RU2174394C2 - Pharmaceutical compositions containing derivatives of n-sulfonylindoline - Google Patents

Abstract

FIELD: organic chemistry, medicine, pharmacy. SUBSTANCE: invention relates to compositions designated for parenteral or oral administration. Compositions have derivative of N-sulfonylindole of the formula (I):

Description

 The invention relates to new pharmaceutical compositions containing N-sulfonylindoline derivatives as active principle.

Эти соединения находятся в форме изомеров конфигурации цис- и транс- относительно связи 2,3-индолина.More specifically, the present invention relates to pharmaceutical compositions intended for parenteral or oral administration and containing as an active principle one or more isomers of N- [5-chloro-3- (2-chlorophenyl) -1- (3,4-dimethoxyphenylsulfonyl ) -3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl] pyrrolidine-2-carboxamide of the formula

These compounds are in the form of isomers of the cis and trans configuration relative to the 2,3-indoline bond.

 In this description, cis isomers are compounds of formula I in which the 2-chlorophenyl and 2-carbamoyl-pyrrolidinecarbonyl groups are on the same side of the ring.

 In contrast, trans isomers are compounds of formula I in which the 2-chlorophenyl and 2-carbamoyl-pyrrolidinecarbonyl groups are each on opposite sides of the ring.

 In addition, the compounds of formula I may be in the form of optical isomers, since they have an asymmetric carbon atom (it is marked with an asterisk in the text).

 The various above-mentioned isomers, as well as mixtures thereof, are included in structural formula I.

 The N-sulfonylindoline derivatives in question are known compounds described in patent application EP 0526348. These compounds have an affinity for vasopressin and oocytocin receptors and are therefore suitable, in particular, in the treatment of the central nervous system, cardiovascular systems and diseases of the gastrointestinal tract.

Это соединение будет называться далее "соединением альфа (α)".Of the isomers, the most representative compound of this type is the compound:
(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 of the general formula

This compound will be referred to hereinafter as the "alpha (α) compound".

 The active principles represented by compounds of formula I, in particular compound α, are extremely hydrophobic substances and for this reason they are very slightly soluble in aqueous medium at physiological pH values, i.e. at a pH of 1.2-7.5.

 It is known at the same time that medicinal substances are better absorbed if they are present in dissolved form in pharmaceutical compositions.

 However, this dissolution, which can be achieved in specific organic solvents with respect to a particular substance, must maintain the dissolved state of the molecule when the pharmaceutical composition is diluted in an aqueous medium so that their efficiency is maximized. Some compositions in the form of microemulsions allow the coexistence of such an organic phase containing a dissolved hydrophobic pharmaceutical substance and an aqueous phase.

 However, when they are administered in pharmaceutical coatings, for example in soft capsules, it is necessary that the liquid pharmaceutical compositions not contain water, since the shells of gelatin are incompatible with aqueous media.

 In addition, the pharmaceutical composition would have to be minimized in order to be available in the form of a gelatin or soft capsule, since this type of pharmaceutical shell should not be too large to be easily taken by the patient.

 The literature describes systems that allow the dissolution of extremely hydrophobic pharmaceutical substances to obtain pharmaceutical compositions produced in gelatin or soft capsules.

 Thus, it was proposed to use lipophilic matrices, such as vegetable or animal oils, which, if necessary, can be combined with lubricants, such as fats, waxes or mineral oils.

 For example, reference can be made to patent EP107085, which describes the use of an oil phase consisting of vegetable oil and a hydrophilic anhydrous water-soluble phase consisting, for example, of polyethylene glycols with a molecular weight of 300 to 20,000, or of propylene glycol, glycerol or mixtures thereof.

 In addition, patent GB 1132518 describes pharmaceutical compositions that contain an active principle soluble in benzyl benzoate, the matrix of which is formed by a mixture of benzyl benzoate and a nonionic hydrophilic surfactant, such as polysorbate 80, if desired, vegetable or animal oil and a co-solvent such as polyethylene glycol.

 However, it is well known that matrices proposed for use in pharmaceutical compositions administered in capsules may not be suitable for all active principles with which they are coupled.

 Preliminary studies carried out within the framework of this invention have shown that the active substances of formula I, namely compound α, are insoluble or very slightly soluble in oils.

 Therefore, those systems that are recommended in the prior art for dissolving hydrophobic compounds should be a priori excluded with respect to the active compounds of formula I.

 Therefore, it would be desirable and of great importance to develop an anhydrous pharmaceutical composition with a high concentration of a hydrophobic compound of formula I, in particular compound α.

 The Applicant has found that it is possible to produce an anhydrous pharmaceutical composition, emulsifiable or microemulsifiable, without a hydrophobic oil phase, containing as the active principle a compound of formula I, which composition can be produced in the form of a tablet, hard gelatin capsule or soft capsule, in which this active principle will be present in dissolved form due to the solubilizing-stabilizing system, spontaneously microdispersible in water.

 Thus, the first object of the invention is an anhydrous dissolving stabilizing system, emulsifiable or microemulsifiable in water, for dissolving derivatives of N-sulfonylindoline of the formula I, containing one or more components selected from amphiphilic compounds, nonionic hydrophilic surfactants and nonionic hydrophilic compounds, possessing simultaneously amphiphilic and surface-active properties, and this system contains at least a mixture of one amphiphilic compound and one non-ionic hydrophilic surfactant, or contains at least one non-ionic hydrophilic compound that has both surface-active and amphiphilic properties.

More specifically, the present invention relates to a solvent / stabilizing system, which contains:
either one or more components selected from amphiphilic compounds such as glycols, such as propylene glycol, polyethylene glycols and glycol ethers (preferably polyethylene glycols and glycol ethers), wherein the system further comprises one or more non-ionic hydrophilic surfactants,
- either one or more non-ionic hydrophilic compounds, which are both amphiphilic and surface-active and which are selected from among saturated polyglycolized glycerides, the system may optionally contain one or more non-ionic hydrophilic surfactants, as well as, if desired, one or several amphiphilic glycol-type compounds, in particular polyethylene glycols.

 The specified solvent / stabilizing system according to the present invention relates, in particular, to a system containing at least two different compounds, one of which acts as an amphiphilic solvent or solubilizing agent, and the other as a non-ionic hydrophilic surfactant.

 However, the system may contain more than two compounds, for example several compounds, as amphiphilic cosolvents or several nonionic hydrophilic surfactants.

 Among this group of compounds, at least two different compounds can also be used, of which either one or the other would act as an amphiphilic solvent and a nonionic hydrophilic surfactant.

 In particular, said solvent / stabilizing system may be limited to one non-ionic hydrophilic compound, acting simultaneously as an amphiphilic solvent or solubilizing agent and as a surfactant.

 The above amphiphilic solvents are usually selected from among glycol type compounds. Preferably, they are selected from one or more polyethylene glycols (PEGs) having an average molecular weight of from about 400 to about 10,000, more specifically from about 400 to about 2000.

 The polyethylene glycol of the above molecular weight can be used individually or in a mixture with one or more polyethylene glycols of various molecular demons.

 The polyethylene glycols used according to the invention are at room temperature either in the form of a liquid or in the form of a semi-solid, depending on the molecular weight. Therefore, these polymers are selected so that the desired solvent / stabilizing system would be in liquid form or, conversely, in semi-solid form.

 Among the polyethylene glycols preferably used in this invention, mention may be made, for example, of polyethylene glycol 400 (or "PEG 400"), which is liquid at room 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 polyethylene glycol 1500 (or "PEG 1500"). All of the above polyethylene glycols, with the exception of PEG 400 (as mentioned above), are semi-solid at room temperature.

 In addition, according to the invention, derivatives of certain polyethylene glycols obtained by the esterification of fatty acid residues with polyethylene glycol and glycerol can be used. The structure of this type of compounds in a semi-solid state at ordinary temperature gives, firstly, an amphiphilic character capable of solubilizing the active principles of formula I, in particular compound α, due to the fatty chains and polyethylene glycol unit present in them, and, secondly, hydrophilic surface-active nature, which allows to stabilize the solution formed when the compound is introduced into the aqueous medium.

 Such compounds are selected from among saturated polyglycolized glycerides called “macrogol glycerides”, that is, from compounds that are a mixture of glycerol mono-, di- or triesters and fatty acids, and polyethylene glycol mono- and diesters and fatty acids. Of greatest interest among them are those compounds whose melting point is close to the temperature of the human body and whose hydrophilic-lipophilic balance (HLB) (i.e. the ratio of hydrophilic and lipophilic groups in a molecule, determined by the WCGRIFIN system (J.Soc. Cosm .Chem., 1, 311 (1949)) is 12-22, preferably 12-18.

The most interesting representatives of this group of compounds are compounds marketed under the trademarks GELUCIRE® 44-14 and GELUCIRE® 50-13. GELUCIRE® 44-14 has been found to be an excellent solubilizing agent for compound α. At 60 ^° C., the solubility of this active compound of formula I is 226 mg / g, determined by the additive method.

Other glycol-type derivatives can also be used as solvent or co-solvent, i.e. amphiphilic compounds with solubility. Such glycol derivatives are selected from among glycol ethers, mainly diethylene glycol ethers such as diethylene glycol mono (C _1-4 ) alkyl ether.

 Among diethylene glycol monoesters, methyl and ethyl esters are commercially available, in particular diethylene glycol monoethyl ether.

 These products may contain some impurities, which for the most part are small amounts of diesters and other compounds formed during their synthesis. However, they can be used to obtain pharmaceutical compositions.

 Among glycol ethers, particularly preferred is the product manufactured by the French company Gattefosse with the trademark TRANSCUTOL®, which is a high purity diethylene glycol monoethyl ether.

 Such glycol ethers can be used individually as an amphiphilic solvent in the solvent / stabilizing system according to the invention or, preferably, in combination in any proportions with one or more low molecular weight polyethylene glycols, i.e. from 400 to 600, as indicated above, because glycol ether is a co-solvent and even a surface-active co-agent.

 The surfactant is usually selected from among non-ionic hydrophilic compounds in which the HLB index is in the range from 12 to 22, preferably from 12 to 18.

 Surfactants of this type include, for example, a copolymer of ethylene oxide and propylene oxide, for example, products marketed under the brands PLURONIC® P94 (HLB = 13.5) and PLURONIC® F27 (HLB = 22), polyethoxylated castor oil, for example marketed under the brand CREMOPHOR® EL (HLB = 13), non-ethoxylated polysorbate, ethoxylated polysorbate, for example polysorbate 80 (HLB = 15), marketed under the brand TWEEN® 80 or MONTANOX® 80 DF, or polysorbate 20, marketed under the brand TWEEH® 20 (HLB = 16.5) or polyethylene hydroxystearate, e.g. hydro system of polyethylene-660 with HLB = 13, produced under the brand name SOLUTOL® HS 15.

 In addition, as alternative surfactants according to the invention, mixtures of such nonionic hydrophilic surfactants can be used, the mixture of which gives an HLB value of 12-22, preferably 12-18.

 A preferred surfactant mixture is a mixture of ethoxylated polysorbate with unethoxylated polysorbate, the HLB index of which is from 12 to 22, preferably 12-18, for example a mixture of polysorbate 80 (HLB = 15) and unethoxylated polysorbate of the SPAN® grade (with HLB = 8 , 6).

Of the solvent / stabilizing systems of the present invention, the following are preferred:
a) either a system consisting of an amphiphilic compound selected from polyethylene glycols with a molecular weight of from 400 to 600 and containing an additional non-ionic hydrophilic surfactant and, if necessary, diethylene glycol ether,
b) either a system consisting of an amphiphilic compound selected from polyethylene glycols with a molecular weight of from 600 to 10,000, for example from 600 to 2,000 or from 2,000 to 10,000, and containing an additional non-ionic hydrophilic surfactant,
c) either a system consisting of a solvent / surfactant selected from saturated polyglycolized glycerides and containing, if necessary, a non-ionic hydrophilic surfactant.

The following solvent systems can be mentioned as preferred solvent / stabilizing systems according to the invention:
- either a system consisting of PEG 400 and polysorbate 80,
- either a system of PEG 400, product TRANSCUTOL® and polysorbate 80,
- either a system of PEG 2000 and polysorbate 80,
- either a mixture in a ratio of 50:50 by weight of PEG 600 / PEG 1500 and polysorbate 80,
- either a system of saturated polyglycolized glycerides of the brand GELUCIRE® 44-14 or GELUCIRE® 50-13.

Therefore, the present invention relates to a solvent / stabilizing anhydrous system, emulsifiable or microemulsible in water, for dissolving (solubilizing) N-sulfonylindoline derivatives of formula I, including:
- either one or more glycol-type amphiphilic compounds selected from propylene glycol and polyethylene glycols with an average molecular weight of 400 to 600, preferably polyethylene glycols, and further comprises one or more non-ionic hydrophilic surfactants with an HLB value of 12 to 22, preferably equal to 12-18; and, if necessary, contains diethylene glycol ether, selected so that the dissolving / stabilizing system is in the form of a liquid,
either one or more glycol-type amphiphilic compounds selected from propylene glycol, polyethylene glycols with an average molecular weight of 400 to 600, and diethylene glycol ethers such as diethylene glycol mono (C _1-4 ) alkyl ether, preferably said polyethylene glycols and said ethers diethylene glycol; moreover, the system additionally contains one or more non-ionic hydrophilic surfactants with an HLB value of 12-22, preferably 12-18, selected so that the formed solvent / stabilizing system is in the form of a liquid,
either one or more glycol-type amphiphilic compounds selected from polyethylene glycols with an average molecular weight of 600 to 2000, and further comprises one or more non-ionic hydrophilic surfactants with an HLB value of 12-22, preferably 12-18, selected so that the resulting solvent / stabilizing system is in semi-solid form,
- either one or more glycol-type amphiphilic compounds selected from polyethylene glycols with an average molecular weight of from 2000 to 10000, and further comprises one or more non-ionic hydrophilic surfactants with an HLB value of 12-22, preferably 12-18, selected so that the resulting solvent / stabilizing system is in semi-solid form,
- either one or more non-ionic hydrophilic compounds, which are both amphiphilic and surface-active and are saturated polyglycolized glycerides formed from mixtures of mono-, di- and triesters of glycerol and fatty acids, as well as from mono- and diesters of polyethylene glycol and fatty acids; moreover, this system may, if necessary, contain one or more non-ionic hydrophilic surfactants with an HLB value of 12-22, preferably 12-18, and also, if necessary, contains one or more glycol-type amphiphilic compounds selected from polyethylene glycols with an average molecular weight of from 600 to 10,000, for example from 600 to 2000, or from 2000 to 10000, selected so that the resulting solvent / stabilizing system is semi-solid.

 As indicated above, the solvent / stabilizing systems according to the present invention can be effectively used to dissolve (solubilize) the compounds of formula I and to form compositions capable of diluting or dispersing in an aqueous medium.

 In the case of the use of such solvent / stabilizing systems containing one or more amphiphilic solvents, such as propylene glycol, low molecular weight polyethylene glycol, diethylene glycol ether or mixtures thereof, and also containing an additional non-ionic hydrophilic surfactant, the corresponding amounts of various components can be determined using the diagrams the equilibrium state of three pseudophases and this allows predicting the behavior in the aqueous medium of compositions formed from compounds of pho mules I and of the solvent / stabilizer system according to the invention.

In figures 1 and 2 presents diagrams in which:
a) in FIG. 1 shows the behavior and characteristics of compositions consisting of 20 mg / ml of compound α in the solvent / stabilizing systems of the invention, for example, in mixtures of PEG 400 with TRANSCUTOL® and polysorbate 80.

 b) in FIG. 2 shows the behavior and characteristics of compositions consisting of 60 ml / mg of compound α in dissolving / stabilizing systems similar to those in FIG. 1.

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

 Analyzing the diagram in FIG. 1, it can be seen that the relative weight ratios of the solvent mixture with compound α, on the one hand, and the stabilizing mixture, on the other hand, determine the contours of the homogeneous zone "A" and the heterogeneous zone "B", corresponding to low concentrations of surfactant.

 The tangent drawn to this heterogeneous zone “B” in the form of a straight line “d” from the top of the “100% water” of the triangle forms a point “P” at the intersection of the opposite side of the triangle, which means anhydrous solvent mixtures with compound α, and additionally stabilizing mixtures or mixtures with a surfactant.

 Above point "P", i.e. for elevated surfactant concentrations, these anhydrous mixtures can be diluted with water because the direct "d" corresponding to any of these surfactant concentrations, i.e. the straight line representing their course of dilution does not cross the heterogeneous zone “B”.

 In this case, it is possible to obtain a purely organic composition from a hydrophobic active principle, which will behave as a true solution, which can be diluted to infinity with water.

 Therefore, this upper zone “A”, located above the straight line “d”, defines the solvent / stabilizing systems that are capable of forming concentrated solutions of compound α.

 These highly stable solutions are capable of forming stable microemulsions in the presence of water in the temperature range commonly used for pharmaceutical compositions.

 In these concentrated solutions of FIG. 1, the amount of compound α can reach 20 mg / ml, if the amphiphilic solvent is a mixture of PEG 400 with the product TRANSCUTOL®, and the stabilizing agent is polysorbate 80.

 On the contrary, if it is necessary to increase the amount of the active principle of the formula I, in particular the compound α, while reducing the amount of the stabilizing agent, as shown in FIG. 2, it is observed, on the one hand, the expansion of the polyphase zone "B" and, on the other hand, that a direct dilution in water "d" crosses this heterogeneous zone.

 Therefore, the preparation of concentrated solutions with compound α (compound α in the solvent / stabilizing system according to the invention), such dilute solutions, would require the use of significant amounts (more than 20%) of stabilizing agents that are poorly compatible with pharmaceutical use.

 Solutions with a high content of compound α, the direct dilution of which crosses the heterogeneous zone "B", are no longer fully diluted solutions, but are solutions dispersible in an aqueous medium, i.e. they are concentrated solutions capable of spontaneously forming a more or less thin emulsion when dispersed in water.

 Surprisingly, observations showed that concentrated dispersible solutions (zone B or B '), qualitatively identical, but containing a lower amount of surfactant, in comparison with concentrated diluted solutions, have properties similar to those of diluted concentrated solutions in the sense that those and other solutions improve membrane permeability, which is expressed in the same increase transepithelial transition of the compounds of formula I, in particular compounds α.

 The existence of such an alternative creates greater opportunities for pharmacists, since there is no need to use only systems capable of giving microemulsifying solutions to obtain concentrated solutions.

 Thus, it becomes possible to significantly increase the concentration of the active principle of formula I.

 So, in the case of water dispersible solutions containing compound α, the concentration of this active principle can increase to 60 mg / ml, i.e. reach a concentration three times greater than the concentration of compound α in a solution diluted with water.

 In addition, even in the case of solutions dispersible in water, these solutions have a good susceptibility to water, since they can contain a practically equal amount of water by weight, while remaining absolutely uniform. This feature is very useful when introducing such solutions into soft capsules in the manufacture of pharmaceutical forms, since it is known that during their manufacture exchanges can occur between the contents and its shell.

 Therefore, the water introduced into the solution does not cause a risk of phase separation in it, since the amount of this exchange is less than 10%. The same property to preserve the homogeneity of the solution is observed when the solution contains up to 5% glycerol, which may occur in the case of some methods for the preparation of pharmaceutical compositions, when using a trihydric alcohol. After drying, the properties of the initial solution are preserved.

 The solvent / stabilizing system according to the present invention is capable of dissolving the active hydrophobic compounds of formula I and can be successfully used to introduce these active principles into pharmaceutical compositions.

Accordingly, a second aspect of the invention is a pharmaceutical composition emulsifiable or microemulsifiable in an aqueous medium, which contains:
- active hydrophobic principle of the formula I,
- the above dissolving / stabilizing system,
- if necessary, a pharmaceutically acceptable excipient or carrier.

In particular, the present invention relates to a pharmaceutical composition which is for injection and contains:
- active hydrophobic principle of the formula I,
- a solvent / stabilizing system in the form of a liquid, which consists of one or more glyphic type amphiphilic compounds selected from propylene glycol, polyethylene glycols with an average molecular weight of 400 to 600, as well as one or more non-ionic hydrophilic surfactants having an HLB index, equal to 12-22, preferably equal to 12-18, such as, for example, polysorbate 80 and, if necessary, diethylene glycol ether, such as the product TRANSCUTOL®,
- a pharmaceutically acceptable carrier.

 As a pharmaceutically acceptable carrier, mainly water or a physiologically acceptable derivative of a ketone is understood, the active principles of formula I, in particular compound α, being readily soluble in these organic compounds.

 For this reason, polyvinylpyrrolidone (PYP), preferably polyvinylpyrrolidone sold under the brand name KOLLIDON® 12 PF or under the brand name KOLLIDON® 17 PF, is the preferred ketone derivative capable of increasing the solubility of the active principle of formula I in compositions for injection.

 In this way, pharmaceutical compositions for injection can be prepared in which the compound of formula I does not exceed 10 mg / ml, i.e. 1 wt.% The compounds of formula 1.

  For example, such compositions may contain 2-6 mg / ml of compound α. In addition, they contain a non-ionic hydrophilic surfactant, such as Polysorbate 80, in a concentration not exceeding 4 wt.% Of the final composition.

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

According to one aspect, the present invention relates to a liquid pharmaceutical composition intended for oral administration and containing:
- active hydrophobic principle of the formula I,
- a dissolving / stabilizing system in the form of a liquid, consisting of one or more glycol-type amphiphilic compounds selected from propylene glycol, polyethylene glycols with an average molecular weight of 400 to 600 and diethylene glycol ethers (the above polyethylene glycols and the above diethylene glycol ethers are preferred), and, in addition to containing one or more non-ionic hydrophilic surfactants with an HLB value of 12-22, preferably 12-18, such as, for example, polysorbate 80 or product PLURONIC® P94.

