WO1998035662A1 - Pharmaceutical composition for oral administration of heterocyclic compounds in the form of quaternary ammonium - Google Patents

Abstract

The invention concerns a pharmaceutical composition for oral administration of heterocyclic compounds in the form of quaternary ammonium, containing: active principle: 0.1 to 15 wt.%; hydrophilic solvent: 0 to 60 wt.%; anionic surfactant 0 to 5 wt.%; polysorbate 80: 0 to. 5 wt.%; macrogoglyceride in sufficient amount. for 100 wt.%, provided that at least one selected constituent between the hydrophilic solvent and the anionic surfactant is present.

Description

Pharmaceutical composition for the oral administration of heterocyclic compounds in quaternary ammonium form

The present invention relates to new pharmaceutical compositions containing as active ingredient 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 formula:

dans laquelle

in which

A ^ is a pharmaceutically acceptable anion;

Am® represents: i - either an Ami ® group of formula:

dans laquelle :

in which :

- Arj represents a phenyl which is unsubstituted or substituted one or more times by a substituent chosen from a halogen atom, a hydroxy, a (Cι-C) alkoxy, a (Cι-C4) alkyl or a trifluoromethyl, said substituents being identical or different; - x is zero or one;

- Wj represents a (Cι-Cg) alkyl or a benzyl group; the substituent Wi being either in the axial position or in the equatorial position; ii - or an Arrn® group of formula:

dans laquelle :

in which :

- Aq, x and Wj are as defined above; - R \ represents a hydroxy; a (C ι-C4) alkoxy; formyloxy; a (Ci -

C3) alkylcarbonyloxy; carboxy; a (Cι-C4) alkoxycarbonyl; a cyano; a

(Cι -C3) alkylcarbonylamino; a mercapto; a (Ci -C4) alkylthio; iii - either an Am ® group of formula: W,

in which :

- A and Wj are as defined above;

- R_2 represents hydrogen; a (Cι-C3) alkyl; a (Cι -C3) alkylcarbonyl; iv - or an Am4® group of formula:

dans laquelle :

in which :

- Aq and x are as defined above;

- p is one or two; v - or an A1115® group of formula:

dans laquelle : - Aq et x sont tels que définis ci-dessus ;

in which: - Aq and x are as defined above;

- Ar represents a phenyl which is unsubstituted or substituted once or twice by a substituent chosen from a halogen atom, a (Cj-C3) alkoxy, a (Cι -C3) alkyl or a trifluoromethyl, said substituents being identical or different; naphthyl; indolyl; - Q and Y represent one of the following groups of values: a) Qi and Y _ι; b) Q2 and Y2 when Am® represents a group Ami ®, Aπr? ®, Am.4® or Am5®; c) Q3 and Y3 when Am® represents an Ami® group, Am2® or an Am.4® group in which Aq represents a phenyl and p is two; d) Q4 and Y4 when Am® represents an Ami®, Am3®, Am4® or Am5® group;

- Q 1 represents hydrogen; - Y represents hydrogen: a (Cj-C4) alkyl; a ω- (Cι-C4) alkoxy- (C2-C4) alkylene; a ω- (Cι-C4) alkylcarbonyloxy- (C2-C4) alkylene; ω-benzoyloxy- (C2-C4) alkylene; ω-hydroxy- (C2-C4) alkylene; a ω- (Cι-C4) alkylthio- (C2-C4) alkylene; a ω- (Cι-C4) alkylcarbonyl- (C2-C4) alkylene; ω-carboxy- (C2-C4) alkylene; a ω- (Cι-C4) alkoxycarbonyl- (C2-C4) alkylene; a ω-benzyloxy-

(C2-C4) alkylene; ω-formyloxy- (C2-C4) alkylene; ω-R3NHCOO- (C2-C4) alkylene; ω-R4R.5NCO- (C2-C4) alkylene; a ω-R.6CONR ₇ - (C2-C4) alkylene; a ω-R8θCONR ₇ - (C2-C4) alkylene; a ω-R4R ₅ NCONR ₇ - (C2-C4) alkylene; a ω-RoSθ2NR ₇ - (C2-C4) alkylene; a ω-cyano- (Cι-C3) alkylene; - Q2 and Y2, together, constitute an ethylene, trimethylene or tetramethylene group;

- Q3 and Y3, together, constitute a group:

O

A₂) -O-CO- A₃) -CH -O-CO- A ) -O-CH₂-CO- A₅) -O-CH₂-CH₂- A₆) -N(Rι₀)-CO-- (CH ₂ ) _n -C- in which n is one, two or three; Q4 and Y4, together, constitute a radical chosen from:

A ₂ ) -O-CO- A ₃ ) -CH -O-CO- A) -O-CH ₂ -CO- A ₅ ) -O-CH ₂ -CH ₂ - A ₆ ) -N (Rι ₀ ) - CO-

T represents - either a group -CO- when Q and Y represent the group Qi and Y \, the group Q2 and Y2 or the group Q4 and Y4 in which Q4 and Y4 together constitute a radical Ai), A5) or Ag );

- or a group -CH2- when Q and Y represent the group Q3 and Y3 or the group Q4 and Y4 in which Q4 and Y4 together constitute a radical A2), A3), A4), Ag) or A ₇ );

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 which is unsubstituted or substituted one or more times by a substituent chosen from a halogen atom; trifluoromethyl; a cyano; hydroxy; a nitro; an amino unsubstituted or substituted one or more times by a (C j -C4) alkyl; a benzylamino; carboxy; a (Cι-Cιo) alkyl; non (C3-C ₇ ) cycloalkyl substituted or substituted one or more times with methyl; a (Cι-Cιo) alkoxy; a (C3-C ₇ ) cycloalkyloxy unsubstituted or substituted one or more times with methyl; a mercapto; a (Cι-Cιo) alkylthio; a (Cι-C6) alkylcarbonyloxy; a (Cι-C ( _j ) alkylcarbonylammo; a benzoylamino; a (Cι-C4) alkoxycarbonyl; a (C3-C ₇ ) cycloalkylcarbonyl; a carbamoyl unsubstituted or substituted once or twice by a (Cι-C4) alkyl; ureido unsubstituted or substituted once or twice in position 3 by a (Cι-C4) alkyl or a (C3-C ₇ ) cycloalkyl; a (pyrrolidin-l-yl) -carbonylamino, said substituents being identical or different;

- a naphthyl which is unsubstituted or substituted one or more times with a halogen, a trifluoromethyl, a (C i -C4) alkyl, a hydroxy or a (C i -C4) alkoxy;

- a pyridyle; thienyl; indolyl; quinolyl; benzothienyl; imidazolyl; - R3 represents a (Cι-C ₇ ) alkyl or a phenyl;

- R4 and R5 each independently represent a hydrogen or a (C 1 -C ₇ ) alkyl; R5 can also represent a (C3-C ₇ ) cycloalkyl, a (C3-

C ₇ ) cycloalkylmethyl, phenyl or benzyl; or else R4 and R5 together with the nitrogen atom to which they are linked constitute a heterocycle chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine or piperazine unsubstituted or substituted in position 4 by a (Cι-C ₄ ) alkyl;

- Rβ represents a hydrogen, a (Cι-C ₇ ) alkyl, a vinyl, a phenyl, a benzyl, a pyridyl or a (C3-C ₇ ) cycloalkyl unsubstituted or substituted by one or more methyls;

- R represents a hydrogen or a (Cι-C ₇ ) alkyl; - Rg represents a (Cι-C ₇ ) alkyl or a phenyl;

- R9 represents a (Cι-C ₇ ) alkyl; an amino unsubstituted or substituted by one or two (Cι-C) alkyls; phenyl unsubstituted or substituted one or more times by a substituent chosen from a halogen atom, a (Cj-C ₇ ) alkyl, a trifluoromethyl, a hydroxy, a (Cι-C) alkoxy, a carboxy, a (Ci - C ₇ ) alkoxycarbonyl, a (Cι-C ₇ ) alkylcarbonyloxy, a cyano, a nitro or an amino not substituted or substituted by one or two (Cι-C ₇ ) alkyls, said substituents being identical or different;

- RlO represents hydrogen or a (Cι-C4) alkyl; as well as its possible salts with mineral or organic acids and their possible solvates. The compounds of formula (I) useful for the invention include the racemates, the optically pure isomers, as well as the axial and equatorial isomers when in the compound of formula (I), Am® represents an Am® group, a group Airn® 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 formula:

dans laquelle :

in which :

- Aq, 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 position 3 by a halogen or a (C \ -

Cιo) alkoxy; are preferred for the invention.

More particularly, the invention relates to pharmaceutical compositions for the oral administration of (S) -l- {2- [3- (3,4-dichlorophenyl) -l- (3-isopropoxyphenylacetyl) piperidin-3-yl ] ethyl} -4-phenyl-1-azoniabicyclo [2.2.2] octane, or SR 140333, of formula:

dans laquelle A⁽-^ est un anion pharmaceutiquement acceptable.

wherein A ⁽ - ^ is a pharmaceutically acceptable anion.

