Claims:WE CLAIM:
1. A stable extended-release composition of cefpodoxime for once daily administration wherein the said composition is characterized by a combination of an organic acid and a silicon dioxide as stabilizer present in the composition in a weight ratio of 1:1 to 1:5 and characteristically gives an extended release of the drug providing the concentration of cefpodoxime more than minimum inhibitory concentration for a period of 40% to 60% duration of dosing interval, wherein the said composition the organic acid and silicon dioxide are present in an intragranular portion of the composition.
2. The stable extended-release composition of cefpodoxime as claimed in claim 1, wherein the composition has a characteristic in-vitro dissolution release profile as determined by USP type II apparatus at 100 r.p.m., in 900 mL of glycine buffer (pH 3) with 0.5% sodium lauryl sulfate at 37°C as follows:
- not more than 50% of cefpodoxime released at 1 hours,
- not more than 65% of cefpodoxime released at 4 hours,
- more than 75% of cefpodoxime released at 16 hours, and
wherein the composition provides a concentration of the drug in the blood above minimum inhibitory concentration for more than 40% of a dosing interval of 24 hours.
3. The stable extended-release composition of cefpodoxime as claimed in claim 1, wherein the cefpodoxime proxetil is present in an amount of ranging from 20% w/w to 50% w/w based on the total weight of the composition.
4. The stable extended-release composition of claim 1, wherein the pH of the composition is in a range of about 2 to about 4.
5. A stable extended-release composition of cefpodoxime, wherein the said composition is characterized by an extended-release of the cefpodoxime from the composition for maintaining a concentration above the minimum inhibitory concentration of the drug for 40% to 60% of the dosage interval, wherein the said composition comprises of cefpodoxime proxetil, stabilizer comprising of an organic acid and a silicon dioxide in a weight ratio of 1:1 to 1:5, wherein the stabilizer combination is present in an intragranular portion of the composition, and
a release controlling agent selected from hydroxypropylmethyl cellulose, methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, carboxy methylcellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate and polyvinyl acetate, wherein the composition has a pH in a range of 2 to 4.
6. The stable extended-release composition of cefpodoxime as claimed in claim 5, wherein the said composition the organic acid is fumaric acid and silicon dioxide is colloidal silica, and release controlling agent is hydroxypropylmethyl cellulose.
7. The stable extended-release composition of cefpodoxime as claimed in claim 6, wherein the said composition the organic acid is fumaric acid and silicon dioxide is colloidal silica, and release controlling agent is hydroxypropylmethyl cellulose selected from Hypromellose K4M and Hypromellose K100LVCR
8. The stable extended-release composition as claimed in claim 1 and 5, wherein the organic acid is selected from 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, and mixtures thereof.
9. The stable extended-release composition as claimed in claim 1 and 5, wherein the silicon dioxide is selected from colloidal silicon dioxide, fumed silica, precipitated silica, light anhydrous silicic acid, silicic anhydride, aluminum magnesium silicate, and mixtures thereof.
10. The stable extended-release composition as claimed in claim 1, wherein the release-controlling agent is selected from the group comprising cellulosic polymers selected from hydroxypropylmethyl cellulose, methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, carboxy methylcellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate butyrate, cellulose acetate, and cellulose acetate trimellitate; acrylic copolymers selected from methacrylic acid copolymers; polyvinyl alcohol; polyvinyl acetate; polyalkylene glycol selected from polyethylene glycol; triglycerides; waxes; lipids; fatty acids or their salts/derivatives; a mixture of polyvinyl acetate and polyvinyl pyrrolidone; and mixtures thereof.
11. The stable extended-release composition of the any of the preceding claims, wherein the composition further comprises one or more pharmaceutically acceptable excipients selected from the group comprising fillers, binders, glidants, disintegrants, lubricants, wetting agents, and combinations thereof.
12. The stable extended-release composition as claimed in claim 13, wherein the composition is a tablet.
13. The stable extended-release composition as claimed in claims 1, wherein the composition is administered once daily in bacterial infection patients and provides a concentration above minimum inhibitory concentration for 40% to 60% of duration of dosage interval.
14. The stable extended-release composition of cefpodoxime as claimed in claim 1 and 5, wherein the said composition on administration provides a concentration of the drug above minimum inhibitory concentration for at least 9.6 hours.
15. A process for the preparation of the extended-release composition of claim 1, wherein the process comprise:
(i) blending cefpodoxime proxetil, a silicon dioxide, an organic acid, and one or more pharmaceutically acceptable excipients;
(ii) optionally granulating the blend of step (i) to form the intragranular part;
(iii) mixing one or more release-controlling agents 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 onto the tablet of step (iv).
wherein in the said process the organic acid and silicon dioxide are blended in the composition in a ratio of 1:1 to 1:5 and are blended in the intragranular part of the composition.

desc:

EXTENDED RELEASE CEFPODOXIME PROXETIL COMPOSITION

SUN PHARMACEUTICAL INDUSTRIES LIMITED
Corporate Office: Sun House, CTS No. 201 B/1, Western Express highway, Goregaon (E), Mumbai-400063, Maharashtra, India.

