MXPA99007507A - Pharmaceutical formulations in dry form for the oral administration of a cyclic quaternary ammonium compound - Google Patents

Abstract

The invention concerns pharmaceutical formulations containing 0.5 to 50 wt.%f a cyclic quaternary ammonium compound and suitable pharmaceutical excipients, and are formulated by wet granulation preferably with polysorbate 80.

Description

PHARMACEUTICAL FORMULATIONS SUBMITTED IN FORM. DRY FOR. THE ORAL ADMINISTRATION OF A CYCLICAL COMPOUND OF QUATERNARY AMMONIUM The present invention concerns new pharmaceutical formulations in dry form for oral administration, containing as an active principle, a cyclic quaternary ammonium compound.

In particular, the invention concerns pharmaceutical formulations for oral administration containing, as an active ingredient, a compound of the formula: in which: - AT is a pharmaceutically acceptable anion; - Am? It represents: REF. 30944 i - either a group J? of formula: in which: - Ari represents a phenyl unsubstituted or substituted one or several times by a substituent selected from a halogen atom, a hydroxy, a (C? -C) alkoxy, a (C 1 -C 4) alkyl or a trifluoromethyl, the aforementioned substituents they are identical or different; - x is zero or one; - i represents a (Ci-Cβ) alkyl or a benzyl group; the substituent Wi that is either in axial position or in equatorial position; ii- either an Am2 group? of formula: in which: - Ari, x and Wi are as defined above; Ri represents a hydroxy; a (C1-C4) alkoxy; a forptyloxy; a (C1-C3) alkylcarbonyloxy; a carboxy; a (Ci- C) alkoxycarbonyl; a cyano; a (C1-C3) alkylcarbonylamino; a mercapto; a (Ci-C alkylthio; iii - either an Am3 group? of formula: in which: - Ari and i are as defined above; - R2 represents hydrogen; a (C1-C3) alkyl; a (Ci-C3) alkylcarbonyl; iv - be it an Am group ?? of formula: in which: - Ari and x are as previously defined; - p is one or two; v - or a group 7Am5? of formula. in which: - Ari and x are as defined above; - Ar represents a phenyl unsubstituted or substituted one or two times by a substituent selected from a halogen atom, a (C 1 -C 3) alkoxy, a (C 1 -C 3) alkyl or a trifluoromethyl, the aforementioned substituents being identical or different; a naphthyl; an indolyl; - Q and Y represent one of the following groups of values: a) Qi and Yi; b) Q2 and Y2 when AmF represents a group Ami ?, Am2 ?, Am4 ?, or Amd ?; c) Q3 and Y3 when Am? represents a group A i ?, m ??, or a group An4f in which Ari represents a phenyl and p is two; d) Q4 and Y4 when Am? represents a group Ami ?, Am3 ?, Am4? - Qi represents hydrogen; - Yi represents hydrogen; a (C1-C4) alkyl; a? - (C1-C4) alkoxy- (C2-C4) alkylene; a? - (C1-C4) alkylcarbonyloxy- (C2-C4) alkylene; a? -benzoyloxy- (C2-C4) alkylene; a? - hydroxyT- (C2-C4) alkylene; a? - (C1-C4) alkylthio- (C2-C4) alkylene; a? - (C1-C4) alkylcarbonyl- (C2-C4) alkylene; a? -carboxy- (C2-C4) alkylene; a? - (Ci-C4) alkoxycarbonyl- (C2-C4) alkylene; a? - benzyloxy- (C2-C4) alkylene; a? - formyloxy- (C2-C4) alkylene; a? - R3NHCOO- (C2-C4) alkylene; a (D-R4R5NCO- (C2-C4) alkylene; a? -R6CONR7- (C2-C4) alkylene; a? -RsOCONR7- (C2-C4) alkylene; an? -R4R5NCONR7- (C2-C4) alkylene; R9SO2NR7- (C2-C4) alkylene, a? -cyano- (C1-C3) alkylene; - Q2 and Y2, together, constitute an ethylene, trimethylene or tetramethylene group; Q3 and Y3, together make up a group: in which n is one, two or three; - Q4 and Y4 together, constitute a radical selected from: Al) -O-CH2- A2) -O-CO- As) -CH2-O-CO- A4) -O-CH2-CO- As) -O-CH2-CH2- Ae) -N (R? O) -CO- Av) -N (R? O) -CO-CO- As) -N (R? O) -CH2-CH2- - T represents - either a group -CO- when Q and Y represent Qi and Yi, Q2 and Y2 or Q4 and Y4 when they constitute, together, a radical Ai), As), or As); - or a group -CH2- when Q and Y represent Q3 and Y3 or Q4 and Y4 when they together constitute a radical A2), A3), A4), Ae) or A7); - A represents either a direct bond or a methylene group when T is -CO-, or a direct bond when T - Z represents: - a phenyl unsubstituted or substituted one or several times by a substituent selected from: a halogen atom; a trifluoromethyl; a cyano; a hydroxy; a nitro; an amino not substituted or substituted one or several times by a (C 1 -C 4) alkyl; a benzylamino; a carboxy; a (C1-C10) alkyl; a (C3-C7) cycloalkyl unsubstituted or substituted one or several times by a methyl; a (C1-C10) alkoxy; a (C3-C7) cycloalkyloxy unsubstituted or substituted one or several times by a methyl; a mercapto; a (C1-C10) alkylthio; a (Ci-Ce) alkylcarbonyloxy; a (Ci-Cβ) alkylcarbonylamino; a benzoylamino; a (C 1 -C 4) alkoxycarbonyl; a (C3-C7) cycloalkylcarbonyl; a carbamoyl unsubstituted or substituted once or twice by an alkyl; a ureide unsubstituted or substituted one or two times in position 3 by a (C1-C4) alkyl or a (C3-C7) cycloalkyl; a (pyrrolidin-1-yl) carbonylamino, said substituents being identical or different; - an unsubstituted or unsubstituted naphthyl one or more times by a halogen, a trifluoromethyl, a (C1-C4) alkyl, a hydroxy or a (C1-C4) alkoxy; - a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; an imidazolyl; - R3 represents a (C1-C7) alkyl or a phenyl; - R4 and Rs each independently represent a hydrogen or a (C1-C7) alkyl; Rs can also represent a (C3-C7) cycloalkyl, a (C3-C7) cycloalkylmethyl, a phenyl or a benzyl; or else R4 and Rs together with the nitrogen atom to which they are attached constitute a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine unsubstituted or substituted in position 4 by a (C1-C4) alkyl; - Re represents a hydrogen, a (Ci-C /) alkyl, an vinyl, a phenyl, a benzyl, a pyridyl or a (C3-C7) cycloalkyl unsubstituted or substituted by one or more methyl; - R7 represents a hydrogen or a (C1-C7) alkyl; - Re represents a (C1-C7) alkyl or a phenyl; R9 represents a (C1-C7) alkyl; an amino not substituted or substituted by one or two (C1-C7) alkyls; a phenyl unsubstituted or substituted one or several times by a substituent selected from: a halogen atom, a (C1-C7) alkyl, a trifluoromethyl, a hydroxy, a (C1-C7) alkoxy, a carboxy, a (C1- C7) alkoxycarbonyl, a (C 1 -C 7) alkylcarbonyloxy, a cyano, a nitro, an amino unsubstituted or substituted by one or two (C 1 -C 7) alkyls, the aforesaid substituents being identical or different; - Rao represents hydrogen or a (C1-C4) alkyl; as well as their possible salts with mineral or organic acids and their possible solvates.

