LU84421A1 - URSODESOXYCHOLIC ACID SALTS, THEIR PREPARATION AND THEIR USE - Google Patents

Description

2.

"Salts of ursodeoxycholic acid, their preparation and their use" _

The present invention relates to pharmaceutically usable, water-soluble salts of ursodeoxycholic acid.

Ursodeoxycholic acid, or 3a, 5 7ß-dihydroxy-6ß-cholan-24-oic acid, is a well-known drug, particularly for its ability to lower the cholesterol content of bile, and is therefore used as a solvent for gallstones made up of cholesterol.

It nevertheless has the disadvantage of being extremely poorly soluble in water, which hinders its use in most pharmaceutical forms. Alkali metal salts can be prepared to overcome this drawback, but they have the disadvantage of bringing with them alkali ions, especially sodium, which are often contraindicated.

The object of the present invention is to develop a salt of ursodeoxycholic acid which is highly soluble in water and does not have the drawbacks of alkali metal salts.

• For this purpose, according to the invention, the salt consists of the reaction product of ursodeoxycholic acid and at least one basic amino acid ^^ 1 ^ »3.

Advantageously, the salt contains approximately 1 to 5 moles, and preferably approximately 1 mole of basic amino acid per mole of ursodeoxycholic acid. The basic amino acid (s) used may or may not be natural, such as, for example, arginine, lysine, histidine and ornitbin.

The basic amino acids according to the present invention may contain one or more asymmetric centers and may therefore exist in the optically active isomeric forms. It is understood that the invention covers the two epimeric forms, such as the levorotatory and dextrorotatory forms, as well as their mixture. Examples of basic levorotatory and dextrorotatory amino acids are D- and L-lysines and .D- and L-arginines.

The invention also relates to the preparation of these salts of ursodeoxycholic acid.

According to a first way of proceeding, the ursodeoxycholic acid is reacted with an aqueous solution containing the basic amino acid (s). After reaction, the water is then separated from the reaction mixture thus obtained, by suitable separation methods, such as evaporation or lyophilization.

Another way of proceeding consists in reacting an aqueous, organic, or hydroorganic solution or dispersion containing the basic amino acid (s) with an organic or hydroorganic solution or dispersion containing ursodeoxycholic acid, with an aqueous solution or suspension containing ursodeoxycholic acid or with ursodex soxycholic acid as such, and to separate the solvent from 4.

reaction mixture thus obtained, by appropriate separation methods, such as filtration, lyophilization or evaporation. Examples of organic solvents used to dissolve or suspend the 5 amino acids and ursodeoxycholic acid are polar organic solvents, such as alcohols, glycols, polyglycols, ketones, dimethylformamide and dimethyl sulfoxide.

It is also possible to use mixtures of.

10 such solvents.

A third way of proceeding consists in bringing one or more salts of the amino acid or basic amino acids in aqueous, organic or hydroorganic solution with ursodeoxycholic acid in aqueous or organic or hydroorganic solution or suspension, and in separating the solvent for the reaction medium by appropriate separation methods, such as by evaporation, lyophilization or filtration. An example of an amino acid salt is lysine carbonate. Examples of precipitation solvents are alkyl acetates, sulfuric ether, dioxane ,. tetrahydro-furan, ketones, alcohols and their mixtures.

Another way of proceeding consists in thoroughly mixing the solid reagents, that is to say the basic amino acid (s) or their salts, with ursodeoxycholic acid. The powder thus obtained is immediately usable for the preparation of preparations to be dissolved at the time of use.

The dissolution of the powder mixture takes place, as is well known, in an appropriate amount of water and a pharmaceutically acceptable organic solvent, such as ethanol. In case the carbo- / 9 / * 5.

nate of an amino acid or a mixture of amino acids is used, the powder obtained, after optional addition of an acid or a mixture of pharmaceutically acceptable acids, and an excess of carbonate the a-5 eide amino, allows obtaining effervescent preparations.

According to the invention, in the four ways of proceeding, the aforementioned treatment is carried out at a temperature of the order of -5 to 100 ° C, and preferably 10 at a temperature in the region of 20 ° C.

Ursodeoxycholic acid is a sterol derivative poorly soluble in water. As already stated, salts are easily formed with basic amino acids, such as arginine, lysine, histidine and ornithine.

