FR2571255A1 - WATER-SOLUBLE PHARMACEUTICAL COMPOSITIONS BASED ON (-) CIS-1,2-EPOXYPROPYLPHOSPHONIC ACID SALTS WITH AMINO ACIDS - Google Patents

Abstract

INVENTION RELATING TO PHARMACEUTICAL COMPOSITIONS. WATER-SOLUBLE PHARMACEUTICAL COMPOSITIONS CONTAINING, AS ACTIVE INGREDIENT, ARGININE SALTS OF (-) CIS-1,2-EPOXYPROPYLPHOSPHONIC ACID, WITH AMINO ACIDS SUCH AS ARGININE, ORNITHINE, LYSINE, IS DESCRIBED. CYSTEINE, ETC. AND CHARACTERIZED BY THE PRESENCE OF AN EXCESS OF FREE AMINO-ACID. APPLICATION TO PARENTERAL OR ORAL TREATMENTS.

Description

-1-257

  The present invention, concerning composi-

  pharmaceutical products, relates more particularly

  to pharmaceutical compositions with antibiotic activity

  that, administered parenterally or as well

as a solution.

  In the Italian patent applications N 41002A / 78 and 26304A / 78 are described salts of formula I LCH3 - CH - 2nH -. Wherein A is an amino acid, such as, for example, lysine, arginine, ornithine, cysteine, methionine, glycine, choline, alanine, beta, etc., while the anionic moiety. is provided by (-) cis-1,2-epoxypropylphosphonic acid, also known compound

  under the name of phosphomycin and used in tea-

  human and veterinary treatment for its antibiotic properties.

  In particular, the arginine salt of phosphomycin

  cine has been shown to have therapeutic properties

unexpected and favorable.

  Compounds I, according to the processes described in said patent applications, are prepared by reaction between substantially equimolar amounts of (-) - cis-1,2-epoxypropylphosphonic acid and amino acid, of

  preferably in aqueous solution or in hydroalcoholic solution

  with methyl or ethyl alcohol.

  The compounds thus obtained have been shown

  However, they are very insoluble, to the point of

  their parenteral administration (intravenous mode) and in the form of solutions. On the other hand, such routes of administration are extremely frequent in the

  clinical practice for antibiotic therapies.

  It has now been found that compounds I, and in particular those in which A represents arginine,

  can be formulated adequately in composi-

  water-soluble substances, having a solubility in water

  between 10 and 20% w / v, by adding a suitable excess amount of salifying amino acids, either during the preparation of said salts, or directly

  before final packaging in pharmaceutical form.

  The amino acid is preferably added in a molar ratio of between about 0.4 and about 0.8,

  and more preferably close to 0.6.

  It is possible to use either amino acids

  or amino acids other than those constituting the cation of salts I. The pH of the solutions obtained according to

  the invention are between physiological values

  acceptable, namely between 6.9 and 7.4 approximately.

  As already indicated, the phosphomycin formulations which are the subject of the present invention, obtained by salification with amino acids

  and containing an excess of these and / or other amino-

  acids, are characterized by high water solubility,

  than similar salts and the possibility of

  to obtain, by means of an also oral administration, higher and more prolonged hematic rates of the antibiotic in its active form. In addition, the compositions according to the invention reveal - with respect to the other phosphomycin salts - a higher tropism.

  for certain organs, including the lungs and kidneys.

  On the other hand, neither the advantageous toxicological characteristics of phosphomycin nor its broad spectrum

  antibacterial are in no way impaired.

  Injectable pharmaceutical compositions,

  object of the present invention, can obviously contain

  Other suitable excipients, the use of which is conventional and well known to those skilled in the art, are also known, as are the sterility conditions.

  of pyrogenicity and isotonicity that these composites

  must be completed for the intended use.

  Still according to the invention it is still possible

  to prepare liquid oral pharmaceutical compositions, such as syrups, oral solutions, effervescent powders, etc. In the case of parenteral administration, the compositions of the invention contain 0.1 to 0.5 g of active ingredient, while in the case of administration

  oral they contain 0.5 to 1 g of active ingredient.

  The daily dosage will obviously depend on the type of diagnosis, the severity of the condition, the age

and the weight of the patient.

  In the following table, given by way of non-limiting example, the water-soluble amino acids used with the respective amounts and the results are cited.

solubility and pH obtained.

BOARD

  Pharmaceutical compositions containing phosphonium salts

  mycine with / arginine (1: 1) and amino acids in excess.

  Amino acids Ratio Solubility pH molar i% Arginine 0.5 10 6.93 Arginine 0.72 13 7.1 Lysine 0.55 9 7.00 Ornithine 0.65 11 7.34 - 4 -

Claims (4)

  1. Water-soluble pharmaceutical compositions   containing a salt of (-) cis-1,2-epoxypropylphosphoric acid   phonic with amino acids, characterized by the fact   that they contain an excess amino acid.   2. Compositions according to claim 1, characterized in that they contain the salt of the acid   (-) cis-11, 2-epoxypropylphosphine with arginine.   3. Compositions according to claim 1 or 2, characterized in that the excess amino acid is arginine. 4. Compositions according to any one of   preceding claims characterized by the fact that   the amino acid is present in a molar ratio included   between 0.4 and 0.8, preferably close to 0.6.