FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"A Process for preparation of stable pharmaceutical composition of sustained release Cefadroxil and probiotic bacteria"
2. APPLICANT
(a) NAME: IPCA LABORATORIES LTD.
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai-400067,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and its use thereof.

Technical Field:
The present invention relates to a process for preparation of pharmaceutical composition in the form of bilayered tablet comprising combination of a Cephalosporin antibiotics or its pharmaceutically acceptable salt thereof along with a probiotic bacteria such as lactobacillus which would prevent occurrence of diarrhea incidents. Cephalosporin antibiotic preferably Cefadroxil and lactobacillus are embedded in two different layers of the composition.
Background and Prior Art:
Cephalosporin antibiotics are a class of beta-lactum antibiotics. Together with cephamycins they belong to a sub-group called cephems. Cefadroxil is Cephalosporin antibiotics and is chemically known as 7-[D-a-amino-a-(p-hydroxyphenyl)acctamido]-3-methyl-3cephem-4-carboxylic acid. Cefadroxil is a well known antibiotic substance having antibacterial activity.
US 6,080,427 relates to uncoated direct compression tablets containing cefadroxil monohydrate as the active ingredient, which are capable of oral administration to human beings by swallowing, chewing or disintegrating in water resulting in a drinkable dispersion.
Cefadroxil is widely used first generation drug of Cephalosporins antibiotics. It is para-hydroxy analog of cephalexin. Virtually any antibiotic can cause antibiotic-associated diarrhea, colitis or pseudomembranous colitis.
Antibiotic-associated diarrhea occurs when antibiotics disturb the natural balance of "good" and "bad" bacteria in the intestinal tract, causing harmful bacteria to proliferate far beyond their normal numbers. The result is often frequent watery bowel movements. Most often, antibiotic-associated diarrhea is fairly mild and clears up shortly after one stop taking the antibiotic. Some of the bacteria that normally inhabit the intestinal tract
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are potentially dangerous. They're usually kept in check by beneficial bacteria unless the delicate balance between the two is disturbed by illness, medications or other factors.
Antibiotics can be especially disruptive to intestinal flora, the bacteria that normally live in the colon, because they destroy beneficial bacteria along with harmful ones. Without enough "good" microorganisms, "bad" bacteria that are resistant to the antibiotic received grow out of control, producing toxins that can damage the bowel wall and trigger inflammation. In addition to disrupting the balance of microorganisms in the digestive tract, antibiotics can also affect the rate of digestion and the breakdown of food.
US 6,120,803 discloses a polymer composition for prolonged delivery of an active agent. A portion of the polymer composition is surrounded by a band of insoluble material that prevents the covered portion of the polymer composition from swelling and provides a segment of the dosage form that is of sufficient rigidity to withstand the contraction of the stomach and delay expulsion of the dosage form from the stomach until substantially all the active agent has been dispensed.
US 5,128,142 discloses a controlled release formulation comprising an absorbate of a mixture of pharmaceutically active ingredients and an inactive substance absorbed on a cross-linked polymer. The inactive substance is selected to modify the dissolution of active ingredients from the cross linked polymer in vivo. The inactive substance is preferably present in the absorbate in an amount of 0.5-3 parts by weight relative to 1 part by weight of the active ingredients.
US 6,083,532 discloses a sustained release tablet composition comprising a drug to be released at a controlled comprising at least three different types of polymers including a pH dependent gelling polymer (e.g. alginate, a carboxyvinyl polymer, or a salt of a carboxymethyl cellulose), a pH independent gelling polymer (e.g. HPMC, HPEC, HPC, HEC, methylcellulose, xanthan gum or polyethylene oxide) and an enteric polymer (e.g. polyacrylate material, cellulose acetate phthalate, cellulose phthalate hydroxy propyl methyl ether).
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US 5,948,440 discloses a controlled release tablet of an active ingredient comprising of Cefaclor, Cephalexin or their pharmaceutically acceptable hydrates, salts or esters as active ingredients, a mixture of hydrophilic polymers preferably hydroxy propyl methylcellulose and optionally contains one or more of a water soluble or water dispersible diluent, such that the therapeutically effective active ingredient is released at a rate for twice daily administration of the pharmaceutical composition.
