MXPA99007557A - Pharmaceutical composition for oral administration of heterocyclic compounds in the form of quaternary ammonium - Google Patents

Abstract

Se describe una composición farmacéutica para administración oral de compuestos heterocíclicos en forma de amonio cuaternario que contienen:principio activo:0.1 a 15%en peso;disolvente hidrofílico:0 a 60%en peso;tensioactivo aniónico 0 a 5%en peso;polisorvato 80:0 a 5%en peso;macroglobicérido en cantidad suficiente para el 100%a condición de por lo menos este presente un constituyente seleccionado entre el disolvente hidrofílico y el tensioactivo aniónico.

Description

PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION OF HETEROCICLIC COMPOUNDS IN THE FORM OF QUATERNARY AMMONIUM Description of the invention The present invention relates to pharmaceutical compositions containing, as an active principle, a heterocyclic compound in the form of quaternary ammonium. In particular, the invention relates to pharmaceutical compositions for oral administration, containing as active ingredient a compound of the formula: 9 r AT, Am® - (CH2) 2-C-CH2-N-T-A-Z (I) Ar wherein: - A ~ is a pharmaceutically acceptable anion; - Am + represents: i - or a group Am? + Of formula: wherein: Ari represents a phenyl unsubstituted or substituted one or more times, by a substituent selected from a halogen atom, a hydroxy, a (C? -C4) alkoxy, a (C? -C4) alkyl or a trifluoromethyl , said substituents being identical or different; - x is zero or one; REF .: 30991 i represents a (C? -C6) alkyl or a benzyl group; substituent i is in axial position or in equatorial position; ii - or an Am2 + group of formula: in which: - Ari, x and Wi are as defined above; - Ri represents a hydroxy; a (C? -C4) alkoxy; a for iloxi; a (C1-C3) alkylcarbonyloxy; a carboxy; a (Cx ~ C4) alkoxycarbonyl; a cyano; a (C1-C3) alkylcarbonylamino; a mercapto; a (C 1 -C 4) alkylthio; iii - or an Am3 + group of formula: in which: - Ari and Wi are as previously defined; R2 represents hydrogen; a (C1-C3) alkyl; a (C1-C3) alkylcarbonyl; iv- or an Arri4 + group of formula: wherein: ri and x are as defined above; - p is one or two; - v- or an Am5 + group of formula: ArHCHz in which: Arx and x are as defined above; - Ar represents a phenyl unsubstituted or substituted once or twice by a substituent chosen from a halogen atom, a (C? -C3) alkoxy, a (Ci-C3) alkyl or a trifluoromethyl, said 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 Am + represents a group Am? +, Am2 +, Am + or A? ri5 +; c) Q3 and Y3 when Am + represents a group Am? +, Am2 +, or an Am + group in which Arx represents a pheni lo and p is cLo s; d) Q4 and Y4 when Am + represents a group Am? +, Am3 +, Am4 + or Api5 +; -Qi represents hydrogen; -Yi represents hydrogen; a (C1-C4) alkyl; a? - (Ci-C4) alkoxy- (C2-C4) alkylene; a? - (Cl-C4) alkylcarbonyloxy- (C2-C4) alkylene; a? -benzoyloxy- (C2-C4) alkylene; a? hydroxy- (C2-C4) alkylene; a? - (C1-C4) alkylthio- (C2-C) alkylene; a? - (C1-C4) alkylcarbonyl- (c2_C4) alkylene; a? -carboxy- (C2-C4) alkylene; a? - (C? _4) alkoxycarbonyl- (C2-C4) alkylene; a? -benzyloxy- (C2-C4) alkylene; a? -cyloxy (C2-C4) alkylene; a CQ-R3NHCOO- (C2-C4) alkylene; a? -R4R5NC0- (C2-C4) alkylene; a? -R6CONR7- (C2-C4) alkylene; a? -R8OCONR7 - (C2-C4) alkylene; a CO-R4R5NCONR7 - (C2-C4) alkylene; a? -R9SO2NR7- (C2-C4) alkylene; a cyano- (C1-C3) alkylene; -Q2 and Y2, together, constitute an ethylene, trimethylene or tetramethylene group, 0 -Q3 and Y3 together, constitute a group: - (CH2) "1. in which n is one, two or three; - Q4 and Y4, together, constitute a radical chosen