Title of Invention	PROCESS FOR PREPARATION OF A BILAYER TABLET
Abstract	Disclosed herein is a process for the preparation of a pharmaceutical composition in the form of a tablet comprising two discrete layers wherein the first sustained release layer is prepared by granulation of a therapeutically effective amount of antibiotic preferably Cloxacillin or Dicloxacillin or its pharmaceutically acceptable salts thereof, with pharmaceutically acceptable excipients, and the second immediate release layer is prepared by mixing a therapeutically effective amount of cephalosporin preferably Cefixime or pharmaceutically acceptable salt and a probiotics preferably Lactobacillus sporogenes spores with pharmaceutically acceptable excipients.

Title of Invention

PROCESS FOR PREPARATION OF A BILAYER TABLET

Abstract

Disclosed herein is a process for the preparation of a pharmaceutical composition in the form of a tablet comprising two discrete layers wherein the first sustained release layer is prepared by granulation of a therapeutically effective amount of antibiotic preferably Cloxacillin or Dicloxacillin or its pharmaceutically acceptable salts thereof, with pharmaceutically acceptable excipients, and the second immediate release layer is prepared by mixing a therapeutically effective amount of cephalosporin preferably Cefixime or pharmaceutically acceptable salt and a probiotics preferably Lactobacillus sporogenes spores with pharmaceutically acceptable excipients.

Full Text	FORM 2 THE PATENTS ACT 1970 (39 of 1970) AND The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rulcl3) 1. TITLE OF THE INVENTION: "SOLID PHARMACEUTICAL DOSAGE FORMS" 2. APPLICANT (S): (a) NAME: FDC Limited (b)NATIONALITY: Indian company incorporated under the Companies Act 1956 (e) ADDRESS: 142-48, S.V. Road, Jogcshwari (West), Mumbai - 400 102, Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed. Technical field The present invention relates to a process for the preparation of a pharmaceutical composition in the form of a tablet comprising two discrete layers wherein the first sustained release layer is prepared by granulation of a therapeutically effective amount of antibiotic preferably Cloxacillin or Dicloxacillin or its pharmaceutical!}' acceptable salts thereof with pharmaceutical!}-' acceptable excipients., and the second immediate release layer is prepared by mixing a therapeutically effective amount of cephalosporin preferably Cefixime or pharmaceutical!)' acceptable salts thereof and a probioties preferably Lactobacillus sporogenes spores with pharmaceutically acceptable excipients. The present invention also relates to the use of this formulation for the treatment of bacterial infections such as respiratory tract infections, skin and soft tissue infections, urinary tract infections, otitis media, pneumonia and cystitis. Background and prior art Cefixime is a third generation orally active, broad spectrum cephalosporin active against a wide range of gram positive and gram negative bacteria. Cefixime is a bactericidal antibiotic and is stable to hydrolysis by many beta-lactamases. Cefixime exhibits good in vitro activity against most of the Enterobacteriaceae. Haemophilus influenzae and Neisseria gonorrhoea (including bela-lactamase producing strains), beta-haemolytic streptococci of groups A and B and Streptococcus pneumoniae. . Against H. influenzae and N. gonorrhoeae Cefixime has been shown to be highly inhibitory to all strengths tested. For H. influenzae, this included strains resistant to i ampicillin, cefaclor, cephalexin, chloramphenicol and colrimoxazole. Cefixime is widely used in the treatment of respiratory tract infections. The drug has shown excellent safety and efficacy in the treatment of these infections. It is even widely prescribed to children. Cefixime despite its potent activity against other gram positive cocci like streptococcus is inactive against staphylococci except Staphylococcus aureus 2 which is considerably less susceptible. Faecal streptococci, Pseudomonas aeruginosa, most anaerobes and Chlamydia trachomatis are insusceptible This makes the drug less effective in common day-to-day infections like respiratory tract infections or skin & soft tissue infections. This is a limitation to the use of a safe cephalosporin like Cefixime. Although Cefixime has been considered as a highly safe and effective drug for the treatment of many bacterial infections, because of its instability in presence of staphylococci hinders not only its therapeutic activity but also clinical outcome. Although Cefixime has been considered as a highly safe and effective drug for the treatment of many bacterial infections, because of its instability in presence of staphylococci hinders not only its therapeutic activity but also clinical outcome. Isoxazolyl penicillins such as Cloxacillin. Dicloxacillin and Oxacillin are penicillinase-resistant.. Based on its spectrum of activity Cloxacillin is classified as second generation penicillin. Cloxacillin is active against gram positive organisms like staphylococci, streptococci, etc. In addition. Cloxacillin is stable to beta lactamases produced by gram positive organisms. Addition of Cloxacillin to Cefixime would provide: a. Effective coverage of all gram positive organisms like staphylococci, streptococci, thereby making the combination effective in a wide range of infections, common day- to-day infections like respiratory tract infections, skin & soft tissue infections etc. b. the combination stable to beta lactamases produced by staphylococci thereby making the combination "tough". Combination of Cefixime and Cloxacillin will meet the challenges of day-to-day infections like respiratory tract infections and skin & soft tissue infections. Cloxacillin is widely accepted and is used in combination with Ampicillin and Amoxyciliin mainly to increase the efficacy of these safe antibiotics in the treatment of 3 staphylococcal infections. In addition, studies have shown synergism between Cloxacillin and Gentamicin. Lactic acid bacilli, the so-called 'friendly bacteria' are a member of natural gastro¬intestinal flora. They are also known as probiotics. Probiotics are the living microbial food ingredients that colonize the intestinal tract and have a beneficial effect on the human health. Lactic acid bacilli are found to be useful in conditions like traveler's diarrhoea, antibiotic induced diarrhoea, infantile diarrhoea, infectious diarrrhoea caused by viruses and bacteria (like diarrhoea due to rotavirus, salmonella, shigella etc.). Lactic acid bacilli when given simultaneously with an antibiotic are capable of colonizing the intestinal tract despite the antibiotic treatment, re-establishing the intestinal microflora. This would reduce the incidence of diarrhoea and Gl disturbance following antibiotic therapy. Diarrhoea and stool changes like soft stools, and loose stools have been the most frequently reported adverse effects with use of Cefixime and Cloxacillin, in adults as well as children. These side effects can interfere with the patient compliance and can result in premature stopping of treatment, which can result in treatment failure. Antibiotic therapy often disrupts the balance of the intestinal microorganisms resulting in abnormal intestinal and bowel function. Lactic acid bacilli are believed to be effective in suppressing the growth of pathogenic microorganisms and re-establishing the normal intestinal flora. This would reduce the incidence of adverse effects like diarrhoea, improve the patient compliance and would result in better cure rates. US 6306391 disclosed a pharmaceutical composition comprising at least one anti infective ingredient as a first active ingredient and at least one microorganism as a second active ingredient. Patent discloses protection of susceplible organisms from the effect of anti infective agent by creating barrier around the microorganism or an anti infective acenl. 4 Japanese Patent No. 1083025 discloses blended preparation of drug resistant live bacterial agent for controlling intestinal function. The said preparation includes anti microbial agent that is blended with anti bacterial agent. However patent does not discloses preparation of the formulation comprising two antibacterial agents. EP1566116 discloses two types of release matrices, a controlled release matrix containing Cloxacillin sodium and an immediate release matrix containing Cefixime Trihydrate, Cloxacillin sodium and Lactobacillus sporogenes. These ingredients of the formulation are processed so as to form a homogenous intimate mixture along with conventional excipients. The mixture is compressed into cores and further coated. ' However none of the above prior arts discloses the bilaver tablet formulation, wherein the sustained release and immediate release layers are separated by two layers. Hence, the present invention is directed to preparation of formulation which contains combination of Cefixime, Cloxacillin or Dicloxacillin and lactic acid bacilli in bilaver tablet form to meet the challenges of day-to-day infections like respiratory tract infections, skin & soft tissue infections, urinary tract infections, otitis media, pneumonia and cystitis Object of the invention The primary object of the present invention is to provide a pharmaceutical composition in the form of a bilaver tablet comprising of antibiotic preferably Cloxacillin or Dicloxacillin or its pharmaceutical!