The benzenesulfonate of SR 140333 hereinafter called compound A is very particularly preferred. The international nonproprietary name for compound A is nolpitantium besilate.

The compounds of formula (I) have been described as antagonists of substance P which is the natural agonist of the NK1 receptors, and therefore have an affinity for these receptors. To administer such compounds orally, it is necessary that they exhibit good absorption, which implies both good solubility in aqueous medium and good capacity to cross the intestinal membrane (M. Rowland and TN Tozer in Clinical pharmacokinetics, 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) being quaternary ammonium remain in ionized form whatever the pH of the medium in which they are found in particular at neutral pH which is the pH of the intestinal medium.

It is known that ionic compounds, in particular quaternary ammonium, hardly cross epithelial membranes (J.P. Labaune in Pharmacokinetics, Fundamental Principles, Masson ed., 1988, 2nd edition, p. 7-33).

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

On this model, the permeability of compound A is 3.4. 10 "? Cm / s. Furthermore, correlations made between the in-vitro results and the in-vivo results have shown that a permeability coefficient of this order corresponds to an absorption of less than 5% for molecules which are completely solubilized. In the present case, studies carried out in rats with compound A in 0.6% aqueous solution in methylcellulose have shown that its estimated absorption is less than 1%.

Thus, to develop an oral galenical formulation for the compounds of formula (I), it is necessary to remedy both their very low solubility in aqueous medium and their poor 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 stoichiometric quantity: one then obtains a pair of ions whose charge is generally neutral. But the pair of ions formed between the cationic part of the compound of formula (I) and the anionic part of the surfactant has a molecular mass greater than that of the compound (I), therefore its hydrophobic character increases and this pair of ions is almost insoluble in water.

It has been found that the intestinal absorption of the pair of ions constituted by a compound of formula (I) and an anionic surfactant decreases compared to that of a compound of formula (I) in the form of ammonium. Nonionic surfactants and absorption improving agents have also been tested to find out their effect on the membrane permeability of a compound of formula (I). These products have been found to have no positive effect.

Derivatives are known which are in semi-solid form at ordinary temperature and which, having both a lipid and an amphiphilic nature can be used to solubilize lipophilic active principles and facilitate their intestinal absorption (Bull. Techn. Gattefossé, 1994, 87, 49-54). Such compounds are chosen from saturated polyglycosylated glycerides consisting of a mixture of monoesters, diesters and triesters of glycerol and of fatty acids whose carbon chains are in Cg-Cig, and of mono and diesters of polyethylene glycol and of fatty acids whose carbon chains are in Cg-Cig. The most interesting of them are:

- lauroyl macrogoglyceride whose melting point is 44 ° C and whose hydrophilic / lipophilic balance (HLB) is 14;

- Macrogoglyceride stearoyl, the melting point of which is 50 ° C. and the hydrophilic / lipophilic balance of which is 13;

- caprylocaproyle macrogoglyceride, oily liquid with a hydrophilic / lipophilic balance of 14.

These compounds are marketed by the company Gattefossé respectively under the brands Gélucire® 44-14, Gélucire® 50-13 and Labrasol®. The compounds (I) of hydrophilic nature are not soluble in such derivatives, in particular they are not soluble in the products Gélucire® 44-14, Gélucire® 50-13 or Labrasol®.

According to the present invention, it has now been found that a compound of formula (I) can be dissolved in a saturated polyglycosylated glyceride provided that at least one of the following constituents is added:

- a hydrophilic solvent

- an anionic surfactant.

The formulation thus obtained makes it possible to improve the bioavailability of the active principle. It is also advantageous to dissolve a compound of formula (I) in a saturated polyglycosylated glyceride by adding both a hydrophilic solvent and an anionic surfactant.

Surprisingly, it has been found that the addition of a particular polysorbate, polysorbate 80, to compound A in solution in the cell culture medium, improves the transepithelial passage on the Caco-2 model. Thus it may be advantageous to add to the formulation determined above a small proportion of polysorbate 80.

Thus, according to one of its aspects, the present invention relates to a pharmaceutical composition for the oral administration of a compound of formula (I) containing: - active principle 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% by weight; provided that at least one constituent chosen from the hydrophilic solvent and the anionic surfactant is present. Preferably, in the absence of an 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, the term macrogoglyceride means the products Gélucire® 44-14, Gélucire® 50-13 or Labrasol® as described above, the product

Gélucire® 44-14 being preferred.