The compounds of formula (I) useful for the invention also comprise racemates, optically pure isomers, as well as axial and equatorial isocyates when in the compound of formula (I), An? represents a groupAni ?, a group Am2 ?, or a group Am3 ?.

The compounds of formula (I) are described in patent applications EP-A-0 512 901, EP-A-0 515 240, EP-AO 559 538, EP-A-0 591 040, WO 95/26 339, EP-A-0 700 382, EP-A-0 723 959 and WO 96/23 787.

Among the compounds of formula (I), those of the formula: in which: - Ari, x and p are as defined for a compound of formula (I); - Ar 'represents a 3,4-dichlorophenyl or a 3,4-difluorophenyl; - Z 'represents a phenyl substituted in position 3 by a halogen or a (Ci-Cio) alkoxy; - AT represents a pharmaceutically acceptable anion; they are preferred for the invention.

More particularly, the invention relates to pharmaceutical formulations in dry forms for oral administration of (S) -l-. { 2- [3- (3- (3-Dichlorophenyl) -1- (3-isopropoxyphenylacetyl) piperidin-3-yl] ethyl} 4-phenyl-1-azoniabicyclo [2.2.2] octane, or SR 140333, of the formula: wherein AT is a pharmaceutically acceptable anion.

The benzenesulfonate of SR 140333, formerly called compound A, is very particularly preferred. The international common name of this compound is nolpitantium besilate.

The compounds of formula (I) have been described as antagonists of the P sub-unit, natural ligand of the NKi receptors and then have an affinity for said receptors. To administer such compounds orally, it is necessary that they present a good absorption, which implies at the same time a good solubility in aqueous medium and a good capacity to cross the intestinal membrane. (M. Rowland and T. N. Tozer in Clinical Pharmacokinetics, Concepts and Applications, Lea and Fehiger, 1989, 2nd ed., Pp. 113-130).

The solubility of the compounds of formula (I) has been studied in different media: their solubility in water is generally less than 5 mg./ml. but they are soluble in hydrophilic solvents, such as alcohols or glycols.

The compounds of formula (I) which are quaternary ammonium, remain in ionized form whatever the pH of the medium in which they are found, particularly at neutral pH which is the pH of the intestinal medium.

It is known that ionic compounds, particularly ammonium quaternaries, hardly penetrate the epithelial membranes (J. P. Labaune in Pharmacokinetics, Fundamental Principles, Masson, 3388, 2nd edition, pp. 7-33).

The cell line Caco-2 has the distinction of differentiating in vi tro to form an epithelial monolayer. This line is classically used to evaluate the epithelial permeability of the compounds (Rev. Ther, Drug Carrier System, 1991, 8 (4), 105-330).

On this model the permeability of compound A put into solution in dimethylsulfoxide (DMSO) is 3.4. 10-7 cms / s. On the other hand, studies carried out, in the rat, with compound A in 6% aqueous solution in methylcellulose, have shown that its estimated absorption is less than 1%.

Nonionic surfactants and absorption enhancing agents have been examined to know their effect on the membrane permeability of a compound of formula (I). It has been found that these products have no positive effect.

In addition, the compounds of formula (I) have other physico-chemical properties that make their formulation difficult. In this way the low density of the compounds of formula (I) is compatible with their formulation by simple dry mixing. On the other hand, these compounds being very electrostatic, have the tendency to stick on surfaces, which is harmful in occasion of possible compression processes.