from: Ai) -0-CH2-A2) -O-CO A3) -CH2-0-CO- A4) -0-CH2-CO-As) -0-CH2-CH2-A6) -N (R? O) -CO- _ A7) -N (R? O) -CO-CO-A8) -N ( R? 0) -CH2-CH2- _ - T represents - or a group -CO- when Q and Y represent the group Q and Yx the group Q2 and Y2 or the group Q4 and Y4 in which Q4 and Y4 constitute, together, a radical Ai), A5), or A8); - or a group CH2- when Q and Y represent group Q3 and Y3 or group Q4 and Y4 in which Q4 and Y constitute, together, a radical A2), A3), A4), A6) or A7); - A represents either a direct bond or a methylene group when T is CO-, or a direct bond 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 unsubstituted 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 several times by a methyl; a (Ci-C10) alkoxy; a (C3-C7) cycloalkyloxy unsubstituted or substituted one or more times by a methyl; a mercapto; a (C1-C10) alkylthio; a (C? -C6) alkylcarbonyloxy; a (C? ~ C6) alkylcarbonylamino; a benzoylamino; a (C? ~ C4) alkoxycarbonyl; a (C3-C7) cycloalkylcarbonyl; a carbamoyl unsubstituted or substituted once or twice by a (C 1 -C 4) alkyl; a ureide unsubstituted or substituted once or twice in position 3 by a (C1-C4) alkyl or a (C3-C7) cycloalkyl; a (pyrrolidinyl-yl) -carbonylamino, said substituents being identical or different; - a naphthyl unsubstituted or substituted one or more times by a halogen, a trifluoromethyl, a (C x C 4) alkyl, a hydroxy or a (C 1 -C 4) alkoxy; a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; an imidazolyl; - R3 represents a (C1-C7) alkyl or a phenyl; - R4 and R5 represent, each independently, a hydrogen or a (C? ~ C7) alkyl; R5 may further represent a (C3-C7) cycloalkyl, a (C-C7) cycloalkylmethyl, a phenyl or a benzyl; or R4 and R5 together with the nitrogen atom to which they are attached constitute a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydrazepine, or the unsubstituted or substituted piperazine in the 4-position by a (Ci-C4) ) I rent; - R6 represents a hydrogen, a (C? -C7) alkyl, a vinyl, a phenyl, a benzyl, a pyridyl or a (C3- C7) cycloalkyl unsubstituted or substituted by one or more methyl groups; - R7 represents a hydrogen or a (C1-C7) alkyl; - R8 represents a (C ~ C7) alkyl or a phenyl; - R9 represents a (C? -C7) alkyl; an amino not substituted or substituted by one or two (C? -C7) alkyls; a phenyl unsubstituted or substituted one or several times by a substituent chosen from a halogen atom, a (Cx-C7) alkyl, a trifluoromethyl, a hydroxy, a (C? ~ C7) alkoxy, a carboxy, a (Ci-C7) alkoxycarbonyl, a (Ci-C7) alkylcarbonyloxy, a cyano, a nitro or an amino unsubstituted or substituted by one or two (C? -C7) alkyls, said substituents being identical or different; - Rio represents hydrogen or (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 comprise both the racemic, the optically pure isomers, as well as the axial and equatorial isomers when in the compound of formula (I), Am + represents an Am? + Group, an Am2 + group or an Am3 + group. The compounds of formula (I) are described in patent applications EP-A-0 512 901, EP-A-0 515 240, EP-A-0 559 538, 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: wherein: - Ari-, x, p and A "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 the 3-position by a halogen or a (Ci-Cio) alkoxy, are preferred according to the invention More precisely, the invention relates to pharmaceutical compositions for oral administration of (S) -l-. {2 - [3- (3,4-dichlorophenyl) -1- (3-sopropoxyphenylacetyl) piperidin-3-yl] ethyl) -4-phenyl-1-azoniabicicy [2.2.2] octane, or SR 140333, of the formula: wherein A is a pharmaceutically acceptable anion.

