AU771490B2 - Stable compositions containing N-propargyl-1-aminoidan - Google Patents

Description

-1- STABLE COMPOSITIONS CONTAINING N-PROPARGYL-1-

AMINOINDAN

FIELD OF THE INVENTION The present invention concerns formulations of racemic, or enantiomers of N-propargyl-l-aminoindan, and especially formulations of the enantiomer of N-propargyl-l-aminoindan (referred to hereinafter as PAI) which is a selective irreversible inhibitor of the Bform of the enzyme monoamine oxidase used, for example, for the treatment S of Parkinson's disease. In the following the enzyme monoamine oxidase will be referred to as MAO and the B-form thereof as MAO-B.

BACKGROUND OF THE INVENTION GB 1 003 686 discloses a group of benzocycloalkane compounds in which the cycloalkane has from five to seven ring members and is substituted by an N-(alkynylalkyl)amino group, and their use as MAO inhibitors. The patent further discloses the use of the subject compounds in admixture with a variety of substances including various alcohols such as a benzyl alcohol, stearyl alcohol, and methanol. The patent, however, does not teach how and by what criteria any of the many possible carriers and other ingredients are selected so as to overcome the stability problem of the product.

-2- The object of the present invention is to provide stable formulations comprising an effective amount of racemic, or R(+)-N-propargyl-1-aminoindan.

For the sake of simplicity, the abbreviation PAI, unless specified otherwise, will be used to denote the enantiomers of N-propargyl-1-aminoindan, as well as their racemic mixtures.

SUMMARY OF THE INVENTION In accordance with the invention it was surprisingly found that the stability of formulations comprising racemic, and R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof can be significantly improved by the incorporation of relatively large amounts of certain alcohols and/or citric acid.

In accordance with the present invention there is provided a pharmaceutical composition in tablet form comprising as an active ingredient a therapeutically effective amount of a R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof, and at least one additional ingredient selected from the group consisting of pentahydric alcohol, a hexahydric alcohol and citric acid.

Preferably, the composition comprises at least 60% by weight of at least one alcohol being a member selected from the group of pentahydric and hexahydric alcohols.

In a preferred embodiment of the present invention the active ingredient is .R(+)-N-propargyl-1-aminoindan.

Preferably the composition comprises at least 70% of said at least one alcohol.

Typically the alcohol used in accordance with of the invention, is a member selected from the group of mannitol, xylitol and sorbitol.

In accordance with the invention the PAl-comprising composition may further include citric acid, preferably in an amount of 0.5 to 2% by weight.

If desired, compositions according to the invention may further comprise 30 magnesium stearate, preferably in an amount of 0.1 to 0.5% by weight. According to this embodiment, where the amount of said at least one alcohol is less than by weight, the composition further comprises citric acid in an amount specified above. Where the amount of said at least one alcohol is at least 70% by weight, the inclusion of citric acid is optional.

-3- The composition of the present invention may optionally also include conventional additives such as fillers, lubricants, disintegrants, glidants, flavoring agents, sweeteners, coloring agents, and the like, all as known per se. Examples of fillers which may be used in accordance with the present invention are lactose, starch, microcrystalline cellulose, maltrin and the like.

The compositions of the present invention may be prepared by methods known per se, familiar to those skilled in the art. For example, PAI and all other ingredients (with the exception of the lubricant, when 10 used) may be screened and mixed thoroughly in a suitable granulating machine. The granulation may occur in the presence of purified water, following which the composition is dried. The dry granulate may then be milled, lubricated and compressed into tablets. PAI itself may be prepared, for example, according to the process described in Example 6B of 15 W095/11016.

The following non-limiting examples are given by way of illustration.

0? EXAMPLES EXAMPLE 1 mg/tablet R(+)-N-propargyl-l-aminoindan mesylate 3.12 Mannitol 62.5 Maltodextrin (Maltrin 150) 36.0 Croscarmellose sodium (Ac-Di-Sol) 2.1 Talc -4- EXAMPLE 2 R(+)-N-propargyl-i-aminoindan mesylate Mannitol Starch Pregelatinized starch Colloidal silicon dioxide Talc Stearic acid mg/tablet 1.56 79.14 10.0 10.0 0.6 r EXAMPLE 3 R(+)-N-propargyl-1-aminoindan mesylate Mannitol Starch Pregelatinized starch Colloidal silicon dioxide Citric acid Talc mg/tablet 3.12 76.58 10.0 10.0 0.6 EXAMPLE 4 R(+)-N-propargyl-l-aminoindan mesylate Mannitol Lactose (hydrous) Starch Glyceryl Behenate (Compitrol 888 ATO) mg/tablet 3.12 69.88 14.0 14.0 EXAMPLE R(+)-N-propargyl-l -aminoindan mesylate Mannitol Starch Starch STA-RX 1500 Colloidal silicon dioxide, Aerosil Hydrogenated vegetable type I (Sterotex Dritex) EXAMPLE 6 mg/tablet 3.12 77.28 10.0 10.0 0.6 In order to compare the compositions of the present invention with those known in the prior art, two of the above formulations were compared with a formulation described in W095/11016.

