Nanoparticle and polymer formulations for thyroid hormone analogs, antagonists, and formulations thereof

• US 9,579,300 B2
• Filed: 02/20/2014
• Issued: 02/28/2017
• Est. Priority Date: 09/15/2003
• Status: Active Grant

• Current Assignee: NanoPharmaceuticals LLC
• Original Assignee: NanoPharmaceuticals LLC
• Inventors: Mousa, Shaker A., Davis, Faith B., Davis, Paul J.
• Primary Examiner(s): Maewall, Snigdha
• Application Number:
  US14/184,889
• Publication Number:
  US 20140199376A1
• Time in Patent Office: 1,104 Days
• US Class Current: 1/1
• 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 31/195 having an amino group
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/4365 the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
• CPC Class Codes: A61K 31/60 Salicylic acid; Derivatives thereof
• CPC Class Codes: A61K 31/65 Tetracyclines
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 39/44 Antibodies bound to carriers
• 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 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 47/68 the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
• CPC Class Codes: A61K 47/6801 Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
• CPC Class Codes: A61K 47/6811 the drug being a protein or peptide, e.g. transferrin or bleomycin
• CPC Class Codes: A61K 47/6937 the polymer being PLGA, PLA or polyglycolic acid
• CPC Class Codes: A61K 47/6939 the polymer being a polysaccharide, e.g. starch, chitosan, chitin, cellulose or pectin
• CPC Class Codes: A61K 49/0008 Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
• CPC Class Codes: A61K 49/085 : conjugated systems
• CPC Class Codes: A61K 49/10 : Organic compounds
• CPC Class Codes: A61K 49/12 : Macromolecular compounds
• CPC Class Codes: A61K 51/0402 : carboxylic acid carriers, fatty acids amino acids A61K51/0406
• CPC Class Codes: A61K 51/0497 : conjugates with a carrier being an organic compounds
• CPC Class Codes: A61K 51/065 : conjugates with carriers being macromolecules
• CPC Class Codes: A61K 9/0048 : Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/5153 : Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: C07K 16/2848 : against integrin beta3-subunit-containing molecules, e.g. CD41, CD51, CD61
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: Y10T 428/2982 : Particulate matter [e.g., sphere, flake, etc.]

Abstract

Disclosed are methods of treating subjects having conditions related to angiogenesis including administering an effective amount of a polymeric Nanoparticle form of thyroid hormone agonist, partial agonist or an antagonist thereof, to promote or inhibit angiogenesis in the subject. Compositions of the polymeric forms of thyroid hormone, or thyroid hormone analogs, are also disclosed.

Claims

1. A composition comprising:

a thyroid hormone analog conjugated to a polymer, wherein conjugation to the polymer results in a particle with a diameter which does not allow the thyroid hormone analog conjugated to the polymer to cross a nucleus membrane and limits thyroid hormone analog activity to only a cell surface receptor wherein upon administration, the conjugated thyroid hormone analog binds to a cell surface receptor integrin α

vβ

3;

a morphogenic protein; and

a bioresorbable carrier.

2. The composition of claim 1 wherein the thyroid hormone analog is selected from a group consisting of levothyroxine (T4), triiodothyronine (T3), 3,5-dimethyl-4-(4 ‘

-hydroy-3’

-isopropylbenzyl)-phenoxy acetic acid (GC-1), or 3,5-diiodothyropropionic acid (DITPA), tetraiodothyroacetic acid (TETRAC), triiodothyroacetic acid (TRIAC), monoclonal antibody LM609, XT 1999 and combinations thereof.

3. The composition of claim 1 wherein the polymer is selected from a group consisting of polyethylene oxide (PEO), polyethylene glycol (PEG), m-PEG, polyvinyl alcohol (PVA), polylactic acid (PLLA), polyglycolic acid (PGA), polyacrylic acid, poly L-lysine, human serum albumin, cellulose derivative, hyaluronic acid, folate linked cyclodextrin/dextran, sarcosine/amino acid spaced polymer, alginate/carrageenan, pectin/chitosan, dextran, collagen, polyamine, polyaniline, polyalanine, polytryptophan, polytyrosine, and combinations thereof.

4. The composition of claim 1 wherein the bioresorbable carrier is selected from a group consisting of laminin, hyaluronic acid, collagen, an extracellular matrix derived from mouse sarcoma cells and a combination thereof.

5. The composition of claim 1 wherein the composition is formulated into a nanoparticle.

6. The composition of claim 1 wherein the nanoparticle is less than 200 nm.

7. The composition of claim 1 wherein the conjugated thyroid hormone analog is encapsulated in a vehicle selected from a group consisting of a liposome, microparticle, nanoparticle and a combination thereof.

8. The composition of claim 1 wherein the composition further includes nerve growth factors.

9. The composition of claim 1 wherein the composition further includes neurogenesis factors.

10. A method for treating a degenerative pathology of the central nervous system by administering the composition of claim 1 comprising:

conjugating a thyroid hormone analog to a polymer;

encapsulating the polymer in a liposome, microparticle or nanoparticle;

administering to a person in need thereof a therapeutic amount of the conjugated thyroid hormone analog.

11. The method of claim 10, wherein the degenerative pathology is selected from the group consisting of Alzheimer'"'"'s disease, Parkinsonism, Huntington'"'"'s chorea, cerebellarspinal adrenoleucodystrophy, trauma, cerebral ischemia, amyotrophic lateral sclerosis, multiple sclerosis and spinal cord injury and a combination thereof.

12. The method of claim 10 wherein the thyroid hormone analog is selected from a group consisting of levothyroxine (T4), triiodothyronine (T3), 3,5-dimethyl-4-(4 ‘

-hydroy-3’

-isopropylbenzyl)-phenoxy acetic acid (GC-1), or 3,5-diiodothyropropionic acid (DITPA), tetraiodothyroacetic acid (TETRAC), triiodothyroacetic acid (TRIAC), monoclonal antibody LM609, XT 1999 and combinations thereof.

13. The method of claim 10 wherein the polymer is selected from a group consisting of polyethylene oxide (PEO), polyethylene glycol (PEG), m-PEG, polyvinyl alcohol (PVA), polylactic acid (PLLA), polyglycolic acid (PGA), polyacrylic acid, poly L-Lysine, human serum albumin, cellulose derivative, hyaluronic acid, folate linked cyclodextrin/dextran, sarcosine/Amino Acid spaced polymer, alginate/carrageenan, pectin/chitosan, dextran, collagen, polyamine, polyaniline, polyalanine, polytryptophan, polytyrosine, and combinations thereof.

14. The method of claim 10 wherein the nanoparticle is approximately less than 200 nm.

15. The method of claim 10 wherein the step of administering includes parenteral, oral, rectal, topical administration, or combinations thereof.

16. The method of claim 10 wherein the step of conjugating includes the formation of an ester or anhydride linkage.

17. The method of claim 10 comprising an additional step of co-administering morphogenic protein, nerve growth factors and/or neurogenesis factors.

18. The method of claim 10 wherein a therapeutic amount is between approximately 200 to 2000 μ

g/day.

19. The method of claim 10 wherein the step of administering occurs prophylactically.