SK75599A3 - Pharmaceutical compositions containing n-sulphonyl indolin 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 generally to novel pharmaceutical compositions comprising an N-sulfonylindoline derivative as an active ingredient.

In particular, the invention relates to pharmaceutical compositions for administration both parenterally and orally, the compositions comprising as active ingredient one or more isomers of N- [5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl) -3hydroxy -2,3-dihydro-1H-indole-2-carbonyl] pyrrolidine-2-carboxamide of formula I

Said compounds are in the form of cis-trans-isomers around the 2,3-indoline bond.

Typically, the cis isomer is a compound of formula I having 2-chlorophenyl and 2-carbamoylpyrrolidone-carbonyl on the same side of the cycle. Conversely, the trans isomer is a compound of formula I having 2-chlorophenyl and 2-carbamoylpyrrolidone-carbonyl on various sides of the cycle.

The compounds of formula I also exist in the form of optical isomers because they have an asymmetric carbon atom (indicated by an asterisk). Formula I encompasses said isomers as well as mixtures thereof.

BACKGROUND OF THE INVENTION

Said N-sulfonylindoline derivatives are known compounds as described in EP 0526348. These compounds exhibit affinity for vasopressin and ocytocin receptors and are therefore particularly useful in the treatment of the central nervous system, cardiovascular system and intestinal tract.

The most important isomers of this series are:

(2 S) -1 - [(2 R, 3 S) - (5-chloro-3- (2-chlorophenyl) -1- (3,4-dimetoxyfenylsulfonyl-3-hydroxy-

2,3-dihydro-1H-indole-2-carbonyl] pyrrolidine-2-carboxamide of formula

This compound is hereinafter referred to as "compound ^with a.

The active compound of the formula I, in particular compound a, is a highly hydrophobic product and therefore has only a low solubility in aqueous medium at physiological pH values, i.e. 1.2 to 7.5.

Drugs are known to be better absorbed when they are in the form of soluble pharmaceutical compositions.

However, it is necessary to maintain this solubility of a particular substance in specific organic solvents while maintaining its maximum efficacy and to maintain (stabilize) this dissolved state of the molecule when the pharmaceutical composition is diluted in an aqueous environment. Certain microemulsion-type compositions allow the coexistence of such an organic phase comprising a solubilized hydrophobic pharmaceutical agent and an aqueous phase.

When administering liquid pharmaceutical compositions in pharmaceutical containers, such as soft capsules, the absence of water is necessary because the gelatin film is incompatible with the aqueous composition. In addition, when administered in the form of a gelatin or soft capsule, the volume of the pharmaceutical composition should be minimal. For the mere absorption of the pharmaceutical composition by the patient itself, the type of pharmaceutical coating is not critical.

Systems are known from the literature for the solubilization of, in particular, hydrophobic pharmaceuticals which are administrable in gelatin or soft capsules.

Lipophilic matrices such as vegetable or animal oils have been proposed which can be combined with lubricants such as fats, waxes or even mineral oils if desired.

For example, EP 107085 discloses the use of an oil phase consisting of a vegetable oil and an anhydrous hydrophilic phase dissolved in water, consisting, for example, of polyethylene glycols having a molecular weight of 300 to 20,000 or even propylene glycol, glycerol or mixtures thereof.

Similarly, GB 1132518 discloses pharmaceutical compositions comprising an active substance dissolved in benzyl benzoate, wherein the matrix consists of benzyl benzoate and a hydrophilic nonionic surfactant such as polysorbate 80 and optionally a mineral or vegetable oil and a cosolvent of ingredients such as polyethylene glycol.

However, it is well known that the use of the prior art matrices for pharmaceutical compositions intended for filling capsules cannot be generalized to any active substance.

For example, the test has shown that the active compounds of the formula I, in particular compound a, are insoluble or only slightly soluble in oils. Therefore, prior art systems for dissolving hydrophobic compositions are not applicable to the active ingredients of the invention. Therefore, it is of interest to develop an anhydrous pharmaceutical composition with a concentrated hydrophobic compound of formula I, for example with compound a.

Surprisingly, it has now been found that it is possible to formulate, without hydrophobic oil phase, an anhydrous emulsifiable or microemulsifiable pharmaceutical composition containing the active ingredient of the formula I, which composition may be intended to be administered in particular in compressed form and gelatin hard or soft capsules containing the active ingredient. and administered in a form contained in a solubilizing / stabilizing system spontaneously microdispersible in water.

SUMMARY OF THE INVENTION

Anhydrous solubilization / stabilization system emulsifiable or microemulsifiable in water for solubilizing the hydrophobic Nsulfonylindoline derivatives of formula I

according to the invention, comprising at least one component selected from the group consisting of an amphiphilic compound, a hydrophilic nonionic surfactant and a hydrophilic nonionic agent having both amphiphilic and surface active properties, wherein the 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 solubilization / stabilization system comprising:

- at least one compound selected from the group consisting of an amphiphilic compound of the glycol type such as propylene glycol, polyethylene glycols and glycol ethers (preferably polyethylene glycols and glycol ethers), the system further comprising at least one nonionic surfactant hydrophilic agent,

at least one hydrophilic nonionic compound simultaneously amphiphilic and surface-active selected from the group consisting of saturated polyglycolized glycerides, a system comprising optionally at least one non-ionic hydrophilic glycol type surfactant such as polyethylene glycols.

In particular, the solubilization / stabilizing system of the invention relates to a system comprising at least two different components, one acting as a solvent or an amphiphilic solubilizer, the other acting as a hydrophilic nonionic surfactant.

In any case, the system may be a combination of more than two components, for example components acting as amphiphilic cosolvents or several nonionic hydrophilic surfactants.

It is also possible to ensure that in this set of at least two different components, one or the other component is capable of co-acting as an amphiphilic solvent and a non-ionic hydrophilic surfactant.

The solubilization / stabilizing system may be limited to the hydrophilic nonionic component alone acting both as a solvent or an amphiphilic solubilizer and as a surfactant.

The appropriate amphiphilic solvents mentioned above are generally selected from glycol type compounds. They are preferably selected from the group consisting of polyethylene glycols (PEG) having a molecular weight of about 400 to about 10,000, preferably about 400 to about 2000. Polyethylene glycol of a given molecular weight can be used alone or in admixture with several polyethylene glycols of different molecular weights.

The polyethylene glycols of the invention are used at ambient temperature either in liquid form or in semi-solid form according to their molecular weight. These polymers are selected according to the desired solubilization / stabilization system for use in liquid or semi-solid form.

Suitable polyethylene glycols of the invention include, for example, polyethylene glycol 400 - "PEG 400" liquid at ambient temperature, polyethylene glycol 1000 - "PEG 1000", polyethylene glycol 1500 - "PEG 1500, polyethylene glycol 2000 -" PEG 2000 ", polyethylene glycol 6000 -" PEG 6000 ", as well as a mixture of 50/50 by weight polyethylene glycol 600 or PEG 600 'and polyethylene glycol 1500 or "PEG 1500", all of which polyethylene glycols are semi-solid at ambient temperature, except for the above polyethylene glycol PEG 400.

