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

610-che-2003 form 3.pdf

610-che-2003 petition.pdf

610-che-2003 power of attorney.pdf

610-che-2003-abstract.pdf

610-che-2003-claims.pdf

610-che-2003-correspondence others .pdf

610-che-2003-description complete.pdf

610-che-2003-form 1.pdf

610-che-2003-form 18.pdf


Patent Number 229292
Indian Patent Application Number 610/CHE/2003
PG Journal Number 12/2009
Publication Date 20-Mar-2009
Grant Date 16-Feb-2009
Date of Filing 29-Jul-2003
Name of Patentee ZAMBON GROUP S.p.A
Applicant Address VIA DELLA CHIMICA, 9, I-36100 VICENZA
Inventors:
# Inventor's Name Inventor's Address
1 RAMPOLDI, LUCA VIA VERDI, 5, 20020 LAINATE
2 PIRRONE LUCA VIA M.L.KING 29, 35020 LEGNARO,
3 FACCIN SARAH VIA TERRAGLIO 84, 30174 MESTRE,
4 GRASSANO ALESSANDRO VIA VOLTUTNO 21, 20052 MONZA,
5 GURRIERI GIOVANNI VIA MONTI LESSINI 7/E, 37023 GREZZANA,
PCT International Classification Number C07G11/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 MI20020A001725 2002-08-01 Italy