The water soluble ursodeoxycholic acid salts require from 0.5 to 5 amino acid molecules and preferably 1 amino acid molecule per ursodeoxycholic acid molecule.

In fact, the ursodeoxycholic acid salts of the invention correspond to the following formula: 1.30 25 1

/ XXX C00H

œ3Î J_] vV ^ OH. η X Λ HO 'rf (f.

6.

in which n, representing the number of amino acid molecules relative to 1 molecule of ursodeoxycholic acid, is between 1 and 5, and preferably between 1 and 2, and X represents the amino acid (s).

The water-soluble ursodeoxycholic acid salts of the present invention can therefore be obtained using known methods for the preparation of salts, and in particular by the aqueous or hydroorganic or organic solution or suspension of one or more amino acids, or by the aqueous or hydroorganic or organic solution or suspension of one or more amino acid salts, at which, while maintaining the temperature between 0 ° C and 100 ° C and preferably at around 20 ° C., the quantity of ursodeoxycholic acid, optionally as such or in the form of an aqueous, organic or hydroorganic solution or suspension, is added, with stirring, in small portions. It will be noted, for this purpose, that the order of addition of the reactants brought into contact can be reversed.

When the solution has become clear, the solvent is removed from the reaction mixture by any suitable separation methods, such as, for example, by lyophilization (aqueous solution) or by moderate heating in vacuo. A water-soluble powder is thus obtained which can be used for the preparation of solid forms (tablets, suppositories, tablets, granules, dragees) and injectable forms. It goes without saying that the solutions of ursodeoxycholic acid salts prepared as explained above can be used immediately in form.

injectable without being lyophilized beforehand, and provided that their ionic strength is acceptable or made such.

A few non-limiting examples of the preparation of the compounds according to the invention are given below.

EXAMPLE 1 To an aqueous solution containing 14.6 g of lysine base in 50 ml, 39.2 g of ursodeoxycholic acid are added gradually and with stirring. The pH is adjusted to 7.5 + 0.5 by adding either ursodeoxycholic acid or lysine base. The solution thus obtained is frozen and lyophilized.

53 g of the lysine salt of ursodeoxycholic acid instantaneously soluble in water and having the following characteristics are obtained:

M.p. 137-142 ° C

Solubility in water: more than 20%. 10% solution pH = 7.8.

By proceeding in the same way with arginine, histidine or ornithine, the corresponding salts are obtained, which are all soluble in water.

EXAMPLE 2 To a solution of 2.92 g of lysine base in 25 ml of water, 7.85 g of ursodeoxycholic aci dissolved in 50 ml of ethanol are added in small portions. After approximately 1 hour of reaction, the solution is evaporated to dryness. The lysine salt of ursodeoxycholic acid thus obtained is in the form of a white powder instantly soluble in water.

Example 3 * To a suspension of 14.6 g of lysine base / y (J / 8i in 150 ml of isopropanol, 39.25 g of ursodeoxycholic acid is added with stirring. The product crystallizes as it is After 2 hours of reaction, the solid is separated by filtration and dried at 60 ° C. About 48 g (90.0%) of lysine salt of ursodeoxycholic acid are obtained.

Example 4 To a solution of 16.8 g of lysine carbonate in a mixture of 20 ml of water and 50 ml of methanol, 39.25 g of ursodeoxycholic acid are added in small portions. After 1 hour of reaction, the clear solution is evaporated under vacuum and 50.5 g (90%) are obtained. The lysine salt of ursodeoxycholic acid thus obtained in the form of a white powder is instantly soluble in water.

The water-soluble ursodeoxycholic acid salts of the present invention have the property of decreasing hepatic secretion of cholesterol and thus of increasing the dissolving power of bile against cholesterol; this property is used in therapy, in particular to dissolve gallstones made up of cholesterol and thus avoid, in certain cases, the recourse to a surgical intervention intended to eliminate these stones.

The ursodeoxycholic acid salts of the invention can be administered in combination with various pharmaceutical excipients, such as diluents, gelling agents, preserving agents, emulsifiers, »sweeteners and flavorings, etc. and this 30 orally, parenterally or rectally.

For oral administration, dragees, granules, lozenges, microgranules, tablets, / i 9 will be used.

capsules, tablets, solutions, syrups, emulsions containing conventional additives or excipients in galenic pharmacy. These dosage forms can release the principle in a normal way or programmed in time.

