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

• US 10,456,409 B2
• Filed: 02/19/2019
• Issued: 10/29/2019
• 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:
  US16/279,421
• Publication Number:
  US 20190175621A1
• Time in Patent Office: 252 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 preventing or treating heterotopic ossification, vascular calcification, or other pathologic calcification in a patient, comprising administering to said patient a combination of:

a) a Hedgehog (Hh) pathway antagonist; and

b) vitamin D, cholecalciferol or a vitamin D analog, wherein the combination of said Hh pathway antagonist and said vitamin D, cholecalciferol or vitamin D analog is effective at preventing or treating said heterotopic ossification, vascular calcification, or other pathologic calcification in said patient.

2. The method of claim 1, wherein said method is used to prevent heterotopic ossification in said patient, and wherein said Hh pathway antagonist and said vitamin D, cholecalciferol or vitamin D analog are administered in a co-timely manner.

3. The method of claim 2, wherein said Hh) pathway antagonist is administered at 1-500 mg/day;

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

4. The method of claim 1, wherein said method is used to prevent vascular calcification or other pathologic calcification in said patient, and wherein said Hh pathway antagonist and said vitamin D, cholecalciferol or vitamin D analog are administered in a co-timely manner.

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

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

6. The method of claim 1, wherein said method is used to treat heterotopic ossification in said patient, and wherein said Hh pathway antagonist and said vitamin D, cholecalciferol or vitamin D analog are administered in a co-timely manner.

7. The method of claim 6, wherein said Hh) pathway antagonist is administered at 1-500 mg/day;

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

8. The method of claim 1, wherein said method is used to treat vascular calcification or other pathologic calcification in said patient, and wherein said Hh pathway antagonist and said vitamin D, cholecalciferol or vitamin D analog are administered in a co-timely manner.

9. The method of claim 8, wherein said Hh) pathway antagonist is administered at 1-500 mg/day;

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

10. A method for preventing or treating heterotopic ossification, vascular calcification, or other pathologic calcification, in a patient, comprising administering to said patient a combination of:

a) a Hedgehog (Hh) pathway antagonist; and

b) a statin, wherein the combination of said Hh pathway antagonist and said statin is effective at preventing or treating said heterotopic ossification, vascular calcification, or other pathologic calcification in said patient.

11. The method of claim 10, wherein said method is used to prevent heterotopic ossification in said patient, and wherein said Hh pathway antagonist and said statin are administered in a co-timely manner.

12. The method of claim 11, wherein said Hh) pathway antagonist is administered at 1-500 mg/day and said statin is administered at 1-500 mg/day.

13. The method of claim 10, wherein said method is used to prevent vascular calcification or other pathologic calcification in said patient, and wherein said Hh pathway antagonist and said statin are administered in a co-timely manner.

14. The method of claim 13, wherein said Hh) pathway antagonist is administered at 1-500 mg/day and said statin is administered at 1-500 mg/day.

15. The method of claim 11, wherein said method is used to treat heterotopic ossification in said patient and wherein said Hh pathway antagonist and said statin are administered in a co-timely manner.

16. The method of claim 15, wherein said Hh) pathway antagonist is administered at 1-500 mg/day and said statin is administered at 1-500 mg/day.

17. The method of claim 12, wherein said method is used to treat vascular calcification or other pathologic calcification in said patient, and wherein said Hh pathway antagonist and said statin are administered in a co-timely manner.

18. The method of claim 17, wherein said Hh) pathway antagonist is administered at 1-500 mg/day;

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

19. The method of claim 13, further comprising administering to said patient vitamin D, cholecalciferol or a vitamin D analog.

20. The method of claim 14, wherein said Hh pathway antagonist and said statin are administered in a single unit dosage form.

21. The method of claim 15, and 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

/or

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

Atorvastatin;

Fluvastatin;

Pravastatin;

Rosuvastatin;

Simvastatin;

Pitavastatin;

Cerivastatin;

Lovastatin; and

Mevastatin.