Field of the Invention
The present invention relates to an extended-release composition of cefuroxime axetil and a process for its preparation.
Background of the Invention
Cefuroxime axetil is a 1-acetoxyethyl ester of cefuroxime. It is a second generation cephalosporin antibiotic with a broad spectrum of activity against gram-positive and gram-negative microorganisms. Cefuroxime axetil as well as its esters are disclosed and claimed in U.S. Pat. No. 4,267,320.
Cefuroxime axetil is known to have poor bioavailability because of its poor aqueous solubility. Further, it is also known that cefuroxime axetil has a tendency to form a gelatinous mass when contacted with aqueous media. These factors results in slow and erratic dissolution from the pharmaceutical compositions which lead to poor bioavailability. Furthermore, cefuroxime axetil is susceptible to degradation in the presence of moisture and alkaline pH.
Extended-release compositions of cefuroxime axetil remain highly desirable as they maintain therapeutic plasma concentration of the antibiotic over a prolonged period of time thereby contributing to better therapeutic action. Further, reducing the dosage administration frequency leads to enhanced patient compliance.
The prior arts disclose extended-release compositions of cefuroxime axetil with improved dissolution and bioavailability.
PCT Publication No. WO 2004/019901 discloses a sustained release pharmaceutical composition of a beta-lactam antibiotic such as cefuroxime axetil comprising a water soluble N-vinyl-2- pyrrolidone/vinyl acetate copolymer, a polysaccharide, a release enhancer, and other pharmaceutically acceptable excipients.
PCT Publication No. WO 2005/067895 discloses a controlled release composition of cefuroxime axetil consisting of cefuroxime axetil, a water soluble hydrophilic agent, and optionally of a rate controlling polymer.
PCT Publication No. WO 2002036126A1 discloses a fast disintegrating controlled release oral composition comprising a core material containing cefuroxime axetil present as controlled release form, the cefuroxime axetil being provided with an outer coating of a copolymer selected from aqueous dispersions of enteric methacrylic acid and methacrylic acid esters anionic copolymers having carboxyl group as the functional group or mixtures thereof and an inner coating of a sustained-release copolymer selected from aqueous dispersions of acrylate and methacrylate pH independent copolymers having quaternary ammonium group as a functional group or mixtures thereof.
There exists a need in the art to formulate alternate extended-release compositions of cefuroxime axetil which are simple, easy to manufacture, and cost effective.
The present invention provides an extended-release composition of cefuroxime axetil which maintains the plasma level above Minimum Inhibitory Concentration (MIC) over a prolonged period of time. The extended-release composition is provided with a once daily dosage regimen which is simple and convenient to use.
It is a further object of the present invention to provide an extended release composition comprising cefuroxime axetil that provides desired serum levels that would continuously exceed the MIC and thus would be more efficacious than the corresponding immediate release formulations.

Summary of the Invention
The present invention relates to an extended-release composition of cefuroxime axetil comprising cefuroxime axetil and one or more of a matrix forming agent, a pore former, and a superdisintegrant. It also relates to a process for its preparation.
The present invention provides an extended-release composition of cefuroxime axetil with minimal gel formation and improved dissolution leading to enhanced bioavailability. Further, the extended-release composition is suitable for once daily dosing which overcomes the problem of multiple administrations and thereby shall provide enhanced patient compliance.

Detailed Description of the Invention
A first aspect of the present invention provides an extended-release pharmaceutical composition comprising cefuroxime axetil, that exhibits the following dissolution profile when tested in a USP type 2 apparatus (paddle) using pH 3 glycine buffer as dissolution medium and using 10 mesh sinker: not more than 50% drug is released after 1 hour; at least 40% of the drug is released after 8-12 hours; atleast 75% of the drug is released after 12-24 hours.
According to one embodiment of this aspect, the dissolution is carried out in 2000ml of dissolution medium using paddle at 150 rpm.
According to another embodiment of this aspect, dissolution is carried out in 1000ml of dissolution medium using paddle at 75 rpm.
According to another embodiment of this aspect, the pharmaceutical composition provides: not more than 50%, preferably not more than 40%, more preferably not more than 30% of the drug is released after 1 hour; about 40%-70% of the drug is released after 8-12 hours; atleast 75% of the drug is released after 12-24 hours, wherein the dissolution is carried out in 2000ml of dissolution medium using paddle at 150 rpm.
According to another embodiment of this aspect, the pharmaceutical composition provides: not more than 50% drug is released after 0.5 hour; at least 40% of the drug is released after 8-12 hours; atleast 75% of the drug is released after 12-24 hours, wherein the dissolution is carried out in 1000ml of dissolution medium using paddle at 75 rpm.
According to one embodiment of the above aspects, the composition is administered once daily.
According to another embodiment of the above aspects, cefuroxime axetil is present in the composition in an amount of not less than 35% by weight, preferably not less than 45% by weight, preferably not less than 55% by weight, more preferably not less than 65% by weight based on the total weight of the composition.
According to another embodiment of the above aspects, the composition comprises a matrix forming agent.
According to another embodiment of the above aspects, the composition further comprises a superdisintegrant.
According to another embodiment of the above aspects, the composition further comprises a pore former.
According to another embodiment of the above aspects, the composition comprises one or more of a matrix forming agent, a superdisintegrant, and a pore former.
According to another embodiment of the above aspects, the composition comprises a matrix forming agent, a superdisintegrant, and a pore former.
According to another embodiment of the above aspects, the matrix forming agent is selected from the group comprising hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, carbomer homopolymer, carrageenan, polyethylene oxide, mixture of PVA and PVP (Kollidone SR), sodium carboxymethyl cellulose, and mixtures thereof.
According to another embodiment of the above aspects, the matrix forming agent is a pH dependent polymer.
According to another embodiment of the above aspects, the superdisintegrant is selected from the group comprising crospovidone, sodium starch glycolate, crosslinked crosscarmellose sodium, and mixtures thereof.
According to another embodiment of the above aspects, the pore former is selected from the group comprising mannitol, lactose, sucrose, pullulan, sodium chloride, polyvinylpyrollidone, hypromellose, polyethylene glycol, polyvinyl alcohol, dextran, and mixtures thereof.
According to another embodiment of the above aspects, the composition further comprises silicon dioxide.
According to another embodiment of the above aspects, the composition further comprises a wetting agent.
According to another embodiment of the above aspects, the composition further comprises an organic acid.
According to another embodiment of the above aspects, silicon dioxide is present in an amount from about 1 weight percent to about 15 weight percent of the composition, preferably from about 2 weight percent to about 6 weight percent of the composition.
According to another embodiment of the above aspects, cefuroxime axetil and silicon dioxide are present in a weight ratio of about 1:0.09 to about 1:0.02.
According to another embodiment of the above aspects, the composition further comprises one or more pharmaceutically acceptable excipient selected from fillers, binders, disintegrants, lubricants, glidants, anti-adherents, coloring agents, flavoring agents, and mixtures thereof.
According to another embodiment of the above aspects, the composition is present in the form of tablets, granules, powder, capsules or pellets.
According to another embodiment of the above aspects, the composition may optionally comprise a coating.
According to another embodiment of the above aspects, the composition upon oral administration provides lower Cmax compared to the Cmax of an immediate release composition having an equal amount of cefuroxime axetil.
According to another embodiment of the above aspects, the composition upon oral administration provides AUC comparable to the AUC of an immediate release composition having an equal amount of cefuroxime axetil.
According to another embodiment of the above aspects, upon oral administration, the composition provides a steady state plasma concentration over the treatment period.
According to another embodiment of the above aspects, upon oral administration, the composition provides T>MIC of 0.5 µg/ml for at least 40% of the dosing interval.
A second aspect of the present invention provides a process for the preparation of an extended-release pharmaceutical composition of cefuroxime axetil comprising:
(i) blending cefuroxime axetil and silicon dioxide with one or more pharmaceutically acceptable excipients;
(ii) optionally granulating the blend of step (i);
(iii) mixing one or more of matrix forming agent; pore former; and superdisintegrant with the blend of step (i) or granules of step (ii);
(iv) compressing the mixture of step (iii) to form a tablet; and
(v) optionally applying a coating composition comprising one or more film-forming polymers and coating additives on the tablet of step (iv).
A third aspect of the present invention provides a method of treating bacterial infections in a mammal comprising administering an extended release pharmaceutical composition comprising cefuroxime axetil suitable for once daily dosing, capable of maintaining T>MIC for atleast 40% of the dosing interval.
The term “extended-release” as used herein, refers to cefuroxime axetil release over a prolonged period of time than is ordinarily experienced after administration of a corresponding immediate-release cefuroxime axetil formulation. In particular, the term “extended-release” as used herein refers to the release of cefuroxime axetil over a period of 6, 8, 12, 16, or 24 hours.
The term “about” as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.
The term “cefuroxime axetil” as used herein, refers to ((RS)-1¬ hydroxyethyl (6R,7R)-7-[2-(2-furyl)glyoxyl-amido]-3-(hydroxymethyl)-8-oxo-5-thia-1¬ azabicyclo[4.2.0]-oct-2-ene-2-carboxylate, 72 -(Z)-(O-methyl-oxime), 1-acetate 3-carbamate. Cefuroxime axetil is present in the extended-release composition of the present invention in an amount of from about100mg to about 2000mg, preferably from about 200mg to about 1500mg, more preferably from about 500mg to about 1300mg. Cefuroxime axetil is present in the composition in an amount of not less than 35% by weight, preferably not less than 45% by weight, preferably not less than 55% by weight, more preferably not less than 65% by weight based on the total weight of the composition.
The term “bioavailability,” as used herein, refers to the fraction of a drug that reaches systemic circulation after oral administration. Parameters used in the measurement of bioavailability are Cmax (maximum plasma concentration), AUC0-t (area under the curve), and Tmax (time to reach maximum plasma concentration), which are well known in the art.
The term “Cmax” as used herein, refers to maximum plasma concentration of cefuroxime produced by the oral administration of the composition of the invention or the immediate release (IR) comparator.
The term “AUC0-24” as used herein, refers to area under the plasma concentration- time curve, over the complete dosing interval of 24 hours.
The term “T>MIC” as used herein, refers to time above MIC, where the minimum inhibitory plasma concentration is defined as 0.5 µg/ml of cefuroxime in plasma.
The term "matrix forming agent", as used herein, refers to the pharmaceutical agents which impart structural integrity and provide mechanical strength to the dosage form, among other functions. Preferred examples of matrix forming agents include, but are not limited to, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxypropyl cellulose, carbomer homopolymer, sodium carboxymethyl cellulose, carrageenan, and mixtures thereof. Preferably the matrix forming agents having viscosity in the range of 80-21000cps calculated by manufacturer recommended procedure are preferred. Further, pH dependent polymers such as acrylic acid derivatives, poly methacrylic acid derivatives (available under the trade name Eudragit), cellulose derivatives, maleic acid copolymers, polyvinyl derivatives etc. may act as matrix forming agent in the present invention. Certain matrix forming agents may also act as pore formers. The percentage of matrix forming agent in the extended-release composition of the present invention ranges from about 1% to about80%, preferably from about 5% to about 60%, more preferably from about 10% to about 40% by weight based on the total weight of the composition.
The term “superdisintegrant” as used herein, refers to pharmaceutical agents which are capable of absorbing water, resulting in physical swelling and expansion. Generally, the formulation containing superdisintegrants swell in presence of gastric fluid, and hence create high pressure within the tablet matrix, which favors for faster disintegration of tablets. However, according to the present invention, the role of superdisintegrant is to absorb high quantity of gastric fluids and hence offer aqueous environment for the matrix system. Preferred examples of superdisintegrant include, but are not limited to crospovidone, sodium starch glycolate, crosslinked crosscarmellose sodium, and mixtures thereof. The percentage of superdisintegrant in the extended-release composition of the present invention ranges from about 0 to about 50%, preferably from about 1% to about 40%, more preferably from about 2% to about 30%, most preferably from about 5% to about 20% by weight based on the total weight of the composition.
The composition of the present invention may further comprise a pore former that enhance the drug release by forming channels within the composition. Preferred examples of pore former include, but are not limited to mannitol, lactose, sucrose, pullulan, sodium chloride, polyvinylpyrrolidone, hypromellose, polyethylene glycol, polyvinyl alcohol, dextran, and mixtures thereof. The percentage of pore former in the extended-release composition of the present invention ranges from about from about 0 to about 40%, preferably from about 1% to about 20%, more preferably from about 2% to about 15% by weight based on the total weight of the composition.
The combination of superdisintegrant and matrix forming agent and pore former, when present in the composition offer different mechanisms such as swelling and matrix forming to control the release of the active ingredient from the composition. Preferably, the matrix forming agent, superdisintegrant and pore former are present in the extragranular portion in the composition. The superdisintegrant or the pore former is present in the composition in a weight ratio of 0.01 to 1.0, preferably 0.1 to 1.0 by weight relative to the weight of the matrix forming agent. The superdisintegrant and the pore former are present in the composition in a weight ratio of 0.5 to 1.0 and 0.4 to 0.75 respectively by weight relative to the weight of the matrix forming agent.
The composition of the present invention may further comprise silicon dioxide, a wetting agent an organic acid.
The term “silicon dioxide” as used herein, refers to a chemical compound which is an oxide of silicon. Silicon dioxide prevents the gel formation of cefuroxime axetil as particles of silicon dioxide get evenly distributed between the particles of cefuroxime axetil, thereby reducing the electric charge and minimizing the attractive forces responsible for gelation. Additionally, silicon dioxide creates an acidic microenvironment around cefuroxime axetil particles, thereby preventing the degradation. Silicon oxide includes both hydrous and anhydrous forms of silicon dioxide. Silicon dioxide can be selected from various available forms such as colloidal silicon dioxide (Aerosil®), fumed silica, precipitated silica, light anhydrous silicic acid, silicic anhydride, and mixtures thereof. In the present invention, silicon dioxide may be present in the intragranular portion or in the extragranular portion. The percentage of silicon dioxide used in the extended-release composition of the present invention ranges from about 1% to about 15%, more specifically about 2% to about 6% by weight based on the total weight of the composition. Further, cefuroxime axetil and silicon dioxide are present in a weight ratio of about 1:0.09 to about 1:0.02.
The “wetting agent” improves solubility of the drug. Preferred examples of wetting agent include, but are not limited to, anionic surfactants such as sodium alkyl sulphates, sodium laurate, dioctyl sodium sulphosuccinate, sodium stearate, potassium stearate and sodium oleate; cationic surfactants such as benzalkonium chloride and bis-2-hydroxyethyl oleylamine, and non-ionic surfactants such as polyethylene glycol and polyoxyethylene esters such as those sold under the registered trademark Tween. Preferably, the wetting agent is sodium lauryl sulfate.
The term “organic acid” as used herein, refers to a pharmaceutically acceptable organic compound which has acidic properties. The organic acid creates an acidic microenvironment around cefuroxime axetil particles. This acidic environment helps to prevent the degradation and improves the dissolution. Examples of organic acids include, but not limited to, fumaric acid, citric acid, tartaric acid, oxalic acid, malic acid, succinic acid, ascorbic acid, pyruvic acid, malonic acid, glutaric acid, adipic acid, gluconic acid, lactic acid, or mixtures thereof.
The term “composition” as used herein, includes any conventional dosage forms such as tablets, granules, powder, capsules or pellets, in particular tablets.
The term “pharmaceutically acceptable excipients” as used herein, refers to excipients that are routinely used in the pharmaceutical compositions. The pharmaceutically acceptable excipients may be selected from the group comprising fillers, binders, disintegrants, lubricants, glidants, anti-adherents, coloring agents, flavoring agents, or combinations thereof.
Examples of fillers or diluents include, but not limited to, lactose, sorbitol, calcium dihydrogen phosphate dihydrates, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, starch, pregelatinized starch, and mixtures thereof.
Examples of binders include, but not limited to, corn starch, pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose (e.g., Prosolv.TM. HD 90), methyl cellulose, hydroxypropyl cellulose (HPC-L), methylcellulose, carboxymethyl cellulose sodium, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and mixtures thereof.
Examples of disintegrants include, but not limited to, cross-linked polyvinyl pyrrolidone, corn starch, and modified starches, agar-agar, calcium carbonate, sodium carbonate, alginic acids, cross- carmellose sodium, sodium starch glycolate, microcrystalline cellulose, hydroxypropyl cellulose, (L-HPC) and mixtures thereof.
Examples of anti-adherents include, but not limited to, magnesium stearate, talc, calcium stearate, glyceryl behenate, stearic acid, and mixtures thereof.
Examples of lubricants and glidants include, but not limited to, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, microcrystalline wax, yellow beeswax, white beeswax, and mixtures thereof.
The coloring agents and flavoring agents of the present invention may be selected
from any FDA approved colors or flavors for oral use.
The extended-release compositions of the present invention can be prepared by any method known in the art such as blending, dry granulation, wet granulation, melt granulation, direct compression, or extrusion-spheronization.
The composition of the present invention may be coated with one or more non-functional coating layers. The non-functional coating layer comprises one or more film-forming polymers and coating additives. Pharmaceutically acceptable coating additives may be plasticizers, opacifiers, coloring agents, polishing agents, and mixtures thereof.
Suitable film-forming polymers are selected from the group comprising cellulose or its derivatives e.g., hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, cellulose acetate, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, and cellulose acetate trimellitate; polyethylene glycol; methacrylic acid polymers e.g., Eudragit®; and polyvinyl pyrrolidone. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used.
Examples of plasticizers include propylene glycol, triethyl citrate, tributyl citrate, dibutyl sebacate, acetyl tributyl citrate, glyceryl monostearate, triacetin, polyethylene glycol, diethyl phthalate, acetylated monoglycerides, diacetylated monoglycerides, cetyl alcohol, and mixtures thereof.
Examples of opacifiers include titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, and mixtures thereof.
The coating may be carried out by using any conventional coating techniques known in the art, such as spray coating in a conventional coating pan or fluidized bed processor, or dip coating.
The extended release cefuroxime axetil composition of the present invention exhibits the following dissolution profile when tested in a USP type 2 apparatus at 150 rpm in 2000ml of pH 3 glycine buffer using 10 mesh sinker: not more than 50%, preferably not more than 40%, more preferably not more than 30% of the drug is released after 1 hour; about 40% - 70% of the drug is released after 8-12 hours; atleast 75% of the drug is released after 12-24 hours.
The extended release cefuroxime axetil composition of the present invention exhibits the following dissolution profile when tested in a USP type 2 apparatus at 75 rpm in 1000ml of pH 3 glycine buffer using 10 mesh sinker: not more than 50%, preferably not more than 40%, more preferably not more than 30% of the drug is released after 1 hour; about 40% - 70% of the drug is released after 8-12 hours; atleast 75% of the drug is released after 12-24 hours.
Major parameters used to qualify the effect of anti-microbial drugs are MIC and time over MIC. It has been reported that (Craig W A, Diagn. Microbiol. Infect. Dis., 25, 213, 1996) for lactam antibiotics that bacteriologic efficacy of 90-100% is achieved when T>MIC is 40-50 % of dosing interval or higher. In some cases the T>MIC of as low as 30 % is also effective. There is a direct correlation between the time above MIC and antimicrobial potency. The composition of the present invention provides controlled delivery of drug to maintain the blood concentration above MIC for prolonged period sufficient to achieve T> MIC for atleast 40% of dosing interval and hence would lead to the desired clinical effect. There is no correlation between AUC values and the drug's efficacy. When compared with the conventional immediate release formulation, the bioavailability (AUC) of the extended release composition of the present invention is found to be comparable and Cmax is found to be lower.
The following examples represent various embodiments according to 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
Ingredients Quantity ( Percent (%) w/w)
Example 1 2 3 4 5 6 7 8
Intragranular
Cefuroxime Axetil 67.36 67.36 67.36 67.36 67.36 67.36 67.36 67.36
Colloidal silicon dioxide 4.56 4.56 4.56 4.56 4.56 4.56 4.56 4.56
Microcrystalline cellulose 1.91 1.91 1.91 1.91 1.91 1.91 1.91 1.91
Sodium stearyl fumarate 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50
Extragranular
Crospovidone 4.43 5.52 5.74 7.22 7.22 7.86 4.43 6.10
Hydroxypropylmethyl cellulose K100LV 15.55 13.91 15.55 12.78 12.78 13.43 14.29 14.47
Mannitol 5.18 5.74 3.88 5.16 5.16 3.88 6.44 4.59
Sodium stearyl fumarate 0.5 0.50 0.50 0.50 0.50 0.50 0.50 0.50
Tablet weight 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00

Procedure:
1. Cefuroxime axetil, microcrystalline cellulose, colloidal silicon dioxide, and sodium stearyl fumarate were sifted and blended.
2. The blend of step 1 was compacted and milled to form granules.
3. Crospovidone, hydroxypropylmethyl cellulose, and mannitol were sifted and mixed.
4. The mixture of step 3 was blended with granules of step 2.
5. Sodium stearyl fumarate was sifted and blended with the mixture of step 4.
6. The mixture of step 5 was compressed into a tablet.

Dissolution Study
The dissolution was performed for tablets of Example 1-8 in 2000 mL of pH 3 glycine buffer at 150 rpm using USP type 2 apparatus using10 mesh sinker. Table 1 provides the dissolution profile of these tablets.
Table 1. Dissolution profile of Examples 1-8 at pH 3 glycine buffer/ 2000 mL at 150 rpm
Time % Drug release
1 2 3 4 5 6 7 8
1 Hrs 8 15 11 33 33 27 12 10
4 Hrs 21 28 20 47 42 31 24 22
8 Hrs 40 43 39 58 58 38 39 38
12 Hrs 56 59 56 71 71 53 54 52
16 Hrs 74 73 72 84 76 66 71 67
20 Hrs 90 88 91 96 94 89 88 86
24 Hrs 98 98 102 99 96 99 101 95

Example 9
Ingredients Quantity ( Percent (%) w/w)
Intragranular
Cefuroxime Axetil 64.88
Colloidal silicon dioxide 4.42
Microcrystalline cellulose 2.38
Sodium stearyl fumarate 0.32
Extragranular
Crospovidone 7.01
Hydroxypropylmethyl cellulose K100LV 12.41
Mannitol 5.34
Sodium stearyl fumarate 0.32
Film Coating
Opadry White 2.91
Tablet weight 100.00

Procedure:
1. Cefuroxime axetil, microcrystalline cellulose, colloidal silicon dioxide, and sodium stearyl fumarate were sifted and blended.
2. The blend of step 1 was compacted and milled to form granules.
3. Crospovidone, hydroxypropylmethyl cellulose, and mannitol were sifted and mixed.
4. The mixture of step 3 was blended with the granules of step 2.
5. Sodium stearyl fumarate was sifted and blended with the mix of step 4.
6. The mixture of step 5 was compressed into a tablet.
7. Opadry® was dispersed in purified water and stirred to form a dispersion.
8. The tablets of step 6 were coated with the dispersion of step 7.

Example 10
Ingredients Quantity ( Percent (%) w/w)
Intragranular
Cefuroxime Axetil 64.88
Colloidal silicon dioxide 4.42
Microcrystalline cellulose 2.38
Sodium stearyl fumarate 0.32
Extragranular
Crospovidone 4.31
Hydroxypropylmethyl cellulose K100LV CR 8.09
Hydroxypropylmethyl cellulose K4M CR 1.62
Mannitol 7.50
Fumaric acid 3.24
Sodium stearyl fumarate 0.32
Film Coating
Opadry White 2.91
Tablet weight 100.00
Procedure:
1. Cefuroxime axetil, microcrystalline cellulose, colloidal silicon dioxide, and sodium stearyl fumarate were sifted and blended.
2. The blend of step 1 was compacted and milled to form granules.
3. Crospovidone, hydroxypropylmethyl cellulose, mannitol, and fumaric acid were sifted and mixed.
4. The mixture of step 3 was blended with the granules of step 2.
5. Sodium stearyl fumarate was sifted and blended with the mixture of step 4.
6. The mixture of step 5 was compressed into tablets.
7. Opadry® was dispersed in purified water and stirred to form dispersion.
8. The tablets of step 6 were coated with the dispersion of step 7.

Example 11 and 12:
Ingredients Quantity ( Percent (%) w/w)
Example 11 Example 12
Intragranular
Cefuroxime Axetil 65.02 50.12
Colloidal silicon dioxide 4.43 1.84
Microcrystalline cellulose 2.39 3.42
Sodium stearyl fumarate 0.49 0.38
Extragranular
Crospovidone 7.57 15.17
Hydroxypropylmethyl cellulose 11.89 18.33
Mannitol 7.95 10.17
Sodium stearyl fumarate 0.27 0.58

Procedure:
The tablets of Example 11 and 12 are prepared by following the same procedure as for Example 10.

Dissolution Study
The dissolution was performed for tablets of Example 11 and 12 in 2000 mL of pH 3 glycine buffer at 150 rpm using USP type 2 apparatus using10 mesh sinker. Table 2 provides the dissolution profile of these tablets.

Table 2. Dissolution profile of Examples 11 and 12 at pH 3 glycine buffer/ 2000 mL at 150 rpm
Time % Drug release
Example 11 Example 12
1 Hrs 23 16
2 Hrs 30 24
4 Hrs 38 39
8 Hrs 48 68
12 Hrs 55 90
16 Hrs 70 103
20 Hrs - 104
24 Hrs 99 104

Pharmacokinetic Studies Under Fed conditions
The tablets of Example 11 (1000mg tablet taken in single oral dose) and Example 12 (Two 500mg tablets taken in single oral dose) were compared with the reference product administered 12 hourly (500mg BID) under fed condition in healthy adult human subjects.The value of T>MIC was observed and is provided in Table 3.
Reference (R): Zinnat®(cefuroxime axetil) 500 mg tablets
Test (T1): Cefuroxime axetil 1000 mg ER tablet (Example 11)
Test (T2): Cefuroxime axetil 500 mg ER tablet (Example 12)

Table 3. Values for T>MIC
Reference Example 11 Example 12
15.00 14.37 12.91
As is evident from the above data in Table 3, the test products provide T>MIC for at least 40% of the dosing interval.

Example 13 - 16:
Ingredients Quantity ( Percent (%) w/w)
Example 13 Example 14 Example 15 Example 16
Intragranular
Cefuroxime Axetil 46.26 46.26 42.96 50.12
Colloidal silicon dioxide 3.15 3.15 2.93 3.42
Sodium lauryl sulphate 2.31 2.31 2.14 2.50
Croscarmellose sodium 3.85 3.85 3.57 4.17
Microcrystalline cellulose 5.97 5.97 5.54 6.46
Extragranular
Crospovidone 10.38 9.92 10.70 29.17
Hydroxypropylmethyl cellulose 20.36 23.07 25.58 3.67
Mannitol 7.26 5.02 6.07 0.50
Sodium stearyl fumarate 0.46 0.46 0.50 100.00

Procedure:
1. Cefuroxime axetil, colloidal silicon dioxide, sodium lauryl sulphate, croscarmellose sodium, and microcrystalline cellulose were sifted and blended.
2. The blend of step 1 was compacted and milled to form granules.
3. Crospovidone, hydroxypropylmethyl cellulose, and mannitol were sifted and mixed.
4. The mixture of step 3 was blended with granules of step 2.
5. Sodium stearyl fumarate was sifted and blended with the mixture of step 4.
6. The mixture of step 5 was compressed into a tablet.

Dissolution Study
The dissolution was performed for tablets of Example 16 in 1000 mL of pH 3 glycine buffer at 75 rpm using USP type 2 apparatus using10 mesh sinker. Table 4 provides the dissolution profile of these tablets.

Table 4. Dissolution profile of Example 16 at pH 3 glycine buffer/ 1000 mL at 75 rpm
Time % Drug release
0.5 Hrs 26.6
1 Hrs 34.7
2 Hrs 41.9
4 Hrs 49.3
8 Hrs 58.9
12 Hrs 67.8
16 Hrs 69.4
20 Hrs 73.9
24 Hrs 78.2

Example 17 - 19:
Ingredients Quantity ( Percent (%) w/w)
Example 13 Example 14 Example 15
Intragranular
Cefuroxime Axetil 42.96 54.68 48.11
Colloidal silicon dioxide 3.00 3.82 3.36
Microcrystalline cellulose 1.47 1.94 1.68
Eudragit S100 42.96 27.34 36.09
Sodium lauryl sulphate 2.14 2.73 2.40
sodium stearyl fumarate 0.32 0.41 0.36
Extragranular
Crospovidone 6.64 8.55 7.44
Sodium stearyl fumarate 0.50 0.55 0.56

Procedure:
1. Cefuroxime axetil, colloidal silicon dioxide, microcrystalline cellulose, Eudragit S100, sodium lauryl sulphate, and sodium stearyl fumarate were sifted and blended.
2. The blend of step 1 was compacted and milled to form granules.
3. Crospovidone was sifted and blended with granules of step 2.
4. Sodium stearyl fumarate was sifted and blended with the mixture of step 3.
5. The mixture of step 4 was compressed into a tablet.

WE CLAIM:

1. An extended-release pharmaceutical composition comprising cefuroxime axetil, that exhibits the following dissolution profile when tested in a USP type 2 apparatus (paddle) using pH 3 glycine buffer as dissolution medium and using 10 mesh sinker: not more than 50% drug is released after 1 hour; at least 40% of the drug is released after 8-12 hours; atleast 75% of the drug is released after 12-24 hours.

2. The pharmaceutical composition according to claim 1, wherein the dissolution is carried out in 2000ml of dissolution medium using paddle at 150 rpm.

3. The pharmaceutical composition according to claim 1, wherein the dissolution is carried out in 1000ml of dissolution medium using paddle at 75 rpm.

4. The pharmaceutical composition according to claim 2, wherein the composition exhibits following dissolution profile: not more than 40%, preferably not more than 30% of the drug is released after 1 hour wherein the dissolution is carried out in 2000ml of dissolution medium using paddle at 150 rpm.

5. The pharmaceutical composition according to Claim 1, wherein the composition is administered once daily.

6. The pharmaceutical composition according to Claim 1, wherein cefuroxime axetil is present in the composition in an amount of not less than 35% by weight, preferably not less than 45% by weight, preferably not less than 55% by weight, more preferably not less than 65% by weight based on the total weight of the composition.

7. The pharmaceutical composition according to Claim 1, wherein the composition comprises one or more of a matrix forming agent, superdisintegrant, and a pore former.

8. The pharmaceutical composition according to Claim 7, wherein the composition further comprises one or more of silicon dioxide, a wetting agent and an organic acid.

9. The pharmaceutical composition according to claim 7 or 8, wherein the composition further comprises one or more pharmaceutically acceptable excipient selected from fillers, binders, disintegrants, lubricants, glidants, anti-adherents, coloring agents, flavoring agents, and mixtures thereof.

10. The pharmaceutical composition according to claim 1, wherein the composition upon oral administration provides T>MIC for at least 40% of the dosing interval.