ACID AS ACTIVE AGENTS

The present invention is related to the pharmaceutical formulation in effervescent form comprising cefixime and clavulanic acid. Prior Art

Cefixime shown with Formula (I) is a third generation cephalosporin antibiotic which is disclosed for the first time in the European patent numbered EP0030630 (Bl) and is indicated for use in treatment of infections caused by gram positive and gram negative bacteria.

The product named as SUPRAX comprises cefixime as active agent and is commercially available in oral tablet or oral suspension forms. Bioavailability of cefixime tablets are in the range of 40-50%. Suspension forms provide 25-50% more bioavailability compared to the bioavailability of the tablet forms.

However, cefixime suspensions present in the state of the art are in the form of powder that is to be constituted with water prior to use. The powder, once constituted, is unstable therefore is has to be consumed in 14 days. For this reason, effervescent forms are proposed as an alternative, in order to eliminate the problems in the prior art. Clavulanic acid that is shown with Formula (II), is a beta-lactamase inhibitor:

Clavulanic acid and its derivatives (such as its salts like potassium clavulanate) are known as beta lactamase inhibitors that inhibit the activity of beta lactamase enzymes that is produced by the bacteria.

In state of the art, there are several studies disclosing combined use of beta lactam antibiotics and beta lactamase enzyme inhibitors for the prevention of antibiotic resistance. In the last years, the resistant bacteria is included into the activity spectrum by developing combined penicilin preparates comprising combination of beta lactamase inhibitors such as clavulanic acid, sulbactam and tazobactam and penicilin derivatives like amoxicillin, ticarcillin, piperacillin.

For example, patent applications numbered W095/28927 and EP 1269996 respectively disclose use of amoxicillin and potassium clavulanate in combined form for treatment of bacterial infection and tablet formulations for this combination. WO97/09042 describes tablet formulations comprising amoxycillin and clavulanic acid in an amount in the ratio of 12: 1 to 20: 1 preferably in the ratio of 14: 1.

However, there are some adverse effects of penicilin antibiotics and their combination products such as diarrhea, oversensitiveness, nausea, neurotoxicity and especially serious allergic reactions. Penicilin allergy is widely common in the society. Although this sensitivity to penicillin is mostly displayed with very mild reactions, death rate due to penicillin allergy is relatively high.

Alternatively, in the state of art the use of the combination of any other beta lactam antibiotics like cephalosporins and beta lactamase enzyme inhibitor is proposed. In the patent application numbered in W094/16696, it is disclosed that the use of the combination of beta lactam antibiotics like penicilin or cephalosporin and clavulanic acid for decreasing the enhanced resistance to beta-lactams can increase the antibacterial activity.

Although, cephalosporin antibiotics like cefixime are effective agents in antimicrobial treatment, solution forms comprising this compound have not yet been developed. The reason for this is the fact that cefixime shows a hydrophobic character and it has solubility and wettability problems upon contact with water.

Additionally, at present state of the art, in the formulations applied orally clavulanic acid is usually found in a pharmaceutically acceptable salt form especially in the form of potassium clavulanate. However, potassium clavulanate has an extremely hygroscopic nature and is sensitive to moisture therefore it is very difficult to formulate this compound. Therefore during its manufacture and use it should be kept away from water and mediums containing water otherwise degradation of the compound may take place. Its water sensitive nature and the fact that it is prone to hydrolysis decreases the stability of the formulations comprising clavulanate and leads to restrictions in these formulations.

In another aspect, cefixime and clavulanate show quite different water solubility properties. Cefixime does not dissolve in water on the other hand clavulanate is freely soluble in water. Low water solubility of cefixime acts as a limiting factor for effective use of this compound in oral solutions.

In the prior art, in the formulations in which the combination of beta lactam antibiotic and beta lactamase inhibitor like cefixime and potasium clavulanate are used, in order to prevent the antibiotic resistance, stability and dissolution problems were seen. Potasium clavulanate loses its activity by degradation when in contact with an aqueous medium due to its sensitivity to moisture and the fact that it is prone to hydrolysis. In this case, formulations having low stability and short shelf-life are obtained. Additionally, non-homogeneous and rough suspensions are formed upon releasing the drug into the water due to the dissolution problem of cefixime in water and thus the absorption and bioavailibility of the active agent decrease.

As is seen, new approaches are needed for obtaining the drug formulations comprising cefixime and clavulanic acid, which have long shelf-life and high stability; which increase the water solubility, absorption and bioavailability of active agent and are used for the treatment of the resistant bacterial infections.