As hydrophilic solvent, an alcohol such as ethanol or a glycol derivative such as propylene glycol or the product Transcutol® which is a monoethyl ether of diethylene glycol can be used. Propylene glycol is the preferred hydrophilic solvent.

As an anionic surfactant, a bile salt such as sodium taurocholate or a sodium alkyl sulphate such as sodium octyl sulphate or preferably sodium lauryl sulphate can be used, the latter being a preferred anionic surfactant according to the invention. The pharmaceutical compositions according to the invention can be in different forms intended for oral administration: capsules, sachets, drops, drinkable ampoules or bottles for example.

Advantageously, the present invention relates to a pharmaceutical composition containing: - active ingredient 0.1% to 15% by weight

- 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% by weight. In a particular way, the present invention relates to a pharmaceutical composition for the 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 Q.S. per 100% by weight; provided that the concentration of active ingredient is less than or equal to 30% by weight of the concentration of hydrophilic solvent.

In another particular way, the present invention relates to a pharmaceutical composition for the 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 Q.S. for 100% by weight.

According to the invention, the anionic surfactant is preferably in stoichiometric quantity with respect to the active principle. The anionic surfactant being introduced in concentrated aqueous solution, the above pharmaceutical composition contains from 0.1 to 12% of water.

When gelatin capsules of the soft or hard capsule type are prepared, the hydrophilic solvent content of the pharmaceutical composition must be compatible with gelatin. Thus the present invention more particularly relates to pharmaceutical compositions for the preparation of capsules containing:

- active ingredient 0.1 to 9% by weight,

- hydrophilic solvent 0 to 30% by weight,

- anionic surfactant 0 to 3% by weight, - polysorbate 80 0 to 5% by weight,

- macrogoglyceride Q.S. per 100% by weight; provided that at least one constituent chosen from the hydrophilic solvent and the anionic surfactant is present.

In particular, pharmaceutical compositions are preferred for the preparation of capsules containing:

- active ingredient 0.1 to 7% by weight,

- hydrophilic solvent 5 to 20% by weight,

- polysorbate 80 0 to 5% by weight,

- macrogoglyceride Q.S. per 100% by weight; provided that the concentration of active ingredient is less than or equal to about

30% by weight of the hydrophilic solvent concentration. Pharmaceutical compositions are also preferred for the preparation of capsules containing:

- active ingredient 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% by weight.

The anionic surfactant is preferably in stoichiometric quantity 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, enteric formulations can also be prepared.

Such formulations are used to protect the active ingredient from high stomach acidity. Such formulations are prepared by coating the capsule with a polymer film insoluble in an acidic environment and soluble in a basic environment. As an example of a film for coating, mention may be made of cellulose acetophthalate, polyvinyl acetophthalate, hydroxypropylmethylcellulose phthalate or methacrylic acid copolymers.

Examples of methacrylic acid copolymer, there may be mentioned methacrylic acid copolymer type C, sold under the trademark EUDRAGIT ^® L30 D-55 by Rohm or 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 some cases, in particular when preparing enteric formulations with gelatin capsules, it may be preferable to cover the capsule with a film coating consisting of a pre-coating before the enteric coating. The pre-coating can be done for example with hydroxypropylcellulose, povidone or a methacrylic acid copolymer combined with suitable excipients. According to a particular embodiment, the present invention relates to a pharmaceutical composition for the oral administration of compound A containing: compound A 0.1 to 9% by weight, propylene glycol 1 to 30% by weight, sodium lauryl sulfate 0 to 3% by weight,

Gélucire® 44-14 Q.S. for 100% by weight. More particularly, the present invention relates to a pharmaceutical composition of formula: compound A 0, 1 to 7% by weight, propylene glycol 5 to 20% by weight,

Gélucire® 44-14 Q.S. for 100% by weight. provided that the concentration of compound A is less than or equal to about 30

% by weight of the propylene glycol concentration.

The present invention also relates to a pharmaceutical composition of formula: compound A 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. per 100% by weight; the sodium lauryl sulphate preferably being in stoichiometric quantity with respect to 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 80.5% 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 as described above, one can proceed as follows when there is no anionic surfactant in the composition: the active principle is placed in suspension in the hydrophilic solvent and heated with stirring to a temperature between 60 ° C and 80 ° C depending on the concentration of active ingredient introduced into the hydrophilic solvent. We add 90% of the macrogoglyceride melted at 60 ° C and then optionally the polysorbate 80. Finish by adjusting to 100% with the sufficient amount of macrogoglyceride.

