Pharmaceutical formulations of amyloid inhibiting compounds

• US 20060251714A1
• Filed: 04/12/2006
• Published: 11/09/2006
• Est. Priority Date: 04/12/2005
• Status: Abandoned Application

• Current Assignee: Bellus Health (Interational) Limited (GSK plc)
• Original Assignee: Bellus Health (Interational) Limited (GSK plc)
• Inventors: Garceau, Denis, Laurin, Julie
• Application Number:
  US11/402,267
• Publication Number:
  US 20060251714A1
• Time in Patent Office: Days
• US Class Current: 424/464
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/2886 having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer of the type active core-drug layer-inactive layer A61K9/209
• CPC Class Codes: A61K 9/485 Inorganic compounds
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Therapeutic formulations and methods for inhibiting amyloid deposition in a subject, whatever its clinical setting, are described. Therapeutic formulations and methods for preventing or treating amyloidosis and/or amyloid-related disease are also described.

Claims

1. An oral formulation comprising an active agent which is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent Alzheimer'"'"'s disease and/or Cerebral Amyloid Angiopathy (CAA), and a pharmaceutically acceptable vehicle,

wherein, when the formulation is administered to a subject, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about from 814 to 6604 ng·

h/mL and a mean Cmax of about from 137 to 1235 ng/mL is achieved.

16. A formulation of claim 1, wherein the formulation is in a form effective for osmotic release, pulsatile release, sustained release, controlled release, extended release or delayed release of the active agent.

17. A method of treating or preventing Alzheimer'"'"'s disease comprising administering to a patient in need thereof an oral formulation of claim 1.

18. The method of claim 17 for treating Alzheimer'"'"'s disease.

19. The method of claim 17, further comprising administering another therapeutic agent effective for treating Alzheimer'"'"'s disease.

20. The method of claim 19, wherein the other therapeutic agent is a cholinesterase inhibitor or an NMDA receptor antagonist.

22. An oral formulation for lessening gastrointestinal side effects in a human patient which occur from administration of an active agent, which is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof in an immediate release dosage form,

wherein the formulation comprises an amount effective to treat or prevent Alzheimer'"'"'s disease and/or Cerebral Amyloid Angiopathy (CAA) of said agent and a pharmaceutically acceptable vehicle, and wherein the formulation results in lesser side effects in comparison to those of said immediate release dosage form, and wherein the formulation is according to claim 1.

23. A formulation of claim 1, wherein the formulation is in a form for release of the active agent which is modified from an immediate release form.

24. A method for stabilizing cognitive function or decreasing the rate of decline in cognitive function or improving cognitive function, in an Alzheimer'"'"'s disease or Cerebral Amyloid Angiopathy (CAA) patient, as assessed by at least one of the following tests:

Clinical Dementia Rating (CDR) scale, Mini-mental State Examination (MMSE), or Alzheimer'"'"'s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), comprising administering to a patient in need thereof an oral formulation of claim 1.

25. A method for stabilizing cognitive function or decreasing the rate of decline in cognitive function or improving cognitive function, in an Alzheimer'"'"'s disease or Cerebral Amyloid Angiopathy (CAA) patient, as assessed by at least one of the following tests:

CIBIC-plus, NPI, DAD, a reduction in whole brain, hippocampal or entorhinal cortex atrophy rates or an improvement in the plasma or CSF level profile of one of the following pathophysiological biomarkers;

tau, phosphorylated-tau, ubiquitin or Aβ

_1-42, comprising administering to a patient in need thereof an oral formulation of claim 1;

provided that the formulation is not a formulation according to Table 2, 3, 4, 5, 6, 7 or 8 herein.

2. An oral formulation comprising an active agent which is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent Alzheimer'"'"'s disease and/or Cerebral Amyloid Angiopathy (CAA), and a pharmaceutically acceptable vehicle,

wherein, when the formulation is administered to a subject, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about from 814 to 6604 ng·

h/mL is achieved.

3. An oral formulation comprising an active agent which is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent Alzheimer'"'"'s disease and/or Cerebral Amyloid Angiopathy (CAA), and a pharmaceutically acceptable vehicle,

wherein, when the formulation is administered to a subject, a mean plasma concentration profile of the active agent having a mean Cmax of about from 137 to 1235 ng/mL is achieved.

4. An oral formulation comprising an active agent which is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent Alzheimer'"'"'s disease, and a pharmaceutically acceptable vehicle,

wherein, when the formulation is administered to a mild to moderate Alzheimer'"'"'s disease patient:

in a dose of 50 mg BID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 1396 ng·

h/mL±

20%, and a mean Cmax of about 310 ng/mL±

20% is achieved;

or

in a dose of 100 mg BID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 2569 ng·

h/mL±

20%, and a mean Cmax of about 618 ng/mL±

20% is achieved;

or

in a dose of 150 mg BID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 3418 ng·

h/mL±

20%, and a mean Cmax of about 624 ng/mL±

20% is achieved.

5. An oral formulation comprising an active agent which is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent Alzheimer'"'"'s disease, and a pharmaceutically acceptable vehicle,

wherein, when the formulation is administered to a mild to moderate Alzheimer'"'"'s disease patient for 12 weeks:

in a dose of 50 mg BID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_ss of about 1975 ng·

h/mL±

20%, and a mean Cmax of about 451 ng/mL±

20% is achieved;

or

in a dose of 100 mg BID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_ss of about 2590 ng·

h/mL±

20%, and a mean Cmax of about 538 ng/mL±

20% is achieved;

or

in a dose of 150 mg BID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_ss of about 3570 ng·

h/mL±

20%, and a mean Cmax of about 639 ng/mL±

20% is achieved.

6. An oral formulation comprising an active agent which is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent Cerebral Amyloid Angiopathy (CAA), and a pharmaceutically acceptable vehicle,

wherein, when the formulation is administered to a Cerebral Amyloid Angiopathy (CAA) patient:

in a dose of 50 mg BID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 1643 ng·

h/mL±

20%, and a mean Cmax of about 346 ng/mL±

20% is achieved;

or

in a dose of 100 mg BID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 2777 ng·

h/mL±

20%, and a mean Cmax of about 552 ng/mL±

20% is achieved;

or

in a dose of 150 mg BID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 3689 ng·

h/mL±

20%, and a mean Cmax of about 857 ng/mL±

20% is achieved.

21. A method of treating or preventing Cerebral Amyloid Angiopathy (CAA) comprising administering to a patient in need thereof an oral formulation of claim 6.

7. An oral formulation comprising an active agent which is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent Cerebral Amyloid Angiopathy (CAA), and a pharmaceutically acceptable vehicle,

wherein, when the formulation is administered to a Cerebral Amyloid Angiopathy (CAA) patient for 12 weeks:

in a dose of 50 mg BID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_ss of about 947 ng·

h/mL±

20%, and a mean Cmax of about 171 ng/mL±

20% is achieved;

or

in a dose of 100 mg BID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_ss of about 3703 ng·

h/mL±

20%, and a mean Cmax of about 806 ng/mL±

20% is achieved;

or

in a dose of 150 mg BID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_ss of about 6753 ng·

h/mL±

20%, and a mean Cmax of about 1031 ng/mL±

20% is achieved.

8. An oral formulation comprising an active agent which is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent Alzheimer'"'"'s disease and/or Cerebral Amyloid Angiopathy (CAA), and a pharmaceutically acceptable vehicle,

wherein, when the formulation is administered to healthy male and female subjects of age ≧

55 years;

in a daily dose of 50 mg of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 1566 ng·

h/mL±

20%, and a mean Cmax of about 469 ng/mL±

20% is achieved;

or

in a daily dose of 100 mg of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 2871 ng·

h/mL±

20%, and a mean Cmax of about 745 ng/mL±

20% is achieved;

or

in a daily dose of 150 mg of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 4497 ng·

h/mL±

20%, and a mean Cmax of about 1029 ng/mL±

20% is achieved.

9. An oral formulation comprising an active agent which is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent Alzheimer'"'"'s disease and/or Cerebral Amyloid Angiopathy (CAA), and a pharmaceutically acceptable vehicle,

wherein, when the formulation is administered to healthy male and female subjects of age ≧

55 years;

in a daily dose of 100 mg of the active agent, and the subjects are in fasted state, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 3289 ng·

h/mL±

20%, and a mean Cmax of about 931 ng/mL±

20% is achieved; and

in a daily dose of 100 mg of the active agent, and the subjects are in a fed state, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 2829 ng·

h/mL±

20%, and a mean Cmax of about 671 ng/mL±

20% is achieved.

10. An oral formulation comprising an active agent which is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent Alzheimer'"'"'s disease and/or Cerebral Amyloid Angiopathy (CAA), and a pharmaceutically acceptable vehicle,

wherein, when the formulation is administered to healthy male subjects of age 18-45 years:

in a dose of 100 mg BID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 1017 ng·

h/mL±

20%, and a mean Cmax of about 282 ng/mL±

20% is achieved;

or

in a dose of 200 mg BID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 3206 ng·

h/mL±

20%, and a mean Cmax of about 517 ng/mL±

20% is achieved.

11. An oral formulation comprising an active agent which is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent Alzheimer'"'"'s disease and/or Cerebral Amyloid Angiopathy (CAA), and a pharmaceutically acceptable vehicle,

wherein, when the formulation is administered to healthy male subjects of age 18-45 years for 12 days:

in a dose of 100 mg BID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_0-12h of about 1434 ng·

h/mL±

20%, and a mean Cmax of about 256 ng/mL±

20% is achieved;

or

in a dose of 200 mg BID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_0-12h of about 4152 ng·

h/mL±

20%, and a mean Cmax of about 581 ng/mL±

20% is achieved.

12. An oral formulation comprising an active agent which is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent Alzheimer'"'"'s disease and/or Cerebral Amyloid Angiopathy (CAA), and a pharmaceutically acceptable vehicle,

wherein, when the formulation is administered to healthy male or female subjects of age ≧

55 years;

in a dose of 200 mg BID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 5503 ng·

h/mL±

20%, and a mean Cmax of about 897 ng/mL±

20% is achieved.

13. An oral formulation comprising an active agent which is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent Alzheimer'"'"'s disease and/or Cerebral Amyloid Angiopathy (CAA), and a pharmaceutically acceptable vehicle,

wherein, when the formulation is administered to healthy male or female subjects of age ≧

55 years for 12 days;

in a dose of 200 mg BID of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_0-12h of about 6287 ng·

h/mL±

20%, and a mean Cmax of about 880 ng/mL±

20% is achieved.

14. An oral formulation comprising an active agent which is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent Alzheimer'"'"'s disease and/or Cerebral Amyloid Angiopathy (CAA), and a pharmaceutically acceptable vehicle,

wherein, when the formulation is administered to healthy male subjects of age 18-45 years:

in a daily dose of 100 mg of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 1421 ng·

h/mL±

20%, and a mean Cmax of about 410 ng/mL±

20% is achieved;

or

in a daily dose of 200 mg of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 2492 ng·

h/mL±

20%, and a mean Cmax of about 661 ng/mL±

20% is achieved;

or

in a daily dose of 300 mg of the active agent, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 4464 ng·

h/mL±

20%, and a mean Cmax of about 904 ng/mL±

20% is achieved.

15. An oral formulation comprising an active agent which is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent Alzheimer'"'"'s disease and/or Cerebral Amyloid Angiopathy (CAA), and a pharmaceutically acceptable vehicle,

wherein, when the formulation is administered to healthy male subjects of age 18-45 years:

in a daily dose of 200 mg of the active agent, and the subjects are in fasted state, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 2397 ng·

h/mL±

20%, and a mean Cmax of about 594 ng/mL±

20% is achieved; and

in a daily dose of 200 mg of the active agent, and the subjects are in a fed state, a mean plasma concentration profile of the active agent having a mean AUC_∞

of about 4497 ng·

h/mL±

20%, and a mean Cmax of about 631 ng/mL±

20% is achieved.

26. An oral formulation comprising an active agent which is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle,

which is effective for stabilizing cognitive function or decreasing the rate of decline in cognitive function, as assessed by at least one of the following tests:

Clinical Dementia Rating (CDR) scale, Mini-mental State Examination (MMSE), or Alzheimer'"'"'s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), in an Alzheimer'"'"'s disease or Cerebral Amyloid Angiopathy (CAA) patient.

27. An oral formulation comprising an active agent which is 3-amino-1-propanesulfonic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable vehicle,

which is effective for stabilizing cognitive function or decreasing the rate of decline in cognitive function, as assessed by at least one of the following tests:

CIBIC-plus, NPI, DAD, a reduction in whole brain, hippocampal or entorhinal cortex atrophy rates or an improvement in the plasma or CSF level profile of one of the following pathophysiological biomarkers;

tau, phosphorylated-tau, ubiquitin or Aβ

_1-42, in an Alzheimer'"'"'s disease or Cerebral Amyloid Angiopathy (CAA) patient;

provided that the formulation is not a formulation according to Table 2, 3, 4, 5, 6, 7 or 8 herein.

28. A method for stabilizing cognitive function or decreasing the rate of decline in cognitive function or improving cognitive function, in an Alzheimer'"'"'s disease or Cerebral Amyloid Angiopathy (CAA) patient, as assessed by at least one of the following tests:

Clinical Dementia Rating (CDR) scale, Mini-mental State Examination (MMSE), Alzheimer'"'"'s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), CDR-SB, CIBIC-plus, NPI, DAD, a reduction in whole brain, hippocampal or entorhinal cortex atrophy rates or or an improvement in the plasma or CSF level profile of one of the following pathophysiological biomarkers;

tau, phosphorylated-tau, ubiquitin or Aβ

_1-42, comprising administering to a patient in need thereof an oral formulation according to Table 2, 3, 4, 5, 6, 7 or 8 herein.