WO2012060793A2

WO2012060793A2 - Process for the preparation of cefdinir formulations

Info

Publication number: WO2012060793A2
Application number: PCT/TR2011/000258
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2010-11-05
Filing date: 2011-11-03
Publication date: 2012-05-10
Also published as: WO2012060789A3; WO2012060793A3; WO2012060789A2; TR201010860A2

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

PROCESS FOR THE PREPARATION OF 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)(hydrox imino) 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. Preparation processes in which the components are mixed by dry blending methods can be preferred in order to prevent the problems resulting from low solubility of cefdinir. 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 physical properties of the tablets. The difficulties encountered during the production of the formulation leads to the problems of physical characteristics of the final product in tablet form such as hardness, friability and dissolution time. Hardness of the tablets is important for carrying tablets without any breaking and using them safely; dispersion time is important for dispersing rapidly of the final product and getting ready for use. Increase in the hardness of the tablet helps lowering the friability of the tablet forms but causes slow dispersion. This leads to the increase of time period it takes to get the drug ready for use and thus leads to an inefficient delivery of the drug.

When the prior art is taken into consideration, there is need for new processes that can be used for preparation of cefdinir formulations providing tablets with optimum hardness values, low friability and rapid dispersion time during their use.

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 a method for the preparation of the formulations comprising cefdinir. It has surprisingly been seen that in the case that 35-70% of the amount of disintegrant and diluent is added to the process intragranularly before granulation; 30-65% of the amount of disintegrant and diluent is added to the process extragranularly after granulation and water is added to granulation solution such that the ratio of the water to cefdinir is in the range of 5:1 to 2:1 by weight, the obtained tablet forms have desired hardness values, thus low friability and high dispersion rate. Therefore, the tablet forms comprising cefdinir prepared by the process of the present invention can be carried safely without any breaking and can get ready for use rapidly resulting in an efficient delivery of the drug.

Accordingly, the first aspect of the present invention is the process for the preparation of the cefdinir formulations formulated in tablet form wherein 35-70% of the amount of disintegrant and diluents is added to the process intragranularly before granulation; 30-65% of the amount of disintegrant and diluent is added to the process extragranularly after granulation and water is added to granulation solution such that the ratio of the water to cefdinir is in the range of 5:1 to 2:1 by weight.

The process pertaining to the present invention is composed of the steps that;

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

II. 35-70% of the total amount of diluent and disintegrant 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 the glidant and the rest of the total amount of diluent and disintegrant.

V. Lubricant is added to the mixture obtained in step IV.

VI. Obtained final mixture is stored in an appropriate pharmaceutical dosage form.

The temperature of drying is also an important parameter affecting on the physical properties of the final tablet product, especially its hardness and friability. It has been observed that when the granules that are obtained in step II are dried at 20-70°C, preferably 25-65°C, the final tablet product has a desirable hardness and a low friability value. Accordingly, another aspect of the present invention is that the granules, which are obtained in step II, are dried at 20-70°C, preferably 25-65°C.

The tablet forms comprising cefdinir which are prepared by the process by the present invention have been obtained to have a very low friability value in the range of 0.01-0.05. Therefore, the tablet forms produced by said process have low friability and thus can be carried safely without breaking during their uses.

The term "pharmaceutical dosage forms" specified in the text comprises solid oral dosage forms such as tablet, film-coated tablet, effervescent tablet, prolonged-release tablet, modified-release tablet, orodispersible tablet. Preferably, formulations of the present invention are in tablet form. An important parameter affecting on the tablet hardness is the tablet compression force applied during compressing the final pharmaceutical composition into tablets. It has been observed that when the applied tablet compression force has a value in the range of 20-200 kN, preferably 40-100 kN., the obtained tablet forms have optimum hardness and low friability values, helping to rapid dispersion of tablets for getting ready for use. According to this, another aspect of the present invention is the process for the preparation of cefdinir formulations formulated in tablet form wherein the tablet compression force applied during compressing the final mixture obtained in step V into tablet form is in the range of 20- 200 kN, preferably 40-100 kN.

Cefdinir which can be used in the formulations prepared by 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.

The water used as granulation solution in the process of the present invention is in the form of deionized water. The diluent that can be used in the formulation prepared by 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 prepared by 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 aluminium silicate and starch or combinations thereof. The formulations prepared by the process of the present invention can comprise the excipients such as binder, glidant, lubricant, effervescent couple in addition to cefdinir, diluent and disintegrant.

The binder used in the formulation prepared by 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 aluminium silicate, methyl cellulose, povidone. Preferably, povidone is used.

The glidant used in the formulation prepared by 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 used in the formulation prepared by 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 formulation prepared by the process of the present invention can comprise 1-3500 mg cefdinir or its pharmaceutically acceptable salts, hydrates, solvates, or the combination thereof in an equivalent amount.

The formulation prepared by the process of the present invention can comprise;

• 10-60% of cefdinir or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms,

• 1-8% of binder,

• 0.3-2.5% of lubricant,

• 0.2-3% of glidant,

• 1-17% of disintegrant,

• 10-40% of diluent in proportion to the total weight of unit dose amount.

The cefdinir formulation prepared by 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 prepared by 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 prepared by the process of the present invention can optionally comprise clavulanic acid in the range of 60-450 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 prepared by the process 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, silicon dioxide, magnesium trisilicate, cellulose powder, fumed silica, 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 10-85%, preferably 20-75%, more preferably 25-70% 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 prepared by 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.

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

In another aspect, the pharmaceutical formulation prepared by the process according to the present invention is used in the 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.

The tablet forms 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; water is added to the granulation process such that the ratio of the water to cefdinir is 3:1 by weight. Cefdinir, 55% of total amount of the disintegrant and diluents are sieved, mixed and granulated with the granulation solution comprising binder. After drying and sieving, obtained granules are mixed with 45% of total amount of the disintegrant and 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; water is added to the granulation process such that the ratio of the water to cefdinir is 4:1 by weight. Cefdinir, 42% of total amount of the disintegrant and diluents are sieved, mixed and granulated with the granulation solution comprising binder. After drying and sieving, obtained granules are mixed with 58% of the total amount of the disintegrant and 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.

COMPARATIVE 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; water is added to the granulation process such that the ratio of the water to cefdinir is 6:1 by weight. Cefdinir is sieved, mixed and granulated with the granulation solution comprising binder. After drying and sieving, obtained granules are mixed with the disintegrant and 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. In this process, whole of the disintegrant and diuent are added to process extragranularly after granulation.

The inventors have studied on the values of the hardness and friability of the cefdinir compositions compressed in the film-coated tablet which are illustrated in Example 1 and Comparative example 1. According to the studies based on the comparison of their hardness and friability values, the results represented in Table 1 are observed. Tablel. Comparative Data of Hardness and Friability of Cefdinir Formulations in Film- coated Tablet Form

Table 1 indicates the comparative data of hardness and friability of the formulations for each example. The results clearly show that hardness of the formulation of example 1 is in the range of 6-8 kP which is the optimum range of tablet hardness and thus the friability of this example is 0.045. However, the hardness of formulation of comparative example 1 is below 6kP which is out of range and thus a tablet form with a high friability value has been obtained, leading to easily friable tablets. Therefore, it can be concluded that the tablets prepared by the process of the present invention, in which 35-70% of the amount of disintegrant and diluents is added to the process intragranularly before granulation; 30-65% of that is added to the process extragranularly after granulation and the ratio of water used for the granulation to cefdinir is in the range of 5:1 to 2:1 by weight, is much preferred via its optimum hardness and friability values.

Claims

1. The process for the preparation of the formulation comprising cefdinir characterized that;

- 35-70% of the amount of disintegrant and diluent is added to the process intragranularly before granulation;

- 30-65% of the amount of disintegrant and diluent is added to the process extragranularly after granulation and

- water is added to granulation solution such that the ratio of the water to cefdinir is in the range of 5:1 to 2:1 by weight.

2. The process for the preparation of the formulation comprising cefdinir according to claim 1 characterized in that said process comprises the steps of;

I. preparing the granulation solution by dissolving the binder in water,

II. sieving 35-70% of the total amount of diluent and disintegrant and cefdinir, mixing them and then granulating them by the prepared granulation solution in fluid bed.

III. drying and sieving the granules that are obtained in step II,

IV. mixing obtained granules with the glidant and the rest of the total amount of diluent and disintegrant,

V. adding lubricant to the mixture obtained in step IV and

VI. storing obtained final mixture in an appropriate pharmaceutical dosage form.

3. The process according to claims 1-2 wherein the granules, which are obtained by granulating cefdinir, diluent and disintegrant with granulation solution, are dried at 20- 70°C.

4. The process according to claims 1-3 wherein the tablet compression force applied during compressing the final mixture obtained in step V into tablet form is in the range of20-200 kN is.

5. The pharmaceutical formulation comprising cefdinir prepared by the process according to claims 1-4 wherein said formulation comprise binder, glidant, lubricant, effervescent couple in addition to cefdinir, diluent and disintegrant

6. The pharmaceutical formulation according to claim 5 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

7. The pharmaceutical formulation according to claim 5 wherein disintegrant 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.

8. The pharmaceutical formulation according to claim 5 wherein 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.

9. The pharmaceutical formulation according to claim 5 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.

10. The pharmaceutical formulation according to claim 9 wherein povidone is used as binder.

11. The pharmaceutical formulation according to claim 5 wherein the glidant is selected from a group comprising magnesium silicate, colloidal silicon dioxide, starch, talc, tribasic calcium phosphate or the combination thereof.

12. The pharmaceutical formulation according to claim 11 wherein silicon dioxide is used as glidant.

13. The pharmaceutical formulation according to claim 5 wherein the lubricant is selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate

14. The pharmaceutical formulation according to claim 13 wherein magnesium dioxide is used as lubricant.

15. The pharmaceutical formulation according to claims 5-14 wherein said formulation can comprise;

10-60% of cefdinir or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms,

- 1-8% of binder,

- 0.3-2.5% of lubricant,

- 0.2-3% of glidant, - 1 - 17% of d isintegrant,

- 10-40% of diluent

in proportion to the total weight of unit dose amount.

16. The pharmaceutical composition according to claims 6-16 wherein said formulation is in the form of tablet, film-coated tablet, effervescent tablet, prolonged-release tablet, modified-release tablet and orodispersible tablet.

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

18. The pharmaceutical formulation according to claim 16-17 wherein the friability value of the tablet or film-coated tablet is in the range of 0.01 to 0.05.

19. The pharmaceutical composition according to claim 5-18 wherein said composition further comprises a second active agent.

20. The pharmaceutical formulation according to claim 5-19 wherein the second active agent used in addition to cefdinir is selected from cephalosporins, beta-lactamases is.

21. The pharmaceutical formulation according to claim 20 wherein clavulanic acid is used as the second active agent.

22. The pharmaceutical formulation according to claim 21 wherein potassium clavulanate is used as the second active agent.

23. The process according to claims 1-4, wherein potassium clavulanate is included in step IV of the process.

24. The formulation according to claims 5-21 wherein said formulation is used in the 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.