WO1992001475A1

WO1992001475A1 - Compositions based on active principles of hydrophobic medicaments solubilizable in an aqueous solvent

Info

Publication number: WO1992001475A1
Application number: PCT/FR1991/000595
Authority: WO
Inventors: Louis Chedid; Pierre Lefrancier
Original assignee: Vacsyn France, S.A.
Priority date: 1990-07-18
Filing date: 1991-07-18
Publication date: 1992-02-06
Also published as: AU8282991A; FR2672496A1; EP0539457A1; FR2672496B3; CA2087536A1; JPH05508653A

Abstract

The invention relates to any composition caracterized in that it is comprised of: on the one hand, an active principle of a medicament or a pharmacologically active substance, water insoluble, said substance being substituted by at least one lipophylic group, and on the other hand, an osidic derivative of which at least one of the hydroxyl functions is substituted by one or a plurality of phosphate or sulphate group or groups, said compound being also substituted by a lipophylic group, the composition being capable of homogeneous solubilization or dispersion in an aqueous solvent. The invention also relates to the use of such compositions, particularly as pharmaceutical compositions dissolved in a physiologically acceptable aqueous solvent.

Description

COMPOSITIONS BASED ON ACTIVE INGREDIENTS OF HYDROPHOBIC DRUGS SOLUBILIZABLE IN AQUEOUS SOLVENT

The invention relates to compositions comprising active principles of hydrophobic drugs, which can nevertheless be dissolved in an aqueous solvent.

The invention also relates to a process for obtaining such compositions, and to their uses in particular as pharmaceutical compositions.

Many products used in the pharmaceutical field, or likely to be used, cannot be dissolved in an aqueous solvent.

This insolubility in an aqueous solvent is particularly disadvantageous for products intended to be administered in an aqueous physiological solution of the type of those usually used for injectable preparations. It is also applicable to products intended to be administered orally and which have reduced efficacy and bioavailability.

Among these pharmacologically active products which are insoluble in an aqueous solvent, mention may be made in particular of lipophilic derivatives of mura yl-peptides, such as those described in European patent n ° 0 165 123 of 10/05/1985, or also in the European patent 4512 dated 03/20/1979.

In fact, these products are immunomodulators capable of increasing the specific immune response (adjuvanted vaccine), or reinforcing non-specific resistance (anti-infectious agent). Very hydrophobic in nature, they give aqueous suspensions which are difficult to disperse in a completely satisfactory manner (in particular with regard to the level of dispersion compatible with the possibility of injecting them into a patient), by using the various means of dissolution or aqueous dispersion. , based on known techniques, in particular mechanical treatments, or even the use of organic solvents or surfactants.

The present invention specifically aims to provide means for the solubilization or homogeneous dispersion in an aqueous solvent of hydrophobic products, such as lipophilic uramyl-peptides, or other active ingredients of lipophilic drugs, carriers of hydrocarbon chains. These sometimes themselves contribute to the low solubility of these products in water, or even to the instability of their aqueous dispersions.

The invention relates generally to a composition capable of being dissolved or dispersed in a homogeneous and stable manner in a pharmaceutically acceptable aqueous solution, characterized by the combination: on the one hand, of a lipophilic active principle of drug or "pharmacologically active substance", comprising at least one hydrocarbon group itself comprising at least 3 carbon atoms, and - on the other hand, of a solubilizing osidic derivative, itself water-soluble, pharmaceutically acceptable, itself carrying a hydrocarbon group having at least 3 carbon atoms and comprising one or more hydroxyl functions, at least one of which is substituted by a phosphate or sulfate group, this osidic derivative being in a sufficient proportion relative to the lipophilic active principle for promote the solubilization or dispersion of the entire composition in an aqueous solution.

The dissolution or dispersion of the two above-defined constituents of the composition apparently involves the constitution of Van der Walls type bonds between their respective hydrocarbon chains. Often the connections of Van der Walls will be all the more effective as they are numerous and therefore, as the hydrocarbon chains will be longer. It goes without saying that these chain lengths must not, especially with regard to the water-soluble sugar derivative, exceed those which would have the effect of excessively increasing its lipophilicity.

It is understood that, in what precedes and what follows, "lipophilic" must be understood as meaning that the substance concerned has in a two-phase system (aqueous solution - organic solution) a partition coefficient favorable to the organic phase; in other words, the lipophilic substance is more soluble in the organic solution than in the aqueous solution. The lipophilic substance can even be practically insoluble in water.

Conversely, and in the present description, the adjective "water-soluble" has the opposite meaning. The partition coefficient of the water-soluble substance in the above two-phase system is in favor of the aqueous phase.

It can be assumed that the solubilizing power of the osidic derivative is attributable to the simultaneous presence in the structure of this osidic derivative of said (or said) group (s) of hypocarbon (s) and of (or) group (s) sulfate or phosphate. Hydrocarbon groups allow the establishment of Van der Waals type connections with the hydrocarbon chain (s) of the active principle and the sulfate or phosphate group (s) allows the solubilization of the non-covalent complex thus formed.

Where appropriate, the lengths of the hydrocarbon chains carried respectively by the lipophilic active substance on the one hand, the water-soluble solubilizing derivative, on the other hand, are chosen so as to favor the establishment of the above-mentioned Van der Waals type bonds.

The pharmacologically active substance can consist of any substance meeting the criteria indicated above. In general, it is noted that the lipophilicity of the pharmacologically active substance can result either from the length of the hydrocarbon chains which it carries, or - and in particular when these hydrocarbon chains are short - from the number of these chains, or even , of course, the combination of the lengths and the number of these hydrocarbon chains.

As already seen, the active substance may comprise any derivative of muramyl-peptide containing a hydrocarbon chain tending to reduce the water solubility of ^τ corresponding muramyl peptide therefore • that it is devoid of said hydrocarbon chain. A preferred category of such so-called "lipophilic" muramyl-peptides is further illustrated below.

Another category of preferred compounds is constituted by saccharide derivatives or analogues, in particular mono- or di-saccharide lipid A. Certain preferred examples of these analogs are mentioned below. Other pharmaceutical substances can also be dissolved using the techniques of the invention.

Among these, mention should be made in particular of the cyclic peptides of the cyclosporin family, for example cyclosporin A (JF Borel et al, Agents Actions - 6 (1976) 1 + 68; is, Immumnology 32 (1977) 1017 ; PJ Tudchka et al., Blood 61 (1983) 318) but also cyclic pseudopeptides, for example valinomycin or polyene macrolides, for example lucensomycin, and the fat-soluble vitamins, in particular vitamins A, D, E, K,

In general, any pharmacologically active substance of the polyene, mono or polysaccharide, polypeptide, cyclic or non-cyclic, or even glycopeptide type, which carries at least one hydrocarbon chain as defined above, can be forming the lipophilic constituent of the compositions according to the invention. The invention applies in particular to the solubilization of pharmacologically active substances, the solubility of which would prove to be insufficient for medical application, whatever the route of administration envisaged, since it comprises a hydrocarbon chain which can be associated, via Van de Waals type bonds, with a corresponding hydrocarbon chain carried by an osidic derivative, as defined above.

As for the water-soluble osidic derivative, it should be noted that the expression "osidic" as used above, and in what follows, relates generally to any product comprising in its structure one (or more) residue ( saccharide (s). In general, any osidic derivative as defined above can be used in the compositions of the invention, provided that this derivative does not lead to a modification of the pharmacological properties of the above-mentioned active substance, such as this the latter would become inactive or toxic.

