Stable compositions containing N-propargyl-1-aminoindan

Details Stable compositions containing N-propargyl-1-aminoindan Stable compositions containing N-propargyl-1-aminoindan

1999-02-22

2000-10-03

Reamer, James H.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

424465, 514647, A61K 946, A61K 31135

Patent

active

061269689

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention concerns formulations of racemic, S(-) or R(+) enantiomers of N-propargyl-1-aminoindan, and especially formulations of the enantiomer R(+) of N-propargyl-1-aminoindan (referred to hereinafter as R(+) PAI) which is a selective irreversible inhibitor of the B-form of the enzyme monoamine oxidase used, for example, for the treatment 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.
The object of the present invention is to provide stable formulations comprising an effective amount of racemic, S(-) 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 PAI can be significantly improved by the incorporation of relatively large amounts of certain alcohols.
In accordance with the present invention there is provided a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a compound being a member selected from the group of racemic, S(-), and R(+)-N-propargyl-1-aminoindan or a pharmaceutically acceptable salt thereof, and 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 PAI-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 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 70% 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.
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 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. R(+) PAI itself may be prepared, for example, according to the process described in Example 6B of W095/11016.
The following non-limiting examples are given by way of illustration.


EXAMPLES



Exampl

REFERENCES:
patent: 3513244 (1970-05-01), Gittos et al.
patent: 5137730 (1992-08-01), Dennis et al.
patent: 5225197 (1993-07-01), Bolt et al.
patent: 5387612 (1995-02-01), Youdim et al.
patent: 5792473 (1998-08-01), Gergely et al.

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