Method and composition of thyroid hormone analogues and nanoformulations thereof for treating anti-inflammatory disorders

• US 9,498,536 B2
• Filed: 04/01/2014
• Issued: 11/22/2016
• Est. Priority Date: 09/15/2005
• Status: Active Grant

• Current Assignee: NanoPharmaceuticals LLC
• Original Assignee: NanoPharmaceuticals LLC
• Inventors: Mousa, Shaker A., Davis, Paul J.
• Primary Examiner(s): Shomer, Isaac
• Application Number:
  US14/242,041
• Publication Number:
  US 20140294931A1
• Time in Patent Office: 966 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/05 Phenols cannabinoids A61K31/658
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/60 Salicylic acid; Derivatives thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/593 Polyesters, e.g. PLGA or polylactide-co-glycolide
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: Y10S 977/773 Nanoparticle, i.e. structure having three dimensions of 100 nm or less
• CPC Class Codes: Y10S 977/906 Drug delivery

Abstract

Thyroid hormone antagonists and their nanoparticle formulations (Nanotetrac™ or Nanotriac™) act at a cell surface receptor to block angiogenesis and tumor cell proliferation. The complex anti-angiogenic performs actions on specific cytokines and chemokines. Thyroid hormone antagonists inhibit expression in tumor cells of cytokine genes, e.g., specific interleukins, and chemokine genes, such as fractalkine (CX3CL1), and chemokine receptor genes (CX3CR1) that are targets in the development of inflammation-suppressant drugs. This application discloses a novel composition of Tetra or Tri-iodothyroacetic acid (tetrac or triac), other thyroid partial agonists or antagonists and their nanoparticle formulations conjugated to polymers and encapsulating non-steroidal anti-inflammatory, anti-inflammatory glucocorticoids, and/or polyphenols for the management of various acute and chronic inflammatory disorders ranging from neurological, vascular, and musculoskeletal disorders.

Claims

1. A composition comprising:

a thyroid hormone analogue conjugated to a polymer, wherein the thyroid hormone analogue is immobilized to a surface of the polymer, wherein said thyroid hormone analogue targets integrin α

vβ

3; and

at least one anti-inflammatory agent encapsulated by the polymer, wherein said at least one anti-inflammatory agent is selected from a non-steroidal anti-inflammatory drug (NSAID), a tyrosine kinase inhibitor, a salicylate, an anti-inflammatory glucocorticoid and an anti-fibrotic agent having anti-inflammatory properties.

2. The composition of claim 1, wherein the thyroid hormone analogue is at least one of tetraiodothyroacetic acid (tetrac) and triiodothyroacetic acid (triac).

3. The composition of claim 1, wherein the polymer is selected from the group consisting of polylactic acid (PLLA), polyglycolic acid (PGA), polyacrylic acid, poly(lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG), poly-L-lysine, chitosan, hyaluronic acid, fatty acids, polyamine, co-polymers thereof and combinations thereof.

4. The composition of claim 1, wherein the polymer is formulated into a nanoparticle.

5. The composition of claim 1, wherein the NSAID is selected from the group consisting of ibuprofen, diclofenac, indomethacin, ketoprofen, naproxen, sulindac, celecoxib, nabumetone, mefenamic acid, oxyphenbutazone, and combinations thereof.

6. The composition of claim 1, further comprising an anti-oxidant polyphenol encapsulated within the polymer.

7. The composition of claim 6, wherein the anti-oxidant polyphenol is at least one of a flavone, an isoflavone, and a flavonoid.

8. The composition of claim 7, wherein the flavonoid is selected from the group consisting of resveratrol, quercetin, myricetin, catechin, epigallocatechin, genistein and combinations thereof.

9. The composition of claim 4, wherein the nanoparticle has a diameter between approximately 10 nm and <

1000 nm.

10. The method of claim 1, wherein the anti-fibrotic agents having anti-inflammatory properties is pirfenidone.

11. The composition of claim 1, further comprising one or more bisphosphonates encapsulated in the polymer.

12. The composition of claim 11, wherein the one or more bisphosphonates are selected from the group consisting of risendronate, alendronate, ibandronate, etidronate, pamidronate, tiludronate, and zoledronic acid.

13. The composition of claim 1, wherein the composition is formulated into a hydrogel.

14. A method for making the composition of claim 1 comprising the steps of:

conjugating a thyroid hormone analogue to a polymer, forming a conjugated thyroid hormone analog; and

encapsulating inside the polymer of the conjugated thyroid hormone analogue at least one of a non-steroidal anti-inflammatory drug (NSAID), a salicylate, an anti-inflammatory glucocorticoid and an anti-fibrotic agent having anti-inflammatory properties.

15. The method of claim 14, wherein the step of encapsulating includes encapsulating the at least one of the non-steroidal anti-inflammatory drug (NSAID), the salicylate, the anti-inflammatory glucocorticoid and the anti-fibrotic agent having anti-inflammatory properties at a dose between 1.0-100 mg.

16. The method of claim 14, further comprising the step of encapsulating the polymer in a liposome, microparticle or nanoparticle.

17. The method of claim 14, wherein the NSAID is selected from the group consisting of ibuprofen, diclofenac, indomethacin, ketoprofen, naproxen, sulindac, celecoxib, nabumetone, mefenamic acid, oxyphenbutazone, and combinations thereof.

18. The method of claim 14, further comprising the step of encapsulating at least one anti-oxidant polyphenol inside the polymer, wherein the anti-oxidant polyphenol is at least one of a flavone, an isoflavone, and a flavonoid.

19. The method of claim 18, wherein the flavonoid is selected from the group consisting of resveratrol, quercetin, myricetin, catechin, epigallocatechin, enistein and combinations thereof.

20. The method of claim 14, wherein the polymer is selected from the group consisting of polylactic acid (PLLA), polyglycolic acid (PGA), polyacrylic acid, polyethylene glycol (PEG), poly-L-lysine, chitosan, hyaluronic acid, fatty acids, polyamine, co-polymers thereof and combinations thereof.

21. A method comprising administering the composition of claim 1 to a subject.

22. The method of claim 21, wherein the step of administering is performed at an interval selected from the group consisting of once a day, every other day and once a week.

23. The method of claim 21, wherein the step of administering occurs topically, systemically, orally, locally at the site of inflammation, and a combination thereof.