Compositions and methods for preventing and treating heterotopic ossification and pathologic calcification

• US 10,548,908 B2
• Filed: 09/13/2017
• Issued: 02/04/2020
• Est. Priority Date: 09/15/2016
• Status: Active Grant

• Current Assignee: Nostopharma, LLC
• Original Assignee: Nostopharma, LLC
• Inventors: Vert-Wong, Ekaterina
• Primary Examiner(s): Henley, III, Raymond J
• Application Number:
  US15/702,758
• Publication Number:
  US 20180071319A1
• Time in Patent Office: 874 Days
• Field of Search: 514167, 514460, 514504, 514577
• 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 mesenchymal stem cells with:

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

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

or

ii) a statin;

or

b) a combination of;

i) an Hh pathway antagonist;

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

iii) a statin;

wherein the compounds of paragraphs a) and b) 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) and b) are administered concomitantly.

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

17. The method of claim 1, wherein, in accordance with paragraph a), said mesenchymal stem cells are contacted with a combination of an Hh pathway antagonist and vitamin D, cholecalciferol or a vitamin D analog.

18. The method of claim 1, wherein, in accordance with paragraph a), said mesenchymal stem cells are contacted with a combination of an Hh pathway antagonist and a statin.

19. The method of claim 1, wherein, in accordance with paragraph b), said mesenchymal stem cells are contacted with a combination of:

an Hh pathway antagonist;

vitamin D, cholecalciferol or a vitamin D analog; and

a statin.

4. A method for treating heterotopic ossification, vascular calcification, or other 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) a combination of;

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

ii) a statin;

or

c) a 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 to the patient in a co-timely manner and wherein the compounds are present in an amount sufficient to make the combination effective at treating said heterotopic ossification, vascular calcification, or other pathologic calcification.

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 treat a patient for heterotopic ossification subsequent to spinal cord damage, traumatic injury, head or brain injuries, burns, bone fractures, muscle injuries, or joint replacement surgery and a therapeutically effective amount of said compounds is administered to said patient.

8. The method of claim 4, wherein said method is used to treat heterotopic ossification resulting from progressive osseous heteroplasia, fibrodysplasia ossificans progressiva or Albright'"'"'s hereditary osteodystrophy and a therapeutically effective amount of said compounds is administered to said patient.

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

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.

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) 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;

     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.

20. The method of claim 4, wherein, in accordance with paragraph a), said patient is administered a combination of an Hh pathway antagonist and vitamin D, cholecalciferol or a vitamin D analog.

21. The method of claim 20, wherein the Hh pathway antagonist and the vitamin D, cholecalciferol or vitamin D analog are administered in a single unit dosage form.

22. The method of claim 20, wherein the Hh pathway antagonist is administered to said patient at 1-500 mg/day;

and vitamin D, cholecalciferol or vitamin D analog is administered to said patient at 300-3000 IU/day.

23. The method of claim 20, 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;

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.

24. The method of claim 4, wherein, in accordance with paragraph a), said patient is administered a combination of an Hh pathway antagonist and a statin.

25. The method of claim 24, wherein the Hh pathway antagonist and the statin are administered in a single unit dosage form.

26. The method of claim 24, wherein said Hh pathway antagonist is administered to said patient at 1-500 mg/day and said statin is administered to said patient at 1-500 mg/ day.

27. The method of claim 24, 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;

     1) phenylarsine;

m) GANT-58;

n) GANT-61;

o) zerumbone; and

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

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

Atorvastatin;

Fluvastatin;

Pravastatin;

Rosuvastatin;

Simvastatin;

Pitavastatin;

Cerivastatin;

Lovastatin; and

Mevastatin.

28. The method of claim 4, wherein, in accordance with paragraph b), said patient is administered a combination of vitamin D, cholecalciferol or a vitamin D analog and a statin.

29. The method of claim 28, wherein the vitamin D, cholecalciferol or vitamin D analog and the statin are administered to a patient in a single unit dosage form.

30. The method of claim 28, wherein the vitamin D, cholecalciferol or vitamin D analog is administered to the patient at 300-3000 IU/day and the statin is administered to said patient at 1-500 mg/ day.

31. The method of claim 28, wherein the said statin is selected from the group consisting of:

Atorvastatin;

Fluvastatin;

Pravastatin;

Rosuvastatin;

Simvastatin;

Pitavastatin;

Cerivastatin;

Lovastatin; and

Mevastatin.

32. The method of claim 4, wherein, in accordance with paragraph c), said patient is administered a combination of:

i) a Hedgehog (Hh) pathway antagonist;

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

c) a statin.

33. The method of claim 32, wherein:

the Hh pathway antagonist;

the vitamin D, cholecalciferol or vitamin D analog; and

the statin are administered to a patient in a single unit dosage form.

34. The method of claim 32, wherein:

the Hh pathway antagonist is administered to said patient at 1-500 mg/day;

the vitamin D, cholecalciferol or vitamin D analog is administered to the patient at 300-3000 IU/day and the statin is administered to said patient at 1-500 mg/ day.

35. The method of claim 32, 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;

     1) phenylarsine;

m) GANT-58;

n) GANT-61;

o) zerumbone; and

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

B) the statin is selected from the group consisting of;

Atorvastatin;

Fluvastatin;

Pravastatin;

Rosuvastatin;

Simvastatin;

Pitavastatin;

Cerivastatin;

Lovastatin; and

Mevastatin.

36. A pharmaceutical composition in unit dosage form comprising:

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

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

or

ii) a statin;

or

b) a combination of;

i) an Hh pathway antagonist;

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

iii) a statin;

wherein the pharmaceutical composition comprises the compounds of either paragraph a) or paragraph b) along with a pharmaceutically acceptable carrier.

37. The pharmaceutical composition of claim 36, wherein, when administered to a patient, the amounts of the compounds of paragraph a) or paragraph b) are sufficient to provide the specific pharmacological response for which the compounds are administered.

38. The pharmaceutical composition of claim 37, wherein the specific pharmacological response is the inhibition of heterotopic ossification, vascular calcification, or other pathologic calcification in a patient.

39. The pharmaceutical composition of claim 36, wherein said unit dosage form comprises:

an Hh antagonist at 1-500 mg;

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

/or a statin at 1-500 mg.

40. The pharmaceutical composition of claim 36, wherein said Hh pathway antagonist is selected from the group consisting of:

zerumbone epoxide;

staurosporinone;

6-hydroxystauro-sporinone;

arcyriaflavin C;

5,6-dihyroxyarcyria-flavin 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.

41. The pharmaceutical composition of claim 36, wherein said statin is selected from the group consisting of:

Atorvastatin;

Fluvastatin;

Pravastatin;

Rosuvastatin;

Simvastatin;

Pitavastatin;

Cerivastatin;

Lovastatin; and

Mevastatin.

42. The pharmaceutical composition of claim 36, wherein in accordance with paragraph a), said pharmaceutical composition comprises a Hedgehog (Hh) pathway antagonist together with a statin.

43. The pharmaceutical composition of claim 36, wherein in accordance with paragraph a), said pharmaceutical composition comprises a Hedgehog (Hh) pathway antagonist together with vitamin D, cholecalciferol or a vitamin D analog.

44. The pharmaceutical composition of claim 36, wherein in accordance with paragraph b), said pharmaceutical composition comprises a Hedgehog (Hh) pathway antagonist;

vitamin D, cholecalciferol or a vitamin D analog; and

a statin.