US 2013.0143956A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0143956A1 Cady et al. (43) Pub. Date: Jun. 6, 2013 (54) LONG-ACTING INJECTABLE MOXIDECTIN (22) Filed: Nov.30, 2012 FORMULATIONS AND NOVEL MOXDECTIN CRYSTAL FORMS Related U.S. Application Data (71) Applicants: Susan Mancini Cady, Yardley, PA (US); (60) Provisional application No. 61/566,336, filed on Dec. Baoqing Ma, Kendall Park, NJ (US); 2, 2011. Robert Clark Chapman, Downingtown, Publication Classification PA (US); Chunhua Yang, Edison, NJ (US); Uday Jain, Plainsboro, NJ (US) (51) Int. Cl. A6IK3I/365 (2006.01) (72) Inventors: Susan Mancini Cady, Yardley, PA (US); (52) U.S. Cl. Baoqing Ma, Kendall Park, NJ (US); CPC .................................... A61 K3I/365 (2013.01) Robert Clark Chapman, Downingtown, USPC ............................ 514/450; 549/264; 264/145 PA (US); Chunhua Yang, Edison, NJ (US); Uday Jain, Plainsboro, NJ (US) (57) ABSTRACT This invention provides for novel antiparasitic and pesticidal forms of moxidectin, including a long-acting polymeric (73) Assignee: Merial Limited, Duluth, GA (US) implant. The resulting compounds may be used in veterinary compositions which are used in treating, controlling and pre (21) Appl. No.: 13/690,185 Venting of endo- and ectoparasite infections in animals. Patent Application Publication Jun. 6, 2013 Sheet 1 of 33 US 2013/0143956 A1 FIG. I. Six: Restivati Masaaaaaaaaaaaaaaaaaaaaaaaaaaa estivate 83 3 R33 Patent Application Publication Jun. 6, 2013 Sheet 2 of 33 US 2013/0143956 A1 FIG 2A Conventional DSC of Moxidectin lot SO9060: ... -- ; : f; : : ^ ‘s 1119°C f ---. f - “r-. f a. -: ; Agree 18649°Cs f 2) skirt" ----. - 23.46°C & i 114.31°CY --.-1N 1.64J/g A. e 173.48°C -3. --- - d : 6.91349 f i. : I i . i : 206.06°C -2.8-i 25 75 125 175 225 Temperature (°C) Patent Application Publication Jun. 6, 2013 Sheet 3 of 33 US 2013/0143956 A1 FIG. 2B Conventional DSC of Moxidectin lot S080701 3.3. ; ; : : - f ”ssaaa. : is irs is 34.6°C f - --- 1,561Jg ; Y- --- f \s s 11-78°C f a. s ---...-- - \ Ny ----r-.2.167J/g f f o A2. --- er 108.13°C :117.10°C ---. ---...--- / w Y/ ---...s. - 2 ses: Y red i s d I s r t r r y r T •r 25 75 25 75 225 Temperature (C) Patent Application Publication Jun. 6, 2013 Sheet 4 of 33 US 2013/0143956 A1 FIG. 3 PRXD of MOxidectin lot S090601 Theta-2Theta deg) Patent Application Publication Jun. 6, 2013 Sheet 5 of 33 US 2013/0143956 A1 FIG. 4 3 - f : : 193OC shai, Ya-Ye : i e f a -3- f **s- f v-Yas :s ^s. **. 104.15°C 3 d : ------- - 3267/g ... 196.18C vis----. : 7,591.J.g / “r.ris-1-X--- : 108.53°C : i d ; i 200.7°C 2 25: 75 T is r 175 225 T Temperature (°C) Patent Application Publication Jun. 6, 2013 Sheet 6 of 33 US 2013/0143956 A1 FIG. 5 ... -- 198OC 2ss s f sc.-si-. 10.7°C / 3. ---. k- 993 186.33°C ? e “--...-3, 19827C A Yale- 114.82°C *::s;12,30J/g Y *:::: * 3. 