EP0941090A1

EP0941090A1 - Pharmaceutical compositions containing n-sulphonyl indolin derivatives

Info

Publication number: EP0941090A1
Application number: EP97950228A
Authority: EP
Inventors: Jean-Claude Gautier; Simon John Fuller
Original assignee: Sanofi SA
Current assignee: Sanofi Aventis France
Priority date: 1996-12-05
Filing date: 1997-12-04
Publication date: 1999-09-15
Also published as: TR199901702T2; NO992724L; CO4910129A1; CA2273990A1; WO1998024430A1; CN1239887A; RU2174394C2; YU23099A; FR2756736B1; MY132819A; SK75599A3; ID23373A; HUP0001386A3; FR2756736A1; NO992724D0; NZ335750A; DZ2362A1; HUP0001386A2; AU716575B2; KR20000069308A

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

Pharmaceutical compositions containing N-Su ^ fonyl indoline derivatives ".

The present invention relates, in general, to new pharmaceutical compositions containing as active principles derivatives of N-sulfonyl indoline.

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

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

By convention, the isomer çjs is called the compounds of formula I in which the 2-chlorophenyl and 2-carbamoyl-pyrrolidinocarbonyl groups are on the same side of the ring.

Conversely, the trans isomer is called the 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 due to the asymmetric carbon represented by the asterisk.

The various 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 patent application EP 0526348. These compounds have revealed an affinity for the receptors for vasopressin and for oxytocin and consequently are useful in particular in the treatment of the central nervous system, of the cardiovascular system and of the gastric sphere.

Among the most representative isomers of this series, there may be mentioned: (2S) 1 - [(2R, 3S) (5-chloro-3- (2-chloroprιenyl) -1- (3,4-dimethoxyphenylsulfonyl) - 3 -hydroxy-2,3-dihydro-1 H-indole-2-carbonyl] -pyrrolidine-2-carboxamide corresponding to the structural formula:

This compound will hereinafter be referred to as "Compound α".

The active principles of formula I, in particular Compound α, are highly hydrophobic products and, for this reason, prove to be very slightly soluble in aqueous medium at physiological pH, that is to say between 1, 2 and 7 , 5.

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

However, this solubilization which can be obtained in organic solvents specific to the substance considered 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. Certain formulations of microemulsion type make it possible to coexist such an organic phase, containing the hydrophobic pharmaceutical substance dissolved, and an aqueous phase.

However, when introduced into pharmaceutical envelopes such as soft capsules, liquid pharmaceutical compositions require an absence 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.

In fact, a pharmaceutical envelope of this type cannot be too large for easy absorption by the patient.

Systems have already been described in the literature allowing the solubilization of particularly hydrophobic pharmaceutical substances with a view to formulating pharmaceutical compositions which can be administered in capsules or soft capsules.

To this end, 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 even mineral oils. Mention may be made, for example, of patent EP 107085 which teaches the use of an oily phase consisting of vegetable oil and a hydrophilic anhydrous hydrosoluble phase formed for example of polyethylene glycols of molecular mass from 300 to 20,000 or alternatively of propylene glycol, glycerol or of their mixtures.

Likewise, in patent GB 1132518, there have been described pharmaceutical compositions containing an active principle 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 cannot be generalized whatever the active substance to be combined.

As proof, orientation tests carried out within the framework of the invention have shown that the active principles of formula I, in particular Compound α, are not or very little soluble in oils.

Consequently, the systems recommended by the state of the art for the solubilization of hydrophobic compounds must, a priori, be excluded with regard to the active ingredients in question. Consequently, the development of an anhydrous pharmaceutical composition and concentrated in hydrophobic compound of formula I, for example Compound α, appears highly desirable and remains of primary interest.

Now, we have now found that it is possible to develop, without a hydrophobic oily phase, an anhydrous, emulsifiable or microemulsifiable pharmaceutical composition containing the active principles of formula I, this composition making it possible to achieve a presentation in particular in tablet form. , hard capsule or soft capsule in which this active ingredient is present in dissolved form in a solubilizing / stabilizing system spontaneously microdispersible in water.

Consequently, a first object of the invention relates to an anhydrous solubilizing / stabilizing system, emulsifiable or microemulsifiable 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 a mixture of an amphiphilic compound and a hydrophilic nonionic surfactant, or at least one nonionic hydrophilic compound endowed with both surfactant and amphiphilic properties. In particular, the invention relates to a solubilizing / stabilizing system as above comprising:

• either one or more constituents chosen from amphiphilic compounds of glycolic type, namely propylene glycol, polyethylene glycols and glycolic ethers (preferably polyethylene glycols and glycolic ethers), the system further comprising one or more hydrophilic nonionic surfactants ,

Or one or more nonionic hydrophilic compounds which are both amphiphilic and surfactants chosen from saturated polyglycolysed glycerides, the system optionally comprising one or more nonionic hydrophilic surfactants, and optionally one or more amphiphilic glycolic type compounds, namely polyethylene glycols.

The solubilizing / stabilizing system of the invention refers in particular to a system comprising at least two different compounds, one acting as 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 even 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 playing both the role of amphiphilic solvent and that of non-ionic hydrophilic surfactant.

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

The amphiphilic solvents mentioned above are generally selected from glycolic-type compounds.

Preferably, they are chosen from one or more polyethylene glycols (PEG) with an average molecular weight of between approximately 400 and approximately 10,000, in particular between approximately 400 and approximately 2000.

In addition, a polyethylene glycol of a given molecular weight can be used alone or alternatively as a mixture with one or more polyethylene glycols of various molecular weight. The polyethylene glycols used in the context of the invention are present at room temperature either in liquid form or in semi-solid form depending on their molecular weight. Consequently, these polymers will be appropriately selected according to whether the desired solubilizing / stabilizing system must be in liquid form or, on the contrary, semi-solid. Among the preferred polyethylene glycols according to the invention, there may be mentioned 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", polyethylene glycol 6000 or "PEG 6000", as well as a 50/50 mixture by weight of polyethylene glycol 600 or "PEG 600" and of polyethylene glycol 1500 or "PEG 1500", all these polyethylene glycols being semi-solid to room temperature, with the exception of PEG-400 as indicated above.

