Title of Invention

A COMPOSITION FOR USE IN THE MANUFACTURE OF SUPPOSITORIES OF ANTIBIOTICS, A PROCESS FOR THE PREPARATION THEREOF AND THE SUPPOSITORIES SO PRODUCED

Abstract The present invention discloses methods of producing suppositories of third generation Cephalosporins such as Cefotaxime for administration by rectal route which comprises of a method of dispersing the antibiotic substance in a fatty base containing a dispersing agent and moulding into suppository. Alternate method of mixing with diluents, disintegrating agents, lubricating agents and compressing and coating into a pharmaceutically acceptable antibiotic suppository is also described.
Full Text FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See Section 10; rule 13)
"A COMPOSITION FOR USE IN THE MANUFACTURE OF SUPPOSITORIES OF ANTIBIOTICS, A PROCESS FOR THE PREPARATION THEREOF AND THE
SUPPOSITORIES SO PRODUCED"
We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Roads, Ahmedabad - 380 015, Gujarat, India,
The following specification describes the nature of the,invention and the manner in


Field of invention:
The present invention relates to a process for manufacture of suppositories of ^
i antibiotics, and the suppositories so produced. Suppositories of the present invention are j
i
useful for rectal administration of antibiotics. More particularly, the invention relates to a I process for manufacture of third generation antibiotics suppositories such as | Cephalosporins. Background of the invention:
Cefotaxime Sodium and other associated third generation Cephalosporins are not absorbed orally and therefore, these antibiotics at present are administered only by injection. This route of administration may not be acceptable or feasible to all patients due to a variety of reasons. The present invention describes a process to make suppositories of such third generation Cephalosporins and thereby solve the problems associated with the injection based administration. Object of the invention:
Suppositories for systemic administration have the following advantages: they require no medical assistance when administered as in the case of injections; they can be easily administered even in case of emergency at night, they give no pain when administered and can be given easily and safely even to infants; they undergo no drug inactivation action by gastric juices, unlike oral dosage and they exert no irritation action on Gastro Intestinal tracts; they can be administered to patients to whom oral administration is impossible; they will be very useful in the rural areas where no medical facilities are available.
It is an object of the present invention to provide a composition as well as method of producing Cefotaxime and other associated third generation Cephalosporins in the form of suppositories which make it possible to achieve the effective absorption of antibiotics without relying on the disadvantageous administration method as mentioned above. Summary of the Invention:
Suppositories for administration of various medicines are known in the prior art. The present invention provides a novel composition as well as process for producing suppositories of Cefotaxime and other associated third generation Cephalosporins which comprises combining the said antibiotic with dispersing agent and moulding into suppository. Preferably, the antibiotic may be mixed with diluents, disintegrating agents,
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lubricating agents and compressed and coated into a pharmaceutically acceptable antibiotic suppository. Detailed Description:
Suppositories of Cefotaxime or any other third generation Cephalosporins can be prepared by either the molding or compression method. Cephalosporins that comprises combining the said antibiotic are mixed with dispersing agent and then molded into suppository. Preferably, the antibiotic may be mixed with diluents, disintegrating agents, lubricating agents and compressed and coated into a pharmaceutically acceptable antibiotic suppository. The fatty base used in the present invention includes fats and oils such as cocoa butter, olive oil, which may be used singly or in combination or semi¬synthetic bases which are glycerides of hydrogenated fatty acids derived from palm-seed oils such as coconut & palm kernel oils.
The dispersing agents include lecithins, sodium lauryl sulphate, dioctylsodiumsulphosuccinate or polysorbates. The diluents include those usually used such as lactose, starch, dicalciumphosphate, celluloses. The distintegrating agents such as crosslinked carboxymethylcellulose, sodium starch glycolate, starch, crosspovidone may be used.
The lubricating agents include those usually used such as stearic acid or stearates, polyethylene glycols, talc, aerosil and hydrogenated vegetable oil. Coating agents include suitable waxes such as cetyl alcohol or polyethylene glycols in suitable polymer such as hydroxypropylmethylcellulose or polyvinylpyrrolidene dissolved in suitable organic solvents such as isopropyl alcohol or specially denatured spirit or methanol.
According to the present invention there is provided a method of producing suppository of Cefotaxime of various strengths. The following examples are by of disclosure (for 500 mg & 1000 mg strength) only and are not to be construed as limiting the scope of the claims or the invention in any manner.
Example 1
COMPOSITION 1 (500 mg Cefotaxime SuppositorvV.
Molded suppository of 500 mg or 1000 mg can be prepared as per the following
composition.

