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

• US 10,130,686 B2
• Filed: 11/21/2016
• Issued: 11/20/2018
• 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:
  US15/357,818
• Publication Number:
  US 20170080058A1
• Time in Patent Office: 729 Days
• Field of Search: None
• 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 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 38/29 Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
• 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 method comprising:

providing 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;

encapsulating inside the polymer of the conjugated thyroid hormone analogue the anti-inflammatory agent selected from the group consisting of a non-steroidal anti-inflammatory drug (NSAID), a tyrosine kinase inhibitor, a salicylate, an anti-inflammatory glucocorticoid, an anti-fibrotic agent having anti-inflammatory properties and combinations thereof to form a composition; and

administering the composition to a patient suffering from an inflammatory condition.

2. The method of claim 1, wherein the thyroid hormone analogue is selected from the group consisting of tetraiodothyroacetic acid (tetrac) and triiodothyroacetic acid (triac).

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

4. The method of claim 1, wherein the step of encapsulating includes encapsulating the anti-inflammatory agent at a dose between 1.0-100 mg.

5. The method of claim 1, further comprising formulating the polymer into a nanoparticle.

6. The method of claim 1, wherein the nanoparticle has a diameter between approximately 10 nm and <

1000 nm.

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

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

9. The method of claim 1, further comprising the step of:

encapsulating an anti-oxidant polyphenol inside the polymer, wherein the anti-oxidant polyphenol is selected from the group consisting of a flavone, an isoflavone, and a flavonoid.

10. The method of claim 9, wherein the flavonoid is selected from the group consisting of resveratrol, quercetin, myricetin, catechin, epigallocatechin, genistein and combinations thereof.

11. The method of claim 1, wherein the inflammatory condition is selected from the group consisting of Alzheimer'"'"'s disease, Parkinson'"'"'s disease, trauma, cerebral ischemia, amyotrophic lateral sclerosis, multiple sclerosis, arthritis, myositis, poikiloderma, rosacea, psoriasis, acne, pityriasis rosea, eczema, and a combination of inflammatory conditions thereof.

12. The method of claim 1, wherein the inflammatory condition is a musculoskeletal condition selected from the group consisting of aches and pains located in the body'"'"'s muscles, joints, tendons, ligaments, nerves, and combination of musculoskeletal conditions thereof.

13. The method of claim 1, wherein the administering step includes administering between approximately 200 to 2000 μ

g of the conjugated thyroid hormone analog and 1.0-100 mg of at least one of the NSAID, anti-oxidant polyphenol, anti-inflammatory glucocorticoid, and combinations thereof.

14. The method of claim 13, 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.

15. The method of claim 14, wherein the step of administering occurs topically, systemically, orally, locally at a site of inflammation, and a combination thereof.

16. The method of claim 14, wherein the site of inflammation is a conjunctival sac, located between an eyelid of the patient.

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

18. The method of claim 1, further comprising the step of:

encapsulating inside the polymer a bisphosphonate.

19. The method of claim 18, wherein the bisphosphonate is selected from the group consisting of risendronate, alendronate, ibandronate, etidronate, pamidronate, tiludronate, and zoledronic acid.

20. The method of claim 1, further comprising the step of:

encapsulating inside the polymer a parathyroid hormone derived peptide, which is optionally teriparatide.