The present invention relates to water dispersible pharmaceutical dosage forms comprising cefdinir as the active agent, and their preparation.

Background of the Invention

The chemical structure of the molecule cefdinir, which has the chemical name (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 and was first disclosed in the patent numbered BE897864, is shown in Formula I. This molecule, which is a third generation cephalosporin, is indicated for the treatment of many diseases 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 of its, there appears some problems in the development of effervescent formulations comprising this molecule and the bioavailability of the final product.

Cefdinir do not get wet or dissolve in water owing to its hydrophobic character, and this results in low bioavailability and problems in the development of water dispersible formulations.

The product under the name OMNICEF ^® is available in capsule and suspension forms on the market. The clinical studies indicate that the bioavailability of the medicament is 120% higher when taken in suspension form compared to its intake in capsule form.

Although suspension forms indicate higher bioavailability, the use of this dosage form brings along the possibility of excessive and/or uncontrolled dose intake particularly in pediatric and geriatric patients. In addition, suspension forms have disadvantages for manufacturers as their physical and chemical stability is problematic; they have short shelf life; they have high manufacture costs; and they create problems in use and carrying. As can be seen, new dosage forms and formulations are required to be developed in order to provide affective dosing, meet the patients' needs and provide alternatives for the patients in need of special consideration, particularly pediatric and geriatric patients.

When the prior art is taken into consideration, it is seen that new stable and user friendly pharmaceutical compositions comprising cefdinir which have long shelf life and high bioavailability are needed to be developed.

The inventors have surprisingly found that the problems in the prior art can be solved with the water dispersible powder, tablet and granule formulation prepared according to the present invention.

Description of the Invention

The subject of the present invention is water dispersible powders, tablets and granules comprising cefdinir; their formulations and the procedures related to their preparation. Surprisingly, it has been found that the obtained composition dissolve in water homogenously and form a transparent solution when the ratio of cefdinir to the organic base is in the range of 5:1 to 1 :5 in the formulations comprising cefdinir which has very low water solubility.

According to this, pharmaceutical dosage forms in the form of water dispersible powder, tablet or granule which are suitable for single dose use; a) have longer shelf life compared to suspension forms due to the fact that they are more stable as they are in solid dosage form, and b) can be taken by the patients more comfortably as they disperse in water homogeneously prior to use and their bioavailability is superior to said solid dosage forms.

Therefore, the water dispersible powder, tablet and granule formulations pertaining to the present invention eliminates the problems resulting from tablet and suspension forms by holding the advantages of both.

According to this, one aspect of the present invention is water dispersible powders, tablets and granules comprising cefdinir as the active agent in which the ratio of cefdinir to the organic base is in the range of 5: 1 to 1 :5. The term "water dispersible powder, tablet and granule" present in the text comprises effervescent tablets, effervescent granules, effervescent powders, water dispersible tablets, water dispersible powders and water dispersible granules.

According to this, primary amines, secondary amines, tertiary amines and/or heterocyclic compounds containing nitrogen can be used as the organic base in the present invention.

The organic base that is to be used in the formulation can be selected from, but not limited to, a group comprising ethanolamine, isopropanolamine, 1-dioxy-l-methylamino-sorbitol, 1- dioxy-1 -methylamino-D-glucitol, tris(hydroxymethyl)aminomethane, N-

(Tri(hydroxymethyl)methyl)glycine, N,N-Bis(2-hydroxyethyl)glycine, 2-methyl aminophenol. Preferably, 1-dioxy-l-methylamino-sorbitol and tris(hydroxymethyl)aminomethane are used.

Cefdinir that can be used in the water dispersible powder, tablet and granule formulations, which are the subject of the present invention, can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystal and amorphous forms or in free form and/or combination thereof.

Another aspect of the present invention is the water dispersible powder, tablet and granule formulations comprising pharmaceutically acceptable excipients in addition to the active agent cefdinir.

Various excipients selected from, but not limited to, a group comprising binders, lubricants, humectants, disintegrants, diluents, sweeteners and optionally an effervescent couple can be used in the water dispersible formulation pertaining to the present invention apart from cefdinir and the organic base.

The binder that can be used in the water dispersible powder, tablet and granule formulations pertaining to the present invention can be selected from, but not limited to, a group comprising ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, methyl cellulose, povidone. Preferably, povidon is used in scope of the present invention.

During the studies they have conducted, the inventors found that the dissolution time of the pharmaceutical composition obtained when 1-10% binder is used is shorter compared to the formulations in which less amounts of binder is used. According to this, another aspect of the present invention is water dispersible powders, tablets and granules which comprise the binder in the ratio of 1-10%, preferably in the ratio of 1-8%, most preferably in the ratio of 2-5% and cefdinir as the active agent.

