Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-16
2001-02-20
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06191137
ABSTRACT:
The present invention relates to a drinkable oral pharmaceutical composition containing 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride.
More specifically, the invention relates to a drinkable composition of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride in aqueous solution with &bgr;-cyclodextrin at an acidic pH.
1-[2-(2-Naphthyl)ethyl]-4-(3-trifluoromethyl- phenyl)-1,2,3,6-tetrahydropyridine, referred to hereinbelow by its code number SR 57746, and its pharmaceutically acceptable salts, in particular its hydrochloride, have been described in EP 0,101,381 as anorexigenic agents and, subsequently, as anti- anxiodepressants (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), anti-free-radical agents (U.S. Pat. No. 5,292,745), cardioprotective agents (U.S. Pat. No. 5,378,709) and as agents which are useful in the treatment of amyotrophic lateral sclerosis (WO 97/15304).
In some of these documents, it is indicated that SR 57746 can be administered in suitable pharmaceutical forms, including the form as a complex with cyclodextrins. However, no complex of this type has ever been described.
The poor solubility of SR 57746 and of its salts in water, in particular hydrochloride (0.03 mg/ml), as well as the instability of the aqueous solutions thus formed, represent a serious problem for the administration and storage of solutions containing this compound. This problem becomes even more serious when it is desired to prepare a drinkable aqueous solution which can be swallowed easily by patients with swallowing problems.
Preliminary studies carried out with standard solubilizing agents, including cyclodextrins (referred to hereinbelow as CDs), have generally led either to insufficient solubilization or to partial degradation of the SR 57746. For example, poor results were obtained with 2-hydroxypropyl-&bgr;-CD, &agr;-CD and &ggr;-CD. The methylated derivatives (such as, for example, RAMEB-CD, “randomized methylated &bgr;-CD”) appeared to give interesting results, but their use in pharmaceutical compositions is, for the time being, not permitted by the European and American pharmacopoeias.
It has now been found that large amounts of SR 57746 hydrochloride can be dissolved, giving stable aqueous solutions, by using &bgr;-cyclodextrin, this solubilization being improved at acidic pHs.
More specifically, it has been confirmed that the above components, in given relative amounts, produce aqueous solutions which are stable over time, even under extreme temperature conditions.
Thus, the subject of the present invention is an aqueous solution containing 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride (hydrochloride of SR 57746), characterized in that it comprises:
a non-zero amount of &bgr;-cyclodextrin (&bgr;-CD) of less than or equal to 50 mg/ml;
a non-zero amount of SR 57746 hydrochloride (in mg/ml) of less than or equal to one-tenth of the amount of &bgr;-CD expressed in mg/ml;
a pharmaceutically acceptable acid or buffer to give a pH of less than or equal to 3;
with the proviso that, for an amount of &bgr;-CD ranging from 30 to 50 mg/ml, the amount of SR 57746 hydrochloride fits the equation:
amount of SR 57746
hydrochloride
(
mg
/
ml
)
≥
[
amount
of
β
-
CD
(
mg
/
ml
)
10
-
3
]
The SR 57746 hydrochloride can be prepared according to the methods described in EP 101,381 or WO 98/28273.
The &bgr;-CD to be used according to the invention is a &bgr;-CD in accordance with the tests of the European and American pharmacopoeias.
The pharmaceutically acceptable acids which can be used according to the present invention are, for example, acetic acid, citric acid, tartaric acid, ascorbic acid, lactic acid, succinic acid or fumaric acid.
These acids can be used as they are or included in buffer systems.
Examples of buffers which can be used according to the invention are acetic acid/sodium or potassium acetate systems; tartaric acid/sodium or potassium tartrate systems; lactic acid/sodium or potassium lactate systems; and ascorbic acid/sodium or potassium ascorbate systems.
Citric acid, in anhydrous or hydrated form, in particular citric acid monohydrate, is particularly advantageous for the preparation of the solution of the invention.
According to a preferred aspect, the present invention relates to an aqueous solution based on 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride (hydrochloride of SR 57746), characterized in that it comprises
a non-zero amount of &bgr;-CD of less than or equal to 50 mg/ml
a non-zero amount of SR 57746 hydrochloride (in mg/ml) of less than or equal to one-tenth of the amount of &bgr;-CD expressed in mg/ml
an amount of citric acid ranging from 0.1 mg/ml to 200 mg/ml
with the proviso that, for an amount of &bgr;-CD ranging from 30 to 50 mg/ml, the amount of SR 57746 hydrochloride fits the equation:
amount of SR 57746
hydrochloride
(
mg
/
ml
)
≥
[
amount
of
β
-
CD
(
mg
/
ml
)
10
-
3
]
Preferred solutions according to the present invention comprise an amount of SR 57746 hydrochloride ranging from 0.1 to 2 mg/ml.
According to a preferred aspect, the solutions of the invention comprise an amount of &bgr;-CD of between 5 and 15 mg/ml.
According to a particularly preferred aspect, the solutions of the invention comprise an amount of SR 57746 hydrochloride ranging from 0.1 to 1.1 mg/ml, an amount of &bgr;-CD of between 5 and 15 mg/ml and an amount of citric acid ranging from 1 to 100 mg/ml, preferably from 5 to 50 mg/ml, advantageously about 10 mg/ml.
Among these solutions, those comprising 0.55 mg/ml or 1.1 mg/ml of SR 57746 hydrochloride, about 10 mg/ml of &bgr;-CD and about 10 mg/ml of citric acid are more advantageous.
It has been found, by 2-dimensional coupled NMR tests, that SR 57746 in water forms with the &bgr;-CD a complex comprising 2 molecules of &bgr;-CD per molecule of SR 57746.
The stoichiometry of this complex was confirmed by microcalorimetry titration studies in aqueous solution in the presence of citric acid monohydrate at about 10 mg/ml.
It has also been found that two molecules of &bgr;-CD encapsulate the molecule of SR 57746 in aqueous solution at the two opposite ends of the SR 57746 compound and that the complex thus obtained is not only very soluble but also very stable in aqueous solution.
The complex formed between a molecule of SR 57746 and two molecules of &bgr;-CD is novel and constitutes a further subject of the present invention.
The solution can be prepared according to the usual techniques, by mixing in water, in any order, the SR 57746 hydrochloride, the &bgr;-CD and the acid or buffer system chosen, in the amounts envisaged by the invention, and stirring the mixture until the constituents have completely dissolved.
The solution can then be purified, for example by ultrafiltration, optionally passed through an autoclave, according to the usual techniques, and then stored as it is or divided into monodose or multidose containers.
The solution according to the present invention can be used in the form of dosage units containing an effective amount of active principle.
Thus, according to another of its aspects, the present invention relates to a drinkable pharmaceutical composition, in dosage units, characterized in that it comprises an aqueous solution as defined above, in which the SR 57746 hydrochloride is present in an amount of from 0.5 to 10 mg per dosage unit, preferably from 1 to 5 mg per dosage unit.
The solution and the composition of the invention can optionally comprise sweeteners or flavouring agents to enhance its taste.
Particularly advantageous pharmaceutical compositions are indicated in Table 1.
TABLE 1
Pharmaceutical compositions in dosage units
SR 57746 hydrochloride
2.2
mg
4.4
mg
&bgr;-CD
40
m
Aleman Claude
Bastard Philippe
Bonnel Marielle
Breul Thierry
Alexander Michael D.
Dupont Paul E.
Henley III Raymond
Sanofi-Synthelabo
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