The technical field of the present invention relates to gastroretentive dosage forms of cephalosporins and process of preparation thereof. The technical field also relates to method of improving bioavailability of cephalosporins, using gastroretentive dosage forms.
Selection of the appropriate route of drug administration is of major importance, since the efficacy of the drug greatly depends thereon. The selection should be based upon pharmacokinetic and pharmacodynamic properties of the drugs. No doubt, the classical immediate release oral dosage forms are the most preferred dosage forms; the major disadvantages of such immediate release dosage forms include repeated frequency of administration and fluctuations in drug plasma levels. Use of oral controlled release preparations circumvents these problems. These delivery systems are designed to deliver the drug in such a way that the drug level is maintained within the therapeutic window, and effective and safe blood levels are maintained for an extended period, as desired.
A variety of controlled release dosage form designs have been reported in the literature. These controlled drug delivery systems are based on different modes of operation and have been variously named, for example, as dissolution controlled systems, diffusion controlled systems, ion exchange resins, osmotically controlled systems, erodable matrix systems, pH independent formulations, and swelling controlled systems.
The absorption of drug from the gastrointestinal tract is dictated by the location of the dosage form in the gastrointestinal tract and the gastrointestinal contents. The gastrointestinal tract provides variable pH conditions, which depends on the location, such as acidic pH in the stomach, which gradually increases towards the lower parts of the intestine. Since dissolution of the drug in the gastrointestinal fluids is a prerequisite for peroral absorption of drugs; the bioavailability is affected by their solubility, which is pH dependent in most of the cases. Therefore drugs having higher solubility at acidic pH remain the main candidates for gastroretentive dosage forms. As the drug remains in the stomach for a longer duration it gets absorbed well, and enhanced bioavailability compared to that of the conventional dosage forms is achieved.
Literature reveals examples wherein gastroretentive system has been used as a technology to enhance the bioavailability of drugs having increased solubility in the stomach or having stomach as their absorption window.
US 3,574,820 describes the use of a gelatin matrix that hydrates in the stomach, gels, swells and cross-links with N-acetyl- homocysteine thiolactone to form a matrix too large to pass through the pylorus.
Stockwell, A. F., et al, in Journal Controlled Release, 3, 167-175 (1986) describes an oral controlled drug delivery system comprising hydrocolloid calcium gelled alginate formulation and sodium bicarbonate.
Numerous patents/applications have been cited in the prior art, which include modifications in the composition of gastro-retentive dosage form for various drugs, including US 4,735,804, US 4,758,436, US 4,767,627, US 4,777,033, US 4,996,058, US 5,651,985, US 5,780,057, US 6,207,197, WO 0038650, WO 04002445 and each of which is incorporated in its entirety by reference herein.
WO 0164183 describes a gastroretentive system, which provides a combination of spatial and temporal control of the drug delivery, specifically for the drug ciprofloxacin. The pharmaceutical composition is prepared by mixing the drug with gas generating component, swelling agent, and one or both of viscolysing and gelling agents.
Use of gastroretentive controlled release dosage form is mainly restricted in the art, for drugs, which are more soluble in the stomach or have stomach as their absorption window.
We have now discovered that gastroretentive dosage forms could be used as a platform technology for poorly bioavailable drugs such as cephalosporins; which undergo extensive preabsorption degradation and efflux in the intestine. Moreover the additional benefits provided by such systems could enhance their bioavailability to surprising levels.
Hence in one general aspect there is provided, a method of improving the bioavailability of cephalosporin by 1.25 times or more than from conventional oral dosage forms, using gastroretentive 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, using gastroretentive 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 dosage forms comprising racemic cefpodoxime proxetil, using S-isomer of cefpodoxime proxetil.
In another general aspect there is provided, a gastroretentive dosage form of cephalosporin comprising cephalosporin, rate controlling agent and gas generating agent.
In another general aspect there is provided, a controlled release gastroretentive dosage form of cephalosporin comprising cephalosporin, rate controlling agent and gas generating agent.
In another general aspect there is provided, a gastroretentive dosage form of cefpodoxime proxetil comprising cefpodoxime proxetil, rate controlling agent and gas generating agent.
In another general aspect there is provided, a controlled release gastroretentive dosage form of cefpodoxime proxetil comprising cefpodoxime proxetil, rate controlling agent and gas generating agent.
In another general aspect there is provided, a gastroretentive dosage form of cefpodoxime proxetil comprising S-isomer of cefpodoxime proxetil, rate controlling agent and gas generating agent.
In another general aspect there is provided, a controlled release gastroretentive dosage form of cefpodoxime proxetil comprising S-isomer of cefpodoxime proxetil, rate controlling agent and gas generating agent.
In another general aspect there is provided, a process for the preparation of gastroretentive dosage form comprising the steps of combining cephalosporin with rate controlling agent, gas generating agent and processing into suitable dosage form.
The gastrointestinal tract, particularly the small intestine, is the primary site for the absorption of nutrients and most drugs. To accommodate the amount of absorption that must take place in the small intestine, the surface area is enlarged by the presence of villi and microvilli. However, before a drug is transferred from the intestinal lumen to the blood, it has to withstand degradation or deactivation by the various components of the luminal contents. Moreover, the drugs are required to pass through several absorption barriers, such as the mucous layer and the intestinal brush-border membrane. Few drugs pass these barriers easily, but there are many, such as cephalosporins, to which these barriers are a serious obstruction.
Cephalosporins, though effective against some of the more resistant bacteria, most of them are poorly absorbed through the mucosal membrane of the intestines and thus, have difficulty reaching the bloodstream. Therefore, these cephalosporins have been less effective when administered by routes other than parenteral.
There are several contributing factors other than solubility, why cephalosporins have low absorption in the intestine after oral administration. First, these antibiotics have high ionization properties that do not allow them to readily penetrate the intestinal mucosal membrane i.e these drugs undergo preabsorption degradation by the enzymes and the chemical environment of the intestine. Second, due to relatively high hydrophilic properties, these antibiotics are generally unstable in an aqueous environment such as intestinal fluid.
Many efforts have been made to develop dosage forms, which are absorbed from some other portion of gastrointestinal tract i.e other than intestine. Stomach could be the best site for such drugs as the enzymes that degrade these are less active in acidic pH. So one of the approach to increase the bioavailability of such drugs is to prepare gastroretentive dosage forms by which the drugs remain there for longer duration and are absorbed well.
Cefpodoxime proxetil is one of the prototype example of cephalosporins having poor bioavailability, commercially available conventional tablets of which show absolute bioavailability of only 50% compared to that of intravenous infusion.
Cefpodoxime proxetil is a non-crystalline, slightly basic compound with a pKa of 3.2, and K (octanoi/water) coefficient of 1.6. Further, it has been found that cefpodoxime proxetil exhibits gel formation and forms a gelatinous mass when in contact with aqueous media (Hamaura T. et.al., ST.P. Pharma Sciences, 1995; 5(4):324). The gel formed does not disintegrate easily leading to poor dissolution and hence absorption of cefpodoxime proxetil from the gastrointestinal tract is greatly reduced.
Systematic studies were conducted to determine the potential reasons for the poor bioavailability of cefpodoxime proxetil.
Solubility studies were conducted at different pH conditions and it was found that cefpodoxime proxetil has pH dependent solubility, which decreases with increase in pH. Though reduced, the solubility at intestinal pH is expected to be sufficient to achieve the desired absorption. Therefore reasons other than solubility are supposed to contribute to poor bioavailability.
Stability studies were done by varying the pH, wherein cefpodoxime proxetil appeared to be highly stable at pH-1.2 and stable up to twelve hours at pH 4.5. However, there was a sudden increase in the degradation at pH 6.8, with about 55% degradation within eight hours and complete degradation occurring in twenty four hours. The results of the study are represented in Figure 1.
So it could be inferred that cefpodoxime proxetil is stable at acidic pH and prone to increased degradation as it moves to lower parts of the gastrointestinal tract.
Regional enzyme metabolic studies were performed for racemic cefpodoxime proxetil, as well as R and S isomers of cefpodoxime proxetil using "Lowery estimation method", using microsomal enzyme fractions prepared from stomach, duodenum, jejunum and ileum of rats. The results of the study, represented in Figures 2, 3, and 4 indicate higher rates of degradation of cefpodoxime proxetil to cefpodoxime acid in jejunum and ileum
fractions compared to that of stomach and duodenum. Moreover, the S isomer of cefpodoxime proxetil degraded at a much slower rate compared to its R isomer.
In vitro rat intestinal "Everted Sac" studies further showed that cefpodoxime proxetil undergoes resorption into the intestinal lumen by efflux mechanism. Cefpodoxime proxetil is absorbed from the intestine into the enterocytes of intestinal membrane, rapidly converted to cefpodoxime acid and effluxed back into the intestinal lumen instead of getting absorbed into the blood circulation, thereby affecting the overall bioavailability. This kind of efflux mechanism is not severe in the stomach, as the enzymes, which catalyze the degradation, are present in minute amounts in the enterocytes of the gastric region.
From the above studies it was concluded that cefpodoxime proxetil is susceptible to degradation/metabolism to cefpodoxime acid, both under the influence of higher intestinal pH and/or non-specific enzymatic action of the contents of intestinal lumen or of the enterocytes in the intestinal membrane. In contrast, the pH as well as the lower degradative action of enzymes in the stomach as well as the enterocytes of the gastric membrane, favors the gastric region as a preferred site for targeting absorption of cephalosporins such as cefpodoxime proxetil. Absorption through the gastric region can be achieved by formulating the cephalosporin antibiotics into suitable gastroretentive dosage forms.
Gastroretentive dosage forms of the present invention may improve the bioavailability by 1.25 times or more, in particular 1.5 times or more than from conventional oral dosage forms. Less amount of cephalosporins would be required to achieve the plasma levels compared to that of conventional oral dosage forms. Hence gastroretentive dosage forms would be cost-effective and have reduced chances of dose-dumping leading to toxicity problems.
The gastric retention of solid dosage forms may be achieved by one or more of the mechanisms of mucoadhesion, flotation, sedimentation, expansion, or by the simultaneous administration of pharmacological agents which delay gastric emptying.
In its simplest form gastroretentive dosage form of the present invention comprises one or more of cephalosporin, release controlling agent, and gas generating agent.
Cephalosporin antibiotic is the general term for a group of antibiotic derivatives of cephalosporin C, which is obtained from the fungus Cephalosporium acremonium. These are wide-spectrum antibiotics used to treat a variety of infections in mammals. They have been grouped into three "generations" based primarily on their spectrum of antibacterial activity. First-generation cepahlosorins include cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, and cephradine and the like. Second-generation cephalosporins include cefaclor, cefamandole, cefmetazole, cefonicid, cefotetan, cefoxitin, cefprozil and cefuroxime and the like. Third-generation cephalosporins include cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftizoxime and ceftraxone and the like. Cephalosporins include free drug form as well as prodrugs, isomers, salts and derivatives thereof. Cephalosporins may be formulated into gastroretentive dosage forms as such or may be formed as molecular dispersion, or complexed or adsorbed on suitable carriers. Cephalosporins may comprise from about 10% w/w to about 85% w/w of the gastroretentive dosage form.
The release controlling agent is an agent, which on contact with water or gastric fluids swells and viscolyzes to trap the gas generated by gas generating agent. It may also absorb water to gel and form a cross-linked stable structure that entraps the generated gas. Thus with passage of time, it results into a hydrodynamically balanced system whereby the matrix is retained in the stomach for an extended period of time. This swollen matrix also helps to control the release of cephalosporins from the dosage form. Examples of release controlling agents include carbohydrate gums such as xanthan gum, tragacanth gum, gum karaya, guar gum, and acacia; water soluble salt of one or more polyuronic acids such as alkali metal salts of alginic acid like sodium alginate, potassium alginate, and ammonium alginate, alkali metal salts of pectic acid; polymers such as hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, polyacrylic acid, cross-linked polyacrylic acid polymer, polyvinylpyrollidone, ethyl cellulose, methyl cellulose, methacrylic acid copolymers, cellulose acetate phthalate, cellulose acetate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate; waxes; lipidic agents such as tripalmitin, tristearin, glycerol behenate, glycerol esters of saturated C12-18 fatty acids; and the like. The
release controlling agent may comprise from about 5% w/w to about 90% w/w, in particular from about 10% w/w to about 80% w/w of the gastroretentive dosage form.
The gas generating agent may consist of a single substance known to produce gas upon contact with gastric fluid, or may consist of a gas generating couple. The gas generating agent interacts with an acid source triggered by contact with water or simply with gastric fluid to generate carbon dioxide or sulfur dioxide that gets entrapped within the hydrated gel matrix of the swelling composition. Examples of the gas generating agents include carbonates such as calcium carbonate or sodium glycine carbonate; bicarbonates such as sodium hydrogen carbonate or potassium hydrogen carbonate; sulfites such as sodium sulfite, sodium bisulfite, or sodium metabisulfite; and the like. These may be used alone or in combination with an acid source as a couple. The acid source may be one or more of an edible organic acid, a salt of an edible organic acid, or mixtures thereof. Examples of organic acids include citric acid, malic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, ascorbic acid, glycine, sarcosine, alanine, taurine, glutamic acid, and the like. The gas generating agent may comprise from about 3% w/w to about 30% w/w, in particular from about 5% w/w to about 25% w/w of the gastroretentive dosage form.
Proper selection of release controlling agents and gas generating agents may provide varied release profiles from gastroretentive dosage forms, ranging from conventional immediate release to controlled release up to few hours.
Besides the above, gastroretentive dosage form may further comprise one or more pharmaceutical^ inert excipients such as dispersing agents, binders, diluents, lubricants/glidants, stabilizers and coloring agents.
Examples of dispersing agents include disintegrants, in particular superdisintegrants, which usually function to promote disintegration of the dosage form by absorbing large amounts of water and thereby swelling. Examples include sodium starch glycolate, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, microcrystalline cellulose, and the like and combinations thereof.
Examples of binders include methylcellulose, hydroxypropyl cellulose, hydroxy propyl methyl cellulose, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan,
pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol and the like and combinations thereof.
Examples of diluents include calcium carbonate, calcium phosphate-dibasic, calcium
phosphate-tribasic, calcium sulfate, magnesium hydroxide, powdered cellulose,
microcrystalline cellulose, dextrates, dextrins, dextrose, fructose, kaolin, lactitol,
lactose, mannitol, sorbitol, starch pregelatinized, sucrose, sugar compressible, sugar
confectioners and the like and combinations thereof.
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 coloring agents include any FDA approved colors for oral use.
In one of the embodiments a solid dispersion of cephalosporin may be prepared by dissolving cephalosporin and a release controlling polymer in a solvent; evaporating the solvent to yield a free flowing mass; sieving the free flowing mass through suitable sieves to yield a homogenous solid dispersion powder.

Effective solvent evaporation, without leading to environmental hazards may be achieved by processes of spray drying, vacuum drying, evaporation in the expansion chamber of the fluidized bed coater, and the like.
Alternatively the solid dispersion of cephalosporin antibiotics or prodrugs may be prepared by hot-melt, co-melt or congealing.
A suitable solvent used for preparing solid dispersion is one in which both cephalosporin and release controlling agent are sufficiently soluble but do not create any stability issues and/or environmental hazards. Specific examples of solvents include ethanol, methanol, isopropyl alcohol, and mixtures thereof.
In another embodiment, gastroretentive dosage form of cephalosporin may be prepared by blending cephalosporin and release controlling agent or a solid dispersion of cephalosporin and release controlling agent, with gas generating agent, and one or more pharmaceutically inert excipients; and processing into a suitable gastroretentive dosage form.
In another embodiment, gastroretentive dosage form of cephalosporin antibiotic may be prepared by blending cephalosporin and release controlling agent or a solid dispersion of cephalosporin and release controlling agent, with gas generating agent, and one or more pharmaceutically inert excipients; granulating the blend; and processing into a suitable gastroretentive dosage form.
Granulation may be carried out by wet or dry granulation, or extrusion-spheronization.
Examples of suitable gastroretentive dosage forms include oral dosage forms such as tablet, capsule, granule, and the like.
The performance of gastroretentive dosage form of the present invention may be analysed by evaluating certain parameters such as floating efficiency and release of the cephalosporin.
The invention is further illustrated by the following examples but they should not be construed as limiting the scope of the invention any way.
Examples

(Table Removed)
Procedure:
1. Cefpodoxime proxetil and rate controlling polymer (ingredient 3, 4, 5, 6, 7 or 8) were dissolved in organic solvent (methanol/chloroform) and spray dried to give a free-flowing solid dispersion powder.
2. Solid dispersion of step 1 was blended with sodium bicarbonate to form a homogenous blend.
3. Blend of step 2 was granulated using dry granulation technique (slugging) and sieved to form gastroretentive granules of suitable size (BSS#28-BSS#18).
Gastroretentive granules prepared above were found to have good floating efficiency, of about 2 hours in 0.1 N HCI media, and released about 80% cefpodoxime proxetil in 2 hours. Further, gastroretentive granules as per the compositions of example 1-7 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 95 %.
In vivo performance of gastroretentive dosage form (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 AUCo-α (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 gastroretentive dosage form in improving the oral bioavailability of cephalosporins.

WE CLAIM:
1. A gastroretentive dosage form of cephalosporin comprising cephalosporin, rate controlling agent and gas generating agent.
2. The gastroretentive dosage form according to claim 1 wherein cephalosporin is selected from the group consisting of first generation cephalosporins such as cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, and cephradine, second generation cephalosporins such as cefaclor, cefamandole, cefmetazole, cefonicid, cefotetan, cefoxitin, cefprozil, and cefuroxime, third generation cephalosporins such as cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftizoxime, and ceftraxone.
3. The gastroretentive dosage form according to claim 2 wherein cephalosporin may comprise from about 10% w/w to about 85% w/w of the gastroretentive dosage form.
4. The gastroretentive dosage form according to claim 1 wherein rate controlling agent is selected from the group consisting of carbohydrate gums such as xanthan gum, tragacanth gum, gum karaya, guar gum, and acacia; water soluble salt of one or more polyuronic acids such as alkali metal salts of alginic acid like sodium alginate, potassium alginate, and ammonium alginate, alkali metal salts of pectic acid; polymers such as hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, polyacrylic acid, cross-linked polyacrylic acid polymer, polyvinylpyrollidone, ethyl cellulose, methyl cellulose, methacrylic acid copolymers, cellulose acetate phthalate, cellulose acetate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate; waxes; lipidic agents such as tripalmitin, tristearin, glycerol behenate, glycerol esters of saturated C12-18 fatty acids; and the like.
5. The gastroretentive dosage form according to claim 4 wherein rate controlling agent may comprise from about 5% w/w to about 90% w/w of the gastroretentive dosage form.
6. The gastroretentive dosage form according to claim 1 wherein gas generating agent is selected from the group consisting of carbonates such as calcium carbonate or sodium glycine carbonate; bicarbonates such as sodium hydrogen
carbonate or potassium hydrogen carbonate; sulfites such as sodium sulfite, sodium bisulfite, or sodium metabisulfite; organic acids such as citric acid, malic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, ascorbic acid, glycine, sarcosine, alanine, taurine, glutamic acid, and the like.
7. The gastroretentive dosage form according to claim 6 wherein gas generating agent may comprise from about 3% w/w to about 30% w/w of the gastroretentive dosage form.
8. The gastroretentive dosage form according to any of the preceding claims wherein dosage form further comprises one or more of pharmaceutically inert excipients selected from the group consisting of dispersing agents, binders, diluents, lubricants/glidants, stabilizers and coloring agents.
9. The gastroretentive dosage form according to any of the preceding claims prepared by a process comprising the steps of combining cephalosporin with rate controlling agent, gas generating agent and processing into suitable dosage form.
10. The gastroretentive dosage form according to claim 9 wherein processing into suitable dosage form includes granulation carried out by wet or dry granulation techniques, or by extrusion-spheronization.
11. The gastroretentive dosage form according to claim 9 wherein dosage form is selected from the group consisting of granule, tablet and capsule.
12. A method of improving the bioavailability of cephalosporin by 1.25 times or more than from conventional oral dosage forms, using gastroretentive dosage form.
13. A method of improving the bioavailability of cefpodoxime proxetil by 1.25 times or more than from dosage forms comprising racemic cefpodoxime proxetil, using S-isomer of cefpodoxime proxetil.
14. A gastroretentive dosage form of cephalosporin as described and illustrated in the examples herein.