HRP20201609T1 - Biorazgradivi hidrogelovi netopivi u vodi bazirani na polietilenglikolu - Google Patents

Biorazgradivi hidrogelovi netopivi u vodi bazirani na polietilenglikolu Download PDF

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HRP20201609T1
HRP20201609T1 HRP20201609TT HRP20201609T HRP20201609T1 HR P20201609 T1 HRP20201609 T1 HR P20201609T1 HR P20201609T T HRP20201609T T HR P20201609TT HR P20201609 T HRP20201609 T HR P20201609T HR P20201609 T1 HRP20201609 T1 HR P20201609T1
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Harald Rau
Ulrich Hersel
Mathias Krusch
Dirk Vetter
Tobias Voigt
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Ascendis Pharma A/S
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Claims (37)

1. Biorazgradivi hidrogel netopiv u vodi baziran na poli(etilenglikolu), koji sadrži dijelove okosnice glavnog lanca povezane zajedno preko dijelova poprečno umreženih povezivača, pri čemu svaki dio poprečno umreženih povezivača završava s najmanje dvije hidrolitički razgradive veze, naznačen time, da dijelovi glavne okosnice imaju molekularnu masu u rasponu od 1 kDa do 20 kDa i imaju strukturu C*-(A-Hyp)x, gdje C* je razgranata jezgra, A je polimerni lanac na bazi poli(etilenglikola), Hyp je hiper-razgranati dendritički dio skupine, x je cijeli broj od 3 do 16; te pritom hiper-razgranati dendritički dio skupine nadalje obuhvaća reaktivne funkcionalne skupine i međupovezane funkcionalne skupine.
2. Biorazgradivi hidrogel prema patentnom zahtjevu 1, naznačen time, da razgranata jezgra obuhvaća poliakohol, oligoalkohol, poliamin ili oligoamin u spojenom obliku.
3. Biorazgradivi hidrogel prema patentnom zahtjevu 1 ili 2, naznačen time, da razgranata jezgra obuhvaća pentaeritritol, tripentaeritritol, heksaglicerin, sukrozu, sorbitol, fruktozu, manitol, glukozu, celulozu, amilozu, škrob, hidroksilakilni škrob, polivinilalkohol, dekstran, hijaluronan, trilizin, tetralizin, pentalizin, heksalizin, heptalizin, oktalizin, nonalizin, dekalizin, undekalizin, dedekalizin, tridekalizin, tetradekalizin, pentadekalizin, oligolizin, polietilenimin ili polivinilamin u spojenom obliku.
4. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 3, naznačen time, da razgranata jezgra obuhvaća pentaeritritol, trilizin, tetralizin, pentalizin, heksalizin, heptalizin, oligolizin, PEI male molekularne mase, heksaglicerin ili tripentaeritritol u spojenom obliku.
5. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 4, naznačen time, da x je cijeli broj od 4 do 8.
6. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 5, naznačen time, da svaka Hyp ima molekularnu masu u rasponu od 0,4 kDa do 4 kDa.
7. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 6, naznačen time, da dijelovi poprečnog povezivača imaju molekularnu masu u rasponu od 0,5 kDa do 5 kDa, te time da je svaki dio poprečnog povezivača baziran na PEG.
8. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 7, naznačen time, da svaki dio glavne okosnice obuhvaća u zbroju najmanje 16 međupovezanih biorazgradivih i reaktivnih funkcionalnih skupina.
9. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 8, naznačen time, da dijelovi glavne okosnice imaju kvaterni ugljik sljedeće formule: C(A-Hyp)4, u kojoj je svaki A neovisno polimerni lanac na bazi poli(etilenglikola), koji je završno priključen na kvaterni ugljik pomoću permanentne kovalentne veze i udaljeni kraj polimernog lanca je kovalentno povezan s dendritičkim dijelom Hyp-skupine, dok svaki dio dendritičke Hyp-skupine posjeduje najmanje četiri funkcionalne skupine koje predstavljaju međupovezane i reaktivne funkcionalne skupine.
10. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 9, naznačen time, da je svaki A neovisno odabran iz formule: –(CH2)nl(OCH2CH2)nX-, gdje nl je 1 ili 2; n je cijeli broj u rasponu od 5 do 50; i X je kemijska funkcionalna skupina koja kovalentno povezuje A i Hyp.
11. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 10, naznačen time, da Hyp uvijek posjeduje najmanje tri grane i najmanje četiri reaktivne funkcionalne skupine.
12. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 11, naznačen time, da Hyp je hiper-razgranati polipeptid.
13. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 12, naznačen time, da Hyp sadrži lizine u spojenom obliku.
14. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 13, naznačen time, da se svaki dio Hyp-skupine sastoji od 5 do 32 lizina.
15. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 14, naznačen time, da Hyp sadrži heptalizinil.
16. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 15, naznačen time, da dijelovi glavne okosnice obuhvaćaju razgranatu jezgru sljedeće formule: [image] u kojoj crtkana linija označava priključenje na preostatak od dijela glavne okosnice.
17. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 16, naznačen time, da dijelovi glavne okosnice obuhvaćaju strukturu sljedeće formule: [image] u kojoj n je cijeli broj od 5 do 50 i crtkana linija označava priključenje na ostatak od molekule.
18. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 17, naznačen time, da dijelovi glavne okosnice obuhvaćaju hiper-razgranate dijelove Hyp-skupine sljedeće formule: [image] u kojoj crtkane linije označavaju priključenje na ostatak molekule i ugljikovi atomi koji su označeni sa zvjezdicama, označavaju S-konfiguraciju.
19. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 18, naznačen time, da dijelovi glavne okosnice sadrže najmanje jedan držač razmaka sljedeće formule: [image] u kojoj jedna od crtkanih linija označava priključenje na hiper-razgranati dio Hyp-skupine, a druga crtkana linija označava priključenje na ostatak molekule; i pritom m je cijeli broj od 2 do 4.
20. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 19, naznačen time, da dijelovi glavne okosnice sadrže najmanje jedan držač razmaka sljedeće formule: [image] u kojoj neoznačena crtkana linija pokazuje priključenje na Hyp; crtkana linija koja je označena sa zvjezdicom pokazuje vezu između hidrogela i N iz tiosukcinimidne skupine, i pritom p je cijeli broj od 0 do 10.
21. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 20, naznačen time, da su dijelovi glavne okosnice povezani zajedno preko dijelova poprečnog povezivača koji sadrži sljedeću strukturu: [image] u kojoj q je cijeli broj od 3 do 100.
22. Biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 21, naznačen time, da se dijelovi poprečnog povezivača sastoje od PEG koji je simetrično povezan preko esterskih veza na dva alfa, omega-alifatska dikarboksilna držača razmaka koji su omogućeni preko dijelova glavne okosnice spojenih na hiper-razgranati dendritički dio skupine preko permanentnih amidnih veza.
23. Konjugat koji obuhvaća hidrogel prema bilo kojem od patentnih zahtjeva 1 do 22, naznačen time, da je hidrogel sastavljen od dijelova glavne okosnice koji su međupovezani pomoću hidrolitički razgradivih veza i dodatno prenosi permanentne veze do molekula držača razmaka ili blokatorskih skupina ili do njihovih kombinacija.
24. Konjugat koji obuhvaća hidrogel prema bilo kojem od patentnih zahtjeva 1 do 22, naznačen time, da je hidrogel sastavljen od dijelova glavne okosnice koji su međupovezani pomoću hidrolitički razgradivih veza i dodatno prenosi permanentne veze do liganda ili do kelatnih skupina.
