MXPA99005621A - Micro-particulate form of a tetrahydropyridin derivative - Google Patents

Abstract

The invention concerns a micro-particulate form of the hydrochlorate of 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin consisting of particles of which at least 55%of the population has a diameter less than 50 micrometers, and pharmaceutical compositions containing it.

Description

MICROPARTICULATED FORM OF A TETRAHYDROPYRIDINE DERIVATIVE DESCRIPTION OF THE INVENTION The present invention relates to a microparticulate form of l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride. 1- [2- (2-Naphthyl) ethyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine, hereinafter referred to by its code number SR 57746, and its pharmaceutically acceptable salts they were described for the first time in EP 0 101 381 as anorectic agents and then as anti-anxiety suppressants (US-5,026,716), anticonstipants (US 5,109,005), neurotrophics (US 5,270,320), anti-free radicals (US 5,292,745) and cardioprotectors (US 5,378,709). In EP 0 101 381, SR 57746 is described in the form of a hydrochloride, referred to as • continued SR 57746 A, and its salt was used in preclinical and clinical trials in healthy volunteers (Phase I) SR 57746, according to this document, is isolated by crystallization from ethanol, particularly from absolute ethanol. REF .: 30351 In the preclinical tests, particularly in the animal pharmacology and toxicology tests, the SR 57746 has presented a constant activity and behavior. Likewise, pharmacokinetic studies in animals have given constant and reproducible results. On the contrary, during the clinical studies carried out in healthy volunteers (Phase I), SR 57746 A administered orally shows a great variability in plasma concentrations and in the pharmacodynamic effects of the active principle. In the first clinical trials in patients affected by very serious diseases, particularly lateral sclerosis to iotrophic, the dose of SR 57746 A was kept very low, namely 2 mg / day and at this dose the product has shown to be promising (.