The benzenesulfonate of SR 14033, hereinafter referred to as compound A, is very particularly preferred.

The international nonproprietary name of compound A is nolpitantium besylate. The compounds of formula (I) have been described as antagonists of substance P which is a natural agonist of NKi receptors. To administer said compounds orally, it is necessary that they present 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 pharinaco inetics, concepts and applications, Lea and Fehiger ed., 1989, 2nd.

Edition, p. 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) given that they are quaternary ammonium remain in ionized form whatever the pH of the medium in which they are found, especially at neutral pH, which is the pH of the intestinal environment. It is known that ionic compounds, especially quaternary ammoniums, have difficulty penetrating the epithelial membranes (J.P. Labaune in Pharmacolcinétique, Principes fondamentaux, Masson ed., 198a, 2nd edition, pp. 7-33). The Caco-2 cell line 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 (Crit., Rev. Ther, Drug Carrier System, 1991 _8 (4), 105-330). In that model, the permeability of compound A is 3.4. 10 ~ 7 cm / s. On the other hand, the correlations made between the in vitro results and the in vivo results have shown that a coefficient of permeability of that order corresponds to an absorption of less than 5% for fully solubilized molecules. In the present case, studies carried out in the rat, with compound A in 0.6% aqueous solution in methylcellulose, have shown that its estimated absorption is less than 1%. Thus, in order to carry out the adjustment of an oral galenic formulation for compounds of formula (I), it is necessary to remedy at the same time its very low solubility in aqueous medium and its weak passage through the intestinal epithelium. To modify the particular cationic character, due to the quaternary ammonium form of the compounds according to the invention, they can be transformed by adding an anionic surfactant in a stoichiometric amount: a pair of ions is obtained whose charge is globally neutral. But the ion pair formed between the cationic part of the compound of formula (I) and the anionic part of the surfactant has a molecular mass superior to that of compound (I), therefore its hydrophobic character increases and this pair of ions is Quasi insoluble in water. It has been found that the intestinal absorption of the ion pair consisting of a compound of formula (I) and an anionic surfactant decreases with respect to that of a compound of formula (I) in the form of ammonium. Nonionic surfactants and agents that improve absorption have also been tested for their "effect on the membrane permeability of a compound of formula (I)." These products have been found to have no positive effect. in semisolid form at ordinary temperature and which, owing to having both a lipid character and an amphiphilic character, can be used to solubilize lipophilic active compounds and facilitate its intestinal absorption (Bulí, Techn. Gattefossé, 1994, 8_7 49-54). Such compounds are chosen from saturated polyglycosylated glycerides consisting of a mixture of glycerol monster, diester and triester and fatty acids whose carbon chains are in Ce-C? &, and polyethylene glycol mono and diesters and fatty acids whose chains Carbonates are in Cg-Cig. The most interesting among them are: the lauroyl macrogoglyceride whose melting point is 44 ° C and whose hydrophilic, lipophilic balance (HLB) is 14; - the stearoyl frameworkgoglyceride whose melting point is 50 ° C and whose hydrophilic, lipophilic balance is 13; - the caprilocaproilo macrogoglicérido, oily liquid whose hydrophilic / lipophilic balance is 14. These compounds are marketed by the company Gattefossé respectively under the brands Géluc? re € 44-14, Gélucire £ 50-13 and Labrasol €. The compounds (I) of hydrophilic nature are not soluble in said derivatives, especially they are not soluble in the products Géluciree 44-14, Gélucire0 ~ 50-13 and Labrasol®. In accordance with the present invention, it has now been discovered that a compound of formula (I) can be solubilized in a saturated polyglycosylated glyceride, with the condition of adding at least one of the following constituents: - a hydrophilic solvent - an anionic surfactant. The formulation thus obtained allows to improve the bioavailability of the active principle. It is also advantageous to solubilize a compound of formula (I) in a saturated polyglycosylated glyceride, adding at the same time a hydrophilic solvent and an anionic surfactant. Surprisingly, it has been discovered that the addition of a particular polysorbate, polysorbate 80, to compound A in solution in cell culture medium improves the transepithelial passage in the Caco-2 model. Therefore, it may be advantageous to add to the above-determined formulation a small proportion of polysorbate 80. Thus, according to one of its aspects, the present invention relates to a pharmaceutical composition for oral administration of a compound of formula (I) containing: - active ingredient 0.1% to 15% by weight, - hydrophilic solvent 0% to 60% by weight, - anionic surfactant 0 to 5% by weight, - polysorbate 80 0 to 5% by weight, - macrogoglyceride in sufficient quantity (Q.S.) for 100% of weight; with the proviso that at least one constituent selected from the hydrophilic solvent and the ammonium surfactant is present. Preferably, in the absence of anionic surfactant, the concentration of active principle is less than or equal to 30% by weight of the concentration of hydrophilic solvent. According to the present invention, by "macrogoglyceride" is meant the products Gélucire® 44-14, Gélucire® 50-13 and Labrasol®, the preferred being the Gélucire® 44-14. As the hydrophilic solvent, an alcohol such as ethanol or a glycol derivative such as propylene glycol or the product Transcutol® which is a diethylene glycol monoethyl ether can be used. Propylene glycol is the preferred hydrophilic solvent. As the anionic surfactant, a bile salt such as sodium taurocholate or a sodium alkyl sulfate such as sodium octyl sulfate or preferably sodium lauryl sulfate can be used, the latter being a preferred anionic surfactant for the invention. The pharmaceutical compositions according to the invention can be presented in different forms intended for oral administration, for example: capsules, sachets drops, drinkable ampoules or bottles.

Advantageously, the present invention has pharmaceutical containing: active ingredient 0.1% to 15% solvent-hydrophilic solvent 1% to 60% by weight, anionic surfactant 0.03% to 5% by weight, polysorbate 80 0 to 5% by weight, - macrogoglyceride QS for 100% of weight. Particularly, the present invention relates to a pharmaceutical composition for oral administration of a compound of formula (I) containing: ~~ - active ingredient 0.1% to 15% by weight - hydrophilic solvent 5 to 60% by weight, - polysorbate 80 0 to 5% by weight, - macrogoglyceride QS for 100% of weight; with the proviso that the concentration of active principle is less than or equal to 30% by weight of the concentration of hydrophilic solvent. In another particular form, the present invention relates to a pharmaceutical composition for oral administration of a compound of formula (I) containing: - active ingredient 0.1% to 15% by weight - hydrophilic solvent 0% to 30% by weight, - anionic surfactant 0.03 to 5% by weight, - polysorbate 80 0 to 5% by weight, - macrogoglyceride QS for 100% of weight; with the proviso that the concentration of active principle is less than or equal to 30% by weight of the concentration of hydrophilic solvent. According to the invention, the anionic surfactant is preferably present in a stoichiometric amount with respect to the active principle. The aforementioned pharmaceutical composition contains from 0.1 to 12% water, since the anionic surfactant has been introduced in concentrated aqueous solution. When soft or hard capsule type gelatin capsules are prepared, the hydrophilic solvent content of the pharmaceutical composition must be compatible with the gelatin. Thus, the present invention has more precisely by "object, pharmaceutical compositions for the preparation of capsules containing: - active substance 0.1% to 9% by weight - hydrophilic solvent 0% to 3Q% by weight, - anionic surfactant 0 at 3% by weight, - polysorbate 80 0 to 5% by weight, - - macrogoglyceride QS for 100% by weight, with the proviso that at least one constituent selected from the hydrophilic solvent and the anionic surfactant is present.

Most particularly, pharmaceutical compositions are preferred for the preparation of capsules containing: active ingredient 0.1 to 7% solvent-hydrophilic solvent 5 to 20% by weight, polysorbate 80 0 to 5% by weight, macrogoglyceride Q.S. for 100% of weight; with the proviso that the concentration of active principle is less than or equal to about 30% by weight in the concentration of hydrophilic solvent. Likewise, pharmaceutical compositions are preferred for the preparation of capsules containing: active substance 0.1 to 7% by weight, hydrophilic solvent 0 to 15% by weight, anionic surfactant 0.03 to 2% by weight, - polysorbate 80 0 to 5% by weight, - macrogoglyceride: Q.S. for 100% of weight. The anionic surfactant is preferably present preferably in a stoichiometric amount with respect to the active principle. Preferably, the pharmaceutical composition according to the invention contains an amount greater than or equal to 1% by weight of hydrophilic solvent, particularly preferably an amount greater than or equal to 1% by weight of propylene glycol.

For pharmaceutical compositions in the form of capsules, it is also possible to prepare enteric formulations. These formulations are used to protect the active substance from strong stomach acidity. Said formulations are prepared by coating the capsule by means of a polymer film insoluble in an acid medium and soluble in a basic medium. By way of example, film for coating can be mentioned cellulose acetofialate, polyvinyl acetophthalate, hydroxypropylmethylcellulose fialate or methacrylic acid copolymers. As an example of methacrylic acid copolymer, mention may be made of the C-type methacrylic acid copolymer sold under the brand name ELDRAGIT® L30 D-55 by ROHM or the copolymer of ethyl acrylate and methacrylic acid marketed under the name of brand KOLL? COAT® 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 by means of a film. constituted by a pre-coating prior to the enteric coating. The pre-coating can be carried out, for example, with hydroxypropylcellulose, povidone or methacrylic acid copolymer associated with suitable excipients. According to a particular embodiment, the present invention relates to a pharmaceutical composition for oral administration of compound A containing: Compound A 0.1 to 9% strength, propylene glycol 1 to 30% by weight, sodium lauryl sulfate 0 to 3% weight, Gélucire 44-14 QS for 100% of weight. More precisely, the present invention relates to a pharmaceutical composition of the formula: Compound A 0.1 to 7% by weight, propylene glycol 5 to 20% by weight, Gellucire® 44-14 Q.S. for 100% of weight. with the proviso that the concentration of compound A is less than or equal to about 3% by weight of the concentration of propylene glycol. The present invention also relates to a pharmaceutical composition for oral administration of compound A which contains: Compound A 0.1 to 7% weight, propylene glycol 1 to 15% by weight, sodium lauryl sulphate 0.03 to 2% by weight, Gélucire® 44-14 Q.S. for 100% of weight. the sodium lauryl sulfate being preferably in a stoichiometric amount with respect to the compound A. According to a particular embodiment, the present invention relates to a pharmaceutical composition for the preparation of capsules containing: Compound A 3.6% by weight, ~~ propylene glycol 15, 9% by weight, Gélucire® 44-14 SO, 5% by weight. According to another particular embodiment, the present invention relates to a pharmaceutical composition for the preparation of capsules containing: Compound A 3.4% by weight, propylene glycol 15.3% by weight, sodium lauryl sulfate 1.5% by weight , water 2.7% by weight, Gélucire® 44-14 77.1% by weight. For the preparation of a pharmaceutical composition such as that described, it is possible to proceed in the following manner when there is no anionic surfactant in the composition: the active principle is placed in suspension in the hydrophilic solvent and heated under stirring to a temperature between 60 ° C and 80 ° C depending on the concentration of active principle introduced into the hydrophilic solvent. 90% of the molten macrogoglyceride is added at 60 ° C then eventually polysorbate 80. It is terminated by adjusting to 100% by the sufficient amount of macrogoglyceride. When the pharmaceutical composition contains an anionic surfactant, you can proceed as follows: the active ingredient is mixed in 90% of macrogoglyceride heated to 60 ° C. To the formed suspension, anionic surfactant dissolved in hot water is added in a minimum of water, then if necessary added the hydrophilic solvent and eventually polysorbate 80. It is finished by adjusting to 100% by the sufficient amount of macrogoglyceride. Most particularly, when preparing enteric formulations, the film of a capsule according to the invention can contain a pre-coating film and a coating film with the following constitution: Pre-coating: Acid copolymer 46.6% methacrylic weight of type C glycerin 4.6% by weight Aqueous solution of 4, 6% weight polysorbate 80 to 33% water 44.2% by weight Coating: Acid copolymer 54, 8% methacrylic weight of type C Glycerin 3.3% by weight Aqueous solution of 0.7% by weight polysorbate '80% 33% water 41.2% by weight The characteristics and advantages of the compositions of the invention will appear in the light of the following description, starting from the compositions given by way of examples. In those examples, the percentages are percentages of weight.