As regards compound A, it is crystallized in the form of needles and its strong electrostatic character leads to the formation of aggregates. On the other hand, the micronization of the product would be potentially dangerous because of the risk of explosion due to the accumulation of loads.

Accordingly, in order to adjust a galenic formulation for the compounds of formula (I), both their very weak solubility and their weak passage of the membranes must be arranged at the same time and arrive at a formulation compatible with the preparation of dry forms.

It has now been found that a pharmaceutically presented formulation can be prepared in dry form for oral administration of a compound of formula (I) using the wet granulation to formulate the product; such pharmaceutical formulations allow both to avoid the accumulation of electrical charges and to improve the bioavailability of the active principle.

Wet granulation is the pharmaceutical operation that allows, with the help of a granulation liquid, to densify a mixture of powders containing the active principle, said mixture constituting the internal phase of the formulation, the wet mass thus obtained that is dry then calibrated before adding the ingredients that constitute the external phase of the aforementioned formulation.

In particular, the present invention concerns pharmaceutical formulations comprising 0.5 to 50% by weight of the compound of formula (I) and pharmaceutically acceptable excipients, formulated by wet granulation.

Accordingly, the formulations of the invention contain the following ingredients expressed as a percentage of the total weight of the formulation: active ingredient 0.5 to 50% binder 1 to 10% disintegrating agent: 0 to 10% anti-adherent 0 to 5% lubricant 0.2 to 5% gliding agent 0 to 15% polisorbatc 80 0 to 201 dye 0 to 2% flavoring 0 to 2 % diluent in sufficient quantity cbp100% Surprisingly, it has been observed that the addition of a particular polysorbate, polysorbate 80, to compound A in solution in the medium of cell culture, improves precisely the transepithelial passage on the Caco model -2.

Preferably, the pharmaceutical formulations according to the invention contain 10 mg. at lOOmg. of polysorbate 80 per dosage unit. More particularly, the pharmaceutical formulations according to the invention contain 15 mg. to 60 mg. of polysorbate 80 per dosage unit.

The pharmaceutical formulations according to the present invention may be in the form of capsules, tablets, sachets or powders.

For pharmaceutical compositions in the form of capsules or tablets, it is also possible to prepare enteric formulations.

Such formulations are used to protect the active ingredient from strong stomach acidity. Such formulations are prepared by coating the capsule or the tablet with an insoluble polymer film in an acidic and soluble environment in a basic environment.

The diluent used in the composition of the present invention can be one or several compounds that are capable of densifying the active principle to obtain the desired mass. Preferred diluents are mineral phosphates such as calcium phosphates; sugars, such as hydrated or anhydrous lactose, mannitol; and cellulose or cellulose derivatives such as, for example, microcrystalline cellulose, maize starch or pregelatinized starch. Most particularly, lactose monohydrate, mannitol, microcrystalline cellulose and maize starch used alone or as a mixture are preferred; for example a mixture of monohydrated lactose and corn starch or a mixture of monohydrated lactose, corn starch and microcrystalline cellulose.

The binder used in the composition of the present invention may be one or more compounds that are capable of densifying a compound of formula (I) by transforming it into larger and denser particles, which have a better slip. Preferred binders are alginic acid, sodium alginate; cellulose and cellulose derivatives, such as sodium carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydropropylmethylcellulose or methylcellulose; the gelatin; the acrylic acid polymers; povidone for example povidone K-30; hydroxypropylmethylcellulose and povidone K-30 which are very particularly preferred binders.

The disintegrating agent used in the composition of the present invention can be one or more compounds that facilitate the disintegration of the prepared formulation when placed in an aqueous medium. Preferred disintegrating agents are cellulose or cellulose derivatives, such as sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, cellulose powder, crospovidone; pre-gelatinized starch, sodium starch glycolonate, sodium carboxymethylstarch or starch. Crospovidone, cross-linked sodium carboxymethylcellulose and sodium carboxymethyl starch are preferred disintegrating agents.

The anti-adherent used in the composition of the present invention may be one or more compounds which are capable of reducing the stickiness of the formulation, for example preventing adhesion to metal surfaces. Preferred antiadhesives are silicon-containing compounds, for example silica or talc.

The slip agent employed in the composition of the present invention may be one or more compounds which are capable of facilitating the slippage of the prepared formulation. Preferred glidants are silicon-containing compounds, for example anhydrous colloidal silica or precipitated silica.

The lubricant used in the composition of the present invention can be one or more compounds which are capable of preventing the problems related to the preparation of dry forms, such as the problems of bonding and / or friction that occur at the level of machines on the occasion of compression or filling. Preferred lubricants are fatty acids or fatty acid derivatives such as calcium stearate, glyceryl monostearate, glyceryl palmito stearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, or acid. stearic; hydrogenated vegetable oils, for example hydrogenated castor oil; polyalkylene glycols, polyethylene glycol; sodium benzoate or talcum. According to the present invention, magnesium stearate or sodium stearyl fumarate are preferred.

The dye used in the formulation of the present invention can be one or several compounds that are capable of giving the desired color in the prepared formulation. The addition of a dye can serve, for example, to distinguish formulations having different dosages in active principle. Preferred dyes are iron oxides.

By way of exemplary film for the enteric coating, mention may be made of cellulose acetophthalate, polyvinyl acetophthalate, hydroxypropylmethyl cellulose phthalate or methacrylic acid copolymers.

By way of example of a methacrylic acid copolymer, mention may be made of the type C methacrylic acid copolymer, marketed under the brand name EUDRAGIT® L30 D-55 by RHOM or the copolymer of ethyl acrylate and methacrylic acid marketed under the brand name KOLLICOAT® MAE 30D by BASF.

