Controlled delivery of bioactive agents from decomposable films

• US 9,198,875 B2
• Filed: 08/17/2009
• Issued: 12/01/2015
• Est. Priority Date: 08/17/2008
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Smith, Renee Chivon, Hammond-Cunningham, Paula T.
• Primary Examiner(s): Azpuru, Carlos
• Assistant Examiner(s): HAGOPIAN, CASEY SHEA
• Application Number:
  US12/542,267
• Publication Number:
  US 20100040674A1
• Time in Patent Office: 2,297 Days
• Field of Search: None
• US Class Current: 1/1
• 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 2300/402 Anaestetics, analgesics, e.g. lidocaine
• CPC Class Codes: A61L 2300/406 Antibiotics
• CPC Class Codes: A61L 2300/41 Anti-inflammatory agents, e.g. NSAIDs
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/604 Biodegradation
• CPC Class Codes: A61L 2300/608 having two or more layers
• CPC Class Codes: A61L 2300/802 Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants
• 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: C08L 5/16 Cyclodextrin; Derivatives thereof

Abstract

A decomposable thin film includes a plurality of multilayer units including a first layer having a first charge and a second layer having a second charge, wherein at least a portion of the multilayers includes a polymeric cyclodextrin associated with a bioactive agent, wherein decomposition of the thin film is characterized by sequential removal of at least a portion of the layers having the first charge and degradation of layers having the second charge and by release of the bioactive agent from a corresponding layers; wherein the decomposable thin film including at least one degradable polyelectrolyte layer that is hydrolyzable.

Claims

1. A decomposable thin film, comprising:

at least one multilayer repeat unit, the multilayer repeat unit including at least a first polyelectrolyte layer and a second polyelectrolyte layer, the first polyelectrolyte layer having a first electrostatic charge and the second polyelectrolyte layer having a second electrostatic charge, the first and second electrostatic charges being opposite, wherein;

the first polyelectrolyte layer comprises a polycyclodextrin; and

the second polyelectrolyte layer comprises a degradable polyelectrolyte,

wherein the polycyclodextrin is non-covalently associated with a bioactive agent, and

wherein the bioactive agent is a hydrophobic molecule.

2. The decomposable thin film of claim 1, wherein:

the degradable polyelectrolyte is hydrolytically degradable.

3. The decomposable thin film of claim 1, wherein the polycyclodextrin is a polymer comprising a cyclodextrin backbone.

4. The decomposable thin film of claim 1, wherein the polycyclodextrin includes one or more cyclodextrin moieties selected from the group consisting of an α

-cyclodextrin, a β

-cyclodextrin, and a γ

-cyclodextrin.

5. The decomposable thin film of claim 4, wherein the one or more cyclodextrin moieties are β

-cyclodextrins.

6. The decomposable thin film of claim 4, wherein the one or more cyclodextrin moieties are selected from the group consisting of a dimethyl-β

-cyclodextrin (DMβ

CD), a trimethyl-β

- cyclodextrin (TMβ

CD), a randomly methylated-β

-cyclodextrin (RMβ

CD), a hydroxyethyl-β

-cyclodextrin (HEβ

CD), a 2-hydroxypropyl-β

-cyclodextrin (HPβ

CD), a 3-hydroxypropyl-β

cyclodextrin (3HPβ

CD), a 2,3-dihydroxypropyl-β

-cyclodextrin (DHPβ

CD), a 2-hydroxyisobutyl-β

-cyclodextrin (HIBβ

CD), a sulphobutylether-β

-cyclodextrin (SBEβ

CD), a carboxymethyl-β

-cyclodextrin, a glucosyl-β

-cyclodextrin (G₁β

CD), and a maltosyl-β

-cyclodextrin (G₂β

CD).

7. The decomposable thin film of claim 6, wherein the one or more cyclodextrin moieties are carboxymethyl-β

-cyclodextrins.

8. The decomposable thin film of claim 1, wherein the polycyclodextrin in non-covalent association with a hydrophobic molecule forms an inclusion complex.

9. The decomposable thin film of claim 1, wherein the polycyclodextrin includes at least one cyclodextrin moiety having a cavity diameter of less than about 0.9 nm as measured between anomeric oxygen atoms.

10. The decomposable thin film of claim 9, wherein the polycyclodextrin includes at least one cyclodextrin moiety having a cavity diameter of less than about 0.7 nm as measured between anomeric oxygen atoms.

