HK1024000B - Micro-particulate form of a tetrahydropyridin derivative - Google Patents

Description

Tetrahydropyridine derivatives in particulate form

The present invention relates to 1- [2- (2-naphthyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride in the form of microparticles.

EP 0101381 describes for the first time 1- [2- (2-naphthyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine (hereinafter denoted by its code No. SR 57746) and its pharmaceutically acceptable salts, and uses them as anorectic agents, which are subsequently used as anxiolytic (US 5026716), anti-constipation (US 5109005), neurotrophic (US5270320), free radical inhibitors (US5292745) and cardioprotective agents (US 5378709).

EP 0101381 describes SR57746 in the form of the hydrochloride salt (hereinafter SR 57746A) and uses this salt in preclinical and clinical trials in healthy volunteers (phase I). According to said document, SR57746 is isolated by crystallization from ethanol (in particular anhydrous ethanol).

SR57746 shows stable activity and action in preclinical testing, especially in pharmacological and toxicological testing in animals. Furthermore, the pharmacokinetic studies in animals also yielded stable and reproducible results.

In contrast, in clinical trials on healthy volunteers, it was found that SR57746A showed high denaturation in plasma concentration and pharmacokinetic effect of the active ingredient.

In the initial clinical trial of patients with cachexia, especially amyotrophic lateral sclerosis, the dose of SR57746A was maintained at a very low level, i.e. 2 mg/day, at which the product proved to be effective (w.g. bradley, article title: New drugs for amyotrophic lateral sclerosis, american society for neurology, 1996, 23-30 days 3-24; p.240-23/240-28).

It has further been found that large scale preparation of SR57746A according to the isolation method described in EP 0101381 has not been successful in producing a product with stable properties to overcome the disadvantages noted in phase I clinical trials.

More particularly, it was found that SR57746A obtained according to the separation method described in EP 0101381 consists of crystals of indefinite size, in particular crystals greater than 150 μm; more particularly at least about 75% of these crystals have a size of 150-600 microns.

It has now been found that when SR57746A is isolated by means of recrystallization from anhydrous ethanol under stirring, the resulting SR57746A consists of crystals, wherein at least 55% of the particles have a particle size of less than 50 microns, and the resulting product has a higher activity when administered orally in human clinical.

It has furthermore been found that by nebulizing a solution of SR57746A in ethanol, optionally containing water, an active ingredient can be obtained in substantially amorphous form, which has a constant absorption level and a very high activity in the human body, thus enabling the active ingredient to be administered in very low doses.

It has also been found that the atomization described makes it possible to produce spherical pellets with a diameter of less than 15 μm in a stable and reproducible manner, and thus to overcome the disadvantages of the separation described in EP 0101381 of SR57746A due to its variability in properties.

Finally, it has been found that the same results can be obtained by micronizing SR57746A, obtained by crystallization from absolute ethanol as described in EP 0101381, giving crystals with a size of less than 50 microns.

Accordingly, in one aspect the present invention relates to 1- [2- (2-naphthyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride in the form of microgranules, wherein at least 55% of the particles have a diameter of less than 50 microns.

The microparticles of the present invention may be microspheres which are easily obtained by atomization or microcrystals obtained by sieving or micronization.

The term "diameter less than 50 microns" applies not only to microspheres but also to crystallites, the latter being similar to microspheres.

The size of the microspheres of the invention is advantageously less than 25 microns, preferably less than 15 microns in diameter. Particularly preferred are particles wherein the majority (80-85%) of the particles are less than 10 microns in diameter.

Fine particles SR57746A, a product consisting of crystal aggregates of which at least 55% of the particles are smaller than 50 μm, can be prepared by recrystallization of a product prepared according to EP 0101381, characterized in that the product is heated in absolute ethanol with stirring, the heating is stopped after complete dissolution and the stirring is stopped when the temperature reaches about 40 ℃, the mixture is then left to stand at room temperature for 16 to 60 hours, followed by vigorous stirring at 10 to 18 ℃, the product is filtered and dried.

On the other hand, fine particles SR57746A of the same size can also be prepared according to the method described in EP 0101381 by: 4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine is reacted with 2- (2-chloroethyl) naphthalene in the presence of triethylamine or 1- (2-naphthylacetyl) -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine is reduced with lithium aluminium hydride, but then the residue consisting of 1- [2- (naphthyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine base is reacted directly with hydrochloric acid in anhydrous ethanol under reflux, and then the procedure is followed as described above.

The microparticles of the present invention can also be prepared as follows: the SR57746A solution is atomized by means of a conventional atomizer, such as a Buchi mini spray dryer, advantageously in (C)₁-C₃) Alkanol (C)₃-C₆) Solutions in alkanones or ethyl acetate, optionally containing water, and preferably atomizing solutions of SR57746A in ethanol containing 0-40% water, the discharge of the pump, the suction, the heating and the flow rate are adjusted such that the inlet temperature reaches 150-190 ℃, the outlet temperature reaches 50-120 ℃ and the partial vacuum is 30-70 mbar.

Atomization of these solutions enables the formation of small spherical particles of a size of less than 50 microns, 80-85% of which may in particular have a diameter of less than 10 microns, and which exhibit a single broad peak at 130-.

The microparticles of the present invention may conveniently be prepared by micronising SR57746A prepared as described in EP 0101381. This micronization can be carried out in a conventional apparatus capable of obtaining microcrystals with a size of less than 50 microns, such AS an ALPINE 200 AS pulverizer, in which SR57746A is fed at a rate of 15-50 kg/hour to the micronization chamber (diameter 200mm), operating at a pressure of 1-6.5 bar, and the product is recovered in a filter bag.

Particularly advantageously, the operating conditions should be such that the population of crystallites obtained has an average particle size of less than 25 microns, preferably less than 15 microns. The preferred operating conditions are such that 80-85% of the resulting crystallite populations have a particle size of less than 10 microns.

If the crystallites obtained in this way are aggregated, the resulting aggregates can be sieved before the preparation of the pharmaceutical composition. However, any aggregation of the crystallites does not alter the absorption of the active ingredient, as shown in the CACO-2 cell assay described below.

To prevent this aggregation from occurring, SR57746A may optionally be micronized in the presence of, for example, mannitol (preferably D-mannitol).

As mentioned above, the microparticles of the present invention have properties that are particularly advantageous for the preparation of pharmaceutical compositions comprising them.

More specifically, it has been demonstrated that the microcrystalline forms not only enable a reduction in their amount in the pharmaceutical composition, but also in particular enable an oral absorption uniformity, with a stable therapeutic response for each patient. In addition, the absorption is independent of feeding factors.

The in vitro absorption of the microcrystals of the invention was determined using the CAC0-2 monolayer model. This test is widely used as a predictive intestinal epithelial drug absorption model (p. artusson, crit. rev. the r. drug, 1991, 8: 305-.

The results obtained show that the dissolution and permeation rates in the medium used (i.e. Hanks solution supplemented with 10% fetal bovine serum and taurocholic acid) differ significantly between micronized or nebulized SR57746A and non-micronized, non-nebulized SR 57746A. More specifically, we have demonstrated that the solubility and permeability of the product after micronization or atomization appear normalized, i.e. become homogeneous.

The above results obtained in vitro were further confirmed in vivo by comparing the observations of two clinical trials conducted on healthy volunteers, the first trial to assess the effect of feeding on oral absorption of SR57746A according to EP 0101381, and the second trial to assess the effect of feeding on oral absorption of SR57746A of example 5 below. In both experiments, the criterion for assessing absorption was the area under the curve of plasma SR57746A concentration as a function of time.

The analysis result shows that: the required dose of SR57746A prepared according to EP 0101381 is three or four times greater than the product of example 5 below, in order to obtain the same absorption when the product is administered after meals. The required dose of SR57746A prepared according to EP 0101381 is about nine times greater than the product of example 5 below, in order to obtain the same absorption when the product is administered on an empty stomach.

It was also surprisingly found in these tests that, with the application of SR57746A, prepared according to EP 0101381, the absorption is two to three times greater when the product is administered after a meal, whereas in the case of the product of example 5, the absorption is the same whether the product is administered on an empty stomach or after a meal.

