Delivery and retention of active agents within the skin
The present application describes the synthesis, formulation and uses of systems comprising agents capable of penetrating skin.
1 . A system comprising a penetrating agent having a structure of formula (I-a):
or pharmaceutically acceptable salt thereof,
wherein
A is or comprises a glycosaminoglycan;
L is selected from an optionally substituted C 1-6 alkylene chain wherein one, two, or three methylene units of L are optionally and independently replaced by —NH—, —O—, —S— or —C(O)—, —NH—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, polyethylene glycol, and a moiety which results from a click reaction, nucleophilic addition, or Michael addition;
R 1 is independently —H, halogen, —CN, optionally substituted C 1-6 aliphatic, optionally substituted 5- to 10-membered heterocyclyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl;
R 2 is —H, halogen, —CN, optionally substituted C 1-6 aliphatic, optionally substituted 5- to 10-membered heterocyclyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; and
m is 1-3.
2 . The system of claim 1 , wherein the penetrating agent has the structure of formula (I-b):
or pharmaceutically acceptable salt thereof.
3 . The system of claim 1 , wherein the penetrating agent has the structure of formula (I-d):
or pharmaceutically acceptable salt thereof.
4 . The system of claim 1 , wherein m is greater than 1.
5 . The system of claim 1 , wherein L is degradable under biological conditions.
6 . The system of claim 1 , wherein the penetrating agent has the structure of formula (I-c):
or pharmaceutically acceptable salt thereof.
7 . The system of claim 1 , wherein the glycosaminoglycan is selected from: hyaluronic acid, heparan sulphate, heparin, chondroitin sulphate, dermatan sulphate, and keratan sulphate.
8 . The system of claim 1 , wherein the glycosaminoglycan is or comprises hyaluronic acid.
9 . The system of claim 1 , wherein the glycosaminoglycan is a glycosaminoglycan-based protein glycan.
10 . The system of claim 1 , wherein the glycosaminoglycan is a glycosaminoglycan-based protein glycan selected from versican, perlecan, glypican, syndecan, and decorin.
11 . The system of claim 1 , wherein the penetrating agent is characterized by a particular degree of lipophilicity sufficient to enhance penetration and/or retention of the penetrating agent across skin when applied to a surface thereof, relative to that observed for A alone.