The technical field of the present invention relates to pharmaceutical composition comprising complex of cefpodoxime proxetil with cyclodextrin; and process of preparation thereof.
Cefpodoxime, a third generation cephalosporin, chemically 1-
(isopropoxycarbonyloxy)ethyl (+)-(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-{(Z)
methoxyimino}acetamido]-3- methoxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2- carboxylate, and its pharmaceutically acceptable acid addition salts has been described in US 4,486,425, which is incorporated in its entirety by reference herein. Cefpodoxime is stable towards hydrolysis by the most commonly found plasmid-mediated, ß-lactamases. The drug has a broad spectrum of antibacterial activity, encompassing both gram negative and gram-positive bacteria while sharing the familiar and relatively benign tolerability profile of other broad-spectrum cephalosporins with regard to both the incidence and severity of adverse events. Thus, rendering it as an effective alternative to currently used ß-lactams for empirical therapy in a wide range of community acquired infections in both adult and pediatric patients. Cefpodoxime is a orally administered as the prodrug cefpodoxime proxetil, which is absorbed and de-esterified by intestinal mucosa to release the active moiety, cefpodoxime.
Cefpodoxime proxetil is categorized as a Class IV drug according to the Biopharmaceutical classification of drugs, having poor solubility and poor permeability. The bioavailability of cefpodoxime proxetil from pharmaceutical compositions is considered to be dissolution rate limited, with an absolute oral bioavailability of only around 50%. Cefpodoxime proxetil is hydrophobic in nature having contact angle with water of greater than 95 degrees. The wettability is further hindered by the fact that cefpodoxime proxetil forms a gelatinous mass when in contact with aqueous media (Hamaura T. et.al., S.T.P. Pharma Sciences, 1995; 5(4):324). The gel formed disintegrates poorly which thereby slows the dissolution and hence the absorption of cefpodoxime proxetil from the gastro-intestinal tract is greatly reduced. In addition to poor solubility, it is rapidly degraded under the influence of alkaline pH as well as by the non-specific enzymes of the gastro-intestinal tract.
Development of pharmaceutical compositions of drugs having an acceptable dissolution and stability, which in turn enhance their bioavailability characteristics, is always a challenging task.
One of the approaches to improve the solubility characteristics of such drugs involves the use of solid dispersions. For example, WO04105728 discloses solid dispersions of cefpodoxime proxetil in a carrier.
Other approaches, includes use of various solubility enhancers, e.g., those reported in D. D. Chow et al, Int. J. Pharm., 28, 95-101, 1986; F. A. Menard et al, Drug Dev. Ind. Pharm., 14(11), 1529-1547, 1988; F. J. Otera-Espinar et al, Int. J. Pharm., 75, 37-44, 1991; and Berand M. Markarian et al, European Patent Publication No. EP 0274444, July 1988.
Numerous documents disclose the use of cyclodextrins and their derivatives to prepare inclusion complexes of poorly soluble drugs, for example, D. Duchene, Cyclodextrins and their Industrial uses, Editions de Sante, Paris, 1987, Chapter 6 (211-257), Chapter 8 (297-350), Chapter 10 (393-439); D. Duchene et al, Acta Pharma Technol. 36(1)6, 1-6, 1990; D. Duchene et al, Drug Dev. Ind. Pharm., 16(17), 2487-2499, 1990; C. Hunter et al, European Patent Publication No. EP 0346006, December 1988. US 4,727,064 and US 5,024,998 further discloses use of chemically modified cyclodextrin derivatives.
US 4,883,785 discloses complex formed of a polyene anti-fungal agent, such as amphotericin B, and cyclodextrin, preferably -cyclodextrin. The complex, which includes amphoterin B, is shown to have improved water solubility and stability over prior amphotericin B anti-fungal agent compositions.
US 4,616,808 discloses an antibacterial solid composition for oral administration, which comprises a lipid soluble cephalosporin compound and a cyclodextrin. The said composition provides much increased in vivo absorbability of a non-ester form of the cephalosporin compound.
Use of cyclodextrin complexes of drugs is known in the art to enhance their solubility and stability, which in turn enhances their bioavailability.
However, we have now discovered that this approach could be specifically used to enhance the solubility and stability of cefpodoxime proxetil, consequently enhancing the bioavailability of cefpodoxime proxetil to appreciable levels.
Hence in one general aspect there is provided a pharmaceutical composition of cefpodoxime proxetil comprising cefpodoxime proxetil and cyclodextrin.
In another general aspect there is provided, a pharmaceutical composition of cefpodoxime proxetil comprising cefpodoxime proxetil and ß-cyclodextrin.
In another general aspect there is provided, a pharmaceutical composition of cefpodoxime proxetil comprising cefpodoxime proxetil and hydroxypropyl p-cyclodextrin.
In another general aspect there is provided a process for the preparation of a pharmaceutical composition of cefpodoxime proxetil comprising the steps of combining cefpodoxime proxetil with cyclodextrin, and processing into a suitable dosage form.
In another general aspect there is provided, a method of improving the bioavailability of cefpodoxime proxetil by 1.25 times or more than from conventional oral dosage forms, by using complexes of cefpodoxime proxetil and cyclodextrin.
In another general aspect there is provided a method for treating bacterial infection in a mammal by administering to the said mammal a pharmaceutical composition of cefpodoxime proxetil comprising cefpodoxime proxetil and cyclodextrin.
Cefpodoxime proxetil is a poorly soluble drug and thus the rate of dissolution remains the limiting step for its absorption. The absolute bioavailability of commercially available cefpodoxime proxetil tablets is only about 50% compared to that of cefpodoxime sodium intravenous infusion. The poor solubility of cefpodoxime proxetil could be further accounted due to its poor wettability, and further to formation of gel when it comes in contact with aqueous media. No doubt, the poor solubility remains the primary reason; the other reasons include its poor stability due to its presystemic degradation to cefpodoxime acid, which is poorly absorbable.
Cefpodoxime proxetil should thereby be released from pharmaceutical compositions in a very soluble form facilitating quick dissolution and reducing the chances of degradation at the absorption site. Complexation of cefpodoxime proxetil with
cyclodextrin takes care of all such problems, and thus the bioavailability is enhanced to appreciable levels compared to that of the commercially available dosage forms.
Complexation of cefpodoxime proxetil with cyclodextrin results in an increase in the wettability of cefpodoxime proxetil. It also helps in the disintegration of the gel layers that may be formed around the cefpodoxime proxetil particles. Cyclodextrin complexation thereby enhances the bioavailability of cefpodoxime proxetil by increasing its effective solubility and by enhancing the rate and extent of dissolution. Additionally, by providing molecular shield, cyclodextrin complexation encapsulates cefpodoxime proxetil at molecular level and thus insulates it against various degradation processes. Further, the various substituents on the cyclodextrin structure slow down enzymatic hydrolysis by lowering the affinity to enzymes. Improved rate of dissolution and reduced degradation makes more and more the cefpodoxime proxetil available at the surface of the biological barrier such a mucosa of the intestine, from where it partitions into the membrane without disrupting the lipid layers of the barrier, thereby improving the overall bioavailability.
Complexation of cefpodoxime proxetil with cyclodextrin as per the present invention may improve the bioavailability by 1.25 times or more than from conventional oral dosage forms. The increased cefpodoxime proxetil efficacy and potency (i.e reduction of the dose required for optimum therapeutic activity), caused by cyclodextrin increased cefpodoxime proxetil solubility, may reduce the drug toxicity by making the drug effective at lower doses. Less amount of cefpodoxime proxetil would be required to achieve the plasma levels of the drug compared to conventional dosage forms. Hence, such compositions would be cost-effective and have reduced chances of dose-dumping leading to toxicity problems. Further it helps in suppressing the bitter taste of cefpodoxime proxetil.
In its simplest version, the pharmaceutical composition of the present invention would comprise cefpodoxime proxetil, cyclodextrin and at least one pharmaceutically inert excipient.
The amount of cefpodoxime proxetil may vary from about 10% w/w to about 90% w/w, in particular from about25% w/w to about 75% w/w of the total weight of composition.
Cyclodextrins (CDs) are cyclic oligosaccharides containing at least six D- (+) glucopyranose units attached by α-(1,4) glucosidic bonds. They have lipophilic inner cavity and hydrophilic outer surface capable of forming non-covalent inclusion complexes with a large variety of guests (drugs). Cyclodextrins of the present invention may comprise combination of one or more of the cyclodextrins. Various factors influence the formation as well as performance of complex, such as type of the cyclodextrin, temperature and method of preparation. Suitable cyclodextrins include the three naturally occurring cyclodextrin α, ß and  CDs (with 6, 7 or 8 glucose units respectively) which differ in their ring size and solubility, and their pharmaceutically acceptable derivatives. In particular, ß-CD and its derivatives that have been widely used in pharmaceutical industry due to its ready availability and cavity size suitable for the widest range of drugs, may be used. Pharmaceutically acceptable derivatives of cyclodextrins include alkyl or dialkyl, hydroxyalkyl (e.g., hydroxypropyl), carboxamide, diethylaminoethyl, carboxymethyl and dihydroxyalkyl (e.g., dihydroxypropyl), suflobutyl derivatives, and the like. Specific examples include hydroxyethyl-ß-CD, hydroxy propyl-ß-CD, sulfobutylether-ß-CD, methyl-ß-CD, dimethyl-ß-CD, randomly dimethylated-ß-CD, randomly methylated-ß-CD, carboxymethyl-ß-CD, carboxymethyl ethyl-ß-CD, diethyl-ß-CD, tri-O-methyl-ß-CD, tri-O-ethyl-ß-CD, tri-O-butyryl-ß-CD, tri-O-valeryl-ß-CD, di-O-hexanoyl-ß-CD, glucosyl-ß-CD, maltosyl-ß-CD, 2-hydroxy-3-trimethyl-ammoniopropyl-ß-CD. The molar ratio of cefpodoxime proxetil and cyclodextrin may vary from about 1:9 to about 9:1.
Pharmaceutically inert excipients of the present invention include one or more of water-soluble polymers, solvents, diluents, binders, disintegrants, surfactants, lubricants/glidants, stabilizers, plasticizers, coloring agents, flavoring agents, suspending agents, sweeteners, buffers and the like.
Water-soluble polymers enhance the cyclodextrin solubilizing effect by increasing the apparent complex stability constant. Examples of water-soluble polymers include hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, polyacrylic acid, cross-linked polyacrylic acid polymer, polyvinylpyrollidone, and the like.
Solvents can improve the solubilizing and stabilising effects of cyclodextrins. Suitable examples of co-solvents include one or more of different grades of polyethylene glycol, propylene glycol, ethanol, methanol, acetone, isopropanol, methylene chloride, hydrochloric acid, sodium hydroxide, water, and the like.
Examples of diluents include calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose- microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like.
Examples of binders include methylcellulose, hydroxypropyl cellulose, HPMC, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like. .
Examples of disintegrants include low-substituted hydroxypropylcellulose L-HPC), sodium starch glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium A-type (Ac-di-sol), starch, crystalline cellulose, hydroxypropyl starch, partly pregelatinized starch, and the like.
The surfactant may be selected from anionic, cationic or non-ionic surface-active agents or surfactants. Suitable anionic surfactants include those containing carboxylate, sulfonate, and sulfate ions such as sodium lauryl sulfate (SLS), sodium laurate, dialkyl sodium sulfosuccinates particularly bis-(2-ethylhexyl) sodium sulfosuccinate, sodium stearate, potassium stearate, sodium oleate and the like. Suitable cationic surfactants include those containing long chain cations, such as benzalkonium chloride, bis-2-hydroxyethyl oleyl amine or the like. 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; polyglycolized glycerides such as Gelucire; polyoxyethylene-polyoxypropylene block co-polymer such as Poloxamer and other alcohols such as propylene glycol, polyethylene glycol, sorbitan, sucrose, and cholesterol.
Examples of lubricants and glidants include colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax and the like and combinations thereof.
Examples of stabilizer include pH adjusting agents, antimicrobial preservatives, antioxidants, and the like. Examples of pH adjusting agents include acids, bases and buffers. Suitable acids may include any organic or inorganic acid such as hydrochloric acid, phosphoric acid, lactic acid, and the like; suitable bases may include any organic or inorganic base such as diethanolamine, triethanolamine, meglumine, trimethanolamine, diethanolamine ethylenediamine, L-lysine, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium oxide, magnesium hydroxide, ammonia, and the like; and suitable buffers include monobasic or dibasic sodium phosphate, sodium ascorbate, sodium citrate, lactate, and the like. Examples of antimicrobial preservatives include benzyl alcohol, phenethyl alcohol, phenoxyethanol, sodium benzoate, methyl paraben, propyl paraben, butyl paraben, and the like. Examples of antioxidants include propyl gallate, demercaprol, butylhydroxyanisole, butylhydroxytoluene, palmityl ascorbate, sodium pyrosulfite, tocopherols e.g alpha-tocopherol (vitamin E), and/or its esters, and the like.
Examples of plasticizers include polyethylene glycol, triethyl citrate, triacetin, diethyl phthalate, dibutyl sebacate, and the like.
Examples of flavoring agents include any FDA approved colors for oral use such as flavoring substances like vanilla, cherry, orange, raspberry, black currant, strawberry, Caramel Chocolate, Mint Cool, Fantasy flavors include yellow plum lemon, aroma, peppermint oil, oil of wintergreen, and the like.
Examples of coloring agents include any FDA approved colors for oral use such as Iron oxide, Lake of Tartrazine, Lake of Quinoline Yellow, Lake of Sunset Yellow and Lake of Erythrosine, Lack of Carmosine Ponceau, Allura Red, and the like.
Examples of suspending agent include polysaccharides such as tragacanth, xanthan gum, bentonite, acacia; lower alkyl ethers of cellulose such as hydroxy and carboxy
derivatives of cellulose ethers, starches such as maize starch, pregelatinized starch; microcrystalline cellulose; silicon dioxide; polyvinylpyrrolidone; and the like.
Examples of sweeteners include monosaccharides such as glucose (dextrose), fructose (levulose); disaccharides such as sucrose, lactose, maltose, cellobiose; other sugars such as ribose, glycerine, sorbitol, xylitol, maltitol, erythritol, inositol, lactitol monohydrate, propylene glycol, galactose, mannose, xylose, rhamnose, glutaraldehyde, invert sugars, mannitol, polyethylene glycol, glycerol aspartame, saccharine, or sorbitol solution, and the like.
Examples of buffers include any acid-base combinations such as succinic, tartaric, lactic, or citric acid with sodium hydroxide or disodium hydrogen phosphate.
The process for preparing complex of cefpodoxime proxetil with cyclodextrin may include any of the conventional techniques known such as co-grinding, kneading, solvent evaporation, co-precipitation, spray drying, freeze-drying, and the like.
In one of the embodiments, complex of cefpodoxime proxetil and cyclodextrin may be prepared by a process comprising the steps of mixing cefpodoxime proxetil and cyclodextrin in a solvent with continuous stirring, filtering to remove the uncomplexed matter, and freeze drying the filtrate to form a solid complex of cefpodoxime proxetil and cyclodextrin.
In another embodiment, complex of cefpodoxime proxetil and cyclodextrin may be prepared by a process comprising the steps of kneading the mixture of cefpodoxime proxetil and cyclodextrin in the form of a paste, and drying to form a solid complex of cefpodoxime proxetil and cyclodextrin.
Alternatively, the complex of cefpodoxime proxetil and cyclodextrin may be adsorbed on a pharmaceutical inert excipient.
The complex of cefpodoxime proxetil and cyclodextrin obtained in any of the embodiments above may be further processed in oral dosage forms using conventional techniques such as comminuting, mixing, granulation, melting, sizing, filling, drying, molding, immersing, coating, compressing, extrusion-spheronization and the like.
Suitable oral dosage forms include tablets, capsules, suspensions/dispersions, solutions, dry syrup, and the like.
Formation of the complex of cefpodoxime proxetil and cyclodextrin may be confirmed by techniques such as dissolution rate determination, differential scanning calorimetry (DSC), powdered X-Ray diffraction (PXRD), thermal gravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FTIR), high-pressure liquid chromatography (HPLC), and the like.
The invention is further illustrated by the following examples, which are for illustrative purposes and are not to be construed as limiting the scope of the inventions.
Examples

(Table Removed) Procedure:
1. Cefpodoxime proxetil and cyclodextrin (ingredient 2, 3 or 4) were added in 0.1 N HCI solution, and stirred at high speed (1000 rpm) for about 12-24 hours.
2. Excess drug was precipitated by increasing pH to about 5.5 to about 6.5 with dilute sodium hydroxide.
3. The free precipitated drug of step 2 was filtered and the filtrate was freeze dried to obtain complex of cefpodoxime proxetil and cyclodextrin.
The complex formed as per the compositions of example 3 were stored at 40° C and cefpodoxime proxetil was analyzed at regular intervals over a period of 2 weeks using a
validated HPLC method, the cefpodoxime proxetil content was found to be at least 90%.
In vivo performance of complex of cefpodoxime proxetil and hydroxypropyl (3-cyclodextrin (T) was evaluated with respect to the Cepodem™ 100 (Marketed By Ranbaxy Lab. Ltd.) tablets (R) in male Sprague-Dawely rats (weight: 250-275 gms) at a dose of 10 mg per kg (equivalent to cefpodoxime acid) body weight, under fasted conditions (with free access to water). All experiments and procedures on animals were conducted in accordance with protocols approved by the Animal Institutional Ethical Committee. Each formulation at the specified dose was administered orally, with the help of oral gauge needle along with saline. Blood samples (0.4-0.5 ml) were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours. Samples were centrifuged to separate plasma and drug content analyzed using a validated HPLC method. Pharmacokinetic parameters Cmax (Maximum plasma concentration), Tmax (Time to attain maximum plasma concentration), AUCo-t (Area under the plasma concentration vs time curve from 0 hours to the time of last sample collected) and AUC0-a (Area under the plasma concentration vs. time curve from 0 hours to infinity) were calculated from the data obtained. The data was analyzed using both MS-Excel™ and using non-linear regression software- PC-NONLIN™. The results of the study are represented in the table below. (Table Removed)

The above results clearly indicate the importance of preparing complex of cefpodoxime proxetil and cyclodextrins in improving the oral bioavailability of cefpodoxime proxetil.

WE CLAIM:
1. A pharmaceutical composition of cefpodoxime proxetil comprising cefpodoxime proxetil and cyclodextrin.
2. The pharmaceutical composition according to claim 1 wherein cefpodoxime proxetil may comprise from about 10% w/w to about 90% w/w of the composition.
3. The pharmaceutical composition according to claim 1 wherein cyclodextrin is selected from α-cyclodextrin, ß-cyclodextrin, -cyclodextrin, and δ-cyclodextrin and its pharmaceutically acceptable derivatives.
4. The pharmaceutical composition according to claim 3 wherein cyclodextrin is p-cyclodextrin derivative selected from the group consisting of hydroxyethyl-ß-CD, hydroxypropyl-ß-CD, sulfobutylether-ß-CD, methyl-ß-CD, dimethyl-ß-CD, randomly dimethylated-ß-CD, randomly methylated-ß-CD, carboxymethyl-ß-CD, carboxymethyl ethyl-ß-CD, diethyl-ß-CD, tri-O-methyl-ß-CD, tri-O-ethyl-ß-CD, tri-O-butyryl-ß-CD, tri-O-valeryl-ß-CD, di-O-hexanoyl-ß-CD, glucosyl-ß-CD, maltosyl-ß-CD, and 2-hydroxy-3-trimethyl-ammoniopropyl-ß-CD.
5. The pharmaceutical composition according to claim 1 wherein molar ratio of cefpodoxime proxetil and cyclodextrin may vary from about 1:9 to about 9:1.
6. The pharmaceutical composition according to any of the preceding claims wherein composition further comprises one or more of pharmaceutically inert excipients selected from the group consisting of one or more of water-soluble polymers, solvents, diluents, binders, disintegrants, surfactants, lubricants/glidants, stabilizers, plasticizers, coloring agents, flavoring agents, suspending agents, sweeteners and buffers.
7. The pharmaceutical composition according to any of the preceding claims prepared by a process comprising the steps of combining cefpodoxime proxetil with cyclodextrin and processing into suitable dosage form.
8. The pharmaceutical composition according to claim 7 wherein dosages form is selected from the group consisting of tablet, capsule, suspension/dispersion, solution, and dry syrup.
9. A method of improving the bioavailability of cefpodoxime proxetil by 1.25 times or more than from conventional oral dosage forms, by using complexes of cefpodoxime proxetil and cyclodextrin.
10. A method for treating bacterial infection in a mammal by administering to the said mammal a pharmaceutical composition of cefpodoxime proxetil comprising cefpodoxime proxetil and cyclodextrin.
11. A pharmaceutical composition of cefpodoxime proxetil as described and illustrated in the examples herein.