It is also possible according to the invention to use derivatives of the corresponding polyethylene glycols prepared by esterification of fatty acid residues with polyethylene glycol or glycerol.

The structure of a compound of this type, semi-solid at the usual temperature, gives the compound an amphiphilic character capable of dissolving the active compounds of formula I, in particular the compound and due to fatty chains and polyethylene moieties which imparts the character of a hydrophilic surfactant suitable for stabilizing the solution when introduced into an aqueous solution. environment.

Such compounds are selected from the group consisting of saturated polyglycolized glycerides, also referred to as macrogolglycerides, i.e. compounds consisting of a mixture of monoesters, diesters and triesters of glycerol and fatty acids, and monoesters and diesters of polyethylene glycol and fatty acids. The most interesting are compounds having a melting point close to the body temperature and their hydrophilic / lipophilic equilibrium, usually defined by their "HLB" value indicating the proportion of hydrophilic groups of the molecule to lipophilic groups according to the GRIFIN WC system (J. Soc. Cosm. Chem. 311, 1949), is 12 to 22, preferably 12 to 18.

Representative compounds of this family are in particular those of the trade names GELUCIRE ^r 44-14 and GELUCIRE ^r 50-13. GELUCIRE ^r 44-14 is a good solubilizer of a. The solubility at 60 ° C of this active compound of formula I, determined by the additive method, is 226 mg / g.

Other glycol-type derivatives, i.e. amphiphilic compounds with solubilizing properties, can also be used as solvents or cosolvents. These glycol derivatives are selected from the group consisting of glycol ethers, generally diethylene glycol ethers, such as C 1 -C 4 diethylene glycol monoalkyl ether. Of the diethylene glycol monoalkyl ethers, commercially available methyl ether and ethyl ether are preferred, especially diethyl glycol monoethyl ether.

These compounds may contain various impurities, which in most cases form a small amount of diethers and other compounds used in their synthesis. In this form, however, they are useful in the manufacture of pharmaceutical compositions.

Commercial product TRANSCUTOL ^r is extremely clean monoethyl diethylene glycol (a product of Gattefosse (FR)) and is very suitable compound glycol ether products of the invention.

Such glycol ethers can be used alone as amphiphilic solvents in a solubilization / stabilization system or preferably in conjunction in all ratios with at least one low molecular weight polyethylene glycol described above, wherein the glycol ether has the role of a co-solvent and even a co-surfactant.

The surfactant is generally selected from nonionic hydrophilic compounds whose HLB of 12 to 22 and preferably 12 to about 18. Surfactants of this type include copolymers of ethylene oxide / propylene oxide, available commercially as PLURONIC P94 ^r (HLB: 13.5) , PLURONIC ^r F127 (HLB: 22), polyethoxylated castor oil commercially available as KREMOPHOR ^r (HLB: 13),

Ί non-ethoxylated polysorbate, ethoxylated polysorbate as polysorbate 80 (HLB: 15) commercially available as TWEEN ^R 80 or MONTANOX ^R 80 DF or polysorbate 20 commercially available as TWEEN ^R 20 (HLB: 16.5) or further polyethylene hydroxy stearate such as polyethylene-660 hydroxystearate (HLB: 13) commercially available as SOLUTOL ^r HS15.

Alternatively, the surfactant used according to the invention may consist of a mixture of such nonionic hydrophilic surfactants, the HLB of which is also 12 to 22, preferably 12 to 18.

Preferred surfactant mixtures include a mixture of ethoxylated polysorbate and nonethoxylated polysorbate having a final HLB value of 12 to 22, preferably 12 to 18, for example a mixture of polysorbate 80 (HLB: 15) and unethoxylated polysorbate is commercially available as SPAN ^R 20 (HLB: 8.6).

Among the solubilization / stabilization systems of the invention, the following compounds are preferred:

(a) an amphiphilic compound selected from the group consisting of polyethylene glycols having a molecular weight of 400 to 600, wherein the system additionally comprises a hydrophilic nonionic surfactant and, optionally, diethylene glycol ether;

b) or an amphiphilic compound selected from the group of polyethylene glycols having a molecular weight of 600 to 10,000, for example 600 to 2,000 or also 2,000 to 10,000, wherein the system additionally comprises a hydrophilic nonionic surfactant,

c) or a solubilizing / surfactant system compound selected from the group consisting of saturated polyglycol glycerides, a system optionally containing a hydrophilic nonionic surfactant.

Of the solubilization / stabilization systems of the invention, systems comprising

- either PEG 400 and polysorbate 80,

- or PEG 400, TRANSCUTOL ^R and polysorbate 80,

- or PEG 2000 and polysorbate 80,

- or a mixture by weight of 50/50 PEG 600 / PEG 1500 and polysorbate 80,

- or saturated polyglycol glycerides GELUCIRE ^R 44-14 or GELUCIRE ^R 50-13.

The invention thus relates to a water-solubilizable / stabilizing anhydrous emulsifiable or microemulsifiable system for solubilizing N-sulfonylindoline derivatives of formula I, comprising:

- at least one amphiphilic glycol type compound selected from the group consisting of propylene glycol and polyethylene glycols having an average molecular weight of 400 to 600, preferably polyethylene glycols, and at least one surface-active hydrophilic nonionic agent having an HLB of 12 to 22, preferably 12 to 18 and optionally such diethylene glycol ether the solubilization / stabilization system formed is in liquid form,

- or a plurality of amphiphilic glycol type compounds selected from the group consisting of propylene glycol and polyethylene glycols having an average molecular weight of 400 to 600 and diethylene glycol ethers such as diethylene glycol monoalkyl ether having 1 to 4 carbon atoms in the alkyl moiety, preferably polyethylene glycol glycols surfactants having an HLB value of 12 to 22, preferably 12 to 18, that the solubilizing / stabilizing system thus formed is in liquid form,

or a plurality of amphiphilic glycol type compounds selected from the group consisting of polyethyleneglycols having an average molecular weight of 600 to 2000, wherein the system further comprises at least one such hydrophilic nonionic surfactant having an HLB value of 12 to 22, preferably 12 to 18, the stabilizing system is in a semi-solid form,

or a plurality of amphiphilic glycol type compounds selected from the group consisting of polyethylene glycols having an average molecular weight of 2000 to 10,000, wherein the system further comprises one or more such hydrophilic nonionic surfactants having an HLB of 12 to 22, preferably 12 to 18, such solubilizing so formed. / the stabilizing system is in a semi-solid form,

or a plurality of hydrophilic nonionic compounds, simultaneously amphiphilic and surface-active, which are saturated polyglycol glycerides consisting of a mixture of monoesters, diesters and triesters of glycerol and fatty acids and monoesters, and diesters of polyethylene glycol and fatty acids, optionally containing at least one such hydrophilic surfactant; an HLB value of 12 to 22, preferably 12 to 18, and optionally at least one amphiphilic glycol type compound selected from the group consisting of polyethylene glycols having an average molecular weight of 600 to 10,000, for example 600 to 2000 or even 2000 to 10,000, that solubilizing / stabilizing system thus formed is in semi-solid form.