Composition for 500 mg of Cefotaxime Sodium:
No. 1 Ingredients me/supv.
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1. Cefotaxime Sodium equivalent to Cefotaxime (Micronised, particle size 100% 2. Hard Fat BP (Witepsol HI5) Supplier : M/s Condea 1095.8
3. Lecithin NF 20.2
4. Hard Fat BP (Suppocire AML) Supplier : M/s Gattefosse 202.0
5. Hard Fat BP (Witepsol W45) Supplier : M/s Condea 202.0
Total Weight 2020.0
1) Hard Fats (Witepsol HI 5), Suppocire AML and Witepsol W45 are melted together at a temperature of 50 - 60°C.
2) The melted material is cooled to about 40°C, Lecithin is added and mixture is stirred for about 10 minutes.
3) Cefotaxime Sodium is then dispersed in the above mixture and stirred for about 15 to 20 minutes. The temperature is maintained throughout at about 40°C.
4) The molten suspension is strained through a suitable mesh of 0.42 mm and molded into suppositories using suitable moulds either manually or by using Form-Fill-Seal Machine.
By way of non-limiting disclosures:
• Other alternatives to Hard Fat include Cocoa Butter or Polyethylene Glycols.
• Other dispersing agents include Sodium Lauryl Sulphate, Dioctylsodiumsulphosuccinate or Polysorbates.
Example 2
COMPOSITION 2 (500 mg Compressed Suppository/ Rectal Tablets):
Rectal tablets or compressed suppositories can be produced by either direct compression
of the drug with the in-actives or by slugging the drug with in-actives by compression or
roller compaction, milling the slugs into granules and mixing the granules with lubricants.

Composition for producing granules bv the slugging or drv granulation method:
No. Ingredients me/supp.
1. Cefotaxime Sodium equivalent to Cefotaxime (Micronised 100% 2. Croscarmellose Sodium BP 18.9
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3. Talc IP 6.3
4. Colloidal Silicon Dioxide IP 6.3
5. Magnesium Stearate IP 6.3
6. Microcrystalline Cellulose IP q.s. (Avicel PH 200) 92.2
Total Weight 630.0
Since drug is added on 100% assay basis, tablet weight is adjusted by varying Microcrystalline Cellulose.
1) Cefotaxime Sodium, Croscarmellose Sodium, Talc, Colloidal Silicon Dioxide, Microcrystalline Cellulose are sifted through 0.42 mm screen.
2) They are mixed using suitable mixer(s) for 10 - 20 minutes.
3) Magnesium Stearate (as a blend lubricant) is added to the above which is then sifted through 0.42 mm screen is added and mixed for 3 to 5 minutes.
4) The lubricated blend is slugged using 20 mm circular flat punches which are suitably coated or plated to prevent sticking by using materials such as Chromium Plated or Teflon Coated or Titanium Nitride Coated.
5) The slugs are then milled using Multi Mill or any other suitable mill and suitable sieve.
6) The granules obtained are then mixed with excipients, that have been sifted through 0.42 mm screen, for 5 mins. in a suitable mixer.

Composition of the tablet - Along with excipients
No. Ingredients mg/supp.
1. Cefotaxime Sodium Granules 630.0
2. Croscarmellose Sodium BP 25.5
3. Sodium Starch Glycollate IP 17.0
4. Talc IP 4.25
5. Colloidal Silicon Dioxide IP 4.25
6. Microcrystalline Cellulose IP (Avicel PH 200) 164.75
7. Magnesium Stearate IP 4.25
Total Weight 850.00
7) The final blend obtained is then compressed using suitable punches which are oval, oblong or bullet shaped and suitably plated or coated to prevent sticking.
8) The tablets obtained are then coated using a coating solution (described below):

Composition of the Coating solution:
No. Ingredients % wAv
1. Isopropyl Alcohol IP 47
2. Methylene Chloride IP "85 47
3. Hydroxypropylmethylcellulose IP (Methocel E5 Premium / DOW) 1
4. Polyethylene Glycol 4000 IP 5
Total Percentage 100
The product obtained above has the following characteristics:
A] Hardness of rectal tablets compressed using bullet shaped punch is about 8 kg/cm2,
B] Thickness is about 5.7 mm,
C] Friability D] Dispersion time is less than 10 minutes &
E] Disintegration time is less than 5 minutes.
F] Tablets are coated to about 2% increase in weight.
By way of non-limiting disclosures:
• Diluents that can also be used are Starch, Lactose, Dibasic Calcium Phosphate or Celluloses.
• Disintegrating agents such as Sodium Starch Glycolate, Starch or Crospovidone may also be used.
• Lubricating agents such as Stearic Acid or Stearates, Polyethylene Glycols or hydrogenated vegetable oil may be used.
Example 3
COMPOSITION 3 (1000 mg Compressed Suppository/ Rectal Tablets):

