Self assembled films for protein and drug delivery applications

• US 9,393,217 B2
• Filed: 10/10/2014
• Issued: 07/19/2016
• Est. Priority Date: 06/14/2007
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Hammond, Paula T., Macdonald, Mara L.
• Primary Examiner(s): Justice, Gina
• Application Number:
  US14/511,589
• Publication Number:
  US 20150086599A1
• Time in Patent Office: 648 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/726 Glycosaminoglycans, i.e. mucopolysaccharides chondroitin sulfate, dermatan sulfate A61K31/737
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 38/1866 Vascular endothelial growth factor [VEGF]
• CPC Class Codes: A61K 38/1875 Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 2300/604 Biodegradation
• CPC Class Codes: A61L 2300/608 having two or more layers
• CPC Class Codes: A61L 2420/02 Methods for coating medical devices
• CPC Class Codes: A61L 2420/08 Coatings comprising two or more layers
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/148 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61L 33/0011 Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
• CPC Class Codes: A61L 33/08 : Polysaccharides
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B82Y 30/00 : Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: Y10T 428/31768 : Natural source-type polyamide [e.g., casein, gelatin, etc.]

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.

Claims

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

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 integer selected from 20, 30, 40, 50, 60 70, and 80.

28. A method of releasing a protein, comprising the steps of:

providing a decomposable thin film of claim 1; and

placing the decomposable thin film in a medium, thereby causing the release of the at least one growth factor.

29. The method of claim 28, wherein the release of the at least one growth factor exhibits linear kinetics over a period of at least M days, wherein M is an integer selected from 5, 10, and 14.

30. The method of claim 28, wherein the release of the at least one growth factor continues over a period of at least K days, wherein K is an integer selected from 5, 10, 15, 20, 25, 30, and 34.

31. The method of claim 28, wherein the at least one growth factor retains at least P % activity after the release, wherein P is an integer selected from 50, 60, 70, 80, and 90.