Title of Invention	PHARMACEUTICAL COMPOSITIONS CONTAINING FOSFOMYCIN TROMETHAMOL
Abstract	This invention relates to a pharmaceutical composition containing Fosfomycin Tromethamol, a stabilizer selected from the compounds as herein described, wherein the stabilizer is used in a molar ratio with respect to Fosfomycin Tromethamol comprised between 10% and 100%, and suitable excipients of pharmaceutical use.

Full Text

'Tharmaceutical compositions with antibiotic activity" The present invention concerns the use of certain salts and aminoacids as stabilizer of the antibiotic Fosfomycin Tromethamol and pharmaceutical compositions containing them. Fosfomycin Tromethamol (hereinafter FT) (The Merck Index XIII Ed., No. 4277, page 755), is a known antibiotic used for the treatment of urinary tract infections and it is the active ingredient, for example, of the drug named MONURIL®. FT is a compound relatively unstable because it presents reactive functional groups and can easily degrade due to the temperature and the humidity. This make difficult the storage of the raw material, the working and the preparation of pharmaceutical compositions (today exclusively in the form of hydrosolubie granulate) and the storage of the ready packages. For its use the granulate is dissolved in water and drunk. The acidity of the stomach too, may cause significant degradation phenomena which, in practice, reduce the amount of the active ingredient available to the absorption. We have now surprisingly found that some substances, when used in mixture with FT. are able to stabilize the antibiotic making it easier to handle for the operations of pharmaceutical technology and making stable the ready packages for a longer time. Furthermore, the degradation of FT at the pH of gastric juice results to be decreased when FT is in association with those substances. Therefore, the object of the present invention is the use of a substance selected from : tribasic sodium or potassium citrate monoacidic sodium or potassium citrate tribasic sodium or potassium phosphate monoacidic sodium or potassium phosphate sodium or potassium carbonate sodium or potassium bicarbonate sodium or potassium tartrate arginine lysine or mixtures thereof. to stabilize Fosfomycin Tromethamol. A second object of the present invention are the pharmaceutical compositions containing Fosfomycin Tromethamol, a compound selected from: tribasic sodium or potassium citrate monoacidic sodium or potassium citrate tribasic sodium or potassium phosphate monoacidic sodium or potassium phosphate sodium or potassium carbonate sodium or potassium bicarbonate sodium or potassium tartrate arginine lysine or mixtures thereof, and excipients suitable for the pharmaceutical use. Flereinalter, the substances the use of which is object of the invention will be jointly indicated as "stabilizer", meaning with that term also mixtures of two or more substances. I— The amount of stabilizer to be used is between 10% and l00% in moles with respect of FT. preferably between 30% and 70% and still more preferably about 50°'o. Among the above reported stabilizers, the presently preferred are tribasic sodium citrate. sodium or potassium carbonate or bicarbonate and arginine. The pharmaceutical compositions object of the invention are prepared from FT and the stabilizer by adding excipients for pharmaceutical use. The pharmaceutical form of FT presently preferred is that of hydrosoluble granules since, due to the relatively high amount of FT to be administered according to the instant posology (5.631 g), the solution obtained from the dissolution of granules in water is the most suitable and well accepted by the patients. With the new compositions of the invention it is possible to obtain formulations in granules but it is also possible to prepare hydrosoluble compositions obtainable by a simple admixture of FT, stabilizer and the other excipients, if any. Suitable excipients for the preparation of hydrosoluble compositions containing FT and a stabilizer are for example natural as well as artificial sweeteners or flavouring. Even if it is possible to add further excipients, useful for example for the granulation process, their use seems not to be necessary. The preparation of compositions of the invention can be conveniently carried out in different ways. It is possible, for example, to prepare a semimanufactured granulate of FT to which successively the stabilizer, the flavouring and the sweetening are mixed and finally the whole is distributed in sachets. Alternatively, all the ingredients of the formulation can be mixed directly together. With the aim to better illustrate the present invention, the following examples are now given. Example 1 The stabilization of FT from the selected stabilizers was evaluated experimentally with the DSC technology; A mechanic mixture of FT (0,02 moles) with each of the stabilizers (0.01 moles) was admixed with 0.05% of water with respect to FT. The DCS technology used for each mixture (scanning 10°C/min.) allow to measure the reaction heat which develops after the melting