Methods for the treatment of systemic disorders treatable with mast cell stabilizers, including mast cell related disorders

• US 10,596,146 B2
• Filed: 02/20/2019
• Issued: 03/24/2020
• Est. Priority Date: 08/07/2015
• Status: Active Grant

• Current Assignee: Respivant Sciences GmbH
• Original Assignee: Respivant Sciences GmbH
• Inventors: Soni, Pravin, Gerhart, William, Armstrong, Robert Craig
• Primary Examiner(s): Gembeh, Shirley V
• Application Number:
  US16/280,837
• Publication Number:
  US 20190183847A1
• Time in Patent Office: 398 Days
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Methods for the treatment of systemic disorders treatable with mast cell stabilizers, including mast cell related disorders, are provided.

Claims

1. A method of treating a subject having a mast cell related disorder, comprising administering to the subject an effective amount of a composition comprising a mast cell stabilizer, wherein the blood of the subject has been determined to have an increased concentration of one or more biomarkers prior to administration of the composition to the subject, and wherein the one or more biomarkers is selected from tryptase, histamine, chymase, interleukin-6, interleukin-4, interleukin-5, interleukin-8, tumor growth factor alpha (TGF-α

), tumor growth factor beta (TGF-β

), tumor necrosis factor alpha (TNF-α

), tumor necrosis factor beta (TNF-β

), fibroblast growth factor 2 (FGF2), nerve growth factor (NGF), vascular endothelial growth factor (VEGF), stem cell factor (SCF), vascular cell adhesion molecule 1 (VCAM-1), ICAM-1 (Intercellular Adhesion Molecule

     1), immunoglobulin E (IgE), matrix metalloproteinase-3 (MMP-3), matrix metallopeptidase-9 (MMP-9), vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor C (VEGF-C), vascular endothelial growth factor D (VEGF-D) macrophage inflammatory protein 1α

(MIP-1α

), N-methyl histamine, methylimidazole acetic acid, and prostaglandin D2.

2. The method of claim 1, wherein the mast cell stabilizer is selected from cromolyn sodium, cromolyn lysinate, ammonium cromoglycate, magnesium cromoglycate, nicardipine, nifedipine, lodoxamide, nedocromil, barnidipine, YC-114, elgodipine, niguldipine, ketotifen, methylxanthines, and quercetin.

3. The method of claim 2, wherein the mast cell stabilizer is selected from cromolyn sodium, cromolyn lysinate, ammonium cromoglycate, and magnesium cromoglicate.

4. The method of claim 3, wherein the mast cell stabilizer is cromolyn sodium.

5. The method of claim 1, wherein the mast cell related disorder is selected from mast cell activation syndrome, idiopathic anaphylaxis, Ig-E and non Ig-E mediated anaphylaxis, allergic disorders, kidney fibrosis, myocardial ischemia, brain conditions associated with mast cells, kidney conditions associated with mast cells, liver conditions associated with mast cells, Parkinson'"'"'s disease, Alzheimer'"'"'s disease, diabetes, sickle cell disease, interstitial cystitis, myocarditis, stroke, transient ischemic attack, neuralgia, radiation cystitis, painful bladder syndrome, hepatitis, hepatic fibrosis, cirrhosis, and painful bladder syndrome.

6. The method of claim 5, wherein the mast cell stabilizer is selected from cromolyn sodium, cromolyn lysinate, ammonium cromoglycate, magnesium cromoglycate, nicardipine, nifedipine, lodoxamide, nedocromil, barnidipine, YC-114, elgodipine, niguldipine, ketotifen, methylxanthines, and quercetin.

7. The method of claim 6, wherein the mast cell stabilizer is selected from cromolyn sodium, cromolyn lysinate, ammonium cromoglycate, and magnesium cromoglicate.

8. The method of claim 7, wherein the mast cell stabilizer is cromolyn sodium.

9. The method of claim 8, wherein the composition comprises from about 1 mg to about 120 mg of cromolyn sodium.

10. The method of claim 9, wherein the composition comprises from about 20 mg to about 60 mg of cromolyn sodium.

11. The method of claim 10, wherein the composition comprises from about 30 mg to about 50 mg of cromolyn sodium.

12. The method of claim 8, wherein administration of the composition to the subject produces in the subject an AUC_(0-∞

) of cromolyn of from about 5.3 ng*hr/mL to about 8.5 ng*hr/mL per milligram of cromolyn sodium administered to the subject.

13. The method of claim 12, wherein administration of the composition to the subject produces in the subject a Cmax of cromolyn from about 2.2 ng/mL to about 3.9 mg/mL per milligram of cromolyn sodium administered to the subject.

14. The method of claim 8, wherein administration of the composition to the subject produces in the subject a Cmax of cromolyn of from about 2.2 ng/mL to about 3.9 mg/mL per milligram of cromolyn sodium administered to the subject.