When the pharmaceutical composition contains an anionic surfactant, it is possible to proceed as described below: the active principle is mixed in 90% of the macrogoglyceride heated to 60 ° C. To the suspension formed, the anionic surfactant dissolved in hot water is added in the minimum amount of water, then, if necessary, the hydrophilic solvent and optionally polysorbate 80 are added. The final step is adjusted to 100% by the sufficient amount of macrogoglyceride.

In particular, when preparing enteric formulations, the coating of a capsule according to the invention may contain a pre-coating film and a coating film having the following constitutions. Pre-coating: methacrylic acid copolymer of type C 46.6% by weight glycerin 4.6% by weight aqueous solution of polysorbate 80 to 33% 4.6% by weight water 44.2% by weight

Coating: methacrylic acid copolymer of type C 54.8% by weight glycerin 3.3% by weight polysorbate solution 80 to 33% 0.7% by weight water 41, 2% by weight

The characteristics and advantages of the compositions according to the invention will appear in the light of the description below, from the compositions given by way of examples. In these examples, the percentages expressed are percentages by weight.

TESTS 1. Test of the solubility of compound A. 1.1: Solubility in water.

The solubility was measured at saturation, after 24 hours, at room temperature; the measurements were carried out by UV spectrometry at λ = 275 nm after calibration in an ethanolic solution.

1.2. Solubilité dans différents solvants.

1.2. Solubility in different solvents.

The instant solubility is evaluated, at ambient temperature, by successive additions of the solvent studied on the compound A in a hemolysis tube, until the clarity is observed.

Given the differences in density, the solubilities are determined by 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

Furthermore, compound A is soluble in dimethylsulfoxide (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

1.4. Study of the solubility in glycerides. Solubility of compound A in Gélucire® 44-14.

1.5. Solubility of compound A in the presence of sodium lauryl sulfate in stoichiometric quantity in water: less than 0.1 μg / ml.

2. Evaluation of the intestinal transepithelial passage of compound A. Caco-2 cells are inoculated on microporous polycarbonate filters coated with collagen. The cell monolayer formed on the filter then makes it possible to separate an apical compartment (mimicking the intestinal lumen) from a basal compartment (mimicking 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 cell barrier by measuring its kinetics of appearance on the basal side. This aqueous medium, of pH = 6.5, has the following composition: NaCl = 8.0 g / 1; KC1 = 0.4 g / 1; CaCl ₂ = 0.19 g / 1; MgCl ₂ = 0.1 g / 1; MgSO ₄ = 0.1 g / 1; Na ₂ HPO ₄ = 0.09 g / 1; KH2PO4 = 0.06 g / 1; NaHCO ₃ = 0.35 g / 1; glucose = 1 g / 1; phenol red = 0.01 g / 1.

We then determine the permeability coefficient P, in cm / s, which characterizes the speed of passage of the molecule through the membrane, namely:

P = (da / dt). (L / A.Co) in which: da / dt = variation of the quantity of test compound crossing the cell monolayer as a function of time (mole / s)

A = area of the monolayer (cm2)

Co = initial concentration of the test compound (mole / 1)

2.1. Coefficient of permeability of compound A introduced into Hank's medium in solution in DMSO.

P = 3.4. 10- ⁷ cm / s.

The permeability of compound A thus measured in solution (in DMSO) indicates an intrinsic characteristic of this compound. This result confirms the very poor ability of compound A to transepithelial passage 2.2. Relative speed of the intestinal transepithelial passage of compound A.

Different formulations were prepared with compound A in order to measure their speed of passage and to 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 sulfate 1.4% - H ₂ O 2.8% Formulation 3:

- Compound A 4.3% - Gélucire® 44-14 91.23%

- sodium lauryl sulfate 1.52% - H ₂ O 2.95%

Formulation 4:

- Compound A 4.31%

- Gélucire® 44-14 91.19%

- sodium octyl sulfate 1.53% - H ₂ O 2.97% Formulation 5:

- Compound A 7.4%

- propylene glycol 28.7%

- Gélucire® 44-14 63.9% Formulation 6:

- Compound A 8%

- propylene glycol 46% - Gélucire® 44-14 46% Formulation 7:

- Compound A 6%

- propylene glycol 34%

- Labrasol® 60%

Each of these formulations causes a marked improvement in the transepithelial passage of compound A and none of these formulations has caused an alteration of the epithelial monolayer.

