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C12) United States Patent (IO) Patent No.: US 10,835,614 B2 Tatara Et Al

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C12) United States Patent (IO) Patent No.: US 10,835,614 B2 Tatara Et Al I1111111111111111 1111111111 111111111111111 IIIII IIIII IIIII IIIIII IIII IIII IIII US010835614B2 c12) United States Patent (IO) Patent No.: US 10,835,614 B2 Tatara et al. (45) Date of Patent: Nov. 17, 2020 (54) POLY(DIOL FUMARATES) AND POLY(DIOL A61K 311506 (2006.01) FUMARATE-CO-SUCCINATES) A61K 47114 (2017.01) (52) U.S. Cl. (71) Applicants:William Marsh Rice University, CPC .......... A61K 471593 (2017.08); A61K 311506 Houston, TX (US); Board of Regents, (2013.01); A61K 47114 (2013.01); A61K The University of Texas System, 4716927 (2017.08); A61L 27118 (2013.01); Austin, TX (US) A61L 27138 (2013.01); A61L 27158 (2013.01); A61P 31/10 (2018.01); C08G 63152 (2013.01) (72) Inventors: Alexander Mitchell Tatara, West (58) Field of Classification Search Dundee, IL (US); Emma Watson, CPC .................................................... A61K 47/593 Wichita, KS (US); Antonios G. Mikos, See application file for complete search history. Houston, TX (US); Dimitrios P. Kontoyiannis, Bellaire, TX (US) (56) References Cited (73) Assignees: William Marsh Rice University, FOREIGN PATENT DOCUMENTS Houston, TX (US); Board of Regents, The University of Texas System, JP 2015/152818 A 8/2015 Austin, TX (US) WO WO 2009/094375 Al * 7/2009 ............. C08G 63/12 ( *) Notice: Subject to any disclaimer, the term ofthis OTHER PUBLICATIONS patent is extended or adjusted under 35 U.S.C. 154(b) by 29 days. Joos et al., Makromolekulare Chemie (1987), 188(6), pp. 1375- 1381. * Jacovic et al., Makromolekulare Chemie (1988), 189(6), pp. 1353- (21) Appl. No.: 16/146,258 1362.* Nikolic, MS et al. "Synthesis and characterization of biodegradable (22) Filed: Sep. 28, 2018 poly(butylene succinate-co-butylene fumarate )s" European Poly­ mer Journal, May 28, 2003, pp. 2183-2185. (65) Prior Publication Data * cited by examiner US 2019/0091343 Al Mar. 28, 2019 Primary Examiner - Brian J Davis Related U.S. Application Data (74) Attorney, Agent, or Firm - Matthew S. Gibson; (63) Continuation of application No. Ryan P. Cox; Reed Smith LLP PCT/US2017 /025084, filed on Mar. 30, 2017. (57) ABSTRACT (60) Provisional application No. 62/315,607, filed on Mar. The disclosure relates to a class of dial-based, unsaturated 30, 2016. aliphatic polyesters that biodegrade into monomers capable of mitigating infection. These poly(diol fumarates) (PDFs) (51) Int. Cl. and poly(diol fumarate-co-succinates) (PDFSs), can be A61K 47159 (2017.01) crosslinked to form networks of scaffolds with antimicrobial A61L 27118 (2006.01) degradation products. Both the dial carbon length and the A61L 27158 (2006.01) degree of available double bonds are tunable, resulting in a C08G 63152 (2006.01) highly controllable