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(12) Patent Application Publication (10) Pub. No.: US 2016/0038592 A1 Yum Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0038592 A1 Yum Et Al 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.
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