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"Formulations Of Ladostigil Tartrate"

Abstract: Disclosed are formulations of ladostigil tartrate, including pharmaceutical compositions, process for the manufacture, and use thereof.

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Patent Information

Application #
Filing Date
10 September 2007
Publication Number
39/2007
Publication Type
INA
Invention Field
PHARMACEUTICALS
Status
Email
Parent Application

Applicants

TEVA PHARMACEUTICAL INDUSTRIES, LTD.
5 BASEL STREET, P.O.BOX 3190, PETACH-TIKVA 49131, ISRAEL.

Inventors

1. DANIELLA LICHT
1 KEREN HA YESOD, RAMAT ILAN, GIVAT SHMUEL 54051, ISRAEL.
2. IOANA LOVINGER
15/3 TLAMIN STREET, GANEI-AVIV, LOD 71338, ISRAEL.
3. FANNY CACIULARU
17 SHAPIRA STREET, PETACH-TIKVA 49491, ISRAEL.
4. ADRIAN GILBERT
60B FLAT, 5 HANKIN STREET, RA'ANANA 43465, ISRAEL.

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.

Documents

Application Documents

# Name Date
1 6992-delnp-2007-abstract.pdf 2011-08-21
1 6992-delnp-2007-pct-237.pdf 2011-08-21
2 6992-delnp-2007-pct-210.pdf 2011-08-21
2 6992-DELNP-2007-Assignment.pdf 2011-08-21
3 6992-delnp-2007-pct-101.pdf 2011-08-21
3 6992-delnp-2007-claims.pdf 2011-08-21
4 6992-delnp-2007-form-5.pdf 2011-08-21
4 6992-DELNP-2007-Correpondence-Others.pdf 2011-08-21
5 6992-delnp-2007-description (complete).pdf 2011-08-21
5 6992-DELNP-2007-Form-3.pdf 2011-08-21
6 6992-delnp-2007-form-1.pdf 2011-08-21
6 6992-delnp-2007-form-2.pdf 2011-08-21
7 6992-delnp-2007-form-1.pdf 2011-08-21
7 6992-delnp-2007-form-2.pdf 2011-08-21
8 6992-delnp-2007-description (complete).pdf 2011-08-21
8 6992-DELNP-2007-Form-3.pdf 2011-08-21
9 6992-DELNP-2007-Correpondence-Others.pdf 2011-08-21
9 6992-delnp-2007-form-5.pdf 2011-08-21
10 6992-delnp-2007-pct-101.pdf 2011-08-21
10 6992-delnp-2007-claims.pdf 2011-08-21
11 6992-delnp-2007-pct-210.pdf 2011-08-21
11 6992-DELNP-2007-Assignment.pdf 2011-08-21
12 6992-delnp-2007-pct-237.pdf 2011-08-21
12 6992-delnp-2007-abstract.pdf 2011-08-21