25. Konjugat prema patentnom zahtjevu 24, naznačen time, da su ligandi odabrani iz skupine koja se sastoji od sljedećih: 4-aminobenzamidin, 3-(2'-aminobenzhidriloksi)tropan, ε-aminokaproil-p-klorobenzilamid, 1-amino-4-[3-(4,6-diklorotriazin-2-ilamino)-4-sulfofenilamino]antrakinon-2-sulfonska kiselina, 2-(2'-amino-4'-metilfeniltio)-N,N-dimetilbenzilamin-dihidroklorid, angiopoietin-1, aptameri, arotinoidna kiselina, avidin, biotin, kalmodulin, kokaetilen, citosporon B, N,N-diheksil-2-(4-fluorofenil)indol-3-acetamid, N,N-dipropil-2-(4-klorofenil)-6,8-dikloro-imidazo[1,2-a]piridin-3-acetamid, 5-fluoro-2'-deoksiuridin-5'-(p-aminofenil)monofosfat, S-heksil-L-glutation, (S,S)-4-fenil-α-(4-feniloksazolidin-2-iliden)-2-oksazolin-2-acetonitril, Pro-Leu-Gly-hidroksamat, 2-(4-(2-trifluorometil)fenil)piperidin-1-karboksamido)benzojeva kiselina, trimetil(m-aminofenil)amonijev klorid, urokortin III, kofaktori kao adenozin-trifosfat, s-adenozil-metionin, askorbinska kislina, kobalamin, koenzim A, koenzim B, koenzim M, koenzim Q, koenzim F420, citidin-trifosfat, flavin-mononukleotid, flavin-adenin-dinukleotid, glutation, haem, lipoamid, menakvinon, metanofuran, metilkobalamin, molibdopterin, NAD+, NADP+, nukleotidni šećeri, 3'-fosfoadenozin-5'-fosfosulfat, piridoksal-fosfat, polihistidini, pirolokinolin-kvinon, riboflavin, streptavidin, tetrahidrobiopterin, tetrahidrometanopterin, tetrahidrofolna kiselina, biotin-karboksil-nosivi protein (BCCP), vezivni protein kitina, FK506 vezivni proteini (FKBP), FLAG-oznaka, zeleni fluorescentni protein, glutation-S-transferaza, hemagglutinin (HA), vezivni protein maltoze, mik-oznaka, NusA, epitop proteina C, S-oznaka, strep-oznaka, tioredoksini i afinitetni skelni proteini.
26. Konjugat prema patentnom zahtjevu 24, naznačen time, da su kelatne skupine odabrane iz skupine koja se sastoji od sljedećih: 2,2'-bipiridil, 1,2-bis(2-aminofenoksi)etan-N,N,N',N'-tetraoctena kiselina, deferoksamin-mesilat, deferiferikrom, dietilentriamin, 2,3-dimerkapto-1-propanol, dimerkapto-sukcinska kiselina, dimetilglioksin, 2,2'-dipiridil, etilen-diamin, etilendiamintetra (metilenfosfonska kiselina), 1,2-bis(2-amino-5-bromofenoksi)etan-N,N,N'N'-tetraoctena kiselina, 8-hidroksikinolin, iminodiacetat, iminodi(metilfosfonska kiselina), L-mimozin, nitrilotriacetat, oksalat, 1,10-fenantrolin, fitinska kiselina, tartrat, 1,4,7,10-tetraazaciklododekan-1,4,7,10-tetraacetat, N,N,N',N'-tetrakis(2-piridilmetil)etilendiamin, triaminotrietilamin, iminodioctena kiselina, tiourea i 2-pikolilamin.
27. Predlijek povezan s nosačem, naznačen time, da obuhvaća biorazgradivi hidrogel prema bilo kojem od patentnih zahtjeva 1 do 22 kao nosač, pri čemu jedan broj permanentnih veza dijelova glavne okosnice, postoji za svaki tranzijentni povezivač L predlijeka, na kojega je kovalentno priključen biološki aktivni dio skupine D.
28. Predlijek povezan s nosačem prema patentnom zahtjevu 27, naznačen time, da tranzijentna veza između D i L je karbamatna, karbonatna, amidna ili esterska veza.
29. Predlijek povezan s nosačem prema patentnom zahtjevu 27 ili 28, naznačen time, da tranzijentni povezivač L predlijeka obuhvaća dio L1 koji je supstituiran s dijelom L2 i pritom je L2 povezan sa skupinom nosača Z, pri čemu je to hidrogel prema bilo kojem od patentnih zahtjeva 1 do 22.