As mentioned above, the solubilizing / stabilizing system of the invention may preferably serve to solubilize the compounds of formula I so as to form dilutable or dispersible compositions in an aqueous environment.

In the case of such solubilization / stabilization systems comprising at least one amphiphilic solvent such as polypropylene glycol, low molecular weight polyethylene glycol, polyethylene glycol ether or mixtures thereof and containing in addition a hydrophilic nonionic surfactant, suitable ratios of the various components on the pseudo-phase phase diagram may be determined. in order to predict the aqueous behavior of the compositions comprising the compound of formula I and the solubilization / stabilization system of the invention.

The accompanying diagrams illustrate the behavior of the compositions of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 illustrates the behavior of the compositions consisting of 20 mg / ml of the compound and the solubilizing / stabilizing system of the invention, such as in PEG 400 / TRANSCUTOL ^R and polysorbate 80, the arrow on the side of the triangle facing up concerns solubilisers and downwardly of solubilizant + Compound A, arrow at the base of the triangle refers to water.

Fig. 2 illustrates the behavior of compositions comprising 60 mg / ml of compound and in the solubilization / stabilization system of FIG. 1, the values for solubilizer, solubilizer + compound system and and for water, water are in the same places as in FIG. First

Fig. 3 illustrates the dissolution kinetics of soft capsules compared to gelatin capsules, the x-axis is time in minutes, the y-axis the percentage of solubilized compound, the square line applies to the soft capsules, the diamond to the gelatin capsules.

The concentration of water, solubilizer and stabilizer increases in these diagrams

Λ 0 to 100% in the direction of the arrows.

FIG. 1, it is evident that, in particular, the equilibrium relative proportions by weight of both the solubilizer / component a and the stabilizer systems define a homogeneous region "A" and a heterogeneous region "B" corresponding to low concentrations of surfactant.

The tangent "d" of the curve defining the heterogeneous region "B", starting from the "WATER 100%" origin, cuts on the opposite side the "P" point representing the anhydrous solubilizer / compound α mixture and the stabilizer or surfactant. Below this point "P", ie at elevated surfactant concentrations, anhydrous mixtures may be water-dilutable because the tangent (line "d") corresponds to each of these surfactant concentrations, ie the line representing their dissolution path does not cross "B" . In this case, it would be possible to obtain a purely organic composition of a hydrophobic active substance, acting as a true solution, infinitely dilutable with water. As a result, the upper region "A" above the line "d" defines solubilization / stabilization systems that can form concentrated solutions of compound a. These highly stabilized solutions are capable of forming, in the presence of water, stable microemulsions within the range of temperatures customary in pharmaceutical formulations.

In concentrated solutions, as shown in FIG. 1, the amount of compound to achieve a 20 mg / ml when the amphiphilic solubilizers a mixture of PEG 400 / TRANSCUTOL ^R and the stabilizer is polysorbate 80th

If, on the other hand, it is desired to increase the proportion of the active compound of the formula I, in particular compound a, and to reduce the stabilizer content, as shown in FIG. 2, it is apparent that either the multiphase region is enlarged, which is the "B" region, or the water solubility line "d" intersects this heterogeneous region. As a result, significant amounts of stabilizing agents (greater than 20%) will be required to obtain dilutable solutions with a concentration of compound a (compound a in the solubilization / stabilization system of the invention), which is not suitable for pharmaceutical applications.

Solutions with higher concentrations of compound, and whose solubility line intersects the heterogeneous region "B ^u, already appear to be fully soluble, but as the dispersible in an aqueous medium, that is as concentrated solutions of spontaneously forming an emulsion more or less fine depending on the dispersion in water.

However, it has surprisingly been found that dispersible concentrated solutions (region B or B ') qualitatively identical, but containing less elevated surfactant concentrations than dilutable concentrated solutions, exhibit analogous properties to those exhibited in dilutable concentrated solutions because they lead to improved membrane permeability which is manifested by an increase identical to the transepithelial permeability of the compounds of formula I, namely the compounds a.

This alternative allows due to greater flexibility, since it is not necessary to take into account individual systems capable of providing microemulsifiable solutions to obtain particularly preferred concentrated solutions. In this way, the concentration of the active compound of the formula I can be increased strongly.

In the case of solutions containing a compound and dispersible in water, the concentration of the active ingredient may be increased up to 60 mg / ml, which is three times the concentration of the water-dilutable solution.

In addition, it appears that, even in the case of water-dispersible solutions, these solutions show a good water-tolerance, since they make it possible to virtually incorporate their weight in water while remaining completely homogeneous. This peculiarity is very useful in introducing such solutions into soft capsules in the preparation of medicaments, since it is known that the interaction between the contents and the package may occur during their manufacture.

As a result, the water just introduced into the solution does not pose a risk of phase separation, since the interchangeable amount is less than 10%. The same peculiarity of maintaining homogeneity is evident if the solution contains up to 5% glycerol, which may occur using certain methods of preparing pharmaceutical compositions containing the trialcohol. After drying, the starting solution is obtained without altering its properties.

The solubilizing / stabilizing system according to the invention, capable of solubilizing the hydrophobic active compounds of the formula I, can be applied differently in terms of incorporating the active compounds into pharmaceutical compositions.

Accordingly, the invention also relates to a pharmaceutical composition microemulsifiable or emulsifiable in an aqueous medium comprising:

a hydrophobic active ingredient of the formula I

the solubilization / stabilization system described above

optionally a suitable pharmaceutical excipient or carrier.

In particular, the invention relates to an injectable pharmaceutical composition comprising:

a hydrophobic active ingredient of the formula I

- a solubilizing / stabilizing system in liquid form, consisting of one or more amphiphilic components of the glycol type, selected from the group consisting of propylene glycol, polyethylene glycols having an average molecular weight of 400 to 600, containing in addition several hydrophilic nonionic surfactants with HLB 12 to 22, preferably 12 to 18, such as polysorbate 80 or a diethylene glycol ether as Transcutol ^r

a suitable pharmaceutical carrier.

As a suitable pharmaceutical carrier, water or a physiologically acceptable ketone derivative is usually used, the active compound of the formula I namely a compound and having been found to be particularly soluble in these organic compounds.

For this reason, polyvinylpyrrolidone (PVP), preferably polyvinylpyrrolidone commercially available and referred to as KOLLIDON * 12PF or polyvinylpyrrolidone commercially available as KOLLIDON * 17PF, is selected which consists of a ketone derivative chosen to take advantage of the solubility of the active compound of formula I in injectable compositions.

Thus, pharmaceutical compositions for administration by injection may be prepared wherein the compositions contain no more than 10 mg / ml or 1% by weight of the compound of formula I. For example, the compositions may contain 2 to 6 mg / ml of compound a. They further comprise a hydrophilic nonionic surfactant such as polysorbate 80 at a concentration not exceeding 4% by weight, based on the composition as a whole. Such isotonic agents have been shown to be physically stable and dilutable in physiological serum or glucose serum.

The invention further relates to a pharmaceutical composition for oral administration comprising:

a hydrophobic active ingredient of the formula I

- a solubilizing / stabilizing system in liquid form, comprising at least one amphiphilic component of the glycol type, selected from the group consisting of propylene glycol, polyethylene glycols having an average molecular weight of 400 to 600, and diethylene glycol ethers (preferably polyethylene glycols and diethylene glycol ethers), HLB agents of 12 to 22, preferably 12 to 18, such as polysorbate 80 or PLURONIC ® P94.

Generally, at least one low molecular weight polyethylene glycol of about 400 to 600 is used for such oral compositions. The preferred polyethylene glycol used is PEG 400. When such polyethylene glycols are used, one or more diethylene glycol ethers, such as methyl ethers or ethyl ethers, are usually added. Preference is given to diethylene as appropriate diethylene glycol ether, thus TRANSCUTOL ^r.

These diethylene glycol ethers are used in concentrations not exceeding preferably 50% by weight, or rather not exceeding 20% by weight, based on the product as a whole.

The hydrophilic nonionic surfactant is preferably selected from the group consisting of an HLB value of 15 or close to 15, and concentrations not exceeding 20% by weight, preferably not exceeding 12% by weight of the composition as a whole are generally used. Therefore, polysorbate 80 is used as the surfactant of the invention.

Similarly, the preferred solubilizing / stabilizing system of the invention consists of a PEG 400 / TRANSCUTOL ^R / polysorbate 80 mixture.

The compositions according to the invention thus formed are in the form of homogeneous and transparent liquids. They may contain the active compound of the formula I in higher concentrations because of their anhydrous character, whereby the concentrations of the compound a can be up to 150 mg / ml or 15% by weight and in particular 60 mg / ml or 6% by weight. Therefore, low administered volumes, for example 0.5 ml containing up to 30 mg of the active ingredient according to the invention are possible.

These pharmaceutical compositions, spontaneously dispersible in an aqueous medium, can receive water without phase disintegration and are therefore suitable for filling into soft gelatin capsules.

Liquid pharmaceutical compositions have proven to be suitable for oral administration as being capable of increasing the rate of transepithelial permeation with the bioavailability of the active compound of formula I.

The invention also relates to a semi-solid pharmaceutical composition for oral administration comprising:

- a hydrophobic active ingredient of the formula I, usually in a quantity not exceeding 15% by weight, based on the composition as a whole,

a semi-solid solubilization / stabilizing system comprising: either at least one amphiphilic component of the glycol type, selected from the group consisting of propylene glycols having an average molecular weight of 600 to 2000, wherein the system further comprises a number of hydrophilic nonionic surfactants with HLB 12 to 22, preferably 12 to 22 18

or at least one amphiphilic component of the glycol type, selected from the group consisting of propylene glycols having an average molecular weight of 2000 to 10,000, wherein the system further comprises a plurality of such hydrophilic nonionic surfactants with HLBs of 12 to 22, preferably 12 to 18, so formed solubilizing / stabilizing the system is in a semi-solid form,

or a plurality of hydrophilic nonionic compounds simultaneously amphiphilic and surface-active, such as polyglycolised saturated glycerides consisting of a mixture of monoesters, diesters and triesters of glycerol and fatty acids and monoesters and diesters of polyethylene glycol and fatty acids, the system optionally containing at least one hydrophilic nonionic surfactant an HLB of 12 to 22, preferably 12 to 18, and optionally at least one amphiphilic glycol type compound selected from the group consisting of polyethylene glycols having an average molecular weight of 600 to 10,000, for example 600 to 2000 or even 2000 to 10,000.

Generally, at least one polyethylene glycol having a molecular weight of 600 to 2000 is used for such oral compositions.

In this case, amphiphilic solvents PEG 1000, PEG 2000, PEG 6000 or a 50/50 PEG 600 / PEG 1500 mixture by weight are preferred according to the invention. In the case of mixtures of different polyethylene glycols, smaller amounts of polymers than mentioned above may be used in combination with polyethylene glycols in the respective amount.

The polyethylene glycols are selected such that the resulting oral composition is suitable, by its viscosity, for filling devices, for example, to form small capsules.

The surfactant hydrophilic nonionic agents are preferably selected from compounds having an HLB value close to 15. In this regard, polysorbate 80 is selected as a suitable surfactant according to the invention. The surfactant is incorporated into the semi-solid compositions in an amount of at most 20%, preferably at most 12%, based on the composition as a whole.

Thus, the preferred solubilization / stabilizing system of the invention consists of PEG 1000 and polysorbate 80 or a 50/50 PEG 600/1500 weight blend or polysorbate 80 or even PEG 2000 and polysorbate 80.

In addition, the solid and waxy polyglycolized glycerides at ambient temperature are selected such that their melting point is close to the body temperature.

In this regard, the commercial products GELUCIRE * 44-14 and GELUCIRE ^r 50-13, which are mixtures of polyglycolized glycerides with a melting point of 44 and 50 ° C, are suitable, their amphiphilic character being determined by the fatty acid chain and polyethylene glycol fraction and having a suitable hydrophilic surface active character (HLB: 14 and 13).

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

Tests have found that GELUCIRE * 44-14 greatly improves membrane permeability and allows rapid trans-transitel permeation of the compound and approximately twice that of the liquid compositions of the invention in soft capsules. A very slight improvement in bioavailability is also observed, which is similar to the liquid formulations of the invention administered in soft capsules.

The invention also relates to a pharmaceutical soft capsule comprising a liquid pharmaceutical composition as described above for oral administration comprising a hydrophilic active ingredient of the formula I and a solubilizing / stabilizing system.

The pharmaceutical compositions of the invention, containing as the solubilizing / stabilizing system the saturated polyglycolized glycerides described above, are hot-formed in a liquid state and solidified by cooling. Therefore, anhydrous and liquid compounds can be heat incorporated into gelatin hard capsules to form the final semi-solid pharmaceutical composition.

Accordingly, the invention further relates to pharmaceutical gelatin capsules comprising a pharmaceutical semi-solid composition for oral administration as described above.

The pharmaceutical compositions of the invention may be prepared by the conventional method of solubilizing the active compound of formula I in selected solvents or solubilisants to which a hydrophilic nonionic surfactant is added, the various components being in a liquid state.

