MODIFIED AND IMMEDIATE RELEASE FORMULATIONS OF MEMANTINE

• US 20070065512A1
• Filed: 06/14/2006
• Published: 03/22/2007
• Est. Priority Date: 06/16/2005
• Status: Abandoned Application

• Current Assignee: Forest Laboratories Holdings Limited (Abbvie Incorporated)
• Original Assignee: Forest Laboratories Incorporated (Abbvie Incorporated)
• Inventors: Dedhiya, Mahendra, Chhettry, Anil, Periclou, Antonia, Rao, Niranjan, Mani, Narasimhan, Rastogi, Suneel
• Application Number:
  US11/424,024
• Publication Number:
  US 20070065512A1
• Time in Patent Office: Days
• US Class Current: 424/469
• CPC Class Codes: A61K 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/485 Inorganic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61K 9/50 Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

The present invention provides immediate release and modified release oral dosage forms. Specifically, the invention provides modified and immediate release pharmaceutical dosage forms containing memantine that exhibit an enhanced release profile and provide reliable absorption. The dosage forms may be used to treat mild, moderate or severe Alzheimer'"'"'s disease or neuropathic pain.

Claims

1. An oral dosage form comprising memantine or a salt thereof, wherein the dosage form comprises 2.5 to 100 mg of memantine or a salt thereof and provides an in vivo plasma profile comprising:

a mean Tmax of about 8 or more hours;

a mean Cmax of less than about 100 ng/ml; and

a mean AUC_0-∞

of more than about 250 ng h/ml.

2. The oral dosage form according to claim 1, wherein the Cmax is less than about 75 ng/ml.

3. The oral dosage form according to claim 1, wherein the Cmax is less than about 50 ng/ml.

4. The oral dosage form according to claim 1, wherein the mean AUC_0-∞

is more than about 500 ng h/ml.

5. The oral dosage form according to claim 1, wherein the mean AUC_0-∞

is more than about 1000 ng h/ml.

54. A method for treating a condition selected from the group selected from Alzheimer'"'"'s disease, autism and neuropathic pain comprising administering to a patient in need thereof the oral dosage form of claim 1.

6. An oral dosage form comprising memantine or a salt thereof, wherein the dosage form comprises 2.5 to 50 mg of memantine or a salt thereof and provides an in vivo plasma profile comprising:

a mean Tmax of about 5 or more hours;

a mean Cmax of less than about 50 ng/ml; and

a mean AUC_0-∞

of more than about 250 ng h/ml.

7. The oral dosage form according to claim 6, wherein the mean AUC_0-∞

is more than about 500 ng h/ml.

8. The oral dosage form according to claim 6, wherein the mean AUC_0-∞

is more than about 1000 ng h/ml.

55. A method for treating a condition selected from the group selected from Alzheimer'"'"'s disease, autism and neuropathic pain comprising administering to a patient in need thereof the oral dosage form of claim 6.

9. An oral dosage form comprising 2.5 to 100 mg memantine or a salt thereof wherein the dosage form has a dissolution rate of the active ingredient of about 70% to about 80% within about 4 hours to about 24 hours and a C_max of less than about 100 ng/ml, wherein the dosage form provides a reduced incidence of adverse events.

56. A method for treating a condition selected from the group selected from Alzheimer'"'"'s disease, autism and neuropathic pain comprising administering to a patient in need thereof the oral dosage form of claim 9.

10. An oral dosage form comprising a plurality of beads, wherein each bead comprises:

a core having a diameter from about 1 μ

m to about 1000 μ

m and an active ingredient comprising memantine or a salt thereof in the range of about 15 to about 350 mg/g of the dosage form,

wherein the oral dosage form has a dissolution rate of the active ingredient of more than about 80% within about the first 60 minutes following entry of the dosage form into a use environment.

11. The oral dosage form according to claim 10, wherein the dissolution rate of the active ingredient is more than about 80% within about the first 30 minutes following entry of the dosage form into a use environment.

12. The oral dosage form according to claim 10, wherein the dissolution rate of the active ingredient is more than about 80% within about the first 15 minutes following entry of the dosage form into a use environment.

13. The oral dosage form according to claim 10, wherein the active ingredient comprises memantine hydrochloride.

14. The oral dosage form according to claim 10, wherein the dosage form exhibits dose-proportionality.

15. The oral dosage form according to claim 10, wherein the dosage form includes less than about 2.5% adduct

16. The oral dosage form according to claim 10, wherein the active ingredient comprises memantine or a salt thereof in the range of about 15 to about 300 mg/g of the dosage form.

17. The oral dosage form according to claim 10, wherein the active ingredient comprises memantine or a salt thereof in the range of about 25 to about 250 mg/g of the dosage form.

18. The oral dosage form according to claim 10, wherein the core comprise a sugar particle, USP, comprising from about 100 to about 950 mg/g of said dosage form.

19. The oral dosage form according to claim 10, further comprising a glidant in an amount of about 1.5 to about 35 mg/g of said dosage form.

20. The oral dosage form according to claim 19, wherein the glidant is present in an amount from about 5 mg/g to about 30 mg/g.

21. The oral dosage form according to claim 10, wherein the bead dosage forms are compressed into a tablet form.

22. The oral dosage form according to claim 10, further comprising a polymer binder coated on the core.

23. The oral dosage form according to claim 22, wherein the polymer binder is selected from the group consisting of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and combinations thereof.

24. The oral dosage form according to claim 22, wherein the polymer binder is hydroxypropyl methylcellulose in an amount from about 15 to about 30 mg/g of the dosage form.

25. The oral dosage form according to claim 22, wherein the polymer binder is povidone an amount from about 1.5 to about 35 mg/g of the dosage form.

26. The oral dosage form according to claim 22, further comprising a seal coating applied over the polymer binder.

27. The oral dosage form according to claim 26, wherein the seal coating is selected from the group consisting of HPMC (Opadry®

), HPC, Eudragit®

RL, Eudragit®

E100, Eudragit®

E 12.5, Eudragit®

E PO, Eudragit®

NE, and mixtures thereof.

28. The oral dosage form according to claim 26, wherein the seal coating is present in amounts ranging from about 2% w/w to about 40% w/w.

29. The oral dosage form according to claim 10, wherein the core comprises a sugar sphere or a microcrystalline cellulose sphere in the range of 620-930 mg/g of the dosage form and each bead further comprises:

Ingredients Range (mg/g) Povidone, USP 1.5-35 Talc, USP 1.5-35

30. The oral dosage form according to claim 10, wherein the core comprises a sugar sphere or a microcrystalline cellulose sphere in the range of 700-850 mg/g of the dosage form, the active ingredient comprises memantine or a salt thereof in the range of about 50 to 300 mg/g of the dosage form and wherein each bead further comprises:

Ingredients Range (mg/g) Povidone, USP 5-30 Talc, USP 5-30

31. The oral dosage form according to claim 10, wherein the core comprises a sugar sphere or a microcrystalline cellulose sphere in the range of 500-950 mg/g of the dosage form, the active ingredient comprises memantine or a salt thereof in the range of about 15 to 300 mg/g of the dosage form and wherein each bead further comprises:

Ingredients Range (mg/g) Hydroxypropyl Methylcellulose (Opadry)  

15-300 Talc, USP 1.5-30 

32. The oral dosage form according to claim 10, wherein the core comprises a sugar sphere or a microcrystalline cellulose sphere in the range of 550-850 mg/g of the dosage form, the active ingredient comprises memantine or a salt thereof in the range of about 25 to 250 mg/g of the dosage form and wherein each bead further comprises:

Ingredients Range (mg/g) Hydroxypropyl Methylcellulose (Opadry)  

15-250 Talc, USP 2.5-25 

57. A method for treating a condition selected from the group selected from Alzheimer'"'"'s disease, autism and neuropathic pain comprising administering to a patient in need thereof the oral dosage form of claim 10.

33. An oral dosage form comprising a plurality of beads, each bead comprising

a core having a diameter from about 1 μ

m to about 1000 μ

m;

an active ingredient comprising memantine or a salt thereof in the range of about 15 to about 350 mg/g of the dosage form; and

a release modifying polymer layer,

wherein the oral dosage form has a dissolution rate of the active ingredient of about 70% to about 80% within about 4 hours to about 24 hours; and

wherein the Cmax is less than about 100 ng/ml.

34. The oral dosage form according to claim 33, wherein the dosage form releases the active ingredient for a period of time from about 6 hours to about 48 hours following entry of the dosage form into a use environment.

35. The oral dosage form according to claim 33, wherein the dosage form has a dissolution rate of the active ingredient of about 30% to about 60% within about 2 hours to about 6 hours.

36. The oral dosage form according to claim 33, wherein the dosage form has a dissolution rate of the active ingredient of about 10% to about 50% within about 1 hour.

37. The oral dosage form according to claim 33, wherein the active ingredient comprises memantine hydrochloride.

38. The oral dosage form according to claim 33, wherein the bead dosage forms are compressed into a tablet form.

39. The oral dosage form according to claim 33, wherein the release modifying polymer is selected from the group consisting of ethylcellulose (Surelease®

), methacrylate (Eudragit®

), methacrylic acid copolymer type C (Acryl-ezeo), and mixtures thereof.

40. The oral dosage form according to claim 33, further comprising an intermediate seal coating over the active ingredient.

41. The oral dosage form according to claim 33, further comprising an over coating coated on the release modifying polymer layer.

42. The oral dosage form according to claim 41, wherein the over coating is selected from the group consisting of HPMC (Opadry®

), HPC, Eudragit®

RL, Eudragit®

E200, Eudragit®

E 12.5, Eudragit®

E PO, Eudragit®

NE, and mixtures thereof.

43. The oral dosage form according to claim 33, wherein the dosage form includes less than about 2.5% adduct.

44. The oral dosage form according to claim 33, wherein the core comprises a sugar sphere or a microcrystalline cellulose sphere in the range of 500-900 mg/g of the dosage form, the active ingredient comprises memantine or a salt thereof in the range of about 15 to 350 mg/g of the dosage form and wherein each bead further comprises:

Ingredients Range(mg/g) Povidone, USP 1.5-35 

Talc, USP 1.5-35 

Ethylcellulose (Surelease 

®

) 100-450 (25% Solid content) Hydroxypropyl Methylcellulose 15-30 (Opadry 

®

)

45. The oral dosage form according to claim 33, wherein the core comprises a sugar sphere or a microcrystalline cellulose sphere in the range of 625-800 mg/g of the dosage form, the active ingredient comprises memantine or a salt thereof in the range of about 50 to 285 mg/g of the dosage form and wherein each bead further comprises:

Ingredients Range(mg/g) Povidone, USP  

5-30 Talc, USP  

5-30 Ethylcellulose (Surelease 

®

) 110-430 (25% Solid content) Hydroxypropyl Methylcellulose 15-25 (Opadry 

®

)

46. The oral dosage form according to claim 33, wherein the core comprises a sugar sphere or a microcrystalline cellulose sphere in the range of 580-850 mg/g of the dosage form, the active ingredient comprises memantine or a salt thereof in the range of about 15 to 325 mg/g of the dosage form and wherein each bead further comprises:

Ingredients Range(mg/g) Povidone, USP 1.5-32 

Talc, USP 1.5-32 

Ethylcellulose (Surelease 

®

) (25% 212-232 Solid content) HPMC (Opadry 

®

) 15-30

47. The oral dosage form according to claim 33, wherein the core comprises a sugar sphere or a microcrystalline cellulose sphere in the range of 625-780 mg/g of the dosage form, the active ingredient comprises memantine or a salt thereof in the range of about 30 to 280 mg/g of the dosage form and wherein each bead further comprises:

Ingredients Range (mg/g) Povidone, USP  

3-28 Talc, USP  

3-28 Ethylcellulose (Surelease 

®

) (25% 212-232 Solid content) HPMC (Opadry 

®

) 15-25

48. The oral dosage form according to claim 33, wherein the core comprises a sugar sphere or a microcrystalline cellulose sphere in the range of 625-780 mg/g of the dosage form, the active ingredient comprises memantine or a salt thereof in the range of about 30 to 280 mg/g of the dosage form and wherein each bead further comprises:

Ingredients Range (mg/g) Povidone, USP  

3-28 Talc, USP  

3-28 Ethylcellulose (Surelease 

®

) (25% 231-430 Solid content) HPMC (Opadry 

®

) 15-25

49. The oral dosage form according to claim 33, wherein the core comprises a sugar sphere or a microcrystalline cellulose sphere in the range of 400-750 mg/g of the dosage form, the active ingredient comprises memantine or a salt thereof in the range of about 15 to 300 mg/g of the dosage form and wherein each bead further comprises:

Ingredients Range (mg/g) Opadry 

®

Clear 15-300 Talc, USP 1-30 Opadry 

®

Clear 10-30 

Ammonio Methacrylate Copolymer NF 75-175 (Eudragit) Ammonio Methacrylate Copolymer NF 0.1-26 

 

Type A, (Eudragit) Triethyl Citrate, NF 2-30 Talc, USP 1-70 Opadry 

®

Clear 10-30 

50. The oral dosage form according to claim 33, wherein the core comprises a sugar sphere or a microcrystalline cellulose sphere in the range of 400-750 mg/g of the dosage form, the active ingredient comprises memantine or a salt thereof in the range of about 15 to 300 mg/g of the dosage form and wherein each bead further comprises:

Ingredients Range (mg/g) Opadry 

®

Clear 15-300 Talc, USP 1-30 Opadry 

®

Clear 10-30 

Ammonio Methacrylate Copolymer NF 235-314 

(Eudragit) Ammonio Methacrylate Copolymer NF 5-48 Type A, (Eudragit) Triethyl Citrate, NF 6-47 Talc, USP 50-120 Opadry 

®

Clear 10-30 

58. A method for treating a condition selected from the group selected from Alzheimer'"'"'s disease, autism and neuropathic pain comprising administering to a patient in need thereof the oral dosage form of claim 33.

51. A composite dosage form comprising an immediate release component and a modified release component,

wherein the immediate release component comprises a first plurality of beads, each bead comprising a first active ingredient comprising memantine or a salt thereof in the range of about 15 to about 350 mg/g of the dosage form, wherein about 80% of the first active ingredient dissolves within about the first 60 minutes following entry of the dosage form into a use environment;

and

wherein the modified release component comprises a second plurality of beads, each bead comprising a second active ingredient comprising memantine or a salt thereof in the range of about 15 to about 350 mg/g of the dosage form, wherein about 70% to about 80% of the second active ingredient dissolves within about 4 hours to about 24 hours following entry of the dosage form into the use environment.

52. The composite dosage form of claim 51, wherein the composite dosage form is compressed into a tablet form.

53. The composite dosage form of claim 51, wherein the composite dosage form comprises from about 2.5 mg to about 100 mg of memantine.

59. A method for treating a condition selected from the group selected from Alzheimer'"'"'s disease, autism and neuropathic pain comprising administering to a patient in need thereof the oral dosage form of claim 51.