For parenteral administration, any suitable vehicle will be used, such as, for example, sterile water, peanut oil or ethyl oleate.

For rectal administration, suppositories, rectal capsules, solutions or jellies will be used.

The active compound can be administered alone or in combination with other active products having similar or different activity.

The recommended doses for oral, intravenous and rectal administration are, for example,

for example, from 10 mg to 2 g, advantageously from 5 to 15 mg / per kg of body weight per day. / W

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Claims (16)

10. 1. Water-soluble ursodeoxycholic acid salt, characterized in that it consists of the reaction product of ursodeoxycholic acid and at least one basic amino acid. 2. Salt according to claim 1, characterized in that the basic amino acid is a levorotatory, dextrorotatory amino acid or a mixture of such acids. 3. Salt according to either of Claims 1 and 2, characterized in that the basic amino acid is chosen from the group formed by arginine, lysine, histidine and ornithine . 4. Salt according to any one of claims 1 to 3, characterized in that it contains approximately 15 1 to 5 moles of basic amino acid per mole of urso deoxycholic acid. 5. Salt according to claim 4, characterized in that it contains approximately 1 mole of basic amino acid per mole of ursodeoxycholic acid. 6. Process for preparing the water-soluble urso deoxycholic acid salt according to any one of claims 1 to 5, characterized in that the basic amino acid is treated in aqueous solution with ursodeoxycholic acid and in that the The water is separated from the reaction mixture thus obtained by any suitable separation methods, such as by evaporation, lyophilization or filtration. 7. Process for the preparation of the water-soluble urso-deoxycholic acid salt according to any one of Claims 1 to 5, characterized in that the basic amino acid in solution or suspension / / y / 11 is treated. Hydroorganic or organic with ursodeoxycholic acid in organic solution or dispersion, in aqueous dispersion or as such, and in that the solvent is separated from the reaction mixture thus obtained by any suitable separation methods, such as by filtration, lyophilization or evaporation. 8. A process for preparing the water-soluble urso-deoxycholic acid salt according to any one of claims 1 to 5, characterized in that a salt of the basic amino acid is treated in aqueous hydroorganic solution or suspension or organic with ursodeoxycholic acid as it is or in aqueous, hydroorganic or organic solution, and in that the solvent is separated from the reaction mixture thus obtained by any suitable separation methods, such as filtration, lyophilization or evaporation. 9. Process for preparing the water-soluble ursodeoxycholic acid salt according to one of claims 1 to 5, characterized in that the ursodeoxycholic acid is intimately mixed with a basic amino acid and a mixture of amino acids. basic or their salts, the ursodeoxycholic acid salt then forming upon dissolution of the mixture in water or a pharmaceutically acceptable organic solvent. 10. Process according to either of Claims 8 and 9, characterized in that the amino acid salt is lysine carbonate. 11. Method according to any one of claims 6 to 10, characterized in that the above-mentioned treatment is carried out at a temperature between / V -5 ° C and 100 ° C. ^ 'i 12. 12. Method according to claim 11, characterized in that the treatment is carried out at a temperature of the order of 20 ° C. 13. Process according to either of Claims 5 and 8 / characterized in that the organic solvent used to dissolve or suspend the amino acid or its salt and the ursodeoxycholic acid is a polar organic solvent or a mixture of polar organic solvents. 14. Pharmaceutical compositions comprising, as active product, at least one water-soluble ursodeoxycholic acid salt according to any one of claims 1 to 5, combined with at least one suitable excipient and / or at least one other therapeutic agent. . 15. Method of using the salts of urso deoxycholic acid according to any one of claims 1 to 5 or of the composition according to claim 14, as an agent capable of lowering the quantities of cholesterol available for the organism, and , in particular its bile concentration, characterized in that salts of ursodeoxycholic acid are administered orally, parenterally or rectally, at daily doses of 10 mg to 2 g per kg of body weight per day. 16. Salts of ursodeoxycholic acid, their preparation and their use, as described above, in particular in the examples given. Drawings: -. plates ..... Aû / .... pages including —A— cover page J ________i_______ pages of description ........ 3 ....... pages of claims ______ descriptive abstract Luxembourg, OCT 12 . 1982 Charles München