TESTS 1. Test for the solubility of compound A. 1.1: Solubility in water. The solubility has been measured by saturation, after 24 hours, at room temperature; the measurements were made by U.V. spectrometry to ? = 275 mm after calibration in an ethanolic solution.

PH 1 3 5 7 9 Concentration of 0.31 0.31 0.31 0.29 0.31 compound A mg / ml 1. 2. Solubility in different solvents. The instantaneous solubility is evaluated at room temperature, by successive additions of the solvent studied in compound A, in a hemolysis tube until observation of limpidity. Taking into account differences in density, in weight / weight. water 0.33 mg / g ethanol 36.5 mg / g methanol 365, 0 mg / g benzyl alcohol > 450.0 mg / g Transcutol 5.0 mg / g polyethylene glycol 400 0.45 mg / g propylene glycol 12 mg / g glycerol oleate 0.64 mg / g peanut oil < 0.2 mg / g Gélucire® 44-14 < 0.2 mg / g On the other hand, compound A is soluble in aspetylsulfoxide (DMSO) at 168 mg / ml. 1.3. Variation of solubility as a function of temperature in propylene glycol.

Solubility of compound A in propylene glycol. T ° C 23 ° C 60sC 80 ° C Concentration of 12 155 350 compound A in mg / g 1. 4. Study of solubility in glycerides. Solubility of compound A in Gélucire® 44-14. T ° C 23 ° C 60 ° C Concentration of compound A < 0.2 0.4 mg / g 1. 5. Solubility of compound A in the presence of sodium lauryl sulphate in stoichiometric amount in water: less than 0.1 μg / ml. 2. Evaluation of the intestinal transepithelial passage of compound A. In microporous polycarbonate filters coated with collagen, Caco-2 cells are seeded. The cell monolayer formed in the filter then allows to separate an apical compartment (which mimics the intestinal lumen) from a basal compartment (which mimics blood circulation). The composition containing the compound to be studied is then placed on the apical side and the passage of that compound, dispersed or solubilized in medium, is evaluated. of Hank, through this cellular barrier measuring its kinetics of appearance of the basal side. That aqueous medium, of pH = 6.5, in the following composition: NaCl = 8.0 g / 1; KCl = 0.4 g / 1; CaCl 2 = 0.19 g / 1; MgCl2 = 0.1 g / 1; MgSO4 = 0.1 g / 1; Na2HP04 = 0.09 g / 1; KH2P04 = 0.06 g / 1; NaHCO 3 = 0.35 g / 1; glucose = 1 g / 1; phenol red = 0.01 g / 1. The coefficient of permeability P, in cm / s, is then determined, which characterizes the rate of passage of the molecule through the membrane, namely: P = (da / dt). (1 / A.Co) in which: da / dt = variation of the amount of compound tested that passes through the cell monolayer as a function of time (mol / s) A = surface of the monolayer (cm2) Co = initial concentration of the tested compound (mol / 1) 2.1. Permeability coefficient of compound A introduced in Hank's medium in DMSO solution. P = 3.4. 10 ~ 7 cm / s. The permeability of the compound A thus measured in solution (in DMSO) indicates an intrinsic characteristic of that compound. This result confirms the very poor fitness of compound A at the transepithelial passage. 2. 2. Relative velocity of the intestinal taixal transep of compound A. Different formulations are prepared with compound A in order to measure its rate of passage and compare it with that of compound A in solution in DMSO. Formulation 1: '- Compound A 4.4% - "propylene glycol 15, 9% - Gélucire® 44-14 79.7% Formulation 2: - Compound A 4.2% - Gélucire® 44-14 76, 3% - propylene glycol 15.3% - sodium lauryl sulphate 1.4% - H20 2- r O "6 Formulation 3: - Compound A 4.3% - Gélucire® 44-14 91.23% - Sodium lauryl sulfate 1.52% - H20 2, 95% Formulation 4: - Compound A 4.31% - Gélucire® 44-14 91.19% - Sodium octyl sulphate 1.53% -H20 2.97% Formulation 5: - Compound A 7.4% - propylene glycol 28.7% - Gélucire® 44-14 63, 9% Formulation 6: - Compound A - propylene glycol 46% - Gélucire® 44-14 46% Formulation 7: - Compound A 6% - propylene glycol 34% - Labrasol 60% Formulation Solution 1 4 5 6 7 DMSO Speed 1 12 15 7 10 8 10 relative Each of these formulations causes a marked improvement of the transepithelial passage of compound A and none of these formulations has caused an alteration of the epithelial monolayer. All these formulations have been observed in an optical microscope. A total solubilization of compound A has been found, except for formulations 3 and 4 in which a part of compound A is in crystalline form.