Optionally, heating is used until the solubilization / stabilization system is fluid. Heating is used in particular when polyethylene glycols with a molecular weight of less than 600 or monoester, diester and triester mixtures of glycerol and fatty acids and monoesters or diesters of polyethylene glycol and fatty acids, in particular GELUCIRE ”44-14 and GELUCIRE * 50-13, are used.

The pharmaceutical compositions of the invention may also be in solid form such as a powder, granules or tablets.

Thus, the invention also relates to a solid pharmaceutical composition for oral administration comprising:

- a hydrophobic active ingredient of the formula I, usually in an amount of not more than 15% by weight, based on the composition as a whole,

- solubilizing / stabilizing system consisting of:

at least one amphiphilic glycol type component selected from the group consisting of propylene glycols having an average molecular weight of 2000 to 10,000, wherein the system further comprises at least one hydrophilic nonionic surfactant with an HLB of 12 to 22, preferably 12 to 18,

- at least one hydrophilic nonionic compound simultaneously amphiphilic and surface-active, such as polyglycolised saturated glycerides consisting of a mixture of monoesters, diesters and triesters of glycerol and fatty acids and monoesters and diesters of polyethylene glycol and fatty acids, the system optionally comprising at least one hydrophilic nonionic surfactant HLB 12 to 22, preferably 12 to 18, and optionally at least one amphiphilic glycol type compound selected from the group consisting of polyethylene glycols having an average molecular weight of 600 to 10,000 and

a pharmaceutically acceptable excipient or carrier.

Like the pharmaceutical semi-solid compositions, the solid pharmaceutical compositions of the invention comprise a surfactant, preferably selected from the group consisting of an HLB value close to 15. The surfactants in the compositions of the invention are therefore polysorbates 20 or 80.

The surfactant is introduced into the solid compositions in an amount of not more than 20%, preferably not more than 12%, by weight of the composition as a whole.

Suitable excipients are incorporated into the surfactant and into the selected solubilization / stabilizing system. Such excipients are selected from the group consisting of lactose, starches, polyvinylpyrrolidone and carboxymethylcellulose.

Thus, the invention also relates to a solid pharmaceutical composition for oral administration in solid form, such as a powder, granules or tablet.

Solid compositions containing various components may be prepared according to the invention in a variety of ways, for example by one or more of the following methods:

(a) mixing the active ingredient components in the form of powder, melting a saturated polyglycol glyceride such as macrogolglyceride or a mixture of polyethylene glycol and a surfactant, granulating the powder mixture with the molten phase and sieving the obtained granules;

b) or the macrogol glyceride or a mixture of polyethylene glycol and a surfactant is melted, the active substance is granulated with the molten phase, the granules formed are sieved and mixed with the remaining excipients,

c) or melting the macrogol glyceride or a mixture of polyethylene glycol and a surfactant, dissolving the active ingredient in this molten phase, admixing the remaining excipients, granulating the excipients and molten phase and sieving the formed granules.

One step in these methods is to obtain a mixture of the active ingredient and the molten macrogolglyceride or molten polyethylene glycol and a surfactant, the mixture optionally containing additional excipients. Such a composition directly constitutes a pharmaceutical semi-solid composition suitable for incorporation into soft capsules.

Generally, however, it is preferred to use the formed granules (according to paragraph a) or c)) or a mixture of granules and excipients (according to paragraph c)) to produce hard gelatine capsules, powders or tablets.

Similarly, granules or mixtures of granules and excipients can be used directly to obtain an oral gelatin capsule composition for incorporation into hard gelatin capsules.

To obtain an oral composition in the form of a powder, the granules or a mixture of granules and excipients can also be crushed and the obtained powder filled into unit sachets.

Optionally, the granules or a mixture of granules and excipients can be compressed into tablets.

Surprisingly, it has been found that the method according to paragraph c) for producing tablets is preferable to the methods according to paragraphs a) and b), since the obtained tablets exhibit dissolution kinetics significantly better than those produced by the two methods.

Tests performed at 37 ^e C in an aqueous medium having a pH of 1.2 with the tablets obtained in the above step c) showed that 15 minutes was dissolved 100% of the active ingredient, whereas for tablets containing the same amount of active ingredient, produced by the process of (a) or (b), less than 50% of the active ingredient is in solution after 60 minutes.

The advantage of the compositions according to the invention is demonstrated by the results of their tests.

1. Evaluation of the penetration of compound and intestinal epithelium

To do this, we will use the living intestinal human cell line "Caco-2" (Crist. Rev. Ther. Drug Carrier System 8 (4), pp. 105-330, 1991). These cells, the peculiarity of which is that they differ in culture to reconstitute the intestinal epithelial model, are used as a model to study the passage of the molecule through the intestinal epithelium and thereby to determine their intestinal absorption.

These Caco-2 cells were coated onto collagen-coated microporous polycarbonate filters. The single-cell layer formed on the filter makes it possible to separate the apical (simulating the intestinal area) from the basal area (simulating the blood circulation).

A composition containing the compound of interest is deposited on the upper side and the passage of the compound, dispersed or dissolved in Hank's environment through this cell barrier is measured by measuring the kinetics of occurrence on the basal side. The aqueous medium with a pH value of 7.4 has the following composition: sodium chloride (8.0 g / l), potassium chloride (0.4 g / l), calcium chloride (0.19 g / l), magnesium chloride ( 0.1 g / l), magnesium sulfate (0.1 g / l), sodium phosphate (0.09 g / l), potassium phosphate (0.06 g / l), sodium bicarbonate (0.35 g / l) ), glucose (1 g / l), phenol red (0.01 g / l).

Calculate the permeability coefficient P in cm / sec, which characterizes the rate of passage of the molecule through the

P = -----------, dt.A.Co where denotes da - change in the amount of test compound passed through the cell monolayer, dt - time function (mol / s),

A - cell monolayer area (cm ² ),

Co - initial compound concentration (mol / l).

The results can also be expressed as a percentage of the tested product that has passed.

First set of exams:

An injectable formulation (hereinafter formulation A) having the composition (percentages are still meant by weight) is tested:

%

compound a 0.40 PEG 400 7.49 polyvinylpyrrolidone polysorbate 80 water Q. S. do Q. S. = sufficient quantity 1.87 1.98 100.00

and comparative agents introduced into the apical region, one consisting of a 100 µm suspension of the compound and in arabic gum (composition I) and the other consisting of the same suspension of the compound and dissolved in the same concentration in dimethylsulfoxide (composition II). The following results are obtained:

means

1% of compound and passed per hour

1.2 ± 0.6

II

A

6.5 ± 0.4

10.5 ± 0.5

These results show a marked improvement in the trans-epithelial permeability of the compound and compared to the control means.

Second group of tests:

The following oral compositions containing Compound a are tested. The following formulations are used by incubating compound a in 50 µl molar amount in Hank's solution.

