% by weight. capsule combined, e.g., less than about 4% by weight, less 0180. In some embodiments, the present disclosure pro than about 3% by weight, or less than about 2% by weight vides a use of (a) a high viscosity liquid carrier material based on the total weight of the composition and the capsule (HVLCM) having a viscosity of at least 5000 cF at 37 C that combined. In some embodiments, the water content of the does not crystallize neat at 25 C and 1 atmosphere, (b) a composition and the capsule combined is from about 5% by Solvent, (c) a rheology modifier and (d) cellulose acetate weight to about 4% by weight, from about 4% by weight to butyrate, for reducing a time-dependent change in an in vitro about 3% by weight, from about 3% by weight to about 2% by release profile of a pharmacologically active agent from a weight, or from about 2% by weight to about 1% by weight composition, wherein the use includes formulating the phar based on the total weight of the composition and the capsule macologically active agent with (a) the high viscosity liquid combined. In some embodiments, the water content of the carrier material (HVLCM) having a viscosity of at least 5000 composition and the capsule combined is about 1.0% by cP at 37 C that does not crystallize neat at 25 C and 1 atmo weight, about 1.5% by weight, about 2% by weight, about sphere, (b) the solvent, (c) the rheology modifier and (d) 2.5% by weight, about 3% by weight, about 3.5% by weight, cellulose acetate butyrate, thereby providing a composition about 4% by weight, about 4.5% by weight, or about 5% by that includes about 35% by weight to about 45% by weight, weight, based on the total weight of the composition and the based on total weight of the composition, of the high viscosity capsule combined. The water content of a composition and liquid carrier material (HVLCM) having a viscosity of at least capsule combined as described in the present disclosure may 5000 cB at 37 C that does not crystallize neat at 25 C and 1 be determined by Karl Fischer titration method as set forth in atmosphere, about 31% by weight to about 45% by weight, USP <921 > Method 1C.. In some embodiments, an AquaStar based on total weight of the composition, of the solvent, about C3000 Karl Fischer Coulometric Titrator may be used in 2% by weight to about 10% by weight, based on total weight connection with the disclosed titration method. of the composition, of the rheology modifier, and the cellu 0.178 The time-dependent change in release performance lose acetate butyrate. Optionally, the composition may be may also be addressed by formulating the various compo provided within a capsule having a water content of less than nents of the composition in specific concentration ranges about 10% by weight, e.g., an HPMC capsule having a water and/or at specific ratios for oral dosage forms. Accordingly, content of less than about 10% by weight, e.g., less than about the present disclosure provides a method of orally adminis 5% by weight. tering a composition, including: reducing a time-dependent 0181. In some embodiments, the present disclosure pro change in an in vitro release profile of a composition by vides a method of orally administering a composition, includ formulating the composition to include, in addition to a phar ing: reducing a time-dependent change in an in vitro release macologically active agent, about 35% by weight to about profile of a composition by formulating the composition to 45% by weight, based on total weight of the composition, of include, in addition to a pharmacologically active agent, a a high viscosity liquid carrier material (HVLCM) having a high viscosity liquid carrier material (HVLCM) having a viscosity of at least 5000 cp at 37°C. that does not crystallize viscosity of at least 5000 cp at 37°C. that does not crystallize neat at 25° C. and 1 atmosphere, about 31% by weight to neat at 25° C. and 1 atmosphere, a solvent; about 2% by about 45% by weight, based on total weight of the composi weight to about 10% by weight, based on total weight of the US 2016/0038592 A1 Feb. 11, 2016 composition, of a rheology modifier, and a cellulose acetate weight of the composition, wherein the composition is for butyrate (CAB), wherein the HVLCM and the solvent are mulated for oral administration, and one or more symptoms present in the composition at a ratio of about 1.3:1.0 to about or signs associated with the Subject’s pain is alleviated. 1.0:1.0; and orally administering the composition. Option Optionally, the composition may be provided within a cap ally, the composition may be provided within a capsule hav sule having a water content of less than about 10% by weight, ing a water content of less than about 10% by weight, e.g., an e.g., an HPMC capsule having a water content of less than HPMC capsule having a water content of less than about 10% about 10% by weight, e.g., less than about 5% by weight. by weight, e.g., less than about 5% by weight. 0182. In some embodiments, the present disclosure pro 0186. In some embodiments, the present disclosure pro vides a method of orally administering a composition, includ vides a method for treating pain in a Subject, the method ing: reducing a time-dependent change in an in vitro release including: orally administering to the Subject a composition profile of a composition by formulating the composition to including an opioid; Sucrose acetate isobutyrate (SAIB); tri include, in addition to a pharmacologically active agent, a acetin: isopropyl myristate (IPM); cellulose acetate butyrate high viscosity liquid carrier material (HVLCM) having a (CAB); hydroxyethyl cellulose (HEC); and silicon dioxide, viscosity of at least 5000 cp at 37°C. that does not crystallize wherein the silicon dioxide is present in the composition in an neat at 25°C. and 1 atmosphere; a solvent; a rheology modi amount from about 2.4% by weight to about 5.4% by weight fier; and a cellulose acetate butyrate (CAB), wherein the relative to the total weight of the composition, wherein the HVLCM, the solvent and the rheology modifier are present in composition is formulated for oral administration, and one or the composition at a ratio of about 1.3:1.0:0.3 to about 1.0:1. more symptoms or signs associated with the Subject’s pain is 0:0.05; and orally administering the composition. Optionally, alleviated. Optionally, the composition may be provided the composition may be provided within a capsule having a within a capsule having a water content of less than about water content of less than about 10% by weight, e.g., an 10% by weight, e.g., an HPMC capsule having a water con HPMC capsule having a water content of less than about 10% tent of less than about 10% by weight, e.g., less than about 5% by weight, e.g., less than about 5% by weight. by weight. 0183 In some embodiments, the present disclosure pro vides a method of orally administering a composition, includ 0187. In some embodiments, the present disclosure pro ing: reducing a time-dependent change in an in vitro release vides a method for treating pain in a Subject, the method profile of a composition by formulating the composition to including: orally administering to the Subject a composition include, in addition to a pharmacologically active agent, a including oxycodone; about 35% by weight to about 45% high viscosity liquid carrier material (HVLCM) having a sucrose acetate isobutyrate (SAIB) relative to the total weight viscosity of at least 5000 cp at 37°C. that does not crystallize of the composition; about 31% by weight to about 45% of neat at 25°C. and 1 atmosphere; a solvent; a rheology modi triacetin relative to the total weight of the composition; about fier; and a cellulose acetate butyrate (CAB), wherein the 2% by weight to about 10% by weight of isopropyl myristate HVLCM, the solvent and the rheology modifier are present in (IPM) relative to the total weight of the composition; about the composition at a ratio Sufficient to increase reproducibil 4% to about 6% by weight of cellulose acetate butyrate ity of release relative to Reference Formulation A when (CAB) relative to the total weight of the composition; about assayed in a USP Apparatus 2 dissolution tester modified to 5% by weight to about 6% by weight of hydroxyethyl cellu have a 20-mesh basket for containing the composition; and lose (HEC) relative to the total weight of the composition; and orally administering the composition. Optionally, the compo about 2.4% by weight to about 5.4% by weight of silicon sition may be provided within a capsule having a water con dioxide relative to the total weight of the composition, tent of less than about 10% by weight, e.g., an HPMC capsule wherein one or more symptoms or signs associated with the having a water content of less than about 10% by weight, e.g., Subject's pain is alleviated. Optionally, the composition may less than about 5% by weight. be provided within a capsule having a water content of less 0184. In some embodiments, the present disclosure pro than about 10% by weight, e.g., an HPMC capsule having a vides a method of orally administering a composition, includ water content of less than about 10% by weight, e.g., less than ing: reducing a storage time-dependent change in a release about 5% by weight. profile of a composition by formulating the composition to 0188 In some embodiments, the present disclosure pro include, in addition to a pharmacologically active agent, vides a method for treating pain in a Subject, the method means for the reducing a storage time-dependent change in a including: orally administering to the Subject a composition release profile of the composition relative to Reference For including oxycodone; about 39% by weight to about 41% mulation A. Optionally, the composition may be provided sucrose acetate isobutyrate (SAIB) relative to the total weight within a capsule having a water content of less than about of the composition; about 38% by weight to about 41% of 10% by weight, e.g., an HPMC capsule having a water con triacetin relative to the total weight of the composition; about tent of less than about 10% by weight, e.g., less than about 5% 2% by weight to about 3% by weight of isopropyl myristate by weight. (IPM) relative to the total weight of the composition; about 0185. In some embodiments, the present disclosure pro 4% to about 6% by weight of cellulose acetate butyrate vides a method for treating pain in a Subject, the method (CAB) relative to the total weight of the composition; about including: orally administering to the Subject a composition 5% by weight to about 6% by weight of hydroxyethyl cellu including an opioid; a high Viscosity liquid carrier material lose (HEC) relative to the total weight of the composition; and (HVLCM) having a viscosity of at least 5000 cF at 37° C. that about 2.5% by weight to about 3.2% by weight of silicon does not crystallize neat at 25°C. and 1 atmosphere; a solvent; dioxide relative to the total weight of the composition, a network former; and silicon dioxide, wherein the silicon wherein one or more symptoms or signs associated with the dioxide is present in the composition in an amount from about Subject's pain is alleviated. Optionally, the composition may 2.4% by weight to about 5.4% by weight relative to the total be provided within a capsule having a water content of less US 2016/0038592 A1 Feb. 11, 2016 than about 10% by weight, e.g., an HPMC capsule having a ing: decreasing the variability of an in vitro release profile of water content of less than about 10% by weight, e.g., less than a composition by including about 2.4% by weight to about about 5% by weight. 5.4% by weight, relative to the total weight of the composi 0189 In some embodiments, the present disclosure pro tion, of mineral particle in the composition, wherein the com vides a method for treating pain in a Subject, the method position also includes a pharmacologically active agent, a including: orally administering to the Subject a composition high viscosity liquid carrier material (HVLCM) having a including about 5% by weight of oxycodone relative to the viscosity of at least 5000 cp at 37°C. that does not crystallize total weight of the composition; about 39% by weight to neat at 25° C. and 1 atmosphere, a solvent, and a network about 41% sucrose acetate isobutyrate (SAIB) relative to the former; and orally administering the composition. Option total weight of the composition; about 38% by weight to ally, the composition may be provided within a capsule hav about 41% of triacetin relative to the total weight of the ing a water content of less than about 10% by weight, e.g., an composition; about 2% by weight to about 3% by weight of HPMC capsule having a water content of less than about 10% isopropyl myristate (IPM) relative to the total weight of the by weight, e.g., less than about 5% by weight. composition; about 4% to about 6% by weight of cellulose 0193 In some embodiments, the present disclosure pro acetate butyrate (CAB) relative to the total weight of the vides a method of orally administering an encapsulated com composition; about 5% by weight to about 6% by weight of position, including: forming a composition including: a phar hydroxyethyl cellulose (HEC) relative to the total weight of macologically active agent, a high viscosity liquid carrier the composition; and about 2.5% by weight to about 3.2% by material (HVLCM) having a viscosity of at least 5000 cp at weight of silicon dioxide relative to the total weight of the 37° C. that does not crystallize neat at 25° C. and 1 atmo composition, wherein one or more symptoms or signs asso sphere, a solvent, a network former, and a mineral particle, ciated with the subject’s pain is alleviated. Optionally, the wherein the mineral particle is present in the composition in composition may be provided within a capsule having a water an amount from about 2.4% by weight to about 5.4% by content of less than about 10% by weight, e.g., an HPMC weight relative to the total weight of the composition; capsule having a water content of less than about 10% by improving an in vitro release profile of the composition by weight, e.g., less than about 5% by weight. encapsulating the composition within a capsule including 0190. In some embodiments, the present disclosure pro hydroxypropyl methylcellulose to form an encapsulated vides a method for treating pain in a Subject, the method composition; and orally administering the encapsulated com including: orally administering to the Subject a composition position. including oxycodone at about 5% by weight relative to the 0194 In some embodiments, the present disclosure pro total weight of the composition. Sucrose acetate isobutyrate vides a method of orally administering an encapsulated com (SAIB) at about 40% by weight relative to the total weight of position, including: forming a composition including: a phar the composition; triacetin at about 39% by weight relative to macologically active agent, a high viscosity liquid carrier the total weight of the composition; isopropyl myristate material (HVLCM) having a viscosity of at least 5000 cp at (IPM) at about 2.5% by weight relative to the total weight of 37° C. that does not crystallize neat at 25° C. and 1 atmo the composition; cellulose acetate butyrate (CAB) at about sphere, a solvent, a network former, and a mineral particle, 4.5% by weight relative to the total weight of the composi wherein the mineral particle is present in the composition in tion; hydroxyethyl cellulose (HEC) at about 5.5% by weight an amount from about 2.4% by weight to about 5.4% by relative to the total weight of the composition; and silicon weight relative to the total weight of the composition; reduc dioxide, wherein the silicon dioxide is present in the compo ing exposure of the composition to water by encapsulating the sition at about 2.9% by weight relative to the total weight of composition within a capsule including hydroxypropyl meth the composition, wherein the composition is formulated for ylcellulose to form an encapsulated composition; and orally oral administration, and one or more symptoms or signs asso administering the encapsulated composition. ciated with the subject’s pain is alleviated. Optionally, the 0.195. In certain embodiments, the compositions of the composition may be provided within a capsule having a water present disclosure may be formulated so as to produce par content of less than about 10% by weight, e.g., an HPMC ticular controlled plasma levels of an active agent over a capsule having a water content of less than about 10% by particular period, e.g., to maintain a plasma level within an weight, e.g., less than about 5% by weight. appropriate therapeutic range. An appropriate therapeutic 0191 In some embodiments, the present disclosure pro range will vary depending on the active agent, but can range vides a method of orally administering a composition, includ from femtogram/mL levels up to above microgram/mL levels ing: improving reproducibility of an in vitro release profile of for a desired period of time. For example, a single dose of a a composition by including about 2.4% by weight to about composition disclosed herein may result in maintenance of 5.4% by weight, relative to the total weight of the composi plasma levels of greater than 5 ng/mL for a period of greater tion, of mineral particle in the composition, wherein the com than 8 hours. In other embodiments, the plasma level position also includes a pharmacologically active agent, a achieved using a single dose may be greater than about 5 high viscosity liquid carrier material (HVLCM) having a ng/mL for a period of greater than about 10hours, greater than viscosity of at least 5000 cp at 37°C. that does not crystallize about 12 hours, greater than about 14 hours, greater than neat at 25° C. and 1 atmosphere, a solvent, and a network about 16 hours, greater than about 18 hours, or greater than former; and orally administering the composition. Option about 20 hours. In yet other embodiments, the plasma level ally, the composition may be provided within a capsule hav achieved using a single dose may be greater than about 5 ing a water content of less than about 10% by weight, e.g., an ng/mL, greater than about 10 ng/mL, greater than about 15 HPMC capsule having a water content of less than about 10% ng/mL, greater than about 20 ng/mL, greater than about 30 by weight, e.g., less than about 5% by weight. ng/mL, greater than about 40 ng/mL, or greater than about 50 0.192 In some embodiments, the present disclosure pro ng/mL for a period of about 4, about 8, about 10, about 12, vides a method of orally administering a composition, includ about 14, about 16, about 18, about 20 or about 24 hours. The US 2016/0038592 A1 Feb. 11, 2016 20 maximum plasma concentration of an active agent may be iting aspects of the disclosure numbered 1-604 are provided reached at a time following administration from between below. As will be apparent to those of skill in the art upon about 0.1 hr to about 24 hr, or from about 0.25 hr to about 10 reading this disclosure, each of the individually numbered hr, or from about 0.25 hr to about 8 hr, or from about 0.5 hr to aspects may be used or combined with any of the preceding or about 6 hr, or from about 0.5 hr to about 4 hr, or from about 0.5 following individually numbered aspects. This is intended to hr to about 2 hr., or from about 0.5 hr to about 1 hr. The time provide Support for all Such combinations of aspects and is to maximum plasma concentration may be adjusted by not limited to combinations of aspects explicitly provided adjusting various components of the controlled release carrier below. system as taught herein. 0201 1. A composition comprising: 0196. The plasma levels obtained may be adjusted by 0202 a pharmacologically active agent; adjusting the dose of the active agent, and/or by adjusting the 0203 about 35% by weight to about 45% by weight, components of the composition, and desirable plasma levels based on total weight of the composition, of a high will depend on therapeutic range or its index for any particu viscosity liquid carrier material (HVLCM) having a vis laractive agent. It is readily within the skill of one in the art to cosity of at least 5000 cp at 37°C. that does not crystal determine the desired therapeutic index. lize neat at 25°C. and 1 atmosphere: 0197) The rate of active agent release from the composi tion may be varied depending on the agent used and the 0204 about 31% by weight to about 45% by weight, dosage required. Release rates may be different in different based on total weight of the composition, of a solvent; parts of the GI tract, and release rates may be averaged over 0205 about 2% by weight to about 10% by weight, the time of transit through the GI tract (approximately 8-24 based on total weight of the composition, of a rheology hrs). Typical average release rates may vary Substantially. For modifier; and many active agents, they may range from about 0.01 to about 0206 a cellulose acetate butyrate. 500 mg/hr, e.g., from about 0.5 to about 250 mg/hr, from 0207 2. The composition of 1, wherein the HVLCM is about 0.75 to about 100 mg/hr, from about 1 to about 100 sucrose acetate isobutyrate (SAIB). mg/hr, from about 2 to about 100 mg/hr, from about 5 to about 0208. 3. The composition of 1 or 2, wherein the composi 100 mg/hr, from about 10 to about 100 mg/hr, from about 10 tion is in a capsule having a water content of less than 10%. to about 80 mg/hr, from about 20 to about 50 mg/hr, or from 0209 4. The composition of any one of 1 to 3, wherein the about 20 to about 40 mg/hr. solvent is a hydrophilic solvent. (0198 Dosage regimens for a particular active agent of 0210 5. The composition of any one of 1 to 4, wherein the interest may be determined by the physician in accordance composition is within a hydroxypropylmethylcellulose with standard practices. Once per day (QD) or twice per day (HPMC) capsule. (BID) dosing may be used to maintain a Sufficient clinical 0211 6. The composition of any one of 1 to 5, wherein the effect, e.g., to maintain pain relief. HVLCM is sucrose acetate isobutyrate (SAIB), the solvent is triacetin, and the rheology modifier is isopropyl Exemplary Non-Limiting Aspects of the Disclosure myristate (IPM). 0199 The present disclosure includes a composition com 0212 7. The composition of any one of 1 to 6, comprising prising: an opioid (e.g., about 2% by weight to about 50% by a mineral particle. weight, relative to the total weight of the composition, of an 0213 8. The composition of 7, wherein the mineral par opioid selected from oxycodone, oxymorphone, hydroc ticle is selected from talc, bentonite and kaolin. odone, and hydromorphone, either in the free base form or a 0214. 9. The composition of 7, wherein the mineral par pharmaceutically acceptable salt form thereof); Sucrose ticle is selected from silicon dioxide, Zinc oxide, magne acetate isobutyrate (SAIB); triacetin; isopropyl myristate sium oxide, titanium oxide, and calcium oxide. (IPM); cellulose acetate butyrate (CAB), wherein the CAB 0215 10. The composition of 7, wherein the mineral par has a number average molecular weight ranging from 66,000 ticle comprises silicon dioxide. Daltons to 83,000 Daltons, and wherein the CAB has at least 0216 11. The composition of any one of 1 to 10, wherein one feature selected from a butyryl content ranging from the pharmacologically active agent is selected from opioid, about 17% to about 38%, an acetyl content ranging from stimulant, and depressant. about 13% to about 30%, and a hydroxyl content ranging 0217 12. The composition of 11, wherein the pharmaco from about 0.8% to about 1.7%; hydroxyethyl cellulose logically active agent is an opioid. (HEC); and silicon dioxide, wherein the silicon dioxide is present in the composition in an amount from about 2.5% by 0218 13. The composition of 11, wherein the pharmaco weight to about 3.0% by weight relative to the total weight of logically active agentis selected from Oxycodone, oxymor the composition. In some embodiments, the composition phone, hydrocodone, and hydromorphone, either in the does not comprise more than 5% water by weight, based on free base form or a pharmaceutically acceptable salt form total weight of the composition. For instance, the composi thereof. tion may comprise water at from about 1.0 to about 2.5% by 0219. 14. The composition of 11, wherein the pharmaco weight (e.g., from about 1.0 to about 2.0% by weight), based logically active agent is oxycodone. on total weight of the composition. In some embodiments, the 0220 15. The composition of any one of 1 to 14, compris composition is contained within a capsule (e.g., a hydroxym ing a Surfactant. ethylcellulose capsule). 0221 16. The composition of 15, wherein the surfactant is 0200 Aspects, including embodiments, of the present saturated polyglycolized glyceride. subject matter described above may be beneficial alone or in 0222 17. The composition of any one of 1 to 16, wherein combination, with one or more other aspects or embodiments. the composition does not comprise more than 5% water by Without limiting the foregoing description, certain non-lim weight, based on total weight of the composition. US 2016/0038592 A1 Feb. 11, 2016

0223 18. The composition of 17, wherein the composition 0245 31. The composition of any one of 26 to 30, wherein does not comprise more than 2.5% water by weight, based the HVLCM is sucrose acetate isobutyrate (SAIB), the on total weight of the composition. Solvent is triacetin, and the rheology modifier is isopropyl 0224. 19. The composition of 17, wherein the composition myristate (IPM). does not comprise more than 2.0% water by weight, based 0246 32. The composition of any one of 26 to 31, com on total weight of the composition. prising a mineral particle. 0225, 20. The composition of any one of 1 to 15, wherein 0247 33. The composition of 32, wherein the mineral the composition comprises water at from about 1.0 to about particle is selected from talc, bentonite and kaolin. 2.5% by weight, based on total weight of the composition. 0248 34. The composition of 32, wherein the mineral 0226, 21. The composition of 20, wherein the composition particle is selected from silicon dioxide, Zinc oxide, mag comprises water at from about 1.0 to about 2.0% by weight, nesium oxide, titanium oxide, and calcium oxide. based on total weight of the composition. 0249 35. The composition of 32, wherein the mineral 0227. 22. The composition of 21, wherein the composition particle comprises silicon dioxide. comprises water at from about 1.0 to about 1.5% by weight, 0250) 36. The composition of any one of 26 to 35, wherein based on total weight of the composition. the pharmacologically active agent is selected from opioid, 0228 23. A composition comprising: stimulant, and depressant. 0229 a pharmacologically active agent; 0251 37. The composition of 36, wherein the pharmaco 0230 about 35% by weight to about 45% by weight, logically active agent is an opioid. 0252) 38. The composition of 36, wherein the pharmaco based on total weight of the composition, of Sucrose logically active agentis selected from Oxycodone, oxymor acetate isobutyrate (SAIB); phone, hydrocodone, and hydromorphone, either in the 0231 about 31% by weight to about 45% by weight, free base form or a pharmaceutically acceptable salt form based on total weight of the composition, of triacetin: thereof. 0232 about 2% by weight to about 10% by weight, 0253 39. The composition of 36, wherein the pharmaco based on total weight of the composition, ofisopropyl logically active agent is oxycodone. myristate (IPM); and about 4% to about 6% of a cellu lose acetate butyrate (CAB), based on total weight of the 0254 40. The composition of any one of 26 to 39, com composition. prising a Surfactant. 0233. 24. The composition of 23, wherein the cellulose 0255 41. The composition of 40, wherein the surfactant is acetate butyrate comprises CAB having a number average saturated polyglycolized glyceride. 0256 42. The composition of any one of 26 to 41, wherein molecular weight ranging from 50,000 Daltons to 100,000 the composition does not comprise more than 5% water by Daltons. weight, based on total weight of the composition. 0234 25. The composition of 23 or 24, wherein the cellu lose acetate butyrate comprises CAB having at least one 0257 43. The composition of 42, wherein the composition feature selected from abutyryl content ranging from about does not comprise more than 2.5% water by weight, based 17% to about 41%, an acetyl content ranging from about on total weight of the composition. 13% to about 30%, and a hydroxyl content ranging from 0258 44. The composition of 42, wherein the composition about 0.5% to about 1.7%. does not comprise more than 2.0% water by weight, based 0235 26. A composition comprising: on total weight of the composition. 0259 45. The composition of any one of 26 to 41, wherein 0236 a pharmacologically active agent; the composition comprises water at from about 1.0 to about 0237 at least 35% by weight of a high viscosity liquid 2.5% by weight, based on total weight of the composition. carrier material (HVLCM) having a viscosity of at least 0260 46. The composition of 45, wherein the composition 5000 cF at 37° C. that does not crystallize neat at 25°C. comprises water at from about 1.0 to about 2.0% by weight, and 1 atmosphere, based on the total weight of the com based on total weight of the composition. position; 0261 47. The composition of 45, wherein the composition 0238 a solvent: comprises water at from about 1.0 to about 1.5% by weight, 0239 about 2% by weight to about 10% by weight, based on total weight of the composition. based on total weight of the composition, of a rheology 0262 48. A composition comprising: modifier; and 0263 a pharmacologically active agent; 0240 a cellulose acetate butyrate (CAB), wherein the 0264 at least 35% by weight of a high viscosity liquid HVLCM and the solvent are present in the composition carrier material (HVLCM) having a viscosity of at least at a ratio of about 1.3:1 to about 1:1. 5000 cF at 37° C. that does not crystallize neat at 25°C. 0241. 27. The composition of 26, wherein the HVLCM is and 1 atmosphere, based on the total weight of the com sucrose acetate isobutyrate (SAIB). position; 0242 28. The composition of 26 or 27, wherein the com 0265 a solvent; position is in a capsule having a water content of less than 0266 a rheology modifier; and 10%. 0267 a cellulose acetate butyrate (CAB), wherein the 0243 29. The composition of any one of 26 to 28, wherein HVLCM, the solvent and the rheology modifier are the solvent is a hydrophilic solvent. present in the composition at a ratio of about 1.3:1.0:0.3 0244, 30. The composition of any one of 26 to 29, wherein to about 1.0:1.0:0.05. the composition is within a hydroxypropylmethylcellulose 0268 49. The composition of 48, wherein the HVLCM is (HPMC) capsule. sucrose acetate isobutyrate (SAIB). US 2016/0038592 A1 Feb. 11, 2016 22

0269 50. The composition of 48 or 49, wherein the com present in the compositionata ratio Sufficient to increase position is in a capsule having a water content of less than reproducibility of release relative to Reference Formu 10%. lation A when assayed in a USP Apparatus 2 dissolution 0270. 51. The composition of any one of 48 to 50, wherein tester modified to have a 20-mesh basket for containing the solvent is a hydrophilic solvent. the composition. 0271 52. The composition of any one of 48 to 51, wherein 0295 71. The composition of 70, wherein the HVLCM is the composition is within a hydroxypropylmethylcellulose sucrose acetate isobutyrate (SAIB). (HPMC) capsule. 0296 72. The composition of any one of 70 to 71, wherein 0272 53. The composition of any one of 48 to 52, wherein the composition is in a capsule having a water content of the HVLCM is sucrose acetate isobutyrate (SAIB), the less than 10%. Solvent is triacetin, and the rheology modifier is isopropyl myristate (IPM). 0297. 73. The composition of any one of 70 to 72, wherein 0273 54. The composition of any one of 48 to 53, com the solvent is a hydrophilic solvent. prising a mineral particle. 0298 74. The composition of any one of 70 to 73, wherein 0274 55. The composition of 54, wherein the mineral the composition is within a hydroxypropyl methylcellulose particle is selected from talc, bentonite and kaolin. (HPMC) capsule. (0275 56. The composition of 54, wherein the mineral 0299 75. The composition of any one of 70 to 74, wherein particle is selected from silicon dioxide, Zinc oxide, mag the HVLCM is sucrose acetate isobutyrate (SAIB), the nesium oxide, titanium oxide, and calcium oxide. Solvent is triacetin, and the rheology modifier is isopropyl 0276 57. The composition of 54, wherein the mineral myristate (IPM). particle comprises silicon dioxide. (0300 76. The composition of any one of 70 to 75, com (0277) 58. The composition of any one of 48 to 57, wherein prising a mineral particle. the pharmacologically active agent is selected from opioid, (0301 77. The composition of 76, wherein the mineral stimulant, and depressant. particle is selected from talc, bentonite and kaolin. 0278 59. The composition of 58, wherein the pharmaco (0302) 78. The composition of 76, wherein the mineral logically active agent is an opioid. particle is selected from silicon dioxide, Zinc oxide, mag 0279 60. The composition of 58, wherein the pharmaco nesium oxide, titanium oxide, and calcium oxide. logically active agentis selected from oxycodone, oxymor phone, hydrocodone, and hydromorphone, either in the (0303 79. The composition of 76, wherein the mineral free base form or a pharmaceutically acceptable salt form particle comprises silicon dioxide. thereof. (0304 80. The composition of any one of 70 to 79, wherein 0280 61. The composition of 58, wherein the pharmaco the pharmacologically active agent is selected from opioid, logically active agent is oxycodone. stimulant, and depressant. 81. The composition of 80, 0281 62. The composition of any one of 48 to 61, com wherein the pharmacologically active agent is an opioid. prising a Surfactant. 0305 82. The composition of 80, wherein the pharmaco 0282 63. The composition of 62, wherein the surfactant is logically active agentis selected from Oxycodone, oxymor Saturated polyglycolized glyceride. phone, hydrocodone, and hydromorphone, either in the 0283 64. The composition of any one of 48 to 63, wherein free base form or a pharmaceutically acceptable salt form the composition does not comprise more than 5% water by thereof. weight, based on total weight of the composition. 0306 83. The composition of 80, wherein the pharmaco 0284 65. The composition of 64, wherein the composition logically active agent is oxycodone. does not comprise more than 2.5% water by weight, based 0307 84. The composition of any one of 70 to 83, com on total weight of the composition. prising a Surfactant. 0285 66. The composition of 64, wherein the composition 0308 85. The composition of 84, wherein the surfactant is does not comprise more than 2.0% water by weight, based saturated polyglycolized glyceride. on total weight of the composition. 0286 67. The composition of any one of 48 to 63, wherein (0309 86. The composition of any one of 70 to 85, wherein the composition comprises water at from about 1.0 to about the composition does not comprise more than 5% water by 2.5% by weight, based on total weight of the composition. weight, based on total weight of the composition. 0287 68. The composition of 67, wherein the composition 0310 87. The composition of 86, wherein the composition comprises water at from about 1.0 to about 2.0% by weight, does not comprise more than 2.5% water by weight, based based on total weight of the composition. on total weight of the composition. 0288 69. The composition of 68, wherein the composition 0311 88. The composition of 86, wherein the composition comprises water at from about 1.0 to about 1.5% by weight, does not comprise more than 2.0% water by weight, based based on total weight of the composition. on total weight of the composition. 0289 70. A composition comprising: 0312 89. The composition of any one of 70 to 85, wherein 0290 a pharmacologically active agent; the composition comprises water at from about 1.0 to about 0291 a high viscosity liquid carrier material (HVLCM) 2.5% by weight, based on total weight of the composition. having a viscosity of at least 5000 cp at 37°C. that does 0313 90. The composition of 89, wherein the composition not crystallize neat at 25°C. and 1 atmosphere: comprises water at from about 1.0 to about 2.0% by weight, 0292 a solvent: based on total weight of the composition. 0293 a rheology modifier; and 0314 91. The composition of 90, wherein the composition 0294 a cellulose acetate butyrate (CAB), wherein the comprises water at from about 1.0 to about 1.5% by weight, HVLCM, the solvent and the rheology modifier are based on total weight of the composition. US 2016/0038592 A1 Feb. 11, 2016

0315 92. A composition comprising: 0342 110. A composition comprising: 0316 a pharmacologically active agent; 0343 oxycodone at about 5% by weight to about 10% 0317 a high viscosity liquid carrier material (HVLCM) by weight relative to the total weight of the composition; and having a viscosity of at least 5000 cp at 37°C. that does 0344 means for reducing a storage time-dependent not crystallize neat at 25°C. and 1 atmosphere: change in an in vitro release profile of the composition 0318 a solvent: Relative to Ref. Formulation A. 0319 a rheology modifier; and 0345 111. The composition of 110, wherein the storage 0320 a cellulose acetate butyrate, time-dependent change in the release profile occurs fol 0321 wherein the composition is encapsulated within a lowing storage for 12 months at 25°C. and 60% RH. hydroxypropylmethylcellulose capsule, and 0346 112. The composition of 110, wherein Reference 0322 wherein the composition within the capsule com Formulation A exhibits more than 10% mean drug release prises less than 5% water by weight, based on total decline, a similarity factor (f) of less than 50, when stored weight of the composition within the capsule. at 40° C./75% RH for a one month period of time relative 0323 93. The composition of 92, wherein the composition to its initial release profile. comprises less than 2% water by weight, based on total 0347 113. A method of orally administering a composi weight of the composition. tion, comprising: 0324) 94. The composition of 92, wherein the HVLCM is 0348 reducing a time-dependent change in an in vitro sucrose acetate isobutyrate (SAIB). release profile of a composition by formulating the com position to include, in addition to a pharmacologically 0325 95. The composition of any one of 92 to 94, wherein active agent, the solvent is a hydrophilic solvent. (0349 about 35% by weight to about 45% by weight, 0326 96. The composition of any one of 92 to 95, wherein based on total weight of the composition, of a high the HVLCM is sucrose acetate isobutyrate (SAIB), the viscosity liquid carrier material (HVLCM) having a Solvent is triacetin, and the rheology modifier is isopropyl viscosity of at least 5000 cF at 37° C. that does not myristate (IPM). crystallize neat at 25°C. and 1 atmosphere, 0327 97. The composition of any one of 92 to 96, com 0350 about 31% by weight to about 45% by weight, prising a mineral particle. based on total weight of the composition, of a solvent, 0328 98. The composition of 97, wherein the mineral 0351 about 2% by weight to about 10% by weight, particle is selected from talc, bentonite and kaolin. based on total weight of the composition, of a rheol 0329 99. The composition of 97, wherein the mineral ogy modifier, and particle is selected from silicon dioxide, Zinc oxide, mag 0352 a cellulose acetate butyrate; and nesium oxide, titanium oxide, and calcium oxide. 0353 orally administering the composition. 0330 100. The composition of 97, wherein the mineral 0354 114. The method of 113, wherein the in vitro release particle comprises silicon dioxide. profile results remain similar, a similarity factor (f) of 0331 101. The composition of any one of 92 to 100, greater than 50, for the composition when stored at 40 wherein the pharmacologically active agent is selected C/75% RH for a one month period of time relative to an from opioid, Stimulant, and depressant. initial release profile. 0332 102. The composition of 101, wherein the pharma 0355 115. The method of 113, wherein the in vitro release cologically active agent is an opioid. profile results remain similar, a similarity factor (f) of 0333 103. The composition of 101, wherein the pharma greater than 60, for the composition when stored at 40 cologically active agent is selected from oxycodone, oxy C/75% RH for a one month period of time relative to an morphone, hydrocodone, and hydromorphone, either in initial release profile. the free base form or a pharmaceutically acceptable salt 0356 116. The method of 113, wherein the in vitro release form thereof. profile results remain similar, a similarity factor (f) of 0334 104. The composition of 101, wherein the pharma greater than 70, for the composition when stored at 40 cologically active agent is oxycodone. C/75% RH for a one month period of time relative to an 0335 105. The composition of any one of 92 to 104, initial release profile. comprising a surfactant. 0357 117. The method of 113, wherein the in vitro release profile results remain similar, a similarity factor (f) of 0336 106. The composition of 105, wherein the surfactant greater than 80, for the composition when stored at 40 is Saturated polyglycolized glyceride. C/75% RH for a one month period of time relative to an O337 107.. A COmoS1t1Onpositi COmorS1ng:prising initial release profile. 0338 a pharmacologically active agent; and 0358 118. The method of 113, wherein the in vitro release 0339 means for reducing a storage time-dependent profile results remain similar, a similarity factor (f) of change in an in vitro release profile of a composition greater than 90, for the composition when stored at 40 relative to Reference Formulation A. C/75% RH for a one month period of time relative to an 0340 108. The composition of 107, wherein the storage initial release profile. time-dependent change in the release profile occurs fol 0359 119. The method of 113, wherein the HVLCM is lowing storage for 12 months at 25°C. and 60% RH. sucrose acetate isobutyrate (SAIB). (0341) 109. The composition of 107, wherein Reference 0360 120. The method of 113 or 119, wherein the com Formulation A exhibits more than 10% mean drug release position is in a capsule having a water content of less than decline, a similarity factor (f) of less than 50, when stored 10%. at 40°C./75% RH for a one month period of time relative 0361 121. The method of any one of 113 to 120, wherein to its initial release profile. the solvent is a hydrophilic solvent. US 2016/0038592 A1 Feb. 11, 2016 24