The hydrocarbon chains carried either by the pharmacologically active substance or by the oside derivative are advantageously themselves lipophilic groups. They notably include:

. either by at least one linear hydrocarbon structure of 3 to 20, in particular of 4 to 20 carbon atoms, comprising where appropriate, one or more ether, ester, thioether, thioester, or amide bond (s), this linear structure being designated hereinafter by "type A" lipophilic group,

. either by at least one branched hydrocarbon structure of 5 to 50, in particular of 10 to 50 carbon atoms, comprising where appropriate, one or more ether, ester, thioether, thioester, or amide bond (s), this branched structure being designated hereinafter by "type B" lipophilic group.

A category of preferred sugar derivatives for the production of compositions in accordance with the invention are those which correspond to the following formula (I):

in which :

R represents a hydrocarbon group comprising at least 3 carbon atoms, in particular a "type A" or "type B" lipophilic group,

- represents H, or OH, or an acetamido, sulfate, sulfamido, phosphate, phosphamido group,

- R ₃ and R ₄ , identical or different, represent either H, or OH, or OCH ₃ , or else a sulfate or phosphate group,

- R represents either H, OH, or 0CH ₃ , or else a dare or osamine residue whose anomeric carbon in position 1 (Cl) is engaged in a glycosidic bond, the positions C2, C3 and C4 being respectively substituted by groups R ' ₂ , R' ₃ , and R ' ₄ respectively having the meanings given above for R ₂ , R ₃ , and R ₄ , and the position C6 by a group R' having the meaning given above for

R, at least one of the groups R ₂ , R'g / R ₃ , R ' ₃ , R ₄ or R' representing a sulfate or phosphate residue.

By way of example of sugar derivatives corresponding to the above-mentioned formula (I), mention may be made of the following compounds:

- α or β-methyl-glycoside N-acetyl-4-sulfate-6-OR- 2-deoxy-glucosamine, - N-acetyl 4-sulfate-6-OR-2-desoxy-glucosamine,

- a or 0-methyl-glycoside 4-sulfate-6-OR-glucopyranose,

- 4-sulfate-6-OR-glucopyranose,

- 6,6'-di-OR-4,4'-di-sulfate-α, α'-D-trehalose, R having the meaning indicated above.

It goes without saying that the lipophilic groups must not be of such a length or in such a number that the whole of the osidic derivative would tend to become insoluble.

Preferred sugar derivatives are chosen from the following compounds:

- α or 0-methyl-glycoside N-acetyl-4-sulfate-6-octanoyl-2-deoxy-glucosamine,

- α or 9-methyl-glycoside-N-acetyl-4-sulfate-6- (2,3-dipalmitoyl) glyceroyl-2-deoxy-glucosamine,

- N-acetyl-4-sulfate-6-octanoyl-2-deoxy-glucosamine,

- N-acetyl-4-sulfate-6- (2, 3-dipalmitoyl) -glyceroyl-2-deoxy-D-glucosamine,

- α or 0-methyl-glycoside 4-tallow ate-6 -octanoyl-glu- copyranoside,

- a or 3-methyl-glycoside 4-sulfate-6- (2, 3-dipalmi-toyl) -glyceroyl-D-glucopyranoside,

- 4-sulfate-6-octanoyl-D-glucopyranose,

- 4-sulfate-6 (2,3-di-palmitoyl) -glyceroyl- glucopyranose

- 4.4 'di-sulfate-6.6' di-octanoyl-α, α'-D-trehalose,

- 4,4'di-sulfate-6,6 • (2,3-dipalmitoyl) -glyceroyl-α-α * - D-trehalose.

Certain categories of compositions in accordance with the invention will be even more - and in a non-limiting manner - illustrated below.

The two hydrocarbon groups, where appropriate, lipophilic by themselves, ensuring respectively a non-covalent association between the pharmacologically active substance and the oside derivative, are linear hydrocarbon structures. Advantageously, however, these groups are such that one of them is composed of a linear hydrocarbon structure, while the other consists of a branched hydrocarbon structure.

The branched hydrocarbon structure is then preferably chosen from those consisting of a branched hydrocarbon chain, the branches of which arise on two adjacent carbon atoms, or at most separated by one carbon atom.

Preferably, the linear hydrocarbon structure must then, in order to associate with the branched hydrocarbon chain, have a sufficient length allowing the establishment of non-covalent bonds, in particular of the Van der Walls type, with at least one of the ramifications of the structure. branched hydrocarbon.

Thus, the association of the pharmacologically active substance and the osidic derivative is effected by means of their respective hydrocarbon or even lipophilic groups, as soon as non-covalent bonds are established which are sufficiently strong to allow the linear hydrocarbon structure, to be maintained in a so-called "sandwich" position between the two branches of the branched hydrocarbon structure.

Preferably, the linear hydrocarbon structure has a number of carbon atoms at most equal to the number of carbon atoms of the branches of the branched hydrocarbon structure.

The association of the osidic derivative as described above, of amphiphilic and water-soluble nature, with the pharmacologically active substance hydrophobic and insoluble in water, allows the homogeneous dispersion of the latter in an aqueous solvent.

A more particular subject of the invention is any composition capable of being dissolved or homogeneously dispersed in an aqueous solvent, characterized in that it comprises:

(1) a pharmacologically active substance, insoluble in water, this substance being substituted:

. either by a "type A" lipophilic group,. either by a "type B" lipophilic group,

(2) an osidic derivative associated noncovalently with the substance (1), this osidic derivative being itself substituted:

. either by at least one "type A" lipophilic group when said pharmacologically active substance is substituted by a "type B" lipophilic group,

. or by at least one "type B" lipophilic group when said pharmacologically active substance is substituted by a "type A" lipophilic group, at least one of the hydroxyl functions of the abovementioned osidic derivative being substituted by one or more , phosphate or sulfate group (s).

In general, any pharmacologically active substance, in particular of a nature insoluble in an aqueous solvent, and onto which is capable of being grafted at least one lipophilic group "type A" or "type B" mentioned above or more generally a shorter hydrocarbon chain, can be used as a pharmacologically active substance included in the compositions of the invention.

The techniques described below as examples for the grafting of these lipophilic groups or hydrocarbon chains on oside derivatives are also applicable to the grafting of chains of the same nature on insoluble pharmacologically active substances, provided that they themselves are devoid of them.

Among the pharmacologically active substances (or lipophilic active principles) entering into the compositions of the invention, mention may be made of the lipophilic muramyl-peptide derivatives corresponding to the following formula (II):

in which

- R represents H or CH ₃ ;

- R 6. represents a group -NH ₂ , -OH or a group -OW

W ₁ being a hydrocarbon group having from 1 to 10 carbon atoms;

X represents an aminoacyl residue from the group comprising alanyl, valyl, isoleucyl, norleucyl, leucyl, threonyl, prolyl, glutaminyl, asparaginyl, ethionyl, tryptophanyl, phenylalanyl, tyrosyl, glycyl; Y represents either OH or NH ₂ or a group -OW ₂ , W ₂ being a hydrocarbon group of 1 to 4 carbon atoms, or else a lipophilic group of type A or of type B,

Z represents either H or a "type A" or "type B" lipophilic group, it being understood however that at least one of the two groups Y and Z is always constituted by a "type A" lipophilic group or "type B";

- n- _| and n ₂ , identical or different, represent zero or 1,

- A, and B, are either identical or different groups respectively comprising from 1 to 3 aminoacyl residues, themselves identical or different from each other, or else a group -NH- (CH ₂ ) _p -CO- with values of p between 2 and 10.

A particularly preferred composition of the invention comprises compounds of the above-mentioned formula (II), in which

- n- _j and n ₂ represent zero,

- Rg represents CH ₃ ,

- R _f . represents -OH, -NH ₂ or -On (CH) H with x, between 1 and 6, with a preference for X _! = 4, -X is L or D-alanyl, L-threonyl, L-valyle,

- when Y represents -0-CH ₂ -CHO (R ₇ ) -CH ₂ 0 (R ₈ ), Z represents H, and when Z represents

O

II

-C-CHO (R ₇ ) -CH ₂ 0 (R ₈ ), Y represents -OH, -NH ₂ or a group -0W _2j W ₂ having the meaning indicated above, and R ₇ and R ₈ being groups palmitoyle.

Another preferred composition of the invention comprises compounds of formula (II) mentioned above, in which: - n, and n represent zero,

- R ₅ represents CH ₃

- R_ represents -OH, or -NH or On (CH ₂ ) H with x ^ between 1 and 6, with a preference for x ₁ ≈4, -X is L or D-alanyl, L-threonyl, L-valyle ,

- when Y represents -0- (CH ₂ ) _x H with x ₂ = 8, Z represents H, and when Z represents -C0 (CH ₂ ) _x H, with x = 8, Y represents -OH, -NH ₂ , or a group -OW, W ₂ having the meaning indicated above.

The biologically active substance capable of being combined with the derivatives of osides, defined above, to form soluble or dispersible compositions in accordance with the invention, may also belong to other categories of products. These are, for example immunomodulatory substances, selected from:

- constituents of bacterial origin, inter alia constituents of the bacterial wall: derivatives of trehalose, in particular of the type of TDM (products of the class of trehalose dimycolates), and lipolysaccharides (LPS) which comprise on the one hand lipid chains and, on the other hand, at least one phosphate or sulfate group:

- lipid fractions obtained from these LPS, in particular "Lipid A" (see for example article by Ernst Th. Rietschel et al entitled "Molecular structure of bacterial endotoxin in relation to bioactivity" (Molecular structure of bacterial endotoxins in relation with their bioactivity) in the work itself entitled "Cellular and molecular aspects of endotoxin reactions" (under the terms of endotoxin-using reactions), under the supervised by A. Nowotny, JJ Spitzer and EJ Ziegler; 1990, Elsevier Science Publishers BV (Biomedical Division), pages 15-32); the formula for "Lipid A" (III) is recalled:

⁽ CH2 ⁾ y ⁽ CH2 ⁾ χ COO CH! III CH3 CH3 (CH2 ⁾ y ⁽ CH2> i \ CH3 CH3 x = 10 y - 12

- analogues of the previous constituents of bacterial origin or of products (natural, hemi-synthetic or synthetic) corresponding to fragments of these constituents of bacterial origin, in particular detoxified derivatives. Particular mention will be made of lipid A derivatives or analogs, mono- or di-saccharide, mono- or diphosphorylated, carrying branched chains or else linear hydrocarbon chains, which may themselves be substituted or not, by linear hydrocarbon chains with means of ester, thioester, ether or thioether bonds, products which, obtained by synthesis or hemisynthesis, have an attenuated toxicity compared to natural Lipid A. A first family is that of analogs or disaccharide derivatives of Lipid A, such as MPL (monophophoryl Lipid A, produced by Ribi immunochem, Research Inc.). These are very hydrophobic structures dispersible in water in a homogeneous manner, in the presence of the above-mentioned derivatives of osides.

These analogues of Lipid A correspond to the general formula (IV),

in which:

R ₄ and R'τ represent H or P0 ₄ , with at least R ₄ or R'.j being a group P0 ₄

R ₂ , R ₃ and R ' ₂ , R' ₃ represent CO-CH (OR) - (CH ₂ ) _X -CH ₃ , x being between 5 and 15, with a preference for x = 10, and R being C0 - (CH ₂ ) y-CH ₃ there being between 5 and 15 with a preference for y = 10 or 12.

A second family is that of the analogs or monosaccharide derivatives of Lipid A, in particular MRL 953 (product described in PL stuetz et al, in Cellular and molecular aspects of endotoxin reaction A. Nowotny, JJ Spitzec, EJ Zlegler editors. (Elsevier Science Publishers ) 1990, pages 129-144).

These analogs and monosaccharide derivatives of Lipid A correspond to the general formula (V):

NHR2

in which :

R., represents H or P0 ₃

R ₂ and R ₃ represent CO-CH (R) - (CH ₂ ) _x -CH ₃ , x being between 5 and 15, with a preference for x = 10, and R being H or OH or also CO- (CH ₂ ) _y -CH ₃ , including between 5 and 15 with a preference for y = 10 or 12,

R represents P0 ₃ if R is not P0 ₃ , or H or one of the meanings given to R ₂ and R ₃ .

For the same hydrophobicity reasons as already mentioned with regard to certain Muramylpeptides, their galenical formulation is often difficult. However, like lipophilic Muramylpeptides, they can lead to homogeneous aqueous solutions or dispersions in the presence of the above-mentioned oside derivative.

The present invention therefore relates to the use of the compositions according to the invention either alone for stimulating the general defenses of the organism, or with an antigen.

The oside derivative and the pharmacologically active substance are, in the combination, advantageously in a weight ratio of 0.25 to 5, in particular from 0.5 to 1.5. The subject of the invention is also the osidic derivatives of formula (I) themselves, since they comprise at least one sulphate group, as well as their process for obtaining according to methods which are conventionally used in synthetic chemistry of mono and oligosaccharides.

By way of illustration, this methodology proceeds in successive steps starting from the ose or the oligosaccharide to be chemically modified, in order to arrive at the desired derivative, specifically substituted in the desired position. To do this, the functions in positions CC ₂ , C ₃ , C ₄ and C ₆ of a ose and those corresponding to an oligosaccharide, are temporarily protected by protective groups (such as benzyl, benzylidene, acetyl ...) introduced specifically and sequentially on the positions which will not ultimately be the subject of the envisaged chemical modification, taking advantage of the differences in reactivity of said functions.

Then the introduction of the lipophilic groups “type A” or “type B” mentioned above or, moreover, of shorter hydrocarbon chains, is advantageously carried out in the following manner: the (or the) primary unprotected hydroxyl functions, can react either in the form substituted by a tosyl group with a fatty acid salt, in the presence of crown ether, or in the free form with a fatty acid chloride, or with the carboxylic function of a fatty acid in the presence of 'a coupling reagent.

After the introduction (or of) the chemical modifications envisaged on the (or the) positions which remain free, the derivative obtained is released (deprotection step) from all of its protective groups to result in the desired mono or oligosaccharide derivative. Where appropriate, the introduction of the phosphate groups (or groups) is carried out prior to the abovementioned deprotection step, by the so-called phosphite triester method described in Perich, JW et al, Tetrahedron Lett. , (1988), 29., 2369.

The introduction of the sulphate group (s) is carried out after the deprotection step mentioned above, in particular by using the trimethylamine-sulfuric anhydride complex according to the method notably described in Ichikawa Y. et al, Carbohydrate Research, 172, (1988), 37-64.

The invention also relates to pharmaceutical compositions comprising a composition of the type described above, or a mixture of these compositions, dispersed in a physiologically acceptable aqueous solvent.

Advantageously, the compositions of the invention can be lyophilized from their aqueous solution or dispersion, and are then in powder form.

These compositions in the form of dry powder, are easily dissolved or dispersed again in an appropriate volume of aqueous solvent.

The invention also relates to a method for modifying the solubility properties of a pharmacologically active substance of type (1) described above, this method consisting in the association of substance (1) with an osidic derivative of type (2). ) as described above, under conditions such that when this combination of (1) and (2) is placed in water, a solution (or a dispersion) is obtained which can be used in particular as an injectable preparation, when the the above-mentioned water is sterile. The solubilization of the phar¬ macologically active substance (1) is such that one obtains a fluid characterized by a weak opalescence (measurable by nephelometry), the latter being even often absent.

This fluid behaves as a solution and is capable of being administered into the body as a solution for injection. The dispersion of a substance in an aqueous medium corresponds to a stable and homogeneous distribution of the molecules of this substance in the mass of this medium, resulting from total or partial solvation by water molecules, and not to a dispersion of this sedimentable substance over time. In particular, no change in physical state is observed in the dispersion within 24 hours of its preparation.

The subject of the invention is also a process for obtaining the compositions described above comprising:

- the solubilization of the sugar derivative (s) in a determined quantity of an aqueous solvent,

the addition, with stirring, to the previously obtained solution, of a determined quantity of one (or more) pharmacologically active substance, either in suspension in an aqueous solvent, or in solution in an organic solvent,

- if necessary, the elimination of the organic solvent,

- if necessary still, lyophilization of the previous solution.

As a variant, the process for obtaining the compositions of the invention is carried out by adding, under the conditions described above, the (or) derivative (s) of sugar to a specified quantity of one (or more) pharmacologically active substance (s).

The invention is further illustrated in the detailed description which follows, without the latter being limiting.

Description of the synthesis of the sodium salt of 6,6 'di-octanoyl-, • -disulfonyl-α, o "-D-trehalose

.6,6'octanoyl-2,3-2 ', 3 •, tetra-O-benzyl-α,' -D-trehalo¬

Dissolution in dry THF (50 ml), under argon, protected from light by 3 mmol of 2.3-2 *, 3'-tetra-0-benzyl-α, α'-D-trehalose (AF Hadfield, L. Hough, and AC Richardson - Carbohyd. Res. 63, (1978), 51) of 7.5 mmol of octanoic acid, and 7.87 mmol of triphenylphosphine. To the solution cooled to 0 ° C, addition over 15 minutes of a solution of diisopropylazodicarboxylate (8.02 mmol) in dry THF (25 ml). Purification on silica 60 H under pressure in the mixture of toluene / CH ₂ Cl ₂ / AcoET: 30/10/5. Oil: m = 2.58 g (90%).

. Sodium salt of 6,6'-dioctanoyl-2,3-2 ', 3'-tetra-0-benzyl-4.4 ¹ -di-sulfonyl-o, α'-D-trehalose.

At 1.5 mmol of the above product in solution in dry DMF (15 ml), addition of 15 mmol of trimethylamine / sulfuric anhydride complex (2.1 g) and incubation at 50 ° C under anhydride conditions for 2 days. Addition of CH ₃ 0H (10 ml), then, extension with chloroform (10 ml) and percolation on Sephadex LH ₂₀ in the mixture CHC1 ₃ -CH ₃ 0H: I / I. After concentration, purification on a 60H silica column under pressure, in the CHC1 ₃ -CH ₃ OH-H ₂ O mixture: 5/15/05 (1.7 g: oil). Dissolution in the DMF-H ₂ 0 mixture: I / I (80 ml) and percolation on a column of Dowex 50 WX4 H ⁺ resin (85 ml) by elution with the same mixture of solvents: neutralization with 0.1N NaOH: lyophilization m = 1.51 g (87%). . Sodium salt of 6,6'-dioctanoyl-4,4'-di-0-sulfonyl-, α * -D-trehalose (C ₂₈ ^H 48 ^Na 2 ° 19 ^s 2 ^: 798.79)

1.5 g of the above derivative, dissolved in 150 ml of a water / alcohol mixture (6.5 / 10), is hydrogenated in the presence of 750 mg of Pd / C at 10%. After filtration, concentration, lyophilization in aqueous solution. Purification on silica 60-G in CHCl ₃ -CH ₃ OH-CH ₃ COOH- H ₂ 0: 40/20/8/2. Concentration, coevaporation with toluene, lyophilization in aqueous solution. Percolation on Sephadex LH ₂₀ in methanol. Drying concentration, lyophilization in solution in water m = 525 mg (51%).

Sulphate content: 2.7 Eq / g (conductimetry). octanoic acid content: 1.97 Eq / mole (CPV).

EXAMPLES OF IMPLEMENTATIONS OF THE Pi OSIDE DERIVATIVE IN COMPOSITIONS CONFORMING TO THE INVENTION

EXAMPLE - I:

1): Description of uses of the aqueous dispersion of MDP-GDF, that is to say the α (N-acetyl-muramyl-L-alanyl- D-isoglutamine) - _/ 3, ₇ -dipalxnitoyl -sn-Gly- cerol, with the compound P ^

- First mode of implementation

10 mg of P ₁ are dissolved in 10 ml of distilled water. To the solution are added 10 mg of MDP-GDP, with vigorous stirring. The aqueous dispersion obtained is of opalescent appearance and does not sediment or very little, (a new agitation makes it possible to obtain the homogeneous dispersion again). After lyophilization, it is possible, by adding water or physiological solution, to reconstitute a dispersion of identical appearance. Second mode of implementation 22

Method of implementation 2.20.57 mg of MDP-GDP are dissolved in 2 ml of chloroform (solution A). 20 mg of P., are dissolved in 1 ml of chloroform (solution B).

The chloroform solutions (A) and (B) are combined. 5 to 10 ml of distilled water are added and a stream of nitrogen is bubbled from the bottom of the tube containing the two phases, until complete elimination of the chloroform.

A homogeneous and stable, slightly opalescent aqueous dispersion is obtained.

The aqueous dispersion is lyophilized and the powder obtained is taken up in an aqueous solvent at the desired concentration. A dispersion of the same appearance and quality is obtained as previously.

The process allows an easy pharmaceutical formulation of the active principles of lipophilic drugs corresponding to the general formula (II). This results in preparations which conserve the pharmacological activities of these products, in particular as a regulator of the immune response, as claimed in European patent No. 0 165 123.

2): Influence of the use of i on the adjuvant activity of MDP-GDP studied in guinea pigs. a) Preparation of the emulsion

1 mg of P ₁ is dissolved in 0.5 ml of physiological solution, this solution is added dropwise to 1 mg of powdered MDP-GDP.

The dispersion obtained is mixed with 0.5 ml of an isotonic solution of ovalbumin at 20 mg / ml. 1 ml of mineral oil (Freund's Incomplete Adjuvant, AIF) is added and the emulsion is carried out. This preparation therefore contains per ml, 0.5 mg of adjuvant, 0.5 mg of P., and 5 mg of ovalbumin b) Methodology

The control batches receive a) water / mineral oil emulsion containing the antigen alone, b) the same emulsion containing the adjuvant molecules alone (MDP-GDP). The experimental batches receive the emulsions containing the P sugar derivative. The injections are made subcutaneously in the rear plantar pads of Hartley male guinea pigs weighing 350 g. After 3 weeks the animals receive intradermally 0.1 ml of physiological solution alone or containing 0.1 ml of ovalbumin. After 48 hours, the induration diameter is measured, which is the sign of the establishment of a state of delayed hypersensitivity. After 24 hours, the animals are sacrificed for cardiac puncture and the sera collected. The titration of the circulating antibodies is carried out by the Elisa method according to the conventional methods, in particular those described in: F.AUDIBERT, L. CHEDID, P. LEFRANCIER and J. CHOAY, Immunol. (1976), (21), 143; and M. JOLIVET, F. AUDIBERT, H. GRAS-MASSE, A. TARTAR, D. SCHLESSINGER, R. WITZ and L. CHEDID, Infect. Immunol. (1987), (55), 1498.

c) Results

The results obtained are recorded in the following table:

IMMUNIZATION HYPERSENSIBILITY ANTI-DELAYED TITLE - ELISA BODY induction diameter mm

AIF 0.0.0.0 22,000, 37,000, 65,000, 95,000

AIF + P, 0.0.0.0 7,000, 8,000, 100 μg 21,000.

AIF + MDP-GDP lOOμg 8,14,15,17 241,000,295,000 325,000,641,000.

AIF + MDP-GDP 5,16,20,25 157,000,275,000, lOOμg + P, 275,000,318.0000. 100 μg

: All animals received 1 mg ovalbumin.

The figures represent the maximum dilution of the serum allowing an optical density equal to that obtained by using a normal serum diluted 50 times.

These results show that MDP-GDP is a strong adjuvant of the cell-mediated response and the humoral response and that the addition of P., did not modify their activity.

3): Influence of the Pi sugar derivative on the immunostimulatory properties of muramyl-peptides. a - Anti-infectious activity

Swiss mice received P MDP-GDP, or MDP-GDP + P ₁ by vein 24 hours before infection with 1 x 10 ⁴ Klebsiella pneumoniae. The solution of F. is added to the MDP-GDP to obtain a preparation containing an equivalent quantity of 2 products (weight / weight).

The results in Table I show that P ₁ alone has no protective action against infection. The comparison of the activity of the different doses of MDP-GDP, alone or with P _1f does not show any significant differences.

It can be concluded from these experiments that the compound P. does not inhibit the anti-infectious activity of MDP-GDP. b - Action of MDP-GDP on the production of circulating TNF

TNF (tumor necrosis factor), is a protein synthesized by cells r_ the monocyte / macrophage line when they are stimulated. LPS (bacterial lipopolysaccharide) is a very powerful inducer of TNF production. Muramyl peptides stimulate the production of TNF in vitro, but they are clearly less effective than LPS. In vivo, the levels of serum TNF produced after administration of muramyl peptides are below or at the limit of detection possibilities.

MDP-GDP, and the other derivatives, which have an anti-infectious action, have the property of increasing the response to the LPS injected after, causing a considerable increase in the level of serum TNF. Table II shows the results of an experiment of this type. We see that the pretreatment is more effective 6 hours before the LPS, in particular in the case of the MDP-GPD + P- ,, association but that 16 hours before, the injection of MDP-GDP still has a potentiating effect. of the answer. c - Action of MDP-GDP in vitro on human blood monocytes.

The blood monocytes are isolated and incubated for 24 hours with different doses of product. The supernatants are removed to measure TNF and IL-6, cytokines which are produced by activated monocytes.

Table III shows that the production of TNF is significant only with 10 μg / ml of MDP-GDP and that the product solubilized with the compound - ^ is of slightly higher activity. The assay of IL-6 gives clearer results and also shows a comparable stimulation of monocytes between MDP-GDP and MDP-GDP solubilized in association with P ^ d - Action on human polynuclear cells

Muramyl-peptides have a direct action on polynuclear cells, which is demonstrated in particular by phagocytosis and the destruction of Candida albicans.

The estimation of this action is made by the ability to incorporate glucose treated by the fungus cells that have remained viable.

In the two experiments reported in Table IV, the unstimulated control cells already have a relatively high basic activity. However, the addition of the muramyl peptide, with or without P- _j , produces an increase in the inhibitory activity of the cells on the growth of the fungus.

In conclusion, whether in experiments carried out in vivo in mice or in vitro with human cells, the solubilization of MDP-GDP by the compound P., never decreases its activity. Compound P.] alone is always inactive. TABLE I

Protective action of MDP-GDP solubilized by the compound Pi in mice infected with Klebsiella pneumoniae

IV treatment, Survival at D + 15% Protection ^* at Dl

37.5 ns 37.5 ns 68.7 P <0.01 37.5 ns

37.5 ns 37.5 ns 43.7 P <0.02

75 P <0.02

*: Statistical calculations are made taking into account for each batch of their respective witnesses. TABLE II

Influence of pretreatment with MDP-GDP solubilized by P ₁ on the TNF response induced by LPS

Treatment with 100 μg LPS iv TNF activity in iv / mouse before LPS 25 μg serum ^*

U / ml μg / l

h-6 P-,

h-6 MDP-GDP / P-,

h-6 MDP-GDP h-6 MDP-GDP / P,

h-16 MDP-GDP h-16 MDP-GDP / P,

: 2 hours after the test injection with the LPS Activity expressed in U / ml and in murine recombinant TNF equivalent, in the cytotoxicity test of the cell line L292.

TABLE III

Action of MDP-GDP in vitro on human monocytes

Stimulant μg / ml Activity in the supernatant

TNF U / ml IL-6 U / ml

<10

Cells at 2 x 10 ^O / BU, incubated for 24 hours with the products.

TABLE IV

Action of MDP-GDP on human polynuclear

Stimulant μg / l Candida growth inhibition (%) 1st exp. 2nd exp.

Polynuclear cells (lx 10 ⁶ / πιl) are incubated with the stimulants for 30 minutes and distributed in the microplate wells with a suspension of C. albicans at 1 x 10 ⁴ / m. After 18 hours, the culture medium is eliminated and the incorporation of ³ HD-glucose by the Candida cells is measured after an incubation of 3 hours. 4) Influence of saccharide derivative of P 1 ^"pyrogenic effect of MDP-GDP.

The pyrogenicity tests were carried out on New Zealand rabbits weighing 3 to 4 kg kept in a containment box. The animals received a dose of product in a volume of 0.5 ml / kg intravenously at time zero and their temperature recorded for 5 hours continuously.

(at) . Assessment of the pyrogenicity of P ₁

Two batches of three rabbits were made up:. group I: 10 μg / kg of T? ι; . group II: 100 μg / kg of P ,.

The recorded temperature differences were:. for group I: 0.15, 0.25; 0.25 ( ^β C), an average of: 0.22 ^β C ± 0.06; . for group II: 0.40, 0.15, 0.30 ( ^β C), ie an average of: 0.28 "C ± 0.12.

This experiment indicates that P ^ is completely devoid of pyrogenic effect in rabbits and under the drastic conditions of a recording carried out for 5 hours.

(b). Evaluation of the pyrogenicity of MDP-GDP in the presence of P ₁

The minimum pyrogenic dose of MDP-GDP previously determined is equal to: 2 μg / kg.

A dose of 10 μg / kg was chosen, which gives an approximate temperature increase of 1 ° C.

Two batches of three rabbits were made up:. group I: 10 μg / kg of MDP-GDP; . group II: 10 μg / kg of MDP-GDP + 10 μg / kg of P- ,.

The recorded temperature differences are:. for group I: 0.70, 0.50, 0.85 (° C), an average of: 0.68 ^β C ± 0.18; . for group II: 1.15, 0.90, 0.65 ( ^β C), or an average of: 0.90 ° C ± 0.25.

A Student statistical test (unpaired two-tailed t test, p = 0.2866) indicates that this difference is not significant and therefore that P. does not induce a synergy of the pyrogenic effect of another product like MDP -GDP.

The dispersed compositions obtained have pharmacological properties which are of the same nature as those reported above for the dispersions of the composition MDP-GDP-P- ,. We return again in 1 • example V to particularly interesting pharmacological results which also use dispersible compositions based on MDP (Thr) '- GDP and P

EXAMPLE II Production of a composition dispersible in an aqueous solution based on α-acetyl-muramyl-L-threonyl-D-isoglutamine) - ^, ₇ -dipalmitoyl-sn -glycerol (MDP (Thr) ^ - GDP)

This dispersion in the presence of the compound PI, is obtained under exactly the same conditions as for the MDP-GDP

EXAMPLE III Production of a composition dispersible in an aqueous solution of a monophosphorylated analogue of Lipid A

2.1 mg of the monophosphorylated derivative of lipid A (MPL produced by Ribi Immunochem. Research, Inc.) is dissolved in 0.5 ml of chloroform (solution A). 3.8 mg of P ^ are dissolved in 1 ml of chloroform (solution B).

The chloroform solutions (A) and (B) are combined. 2 to 3 ml of distilled water are added and a stream of nitrogen is bubbled from the bottom of the tube containing the two phases, until complete elimination of the chloroform. A homogeneous and stable, slightly opalescent aqueous dispersion is obtained.

Biological properties of the aqueous dispersion of MPL (monophosphoryl Lipid A, Ribi immunochem. Research, Inc.) with compound P ₁

Antibacterial activity.

MPL is dissolved according to the procedure recommended by Ribi immunochem. Research, Inc .. From a solution in the chloroform: methanol mixture (4: 1) of 20 mg of MPL, a stock solution containing 4 mg / ml of MPL is thus prepared, then by addition of physiological serum free of calcium, 2 mg / ml solution.

The test is carried out as described in Example 1, paragraph 3a.

Compound P ₁ does not alter the protective effect of MPL against infection by K. pneumoniae.

TABLE V Protective effect of MPL (Ribi immunochem. Research Inc.) alone or in the presence of compound P _1f against infection by a high dose (4 × 10 5) of K. pneumoniae, in Swiss mice .

SURVIVORS / TOTAL TREATMENT

ON DAY + 15

0/8

0/8 4/8 7/8

1/8 4/8

8/8

EXAMPLE IV Aqueous dispersion of a monosaccharide analog of Lipid A, MRL 953 (monophosphorylated monosaccharide analog), of formula VI, with the compound P ₁

a) Production of the dispersion

10.65 mg of MRL 953 are dissolved in 0.5 ml of chloroform (solution A). 16.91 mg of P, are dissolved in 0.5 ml of chloroform (solution B).

The chloroform solutions (A) and (B) are combined. 2 to 3 ml of water are added and a stream of nitrogen is bubbled from the bottom of the tube containing the two phases, until the chloroform is completely eliminated. A homogeneous and stable aqueous dispersion is obtained, very slightly opalescent.

The aqueous dispersion is lyophilized and the powder obtained is taken up in an aqueous solvent at desired concentration. A dispersion of the same appearance and quality is obtained as above, b) Biological properties of the aqueous dispersion of the

MRL 953 with compound P ₁

Antibacterial activity (Figures l (a) and l (b)

The protective effect against infection by K pneumoniae was evaluated in female Swiss mice (5 to 6 weeks old).

The mice received the day before the intravenous injection:

- 0.2 ml of physiological saline,

- LPS (lipopolysaccharide from Sal onella enteritidis) suspended in 0.2 ml of physiological saline,

0.2 ml of (1) the aqueous dispersion of P., + MRL 953, containing 30, 10, 3 and 1 μg of MRL 953 (2) the dispersion in a glucose solution of MRL 953, containing 30, 10, 3, and 1 mg of MRL 953. Infection with K. pneumoniae is carried out by intravenous injection of a suspension of 0.2 ml of a suspension of bacteria (containing 4.5 × 10 ³ bacteria). Mortality is noted during the two weeks following inoculation of the bacteria.

The comparison of Figures l (a) and l (b) shows that the protective effect of MRL 953 is comparable, regardless of the dispersion method used. Figures l (a) and l (b) indeed include curves representative of the variations in the percentages of surviving mice (% on the ordinate axes) as a function of time (T in days on the abscissa axes) when the substances studied (LPS and MPL953) were administered at the doses indicated on the right of the figures, in the form dispersed in: - a glucose solution (figure l (a)) - a solution of the derivative of oside P., (figure l (b))

It results from an examination of the figures that the protective effect of the substances studied, more particularly MRL953, against infection by K. pneumoniae in mice is of the same order of magnitude in both cases . It would even be more effective, when MLR953 is administered in the form of a dispersion, in combination with the derivative of oside P- ,.

EXAMPLE V Influence of the dispersions according to the invention on the biological properties of a third active principle

The association of certain muramylpeptides with an oside derivative can very advantageously lead to a third active principle:

. either an increase in the biological activity of the third active ingredient,

. either a decrease in the toxicity of this third active ingredient,

. either both.

So, for example, we notice:

. a significant increase in the antiviral activity of interferon, when the latter active principle is administered after administration of the combination of MDP (Thr) ¹ -GDP and of compound P-, under the conditions allowing the formation of their aqueous dispersion;

. a decrease in the toxic synergy of LPS with a muramylpeptide having a certain pyrogenic effect, for example the MDP-GDP of compound P _{1 #} under conditions corresponding to those already described in the previous examples. In particular doses of LPS, lethales for the mouse when administered alone, are no longer administered when these same

These are admitted in association with the mixture of MDP-GDP and the compound P ,.

In other words, the invention also relates to the application of the compositions according to the invention to the modulation of biological properties of third-party compounds, administered concomitantly or not.

These modulation effects are further illustrated in a nonlimiting manner by the examples, the results of which are reported below.

(1) - influence of the use of compound P ₁ on the immunostimulatory properties of lipophilic muramylpeptides a) - Increase of the antiviral activity of interferon by MDP (Thr) ¹ -GDP The experimental model is 1 * encephalomyocarditis the mouse. The animals are male mice (Swiss, 17 g). They receive by the intraperitoneal route either an aqueous suspension of the only MDP (Thr) ¹ -GDP, or an aqueous dispersion of MDP (Thr) ¹ -GDP and of compound

Pi-

After 24 hours, they are injected with the virus

Encephalomyocarditis intraperitoneally at the rate of 100 times the LD 50. One hour after this injection, some animals receive intraperitoneally 25,000 U.l. mouse interferon a, β.

Table VI presents the results obtained. As a result, the use of compound P does not decrease, but on the contrary increases the antiviral activity proper to MDP (Thr) ¹ -GDP, and the effect of potentiating the antiviral activity of interferon by this. lipophilic muramylpeptide. TABLE VI

Increased antiviral activity of interferon a, β against infection by the encephalomyocarditis virus, in mice

TREATMENT i.p. INTERPERON, β% SURVIVAL AT D - 1

Witness - 0%

P (600 μg) - 0%

MDP (Thr) ¹ -GDP (600 μg) - 20%

| CDM (Thr) ¹ -GDP (600 μg) - 35%

+ 30%

P, (600 μg) + 30%

MDP (Thr) ¹ -GDP (600 μg) + 46% | P, (600 μg) +

| MDP (Thr) -GDP (600 μg) + 70%

b) - Influence of a pre-treatment with lipophilic muramylpeptides on the production of circulating TNF following the injection of LPS or of a synthetic analogue of Lipid A (Table VII) Swiss mice receive an intravenous injection of:

- 0.2 ml of physiological saline,

- MDP-GDP suspended in 0.2 ml of physiological saline,

- MDP (Thr) ¹ -GDP in aqueous suspension, alone, or in aqueous dispersion, in the presence of compound P ,,

- Murabutide in solution in 0.2 ml of physiological saline. The preceding intravenous injection is made 6 hours before the injection of LPS (S. enteritidis) in physiological saline or else MRL 953 dispersed in physiological saline in the presence of P ,.

The animals are bled in the abdominal aorta 1.5 to 2 hours (optimum response time) after this last injection. TNF activity is evaluated by the cytotoxicity test being measured by the number of viable cells. One unit of TNF represents the concentration which produces 50% cytotoxicity under the given conditions.

Aqueous suspensions of lipophilic MDP stimulate the TNF response to stimulation by LPS or by the aqueous dispersion of MRL 953 in the presence of P ,. This effect is slightly accentuated with the aqueous dispersions of these lipophilic MDPs in the presence of the compound P- ,.

TABLE VII

Influence of a pre-treatment with a lipophilic MDP on the production of serum TNF following the injection of LPS or of a synthetic analogue of Lipid A (MRL 953).

| MDP (Thr) ¹ -GDP 100 μg

1+ P, LPS 7.347

c) - Reduction of the toxic synergy of LPS and MDP-GDP in the presence of compound P, (TABLE VIII)

MDP-GDP, suspended in 0.2 ml of physiological saline, alone, or in a glucose solution in the presence of pluronic acid (F 68, SERVA), or else in dispersion in 0.2 ml of physiological saline in presence of compound P _1f is administered intravenously with LPS (S. enteritidis) to Swiss adrenalecto isis mice.

Mortality is noted in 3 days, but it most often occurs in 24 to 48 hours.

Suspensions of MDP-GDP in physiological saline or in a glucose solution of pluronic acid increases the toxicity of the LPS injected simultaneously. The dispersion of MDP-GDP in the presence of P., reduces this effect.

This reduction in the toxic effect is not due to a direct effect of the compound P ₁ on the LPS; the toxicity remains in normal mice in the presence of the compound P. (results not shown).

It will be noted that the advantage of these results lies in the fact that the association with the oside derivative makes it possible to envisage the use in vivo of a greater number of lipophilic products, for example lipophilic muramylpeptides which, such MDP-GDP, may have some residual pyroginicity, without having to fear significant toxic synergy, in vivo, of these products with the LPS of infectious organisms possibly present in the host. TABLE VIII

Reduction of the toxic synergy of LPS and MDP-GDP in the presence of P ^

Claims

1. Composition capable of being dissolved or dispersed in a homogeneous and stable manner in a pharmaceutically acceptable aqueous solution, characterized by the combination: on the one hand, of a lipophilic active principle of drug or "pharmacologically active substance", comprising at least at least one hydrocarbon group comprising itself at least 3 carbon atoms, and - on the other hand, of a solubilizing osidic derivative, itself water-soluble, pharmaceutically acceptable, itself carrying a hydrocarbon group comprising at least 3 carbon and comprising one or more hydroxyl functions, at least one of which is substituted by a phosphate or sulphate group, this osidic derivative being in a proportior. sufficient with respect to the lipophilic active principle to promote the solubilization or the dispersion of the whole of the composition in an aqueous solution.

2. Composition according to claim 1, characterized in that the pharmacologically active lipophilic substance is a substance of saccharide, peptide or polypeptide type, of cyclic nature or not, glycopeptides of cyclic nature or not, carrying at least one hydrocarbon chain comprising at least three carbon atoms.

3. Composition according to claim 1 or claim 2, characterized in that the hydrocarbon group consists of:

. either by at least one linear hydrocarbon structure of 3 to 20, in particular of 4 to 20 carbon atoms, comprising where appropriate, one or more ether, ester, thioether, thioester bond, or amide, this linear structure being designated hereinafter by "type A" lipophilic group,

4. Composition according to claim 1 or claim 3, characterized in that the pharmacologically active substance is a lipophilic derivative of muramyl-peptide.

5. Composition according to claim 4, characterized in that the pharmacologically active substance is chosen from the compounds corresponding to the following formula (II):

) _ ₂ - Y

in which

- R represents H or CH;

- R represents a group - NH ₂ , -OH or a group -OW- _j ,

W., being a hydrocarbon group having from 1 to 10 carbon atoms; X represents an aminoacyl residue from the group comprising alanyl, valyl, isoleucyl, norleucyl, leucyl, threonyl, prolyl, glutaminyl, asparaginyl, methionyl, tryptophanyl, phenylalanyl, tyrosyl, glycyl;

Y represents either OH or NH ₂ or a group -OW ₂ , W ₂ being a hydrocarbon group of 1 to 4 carbon atoms, or even a lipophilic group "of type A" or "of type B",

- Z represents either H or a lipophilic group "type A" or "type B", it being understood however that at least one of the two groups Y and Z is always constituted by a lipophilic group of type A or B;

- n- _| and n ₂ , identical or different, represent zero or 1,

- A _T and B, are either identical or different groups respectively comprising from 1 to 3 aminoacyl residues, themselves identical or different from each other, or else a group -NH- (CH ₂ ) _p -CO- with values of p between 2 and 10.

6. Composition according to claim 5, characterized in that the pharmacologically active substance is chosen from the compounds of formula (II) in which:

- n, and n ₂ represent zero,

- R ₅ represents CH ₃ ,

- R _$ represents -OH, -NH ₂ or -On (CH) H with x ^ included

^{2 X} 1 between 1 and 6, with a preference for x ₁ = 4,

- X is L or D-alanyl, L-threonyl, L-valyle,

- when Y represents -0-CH -CHO (R ₇ ) -CH ₂ 0 (R ₈ ), Z represents H, and when Z represents

O -C-CHO (R ₇ ) -CH ₂ 0 (R ₈ ), Y represents -OH, -NH ₂ or a group -OW _2j W having the meaning indicated in claim 6, and R ₇ and R ₈ being groups palmitoyles.

7. Composition according to claim 5, characterized in that the pharmacologically active substance is chosen from the compounds of formula (II) in which:

- n, and n ₂ represent zero,

- Rg represents CH ₃ ,

- Ra represents -OH, or -NH or -On (CH ₂ ) H with x, between 1 and 6, with a preference for x-≈4,

- X is L or D-alanyl, L-threonyl, L-valyle,

- when Y represents -0- (CH ₂ ) _x H with x ₂ = 8, Z

2 represents H, and when Z represents -CO (CH ₂ ) _x H, with x ₂ = 8, Y represents -OH, -NH ₂ , or a group -OW ₂ , W ₂ having the meaning indicated in claim 6.

8. Composition according to claim 1, characterized in that the pharmacologically active substance is formed from constituents of bacterial origin, inter alia constituents of the bacterial wall: derivatives of trehalose, in particular of the TDM type (products of the class trehalose dimycolates), lipolysaccharides (LPS), comprising on the one hand lipid chains and, on the other hand, at least one phosphate or sulfate group.

9. Composition according to claim 1, characterized in that the substance p rmacologically active is a lipid fraction ot anue from these LPS, in particular "Lipid A", this fraction comprising at least one phosphate or sulfate group.

10. Composition according to claim 9, characterized in that the substance pharmacologically active is formed of lipid A derivatives or analogs, mono- or di-saccharide, mono- or diphosphorylated, carrying branched chains or even linear hydrocarbon chains, which can themselves be substituted or not, by linear hydrocarbon chains by means of ester, thioester, ether or thioether bonds.

11. Composition according to any one of claims 8 to 10, characterized in that the pharmacologically active substance consists of a monophosphorylated lipid A, in particular MPL.

12. Composition according to any one of claims 8 to 10, characterized in that the pharmacologically active substance consists of an analog of lipid A corresponding to the general formula (IV),

NHR ^' 2

in which:

R ₄ and R'τ represent H or P0, with at least R ^ or R ', being a group P0 ₄

R ₂ , R ₃ and R * ₂ , R * ₃ represent C0-CH (0R) - (CH ₂ ) _x -CH ₃ , x being between 5 and 15, with a preference for x = 10, and R being CO - (CH ₂ ) y-CH ₃ being between

5 and 15 with a preference for y = 10 or 12.

13. Composition according to any one of claims 8 to 10, characterized in that the pharmacologically active substance consists of a monosaccharide derivative of lipid A corresponding to the general formula (V):

NHR2 in which:

R, represents H or P0 ₃

R and R ₃ represent CO-CH (R) - (CH ₂ ) _X -CH ₃ , x being between 5 and 15, with a preference for x = 10, and R being H or OH or also C0- (CH ₂ ) _y -CH ₃ , including between 5 and 15 with a preference for y = 10 or 12,

R ₄ represents PC ^ if R ₁ is not P0 ₃ , or H or one of the meanings given to R and R ₃ .

14. Composition according to claim 13, characterized in that the monosaccharide derivative of lipid A is the compound of formula VI:

15. Composition according to any one of claims 1 or 2, characterized in that the pharmacologically active lipophilic substance is a substance of cyclic peptide type, such as a cyclosporine.

16. Composition according to claim 1 or claim 2, characterized in that the pharmacologically active substance is a substance of peptide type, such as gramicidin, or a substance of macrolide type, such as leucensomycin, or a substance of pseudopeptide type , such as valinomycin, or a fat-soluble vitamin, in particular of the vitamin A, D, E, K type,

17. Composition according to any one of claims 1 to 16, characterized in that the osidic derivative is represented by the following formula (I):

in which :

- R represents H, or OH, or an acetamido, sulfate, sulfamido, phosphate, phosphamido group,

- R represents either H, OH, or OCH ₃ , or else a dare or osamine residue whose ano eric carbon in position 1 (Cl) is engaged in a glycosidic bond, the positions C2, C3 and C4 being respectively substituted by groups R ' ₂ , R' ₃ , and R ' ₄ having respectively the meanings given above for R ₂ , R ₃ , and R ₄ , and position C6 by a group R' having the meaning given above for

R, at least one of the groups R ₂ , R ', R ₃ , R' ₃ , R ₄ or R ' ₄ representing a sulfate or phosphate residue.

18. Composition according to Claim 17, characterized in that the group R or the group R 'consists of: . or by at least one linear hydrocarbon structure of 3 to 20, in particular of 4 to 20 carbon atoms, comprising where appropriate, an ether, ester, thioether, thioester, or amide bond, this linear structure being designated below by group "type A" lipophilic,

19. Composition according to Claim 17 or Claim 18, characterized in that the osidic derivative is chosen from the following compounds:

- or / 3-methyl-glycoside N-acetyl-4-sulfate-6-0R- 2-deoxy-glucosamine,

- N-acetyl 4-sulfate-6-0R-2-deoxy-glucosamine,

- a or 0-methyl-glycoside 4-sulfate-6-OR-glucopyranose,

- 4-sulfate-6-OR-glucopyranose,

- 6,6'-di-OR-4,4 • -di-sulfate-α, • -D-trehalose,

R having the meaning given in claim 17 or 18.

20. Composition according to claim 17, characterized in that the osidic derivative is chosen from the following compounds:

- a or j8-methyl-glycoside N-acety1-4-sulfate-6-octanoyl-2-deoxy -glucosamine,

- α or / S-methyl-glycoside-N-acetyl-4-sulfate-6- (2,3-dipalmitoyl) glyceroyl-2-deoxy-glucosamine,

- N-acetyl-4-sulfate-6-octanoyl-2-deoxy-glucosamine,

- N-acetyl-4-sulfate-6- (2,3-dipalmitoyl) -glyceroyl-2-deoxy-D-glucosamine, - or 0-methyl-glycoside 4-sulfate-6-octanoyl-glu- copyranoside,

- a or? -methyl-glycoside 4-sulfate-6- (2,3-dipalmi-toyl) -glyceroyl-D-glucopyranoside,

- 4-sulfate-6-octanoyl-D-glucopyranose,

- 4-suyl-D-glucopyranoside,

- 4-sulfate-6-octanoyl-D-glucopyranose,

- 4-sulfate-6 (2,3-di-pal itoyl) -glyceroyl- glucopyranose

- 4.4 'di-sulfate-6.6' di-octanoyl-α, α'-D-trehalose,

- 4,4'di-sulfate-6,6 '(2,3-dipalmitoyl) -glyceroyl-α-α • - D-trehalose.

21. Composition according to any one of claims 18 to 20 in combination with any one of claims 3 to 8, characterized in that it comprises:

.

22. Composition according to any one of claims 18 to 20 in combination with one any one of claims 9 to 13, characterized in that it comprises:

23. Composition according to any one of claims 1 to 22, characterized in that the oside derivative and the pharmacologically active substance are advantageously in a weight ratio of 0.25 to 4, in particular from 0.5 to 1.5 .

24. Composition according to any one of claims 1 to 23, characterized in that it is in the anhydrous state, in particular in the form of lyophilisate.

25. Pharmaceutical composition, characterized in that it comprises a composition according to any one of claims 1 to 24, where appropriate in combination with a pharmaceutically acceptable vehicle, either in the anhydrous state or in the state dispersed in a physiologically acceptable aqueous solvent.

26. Oside derivative corresponding to the following general formula (I):

in which

- R represents a hydrocarbon group comprising at least 3 carbon atoms,

- R represents either H, OH, or OCH ₃ , or a dare or osamine residue whose anomeric carbon in position 1 (Cl) is engaged in a glycosidic bond, the positions C2, C3 and C4 being respectively substituted by groups R ' ₂ , R' ₃ , and R 'respectively having the meanings given above for R, R ₃ , and R ₄ , and the position C6 by a group R' having the meaning given above for

R, at least one of the groups R ₂ , R ' ₂ , R ₃ , R * ₃ , R ₄ or R' representing a sulfate or phosphate residue, it being understood that at least one of the preceding groups is a sulfate group .

27. An oside derivative according to claim 26, characterized in that the group R or the group R * consists of: . or by at least one linear hydrocarbon structure of 3 to 20, in particular of 4 to 20 carbon atoms, comprising where appropriate, an ether, ester, thioether, thioester, or amide bond, this linear structure being designated below by group "type A" lipophilic,

28. An oside derivative according to claim 26 or claim 27, corresponding to one of the following formulas:

- α or 3-methyl-glycoside N-acetyl-4-sulfate-6-OR- 2-deoxy-glucosamine,

- N-acetyl 4-sulfate-6-OR-2-desoxy-glucosamine,

- α or / 3-methyl-glycoside 4-sulfate-6-OR-glucopyranose,

- 4-sulfate-6-OR-glucopyranose,

- 6,6'-di-OR-4,4'-di-sulfate-α, α • -D-trehalose,

R having the meaning given in claim 26 or claim 27.

29. Oside derivative according to claim 26, corresponding to one of the following formulas:

- α or / 3-methyl-glycoside N-acetyl-4-sulfate-6-octanoyl-2-deoxy-glucosamine,

- a or j9-methyl-glycoside-N-acetyl-4-sulfate-6- (2,3-dipalmitoyl) glyceroy1-2-deoxy-glucosamine,

- N-acetyl-4-sulfate-6-octanoyl-2-deoxy-glucosamine,

- N-acety1-4-sulfate-6- (2,3-dipalmitoyl) -glyceroyl-2-deoxy-D-glucosamine,

- α or) 3-methyl-glycoside 4-sulfate-6-octanoyl-glu- copyranoside, - or 0-methyl-glycoside 4-sulfate-6- (2,3-dipalmi-toyl) -glyceroyl-D-glucopyranoside,

- 4-sulfate-6-octanoyl-D-glucopyranose,

- 4-sulfate-6 (2,3-di-palmitoyl) -glyceroyl- glucopyranose

- 4.4 'di-sulfate-6.6' di-octanoyl-α, α'-D-trehalose,

- 4.4 ^" di-sulfate-6.6" (2, 3-dipalmitoyl) -glyceroyl-α-α'- D-trehalose.