15. The method of claim 1, wherein the composition is administered to the subject by inhalation administration, oral administration, parenteral administration, subcutaneous administration, topical administration, buccal administration, nasal administration, rectal administration, vaginal administration, or sublingual administration.

16. The method of claim 15, wherein the composition is administered to the subject by inhalation administration.

17. The method of claim 16, wherein the composition is administered to the subject with an inhaler selected from a dry powder inhaler, metered dose inhaler, nebulizer, or soft mist inhaler.

18. The method of claim 17, wherein the composition is administered to the subject with a nebulizer.

19. The method of claim 18, wherein the composition is administered to the subject with a high-efficiency nebulizer.

20. The method of claim 19, wherein the high-efficiency nebulizer provides an aerosol of the composition having an RF (≤

3.3 μ

m) of at least about 30%.

21. The method of claim 19, wherein the high-efficiency nebulizer provides an aerosol of the composition having an RF (≤

5 μ

m) of at least about 65%.

22. The method of claim 1, wherein the mast cell stabilizer is cromolyn sodium and the composition has an osmolality of between about 30 mOsm/kg to about 145 mOsm/kg.

23. The method of claim 1, wherein the one or more biomarkers is selected from tryptase, chymase, tumor growth factor beta (TGF-β

), stem cell factor (SCF), matrix metalloproteinase-3 (MMP-3), and matrix metallopeptidase-9 (MMP-9).

24. The method of claim 23, wherein the biomarker is tryptase.

25. The method of claim 23, wherein the biomarker is chymase.

26. The method of claim 23, wherein the biomarker is tumor growth factor beta (TGF-β

).

27. The method of claim 23, wherein the biomarker is stem cell factor (SCF).

28. The method of claim 23, wherein the biomarker is matrix metalloproteinase-3 (MMP-3).

29. The method of claim 23, wherein the biomarker is matrix metallopeptidase-9 (MMP-9).

30. The method of claim 1, wherein

(a) the mast cell stabilizer is cromolyn sodium;

(b) the composition is administered to the subject with an inhaler that provides an aerosol of the composition having an RF (≤

3.3 μ

m) of at least about 30%; and

(c) administration of the composition to the subject produces in the subject an AUC(0-∞

) of cromolyn of from about 5.3 ng*hr/mL to about 8.5 ng*hr/mL per milligram of cromolyn sodium administered to the subject.

31. The method of claim 30, wherein the inhaler is a high-efficiency nebulizer.

32. The method of claim 30, wherein the biomarker is tryptase.

33. The method of claim 30, wherein the biomarker is chymase.

34. The method of claim 30, wherein the biomarker is tumor growth factor beta (TGF-β

).

35. The method of claim 30, wherein the biomarker is stem cell factor (SCF).

36. The method of claim 30, wherein the biomarker is matrix metalloproteinase-3 (MMP-3).

37. The method of claim 30, wherein the biomarker is matrix metallopeptidase-9 (MMP-9).

38. The method of claim 30, wherein administration of the composition to the subject produces in the subject a Cmax of cromolyn from about 2.2 ng/mL to about 3.9 mg/mL per milligram of cromolyn sodium administered to the subject.

39. The method of claim 30, wherein the inhaler provides an aerosol of the composition having an RF (≤

5 μ

m) of at least about 65%.

40. The method of claim 1, wherein

(a) the mast cell stabilizer is cromolyn sodium;

(b) the composition is administered to the subject with an inhaler that provides an aerosol of the composition having an RF (≤

3.3 μ

m) of at least about 30%; and

(c) administration of the composition to the subject produces in the subject a Cmax of cromolyn of from about 2.2 ng/mL to about 3.9 mg/mL per milligram of cromolyn sodium administered to the subject.

41. The method of claim 40, wherein the inhaler is a high-efficiency nebulizer.

42. The method of claim 40, wherein the biomarker is tryptase.

43. The method of claim 40, wherein the biomarker is chymase.

44. The method of claim 40, wherein the biomarker is tumor growth factor beta (TGF-β

).

45. The method of claim 40, wherein the biomarker is stem cell factor (SCF).

46. The method of claim 40, wherein the biomarker is matrix metalloproteinase-3 (MMP-3).

47. The method of claim 40, wherein the biomarker is matrix metallopeptidase-9 (MMP-9).

48. The method of claim 40, wherein administration of the composition to the subject produces in the subject a Cmax of cromolyn of from about 2.2 ng/mL to about 3.9 mg/mL per milligram of cromolyn sodium administered to the subject.

49. The method of claim 40, wherein the inhaler provides an aerosol of the composition having an RF (≤

5 μ

m) of at least about 65%.