The best result is obtained with formulation 2, which combines the formation of the ion pair with sodium lauryl sulphate and the use of the mixture Gelucire® 44-14 and propylene glycol. EXAMPLE 1: Capsule Compound A 4.4% propylene glycol 15.9% Gélucire® 44-14 79.7% for a white-opaque capsule size 1 The active substance is solubilized in propylene glycol at 70 ° C then under mechanical agitation, incorporated the solution obtained in Gélucire® 44-14 at 60 ° C finally the capsule is filled at 40 ° C. EXAMPLE 2: Capsule Compound A 4.2% propylene glycol 15.3% sodium lauryl sulfate in 34% aqueous solution 1.4% water 2.8% Gélucire® 44-14 76.3% for a white-opaque capsule size 1 The active ingredient is mixed with 90% Gélucire® 44-14, heated at 60 ° C. The aqueous solution of sodium lauryl sulphate is then added with the Gélucire 44-14 remaining. It is incorporated into the capsule after cooling to 40 ° C. EXAMPLE 3: Liquid Form for Bottle Compound A 6.0% Propylene Glycol 34.0% Labrasol® 60.0% EXAMPLE 4: Drinkable Ampoule Compound A 8.0% Propylene Glycol 46.0% Gellucire® 44-14 46.0% EXAMPLE 5: Capsule Compound A 4.5% propylene glycol 15.0% Gélucire® 44-14 80.5% EXAMPLE 6: Capsule Compound A 4.4% propylene glycol 13.0% sodium lauryl sulphate 1.5% water 3.0% Gélucire® 44-14 78.1% EXAMPLE 7: Liquid for bottle Compound A 8.0% propylene glycol 27.5% polysorbate 80 2.0% Labrasol® 62.5% EXAMPLE 8: Bottle Fluid - Compound A 1, 5% Propylene Glycol 20.5% Polysorbate 80 2.0% Sodium Lauryl Sulfate 2.6% Water 4.9% Labrasol® 62.5% EXAMPLE 9: Enteric Capsule Prepare a capsule according to example 1, and a film of 2 layers is applied: one of pre-coating and the other of coating. Pre-coating: Eudragit® L30 D-55 46.6% glycerin 4, 6% aqueous solution of polysorbate 80 33% 4.6% water 44.2% Coating: Eudragit® L30D-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 the conventional one for manufacturing of the objects or products to which it refers-

Claims (26)

