CROSSLINKED HYALURONIC ACID DRUG CONJUGATE, PHARMACEUTICAL COMPOSITION COMPRISING IT AND SAID PHARMACEUTICAL COMPOSITION FOR USE IN THE TREATMENT OF A DISORDER ASSOCIATED WITH PATHOLOGICAL ANGIOGENESIS

Abstract

This article relates to hydrogel prodrug compositions comprising crosslinked hyaluronic acid (HA), or a derivative or salt thereof, wherein the crosslinking system comprises a biodegradable spacer, the crosslinked HA comprises a drug-connector conjugate, and the connector is capable of releasing the drug under physiological conditions. This article further relates to methods for preparing the hydrogel prodrug compositions. This article also relates to methods for treating an eye condition using the hydrogel compositions.

Claims

1. A crosslinked hyaluronic acid drug conjugate characterized in that it comprises 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, comprising the units: FOLLOW FORMULA 1 AND FORMULA 2; and each 2B comprises a plurality of linearly connected units, comprising the units: FOLLOW FORMULAS 3, 4 AND 5; wherein an unmarked dashed line indicates a point of attachment to an adjacent unit on a dashed line marked with #, or to a hydrogen, a dashed line marked with # indicates a point of attachment to an adjacent unit on an unmarked dashed line, or to a hydroxyl; and a dashed line marked with * indicates a cross-linking point between a Z 3 unit of 2A and a Z 4 unit of 2B, such that at least one 2A is cross-linked with at least one 2B; drug is ranibizumab;Ra1 and Ra2 are each independently hydrogenated; C1-4 alkyl; an alkali metal ion, an ammonium ion, or an alkali metal ion; 2A includes a total of s units, where s is from 25 to 2500, where: the number of Z1 units in 2A is from 0.8s to 0.99s, and the number of Z3 units is from 0.1s to 0.01s; 2B comprises a total of t units, where t is from 25 to 2500, where: the number of Z1 units in 2B is from 0.75t to 0.94t; the combined number of Z2 and Z4 units is from 0.14t to 0.06t; the number of Z2 units is at least 0.01t; and the number of Z4 units is at least 0.01t; and wherein the drug is coupled solely to polymer 2B and wherein the effective ocular half-life of the cross-linked hyaluronic acid drug conjugate is at least 10 times longer than that of the unmodified drug. Twelve claims follow;