US 12,478,680 B2
Hydrogels with biodegradable crosslinking
Gary W. Ashley, Alameda, CA (US); Daniel V. Santi, San Francisco, CA (US); and Jeffrey C. Henise, San Francisco, CA (US)
Assigned to ProLynx LLC, San Francisco, CA (US)
Filed by ProLynx LLC, San Francisco, CA (US)
Filed on Sep. 7, 2022, as Appl. No. 17/930,381.
Application 16/557,243 is a division of application No. 15/486,215, filed on Apr. 12, 2017, granted, now 10,398,779, issued on Sep. 3, 2019.
Application 17/930,381 is a continuation of application No. 16/557,243, filed on Aug. 30, 2019, granted, now 11,454,861.
Application 15/486,215 is a continuation of application No. 14/343,819, granted, now 9,649,385, issued on May 16, 2017, previously published as PCT/US2012/054278, filed on Sep. 7, 2012.
Claims priority of provisional application 61/531,990, filed on Sep. 7, 2011.
Prior Publication US 2023/0135347 A1, May 4, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 47/34 (2017.01); A61K 9/06 (2006.01); A61K 47/30 (2006.01); A61K 47/50 (2017.01); A61K 47/60 (2017.01); A61K 47/61 (2017.01); A61K 47/69 (2017.01); A61L 15/26 (2006.01); A61L 15/44 (2006.01); A61L 15/60 (2006.01); A61L 15/64 (2006.01); A61L 27/18 (2006.01); A61L 27/52 (2006.01); A61L 27/54 (2006.01); A61L 27/58 (2006.01); C07C 271/08 (2006.01); C07C 317/18 (2006.01); C08J 3/075 (2006.01); C09B 23/01 (2006.01); G02F 1/361 (2006.01)
CPC A61K 47/34 (2013.01) [A61K 9/06 (2013.01); A61K 47/30 (2013.01); A61K 47/50 (2017.08); A61K 47/60 (2017.08); A61K 47/61 (2017.08); A61K 47/6903 (2017.08); A61L 15/26 (2013.01); A61L 15/44 (2013.01); A61L 15/60 (2013.01); A61L 15/64 (2013.01); A61L 27/18 (2013.01); A61L 27/52 (2013.01); A61L 27/54 (2013.01); A61L 27/58 (2013.01); C07C 271/08 (2013.01); C07C 317/18 (2013.01); C08J 3/075 (2013.01); C09B 23/0025 (2013.01); C09B 23/0033 (2013.01); C09B 23/0066 (2013.01); C09B 23/0075 (2013.01); G02F 1/3611 (2013.01); G02F 1/3612 (2013.01); G02F 1/3614 (2013.01); G02F 1/3615 (2013.01); C08G 2650/30 (2013.01); C08J 2300/16 (2013.01); C08J 2305/08 (2013.01); C08J 2371/02 (2013.01); Y10T 428/261 (2015.01)] 16 Claims
 
1. A hydrogel that is biodegradable under physiological conditions, wherein the hydrogel comprises one or more hyaluronic acid polymers crosslinked by a linker that decomposes by a beta elimination reaction,
wherein said linker is of Formula (1):

OG Complex Work Unit Chemistry
wherein for each linker of formula (1):
m of formula (1) is 0 or 1;
X of formula (1) is

OG Complex Work Unit Chemistry
wherein
T* is O, S, or NR6, wherein R6 is H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl;
z is 1-6;
Y is (OCH2CH2)p, wherein p is 1-100; and
Z2 is a first functional group that is coupled to a first cognate functional group on a hyaluronic acid polymer;
one of R1, R2, or R5 comprises a second functional group that is coupled to a second cognate functional group on a hyaluronic acid polymer,
wherein each said first functional group and said second functional group comprises N3, NH2, NH—CO2tBu, SH, StBu, maleimide, CO2H, CO2tBu, 1,3-diene, cyclopentadiene, furan, alkyne, cyclooctyne, acrylate, or acrylamide;
with the proviso that:
(1) when one of R5 of formula (1) comprises a second functional group that is coupled to a second cognate group of a hyaluronic acid polymer, the remaining R5 of formula (1) is H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, (OCH2CH2)p O-alkyl wherein p=1-1000, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl: and
(a) R1 and R2 of formula (1) are independently CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4;
(b) R1 and R2 of formula (1) may be joined to form a 3-8 membered ring;
(c) R1 of formula (1) is CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4; and R2 of formula (1) is H, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; or
(d) R2 of formula (1) is CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4; and R1 of formula (1) is H, optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; or
(2) when R1 of formula (1) comprises a second functional group that is coupled to a second cognate group of a hyaluronic acid polymer: R2 of formula (1) is CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4; and each R5 of formula (1) is independently H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, (OCH2CH2)p O-alkyl wherein p=1-1000, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; or
(3) when R2 of formula (1) comprises a second functional group that is coupled to a second cognate group of a hyaluronic acid polymer: R1 of formula (1) is CN, NO2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl, optionally substituted alkynyl, COR3, SOR3, SO2R3, or SR4; and each R5 of formula (1) is independently H, optionally substituted alkyl, optionally substituted alkenylalkyl, optionally substituted alkynylalkyl, (OCH2CH2)p O-alkyl wherein p=1-1000, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
wherein
R3 is selected from the group consisting of (i) H; (ii) optionally substituted alkyl; (iii) optionally substituted aryl; (iv) optionally substituted arylalkyl; (v) optionally substituted heteroaryl; (vi) optionally substituted heteroarylalkyl; (vii) OR9; and (viii) NR92;
R4 is selected from the group consisting of (i) optionally substituted alkyl; (ii) optionally substituted aryl; (iii) optionally substituted arylalkyl; (iv) optionally substituted heteroaryl; and (v) optionally substituted heteroarylalkyl; and
each R9 is independently H or optionally substituted alkyl, or both R9 groups taken together with the nitrogen to which they are attached form a heterocyclic ring.