According to another aspect, the inventors have found that having the ratio of cefdinir to the binder in the range of 5:1 to 1 :5, most preferably in the range of 4:1 to 2:1 has a positive effect on the solubility of cefdinir in water.

According to this, another aspect of the present invention is water dispersible powder, tablet and granule formulations wherein the ratio of cefdinir to the binder is in the range of 5:1 to 1 :5, most preferably in the range of 4:1 to 2:1 and which comprises cefdinir as the active agent.

The lubricant that can be used in water dispersible powder, tablet and granule formulations of the present invention can be selected from, but not limited to, a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate. Preferably, PEG 6000 is used as lubricant in the formulations pertaining to the present invention.

The humectant that can be used in water dispersible powder, tablet and granule formulations of the present invention can be selected from, but not limited to, a group comprising anhydrous sodium sulphate, silica gel and potassium carbonate.

The disintegrant that can be used in water dispersible powder, tablet and granule formulations of the present invention can be selected from, but not limited to, a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methyl cellulose, povidone, magnesium aluminum silicate and starch or combinations thereof.

The diluent that can be used in water dispersible powder, tablet and granule formulations of the present invention can be selected from, but not limited to, a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch and xylitol or combinations thereof. The sweetener that can be used in water dispersible powder, tablet and granule formulations of the present invention can be selected from, but not limited to, a group comprising acesulfame, aspartame, dextrose, fructose, glucose, lactitol, maltitol, maltose, sorbitol, saccharine, saccharine sodium, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose, xylitol or combinations thereof. Preferably, sucrose, aspartame, sodium chloride or a combination thereof is used in the formulations according to the present invention.

It is known that cefdinir has a rather bitter taste and masking this taste leads to problems in the development of especially oral formulations. As a result of the studies they have conducted, the inventors found that the bitter taste of cefdinir is successfully masked in the formulations in which the ratio of the sweetener to cefdinir is in the range of 5:1 to 1:1, preferably 4:1, most preferably 3:1.

According to this, another characteristic of the water dispersible formulations pertaining to the present invention is that the ratio of cefdinir to the sweetener in said formulations is 5:1, preferably in the ratio of 4:1, most preferably in the ratio of 3:1.

In scope of the present invention, preferably sucralose and/or sodium chloride or a composition comprising a combination thereof, most preferably a combination of sucralose and sodium chloride is used.

It has been specified in the studies conducted that the ratio of the agents used in the sweetener composition to each other is significant in masking the taste. According to this, it has been found that the taste of cefdinir is successfully masked in the formulations in which the ratio of sodium chloride to sucralose is in the range of 6:1 to 1:1, preferably 4:1, most preferably 3:1.

The effervescent couple that can be used in water dispersible powder, tablet and granule formulations pertaining to the present invention can be selected from organic acids such as citric acid, tartaric acid, malic acid, fumaric acid etc. and basic agents such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and potassium hydrogen carbonate etc.

In water dispersible powder, tablet and granule formulation of the present invention, 1-4000 mg cefdinir or its pharmaceutically acceptable salts, hydrates, solvates or combinations thereof in an amount equal to this can be used. The water dispersible powder, tablet and granule formulation of the present invention can comprise 5-60% cefdinir or pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystal and amorphous forms of cefdinir and 1-30% organic base; 1-10% binder; 0.1-3% lubricant; 0.1-5% sweetener and/or taste regulating agent, 0-30% diluent; 0-20% disintegrant; 0-10% humectant; 0.1-8% coloring agent and/or flavoring agent and 0-90% effervescent couple with respect to the total amount of unit dose.

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

According to this, the process in scope of the present invention comprises the granulation of the active agent cefdinir through conventional wet and/or dry granulation methods present in the prior art or mixing cefdinir and the other excipients through dry blending method and then powderizing them and optionally compressing them in tablet compressing machine to obtain tablet forms.

EXAMPLE 1: Formulation and process for the preparation of effervescent granule

The formulation to be used in scope of said invention comprises granulating sodium hydrogen carbonate and cefdinir with hydrous organic base solution; then adding citric acid and sweetener into the obtained granule and granulating the mixture obtained with binder solution; following this, adding lubricant, coloring agent, sweetener and flavoring agent to the granule mixture obtained and mixing it again; then optionally compressing the obtained mixture in tablet compressing machine to obtain tablets.

According to another aspect, the present invention relates to the use of the water dispersible powder, tablet and granule formulations comprising cefdinir and pharmaceutically acceptable excipients in the manufacture of a medicament to be used in the treatment of infections caused by gram negative and gram positive bacteria.

According to another aspect of the present invention, the pharmaceutical composition prepared according to the present invention is used in the manufacture of a medicament so as to be used in upper respiratory infections such as ear, nose, throat, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as pyelonephritis, cystitis and urethritis; skin or soft tissue infections such as froncle, pyoderma, impetigo; in the treatment and prophylaxis of gonorrhea and lyme diseases.