WO2014123500A1

WO2014123500A1 - Pharmaceutical formulations comprising cefpodoxime proxetil and clavulanic acid

Info

Publication number: WO2014123500A1
Application number: PCT/TR2014/000031
Authority: WO
Inventors: Mahmut BILGIÇ
Original assignee: Individual
Current assignee: Individual
Priority date: 2013-02-11
Filing date: 2014-02-11
Publication date: 2014-08-14
Anticipated expiration: 2015-08-11

Abstract

The present invention relates to cefpodoxime and clavulanic acid containing pharmaceutical formulations used for the treatment of susceptible microorganisms. Said formulations are characterized by their tablet form.

Description

PHARMACEUTICAL FORMULATIONS COMPRISING CEFPODOXIME PROXETIL

AND CLAVULANIC ACID

Cefpodoxime proxetil was first described in patent application no. EP0049118. In said document, cefpodoxime proxetil was described as effective in treatment of infections caused by gram positive and gram negative bacteria.

Cefpodoxime proxetil is a third generation cephalosporin ester and used in treatment of upper respiratory tract and urinary tract infections. Like other beta-lactam antibiotics, cefpodoxime proxetil is a bactericidal antibiotic. It inhibits the synthesis of bacterial cell wall by binding to specific penicillin-binding proteins located in the inner surface of the wall. The specificity of cefpodoxime depends on the identification of and binding capacity for these proteins.

Cefpodoxime proxetil is orally administered as tablet and suspension. Following oral administration, approximately 50% of the dose is absorbed by body. Proxetil form with its non-crystalline structure is absorbed via gastrointestinal route, hydrolyzed by non-specific esterases located at intestinal wall or plasma and converted into parent molecule cefpodoxime acid. Low oral bioavailability of cefpodoxime proxetil mostly results from its low solubility in water and gelation in acidic media.

In addition to low solubility, other properties of cefpodoxime proxetil are its powder form and its structure with poor viscosity properties. These properties of the antibiotic both reduce the solubility of formulation containing it and prevent achievement of weight uniformity. As the proper flow is not achieved in the formulation due to the poor flow properties, uniformity of weight could not be obtained while also the amount of active substance per unit dosage form differs. This results in loss in the treatment efficacy of dosage form taken.

Beta-lactam antibiotics can be used in combination with beta-lactamase inhibitors to improve their treatment efficacy. Co-administration of cefpodoxime proxetil and clavulanic acid, a beta-lactamase inhibitor, causes stability problems due to the moisture-sensitive nature of clavulanic acid and also negatively affects the stability of formulations comprising this combination with low solubility.

As it is seen, moisture resistant cefpodoxime-clavulanic acid formulations are needed which improve the solubility and thus, the bioavailability of cefpodoxime and which show good flow properties. The inventors, in their studies addressing this need, have determined that the ratio of amount of lubricant to amount of anti-adherent in the formulation has significant effects on flow pattern. .

Description of Invention The present invention relates to pharmaceutical tablet formulations comprising the combination of cefpodoxime proxetil and clavulanic acid. The inventors, in their studies, have discovered that if ratio of lubricant to anti-adherent in said formulations is in the range of 5: 1 to 1 :5 and preferably 3:1 to 1 :3 by weight, a satisfactory flow pattern and thus, desired uniformity of weight and solubility properties are achieved for the formulations. Accordingly, in the first embodiment of formulations of the present invention which comprise the combination of cefpodoxime proxetil and clavulanic acid, the ratio of lubricant to anti- adherent is 5:1 to 1 :5 and preferably 3:1 to 1 :3 by weight.

Lubricant to be used in formulation of the present invention may be selected from a group comprising magnesium silicate, silicon dioxide, colloidal silicon dioxide, starch, talc, calcium phosphate tribasic or combinations thereof.

Lubricant in formulation of the present invention is preferably colloidal silicon dioxide.

Anti-adherent to be used in formulation of the present invention may be selected from a group comprising talc, stearates, colloidal silicon dioxide, sodium sulfate, starch, leucine or combinations thereof.

