FR2756736A1 - PHARMACEUTICAL COMPOSITIONS CONTAINING N-SULFONYL INDOLINE DERIVATIVES - Google Patents

Abstract

The invention concerns an anhydrous solubilising/stabilising system, emulsifiable or microemulsifiable in water, for the solubilisation of hydrophobic N-sulphonyl indolin derivatives of formula (I) characterised in that it contains one or several constituents selected among amphiphilic compounds, non-ionic hydrophilic surfactants and non-ionic hydrophilic compounds having both amphiphilic and surface-active properties, being understood that said system contains either at least a mixture of an amphiphilic compound and a non-ionic hydrophilic surfactant, or a non-ionic hydrophilic compound having both surface-active and amphiphilic properties.

Description

 The present invention relates, in general, to novel pharmaceutical compositions containing Nsulfonyl indoline derivatives as active ingredients.

In particular, the invention relates to pharmaceutical compositions either for parenteral administration or for oral administration containing, as active ingredients, one or more isomers of N- [5-chloro-3- (2-chlorophenyl)] - [3,4] - dimethoxyphenylsulfonyl) -3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl] -pyrrolidine-2-carboxamide of formula:

 These compounds of formula I above are indeed in the form of cis-trans isomers around the bond 2,3 of indoline.

 By convention, the cis isomer is the compounds of formula I in which the 2-chlorophenyl and 2-carbamoylpyrrolidinocarbonyl groups are on the same side of the ring.

 In contrast, trans-isomers are those compounds of formula I in which these 2-chlorophenyl and 2-carbamoyl-pyrrolidinocarbonyl groups are each on one side of the ring.

 In addition, these compounds of formula I are in the form of optical isomers because of the asymmetric carbon represented by the asterisk.

 The different isomers mentioned above as well as their mixtures are part of formula I.

 The N-sulfonyl indoline derivatives in question are known compounds which have been described in the patent application EP 0526348. These compounds have revealed an affinity for the vasopressin and oxytocin receptors and are therefore particularly useful in the treatment of the central nervous system, the cardiovascular system and the gastric sphere.

Among the most representative isomers of this series are:
(2S) 1 - [(2R, 3S) (5-Chioro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2,3-dihydro-1H-indole- 2-carbonyl] -pyrrolidine-2-carboxamide corresponding to the structural formula:

 This compound will be referred to hereafter as "compound a".

 The active ingredients of formula I, in particular Compound a, are highly hydrophobic products and, for this reason, are very poorly soluble in aqueous medium at physiological pH, that is to say between 1.2 and 7. 5.

 However, it is known that drug substances are better resorbed if they are in dissolved form in pharmaceutical compositions.

 However, this solubilization which can be obtained in organic solvents specific to the substance under consideration must, in order to maintain its maximum efficiency, maintain (stabilize) this solubilized state of the molecule during the dilution of the pharmaceutical composition in an aqueous medium. Some microemulsion-type formulations make it possible to coexist such an organic phase, containing the solubilized hydrophobic pharmaceutical substance, and an aqueous phase.

 However, when they are introduced into pharmaceutical envelopes such as soft capsules, liquid pharmaceutical compositions require a lack of water, the gelatin-based tunic being incompatible with an aqueous formulation.

 In addition, the volume of pharmaceutical composition to be administered should be minimized so that such a presentation, in the form of a capsule or soft capsule is possible.

 Indeed, a pharmaceutical envelope of this type can not be too large for easy absorption by the patient.

 Systems have already been described in the literature enabling the solubilization of particularly hydrophobic pharmaceutical substances in order to formulate pharmaceutical compositions that can be administered in capsules or in soft capsules.

 For this purpose, lipophilic matrices such as vegetable or animal oils have been proposed which, if necessary, can be combined with lubricating agents such as fats, waxes or mineral oils.

 There may be mentioned, for example, EP 107085, which teaches the use of an oily phase consisting of vegetable oil and a water-soluble anhydrous hydrophilic phase formed, for example, of polyethylene glycols with a molecular weight of 300 to 20000, or else propylene glycol, glycerol or of their mixtures.

 Similarly, GB 1132518 discloses pharmaceutical compositions containing an active ingredient soluble in benzyl benzoate, the matrix of which consists of an assembly formed by benzyl benzoate and a nonionic hydrophilic surfactant such as polysorbate 80 and optionally a mineral or vegetable oil and a co-solvent such as a polyethylene glycol.

 However, it is well known that matrices already proposed for use in pharmaceutical compositions to be introduced into capsules can not be generalized regardless of the active substance to be combined.

 As proof, orientation tests carried out in the context of the invention have shown that the active ingredients of formula 1, in particular compound a, are not or very slightly soluble in oils.

 Therefore, the systems recommended by the state of the art for the solubilization of hydrophobic compounds must, a priori, be rejected with respect to the active principles in question.

 Accordingly, the development of an anhydrous pharmaceutical composition and concentrated hydrophobic compound of formula I, for example Compound a, appears highly desirable and remains of paramount interest.

 However, it has now been found that it is possible to produce, without hydrophobic oily phase, an anhydrous, emulsifiable or microemulsifiable pharmaceutical composition containing the active ingredients of formula I, this composition making it possible to obtain a presentation in particular in the form of a capsule hard or soft capsule in which this active ingredient is present in dissolved form in a solubilizing system I stabilizing spontaneously microdispersible in water.

 Accordingly, a first subject of the invention relates to an anhydrous, emulsifiable or microemulsifiable solubilizing / stabilizing system in water, for the solubilization of the N-sulfonyl indoline derivatives of formula I, comprising one or more constituents chosen from amphiphilic compounds. , nonionic hydrophilic surfactants and nonionic hydrophilic compounds having both amphiphilic and surfactant properties, it being understood that said system comprises either at least one mixture of an amphiphilic compound and a nonionic hydrophilic surfactant, or at least one nonionic hydrophilic compound having both surfactant and amphiphilic properties.

In particular, the invention relates to a stabilizing solubilizing system as above comprising:
one or more constituents chosen from amphiphilic compounds of the type
glycolic acid, ie polyethylene glycols and glycol ethers, the system
further comprising one or more nonionic hydrophilic surfactants,
or one or more compounds both amphiphilic and surfactant chosen from
saturated polyglycolysed glycerides, the system optionally comprising a
or more nonionic hydrophilic surfactants, and optionally one or
several amphiphilic compounds of the glycolic type, namely
polyethylene glycols.

 The solubilizer / stabilizer system of the invention refers in particular to a system comprising at least two different compounds, one acting as an amphiphilic solvent or solubilizer, the other as a nonionic hydrophilic surfactant.