Antibiotic-associated diarrhea is a common clinical problem occurring in up to 25% of patients, the clinical and economic costs of antibiotic-associated diarrhea are significant and better treatments are needed.
Probiotics may offer potential effective therapy for antibiotic-associated diarrhea by restoring intestinal microbial balance. A number of different probiotics have been evaluated in the prevention and treatment of antibiotic-associated diarrhea in adults and children, including the nonpathogenic yeast Saccharomyces boulardii and multiple lactic-acid fermenting bacteria such as Lactobacillus rhamnosus GG (LGG).
The term "probiotics" is in general defined to be "living microorganisms capable of improving the balance of the enterobacterial flora in a host to thus bring beneficial effects on the host" (Fuller R.: Gut, 1991, 32:439 42). In addition, it has been reported that the probiotics typically represented by lactic acid bacteria possess a wide variety of functions as will be detailed below (Sanders M E & Huis in't Veld J: Antonie van Leeuwenhoek, 1999, 76: 293 315): 1) Assistance of lactose-digestion; 2) resistance to enterobacteria; 3) inhibition of the occurrence of colon cancer; 4) inhibition of small intestinal bacteria-excess proliferation; 5) immuno-modulating effects; 6) anti-allergic effects; 7) effects of reducing blood lipid concentration; 8) hypotensive effects; 9) inhibition of urinary tract-infection; 10) inhibition of Helicobacter pylori infection; and 11) inhibition of hepatic encephalopathy. Moreover, it has also been proved that the tooth-brushing with lactic acid bacteria is quite effective even for the prevention or treatment of periodontitis (IMAI, Tatsuya: Tooth-Brushing with Lactic Acid Bacteria for Curing Periodontitis
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Within 3 Days, published by MAKINO Publishing Company,2000).
As has been discussed above, it has been elucidated that the probiotics may improve the balance of not only the enterobacterial flora, but also bacterial florae in oral cavity, stomach and other digestive tracts as well as primogenital bacterial flora such as the intra-vaginal flora to thus bring beneficial effects on the host.
Lactic acid bacteria to be used in probiotics products are selected on the basis of the criteria or requirements such as the stability, the resistance to the acid in the stomach, the resistance to bile, the stability during manufacture of a product or the stability of the bacteria in the product, the adhesion to mucous membranes, the bacterial inhibitory effects and the ability of stimulating immuno responses (Sanders M E & Huis in't Veld J: Antonie van Leeuwenhoek, 1999, 76: 293 315).
However, a problem arises such that the lactic acid bacteria are discharged soon from, for instance, digestive tract and therefore, the products fail to maintain and show the desired functions of probiotics.
Supplementation of beneficial probiotic bacterial flora, such as Lactobacillus acidophilus, Bifidobacterium bifidus and Lactobacillus cassei, preferably in the form of a varied, vigorous and abundant culture, will restore the healthy intestinal ecology and stabilize the mucosal lining of the gut. A supplemental dosage of at least one billion organisms per day is necessary to achieve the critical mass of bacterial restoration and successfully reinvigorate healthy intestinal ecology.
Commercial probiotic preparations are generally comprised of mixtures of Lactobacilli and Bifidobacteria, although yeast such as Saccharomyces has also been utilized.
Unfortunately, most, if not all, lactic acid-producing or probiotic bacteria are extremely sensitive to common antibiotic compounds. During a normal course of antibiotic therapy; many individuals develop a number of deleterious physiological side-effects including: diarrhea, intestinal cramping, and sometimes constipation. These side-effects are

primarily due to the non-selective action of antibiotics, as antibiotics do not possess the ability to discriminate between beneficial, non-pathogenic and pathogenic bacteria, both bacterial types are killed by these agents. Thus, individuals taking antibiotics offer suffer from gastrointestinal problems as a result of the beneficial microorganisms (i.e. intestinal flora), which normally colonize the gastrointestinal tract, being killed or severely attenuated. The resulting change in the composition of the intestinal flora can result in vitamin deficiencies when the vitamin-producing intestinal bacteria are killed, diarrhea and dehydration and, more seriously, illness should a pathogenic organism overgrow and replace the remaining beneficial gastrointestinal bacteria.