}' acceptable salts thereof, cephalosporin preferably Cefixime or pharmaceutically acceptable salt and a probiotics preferably Lactobacillus sporogenes spores. Another object of the invention is to provide a process for the preparation of a pharmaceutical composition in the form of a tablet comprising two discrete layers wherein the first sustained release layer is prepared containing an antibiotic preferably Cloxacillin or Dicloxacillin or its pharmaceutically acceptable salts thereof, and the second immediate release layer is prepared by mixing a therapeutically effective amount 3 of cephalosporin preferably Cefixime or pharmaceuticaily acceptable salt and a probiotics preferably Lactobacillus sporogenes spores. Summary of the invention In accordance with the above objectives, the present invention provides a process for the preparation of a pharmaceutical composition in the form of a tablet comprising two discrete layers wherein the first sustained release layer is prepared by granulation of a therapeutically effective amount of antibiotic preferably Cloxacillin or Dicloxacillin or its pharmaceuticaily acceptable salts thereof, with pharmaceuticaily acceptable excipients., and the second immediate release layer is prepared by mixing a therapeutically effective amount of cephalosporin preferably Cefixime or pharmaceuticaily acceptable salt and a probiotics preferably Lactobacillus sporogenes spores with pharmaceuticaily acceptable excipients. Detailed description of the invention Accordingly, the present invention provides a process for the preparation of a pharmaceutical composition in the form of a tablet comprising two discrete layers wherein the first sustained release layer is prepared by granulation of a therapeutically effective amount of antibiotic preferably Cloxacillin or Dicloxacillin or its pharmaceuticaily acceptable salts thereof with pharmaceuticaily acceptable excipients., and the second immediate release layer is prepared by mixing a therapeutically effective amount of cephalosporin preferably Cefixime or pharmaceuticaily acceptable salt and a probiotics preferably Lactobacillus sporogenes spores with pharmaceuticaily acceptable excipients. The process for making a pharmaceutical composition in the form of a tablet in accordance with the present invention involves following steps I. granulating Cloxacillin or Dicloxacillin or its pharmaceuticaily acceptable salts thereof in 30 to 90% preferably 70-90% of the total mass of sustained release layer; with a binder and drying: or alternatively mixing Cloxacillin or Dicloxacillin or its 6 pharmaceutically acceptable salts thereof in 30 to 90% preferably 70-90%) of the total mass of sustained release layer with a binder followed by converting the above mix into granules by slugging, compacting and sizing;, 2. blending the said granules from step (1) with a polymer and with or without diluent and followed by lubricating with a lubricant. 3. sifting and mixing Cefixime or pharmaceutical!}*' acceptable salt thereof in 15 to 65 % preferably 40 to 50% of total mass of immediate release layer with coloring agent, surfactant and lubricant in a blender followed by compressing and deslugging the blend using compression machine and multimill respectively; 4. sifting and mixing Lactobacillus sporogenes in 1 to 50% preferably 2.5 to 20% of the total mass of immediate release layer with or without diluent, coloring agent in blender and granulating the said blend using methacrylic polymer followed by sifting and drying of the granules in tray dryer; 5. sizing the dried granules to form uniform granules: 6. lubricating the granules obtained in step (3) and (4) followed by compressing with the step (2) granules using bilayer compressing machine: and 7. optionally coating the compressed tablet with coating suspension in an auto coater. The use of a binder render tablets extremely poor in self disintegrating properties. In the present invention a binder is selected from group of cellulose derivatives, polyacrylic acid derivatives, monosaccharides, starch, polyvinyl pyrollidone, alginates and its salts, natural gums preferably cellulose derivatives, polyacrylic acid derivatives, methacrylic acid derivatives most preferably ethyl cellulose and methacrylate co-polymer. A mass of binder is typically present in an amount of I to30% preferably 3 to 10% of total mass of sustained release layer and 0.05 to 5% preferably 0.1 to 1% total mass of immediate release laver. 7 A diluent is selected from group of cellulose derivatives, sugars, inorganic phosphates preferably microcrystalline cellulose, croscarmillose sodium, lactose, mannitol, calcium phosphate most preferably microcrystalline cellulose, croscarmillose sodium and dibasic calcium phosphate. A mass of diluent is typically present in an amount of I to30% preferably 3 to 10% of total mass of sustained release layer and 0.5 lo 15% preferably 2.5 to 5% total mass of immediate release layer. A rate retarding polymers includes polyacrylic acid, cellulose derivatives, carbomer. alginates, methacrylate, polyethylenes, fatty acid esters, long chain fatty acids preferably alkyl cellulose, carbomer and methacrylate co-polymers most preferably carbomer ranging from 1 to 30% preferably 3 to 10% of total mass of sustained release layer. Lubricant selected from group of talc, stearic acid, metallic stearates. fatty acids, hydrogenated fatty acid, wax and fatty acid esters preferably talc, magnesium stearate and calcium stearate most preferably magnesium stearate Surfactant is selected from group of polysorbate. sodium Iauryl sulphate, triglycerides, fatty acid esters preferably polysorbates and sodium Iauryl sulphate most preferably sodium Iauryl sulphate ranging from 0.1 to 3% preferably 0.5 to 1.5% of total mass of immediate release layer The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, il being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention. 