*oo Formulation of W095/11016 (Example 20 R(+)-N-propargyl-l-aminoindan HCI Lactose (hydrous) Pregelatinized starch Microcrystalline cellulose Sodium starch glycolate Talc Magnesium stearate mg/tablet 1.56 50.0 36.0 14.0 2.14 This formulation, as well as those described under Examples 2 and 3 of the present application were subjected to 6 months at 40aC and humidity. The percentage of degradants of the active material was assayed at the end of the six month period.

-6- The following procedure was adopted to determine the degradation of the formulations prepared. The tablets were finely powdered and extracted with a diluent such as a mixture of water, acetonitrile and perchloric acid. An aliquot of the extraction product was injected into an HPLC and eluted using the same mixture as said diluent mixture. The area corresponding to the PAI compound was determined as was that of any other major peak. The calculations of degradation percent was made by comparing the areas of the measured peaks with those obtained from the standard preparation.

It was found that the formulation prepared according to the disclosure of Example 20 of W095/11016 contained after storage 3.08% degradants whereas the formulations of Examples 2 and 3 contained 0.51% and less than 0.1% degradants, respectively.

EXAMPLE 7 Formulations according to the present invention and others according to the description given in Example 20 of W095/11016 were prepared containing the ingredients shown in Table 1. The formulations described in this Table are designated "PCT" when prepared in accordance with the disclosure in W095/11016, or by a number which corresponds to the number of the Example in the present application, in which they are described. The qualifying symbols of A, B, C or D appearing next to some of these designations denote certain variations in said formulations. The percentage of degradation, presented in Table 2, was calculated for all the formulations of Table 1, after storing them for 1 month at 55°C or for 6 months at 40 0 C and 75% humidity. Those formulations stored according to the latter storing conditions are marked in the Table with an astrix As can be seen from Table 2, the stabilities of all the compositions of the present invention was superior to those of the prior art.

9 9 9* *9 **9

TAMI

N-Pilpag- 1.56 ?r n.iI- 36.0 14.0 SIca I acid NP 50.0 2.14 M rncslum 0.5 Tl 105.2

T

5.0 1.0 Ing 7.81 47.0 1 2A I I I I I I ng 3.12 I I I I I I I I I -mg I nip I ing -1 ma I flig- I I mg lll b b 1 .56b I 613,12 1 1.56 11.56 1.56 1.56 I 3.12 3.12 1.56 1.56 1 1.56 1.56 I I I I L I 1 62.5 62.5 79.14 1 78.44 1 76.58 77.44 69.88 77.28] 7S.8 78.87 78.87 1 I I I 47.0 36.0 36.0 360 1.36.0 10.0 1 10.0 1 10.6 10.0 I Ilo0. I 10.0 1000 10.0 SI -1 I-4- I I 1 10.0

J

10.0 1 14.0 1 10.0 1 10.0 1 10.0 20.0 14.0 50.0 2.2 0.5 20.0 66.0 2.99 0.7 0.6 0.6 0.6 0.6 0.6 0.6 06 0.6 0.6 0.6 14.0 14.0 14.0 2.0 2.0 20 2.0 2.0 2.0 2.0 2.0 50.0 47.44 46.44 4.1 66.0 3.0 2.14 2.14 1 2.14 _I I I---1-I1 I I 1 0.52 0.1 0.5 10.5 0.5 ~1--l1 1 I 1 I 1143.2 104.7 146.0 1105.221 105.74 106.8 105.2 I 0n.2 105.3 104.6 105.3 104.61103.01103.0 105.13 103.53 105.53 105.0 105.0 I I I L~ Table 2 Examiple NO: %Y Degradm'IS Nnr~~o 4 6T

C)

74 7 0744 V r Sorbitol XyIiInI Magnesi~p\ CCKJk Citric acid 1 4

I

Soibliol Xylilol Magnesim sicaTale z citfic acid

I

p ~g 047 n n47I ng~; 0.1 0(47 7S

Claims (30)

1. A pharmaceutical composition in tablet form comprising as an active ingredient a therapeutically effective amount of R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof, and at least one additional ingredient selected from the group consisting of pentahydric alcohol, a hexahydric alcohol and citric acid.