 Typically, one or more polyethylene glycols (PEGs) with a low molecular weight of about 400-600 are used to prepare such compositions for oral administration. PEG 400 is preferably used as polyethylene glycol.

 When using such compositions, polyethylene glycols are usually used in conjunction with one or more diethylene glycol ethers, such as methyl or ethyl ethers. However, diethylene glycol monoethyl ether is preferred as diethylene glycol ether, i.e. TRANSCUTOL® brand product described above.

 These diethylene glycol ethers are used in concentrations preferably not exceeding 50 wt.%, More preferably not more than 20 wt.% Of the final composition.

 The non-ionic hydrophilic surfactant is preferably selected from among substances of this class with an HLB index equal to or close to 15, and usually this substance is used in concentrations not exceeding 20%, preferably 12 weight. % by weight of the final composition. Polysorbate 80 is the most preferred surfactant for the purposes of this invention. Thus, the most preferred solvent / stabilizing system according to the invention is a mixture of PEG 400, TRANSCUTOL® product and Polysorbate 80.

 Thus obtained compositions according to the present invention are in the form of homogeneous and transparent liquids. Since they are anhydrous, they can have a high content of the active principle of formula I, and these contents can reach 150 mg / ml, i.e. 15 wt.%, And, in particular, for compound α, this concentration reaches 60 mg / ml or 6 wt.%.

 This allows you to enter dosage forms in very small volumes, for example 0.5 ml, with an active principle of up to 30 mg.

 These pharmaceutical compositions, spontaneously dispersible in an aqueous medium and capable of taking water without disturbing their phase equilibrium, therefore become compatible with such a coating material as gelatin and can form gelatinous or soft capsules.

 In addition, these liquid pharmaceutical compositions for oral administration are able to increase the rate of transepithelial transition, as well as increase the bioavailability of the active principles of formula I.

According to another aspect, the present invention relates to a semi-solid pharmaceutical composition, which is intended for oral administration and contains:
- active hydrophobic principle of the formula I, usually in a concentration not exceeding 15 wt.% by weight of the composition,
- a semi-solid dissolving / stabilizing system containing:
or one or more glycol-type amphiphilic compounds selected from polyethylene glycols with an average molecular weight of 600 to 2000, the system further comprising one or more non-ionic hydrophilic surfactants with an HLB value of 12-22, preferably 12-18,
or one or more glycol-type amphiphilic compounds selected from polyethylene glycols with an average molecular weight of from 2000 to 10000, the system additionally containing one or more non-ionic hydrophilic surfactants with an HLB value of 12-22, preferably 12-18, as a result, the thus obtained dissolving / stabilizing system is in semi-solid form;
or one or more non-ionic hydrophilic compounds, which are both amphiphilic and surfactants and which are saturated polyglycolized glycerides, consisting of mixtures of mono-, di- and triesters of glycerol and fatty acids, and mixtures of mono- and diesters of polyethylene glycol and fatty acids, moreover, the system, if necessary, contains one or more non-ionic hydrophilic surfactants with an HLB value of 12-22, preferably 12-18, and also, if not bhodimosti comprises one or more amphiphilic compounds of the glycol type, selected from polyethylene glycols having an average molecular weight from 600 to 10,000, for example from 600 to 2,000, or from 2,000 to 10,000.

 Typically, in the manufacture of such compositions for oral administration, one or more polyethylene glycols with a molecular weight of from 600 to 2000 are used.

 Thus, the preferred amphiphilic solvents according to the invention are PEG 1000, PEG 2000, PEG 6000, or a 50:50 mixture by weight of PEG 600 and PEG 1500.

 In the case of mixtures of various polyethylene glycols, small amounts of polymers outside the above range may be used in combination with polyethylene glycols within the above range. However, polyethylene glycols should be selected so that the final composition for oral administration is compatible in terms of viscosity with the requirements of filling equipment, such as soft capsule filling equipment.

 As for the nonionic hydrophilic surfactant, it is preferably selected from compounds with an HLB index close to 15. In this regard, polysorbate 80 is most suitable. However, the amount of this surfactant introduced into the composition of these semi-solid compositions should not exceed 20%, preferably 12% by weight of the weight of the final composition.

 Thus, the solvent / stabilization system used preferably consists of PEG 1000 and Polysorbate 80, or a 50:50 mixture by weight of PEG 600 and PEG 1500, or a 50:50 mixture by weight of PEG 600 and Polysorbate 80, or a similar mixture PEG 2000 with Polysorbate 80.

 In addition, polyglycolized glycerides having a solid or waxy consistency at room temperature are chosen so that their dilution temperature is close to the temperature of the human body.

In this regard, products of the CELUCIRE® 44-14 and CELUCIRE® 50-13 brands are the most preferred mixtures of polyglycolized glycerides, since their dilution temperature is 44 ^° C and 50 ^° C, respectively, they are amphiphilic due to the presence of chains of fatty acids and polyethylene glycol unit, and due to the fact that they have a favorable hydrophilic surface-active character (HLB index of 14 and 13, respectively).

 Like the above-described liquid pharmaceutical compositions for oral administration, semi-solid pharmaceutical compositions can be administered to patients in a reduced volume due to the high solubility of the active principles of formula I in said mixture of polyglycolized glycerides.

 In addition, as a result of experiments, it was noted that the product CELUCIRE® 44-14, in particular, increases membrane permeability and allows to increase the rate of transepithelial transfer of compound α by about two times, compared with the rate that is achievable with the introduction of liquid compositions introduced into soft capsules.

 In addition, a marked increase in the bioavailability of the active principles was noted, and this increase is similar to what was noted in relation to the liquid compositions according to the invention when taken in soft capsules.

 Therefore, another object of the present invention is a soft pharmaceutical capsule containing the specified liquid pharmaceutical composition for oral administration, i.e. capsule containing a hydrophobic active principle of the formula I and a dissolving / stabilizing system.

 Pharmaceutical compositions containing the above-described saturated polyglycolized glycerides as a solvent / stabilizer are prepared by heating in a liquid state and solidify upon subsequent cooling. Therefore, these anhydrous and liquid compositions can be introduced hot in hard gelatine capsules, ultimately obtaining a semi-solid pharmaceutical composition.

 Accordingly, another object of the present invention is a gelatin pharmaceutical capsule containing the semi-solid pharmaceutical composition for oral administration described above.

 The pharmaceutical compositions of the invention can be prepared in a conventional manner by dissolving the active principle of formula I in one or more selected solvents or solubilizing agents to which a non-ionic hydrophilic surfactant is added, all of which are in a liquid state.

 If necessary, the solvent / stabilizing system is heated until a liquid mixture is obtained. Such heating is especially recommended when using polyethylene glycols with a molecular weight of more than 600, or a mixture of mono-, di- and triesters of glycerol and fatty acids and mono- and diesters of polyethylene glycol and fatty acids, in particular CELUCIRE® 44- products 14 and CELUCIRE® 50-13.

 The pharmaceutical compositions of the invention may also be in the form of powders, granules and tablets.