8 Examples: Example I Sr No. Material UOM Qty/ Tab Dicloxacillin part 1. Dicloxacillin sodium mg 569.6 2. Ethyl Cellulose mg 27.3 •> J. Dichloromethane ml 0.2 4. Carbomer mg 25 5. Cross Carmellose Sodium mg 15 6. Magnesium Stearate mg 6.3 Lactic acid bacillus part 7. Lactic Acid Bacillus Spores {150 billion spores/gm) mg 75 (11.25 billion spores) 8. Microcrystalline Cellulose mg 26.2 9. Titanium Dioxide mg 11.9 10. Methacrvlic Acid Copolymer mg 0.9 11. Purified Water ml 0.067 Cefiximc part 12. Cefixirne Trihydrate mg 224 13. Quinoline Yellow Lake mg 1 14. Sodium Lauryl Sulphate mg J 15. Magnesium Stearate mg 3 Lubrication 16. Quinoline Yellow mg 1 17. Macrocrystalline Cellulose mg 74 18. Dicalcium Phosphate mg 31 19. Croscarmellose Sodium mg 36 20. Colloidal Silicon Dioxide mg 5 21. Magnesium Stearate mg 4 Coating 22. Opadry Yellow mg 30 23. Isopropy! Alcohol ml 0.405 24. Dichloromethane ml 0.27 9 Example 2 Sr No. Material UOM Qty/ Tab Cloxacillin part 1 Cloxacillin Sodium mg 573.15 Ethyl Cellulose mg 27.31 J Dichloromethane ml 0.145 4 Carbomer mg 36.75 5 Microcrystalline Cellulose mg 43.49 6 Magnesium Stearate mg 6.29 Lactic acid bacillus part 7 Lactic Acid Bacillus Spores (6 billion sporcs/gm) mg 105 (0.63 billion spores) 8 Betacyclodextrin mg 11.44 9 Quinolinc Yellow mg 0.06 1 3. Methacrylic Acid Copolymer. mg 4.5 Cefixime part 11. Cefixime Trihydrate mg 235.2 12. Quinollne Yellow mg 1 13. Sodium Lauryl Sulphate mg 3 14. Magnesium Stearate mg i j Lubrication 15. Ouinoline Yellow mg 1 16. Microcrystalline Cellulose mg 15.8 17. Dicalcium Phosphate mg 31 18. Croscarmcllose Sodium mg 26 19. Colloidal Silicon Dioxide mg 5 20. Magnesium Stearate mg 4 Coating 21. Opadrv Yellow mg 33.6 22. Isopropyl Alcohol ml 0.336 23. Dichloromethane ml 0.224 10 Example 3 Example 4 Sr No. Material UOM Qty/ Tab Dicloxacillin part 1. Dicloxacillin sodium mg 569.6 2. Ethvl Cellulose mg 27.3 • Magnesium Stearate mg 2 4. Carbomer mg 25 5. Cross Carmellose Sodium mg 15 6. Magnesium Stearate mg 4.3 Lactic acid bacillus part 7. Lactic Acid Bacillus Spores {i 50 billion spores/gm) mg 75 (11.25 billion 8. Macrocrystalline Cellulose mg 26.2 9. Titanium Dioxide mg 11.9 10. Methacrviic Acid Copolymer mg 0.9 11. Purified Water ml 0.067 Cefixime part 12. Ceflxirne Trihydrate mg 224 13. Quinoline Yellow Lake mg 1 14. Sodium Lauryl Sulphate mg J 15. Magnesium Stearate mg 1 Lubrication 16. Quinoline Yellow mg 1 17. Macrocrystalline Cellulose mg 74 18. Dicalcium Phosphate mg 31 19. Croscarmellose Sodium mg 36 20. Colloidal Silicon Dioxide mg 5 21. Magnesium Stearate mg 4 Sr No. Materia! UOM Qty/ Tab Cloxacillin part 1. Cloxacillin Sodium mg 573.16 2. Ethyl Cellulose mg 27.31 II Magnesium Stearate mg 2 4. Carbomer mg 36.75 5. Microcrystalline Cellulose mg 43.49 6. Magnesium Stearate mg 4.29 Lactic acid bacillus part 7. Lactic Acid Bacillus Spores (6 billion spores/gm) mg 105 (0.63 billion 8. Betacyclodextrin mg 11.44 9. Quinolinc Yellow mg 0.06 10. Methacrylic Acid Copolymer mg 4.5 Cefiximc part 11. Cefixime Trihydrate mg 235.2 12. Quinollne Yellow mg 1 13. Sodium Lauryl Sulphate mg ■I 14. Magnesium Stearate mg j Lubrication 15. Ouinoline Yellow mg 1 16. Microcrystalline Cellulose mg 15.8 17. Dicalcium Phosphate mg 31 18. Croscarmcllose Sodium mg 26 19. Colloidal Silicon Dioxide mg 5 20. Magnesium Stearate mg 4 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. 12 We claim 1. A process for the preparation of a pharmaceutical composition in the form of a tablet comprising two discrete layers wherein the first sustained release layer is prepared by granulation of a therapeutically effective amount of antibiotic preferably Cloxacillin or Dicloxacillin or its pharmaceutically acceptable salts thereof, with pharmaceutically acceptable excipients.. and the second immediate release layer is prepared by mixing a therapeutically effective amount of cephalosporin preferably Cefixime or pharmaceutically acceptable salt and a probiotics preferably Lactobacillus sporogenes spores with pharmaceutically acceptable excipients. 2. The process for the preparation of a pharmaceutical composition in the form of a tablet as claimed in claim 1, comprising following steps a) granulating Cloxacillin or Dicloxacillin or its pharmaceutically acceptable salts thereof in 30 to 90% preferably 70-90% of the total mass of sustained release layer; with a binder and drying or alternatively mixing Cloxacillin or Dicloxacillin or its pharmaceutically acceptable salts thereof in 30 to 90% preferably 70-90% of the total mass of sustained release layer with a binder followed by converting the above mix into granules by slugging, compacting and sizing; b) blending the said granules from step (a) with a polymer and with or without diluent, followed by lubricating with a lubricant, c) sifting and mixing Cefixime or pharmaceutically acceptable salt thereof in 15 to 65 % preferably 40 to 50% of total mass of immediate release layer along with coloring agent, surfactant and lubricant in a blender followed by compressing and deslugging the blend using compression machine and multimill respectively; d) sifting and mixing Lactobacillus sporogenes in 1 to 50% preferably 2.5 to 20% of them total mass of immediate release layer with or without diluent, coloring agent in blender and granulating the said blend using methacrylic polymer followed by sifting and drying of the granules in tray dryer, e) sizing of the dried granules to form uniform granules, 13 f) lubricating the granules obtained in step (c) and (d) followed by compressing with the step (b) granules using bilayer compressing machine; and g) optionally coaling the compressed tablet with coating suspension in an auto coaler. 3. The process as claimed in claim 2.. wherein said binder is selected from group of cellulose derivatives, polyacrylic acid derivatives, monosaccharides, starch, polyvinyl pyrollidone. alginates and its salts and natural gums preferably cellulose derivatives, pofyacryfic acid derivatives, metharyfic acid derivatives most preferably ethyl cellulose and methacrylate co-polymer. 4. The process as claimed in claim 3. wherein said binder is typically present in an amount of 1 to30% preferably 3 to 10% of total mass of sustained release layer and 0.05 to 5% preferably 0.1 to I % total mass of immediate release layer. 5. The process as claimed in claim 2. wherein said diluent is selected from group of cellulose derivatives, sugars, inorganic phosphates preferably microcrystalline ceffurose. factose, mannrtof. calcium phosphate most preferab/y microcrystaffine cellulose and dibasic calcium phosphate. 6. The process as claimed in claim 5, wherein said diluent is, typically present in an amount of 1 to 30%. preferably 3 to 10% of total mass of sustained release layer and 0.5 to 15% preferably 2.5 to 5% of the total mass of immediate release layer. 7. The process as claimed in claim 2., wherein said polymer is selected from group of polyacrylic acid, cellulose derivatives, carbomer, alginates, methacrylate, polyethylenes. fatly acid esters, long chain fatty acids preferably alkyl cellulose. carbomer and methacrylate co-polymers most preferably carbomer. 8. The process as claimed in claim 7, wherein said polymer is used in the range of I to 30% preferably 3 to 10% of total mass of sustained release layer. 14 9. The process as claimed in claim 2, wherein the lubricant is selected from group of Talc, stearic acid, metallic stearates, fatty acids, hydrogenated fatty acid, wax and fatty acid esters preferably Talc, magnesium stearate and calcium stearate most preferably magnesium stearate 10. The process as claimed in claim 2, wherein the surfactant is selected from group of polysorbate, sodium lauryl sulphate, triglycerides, fatty acid esters preferably poly sorbates and sodium lauryl sulphate used in an amount ranging from 0.1 to 15 3% preferably 0.5 to 1.5% of total mass of immediate release layer.

