TECHNICAL FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising micronized particles of cefditoren pivoxil and processes thereof. The present invention also provides the process of preparing micronized particles of cefditoren
pivoxil.
BACKGROUND OF THE INVENTION
Cefditoren is an orally deliverable third generation cephalosporin antibiotic. Chemically it is represented as-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(4-methylthiazol- -5-yl)vinyl]-3-cephem-4-carboxylic acid (syn-isomer, cis-isomer). Cefditoren synthesis is disclosed in U.S. Pat. Nos. 4,839,350 and 4,918,068.
Cefditoren pivoxil is a prodrug of Cefditoren, which is synthesized by esterification of 2-carboxyl group of Cefditoren with pivaloyloxymethyl (pivoxil) group. It exhibits improved oral absorption and is quickly hydrolyzed to cefditoren by enzymatic esterases upon absorption. Cefditoren has a low toxicity to mammals but exhibits a very broad antibacterial spectrum against gram-positive and gram-negative bacteria. It is indicated for the treatment of acute bacterial exacerbation of chronic bronchitis, community-acquired pneumonia, pharyngitis/tonsillitis and uncomplicated skin and skin-structure infections.
Pharmaceutical formulation currently approved for the administration of cefditoren is cefditoren pivoxil tablet, commercially available under the trade name SPECTRACEF®. These tablets are being marketed by Meiji Seika Kaisha, Japan and are covered by a patent, US 5,958,915. This patent describes a composition of cefditoren pivoxil with a water-soluble casein salt. Addition of casein salt enhances the solubility and minimizes the bitterness of the drug. However, this preparation has a disadvantage that it could not be administered to a patient suffering from lactose intolerance syndrome since casein is a protein derived from milk.
Marketed formulation contains amorphous form of cefditoren pivoxil. Amorphous formulation provides enhanced solubility and bioavailability characteristics. Further, PCT application W02006/100574 filed by Ranbaxy Laboratories Limited relates to amorphous cefditoren pivoxil granules having improved solubility, absorption and wetting characteristics.
Though having a higher solubility amorphous form has certain disadvantages that overweigh the enhanced solubility effect. For example amorphous form is thermodynamically unstable and therefore shows some tendency to crystallize spontaneously. In addition, it is found that most of amorphous materials are very fine and fluffy, with relatively low bulk and tap density. This property makes it difficult to formulate them into a dosage form having uniform weight, hardness and other desirable tablet properties.
Various approaches have been tried in the prior art to obtain compositions of cefditoren pivoxil having improved solubility as well as stability. One such approach includes the preparation of crystallographically stable, co precipitated composition comprising mixtures of amorphous cefditoren with a water-soluble high molecular additive as described in US granted patent nos. 6,342,493 and 6,486,149. Water-soluble high-molecular additive include pharmaceutically acceptable, water-solubilized derivative of cellulose or pluran, carrageenan, polyvinylpyrrolidone or an alginic acid ester of polypropylene glycol. The water-soluble high-molecular additive co-existent in admixture with the Cefditoren pivoxil in the solid particles possesses a function capable of inhibiting the molecules of Cefditoren pivoxil from undergoing their crystallization. Therefore these particles are crystallographically stable and maintain their amorphous state even after storage for a long period of time.
Another approach tried in the prior art includes the conversion of amorphous form into the more stable crystalline form. A patent issued to Meiji Seika Kaisha Ltd. US 6,294,669 describes the crystalline form of cefditoren pivoxil and process for preparing the same. Though having high purity, high heat stability and in addition satisfactory stability even when stored under high humidity conditions crystalline cefditoren pivoxil suffers from the disadvantage of low solubility.
Therefore in the light of foregoing there exists a need for a pharmaceutical composition having appreciable solubility and stability characteristics, without using a high molecular weight additive. Therefore there is a need for a pharmaceutical composition comprising highly stable crystalline form of cefditoren pivoxil and still having solubility and dissolution characteristics comparable to or better than that of the amorphous form.
The present inventors have found that by micronizing cefditoren pivoxil its solubility characteristics are remarkably improved and as a result, a pharmaceutical composition having an improved dissolution profile can be obtained.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising micronized cefditoren pivoxil and processes thereof. It is also directed to the process for the preparation of micronized cefditoren pivoxil.
One of the aspects of the present invention provides the pharmaceutical composition comprising micronized particles of cefditoren pivoxil having d0.5 between 1 urn to 40
urn.
According to another embodiment the present invention relates to pharmaceutical composition comprising micronized particles of cefditoren pivoxil having do.5 between 2 µm to 20 urn.
According to still another embodiment the present invention relates to pharmaceutical composition comprising micronized particles of cefditoren pivoxil having d0.5 between 2 µm to 20 urn and do 9 between 5 µm to 40 urn.
In still another embodiment the pharmaceutical composition according to the present invention is in the form of a tablet, dispersible tablet, capsule, granule, pellet, bead, powder, suspension, elixir or syrup. More particularly the composition of the present invention is in the form of a tablet.
According to yet another embodiment pharmaceutical composition of the present invention further comprises one or more pharmaceutically acceptable excipients selected from the group comprising diluents, binders, wetting agents, disintegrants, lubricants, coloring agents or flavoring agents.
According to still another embodiment the pharmaceutical composition of the present invention comprises micronized cefditoren pivoxil in an amount of 2 % to 80 % by weight of the composition.
Another aspect of the present invention provides micronized particles of cefditoren pivoxil having d0.5 between 1 urn to 40 µrn.
Another embodiment of the present invention relates to micronized particles of cefditoren pivoxil having d0.5 between 2 µm to 20 µrn.
Still another embodiment of the present invention relates to micronized particles of cefditoren pivoxil having d0.5 between 2 µm to 20 µm and d0. 9 between 5 µm to 40
µm.
Another aspect of the present invention relates to a process of preparing micronized particles of cefditoren pivoxil wherein the said process is selected from the group comprising conventional comminution techniques and solution based phase separation techniques.
According to one of the embodiments the comminution technique comprises grinding or milling in an air-jet mill or impact mill, a ball mill, a vibration mill, mortar mill or pen mill. Particularly the micronized particles of cefditoren pivoxil of the present invention are prepared by milling in an air-jet mill or impact mill.
According to another embodiment solution based phase separation technique comprises lyophilization, supercritical antisolvent (SAS) precipitation process, precipitation by rapid expansion from supercritical solutions (RESS), rapid expansion from super critical to aqueous solution (RESAS), spray drying or a combination of two or more processes.
According to yet another aspect pharmaceutical composition comprising micronized particles of cefditoren pivoxil is prepared by blending cefditoren pivoxil with one or more pharmaceutically acceptable excipients. Further blend is either directly compressed or formulated into granules using wet or dry granulation techniques. Particularly the composition of the present invention is prepared using wet granulation technique.
In another aspect there is provided a method of treating acute bacterial exacerbation of chronic bronchitis, community-acquired pneumonia and pharyngitis/tonsillitis by administering to a person in need thereof a pharmaceutical composition of the present invention.
According to yet another aspect composition of the present invention can also be administered in combination with other antibacterial agents, for the prophylaxis or therapy of diseases induced by gram-positive bacteria or gram-negative bacteria.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel pharmaceutical composition comprising micronized cefditoren pivoxil and processes thereof. It also relates to the process of preparation of micronized cefditoren pivoxil.
The term "cefditoren pivoxil" as used herein includes crystalline cefditoren pivoxil. In the compositions of the present invention cefditoren pivoxil may be utilized in an amount ranging from 2 to 80% (w/w) based on the total weight of the pharmaceutical composition.
As used herein, the phrase "micronized cefditoren pivoxil" means particles of cefditoren pivoxil having d0.5 between 1µm to 40 µm, particularly between 2 µm to 20 urn. Particularly it relates to cefditoren pivoxil particles having d0.5 between 2 µm to 20 µm and do 9 between 5 µm to 40 µm.
The term "d0.5" as used herein with reference to the size of micronized cefditoren pivoxil particles, indicates that about 50 volume % of particles measured have a size less than the defined d0.5 value and that about 50 volume % of particles measured have a size greater than the defined d0.5 value. The term "d0.9" as used herein indicates that about 90 volume % of particles measured have a size less than the defined d0.9 value and that about 10 volume % of particles measured have a size greater than the defined d0 .9 value.
The phrase "therapeutically effective amount'' as used herein means the dosage that is sufficient to provide the specific pharmacological response for which the cefditoren pivoxil is being administered. The "therapeutically effective amount" will vary depending on the severity of the disease, age, weight, physical condition and the responsiveness of the subject.
The process of micronizing cefditoren pivoxil according to the present invention may comprise either solution based phase separation techniques or conventional comminution techniques.
Solution based phase separation techniques for preparing micronized cefditoren pivoxil particles include lyophilization, supercritical antisolvent (SAS) precipitation process, precipitation by rapid expansion from supercritical solutions (RESS), rapid expansion from super critical to aqueous solution (RESAS), spray drying or a combination of two or more processes.
Conventional comminution technique for preparing micronized cefditoren pivoxil particles include grinding or milling in an air-jet mill or impact mill, a ball mill, a vibration mill, mortar mill or pen mill. Particularly an air jet mill or micronizer is used in the present invention due to its ability to produce particles of small size in a narrow size distribution.
Micronization of cefditoren pivoxil of the present invention is carried out in an accelerated air-jet mill wherein collision of drug particles with each other under a high-pressure stream of air causes reduction of particle size and increases the specific surface area of the material, manifolds. The period of milling varies
depending on the size of the mill, the velocity of the air, the type of feed material and the quantity of feed material.
The particle size distribution of cefditoren pivoxil particles of the present invention may be determined using optical microscopic method, sedimentation techniques for example pipette analysis using an Andreassen pipette, sedimentation scale, photosedimentometer or sedimentation in a centrifugal force field, pulse methods, for example using a Coulter counter, or sorting by means of gravitational or centrifugal force, sieve analysis, laser diffraction or ultrasound attenuation spectroscopy. The particle size distribution of cefditoren pivoxil particles of the present invention is particularly determined by Laser diffraction using a Malvern® Mastersizer laser diffraction instrument.
The present invention further provides pharmaceutical composition comprising micronized cefditoren pivoxil, wherein the said composition may be in the form of tablets, dispersible tablets, capsules, granules, beads, pellets, powder, suspension, emulsion, syrups or elixirs. The composition of the present invention can also be formulated for parenteral (e.g., intravenous, intramuscular, or subcutaneous), nasal, rectal, ocular, local (e.g., in powder, ointment, or drop form), intracisternal, intraperitoneal or topical administration. Particularly the compositions of the present invention are formulated into tablets, capsules or dispersible tablets.
The pharmaceutical composition comprising micronized cefditoren pivoxil may further comprise one or more pharmaceutically acceptable excipients selected from a group comprising but not limited to diluents, binders, wetting agents, disintegrants, lubricants, coloring agents flavoring agents or any other excipients known in the art.
Suitable examples of diluents include, but are not limited to, corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, starch, pregelatinized starch or mixtures thereof.
Suitable examples of binders include, but are not limited to polyvinylpyrrolidone, starch mucilage, pregelatinized starch, sodium alginate, alginic acid, acacia mucilage, tragacanth, hydroxypropylmethyl cellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, microcrystalline cellulose, ethyl cellulose, polyethylene glycol, hydroxyethyl cellulose, hydroxy propyl cellulose, methyl cellulose, polymethacrylates, carboxyvinyl polymers, carbopols, and combinations thereof.
Suitable examples of disintegrants include, but are not limited to, cross-linked polyvinylpyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose (crosscarmellose sodium), calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low-substituted hydroxypropyl cellulose and combinations thereof.
Surfactants/wetting agents include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical compositions. These include but are not limited to, polyethoxylated fatty acid esters, polyethylene glycol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, polyethylene glycol sorbitan fatty acid esters, sugar esters, polyoxyethylene-polyoxypropylene block copolymers, ionic surfactants, derivatives of fat soluble vitamins, and mixtures thereof. Suitable examples include sodium lauryl sulphate, sodium dodecyl sulphate, polyoxyethylene castor oil derivatives, for example, tweens, polyoxyethylene-polyoxypropylene block copolymers, for example, poloxamer, or mixtures thereof.
Examples of lubricants and glidants include, but are not limited to, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax or mixtures thereof.
Coloring agents and flavoring agents may be selected from any FDA approved colors and flavors for oral use.
The pharmaceutical composition of the present invention may be formulated in accordance with any of the conventional procedure known in the field of art, for example, milling, sieving, slugging, kneading, granulating, tabletting, coating, etc. These steps may be carried out in the conventional manner.
The pharmaceutical composition according to the present invention comprising micronized cefditoren pivoxil may be administered to treat bacterial infections in mammals. Bacteria referred to herein include, for example gram-positive bacteria, such as staphylococcus and streptococcus, gram-negative bacteria, such as Escherchia coli, Branhamella catarrhalis, Klebsiella, Proteus, and Haemophilus influenzae, and anaerobes such as Peptostreptococcus, Propionibacterium acnes, and Bacteriocides. Further, the composition according to the present invention is useful for the prophylaxis or therapy of diseases induced by gram-positive bacteria or gram-negative bacteria.
Further, pharmaceutical compositions described herein can also be administered in combination with other antibacterial agents, for the prophylaxis or therapy of diseases induced by gram-positive bacteria or gram-negative bacteria.
The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
EXAMPLE 1
Process of micronization of cefditoren pivoxil
Cefditoren pivoxil was micronized using an air-jet mill with compression air pressure of 6 PSIG to give a powder having d0.5 of 2.37pm and do 9 of 6pm.
EXAMPLE 2
Tablets comprising micronized cefditoren pivoxil

(Table Removed)
Process:
(i) Micronized cefditoren pivoxil, mannitol and intragranular croscarmellose sodium were sieved and blended together.
(ii) Hydroxy propyl cellulose was dissolved in purified water. (iii) Blend of step (i) was granulated using the binder solution of step (ii). (iv) Granules of step (iii) were dried in a fluidized bed dryer. (v) Dried granules of step (iv) were sieved.
(vi)Magnesium stearate and extragranular croscarmellose sodium were sieved and mixed with granules of step (v). (vii) Finally the blend of step (vi) was compressed into tablets.
EXAMPLE 3
Tablets comprising unmicronized cefditoren pivoxil were prepared with the ingredients similar to Example 2 using unmicronized cefditoren pivoxil (having do.5 more than 100um).
Comparison of in-vitro dissolution profile
The tablets of cefditoren pivoxil prepared as per the compositions of examples 2 & 3 were subjected to dissolution studies in 900 ml of 0.1N HCI at 37 °C using USP apparatus II with paddle speed at 50 rpm. Table 1 provides comparative dissolution profile of tablets comprising micronized (Example 2) and unmicronized cefditoren pivoxil (Example 3).
Table 1
(Table Removed)

WE CLAIM:
1. A pharmaceutical composition comprising micronized particles of cefditoren pivoxil having do.5 between 1 urn to 40 urn and one or more pharmaceutically acceptable excipients.
2. The pharmaceutical composition of claim 1 wherein said micronized particles of cefditoren pivoxil have do.5 between 2 urn to 20 urn and d0.9 between 5 urn to 40 urn.
3 The pharmaceutical composition according to claim 1 wherein cefditoren pivoxil is present in an amount of about 2% to about 80% by weight of the composition.
4. The pharmaceutical composition of claim 1 wherein said micronized particles of cefditoren pivoxil are prepared by a process selected from conventional comminution techniques or solution based phase separation techniques.
5. The pharmaceutical composition of claim 4 wherein said micronized particles of cefditoren pivoxil are prepared using an air-jet mill.
6. The pharmaceutical composition of claim 1 wherein said composition is in the form of a tablet dispersible tablet, capsule, granule, pellet, bead, powder, suspension, elixir or syrup.
7 The pharmaceutical composition of claim 1 wherein said one or more
pharmaceutically acceptable excipients are selected from a group comprising diluents, binders, wetting agents, disintegrants, lubricants, coloring agents or flavoring agents.
8. Cefditoren pivoxil particles having d0 .5 between 1 urn to 40 µm.
9. Cefditoren pivoxil particles according to claim 8 wherein said particles have d0 5 between 2 urn to 20 µm and d0.9 between 5 µm to 40 urn.
10. A pharmaceutical composition comprising therapeutically effective amount of micronized cefditoren pivoxil substantially as described and illustrated herein.