WO2012060789A2

WO2012060789A2 - Production method for cefdinir formulations

Info

Publication number: WO2012060789A2
Application number: PCT/TR2011/000254
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: WO2012060793A3; WO2012060789A3; TR201010860A2; WO2012060793A2

Abstract

The present invention relates to processes to be used for preparation of formulations comprising cefdinir as the active agent and pharmaceutical compositions to be obtained by this process.

Description

PRODUCTION METHOD FOR CEFDINIR FORMULATIONS

The present invention relates to processes that can be used for preparation of tablet forms comprising cefdinir as the active agent and pharmaceutical compositions to be obtained with this process. Background of the Invention

Cefdinir, the chemical name of which is (6R, 7R)-7-[[(2Z)-(2-amino-4- thiazolyl)(hydroxyimino) acetyl]amino]-3-ethynyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene- 2-carboxylic acid, was first disclosed in the patent numbered BE897864. The chemical structure of cefdinir is seen in Formula 1. This third generation molecule is indicated for the treatment of infections caused by gram positive and gram negative bacteria.

Formula I

Physically appearing as a white powder, cefdinir has quite low solubility in common organic solvents such as methanol, ethanol, acetonitrile and in water. Due to this property, some problems are seen while developing formulations comprising this molecule. The difficulties encountered during the production of the formulation pose problems for physical characteristics of the end production, for instance in providing dose uniformity and in parameters such as hardness and dispersion time. This is disadvantageous for patients' use of drugs and poses problems for bioavailability parameters due to the fact that finished production has not dose uniformity. Production methods in which the components are mixed by dry blending methods can be preferred in order to prevent problems that low solubility of cefnidir poses. However, it has been seen that in the case of tabletting the formulations produced by this method, the pharmaceutical composition prepared with said process fails to provide desired tablet hardness and friability value of the said tablets are inappropriate. One of the problems frequently encountered in development of formulations is agglomeration of the active agent when it comes into contact with water in the processes in which wet granulation is used due to its hydrophobic characteristic and correspondingly dose uniformity cannot be provided.

When the prior art is taken into consideration, there is need for new processes that can be used for preparation of formulations comprising cefdinir which are stable, have high bioavailability and long shelf life.

Surprisingly, the inventors have found that the present problems in the prior art can be solved by using the process of the present invention for preparation of the formulations comprising cefdinir. Description of the Invention

The subject matter of the present invention is use of a production method composed of the following steps for production of formulations comprising cefdinir. According to this, said process is composed of the steps that;

I. Granulation solution is prepared by dissolving the disintegrant in water.

II. 30-80% of the total diluent amount, 30-80% of the total disintegrant amount and cefdinir are sieved, mixed and granulated with prepared granulation solution in fluid bed.

III. Obtained granules are dried and sieved.

IV. Obtained granules are mixed with 20-70% of the total diluent amount, 20-70-% of the total disintegrant amount and the glidant.

V. Lubricant is added to the obtained mixture.

VI. Obtained composition is stored in an appropriate pharmaceutical dosage form. Thanks to the process of the present invention;

• Agglomeration of cefdinir is prevented when it comes into contact with water and thus dose uniformity is attained in the end product, and

• Very low friability value, for instance friability value in the range of 0,0 to 0,05, is provided in the case of tabletting the formulation prepared by this method.

According to this, another aspect of the invention is use of the process specified above for production of compositions comprising cefdinir. The term "pharmaceutical dosage forms" specified in the text comprises solid oral dosage forms such as tablet, film-coated tablet, capsule, prolonged-release tablet, modified-release tablet, effervescent tablet, orodispersible tablet, sachet, dry powder to form suspension and liquid dosage forms such as suspension. Preferably, formulations of the present invention are in tablet form.

Cefdinir which can be used in water soluble powder, tablet and granule formulations 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 free form and/or the combination thereof. The water used as granulation solution in the process of the present invention is in the form of deionized water.

The ratio of the water to cefdinir is in the range of 10:1 and 1 :1, preferably in the range of 6:1 and 2:1.

In another aspect, disintegrant and diluent amount added in step II and step IV of the present invention is in the range of 30-80% in step II, in the range of 20-70% in step IV.

As a result of the studies conducted, the inventors have found that use of disintegrant and diluent preferably in the range of 48-53 % in step II, and use of disintegrant and diluent in the range of 47-52% in step IV have positive effects on reducing tablet friability.

The binder that can be used in the formulation to be produced according to the process of 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, povidone is used.

The diluent that can be used in the formulation to be produced according to the process of the present invention 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, xylitol or combinations thereof.

The disintegrant that can be used in the formulation to be produced according to the process of the present invention can be selected from 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 glidant that can be used in the formulation to be produced according to the process of the present invention can be selected from a group comprising magnesium silicate, colloidal silicon dioxide, starch, talc, tribasic calcium phosphate or combinations thereof. Preferably, colloidal silicon dioxide is used as glidant in the formulation of the present invention.

The lubricant that can be used in the formulation to be produced according to the process of 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, magnesium stearate is used as lubricant in the formulation of the present invention.

The effervescent formulation to be produced with the process of the present invention can comprise 1-4000 mg cefdinir or its pharmaceutically acceptable salts, hydrates, solvates, or the combination thereof in an equivalent amount.

The effervescent formulation to be produced with the process of the present invention can comprise;

• 5-60% of cefdinir or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms,

• 1-10% of binder,

• 0,1-3% of lubricant,

• 0,1-5% of glidant,

• 0,1-20% of disintegrant,

• 1-30% of diluent in proportion to the total weight of unit dose amount.

The cefdinir formulation to be produced with the process of the present invention can optionally comprise a second active agent. The second active agent can be selected from cephalosporins, beta-lactamases. Preferably, clavulanic acid or its derivatives is used. Clavulanic acid that can optionally be used in the cefdinir formulation to be prepared with the process 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 free form and/or the combination thereof. Preferably, potassium clavulanate is used. The cefdinir formulation to be produced by the process of the present invention can optionally comprise clavulanic acid in the range of 50-500 mg or its pharmaceutically acceptable salts, hydrates, solvates or the 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 in the pharmaceutical composition of the present invention is preferably used with a humectant in the ratio of 1 : 1.

One or more of the substances comprising silica; colloidal silica, for instance colloidal silica anhydrous, for example Aerosil® 200, magnesium trisilicate, cellulose powder, Cabosil®, magnesium oxide, calcium silicate, Syloid®, starch, microcrystalline cellulose, talc can be used as the humectants. In the cefdinir formulation to be produced by the process of the present invention, potassium clavulanate is preferably used with microcrystalline cellulose in the ratio of 1 : 1.

The cefdinir formulation to be produced by the process of the present invention can comprise 5-90%, preferably 10-80%, more preferably 20-60% of clavulanic acid in proportion to total weight of unit dose amount or its pharmaceutically acceptable salts, hydrates, solvates or the combination thereof in an equivalent amount.

According to this, in the case of using potassium clavulanate as the second active agent in the formulation to be produced with the process of the present invention, said second active agent is included in the process with the humectant in step IV.

In another aspect, potassium clavulanate as combined with microcrystalline cellulose can be mixed with the granules comprising cefdinir along with disintegrant, glidant and diluent dryly.

Water soluble tablets 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 as the active agent.

The cefdinir formulation specified above is prepared as follows by using the process of the present invention; cefdinir, 50% of total amount of the disintegrant, 50% of total amount of the diluent are sieved, mixed and granulated with the granulation solution comprising binder. After drying and sieving, obtained granules are mixed with 50% of total amount of the disintegrant and 50% of total amount of the diluent and the glidant. Lubricant is added to the end mixture. Then the obtained composition is compressed in tablet form and coated with the film coating agent.

EXAMPLE 2: The formulation and process for preparation of film-coated tablet comprising cefdinir and potassium clavulanate as the active agent.

The cefdinir formulation specified above is prepared as follows by using the process of the present invention; cefdinir, 48% of total amount of the disintegrant, 53% of total amount of the diluent are sieved, mixed and granulated with the granulation solution comprising binder. After drying and sieving, obtained granules are mixed with 52% of the total amount of the disintegrant, 47% of the total amount of the diluent, mixture of potassium clavulanate, and microcrystalline cellulose and the glidant. Lubricant is added to the end mixture. Then, the obtained composition is compressed in tablet form and coated with the film coating agent.

In another aspect, the present invention relates to use of effervescent formulations comprising pharmaceutically acceptable excipients in addition to cefdinir as the active agent in treatment of infections caused by gram positive and gram negative bacteria.

In another aspect, the pharmaceutical formulation prepared according to said invention is used for production of a drug to be used in treatment and prophylaxis of upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as pyelonephritis, cystitis and urethritis; skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases.

Claims

1. The process so as to be used for preparation of the formulation comprising cefdinir characterised in that

I. Granulation solution is prepared by dissolving the binder in water.

II. 30-80% of total amount of the diluent, 30-80% of the total amount of the disintegrant and cefdinir are sieved, mixed and granulated with the prepared granulation solution in fluid bed.

III. Obtained granules are dried and sieved.

IV. Obtained granules are mixed with 20-70% of total amount of the diluent, 20-70% of total amount of the disintegrant and the glidant.

V. Lubricant is added to obtained mixture.

VI. Obtained composition is stored in an appropriate dosage form.

2. The process to be used for preparation of the formulation comprising cefdinir according to claim 1 , wherein the ratio of water used for granulation to cefdinir is in the range of 10:1 and 1 :1.

3. The process to be used for preparation of the formulation comprising cefdinir according to claim 2, wherein the ratio of water used for granulation to cefdinir is in the range of 6: 1 and 2:1.

4. The process to be used for preparation of the formulation comprising cefdinir according to claim 1 , wherein the amount of disintegrant and diluent added in step II and step IV of the process is in the range of 30-80% in step II, in the range of 20-70% in step IV.

5. The process to be used for preparation of the formulation comprising cefdinir according to claim 4, wherein the amount of disintegrant and diluent added in step II and step IV of the process is in the range of 48-53% in step II, 47-52% in step IV.

6. The cefdinir formulation produced with the process claimed in claim 1, wherein said formulation can be in the form of tablet, film-coated tablet, capsule, prolonged-release tablet, modified-release tablet, effervescent tablet, orodispersible tablet, sachet, dry powder to form suspension.

7. The cefdinir formulation according to claim 6, wherein said formulation is in the form of tablet or film-coated tablet.

8. The cefdinir formulation according to claim 7, wherein the friability value of the tablet or film-coated tablet is in the range of 0,0 to 0,05.

9. The cefdinir formulation produced with the process claimed in claim 1, wherein cefdinir is in the form of solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or the combination thereof.

10. The cefdinir formulation produced with the process claimed in claim 1, wherein the binder is selected from a group comprising ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, methyl cellulose, povidone.

11. The cefdinir formulation according to claim 10, wherein povidone is used as binder.

12. The cefdinir formulation produced with the process claimed in claim 1, wherein the diluent is 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, xylitol.

13. The cefdinir formulation produced with the process claimed in claim 1, wherein the disintegrant to be used in said formulation is selected from 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 the combinations thereof.

14. The cefdinir formulation produced with the process claimed in claim 1, wherein the glidant to be used in said formulation is selected from a group comprising magnesium silicate, colloidal silicon dioxide, starch, talc, tribasic calcium phosphate or the combination thereof.

15. The cefdinir formulation according to claim 14, wherein silicon dioxide is preferably used as glidant.

16. The cefdinir formulation produced with the process claimed in claim 1, wherein the lubricant to be used in said formulation is selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate.

17. The cefdinir process according to claim 16, wherein magnesium dioxide is preferably used as lubricant.

18. The formulation prepared according to process claimed in claim 1, wherein said formulation can comprise; • 5-60% of cefdinir or pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms,

• 1-10% of binder,

• 0.1-3% of lubricant,

• 0.1-5% of glidant,

• 0.1 -20% of disintegrant,

• 1-30% of diluent. in proportion to the total weight of unit dose amount.

19. The formulation prepared according to the process claimed in claim 1, wherein the second active agent selected from cephalosporins, beta-lactamases can be used in addition to cefdinir.

20. The formulation according to claim 19, wherein clavulanic acid, preferably potassium clavulanate is used as the second active agent.

21. The formulation according to claim 20, wherein potassium clavulanate is included in step IV of the process claimed in claim 1.

22. The formulation prepared according to process claimed in claim 1, wherein said formulation is used for production of a drug to be used in treatment and prophylaxis of upper respiratory tract infections such as otorhinolaryngological diseases, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as pyelonephritis, cystitis and urethritis; skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases.