FIELD OF THE INVENTION
This invention in general relates to a stable pharmaceutical composition comprising fosfomycin or its pharmaceutically acceptable salts or derivatives and at least one or more pharmaceutically acceptable excipients. The pharmaceutical composition formulated into granules and/or powder for oral solution or ready to use solution or other dosage forms, which can be dispensed in a unit dose pack and/or multiple dose pack. The invention also provides a process for manufacturing such compositions.

BACKGROUND OF THE INVENTION

Fosfomycin is a synthetic, broad spectrum, bactericidal antibiotic. Chemically, fosfomycin is known as phosphonic acid derivative, is available as (1R,2S) -(1,2-epoxypropyl) phosphonic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1). It is commercialized as the tromethamine or tromethamol salt and is structurally designated as:

In the United States, fosfomycin tromethamine is available as MONUROL® Granules for oral solution manufactured by Zambon and marketed by Allergan. Each single-dose sachet contains the equivalent of 3 grams of fosfomycin. Fosfomycin is indicated for the treatment of uncomplicated urinary tract infections (acute cystitis) in women due to susceptible strains of Escherichia coli and Enterococcus faecalis. The recommended dosage of MONUROL® for women 18 years of age and older for uncomplicated urinary tract infection (acute cystitis) is one sachet. MONUROL® may be taken with or without food. It should not be taken in its dry form and always be mixed with water before ingesting.

US4863908 and US5191094 patent assigned to Zambon Switzerland Ltd. discloses fosfomycin tromethamine and its pharmaceutical composition in the form of sachets.

US7303755 patent assigned to Zambon Group SpA discloses a process for stabilizing a fosfomycin tromethamol composition using stabilizers in an amount between 10% to 100% in moles with respect of fosfomycin tromethamine.

US8604078 patent assigned to Picornell Darder Carlos discloses a stable solid fosfomycin trometamol composition comprising fosfomycin, glycine wherein the composition is substantially free of sugars and sugar alcohols.

Fosfomycin tromethamine is unstable because of its reactive functional groups and can easily degrade due to the temperature and relative humidity. The acidic condition of the stomach may also cause significant degradation which may also reduce the absorption of the drug. Therefore, to maintain the stability of the pharmaceutical composition throughout the shelf life is difficult.
There exists a long-felt need to develop stable fosfomycin granules for oral solution or ready to use solution dosage form with composition containing minimum amount of stabilizer.
The inventors of the present invention propose a stable composition using pH-regulating agents so that the antimicrobial activity of the antibiotic remains unchanged and circumvent degradation issue of the product.
The inventors of the present invention propose a stable pharmaceutical composition of fosfomycin or its pharmaceutically acceptable salts or derivatives, which is expected to exhibit desired pharmaceutical technical attribute.

SUMMARY OF THE INVENTION

It is a principal object of this invention, to develop a stable pharmaceutical composition comprising fosfomycin or its pharmaceutically acceptable salts or derivatives using definite ratio of pH regulating agent to fosfomycin or its pharmaceutically acceptable salts or derivatives.
Another object of the invention is to develop the pharmaceutical composition in the form of granules for oral solution dosage form which can be dispensed in a unit dose pack and/or multiple dose pack. The invention also provides a process for manufacturing such compositions.
Another object of the present invention is to develop a stable pharmaceutical composition comprising fosfomycin or its pharmaceutically acceptable salts or derivatives using a manufacturing process which is consistent and therefore feasible for industrial production, while maintaining stability and pharmaceutical equivalence to the reference formulation.

DESCRIPTION OF THE INVENTION
The present invention can be more readily understood by reading the following detailed description of the invention and study of the included examples.
As used herein, the term “composition”, as in pharmaceutical composition, is intended to encompass a drug product comprising fosfomycin or pharmaceutically acceptable salt or derivative thereof, and the other inert ingredient(s) (pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with “formulation” and “dosage form”. Pharmaceutical composition of the invention includes, but is not limited to, powder for oral suspension, ready to use suspension, ready to use solution, soluble tablets, dispersible tablets, orally disintegrating tablet, chewable tablet, oral solutions, powder for oral solution, granule for oral solution and pellets, beads, minitabs, spherules, beadlets, microcapsules, millispheres, microspheres, suspension, solution, powder, granules, spheroids and the like filled in sachet. Preferably, the pharmaceutical composition refers to powder or granules. More preferably, the pharmaceutical composition refers to powder for oral suspension/solution or granules for oral suspension/solution.

