Methods for treating lower urinary tract disorders using alpha2delta subunit calcium channel modulators with smooth muscle modulators

• US 20040198822A1
• Filed: 03/22/2004
• Published: 10/07/2004
• Est. Priority Date: 03/21/2003
• Status: Abandoned Application

• Current Assignee: Dynogen Pharmaceuticals, Inc. (Edusa Pharmaceuticals, Inc.)
• Original Assignee: Dynogen Pharmaceuticals, Inc. (Edusa Pharmaceuticals, Inc.)
• Inventors: Thor, Karl Bruce, Landau, Steven B., Brettman, Lee R., Fraser, Matthew Oliver, Ricca, Daniel J., Burgard, Edward C.
• Application Number:
  US10/805,977
• Publication Number:
  US 20040198822A1
• Time in Patent Office: Days
• US Class Current: 514/561
• 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 31/195 having an amino group
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/12 Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10

Abstract

A method is provided for using α₂δ subunit calcium channel modulators or other compounds that interact with the α₂δ calcium channel subunit in combination with one or more compounds with smooth muscle modulatory effects to treat and/or alleviate the symptoms associated with painful and non-painful lower urinary tract disorders in normal and spinal cord injured patients. According to the present invention, α₂δ subunit calcium channel modulators include GABA analogs (e.g. gabapentin and pregabalin), fused bicyclic or tricyclic amino acid analogs of gabapentin, and amino acid compounds. Compounds with smooth muscle modulatory effects include antimuscarinics, β3 adrenergic agonists, spasmolytics, neurokinin receptor antagonists, bradykinin receptor antagonists, and nitric oxide donors.

Claims

1. A method for treating a lower urinary tract disorder characterized by having at least one symptom selected from the group consisting of urinary frequency, urinary urgency, and nocturia, which comprises administering to an individual in need thereof a therapeutically effective amount of a first component that is an α

₂δ

subunit calcium channel modulator, in combination with a second component that is a smooth muscle modulator.

2. The method of claim 1, wherein said first component and said second component are contained within a single pharmaceutical formulation.

3. The method of claim 1, wherein said first component and said second component are contained within separate pharmaceutical formulations.

4. The method of claim 3, wherein said first component and said second component are administered concurrently.

5. The method of claim 3, wherein said first component and said second component are administered sequentially.

6. The method of claim 1, wherein the α

₂δ

subunit calcium channel modulator is a GABA analog.

7. The method of claim 6, wherein the GABA analog is Gabapentin or an acid, salt, enantiomer, analog, ester, amide, prodrug, active metabolite, or derivative thereof.

8. The method of claim 6, wherein the GABA analog is Pregabalin or an acid, salt, enantiomer, analog, ester, amide, prodrug, active metabolite, or derivative thereof.

9. The method of claim 1, wherein said smooth muscle modulator is selected from the group consisting of:

antimuscarinics, β

3 adrenergic agonists, spasmolytics, neurokinin receptor antagonists, bradykinin receptor antagonists, and nitric oxide donors.

10. The method of claim 9, wherein said smooth muscle modulator is an antimuscarinic.

11. The method of claim 10, wherein the antimuscarinic is Oxybutynin or an acid, salt, enantiomer, analog, ester, amide, prodrug, active metabolite, or derivative thereof.

12. The method of claim 10, wherein the antimuscarinic is Tolterodine or an acid, salt, enantiomer, analog, ester, amide, prodrug, active metabolite, or derivative thereof.

13. The method of claim 10, wherein the antimuscarinic is Propiverine or an acid, salt, enantiomer, analog, ester, amide, prodrug, active metabolite, or derivative thereof.

14. The method of claim 10, wherein the antimuscarinic is Solifenacin monohydrochloride or an acid, salt, enantiomer, analog, ester, amide, prodrug, active metabolite, or derivative thereof.

15. The method of claim 1, wherein said α

₂δ

subunit calcium channel modulator is Gabapentin or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof, and wherein said smooth muscle modulator is Oxybutynin or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof.

16. The method of claim 1, wherein said α

₂δ

subunit calcium channel modulator is Pregabalin or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof, and wherein said smooth muscle modulator is Oxybutynin or acids, salts, enantiomers, analogs, esters, amides, prodrugs, active metabolites, and derivatives thereof.

17. The method of claim 1, wherein said first component and said second component are administered on an as-needed basis.

18. The method of claim 1, wherein said first component and said second component are administered prior to commencement of an activity wherein suppression of the symptoms of a lower urinary tract disorder would be desirable.

19. The method of claim 18, wherein said first component and said second component are administered from about 0 to about 3 hours prior to commencement of an activity wherein suppression of said symptoms would be desirable.

20. The method of claim 1, wherein said first component and said second component are administered orally, transmucosally, sublingually, buccally, intranasally, transurethrally, rectally, by inhalation, topically, transdermally, parenterally, intrathecally, vaginally, or perivaginally.

21. The method of claim 1, wherein said first component and said second component are administered to treat overactive bladder or the irritative or obstructive symptoms of benign prostatic hyperplasia.

22. The method of claim 1, wherein said first component and said second component are administered to treat urinary frequency.

23. The method of claim 1, wherein said first component and said second component are administered to treat urinary urgency.

24. The method of claim 1, wherein said first component and said second component are administered to treat nocturia.

25. The method of claim 1, wherein at least one detrimental side effect associated with single administration of said first component or single administration of said second component is lessened by concurrent administration of said first component and said second component.

26. The method of claim 25 wherein said first component and said second component are administered to treat overactive bladder or the irritative or obstructive symptoms of benign prostatic hyperplasia.

27. A method for treating a lower urinary tract disorder characterized by having at least one symptom selected from the group consisting of urinary frequency, urinary urgency, and nocturia, comprising administering to an individual in need thereof a therapeutically effective amount of at least one component selected from an α

₂δ

subunit calcium channel modulator and a smooth muscle modulator.

28. A pharmaceutical composition comprising a first component that is an α

₂δ

subunit calcium channel modulator, in combination with a second component that is a smooth muscle modulator, wherein said first component and said second component are in amounts sufficient to treat a lower urinary tract disorder characterized by having at least one symptom selected from the group consisting of urinary frequency, urinary urgency, and nocturia.

29. A pharmaceutical composition comprising a first component that is Gabapentin or pharmaceutically acceptable acids, salts, esters, amides, prodrugs, or active metabolites thereof, in combination with a second component that is Oxybutynin or pharmaceutically acceptable acids, salts, esters, amides, prodrugs, or active metabolites thereof, wherein said first component and said second component are in amounts sufficient to treat a lower urinary tract disorder characterized by having at least one symptom selected from the group consisting of urinary frequency, urinary urgency, and nocturia.

30. The pharmaceutical composition of claim 29 wherein said first component is present in an amount from about 50 mg to about 2400 mg, and wherein said second component is present in an amount equal to or less than about 5 mg.

31. The pharmaceutical composition of claim 30 wherein said first component is in an amount of about 200 mg.

32. The pharmaceutical composition of claim 30 wherein said second component is in an amount of about 2.5 mg.

33. The pharmaceutical composition of claim 30 wherein said second component is in an amount of about 1.25 mg.

34. A pharmaceutical composition comprising a first component that is Pregabalin or pharmaceutically acceptable acids, salts, esters, amides, prodrugs, or active metabolites thereof, in combination with a second component that is Oxybutynin or pharmaceutically acceptable acids, salts, esters, amides, prodrugs, or active metabolites thereof, wherein said first component and said second component are in amounts sufficient to treat a lower urinary tract disorder characterized by having at least one symptom selected from the group consisting of urinary frequency, urinary urgency, and nocturia.

35. A pharmaceutical composition for the treatment of a lower urinary tract disorder characterized by having at least one symptom selected from the group consisting of urinary frequency, urinary urgency, and nocturia, comprising a first component that is Gabapentin or pharmaceutically acceptable acids, salts, esters, amides, prodrugs, or active metabolites thereof, in combination with a second component that is Oxybutynin or pharmaceutically acceptable acids, salts, esters, amides, prodrugs, or active metabolites thereof, wherein said first component and said second component are present in a ratio from about 1:

1 to about 800;

1 or from about 1;

1 to about 1;

800, respectively, based on a fraction of their respective ED₅₀ values.

36. A combination for the treatment of a lower urinary tract disorder characterized by having at least one symptom selected from the group consisting of urinary frequency, urinary urgency, and nocturia, comprising a first component that is Gabapentin or pharmaceutically acceptable acids, salts, esters, amides, prodrugs, or active metabolites thereof, in combination with a second component that is Oxybutynin or pharmaceutically acceptable acids, salts, esters, amides, prodrugs, or active metabolites thereof, wherein said first component and said second component are in a weight/weight ratio of from 1:

1 to about 800;

1 or from about 1;

1 to about 1;

800, respectively.

37. A pharmaceutical composition comprising Oxybutynin, wherein said Oxybutynin is in an amount less than about 2.5 mg.

38. A packaged kit for a patient to use in the treatment of a lower urinary tract disorder characterized by having at least one symptom selected from the group consisting of urinary frequency, urinary urgency, and nocturia, comprising:

at least one component selected from an α

₂δ

subunit calcium channel modulator and a smooth muscle modulator;

a container housing said component or components during storage and prior to administration; and

instructions for carrying out drug administration of an α

₂δ

subunit calcium channel modulator with a smooth muscle modulator in a manner effective to treat said lower urinary tract disorder.

39. The packaged kit of claim 38 wherein said first component and said second component are contained in the same pharmaceutical formulation.

40. The packaged kit of claim 39 wherein said first component is Gabapentin or pharmaceutically acceptable acids, salts, esters, amides, prodrugs, or active metabolites thereof, and wherein said second component is Oxybutynin or pharmaceutically acceptable acids, salts, esters, amides, prodrugs, or active metabolites thereof.

41. The packaged kit of claim 38 wherein said first component and said second component are contained in separate pharmaceutical formulations.

42. The packaged kit of claim 41 wherein said instructions include directions for carrying out drug administration of said first component and said second component sequentially or concurrently.

43. The packaged kit of claim 42 wherein said first component is Gabapentin or pharmaceutically acceptable acids, salts, esters, amides, prodrugs, or active metabolites thereof, and wherein said second component is Oxybutynin or pharmaceutically acceptable acids, salts, esters, amides, prodrugs, or active metabolites thereof.