Hydrogel cross-linked hyaluronic acid prodrug compositions and methods

A cross-linked 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:
• each 2B comprises a plurality of linearly connected units, the units consisting essentially of:
• wherein
• an unmarked dashed line indicates a point of attachment to an adjacent unit at a dashed line marked with #, or to a hydrogen,
• a dashed line marked with # indicates a point of attachment to an adjacent unit at an unmarked dashed line, or to a hydroxyl;
• 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 between points of attachment on a unit Z3 of 2A and a unit Z4 of 2B;
• Drug is a therapeutic agent;
• Ra1 and Ra2 are each independently is hydrogen;
• C1-4 alkyl;
• an alkali metal ion, an ammonium ion, or an alkaline earth metal ion;
• L2 is a reversible prodrug linker;
• L4 is an optionally biodegradable spacer and may be the same or different in Z2 and Z4;
• 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 comprising a total of t units wherein t is from 25 to 2500, wherein;
• the number of Z1 units in 2B is from about 0.75 t to about 0.94 t;
• 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.