US6461607 or US application no. 20030031659 discloses compositions and methodologies for the utilization of probiotic organisms in therapeutic compositions.
Lactobacilli have also been examined as a treatment of urinary-tract infections (Am. J. Health Syst. Pharm. 2001, 58 (12): p 1101-1109). For example the installation of Lactobacillus, and stimulation of indigenous organisms, has been employed to prevent recurrence of urinary tract infections (Microecol.Ther.: 32-45). The role of Lactobacilli in preventing urogenital and intestinal infections has also been investigated (Intl. Dairy J 1998.8 : 555-562).
US 5,032, 399 discloses therapeutically beneficial strains of L. acidophilus and especially a strain characterized in that an average of at least 50 bacteria were found to adhere to one human small intestinal mucosal cell after a five minute incubation of the bacteria with the cell. The strain was also characterized with respect to lactic acid production and hardy growth.
WO 99/45099 discloses a novel strain of L. plantarum LB931. This strain can be used for treating or preventing urogenital infections. The strain was able to adhere well to vaginal epithelial cells as well as to inhibitor) prevent growth of different bacterial strains.
US 6, 093, 394 (WO 98/46261) discloses novel strains, e.g. L. crispatus CTV 05, isolated
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from vaginal smears. The strain is characterized by an increased ability to adhere to vaginal epithelial cells and to produce hydrogen peroxide. The L. crispatus CTV-05 was found to have a percent vaginal epithelial cell (VEC) cohesion value of greater than 50%. The percent VEC cohesion value is defined as the percentage of VECs to which at least one Lactobacillus cell has adhered in the total number of VECs in an identified group.
EP0956858 discloses the use of different Lactobacillus strains alone or in combination. The strains were selected based on their ability to adhere to HeLa cells and to produce hydrogen peroxide.
WO 97/29762 discloses compositions comprising extract of plant species of Ericaceae family and a culture of at least one species of microencapsulated bacteria such as Lactobacillus and/or Bifidobacterium. The composition is useful in preventing and/or treating urogenital and intestinal disorders.
In EP1485463 Novel Lactobacilli strains such as Lactobacillus acidophilus strain Lba EB01 (Lba EB01), Lactobacillus paracasei strain Lbp PB01 (Lbp PB01) and strains with essentially the same advantageous properties which alone or in combination can be used as probiotics or together with a prebiotic as a synbiotic for prevention or treatment of vaginal infections, urogenital infections and gastrointestinal diseases. This patent discloses a novel gastric acid- and bile salt-resistant. Lactobicillus isolates having the ability to lower and assimilate serum cholesterol and to use thereof.
However, after being ingested into the human body, lactic acid bacteria encounter pressure from the gastrointestinal environment and specificity of intestinal absorption. Therefore, lactic acid bacteria have to first overcome the unfavorable environment of the digestive system and colonize the intestinal tract in order to grow and exert their reaction(s) in the intestinal tract. Further, Lactobacillus acidophilus strains are a group of bacteria having complex nutritional requirements. The bacteria are relatively stable in fermented milk. However, the bacteria in commercially available products (in forms of dry powder, grains, tablets) can hardly remain viable after long-term storage at room or
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refrigerated temperature so that the level of the bacteria cannot be easily maintained at an initial storage level. Accordingly, the actual number of bacteria in a non-fermented milk product is often less than that indicated on the product label. Hence, how to maintain the level of lactic acid bacteria in lactic acid bacteria products during marketing and storage is of utmost importance to manufacturers.
Furthermore, screening bacteria to obtain bacterial strains having good resistance to acids and bile salts and capable of lowering serum cholesterol is an important subject in the development of excellent Lactobacillus products.
There are a number of studies on lactic acid bacteria worldwide. Many of the patents and publications on the acid tolerance and cholesterol lowering ability of Lactobacillus species are directed to Lactobacillus acidophilus, and are largely concerned with bile- and acid-resistant bacterial strains, or are mainly focused on their ability to reduce cholesterol and bile tolerance. At present, studies carried out on the bile tolerance of Lactobacillus sp. emphasizes that the bacterial strains can grow in an environment containing 0.3% glycoholate, and acid tolerance is tested using media at pH 2, the acidic condition occurring in the gastrointestinal tract at the initial stage of gastric juice secretion.
Proper balance of friendly bacteria in the digestive tract is critical, not only after birth, but also when humans and animals are under stress or being treated with antibiotics. Theoretically, if beneficial organisms could be enhanced and potential pathogens inhibited. The use of organisms for this purpose is termed as probiosis meaning 'for life'. This is in contrast by antibiotics which means 'against life'. Because of their sometimes broad-spectrum antimicrobial activity, antibiotics often kill the normal desirable microflora of the intestinal tract. Potentially pathogenic bacteria may then fill this void. Thus probiotics like lactic acid bacillus are a promising alternative among the individual who have adverse reactions to antibiotics.
Indian patent No INI89626 describes a process for the preparation of stable pharmaceutical formulations containing an antibacterial substances and microorganisms
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that is effective and prevents occurrences of customary diarrhea associated with antibiotic therapy. This formulation wherein form of liquid dosage, reconstitute dry powder or as in dispersible tablet.
Cefadroxil, has less (1.2hrs) half life, needs prolonged minimum inhibitory concentration for effective antibacterial therapy and better patient compliances. Cefadroxil, an antibiotic, kills lactic acid bacillus spores when combined together. Thus, it is rational to use bilayered tablet with cefadroxil as sustained release layer and lactobacillus as conventional release layer for enhanced therapeutic efficacy.
Objective:
This object of the invention is to develop a process for preparation of a stable pharmaceutical composition comprising cefadroxil or pharmaceutically acceptable salt thereof along with probiotic bacteria which would prevent occurrence of diarrhea incidents.
Summary Of The Invention:
The present invention relates to a process for preparation of dual release drug profile comprising of two active ingredients, Cefadroxil and probiotics such as lactobacillus which are formulated in a single dosage. The process involves use of hydrophilic (hydroxy propyl methyl cellulose) polymers, which helps to extend release of drug over specific period of time and method of preparation thereof. As the product is dual release drug and formulated by dual release drug absorption system it is mentioned as Duredas technology.
The said pharmaceutical composition of cefadroxil monohydrate and lactobacillus according to the invention is preferably in the solid dosage form, such as tablets, pills, granules, capsules or sachets, preferably bilayered tablets.
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Detailed Description:
The present invention relates to novel stable solid pharmaceutical compositions for oral administration that comprises two incompatible substances an antibacterial drug such as cefadroxil and a probiotic bateria such as lactobacillus, along with pharmaceutically acceptable excipients.
The said composition further provides two drugs combination therapy wherein, one is sustained release antibiotic agent and it involves use of hydrophilic polymer such as hydroxypropyl methyl cellulose K15 M and is used in both, granulation and blending stage, which provides sustained release of one active drug over specific period of time and other is probiotic agent such as lactobacillus to restored beneficial intestinal microflora in conventional release layer.
The present invention provides the pharmaceutically stable composition which improves patient compliances to the antibacterial substances therapy by providing medicament in to once a day only and reduces dose of antibacterial agent.
The probiotic bacteria used is preferably lactobacillus in the range of 20 to 100 million spores preferably, 90 million spores.
Another embodiment of the present invention is to reduce the dose of one of the active ingredient by stable pharmaceutical compositions dual release hence, it is important to formulate the product as dual release drug absorption system.
The present pharmaceutical composition comprises cefadroxil monohydrate and lactobacillus in combination with pharmaceutically acceptable excipients selected from diluents, binders, preservatives, pH adjuster, alkalizing agent, disintegrating agents, film formers, lubricants and/or glidants.
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The present invention relates to a process for dual release drug comprising of two active ingredients, which are formulated in a single dosage form providing different release profile. It involves use of a hydrophilic polymer preferably, hydroxypropyl methyl cellulose K15 M which helps to extend release of drug over specific period of time.
There exists a need to provide a method for dual release drug wherein formulated by dual release drug absorption system (Duredas).
An embodiment of the present invention provides a process for preparing a stable pharmaceutical composition comprising a cefadroxil monohydrate and lactobacillus.