Accordingly, another object of the present invention is a solid pharmaceutical composition for oral administration, which contains:
- active hydrophobic principle of the formula I, usually in a concentration not exceeding 15 wt.% by weight of the final composition,
- a solvent / stabilizing system containing:
or one or more glycol-type amphiphilic compounds selected from polyethylene glycols with an average molecular weight of from 2000 to 10000, the system further comprising one or more non-ionic hydrophilic surfactants having an HLB value of 12-22, preferably 12-18,
or one or more non-ionic hydrophilic compounds that are both amphiphilic and surface-active and which are saturated polyglycolized glycerides consisting of mixtures of mono-, di- and triesters of glycerol and fatty acids, and mono- and diesters of polyethylene glycol and fatty acids moreover, the system, if necessary, may contain one or more nonionic hydrophilic surfactants with an HLB value of 12-22, preferably 12-18, as well as, if necessary spine, one or several amphiphilic compounds of the glycol type, selected from polyethylene glycols having an average molecular weight from 600 to 10,000,
- a pharmaceutically acceptable excipient or carrier.

 As in the case of the semi-solid pharmaceutical compositions described above, the solid pharmaceutical compositions contain a surfactant, preferably selected from compounds having an HLB index close to 15. In this regard, polysorbates 20 or 80 are surfactants that are most suitable for the purposes of the present inventions.

 The specified surfactant is introduced into the proposed solid composition in a concentration not exceeding 20 wt.% By weight of the composition, preferably not exceeding 12 wt.%.

 In addition, suitable excipients are added to the active principle and to the selected solvent / stabilizing system. Excipients are selected from compounds such as, for example, lactose, starches, polyvinylpyrrolidone, carboxymethyl cellulose.

 So, the present invention also relates to a solid pharmaceutical composition for oral administration, and this composition may be in the form of powders, granules or tablets.

The proposed solid compositions can be manufactured in various ways, for example, using one of the methods described below, based on various selected components:
or
a) the components are mixed together in powder form, including the active principle, the saturated polyglycolized glyceride is melted, i.e. macrogol glyceride, or a mixture of polyethylene glycol with a surfactant, then granulate a mixture of powders with a molten phase and finally sift the resulting granules,
or
b) melt the macrogol glyceride or a mixture of polyethylene glycol with a surfactant, granulate the active principle with the molten phase, sift the resulting granules and mix them with the remaining excipients,
or
c) macrogol glyceride or a mixture of polyethylene glycol with a surfactant is melted, the active principle is dissolved in the obtained molten phase, the remaining excipients are mixed, this excipient mixture is granulated with the molten phase, and the resulting granules are sieved.

 One of the operations in all of these methods is to obtain a mixture of the active principle with molten macrogol-glyceride or with a molten mixture of polyethylene glycol and a surfactant, moreover, if necessary, this mixture may contain additional excipients.

 At this stage of the process, the resulting mixture can be used to prepare semi-solid pharmaceutical compositions by introducing the mixture into soft capsules. However, as a rule, it is preferable to use the obtained granules (see method a) or c)) or a mixture of granules and excipients (method c)) for the manufacture of hard gelatine capsules, powders or tablets.

 So, to obtain a composition for oral administration in the form of gelatin capsules, granules or a mixture of granules with excipients can be directly used, filling them with hard gelatin capsules.

 Similarly, to obtain an oral composition in powder form, you can grind these granules or this mixture of granules with excipients and pack the resulting powder in disposable bags.

 And finally, if necessary, tablets can be formed by direct compression of these granules or this mixture of granules with excipients.

 However, it was unexpectedly found that method c) is preferred over methods a) and b) in the manufacture of tablets for the same reason that tablets obtained by method c) have much more favorable dissolution kinetics than tablets obtained by the other two ways.

Thus, experiments carried out at 37 ^o C in an aqueous medium at pH 1.2, with tablets obtained by method c) showed that after 15 minutes, 100% of the active principle was dissolved, while in tablets obtained by methods a) and b ) and containing the same amount of active principle, after 60 minutes less than 50% of this active principle passed into solution.

 The properties and advantages of the proposed compositions will become more apparent in light of the following description of specific compositions given as examples.

1. Assessment of the ability of compound α to penetrate intestinal epithelial tissues
A line of human cells taken from the human colon was used for these studies.

 The investigated cell culture is called "Saso-2" and is described in the journal Crist. Rev. Ther. Drug Carrier System 8 (4), 105-330, 1991. These cells, which have the ability to differentiate in culture and recreate the model of intestinal epithelium, were used as a model to study the passage of a molecule through the intestinal epithelium and, therefore, to evaluate its absorption by the intestines.

 Caco-2 culture cells were plated on microporous filters made of polycarbonate and coated with a layer of collagen. The cell monolayer formed on the filter allows you to separate the apical section (which simulates the opening of the intestine into the lumen) from the base section (simulating blood circulation).

Then, from the apical part of the layer, a composition containing the compound to be studied is placed and the passage of this compound, dispersed or dissolved in the Hank medium, through the cell barrier is evaluated by measuring the kinetics of the appearance of this compound on the base side of the layer. The aqueous medium used has a pH of 7.4 and the following composition: NaCl = 8.0 g / l; KCl = 0.4 g / l; CaCl ₂ = 0.19 g / l; MgCl ₂ = 0.1 g / l; MgSO ₄ = 0.1 g / l; Na ₂ HPO ₄ = 0.09 g / l; KH ₂ PO ₄ = 0.06 g / l; NaHCO ₃ = 0.35 g / l; glucose = 1 g / l, phenol red = 0.01 g / l.

в которой da/dt = изменение количества изучаемого соединения, проходящего через моноклеточный слой в зависимости от времени, моль/сек,
А = площадь монослоя, см²,
Co = начальная концентрация изучаемого соединения, моль/л.Then determine the coefficient of permeability P, cm / sec, characterizing the speed of passage of the molecule through the membrane according to the formula

in which da / dt = change in the amount of the studied compound passing through the monocellular layer depending on time, mol / s,
A = monolayer area, cm ² ,
Co = initial concentration of the studied compound, mol / L.

 You can also express these results in% of the studied compounds that have passed through the membrane.

 The first series of experiments.

The object of the experiment was the composition for injection (referred to below as Composition A) of the following composition, wt.%:
Compound α - 0.4
PEG 400 - 7.49
Polyvinylpyrrolidone - 1.87
Polysorbate 80 - 1.98
Water - Up to 100
The experiment was carried out in comparison with control compositions placed in the apical part of the layer, one of which (Composition I) was a suspension of 100 μm of compound α in gum arabic, and the other (Composition II) was a solution of the same amount of compound α in dimethyl sulfoxide.

The following results were obtained:
Composition -% transfer of compound α per hour
I - 1.2 ± 0.6
II - 6.5 ± 0.4
A - 10.5 ± 0.5
These results clearly show an improvement in the passage of compound α through epithelial tissues compared to control compositions.

Second series of experiments
The object of these experiments were the following compositions for oral administration, in which the studied compound was compound α. The following compositions were used so that compound α was incubated at 50 μm in a Hank solution.

 a) Concentrated anhydrous dilutable compositions are given in table. 1.

b) Concentrated anhydrous dispersible compositions are given in table. 2
Then the CE compositions were diluted with Hank medium, and compositions F and G were dispersed in this medium.