It is also possible to use, within the framework of the invention, specific polyethylene glycol derivatives resulting from the esterification of fatty acid residues with polyethylene glycol and glycerol. The structure of this type of compound, semi-solid at ordinary temperature, first gives it an amphiphilic character, capable of dissolving the active principles of formula I, in particular the

Compound α, owing to the fatty chains and the polyethylene glycol motif which constitute it, then a hydrophilic surfactant character suitable for stabilizing the solution formed during its introduction into an aqueous medium.

Such compounds are chosen from saturated polyglycolysed glycerides also designated macrogolglycerides, that is to say compounds consisting of a mixture of monoesters, diesters and triesters of glycerol and fatty acids, and polyethylene glycol mono and diesters and fatty acids. The most interesting of them are those which have a melting point close to body temperature and whose hydrophilic / lipophilic balance, commonly defined by its "HLB" value reflecting the proportion of hydrophilic groups compared to lipophilic groups of the molecule according to the GRIFIN WC system [J. Soc. Cosm. Chem., 1, 31 1 (1949)], is between 12 and 22, preferably between 12 and 18.

Compounds particularly representative of this series are those sold under the brands GELUCIRE® 44-14 and GELUCIRE® 50-13. The GELUCIRE® 44-14 product also proves to be an excellent solubilizer for Compound α. At 60 ° C, the solubility of this active principle of formula I, determined by the method of additions, is 226 mg / g.

Other glycolic derivatives can be used as solvent or cosolvent in the context of the invention, that is to say amphiphilic compounds endowed with a solubilizing power. Such glycol derivatives are chosen from glycol ethers, in general from diethylene glycol ethers such as a mono (C, -

C ₄ ) diethylene glycol alkyl ether.

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

These products may contain some impurities constituted in most cases by small amounts of diethers and other compounds which appeared during their synthesis. They can nevertheless be used in this form to prepare pharmaceutical compositions. The brand product TRANSCUTOL ^®, diethylene glycol monoethylether extremely pure sold by Gattefosse (FR), is a particularly preferred glycol ether for the purposes of the invention.

Such glycolic ethers can be used alone as an amphiphilic solvent in the solubilizing / stabilizing system of the invention or preferably combined in all proportions with one or more polyethylene glycols of low molecular weight, that is to say between 400 and 600 such as described above where this glycolic ether then plays the role of co-solvent and even of co-surfactant. As for the surfactant, it is generally chosen from non-ionic hydrophilic compounds whose HLB value is between 12 and 22, preferably between 12 and 18.

Surfactants of this type may for example be an ethylene oxide / propylene oxide such as those sold under the trademarks PLURONIC ^® P94 (HLB: 13.5) and PLURONIC ® F127 (HLB: 22), an oil polyethoxylated castor such as that marketed under the brand CREMOPHOR ^® EL (HLB: 13), a non-ethoxylated polysorbate, an ethoxylated polysorbate such as polysorbate 80 (HLB: 15) marketed under the brand TWEEN ^® 80 or MONTANOX ^® 80 DF or polysorbate 20 sold under the trademark TWEEN ^® 20 (HLB: 16.5), or a polyethylene hydroxystearate such as polyethylene hydroxystearate - 660 (HLB: 13) marketed 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, a mixture whose HLB value would also be between 12 and 22, preferably between 12 and 18.

As a preferred surfactant mixture, there may be mentioned a mixture of ethoxylated polysorbate and non-ethoxylated polysorbate such that the final HLB value would be between 12 and 22, preferably between 12 and 18, for example a mixture of polysorbate 80 (HLB: 15 ) and non ethoxylated polysorbate sold under the trade mark SPAN ^® 20 (HLB: 8.6).

Among the solubilizing / stabilizing systems of the invention, those generally consisting of: a) either of an amphiphilic compound chosen from polyethylene glycols of molecular weight between 400 and 600, the system further comprising a nonionic hydrophilic surfactant and optionally a diethylene glycol ether b) or of an amphiphilic compound chosen from polyethylene glycols of molecular weight between 600 and 10,000, for example between 600 and 2000 or even between 2000 and 10,000, the system further comprising a nonionic hydrophilic surfactant c) either of a solubilizing / surfactant compound chosen from saturated polyglycolysed glycerides , the system optionally comprising a nonionic hydrophilic surfactant. As preferred solubilizing / stabilizing systems, according to the invention, the systems formed can be envisaged:

• either PEG 400 and polysorbate 80. • or PEG 400, TRANSCUTOL® product and polysorbate 80.

• either PEG 2000 and polysorbate 80.

• or a 50/50 mixture by weight of PEG 600 / PEG 1500 and polysorbate 80.

• either of saturated polyglycolysed glycerides of the brand GELUCIRE® 44-14 or GELUCIRE® 50-13.

Consequently, the invention relates to an anhydrous solubilizing / stabilizing system emulsifiable or microemulsifiable in water for the solubilization of the N-sulfonyl indoline derivatives of formula I comprising:

Either one or more amphiphilic compounds of glycolic type chosen from propylene glycol, and polyethylene glycols of average molecular weight between 400 and 600, preferably such polyethylene glycols, and further comprising one or more nonionic hydrophilic surfactants of HLB value included between 12 and 22, preferably between 12 and 18, and optionally a diethylene glycol ether, so that the solubilizing / stabilizing system thus formed is in liquid form.

Or one or more amphiphilic glycolic type compounds chosen from propylene glycol, polyethylene glycols of average molecular weight between 400 and 600 and ethers of diethylene glycol such as a mono (C _r C ₄ ) alkyl ether of diethylene glycol, preferably said polyethylene glycols and said diethylene glycol ethers, the system further comprising one or more nonionic hydrophilic surfactants with an HLB value of between 12 and 22, preferably between 12 and 18, such that the solubilizing / stabilizing system thus formed is in liquid form. • either one or more amphiphilic glycolic type compounds chosen from polyethylene glycols of average molecular weight between 600 and 2000, the system further comprising one or more non-ionic hydrophilic surfactants of HLB value between 12 and 22, preferably between 12 and 18, such that the solubilizing / stabilizing system thus formed is in semi-solid form.

Either one or more amphiphilic glycolic type compounds chosen from polyethylene glycols of average molecular weight between 2000 and 10000, the system further comprising one or more nonionic hydrophilic surfactants of HLB value between 12 and 22, preferably between 12 and 18, such that the solubilizing / stabilizing system thus formed is in semi-solid form.