Anti-adherent in formulation of the present invention is preferably talc. In one embodiment of the present invention, the ratio of colloidal silicon dioxide to talc in the formulation is 5:1 to 1 :5 and preferably 3:1 to 1 :3 by weight.

Studies conducted to improve the viscosity of pharmaceutical formulations comprising cefpodoxime proxetil and clavulanic acid, have surprisingly revealed that the viscosity of formulation is changed when a lubricant with a specific surface area is used in the formulation. Based on the results of studies performed, tablet formulations with desired viscosity properties were obtained when specific surface area of the lubricant was between 125 and 300 m²/g, and preferably between 150 and 250 m²/g.

In another embodiment, specific surface area of the lubricant used in the tablet formulations of the present invention is between 125 and 300 m²/g and preferably between 150 and 250 m²/g.

Cefpodoxime proxetil-clavulanic acid formulations of the present invention may contain at least one pharmaceutically acceptable excipient in addition to lubricant and anti-adherent.

At least one excipient to be used in formulations of the present invention may be selected from a group comprising disintegrants, diluents, surfactants, glidants and film-coating agents.

Disintegrant to be used in formulation of the present invention may be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch and sodium starch glycolate. Diluent to be used in formulations of the present invention may be selected from a group comprising microcrystalline cellulose, silicified microcrystalline cellulose, cellulose acetate, modified cellulose and/or combinations thereof.

Surfactant to be used in formulations of the present invention may be selected from a group comprising cetrimide, docusate sodium, glyceryl monooleate, sorbitan esters and sodium lauryl sulfate and/or combinations thereof.

Glidant to be used in formulations of the present invention may be selected from a group comprising calcium stearate, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate and sodium benzoate. Formulations of the present invention may be prepared in any of the oral tablet forms such as film-coated tablets, extended-release tablets, modified-release tablets, effervescent tablets, orodispersible tablets and chewable tablets.

Formulations of the present invention are preferably prepared in film-coated tablet form. Film-coating agent used for the film-coating of tablet obtained in formulations of the present invention may be selected from a group comprising titanium dioxide, polyvinyl alcohol, polyethylene glycol, talc, lecithin or combinations thereof. For example, film-coating agent marketed under the trademark of Opadry Yellow® can be used.

As the moisture sensitivity of clavulanic acid contained in formulations of the present invention is high, said formulations are not desired to have a moisture-sensitive nature. In order to avoid this situation that may have a negative effect on stability of clavulanic acid, the inventors have conducted studies to prevent the formulation from readily absorbing the moisture. Based on these studies, they observed that the moisture has fewer effects on formulation and clavulanic acid can maintain its stability if bulk density of diluent used in the formulation is in the range of 0.15-0.70 g/ml, preferably in the range of 0.20-0.55 g/ml and most preferably in the range of 0.20-0.40 g/ml.

Accordingly, in another embodiment of cefpodoxime proxetil - clavulanic acid formulations of the present invention, bulk density of diluent used in the formulation is between 0.1 and 0.70 g/ml, preferably between 0.20 and 0.55 g/ml and most preferably between 0.20-0.40 g/ml.

Preferably, microcrystalline cellulose is used as diluent in formulations of the present invention.

Solubility problem experienced with cefpodoxime proxetil due to its nature also negatively affects the disintegration time of formulation in tablet form. After determining that tablet disintegration times are insufficient, the inventors have performed studies and discovered that the desired values of disintegration time could be obtained when formulation contains a disintegrant combination composed of a first and a second disintegrant and when the ratio of first disintegrant to second disintegrant is 5:1 to 1 :5 and preferably 3: 1 to 1 :2 by weight. Accordingly, in one embodiment of formulations of the present invention, the ratio of first disintegrant to second disintegrant, which compose the disintegrant combination, is 5:1 to 1 :5 and preferably 3: 1 to 1 :2 by weight.

Carboxymethyl cellulose calcium or croscarmellose sodium are preferably used as the first disintegrant in formulations of the present invention.

Starch is preferably used as the second disintegrant in formulations of the present invention.

In another embodiment of formulations of the present invention, the ratio of carboxymethyl cellulose calcium or croscarmellose sodium to starch, which compose the disintegrant combination, is 5:1 to 1 :5 and preferably 3:1 to 1 :2 by weight. Formulations of the present invention comprising cefpodoxime proxetil with poor viscosity properties and clavulanic acid that is moisture-sensitive are susceptible to aggregate formation during manufacture. In order to prevent the agglomeration, amount of disintegrant in the formulation should be adjusted to resolve this issue during manufacture and ensure a sufficient disintegration time for obtained tablet after manufacture. The inventors have surprisingly obtained tablets with mentioned properties when the ratio of amount of cefpodoxime proxetil to total amount of disintegrant is 10:1 to 1 :1 and preferably 6:1 to 1 :1 by weight.

Thus, in another embodiment of the present invention, the ratio of amount of cefpodoxime proxetil to total amount of disintegrant is 10:1 to 1 : 1 and preferably 6:1 to 1 : 1 by weight. In formulations of the present invention, the first active ingredient, cefpodoxime proxetil may be used at a rate of 10-70%, preferably of 15-65% and most preferably of 20-60% of the tablet weight.

The second active ingredient, clavulanic acid and its derivative potassium clavulanate are extremely sensitive to moisture. Therefore, potassium clavulanate is used together with a desiccant in pharmaceutical composition of the present invention preferably in a ratio of 1 : 1.

One or more of the followings may be used as desiccant: silica, colloidal silica, e.g. colloidal silica anhydrous, e.g. Aerosil^® 200, magnesium trisilicate, pulverized cellulose, Cabosil^®, magnesium oxide, calcium silicate, Syloid^®, starch, microcrystalline cellulose and talc. Potassium clavulanate is used together with Syloid" or microcrystalline cellulose in pharmaceutical composition of the present invention preferably in a ratio of 1 : 1.

Cefpodoxime - clavulanic acid formulations of the present invention may contain cefpodoxime proxetil, potassium clavulanate, diluent, disintegrant, surfactant, anti-adherent, lubricant, glidant and film-coating agent, respectively, at a rate of 10-70%, 1 -60%, 5-25%, 5-30%, 0.5-3%, 0.1-2%), 0.1-2%, 0.1-2.5% and 1-10% of the total weight of unit dose.

In another embodiment, the present invention relates to processes used for preparation of formulations comprising cefpodoxime proxetil and clavulanic acid as active ingredients as well as pharmaceutically acceptable excipients.

Accordingly, the process in scope of the present invention covers the steps of granulation of active ingredients, cefpodoxime and/or clavulanic acid by conventional wet and/or dry granulation methods or pulverization of cefpodoxime, clavulanic acid and other excipients by mixing with dry blending method and compression of the same in tablet form.

The method used to prepare cefpodoxime - clavulanic acid formulations of the present invention may comprise the following steps:

• mixing the cefpodoxime proxetil and at least one pharmaceutically acceptable excipient,

• compacting the obtained mixture for at least one time,

• adding at least one pharmaceutically acceptable excipient and mixture of clavulanic acid : desiccant and mixing,

• mixing the granules of Step 2 with powder of Step 3 ,

• adding the glidant and transferring the final mixture to tablet compression

The method used to prepare cefpodoxime - clavulanic acid formulations of the present invention may comprise_.the following steps:

• compacting the obtained mixture for 3 times,

• adding and mixing at least one pharmaceutically acceptable excipient,

• adding at least one pharmaceutically acceptable excipient and mixture of clavulanic acid : desiccant and mixing, adding the glidant and transferring the final mixture to tablet compression

Formulations of the present invention may be used in treatment of infections including upper respiratory tract infections (tonsillitis, pharyngitis, acute sinusitis, acute otitis media (only in children), lower respiratory tract infections (acute bronchitis, pneumonia, superinfections of chronic obstructive pulmonary disease), uncomplicated lower and upper urinary tract infections, uncomplicated gonococcal urethritis, skin and soft tissue infections.

Claims

1. A formulation comprising the combination of cefpodoxime proxetil and clavulanic acid, wherein the ratio of lubricant to anti-adherent in formulation is 5:1 to 1 :5 by weight.