All these formulations were observed under an optical microscope. A complete solubilization of compound A has been observed, except for formulations 3 and 4 in which part of the 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 sulfate and the use of the mixture Gélucire® 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 principle is dissolved in propylene glycol at 70 ° C. then, with mechanical stirring, the solution obtained is incorporated 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 1.4% in aqueous solution at 34% water 2.8%

Gélucire® 44-14 76.3% for a white-opaque capsule size 1. The active ingredient is mixed with 90% of Gélucire® 44-14 heated to 60 ° C. The aqueous solution of sodium lauryl sulfate is added and then adjusted with the remaining Gélucire® 44-14. It is incorporated into the capsule after cooling to 40 ° C. EXAMPLE 3 Liquid form for vial compound A 6.0% propylene glycol 34.0%

Labrasol® 60.0%

EXAMPLE 4 Oral ampoule compound A 8.0% propylene glycol 46.0% Gélucire® 44-14 46.0%

EXAMPLE 5 Capsule compound A 4.5% propylene glycol 15.0%

Gélucire® 44-14 80.5% EXAMPLE 6: Compound A 4.4% propylene glycol 13.0% sodium lauryl sulfate 1.5% water 3.0%

Gélucire® 44-14 78.1%

EXAMPLE 7 Liquid for vial compound A 8.0% propylene glycol 27.5% polysorbate 80 2.0%

Labrasol® 62.5%

EXAMPLE 8 Liquid for vial compound A 7.5% propylene glycol 20.5% polysorbate 80 2.0% sodium lauryl sulfate 2.6% water 4.9%

Labrasol® 62.5%

EXAMPLE 9 Enteric Capsule

A capsule is prepared according to Example 1 and a coating is applied in 2 layers: one for pre-coating and the other for coating. Pre-coating:

Eudragit ^® L30 D-55 46.6% glycerin 4.6% aqueous polysorbate solution 80 to 33% 4.6% water 44.2%

Coating:

Eudragit L30 D-55 54.8% glycerin 3.3% aqueous polysorbate solution 80 to 33% 0.7% water 41.2%

Claims

1. Pharmaceutical composition for the oral administration of an active principle of formula:

in which : - A ^ ¹ is a pharmaceutically acceptable anion; - Am® is: i - either a group Ami® ^e formula:

in which : - Aq represents a phenyl which is unsubstituted or substituted one or more times with a substituent chosen from a halogen atom, a hydroxy, a (Cι-C4) alkoxy, a (Cj-C4) alkyl or a trifluoromethyl, said substituents being identical or different; - x is zero or one; - Wj represents a (Cι-Cg) alkyl or a benzyl group; the substituent Wj being either in the axial position or in the equatorial position; ii - either an Am2® group of formula:

in which : - Aq, x and Wi are as defined above; - Ri represents a hydroxy; a (Cι-C4) alkoxy; formyloxy; a (Cj- C3) alkylcarbonyloxy; carboxy; a (Cι-C4) alkoxycarbonyl; a cyano; a (Cι-C3) alkylcarbonylamino; a mercapto; a (Cι-C4) alkylthio; iii - either an Am3® group of formula:

in which : - Aq and Wi are as defined above; - R2 represents hydrogen; a (Cι-C3) alkyl; a (Cι-C3) alkylcarbonyl; iv - or an Am4® group of formula:

in which: - Aq and x are as defined above; - p is one or two; v - either an Am5® group of formula:

in which : - Aq and x are as defined above; - Ar represents a phenyl which is unsubstituted or substituted once or twice by a substituent chosen from a halogen atom, a (Cj-C3) alkoxy, a (C - C3) alkyl or a trifluoromethyl, said substituents being identical or different; naphthyl; indolyl; - Q and Y represent one of the following groups of values: a) Qι and Y _ι; b) Q2 and Y2 when Am® represents an Ami®, Aπr? ®, Am4® or Am5® group c) Q3 and Y3 when Am® represents an Ami® group, Aπv) ® or an Arri4® group in which Aq represents a phenyl and p is two; d) Q4 and Y4 when Am® represents an Ami®, Am3®, Am4® or Am5® group - Q 1 represents hydrogen; - Yi represents hydrogen; a (Cι-C4) alkyl; ω- (Cj-C4) alkoxy- (C2-C4) alkylene; a ω- (Cι-C4) alkylcarbonyloxy- (C2-C4) alkylene; ω- benzoyloxy- (C2-C4) alkylene; ω-hydroxy- (C2-C4) alkylene; ω- (Cj-C4) alkylthio- (C2-C4) alkylene; a ω- (Cι-C4) alkylcarbonyl- (C2-C) alkylene; ω-carboxy- (C2-C4) alkylene; a ω- (Cι-C4) alkoxycarbonyl- (C2-C4) alkylene; ω-benzyloxy- (C2-C4) alkylene; ω-formyloxy- (C2-C4) alkylene; ω- R3NHCOO- (C2-C4) alkylene; ω-R4R5NCO- (C2-C4) alkylene; a ω- R6CONR7- (C2-C ^" 4) alkylene; a ω-RgOCONR ₇ - (C2-C4) alkylene; a ω- R4R5NCONR ₇ - (C2-C4) alkylene; a ω-R9S02NR ₇ - (C2-C) alkylene; a ω- cyano- (Cι-C3) alkylene; - Q2 and Y2, together, constitute an ethylene, trimethylene or tetramethylene group; - Q3 and Y3, together, constitute a group: O II - (CH ₂ ) _n -C- in which n is one, two or three; - Q4 and Y4, together, constitute a radical chosen from: Aι) -O-CH ₂ - A ₂ ) -O-CO- A ₃ ) -CH2-O-CO- A ₄ ) -O-CH ₂ -CO- A ₅ ) -O-CH ₂ -CH ₂ - A ₆ ) -N (Rιo) -CO- A ₇ ) -N (Rι ₀ ) -CO-CO-

