WO2012060788A1

WO2012060788A1 - Formulations of cephalosporins with controlled moisture content

Info

Publication number: WO2012060788A1
Application number: PCT/TR2011/000253
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Individual
Current assignee: Individual
Priority date: 2010-11-05
Filing date: 2011-11-03
Publication date: 2012-05-10
Anticipated expiration: 2013-05-05
Also published as: TR201009167A2; WO2012060785A1

Abstract

The present invention relates to granules comprising cephalosporin group molecules as the active agent; the pharmaceutical compositions comprising said granules and a production method that shall be used for preparation of said compositions.

Description

FORMULATIONS OF CEPHALOSPORINS WITH CONTROLLED MOISTURE CONTENT

The present invention relates to granules comprising cephalosporin molecules as active agent; pharmaceutical compositions comprising said granules and a production method for preparation of said compositions. Background of the Invention

Cephalosporins were first isolated in 1948 and first generation cephalosporins were produced and released in 1960.

Cephem derivative 7- amino-cephalosporinic acid (formula 1) constitutes the basic core of cephalosporins. Cephalosporins are classified into different generations according to a classification method which is chronological and practical in terms of reflecting the improvement in antibacterial spectrum.

FORMULA 1

Antibiotics belonging to cephalosporin group are characterised by the lactam ring in their chemical structure. Since lactam rings are not durable to water, such molecules disintegrate when they come into contact with water and undesirable by products emerge. As water is a frequently used solvent in chemical processes, this problem is observed in pharmaceutical compositions prepared by using water. This situation causes lower active substance amount in the final product than expected and this consequently causes lower dose. Therefore, different methods should be developed for preparation of stabile cepholosporin group of products.

During the studies they conducted, the inventors have observed that amount of by products formed by the disintegration of the lactame ring is rather low in the pharmaceutical compositions wherein the granules which are obtained after the granules comprising cephalosporin group molecules granulated with various excipients and water during the process are dried at 40°C such that they have a maximum moisture content of 1% are used. By this means, pharmaceutical compositions produced with the granules of the present invention are more stabile and dose precision is provided.

According to this, the present invention relates to granules which have a maximum moisture content of 1% and comprise cepholosporin group molecules as the active agent. The term "cepholosporin group molecules" stated in the text comprises cepholosporin group molecules such as cefpodoxime, cefditoren, cefdinir, cefixime, cefuroxime, cefaclor, ceftibuten, cefprozil, cefepime and cefetamet.

Cefpodoxime can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof. Preferably, cefpodoxime proxetil is used.

Cefditoren can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof. Preferably, cefditoren pivoxil is used.

Cefdinir can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.

Cefixime can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof. Cefixime can be in monohydrate, dihydrate or trihydrate form before granulation.

Cefuroxime can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof. Preferably, cefuroxime axetil is used.

Cefaclor can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.

Ceftibuten can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof. Ceftibuten can be in monohydrate, dihydrate or trihydrate form before granulation.

Cefprozil can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.

Cefetamet can be in the form of its pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof. Preferably, cefetamet pivoxil is used.

The said granules which have a maximum moisture content of 1% and comprise cephalosporin group molecules as active agent can comprise various excipients such as binders, diluents, disintegrants, sweeteners, lubricants, effervescent couples, glidants along with the active agent.

In another aspect, the present invention relates to pharmaceutical compositions comprising granules which have a maximum moisture content of 1% and comprise cephalosporin group molecules as the active agent.

In another aspect, pharmaceutical compositions comprising granules which have a maximum moisture content of 1% and comprise cephalosporin group molecules as the active agent can comprise various excipients such as binders, diluents, disintegrants, lubricants, glidants, effervescent couple and sweetener in addition to said granules. The disintegrant that can be used in the granules of the present invention and in the formulations comprising these granules can be selected from a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicone dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methylcellulose, povidone, magnesium aluminum silicate and starch or combinations thereof. The binder that can be used in the granules of the present invention and in the formulations comprising these granules can be selected from a group comprising ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, methylcellulose, polyvinylpyrrolidone.

The lubricant that can be used in the granules of the present invention and in the formulations comprising these granules can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate and sodium benzoate.

The diluent that can be used in the granules of the present invention and in the formulations comprising these granules can be selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch and xylitol or combinations thereof.

The glidant that can be used in the granules of the present invention and in the formulations comprising these granules can be selected from a group comprising magnesium silicate, silicone dioxide, starch, talc, tribasic calcium phosphate or the combination thereof.

The sweetener that can be used in the granules of the present invention and in the formulations comprising these granules can be selected from 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.

The effervescent couple that can be used in the granules of the present invention and in the formulations comprising these granules can be selected from organic acids such as citric acid, tartaric acid, malic acid, fumaric acid etc. and from basic agents such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and potassium hydrogen carbonate etc. The formulations comprising the granules of the present invention can be in different dosage forms, for instance; tablet, capsule, film-coated tablet, sachet, suspension, effervescent tablet, orodispersible tablet, prolonged-release tablet, modified-release tablet. Preferably, these formulations comprising the granules of the present invention are in the form of tablet or film- coated tablet. The granules of the present invention and the formulations comprising these granules can comprise 1 -4000 mg cephalosporin or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in an equivalent amount.

The pharmaceutical compositions comprising granules of the present invention which have a maximum moisture content of %1 and comprise cephalosporin group molecules as the active agent can further comprise an active agent along with the said granules and the excipients specified above.

The second active substance can be selected from cephalosporins or beta-lactamases. Preferably, clavulanic acid is used or derivatives thereof. The clavulanic acid that can be used optionally in the pharmaceutical composition comprising granules of the present invention can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or in free form and/or the combination thereof. Preferably, potassium clavulanate is used.

According to this, said composition can comprise clavulanic acid in the range of 50-500 mg or its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in an equivalent amount.

Clavulanic acid and its derivatives (e.g. potassium clavulanate) are extremely susceptible to moisture. To this respect, potassium clavulanate is preferably used with a humectant in the ratio of 1 : 1 in the pharmaceutical composition of the present invention. One or more of the substances comprising silica; colloidal silica, for instance colloidal silica anhydrous, for instance Aerosil® 200, magnesium trisilicate, cellulose powder, Cabosil® magnesium oxide, calcium silicate, Syloid®, starch, microcrystalline cellulose, talc can be used as the humectant.

In the pharmaceutical composition of the present invention, potassium clavulanate is preferably used with syloid in the ratio of 1 : 1.

The pharmaceutical composition comprising granules of the present invention comprises 10- 90%, preferably 40-80% of cephalosporin or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms, and 0,1-10% binder; 0,1-10%, lubricant; 0-5% sweetener; 0,1-30%) diluent; 6-15%) disintegrant; 0-85% effervescent couple; 0,1-5% glidant; 0-90% clavulanic acid or an equivalent amount of its pharmaceutically acceptable salts, hydrates, solvates or the combination thereof in proportion to the total weight of unit dose amount.

In another aspect, the present invention relates to a process that shall be used for preparation of granules which have a moisture content less than 1% and comprise cephalosporin as the active agent. According to this, the process for preparation of said granules is composed of the following steps;

• Granulation solution is prepared by solving the binder in water,

• Cephalosporin, diluent and disintegrant are granulated with the granulation solution prepared,

• Obtained granules are dried at 40 °C such that they have a maximum moisture content of 1%.

In another aspect, the present invention relates to processes that can be used for preparation of pharmaceutical compositions comprising said granules. According to this, the process for preparation of pharmaceutical compositions comprising said granules is composed of the following steps;

• Granules which have a maximum moisture content of 1% and comprise cephalosporin are sieved,

• Granules are blended with diluent, disintegrant, glidant and the second active agent -if available- and effervescent couple,

• Lubricant is added into the mixture obtained.

