Methods for the treatment of mast cell related disorders with mast cell stabilizers

• US 10,238,625 B2
• Filed: 08/05/2016
• Issued: 03/26/2019
• Est. Priority Date: 08/07/2015
• Status: Active Grant

• Current Assignee: Respivant Sciences GmbH
• Original Assignee: Respivant Sciences GmbH
• Inventors: Gerhart, William, Soni, Pravin, Tutuncu, Ahmet
• Primary Examiner(s): Gembeh, Shirley V
• Application Number:
  US15/750,809
• Publication Number:
  US 20180228761A1
• Time in Patent Office: 963 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

Abstract

Methods for the treatment of systemic mast cell related 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 a composition comprising cromolyn, or a salt thereof;

wherein the composition is administered to the subject using a high-efficiency nebulizer and produces in the subject an AUC<sub>(0-∞

)</sub> of cromolyn greater than about 5.3 ng*h/mL per milligram of cromolyn, or a salt thereof, administered to the subject; and

wherein the mast cell related disorder is selected from primary biliary cirrhosis, secondary sclerosing cholangitis due to mast cell cholangiopathy, itching caused by or associated with primary biliary cirrhosis, bronchiolitis obliterans syndrome after lung transplantation, bronchopulmonary dysplasia in infants, cardiac fibrosis, atrial fibrosis, primary sclerosing cholangitis (PSC), chronic pelvic pain syndrome (prostatitis), viral pneumonia caused by respiratory syncytial virus, and interstitial lung disease.

2. The method of claim 1, wherein the mast cell related disorder is selected from primary biliary cirrhosis, secondary sclerosing cholangitis due to mast cell cholangiopathy, itching caused by or associated with primary biliary cirrhosis, primary sclerosing cholangitis (PSC), interstitial lung disease and bronchopulmonary dysplasia in infants.

3. The method of claim 1, wherein the salt of cromolyn is selected from cromolyn sodium, cromolyn lysinate, ammonium cromoglycate, and magnesium cromoglicate.

4. The method of claim 3, wherein the salt of cromolyn is cromolyn sodium.

5. The method of claim 4, wherein the composition comprises greater than about 2% cromolyn sodium.

6. The method of claim 5, wherein the composition comprises greater than about 4% cromolyn sodium.

7. The method of claim 6, wherein the composition comprises greater than about 6% cromolyn sodium.

8. The method of claim 4, wherein the composition comprises from about 1 mg to about 120 mg of cromolyn sodium.

9. The method of claim 4, wherein the composition comprises from about 20 mg to about 60 mg of cromolyn sodium.

10. The method of claim 4, wherein the composition comprises from about 30 mg to about 50 mg of cromolyn sodium.

11. The method of claim 3, wherein the mast cell related disorder is selected from primary biliary cirrhosis, secondary sclerosing cholangitis due to mast cell cholangiopathy, itching caused by or associated with primary biliary cirrhosis, primary sclerosing cholangitis (PSC), interstitial lung disease and bronchopulmonary dysplasia in infants.

12. The method of claim 4, wherein the mast cell related disorder is selected from primary biliary cirrhosis, secondary sclerosing cholangitis due to mast cell cholangiopathy, itching caused by or associated with primary biliary cirrhosis, primary sclerosing cholangitis (PSC), interstitial lung disease and bronchopulmonary dysplasia in infants.

13. The method of claim 1, wherein the high-efficiency nebulizer produces an aerosol of the composition having an RF (≤

3.3 μ

m) of at least about 30%.

14. The method of claim 13, wherein the aerosol further has an RF (≤

5 μ

m) of at least about 65%.

15. The method of claim 1, wherein administration of the composition produces in the subject an AUC_(0-∞

) of cromolyn greater than about 6.6 ng*h/mL per milligram of cromolyn, or a salt thereof, administered to the subject.

16. The method of claim 15, wherein administration of the composition to the subject further produces in the subject a C_max of cromolyn greater than about 2.2 ng/mL per milligram of cromolyn, or a salt thereof, administered to the subject.

17. The method of claim 15, wherein administration of the composition to the subject further produces in the subject a C_max of cromolyn greater than about 3 ng/mL per milligram of cromolyn, or a salt thereof, administered to the subject.

18. The method of claim 15, wherein administration of the composition to the subject further produces in the subject a C_max of cromolyn greater than about 3.9 ng/mL per milligram of cromolyn, or a salt thereof, administered to the subject.

19. The method of claim 1, wherein administration of the composition produces in the subject an AUC_(0-∞

) of cromolyn greater than about 8.5 ng*h/mL per milligram of cromolyn, or a salt thereof, administered to the subject.

20. The method of claim 19, wherein administration of the composition to the subject further produces in the subject a C_max of cromolyn greater than about 2.2 ng/mL per milligram of cromolyn, or a salt thereof, administered to the subject.

21. The method of claim 19, wherein administration of the composition to the subject further produces in the subject a C_max of cromolyn greater than about 3 ng/mL per milligram of cromolyn, or a salt thereof, administered to the subject.

22. The method of claim 19, wherein administration of the composition to the subject further produces in the subject a C_max of cromolyn greater than about 3.9 ng/mL per milligram of cromolyn, or a salt thereof, administered to the subject.

23. The method of claim 1 and wherein the composition has an osmolality of between about 30 mOsm/kg to about 145 mOsm/kg.

24. The method of claim 1, wherein administration of the composition to the subject further produces in the subject a C_max of cromolyn greater than about 2.2 ng/mL per milligram of cromolyn, or a salt thereof, administered to the subject.

25. The method of claim 1, wherein administration of the composition to the subject further produces in the subject a C_max of cromolyn greater than about 3 ng/mL per milligram of cromolyn, or a salt thereof, administered to the subject.

26. The method of claim 1, wherein administration of the composition to the subject further produces in the subject a C_max of cromolyn greater than about 3.9 ng/mL per milligram of cromolyn, or a salt thereof, administered to the subject.

27. The method of claim 1, wherein the mast cell related disorder is primary sclerosing cholangitis (PSC).

28. The method of claim 1, wherein the mast cell related disorder is interstitial lung disease.

29. The method of claim 1, wherein the mast cell related disorder is bronchopulmonary dysplasia in infants.

30. A method of treating a subject having a mast cell related disorder, comprising administering to the subject a composition comprising cromolyn, or a salt thereof;

wherein the composition is administered to the subject using a high-efficiency nebulizer and produces in the subject a C_max of cromolyn greater than about 2.2 ng/mL per milligram of cromolyn, or a salt thereof, administered to the subject; and

wherein the mast cell related disorder is selected from primary biliary cirrhosis, secondary sclerosing cholangitis due to mast cell cholangiopathy, itching caused by or associated with primary biliary cirrhosis, bronchiolitis obliterans syndrome after lung transplantation, bronchopulmonary dysplasia in infants, cardiac fibrosis, atrial fibrosis, primary sclerosing cholangitis (PSC), chronic pelvic pain syndrome (prostatitis), viral pneumonia caused by respiratory syncytial virus, and interstitial lung disease.

31. The method of claim 30, wherein administration of the composition to the subject produces in the subject a C_max of cromolyn greater than about 3 ng/mL per milligram of cromolyn, or a salt thereof, administered to the subject.

32. The method of claim 31, wherein the mast cell related disorder is selected from primary biliary cirrhosis, secondary sclerosing cholangitis due to mast cell cholangiopathy, itching caused by or associated with primary biliary cirrhosis, primary sclerosing cholangitis (PSC), interstitial lung disease and bronchopulmonary dysplasia in infants.

33. The method of claim 30, wherein administration of the composition to the subject produces in the subject a C_max of cromolyn greater than about 3.9 ng/mL per milligram of cromolyn, or a salt thereof, administered to the subject.

34. The method of claim 33, wherein the mast cell related disorder is selected from primary biliary cirrhosis, secondary sclerosing cholangitis due to mast cell cholangiopathy, itching caused by or associated with primary biliary cirrhosis, primary sclerosing cholangitis (PSC), interstitial lung disease and bronchopulmonary dysplasia in infants.

35. The method of claim 30, wherein the salt of cromolyn is selected from cromolyn sodium, cromolyn lysinate, ammonium cromoglycate, and magnesium cromoglicate.

36. The method of claim 35, wherein the salt of cromolyn is cromolyn sodium.

37. The method of claim 35, wherein the mast cell related disorder is selected from primary biliary cirrhosis, secondary sclerosing cholangitis due to mast cell cholangiopathy, itching caused by or associated with primary biliary cirrhosis, primary sclerosing cholangitis (PSC), interstitial lung disease and bronchopulmonary dysplasia in infants.

38. The method of claim 36, wherein the mast cell related disorder is selected from primary biliary cirrhosis, secondary sclerosing cholangitis due to mast cell cholangiopathy, itching caused by or associated with primary biliary cirrhosis, primary sclerosing cholangitis (PSC), interstitial lung disease and bronchopulmonary dysplasia in infants.

39. The method of claim 30, wherein the high-efficiency nebulizer produces an aerosol of the composition having an RF (≤

3.3 μ

m) of at least about 30%.

40. The method of claim 39, wherein the aerosol further has an RF (≤

5 μ

m) of at least about 65%.

41. The method of claim 30, wherein the mast cell related disorder is selected from primary biliary cirrhosis, secondary sclerosing cholangitis due to mast cell cholangiopathy, itching caused by or associated with primary biliary cirrhosis, primary sclerosing cholangitis (PSC), interstitial lung disease and bronchopulmonary dysplasia in infants.

42. The method of claim 30, wherein the mast cell related disorder is primary sclerosing cholangitis (PSC).

43. The method of claim 30, wherein the mast cell related disorder is interstitial lung disease.

44. The method of claim 30, wherein the mast cell related disorder is bronchopulmonary dysplasia in infants.

45. A method of treating a subject having a mast cell related disorder, comprising administering to the subject a composition comprising cromolyn sodium;

wherein the composition is administered to the subject using a high-efficiency nebulizer and produces in the subject a C_max of cromolyn greater than about 2.2 ng/mL per milligram of cromolyn sodium administered to the subject and an AUC<sub>(0-∞

)</sub> of cromolyn greater than about 5.3 ng*h/mL per milligram of cromolyn sodium administered to the subject;

wherein the high-efficiency nebulizer produces an aerosol of the composition having an RF (≤

3.3 μ

m) of at least about 30% and an RF (≤

5 μ

m) of at least about 65%; and

wherein the mast cell related disorder is selected from primary biliary cirrhosis, secondary sclerosing cholangitis due to mast cell cholangiopathy, itching caused by or associated with primary biliary cirrhosis, bronchiolitis obliterans syndrome after lung transplantation, bronchopulmonary dysplasia in infants, cardiac fibrosis, atrial fibrosis, primary sclerosing cholangitis (PSC), chronic pelvic pain syndrome (prostatitis), viral pneumonia caused by respiratory syncytial virus, and interstitial lung disease.

46. The method of claim 45, wherein the mast cell related disorder is selected from primary biliary cirrhosis, secondary sclerosing cholangitis due to mast cell cholangiopathy, itching caused by or associated with primary biliary cirrhosis, primary sclerosing cholangitis (PSC), interstitial lung disease and bronchopulmonary dysplasia in infants.