The following specification particularly describes the invention and the manner in which it is to be performed.
Cross Reference
This present patent application is an invention comprising an improvement in or a modification of the invention claimed in the specification of the main patent applied for in Indian Patent application number 201717020265 dated June 09, 2017, which is a national phase application of PCT/IB2015/059254 dated Dec 01, 2015. The complete specification of the Indian Patent application number 201717020265 is incorporated herein by reference.
Field of the Invention
The present invention relates to an improved stable extended-release composition of cefpodoxime and a process for its preparation. The composition comprises cefpodoxime proxetil, a stabilizer, and a release-controlling agent, wherein the composition is characterized by having a pH of less than 4. The composition is suitable for once-daily dosing for effectively treating bacterial infections.
Background of the Invention
Cefpodoxime proxetil, a third generation cephalosporin antibiotic, is known to have poor bioavailability because of its hydrophobic nature and poor aqueous solubility. Further, it has been reported that cefpodoxime exhibits gel formation and forms a gelatinous mass when it is in contact with aqueous media. These factors result in slow and erratic dissolution from the pharmaceutical compositions which lead to poor bioavailability. Besides, cefpodoxime proxetil is susceptible to degradation in the presence of moisture, heat, and alkaline pH.
Cefpodoxime proxetil has been widely used for treatment of infections caused by gram positive and gram negative bacteria. It is available in the form of a tablet or granules for oral suspension with a twice daily dosage regimen.
The primary goal of an antibiotic dosage regimen is to maximize the time during which the microorganism is exposed to the drug, since the bactericidal activity correlates more to duration, when blood concentration is above minimum inhibitory concentration (MIC) than to magnitude of dose. Consequently, it is expected that the concentration of cefpodoxime above the MIC for 40% to 60% duration of dosage interval should achieve optimal clinical results.
Extended-release compositions of cefpodoxime proxetil 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 art discloses extended-release compositions of cefpodoxime proxetil with improved dissolution and bioavailability.
PCT Publication No. WO 2004/019901 discloses a sustained release pharmaceutical composition of a beta lactam antibiotic, such as cefpodoxime proxetil, a mixture of polymers comprising a water soluble N-vinyl-2-pyrrolidone/vinyl acetate copolymer and polysaccharide(s); a release enhancer(s); and other pharmaceutically acceptable excipients.
PCT Publication No. WO 2008/010784 discloses a controlled release nano-particulate composition of a cephalosporin, such as cefpodoxime proxetil, comprising particles of a cephalosporin with an effective average particle size of less than 2000 nm and at least one surface stabilizer.
There remains a need in the art to formulate alternate extended-release compositions of cefpodoxime proxetil which are simple, easy to manufacture, and cost effective.
The present invention provides an improved stable extended-release compositions of cefpodoxime proxetil which maintain the plasma level over a prolonged period of time. The extended-release compositions are provided with a once daily dosage regimen which is simple and convenient to use. Further, the extended-release compositions are provided with improved dissolution and reduced gel formation of cefpodoxime proxetil, leading to enhanced bioavailability and stability.
Summary of the Invention
The present invention relates to an improved stable extended-release composition of cefpodoxime comprising cefpodoxime proxetil, a stabilizer comprising a combination of an organic acid and a silicon dioxide present in the composition in a ratio of 1:1 to 1:5, and a release-controlling agent, wherein the composition is characterized by having a pH of less than about 4. It also relates to a process for preparation of an improved stable extended-release composition of cefpodoxime with characteristic release profile. Further, the extended-release composition is suitable for once daily dosing which effectively overcomes the problem of multiple administrations and thereby shall provide enhanced patient compliance.
Brief Description of the Drawing
Figure-1: Mean Plasma concentration time graph for Cefpodoxime 200 mg and 400 mg strength formulation of present invention.
Figure-2: Visual Observation Study to evaluate the formulation according to present invention with silicon dioxide and organic acid and comparison with formulation not having these components either individually or in combination in the intragranular portion.