2. A formulation according to Claim 1 , wherein the ratio of lubricant to anti-adherent in formulation is 3:1 to 1 :3 by weight.

3. A formulation according to Claims 1-2, wherein the lubricant used in formulation is selected from a group comprising magnesium silicate, silicon dioxide, colloidal silicon dioxide, starch, talc, calcium phosphate tribasic or combinations thereof.

4. A formulation according to Claim 3, wherein the lubricant used in formulation is colloidal silicon dioxide.

5. A formulation according to Claims 1-4, wherein the anti-adherent used in formulation is selected from a group comprising talc, stearates, colloidal silicon dioxide, sodium sulfate, starch, leucine or combinations thereof.

6. A formulation according to Claim 5, wherein the anti-adherent used in formulation is talc.

7. A formulation according to any of the preceding claims, wherein the ratio of colloidal silicon dioxide to talc in the formulation is 5:1 to 1 :5 and preferably 3:1 to 1 :3 by weight.

8. A formulation according to any of the preceding claims, wherein the specific surface area of the lubricant is between 125 and 300 m²/g.

9. A formulation according to Claim 8, wherein the specific surface area of the lubricant is between 150 and 250 m²/g.

10. A formulation according to any of the preceding claims, wherein at least one excipient to be used in formulations in addition to lubricant and anti-adherent is selected from a group comprising disintegrants, diluents, surfactants, glidants and film-coating agents.

1 1. A formulation according to Claim 10, wherein the disintegrant is selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch and sodium starch glycolate.

12. A formulation according to any of the preceding claims, wherein the formulations are prepared in any of the tablet forms such as film-coated tablets, extended-release tablets, modified-release tablets, effervescent tablets, orodispersible tablets and chewable tablets.

13. A formulation according to Claim 12, wherein the formulation is prepared in film- coated tablet form.

14. A formulation according to any of the preceding claims, wherein the bulk density of diluent used in formulation is between 0.15 and 0.70 g/ml.

15. A formulation according to Claim 14, wherein the bulk density of diluent used in formulation is between 0.20 and 0.55 g/ml.

16. A formulation according to Claim 15, wherein the bulk density of diluent used is between 0.20 and 0.40 g/ml.

17. A formulation according to Claims 14-16, wherein the diluent used is microcrystalline cellulose.

18. A formulation according to any of the preceding claims, wherein the formulation contains a disintegrant combination comprising a first and a second disintegrant.

19. A formulation according to Claim 18, wherein the ratio of first disintegrant to second disintegrant, which compose the disintegrant combination, is between 5: 1 and 1 :5 by weight.

20. A formulation according to Claim 19, wherein the ratio of first disintegrant to second disintegrant, which compose the disintegrant combination, is between 3: 1 and 1 :2 by weight.

21. A formulation according to Claims 19-20, wherein carboxymethyl cellulose calcium or croscarmellose sodium are used as the first disintegrant.

22. A formulation according to Claims 19-21, wherein starch is used as second disintegrant.

23. A formulation according to any of the preceding claims, wherein the ratio of amount of cefpodoxime proxetil to total amount of disintegrant is 10:1 to 1 : 1 by weight.

24. A formulation according to Claim 23, wherein the ratio of amount of cefpodoxime proxetil to total amount of disintegrant is 6: 1 to 1 : 1 by weight.

25. A formulation according to any of the preceding claims, wherein the formulation contains cefpodoxime proxetil, potassium clavulanate, diluent, disintegrant, surfactant, anti -adherent, lubricant, glidant and film-coating agent, respectively, at a rate of 10- 70%, 15-60%, 5-25%, 5-30%, 0.5-3%, 0.1 -2%, 0.1 -2%, 0.1-2.5% and 1 -10% of the total weight of unit dose.

26. A formulation according to any of the preceding claims, wherein the process used to prepare the formulation covers the steps of granulation of active ingredients, cefpodoxime and/or clavulanic acid by conventional wet and/or dry granulation methods or pulverization of cefpodoxime, clavulanic acid and other excipients by mixing with dry blending method and compression of the same in tablet form.