11. The decomposable thin film of claim 10, wherein the polycyclodextrin includes at least one cyclodextrin moiety having a cavity diameter of less than about 0.6 nm as measured between anomeric oxygen atoms.

12. The decomposable thin film of claim 1, wherein the bioactive agent is a Class II or Class IV compound according to the Biopharmaceutical Classification System (BCS).

13. The decomposable thin film of claim 1, wherein the bioactive agent is selected from the group consisting of an anti-inflammatory drug, an anti-cancer drug, an antibiotic, an anti-coagulant, an anesthetic, and an anti-glaucoma drug.

14. The decomposable thin film of claim 13, wherein the bioactive agent is an anti-inflammatory drug selected from the group consisting of celecoxib, carprofen, dexamethasone, diclofenac, flurbiprofen, hydrocortisone, indomethacin, naproxen, ketoprofen, meloxicam, nimesulide, piroxicam, prednisolone, rofecoxib, tiaprofenic acid, and valdecoxib.

15. The decomposable thin film of claim 13, wherein the bioactive agent is an anti-cancer drug selected from the group consisting of camptothecin, imatinib, mitomycin, saponin, and combinations thereof.

16. The decomposable thin film of claim 13, wherein the bioactive agent is an antibiotic selected from the group consisting of ampicillin, cetofiam, chloramphenicol, ciprofloxacin, cephalosporin, mitomycin, saponin, and triclosan.

17. The decomposable thin film of claim 13, wherein the bioactive agent is an anesthetic selected from the group consisting of alfaxalone, benzocaine, bupivacaine, fentanyl, and propofol.

18. The decomposable thin film of claim 13 wherein the bioactive agent is pilocarpine.

19. The decomposable thin film of claim 1, wherein the bioactive agent is a food flavoring agent.

20. The decomposable thin film of claim 1, wherein the degradable polyelectrolyte is a polymer selected from one or more members of the group consisting of a polyester, a polyanhydride, a polyorthoester, a polyphosphazene, and a polyphosphoester.

21. The decomposable thin film of claim 20, wherein the polymer is a polyester 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].

22. The decomposable thin film of claim 21, wherein the polyester is a poly(β

-amino ester) that includes a repeating unit represented by a structural formula selected from the group consisting of

23. The decomposable thin film of claim 22, wherein the poly(β

-amino ester) includes a repeating unit represented by a structural formula selected from the group consisting of;

24. The decomposable thin film of claim 23, wherein the repeating unit is represented by a structural formula selected from the group consisting of:

25. The decomposable thin film of claim 24, wherein the repeating unit is represented by the structural formula

26. The decomposable thin film of claim 1, wherein at least a portion of the degradable polyelectrolyte layers comprises a polymer selected from poly(styrene sulfonate), poly(acrylic acid), linear poly(ethylene imine), poly(diallyl dimethyl ammonium chloride), poly(allylamine hydrochloride), and combinations thereof.

27. The decomposable thin film of claim 1, wherein the degradable polyelectrolyte is degradable via a process selected from the group consisting of hydrolytic degradation, thermal degradation, enzymatic degradation, and photolytic degradation.

28. The decomposable thin film of claim 1, wherein at least a portion of the degradable polyelectrolyte layers comprises a biodegradable polymer.

29. The decomposable thin film of claim 28, wherein the biodegradable polymer is selected from polyhydroxyacids;

polypropylfumerates;

polycaprolactones;

polyamides;

poly(amino acids);

polyacetals;

polyethers;

biodegradable polycyanoacrylates;

biodegradable polyurethanes;

polysaccharides; and

co-polymers, mixtures, and adducts thereof.

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

31. The decomposable thin film of claim 1, further including a substrate, optionally coated by a primer layer, in contact with the thin film.

32. The decomposable thin film of claim 1, wherein the film comprises at least 10 multilayer repeat units.

33. The decomposable thin film of claim 32, wherein the film comprises at least 20 multilayer repeat units.

34. The decomposable thin film of claim 1, wherein the multilayer repeat unit further includes a third polyelectrolyte layer.

35. The decomposable thin film of claim 34, wherein the multilayer repeat unit further includes a fourth polyelectrolyte layer comprising a degradable polyelectrolyte.

36. The decomposable thin film of claim 3, wherein the polycyclodextrin is a polymer comprising cyclodextrin as a pendant group.