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(12) Patent Application Publication (10) Pub. No.: US 2015/0290211 A1 BOSSE Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2015/0290211 A1 BOSSE Et Al US 20150290211A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0290211 A1 BOSSE et al. (43) Pub. Date: Oct. 15, 2015 (54) PHARMACEUTICAL COMPOSITIONS cation No. 62/091,793, filed on Dec. 15, 2014, provi sional application No. 62/093,093, filed on Dec. 17, (71) Applicant: LOCL Pharma, Inc., Georgetown, DE 2014, provisional application No. 62/104,429, filed on (US) Jan. 16, 2015. (72) Inventors: Paul BOSSE, Jupiter, FL (US); John Publication Classification AMELING, Jupiter, FL (US); Bernard SCHACHTEL, Jupiter, FL (US); (51) Int. Cl. William KOZAREK, Jensen Beach, FL A63/545 (2006.01) (US) A63/67 (2006.01) 21) Appl. No.: 14/683,886 A613 L/485 (2006.01) (21) Appl. No.: 9 (52) U.S. Cl. 1-1. CPC ........... A6 IK3I/5415 (2013.01); A61 K3I/485 (22) Filed: Apr. 10, 2015 (2013.01); A61 K3I/I67 (2013.01) Related U.S. Application Data (57) ABSTRACT (60) Provisional application No. 61/977,845, filed on Apr. 10, 2014, provisional application No. 62/020,597, Provided herein are methods and compositions for effective filed on Jul. 3, 2014, provisional application No. pain treatment, which also reduce or eliminate adverse 62/029,776, filed on Jul. 28, 2014, provisional appli effects. US 2015/0290211 A1 ------------------------«-----------------------|------------------------, O 60 }} } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } } Figure 1 Patent Application Publication Oct. 15, 2015 Sheet 2 of 27 US 2015/0290211 A1 :88::::::::::::::::::::::::::::::::::::::: :8:3 * Figure 2A Patent Application Publication Oct. 15, 2015 Sheet 4 of 27 US 2015/0290211 A1 8:88 $3 3:38.83 ::::::::::::: **- \ f / 8: -axx f as ; S&888& FCK A 33x & -. A AAYAawaTEST. && H 8883 ff N ^ wo • awww. A K/- 88s. gy Figure 2C Patent Application Publication Oct. 15, 2015 Sheet 5 of 27 US 2015/0290211 A1 Friabilator Apparatus for Friability Measurements 2870 it 4.0 inn 9 inside diameter : 80.3 it 5.0 mm xxx* x 10.0+0.1mm inside radius 9 diameter 9 25.0 is 0.5 mm s x diameter 9 9 302.5 it 4. On 9 -- xx. diameter 38.0 it 2.0 inn 9 Figure 3 Patent Application Publication Oct. 15, 2015 Sheet 6 of 27 US 2015/0290211 A1 Tablet Orientations in Hardless Measurements Face of Plunger Face of Phanger Capsule-Shaped Figure 4 Patent Application Publication Oct. 15, 2015 Sheet 7 of 27 US 2015/0290211 A1 HC Disso APAP PMZ Thickness || Hardness Friability 5 1O 15 5 10 15 5 10 15 kp % % 6.14 22.2 O.OO 63 76 83 73 82 85 98 || 101 || 101 6.24 17.5 O.05 64 || 8 || 87 78 || 9 || 96 80 86 86 6.26 18.0 65 77 85 78 85 89 95 98 100 6,37 160 O.13 42 637 16.5 0.10 AO 6.43 15. 0.13 43 6,44 16.3 O, OS 52 7O 82 69 || 8 || 87 91. 94 95 69 74 85 88 90 9 96 88 92 94 6,85 110 O.08 59 71 79 75 83 86 65 79 88 6.95 10.4 60 80 88 69 96 92 91. 95 96. 6.99 9.O 0.40 45 704 9.5 0.44 46 7.13 92 O.65 48 7.3 8.7 72 87 94 8O 94 99 86 93 94 7.5 8.4 O.90 A7 Formulation Aabet Width (in) ength (in) OO3430 O6.795 Figure 5 Patent Application Publication Oct. 15, 2015 Sheet 8 of 27 US 2015/0290211 A1 Friability Vs Hardness Friability Hardness (kp} — Power (Series) Figure 6 Patent Application Publication Oct. 15, 2015 Sheet 9 of 27 US 2015/0290211 A1 Friability Vs Thickness Friability g 88: 8.33 8.33 3.88: 8.8 3.33 3.383 3.38 Thickness (mm) - Expon. (Series) Figure 7 Patent Application Publication Oct. 15, 2015 Sheet 10 of 27 US 2015/0290211 A1 Hardness (kp) 88: - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -------. .is....s...s...s.ly. ... .s.... s.s....s... .s. s.s.. .....v....y.a... s.v.ss.v. iv. ...v.3.xx...s. i. s.s.si.v.v. ......... ... ... i.i. ... Thickness (nm) — Expon. () Patent Application Publication Oct. 15, 2015 Sheet 11 of 27 US 2015/0290211 A1 Dissolution % s: 8 : is . 33 3 : Hardness (kp) 3. is six; N.3ines: 3; sing-in. Figure 9 Patent Application Publication Oct. 15, 2015 Sheet 12 of 27 US 2015/0290211 A1 Dissolution % S8 88: 33 38 33.3 3.3 : 3 x 333 3.3 Hardness (kp) :::::::: an is8& 3: 8:none one- i.e3: 38883 Figure 10 Patent Application Publication Oct. 15, 2015 Sheet 13 of 27 US 2015/0290211 A1 338 :::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: 3. 33 33, S3 3.3 83.3 Hardness (kp) is is: Ne::::83rtistine-N- Figure 11 Patent Application Publication Oct. 15, 2015 Sheet 14 of 27 US 2015/0290211 A1 HC Dissolution Vs Thickness Dissolution % Thickness (nm) 3888 anr 3:8:3: 388 in an i:3&& 33 8:38: Patent Application Publication Oct. 15, 2015 Sheet 15 of 27 US 2015/0290211 A1 APAP Dissolution Vs Thickness 3:38 338 :::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: : Dissolution : 3.38 3.3 s: is: 88: 28 2.83 : Thickness (nm) 8 33:8: 3. 