Abstract: Disclosed are formulations of ladostigil tartrate, including pharmaceutical compositions, process for the manufacture, and use thereof.
1. A pharmaceutical composition comprising R(+)-6-(Nmethyl, N-ethyl-carbamoyloxy)-N'-propargyl-1-aminoindan 1/2 tartrate, at least one pharmaceutically acceptable cxcipient and up to 5% by weight of the composition of water.
2. The pharmaceutical composition of claim 1, comprising 2-5% water.
3. The pharmaceutical composition of claim 2, comprising 2-3.5% water.
4. A pharmaceutical composition comprising R(+)-6-(Nmethyl, N-ethyl-carbamoyloxy)-N'-propargyl-1-aminoindan 1/2 tartrate, at least one pharmaceutically acceptable excipient and no more than 0.5% by weight of the composition of magnesium stearate.
5. The pharmaceutical composition of claim 4, free of magnesium stearate.
6. A pharmaceutical composition comprising R(+)-6-(Nmethyl, N-ethyl-carbamoyloxy)-N'-propargyl-1-aminoindan 1/2 tartrate, at least one pharmaceutically acceptable excipient and no more than 1.5% by weight of the composition of sodium stearyl fumarate.
7. The composition of claim 6, comprising no more than 0.5% by weight of the composition of sodium stearyl fumaratta.
8. The pharmaceutical composition of claim 6, free of sodium stearyl fumarate.
9. The pharmaceutical composition of any one of claims 1 to 3 or 6 to 8, wherein no more than 0.5% by weight of the composition is magnesium stearate,
10. The pharmaceutical composition of claim 9, free of magnesium stearate.
11. The pharmaceutical composition of any of claims 1 to 3, 9 or 10, wherein no more than 0.5% by weight of the composition is sodium stearyl fumarate.
12. The pharmaceutical composition of claim 11, free of sodium stearyl fumarate.
13. The pharmaceutical composition of any of claims 1 to 12, wherein no more than 0.5% by weight of the composition is stearic acid.
14. The pharmaceutical composition of claim 13, tree of stearic acid.
15. The pharmaceutical composition of any one of claims 1- 12, wherein the at least one pharmaceutically acceptable excipient is a first filler, a second filler, a disintegrant, a flow agent, a binder or a lubricant.
16. The pharmaceutical composition of claim 15, wherein the lubricant is talc. L7. The pharmaceutical composition of claim 16, wherein talc is present in an amount of up to 4% by weight of the composition.
18. The pharmaceutical composition of claim 16, wherein the lubricant further comprises stearic acid.
19. The pharmaceutical composition of claim 18, wherein the stearic acid is present in an amount of up to 2% by weight of the composition.
20. The pharmaceutical composition of claim 15, wherein the lubricant is stearic acid,
21. The pharmaceutical composition of claim 20, free of talc.
22. Tha pharmaceutical composition of claim 15, 16 or 17, free of stearic acid.
23. The pharmaceutical composition of any one of claims 15- 22, wherein the first filler is mannitol present in an amount of 6 to 16% by weight, the second filler is mannitol granulate present in an amount of 0 to 56% by weight, the disintegrant is starch present in an amount of 15 to 38% by weight, the flow agent is colloidal silicon dioxide present in an amount of 1 to 2% by weight, and the binder is polyvinylpyrolidone present in an amount of 3 to 8% by weight.
24. The pharmaceutical composition of any one of claims 15- 19, wherein the first filler is mannitol present in an amount of 6.6% by weight, the second filler is mannitol 31 - -ae-- granulate present in an amount of 56.1% by weight, the disintegrant is starch present in an amount of 15.2% by weight, the flow agent is colloidal silicon dioxide present in an amount of 0.9% by weight, the binder is polyvinylpyrolidone present in an amount of 3.4% by weight, and the lubricant is talc in an amount of 3.8% by weight and stearic acid in an amount of 1.9% by weight.
25. The pharmaceutical composition of any one of claims 15- 19, wherein the first filler is mannitol present in an amount of 16.4% by weight, the disintogrant is starch present in an amount of 37.4% by weight, the flow agent ia colloidal silicon dioxide present in an amount of 2.1% by weight, the binder is polyvinylpyrolidone present in an amount of 8.4% by weight, and the lubricant is talc in an amount of 3.7% by weight and stearic acid in an amount of 1.9% by weight.
26. The pharmaceutical composition of any of claims 1-25 in the form of tablets, capsules, pills, powders, or granules.
27. The pharmaceutical composition of claim 26 in tablet torin.
28. The pharmaceutical composition of claim 26 in capsule form.
29. The pharmaceutical composition of any one of claims 1- 27, which upon administration to a human subject provides a maximum blood plasma concentration of R(+)- 6-(N-methyl, N-ethyl-carbamoyloxy)-N'-propargyl-1- aminoindan of at least 0.7 nmol/mL.
30. A pharmaceutical composition comprising R(+)-6-(Nmethyl, N-ethyl-carbamoyloxy)-N'-propargyl-1-aminoindan 1/2 tartrate and a pharmaceutically acceptable carrier, formulated so as to provide upon administration to a human subject a maximum blood plasma concentration of R(+)-6-(N-methyl, N-ethyl-carbamoyloxy)-N'-propargyl-1- aminoindan of at least 0.7 nmol/mL.
31. The pharmaceutical composition of claim 30, formulated so as Lo provide in the human subject a blood plasma concentration of R(+)-6-(N-methyl, N-ethylcarbamoyloxy) -N' -propargyl-1-aminoindan of at least 0.01 ninol/mL twelve hours after dosing.
32. The pharmaceutical composition of claim 30, formulated so as to provide in the human subject a blood plasma concentration of R(+)-6-(N-methyl, N-ethylcarbamoyloxy) -N' -propargyl-1-aminoindan of at least 1.88 nmol/mL.
33. The pharmaceutical composition of claim 30, formulated so as to provide a monoamiiie oxidase B inhibition of 59%-91% upon administration to a human subject as determined by liquid scintillation counting.
34. The pharmaceutical composition of claim 33, formulated so as to provide a monoamine oxidase B inhibition of 75% upon administration to a human subject as determined by liquid scintillation counting. - &3T-
35. The pharmaceutical composition of claim 30, formulated so as to provide a 28%-86% decrease of 3,4- dihydroxyphenylglycol plasma concentration upon administration to a human subject as determined by liquid scintillation counting.
36. The pharmaceutical composition of claim 35, formulated so as to provide a 57% decrease of 3,4- dihydroxyphenylglycol plasma concentration upon administration to a human subject as determined by liquid scintillation counting.
37. The pharmaceutical composition of any one of claim 30- 36, wherein the pharmaceutical composition administered comprises 25-105 mg R(+)-6-(N-methyl, N-ethylcarbamoyloxy) -N' -propargyl-1-aminoindan L/4 tartrate.
38. A method for inducing in a human subject a maximum blood plasma concentration of R(+)-6-(N-methyl, Nuthyl- carbamoyloxy)-N' -propargyl-1-aminoindan of at least 0.7 nmol/mL after one administration, comprising administering orally to the human subject a solid pharmaceutical composition comprising R(+)-6-(N-methyl, N-ethyl-carbamoyloxy)-N'-propargyl-1-aminoindan V4 tartrate and a pharmaceutically acceptable carrier so as to induce in the subject the blood plasma concentration.
39. The method of claim 38, wherein the blood plasma concentration of R(+)-6-(N-methyl, N-ethylcarbamoyloxy) -N' -propargyl-1-aminoindan 12 hours after administration is at least 0.01 nmol/mL.
40. The method of claim 38 or 39, wherein the maximum blood plasma concentration of R(+)-6-(N-methyl, N-ethylcarbamoyloxy)- N'-propargyl-1-aminoindan is 1.88 nmol/mL.
41. The method of any one of claims 38-40, wherein the pharmaceutical composition administered comprises 25- 105 mg R(+)-6-(N-methyl, N-ethyl-carbamoyloxy)-N'- propargyl-1-aminoindan V4 tartrate. A method of treating a subject afflicted with Parkinson's disease, Alzheimer's disease or dementia, depression or a neurological disorder comprising administering to the subject the pharmaceutical composition of any of claims 1-37.
43. The method of claim 42, wherein the subject is afflicted with a neurological disorder and the neurological disorder is epilepsy, narcolepsy, amyotrophic lateral sclerosis ("ALS"), memory disorders, panic, posttraumatic stress disorder ("PTSD"), sexual dysfunction, attention deficit and hyperactivity syndrome ("ADHD"), attention deficit disorder, or Tourette's syndrome.
44. The method of claim 42, wherein the subject is afflicted with dementia and the dementia is static dementia, Alzheimer's-type dementia, senile dementia, prosenile dementia, progressive dementia, vascular dementia or Lewy body dementia.
45. The method of claim 42, wherein the subject is afflicted with Alzheimer's disease. 34
46. The method of claim 42, wherein the subject is afflicted with Parkinson's disease.
47. A process for making the pharmaceutical composition of any of claims 1-37 comprising the step of wet granulation.
48. The process of claim 47, comprising the step of wet granulation in the absence of water addition.
49. The process of claim 47 or 48, wherein the step of wet granulation is performed in the presence of isopropanol.
50. The process of any one of claims 47 to 49, wherein the process is performed in the absence of ethanol.
51. A pharmaceutical composition, a method for inducing in a human subject a maximum blood plasma concentration, and a method of treating diseases such as herein described with reference to the foregoing examples.
| # | Name | Date |
|---|---|---|
| 1 | 6992-delnp-2007-pct-237.pdf | 2011-08-21 |
| 2 | 6992-delnp-2007-pct-210.pdf | 2011-08-21 |
| 3 | 6992-delnp-2007-pct-101.pdf | 2011-08-21 |
| 4 | 6992-delnp-2007-form-5.pdf | 2011-08-21 |
| 5 | 6992-DELNP-2007-Form-3.pdf | 2011-08-21 |
| 6 | 6992-delnp-2007-form-2.pdf | 2011-08-21 |
| 7 | 6992-delnp-2007-form-1.pdf | 2011-08-21 |
| 8 | 6992-delnp-2007-description (complete).pdf | 2011-08-21 |
| 9 | 6992-DELNP-2007-Correpondence-Others.pdf | 2011-08-21 |
| 10 | 6992-delnp-2007-claims.pdf | 2011-08-21 |
| 11 | 6992-DELNP-2007-Assignment.pdf | 2011-08-21 |
| 12 | 6992-delnp-2007-abstract.pdf | 2011-08-21 |