Compositions and Methods for Preventing and Treating Heterotopic Ossification and Pathologic Calcification

• US 20180071319A1
• Filed: 09/13/2017
• Published: 03/15/2018
• Est. Priority Date: 09/15/2016
• Status: Active Grant

• Current Assignee: Nostopharma, LLC
• Original Assignee: Nostopharma, LLC
• Inventors: VERT-WONG, Ekaterina
• Granted Patent: US 10,548,908 B2
• Time in Patent Office: Days
• CPC Class Codes: A23L 33/155 Vitamins A or D
• 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 31/22 of acyclic acids, e.g. pravastatin
• CPC Class Codes: A61K 31/366 having six-membered rings, e.g. delta-lactones
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/593 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61L 2400/02 Treatment of implants to prevent calcification or mineralisation in vivo
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: C12N 2500/05 Inorganic components
• CPC Class Codes: C12N 2500/38 Vitamins
• CPC Class Codes: C12N 2501/315 Prolactin
• CPC Class Codes: C12N 2501/36 Somatostatin
• CPC Class Codes: C12N 2501/41 Hedgehog proteins; Cyclopamine (inhibitor)
• CPC Class Codes: C12N 2501/999 Small molecules not provided for elsewhere
• CPC Class Codes: C12N 2506/1353 from bone marrow mesenchymal stem cells (BM-MSC)
• CPC Class Codes: C12N 5/0654 : Osteocytes, Osteoblasts, Odontocytes; Bones, Teeth
• CPC Class Codes: C12N 5/0663 : Bone marrow mesenchymal stem cells (BM-MSC)

Abstract

The present invention is directed to compositions and methods for the prevention or treatment of treatment of heterotopic ossification, vascular calcification, or pathologic calcification.

Claims

1. A method for inhibiting osteogenesis in mesenchymal stem cells, comprising contacting said cells with:

a) a combination of an Hedgehog (Hh) pathway antagonist together with;

i) vitamin D, cholecalciferol or a vitamin D analog;

or

ii) a statin;

b) the combination of;

i) vitamin D, cholecalciferol or a vitamin D analog; and

ii) a statin;

c) the combination of;

i) an Hh pathway antagonist;

ii) vitamin D, cholecalciferol or a vitamin D analog; and

iii) a statin;

d) vitamin D, cholecalciferol or a vitamin D analog administered in the absence of an Hh pathway antagonist or a statin;

or a statin administered in the absence of an Hh pathway antagonist, vitamin D, cholecalciferol or a vitamin D analog;

wherein the compounds of paragraphs a), b) and c), are administered to cells in a co-timely manner, and wherein the dosage of each compound is sufficient to make the combination effective at inhibiting osteogenesis.

2. The method of claim 1, wherein the compounds of paragraphs a), b) and c) are administered concomitantly.

3. The method of claim 1, wherein the combination set forth in paragraph a), b) or c) produces a greater degree of inhibition than any components of the combination can produce when used in the absence of all of the components.

4. A method for preventing or treating heterotopic ossification, vascular calcification, or pathologic calcification in a patient, comprising:

administering to said patient;

a) a combination of a Hedgehog (Hh) pathway antagonist together with;

i) vitamin D, cholecalciferol or a vitamin D analog;

or

ii) a statin;

b) the combination of;

i) vitamin D, cholecalciferol or a vitamin D analog; and

ii) a statin;

c) the combination of;

i) a Hh pathway antagonist;

ii) vitamin D, cholecalciferol or a vitamin D analog; and

iii) a statin.

d) vitamin D, cholecalciferol or a vitamin D analog administered in the absence of an Hh pathway antagonist or a statin;

or a statin administered in the absence of an Hh pathway antagonist, vitamin D, cholecalciferol or a vitamin D analog;

wherein the compounds of paragraphs a), b) and c), are administered to cells in a co-timely manner, and wherein the dosage of each compound is sufficient to make the combination effective at inhibiting osteogenesis.

5. The method of claim 4, wherein the compounds of paragraphs a), b) and c), are administered concomitantly.

6. The method of claim 4, wherein said compounds are administered to a patient in a single unit dosage form.

7. The method of claim 4, wherein said method is used to prevent or treat heterotopic ossification subsequent to spinal cord damage, traumatic injury, head or brain injuries, burns, bone fractures, muscle injuries, or joint replacement surgery.

8. The method of claim 4, wherein said method is used to prevent or treat heterotopic ossification resulting from progressive osseous heteroplasia, fibrodysplasia ossificans progressiva or Albright'"'"'s hereditary osteodystrophy.

9. The method of claim 4, wherein said Hh) pathway antagonist is administered to said patient at 1-500 mg/day;

vitamin D, cholecalciferol or a vitamin D analog is administered at 300-3000 IU/day; and

said statin is administered at 1-500 mg/day.

10. The method of claim 9, wherein said compounds are administered to a patient in a single unit dosage form.

11. The method of claim 4, wherein said Hh pathway antagonist is a ligand that binds to the Sonic receptor and prevents activation;

an antibody that binds to either Sonic, Desert or Indian or to the receptor for these ligands;

or an siRNA that inhibits the expression of one or more genes activated by the Hh pathway.

12. The method of claim 4, wherein said Hh pathway antagonist is selected from the group consisting of:

a) zerumbone epoxide;

b) staurosporinone;

c) 6hydroxystauro-sporinone;

d) arcyriaflavin C;

e) 5,6-dihyroxyarcyriaflavin A;

f) physalin F;

g) physalin B;

h) cyclopamine;

i) HPI-1, HPI-2;

HPI-3;

or HPI-4;

j) arsenic trioxide (ATO);

k) sodium arsenite;

     1) phenylarsine;

m) GANT-58;

n) GANT-61;

o) zerumbone; and

p) inhibitors of the expression of the genes Ptch1, Gli1 or HIP.

13. The method of claim 4, wherein said Hh pathway antagonist is arsenic trioxide (ATO).

14. The method of claim 13, wherein ATO is administered to said patient at a dosage of between 0.05 to 0.20 mg/kg/day.

15. The method of claim 4, wherein said statin is selected from the group consisting of:

Atorvastatin;

Fluvastatin;

Pravastatin;

Rosuvastatin;

Simvastatin;

Pitavastatin;

Cerivastatin;

Lovastatin; and

Mevastatin.

16. The method of claim 4, wherein the combination set forth in paragraph a), b) or c) is more effective at inhibiting heterotopic ossification, vascular calcification, or pathologic calcification in a patient than any components of the combination can produce when used in the absence of all of the components.

17. A pharmaceutical composition in unit dosage form comprising as components:

a) a combination of a Hedgehog (Hh) pathway antagonist together with;

i) vitamin D, cholecalciferol or a vitamin D analog;

or

ii) a statin;

b) the combination of;

i) vitamin D, cholecalciferol or a vitamin D analog; and

ii) a statin;

c) the combination of;

i) an Hh pathway antagonist;

ii) vitamin D, cholecalciferol or a vitamin D analog; and

iii) a statin;

wherein the respective amounts of these components are effective upon administration of one or more of said unit dosage forms to said patient, to be therapeutically effective.

18. The pharmaceutical composition of claim 17, wherein said unit dosage form is for oral administration and comprises:

an Hh antagonist at 1-500 mg;

vitamin D, cholecalciferol or a vitamin D analog at 300-3000 IU; and

a statin at 1-500 mg.

19. The pharmaceutical composition of claim 17, wherein said Hh pathway antagonist is selected from the group consisting of:

zerumbone epoxide;

staurosporinone;

6-hydroxystauro-sporinone;

arcyriaflavin C;

5,6-dihyroxyarcyriaflavin A;

physalin F;

physalin B;

cyclopamine;

HPI-1, HPI-2;

HPI-3, or HPI-4;

arsenic trioxide;

sodium arsenite;

phenylarsine;

GANT-58;

GANT-61;

zerumbone; and

inhibitors of the expression of the genes Ptch1, Gli1 or HIP.

20. The pharmaceutical composition of claim 17, wherein said statin is selected from the group consisting of:

Atorvastatin;

Fluvastatin;

Pravastatin;

Rosuvastatin;

Simvastatin;

Pitavastatin;

Cerivastatin;

Lovastatin; and

Mevastatin.