 However, this system can combine more than two compounds, for example several compounds acting as amphiphilic co-solvents or several nonionic hydrophilic surfactant compounds.

 It is also conceivable that among this set of at least two different compounds, one or the other is capable of acting both as an amphiphilic solvent and as a nonionic hydrophilic surfactant.

 In particular, this stabilizing solubilizing system can be limited to a single nonionic hydrophilic compound acting both as an amphiphilic solvent or solubilizer and as a surfactant.

 The amphiphilic solvents referred to above are generally selected from glycolic type compounds.

 Preferably, they are selected from one or more polyethylene glycols (PEG) of average molecular weight between about 400 and about 2000.

 In addition, a polyethylene glycol of a given molecular weight may be used alone or in admixture with one or more polyethyleneglycols of varying molecular weight.

 The polyethylene glycols used in the context of the invention are present at ambient temperature either in liquid form or in semi-solid form according to their molecular weight. Accordingly, these polymers will be appropriately selected depending on whether the desired solubilizer / stabilizer system should be in liquid or semi-solid form.

 Preferred polyethylene glycols according to the invention include, for example, polyethylene glycol 400 or "PEG 400" liquid at ordinary temperature, polyethylene glycol 1000 or "PEG 1000", polyethylene glycol 1500 or "PEG 1500", polyethylene glycol 2000 or "PEG 2000", as well as a mixture of 50/50 by weight of polyethylene glycol 600 or "PEG 600" and polyethylene glycol 1500 or "PEG 1500", all these polyethylene glycols being semi-solid at room temperature, with the exception of PEG-400 as indicated above.

 It is also possible to use, in the context of the invention, particular polyethylene glycol derivatives resulting from the esterification of fatty acid residues by polyethylene glycol and glycerol. The structure of this type of compound, semi-solid at ordinary temperature, first confers on it an amphiphilic character, capable of solubilizing the active ingredients of formula I, in particular compound a, because of the fatty chains and the polyethylene glycol unit. which constitute it, then a hydrophilic surfactant characteristic suitable for stabilizing the solution formed when it is introduced into an aqueous medium.

 Such compounds are selected from saturated polyglycolized glycerides consisting of a mixture of monoesters, diesters and triesters of glycerol and fatty acids, and mono and diesters of polyethylene glycol and fatty acids. The most interesting of these are those which have a melting point close to body temperature and whose hydrophilic / lipophilic balance, commonly defined by its HLB value, reflects the proportion of hydrophilic groups with respect to the lipophilic groups of the molecule. according to the GRIFIN WC system [J. Soc.

Cosm. Chem., 1, 311 (1949)] is between 12 and 18.

Particularly representative compounds of this series are those sold under the trade names GELUCIREs 44-14 and GELUCIREX 50-13. The product GELUCIREs 44-14 proves to be an excellent solubilizer
Compound a. At 60 ° C, the solubility of this active ingredient of formula I, determined by the addition method, is 226 mg / g.

 Other derivatives of glycolic type can be used as solvent or cosolvent in the context of the invention, that is to say amphiphilic compounds having a solubilizing power. Such glycol derivatives are selected from glycol ethers, generally from diethylene glycol ethers such as a diethylene glycol mono (C1-C4) alkyl ether.

 Among the monoethers of diethylene glycol, the methyl and ethyl ethers which are marketed, in particular diethylene glycol monoethyl ether, are preferred.

 These products may contain some impurities constituted in most cases by small amounts of diethers and other compounds that appeared during their synthesis. They are nevertheless usable in this form for preparing pharmaceutical compositions.

 The TRANSCUTOL branded product, an extremely pure diethylene glycol monoethyl ether sold by the company Gattefosse (FR), constitutes a glycolic ether which is particularly preferred for the purposes of the invention.

 Such glycol ethers may be used alone as an amphiphilic solvent in the solubilizing / stabilizing system of the invention or preferably associated in all proportions with one or more low molecular weight polyethylene glycols, that is to say between 400 and 600 such described above where this glycolic ether then acts as a co-solvent and even a co-surfactant.

 As for the surfactant, it is generally chosen from hydrophilic nonionic compounds whose HLB value is between 12 and 18.

 Surfactants of this type may be, for example, an ethylene oxide / propylene oxide copolymer such as that marketed under the trademark PLURONICs P94 (HLB: 13.5), a polyethoxylated castor oil such as that marketed under the trademark CREMOPHOR. Q EL (HLB 13), a non-ethoxylated polysorbate, an ethoxylated polysorbate such as polysorbate 80 (HLB 15) sold under the trademark TWEENS 80 or MONTANOX 80 DF or polysorbate 20 sold under the trade name TWEENs 20 (HLB 16.5) or a polyethylene hydroxystearate such as polyethylene-660 hydroxystearate (HLB: 13) sold under the trademark SOLUTOL HS15.

 In addition, the surfactant used in the context of the present invention may alternatively be constituted, by a mixture, of such nonionic hydrophilic surfactant compounds, mixture whose HLB value would also be between 12 and 18.

 As a preferred surfactant mixture, mention may be made of a mixture of ethoxylated polysorbate and non-ethoxylated polysorbate such that the final HLB value would be between 12 and 18, for example a mixture of polysorbate 80 (HLB: 15) and of un-ethoxylated polysorbate marketed under the trademark SPATS 20 (H LB: 8.6).

Among the stabilizing solubilizing systems I of the invention, those consisting of: a) an amphiphilic compound chosen from polyethylene glycols of weight are generally preferred;
molecular weight ranging from 400 to 600, the system further comprising an agent
nonionic hydrophilic surfactant and optionally a diethylene glycol ether b) an amphiphilic compound chosen from polyethylene glycols of weight
molecular weight ranging from 600 to 2000, the system further comprising an agent
nonionic hydrophilic surfactant c) a solubilizing / surfactant compound selected from glycerides
saturated polyglycolysed, the system optionally comprising an agent
nonionic hydrophilic surfactant.

As preferred solubilizing / stabilizing systems, according to the invention, it is possible to envisage the systems formed:
PEG 400, TRANSCUTOL product and polysorbate 80.
either PEG 2000 and polysorbate 80.
either a 50/50 by weight mixture of PEG 600 / PEG 1500 and polysorbate 80. e either of saturated polyglycolysed GELUCIRE 44-14 glycerides or
GELUCIRE 50-13.

Accordingly, the invention relates to an emulsifiable or water-microemulsifiable anhydrous solubilizer / stabilizer system for solubilizing the N-sulfonyl indoline derivatives of formula I comprising:
one or more amphiphilic compounds of the glycolic type chosen from
polyethylene glycols of average molecular weight between 400 and 600 and
further comprising one or more nonionic hydrophilic surfactants
HLB value between 12 and 18, and optionally an ether of
diethylene glycol, so that the solubilizing / stabilizing system and
formed either in liquid form.
one or more amphiphilic compounds of the glycolic type chosen from
polyethylene glycols of average molecular weight between 400 and 600 and
diethylene glycol ethers such as a diethylene glycol mono (C1-C4) alkyl ether, the
system further comprising one or more non-hydrophilic surfactants
ionic values of HLB between 12 and 18, so that the system
solubilizer / stabilizer thus formed either in liquid form.
one or more amphiphilic compounds of the glycolic type chosen from
polyethylene glycols of average molecular weight between 600 and 2000, the
system further comprising one or more non-hydrophilic surfactants
ionic values of HLB between 12 and 18, so that the system
solubilizer / stabilizer thus formed is in semi-solid form.
either one or more hydrophilic nonionic compounds both amphiphilic and
surfactants, which are saturated polyglycolysed glycerides consisting of mixtures
monoesters, diesters and triesters of glycerol and fatty acids, and mono and
diesters of polyethylene glycol and fatty acids, the system comprising
optionally one or more nonionic hydrophilic surfactants of
HLB value between 12 and 18 and optionally one or more compounds
glycolic type amphiphiles selected from polyethylene glycols of weight
average molecular weight between 600 and 2000, so that the system
solubilizer / stabilizer thus formed is in semi-solid form.

 As indicated above, the solubilizer / stabilizer systems of the invention can be used advantageously to solubilize the compounds of formula I so as to form dilutable or dispersible compositions in an aqueous medium.

In the case of such solubilizer / stabilizer systems involving one or more amphiphilic solvents such as a low molecular weight polyethylene glycol, a diethylene glycol ether or mixtures thereof and further comprising a nonionic hydrophilic surfactant, the suitable proportions of the various components on a pseudo-ternary phase diagram so as to predict the behavior, in an aqueous medium, of compositions formed of a compound of formula
I and a stabilizing solubilizing system I according to the invention.

Figures I and 2 in the appendix show such diagrams in which: a) Figure 1 shows the behavior of compositions formed from
20 mg / ml of Compound a in solubilizing / stabilizing systems of the invention,
for example PEG 400 / product TiRANSCUTOLs and polysorbate 80 mixtures. b) FIG. 2 shows the behavior of compositions formed from
60mg / ml of Compound a in solubilizer / stabilizer systems similar to
those envisaged in Figure 1.

 On these diagrams, the relative concentrations of water, solubilizer and stabilizer increase from 0 to 100% in the directions indicated by the arrows.

 From the diagram of FIG. 1, it is observed in particular that the relative weight proportions of solubilizer / compound mixtures on the one hand and of stabilizer on the other hand, determine a homogeneous "A" zone and a corresponding heterogeneous "B" zone. at low concentrations of surfactant.

 The tangent to this heterogeneous zone "B" represented by the line "d", brought from the top "100% WATER", determines on the opposite side a point "P" representing the anhydrous mixtures of solubilizer I Compound a and, additionally , stabilizer or surfactant.

 Above this point "P", that is to say for increased concentrations of surfactant, these anhydrous mixtures may be dilutable in water since the line "d" corresponding to each of these concentrations, surfactant c ' that is, the straight line representative of their dilution path, will not intersect the heterogeneous zone "B".

 In this case, we can obtain a purely organic formulation of a hydrophobic active ingredient behaving as a true solution, infinitely dilutable in water.

 This upper zone "A", with respect to the straight line "d", therefore defines solubilizing / stabilizing systems capable of forming concentrated solutions of Compound a.

 These high stability solutions are capable in the presence of water of providing stable microemulsions in the temperature ranges generally used for pharmaceutical compositions.

 In these concentrated solutions, as represented in FIG. 1, the amount of Compound a can be up to 20 mg / ml when the amphiphilic solubilizer is a PEG 4001 mixture produced TiRANSCUTOL2 and the stabilizer is polysorbate 80.

If, on the other hand, it is desired to increase the proportion of active ingredient of formula
I especially of Compound a and to decrease that by stabilizing, as represented in FIG.
2, it is observed on the one hand that the multiphase zone widens, or "B", and on the other hand that the dilution line in the water cuts this heterogeneous zone.

 Therefore, obtaining concentrated solutions of the dilutable Compound a (Compound a in a solubilizing / stabilizing system of the invention) would require large amounts of stabilizing agents (greater than 20%) which are poorly compatible with a pharmaceutical application.

 The solutions concentrated in Compound a whose dilution line intersects the heterogeneous zone "B" do not appear as fully dilutable but dispersible in aqueous medium, that is to say as concentrated solutions spontaneously forming an emulsion more or less fine when dispersed in water.

 Surprisingly, it has been observed that dispersible concentrated solutions (zone B or B ') which are qualitatively identical but which, however, have lower concentrations of surfactant than concentrated dilutable solutions, have qualities analogous to those evidenced by these concentrations. concentrated dilutable solutions in that they all lead to an improvement in membrane permeability resulting in an identical increase in the transepithelial passage of the compound of formula I in particular of Compound a.

 This alternative therefore allows greater flexibility since it is not necessary to consider only systems capable of giving microemulsifiable solutions to obtain particularly advantageous concentrated solutions.

 In this way, the concentration of active ingredient of formula I can be greatly increased.

 In the case of solutions containing Compound a, dispersible in water, the concentration of this active ingredient can be up to 60 mg / ml, a concentration 3 times greater than that of the solution dilutable in water.

 Moreover, it will be noted that even in the case of water-dispersible solutions, these have a good aqueous tolerance since they can practically incorporate their weight of water while remaining completely homogeneous. This feature is of great utility when introducing such solutions in soft capsules for the preparation of pharmaceutical forms because it is known that exchanges between content and envelope can occur during this manufacture.

 Consequently, the water momentarily incorporated in the solution will not be likely to cause phase shift of those since the quantity exchanged is less than 10%. After drying, we will find the original solution without these variations have changed the properties.

 The solubilizing / stabilizing system of the invention capable of solubilizing the hydrophobic active ingredients of formula I can be used effectively to introduce these active ingredients into pharmaceutical compositions.

Accordingly, another object of the invention relates to a pharmaceutical composition, microemulsifiable or emulsifiable in an aqueous medium, comprising:
a hydrophobic active ingredient of formula I
a solubilizing system I stabilizing as described above
optionally a suitable excipient or pharmaceutical vehicle.

In particular, the invention relates to an injectable pharmaceutical composition comprising:
a hydrophobic active ingredient of formula I
a solubilizing / stabilizing system in liquid form consisting of one or
several amphiphilic compounds of glycolic type chosen from
polyethylene glycols of average molecular weight between 400 and 600, and
further comprising one or more nonionic hydrophilic surfactants
HLB between 12 and 18 such as for example polysorbate 80, and
optionally a diethylene glycol ether such as TRANSCUTOL
a suitable pharmaceutical vehicle.

 As a suitable pharmaceutical vehicle is essentially meant water or a physiologically acceptable ketone derivative, the active ingredients of formula I, especially Compound a having proved particularly soluble in these organic compounds.

 For this reason, a polyvinylpyrrolidone (PVP), preferably polyvinylpyrrolidone sold under the trademark Kollidon® 12PF or polyvinylpyrrolidone sold under the trade name KOLLIDON017PF, is a ketone derivative of choice for further promoting the solubility of the active ingredient of formula I in injectable compositions.

 In this way, pharmaceutical compositions for administration by injection can be prepared, these compositions not exceeding 10 mg / ml or 1% by weight of compound of formula I.

 For example, such compositions may contain from 2 to 6 mg / ml of Compound a.

 They will also comprise a nonionic hydrophilic surfactant such as polysorbate 80 at a concentration not exceeding 4% by weight of the final composition.

 Such isotonic compositions have been found to be physically stable and dilutable in physiological serum or in glucose serum.

According to another of its aspects, the invention relates to a liquid pharmaceutical composition for oral administration comprising:
a hydrophobic active ingredient of formula I
a solubilizing system I stabilizing in liquid form consisting of one or
several amphiphilic compounds, glycolic type selected from
polyethylene glycols of average molecular weight between 400 and 600 and
diethylene glycol ethers, the system further comprising one or more
nonionic hydrophilic surfactants of HLB between 12 and 18 such that
for example polysorbate 80 or the product brand PLURONICs P 94.

Generally, in the context of such oral compositions, one or more polyethylene glycols of low molecular weight that is to say between about 400 and about 600. The polyethylene glycol used preferably is PEG 400.

 When such polyethylene glycols are used, one or more diethylene glycol ethers such as methyl or ethyl ethers are generally associated. However, diethylene glycol monoethyl ether is recommended as the preferred diethylene glycol ether, that is the TRANSCUTOL @ brand product.

 These ethers of diethylene glycol will however be used at concentrations not exceeding, preferably 50% by weight or better not exceeding 20% by weight of the final composition.

 As for the nonionic hydrophilic surfactant, it is preferably chosen from compounds having an HLB of 15 or close to 15, and it is generally used at concentrations not exceeding 12% by weight of the final composition. As such, polysorbate 80 is a surfactant of choice for the purposes of the invention.

 Thus, a particularly preferred solubilizing / stabilizing system according to the invention consists of a mixture PEG 4001 produced TRANSCUTOLs / polysorbate 80.

 The compositions of the invention thus formed are in the form of homogeneous and transparent liquids. They can contain high concentrations of active ingredient of formula I because of their anhydrous character, these concentrations being able to reach up to 150 mg / ml or 15% by weight, more particularly 60 mg / ml or 6% by weight of Compound a.

 For this reason, small volumes of administration may be envisaged, for example 0.5 ml containing up to 30 mg of this same active ingredient.

 These pharmaceutical compositions, spontaneously dispersible in aqueous medium, while being able to accept water without phase shift, become compatible

 Moreover, these liquid pharmaceutical compositions for oral administration have proved to be able to increase the transepithelial transport rate as well as the bioavailability of the active ingredients of formula I.

According to another of its aspects, the invention relates to a semi-solid pharmaceutical composition for oral administration comprising:
a hydrophobic active ingredient of formula I, generally at a concentration
not exceeding 15% by weight of the composition,
a solubilizer / semi-solid stabilizer system comprising:
one or more amphiphilic compounds of the glycolic type chosen from
polyethylene glycols of average molecular weight between 600 and 2000, the
system further comprising one or more hydrophilic surfactants
nonionic compounds with an HLB value between 12 and 18,
either one or more hydrophilic nonionic compounds both amphiphilic and
surfactants which are saturated polyglycolysed glycerides consisting of
mixtures of monoesters, diesters and triesters of glycerol and fatty acids, and
mono and diesters of polyethylene glycol and fatty acids, the system
optionally comprising one or more hydrophilic surfactants
non-ionic HLB value between 12 and 18, and optionally one or
several amphiphilic compounds of glycolic type chosen from
polyethylene glycols of average molecular weight between 600 and 2000.

 Generally, in the context of such oral compositions, one or more polyethylene glycols of molecular weight between 600 and 2000 are used.

As such, the PEG 1000, the PEG 2000, or a 50/50 mixture by weight of PEG 600 /
PEG 1500 are preferred amphiphilic solvents according to the invention.

 In the case of mixtures of various polyethylene glycols, small proportions of these polymers outside the previously fixed range may be used in combination with polyethylene glycols included in the range in question.

 However, these polyethylene glycols will be selected in such a way that the resulting oral composition is compatible in particular with regard to viscosity with filling equipment, for example for the constitution of soft capsules.

 As for the nonionic hydrophilic surfactant, it is preferably chosen from compounds having an HLB close to 15. As such, polysorbate 80 is a surfactant of choice for the purposes of the invention.

 This surfactant will however be incorporated in the semi-solid compositions in question at a concentration not exceeding 12% by weight thereof.

 Thus, a solubilizer / stabilizer system preferably used consists of PEG 1000 and polysorbate 80 or a 50/50 by weight mixture of PEG 600/1500 as well as polysorbate 80 or alternatively PEG 2000 and polysorbate 80.

 In addition, the polyglycolysed glycerides of solid and waxy consistency at room temperature will be selected so that their liquefaction temperature is close to body temperature.

 As such, the products marked GELUCIRE2 44-14 and GELUCIREe 50-13 are polyglycolysed glyceride mixtures of choice due to their liquefaction temperature of 44 ° C and 50 ° C, respectively, their amphiphilic character conferred by fatty acids and the polyethylene glycol unit and by their favorable hydrophilic surfactant character (HLB: 14 and 13 respectively).

 As in the case of liquid pharmaceutical compositions for oral administration above, the semi-solid pharmaceutical compositions may be administered in a reduced volume because of the high solubility of the active ingredients of formula I in this type of polyglycolysed glyceride mixture.

 In addition, it has been noted in experimental tests that the product GELUCIREe 44-14, in particular, improves the membrane permeability and allows a transepithelial transport rate of the Compound at about two times higher than that obtained with the liquid compositions of the invention. invention introduced in soft capsule.

 Similarly, a very marked improvement in bioavailability has been observed, this improvement being similar to that recorded with the liquid compositions of the invention that can be used in soft capsules.

 The pharmaceutical compositions of the invention containing as solubilizer / stabilizer saturated polyglycolized glycerides as described above are hot formed in the liquid state and then solidify by cooling. Therefore, these hydrous and liquid compositions can be hot-introduced into hard capsules to ultimately form a semi-solid pharmaceutical composition.

 Accordingly, another object of the invention relates to a pharmaceutical soft capsule containing a liquid pharmaceutical composition for oral administration as described above, that is to say containing a hydrophobic active ingredient of formula I and a solubilizing system. stabilizing.

 Another subject of the invention relates to a pharmaceutical capsule containing a semi-solid pharmaceutical composition for oral administration as described above.

 The pharmaceutical compositions of the invention may be prepared in a conventional manner by solubilizing the active ingredient of formula I in the selected solvent (s) or solubilizer (s) to which the nonionic hydrophilic surfactant has been added, these various constituents being in liquid form.

 If necessary, the stabilizing solubilizing system I will be heated until a liquid mixture is obtained.

 This heating operation is particularly suitable when using polyethylene glycols of molecular weight> 600 or mixtures of monoesters, diesters and triesters of glycerol and of fatty acid, and mono and diesters of polyethylene glycol and fatty acids including the products. GELUCIREs 44-14 and GELUCIREI 50-13.

The characteristics and advantages of the compositions according to the invention will become apparent in the light of the description below from compositions given by way of examples.

I. Assessment of intestinal transepithelium passage from the comPose
For this purpose, an immortalized human cell line of colonic origin has been used.
"Caco-2" as described in Crist. Rev, Ther. Drug Carrier System 8 (4), 105330, 1991. These cells, which have the distinction of differentiating in culture to reconstitute a model of intestinal epithelium, are used as a model to study the passage of a molecule through an intestinal epithelium and, therefore, to estimate its intestinal absorption.

 On microporous polycarbonate filters coated with collagen, these Caco-2 cells are seeded. The cellular monolayer formed on the filter then makes it possible to separate an apical compartment (mimicking the intestinal lumen) of 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, pH = 7.4, has the following composition: NaCl = 8.0girl; KCl = 0.4g / l;
CaCl 2 = 0.19 g / l; MgCl 2 = 0.1 g / l; MgSO4 = 0.1 g / l; Na2HPO4 = 0.09g / l; KH2PO4 = 0.06g / l;
NaHCO3 = 0.35g / l; glucose = 1 g / l; phenol red = 0.01g / l.

The coefficient of permeability P, in cm / sec, which characterizes the rate of passage of the molecule through the membrane is then determined, namely:
da
P =
dt.A.Co
in which:
da
--- = variation in the amount of test compound passing through the cell monolayer
dt as a function of time (mole / s)
A = surface of the monolayer (cm2)
Co = initial concentration of test compound (mole / l)
These results can also be expressed in% of product tested transported 1st series of tests
An injectable composition (hereinafter Composition A) of formulation has been experimented
% in weight
Compound a 0.4
PEG 400 7.49
Polyvinylpyrrolidone 1.87
Polysorbate 80 1.98
Water QS 100 QS = sufficient amount, compared with control compositions placed in the apical compartment consisting of one 100 molar suspension of Compound a in gum arabic (Composition I), the other of the same Compound a solubilized at the same concentration in dimethylsulfoxide (Composition II).

The following results were obtained:

<tb> Composition <SEP>% <SEP> of <SEP> Compound <SEP> a <SEP> transport <SEP> by <SEP> hour
<tb><SEP> 1,2 + 0,6 <SEP>
<tb><SEP> It <SEP> 6.5 + 04 <SEP>
<tb><SEP> A <SEP> 10.5 # 0.5
<Tb>
These results show a clear improvement in the transepithelial passage of Compound a relative to the control compositions.

2nd series of tests
The following compositions for oral administration have been tested in which the test compound is Compound a. The compositions below were used such that compound a was incubated at 50p molar in Hank's solution. a) Dilutable anhydrous concentrated compounds

<tb><SEP> Composition <SEP> C <SEP> D <SEP> E
<tb><SEP> Compound <SEP> a <SEP> 2% <SEP> 2% <SEP> 2%
<tb><SEP> PEG <SEP> 400 <SEP> 89% <SEP> - <SEP> 33.5%
<tb> TRANSCUTOLs <SEP> - <SEP> 89% <SEP> 55.5%
<tb><SEP> Polysorbate <SEP> 80 <SEP> 9% <SEP> 9% <SEP> 9%
<tb> b) Dispersible anhydrous concentrate composition

<tb> Composition <SEP> F <SEP> G
<tb><SEP> Compound <SEP> a <SEP> 6% <SEP> 6%
<tb><SEP> PEG <SEP> 400 <SEP> 33% <SEP> 33%
<tb><SEP> TRANSCUTOL # <SEP><SEP> 55% <SEP> 55%
<tb><SEP> Polysorbate <SEP> 80 <SEP> - <SEP> 6%
<tb><SEP> PLURONICs <SEP> P94 <SEP> 6%
<Tb>
Compositions C to G were diluted (Compositions C to E) or dispersed (Compositions F and G) in Hank's medium.

For comparison, the passage of Compound a in control compositions was also evaluated, i.e. compound a was solubilized at the same concentration in dimethylsulfoxide (Composition II) and then dispersed in Hank's medium. or the compound a (Composition III) is suspended in the medium of
Hank as well as the passage of Compound A in a composition without surfactant
formulation:
Composition IV
6% compound
PEG 400 35%
TRANSCUTOL # 59%
The coefficient of permeability of Compound a in the control composition in
suspension (Composition III) was reduced to 1 while the other coefficients
been expressed in relation to this witness.

The following results were obtained:

<tb><SEP> Compositions
<tb><SEP> Coefficient of <SEP><SEP> Thinning <SEP> Dispersible Indicators
<tb> permeability <SEP> It <SEP> III <SEP> c <SEP> D <SEP> E <SEP> F <SEP> G <SEP> | <SEP> IV
<tb> by <SEP> ratio <SEP> 8.33 # <SEP> 1 # 0.16 <SEP><SEP> 10.8 # <SEP><SEP> 10.4 # <SEP><SEP> 10 , 8 # <SEP><SEP> 10.8 # <SEP><SEP> 14.2 # <SEP><SEP> 5.08 #
<tb> with <SEP> control <SEP> 0.78 <SEP> 1.1 <SEP> 1.2 <SEP> 1.0 <SEP> 1.0 <SEP> 1.2 <SEP> 1,2
<Tb>
These results show that among the compositions studied the surfactant-free formulation (Composition IV) does not improve the passage with respect to the solution in dimethylsulfoxide (Composition II). However, an improvement is observed compared to the control in suspension (Composition III). This improvement is particularly clear when comparing the formulations with the surfactant to the suspension formulation (Composition 1F1) since the passage is at least multiplied by 10.

In addition, it will be noted that:
the two co-solvents tested ie PEG 400 or PEG 400 / product
TRANSCUTOL &commat; present in dilutable formulations do not differentiate
in terms of transepithelial passage.
having practically dispersible formulations and not totally
dilutable does not appear discriminating.
the presence of the surfactant favorably influences the passage since the
coefficient of permeability is at least 2 times higher than in the case of the
composition without surfactant (Composition IV). This favorable influence of
surfactant is related to its stabilizing effect and / or promoter.

3rd series of tests
The composition H of the invention used in soft capsule was tested, namely:
ComPosition H
21 mg compound
PEG 400 294 mg
TRANSCUTOLs 21 mg
Polysorbate 80 14 mg
350 mg compared with compositions of concentration analogous to Compound a but not included in the invention:
Composition V: Compound Suspended in Hank Culture Medium
Composition VI: Compound dissolved in dimethylsulfoxide and
introduced into the culture medium of Hank
Composition VII (usable in capsule):
Compound at 20.00 mg
Modified corn starch 131.45 mg
Lactose monohydrate
(extra fine crystals) 311.75 mg
Talc 9,60 mg
Colloidal Silica Anhydrous 2.40 mg
Magnesium stearate 4.80 mg
480.00 mg
The above compositions were used such that Compound a was incubated at 100 molar in Hank's solution.

The relative percentages of Compound transported from the basal side to the 6 hour time were then determined and the results were expressed in relation to the result of the test.
Composition V (suspension) reduced to 1.

The following results were obtained:

<tb> Composition <SEP> Percentages
<tb><SEP> 1.0 + 0.4 <SEP>
<tb><SEP> VI <SEP> 10.1 # 0.8
<tb><SEP> VII <SEP> 2,80,3 <SEP>
<tb><SEP> H <SEP> 11.2 + 0.7 <SEP>
<Tb>
These results show that Compositions VI, Vll and H improve the passage of
Compound a with respect to the suspension of this compound (Composition V).

However, the improvement provided by the composition Vll usable in capsule is much lower than the improvement recorded with the soluble Composition VI using dimethylsulfoxide. Composition H, which can be used in soft capsule, allows for a very strong improvement of the passage, an improvement which is even greater than that observed with the solution of Compound a in dimethylsulfoxide (Composition VI).

They further confirm that the solubilization step has a decisive impact on the transepithelial passage of Compound a and that the surfactant exhibits an absorption promoter effect while maintaining the solubilized state.

4th series of tests
The following compositions were used on Caco-2 cells in quantities such that the
Compound a is incubated at 100 molar in a solution of Hank supplemented with taurocholic acid and phospholipid at 37 ° C.
Thus, the semisolid compositions L, M and N of the invention and a composition K not included in the invention compared with the liquid composition J of the invention, namely:

<tb><SEP> Composition <SEP> J <SEP> K <SEP> L <SEP> M <SEP> N
<tb><SEP> Compound <SEP> a <SEP> 6% <SEP> 6% <SEP> 6% <SEP> 6% <SEP> 12%
<tb><SEP> PEG <SEP> 400 <SEP> 83.9% <SEP> - <SEP> - <SEP> - <SEP> - <SEP>
<tb><SEP> PEG <SEP> 600 <SEP> - <SEP> 47% <SEP> 45% <SEP> - <SEP>
<tb><SEP> PEG <SEP> 1500 <SEP> - <SEP> 47% <SEP> 45% <SEP> - <SEP>
<tb> GELUCIRE &commat; 44-14 <SEP><SEP>.<SEP> - <SEP> - <SEP> 94% <SEP> 88%
<tb><SEP> TRANSCUTOL # <SEP><SEP> 6.1% <SEP> - <SEP> - <SEP> - <SEP>
<tb><SEP> Polysorbate <SEP> 80 <SEP> 4.0% <SEP> - <SEP> 4% <SEP> - <SEP>
The coefficient of permeability of the Reference Composition J was reduced to 1 while the other coefficients were expressed with respect to this reference composition.

The following results were obtained:

<tb><SEP> Composition
<tb> Coefficient <SEP> of <SEP> J <SEP> K <SEP> L <SEP> M <SEP> N
<tb><SEP> permeability <SEP> 1 <SEP> 0.67 <SEP> 0.98 <SEP> 1.9 <SEP>. <SEP> 2.45
<Tb>
These results show that the transition from PEG 400 to 50/50 PEG 600 /
PEG 1500 (Composition L) does not modify the coefficient of permeability measured on Caco-2 cells, when the surfactant in this case polysorbate 80 remains present in the composition.

Furthermore, it is observed that GELUCIREs 4414-based M and N compositions allow a transepithelial transport rate approximately twice as high as that obtained with Composition J used in soft capsules.

 It even seems that a margin of progression exists with the product GELUCIRES 4414 which allows a higher concentration of Compound and improves membrane permeability on Caco-2 cells.

From all the tests carried out on these Caco-2 cells, it has notably been possible to conclude that the compositions of the invention make it possible to improve the transmembrane passage with respect to the reference compositions without causing a destructuring effect of this membrane.

II. Kinetics of dissolution of soft capsules containing Compound a
The dissolution kinetics of soft capsules dosed at 21 mg of
Compound a, these capsules containing 350 mg of Composition H compared to those of dry form capsules dosed with 20 mg of Compound a containing 480 mg of
Composition VII.

 This dissolution was practiced at 37 ° C. in hydrochloric acid of pH = 1.2, the stirring speed being 100 rpm.

 The results show a clear improvement in the dissolution kinetics of the soft capsules compared to that of the capsules: as soon as the capsules are opened after 7 min, a complete dissolution of Compound a is observed, whereas only 65% is reached after 15 min in the case of capsules as shown in Figure 3 in the appendix.

 In addition, if the dissolution medium of the soft capsules is filtered, it is observed that all the Compound a is in microdispersed form of size <0.2 micron.

 Similar assays performed with Compound A formulations in GELUCIRES 44-14 product showed a transport rate approximately 2 times higher than that obtained with the formulation of Composition VII.

III. In vivo tests in dogs
Plasma assays were carried out in the dog after oral administration of 20 mg of Compound a in the form of Composition H introduced in soft capsule or in the form of Composition VII introduced in hard capsule.

With respect to the hard capsule, the administration of the soft capsule containing the
Composition H results in:
a decrease in the variability of plasma levels
a relative bioavailability increased by a factor of 3 to 4
a maximum concentration (C max) increased by a factor of 3
IV. In vivo tests in humans
The microdispersible liquid composition H was compared with two other formulations of the same concentration of compound introduced in hard capsules, one with a micronised active ingredient, the other with a non-micronised active ingredient.

For this purpose clinical trials were carried out on 24 healthy male volunteers who received 100mu of Compound a: 1) fasting in the form of capsules containing Composition VII obtained from
A non-micronized compound (Treatment A) 2) in the form of capsules containing Composition VII obtained from
Micronized compound (Treatment B) 3) in the form of capsules containing Composition VII obtained from the Compound
micronized, as well as food (Treatment C) 4) fasting in the form of soft capsules containing Composition H (Treatment D)
Blood tests were then performed 0; 0.25; 0.5; 1; 1.5; 2, 3, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours after administration, then the maximum concentrations of Compound a (C max) and the area under the curves defined by the concentration of Compound a as a function of time (AUC).

The results were expressed with respect to the result of Treatment A reduced to 1

<tb> Processing <SEP> C <SEP> Max <SEP> AUC <SEP> Report <SEP> Report
<tb><SEP> (ngIml) <SEP> (ng.h / ml) <SEP> of <SEP> C <SEP> max <SEP> of <SEP> AUC
<tb><SEP> A <SEP> 5.50 <SEP> 39.47 <SEP> 1 <SEP> 1
<tb><SEP> B <SEP> 23.26 <SEP> 93.45 <SEP> 4.2 <SEP> 2.4
<tb><SEP> C <SEP> 38.12 <SEP> 142.46 <SEP> 6.9 <SEP> 3.6
<tb><SEP> D <SEP> 121.31 <SEP> 231.16 <SEP> 22.1 <SEP> 5.9
<Tb>
These results show a very important increase in the bioavailability for composition H, namely:
a max C multiplied by 22
a relative bioavailability multiplied by 6 in favor of the composition of the invention.

The following nonlimiting examples illustrate the preparation of pharmaceutical forms according to the invention:
EXAMPLE 1 Iniectable ComPosition of ComPose
An injectable formulation formulation is prepared
% in weight
Compound a 0.4
PEG 400 7.49
PVP KOLLIDON 12 PF 1.87
TWEEN 80 1.98
WATER for injection sufficient amount 100 by applying the following method:
The solubilizing solvent of Compound a is first prepared by mixing 50 parts of KOLLIDONO 12 PF PVP containing 25% of water with 50 parts of PEG 400 so as to constitute a solvent consisting of 12.5% PVP KOLLIDON 12PF. 37.5% water and 50% PEG 400.

26 mg of Compound a per g of solubilization solvent thus constituted are then incorporated and 0.2 g of this mixture is taken, to which 0.026 g of polysorbate 80 is added with stirring. 1.074 g of water for injectable preparation is then introduced and homogenizes at room temperature.

EXAMPLE 2
Soft capsule of Compound a
Soft capsules containing a composition of the following formulation are obtained
% in weight
Composed at 6
PEG 400 83.9 TRANSCUTOLS 6.1 MONTANOX # 80 DF 4 by applying the following method:
The solubilizer / stabilizer system is first prepared from:
% in weight
PEG 400 89.25 TRANSCUTOL # 6.5 MONTANOXS 80 DF 4.25 then, with mechanical stirring and at room temperature, 60 mg of
Compound a by g of final composition.

After solubilization, the formed composition is introduced in soft capsules.

EXAMPLE 3
Compound capsule a
Hard capsules are obtained containing a composition of the following formulation:
% in weight
Compound a 6 GELUCIRE # 44-14 94 by applying the following method:
With magnetic stirring, Compound a is solubilized directly in the product GELUCIRF 44-14 at controlled temperature (approximately 55 ° C.).

After solubilization, the formed composition is introduced into capsules and cooled.

EXAMPLE 4
Compound capsule a
Hard capsules are obtained containing a composition of the following formulation:
% in weight
Composed at 6
PEG 600 45
PEG 1500 45 TWEENS 80 4 by applying the following method:
With stirring and at a temperature of 55 ° C., a PEG 600 / PEG 1500 50/50 by weight mixture is prepared until homogenization.

429 of product TWEEN # 80 are then incorporated for 100 g of PEG 600 I mixture.
PEG 1500 so as to constitute a product solution TWEEN8 80 at 4% in PEG 6001 PEG 1500 mixture.

The mixture is stirred at 55 ° C. until homogenization, then the compound is introduced at 55 ° C. directly into the stabilizing solubilizer system I thus constituted.

Following the methods described in Examples 2 to 4 above, soft capsules or capsules containing the following formulation compositions were prepared.

The percentages are expressed by weight relative to the weight of the final composition.

EXAMPLE 5
Composed at 12.5% PEG 2000 79.5% TWEENs 20 8%
EXAMPLE 6
12.5% compound
PEG 2000 79.5%
TWEENs 80 8%
EXAMPLE 7
Composed at 12.5% PEG 2000 79.5% TWEEN # 80 / SPAN # 20 (69/31) 8%
EXAMPLE 8
12.5% compound
PEG 2000 75.5% TWEEN # 20 12%
EXAMPLE 9
12.5% compound
PEG 2000 75.5% TWEEN # 80 12%
EXAMPLE 10
12.5% compound
PEG 2000 75.5%
TWEEN 80 / SPAN # 20 (69/31) 12%
EXAMPLE 11
Composed at 12.5% PEG 2000 75.5% GELUCIRES 44-14 12%
EXAMPLE 12
12.5% compound
PEG 2000 75.5%
GELUCIRE 50-13 12%
EXAMPLE 13
12.5% compound
GELUCIRE 44-14 87.5%
EXAMPLE 14
12.5% compound TWEEN 80 8%
GELUCIRE 44-14 79.5%
EXAMPLE 15
12.5% compound TWEEN # 80 12% GELUCIRF 44-14 75.5%
EXAMPLE 16
12.5% compound
GELUCIRE 50-13 87.5%
EXAMPLE 17
12.5% compound
TWEEN "80 8%
GELUCIRE 50-13 79.5%
EXAMPLE 18
12.5% compound TWEEN # 80 12%
GELUCIRE 50-13 75.5%
EXAMPLE 19
6% compound
PEG 400 90% TWEEN # 80 4%

Claims (22)

1. A solubilizing system I anhydrous stabilizer, emulsifiable or microemulsifiable in water, for the solubilization of hydrophobic derivatives of N-sulfonyl indoline of formula: characterized in that it comprises one or more constituents selected from amphiphilic compounds, agents nonionic hydrophilic surfactants and nonionic hydrophilic compounds having both amphiphilic and surfactant properties, it being understood that said system comprises either at least one mixture of an amphiphilic compound and a nonionic hydrophilic surfactant, or at least one nonionic hydrophilic compound having both surfactant and amphiphilic properties. Stabilizing solubilizing system according to Claim 1, characterized in that  comprises one or more amphiphilic compounds of glycolic type chosen from  polyethylene glycols and glycol ethers, the system comprising  also one or more nonionic hydrophilic surfactants. Solubilizing / stabilizing system according to Claim 1, characterized in that  comprises one or more non-ionic hydrophilic compounds at a time  amphiphiles and surfactants chosen from saturated polyglycolized glycerides, the  system optionally comprising one or more surfactants  hydrophilic nonionic and optionally one or more amphiphilic compounds  glycolic type. Solubilizer / stabilizer system according to Claim 1 or 2, characterized in that  it is in liquid form and comprises one or more amphiphilic compounds of  glycolic type selected from polyethylene glycols of average molecular weight  between 400 and 600, the system further comprising one or more agents  hydrophilic nonionic surfactants with an HLB value of between 12 and 18 and  optionally a diethylene glycol ether. Solubilizer / stabilizer system according to Claim 1 or 2, characterized in that  it is in liquid form and comprises one or more amphiphilic compounds of  glycolic type selected from polyethylene glycols of average molecular weight  between 400 and 600 and diethylene glycol ethers, the system comprising  also one or more valuable nonionic hydrophilic surfactants  HLB between 12 and 18. A solubilizer / stabilizer system according to Claim 1 or 2, characterized in that  that it is in semi-solid form and comprises one or more compounds  glycolic type amphiphiles selected from polyethylene glycols of weight  average molecular weight between 600 and 2000, the system also comprising  one or more nonionic hydrophilic surfactants of HLB value  between 12 and 18. A solubilizer / stabilizer system according to claim 1 or 3, characterized in that  that it is in semi-solid form and comprises one or more compounds  hydrophilic nonionic both amphiphilic and surfactant which are derivatives  saturated polyglycolysed glycerides consisting of mixtures of monoesters, diesters  and triesters of glycerol and fatty acids, and mono and diesters of  polyethylene glycol and fatty acids, the system optionally comprising one or  several nonionic hydrophilic surfactants of HLB value included  between 12 and 18 and optionally one or more amphiphilic compounds of the type  glycolic acid selected from polyethylene glycols of average molecular weight  between 600 and 2000. Solubilizer / stabilizer system according to one of Claims 1, 2, 4 or 5,  characterized in that the amphiphilic compound, which is a polyethylene glycol of  average molecular weight between 400 and 600 is polyethylene glycol 400. Solubilizer / stabilizer system according to one of Claims 1, 2, 6 or 7,  characterized in that the amphiphilic compound, which is a polyethylene glycol of  average molecular weight between 600 and 2000, is polyethylene glycol  1000, polyethylene glycol 2000 or a 50/50 mixture by weight of  polyethylene glycol  600 / polyethylene glycol 1500.  10.System solubilizing system I according to one of Claims 7, characterized  in that the surfactant is polysorbate 80.  Solubilizer / stabilizer system according to one of Claims 1, 2, 4 or 5,  characterized in that the amphiphilic compound which is a glycolic ether, is a  mono (C1-C4) diethylene glycol alkyl ether. Solubilizer / stabilizer system according to Claim 11, characterized in that  the diethylene glycol mono (C1-C4) alkyl ether is monoethyl ether of the  diethylene glycol brand TRANSCUTOL &commat;.  A stabilizing solubilizing system according to one of claims 1, 3 or 7,  characterized in that the compound both amphiphilic and surfactant is a mixture  glycerol monoesters, diesters and triesters, and monoesters and diesters of  polyethylene glycol, GELUCIREX brand mixture 44-14 or GELUCIREe 50-13. 14.Microemulsifiable or emulsifiable pharmaceutical composition in a medium  aqueous, characterized in that it comprises:  a hydrophobic derivative of N-sulfonyl indoline according to Claim 1  a stabilizing solubilizing system according to one of claims 1 to 13  optionally a suitable excipient or pharmaceutical vehicle. 15.Pharmaceutical composition according to Claim 14 for administration  injectable, characterized in that it comprises:  a hydrophobic derivative of N-sulfonyl indoline according to Claim 1  a solubilizing / stabilizing system according to one of Claims 4, 8, 10, 11  and 12  a suitable pharmaceutical vehicle. 16.Pharmaceutical composition according to Claim 15, characterized in that the  Pharmaceutical vehicle is water and / or polyvinylpyrrolidone. 17.Pharmaceutical composition according to Claim 15 or 16, characterized in that  that the hydrophobic derivative of N-sulfonyl indoline does not exceed 1% by weight of the  composition. 18.Pharmaceutical composition according to Claim 14 in liquid form and for  oral administration, characterized in that it comprises:  a hydrophobic derivative of N-sulfonyl indoline according to Claim 1  a stabilizing solubilizing system according to one of claims 5, 8, 10 and  12. 19.The pharmaceutical composition according to claim 14 in semi-solid form and  for oral administration, characterized in that it comprises:  a hydrophobic derivative of N-sulfonyl indoline according to Claim 1  a solubilizing / stabilizing system according to one of Claims 6, 7, 9, 10 and  13. 20.Pharmaceutical composition according to Claim 18 or 19, characterized in that  that the hydrophobic derivative of N-sulfonyl indoline does not exceed 15% by weight of the  composition. 21.Pharmaceutical composition according to one of Claims 15 to 17, characterized  in that, in the solubilizing / stabilizing system, the diethylene glycol ether  does not exceed 50% by weight of the composition. 22.Pharmaceutical composition according to one of Claims 15 to 17, characterized  in that the solubilizing / stabilizing system contains a surfactant  hydrophilic non-ionic strength at a concentration not exceeding 4% by weight of the  composition. 23.Pharmaceutical composition according to one of Claims 15 to 21, characterized  in that the solubilizing / stabilizing system contains a surfactant  hydrophilic non-ionic strength at a concentration not exceeding 12% by weight of the  composition. 24.The pharmaceutical composition according to one of Claims 14 to 23, characterized  in that the hydrophobic derivative of N-sulfonyl indoline is (2S) 1 - [(2R, 3S) (5)  chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3-hydroxy, 3-dihydro-  1H-indole-2-carbonyl] -pynroidine-2-carboxamide. 25.Pharmaceutical soft capsule, characterized in that it contains a  pharmaceutical composition in liquid form for oral administration according to  one of claims 18, 20, 23 or 24. 26.Pharmaceutical capsule, characterized in that it contains a composition  pharmaceutical form in semi-solid form for oral administration according to one of  Claims 19, 20, 23 or 24.