G. Bradley, presentation entitled "New drugs for amyotrophic lateral sclerosis", meeting of the American Academy of Neurology, March 23-30, 1996; • pages 240-23 / 240/28). It has also been found that in the preparation of larger quantities of SR 57746 A according to the isolation procedure described in EP 0 101 381 it has not been possible to obtain a product with the constant characteristics that allows to solve the drawbacks observed during the studies Phase I clinics. More particularly, it has been found that according to the isolation procedure described in EP 0 101 381 an SR 57746 A composed of crystals whose size is not constant and, particularly, is greater than 150 micrometers is obtained. , more particularly it is 150-600 micrometers in at least about 75% of the crystals. It has now been found that by isolating SR 57746 A by recrystallization from absolute ethanol under stirring, an SR 57746 A is obtained consisting of crystals of which at least 55% of the whole have a size of less than 50 micrometers and the product thus obtained has a higher activity when administered orally in a human clinic. It has also been found that by subjecting a solution of SR 57746 A in ethanol, which optionally contains water, to an atomization operation, an active substance is obtained in an essentially amorphous form which has a constant degree of absorption in man and a very high activity. -evada that allows the administration of the active principle at very small doses. It has also been found that said atomization gives small spherical particles whose diameter is less than 15 micrometers, in a constant and reproducible manner, allowing to solve the disadvantages due to the variability of the characteristics of SR 57746 A isolated as described in EP 0 101 381. It has further been found that an identical result is obtained by icronization of SR 57746 A obtained by crystallization in absolute ethanol, as described in EP 0 101 381, so as to obtain crystals of size less than 50 microns. A) Yes, according to one of its aspects, the present invention has as its object a microparticulate form of l- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-hydrochloride. -tetra- hydropyridine composed of microparticles, of which at least 55% of the set has a diameter of less than 50 micrometers. The microparticles according to the present invention can be microspheres that can be obtained by atomization or microcrystals obtained by sieving or by micronization. The expression "diameter less than 50 micrometers" refers to both the microspheres and the microcrystals, the latter being assimilable to the microspheres. Advantageously, the size of the microparticles according to the present invention corresponds to a diameter of less than 25 microns, preferably less than 15 microns. Particularly preferred are microparticles which have for the most part (80-85%) a diameter of less than 10 micrometers. An SR 57746 A having a fine granulometry, namely, a product formed by a set of crystals of which at least 55% have a size of less than 50 microns can be prepared by recrystallization of the product obtained according to EP 0 101 381 characterized in that said product is heated in absolute ethanol under stirring, heating is stopped when the solution is complete and stirring when the temperature reaches about 40 ° C, the mixture is left for 16 to 60 hours at room temperature, then stir vigorously at 10-18 ° C, filter and dry. Alternatively, an SR 57746 A having the same fine granulometry can be obtained by operating as described in EP 0 101 381, by reacting the 4- (3-trifluoromethylphenyl) -1,2,6,6-tetrahydropyridine with the 2- (2-chloroethyl) naphthalene in the presence of triethylamine or by subjecting 1- (2-naphthylacetyl) -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine to a reduction with lithium hydride and aluminum, but then taking up again the residue constituted by 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,6,6-tetrahydropyridine base directly with hydrochloric acid in absolute ethanol at reflux and operating below as illustrated above. The microparticles according to the present invention can also be prepared by atomization of solutions of SR 57746 A, advantageously in (C? ~ C3) alkane, in (C3-C6) • alkanones or in ethyl acetate optionally in the presence of water, preferably by atomization of a solution of SR 57746 A in ethanol containing 0 to 40% water, in a classic atomizer, for example, a mino Buchi Spray Dryer, regulating the flow of the pump, the suction, the heating, the current flow in order to establish an inlet temperature between 150 and 190 ° C, an outlet temperature between 50 and 120 ° C and a depression of 30 to 70 mbar. By atomization of these solutions, small spherical particles smaller than 50 micrometers are obtained, of which particularly 80-85% may have a diameter of less than 10 micrometers, which, in differential differential chromatography (DSC) carried out using a DSC7 Per in Elmer apparatus, calibrated with reference to indium and cyclohexane, presenting a single widened peak of 130 to 160 ° C, the maximum of which is 146 ± 3 ° C. Advantageously, the microparticles according to the present invention are prepared by micronization of SR 57746 A obtained as described in EP 0 101 381. This micronization can be carried out in a conventional apparatus that allows obtaining microcrystals having a size of less than 50 micrometers, example, in an Alpine 200 AS micronizer, introducing SR 57746 A in the micronization chamber (diameter of 200 mm) at a speed of 15 to 50 kg / hour and a working pressure of 1 to 6.5 bar and recovering the product in a filter bag. It is particularly advantageous to operate under conditions which make it possible to obtain microcrystals whose particle set has an average size of less than 25 micrometers, or better still, less than 15 micrometers. Preferably, it is operated in order to obtain a set of microcrystals of which 80-85% have a size of less than 10 micrometers. If the microcrystals thus obtained tend to aggregate, the aggregates can be screened before preparing the pharmaceutical compositions * ^. The eventual aggregation of the microcrystals does not, however, change the absorption of the active principle, as has been demonstrated in the test of the CACO-2 cells illustrated below. To prevent such aggregation, SR 57746 A can be micronised if necessary, for example, of mannitol, preferably of D-mannitol. As indicated above, the microparticles according to the present invention possess properties that make them particularly advantageous for the preparation of the compositions containing them. More particularly, it has been shown that the microcrystalline form not only makes it possible to reduce the amount of doses present in the pharmaceutical compositions but, above all, makes it possible to make oral absorption uniform and thus have a constant therapeutic response of each patient. In addition, said absorption is independent of the feeding conditions. A study which relates to the determination of the absorption in vi tro of the microparticles according to the present invention has been carried out using the mono-layer model CACO-2. This test, widely used as an intestinal epithelial model to predict the absorption of drugs (P. Artusson, Crit. Rev. 'Ther. Drug, 1991, 8: 305-330) has allowed to demonstrate the significant differences of dissolution and permeability of the SR 57746 A micronized in relation to SR 57746 A not micronized • nor atomized. The results obtained show that, in the medium used (Hauk's solution added with 10% fetal calf serum and taurocholic acid), dissolution and permeability rates are significantly different for SR 57746 A micronized or atomized in relation to SR 57746 A not micronized or atomized. More particularly, it has been shown that the dissolution and the permeability are normalized, namely, made uniform, after micronization or atomization. The results obtained in vi tro were confirmed in vi ve comparing the observations obtained in two clinical studies in healthy volunteers: the first study evaluates the effect of feeding on the oral absorption of SR 57746 A obtained according to EP 0 101 381 and the second study evaluates the effect of feeding on oral absorption of SR 57746 A of Example 5 indicated below. In the two studies, the absorption evaluation criterion was the area under the curve of plasma concentrations of SR 57746 as a function of time. The analysis of the results showed that: - when the administration is carried out with the meal, a dose of SR 57746 A prepared according to EP 0 101 381 is required three to four times higher than that of the product of Example 5 indicated below to get the same absorption; when the administration is carried out on an empty stomach, a dose of SR 57746 A prepared according to EP 0 101 381 is required approximately nine times higher than that of the product of Example 5 indicated below to obtain the same absorption. In these studies it has been found, surprisingly, that in the case of the administration of SR 57746 A prepared according to EP 0 101 381, absorption is two to three times higher when the product is taken with food while in the case of the administration of the product of Example 5, the absorption is the same whether the product is administered fasting or with food. These results show the interest of the present invention that allows to supply a product that has a better absorption that is not influenced by the ingestion of food. Thus, according to another of its aspects, the present invention relates to pharmaceutical compositions containing, as an active ingredient, a microparticulate form of the l- [2- (2-naphthyl) ethyl] -4- (3- trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine constituted by microparticles of which at least 55% of the whole have a size of less than 50 microns, advantageously less than 25 microns, preferably for 80-85% of the particles, lower at 10 micrometers. The amount of active principle to be administered depends on the nature and severity of the conditions to be treated as well as the weight of the patients. However, the amount of active ingredient present in the dosage unit can be from 0.1 to 5 mg, advantageously from 0.5 to 3 mg, preferably 2 mg (calculated on free base). Preferred unit doses will generally comprise 0.5, 1, 1.5, 2, 2.5 or 5 mg (calculated on a free basis) of the micronized product. These unit doses will normally be administered once or several times per day, for example, once or twice a day, with the overall dose in man varying between 0.2 and 10 mg per day, advantageously between 1 and 6 mg per day (calculated on the basis of free) . In the pharmaceutical compositions of the present invention, the active ingredient can be administered, in unit dosage forms mixed with classical pharmaceutical carriers, to animals and humans for the treatment of the conditions indicated in US Pat. Nos. 5,026,716, 5,109 .005, 5,270,320. 5,292,745 and 5,378,709, in particular for the treatment of neurodegeneration. Suitable unit administration forms include the optionally scored tablets, capsules, powders, granules. When preparing a solid composition in the form of tablets, the active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets of sucrose or other suitable substances can be coated or they can also be treated in such a way that they have a prolonged or delayed activity and that they release in a continuous manner a predetermined quantity of active principle. A capsule preparation is obtained by mixing the active ingredient with a diluent and pouring the obtained mixture into the soft or hard capsules. The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.

