Composition with sustained release of levodopa and carbidopa

Details Composition with sustained release of levodopa and carbidopa Composition with sustained release of levodopa and carbidopa

2001-05-29

2003-03-11

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Matrices

C424S489000, C424S488000

Reexamination Certificate

active

06531153

ABSTRACT:

SUBJECT AND SUMMARY OF THE INVENTION
The present invention consists of a formulation with sustained release of a combination of two active principles, namely levodopa and carbidopa.
PRIOR ART
In the case of two combined active principles, it is desirable, for certain dosage forms, for them to have:
an extended release of the two active principles over a period of several hours, and with identical release profiles for the two substances;
a stability of the formulation over time, for example over a period of at least 6 months under accelerated conditions as described in the European and American pharmacopoeias.
This is particularly true for levodopa and carbidopa combinations. Specifically, carbidopa is a relatively fragile molecule and formulations containing this product often show relatively poor conservation, particularly at high temperature and high humidity.
Various formulations corresponding to a levodopa/carbidopa combination with sustained release are disclosed in the literature.
Document U.S. Pat. No. 5 840 756 discloses a matrix based on hydroxypropylmethylcellulose, hydroxypropylcellulose an a carboxyvinyl polymer and containing different proportions of levodopa and carbidopa. This formulation is obtained by direct compression of the mixture of the constituents. The drawback of such a process lies in the difficulty in obtaining a uniform distribution of the active principles during direct compression. This formulation does not have good stability.
Document EP-A-0 253 490 discloses a formulation of levodopa and carbidopa uniformly dispersed in a polymeric matrix consisting of a mixture of two polymers, one of which is water-soluble, such as hydroxypropyl(methyl)cellulose, and the other of which is weakly soluble, such as polyvinyl acetate/crotonic acid copolymer. Such a formulation is, firstly, complex (it requires the steps of mixing the active compounds with an aqueous-alcoholic solution of the polymers, drying, grinding, mixing with the lubricant and finally compressing into tablets), and secondly there is no indication as to the stability of the preparation.
No formulation of the prior art makes it possible simultaneously to obtain a parallel sustained release of the two principles with high stability over time, while at the same time being simple in its composition and implementation.
SUMMARY OF THE INVENTION
The invention relates to a pharmaceutical composition comprising a therapeutically effective amount of levodopa and of carbidopa, dispersed in a hydrophilic matrix, said composition further comprising an organic acid.
According to one embodiment, the organic acid is chosen from fumaric acid, citric acid, ascorbic acid, maleic acid, glutamic acid, malonic acid and oxalic acid.
According to one embodiment, the organic acid represents from 0.2% to 5% by weight relative to the weight of the composition.
According to one embodiment, the hydrophilic matrix represents from 10% to 80% by weight relative to the weight of the composition.
According to one embodiment, the hydrophilic matrix comprises hydroxypropylmethylcellulose.
According to one embodiment, the hydrophilic matrix comprises, as a percentage by weight relative to the weight of the composition, between 5% and 40% of hydroxypropylmethylcellulose with a viscosity of about 50 cP and between 5% and 40% by weight of hydroxypropylmethylcellulose with a viscosity of about 3 cP.
According to one embodiment, the hydrophilic matrix moreover comprises an insoluble substance.
According to one embodiment, the insoluble substance is microcrystalline cellulose.
According to one embodiment, the levodopa is present in an amount of between 50 mg and 300 mg.
According to one embodiment, the carbidopa is present in an amount of between 10 mg and 80 mg.
According to one embodiment, the composition is in the form of granules compressed together.
The composition according to the invention is useful in the treatment of Parkinson's disease.
The invention also relates to a process for preparing a composition according to the invention, comprising granulation of the various components and compression of the granules obtained.
According to one embodiment, the granulation is carried out in a fluidized bed.


REFERENCES:
patent: 4424235 (1984-01-01), Sheth et al.
patent: 5190763 (1993-03-01), Edgren et al.
patent: 5525631 (1996-06-01), Milman et al.
patent: 5532274 (1996-07-01), Wenzel et al.
patent: 0 253 490 (1998-01-01), None
patent: WO 99/04765 (1999-02-01), None

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