To increase the elasticity of the coating film, plasticizers can be added, such as for example: a polyethylene glycol, 1, 2-propylene glycol, dibutyl phthalate or a citrate.

In certain cases, in particular when preparing enteric formulations with gelatin capsules, it may be preferable to coat the capsule with a film constituted by a pre-coating before the enteric coating. The pre-coating to be made for example with hydroxypropylcellulose, povidone or a copolymer of methacrylic acid associated with appropriate excipients.

According to the present invention, the pharmaceutical formulations are prepared by a wet granulation process which is characterized in that: a) For the internal phase, the active principle, the diluent, optionally the binder, possibly the polysorbate 80, and optionally the dye are mixed at room temperature; b) moistened with purified water as a granulation liquid; c) it is dried, then the wet mass thus obtained is calibrated; d) to the calibrated dried grains thus obtained, the external phase ingredients are added, namely the disintegrating agent, the anti-adherent, the gliding agent and optionally the colorant and / or the flavorant.

According to the present invention, a particular embodiment consists in incorporating the polysorbate 80 into the purified water to proceed to the wet granulation.

According to another particular embodiment, the binder is incorporated into the purified water to proceed with the wet granulation.

When preparing enteric formulations, the film of a capsule or of a tablet according to the invention may contain a coating film having the following composition (by weight): Coating: copolyase of matacrylic acid of type C 54.8 glycerin 3.3% solution of polysorbate 80 to 33% 0.7% water 41.2% For the; -.- licula of enteric capsules, it is preferable to proceed first to a pre-coating with a film having the following composition (by weight): Pre-coating: Type C methacrylic acid copolymer 46.6% glycerin 4.6% aqueous 33% polysorbate 80 solution 4.6% water 44.2 * More particularly, the present invention relates to a pharmaceutical formulation for oral administration of a compound of formula (I) containing in weight: active ingredient 0.5 to 20% binder 2.5 to 6% degreasing agent 0 to 5% non-stick 0 to 3% lubricant 0.5 to 3% slip agent 0 to 5% polysorbats 80 0 to 20% dye 0 to 2% flavoring 0 a 2% dbluyente cbp 100% According to a particular embodiment, the present invention concerns a pharmaceutical formulation for oral administration containing weight: compound A 0.5 to 10 lactose monohydrate 60 to 80 \ cornstarch 15 to 25 \ povidone K-30 2 to 5% polysorbate 80 0 to 20% magnesium stearate 1% Preferably, the pharmaceutical compositions according to the invention contain from 10 to 100 mg. and more particularly 15 mg. to 60 mg. of polysorbate 80 per dosage unit. This compound is according to a preferred embodiment, added with water for granulation.

Accordingly, the present invention has very particularly for pharmaceutical formulations for oral administration of a compound A having one of the following formulations: i) in the internal phase: compound A 0.7% lactose monohydrate 75.3% corn starch 20% povidone K-30 30% purified water for wet granulation in sufficient quantity in the external phase: magnesium stearate 1% ii) in the internal phase: compound A 7.9% lactose monohydrate 68.1% corn starch 20% povidone K-30 3% purified water for granulation in sufficient quantity in the external phase: magnesium stearate 1% iii) in the internal phase: compound A 3.1% lactose monohydrate 66.6% corn starch 20% povidone K-30 3.0% purified water for wet granulation in sufficient quantity polysorbate 80 6.3% in the external phase: magnesium stearate 1.0% In this last formulation the polysorbate 80 can be incorporated into the water for Lon granulation, The characteristics and advantages of the above compositions will be apparent from the description below, from the compositions given by way of examples.

TEST 1. Solubility of compound A The solubility in water has been measured at saturation, after 24 hours, at room temperature; The measurements have been made by UV spectrometry to? = 275 nm after calibration with an ethanolic pH solution Concentration in compound A (mg./ml.) 0.31 0.31 0.31 0.29 0.31 It is well seen that this solubility is weak and not dependent on pH.

On the other hand, compound A is soluble in dimethyl sulfoxide (DMSO) at 168 mg./ml .; 2. Evaluation of the intestinal transepithelial passage of compound A.

On microporous polycarbonate filters coated with collagen, Caco-2 cells are seeded. The cell monolayer formed on the filter then allows to separate an apical compartment (similar to the intestinal lumen) from a basal compartment (similar to the blood circulation).

The composition containing the compound to be studied is then placed on the apical side and the passage of this compound, dispersed or solubilized in Hank's medium, is evaluated through this cellular barrier, measuring its kinetics of appearance of the basal side. This aqueous medium, of pH = 6.5, has the following composition: NaCl = 8.0 g./l; KC1 = 0.4 g./l; CaCl? = 0.19 g./l .; MgCl 2 = 0.1 g / l; MgSO 4 = 0.1 g / l; Na2HP04 = 0.09 g./l .; KH2PO4 = 0.06 g / l; NaHC? 3 = 0.35 g./l .; glucose = 1 g./l; phenol red '= 0.01 g./l.

The transepithelial passage of the following formulation 1, made by wet granulation according to the invention, has been studied: Formulation 1 compound A 0.7% lactose monohydrate 75.3% corn starch 20% povidone K-30 3.0% magnesium stearate 1.0% On the Caco-2 model, the rate of passage of compound A in formulation 1 is multiplied by 3 in relation to that of compound A in suspension in the cell culture medium. Accordingly, thanks to formulation 1, the rate of passage of compound A is similar to the measurement when compound A is in solution in DMSO. The formulation 1 then allows to completely correct the characteristic of weak solubility of compound A.