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

1. Pharmaceutical composition for oral administration to an active principle of the formula: T T A, Am - (CH2) 2-C-CH2-N-T-A-Z (I) Ar in which: - A "is a pharmaceutically acceptable anion; - Am + represents: i - or an Am? + Group of the 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? -C4) alkoxy, a (C: -C4) alkyl or a trifluoromethyl, said substituents being identical or different; - x is zero or one; Wi represents a (C -Ce) alkyl or a benzyl group; the substituent x is in the axial position or in the equatorial position; ii - or an Am2 + group of formula: , in which: - Arl, x and Wx are as defined above; - Ri represents a hydroxy; a (C1-C4) alkoxy; a formyloxy; a (C1-C3) alkylcarbonyloxy; a carboxy; a (C ± - C4) alkoxycarbonyl; a cyano; a (C1-C3) alkylcarbonylamino; a mercapto; a (C -C4) alkylthio; iii - or an Am3 + group of formula: in which: Arx and Wi are as defined above; - R2 represents hydrogen; a . { C1-C3) alkyl; a (C1-C3) alkylcarbonyl; iv- or an Am4 + group of formula: in which: Ar: and x are as defined above; - p is one or two; v- or an Am5 + group of formula in which: Arx and x are as defined above; -Ar represents a phenyl unsubstituted or substituted once or twice by a substituent chosen from a halogen atom, a (C1-C3) alkoxy, a (Cx-C3) alkyl or a trifluoromethyl, said substituents being identical or different; a naphlyl; a mdolyl; -Q and Y represent one of the following groups of values: a) Qi and Yi; b) Q2 and Y2 when Am "represents a group Am? +, Am; *, Am4 + or Am5 +; c) Q3 and Y3 when Am + represents a group Am? +, Am2 +, or an Am4 + group in which Arx represents a phenyl and p is two, d) Q4 and Y4 when Am * represents a group Amx +, Am3 +, Am, "or Am5t; - Qi represents hydrogen; -Yi represents hydrogen; a (C: ~ C4) alkyl; a? - (C? ~ C) alkoxy- (C2-C4) alkylene; a? - (C .. C4) alkylcarbonyloxy- (C2-C4) alkylene; a? -benzoyloxy- (2- C4) alkylene; a? -hydroxy- (C; -C4) alkylene; a? - (C-C) alkylthio- (C2-C4) alkylene; a? - (Ci-C4) alkylcarbonyl- (C2-C) alkylene; a? -carboxy- (C2-C4) alkylene; a? -? C-C4) alkoxycarbonyl- (C2-C4) alkylene; a? -benzyloxy- (C2-C4) alkylene; a? -formyloxy- (C2-C4) alkylene; a? - R3NHC00- (C2-C4) alkylene; a CO-R4R5NCO- (C2-C4) alkylene; a? -R6CONR7- (C2-C4) alkylene; a? -R8OCONR7 - (C2-C4) alkylene; a CO-R4R5NCONR7 - (C2-C4) alkylene; a? -R9502NR7-C (C-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: - (CH2) n-¿-_ in which n is one, two or three; - Q and Y4, together, constitute a radical selected from Ai) -O-CH2-A2) -O-CO A3) CH2-O-CO-A4) -O-CH2-CO-A5) -O-CH2-CH2 - A6) -N (R? 0) -CO- A7) -N (RIQ) -CO-CO- A8) -N (R? O) -CH2-CH2- - T represents - or a group CO- when Q and Y represent the group Qi and Yx the group Q2 and Y2 or the group Q4 and Y4 in which Q4 e Y4 constitute, together, a radical A:), A5), or As); - or a group CH2- when Q and Y represent group Q3 and Y3 or group Q4 and Y4 in which Q4 and Y4 constitute, together, a radical A2), A3), A4), A5) or A-); - A represents either a direct bond or a methylene group when T is -CO-, or a direct bond when T is CH2 ~; Z represents: a phenyl unsubstituted or substituted one or more 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? ~ C) alkyl; a benzylamino; a carboxy; a (Ci-Cio) alkyl; a (C3-C7) cycloalkyl unsubstituted or substituted one or several times by a methyl; a (C? ~ C? o) aicoxi; a (C3-C7) cycloalkyloxy unsubstituted or substituted one or more times by a methyl; a mercapto; a (C1-C10) alkylthio; a (Ci-Cg) alkylcarbonyloxy; a (Ci-C?) alkylcarbonylamino; a benzoylamino; a (Ci-C4) alkoxycarbonyl; a (C3-C7) cycloalkylcarbonyl; a carbamoyl unsubstituted or substituted one or two times by a (C1-C4) alkyl; a ureide unsubstituted or substituted once or twice in position 3 by a (C? -C4) alkyl or a (C3-C7) cycloalkyl; a (pyrrolidin-1-yl) -carbonylamino, said substituents being identical or different; - a naphlyl unsubstituted or substituted one or several times by a halogen, a trifluoromethyl, a (C-C4) alkyl, a hydroxy or a (C? -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 R5 represent, each independently, a hydrogen or a (C1-C7) alkyl; R5 may further represent a (C3-C7) cycloalkyl, a (C3-C7) cyclaalkylmethyl, a phenyl or a benzyl; or R4 and R5 together with the nitrogen atom to which they are attached constitute a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydrazepine, or the unsubstituted or substituted piperazine in position 4 by a (Ci-C4) ) I rent; - Re represents a hydrogen, a (C1-C7) alkyl, a vinyl, a phenyl, a benzyl, a pyridyl or a (C3-C-) cycloalkyl unsubstituted or substituted by one or more methyl; - R7 represents a hydrogen or a (C1-C7) alkyl; - - R8 represents a (C1-C7) alkyl or a phenyl; - R9 represents ~ a (C: -C7) alkyl; an ammo unsubstituted or substituted by one or two (C: -C7) alkyl; an n-phenyl substituted or substituted one or several times by a substituent selected from a halogen atom, a (C:-C7) alkyl, a trifluoromethyl, a hydroxy, a > '^ -C7) alkoxy, a carboxy, a (C 1 -C 7) alkoxycarbonyl, a (C: -C 7) alkylcarbonyloxy, a cyano, a nitro or an amino unsubstituted or substituted by one or two (C 1 -C 7) alkyls, said substituents being identical or different; - Rio represents hydrogen or a (C? -C4) alkyl; or one of its possible salts with mineral or organic acids or one of its possible solvates; characterized in that it contains: - active substance 0.1% to 15% by weight, - hydrophilic solvent 0% to 60% by weight, - aionic surfactant 0 to 5% by weight, - polysorbate 80 0 to 5% by weight, macrogoglyceride in sufficient quantity : Q.S. for 100% of weight; provided that at least one constituent selected from the hydrophilic solvent and the anionic surfactant is present.

2. Pharmaceutical composition according to claim 1, characterized in that the active principle is a compound of the formula: A N-CO-CH2-Z '(F) wherein: - Ari, x, p and A "are as defined for a compound of formula (I) in claim 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

3. Pharmaceutical composition according to claim 1 or 2, characterized in that the active principle is (S) -1-. - [3- (3, 4-dichlorophenyl) -1- (3-isopropoxyphenylacetyl) piperidin-3-yl] ethyl} -4-phenyl-1-azon-abicyclo [2.2.2] octane, of the formula: wherein "A" is a pharmaceutically acceptable anion

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

5 . Pharmaceutical composition according to any of claims 1 to 4, indistinctly, characterized in that it contains: - active ingredient 0.1% to 15% weight or - hydrophilic solvent 1% at 6 C% weigh, - anionic surfactant 0.03% a 5 weight, - polysorbate 80 0 to 5% by weight, - macrogoglyceride Q.S. for 100% of weight.