30. Predlijek povezan s nosačem prema bilo kojem od patentnih zahtjeva 27 do 29, naznačen time, da -L je nebiološki aktivni dio povezivača -L1 koji je predstavljen sljedećom formulom (VI): [image] gdje crtkana linija označava priključenje na primarnu ili sekundarnu amino skupinu od biološki aktivnog dijela skupine D koji sadrži amin, pomoću stvaranja amidne veze; i pritom X, X1, X2, R1, R1a, R2, R2a, R3 i R3a iz formule (VI), imaju sljedeće značenje: X je C(R4R4a); N(R4); O; C(R4R4a)-C(R5R5a); C(R5R5a)-C(R4R4a); C(R4R4a)-N(R6); N(R6)-C(R4R4a); C(R4R4a)-O; ili O-C(R4R4a); X1 je C; ili S(O); X2 je C(R7, R7a); ili C(R7, R7a)-C(R8, R8a); R1, R1a, R2, R2a, R3, R3a, R4, R4a, R5, R5a, R6, R7, R7a, R8, R8asu neovisno odabrani iz skupine koja se sastoji od H; i C1-4-alkila; prema potrebi, jedan ili više od parova R1a/R4a, R1a/R5a, R4a/R5a, R7a/R8a, tvore kemijsku vezu; prema potrebi su jedan ili više od parova R1/R1a, R2/R2a, R4/R4a, R5/R5a, R7/R7a, R8/R8a spojeni zajedno s atomom na kojega su priključeni, za tvorbu C3-7-cikloalkila; ili 4-7-članog heterociklila; prema potrebi su jedan ili više od parova R1/R4, R1/R5, R1/R6, R4/R5, R7/R8, R2/R3 spojeni zajedno s atomima na koje su priključeni, za tvorbu prstena A; prema potrebi su R3/R3a spojeni zajedno s dušikovim atomom na kojega su priključeni, za tvorbu 4-7-člang heterocikla; A je odabran iz skupine koja se sastoji od sljedećih: fenil; naftil; indenil; indanil; tetralinil; C3-10-cikloalkil; 4-7-člani heterociklil; i 9-11-člani heterobiciklil; i pritom je L1 supstituiran s jednom skupinom L2-Z te je prema potrebi dodatno supstituiran, uz uvjet da vodik koji je označen sa zvjezdicom u formuli (VI), nije zamijenjen supstituentom; pri čemu L2 je jednostruka kemijska veza ili držač razmaka; i Z je odgovarajući hidrogel prema bilo kojem od patentnih zahtjeva 1 do 21.
31. Predlijek povezan s nosačem prema bilo kojem od patentnih zahtjeva 27 do 30, naznačen time, da je biološki aktivni dio skupine odabran iz skupine koja se sastoji od polipeptida, proteina, oligonukleotida te biološki aktivnih ostataka male molekule.
32. Predlijek povezan s nosačem prema bilo kojem od patentnih zahtjeva 27 do 31, naznačen time, da je L2 priključen na Z preko terminalne skupine koja ima sljedeću strukturu: [image] gdje crtkane linije označavaju odgovarajuće priključenje na L2 odnosno Z.
33. Farmaceutski pripravak, naznačen time, da obuhvaća predlijek prema bilo kojem od patentnih tzahtjeva 27 do 32 ili njegovu farmaceutski prihvatljivu sol, zajedno s farmaceutski prihvatljivim pomoćnim sredstvom.
34. Predlijek prema bilo kojem od patentnih zahtjeva 27 do 32, ili farmaceutski pripravak prema patentnom zahtjevu 33, naznačen time, da se upotrebljava kao medikament.
35. Postupak za proizvodnju hidrogela, naznačen time, da obuhvaća sljedeći korak: (a) reakciju reagensa glavne okosnice koji ima sljedeću formulu: [image] u kojoj je n cijeli broj od 3 do 100; s reagensom poprečnog povezivača sljedeće formule: [image] pri čemu q je cijeli broj od 3 do 100: svaki m neovisno predstavlja cijeli broj od 2 do 4; u odnosu amin/aktivni ester u iznosu od 2:1 do 1,05:1, koji rezultira u opterećenju hidrogela od 0,02 do 2 mmol amina po gramu hidrogela; te time, da se reagensi rastapaju u aprotičkom otapalu u prisutnosti prikladne lužine.
36. Hidrogel, naznačen time, da se može dobiti putem postupka prema patentnom zahtjevu 35.
37. Hidrogel prema bilo kojem od patentnih zahtjeva 1 do 21 ili 36, naznačen time, da se nalazi u obliku obloge, prepleta, stenta ili mikročestica koje se dobivaju pomoću usitnjavanja putem mehaničkih postupaka kao što su miješanje, drobljenje, rezanje stlačivanjem ili mljevenje, te prema potrebi prosijavanje.
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