class of antimicrobial polymers useful A61L 27138 (2006.01) for cell scaffolds and drug delivery systems and devices. A61K 47169 (2017.01) A61P31/10 (2006.01) 20 Claims, 32 Drawing Sheets U.S. Patent Nov. 17, 2020 Sheet 1 of 32 US 10,835,614 B2 Monomer: Diol Di-Acid Structure: H H Fig. l (e) (d) (b) (a) (c) (f) 0 0 H O, OH H H H H H H H ;t_ J, 0 0-H u- T ' H H H H H H H H 0 O (e) (c) (a) (b) (d) n Fig. 2A U.S. Patent Nov. 17, 2020 Sheet 2 of 32 US 10,835,614 B2 ...d .. o ~- -,ll·.... -~· N= • ~ ··•~ ·-·& U.S. Patent Nov. 17, 2020 Sheet 3 of 32 US 10,835,614 B2 U.S. Patent Nov. 17, 2020 Sheet 4 of 32 US 10,835,614 B2 ~ ·~•:., :l 0 0 .J:: J:: ~.. l ·~.·~ '¾ .">;{ f*ii<..t. •t--.... ¾ ¾ .~ II 0 0 0 0 O..,,.. ·.. r*\ . 0 0 0 ~ 0 0 ·O·..... -.: .• 0 0 0 .~.. ·~· ro © ·~ N ('.eo·•·.·····•·) .❖ :J4DIBM Je1noa10li\J U.S. Patent Nov. 17, 2020 Sheet 5 of 32 US 10,835,614 B2 .0 ·-~..bl)* U.S. Patent Nov. 17, 2020 Sheet 6 of 32 US 10,835,614 B2 0 ;....:: . U ,, ,.. ''. )@tllllllllllllllllllllllllllllllllll =tr~ ol:i ·-~ 0 U.S. Patent Nov. 17, 2020 Sheet 7 of 32 US 10,835,614 B2 a C b h gg Fig. 6A U.S. Patent Nov. 17, 2020 Sheet 8 of 32 US 10,835,614 B2 a 80 d d e f g h rn Decanedio! .t:0:::-.l''"'('< 0 .,1_-0 ~ .. "❖/ F'ig. 68 U.S. Patent Nov. 17, 2020 Sheet 9 of 32 US 10,835,614 B2 i:o m~ a> 0 m ~ !* l o::: l ll i i l l < ;...•...,.; •l""'--·.. / bn / ·~- l !l l i ' :,w,w,w,w,,w,w,•,w,•,;,•,•,•,•,•,•,•,•,•,•,•,;,•,•,,•,•,•,•,•,•,•,•,;,•,•,•,•,•,•,•,•,•,•,•,•,•,•,•,•,•,,•,•,•,•,•,•,;,•,•,•,•,•,•,•,•,•,•,•,;,•,•,•,•,•,•,•,,•,•,•,;,•,•,•,•,•,•,•,•,•,•,•,•:•,•. t.{) U.S. Patent Nov. 17, 2020 Sheet 10 of 32 US 10,835,614 B2 0 0;; X .~~ O" .~ ''0 + :~':$/ '6~C<•' ,<:<'' {lz:f.~ '·;·.,:.r•,::::::·;\?.:::::::::::L,,c;_. - ······J.:'.:~ t> J~ •O • ;f.. 1•~ O..·f-::1•.6."'. N• ~· ~Fe J g i::... + U.S. Patent Nov. 17, 2020 Sheet 11 of 32 US 10,835,614 B2 =0~ ~ • -~t.1£ ~ 0 \ r.I I :c U.S. Patent Nov. 17, 2020 Sheet 12 of 32 US 10,835,614 B2 ,.............;:. ....,.,.,) ;;::::,·,;,:,:::::z- I .:; --- .,.:««':':"'"'/ ~ . -:«-W:::.... s ............. ~ ~:: r;b~;:::;r·_,;. -».-; .• ·1V .:· :~ -: t -:· :......,_.:- . t -~v-,. ~V.Y+~"<: ""-!lo ~.y """!lo~ V '°-~-~ "'·" +-~ ,...,. ~-~ v-,. ~V:v-,. l!f.v.v+• ~ ,;-+~"<'."' j l ··•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.•.~· :-:{l.l U.S. Patent Nov. 17, 2020 Sheet 13 of 32 US 10,835,614 B2 .Fig. 10B U.S. Patent Nov. 17, 2020 Sheet 14 of 32 US 10,835,614 B2 f'ig. 10c U.S. Patent Nov. 17, 2020 Sheet 15 of 32 US 10,835,614 B2 Ii'ig. 1on U.S. Patent Nov. 17, 2020 Sheet 16 of 32 US 10,835,614 B2 Fig. 11A 10 06 Carbom 008 Carbons ■ rn Carbon::; 8 b () 50 100 An1otmt of FA (n1ol~{)). Fig. 11B a a 10 b b 8 ,.-i--.,.. .