In the pharmaceutical compositions according to the present invention, the active principle may also be in the form of inclusion complex in cyclodextrins, their ethers or their esters. The compositions of the invention can also be prepared by an extrusion-spheronization process that allows to obtain spheroids having the desired size. By means of this process, the SR 57746 A is mixed in microparticles, preferably atomized or micronized, with the excipients and with demineralized water, the mass obtained is subjected to a granulation and an extrusion in order to obtain an extrusion mass that It flows freely through the holes that have the desired diameter, the extruded material is spheronized in order to obtain spheroids whose diameter is that of the holes, the spheroids thus obtained are dried and preferably, they are introduced into the capsules. In this way SR 57746 A and the excipients are mixed so as to obtain a ready-to-use pharmaceutical composition. The following examples illustrate the invention.

EXAMPLE 1 Operating under the conditions described in Example 1 of EP 0 101 381, the 4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydro-pyridine is reacted in the presence of triethylamine with the - (2-Chloroethyl) naphthalene in ethanol at reflux for 24 hours. The mixture is concentrated to dryness, the residue is taken up in ethyl ether and the etherified solution, filtered and washed with water, is dried and evaporated. The 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride is then isolated in the following manner: the residue is taken up in hydrochloric acid 100% ethanol and heated to reflux with stirring. When the solution is complete, heating is stopped and allowed to cool under agitation. After about ten minutes, stirring is stopped and the mixture is left at room temperature for 48 hours. It is filtered, the precipitate is washed with absolute ethanol, the cake is redissolved in absolute ethanol with pneumatic stirring, filtered and dried at 40 ° C under vacuum. Thus, with an overall yield of 10%, an SR 57746 A is obtained whose particle distribution is given in Table 1.

TABLE 1 Size in microns Percentage 4.0-6.0 0.8 6.0-8.0 2.6 8.0-10.0 3.8 10.0-14.0 6.3 14.0-20.0 6.4 20.0-30.0 13.9 30.0-40.0 15.8 40.0-50.0 9. 6 50.0-60.0 4.9 60.0-70.0 3.4 70.0-80.0 1.8 80.0-90.0 1.9 90.0-100.0 1.8 100.0-150.0 8.1 150.0-200.0 6.2 200.0-300.0 7.5 300.0-400.0 3.6 400.0-500.0 1.6 500.0-600.0 0.1 The microparticle form of SR 57746 A enid contains 59.2% particles having or less than 50 microns.

EXAMPLE 2 A mixture of 636 g of SR 57746 A, obtained as described in EP 0 101 381 and formed of crystals, of which 77% have a size between 150 and 600 microns, in 5 volumes of absolute ethanol is heated to reflux under stirring until complete dissolution of the product, then the heating is stopped and, when the temperature reaches 40 ° C the stirring is stopped and the mixture is left for 16 hours at room temperature. The mixture is brought to 16 ° C under vigorous stirring and, after 10-20 minutes under these conditions, it is filtered and dried under vacuum at 40 ° C for 24 hours. 415 g of SR 57746 A are thus obtained, constituted by a group of microparticles of which 60.3% have a size of less than 50 micrometers.

EXAMPLE 3 A solution of 3 g of SR 57746 A in 300 ml of ethanol is atomized in a "mino Buchi Spray Dryer" according to the principle of parallel stream nozzle atomization, regulating the flow rate of the pump, the suction, heating and current flow so as to have an inlet temperature of 172 ° C, an outlet temperature of 107 ° C and a depression of 40 mbar. Under these conditions, a product of a single widened peak in DSC is obtained with the maximum at 145 ° C. The particles obtained are spherical and the very homogeneous set does not exceed 5 micrometers in average size.

EXAMPLE 4 A solution of 3 g of SR 57746 A in 210 ml of ethanol and in 90 ml of water is atomized in an apparatus as described in Example 3, according to the principle of parallel stream nozzle atomization, regulating the flow of the pump, suction, heating and current flow so as to have an inlet temperature of 172 ° C, an outlet temperature of 63 ° C and a depression of 60 mbar. Under these conditions, an atomized, essentially amorphous SR 57746 A is obtained which, in the DSC thermogram, showed a single widened peak with a maximum at 147.6 ° C. The obtained particles are spherical and the very homogeneous set does not exceed 5 micrometers of average size.

EXAMPLE 5 In the micronization chamber (diameter 200 mm) of an Alpine 200 AS micronizer, 24 kg of SR 57746 A are introduced at a rate of 25 kg / hour and a working pressure of 6.5 bar and the product thus micronized is recovered in a filter bag. A micronized SR 57746 A is thus obtained having a particle distribution according to which all of the particles have a size of less than 20 micrometers and 85% of the particles have a size of less than 10 micrometers.

EXAMPLE 6 Pharmaceutical composition containing, as an active ingredient, micronized SR 57746 A according to Example 5 indicated above: Active principle 2.192 mg Corn starch 141-218 mg Colloidal anhydrous silica 0.200 mg Magnesium stearate 0.400 mg The active substance is sieved to 0.2 mm, then premixed with the excipients. This mixture is sieved at 0.315 mm, mixed again, then sieved again at 0.315 mm. After a last mixture, the composition is introduced into gelatin capsules No. 3, at a rate of 170 mg of composition containing an amount of micronized SR 57746 A corresponding to 2 mg of l- [2- (2-naphthyl) hydrochloride ) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine base.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (12)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A microparticulate form of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine hydrochloride composed of particles of which at least 55% of the total It has a diameter less than 50 micrometers.

2. A microparticle form according to claim 1, characterized in that the diameter of the particles is less than 25 micrometers.

3. A microparticle form according to claim 2, characterized in that the diameter of the particles is less than 15 microns.

4. A form in microparticles according to claim 3, characterized in that the diameter of 80-85% of the set of particles is less than 10 micrometers.

5. A microparticle form according to one of claims 1 to 4, characterized in that the particles are microspheres.

6. A microparticle form according to claim 5, characterized in that the microparticles are composed of the hydrochloride of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6 tetrahydropyridine in an essentially amorphous form.

7. A microparticle form according to one of claims 1 to 4, characterized in that the particles are micronized crystals.

8. A pharmaceutical composition containing, as an active ingredient, a microparticle form according to one of claims 1 to 7.

9. A composition according to claim 8, characterized in that it is in a dosage unit form.

10. A composition according to claim 9, characterized in that each dosage unit contains 0.1 to 5 mg of active principle (calculated on free base).

11. A composition according to claim 10, characterized in that each dosage unit contains from 0.5 to 3 mg of active principle (calculated on free base).

12. A composition according to claim 11, characterized in that each dosage unit contains 2 mg of active principle (calculated on free base).