WO2011093831A2

WO2011093831A2 - Effervescent formulations comprising cefprozil as active agent

Info

Publication number: WO2011093831A2
Application number: PCT/TR2011/000036
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Individual
Current assignee: Individual
Priority date: 2010-01-29
Filing date: 2011-01-31
Publication date: 2011-08-04
Anticipated expiration: 2012-07-29
Also published as: WO2011093828A2; WO2011093831A3; WO2011093828A3; TR201000689A1; EP2528593A2

Abstract

Present invention relates to pharmaceutical formulations formulated in effervescent form comprising cefprozil active agent and the process for their preparations.

Description

EFFERVESCENT FORMULATIONS COMPRISING CEFPROZIL AS ACTIVE

AGENT

Present invention relates to pharmaceutical formulations formulated in effervescent form comprising cefprozil active agent and the process for their preparation. Background of the invention

Cefprozil, which is a second generation cephalosporin, was first disclosed in the patent numbered US4520022 and its chemical name is 8-[2-amino-2-(4-hydroxyphenyl)-acetyl] amino-7-oxo-4-prop-l-enyl-2-thia-6- azabicyclo [4.2.0]oct-4-ene-5-carboxylic acid. Cefprozil shown with Formula 1 is indicated for use in treatment of bronchitis, ear infections, skin infections and for treatment of other infections.

Formula I

In the prior art, the formulations comprising cefprozil as active agent are present in tablet, capsule or oral suspension forms. For example, the pharmaceutical formulations sold in the market under the tradename CEFZIL^®, are present in tablet form comprising 250 and 500 mg cefprozil and in oral suspension form comprising 125 mg/5 ml and 250 mg/5 ml of cefprozil.

Tablet forms comprising 250 and 500 mg active agent in one dose become bigger in size when formulated with excipients. Accordingly, oral tablet and capsule dosage forms cause difficulty in swallowing especially for old people and children since they are difficult to swallow even though they are aclministered with water and have an unpleasant taste. This case impedes the drug intake and affects the efficacy of the treatment negatively. Moreover, bioavailability of oral dosage forms is far less than that of suspension forms.

However, suspension forms cause some problems such as; possibility to intake high and/or uncontrolled dose, the problems related to their physical and chemical stabilities after they are diluted with water and the difficulties in their usage and transferring. As is seen, new approaches are needed for obtaining formulations which are stable, which provides an efficient dosing and ease of use for especially pediatric and geriatric patients, which can disperse quickly and form a homogeneous suspension and have a high bioavailability. 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 cefprozil and process for the preparation of these formulations. Surprisingly, it is seen that effervescent forms formulated with the formulation comprising 10-50% of cefprozil, 50-90 % of effervescent couple, 1-10% of binder and 1-15% of at least one pharmaceutically acceptable excipient with respect to the total weight of unit dose, homogeneously and quickly disperse in water, provide effective dosing and ease of use, appeal to a wider patient profile and are stable and highly bioavailable. Accordingly, the first aspect of the present invention is effervescent formulations comprising 10-50% of cefprozil, 50-90% of effervescent couple, 1-10% of binder and 1-15% of at least one pharmaceutically acceptable excipient with respect to the total weight of unit dose.

"Effervescent formulations" term used in the text comprises effervescent tablets, effervescent granules and effervescent powders. Preferably effervescent formulations in accordance with the present invention are in the tablet form.

Effervescent powder, granule or tablet forms are more advantageous compared to the conventional forms due to the fact that they disperse quickly. Effervescent formulations disperse quickly and simultaneously and they disperse the active agents into the aqueous medium. Therefore, drug provides a homogeneous suspension by quickly dispersing in water and the bioavailability of the active agent increases considerably. Furthermore, since the effervescent forms are more stable due to the fact that they are in solid form, they have a longer shelf-life compared to suspension forms. Effervescent dosage forms that are suitable for single dose usage provides a controlled dose intake. Cefprozil that is used in the formulations formulated in effervescent form in accordance with the present invention can be present in the form of its solvates, hydrates, esters, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystal and amorphous forms or in free form and/or as a combination thereof. Cefprozil 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 monohydrate.

Effervescent formulations according to present invention may comprise effective amount of cefprozil, an effective effervescent couple and additionally at least one excipient which is selected from a group comprising pharmaceutically acceptable amounts of binder, lubricant and sweetener.

Accordingly, effervescent formulation according to present invention 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 aqueous solution.

Effervescent acid that is used in the effervescent formulation according to the present invention is selected from a group comprising pharmaceutically acceptable acids; 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.

Effervescent formulations in accordance with the present invention comprises cefprozil, 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.

Binder used in the effervescent formulation in accordance with the present invention can be selected from, but not limited with, a group comprising ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, methyl cellulose, polyvinylpyrrolidone and povidone. Preferably polyvinylpyrrolidone is used.

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

Flavoring agents used in the present invention can be selected from a group comprising blackberry flavor, banana flavor, strawberry flavor, lemon flavor, orange flavor, peach flavor, vanilla flavor or similar natural fruits or might have the flavor of a natural herb.

In effervescent formulations in accordance with the present invention, cefprozil in the range of 50-5000 mg or its pharmaceutically acceptable salts, hydrates, solvates or combinations thereof in an amount equivalent to that can be used.

Inventors have seen that effervescent formulations, in which cefprozil: binder ratio is in the range of 30:1 to 5:1, preferably 25:1 to 10:1, more preferably 20:1 to 12:1, are more stable and suitable for usage and transferring and can disperse more quickly. . In this aspect, the present invention is related to effervescent formulations wherein cefprozil: binder ratio is in the range of 30:1 to 5:1, preferably 25:1 to 10:1, more preferably 20:1 to 12:1.

