CONTROLLED DELIVERY OF BIOACTIVE AGENTS FROM DECOMPOSABLE FILMS

• US 20100040674A1
• Filed: 08/17/2009
• Published: 02/18/2010
• 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.
• Granted Patent: US 9,198,875 B2
• Time in Patent Office: Days
• US Class Current: 424/443
• 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:

a plurality of multilayer units comprising a first layer having a first charge and a second layer having a second charge, wherein;

at least a portion of the multilayers comprises a polymeric cyclodextrin associated with a bioactive agent;

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 layer; and

the decomposable thin film comprises at least a degradable polyelectrolyte layer, wherein the degradable polyelectrolyte is hydrolyzable.

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

the thin film comprises alternating cationic and anionic layers, and decomposition of the thin film is characterized by hydrolytic degradation of at least a portion of a layer selected from the group consisting of the cationic layers, the anionic layers, and both.

3. The decomposable thin film of claim 1, wherein the polymeric cyclodextrin comprises a cyclodextrin backbone, a cyclodextrin as a pendant group, or both.

4. The decomposable thin film of claim 1, wherein the cyclodextrin is selected from the group consisting of α

-cyclodextrins, β

-cyclodextrins, γ

-cyclodextrins, derivatives thereof, and combinations thereof.

5. The decomposable thin film of claim 4, wherein the cyclodextrin is a cyclodextrin or a derivative thereof.

6. The decomposable thin film of claim 4, wherein the polymeric cyclodextrin is selected from the group consisting of dimethyl-β

-cyclodextrin (DMβ

CD), trimethyl-β

-cyclodextrin (TMβ

CD), randomly methylated-β

-cyclodextrin (RMβ

PCD), hydroxyethyl-β

-cyclodextrin (HEβ

CD), 2-hydroxypropyl-β

-cyclodextrin (HPβ

CD), 3-hydroxypropyl-β

-cyclodextrin (3HPβ

CD), 2,3-dihydroxypropyl-β

-cyclodextrin (DHPβ

CD), 2-hydroxyisobutyl-β

-cyclodextrin (HIBβ

CD), sulphobutylether-β

-cyclodextrin (SBEβ

CD), carboxymethyl-β

-cyclodextrin, glucosyl-β

-cyclodextrin (G₁β

CD), maltosyl-β

-cyclodextrin (G₂β

CD), derivatives thereof, and combinations thereof.

7. The decomposable thin film of claim 6, wherein the cyclodextrin is carboxymethyl-β

-cyclodextrin.

8. The decomposable thin film of claim 1, wherein at least one cyclodextrin molecule within the polymeric cyclodextrin forms a complex with the bioactive agent.

9. The decomposable thin film of claim 8, wherein the complex is an inclusion complex.

10. The decomposable thin film of claim 1, wherein the bioactive agent is a hydrophobic molecule.

11. The decomposable thin film of claim 1, wherein the bioactive agent or a portion of the bioactive agent has a largest dimension less than about 0.9 nm.

12. The decomposable thin film of claim 11, wherein the bioactive agent or a portion of the bioactive agent has a largest dimension less than about 0.7 nm.

13. The decomposable thin film of claim 12, wherein the bioactive agent or a portion of the bioactive agent has a largest dimension less than 0.6 nm.

14. 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).

15. The decomposable thin film of claim 1, wherein the bioactive agent is selected from the group consisting of anti-inflammatory drugs, anti-cancer drugs, antibiotics, anti-coagulants, anesthetics, and anti-glaucoma drugs.

16. The decomposable thin film of claim 15, 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, valdecoxib.

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

18. The decomposable thin film of claim 15, wherein the bioactive agent is an antibiotic selected from the group consisting of ampicillin, cetofiam, chloramphenicol, ciprofloxacin, cephalosporin, mitomycin, saponin, triclosan, and combinations thereof.

19. The decomposable thin film of claim 15, wherein the bioactive agent is an anesthetic selected from the group consisting of alfaxalone, benzocaine, bupivacaine, fentanyl, propofol, and combinations thereof.

20. The decomposable thin film of claim 15 wherein the bioactive agent is pilocarpine.

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

22. The decomposable thin film of claim 1, wherein at least a portion of the degradable polyelectrolyte layers comprises a polyelectrolyte selected from the group consisting of a synthetic polyelectrolyte, a natural polyelectrolyte, and both.

23. The decomposable thin film of claim 1, wherein at least a portion of the degradable polyelectrolyte layers comprises a polymer selected from polyesters, polyanhydrides, polyorthoesters, polyphosphazenes, polyphosphoesters, and combinations thereof.

24. The decomposable thin film of claim 23, wherein the polymer is a polyester selected from the group consisting of poly(β

-amino ester)s, poly(L-lactide-co-L-lysine), poly(serine ester), poly(4-hydroxy-L-proline ester), poly[α

-(4-aminobutyl)-L-glycolic acid], and any combination thereof.

25. The decomposable thin film of claim 24, wherein the polyester is a poly(β

-amino ester) selected from the group consisting of

26. The decomposable thin film of claim 25, wherein the poly(β

-amino ester) is selected from the group consisting of;

27. The decomposable thin film of claim 26, wherein the poly(β

-amino ester) is selected from the group consisting of;

28. The decomposable thin film of claim 27, wherein the poly(β

-amino ester) is

29. The decomposable thin film of claim 25, wherein the poly(β

-amino ester) is synthesized using diacrylate monomers selected from the group consisting of;

1,3-propanediol diacrylate, 1,4-butanediol diacrylate, 1,6-hexanediol diacrylate, 1,9-nonanediol diacrylate, neopentyl glycol diacrylate, trimethylolpropane benzoate diacrylate, 2,2,3,3,4,4,5,5-Octafluoro-1,6-hexanediol diacrylate, trimethylolpropane ethoxylate methyl ether diacrylate, 1,4-cyclohexanedimethyl diacdrylate, and combinations thereof.

30. The decomposable thin film of claim 29, wherein the poly(β

-amino ester) is synthesized using 1,6-hexanediol diacrylate.

31. 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.

32. The decomposable thin film of claim 1, wherein the degradation is characterized by at least one characteristic selected from the group consisting of hydrolytic, thermal, enzymatic, and photolytic.

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

34. The decomposable thin film of claim 33, 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.

35. The decomposable thin film of claim 1, wherein the thin film is adapted and constructed as a hollow shell.

36. The decomposable thin film of claim 1, wherein the thin film is deposited on a substrate.

43. The decomposable thin film of claim 1, wherein the multilayer units comprise bilayer units of the structure (polyelectrolyte layer having the first charge/cyclodextrin and bioactive agent layer having the second charge).

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

45. The decomposable thin film of claim 44, wherein the film comprises at least 20 multilayer units.

37-42. -42. (canceled)

46. A method of releasing a bioactive agent from a thin film comprising:

providing a decomposable thin film comprising a plurality of multilayers including a first layer having a first charge and a second layer having a second charge, wherein;

at least one of the layers comprises a polymeric cyclodextrin;

the bioactive agent is associated with a cyclodextrin in at least one of the layers; and

the decomposable thin film includes at least one degradable polyelectrolyte layer, wherein the degradable polyelectrolyte is hydrolyzable; and

placing the thin film in a medium in which at least a portion of the thin film decomposes via substantially sequential removal of at least a portion of the layers having the first charge and degradation of layers having the second charge.

47-48. -48. (canceled)

50-52. -52. (canceled)