The present invention relates to pharmaceutical tablet formulations comprising cefuroxime axetil to be used in the treatment of upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as cystitis and urethritis; and skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases caused by gram positive and gram negative bacteria.

Cefuroxime axetil was first disclosed with the patent application numbered US3974153. In said document, cefuroxime axetil was indicated to be effective for use in treatment of upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as cystitis and urethritis; and skin and soft tissue infections such as furuncle, pyoderma, impetigo; in the treatment of gonorrhea and lyme diseases caused by gram positive and gram negative bacteria.

Cefuroxime axetil physically appears in the forms of suspension and 100-5000 mg tablets on the market.

In the sense of pharmaceutical technology, physical properties of dosage form for every type of tablet dosage form are directly related to durability in storage conditions; dissolution and bioavailability of the dosage form obtained.

One of the physical properties important in pharmaceutical formulations is tablet hardness. Tablet hardness provides resistance of tablets to storage, transport, coating and erosion- breakage before usage. Erosion, friability or breakage of tablets is often caused by low hardness and this case leads to the loss of active agent and changes the amount of dose taken. Another consequence of low hardness is the erosion of tablet surface during coating process and dosage forms which have uneven surfaces leading to variable amounts of active agent in the final product while producing coated tablet forms.

On the other hand, dispersibility and solubility of a tablet is also dependent on its hardness. Tablets that are too hard do not disperse or dissolve adequately; in this case, bioavailability of said dosage forms will decrease and therefore the time for desired biological response to occur will 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. Furthermore, tablet hardness is influenced by many parameters such as the types of active agents and excipients used, particle sizes thereof, flowability of the powder or granules prepared for tablet compression. The particle size of the active agent therefore gains importance considering weight uniformity of the formulation. The homogeneity of the composition can be lost if the proper flow is not provided. This case leads to the loss of the weight uniformity and variations of the drug dose taken in each tablet. Consequently, the efficiency of the treatment decreases because of weight and content uniformity loss observed in the dosage forms obtained. When all of these parameters are considered, the particle size of the active agent and the tablet hardness should be in a specific range to

• provide good flow properties of the formulation,

• ensure the amount of the drug taken in each dose and eventually

• increase the bioavailability of the drug by being dissolved adequately. As a result of the development studies conducted on pharmaceutical tablet formulations, the inventors have found that the required physical parameters such as hardness and solubility are achieved when the tablet formulations of the present invention comprising cefuroxime axetil and at least one pharmaceutically acceptable excipient wherein tablet hardness value is between 3 kP and 50 kP, preferably 4 kP and 40 kP, more preferably 5 kP and 30 kP and the dlOO value of cefuroxime axetil is in the range of 1500-200 μιη, preferably 1300-250 μηι, more preferably 1000-300.

According to this, another characteristic of the tablet formulations of the present invention is that said tablet formulations comprise cefuroxime axetil as active agent and at least one pharmaceutically acceptable excipient is characterized in that the · tablet hardness value is between 3 kP and 50 kP and

• dlOO value of cefuroxime axetil is in the range of 1500-200 μηι.

Another characteristic of the tablet formulations of the present invention is that said tablet formulations comprise cefuroxime axetil as active agent and at least one pharmaceutically acceptable excipient is characterized in that the • tablet hardness value is between 4 kP and 40 kP and

• dl 00 value of cefuroxime axetil is in the range of 1300-250 μηι.

A further characteristic of the tablet formulations of the present invention is that said tablet formulations comprise cefuroxime axetil as active agent and at least one pharmaceutically acceptable excipient and are characterized in that the

• tablet hardness value is between 5 kP and 30 kP and

• dlOO value of cefuroxime axetil is in the range of 1000-300 μηι.

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.

The pharmaceutical formulation of the present invention is preferably in the form of film- coated tablet.

The term "dlOO value" denotes the value of the particle size up to which cumulatively 100% of the particles in the particle size distribution were found to lie. The pharmaceutical formulations of the present invention comprise at least one pharmaceutically acceptable excipient selected from the group comprising disintegrant, diluent, lubricant, glidant, binder.

The diluent that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol or combinations thereof.

The lubricant that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising calcium stearate, magnesium stearate, polythylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or combinations thereof. The glidant that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising tribasic calcium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc 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.