Full Text

FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulcl3)
1. TITLE OF THE INVENTION:
"SOLID PHARMACEUTICAL DOSAGE FORMS"

2. APPLICANT (S):
(a) NAME: FDC Limited
(b)NATIONALITY: Indian company incorporated under the Companies Act 1956
(e) ADDRESS: 142-48, S.V. Road, Jogcshwari (West), Mumbai - 400 102, Maharashtra, India.

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field
The present invention relates to a process for the preparation of a pharmaceutical composition in the form of a tablet comprising two discrete layers wherein the first sustained release layer is prepared by granulation of a therapeutically effective amount of antibiotic preferably Cloxacillin or Dicloxacillin or its pharmaceutical!}' acceptable salts thereof with pharmaceutical!}-' acceptable excipients., and the second immediate release layer is prepared by mixing a therapeutically effective amount of cephalosporin preferably Cefixime or pharmaceutical!)' acceptable salts thereof and a probioties preferably Lactobacillus sporogenes spores with pharmaceutically acceptable excipients.
The present invention also relates to the use of this formulation for the treatment of bacterial infections such as respiratory tract infections, skin and soft tissue infections, urinary tract infections, otitis media, pneumonia and cystitis.
Background and prior art
Cefixime is a third generation orally active, broad spectrum cephalosporin active against a wide range of gram positive and gram negative bacteria. Cefixime is a bactericidal antibiotic and is stable to hydrolysis by many beta-lactamases. Cefixime exhibits good in vitro activity against most of the Enterobacteriaceae. Haemophilus influenzae and Neisseria gonorrhoea (including bela-lactamase producing strains), beta-haemolytic streptococci of groups A and B and Streptococcus pneumoniae. .
Against H. influenzae and N. gonorrhoeae Cefixime has been shown to be highly
inhibitory to all strengths tested. For H. influenzae, this included strains resistant to
i
ampicillin, cefaclor, cephalexin, chloramphenicol and colrimoxazole.
Cefixime is widely used in the treatment of respiratory tract infections. The drug has shown excellent safety and efficacy in the treatment of these infections. It is even widely prescribed to children. Cefixime despite its potent activity against other gram positive cocci like streptococcus is inactive against staphylococci except Staphylococcus aureus
2

which is considerably less susceptible. Faecal streptococci, Pseudomonas aeruginosa, most anaerobes and Chlamydia trachomatis are insusceptible This makes the drug less effective in common day-to-day infections like respiratory tract infections or skin & soft tissue infections. This is a limitation to the use of a safe cephalosporin like Cefixime.
Although Cefixime has been considered as a highly safe and effective drug for the treatment of many bacterial infections, because of its instability in presence of staphylococci hinders not only its therapeutic activity but also clinical outcome.
Although Cefixime has been considered as a highly safe and effective drug for the treatment of many bacterial infections, because of its instability in presence of staphylococci hinders not only its therapeutic activity but also clinical outcome.
Isoxazolyl penicillins such as Cloxacillin. Dicloxacillin and Oxacillin are penicillinase-resistant.. Based on its spectrum of activity Cloxacillin is classified as second generation penicillin.
Cloxacillin is active against gram positive organisms like staphylococci, streptococci, etc. In addition. Cloxacillin is stable to beta lactamases produced by gram positive organisms. Addition of Cloxacillin to Cefixime would provide:
a. Effective coverage of all gram positive organisms like staphylococci, streptococci,
thereby making the combination effective in a wide range of infections, common day-
to-day infections like respiratory tract infections, skin & soft tissue infections etc.
b. the combination stable to beta lactamases produced by staphylococci thereby making
the combination "tough".
Combination of Cefixime and Cloxacillin will meet the challenges of day-to-day infections like respiratory tract infections and skin & soft tissue infections.
Cloxacillin is widely accepted and is used in combination with Ampicillin and Amoxyciliin mainly to increase the efficacy of these safe antibiotics in the treatment of
3

staphylococcal infections. In addition, studies have shown synergism between Cloxacillin and Gentamicin.
Lactic acid bacilli, the so-called 'friendly bacteria' are a member of natural gastro¬intestinal flora. They are also known as probiotics.
Probiotics are the living microbial food ingredients that colonize the intestinal tract and have a beneficial effect on the human health.
Lactic acid bacilli are found to be useful in conditions like traveler's diarrhoea, antibiotic induced diarrhoea, infantile diarrhoea, infectious diarrrhoea caused by viruses and bacteria (like diarrhoea due to rotavirus, salmonella, shigella etc.).
Lactic acid bacilli when given simultaneously with an antibiotic are capable of colonizing the intestinal tract despite the antibiotic treatment, re-establishing the intestinal microflora. This would reduce the incidence of diarrhoea and Gl disturbance following antibiotic therapy.
Diarrhoea and stool changes like soft stools, and loose stools have been the most frequently reported adverse effects with use of Cefixime and Cloxacillin, in adults as well as children. These side effects can interfere with the patient compliance and can result in premature stopping of treatment, which can result in treatment failure. Antibiotic therapy often disrupts the balance of the intestinal microorganisms resulting in abnormal intestinal and bowel function. Lactic acid bacilli are believed to be effective in suppressing the growth of pathogenic microorganisms and re-establishing the normal intestinal flora. This would reduce the incidence of adverse effects like diarrhoea, improve the patient compliance and would result in better cure rates.
US 6306391 disclosed a pharmaceutical composition comprising at least one anti infective ingredient as a first active ingredient and at least one microorganism as a second active ingredient. Patent discloses protection of susceplible organisms from the effect of anti infective agent by creating barrier around the microorganism or an anti infective acenl.
4

Japanese Patent No. 1083025 discloses blended preparation of drug resistant live bacterial agent for controlling intestinal function. The said preparation includes anti microbial agent that is blended with anti bacterial agent. However patent does not discloses preparation of the formulation comprising two antibacterial agents.
EP1566116 discloses two types of release matrices, a controlled release matrix containing Cloxacillin sodium and an immediate release matrix containing Cefixime Trihydrate, Cloxacillin sodium and Lactobacillus sporogenes. These ingredients of the formulation are processed so as to form a homogenous intimate mixture along with conventional excipients. The mixture is compressed into cores and further coated. '
However none of the above prior arts discloses the bilaver tablet formulation, wherein the sustained release and immediate release layers are separated by two layers. Hence, the present invention is directed to preparation of formulation which contains combination of Cefixime, Cloxacillin or Dicloxacillin and lactic acid bacilli in bilaver tablet form to meet the challenges of day-to-day infections like respiratory tract infections, skin & soft tissue infections, urinary tract infections, otitis media, pneumonia and cystitis
Object of the invention
The primary object of the present invention is to provide a pharmaceutical composition in the form of a bilaver tablet comprising of antibiotic preferably Cloxacillin or Dicloxacillin or its pharmaceutical!}' acceptable salts thereof, cephalosporin preferably Cefixime or pharmaceutically acceptable salt and a probiotics preferably Lactobacillus sporogenes spores.
Another object of the invention is to provide a process for the preparation of a pharmaceutical composition in the form of a tablet comprising two discrete layers wherein the first sustained release layer is prepared containing an antibiotic preferably Cloxacillin or Dicloxacillin or its pharmaceutically acceptable salts thereof, and the second immediate release layer is prepared by mixing a therapeutically effective amount
3

of cephalosporin preferably Cefixime or pharmaceuticaily acceptable salt and a probiotics preferably Lactobacillus sporogenes spores.
Summary of the invention
In accordance with the above objectives, the present invention provides a process for the preparation of a pharmaceutical composition in the form of a tablet comprising two discrete layers wherein the first sustained release layer is prepared by granulation of a therapeutically effective amount of antibiotic preferably Cloxacillin or Dicloxacillin or its pharmaceuticaily acceptable salts thereof, with pharmaceuticaily acceptable excipients., and the second immediate release layer is prepared by mixing a therapeutically effective amount of cephalosporin preferably Cefixime or pharmaceuticaily acceptable salt and a probiotics preferably Lactobacillus sporogenes spores with pharmaceuticaily acceptable excipients.
Detailed description of the invention
Accordingly, the present invention provides a process for the preparation of a pharmaceutical composition in the form of a tablet comprising two discrete layers wherein the first sustained release layer is prepared by granulation of a therapeutically effective amount of antibiotic preferably Cloxacillin or Dicloxacillin or its pharmaceuticaily acceptable salts thereof with pharmaceuticaily acceptable excipients., and the second immediate release layer is prepared by mixing a therapeutically effective amount of cephalosporin preferably Cefixime or pharmaceuticaily acceptable salt and a probiotics preferably Lactobacillus sporogenes spores with pharmaceuticaily acceptable excipients.
The process for making a pharmaceutical composition in the form of a tablet in accordance with the present invention involves following steps
I. granulating Cloxacillin or Dicloxacillin or its pharmaceuticaily acceptable salts thereof in 30 to 90% preferably 70-90% of the total mass of sustained release layer; with a binder and drying: or alternatively mixing Cloxacillin or Dicloxacillin or its
6

pharmaceutically acceptable salts thereof in 30 to 90% preferably 70-90%) of the total mass of sustained release layer with a binder followed by converting the above mix into granules by slugging, compacting and sizing;,
2. blending the said granules from step (1) with a polymer and with or without diluent and followed by lubricating with a lubricant.
3. sifting and mixing Cefixime or pharmaceutical!}*' acceptable salt thereof in 15 to 65 % preferably 40 to 50% of total mass of immediate release layer with coloring agent, surfactant and lubricant in a blender followed by compressing and deslugging the blend using compression machine and multimill respectively;
4. sifting and mixing Lactobacillus sporogenes in 1 to 50% preferably 2.5 to 20% of the total mass of immediate release layer with or without diluent, coloring agent in blender and granulating the said blend using methacrylic polymer followed by sifting and drying of the granules in tray dryer;
5. sizing the dried granules to form uniform granules:
6. lubricating the granules obtained in step (3) and (4) followed by compressing with the step (2) granules using bilayer compressing machine: and
7. optionally coating the compressed tablet with coating suspension in an auto coater.
The use of a binder render tablets extremely poor in self disintegrating properties. In the present invention a binder is selected from group of cellulose derivatives, polyacrylic acid derivatives, monosaccharides, starch, polyvinyl pyrollidone, alginates and its salts, natural gums preferably cellulose derivatives, polyacrylic acid derivatives, methacrylic acid derivatives most preferably ethyl cellulose and methacrylate co-polymer. A mass of binder is typically present in an amount of I to30% preferably 3 to 10% of total mass of sustained release layer and 0.05 to 5% preferably 0.1 to 1% total mass of immediate release laver.
7

A diluent is selected from group of cellulose derivatives, sugars, inorganic phosphates preferably microcrystalline cellulose, croscarmillose sodium, lactose, mannitol, calcium phosphate most preferably microcrystalline cellulose, croscarmillose sodium and dibasic calcium phosphate. A mass of diluent is typically present in an amount of I to30% preferably 3 to 10% of total mass of sustained release layer and 0.5 lo 15% preferably 2.5 to 5% total mass of immediate release layer.
A rate retarding polymers includes polyacrylic acid, cellulose derivatives, carbomer. alginates, methacrylate, polyethylenes, fatty acid esters, long chain fatty acids preferably alkyl cellulose, carbomer and methacrylate co-polymers most preferably carbomer ranging from 1 to 30% preferably 3 to 10% of total mass of sustained release layer.
Lubricant selected from group of talc, stearic acid, metallic stearates. fatty acids, hydrogenated fatty acid, wax and fatty acid esters preferably talc, magnesium stearate and calcium stearate most preferably magnesium stearate
Surfactant is selected from group of polysorbate. sodium Iauryl sulphate, triglycerides, fatty acid esters preferably polysorbates and sodium Iauryl sulphate most preferably sodium Iauryl sulphate ranging from 0.1 to 3% preferably 0.5 to 1.5% of total mass of immediate release layer
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, il being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
8

Examples:
Example I

Sr
No. Material UOM Qty/ Tab
Dicloxacillin part
1. Dicloxacillin sodium mg 569.6
2. Ethyl Cellulose mg 27.3
•> J. Dichloromethane ml 0.2
4. Carbomer mg 25
5. Cross Carmellose Sodium mg 15
6. Magnesium Stearate mg 6.3
Lactic acid bacillus part
7. Lactic Acid Bacillus Spores {150 billion spores/gm) mg 75
(11.25 billion spores)
8. Microcrystalline Cellulose mg 26.2
9. Titanium Dioxide mg 11.9
10. Methacrvlic Acid Copolymer mg 0.9
11. Purified Water ml 0.067

Cefiximc part
12. Cefixirne Trihydrate mg 224
13. Quinoline Yellow Lake mg 1
14. Sodium Lauryl Sulphate mg J
15. Magnesium Stearate mg 3
Lubrication
16. Quinoline Yellow mg 1
17. Macrocrystalline Cellulose mg 74
18. Dicalcium Phosphate mg 31
19. Croscarmellose Sodium mg 36
20. Colloidal Silicon Dioxide mg 5
21. Magnesium Stearate mg 4
Coating
22. Opadry Yellow mg 30
23. Isopropy! Alcohol ml 0.405
24. Dichloromethane ml 0.27
9

Example 2

Sr No. Material UOM Qty/ Tab
Cloxacillin part
1 Cloxacillin Sodium mg 573.15
Ethyl Cellulose mg 27.31
J Dichloromethane ml 0.145
4 Carbomer mg 36.75
5 Microcrystalline Cellulose mg 43.49
6 Magnesium Stearate mg 6.29
Lactic acid bacillus part
7 Lactic Acid Bacillus Spores (6 billion sporcs/gm) mg 105
(0.63 billion
spores)
8 Betacyclodextrin mg 11.44
9 Quinolinc Yellow mg 0.06
1 3. Methacrylic Acid Copolymer. mg 4.5

Cefixime part
11. Cefixime Trihydrate mg 235.2
12. Quinollne Yellow mg 1
13. Sodium Lauryl Sulphate mg 3
14. Magnesium Stearate mg i j
Lubrication
15. Ouinoline Yellow mg 1
16. Microcrystalline Cellulose mg 15.8
17. Dicalcium Phosphate mg 31
18. Croscarmcllose Sodium mg 26
19. Colloidal Silicon Dioxide mg 5
20. Magnesium Stearate mg 4
Coating
21. Opadrv Yellow mg 33.6
22. Isopropyl Alcohol ml 0.336
23. Dichloromethane ml 0.224
10

Example 3
Example 4

Sr
No. Material UOM Qty/ Tab
Dicloxacillin part
1. Dicloxacillin sodium mg 569.6
2. Ethvl Cellulose mg 27.3 •
Magnesium Stearate mg 2
4. Carbomer mg 25
5. Cross Carmellose Sodium mg 15
6. Magnesium Stearate mg 4.3
Lactic acid bacillus part
7. Lactic Acid Bacillus Spores
{i 50 billion spores/gm) mg 75
(11.25
billion
8. Macrocrystalline Cellulose mg 26.2
9. Titanium Dioxide mg 11.9
10. Methacrviic Acid Copolymer mg 0.9
11. Purified Water ml 0.067

Cefixime part
12. Ceflxirne Trihydrate mg 224
13. Quinoline Yellow Lake mg 1
14. Sodium Lauryl Sulphate mg J
15. Magnesium Stearate mg 1
Lubrication
16. Quinoline Yellow mg 1
17. Macrocrystalline Cellulose mg 74
18. Dicalcium Phosphate mg 31
19. Croscarmellose Sodium mg 36
20. Colloidal Silicon Dioxide mg 5
21. Magnesium Stearate mg 4

Sr
No. Materia! UOM Qty/ Tab
Cloxacillin part
1. Cloxacillin Sodium mg 573.16
2. Ethyl Cellulose mg 27.31
II

Magnesium Stearate mg 2
4. Carbomer mg 36.75
5. Microcrystalline Cellulose mg 43.49
6. Magnesium Stearate mg 4.29
Lactic acid bacillus part
7. Lactic Acid Bacillus Spores (6 billion spores/gm) mg 105
(0.63 billion
8. Betacyclodextrin mg 11.44
9. Quinolinc Yellow mg 0.06
10. Methacrylic Acid Copolymer mg 4.5

Cefiximc part
11. Cefixime Trihydrate mg 235.2
12. Quinollne Yellow mg 1
13. Sodium Lauryl Sulphate mg ■I
14. Magnesium Stearate mg j
Lubrication
15. Ouinoline Yellow mg 1
16. Microcrystalline Cellulose mg 15.8
17. Dicalcium Phosphate mg 31
18. Croscarmcllose Sodium mg 26
19. Colloidal Silicon Dioxide mg 5
20. Magnesium Stearate mg 4
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.
12

We claim
1. A process for the preparation of a pharmaceutical composition in the form of a tablet comprising two discrete layers wherein the first sustained release layer is prepared by granulation of a therapeutically effective amount of antibiotic preferably Cloxacillin or Dicloxacillin or its pharmaceutically acceptable salts thereof, with pharmaceutically acceptable excipients.. and the second immediate release layer is prepared by mixing a therapeutically effective amount of cephalosporin preferably Cefixime or pharmaceutically acceptable salt and a probiotics preferably Lactobacillus sporogenes spores with pharmaceutically acceptable excipients.
2. The process for the preparation of a pharmaceutical composition in the form of a tablet as claimed in claim 1, comprising following steps

a) granulating Cloxacillin or Dicloxacillin or its pharmaceutically acceptable salts thereof in 30 to 90% preferably 70-90% of the total mass of sustained release layer; with a binder and drying or alternatively mixing Cloxacillin or Dicloxacillin or its pharmaceutically acceptable salts thereof in 30 to 90% preferably 70-90% of the total mass of sustained release layer with a binder followed by converting the above mix into granules by slugging, compacting and sizing;
b) blending the said granules from step (a) with a polymer and with or without diluent, followed by lubricating with a lubricant,
c) sifting and mixing Cefixime or pharmaceutically acceptable salt thereof in
15 to 65 % preferably 40 to 50% of total mass of immediate release layer
along with coloring agent, surfactant and lubricant in a blender followed
by compressing and deslugging the blend using compression machine and
multimill respectively;
d) sifting and mixing Lactobacillus sporogenes in 1 to 50% preferably 2.5 to 20% of them total mass of immediate release layer with or without diluent, coloring agent in blender and granulating the said blend using methacrylic polymer followed by sifting and drying of the granules in tray dryer,
e) sizing of the dried granules to form uniform granules,
13

f) lubricating the granules obtained in step (c) and (d) followed by
compressing with the step (b) granules using bilayer compressing
machine; and
g) optionally coaling the compressed tablet with coating suspension in an
auto coaler.
3. The process as claimed in claim 2.. wherein said binder is selected from group of cellulose derivatives, polyacrylic acid derivatives, monosaccharides, starch, polyvinyl pyrollidone. alginates and its salts and natural gums preferably cellulose derivatives, pofyacryfic acid derivatives, metharyfic acid derivatives most preferably ethyl cellulose and methacrylate co-polymer.
4. The process as claimed in claim 3. wherein said binder is typically present in an amount of 1 to30% preferably 3 to 10% of total mass of sustained release layer and 0.05 to 5% preferably 0.1 to I % total mass of immediate release layer.
5. The process as claimed in claim 2. wherein said diluent is selected from group of cellulose derivatives, sugars, inorganic phosphates preferably microcrystalline ceffurose. factose, mannrtof. calcium phosphate most preferab/y microcrystaffine cellulose and dibasic calcium phosphate.
6. The process as claimed in claim 5, wherein said diluent is, typically present in an
amount of 1 to 30%. preferably 3 to 10% of total mass of sustained release layer and 0.5 to 15% preferably 2.5 to 5% of the total mass of immediate release layer.
7. The process as claimed in claim 2., wherein said polymer is selected from group of polyacrylic acid, cellulose derivatives, carbomer, alginates, methacrylate, polyethylenes. fatly acid esters, long chain fatty acids preferably alkyl cellulose. carbomer and methacrylate co-polymers most preferably carbomer.
8. The process as claimed in claim 7, wherein said polymer is used in the range of I to 30% preferably 3 to 10% of total mass of sustained release layer.
14

9. The process as claimed in claim 2, wherein the lubricant is selected from group of
Talc, stearic acid, metallic stearates, fatty acids, hydrogenated fatty acid, wax and
fatty acid esters preferably Talc, magnesium stearate and calcium stearate most
preferably magnesium stearate
10. The process as claimed in claim 2, wherein the surfactant is selected from group
of polysorbate, sodium lauryl sulphate, triglycerides, fatty acid esters preferably
poly sorbates and sodium lauryl sulphate used in an amount ranging from 0.1 to
15
3% preferably 0.5 to 1.5% of total mass of immediate release layer.

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Patent Number

270905

Indian Patent Application Number

668/MUM/2009

PG Journal Number

05/2016

Publication Date

29-Jan-2016

Grant Date

27-Jan-2016

Date of Filing

23-Mar-2009

Name of Patentee

FDC LIMITED

Applicant Address

142-48, S. V. ROAD, JOGESHWARI (W), MUMBAI

Inventors:

#	Inventor's Name	Inventor's Address
1	CHANDAVARKAR MOHAN ANAND	7A, CHAND TERRACES, 0PP. HOLY FAMILY HOSPITAL, ST. ANDREWS ROAD. BANDRA (WEST), MUMBAI- 400050,
2	JINDAL, KOUR CHAND	FLAT NO. G 205/206, PALM COURT LINK ROAD, MALAD (WEST), MUMBAI-400064,
3	PATADIA, NILESH PARMANAND	AVANTI B-51, HARIDAS NAGAR, SHIMPOLI ROAD, BORIVALI (WEST), MUMBAI - 400092,

PCT International Classification Number

A61K31/00; A61K31/43; A61K31/431

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA