US 12,246,070 B2
Hydrogel cross-linked hyaluronic acid prodrug compositions and methods
Sebastian Stark, Heidelberg (DE); Thomas Knappe, Heidelberg (DE); Harald Rau, Heidelberg (DE); Nicola Bisek, Heidelberg (DE); Burkhardt Laufer, Heidelberg (DE); Samuel Weisbrod, Heidelberg (DE); and Tobias Voigt, Heidelberg (DE)
Assigned to Ascendis Pharma A/S, Hellerup (DK)
Filed by Ascendis Pharma A/S, Hellerup (DK)
Filed on Mar. 27, 2023, as Appl. No. 18/190,862.
Application 18/190,862 is a continuation of application No. 16/575,749, filed on Sep. 19, 2019, granted, now 11,642,415.
Application 16/575,749 is a continuation of application No. PCT/US2018/023857, filed on Mar. 22, 2018.
Claims priority of provisional application 62/475,094, filed on Mar. 22, 2017.
Prior Publication US 2023/0414770 A1, Dec. 28, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 47/61 (2017.01); A61K 9/00 (2006.01); A61K 39/395 (2006.01); A61K 47/69 (2017.01)
CPC A61K 47/61 (2017.08) [A61K 9/0019 (2013.01); A61K 9/0048 (2013.01); A61K 39/395 (2013.01); A61K 47/6903 (2017.08)] 4 Claims
 
1. A cross-linked hyaluronic acid (HA)-drug conjugate comprising a plurality of hyaluronic acid polymers 2A and a plurality of hyaluronic acid polymers 2B, wherein:
each 2A comprises a plurality of linearly connected units, the units consisting essentially of:

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each 2B comprises a plurality of linearly connected units, the units consisting essentially of:

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wherein
an unmarked dashed line indicates a point of attachment to an adjacent unit at a dashed line marked with #, or to a hydrogen, of each 2A or 2B polymer;
a dashed line marked with # indicates a point of attachment to an adjacent unit at an unmarked dashed line, or to a hydroxyl of each 2A or 2B polymer; and
a dashed line marked with * indicates a point of or for attachment, wherein at least one 2A is cross-linked to at least one 2B via the points of or for attachment on a unit (Z3) of 2A and a unit (Z4) of 2B;
Drug is ranibizumab;
Ra1 and Ra2 are each independently hydrogen; C1-4 alkyl; an alkali metal ion, an ammonium ion, or an alkaline earth metal ion;
L2 comprises a reversible prodrug linker; L4 comprises a spacer; wherein the unit (Z4) is

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the unit (Z2) is

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2A comprises a total of s units wherein s is from 25 to 2500, wherein;
the number of (Z1) units in 2A is from about 0.8 s to about 0.99 s, and
the number of (Z3) units is from about 0.1 s to about 0.01 s;
2B comprises a total of t units wherein t is from 25 to 2500, wherein;
the number of (Z1) units in 2B is from about 0.75t to about 0.94t;
the combined number of (Z2) and (Z4) units is from about 0.14 t to about 0.06 t;
the number of (Z2) units is at least 0.01 t; and
the number of (Z4) units is at least 0.01 t.