As a comparison, the passage of compound α in the control compositions was evaluated; for this, compound α was dissolved in the same concentration in dimethyl sulfoxide (Composition II) and then dispersed in Hank medium, or compound α was suspended in Hank medium (Composition III), and patency was also evaluated compounds α in a composition not containing a surfactant of the following composition:
Composition IV
Compound α - 6%
PEG 400 - 35%
TRANSCUTOL®. - 59%
The permeability coefficient P of compound α in the control composition in the form of a suspension (Composition III) was taken as unity, other corresponding coefficients were expressed in relation to this control composition.

 The following results were obtained (table. 3).

 The results obtained show that, among the studied compositions, Composition IV, which does not contain a surfactant, does not improve the permeability of compound α in comparison with a solution in dimethyl sulfoxide (Composition II), but an improvement is noted in comparison with the control Composition III in the form of a suspension. This improvement is especially pronounced when comparing surfactant containing compositions with Composition III in suspension form, as permeability is increased by at least 10 times.

In addition, the following should be noted:
- both co-solvents studied, namely: PEG 400 or PEG 400 / TRANSCUTOL® product present in dilutable compositions, do not differ from each other in the sense of passage of compound α through the epithelium,
- the fact that some compositions are practically dispersible, but not completely dilutable, does not create a difference between them;
- the presence of a surfactant favorably affects the passage of compound α through the epithelium, since the permeability coefficient is at least doubled compared to a composition that does not contain a surfactant (Composition IV). This beneficial effect of the surfactant is associated with its stabilizing and / or promoting effect.

Third series of experiments
The Composition H of the invention, administered in a soft capsule, was studied. Its composition is as follows:
Composition H
Compound α - 21 mg
PEG 400 - 294 mg
TRANSCUTOL® - 21 mg
Polysorbate 80 - 14 mg - 350 mg
For comparison, we used compositions with a similar concentration of compound α, but not corresponding to the invention:
Composition V: compound α suspended in Hank culture medium,
Composition VI: compound α dissolved in dimethyl sulfoxide, then introduced into the Hank culture medium.

Composition VII (used in a gelatin capsule):
Compound α - 20.00 mg
Modified Corn Starch - 131.45 mg
Lactose Monohydrate (extra-fine crystals) - 311.75 mg
Talcum - 9.60 mg
Anhydrous Colloidal Silicon Dioxide - 2.40 mg
Magnesium Stearate - 4.80 mg - 480.00 mg
In the above compositions, compound α was incubated at a concentration of 100 μm in a Hank solution.

 Then, the relative percentage of the transition of compound α to the base side of the layer was determined within 6 hours and the results were expressed in relation to the result obtained with Composition V (suspension), taken as a unit.

The following results were obtained:
Composition -% Transfer
V - 1.0 ± 0.4
VI - 10.1 ± 0.8
VII - 2.8 ± 0.3
H - 11.2 ± 0.7
The results show that Compositions VI, VII and H improve the passage of compound α compared to a suspension containing this compound (Composition V).

 However, the improvement achieved with Composition VII used in a gelatin capsule is less than the improvement noted with Composition VI soluble in dimethyl sulfoxide. As for Composition H used in a soft capsule, it dramatically improves the permeability of compound α, and this improvement even surpasses that achieved with a solution of compound α in dimethyl sulfoxide (Composition VI).

 In addition, these results confirm that the dissolution step is critical for the passage of compound α through the epithelium and that the surfactant does create a promoting effect upon absorption of the compound, while maintaining the dissolved state.

Fourth series of experiments
The following compositions were studied in Caco-2 cell culture in such quantities that compound α was incubated at a concentration of 100 μm in a Hank solution, to which taurocholic acid and phospholipid were added at 37 ^° C.

 We studied the semi-solid compositions L, M, and N according to the invention and composition K not corresponding to the invention, and compared with the liquid composition according to the invention (Table 4).

 The permeability coefficient of the reference Composition J was taken as unity, while all other coefficients were expressed with respect to this reference composition.

 The following results were obtained (table. 5).

 The results show that the transition from the use of PEG 400 to the use of a mixture of 50:50 PEG 600; PEG 1500 (Composition L) does not change the permeability coefficient measured on a Caco-2 culture if a surfactant is present in the composition (in this case, Polysorbate 80).

 In addition, it was noted that Compositions M and N based on the GELUCIRE® 44-14 product can almost double the rate of passage through the epithelium compared to Composition J used in a soft capsule. It seems that even the GELUCIRE® 44-14 product creates even greater advantages, since it allows increasing the concentration of compound α and improving the membrane permeability of Caco-2 cells.

 Based on all tests conducted on Caco-2 cell cultures, it can be concluded that the compositions of the invention improve membrane permeability compared to reference compositions without causing membrane damage.

II. Dissolution kinetics of soft capsules containing compound α
The dissolution kinetics of soft capsules containing 21 mg of compound α were studied, these capsules containing 350 mg of Composition H, and compared with the dissolution kinetics of dry gelatin capsules containing 20 mg of compound α, and capsules containing 480 mg of Composition VII.

Dissolution was carried out at 37 ^° C. in hydrochloric acid with a pH of 1.2 with a stirring speed of 100 rpm.

 The results indicate a clear improvement in the dissolution kinetics of soft capsules compared to gelatin capsules: after opening the capsules after 7 minutes, complete dissolution of compound α was observed, whereas in the case of gelatin capsules, only 65% dissolution was achieved after 15 minutes, as shown in FIG. 3.

 In addition, if you filter the liquid medium formed after dissolution of the soft capsules, it is observed that the entire amount of compound α is in a microdispersed state with a particle size of less than 0.2 microns.

 Similar studies conducted with compositions based on compound α found in the GELUCIRE® 44-14 product showed a transfer rate of almost twice that of Composition VII.

Ill. In vivo experiments on a dog
The plasma of the dog was examined, which was orally administered with 20 mg of compound α, either in the form of Composition H in a soft capsule or in the form of Composition VII in a hard gelatin capsule.

Reception of a soft capsule containing, in comparison with the reception of a hard gelatin capsule, gave the following results:
- reduction of changes in plasma parameters,
- relative bioavailability increased by 3-4 times,
- the maximum concentration (C _max ) increased 3 times.

IV. In vivo human experience
The liquid microdispersible Composition H was compared with two other compositions having the same concentration of compound α and enclosed in a hard gelatin capsule, one of these compositions containing a micronized active principle and the other a non-micronized active principle.

To this end, conducted clinical trials on 24 healthy male volunteers who took 100 mg of compound α:
1) on an empty stomach in the form of gelatin capsules containing Composition VII obtained with non-micronized compound α (treatment A),
2) on an empty stomach in the form of gelatin capsules containing Composition VII obtained with micronized compound α (treatment B),
3) in the form of gelatin capsules containing Composition VII, obtained with 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).

Then, blood tests were performed after 0; 0.25; 0.5; 1; 1.5; 2, 3, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours after taking the capsules. Next, we measured the maximum concentrations (C _max ) of compound α, and also measured the area under the curves depicting the concentration of compound α as a function of time (parameter AUC).

 All the results were expressed in relation to the result of treatment A, which is accepted per unit (table. 6).

The results indicate a very significant increase in the bioavailability coefficient in the case of taking Composition H, namely;
- indicator C _max increased by 22 times,
- relative bioavailability increased 6 times.

 All this speaks in favor of the proposed composition. The following examples, which are not restrictive, illustrate the preparation of pharmaceutical forms according to the present invention.

EXAMPLE 1. Composition with compound α for injection
Prepare an injectable composition of the following composition, wt.%:
Compound α - 0.4
PEG 400 - 7.49
PVP KOLLIDON® 12 PF - 1.87
Twin 80 - 1.98
Water for injection - Up to 100
According to the following procedure:
first, a solvent is prepared to dissolve the compound α by mixing 50 parts of PVP KOLLIDON® 12 PF containing 25% water with 50 parts of PEG 400 so that the resulting solution contains 12.5% PVP KOLLIDON® 12 PF, 37.5% water and 50% PEG 400. Then 26 mg of compound α per 1 gram of the obtained solvent is introduced, 0.2 g is taken from this mixture and 0.026 g of polysorbate 80 is added to them with stirring. Then, 1.074 g of water of the injected preparation is added and homogenized at room temperature.

EXAMPLE 2. Soft capsule with compound α
Soft capsules are prepared containing a composition of the following composition, wt.%:
Compound α - 6
PEG 400 - 83.9
TRANSCUTOL® - 6.1
MONTANOX® 80 DF - 4
According to the following procedure:
First, a dissolving / stabilizing system is prepared, based on the following components, wt.%:
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 per 1 g of the final composition is introduced. After dissolution, the finished composition is administered in soft capsules.

EXAMPLE 3. Gelatin capsule with compound α
Hard gelatin capsules are prepared containing a composition of the following composition, wt.%:
Compound α - 6
GELUCIRE® 44-14 - 94
To do this, with magnetic stirring, dissolve the compound α directly in the product GELUCIRE® 44-14 at a controlled temperature (about 55 ^o C). After dissolution, the gelatin capsules are filled with the finished composition and cooled.

EXAMPLE 4. Gelatin capsule with compound α
Hard gelatin capsules are prepared containing a composition of the following composition, wt.%:
Compound α - 6
PEG 600 - 45
PEG 1500 - 45
TWIN® 80 - 4
Using the following procedure: with stirring and at a temperature of 55 ^o C prepare a mixture of 50:50 by weight of PEG 600 and PEG 1500, after which the mixture is homogenized. Then, 42 g of TWIN® 80 product are introduced per 100 g of a mixture of PEG 600 / PEG 1500 so that
in order to obtain a solution containing 4% of TWIN® 80 product in a PEG 600 / PEG 1500 mixture. The mixture was stirred at 55 ^° C until homogenization, after which, at a temperature of 55 ^° C, compound α was introduced directly into the resulting solvent / stabilizing system.

 Using the techniques described above in Examples 2-4, soft capsules or gelatin capsules containing the compositions of the following composition were prepared.

 The content is indicated in wt.% By weight of the final composition.

 EXAMPLE 5

Compound α - 12.5%
PEG 2000 - 79.5%
TWIN® 20 - 8%
EXAMPLE 6

Compound α - 12.5%
PEG 2000 - 79.5%
TWEEN® 20 - 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® 20 - 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%
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. Tablets with compound α
Get tablets of the following composition (table. 7).

 The tablets were prepared by the following method.

The GELUCIRE® 44-14 product is melted at 60 ^° C. and compound α is dissolved in the resulting melt. The remaining excipients are mixed and the resulting mixture is granulated with a solution of compound α. Sieve the obtained granules and compress.

EXAMPLE 28. Gelatin capsules with compound α
Gelatin capsules of a composition identical to the composition of the tablets of Example 27 are obtained. For this, the GELUCIRE® 44-14 product is melted at 60 ^° C and compound α is dissolved in the melt obtained. The remaining excipients are mixed and the resulting mixture is granulated with a solution of compound α. The granules obtained are sieved and filled with gelatin capsules.

EXAMPLE 29. Tablets, the content of the compound α
Get tablets of the following composition (table. 8).

 Tablets are made as follows.

A mixture of PEG 2000 and product TWEEN® 20 is melted at 60 ^° C. and compound α is dissolved in the resulting melt. The remaining excipients are mixed and the resulting mixture is granulated with a solution of compound α. The granules obtained are washed and compressed to form tablets. The dissolution tests of the obtained tablets, carried out at 37 ^° C. in an aqueous medium with pH = 1.2, showed that after 15 minutes the compound α was completely dissolved.

 EXAMPLE 30

According to the above procedure, tablets of the following composition are obtained:
Compound α - 50 mg
Lactose Monohydrate - 690 mg
Pregelatinized Starch - 1002 mg
Polyvinylpyrrolidone - 58.18 mg
Sodium carboxymethyl cellulose - 115.1 mg
PEG 6000 - 302 mg
TWEEN® 20 - 48 mg - 2265.28 mg
EXAMPLE 31. Gelatin capsules containing compound α
Capsules of a composition similar to that of Example 29 are prepared by melting a PEG 2000 / TWEEN® 20 mixture at 60 ^° C. Compound α is dissolved in the resulting melt. The remaining excipients are mixed and the resulting mixture is granulated with a solution of compound α. The granules obtained are sieved and introduced into gelatin capsules.

Example 32
PEG 400 - 79%
Twin 80 - 21%
Example 33
PEG 400 - 89.25%
TRANSCUTOL - 6.5%
MONTANOX - 4.25%
Example 34
GELUCIRE 44-14 - 100%
Example 35
PEG 600 - 48%
PEG 1500 - 48%
Twin 80 - 4%
Example 36
PEG 2000 - 91%
Twin 20 - 9%
Example 37
PEG 2000 - 91%
Twin 80 - 9%
Example 38
PEG 2000 - 91%
Twin 80 / SPAN 20 (69/31) - 9%
Example 39
PEG 2000 - 86%
Twin 20 - 14%
Example 40
PEG 2000 - 86%
Twin 80 - 14%
Example 41
PEG 2000 - 86%
Twin 80 / Twin 20 (69/31) - 14%
Example 42
PEG 2000 - 86%
GELUCIRE 44-14 - 14%
Example 43
PEG 2000 - 86%
GELUCIRE 50-13 - 14%
Example 44
GELUCIRE 44-14 - 91%
Twin 80 - 9%
Example 45
GELUCIRE 44-14 - 86%
Twin 80 - 14%
Example 46
GELUCIRE 50-13 - 100%
Example 47
Twin 80 - 9%
GELUCIRE 50-13 - 91%
Example 48
Twin 80 - 14%
GELUCIRE 50-13 - 86%
Example 49
PEG 400 - 96%
Twin 80 - 4%
Example 50
PEG 400 - 96%
PLURONIC F127 - 4%
Example 51
PEG 400 - 78%
PLURONIC F127 - 22%
Example 52
PEG 400 - 95%
PLURONIC F127 - 5%
Example 53
PEG 400 - 76%
PLURONIC F127 - 24%
Example 54
PEG 2000 - 77%
Twin 80 - 23%
Example 55
PEG 2000 - 82%
Twin 80 - 18%
Example 56
PEG 2000 - 82%
Twin / SPAN 20 (69/31) / - 18% m

Claims (29)

1. Anhydrous dissolving and stabilizing system, emulsifiable or microemulsible in water, designed to dissolve a hydrophobic derivative of N-sulfonylindoline of the formula

containing at least one or more non-ionic hydrophilic compounds having both surface-active and amphiphilic properties, or at least one mixture of at least one amphiphilic compound and a non-ionic hydrophilic surfactant.  2. The anhydrous solvent and stabilizing system according to claim 1, containing one or more glyphic type amphiphilic compounds selected from propylene glycol, polyethylene glycols and glycol ethers, the system also containing one or more non-ionic hydrophilic surfactants.  3. The solvent and stabilizing system according to claim 1, containing one or more non-ionic hydrophilic compounds that simultaneously have amphiphilic and surface-active properties and which are selected from saturated polyglycolized glycerides, and this system may, if necessary, contain one or more non-ionic surface -active hydrophilic substances, if necessary, one or more amphiphilic compounds of the glycol type.  4. The solvent and stabilizing system according to claim 1 or 2, which is in the form of a liquid and contains one or more amphiphilic compounds of the glycol type selected from propylene glycol and polyethylene glycols with an average molecular weight of 400 to 600, and this system additionally contains one or more nonionic hydrophilic surfactants with a hydrophilic lipophilic balance (HLB) of 12 to 22, and also, if necessary, contains diethylene glycol ether.  5. The solvent and stabilizing system according to claim 1 or 2, which is in the form of a liquid and contains one or more glyphic type amphiphilic compounds selected from propylene glycol and polyethylene glycols with an average molecular weight of 400 to 600 and diethylene glycol ethers, said system containing also one or more non-ionic hydrophilic surfactants with a value of the specified indicator HLB from 12 to 22.  6. The solvent and stabilizing system according to claim 1 or 2, which is in semi-solid form and contains one or more glycol-type amphiphilic compounds selected from polyethylene glycols with an average molecular weight of from 600 to 2000, and this system also contains one or more non-ionic hydrophilic surfactants with an HLB index of 12 to 22.  7. The solvent and stabilizing system according to claim 1 or 2, which is in semi-solid form and contains one or more glycol-type amphiphilic compounds selected from polyethylene glycols with a molecular weight of from 2000 to 10000, and this system also contains one or more nonionic hydrophilic surfactants -active substances with a value of the specified indicator HLB equal to from 12 to 22.  8. The solvent and stabilizing system according to claim 1 or 3, which is in semi-solid form and contains one or more nonionic hydrophilic compounds having simultaneously amphiphilic and surface-active properties, which are derivatives of saturated polyglycolized glycerides, which are mixtures of complex mono-, di- and triesters of glycerol and fatty acids and mixtures of mono- and diesters of polyethylene glycol and fatty acids, moreover, this system, if necessary, contains one or more nonionic hydrophilic surfactants with a value of the indicated HLB index equal to 12-22, and, if necessary, one or more amphiphilic glycol-type compounds selected from polyethylene glycols with an average molecular weight of 600 to 10,000.  9. The solvent and stabilizing system according to any one of paragraphs. 1, 2, 4 or 5, in which the amphiphilic compound is a polyethylene glycol with an average molecular weight of 400 to 600 and is a polyethylene glycol 400.  10. The solvent and stabilizing system according to any one of claims 1, 2, 6 or 8, in which the amphiphilic compound is a polyethylene glycol with an average molecular weight of from 600 to 2000 and is, in particular, polyethylene glycol 1000, polyethylene glycol 2000 or a mixture of polyethylene glycol 600 and polyethylene glycol 1500 in a weight ratio of 50: 50.  11. The solvent and stabilizing system according to any one of claims 1 to 8, in which the surface-active substance is polysorbate 80. 12. The solvent and stabilizing system according to any one of claims 1, 2, 4 or 5, in which the amphiphilic compound, which is a simple glycol ether, is a simple mono (C _1-4 ) diethylene glycol alkyl ether. 13. The solvent and stabilizing system of claim 12, wherein the diethylene glycol mono (C _1-4 ) alkyl ether is TRANSCUTOL ^® brand monoethyl ether diethylene glycol. 14. The solvent and stabilizing system according to claims 1, 3 or 8, in which the compound, which has both amphiphilic and surface-active properties, is a mixture of glycerol mono-, di- and triesters and polyethylene glycol mono- and diesters, in in particular, a mixture of the brand GELUCIRE ^® 44-14 or GELUCIRE ^® 50-13.  15. A pharmaceutical composition microemulsifiable or emulsifiable in an aqueous medium containing the hydrophobic derivative of N-sulfonylindoline according to claim 1, a dissolving and stabilizing system according to any one of claims 1 to 14 and, if necessary, a pharmaceutically acceptable excipient or carrier.  16. The pharmaceutical composition according to item 15, intended for injection, which contains a hydrophobic derivative of N-sulfonylindoline according to claim 1, a dissolving and stabilizing system according to claim 4 and, if necessary, including components according to claims 9, 11, 12 or 13 and a pharmaceutically acceptable carrier.  17. The pharmaceutical composition according to clause 16, in which the pharmaceutically acceptable carrier is water and / or polyvinylpyrrolidone.  18. The pharmaceutical composition according to clause 16 or 17, in which the content of the hydrophobic derivative of N-sulfonylindoline does not exceed 1 wt.% By weight of the composition.  19. The pharmaceutical composition according to item 15 in the form of a liquid intended for oral administration containing a hydrophobic derivative of N-sulfonylindoline according to claim 1, a dissolving and stabilizing system described in claim 5, optionally including components according to claims 9, 11 or 13.  20. The pharmaceutical composition according to item 15 in semi-solid form, intended for oral administration, containing the hydrophobic derivative of N-sulfonylindoline according to claim 1, a dissolving and stabilizing system according to any one of claims 6, 7 or 8, optionally including components according to claims. 10, 11 or 14.  21. The pharmaceutical composition according to claim 19 or 20, in which the content of the hydrophobic derivative of N-sulfonylindoline does not exceed 15 wt.% By weight of the composition.  22. The pharmaceutical composition according to any one of paragraphs.16-18, in which in the solvent and stabilizing system the content of diethylene glycol ether does not exceed 50 wt.% By weight of the composition.  23. The pharmaceutical composition according to any one of paragraphs.16-18, in which the solvent and stabilizing system contains a non-ionic hydrophilic surfactant in an amount not exceeding 4 wt.% By weight of the composition.  24. The pharmaceutical composition according to item 15 in solid form, intended for oral administration, containing a hydrophobic derivative of N-sulfonylindoline according to claim 1, a dissolving and stabilizing system according to any one of claims 7 or 8, and, if necessary, including components according to claim .11 or 14, a pharmaceutically acceptable excipient or carrier.  25. The pharmaceutical composition according to any one of claims 19-24, wherein the solvent and stabilizing system contains a nonionic hydrophilic surfactant in a concentration not exceeding 12% by weight of the composition.  26. The pharmaceutical composition according to any one of claims 15 to 25, wherein the hydrophobic derivative of N-sulfonylindoline is (2 S) 1 - [(2R, 3 S) (5-chloro-3- (2-chlorophenyl) -1- ( 3,4-dimethoxyphenylsulfonyl) -3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl] pyrrolidine-2-carboxamide.  27. The pharmaceutical composition according to any one of paragraphs.24-26, in the form of a powder, granules or tablets.  28. A soft pharmaceutical capsule containing a liquid pharmaceutical composition for oral administration, according to one of claims 19, 21, 25 or 26.  29. A gelatin capsule containing a semi-solid pharmaceutical composition for oral administration according to any one of claims 20, 21, 25 or 26.

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