To the formulation described above, placed in the Hank's medium, different nonionic surfactants or agents known to improve the absorptions such as that of the Cs-Cio fatty acids or one of their derivatives have been added and the relative velocity has been measured. of the intestinal transepiteliall step of compound A in its formulations.

Formulation Concentration Speed of the relative agent transport (mg./l) relative Formulation 1 0 1 ± 0.20 1 + polysorbate 60 100 0.51 ± 0.22 200 0. 62 ± 0. fifteen 1-poiisorbate 80 100 2.7711.53 200 4.39 + 0.25 1 + Cremophor® RH 40 100 0.66 ± 0.40 200 0.51 + 0.18 1 + Synperonic® 44 100 0.92 ± 0.10 200 1.48 ± 0.24 1 + Synperonic® 127 100 0.85 ± 0.06 200 1.1910.17 1 + Span® 20 100 0.73 ± 0.48 200 0.60 + 0.28 1 + caprylic acid 100 0.3910.03 200 0.3410.01 1 + monocapryloyl 100 0.2710.06 glycerol 200 0.5610.11 In the different formulations studied, the compound A that is dissolved by the constituents of the formulation 1, is the effect of the different agents on the absorption of the compound A that is measured.

Only polysorbate 80 (100 and 200 mg./l.) Added to formulation 1 causes a marked increase in the rate of transport of compound A, when the other non-ionic surfactants or agents that improve absorption, whether or not they have an effect, or they decrease the transport speed.

On the other hand, it has been verified that the polysorbate 80 does not cause alteration of the epithelial membrane, and this up to a high concentration (4800 mg./l).

According to the data of the literature, the intestinal volume is approximately 250 ml. (J. B. Dressmann et al., J. Phar. Sci., 1985, 74, 588-589). In the examinations carried out previously, the concentration of the agent in the Hank's medium corresponds then to the amount of said agent that would be present per dosage unit of the formulation. Therefore, polysorbate 80 concentrations of 100 mg./l correspond respectively to amounts of 25 mg. and 50 mg. per dosage unit. 3. . In vivo evaluation of the absorption of compound A.

In the anesthetized dog, hypotension is induced by succesive administrations of [Sar9.Met (O2) '] substance P, intravenously at a dose of 5 ng / kg. and the inhibitory effect of this hypotension is studied by administration of compound A in different formulations.

By intraduodenal route, the administration of compound A in solution at a dose of 0.35 mg./Kg. allows to restore blood pressure while its administration in suspension at a dose of 0.35 mg./Kg. it has no effect on blood pressure.

By "solution", it is understood that compound A is in the physiological saline after dissolution by ethanol or DMSO. By "suspension", compound A is understood to be in an aqueous solution containing 6% methylcellulose.

At the dose of 1 mg./Kg., Orally, compound A allows blood pressure to be restored if it is administered in solution, while it has no effect on pressure if it is administered pure in a capsule.

Pure compound A in capsule has also been administered at a dose of 3 mg./Kg. orally; and at a dose of 10 mg./Kg. orally. The effect on blood pressure is weak at 3 mg./Kg. while it is maximum at 10 mg./Kg.

Finally, the anesthetized dog was administered the compound A formulated according to the formulation 1 of the present invention, at a dose of 3 mg./kg. and it has been found that the effect on blood pressure is identical to that observed when compound A is administered at 1 mg./kg. orally in solution in ethanol or in DMSO.

These results show that the inhibitory effect of compound A compared to that of hypotension induced by [San. et (O2) 11] substance P, manifests only when compound A is administered in solution.

It is seen that the formulation 1 allows to divide by 3 the active dose of the compound A. This shows the interest of such a formulation to solubilize the compound A and to improve its intestinal absorption.

In the present description and in the subsequent examples the amounts of the ingredients are expressed as a percentage by weight in relation to the total weight of the pharmaceutical formulation.

EXAMPLE 1: Capsules compound A 3.125 mg. or 0.79% lactose monohydrate c.b.p. 75.21% corn starch 79 mg. 20.00 povidone K-30 11.85 mg. 3.0% magnesium stearate 3.95 mg. 1.0% for a finished size 0 capsule of 395 mg.

EXAMPLE 2: Capsules Compound A 31,. 5 mg. 7.9% lactose monohydrate c.b.p. 68.1% corn starch 79 mg. 20.% povidone K-30 11.85 mg. 3.0% magnesium stearate 3.95 mg. 1.0% for a finished O-size capsule of 395 mg.

EXAMPLE 3: Capsules Compound A 12.50 mg. that is, 3.1% lactose monohydrate 262.7 mg. 66.6% corn starch 79 mg. 20.00 povidone K-30 11.85 mg. 3.0% polysorbate 80 25 mg 6.3% magnesium stearate 3.95 mg. 1.0% for a finished capsule size C of 395 mg, EXAMPLE 4: Capsules Compound A 6.25 mg. < or 1.6% lactose monohydrate c.b.p. 69.4% corn starch 79 mg. 20.00% polysorbate 80 20 mg. 5.0% povidone K-30 11.85 mg. 3.0% magnesium stearate 3.95 mg. 1.0% for a finished O-size capsule of 395 mg.

EXAMPLE 5: Capsules Compound A 62.5 mg. or 15.6% lactose monohydrate c.b.p. 50.3% maiz starch 70 mg. 17.60% polysorbate 80 50 mg. 12.5% povidone K-30 12.00 mg. 3.0% magnesium stearate 4.0 mg. 1.0% for a finished 0-size capsule of 400 mg.

