WO2012060791A2

WO2012060791A2 - Production method for pharmaceutical compositions comprising cefdinir

Info

Publication number: WO2012060791A2
Application number: PCT/TR2011/000256
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: TR201009166A2; WO2012060791A3

Abstract

The present invention relates to a production method to be used for preparation of pharmaceutical dosage forms comprising cefdinir as the active agent.

Description

PRODUCTION METHOD FOR PHARMACEUTICAL COMPOSITIONS

COMPRISING CEFDINIR

The present invention relates to a production method that shall be used for preparation of pharmaceutical dosage forms comprising cefdinir as the active agent.

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- 1 -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 cephalosporin molecule is indicated for the treatment of many infections caused by gram positive and gram negative bacteria.

Formula I

Physically appearing as 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 observed while developing formulations comprising this molecule.

It has a crucial importance for patients and treatment efficiency that each dosage form can show similar physiological efficiency. Similar physiological efficiency of each dose can be possible with weight uniformity. The important factor for weight uniformity is to provide appropriate flow rate of the formulation prepared.

Another problem that the patients encounter is that these high dose drugs become too large in size when they are formulated and it is quite difficult to swallow these large dosage forms.

As seen, it is required to develop processes which enable to prepare formulations having appropriate flow rate and therefore dose uniformity in smaller dosage forms in order to provide effective and easy treatment to patients receiving cefdinir treatment. Description of the Invention:

The present invention relates to a process to be used for preparation of pharmaceutical compositions comprising cefdinir. The inventors have unexpectedly found that the flow rate of the formulation acquired by compacting the composition comprising cefdinir and at least one excipient initially, and then sieving the composition with a 25-60 mesh sieve is at desired level and in this way, weight uniformity is provided. At the same time, the formulation prepared according to this process has been formulated in smaller dosage forms.

According to this, the process of the present invention is composed of the following steps;

I. Mixing cefdinir and at least one excipient dryly and sieving the mixture with a sieve, the mesh size of which is minimum 60,

II. If available, mixing the other excipients and sieving the mixture with at least a 60 mesh sieve,

III. Mixing the two mixtures prepared in step I and II together,

IV. Compacting the obtained powder mixture in the compactor at least once,

V. Sieving the compacted composition with a 25-60 mesh sieve,

VI. Mixing the obtained powder,

VII. Storing the mixture in an appropriate pharmaceutical dosage form.

The term "pharmaceutical dosage forms" stated in the text refers to the solid 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, the formulations of the present invention are stored in capsules.

The term "storing in an appropriate pharmaceutical dosage form" stated in the text refers to preparation of the pharmaceutical composition prepared according to the process of the present invention in the form of any dosage form specified above.

According to this, another aspect of the invention is cefdinir compositions in capsule form prepared according to the process of the present invention.The compacting step in the process of the present invention is repeated at least once, preferably 1-5 times, more preferably 1-3 times. The compacting pressure should have a value in an optimum range in order to enable the powder mixture obtained by mixing cefdinir and excipients to have desirable physical properties. Because, the powder mixture with desirable physical properties can provide an appropriate flow rate and dose uniformity in each dosage form. The inventors have seen that when the powder mixture obtained by mixing cefdinir and excipients is compacted with a compacting pressure having a value in the range of 1-200 bar, preferably 3-150 bar, more preferably 5-120 bar, most preferably 10-100 bar the powder mixture has an appropriate flow rate and thus dose uniformity in each dosage form which in turn results in providing effective and easy treatment.

Accordingly, the present invention is related to the process wherein the powder mixture obtained by mixing cefdinir and excipients is compacted with a compacting pressure having a value in the range of 1-200 bar, preferably 3-150 bar, more preferably 5-120 bar, most preferably 10-100 bar.

After compacting the powder mixture comprising cefdinir and other excipients prepared by the process of the present invention, the compacted composition is sieved with a sieve. Accordingly, the inventors have observed that the compacted composition, which is sieved such that the powder particles having an average particle size in the range of 100-1000 μηι, preferably 200-900 μιη, more preferably 250-750 μηι have desirable flowing properties during preparing dosage form with the formed composition, for example when filling the obtained composition into the capsules, and thus provide the dose uniformity resulting in an efficient treatment.

According to this, the present invention is related to the process wherein after compacting the powder mixture comprising cefdinir and other excipients, the compacted mixture is sieved such that the powder particles have an average particle size in the range of 100-1000 μιη, preferably 200-900 μπι and more preferably 250-750 μιη. Cefdinir used in the formulations which are prepared according to 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 combinations thereof.

The pharmaceutical composition to be prepared according to process of the present invention comprises at least one pharmaceutically acceptable excipient along with cefdinir. The excipients in said composition can be selected from a group comprising binders, lubricants, humectants, disintegrants, diluents, sweeteners and/or glidant.

