The present invention relates to pharmaceutical tablet formulations comprising ceftibuten to be used in the treatment of infectious diseases caused by gram positive and gram negative bacteria. Ceftibuten was firstly disclosed in the patent application numbered US 4634697. In said document, ceftibuten was indicated to be effective in the treatment of infectious diseases caused by gram positive and gram negative bacteria.

Ceftibuten is available in the forms of 400 mg capsule, 400 mg tablet and 36 mg/ml oral suspension on the market. In terms of pharmaceutical technology, physical properties of every tablet dosage form are directly related to durability in storage conditions; dissolution and bioavailability of an obtained dosage form.

The resistance of tablets to storage, transport, coating and erosion-breakage before use is provided by an important physical parameter which is tablet hardness. Low hardness of tablets leads to erosion, friability or breakage and causes the loss of active agent and thus decrease in the amount of dose taken. In the case of producing coated tablet forms a further consequence of low hardness is the erosion of tablet surface during coating process and this leads to dosage forms that have uneven surfaces and variable amounts of active agent in the final product On the other hand, dispersibility and solubility of a tablet is also dependent on the hardness. High hardness of the tablet decreases its dispersion rate hence the time for desired response to occur will eventually extend. The same case is also true for all types of tablets such as effervescent, film-coated, soluble, extended-release, modified-release, delayed-release tablets etc. Attaining appropriate tablet hardness is influenced by many parameters such as the types of active agents and excipients used, their particle sizes, flowability of the powder or granules prepared for tablet compression and tablet compression force.

When all these parameters are taken into consideration, tablet hardness value is aimed to be low enough to disintegrate fast in gastric media or in water in case of effervescent tablet formulations but high enough to preserve tablet integrity from production to use during packaging, carrying and storing phases.

As a result of the development studies they conducted on pharmaceutical tablet formulations comprising ceftibuten, the inventors have found that the required mechanical tablet resistance, the required dissolution rate and accordingly the desired bioavailability are attained with the tablet formulations comprising ceftibuten in the range of 5-45%, preferably 10-40%, more preferably 10-35% by weight and having a tablet hardness value between 3 kP and 50 kP.

According to this, the tablet formulations of the present invention is characterized in that said tablet formulations comprise ceftibuten as active agent and at least one pharmaceutically acceptable excipient wherein the

• amount of ceftibuten is in the range of 5-45% by weight and

• tablet hardness value is in the range of 3 kP and 50 kP.

Another characteristic of the tablet formulations of the present invention is that said tablet formulations comprise ceftibuten as active agent and at least one pharmaceutically acceptable excipient and the amount of ceftibuten is in the range of 10-40%, preferably 10-35% by weight.

A further characteristic of the tablet formulations of the present invention is that said tablet formulations comprise ceftibuten as active agent and at least one pharmaceutically acceptable excipient and have a tablet hardness value in the range of 4 kP and 40 kP, preferably 5 kP and 30 kP.

The term "tablet" used throughout the text refers to tablet types such as tablet, effervescent tablet, film-coated tablet, enteric-coated tablet, orodispersible tablet, water-soluble tablet, extended-release tablet, modified-release tablet, delayed-release tablet.

In a preferred embodiment of the invention, the pharmaceutical formulation of the present invention is in effervescent tablet dosage form.

Ceftibuten comprised in the pharmaceutical formulations of the present invention can be in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure; and in crystalline, amorphous forms or combinations thereof in terms of polymorphic structure. The active agent ceftibuten is preferably in hydrate form, more preferably in the form of ceftibuten dihydrate.

The pharmaceutical formulations of the present invention comprise at least one pharmaceutically acceptable excipient selected from the group comprising disintegrants, lubricants, binders, effervescent couple composed of at least one effervescent acid and at least one effervescent base, sweeteners and/or taste regulating agents, flavoring agents.

The lubricant that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or combinations thereof.

The binder that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, povidone, starch or combinations thereof.

The effervescent acids that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid; and said effervescent bases can selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate or combinations thereof.