The process for preparing formulation comprises (i) non-aqueous granulating of cefadroxil monohydrate and an extend release granules comprising a of hydrophilic (hydroxy propyl methyl cellulose) polymers, along with selected excipients, (ii) lactobacillus together with selective excipients, (iii) compressing of (i) and (ii) into two layer tablets characterized by the presence of the two drug substances in two different layers with or without coating.
The said diluents are microcrystalline cellulose or Avicel pH 2 and are used in the range of 2 to 95% of tablet weight.
The said binders are selected from the group containing polyvinylpyrrolidone and are present in the range of 3 to 15%.
The said disintegrants are selected from the group containing starch, derivative of starch, preferably sodium starch glycolate in the range of 1 -6%.
The said Lubricants are selected from the group consisting of magnesium stearate and colloidal silicon dioxide. Magnesium stearate is present in the range of 0.25% to 5.0% and colloidal silicon dioxide is present in the range of 0.1% to 0.5%.
The Glidant used is purified talc and is present in the range of 0.1% to 1.92%.
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The said polymer a hydrophilic polymer used is hydroxy propyl methyl cellulose in the range of 0.45% to 1.0%.
Colors are selected from the group consisting of iron red oxide and Quinoline yellow and is present in the range of 0.1 to 5%.
Other miscellaneous auxiliaries required for processing the product and maintaining stability.
The said compositions of Cefadroxil monohydrate and lactobacillus are physically and chemically stable over its shelf life period.
The said pharmaceutical composition of Cefadroxil monohydrate and lactobacillus according to the invention is preferably in the solid dosage form, such as tablets, pills, granules, capsules or sachets, preferably bilayered tablets.
The process of preparation of pharmaceutical composition comprises of; granulating cefadroxil monohydrate together with selected excipients by non-aqueous granulation process, blending the said granules of cefadroxil with lubricants and glidants; wherein a hydrophilic polymer, hydroxypropyl methyl cellulose K15 M are used both in granulation and blending stage; blending the Lactic acid bacillus spores with disintegrants, lubricants and glidants and compressing the said two blends into bilayered tablet where each layer represents blend comprising single active ingredient with excipients.
The following examples illustrate various aspects of the present invention:
Example 1
Cefadroxil granules: Contains l000mg cefadroxil monohydrate equivalent to l000mg
cefadroxil along with the following excipients.
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Sr. No. Ingredient Qty % w/w of total weight
1 Cefadroxil monohydrate 87.69%
2 Microcrystalline cellulose 2.832%
3 Hydroxypropyl methyl cellulose K15 M 6.122%
4 Polyvinylpyrrolidone K90 1.951 %
5 Magnesium stearate 0.987%
6 Isopropyl alcohol qs
7 Talc 0.408
Preparation of cefadroxil granules:
Cefadroxil monohydrate sifted through mesh #20 whereas microcrystalline cellulose, hydroxy propyl methyl cellulose, a hydrophilic polymer sifted through mesh #40 and all were mixed geometrically. This blend was granulated with mixture of polyvinylpyrrolidone 90 and isopropyl alcohol using non-aqueous wet granulation. The wet granules were milled through mesh #8. Granules are initially air-dried and then at about 55°C.
Dried granules were sifted through mesh #20 and lubricated with magnesium stearate, talc and a hydrophilic hydroxy propyl methyl cellulose polymer. This is sustained release layer.
Lactic acid bacillus 90 million spores

Sr. No. Ingredient Qty % w/w of total weight
1 Lactic acid bacillus 11.588%
2 Avicel pH 102 66.411%
3 Colloidal silicon dioxide 0.57%
4 Sodium starch glycolate 2.285%
5 Talc 0.57%
6 Iron oxide Red 0.57%
7 Magnesium stearate 0.857%
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Avicel pH 102, colloidal silicon dioxide, sodium starch glycolate and talc were mixed geometrically after sifting through mesh #40. Iron oxide red colour was sifting through mesh #100 and mixed geometrically with above blend. This coloured blend than mixed geometrically with Lactic acid bacillus spores after sifting then through mesh #40 and finally the mixture is lubricated with magnesium stearate. This phase is conventional release layer.
