WO2013109203A1

WO2013109203A1 - Tablet formulations comprising cefditoren pivoxil

Info

Publication number: WO2013109203A1
Application number: PCT/TR2013/000015
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2012-01-18
Filing date: 2013-01-16
Publication date: 2013-07-25
Also published as: WO2013109204A1

Abstract

The present invention relates to pharmaceutical tablet formulations comprising cefditoren pivoxil to be used in the treatment of the infectious diseases caused by gram positive and gram negative bacteria.

Description

TABLET FORMULATIONS COMPRISING CEFDITOREN PIVOXIL

The present invention relates to pharmaceutical tablet formulations comprising cefditoren pivoxil to be used in the treatment of the infectious diseases caused by gram positive and gram negative bacteria. Cefditoren pivoxil was first disclosed in the patent application numbered EP0175610. In said document, cefditoren pivoxil was indicated to be effective in the treatment of infectious diseases caused by gram positive and gram negative bacteria.

Cefditoren pivoxil is available in 200 and 400 mg oral dosage forms on the market.

In the sense of pharmaceutical technology, physical properties of dosage form for every type of tablet dosage form are directly related to durability in storage conditions; dissolution and bioavailability of the dosage form obtained.

An important physical parameter in pharmaceutical tablet formulations is tablet hardness and it is related to resistance of tablets to storage, transport, coating and erosion and breakage before usage. The fact that tablets with low hardness are more exposed to erosion, friability or breakage results in;

I. loss of active agent and thus decrease in the amount of dose taken;

II. erosion of tablet surface during coating process and dosage forms which have uneven surfaces and variable amounts of active agent in the final product while producing coated tablet forms. Furthermore, tablet hardness is closely related to dispersibility and solubility of a tablet. If tablets are too hard to disperse or dissolve adequately; bioavailability of said dosage forms will decrease and therefore the time for desired biological response to occur will extend. The same scenario is also valid for all types of tablets such as effervescent, film-coated, soluble, extended-release, modified-release, delayed-release tablets etc. Attaining appropriate tablet hardness is influenced by many parameters such as the forms of active agents and excipients used, particle sizes thereof, flowability of the powder or granules prepared for tablet compressing and tablet compression force.

Considering all of these parameters, hardness values of the tablets are aimed to be low enough to disintegrate fast in the stomach but high enough to preserve tablet uniformity during manufacturing. Therefore, tablet formulations of the present invention should have an appropriate excipient' composition and compressing said formulation in the form of tablets should be under an appropriate compression force.

As a result of the development studies conducted on pharmaceutical tablet formulations comprising cefditoren pivoxil, the inventors have found that the desired mechanical tablet resistance, the desired dissolution rate and accordingly the desired bioavailability are achieved when the tablet compression force used for compressing said formulations in the form of tablets is between 3 kN and 50 kN and wherein said formulations comprise a disintegrant combination composed of a first and a second disintegrant. According to this, the pharmaceutical tablet formulation of the present invention comprising cefditoren pivoxil as active agent with at least one pharmaceutically acceptable excipient, is characterized in that

• the tablet compression force used for tablet compression is between 3 to 50 kN and

· said tablet formulation comprises a disintegrant combination composed of a first and a second disintegrant.

A characteristic feature of the tablet formulations of the present invention is that said tablet formulations comprise cefditoren pivoxil as active agent, at least one pharmaceutically acceptable excipient and the tablet compression force used for compressing said formulations in the form of tablets is between 4 kN and 45 kN.

Another characteristic of the tablet formulations of the present invention is that said tablet formulations comprise cefditoren pivoxil as active agent, at least one pharmaceutically acceptable excipient and the tablet compression force used for compressing said formulations in the form of tablets is between 5 kN and 40 kN. The disintegrant that can be used in the pharmaceutical formulations of the invention can be selected from the group comprising microcrystalline cellulose, crosspovidone, croscarmellose sodium, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, hydroxypropyl cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate The appropriate excipient composition of the tablet formulations plays an important role in the tablet hardness and resistance of the tablet during manufacturing processes such as compression and coating. Based on the studies conducted by the inventors, it has been found that if the ratio of the first disintegrant to the second one is 1 :5 to 5: 1 by weight, the tablet is more resistant for abovementioned processes and the loss of active agent is avoided thus the amount of dose taken is ensured.

According to these studies, another characteristic feature of the invention is that the ratio of the first disintegrant to the second one is 1 :5 to 5: 1, preferably 1 :3 to 3:1 by weight

The first disintegrant that can be used in the pharmaceutical formulation of the invention is preferably microcrystalline cellulose.

The second disintegrant that can be used in the pharmaceutical formulation of the invention is preferably crosspovidone.

The ratio of microcrystalline cellulose to crosspovidone is 1 :5 to 5: 1, preferably 1 :3 to 3:1 by weight. The pharmaceutical tablet formulation of the present invention can be in the form of any of tablet, effervescent tablet, film-coated tablet, enteric-coated tablet, orodispersible tablet, water-soluble tablet, extended-release tablet, modified-release tablet, delayed-release tablet dosage forms.

The pharmaceutical tablet formulation of the present invention is preferably in the form of film-coated tablet.

Cefditoren pivoxil comprised in the pharmaceutical formulations of the present invention can be in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure; and in crystalline, amorphous forms or combinations thereof in terms of polymorphic structure. The pharmaceutical formulations of the present invention comprise at least one pharmaceutically acceptable excipient, in addition to the active agent and disintegrant, selected from the group comprising, diluent, lubricant, glidant, preservative, pH regulating agent, film coating agent. The diluent that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol or combinations thereof.

The lubricant that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or combinations thereof. The lubricant that can be used in the pharmaceutical formulations of the invention is preferably magnesium stearate.

The glidant that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising tribasic calcium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc or combinations thereof. The glidant that can be used in the pharmaceutical formulations of the invention is preferably colloidal silicon dioxide.

The preservative that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising sorbic acid, sodium sorbate, potassium sorbate, sodium benzoate, potassium benzoate, calcium benzoate, sodium propionate, potassium propionate, calcium propionate and sodium tripolyphosphate.

The preservative that can be used in the pharmaceutical formulations of the invention is preferably sodium tripolyphosphate.

The pH regulating agent that can be used in the pharmaceutical formulations of the invention can be selected from a group comprising citrate, phosphate, carbonate, tartarate, fumarate, acetate and amino acid salts, sodium caseinate, potassium caseinate, calcium caseinate or combinations thereof.

The pH regulating agent that can be uses in the pharmaceutical formulations of the invention is preferably sodium caseinate. The pharmaceutical tablet formulation of the present invention can be treated with film coating agents such as sugar-based coating agents, water-soluble film coating agents, enteric coating agents and delayed release coating agents or a coating composition comprising any combination thereof. As sugar-based coating agent, saccharose can be used alone or together with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum arabic, polyvinylpyrrolidone and pullulan or any combination thereof.

Water-soluble film coating agents can be selected from a group comprising cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethyl amino acetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone; polysaccharides such as pullulan or combinations thereof.

Enteric coating agents can be selected from a group comprising cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances such as shellac or combinations thereof.

Other film coating agents can be selected from a group comprising titanium dioxide, polyvinyl alcohol, polyethylene glycol, talc, lecithin and/or combinations thereof. For example, a film coating agent branded as Opadry® can be used in the present invention.

During the development process of cefditoren pivoxil formulations, the inventors have observed that the appropriate excipient composition of the tablet is important in order to apply the desired compression force during tablet compression. Consequently, the inventors have surprisingly found that the ratio of total amount of disintegrant to total amount of diluent should be 5:1 to 1 :5 by weight in order to perform a compression force claimed in the present invention.

According to this, another aspect of the present invention is that the ratio of total amount of disintegrant to total amount of diluent should be 5:1 to 1 :5, more preferably 2:1 to 1 :2 by weight. In a preferred embodiment of the invention, the pharmaceutical formulations of the invention comprise cefditoren pivoxil in the range of 30-70%, more preferably in the range of 35-60% by weight.

In a further preferred embodiment of the invention, the pharmaceutical formulation of the invention comprises 25 to 80%) of cefditoren pivoxil, 15 to 30% of disintegrant, 5 to 25% of diluents, 0.5 to 5% of lubricant, 1 to 5% of glidant, 3 to 10% of pH regulating agent 0.1 to 1% preservative and 1 to 10% of film coating agent in proportion to total weight of the formulation.

In a preferred embodiment of the invention, the pharmaceutical formulation of the invention can be obtained by a method comprising the steps of;

• Mixing cefditoren pivoxil with a first disintegrant, glidant and at least one pharmaceutically acceptable excipient to obtain a first mixture,

• Half of the lubricant is added to the first mixture and dry granulated by slugging/deslugging,

· Obtained granules are mixed with lubricant, a second disintegrant and at least one pharmaceutically acceptable excipient,

• The formed blend is lubricated with the rest of the lubricant and then compressed into tablets,

• Obtained tablets are coated with a coating solution containing a film-coating agent. Another problem of cefditoren pivoxil tablet formulation is the erosion of tablet surface during coating process and dosage forms which have uneven surfaces and variable amounts of active agent in the final product while producing coated tablet forms. In order to eliminate those problems, the inventors have conducted studies on the coating processes and have observed that use of a specific amount of lubricant in the formulation and use of lubricant before and during the lubrication step prevents the erosion of tablet surface during coating process. Thus, when half of the lubricant is added to the formulation before lubrication and the rest of the lubricant is added during lubrication and when the tablet formulation of the present invention comprises lubricant in the range of 0.5 to 5% by weight, the obtained tablets have even surfaces and dose uniformity is provided. In that aspect, another characteristic of the method used to prepare tablet formulations of the present invention is that • half of the lubricant is added to the formulation before lubrication and the rest of the lubricant is added during lubrication and

• said tablet formulations comprise lubricant in the range of 0.5 to 5% by weight.

In a further preferred embodiment of the invention, tablet formulations of the present invention is that said tablet formulations comprise lubricant in the range of 1 to 3% by weight. In a preferred embodiment of the invention, the pharmaceutical formulation of the invention can be used in the treatment of the infectious diseases caused by gram positive and gram negative bacteria.

Example 1: Formulation and process for preparation of cefditoren pivoxil film tablet

The production method to be applied for the tablet formulations to be prepared according to the formulation given above is as follows;

• Mixing cefditoren pivoxil with a first disintegrant, glidant, diluent, pH agent and preservative to obtain a first mixture, Half of the lubricant is added to the first mixture and dry granulated by slugging/deslugging, ^'

Obtained granules are mixed with lubricant, a second disintegrant, glidant and diluent, The formed blend is lubricated with the rest of the lubricant and then compressed into tablets,

Obtained tablets are coated with a coating solution containing a film-coating agent.

Claims

1. A pharmaceutical tablet formulation comprising cefditoren pivoxil as active agent with at least one pharmaceutically acceptable excipient, characterized in that

• said tablet formulation comprises a disintegrant combination composed of a first and a second disintegrant.

2. The pharmaceutical tablet formulation according to claim 1 , characterized in that the tablet compression force used for tablet compression is between 4 and 45 kN.

3. The pharmaceutical tablet formulation according to claim 2, characterized in that the tablet compression power used for tablet compression is between 5 and 40 kN.

4. The pharmaceutical tablet formulation comprising cefditoren pivoxil according to claims 1-3 wherein disintegrant is selected from the group comprising microcrystalline cellulose, crosspovidone, croscarmellose sodium, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, hydroxypropyl cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.

5. The pharmaceutical tablet formulation comprising cefditoren pivoxil according to claim 4 wherein microcrystalline cellulose is used as first disintegrant.

6. The pharmaceutical tablet formulation comprising cefditoren pivoxil according to claim 4 wherein crosspovidone is used as second disintegrant.

7. The pharmaceutical tablet formulation comprising cefditoren pivoxil according to claims 1 -6 characterized in that the ratio of first disintegrant to second disintegrant is 1 :5 to 5:0.

8. The pharmaceutical tablet formulation comprising cefditoren pivoxil according to claim 7 characterized in that the ratio of first disintegrant to second disintegrant is 1 :3 to 3:1.

9. The pharmaceutical tablet formulation according to any of the preceding claims, characterized in that said tablet formulation is in the form of any of tablet, effervescent tablet, film-coated tablet, enteric-coated tablet, orodispersible tablet, water-soluble tablet, extended-release tablet, modified-release tablet, delayed-release tablet dosage forms.

10. The pharmaceutical tablet formulation according to claim 9, characterized in that said formulation is in the form of film-coated tablet.

11. The pharmaceutical tablet formulation according to any of the preceding claims, characterized in that cefditoren pivoxil is in the form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure; and in amorphous or crystalline forms or combinations thereof in terms of polymorphic structure.

12. The pharmaceutical tablet formulation according to any of the preceding claims, characterized in that at least one pharmaceutically acceptable excipient to be used with cefditoren pivoxil and disintegrant is selected from the group comprising diluent, lubricant, glidant, preservative, pH regulating agent.

13. The pharmaceutical tablet formulation according to claim 12, wherein diluent is selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol or combinations thereof.

14. The pharmaceutical tablet formulation according to claim 12, wherein lubricant is selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate or combinations thereof.

15. The pharmaceutical tablet formulation comprising cefditoren pivoxil according to claims 1-14 characterized in that ratio of total amount of disintegrant to total amount of diluent is 5:1 to 1 :5.

16. The pharmaceutical tablet formulation comprising cefditoren pivoxil according to claims 15 characterized in that the ratio of total amount of disintegrant to total amount of diluents is 2:1 to 1 :2.

17. The pharmaceutical tablet formulation comprising cefditoren pivoxil according to any preceding claims wherein said formulation comprise cefditoren pivoxil in the range of 30-70% by weight.

18. The pharmaceutical tablet formulation comprising cefditoren pivoxil according to claim 17, wherein said formulation comprise cefditoren pivoxil in the range of 35-

60% by weight.

19. The pharmaceutical tablet formulation comprising cefditoren pivoxil according to any preceding claims, wherein said formulation comprises 30 to 70% of cefditoren pivoxil, 15 to 30% of disintegrant, 5 to 25% of diluent, 0.5 to 5% of lubricant, 1 to 5% of glidant, 3 to 10% of pH regulating agent, 0.1 to 1% preservative and 1 to 10% of film coating agent in proportion to total weight of the formulation.

20. The method for the preparation of a pharmaceutical composition according to any preceding claims, wherein said method comprises a process of

• Obtained granules are mixed with lubricant, a second disintegrant and at least one pharmaceutically acceptable excipient,

• Obtained tablets are coated with a coating solution containing a film-coating agent.

21. The method for the preparation of a pharmaceutical composition according to claim 20, wherein said method the method used to prepare tablet formulations of the present invention is characterized in that

• half of the lubricant is added to the formulation before lubrication and the rest of the lubricant is added during lubrication and

22. The method for the preparation of a pharmaceutical composition according to claims 20-21 wherein said tablet formulations comprise lubricant in the range of 1 to 3% by weight.