According to this, the granules are sieved with a sieve, mesh size of which is in the range of 0,5-5 mm, preferably in the range of 1-3 mm.

The pharmaceutical composition obtained is stored in a required dosage form. It is preferably compressed in tablet form and optionally packed with commercially available coating agents by using the techniques in the prior art.

Tablet hardness should be at desired level in order to compress the pharmaceutical composition in tablet form. The inventors have found that 96%- 100% diluent and disintegrant in proportion to the diluent and disintegrant amount used for preparation of the granules should be added to the pharmaceutical composition comprising said granules and the other excipients so as to obtain desired tablet hardness for preparation of the pharmaceutical compositions comprising granules which have a maximum moisture content of 1% and comprise cephalosporin as the active agent.

According to this, another aspect of the present invention is to use 96% - 100% diluent and disintegrant in proportion to the diluent and disintegrant amount used for obtaining granules for preparation of the pharmaceutical composition comprising granules which have a maximum moisture content of 1% and comprise cephalosporin as the active agent.

The pharmaceutical composition comprising granules of the present invention can be used in treatment of upper respiratory infections, such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections, such as pneumonia, acute bronchitis and acute exacerbation of acute bronchitis; genitourinary infections, such as pyelonephritis, cystitis, urethritis; skin and soft tissue infections, such as furuncle, pyoderma, impetigo; and such diseases as community-acquired pneumonia, acute maxillary sinus infection. The subject of the present invention can be prepared as specified below, yet the invention is not restricted to these examples;

Example 1: Formulation and process for preparation of film-coated tablet comprising cefdinir.

Process:

Cefdinir is mixed with a part of the diluent and a part of the disintegrant and granulated with the granulation solution composed of aqueous solution of the binder. Obtained granules are dried at 40 °C such that they have a maximum moisture content of 1% and sieved with a 1-3 mm mesh sieve. Obtained granules are mixed with the diluent and disintegrant, glidant and the other excipients. Then lubricant is added and the mixture is mixed again. Obtained mixture is loaded into tablet compression machine and then tablets are coated with an appropriate coating agent. Example 2: Formulation and process for preparation of tablet comprising cefdinir and potassium clavulanate.

Process: Cefdinir is mixed with a part of the diluent and a part of the disintegrant and granulated with granulation solution composed of aqueous solution of the binder. Obtained granules are dried at 40 °C such that they have a maximum moisture content of 1%; and sieved with a 1-3 mm mesh sieve. Then potassium clavulanate, diluent, and the rest of the disintegrant, glidant and the other excipients are added and said granules are mixed. Then lubricant is added and the mixture is mixed again. Obtained mixture is loaded into tablet compression machine and then tablets are coated with an appropriate coating agent.

Claims

CLAIMS:

1. A granule comprising cephalosporin group molecules characterised in that said granules have a maximum moisture content of 1%.

2. The granule according to claim 1, wherein cephalosporin group molecules can be selected from a group comprising cefpodoxime, cefditoren, cefdinir, cefixime, cefuroxime, cefaclor, ceftibuten, cefprozil and cefetamet.

3. The granule according to claim 2, wherein cephalosporin group molecules can be in the form of their pharmaceutically acceptable esters, solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or a combination thereof.

4. The granule according to claim 1, wherein said granule comprises various excipients along with active agent.

5. The granule according to claim 4, wherein said granule comprises excipients such as binders, diluents, disintegrants, sweeteners, lubricants, glidants along with active agent.

6. The pharmaceutical composition comprising cephalosporin group molecules, wherein said composition comprises granules prepared according to claim 1 and various excipients in addition.

7. The pharmaceutical composition according to claim 6, wherein the excipients comprised in said composition can be selected from a group comprising binders, diluents, disintegrants, sweeteners, lubricants, effervescent couple, glidants.

