Title of Invention

DRINKABLE PHARMACEUTICAL COMPOSITION

Abstract The present invention relates to an aqueous solution containing 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride (hydrochloride of SR 57746), also comprising β-cyclodextrin (β-CD) and a pharmaceutically acceptable acid or buffer to give a pH of less than or equal to 3.
Full Text The present invention relates to a drinkable oral pharmaceutical composition containing l-[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 p-cyclodextrin at an acidic pH.
l-[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 (US 5,026,716), anticonstipation agents (US 5,109,005), neurotrophic agents {US 5,270,320), anti-free-radical agents (US 5,292,745), cardioprotective agents (US 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-p-CD, a-CD and y-CD. The methylated derivatives (such as, for example, RAMEB-CD, "randomized methylated P-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 p-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 P-cyclodextrin (p-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 p-CD expressed in mg/ml;
a pharraaceutically acceptable acid or buffer to
give a pH of less than or equal to 3;
with the proviso that, for an amount of p-CD ranging
from 30 to 50 rag/ml, the amount of SR 57746
hydrochloride fits the equation:
amount of SR 57746
hydrochloride (mg/ml) >
amount of p-CD (mg/ml) -10
The SR 57746 hydrochloride can be prepared according to the methods described in EP 101,381 or WO 98/28273.
The p-CD to be used according to the invention is a p-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 l-[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 p-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 p-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 p-CD ranging
from 30 to 50 mg/ml, the amount of SR 57746
hydrochloride fits the equation:
amount of SR 577 4 6
hydrochloride (mg/ml) >
amount of p-CD (mg/ml) -10
Preferred solutions according to the present invention comprise an amount of SR 5774 6 hydrochloride ranging from 0.1 to 2 mg/ml.

According to a preferred aspect, the solutions of the invention comprise an amount of p-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 p-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/nl of SR 57746 hydrochloride, about 10 mg/ml of p-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 P-CD a complex comprising 2 molecules of p-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 p-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 p-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 p-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 raultidose 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.

Whether or not they have been passed through an autoclave, the pharmaceutical compositions according to the present invention proved to be very stable on storage, under the following conditions:
- a temperature of between 5°C and 40°C
- storage for 3 months.
The compositions of the invention, in dosage units, can be packaged according to the usual practice, for example in glass, polycarbonate, polyvinyl chloride, polyethylene or polypropylene bottles and sealed with pharmaceutically acceptable stoppers, for example stoppers made of chlorobutyl or bromobutyl elastomer, optionally lined with Teflon and covered, where appropriate, with a suitable cap.

Example
Solution of SR 57746 at 0.5 mg/ml
220 mg of SR 57746 hydrochloride (corresponding
to 200 mg of SR 57746 free base), 4 g of p-CD
(Roquette Freres, in accordance with the tests
of the European and American pharmacopoeias)
and 4.2 g of citric acid monohydrate in 400 ml
of water are mixed together at room
temperature, in the open air or in the absence
of oxygen or under a cover of nitrogen, in any
order, and are stirred until completely
dissolved.
4 ml of solution are divided into 9 ml white
glass bottles; the bottles are sealed with
stoppers made of chlorobutyl elastomer and the
stopper is covered with an aluminium cap.


We claim:
l.An Aqueous solution containing l-[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 P-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 P-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 P-CD ranging from 30 to 50 mg/ml, the amount of SR 57746 hydrochloride fits the equation:
amount of SR 57746

2. The solution according to Claim 1, in which the pharmaceutically acceptable acid
is chosen from acetic acid, tartaric acid, ascorbic acid, lactic acid, succinic acid,
fumaric acid and citric acid, as they are or included in buffer systems.
3. The solution according to Claim 2,in which the pharmaceutically acceptable acid is citric acid.
4. The solution according to Claim 3, in which the citric acid is present in amounts ranging from 0.1 mg/ml to 200 mg/ml.
5. The solution according to Claim 1, wherein that it comprises an amount of SR 57746 hydrochloride ranging from 0.1 to 2 mg/ml.
6. The solution according to Claim 1, wherein that it comprises an amount of β-CD of between 5 and 15 mg/ml.

7. The solution according to Claim 1, wherein that it comprises an amount of SR 57746 hydrochloride ranging from 0.1 to 1.1 mg/ml, an amount of β -CD of between 5 and 15 mg/ml and an amount of citric acid ranging from 1 to 100 mg/ml.
8. The solution according to Claim 7, wherein that it comprises 0.55 mg/ml of SR 57746 hydrochloride, an amount of β-CD of about 10 mg/ml and an amount of citric acid of about 10 mg/ml.
9. The solution according to Claim 7, wherein that it comprises 1.1 mg/ml of SR
57746 hydrochloride, an amount of β-CD of about 10 mg/ml and an amount of citric
acid of about 10 mg/ml.
10. A drinkable pharmaceutical composition in dosage units, wherein that it
comprises the aqueous solution according to Claim 1, in which the SR 57746
hydrochloride is present in an amount of from 0.5 to 10 mg per dosage unit.
11. The composition according to claim 10, in which the SR 57746 hydrochloride is present in an amount of from 1 5 per dosage unit.
12. The composition according to claim 11, wherein that it comprises the aqueous solution according to Claim 2.
13. The composition according to claim 11, wherein that it comprises the aqueous solution according to claim 3.
14. The composition according to claim 11, wherein that it comprises the aqueous
solution according to claim 4.
15. The composition according to claim 11, wherein that it comprises the aqueous solution according to claim 5.
16. The composition according to claim 11, wherein that it comprises the aqueous solution according to claim 6.

17. The composition according to claim 11, wherein that it comprises the aqueous
solution according to claim 7.
18. The drinkable pharmaceutical composition according to claim 11, wherein it
comprises 2.2 mg of SR 57746 hydrochloride, 40 mg of β -CD, 42 mg of
citric acid monohydrate and water, the total volume of the composition being 4 ml.
19. The drinkable pharmaceutical composition according to claim 11, wherein that it
comprises 4.4 mg of SR 57746 hydrochloride, 40 mg of β -CD, 42 mg of citric acid
monohydrate and water, the total volume of the composition being 4 ml.
20. An aqueous solution as claimed in claim 1 containing one molecule of SR 57746
and two molecules of β-CD.

Documents:

2858-mas-1998 abstract-duplicate.pdf

2858-mas-1998 abstract.pdf

2858-mas-1998 claims-duplicate.pdf

2858-mas-1998 claims.pdf

2858-mas-1998 correspondence-others.pdf

2858-mas-1998 correspondence-po.pdf

2858-mas-1998 description (complete)-duplicate.pdf

2858-mas-1998 description (complete).pdf

2858-mas-1998 form-1.pdf

2858-mas-1998 form-19.pdf

2858-mas-1998 form-26.pdf

2858-mas-1998 form-4.pdf

2858-mas-1998 form-6.pdf

2858-mas-1998 others.pdf

2858-mas-1998 petition.pdf


Patent Number 211758
Indian Patent Application Number 2858/MAS/1998
PG Journal Number 52/2007
Publication Date 28-Dec-2007
Grant Date 09-Nov-2007
Date of Filing 24-Dec-1998
Name of Patentee SANOFI SYNTHELABO
Applicant Address 174 AVENUE DE FRANCE, 75013 PARIS,
Inventors:
# Inventor's Name Inventor's Address
1 THIERRY BREUL 118 AVENUE F. DE LESSEPS, 34110 FRONTIGNAN,
2 CLAUDE ALEMAN 7 ROUTE DE FABREGUES, 34660 COURNONTERAL,
3 PHILIPPE BASTARD 189 RUE EDMOND LAUTARD, 34080 MONTPELLIER,
4 ARIELLE BONNEL MAS DE BONNEL, 34660 COURNONSEC,
PCT International Classification Number A61K 31/4418
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 97 16529 1997-12-24 France