Another problem observed in cefuroxime axetil tablet formulations is low dissolution of the tablet forms due to the high hardness. The inventors have conducted studies on finding the desired formulation in order to have the required hardness of the tablet enough to resist the manufacturing process but also soluble enough to provide the necessary bioavailability for the patients. Based on these studies, it is observed that the ratio of cefuroxime axetil: disintegrant should be in the range of 10: 1 to 1 :2, preferably 8:1 to 1 :1 by weight. In this regard, a characteristic feature of the present invention is that the ratio of cefuroxime axetil: disintegrant is in the range of 10: 1 to 1 :2, preferably 8: 1 to 1 : 1 by weight.

A further need of the tablet formulations comprising cefuroxime axetil is the use of excipients in required amounts such that the required tablet hardness and dissolution rate are attained. Accordingly, it is observed that the cefuroxime axetil tablets have these desired physical properties when the ratio of disintegrant to diluent is in the range of 7:1 to 1 :7, preferably 5: 1 to 1 :5 by weight.

Another characteristic of the present invention is that the ratio of disintegrant to diluent is in the range of 7:1 to 1 :7, preferably 5:1 to 1 :5 by weight.

The pharmaceutical formulations of the invention comprising cefuroxime axetil as active agent comprise cefuroxime axetil in the range of 25 to 90%, preferably in the range of 40 to 80%, more preferably in the range of 45 to 75% by weight.

Said tablet formulations can optionally be treated with film-coating agents, for instance sugar- based coating agents, water-soluble film-coating agents, enteric coating agents, coating agents prepared to provide various release properties (such as fast release, slow release, controlled release) or coating compositions comprising any combination thereof. As sugar-based coating agent, saccharose can be used on its own or optionally with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatin, gum arabic, polyvinylpyrrolidone and pullulan or any combination thereof.

The water-soluble film-coating agents can be selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan; or combinations thereof.

The enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S; and natural substances such as shellac; or combinations thereof.

Other film coating agents can be selected from a group comprising titanium dioxide, polyvinyl alcohol, polyethylene glycol, talc, lecithin and/or combinations thereof. For example, a film coating agent branded as Opadry® can be used in the present invention.

The preparation method of the formulations of the invention comprises formulating the active agent with an appropriate excipient composition and compressing said formulation in the form of tablets under an appropriate compression force. A characteristic of the tablet formulations of the present invention is that said tablet formulations comprise cefuroxime axetil as active agent, at least one pharmaceutically acceptable excipient and the tablet compression force used for compressing said formulations in the form of tablets is between 3 kN and 50 kN.

A characteristic feature of the tablet formulations of the present invention is that said tablet formulations comprise cefuroxime axetil as active agent, at least one pharmaceutically acceptable excipient and the tablet compression force used for compressing said formulations in the form of tablets is between 4 kN and 45 kN.

Another characteristic of the tablet formulations of the present invention is that said tablet formulations comprise cefuroxime axetil as active agent, at least one pharmaceutically acceptable excipient and the tablet compression power used for compressing said formulations in the form of tablets is between 5 kN and 40 kN.

The tablet formulations of the invention can be produced in accordance with any of the production methods given below; 1. Mixing disintegrant with at least one other excipient,

2. Adding cefuroxime axetil as active agent forming a first mixture,

3. Adding at least one other excipient to the first mixture,

4. Forming a second mixture with disintegrant and at least one other excipient,

5. Combining these two mixtures and lubricating it with lubricant forming a final mixture,

6. Compressing the final mixture into tablet dosage form,

7. Coating the tablet with a coating solution containing a film-coating agent,

The pharmaceutical composition of the invention can be used for upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as pyelonephritis, cystitis and urethritis; skin and soft tissue infections such as furuncle, pyoderma, impetigo; in the prophylaxis and treatment of gonorrhea and lyme 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. Film-Coated Tablet Formulation

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

1. Mixing disintegrant with at least one other excipient,

2. Adding cefuroxime axetil as active agent forming a first mixture,

3. Adding at least one other excipient to the first mixture,

4. Forming a second mixture with disintegrant and at least one other excipient,

5. Combining these two mixtures and lubricating it with lubricant forming a final mixture,

6. Compressing the final mixture into tablet dosage form,

7. Coating the tablet with a coating solution containing a film-coating agent,