The binder that can be used in the cefdinir formulation to be prepared according to the process of the present invention can be selected from a group comprising ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxyproyl cellulose, hypromellose, magnesium aluminum silicate, methyl cellulose, povidone.

The lubricant that can be used in the cefdinir formulation to be prepared 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 and sodium benzoate.

The humectant that can be used in the cefdinir formulation to be prepared according to the process of the present invention can be selected from a group comprising anhydrous sodium sulphate, silica gel and potassium carbonate.

The disintegrant that can be used in the cefdinir formulation to be prepared 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. Preferably, carboxymethyl cellulose sodium or carboxymethyl cellulose calcium or a disintegrant composition comprising carboxymethyl cellulose sodium and carboxymethyl cellulose calcium is used. More preferably, carboxymethyl cellulose calcium is used.

The diluent that can be used in the cefdinir formulation to be prepared 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 sweetener that can be used in the cefdinir formulation to be prepared according to the process of the present invention can be selected from a group comprising acesulfame, aspartam, dextrose, fructose, glucose, lactitol, maltitol, maltose, sorbitol, saccharine, saccharine sodium, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose and xylitol or combinations thereof.

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

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

The water dispersible powder, tablet and granule formulation of the present invention can comprise cefdinir or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms in the range of 10 - 90%, preferably in the range of 40 - 80 % and the binder in the range of 0-10 %, the lubricant in the range of 0,1-10 %, the sweetener in the range of 0-5 %, the diluent in the range of 0-30%, the disintegrant in the range of 10-35 %, the humectant in the range of 0- 10%, the glidant in the range of 0,1 - 5 % in proportion to total weight of unit dose.

The cefdinir formulation to be prepared 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 derivatives thereof is used.

According to this, another aspect of the present invention relates to a process that can be used for preparation of pharmaceutical compositions comprising cefdinir and clavulanic acid or a combination of its derivatives and at least one pharmaceutically acceptable excipient.

Clavulanic acid that can be used optionally in the pharmaceutical composition 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 in the present invention.

The pharmaceutical composition of the present invention can comprise clavulanic acid in the range of 50-500 mg or its pharmaceutically acceptable salts, hydrates, solvates or 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, magnesium trisilicate, cellulose powder, 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 of the present invention can comprise clavulanic acid in the range of 5-90%, preferably in the range of 10-80% in proportion to total weight of unit dose amount or its pharmaceutically acceptable salts, hydrates, solvates or combination thereof in an equivalent amount.

Another aspect of the present invention is that the pharmaceutical composition prepared according to said invention is used in treatment of diseases related with infections caused by gram negative and gram positive bacteria.

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 capsules comprising cefdinir

Process:

Cefdinir and the disintegrant are mixed with at least one excipient and the mixture is sieved with a 60 mesh sieve. The other excipients are sieved with a 60 mesh sieve separately and these two mixtures are mixed together. The mixture is compacted in the compactor (Alexanderwerk). The compacted composition is sieved with a 25 mesh sieve. Obtained powder is put into the capsule powder filling machine.

EXAMPLE 2: Formulation and process for preparation of capsules comprising cefdinir and potassium clavulanate.

Process:

Cefdinir, disintegrant and at least one excipient are mixed and the mixture is sieved with a 60 mesh sieve. Potassium clavulanate and other excipients are mixed separately and the mixture is sieved with a 60 mesh sieve. These two mixtures are mixed together. The mixture is compacted in the compactor (Alexanderwerk). The compacted composition is sieved with a 25 mesh sieve. Obtained powder is put into the capsule powder filling machine.

Claims

CLAIMS:

1. A process to be used for preparation of formulations comprising cefdinir characterised in that said pharmaceutical composition comprising cefdinir and at least one excipient is prepared by being compacted at least once initially and then sieved with a 25-60 mesh sieve.

A process to be used for preparation of cefdinir formulations comprising at least one initial compacting of cefdinir and at least one pharmaceutically acceptable excipient and then sieving obtained compact with a 25-60 mesh sieve.

2. The process according to claim 1, wherein said process is composed of the following steps;

I. Mixing cefdinir and at least one excipient and sieving the mixture with at least a 60 mesh sieve,

II. Mixing the other excipients if available and sieving the mixture with at least a 60 mesh sieve.

III. Mixing the two mixtures obtained in step I and step II together,

IV. Compacting the obtained powder mixture in a compactor at least once,

V. Sieving the compacted mixture with a 25-60 mesh sieve.

VI. Mixing the obtained powder,

VII. Storing the mixture in an appropriate pharmaceutical dosage form.

3. The process according to claims 1-2 characterised in that compacting step of the process is repeated at least once, preferably 1-5 times, more preferably 1-3 times.

4. The process according to claims 1-3 characterised in that the powder mixture obtained by mixing cefdinir and excipients is compacted with a compacting pressure having a value in the range of 1-200 bar.

5. The process according to claim 4 characterised in that the powder mixture obtained by mixing cefdinir and excipients is compacted with a compacting pressure having a value in the range of 3-150 bar.

6. The process according to claim 5 characterised in that the powder mixture obtained by mixing cefdinir and excipients is compacted with a compacting pressure having a value in the range of 5-120 bar.

7. The process according to claims 1-6 characterised in that after compacting the mixture comprising cefdinir and other excipients, the compacted mixture is sieved such that the powder particles have an average particle size in the range of 100-1000 μηι.

8. The process according to claim 7 characterised in that after compacting the mixture comprising cefdinir and other excipients, the compacted mixture is sieved such that the powder particles have an average particle size in the range of 200-900 μπι.

9. The process according to claim 8 characterised in that after compacting the mixture comprising cefdinir and other excipients, the compacted mixture is sieved such that the powder particles have an average particle size in the range of 250-750 μπι.

10. The pharmaceutical formulation prepared by the process according to claim 1-9, wherein the appropriate pharmaceutical dosage form in which the formulation shall be stored is tablet, film-coated tablet, capsule, prolonged-release tablet, modified-release tablet, effervescent tablet, orodispersible tablet, sachet, suspension.

11. The pharmaceutical formulation according to claim 10, wherein the appropriate pharmaceutical dosage form in which the formulation shall be stored is capsule.

12. The pharmaceutical formulation according to claims 10-11 characterised in that the formulations comprise at least one pharmaceutically acceptable excipient along with cefdinir.

13. The formulation according to claims 10- 12, wherein cefdinir is in the form of its solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms or free form and/or combinations thereof.

14. The formulation according to claims 10-13, wherein at least one excipient is selected from a group comprising binders, lubricants, humectants, disintegrants, diluents, sweeteners and/or glidant.

15. The formulation according to claim 14, 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.

16. The formulation according to claim 14, wherein the lubricant is selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, PEG 6000, polyvinyl alcohol, potassium benzoate, sodium benzoate.

17. The formulation according to claim 14, wherein the humectant is selected from a group comprising anhydrous sodium sulphate, silica gel and potassium carbonate.

18. The formulation according to claim 14, wherein the disintegrant is selected from 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.

19. The formulation according to claim 18, wherein carboxymethyl cellulose sodium or carboxymethyl cellulose calcium or a disintegrant composition comprising the combination thereof is used as disintegrant.

20. The formulation according to claim 19, wherein carboxymethyl cellulose calcium is used as disintegrant.

21. The formulation according to claim 14, 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 or combinations thereof.

22. The formulation according to claim 14, wherein the sweetener is selected from a group comprising acesulfame, aspartam, dextrose, fructose, glucose, lactitol, maltitol, maltose, sorbitol, saccharine, saccharine sodium, sodium cyclamate, sucralose, sodium chloride, potassium chloride, sucrose and xylitol or combinations thereof.

23. The formulation according to claim 14, wherein the glidant is selected from a group comprising magnesium silicate, silicon dioxide, starch, talc, tribasic calcium phosphate or a combination thereof.

24. The formulation according to claim 23, wherein silicon dioxide is used as glidant.

25. The formulation according to claims 10-24, wherein the formulation comprises cefdinir in the range of 1-4000 mg or its pharmaceutically acceptable salts, hydrates, solvates or the combination thereof in an equivalent amount.

26. The formulation according to claims 14-25, wherein the formulation comprises cefdinir or its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms in the range of 10 - 90%, preferably in the range of 40 - 80 % and the binder in the range of 0-10 %, the lubricant in the range of 0.1-10 %, the sweetener in the range of 0-5 %, the diluent in the range of 0-30%, the disintegrant in the range of 10-35 %, the humectant in the range of 0-10%, the glidant in the range of 0.1-5 % in proportion to total weight of unit dose.

27. The formulation according to claims 10-26, wherein a second active agent is used optionally.

28. The formulation according to claim 27, wherein the second active agent can be selected from cephalosporins or beta-lactamases.

29. The formulation according to claim 28, wherein the second active agent is selected from clavulanic acid and/or derivatives thereof.

30. The formulation according to claim 29, wherein the clavulanic acid can be in the form of its solvates, hydrates, enantiomers, racemates, organic salts, polymorphs, crystalline and amorphous forms or free form and/or combinations thereof.

31. The formulation according to claim 30, wherein potassium clavulanate is used as the second active agent.