These results illustrate the value of the present invention, i.e. the invention is able to provide a product with better absorption characteristics, the absorption of which is not affected by the intake of food.

Thus, in a further aspect, the present invention also relates to a pharmaceutical composition comprising as active ingredient 1- [2- (2-naphthyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 4-tetrahydropyridine hydrochloride in particulate form, wherein at least 55% of the particles have a size of less than 50 microns, advantageously less than 25 microns, and preferably 80-85% of the particles have a size of less than 10 microns.

The amount of active ingredient administered will depend on the nature and severity of the condition being treated and the weight of the patient. However, the amount of active ingredient in a dosage unit may be in the range 0.1 to 5mg, advantageously 0.5 to 3mg, and preferably 2mg (based on the free base). Preferred unit doses will generally contain 0.5, 1, 1.5, 2, 2.5 or 3mg (based on the free base) of the micronised product.

These unit doses will generally be administered one or more times per day, for example once or twice a day, in humans, in a total dose of from 0.2 to 10mg per day, more advantageously from 1 to 6mg per day (based on the free base).

In the pharmaceutical compositions of the present invention, the active ingredient may be administered to animals and humans in dosage unit form in admixture with conventional pharmaceutical carriers for the treatment of diseases described in US5026716, US 5109005, US5270320, US5292745 and US5378709, in particular for the treatment of neurodegenerative diseases. Suitable unit dosage forms include tablets (which may be in divided form), gelatin capsules, powders and granules.

When preparing solid compositions in the form of tablets, the active ingredient is mixed with pharmaceutically acceptable excipients such as gelatin, starch, lactose, magnesium stearate, talc, acacia, and the like. These tablets may be coated with sucrose or other suitable material, or they may be treated to provide sustained or delayed release activity as well as continuous release of a predetermined amount of the active ingredient.

Formulations in the form of gelatin capsules may be prepared as follows: the active ingredient is mixed with a diluent and the resulting mixture is filled into soft or hard gelatin capsules.

The active ingredient may also be formulated in microcapsules, optionally containing one or more carriers or additives.

In the pharmaceutical composition of the present invention, the active ingredient may also be in the form of an inclusion complex of cyclodextrin, its ether or its ester.

The composition of the present invention can also be prepared by extrusion-spheronization methods, which in turn allow obtaining spheroids of the desired size. In this process, the fine particles SR57746A (preferably atomized or micronized) are mixed with excipients and demineralized water, the resulting mass is granulated, extruded to give an extrudate that can freely flow through a small hole of the desired diameter, the resulting extrudate is spheronized to give spheroids of the same diameter as the small hole, the resulting spheroids are dried and preferably they are filled into capsules. SR57746A is thus mixed with the excipients, resulting in a ready-to-use pharmaceutical composition.

The invention is illustrated by the following examples.

Example 1

Operating under the conditions described in example 1 of EP 0101381, 4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine is reacted with 2- (2-chloroethyl) naphthalene in ethanol at reflux for 24 hours in the presence of triethylamine. The mixture is concentrated to dryness, the residue is dissolved in diethyl ether, filtered and the diethyl ether solution is washed with water, dried and evaporated.

1- [2- (2-naphthyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride is subsequently isolated in the following manner: the residue was treated with hydrochloric acid in 100 ethanol and the mixture was refluxed with stirring. When completely dissolved, the heating was stopped and the solution was then cooled with stirring. After about 10 minutes, the stirring was stopped and the mixture was left at room temperature for 48 hours. The precipitate is filtered off, washed with absolute ethanol, and the filter cake is then made into a paste in absolute ethanol with pneumatic stirring, filtered and dried under vacuum at 40 ℃.

This gave SR57746A with the particle size distribution shown in Table I in a total yield of 10%.

TABLE I

Particle size (micrometer) percent

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 resulting granular form of SR57746A contained 59.2% of the particles having a particle size of less than 50 microns.

Example 2

A mixture of 636g of SR57746A (prepared as described in EP 0101381, in which 77% of the crystallites have a size of 150-600 μm) and 5 volumes of anhydrous ethanol was heated under reflux with stirring until complete dissolution of the product, after which the heating was stopped and the mixture was allowed to stand at room temperature for 16 hours, when the temperature had risen to 40 ℃. After 10-20 minutes under vigorous stirring to 16 ℃ under these conditions, the product is filtered off and dried under vacuum at 40 ℃ for 24 hours. This gave 415g of SR57746A which consisted of particles with 60.3% of the particles having a particle size of less than 50 μm.

Example 3

A solution of 3g SR57746A in 300ml ethanol was atomized with a Buchi mini spray dryer according to the co-current nozzle atomization principle, the pump discharge, suction, heating and flow rates were adjusted to achieve an inlet temperature of 172 ℃, an outlet temperature of 107 ℃ and a partial vacuum of 40 mbar. Under these conditions, a product with a single broad peak in the DSC (maximum peak at 145 ℃) was obtained. The resulting particles are spheroids and the average particle size of the very uniform population does not exceed 5 microns.

Example 4

A solution of 3g SR57746A in 210ml ethanol and 90ml water was atomized with the apparatus described in example 3, according to the co-current nozzle atomization principle, the pump discharge, suction filtration, heating and flow rates were adjusted to achieve an inlet temperature of 172 ℃, an outlet temperature of 63 ℃ and a partial vacuum of 60 mbar. Under these conditions, a substantially amorphous nebulised SR57746A was obtained, which showed a single broad peak in the DSC thermogram (maximum peak at 147.6 ℃). The resulting particles are spheroids and the average particle size of the very uniform population does not exceed 5 microns.

Example 5

24kg of SR57746A were fed at a rate of 25 kg/hour into the micronization chamber (diameter 200mm) of an ALPINE 200 AS micronizer, at an operating pressure of 6.5 bar, and the product thus micronized was recovered in a filter bag. This resulted in micronized SR57746A with a particle size distribution such that all particles had a particle size of less than 20 microns and 85% had a particle size of less than 10 microns.

Example 6

Pharmaceutical composition comprising as active ingredient micronized SR57746A of example 5 above:

active ingredient 2.192mg

Corn starch 141.218mg

0.200mg of anhydrous colloidal silica

Magnesium stearate 0.400mg

The active ingredient is sieved through a 0.2mm sieve and then premixed with excipients. This mixture was sieved through a 0.315 sieve, remixed, and then sieved through a 0.315mm sieve. After the final mixing, the composition was filled into a size 3 gelatin capsule in an amount of 170mg of the composition, which contained micronized SR57746A in an amount equivalent to 2mg of 1- [2- (2-naphthyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine base.

Claims (12)

1. Microparticles of 1- [2- (2-naphthyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride consisting of particles wherein at least 55% of the particles have a diameter of less than 50 microns.

2. Microparticles according to claim 1, characterized in that: the particle diameter is less than 25 microns.

3. The microparticle according to claim 2, characterized in that: the particle diameter is less than 15 microns.

4. Microparticles according to claim 3, characterized in that: 80-85% of the particles have a diameter of less than 10 microns.

5. Microparticles according to any one of claims 1 to 4, characterized in that: the particles are spheroids.

6. Microparticles according to claim 5, characterized in that: the spheroids are composed of 1- [2- (2-naphthyl) ethyl ] -4- (3-trifluoromethylphenyl) -1, 2, 3, 6-tetrahydropyridine hydrochloride in a substantially amorphous form.

7. Microparticles according to any one of claims 1 to 4, characterized in that: the particles are micronized crystals.

8. A pharmaceutical composition comprising the microparticle of any one of claims 1 to 7 as an active ingredient.

9. Composition according to claim 8, characterized in that: it is in dosage unit form.

10. Composition according to claim 9, characterized in that: each dosage unit contains 0.1-5mg of active ingredient (calculated as free base).

11. Composition according to claim 10, characterized in that: each dosage unit contains 0.5-3mg of active ingredient (calculated as free base).

12. Composition according to claim 11, characterized in that: each dosage unit contained 2mg of active ingredient (calculated as free base).