The inventors have surprisingly found that the problems in the prior art can be solved by the effervescent formulations that are prepared in accordance with the present invention. Description of the Invention

The present invention is related to effervescent formulations comprising cefixime as active agent and process for the preparation of these formulations. Surprisingly, it is seen that effervescent forms formulated with the formulation comprising 5-40% of cefixime, 1-20% of the mixture of potasium clavulanate: humidity absorbing agent (1 :1), 25-75 % of effervescent couple and 1- 15%) of at least one pharmaceutically acceptable excipient are quite stable and form a homogeneous solution by completely dissolving in water. Accordingly, the present invention is related to the effervescent formulations comprising 5-40% of cefixime, 1-20% of the mixture of potasium clavulanate: humidity absorbing agent (1 :1), 25- 75% of effervescent couple and 1-15% of at least one pharmaceutically acceptable excipient.

"Effervescent formulations" term used in the text comprises effervescent tablets, effervescent granules and effervescent powders.

Effervescent powder, granule or tablet forms are more advantageous compared to the conventional forms due to the fact that they quickly disperse. Effervescent formulations disperse quickly and simultaneously and they disperse the active agents into the aqueous medium. The period between the dissolution of the formulation in water and swallowing the obtained solution is shorter compared to that of the other solution formulations. The consumption of the dose right after the dissolution prevents degradation of the active agents with water. Moreover, effervescent formulations provide ease of use for pediatric and geriatric patients since the formulations in the suspension form are administered to the body orally after dissolving in the aqueous medium rapidly. In this aspect, effervescent formulations in accordance with the present invention are aimed at eliminating the factors causing the antibiotic resistance and are prepared for use in the treatment of resistant bacterial infections.

Cefixime that can be used in the effervescent formulations in accordance with the present invention can be present in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystal and amorphous forms or in free form and/or as a combination thereof.

Cefixime that is used in the present invention can be present in one of the forms of monohydrate, dihydrate, trihydrate and/or anhydrous. Preferably, it is present in the form of cefixime trihydrate. The term "clavulanic acid" refers to clavulanic acid and/or its pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystal forms, amorphous forms and/or combinations thereof. The term cefixime refers to cefixime and/or its pharmaceutically acceptable salts, esters, polymorphs, crystal forms and amorphous forms and/or combinations of thereof. Clavulanic acid used in the present invention is in the form of alkali metal salt, preferably potasium clavulanate. Pharmaceutical formulations according to present invention may comprise effective amount of cefixime, effective amount of potassium clavulanate, an effective effervescent couple and additionally at least one excipient selected from a group comprising pharmaceutically acceptable amount of binder, lubricant, sweeteners. Accordingly, effervescent formulation comprises a mixture of components which gives off carbon dioxide gas upon contact with water. This type of effervescent components are generally an acid or an acidic salt which may give off carbon dioxide gas upon contact with an alkali or alkali earth metal carbonate or hydrogen carbonate and an aqueous solution.

Effervescent acid that is used in the effervescent formulation according to the present invention is selected from a group comprising anhydrous organic or inorganic pharmaceutically acceptable acid anhydrous; especially organic acids such as citric acid, tartaric acid, malic acid, fumaric acid, ascorbic acid, acetic acid, adipic acid, succinic acid, acetylsalicylic acid and/or acidic salts such as sodium citrate, sodium acetate, sodium dihydrogen phosphate, sodium acid pyrophosphate and sodium acid sulphite. Preferably, citric acid is used. Alkali component that is used as effervescent base in the effervescent formulation according to the present invention can be selected from, but not limited with, sodium hydrogen carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium hydrogen carbonate, sodium glycine carbonate, lysine carbonate, arginine carbonate and calcium carbonate. Preferably, sodium hydrogen carbonate is used. The inventors have found that the ratio of cefixime active agent to the effervescent couple is important for disintegration of formulation in a short time and dissolution of the active agent easily. As a result of the studies, it has been observed that the formulations, in which effervescent couple: cefixime ratio is in the range of 15: 1 to 3: 1, preferably 12: 1 to 3:1, more preferably 8: 1 to 4:1 , disintegrate rapidly in water and cefixime active agent which has low water solubility dissolves easily in water.

In this aspect, the present invention is related to the effervescent formulation, in which effervescent couple: cefixime ratio is in the range of 15: 1 to 3: 1, preferably 12: 1 to 3: 1, more preferably 8:1 to 4:1.

Effervescent formulation in accordance with the present invention comprises cefixime, potassium clavulanate, effervescent couple and additionally at least one excipient which is selected from a group comprising pharmaceutically acceptable amounts of binder, lubricant, sweetener and/or taste regulator, diluents, disintegrant, flavoring agent, coloring agent, surfactant, anti-foaming agent, humectants, acidic agent, basic agent.

Clavulanic acid and its derivatives (for example potassium clavulanate) are very sensitive to humidity. For this reason, in formulations of the present invention potassium clavulanate can be used with a humidity absorbing agent, wherein ratio of potassium clavulanate to humidity absorbing agent is preferably in the ratio of 1 : 1.

As humidity absorbing agent one or more of agents which can be selected from the group comprising silica, colloidal silica, such as colloidal silica anhydrous, magnesium trisilicate, powdered cellulose, magnesium oxide, calcium silicate, Syloid®, starch, microcrystalline cellulose and talk. In the present invention preferably Syloid® or microcrystalline cellulose is used.

In formulations of the present invention potassium clavulanate is preferably used with syloid or microcrystalline cellulose in an amount in the ratio of 1 : 1.

Binder used in the effervescent formulation in accordance with the present invention can be selected from, but not limited with, potato starch, wheat starch, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hypromellose and polyvinylpyrrolidone (P.V.P.) and povidone. Preferably, povidone is used.

Lubricant used in the effervescent formulation in accordance with the present invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate. Preferably, PEG 6000 is used.

Sweetener and/or taste regulator that can be used in effervescent formulations of the present invention can be selected from a group of acesulfame, aspartame, dextrose, fructose, maltitol, xylitol, saccharine, sodium cyclamate, sucralose, sucrose, saccharin, saccharin sodium, lactitol, maltitol, maltose, sorbitol, sodium cyclamate, sucrose and xylitol or a combination thereof. Preferably, sodium chloride and/or sucralose is used.

Flavoring agents used in the present invention can be selected from a group comprising banana flavor, strawberry flavor, blackberry flavor, lemon flavor, orange flavor, peach flavor, vanilla flavor or similar natural fruits or might have the flavor of a natural herb. Coloring agent used in the present invention can be selected from titanium dioxide pigments, indigo, carmine, beta carotene and iron oxide pigments. Preferably, beta carotene is used.

Tablets, granules and/or powders according to invention may comprise cefixime and potassium clavulanate in amounts up to maximum allowed daily dose in the unit dosage forms. In single dose of the formulations according to present invention; approximately 50 to 1200 mg of cefixime and approximately 20 to 350 mg of potassium clavulanate can be used.

In formulations of the present invention, ratio of cefixime and potassium clavulanate is in the range of 1 :0.01 to 1 : 10 by weight.

In another aspect, the present invention is related to the effervescent formulations comprising cefixime in an amount of 5-40%, mixture of potasium clavulanate: humidity absorbing agent in an amount of (1 :1) 1-20%, effervescent couple in an amount of 25-75% , binder in an amount of 1-5 %, lubricant in an amount of 0.1-2 %, sweetener in an amount of 0.2-5 % by weight and at least one pharmaceutically acceptable excipient.

Although potassium clavulanate is the most stable form of clavulanic acid, it is unstable against humidity. For this reason, formulations comprising clavulanic acid derivatives such as potassium clavulanate should be prepared under dry conditions, preferably at 0.5% of humidity and at a tenmperature of at least 20 °C. If applicable the components of the formulation may be dried beforehand.

Effervescent formulations in accordance with the present invention is used for the manufacture of a medicament for use in the treatment of upper respiratory tract infections (acute otitis media, acute sinusitis, acute streptococci tonsilo pharangitis), urinary tract infections, commonly acquired pneumonia and skin and soft tissue infections.

In another aspect, the present invention is related to the process for the preparation of pharmaceutical combinations comprising cefixime as active agent and pharmaceutically acceptable excipients. Accordingly, the process according to the present invention is a method that comprises spray granulation of only cefixime among the active agents that are used in the composition. Said method comprises the steps of the blending of cefixime with effervescent couple and pharmaceutically acceptable excipients and granulating them with water; preparation of granulates by drying the obtained granules; preparation of the final mixture by adding potassium clavulanate: humidity absorbing agent (1 :1) mixture, lubricant and at least one pharmaceutically acceptable excipient to the granulate and optionally compressing the final mixture in the form of tablets.

Examples seen below are given for demonstrating the invention. These examples do not limit the scope of the invention and they are evaluated with respect to the description of the invention given above.

EXAMPLE

1. Effervescent formulation

For preparation of granules comprising cefixime, effervescent couple, binder and sweetener are blended and the obtained mixture is granulated with the granulation liquid consisting of deionized water. The obtained granules are dried and sieved. Potassium clavulanate: Syloid (1 :1) mixture, lubricant and at least one pharmaceutically acceptable excipient are added to cefixime granulate and the final mixture is prepared. The final mixture is compressed in the form of tablets.