2. The pharmaceutical composition of claim 1, wherein the composition comprises at least one alcohol, wherein said at least one alcohol comprises at least by weight of the total composition.

3. The pharmaceutical composition of claim 1, wherein the alcohol is selected from the group consisting of mannitol, xylitol and sorbitol.

4. The pharmaceutical composition of claim 1, comprising at least one alcohol and citric acid.

5. The pharmaceutical composition of claim 4, wherein the amount of citric acid is 0.5 to 2% by weight of the total composition.

6. The pharmaceutical composition of claim 1, further comprising magnesium stearate.

7. The pharmaceutical composition of claim 6, wherein the amount of magnesium stearate is 0.1 to 0.5% by weight of the total composition.

8. The pharmaceutical composition of claim 4, in which the amount of said at least one alcohol is between 60% and 70% of the total composition.

9. The pharmaceutical composition of claim 1, wherein said active ingredient is R(+)-N-propargyl-1-aminoindan.

The pharmaceutical composition of claim 1, comprising at least one alcohol in an amount less than 70% by weight of the pharmaceutical composition and further comprising citric acid in an amount from 0.5 to 2% by weight of the pharmaceutical composition.

11. A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of R(+)-N-propargyl-l-aminoindan or a pharmaceutically acceptable salt thereof, and at least one additional ingredient selected from the group consisting of a pentahydric alcohol, a hexahydric alcohol and citric acid.

12. The pharmaceutical composition of claim 11, wherein the composition comprises at least one alcohol, wherein said at least one alcohol comprises at least 60% by weight of the total composition.

13. The pharmaceutical composition of claim 11, wherein the alcohol is selected from the group consisting of mannitol, xylitol and sorbitol.

14. The pharmaceutical composition of claim 11, comprising at least one alcohol and citric acid.

The pharmaceutical composition of claim 14, wherein the amount of citric acid is 0.5 to 2% by weight of the total composition. ooooo S

16. The pharmaceutical composition of claim 11, further comprising magnesium stearate.

17. The pharmaceutical composition of claim 16, wherein the amount of magnesium stearate is 0.1 to 0.5% by weight of the total composition. ooee•

18. The pharmaceutical composition of claim 14, in which the amount of said at eleast one alcohol is between 60% and 70% of the total composition es n achli bten6% n 0 foh oa cmoiin 11

19. The pharmaceutical composition of claim 11, wherein said active ingredient is R(+)-N-propargyl-1 -aminoindan.

20. A pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof, and at least 75% by weight of at least one alcohol selected from the group consisting of mannitol, xylitol and sorbitol.

21. The pharmaceutical composition of claim 20, wherein the amount of R propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof is 3.0% or less by weight of the composition, and wherein the alcohol is at least 75% by weight of the composition.

22. The pharmaceutical composition of claim 21, wherein the alcohol is mannitol.

23. The pharmaceutical composition of claim 2, wherein the amount of propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof is 3.0% or less by weight of the composition. *l* I i 11A

24. The pharmaceutical composition of claim 12, wherein the amount of propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof is 3.0% or less by weight of the composition.

The pharmaceutical composition of claim 11, comprising at least one alcohol in an amount less than 70% by weight of the pharmaceutical composition and further comprising citric acid in an amount of 0.5 to 2% by weight of the pharmaceutical composition.

26. The pharmaceutical composition of claim 1, wherein said active ingredient is a pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindan.

27. The pharmaceutical composition of claim 26, wherein the pharmaceutically acceptable salt is the mesylate salt.

28. The pharmaceutical composition of claim 11, wherein said active ingredient is a pharmaceutically acceptable salt of R(+)-N-propargyl-1-aminoindan.

29. The pharmaceutical composition of claim 28, wherein the pharmaceutically acceptable salt is the mesylate salt.

30. A pharmaceutical composition substantially as hereinbefore described with 25 reference to any one of the Examples 1 to DATED THIS THIRTEENTH DAY OF JANUARY, 2004. TEVA PHARMACEUTICAL INDUSTRIES LTD 30 BY 0 PIZZEYS PATENT TRADE MARK ATTORNEYS