• either one or more non-ionic hydrophilic compounds, both amphiphilic and surfactants, which are saturated polyglycolysed glycerides consisting of mixtures of monoesters, diesters and triesters of glycerol and fatty acids, and polyethylene glycol mono and diesters of acids fatty, the system optionally comprising one or more nonionic hydrophilic surfactants of HLB value between 12 and 22, preferably between 12 and 18 and optionally one or more amphiphilic compounds of glycolic type chosen from polyethylene glycols of average molecular weight between 600 and 10,000, for example between 600 and 2000 or alternatively between 2000 and 10,000, so that the solubilizing / stabilizing system thus formed is in semi-solid form.

As indicated previously, the solubilizing / stabilizing systems of the invention can advantageously serve to solubilize the compounds of formula I so as to form compositions which are dilutable or dispersible in an aqueous medium.

In the case of such solubilizing / stabilizing systems involving one or more amphiphilic solvents such as propylene glycol, a low molecular weight polyethylene glycol, a diethylene glycol ether or their mixtures and also comprising a nonionic hydrophilic surfactant, the proportions can be determined. suitable of the various constituents on a pseudo-ternary phase diagram so as to predict the behavior, in aqueous medium, of compositions formed of a compound of formula I and of a solubilizing / stabilizing system according to the invention. Figures I and 2 in the appendix represent such diagrams on which: a) FIG. 1 shows the behavior of compositions formed from

20mg / ml of compound α in systems solubilizer / stabilizer of the invention, for example mixtures PEG 400 / product TRANSCUTOL ^® and Polysorbate 80. b) is shown in Figure 2 formed compositions of the behavior of

60mg / ml of Compound α in solubilizing / stabilizing systems similar to those envisaged in Figure 1.

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

From the diagram in FIG. 1, it is observed in particular that the relative weight proportions of solubilizing / Compound α mixtures on the one hand and of stabilizer on the other hand, determine a homogeneous zone "A" and a corresponding heterogeneous zone "B" at low concentrations of surfactant. The tangent to this heterogeneous zone "B" materialized by the line "d", carried from the top "WATER 100%", determines on the opposite side a point "P" representing the anhydrous mixtures of solubilizer / Compound α and, in addition , stabilizer or surfactant.

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

In this case, it will be possible to obtain a purely organic formulation of a hydrophobic active principle behaving like a true solution, infinitely dilutable in water.

This upper zone "A", with respect to the line "d", consequently defines solubilizing / stabilizing systems capable of forming solutions concentrated in Compound α. 1 1 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 such concentrated solutions, as shown in Figure 1, the amount of Compound α may reach 20 mg / ml when the amphiphilic solubilizing agent is a mixture PEG 400 / TRANSCUTOL ^® product and the stabilizer is polysorbate 80.

If, on the other hand, it is sought to increase the proportion of active principle of formula I, in particular of Compound α and to decrease that by stabilizing, as shown in FIG. 2, it is observed on the one hand that the multiphase zone widens , that is "B '", and on the other hand that the straight line of dilution in water "d" cuts this heterogeneous zone.

Consequently, obtaining dilutable solutions of Compound α (Compound α in a solubilizing / stabilizing system of the invention) which can be diluted, would require significant quantities of stabilizing agents (greater than 20%) which are not very compatible with a pharmaceutical application.

Solutions concentrated in Compound α whose dilution line intersects the heterogeneous zone "B '" are no longer completely 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 concentrated dispersible solutions (zone B or B ') qualitatively identical but nevertheless comprising lower concentrations of surfactant than concentrated dilutable solutions have qualities similar to those demonstrated with these concentrated dilutable solutions in that they all lead to an improvement in the membrane permeability resulting in an identical increase in the transepithelial passage of the compound of formula I, in particular of the Compound α. This alternative therefore allows greater flexibility since it is not necessary to take into account 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 α, dispersible in water, the concentration of this active principle can be up to 60 mg / ml, a concentration 3 times higher than that of the solution dilutable in water.

Furthermore, it will be noted that even in the case of solutions dispersible in water, these have good aqueous tolerance since they can practically incorporate their weight of water while remaining completely homogeneous.

This feature is of great use during the introduction of such solutions into 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 risk causing it to phase out since the quantity exchanged is less than 10%. The same particularity is observed in maintaining homogeneity when the solution contains up to 5% glycerol, which may be the case when using certain processes for the preparation of pharmaceutical compositions using this trialcool. After drying, the initial solution will be found without these variations having modified its properties. The solubilizing / stabilizing system of the invention capable of solubilizing the hydrophobic active principles of formula I can be validly used with a view to introducing these active principles into pharmaceutical compositions.

Consequently, another subject 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 / stabilizing system as described above

• possibly an appropriate pharmaceutical excipient or 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 more glycolic-type amphiphilic compounds chosen from propylene glycol, polyethylene glycols of average molecular weight included 13 between 400 and 600, and further comprising one or more nonionic hydrophilic surfactants of HLB between 12 and 22, preferably between 12 and 18 such as for example polysorbate 80, and optionally a diethylene glycol ether such as the product TRANSCUTOL® “an appropriate pharmaceutical vehicle.

As suitable pharmaceutical vehicle, is essentially meant water or a physiologically acceptable ketone derivative, the active principles of formula I, in particular Compound α having been shown to be 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 trademark Kollidon ^® 17PF, is a keto derivative of choice to further promote the solubility of the active ingredient of the formula I injectable compositions. In this way, pharmaceutical compositions for administration by injection can be prepared, these compositions not exceeding 10 mg / ml, ie 1% by weight of compound of formula I.

For example, such compositions can contain from 2 to 6 mg / ml of Compound α. 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 saline 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 / stabilizing system in liquid form consisting of one or more amphiphilic compounds, of glycolic type chosen from propylene glycol, polyethylene glycols of average molecular weight between 400 and 600 and ethers of diethylene glycol, (preferably said polyethylene glycols and said diethylene glycol ethers), the system further comprising one or more non-hydrophilic surfactants ionic HLB between 12 and 22, preferably between 12 and 18 such as for example polysorbate 80 or the product brand PLURONIC® P 94. Generally, in the context of such oral compositions, one or more polyethylene glycols of low molecular weight, that is to say between 5 approximately 400 and approximately 600. The polyethylene glycol preferably used is PEG 400.

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

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

As for the nonionic hydrophilic surfactant, it is preferably chosen

15 among compounds having an HLB of 15 or close to 15, and it is generally used at concentrations not exceeding 20%, preferably not exceeding 12% by weight of the final composition. As such, polysorbate 80 constitutes 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 of PEG 400 / TRANSCUTOL® product / polysorbate 80.

The compositions of the invention thus formed are in the form of homogeneous and transparent liquids. They may contain high concentrations of active principle of formula I due to their anhydrous nature, these 5 concentrations being able to reach up to 150 mg / ml or 15% by weight, more particularly 60mg / ml or 6% by weight of Compound α.

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

These pharmaceutical compositions, spontaneously dispersible in an aqueous medium, while being able to accept water without phase shift, become compatible, consequently with a soft capsule type capsule setting.

Furthermore, these liquid pharmaceutical compositions for oral administration have been shown to increase the speed of transepithelial transport as well as the bioavailability of the active principles 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 principle of formula I, generally at a concentration not exceeding 15% by weight of the composition,

5 • a semi-solid solubilizing / stabilizing system comprising: either one or more amphiphilic compounds of glycolic type chosen from polyethylene glycols of average molecular weight between 600 and

2000, the system further comprising one or more nonionic hydrophilic surfactants with an HLB value of between 12 and 22, preferably between 12 and 18,

Either one or more amphiphilic compounds of glycolic type chosen from polyethylene glycols of average molecular weight between 2000 and 10000, the system further comprising one or more hydrophilic nonionic surfactants of HLB value between 12 and 22, preferably

15 between 12 and 18, so that the solubilizing / stabilizing system thus formed is in semi-solid form. either one or more hydrophilic nonionic compounds which are both amphiphilic and surfactants, which are saturated polyglycolysed glycerides consisting of mixtures of monoesters, diesters and triesters of glycerol and 0 of fatty acids, and polyethylene glycol mono and diesters of acids fatty, the system optionally comprising one or more nonionic hydrophilic surfactants of HLB value between 12 and

22, preferably between 12 and 18, and optionally one or more glycolic-type amphiphilic compounds chosen from polyethylene glycols of average molecular weight between 600 and

10,000, for example between 600 and 2000 or even between 2000 and

10,000.

Generally, in the context of such oral compositions, one or more polyethylene glycols of molecular weight between 600 and 2000 are used. As such, PEG 1000, PEG 2000, PEG 6000 or a 50/50 mixture by weight of PEG 600 / PEG 1500 constitute preferred amphiphilic solvents according to the invention.

In the case of mixtures of various polyethylene glycols, it is possible to use small proportions of these polymers situated outside the fixed range previously 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 in terms of 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 constitutes a surfactant of choice for the purposes of the invention. This surfactant will however be incorporated into the semi-solid compositions in question at a concentration not exceeding 20%, preferably not exceeding 12% by weight thereof.

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

In addition, the polyglycolysed glycerides, of solid and waxy consistency at room temperature will be selected in such a way that their liquefaction temperature is close to body temperature. As such, the products marked GELUCIRE ^® 44-14 and GELUCIRE ^® 50-13 constitute mixtures of polyglycolysed glycerides of choice because of their liquefaction temperature of 44 ° C and 50 ° C respectively, of their amphiphilic nature conferred by fatty acid chains and the polyethylene glycol motif and by their favorable hydrophilic surfactant nature (HLB: 14 and 13 respectively). As in the case of the liquid pharmaceutical compositions for oral administration above, the semi-solid pharmaceutical compositions may be administered in a reduced volume given the high solubility of the active principles of formula I in this type of mixture of polyglycolysed glycerides. In addition, it has been observed in experimental tests that the product

GELUCIRE ^® 44-14, in particular, improves the membrane permeability and allows a transepithelial transport speed of the Compound α approximately twice as high as that obtained with the liquid compositions of the invention introduced in soft capsule. Similarly, a very marked improvement in bioavailability was observed, this improvement being analogous to that recorded with the liquid compositions of the invention which can be used in soft capsules.

Consequently, another subject 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 principle of formula I and a solubilizing system / stabilizing.

The pharmaceutical compositions of the invention containing, as solubilizer / stabilizer, saturated polyglycolysed glycerides as described above are hot formed in the liquid state and then solidify by cooling.

Consequently, these anhydrous and liquid compositions can be introduced hot in hard capsules to ultimately form a semi-solid pharmaceutical composition.

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

The pharmaceutical compositions of the invention can be prepared in a conventional manner by dissolving the active principle of formula I in the chosen solvent (s) or solubilizer (s) to which the non-ionic hydrophilic surfactant has been added, these various constituents being in liquid form.

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

This heating operation is particularly indicated when polyethylene glycols of molecular weight> 600 or mixtures of monoesters, diesters and triesters of glycerol and fatty acid, and of polyethylene glycol mono and diesters of fatty acids, in particular the products, are used. GELUCIRE® 44-14 and

GELUCIRE® 50-13.

The pharmaceutical compositions of the invention can also be presented in solid form such as powder, granule or tablet. Consequently, another subject of the invention relates to a solid pharmaceutical composition for oral administration comprising:

• a hydrophobic active principle of formula 1, generally at a concentration not exceeding 15% by weight of the composition

• a solubilizing / stabilizing system comprising: - either one or more amphiphilic compounds, of glycolic type chosen from polyethylene glycol of average molecular weight between

2000 and 10000, the system comprising or in addition to one or more nonionic hydrophilic surfactants of HLB value between 12 and 22, preferably between 12 and 18,

- or one or more non-ionic hydrophilic compounds which are both amphiphilic and surfactants, which are saturated polyglycolysed glycerides consisting of mixtures of monoesters, diesters and triesters of glycerol and fatty acids, and of mono and diester of polyethylene glycol and of fatty acids, the system optionally comprising one or more nonionic hydrophilic surfactants with an HLB value of between 12 and 22 "preferably between 12 and 18, and optionally one or more amphiphilic compounds of glycolic type chosen from polyethylene glycols of average molecular weight included between 600 and 10,000 • ^• an appropriate excipient or pharmaceutical vehicle

As for the semi-solid pharmaceutical compositions, the solid pharmaceutical compositions of the invention will comprise a surfactant preferably chosen from compounds having an HLB close to 15. As such, the polysorbates 20 or 80 constitute surfactants which are particularly advantageous for the purposes of the invention.

This surfactant will however be introduced into the solid compositions in question at a concentration not exceeding 20% by weight thereof, preferably not exceeding 12%.

Furthermore, suitable excipients will be incorporated into the active principle and into the solubilizing / stabilizing system chosen.

Such excipients can be selected from compounds such as for example lactose, starches, polyvinylpyrrolidone, carboxymethylcellulose.

Consequently, the invention also relates to a solid pharmaceutical composition for oral administration, this composition being in the form of a powder, a granule or a tablet.

The solid compositions of the invention can be prepared in various ways, for example by applying one of the methods below from the various ingredients selected: a) mixing all the ingredients in powder form, including the active principle, melting the saturated polyglycolysed glyceride, that is to say the macrogolglyceride or the polyethylene glycol / surfactant mixture, then granulating the powder mixture with the molten phase, and the granules obtained are screened either b) the macrogolglyceride or the polyethylene glycol / surfactant mixture is melted, the active principle is granulated, the granules formed are screened and mixed with the remaining excipients or c) the macrogolglyceride or the polyethylene glycol / surfactant mixture is melted, the active principle is dissolved in this molten phase, the remaining excipients are mixed, this mixture of excipients is granulated with the molten phase and then the granules formed are sieved. One of the steps in these methods consists in obtaining a mixture from the active ingredient and molten macrogolglyceride or polyethylene glycol / molten surfactant, this mixture possibly containing additional excipients.

At this stage, it is possible to use such a mixture for the constitution of semi-solid pharmaceutical compositions by introducing it into soft capsules.

However, it is generally preferred to use the granules formed (paragraph a) or c) above) or the mixture formed of granules and excipients (paragraph c) above) for the constitution of hard capsules, powders or tablets.

Thus, to obtain an oral composition in the form of a capsule, the granules in question or the mixture of granules and excipients in question can be used directly by introducing them into hard capsules.

Likewise, to obtain an oral composition in powder form, these granules or this mixture of granules and excipients can be ground and then the powder obtained is distributed in unitary sachets.

Finally, it is possible, if necessary, to form tablets by direct compression of these granules or of this mixture of granules and excipients. However, it has been noticed quite unexpectedly that method c) above proves to be superior to methods a) and b) for the formation of tablets in that the tablets obtained have a much higher dissolution kinetics than that presented by tablets formed by application of the other two methods.

Thus, tests carried out at 37 ° C. in an aqueous medium of pH = 1, 2 with tablets obtained according to this method c) have shown that after 15 minutes, 100% of the active principle is dissolved, whereas at the start of tablets containing the same amount of active ingredient but obtained according to methods a) or b), there is less than 50% of this active ingredient in solution after 60 minutes.

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

I. Evaluation of the intestinal transepithelium passage of Compound α

For this purpose, an immortalized human cell line of colonic origin was used.

"Caco-2" as described in Crist. Rev. Ther. Drug Carrier System 8 (4), 105-330, 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 a intestinal epithelium and, therefore, to estimate its intestinal absorption.

These Caco-2 cells are seeded on microporous polycarbonate filters coated with collagen. The cell monolayer formed on the filter then makes it possible to separate an apical compartment (mimicking the intestinal lumen) from a basal compartment (mimicking the blood circulation).

The composition containing the compound to be studied is then placed on the apical side and the passage of this compound, dispersed or solubilized in Hank's medium, is evaluated through this cell barrier by measuring its kinetics of appearance on the basal side. This aqueous medium, of pH = 7.4, has the following composition: NaCl = 8.0 g / l; KCI = 0.4g / l; CaCl ₂ = 0.19 g / l; MgCI ₂ = 0.1 g / l; MgS0 ₄ = 0.1 g / l; Na ₂ HP0 ₄ = 0.09g / l; KH ₂ P0 ₄ = 0.06 g / l; NaHC0 ₃ = 0.35 g / l; glucose = 1 g / l; phenol red ^' = 0,01g / l. The coefficient of permeability P is then determined, in cm / sec, which characterizes the speed of passage of the molecule through the membrane, namely:

da

P = dt.A.Co

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

A = surface of the monolayer (cm ² ) Co = initial concentration of the test compound (mole / 1)

We can also express these results in% of tested product transported

1 st series of tests We tested an injectable composition (hereafter Composition A) of formulation:

% by weight Compound α 0.4

PEG 400 7.49

Polyvinylpyrrolidone 1, 87

Polysorbate 80 1, 98

Water QS ^' 100

QS ^* = sufficient quantity, compared to control compositions placed in the apical compartment consisting of one of a 100 μm suspension of Compound α in gum arabic (Composition I), the other of the same Compound α dissolved in the same concentration in dimethyl sulfoxide (Composition II). The following results were obtained: 99

These results show a clear improvement in the transepithelial passage of Compound α compared to the control compositions.

2nd series of tests

The following compositions have been tested for oral administration in which the compound to be studied is Compound α. The compositions below were used so that the compound α is incubated at 50 μmol in Hank's solution.

a) Concentrable anhydrous dilutable compositions

B) Concentrated anhydrous dispersible composition

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 α was also evaluated in control compositions, that is to say that the compound α is dissolved at the same concentration in dimethylsulfoxide (Composition II) and then dispersed in Hank's medium. or the compound α (Composition III) is suspended in Hank's medium as well as the passage of the Compound α in a composition without surfactant of formulation: Composition IV

Compound α 6%

PEG 400 35%

TRANSCUTOL® 59%

The coefficient of permeability of Compound α in the control composition in suspension (Composition III) has been reduced to 1 while the other coefficients have been expressed relative to this control. The following results were obtained:

These results show that among the compositions studied, the formulation devoid of surfactant (Composition IV) does not improve the passage compared to the solution in dimethylsulfoxide (Composition II). However, an improvement is observed compared to the suspension control (Composition III). This improvement is particularly marked when the formulations with the surfactant are compared with the suspension formulation (Composition

III) since the passage is at least multiplied by 10.

In addition, it will be noted that:

• the two co-solvents tested, namely PEG 400 or PEG 400 / TRANSCUTOL® product, present in the dilutable formulations do not differ in terms of transepithelial passage.

• the fact of having formulations which are practically dispersible and not totally dilutable does not appear to be discriminating.

• the presence of the surfactant favorably influences the passage since the permeability coefficient is at least 2 times higher than in the case of the composition without surfactant (Composition IV). This favorable influence of the surfactant is linked to its stabilizing and / or promoter effect.

3rd series of tests We tested Composition H of the invention which can be used in a soft capsule, namely:

Composition H

Compound α 21 mg

PEG 400 294 mg

TRANSCUTOL® 21 mg

Polysorbate 80 14 mg

350 mg and this compared to compositions of similar concentration in Compound α but not included in the invention:

Composition V: Compound α suspended in Hank's culture medium

Composition VI: Compound α dissolved in dimethyl sulfoxide and then introduced into Hank's culture medium Composition VII (usable in capsule): Compound α 20.00 mg

Modified corn starch 131, 45 mg

Lactose monohydrate

(extra fine crystals) 311, 75 mg

Talc 9.60 mg

Colloidal anhydrous silica 2.40 mg

Magnesium stearate 4.80 mg

480.00 mg

The above compositions were used so that Compound α was incubated at 100 μmol in Hank's solution.

The relative percentages of Compound α transported from the basal side at time 6 hours were then determined and the results were expressed relative to the result of the

Composition V (suspension) reduced to 1.

The following results were obtained:

These results show that Compositions VI, VII and H improve the passage of Compound α compared to the suspension of this compound (Composition V). However, the improvement provided by Composition VII which can be used as a capsule is much less than the improvement recorded with Composition VI soluble using dimethyl sulfoxide. Composition H, which can be used in a soft capsule, allows a very strong improvement in the passage, an improvement which even turns out to be greater than that observed with the solution of Compound α in dimethyl sulfoxide (Composition VI). They further confirm that the solubilization step has a decisive impact on the transepithelial passage of Compound α and that the surfactant has an absorption promoting effect while maintaining the solubilized state.

4th series of tests

The compositions below were used on Caco-2 cells in quantities such that Compound α is incubated at 100 μmol in a Hank solution added with taurocholic acid and phospholipid at 37 ° C.

Thus, the semi-solid compositions L, M and N of the invention and a composition K not included in the invention were tested compared to the liquid composition J of the invention, namely:

The coefficient of permeability of the reference Composition J has been reduced to 1 while the other coefficients have been expressed relative to this reference composition. The following results were obtained:

These results show that the transition from PEG 400 to the 50/50 mixture PEG 600 /

PEG 1500 (Composition L) does not modify the measured permeability coefficient 27 on Caco-2 cells, when the surfactant, in this case polysorbate 80, remains present in the composition.

In addition, it is observed that compositions M and N based on GELUCIRE® product

44-14 allow a transepithelial transport speed approximately twice as high as that obtained with Composition J usable in soft capsule.

It even seems that there is room for improvement with the GELUCIRE® product

44-14 which authorizes a higher concentration of Compound α and improves the membrane permeability on Caco-2 cells.

From all the tests carried out on these Caco-2 cells, it has been possible in particular to conclude that the compositions of the invention allow an improvement in the transmambranar passage compared to the reference compositions without causing a destructuring effect on this membrane.

II. Kinetics of dissolution of soft capsules containing the Compound α - The kinetics of dissolution of soft capsules dosed with 21 mg of Compound α, these capsules containing 350 mg of Composition H were determined, compared with those of capsules in dry form dosed with 20 mg of Compound α containing 480 mg of Composition VII.

This dissolution was carried out at 37 ° C. in hydrochloric acid of pH = 1.2, the stirring speed being 100 revolutions / min.

The results show a clear improvement in the kinetics of dissolution of the soft capsules compared to that of the capsules: from the opening of the capsules, ie after 7 min, a total dissolution of the Compound α is observed, while it is only 65% after 15 min in the case of capsules as shown in Figure 3 in the appendix.

In addition, if the medium for dissolving the soft capsules is filtered, it is observed that all of the α compound is in microdispersed form of size <0.2 micron.

Similar tests carried out with formulations of Compound α in the product GELUCIRE® 44-14 have shown a transport speed 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 dogs after oral administration of 20 mg of Compound α either in the form of Composition H introduced in soft capsule or in the form of Composition VII introduced in hard capsule. Compared to the hard capsule, the administration of the soft capsule containing the

Composition H results in:

• decreased variability in plasma levels

• relative bioavailability increased by a factor of 3 to 4

• a maximum concentration (C max) increased by a factor of 3 IV. In vivo human trials

Composition H microdispersible liquid was compared with two other formulations of the same concentration of Compound α introduced in hard capsule, one with micronized active ingredient, the other with non-micronized active ingredient.

To this end, clinical trials were carried out on 24 healthy male volunteers who received 100 mg of Compound α:

1) fasting in the form of capsules containing Composition VII obtained from non-micronized Compound α (Treatment A)

2) fasting in the form of capsules containing Composition VII obtained from micronized Compound α (Treatment B)

3) in the form of capsules containing Composition VII obtained from Micronized Compound α, as well as food (Treatment C)

4) on an empty stomach in the form of soft capsules containing Composition H (Treatment

D)

Blood assays 0 were then performed; 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 α (C max) were then noted as well as the area under the curves defined by the concentration of Compound α as a function of time (AUC).

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

These results show a very significant increase in bioavailability for composition H, namely:

• a C max multiplied by 22

• a relative bioavailability multiplied by 6 5 in favor of the composition of the invention.

The following nonlimiting examples illustrate the preparation of pharmaceutical forms according to the invention:

EXAMPLE 1 Injectable composition of Compound α l o An injectable composition of formulation is prepared

% by weight Compound α 0.4

PEG 400 7.49

PVP KOLLIDON ^® 12 PF 1, 87

TWEEN ^® 80 1, 98

WATER for injection sufficient quantity 100

by applying the following process:

First the solvent for the solubilization of Compound α is prepared by mixing 50 parts of PVP KOLLIDON ^® 12 PF containing 25% water with 50 parts of PEG 400 5 so as to constitute a solvent formed of 12.5% of PVP KOLLIDON ^® 12PF,

37.5% water and 50% PEG 400.

26 mg of Compound α are then incorporated per g of solubilizing solvent thus constituted 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 is then introduced for injection. 0 and homogenized at room temperature.

EXAMPLE 2

Soft capsule of Compound α

Soft capsules are obtained containing a composition of the following formulation: % by weight Compound α 6

PEG 400 83.9

TRANSCUTOL ^® 6.1

MONTANOX ^® 80 DF 4 by applying the following process: First, the solubilizing / stabilizing system is prepared from:

% by weight PEG 400 89.25

TRANSCUTOL ^® 6.5

MONTANOX ^® 80 DF 4.25 then, with mechanical stirring and at room temperature, 60 mg of compound α are incorporated per g of final composition.

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

EXAMPLE 3 Capsule of Compound α Hard capsules are obtained containing a composition of the following formulation:

% by weight Compound α 6

GELUCIRE ^® 44-14 94 by applying the following process:

With magnetic stirring, the Compound α is dissolved directly in the GELUCIRE ^® 44-14 product at controlled temperature (approximately 55 ° C).

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

EXAMPLE 4

Capsule of Compound α

Hard capsules are obtained containing a composition of the following formulation:

% by weight Compound α 6

PEG 600 45

PEG 1500 45

TWEEN ^® 80 4 by applying the following process:

With stirring and at a temperature of 55 ° C., a PEG 600 / mixture is prepared

PEG 1500 50/50 by weight until homogenized.

Is incorporated then produces 42g TWEEN ^® 80 100g of PEG 600 mixture /

PEG 1500 so as to form a product solution TWEEN ^® 80-4% in the PEG mixture 600 / PEG 1500.

The mixture is stirred at 55 ° C. until homogenized and then the Compound α is introduced directly at 55 ° C. into the solubilizing / stabilizing system thus formed.

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

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

EXAMPLE 5

Compound α 12.5%

PEG 2000 79.5%

TWEEN ^® 20 8%

EXAMPLE 6

Compound α 12.5% PEG 2000 79.5% TWEEN ^® 80 8%

EXAMPLE 7

Compound α 12.5% PEG 2000 79.5%

TWEEN ^® 80 / SPAN ^® 20 (69/31) 8%

EXAMPLE 8

Compound α 12.5% PEG 2000 75.5% TWEEN ^® 20 12% EXAMPLE 9

Compound α 12.5% PEG 2000 75.5% TWEEN ^® 80 12%

EXAMPLE 10

Compound α 12.5%

PEG 2000 75.5%

TWEEN ^® 80 / SPAN ^® 20 (69/31) 12%

EXAMPLE 11

Compound α 12.5%

PEG 2000 75.5%

GELUCIRE ^® 44-14 12%

EXAMPLE 12

Compound α 12.5%

PEG 2000 75.5%

GELUCIRE ^® 50-13 12%

EXAMPLE 13

Compound α 12.5%

GELUCIRE ^® 44-14 87.5%

EXAMPLE 14

Compound α 12.5%

TWEEN ^® 80 8%

GELUCIRE ^® 44-14 79.5%

EXAMPLE 15

Compound α 12.5%

TWEEN ^® 80 12%

GELUCIRE ^® 44-14 75.5% 33 EXAMPLE 16

Compound α 12.5%

GELUCIRE ^® 50-13 87.5%

EXAMPLE 17

Compound α 12.5%

TWEEN ^® 80 8%

GELUCIRE ^® 50-13 79.5%

EXAMPLE 18

Compound α 12.5%

TWEEN ^® 80 12%

GELUCIRE ^® 50-13 75.5%

EXAMPLE 19

Compound α 6% PEG 400 90% TWEEN ^® 80 4%

EXAMPLE 20

Compound α 6%

PEG 400 90%

PLURONIC ^® F127 4%

EXAMPLE 21

Compound α 6%

PEG 400 74%

PLURONIC ^® F127 20%

EXAMPLE 22

Compound α 15% PEG 400 81% PLURONIC ^® F127 4% EXAMPLE 23

Compound α 15% PEG 400 65% PLURONIC ^® F127 20%

EXAMPLE 24

Compound α 12.5% PEG 2000 67.5% TWEEN ^® 80 20%

EXAMPLE 25

Compound α 12.5% PEG 2000 71, 5% TWEEN ^® 20 16%

EXAMPLE 26

Compound α 12.5%

PEG 2000 71.5%

TWEEN ^® 80 / SPAN®20 (69/31) 16%

EXAMPLE 27

Compound Tablet α

The following formulation tablets are obtained

by applying the following process:

The GELUCIRE® 44-14 product is melted at around 60 ° C. and then the compound α is dissolved therein. The remaining excipients are then mixed and the mixture obtained is granulated with the solution of compound α. The granules obtained are sieved and compressed.

EXAMPLE 28

Capsule of compound α

Capsules with the same formulation as in Example 27 are obtained by melting the product GELUCIRE® 44-14 at 60 ° C and then dissolving the compound α therein. The remaining excipients are then mixed and the mixture obtained is granulated with the solution of compound α. The sieves are screened and the granules formed are introduced into capsules.

EXAMPLE 29

Compound α tablet

The following formulation tablets are obtained

by applying the following process:

The PEG 2000 / TWEEN®20 mixture is melted at approximately 60 ° C. and then the compound α is dissolved therein. 36 The remaining excipients are then mixed and the mixture formed is granulated with the solution of compound α. The granules obtained are sieved and compressed.

Dissolution tests carried out at 37 ° C. in an aqueous medium of pH = 1.2 with the tablet thus obtained have shown that after 15 minutes, this compound α is completely dissolved.

EXAMPLE 30

Using an identical process, tablets of the following formulation were prepared:

EXAMPLE 31

Capsule of compound α

Capsules with the same formulation as in Example 29 are obtained by melting the PEG 2000 / TWEN®20 mixture, at around 60 ° C and dissolving the compound α therein. The remaining excipients are mixed and the mixture formed is then granulated with the solution of compound α. The sieves are introduced and the granules obtained are introduced into capsules.

Claims

1. Anhydrous solubilizing / stabilizing system, 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 chosen from amphiphilic compounds, nonionic hydrophilic surfactants and nonionic hydrophilic compounds endowed with both amphiphilic and surfactant properties, it being understood that said system comprises either at least one mixture an amphiphilic compound and a nonionic hydrophilic surfactant, ie at least one nonionic hydrophilic compound endowed with both surfactant and amphiphilic properties.

2. Solubilizing / stabilizing system according to Claim 1, characterized in that it comprises one or more amphiphilic compounds of glycolic type chosen from propylene glycol, polyethylene glycols and glycolic ethers, the system also comprising one or more nonionic hydrophilic surfactants .

3. Solubilizing / stabilizing system according to Claim 1, characterized in that it comprises one or more non-ionic hydrophilic compounds which are both amphiphilic and surfactants chosen from saturated polyglycolysed glycerides, the system optionally comprising one or more non-ionic hydrophilic surfactants and optionally one or more glycolic-type amphiphilic compounds.

4. Solubilizing / stabilizing 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 chosen from propylene glycol and polyethylene glycols of average molecular weight between 400 and 600, the system further comprising one or more nonionic hydrophilic surfactants of HLB value between 12 and 22 and optionally a diethylene glycol ether.

5. Solubilizing / stabilizing 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 chosen from propylene glycol, polyethylene glycols of average molecular weight between 400 and 600 and diethylene glycol ethers, the system also comprising one or more nonionic hydrophilic surfactants with an HLB value of between 12 and 22.

6. solubilizing / stabilizing system according to claim 1 or 2, characterized in that it is in semi-solid form and comprises one or more amphiphilic compounds of glycolic type chosen from polyethylene glycols of average molecular weight between 600 and 2000, the system also comprising one or more nonionic hydrophilic surfactants with an HLB value of between 12 and 22.

7. Solubilizing / stabilizing system according to Claim 1 or 2, characterized in that it is in semi-solid form and comprises one or more amphiphilic compounds of glycolic type chosen from polyethylene glycols of molecular weight between 2,000 and 10,000, the system also comprising one or more nonionic hydrophilic surfactants with an HLB value of between 12 and 22.

8. Solubilizing / stabilizing system according to Claim 1 or 3, characterized in that it is in semi-solid form and comprises one or more non-ionic hydrophilic compounds which are both amphiphilic and surfactants which are derived from saturated polyglycolysed glyceride derivatives made up of mixtures monoesters, diesters and triesters of glycerol and fatty acids, and monoesters and diesters of polyethylene glycol and fatty acids, the system optionally comprising one or more nonionic hydrophilic surfactants of HLB value between 12 and 22 and optionally a or several amphiphilic glycolic type compounds chosen from polyethylene glycols of average molecular weight between 600 and 10,000.

9. Solubilizing / stabilizing 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.

10. Solubilizing / stabilizing system according to one of Claims 1, 2, 6 or

8, 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.

11. Solubilizing / stabilizing system according to one of Claims 1 to 8, characterized in that the surfactant is polysorbate 80.

12. Solubilizing / stabilizing 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 (C ^ C alkyl ether of diethylene glycol.

13. Solubilizing / stabilizing system according to Claim 12, characterized in that the mono (CC ₄ ) alkyl ether of diethylene glycol is the monoethyl ether of diethylene glycol of the TRANSCUTOL® brand.

14. Solubilizing / stabilizing system according to one of Claims 1, 3 or 8, characterized in that the compound, both amphiphilic and surfactant, is a mixture of monoesters, diesters and triesters of glycerol, and mono and diesters of polyethylene glycol, mixture of trademark Gelucire® 44-14 or 50-13 Gelucire ^®.

15. Microemulsifiable or emulsifiable pharmaceutical composition in an aqueous medium, 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 1 to 14

• possibly an appropriate pharmaceutical excipient or vehicle.

16. Pharmaceutical composition according to Claim 15 for injectable administration, characterized in that it comprises: • a hydrophobic derivative of N-sulfonyl indoline according to Claim 1

• a solubilizing / stabilizing system as defined in Claim 4 and optionally comprising the additional characteristics of claims 9, 11, 12 or 13.

• an appropriate pharmaceutical vehicle.

17. Pharmaceutical composition according to Claim 16, characterized in that the pharmaceutical vehicle is water and / or a polyvinylpyrrolidone.

18. Pharmaceutical composition according to Claim 16 or 17, characterized in that the hydrophobic derivative of N-sulfonyl indoline does not exceed 1% by weight of the composition.

19. Pharmaceutical composition according to Claim 15 in liquid 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 as defined in Claim 5 optionally comprising the additional characteristics of claims 9, 11 or 13.

20. Pharmaceutical composition according to Claim 15 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 as defined in one of the Claims

6, 7 or 8 and optionally comprising the additional features of claims 10, 11 or 14.

21. Pharmaceutical composition according to Claim 19 or 20, characterized in that the hydrophobic derivative of N-sulfonyl indoline does not exceed 15% by weight of the composition.

22. Pharmaceutical composition according to one of Claims 16 to 18 characterized in that, in the solubilizing / stabilizing system, the diethylene glycol ether does not exceed 50% by weight of the composition.

23. Pharmaceutical composition according to one of Claims 16 to 18, characterized in that the solubilizing / stabilizing system contains a nonionic hydrophilic surfactant at a concentration not exceeding 4% by weight of the composition.

24. Pharmaceutical composition according to claim 15 in 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 7 or 8 and optionally comprising the additional characteristics of claims 11 or 14

• an appropriate pharmaceutical excipient or vehicle.

25. Pharmaceutical composition according to one of Claims 19 to 24, characterized in that the solubilizing / stabilizing system contains a nonionic hydrophilic surfactant at a concentration not exceeding 12% by weight of the composition.

26. Pharmaceutical composition according to one of Claims 15 to 25, 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-2,3-dihydro-1H-indole-2-carbonyl] -pyrrolidine-2-carboxamide.

27. Soft pharmaceutical capsule, characterized in that it contains a pharmaceutical composition in liquid form for oral administration according to one of Claims 19, 21, 25 or 26.

28. Pharmaceutical capsule, characterized in that it contains a pharmaceutical composition in semi-solid form for oral administration according to one of Claims 20, 21, 25 or 26.

29. Pharmaceutical composition according to one of claims 24 to 26, characterized in that it is in the form of a powder, a granule or a tablet.