Self assembled films for protein and drug delivery applications

Patent metadata

Field	Value
Publication number	US-9393217-B2
Application number	US-201414511589-A
Country	US
Kind code	B2
Filing date	Oct 10, 2014
Priority date	Jun 14, 2007
Publication date	Jul 19, 2016
Grant date	Jul 19, 2016

Abstract

Provided are systems for controlled release of proteins from decomposable thin films constructed by layer-by-layer deposition. Such films generally comprise alternating layers of polymers and proteins, and may further comprise additional layers of polyions. In some embodiments, decomposable thin films and methods of using such films allow proteins to be released over an extended period of time and/or retention of as much as 100% of function of released protein.

First claim

We claim:

1. A decomposable thin film comprising at least one tetralayer unit, the tetralayer unit comprising:
a degradable polyelectrolyte layer having a first electrostatic charge;
a first polysaccharide layer disposed next to the degradable polyelectrolyte layer, the polysaccharide layer having a second electrostatic charge, the first and second electrostatic charges being opposite;
a carrier layer disposed next to the first polysaccharide layer, the carrier layer including at least one growth factor; and
a second polysaccharide layer disposed next to the carrier layer.

2. The decomposable thin film of claim 1 , wherein the at least one growth factor is a vascular endothelial growth factor (VEGF), a bone morphogenic protein 2 (BMP-2), a bone morphogenic protein 4 (BMP-4), or a basic fibroblast growth factor (bFGF).

3. The decomposable thin film of claim 1 , wherein the degradable polyelectrolyte is a hydrolysable polyelectrolyte.

4. The decomposable thin film of claim 1 , wherein the carrier layer has a third electrostatic charge and the second polysaccharide layer has a fourth electrostatic charge, and wherein the first, the second, the third, and the fourth electrostatic charges are alternating anionic and cationic charges.

5. The decomposable thin film of claim 1 , wherein the carrier layer consists of a protein.

6. The decomposable thin film of claim 1 , wherein the degradable polyelectrolyte layer includes a polyelectrolyte selected from the group consisting of a synthetic polyelectrolyte, a natural polyelectrolyte, and a hybrid of a synthetic and a natural polyelectrolyte.

7. The decomposable thin film of claim 1 , wherein the degradable polyelectrolyte layer includes one or more polyelectrolytes selected from the group consisting of a polyester, a polyanhydride, a polyorthoester, a polyphosphazene, and a polyphosphoester.

8. The decomposable thin film of claim 1 , wherein the degradable polyelectrolyte layer is a polymer that includes one or more polyesters selected from the group consisting of a poly(β-amino ester), a poly(L-lactide-co-L-lysine), a poly(serine ester), a poly(4-hydroxy-L-proline ester), and a poly[α-(4-aminobutyl)-L-glycolic acid].

9. The decomposable thin film of claim 1 , wherein the degradable polyelectrolyte layer is a poly(β-amino ester) that includes a repeating unit represented by a structural formula selected from the group consisting of

wherein:
each linker B is independently a carbon chain of 1 to 30 carbon atoms or a heteroatom-containing carbon chain of 1 to 30 atoms, each of which is optionally substituted with at least one group selected from a branched or unbranched alkyl, a branched or unbranched alkenyl, a branched or unbranched alkynyl, an amino, an alkylamino, a dialkylamino, a trialkylamino, an aryl, a ureido, a heterocyclic, an aromatic heterocyclic, a cyclic, an aromatic cyclic, a halogen, hydroxyl, an alkoxy, a cyano, an amide, a carbamoyl, a carboxylic acid, an ester, a carbonyl, a carbonyldioxyl, an alkylthioether, or a thiol group;
each R 1 is independently hydrogen, a branched and unbranched alkyl, a branched or unbranched alkenyl, a branched or unbranched alkynyl, an aryl, a halogen, a hydroxyl, an alkoxy, a carbamoyl, a carboxyl ester, a carbonyldioxyl, an amide, a thiohydroxyl, an alkylthioether, an amino, an alkylamino, a dialkylamino, a trialkylamino, a cyano, a ureido, a substituted alkanoyl, a cyclic, a cyclic aromatic, a heterocyclic, and an aromatic heterocyclic group, each of which is further optionally substituted with at least one substituent selected from the group consisting of a branched or unbranched alkyl, a branched or unbranched alkenyl, a branched or unbranched alkynyl, an amino, an alkylamino, a dialkylamino, a trialkylamino, an aryl, a ureido, a heterocyclic, an aromatic heterocyclic, a cyclic, an aromatic cyclic, a halogen, a hydroxyl, an alkoxy, a cyano, an amide, a carbamoyl, a carboxylic acid, an ester, a carbonyl, a carbonyldioxyl, an alkylthioether, and a thiol group; and
n is an integer greater than or equal to 5.

10. The decomposable thin film of claim 9 , wherein the repeating unit is represented by the following structural formula

11. The decomposable thin film of claim 9 , wherein the repeating unit is represented by the following structural formula

12. The decomposable thin film of claim 9 , wherein the repeating unit is represented by the following structural formula

13. The decomposable thin film of claim 1 , wherein the degradable polyelectrolyte layer is a polymer that includes one or more of a poly(styrene sulfonate), a poly(acrylic acid), a linear poly(ethylene imine), a poly(diallyl dimethyl ammonium chloride), and a poly(allylamine hydrochloride).

14. The decomposable thin film of claim 1 , wherein the degradable polyelectrolyte is a hydrolysable polyelectrolyte, a thermal degradable polyelectrolyte, an enzymatically degradable polyelectrolyte, or photolyticaly degradable polyelectrolyte.

15. The decomposable thin film of claim 1 , wherein the degradable polyelectrolyte includes a biodegradable polymer.

16. The decomposable thin film of claim 15 , wherein the biodegradable polymer includes one of more polymer selected from a polyhydroxyacid, a polypropylfumerate, a polycaprolactone, a polyamide, a poly(amino acid), a polyacetal, a polyether, a polycyanoacrylate, a polyurethane, and a polysaccharide.

17. The decomposable thin film of claim 1 , wherein the decomposable thin film is a hollow shell.

18. A device comprising a substrate and the decomposable thin film of claim 1 , wherein the decomposable thin film is disposed on the substrate.

19. The device of claim 18 , wherein the substrate is non-planar.

20. The device of claim 18 , wherein the substrate is a particle, a tube, a sphere, a strand, a coiled strand, or a capillary network.

21. The device of claim 18 , wherein the substrate is hydrolytically degradable.

22. The device of claim 18 , wherein the substrate includes a bioactive agent.

23. The device of claim 18 , wherein the substrate includes at least one material selected from a metal, a metal oxide, a plastic, a ceramic, a silicon, a glass, a mica, a graphite, a hydrogel.

24. The decomposable thin film of claim 1 , wherein the first polysaccharide layer includes a first polysaccharide, the second polysaccharide layer includes a second polysaccharide, and wherein the first and the second polysaccharides are the same.

25. The decomposable thin film of claim 1 , wherein the first polysaccharide layer and the second polysaccharide layer each includes a polysaccharide independently selected from the group consisting of heparin sulfate, chondroitin sulfate, hyaluronic acid, and dextran sulfate.

26. The decomposable thin film of claim 1 , wherein the decomposable thin film comprises at least 10 tetralayer units.

27. The decomposable thin film of claim 26 , wherein the decomposable thin film comprises at least N tetralayer units, wherein N is an

Assignees

• Massachusetts Inst Technology

Inventors

• Hammond Paula T
• Macdonald Mara L

Classifications

• A61K31/727

  Heparin; Heparan · CPC title

• A61L33/08

  Polysaccharides · CPC title

• A61L31/10

  Macromolecular materials · CPC title

• A61L31/16

  Biologically active materials, e.g. therapeutic substances {(A61L31/047 takes precedence)} · CPC title

• A61L2300/42

  Anti-thrombotic agents, anticoagulants, anti-platelet agents · CPC title