In another aspect, the present invention is related to the effervescent formulations comprising cefprozil in an amount of 10-50%, effervescent couple in an amount of 50-90%, binder in an amount of 1-10 %, lubricant in an amount of 0.1-3 %, sweetener in an amount of 0.1-5 % by weight and at least one pharmaceutically acceptable excipient.

In another aspect, the present invention is related to the process for the preparation of pharmaceutical combinations comprising cefprozil as active agent and pharmaceutically acceptable excipients.

In this aspect, the present invention is related to the process comprising the steps of blending effervescent couple, binder and taste regulator and granulating them, obtaining the final mixture by adding cefprozil, lubricant and at least one pharmaceutically acceptable excipient into the obtained granules and preferably compressing the final mixture in the form of tablets. In another aspect the present invention is related to the use of effervescent formulations comprising cefprozil as active agent and pharmaceutically acceptable excipients for treatment of the infections caused by gram positive and gram negative bacteria.

Although it is not limited by these examples, efervescent formulations in accordance with the present invention can be prepared according to the following examples. EXAMPLE 1: Formulation and process for the preparation of effervescent tablet.

Formulation that can be used in the present invention is obtained by blending effervescent couple, taste regulator and binder and granulating them, adding cefprozil and sweetener to the obtained granules and adding flavoring agent and lubricant to the mixture and blending them. The obtained mixture is compressed into tablets in the tablet pressing machine.

Claims

1. A pharmaceutical composition formulated in effervescent form characterized in that said composition comprises 10-50% of cefprozil, 50-90% of effervescent couple, 1-10% of binder and 1-15% of at least one pharmaceutically acceptable excipient with respect to the total weight of the unit dose.

2. A pharmaceutical composition according to claim 1, wherein said composition comprises cefprozil and/or its salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystal and amorphous forms or in free form and/or a combination thereof.

3. A pharmaceutical composition according to claim 2, wherein cefprozil is present in one of the forms of monohydrate, dihydrate, trihydrate and/or in anhydrous form.

4. A pharmaceutical composition according to claim 3, wherein cefprozil is present in monohydrate form.

5. A pharmaceutical composition according to claim 1, wherein said composition is in the form of effervescent powder, granule or tablet.

6. A pharmaceutical composition according to claim 5, wherein said composition is in the form of effervescent tablet.

7. A pharmaceutical composition according to claim 1, wherein the amount of cefprozil in one unit dose is in the range of 50-1000 mg.

8. A pharmaceutical composition according to claim 1, wherein said formulation comprises as effervescent couple; an alkali component and an acid or an acidic salt which upon contact with aqueous solution gives off carbon dioxide.

9. A pharmaceutical formulation according to claim 8, wherein alkali component that is used as effervescent base is selected from basic agents such as sodium hydrogen carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium hydrogen carbonate, sodium glycine carbonate, lysine carbonate, arginine carbonate and calcium carbonate.

10. A pharmaceutical formulation according to claim 9, wherein sodium hydrogen carbonate is used as alkali component.

11. A pharmaceutical formulation according to claim 8, wherein effervescent acid is selected from a group pharmaceutically acceptable acids 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.

12. A pharmaceutical formulation according to claim 11, wherein citric acid is used as effervescent acid.

13. A pharmaceutical formulation according to claim 1, wherein binder is selected from a group comprising ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, methyl cellulose, polyvinylpyrrolidone and povidone.

14. A pharmaceutical formulation according to claim 13, wherein polyvinylpyrrolidone is used as binder.

15. A pharmaceutical formulation according to claim 1, wherein said composition comprises cefprozil, 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.

16. A pharmaceutical formulation according to claim 15, wherein lubricant is selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate.

17. A pharmaceutical formulation according to claim 16, wherein PEG 6000 is used as lubricant.

18. A pharmaceutical formulation according to claim 15, wherein sweetener and/or taste regulator is selected from acesulfame, aspartame, dextrose, fructose, glycose, lactitol, maltitol, maltose, sorbitol, saccharin, saccharin sodium, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose and xylitol or a combination thereof.

19. A pharmaceutical formulation according to claim 18, wherein sodium chloride and/or sucralose is used as sweetener and/or taste regulator.

20. A pharmaceutical formulation according to claim 15, wherein flavoring agent is selected from a group comprising blackberry flavor, banana flavor, strawberry flavor, lemon flavor, orange flavor, peach flavor, vanilla flavor or similar natural fruits or might have the flavor of a natural herb.

21. A pharmaceutical formulation according to claim 1, wherein cefprozil: binder ratio is in the range of 30: 1 and 5:1.

22. A pharmaceutical formulation according to claim 21, wherein cefprozil: binder ratio is in the range of 25:1 and 10:1.

23. A pharmaceutical formulation according to claim 22, wherein cefprozil: binder ratio is in the range of 20:1 and 12:1.

24. A pharmaceutical formulation according to claim 1, wherein said composition comprises cefprozil in an amount of 10-50%, effervescent couple in an amount of 50-90%, binder in an amount of 1-10 %, lubricant in an amount of 0.1-3 %, sweetener in an amount of 0.1-5

% by weight and at least one pharmaceutically acceptable excipient.

25. A process for the preparation of the pharmaceutical composition according to claims 1-24, wherein said process comprises the steps of blending effervescent couple, binder and taste regulator and granulating them, obtaining the final mixture by adding cefprozil, lubricant and at least one pharmaceutically acceptable excipient into the obtained granules.

26. A pharmaceutical composition according to claims 1-25, wherein said composition is used in the treatment of the infections caused by gram positive and gram negative bacteria.