~ C 6 ,..1::: ·-·~ 4 <;. ') ,;;,_ 0 50 100 U.S. Patent Nov. 17, 2020 Sheet 17 of 32 US 10,835,614 B2 Fig. 1 lC 40 06 Carbons 88 Caibons I 10 Carbons 30 a a b b ;::s~ iO 0:::: ·'-'·· 10 33 50 100 A111ount of FA (11101%:i) .Fig. lH) 06 Carbons sS Carbons I rn Carbons a a 40 b b d d 30 e •···< 2-0· -- . ~· 10 0 33 100 U.S. Patent Nov. 17, 2020 Sheet 18 of 32 US 10,835,614 B2 Fig. llE 30 06 Carbons rns Carbons I WCarbons i, a 20 b b b cc.I::; C d 10 0 50 100 Amount ofFA (n1ol%,) Fig. llF 30 b e 20 10 0 33 50 100 An1otmt of FA (n1ol?/~) U.S. Patent Nov. 17, 2020 Sheet 19 of 32 US 10,835,614 B2 --------------- g U.S. Patent Nov. 17, 2020 Sheet 20 of 32 US 10,835,614 B2 Fig. 12B o6C•Jbons ID 8C:.:i1bons 110 Carbons :l 100 80 ~--"' 40 20 33 50 100 Arnount of FA (moi%) :Fig. 12C o6Carbons ID 8Carbons 11OCarbons h 100 f 33 50 100 Amtmni- offA (moll%) U.S. Patent Nov. 17, 2020 Sheet 21 of 32 US 10,835,614 B2 Fig. 13 ,-. u 6 ·-.._.,,:n:: ~ ..c0 8 ~ ;z: ~ 0 8 ..c ro~ '...,I' ' .....0 0 10 33 50 100 Arnount of FA (11101'%) U.S. Patent Nov. 17, 2020 Sheet 22 of 32 US 10,835,614 B2 Fig. 14A 06 Carbons 88 CarlKms 110 Carbnns 60 · a .-. 4() .~~,._ ls< ~ Vo;. 20 {) 50 WO Amount of FA (tnnt:-~) Fig. 14B o6Lirbom oo 8Carbons I H) Carbons 60 a b 33 50 lOO Amount of FA (motVi,) U.S. Patent Nov. 17, 2020 Sheet 23 of 32 US 10,835,614 B2 Ji'ig. 14C o6Carbons rn sCarbons I rn Carbons 14 12 b b b b b b HJ 33 50 100 Amount ofFA(mol%) Fig. 14D o6Cadmns rn 8Carbons I IO Car!xms 14 12 w b b f r -2 50 10-0 Amount: of FA {mol~'ll) U.S. Patent Nov. 17, 2020 Sheet 24 of 32 US 10,835,614 B2 Fig. 15 1000 n 800 h b C C C ..-. d tl d l ~ 600 ~ M '••"••1A,,.,,'- <.> ~ 400 200 0 J3 50 100 An1ount ofEA. (n:10N'o) 06 Carbons 008 Carbons ■ 10 Carbons U.S. Patent Nov. 17, 2020 Sheet 25 of 32 US 10,835,614 B2 Fig. l6A 0 (c} (e) (d) (b) 0 OH (d) {e) (c} (e) n 0 U.S. Patent Nov. 17, 2020 Sheet 26 of 32 US 10,835,614 B2 ro O'O t ,: ::: :: -.A: ~ ·•:• - :«: :f.. :-·• ·~ ,.,.,.J a @ .,.,.,.,.,.,.,.,.,.,.,.,.,.,.,.,.....,,......,..___.,,J ~ --~ ··································································································•:-:-..,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,.....1 g,J' .......·.······································------------~ Q U.S. Patent Nov. 17, 2020 Sheet 27 of 32 US 10,835,614 B2 Fig. 17 U.S. Patent Nov. 17, 2020 Sheet 28 of 32 US 10,835,614 B2 Fig. 18A 200 .· • • • • + • 40 U.S. Patent Nov. 17, 2020 Sheet 29 of 32 US 10,835,614 B2 Fig. 18B • • • • • .Ii ❖:• 0 ---------------- - 0 2. 4 U.S. Patent Nov. 17, 2020 Sheet 30 of 32 US 10,835,614 B2 Fig. 19 At Harvest 24 Hours of Culture Wet Mount U.S. Patent Nov. 17, 2020 Sheet 31 of 32 US 10,835,614 B2 Fig. 20A Group 1 Group 2 Group4 Day 3: Oay9•: -5mm Fig. 20B ~ 100 <ll '- a a a <t "O 80 C: ti b ~~ 0 60 :?.'.~" .E <ll 40 'I> <)$ t 20 n$ .._<, 0 •'•'•'•'•'•'•'•'•'•'•'•'•'•'•'• B"'' Group 1 Group 2 (;raHp 3 Groop4 U.S. Patent Nov. 17, 2020 Sheet 32 of 32 US 10,835,614 B2 Fig. 21A. 1.E+06 a a a 1.E+05 b b b -J 1)E+04 E :5 1.E+03 t.L. u 1.E+02 1.E+01 1)E+OO .,.~,,.,.,.,.,.,.,.,.,.,.,.,.,.,.,..,.,.,.,.,.,.,.,.,.,.,.,.,.,.,.,.,.,.,.,.,.,.,.,.,.
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