WO2008057058A1

WO2008057058A1 - Oral pharmaceutical compositions

Info

Publication number: WO2008057058A1
Application number: PCT/TR2006/000056
Authority: WO
Inventors: Abdullah Uslu
Original assignee: Nobel Ilac Sanayii Ve Ticaret As
Priority date: 2006-11-10
Filing date: 2006-11-10
Publication date: 2008-05-15

Abstract

Oral pharmaceutical compositions for cefpodoxime proxetil or cefditoren pivoxil attained through dry compression, exhibiting enhanced dissolution and wettability.

Description

DESCRIPTION

ORAL PHARMACEUTICAL COMPOSITIONS

Field of the invention

The present invention relates to the oral tablet formulation for cefpodoxime proxetil or cefditoren pivoxil by dry compression, exhibiting enhanced dissolution and wettability that is attained through usage of co-processed cellulose, wherein the co-processed cellulose is present in an amount of 30 or greater weight percent based on the weight of the drug.

Background of the invention

Initially, cephalosporins were isolated from a fungus Cephalosporium acremonium in 1948 by Brotzu. These β-lactam antibiotics have low toxicity for the host and broad antibacterial spectrum for microorganisms. Antibacterial and pharmacological properties of cephalosporins could be modified mainly by substitution in the 3rd and 7th positions of the molecule. With this method, half a century long, various cephalosporins have been developed and classified according to their general anti-microbial features. Three generations of cephalosporins are recognized and the fourth has been grouped. Each newer generation of cephalosporins has a wide anti-bacterial spectrum against gram-negative organisms but a narrower antibacterial spectrum against gram-positive organisms than the preceding generation.

The bactericidal activity of cephalosporins results from its inhibition of bacterial cell wall synthesis.

Cephalexin, cefdinir, cefaclor, cefadroxil, loracarbef, cefprozil, cefixime, cefpodoxime proxetil, ceftibuten, cefditoren pivoxil and cefuroxime axetil are absorbed after oral administration and can be given by this route.

Cefpodoxime proxetil is an orally administered, semi-synthetic third generation agent very similar in activity in cefixime, except that it is slightly more active against S. aureus. Cefpodoxime proxetil is an ester prodrug of the active free acid metabolite cefpodoxime and has little antibacterial activity until hydrolized in vivo to cefpodoxime. It's chemical name is (6R,7R)-7-[[(2Z)-(2-Amino-4-thiazolyl) (methoxyimino)acetyl]amino]-3- (methoxymethyl)-8-oxo-5-thia-l-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid 1-[[(1- methylethoxy) carbonyl] oxyjethyl ester. Cefpodoxime and its pharmaceutically acceptable acid addition salts are disclosed in US patent 4,486,425.

Following oral administration, cefpodoxime proxetil is de-esterified to its active metabolite cefpodoxime in the intestinal epithelium, to release active cefpodoxime in the blood stream. Esterification of the carboxy C-4 group of cefpodoxime results in a more lipophilic form of the drug that is more readily absorbed from the gastrointestinal tract.

Over the recommended dosing range (100 to 800 mg) the rate and extent of cefpodoxime absorption exhibited dose-dependency. Over the recommended dosing range, the t_max was approximately 2 to 3 hours and tm ranged from 2 to 3 hours. Approximately 50% of the administered dose was absorbed systemically, whilst the absorption is increased in the presence of food. However absorption is decreased under conditions of low gastric acidity and also with the concurrent administration of antacids.

For current therapeutic practice cefpodoxime proxetil is commercially available as both tablet and oral suspension.

Generally, therapeutic efficiency of the drugs tightly depends on their pharmaceutical dosage forms. Design of pharmaceutical formulation achieves essential drug level into the blood stream. Therapeutically effective amount of active ingredient should be absorbed to the blood circulation. There are several contributing factors to the low absorption in the intestines of third generation cephalosporins after oral administration. Characteristics of the drug substance itself, (solubility in water, its chemical stability, and molecular weight) and inactive ingredients of formulation, patient's condition may affect the absorption rate and absorption extent.

In the clinical practice, the most preferred route of antibacterial treatment is orally. But many cephalosporins, such as cephalotin and cefazolin, are widely used for parenteral administration because of their poor bioavailability. Cefuroxime axetil, cefixime trihydrate, cefadroxil, cefpodoxime proxetil, cefprozil, cefditoren, cephedrine and cefaclor are currently marketed as orally active cephalosporins.

Wettability is an important problem for some raw materials in pharmaceutical industry, especially by materials non-soluble or slightly soluble in aqueous medium. Improving the wettability of the drug's particles is a critical step of formulation development. Since cefpodoxime proxetil is a highly hydrophobic drug, when it contacts with aqueous medium, it turns to gel form resulting in slow dissolution and hence poor bioavailability. These characteristics are modified by suitable formulation.

PCT application WOO 1/97851 describes some compositions and methods for increasing absorption of antibacterial agents, particularly third generation cephalosporins by combining with a cationic binding agent and a biopolymer, and optionally, an absorption enhancer.

PCT application WO04/006917 describes a dispersible β-lactam antibiotic comprising tablet. Although dispersible dosage forms are not as bioavailable as aqueous suspension formulation, they are easily swallowed by the very young or elderly patients.

EP1365764 especially mentioned oral pharmaceutical composition of cefpodoxime proxetil. This patent relates to a method for enhancing the dissolution and bioavailability of cefpodoxime proxetil, which is attained through adsorption of the micronized drug on to a pharmaceutical carrier to form cefpodoxime-carrier adsorbates. According to this invention, cefpodoxime proxetil adsorbed onto a pharmaceutical carrier such as cellulose ether, acrylic polymer, natural gum, and mixtures thereof.

Some pharmaceutical excipients contain polymers such as povidone, crosspovidone, hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), carboxymethyl cellulose (CMC, CMC Na, CMC Ca etc.) use to facilitate the wettability and dissolution of the drug. Also contain other polymers, which are combination of microcrystalline cellulose and carboxymethyl cellulose sodium, known as co-processed cellulose or dispersible cellulose. These are water insoluble dispersible colloidal excipients that are used as suspending agent/thickener in pharmaceutical suspensions and emulsions.

Four types of water dispersible celluloses, which are co-processed forms of microcrystalline cellulose, prepared by chemical depolymerisation of highly purified wood pulp, the original crystalline areas of the fibres being combined with sodium carboxymethyl cellulose and spray-dried, have been marketed under the trade names Avicel® RC-501 (containing 7.1-11.9% of sodium carboxylmethyl cellulose), Avicel® RC-581 (containing 8.3-13.8% of sodium carboxymethyl cellulose), Avicel® RC-591 (containing 8.3-13.8% of sodium carboxymethyl cellulose) and Avicel® CL-611 (containing 11.3-18.8% of sodium carboxymethyl cellulose).

These hygroscopic excipients supply a structured dispersion vehicle exhibiting a high degree of thixotropy and achieving superior suspension stability in a formulation. Final product viscosity/gel strength and methods of dispersion, are required for completion of the activation, and are main diversities between the types of co-processed Avicel^®s.

To achieve maximum dispersion, RC-501 and RC-581 require high shear mixing while RC-591 and CL-611 require low to moderate shear mixing. With these excipients, 60% of the particles in the dispersion are less than 0.2 μm when properly dispersed.

Avicel^®RC-591 and Avicel^®CL-611 have high wettability characteristic and they are well known in the pharmaceutical art for their usage in the preparation of pharmaceutical suspensions and emulsions to give thickness to obtain the suspension. This use has been mentioned in the prior patents numerous times, e.g. in WO9321923, WO02072102, WO05016314, WO05016313, WO04037259, WO03105808, EP1200066, EP1025859, EP0843998, WO8606626.

Although the usage of microcrystalline cellulose along with carboxymethyl cellulose sodium in a tablet formulation is well known in the art, usage of their co-processed combination as co-processed cellulose in a tablet formulation is not. Examples of the usage of microcrystalline cellulose along -with carboxymethyl cellulose sodium can be found in various patents, such as US20030176391, EP00408273, WO00025751, US2003143293, US2004096496, EP6083532 and WO04006917.

The usage of co-processed cellulose in tablet formulations is first described in US 5837292. A fast-disintegrating and fast dissolving granulate formulation has been described, containing high amount of active ingredient, having a solubility in water of l :>10, and <15 wt %, most preferably 2-5 wt %, of a water dispersible hydrocolloid, the percentage based on the weight of the said drug. The composition is obtained by wet granulation.

An objective of the present invention is to provide a pharmaceutical cephalosporin formulation which can be administered to a patient and not only improves wettability of the cephalosporin, but also further improves absorbability through the intestinal tracts.

Summary of the Invention

This invention relates to the improvement in the wettability of cephalosporins, namely cefpodoxime proxetil and cefditoren pivoxil.

The main objective of the present invention is to provide an oral tablet composition wherein the wettability of cephalosporin antibiotics is enhanced, thereby ensuring an improvement in dissolution properties.

This improvement is attained through usage of co-processed cellulose (microcrystalline cellulose and carboxymethyl cellulose sodium), wherein the co-processed cellulose is present in an amount of 30 or greater weight percent based on the weight of the drug, and by the usage of dry compression for the formulation.

For the current developed formulation, the market products Avicel^®RC-591 and/or Avicel^®CL-611 are used. As described herein, the present invention resides in a pharmaceutical composition for oral administration which comprises pharmaceutically effective amount of a cefpodoxime proxetil or cefditoren pivoxil and co-processed cellulose, together with other excipients. Also, the subject pharmaceutical composition may optionally be coated.

Detailed Description of the Invention

Cephalosporins are known to have wettability problems as an active ingredient. The low wettability and dissolution properties of cephalosporins greatly influence the bioavailability.

Most of the cephalosporins, especially cefpodoxime proxetil and cefditoren pivoxil, are highly hydrophobic drugs. In contact with the aqueous medium, they turn to gel form, resulting in stability problems and slow dissolution causing poor bioavailability. Therefore usage of wet granulation technique is not suitable for the formulation of these drugs.

In the light of the above, in order to eliminate the stability problem, dry granulation is preferred for our formulation, comprising the steps of: • subjecting a mixture of the active agent and additives to compression by compressing said mixture to form a comprimate;

• converting the comprimate to form a granulate and

• compressing the granulate to form the compressed solid oral dosage form.

During the formulation development our experiments have revealed that, the usage of co- processed cellulose in the formulation surprisingly eliminates the flowability, wettability and dissolution problems of cephalosporin tablets. However, in order to achieve the dry granulation, the amount of the co-processed cellulose in the formulation cannot be less than 30%.

The other excipients of this formulation are chemically inert excipients that are commonly used in the pharmaceutical formulations, like filler, disintegrant, binder, glidiant, lubricant and surfactant. Moreover anti-adherant, anti-friction agents, buffering agents, sweetening, coloring and/or flavoring agents, coating agents... etc. can also be used.

The following examples illustrates this invention and are not to be construed as limiting the scope but read in conjunction with the description above, which provide further understanding of the present invention and an outline of the process for preparing the composition of the invention.

Example Formulations:

Example 1:

Cefpodoxime proxetil, Avicel CL-611 and a part of Sodium lauryl sulphate are sieved and blended. This mixture is compressed in the compactor.

The compacts are broken in order to obtain dry granules.

The dry granules are sieved and then transferred to the mixer.

The rest of Sodium lauryl sulphate and HPC-L are sieved as the outer phase and blended with the powder mixture.

The sieved magnesium stearate is added to the mixture and the mixture is blended.

The mixture is then compressed into tablets and optionally coated with film. Example 2:

Ingredients % Amount

Cefpodoxime proxetil 59.3

Avicel RC 591 34.66

Sodium lauryl sulphate 3.18

Hydroxy propyl cellulose (HPC-L) 1.64

Aerosil 200 0.4

Magnesium stearate 0.82 total 100

- Cefpodoxime proxetil, Avicel RC-591, HPC-L, Aerosil 200 and a part of sodium lauryl sulphate is sieved and blended. This mixture is compressed in the compactor.

- The compacts are broken in order to obtain dry granules.

- The dry granules are sieved and then transferred to the mixer.

- The rest of sodium lauryl sulphate is sieved as the outer phase and blended with the powder mixture.

- The sieved magnesium stearate is added to the mixture and the mixture is blended.

- The mixture is then compressed into tablets and optionally coated with film.

Explanation of the Figures

The first 3 figures show the difference between the dissolution profiles of the market product and our formulation in Example 2, for 3 different pH values.

It should be noted that, none of the market products contain neither Avicel^® RC-591 nor Avicel^® CL-611. Podomexef^® tablets have been chosen as the reference market product for the specific case.

Figure-2 shows the dissolution profiles in USP-29 method's medium (buffer pH:3, 900 mL, 75 rpm, tolerance not less than 70% in 30 minutes), Figure- 1 shows the dissolution profiles for pH:1.2 and Figure-3 shows the dissolution profiles for pH:6.8. In first 5 minutes, our tablet's dissolution for pH: 1.2 is more than 87%, while the market product's dissolution is only 76%. Also for the first 5 minutes our tablet's dissolution is 61% in pH: 3 and 53% in pH: 6.8, which is 12% more than the market product for both of the mediums.

At the end of 15 minutes, our tablet's dissolution is 94% in pH: 1.2, 90% in pH: 3 and 75% in pH: 6.8 while the market product's dissolution is 97% in pH: 1.2, 86% in pH: 3 and 66% inpH: 6.8.

After 30 minutes, dissolutions of our tablet in pH: 1.2, 3 and 6.8 are 94%, 98% and 83% respectively, while the market product's dissolutions are respectively 98%, 93% and 71% for the same mediums.

In comparison, as you may note from the above values and as it can be seen from the figures, although similar dissolution profiles are observed in pH: 1.2, our dissolution values are more than the market product in ρH:3 and pH:6.8.

Also we wish to underline the fact that although the tolerance in pH:3 should not be less than 70% in 30 minutes according to USP-29 method, our formulation reach more than 70% dissolution in first 10 minutes in this pH.

Furthermore, a Figure 4 has been added in order to show that, the co-processed cellulose product is different than plain mixture of microcrystalline cellulose and carboxymethyl cellulose sodium. Figure 4 shows the difference between the dissolution profiles of two different tablet formulations prepared by dry granulation, which had been compared in pH:1.2 and 75 rpm.

One of the dissolution profiles belongs to the formulation in Example 2 and the other tablet formulation belongs to the tablet formulation below, which is prepared without co- processed cellulose but with the addition of microcrystalline cellulose and carboxymethyl cellulose sodium separately. Ingredients % Amount

NaCMC 3.S

MCC 31.16 total 34.66

Ceφodoxime proxetil ₅9.3

Sodium lauryl sulphate 3.18

Hydroxy propyl cellulose (HPC-L) 1.64

Aerosil 200 0.4

Magnesium stearate 0.82 total 100

As you may also note from Figure-4 that, dissolutions of the tablet formulation with Avicel RC-591 in first 5, 15 and 30 minutes are 87%, 94% and 94% respectively, while the other tablet formulation's dissolution values are respectively 27%, 48% and 58% for the same medium.

Claims

1. A pharmaceutical composition attained through dry compression, for oral administration of cefpodoxime proxetil or cefditoren pivoxil, characterized with the usage of co-processed cellulose in the formulation with other excipients, wherein the co-processed cellulose is present in an amount of 30 or greater weight percent based on the weight of the drug.

2. The pharmaceutical composition according to claim 1 wherein the co-processed cellulose is preferably the market product Avicel^®RC-591 and/or Avicel^®CL-611.

3. The pharmaceutical composition according to any one of the claims 1 to 2 wherein the oral dosage form is tablet.

4. The pharmaceutical composition according to claim 3 wherein the tablet is a film coated tablet.

5. The pharmaceutical composition according to any one of the claims 1 to 4 wherein the formulation also contains, but not limiting with other excipients like filler, binder, glidiant, lubricant and surfactant.

6. The pharmaceutical composition according to claim 5 wherein the binder is preferably Hydroxypropyl cellulose (HPC-L).

7. The pharmaceutical composition according to claim 5 wherein the glidiant is preferably colloidal Silicon dioxide.

8. The pharmaceutical composition according to claim 7 wherein the colloidal silicon dioxide is preferably Aerosil 200.

9. The pharmaceutical composition according to claim 5 wherein the lubricant is preferably Magnesium stearate.

10. The pharmaceutical composition according to claim 5 wherein the surfactant is Sodium lauryl sulphate.

11. A pharmaceutical composition attained through dry compression, for oral administration of cefpodoxime proxetil or ceftidoren pivoxil, characterized in that, dissolution of the composition is 90% in pH:3 at the end of 15 minutes.

12. A pharmaceutical composition attained through dry compression, for oral administration of cefpodoxime proxetil or ceftidoren pivoxil, characterized in that, dissolution of the composition is 98% in pH:3 at the end of 30 minutes.