EXAMPLE 6: Capsules Compound A 6.25 mg. or 1.4% anitol c.b.p. ß9.2% polysorbate 80 20.0 mg. 4.4% hydroxypropylmethylcellulose 13.5 mg. 3.0% cross-linked sodium carboxymethicellulose 4.5 mg. 1.0% magnesium stearate 4.5 mg. 1.0% for a finished O-size capsule of 450 mg.

EXAMPLE 7: Capsules Compound A 62.5 mg. or 13.8% mannitol c.b.p. 68.1% polysorbate 80 50.0 mg. 11.1% hydroxypropylmethylcellulose 22.5 mg. 5.0% crosslinked sodium eticellulose carboxy 4.5 mg. 1.0% magnesium stearate 4.5 mg. 1.0% for a finished O-size capsule of 450 mg.

EXAMPLE 8: Tablets compound A 6.25 mg. or 2.1% lactose monohydrate c.b.p. 69.7% corn starch 50 mg. 16.6% povidone K-30 9.0 mg. 3.0% polysorbate 80 20 mg. f .6% sodium carboxymethylcellulose 3.0 mg. 1.0% magnesium stearate 3.0 mg. 1.0% for a 300 mg finished tablet, EXAMPLE 9: Compound tablets A 6.25 mg. or 2.1% lactose monohydrate c.b.p. 74.3% povidone K-30 9.0 mg. 3.0% polysorbate 80 50 mg. 16.6% sodium carboxymethyl starch 3.0 mg. 1.0% anhydrous colloidal silica 6.0 mg. 2.8% magnesium stearate 3.0 mg. 1.0% for a 300 mg finished tablet, EXAMPLE 10: tablets Compound A 62.5 mg. or 12.5 lactose monohydrate c.b.p. 52.5 corn starch 50 mg. 10% microcrystalline cellulose 50 mg. 10% hydroxypropylcellulose 25 mg. 5% polysorbate 80 20 mg. 4% poliplasdone 15 mg. 3% sodium stearyl fumarate 15 ms. 3% for a finished 500 mg tablet.

EXAMPLE 11: tablets compound A 62.5 mg. or 12.5 lactose monohydrate c. b. p. 73 9 polysorbate 80 50 mg. 10% sodium carboxymethylstarch 3 mg. 0 6 anhydrous colloidal silica 10 mg. 2% magnesium stearate 5 mg. 1% for a finished tablet of 500 mg.

EXAMPLE 12: Envelopes compound A 100 mg. that is, 10% lactose monohydrate 610 mg. 61% corn starch 200 mg. 20% polysorbate 80 50 mg. 5% cross-linked sodium carboxymethylcellulose 30 mg. 3% magnesium stearate 10 mg. 1% for an envelope full of 1000 mg.

EXAMPLE 13: Enteric Capsules A capsule according to example 1 is prepared and a film is applied in two layers: one of pre-coating and another of coating.

Pre-coating: Eudragit®L30 D-55 46.6% glycerin 4.6% aqueous solution of polysorbate 80 to 33 '4.6% water 44.2% Coating: Eudragit® L30 D-55 54.8% glycerin 3.3% aqueous solution of polysorbate 80 to 33 0.7% water 41.2% It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, it is claimed as property in the following,

Claims (28)