Detailed Description of the Invention
A first aspect of the present invention provides an improved stable extended-release composition of cefpodoxime comprising cefpodoxime proxetil, a stabilizer comprising a combination of an organic acid and a silicon dioxide present in the composition in a ratio of 1:1 to 1:5, and a release-controlling agent, wherein the composition is characterized by having a pH of less than about 4.
In one of the embodiment of the above aspect, the pH of the composition is in a range of about 2 to about 4. In a more preferred embodiment of the above aspect, the pH of the composition is in a range of about 3 to about 4.
A second aspect of the present invention provides a stable extended-release composition of cefpodoxime comprising cefpodoxime proxetil, a stabilizer, and a release-controlling agent, wherein the composition is characterized by having an in-vitro dissolution release profile as determined by USP type II apparatus at 100 r.p.m., in 900 mL of glycine buffer (pH 3) with 0.5% sodium lauryl sulfate at 37°C as follows:
- not more than 50% of cefpodoxime released at 1 hours,
- not more than 65% of cefpodoxime released at 4 hours,
- more than 75% of cefpodoxime released at 16 hours.
A third aspect of the present invention provides a stable extended-release composition of cefpodoxime comprising cefpodoxime proxetil, a stabilizer, and a release-controlling agent, wherein the cefpodoxime proxetil is present in an amount of not more than about 55% w/w based on the total weight of the composition.
In one of the embodiment of the above aspects, the stabilizer is a combination of an organic acid and a silicon dioxide present in an intragranular portion of the composition.
In another embodiment of the above aspects, the organic acid and the silicon dioxide are present in a weight ratio of about 1:1 to 1:5.
In another embodiment of the above aspects, the silicon dioxide and cefpodoxime proxetil are present in a weight ratio of about 1:1 to about 1:10.
In another embodiment of the above aspects, the organic acid and cefpodoxime proxetil are present in a weight ratio of about 1:5 to about 1:35, preferably about 1:15 to about 1:35.
In another embodiment of the above aspects, the stable extended-release composition of cefpodoxime further comprises one or more pharmaceutically acceptable excipients.
In another embodiment of the above aspects, the stable extended-release composition of cefpodoxime is administered once daily for treating bacterial infections.
A fourth aspect of the present invention provides a process for the preparation of an extended-release composition of cefpodoxime comprising:
(i) blending cefpodoxime proxetil, a silicon dioxide, an organic acid, and one or more pharmaceutically acceptable excipients;
(ii) optionally granulating the blend of step (i);
(iii) mixing one or more release-controlling agents 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 onto the tablet of step (iv)
wherein in the above said process the combination of organic acid and silicon dioxide in a ratio of 1:1 to 1:5 are blended in the intragranular part of the composition.
The term “extended-release,” as used herein, refers to cefpodoxime proxetil release over a longer period of time than is ordinarily experienced after administration of a corresponding immediate-release cefpodoxime proxetil formulation. In particular, the term “extended-release” as used herein refers to the release of cefpodoxime proxetil 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 “cefpodoxime proxetil,” as used herein, refers to (RS)-1(isopropoxycarbonyloxy) ethyl (+)-(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-{(Z)methoxyimino}acetamido]-3-methoxy methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate. The cefpodoxime proxetil used in the extended-release composition of the present invention is present an amount of not more than about 55% w/w based on the total weight of the composition. Preferably, it is present in a range of about 25% to about 55% w/w based on the total weight of the composition. More preferably, it is present in a range of about 27% to about 50% w/w based on the total weight of the composition.
The term “stabilizer,” as used herein, means a compound that prevents the degradation of cefpodoxime proxetil. The stabilizer as used herein is a combination of an organic acid and a silicon dioxide particularly used in the intragranular part of the composition. The organic acid and silicon dioxide are present in a weight ratio of about 1:1 to 1:5.
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 cefpodoxime proxetil particles. This acidic environment helps to prevent degradation and improve dissolution. Suitable examples of organic acids are selected from the group comprising 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, and mixtures thereof. The percentage of organic acid used in the extended-release composition of the present invention ranges from about 0.5% to about 15% w/w, based on the total weight of the composition. Further, the organic acid and cefpodoxime proxetil are present in a weight ratio of about 1:5 to about 1:35, preferably about 1:15 to about 1:35.
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 cefpodoxime proxetil as particles of silicon dioxide get evenly distributed between the particles of cefpodoxime proxetil, thereby reducing the electric charge and minimizing the attractive forces responsible for gelation. Additionally, silicon dioxide creates an acidic microenvironment around cefpodoxime proxetil particles, thereby preventing the degradation. The silicon oxide includes both hydrous and anhydrous forms of silicon dioxide. The silicon dioxide can be selected from various available forms such as colloidal silicon dioxide, fumed silica, precipitated silica, light anhydrous silicic acid, silicic anhydride, aluminum magnesium silicate, and mixtures thereof. The percentage of silicon dioxide used in the extended-release composition of the present invention ranges from about 1% to about 15% w/w, based on the total weight of the composition. Further, silicon dioxide and cefpodoxime proxetil are present in a weight ratio of about 1:1 to about 1:10.
The term “stable” as used herein, means not more than 10% w/w of total related substances are formed on storage at a temperature of 40°C and a relative humidity of 75% or at a temperature of 25°C and a relative humidity of 60% for a period of at least three months to the extent necessary for the sale and use of the extended-release cefpodoxime composition.
In the present invention, mixing of cefpodoxime proxetil with silicon dioxide and organic acid is done by conventional methods known in the art.
The term “release-controlling agent,” as used herein, refers to an agent that helps to control the release of cefpodoxime proxetil. Suitable examples of release-controlling agents are selected from the group comprising cellulosic polymers such as hydroxypropylmethyl cellulose e.g., Hypromellose K4M and Hypromellose K100 LVCR, methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, carboxy methylcellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate butyrate, cellulose acetate, and cellulose acetate trimellitate; acrylic copolymers such as methacrylic acid copolymers, e.g., Eudragit® RS, Eudragit® RL, and Eudragit® NE 30 D; polyvinyl alcohol; polyvinyl acetate; polyalkylene glycol such as polyethylene glycol; triglycerides; waxes, e.g., Compritol®, Lubritab®, and Gelucire®; lipids; fatty acids or their salts/derivatives; a mixture of polyvinyl acetate and polyvinyl pyrrolidone, e.g., Kollidon® SR; and mixtures thereof. The release-controlling agent may control the release of cefpodoxime proxetil based on a matrix or a reservoir system. The percentage of release-controlling agent used in the extended-release composition of the present invention ranges from about 5% to about 30% w/w, based on total weight of the composition.
The term "Intragranular" refers to being or occurring within granules of the composition i.e. granules comprising pharmaceutically acceptable active ingredients, a first pharmaceutically acceptable excipient component selected from the group comprising of a filler, binder, stabilizer, wetting agent, a glidant and/or a solvent. All these elements fall under an intragranular part of a composition.
The term "Extragranular" refers to the addition of pharmaceutically acceptable components to a material following granulation i.e a said extra-granular fraction comprising a second pharmaceutically acceptable excipient component, wherein said second pharmaceutically acceptable excipient component is selected from the group comprising of a disintegrants, release controlling agent, a diluent, binder, a lubricant, a glidant and/or a like thereof.
The term “composition,” as used herein includes tablets, granules, powders, capsules, pellets, or spheroids, in particular tablets.
The term “pharmaceutically acceptable excipients,” as used herein, refers to excipients that are routinely used in pharmaceutical compositions. The pharmaceutically acceptable excipients may comprise fillers, binders, glidants, disintegrants, lubricants, wetting agents, and combinations thereof.
Suitable fillers are selected from the group comprising microcrystalline cellulose, mannitol, sorbitol, lactose, dibasic calcium phosphate, sodium phosphate, kaolin, calcium carbonate, sodium carbonate, calcium sulfate, starch, magnesium oxide, cellulose acetate, dextrates, dextrin, erythritol, maltodextrin, maltose, sodium chloride, and mixtures thereof.
Suitable binders are selected from the group comprising polyvinyl pyrrolidone; celluloses e.g., methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, and sodium carboxy methyl cellulose; polymethacrylates; carboxyvinyl polymers; gums e.g., acacia, alginic acid, sodium alginate, tragacanth, and guar gum; sugars e.g., lactose, liquid glucose, sucrose, and dextrin; polydextroses; starch or its derivatives; kaolin; povidone; copovidone; polyethylene oxide; polyvinyl alcohol; poly-N-vinyl amide; polyethylene glycol; gelatin; polypropylene glycol; glyceryl behenate; oils e.g., hydrogenated vegetable oil, castor oil, and sunflower oil; zein; paraffin; higher aliphatic alcohols; higher aliphatic acids; fatty acid esters; fatty acid glycerides; agar; chitosan; maltodextrin; magnesium aluminum silicate; inulin; waxes; and mixtures thereof.
Suitable glidants/lubricants are selected from the group comprising sodium stearyl fumarate, calcium stearyl fumarate, magnesium stearate, aluminum stearate, calcium stearate, zinc stearate, silica, calcium silicate, magnesium silicate, aluminum silicate, colloidal silicon dioxide, polyethylene glycol, poloxamer, cornstarch, talc, polyvinyl alcohol, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, potassium benzoate, sodium benzoate, mineral oil, palmitic acid, myristic acid, stearic acid, hydrogenated vegetable oil, sodium lauryl sulfate, and mixtures thereof.
Suitable disintegrants are selected from the group comprising cross-linked polyvinyl pyrrolidone (crospovidone); starches e.g., starch, pregelatinized starch, hydroxypropyl starch, sodium carboxymethyl starch, and sodium starch glycolate; cellulose or its derivatives e.g., low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, carboxymethyl calcium cellulose, and microcrystalline cellulose; gums e.g., guar gum, sodium alginate, calcium alginate, and alginic acid; ion-exchange resins e.g., polacrillin potassium; clays e.g., bentonite and veegum; povidone; cross-linked polyvinyl pyrrolidone; formalin-casein; chitosan; magnesium aluminum silicate; colloidal silicon dioxide; and mixtures thereof.
Suitable wetting agents are selected from the group comprising surfactants such as nonionic, cationic, anionic, and zwitterionic surfactants. Suitable anionic surfactants include those containing carboxylate, sulfonate, and sulfate ions such as sodium lauryl sulfate, sodium laurate, dialkyl sodium sulfosuccinates, particularly bis-(2-ethylhexyl) sodium sulfosuccinate, sodium stearate, potassium stearate, and sodium oleate. Suitable cationic surfactants include those containing long chain cations, such as benzalkonium chloride and bis-2-hydroxyethyl oleyl amine. Suitable non-ionic surfactants include polyoxyethylene sorbitan fatty acid esters; fatty alcohols such as lauryl, cetyl, and stearyl alcohols; glyceryl esters such as the naturally occurring mono-, di-, and tri-glycerides; fatty acid esters of fatty alcohols and other alcohols such as propylene glycol, polyethylene glycol, sorbitan, sucrose, and cholesterol.
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, direct compression, melt granulation, or extrusion-spheronization.
The extended-release compositions of the present invention may further comprise an immediate-release portion of cefpodoxime proxetil.
The tablet 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.
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; waxes e.g., 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.
Pharmaceutically acceptable coating additives may be selected from the group consisting of film-forming polymers, binders, diluents, plasticizers, opacifiers, coloring agents, lubricants, and pore-formers.
Suitable plasticizers are selected from the group comprising triethyl citrate, dibutyl sebacate, acetylated triacetin, tributyl citrate, glycerol tributyrate, acetyl tributyl citrate, diacetylated monoglyceride, rapeseed oil, olive oil, sesame oil, glycerin, sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, and combinations thereof.
Suitable opacifiers are selected from the group comprising titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, and combinations thereof.
Suitable pore-formers are selected from the group comprising polyethylene glycols e.g., polyethylene glycol 6000 and polyethylene glycol 400; celluloses e.g., hydroxypropylmethyl cellulose, hydroxypropyl cellulose, and methyl cellulose; polysaccharides e.g., alginates, xanthan gum, chitosan, carrageenan, and dextran; polyalkylene oxides e.g., polyethylene oxide; vinyl acetate copolymers; methacrylic acid copolymers; maleic anhydride/methyl vinyl ether copolymers; carboxyvinyl polymers; and combinations thereof.
Coating may be performed by applying the coating composition as a solution/suspension/blend using any conventional coating technique known in the prior art, such as spray coating in a conventional coating pan or fluidized bed processor, dip coating, or compression coating.
Examples of solvents used for preparing the solution/dispersion of coating substances and for granulation include methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, purified water, and the like.
The extended-release composition of the present invention maintains the drug concentration in blood above MIC for more than 40% of dosing interval so as to achieve the desired clinical effect.
The invention may be further illustrated by the following examples, which is for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
EXAMPLES
Example 1
Ingredients Quantity (mg/tablet)
Intragranular
Cefpodoxime proxetil 521.79
Microcrystalline cellulose 78.21
Fumaric acid 40.00
Colloidal silicon dioxide 84.00
Sodium lauryl sulphate 30.00
Sodium stearyl fumarate 6.00
Extragranular
Crospovidone 150.00
Hypromellose K4M 140.00
Hypromellose K100 LVCR 40.00
Polyvinyl pyrrolidone 10.00
Mannitol 94.00
Sodium stearyl fumarate 6.00
Tablet weight 1200.00
Coating
Opadry® 48.00
Purified water q.s.
Coated Tablet weight 1248.00
pH 3.21

Procedure:
1. Cefpodoxime proxetil, microcrystalline cellulose, fumaric acid, colloidal silicon dioxide, sodium lauryl sulfate, 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 (Hypromellose K4M Cr and Hypromellose K100 LVCR), polyvinyl pyrrolidone, and mannitol were sifted and mixed.
4. The mixture of step 3 was mixed 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.
7. Opadry® was dispersed in purified water and stirred to form a dispersion.
8. The tablet of step 6 was coated with the dispersion of step 7.
pH Determination
The pH of the extended-release tablet of cefpodoxime proxetil prepared as per Example 1 was determined by crushing the extended-release tablet using a mortar and pestle. The crushed powder was transferred to a flask containing 100 mL of purified water. The flask was shaken for 5 minutes and the pH of the medium was measured. The pH of the composition prepared as per Example 1 was found to be 3.21.
In-Vitro Release Studies
The in-vitro dissolution profile of the extended-release tablet of cefpodoxime proxetil prepared as per Example 1 was determined using a USP type II apparatus at 100 r.p.m., in 900 mL of glycine buffer (pH 3) + 0.5% sodium lauryl sulfate using 10 mesh sinkers at 37°C. The results of the release studies are represented in Table 1.
Table 1: Percentage (%) of the In-Vitro Cefpodoxime Release in USP Type II Apparatus (Media: Glycine buffer (pH 3) + 0.5% sodium lauryl sulfate, 900 mL, at 100 r.p.m.)
Time (hours) Percentage (%) of Cefpodoxime Release
1 36
4 56
10 79
16 93

Stability
The extended-release tablets of cefpodoxime proxetil prepared as per Example 1 were stored at a temperature of 40°C and a relative humidity (RH) of 75% for a period of three and six months, and analyzed for cefpodoxime content by an HPLC method. The results of the analysis are represented in Table 2.
Table 2: Stability Data for the Cefpodoxime Proxetil Extended Release Tablets
Conditions
(40oC/75% RH) Assay (%) Related substances
(% w/w)
Initial 100.9 4.2
3 Months 95.0 5.5
6 Months 97.7 6.4

Examples 2
Ingredients Quantity (mg/tablet)
Intragranular
Cefpodoxime proxetil 521.79
Microcrystalline cellulose 78.21
Fumaric acid 40.00
Colloidal silicon dioxide 84.00
Sodium lauryl sulphate 30.00
Sodium stearyl fumarate 6.00
Extragranular
Crospovidone 150.00
Hydroxypropylmethyl cellulose 180.00
Polyvinyl pyrrolidone 10.00
Mannitol 94.00
Sodium stearyl fumarate 6.00
Core Tablet weight 1200.00
Opadry® 48.00
Purified water q.s.
Tablet weight 1248.00

Procedure:
1. Cefpodoxime proxetil, microcrystalline cellulose, fumaric acid, colloidal silicon dioxide, sodium lauryl sulfate, 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, polyvinyl pyrrolidone, 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.
7. Opadry® was dispersed in purified water and stirred to form a dispersion.
8. The tablet of step 6 was coated with the dispersion of step 7.

Examples 3-6
Example 3 4 5 6
Ingredients Quantity (mg/tablet)
Intragranular
Cefpodoxime proxetil 521.79 521.79 521.79 521.79
Microcrystalline cellulose 78.21 78.21 78.21 78.21
Fumaric acid 62.00 62.00 62.00 62.00
Colloidal silicon dioxide 63.00 63.00 63.00 63.00
Sodium lauryl sulphate 29.00 29.00 29.00 29.00
Sodium stearyl fumarate 6.00 6.00 6.00 6.00
Extragranular
Crospovidone 150.00 150.00 150.00 150.00
Hypromellose® K4M 80.00 80.00 100.00 150.00
Hypromellose® K100 LVCR 120.00 100.00 50.00 34.47
Polyvinyl pyrrolidone 40.00 40.00 70.00 50.00
Mannitol 44.47 64.47 64.47 50.00
Sodium stearyl fumarate 6.00 6.00 6.00 6.00
Core tablet weight 1200.47 1200.47 1200.47 1200.47

Procedure:
1. Cefpodoxime proxetil, microcrystalline cellulose, fumaric acid, colloidal silicon dioxide, sodium lauryl sulfate, and sodium stearyl fumarate were sifted and blended.
2. The blend of step 1 was compacted and milled to form the granules.
3. Crospovidone, hydroxypropylmethyl cellulose (Hypromellose® K4M CR and Hypromellose® K100 LVCR), polyvinyl pyrrolidone, and mannitol were sifted and mixed.
4. The mixture of step 3 was mixed 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.

Examples 7-8
Example 7 8
Ingredients Quantity (mg/tablet)
Intragranular
Cefpodoxime proxetil 521.79 521.79
Microcrystalline cellulose 78.21 78.21
Tartaric acid 40.00 40.00
Colloidal silicon dioxide 84.00 -
Aluminum magnesium silicate - 84.00
Sodium lauryl sulphate 30.00 30.00
Sodium stearyl fumarate 6.00 6.00
Extragranular
Crospovidone 150.00 150.00
Hypromellose® K4M 150.00 150.00
Hypromellose® K100 LVCR 60.00 60.00
Polyvinyl pyrrolidone 10.00 10.00
Mannitol 64.00 64.00
Sodium stearyl fumarate 6.00 6.00
Total Weight 1200.00 1200.00
pH 3.03 3.63

Procedure:
1. Cefpodoxime proxetil, microcrystalline cellulose, tartaric acid, colloidal silicon dioxide/aluminum magnesium silicate, sodium lauryl sulfate, and sodium stearyl fumarate were sifted and blended.
2. The blend of step 1 was compacted and milled to form the granules.
3. Crospovidone, hydroxypropylmethyl cellulose (Hypromellose® K4M CR and Hypromellose® K100LVCR), polyvinyl pyrrolidone, and mannitol were sifted and mixed.
4. The mixture of step 3 was mixed 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.

Examples 9-13
Example 9 10 11 12 13
Ingredients Quantity (mg/tablet)
Cefpodoxime Proxetil 521.79 260.89 260.89 260.89 260.89
Microcrystalline cellulose 78.21 39.11 39.11 39.11 39.11
Fumaric Acid 40.00 20.00 20.00 20.00 20.00
Colloidal silicon dioxide 84.00 42.00 42.00 42.00 42.00
Sodium lauryl sulphate 30.00 15.00 15.00 15.00 15.00
Sodium stearyl fumarate 6.00 3.00 3.00 3.00 3.00
Extragranular
Crospovidone 150.00 190.18 200.10 210.10 210.10
Hypromellose K4M 140.00 99.90 99.90 89.90 89.90
Hypromellose K100 LVCR 40.00 79.92 70.00 70.00 60.00
Polyvinyl pyrrolidone 10.00 10.00 10.00 10.00 10.00
Mannitol 94.00 134.00 134.00 134.00 144.00
Sodium stearyl fumarate 6.00 6.00 6.00 6.00 6.00
Tablet Weight 1200.00 900.00 900.00 900.00 900.00
Coating
Opadry® 48.00 27.00 27.00 27.00 27.00
Purified water q.s. q.s. q.s. q.s. q.s.
Coated tablet weight 1248.00 927.00 927.00 927.00 927.00

Procedure:
1. Cefpodoxime proxetil, microcrystalline cellulose, fumaric acid, colloidal silicon dioxide, sodium lauryl sulfate, and sodium stearyl fumarate were sifted and blended.
2. The blend of step 1 was compacted and milled to form the granules,
3. Crospovidone, hydroxypropylmethyl cellulose (Hypromellose K4M CR and Hypromellose K100LVCR), polyvinyl pyrrolidone, and mannitol were sifted and mixed,
4. The mixture of step 3 was mixed 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,
7. Opadry® was dispersed in purified water and stirred to form a dispersion, and
8. The tablet of step 6 was coated with the dispersion of step 7.
In-Vitro Release Studies
The in-vitro dissolution of the extended release tablets of cefpodoxime proxetil prepared as per Examples 9-13 were determined using a USP type II apparatus at 100 rpm, in 900 mL of glycine buffer (pH 3) + 0.5% sodium lauryl sulfate using 10 mesh sinkers at 37°C. The results of the release studies are represented in Table 3.
Table 3: Percentage (%) of the In-Vitro Cefpodoxime Proxetil Release in USP Type II Apparatus (Media: Glycine buffer (pH 3) + 0.5% sodium lauryl sulfate, 900 mL, and 100 r.p.m.)
Example 9 10 11 12 13
Time (hours) Percentage (%) of Cefpodoxime Proxetil Release
1 33 23 25 30 33
2 44 35 34 42 44
4 58 51 50 58 60
6 - 64 62 70 73
8 79 76 73 82 84
12 93 91 89 94 94
16 98 96 94 98 97

Examples 14 (a-f)
Example 14(a) 14(b) 14(c) 14(d) 14(e) 14(f)
Ingredients Quantity (400 mg/tablet) Quantity (200 mg/tablet)
Cefpodoxime Proxetil 580.79 570.89 560.90 260.91 280.45 290.91
Microcrystalline cellulose 88.21 85.43 82.09 49.11 41.045 34.33
Fumaric Acid 10.00 22.00 20.00 30.00 10.000 20.00
Colloidal silicon dioxide 81.00 80.00 84.00 52.00 42.000 62.00
Sodium lauryl sulphate 28.00 35.00 30.00 19.00 15.000 12.00
Sodium stearyl fumarate 8.00 5.00 6.00 4.00 3.000 2.00
Extragranular
Crospovidone 165.00 170.18 200.00 230.10 220.00 235.10
Hypromellose K4M 12.00 8.00 5.00 11.90 5.00 7.90
Hypromellose K100 LVCR 96.00 101.92 104.00 95.10 104.00 100.17
Polyvinyl pyrrolidone 10.00 10.00 10.00 10.00 10.00 10.00
Mannitol 88.00 90.00 80.00 144.00 154.50 148.00
Sodium stearyl fumarate 8.00 5.00 6.00 4.00 3.00 2.00
Core Tablet Weight 1166.00 1183.42 1187.99 911.12 887.99 924.41
Coating
Opadry® 44.00 51.00 42.00 27.00 31.50 27.00
Purified water q.s. q.s. q.s. q.s. q.s. q.s.
Total weight 1210.00 1234.42 1229.99 938.12 919.50 951.41

Procedure:
1. Cefpodoxime proxetil, microcrystalline cellulose, fumaric acid, colloidal silicon dioxide, sodium lauryl sulfate, were sifted and blended, (The silicon oxide includes both hydrous and anhydrous forms of silicon dioxide)
2. Sodium stearyl fumarate sifted and blended with step 1) blend,
3. The blend of step 2 was compacted and milled to form the granules (Intragranular part),
4. Crospovidone, hydroxypropylmethyl cellulose (Hypromellose K4M CR and Hypromellose K100LVCR), polyvinyl pyrrolidone, and mannitol were sifted and mixed,
5. The intragranular part of step 3 was mixed with material of step 4,
6. Sodium stearyl fumarate was sifted and blended with the mixture of step 5 (Extragranular part).
7. The mixture of step 6 was compressed into a tablet.
8. Opadry® was dispersed in purified water and stirred to form a dispersion.
9. The tablet of step 7 was coated with the dispersion of step 8.
Observation: While preparing the formulation of Example 14 the applicant also observed that when the critical components of the present formulation such as organic acid and silicon dioxide where used in the Extragranular portion instead of intragranular portion there was difficulty in formulation, and a stable formulation could not be achieved. The possible reason for such stability issue was:
i. when such stabilizer components are used in Extragranular part there was no intimate mixing of the organic acid & silicon dioxide due to which the formulators faced issue in stability of formulation and the desired dissolution profile and bioavailability cannot be achieved.
ii. when colloidal silica (silicon dioxide) is used in the present quantities in the Extragranular portion there was issue with the compressibility of the tablet hence process difficulties were faced during tableting.
Based on above it was concluded to keep the organic acid and silicon dioxide in the intragranular part of the composition to get the desired synergy of the components to achieve a stable and a prolonged duration of drug concentration greater than MIC.

In-Vitro Release Studies
The in-vitro dissolution of the extended release tablets of cefpodoxime proxetil prepared as per Examples 14-19 were determined using a USP type II apparatus at 100 rpm, in 900 mL of glycine buffer (pH 3) + 0.5% sodium lauryl sulfate using 10 mesh sinkers at 37°C.
Bioavailability Study
Bioavailability study was conducted with Cefpodoxime Proxetil Extended Release tablets 400 mg as once daily under fed conditions and the resultant pharmacokinetic parameters were presented in Table 4 below:
Table 4: Pharmacokinetic data of Example 14:
pK Parameter Example 14 (400 mg) Example 1 WO 2004/019901
Cmax (µg/ml) 4.96 1.418
AUC0-t (µg/ml) 33.107 14.027

Observation: Based on pharmacokinetic profile achieved for 400 mg strength it was found to be more bioavailable, the bioavailability values were nearly double when compared with prior sustained release formulation data as disclosed in PCT publication WO 2004/019901.
Efficacy study (Pharmacodynamic endpoint)
For evaluation of efficacy of the cefpodoxime proxetil composition, the base criteria is time dependent minimal inhibitory concentration (MIC) during antibiotic therapy. So the target was to achieve a concentration of drug greater than MIC for maximum duration (i.e. T>MIC). So experiments were conducted to determine the pharmacodynamic endpoint of the tablets in example 14 and its comparison with the Example 1 SR formulation of WO 2004/019901. The comparison data is provided in Table 5 below:
Table 5: Pharmacodynamic endpoint comparison for efficacy:
Parameter Example 1 400 mg
(WO 2004/019901) Example 14
(400 mg)
T > MIC (hours) 1 mcg/ml ~ 5 hours 9.9 hours

Observation: The 400 mg ER formulation of example 14 showed a Cefpodoxime Proxetil duration of exposure above MIC (T>MIC) for 9.9 hours (Figure-1), whereas the SR formulation of Example 1 (of WO 2004/019901) showed a duration of exposure above MIC (T>MIC) for nearly 5 hours which is less than the required duration of exposure above MIC (i.e. should be at least 9.6 hours) to be desirable for once daily regime (i.e. 40% to 60% duration for dosing interval for a 400 mg strength) of effective antibiotic therapy for Cefpodoxime Proxetil.
Therefore the formulation of present invention provides time dependent beneficial bactericidal effect by maintaining drug concentrations above the minimum inhibitory concentration, thus meets the pharmacodynamic endpoint for effective once daily regime.
Example 15: Critical component evaluation
To determine the criticality of the components used in the Cefpodoxime Extended Release composition an experimental trial was done based on which prototype composition were prepared with following strategy:
Example 15 a: Composition with both organic acid and silicon dioxide.
Example 15 b: Composition without both organic acid and silicon dioxide.
Example 15 c: Composition with no organic acid but with silicon dioxide.
Example 15 d: Composition with organic acid and no silicon dioxide.
Dissolution study of above samples and there composition is provided in below Table-6:
Table 6: Dissolution study of different batches of cefpodoxime
Examples Quantity (mg/tablet)
15(a) 15(b) 15(c) 15(d)
Intragranular
Cefpodoxime Proxetil IP Eq. to Cefpodoxime 47.39 47.39 47.39 47.39
Microcrystalline cellulose IP 7.19 15.86 15.19 14.19
Fumaric Acid 1.67 - - 1.67
Colloidal Anhydrous Silica 7.00 - 0.66 -
Sodium lauryl sulfate 2.50 2.50 2.50 2.50
Sodium stearyl fumarate 0.50 0.50 0.50 0.50
Extragranular Quantity (mg/tablet)
Crospovidone IP 16.67
Hypromellose IP (K4M) 0.42
Hypromellose IP (K100LVCR) 8.67
Povidone IP 0.83
Mannitol IP 6.67
Sodium stearyl fumarate 0.50
Total weight 100.00
Dissolution Cefpodoxime % release
15 minutes 60 3 2 3
30 minutes 77 5 6 7
1 hour 86 10 12 12
4 hour 100 38 37 39
8 hour 98 70 76 78
20 hour 105 73 82 80
Results and Observations Complete release Poor and hindered release of Cefpodoxime proxetil

Observation: The dissolution results in the above table 6 shows that the presence of organic acid and silicon dioxide is critical for the integral functioning of the composition according to present invention and when any one of the components either organic acid or silicon dioxide or both are absent then the drug release from the formulation is hindered and actual therapy cannot be delivered hence will lead to failure of therapy.
Further the visual appearance of the formulations of Example 15 (a-d) were also analyzed and as shown in Figure-2 and the visual examination reveals that the tablets without Fumaric acid (organic acid) and colloidal silicon dioxide (silicon dioxide) both (Example 15(b)) or any one component (Example 15(c) and 15(d)), forms gel and subsequently, the release is retarded, as Cefpodoxime Proxetil does not get dissolved and release is incomplete. After 30 minutes the visual apperance of samples 15 c-d shows that the tablet is not dissolved and remains nearly in intact form and after 3 hours the viual appearance reveals formation of gel and thus retardation of release. The undissolved Cefpdoxime Proxetil is poorly absorbed. Therefore, a formulation without organic acid and colloidal silicon dioxide will have lower bioavailability compared to composition having both the components in the intragranular portion of the formulation.
Based on above observation it can be assumed that the present invention composition has critical advantage over prior compositions as the organic acid in the intragranular portion of the formulation creates an acidic microenvironment around cefpodoxime proxetil particles and such acidic environment due to presence of organic acid helps to prevent degradation and improve dissolution. Further the presence of silicon dioxide in conjugation with organic acid prevents the gel formation of cefpodoxime proxetil as particles of silicon dioxide get evenly distributed between the particles of cefpodoxime proxetil, thereby reducing the electric charge and minimizing the attractive forces responsible for gelation. Additionally, silicon dioxide creates an acidic microenvironment around cefpodoxime proxetil particles, thereby preventing the degradation.