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

• US 20190175621A1
• Filed: 02/19/2019
• Published: 06/13/2019
• Est. Priority Date: 09/15/2016
• Status: Active Grant

• Current Assignee: Nostopharma, LLC
• Original Assignee: Nostopharma, LLC
• Inventors: VERT-WONG, Ekaterina
• Granted Patent: US 10,456,409 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 preventing or treating heterotopic ossification, vascular calcification, or pathologic calcification, comprising administering a therapeutically effective amount of a combination of compounds selected from the group consisting of:

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; and

c) the combination of;

i) a Hh pathway antagonist;

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

iii) a statin.

wherein the compounds of paragraphs a), b) and c), are administered in a co-timely manner.

2. The method of claim 1, wherein, in accordance with paragraph a), a combination of a Hedgehog (Hh) pathway antagonist and vitamin D, cholecalciferol or a vitamin D analog is concomitantly administered to a patient.

3. The method of claim 2, wherein:

a) said compounds are administered in a single unit dosage form; and

b) said Hh) pathway antagonist is administered at 1-500 mg/day; and

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

4. The method of claim 2, wherein said combination is administered subsequent to spinal cord damage, traumatic injury, head or brain injuries, burns, bone fractures, muscle injuries, or joint replacement surgery.

5. The method of claim 2, wherein said combination is administered to prevent or treat heterotopic ossification resulting from progressive osseous heteroplasia, fibrodysplasia ossificans progressiva or Albright'"'"'s hereditary osteodystrophy.

6. The method of claim 2, wherein said Hh pathway antagonist is selected from the group consisting of:

a) zerumbone epoxide;

b) staurosporinone;

c) 6-hydroxystauro-sporinone;

d) arcyriaflavin C;

e) 5,6-dihyroxyarcyriaflavin A;

0 physalin F;

g) physalin B;

h) cyclopamine;

i) HPI-1, HPI-2;

HPI-3;

or HPI-4;

j) arsenic trioxide (ATO);

k) sodium arsenite;

l) phenylarsine;

m) GANT-58;

n) GANT-61;

o) zerumbone; and

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

7. The method of claim 1, wherein, in accordance with paragraph a), a combination of a Hedgehog (Hh) pathway antagonist and a statin is concomitantly administered to a patient.

8. The method of claim 7, wherein:

a) said compounds are administered in a single unit dosage form; and

b) said Hh) pathway antagonist is administered at 1-500 mg/day; and

statin is administered at 1-500 mg/day.

9. The method of claim 7, wherein said combination is administered subsequent to spinal cord damage, traumatic injury, head or brain injuries, burns, bone fractures, muscle injuries, or joint replacement surgery.

10. The method of claim 7, wherein said method is administered to a patient to prevent or treat heterotopic ossification resulting from progressive osseous heteroplasia, fibrodysplasia ossificans progressiva or Albright'"'"'s hereditary osteodystrophy.

11. The method of claim 7, wherein:

A. said Hh pathway antagonist is selected from the group consisting of;

a) zerumbone epoxide;

b) staurosporinone;

c) 6-hydroxystauro-sporinone;

d) arcyriaflavin C;

e) 5,6-dihyroxyarcyriaflavin A;

0 physalin F;

g) physalin B;

h) cyclopamine;

i) HPI-1, HPI-2;

HPI-3;

or HPI-4;

j) arsenic trioxide (ATO);

k) sodium arsenite;

l) phenylarsine;

m) GANT-58;

n) GANT-61;

o) zerumbone; and

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

/or

B. said statin is selected from the group consisting of;

Atorvastatin;

Fluvastatin;

Pravastatin;

Rosuvastatin;

Simvastatin;

Pitavastatin;

Cerivastatin;

Lovastatin; and

Mevastatin.

12. The method of claim 1, wherein, in accordance with paragraph b), a combination of vitamin D, cholecalciferol or a vitamin D analog and a statin is concomitantly administered to a patient.

13. The method of claim 12, wherein:

a) said compounds are administered in a single unit dosage form; and

b) said 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.

14. The method of claim 12, wherein said combination is administered to a patient subsequent to spinal cord damage, traumatic injury, head or brain injuries, burns, bone fractures, muscle injuries, or joint replacement surgery.

15. The method of claim 12, wherein said method is administered to a patient to prevent or treat heterotopic ossification resulting from progressive osseous heteroplasia, fibrodysplasia ossificans progressiva or Albright'"'"'s hereditary osteodystrophy.

16. The method of claim 12, wherein said statin is selected from the group consisting of:

Atorvastatin;

Fluvastatin;

Pravastatin;

Rosuvastatin;

Simvastatin;

Pitavastatin;

Cerivastatin;

Lovastatin; and

Mevastatin.

17. The method of claim 1, wherein, in accordance with paragraph c), a combination of:

a Hh pathway antagonist;

vitamin D, cholecalciferol or a vitamin D analog; and

a statin;

is concomitantly administered to a patient.

18. The method of claim 17, wherein:

a) said compounds are administered in a single unit dosage form; and

b) said Hh) pathway antagonist is administered 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.

19. The method of claim 17, wherein said combination is administered subsequent to spinal cord damage, traumatic injury, head or brain injuries, burns, bone fractures, muscle injuries, or joint replacement surgery.

20. The method of claim 17, wherein said combination is administered to a patient to prevent or treat heterotopic ossification resulting from progressive osseous heteroplasia, fibrodysplasia ossificans progressiva or Albright'"'"'s hereditary osteodystrophy.

21. The method of claim 18, wherein:

A. said Hh pathway antagonist is selected from the group consisting of;

a) zerumbone epoxide;

b) staurosporinone;

c) 6-hydroxystauro-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;

l) phenylarsine;

m) GANT-58;

n) GANT-61;

o) zerumbone; and

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

/or

B. said statin is selected from the group consisting of;

Atorvastatin;

Fluvastatin;

Pravastatin;

Rosuvastatin;

Simvastatin;

Pitavastatin;

Cerivastatin;

Lovastatin; and

Mevastatin.