A bilayered tablet was produced by two stage pressing procedure:
The granules of sustained release layer are compressed first and the conventional release
layer is then added and is pressed to form another layer.
The tablet is weighing 1400 mg ± 5% (containing 1225mg of sustained release layer and
175 mg of conventional release layer) and is 21 x 9.5 mm in dimension.
Example 2:
Cefadroxil granules: Contains l000mg cefadroxil monohydrate equivalent to l000mg cefadroxil along with the following excipients.

Sr. No. Ingredient Qty % w/w of total weight
1 Cefadroxil monohydrate 87.91%
2 Microcrystalline cellulose 3.273%
3 Hydroxypropyl methyl cellulose K15 M 6.17%
4 Polyvinylpyrrolidone K90 1.636%
5 Magnesium stearate 0.998%
6 Isopropyl alcohol qs
Preparation of cefadroxil granules:
Cefadroxil monohydrate sifted through mesh #20 whereas microcrystalline cellulose, hydroxy propyl methyl cellulose, a hydrophilic polymer sifted through mesh #40 and all were mixed geometrically. This blend was granulated with mixture of
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polyvinylpyrrolidone 90 and isopropyl alcohol using non-aqueous wet granulation.
Granules were milled through mesh #8. Granules are dried at about 55°C.
Dried granules were sifted through mesh #20 and lubricated with magnesium stearate and
a hydrophilic hydroxy propyl methyl cellulose polymer. This phase is sustained release
layer.
Lactic acid bacillus 90 million spores

Sr. No. Ingredient Qty % w/w of total weight
1 Lactic acid bacillus 10.14%
2 Avicel pH 102 85.11%
3 Colloidal silicon dioxide 0.5%
4 Sodium starch glycolate 2.75%
5 Talc 0.5%
6 Iron oxide Red 0.25%
7 Magnesium stearate 0.75%
Avicel pH 102, colloidal silicon dioxide, sodium starch glycolate and talc were mixed geometrically after sifting through mesh #40. Iron oxide red colour was sifting through mesh #100 and mixed geometrically with above blend. This coloured blend than mixed geometrically with Lactic acid bacillus spores after sifting then through mesh #40 and finally the mixture is lubricated with magnesium stearate. This phase is conventional release layer.
A bilayered tablet was produced by two stage pressing procedure:
The granules of sustained release layer are compressed first and the conventional release
layer is then added and is pressed to form another layer.
The tablet is weighing 1400 mg ± 5% (containing 1225mg of sustained release layer and
175 mg of conventional release layer) and is 21 x 9.5 mm in dimension.
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Example 3:
Cefadroxil granules: Contains l000mg cefadroxil monohydrate equivalent to l000mg cefadroxil along with the following excipients.

Sr. No. Ingredient Qty % w/w of total weight
1 Cefadroxil monohydrate 87.89%
2 Microcrystalline cellulose 3.31%
3 Hydroxypropyl methyl cellulose K15 M 5.62%
4 Polyvinylpyrrolidone K90 1.65%
5 Magnesium stearate 0.99%
6 Isopropyl alcohol Qs
7 Quinoline yellow 0.12%
8 Talc 0.41%
Preparation of cefadroxil granules:
Cefadroxil monohydrate sifted through mesh #20 whereas microcrystalline cellulose, a hydrophilic polymer, hydroxy propyl methyl cellulose and quinoline yellow sifted through mesh #40 and all were mixed geometrically. This blend was granulated with mixture of polyvinylpyrrolidone 90 and isopropyl alcohol using non-aqueous wet granulation. The wet granules were milled through mesh #8. Granules are dried at fluidized bed drier.
Dried granules were sifted through mesh #16 and lubricated with magnesium stearate, talc and a hydrophilic hydroxy propyl methyl cellulose polymer. This phase is sustained release layer.
