Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-06
2002-12-03
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S346000
Reexamination Certificate
active
06489334
ABSTRACT:
The present invention relates to a method of crystallizing a tetrahydropyridine derivative, to the novel crystalline forms thereby obtained and to a pharmaceutical composition containing said tetrahydropyridine derivative in a given crystalline form as the active principle.
The present invention relates more particularly to a method of crystallizing [-2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, to three crystalline forms of this product, to a defined mixture of two of these three forms and to a pharmaceutical composition containing one of said forms or a mixture of two of said forms.
1-[2-(2-Naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, hereafter designated by its code number SR 57746, and its pharmaceutically acceptable salts were first described in EP 0 101 381 as anorexigenic agents and subsequently as antianxiodepressants (U.S. Pat. No. 5,026,716), anticonstipation agents (U.S. Pat. No. 5,109,005), neurotrophic agents (U.S. Pat. No. 5,270,320), free radical inhibitors (U.S. Pat. No. 5,292,745) and cardioprotective agents (U.S. Pat. No. 5,378,709).
EP 0 101 381 describes SR 57746 in the form of the hydrochloride, hereafter called SR 57746 A, and this salt was used in preclinical and clinical trials on healthy volunteers. According to said document, SR 57746 A is isolated by crystallization from ethanol, especially absolute ethanol.
In the preclinical trials, especially in the animal pharmacology and toxicology tests, SR 57746 A showed a constant activity and behavior. Likewise, the pharmacokinetic studies on animals gave constant and reproducible results.
By contrast, in the clinical trials carried out on healthy volunteers (Phase I), SR 57746 A was found to show a high variability in the plasma concentrations and the pharmacodynamic effects of the active principle.
In the first clinical trials on patients suffering from very serious diseases, especially amyotrophic lateral sclerosis, the dose of SR 57746 A was kept very low, namely 2 mg/day, at which dose the product proved promising (W. G. Bradley, paper entitled “New drugs for amyotrophic lateral sclerosis”, American Academy of Neurology meeting, Mar. 23-30, 1996; pages 240-23/240-28).
It has furthermore been found that the preparation of larger amounts of SR 57746 A by the method of isolation described in EP 0 101 381 does not successfully yield a product with constant characteristics which makes it possible to overcome the disadvantages noted in the Phase I clinical trials.
It was found more particularly that, by the method of isolation described in EP 0 101 381, the SR 57746 A obtained consists of crystals whose size is not constant and specifically is greater than 150 micrometers; more particularly, it is 150-600 micrometers for at least about 75% of the crystals.
Moreover, it has been found that the SR 57746 A obtained by the method described in EP 0 101 381 consists of at least 3 different forms, as demonstrated by differential scanning calorimetry.
Finally, it has been found that the respective ratios of the different forms are not constant in different production lots of SR 57746 A, making it difficult to control the characteristics of the starting material for the manufacture of pharmaceutical compositions.
It has now been found that by carrying out the crystallization of SR 57746 A under suitable and constant conditions in terms of solvent, stirrer speed and cooling rate, it is possible to isolate the compound in three different crystalline forms or as a mixture of two of these three forms in fixed and reproducible ratios.
More particularly, it has been found that:
form I of SR 57746 A is obtained by cooling a solution of SR 57746 A in an ethanol/concentrated hydrochloric acid mixture, without stirring;
form II of SR 57746 A is obtained by cooling a solution of SR 57746 A in absolute ethanol or in an ethyl acetate/water mixture under controlled conditions of cooling rate and stirrer speed;
form III of SR 57746 A is obtained by cooling a solution of SR 57746 A in dimethyl sulfoxide; and
a mixture of form I and form III in fixed and reproducible proportions is obtained by cooling a solution of SR 57746 A in an ethanol/water mixture.
It has also been found that these novel crystalline forms, either by themselves or in fixed mixtures of two of said forms, are absorbed uniformly and reproducibly and make it easy to establish the optimum dosage of the active principle. Over and above the improvements in pharmacokinetic and pharmacodynamic terms, the ability to control the reproducibility of the composition of SR 57746 A in crystalline form is very advantageous as far as marketing of the drug is concerned.
Finally, it has been found that if the novel crystalline forms or the mixtures of two of said forms consist of very small crystals, especially micronized crystals, the activity of the active principle increases substantially and its absorption is uniform and constant, thus making it possible to administer small dosages with a very good therapeutic response and at the same time totally to control the potential side effects.
REFERENCES:
patent: 4521428 (1985-06-01), Nisato et al.
Caron Antoine
Franc Bruno
Monnier Olivier
Alexander Michael D.
Dupont Paul E.
Huang Evelyn Mei
Sanofi-Synthelabo
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