8. The excipient according to claim 5 and claim 7, wherein the disintegrant can be selected from a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicone dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methylcellulose, povidone, magnesium aluminum silicate and starch or combinations thereof.

9. The excipient according to claim 5 and claim 7, wherein the binder can be selected from a group comprising ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, methylcellulose, polyvinylpyrrolidone.

10. The excipient according to claim 5 and claim 7, wherein the lubricant can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate.

11. The excipient according to claim 5 and claim 7, wherein the diluent can be selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch and xylitol or combinations thereof.

12. The excipient according to claim 5 and claim 7, wherein the glidant can be selected from a group comprising magnesium silicate, silicone dioxide, starch, talc and tribasic calcium phosphate or combinations thereof.

13. The excipient according to claim 5 and claim 7, wherein the sweetener can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, glucose, lactitol, maltitol, maltose, sorbitol, saccharine, saccharine sodium, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose and xylitol or combinations thereof.

14. The excipient according to claim 5 and claim 7, wherein the effervescent couple can be selected from organic acids such as citric acid, tartaric acid, malic acid, fumaric acid etc. and from basic agents such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and potassium hydrogen carbonate etc.

15. The formulation according to claim 6, wherein said formulation can be in the form of tablet, capsule, film-coated tablet, sachet, suspension, effervescent tablet, orodispersible tablet, prolonged-release tablet, modified-release tablet.

16. The formulation according to claim 15, wherein said formulation is in the form of tablet or film-coated tablet.

17. The formulation according to claim 6, wherein said formulation can further comprise at least one more active agent along with the granules and excipients according to claim 1.

18. The formulation according to claim 17, wherein the other active agent can be selected from cephalosporin or beta-lactamase group of substances.

19. The formulation according to claim 18, wherein the other active agent is a substance from beta-lactamase group.

20. The formulation according to claim 19, wherein the other active agent is clavulanic acid or a pharmaceutically acceptable salt thereof.

21. The pharmaceutical composition according to claim 6, wherein the said composition comprises 10-90%, preferably 40-80% of cephalosporin or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms, and 0,1-10% binder; 0,1-10%, lubricant; 0- 5% sweetener ; 0,1-30% diluent; 6-15% disintegrant; 0-85% effervescent couple; 0,1-5% glidant; 0-90% clavulanic acid or an equivalent amount of its pharmaceutically acceptable salts, hydrates, solvates or a combination thereof in proportion to the total weight of unit dose amount.

22. The pharmaceutical composition according to claims 6-21, wherein 96% - 100% diluent and disintegrant in proportion to the amount of the diluent and the disintegrant used for obtaining granules are used for preparation of said composition.

23. The granule according to claim 1, wherein said granules are sieved with a 0.5 - 5 mm mesh sieve after they are dried.

24. The granule according to claim 23, wherein said granules are sieved with a 1-3 mm mesh sieve after they are dried.

25. A method that can be used for preparation of the granules claimed in claim 1, wherein said method comprises the following steps;

• Granulation solution is prepared by solving the binder in water,

• Cephalosporin, diluent and disintegrant are granulated with prepared granulation solution.

26. The method that can be used for preparation of the pharmaceutical composition claimed in claim 6, wherein said method comprises the following steps;

· Granules prepared according to claim 25 are sieved,

• Granules are mixed with the diluent, disintegrant, glidant, the second active agent -if available- and effervescent couple,

• Lubricant is added to the mixture.

27. The granule and the pharmaceutical composition comprising said granule according to any claims claimed above, wherein said granule and composition are used in the production of a drug to be used in treatment of upper respiratory infections such as, otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as, pneumonia, acute bronchitis and acute exacerbation of chronic bronchitis; genitourinary infections such as, pyelonephritis, cystitis, urethritis; skin and soft tissue infections such as, furuncle, pyoderma, impetigo; and such diseases as community-acquired pneumonia, acute maxillary sinus infection.