0362. 122. The method of any one of 113 to 121, wherein 0379 139. The method of 138, wherein the in vitro release the composition is within a hydroxypropyl methylcellulose profile results remain similar, a similarity factor (f) of (HPMC) capsule. greater than 50, for the composition when stored at 40 0363 123. The method of any one of 113 to 122, wherein C/75% RH for a one month period of time relative to an the HVLCM is sucrose acetate isobutyrate (SAIB), the initial release profile. Solvent is triacetin, and the rheology modifier is isopropyl 0380 140. The method of 138, wherein the in vitro release myristate (IPM). profile results remain similar, a similarity factor (f) of 0364) 124. The method of any one of 113 to 123, wherein greater than 60, for the composition when stored at 40 the composition comprises a mineral particle. C/75% RH for a one month period of time relative to an 0365 125. The method of 124, wherein the mineral par initial release profile. ticle is selected from talc, bentonite and kaolin. 0381. 141. The method of 138, wherein the in vitro release 0366 126. The method of 124, wherein the mineral par profile results remain similar, a similarity factor (f) of ticle is selected from silicon dioxide, Zinc oxide, magne greater than 70, for the composition when stored at 40 sium oxide, titanium oxide, and calcium oxide. C/75% RH for a one month period of time relative to an 0367. 127. The method of 124, wherein the mineral par initial release profile. ticle comprises silicon dioxide. 0382. 142. The method of 138, wherein the in vitro release 0368 128. The method of any one of 113 to 127, wherein profile results remain similar, a similarity factor (f) of the pharmacologically active agent is selected from opioid, greater than 80, for the composition when stored at 40 stimulant, and depressant. C/75% RH for a one month period of time relative to an 0369 129. The method of 128, wherein the pharmacologi initial release profile. cally active agent is an opioid. 0383. 143. The method of 138, wherein the in vitro release 0370 130. The method of 128, wherein the pharmacologi profile results remain similar, a similarity factor (f) of cally active agent is selected from oxycodone, oxymor greater than 90, for the composition when stored at 40 phone, hydrocodone, and hydromorphone, either in the C/75% RH for a one month period of time relative to an free base form or a pharmaceutically acceptable salt form initial release profile. thereof. 0384 144. Use of (a) a high viscosity liquid carrier mate 0371) 131. The method of 128, wherein the pharmacologi rial (HVLCM) having a viscosity of at least 5000 cF at 37 cally active agent is oxycodone. C that does not crystallize neat at 25°C. and 1 atmosphere, 0372 132. The method of any one of 113 to 131, wherein (b) a solvent, (c) a rheology modifier and (d) cellulose the composition does not comprise more than 5% water by acetate butyrate, for reducing a time-dependent change in weight, based on total weight of the composition. an in vitro release profile of a pharmacologically active 0373) 133. The method of 132, wherein the composition agent from a composition, wherein the use comprises for does not comprise more than 2.5% water by weight, based mulating the pharmacologically active agent with (a) the on total weight of the composition. high viscosity liquid carrier material (HVLCM) having a 0374 134. The method of 132, wherein the composition viscosity of at least 5000 cp at 37° C. that does not crys does not comprise more than 2.0% water by weight, based tallize neat at 25 Cand 1 atmosphere, (b) the solvent, (c) the on total weight of the composition. rheology modifier and (d) cellulose acetate butyrate, 0375) 135. The method of any one of 113 to 131, wherein thereby providing a composition that comprises about 35% the composition comprises water at from about 1.0 to about by weight to about 45% by weight, based on total weight of 2.5% by weight, based on total weight of the composition. the composition, of the high viscosity liquid carrier mate 0376) 136. The method of 135, wherein the composition rial (HVLCM) having a viscosity of at least 5000 cF at 37° comprises water at from about 1.0 to about 2.0% by weight, C. that does not crystallize neat at 25°C. and 1 atmosphere, based on total weight of the composition. about 31% by weight to about 45% by weight, based on 0377 137. The method of 136, wherein the composition total weight of the composition, of the solvent, about 2% by comprises water at from about 1.0 to about 1.5% by weight, weight to about 10% by weight, based on total weight of based on total weight of the composition. the composition, of the rheology modifier, and the cellu 0378 138. A methodofreducing a time-dependent change lose acetate butyrate. in an in vitro release profile of a pharmacologically active 0385) 145. The use of 144, wherein the in vitro release agent from a composition, wherein the method comprises profile results remain similar, a similarity factor (f) of formulating the pharmacologically active agent with (a) a greater than 50, for the composition when stored at 40 high viscosity liquid carrier material (HVLCM) having a C/75% RH for a one month period of time relative to an viscosity of at least 5000 cp at 37° C. that does not crys initial release profile. tallize neat at 25°C. and 1 atmosphere, (b) a solvent, (c) a 0386 146. The use of 144, wherein the in vitro release rheology modifier and (d) cellulose acetate butyrate, Such profile results remain similar, a similarity factor (f) of that the composition comprises about 35% by weight to greater than 60, for the composition when stored at 40 about 45% by weight, based on total weight of the compo C/75% RH for a one month period of time relative to an sition, of the high viscosity liquid carrier material (HV initial release profile. LCM) having a viscosity of at least 5000 cB at 37° C. that (0387 147. The use of 144, wherein the in vitro release does not crystallize neat at 25°C. and 1 atmosphere, about profile results remain similar, a similarity factor (f) of 31% by weight to about 45% by weight, based on total greater than 70, for the composition when stored at 40 weight of the composition, of the solvent, about 2% by C/75% RH for a one month period of time relative to an weight to about 10% by weight, based on total weight of initial release profile. the composition, of the rheology modifier, and the cellu 0388. 148. The use of 144, wherein the in vitro release lose acetate butyrate. profile results remain similar, a similarity factor (f) of US 2016/0038592 A1 Feb. 11, 2016

greater than 80, for the composition when stored at 40 (0407 160. The method of any one of 150 to 159, wherein C/75% RH for a one month period of time relative to an the HVLCM is sucrose acetate isobutyrate (SAIB), the initial release profile. Solvent is triacetin, and the rheology modifier is isopropyl 0389. 149. The use of 144, wherein the in vitro release myristate (IPM). profile results remain similar, a similarity factor (f) of (0408 161. The method of any one of 150 to 160, wherein greater than 90, for the composition when stored at 40 the composition comprises a mineral particle. C/75% RH for a one month period of time relative to an 04.09 162. The method of 161, wherein the mineral par initial release profile. ticle is selected from talc, bentonite and kaolin. 0390 150. A method of orally administering a composi 0410 163. The method of 161, wherein the mineral par tion, comprising: ticle is selected from silicon dioxide, Zinc oxide, magne 0391 reducing a time-dependent change in an in vitro sium oxide, titanium oxide, and calcium oxide. release profile of a composition by formulating the com 0411 164. The method of 161, wherein the mineral par position to include, in addition to a pharmacologically ticle comprises silicon dioxide. active agent, 0412 165. The method of any one of 150 to 164, wherein 0392 at least 35% by weight of a high viscosity liq the pharmacologically active agent is selected from opioid, uid carrier material (HVLCM) having a viscosity of at stimulant, and depressant. least 5000 cFat 37° C. that does not crystallize neat at 0413 166. The method of 165, wherein the pharmacologi 25°C. and 1 atmosphere, cally active agent is an opioid. 0393 a solvent: 0414, 167. The method of 165, wherein the pharmacologi 0394 about 2% by weight to about 10% by weight, cally active agent is selected from oxycodone, oxymor based on total weight of the phone, hydrocodone, and hydromorphone, either in the 0395 composition, of a rheology modifier, and free base form or a pharmaceutically acceptable salt form 0396 a cellulose acetate butyrate (CAB), wherein thereof. the HVLCM and the solvent are present in the com 0415 168. The method of 165, wherein the pharmacologi position at a ratio of about 1.3:1.0 to about 1.0:1.0: cally active agent is oxycodone. and 0416) 169. The method of any one of 150 to 168, wherein 0397 orally administering the composition. the composition does not comprise more than 5% water by 0398. 151. The method of 150, wherein the in vitro release weight, based on total weight of the composition. profile results remain similar, a similarity factor (f) of 0417 170. The method of 169, wherein the composition greater than 50, for the composition when stored at 40 does not comprise more than 2.5% water by weight, based C/75% RH for a one month period of time relative to an on total weight of the composition. initial release profile. 0418 171. The method of 169, wherein the composition 0399. 152. The method of 150, wherein the in vitro release does not comprise more than 2.0% water by weight, based profile results remain similar, a similarity factor (f) of on total weight of the composition. greater than 60, for the composition when stored at 40 0419 172. The method of any one of 150 to 168, wherein C/75% RH for a one month period of time relative to an the composition comprises water at from about 1.0 to about initial release profile. 2.5% by weight, based on total weight of the composition. 0400 153. The method of 150, wherein the in vitro release 0420, 173. The method of 172, wherein the composition profile results remain similar, a similarity factor (f) of comprises water at from about 1.0 to about 2.0% by weight, greater than 70, for the composition when stored at 40 based on total weight of the composition. C/75% RH for a one month period of time relative to an 0421 174. The method of 173, wherein the composition initial release profile. comprises water at from about 1.0 to about 1.5% by weight, 0401 154. The method of 150, wherein the in vitro release based on total weight of the composition. profile results remain similar, a similarity factor (f) of 0422 175. A method of orally administering a composi greater than 80, for the composition when stored at 40 tion, comprising: C/75% RH for a one month period of time relative to an 0423 reducing a time-dependent change in an in vitro initial release profile. release profile of a composition by formulating the com 04.02 155. The method of 150, wherein the in vitro release position to include, in addition to a pharmacologically profile results remain similar, a similarity factor (f) of active agent, greater than 90, for the composition when stored at 40 0424 at least 35% by weight of a high viscosity liq C/75% RH for a one month period of time relative to an uid carrier material (HVLCM) having a viscosity of at initial release profile. least 5000 cFat 37° C. that does not crystallize neat at 0403 156. The method of any one of 150 to 155, wherein 25°C. and 1 atmosphere: the HVLCM is sucrose acetate isobutyrate (SAIB). 0425 a solvent: 0404 157. The method of any one of 150 to 156, wherein 0426 a rheology modifier; and the composition is in a capsule having a water content of 0427 a cellulose acetate butyrate (CAB), wherein less than 10%. the HVLCM, the solvent and the rheology modifier 04.05 158. The method of any one of 150 to 157, wherein are present in the composition at a ratio of about the solvent is a hydrophilic solvent. 1.3:1.0:0.3 to about 1.0:1.0:0.05; and 0406 159. The method of any one of 150 to 158, wherein 0428 orally administering the composition. the composition is within a hydroxypropyl methylcellulose 0429, 176. The method of 175, wherein the in vitro release (HPMC) capsule. profile results remain similar, a similarity factor (f) of US 2016/0038592 A1 Feb. 11, 2016 26

greater than 50, for the composition when stored at 40 0449) 196. The method of 194, wherein the composition C/75% RH for a one month period of time relative to an does not comprise more than 2.0% water by weight, based initial release profile. on total weight of the composition. 0430. 177. The method of 175, wherein the in vitro release 0450 197. The method of any one of 175 to 193, wherein profile results remain similar, a similarity factor (f) of the composition comprises water at from about 1.0 to about greater than 60, for the composition when stored at 40 2.5% by weight, based on total weight of the composition. C/75% RH for a one month period of time relative to an 0451 198. The method of 197, wherein the composition initial release profile. comprises water at from about 1.0 to about 2.0% by weight, 0431, 178. The method of 175, wherein the in vitro release based on total weight of the composition. profile results remain similar, a similarity factor (f) of 0452) 199. The method of 198, wherein the composition greater than 70, for the composition when stored at 40 comprises water at from about 1.0 to about 1.5% by weight, C/75% RH for a one month period of time relative to an based on total weight of the composition. initial release profile. 0453 200. A method of orally administering a composi 0432 179. The method of 175, wherein the in vitro release tion, comprising: profile results remain similar, a similarity factor (f) of 0454 reducing a time-dependent change in an in vitro greater than 80, for the composition when stored at 40 release profile of a composition by formulating the com C/75% RH for a one month period of time relative to an position to include, in addition to a pharmacologically initial release profile. active agent, 0433 180. The method of 175, wherein the in vitro release 0455 a high viscosity liquid carrier material (HV profile results remain similar, a similarity factor (f) of LCM) having a viscosity of at least 5000 cF at 37° C. greater than 90, for the composition when stored at 40 that does not crystallize neat at 25° C. and 1 atmo C/75% RH for a one month period of time relative to an sphere; initial release profile. 0456 a solvent: 0434 181. The method of any one of 175 to 180, wherein 0457 a rheology modifier; and the HVLCM is sucrose acetate isobutyrate (SAIB). 0458 a cellulose acetate butyrate (CAB), wherein 0435 182. The method of any one of 175 to 181, wherein the HVLCM, the solvent and the rheology modifier the composition is in a capsule having a water content of are present in the composition at a ratio Sufficient to less than 10%. increase reproducibility of release relative to Refer 0436 183. The method of any one of 175 to 182, wherein ence Formulation A when assayed in a USP Appara the solvent is a hydrophilic solvent. tus 2 dissolution tester modified to have a 20-mesh 0437 184. The method of any one of 175 to 183, wherein basket for containing the composition; and the composition is within a hydroxypropyl methylcellulose 0459 orally administering the composition. (HPMC) capsule. 0460 201. The method of 200, wherein the in vitro release 0438 185. The method of any one of 175 to 184, wherein profile results remain similar, a similarity factor (f) of the HVLCM is sucrose acetate isobutyrate (SAIB), the greater than 50, for the composition when stored at 40 Solvent is triacetin, and the rheology modifier is isopropyl C/75% RH for a one month period of time relative to an myristate (IPM). initial release profile. 0439 186. The method of any one of 175 to 185, wherein 0461) 202. The method of 200, wherein the in vitro release the composition comprises a mineral particle. profile results remain similar, a similarity factor (f) of 0440 187. The method of 186, wherein the mineral par greater than 60, for the composition when stored at 40 ticle is selected from talc, bentonite and kaolin. C/75% RH for a one month period of time relative to an 0441 188. The method of 186, wherein the mineral par initial release profile. ticle is selected from silicon dioxide, Zinc oxide, magne 0462. 203. The method of 200, wherein the in vitro release sium oxide, titanium oxide, and calcium oxide. profile results remain similar, a similarity factor (f) of 0442 189. The method of 186, wherein the mineral par greater than 70, for the composition when stored at 40 ticle comprises silicon dioxide. C/75% RH for a one month period of time relative to an 0443) 190. The method of any one of 175 to 189, wherein initial release profile. the pharmacologically active agent is selected from opioid, 0463. 204. The method of 200, wherein the in vitro release stimulant, and depressant. profile results remain similar, a similarity factor (f) of 0444 191. The method of 190, wherein the pharmacologi greater than 80, for the composition when stored at 40 cally active agent is an opioid. C/75% RH for a one month period of time relative to an 0445 192. The method of 190, wherein the pharmacologi initial release profile. cally active agent is selected from oxycodone, oxymor 0464. 205. The method of 200, wherein the in vitro release phone, hydrocodone, and hydromorphone, either in the profile results remain similar, a similarity factor (f) of free base form or a pharmaceutically acceptable salt form greater than 90, for the composition when stored at 40 thereof. C/75% RH for a one month period of time relative to an 0446. 193. The method of 190, wherein the pharmacologi initial release profile. cally active agent is oxycodone. 0465. 206. The method of any one of 200 to 205, wherein 0447 194. The method of any one of 175 to 193, wherein the HVLCM is sucrose acetate isobutyrate (SAIB). the composition does not comprise more than 5% water by 0466 207. The method of any one of 200 to 206, wherein weight, based on total weight of the composition. the composition is in a capsule having a water content of 0448 195. The method of 194, wherein the composition less than 10%. does not comprise more than 2.5% water by weight, based 0467. 208. The method of any one of 200 to 207, wherein on total weight of the composition. the solvent is a hydrophilic solvent. US 2016/0038592 A1 Feb. 11, 2016 27

0468. 209. The method of any one of 200 to 208, wherein 0488 228. A composition comprising: the composition is within a hydroxypropyl methylcellulose 0489 a pharmacologically active agent; (HPMC) capsule. 0490 a high viscosity liquid carrier material (HVLCM) 0469 210. The method of any one of 200 to 209, wherein having a viscosity of at least 5000 cp at 37°C. that does the HVLCM is sucrose acetate isobutyrate (SAIB), the not crystallize neat at 25°C. and 1 atmosphere: Solvent is triacetin, and the rheology modifier is isopropyl 0491 a solvent; myristate (IPM). 0492 a network former; and 0470 211. The method of any one of 200 to 210, wherein 0493 a mineral particle, wherein the mineral particle is the composition comprises a mineral particle. present in the composition in an amount from about 0471. 212. The method of 211, wherein the mineral par 2.4% by weight to about 5.4% by weight relative to the ticle is selected from talc, bentonite and kaolin. total weight of the composition. 0494 229. The composition of 228, wherein the mineral 0472. 213. The method of 211, wherein the mineral par particle is selected from talc, bentonite and kaolin. ticle is selected from silicon dioxide, Zinc oxide, magne 0495 230. The composition of 228, wherein the mineral sium oxide, titanium oxide, and calcium oxide. particle is selected from silicon dioxide, Zinc oxide, mag 0473 214. The method of 211, wherein the mineral par nesium oxide, titanium oxide, and calcium oxide. ticle comprises silicon dioxide. 0496 231. The composition of 228, wherein the mineral 0474) 215. The method of any one of 200 to 214, wherein particle comprises silicon dioxide. the pharmacologically active agent is selected from opioid, 0497 232. The composition of 228, wherein the pharma stimulant, and depressant. cologically active agent is selected from opioid, stimulant, 0475 216. The method of 215, wherein the pharmacologi and depressant. cally active agent is an opioid. 0498 233. The composition of 228, wherein the pharma 0476) 217. The method of 200, wherein the pharmacologi cologically active agent is an opioid. cally active agent is selected from oxycodone, oxymor 0499 234. The composition of 228, wherein the pharma phone, hydrocodone, and hydromorphone, either in the cologically active agent is selected from oxycodone, oxy free base form or a pharmaceutically acceptable salt form morphone, hydrocodone, and hydromorphone, either in thereof. the free base form or a pharmaceutically acceptable salt 0477 218. The method of 200, wherein the pharmacologi form thereof. cally active agent is oxycodone. 0500 235. The composition of 228, wherein the pharma 0478 219. The method of any one of 200 to 218, wherein cologically active agent is oxycodone. the composition does not comprise more than 5% water by (0501) 236. The composition of any one of 228 to 235, weight, based on total weight of the composition. wherein the HVLCM is sucrose acetate isobutyrate 0479. 220. The method of 219, wherein the composition (SAIB). does not comprise more than 2.5% water by weight, based (0502. 237. The composition of any one of 228 to 236, on total weight of the composition. comprising about 35% by weight to about 45% by weight 0480 221. The method of 219, wherein the composition of the HVLCM relative to the total weight of the compo does not comprise more than 2.0% water by weight, based sition. on total weight of the composition. (0503 238. The composition of any one of 228 to 237, wherein the solvent is selected from triacetin, N-methyl 0481) 222. The method of any one of 200 to 218, wherein 2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl the composition comprises water at from about 1.0 to about lactate, propylene carbonate and glycofurol. 2.5% by weight, based on total weight of the composition. (0504) 239. The composition of any one of 228 to 238, 0482 223. The method of 222, wherein the composition wherein the solvent comprises triacetin. comprises water at from about 1.0 to about 2.0% by weight, (0505 240. The composition of any one of 228 to 238, based on total weight of the composition. wherein the solvent comprises N-methyl-2-pyrrolidone. 0483 224. The method of 223, wherein the composition (0506. 241. The composition of any one of 228 to 238, comprises water at from about 1.0 to about 1.5% by weight, wherein the solvent comprises 2-pyrrolidone. based on total weight of the composition. (0507 242. The composition of any one of 228 to 238, 0484 225. A method of orally administering a composi wherein the solvent comprises dimethylsulfoxide. tion, comprising: (0508 243. The composition of any one of 228 to 238, 0485 reducing a storage time-dependent change in a wherein the solvent comprises ethyl lactate. release profile of a composition by formulating the com (0509. 244. The composition of any one of 228 to 238, position to include, in addition to a pharmacologically wherein the solvent comprises propylene carbonate. active agent, means for the reducing a storage time 0510) 245. The composition of any one of 228 to 238, dependent change in a release profile of the composition wherein the solvent comprises glycofurol. relative to Reference Formulation A. 0511 246. The composition of any one of 228 to 245, 0486 226. The method of 225, wherein the storage time comprising about 31% by weight to about 45% by weight dependent change in the release profile occurs following of the solvent relative to the total weight of the composi storage for 12 months at 25°C. and 60% RH. tion. 0487. 227. The method of 225, wherein Reference Formu 0512 247. The composition of 246, comprising about lation A exhibits more than 10% mean drug release decline, 38% by weight to about 41% by weight of the solvent a similarity factor (f) of less than 50, when stored at 40° relative to the total weight of the composition. C./75% RH for a one month period of time relative to its 0513 248. The composition of any one of 228 to 247, initial release profile. further comprising a rheology modifier. US 2016/0038592 A1 Feb. 11, 2016 28

0514 249. The composition of 248, wherein the rheology at from about 2.5% by weight to about 2.9% by weight modifier is selected from isopropyl myristate (IPM), relative to the total weight of the composition. caprylic?capric triglyceride, ethyl oleate, triethyl citrate, 0534 269. The composition of any one of 228 to 268, dimethyl phthalate and benzyl benzoate. wherein the composition has a complex viscosity of from 0515 250. The composition of 248, wherein the rheology about 100 Pa's to about 300 Pa's, wherein the complex modifier is IPM. viscosity is determined at a constant strain of 0.5%, a 0516 251. The composition of 248, wherein the rheology frequency of 1 Hz, and a temperature of 25°C. modifier is caprylic/capric triglyceride. 0535 270. The composition of any one of 228 to 269, 0517 252. The composition of 248, wherein the rheology wherein the composition has a complex viscosity of from modifier is ethyl oleate. about 120 Pa's to about 250 Pas, wherein the complex 0518) 253. The composition of 248, wherein the rheology viscosity is determined at a constant strain of 0.5%, a modifier is triethylcitrate. frequency of 1 Hz, and a temperature of 25°C. 0519 254. The composition of 248, wherein the rheology 0536 271. The composition of any one of 228 to 270, modifier is dimethyl phthalate. wherein the composition has a complex viscosity of from 0520 255. The composition of 248, wherein the rheology about 140 Pa's to about 200 Pas, wherein the complex modifier is benzyl benzoate. viscosity is determined at a constant strain of 0.5%, a 0521. 256. The composition of any one of 248 to 255, frequency of 1 Hz, and a temperature of 25°C. comprising about 2% by weight to about 10% by weight of the rheology modifier relative to the total weight of the 0537 272. The composition of any one of 228 to 271, composition. wherein the ratio of the HVLCM to the solvent in the 0522 257. The composition of any one of 228 to 256, composition is about 0.6:1 to 1.6:1. wherein the network former is selected from cellulose 0538 273. The composition of 272, wherein the ratio of acetate butyrate (CAB), cellulose acetate phthalate, ethyl the HVLCM to the solvent in the composition is about cellulose, hydroxypropylmethyl cellulose and cellulose O.8:1 to 1.5:1. triacetate. 0539 274. The composition of 273, wherein the ratio of 0523 258. The composition of any one of 228 to 257, the HVLCM to the solvent in the composition is about wherein the network former comprises cellulose acetate O.9:1 to 1.5:1. butyrate (CAB). (0540 275. The composition of any one of 228 to 272, 0524 259. The composition of any one of 228 to 258, wherein the composition comprises: wherein the network former comprises CAB having a num (0541 about 35% by weight to about 45% by weight of beraverage molecular weight ranging from 50,000 Daltons the HVLCM relative to the total weight of the composi to 100,000 Daltons. tion, 0525 260. The composition of any one of 228 to 259, (0542 about 31% by weight to about 45% by weight of wherein the network former comprises CAB having at least the solvent relative to the total weight of the composi one feature selected from a butyryl content ranging from tion, and about 17% to about 41%, an acetyl content ranging from (0543 about 2% by weight to about 10% by weight of about 13% to about 30%, and a hydroxyl content ranging the network former relative to the total weight of the from about 0.5% to about 1.7%. composition. 0526 261. The composition of any one of 228 to 260, 0544, 276. The composition of 275, comprising about further comprising a hydrophilic agent. 0.1% by weight to about 8% by weight of a rheology 0527 262. The composition of 261, wherein the hydro modifier relative to the total weight of the composition. philic agent is selected from hydroxyethyl cellulose (0545 277. The composition of 275 to 276, comprising (HEC), hydroxypropyl cellulose, caboxymethyl cellulose, about 2% by weight to about 10% by weight of a hydro polyethylene glycol and polyvinylpyrrolidone. philic agent. 0528 263. The composition of 261, wherein the hydro philic agent comprises HEC. (0546 278. The composition of any one of 228 to 277, 0529 264. The composition of any one of 228 to 263, wherein the composition comprises: wherein the mineral particle is present in the composition (0547 about 39% by weight to about 41% by weight of in an amount from about 2.5% by weight to about 4.0% by the HVLCM relative to the total weight of the composi weight relative to the total weight of the composition. tion, 0530 265. The composition of any one of 228 to 264, (0548 about 38% by weight to about 40% by weight of wherein the mineral particle is present in the composition the solvent relative to the total weight of the composi in an amount from about 2.5% by weight to about 3.5% by tion, and weight relative to the total weight of the composition. (0549) about 4% by weight to about 6% by weight of the 0531. 266. The composition of any one of 228 to 265, network former relative to the total weight of the com wherein the mineral particle is present in the composition position. in an amount from about 2.5% by weight to about 3.2% by 0550) 279. The composition of any one of 228 to 278, weight relative to the total weight of the composition. comprising about 2% by weight to about 3% by weight of 0532. 267. The composition of any one of 228 to 266, a rheology modifier relative to the total weight of the com wherein the mineral particle is present in the composition position. in an amount from about 2.5% by weight to about 3.0% by 0551 280. The composition of any one of 228 to 279, weight relative to the total weight of the composition. comprising about 5% by weight to about 6% by weight of 0533. 268. The composition of any one of 228 to 267, a hydrophilic agent relative to the total weight of the com wherein the mineral particle is present in the composition position. US 2016/0038592 A1 Feb. 11, 2016 29

0552 281. The composition of any one of 228 to 280, about 5% by weight to about 6% by weight relative to the wherein the HVLCM is SAIB, the solvent is triacetin, and total weight of the composition. the network former is CAB. (0576. 298. The composition of 296 or 297, comprising 0553 282. The composition of 281, comprising IPM. about 38% by weight to about 41% by weight of the tri 0554 283. The composition of 281 or 282, comprising acetin relative to the total weight of the composition. HEC. (0577. 299. The composition of any one of 296 to 298, 0555 284. The composition of any one of 228 to 283, comprising about 2% by weight to about 3% by weight of wherein the pharmacologically active agent is present in the IPM relative to the total weight of the composition. the composition at about 2% by weight to about 50% by (0578 300. The composition of any one of 296 to 299, weight relative to the total weight of the composition. wherein the CAB has a number average molecular weight 0556. 285. The composition of any one of 228 to 284, ranging from 66,000 Daltons to 83,000 Daltons. wherein the composition is contained within a capsule. (0579 301. The composition of any one of 296 to 300, 0557 286. The composition of any one of 228 to 285, wherein the CAB has at least one feature selected from a wherein the composition is contained within a capsule butyryl content ranging from about 17% to about 38%, an comprising hydroxypropyl methylcellulose. acetyl content ranging from about 13% to about 30%, and 0558 287. The composition of any one of 228 to 286, a hydroxyl content ranging from about 0.8% to about 1.7%. wherein the composition is contained within a hard capsule 0580 302. The composition of any one of 296 to 301, comprising hydroxypropyl methylcellulose. wherein the silicon dioxide is present in the composition in 0559) 288. The composition of any one of 228 to 287, an amount from about 2.5% by weight to about 3.5% by comprising a surfactant. weight relative to the total weight of the composition. 0560) 289. The composition of 288, wherein the surfactant 0581. 303. The composition of any one of 296 to 302, is Saturated polyglycolized glyceride. wherein the silicon dioxide is present in the composition in 0561) 290. The composition of any one of 228 to 289, an amount from about 2.5% by weight to about 3.2% by wherein the composition does not comprise more than 5% weight relative to the total weight of the composition. water by weight, based on total weight of the composition. 0582. 304. The composition of any one of 296 to 303, 0562 291. The composition of 290, wherein the compo wherein the silicon dioxide is present in the composition in sition does not comprise more than 2.5% water by weight, an amount from about 2.5% by weight to about 3.0% by based on total weight of the composition. weight relative to the total weight of the composition. 0563. 292. The composition of 290, wherein the compo 0583. 305. The composition of any one of 296 to 304, sition does not comprise more than 2.0% water by weight, wherein the silicon dioxide is present in the composition in based on total weight of the composition. an amount from about 2.5% by weight to about 2.9% by 0564. 293. The composition of any one of 228 to 289, weight relative to the total weight of the composition. wherein the composition comprises water at from about 1.0 0584 306. The composition of any one of 296 to 305, to about 2.5% by weight, based on total weight of the wherein the composition has a complex viscosity of from composition. about 100 Pa's to about 300 Pa's, wherein the complex 0565 294. The composition of 293, wherein the compo viscosity is determined at a constant strain of 0.5% and a sition comprises water at from about 1.0 to about 2.0% by frequency of 1 Hz, and a temperature of 25°C. weight, based on total weight of the composition. 0585 307. The composition of any one of 296 to 306, 0566 295. The composition of 294, wherein the compo wherein the composition has a complex viscosity of from sition comprises water at from about 1.0 to about 1.5% by about 120 Pa's to about 250 Pas, wherein the complex weight, based on total weight of the composition. viscosity is determined at a constant strain of 0.5% and a 0567 296. A composition comprising: frequency of 1 Hz, and a temperature of 25°C. 0568 an opioid; 0586) 308. The composition of any one of 296 to 307, 0569 sucrose acetate isobutyrate (SAIB); wherein the composition has a complex viscosity of from 0570 triacetin: about 140 Pa's to about 200 Pas, wherein the complex (0571 isopropyl myristate (IPM); viscosity is determined at a constant strain of 0.5% and a (0572 cellulose acetate butyrate (CAB); frequency of 1 Hz, and a temperature of 25°C. (0573 hydroxyethyl cellulose (HEC); and 0587 309. The composition of any one of 296 to 308, 0574 silicon dioxide, wherein the silicon dioxide is wherein the opioid is selected from oxycodone, oxymor present in the composition in an amount from about phone, hydrocodone, and hydromorphone, either in the 2.4% by weight to about 5.4% by weight relative to the free base form or a pharmaceutically acceptable salt form total weight of the composition. thereof. (0575 297. The composition of 296, wherein the SAIB is 0588 310. The composition of any one of 296 to 309, present in the composition in an amount from about 35% wherein the opioid is oxycodone. by weight to about 45% by weight relative to the total 0589) 311. The composition of any one of 296 to 310, weight of the composition, the triacetin is present in the wherein the opioid is present in the composition at about composition in an amount from about 31% by weight to 5% by weight relative to the total weight of the composi about 45% by weight relative to the total weight of the tion. composition, the IPM is present in the composition in an 0590 312. The composition of any one of 296 to 311, amount from about 2% by weight to about 10% by weight wherein the composition does not comprise more than 5% relative to the total weight of the composition, the CAB is water by weight, based on total weight of the composition. present in the composition at about 4% to about 6% by 0591 313. The composition of 312, wherein the compo weight relative to the total weight of the composition, and sition does not comprise more than 2.5% water by weight, the HEC is present in the composition in an amount from based on total weight of the composition. US 2016/0038592 A1 Feb. 11, 2016 30

0592) 314. The composition of 312, wherein the compo- 0.617 about 4% to about 6% by weight of cellulose sition does not comprise more than 2.0% water by weight, acetate butyrate (CAB) relative to the total weight of the based on total weight of the composition. composition; 0593 315. The composition of any one of 296 to 311, 0618 about 5% by weight to about 6% by weight of wherein the composition comprises water at from about 1.0 hydroxyethyl cellulose (HEC) relative to the total to about 2.5% by weight, based on total weight of the weight of the composition; and composition. 0619 about 2.5% by weight to about 3.2% by weight of 0594 316. The composition of 315, wherein the compo- silicon dioxide relative to the total weight of the compo sition comprises water at from about 1.0 to about 2.0% by sition. weight, based on total weight of the composition. 0620 321. A composition comprising: 0595 317. The composition of 316, wherein the compo- 0621 oxycodone at about 5% by weight relative to the sition comprises water at from about 1.0 to about 1.5% by total weight of the composition; weight, based on total weight of the composition. 0622 sucrose acetate isobutyrate (SAIB) at about 40% 0596 318. A composition comprising: by weight relative to the total weight of the composition; 0597 oxycodone: 0623 triacetin at about 39% by weight relative to the 0598 about 35% by weight to about 45% sucrose total weight of the composition; acetate isobutyrate (SAIB) relative to the total weight of 0624 isopropyl myristate (IPM) at about 2.5% by the composition; weight relative to the total weight of the composition; 0599 about 31% by weight to about 45% of triacetin 0625 cellulose acetate butyrate (CAB) at about 4.5% relative to the total weight of the composition; by weight relative to the total weight of the composition; 0600 about 2% by weight to about 10% by weight of 0626 hydroxyethyl cellulose (HEC) at about 5.5% by isopropyl myristate (IPM) relative to the total weight of weight relative to the total weight of the composition; the composition; and 0601 about 4% to about 6% by weight of cellulose 0627 silicon dioxide at about 2.9% by weight relative acetate butyrate (CAB) relative to the total weight of the to the total weight of the composition. composition; 0628 322. A composition comprising: 0602 about 5% by weight to about 6% by weight of 0629 oxycodone at about 5% by weight relative to the hydroxyethyl cellulose (HEC) relative to the total total weight of the composition; weight of the composition; and 0630 sucrose acetate isobutyrate (SAIB) at about 40% 0603 about 2.4% by weight to about 5.4% by weight of by weight relative to the total weight of the composition; silicon dioxide relative to the total weight of the compo 0631 triacetin at about 39% by weight relative to the sition. total weight of the composition; 0604) 319. A composition comprising: 0632 isopropyl myristate (IPM) at about 2.5% by 0605 oxycodone: weight relative to the total weight of the composition; 0606 about 39% by weight to about 41% sucrose 0633 cellulose acetate butyrate (CAB) at about 4.5% acetate isobutyrate (SAIB) relative to the total weight of by weight relative to the total weight of the composition; the composition; 0634 hydroxyethyl cellulose (HEC) at about 5.5% by 0607 about 38% by weight to about 41% of triacetin weight relative to the total weight of the composition; relative to the total weight of the composition; and 0608 about 2% by weight to about 3% by weight of 0635 silicon dioxide at about 2.9% by weight relative isopropyl myristate (IPM) relative to the total weight of to the total weight of the composition, wherein the com the composition; position is encapsulated in a hydroxypropylmethylcel 0609 about 4% to about 6% by weight of cellulose lulose (HPMC) capsule. acetate butyrate (CAB) relative to the total weight of the 0636, 323. A composition comprising: composition; 0637 a pharmacologically active agent; 0610 about 5% by weight to about 6% by weight of 0638 a high viscosity liquid carrier material (HVLCM) hydroxyethyl cellulose (HEC) relative to the total having a viscosity of at least 5000 cp at 37°C. that does weight of the composition; and not crystallize neat at 25°C. and 1 atmosphere: 0611 about 2.5% by weight to about 3.2% by weight of 0639 a solvent; silicon dioxide relative to the total weight of the compo 0640 a network former; and sition. 0641 a mineral particle, wherein the HVLCM, the sol 0612 320. A composition comprising: vent, the network former, and the mineral particle are 0613 about 5% by weight of oxycodone relative to the present in a ratio Sufficient to reduce a storage time total weight of the composition; dependent change in an in vitro release profile of a 0614 about 39% by weight to about 41% sucrose composition relative to Reference Formulation A. acetate isobutyrate (SAIB) relative to the total weight of 0642 324. The composition of 323, wherein Reference the composition; Formulation A exhibits more than 10% mean drug release 0615 about 38% by weight to about 41% of triacetin decline, a similarity factor (f.) of less than 50, when stored relative to the total weight of the composition; at 40° C./75% RH for a one month period of time relative 0616 about 2% by weight to about 3% by weight of to its initial release profile. isopropyl myristate (IPM) relative to the total weight of 0643) 325. The composition of 323, wherein the mineral the composition; particle is selected from talc, bentonite and kaolin. US 2016/0038592 A1 Feb. 11, 2016

0644, 326. The composition of 323, wherein the mineral 0668 350. The composition of 344, wherein the rheology particle is selected from silicon dioxide, Zinc oxide, mag modifier is dimethyl phthalate. nesium oxide, titanium oxide, and calcium oxide. 0669 351. The composition of 344, wherein the rheology (0645) 327. The composition of 323, wherein the mineral modifier is benzyl benzoate. particle comprises silicon dioxide. 0670) 352. The composition of any one of 344-351, com 0646 328. The composition of 323, wherein the pharma prising about 2% by weight to about 10% by weight of the cologically active agent is selected from opioid, stimulant, rheology modifier relative to the total weight of the com and depressant. position. 0647 329. The composition of 323, wherein the pharma 0671 353. The composition of any one of 323 to 351, cologically active agent is an opioid. wherein the network former is selected from cellulose 0648. 330. The composition of 323, wherein the pharma acetate butyrate (CAB), cellulose acetate phthalate, ethyl cologically active agent is selected from oxycodone, oxy cellulose, hydroxypropyl methylcellulose and cellulose morphone, hydrocodone, and hydromorphone, either in triacetate. the free base form or a pharmaceutically acceptable salt 0672 354. The composition of any one of 323 to 353, form thereof. wherein the network former comprises cellulose acetate 0649) 331. The composition of 323, wherein the pharma butyrate (CAB). cologically active agent is oxycodone. 0673 355. The composition of any one of 323 to 354, 0650) 332. The composition of any one of 323 to 331, wherein the network former comprises CAB having a num wherein the HVLCM is sucrose acetate isobutyrate beraverage molecular weight ranging from 50,000 Daltons (SAIB). to 100,000 Daltons. 0651 333. The composition of any one of 323 to 332, 0674) 356. The composition of any one of 323 to 355, comprising about 35% by weight to about 45% by weight wherein the network former comprises CAB having at least of the HVLCM relative to the total weight of the compo one feature selected from a butyryl content ranging from sition. about 17% to about 41%, an acetyl content ranging from 0652) 334. The composition of any one of 323 to 333, about 13% to about 30%, and a hydroxyl content ranging wherein the solvent is selected from triacetin, N-methyl from about 0.5% to about 1.7%. 2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl 0675 357. The composition of any one of 323 to 356, lactate, propylene carbonate and glycofurol. further comprising a hydrophilic agent. 0653 335. The composition of any one of 323 to 334, 0676 358. The composition of 357, wherein the hydro wherein the solvent comprises triacetin. philic agent is selected from hydroxyethyl cellulose 0654) 336. The composition of any one of 323 to 334, (HEC), hydroxypropyl cellulose, caboxymethyl cellulose, wherein the solvent comprises N-methyl-2-pyrrolidone. polyethylene glycol and polyvinylpyrrolidone. 0655 337. The composition of any one of 323 to 334, 0677 359. The composition of 357, wherein the hydro wherein the solvent comprises 2-pyrrolidone. philic agent comprises HEC. 0656) 338. The composition of any one of 323 to 334, 0678 360. The composition of any one of 323 to 359, wherein the solvent comprises dimethylsulfoxide. wherein the mineral particle is present in the composition 0657 339. The composition of any one of 323 to 334, in an amount from about 2.5% by weight to about 4.0% by wherein the solvent comprises ethyl lactate. weight relative to the total weight of the composition. 0658 340. The composition of any one of 323 to 334, 0679) 361. The composition of any one of 323 to 360, wherein the solvent comprises propylene carbonate. wherein the mineral particle is present in the composition 0659 341. The composition of any one of 323 to 334, in an amount from about 2.5% by weight to about 3.5% by wherein the solvent comprises glycofurol. weight relative to the total weight of the composition. 0680 362. The composition of any one of 323 to 361, 0660 342. The composition of any one of 323 to 341, wherein the mineral particle is present in the composition comprising about 31% by weight to about 45% by weight in an amount from about 2.5% by weight to about 3.2% by of the solvent relative to the total weight of the composi weight relative to the total weight of the composition. tion. 0681 363. The composition of any one of 323 to 362, 0661 343. The composition of 342, comprising about wherein the mineral particle is present in the composition 38% by weight to about 41% by weight of the solvent in an amount from about 2.5% by weight to about 3.0% by relative to the total weight of the composition. weight relative to the total weight of the composition. 0662. 344. The composition of any one of 323 to 343, 0682. 364. The composition of any one of 323 to 363, further comprising a rheology modifier. wherein the mineral particle is present in the composition 0663 345. The composition of 344, wherein the rheology at from about 2.5% by weight to about 2.9% by weight modifier is selected from isopropyl myristate (IPM), relative to the total weight of the composition. caprylic?capric triglyceride, ethyl oleate, triethyl citrate, 0683 365. The composition of any one of 323 to 364, dimethyl phthalate and benzyl benzoate. wherein the composition has a complex viscosity of from 0664 346. The composition of 344, wherein the rheology about 100 Pa's to about 300 Pa's, wherein the complex modifier is IPM. viscosity is determined at a constant strain of 0.5% and a 0665 347. The composition of 344, wherein the rheology frequency of 1 Hz, and a temperature of 25°C. modifier is caprylic/capric triglyceride. 0684 366. The composition of any one of 323 to 365, 0666 348. The composition of 344, wherein the rheology wherein the composition has a complex viscosity of from modifier is ethyl oleate. about 120 Pa's to about 250 Pas, wherein the complex 0667 349. The composition of 344, wherein the rheology viscosity is determined at a constant strain of 0.5% and a modifier is triethylcitrate. frequency of 1 Hz, and a temperature of 25°C. US 2016/0038592 A1 Feb. 11, 2016 32

0685 367. The composition of any one of 323 to 366, (0706 382. The composition of any one of 323 to 381, wherein the composition has a complex viscosity of from wherein the composition is contained within a capsule about 140 Pa's to about 200 Pas, wherein the complex comprising hydroxypropylmethylcellulose. viscosity is determined at a constant strain of 0.5% and a (0707 383. The composition of any one of 323 to 382, frequency of 1 Hz, and a temperature of 25°C. wherein the composition is contained within a hard capsule 0686 368. The composition of any one of 323 to 367, comprising hydroxypropylmethylcellulose. wherein the ratio of the HVLCM to the Solvent in the (0708. 384. The composition of any one of 296-310, composition is about 0.6:1 to 1.6:1. wherein the opioid is present in the composition at about 0687 369. The composition of 368, wherein the ratio of 5% by weight relative to the total weight of the composi the HVLCM to the solvent in the composition is about tion. O.8:1 to 1.5:1. (0709) 385. The composition of any one of 396-311, 0688 370. The composition of 369, wherein the ratio of wherein the composition does not comprise more than 5% the HVLCM to the solvent in the composition is about water by weight, based on total weight of the composition. O.9:1 to 1.5:1. 0710) 386. The composition of 312, wherein the compo 0689) 371. The composition of any one of 323 to 370, sition does not comprise more than 2.5% water by weight, wherein the composition comprises: based on total weight of the composition. (0690 about 35% by weight to about 45% by weight of 0711 387. The composition of 312, wherein the compo the HVLCM relative to the total weight of the composi sition does not comprise more than 2.0% water by weight, tion, based on total weight of the composition. (0691 about 31% by weight to about 45% by weight of 0712. 388. The composition of any one of 296-311, the solvent relative to the total weight of the composi wherein the composition comprises water at from about 1.0 tion, and to about 2.5% by weight, based on total weight of the (0692 about 2% by weight to about 10% by weight of composition. the network former relative to the total weight of the 0713 389. The composition of 315, wherein the compo composition. sition comprises water at from about 1.0 to about 2.0% by 0693 372. The composition of 371, comprising about weight, based on total weight of the composition. 0.1% by weight to about 8% by weight of a rheology 0714 390. The composition of 316, wherein the compo modifier relative to the total weight of the composition. sition comprises water at from about 1.0 to about 1.5% by (0694 373. The composition of 371 or 372, comprising weight, based on total weight of the composition. about 2% by weight to about 10% by weight of a hydro 0715. 391. A composition comprising: philic agent. 0716 a pharmacologically active agent; 0717 a high viscosity liquid carrier material (HVLCM) (0695 374. The composition of any one of 323 to 373, having a viscosity of at least 5000 cp at 37°C. that does wherein the composition comprises: not crystallize neat at 25°C. and 1 atmosphere: (0696) about 39% by weight to about 41% by weight of 0718 a solvent; the HVLCM relative to the total weight of the composi 0719 a network former; and tion, 0720 a mineral particle, wherein the HVLCM, the sol (0697) about 38% by weight to about 40% by weight of vent, the network former, and the mineral particle are the solvent relative to the total weight of the composi present in a ratio Sufficient to reduce inter-capsule Vari tion, and ability in an in vitro release profile of the composition (0698 about 4% by weight to about 6% by weight of the relative to Reference Formulation A, when assayed in a network former relative to the total weight of the com USP Apparatus 2 dissolution tester modified to have a position. 20-mesh basket for containing the composition. (0699 375. The composition of any one of 323-374, com 0721 392. The composition of 391, wherein the reduction prising about 2% by weight to about 3% by weight of a in inter-capsule variability is evidenced by a % RSD of less rheology modifier relative to the total weight of the com than 10% at t=2 hr. position. 0722 393. The composition of 391, wherein the reduction (0700 376. The composition of any one of 323-375, com in inter-capsule variability is evidenced by a % RSD of less prising about 5% by weight to about 6% by weight of a than 10% at t=6 hr. hydrophilic agent relative to the total weight of the com 0723. 394. The composition of 391, wherein the mineral position. particle is selected from talc, bentonite and kaolin. (0701 377. The composition of any one of 323 to 376, 0724 395. The composition of 391, wherein the mineral wherein the HVLCM is SAIB, the solvent is triacetin, and particle is selected from silicon dioxide, Zinc oxide, mag the network former is CAB. nesium oxide, titanium oxide, and calcium oxide. (0702 378. The composition of 377, comprising IPM. 0725 396. The composition of 391, wherein the mineral (0703. 379. The composition of 377 or 378, comprising particle comprises silicon dioxide. HEC. 0726) 397. The composition of 391, wherein the pharma (0704) 380. The composition of any one of 323 to 379, cologically active agent is selected from opioid, stimulant, wherein the pharmacologically active agent is present in and depressant. the composition at about 2% by weight to about 50% by 0727 398. The composition of 391, wherein the pharma weight relative to the total weight of the composition. cologically active agent is an opioid. (0705) 381. The composition of any one of 323 to 380, 0728 399. The composition of 391, wherein the pharma wherein the composition is contained within a capsule. cologically active agent is selected from oxycodone, oxy US 2016/0038592 A1 Feb. 11, 2016

morphone, hydrocodone, and hydromorphone, either in (0752 423. The composition of any one of 391 to 422, the free base form or a pharmaceutically acceptable salt wherein the network former comprises cellulose acetate form thereof. butyrate (CAB). 0729 400. The composition of 391, wherein the pharma (0753. 424. The composition of any one of 391 to 423, cologically active agent is oxycodone. wherein the network former comprises CAB having a num (0730 401. The composition of any one of 391 to 400, beraverage molecular weight ranging from 50,000 Daltons wherein the HVLCM is sucrose acetate isobutyrate to 100,000 Daltons. (SAIB). (0754) 425. The composition of any one of 391 to 424, (0731 402. The composition of any one of 391 to 401, wherein the network former comprises CAB having at least comprising about 35% by weight to about 45% by weight one feature selected from a butyryl content ranging from of the HVLCM relative to the total weight of the compo about 17% to about 41%, an acetyl content ranging from sition. about 13% to about 30%, and a hydroxyl content ranging (0732 403. The composition of any one of 391 to 402, from about 0.5% to about 1.7%. wherein the solvent is selected from triacetin, N-methyl 2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl (0755 426. The composition of any one of 391 to 425, lactate, propylene carbonate and glycofurol. further comprising a hydrophilic agent. (0733 404. The composition of any one of 391 to 403, (0756 427. The composition of 426, wherein the hydro wherein the solvent comprises triacetin. philic agent is selected from hydroxyethyl cellulose (0734 405. The composition of any one of 391 to 403, (HEC), hydroxypropyl cellulose, caboxymethyl cellulose, wherein the solvent comprises N-methyl-2-pyrrolidone. polyethylene glycol and polyvinylpyrrolidone. (0735. 406. The composition of any one of 391 to 403, (0757 428. The composition of 426, wherein the hydro wherein the solvent comprises 2-pyrrolidone. philic agent comprises HEC. (0736. 407. The composition of any one of 391 to 403, (0758) 429. The composition of any one of 391 to 428, wherein the solvent comprises dimethylsulfoxide. wherein the mineral particle is present in the composition (0737 408. The composition of any one of 391 to 403, in an amount from about 2.5% by weight to about 4.0% by wherein the solvent comprises ethyl lactate. weight relative to the total weight of the composition. (0738 409. The composition of any one of 391 to 403, (0759 430. The composition of any one of 391 to 429, wherein the solvent comprises propylene carbonate. wherein the mineral particle is present in the composition (0739 410. The composition of any one of 391 to 403, in an amount from about 2.5% by weight to about 3.5% by wherein the solvent comprises glycofurol. weight relative to the total weight of the composition. 0740 411. The composition of any one of 391 to 410, 0760 431. The composition of any one of 391 to 430, comprising about 31% by weight to about 45% by weight wherein the mineral particle is present in the composition of the solvent relative to the total weight of the composi in an amount from about 2.5% by weight to about 3.2% by tion. weight relative to the total weight of the composition. 0741. 412. The composition of 411, comprising about 0761. 432. The composition of any one of 391 to 431, 38% by weight to about 41% by weight of the solvent wherein the mineral particle is present in the composition relative to the total weight of the composition. in an amount from about 2.5% by weight to about 3.0% by 0742 413. The composition of any one of 391 to 412, weight relative to the total weight of the composition. further comprising a rheology modifier. 0762. 433. The composition of any one of 391 to 432, 0743 414. The composition of 413, wherein the rheology wherein the mineral particle is present in the composition modifier is selected from isopropyl myristate (IPM), caprylic?capric triglyceride, ethyl oleate, triethyl citrate, at from about 2.5% by weight to about 2.9% by weight dimethyl phthalate and benzyl benzoate. relative to the total weight of the composition. 0744. 415. The composition of 413, wherein the rheology 0763) 434. The composition of any one of 391 to 433, modifier is IPM. wherein the composition has a complex viscosity of from 0745) 416. The composition of 413, wherein the rheology about 100 Pa's to about 300 Pa's, wherein the complex modifier is caprylic/capric triglyceride. viscosity is determined at a constant strain of 0.5% and a 0746 417. The composition of 413, wherein the rheology frequency of 1 Hz, and a temperature of 25°C. modifier is ethyl oleate. 0764) 435. The composition of any one of 391 to 434, 0747 418. The composition of 413, wherein the rheology wherein the composition has a complex viscosity of from modifier is triethylcitrate. about 120 Pa's to about 250 Pas, wherein the complex 0748. 419. The composition of 413, wherein the rheology viscosity is determined at a constant strain of 0.5% and a modifier is dimethyl phthalate. frequency of 1 Hz, and a temperature of 25°C. 0749 420. The composition of 413, wherein the rheology 0765 436. The composition of any one of 391 to 435, modifier is benzyl benzoate. wherein the composition has a complex viscosity of from 0750 421. The composition of any one of 413-420, com about 140 Pa's to about 200 Pas, wherein the complex prising about 2% by weight to about 10% by weight of the viscosity is determined at a constant strain of 0.5% and a rheology modifier relative to the total weight of the com frequency of 1 Hz, and a temperature of 25°C. position. 0766 437. The composition of any one of 391 to 436, (0751 422. The composition of any one of 391 to 420, wherein the ratio of the HVLCM to the solvent in the wherein the network former is selected from cellulose composition is about 0.6:1 to 1.6:1. acetate butyrate (CAB), cellulose acetate phthalate, ethyl 0767 438. The composition of 437, wherein the ratio of cellulose, hydroxypropylmethyl cellulose and cellulose the HVLCM to the solvent in the composition is about triacetate. O.8:1 to 1.5:1. US 2016/0038592 A1 Feb. 11, 2016 34

0768 439. The composition of 438, wherein the ratio of 0790. 455. The composition of 453, wherein the compo the HVLCM to the solvent in the composition is about sition does not comprise more than 2.0% water by weight, O.9:1 to 1.5:1. based on total weight of the composition. 0769 440. The composition of any one of 391 to 439, 0791) 456. The composition of any one of 391-452, wherein the composition comprises: wherein the composition comprises water at from about 1.0 (0770 about 35% by weight to about 45% by weight of to about 2.5% by weight, based on total weight of the the HVLCM relative to the total weight of the composi composition. tion, 0792 457. The composition of 456, wherein the compo (0771) about 31% by weight to about 45% by weight of sition comprises water at from about 1.0 to about 2.0% by the solvent relative to the total weight of the composi weight, based on total weight of the composition. tion, and 0793 458. The composition of 457, wherein the compo (0772 about 2% by weight to about 10% by weight of sition comprises water at from about 1.0 to about 1.5% by the network former relative to the total weight of the weight, based on total weight of the composition. composition. 0794. 459. A composition comprising: 0773) 441. The composition of 440, comprising about 0795 a pharmacologically active agent; 0.1% by weight to about 8% by weight of a rheology 0796 a high viscosity liquid carrier material (HVLCM) modifier relative to the total weight of the composition. having a viscosity of at least 5000 cp at 37°C. that does 0774. 442. The composition of 440 or 441, comprising not crystallize neat at 25°C. and 1 atmosphere: about 2% by weight to about 10% by weight of a hydro 0797 a solvent; philic agent. 0798 a network former; and (0775. 443. The composition of any one of 391 to 442, 0799 a mineral particle, wherein the HVLCM, the sol wherein the composition comprises: vent, the network former, and the mineral particle are (0776) about 39% by weight to about 41% by weight of present in a ratio Sufficient to provide an in vitro release the HVLCM relative to the total weight of the composi profile characterized by an inter-capsule variability hav inga% RSD of less than 10% at t=2 hr as determined by tion, an in vitro dissolution assay using a USP Apparatus 2 (0777 about 38% by weight to about 40% by weight of dissolution tester modified to have a 20-mesh basket for the solvent relative to the total weight of the composi containing the composition. tion, and 0800. 460. A composition comprising: (0778 about 4% by weight to about 6% by weight of the 0801 oxycodone at about 5% by weight to about 10% network former relative to the total weight of the com by weight relative to the total weight of the composition; position. 0802 sucrose acetate isobutyrate (SAIB); 0779 444. The composition of any one of 391-443, com 0803 triacetin: prising about 2% by weight to about 3% by weight of a (0804 isopropyl myristate (IPM); rheology modifier relative to the total weight of the com position. (0805 cellulose acetate butyrate (CAB); (0806) hydroxyethyl cellulose (HEC); and 0780. 445. The composition of any one of 391-444, com 0807 silicon dioxide, wherein the sucrose acetate prising about 5% by weight to about 6% by weight of a isobutyrate (SAIB), triacetin, isopropyl myristate hydrophilic agent relative to the total weight of the com (IPM), cellulose acetate butyrate (CAB), hydroxyethyl position. cellulose (HEC), and silicon dioxide, are present in a 0781 446. The composition of any one of 391 to 445, ratio Sufficient to reduce a storage time-dependent wherein the HVLCM is SAIB, the solvent is triacetin, and change in an in vitro release profile of the composition the network former is CAB. relative to Reference Formulation A. 0782) 447. The composition of 446, comprising IPM. (0808 461. The composition of 460, wherein Reference 0783 448. The composition of 446 or 447, comprising Formulation A exhibits more than 10% mean drug release HEC. decline, a similarity factor (f) of less than 50, when stored 0784 449. The composition of any one of 391 to 448, at 40° C./75% RH for a one month period of time relative wherein the pharmacologically active agent is present in to its initial release profile. the composition at about 2% by weight to about 50% by 0809 462. A composition comprising: weight relative to the total weight of the composition. 0810 oxycodone at about 5% by weight to about 10% 0785 450. The composition of any one of 391 to 449, by weight relative to the total weight of the composition; wherein the composition is contained within a capsule. 0811 sucrose acetate isobutyrate (SAIB); 0786 451. The composition of any one of 391 to 450, 0812 triacetin: wherein the composition is contained within a capsule 0813 isopropyl myristate (IPM); comprising hydroxypropyl methylcellulose. 0814 cellulose acetate butyrate (CAB); 0787 452. The composition of any one of 391 to 451, 0815 hydroxyethyl cellulose (HEC); and wherein the composition is contained within a hard capsule 0816 silicon dioxide, wherein the sucrose acetate comprising hydroxypropyl methylcellulose. isobutyrate (SAIB), triacetin, isopropyl myristate 0788) 453. The composition of any one of 391-452, (IPM), cellulose acetate butyrate (CAB), hydroxyethyl wherein the composition does not comprise more than 5% cellulose (HEC), and silicon dioxide, are present in a water by weight, based on total weight of the composition. ratio sufficient to reduce inter-capsule variability rela 0789 454. The composition of 453, wherein the compo tive to Formulation A when assayed in a USP Apparatus sition does not comprise more than 2.5% water by weight, 2 dissolution tester modified to have a 20-mesh basket based on total weight of the composition. for containing the composition. US 2016/0038592 A1 Feb. 11, 2016 35

0817. 463. The composition of 462, wherein the reduction Reference Formulation A when assayed in a USP Appa in inter-capsule variability is evidenced by a % RSD of less ratus 2 dissolution tester modified to have a 20-mesh than 10% at t=2 hr. basket for containing the composition. 0818 464. The composition of 462, wherein the reduction 0838 471. The composition of 470, wherein Reference in inter-capsule variability is evidenced by a % RSD of less Formulation A exhibits more than 10% mean drug release than 10% at t=6 hr. decline, a similarity factor (f.) of less than 50, when stored 0819 465. A composition comprising: at 40° C./75% RH for a one month period of time relative 0820 oxycodone at about 5% by weight to about 10% to its initial release profile. by weight relative to the total weight of the composition; 0839 472. A method for treating pain in a subject, the 0821 sucrose acetate isobutyrate (SAIB); method comprising: 0822 triacetin: 0840 orally administering to the subject a composition 0823 isopropyl myristate (IPM); comprising 0824 cellulose acetate butyrate (CAB); 0841 an opioid; 0825 hydroxyethyl cellulose (HEC); and 0842) a high viscosity liquid carrier material (HV 0826 silicon dioxide, wherein the sucrose acetate LCM) having a viscosity of at least 5000 cF at 37° C. isobutyrate (SAIB), triacetin, isopropyl myristate that does not crystallize neat at 25° C. and 1 atmo (IPM), cellulose acetate butyrate (CAB), hydroxyethyl sphere; cellulose (HEC), and silicon dioxide, are present in a 0843 a solvent: ratio sufficient to provide an in vitro release profile char 0844 a network former; and acterized by an inter-capsule variability having a '% RSD 0845 silicon dioxide, wherein the silicon dioxide is of less than 10% at t=2 hr as determined by an in vitro present in the composition in an amount from about dissolution assay using a USP Apparatus 2 dissolution 2.4% by weight to about 5.4% by weight relative to tester modified to have a 20-mesh basket for containing the total weight of the composition, wherein the com the composition. position is formulated for oral administration, and one 0827. 466. A composition comprising: or more symptoms or signs associated with the Sub 0828 a pharmacologically active agent; and jects pain is alleviated. 0829 combined amounts of a high viscosity liquid car 0846 473. The method of 472, wherein the opioid is rier material (HVLCM) having a viscosity of at least selected from Oxycodone, oxymorphone, hydrocodone, 5000 cF at 37° C. that does not crystallize neat at 25°C. and hydromorphone, either in the free base form or a phar and 1 atmosphere, a solvent, a rheology modifier, silicon maceutically acceptable salt form thereof dioxide, and a cellulose acetate butyrate, wherein the 0847 474. The method of 472 or 473, wherein the opioid combined amounts are sufficient to increase reproduc is oxycodone. ibility of release with respect to inter-capsule variability 0848. 475. The methodofany one of 472-474, wherein the relative to Reference Formulation A when assayed in a HVLCM is sucrose acetate isobutyrate (SAIB). USP Apparatus 2 dissolution tester modified to have a 0849 476. The method of any one of 472 to 475, wherein 20-mesh basket for containing the composition. the composition comprises about 35% by weight to about 0830, 467. The composition of 466, wherein the increase 45% by weight of the HVLCM relative to the total weight in reproducibility of release is evidenced by a % RSD of of the composition. less than 10% at t=2 hr. 0850 477. The methodofany one of 472-475, wherein the 0831 468. The composition of 466, wherein the increase solvent is selected from triacetin, N-methyl-2-pyrrolidone, in reproducibility of release is evidenced by a % RSD of 2-pyrrolidone, dimethylsulfoxide, ethyl lactate, propylene less than 10% at t=6 hr. carbonate and glycofurol. 0832 469. A composition comprising: 0851 478. The methodofany one of 472-477, wherein the 0833 a pharmacologically active agent; and Solvent comprises triacetin. 0834 combined amounts of a high viscosity liquid car 0852 479. The method of any one of 472 to 478, wherein rier material (HVLCM) having a viscosity of at least the composition comprises about 31% by weight to about 5000 cF at 37° C. that does not crystallize neat at 25°C. 45% by weight of the solvent relative to the total weight of and 1 atmosphere, a solvent, a rheology modifier, silicon the composition. dioxide, and a cellulose acetate butyrate, wherein the 0853 480. The method of 479, wherein the composition combined amounts are Sufficient to provide an in vitro comprises about 38% by weight to about 41% by weight of release profile characterized by an inter-capsule Vari the solvent relative to the total weight of the composition. ability having a % RSD of less than 10% at t=2 hr as 0854 481. The method of any one of 472 to 480, wherein determined by an in vitro dissolution assay using a USP the composition further comprises a rheology modifier. Apparatus 2 dissolution tester modified to have a 0855 482. The method of 481, wherein the rheology 20-mesh basket for containing the composition. modifier is selected from isopropyl myristate (IPM), 0835 470. A composition comprising: caprylic?capric triglyceride, ethyl oleate, triethyl citrate, 0836 a pharmacologically active agent; and dimethyl phthalate and benzyl benzoate. 0837 combined amounts of a high viscosity liquid car 0856) 483. The methodofany one of 472-480, wherein the rier material (HVLCM) having a viscosity of at least composition further comprises IPM. 5000 cF at 37° C. that does not crystallize neat at 25°C. 0857 484. The method of 483, wherein the composition and 1 atmosphere, a solvent, a rheology modifier, silicon comprises about 2% by weight to about 10% by weight of dioxide, and a cellulose acetate butyrate, wherein the the IPM relative to the total weight of the composition. combined amounts are sufficient to increase reproduc 0858 485. The methodofany one of 472-482, wherein the ibility of release with respect to storage time relative to network former is selected from cellulose acetate butyrate US 2016/0038592 A1 Feb. 11, 2016 36

(CAB), cellulose acetate phthalate, ethyl cellulose, 0874 501. The methodofany one of 472-500, wherein the hydroxypropylmethyl cellulose and cellulose triacetate. composition comprises: 0875 about 35% by weight to about 45% by weight of 0859 486. The method of any one of 472 to 485, wherein the HVLCM relative to the total weight of the composi the network former comprises CAB. tion, 0860 487. The method of any one of 472 to 486, wherein 0876 about 31% by weight to about 45% by weight of the network former comprises CAB having a number aver the solvent relative to the total weight of the composi age molecular weight ranging from 66,000 Daltons to tion, and 83,000 Daltons. 0877 about 2% by weight to about 10% by weight of the network former relative to the total weight of the 0861) 488. The method of any one of 472 to 487, wherein composition. the network former comprises CAB having at least one 0878 502. The method of 501, comprising about 0.1% by feature selected from abutyryl content ranging from about weight to about 8% by weight of a rheology modifier 17% to about 38%, an acetyl content ranging from about relative to the total weight of the composition. 13% to about 30%, and a hydroxyl content ranging from 0879 503. The method of 501 or 502, comprising about about 0.8% to about 1.7%. 2% by weight to about 10% by weight of a hydrophilic 0862 489. The methodofany one of 472-488, wherein the agent. composition comprises a hydrophilic agent. 0880) 504. The method of any one of 472 to 503, wherein the composition comprises: 0863. 490. The method of 489, wherein the hydrophilic 0881 about 39% by weight to about 41% by weight of agent is selected from hydroxyethyl cellulose (HEC), the HVLCM relative to the total weight of the composi hydroxypropyl cellulose, caboxymethyl cellulose, poly tion, ethylene glycol and polyvinylpyrrolidone. 0882 about 38% by weight to about 40% by weight of 0864. 491. The methodofany one of 472-490, wherein the the solvent relative to the total weight of the composi silicon dioxide is present in the composition in an amount tion, and from about 2.5% by weight to about 3.5% by weight rela 0883 about 4% by weight to about 6% by weight of the tive to the total weight of the composition. network former relative to the total weight of the com position. 0865. 492. The methodofany one of 472-491, wherein the 0884 505. The method of any one of 472-504, comprising silicon dioxide is present in the composition in an amount about 2% by weight to about 3% by weight of a rheology from about 2.5% by weight to about 3.2% by weight rela modifier relative to the total weight of the composition. tive to the total weight of the composition. 0885 506. The methodofany one of 472-505, wherein the 0866 493. The methodofany one of 472-492, wherein the composition comprises about 5% by weight to about 6% by silicon dioxide is present in the composition in an amount weight of a hydrophilic agent relative to the total weight of from about 2.5% by weight to about 3.0% by weight rela the composition. tive to the total weight of the composition. 0886) 507. The methodofany one of 472-506, wherein the 0867 494. The methodofany one of 472-493, wherein the HVLCM is SAIB, the solvent is triacetin, and the network silicon dioxide is present in the composition at about 2.5% former is CAB. by weight to about 2.9% by weight relative to the total 0887 508. The method of 507, wherein the composition weight of the composition. comprises IPM. 0868 495. The method of any one of 472 to 494, wherein 0888 509. The method of 507 or 508, wherein the com the composition has a complex viscosity of from about 100 position comprises HEC. 0889 510. The method of any one of 472 to 509, wherein Pa's to about 300 Pas, wherein the complex viscosity is the pharmacologically active agent is present in the com determined at a constant strain of 0.5% and a frequency of position at about 2% by weight to about 50% by weight 1 Hz and a temperature of 25°C. relative to the total weight of the composition. 0869 496. The method of any one of 472 to 495, wherein (0890. 511. The method of any one of 472 to 510, wherein the composition has a complex viscosity of from about 120 the composition is contained within a capsule. Pa's to about 250 Pas, wherein the complex viscosity is (0891 512. The method of any one of 472 to 511, wherein determined at a constant strain of 0.5% and a frequency of the composition is contained within a capsule comprising 1 Hz and a temperature of 25°C. hydroxypropyl methylcellulose. 0870 497. The method of any one of 472 to 496, wherein (0892 513. The method of any one of 472 to 512, wherein the composition has a complex viscosity of from about 140 the composition is contained within a hard capsule com Pa's to about 200 Pas, wherein the complex viscosity is prising hydroxypropyl methylcellulose. determined at a constant strain of 0.5% and a frequency of (0893 514. The methodofany one of 472-513, wherein the 1 Hz and a temperature of 25°C. composition is administered no more than twice in a 0871) 498. The method of any one of 472 to 497, wherein 24-hour period. the ratio of the HVLCM to the solvent in the composition (0894) 515. The methodofany one of 472-514, wherein the is about 0.6:1 to 1.6:1. composition does not comprise more than 5% water by weight, based on total weight of the composition. 0872 499. The method of 498, wherein the ratio of the (0895 516. The method of 515, wherein the composition HVLCM to the solvent in the composition is about 0.8:1 to does not comprise more than 2.5% water by weight, based 15:1. on total weight of the composition. 0873 500. The method of 499, wherein the ratio of the (0896 517. The method of 515, wherein the composition HVLCM to the solvent in the composition is about 0.9:1 to does not comprise more than 2.0% water by weight, based 15:1. on total weight of the composition. US 2016/0038592 A1 Feb. 11, 2016 37

(0897. 518. The methodofany one of 472-514, wherein the from about 2.5% by weight to about 3.0% by weight rela composition comprises water at from about 1.0 to about tive to the total weight of the composition. 2.5% by weight, based on total weight of the composition. (0916 529. The methodofany one of 521-528, wherein the (0898 519. The method of 518, wherein the composition silicon dioxide is present in the composition in an amount comprises water at from about 1.0 to about 2.0% by weight, from about 2.5% by weight to about 3.0% by weight rela based on total weight of the composition. tive to the total weight of the composition. (0899 520. The method of 519, wherein the composition (0917 530. The methodofany one of 521-529, wherein the comprises water at from about 1.0 to about 1.5% by weight, silicon dioxide is present in the composition in an amount based on total weight of the composition. from about 2.5% by weight to about 2.9% by weight rela 0900 521. A method for treating pain in a subject, the tive to the total weight of the composition. method comprising: (0918 531. The method of any one of 105 to 530, wherein 0901 orally administering to the subject a composition the composition has a complex viscosity of from about 100 comprising Pa's to about 300 Pas, wherein the complex viscosity is (0902 an opioid; determined at a constant strain of 0.5% and a frequency of (0903 sucrose acetate isobutyrate (SAIB); 1 Hz and a temperature of 25°C. 0904 triacetin: (0919 532. The method of any one of 105 to 531, wherein (0905 isopropyl myristate (IPM); the composition has a complex viscosity of from about 120 (0906 cellulose acetate butyrate (CAB); Pa's to about 250 Pas, wherein the complex viscosity is (0907 hydroxyethyl cellulose (HEC); and determined at a constant strain of 0.5% and a frequency of 0908 silicon dioxide, wherein the silicon dioxide is 1 Hz and a temperature of 25°C. present in the composition in an amount from about 0920. 533. The method of any one of 105 to 532, wherein 2.4% by weight to about 5.4% by weight relative to the composition has a complex viscosity of from about 140 the total weight of the composition, wherein the com Pa's to about 200 Pas, wherein the complex viscosity is position is formulated for oral administration, and one determined at a constant strain of 0.5% and a frequency of or more symptoms or signs associated with the Sub 1 Hz and a temperature of 25°C. jects pain is alleviated. 0921 534. The methodofany one of 521-533, wherein the 0909 522. The method of 521, wherein the SAIB is opioid is selected from oxycodone, oxymorphone, hydro present in the composition in an amount from about 35% codone, and hydromorphone, either in the free base form or by weight to about 45% by weight relative to the total a pharmaceutically acceptable salt form thereof. weight of the composition, the triacetin is present in the 0922) 535. The methodofany one of 521-534, wherein the composition in an amount from about 31% by weight to opioid is oxycodone. about 45% by weight relative to the total weight of the 0923 536. The methodofany one of 521-535, wherein the composition, the IPM is present in the composition in an opioid is present in the composition at about 5% by weight amount from about 2% by weight to about 10% by weight relative to the total weight of the composition. relative to the total weight of the composition, the CAB is 0924. 537. The methodofany one of 521-536, wherein the present in the composition at about 4% by weight to about composition is encapsulated for oral administration. 6% by weight relative to the total weight of the composi 0925 538. The method of any one of 521 to 537, wherein tion, and the HEC is present in the composition in an the composition is contained within a capsule. amount from about 5% by weight to about 6% by weight 0926 539. The method of any one of 521 to 538, wherein relative to the total weight of the composition. the composition is contained within a capsule comprising 0910 523. The method of 521 or 522, wherein the com hydroxypropyl methylcellulose. position comprises about 38% by weight to about 41% by 0927. 540. The method of any one of 521 to 539, wherein weight of the triacetin relative to the total weight of the the composition is contained within a hard capsule com composition. prising hydroxypropyl methylcellulose. (0911 524. The method of any one of 521 to 523, wherein the composition comprises about 2% by weight to about 0928 541. The methodofany one of 521-537, wherein the 3% by weight of the IPM relative to the total weight of the composition is administered no more than twice in a composition. 24-hour period. (0912 525. The method of any one of 521 to 524, wherein 0929 542. The methodofany one of 521-541, wherein the the CAB has a number average molecular weight ranging composition does not comprise more than 5% water by from 66,000 Daltons to 83,000 Daltons. weight, based on total weight of the composition. (0913 526. The method of any one of 521 to 525, wherein 0930) 543. The method of 542, wherein the composition the network former comprises CAB having at least one does not comprise more than 2.5% water by weight, based feature selected from abutyryl content ranging from about on total weight of the composition. 17% to about 38%, an acetyl content ranging from about 0931 544. The method of 542, wherein the composition 13% to about 30%, and a hydroxyl content ranging from does not comprise more than 2.0% water by weight, based about 0.8% to about 1.7%. on total weight of the composition. (0914 527. The methodofany one of 521-526, wherein the 0932 545. The methodofany one of 521-541, wherein the silicon dioxide is present in the composition in an amount composition comprises water at from about 1.0 to about from about 2.5% by weight to about 3.2% by weight rela 2.5% by weight, based on total weight of the composition. tive to the total weight of the composition. 0933 546. The method of 545, wherein the composition (0915 528. The methodofany one of 521-527, wherein the comprises water at from about 1.0 to about 2.0% by weight, silicon dioxide is present in the composition in an amount based on total weight of the composition. US 2016/0038592 A1 Feb. 11, 2016 38

0934 547. The method of 546, wherein the composition 0959 about 4% to about 6% by weight of cellulose comprises water at from about 1.0 to about 1.5% by weight, acetate butyrate (CAB) relative to the total weight of based on total weight of the composition. the composition; 0935. 548. A method for treating pain in a subject, the 0960 about 5% by weight to about 6% by weight of method comprising: hydroxyethyl cellulose (HEC) relative to the total 0936 orally administering to the subject a composition weight of the composition; and about 2.5% by weight comprising to about 3.2% by weight of silicon dioxide relative to 0937 oxycodone; the total weight of the composition, wherein one or 0938 about 35% by weight to about 45% sucrose more symptoms or signs associated with the Subjects acetate isobutyrate (SAIB) relative to the total weight pain is alleviated. of the composition; 0961 551. A method for treating pain in a subject, the 0939 about 31% by weight to about 45% of triacetin method comprising: relative to the total weight of the composition; 0962 orally administering to the subject a composition (0940 about 2% by weight to about 10% by weight of comprising isopropyl myristate (IPM) relative to the total weight 0963 oxycodone at about 5% by weight relative to of the composition; the total weight of the composition; (0941 about 4% to about 6% by weight of cellulose 0964 sucrose acetate isobutyrate (SAIB) at about acetate butyrate (CAB) relative to the total weight of 40% by weight relative to the total weight of the the composition; composition; (0942 about 5% by weight to about 6% by weight of 0965 triacetin at about 39% by weight relative to the hydroxyethyl cellulose (HEC) relative to the total total weight of the composition; weight of the composition; and 0966) isopropyl myristate (IPM) at about 2.5% by (0943 about 2.4% by weight to about 5.4% by weight weight relative to the total weight of the composition; of silicon dioxide relative to the total weight of the 0967 cellulose acetate butyrate (CAB) at about 4.5% composition, wherein one or more symptoms or signs by weight or 4.7% by weight relative to the total associated with the subjects pain is alleviated. weight of the composition; 0944 549. A method for treating pain in a subject, the 0968 hydroxyethyl cellulose (HEC) at about 5.5% method comprising: by weight relative to the total weight of the composi 0945 orally administering to the subject a composition tion; and comprising 0969 silicon dioxide, wherein the silicon dioxide is present in the composition at about 2.9% by weight 0946 oxycodone; relative to the total weight of the composition, (0947 about 39% by weight to about 41% sucrose wherein the composition is formulated for oral acetate isobutyrate (SAIB) relative to the total weight administration, wherein one or more symptoms or of the composition; signs associated with the Subject's pain is alleviated. (0948 about 38% by weight to about 41% of triacetin 0970) 552. The method of 550, wherein the composition is relative to the total weight of the composition; contained within a capsule. (0949 about 2% by weight to about 3% by weight of 0971 553. The method of 550 or 552, wherein the com isopropyl myristate (IPM) relative to the total weight position is contained within a capsule comprising hydrox of the composition; ypropyl methylcellulose. 0950 about 4% to about 6% by weight of cellulose 0972 554. The method of any one of 550 to 553, wherein acetate butyrate (CAB) relative to the total weight of the composition is contained within a hard capsule com the composition; prising hydroxypropyl methylcellulose. 0951 about 5% by weight to about 6% by weight of 0973 555. The method any one of 550-554, wherein the hydroxyethyl cellulose (HEC) relative to the total composition is administered no more than twice in a weight of the composition; and 24-hour period. 0952 about 2.5% by weight to about 3.2% by weight 0974 556. A method of orally administering a composi of silicon dioxide relative to the total weight of the tion, comprising: composition, wherein one or more symptoms or signs 0975 improving reproducibility of an in vitro release associated with the subjects pain is alleviated. profile of a composition by including about 2.4% by 0953 550. A method for treating pain in a subject, the weight to about 5.4% by weight, relative to the total method comprising: weight of the composition, of mineral particle in the 0954 orally administering to the subject a composition composition, wherein the composition also includes a comprising pharmacologically active agent, a high viscosity liquid 0955 about 5% by weight of oxycodone relative to carrier material (HVLCM) having a viscosity of at least the total weight of the composition; 5000 cF at 37° C. that does not crystallize neat at 25°C. 0956 about 39% by weight to about 41% sucrose and 1 atmosphere, a solvent, and a network former, and acetate isobutyrate (SAIB) relative to the total weight 0976 orally administering the composition. of the composition; 0977 557. A method of orally administering a composi 0957 about 38% by weight to about 41% of triacetin tion, comprising: relative to the total weight of the composition; 0978 decreasing the variability of an in vitro release 0958) about 2% by weight to about 3% by weight of profile of a composition by including about 2.4% by isopropyl myristate (IPM) relative to the total weight weight to about 5.4% by weight, relative to the total of the composition; weight of the composition, of mineral particle in the US 2016/0038592 A1 Feb. 11, 2016 39

composition, wherein the composition also includes a CAB having a number average molecular weight ranging pharmacologically active agent, a high viscosity liquid from 50,000 Daltons to 100,000 Daltons. carrier material (HVLCM) having a viscosity of at least 1004 566. The composition of any one of 1-112, 228-471 5000 cF at 37° C. that does not crystallize neat at 25°C. and 560-565, wherein the cellulose acetate butyrate is a and 1 atmosphere, a solvent, and a network former, and CAB having at least one feature selected from a butyryl 0979 orally administering the composition. content ranging from about 17% to about 41%, an acetyl 0980 558. A method of orally administering an encapsu content ranging from about 13% to about 30%, and a lated composition, comprising: hydroxyl content ranging from about 0.5% to about 1.7%. 0981 formingOrm1ng a COmoS1t1Onpositi COmr1S1ng:prising 1005 567. The composition of any one of 1-112, 228-471 0982) a pharmacologically active agent, and 560-566, comprising a surfactant. 0983 a high viscosity liquid carrier material (HV 1006. 568. The composition of 567, wherein the surfactant LCM) having a viscosity of at least 5000 cB at 37° C. is Saturated polyglycolized glyceride. that does not crystallize neat at 25° C. and 1 atmo 1007 569. The composition of any one of 1-112, 228-471 sphere, and 560-568, comprising a hydrophilic agent. 0984 a solvent, 0985 a network former, and 1008 570. The composition of 569, wherein the hydro 0986 a mineral particle, wherein the mineral particle philic agent is selected from hydroxyethyl cellulose is present in the composition in an amount from about (HEC), hydroxypropyl cellulose, caboxymethyl cellulose, 2.4% by weight to about 5.4% by weight relative to polyethylene glycol and polyvinylpyrrolidone. the total weight of the composition; 1009. 571. The composition of any one of 569-570, 0987 improving an in vitro release profile of the com wherein the hydrophilic agent comprises HEC. position by encapsulating the composition in a capsule 1010) 572. The composition of any one of 1-112, 228-471 comprising hydroxypropyl methylcellulose to form an and 560-571, wherein the composition has a complex vis encapsulated composition; and cosity of from about 100Pasto about 300Pas, wherein the 0988 orally administering the encapsulated compo complex viscosity is determined at a constant strain of sition. 0.5% and a frequency of 1 Hz and a temperature of 25°C. 0989 559. A method of orally administering an encapsu 1011 573. The composition of any one of 1-112, 228-471 lated composition, comprising: and 560-572, wherein the composition has a complex vis 0990 forming a composition comprising: cosity of from about 120Pasto about 250 Pas, wherein the 0991 a pharmacologically active agent, complex viscosity is determined at a constant strain of 0992 a high viscosity liquid carrier material (HV 0.5% and a frequency of 1 Hz and a temperature of 25°C. LCM) having a viscosity of at least 5000 cB at 37° C. 1012 574. The composition of any one of 1-112, 228-471 that does not crystallize neat at 25° C. and 1 atmo and 560-573, wherein the composition has a complex vis sphere, cosity of from about 140 Pasto about 200Pas, wherein the 0993 a solvent, complex viscosity is determined at a constant strain of 0994 a network former, and 0.5% and a frequency of 1 Hz and a temperature of 25°C. 0995 a mineral particle, wherein the mineral particle 1013 575. The composition of any one of 1-112, 228-471 is present in the composition in an amount from about and 560-574, wherein the pharmacologically active agent 2.4% by weight to about 5.4% by weight relative to is present in the composition in an amount from about 0.1% the total weight of the composition; by weight to about 30% by weight relative to the total 0996 reducing exposure of the composition to water by weight of the composition. encapsulating the composition in a capsule comprising 1014 576. The composition of 575, wherein the pharma hydroxypropyl methylcellulose to form an encapsulated cologically active agent is present in the composition in an composition; and amount from about 1% by weight to about 10% by weight 0997 orally administering the encapsulated composi relative to the total weight of the composition. tion. 1015 577. The composition of any one of 1-112, 228-471 0998 560. The composition of any one of 1-112 and 228 and 560-576, wherein the mineral particle is present in the 471, wherein the solvent is selected from triacetin, N-me composition in an amount from about 2.4% by weight to thyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, about 5.4% by weight relative to the total weight of the ethyl lactate, propylene carbonate and glycofurol and mix composition. tures thereof 1016 578. The composition of 577, wherein the mineral 0999 561. The composition of 560, wherein the solvent particle is present in the composition in an amount from comprises triacetin. about 2.5% by weight to about 4.0% by weight relative to 1000 562. The composition of 561, wherein the solvent is the total weight of the composition. triacetin. 1017 579. The composition of 577, wherein the mineral 1001 563. The composition of any one of 1-112, 228-471 particle is present in the composition in an amount from and 560-562, wherein the rheology modifier is selected about 2.5% by weight to about 3.5% by weight relative to from isopropyl myristate (IPM), caprylic/capric triglycer the total weight of the composition. ide, ethyl oleate, triethyl citrate, dimethyl phthalate and 1018 580. The composition of 577, wherein the mineral benzyl benzoate. particle is present in the composition in an amount from 1002 564. The composition of 563, wherein the rheology about 2.5% by weight to about 3.2% by weight relative to modifier is isopropyl myristate (IPM). the total weight of the composition. 1003 565. The composition of any one of 1-112, 228-471 1019 581. The composition of 577, wherein the mineral and 560-564, wherein the cellulose acetate butyrate is a particle is present in the composition in an amount from US 2016/0038592 A1 Feb. 11, 2016 40

about 2.5% by weight to about 3.0% by weight relative to composition in an amount from about 31% by weight to the total weight of the composition. about 45% by weight relative to the total weight of the 1020 582. The composition of 577, wherein the mineral composition, the IPM is present in the composition in an particle is present in the composition at from about 2.5% by amount from about 2% by weight to about 10% by weight weight to about 2.9% by weight relative to the total weight relative to the total weight of the composition, the CAB is of the composition. present in the composition at about 4% to about 6% by 1021 583. A composition as defined in any one of 1-112, weight relative to the total weight of the composition, and 228-471 and 560-582, for use as a medicament. the HEC is present in the composition in an amount from 1022 584. A composition as defined in any one of 1-112, about 5% by weight to about 6% by weight relative to the 228–471 and 560-582, for use in a method of treating pain, total weight of the composition. wherein the composition comprises an opioid. 1045 591. The composition of 589 or 590, comprising 1023 585. Use of a composition as defined in any one of about 38% by weight to about 41% by weight of the tri 1-112, 228-471 and 560-582 for the manufacture of a acetin relative to the total weight of the composition. medicament for treating pain, wherein the composition comprises an opioid. 1046 592. The composition of any one of 589 to 591, 1024 586. A method for treating pain in a subject, the comprising about 2% by weight to about 3% by weight of method comprising administering to the Subject a compo the IPM relative to the total weight of the composition. sition as defined in any one of 1-112,228–471 and 560-582, 1047 593. The composition of any one of 589 to 592, wherein the composition comprises an opioid and wherein wherein the composition has a complex viscosity of from one or more symptoms or signs associated with the Sub about 100 Pa's to about 300 Pa's, wherein the complex ject's pain is alleviated. viscosity is determined at a constant strain of 0.5% and a 1025 587. A composition comprising: frequency of 1 Hz, and a temperature of 25°C. 1026 a pharmacologically active agent; 1048 594. The composition of any one of 589 to 593, 1027 a high viscosity liquid carrier material (HVLCM) wherein the composition has a complex viscosity of from having a viscosity of at least 5000 cp at 37°C. that does about 120 Pa's to about 250 Pas, wherein the complex not crystallize neat at 25°C. and 1 atmosphere; and viscosity is determined at a constant strain of 0.5% and a 1028 a cellulose acetate butyrate, frequency of 1 Hz, and a temperature of 25°C. 1029 wherein the composition is encapsulated within a 1049 595. The composition of any one of 589 to 594, hydroxypropylmethylcellulose capsule, and wherein the composition has a complex viscosity of from 1030 wherein the composition within the capsule com about 140 Pa's to about 200 Pas, wherein the complex prises less than 5% water by weight, based on total viscosity is determined at a constant strain of 0.5% and a weight of the composition within the capsule. frequency of 1 Hz, and a temperature of 25°C. 1031 588. A composition comprising: 1050 596. The composition of any one of 589 to 595, 1032 a pharmacologically active agent; wherein the opioid is selected from oxycodone, oxymor 1033 a high viscosity liquid carrier material (HVLCM) phone, hydrocodone, and hydromorphone, either in the having a viscosity of at least 5000 cp at 37°C. that does free base form or a pharmaceutically acceptable salt form not crystallize neat at 25°C. and 1 atmosphere: thereof. 1034 a network former; and 1035 a mineral particle, wherein the mineral particle is 1051) 597. The composition of any one of 589 to 596, present in the composition in an amount from about wherein the opioid is oxycodone. 2.5% by weight to about 3.0% by weight relative to the 1052 598. The composition of any one of 589 to 597, total weight of the composition. wherein the opioid is present in the composition at about 1036 589. A composition comprising: 5% by weight relative to the total weight of the composi 1037 an opioid; tion. 1038 sucrose acetate isobutyrate (SAIB); 1053 599. The composition of any one of 589 to 598, 1039 triacetin: wherein the composition does not comprise more than 5% 1040 isopropyl myristate (IPM); water by weight, based on total weight of the composition. 1041 cellulose acetate butyrate (CAB), wherein the 1054 600. The composition of 599, wherein the compo CAB has a number average molecular weight ranging sition does not comprise more than 2.5% water by weight, from 66,000 Daltons to 83,000 Daltons, and wherein the based on total weight of the composition. CAB has at least one feature selected from a butyryl 1055 601. The composition of 599, wherein the compo content ranging from about 17% to about 38%, an acetyl sition does not comprise more than 2.0% water by weight, content ranging from about 13% to about 30%, and a based on total weight of the composition. hydroxyl content ranging from about 0.8% to about 1056 602. The composition of any one of 589 to 601, 1.7%; wherein the composition comprises water at from about 1.0 1042 hydroxyethyl cellulose (HEC); and to about 2.5% by weight, based on total weight of the 1043 silicon dioxide, wherein the silicon dioxide is composition. present in the composition in an amount from about 2.5% by weight to about 3.0% by weight relative to the 1057 603. The composition of 602, wherein the compo total weight of the composition. sition comprises water at from about 1.0 to about 2.0% by 1044 590. The composition of 589, wherein the SAIB is weight, based on total weight of the composition. present in the composition in an amount from about 35% 1058 604. The composition of 603, wherein the compo by weight to about 45% by weight relative to the total sition comprises water at from about 1.0 to about 1.5% by weight of the composition, the triacetin is present in the weight, based on total weight of the composition. US 2016/0038592 A1 Feb. 11, 2016

EXAMPLES TABLE 1 A-continued 1059. The following examples are put forth so as to pro Component Function % Wiw vide those of ordinary skill in the art with a complete disclo Sure and description of how to make and use the present Colloidal silicon dioxide Suspending agent, viscosity 1.90 (CSD) modifier invention, and are not intended to limit the scope of what the Butylated hydroxytoluene (BHT) Antioxidant O.O2 inventors regard as their invention nor are they intended to Hard shell capsule Dosage form encapsulation Gelatin represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, tem 1062. In vitro analysis of Reference Formulation A has perature, etc.) but some experimental errors and deviations shown that it may exhibit time-dependent changes in drug should be accounted for. Unless indicated otherwise, parts are release performance. This is shown, for example, in FIG. 1A, parts by weight, molecular weight is weight average molecu wherein Reference Formulation A (with BHT) stored at 25° lar weight, temperature is in degrees Celsius, and pressure is C./60% RH for a 22 months period exhibited a decrease in the at or near one atmosphere. Standard abbreviations may be mean release profile for oxycodone. used, e.g., S or sec, second(s); min, minute(s); h or hr, hour(s): and the like. Example 2A Example 1 Gelatin Vs. HPMC Capsules 1063. It was hypothesized that phase immiscibility could Time-Dependent Changes in Drug Release be responsible for the time dependent changes in drug release Performance of Reference Formulation performance observed for Reference Formulation A. It was 1060 Reference Formulation A is a capsule product that further hypothesized that reducing the amount of available provides extended release of oral oxycodone. The product is water by changing the capsule shell from gelatin (~13-16% formulated to resist tampering and abuse. Although the prod w/w water) to HPMC (~4-6% w/w water) could minimize uct is a semi-solid matrix, the composition is manufactured these effects. by a standard liquid-fill manufacturing process. A common Viscous composition of the active pharmaceutical ingredient Materials and Methods (API), colloidal silicon dioxide (CSD) and hydroxyethyl cel 1064 Dissolution data utilizing the Apparatus 2 method lulose (HEC) suspended in a cellulose acetate butyrate (described below) for Reference Formulation A in gelatin or (CAB)/sucrose acetate isobutyrate (SAIB)/triacetin (TA)/iso HPMC capsules stored up to 12 months at 25°C/60% RH, propyl myristate (IPM)/Butylated hydroxytoluene (BHT) 30° C./65% RH and 40° C./75% RH are shown in FIG. 1B, Solution is filled into a range of capsule sizes to accommodate Panels A and B. various dosage strengths. 1065. Twelve capsules from each formulation were tested 1061. The composition of Reference Formulation A is as with USP Apparatus 2 to evaluate the effect on inter-capsule provided below in Table 1A. dissolution variability. The release rate of oxycodone base was determined using a USP Apparatus 2 dissolution tester. TABLE 1A Dissolution medium containing 1000 ml 0.1 NHCl with 0.5% (w.fw) SDS was maintained at 37° C. with 100 rpm Component Function % Wiw paddle speed over the course of the 24 hour dissolution test. A Micronized oxycodone base Active Pharmaceutical S.13 20 mesh screen hanging basket was incorporated to hold the Ingredient test article and the paddle speed was set to 100 rpm. The Sucrose acetate isobutyrate An esterified sucrose 40.98 standard sampling time points were 0.5, 2, 3, 6, 12 and 24 (SAIB) derivative, that is a high viscosity, hydrophobic hours. A 1 mL sample was taken at each time point and carrier assayed using reverse-phase HPLC at 240 nm wavelength. molecule, which is the base The mobile phase included 0.35% (w/v) SDS/0.7% (v/v) component in the extended release matrix acetic acid/44% (v/v) acetonitrile in water. Triacetin (TA) Hydrophilic solvent that 27.32 1066 Separately, the total water content of a freshly pre participates in the dissolution pared Reference Formulation A formulation in gelatin vs. or Suspension of other HPMC capsules was determined. Two preparations were components in the extended release matrix tested for each formulation. The % water (or moisture) was Isopropyl Myristate (IPM) Rheology modifier that 1423 determined by Karl Fischer Coulometric Apparatus and each participates preparation utilized 5 capsules. in the control of drug diffusion from Results the extended release matrix Cellulose acetate butyrate Polymer additive for abuse 4.74 1067 The results for the dissolution experiments are pro (CAB) deterrence and extended release vided in FIG. 1B, Panels A and B. As shown in Panel A, Hydroxyethyl cellulose Non-ionic, water soluble S.69 Reference Formulation A in gelatin capsules exhibits a (HEC) polymer that decrease in the mean release profile following storage for 12 participates in the control of drug months at 25°C., 6 months at 30°C., 6 months at 40° C. and diffusion from the extended 3 months at 40° C. relative to the initial release profile. In release contrast, Reference Formulation A in HPMC capsules exhib matrix ited a more stable dissolution profile following storage under the above conditions, with the exception of the 40°C. storage US 2016/0038592 A1 Feb. 11, 2016 42 conditions. Inter-capsule dissolution variability was not sig TABLE 1B nificantly reduced for Formulation A in HPMC relative to Formulation A in gelatin under the above testing conditions. Time point (hour) O.S 2 3 6 12 24 1068 The total average water content of Reference For Test 1 Dissolution Results, Lot # 1 (n = 6) in gelatin capsules mulation A in gelatin vs. HPMC capsules was found to be 2.2% w/w vs. 1.4% w/w respectively. 1 21 39 46 62 76 85 2 29 52 59 72 83 89 3 23 45 53 69 81 86 Example 2B 4 21 40 48 65 83 88 5 19 36 43 57 76 85 Gelatin Vs. HPMC Capsules 6 19 43 S4 70 81 85 Mean 22 43 51 66 8O 86 1069. This study compared two lots of Formulation A (40 SD 4 6 6 6 3 2 mg) prepared without BHT and with the same bulk mass filled % RSD 18 14 12 9 4 2 into size 00 Licaps(R (gelatin) (Lot #1) and Vcaps(R Plus Test 2 Dissolution Results, Lot #1 (n = 12) in gelatin capsules (HPMC) capsules (Lot #2). The lots were tested for in vitro 1 27 49 57 72 84 88 2 29 51 60 74 86 91 dissolution and Viscoelastic parameters. In addition, the cap 3 24 45 52 68 78 84 sule shells were evaluated by Karl Fischer titration for its 4 22 39 45 60 75 85 potential property change. 5 24 41 49 63 81 89 6 24 43 50 65 82 90 Materials and Methods 7 22 46 53 66 78 85 8 21 38 43 56 70 83 9 31 S4 62 74 85 89 1070 Dissolution Testing 10 30 51 58 72 85 91 1071. Two separate tests of the two lots were performed 11 24 50 58 70 82 89 after storage of the lots for approximately 12 months at 25° 12 22 39 45 58 74 88 C./60% RH. The release rate of oxycodone base was deter Mean 25 45 53 66 8O 88 mined using a USP Apparatus 3 dissolution tester. Dissolu SD 4 6 6 6 5 3 tion medium containing 250 ml 0.1 NHCl with 0.02% (w/w) % RSD 16 13 13 9 6 3 SDS was maintained at 37°C. with 45 dpm (dips per minute) over the course of the 24 hour dissolution test. An glass inner sample tube with two ends covered with 20 mesh SS316 was TABLE 1C incorporated to hold the test article. The standard sampling time points were 0.5, 2, 3, 6, 12 and 24 hours. A 1 mL sample Test 1 Dissolution Results, Lot # 2 (n = 6) in HPMC capsules was taken at each time point and assayed using reverse-phase Time point (hour) O.S 2 3 6 12 24 HPLC at 240 nm wavelength. The mobile phase included 1 17 45 55 73 85 88 0.35% (w/v) SDS/0.7% (v/v) acetic acid/44% (v/v) acetoni 2 18 53 65 82 90 90 trile in water. 3 2O 35 41 53 70 83 1072. The results of the dissolution testing experiment are 4 14 34 45 63 78 85 5 18 38 46 63 8O 86 provided in Tables 1B-1D below and FIGS. 1C and 1D. 6 19 45 53 67 81 88 1073 Rheology Testing Mean 18 42 51 67 81 87 1074 The rheology test was carried out in parallel plates SD 2 7 9 10 7 3 (PP25) at 25° C. using an Anton Paar MCR301 rheometer. % RSD 11 17 18 15 9 3 The sample was exposed to a constant angular frequency (10 s') of increasing dynamic strain (0.1 to 100%). 1075 Water Content by Karl Fischer Titration TABLE 1D 1076 Water content of the capsule shell of the two lots was evaluated by Karl Fischer titration using an AquaStar C3000 Test 2, Dissolution Results, Lot # 2 (n = 12) in HPMC capsules Karl Fischer Coulometric Titrator. In this experiment, the formulation was completely exuded from the capsule. The Time point (hour) O.S 2 3 6 12 24 capsule shell was cut into Small pieces and placed inside a 1 18 48 61 8O 88 91 2 18 30 34 43 60 78 clear sample vial. The vial was crimped with a metal seal cap. 3 10 29 37 S4 73 87 In a second vial, which was used as a blank sample, a suffi 4 18 42 51 69 84 90 cient amount of anhydrous methanol was transferred to the 5 18 33 43 60 81 88 vial, and the vial was crimped with a metal seal cap. Approxi 6 16 37 47 68 83 89 7 21 45 55 77 90 94 mately 1.2 mL of anhydrous methanol from the second vial 8 2O 42 53 73 86 91 was added to the sample vial and the weight of methanol 9 19 39 49 71 88 92 introduced was recorded. The sample vial was placed in a 10 2O 50 60 74 84 89 11 22 58 70 85 93 93 mechanical shaker mixing at 300 rpm for about 60 minutes. 12 29 S4 65 79 90 93 The percentage water content in the sample was determined Mean 19 42 52 69 83 90 by weight gained and calculated against methanol standards. SD 4 9 11 12 9 4 % RSD 21 21 21 17 11 4 Results 1077 Dissolution Testing Results 1079 FIG. 1C illustrates the dissolution profiles for the 1078. The results of the dissolution testing are provided in data provided in Tables 1B and 1C. The dissolution profiles Tables 1 B-1D below and in FIGS. 1C and 1D. for both the gelatin and HPMC lots were very similar between US 2016/0038592 A1 Feb. 11, 2016