4.953.3/g173.18°C S-i- f s f t 202.7°C 25 75 125 175 225 Temperature (°C) Patent Application Publication Jun. 6, 2013 Sheet 7 of 33 US 2013/0143956 A1 FIG. 6 'srx & i x.--- f ---. 110.98°C 88.43°C f ------, 1,895J/g Sik.**x. 20353°C- Y - / 15.39°C-- *x.se: *-3--- 12.68Jig : 73.55°C 7.051Jig 25 75 25 75 225 Temperature (C) Patent Application Publication Jun. 6, 2013 Sheet 8 of 33 US 2013/0143956 A1 FIG. 7 & a. so - Yale 3) s f Y-a- tec S s a \ Ast 2 Yae -------; **- y A š. e 162.54c ---.S. Y s e 28.3%ig r- - : s C- y i i -. -) Non-reversible Heat Flow ------ - ? Y,\ \ i| - . & ”O.S is92 I ss., - 2 2 S f--- ...if12.15°C) I'--------...-a-ka-i. t A2 i w 17.18Jig s: : 40.5°C 36.2°C W . - 0.8 Non-reversible Heat Flow (W/g) Y 22.84°C s: - - r-ir-i -r r-, -:0 A. 90 40 19C 240 Temperature (C) FIG. 8 Moxidectin after 190 °C bath c -------------------------------------------------------------------------------------------------------------------------------------- S. 2. s Theta-2Theta (deg) Patent Application Publication Jun. 6, 2013 Sheet 9 of 33 US 2013/0143956 A1 FIG. 9 Moxidectin ot O906O1 035: 30: 025 020: 0. s 005 Wave numbers (cm) Patent Application Publication Jun. 6, 2013 Sheet 10 of 33 US 2013/0143956 A1 FIG 10 Moxidectirot O906O1 i as iv r . v-Y ---------- is v W.A.A.A.R.' ot Ososol, he at 185°C Raman Shift (cm) Patent Application Publication Jun. 6, 2013 Sheet 11 of 33 US 2013/0143956 A1 FIG. 1 1 (1/2) Patent Application Publication Jun. 6, 2013 Sheet 12 of 33 US 2013/0143956 A1 FIG. I. 1 (2/2) Patent Application Publication Jun. 6, 2013 Sheet 13 of 33 US 2013/0143956 A1 FIG. 12 FIG. 13 PXRD of Air-dried Moxidectin/MeCH crystals Theta-2Theta (deg) Patent Application Publication Jun. 6, 2013 Sheet 14 of 33 US 2013/0143956 A1 Temperature (C) FIG. I.5 88. 21158°C 43.8 s DSC of air-dried moxidectin MeCH crystals 213.66°C -3.3--- -T- -T --- -- t 25 75 25 175 225 Temperature (C) Patent Application Publication Jun. 6, 2013 Sheet 15 of 33 US 2013/0143956 A1 FG 7 *** Patent Application Publication Jun. 6, 2013 Sheet 16 of 33 US 2013/0143956 A1 s: - - - - - - - - - - - - - - - - -:-:- Delta Y -1187.4% \ TGA of air-dried moxidectin/EtOH crystals . Temperature (C) Patent Application Publication Jun. 6, 2013 Sheet 17 of 33 US 2013/0143956 A1 FIG. 19 DSC of air-dried moxidectin/EtOH crystals y f * 8-s-Xs. ---------- ---. * -----------. &*- : :: : 3.2 - g : 2.8- r y 25 75 125 175 FIG. 20 88: - Se: DSC of vacuum-dried moxidectin/EtOH crystals Y . : s - ---. : --- : : ---. -------------- : ---. - : --- ^. -3.3 :: -r- 2.8 .i y 25 75 125 75 225 Patent Application Publication Jun. 6, 2013 Sheet 18 of 33 US 2013/0143956 A1 Patent Application Publication Jun. 6, 2013 Sheet 19 of 33 US 2013/0143956 A1 Patent Application Publication Jun. 6, 2013 Sheet 20 of 33 US 2013/0143956 A1 FIG. 24 Patent Application Publication Jun. 6, 2013 Sheet 21 of 33 US 2013/0143956 A1 FIG. 25 ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- C - - - - . PXRD of air-dried moxidectin/PA crystals 3 - - - . : Patent Application Publication Jun. 6, 2013 Sheet 22 of 33 US 2013/0143956 A1 TGA of air-dried moxidectin/PA crystals Delta Yc-14.8.76% FIG. 28 27.9°C 358.3.g 125 75 225 275 Patent Application Publication Jun. 6, 2013 Sheet 23 of 33 US 2013/0143956 A1 FIG. 29 4 : 278.75°C DSC of vacuum-dried moxidectin/PA 8. 