3s gir ano. 388 (38 system.N. spear (; as: Figure 13 Patent Application Publication Oct. 15, 2015 Sheet 16 of 27 US 2015/0290211 A1 PMZ Dissolution Vs Thickness Dissolution % 8.8 8. 3.38 8.3: 888 83 8 .33 Thickness (nm) 3 & 8::::: 3. 38 is one :38& 33 sin on- &ix:3; is is: Patent Application Publication Oct. 15, 2015 Sheet 17 of 27 US 2015/0290211 A1 "A- Hydrocodone 2. 8 SS 6 S. 4. 12 - (- m-m-m-m-m-m-m-m-m- wA (Formulation A- Fasted) O : B (Formulation A- Fed) 8 a 6 4 a 2 O 1. 2 3 4. 5 Hours Figure 15 B. Hydrocodone 2 1. O w8x A (Formulation A- Fasted) B (Formulation A- Fed) x C (Comparator- Fasted) x D (Comparator- Fed) s Patent Application Publication Oct. 15, 2015 Sheet 18 of 27 US 2015/0290211 A1 Figure 16A. Acetaminophen 4. 5 4. 3. 2. w8x A (Formulation A- Fasted) B (Formulation A- Fed) w:x C (Comparator- Fasted) O.1. xx D (Comparator- Fed) Figure. B. Acetaminophen 4. 3. 2. wA (Formulation A. Fasted) B (Formulation A- Fed) 1. XC (Comparator- Fasted) O xx D (Comparator- Fed) Patent Application Publication Oct. 15, 2015 Sheet 19 of 27 US 2015/0290211 A1 Figure 7A . Promethaz ine Hours Fi Promethazine Hours Patent Application Publication Oct. 15, 2015 Sheet 20 of 27 US 2015/0290211 A1 s e o w s c C e O c A C S. 9Z E 2 s 2 ta E - ; : e ra e e All < s E E c r t E C - & & grim Mean and Standard Deviation Patent Application Publication Oct. 15, 2015 Sheet 21 of 27 US 2015/0290211 A1 §ž.š.«******************************* ä********** Incidence Rate Patent Application Publication Oct. 15, 2015 Sheet 22 of 27 US 2015/0290211 A1 Incidence Rate Patent Application Publication Oct. 15, 2015 Sheet 23 of 27 US 2015/0290211 A1 ?********************************* §***„…„…„.43*********** & Incidence Rate Patent Application Publication Oct. 15, 2015 Sheet 24 of 27 US 2015/0290211 A1 i Mean and Standard Deviation Patent Application Publication Oct. 15, 2015 Sheet 25 of 27 US 2015/0290211 A1 Percent of Patients Patent Application Publication Oct. 15, 2015 Sheet 26 of 27 US 2015/0290211 A1 dnou!)queuneauL x8 s Percent of Patients US 2015/0290211 A1 Oct. 15, 2015 PHARMACEUTICAL COMPOSITIONS cation during the initial 6 hours or initial 24 hours post administration. In some instances, the rescue medication is a CROSS-REFERENCE Supplemental antiemetic. In some instances, the rescue medi 0001. This application claims the benefit of U.S. Provi cation is a Supplemental analgesic. In some instances, the sional Application No. 61/977,845, filed on Apr. 10, 2014, Subject is administered the pharmaceutical composition U.S. Provisional Application No. 62/020,597, filed on Jul. 3, every four to six hours. In some instances, the Subject is 2014, U.S. Provisional Application No. 62/029,776, filed on administered the pharmaceutical composition two to six Jul. 28, 2014, U.S. Provisional Application No. 62/091,793, times over the first 24 hours. In some instances, the Subject is filed on Dec. 15, 2014, U.S. Provisional Application No. administered the pharmaceutical composition one to six 62/093,093, filed on Dec. 17, 2014, and U.S. Provisional times after the first 24 hours. In some instances, the Subject is Application No. 62/104,429, filed on Jan. 16, 2015, all of administered the pharmaceutical composition no more than which are incorporated herein by reference in their entirety. six times every 24 hours. In some instances, the Subject is administered the pharmaceutical composition periodically INCORPORATION BY REFERENCE over 1-28 days. In some instances, the Subject is administered 0002 All publications, patents, and patent applications the pharmaceutical composition periodically over 1-21 days. disclosed herein are incorporated by reference to the same In some instances, the Subject is administered the pharmaceu extent as if each individual publication, patent, or patent tical composition periodically over 1-14 days. In some application was specifically and individually indicated to be instances, the Subject is administered the pharmaceutical incorporated by reference. In the event of a conflict between composition periodically over 1-7 days. In some instances, a term disclosed herein and a term in an incorporated refer the Subject is administered the pharmaceutical composition ence, the term herein controls. periodically over 1-5 days.
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