“Fosfomycin” as used herein refers to the free acid form, its salts, esters, solvates, polymorphs, derivatives, enantiomers or mixtures thereof. Preferably, the salt of fosfomycin is tromethamine salt.

The term "excipient" means a pharmacologically inactive component such as a diluents or fillers or carriers, binders, sweeteners, flavors, surfactants, pH regulating agents, taste masking agents, lubricants and mixtures thereof. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. Co-processed excipients are also covered under the scope of present invention. Further, excipient may be in the form of powders or in the form of dispersion. Combination of excipients performing the same function may also be used to achieve desired formulation characteristics.

The term “pH regulating agent” used herein refers to a stabilizing agent, alkalizing agents, buffering agents, pH modifiers and antioxidants.

As used herein, the term "about" means ± approximately 10% of the indicated value.
The term “w/w” as used herein refers the total weight of the composition.

The “dry powder composition” or “Unit dosage form” or “granules for oral solution” can be in the form of powder, granules, pellets, bead, cores, spheroids or multiparticulates.

The term “particle form” used herein refers to a plurality of discrete or aggregated particles, pellets, beads, spheroids, granules, spheres or mixture thereof, irrespective of their size, shape or morphology.

The term “substantially free” as used herein refers to the amount which is in range from 0-5% w/w by total weight of the composition.
The term “sachet” as used herein refers to any suitable container, package or bag to contain the dry powder composition. The sachet may be formed of any suitable material, including plastic, metal foil, paper or a combination thereof. Sachet can be three layered with sandwiched polyethylene terephthalate (PET)/aluminium/polyethylene layers or four layered or more with addition of more layers of PET/aluminium/polyethylene to provide robust protection to moisture sensitive drugs. The sachet may be provided with any suitable means for opening thereof, including a perforated region or a nick in the edge of the sachet for ease of tearing. The sachet may be of any suitable size. The sachet is sealed using any appropriate method. Particularly, the sachet is disposable. Sachet can be a child resistant container.

An embodiment of the present invention relates to a stable pharmaceutical composition for oral administration comprising fosfomycin or its pharmaceutically acceptable salts or derivatives using minimum amount of pH regulating agent.

Another embodiment of the present invention relates to a stable pharmaceutical composition for oral administration comprising:
a) fosfomycin or its pharmaceutically acceptable salts or derivatives in the range of from about 10.0-95.0% w/w
b) a pH regulating agent in the range of from about 1.0-10.0% w/w and
c) at least one or more pharmaceutical excipient.

Another embodiment of the present invention relates to a stable pharmaceutical composition for oral administration comprising:
a) fosfomycin or its pharmaceutically acceptable salts or derivatives
b) a pH regulating agent and
c) at least one or more pharmaceutical excipient
wherein the molar ratio of pH regulating agent to fosfomycin is 0.01:1.0 to 1.0:1.0.

Yet another embodiment of present invention relates to a stable pharmaceutical composition for oral administration comprising:
a) fosfomycin or its pharmaceutically acceptable salts or derivatives
b) a pH regulating agent selected from the group comprising calcium phosphate tribasic, sodium hydroxide, potassium hydroxide, magnesium oxide, magnesium silicate, calcium silicate/calcium metasilicate, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate dibasic dihydrate, sodium sulfite, potassium sulfite, ammonium bicarbonate, lithium bicarbonate, magnesium bicarbonate, meglumine, calcium bicarbonate or zinc bicarbonate and mixtures thereof.
c) at least one or more pharmaceutical excipient.

Another embodiment of present invention relates to a stable pharmaceutical composition for oral administration comprising:
a) fosfomycin or its pharmaceutically acceptable salts or derivatives
b) a pH regulating agent selected from the group comprising calcium phosphate tribasic, sodium hydroxide, potassium hydroxide, magnesium oxide, magnesium silicate, calcium silicate/calcium metasilicate, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate dibasic dihydrate, sodium sulfite, potassium sulfite, ammonium bicarbonate, lithium bicarbonate, magnesium bicarbonate, meglumine, calcium bicarbonate or zinc bicarbonate and mixtures thereof.
c) at least one or more pharmaceutical excipient,
wherein the molar ratio of pH regulating agent to fosfomycin is 0.01:1.0 to 1.0 :1.0.