116.68°C 2. “r-.............. 11779°C(1) 17.70°C “r........ 264.76°C 44, J/g 3 -i------------~~~~~~~~~~~ 25 75 125 175 225 275 Patent Application Publication Jun. 6, 2013 Sheet 24 of 33 US 2013/0143956 A1 FIG. 31 3. PXRD of air-dried moxidectin/ n-Butanol crystals 38) - . s s s s s s TGA of air-dried noxidectin? n-Butanol crystals Sri - - - - - - - - - - - - - - -... Delta Y = 14.938% . Patent Application Publication Jun. 6, 2013 Sheet 25 of 33 US 2013/0143956 A1 3.3 : s DSC of air-dried moxidectin f n-Butano crystals 3.3 - 21.92* 45, 40.J.g f t47.32°C 34.83°C 21469C --- is 25 DSC of vacuum-dried moxidectin? n-Butanol crystals at 60 C - - 8.4 N. ris ? s: y ^ - s - “r----...-r --- --- 8. --------- -8.8 25- is s is 25 Patent Application Publication Jun. 6, 2013 Sheet 26 of 33 US 2013/0143956 A1 FIG 35 PXRD of noxidectin/n-Butano S3 . crystals after vacuum drying at 65 °C se is l's 2i. S 3, 3.3 : : DSC of vacuum-dried moxidectin/n-Butanol crystals at RT : : 65°C 29.57°C 32.84 - : -3.3 ---. 24.78Jig -** am 9 - ---...-- -- . : Ys...--^ ---.” : i y : i -- : : i : i : : 5 : 88.00°C : : 232.93C : 33.-- r : 25 75 25 175 225 Patent Application Publication Jun. 6, 2013 Sheet 27 of 33 US 2013/0143956 A1 FIG. 37 : - : Patent Application Publication Jun. 6, 2013 Sheet 28 of 33 US 2013/0143956 A1 FIG. 39 SS . ionioi--oxo TGA of air-dried noxidectin/MCH crystals : FIG. 40 DSC of air-dried moxidectin/MCH crystals 3.5- / v. ---------. * i “r-ra-re--... - -1.8- 25 75 125 75 223 Patent Application Publication Jun. 6, 2013 Sheet 29 of 33 US 2013/0143956 A1 (Y s & s: t - ; w w s v Patent Application Publication Jun. 6, 2013 Sheet 30 of 33 US 2013/0143956 A1 FIG 42 Patent Application Publication Jun. 6, 2013 Sheet 31 of 33 US 2013/0143956 A1 ***********… (~~~~)-g(0- Patent Application Publication Jun. 6, 2013 Sheet 32 of 33 US 2013/0143956 A1 FIG. 44 in Vitro Release of Formulation (75:25 DEG, 0.4 iv) -O-438-148 O 5 10 15 20 25 3O 35 Elapsed Time, days FIG. 45 -Are Ot OO588-17 O 5 1 O 15 20 25 30 35 ELAPSED TIME (days) Patent Application Publication Jun. 6, 2013 Sheet 33 of 33 US 2013/0143956 A1 1,000 0.100 ovo. -0-Average Moxidectin Plasma levels 0.010 to- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -: O 50 1 OO 150 20 250 US 2013/014395.6 A1 Jun. 6, 2013 LONG-ACTING INUECTABLE MOXDECTIN “tune' the polymer/beneficial agent formulation to enable it FORMULATIONS AND NOVEL MOXDECTIN to be stable and to release at the desired rate.