the two tests. However, the variation was higher in general for TABLE 1 F-continued the HPMC lot (FIG. 1D). During the first test, visual obser Vations and photographic evidences were taken at 30 minutes Water Content of Lot #1 (gelatin) by Karl Fischer Titration and 20 hours. At 30 minutes, the HPMC lot remained in one Weight of single piece while the gelatin lot broke into fragments. How the Capsule Water content ever, at the later time (20 hours) the HPMC lot was seen in Sample ID (%) (g) Change (%) more small sized pieces. Without intending to be bound by #3 (Licaps) O.118 12.0 -3.0 any particular theory, presumably the HPMC lot was more Average O. 111 11.5 -3.5 prone to fragmentation after being exposed to the aqueous Standard deviation O.O11 0.4 0.4 medium and the fragmentation rate might be more variable 96 CV 9.5 3.7 -12.2 than the gelatin capsules. 1080 Rheology Testing Results 1081 Table 1E summarizes the viscoelastic outputs of lots TABLE 1G 1 and 2 at the linear viscoelastic (LVE) range. The absolute Water Content of Lot #2 (HPMC) by Karl Fischer Titration differences of viscosity m, storage modulus G', and loss Weight of modulus G" were 7 Pas, 43 Pa, and 56 Pa, respectively lower the Capsule Water content for the HPMC lot than the gelatin lot. The viscosity differ Sample ID (%) (g) Change (%) ences between the type of capsules are greater than the ana Intact empty Vcaps Plus O. 119 5.9 lytical method variation, which has an estimated Standard #1 (Vcaps Plus) O.115 4.2 -1.7 deviation of approximately +2 Pas, 8 Pa and 14 Pa form, G #2 (Vcaps Plus) O.126 4.4 -1.6 and G", respectively. Although the Formulation A (without #3 (Vcaps Plus) O.129 4.3 -1.6 BHT) stored in gelatin capsules had a higher viscosity value Average O.123 4.3 -1.6 than the formulation stored in HPMC capsules, this differ Standard deviation O.OO7 O.1 O.1 ence did not appear to influence their dissolution profiles. 96 CV 6.1 1.8 -4.8 TABLE 1E Example 3 all values at LVE range Preparation of Extended Release Oxycodone Complex Storage Loss Damping Yield Compositions for PK and BA Analysis viscosity in modulus modulus factor Stress' 1084 Compositions were prepared, for example, as fol Sample (Pas) G' (Pa) G" (Pa) tanö (Pa) lows to provide the compositions indicated in Table 2 (be Lot #1 (Licaps) 63 3O8 553 18O 55.3 low). Sucrose Acetate Isobutyrate (SAIB) was transferred Lot #2 (Vcaps 56 26S 497 1.87 58.7 into a Ross mixer at an elevated temperature (50° C.) and Plus) dissolved in triacetin (TA) and isopropyl myristate (IPM) and Absolute 7 43 56 -O.O7 -3.4 uniformly mixed. When present in the composition, butylated difference hydroxytoluene (BHT) was added prior to uniformly mixing at 5% tolerance of storage modulus G with TA and IPM. Colloidal silicon dioxide (CSD) particles were added into the SAIB solution in the Ross mixer and were dispersed uniformly. Cellulose acetate butyrate (CAB) par 1082 Water Content Results ticles were sieved and fed into the Ross mixer and dispersed 1083. The results of the Karl Fischer Titration are summa and dissolved in the content of the mixer at the elevated rized in Tables 1F and 1G below. The water content for the temperature. The oxycodone particles were introduced into intact non-used capsule shells was found to be as anticipated, the Ross mixer and dispersed in the content of the mixer, i.e. 15% for the gelatin shell and 5.9% for the HPMC shell. keeping the same process temperature. Hydroxyethyl cellu The water contents for the Formulation A (without BHT) lose (HEC) was then added into the Ross mixer and dispersed. exposed capsule shells were 3.5% lower for the gelatin lot In order to assure complete dispersion of all particles (oxyc (11.5%) and 1.6% lower for the HPMC lot (4.3%), compared odone, SiO2, HEC), high shear mixers (dispenser and emul to the respective intact capsules. The Formulation A (without sifier) may be used for pre-set time periods after the introduc BHT) gelatin capsule shells lost more water than the Formu tion of these solid particles into the Ross mixer. lation A (without BHT) HPMC capsule shells. Without 1085 For the capsule filling operation, the compositions intending to be bound by any particular theory, the greater were transferred from the Ross mixer via a temperature con water content reduction for the gelatin lot may have occurred trolled (or insulated) (at 50-60° C.) pump and hoses to the between the shell and the bulk mass. capsule filling equipment. The temperature of the composi tions was maintained at 50-60° C. during the capsule filling TABLE1F operations. 1086 Individual compositions were encapsulated within Water Content of Lot #1 (gelatin) by Karl Fischer Titration size 4 (5 mg dose) or size 00 (40 mg dose) gelatin or HPMC Weight of capsules. Encapsulation was achieved using a Capsugel CFS the Capsule Water content 1000TM apparatus. It was observed that increasing the tem Sample ID (%) (g) Change (%) perature of the composition and the filling pump, e.g., from Intact empty Licaps O. 120 1S.O about 60° C. to about 75°C., reduced the stringiness of the #1 (Licaps) O.098 11.2 -3.8 composition, thereby facilitating the separation of the com #2 (Licaps) O. 116 11.3 -3.7 position from the nozzle into the capsule shell and allowing clean movement to the next capsule station. The reduced US 2016/0038592 A1 Feb. 11, 2016 44 stringiness of the composition also allowed the motor speed lation A. The oral solution was included for the purpose of setting (fill rate) to be increased, e.g., to a motor speed set exploratory in vitro in vivo correlation analysis. point range of about 50% to about 60% (500-600 capsules per hour). Size 00 capsules were successfully filled using, e.g., a TABLE 3 1.8 mm filling nozzle. Size 4 capsules were successfully filled using, e.g., a 2.0-2.2 mm nozzle. An exemplary composition Reference Formulation A Gelatin capsule shell, 40 preparation and encapsulation method is depicted graphically (withouithout BHT ) mg oxycodoned Ref{{Ce in FIG. 2. Formulation 1 HPMC capsule shell, 40 Test 1087. The compositions indicated in Table 2 (below) were (Referentiyin A. mg oxycodone prepared for use in Examples 4-6 below. Composition CO- Formulationl 2 HPMC capsule shell Test ponents were blended and individual compositions were without HEC, 40 mg encapsulated within gelatin or HPMC capsules as described oxycodone above. TABLE 2 % w/w of component of each formulation Formulation Identification Reference 1 (Reference Formulation Formulation A in Gelatin A in HPMC Composition without BHT) without BHT) 2 3 4 5 6 7 8 9 Micronized S.13 S.13 S.13 S.13 S.13 S.13 S.13 S.13 S.13 S.13 oxycodone base Sucrose acetate 40.99 40.99 46.69 48.11 40.98 40.98 36.74 38.98 40.38 39.98 isobutyrate (SAIB) Triacetin (TA) 27.32 27.32 27.32 27.31 32.55 39.08 37.56 39.08 39.08 39.08 Isopropyl 1423 1423 1423 7.12 9.OO 2.48 8.25 2.48 2.48 2.48 Myristate (IPM) Cellulose acetate 4.74 4.74 4.74 4.74 4.74 4.74 4.74 4.74 4.74 4.74 butyrate (CAB) Hydroxyethyl S.69 S.69 O.OO S.69 S.69 S.69 S.69 S.69 S.69 S.69 cellulose (HEC) Colloidal silicon 1.90 1.90 1.90 1.90 1.90 1.90 1.90 3.90 2.50 2.90 dioxide (CSD) Capsule Shell Gelatin HPMC HPMC HPMC HPMC HPMC HPMC HPMC HPMC HPMC

Example 4 TABLE 3-continued PK Analysis of Extended Release Oxycodone Reference Formulation A Gelatin capsule shell, 40 Compositions (Ref. Formualtion A and Formulations (withouithout BHT ) mg oxycodoned Ref{{Ce 2, 3 and 4) Formulation 3 HPMC capsule shell with Test 50% reduced IPM content and increase in SAIB, 40 Materials and Methods mg oxycodone Oral solution Oral solution of Oral solution 1088. This study was an open-label, single-dose, random- oxycodone 40 mg ized, crossover study of the pharmacokinetics and bioavail ability of oxycodone after administration of 40 mg doses of four extended release oxycodone compositions and oxyc odone in solution in fed state to healthy volunteers. Results 1089. The study was intended to evaluate the in vivo per formance of several variants of Reference Formulation A 1091. The mean plasma oxycodone concentration profiles (primarily HEC, IPM, and SAIB) and the effect of changing are shown in FIG. 3. The mean (CV%) values for the oxyc the capsule shell from gelatin to hydroxylpropyl methylcel odone PK parameters are summarized in Table 4, below, lulose (HPMC). along with the geometric mean ratios and 90% confidence 1090 The study was conducted as an open-label, single intervals for each test composition relative to the Reference dose, 5-way crossover study in 16 healthy adult volunteers. Formulation A. Compared with the rapid oral absorption The treatments (Reference Formulation A, three modified characteristics of the oral solution, Reference Formulation A oxycodone compositions Formulation 1 (Reference Formu and the 3 modified oxycodone compositions demonstrated lation A in HPMC), Formulation 2 and Formulation3, and an drug delivery characteristics consistent with extended release oral oxycodone solution; see Table 3) were administered of the Reference Formulation A. The results demonstrated under naltrexone blockade and following ingestion of an that changing the capsule shell from gelatin to HPMC did not intermediate-size breakfast (~450 calories). The primary significantly affect the controlled-release characteristics of objective was to estimate the pharmacokinetics and bioavail the composition based on the geometric mean ratios for C. ability of oxycodone following single oral 40 mg doses of and AUC. In contrast, the C and AUC values for the test three modified compositions relative to the Reference Formu Formulations 2 and 3, which involved significant changes in US 2016/0038592 A1 Feb. 11, 2016 excipients—either a removal of HEC (Formulation 2) or a parts. In Part I, three modified oxycodone compositions (For 50% reduction in IPM and corresponding increase in SAIB mulations 4, 5, and 6) were compared with Reference For the key hydrophobic constituent of Reference Formulation mulation A using a standard single-dose, 4-period, crossover A—(Formulation 3), were generally slightly lower on C (by approx. 15-20%) than those for Reference Formulation A study design, with at least a one-week washout period even though their controlled-release characteristics were between doses. Following the completion of Part I, the phar retained as compared with the oral solution (Table 4). How macokinetic results were reviewed and the test composition ever, AUC point estimates were similar to the Reference that had the PK profile closest to that of Reference Formula Formulation A (within approx. 90-100% of Reference For tion A was selected for Part II (Period 5) to evaluate dose mulation A). proportionality of the 5 mg strength. After completion of Part TABLE 4 PK Summary

Reference Formulation A (without Formulation Formulation Formulation Oral Parameter BHT) 1 2 3 Solution (Units) (N = 14) (N = 16) (N = 14) (N = 13) (N = 14) C (ng/mL) 62.8 (34) 58.5 (26) 51.1 (26) 55.0 (36) 116 (20) Tax (hr) 5.0 (2.0-6.0) 6.0 (2.0-6.0) 6.0 (4.0-6.1) 4.0 (2.0-8.0) 2.0 (0.5-6.0) AUCs, 752 (12) 745 (21) 691 (27) 676 (24) 817 (17) (nghrimL) AUC 772 (13) 764 (22) 712 (28) 708 (23) 818 (17) (nghrimL) t12 (hr) 7.88 (3.01) 8.01 (3.03) 8.56 (2.66) 9.72 (3.86) 5.83 (0.58) Geometric mean (% CV) for AUC, C.; median (range) for T: arithmetic mean (SD) for t2. BA Assessment Bioavailability (%) Relative to Formulation A 90% Confidence Interval

Parameter Formulation 1 Formulation 2 Formulation 3

Cmax 92.8 (77.5, 111.0 80.1 (66.5, 96.4 87.5 (72.5, 105.6) AUC 100.5 (91.4, 110.5) 92.1 (83.5, 101.5) 91.683.0, 101.1

Example 5 II, the protocol was amended to estimate the relative bioavail ability of an additional composition (Formulation 7), as part PK and BA Analysis of Extended Release of an add-on, fixed-sequence study design (Part III, Period 6), Oxycodone Compositions (Ref. Formualtion A and in the same study population. Formulations 4, 5, 6, 7 and 1094 All compositions were administered under naltrex one blockade and following ingestion of an intermediate-size Materials and Methods breakfast (~450 calories). 1092. This study was intended to evaluate the in vivo per formance of several variants of Reference Formulation A Results (primarily changes in the relative amounts of TA and IPM). In addition, Formulation 7 a slight variant of Formulation 5, 1095 The mean plasma Oxycodone concentration profiles differing only with respect to silicon dioxide (CSD) con and Summary statistics for oxycodone PK parameters follow tent—was evaluated as an add-on treatment arm to complete ing single oral doses of each composition tested in this study the study. Likewise, the pharmacokinetics and dose propor are shown in FIG. 4 and Table 5, respectively. The initial study tionality of a 5 mg dose of the 40 mg test Formulation 5 after results indicated that Formulation 5 had the oxycodone PK the initial 4-way crossover portion of the study with Refer and BA characteristics closest to Reference Formulation A ence Formulation A, 4, 5, and 6 was completed. HPMC cap Sule shells were used in each modified oxycodone composi with respect to in vivo performance. Therefore, Formulation tion, while gelatin capsule shells were used for Reference 5 was selected to establish the dose-proportionality relation Formulation A. ship between the 5 mg and 40 mg dosage strengths. The 1093. This was an open-label, single-dose, randomized, statistical analysis results for relative bioavailability of For crossover study in healthy adult (18-55 years) male and mulations 4, 5, 6, and 7 vs. Reference Formulation A, and for female volunteers. Twenty (N=20) subjects who met study the dose proportionality relationship with the 5 mg dosage eligibility criteria were enrolled. The study occurred in three form (Formulation 5) are also shown in Table 5. US 2016/0038592 A1 Feb. 11, 2016

TABLE 5 PK Summary

Reference Formulation A Parameter (without BHT) Formulation 4 Formulation 5 Formulation 6 Formulation 7 Formulation 5 (Units) (N = 19) (N = 20) (N = 20) (N = 20) (N = 18) (N = 19) Dose 40 mg 40 mg 40 mg 40 mg 40 mg 5 mg C (ng/mL) 41.3 (41) 32.6 (29) 46.4 (39) 52.1 (35) 35.5 (37) 4.88 (29) Tax (hr) 4.0 (2.0-8.0) 6.0 (4.0-12.0) 6.0 (4.0-8.0) 4.0 (2.0-12.0) 6.0 (4.0-14.0) 4.0 (2.0-8.0) AUCs, 581 (23) 523 (25) 592 (22) 587 (19) 571 (19) 62.8 (27) (nghrimL) AUC 605 (23) 544 (24) 600 (22) 596 (19) 580 (19) 66.4 (26) (nghrimL) t12 (hr) 920 - 2.91 8.95 - 2.83 6.70 + 1.14 7.07 - 181 6.36 - 1.74 865 - 2.74

BA Assessment Parameter Bioavailability (%) Relative to Formulation A 90% Confidence Interval Formulation 4 5 6 7 5b Dose 40 mg 40 mg 40 mg 40 mg 5 mg Cmax 79.568.6, 92.1 113.3 (97.7, 131.3 127.2 109.7, 147.3 85.1734, 98.6 84.1 (72.0, 98.2 AUC 89.284.4, 94.2 98.493. 1, 104.0 97.8 92.6, 103.3 93.5 (87.2, 100.2 88.7 81.1, 97.1 Geometric mean (% CV) for AUC, C, median (range) for Ti; arithmetic mean (+SD) for ti, similar in composition to Formulation 5 except for drug content (5 mg) dose-normalized comparison relative to Formulation 5

1096. The above results indicate that each modified com relative bioavailability of oxycodone following oral admin position tested behaved like a controlled-release composition istration of 40 mg doses. similar to the Reference Formulation A, with median T. values ranging between 4 and 6 hours (compared with 1-hour 1101 The test compositions in this study were prepared when oxycodone is administered as an immediate-release based on the results from Example 5 above, which suggested composition; data not shown). The study also revealed that that making intermediate adjustments to the CSD content— changing the ratio of certain excipients in the Reference For i.e., relative to the 1.9% CSD content in Formulation 5 and the mulation A can result in varying degrees of changes in oxy 3.9% CSD content in Formulation 7 had the potential to codone C (approx. -21% to +27%), with similar extent of bioavailability. provide in vivo drug delivery characteristics of the modified 1097. Of the three compositions tested. Formulation 5, oxycodone composition similar to Reference Formulation A. with a C ratio of approximately 113% and 90% CI of This study was designed to evaluate the PK and bioavailabil 97.7-131.3%, was considered closest to the Reference For ity of single oral 40 mg doses of modified compositions mulation A and, therefore, was selected for evaluation at the (Formulations 8 and 9) compared with Reference Formula 5 mg dose in Part II to assess the dose proportionality rela tion A. tionship. In general, there was a dose-related increase in oxycodone C (4.9 ng/mL vs. 46.4 ng/mL) and AUC, 1102 This was a randomized, open-label, single-dose, (66.4 ngh/mL vs. 600 ngh/mL) as shown in Table 5. 4-treatment, 4-period, crossover study in healthy Volunteers. 1098. After completing the PK evaluations for Reference Eighteen (18) subjects aged 18-55 years who met inclusion Formulation A and and exclusion criteria were enrolled. Two test modified oxy 1099 Formulations 4, 5, and 6, an additional treatment codone compositions (i.e., Formulations 8 and 9.) and the arm was added to the study to determine the bioavailability of Formulation 7 (a slight variant of Formulation 5 with Reference Formulation A were evaluated under fed condi increased CSD content). The results of this study suggest that tions. increasing CSD in the composition from 1.9% to 3.9% can 1103 All subjects were to be administered 50 mg of nal potentially decrease C by approximately 15% relative to trexone HCl by mouthat the following times: 12 hours before, Reference Formulation A, without substantially impacting 30 minutes before, and 12 hours after study drug administra the extent of absorption. tion to minimize the risk of opioid-related AEs. The results Example 6 are shown below.

PKAnalysis of Extended Release Oxycodone Results Compositions (Ref. Formualtion A and Formulations 8 and 9) 1104. The mean plasma Oxycodone concentration profiles for oxycodone PK parameters following single oral doses of Materials and Methods each composition tested in the study are shown in FIG. 5. The 1100 This study was an open-label, single-dose, random Summary statistics and statistical analysis are given in Table ized crossover study to evaluate the pharmacokinetics and 6, below. US 2016/0038592 A1 Feb. 11, 2016 47

TABLE 6 PK Sumary

Parameter Reference Formulation (Units) A (without BHT) Formulation 8 Formulation 9

N 18 18 18 Cmax 31.2 (50) 32.8 (36) 34.8 (34) (ng/mL) T(hr) 4.0 (4.0-8.0) 6.0 (4.0-16.0) 6.0 (4.0-12.0) AUCs, 396 (37) 454 (29) 447 (28) (nghrimL) AUC 403 (37) 461 (29) 453 (28) (nghrimL) t12 (hr) 7.4 1.7 71 - 1.4 6.7 - 1.9 Geometric mean (% CV) for AUC, C.; median (range) for T.; arithmetic mean (SD) for t2. BA Assessment Bioavailability (%) Relative to Formulation A Parameter 90% Confidence Interval Formulation 8 9 Cmax 105.287.6, 126.3 111.7 93.0, 134.1 AUC 114.5 104.6, 125.4 112.4102.7, 123.1

1105 The results of the relative BA study indicate that the 1107 Reference Formulation A (without BHT) and For two modified oxycodone compositions (Formulations 8 and mulations 1 to 3 stored up to 12 months and Formulations 4 to 9) had similar in vivo characteristics with respect to the rate 6 stored up to 6 months at accelerated conditions (40°C./75% and extent of oxycodone absorption. Each test composition RH) and long term storage conditions (25°C./60% RH) are had qualitatively similar PK profiles and bioavailability val shown in Table 7 and Table 8. ues, consistent with the desired controlled-release character istics for a modified oxycodone composition. The C and 1108 Twelve capsules from each composition were tested AUC ratios for Formulations 8 and 9 were both slightly higher with USP Apparatus 2 to evaluate the effect on inter-capsule compared to Reference Formulation A, which seemed to dissolution variability. The release rate of oxycodone base underperform slightly with respect to oxycodone exposure was determined using a USP Apparatus 2 dissolution tester. parameters (C and AUC). Nevertheless, there was no Dissolution medium containing 1000 ml 0.1 NHCl with apparent difference in oxycodone bioavailability (C, or 0.5% (w.fw) SDS was maintained at 37° C. with 100 rpm AUC) with the CSD content used in this study for Formula paddle speed over the course of the 24 hour dissolution test. A tion 8 (2.5%) and Formulation 9 (2.9%) based on similar 20 mesh screen hanging basket was incorporated to hold the point estimates and overlapping 90% confidence intervals of test article and the paddle speed was set to 100 rpm. The Test/Reference ratios. Overall, the preliminary study results standard sampling time points were 0.5, 2, 3, 6, 12 and 24 indicated that Formulation 8 and 9 were indistinguishable hours. A 1 mL sample was taken at each time point and with respect to PK and bioavailability. assayed using reverse-phase HPLC at 240 nm wavelength. Example 7 The mobile phase included 0.35% (w/v) SDS/0.7% (v/v) Dissolution Performance for Reference Formulation acetic acid/44% (v/v) acetonitrile in water. A and Formulations 1-6 Results Materials and Methods 1106 Dissolution data utilizing the Apparatus 2 method 1109 The results of the in vitro dissolution analysis are (described below) for shown in Table 7 and Table 8 below. TABLE 7

Ref. Formulation A Formulation 1 Formulation 2 Formulation 3 Storage Check Mean Range Mean Range Mean Range Mean Range Conditions Point Hours (%) (%) Hours (%) (%) Hours (%) (%) Hours (%) (%)

Initial O 2 23 20-31 2 22 18-31 2 24 18-30 2 18 15-27 6 48 42-56 6 43 33-58 6 38 28-48 6 34 28-46 24 96 86-104 24 87 68-1OO 24 59 46-74 24 64 SO-80 25 C.60% 3 2 22 17-28 2 27 22-30 2 18 15-21 2 17 12-24 RH months 6 44 37-52 6 48 37-55 6 31 25-37 6 29 23-41 24 94 85-100 24 86 7S-94 24 56 44-69 24 56 42-71 6 2 21 16-28 2 24 19-28 2 21 17-24 2 18 13-2S months 6 42 36-54 6 44 36-49 6 39 34-42 6 32 2S-43 24 94 80-101 24 93 90-108 24 66 58-72 24 60 53-72