(a) Concentrated dilutable non-aqueous means

means C D E compound a 2% 2% 2.0% PEG 400 89% - 33.5% Transcutol? - 89% 55,5% Polysorbate 80 9% 9% 9.0%

b) Concentrated dispersible anhydrous compositions

means F G compound a 6% 6% PEG 400 33% 33% TRANSCUTOI? 55% 55% Polysorbate 80 - 6% PLURONIC " 6% -

Formulations C to G are diluted (formulation C to E) or dispersed (formulation F and G) in Hank's environment.

For comparison, also the permeation of the compound and the control means, the compound a is dissolved in the same concentration in dimethylsulfoxide (formulation II) and then dispersed in Hank's environment or compound a (formulation III) is suspended in Hank's environment as well as without surfactant with the following composition:

Compound IV compound and 6%

PEG 400 35% TRANSCUTOL * '59%

The permeability coefficient of the compound a in the control agent suspension (composition III) is evaluated as 1 and the other factors are expressed relative to that control agent. The results are shown in the table.

means

control dilutable dispersible II III C D E F G IV 8.33 1.00 10.8 10.4 10.8 10.8 14.2 5.08 ± 0.78 ± 0.16 ± 1.1 ± 1.2 ± 1.0 ± 1.0 ± 1.2 ± 1.2

These results demonstrate that of the compositions studied, the surfactant-free formulation (formulation IV) does not improve permeability compared to the dimethylsulfoxide solution (formulation II). An improvement over control suspension formulation (formulation III) is evident. This improvement is particularly evident when comparing the surfactant compositions with the suspending agent (composition III), since the permeability is at least ten times.

In general:

both co-solvents tested, namely PEG 400 and PEG 400 / product

TRANSCUTOL ^r contained in bodily diluted formulations. do not * differ in transepithelial transmission,

- it is irrelevant whether the composition is dilutable or dispersible,

the presence of surfactants favorably affects permeability since the permeability coefficient is at least twice that of non-surfactant compositions (composition IV); this beneficial effect of the surfactants is based on their stabilizing and / or supportive effect.

Third group of tests

The formulation H according to the invention applicable to soft capsules is tested:

Formulation H compound a 21 mg PEG 400 294 mg TRANSCUTOL " 21 mg Polysorbate 80 14 mg 350 mg

as compared to compositions having a similar content of compound a but not falling within the scope of the invention.

Composition V: compound and in Hank's suspension

Composition VI: compound a in dimethylsulfoxide and introduced into the culture

Hank's environment

Formulation VII (applicable to gelatin capsule):

compound a 20.00 mg modified corn starch 131.45 mg lactose monohydrate (very fine crystals) 311.75 mg talc anhydrous colloidal silica magnesium stearate

9.60 mg

2.40 mg

4,80 mg

480,00 mg

Said compositions are used by incubating compound a in a 100 µm molar amount of Hank's solution.

The relative percentage of transported compound a on the basal side is determined after six hours and the results are expressed relative to the results of composition V (suspension), evaluated as 1.

means

IN

VI

VII

H

percentage

I, 0 ± 0.4

10.1 ± 0.8

2.8 ± 0.3

II, 2 ± 0.7

These results demonstrate that compositions VI, VII and H improve the permeability of the compound and compared to the suspension of the compound (composition V).

Nevertheless, the improvement for formulation VII useful in a gelatin capsule is much less than that observed for formulation VI dissolved in dimethylsulfoxide. Formulation H, useful in soft capsules, as such allows a very strong improvement in permeability, even higher than that observed with compound solution and dimethylsulfoxide (composition VI).

In addition, the results confirm that the solubilization step has a decisive influence on the trans-epithelial permeability of the compound and that the surfactant promotes absorption while maintaining solubility.

Fourth group of tests

In the case of Caco-2, the following compositions are used in such an amount that Compound a is incubated in 100 µl molar amount of Hank's solution with the addition of taurocholic acid and phospholipid at 37 ° C.

Similarly, the semi-solid compositions L, M and N of the invention and the composition K, not falling within the scope of the invention, are examined in comparison with the liquid composition J of the invention:

means J The L M N compound a 6.0% 6% 6% 6% 6% PEG 400 83.9% - - - - PEG 600 - 47% 45% - - PEG1500 - 47% 45% - - GELUCIRE ”44-14 - - - 94% 88% TRANSCUTOL ^r 6,1% - · - - - Polysorbate 80 4.0% - 4% - -

The permeability coefficient of composition J is evaluated as

1, while the other factors are expressed relative to composition J.

Results obtained:

J

factor

means K L M N

transmissibility

0.67 0.98 1.9

2.45

These results show that the permeability of PEG 400 or 50/50 PEG 600 / PEG 1500 (composition L) does not alter the permeability coefficient measured on Caco-2 cells when the surfactant contained in polysorbate 80 remains in the composition.

It is further evident that the GELUCIRE ® 44-14 based M and N compositions, which allow approximately two times the rate of transepithelial permeability than that of composition J, can be used in soft capsules. In addition, there appears to be slight progression with GELUCIRE * 44-14, which shows a higher concentration of compound and improves membrane permeability in Caco-2 cells.

In particular, the Caco-2 cell assays indicate that the compositions of the invention allow for improved transmembrane permeability compared to control comparatives, without destructive action on the membrane.

II Kinetics of Dissolution of Soft Capsules Containing Compound a

The dissolution kinetics of soft capsules filled with 21 mg of Compound a are investigated on capsules containing 350 mg of Compound H as compared to gelatin capsules in dry form at a dose of 20 mg of Compound and containing 480 mg of Compound VII.

Dissolution is carried out at 37 ° C in hydrochloric acid at pH = 1.2 with stirring at 100 rpm.

The results clearly show an improvement in the dissolution kinetics of the soft capsules over the gelatin capsules: from the opening of the capsule after approximately seven minutes, complete dissolution of compound a is evident, while achieving only 65% dissolution after 15 minutes for the gelatin capsule. Third

In addition, if the dissolution medium of the soft capsules is filtered, it is apparent that all of the compound a is in the form of a microdispersion having a particle size greater than 0.2 µm.

Similar tests carried out with the Compound and vGELUCIRE * 44-14 formulations show a transport rate approximately twice that of the formulation obtained with Form VII.

III In vivo tests on dogs

Plasma dosing is carried out in the case of a dog after oral administration of 20 mg of Compound a, both as a formulation H in a soft capsule and as a formulation VII in a hard capsule. Compared to a hard capsule, administration in the form of a soft capsule containing formulation H is characterized by:

- reducing the variation in plasma,

- three to four times the bioavailability,

- three-fold increased maximum concentration (C max).

IV In vivo tests on humans

The liquid microdisperse formulation H is compared to two other formulations having the same concentration of compound a, introduced into a hard capsule, both with the micronized active ingredient and the non-micronized active ingredient.

Clinical trials are conducted with 24 healthy male volunteers given 100 mg of compound a.

1) fasted in the form of gelatin capsules containing composition VII with a non-micronized compound; and (treatment A)

2) fasted in the form of capsules containing composition VII with a micronized compound and (treatment B)

3) in the form of gelatin capsules containing composition VII with a micronized compound and also as a diet (treatment C)

4) fasted in the form of soft capsules containing composition H (treatment D).