peak of FT, due to the degradation reaction. A reduced heat development indicates a higher stabilization, the amount of FT being the same. The following values were obtained: FT (single substance) =271.03±16.73 (J/g) FT+sodium citrate tribasic (dihydrate) =119.19± 7.47 (J/g) FT+sodium bicarbonate =143.32± 4.92 (J/g) FT+sodium carbonate -115.84± 9.89 (J/g) FT+arginine =175.25± 9.41 (J/g) The obtained data show as FT was effectively stabilized by adding the above mentioned substances. The heat of the degradation reaction, with the same amount of FT, was reduced in percentages between about 35 and 70%. Example 2 The stabilization of FT in simulated gastric juice was evaluated by reproducing the use conditions of the patient: 5.631 g of FT were additioned with 0.01 moles of the selected stabilizer and were dissolved in water (180 ml). The solution was poured in simulated gastric juice (100 ml, pH 1) and the degradation was measured as percentage recovery of the active ingredient in time. Already after 30 minutes the recovery of FT without stabilizer was 82% while with the stabilizer the recovery was 90%. Example 3 The following pharmaceutical compositions were prepared by simple admixture of the ingredients. Composition 1 Fosfomycin Tromethamol 5.631 g Sodium citrate dihydrate 1-125 g Aspartame 0.100 g Tangerine flavour 0.100 g Orange flavour 0.100 g Composition 2 Fosfomycin Tromethamol 5.631 g Sodium citrate dihydrate 0.500 g Sodium bicarbonate 0.840 g Aspartame 0.100 g Tangerine flavour 0.100 g Orange flavour 0.100 g Composition 3 Fosfomycin Tromethamol 5.631 g Sodium bicarbonate 1 • 127 g Sodium carbonate 0.200 g Sucrose 2.000 g Tangerine flavour 0.100 g Lemon flavour 0.100 g Composition 4 Fosfomycin Tromethamol 5.631 g Sodium citrate dihydrate 0.734 g Sodium citrate monoacid 0.987 g Fructose 2.500 g Tangerine flavour 0.100 g Lemon flavour 0.100 g Composition 5 Fosfomycin Tromethamol 5.631 g L-arginine 1.470 g Sodium Saccharin 0.010 g Sucrose 2.100 g Tanuerine flavour 0.100 a OrangS flavour 0.100 g Composition 6 Fosfomycin Tromethamol 5.631 g L-arginine 0.500 g Lysine O.lOOg Aspartame 0.100 g Tangerine flavour 0.100 g Orange flavour 0.070 g Composition 7 Fosfomycin Tromethamol 5.631 g Sodium citrate dihydrate 0.500 g Sodium carbonate 0.500 g Aspartame O.lOOg Tangerine flavour 0.070 g Orange flavour 0.070 g Composition 8 Fosfomycin Tromethamol 5.631 g Sodium citrate dihydrate 1.000 g L-arginine 0.050 g Aspartame 0.070 g Orange flavour 0.150 g Lemon flavour 0.030 g Composition 9 Fosfomycin Tromethamol 5.631 g Sodium citrate dihydrate 1.800 g Sodium saccharin 0.040 g Sucrose 1.500 g Tangerin flavour 0.100 g Lemon flavour 0.100 g Composition 10 Fosfomycin Tromethamol 5.631 g Sodium citrate dihydrate L125 g Sorbitol 1.000 g Aspartame 0.070 g Tangerine flavour 0.100 g Orange flavour 0.100 g WE Claim 1. Use of a substance selected from: - tribasic sodium or potassium citrate - monoacidic sodium or potassium citrate - tribasic sodium or potassium phosphate - monoacidic sodium or potassium phosphate - sodium or potassium carbonate - sodium or potassium bicarbonate - sodium or potassium tartrate - arginine - lysine or mixtures thereof, to stabilize Fosfomycin Tromethamol. 2. Use as stabilizer of a compound of claim 1, characterized in that the compound is selected among tribasic sodium citrate, sodium carbonate or arginine. 3. Use as stabilizer of a compound of claim 1, characterized in that the compound is used in a molar ratio with respect to FT comprised between 10% and 100%, preferably between 30% and 70% and still more preferably about 50%. 4. Pharmaceutical compositions containing Fosfomycin Tromethamol, a compound selected from: - tribasic sodium or potassium citrate - monoacidic sodium or potassium citrate - tribasic sodium or potassium phosphate - monoacidic sodium or potassium phosphate - sodium or potassium carbonate - sodium or potassium bicarbonate - sodium or potassium tartrate - arginine - lysine or mixtures thereof, and suitable excipients of pharmaceutical use. 5. A composition according to claim 4, in the form of soluble granulate. 6. A composition according to claim 5 wherein the amount of FT contained for single dose is 5.631 g. 7. A composition according to claim 1 wherein the substance with stabilizing activity is selected among tribasic sodium citrate, sodium carbonate and arginine. 8. A composition according to claim 1 wherein the substance with stabilizing activity is used in a molar ratio with respect to FT comprised between 10% and 100%, preferably between 30% and 70% and still more preferably about 50%. 9. A composition, substantially as hereinabove described and exemplified.

Documents:

610-che-2003 description (complete) granted.pdf

610-che-2003 form 1.pdf

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610-che-2003 petition.pdf

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610-che-2003-abstract.pdf

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610-che-2003-description complete.pdf

610-che-2003-form 1.pdf

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