1. Pharmaceutical formulation presented in dry form for the oral administration of an active principle of formula: A®, A? S [CH? ,,)): -? CC - CCHH ,, - NN-.TT-A-Z (I) Ar in which - AT is a pharmaceutically acceptable anion: Amf represents: either an AmiF group of formula: wherein: Ap represents a phenyl unsubstituted or substituted one or several times by a substituent selected from a halogen atom, a hydroxy, a (Ci ^ C4) alkoxy, a (C 1 -C 4) alkyl or a trifluoromethyl, the mentioned substituents being identical or different; - x is zero, or one; - Wi represents a (Ci-Cβ) alkyl or a benzyl group; the Wi substituent that is either in axial position or in equatorial position; ii- either an Am2 group of formula: in which: - Ari, x and Wi are as defined above; Ri represents a hydroxy; a (C1-C4) alkoxy; a formyloxy; a (Ci- C3) alkylcarbonyloxy; a carboxy; a (Ci-C4) alkoxycarbonyl; a cyano; a (C1-C3) alkylcarbonylamino; a mercapto; a (C 1 -C 4) alkylthio; iii- either a group ApF of formula: in which; - Ari and Wi are as defined above; - R2 represents hydrogen; a (C1-C3) alkyl; a (Ci- C3) alkylcarbonyl; iv- either an Am4F group of formula: in which: Ari and x are as defined above; - p is one or two; v- or an AmsF group of formula: in which; Ari and x are as defined above; - Ar represents a phenyl unsubstituted or substituted one or two times by a substituent selected from: a halogen atom, a (C1-C3) alkoxy, a (Ci-Ca) alkyl, a trifluoromethyl, the mentioned substituents which are identical or different: a naphthyl; an indolyl; - Q and Y represent one of the following groups of values: a) Qi and Yi; b) Q2 and Y2 when AmF represents an AmiF group, Am f, Am4®, Ó Am5 ©; c) Q3 and Y3 when AmF represents a group Ami ?, Am2®, or an Am4® group, in which Ari represents a phenyl and p is two; d) Q4 and Y4 when AmF, represents a group AmiF, Am3f, Am4f or Amsf; - Qi represents hydrogen, - Yi represents hydrogen; a . { C1-C4) alkyl; a? - (C1-C4) alkoxy- (C2-C4) alkylene; a? - (C1-C4) alkylcarbonyloxy-. { C2-C4) alkylene; a? -benzoyloxy- (C2-C4) alkylene; a? -hydroxy- (C2-C4) alkylene; a? - (C? -C4) alkylthio- (C2-C4) alkylene; a? - (C1-C4) alkylcarbonyl- (C2-C4) alkylene ©; a? - cerboxx (L ..- C) alkylene; a? - (C? C4) alkoxycarbonyl- (C2-C4) alkylene; a? - benzyloxy- (C2-C4) alkylene; a? - formyloxy- (C2- C4) alkylene; a? - R3NHCOO- (C2- C4) alkylene; a? - R4RsNCO- (C2-C4) alkylene; a? - R6C NR7- (C2-C4) alkylene; a? -RsOCONR? - (C2-C4) alkylene; a? - R4R5NCONR7- (C2-C4) alkylene; a (U-R9SO2NR7- (C2-C4) alkylene; a? -cyano- (Ci- C3) alkylene; Q2 and Y2, together, constitute an ethylene, trimethylene or tetramethylene group; - Q3 and Y3, together, constitute a group: in which n is one, two or three; - Q4 and Y4, together, constitute a radical selected from; Ai) -0-CH2-A2) -O-CO-A3) -CH2-O-CO-A. -O-CH2-CO-Ae) -N (R? O) -CO-A7) -N (R? O) -CO-CO-As) -N (R? O) -CH2-CH2- - T represents - either a group -CO- when Q and Y represent Qi and Yi, Q2 and Y2 and Q4 and Y4 when they constitute, together, a radical Ai), As) or As); - or a group -CH2- when Q and Y represent Q3 and Y3 or Q4 and Y4 when they together constitute a radical A2), A3), A4), Ae) or A7); - A represents either a direct bond or a methylene group when T is -C0-. or a direct union when T is -CH2-; - Z, represents: - a phenyl unsubstituted or substituted one or several times by a substituent selected from a halogen atom; a trifluoromethyl; a cyano; a hydroxy; a nitro; an amino not substituted or substituted one or more times by a (C 1 -C 4) alkyl; a benzylamino; a carboxy; a (C1-C10) alkyl; a (C3-C7) cycloalkyl unsubstituted or substituted one or more times by a methyl, a (C-Cyclo) alkoxy; a (CJ-C7) cycloalkyloxy unsubstituted or substituted one or several times by a methyl; a mercapto; a (Ci- Cio) alkylthio; a (Ci- Ce) alkylcarbonyloxy; a (Ci- Ce) alkylcarbonylamino: a benzoylamino; a (C 1 -C 4) alkoxycarbonyl; a (C3-C) cycloalkylcarbonyl; a carbamoyl unsubstituted or substituted one or two times by a (Ci- C4) alkyl; a ureide unsubstituted or substituted one or two times in position 3 by a (C1-C4) alkyl or a (C3-C7) cycloalkyl; a (pyrrolidin-1-yl) carbonylamino, the mentioned substituents which are identical or different; - a naphthyl unsubstituted or substituted one or more times by a halogen, a trifluoromethyl, a (C1-C4) alkyl, a hydroxy, a (C1-C4) alkoxy; - a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; an imidazolyl; - R3 represents a (C1-C7) alkyl or a phenyl; - R4 and Rs each independently represent a hydrogen or a (Ci- C7) alkyl; Rs may further represent a (C3-C7) cycloalkyl, a (C3 ~ C7) cycloalkylmethyl, a phenyl or a benzyl; or R4 and Rs together with the nitrogen atom to which it is attached form a heterocycium selected from acetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazapine and piperazine unsubstituted or substituted in position 4 by a (Ci- C4) alkyl; - Re represents a hydrogen, a (C1-C7) alkyl, a vinyl, a phenyl, a benzyl, a pyridyl or a (C3-Cv) cycloalkyl unsubstituted or substituted by one or more methyl; - R7 represents a hydrogen or a C1-C7) alkyl; - Rs represents a (Ci- C7) alkyl or a phenyl; - R9 represents a (C1-C7) alkyl; an amino not substituted or substituted by one or two (C1-C7) alkyls; a phenyl unsubstituted or substituted one or several times by a substituent selected from a halogen atom, a (C1-C7) alkyl, a trifluoromethyl, a hydroxy, a (C1-C7) alkoxy, a carboxy, a (C-C) alkoxycarbonyl, a (Ci- C) alkylcarbonyloxy, a cyano, a nitro, an amino unsubstituted or substituted by one or two (Ccyc) alkyls, the mentioned substituents which are identical or different; Rio represents hydrogen or ur (C 1 -C 4) alkyl; or one of its possible salts with mineral or organic acids and one of its possible solvates, formulated by wet granulation, containing as a percentage of the total weight of the formulation: - active principle 0.5 to 50% - binder 1 to 10% - disintegrating agent 0 to 10% - anti-adhesive 0 to 5% - lubricant 0.2 to 5% - gliding agent 0 to 15% - polysorbate 80 0 to 20% - dye 0 to 2% - flavoring 0 to 2% diluent cbp 100%, characterized by 10 mg. to 100 mg. of polysorbate 80 per dosage unit.

2. Pharmaceutical formulation according to claim 1 which is characterized in that the active principle is a compound of the formula: in which: - Ari, x and p are 'as defined for a compound of formula (I) in claim 1; - Ar 'represents a 3,4-dichlorophenyl or a 3,4-difluorophenyl; Z 'represents a phenyl substituted in the 3-position by a halogen or a (C-Cyclo) alkoxy; - AT represents a pharmaceutically acceptable anion.