Blood collection is performed 0; 0.25; 0.5; 1; 1.5; 2; 3; 4; 5; 6; 8; 12; 16; 24; 48 and 72 hours after administration, the concentrations of compound α (C max) and the area under compound concentration versus time (AUC) curves were determined.

The results are expressed in relation to the results of treatment A, evaluated as 1.

treatment

C max

AUC

Ratio Ratio

(Ng / ml) (Ng.h / mL) k C max to AUC A 5.5 39,47 1.00 1.00 B 23,26 93.45 4.20 2.40 C 38.12 142.46 6.90 3.60 D 121.31 231.16 22,10 5.0

These results show a very significant increase in the bioavailability of Composition H, namely:

- 22 times C max

6 times the relative bioavailability for the composition of the invention.

The invention is illustrated, but not limited, by the following examples. Parts and percentages are by weight unless otherwise indicated.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Injectable composition comprising a

An injectable formulation of the following composition is prepared:

component Percent compound a 0.40 PEG 400 7.49 PVP COLLIDON * 12 PF 1.87 TWEEN ^R 80 1.98 water to 100.00

and proceed as follows:

First, was prepared a solvent to solubilize the compound, and by mixing 50 parts of PVP 12 PF KOLLIDON ^R containing 25% water to 50 parts PEG-400 to form a solvent consisting of 12.5% PVP Kollidon 12 PF, 37.5% water and 50% PEG 400 .

26 mg of compound per gram of solvent are introduced into the solvent thus prepared and 0.2 g of this aqueous mixture is withdrawn and 0.026 g of polysorbate 80 are added with stirring. 1.074 g of water is added to form an injectable solution which is homogenized at ambient temperature.

Example 2

Soft capsules with compound a

compound a 12.5% PEG 2000 79.5% TWEEN ^r 8,0%

Example 7

compound a 12.5% PEG 2000 79.5%

TWEEN ^R 80 / SPAN ^R 20 (69/31) 8.0%

Example 8

compound a 12.5% PEG 2000 75.5% TWEEN ^R 20 12.0%

Example 9

compound a 12.5% PEG 2000 TWEEN ^r 75.5% 12.0%

Example 10

compound a 12.5% PEG 2000 75.5% TWEEN ^R 80 / SPAN ^R (69/31) 12.0%

Example 11

compound a 12.5% PEG 2000 75.5% GELUCIRE ^r 44-14 12.0%

Example 12

compound a 12.5% PEG 2000 75.5% GELĽICIRE ^r 50-13 12.0%

Example 13 compound and GELUCIRE ^r 44-14 12.5% 87.5% Example 14 compound a 12.5% TWEEN ^r 8.0 GELUCIRE ^r 44-14 79.5% Example 15 compound a 12.5% TWEEN ^r 12.0% GELUCIRE ”44-14 75.5% Example 16 compound a 12.5% GELUCIRE ^R 50-13 87.5% Example 17 compound a 12% TWEEN ^R 80 8% GELUCIRE ^r 50-13 79% Example 18 compound a 12% TWEEN ^r 12% GELUCIRE ^r 50-13 75% Example 19 compound a 6% PEG 400 90% TWEEN ^r 4%

Example 20 compound a 6% PEG 400 90% PLURONIC * F127 4% Example 21 compound a 6% PEG 400 74% PLURONIC ^r F127 20% Example 22 compound a 15% PEG 400 81% PLURONIC ^r F127 4% Example 23 compound a 15,0% PEG 400 65.0% PLURONIC ^r F127 20.0% Example 24 compound a 12.5% PEG 2000 67.5% TWEEN ^r 20.0% Example 25 compound a 12.5% PEG 2000 71,5% TWEEN ^r 16.0% Example 26 compound a 12.5%

PEG 2000 71.5%

TWEEN ^r 80 / SPAN ^r (69/31) 16.0%

Example 27

Tablets with Compound a

Tablets of the following composition are prepared:

mg % compound a 50.00 2.21 lactose monohydrate 690.00 30.46 pregelatinized starch 1002.00 44,23 polyvinylpyrrolidone 58.18 2.57 sodium carboxymethylcellulose 115.10 5.08 GELUCIRE ^r 44-14 350.00 15.45

2,265.28

100.00

At a temperature of about 60 ° C, GEĽUCIRE ^r 44-14 is melted to dissolve compound a. The remaining excipients are mixed and the resulting mixture is granulated with a solution of compound a. The obtained granules are sieved and pressed.

Example 28

Gelatin capsules with compound a

Gelatin capsules of the same composition as in Example 27 are obtained by melting at 60 ° C GELUCIRE ^R 44-14 and melting compound a. The remaining excipients are mixed and the resulting mixture is granulated with a solution of compound a. After sieving, the obtained granules are introduced into gelatin capsules.

Example 29

Tablets with Compound a

Tablets of the following composition are prepared:

mg % wt. compound a 50.00 2.21 lactose monohydrate 690.00 30.46 pregelatinized starch 1002.00 44,23 polyvinylpyrrolidone 58.18 2.57 sodium carboxymethylcellulose 115.10 5.08 PEG 2000 302.00 13.33 TWEEN ^r 48,00 2.12 2,265.28 100.00

At about 60 ° C, PEG 2000 / TWEEN ^R 20 is melted and compound a is melted. The remaining excipients are mixed and the resulting mixture is granulated with a solution of compound a. The granules obtained are sieved and pressed.

Solubility tests at 37 ° C in an aqueous medium of pH 1.2 with the tablets thus obtained showed that the compound a completely dissolved after 15 minutes.

Example 30

Tablets of the following composition are prepared:

mg compound a 50.00 lactose monohydrate 690.00 pregelatinized starch 1002.00 polyvinylpyrrolidone 58.18 sodium carboxymethylcellulose 115.10 PEG 6000 302.00 TWEEN ^R 20 48,00 2,265.28

Example 31

Gelatin capsules containing a

Gelatin capsules of the same composition as in Example 29 were prepared by melting PEG 2000 / TWEEN ^R 20 at about 60 ° C and dissolving compound a in the melt. The remaining excipients are mixed and the resulting mixture is granulated with a solution of compound a. After sieving, the formed granules are introduced into capsules.

Industrial usability

Solubilizing / stabilizing anhydrous system, emulsifiable or microemulsifiable in water for the manufacture of pharmaceutical compositions containing, as an active ingredient, sparingly water-soluble N-sulfonylindoline derivatives.

Claims (29)

PATENT CLAIMS A solubilizing / stabilizing anhydrous system, emulsifiable or microemulsifiable in water, for solubilizing hydrophobic Nsulfonylindoline derivatives of formula I, characterized in that it comprises at least one component selected from the group consisting of an amphiphilic compound, a hydrophilic nonionic surfactant and hydrophilic nonionic amine and surfactant properties, wherein the 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. Solubilization / stabilization system according to claim 1, characterized in that it comprises at least one amphiphilic compound of the glycol type, such as propylene glycol, polyethylene glycols and glycol ethers, wherein the system comprises at least one nonionic surfactant hydrophilic agent. A solubilization / stabilizing system according to claim 1, characterized in that it comprises at least one hydrophilic nonionic compound simultaneously amphiphilic and surface-active, selected from the group consisting of saturated polyglycolized glycerides, a system comprising optionally at least one nonionic hydrophilic surfactant and optionally at least one amphiphilic a glycol type compound. Solubilization / stabilization system according to claim 1 or 2, characterized in that it is liquid and contains at least one or an amphiphilic glycol type compound selected from the group consisting of propylene glycol and polyethylene glycols having an average molecular weight of 400 to 600 and additionally at least one nonionic hydrophilic surfactant. an active agent having an HLB of 12 to 22 and optionally diethylene glycol ether. 5. The solubilization / stabilization system of claim 1 or 2, which is liquid and comprises at least one amphiphilic glycol type compound selected from the group consisting of propylene glycol, polyethylene glycols having an average molecular weight of 400 to 600, and diethylene glycol ethers, additionally containing at least one nonionic. a hydrophilic surfactant having an HLB of 2 to 22. The solubilization / stabilizing system of claim 1 or 2, which is semi-solid and comprises at least one amphiphilic glycol type compound selected from the group consisting of polyethylene glycols having an average molecular weight of 600 to 2000 and an additional at least one nonionic hydrophilic surfactant of HLB 12 to 22. Solubilization / stabilization system according to claim 1 or 2, characterized in that it is semi-solid and contains at least one amphiphilic compound of the glycol type selected from the group consisting of polyethylene glycols having an average molecular weight of 2000 to 10,000 and additionally at least one nonionic hydrophilic surfactant. HLB 12 to 22. Solubilization / stabilization system according to claim 1 or 3, characterized in that it is semi-solid and contains at least one hydrophilic nonionic agent simultaneously amphiphilic and surface-active, which are saturated polyglycolized glyceride derivatives consisting of mixtures of monoesters, diesters and triesters of glycerol and fatty acids and monoesters and diesters of polyethylene glycol and fatty acids, and optionally at least one nonionic hydrophilic surfactant having an HLB of 12 to 22 and optionally at least one amphiphilic polyethylene glycol type compound having an average molecular weight of 600 to 10,000. Solubilization / stabilization system according to claim 1, 2, 4 or 5, characterized in that the amphiphilic compound which is a polyethylene glycol having an average molecular weight of 400 to 600 is polyethylene glycol 400. Solubilization / stabilization system according to claim 1, 2, 6 or 8, characterized in that the amphiphilic compound, which is a polyethylene glycol having an average molecular weight of 600 to 2000, is polyethylene glycol 1000, polyethylene glycol 2000 or a mixture of 50/50 by weight polyethylene glycol 600 and polyethylene glycol 1500. The solubilization / stabilization system of claims 1 to 8, wherein the surfactant is polysorbate 80. Solubilization / stabilization system according to claim 1, 2, 4 or 5, characterized in that the amphiphilic compound which is the glycol ether is diethylene glycol monoalkyl ether having 1 to 4 carbon atoms in the alkyl moiety. The solubilization / stabilization system of claim 12, wherein the C 1 -C 4 diethylene glycol monoalkyl ether is TRANSCUTOL ® diethylene glycol monoethyl ether. Solubilization / stabilizing system according to claim 1, 3 or 8, characterized in that the amphiphilic surfactant is a mixture of monoesters, diesters and triesters of glycerol and monoesters and diesters of polyethylene glycol, a mixture with the trade name GELUCIRE ^r 44-14 or GELUCIRE ^R 50 -13. 15. A pharmaceutical composition microemulsifiable or emulsifiable in an aqueous medium, comprising: - a hydrophobic N-sulfonylindoline derivative according to claim 1, a solubilization / stabilization system according to claims 1 to 14 and optionally an excipient or a suitable pharmaceutical carrier. A pharmaceutical composition according to claim 15 for injection, which comprises it - a hydrophobic N-sulfonylindoline derivative according to claim 1, - solubilization / stabilization system according to claim 4 and having optionally additional properties according to claim 9, 11, 12 or 13 and a suitable pharmaceutical carrier. Pharmaceutical composition according to claim 16, characterized in that the pharmaceutical carrier is water and / or polyvinylpyrrolidone. The pharmaceutical composition according to claim 16 or 17, wherein the hydrophobic N-sulfonylindoline derivative does not exceed 1% by weight of the composition. A pharmaceutical composition according to claim 15, for liquid and oral administration, comprising - a hydrophobic N-sulfonylindoline derivative according to claim 1 - a solubilizing / stabilizing agent according to claim 5 and having optionally additional properties according to claims 9, 11 or 13. 20. A pharmaceutical composition according to claim 15 which is semi-solid and for oral administration which comprises it - a hydrophobic N-sulfonylindoline derivative according to claim 1, - solubilizing / stabilizing agent according to claim 6, 7 or 8 and having optionally additional properties according to claims 10, 11 or 14. A pharmaceutical composition according to claim 19 or 20 wherein the hydrophobic N-sulfonylindoline derivative does not exceed 15% by weight of the composition. Pharmaceutical composition according to claims 16 to 18, characterized in that in the solubilization / stabilization system the diethylene glycol ether does not exceed 50% by weight of the composition. Pharmaceutical composition according to claims 16 to 18, characterized in that in the solubilizing / stabilizing system, the hydrophobic nonionic surfactant does not exceed 4% by weight of the composition. 24. A pharmaceutical composition according to claim 15 which is solid and for oral administration which comprises it - a hydrophobic N-sulfonylindoline derivative according to claim 1, - a solubilization / stabilization system according to claim 7 or 8 and having optionally additional properties according to claims 11 or 14, and a suitable pharmaceutical excipient or carrier. Pharmaceutical composition according to claims 19 to 24, characterized in that in the solubilizing / stabilizing system, the hydrophobic nonionic surfactant does not exceed 12% by weight of the composition. Pharmaceutical composition according to claims 15 to 25, characterized in that the hydrophobic N-sulphonylindoline derivative is (2S) -1 - [(2R, 3S) - (5-chloro-3- (2-chlorophenyl) -1- (3, 2-chlorophenyl)). 4-dimethoxyphenylsulfonyl) -3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl] pyrrolidine-2-carboxamide. A pharmaceutical soft capsule comprising a liquid pharmaceutical composition for oral administration according to claims 19, 21, 25 or 26. A pharmaceutical gelatin capsule comprising a semi-solid pharmaceutical composition for oral administration according to claims 20, 21, 25 or 26. Pharmaceutical composition according to claims 24 to 26, characterized in that it is in the form of a powder, granules or tablets.