The sweetener and/or the taste regulating agent that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride or combinations thereof. The flavoring agent that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising flavors such as menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and the like or combinations thereof.

In effervescent tablet formulations, the solubility of the tablet is especially dependent on the choice of effervescent couple composed of an effervescent acid and an effervescent base and their amount with regard to the active agent or other excipients. To improve the solubility of effervescent tablet formulations comprising ceftibuten, the inventors have made studies on the content of the formulation and observed that if the ratio of effervescent couple to ceftibuten is in the range of 10:1 to 1 :1 preferably 8: 1 to 1 : 1 and more preferably 7:1 to 2: 1 by weight; said formulations have the required solubility in water. Accordingly, a further embodiment of the present invention is that the ratio of effervescent couple to ceftibuten is in the range of 10:1 to 1 : 1 , preferably 8: 1 to 1 : 1 and more preferably 7: 1 to 2:1 by weight.

Furthermore, another problem observed in pharmaceutical formulations comprising ceftibuten is the precipitation of the granules after being dissolved in water due to their low solubility. In order to prevent this type of precipitation and formation of agglomerates, the inventors of the present invention have developed formulations by adjusting the ratio of effervescent base to effervescent acid. Eventually, these studies showed that the ratio of effervescent base to effervescent acid should be in the range of 5: 1 to 1 :5, preferably 3: 1 to 1 :3 and more preferably 3:1 to 1 :1 by weight to eliminate the abovementioned granule precipitation problem.

In this regard, a preferred embodiment of the invention is that the ratio of effervescent base to effervescent acid is in the range of 5:1 to 1 :5, preferably 3:1 to 1 :3 and more preferably 3:1 to 1 : 1 by weight.

One of the excipients playing role in the homogenity of the formulation and therefore in its solubility is the binder. In tablet formulations of the present invention, it is observed that the ratio of ceftibuten to binder should be in the range of 15:1 to 1 :1 by weight for ensuring the integrity of the tablet during manufacturing and before use but also having good disintegration in water for patient compliance.

According to a preferred embodiment of the invention, the pharmaceutical tablet formulations of the present invention is characterized in that the ratio of ceftibuten to binder is in the range of 15:1 to 1 : 1, preferably 13:1 to 3:1 by weight.

The tablet formulations of the invention can be produced in accordance with the production method given below;

• Preparing a granulation solution comprising a part of the binder as a first step, .

Forming a mixture to be granulated containing effervescent acid, effervescent base, the rest of the binder and a first sweetener,

Granulating this mixture with the granulation solution prepared in the first step, Drying formed granules and sieving them,

Adding ceftibuten, lubricant, flavoring agent and a second sweetener to the sieved granules,

Compressing said granules into tablets.

Moreover, during the development studies of the ceftibuten tablet formulations, it is observed that the integrity of the formulation is more preserved during the compression if the binder is used in two different stages of the preparation process. Surprisingly, when the 80 to 50% of the binder is used in the granulation step and the rest is used in the mixture to be granulated, the granules formed are more resistant to compression force applied in tablet compression.

In a more preferred embodiment of the present invention, the production method used to prepare the ceftibuten formulations is characterized in that the 80 to 50% of the binder, preferably 70 to 60% is used in the granulation step and the rest is used in the mixture to be granulated.

The pharmaceutical composition of the invention can be used in the prevention and treatment of infectious diseases caused by gram positive and gram negative bacteria. The examples below are given to explain the pharmaceutical compositions of the invention and the preparation methods thereof; the scope of the invention cannot be limited to these examples.

EXAMPLE

1. Effervescent Tablet Formulation Comprising Ceftibuten

The production method for the tablet formulations to be prepared according to the formulation given above is as follows;

• Preparing a granulation solution comprising a part of the binder as a first step,

• Forming a mixture containing effervescent acid, effervescent base, the rest of the binder and a first sweetener,

• Granulating this mixture with the granulation prepared in the first step,

• Drying formed granules and sieving them,

• Adding ceftibuten, lubricant, flavoring agent and a second sweetener to the sieved granules,

• Compressing said granules into tablets.