- T represents - either a group -CO- when Q and Y represent the group Qi and Yl, the group Q2 and Y2 or the group Q4 and Y4 in which Q4 and Y4 together constitute a radical Ai), A5) or Ag ); - Or a group -CH2- when Q and Y represent the group Q3 and Y3 or the group Q4 and Y4 in which Q4 and Y4 together constitute a radical A ₂ ), A3), A4), Ag) 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: - phenyl unsubstituted or substituted one or more times by a substituent chosen from a halogen atom; trifluoromethyl; a cyano; hydroxy; a nitro; an amino unsubstituted or substituted one or more times by a (C1-C4) alkyl; a benzylamino; carboxy; a (Cι-Cιo) alkyl; a (C3-C ₇ ) cycloalkyl unsubstituted or substituted one or more times with methyl; a (Cι-Cιo) alkoxy; a (C3-C ₇ ) cycloalkyloxy unsubstituted or substituted one or more times with methyl; a mercapto; a (Cι-Cιo) alkylthio; a (Cj- Co alkylcarbonyloxy; a (Cι-C ₍ 3) alkylcarbonylamino; a benzoylamino; a (Cι-C4) alkoxycarbonyl; a (C3-C ₇ ) cycloalkylcarbonyl; a carbamoyl unsubstituted or substituted once or twice by a ( Cj-C4) alkyl; non ureido substituted or substituted once or twice in position 3 by a (Cι-C4) alkyl or a (C3-C ₇ ) cycloalkyl; a (pyrrolidin-1-yl) -carbonylamino. said substituents being the same or different; - a naphthyl which is unsubstituted or substituted one or more times with a halogen, a trifluoromethyl, a (C i -C4) alkyl, a hydroxy or a (C i -C4) alkoxy; - a pyridyle; thienyl; indolyl; quinolyl; benzothienyl; imidazolyl; - R3 represents a (Cι-C ₇ ) alkyl or a phenyl; - R4 and R5 each independently represent a hydrogen or a (C 1 -C ₇ ) alkyl; R5 can also represent a (C3-C ₇ ) cycloalkyl, a (C3- C ₇ ) cycloalkylmethyl, phenyl or benzyl; or else R4 and R5 together with the nitrogen atom to which they are linked constitute a heterocycle chosen from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine or piperazine unsubstituted or substituted in position 4 by a (Cι-C ₄ ) alkyl; - Rg represents a hydrogen, a (Cι-C ₇ ) alkyl, a vinyl, a phenyl, a benzyl, a pyridyl or a (C3-C) cycloalkyl unsubstituted or substituted by one or more methyls; - R ₇ represents a hydrogen or a (Cι-C ₇ ) alkyl; - Rg represents a (Cι-C ₇ ) alkyl or a phenyl; - R9 represents a (Cι-C ₇ ) alkyl; an amino not substituted or substituted by one or two (Cι-C ₇ ) alkyls; a phenyl which is unsubstituted or substituted one or more times with a substituent chosen from a halogen atom, a (Cι-C ₇ ) alkyl, a trifluoromethyl, a hydroxy, a (Cι-C ₇ ) alkoxy, a carboxy, a ( Cj- C ₇ ) alkoxycarbonyl, a (C -C) alkylcarbonyloxy, a cyano, a nitro or an amino not substituted or substituted by one or two (Cι-C ₇ ) alkyls, said substituents being identical or different; - RlO represents hydrogen or a (Cι-C4) alkyl; or one of its optional salts with mineral or organic acids or one of their optional solvates; characterized in that it contains: - 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, - sufficient macrogoglyceride (QS) for 100% by weight; provided that at least one constituent chosen 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 formula:

in which : - Aq, x, p and A ^ ⁾ 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 position 3 by a halogen or a (Cj-Cιo) alkoxy. 3. Pharmaceutical composition according to claim 1 or 2, characterized in that the active principle is (S) -l- {2- [3- (3,4-dichlorophenyl) -l- (3-isopropoxyphenylacetyl) piperidin-3 -yl] ethyl} -4-phenyl-1-azoniabicyclo [2.2.2] octane, of formula:

wherein A ^ is a pharmaceutically acceptable anion. Pharmaceutical composition according to any one of Claims 1 to 3, characterized in that the active principle is nolpitantium besilate. Pharmaceutical composition according to any one of Claims 1 to 4, containing: - active ingredient 0.1% to 15% by weight, - hydrophilic solvent 1% to 60% by weight, - anionic surfactant 0.03% to 5% by weight, - polysorbate 80 0 to 5% by weight, - macrogoglyceride QSpour 100% by weight. 6. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that it is in the form of capsules, sachets, drops, drinkable ampoules or bottles. 7. Pharmaceutical composition according to any one of claims 1 to 6, characterized in that the macrogoglyceride is chosen from Gélucire® 44-14, Gélucire® 50-13 or Labrasol®. 8. Pharmaceutical composition according to claim 7, characterized in that the macrogoglyceride is Gélucire® 44-14. 9. Pharmaceutical composition according to any one of claims 1 to 8, characterized in that the hydrophilic solvent is chosen from ethanol, propylene glycol or Transcutol®. 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, characterized in that the anionic surfactant is chosen from a bile salt or a sodium alkyl sulfate. 12. Pharmaceutical composition according to claim 11, characterized in that the anionic surfactant is sodium lauryl sulfate. 13. Pharmaceutical composition according to any one of claims 1 to 12, containing an amount 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 stoichiometric quantity with respect to the active principle. 15. Pharmaceutical composition according to any one of claims 1 to 14, characterized in that the anionic surfactant is incorporated in the formulation in concentrated aqueous solution. 16. Pharmaceutical composition according to any one of claims 1 to 9, containing: - active ingredient 0.1 to 15% by weight, - hydrophilic solvent 5 to 60% by weight, - polysorbate 80 0 to 5% by weight, - QS macrogoglyceride for 100% by weight; provided that the concentration of active ingredient is less than or equal to 30% by weight of the concentration of hydrophilic solvent. 17. Pharmaceutical composition according to any one of claims 1 to 15, 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 Q.S. for 100% by weight. 18. Pharmaceutical composition according to any one of claims 1 to 15, containing: - active ingredient 0.1 to 9% by weight, - hydrophilic solvent 0 to 30% by weight, - anionic surfactant 0 to 3% by weight, - polysorbate 80 0 to 5% by weight, - macrogoglyceride Q.S. per 100% by weight; provided that at least one constituent chosen from the hydrophilic solvent and the anionic surfactant is present. 19. Pharmaceutical composition according to claim 18, containing: - active ingredient 0.1 to 7% by weight, - hydrophilic solvent 5 to 20% by weight, - polysorbate 80 0 to 5% by weight, - macrogoglyceride Q.S. per 100% by weight; provided that the concentration of active ingredient is less than or equal to about 30% by weight of the concentration of hydrophilic solvent. 20. Pharmaceutical composition according to claim 18, containing: - active ingredient 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% by weight. 21. Pharmaceutical composition according to any one of claims 1 to 15, containing: - nolpitantium besilate 0.1 to 9% by weight, - propylene glycol 1 to 30% by weight, - sodium lauryl sulfate 0 to 3% by weight, - Gélucire® 44-14 Q.S. for 100% by weight. 22. Pharmaceutical composition according to claim 21, containing: - nolpitantium besilate 0.1 to 7% by weight, - propylene glycol 5 to 20% by weight, - Gélucire® 44-14 QS for 100% by weight; provided that the concentration of nolpitantium besilate is less than or equal to about 30% by weight of the concentration of propylene glycol. 23. Pharmaceutical composition according to claim 21, containing: - nolpitantium besilate 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% by weight. 24. Pharmaceutical composition according to claim 21, containing: - nolpitantium besilate 3.6% by weight, . - propylene glycol 15.9% by weight, - Gélucire® 44-14 80.5% by weight. 25. Pharmaceutical composition containing: - nolpitantium besilate 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. 26. Pharmaceutical composition according to any one of claims 1 to 25 characterized in that it is in the form of an enteric capsule.