AGENT

Present invention is related to water dispersible pharmaceutical dosage forms comprising cefdinir as active agent and methods for preparation of these. Background of the invention

Cefdinir molecule which is shown with Formula I was first disclosed in the patent numbered BE897864 and its chemical name is (6R,7R)-7-[[(2Z)-(2-amino-4- thiazolil)(hydroxyimino)acetyl] amino]-3-ethenyl-8-oxo-5-thia-l -azabicyclo[4.2.0]oct-2-en-2- carboxylic acid. The molecule which is a third generation cephalosporin, is indicated for the treatment of several illnesses caused by gram positive and gram negative bacteria.

Formula I

Cefdinir which physically appears as a white powder has very poor solubility in common organic solvents such as methanol, ethanol, and acetonitrile and in water. Due to this property there are some problems while developing formulations comprising this molecule and in the bioavailability of the finished product.

The product sold in the market under the tradename OMNICEF ^® is present in capsule and suspension forms. Clinic studies show that the bioavailability of the suspension product is 120% more than the bioavailability of the product in capsule form.

Although the suspension forms have higher bioavailability, use of this dosage form especially for pediatric and geriatric patients brings about the possibility of taking high and/or uncontrolled dose. Additionally, the fact that the suspensions have physical and chemical stability problems, they have short shelf life and high production costs and the fact that they cause problems while transporting and use are disadvantageous for the manufacturers.

Due to the reasons stated above it is necessary to provide new dosage forms in antibiotic theraphy in order to provide effective dosing, meet patient requirements and to offer different alternatives to patients having special conditions, such as pediatric and geriatric patients. When state of the art is taken into account it is seen that it is necessary to develop; new pharmaceutical compositions comprising cefdinir that are stable, have long shelf life, easy to use and that have high bioavailability and different dosage forms.

Inventors have surprisingly found that the problems present in the state of the art can be solved by the water dispersible powder, tablet, granule formulations prepared according to the present invention.

Detailed description of the invention

Subject matter of the present invention is related to water dispersible powders, tablet and granules comprising cefdinir as the active agent, formulations of these water dispersible powders, tablet and granules comprising cefdinir as the active agent anf process for preparation thereof. Surprisingly it was seen that when cefdinir, which is characterized with its low water solubility, is formulated with the water dispersible powder, tablet, granule formulation disclosed in the present invention it disperses in water and forms homogenous cefdinir solution.

Accordingly, pharmaceutical dosage forms that are in the form of water dispersible powder, tablet or granule and suitable for use as a single dose; a) Will be have a longer shelf life compared to the suspension forms since the dosage form in solid form is more stable and

b) Has higher bioavailability and is easier to use for the patients compared to the solid dosage forms since it dissolves in water and disperses homogeneously prior to use. Therefore water dispersible powder, tablet and granule formulation of the present invention has combined the advantages of the tablet and suspension forms and removes the disadvantages arising from these forms.

The term "water dispersible powder, tablet and granule" comprises effervescent tableti effervescent granules, effervescent powders, water dispersible tablets, water dispersible powders and water dispersible granules, water soluble tablets, water soluble powders, water soluble granules.

Accordingly one aspect of the present invention is water dispersible powders, tablets and granules comprising cefdinir as active agent. Another aspect of the invention is water dispersible powder, tablet and granule formulations comprising pharmaceutically acceptable excipients in addition to cefdinir which is used as an active agent.

Cefdinir has a hydrophobic character and for this reason it has wetting and low solubility problems. This leads to low bioavailability and problems related to development of water dispersible formulations.

Upon the investigations related to development of water dispersible powder, tablet and granule forms, inventors have unexpectedly found that use of organic base in the formulation is effective for solving the water solubility problem of cefdinir. Accordingly, in the present invention primary, secondary, tertiary amines and/or nitrogen containing heterocyclic compounds can be used as organic base.

Organic base that can be used in the formulation can be selected from a group comprising ethanolamine, isopropanolamine, 1-deoxy-l-methylamino-sorbitol, 1-deoxy-l-methylamino-D- glucitol, tris(hydroxymethyl)aminomethane, N-(tri(hydroxymethyl)methyl)glycine, N,N-Bis(2- hydroxyethyl)glycine, 2-methyl aminophenol. Preferably 1-deoxy-l-methylamino-sorbitol and tris(hydroxymethyl)aminomethane are used.

Cefdinir which can be used in the water dispersible powder, tablet and granule formulations of the present invention can be present in the form of its solvates, hydrates, enetiomers, racemates, organic salts, inorganic salts, polymorphs, crystal and amorphous forms or in free form and/or as a combination of these.

In the said formulation in addition to cefdinir and organic base several other excipients such as binders, lubricants, humectants, disintegrants, basic agents, acidic agents, sweeteners and optionally effervescent couples can be used.

In water dispersible powder, tablet and granule formulation of the invention, binder can be selected from, but not limited with, a group comprising ethyl cellulose, gelatine, hydroxy ethyl cellulose, hydroxy methyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, methyl cellulose, povidone.

In water dispersible powder, tablet and granule formulation of the invention, lubricant can be selected from, but not limited with, a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG6000, polyvinyl alcohol, potassium benzoate, sodium benzoate. In water dispersible powder, tablet and granule formulation of the invention, humectant can be selected from, but not limited with, a group comprising anhydrous sodium sulphate, silica gel and potassium carbonate.

In water dispersible powder, tablet and granule formulation of the invention, disintegrant can be selected from, but not limited with, a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methyl cellulose, povidone, magnesium aluminium silicate, starch or a combination thereof.

In water dispersible powder, tablet and granule formulation of the invention, diluent can be selected from, but not limited with, a group comprising calcium carbonate, calcium sulfate, dibasic calcium phophate, tribasic calcium sulfate, calcium sulfate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrine, maltose, mannitol, sodium chloride, sorbitol, starch, xylitol or a combination thereof.

In water dispersible powder, tablet and granule formulation of the invention, basic agent can be selected from, but not limited with, a group comprising potassium carbonate, potassium citrate, potassium hydroxide, sodium carbonate, sodium bicarbonate or combinations thereof.

In water dispersible powder, tablet and granule formulation of the invention, acidic agent can be selected from, but not limited with, a group comprising acetic acid, citric acid, lactic acid, malic acid, phosphoric acid, propionic acid, tartaric acid or combinations thereof. In water dispersible powder, tablet and granule formulation of the invention, sweetener can be selected from, but not limited with, a group comprising acesulfame, aspartamate, dextrose, fructose, glucose, lactitol, maltitol, maltose, sorbitol, saccharide, sodium saccharide, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose, xylitol or combinations thereof. In water dispersible powder, tablet and granule formulation of the invention, effervescent couple which is optionally used can be selected from, but not limited with, a group comprising citric acid, tartaric acid, malic acid, furmaric acid etc as organic acid and sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate etc. as organic base.

In water dispersible powder, tablet and granule formulation of the invention, 1-4000 mg of cefdinir or pharmaceutical salts, hydrates, solvates or a combination thereof in an amount equivalent to that can be used. In water dispersible powder, tablet and granule formulation of the invention; 5-60% of cefdinir or pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystal/amorphous forms, 1-30% organic base, 1-30% binder, 0.1-3 % lubricant, % 0.1-5%) sweetener, 0.1-8 % coloring and/or flavouring agent and optionally 0- 90% effervescent couple in an amount by total weight of the unit dose can be used.

In another aspect present invention relates to processes used for the preperation of water dispersible powder, tablet and granule formulations comprising cefdinir as active agent and pharmaceutically acceptable excipients.

Accordingly, process used in present invention comprises granulation of cefdinir with conventional dry and/or wet granulation methods known in the art or mixing cefdinir and other excipients with a dry blending method and optionally pressing them in tablet form.

Water dispersible powder, tablet or granules according to the present invention can be prepared according to the examples given below. The examples are given for the sake of demonstrating the invention and the invention is not limited with these examples. . EXAMPLE 1: Formulation and process for preperation of effervescent granules

Formulation is obtained by granulation of sodium hydrogen carbonate and cefdinir with aqueous solution of organic base and then mixing the formed granules with citric acid and sweetener. The formed mixture is then granulated with a solution of binder. The granule obtained after this step is mixed with lubricant, coloring agent, sweetener and flavouring agent and optionally it can be compressed to obtain tablets. EXAMPLE 2: Formulation and process for preperation of water dispersible granules

Formulation can be obtained by granulation of cefdinir with aqueous solution of organic base and then mixing the formed granules with sweetener. The formed mixture is then granulated with a solution of binder. The granule obtained after this step is mixed with lubricant, coloring agent, sweetener and flavouring agent and optionally it can be compressed to obtain tablets.

In another aspect present invention relates to use of water dispersible powder, tablet and granule formulations comprising cefdinir and in addition to that pharmaceutically acceptable excipients for the treatment of infections caused by gram positive and gram negative bacteria.