Stereocomplex hydrogels with tunable degradation times
The present invention relates to stereocomplex hydrogels for drug delivery and tissue engineering. The hydrogels comprise block or graft polymers with at least one hydrophilic region and at least two enantiomerically enriched degradable regions, which may represent grafts or terminal blocks. In the hydrogels, degradable regions of opposite chirality form racemic crystallites, leading to the physical crosslinking of the polymers. Furthermore, the significance of the terminal groups of the degradable blocks for the degradability of the hydrogel is disclosed. Hydrogels from polymers whose degradable regions are characterised by the absence of terminal hydroxyl groups are shown to be particularly stable, having long lifetimes and a high potential for sustained drug release over extended periods such as weeks or months. In other aspects, the invention provides methods for the preparation of hydrogel compositions, kits from which the hydrogels can be prepared, and uses of the hydrogels.
1 . A stereocomplex hydrogel composition, comprising a mixture of a first and a second polymer,
wherein each first and each second polymer has at least one hydrophilic region and at least two oligomeric degradable regions which are hydrolysable under physiological conditions and which comprise enantiomerically enriched chiral monomeric units, and
wherein at least one of the degradable regions of the first polymer and at least one of the degradable regions of the second polymer have predominantly opposite chirality, and
wherein at least some of the degradable regions present in the composition are do not contain free terminal hydroxyl groups.
2 . The composition of claim 1 , wherein at least one of the first and the second polymer is a graft polymer, of which the hydrophilic region is the backbone and the degradable regions are the side chains.
3 . The composition of claim 2 , wherein said graft polymer has an average degree of substitution (DS) between about 2% and about 15%.
4 . The composition of claim 2 , wherein the side chains of said graft polymer have an average degree of polymerisation (DP) in the range of about 7% to 15%.
5 . The composition of claim 2 , wherein the side chains of said graft polymer have a polydispersity of not more than about 1.5%.
6 . The composition of claim 1 , wherein at least one of the first and the second polymer is a block polymer comprising three or more blocks, and wherein the degradable regions form at least the terminal blocks of said block polymer.
7 . The composition of claim 6 , wherein at least one of the first and the second polymer is an ABA block polymer, wherein the hydrophilic region forms the central B block.
8 . The composition of claim 1 , wherein the degradable region is attached to the hydrophilic region via a linking group selected from the group consisting of ester groups, amide groups, and urethane groups.
9 . The composition of claim 8 , wherein the linking group is hydrolytically more stable than the degradable region.
10 . The composition of claim 1 , wherein the hydrophilic region of at least one of the first and the second polymer is derived from a member of the group consisting of
polysaccharides including dextran, starch, cellulose and cellulose derivatives, alginates, pectin, and chitosan;
polypeptides including albumin, lysozyme, poly(amino acids), including poly(lysine) and related copolymers, poly(glutamic acid) and related copolymers;
poly(acrylates)/(acrylamides) including poly(alkyl acrylates)/(alkyl acrylamides) including poly(methacrylate), poly(hydroxyethyl methacrylate), poly(hydroxypropyl methacrylate), poly(hydroxyethyl methacrylamide), poly(hydroxypropyl methacrylamide); and
poly(vinylalcohol), poly(ethylene glycol), water soluble polyphosphazenes, and
mixtures thereof.
11 . The composition of claim 1 , wherein the degradable regions of at least one of the first and the second polymer are predominantly composed of enantiomerically enriched (L)- and/or (D)-lactate units.
12 . The composition of claim 11 , wherein at least some of the degradable regions predominantly composed of enantiomerically enriched (L)- and/or (D)-lactate units further comprise monomeric units selected from glycolate, ε-caprolactone, and βpropiolactone units.
13 . The composition of claim 1 , wherein essentially all degradable regions of the first polymer are of opposite chirality to essentially all degradable regions of the second polymer.
14 . The composition of claim 1 , wherein at least some of the degradable regions of the first or second polymer bear terminal acyl groups.
15 . The composition of claim 1 , which is shaped as a plurality of microparticles, as a sheet, or a single implantable unit.
16 . The composition of claim 1 , further comprising a pharmaceutically active compound.
17 . The composition of claim 16 , wherein the pharmaceutically active compound is a protein.
18 . A method for preparing the composition of claim 1 , comprising a step of combining the first polymer and the second polymer in the presence of water and, optionally, other excipients.
19 . The method of claim 18 , wherein the step of combining the first and the second polymer is conducted in the presence of a pharmaceutically active compound.
20 . A kit for the preparation of the composition of claim 1 , comprising a first component comprising the first polymer and a second component comprising the second polymer.
21 . A kit for the preparation of the composition of claim 1 , comprising a first component comprising the first and the second polymer, and a second component comprising water.
22 . The kit of claim 21 , wherein said first component comprises a xerogel capable of forming a stereocomplex hydrogel upon hydration.
23 . The kit of claim 20 , further comprising a pharmaceutically active compound.
24 . (canceled)
25 . The kit of claim 21 , further comprising a pharmaceutically active compound.
26 . An injectable or implantable pharmaceutical formulation, a wound dressing, or a replacement tissue that comprises the composition of claim 1.