Lactic acid bacillus 90 million spores

Sr. No. Ingredient Qty % w/w of total weight
1 Lactic acid bacillus 10.14%
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2 Avicel pH 102 85.11%
3 Colloidal silicon dioxide 0.5%
4 Sodium starch glycolate 2.75%
5 Talc 0.5%
6 Magnesium stearate 1%
Lactic acid bacillus spores, Avicel pH 102, colloidal silicon dioxide, sodium starch glycolate and talc were mixed geometrically after sifting through mesh #40. This blend is lubricated with magnesium stearate. This phase is conventional release layer.
A bilayered tablet was produced by two stage pressing procedure:
The granules of sustained release layer are compressed first and the conventional release
layer is then added and is pressed to form another layer.
The tablet is weighing 1410 mg ± 5% (containing 1210mg of sustained release layer and
200 mg of conventional release layer) and is 21 x 9.5 mm in dimension.
Example 4:
Cefadroxil granules: Contains l000mg cefadroxil monohydrate equivalent to l000mg cefadroxil along with the following excipients.

Sr. No. Ingredient Qty % w/w of total weight
1 Cefadroxil monohydrate 88.28%
2 Microcrystalline cellulose 2.32%
3 Hydroxypropyl methyl cellulose K15 M 5.92%
4 Polyvinylpyrrolidone K90 1.96%
5 Magnesium stearate 0.84%
6 Isopropyl alcohol Qs
7 Quinoline yellow 0.28%
8 Talc 0.41%
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Preparation of cefadroxil granules:
Cefadroxil monohydrate sifted through mesh #20 whereas microcrystalline cellulose, a hydrophilic polymer, hydroxy propyl methyl cellulose, quinoline yellow sifted through mesh #40 and all were mixed geometrically. This blend was granulated with mixture of polyvinylpyrrolidone 90 and isopropyl alcohol using non-aqueous wet granulation. The wet granules were milled through mesh #8. Granules are dried at fluidized bed drier. Dried granules were sifted through mesh #16 and lubricated with magnesium stearate, talc and hydrophilic polymer, hydroxy propyl methyl cellulose. This phase is sustained release layer.
Lactic acid bacillus 90 million spores

Sr. No. Ingredient Qty % w/w of total weight
1 Lactic acid bacillus 10.14%
2 Avicel pH 102 85.11%
3 Colloidal silicon dioxide 0.5%
4 Sodium starch glycolate 2.75%
5 Talc 0.5%
6 Magnesium stearate 1%
Avicel pH 102, colloidal silicon dioxide, sodium starch glycolate and talc were mixed geometrically after sifting through mesh #40. This blend than mixed geometrically with Lactic acid bacillus spores after sifting then through mesh #40 and finally the mixture is lubricated with magnesium stearate. This phase is conventional release layer.
A bilayered tablet was produced by two stage pressing procedure:
The granules of sustained release layer are compressed first and the conventional release
layer is then added and is pressed to form another layer.
The tablet is weighing 1417 mg ± 5% (containing 1217mg of sustained release layer and
200 mg of conventional release layer) and is 21 x 9.5 mm in dimension.
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The dissolution profile of the modified release composition is studies and shown as
follows:
Dissolution profile:

Hrs. Limits Results
2 30-60% 44.27%
6 60%- 85% 71.00%
12 NLT 80% 88.84%
The pharmaceutical composition of is physically and chemically stable over its shelf life period. The stability data is as follows:

Test Specification Hrs. Initial After 03 months
white / yellow coloured,
Appearance bilayered, oval, biconvex, plain tablets Complies Complies
30±2°C & 65±5%Rh 2 hrs 30-60% 6 hrs 60%- 85% 2 44.27% 49.11%
6 71.00% 72.75%
12 88.84% 88.72%
Dissolution 8 hrs NLT 80%
, 25±2°C & 60±5%Rh 2 hrs 30-60% 6 hrs 60%- 85% 2 44.27% 46.83%
6 71.00% 69.49%
12 88.84% 88.20%
8 hrs NLT 80%
30±2°C & 65±5%Rh ND 101.39%
Assay 90%-110%
25±2°C & 60±5%Rh ND 99.08%
NLT 90%
The assay for Lactic acid bacillus is as follows:
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Test Specification Initial After 3 months
Assay In accelerated conditions NLT 90% 274.44% 117.77%
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
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We Claim:
1. Process for preparation of stable bilayered tablet compositions with Duredas
technology comprising an antibacterial agent such as cefadroxil; and probiotic
bacteria, such as lactobacillus, wherein lactobacillus is incorporated as
conventional release component and cefadroxil is incorporated as sustained
release component; involving the following steps:
a. granulating cefadroxil with pharmaceutically acceptable excipients by
non-aqueous granulation process and blending the said granules of
cefadroxil with hydrophilic polymer, diluent, disintegrants, binders,
lubricants and glidants, color, retarded polymers to form a blend (a);
b. admixing lactobacillus with pharmaceutically acceptable excipients with
diluent, binder, disintegrants, lubricants, glidants and colour to form a
blend (b);
c. compressing the said blend (a) and blend (b) into a bilayered tablet
wherein each layer represents blend (a) or blend (b) comprising the said
single active ingredient with the said excipients.
2. Process for the stable pharmaceutical compositions as claimed in claim 1, wherein the said cefadroxil is in the form of salts selected from cefadroxil monohydrate or hemihydrate, preferably cefadroxil monohydrate in range of 500 to 1000 mg, preferably l000mg.
3. Process for the stable pharmaceutical compositions as claimed in claim 1, wherein, the lactobacillus spores is present in the range of 20 to 100 million spores, preferably 90 million spores.
4. Process for the stable pharmaceutical compositions as claimed in claim 1, wherein, the hydrophilic polymer is Hydroxypropyl methyl cellulose K15 M.
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5. Process for the stable pharmaceutical compositions as in claim 1, wherein the diluents are selected from the group consisting of microcrystalline cellulose and Avicel pH 2 preferably in the range of 2 to 95% of tablet weight.
6. Process for the stable pharmaceutical compositions as in claim 1, wherein, the
binders are selected from the group consisting of microcrystalline cellulose or
polyvinylpyrrolidone preferably polyvinylpyrrolidone particularly
polyvinylpyrrolidone K90.
7. Process for the stable pharmaceutical compositions as in claim 1, wherein the binders are present in the range of 3 to 15% wt. of tablet weight.
8. Process for the stable pharmaceutical compositions as in claim 1, wherein disintegrants are selected from the group consisting of starch or it's, derivative, preferably sodium starch glycolate.
9. Process for the stable pharmaceutical compositions as in claim 1, wherein the disintegrants are present in the range of 1-6 % wt. of tablet weight.
10. Process for the stable pharmaceutical compositions as in claim 1, wherein lubricants are selected from the group consisting of magnesium stearate, and colloidal silicon dioxide.
11. Process for the stable pharmaceutical compositions as in claim 1, wherein magnesium stearate used is in the range of 0.25% to 5.0% and colloidal silicon dioxide is used in the range of 0.1% to 0.5%.
12. Process for the stable pharmaceutical compositions as in claim 1, wherein the glidant is purified talc and is used in range of 0.1% to 1.92%.
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13. Process for the stable pharmaceutical compositions as in claim 1, wherein retarded polymers selected are hydrophilic polymer preferably hydroxy propyl methyl cellulose, used in the range of 0.45% to 1.0%.
14. Process for the stable pharmaceutical compositions as in claim 1, wherein colorant such as iron oxide yellow and Quinoline yellow and are used in the range of0.1%to5%.
15. Process for the stable pharmaceutical compositions as in claim 1, wherein solvent used is isopropyl alcohol in range of 0.5 to 2%.
16. Process for the stable pharmaceutical compositions as claimed in claim 1,
wherein the compositions are tablet or capsule, preferably tablet particularly
bilayered tablet.
17. Stable pharmaceutical compositions as claimed in any of the preceding claims 1
to 12 and their process of preparation as described herein with reference to the
foregoing examples 1-4.



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Abstract;
A process for the preparation of pharmaceutical composition in the form of bilayered tablet comprising pharmaceutically acceptable combination of Cephalosporin antibiotics such as Cefadroxil incorporated as sustained release component and probiotic bacteria such as lactobacillus incorporated as conventional release component. The bilayered tablet composition is prepared by two stage pressing method i.e. compressing a granulation of one active agent onto a previously compressed granulation of another active agent.
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