In an embodiment of the present invention, the pH regulating agents are selected from the group comprising calcium phosphate tribasic, sodium hydroxide, potassium hydroxide, magnesium oxide, magnesium silicate, calcium silicate/calcium metasilicate, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate dibasic dehydrate, sodium sulfite, potassium sulfite, ammonium bicarbonate, lithium bicarbonate, magnesium bicarbonate, calcium bicarbonate or zinc bicarbonate, meglumine, citric acid, tartaric acid, phosphoric acid, sodium metabisulfite, potassium metabisulfite; tocopherol, sesamol, guaiac resin, thiol derivatives, L-cysteine and mixtures thereof.

Another embodiment of the present invention relates to a process for preparing a stable solid oral pharmaceutical composition wherein the process comprises of:
a) dissolving pH regulating agent in an adequate amount of solvent
b) granulating fosfomycin or its pharmaceutically acceptable salts or derivatives with the solution of step (a)
c) passing the wet mass as obtained in step (b) through suitable size sieve and drying the granules
d) passing the resultant granules through a suitable size mesh and mixing the granules with sweeteners, flavoring agents, lubricants and glidants.
e) filling the blend of step (d) into sachets.

An embodiment of the present invention relates to a stable pharmaceutical composition, wherein the composition is in the form of granules for oral solution, powder for oral solution, ready to use solution, ready to use suspension, soluble tablets, dispersible tablets, orally disintegrating tablet, chewable tablet.

Another embodiment of the present invention relates to a stable pharmaceutical composition, wherein the at least one or more pharmaceutically acceptable excipients are selected from the group comprising of diluents or fillers or carriers, binders, sweeteners, flavors, surfactants, pH regulating agent, glidants, lubricants, taste masking agents or mixtures thereof.

An embodiment of the present invention relates to a stable pharmaceutical composition for oral administration comprising fosfomycin or its pharmaceutically acceptable salts or derivatives and at least one or more pharmaceutically acceptable excipients, wherein the said composition is substantially free of sodium or potassium citrate; sodium or potassium phosphate; sodium or potassium carbonate or bicarbonate; sodium or potassium tartrate; arginine; glycine and lysine.

In an embodiment of the present invention relates to a stable pharmaceutical composition comprising fosfomycin or its pharmaceutically acceptable salts or derivatives from about 10% to about 95% by weight of the total composition and one or more pharmaceutically acceptable excipients from about 0.1 to about 70.0% by weight of the total composition; wherein the said composition is substantially free of sodium or potassium citrate; sodium or potassium phosphate; sodium or potassium carbonate or bicarbonate; sodium or potassium tartrate; arginine; glycine and lysine.

In another embodiment of the present invention relates to a process for preparing a stable pharmaceutical composition, the process comprising the steps combining fosfomycin or its pharmaceutically acceptable salts or derivatives with at least one or more pharmaceutically acceptable excipients; wherein the said composition is substantially free of sodium or potassium citrate; sodium or potassium phosphate; sodium or potassium carbonate or bicarbonate; sodium or potassium tartrate; arginine; glycine and lysine.

Yet another embodiment of the present invention relates to a process for the preparation of a granules for oral solution, powder for oral solution, granules or multiparticulates of fosfomycin or pharmaceutically acceptable salt or derivative thereof by using conventional methods known in the art but not limited to blending, mixing, granulation, hot-melt extrusion, spray drying, spray coating techniques. The formulation so formed may be administered directly or incorporated into/processed to pharmaceutical compositions for oral administration.

In yet another embodiment of the present invention relates to a stable pharmaceutical composition in the form of a granules/powder for oral solution comprising fosfomycin or its pharmaceutically acceptable salt or derivative thereof, wherein fosfomycin or its pharmaceutically acceptable salt or derivatives has a particle size distribution D90 less than about 200 µm, D50 is less than about 100 µm and D10 is less than about 50 µm. Preferably, particle size distribution is D90 is less than about 100 µm, D50 is less than about 70 µm and D10 is less than about 30 µm. The particle size can be measured by suitable techniques such as Laser light scattering (e.g. Malvern Light Scattering), Coulter counter, microscopy and any other technique known in the art.

In another embodiment, a stable pharmaceutical composition in the form of granules/powder for oral solution comprising fosfomycin or pharmaceutically acceptable salt or derivative thereof, wherein the particle size of granules/powders has an average diameter of about 0.6 mm to about 1.2 mm; preferably from about 0.7 mm to about 1.0 mm.

In another embodiment of the present invention, the stable pharmaceutical composition comprising fosfomycin or pharmaceutically acceptable salt or derivative thereof having a bulk density in the range from 0.72 g/ml to 0.82 g/ml and tapped density in the range from 0.76 g/ml to 0.84 g/ml.

Yet in another embodiment, of the present invention, relates to a stable pharmaceutical composition comprising fosfomycin or pharmaceutically acceptable salt or derivative thereof are stable at 40 °C and 75% relative humidity at least for a period of atleast 3 months.

Another embodiment of the present invention, relates to a stable pharmaceutical composition comprising fosfomycin or pharmaceutically acceptable salt or derivative thereof in an amount from about 100 mg to about 6000 mg, preferably 500 mg to about 4000 mg; more preferably 500 mg to about 3000 mg.

Another aspect of the present invention provides a stable pharmaceutical composition in the form of dry granules as a unit dose pack comprising an active ingredient and at least one pharmaceutically acceptable excipient.

Another aspect of the present invention provides a process for the preparation of a unit dose pack comprising the steps of:
a) preparing a pharmaceutical composition in the form of dry granules of an active ingredient and one or more pharmaceutically acceptable excipient;
b) filling the dry granules pharmaceutical composition into a unit dose pack; and
c) sealing the pack.

In another embodiment of the present invention, the granules for oral solution comprising fosfomycin or pharmaceutically acceptable salt or derivative thereof can be administered by mixing with water before ingestion. The present invention further relates to a stable pharmaceutical composition of an active ingredient for oral administration, packed in a unit dose pack and/or multiunit dose pack. The unit dose pack sachet of fosfomycin or pharmaceutically acceptable salt or derivative thereof need to be poured into 3 to 4 ounces of water (1/2 cup) and stir to dissolve.

Another embodiment of the present invention provides a stable pharmaceutical composition in the form of dry granules/powder which can be consumed after reconstitution in water or any another suitable liquid. The reconstituted composition can be a solution, dispersion or suspension. Particularly, the reconstituted composition is a solution.

In further embodiment, the present invention includes method of using the stable pharmaceutical composition in the form of granules for oral solution comprising fosfomycin or pharmaceutically acceptable salt or derivative thereof for the treatment of uncomplicated urinary tract infections (acute cystitis) in women due to susceptible strains of Escherichia coli and Enterococcus faecalis.

In particular, the present invention discloses a stable pharmaceutical composition comprising fosfomycin or its pharmaceutically acceptable salts or derivatives, which are expected to exhibit desired pharmaceutical technical attribute such as drug release, assay and stability are comparable to US marketed product (MONUROL® Granules for solution).

Another embodiment of the present invention also provides a process for the preparation of a stable pharmaceutical composition in the form of granules or powders of fosfomycin or pharmaceutically acceptable salt or derivative thereof, comprising the steps of; (a) dry blending the drug and excipients, (b) granulation (aqueous or non-aqueous) of the mass using binder solution containing pH regulating agent (c) screening of granules, (d) blending of screened granules with other one or more excipients selected from the group comprising of a diluents or fillers or carriers, binders, sweeteners, flavors, surfactants, pH regulating agent, taste masking agents, preservatives and mixtures thereof and dispensing in a sachet.

The pharmaceutical composition of the present invention can be packaged in a suitable pack/container such as amber colored polyethylene terephthalate (PET) bottle, glass bottle, high density polyethylene (HDPE) bottle, low density polyethylene (LDPE) bottle, polypropylene (PP) bottle, packets, pouches, sachets and the like. The glass or plastic bottle is provided with a child proof closure. The package can include a syringe (marked in mL) for ease of dosing.

Pack chosen are made of material which is non-reactive with the solution and/or granules for oral solution for reconstitution. Containers for use in the storage of the oral solution may be used to administer a multiple dose of fosfomycin tromethamine.

In another embodiment of the present invention, there is provided a process for the preparation of a granules for oral solution composition comprising fosfomycin or its pharmaceutically acceptable salts thereof by using conventional methods known in the art but not limited to blending, mixing, granulation, hot-melt extrusion, spray drying, spray coating techniques. Suitable solvents include aqueous or organic solvents. Preferable solvents include, but are not limited to, water, esters such as ethyl acetate; ketones such as acetone; alcohols such as methanol, ethanol, isopropanol, butanol; dichloromethane, chloroform, dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), ether, diethyl ether and combinations thereof. Preferably, the solvent used during wet mass preparation is water.

In another embodiment of the invention, wet granulation can be performed using Rapid mixer granulator, Fluid bed granulator, Planetary mixer and the like; dry blending can be performed in V-blender or key blender; spheronization can be performed using Fuji Paudal spheronizer or by any other method known in the art.

In another embodiment of the present invention relates to a process for the preparation of a ready to use liquid solution of fosfomycin or pharmaceutically acceptable salt or derivative thereof, comprising combining various components using conventional equipments such as overhead stirrers, ultrasonifiers, mills, homogenizers operating at an RPM range of about 100-8000 RPM, or as per requirement, manufacturing and heating tank with or without vacuum application assembly known in the art or industry practice. Many different orders of adding components to the stirrer can be employed. This can be followed by addition of liquid carrier (such as aqueous and/or non-aqueous), viscosity agent, sweetening agent, taste masking agent and the like. pH of the solution is adjusted to desired value using aqueous buffering agents as needed.

Diluents or fillers or carriers are substances which usually provide bulk to the composition. Various useful fillers or diluents include, but are not limited to microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, polydextrose, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, trehalose and xylitol, or mixtures thereof. The diluent is present in an amount of about 5.0% to about 98.0% w/w of the total composition.

Binders impart cohesiveness to formulation. Various useful binders include, but are not limited to hypromellose, acacia, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, hydroxypropylcellulose, maltose, methylcellulose, povidone, copovidone, starch, polyvinyl alcohol or polyethylene oxide, or mixtures thereof. The binder may constitute from about 0.1% to about 20.0%w/w by the pharmaceutical composition.

Glidants improve flowability and accuracy of dosing. Since the present invention relates to an oral pharmaceutical composition, it is imperative to use glidant(s) to achieve desirable flowability of the active. Glidants used in the composition include, but are not limited to tribasic calcium phosphate, calcium silicate, cellulose powdered, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, starch and talc or mixtures thereof. The amount of glidant ranges from about 0.1% to about 5.0% w/w of the composition.

Surfactants or surface-active agents improve wettability of the dosage form and/or enhance its dissolution. Surfactants contemplated in the present invention include but are not limited to anionic surfactants, amphoteric surfactants, non-ionic surfactants and macromolecular surfactants. Suitable examples of anionic surfactants include but are not limited to sodium lauryl sulphate, sodium stearyl fumarate, sodium cetyl stearyl sulphate or sodium dioctyl sulphosuccinate etc. Suitable example of an amphoteric surfactant include but is not limited to lecithin. Suitable examples of non-ionic surfactants include but is not limited to cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, cholesterol, sorbitan fatty acid esters such as sorbitan mono-oleate, polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 20, polyoxyethylene fatty acid glycerides such as macrogol 1000 glycerol monostearate, polyoxyethylene fatty acid esters such as polyoxyl 40 stearate, polyoxyethylene fatty alcohol ethers such as polyoxyl 10 oleyl ether, glycerol fatty acid esters such as glycerol monostearate, commercially available SEPITRAP® 80 or SEPITRAP® 4000 etc. The surfactant may constitute from about 0.1% to about 5.0%w/w of the composition.

Disintegrants selected from the group comprising crospovidone, modified starches, croscarmellose sodium, sodium starch glycolate, low substituted hydroxypropyl cellulose and carboxymethylcellulose calcium. These disintegrants are also known as superdisintegrants. The disintegrant may constitute from about 0.1% to about 20.0% w/w of the pharmaceutical composition.

Various useful preservatives include, but are not limited to, parabens such as methylparaben, propylparaben, butyl paraben and their salts, sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, methyl hydroxybenzoate, ethyl para-hydroxybenzoate, sodium ethyl para-hydroxybenzoate, sodium metabisulphite, chlorhexidine, diazolidinyl urea, sodium citrate, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), tocopherol, ethylenediamine tetraacetic acid, propyl gallate, quaternary compounds, e.g. benzalkonium chloride and cetylpyridinium chloride, phenyl ethyl alcohol and the like. In particular, the preservative is selected from benzoic acid and its salts and parabens. The preservative is present in an amount of about 0.001% w/w to about 3.0% w/w of the composition.

pH regulating agents are used to help maintaining the desirable properties of the product until it is consumed by the end-user. Various useful pH regulating agent include, but are not limited to, magnesium oxide, calcium phosphate tribasic, sodium hydroxide, potassium hydroxide, magnesium oxide, magnesium silicate, calcium silicate/calcium metasilicate, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate dibasic dehydrate, sodium sulfite, potassium sulfite, ammonium bicarbonate, lithium bicarbonate, magnesium bicarbonate, meglumine, calcium bicarbonate or zinc bicarbonate and mixtures thereof.

Various useful antioxidants include, but are not limited to, ascorbic acid, tert-butylhydroquinone, sodium pyrosulfite, glutathione, sodium bisulfite, sodium sulfite, a-tocopherol, a-tocopherol acetate, monothioglycerol, cysteine, ascorbyl palmitate, acetylcysteine, dithiothreitol, sodium metabisulfite, thiourea, sodium thiosulfate, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT) and propyl gallate.

Various useful sweetening agents include, but are not limited to, sugar or sugar alcohol such as sucrose, saccharose, dextrose, sucralose, sorbitol, neotame, aspartame, Acesulfame K, fructose, mannitol and invert sugar and sugar substitutes such as saccharin sodium. Sugar or a sugar alcohol can also act as filler. Preferably sweetening agent used is sodium saccharin, saccharose, sucralose, neotame. The amount of sweetening agent ranges from about 0.05% to about 50% by weight of the composition.

Various useful flavoring agents, include, but are not limited to, flavors such as banana, lemon, orange, grape, lime and grapefruit, vanilla, and fruit essence, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, wild cherry, walnut, chocolate, pineapple, apricot; synthetic flavor oils, mandarin, tangerine flavor, and flavoring aromatics and/or natural oils, extracts from plant leaves, flowers, fruits such as cinnamon oil, oil of wintergreen, peppermint oils, clove oil, citrus oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, mint and cassia oil; maltol, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltitol, and tartaric acid and combinations thereof. Preferably, wild cherry, walnut, chocolate, pineapple, apricot, Anise, banana and orange. Flavoring agent is present in the concentration of 0.1 - 1.0 % w/w. Although flavoring agent in lesser concentrations than 0. l% w/w or in higher concentrations than l% w/w can be used, use of flavoring agent concentration in the vicinity of 0.4 % w/w gives better composition. The concentration of flavoring agent is flavor specific and may be modulated depending upon the flavor(s) used.

Suitable coloring agent are selected from the group comprising FD&C (Federal Food, Drug and Cosmetic Act) approved coloring agents, natural coloring agents, natural juice concentrates, pigments such as iron oxide, titanium dioxide, and zinc oxide, and combinations thereof.

Other excipients are selected from the group comprising gums such as xanthan gum, carrageenan gum, acacia, guar gum, locust bean gum, gum tragacanth; celluloses such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, mixture of microcrystalline cellulose and carboxymethylcellulose (Avicel® RC); polyvinylpyrrolidone; alginic acid; alginate; sodium alginate; bentonite; carbomers (carboxyvinyl polymers) such as those available under the trade name Carbopol®; cetostearyl alcohol; maltodextrin; polyvinyl alcohol; colloidal silicon dioxide, propylene carbonate; propylene glycol; sodium starch glycolate; starch; acrylic polymers etc. These excipients are present in an amount ranging from about 0.05% to about 20% w/w of the composition. In a particular embodiment, the dry powder compositions is substantially free of suspending agents.

Various useful isotonizing agent include, but are not limited to, sodium chloride, mannitol, D-sorbitol, glucose, glycerin or the like.

Various useful taste masking agents include, but are not limited to, water soluble and/or insoluble polymeric excipient, water insoluble non-polymeric excipient, adsorbent, carbomer, alkali metal chlorides or an alkaline earth metal chlorides or a derivative, inclusion compounds like cyclodextrins or its derivatives, ion-exchange resins and mixtures thereof.

Various water-soluble polymers include but are not limited to cellulose derivatives such as soluble alkyl- or hydroalkylcellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethylethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, etc., acidic cellulose derivatives, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum arabic, xanthans, alginates, polyacrylic acid, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, chitosan and derivatives thereof, shellac and derivatives thereof, waxes and fat substances. If desired, the films may contain additional adjuvants for coating such as plasticizers, polishing agents, colorants, pigments, antifoaming agents, opacifiers, antisticking agents, and the like.

In another embodiment of the invention, acrylate and water insoluble polymers suitable for use in the present invention include, but are not limited to, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), ethylcellulose (EC), polyvinyl acetate phthalate methylcellulose acetate phthalate (MCAP) and methacrylic acid copolymers or its derivatives. Kollicoat® from Evonik Industries, Colorcon, Eastman Chemical and BASF Fine Chemicals respectively. Acrylate polymers or Methacrylic acid copolymers or its derivatives are selected from the group comprising different grades of Poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1:2:1, Poly(methacrylic acid, methyl methacrylate) 1:2, Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2, Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1, Poly(methacrylic acid, ethyl acrylate) 1:1.

In another embodiment the present invention includes particle size of free drug particulate form of fosfomycin or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein particle diameter at 90% cumulative volume (d90) is less than about 100 µm, preferably less than 50 µm. Particle diameter at X% cumulative particle size reduction can be performed by techniques including but not limited to fluid energy milling, ball milling, colloid milling, roller milling, hammer milling and the like. Particle size and particle size distribution can be measured by techniques such as Laser light scattering (e.g. Malvern Light Scattering), Coulter counter, microscopy and the like.

In yet another embodiment of the invention, the stable pharmaceutical composition of fosfomycin or its pharmaceutically acceptable salt or derivative thereof is packed in a packaging material selected from the group comprising of foil, pouch, sachet, capsule, bottle, container or other suitable package.

The stable pharmaceutical composition for oral dosage form prepared by the above mentioned process can be subjected to in vitro dissolution evaluation according to Test 711 "Dissolution" in the United States Pharmacopoeia 37, United States Pharmacopoeial Convention, Inc., Rockville, Md., 2014 ("USP") to determine the rate at which the active substance is released from the dosage form, and the content of the active substance can be determined in solution by high performance liquid chromatography. When comparing the test and reference products, dissolution profiles should be compared using a similarity factor (f2). The similarity factor is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) of dissolution between the two curves.
f2 = 50 • log {[1 + (1/n)St=1n (Rt - Tt)2]-0.5 • 100}
Two dissolution profiles are considered similar when the f2 value is equal to or greater than 50.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail method for the preparation and testing of fosfomycin pharmaceutical composition. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. Following examples are set out to illustrate the invention and do not limit the scope of the present invention.

EXAMPLES
The following non-limiting examples are intended to further illustrate certain preferred embodiments of the invention. They are, however not intended to be limiting the scope of the present invention in any way.
Pharmaceutical composition of fosfomycin tromethamine may be prepared by using quantitative formula as given in the following examples:
Example 1
Composition
S. No. Ingredients %w/w
1. Fosfomycin Tromethamine 10.0-95.0
2. Microcrystalline cellulose 1.0-40.0
3. Calcium metasilicate 1.0-10.0
4. Saccharin 0.05-2.5
5. Sucrose 0.5-10.0
6. Orange flavor 0.1-1.0
7. Purified Water q.s.

Example 2
Composition
S. No. Ingredients %w/w
1. Fosfomycin Tromethamine 10.0-95.0
2. Magnesium hydroxide 1.0-10.0
3. Aspartame 0.05-2.5
4. Sucrose 0.5-10.0
5. Mandarin Flavor 0.1-1.0
6. Isopropyl alcohol / Dichloromethane/ ethanol q.s.

Example 3
Composition
S. No. Ingredients %w/w
1. Fosfomycin Tromethamine 10.0-95.0
2. Magnesium oxide 1.0-10.0
3. Sucralose 0.05-2.5
4. Sucrose 0.5-10.0
5. Mandarin Flavour 0.1-1.0
6. Orange flavor 0.1-1.0

Preferred method of manufacture: Dry blending/Wet granulation/Dry granulation.

We claim:
1. A stable pharmaceutical composition for oral administration comprising:
a) fosfomycin or its pharmaceutically acceptable salts or derivatives
b) a pH regulating agent selected from the group consisting of calcium phosphate tribasic, sodium hydroxide, potassium hydroxide, magnesium oxide, magnesium silicate, calcium silicate/calcium metasilicate, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate dibasic dehydrate, sodium sulfite, potassium sulfite, ammonium bicarbonate, lithium bicarbonate, magnesium bicarbonate, meglumine, calcium bicarbonate or zinc bicarbonate and mixtures thereof;
c) at least one or more pharmaceutical excipient.

2. A stable pharmaceutical composition for oral administration comprising:
a) fosfomycin or its pharmaceutically acceptable salts or derivatives;
b) a pH regulating agent selected from the group comprising calcium phosphate tribasic, sodium hydroxide, potassium hydroxide, magnesium oxide, magnesium silicate, calcium silicate/calcium metasilicate, magnesium carbonate, magnesium hydroxide, sodium hydroxide, potassium hydroxide, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate dibasic dehydrate, sodium sulfite, potassium sulfite, ammonium bicarbonate, lithium bicarbonate, magnesium bicarbonate, meglumine, calcium bicarbonate or zinc bicarbonate and mixtures thereof;
c) at least one or more pharmaceutical excipient;
wherein the molar ratio of pH regulating agent to fosfomycin is 0.01:1.0 to 1.0 :1.0.

3. The stable pharmaceutical composition according to claim 1 and 2, wherein at least one or more pharmaceutically acceptable excipients are selected from the group comprising of diluents, binders, sweeteners, flavors, surfactants, taste masking agents, preservatives or mixtures thereof.

4. A process for preparing a stable solid oral pharmaceutical composition wherein the process comprises of:
a) dissolving pH regulating agent in an adequate amount of water
b) granulating fosfomycin or its pharmaceutically acceptable salts or derivatives with the solution of step (a)
c) passing the wet mass as obtained in step (b) through suitable size sieve and drying the granules
d) passing the resultant granules through a suitable size mesh and mixing the granules with sweeteners, flavoring agent, lubricants and glidants.
e) Filling the blend of step (d) into sachets.

5. The stable pharmaceutical composition according to claim 1, 2 and 4, wherein the composition is in the form of powder for oral solution, granules for oral solution, ready to use solution, soluble tablets, dispersible tablets, orally disintegrating tablet or chewable tablet.

6. The stable pharmaceutical composition according to claims 1, 2 and 4, wherein the flavors are selected from the group comprising orange, grape, strawberry, raspberry, cherry, chocolate, pineapple, citrus oil, citric acid, or mixtures thereof.

7. The stable pharmaceutical composition according to claims 1, 2 and 4, wherein the sweeteners are selected from the group consisting of sucrose, dextrose, sucralose, sorbitol, saccharose, neotame, aspartame, acesulfame K, fructose, mannitol, saccharin sodium, saccharose or mixtures thereof.

8. The stable pharmaceutical composition for oral administration in the form of granules for oral solution consisiting of fosfomycin or its pharmaceutically acceptable salt or derivative thereof, wherein fosfomycin or its pharmaceutically acceptable salt or derivatives have a particle size distribution D90 less than about 200 µm.

9. The stable pharmaceutical composition according to the preceding claims is packed in a packaging material selected from the group comprising of foil, pouch, sachet, capsule, bottle, container or other suitable package.

10. The stable pharmaceutical composition according to the preceding claims is used for the treatment of uncomplicated urinary tract infections (acute cystitis) in women due to susceptible strains of Escherichia coli and Enterococcus faecalis.