3. Pharmaceutical formulation according to any one of claims 1 or 2, which is characterized in that the active principle is (S) -1-. { 2- [3- (3, 4- dichlorophenyl) -1- ((3-isopropoxyphenylacetyl) piperidin-3-yl] ethyl} - 4-phenyl-1-nitroniabicyclo [2.2.2] octane, of the formula: wherein AT is a pharmaceutically acceptable anion.

4. Pharmaceutical formulation according to any one of claims 1 to 3, characterized in that the active ingredient is nolpitantiu besylate.

5. Pharmaceutical formulation according to any one of claims 1 to 4, which is characterized in that it contains 15 mg. to 60 mg. of polysorbate 80 per dosage unit.

6. Pharmaceutical formulation according to any one of claims 1 to 5, characterized in that it is in the form of capsules, tablets, sachets or powders.

7. Pharmaceutical formulation according to any one of claims 1 to 6, characterized in that the diluent is a compound or a mixture of compounds selected from calcium phosphates, hydrated or anhydrous lactose, mannitol, microcrystalline cellulose, starch, corn starch or pregelatinized starch.

8. Pharmaceutical formulation according to claim 7, characterized in that the diluent is a compound or a mixture of compounds selected from lactose monohydrate, mannitol, microcrystalline cellulose and corn starch.

9. Pharmaceutical formulation according to one of claims 7 or 8, characterized in that the diluent is a mixture of monohydrated lactose and corn starch or a mixture of monohydrated lactose, corn starch and microcrystalline cellulose.

10. Pharmaceutical formulation according to any one of claims 1 to 9, characterized in that the binder is a compound or a mixture of compounds selected from alginic acid, sodium alginate; cellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose or methylcellulose; the gelatin; the acrylic acid polymers; the povidone K-30.

11. Pharmaceutical formulation according to claim 10, characterized in that the binder is selected from hydroxypropylmethylcellulose and povidone K-30.

12. Pharmaceutical formulation according to any one of claims 1 to 11, characterized in that the disintegrating agent is a compound or mixture of compounds selected from cellulose, sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, cellulose in powder, crospovidone; the pregelatinized starch, the sodium starch glycolonate, the sodium carboxymethyl starch and the starch.

13. Pharmaceutical formulation according to claim 12, characterized in that the disintegrating agent is selected from crospovidone, cross-linked sodium carboxymethylcellulose, and sodium carboxymethyl starch.

14. Pharmaceutical formulation according to any one of claims 1 to 13, which is characterized in that the anti-adherent is selected from silica and talc.

15. Pharmaceutical formulation according to any one of claims 1 to 14, characterized in that the slip agent is selected from the anhydrous colloidal silica and the precipitated silica.

16. Pharmaceutical formulation according to any one of claims 1 to 15, characterized in that the lubricant is a compound or a mixture of compounds selected from calcium stearate, glyceryl monostearate, glyceryl palmito stearate, magnesium stearate, lauryl sulfate of sodium, sodium stearyl fumarate, is zinc stearate, or stearic acid; hydrogenated castor oil, polyalkylene glycols, polyethylene glycol, sodium benzoate and talc.

17. Pharmaceutical formulations according to claim 16, characterized in that the lubricant is selected from magnesium stearate and sodium stearyl fumarate.

18. Pharmaceutical formulation according to any one of claims 1 to 17, containing: active principle. 0.5 to 20% binder 2.5 to 6% disintegrating agent 0 to 5% non-stick 0 to 3% lubricant 0.5 to 3% slip agent 0 to 5% polysorbate 80 0 to 20% dye 0 to 2% flavoring 0 to 2% diluent cbp 100%

19. Pharmaceutical formulation according to any one of claims 1 to 18, containing: nolpitantium besilate 0.5 to 10 la lactose monohydrate 60 to 80% corn starch 15 to 25% povidone K-30 2 to 5% polysorbate 80 0 to 20% magnesium stearate 1%

20. Pharmaceutical formulation according to claim 19 which contains in the internal phase: nolpitantium besylate 3.1% lactose monohydrate 66.6% corn starch 20% povidone K-30 3% purified water for wet granulation c.b.p. polysorbate 80 6.3% in the external phase: magnesium stearate 1%

21. Pharmaceutical formulation according to any one of claims 1 to 20 for the preparation of enteric capsules.

22. Pharmaceutical formulation according to any one of claims 1 to 20 for the preparation of enteric tablets.

23. Process for the preparation of pharmaceutical formulations according to any one of claims 1 to 22, characterized in that: a) for the internal phase is mixed at temperatur? environment the active principle, the diluent, possibly the binder; b) moistened with purified water; :) it is dried and the moist mass is calibrated thus obtaining aa; d) to the calibrated dry grains thus obtained, the external phase ingredients are added, for example the lubricant, the disintegrating agent, the anti-adherent, the slip agent, and to what is polysorbate 80 is added in either step a) or in stage b).

24. Process according to claim 23, characterized in that a dye is also incorporated in stage a) or in step d).

25. Process according to claim 23 or 24 which is characterized in that a flavorant is also incorporated in step d).

26. Process according to any one of claims 23 to 25, characterized in that in step b) the polysorbate 80 is incorporated in the purified water.

27. Process according to any one of claims 23 to 26, characterized in that in step b) the binder is incorporated in the purified water instead of incorporating it in step a).

28. Process according to any one of claims 23 to 7 for the preparation of enteric formulations.