Method for Treating a Restless Limb Disorder

• US 20080274061A1
• Filed: 05/02/2008
• Published: 11/06/2008
• Est. Priority Date: 05/04/2007
• Status: Abandoned Application

• Current Assignee: UCB Pharma GmbH (UCB SA)
• Original Assignee: UCB Pharma GmbH (UCB SA)
• Inventors: Sachse, Richard, Schollmayer, Erwin, Braun, Marina
• Application Number:
  US12/114,348
• Publication Number:
  US 20080274061A1
• Time in Patent Office: Days
• US Class Current: 424/45
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/40 Cyclodextrins; Derivatives thereof
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A method for treating a restless limb disorder such as restless legs syndrome in a subject comprises administering, transmucosally in the oronasopharyngeal chamber of the subject, one or more doses of rotigotine or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein each such dose comprises an amount effective to reduce occurrence and/or severity of one or more symptoms of the disorder, but wherein the total of all such doses in a 24-hour period does not exceed about 450 μg rotigotine free base equivalent.

Claims

1. A method for treating a restless limb disorder in a subject, comprising administering, transmucosally in the oronasopharyngeal chamber of the subject, one or more doses of rotigotine or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein each such dose comprises an amount effective to reduce occurrence and/or severity of one or more symptoms of the disorder, but wherein the total of all such doses in a 24-hour period does not exceed about 450 μ

g rotigotine free base equivalent.

2. The method of claim 1, wherein the rotigotine or salt, prodrug or metabolite thereof is administered intranasally.

3. The method of claim 1, wherein the rotigotine or salt, prodrug or metabolite thereof is administered in monotherapy.

4. The method of claim 1, wherein the rotigotine or salt, prodrug or metabolite thereof is administered in co-therapy with another active agent for treatment of the disorder or a condition associated therewith.

5. The method of claim 1, wherein the subject is human.

6. The method of claim 5, wherein the disorder comprises restless legs syndrome (RLS).

7. The method of claim 6, wherein the dose of rotigotine or salt, prodrug or metabolite thereof is effective to reduce severity of sensory symptoms of RLS by at least about 1 point on a 0 to 10 scale within a period of about 4 hours after administration.

8. The method of claim 6, wherein the dose of rotigotine or salt, prodrug or metabolite thereof is effective to reduce severity of sensory symptoms of RLS by at least about 2 points on a 0 to 10 scale within a period of about 1 hour after administration.

9. The method of claim 6, wherein the dose of rotigotine or salt, prodrug or metabolite thereof is effective to effect improvement in sensory symptoms of RLS on a 0 to 10 scale within a period of about 20 minutes after administration.

10. The method of claim 6, wherein the dose of rotigotine or salt, prodrug or metabolite thereof is effective to reduce severity of motor symptoms of RLS by at least about 3 PLMWI points within a period of about 4 hours after administration.

11. The method of claim 6, wherein the dose of rotigotine or salt, prodrug or metabolite thereof is effective to reduce severity of motor symptoms of RLS by at least about 10 PLMWI points within a period of about 1 hour after administration.

12. The method of claim 5, wherein the disorder comprises periodic limb movement disorder (PLMD).

13. The method of claim 5, wherein the dosage amount is about 10 to about 450 μ

g rotigotine free base equivalent per administration.

14. The method of claim 5, wherein the dosage amount is about 100 to about 450 μ

g rotigotine free base equivalent per administration.

15. The method of claim 1, wherein the rotigotine or salt, prodrug or metabolite thereof is administered during or within about 2 hours prior to a period of relative immobilization of a limb or limbs affected by the disorder.

16. The method of claim 15, wherein the disorder is RLS and the rotigotine or salt, prodrug or metabolite thereof is administered during or within about 2 hours prior to a wakeful sedentary period or a sleep period.

17. The method of claim 1, wherein the rotigotine or salt, prodrug or metabolite thereof is administered as an active ingredient of an oronasopharyngeally deliverable pharmaceutical composition.

18. The method of claim 17, wherein the composition is formulated to deliver rotigotine in a manner effective to provide a maximum level of rotigotine in plasma of the subject within about 2 hours after administration.

19. The method of claim 17, wherein the composition is formulated to deliver rotigotine in a manner effective to provide a sufficient level of rotigotine in plasma of the subject to be efficacious in reducing one or more symptoms of the disorder for a period lasting at least about 2 hours.

20. The method of claim 17, wherein the composition is a sprayable liquid or insufflatable powder and is administered intranasally.

21. The method of claim 20, wherein the composition is administered in a metered dose from a nasal applicator.

22. The method of claim 21, wherein the composition is a sprayable liquid and the applicator comprises an atomization device.

23. The method of claim 17, wherein the composition comprises an acid addition salt of rotigotine in solution in an aqueous medium.

24. The method of claim 23, wherein the salt is rotigotine hydrochloride.

25. The method of claim 23, wherein the concentration of rotigotine free base equivalent in the composition is about 0.5 to about 5 mg/ml.

26. The method of claim 23, wherein a dosage volume of about 25 to about 250 μ

l of the composition provides a rotigotine free base equivalent dose of about 25 to about 450 μ

g.

27. The method of claim 23, wherein the aqueous medium further comprises a pharmaceutically acceptable solubility enhancing agent for the rotigotine salt.

28. The method of claim 27, wherein the solubility enhancing agent comprises α

-cyclodextrin.

29. The method of claim 28, wherein the concentration of α

-cyclodextrin in the composition is about 10 to about 100 mg/ml.

30. The method of claim 23, wherein the administration is intranasal and the composition so administered is one that (a) comprises, in an aqueous medium, an acid addition salt of rotigotine in a rotigotine free base equivalent concentration of about 0.5 to about 5 mg/ml, and α

-cyclodextrin in a concentration of about 10 to about 100 mg/ml;

or (b) is substantially bioequivalent thereto.

31. The method of claim 23, wherein the administration is intranasal and the composition so administered is one that (a) consists essentially of

rotigotine HCl, 2.5 mg/ml;

α

-cyclodextrin, 50 mg/ml;

glycerol, 31.2 mg/ml;

citric acid, q.s. for pH adjustment to approximately 5.8; and

PBS, q.s. to 1 ml;

or (b) is substantially bioequivalent thereto.

32. The method of claim 23, wherein the administration is intranasal and the composition so administered is one that (a) consists essentially of

rotigotine HCl, 1.25 mg/ml;

α

-cyclodextrin, 25 mg/ml;

glycerol, 31.2 mg/ml;

citric acid, q.s. for pH adjustment to approximately 5.8; and

PBS, q.s. to 1 ml;

or (b) is substantially bioequivalent thereto.

33. A pharmaceutical article comprising (a) a reservoir containing a composition that comprises, in a pharmaceutically acceptable vehicle, rotigotine or a pharmaceutically acceptable salt, prodrug or metabolite thereof in an amount providing one or more doses;

and (b) indicia, on the reservoir or in or on packaging thereof, for oronasopharyngeal administration of said one or more doses in an amount not exceeding about 450 μ

g rotigotine free base equivalent per day, for treatment of a restless limb disorder.

34. The article of claim 33, wherein the composition is formulated for intranasal administration.

35. The article of claim 33, wherein the reservoir is adapted for functional connection to a dispenser for dispensing a dosage unit of the composition from the reservoir as an aerosol, atomized spray, liquid drops or insufflatable powder.

36. The article of claim 33, further comprising a dispenser functionally connected or connectable to the reservoir for dispensing a dosage unit of the composition from the reservoir as an aerosol, atomized spray, liquid drops or insufflatable powder.

37. The article of claim 36, wherein the dispenser is adjusted or adjustable to deliver a metered dose.

38. A pharmaceutical dosage unit comprising, in a pharmaceutically acceptable vehicle, rotigotine or a pharmaceutically acceptable salt, prodrug or metabolite thereof in an amount of about 10 to about 450 μ

g rotigotine free base equivalent in an atomized oronasopharyngeally deliverable composition.

39. A pharmaceutical dosage unit comprising, in a pharmaceutically acceptable vehicle, rotigotine or a pharmaceutically acceptable salt, prodrug or metabolite thereof in an amount of about 10 to about 450 μ

g rotigotine free base equivalent, wherein the dosage unit has a pH of about 4.5 to about 6.0.

40. A pharmaceutical dosage unit comprising, in a pharmaceutically acceptable vehicle, rotigotine or a pharmaceutically acceptable salt, prodrug or metabolite thereof in an amount of about 10 to about 450 μ

g rotigotine free base equivalent, wherein the dosage unit is in a metered amount of about 40 to about 200 μ

l.

41. A pharmaceutical dosage unit comprising, in a pharmaceutically acceptable vehicle, rotigotine or a pharmaceutically acceptable salt, prodrug or metabolite thereof in an amount of about 10 to about 450 μ

g rotigotine free base equivalent, wherein the dosage unit has a viscosity of about 0.5 to about 1.5 mm²/s.

42. A pharmaceutical kit comprising (a) a composition that comprises, in a pharmaceutically acceptable vehicle, rotigotine or a pharmaceutically acceptable salt, prodrug or metabolite thereof in an amount providing one or more doses;

and (b) a document having indicia for oronasopharyngeal administration of said one or more doses in an amount not exceeding about 450 μ

g rotigotine free base equivalent per day, in treatment of a restless limb disorder.

44. The kit of claim 42, wherein at least the second dopamine agonist comprises rotigotine or a pharmaceutically acceptable salt, prodrug or metabolite thereof.

45. The kit of claim 42, wherein the first dopamine agonist comprises rotigotine or a pharmaceutically acceptable salt, prodrug or metabolite thereof, formulated for transdermal or parenteral administration, and the second dopamine agonist comprises rotigotine or a pharmaceutically acceptable salt, prodrug or metabolite thereof, formulated for intranasal administration.

47. The regimen of claim 45, wherein at least the second dopamine agonist comprises rotigotine or a pharmaceutically acceptable salt, prodrug or metabolite thereof.

48. The regimen of claim 45, wherein the first dopamine agonist comprises rotigotine or a pharmaceutically acceptable salt, prodrug or metabolite thereof and is administered transdermally or parenterally, and the second dopamine agonist comprises rotigotine or a pharmaceutically acceptable salt, prodrug or metabolite thereof and is administered intranasally.

50. The method of claim 48, wherein the dopamine agonist comprises amantadine, apomorphine, bromocriptine, cabergoline, carmoxirole, (S)-didesmethylsibutramine, dopexamine, fenoldopam, ibopamine, lergotrile, lisuride, memantine, mesulergine, pergolide, piribedil, pramipexole, quinagolide, ropinirole, rotigotine, roxindole, talipexole, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a combination thereof.

51. The method of claim 48, wherein the dopamine agonist comprises rotigotine or a pharmaceutically acceptable salt, prodrug or metabolite thereof.

52. The method of claim 48, wherein the dopamine agonist is administered intranasally.

43. A pharmaceutical kit comprising (a) an oral, transdermal or parenteral formulation comprising a first dopamine agonist in an amount effective for chronic treatment of a restless limb disorder;

and (b) an oronasopharyngeal formulation comprising a second dopamine agonist in an amount effective for p.r.n. treatment to reduce occurrence and/or severity of one or more breakthrough symptoms of the disorder;

wherein the first and second dopamine agonists are the same or different.

46. A regimen for managing a restless limb disorder in a subject, comprising (a) administering a first dopamine agonist to the subject by an oral, transdermal or parenteral route in an amount effective for chronic treatment of the disorder;

and (b) administering, transmucosally in the oronasopharyngeal chamber of the subject, a second dopamine agonist in an amount effective for p.r.n. treatment to reduce occurrence and/or severity of one or more breakthrough symptoms of the disorder;

wherein the first and second dopamine agonists are the same or different.

49. A method for treating intermittent RLS in a subject, comprising administering a dopamine agonist transmucosally in the oronasopharyngeal chamber of the subject, in an amount effective to reduce occurrence and/or severity of one or more RLS symptoms.