6. Pharmaceutical composition according to any of claims 1 to 5, indistinctly, characterized in that it is presented in the form of capsules, sachets, drops, drinkable ampoules or flasks.

7. Pharmaceutical composition according to any one of claims 1 to 6, characterized in that the macrogoglyceride is chosen from Gellucire € 44-14, Gellucire € 50-13 or Labrasol. "

8. Pharmaceutical composition according to claim 7, characterized because the macrogoglyceride is the Gelucire £ 44-14.

9. Pharmaceutical composition according to any one of claims 1 to 8, interchangeably, characterized in that the hydrophilic solvent is chosen from ethanol, propylene glycol or Transcutol'1.

10. Pharmaceutical composition according to claim 9, characterized in that the hydrophilic solvent is propylene glycol.

11. Pharmaceutical composition according to any one of claims 1 to 10, indistinctly, characterized in that the anionic surfactant is chosen from a bile salt or sodium alkyl sulfate.

12. Pharmaceutical composition according to claim 11, characterized in that the anionic surfactant is sodium lauryl sulphate.

13. Pharmaceutical composition according to any of the 1 to 12, indistincting reagents, characterized by a quantity greater than or equal to 1% by weight of hydrophilic solvent.

14. Pharmaceutical composition according to any one of claims 1 to 13, characterized in that the anionic surfactant is in a stoichiometric amount with respect to the active ingredient

15. Pharmaceutical composition according to any of claims 1 to 14, indistinctly, characterized in that the anionic surfactant It is incorporated into the formulation in concentrated aqueous solution.

16. Pharmaceutical composition according to any one of claims 1 to 9, characterized in that it contains: - active ingredient 0.1% to 15% by weight - hydrophilic solvent 5 to 60% by weight, - polysorbate 80 0 to 5% by weight , - macrogoglyceride QS for 100% of weight; with the proviso that the concentration of active principle is less than or equal to 30% by weight of the concentration of hydrophilic solvent.

17. Pharmaceutical composition according to any of the. claims 1 to 15, indistinctly, characterized in that it contains: active substance 0.1% to 15% by weight hydrophilic solvent 0% to 30% by weight, polysorbate 8 0.0 0 to 5% by weight, macrogoglyceride Q.S. for 100% of weight;

18. Pharmaceutical composition according to any one of claims 1 to 15, characterized in that it contains: - active substance 0.1% to 9% by weight - hydrophilic solvent 0 to 30% by weight, - anionic surfactant 0 to 3% by weight , - polysorbats 80 0 to 5% by weight, - macrogoglyceride QS for 100% of weight; with the proviso that at least one constituent selected from the hydrophilic solvent and the anionic surfactant is present.

19. Pharmaceutical composition according to claim 18, characterized in that it contains: active substance 0.1 to 7% by weight hydrophilic solvent 5 to 20% by weight, - polysorbate 80 0 to 5% by weight, - macrogoglyceride Q.S. for 100% of weight; with the proviso that the concentration of active principle is less than or equal to about 30% by weight of the concentration of hydrophilic solvent.

20. Pharmaceutical composition according to claim 18, characterized in that it contains: - active substance 0.1 a7% by weight - hydrophilic solvent 0 to 15% by weight, - anionic surfactant 0.03 to 2% by weight, - polysorbate 80 0 a 5% by weight, - macrogoglyceride Q. S. for 100% of weight.

21. Pharmaceutical composition according to any one of claims 1 to 15, indistinctly, characterized in that it contains: - nolpitantium besylate 0.1 to 9% by weight, - propylene glycol 1 to 30% by weight, - sodium lauryl sulphate 0 to 3% weight, - Gélucire € 44-14 QS for 100% of weight.

22. Pharmaceutical composition according to claim 21, characterized in that it contains: - nolpitantium besylate 0.1 to 7% by weight, - propylene glycol 5 to 20% by weight, - Gélucire- 44-14 Q.S. for 100% of weight. provided that the concentration of nolpitantium besiiato is less than or equal to about 30% by weight of the concentration of hydrophilic solvent.

23. Pharmaceutical composition according to claim 21, characterized in that it contains: - nolpitantium besylate 0.1 to 7% by weight, - propylene glycol 1 to 15% by weight, sodium lauryl sulfate 0, 03 to 2% by weight, - Gélucire® 44-14 Q.S. for 100% of weight.

24. Pharmaceutical composition according to claim 21, characterized in that it contains: - nolpitantium besylate 3.6% by weight, - propylene glycol 15, 9% by weight, - Gellucire ^ 44-14 80.5% by weight.

25. p-pp-ri farpß-eutica, cara-? Brized because ocpti / Jan: - nolpitantium besylate 3.4% by weight, - propylene glycol 15.3% by weight, - sodium lauryl sulphate 1.5% by weight , - Gélucire® 44-14 77.1% by weight.

26. Pharmaceutical composition according to any of claims 1 to 25, indistinctly, characterized in that it is presented in the form of an enteric capsule.