Composition for rectal tablets of 1000 mg by slugging method
No. Ingredients mg/supp.
1. Cefotaxime Sodium equivalent to Cefotaxime 1000.00
2. Croscarmellose Sodium BP 37.80
3. Talc IP 6.30
4. Colloidal Silicon Dioxide IP 6.30
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5. Magnesium Stearate IP 6.30
6. Cellactose 80 (Meggle) 203.30
Total Weight 1260.00
Since drug is added on 100% assay basis tablet weight is adjusted by varying Cellactose 80.
1. Cefotaxime Sodium, Croscarmellose Sodium, Talc, Colloidal Silicon Dioxide and Cellactose 80 are sifted through 0.42mm screen;
2. Then they are mixed using suitable mixer for 10 - 20 minutes.
3. To the above blend lubricant Magnesium Stearate that has been sifted through 0.42mm screen is added and mixed for 3 to 5 minutes.
4. The lubricated blend is slugged using 20mm circular flat punches that are suitably plated or coated to prevent sticking.
5. The slugs are then milled using Multi Mill or any other suitable mill and suitable sieve.
6. The granules obtained are mixed with the following excipients that have been sifted through 0.42mm screen, for 5 minutes in a suitable mixer.

Composition of the tablet ~ Along with excipients
No. Ingredients mg /rectal tablet
1. Cefotaxime Granules 1260.0
2. Croscarmellose Sodium BP 51.0
3. Cellactose 80 (Meggle) 363.5
4. Magnesium Stearate IP 8.5
5. Talc IP 8.5
6. Colloidal Silicon Dioxide IP 8.5
Total Weight 1700.00
7. The final blend obtained is then compressed using suitable punches which are oval, oblong or bullet shaped and suitably plated or coated to prevent sticking.
8. The tablets are then coated using a coating solution.

Composition of the Coating solution:
No. Ingredients % wAv
1. Isopropyl Alcohol IP 47
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2. Methylene Chloride IP "85 47
3. Hydroxypropylmethylcellulose IP (Methocel E5 Premium / DOW) 1
4. Polyethylene Glycol 4000 IP 5
100
The product obtained above has the following characteristics:
A] Hardness of rectal tablets compressed using bullet shaped punch is about 9 kg/cm2,
B] Thickness is about 8 mm,
C] Friability D] Dispersion time is less than 10 minutes &
E] Disintegration time is less than 5 minutes.
F] Tablets are coated to about 2% increase in weight.
By way of non-limiting disclosures:
• Diluents that can also be used are Starch, Lactose, Dibasic Calcium Phosphate or Celluloses.
• Disintegrating agents such as Sodium Starch Glycolate, Starch or Crospovidone may also be used.
• Lubricating agents such as Stearic Acid or Stearates, Polyethylene Glycols or hydrogenated vegetable oil may be used.
It will be clear from the above that the composition of the present invention is synergistic composition having improved and unexpected properties.
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We claim:
1. A suppository for rectal administration comprising a mixture of anti-biotic of the kind such as herein described with Glycerides, and a conventional surface-active agent, wherein the amount of said antibiotic is in the range of from 20 to 60% by weight of said composition and the amount of said surface-active agent is between 0.2 to 5% of weight of said composition.
2. A suppository as claimed in claim 1 wherein the antibiotic is a third generation Cephalosporin.
3. A suppository of as claimed in claim 1 wherein the antibiotic is Cefotaxime Sodium.
4. A suppository as claimed in claim 1 wherein the Glycerides used are glycerides of Hydrogenated fatty acids.
5. A suppository as claimed in any preceding claim wherein the surface-active agent is Lecithin.
6. A suppository as claimed in any preceding claim wherein said mixture optionally comprises, diluents, disintegrating agents, glidants and lubricants coated with waxes in presence of polymers and organic solvents.
7. A suppository as claimed in claim 6 wherein the diluents used are Microcrystalline Cellulose or Cellactose.
8. A suppository as claimed in claim 6 wherein the disintegrating agent is present in an amount of 1 to 15% by weight.
9. A suppository as claimed in claims 6 to 8 wherein the disintegrating agent used is Croscarmellose Sodium.
10. A suppository as claimed in claim 6 to 9 wherein the glidant is present in an amount of from 0.5 to 3% by weight.
11. A suppository as claimed in claim 6 to 10 wherein the glidants used are Talc and/or colloidal Silicon Dioxide.
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12. A suppository as claimed in any one of claims 6 to 11 wherein the lubricant is present in an amount of from 0.2 to 3% by weight.
13. A suppository as claimed in claim 6 to 12 wherein the lubricant used is Magnesium Stearate.
14. A suppository as claimed in claim 6 to 13 wherein the waxes used are Cetyl Alcohol or Polyethylene Glycols.
15. A suppository as claimed in claim 6 to 14 wherein the polymer used is Hydroxypropylmethylcellulose.
16. A suppository as claimed in claims 6 to 15 wherein the organic solvents used are Isopropyl Alcohol or Specially Denatured Spirit or Acetone.
17. A process to manufacture a suppository as claimed in any preceding claims which comprises dispersing an antibiotic substance of the kind such as herein described with Glycerides, and a conventional surface-active agent in a fatty base containing a dispersing agent and molding the mixture so formed into a pharmaceutically acceptable suppository, wherein the amount of said antibiotic is in the range of from 20 to 60% by weight of said composition and the amount of said surface-active agent is between 0.2 to 5% of weight of said composition.
18. A process as claimed in claim 17 wherein said mixture is optionally mixed with diluents, disintegrating agents, lubricating agents and compressing it into tablets using punches which are coated or plated and coating the tablets so formed with waxes in presence of polymers and organic solvents to make a pharmaceutically acceptable antibiotic suppository.
Date this the 31st day of March 2003
H.Subramaniam of SUBRAMANIAM, NATARAJ & ASSOCIATES Attorney for the Applicants

Documents:

181-mum-2002-abstract(3-8-2007).pdf

181-mum-2002-abstract(granted)(27-11-2007).doc

181-mum-2002-cancelled pages(27-2-2002).pdf

181-mum-2002-claims(granted)-(27-11-2007).doc

181-mum-2002-claims(granted)-(27-11-2007).pdf

181-mum-2002-correspondence(6-12-2007).pdf

181-mum-2002-correspondence(ipo)-(21-2-2008).pdf

181-mum-2002-form 1(10-4-2002).pdf

181-mum-2002-form 1(13-8-2007).pdf

181-mum-2002-form 1(5-3-2004).pdf

181-mum-2002-form 18(29-12-2005).pdf

181-mum-2002-form 2(granted)-(27-11-2007).doc

181-mum-2002-form 2(granted)-(27-11-2007).pdf

181-mum-2002-form 3(27-2-2002).pdf

181-mum-2002-form 3(6-12-2007).pdf

181-mum-2002-form 4(1-4-2003).pdf

181-mum-2002-form 5(1-4-2003).pdf

181-mum-2002-form 5(6-12-2007).pdf

181-mum-2002-form 6(8-3-2004).pdf

181-mum-2002-power of authority(10-4-2002).pdf

181-mum-2002-power of authority(13-8-2007).pdf


Patent Number 215097
Indian Patent Application Number 181/MUM/2002
PG Journal Number 13/2008
Publication Date 28-Mar-2008
Grant Date 21-Feb-2008
Date of Filing 27-Feb-2002
Name of Patentee CADILA HEALTHCARE LIMITED
Applicant Address ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD 380 015, GUJARAT
Inventors:
# Inventor's Name Inventor's Address
1 JANI, RAJENDRAKUMAR HARIPRASAD GERMAN REMEDIES LIMITED, A-SHIVASAGAR ESTATE, DR. A. BESANT ROAD, WORLI, MUMBAI - 400 018,
2 DURVE, RAVINDRA SADASHIV GERMAN REMEDIES LIMITED, M VASANJI ROAD, ANDHERI (E), WORLI, MUMBAI - 400 093
3 HEGDE, VEENA SAVITRI RAMACHANDRA GERMAN REMEDIES LIMITED, M VASANJI ROAD, ANDHERI (E), WORLI, MUMBAI - 400 093
PCT International Classification Number A61K31/00 A61K31/545 A61K9/02
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA