Specification
FORMULATIONS OF IADO9TIGIL TARTRATE
Throughout this application various publications, published
patent applications, and published patents are referenced.
The disclosures of these publications in their entireties
are hereby incorporated by reference into this application
in order to more fully describe the state of the art to
which this invention pertains.
Field of the Invention
The present invention relates to formulations of tartrate
salt of R{+)-6-(N-methyl, N-ethyl-carbamoyloxy) -N' -
propargy1-1-aminoindan.
Background of the Invention
PCT Application Publication No. W098/27055 discloses
indanylamine and aminotetralin derivative compounds, such as
those of Formula I below, which are useful to treat
depression, Attention Deficit Disorder (ADD), Attention
Deficit and Hyperactivity Disorder (ADHD), Tourette's
Syndrome, Alzheimer's Disease and other dementias. The
indanylamine derivatives disclosed have been show to have
biological effects in animal models of neurological disease.
In addition, PCT Application Publication No. WO98/27055
discloses methods for preparation of the indanylamine
derivative compounds.
Formula I:
(X)m
(CH^b
wherein b is 1 or 2; m is 0-3; Y is 0 or S; X is halo; RI is
hydrogen or Ci-a alkyl; Ra is hydrogen, Ci_4 alkyl, or
optionally substituted propargyl; and RS and R4 are each
independently hydrogen, CI-B alkyl, Ce_i2 aryl, Cg-iz aralkyl,
aach optionally halo substituted.
R( + )-6-(N-methyl,N-ethyl-carbamoyloxy)-N1-propargyl -1-
aminoindan, also known as (3R)-3-(prop-2-ynylamino)-2,3,-
dihydro-lH-inden-5-yl ethylmethylcarbamate, is disclosed in
PCT Application Publication No. W098/27055, specifically
M
compound 76 in Table 5. In addition, salts are disclosed,
including the 1/2 L-tartrate salt. This salt has been given
the nonproprietary name ladostigil tartrate. Its CAS
registry number is 209394-46-7.
Specific pharmaceutical compositions, i.e., formulations,
comprising ladostigil tartrate suited for storage and
desired pharmacokinetics have not been previously disclosed.
r
Suramary of the Invention
The subject invention provides a formulation comprising
tartrate salt crystals of R(+) -6- (N-methyl, N-ethylcarbamoyloxy)
-N' -propargyl-1-aminoindan.
The subject invention also provides a pharmaceutical
composition comprising R(+) -6- (N-methyl, N-ethylcarbamoyloxy)
-N' -propargyl-1-aminoindan 1/2 tartrate, at least
one pharmaceutically acceptable excipient and up to 5% by
weight of the composition of water.
The subject invention also provides a pharmaceutical
composition comprising R(+) -6- (N-methyl, N-ethylcarbamoyloxy)
-N' --propargyl-1-aminoindan % tartrate, at least
one pharmaceutically acceptable excipient and no more than
0.5% by weight of the composition of magnesium stearate.
The subject invention also provides a pharmaceutical
composition comprising R(+) -6- (N-methyl , N-ethylcarbamoyloxy)
-N' -propargyl-1-aminoindan % tartrate, at least
one pharmaceutically acceptable excipient and no more than
1.5% by weight of the composition of sodium stearyl
fumarate.
The subject invention also provides a pharmaceutical
composition comprising R(+) -6- (N-methyl , N-ethylcarbamoyloxy)
-N' ~propargyl-l-aminoindan V4 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
nmcl /mL .
The subject invention also provides a method for inducing in
a human subject a maximum blood plasma concentration of
R(+)-6--79
6
-76
-73
7
L -54
-30
8
-64
-13
AUC (ng*hr/mL)
ladostigil (M)
Iddostigil (T)
314
246
589
2305
1005
1449
927
482
436
398
551
901
52
118
500
350
Cmax (nmol
ladostigil (M)
ladostigil ( T )
1.1
0 . 7
1.2
3 .8
3.5
3.9
3.9
1.6
1.4
1.0
1.5
2 . 5
0.2
0 . 4
1.7
1.3
Mean Cmax after dosing and mean Cmin (concentration at predose)
of ladostigil tartrate at maintenance analysis (M) and
at termination analysis (T) were determined and are listed
in Table 12, as well as half life (t1/2) at termination. The
concentration measurements are expressed in nmol/ml and the
t1/2 is expressed in terms of hours.
Table 12: Pharmacokinetic Analysis
Analyte
Ladcstigil
Tartrate
Cmi,i (M)
C .0164
C;nin (T)
0.0109
Cinax (M)
2 . 0 2
Cmax (T)
1.88
tl/2
1.08
Monoamine oxidase B ("MAO-B") inhibition in plasma samples
from the a forementioned patients was determined at baseline
and at termination analysis using liquid scintillation
counting. The percent inhibition was calculated for each
patient, and the mean percent inhibition was then determined
to be 75% (standard deviation=16) at the termination
analysis .
Docrease of 3,4-dihydroxyphenylglycol ("DHPG") in plasma is
indicative of monoamine oxidase inhibition, especially in
the brain. DHPG plasma concentrations were measured in 6 of
the aforementioned patients at baseline and at termination
analysis, using HPLC equipped with an electrochemical
detector.
The decrease in DHPG concentration in the six patients was
determined. The average decrease in DHPG concentration was
determined to be 57% with a standard deviation of 29.
The data show that the analytes were present at pre-dose
(which corresponds to 12 hours after the previous dose) both
at maintenance and at termination analyses.
There is evidence of significant MAO-B inhibition.
Cholinesterase inhibition at pre-dose administration both at
maintenance and at termination analyses was also evident.
What is claimed:
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.