MXPA00003406A - Bile acid salts of metals with physiological action and the use thereof in therapy - Google Patents

Abstract

The present invention relates to bile acid metal salts of therapeutical interest, as well as to pharmaceutical and veterinary compositions containing said salts.

Description

'METALLIC ACIDS OF ACID BÉljl ON PHYSIOLOGICAL ACTION AND USE OF THEM IN THERAPY DESCRIPTIVE MEMORY The present invention relates to metal salts of bile acid that can be used for therapeutic purposes. The invention also relates to pharmaceutical and veterinary compositions containing these salts. There are several metal cations that fulfill a physiological function: in addition to iron, which is a component of hemoglobin, different amounts of zinc, copper, selenium, molybdenum, cobalt, manganese, etc., known as trace elements, are needed for Enzymatic and physiological systems work correctly. Normally, these elements are absorbed through the diet, but there are pathological conditions or food deficiencies in which it is convenient to administer salts or complexes as a pharmacological supply or food supplement. The problem is especially important in the case of iron, whose administration is frequently required for the treatment of anemia due to iron deficiency. For this purpose, salts such as ferrous gluconate or ferrous sulfate or iron complexes with succinylated proteins are currently used.

Currently, it has been discovered that the aforementioned metallic salts of bile acid provide high and gradual absorption of the metal cation which can be transported selectively to the enterohepatic circle. The use of bile acids as vehicles for iron or trace elements has been particularly advantageous and allows to overcome some of the disadvantages of the compounds of prior art. In fact, bile acids, acting as penetration factors of the intestinal barrier, provide a higher bioavailability, thanks also to its recycling effect through the enterohepatic circle, thus ensuring a dynamic gradual absorption. Furthermore, in the particular case of iron salts, adverse side effects common to the oral administration of these compounds are avoided, such as constipation, gastroenteric intolerance, meteorism and epigastralgia. It is possible to prepare the salts of this invention using conventional methods, by reacting the natural bile acids or derivatives thereof with metal hydroxides or by exchange reactions between suitable metal salts and an alkaline bile acid or alkaline earth salts. Among natural bile acids are colic acid, deoxycholic acid, chenodeoxycholic acid, chenoic acid, ursocholic acid, ursodeoxycholic acid and hiodeoxycholic acid, and the corresponding tauro- and gl-conjugates. Natural bile acids can be optionally derivatized by introducing more salivary acid groups, for example by reacting them with dicarboxylic acid anhydrides or polycarboxylic acid, such as succinic, glutaric and cyclohexanedicarboxylic acids. Some of these derivatives "are known and can be prepared according to conventional methods, such as those described in Italian Patent No. 1,163,090. A different approach is the ketalization of the keto groups present in the bile acid molecule with tartaric acid, and of hiocholic acid with ketomalonic acid. The presence of more salivable groups per bile acid molecule provides an increase in the molar ratio of the metal cation / bile acid, when this is convenient for therapeutic and application purposes. The natural or semi-synthetic bile acids can be salified according to the invention with metals selected from a group consisting of iron (II), iron (III), copper (I), copper (II), zinc, cobalt, molybdenum, platinum. , gold, manganese, vanadium, selenium, tin and nickel. Particular preference is given to ferrous or ferric salts, preferably ferric salts, which can be used for the treatment of iron deficiencies in humans and animals. For the intended therapeutic applications or for other uses, the salts of the invention can be formulated into pharmaceutical compositions, in accordance with conventional techniques and excipients such as those described in the Remnant = s | ¡¡f * armaceut¡cal Sciences Handbook , Mack. Pub., N.Y., U.S.A. Among these compositions are the capsules, the tablets, the syrups or the ingestible solutions, the gastric and / or controlled release forms and the like. The daily dose will depend on the type of cation: in the case of iron, the salts of the invention can be administered in doses ranging from 100 mg to 3 g, from one to four times a day. The salts of the invention can also be present in the composition of formulations for human or veterinary consumption, optionally in combination with other components that have some utility or serve as supplements. The following examples illustrate the invention in more detail.

EXAMPLE 1 Preparation of iron (II) salts of bile acid Preparation 10 g of acid are dissolved in 7.5 volumes of water with the minimum amount of sodium hydroxide (equal to 10%, 20% for the emisuccinate), at a pH of 8. Upon completion of the dissolution, the mixture is added to a temperature of 35 ° C, without stopping stirring, to an aqueous solution of FeCI3 6 H2O, prepared by dissolving 2 aßj (stoichiometric + 10% excess to cholic or dehydrocholic acid 2.53 g (stoichiometric + excess % of the deoxycholic, chenocolic and ursodeoxycholic acids), or 5.02 g (stoichiometric + 10% excess of the emisuccinate) of ferric salt slowly dissolved in 25 ml of water. The mixture is stirred until a total precipitation is obtained and subsequently the precipitate is washed until the chlorides disappear. Performance: greater than 95%. The characteristics of the salts obtained are illustrated below.

Salt p.f. Iron content Ferric cholate (3a, 7a, 12a-trihydroxy-5β- 7, QOp 4.07-4.67 colanate) ferric Deoxycolate ferric (3a, 12a-dihydroxy- 218-219 ° C 4.24-4.84 5β-colanate) ferric ferric dehydrocolate (3, 7 , 12, 5ß- i6-218 ° C 4.13-4.73 tricetocolanato) ferric ferric chenodeoxycholate (3a, 7a- 214-218 ° C 4.24-4.84 dihydroxy-5ß-colanato) ferric ferric ursodeoxycholate (3a, 7a- 200 ° C 4.24- 4.84 dihydroxy-5β-colanate) ferric ferric hiodeoxycholate (3a, 6a-193 ° C 4.24-4.84 dihydroxy-5-β-β-colanate) ferric disuccinyl ursodeoxycholate 268-270 ° C 8.05-9.25 (bio-emisuccinate-3a, 7a-dihydroxy-5ß-colanate) ferric

Claims (9)

1. - Acid salts selected from a group consisting of iron (III), copper (I), copper (II), zinc, cobalt, molybdenum, platinum, gold, manganese, vanadium, selenium, tin and nickel.

2. The salts according to claim 1, further characterized in that the metal is iron (III).

3. The salts according to claims 1 and 2, further characterized in that the bile acid is selected from a group consisting of cholic acid, deoxycholic acid, chenodeoxycholic acid, chenoic acid, ursocholic acid, ursodeoxycholic acid, hiodeoxycholic acid and the corresponding tauro- and glyco-conjugates.

4. The salts according to claims 1 to 3, characterized in that they are derived with other salivable groups.

5. The salts according to claim 4, further characterized in that the salifying groups mentioned above are selected from dicarboxylic or polycarboxylic acids, preferably succinic, glutaric or cyclohexanedicarboxylic acids.

6. The salts according to claims 1 to 3, further characterized in that the keto groups are ketalized with tartaric acid.

7. The use of salts of orm ad with claims 1 to 6 or of ferrous salts of bile acid, for the preparation of a medicament for supplying trace elements to the enterohepatic circle.

8. The use of an iron salt according to claims 1 to 6 for the preparation of a medicament for administering iron therapies.

9. Pharmaceutical compositions containing an effective amount of at least one salt according to claims 1 to 6 as an active ingredient, added to a mixture together with conventional vehicles and excipients.